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Method for preparing bimatoprost midbody

A technology of mixture and tetrahydrofuran, which is applied in the field of preparation of bimatoprost intermediates, can solve the problems of difficult industrial scale-up production and harsh reaction conditions, and achieve the effects of easy post-processing, simple operation and mild conditions

Active Publication Date: 2013-04-03
ZHONGSHUAI PHARMA SCI & TECH CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The synthesis method involved in this document has harsh reaction conditions, and the reaction temperature requires -78°C, making it difficult to realize industrial scale-up production

Method used

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  • Method for preparing bimatoprost midbody
  • Method for preparing bimatoprost midbody

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0029] A method for preparing 2-oxo-4-phenylbutyl dimethyl phosphate, comprising the steps of:

[0030] The first step, prepare lithium diisopropylamide tetrahydrofuran solution

[0031] (1) Under stirring, add 14.6 g of diisopropylamine and 30 mL of anhydrous tetrahydrofuran into a 250 mL reactor and mix uniformly to prepare mixture a;

[0032] (2) Under stirring, gradually add (2.5 M, 98.87 mL) n-butyllithium n-hexane solution dropwise to mixture a in an ice-water bath. After the dropwise addition, control the temperature at 0°C and continue stirring, and stop the reaction after 30 min. Stirring makes diisopropylamide lithium tetrahydrofuran solution;

[0033] The second step, preparation of dimethyl 2-oxo-4-phenylbutyl phosphate

[0034] (1) Under stirring, add 0.112 mol of ethyl 3-phenylpropionate, 200 mL of anhydrous tetrahydrofuran, and 0.118 mol of dimethyl methyl phosphate into a 500 mL single-necked flask and mix uniformly to obtain mixture b;

[0035] (2) Un...

Embodiment 2

[0040] A method for preparing 2-oxo-4-phenylbutyl dimethyl phosphate, comprising the steps of:

[0041] The first step, prepare lithium diisopropylamide tetrahydrofuran solution

[0042] (1) Under stirring, add 292 g of diisopropylamine and 5 L of anhydrous tetrahydrofuran into a 10 L reactor and mix uniformly to prepare mixture a;

[0043] (2) Under stirring, gradually add (2.5 M, 2 L) n-butyllithium cyclohexane solution dropwise to mixture a in an ice-water bath. After the dropwise addition, control the temperature at 0°C and continue stirring for 100 min. Stop stirring to obtain diisopropylamide lithium tetrahydrofuran solution;

[0044] The second step, preparation of dimethyl 2-oxo-4-phenylbutyl phosphate

[0045] (1) Under stirring, add 2.24 mol of ethyl 3-phenylpropionate, 4L of anhydrous tetrahydrofuran, and 2.42 mol of dimethyl methyl phosphate into a 20L reactor and mix uniformly to prepare mixture b;

[0046] (2) Under stirring, gradually add the diisopropy...

Embodiment 3

[0051] A method for preparing 2-oxo-4-phenylbutyl dimethyl phosphate, comprising the steps of:

[0052] The first step, prepare lithium diisopropylamide tetrahydrofuran solution

[0053] (1) Under stirring, add 58.4 g of diisopropylamine and 120 mL of anhydrous tetrahydrofuran into a 500 mL reactor and mix uniformly to prepare mixture a;

[0054] (2) Under stirring, gradually add (2.5 M, 395.5 mL) n-butyllithium n-hexane solution dropwise to mixture a under an ice-water bath. After the dropwise addition, control the temperature at 0°C and continue stirring for 60 min. Stop stirring to obtain diisopropylamide lithium tetrahydrofuran solution;

[0055] The second step, preparation of dimethyl 2-oxo-4-phenylbutyl phosphate

[0056] (1) Under stirring, add 0.448 mol of ethyl 3-phenylpropionate, 800 mL of anhydrous tetrahydrofuran, and 0.472 mol of dimethyl methyl phosphate into a 3L single-necked flask and mix uniformly to obtain mixture b;

[0057] (2) Under stirring, gr...

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Abstract

The invention belongs to the field of pharmaceutical synthesis, and in particular relates to a method for preparing a bimatoprost midbody 2-oxo-4-dimethyl benzyl butyl phosphonate. The method comprises the following steps of: putting dimethyl methylphosphonate and 3-ethyl phenylpropiolate into anhydrous tetrahydrofuran / lithium diisopropylamide to react for 0.5-4 hours at the constant temperature ranging from-15 to 0 DEG C and; performing lamella chromatography detection on spots without raw materials; dipping 5mol / L hydrochloric acid until a pH value of the system equals to 3.0-4.0; raising the temperature to be room temperature; condensing and removing tetrahydrofuran; adding the water to dilute; extracting by ethyl acetate; washing an organic phase twice by using 5mol / L hydrochloric acid; washing the organic phase twice by the water; washing the organic phase twice by saturated saline solution; drying the organic phase by anhydrous sodium sulfate; and pumping the organic phase to reach constant weight by a vacuum oil pump after pressure reduction condensation to obtain a product. The method is simple in production process, mild in conditions and easy to industrially produce.

Description

technical field [0001] The invention belongs to the field of drug synthesis, and in particular relates to a preparation method of a bimatoprost intermediate. Background technique [0002] Glaucoma is a type of eye disease in which high intraocular pressure (IOP) causes damage to the optic nerve. The main goal of treatment is to prevent vision loss from damage to the optic nerve caused by high intraocular pressure (IOP). Current glaucoma treatment aims to reduce IOP. Bimatoprost eye drops (0.03% bimatoorost, LumiganTM, Allergan company) is the local ophthalmic preparation approved by U.S. FDA in 2001, containing bimatoprost 0.3 mg / mL, benzalkonium chloride 0.05mg / mL, pH value 6.8~7.8, belonging to synthetic prostamide F 2α derivative. Its IOP-lowering effect is strong and long-acting, and it is mainly used clinically for the treatment of slow open-angle glaucoma (POAG) and ocular hypertension (OHT). The chemical name of bimatoprost is (Z)-7-[(1R,2R,3R,5S)-3,5-dihydroxy-2-[...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07F9/40
Inventor 王军刘杰孟松峰
Owner ZHONGSHUAI PHARMA SCI & TECH CO LTD
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