Preparation method of omeprazole intermediate

An omeprazole and intermediate technology, applied in the direction of organic chemistry, etc., can solve the problem of high total molar yield, and achieve the effects of high molar yield, high conversion rate and mild reaction conditions

Active Publication Date: 2022-07-29
南京红太阳医药研究院有限公司 +2
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  • Description
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Problems solved by technology

[0013] The invention aims at the problems existing in the existing preparation method of 2-chloromethyl-4-methoxy-3,5-lutidine hydrochloride, and provides a kind of raw material which is cheap and easy to obtain, with low toxicity and less process waste. , the preparation method of 2-chloromethyl-4-methoxyl-3,5-lutidine hydrochloride suitable for industrialized production, the total molar yield of the method is high, 2-chloromethyl-4-methoxyl The purity of 3,5-lutidine hydrochloride is high

Method used

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  • Preparation method of omeprazole intermediate

Examples

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Effect test

Embodiment 1

[0048] Preparation of 4-nitro-3,5-dimethyl-1-pyridine nitrogen oxide (intermediate 1)

[0049] Add 246.3g (2mol) 3,5-lutidine nitrogen oxide, 300g concentrated sulfuric acid (concentration 98%) to the reaction flask, heat up to 90 ℃, start to drip 385.7g (concentration 98%, 6mol) nitric acid and The mixed acid of 360g concentrated sulfuric acid (concentration 98%, 3.6mol) was added dropwise within 3.5h. After the dropwise addition was completed, the reaction was incubated and controlled by HPLC. In ice water, introduce ammonia gas under stirring to adjust pH to 2-3; control system temperature at 0 °C, continue stirring, filter, and collect filter cake; filter cake is dried under reduced pressure at 45 °C (vacuum degree≤-0.08MPa) to constant 323.9 g of 4-nitro-3,5-dimethyl-1-pyridine nitroxide (Intermediate 1) was obtained as a pale yellow solid, molar yield 96.3%, HPLC: 99.4%.

[0050] Preparation of 4-methoxy-3,5-lutidine-1-nitrogen oxide (intermediate 2)

[0051] 32.0g (0....

Embodiment 2

[0060] Preparation of Intermediate 1

[0061] Add 246.3g (2mol) 3,5-lutidine nitrogen oxide, 300g concentrated sulfuric acid (concentration 98%) to the reaction flask, heat up to 80°C, start dropwise addition of 385.7g (concentration 98%, 6mol) nitric acid and The mixed acid of 420g concentrated sulfuric acid (concentration 98%, 4.2mol) was added dropwise within 4h. After the dropwise addition was completed, the reaction was kept warm and controlled by HPLC. After the reaction was completed for 5h, the reaction of the raw materials was complete; In the water, pour liquid ammonia under stirring to adjust the pH to 2-3; control the temperature of the system at 0 °C, continue stirring, filter, and collect the filter cake; the filter cake is dried under reduced pressure at 45 °C (vacuum degree≤-0.08MPa) to constant weight , to obtain 330.2 g of 4-nitro-3,5-dimethyl-1-pyridine nitrogen oxide (Intermediate 1), a pale yellow solid, molar yield 98.2%, HPLC: 99.5%.

[0062] Preparatio...

Embodiment 3

[0072] Preparation of Intermediate 1

[0073] 246.3g (2mol) of 3,5-lutidine nitrogen oxide, 300g of concentrated sulfuric acid (98% concentration) were added to the reaction flask, the temperature of the system was increased to 110°C, and 385.7g (98% concentration, 6mol) of nitric acid and The mixed acid of 600g concentrated sulfuric acid (concentration 98%, 6mol) was added dropwise within 4.5h, the reaction was kept warm, controlled by HPLC, and the reaction of the raw materials was complete after 5h of reaction; the reaction solution was cooled to room temperature, added dropwise to 1000g of ice water, and stirred Introduce liquid ammonia, adjust the pH to 3-4; control the temperature of the system at 0 °C, continue stirring, filter, collect the filter cake, and dry the filter cake under reduced pressure at 45 °C (vacuum degree≤-0.08MPa) to constant weight to obtain 4- Nitro-3,5-dimethyl-1-pyridine nitrogen oxide (Intermediate 1) 327.6 g, pale yellow solid, molar yield 97.4%...

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Abstract

The invention belongs to the field of pharmaceutical chemicals, and discloses a preparation method of an omeprazole intermediate 2-chloromethyl-4-methoxy-3, 5-dimethyl pyridine, which comprises the following steps: by taking 3, 5-dimethyl pyridine nitrogen oxide as a starting raw material, carrying out nitration reaction on the 3, 5-dimethyl pyridine nitrogen oxide and nitric acid in mixed acid of nitric acid and sulfuric acid to prepare 4-nitro-3, 5-dimethyl pyridine nitrogen oxide, and carrying out reaction on the 4-nitro-3, 5-dimethyl pyridine nitrogen oxide and the nitric acid to prepare the omeprazole intermediate 2-chloromethyl-4-methoxy-3, 5-dimethyl pyridine. The preparation method comprises the following steps: firstly, preparing 2-chloromethyl-4-methoxy-3, 5-dimethyl-1-pyridine nitrogen oxide, and then sequentially carrying out a methoxy substitution reaction, a vismeier reaction, a reduction reaction and a chlorination reaction to obtain the 2-chloromethyl-4-methoxy-3, 5-dimethylpyridine hydrochloride. The 3, 5-dimethyl pyridine nitrogen oxide is taken as the raw material, the conversion rate of the raw material in each step is high, the purity of the intermediate is high, the molar yield is high, the 3, 5-dimethyl pyridine nitrogen oxide can be directly used for the reaction in the next step without refining, the purity of the target product can reach 99.8% or above, the total molar yield can reach 85% or above, and the method is more suitable for industrial production.

Description

technical field [0001] The invention belongs to the field of medicine and chemical industry, and relates to a preparation method of an omeprazole or esomeprazole intermediate, in particular to an omeprazole or esomeprazole intermediate 2-chloromethyl- The preparation method of 4-methoxy-3,5-lutidine. Background technique [0002] The chemical name for omeprazole is 5-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridyl)methyl]sulfinyl]-1H-benzo Imidazole, the chemical structure is as follows: [0003] [0004] Omeprazole was first synthesized in 1979 by Sweden's Astra (now AstraZeneca), launched in 1987, and was approved by the U.S. Food and Drug Administration (FDA) for the first time in the United States in 1989. Omeprazole is a proton pump inhibitor that can effectively inhibit the secretion of gastric acid, and also has an inhibitory effect on the secretion of pepsin. Hemoglobin, arterial oxygen partial pressure, carbon dioxide partial pressure and arterial blood pH. Ome...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D213/68C07D213/89
CPCC07D213/68C07D213/89Y02P20/55
Inventor 李维思黄双许林菊高倩桂清
Owner 南京红太阳医药研究院有限公司
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