CN103570549A - Novel method for synthesizing Tafluprost - Google Patents

Novel method for synthesizing Tafluprost Download PDF

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CN103570549A
CN103570549A CN201310472596.0A CN201310472596A CN103570549A CN 103570549 A CN103570549 A CN 103570549A CN 201310472596 A CN201310472596 A CN 201310472596A CN 103570549 A CN103570549 A CN 103570549A
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solvent
formula
compounds
acid
tafluprost
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CN103570549B (en
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杨波
李延华
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Chak Enyuan (tianjin) Medical Technology Co Ltd
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    • 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
    • C07C67/31—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group by introduction of functional groups containing oxygen only in singly bound form
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C67/00—Preparation of carboxylic acid esters
    • C07C67/08—Preparation of carboxylic acid esters by reacting carboxylic acids or symmetrical anhydrides with the hydroxy or O-metal group of organic compounds
    • 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
    • C07C67/307—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group by introduction of halogen; by substitution of halogen atoms by other halogen atoms
    • 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
    • C07C69/736—Ethers the hydroxy group of the ester being etherified with a hydroxy compound having the hydroxy group bound to a carbon atom of a 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
    • C07C69/738—Esters of keto-carboxylic acids or aldehydo-carboxylic acids
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D309/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings
    • C07D309/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having no double bonds between ring members or between ring members and non-ring members
    • C07D309/08—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D309/10—Oxygen atoms
    • C07D309/12—Oxygen atoms only hydrogen atoms and one oxygen atom directly attached to ring carbon atoms, e.g. tetrahydropyranyl 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

Abstract

The invention relates to a novel method for synthesizing Tafluprost and intermediate compounds involved in the same. The method comprises the following steps: properly protecting Corey Lactone, performing DIBAL reduction, performing Wittig reaction, performing carboxyl protection, and performing Swern oxidation to obtain a general intermediate compound 1; and by using the general intermediate compound 1 as a raw material, reacting through multiple steps to obtain the Tafluprost and intermediate compounds obtained in all the reaction steps.

Description

A kind of novel method of synthetic tafluprost
Technical field
The present invention relates to a kind of novel method of tafluprost, and the midbody compound relating in novel method.
Background technology
The tafluprost that Merk company releases is a kind of Novel prostate element derivative, it is the first prostaglandin analogue eye drop that does not contain sanitas, be used for the treatment of open angle glaucoma, main mechanism is to promote aqueous humor to discharge through uveal tract sclera approach, thereby reduces intraocular pressure.
The synthetic general employing Corey Lactone of tafluprost is raw material, through oxidation, connects ω chain; fluoridize DIBAL reduction, Wittig reaction; esterification and corresponding protection and deprotection steps obtain the finished product, as Tetrahedron Letters45 (2004) 1527-1529
Figure BDA0000394200520000011
Summary of the invention
The difference of considering most of PGF and PGE series derivates is ω chain; so reference Coll Czech Chem Comm of the present invention (1997) 62(8) 1325; with Corey Lactone, suitably protect and reduce by DIBAL; Wittig reaction; carboxy protective; Swern oxidation obtains a general intermediate 1, as raw material, through the reaction of number step, obtains tafluprost.
Figure BDA0000394200520000021
Particularly, comprise the steps:
(A) by Horner-Wadsworth-Emmons, reacted and connected side chain, alkali used can be selected butyllithium, t-BuOK, LiOH.H 2o, Et 3n/LiCl etc., solvent can be selected methylene dichloride, toluene, tetrahydrofuran (THF) etc.;
(B) under acidic conditions, slough THP protecting group, acid can be selected hydrochloric acid, acetic acid, and tosic acid, trifluoroacetic acid etc., solvent can be selected methyl alcohol, ethanol, Virahol, tetrahydrofuran (THF) etc.;
(C) acetylization reaction, reagent can be selected diacetyl oxide, Acetyl Chloride 98Min. etc., solvent can be used methylene dichloride, ethylene dichloride, chloroform, toluene, acetonitrile etc.;
(D) fluoridation, the optional Deoxofluor of fluorination reagent, sulfur trifluoride, sulfur trifluoride morpholine etc., solvent can be selected methylene dichloride, chloroform, toluene etc.;
(E) ethanoyl hydrolysis reaction, solvent is used Virahol, and alkali is used sodium Metal 99.5 and the on-the-spot sodium isopropylate generating of Virahol.
Embodiment
Embodiment 1.
(Z)-7-((1R, 2R, 3R, 5S)-5-acetoxyl group-2-((E)-3-oxo-4-benzene oxygen but-1-ene-1-yl)-3-((tetrahydrochysene-2H-pyrans-2-yl) oxygen base) pentamethylene base) heptan-5-isopropyl gadoleate 2.
3.6 grams of 2-oxo-3-benzene oxygen propyl phosphonic acid methyl esters 7 are dissolved in 30 milliliters of methylene dichloride, add 0.58 gram of LiOH.H 2o; 0.05 gram of Tetrabutyl amonium bromide; stirring at room 1 hour. add 5 grams of (Z)-7-((1R; 2R; 3R; 5S)-5-acetoxyl group-2-formyl radical-3-((tetrahydrochysene-2H-pyrans-2-yl) oxygen base) cyclopentyl) solution that heptan-5-isopropyl gadoleate 1 mixes with 60 milliliters of methylene dichloride; continue stirring at room 15 hours; TLC detects without raw material, by salt washing 2 times for reaction solution, anhydrous sodium sulfate drying; concentrated; obtain 2 weak yellow liquid 5.6g. productive rate 85.4%. and be directly used in subsequent reactions. get sample and cross silica gel and purify, ethyl acetate/normal hexane (1:2) wash-out, obtains 2 yellow liquid. 1h-NMR (CDCl 3, 300MHz) δ (ppm): 1.23 (d, 6H), 1.45-2.05(m, 13H), 2.07 (s, 3H), 2.16 (m, 1H), 2.24 (t, 2H), 2.42-2.59 (m, 1H), 2.65-2.79 (m, 1H), 3.40 (m, 1H), 3.67-3.81 (m, 1H), 3.98-4.15 (m, 1H), 4.46-4.56(m, 1H), 4.71 (d, 2H), 5.00 (m, 1H), 5.09 (m, 1H), 5.30 (m, 2H), 6.57 (dd, 1H), 6.90-7.02 (m, 4H), 7.31 (m, 2H).
Embodiment 2
(Z)-7-((1R, 2R, 3R, 5S)-5-acetoxy-3-hydroxyl-2-((E)-3-oxo-4-benzene oxygen but-1-ene-1-yl) cyclopentyl) heptan-5-isopropyl gadoleate 3.
25.6 grams of products that upper step obtains dissolve with 100 milliliters of THF, add 8 ml waters, 0.8 gram of tosic acid, and 40 degree stir 3 hours, and TLC is residual without raw material, is poured onto 100 milliliters of saturated NaHCO 3in the aqueous solution, under stirring, add solid NaHCO 3powder is to without bubble formation, and the most of THF of pressure reducing and steaming, with 100ml X3 dichloromethane extraction, merges organic phase, concentrated, crosses silica gel, with ethyl acetate/normal hexane (1:2) wash-out, obtains 4.2 grams of 3 weak yellow liquids. productive rate 88.3%. 1h-NMR (CDCl 3, 300MHz) δ (ppm): 1.23 (d, 6H), 1.63-2.03 (m, 7H), 2.08 (s, 3H), 2.16 (m, 1H), 2.26 (t, 2H), 2.54 (m, 2H), 4.06(m, 1H), 4.73 (s, 2H), 5.02 (m, 1H), 5.16 (m, 1H), 5.31 (m, 2H), 6.60 (d, 1H), 6.89-6.96 (m, 3H), 7.01 (m, 1H), 7.32 (m, 2H).
Embodiment 3
(Z)-7-((1R, 2R, 3R, 5S)-3,5-di-acetyl oxygen base-2-((E)-3-oxo-4-benzene oxygen but-1-ene-1-yl) cyclopentyl) heptan-5-isopropyl gadoleate 4.
4.2 35 milliliters of pyridines of gram 3 use dissolve; add 0.1 gram of DMAP, nitrogen protection borehole cooling to 0 degree, adds 4.3 ml acetic anhydride; stirring at room 1.5 hours; TLC detects without raw material, is poured onto in 100 milliliters of frozen water, by 50ml X4 ethyl acetate, extracts; merge organic phase; wash with water, 0.5N dilute hydrochloric acid is washed, NaHCO 3the aqueous solution is washed, and salt washing is concentrated, crosses silica gel, with ethyl acetate/normal hexane (1:2) wash-out, obtains 3.5 grams of 4 weak yellow liquids. productive rate 76.5%. 1h-NMR (CDCl 3, 300MHz) δ (ppm): 1.23 (d, 6H), 1.63-1.86 (m, 4H), 1.98 (s, 3H), 1.99-2.08 (m, 3H), 2.09 (s, 3H), 2.16 (m, 1H), 2.24 (t, 2H), 2.57 (m, 1H), 2.75 (m, 1H), 4.73 (s, 2H), 5.01 (m, 1H), 5.13 (m, 1H), 5.34 (m, 2H), 6.51 (d, 1H), 6.89-7.12 (m, 4H), 7.32 (m, 2H).
Embodiment 4
(Z)-7-((1R, 2R, 3R, 5S)-3,5-di-acetyl oxygen base-2-((E)-3, the fluoro-4-benzene of 3-bis-oxygen but-1-ene-1-yl) cyclopentyl) heptan-5-isopropyl gadoleate 5
30 milliliters of methylene dichloride of 2.6 gram of 4 use dissolve, and add 5.3 milliliters of two (2-methoxyethyl) amino sulfur trifluorides (Deoxofluro), and stirring at room 72 hours, is poured onto 100 milliliters of saturated NaHCO 3in the aqueous solution, phase-splitting after stirring, 50 milliliters of dichloromethane extraction water for, merge after organic phase, concentrated, cross silica gel, use ethyl acetate/normal hexane (1:3) wash-out, obtain 2.1 grams of 5 yellow liquids. productive rate 77.4%. 1h-NMR (CDCl 3, 300MHz) δ (ppm): 1.23 (d, 6H), 1.69-1.82 (m, 5H), 1.96-2.06 (m.2H), 1.99 (s, 3H), 2.08 (s, 3H), 2.12-2.22 (m, 1H), 2.24 (t, 2H), 2.58 (m, 1H), 2.69 (m, 1H), 4.20 (t, 2H), 4.98 (m, 1H), 5.02 (m, 1H), 5.13 (t, 1H), 5.34 (m, 2H), 5.84 (dt, 1H), 6.13 (m, 1H), 6.92 (d, 2H), 7.03 (t, 1H), 7.32 (t, 2H).
Embodiment 5
(Z)-7-((1R, 2R, 3R, 5S)-3,5-dihydroxyl-2-((E)-3, the fluoro-4-benzene of 3-bis-oxygen but-1-ene-1-yl) cyclopentyl) heptan-5-isopropyl gadoleate 6 (tafluprost)
2.1 10 milliliters of Virahols of gram 5 use dissolve, add by 5 milliliters of Virahols and 0.3 gram of sodium isopropylate solution that sodium Metal 99.5 is made into, 50 degree stir 4 hours, TLC is residual without raw material. reaction solution is poured onto in the aqueous citric acid solution of 30 milliliter 3%, the most of Virahol of pressure reducing and steaming, by 20ml X3 ethyl acetate, extract, merge organic phase, use NaHCO 3solution is washed, and concentrated rear column chromatography, obtains 1.5 grams of tafluprosts 6, productive rate 84.7%. with ethyl acetate/normal hexane (1:1) wash-out 1h-NMR (CDCl 3, 300MHz) δ (ppm): 1.23 (d, 6H), 1.57-1.70 (m, 3H), 1.84 (d, 1H), 2.04-2.15 (m.4H), 2.25 (t, 2H), 2.28-2.36 (m, 1H), 2.42-2.49 (m, 1H), 4.01 (m, 1H), 4.20 (m, 3H), 4.99 (m, 1H), 5.38 (m, 2H), 5.79 (dt, 1H), 6.10 (m, 1H), 6.92 (d, 2H), 7.01 (t, 1H), 7.30 (t, 2H).

Claims (6)

1. as following formula, prepare the method for tafluprost 6
Figure FDA0000394200510000011
2. preparation method according to claim 1, is characterized in that comprising the steps:
(A) by Horner-Wadsworth-Emmons, reacted and connected side chain, alkali used can be selected butyllithium, t-BuOK, LiOH.H 2o, Et 3n/LiCl, solvent can be selected methylene dichloride, toluene, tetrahydrofuran (THF);
(B) under acidic conditions, slough THP protecting group, acid can be selected hydrochloric acid, acetic acid, and tosic acid, trifluoroacetic acid, solvent can be selected methyl alcohol, ethanol, Virahol, tetrahydrofuran (THF);
(C) acetylization reaction, reagent can be selected diacetyl oxide, Acetyl Chloride 98Min., solvent can be used methylene dichloride, ethylene dichloride, chloroform, toluene, acetonitrile;
(D) fluoridation, the optional Deoxofluor of fluorination reagent, sulfur trifluoride, sulfur trifluoride morpholine, solvent can be selected methylene dichloride, chloroform, toluene;
(E) ethanoyl hydrolysis reaction, solvent is used Virahol, and alkali is used sodium Metal 99.5 and the on-the-spot sodium isopropylate generating of Virahol.
3. formula 2 compounds:
Figure FDA0000394200510000012
4. formula 3 compounds
Figure FDA0000394200510000021
5. formula 4 compounds
Figure FDA0000394200510000022
6. formula 5 compounds
Figure FDA0000394200510000023
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Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN103804195A (en) * 2014-01-26 2014-05-21 天泽恩源（天津）医药技术有限公司 Novel method of synthesizing tafluprost
CN103819436A (en) * 2014-02-21 2014-05-28 天泽恩源（天津）医药技术有限公司 Crystal form of (3aR,4R,5R,6aS)-4-((E)-3,3-difluoro-4-phenoxylbutyl-1-alkyl-1-yl)-2-oxohexahydro-2H-cyclopentane[b]furan-5-benzoate, and preparation method of corresponding crystals thereof
CN104513186A (en) * 2015-01-13 2015-04-15 宁波第二激素厂 Preparation method of optically pure dextro cloprostenol sodium
CN113816856A (en) * 2021-10-19 2021-12-21 上海京河医药科技有限公司 Method for synthesizing tafluprost

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CN1774417A (en) * 2001-05-31 2006-05-17 梵泰克实验室有限公司 A new process for the preparation of 17-phenyl-18, 19, 20-trinor-PGF2A and its derivatives

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US5985920A (en) * 1996-12-26 1999-11-16 Asahi Glass Company Ltd. Difluoroprostaglandin derivatives and their use
CN1774417A (en) * 2001-05-31 2006-05-17 梵泰克实验室有限公司 A new process for the preparation of 17-phenyl-18, 19, 20-trinor-PGF2A and its derivatives

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Title
YASUSHI MATSUMURA等: "Synthesis of the highly potent prostanoid FP receptor agonist, AFP-168: a novel 15-deoxy-15,15-difluoroprostaglandin F2α derivative", 《TETRAHEDRON LETTERS》, vol. 45, no. 7, 9 February 2004 (2004-02-09), pages 1527 - 1529 *

Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN103804195A (en) * 2014-01-26 2014-05-21 天泽恩源（天津）医药技术有限公司 Novel method of synthesizing tafluprost
CN103804195B (en) * 2014-01-26 2016-06-15 天泽恩源（天津）制药有限公司 A kind of method synthesizing tafluprost
CN103819436A (en) * 2014-02-21 2014-05-28 天泽恩源（天津）医药技术有限公司 Crystal form of (3aR,4R,5R,6aS)-4-((E)-3,3-difluoro-4-phenoxylbutyl-1-alkyl-1-yl)-2-oxohexahydro-2H-cyclopentane[b]furan-5-benzoate, and preparation method of corresponding crystals thereof
CN104513186A (en) * 2015-01-13 2015-04-15 宁波第二激素厂 Preparation method of optically pure dextro cloprostenol sodium
CN113816856A (en) * 2021-10-19 2021-12-21 上海京河医药科技有限公司 Method for synthesizing tafluprost

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