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Preparation method of carboprost

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

Active Publication Date: 2021-10-26
HEBEI CHEM & PHARMA COLLEGE
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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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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  • Preparation method of carboprost
  • Preparation method of carboprost
  • Preparation method of carboprost

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0028] 1) Crude carboprost combined with NHS:

[0029]

[0030] Add 150mL acetonitrile in the four-neck flask, add 10.00g of carboprost crude product (its carboprost content is 52.71% as detected by HPLC) in 150mL acetonitrile, then add 4.39g N, N'-carbonyldiimidazole, N 2 After replacement, let stand at room temperature for 2 hours.

[0031] Add 4.68g of N-hydroxysuccinimide dropwise into a four-necked flask, and keep it at room temperature for 2 hours after dropping. HPLC tracking shows that the reaction solution is concentrated under reduced pressure after the raw materials are completely reacted to obtain 16.99g of a light yellow amorphous substance; 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 ester:

[0033]

[003...

Embodiment 2

[0039] 1) Crude carboprost combined with NHS:

[0040]

[0041] Add 150mLDMF in the four-neck flask, add 10.00g of carboprost crude product (HPLC detects that its carboprost content is 51.54%) in 150mLDMF, then add 4.39g N,N'-carbonyldiimidazole, N 2 After replacement, let stand at room temperature for 2 hours.

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

[0043] 2) Preparation of carboprost ester:

[0044]

[0045] Add all the light yellow amorphous substance obtained in the previous step into the four-neck flask, then add 100mL methyl tert-butyl ether and 10mL cyclohexane, heat up to 40°C while stirring, keep warm for 2h, then cool down to room temperature, a...

Embodiment 3

[0050] 1) Crude carboprost combined with NHS:

[0051]

[0052] Add 150mL tetrahydrofuran in the four-necked flask, add 10.00g of carboprost crude product (its carboprost content is 53.55% as detected by HPLC) in 150mL tetrahydrofuran, then add 4.39g N,N'-carbonyldiimidazole, N 2After replacement, let stand at room temperature for 2 hours.

[0053] Add 4.68g of N-hydroxysuccinimide dropwise into a four-necked flask, and keep it at room temperature for 2 hours after dropping. HPLC tracking shows that the reaction solution is concentrated under reduced pressure to obtain 17.02g of a light yellow amorphous substance.

[0054] 2) Preparation of carboprost ester:

[0055]

[0056] Add all the light yellow amorphous substance obtained in the previous step into the four-neck flask, then add 100mL of methyl tert-butyl ether and 10mL of methylcyclohexane, heat up to 30°C while stirring, keep warm for 2h, then cool down to room temperature, and statically Set aside for 2h, a pal...

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Abstract

The invention relates to a preparation method of carboprost, the preparation method specifically comprises the following steps: after a carboprost crude product completely reacts with a hydroxyl-containing imine compound in a polar aprotic solvent, adding a crystallization solvent, stirring and crystallizing to obtain carboprost ester, and hydrolyzing to obtain carboprost. According to the technical scheme, the carboprost is prepared in a high-yield and high-purity mode through the method of combining the carboprost crude product with NHS and then conducting crystallization and hydrolysis, the method has the advantages of being easy and convenient to operate and environmentally friendly, and the problem that the yield is low in an existing carboprost preparation method is solved.

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, usually in the form of carboprost trometamol, which is used to promote the regular contraction of the uterus, and its structural formula is as follows: [0003] [0004] Carboprost is usually prepared by organic synthesis. Due to its complex process, the synthetic product contains impurities. There are usually two types 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 carboxyl-substituted carbon chain. There are significant differences in the pharmacological effects, metabolic processes and toxicity of the enantiomers of chiral drugs in the human body, and the above two impurities are different from carboprost in terms of curative effect and safety. Usually column chroma...

Claims

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Application Information

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