The invention discloses a method for the preparation of tert-butyl6-chloro-3,5-
dioxohexanoate from Meldmm's acid derivative and its use for the preparation of tert-butyl
5 (4R,6S)-(6-hydroxymethyl-2,2-dimethyl1-,3 - dioxan-4-y1)acetate (BHA), Rosuvastatin and
Atorvastatin.
BHA is an intermediate in the preparation of Rosuvastatin and Atorvastatin, which are active
pharmaceutical ingredients used in respective dmgs to treat high cholesterol and related
10 conditions, and to prevent cardiovascular disease. BHA is prepared from a 3,5-dioxo
hexanoate ester.
EP 1024139 B discloses a method for preparation of BHA comprising a reaction of an acetate
ester with a hydroxybutyric acid derivative to get the intermediate 3,5-dioxo hexanoate ester.
15
Tetrahedron 55 (1999) 4783-4792 discloses the synthesis of 3,6- and 5,6-dialkyl-4-hydroxy-2-
pyrones with the help of Meldmm's acid.
WO 01172706 A discloses a multistep method for the preparation of BHA and implicitly
20 discloses a precursor, which is the condensation product of a beta-keto butyric acid derivative
with meldmm's acid; the hydrolysis thereof provides the respective 3,5-dioxohexanoic acid
derivative, the precursor of BHA. The advantages of the instant invention compared to the
process disclosed in WO 01172706 A are discussed below.
25 The known processes for the preparation of the intermediate 3,5-dioxo hexanoate ester which
is used in the preparation of BHA are multi step procedures involving metal containing bases,
e.g. derived from lithium or magnesium. There was a need for a simplified process for the
preparation of the intermediate 3,5-dioxo hexanoate ester, which necessitates less steps, no
use of metal containing bases derived from magnesium or lithium, and provides for higher
30 yields and purer products, which can be isolated in an uncomplicated way. Surprisingly, using
a Meldmm's acid intermediate, an efficient method was found.
The following abbreviations are used, if not otherwise stated:
In the following text, halogen means F, C1, Br or I, preferably C1, Br or I; more preferably C1
or Br; alkyl means linear and branched alkyl; unless otherwise specified.
Subject of the invention is a method (B) for the preparation of a compound of formula (11);
10 method (B) comprises a step (C) and a step (B);
step (B) is done after step (C);
step (C) comprises a reaction (C) of a compound of formula (VI) with a compound (C) to
provide a compound of formula (IV);
20 the compound (C) is selected from the group consisting of C12, Br2 and ClBr;
step (B) comprises a reaction (B) of the compound of formula (IV), which has been prepared
in step (C), with a compound of formula (V) in the presence of a base (B);
R1-IV and R3 are identical or different and independently from each other C1 or Br;
base (B) is selected from the group consisting of N(R4)(R5)R6, 1,4-diazabicyclo [2.2.2]
5 octane, a hexamethyldisilazide, a C1-4 alkoxide salt of, a Cl-10 carboxylate salt of, a
carbonate salt of, a hydrogen carbonate salt of, a phosphate salt of, a
monohydrogenphosphate salt of or a dihydrogenphosphate salt of Na, of K or of Li, 1,8-
diazabicyclo[5.4.0]undec-7-ene,N aNH2, KNH2, NaH, KH, CaH2, pyridine, pyridine
substituted with 1 or 2 identical or different substituents independently from each other
selected from the group consisting of methyl, ethyl and N(R14)R15; morpholine,
methylmorpholine, methylpiperidine, imidazol, benzimidazol, 2-methylimidazole, 4-
methylimidazole, 2-ethylimidazole, 2-ethyl-4-methylimidazole, 2-isopropylimidazole, 2-
phenylimidazole, 4-phenylimidazole, picoline, CsC03, NaOH, KOH, Ca(OH)2, n-butyl
lithium (BuLi), sec-butyl lithium, tert-butyl lithium, hexyl lithium, methyl lithium and
mixtures thereof;
R4, R5, R6 are identical or different and independently from each other selected from the
group consisting of H, Cl-15 alkyl, C5-6 cycloalkyl, (C(R16)R17),N(R12)R13 and phenyl,
with the proviso, that at least one of the residues R4, R5 or R6 is not H;
20 R12 and R13 are identical or different and independently from each other H or Cl-15 alkyl;
m is 2, 3, 4, 5 or 6;
R14 and R15 are identical or different and independently from each other methyl or ethyl;
R16 and R17 are identical or different and independently from each other selected from the
group consisting of H, methyl and ethyl;
2 5
with the proviso, that if Rl in formula (11) is CN, then
step (B) comprises additionally a reaction (B-add), the reaction (B-add) is done after the
reaction (B), of the reaction product of the reaction (B) with a compound (B);
compound (B) is selected from the group consisting of NaCN, KCN, Si(R9)(RlO)(Rll)CN,
3 0 HCN, tetrabutylammonium cyanide, 1-cyano benzotriazole and triselenium dicyanide
and mixtures thereof;
R9, R10 and R11 are identical or different and independently from each other selected
from the group consisting of C1-4 alkyl and phenyl.
Formula (IV) comprises all possible tautomeric forms of compound of formula (IV).
5 Formula (V) comprises all possible tautomeric forms of compound of formula (V).
Base (B), compound of formula (IV) and compound of formula (V) can be added in any
sequence.
Preferably, base (B) is used to deprotonate the CH2 moiety of the compound of formula (V).
10 Preferably, deprotonated compound of formula (V) is added to compound of formula (IV) or
vice versa.
The reaction product of the reaction (B), which is reacted with a compound (B) in the reaction
(B-add) of step (B) after the reaction (B), is a compound of formula (11-R1-IV);
15
wherein R1-IV is defined as above, also with all its preferred embodiments.
Formula (11-R1-IV) comprises all possible tautomeric forms of compound of formula (11-R1-
20 IV) .
Compounds of formulae (IV) and (V) are known compounds and can be prepared by known
methods.
25 Preferably, R1-IV and R3 are identical and are C1 or Br.
Preferably, R1-IV and R3 are C1.
Preferably, R4, R5, R6 are identical or different and independently from each other selected
from the group consisting of cyclohexyl, phenyl, methyl, ethyl, n-propyl, iso-propyl,
3 0 n-butyl, iso-butyl, sec-butyl, tert-butyl and (CH2)mN(R12)R13;
R12 and R13 are identical or different and independently from each other selected from the
group consisting of H, methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl,
sec-butyl and tert-butyl;
m is 2, 3 or 4;
5 R14 and R15 are methyl.
More preferably, R4, R5, R6 are identical or different and independently from each other
selected from the group consisting of cyclohexyl, phenyl, methyl, ethyl, n-propyl, isopropyl
and (CHz)rnN(Rl2)R13 ;
R12 and R13 are identical or different and independently from each other selected from the
10 group consisting of H, methyl, ethyl, n-propyl and iso-propyl;
m is 2, 3 or 4;
R14 and R15 are methyl.
Even more preferably, R4, R5, R6 are selected from the group consisting of cyclohexyl,
phenyl, methyl, ethyl, n-propyl, iso-propyl and (CH2)rnN(Rl2)R13;
15 R12 and R13 are selected from the group consisting of H, methyl, ethyl, n-propyl and iso-
P ~ ~1P; Y
m is 2;
R14 and R15 are methyl.
Especially, R4, R5, R6 are methyl or ethyl and (CHz)mN(R12)R13;
20 R12 and R13 are H, methyl or ethyl;
m is 2;
R14 and R15 are methyl.
Base (B) must have the capability to deprotonate the CH2 moiety of the compound of formula
2 5 (V). Preferably, the pKa value of the corresponding protonated form of base (B) is from 5
to 40, more preferably from 6 to 18, even more preferably from 6 to 13.
Preferably, base (B) is selected from the group consisting of N(R4)(R5)R6, 1,4-diazabicyclo
[2.2.2] octane, a hexamethyldisilazide, a C1-4 alkoxide salt of, a Cl-10 carboxylate salt of,
3 0 a carbonate salt of, a hydrogen carbonate salt of, a phosphate salt of, a
monohydrogenphosphate salt of or a dihydrogenphosphate salt of Na, of K or of Li, 1,8-
diazabicyclo[5.4.0]undec-7-ene,N aNH2, KNH2, NaH, KH, CaH2, pyridine, pyridine
substituted with 1 or 2 independently selected identical or different C1-2 alkyl residues,
N,N-dimethyl-4-pyridinamine,m orpholine, 4-methylmorpholine, 1- methylpiperidine,
imidazol, benzimidazol, 2-methylimidazole, 4-methylimidazole, 2-ethylimidazole, 2-
picoline, CsC03, NaOH, KOH, Ca(OH)2 and mixtures thereoc
with R4, R5 and R6 as defined herein, also with all their preferred embodiments.
5 More preferably, base (B) is selected from the group consisting of N(R4)(R5)R6, 1,4-
diazabicyclo [2.2.2] octane, a hexamethyldisilazide, a C1-4 alkoxide salt of, a Cl-10
carboxylate salt of, a carbonate salt of, a hydrogen carbonate salt of, a phosphate salt of, a
monohydrogenphosphate salt of or a dihydrogenphosphate salt of Na, of K or of Li, 1,8-
diazabicyclo[5.4.0]undec-7-ene,p yridine, pyridine substituted with 1 or 2 independently
10 selected identical or different C1-2 alkyl residues, N,N-dimethyl-4-pyridinamine,
morpholine, 4-methylmorpholine, 1-methylpiperidine, imidazol, benzimidazol, 2-
methylimidazole, 4-methylimidazole, 2-ethylimidazole, 2-ethyl-4-methylimidazole, 2-
isopropylimidazole, 2-phenylimidazole, 4-phenylimidazole, picoline, NaOH, KOH,
Ca(OH)2 and mixtures thereoc
15 R4, R5, R6 are methyl or ethyl and (CH2)rnN(R12)R13 ;
R12 and R13 are H, methyl or ethyl;
m is 2;
R14 and R15 are methyl.
20 Even more preferably, base (B) is selected from the group consisting of N(R4)(R5)R6, 1,4-
diazabicyclo [2.2.2] octane, a hexamethyldisilazide, a C1-4 alkoxide salt of, a Cl-10
carboxylate salt of, a carbonate salt of, a hydrogen carbonate salt of, a phosphate salt of, a
monohydrogenphosphate salt of or a dihydrogenphosphate salt of Na, of K or of Li, 1,8-
diazabicyclo[5.4.0]undec-7-ene,p yridine, pyridine substituted with 1 or 2 independently
2 5 selected identical or different C1-2 alkyl residues, N,N-dimethyl-4-pyridinamine,
morpholine, imidazol, benzimidazol, 2-methylimidazole, 4-methylimidazole, 2-
ethylimidazole, 2-ethyl-4-methylimidazole, 2-isopropylimidazole, 2-phenylimidazole, 4-
phenylimidazole, picoline, NaOH, KOH, Ca(OH)2 and mixtures thereof;
R4, R5, R6 are methyl or ethyl and (CHz)rnN(R12)R13;
30 R12 and R13 are H, methyl or ethyl;
m is 2;
R14 and R15 are methyl.
Especially, the base (B) is selected from the group consisting of NEt3,
tetramethylethylendiamine and N,N-dimethyl-4-pyridinamine and mixtures thereof.
Preferably, R9, R10 and R11 are identical and are selected from the group consisting of C1-4
5 alkyl.
More preferably, R9, R10 and R11 are methyl.
Also other CN sources, which act as equivalents to those listed for compound (B), can be
used.
10 Preferably, compound (B) is NaCN or KCN.
Reaction (B) can be done in a solvent (B). Preferably, the solvent (B) is selected from the
group consisting of hexanes, heptanes, dichloromethane, dichloroethane, chloroform,
carbon tetrachloride, toluene, xylene, mesitylene, dioxane, methyl tert-butyl ether and
mixtures thereof.
Preferably, the solvent (B) is dichloromethane
Preferably, the reaction temperature of reaction (B) is from -78 to 100 OC, more preferably
20 from -50 to 50 OC, even more preferably from -25 to 25 OC, especially from -15 to 25 "C.
Preferably, the reaction (B) is done at a pressure of from atmospheric pressure to 60 bar, more
preferably of from atmospheric pressure to 10 bar, even more preferably of from atmospheric
pressure to 2 bar, especially at atmospheric pressure.
2 5
Preferably, the reaction time of reaction (B) is from 5 min to 24 h, more preferably from 5
min to 12 h, even more preferably from 1 h to 5 h, especially from 2 h to 3 h.
Preferably, the amount of compound of formula (V) is from 0.5 to 10 mol equivalent, more
30 preferably from 0.9 to 5 mol equivalent, even more preferably from 0.95 to 1.25 mol
equivalent, especially from 0.98 to 1.05 mol equivalent, of the mol of compound of formula
(IV).
Preferably, the amount of solvent (B) is from 1 to 100 fold, more preferably from 5 to 50 fold,
even more preferably from 5 to 20 fold, especially from 5 to 15 fold, of the weight of
compound of formula (IV).
5 Preferably, the molar amount of base (B) is from 0.5 to 10 fold, more preferably from 0.95 to
3 fold, of the molar amount of compound of formula (V).
Preferably, the reaction (B) is done under inert atmosphere.
10 After the reaction (B), the compound of formula (11) can be isolated from the reaction mixture
resulting from reaction (B) by standard methods known to the skilled person such as
acidification, filtration, evaporation of volatile components, extraction, washing, drying,
concentration, crystallization, distillation and any combination thereof.
15 Optionally, any organic phase can be dried, preferably with magnesium sulphate or sodium
sulphate.
Optionally, compound of formula (11) can be separated from the reaction mixture by addition
of an acid (B).
20
Therefore further subject of the invention is a method (B), which comprises further a step
(ACID);
step (ACID) is done after step (B);
step (ACID) comprises combining the reaction mixture prepared in step (B) with an acid (B).
2 5
In step (ACID) the reaction mixture prepared in step (B) can be added to acid (B) or vice
versa.
Acid (B) is selected from the group consisting of polymeric sulfonic acid resin, toluene
30 sulfonic acid, HC1, HzS04, citric acid, tartaric acid, acetic acid, ammonium chloride, oxalic
acid, phosphoric acid and mixtures thereof, preferably acid (B) is a polymeric sulfonic acid
resin.
Preferably, acid (B) is used without water or at least as a mixture with only a small amount of
water, when acid (B) is added to the reaction mixture of step (B), e.g. as gas in case of HC1,
without crystal water in the case of e.g. citric or tartaric acid, or as conc. HzS04 in case of
sulphuric acid.
5 The water content of acid (B) in this case is preferably 0 to 5 % by weight, more preferably 0
to 2.5 % by weight, even more preferably 0 to 2 % by weight, the % by weight being based on
the total weight of acid (B).
When the reaction mixture of step (B) is added to acid (B), then acid (B) is preferably used as
10 a mixture with water, and the water content of acid (B) is preferably 0.5 to 99 % by weight.
Preferably, no water is added in step (B). When no water is added in step (ACID), then water
or a mixture of acid (B) with water can be added after step (ACID).
15 Preferably, the amount of acid (B) is 0.5 to 10, more preferably 1 to 3, even more preferably
1.2 to 2 mol equivalents in case when acid (B) is not a polymeric sulfonic acid resin, whereas
in case when acid (B) is a polymeric sulfonic acid resin, then acid (B) is used in an amount of
0.5 to 10, more preferably 1 to 5, even more preferably 1.3 to 2 mol equivalents of sulfonic
acid groups of acid (B), the mol equivalents being based on the molar amount of base (B).
20
Preferably, acid (B) is added in such an amount, that the pH is adjusted to 0 to 7, more
preferably 0.5 to 7, even more preferably 1 to 7, especially 1 to 4, more especially 1 to 2.
The polymeric sulfonic acid resin is preferably an acidic cation exchange resin, more
25 preferably a strongly acidic cation exchange resin, for example such as used in heterogeneous
acid catalysis.
Preferably, the polymeric sulfonic acid resin has an average molecular weight of from 1000 to
1000000 D; and/or
30 preferably a concentration of acid sites of from 1 to 15, more preferably of from 1 to 11.6,
even more preferably of from 1 to 10, especially of from 1 to 8, more especially of from 1
to 7 equivalents per kg resin; and/or
preferably an acid number of from 1 to 650, more preferably of from 1 to 560, even more
preferably of from 1 to 450, especially of from 1 to 350, more especially of from 50 to
650, even more especially of from 1 to 560, in particular of from 50 to 450, more in
particular of from 50 to 350; and/or
preferably a particle size of from 4 to 800 mesh, more preferably 4 to 400 mesh.
The concentration of acid sites is determined by the Master Test Method MTM 0232, Edition
1.4, O Rohm and Haas Company, 1998, wherein the CATALYST VOLATILES are
determined by the Master Test Method MTM 0126, Edition 1.6, O Rohm and Haas
Company, 2000.
The acid number is determined according to DIN EN IS0 3682. For further explanation of the
acid number and for its relation to the concentration of acid sites see "BASF Handbuch
Lackiertechnik", Artur Goldschmidt and Hans-Joachim Streitberger, Vincentz Verlag,
2002, ISBN 3-87870-324-4, chapter 2.3.2.2 (pages 272 to 273). According to the
teaching therein, an concentration of acid sites of 1 equivalents per kg equals an acid
number of 56, therefore a concentration of acid sites of 4.7 equivalents per kg equals an
acid number of 263.
15
Especially, the polymeric sulfonic acid resin is selected from the group consisting of
sulfonated polystyrene resins, sulfonated polystyrene resins crosslinked with divinyl benzene
and poly(2-acrylamido-2-methyl- 1 -propanesulfonic acid)
20 Sulfonated polystyrene resins crosslinked with divinyl benzene are also called
divinylbenzene-styrenesulfonic acid copolymer.
One example for a polymeric sulfonic acid resin is AmberlystB 15 DRY.
25 After addition of acid (B) the mixture can be filtered
Preferably, any volatile components of the reaction mixture are removed by evaporation under
reduced pressure.
Any concentration is preferably done by distillation, preferably under reduced pressure.
3 0
Even more preferably, the reaction mixture is acidified, the organic phase is separated and
concentrated.
Especially, acid (B) is a polymeric sulfonic acid resin and solvent (B) is chosen in such a way,
that acid (B) is insoluble in solvent (B). Thereby after acidification by addition of the
polymeric sulfonic acid resin the reaction mixture can be filtered, thereby filtering off the
resin, and the compound is isolated by evaporation of solvent (B). Thereby no water needs to
5 be added.
The compound of formula (11) can be purified by standard methods known to the skilled
person, preferably by crystallization or distillation under reduced pressure.
10 Compound of formula (VI) is a known compound and can be prepared by known methods.
Preferably, compound (C) is C12 or Br2, more preferably C12.
Even more preferably, compound (C) is C12, R1-IV and R3 are C1 and R1 is C1 or CN.
15 Reaction (C) can be done in a solvent (C). Preferably, the solvent (C) is selected from the
group consisting of hexane, heptane, dichloromethane, dichloroethane, chloroform,
carbon tetrachloride, toluene, xylene, mesitylene, dioxane, methyl tert-butyl ether and
mixtures thereof.
20 Preferably, the solvent (C) is dichloromethane
Preferably, the reaction temperature of reaction (C) is from -78 to 100 OC, more preferably
from -40 to 40 OC, even more preferably from -25 to 25 OC, especially from -20 to 20 OC.
25 Preferably, the reaction (C) is done at a pressure of from atmospheric pressure to 60 bar, more
preferably of from atmospheric pressure to 10 bar, even more preferably of from atmospheric
pressure to 2 bar, especially at atmospheric pressure.
Preferably, the reaction time of reaction (C) is from 1 min to 24 h, more preferably from I
30 min to 12 h, even more preferably from 1 min to 6 h, especially from 10 min to 2 h.
Preferably, the amount of compound (C) is from 0.9 to 10 mol equivalent, more preferably
from 0.95 to 2 mol equivalent, even more preferably from 0.98 to 1.05 mol equivalent, of the
mol of compound of formula (VI).
Preferably, the amount of solvent (C) is from 1 to 100 fold, more preferably from 5 to 50 fold,
even more preferably from 5 to 20 fold, especially from 5 to 15 fold, of the weight of
compound of formula (VI).
5
Preferably, the reaction (C) is done under inert atmosphere.
After the reaction (C), the compound of formula (IV) can be isolated from the reaction
mixture resulting from reaction (C) by standard methods known to the skilled person such as
10 acidification, filtration, evaporation of volatile components, extraction, washing, drying,
concentration, crystallization, distillation and any combination thereof.
Compound of formula (IV) can also be not isolated, but used directly for the next reaction
without isolation.
15 Optionally, any organic phase can be dried, preferably with magnesium sulphate or sodium
sulphate.
Preferably, method (B) comprises further a step (A), with method (B) as defined herein, also
with all its preferred embodiments;
20 step (A) is done after step (B);
step (A) comprises a reaction (A) of compound of formula (11), which has been prepared in
step (B), with a compound of formula (111) to provide compound of formula (I);
R2 is C1-4 alkyl.
3 0
Formula (I) comprises all possible tautomeric forms of compound of formula (I).
Formula (11) comprises all possible tautomeric forms of compound of formula (11).
Possible tautomers of compound of formulae (I) are inter alia compound of formula (I-a),
compound of formula (I-b) and compound of formula (I-c).
10 Possible tautomers of compound of formulae (11) are inter alia compound of formula (11-a),
compound of formula (11-b) and compound of formula (11-c).
Preferably, R1 is C1 or CN
More preferably, compound (C) is C12, R1-IV and R3 are C1 and R1 is C1 or CN.
Preferably, R2 is selected from the group consisting of methyl, ethyl, n-propyl, iso-propyl, n-
5 butyl, iso-butyl, sec-butyl and tert-butyl;
more preferably, R2 is ethyl or tert-butyl;
even more preferably, R2 is tert-butyl.
Especially, R1 is C1 or CN, and R2 is tert-butyl.
More especially, R1 is C1 or CN, R2 is tert-butyl, compound (C) is C12 and R1-IV and R3 are
10 C1.
Reaction (A) can be done in a solvent (A). Any solvent that does not interfere with the
reaction and has a boiling point of preferably 50 OC or more can in principle be used.
Preferably, solvent (A) is selected from the group consisting of hexane, heptane,
15 dichloromethane, dichloroethane, chloroform, toluene, xylene, mesitylene, dioxane,
N,N-di-C1-4 alkyl C1-4 monocarboxamide, di-Cl-2 alkyl sulfoxide and mixtures thereof.
Preferably, the compound of formula (111) serves also as solvent (A).
Preferably, the compound of formula (111) serves also as solvent (A) and no further solvent
(A) is used.
Preferably, the reaction temperature of reaction (A) is from -40 to 180 OC, more preferably
from 20 to 100 OC, even more preferably from 20 to 150 OC, especially from 30 to 90 OC,
more especially from 40 to 85 "C.
2 5
Preferably, the reaction (A) is done at a pressure of from atmospheric pressure to 60 bar, more
preferably of from atmospheric pressure to 10 bar, even more preferably of from atmospheric
pressure to 2 bar, especially at atmospheric pressure.
30 Preferably, the reaction time of reaction (A) is from 5 min to 48 h, more preferably 5 min to
24 h, more preferably from 1 h to 8 h, even more preferably from 1 h to 3 h.
Preferably, the amount of compound of formula (111) is from 1 to 200 rnol equivalent, more
preferably from 1 to 100 rnol equivalent, even more preferably from 1 to 50 rnol equivalent,
of the rnol of compound of formula (11)
5 Preferably, the amount of solvent (A) is from 0.1 to 100 fold, more preferably from 0.1 to 50
fold, even more preferably from 0.1 to 20 fold, especially from 0.1 to 10 fold, of the weight of
compound of formula (11).
Usually, the amount of solvent (A) is at least 2 or 5 fold of the weight of compound of
formula (11), therefore further possible ranges are preferably 2 to 100 fold, more preferably
10 from 2 to 50 fold, even more preferably from 2 to 20 fold, especially from 2 to 10 fold, of the
weight of compound of formula (11); or
preferably 5 to 100 fold, more preferably from 5 to 50 fold, even more preferably from 5 to 20
fold, especially from 5 to 10 fold, of the weight of compound of formula (11).
15 If compound of formula (111) is not used as solvent, then preferably the amount of compound
of formula (111) is from 1 to 2 rnol equivalent, more preferably from 1 to 1.5 rnol equivalent,
even more preferably from 1.1 to 1.5 rnol equivalent, of the rnol of compound of formula (11).
Reaction (A) can be done in the presence of an acid (A).
20 Preferably, acid (A) is selected from the group consisting of polymeric sulfonic acid resin,
toluene sulfonic acid, HC1, HzS04, citric acid, tartaric acid, acetic acid, ammonium
chloride, oxalic acid, phosphoric acid and mixtures thereof, preferably acid (A) is a HC1.
Preferably, the amount of acid (A) is from 0.1 to 100 fold, more preferably from 0.1 to 50
25 fold, even more preferably from 0.1 to 20 fold, especially from 0.1 to 10 fold, of the weight of
compound of formula (11).
Acid (A) is used without water or as a mixture with water, eg. as aqueous HC1 or as aqueous
or conc. HzS04.
3 0
The water content of acid (A) is preferably 0 to 99 % by weight, the % by weight being based
on the total weight of acid (A).
Preferably, the reaction (A) is done under inert atmosphere
After the reaction (A), the compound of formula (I) can be isolated from the reaction mixture
resulting from reaction (A) by standard methods known to the skilled person such as
filtration, evaporation of volatile components, extraction, washing, drying, concentration,
5 crystallization, distillation and any combination thereof.
Optionally, colored impurities can be removed by conventionally known treatment with
charcoal, eg by treatment with charcoal of the reaction mixture from reaction (B) and/or from
reaction (A).
10
Optionally, any organic phase can be dried, preferably with magnesium sulphate or sodium
sulphate.
Preferably, any volatile components of the reaction mixture are removed by evaporation under
15 reduced pressure.
Any concentration is preferably done by distillation, preferably under reduced pressure.
The compound of formula (I) can be purified, preferably by crystallization or distillation
20 under reduced pressure.
Step (ACID) is done after step (B) and before step (A).
Preferably, step (B), optionally step (ACID), and then step (A) are done consecutively without
25 isolating compound of formula (11).
Preferably, an optional solvent (B) and an optional solvent (A) are identical.
More preferably, step (B) and step (A) are done in one pot, and an optional solvent (B) and an
optional solvent (A) are identical.
3 0
Preferably, step (C) and step (B) are done consecutively without isolating the compound of
formula (IV).
Preferably, an optional solvent (C) and an optional solvent (B) are identical.
More preferably, step (C) and step (B) are done in one pot, and an optional solvent (C) and an
optional solvent (B) are identical.
Preferably, step (C), step (B) and step (A) are done consecutively without isolating the
5 compounds of formulae (IV) and (11).
Preferably, an optional solvent (C), an optional solvent (B) and an optional solvent (A) are
identical.
More preferably, step (C), step (B) and step (A) are done in one pot, and an optional solvent
10 (C), an optional solvent (B) and an optional solvent (A) are identical.
In another preferred embodiment, step (ACID) is done after step (B), compound of formula
(11) is isolated, and then step (A) is done and solvent (A) is compound of formula (111); more
preferably acid (B) is a polymeric sulfonic acid resin and solvent (B) is chosen in such a way,
15 that acid (B) is insoluble in solvent (B).
Each of the steps (C), (B), (A) and the optional step (ACID) can be done continuously in a
flow reactor. Steps (C) and (B), or steps (C), (B), (A) and the optional step (ACID) can also
be done consecutively and continuously in a flow reactor without isolation of any
20 intermediate.
Suitable flow reactors are known in the art, there is no specific requirement for a suitable flow
reactor to carry out any of the steps (C), (B) or (A) continuously.
25 Further subject of the invention is a method (PREP) for the preparation of a compound
selected from the group consisting of compound of formula (X), compound of formula
(XI), compound of formula (XII), Rosuvastatin and Atorvastatin;
5 method (PREP) comprises the step (C) and the step (B);
step (C), step (B) and R1 are as defined herein, also with all their preferred embodiments;
R2 is as defined herein, also with all its preferred embodiments;
R7 ~sO-C(O)CH~,OH~~CHZ-NHZ.
10 In one preferred embodiment, method (PREP) comprises also the step (ACID).
In another preferred embodiment, method (PREP) comprises also the step (A).
In another preferred embodiment, method (PREP) comprises also the step (ACID) and the
step (A).
15 Compound of formula (X), compound of formula (XI), compound of formula (XII),
compound of formula (XIII), Rosuvastatin and Atorvastatin are known compounds.
The methods for preparation of compound of formula (X), of compound of formula (XI), of
compound of formula (XII), of compound of formula (XIII), of Rosuvastatin and of
Atorvastatin using compound of formula (11) as intermediate are known.
The method of the present invention does not necessitate mandatorily the use of metal derived
bases. It provides the compounds of formulae (I) and (11) in high yields and high purities, the
compounds have bright, white color. Compound of formula (11) can be isolated after the
reaction in an easy way, especially a mixture of an organic and an aqueous phase separates in
the two phases fast and unambiguously, which facilitates isolation considerably. Another easy
way to isolate the compounds is the addition of an acid, preferably of an insoluble polymeric
sulfonic acid resin, filtration and evaporation of solvent, thereby the use of water can be
omitted.
WO 20121130919 PCTlEP20121055581
19
The method is environmentally uncritical; it does not use toxic substances.
Further advantage is the fact, that the disclosed methods can be done at temperature well
above -78 "C, which are conventionally used in methods, where the C6 scaffold of compound
of formula (I) is built up from a reaction of a C4 precursor with an acetic acid ester derivative,
5 for example by aldol condensation and similar reactions.
Further advantages of reaction (A) are the side products: only carbon dioxide and acetone are
generated as side products, therefore reaction (A) is an environmentally friendly method. The
acetone can even be isolated and used for other purposes.
The WO 01172706 A discloses in examples 1.4 and 1.5 a process comprising 6 steps, when
10 calculated from the starting C2 building block, which could be applied for the preparation of
compound of formula (I), which is the precursor of BHA: 1. Chloroacetic acid is converted to
its acid chloride, 2. then reacted with Meldmm's acid, 3. then converted by hydrolysis to the
respective butyric acid derivative, 4. then again converted into the acid chloride, 5. reacted a
second time with Meldmm's acid and 6. finally converted by esterfication into the respective
15 derivative of compound of formula (I). Two equivalents each of Meldmm's acid, chlorine,
base and alcohol is needed.
The process of the instant invention allows for the preparation of compound of formula (I),
which is the precursor of BHA in a 4 step process: 1. acetic acid is converted into diketene, 2.
diketene is converted with C12 into the chlorinated butyric acid chloride derivative, 3. then
20 reacted with Meldmm's acid, and 4. finally converted by esterfication into compound of
formula (I). Only one equivalent Meldmm's acid, chlorine, base and alcohol are needed.
Furthermore, no magnesium or lithium derived bases are necessary as is the case in the WO
01172706 A for the process according to scheme-2 or according to its step b) of claim 8.
Furthermore, a chlorinating agent of the invention is C12, which is inexpensive compared to
25 oxalylchloride, thionylchloride or PC15, which are disclosed on page 8 of the WO 01172706 A
as possible chlorinating agents. No waste or by products such as CO2, CO, SO2, SO3 or
phosphor derivatives are produced in the step, when the chlorine is introduced into the
precursor.
The process of the invention allows to carry out reaction (C) and reaction (B) consecutively
30 without isolation of the intermediate compound of formula (IV), the two reaction can be done
in the same solvent and even in one pot.
Continuous reaction mode can easily be applied.
The process of the invention provides for bright, white solids in high yields, the solids are
obtained as suspensions which show good filtration behaviour.
Compared to WO 01172706 A, no free acid as intermediate occurs, which has naturally an
enhanced solubility in water and therefore complicates its isolation from an organic phase
used in the reaction. The process of WO 01172706 disclosed in examples 1.4 and 1.5 and
scheme-1 starts with a free C2-carboxylic acid and a further free C4 carboxylic acid is
5 isolated as intermediate.
Examples
List of Abbreviations and Raw materials
Amberlyst 15 B DRY CAS 393 89-20-3; divinylbenzene-styrenesulfonic acid copolymer,
strongly acidic cation exchange resin used as a heterogeneous acid catalysis; suitable
5 for non-aqueous catalysis, and has a concentration of acid sites of at least 4.7 eqlkg.
Amberlyst 15 B DRY is a product of Rohm and Haas, and was used with the
specifications of August 2005.
DBU 1,8-Diazabicyclo[5.4.0]undec-7-ene
DMAP N,N-Dimethyl-4-pyridinamine
10 TMEDA Tetramethylethylendiamine
Example la
To a solution of a compound of formula (VI) (5.25 g, 62.4 mmol) in dichloromethane (50
15 mL) of -15 OC, C12 (4.43 g, 62.4 mmol) was added during 30 min at -15 OC. A solution of
compound of formula (1) was formed.
20 This solution of compound of formula (1) was then added within 45 min to a mixture
consisting of a compound of formula (V) (9 g, 62.4 mmol), NEt3 (12.65 g, 124.9 mmol) and
dichloromethane (50 mL) of -15 OC. The resulting reaction mixture was stirred for 2 h at 0 OC.
AmberlystB 15 DRY (18 g) was added and the reaction mixture was no longer cooled and
allowed to warm to room temperature. The AmberlystB 15 DRY was filtered off and aqueous
25 HC1 (lM, 100 mL) was added to the filtrate. The phases were separated, the organic phase
was dried over Na2S04, filtered and concentrated under reduced pressure to provide the
compound of formula (2) as a solid (15.1 g, 92 %).
1 H NMR (400 MHz, CDC13): 6 1.75 (s, 6H), 4.26 (s, 2H), 4.29 (s, 2H), 14.8 (s, 1H)
Example lb
5 To a solution of a compound of formula (VI) (17.5 g, 0.21 mol) in dichlorornethane (90 mL)
at -15 "C, Cl2 (14.76 g, 0.21 mol) was added during 120 min. The reaction mixture was stirred
at -10 "C for 45 min. A solution of compound formula (1) was formed. To this solution of
compound of formula (1) was then added within 60 min a mixture consisting of a compound
of formula (V) (30 g, 0.21 rnol), NEt3 (42.13 g, 0.42 mol) and dichlorornethane (100 mL)
10 of -15 "C. The resulting reaction mixture was stirred for 16 h at 0 "C. The reaction mixture
was acidified with HC1 (lM, 100 mL) at room temperature resulting in a dark brown mixture.
The two phases could not be observed unambiguously, phase separation was therefore done
based on calculated expected volumes of the expected phases. The phases were separated, the
organic phase was extracted 3 times and was dried over Na2S04. The solids were filtered off,
15 filtration was slow. The remaining solvent was removed in vacuo to provide the compound of
formula (2) as a dark brown solid (52.2 g, 96 %).
Example lc
To a solution of a compound of formula (VI) (5.25 g, 62.4 mmol) in dichlorornethane (50
20 mL) at -15 "C, Cl2 (4.43 g, 62.4 mmol) was added during 35 min. A solution of compound
formula (1) was formed. This solution of compound of formula (1) was then added within 60
min to a mixture consisting of a compound of formula (V) (9 g, 62.4 mmol), NEt3 (12.65 g,
124.9 mmol) and dichlorornethane (54 mL) at -15 "C. The resulting reaction mixture was
stirred for 2.5 h at 0 "C. AmberlystB 15 DRY (18 g) was added and stirring was continued for
25 30 min. The reaction mixture was then allowed to warm to room temperature. The
AmberlystB 15 DRY was filtered off; the reaction mixture was filtered over celiteQ and
finally concentrated to dryness to yield the compound of formula (2) as a solid (14.2 g, 87 %).
Example Id
30 To a solution of a compound of formula (VI) (10.5 g, 0.13 mol) in dichlorornethane (108 mL)
at -20 "C, Cl2 (8.86 g, 0.13 mol) was added during 105 min. A solution of compound formula
(1) was formed. This solution of compound of formula (1) was then added within 90 min to a
mixture consisting of a compound of formula (V) (18 g, 0.13 rnol), NEt3 (25.28 g, 0.25 mol)
and dichlorornethane (1 10 mL) at -15 "C. The resulting reaction mixture was stirred for 2.5 h
at -10 "C. AmberlystB 15 DRY (32 g) was added and stirring was continued for 30 min at
0 "C. The reaction mixture was then filtered over silica; then acidified with HC1 (lM, 150
mL) at 2" C. The phases were separated, the aqueous phase was extracted with
dichlorornethane (100 mL) and the combined organic phases were dried over Na2S04, filtered
5 and concentrated under reduced pressure to provide the compound of formula (2) as a solid
(28.3 g, 86 %).
Example le
To a solution of a compound of formula (VI) (7.87 g, 0.09 mol) in dichlorornethane (77 mL)
10 at -15 "C, Cl2 (6.44 g, 0.09 mol) was added during 60 min. The reaction mixture was stirred at
-10 "C for 75 min. A solution of compound formula (1) was formed. To this solution of
compound of formula (1) was then added within 60 min a mixture consisting of a compound
of formula (V) (10.8 g, 0.07 rnol), NEt3 (16.68 g, 0.16 mol) and dichlorornethane (80 mL)
of -1 5 "C. The resulting reaction mixture was stirred for 16 h at -10 "C. The reaction mixture
15 was acidified to pH 1 with gaseous HC1 (6 g) at 5 "C resulting in a yellow-brownish reaction
mixture. Water (120 mL) was added and the phases were separated, and dried over Na2S04.
The solvent was removed in vacuo to provide the compound of formula (2) as a yellow solid
(19.7 g, 80 %).
20 Example If
To a solution of a compound of formula (VI) (7.87 g, 0.09 mol) in dichlorornethane (77 mL)
at -15 "C, Cl2 (6.44 g, 0.09 mol) was added during 60 min. The reaction mixture was stirred at
-10 "C for 75 min. A solution of compound formula (1) was formed. To this solution of
compound of formula (1) was then added within 60 min a mixture consisting of a compound
25 of formula (V) (10.8 g, 0.07 rnol), NEt3 (16.68 g, 0.16 mol) and dichlorornethane (80 mL)
of -1 5 "C. The resulting reaction mixture was stirred for 16 h at -10 "C. The reaction mixture
was acidified to pH 1 with conc. HzS04 (13.3 g) at 5 "C resulting in a yellow brownish
mixture. Water (120 mL) was added and the phases were separated, and dried over Na2S04.
The solvent was removed in vacuo to provide the compound of formula (2) as a brown solid
30 (16.3 g, 66 %).
Example lg
To a solution of a compound of formula (VI) (39.4 g, 0.469 mol) in dichlorornethane (340
mL) at -15 "C, Cl2 (33.3 g, 469 mol) was added during 120 min. The reaction mixture was
WO 20121130919 PCTlEP20121055581
24
stirred at -10 "C for 180 min. A solution of compound formula (1) was formed. To this
solution of compound of formula (1) was then added within 120 min a mixture consisting of a
compound of formula (V) (52 g, 0.361 mol), TMEDA (83.9 g, 0.722 mol) and
dichloromethane (340 mL) of -5 "C. The resulting reaction mixture was stirred for 4 h at -5
5 "C. The reaction mixture was transferred into aqueous solution of HC1 (5% by weight of HC1,
based on the total weight of the aqueous solution of HC1, 658 g) at 5 "C resulting in a yellow
brownish mixture with a pH below 2. After the phases were separated, the solvent was
removed in vacuo to provide the compound of formula (2) as a brown solid with a purity of
80% (101 g, 86 % yield).
10
Example 2a
A mixture of compound of formula (2) (7.5 g, 28.3 mmol), prepared according to example 1,
and tert-butanol (75 mL, 0.81 mol) was stirred at reflux for 2.5 h. The resulting reaction
mixture was filtered over silica and concentrated under reduced pressure to provide
15 compound of formula (3) (6.4 g, 96 %).
1 H NMR (400 MHz, CDC13): ratio of an en01 form (-ef) / a keto form (-kf) = 86 : 14 (area :
20 area); 6 1.48 (s, 9H-ef), 1.49 (s, 9H-kf), 3.3 1 (s, 2H-ef), 3.49 (s, 2H-kf), 3.92 (s, 2H-kf), 4.06
(s, 2H-ef), 4.20 (s, 2H-kf), 5.97 (s, 1H-ef)
Example 2b
A mixture of compound of formula (2) (5.2 g, 19.8 mmol), prepared according to example 1,
25 and tert-butanol (52 mL, 0.55 mol) was stirred at reflux for 2.5 h. The resulting reaction
mixture was concentrated under reduced pressure to provide compound of formula (3) (4.5 g,
97 %).
Example 2c
30 A mixture of compound of formula (2) (20 g, 76 mmol), prepared according to example 1,
tert-butanol (56 g, 0.76 mol) and p-toluene sulfonic acid monohydrate (0.66 g, 4 mmol) was
stirred at 50°C for 3.5 h. The resulting reaction mixture was dissolved in DCM (150 ml) and
washed with water (150 ml). The organic phase was mixed with water (150 ml), aqueous
NaOH (25 % wlw) was added until the pH was 8.0 to 9.0, after phase separation aqueous 0.5
N HC1 was added until the pH was 2.5 to 3.5, and the mixture was concentrated under
reduced pressure to provide compound of formula (3) (14 g, yield of 63%)

We Claim
I . A method (B) for the preparation of a compound of formula (11);
it1 is CI, Br and CN;
method (B) colnprises a step (C) and a step (B);
step (B) is done after step (C);
step (C) comprises a reaction (C) of a compound of formula (Vt) with a compound (C) to
provide a compound of formula (IV);
the compound (C) is selected from the group consisting of Clz, Brz and CIBr;
step (8) comprises a reaction (El) of the compound of formula (IV), which has been prepared
in step (C), with a compound of formula (V) in the presence of a bass (B);
R 1 -IV and R3 are identical or different and independently from each other C1 or Br;
base (B) is selected from the group consisting oFN(R4)(RS)R6, 1,4-diazabicyclo [2.2.2]
octane, a Rexamethyldisilazide, a C14 alkoxide sall of, a C,-IOc arboxylate salt of, a
carbollate salt of, a hydrogen carbonale salt of, a phosphate salt of, a
monohydrogenphospha~es alt of or a dihydrogenphosphate salt of Na, ofK or of Li, 1,8-
diazabicyclo[5.4.0]undffi-7-ene, NaNH2, KNH2, NaH, KH, CaHl, pyridine, pyridine
substituted with 1 or 2 identical or different substituents independently from each othcr
selected fiorn the group consisting of methyl, ethyl and N(R14)RlS; morpholine,
methylmorpholine, methylpipetidine, imidarol, bemimidazol, 2-methylimidazole, 4-
methy limidazole, 2-ethylimidazolc, 2-cthy1-Q-methylimidazole,2 -isopropylirnidazole, 2-
phenylimidazole, 4-phenylimidmle, picoline, CsC03, NaON, KOH, Ca(OH)z, n-butyl
lithium (BuLi), sec-buvl lithium, art-butyl lithium, hexyl lithium, methyi lithium and
mixtures ?hartof;
R4, RS, R6 are identical or different and independently from each ocher selected from the
group consisting of H, CI-ISa lkyl, Cs4 cycloalkyl, (C(R16)R17),N(RlZ)Ri 3 and phenyl,
with the proviso, that at least one of the residues R4, R5 or R6 is not H;
R12 and R13 are identical or different and independently from eaoh other H or Ci.ls alkyl;
tn is 2, 3,4, 5 or 6;
R14 and R15 we identical or different and independently from each other mcthyI or ethyl;
R 16 and R 17 are identical or different and independently from each othcr selected from the
group consisting of H, ~nethyla nd ethyl;
with tht proviso, that if Rl in formula (11) is CN, then
step (B) comprises additionally a reaction (B-add), the reaction (8-add) is done after the
reaction (B), of the reaction product of the reaction (B) with a compound (B);
compound (B) is wttcted from the group consisting of NaCN, KCN, Si(Rg)(RIO)(Rl I)(%,
HCN, tetrabutylammonium cyanide, I-cyano benzotrimb and triseleniurn dicyanide
and mixtures thereof;
R9, R I O and R I 1 are identical or different and independently from each other selected
from the group consisting of Ci4 alkyl and phenyl.
2. Method (B) according to claim 1, wherein
RL-IV and R3 are identical and are C1 or Br.
3. Method (U) according to claim I or 2, wherein
base (8) is selected Erom the group consisting of N(R4)(RS)R6, Id-diazabicyolo 12.2.2)
octane, a hexamethyldisilazide, a Cl.4 aIkoxidc salt of, a Cl.l~ carboxy tate salt of, a
carbonate salt of, a hydrogen carbonate salt of, a phosphate salt of, a
monohydrogenphosphate salt of or a dihydmgenphosphate salt of Na, of K or of Li, 1,8-
di~bicycIo[5.4.O]undecC7-eneN, aNH2, KNH2, NaH, KH, CaH2, pyridine, pyridine
substituted with 1 ar 2 independently selected identical or different C1.3 alkyl residues,
N,N-dirnethyl-epyidinmine, morpholine, 4-methylrnorpholioe, 1-methylpiperidine,
imidazoi, benzimidami, 2-methylimidazole, 4-methylimidazoIe, 2-ethylimtdazale, 2-
ethyl-4-mcthylimiduole, 2-isopropylimidazole, 2-phenylimidazole, Cphcnylimidazole,
picoline, CsC03, NaOH, KOH, Ca(Om and mixtures thereof;
with R4, R5 and R6 as defined in claim I .
4. Method (B) according to one or more of claims I to 3, wherein
K4, K5, R6 are identical or different and independently from each other selected from the
grbup consisting of cydohexy 1, phenyl, methy I, ethy 1, n-propyl, iso-propyl, n-butyl,
iso-butyl, see-butyl, t&-butyl and (CH2),N(R12)R1 3;
R I 2 and R 13 are identical or different and independently from ewh other selected from the
group consisting of W, methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl,
sec-butyl and tert-butyl;
m is 2,3 or 4;
R 14 and R15 are methyl.
5. Method (0) according to one or more of claims 1 to 2, wherein
base (5) is selected from the group consisting of NEt3, tetramethylethy lendiamine and N;Ndimethyl-
4pyridinamine and mixtures thereof.
6. Method (B) according to one or more of claims 1 to 5, wherein
R9, R10 and R1 I are identical and are selected from the p u p consisting of CIA alkyl.
7. Method (8) according to one or more of claims 1 to 6, wherein
compoutld (B) is NaCN or KCN,
8, Meil~od(B ) according to one or more of claims 1 to 7, wherein
reaction (B) is done in a solvent (B), solvent (B) is selected from the group consisting of
hexanes, heptanes, dichloromethane, dichlor~ethanec~hl oroform, carbon tetrachloride,
toluene, xylent, rnesityiene, dioxane, methyl tert-butyl ether and mixtures thereof.
9. Method (8) according to one or more of claims 1 to 8, wherein
compound (C) is Cli or Br2.
10. Method (B) according to one or mare of claims 1 to 9, wherein
reaction (C) is done in a solvent (C), solvent $2) is selected from the group consisting of
hexane, heptane, dichloromethane, dichloroethane, chloroform, carbon tetrachloride,
toIuene, xyIene, rnesitylene, dioxane, methyl tert-butyl ethcr and mixtures thereof.
1 1. Method (B) according to one or more of claims 1 to 10, wherein
co~npound (C) is Clz, R1-IV and R3 are CI and Rt is CI or CN.
12. Method (B) according to one or more of claims 1 to 1 1, wherein
tnetbod (B) comprises a step (ACID);
step (ACID) is done after step (13);
step (ACID) comprises combining the reaction mixture prepared in step (B) with an acid (B);
acid (3) is selected from the group consisting of polymeric sulfonic acid resin, toluene
sulfonic acid, WC1, HzS04, citrio acid, tartaric acid, acetic acid, ammonium chloride,
oxalic acid, phosphoric acid and mixtures thereof,
13. Method (B) according to claim 12, wherein
acid (B) is a polymeric sulfonic acid resin.
14. Method (B) according to one or more of cioi~ns1 to 10, wherein
llletllod (R) comprises krther a step (A);
step (A) is done after step (B);
step (A) comprises a reaction (A) of compound of formula (111, which has been prepared in
step (B), with a wmpound of formula (111) to provide compound of formula (I);
R2 is C 1.4 alkyl.
15. Method (8) according to claim 14, wherein
R1 is CI or CN.
16. Method (B) accoiding to claim 14 or 1 I, wherein
R2 is ethyl or tat-butyl.
17. Method (B) according to one or more of claims 14 to 16, wherein
method (B) comprises step (ACID);
step (ACID) is as defined in claim 12;
step (ACID) is done before step (A).
18. Method (B) according to claim 17, wherein
acid (B) is a polymeric sulfonic a~idre sin.
19. A method (PREP) for the preparation of a compound selected from the group
consisting of compound of formula (X), compound of formula (XI), compound of
formula (XII), Rosuvastatin and Atorvastatin;
method (PREP) comprises the step (C) and the step (B);
step (C), step (6) and RI am as defined in claim 1;
R2 is as defined in claim 14;
R7 is 0-C(O)CH3, OH or CH2-NH2.
20. Method (PREP) according to claim 19, wherein method (PREP) cotnprises step (ACID);
step (ACID) is as defined in claim 12,