Process for the synthesis of cyclic carbamates
and suitable salts thereof, wherein R through R5 are as defined below.
Another aspect of the invention is directed to a process for the synthesis of a chiral
propargylic alcohol as the starting compound to produce said cyclic carbamate described
above. Some of the cyclic carbamates of formula I are key intermediates for the
preparation of pharmaceuticals and agrochemicals and as precursors for compounds in the
material sciences.
WO-A-98/27073 provides a cyclisation reaction of the o-aminobenzyl alcohol (SD573) of
formula
with phosgene in an organic solvent system containing heptanes and tetrahydrofuran to
obtain DMP-266 of formula I, wherein R is trifluoromethyl, R2 is cyclopropyl, R3 is 6-
chloro, R4 is hydrogen and R5 is hydrogen. WO-A-98/51676 and WO-A-99/61026 provide
a related cyclisation process of such an o-aminobenzyl alcohol with phosgene in a biphasic
solvent system comprising methyl rt-butyl ether/water or toluene/water in the presence of
potassium hydrogencarbonate.
In the art there are several methods published for the preparation of the compound of
which is the precursor compound before cyclisation. The processes in the art need more
than one protic agent and sometimes a high amount of a zinc catalyst. Since the product of
the cyclisation is the API (active pharmaceutical ingredient) it is important to reduce heavy
metal catalysts as much as possible.
Jiang et al. disclosed in Tetrahedron Lett. 2002, 43, 8323-8325 and J. Org. Chem. 2002,
67, 9449-945 1 the reaction of acetylene derivatives with aldehydes and ketones in the
presence of equimolar amounts of a Zn(II) compound to give several racemic propargylic
alcohols. Chiral compounds are not mentioned at all.
WO-A-95/20389, WO-A-96/37457, WO 98/30543 and WO 98/30540 disclose several
processes for the production of chiral propargylic alcohols useful for the synthesis of
pharmaceuticals. WO-A-98/51676 disclose a process wherein by addition of a first chiral
and optionally a second additive in a zinc(II) mediated reaction the chiral product is
obtained in high enantiomeric excess. The disadvantage of said process is the use of high
amounts of expensive zinc catalysts and chiral compounds.
A further task for the present invention was therefore to supply an alternative process for
the production of chiral propargylic alcohol with high enantiomeric excess. A further
problem was to reduce the amounts of catalyst and other components to be added during
the reaction in order to facilitate the workup procedures of the product and to promote
industrial production.
The problem to be solved was to supply an alternative process for the production of the
compound of formula I in high yield and quality.
The problem is solved by the present invention.
Provided is a process for the preparation of a compound of formula
and/or a suitable salt thereof, wherein
R1 is selected from the group consisting of hydrogen, linear or branched Ci- -alkyl or
(Ci- -alkoxy)carbonyl, any alkyl or alkoxy optionally being substituted with one or more
halogen atoms,
R is selected from the group consisting of linear or branched Ci- -alkyl,
(Ci -6-alkoxy)carbonyl, C3- -alkenyl, C3-6-alkynyl and C3-6-cycloalkyl, wherein each alkyl,
alkoxy, alkenyl, alkynyl and cycloalkyl can carry a further substituent selected from the
group consisting of aryl, aralkyl, Ci-6-alkyl and (l'-R 3)-C3 -6-cycloalkyl, wherein R3 is
hydrogen, methyl or ethyl, and wherein any alkyl, cycloalkyl, aryl, and aralkyl is
optionally substituted with one or more halogen atoms, cyano, Ci-6-alkyl,
C3-6-cycloalkyl, -NR4R5, -SR6, S(O) R6 or S(0 2)R6, and/or -OR 7, with R6 is C1-6-alkyl,
optionally substituted with one or more halogen atoms,
R7 is hydrogen or Ci- -alkyl, optionally substituted with one or more halogen atoms, where
(a) R4 and R5 are independently selected from hydrogen or Ci- -alkyl, or
(b) R4 is hydrogen and R5 is C2- -acyl or (Ci -6-alkoxy)carbonyl, wherein each acyl and
alkoxy in R5 in turn is optionally substituted with one or more halogen atoms, or
(c) R4 and R5 together with the nitrogen atom form a 5 to 7 membered heterocyclic ring, or
(d) R4 and R5 together are =CH-aryl, the aryl moiety optionally being substituted with one
or more substituents selected from halogen atoms, -NH2, -NH(Ci- -alkyl), -N(Ci- -alkyl)2
or Ci-6-alkyl, or
(e) R4 and R5 together are =CH-N(C,-6-alkyl)2,
R6 is C - -alkyl, optionally substituted with one or more halogen atoms, and
R7 is hydrogen or C -6-alkyl, optionally substituted with one or more halogen atoms,
R and are independently selected from the group consisting of hydrogen, halogen
atom, and Ci-6-alkyl optionally substituted with one or more halogen atoms,
R10 is hydrogen or a group selected from the group consisting of aryl, aralkyl,
and (Ci - -alkoxy)carbonyl, wherein the aryl moiety in any aryl or aralkyl is optionally
substituted with one or more substituents selected from Ci- -alkyl, Ci-6-alkoxy or
C3-g-cycloalkyl, each alkyl, alkoxy or cycloalkyl substituent is optionally substituted with
one or more halogen atoms,
said process comprising the reaction of a compound of formula
and/or a suitable salt thereof,
wherein R1, R2, R8, R9 and R 0 are as defined above,
with a cyclisation agent selected from phosgene, diphosgene, triphosgene and mixtures
thereof,
characterized in that the reaction is carried out in the presence of an aqueous base, and a
water-immiscible organic solvent, wherein at least 90%-w/w of said organic solvent
consisting of at least one compound selected from the group consisting of C2-5-alkyl
C2-5-carboxylates and mixtures of at least one C2-5-alkyl C2-5-carboxylate with at least one
C5 -8-alkane.
In a preferred embodiment the present method is applicable to optically active compounds
of formula II. After the cyclisation the substituents R1 and - CºC-R2 attached to the
carbinol carbon atom of formula I have the same configuration then in the respective
compound of formula II.
Here and hereinbelow the term "alkyl" represents a linear or branched alkyl group. By
using the form "C -n-alkyl" is meant having 1 to n carbon atoms. Ci- -alkyl represents for
example methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, t r/-butyl, pentyl or
hexyl.
Here and hereinbelow the term "alkenyl" represents a linear or branched group carrying at
least one carbon-carbon double bound. By using the form "C3-n-alkenyl" is meant the main
chain of the alkenyl group having 3 to n carbon atoms. C3^-alkenyl represents for example
propen-2-yl, propen-3-yl (allyl), buten-l-yl or hexen-l-yl.
Here and hereinbelow the term "alkynyl" represents a linear or branched group carrying at
least one carbon-carbon triple bound. By using the form "C3 -n-alkynyl" is meant the main
chain of the alkynyl group having 3 to n carbon atoms. C3- -alkynyl represents for example
1-propynyl, 3-propynyl or 1-hexynyl.
Here and hereinbelow the term "alkoxy" represents a linear or branched alkoxy group. By
using the form "Ci-n-alkoxy" the alkyl group is meant having 1 to n carbon atoms.
C -6-alkoxy represents for example methoxy, ethoxy, propoxy, isopropoxy, butoxy,
isobutoxy, ec-butoxy, er t-butoxy, pentyloxy and hexyloxy.
Here and hereinbelow the term "C3-n-cycloalkyl" represents a cycloaliphatic group having
3 to n ring carbon atoms. C3 -8-cycloalkyl is selected from the group consisting of
cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl.
Here and hereinbelow the term "aryl" represents an aromatic or heteroaromatic group,
selected from the group consisting of phenyl, naphth-l-yl, naphth-2-yl, furan-2-yl, furan-
3-yl, thiophen-2-yl, thiophen-3-yl, benzo[b]furan-2-yl and benzo[b]thiophen-2-yl.
Here and hereinbelow the term "aralkyl" represents a group consisting of an alkyl and an
aryl moiety, wherein the alkyl moiety of the aralkyl residue is a Ci- alkyl group and the
aryl moiety is selected from the group consisting of phenyl, 1-naphthyl, 2-naphthyl, furan-
2-yl, furan-3-yl, thiophen-2-yl, thiophen-3-yl, benzo[b]furan-2-yl and benzo[b]thiophen-
2-yl.
Here and hereinbelow the term "C2-5-alkyl C 2-s-carboxylate" represents an carboxylic acid
ester consisting of C^-alkyl an acyl and an alkoxy moiety, wherein the acyl moiety is
selected from acetyl, propionyl, butyryl, isobutyryl, pentanoyl, -pentanoyl, secpentanoyl
and pivaloyl, and Ci- alkyl group and
Here and hereinbelow the term "Cs-s-alkane" represents a linear or branched aliphatic or a
cycloaliphatic hydrocarbon having 5 to 8 carbon atoms. In industrial chemistry medium
chained aliphatic hydrocarbons such as hexanes, heptanes and octanes often are used as
mixtures of the respective linear hydrocarbons together with its branched, i.e. isomeric,
forms. Though, «-hexane, «-heptane and -octane can be used also in pure form.
Here and hereinbelow the term "dialkyl" independently means to alkyl groups attached to a
connecting atom. For example in a dialkylzinc (II) compound, two alkyl groups are
attached to zinc, whereas in dialkylamino the two alkyl groups are attached to nitrogen.
In contrast to prior attempts it is surprisingly not required to control the pH of the reaction
mixture in a certain range, although the formation of by-products is limited while keeping
the pH of the aqueous phase at a pH between about pH 6 to 11. Also at a too much acidic
pH the compounds of formula I or II might be extracted from the water-immiscible solvent
into the aqueous phase. Adjustment of the pH can be carried out for example by precharging
a suitable base in the reaction vessel and/or by controlled addition of a suitable
base, preferably a water miscible and/or soluble base, more preferably an inorganic or
organic base selected from the group consisting of alkali or alkaline earth metal carbonates,
hydrogencarbonates and hydroxides, piperidine, Ci-4-alkylpiperidines, pyridine, Ci-4-alkylpyridines,
morpholine and tri-Ci -4-alkylamines. Weak bases such as alkali or alkaline earth
metal carbonates, hydrogencarbonates are preferred.
When as compound of formula II, a chiral o-aminobenzyl alcohol is used as a starting
compound in the process, i.e. wherein R to R5 is as defined above with the proviso that R
and R2 are not identical, the confirmation of the starting compound is maintained in the
compound of formula I. In a preferred embodiment the reaction is carried out with
compounds where R and R2 are not identical.
In a further preferred embodiment in compound of formula II the substituent R1 is
Ci-4 -perfluoroalkyl, R2 is 2-cyclopropyl-ethynyl or 2-(l-methyl-cyclopropyl)-ethynyl, R8 is
a halogen atom in para-position to the amino group, preferably chlorine, R9 is hydrogen
and R10 is hydrogen..
In a another preferred embodiment in compound of formula II the substituent R is
Ci-4-perfluoroalkyl, R2 is 2-cyclopropyl-ethynyl or 2-(l-methyl-cyclopropyl)-ethynyl, R8 is
a halogen in p ara-position to the amino group, preferably chlorine, and R9 and R10 are
hydrogen.
The reaction preferably is carried out with the free base of formula II as starting
compound, though also a salt of said base with an inorganic or organic acid can be used.
Suitable salts are for example hydrochlorides, sulfonates, methanesulfonates, oxalates or
tartrates. Since the free base of formula II is an amine, usually such salts contain an excess
amount of acid. Thus, useful are stoichiometric and non-stoichiometric mixtures and/or
salts of the compound of formula II and at least one acid. A preferred salt is a methanesulfonate
which comprises about 1: 1 to 1.5:1 molar equivalents of methanesulfonic acid to
the free amino base of formula II. Where appropriate, an additional amount of the base to
neutralize the effect of hydrolysis of an acidic salt has to be taken into consideration, to
avoid side reactions since the cyclisation of the present process preferably is carried out at
a pH of the aqueous phase between about pH 6 to 11. In case of a strongly acidic salt, such
as a methanesulfonate, an additional step to release the free base might be useful. In a
preferred embodiment liberating the free base from an acidic salt can be performed in a
mixture of a water-immiscible organic solvent and a weak aqueous base, preferably a water
miscible and/or soluble base, more preferably an inorganic or organic base selected from
the group consisting of alkali or alkaline earth metal carbonates, hydrogencarbonates,
phosphates, and hydroxides; ammonium carbonate, hydrogencarbonate, phosphate, and
aqueous ammonia; piperidine, Ci-4 -alkylpiperidines, pyridine, C -alkylpyridines,
morpholine and tri-Ci^-alkylamines.
If a salt of the compound of formula II is liberated in an additional step before cyclisation,
in a preferred embodiment, the liberation takes place in the same solvent then the
cyclisation to allow easy handling. Since the solvent in the present invention is deemed to
be water-immiscible, the base liberation can be carried our easily by extracting the organic
solvent with an aqueous base.
As outlined above, in a preferred embodiment the organic solvent of the extraction mainly
consists of at least one compound selected from C2-5-alkyl C2 - 5-carboxylates and mixtures
of at least one C2-5-alkyl C2-5-carboxylate with at least one C5 -8-alkane. Most preferred
solvents are selected from acetates, hexanes, heptanes and mixtures thereof.
In the present process phosgene or its two equivalents diphosgene and triphosgene can be
used equivalently as cyclisation agent, either in pure form or as a mixture. By using
phosgene, diphosgene and triphosgene as cyclisation agents in the above described process
one should be aware that 1 molar equivalent of diphosgene replaces 2 molar equivalents of
phosgene, while 1 molar equivalent of triphosgene replaces 3 molar equivalents of
phosgene. The reactivity of all three compounds is essentially identical.
Phosgene is a gas, diphosgene is a liquid and triphosgene is a solid at standard conditions
(20 °C, 1bar), respectively. Thus, it depends mainly on the desired reaction conditions and
local availability which cyclisation agent is used.
In a preferred embodiment in the process as described above the cyclisation agent is
provided in gaseous form.
In another preferred embodiment in the process as described above the cyclisation agent is
provided in liquid form, either in pure form, as a solution or as a suspension. Phosgene,
diphosgene and triphosgene can be dissolved in an aprotic solvent to be provided in liquid
form.
In yet another preferred embodiment in the process as described above the cyclisation
agent is provided in solid form.
In order to improve workup procedure it might be useful to supply the cyclisation agent in
slight excess. In the process as described above, the molar ratio of the cyclisation agent,
calculated in molar equivalents of phosgene, to the compound of formula II should be in a
range from 1:4, preferably in the range of 1:1 to 2.5: 1, more preferably in the range of
1.1 : 1 to 1.5:1. Generally, the most preferred molar ratio is about 1.2: 1. It has to be noted
that surprisingly even a large excess of the molar ratio of phosgene equivalents to the
compound of formula II 10:1 has almost no negative effect in view of the product
formation.
A requirement for the present invention is that the base is a water-miscible and/or -soluble
base to allow extraction of the base into the aqueous phase after completion of the
cyclisation.
The base used in the reaction can be an inorganic or organic base.
Examples for inorganic bases are alkali or alkaline earth metal carbonates,
hydrogencarbonates and hydroxides.
Examples of suitable organic bases are piperidine, Ci-4-alkylpiperidines, pyridine,
Ci-4-alkylpyridines, morpholine or tri-Ci.-t-alkylamines, wherein any of the alkyl moieties
are independently selected from the group consisting of methyl, ethyl, propyl, isopropyl,
butyl, isobutyl, sec-butyl and tert-butyl. Using weak bases like alkali or alkaline earth
metal carbonates, hydrogencarbonates or a combination of different bases with different
p¾ establishes a buffered system. With strong bases like alkali or alkaline earth metal
hydroxides a parallel dosage of phosgene and the base might be of advantage.
The process as described above, wherein the weight ratio of water to the organic solvent is
in the range from 1:1 to 5:1, preferably in the range from 2:1 to 3.5:1.
In a preferred embodiment at least 90%-w/w of said organic solvent consists of at least one
compound selected from the group consisting of C2-5-alkyl C2 - 5-carboxylates and mixtures
of at least one C2-5-alkyl C 2-5-carboxylate with at least one Cs-s-alkane.
In a further preferred embodiment at least 95%-w/w, even more preferred at least
98%-w/w, of said organic solvent consists of at least one compound selected from the
group consisting of C2 - 5-alkyl C2-5-carboxylates and mixtures of at least one C2-5-alkyl
C - -carboxylate with at least one C 5- -alkane. In another preferred embodiment the waterimmiscible
organic solvent, consisting of at least one compound selected from the group
consisting of C2-5-alkyl C2-5-carboxylates and mixtures of at least one C2 - 5-alkyl
C2 - 5-carboxylate with at least one C5-8-alkane.
Compounds forming the maximum 10%-w/w, in a preferred embodiment maximum
5%-w/w and in an even more preferred embodiment maximum 2%-w/w part, of the solvent
different from the group consisting of C 2-5-alkyl C2-5-carboxylates and mixtures of at least
one C2- -alkyl C2-5-carboxylate with at least one C5-8-alkane, are defined to be additional
organic co-solvent. The term "additional organic co-solvent" comprises also mixtures of
more than one organic compound.
The additional organic co-solvent is also required to be immiscible with water and shall not
act as solubilizer or emulsifier between the aqueous and the organic phase in the reaction
mixture. The additional co-solvent must be miscible with the at least one compound
selected from the group consisting of C 2-5-alkyl C2 - 5-carboxylates and mixtures of at least
one C2-5-alkyl C2-5-carboxylate with at least one C5-8-alkane in the presence of water. The
additional co-solvent, at least after being solved in the water-immiscible solvent is required
to have a lower density than water to avoid separation of the solvents into three phases.
The additional organic solvent may comprise compounds selected from the group
consisting of aromatic compounds such as benzene, toluene, substituted naphthalenes, or
fully or partially hydrogenated compounds such as decalin or tetralin.
Preferably, the C2-5-alkyl C2-5-carboxylate is selected from the group consisting of
C2-5-alkyl acetates, C2-5-alkyl propionates, and C2- -alkyl butyrates.
In a further preferred embodiment the C2-5-alkyl C2- -carboxylate is selected from the
group consisting of C2. -alkyl acetates and C2 - 5-alkyl propionates.
Expediently, the C5-8-alkane is selected from the group consisting of pentanes,
cyclopentane, hexanes, cyclohexane, heptanes, cycloheptane and octanes.
Even more expediently, the C5-8-alkane is selected from the group consisting of hexanes,
cyclohexane, heptanes and cycloheptane, preferably from heptanes.
Preferably, the cyclization is carried out at a temperature from -30 to +40 °C, even more
preferably from 0 to +20 °C.
The workup procedures of the compound of formula I for removal of excess phosgene,
diphosgene or triphosgene and organic solvents to facilitate crystallization are preferably
carried out as known in the art.
According to the invention the product can be obtained with normal liquid-liquid
extraction. The product is dissolved as the free base in said organic solvent comprising at
least one compound selected from C2-5-alkyl C2- -carboxylates and mixtures of at least one
C2-5-alkyl C2-5-carboxylate with at least one C5-8-alkane.
After extraction the product can be directly crystallized in the organic solvent. Thus
cyclisation, optional liquid-liquid extraction and crystallization can be carried out without
any solvent change regarding the organic solvent. Advantageously the crystallization is
carried out by seeding the organic solvent comprising the product with seed crystals of the
product.
The present process also comprises a new process for the preparation of the compounds of
formula II, thus we also claim the preparation of the process as mentioned above, wherein
the compound has been obtained by the process as follows. Only the main process as
mentioned above is recited. For the avoidance of doubt, all preferred embodiments
mentioned above also apply to the following process.
Provided is a process for the preparation of a compound of formula
and/or a suitable salt thereof,
said process comprising the reaction of a com ound of formula
and/or suitable salts thereof,
wherein R , R , R°, R and R, are as defined above,
with a cyclisation agent selected from phosgene, diphosgene, triphosgene and mixtures
thereof,
wherein the reaction is carried out in the presence of an aqueous base, and a waterimmiscible
organic solvent, wherein at least 90%-w/w of said organic solvent consisting of
at least one compound selected from the group consisting of C2- -alkyl C - 5-carboxylates
and mixtures of at least one C2-5-alkyl C 2- -carboxylate with at least one C5-8-alkane, and
wherein the compound of formula II is obtained by a process comprising the steps of
(i) reacting a protic chiral auxiliary with a diorganylzinc(II) compound, in the presence of
an aprotic solvent, at a temperature in the range of 0 to 40 °C, and
(ii) keeping the mixture of step (i), preferably under stirring, in a first maturation period
until the reaction is completed, but of at least 20 min, preferably between about 20 to
120 min, and
(iii) reacting to the mixture obtained after step (ii) with a compound of formula
HI,
wherein R is as defined above,
(iv) keeping the mixture of step (iii), preferably under stirring, in a second maturation
period until the reaction is completed, but of at least 0 min, preferably between about 10
to 120 min, and
(v) reacting to the mixture obtained after step (iv) a compound of formula
wherein R1, R8, R9 and R10 are as defined above, and an organolithium base and/or another
alkali metal organyl at a temperature in the range of 0 to 40 °C, and
(vi) keeping the mixture obtained in step (v) to 10 to 50 °C until the reaction is completed,
to obtain the compound of formula II.
The major advantages of the present process are the reduction of the zinc(II) catalyst in
view of the compound of formula IV, the need of only one protic compound to first react
with the zinc(II) catalyst, especially the possibility to avoid addition of fluorinated
alcohols.
In contrast to known processes which requires the addition of two different proton sources,
wherein an additional proton source can be methanol, ethanol, propanol, isopropyl alcohol,
butanol, isobutanol, sec-butanol, tert-butanol, pentanol, (CH3)3CCH OH,
(CH3)3CCH(CH3)OH, Cl3CCH2OH, CF3CH2OH, CH2=CHCH2OH, (CH3)2NCH2CH2OH
or even another chiral compound. The present process can be carried out with only one
proton source, which at the same time acts as a chiral auxiliary. A preferred proton source
in that sense is an ephedrine derivative, more preferably a phenylnorephedrine derivative
(PNE derivative).
The present process relies on a specific order of addition of the compounds of the
diorganylzinc(II) compound, the compounds of formulae III and IV comprising the two
maturation periods of steps (ii) and (iv), respectively. The term "until the reaction is
completed" in steps (ii), (iv) and (vi) means that at least 90% conversion, preferably at
least 95%, more preferably 98%, is reached in the respective step. The course of
conversion can be followed for example by calorimetric measurements, "React IR" or FTIR.
Also possible are off-line methods such as gas chromatography or HPLC. It is possible
to establish a correlation between conversion and the output of analytical methods easily
with computer aided systems. We suspect that maybe in the first maturation period a first
catalytic species if formed, while in the second maturation step a second catalytic species
is formed. The first catalytic species might comprise a compound of formula
(alkyl)Zn(chiral auxiliary) which might be solved in the mixture or aggregated. The second
catalytic species might comprise a compound of formula (CºC-R )Zn(chiral auxiliary),
wherein R2 is as defined above. By using diethylzinc ethane evolution of approx. 1
equivalent in respect to diethylzinc could be observed in steps (ii) and (iv), respectively.
Ethane formation could be detected during the diethylzinc addition. The ethane release was
observed with a delay with respect to the diethylzinc addition. It is assumed that ethane
was first dissolved in the reaction solution and then released to the gas phase. -NMR
analysis shows that some ethane remained dissolved in the reaction mixture. The structures
of the catalytic species can be only proposed because of the difficulties to separate the
catalytic species from the respective precursors. Especially, since catalytic species would
be highly sensitive to air and humidity.
In step (v) the addition of the compound of formula IV and the organolithium base and/or
the other alkali metal organyl, are fed simultaneously, either separately or as a mixture.
Advantageously, dosage of the organolithium base and/or the other alkali metal organyl
starts ahead of the dosage of the compound of formula IV, preferably up to 20 min ahead,
more preferably up to about 10 min ahead.
The process is designed to obtain the compound of formula I with an enantiomeric purity
(ep) of at least 90%, preferably with an ep of at least 95%, more preferred of at least 96%,
and even more preferred of at least 97%.
The protic chiral auxiliary induces the formation of the desired enantiomer during reaction
of the compounds of formulae III and IV. The expression "protic chiral auxiliary" means
that the chiral auxiliary comprises at least one proton which can be easily removed, most
preferred in a hydroxy 1group.
In a preferred embodiment the chiral auxiliary is selected from protic N,N-disubstituted
ephedrine derivatives.
Suitable protic N,N-disubstituted ephedrine derivatives are for example diastereoisomers of
2-(di-C 1-4-alkylamino)-l-phenyl-propan-l-ols, such as 2-(dimethylamino)-l-phenylpropan-
1-ol, 2-(diethylamino)- 1-phenyl-propan- 1-ol, 2-(diisopropylamino)- 1-phenylpropan-
l-ol, and 2-(dibutylamino)-l -phenyl-propan- l-ol; 2-(N,N-C4 -6-alkylene)-l -phenylpropan-
1-ols, such as l-phenyl-2-(piperidinyl)propan-l-ol and 1-phenyl-2-(pyrrolidinyl)-
propan- l-ol, and 2-( 1-heteroary 1)- 1-phenyl-propan- 1-ols, such as 1-phenyl-2-( 1-pyridinyl)-
propan-l-ol, l-phenyl-2-(l-piridinyl)propan-l-ol and . More specific examples are
(li?,2S)-2-(dimethylamino)-l -phenyl-propan- l-ol (CAS [552-79-4]), (lS,2J?)-2-(dimethylamino)-
l -phenyl-propan- l-ol (CAS [42151-56-4]), (l#,2/?)-2-(dimethylamino)-l -phenylpropan-
l-ol (CAS [14222-20-9]), (lS,25)-2-(dimethylamino)-l -phenyl-propan- l-ol (CAS
[51018-28-1]), ( l ,2S)-l-phenyl-2-(pyrrolidinyl)propan-l-ol (CAS [127641-25-2]),
( 5,2/?)- l-phenyl-2-(pyrrolidinyl)propan- l-ol (CAS [123620-80-4] = (1S,2#)-PNE),
(1R,2R)- 1-phenyl-2-(pyrrolidinyl)propan- 1-ol and ( 5,25)- 1-phenyl-2-(pyrrolidinyl)-
propan-l-ol.
In a preferred embodiment the protic chiral auxiliary is (l/?,25)-phenylnorephedrine
(( ,2 )-PNE or ( 1S,2R)- l-phenyl-2-(pyrrolidinyl)propan- l-ol) to obtain ((5)-2-(2-amino5-
chlorophenyl)-4-cyclopropyl-l,l,l-trifluorobut-3-yn-2-ol (DMP-266) or one of its salts,
from l-(2-amino-5-chlorophenyl)-2,2,2-trifluoroethanone and cyclopropylacetylene.
The amount of the zinc(II) catalyst needed in the reaction can be reduced remarkably
compared to processes known in the art. It must be noted that the amount of the zinc(II)
catalyst can be surprisingly much lower than the amount of the chiral auxiliary.
In a preferred embodiment the molar ratio of the protic chiral auxiliary to the
diorganylzinc(II) compound is in the range of 1.5:1 to 1:1, preferably in the range of 1.3:1
to 1.2: 1, most preferred at about 1.24: 1.
The chiral auxiliary mediates the catalytic process. Although one would expect that
zinc(II) catalyst and the protic chiral auxiliary form a zinc(II) complex with a certain
stoichiometry it is not necessary to add the chiral auxiliary and the zinc(II) catalyst in
equimolar amounts. Preferably the amount of the chiral auxiliary is slightly higher than the
amount of the diorganylzinc(II) catalyst.
Suitable diorganylzinc(II) compounds are for example selected from di(Ci - -alkyl) and
di(C 3-6-cycloalkyl), wherein the alkyl moieties are selected from the group consisting of
methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl and r t-butyl, pentyl, hexyl,
heptyl, and octyl, and wherein the cycloalkyl moieties are selected from the group
consisting of cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.
In another embodiment the diorganylzinc(II) compound is diphenylzinc or Zn(OTf)2,
wherein OTf denotes a "triflate" (trifluoromethanesulfonate) group.
In a preferred embodiment in step (i) the molar ratio of the protic chiral auxiliary to the
compound of formula III is in the range of 1:1 to 1:10, preferably in the range of 1:2 to 1:6,
more preferably of 1:3 to 1:6.
Addition of the compound of formula III can be carried out at a temperature from 0 to
+40 °C, preferably from +10 to about +30 °C.
In a preferred embodiment the compound of formula II is selected from the group
consisting of terminal C3_8-alkylalkynes, cyclopropylacetylene, (l'-methyl)-cyclopropylacetylene
and phenylacetylene.
It is recommended, that in step (iii) the compound of formula II is used in a molar ratio to
the compound of formula IV of :0.6 to 1:1.3
In a preferred embodiment the compounds of formula II are selected from the group
consisting of p-methylbenzaldehyde, /?-fluorobenzaldehyde, p-cyanobenzaldehyde,
p-methoxybenzaldehyde, naphthalenealdehyde, cinnamaldehyde, C 3-20-alkane aldehydes,
cyclohexyl carbaldehyde, cyclohexyl metyl ketone, methyl 4-metylcyclohexyl ketone,
1,1,1-trifluoroacetophenone and 2-(trifluoroaceto)-4-chloro-anilin.
In a further preferred embodiment the organolithium base is added in a molar ratio to the
compound of formula III in the range of 1:0.8 to 1:1.5, preferably of 1:0.8 to 1:1.2.
A suitable organolithium base in the present process is selected from the group consisting
of (C1-6-alkyl)lithium, lithium diisopropylamide (LDA), lithium hexamethyldisilazide
(LiHMDS), phenyllithium, and naphthyllithium.
Preferably the organolithium base is an organolithium compound or a lithium organic salt.
In preferred embodiment such organometallic lithium compound is selected from the group
consisting of phenyllithium and (Ci - -alkyl)lithium.
Preferably said (Ci . 6-alkyl)lithium is selected from the group consisting of methyllithium,
-butyllithium, sec-butyllithium, t r t-butyllithium, and hexyllithium.
In a further preferred embodiment the lithium organic salt is a lithium
Preferably the other alkali metal organyl is selected from sodium or potassium
Ci- -alkoxides, sodium or potassium diisopropylamine, and sodium or potassium
hexamethyldisilazide.
The organolithium base and/or the other alkali metal organyl can be used either
independently or in mixtures of at least two different species.
During the addition of the organolithium base and/or the other alkali metal organyl the
reaction mixture is preferably kept at a temperature from about +10 to +30 °C.
In the present process the aprotic solvent preferably is selected from the group consisting
of aprotic non-polar solvents, aprotic polar solvents and mixtures thereof.
The solvents of agents added in solution may be selected independently of each other.
Particularly preferred the solvent is selected from the group consisting of tetrahydrofuran,
benzene, chlorobenzene, o-, m-, p-dichlorobenzene, dichloromethane, toluene, ø-, m-, and
-xylene, hexanes, heptanes, cyclohexane, pentane, 1,4-dioxane, cyclohexane, diethyl
ether, r t-butyl methyl ether, diisopropyl ether, N-methylpyrrolidine, and mixtures thereof.
Examples:
The chiral alkynylation reaction (Examples 1, 2, and 4) was performed two times with the
respective starting compounds. Once using (l/?,2S)-l-phenyl-2-(pyrrolidinyl)propan-l-ol
((1 ,2S)-PNE) as ligand and once using (l ,2S)-l-phenyl-2-(pyrrolidinyl)propan-l-ol
((15,2i?)-PNE) as ligand. This allowed the unambiguous assignment of the two
enantiomers of the products by HPLC. In the experimental details below, only the
experiments using ( l S ,2i?)-PNE are described in detail because there was no major
difference between ( l ?,2 -PNE and (15,2L)-RNE . For the all examples using cyclopropylacetylene
addition to a diethylzinc catalyst, an ethane release could be observed as
well as described in Example 1. The configuration of the products of example 2 to 4 were
tentatively assigned based on the assumption that reaction in presence of ligand (15,2/?)-
PNE gives preferably the product with (^-configuration in analogy to Example 1 (SD573
process), where the configuration of both enantiomers are well known. In the SD573
process (1 ?,2S)-PNE gives preferably the product with (S)-configuration. Procedures for
analytical methods A to D are attached after the examples.
In all cyclisation examples, except where not expressively mentioned, the ee was not
measured since in all cyclisation examples with final ee-measurement the product (for
example DMP-266) always corresponded to the ee of the respective starting compound, for
example in case of cyclisation of SD573-MSA or SD573 free base (CAS [209412-27-7],
99.6% ee) to DMP-266.
ee = enantiomeric excess = ((S)-(R))/((S)+(R))
ep = enantiomeric purity = (S)/((S)+(R))
Example 1: (5)-2-(2-Amino-5-chlorophenyl)-4-cyclopropyl-l,l,l-trifluorobut-3-yn-2-
o mesylate (2:3 mol/mol) (SD573-MSA)
A solution of (li?,25)-PNE (18.1%-w/w, 171.6 g, 151 mmol) in a THF/toluene mixture
(9:l-w/w) was charged in a vessel and cooled to 17 °C. A solution of diethylzinc in toluene
(29%-w/w, 52.0 g, 122 mmol) was added at 15 to 20 °C and the mixture was aged at said
temperature for 30 min. Ethane (approx. 1 equivalent in respect to diethylzinc) was formed
during the diethylzinc addition and partially released from the reaction mixture. The ethane
release is observed with a delay with respect to the diethylzinc addition, since ethane is
first dissolved in the reaction solution and then released to the gas phase. According to
Ή -NMR analysis some ethane remained dissolved in the reaction mixture. A solution of
cyclopropylacetylene (compound of formula III, wherein R is cyclopropyl) in toluene
(70%-w/w, 57.0 g, 600 mmol) was added at 15 to 20 °C and the resulting mixture was aged
at 20 °C for 1 h. During the addition of cyclopropylacetylene additional ethane (approx. 1
equivalent in respect to diethylzinc) was formed and released to the gas phase. A solution
of butyllithium (BuLi) in toluene (157.6 g, 2.92 mol/kg, 460 mmol) and a solution of l-(2-
amino-5-chlorophenyl)-2,2,2-trifluoroethanone (SD570, compound of formula IV, wherein
R1 is trifluoromethyl, R8 is 5-chloro, R9 is hydrogen and R10 is hydrogen) (40.1%-w/w,
278.0 g, 500 mmol) in THF/toluene (l:l-w/w) were added in parallel to the reaction
mixture at 20 °C within 180 min. The addition of BuLi was started 10 min in advance of
the SD570 addition. Butane was formed during BuLi addition. However, most of the
butane remained dissolved in the reaction mixture and only weak gas formation was
observed. The course of reaction can be followed online, for example by calorimetric
measurements or by "React IR" also called "in-situ FTIR". After complete addition of
SD570 the reaction mixture was stirred for 30 min at 20 °C, then heated to 30 °C over a
period of 60 min and aged for 6 h at 30 °C. The reaction mixture was stirred at 0 °C
overnight, diluted with toluene (2 18 g) at 20 °C and quenched by addition of aqueous citric
acid ( 1 M, 375 g). After stirring for 15 min the phases were separated and the aqueous
phase was discarded. The organic phase was successively washed with water (76 g),
aqueous NaHC0 3 solution (5%-w/w, 200 g), and again water (100 g). The organic phase
was partially concentrated, then diluted with toluene (250 g), again partially concentrated
and diluted with toluene (976 g residue). The enantiomeric purity (ep) of (5)-2-(2-amino-5-
chlorophenyl)-4-cyclopropyl-l,l,l-trifluorobut-3-yn-2-ol (SD573) in the crude product
was approx. 96 to 97% according to Method B. Although not belonging to the preparation
process, described is also a process to transfer the product in a more stable form as a
methanesulfonic acid salt. The residue was diluted with isopropyl alcohol (126.6 g). Then
methanesulfonic acid (43.3 g) was added over a period of 30 min at 30 °C. Seeding crystals
(between 1 and 10 mg) were added and the mixture aged for 30 min at 30 °C. A second
portion of methanesulfonic acid (26.5 g) was added over a period of 60 min at 30 °C. The
resulting solution was aged for 30 min at 30 °C and later cooled to 5 °C over a period of
60 min. After further aging at 5 °C for 30 min, the product was filtered and washed with
cold toluene/isopropyl alcohol (10:l-w/w, 262 g) at 5 °C. The wet methanesulfonic acid
salt of SD573 ((5)-2-(2-amino-5 -chlorophenyl)-4-cyclopropyl- 1,1,1 -trifluorobut-3 -yn-2-ol
mesylate (2:3 mol/mol, SD573-MSA, compound of formula II, wherein R1 is
trifiuoromethyl, R is cyclopropyl, R is 5-chloro, R is hydrogen and R is hydrogen) was
dried in vacuo at 40 °C to obtain 188.3 g (432 mmol, 86.5% yield). SD573-MSA was
obtained with a purity of 99.9% and 99.7% ep, according to Method A.
Example 2 : (R)-2-(2-A ninobiphenyl-3-yl)-4-cyclopropyl-l ,l l -tri fl uorobut-3-yn-2-ol
methanesulfonate (1:1 mol/mol)
(\S,2R)-?NE (20.3 g, 18.0 mmol) in THF/toluene (9:l-w/w, 18.2%-w/w) was charged
under a nitrogen atmosphere to a dry, jacketed 150 mL-reactor with agitator. Diethylzinc in
toluene (29.9%-w/w, 6.48 g, 15.7 mmol) was added by syringe keeping the temperature at
17 to 22 °C and the mixture was aged for 30 min at 17 °C. Cyclopropylacetylene in toluene
(69.6%-w/w, 6.84 g, 72.0 mmol) was added at 7 °C and the resulting mixture was aged
for about 60 min at 20 °C. To the reaction mixture BuLi in toluene (3.06 mol/kg, 19.9 g,
60.9 mmol) and (l-(4-aminobiphenyl-3-yl)-2,2,2-trifluoroethanone (CN46225, compound
of formula IV, wherein R1 is trifluoromethyl, R8 is 5-phenyl, R9 is hydrogen and R 0 is
hydrogen) (43.0%-w/w, 37.0 g, 60 mmol) in THF/toluene ( 1:l-w/w) were added in parallel
over a period of 3 h at 20 °C. The addition of BuLi was started about 0 min in advance of
the CN46225 addition. After complete addition of BuLi and CN46225, the reaction
mixture was stirred for 30 min at 20 °C, then heated over a period of 1 h to 30 °C and aged
for 6 h at 30 °C. The reaction mixture was stirred overnight at 0 °C. HPLC indicated
94.3% conversion and 95.6% ep, according to Method B. The reaction mixture was diluted
with toluene (27.6 g) at room temperature and quenched by adding aqueous citric acid
( 1 M, 45.3 g). The phases were separated and the aqueous phase was discarded. The
organic phase was successively washed with water (9. 1 g), aqueous NaHC0 3 (5%-w/w,
24.2 g) and water (12.0 g). The organic phase was heated under reduced pressure to partly
remove THF while toluene is added to finally reach a THF poor residue (54.5 g) of
(i?)-2-(4-aminobiphenyl-3-yl)-4-cyclopropyl-l,l,l-trifluorobut-3-yn-2-ol (CN46630,
compound of formula II, wherein R1 is trifluoromethyl, R2 is cyclopropyl, R8 is 5-phenyl,
R9 is hydrogen and R10 is hydrogen). The residue was diluted with isopropyl alcohol
(16.7 g) and toluene (60.0 g). A first portion of methanesulfonic acid (5.48 g, 57.0 mmol)
was added by a syringe pump over a period of 30 min at 30 °C. Seeding crystals (a small
portion between 1 and 10 mg) were added and the mixture was aged for 30 min at 30 °C. A
second portion of methanesulfonic acid (2.88 g, 30.0 mmol) was added by syringe pump
over a period of 45 min at 30 °C. The mixture was stepwise aged and cooled over 1 h
45 min to finally reach 5 °C. The product was filtered, and the filter cake was washed with
toluene/isopropyl alcohol (10: 1-w/w, 27.0 g) and dried in vacuo at 40 °C. The dry product
(i?)-2-(4-aminobiphenyl-3-yl)-4-cyclopropyl- 1,1,1 -trifluorobut-3-yn-2-ol methanesulfonate
( 1: 1 mol/mol, CN46630-MSA) (15.2 g, 35.6 mmol, 59% yield) was obtained as an offwhite
solid (99.4% purity and 99.7% ep, according to Method B). The combined mother
liquor and wash liquor was concentrated (46.7 g residue). During storage overnight at 3 °C
a white solid crystallized from the residue. The product was filtered, washed with toluene,
and then toluene/isopropyl alcohol (10: 1-w/w, 0 g) was added. After stirring the slurry for
60 min at 30 °C the mixture was cooled to 3 °C and filtered. The product was washed with
toluene/isopropyl alcohol (10:l-w/w) and dried in vacuo at 40 °C. CN46630-MSA (second
crop, 3.8 g, 8.0 mmol, 13% yield) was obtained as off-white solid (89.7% purity at 99.7%
ep, according to Method B).
Example 3: (R)-4-(Cyclopropylethynyl)-6-phenyl-4-(trifluoromethyl)-l,4-dihydro-2 - -
3,1-benzoxazin-2-one
(R)-2-(4- Aminobiphenyl-3-yl)-4-cyclopropyl- 1,1,1 -trifluorobut-3-yn-2-ol methanesulfonate
(CN46630-MSA) of example 2 (14.7 g, 34.4 mmol) in ethyl acetate/heptanes
(1:1 v/v, 27.9 g) was charged in a jacketed 150 mL-reactor with agitator and off-gas
scrubber with caustic soda. After addition of aqueous Na2C0 3 (12%-w/w, 32.3 g,
36.4 mmol, formation of gas during addition!) the mixture was stirred for 15 min at 15 °C.
The aqueous phase was separated and discarded. Aqueous Na2C0 3 (12%-w/w, 4 g,
46 mol) and ethyl acetate (20 g) were charged to the organic phase. Triphosgene (4.41 g,
14.9 mmol) was added in portions over a period of 25 min at 10 °C. The reaction mixture
was stirred for 2 h at 8 °C. The mixture was diluted with ethyl acetate (45 g) and the phases
were separated. The aqueous phase was discarded. The organic phase was washed with
water (12 mL), dried over MgS0 4, filtered and concentrated and dried at 50 °C under
reduced pressure to obtain (/?)-4-(cyclopropylethynyl)-6-phenyl-4-(trifluoromethyl)-
l,4-dihydro-2 H-3,l-benzoxazin-2-one (CN46685, compound of formula I, wherein R1 is
trifluoromethyl, R2 is cyclopropyl, R8 is 6-phenyl, R9 is hydrogen and R10 is hydrogen)
(12.1 g, 33.9 mmol, 98%) as a yellowish solid (99.5% purity, according to Method C).
Example 4: (R )-2-(2-Amino-5-fluorophenyl)-4-cyclopropyl-l,l»l-trifluorobut-3-yn-2-
ol methanesulfonate (2:3 mol/mol)
(15,2i?)-PNE ( 18.2%-w/w, 20.3 g, 18.0 mmol) in THF/toluene (9: 1-w/w) was charged
under nitrogen to a dry, jacketed 150 mL-reactor with agitator. Diethylzinc in toluene
(29.9%- w/w, 6.20 g, 15.0 mmol) was added by syringe while keeping the temperature at
17 to 22 °C. Then the mixture was aged for 30 min at 17 °C. Cyclopropylacetylene in
toluene (69.6%- w/w, 6.82 g, 71.8 mmol) was added at 17 °C and the reaction mixture was
aged for 60 min at 20 °C. To the reaction mixture BuLi in toluene (19.3 g, 3.06 mol/kg,
59.1 mmol) and l-(2-amino-5-fluorophenyl)-2,2,2-trifluoroethanone (CAS [214288-07-0],
CN46221, compound of formula IV, wherein R1 is trifluoromethyl, R8 is 5-fluoro, R9 is
hydrogen and R10 is hydrogen) (36.9%-w/w, 33.7 g, 60.0 mmol) in THF/toluene ( :1-w/w)
were added in parallel over a period of 3 h at 20 °C. The addition of BuLi was kept 10 min
in advance of the CN4622 1 addition. After completed addition the reaction mixture was
stirred at 20 °C for 30 min, heated over a period of 60 min to 30 °C and aged for 6 h at
30 °C. The reaction mixture was stirred overnight at 0 °C. HPLC indicated 82.4%
conversion and 96.0% ep of (i?)-2-(2-amino-5-fluorophenyl)-4-cyclopropyll,
l,l-trifluorobut-3-yn-2-ol (CN46619) according to Method B. The reaction mixture was
diluted with toluene (27.6 g) and quenched by adding aqueous citric acid ( 1 M, 45.3 g).
The phases were separated and the aqueous phase was discarded. The organic phase was
successively washed with water (9.1 g), aqueous NaHC0 3 (5%-w/w, 24.2 g) and water
(12.0 g). The organic phase was alternating concentrated and diluted with toluene to
remove THF. The obtained residue (51.0 g) was diluted with isopropyl alcohol (16.7 g)
and toluene (60.0 g). Methanesulfonic acid (8.36 g, 87.0 mmol) was added by a syringe
pump over a period of 75 min at 30 °C. The mixture was aged and cooled stepwise over
2 h 0 min to reach 5 °C before the mixture was filtered. The filter cake was washed with
toluene/isopropyl alcohol (10:l-w/w, 27.0 g) and dried under reduced pressure at 40 °C.
The dry product (i?)-2-(2-amino-5-fluorophenyl)-4-cyclopropyl- 1,1,1 -trifluorobut-3-yn-
2-ol methanesulfonate (2:3 mol/mol, CN46619-MSA, compound of formula II, wherein R1
is trifluoromethyl, R2 is cyclopropyl, R8 is 5-fluoro, R9 is hydrogen and R 0 is hydrogen)
(19.46 g, 46.6 mmol, 78% yield) was obtained as a yellowish solid (99.8%-w/w by
1H-NMR, and 99.8% ep, according to Method B).
Example 5: (R)-4-(Cyclopropylethynyl)-6-fluoro-4-(trifluoromethyI)-l,4-dihydro-
2//-3,l-benzoxazin-2-one
(i?)-2-(2-Amino-5-fluorophenyl)-4-cyclopropyl- 1,1,1 -trifluorobut-3-yn-2-ol
methanesulfonate (CN46619-MSA) of example 4 (14.0 g, 33.5 mmol) in ethyl
acetate/heptanes (40 g, 6/4 v/v) was charged to a jacketed 150 mL-reactor with agitator and
off-gas scrubber with caustic soda. After addition of aqueous Na2C0 3 (12%-w/w, 26.9 g,
30.3 mmol) the mixture was stirred for 5 min at 15 °C. The aqueous phase was separated
and discarded. Aqueous Na2C0 3 (12%-w/w, 34.1 g, 38.4 mmol) was charged to the
organic phase, then triphosgene (3.73 g, 12.6 mmol) was added in portions over a period of
25 min at 0 °C. The reaction mixture was stirred for 2 h at 8 °C. The mixture was charged
with heptanes (15.9 g), the phases were separated and the aqueous phase discarded. The
organic phase was washed with water (12 mL), dried over MgS0 , filtered and
concentrated to dryness. After drying under vacuum at 50 °C, the product
(/?)-4-(cyclopropylethyny l)-6-fluoro-4-(trifluoromethy 1)- 1,4-dihydro-2 H-3, -benzoxazin-
2-one (CN46686, compound of formula I, wherein R is trifluoromethyl, R2 is cyclopropyl,
R8 is 6-fluorophenyl, R9 is hydrogen and R10 is hydrogen 9.78 g, 32.7 mmol, 97%) was
obtained as a yellowish solid (99.4% purity, according to Method C).
Example 6: Cyclisation of SD573 with diphosgene
Aqueous Na C0 3 ( 12%-w/w, 183 g, 0.206 mol) was charged to SD573-MSA
((5)-2-(2-amino-5-chlorophenyl)-4-cyclopropyl-l ,1,1-trifluorobut-3-yn-2-ol mesylate (2:3
mol/mol) = methanesulfonate of the S-enantiomer of the compound of formula II, wherein
R is trifluoromethyl, R is cyclopropyl, R is 5-chloro, R is hydrogen and R is
hydrogen; 100 g, 0.23 mol, corresponding to 66.8 g of SD573 free base, 99.6% ee,
prepared accordingly to Example 1) in ethyl acetate/heptanes (203 g, 1.5:1 v/v). The
mixture was stirred for 5 min at 15 °C. Hydrolysis of the mesylate ended at about pH 9.0 of
the aqueous phase. Then a phase separation was performed and the aqueous phase was
removed. Aqueous Na2C0 3 ( 12%-w/w, 232 g, 0.262 mol) was charged to the organic
phase. To the biphasic mixture, liquid diphosgene (24 g, 120 mmol) was added in 90 min
at 12 °C. After a conversion of more than 99.7% was reached, according to Method C,
heptanes (204 g) were charged. The reaction mixture was then heated to 20 °C, the
aqueous phase was separated and discarded, while the organic phase was washed with
water (about 80 g). The organic layer was heated under reduced pressure, ethyl acetate
distilled off and heptanes were charged to the reaction mixture to achieve a residual ethyl
acetate content of 5.5%-w/w and a ratio of heptanes to organic matter of 10 L/kg in view of
originally added SD573-MSA. Then the mixture was heated to dissolve all organic matter.
The solution was seeded with 0.8 g of DMP-266 (DMP-266 = S-enantiomer of the
compound of formula I, wherein R is trifluoromethyl, R2 is cyclopropyl, R8 is 6-chloro, R9
is hydrogen and R10 is hydrogen) at 55 °C and stirred for about 15 min at 55 °C. The
mixture was then cooled to 50 °C and hold for 120 min. Then the mixture was further
cooled within 2 h from 50 °C to 25 °C and within another 2 h ramp to about -10 °C.
Finally, the mixture was stirred for about 1 h at -10 °C maximum and then filtered. The
filter cake (wet product) was washed with pre-cooled heptanes (2x50 mL) at 0 °C
maximum. The solid was dried in vacuo to yield 94.2% (68.4 g, 216 mmol) of DMP-266 at
a purity of 99.9%-w/w according to Method D. The sample comprises 99.8%-w/w
S-enantiomer, i.e. an enantiomeric excess (ee) of 99.6%.
Example 7: Cyclisation of SD573 with diphosgene
Aqueous Na2C0 3 (12%-w/w 91.5 g, 0.103 mol) was charged to SD573 -MSA (50 g,
0.1 15 mol, corresponding to 33.4 g of SD573 free base, 99.6% ee, prepared accordingly to
Example 1) in ethyl acetate/heptanes (101.5 g, 1.5/1 v/v). The mixture was stirred for 5
min at 1 °C. Hydrolysis of the mesylate ended at pH 6.4 in the aqueous phase. A phase
separation was performed and the aqueous phase was removed. The remaining organic
phase was cooled to 12 °C and aqueous Na2C0 3 (12%-w/w, 106 g, 0.12 mol) was charged.
To the biphasic mixture, liquid diphosgene ( 11.4 g, 57 mmol) was added in 90 min at
12 °C. After a total conversion was reached according to Method C, heptanes (68.8 g) was
charged. The reaction mixture was then heated to 20 °C, stirred 30 min and the aqueous
phase was removed. The organic phase was heated under reduced pressure, ethyl acetate
was distilled off and heptanes charged to the reaction mixture to achieve a residual ethyl
acetate content of 4.4 w% and a ratio of heptanes to organic matter of 6.5 L/kg in view of
originally added SD573 -MSA. Then the obtained mixture was heated to dissolve all
organic matter. The solution was seeded with DMP-266 (0.4 g) at 55 °C and stirred for
about 15 min at 55 °C. The mixture was then cooled to 50 °C and hold for 120 min. The
mixture was further cooled in 2 h from 50°C to 25°C and within another 2 h to -10 °C
maximum. The mixture finally was stirred for about 1 h at -13 °C and then filtered. The
filter cake (wet product) was washed with pre-cooled heptanes (2x50 mL) at 0 °C
maximum. The solid was dried in vacuo to yield 92.1% (33.45 g, 105 mmol) of DMP-266
of a purity of 99.9%-w/w according to Method D. The sample comprises 99.8%-w/w S
enantiomer, i.e. 99.6% ee.
Example 8: Cyclisation of SD573 with triphosgene
SD573-MSA (50 g, 0.1 14 mol, corresponding to 33.4 g of SD573 free base, 99.6% ee,
prepared accordingly to Example 1) was dissolved in an ethyl acetate/heptanes mixture
(164 g, 1:1 v/v) and charged with aqueous Na2C0 3 (12%-w/w, 91.5 g, 0.104 mol). After
hydrolysis of the mesylate a pH of about 7.0 was measured in the aqueous phase. The
mixture was stirred for at least 5 min at 15 °C. Then a phase separation was performed and
the aqueous phase was removed. The mixture was cooled below 12 °C and aqueous
Na2C0 3 (12%-w/w, 1 6 g, 0.131 mol) was charged. To the biphasic mixture, triphosgene
(12.5 g, 42 mmol) was added at 10 °C maximum in five portions within 90 min. The
mixture was stirred further 5 min below 15 °C. After a total conversion was reached
according to Method C, heptanes (54 g) was charged. The reaction mixture was then
heated to 20 °C and the aqueous phase was removed. The organic phase was washed with
water (40 g) and then heated under reduced pressure, ethyl acetate distilled off and
heptanes charged to the reaction mixture to achieve a residual ethyl acetate content of
4.6%-w/w and a ratio of heptanes to organic matter of 6.5 L/kg in view of originally added
SD573-MSA. The solution was seeded with DMP 266 (0.4 g) at 57 °C and stepwise cooled
under stirring at -10 °C within 2 h 15 min. The mixture was stirred at -10 °C maximum
overnight and then filtered. The filter cake was washed with pre-cooled heptanes
(2x25 mL) at 0 °C maximum. The solid was dried in vacuo to yield 95% of DMP-266
(34.22 g, 108 mmol) at a purity of 100%-w/w, according to Method D. The sample
comprises 99.8%-w/w S-enantiomer, i.e. 99.6% ee.
Example 9 : Cyclisation of SD573 with triphosgene
SD573-MSA (100 g, 0.23 mol, corresponding to 66.8 g of SD573 free base, 99.6% ee,
prepared accordingly to Example 1) was dissolved in ethyl acetate/heptanes (203 g, 1.5:1
v/v) and charged with aqueous Na2C0 3 (12%-w/w, 183 g, 0.207 mol) at about 15 °C. A pH
of 7 to 9 was reached in the aqueous phase. The mixture was stirred for 5 min at 5 °C.
Then the phase separation was performed and the aqueous phase was removed. The
mixture was cooled below 12 °C and aqueous Na2C0 3 (12%-w/w, 232 g, 0.263 mol) was
charged. To the biphasic mixture, triphosgene (24.08 g, 8 1 mmol) was added in 10 portions
within 120 min at less than 12 °C. The mixture was stirred further 10 min at about 12°C.
After a total conversion was reached according to Method C, heptanes (204 g) were
charged. The reaction mixture was then heated to 20 °C and the aqueous phase was
removed. The organic phase was washed with water (80 g) and then heated under reduced
pressure to partially remove ethyl acetate, while heptanes were charged to the reaction
mixture to achieve a residual ethyl acetate content of 5.8%-w/w and a ratio of heptanes to
organic matter of 7.0 L kg in view of originally added SD573-MSA. The solution was
seeded with DMP-266 (0.8 g) at 55 °C and stirred for 15 min. Then the mixture was cooled
to 50 °C within 20 min, hold for 2 h, cooled to 25 °C within 2 h, cooled to about -10 °C
within 2 h. After cooling to about -10 °C and stirring overnight the mixture was filtered.
The isolated product was washed with pre-cooled heptanes (2x50 mL) at -10 °C
maximum. The solid was dried in vacuo to yield 85.4% DMP-266 (62 g, 19.6 mmol) at a
purity of 100%-w/w, according to Method D. The sample comprises 99.8%-w/w
S-enantiomer, i.e. 99.6% ee.
Example 10: Cyclisation of SD573 with triphosgene
Aqueous Na2C0 3 (14%-w/w, 135 g, 0.178 mol) was charged to SD573 free base (33.4 g,
0.1 15 mol) in ethyl acetate/heptanes (70.4 g of 45:55 v/v) at 15 °C. The mixture was
cooled to 8 °C and triphosgene in heptanes (26.8%-w/w, 112 g, 101 mmol) was added
within 60 min, while the temperature was kept at 5 °C to 1 °C. After 60 min a total
conversion was reached, according to Method C. The reaction mixture was heated to
25 °C. Then a phase separation was performed and the aqueous phase was removed. The
organic phase was heated under reduced pressure, ethyl acetate partly was distilled off and
heptanes were charged to the reaction mixture to achieve a residual ethyl acetate content of
about 2.5%-w/w and a ratio of heptanes to organic matter of about 15 L kg in view of
originally added SD573 free base. Then the mixture was heated to dissolve all organic
matter and afterwards seeded with DMP-266 (overall 1.4 g) at 55 °C. No product
crystallized and therefore the organic phase was heated under reduced pressure to partially
remove ethyl acetate, while heptanes were charged to the reaction mixture to achieve a
residual ethyl acetate content of less then 3% (w/w) and a ratio of heptanes to organic
matter of about 15 L kg in view of originally added SD573 free base. Then the mixture
was heated to dissolve all organic matter and afterwards seeded with DMP-266 ( 1.5 g) at
5 1 °C and stirred for about 140 h at 5 1 °C. The slurry was stepwise cooled under stirring
within 4 h to reach -15 °C. The slurry was stirred for 16 h at -15 °C and then filtered. The
isolated product was washed with pre-cooled heptanes (2x55 mL) at -10 °C maximum.
The solid was dried in vacuo to yield 92.9% (33.7 g, 107 mmol) of DMP-266, at a purity of
99.6%-w/w, according to Method D. The sample comprises 99.8%-w/w S-enantiomer, i.e.
99.6% ee.
Example 11: Cyclisation of SD573 with triphosgene
Aqueous Na2C0 3 (12%-w/w, 91.5 g, 0.103 mol) was charged to SD573-MSA (50 g,
0.1 15 mol, corresponding to 33.4 g of SD573 free base, prepared accordingly to Example
1) in ethyl acetate/heptanes (90.8 g, 55/45 v/v). The mixture was stirred for 5 min at 15 °C
resulting in a pH of 6.8 of the aqueous phase. Then a phase separation was performed and
the aqueous phase was removed. The organic phase was heated under reduced pressure and
the solvent was partially removed (32.3 g, 4 1 mL) to obtain a ratio of SD573 free base to
solvent of about 1:1.75 (w/w). The distillate contained about 53.2 w% of ethyl acetate. The
mixture comprising the SD573 free base was cooled to 12 °C and aqueous Na2C0 3
(12%-w/w, 96 g, 0.109 mol) was charged. To the biphasic mixture, triphosgene in ethyl
acetate (31%-w/w, 32.7 g, 34 mmol) was added in 66 min at 7 to 12 °C. The mixture was
stirred 15 min at 12 °C maximum. After a conversion of 90.2% was reached, according to
Method C, additional heptanes (86 g) were charged and the reaction mixture was heated to
20 °C. Then a phase separation was performed and the aqueous phase was removed. The
organic phase was heated under reduced pressure to partially remove ethyl acetate while
heptanes were charged to the organic phase to achieve a residual ethyl acetate content of
6.8%-w/w (target 3 to 7%-w/w) and a ratio of heptanes to organic matter of 6.8 L/kg in
view of originally added SD573-MSA. The solution was seeded with DMP-266 (0.4 g) at
47 °C and stirred for 150 min at 47 to 55 °C. Then the mixture was slowly cooled to -10 °C
and filtered. The filter cake was washed with pre-cooled heptanes (2x25 mL) at -10 °C
maximum. The solid was dried in vacuo to yield 81.1% (29.46 g, 0.093 mmol) of DMP-
266 of a purity of 97.2%-w/w according to Method D.
Example 12: Cyclisation of SD573 with triphosgene
Aqueous Na C0 3 (12%-w/w, 275.1 g, 0.31 1 mol) was charged to SD573-MSA (150 g,
0.345 mol, corresponding to 100.2 g of SD573 free base, prepared accordingly to Example
1) in ethyl acetate/heptanes (272.1 g, 55/45 v/v). After stirring the mixture for 5 min at
15 °C a pH of 7.7 was measured. Then a phase separation was performed and the aqueous
phase was discarded. The organic phase (ethyl acetate/heptanes ratio of 61.5/38.5 w/w)
was split into 3 parts each comprising about 33 g of SD573 free base. With an aim to test
the stability of SD573 free base in ethyl acetate/heptanes mixtures, the 1st part was stored
for 4 days at 4 °C before performing Example 12.1, the 2nd part was stored for 7 days at
4 °C before performing Example 12.2, and the 3rd part was stored for 10 days at 4 °C
before performing Example 12.3.
Example 12.1:
The 1st part of the organic phase of Example 12 ( 123.5 g) was heated under reduced
pressure to partially remove the solvent until the distillate contained 60 w% of ethyl acetate
(about 33 g). The remaining mixture was cooled to 12 °C and aqueous Na2C0 3 (12%-w/w,
1 7 g, 0.132 mol) was charged. To the biphasic mixture, triphosgene in ethyl acetate
(36%-w/w, 35 g, 42 mmol) was added in 60 min at less than 12 °C. The mixture was
stirred 15 min at less than 12 °C. After a total conversion was reached according to Method
C, heptanes (86 g) were charged and the reaction mixture was heated to 20 °C. Then a
phase separation was performed and the aqueous phase was removed. The organic phase
was washed with water (40 g). The organic phase was heated under reduced pressure to
party remove ethyl acetate, while heptanes were charged to the reaction mixture to achieve
a residual ethyl acetate content of 5.5%-w/w (target 3 to 7%-w/w). A ratio of heptanes to
organic matter of 6.3 L kg in view of originally added SD573-MSA was obtained for
crystallisation. The solution was seeded with DMP-266 (0.4 g) at 57 °C and stirred for
15 min at the seeding temperature. The mixture was stepwise cooled under stirring
to -15 °C within 6 h 20 min, stirred overnight at -10 °C and finally filtered. The filter cake
was washed with pre-cooled heptanes (2^25 mL) at -10 °C maximum. The solid was dried
in vacuo to yield 89.4% (32.17 g, 102 mmol) of DMP-266 at a purity of 100%-w/w
according to Method D.
Example 12.2:
The 2nd part of the organic phase of Example 12 (122.0 g) was heated under reduced
pressure to partially remove the solvent until the distillate contained 53 w% of ethyl acetate
(about 3 1 g). The mixture was cooled to 12 °C and aqueous Na2C0 3 (12%-w/w, 117 g,
0.132 mol) was charged. To the biphasic mixture triphosgene in ethyl acetate (36%-w/w,
35 g, 42 mmol) was added in 60 min at 12 °C maximum. The mixture was stirred for
15 min at 12 °C maximum. A total conversion was obtained according to Method C.
Heptanes (86 g) were charged and the reaction mixture was heated to 20 °C. Then a phase
separation was performed and the aqueous phase was removed. The organic phase was
washed with water (40 g) and then heated under reduced pressure to partially remove ethyl
acetate, while heptanes were charged to the reaction mixture to achieve a residual ethyl
acetate content of 5.7%-w/w (target 3 to 7%-w/w). A ratio of heptanes to organic matter of
6.4 L/kg in view of originally added SD573-MSA was obtained for crystallisation. The
mixture was seeded with DMP-266 (0.4 g) at 57 °C and stepwise cooled under stirring
within 6 h to reach -15 °C. Then the mixture was stirred at -10 °C overnight and filtered.
The filter cake was washed with pre-cooled heptanes (2*50 mL) at -10 °C maximum. The
solid was dried in vacuo to yield 89.5% (32.21 g, 102 mmol) of DMP-266 at a purity of
100%-w/w according to Method D.
Example 12.3:
The 3rd part of the organic phase of Example 12 (122.5 g) was heated under reduced
pressure to partially remove the solvent until the distillate contained 53.6 w% of ethyl
acetate (about 32.3 g). The mixture was cooled to 9 °C before aqueous Na2C0 3 (12%-w/w,
117 g, 0.132 mol) was charged. To the biphasic mixture triphosgene in ethyl acetate
(36%-w/w, 35 g, 42 mmol) was added in 60 min at 12 °C maximum and the mixture stirred
for 1 h at 12 °C maximum. A total conversion was obtained according to Method C.
Heptanes (86 g) were charged and the reaction mixture was heated to 20 °C. A phase
separation was performed and the aqueous phase was removed. The organic phase was
washed with water (40 g) and then heated under reduced pressure to partially remove ethyl
acetate, while heptanes were charged to the reaction mixture to achieve a residual ethyl
acetate content of 5.8%-w/w. A ratio of heptanes to organic matter of 6.2 L/kg in view of
originally added SD573-MSA was obtained for crystallisation. The mixture was seeded
with DMP-266 (0.4 g) at 57 °C and stepwise cooled under stirring to -15 °C within 6 h.
The mixture was stirred at -10 °C overnight and then filtered. The filter cake was washed
with pre-cooled heptanes (2x25 mL) at -10 °C maximum. The solid was dried in vacuo to
yield 90% of DMP-266 (32.4 g, 103 mmol) at a purity of 100%-w/w according to
Method D.
Example 13: Cyclisation of SD573 with triphosgene
Aqueous Na2C0 3 (14%-w/w, 160 g, 0.21 1 mol) was charged to SD573-MSA (100 g,
0.229 mol, corresponding to 66.8 g of SD573 free base, prepared accordingly to Example
1) in ethyl acetate/heptanes (158.8 g 1/1 v/v). The mixture was stirred at approx. 15 °C
resulting in a pH of 6.8 of the aqueous phase. Then a phase separation was performed and
the aqueous phase was removed. The organic phase was cooled to 12 °C and aqueous
Na2C0 3 (14%-w/w, 214 g, 0.283 mol) was charged. To the biphasic mixture triphosgene in
ethyl acetate (35.7%-w/w, 67.2 g, 8 mmol) was added in 60 min at 12 °C maximum. The
mixture was stirred for 30 min at 12°C maximum. Heptanes (96 g) were charged and a
total conversion was obtained according to Method C. The reaction mixture was heated to
20 °C. Then a phase separation was performed and the aqueous phase was removed.
Aqueous Na2C0 3 (14%-w/w, 92 g, 0.121 mol) was added to the organic phase and stirred
for 25 min at 20 °C. Then a phase separation was performed and the aqueous phase was
removed. The organic phase (360 g) was split into two parts.
Example 13.1:
The 1st part of the organic phase of Example 8 (180 g) was washed with water (80 g),
phase separation was performed and the aqueous phase was removed. Then the organic
phase was heated under reduced pressure, ethyl acetate partially distilled off and heptanes
charged to the reaction mixture to achieve a residual ethyl acetate content of 3%-w/w
(target 3 to 7%-w/w) was obtained. Finally total 10 L/kg SD573-MSA heptanes was
achieved for the crystallisation. The solution was seeded with DMP-266 (0.2 g) at 55 °C
and stepwise cooled under stirring to -15 °C within 7 h. The mixture was stirred at -15 °C
overnight and then filtered. The filter cake was washed with pre-cooled heptanes
(2x50 mL) at -10 °C maximum. The solid was dried in vacuo to yield 93% (33.47 g,
105 mmol) of DMP-266, the purity is 98.8%-w/w, according to Method D.
Example 13.2:
The 2nd part of the organic phase of Example 8 (180 g) was heated under reduced pressure
to partially remove ethyl acetate, while heptanes were charged to the reaction mixture, to
achieve a residual ethyl acetate content of 3.4%-w/w (target 3 to 7%-w/w). A ratio of
heptanes to organic matter of 10 L/kg in view of originally added SD573-MSA was
obtained for crystallisation. The mixture was seeded with 0.2 g of DMP-266 at 55 °C and
stepwise cooled under stirring within 6 h 40 min to reach -15 °C. The mixture was stirred
at -10 °C overnight and then filtered. The filter cake was washed with pre-cooled heptanes
(2x50 mL) at -10 °C maximum. The solid was dried in vacuo to yield 96% (34.87 g,
1 0 mmol) of DMP-266 at a purity of 97.7%-w/w according to Method D.
Example 14: Cyclisation of SD573 with triphosgene
Aqueous Na2C0 3 (14%-w/w ,80 g, 0.106 mol) was charged to SD573-MSA (50 g,
0.1 15 mol, corresponding to 33.4 g of SD573 free base, prepared accordingly to Example
1) in of ethyl acetate/heptanes (79.4 g, 1/1 v/v) and charged. After stirring for 15 min a pH
of 6.4 was measured in the aqueous phase. The mixture was stirred for 5 min at 15 °C.
Then a phase separation was performed and the aqueous phase was removed. The mixture
was cooled to 12 °C and aqueous Na2C0 3 (14%-w/w, 107 g, 0.141 mol) was charged.
Triphosgene in ethyl acetate (35.7%-w/w, 33.6 g, 40.5 mmol) was added to the biphasic
mixture for 60 min at 12 °C maximum. The mixture was stirred 30 min at 12°C maximum.
Heptanes (48 g) were charged and a total conversion was obtained according Method C.
The reaction mixture was heated to 20 °C. Then a phase separation was performed and the
aqueous phase was removed. The organic phase was washed with water (80 g) and then
heated under reduced pressure, to partially remove ethyl acetate, while heptanes were
charged to the reaction mixture, to achieve a residual ethyl acetate content of 3.2%-w/w. A
ratio of heptanes to organic matter of 9.6 L/kg in view of originally added SD573-MSA
was obtained for crystallisation. The mixture was seeded with 0.2 g of DMP-266 at 55 °C,
and stepwise cooled under stirring within 7 h to reach -15 °C. The mixture was stirred
at -15 °C overnight and then filtered. The filter cake was washed with pre-cooled heptanes
(50 mL) at -10 °C maximum. The solid was dried in vacuo to yield 97% (34.49 g,
110 mmol) of DMP-266 at a purity of 96.5%-w/w according to Method D.
Example 15: Cyclisation of SD573 with triphosgene
Aqueous Na2C0 3 (14%-w/w, 80 g, 0.106 mol) was charged to SD573-MSA (50 g,
0.1 14 mol, corresponding to 33.4 g of SD573 free base, prepared accordingly to Example
1) in ethyl acetate/heptanes (79.4 g, 1/1 v/v). After stirring for 15 min a pH of 6.1 was
measured in the aqueous phase. The mixture was stirred for 5 min at 15 °C. Then the phase
separation was performed and the aqueous phase was removed. The mixture was cooled to
12 °C and aqueous Na2C0 3 (14% w/w, 135 g, 0.178 mol) was charged. To the biphasic
mixture triphosgene in ethyl acetate (35.7%-w/w, 33.6 g, 40.5 mmol) was added in 60 min
at 12 °C maximum. The mixture was stirred 30 min at 12°C maximum. Heptanes (48 g)
were charged and a total conversion was obtained according to Method C. The reaction
mixture was heated to 20 °C. Then a phase separation was performed and the aqueous
phase was removed. The organic phase was washed with water (80 g) and then heated
under reduced pressure to partially remove ethyl acetate, while heptanes were charged to
the reaction mixture, to achieve a residual ethyl acetate content of 2.8%-w/w. A ratio of
heptanes to organic matter of 9.5 L/kg in view of originally added SD573 -MSA was
obtained for crystallisation. The solution was seeded with DMP-266 (0.2 g) at 55 °C and
stepwise cooled under stirring within 4 h 35 min to reach to -15 °C. The mixture was
stirred overnight at -15 °C and then filtered. The filter cake was washed with pre-cooled
heptanes (2x50 mL) at -10 °C maximum. The solid was dried in vacuo to yield 97.6% of
DMP-266 (35.12 g, 111 mmol) at a purity of 95.1%-w/w according to Method D.
Example 16: Cyclisation of SD573 with phosgene
Aqueous Na C0 3 (12%-w/w, 183 g, 0.207 mol) was charged to SD573 -MSA (100 g,
0.228 mol, corresponding to 66.8 g of SD573 free base, prepared accordingly to Example
1) in ethyl acetate/heptanes (203 g, 1.5:1 v/v). After stirring for 1 min a pH of 7.2 was
measured in the aqueous phase. The mixture was stirred for 5 min at 15 °C. Then the phase
separation was performed and the aqueous phase was removed. The mixture was cooled to
12 °C and aqueous Na2C0 3 (12%-w/w, 232 g, 0.263 mol) was charged. Phosgene (24.8 g,
251 mmol) was added to the biphasic mixture in 90 min at 12 °C maximum. Heptanes
(136 g) were charged to the mixture and a total conversion was obtained according to
Method C. The reaction mixture was heated to 20 °C. Then a phase separation was
performed and the aqueous phase was removed. The organic phase was washed with water
(80 g) and then heated under reduced pressure to partially remove ethyl acetate, while
heptanes were charged to the reaction mixture, to achieve a residual ethyl acetate content
of less then 7%-w/w. A ratio of heptanes to organic matter of 9.7 L/kg in view of originally
added SD573 -MSA was obtained for crystallisation. The solution was seeded with
DMP-266 (0.8 g) at 55 °C, stepwise cooled under stirring within 6 h 15 min to
reach -15 °C and then filtered. The filter cake was washed with pre-cooled heptanes
(2x50 mL) at 0 °C maximum. The solid was dried in vacuo to yield 95.7% of DMP-266
(68.91 g, 218 mmol) at a purity of 100%-w/w according to Method D.
Example 17: Cyclisation of SD573 with phosgene
SD573 -MSA (50 g, 0.1 4 mol, corresponding to 33.4 g of SD573 free base, prepared
accordingly to Example 1) was dissolved in ethyl acetate/heptanes (102 g, 55:45 v/v) and
charged with aqueous Na2C0 3 (12%-w/w, 9 1 g, 0.103 mol). After stirring for 15 min a pH
of about 7 was measured in the aqueous phase. The mixture was stirred for 5 min at 15 °C.
Then the phase separation was performed and the aqueous phase was separated and
discarded. The organic phase was cooled to 1 °C and charged with aqueous Na2C0 3
(12%-w/w, 157 g, 0.178 mol). To the biphasic mixture phosgene (16.9 g, 171 mmol) was
added in 130 min at 12 °C maximum. Heptanes (43 g) were charged and a total conversion
was obtained according to Method C. The reaction mixture was heated to 20 °C. Then a
phase separation was performed and the aqueous phase was removed. The organic phase
was washed with water (80 g) and then heated under reduced pressure to partially remove
ethyl acetate, while heptanes were charged to the reaction mixture, to achieve a residual
ethyl acetate content of 3.5%-w/w. A ratio of heptanes to organic matter of ca. 10 L/kg in
view of originally added SD573 -MSA was obtained for crystallisation. The solution was
seeded with DMP-266 (0.4 g) at 62 °C and stepwise cooled under stirring to -5 °C
overnight and then filtered. The filter cake was washed with pre-cooled heptanes
(2x50 mL) at 0 °C maximum. The solid was dried in vacuo to yield 93% of DMP-266
(33.86 g, 107 mmol) at a purity of 98.5%-w/w according to Method D.
Example 18: (5)-2-(2-Amino-5-methylphenyl)-4-cyclopropyl-l,l,l-t» 'fluorobut-3-yn-
2-ol
A solution of ( l ,2S)-PNE (17.6%-w/w, 21.0 g, 18.0 mmol) in a THF/toluene mixture
(9:l-w/w) was charged in a vessel at room temperature. A solution of diethylzinc in
toluene (29.9%-w/w, 6.10 g, 14.8 mmol) was added at 17 to 25 °C and the mixture was
aged at said temperature range for 30 min. A solution of cyclopropylacetylene (compound
of formula III, wherein R is cyclopropyl) in toluene (69.6%-w/w, 8.55 g, 90.0 mmol) was
added at 18 °C and the resulting mixture was aged at 20 °C for 60 min. A solution of BuLi
in toluene (3.09 mol/kg, 17.6 g, 54.4 mmol) and a solution of l -(2-amino-5-methylphenyl)-
2,2,2 -trifluoroethanone (CN46217, compound of formula IV, wherein R1 is
trifluoromethyl, R8 is 5-methyl, R9 is hydrogen and R10 is hydrogen) (36.5%-w/w, 33.4 g,
60.0 mmol) in toluene/THF ( 1: 1-w/w) were added in parallel to the reaction mixture at
20 °C within 3 h. The addition of BuLi was started 10 min in advance of the CN46217
addition. After completed addition of CN46217 the reaction mixture was stirred for 30 min
at 20 °C, then heated to 30 °C over a period of 60 min and aged for 6 h at 30 °C. The
reaction mixture was stirred at 0 °C overnight. HPLC (Method B) indicated 72.3%
conversion and 96.7% enantiomeric purity. The reaction mixture was diluted with toluene
(25.8 g) and quenched by addition of aqueous citric acid ( 1 M, 73.9 g). After stirring for
5 min the phases were separated and the aqueous phase was discarded. The organic phase
was successively washed with water (9.1 g), aqueous NaHC0 3 solution (5%-w/w, 24.0 g),
and water (12.0 g). The organic phase was partially concentrated (60 g residual solution),
diluted with toluene (30 g), and partially concentrated again (52 g residue). The residue
was diluted with toluene (65 g), cooled to 5 °C and aged over night. The crystals were
filtered, washed with cold (approx. 5 °C) toluene (10 g) and dried under vacuum at 40 °C.
The wet product (10.8 g) obtained as off-white solid with a purity of 99.2 and 100% ep
according to method B. The crude product was purified by slurring it in a mixture of
toluene (10 itiL) and heptane (40 mL) at room temperature for 1 h, filtered and dried at
40 °C in vacuo. The product (compound of formula II, wherein R1 is trifiuoromethyl, R2 is
cyclopropyl, R8 is 5-methyl, R9 is hydrogen and R 0 is hydrogen) was obtained as white
solid (10.6 g, 38 mmol, 64% yield) with a purity of 99.4% and 100% ep according to
method B. The assay was 97.0%-w/w according to -NMR.
Example 19: (S)-4-(Cyclopropylethynyl)-6-methyl-4-(trifluoromethyl)-l,4-dihydro-
2H-3,l-benzoxazin-2-one
(25)-2-(2-Amino-5-methylphenyl)-4-cyclopropyl- 1,1,1 -trifluorobut-3-yn-2-ol (CN46624)
obtained according example 18 (97.0%-w/w, 10.0 g, 36.0 mmol) in ethyl acetate/heptanes
(2:1 -w/w, 30 g) was charged to a jacketed 150 mL-reactor with agitator and off-gas
scrubber with caustic soda. The reaction mixture was cooled to 7 °C and aqueous Na2C0 3
solution (12%-w/w, 33.5 g) was added. Triphosgene (3.67 g, 12.4 mmol) was added in
portions over a period of 25 min at 7 to 15 °C. The reaction mixture was stirred for 5 min
at 8 °C and sampled for conversion control (99.8% conversion according to method C).
The precipitated solid was dissolved by adding ethyl acetate (25 g) and the phases were
separated. The organic phase was washed with water (10 g), dried over MgS0 4, filtered
and concentrated under vacuum to dryness. The crude product ( 11.6 g) was obtained as a
white solid (purity 96.9% according to HPLC method C). Hexane (20 mL) was added ct
and the mixture was stirred for 1 h at room temperature. The product was filtered, washed
with cold hexane (10 mL) and dried at 35 °C under vacuum. The product (compound of
formula I, wherein R1 is trifluoromethyl, R2 is cyclopropyl, R8 is 6-methyl, R9 is hydrogen
and R10 is hydrogen) was obtained as white solid (9.76 g, 32.9 mmol, 91% yield) with a
purity of 98.8% according to method C and an assay of 99.6%w-/w according to -NMR.
Example 20: 2-(2-Amino-5-chlorophenyl)-l,l,l-trifluorooct-3-yn-2-ol
methanesulfonate (2:3 mol/mol)
Example 20.1: (R)-2-(2-Amino-5-chlorophenyl)-l,l,l-trifluorooct-3-yn-2-ol
methanesulfonate (2:3 mol/mol)
A solution of (15,2L)-RNE (18.7%-w/w, 19.7 g, 18.0 mmol) in THF/toluene (9:l-w/w) was
charged to a vessel at room temperature. A solution of diethylzinc in toluene (29.9%-w/w,
6.10 g, 14.8 mmol) was added at 17 to 25 °C and the mixture was aged at said temperature
for 30 min, 1-hexyne (97%-w/w, 6.10 g, 72.0 mmol, compound of formula III, wherein R
is -butyl) was added at 18 °C and the resulting solution was aged at 20 °C for 60 min. A
solution of BuLi in toluene (3.09 mol/kg, 17.8 g, 55.0 mmol) and a solution of l-(2-amino-
5-chlorophenyl)-2,2,2-trifluoroethanone (CN233 15, a compound of formula IV, wherein
R1 is trifluoromethyl, R8 is 5-chloro, R9 is hydrogen and R10 is hydrogen) in toluene/THF
( 1: 1 w/w) (39.6%-w/w, 33.8 g, 60.0 mmol) were added in parallel to the reaction mixture
at 20 °C within 3 h. The addition of BuLi was started 10 min in advance of the CN23315
addition. After completed addition of CN23315 the reaction mixture was stirred for 30 min
at 20 °C, then heated to 30 °C over a period of 60 min and aged for 6 h at 30 °C. The
reaction mixture was stirred at 0 °C overnight. HPLC (Method B) indicated 89.6%
conversion. The reaction mixture was diluted with toluene (25.8 g) and quenched by
addition of aqueous citric acid solution ( 1 M, 44.1 g). After stirring for 5 min the phases
were separated and the organic phase successively washed with water (9. 1 g), aqueous
NaHC0 3 solution (5%-w/w, 24.0 g) and water (12.0 g). The organic phase was partially
concentrated (51 g residual solution), diluted with toluene (30 g), and partially
concentrated again (58 g residue). The residue was diluted with toluene (59 g) and
isopropyl alcohol (1.50 g). Methanesulfonic acid (10.48 g, 114 mmol) was added at 30 °C
over a period of 30 min and the mixture was stirred for 30 min. A second portion
methanesulfonic acid (2.89 g, 30 mmol) was added at 30 °C over a period of 30 min. The
mixture was stirred at 30 °C for 30 min, cooled to 5 °C over a period of 60 min, and aged
at 5 °C for 30 min. The crystals were filtered, washed with cold toluene (10 g) and dried
under vacuum at 40 °C. The crude product (19.3 g) was obtained as yellowish solid with a
purity of 93.3% and 99.6% ep according to method B. The product was further purified by
slurring it in a mixture of toluene (100 mL) and isopropyl alcohol (2 mL) at room
temperature for 3 h. The product (MSA salt of (/?)-CN47583, compound of formula II,
wherein R1 is trifluoromethyl, R2 is w-butyl, R8 is 5-chloro, R9 is hydrogen and R10 is
hydrogen) was filtered, washed with toluene (10 mL) and dried at 40 °C under vacuum.
The product was obtained as white solid (17.1 g, 35.3 mmol, 59% yield) with a purity of
93.3% and 99.9% ep according to method B, and an assay of 92.8%w-/w according to
-NMR.
Example 20.2: (S)-2-(2-Amino-5-chlorophenyl)-l,l,l-trifluorooct-3-yn-2-ol
methanesulfonate (2:3 mol/mol)
Example 20.1 was repeated with (1-/?,2S)-PNE as chiral ligand to obtain the (S)-enantiomer
ofCN47583.
A solution of ( 1L,25)-RNE (17.6%-w/w, 42.0 g, 36.0 mmol) in THF/toluene (9:l-w/w) was
charged a vessel at room temperature. A solution of diethylzinc in toluene (29.9%-w/w,
12.0 g, 29.05 mmol) was added at 17 to 25 °C and the mixture was aged at said
temperature for 30 min, 1-hexyne (97%-w/w, 13.21 g, 156.0 mmol, compound of formula
III, wherein R2 is -butyl) was added at 8 °C and the resulting solution was aged at 20 °C
for 60 min. A solution of BuLi in toluene (3.09 mol/kg, 35.53 g, 109.8 mmol) and a
solution of l-(2-amino-5-chlorophenyl)-2,2,2-trifluoroethanone (CN23315, a compound of
formula IV, wherein R1 is trifluoromethyl, R8 is 5-chloro, R9 is hydrogen and R10 is
hydrogen) in toluene/THF (1:1 w/w) (39.6%-w/w, 67.75 g, 120.0 mmol) were added in
parallel to the reaction mixture at 20 °C within 3 h. The addition of BuLi was started
10 min in advance of the CN23315 addition. After completed addition of CN23315 the
reaction mixture was stirred for 30 min at 20 °C, then heated to 30 °C over a period of
60 min and aged for 6 h at 30 °C. The reaction mixture was stirred at 0 °C overnight.
HPLC (Method B) indicated 81.9% conversion. The reaction mixture was diluted with
toluene (5 1.6 g) and quenched by addition of aqueous citric acid solution ( 1 M, 88.2 g).
After stirring for 15 min the phases were separated and the organic phase successively
washed with water (18.1 g), aqueous NaHC0 3 solution (5%-w/w, 48.0 g) and water
(24.0 g). The organic phase was partially concentrated ( 1 0 g residual solution), diluted
with toluene (60 g), and partially concentrated again ( 14 g residue). The residue was
diluted with toluene (120 g). Isopropyl alcohol (3.2 g) was added. Methanesulfonic acid
(10.96 g, 14 mmol) was added at 30 °C over a period of 30 min and the mixture was
stirred for 30 min. A second portion methanesulfonic acid (5.78 g, 60 mmol) was added at
30 °C over a period of 30 min. The mixture was stirred at 30 °C for 30 min, cooled to 5 °C
over a period of 60 min, and aged at 5 °C for 30 min. The crystals were filtered, washed
with cold toluene/isopropyl alcohol (98:1, 1 25 mL, 2x120 mL) and dried under vacuum
at 40 °C. The product (MSA salt of compound of formula II, wherein R1 is trifluoromethyl,
R is w-butyl, R is 5-chloro, R is hydrogen and R is hydrogen, 28.57 g) was obtained as
slightly beige solid (96.5%w-/w assay according to -NMR).
Example 21: (R)-6-Chloro-4-(hex-l-yn-l-yl)-4-(trifluoromethyl)-l,4-dihydro-2 H-
3,1 -benzoxazin-2-one
(R)-2-(2-Amino-5-chlorophenyl)- 1,1,1 -trifluorooct-3-yn-2-ol methanesulfonate
((/?)-CN47583) obtained according to example 20.1 (92.8%-w/w as methanesulfonate 2:3
mol/mol, 15.0 g, 30.9 mmol) in ethyl acetate/heptanes (2:l-w/w, 30 g) was charged to a
jacketed 150 mL-reactor with agitator and off-gas scrubber with caustic soda. The reaction
mixture was cooled to 15 °C and aqueous Na2C0 3 solution (12%-w/w, 27 g, formation of
gas during addition!) was added, and then the mixture was stirred for 5 min at 15 °C. The
aqueous phase was separated and removed. Aqueous Na2C0 3 solution (12%-w/w, 33 g)
was added to the organic phase. Triphosgene (3.62 g, 12.2 mmol) was added in portions
over a period of 25 min at 7 to 15 °C. The reaction mixture was stirred for 15 min at 8 °C
and sampled for conversion control (conversion more than 99% according to method C).
The phases were separated. The organic phase was dried over MgS0 4, filtered and
concentrated under vacuum to dryness. The crude product ( 1.4 g) was obtained as yellow
oil (purity more than 99.0 % according to method C). A sample was cooled to 5 °C and it
slowly solidified. The crude product was slurried in hexane (10 mL) for 2 h at room
temperature. The product was filtered, washed with cold (approx. 5°C) hexane (5 mL) and
dried at 30 °C under vacuum. The product ((7?)-compound of formula I, wherein R is
trifluoromethyl, R2 is w-butyl, R8 is 6-chloro, R9 is hydrogen and R10 is hydrogen) was
obtained as white solid (7.73 g, 22.7 mmol, 73% yield) with a purity of more than 99.0%
according to method C and an assay of 97. 1%-w/w according to -NMR. Concentration
of the mother liquor to dryness under vacuum afforded additional product as yellow solid
(2.54 g,
7.2 mmol, 23% yield) with a purity of 98% according to method C and an assay of 93.6%-
w/w according to -NMR.
Example 22: (S )-6-Chloro-4-(hex-l-yn-l-yl)-4-(trifluoromethyl)-l,4-dihydro-2i/-3,lbenzoxazin-
2-one
(S)-2-(2-Amino-5-chlorophenyl)- 1,1,1 -trifluorooct-3-yn-2-ol methanesulfonate (( -
CN47583) obtained according to example 20.2 (96.5%-w/w as methanesulfonate 2:3
mol/mol, 15.0 g, 32.2 mmol) in ethyl acetate/heptanes (2:l-w/w, 30 g) was charged to a
jacketed 150 mL-reactor with agitator and off-gas scrubber with caustic soda. The reaction
mixture was cooled to 15 °C and aqueous Na2C0 3 solution (12%-w/w, 27 g, formation of
gas during addition!) was added, and then the mixture was stirred for 5 min at 15 °C. The
aqueous phase was removed. And aqueous Na2C0 3 solution (12%-w/w, 33 g) was added to
the organic phase. A solution of triphosgene (0.73 g, 2.5 mmol) in diphosgene (2.90 g,
14.7 mmol) was added to the reaction mixture over a period of 30 min at 7 to 11 °C. The
reaction mixture was stirred at 8 °C for 20 min. The reaction mixture was sampled for
conversion control until a conversion of more than 99% was reached (according to method
C). The phases were allowed to separate. The aqueous phase was removed. The organic
phase was dried over MgS0 4, filtered and concentrated to dryness. The crude product
( 10.5 g, 31.1 mmol, 97% yield) was obtained as yellow solid (purity >99.0%, HPLC
method C, 98.6%-w/w assay by -NMR). The crude product was slurried in hexane
(10 mL) for 3 h at room temperature. The product was filtered, washed with cold (approx.
5 °C) hexane (5 mL) and dried at 30 °C under vacuum. The product ((S )-compound of
formula I, wherein R1 is trifluoromethyl, R2 is w-butyl, R8 is 6-chloro, R9 is hydrogen and
R10 is hydrogen) was obtained as white solid (8.25 g, 24.6 mmol, 77% yield) with a purity
of more than 99.0% (according to method C) and assay 99.1%-w/w according to -NMR.
Concentration of the mother liquor to dryness under vacuum afforded additional product as
yellow solid (1.58 g) with a purity of 97% (according to method C).
Example 23: Cyclisation of SD573 (free base) with diphosgene in triphosgene
Triphosgene (5.12 g, 17 mmol) was added to diphosgene (20.16 g, 101 mmol) at 8 °C and
the mixture was aged under rigorous stirring for 30 min (until all triphosgene was
dissolved).
In another vessel, aqueous Na2C0 3 (12%-w/w, 235 g, 266 mmol) was charged at 8 °C to
SD573 free base (compound of formula II, wherein R1 is trifluoromethyl, R2 is
cyclopropyl, R8 is 5-chloro, R9 is hydrogen and R10 is hydrogen, 67.0 g, 0.231 mol) in
heptane (68.3 g) and ethyl acetate (136.1 g). Then the solution of triphosgene in
diphosgene was added at 8 to 11 °C within 90 min. The mixture was aged further 45 min at
8 °C. The mixture was warmed to 15 °C within ca. 30 min and aged further 30 min at
15 °C, total conversion was reached according to Method C. Heptane (137 g) was added at
5 °C and the mixture was aged for further 60 min at 15 °C. The mixture was warmed to
9 °C and water (80 g) was added. The phases were separated and the aqueous phase was
removed. The organic phase was distilled and heptane continuously added until 5.4-w/w%
of ethyl acetate remained (concentration of the heptane solution was approx. 9.5 mL/g of
SD573). The mixture was seeded at 58 °C with DMP-266 (0.8 g) and the suspension was
stirred further 120 min at 58 °C, cooled to 25 °C within 120 min, cooled to -13 °C within
120 min, stirred further ca. 30 min at -13 °C and filtered. The wet cake was washed at -8
°C two times with heptane (pre-cooled at -8°C, 50 mL). The cake was dried for 8 h at 80
°C under vacuum. 90.2% yield (65.99 g, 209 mmol) of product (DMP-266, compound of
formula I, wherein R1 is trifluoromethyl, R2 is cyclopropyl, R8 is 6-chloro, R9 is hydrogen
and R10 is hydrogen) were obtained with a purity of 100%-w/w according to Method D.
Crystal form I was obtained according to X-ray analysis.
Comparative Example 1: Cyclisation of SD573 with triphosgene, homogeneous
Aqueous Na2C0 3 (10.6 g, 0.126 mol) was charged at 25 °C to SD573 free base (25.13 g,
0.087 mol) in acetonitrile (25 mL) in a 500 mL-reactor. The mixture was cooled to -12 °C
and a solution of triphosgene in acetonitrile (19.7%-w/w, 63.63 g, 42 mmol) was added
within 40 min at -10 to -5 °C. After 90 min a total conversion was reached according to
Method C. The reaction mixture was heated to 25 °C, neutralized at 20 °C to 25 °C with
Na2C0 3, washed with water and then filtered. The mixture was cooled to -10 °C and water
(7.5 g) was added dropwise. The slurry was filtered and the product was isolated. The wet
cake was dried in vacuo to give the final product with 5% yield ( 1.89 g, 6 mmol). The
purity was 97.3%-w/w according to Method D.
Comparative Example 2: Cyclisation of SD573 with triphosgene, homogenous
To SD573 free base (25.04 g, 0.086 mol) dissolved in acetone (25 mL) in a
500 mL-reactor, Na2C0 3 (10.6 g, 0.126 mol) and water (50 mL) were charged at 25 °C.
The mixture was cooled to -12 °C and a solution of triphosgene in acetonitrile (24%-w/w,
52 g, 42 mmol) was added at -10 to -5 °C within 55 min. After 60 min a conversion of
98.1%-w/w was reached, according to Method C. The reaction mixture was heated to
25 °C. After further 100 min a conversion of 98.8%-w/w was reached, according to
Method C. Triphosgene (0.69 g) was added. After 180 min a total conversion was reached,
according to Method C. The reaction mixture was neutralized at 20 °C to 25 °C with
Na C0 3 and then filtered. The filter was washed with water (12.5 g). To the filtrate water
(100 mL) was added at 25 °C. Because after 15 h no product precipitated, the mixture was
cooled to -10 °C and filtered to obtain crop 1. To the filtrate water (200 mL) was added
at -10 °C and the suspension was filtered again to obtain crops 2. Precipitation was
repeated with further water (100 mL) addition to the filtrate of crop 2 to obtain crop 3. The
combined crops ( 1 to 3) of wet product were dried in vacuo to obtain 84.5% yield (22.39 g,
7 1 mmol). The purity was 96.9%-w/w according to Method D.
Comparative Example 3: Cyclisation of SD573 with triphosgene, homogenous
To SD573 free base (25.1 1 g, 0.087 mol) dissolved in THF (25 mL) in a 500 mL-reactor,
Na C0 3 (10.6 g, 0.126 mol) and water (50 mL) was charged at 25 °C. The mixture was
cooled to -12 °C and a solution of triphosgene in THF (22.1%-w/w, 56.5 g, 42 mmol) was
added between -10 °C to -5 °C within 36 min. After 120 min a conversion of 96.2%-w/w
was reached, according to Method C. The reaction mixture was heated to 25 °C. After
further 100 min a conversion of 97.7% (w/w) was reached, according to Method C.
Triphosgene (0.68 g) was added. Further small portions of triphosgene were added until
99.6% (w/w) conversion was reached. The reaction mixture was neutralized between 20 to
25 °C with Na2C0 3 and then filtered. To the mixture water (325 g) was added at 25 °C.
The mixture was cooled to 0 °C and filtered (crop 1). To the product remaining in the
vessel further water (200 mL) was added at 5 °C; and the mixture was filtered (crop 2). To
the product remaining in the vessel further water (100 mL) was added at 5 °C; and the
mixture was filtered (crop 3). The combined crops ( 1 to 3) of wet product were dried in
vacuo to obtain 56.5% yield (15.53 g, 49 mmol). The purity was 98.1%-w/w according to
Method D.
Comparative Example 4: Cyclisation of SD573 with triphosgene
Aqueous Na2C0 3 (21.5 g, 0.256 mol, in 100 mL of water) was charged at 25 °C to SD573
free base (50.1 g, 174 mmol) in acetonitrile (50 mL) in a 1 L reactor. After the Na2C0 3
addition the used equipment which contained the SD573 free base was rinsed with 10 mL
of water. The mixture was cooled to -12 °C and a solution of triphosgene in acetonitrile
(24.3%-w/w, 103.3 g, 84 mmol) was added within 30 min at -10 to -5 °C. The solution of
triphosgene in acetonitrile as described in WO2010/032259A example 1 was too
concentrated, all triphosgene was not dissolved, therefore after the triphosgene addition the
used equipment which contained the triphosgene was rinsed with 5 mL of acetonitrile.
After 60 min at -12 °C the mixture was warmed to 25 °C and total conversion was reached
according to Method C. Water (65 mL) to reach the same dilution as described in
WO2010/032259A was added at 25 °C. Contrary to the teaching of WO2010/032259A no
precipitation occurred at 10 °C, so the mixture was cooled to -5 °C and then filtered. To
remove the product completely, the reactor was rinsed with water (200 mL), which was
used afterwards to wash the wet filter cake. The filter cake was dried in vacuo to give the
final product with 34.2% yield (18.63 g, 6 mmol). The purity was 100%-w/w according to
Method D.
Analytical Methods:
Method A: (HPLC method used for the determination of the enantiomeric purity)
Column: Chiralpak ® AD, 250x4 .6 mm; Temperature: 40°C; Flow: 1.0 mL/min; Mobile
Phase: hexane/isopropyl alcohol = 75:25 (v/v); UV Detection: 260 nm
Method B: (HPLC method used for conversion, purity and enantiomeric purity):
Column: Chiralpak ® AD-H, 250x4 .6 mm; Temperature: 40 °C; Flow: 1.0 mL/min; Mobile
phase: hexane/isopropyl alcohol = 89:1 1 (v/v); UV Detection: 260 n
Method C: (HPLC method used for the determination of the purity):
Column: Zorbax® RX-C18, 250x4 .6 mm, 5 micrometer; Temperature: 40°C; Flow:
1.5 mL/min; Mobile phase A: 50 %-w/w buffer / 50 %-w/w MeCN; Mobile phase B:
MeCN; Buffer: 0.1 %-w/w H3P0 in water, pH adjusted to 3.6; Gradient: 0 min 0 %-w/w
B to 30 min 90 %-w/w B; UV Detection: 250 nm
Method D: (HPLC method used for the determination of the purity):
Column: Zorbax® SB-CN, 150x4 .6 mm; Temperature: 40°C; Flow: .5 mL/min; Mobile
phase A: 90 %-w/w water/10 %-w/w MeOH + 0.05 %-w/w TFA (v/v); Mobile phase B:
90% water/10 %-w/w MeOH + 0.05 %-w/w TFA (v/v); Gradient: 16 min 40 %-w/w to
50% B, 7 min to 65 %-w/w B, 5 min to 70% B, 1 min to 80% of B, 2 min hold 80 %-w/w
B, 1 min to 40 %-w/w B; UV Detection: 250 nm

Claims
1. A process for the preparation of a compound of formula
and/or a suitable salt thereof,
wherein
R1 is selected from the group consisting of hydrogen, linear or branched Ci- -alkyl or
(Ci - -alkoxy)carbonyl, any alkyl or alkoxy optionally being substituted with one or
more halogen atoms,
R is selected from the group consisting of linear or branched Ci-6-alkyl,
(Ci - -alkoxy)carbonyl, C3- -alkenyl, C3 -6-alkynyl and C3-6-cycloalkyl, wherein each
alkyl, alkoxy, alkenyl, alkynyl and cycloalkyl can carry a further substituent selected
from the group consisting of aryl, aralkyl, Ci- -alkyl and (l'-R )-C3 - -cycloalkyl,
wherein R is hydrogen, , methyl or ethyl, and wherein any alkyl, cycloalkyl, aryl,
and aralkyl is optionally substituted with one or more halogen atoms, cyano,
C -6-alkyl, C3-6-cycloalkyl, -NR4R5, -SR6, S(O) R6 or S(0 2)R6, and/or -OR 7, with R6
is Ci- -alkyl, optionally substituted with one or more halogen atoms,
R is hydrogen or Ci-6-alkyl, optionally substituted with one or more halogen atoms,
where
(a) R4 and R5 are independently selected from hydrogen or Ci-6-alkyl, or
(b) R4 is hydrogen and R5 is C2- -acyl or (Ci - -alkoxy)carbonyl, wherein each acyl
and alkoxy in R5 in turn is optionally substituted with one or more halogen atoms, or
(c) R4 and R5 together with the nitrogen atom form a 5 to 7 membered heterocyclic
ring, or
(d) R4 and R5 together are =CH-aryl, the aryl moiety optionally being substituted
with one or more substituents selected from halogen atoms, -NH2, -NH(Ci -6-alkyl),
-N(Ci -6-alkyl) 2 or or
(e) R4 and R5 together are =CH-N(C,- -alkyl)2,
R6 is C - -alkyl, optionally substituted with one or more halogen atoms, and
R7 is hydrogen or Ci-6-alkyl, optionally substituted with one or more halogen atoms,
R8 and R9 are independently selected from the group consisting of hydrogen, halogen
atom, and C - -alkyl optionally substituted with one or more halogen atoms,
R 0 is hydrogen or a group selected from the group consisting of
said process comprising the reaction of a compound of formula
and/or a suitable salt thereof,
wherein R , R2, R8, R9 and R10 are as defined above,
with a cyclisation agent selected from phosgene, diphosgene, triphosgene and
mixtures thereof,
wherein the reaction is carried out in the presence of an aqueous base and a waterimmiscible
organic solvent, wherein at least 90% of said organic solvent consists of
at least one compound selected from the group consisting of C2-5-alkyl
C2-5-carboxylates and mixtures of at least one C2-5-alkyl C2-5-carboxylate with at least
one C5-8-alkane.
2. The process of claim 1, wherein the cyclisation agent is provided in gaseous form.
3. The process of claim 1, wherein the cyclisation agent is provided in liquid form.
4. The process of claim 1, wherein the cyclisation agent is provided in solid form.
5. The process of any of claims 1 to 4, wherein the molar ratio of the cyclisation agent,
calculated in molar equivalents of phosgene, to the compound of formula II is in a
range from 1:1 to 4 :1, preferably from 1: 1 to 2.5 :1.
6. The process of any of claims 1 to 5, wherein the weight ratio of water to the organic
solvent(s) is in the range from 1: 1 to 5:1.
7. The process of any of claims 1 to 6, wherein at least 90% of said organic solvent
consists of at least one compound selected from the group consisting of C2-5-alkyl
C -5-carboxylates and mixtures of at least one C -5-alkyl C2 - 5-carboxylate with at least
one C 5- -alkane.
8. The process of any of claims 1 to 7, wherein the C2-5-alkyl C2-5-carboxylate is
selected from the group consisting of C2-5-alkyl acetates, C2-5-alkyl propionates, and
C2. -alkyl butyrates.
9. The process of any of claims 1 to 8, wherein the C -5-alkyl C 2-5-carboxylate is
selected from the group consisting of C2-5-alkyl acetates and C2-5-alkyl propionates.
10. The process of any of claims 1 to 9, wherein the C5-8-alkane is selected from the
group consisting of pentanes, cyclopentane, hexanes, cyclohexane, heptanes,
cycloheptane and octanes.
11. The process of any of claims 1 to 10, wherein the Cs-g-alkane is selected from the
group consisting of hexanes, cyclohexane, heptanes and cycloheptane, preferably
from heptanes.
12. The process of any of claims 1 to 11, wherein the reaction is carried out at a
temperature from -30 to +40 °C.
13. The process of any of claims 1 to 12, wherein the reaction is carried out at a
temperature from 0 to +20 °C.
The process of any of claims 1 to 13, wherein the compound of formula
wherein R1, R2, R8, R9, R10 and are as defined above,
is obtained by a process comprising the steps of
(i) reacting a protic chiral auxiliary with a diorganylzinc(II) compound, in the
presence of an aprotic solvent, at a temperature in the range of 0 to 40 °C, and
(ii) keeping the mixture of step (i), preferably under stirring, in a first maturation
period until the reaction is completed, but of at least 20 min, and
(iii) reacting the mixture obtained after step (ii) with a compound of formula
wherein R2 is as defined above, and
(iv) keeping the mixture of step (iii), preferably under stirring, in a second maturation
period until the reaction is completed, but of at least 10 min, and
(v) reacting the mi rmula
wherein R1, R8, R9 base and/or
the other alkali metal organyl, at a temperature in the range of 0 to 40 °C, and
(vi) keeping the mixture obtained in step (v) to 10 to 50 °C until the reaction is
completed, to obtain the compound of formula II.
15. The process of claim 14, wherein the protic chiral auxiliary is selected from the
group consisting of N,N -disubstituted ephedrine derivatives.
16. The process of claims 14 or 15, wherein the molar ratio of the protic chiral auxiliary
to the diorganylzinc(II) compound is in the range of 1.5: 1 to 1:1.
17. The process of any of claims 14 to 16 wherein the diorganylzinc(II) compound is
selected from the group consisting of di(Ci -8-alkyl) and di(C3 - -cycloalkyl), wherein
the alkyl moieties are selected from the group consisting of methyl, ethyl, propyl,
isopropyl, butyl, isobutyl, sec-butyl and ter/-butyl, pentyl, hexyl, heptyl, and octyl,
and wherein the cycloalkyl moieties are selected from the group consisting of
cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.
18. The process of any of claims 14 to 17, wherein in step (i) the molar ratio of the protic
chiral auxiliary to the compound of formula IV is in the range of 1:1 to 1:10,
preferably in the range of 1:2 to 1:6, more preferably of 1:3 to 1:6.
19. The process of any of claims 14 to 18, wherein in step (iii) the compound of formula
II is used in a molar ratio to the compound of formula IV of :0.6 to 1:1.3.
20. The process of any of claims 14 to 19, wherein the organolithium base and/or the
other alkali metal organyl is added in a molar ratio to the compound of formula IV
from 1:0.8 to 1:1.5.
21. The process of any of claims 14 to 20, wherein the organolithium base is selected
from the group consisting of (Ci - -alkyl)lithium, lithium diisopropylamide (LDA),
lithium hexamethyldisilazide (LiHMDS), phenyllithium, and naphthyllithium.
22. The process of claim 21, wherein the (Ci - -alkyl)lithium is selected from the group
consisting of methyllithium, n-butyllithium, ec-butyllithium, ter/-butyllithium, and
hexyllithium.
23. The process of any claims 1 to 22, wherein the other alkali metal organyl is selected
from sodium or potassium sodium or potassium diisopropylamine,
and sodium or potassium hexamethyldisilazide.
24. The process of any of claims 14 to 23, wherein the temperature during the addition of
the base is of from +10 to +30 °C.
The process of any of claims 14 to 24, wherein the aprotic solvent is selected from
the group consisting of aprotic non-polar solvents, aprotic polar solvents and
mixtures thereof.