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An intermediate and key technology, applied in the field of pharmaceutical synthesis, can solve the problems of many reaction impurities, low synthesis process yield, high price, etc., and achieve the effects of optimizing the preparation process, shortening the process flow, and reducing the production cost.
Active Publication Date: 2018-05-22
凯方医药科技(上海)有限公司
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Problems solved by technology
[0006] In the above method, the raw material trifluorosulfonic anhydride used is highly corrosive, the amount of catalyst used is as high as 0.1 equivalent, the price is expensive, and the yield after the reaction is low, which is largely related to the instability of the intermediate and the biborate produced during coupling. , resulting in a lot of impurities in the reaction, the post-treatment needs to pass through a silica gel column to purify, and the content of heavy metals in the product is difficult to effectively control to the level required for pharmaceutical intermediates
Therefore, on the whole, the yield of the existing synthetic process is low, difficult to purify, and the economic benefit is not good
Method used
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Embodiment 1
[0033] The first step: the synthesis of methyl 4,4-dimethyl-2-cyclohexanone carboxylate
[0034] In a reaction flask, dissolve 100 g (0.79 mol) of 3,3-dimethylcyclohexanone in 500 mL of tetrahydrofuran, cool to -20°C to -30°C, and add dropwise 1mol / L LDA (lithium diisopropylamide ) tetrahydrofuran solution 870mL (0.87mol), warm up to 0°C, stir for 1 hour, cool down to -20°C, add 93g (1.03mol) of dimethyl carbonate dropwise, rise to 0°C, react for 2 hours, TLC monitors that the reaction is complete , add 1M dilute hydrochloric acid to adjust the pH to 6-7, separate the layers, extract the aqueous phase with ethyl acetate twice, combine the organic phases, dry over sodium sulfate, and concentrate under reduced pressure to obtain 4,4-dimethyl-2-cyclohexanone 134.3 g of methyl formate, yield 92%.
[0037] The second step: the synthesis of methyl 2-(4-chlorophenyl)-4...
example example 2
[0041] The first step: with reference to the operation of the first step in Example 1, change the reaction conditions to obtain the results in Table 1.
[0042] Table 1
[0043] experiment number
Alkali class
solvent
temperature reflex
yield
1
LDA
toluene
-20°C to 0°C
85％
2
LDA
Tetrahydrofuran
-70°C to -60°C
92％
3
HMDSL
Tetrahydrofuran
-30°C to -20°C
90％
4
t-BuOK
Tetrahydrofuran
-20°C to 0°C
0％
[0044] The second step: with reference to the second step operation of the embodiment, change the following conditions to obtain the results in Table 2
[0045] Table 2
[0046]
[0047]
[0048] Experiment number 7* is to replace p-toluenesulfonylhydrazide with 2,4,6-triisopropylbenzenesulfonylhydrazide.
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Abstract
The invention discloses a preparation method of a venetoclax key intermediate, belonging to the technical field of pharmaceutical synthesis. The method comprises the steps of enabling deprotonated 3,3'-dimethylcyclohexanone to react with dimethyl carbonate so as to obtain methyl 4,4-dimethyl-2-cyclohexanonecarboxylate; then, enabling the product to react with para chlorobromobenzene, inorganic base, aryl sulfonyl hydrazide and the like by using a one-pot method under the condition of palladium catalysis so as to obtain the product methyl 2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-ene-1-carboxylate. The preparation method provided by the invention is simple, convenient and stable in technological operation, high in yield and environmentally-friendly; compared with the existing process, themethod is low in price of raw materials and easy in obtaining of raw materials, greatly lowers the production cost of the existing venetoclax intermediate, and is beneficial to the industrial large-scale production.
Description
technical field [0001] The invention belongs to the technical field of drug synthesis, and in particular relates to a preparation method of a key intermediate of venetoclax. Background technique [0002] Venetoclax (ABT-199; Venetoclax) is a selective inhibitor of B-cell lymphoma factor 2 (BCL-2) indicated for the treatment of chronic lymphocytic leukemia with refractory or relapsed deletion Patients with 17p mutation gene. [0003] Methyl 2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-ene-1-carboxylate, English name: Methyl2-(4-chlorophenyl)-4,4-dimethylcyclohex-1- ene-1-carboxylate, molecular formula C16H19ClO2. As the key intermediate of venetoclax, however, there are not many public literature reports, and the existing synthetic route is as follows: [0004] The reaction of methyl 4,4-dimethyl-2-cyclohexanone with trifluoromethanesulfonic anhydride produces 2-(trifluoromethanesulfonyl)-4,4-dimethylcyclohex-1-ene-1- Carboxylate methyl ester, followed by Suzuki coupling of ...
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