A new process for the preparation of 17-phenyl-18, 19, 20-trinor-PGF2A and its derivatives

A technology of prostaglandins and derivatives, applied in organic chemistry methods, active ingredients of anhydrides/acids/halides, organic chemistry, etc., can solve problems such as no recovery of by-products

Inactive Publication Date: 2006-05-17
FINETECH LAB
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Problems solved by technology

[0009] However, this approach is problematic because (a) the by-product [6a] is not recovered; (b) it is difficult to obtain the desired compound [5] (C 1 =C 2 and R 2 = H) Separation of by-products [6a] and (c) At such low temperatures, it is difficult to scale up [5] (C 1 =C 2 and R 2 = H) highly exothermic reduction reaction

Method used

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  • A new process for the preparation of 17-phenyl-18, 19, 20-trinor-PGF2A and its derivatives
  • A new process for the preparation of 17-phenyl-18, 19, 20-trinor-PGF2A and its derivatives
  • A new process for the preparation of 17-phenyl-18, 19, 20-trinor-PGF2A and its derivatives

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Experimental program
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Effect test

Embodiment 1

[0066] (3aR, 4R, 5R, 6aS)-hexahydro-4-(3-oxo-5-phenyl-1E-pentenyl)-5-(p-phenylbenzoyloxy)-2H-cyclopentyl [b]furan-2-one[4a]

[0067]

[0068] Wherein PPB is p-phenylbenzoyloxy.

[0069] Flowchart 6

[0070] 1) Preparation of dimethyl (2-oxo-4-phenylbutyl) phosphonate

[0071] 1.1) 1-Bromo-4-phenyl-2-butanone

[0072] A freshly prepared solution of bromine (258.9 g) in methanol (600 mL) was added dropwise to continuously stirred benzyl acetone in methanol (600 mL) at 7 to 10 °C during 1 h 20 min (222.3g) in solution. To maintain the necessary temperature (7 to 10 °C) because of the highly exothermic reaction, the flask should be immersed in an ice-water bath. After the bromine red color disappeared, water (1500 mL) was added to the mixture, and the resulting mixture was stirred overnight. The resulting organic layer (at the top) was separated and the aqueous phase was extracted with dichloromethane (2 x 600 mL). The combined organic layers ...

Embodiment 2

[0082] (3aR, 4R, 5R, 6aS)-hexahydro-5-(p-phenylbenzoyloxy)-4-[(3S)-5-phenyl-3-[(tetrahydro-2H-pyran- 2-yl) oxygen] -1E-pentenyl] -2H-cyclopentene [b] furan-2-one [5] (C 1 =C 2 , R 1 = PPB and R 2 =THP)

[0083]

[0084] Flowchart 7

[0085] 1) (3aR, 4R, 5R, 6aS)-hexahydro-4-[(3S) and (3R)-3-hydroxy-5-phenyl-1E-pentenyl]-5-(p-phenylbenzyl Acyloxy)-2H-cyclopenta[b]furan-2-one[5a](R 1 =PPB) and [6a](R 1 =PPB)

[0086] Prepared by dissolving (-)-B-chlorobis(dimethylmethyleneoxybicyclooctyl)camphenylborane (26.0g) in THF (150mL) at -23 to -25°C The solution of was added dropwise to a stirred solution of compound [4a] (26.0 g) dissolved in THF (250 mL). The resulting mixture was stirred at this temperature for 8 hours (TLC monitoring), then the reaction was quenched by adding 30 mL of methanol at -23 to -25 °C. The temperature of the resulting solution was raised to room temperature, and stirred at this temperature for 14 hours. The mixtur...

Embodiment 3

[0100] (3aR, 4R, 5R, 6aS)-hexahydro-5-(p-phenylbenzoyloxy)-4-[(3R)-5-phenyl-3-[(tetrahydro-2H-pyran- 2-yl) oxygen] pentyl] -2H-cyclopenta[b] furan-2-one [5] (C 1 -C 2 , R 1 = PPB and R 2 =THP)

[0101]

[0102] Wherein PPB is p-phenylbenzoyl and THP is tetrahydro-2H-pyran-2-yl.

[0103] Flowchart 8

[0104] Compound [5] (C 1 =C 2 , R 1 = PPB and R 2 = A mixture of THP) (80.0 g), palladium on carbon catalyst (16 g) and ethyl acetate (1.0 L) for 3 hours. The reaction mixture was then filtered and evaporated under reduced pressure. The resulting oily residue was crystallized from a 4:1 (volume ratio) mixture of hexane and ethyl acetate to give 71.4 g (89% yield) of compound [5] (C 1 -C 2 , R 1 = PPB and R 2 =THP), its melting point is 103~105℃, [α] D 20 is -107° (c 1.0, MeCN). 1 HNMR (CDCl 3 )δ: 8.03(d, J=8Hz, 2H); 7.60-7.67(m, 4H); 7.36-7.48(m, 3H); 7.14-7.24(m, 5H); 5.20-5.30(m, 1H); 5.00-5.15 (m, 1H); 4.50-4.70 (m, 1H); 3.89-3.95 (...

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Abstract

The present invention provides a new and effective process for the synthesis of 17-phenyl-18,19,20-trinor-PGF2 alpha and its derivatives, including the anti-glaucoma drugs Bimatoprost and Latanoprost. The benefit of the present invention rises inter alia from the fact that a major intermediate involved in the synthesis of the above compounds may be isolated from a mixture containing also an undesired isomer, by crystallization. In addition, the undesired isomer may be oxidized to give the starting compound, which is then recycled.

Description

technical field [0001] The present invention relates to 17-phenyl-18,19,20-nortrimethyl-prostaglandin F 2α (trinor-PGF 2α ) and a new preparation method of derivatives thereof. Background technique [0002] 17-Phenyl-18,19,20-nortrimethyl-prostaglandin F represented by formula [1b] 2α and its derivatives are synthetic prostaglandin structural analogs and have ocular hypotensive activity (B.Resul et al., J.Med.Chem., 1993, 36, page 243, and U.S. Patent 5,688,819): [0003] [0004] in [0005] The bond between carbons 1 and 2 is a single bond (C 1 -C 2 ) or double bond (C 1 =C 2 ), R 6 selected from the group consisting of alkoxy and alkylamino. 17-Phenyl-18,19,20-destrimethyl-prostaglandin F 2α N-acetamide (Bimatoprost) (New Drug Application (NDA) 21-275 published by FDA) and 13,14-dihydro-17-phenyl-18,19,20-destrimethyl-prostate Prime F 2α Isopropyl ester (Latanoprost) (The Merck Index, 12th Edition, 5787) is thought to reduce intraocular pressure by increasi...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07C405/00A61K31/557C07D407/12C07B61/00
CPCC07C405/00
Inventor 阿里·L·古斯特曼真纳迪·尼斯涅维奇马里纳·埃庭戈伊戈尔·萨尔茨曼列弗·尤多维奇鲍里斯·佩尔提斯克弗
Owner FINETECH LAB
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