A kind of preparation method of carboprost

A technology of carboprost and esterification, which is applied in the field of preparation of carboprost, can solve the problems of complex post-processing and low combined yield, and achieve the effects of simple post-processing, low production cost, and reduced separation difficulty

Active Publication Date: 2022-05-27
HEBEI CHEM & PHARMA COLLEGE
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  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0006] The present invention aims at the problem of low combined yield in the existing method for preparing carboprost and the problem of complicated post-treatment, and proposes a new preparation method, by combining the crude carboprost with N-hydroxysuccinimide The method of crystallization and hydrolysis realizes the preparation of carboprost with high yield and high purity, which has the advantages of easy operation and environmental friendliness

Method used

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  • A kind of preparation method of carboprost
  • A kind of preparation method of carboprost
  • A kind of preparation method of carboprost

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0028] 1) Crude Carboprost is combined with NHS:

[0029]

[0030] Add 150 mL of acetonitrile to a four-necked flask, add 10.00 g of crude carboprost (the carboprost content was 52.71% detected by HPLC) into 150 mL of acetonitrile, and then add 4.39 g of N,N'-carbonyldiimidazole, N 2 After replacement, stand at room temperature for 2h.

[0031] 4.68g of N-hydroxysuccinimide was added dropwise to a four-necked flask, kept at room temperature for 2h after the drop was completed, HPLC tracking showed that the reaction of the raw materials was complete and the reaction solution was concentrated under reduced pressure to obtain 16.99g of pale yellow amorphous; 1 H NMR (500 MHz, Chloroform-d): δ5.71(t,1H), 5.69(m,1H), 5.46-5.44(m,2H), 3.29(t,1H), 3.21(m,1H), 2.76-2.73(m, 4H), 2.26-2.23(m, 3H), 2.15-2.11(t, 3H), 1.98-1.96(t, 2H), 1.92-1.90(t, 2H), 1.81(t, 2H) ), 1.65(d, 1H), 1.60(m, 2H), 1.44-1.41(m, 5H), 1.33-1.29(m, 6H), 0.96(t, 3H).

[0032] 2) Preparation of carboprost este...

Embodiment 2

[0039] 1) Crude Carboprost is combined with NHS:

[0040]

[0041] Add 150mL DMF to a four-necked flask, add 10.00g crude carboprost (the carboprost content was 51.54% detected by HPLC) into 150mL DMF, and then add 4.39g N,N'-carbonyldiimidazole, N 2 After replacement, stand at room temperature for 2h.

[0042] 4.68g of N-hydroxysuccinimide was added dropwise to a four-necked flask, and kept at room temperature for 2h after dropping. HPLC tracking showed that the reaction of the raw materials was completed, and the reaction solution was concentrated under reduced pressure to obtain 16.78g of pale yellow amorphous.

[0043] 2) Preparation of carboprost ester compound:

[0044]

[0045] Into the four-necked flask, add all the light yellow amorphous obtained in the previous step, then add 100 mL of methyl tert-butyl ether and 10 mL of cyclohexane, heat up to 40°C while stirring, keep warm for 2 hours, then drop to room temperature, and let stand for 2 hours , a light yell...

Embodiment 3

[0050] 1) Crude Carboprost is combined with NHS:

[0051]

[0052] In a four-necked flask, add 150 mL of tetrahydrofuran, add 10.00 g of crude carboprost (the carboprost content was 53.55% detected by HPLC) into 150 mL of tetrahydrofuran, and then add 4.39 g of N,N'-carbonyldiimidazole, N 2After replacement, stand at room temperature for 2h.

[0053] 4.68g of N-hydroxysuccinimide was added dropwise to a four-necked flask, and kept at room temperature for 2h after dropping. HPLC tracking showed that the reaction of the raw materials was complete, and the reaction solution was concentrated under reduced pressure to obtain 17.02g of pale yellow amorphous.

[0054] 2) Preparation of carboprost ester compound:

[0055]

[0056] Into the four-necked flask, add all the pale yellow amorphous obtained in the previous step, then add 100 mL of methyl tert-butyl ether and 10 mL of methyl cyclohexane, and heat up to 30°C while stirring, keep the temperature for 2 hours and then drop...

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Abstract

The invention relates to a preparation method of carboprost, specifically, after the crude carboprost is completely reacted with a hydroxyl-containing imine compound in a polar aprotic solvent, a crystallization solvent is added to stir and crystallize to obtain a carboprost ester, Hydrolysis to obtain carboprost. The technical scheme of the present invention realizes the preparation of carboprost with high yield and high purity by combining the crude carboprost with NHS and then crystallizing and hydrolyzing it, which has the advantages of easy operation and environmental friendliness, and avoids the existing preparation The problem of low yield in the method of carboprost.

Description

technical field [0001] The invention belongs to the technical field of organic synthesis, and in particular relates to a preparation method of carboprost. Background technique [0002] Carboprost is a prostaglandin compound, which is usually used in the form of carboprost tromethamine to promote regular uterine contractions. Its structural formula is as follows: [0003] [0004] Carboprost is usually prepared by organic synthesis. Due to its complicated process, the synthetic product contains impurities. There are usually two kinds of impurities, one is the chiral isomer on the 15th carbon, and the other is The trans isomer at the double bond position of the carboxy-substituted carbon chain. There are significant differences in the pharmacological effects, metabolic processes and toxicity of enantiomers of chiral drugs in the human body, and the above two impurities are different from carboprost in terms of efficacy and safety. Separation is usually carried out by colu...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07C405/00C07D207/46
CPCC07C405/00C07D207/46C07C2601/08C07B2200/07
Inventor 张静
Owner HEBEI CHEM & PHARMA COLLEGE
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