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Carboprost 15-site isomer separation method

A technology of carboprost and isomers, which is applied in the field of impurity separation of carboprost 15-tertiary alcohol R isomers, can solve the problems of complex molecules, difficulties and uncertainties in industrialized large-scale production, etc.

Pending Publication Date: 2021-04-13
CHEMVON BIOTECH CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0012] Among them, the selectivity of the hemiacetal hydroxyl group and the 15th tertiary hydroxyl group needs to be verified. At the same time, there is a bibenzoyl group in the molecule, and a chiral camphorsulfonyl group is introduced at the same time, which makes the whole molecule more complicated, resulting in a three-step yield of only 17 %, which brings difficulties and uncertainties to subsequent industrialized mass production

Method used

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  • Carboprost 15-site isomer separation method
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  • Carboprost 15-site isomer separation method

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0035] Embodiment 1 carries out example with protecting agent R=TBS

[0036] Step 1: Synthesize 60 g of compound A as a white solid according to the record in paragraph 0166-0178 of patent CN108602769A, with a yield of 95%.

[0037]Step 2: In a 2L three-necked flask, add compound A (55.0g, 145mmol), then add 800mL of toluene, under the protection of nitrogen, cool to below -50°C, start adding 3M MeMgCl tetrahydrofuran solution (120mL) dropwise, and detect the raw materials by TLC Disappeared completely, stopped responding. The temperature of the reaction solution was raised to 0° C., and 500 mL of a saturated ammonium chloride aqueous solution was slowly added dropwise thereto, and then a 3M aqueous hydrochloric acid solution was added dropwise until the pH=3-4. The organic layer was separated, and the aqueous layer was extracted with 200 mL of ethyl acetate. The organic phases were combined, washed successively with saturated aqueous sodium bicarbonate solution and saturated...

Embodiment 2

[0042] Embodiment 2 carries out example with protecting agent R=TES

[0043] Step 1: Synthesize 6.0 g of Compound A as a white solid according to the record in paragraph 0166-0178 of patent CN108602769A, with a yield of 95%.

[0044] Step 2: In a 2L three-necked flask, add compound A (5.5g, 14.5mmol), then add 80mL of toluene, under the protection of nitrogen, cool to below -50°C, start to drop 3M MeMgCl tetrahydrofuran solution (12mL), TLC detection The starting material disappeared completely and the reaction was stopped. The temperature of the reaction solution was raised to 0° C., and 50 mL of a saturated ammonium chloride aqueous solution was slowly added dropwise thereto, and then a 3M aqueous hydrochloric acid solution was added dropwise until the pH=3-4. The organic layer was separated, the aqueous layer was extracted with 20 mL of ethyl acetate, the organic phases were combined, washed successively with saturated aqueous sodium bicarbonate solution and saturated brin...

Embodiment 3

[0049] Embodiment 3 carries out example with protecting agent R=Bz

[0050] Step 1: Synthesize 30 g of compound A as an oily liquid according to the record in paragraph 0166-0178 of patent CN108602769A, with a yield of 80%.

[0051] Step 2: In a 1L three-neck flask, add compound A (25.0g), then add 400mL of toluene, under the protection of nitrogen, cool to below -50°C, start adding 3M MeMgCl tetrahydrofuran solution (60mL) dropwise, TLC detects that the raw material completely disappears , stop responding. The temperature of the reaction solution was raised to 0° C., and 250 mL of a saturated ammonium chloride aqueous solution was slowly added dropwise thereto, and then a 3M aqueous hydrochloric acid solution was added dropwise until the pH=3-4. The organic layer was separated, and the aqueous layer was extracted with 100 mL of ethyl acetate. The organic phases were combined, washed successively with saturated aqueous sodium bicarbonate solution and saturated brine, and drie...

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Abstract

The invention discloses a carboprost 15-site isomer impurity separation technical method, and belongs to the technical field of pharmaceutical chemical separation. The method comprises the steps: carrying out PG protection on the compound B with the 15-site hydroxyl tertiary alcohol to obtain 15-site S-type carboprost D and 15-site R-type carboprost E (forming the 15-site hydroxyl tertiary alcohol compound C), and separating to obtain a pure product of the 15-site carboprost D or the 15-site carboprost E. On the basis, the invention also provides a method for preparing the carboprost series products, wherein the method is suitable for industrial amplification. According to the method, after proper protecting group derivation, the isomer can be separated by adopting common silica gel column chromatography, the operation is simple, the quality of the obtained product meets the requirement, the production cost is greatly reduced, and the comprehensive benefit of the product is improved.

Description

technical field [0001] The invention relates to the technical field of medicinal chemical separation, in particular to a new method for the separation of impurities in the R isomer of the 15-position carprostaglandin tertiary alcohol. Background technique [0002] Prostaglandins (PGs for short) are a class of important endogenous products with a wide range of physiological activities. PGs exist in the tissues of almost all mammals, play an important role in the reproductive system, digestive system, respiratory system and cardiovascular system, and participate in physiology and pathology such as temperature regulation, inflammatory response, glaucoma, pregnancy, hypertension, ulcer and asthma process. [0003] The structural characteristics of PGs are: a five-membered alicyclic ring and two side chains, the upper side chain usually has 7 carbons, and the lower side chain has 8 carbons to form 20-carbon unsaturated fatty acids and their analogs. PGs were first discovered an...

Claims

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Application Information

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IPC IPC(8): C07C405/00C07D307/935C07C215/10C07C213/08
CPCC07C405/00C07D307/935C07C215/10C07C213/08C07B2200/07C07C2601/08Y02P20/55
Inventor 王方道王东王猛吴伟锋
Owner CHEMVON BIOTECH CO LTD
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