CN103570549B - A kind of method of synthesizing tafluprost - Google Patents

A kind of method of synthesizing tafluprost Download PDF

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CN103570549B
CN103570549B CN201310472596.0A CN201310472596A CN103570549B CN 103570549 B CN103570549 B CN 103570549B CN 201310472596 A CN201310472596 A CN 201310472596A CN 103570549 B CN103570549 B CN 103570549B
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solvent
formula
compound
acid
virahol
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CN103570549A (en
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杨波
李延华
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Chak Enyuan (tianjin) Pharmaceutical Co Ltd
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Chak Enyuan (tianjin) Pharmaceutical Co Ltd
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    • 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
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    • Y02P20/00—Technologies relating to chemical industry
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    • Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

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Abstract

The present invention relates to a kind of method of synthesizing tafluprost, and the midbody compound related in method.With Corey? through DIBAL reduction after Lactone suitably protects, Wittig reacts, carboxy protective, and Swern oxidation obtains a versatile intermediates 1, as raw material, is obtained by reacting tafluprost through several step, and respectively walks the midbody compound be obtained by reacting.

Description

A kind of method of synthesizing tafluprost
Technical field
The present invention relates to a kind of novel method of tafluprost, and the midbody compound related in novel method.
Background technology
The tafluprost that Merk company releases is a kind of Novel prostate element derivative, first not containing the prostaglandin analogue eye drop of sanitas, be used for the treatment of open angle glaucoma, main mechanism promotes that aqueous humor is discharged through uveal scleral approach, thus reduce intraocular pressure.
The synthesis of tafluprost generally adopts CoreyLactone to be raw material, through oxidation, connects ω chain; fluoridize, DIBAL reduces, and Wittig reacts; esterification and accordingly protection and deprotection steps obtain the finished product, as TetrahedronLetters45 (2004) 1527-1529
Summary of the invention
Consider that the difference of most of PGF and PGE series derivates is ω chain; so reference CollCzechChemComm (1997) 62(8 of the present invention) 1325; reduce through DIBAL after suitably protecting with CoreyLactone; Wittig reacts; carboxy protective; Swern oxidation obtains a versatile intermediates 1, as raw material, is obtained by reacting tafluprost through several step.
Particularly, comprise the steps:
(A) by Horner-Wadsworth-Emmons reaction forming side chain, alkali used can select butyllithium, t-BuOK, LiOH.H 2o, Et 3n/LiCl etc., solvent can select methylene dichloride, toluene, tetrahydrofuran (THF) etc.;
(B) slough THP protecting group under acidic conditions, acid can select hydrochloric acid, acetic acid, tosic acid, trifluoroacetic acid etc., and solvent can select methyl alcohol, ethanol, Virahol, tetrahydrofuran (THF) etc.;
(C) acetylization reaction, reagent can select diacetyl oxide, Acetyl Chloride 98Min. etc., and solvent can use methylene dichloride, ethylene dichloride, chloroform, toluene, acetonitrile etc.;
(D) fluoridation, the optional Deoxofluor of fluorination reagent, sulfur trifluoride, sulfur trifluoride morpholine etc., solvent can select methylene dichloride, chloroform, toluene etc.;
(E) ethanoyl hydrolysis reaction, solvent uses Virahol, the sodium isopropylate that alkali uses sodium Metal 99.5 and Virahol scene to generate.
Embodiment
Embodiment 1.
(Z)-7-((1R, 2R, 3R, 5S)-5-acetoxyl group-2-((E)-3-oxo-4-benzene oxygen but-1-ene-1-base)-3-((tetrahydrochysene-2H-pyrans-2-base) 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 temperature 1 hour. add 5 grams of (Z)-7-((1R, 2R, 3R, 5S)-5-acetoxyl group-2-formyl radical-3-((tetrahydrochysene-2H-pyrans-2-base) oxygen base) cyclopentyl) solution that heptan ,-5-isopropyl gadoleate 1 mixed with 60 milliliters of methylene dichloride, continue stirring at room temperature 15 hours, TLC detects without raw material, reaction solution salt is washed 2 times, anhydrous sodium sulfate drying, concentrated, the weak yellow liquid 5.6g. productive rate 85.4%. obtaining 2 is directly used in subsequent reactions. and get sample and cross purified on silica gel, ethyl acetate/normal hexane (1:2) wash-out, obtain the yellow liquid of 2. 1h-NMR (CDCl 3, 300MHz) and 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-base) cyclopentyl)-5-isopropyl gadoleate in heptan 3.
The product that upper step obtains 25.6 grams 100 milliliters of THF dissolve, and add 8 ml waters, 0.8 gram of tosic acid, 40 degree of stirrings 3 hours, and TLC remains without raw material, is poured onto 100 milliliters of saturated NaHCO 3in the aqueous solution, under stirring, add solid NaHCO 3powder generates to bubble-free, and pressure reducing and steaming major part THF, uses 100mlX3 dichloromethane extraction, merge organic phase, concentrated, crosses silica gel, with ethyl acetate/normal hexane (1:2) wash-out, obtains the weak yellow liquid 4.2 grams of 3. productive rate 88.3%. 1h-NMR (CDCl 3, 300MHz) and 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-base) cyclopentyl) heptan-5-isopropyl gadoleate 4.
4.2 grams 3 with 35 milliliters of pyridinium dissolution; add 0.1 gram of DMAP, nitrogen protection borehole cooling to 0 is spent, and adds 4.3 ml acetic anhydride; stirring at room temperature 1.5 hours; TLC detects without raw material, is poured onto in 100 milliliters of frozen water, extracts by 50mlX4 ethyl acetate; merge organic phase; wash with water, 0.5N dilute hydrochloric acid is washed, NaHCO 3the aqueous solution is washed, and salt is washed, concentrated, crosses silica gel, with ethyl acetate/normal hexane (1:2) wash-out, obtains the weak yellow liquid 3.5 grams of 4. productive rate 76.5%. 1h-NMR (CDCl 3, 300MHz) and 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)-3,3-bis-fluoro-4-benzene oxygen but-1-ene-1-base) cyclopentyl) heptan-5-isopropyl gadoleate 5
Dissolve with 30 milliliters of methylene dichloride for 2.6 gram 4, add 5.3 milliliters of two (2-methoxyethyl) amino sulfur trifluorides (Deoxofluro), stirring at room temperature 72 hours, is poured onto 100 milliliters of saturated NaHCO 3in the aqueous solution, phase-splitting after stirring, aqueous phase 50 milliliters of dichloromethane extraction, after merging organic phase, concentrated, cross silica gel, with ethyl acetate/normal hexane (1:3) wash-out, obtain the yellow liquid 2.1 grams of 5. productive rate 77.4%. 1h-NMR (CDCl 3, 300MHz) and 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)-3,3-bis-fluoro-4-benzene oxygen but-1-ene-1-base) cyclopentyl)-5-isopropyl gadoleate 6 in heptan (tafluprost)
2.1 grams 5 dissolve with 10 milliliters of Virahols, add the sodium isopropylate solution be made into by 5 milliliters of Virahols and 0.3 gram of sodium Metal 99.5,50 degree of stirrings 4 hours, TLC remains without raw material. reaction solution is poured onto in the aqueous citric acid solution of 30 milliliter 3%, pressure reducing and steaming major part Virahol, extract by 20mlX3 ethyl acetate, merge organic phase, use NaHCO 3solution is washed, and column chromatography after concentrated, obtains 1.5 grams of tafluprosts 6 with ethyl acetate/normal hexane (1:1) wash-out, productive rate 84.7%. 1h-NMR (CDCl 3, 300MHz) and 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 prepares the method for tafluprost 6
。
2. preparation method according to claim 1, is characterized in that comprising the steps:
(A) by Horner-Wadsworth-Emmons reaction forming side chain, alkali used is selected from butyllithium, t-BuOK, LiOH.H 2o, Et 3n/LiCl, solvent is selected from methylene dichloride, toluene, tetrahydrofuran (THF);
(B) slough THP protecting group under acidic conditions, acid is selected from hydrochloric acid, acetic acid, tosic acid, trifluoroacetic acid, solvent selected from methanol, ethanol, Virahol, tetrahydrofuran (THF);
(C) acetylization reaction, reagent is selected from diacetyl oxide, Acetyl Chloride 98Min., and solvent is selected from methylene dichloride, ethylene dichloride, chloroform, toluene, acetonitrile;
(D) fluoridation, fluorination reagent is selected from Deoxofluor, sulfur trifluoride, sulfur trifluoride morpholine, and solvent is selected from methylene dichloride, chloroform, toluene;
(E) ethanoyl hydrolysis reaction, solvent uses Virahol, the sodium isopropylate that alkali uses sodium Metal 99.5 and Virahol scene to generate.
3. formula 2 compound:
4. formula 3 compound
5. formula 4 compound
6. formula 5 compound
CN201310472596.0A 2013-10-11 2013-10-11 A kind of method of synthesizing tafluprost Active CN103570549B (en)

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Publication number Priority date Publication date Assignee Title
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
CN104513186B (en) * 2015-01-13 2016-10-05 宁波第二激素厂 A kind of preparation method of optically pure dextrorotation 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

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1187486A (en) * 1996-12-26 1998-07-15 旭硝子株式会社 Difluoroprostaglundin 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

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1187486A (en) * 1996-12-26 1998-07-15 旭硝子株式会社 Difluoroprostaglundin Derivatives and their use
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

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
Synthesis of the highly potent prostanoid FP receptor agonist, AFP-168: a novel 15-deoxy-15,15-difluoroprostaglandin F2α derivative;Yasushi Matsumura等;《Tetrahedron Letters》;20040209;第45卷(第7期);1527–1529 *

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