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Preparation method of imidazole medical intermediate KK-42

A technology of KK-42 and intermediates, which is applied in the field of preparation of imidazole pharmaceutical intermediates KK-42, can solve the problems of unsuitability for industrial production and high toxicity, and achieve low cost, high reaction yield and high product purity Effect

Inactive Publication Date: 2019-03-08
重庆科脉生物化工有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0007] From the perspective of the synthetic route, special reagents are needed in the synthetic process, the toxicity is high, and the product needs to be separated by column chromatography, which is not suitable for industrial production

Method used

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  • Preparation method of imidazole medical intermediate KK-42
  • Preparation method of imidazole medical intermediate KK-42
  • Preparation method of imidazole medical intermediate KK-42

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0026] Add 6-methyl-5-heptene-2-bromo (190g, 1mol) and 180mL triethyl phosphite into the autoclave, slowly raise the temperature to 120°C for reaction, and monitor the reaction by TLC, the reaction system does not need to be purified Proceed directly to the next reaction.

[0027] Add 500mL of anhydrous tetrahydrofuran to the above reaction system, lower the reaction system to -5°C, add sodium hydride (80wt%, 2mol) and DBU 15.2g, keep the low temperature, slowly add 1-benzyl-1H-imidazole-5 - Formaldehyde 186g (1mol), stirring reaction TLC monitors after the reaction finishes, adds methylene chloride to the reaction system, and slowly adds ice water, after layering, the organic phase is washed with water three times and dried, spin-dried, and use 600mL volume ratio as The 1:10 mixed solution of ethyl acetate and petroleum ether was recrystallized to obtain the target product KK-42 with a yield of 95.2% and a purity of 99.3%.

Embodiment 2

[0029] Add 6-methyl-5-heptene-2-bromide (190g, 1mol) and 180mL triethyl phosphite into the autoclave, and slowly raise the temperature to 150°C for reaction. After the reaction is monitored by TLC, the reaction system does not need to be purified Proceed directly to the next reaction.

[0030] Add 500mL of anhydrous tetrahydrofuran to the above reaction system, lower the reaction system to -5°C, add sodium hydride (80wt%, 2mol) and DBU 15.2g, keep the low temperature, slowly add 1-benzyl-1H-imidazole-5 - Formaldehyde 186g (1mol), stirring reaction TLC monitors after the reaction finishes, adds methylene chloride to the reaction system, and slowly adds ice water, after layering, the organic phase is washed with water three times and dried, spin-dried, and use 600mL volume ratio as The 1:10 mixed solution of ethyl acetate and petroleum ether was recrystallized to obtain the target product KK-42 with a yield of 94.2% and a purity of 99.0%.

Embodiment 3

[0032] Add 6-methyl-5-heptene-2-bromo (190g, 1mol) and 430mL triethyl phosphite into the autoclave, slowly raise the temperature to 150°C for reaction, monitor the reaction by TLC, and distill it off under reduced pressure The unreacted triethyl phosphite and the residue were directly subjected to the next reaction without purification.

[0033] Add 500 mL of anhydrous tetrahydrofuran to the above distillation residue, lower the reaction system to 40 °C, add potassium tert-butoxide (2 mol) and 30.4 g of DBU, keep the temperature, and slowly add 1-benzyl-1H-imidazole-5- Formaldehyde 186g (1mol), stirring reaction TLC monitoring after the reaction is over, add water to the reaction system, after layering, the organic phase is washed with water three times and then dried, spin-dried, with 400mL of ethyl acetate and sherwood oil with a volume ratio of 1:10 The mixed solution was recrystallized to obtain the target product KK-42 with a yield of 97.2% and a purity of 98.5%.

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Abstract

The invention discloses a preparation method of an imidazole medical intermediate KK-42. The method comprises the following steps: utilizing a compound 6-methyl-5-heptylene-2-bromine as an initial material, enabling the 6-methyl-5-heptylene-2-bromine and triethyl phosphite to react to produce an intermediate, directly reacting with 1-benzyl-1H-imidazole-5-formaldehyde without separation, and producing the target product KK-42 at high selectivity under catalysis of DBU (Diazabicyclo). The preparation method disclosed by the invention has the advantages of being high in yield, low in cost, economic, environmental-friendly, applicable to industrialization, high in product purity and the like, and is a synthetic method with high industrial production value.

Description

technical field [0001] The invention belongs to the technical field of synthesis of pharmaceutical intermediates, in particular to a preparation method of imidazole pharmaceutical intermediate KK-42. Background technique [0002] KK-42 (structural formula I), the Chinese chemical name is 1-benzyl-5-[(E)-2,6-dimethyl-1,5-heptadiene], the English name is 1-benzyl-5- [(E)-2,6-dimethyl-1,5-heptadienyl]imidazole is an imidazole substance that can promote the growth of insects. [0003] [0004] Studies have shown that KK-42 can not only significantly promote the growth of shrimp, but also improve the survival rate of juvenile shrimp. Because KK-42 can significantly down-regulate the key enzymes in the synthesis pathway of methyl farnesoate (MF)-farnesic acid O-methyltransferase (FAMeT), 3-hydroxy-3-methyl-glutaryl reductase The expression of A(HMGR) reduces the titer of hemolymph MF. At present, only one document (Agricultural and Biological Chemistry (1985), 49(2), 483-486...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D233/58
CPCC07D233/58
Inventor 崔振伟张玮玮张甫青
Owner 重庆科脉生物化工有限公司
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