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Process for the preparation of lubiprostone and intermediates thereof

A technology for lubiprostone and compounds, applied in the field of preparing lubiprostone, capable of solving problems such as difficulty in lubiprostone purification

Active Publication Date: 2020-01-21
CHIROGATE INT
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Since the polarity of these by-products is very close to that of the main product with a single bond, it is almost impossible to completely remove the hydrogenated by-products using silica gel chromatography, so this method faces extreme challenges in the purification of lubiprostone in industrial mass production. great difficulty

Method used

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  • Process for the preparation of lubiprostone and intermediates thereof
  • Process for the preparation of lubiprostone and intermediates thereof
  • Process for the preparation of lubiprostone and intermediates thereof

Examples

Experimental program
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preparation example Construction

[0027] Preparation of Lubiprostone

[0028] The present invention provides a method for preparing lubiprostone, such as the reaction shown in the following scheme C:

[0029] Process C

[0030]

[0031] As shown in step a of scheme C, by the photoactive cyclopentenone of formula 1 (wherein R 1 is C 1-7 Alkyl, aryl or aralkyl, each of which is unsubstituted or C 1-4 Alkyl, nitro, halogen or alkoxy substituted, and P 1 is a hydroxyl protecting group) and a compound derived from formula 2 (wherein X is Cl, Br or I, and P 2 Be the coupling reaction of the ω-side chain unit of the cuprate of hydroxy protecting group or P) to prepare formula 3 compounds (wherein R 1 is C 1-7 Alkyl, aryl or aralkyl, each of which is unsubstituted or C 1-4 Alkyl, nitro, halogen or alkoxy substituted, and P 1 and P 2 independently a hydroxyl protecting group); the coupling reaction is preferably carried out at a temperature in the range of about -100°C to about 40°C.

[0032] Suitable hydr...

example 1

[0050] 4,4-Difluoro-3-keto-octanoic acid ethyl ester

[0051]

[0052] The 20 liter four-necked flask was flame dried and cooled under nitrogen. Diisopropylamine (585 g, 5.78 mol) dissolved in 4.7 L of anhydrous tetrahydrofuran was added to the reaction flask, followed by the dropwise addition of n-butyllithium (3.6 L, 1.6 M in hexane solution) and stirred for 1 hour. Next, ethyl acetate (509 g, 5.78 mol) was slowly added to the lithium solution. After 30 minutes, ethyl 2,2-difluorohexanoate (520 g, 2.89 mol) was added to the reaction flask at -70°C. The reaction mixture was stirred for 30 minutes and checked for reactivity using thin layer chromatography (TLC). The mixture was quenched with 5 L of saturated aqueous ammonium chloride and stirred for 10 minutes. The mixture was phase separated and the aqueous layer was extracted with 1 L of toluene. The organic layer was dried over anhydrous magnesium sulfate and the solid was filtered. The solvent was evaporated under...

example 2

[0056] 4,4-Difluorooctane-1,3-diol

[0057]

[0058] Sodium borohydride (253 g, 6.69 mol) was added to dissolve the crude ester product of Example 1 (875 g) in 4.5 L of ethanol at ambient temperature. The reaction mixture was stirred for 2 hours and checked for reactivity using TLC. Next, the reaction mixture was adjusted to a neutral solution with 3N aqueous hydrochloric acid solution. The aqueous solution was concentrated and ethanol was removed. The aqueous solution was extracted twice with 2.5 L of ethyl acetate. The organic layer was concentrated under vacuum. The crude 1,3-diol product was purified by silica gel chromatography using a mixture of hexane and ethyl acetate as a gradient eluent. The yield of 1,3-diol compound was 306 g (58%, two steps).

[0059] 1 H-NMR (CDCl 3 ): δ3.760~3.893(m, 5H), 1.678~1.922(m, 4H), 1.291~1.505(brs, 4H), 0.897(t, 3H)

[0060] 13 C-NMR (CDCl 3 ): δ123.997(t), 71.396(t), 60.040, 32.040(t), 31.561, 23.379(t), 22.461, 13.777

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Abstract

The present invention relates to a novel process for preparing Lubiprostone and novel intermediates prepared from the process. The process of the present invention does not generate hydrogenated by-products that are difficult to be removed, and thus enables the production of Lubiprostone in an efficient and economical way.

Description

technical field [0001] The present invention relates to a novel process for the preparation of lubiprostone and novel intermediates thereof. Background technique [0002] Lubiprostone is a drug used in the treatment of conditions such as chronic idiopathic constipation, mainly irritable bowel syndrome-associated constipation in women, and opioid-induced constipation Active pharmaceutical ingredients in. In the prior art, such as EP0430551, US 7812182, US 7928252, US 8309744, US 9382272 and CN 103787942, the current method for synthesizing lubiprostone is to use Corey lactone (Corey lactone) or its derivatives as Starting materials, the α-side chain and ω-side chain of lubiprostone were respectively constructed by a two-step Wittig reaction as shown in Scheme A below. However, Corey's method requires at least 8 to 12 synthetic steps, so its yield is low. [0003] Process A [0004] [0005] As shown in Scheme B below, the methods disclosed in the prior art, such as US...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D311/94C07C67/343C07C69/716C07C31/38C07C29/62
CPCC07D311/94C07C69/716C07C31/38C07C405/00C07C2601/08C07F7/1804C07D307/20Y02P20/55C07C51/09C07C51/377C07C59/215C07C67/317C07C51/373C07F7/0812C07C31/40C07D307/06
Inventor 魏士益许敏冠
Owner CHIROGATE INT
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