Novel synthesis method of lobaplatin intermediate

An intermediate, a new synthesis technology, applied in organic chemistry methods, chemical instruments and methods, preparation of organic compounds, etc., can solve the problems of harsh reaction conditions, large environmental pollution, low yields, etc., to achieve mild reaction conditions, reduced Production cost and yield improvement effect

Active Publication Date: 2021-09-21
上海寻科生物医药科技有限公司
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  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0008] In the reaction process, flammable, explosive and highly toxic acrylonitrile is used, and it must be reacted at high temperature and high pressure, which causes considerable pollution to the environment. Moreover, the first product obtained is a mixed product of cis and trans, which needs to be rectified to obtain the obtained product. trans-1,2-dicyanocyclobutane
Because the reaction conditions are very harsh and the yield is extremely low, it is almost impossible to be used for industrial production and promotion

Method used

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  • Novel synthesis method of lobaplatin intermediate
  • Novel synthesis method of lobaplatin intermediate
  • Novel synthesis method of lobaplatin intermediate

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0038] The synthesis of 1,1,4-tricarboxylic acid methyl ester butane (II), the reaction formula is as follows:

[0039]

[0040] Concrete preparation process is as follows:

[0041] (1) Under nitrogen protection, put N,N'-dimethylformamide (500mL), dimethyl malonate (50.00g, 0.378mol) and anhydrous potassium carbonate (78.46g, 0.568mol) into the reaction flask and methyl 4-bromobutyrate (82.22 g, 0.454 mol). Stir the reaction at room temperature. After GC detection detects that the raw material dimethyl malonate disappears, add 2N hydrochloric acid solution, and then extract with ethyl acetate (250mL*3). The obtained organic phases are combined and washed with saturated brine. Dry over sodium sulfate, filter and concentrate to give the product 1,1,4-tricarboxylic acid methyl butane (II) (86.15 g, yield 98%) as a colorless transparent liquid.

[0042] (2) GC and nuclear magnetic analysis are carried out to product, wherein, GC analysis result is as shown in table 1, and nu...

Embodiment 2

[0046] The synthesis of 1,1,4-methyl tricarboxylate-4-bromobutane (III), the reaction formula is as follows:

[0047]

[0048] Concrete preparation process is as follows:

[0049](1) Add 1,1,4-tricarboxylic acid methyl butane (II) (80.00g, 0.344mol) and dichloromethane (800mL) into the reaction flask under nitrogen protection, and cool to -10°C-0 ℃, add dibromohydantoin (103.42g, 0.362mol) in dichloromethane (200mL) dropwise, after the dropwise addition, continue to control the temperature at 10-20℃ and stir the reaction, the raw material 1,1,4-tricarboxylate is detected by GC After methyl butane(II) / 1,1,4-tricarboxylic acid methyl-4-bromobutane(III)<5%, the reaction is over, add water to quench the reaction, separate the liquid, and use the water phase again Dichloromethane (200mL*2) was extracted, and the obtained organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated to obtain a light yellow transparent ...

Embodiment 3

[0054] The synthesis of 1,1,2-tricarboxylic acid methyl cyclobutane (IV), the reaction formula is as follows:

[0055]

[0056] Concrete preparation process is as follows:

[0057] (1) Methyl 1,1,4-tricarboxylate-4-bromobutane (III) (85.00g, 0.273mol), N,N'-dimethylformamide (850mL) and carbonic acid Potassium (75.52g, 0.546mol) was added to the reaction flask, and the reaction was stirred at 20°C-30°C. GC detected that the raw material 1,1,4-tricarboxylic acid methyl ester-4-bromobutane (III) disappeared, and the reaction was completed. Add water to quench the reaction, and then extract with dichloromethane. The obtained organic phase is successively washed with 2N hydrochloric acid solution, water and saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated to obtain the product brownish-yellow transparent liquid, the crude product 1,1,2-Tricarboxylate methyl cyclobutane, purified by distillation, collect the desired product fraction (collection te...

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Abstract

The invention relates to the technical field of medicine synthesis, in particular to a novel synthesis method of a lobaplatin intermediate, the method comprises the following steps: taking low-toxicity dimethyl malonate as an initial raw material, carrying out coupling, bromination, cyclization, hydrolysis, amidation and dehydration reaction to synthesize high-purity trans-1, 2-dicyanocyclobutane. In the whole route synthesis, all adopted raw and auxiliary materials are easy to purchase, low in price and low in toxicity, the reaction conditions are not harsh and uncontrollable, the reaction conditions of each step can be suitable for amplified production, although the reaction steps are increased, the yield of the product is greatly improved, so that the cost is greatly reduced, and the purity of the obtained trans-1,2-dicyanocyclobutane is improved and completely meets the subsequent use requirements, and the market competitiveness is greatly improved.

Description

technical field [0001] The invention relates to the technical field of drug synthesis, in particular to a novel synthesis method of a lobaplatin intermediate. Background technique [0002] Lobaplatin: LBP, D-19466, its chemical name is: trans-1,2-diaminomethyl-cyclobutane-lactate platinum (II), the structural formula is as follows: [0003] [0004] Lobaplatin is a third-generation platinum-based antineoplastic drug originally developed by ASTA Medica AG of Germany. Lobaplatin belongs to the antineoplastic drugs of the alkylating agent class, most of which are combined with chemotherapy, and are often used in chronic myeloid leukemia, advanced breast cancer, and small cell lung cancer. In September 2004, Hainan Changan International Pharmaceutical successfully transformed the intellectual property rights of lobaplatin in China, obtained the exclusive production and management patent, and obtained the national first-class new drug registration certificate (lobaplatin API ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07C253/22C07C255/46
CPCC07C253/22C07C51/09C07C67/30C07C67/307C07C67/343C07C2601/04C07B2200/07C07C255/46C07C61/04C07C69/74C07C69/63C07C69/34Y02P20/55
Inventor 张甲丁
Owner 上海寻科生物医药科技有限公司
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