WO2010104344A2 - Process for preparing prostaglandin derivatives - Google Patents

Process for preparing prostaglandin derivatives Download PDF

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WO2010104344A2
WO2010104344A2 PCT/KR2010/001529 KR2010001529W WO2010104344A2 WO 2010104344 A2 WO2010104344 A2 WO 2010104344A2 KR 2010001529 W KR2010001529 W KR 2010001529W WO 2010104344 A2 WO2010104344 A2 WO 2010104344A2
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Prior art keywords
process according
derivative
compound
formula
following formula
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PCT/KR2010/001529
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French (fr)
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WO2010104344A3 (en
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Changyoung Oh
Kee Young Lee
Yong Hyun Kim
Jae Eun Joo
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Yonsung Fine Chemical Co., Ltd.
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Priority to JP2011553956A priority Critical patent/JP5490155B2/en
Priority to US13/255,417 priority patent/US9126898B2/en
Publication of WO2010104344A2 publication Critical patent/WO2010104344A2/en
Publication of WO2010104344A3 publication Critical patent/WO2010104344A3/en
Priority to US13/901,170 priority patent/US20130253218A1/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C233/00—Carboxylic acid amides
    • C07C233/01—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms
    • C07C233/02—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having nitrogen atoms of carboxamide groups bound to hydrogen atoms or to carbon atoms of unsubstituted hydrocarbon radicals
    • C07C233/11—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having nitrogen atoms of carboxamide groups bound to hydrogen atoms or to carbon atoms of unsubstituted hydrocarbon radicals with carbon atoms of carboxamide groups bound to carbon atoms of an unsaturated carbon skeleton containing six-membered aromatic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C67/00—Preparation of carboxylic acid esters
    • C07C67/30—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group
    • C07C67/317—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group by splitting-off hydrogen or functional groups; by hydrogenolysis of functional groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C405/00—Compounds containing a five-membered ring having two side-chains in ortho position to each other, and having oxygen atoms directly attached to the ring in ortho position to one of the side-chains, one side-chain containing, not directly attached to the ring, a carbon atom having three bonds to hetero atoms with at the most one bond to halogen, and the other side-chain having oxygen atoms attached in gamma-position to the ring, e.g. prostaglandins ; Analogues or derivatives thereof
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C69/00—Esters of carboxylic acids; Esters of carbonic or haloformic acids
    • C07C69/52—Esters of acyclic unsaturated carboxylic acids having the esterified carboxyl group bound to an acyclic carbon atom
    • C07C69/587—Monocarboxylic acid esters having at least two carbon-to-carbon double bonds
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C69/00—Esters of carboxylic acids; Esters of carbonic or haloformic acids
    • C07C69/608—Esters of carboxylic acids having a carboxyl group bound to an acyclic carbon atom and having a ring other than a six-membered aromatic ring in the acid moiety
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C69/00—Esters of carboxylic acids; Esters of carbonic or haloformic acids
    • C07C69/612—Esters of carboxylic acids having a carboxyl group bound to an acyclic carbon atom and having a six-membered aromatic ring in the acid moiety
    • C07C69/618—Esters of carboxylic acids having a carboxyl group bound to an acyclic carbon atom and having a six-membered aromatic ring in the acid moiety having unsaturation outside the six-membered aromatic ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C69/00—Esters of carboxylic acids; Esters of carbonic or haloformic acids
    • C07C69/66—Esters of carboxylic acids having esterified carboxylic groups bound to acyclic carbon atoms and having any of the groups OH, O—metal, —CHO, keto, ether, acyloxy, groups, groups, or in the acid moiety
    • C07C69/73—Esters of carboxylic acids having esterified carboxylic groups bound to acyclic carbon atoms and having any of the groups OH, O—metal, —CHO, keto, ether, acyloxy, groups, groups, or in the acid moiety of unsaturated acids
    • C07C69/734—Ethers
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2601/00—Systems containing only non-condensed rings
    • C07C2601/06—Systems containing only non-condensed rings with a five-membered ring
    • C07C2601/08—Systems containing only non-condensed rings with a five-membered ring the ring being saturated
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
    • Y02P20/00—Technologies relating to chemical industry
    • Y02P20/50—Improvements relating to the production of bulk chemicals
    • Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

Definitions

  • the present invention relates to a process for efficiently preparing a prostaglandin derivative with high purity and an intermediate therefor.
  • Prostaglandin derivatives particularly travoprost, bimatoprost and latanoprost of the following formula (2) have been extensively used due to their clinical effects such as reducing intraocular pressure and promoting hair and eyelash growth.
  • the prostaglandin derivatives have been conventionally prepared through many synthetic steps in poor yields.
  • the most common commercial processes use Corey lactone as a starting material to produce the prostaglandin derivatives, as shown in the following Reaction Scheme 1 ( see E.J. Corey et al., J. Amer. Chem. Soc., 91, 5675-5677, 1969).
  • Corey lactone is expensive and the processes require a chromatographic separation for removing ⁇ -OH which is produced as a by-product on the reduction of 15-ketone group into ⁇ -OH after the introduction of ⁇ -chain. Therefore, the processes are unsuitable for large-scale production of the prostaglandin derivatives in terms of poor yields and high costs.
  • the ⁇ -OH produced as a by-product may be reduced by using a chiral borane compound as a stereoselective reducing agent, but the chiral borane compound is also very expensive.
  • PGF prostaglandin F
  • PGE prostaglandin E
  • the present inventors have endeavored to overcome the above problems and found that a highly pure PGF derivative having little or no ⁇ -OH can be efficiently prepared by removing the protecting group of the prostaglandin E (PGE) derivative obtained from conjugate addition and then stereoselectively reducing the ketone group on the cyclopentanone ring.
  • PGE prostaglandin E
  • An object of the present invention is, therefore, to provide a process for efficiently preparing a PGF derivative with high purity.
  • Another object of the present invention is to provide a novel intermediate used in said process.
  • One aspect of the present invention relates to a process for preparing a prostaglandin F (PGF) derivative of the following formula (1), which comprises the steps of:
  • X is O or NH
  • Y is ⁇ -OH or difluoro, preferably ⁇ -OH;
  • Y' is ⁇ -OPG or difluoro, preferably ⁇ -OPG;
  • Z is CH 2 , O or S, preferably CH 2 or O;
  • R is H or C 1 -C 5 alkyl, preferably C 1 -C 5 alkyl
  • R' is C 1 -C 5 alkyl, C 3 -C 7 cycloalkyl or aryl, preferably phenyl optionally substituted by C 1 -C 5 haloalkyl or halogen, more preferably CF 3 , Cl or F, most preferably CF 3 ;
  • PG is a hydroxy protecting group, preferably tetrahydropyranyl, trimethylsilyl, triethylsilyl or t-butyldimethylsilyl, more preferably triethylsilyl.
  • C 1 -C 5 alkyl as used herein means a straight or branched hydrocarbon having 1 to 5 carbon atoms, which includes methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, s-butyl, t-butyl, n-pentyl, etc., but is not limited thereto.
  • C 3 -C 7 cycloalkyl as used herein means a cyclic hydrocarbon having 3 to 7 carbon atoms, which includes cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, etc., but is not limited thereto.
  • aryl as used herein includes all of aromatic group, heteroaromatic group and partially reduced derivatives thereof.
  • the aromatic group means a 5 to 15-membered simple or fused ring.
  • the heteroaromatic group means an aromatic group containing at least one atom selected from oxygen, sulfur and nitrogen. Examples of the aryl include phenyl, naphthyl, pyridinyl, furanyl, thiophenyl, indolyl, quinolinyl, imidazolinyl, oxazolyl, thiazolyl, tetrahydronaphthyl, etc., but are not limited thereto.
  • the C 1 -C 5 alkyl, C 3 -C 7 cycloalkyl and aryl may have one or more hydrogens substituted by C 1 -C 5 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 10 cycloalkyl, C 1 -C 5 haloalkyl, C 1 -C 5 alkoxy, C 1 -C 5 thioalkoxy, aryl, acyl, hydroxy, thio, halogen, amino, alkoxycarbonyl, carboxyl, carbamoyl, cyano, nitro, etc.
  • the prostaglandin E (PGE) derivative of formula (6) is prepared by removing the hydroxy protecting group of the protected PGE derivative of formula (5).
  • the deprotection may be carried out under an acidic condition.
  • silyl protecting groups may be deprotected by using various fluoride compounds.
  • the acidic condition for silyl protecting groups may be provided by the use of d-HCl, an aqueous NaHSO 4 solution, pyridinium p-toluensulfonate (PPTS), etc.
  • PPTS pyridinium p-toluensulfonate
  • fluoride compounds include tetrabutylammonium fluoride (Bu 4 N + F - ), hydrogen fluoride-pyridine (HF-pyridine), fluorosilicic acid (H 2 SiF 6 ), etc., but are not limited thereto.
  • the compound of formula (5) having a carbon-carbon double bond at 13 and 14 position may be prepared by converting an alkenyl tin compound of the following formula (3) to its cuprate, followed by conjugate addition to a cyclopentenone compound of the following formula (4), according to a known method ( see J. Am. Chem. Soc. 1988, 110, 2641-2643).
  • the alkenyl tin compound of formula (3) is added to a solution of Me 2 Cu(CN)Li 2 and converted to a higher order mixed cuprate of the following formula (7), which is subjected to conjugate addition to the cyclopentenone compound of formula (4).
  • the above reaction is preferably carried out in a mixture of tetrahydrofuran (THF) and hexane or a mixture of THF and ether, most preferably a mixture of THF and diethyl ether, as a solvent.
  • THF tetrahydrofuran
  • ether a mixture of THF and ether, most preferably a mixture of THF and diethyl ether, as a solvent.
  • the conjugate addition is preferably carried out in a low temperature of -60 °C or less.
  • the alkenyl tin compound of formula (3) may be prepared by reacting a ⁇ -chain precursor containing a terminal acetylene group with Bu 3 SnH, according to a known method ( see J. Am. Chem. Soc. 1988, 110, 2641-2643).
  • the compound of formula (5) having a carbon-carbon single bond at 13 and 14 position may be prepared by the method disclosed in WO 02/090324.
  • the prostaglandin F (PGF) derivative of formula (1) is prepared by stereoselectively reducing the ketone group on the cyclopentanone ring of the compound of formula (6).
  • a reducing agent used in the present invention includes sodium borohydride (NaBH 4 ), L-selectride, N-selectride, K-selectride, LS-selectride, 2,6-di-tert-butyl-4-methyl phenol and diisobutyl aluminium hydride (DIBAL), etc., but is not limited thereto.
  • NaBH 4 sodium borohydride
  • L-selectride L-selectride
  • N-selectride N-selectride
  • K-selectride K-selectride
  • LS-selectride 2,6-di-tert-butyl-4-methyl phenol and diisobutyl aluminium hydride (DIBAL), etc.
  • DIBAL diisobutyl aluminium hydride
  • 2,6-di-tert-butyl-4-methyl phenol and DIBAL leads to stereoselective preparation of ⁇ -OH compound having no ⁇ -OH.
  • the reduction is carried out by reacting 2,6-di-tert-butyl-4-methyl phenol in an amount of 2 to 10 equivalents, preferably 5 equivalents with DIBAL in an amount of 2 to 5 equivalents, preferably 4 equivalents in toluene as a solvent at -10 to 10 °C, preferably 0 °C for 1 to 2 hours, preferably 1 hour; lowering the temperature of the reaction solution to -70 °C; adding the compound of formula (6) thereto, followed by stirring for 1 to 3 hours, preferably 2 hours; raising the temperature of the reaction solution to -40 to -20 °C, preferably -30 °C; and stirring the reaction solution for 3 to 6 hours, preferably 4 hours.
  • the prostaglandin F (PGF) derivative of formula (1) wherein X is NH may be prepared by reacting the PGF derivative of formula (1) wherein X is O and R is methyl, with RNH 2 .
  • the above reaction is preferably carried out at room temperature.
  • Examples of the prostaglandin F (PGF) derivative of formula (1) prepared by the present process include travoprost, bimatoprost and latanoprost, which are widely used due to their clinical effects such as reducing intraocular pressure and promoting hair and eyelash growth.
  • travoprost, bimatoprost and latanoprost can be prepared with high purity of 99.5% or more by further comprising the step of purifying them by HPLC using a mixture of hydrocarbon and alcohol, preferably a mixture of n-hexane and anhydrous ethanol or a mixture of n-heptane and anhydrous ethanol, or a mixture of dichloromethane and alcohol, preferably a mixture of dichloromethane and isopropanol.
  • Another aspect of the present invention relates to a compound of the following formula (8), which is an intermediate of travoprost, and a compound of formula (9), which is an intermediate of bimatoprost.
  • the prostaglandin F (PGF) derivative can be efficiently prepared with high purity by removing the protecting group of the protected prostaglandin E (PGE) derivative obtained from conjugate addition and then stereoselectively reducing the ketone group on the cyclopentanone ring of the PGE derivative.
  • the ⁇ -OH compound having no ⁇ -OH can be stereoselectively prepared using 2,6-di-tert-butyl-4-methyl phenol and diisobutyl aluminium hydride (DIBAL) as a reducing agent.
  • DIBAL diisobutyl aluminium hydride
  • 2,6-Di-tert-butyl-4-methyl phenol (560 g) was dissolved in toluene (6.5 L), followed by cooling to 0 °C, and DIBAL (1.0 M toluene, 2.05 L) was added dropwise thereto for 1 hour.
  • the resulting reaction solution was cooled to -70 °C, and compound (6-II) (205 g) dissolved in toluene (1.6 L) was added dropwise thereto.
  • the resulting reaction solution was stirred for about 2 hours, and its temperature was slowly raised to -40 to -20 °C, followed by stirring for 4 hours. After the reaction was completed, an aqueous 2N hydrochloric acid solution (2.5 L) was added.

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Abstract

The present invention relates to a process for preparing a prostaglandin derivative and an intermediate therefor. In accordance with the present invention, the prostaglandin F (PGF) derivative can be efficiently prepared with high purity by removing the protecting group of a protected prostaglandin E (PGE) derivative obtained from conjugate addition and then stereoselectively reducing the ketone group on the cyclopentanone ring of the PGE derivative.

Description

PROCESS FOR PREPARING PROSTAGLANDIN DERIVATIVES
The present invention relates to a process for efficiently preparing a prostaglandin derivative with high purity and an intermediate therefor.
Prostaglandin derivatives, particularly travoprost, bimatoprost and latanoprost of the following formula (2) have been extensively used due to their clinical effects such as reducing intraocular pressure and promoting hair and eyelash growth.
Figure PCTKR2010001529-appb-I000001
The prostaglandin derivatives have been conventionally prepared through many synthetic steps in poor yields. The most common commercial processes use Corey lactone as a starting material to produce the prostaglandin derivatives, as shown in the following Reaction Scheme 1 (see E.J. Corey et al., J. Amer. Chem. Soc., 91, 5675-5677, 1969). However, Corey lactone is expensive and the processes require a chromatographic separation for removing β-OH which is produced as a by-product on the reduction of 15-ketone group into α-OH after the introduction of ω-chain. Therefore, the processes are unsuitable for large-scale production of the prostaglandin derivatives in terms of poor yields and high costs. The β-OH produced as a by-product may be reduced by using a chiral borane compound as a stereoselective reducing agent, but the chiral borane compound is also very expensive.
[Reaction Scheme 1]
Figure PCTKR2010001529-appb-I000002
To overcome the above disadvantages, it was suggested to prepare the prostaglandin derivatives by conjugate addition of ω-chain including α-OH to cyclopentenone derivatives having α-side chain, as shown in the following Reaction Scheme 2. In particular, a process developed by Lipshuts et al. can stereoselectively introduce ω-chain by using higher order mixed organocuprate (see US Patent Nos. 4,785,124, 4,904,820, 4,952,710 and 5,055,604, and WO 02/090324).
[Reaction Scheme 2]
Figure PCTKR2010001529-appb-I000003
Such process requires that, in order to synthesize prostaglandin F (PGF) derivatives, the ketone group on the cyclopentanone ring of the prostaglandin E (PGE) derivatives obtained from the conjugate addition should be stereoselectively reduced to α-OH. The use of sodium borohydride (NaBH4) as a reducing agent gives the PGF derivatives in the form of a 6:4 mixture of α-OH and β-OH, and the use of a bulky hydride such as L-selectride, N-selectride, K-selectride and LS-selectride gives the PGF derivatives in increased selectivity of 9:1 (α:β ratio). However, a significant amount of β-OH should be still removed by using a difficult method causing large yield loss.
Therefore, there has been a need to develop a process for more stereoselectively reducing the ketone group on the cyclopentanone ring of the prostaglandin E derivatives.
The present inventors have endeavored to overcome the above problems and found that a highly pure PGF derivative having little or no β-OH can be efficiently prepared by removing the protecting group of the prostaglandin E (PGE) derivative obtained from conjugate addition and then stereoselectively reducing the ketone group on the cyclopentanone ring.
An object of the present invention is, therefore, to provide a process for efficiently preparing a PGF derivative with high purity.
Another object of the present invention is to provide a novel intermediate used in said process.
One aspect of the present invention relates to a process for preparing a prostaglandin F (PGF) derivative of the following formula (1), which comprises the steps of:
(i) removing the hydroxy protecting group of a protected prostaglandin E (PGE) derivative of the following formula (5) to give a prostaglandin E (PGE) derivative of the following formula (6); and
(ii) stereoselectively reducing the ketone group on the cyclopentanone ring of the compound of the following formula (6):
Figure PCTKR2010001529-appb-I000004
Figure PCTKR2010001529-appb-I000005
Figure PCTKR2010001529-appb-I000006
wherein,
Figure PCTKR2010001529-appb-I000007
is a single or double bond;
X is O or NH;
Y is α-OH or difluoro, preferably α-OH;
Y' is α-OPG or difluoro, preferably α-OPG;
Z is CH2, O or S, preferably CH2 or O;
R is H or C1-C5 alkyl, preferably C1-C5 alkyl;
R' is C1-C5 alkyl, C3-C7 cycloalkyl or aryl, preferably phenyl optionally substituted by C1-C5 haloalkyl or halogen, more preferably CF3, Cl or F, most preferably CF3; and
PG is a hydroxy protecting group, preferably tetrahydropyranyl, trimethylsilyl, triethylsilyl or t-butyldimethylsilyl, more preferably triethylsilyl.
The term "C1-C5 alkyl" as used herein means a straight or branched hydrocarbon having 1 to 5 carbon atoms, which includes methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, s-butyl, t-butyl, n-pentyl, etc., but is not limited thereto.
The term "C3-C7 cycloalkyl" as used herein means a cyclic hydrocarbon having 3 to 7 carbon atoms, which includes cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, etc., but is not limited thereto.
The term "aryl" as used herein includes all of aromatic group, heteroaromatic group and partially reduced derivatives thereof. The aromatic group means a 5 to 15-membered simple or fused ring. The heteroaromatic group means an aromatic group containing at least one atom selected from oxygen, sulfur and nitrogen. Examples of the aryl include phenyl, naphthyl, pyridinyl, furanyl, thiophenyl, indolyl, quinolinyl, imidazolinyl, oxazolyl, thiazolyl, tetrahydronaphthyl, etc., but are not limited thereto.
The C1-C5 alkyl, C3-C7 cycloalkyl and aryl may have one or more hydrogens substituted by C1-C5 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C10 cycloalkyl, C1-C5 haloalkyl, C1-C5 alkoxy, C1-C5 thioalkoxy, aryl, acyl, hydroxy, thio, halogen, amino, alkoxycarbonyl, carboxyl, carbamoyl, cyano, nitro, etc.
The process of the present invention is, hereinafter, described in more detail referring to the following Reaction Scheme 3.
[Reaction Scheme 3]
Figure PCTKR2010001529-appb-I000008
Step 1 : Preparation of Prostaglandin E (PGE) Derivative of Formula (6)
The prostaglandin E (PGE) derivative of formula (6) is prepared by removing the hydroxy protecting group of the protected PGE derivative of formula (5).
The deprotection may be carried out under an acidic condition. Particularly, silyl protecting groups may be deprotected by using various fluoride compounds.
The acidic condition for silyl protecting groups may be provided by the use of d-HCl, an aqueous NaHSO4 solution, pyridinium p-toluensulfonate (PPTS), etc. Preferably, PPTS is used in a catalytic amount in a mixture of acetone and water. Examples of the fluoride compounds include tetrabutylammonium fluoride (Bu4N+F-), hydrogen fluoride-pyridine (HF-pyridine), fluorosilicic acid (H2SiF6), etc., but are not limited thereto.
The compound of formula (5) having a carbon-carbon double bond at 13 and 14 position may be prepared by converting an alkenyl tin compound of the following formula (3) to its cuprate, followed by conjugate addition to a cyclopentenone compound of the following formula (4), according to a known method (see J. Am. Chem. Soc. 1988, 110, 2641-2643).
Figure PCTKR2010001529-appb-I000009
Figure PCTKR2010001529-appb-I000010
Preferably, the alkenyl tin compound of formula (3) is added to a solution of Me2Cu(CN)Li2 and converted to a higher order mixed cuprate of the following formula (7), which is subjected to conjugate addition to the cyclopentenone compound of formula (4).
Figure PCTKR2010001529-appb-I000011
The above reaction is preferably carried out in a mixture of tetrahydrofuran (THF) and hexane or a mixture of THF and ether, most preferably a mixture of THF and diethyl ether, as a solvent.
The conjugate addition is preferably carried out in a low temperature of -60 ℃ or less.
The alkenyl tin compound of formula (3) may be prepared by reacting a ω-chain precursor containing a terminal acetylene group with Bu3SnH, according to a known method (see J. Am. Chem. Soc. 1988, 110, 2641-2643).
Meanwhile, the compound of formula (5) having a carbon-carbon single bond at 13 and 14 position may be prepared by the method disclosed in WO 02/090324.
Step 2 : Preparation of Prostaglandin F (PGF) Derivative of Formula (1)
The prostaglandin F (PGF) derivative of formula (1) is prepared by stereoselectively reducing the ketone group on the cyclopentanone ring of the compound of formula (6).
A reducing agent used in the present invention includes sodium borohydride (NaBH4), L-selectride, N-selectride, K-selectride, LS-selectride, 2,6-di-tert-butyl-4-methyl phenol and diisobutyl aluminium hydride (DIBAL), etc., but is not limited thereto. Preferably, 2,6-di-tert-butyl-4-methyl phenol and DIBAL are used.
The use of 2,6-di-tert-butyl-4-methyl phenol and DIBAL leads to stereoselective preparation of α-OH compound having no β-OH. Generally, the reduction is carried out by reacting 2,6-di-tert-butyl-4-methyl phenol in an amount of 2 to 10 equivalents, preferably 5 equivalents with DIBAL in an amount of 2 to 5 equivalents, preferably 4 equivalents in toluene as a solvent at -10 to 10 ℃, preferably 0 ℃ for 1 to 2 hours, preferably 1 hour; lowering the temperature of the reaction solution to -70 ℃; adding the compound of formula (6) thereto, followed by stirring for 1 to 3 hours, preferably 2 hours; raising the temperature of the reaction solution to -40 to -20 ℃, preferably -30 ℃; and stirring the reaction solution for 3 to 6 hours, preferably 4 hours.
Alternatively, the prostaglandin F (PGF) derivative of formula (1) wherein X is NH may be prepared by reacting the PGF derivative of formula (1) wherein X is O and R is methyl, with RNH2.
The above reaction is preferably carried out at room temperature.
Examples of the prostaglandin F (PGF) derivative of formula (1) prepared by the present process include travoprost, bimatoprost and latanoprost, which are widely used due to their clinical effects such as reducing intraocular pressure and promoting hair and eyelash growth. According to the present invention, travoprost, bimatoprost and latanoprost can be prepared with high purity of 99.5% or more by further comprising the step of purifying them by HPLC using a mixture of hydrocarbon and alcohol, preferably a mixture of n-hexane and anhydrous ethanol or a mixture of n-heptane and anhydrous ethanol, or a mixture of dichloromethane and alcohol, preferably a mixture of dichloromethane and isopropanol.
Another aspect of the present invention relates to a compound of the following formula (8), which is an intermediate of travoprost, and a compound of formula (9), which is an intermediate of bimatoprost.
Figure PCTKR2010001529-appb-I000012
Figure PCTKR2010001529-appb-I000013
In accordance with the present invention, the prostaglandin F (PGF) derivative can be efficiently prepared with high purity by removing the protecting group of the protected prostaglandin E (PGE) derivative obtained from conjugate addition and then stereoselectively reducing the ketone group on the cyclopentanone ring of the PGE derivative. Particularly, the α-OH compound having no β-OH can be stereoselectively prepared using 2,6-di-tert-butyl-4-methyl phenol and diisobutyl aluminium hydride (DIBAL) as a reducing agent.
The present invention is further illustrated by the following examples, which are not to be construed to limit the scope of the invention.
Example 1: Preparation of Compound (8)
Figure PCTKR2010001529-appb-I000014
Copper cyanide (30 g) was dissolved in THF (680 ml), followed by cooling to 0 ℃, and methyllithium (1.6 M diethyl ether, 445 ml) was added dropwise thereto. The resulting reaction solution was stirred for 10 to 20 minutes, and compound (3-I) (215 g) dissolved in THF (200 ml) was added thereto. The resulting reaction solution was stirred for 1.5 to 2 hours, followed by cooling to -70 ℃, and compound (4-I) (90 g) dissolved in THF (680 ml) was rapidly added thereto, and then the temperature of the reaction solution was slowly raised to -45 ℃. After the reaction was completed, the resulting reaction solution was added to a mixture of aqueous ammonium chloride solution/ammonia water (9:1, 1.8 L) and diethyl ether (2 L), followed by stirring at room temperature for 1 to 2 hours. The organic layer was separated, dried over sodium sulfate (1 kg), filtered and concentrated. The resulting residue was subjected to chromatography (eluent: n-hexane:ethyl acetate = 10:1) to give the target compound (127 g, Yield: 75 %).
Example 2: Preparation of Compound (6-I)
Figure PCTKR2010001529-appb-I000015
Pyridinium p-toluensulfonate (PPTS, 2.3 g) was added to compound (8) (127 g) dissolved in a mixture of acetone (1.2 L) and water (0.25 L), followed by stirring at room temperature for 12 hours. After the reaction was completed, the resulting reaction solution was concentrated under vacuum, and ethyl acetate (1.5 L) and water (1 L) were added thereto, followed by stirring. The organic layer was separated, dried over sodium sulfate (1 kg), filtered and concentrated. The resulting residue was subjected to chromatography (eluent: n-hexane:ethyl acetate = 1:3) to give the target compound (78 g, Yield: 89 %).
Example 3: Preparation of Travoprost
Figure PCTKR2010001529-appb-I000016
2,6-Di-tert-butyl-4-methyl phenol (172 g) was dissolved in toluene (2 L), followed by cooling to 0 ℃, and DIBAL (1.0 M toluene, 625 ml) was added dropwise thereto for 1 hour. The resulting reaction solution was cooled to -70 ℃, and compound (6-I) (78 g) dissolved in toluene (0.5 L) was added dropwise thereto. The resulting reaction solution was stirred for about 2 hours, and its temperature was slowly raised to -40 to -20 ℃, followed by stirring for 4 hours. After the reaction was completed, an aqueous 2N hydrochloric acid solution (1 L) was added. The organic layer was separated, dried over sodium sulfate (1 kg), filtered and concentrated. The resulting residue was subjected to chromatography (eluent: n-hexane:ethyl acetate = 1:5) to give travoprost (Purity: 96 % or more). The obtained compound was subjected to preparative HPLC (eluent: dichloromethane:isopropanol = 90:10) to give highly pure travoprost (50 g, Purity: 99.5% or more, Yield: 63%).
Example 4: Preparation of Compound (9)
Figure PCTKR2010001529-appb-I000017
Copper cyanide (98 g) was dissolved in THF (2.2 L), followed by cooling to 0 ℃, and methyllithium (1.6 M diethyl ether, 1.44 L) was added dropwise thereto. The resulting reaction solution was stirred for 10 to 20 minutes, and compound (3-II) (598 g) dissolved in THF (1.4 L) was added thereto. The resulting reaction solution was stirred for 1.5 to 2 hours, followed by cooling to -70 ℃, and compound (4-II) (270 g) dissolved in THF (2.2 L) was added thereto for 15 minutes, and then the temperature of the reaction solution was slowly raised to -45 ℃. After the reaction was completed, the resulting reaction solution was added to a mixture of aqueous ammonium chloride solution/ammonia water (9:1, 7.0 L) and diethyl ether (3.5 L), followed by stirring at room temperature for 1 to 2 hours. The organic layer was separated, dried over sodium sulfate (1 kg), filtered and concentrated. The resulting residue was subjected to chromatography (eluent: n-hexane:ethyl acetate = 10:1) to give the target compound (420 g, Yield: 88 %).
Example 5: Preparation of Compound (6-II)
Figure PCTKR2010001529-appb-I000018
Pyridinium p-toluensulfonate (PPTS, 8.8 g) was added to compound (9) (420 g) dissolved in a mixture of acetone (4.3 L) and water (0.83 L), followed by stirring at room temperature for 12 hours. After the reaction was completed, the resulting reaction solution was concentrated under vacuum, and ethyl acetate (5.0 L) and water (2.0 L) were added thereto, followed by stirring. The organic layer was separated, dried over sodium sulfate (1 kg), filtered and concentrated. The resulting residue was subjected to chromatography (eluent: n-hexane:ethyl acetate = 1:3) to give the target compound (205 g, Yield: 76 %).
Example 6: Preparation of Compound (1-I)
Figure PCTKR2010001529-appb-I000019
2,6-Di-tert-butyl-4-methyl phenol (560 g) was dissolved in toluene (6.5 L), followed by cooling to 0 ℃, and DIBAL (1.0 M toluene, 2.05 L) was added dropwise thereto for 1 hour. The resulting reaction solution was cooled to -70 ℃, and compound (6-II) (205 g) dissolved in toluene (1.6 L) was added dropwise thereto. The resulting reaction solution was stirred for about 2 hours, and its temperature was slowly raised to -40 to -20 ℃, followed by stirring for 4 hours. After the reaction was completed, an aqueous 2N hydrochloric acid solution (2.5 L) was added. The organic layer was separated, dried over sodium sulfate (1 kg), filtered and concentrated. The resulting residue was subjected to chromatography (eluent: n-hexane:ethyl acetate = 1:5) to give the target compound (155 g, Yield: 76%).
Example 7: Preparation of Bimatoprost
Figure PCTKR2010001529-appb-I000020
Compound (1-I) (155 g) was added to a 70% aqueous solution of ethylamine (3.0 L), followed by stirring at room temperature for 60 hours. After the reaction was completed, the resulting reaction solution was concentrated to be its half level under reduced pressure, neutralized with a 2M aqueous solution of sodium hydrogensulfate (3.0 L, pH = 4~5) and extracted with ethyl acetate (3.0 L). The organic layer was dried over sodium sulfate (1 kg), filtered and concentrated. The resulting residue was subjected to preparative HPLC (eluent: n-hexane:anhydrous ethanol = 90:10), concentrated, and crystallized with diethyl ether (1.5 L). The resulting solid was filtered and dried under vacuum to give highly pure bimatoprost (100 g, Purity: 99.5% or more, Yield: 62%).
Example 8: Preparation of Compound (6-III)
Figure PCTKR2010001529-appb-I000021
Pyridinium p-toluensulfonate (PPTS, 4.3 g) was added to compound (5-I) (217 g) dissolved in a mixture of acetone (1.2 L) and water (0.2 L), followed by stirring at room temperature for 12 hours. After the reaction was completed, the resulting reaction solution was concentrated under vacuum, and ethyl acetate (1.5 L) and water (1.0 L) were added thereto, followed by stirring. The organic layer was separated, dried over sodium sulfate (1 kg), filtered and concentrated. The resulting residue was subjected to chromatography (eluent: n-hexane:ethyl acetate = 1:3) to give the target compound (128 g, Yield: 90 %).
Example 9: Preparation of Latanoprost
Figure PCTKR2010001529-appb-I000022
2,6-Di-tert-butyl-4-methyl phenol (408 g) was dissolved in toluene (3.7 L), followed by cooling to 0 ℃, and DIBAL (1.0 M toluene, 1484 ml) was added dropwise thereto for 1 hour. The resulting reaction solution was stirred at the same temperature for 1 hour, cooled to -70 ℃, and compound (6-III) (128 g) dissolved in toluene (128 ml) was added dropwise thereto. The resulting reaction solution was stirred at the same temperature for about 2 hours, and its temperature was slowly raised to -40 to -20 ℃, followed by stirring for 4 hours. After the reaction was completed, an aqueous 2N hydrochloric acid solution (1.8 L) was added. The organic layer was separated, dried over sodium sulfate (1 kg), filtered and concentrated. The resulting residue was subjected to chromatography (eluent: n-hexane:ethyl acetate = 1:3) to give latanoprost (Purity: 96 % or more). The obtained compound was subjected to preparative HPLC (eluent: heptane:anhydrous ethanol = 94:6) to give highly pure latanoprost (96 g, Purity: 99.8% or more, Yield: 75%).

Claims (20)

  1. A process for preparing a prostaglandin F (PGF) derivative of the following formula (1), which comprises the steps of:
    (i) removing the hydroxy protecting group of a protected prostaglandin E (PGE) derivative of the following formula (5) to give a prostaglandin E (PGE) derivative of the following formula (6); and
    (ii) stereoselectively reducing the ketone group on the cyclopentanone ring of the compound of the following formula (6):
    Figure PCTKR2010001529-appb-I000023
    Figure PCTKR2010001529-appb-I000024
    Figure PCTKR2010001529-appb-I000025
    wherein,
    Figure PCTKR2010001529-appb-I000026
    is a single or double bond;
    X is O or NH;
    Y is α-OH or difluoro;
    Y' is α-OPG or difluoro;
    Z is CH2, O or S;
    R is H or C1-C5 alkyl;
    R' is C1-C5 alkyl, C3-C7 cycloalkyl or aryl; and
    PG is a hydroxy protecting group.
  2. The process according to claim 1, wherein
    Figure PCTKR2010001529-appb-I000027
    is a single or double bond;
    X is O or NH;
    Y is α-OH;
    Y' is α-OPG;
    Z is CH2 or O;
    R is C1-C5 alkyl;
    R' is phenyl optionally substituted by C1-C5 haloalkyl or halogen; and
    PG is a hydroxy protecting group.
  3. The process according to claim 1, wherein
    Figure PCTKR2010001529-appb-I000028
    is a single or double bond;
    X is O or NH;
    Y is α-OH;
    Y' is α-OPG;
    Z is CH2 or O;
    R is C1-C5 alkyl;
    R' is phenyl optionally substituted by CF3, Cl or F; and
    PG is a hydroxy protecting group.
  4. The process according to claim 1, wherein
    Figure PCTKR2010001529-appb-I000029
    is a single or double bond;
    X is O or NH;
    Y is α-OH;
    Y' is α-OPG;
    Z is CH2 or O;
    R is C1-C5 alkyl;
    R' is phenyl optionally substituted by CF3; and
    PG is a hydroxy protecting group.
  5. The process according to any one of claims 1 to 4, wherein the hydroxy protecting group is tetrahydropyranyl, trimethylsilyl, triethylsilyl or t-butyldimethylsilyl.
  6. The process according to claim 5, wherein the hydroxy protecting group is triethylsilyl.
  7. The process according to any one of claims 1 to 4, wherein the hydroxy protecting group of the protected PGE derivative of formula (5) is removed under an acidic condition in step (i).
  8. The process according to claim 7, wherein the acidic condition is provided by the use of pyridinium p-toluensulfonate (PPTS).
  9. The process according to any one of claims 1 to 4, wherein the protected PGE derivative of formula (5) in which
    Figure PCTKR2010001529-appb-I000030
    is a double bond is prepared by converting an alkenyl tin compound of the following formula (3) to its cuprate, and subjecting the cuprate to conjugate addition to a cyclopentenone compound of the following formula (4):
    Figure PCTKR2010001529-appb-I000031
    Figure PCTKR2010001529-appb-I000032
  10. The process according to claim 9, wherein the alkenyl tin compound of formula (3) is added to a solution of Me2Cu(CN)Li2 and converted to a higher order mixed cuprate of the following formula (7):
    Figure PCTKR2010001529-appb-I000033
  11. The process according to any one of claims 1 to 4, wherein the reduction in step (ii) is carried out by using a reducing agent selected from the group consisting of sodium borohydride (NaBH4), L-selectride, N-selectride, K-selectride, LS-selectride, and 2,6-di-tert-butyl-4-methyl phenol and diisobutyl aluminium hydride (DIBAL).
  12. The process according to claim 11, wherein the reducing agent is 2,6-di-tert-butyl-4-methyl phenol and diisobutyl aluminium hydride (DIBAL).
  13. The process according to any one of claims 1 to 4, wherein the prostaglandin F (PGF) derivative of formula (1) in which X is NH is prepared by reacting the PGF derivative of formula (1) in which X is O and R is methyl, with RNH2.
  14. The process according to any one of claims 1 to 4, which further comprises the step of purifying the prostaglandin F (PGF) derivative of formula (1) by HPLC using a mixture of hydrocarbon and alcohol or a mixture of dichloromethane and alcohol.
  15. The process according to claim 14, wherein the mixture of hydrocarbon and alcohol is a mixture of n-hexane and anhydrous ethanol or a mixture of n-heptane and anhydrous ethanol.
  16. The process according to claim 14, wherein the mixture of dichloromethane and alcohol is a mixture of dichloromethane and isopropanol.
  17. Travoprost having a purity of 99.5% or more.
  18. Bimatoprost having a purity of 99.5% or more.
  19. A compound of the following formula (8):
    Figure PCTKR2010001529-appb-I000034
  20. A compound of the following formula (9):
    Figure PCTKR2010001529-appb-I000035
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CN103588692A (en) * 2012-08-15 2014-02-19 台湾永光化学工业股份有限公司 Method for purifying fluorine-containing prostaglandin using preparative high performance liquid chromatography
CN104297352A (en) * 2013-07-16 2015-01-21 天津金耀集团有限公司 Method of analyzing travoprost content and related compounds
CN110172033A (en) * 2013-08-15 2019-08-27 佳和桂科技股份有限公司 It is used to prepare the method and intermediate of the prostaglandin of isomer-free
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US9994543B2 (en) 2013-08-15 2018-06-12 Chirogate International Inc. Processes and intermediates for the preparations of isomer free prostaglandins
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US10100028B2 (en) 2013-09-30 2018-10-16 Patheon Api Services Inc. Synthesis routes for prostaglandins and prostaglandin intermediates using metathesis
WO2015136317A1 (en) 2014-03-13 2015-09-17 CHINOIN Gyógyszer és Vegyészeti Termékek Gyára Zrt. New process for the preparation of high purity prostaglandins
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US9670234B2 (en) 2014-07-10 2017-06-06 Scinopharm Taiwan, Ltd. Metal-catalyzed asymmetric 1,4-conjugate addition of vinylboron compounds to 2-substituted-4-oxy-cyclopent-2-en-1-ones yielding prostaglandins and prostaglandin analogs
US20160009740A1 (en) * 2014-07-10 2016-01-14 Scinopharm Taiwan, Ltd. Metal-catalyzed asymmetric 1,4-conjugate addition of vinylboron compounds to 2-substituted-4-oxy-cyclopent-2-en-1-ones yielding prostaglandins and prostaglandin analogs
AU2015287220B2 (en) * 2014-07-10 2019-08-01 Scinopharm Taiwan, Ltd. Metal-catalyzed asymmetric 1,4-conjugate addition of vinylboron compounds to 2-substituted-4-oxy-cyclopent-2-en-1-ones yielding prostaglandins and prostaglandin analogs
WO2016005943A1 (en) * 2014-07-10 2016-01-14 Scinopharm Taiwan, Ltd. Metal-catalyzed asymmetric 1,4-conjugate addition of vinylboron compounds to 2-substituted-4-oxy- cyclopent-2-en-l-ones yielding prostaglandins and prostaglandin analogs
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