Mivacurium chloride intermediate and method for synthesizing Mivacurium Chloride using mivacurium chloride intermediate

A technology for Micuronium chloride and an intermediate is applied in the field of Micuronium chloride intermediate and synthesizing Micuronium chloride, which can solve the problems of easy moisture absorption and deterioration, complicated and complicated processing and purification, residual and the like, and achieves simple reaction and operation, The effect of green process and stable starting material

Inactive Publication Date: 2018-09-07
武汉嘉诺康医药技术有限公司
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AI Technical Summary

Problems solved by technology

[0007] Because the compound shown in the intermediate formula 6 is a quaternary ammonium salt, it is very easy to absorb moisture and deteriorate, it is very difficult to preserve and weigh in the industrial production process, and because it is a mixture (isomer 6A and 6B of the compound shown in the formula 6), conventional Purification methods such as recrystallization and column passing are not applicable, and can only be purified by solvent beating and extraction washing, which brings great trouble to the purification of the final product micuronium chloride in the next step
[0008] In the reaction of the compound shown in the second step formula 6 with E-oct-4-ene-1,8-dioic acid, in the prior art, E-oct-4-ene-1,8-dioic acid is converted into an acid chloride reaction, The use of thionyl chloride requires the reaction to be strictly anhydrous, with extremely high requirements for equipment and operation, and the post-reaction treatment and purification are also very cumbersome and complicated
[0011] However, genotoxic impurities 4-dimethylaminopyridine and N,N'-dicyclohexylcarbodiimide were introduced in the final synthesis of the final product
However, genotoxic impurities have extremely low limits in the quality analysis of raw materials, and this route brings great disadvantages to product post-processing. At the same time, the by-product N,N'-dicyclohexylcarbodiimide Hexylurea is extremely residue-prone and very difficult to remove
[0012] The applicant has found that the preparation method of mivacurium chloride is rarely reported at home and abroad. In view of the deficiencies in the prior art, the present invention aims to provide a new economical and practical preparation method suitable for industrial production

Method used

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  • Mivacurium chloride intermediate and method for synthesizing Mivacurium Chloride using mivacurium chloride intermediate
  • Mivacurium chloride intermediate and method for synthesizing Mivacurium Chloride using mivacurium chloride intermediate
  • Mivacurium chloride intermediate and method for synthesizing Mivacurium Chloride using mivacurium chloride intermediate

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preparation example Construction

[0048] The preparation method of 3-hydroxypropyl p-toluenesulfonate is as follows:

[0049]

[0050] Add 100mL triethylamine to 76g (1.0mol) 1,3-propanediol and 150mL dichloromethane, N 2 Cool to 0°C under protection, add 95 g (0.50 mol) of p-toluenesulfonyl chloride dropwise to the above solution, and stir overnight at room temperature. Wash with 150mL of water and 150mL of 1mol / L dilute hydrochloric acid. After completion, the organic phase was anhydrous Na 2 SO 4 After drying, the crude product was spin-dried to obtain the crude product, which was directly put into the reaction when used.

Embodiment 1

[0051] A kind of synthetic method of mivacurium chloride of embodiment 1, comprises the steps:

[0052] Step 1: Condensation Reaction

[0053] Add 5.0g of E-oct-4-ene-1,8-dioic acid into 25mL of thionyl chloride, heat and reflux for 3 hours, cool to room temperature after the reaction is completed, spin dry and dissolve with 50mL of dichloromethane, and then Slowly add dropwise at around ℃ into 60mL dichloromethane dissolved with 5.6g 3-chloropropanol, and react at 25℃ for 10 hours after the dropwise addition is completed. After the reaction was completed, 50mL of 1M sodium hydroxide was added to quench the reaction. After separation, the organic phase was dried with anhydrous sodium sulfate and spin-dried to obtain the compound E-oct-4-ene-1,8-dioic acid di- 3-chloropropyl ester 8.3g (yield 86%) light yellow oily liquid, purity 95.6%.

[0054] HNMR (CDCl 3 )δ5.41(2H,m),4.16(4H,m),3.56(4H,m),2.31(4H,m),2.25(4H,m),2.03(4H,m).

[0055] MS (ESI) m / z 326.2.3 (M+1).

[0056] S...

Embodiment 2

[0067] A kind of synthetic method of mivacurium chloride of embodiment 2, comprises the steps:

[0068] Step 1: Condensation Reaction

[0069] Add 5g of E-oct-4-ene-1,8-dioic acid into 25mL of thionyl chloride, heat to reflux for 3 hours, cool to room temperature after the reaction is completed, spin dry, dissolve with 50mL of dichloromethane, and then Slowly add it dropwise to 100mL tetrahydrofuran dissolved with 33.5g 3-iodopropanol, and react at 0°C for 24 hours after the dropwise addition is completed. HPLC detected that the reaction was complete, and 50 mL of 1M sodium hydroxide was added to quench the reaction. After liquid separation, the organic phase was dried over anhydrous sodium sulfate. Spin-dry to obtain 12.1 g (yield 81.6%) of compound E-oct-4-ene-1,8-dioic acid di-3-iodopropyl ester, a light yellow oily liquid with a purity of 95.3%.

[0070] HNMR (CDCl 3 )δ5.41(2H,m),4.11(4H,m),3.19(4H,m),2.34(4H,m),2.28(4H,m),2.10(4H,m)

[0071] MS (ESI) m / z 509.2 (M+1)....

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Abstract

The invention belongs to the technical field of synthesis of pharmaceutical compounds, and particularly discloses an improved Mivacurium Chloride intermediate suitable for industrial production and amethod for synthesizing Mivacurium Chloride using the mivacurium chloride intermediate. The method uses (E)-Oct-4-ene-1,8-dioicacid and (R)-(+)-5'-Methoxylaudanosine as starting materials to prepare the Mivacurium Chloride by a two-step reaction. The starting materials are cheap and easy to obtain, and a product with a purity of 98% or more can be obtained by simple post-treatment steps such as liquid separation extraction and concentration after a first step and simple extraction or beating in a second step. The process reaction and post-treatment operation are simple, and the obtained product has high quality and can meet use requirements without further purification. The process is simple and practical, and is very suitable for industrial production.

Description

technical field [0001] The invention belongs to the technical field of synthesis of pharmaceutical compounds. Specifically, the invention relates to a mivacuronium chloride intermediate suitable for industrial production and a method for synthesizing mivacurium chloride using the intermediate. Background technique [0002] Mivacurium chloride is a short-acting benzylisoquinoline non-depolarizing muscle relaxant developed by Abbott lab and first listed in the United States in 1992. It is mainly used as an auxiliary drug for general anesthesia clinically. Pine has fast onset of effect (2 minutes), short duration (15 minutes), and rapid onset with increasing dose, but the duration of action is not prolonged. The usual dose has no effect on the cardiovascular system, and the effect of promoting the release of histamine is small. , has no effect on intracranial pressure and intraocular pressure, and is used for tracheal intubation and maintenance of muscle relaxation. The drug ha...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07C309/66C07C309/73C07C303/28C07D217/20
CPCC07C303/28C07C309/66C07C309/73C07D217/20
Inventor 魏文国王亚军
Owner 武汉嘉诺康医药技术有限公司
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