FORM 2
THE PATENTS ACT 1970
[39 OF 1970]
&
THE PATENTS RULES, 2003
COMPLETE SPECIFICATION
[see section 10 and rule13]
A NOVEL PROCESS FOR THE PREPARATION OF PROSTAGLANDINS
AND INTERMEDIATES THEREOF
Name and address of the Applicant: BIOCON LIMITED, 20th KM, Hosur Road,
Electronic City P.O., Bangalore – 560 100, Karnataka, India
Nationality: IN
The following specification particularly describes the nature of the invention and the manner in
which it is to be performed.
2
FIELD OF THE INVENTION
The present invention relates to a novel process for the preparation of prostaglandins
and prostaglandin analogues. The present invention further relates to novel synthetic
intermediates that are used in the preparation of prostaglandins and prostaglandin
analogues.
BACKGROUND AND PRIOR ART OF THE INVENTION
Ocular hypertension and glaucoma can be effectively controlled using prostaglandin
related drugs. Glaucoma is an eye disorder characterized by increased intraocular
pressure and gradual loss of the visual field. An abnormally high intraocular pressure is
commonly known to be detrimental to the eye, and there are clear indications that, in
glaucoma patients, this probably is the most important factor causing degenerative
changes in the retina. Unless treated successfully glaucoma will lead to blindness
sooner or later, its course towards that stage is typically slow with progressive loss of
the vision.
WO 90/02553 describes the use of prostaglandin derivatives of PGA, PGB, PGD, PGE
and PGF, in which the omega chain has been modified with the common feature of
containing a ring structure, for the treatment of glaucoma or ocular hypertension. The
invention relates also to ophthalmic compositions, containing an active amount of these
prostaglandin derivatives, and the manufacture of such compositions. WO 93/00329
describes the novel process for the preparation of 13, 14-dihydro-15(R)-17-phenyl-18,
19, 20-trinor- -PGF2α esters.
The present invention is to provide a novel process for the preparation of
prostaglandins and prostaglandin analogues in good yield, in large amounts and with
desired purity. The present process minimizes the formation of impurities
Further, this invention provides process for the preparation of novel intermediates used
in the preparation of prostaglandins and their analogues.
OBJECTIVES OF THE INVENTION
First objective of the present invention is to provide a process for preparation of
prostaglandins.
3
Second objective of the present invention is to provide a process for preparation of
prostaglandins and also a process to prepare its intermediates.
STATEMENT OF THE INVENTION
Accordingly, the present invention is in relation to a process for preparing compound of
formula;
OH
HO R1
O
R
HO
(K)
wherein R is selected from the group consisting of C1-C7 alkyl; C7-C17 aralkyl wherein
the aryl group is unsubstituted or substituted with one to three substituents selected
from the group consisting of C1-C6 alkyl, halo and CF3; and (CH2)nOR2 wherein n is
from 1 to 3 and R2 represents a C6-C10 aryl group which is unsubstituted or substituted
with one to three substituents selected from the group consisting of C1-C6 alkyl, halo
and CF3; and R1 is selected from OR3 and NHR3 wherein R3 is C1-C6 alkyl, H, and
dashed lines (----- )represents a double bond or a single bond comprises; a). reacting
compound of formula ‘I’ with haloalkane or ethylamine,
OH
OR4
R
OR5
OH
O
(I)
Wherein, R described as above, dashed line represents single or double bonds, R4 and
R5 represents, R4 = R5=CH2OCH2CH2CH2CH3; R4 =H, R5=CH2OCH2CH2CH2CH3; R4
= CH2OCH2CH2CH2CH3, R5=H to form compound of formula ‘J’ and,
4
OH
OR4
R
OR5
R1
O
(J)
Wherein, R, R1, dashed line, R4 and R5 as described above; and b). deprotecting
compound of formula ‘J’; A compound of formula;
O
O
OR4
R
OR5
Wherein R described as above, R4 and R5 represents, R4 = R5=CH2OCH2CH2CH2CH3;
R4 =H, R5=CH2OCH2CH2CH2CH3; R4 = CH2OCH2CH2CH2CH3, R5=H; a compound of
formula;
Wherein R described as above, dashed lines represents single or double bonds, R4 and
R5 represents, R4 = R5=CH2OCH2CH2CH2CH3; R4 =H, R5=CH2OCH2CH2CH2CH3; R4
= CH2OCH2CH2CH2CH3, R5=H; a compound of formula;
5
Wherein R described as above, dashed lines represents single or double bonds, R4 and
R5 represents, R4 = R5=CH2OCH2CH2CH2CH3; R4 =H, R5=CH2OCH2CH2CH2CH3; R4
= CH2OCH2CH2CH2CH3, R5=H; a compound of formula;
Wherein R described as above, dashed lines represents single or double bonds, R4 and
R5 represents, R4 = R5=CH2OCH2CH2CH2CH3; R4 =H, R5=CH2OCH2CH2CH2CH3; R4
= CH2OCH2CH2CH2CH3, R5=H; and a compound
6
Wherein R described as above, dashed lines represents single or double bonds, R4 and
R5 represents, R4 = R5=CH2OCH2CH2CH2CH3; R4 =H, R5=CH2OCH2CH2CH2CH3; R4
= CH2OCH2CH2CH2CH3, R5=H
DETAILED DESCRIPTION
The present invention is in relation to a process for preparing compound of formula;
OH
HO R1
O
R
HO
(K)
wherein R is selected from the group consisting of C1-C7 alkyl; C7-C17 aralkyl
wherein the aryl group is unsubstituted or substituted with one to three substituents
selected from the group consisting of C1-C6 alkyl, halo and CF3; and (CH2)nOR2
wherein n is from 1 to 3 and R2 represents a C6-C10 aryl group which is
unsubstituted or substituted with one to three substituents selected from the group
consisting of C1-C6 alkyl, halo and CF3; and R1 is selected from OR3 and NHR3
wherein R3 is C1-C6 alkyl, H, and dashed lines (----- )represents a double bond or a
single bond comprises; a). reacting compound of formula ‘I’ with haloalkane or
ethylamine,
7
OH
OR4
R
OR5
OH
O
(I)
Wherein, R described as above, dashed line represents single or double bonds, R4 and
R5 represents, R4 = R5=CH2OCH2CH2CH2CH3; R4 =H, R5=CH2OCH2CH2CH2CH3; R4
= CH2OCH2CH2CH2CH3, R5=H to form compound of formula ‘J’ and,
OH
OR4
R
OR5
R1
O
(J)
Wherein, R, R1, dashed line, R4 and R5 as described above; and b). deprotecting
compound of formula ‘J’.
In another embodiment of the invention deprotection is done using cerium (III) chloride
heptahydrate and sodium iodide in the presence of organic solvent.
In yet another embodiment of the invention organic solvent is selected from a group
comprising acetonitrile, ethanol, methanol, acetone and isopropyl alcohol.
In still another embodiment of the invention the compound K is any one of following
compound;
8
OH
HO
HO
O
O
CH3
H3C
OH
HO
HO
NH
O
CH3
OH
HO
HO
O
O
CH3
H3C
O CF3
OH
HO
HO
OH
O
O Cl
OH
HO
HO
OH
O
CH3
OH
HO
O
OH
O
CH3
OH
HO
O
O
O
CH3
CH3
CH3
In still another embodiment of the invention process for the preparation of compound
of formula ‘I’ comprises;
a). Reacting compound of formula ‘A’
O
O
OP
OH (A)
with dimethylsulphoxide, oxalylchloride and triethylamine in the presence of organic
solvent to get compound of formula ‘B’, wherein P is selected from the group
9
consisting of COX; in which X represents C1 to C6 alkyl, C6-C10 aryl which may be
substituted or unsubstituted with one to three substituents independently selected from
the group consisting of halo, C1 to C6 alkyl, unsubstituted C6 to C10 aryl,
O
O
O
OP
(B)
b). reacting compound of formula ‘B’ with
O O
P
O
CH3
O CH3
O
Y
Wherein Y is selected from the group consisting of alkyl, aryl wherein aryl group is
unsubstituted or substituted with one to three substituents selected from the group
consisting of C1-C6 alkyl, halo and CF3; and (CH2)nOR2 wherein n is from 1 to 3 and R2
represents a C6-C10 aryl group which is unsubstituted or substituted with one to three
substituents selected from the group consisting of C1-C6 alkyl, halo and CF3 in the
presence of organic solvent to form compound of formula ‘C’
O
O
OP
R
O
(C)
wherein R is selected from the group consisting of C1-C7 alkyl; C7-C17 aralkyl
wherein the aryl group is unsubstituted or substituted with one to three substituents
selected from the group consisting of C1-C6 alkyl, halo and CF3; and (CH2)nOR2
wherein n is from 1 to 3 and R2 represents a C6-C10 aryl group which is unsubstituted
10
or substituted with one to three substituents selected from the group consisting of C1-
C6 alkyl, halo and CF3 and P is as described above,
c). by selective reduction of compound ‘C’ using Borane N,N’-diethylaniline complex
in the presence of Corey catalyst to compound ‘D’,
O
O
OP
R
OH
(D)
Wherein P and R are as described above,
d). deprotecting compound of formula D using base in organic solvent to get
compound of formula E,
O
O
OH
R
OH
(E)
e). hydroxyl groups of compound E further protected to form compound of formula F,
O
O
OR4
R
OR5
(F)
Wherein R described as above, R4 and R5 represents,
11
R4 = R5=CH2OCH2CH2CH2CH3; R4 =H, R5=CH2OCH2CH2CH2CH3;
R4 = CH2OCH2CH2CH2CH3, R5=H
f). compound of formula F optionally hydrogenated using palladium on carbon in the
presence of organic solvent, further reducing the oxo group of this compound reduced
to compound of formula H using DIBAL-H in the presence of organic solvent,,
O
OH
OR4
R
OR5
(H)
wherein the dashed line represents a double bond or a single bond; R, R4 and R5
represents as described above
g). compound of formula H further reacted with compound of formula
PPh3(CH2)4COOH in the presence of NaHMDS in organic solvent
In still another embodiment of the invention organic solvent is selected from a group
comprising of alcohols, esters, tetrahydrofuran, pet ether, hexane, acetone and
acetonitrile.
In still another embodiment of the invention said alcohols are selected from C1 to C4
alcohols.
In still another embodiment of the invention said esters are selected from ethyl acetate
or butyl acetate.
In still another embodiment of the invention base is selected from potassium carbonate,
sodium carbonate or sodium bi carbonate.
12
The present invention is in relation to a compound of formula;
O
O
OR4
R
OR5
Wherein R described as above, R4 and R5 represents,
R4 = R5=CH2OCH2CH2CH2CH3; R4 =H, R5=CH2OCH2CH2CH2CH3;
R4 = CH2OCH2CH2CH2CH3, R5=H
The present invention is in relation to a compound of formula;
Wherein R described as above, dashed lines represents single or double bonds, R4 and
R5 represents, R4 = R5=CH2OCH2CH2CH2CH3; R4 =H,
R5=CH2OCH2CH2CH2CH3; R4 = CH2OCH2CH2CH2CH3, R5=H.
The present invention is in relation to a compound of formula;
13
Wherein R described as above, dashed lines represents single or double bonds, R4 and
R5 represents, R4 = R5=CH2OCH2CH2CH2CH3; R4 =H, R5=CH2OCH2CH2CH2CH3; R4
= CH2OCH2CH2CH2CH3, R5=H
The present invention is in relation to a compound of formula;
Wherein R described as above, dashed lines represents single or double bonds, R4 and
R5 represents, R4 = R5=CH2OCH2CH2CH2CH3; R4 =H,
R5=CH2OCH2CH2CH2CH3; R4 = CH2OCH2CH2CH2CH3, R5=H
The present invention is in relation to a compound
14
Wherein R described as above, dashed lines represents single or double bonds, R4 and
R5 represents, R4 = R5=CH2OCH2CH2CH2CH3; R4 =H, R5=CH2OCH2CH2CH2CH3; R4
= CH2OCH2CH2CH2CH3, R5=H
The present invention provides a process for the preparation of prostaglandins and
prostaglandin analogues. Ideally the synthetic route will be generally applicable to a
variety of prostaglandin compounds and will provide high yields.
Accordingly, the present invention provides a process for the preparation of
prostaglandins and prostaglandin analogues having the formula (K):
wherein R is selected from the group consisting of C1-C7 alkyl; C7-C17 aralkyl wherein
the aryl group is unsubstituted or substituted with one to three substituents selected
from the group consisting of C1-C6 alkyl, halo and CF3; and (CH2)nOR2 wherein n is
from 1 to 3 and R2 represents a C6-C10 aryl group which is unsubstituted or substituted
15
with one to three substituents selected from the group consisting of C1-C6 alkyl, halo
and CF3; and R1 is selected from OR3 and NHR3 wherein R3 is C1-C6 alkyl, H; and
dashed lines represents a double bond or a single bond.
The following scheme 1 shows the synthesis of prostaglandins of formula (K) starting
from Corey lactone.
16
17
The present invention provides a process for the preparation of prostaglandins and
prostaglandin analogues. Ideally the synthetic route will be generally applicable to a
variety of prostaglandin compounds and will provide high yields.
Accordingly, the present invention provides a process for the preparation of
prostaglandins and prostaglandin analogues having the formula (K):
OH
HO R1
O
R
HO
(K)
(a)
wherein R is selected from the group consisting of C1-C7 alkyl; C7-C17 aralkyl wherein
the aryl group is unsubstituted or substituted with one to three substituents selected
from the group consisting of C1-C6 alkyl, halo and CF3; and (CH2)nOR2 wherein n is
from 1 to 3 and R2 represents a C6-C10 aryl group which is unsubstituted or substituted
with one to three substituents selected from the group consisting of C1-C6 alkyl, halo
and CF3; and R1 is selected from OR3 and NHR3 wherein R3 is C1-C6 alkyl, H; and
formula (a) represents a double bond or a single bond.
In one of the aspects of present invention, there is provided a process for the production
of a compound of formula (B):
O
O
O
OP
(B)
wherein P is selected from the group consisting of COX; wherein X represents C1 to
C6 alkyl, C6-C10 aryl which may be un substituted or substituted with one to three
substituents independently selected from the group consisting of halo, C1 to C6 alkyl,
unsubstituted C6 to C10 aryl;
18
the process comprising subjecting a compound of formula (A)
O
O
OP
OH (A)
where P represents as described above
to an oxidation reaction using dimethylsulphoxide, oxalylchloride and triethylamine
(Swern oxidation). Dimethylsulphoxide is activated by using oxalylchloride and
dichloromethane as solvent. The aldehyde thus obtained (which is in dichloromethane)
is taken for the next stage.
Advantageously, in the present method of oxidation of the compound of formula (A)
using dimethylsulphoxide, oxalyl chloride and triethylamine (Swern oxidation), is a
controllable reaction, minimizing the formation of acid. The aldehyde (B) in solution
obtained in this step can be employed in the subsequent step without isolating aldehyde.
In a further aspect of present invention, there is provided a process for production of a
compound of formula (D):
O
O
OP
R
OH
(D)
wherein R is selected from the group consisting of C1-C7 alkyl; C7-C17 aralkyl wherein
the aryl group is unsubstituted or substituted with one to three substituents selected
from the group consisting of C1-C6 alkyl, halo and CF3; and (CH2)nOR2 wherein n is
from 1 to 3 and R2 represents a C6-C10 aryl group which is unsubstituted or substituted
with one to three substituents selected from the group consisting of C1-C6 alkyl, halo
and CF3 ; and P represents as described above.
19
the process comprising subjecting a compound of formula (C)
O
O
OP
R
O
(C)
wherein P and R represent as described above.
to a selective reduction reaction using Borane N,N’-diethylaniline complex. The side
chain oxo group (C) is reduced selectively to alcohol (D) by using Borane N,N’-
diethylaniline complex in the presence of a chairal oxazaborolidine catalyst (“Corey
catalyst”) to achieve desired isomer.
The advantage of the present method of selective reduction using Borane N,N’-
diethylaniline complex in the presence of a chairal oxazaborolidine catalyst (“Corey
catalyst”) is to achieve greater selectivity towards the production of major amount of
desired isomer. Any undesired isomer which may be formed may be separated by
chromatographic techniques such as flash column chromatography.
Thus, preferred reagent for the reduction of oxo (C) compound to alcohol (D) is borane
N,N’-diethylailine complex in the presence of a chairal oxazaborolidine catalyst
(“Corey catalyst”). The use of borane N,N’-diethylailine complex with a Corey catalyst
is preferred because the reaction takes place with excellent selectivity. In fact, a marked
improvement in selectivity is observed when compared with reaction using boranedimethylsulphide
complex.
According to another aspect of present invention, there is provided a process for the
production of a compound of formula (F)
20
O
O
OR4
R
OR5
(F)
wherein R4and R5 is alkoxyalkoxyalkyl, R4=R5=CH2OCH2CH2OCH3; R4=H, R5=
CH2OCH2CH2OCH3; or R4= CH2OCH2CH2OCH3;, R5=H; and R represents as
described above
the process comprising protecting hydroxyl groups of a compound formula (E):
O
O
OH
R
OH
(E)
wherein R represents as described above.
the hydroxyl groups are protected using alkoxyalkoxyalkyl group. The hydroxyl groups
of compound (E) are protected by using 2-methoxyethoxymethyl chloride (MEM
chloride).
The use of alkoxyalkoxyalkyl protecting groups in the present process has a particular
advantage compared with the prior art process employing benzoyl and paraphenylbenzoyl
protecting groups because alkoxyalkoxyalkyl protecting groups are
stable to the subsequent reduction reaction with e.g. DIBAL-H (diisobutylaluminium
hydride). Alkoxyalkoxyalkyl protecting groups have further advantage in that they
generally increase the lipophilic character of the molecule, so that their derivatives are
readily soluble in organic solvents.
According to another aspect of present invention, there is provided a process for the
production of a compound of formula (G):
21
O
O
OR4
R
OR5
(G)
wherein the dashed line represents a double bond or a single bond; R, R4 and R5
represents as described above
the process comprising hydrogenating a compound formula (F) using palladium on
carbon in the presence of ethyl acetate as solvent.
According to another aspect of present invention, there is provided a process for the
production of a compound of formula (H):
O
OH
OR4
R
OR5
(H)
wherein the dashed line represents a double bond or a single bond; R, R4 and R5
represents as described above
the process comprising reducing the lactone oxo group a compound formula (G) using
DIBAL-H (diisobutylaluminium hydride) in the presence of tetrahydrofuran.
According to another aspect of present invention, there is provided a process for the
production of a compound of formula (I):
22
OH
OR4
R
OR5
OH
O
(I)
wherein the dashed line represents a double bond or a single bond; R, R4 and R5
represents as described above
the process comprising subjecting a compound of formula (H) to a Wittig reaction with
(4-carboxybutyl)triphenylphosphonium bromide using sodium hexamethyldisilazane
(NaHMDS) as a base and tetrahydrofuran as solvent.
The advantage of the present method of Wittig reaction using sodium
hexamethyldisilazane (NaHMDS)is improvement in the yield compared to potassiumtert-
butoxide. The other advantage of using alkoxyalkoxyalkyl protecting groups in the
Wittig reaction is that the formation of desired cis-isomer is favored.
According to another aspect of present invention, there is provided a process for the
production of a compound of formula (J):
OH
OR4
R
OR5
R1
O
(J)
wherein the dashed line represents a double bond or a single bond; R, R4 and R5
represents as described above and R1 is selected from OR3 and NHR3 wherein R3 is C1-
C6 alkyl, H;
the process comprising subjecting a compound of formula (I) to reaction with an alkyl
halide of formula, R’-X wherein R’ represents C1 to C6 alkyl groups or C3 to C8
23
cycloalkyl groups and X represents halogens such as chloro, bromo, or iodo, in the
presence of DBU (1,8-Diazabicyclo[5.4.0]undec-7-ene) and acetone as solvent.
The ester thus obtained is converted into its amide in the presence of amines of formula
R”-NH2 , wherein R” represents C1-C6 alkyl, H;
According to another aspect of present invention, there is provided a process for the
production of a compound of formula (K):
OH
HO
R
HO
R1
O
(K)
wherein R is selected from the group consisting of C1-C7 alkyl; C7-C17 aralkyl wherein
the aryl group is unsubstituted or substituted with one to three substituents selected
from the group consisting of C1-C6 alkyl, halo and CF3; and (CH2)nOR2 wherein n is
from 1 to 3 and R2 represents a C6-C10 aryl group which is unsubstituted or substituted
with one to three substituents selected from the group consisting of C1-C6 alkyl, halo
and CF3; and R1 is selected from OR3 and NHR3 wherein R3 is C1-C6 alkyl, H; the
dashed line represents a double bond or a single bond.
the process comprising deprotection of hydroxyl groups in compound of formula (J), by
using cerium chloride and sodium iodide in the presence of acetonitrile as solvent at
reflux temperatures.
The process of the present invention is particularly applicable for the production of
prostaglandins and prostaglandin analogues. The process is particularly useful for the
production of compounds selected the group consisting of
24
OH
HO
HO
O
O
CH3
H3C
OH
HO
HO
NH
O
CH3
OH
HO
HO
O
O
CH3
H3C
O CF 3
OH
HO
HO
OH
O
O Cl
OH
HO
HO
OH
O
CH3
OH
HO
O
OH
O
CH3
OH
HO
O
O
O
CH3
CH3
CH3
In a preferred embodiment, the present invention provides a process for the production
of Latanoprost, Bimatoprost and Travoprost as mentioned below in scheme 2 and
scheme 3.
25
O
O
OPPB
OH
O
O
O
OPPB
(CH 3O) 2POCH 2CO(CH 2)2C6H5
NaH,
O
O
OPPB
O
Me-CBS/ DEANB
O
O
OPPB
OH
Oxallyl chloride, DMSO
EtOAc, TEA
Pd/C
O
O
OH
OH
K2CO3
MeOH
O
O
OR4
OR5
DIBAL-H
THF, -60 to -65°C THF, -60 to -65°C
O
OH
OR4
OR5
Ph3P(CH 2)4COOH
NaHMDS, THF, RT
DBU
MeI/Acetone
LATANOPROST
MEM chloride
O
O
OR4 OR5
a. R deprotection 4=R5= CH 2OCH 2CH2OCH 3
b. R 4= H, R 5= CH 2OCH 2CH2OCH 3
c. R 4= CH 2OCH 2CH2OCH 3, R 5=H
Swern oxidation
OH
OR4
OR5
OH
O OH
OR4
OR5
O
O
CH3
OH
OR4
OR5
NH
O
CH3
CeCl 3, NaI, ACN, reflux
DIBAL-H
THF, -60 to -65°C THF, -60 to -65°C
O
OH
OR4 OR5
OH
OR4
OR5
O
O
CH3
CH3
OH
HO
HO
O
O
CH3
CH3
Ph3P(CH 2)4COOH
NaHMDS, THF, RT
DBU
ICH(CH 3)2/Acetone
CeCl 3, NaI, ACN, reflux
deprotection
OH
OR4
OR5
OH
O
OH
HO
HO
NH
O
CH3
ethylamine
SCHEME 2 BIMATOPROST
(i)
(ii)
(iii)
(iv) (v)
(vi)
(vii) (xi)
(viii)
(ix)
(x)
(xii)
(xiii)
(xiv)
26
O
O
OPPB
OH
O
O
O
OPPB NaH,
O
O
OPPB
O
O
F3C
Me-CBS/ DEANB
O
O
OPPB
O
OH
F3C
Oxallyl chloride, DMSO
O
O
OH
OH
O
F3C
K2CO3
MeOH
O
OH
OR4
OR5
O
F3C
Ph3P(CH2)4COOH
NaHMDS, THF, RT
DBU
2-iodopropane/Acetone
MEM chloride
O
O
OR4
OR5
O
F3C
deprotection
a. R4=R5= CH2OCH2CH2OCH3
b. R4= H, R5= CH2OCH2CH2OCH3
c. R4= CH2OCH2CH2OCH3, R5=H
Swern oxidation
OH
OR4 O
OR5
O
O
CH3
CH3
CF3
CeCl3, NaI, ACN, reflux
DIBAL-H
THF, -60 to -65°C
OH
OR4 O
OR5
OH
O
CF3
OH
HO O
HO
O
O
CH3
CH3
CF3
TRAVOPROST SCHEME 3
(i)
(ii)
(xv)
(xvi) (xvii)
(xviii)
(xx) (xxi)
O
O
P
O
CH3
O CH3
O
CF3
(xix)
27
DEFINITIONS AND CONVENTIONS
The definitions and explanations below are for the terms as used throughout this entire
document including both the specification and the claims.
DEFINITIONS
All temperatures are in degrees Celsius.
MTBE refers to methyl t-butyl ether.
TLC refers to thin-layer chromatography.
THF refers to tetrahydrofuran.
THP refers to tetrahydropyranyl.
NaHMDS refers to sodium hexamethyldisilazane.
MEM Chloride refers to 2-methoxyethoxymethyl chloride.
DIBAL-H refers to disiobutylaluminium hydride.
DBU refers to 1,8-Diazabicyclo[5.4.0]undec-7-ene.
(R)-N-MeCBS refers to (R)-methyl oxazaborolidine in toluene (1 M solution).
RT refers to room temperature
ACN refers to acetonitrile.
CeCl3 refers to Cerium chloride
NaI refers to sodium Iodide.
g refers to gram
v refers to volume
h refers to hours
DMSO refers to dimethylsulphoxide
DEANB refers to Borane N,N’-diethylaniline complex
28
Chromatography (column and flash chromatography) refers to purification/separation
of compounds .It is understood that the appropriate fractions are pooled and
concentrated to give the desired compound(s).
The technology of the instant Application is further elaborated with the help of
following examples. However, the examples should not be construed to limit the scope
of the invention.
EXAMPLE 1:
Preparation of (3aR,4R,6aS)-4-formyl-2-oxohexahydro-2H-cyclopenta[b]furan-5-
yl biphenyl-4-carboxylate (compound - ii)
A solution of oxalyl chloride (50 mL, 0.284 moles) in dry dichloromethane (7.5 L)
was chilled to -70° C under nitrogen atmosphere. Added slowly dimethylsulphoxide
(DMSO) (44.3 g, 0.568 moles) to the reaction mixture at -70° C and stirred at that
temperature for 30 minutes. Then added Corey lactone (compound (i))(50 g, 0.142
moles) dissolved in dichloromethane (500 mL) to the reaction mixture at -70°C and
stirred for one hour at that temperature. Then added triethylamine (72 g, 0.7102 moles)
and stirred for one hour. The reaction completion was monitored by TLC. After the
reaction completion, the mass was quenched with saturated ammonium chloride
solution (50 mL). The organic layer was separated, washed with saturated sodium
chloride solution and dried over sodium sulphate. The organic layer was filtered and
carried the organic layer (compound (ii)) immediately to the next step.
EXAMPLE 2:
Preparation of (3aR,4R,6aS)-2-oxo-4-((E)-3-oxo-5-phenylpent-1-enyl)hexahydro-
2H-cyclopenta[b]furan-5-yl biphenyl-4-carboxylate(compound-iii)
A solution of dimethyl (2-oxo-4-phenylbutyl)phosphonate (34 g, 0.1349 moles) in
dichloromethane(1 L) was added drop wise at 0° C to a suspension of 60 % sodium
hydride(5.7 g,0.1420 moles) in dichloromethane (1 L). The mixture was stirred at 0° C
for one hour. The solution of aldehyde (compound (ii)) (50 g, 0.1428 moles) in
dichloromethane prepared in the previous stage was added drop wise to the mixture at
29
0-5° C. The reaction completion was monitored by TLC. After the reaction completion,
filtered the reaction mass over celite bed and filtrate was washed with water (1 L),
saturated sodium chloride solution (1 L). The organic layer was dried over sodium
sulphate, filtered and concentrated under reduced pressure to residue. The crude brown
residue (compound (iii)(65 g) was taken for the next step.
EXAMPLE 3:
Preparation of (3aR,4R,6aS)-4-((S,E)-3-hydroxy-5-phenylpent-1-enyl)-2-
oxohexahydro-2H-cyclopenta[b]furan-5-yl biphenyl-4-carboxylate (compound-iv)
A 1M solution of (R)-N-MeCBS (14 mL, 0.01354 moles) was added drop wise at 25° C
to the solution of compound(iii) (65 g, 0.1354 moles) in THF (2 L) under nitrogen
atmosphere. Stirred for 30 minutes at 25° C, then chilled the reaction mixture to -20° C,
added Borane N,N’-diethylaniline complex (DEANB)(11.1 mL, 0.1624 moles)at -20°
C and slowly raised the temperature to 0°C. The reaction completion was monitored by
TLC. After the reaction completion, quenched the reaction mass with methanol (130
mL) and acidified to pH 3 using 1.5 N HCl (130 mL). Added ethylacetate (1 L) and
water (500 mL), the organic layer was separated, washed with water (500 mL),
saturated sodium chloride solution (250mL) and dried over sodium sulphate. The
organic layer was concentrated under reduced pressure to residue. The brown residue
was purified by flash column chromatography to separate the desired isomer to obtain
the title compound (iv) as white solid (20 g).
EXAMPLE 4:
Preparation of (3aR,4R,5R,6aS)-5-hydroxy-4-[(1E,3S)-3-hydroxy-5-phenylpent-1-
en-1-yl]hexahydro-2H-cyclopenta[b]furan-2-one(compound -v)
Potassium carbonate (3.4 g, 0.024moles) was added to a solution of compound (iv) (20
g, 0.0414 moles) dissolved in methanol (200 mL). The reaction mixture was stirred at
25° C for 2 h. The reaction completion was monitored by TLC. After the reaction
completion pH of the mass was adjusted to 6 using 1.5 N HCl. The reaction mass was
concentrated to remove methanol. Added ethylacetate (500 mL) and water (250 mL),
stirred for 5 minutes and the layers were separated. the organic layer was washed with
saturated sodium chloride solution and dried over sodium sulphate. The organic layer
was concentrated under reduced pressure to residue. The yellow oil obtained was
purified by column chromatography to get compound (v)( light yellow oil) (10 g).
30
EXAMPLE 5:
Preparation of (3aR,4R,5R,6aS)-5-((2-methoxyethoxy)methoxy)-4-((R)-3-((2-
methoxyethoxy)methoxy)-5-phenylpentyl)hexahydro-2H-cyclopenta[b]furan-2-
one(compound -vi)
A solution of compound (v) (10 g, 0.0330 moles) in dry dichloromethane (210 mL) was
chilled to 0°C under nitrogen blanket. Added diisopropylethylamine (31.3 mL, 0.1819
moles) and methoxyethoxymethyl chloride (MEM chloride) (15 mL, 0.1322 moles) to
the reaction mixture at 0°C. Then slowly raised the temperature to 25° C, stirred for 8
hours at that temperature. The reaction completion was monitored by TLC. After the
reaction completion, the mass was quenched with water (100 mL). The layers were
separated and the organic layer was washed with saturated sodium chloride solution (50
mL) and dried over sodiumsulphate. The organic layer was concentrated under reduced
pressure to syrup stage (12 g). The brown syrup (compound (vi)) was taken to next
stage without purification.
EXAMPLE 6:
Preparation of (3aR,4R,5R,6aS)-5-((2-methoxyethoxy)methoxy)-4-((R)-3-((2-
methoxyethoxy)methoxy)-5-phenylpentyl)hexahydro-2H-cyclopenta[b]furan-2-
one(compound -vii)
Added palladium on carbon (1.2 g, 50% wet) to a solution of compound (vi) in
ethylacetate (120 mL). Added triethylamine (1.2 mL) and stirred under Hydrogen
pressure (2 Kg/Cm2) at 25°C for 2 h. the reaction completion was monitored by TLC.
After the reaction completion the mass was filtered over celite bed. The clear filtrate
was concentrated under reduced pressure to syrup. The syrup (compound (viii)) thus
obtained was taken to nest stage without purification.
EXAMPLE 7:
Preparation of (3aR,4R,5R,6aS)-5-((2-methoxyethoxy)methoxy)-4-((R)-3-((2-
methoxyethoxy)methoxy)-5-phenylpentyl)hexahydro-2H-cyclopenta[b]furan-2-
ol(compound -viii)
A solution of compound (vii) (12 g, 0.0248 moles) in dry toluene (360 mL) was cooled
to -65° C under nitrogen atmosphere. Added DIBAL-H (75 mL, 0.0744 moles) drop
31
wise at -60° C to -65° C. The reaction mass was stirred at at -60° C to -65° C for one
hour and reaction completion was monitored by TLC. After reaction completion, the
mass was quenched with methanol (112.5 mL) and stirred at 25°C for one hour. The
mass was filtered over celite bed and the filtrate was concentrated under reduced
pressure to reside. The residue was dissolved in ethyl acetate (500 mL), added water
(250 mL), stirred and the layers were separated. The ethyl acetate layer was washed
with saturated sodium chloride solution (50 mL), dried over sodium sulphate and
filtered. The organic layer was concentrated under reduced pressure to syrup stage (10
g). The syrup (compound (viii) thus obtained was taken to next step without
purification.
EXAMPLE 8:
Preparation of (Z)-7-((1R,2R,3R,5S)-5-hydroxy-3-((2-methoxyethoxy)methoxy)-2-
((R)-3-((2-methoxyethoxy)methoxy)-5-phenylpentyl)cyclopentyl)hept-5-enoic
acid(compound -ix)
1M solution of NaHMDS (156 mL, 0.1568moles) was added to the suspension of (4-
carboxy butyl) triphenyl phosphonium bromide (35 g, 0.0784moles) in dry THF (350
mL) under nitrogen atmosphere at 25° C. The solution turned orange and mixture was
stirred for 30 minutes. Added compound (viii) (10 g, 0.0206 moles) dissolved in dry
THF (20 mL) to the reaction mixture, the solution turned brownish. The reaction mass
was stirred at 25° C for 1.5 h and the reaction completion was monitored by TLC. After
the reaction completion, the mass was quenched with water (1 L) and the layer was
washed with ethyl acetate (200 mL). The pH of aqueous layer was adjusted to 5 by
using 2 % citric acid solution (100 mL) and product was extracted to ethyl actate
(2X500 mL). The combined organic layer was washed with saturated sodium chloride
solution (100 mL) and dried over sodiumsulphate. The layer was filtered and
concentrated under reduced pressure to get brown syrup (compound (ix)) (25 g).
EXAMPLE 9:
Preparation of (Z)-isopropyl 7-((1R,2R,3R,5S)-5-hydroxy-3-((2-
methoxyethoxy)methoxy)-2-((R)-3-((2-methoxyethoxy)methoxy)-5-
phenylpentyl)cyclopentyl)hept-5-enoate(compound-x)
2-iodopropane (25 mL, 0.2470moles) and DBU (37 mL, 0.2470 moles) was added to
stirred solution of compound (ix) (25 g, 0.0441 moles) in dry acetone (500 mL) under
32
nitrogen at 25°C. The mass was stirred at that temperature for 8 hours and the reaction
completion was monitored by TLC. After the reaction completion the mass was
concentrated under reduced pressure to remove acetone. Added 2 % citric acid solution
(250 mL) and the product was extracted to ethyl acetate (500 mL). The organic layer
was washed with water (200 mL), saturated sodium chloride solution (100 mL) and
dried over sodiumsulphate. The layer was filtered and concentrated under reduced
pressure to syrup stage (26 g). The syrup (compound (x)) thus obtained was taken to
next step without purification.
EXAMPLE 10:
Preparation of (Z)-isopropyl 7-((1R,2R,3R,5S)-3,5-dihydroxy-2-((R)-3-hydroxy-5-
phenylpentyl)cyclopentyl)hept-5-enoate (Latanoprost)
Added cerium (III) chloride heptahydrate (16 g, 0.0427 moles) and sodium iodide (4 g,
0.0256 moles) to solution of compound(x) (26 g, 0.0427moles) in acetonitrile (260 mL)
and contents were refluxed at 80-85° C for 2 h. The reaction completion was monitored
by TLC. After the reaction completion the mass was concentrated under reduced
pressure to remove acetonitrile. The residue was diluted with water (200 mL) and the
product was extracted with ethyl acetate (500 mL). The ethyl acetate layer was washed
with saturate sodium chloride solution (100 mL), dried over sodium sulphate and
filtered. The layer was concentrated under reduced pressure to obtain crude
Latanoprost. The crude Latanoprost was purified by colum chromatagraph and was
further purified by prep HPLC to obtain Latanoprost of purity greater than 99 % (4 g).
EXAMPLE 11:
Preparation of (3aR,4R,5R,6aS)-4-((S,E)-3-((2-methoxyethoxy)methoxy)-5-
phenylpent-1-enyl)hexahydro-2H-cyclopenta[b]furan-2,5-diol(compound -xi)
A solution of compound (vii) with mono MEM protected [(3aR,4R,5R,6aS)-5-hydroxy-
4-((S,E)-3-((2-methoxyethoxy)methoxy)-5-phenylpent-1-enyl)hexahydro-2Hcyclopenta[
b]furan-2-one] (12 g, 0.0307 moles) in dry toluene (360 mL) was cooled to
-65° C under nitrogen atmosphere. Added DIBAL-H (92 mL, 0.0921 moles) drop wise
at -60° C to -65° C. The reaction mass was stirred at at -60° C to -65° C for one hour
and reaction completion was monitored by TLC. After reaction completion, the mass
was quenched with methanol (112.5 mL) and stirred at 25°C for one hour. The mass
was filtered over celite bed and the filtrate was concentrated under reduced pressure to
33
reside. The residue was dissolved in ethyl acetate (500 mL), added water (250 mL),
stirred and the layers were separated. The ethyl acetate layer was washed with saturated
sodium chloride solution (50 mL), dried over sodium sulphate and filtered. The organic
layer was concentrated under reduced pressure to syrup stage (10 g). The syrup
(compound (viii) thus obtained was taken to next step without purification.
EXAMPLE 12:
Preparation of (Z)-methyl 7-((1R,2R,3R,5S)-3,5-dihydroxy-2-((S,E)-3-((2-
methoxyethoxy)methoxy)-5-phenylpent-1-enyl)cyclopentyl)hept-5-enoate
(compound -xii)
1M solution of NaHMDS (193 mL, 0.1936 moles) was added to the suspension of (4-
carboxy butyl) triphenyl phosphonium bromide (43 g, 0.0968moles) in dry THF (350
mL) under nitrogen atmosphere at 25° C. The solution turned orange and mixture was
stirred for 30 minutes. Added compound (viii) (10 g, 0.0254 moles) dissolved in dry
THF (20 mL) to the reaction mixture, the solution turned brownish. The reaction mass
was stirred at 25° C for 1.5 h and the reaction completion was monitored by TLC. After
the reaction completion, the mass was quenched with water (1 L) and the layer was
washed with ethyl acetate (200 mL). The pH of aqueous layer was adjusted to 5 by
using 2 % citric acid solution (100 mL) and product was extracted to ethyl actate
(2X500 mL). The combined organic layer was washed with saturated sodium chloride
solution (100 mL) and dried over sodiumsulphate. The layer was filtered and
concentrated under reduced pressure to get brown syrup (compound (ix)) (25 g).
EXAMPLE 13:
Preparation of (Z)-methyl 7-((1R,2R,3R,5S)-3,5-dihydroxy-2-((S,E)-3-((2-
methoxyethoxy)methoxy)-5-phenylpent-1-enyl)cyclopentyl)hept-5-
enoate(compound -xiii)
Methyl iodide (18.3 mL, 0.2941moles) and DBU (44 mL, 0.2941 moles) was added to
stirred solution of compound (ix) (25 g, 0.0525 moles) in dry acetone (500 mL) under
nitrogen at 25°C. The mass was stirred at that temperature for 8 hours and the reaction
completion was monitored by TLC. After the reaction completion the mass was
concentrated under reduced pressure to remove acetone. Added 2 % citric acid solution
(250 mL) and the product was extracted to ethyl acetate (500 mL). The organic layer
34
was washed with water (200 mL), saturated sodium chloride solution (100 mL) and
dried over sodiumsulphate. The layer was filtered and concentrated under reduced
pressure to syrup stage (26 g). The syrup (compound (x)) thus obtained was taken to
next step without purification.
EXAMPLE 14:
Preparation of (Z)-7-((1R,2R,3R,5S)-3,5-dihydroxy-2-((S,E)-3-((2-
methoxyethoxy)methoxy)-5-phenylpent-1-enyl)cyclopentyl)-N-ethylhept-5-
enamide (compound -xiv)
Aqueous ethylamine (70%, 1L, 40 v) was added to crude compound (xiii) and stirred
for 24 h at 25° C. The reaction completion was monitored by TLC. After the reaction
completion, the mass was neutralised by using sodium hydrogen sulphate solution (5 %
solution). The product was extracted to dichloromethane (500 mL) and the organic
layer was washed with water (200 mL), saturated sodium chloride solution (50 mL) and
dried over sodiumsulphate. The layer was filtered and concentrated to residue (26 g).
The light brown solid (compound (xiv)) was taken for deprotection without
purification.
EXAMPLE 15:
Preparation of (Z)-7-((1R,2R,3R,5S)-3,5-dihydroxy-2-((S,E)-3-hydroxy-5-
phenylpent-1-enyl)cyclopentyl)-N-ethylhept-5-enamide (Bimatoprost)
Added cerium (III) chloride heptahydrate (16 g, 0.0427 moles) and sodium iodide (4 g,
0.0256 moles) to solution of compound(x) (26 g, 0.0427moles) in acetonitrile (260 mL)
and contents were refluxed at 80-85° C for 2 h. The reaction completion was monitored
by TLC. After the reaction completion the mass was concentrated under reduced
pressure to remove acetonitrile. The residue was diluted with water (200 mL) and the
product was extracted with ethyl acetate (500 mL). the ethyl acetate layer was washed
with saturate sodium chloride solution (100 mL), dried over sodium sulphate and
filtered. The layer was concentrated under reduced pressure to obtain crude
Bimatoprost. The crude Bimatoprost was purified by column chromatography method.
The pure fractions from the column were pooled and concentrated to syrup stage and
the product was crystallized by using diethyl ether. The product Bimatoprost obtained
was of purity greater than 99 % (4 g).
35
EXAMPLE 16:
Preparation of (3aR,4R,5R,6aS)-2-oxo-4-((E)-3-oxo-4-(3-
(trifluoromethyl)phenoxy) but-1-enyl)hexahydro-2H-cyclopenta[b]furan-5-yl
biphenyl-4-carboxylate (compound -xv)
A solution of dimethyl 2-oxo-3-(3-(trifluoromethyl)phenoxy)propylphosphonate (44 g,
0.1349 moles) in dichloromethane(1 L) was added drop wise at 0° C to a suspension of
60 % sodium hydride(5.7 g,0.1420 moles) in dichloromethane (1 L). The mixture was
stirred at 0° C for one hour. The solution of aldehyde (compound (ii)) (50 g, 0.1428
moles) in dichloromethane prepared in the previous stage was added drop wise to the
mixture at 0-5° C. The reaction completion was monitored by TLC. After the reaction
completion, filtered the reaction mass over celite bed and filtrate was washed with
water (1 L), saturated sodium chloride solution (1 L). The organic layer was dried over
sodium sulphate, filtered and concentrated under reduced pressure to residue. The crude
brown residue (compound (xv) (61 g) was taken for the next step.
EXAMPLE 17:
Preparation of (3aR,4R,5R,6aS)-4-((R,E)-3-hydroxy-4-(3-
(trifluoromethyl)phenoxy) but-1-enyl)-2-oxohexahydro-2H-cyclopenta[b]furan-5-
yl biphenyl-4-carboxylate (compound -xvi)
A 1M solution of (R)-N-MeCBS (11 mL, 0.0110 moles) was added drop wise at 25° C
to the solution of compound (xv) (61 g, 0.1107 moles) in THF (2 L) under nitrogen
atmosphere. Stirred for 30 minutes at 25° C, then chilled the reaction mixture to -20° C,
added Borane N,N’-diethylaniline complex (DEANB) (20 mL, 0.110 moles)at -20° C
and slowly raised the temperature to 0°C. The reaction completion was monitored by
TLC. After the reaction completion, quenched the reaction mass with methanol (130
mL) and acidified to pH 3 using 1.5 N HCl (130 mL). Added ethylacetate (1 L) and
water (500 mL), the organic layer was separated, washed with water (500 mL),
saturated sodium chloride solution (250 mL) and dried over sodium sulphate. The
organic layer was concentrated under reduced pressure to residue. The brown residue
was purified by flash column chromatography to separate the desired isomer to obtain
the title compound (xvi) light yellow liquid (23 g).
36
EXAMPLE 18:
Preparation of (3aR,4R,5R,6aS)-5-hydroxy-4-((R,E)-3-hydroxy-4-(3-
(trifluoromethyl) phenoxy)but-1-enyl)hexahydro-2H-cyclopenta[b]furan-2-one
(compound -xvii)
Potassium carbonate (3.4 g, 0.0249 moles) was added to a solution of compound (xvi)
(23 g, 0.0415 moles) dissolved in methanol (200 mL). The reaction mixture was stirred
at 25° C for 2 h. The reaction completion was monitored by TLC. After the reaction
completion pH of the mass was adjusted to 6 using 1.5 N HCl. The reaction mass was
concentrated to remove methanol. Added ethylacetate (500 mL) and water (250 mL),
stirred for 5 minutes and the layers were separated. The organic layer was washed with
saturated sodium chloride solution and dried over sodium sulphate. The organic layer
was concentrated under reduced pressure to residue. The yellow oil obtained was
purified by column chromatography to get compound (xvii) (light yellow oil) (10 g).
EXAMPLE 19:
Preparation of (3aR,4R,5R,6aS)-5-((2-methoxyethoxy)methoxy)-4-((R,E)-3-((2-
methoxyethoxy)methoxy)-4-(3-(trifluoromethyl)phenoxy)but-1-enyl)hexahydro-
2H-cyclopenta[b]furan-2-one (compound -xviii)
A solution of compound (xvii) (10 g, 0.0268 moles) in dry dichloromethane (210 mL)
was chilled to 0°C under nitrogen blanket. Added diisopropylethylamine (25.6 mL,
0.1474 moles) and methoxyethoxymethyl chloride (MEM chloride) (13.8 mL, 0.1208
moles) to the reaction mixture at 0°C. Then slowly raised the temperature to 25° C,
stirred for 8 hours at that temperature. The reaction completion was monitored by TLC.
After the reaction completion, the mass was quenched with water (100 mL). The layers
were separated and the organic layer was washed with saturated sodium chloride
solution (50 mL) and dried over sodiumsulphate. The organic layer was concentrated
under reduced pressure to syrup stage (13 g). The light brown syrup (compound
(xviii)) was taken to next stage without purification.
EXAMPLE 20:
Preparation of ((3aR,4R,5R,6aS)-5-((2-methoxyethoxy)methoxy)-4-((R,E)-3-((2-
methoxyethoxy)methoxy)-4-(3-(trifluoromethyl)phenoxy)but-1-enyl)hexahydro-
2H-cyclopenta[b]furan-2-ol (compound -xix)
37
A solution of compound (xviii) (13 g, 0.0237 moles) in dry toluene (360 mL) was
cooled to -65° C under nitrogen atmosphere. Added DIBAL-H (71 mL, 0.0711 moles)
drop wise at -60° C to -65° C. The reaction mass was stirred at at -60° C to -65° C for
one hour and reaction completion was monitored by TLC. After reaction completion,
the mass was quenched with methanol (112.5 mL) and stirred at 25°C for one hour. The
mass was filtered over celite bed and the filtrate was concentrated under reduced
pressure to reside. The residue was dissolved in ethyl acetate (500 mL), added water
(250 mL), stirred and the layers were separated. The ethyl acetate layer was washed
with saturated sodium chloride solution (50 mL), dried over sodium sulphate and
filtered. The organic layer was concentrated under reduced pressure to syrup stage (12
g). The syrup (compound (xix) thus obtained was taken to next step without
purification.
EXAMPLE 21:
Preparation of (Z)-7-((1R,2R,3R,5S)-5-hydroxy-3-((2-methoxyethoxy)methoxy)-2-
((R,E)-3-((2-methoxyethoxy)methoxy)-4-(3-(trifluoromethyl)phenoxy)but-1-
enyl)cyclopentyl)hept-5-enoic acid (compound -xx)
1M solution of NaHMDS (166 mL, 0.1658 moles) was added to the suspension of (4-
carboxy butyl) triphenyl phosphonium bromide (36.7 g, 0.0829 moles) in dry THF (350
mL) under nitrogen atmosphere at 25° C. The solution turned orange and mixture was
stirred for 30 minutes. Added compound (xix) (12 g, 0.0218 moles) dissolved in dry
THF (20 mL) to the reaction mixture, the solution turned brownish. The reaction mass
was stirred at 25° C for 1.5 h and the reaction completion was monitored by TLC. After
the reaction completion, the mass was quenched with water (1 L) and the layer was
washed with ethyl acetate (200 mL). The pH of aqueous layer was adjusted to 5 by
using 2 % citric acid solution (100 mL) and product was extracted to ethyl actate
(2X500 mL). The combined organic layer was washed with saturated sodium chloride
solution (100 mL) and dried over sodiumsulphate. The layer was filtered and
concentrated under reduced pressure to get brown syrup (compound (xx)) (28 g).
EXAMPLE 22:
Preparation of (Z)-isopropyl 7-((1R,2R,3R,5S)-5-hydroxy-3-((2-
methoxyethoxy)methoxy)-2-((R,E)-3-((2-methoxyethoxy)methoxy)-4-(3-
(trifluoromethyl)phenoxy)but-1-enyl)cyclopentyl)hept-5-enoate (compound -xxi)
38
2-iodopropane (25 mL, 0.2470moles) and DBU (37 mL, 0.2470 moles) was added to
stirred solution of compound (ix) (28 g, 0.0441 moles) in dry acetone (500 mL) under
nitrogen at 25°C. The mass was stirred at that temperature for 8 hours and the reaction
completion was monitored by TLC. After the reaction completion the mass was
concentrated under reduced pressure to remove acetone. Added 2 % citric acid solution
(250 mL) and the product was extracted to ethyl acetate (500 mL). The organic layer
was washed with water (200 mL), saturated sodium chloride solution (100 mL) and
dried over sodiumsulphate. The layer was filtered and concentrated under reduced
pressure to syrup stage (26 g). The syrup (compound (xxi)) thus obtained was taken to
next step without purification.
EXAMPLE 23:
Preparation of (Z)-isopropyl 7-((1R,2R,3R,5S)-3,5-dihydroxy-2-((R,E)-3-hydroxy-
4-(3-(trifluoromethyl)phenoxy)but-1-enyl)cyclopentyl)hept-5-enoate (Travoprost)
Added cerium (III) chloride heptahydrate (14.3 g, 0.0384 moles) and sodium iodide
(3.4 g, 0.0230 moles) to solution of compound(x) (26 g, 0.0384 moles) in acetonitrile
(260 mL) and contents were refluxed at 80-85° C for 2 h. The reaction completion was
monitored by TLC. After the reaction completion the mass was concentrated under
reduced pressure to remove acetonitrile. The residue was diluted with water (200 mL)
and the product was extracted with ethyl acetate (500 mL). The ethyl acetate layer was
washed with saturate sodium chloride solution (100 mL), dried over sodium sulphate
and filtered. The layer was concentrated under reduced pressure to obtain crude
Travoprost. The crude Travoprost was purified by colum chromatagraph and was
further purified by prep HPLC to obtain Travoprost of purity greater than 99 % (5 g).
39
We claim:
1. A process for preparing compound of formula;
OH
HO R1
O
R
HO
(K)
wherein R is selected from the group consisting of C1-C7 alkyl; C7-C17 aralkyl
wherein the aryl group is unsubstituted or substituted with one to three substituents
selected from the group consisting of C1-C6 alkyl, halo and CF3; and (CH2)nOR2
wherein n is from 1 to 3 and R2 represents a C6-C10 aryl group which is
unsubstituted or substituted with one to three substituents selected from the group
consisting of C1-C6 alkyl, halo and CF3; and R1 is selected from OR3 and NHR3
wherein R3 is C1-C6 alkyl, H, and dashed lines (----- )represents a double bond or a
single bond comprises;
a). reacting compound of formula ‘I’ with haloalkane or ethylamine,
OH
OR4
R
OR5
OH
O
(I)
Wherein, R described as above, dashed line represents single or double bonds,
40
R4 and R5 represents, R4 = R5=CH2OCH2CH2CH2CH3; R4 =H,
R5=CH2OCH2CH2CH2CH3; R4 = CH2OCH2CH2CH2CH3, R5=H to form compound of
formula ‘J’ and,
OH
OR4
R
OR5
R1
O
(J)
Wherein, R ,R1, dashed line, R4 and R5 as described above; and
b). deprotecting compound of formula ‘J’.
2. The process as claimed in claim 1, wherein said deprotection is done using cerium
(III) chloride heptahydrate and sodium iodide in the presence of organic solvent.
3. The process as claimed in claim 2, wherein organic solvent is selected from a group
comprising acetonitrile, ethanol, methanol, acetone and isopropyl alcohol.
4. The process as claimed in claim 1, wherein the compound K is any one of following
compound;
OH
HO
HO
O
O
CH3
H3C
OH
HO
HO
NH
O
CH3
41
OH
HO
HO
O
O
CH3
H3C
O CF3
OH
HO
HO
OH
O
O Cl
OH
HO
HO
OH
O
CH3
OH
HO
O
OH
O
CH3
OH
HO
O
O
O
CH3
CH3
CH3
5. The process as claimed in claim 1, wherein process for the preparation of compound
of formula ‘I’ comprises;
a). Reacting compound of formula ‘A’
O
O
OP
OH (A)
with dimethylsulphoxide, oxalylchloride and triethylamine in the presence of organic
solvent to get compound of formula ‘B’, wherein P is selected from the group
consisting of COX; in which X represents C1 to C6 alkyl, C6-C10 aryl which may be
substituted or unsubstituted with one to three substituents independently selected from
the group consisting of halo, C1 to C6 alkyl, unsubstituted C6 to C10 aryl,
42
O
O
O
OP
(B)
b). reacting compound of formula ‘B’ with
O O
P
O
CH3
O CH3
O
Y
Wherein Y is selected from the group consisting of alkyl, aryl wherein aryl group is
unsubstituted or substituted with one to three substituents selected from the group
consisting of C1-C6 alkyl, halo and CF3; and (CH2)nOR2 wherein n is from 1 to 3 and R2
represents a C6-C10 aryl group which is unsubstituted or substituted with one to three
substituents selected from the group consisting of C1-C6 alkyl, halo and CF3 in the
presence of organic solvent to form compound of formula ‘C’
O
O
OP
R
O
(C)
wherein R is selected from the group consisting of C1-C7 alkyl; C7-C17 aralkyl wherein
the aryl group is unsubstituted or substituted with one to three substituents selected
from the group consisting of C1-C6 alkyl, halo and CF3; and (CH2)nOR2 wherein n is
from 1 to 3 and R2 represents a C6-C10 aryl group which is unsubstituted or substituted
43
with one to three substituents selected from the group consisting of C1-C6 alkyl, halo
and CF3 and P is as described above,
c). by selective reduction of compound ‘C’ using Borane N,N’-diethylaniline complex
in the presence of Corey catalyst to compound ‘D’,
O
O
OP
R
OH
(D)
Wherein P and R are as described above,
d). deprotecting compound of formula D using base in organic solvent to get
compound of formula E,
O
O
OH
R
OH
(E)
e). hydroxyl groups of compound E further protected to form compound of
formula F,
O
O
OR4
R
OR5
(F)
44
Wherein R described as above, R4 and R5 represents,
R4 = R5=CH2OCH2CH2CH2CH3; R4 =H, R5=CH2OCH2CH2CH2CH3;
R4 = CH2OCH2CH2CH2CH3, R5=H
f). compound of formula F optionally hydrogenated using palladium on carbon in the
presence of organic solvent, further reducing the oxo group of this compound reduced
to compound of formula H using DIBAL-H in the presence of organic solvent,,
O
OH
OR4
R
OR5
(H)
wherein the dashed line represents a double bond or a single bond; R, R4 and R5
represents as described above
g). compound of formula H further reacted with compound of formula
PPh3(CH2)4COOH in the presence of NaHMDS in organic solvent
6. The process as claimed in claim 5, wherein organic solvent is selected from a group
comprising of alcohols, esters, tetrahydrofuran, pet ether, hexane, acetone and
acetonitrile.
7. The process as claimed in claim 6, wherein said alcohols are selected from C1 to C4
alcohols.
8. The process as claimed in claim 6, wherein said esters are selected from ethyl acetate
or butyl acetate.
9. The process as claimed in claim 5, wherein base is selected from potassium
carbonate, sodium carbonate or sodium bi carbonate.
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10. A compound of formula;
O
O
OR4
R
OR5
Wherein R described as above, R4 and R5 represents,
R4 = R5=CH2OCH2CH2CH2CH3; R4 =H, R5=CH2OCH2CH2CH2CH3;
R4 = CH2OCH2CH2CH2CH3, R5=H
11. A compound of formula;
Wherein R described as above, dashed lines represents single or double bonds, R4 and
R5 represents, R4 = R5=CH2OCH2CH2CH2CH3; R4 =H,
R5=CH2OCH2CH2CH2CH3; R4 = CH2OCH2CH2CH2CH3, R5=H
46
12. A compound of formula;
Wherein R described as above, dashed lines represents single or double bonds, R4 and
R5 represents, R4 = R5=CH2OCH2CH2CH2CH3; R4 =H,
R5=CH2OCH2CH2CH2CH3; R4 = CH2OCH2CH2CH2CH3, R5=H
13. A compound of formula;
Wherein R described as above, dashed lines represents single or double bonds, R4 and
R5 represents, R4 = R5=CH2OCH2CH2CH2CH3; R4 =H,
R5=CH2OCH2CH2CH2CH3; R4 = CH2OCH2CH2CH2CH3, R5=H
47
14. A compound
Wherein R described as above, dashed lines represents single or double bonds, R4 and
R5 represents, R4 = R5=CH2OCH2CH2CH2CH3; R4 =H,
R5=CH2OCH2CH2CH2CH3; R4 = CH2OCH2CH2CH2CH3, R5=H
Dated this 05th day of November 2009
M. SURESH GUPTA
Of K&S Partners
Agent for the Applicant