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A kind of preparation method of bimatoprost key intermediate

A technology for bimatoprost and intermediates, which is applied in the field of preparation of key intermediates of bimatoprost, and can solve problems such as tediousness, reduced yield, and increased cost

Active Publication Date: 2020-08-18
CHANGZHOU BOHIV PHARM TECH CO LTD
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  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0006] The synthesis of bimatoprost is obtained through the preparation of key intermediate (II), and the method of asymmetric reduction in the past is usually (—)-diisopine pinocampyl chloride borane ((-)-DIP-chloride) or R-CBS Reduction, the chiral purity of the obtained intermediate (II) is generally II-3S:II-3R=95:5 or 93:7, the bimatoprost synthesized through the intermediate, the R-isomer in the final product If it is too large, in order to meet the purity requirements of the drug, it must be removed by cumbersome derivative crystallization methods or preparative chromatography methods, resulting in a decrease in yield and a substantial increase in cost

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  • A kind of preparation method of bimatoprost key intermediate
  • A kind of preparation method of bimatoprost key intermediate
  • A kind of preparation method of bimatoprost key intermediate

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[0053] The preparation method of bimatoprost key intermediate II

[0054] The invention provides a preparation method capable of obtaining bimatoprost key intermediate II (II-3S) with high chiral purity.

[0055] Specifically, the present invention provides a method for preparing bimatoprost key intermediate II, comprising the steps of:

[0056]

[0057] In an inert solvent (such as tetrahydrofuran THF), in the presence of (S)-BINAL-H, the intermediate I is reduced to obtain intermediate II (containing 3S (as shown in formula II-3S) and 3R (as shown in formula II-3S) and 3R (as shown in formula II-3R) two isomers), and S-type isomer II-3S:R-type isomer II-3R>99.5:0.5 (molar ratio).

[0058] Preferably, in the formula, (S)-BINAL-H is a compound shown in formula III

[0059]

[0060] Among them, R is CH 3 or C 2 h 5 .

[0061] Preferably, the preparation method comprises the steps of:

[0062] Step 1: Preparation of (S)-BINAL-H:

[0063] Under the protection of argon...

Embodiment 1

[0074] Step 1: Under the protection of argon, add tetrahydrofuran solution (375.0ml, 0.3mol, concentration 0.8mol / L) of lithium aluminum tetrahydride into the reaction flask, add methanol (9.6g, 0.3mol) in tetrahydrofuran dropwise at 20-30°C (96.0ml) solution, continue to dropwise add S-binaphthol (85.9g, 0.3mol) in tetrahydrofuran (490.0ml) solution, after addition, stir at 20-30°C for 30-60 minutes to obtain (S)-BINAL- H.

[0075] Step 2: Under the protection of argon, cool the (S)-BINAL-H solution in step 1 to -105--95°C, add intermediate I (30.0g, 0.1mol) in tetrahydrofuran (300.0ml) and stir for 30 Minutes later, raise the temperature to -80--70°C and stir until the reduction reaction is complete. Post-treatment, add 50.0ml of methanol, slowly rise to room temperature, filter, add water to the filtrate, stir and separate with ethyl acetate, and wash the water layer with ethyl acetate The ester was back-extracted, the organic layers were combined, washed with saturated br...

Embodiment 2

[0078] Step 1: Under the protection of argon, add tetrahydrofuran solution (375.0ml, 0.3mol, concentration 0.8mol / L) of lithium aluminum tetrahydride into the reaction flask, and add ethanol (13.8g, 0.3mol) in tetrahydrofuran dropwise at 20-30°C (96.0ml) solution, continue to dropwise add S-binaphthol (85.9g, 0.3mol) in tetrahydrofuran (490.0ml) solution, after addition, stir at 20-30°C for 30-60 minutes to obtain (S)-BINAL- H.

[0079] Step 2: Under the protection of argon, cool the (S)-BINAL-H solution in step 1 to -105--95°C, add intermediate I (30.0g, 0.1mol) in tetrahydrofuran (300.0ml) and stir for 30 Minutes later, raise the temperature to -80--70°C and stir until the reduction reaction is complete. Post-treatment, add 50.0ml of methanol, slowly rise to room temperature, filter, add water to the filtrate, stir and separate with ethyl acetate, and wash the water layer with ethyl acetate The ester was back-extracted, the organic layers were combined, washed with saturate...

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Abstract

The invention relates to a preparation method of a key intermediate II of bimatoprost, and particularly provides a method which comprises the following steps of synthesizing (S)-BINAL-H firstly and then enabling an intermediate I to be reduced to the key intermediate of the bimatoprost under the existence of (S)-BINAL-H. The method can be used for obtaining the intermediate II with high chiral purity. The intermediate can be used for synthesizing the bimatoprost with the high chiral purity.

Description

technical field [0001] The invention belongs to the field of pharmacy, in particular to a preparation method of a bimatoprost key intermediate Background technique [0002] The chemical name of bimatoprost is: (Z)-7-[(1R,2R,3R,5S)-3,5-dihydroxy-2-[(E,3S)-3-hydroxy-5- phenylpent-1-enyl]cyclopentyl]-N-ethylhept-5-enamide. English chemical name: (Z)-7-[(1R,2R,3R,5S)-3,5- [0003] The structural formula of Dihydroxy-2-[(E,3S)-3-hydroxy-5-phenylpent-1-enyl]cyclopentyl]-N-ethylhep t-5-enamide is as follows: [0004] [0005] Bimatoprost is a PGF2α analogue. Bimatoprost reduces IOP by increasing aqueous humor outflow from trabecular meshwork channels and uveoscleral channels, and reducing superficial scleral venous pressure. Studies by Brukaker and others have shown that dropping 0.03% bimatoprost to normal volunteers can reduce intraocular pressure by 20%, the tension resistance of aqueous humor outflow by 26%, and the surface resistance of aqueous humor outflow by 31%. Bim...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D307/93
CPCC07B2200/07C07D307/93
Inventor 刘向群李强陈宣福
Owner CHANGZHOU BOHIV PHARM TECH CO LTD
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