Chiral pyrrolidine compound and preparation method thereof

A technology of compound and pyrrolidine, which is applied in the field of chiral pyrrolidine compound and its preparation, can solve the problems affecting the manufacturing cost of doripenem chiral side chains, the difficulty of high-content side chain compounds, and the difficulty of industrialization, etc., to achieve Easy to purify, reduce dosage, good effect of purity

Active Publication Date: 2014-06-25
石家庄万尚医药科技有限公司 +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0032] The advantage of this method is that the conversion of hydroxyl group to sulfonamide is completed in one step, but the following by-products are introduced during the reaction, PPh 3 , POPh 3 , DIAD / DEAD and its reduction products. Different crystallization methods and product separation are mentioned in the literature of these by-products, but they are all difficult to remove. Because the by-products are less polar and the content is too high, it is difficult to obtain high content by recrystallization. High Yield of Side Chain Compounds
Finally, it affects the manufacturing cost of the chiral side chain of doripenem, making it difficult to achieve industrialization

Method used

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  • Chiral pyrrolidine compound and preparation method thereof
  • Chiral pyrrolidine compound and preparation method thereof
  • Chiral pyrrolidine compound and preparation method thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0069] Under nitrogen atmosphere, mix compound I (131.1g, 1mol) with methanol (655ml) to obtain a suspension, stir for 5 minutes and mix well, then cool to -10°C, control the temperature at -5~0°C and add thionyl chloride (119g) dropwise , 1mol), add it in 30 minutes. Stir at 15~20°C for 5 hours. After the reaction is detected by TLC, the temperature is reduced to -5°C, and the temperature is controlled below 10°C by adding sodium hydroxide to adjust the pH to 7, adding potassium carbonate (165.9g, 1.2mol), and continuing to control the temperature for 5~10 Add allyl chloroformate (120.5g, 1mol) dropwise at ℃ and stir for 2.5 hours at the same temperature. After the reaction is detected by TLC, remove potassium chloride and excess potassium carbonate by filtration, add water (700ml) and dichloromethane 390ml to the filtrate and stir well . The organic layer was separated, and the aqueous layer was extracted once with 200 ml of dichloromethane. The organic layer was washed with...

Embodiment 2

[0072] Under nitrogen atmosphere, mix compound I (131.1g, 1mol) with methanol (655ml) to obtain a suspension, stir for 5 minutes and mix well, control the temperature at 15~20℃ and add thionyl chloride (238g, 2mol) dropwise for 50 minutes Finish adding. Stir at 35~40°C for 2 hours. After the reaction is detected by TLC, the temperature is reduced to 0°C, and the temperature is controlled below 10°C by adding potassium hydroxide to adjust the pH to 8, adding triethylamine (151.8g, 1.5mol), and continuing to control the temperature for 20-25 Allyl chloroformate (156.7 g, 1.3 mol) was added dropwise at °C, and stirred at the same temperature for 0.5 hours. After the reaction was detected by TLC, 199.5 g of III was obtained as in Example 1, with a yield of 87.0%.

[0073] (B) Compound III → Compound IV

Embodiment 3

[0075] Under a nitrogen atmosphere, mix compound III (200g, 0.87mol) obtained in Example 1 with dichloromethane (1000ml), then add triethylamine (132g, 1.30mol), control the temperature at -20~-10℃, and add dropwise Methanesulfonyl chloride (148.4 g, 1.3 mol) was dripped and the mixture was stirred for 30 minutes. After the reaction was detected by TLC, the reaction mixture was continuously washed with 300 ml of 2N hydrochloric acid and saturated brine, dried over magnesium sulfate, and concentrated in vacuo to obtain an oily product, that is, compound IV was 255.1 g, and the yield was 95.4%.

[0076] 1 H NMR (500MHz, CDCl 3 )Δ: 5.64(m,1H), 5.34–5.20 (d, 2H), 4.89(m,1H), 4.21(m,1H), 3.88 (s,3 H), 3.85 (m,1 H), 3.82 -3.67 (m, 3 H), 3.12 (s, 3H), 2.10-2.09 (m, 2 H).

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Abstract

The invention relates to a chiral pyrrolidine compound and a preparation method thereof, in particular to a preparation method of a compound (IX). The chiral pyrrolidine compound is used as a Doripenem intermediate. According to the compound, sulfydryl is protected by adopting aroyl, amino is protected by using allyloxycarbonyl, bromide is prepared, a sulfamide group is used for substitution, the prepared compound is feasible in process route, and industrial production can be realized. The chiral pyrrolidine compound is high in quality, is a tabular crystal, and is easily purified; and the purity can be accurately measured by using HPLC (High Performance Liquid Chromatography), and the defects of content measured by using a titration or derivation method, and the like are avoided. When the Doripenem is synthesized by connecting with a Doripenem mother nucleus, the utilization rate of the mother nucleus is increased, the purification process of the Doripenem bulk pharmaceutical chemicals is simplified, the consumption of a hydrogenation catalyst is reduced, byproducts are prevented from being introduced due to deprotection of aluminum trichloride, protecting groups are finally transformed into gas which is completely removed, so that the Doripenem bulk pharmaceutical chemicals are high in yield and good in purity, and are reduced in manufacture cost. The compound is shown in the description, wherein Ar=Ph, PhCH2, 4-NO2Ph and 4CH3Ph.

Description

Technical field [0001] The invention relates to a chiral pyrrolidine compound and a preparation method thereof. The compound is used as a novel chiral side chain of donipenem. Background technique [0002] Doripenem (S-4661) is a new broad-spectrum antibiotic of carbapenem developed by Shionogo Company. It was first listed in Japan in December 2005 under the trade name Finibax. . In May 2003, Peninsula Pharmaceuticals and Shiono Yoshino reached an agreement on the transfer of the patent use rights of Donipenem, and obtained its development and sales rights in North America. In 2005, Johnson & Johnson obtained the right to develop and market the drug from the Japanese Salt Industry Corporation. In October 2007, the U.S. Food and Drug Administration (FDA) approved Donipenem injection for the treatment of complicated intra-abdominal infections and complicated urine. Road infection, the trade name is Doribax, the specification is 500mg. Donipenem's US patent will end on August 14,...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D207/12
CPCY02P20/55
Inventor 张敬栓程喜伟霍竹林刘少倩尚慕宏李玮
Owner 石家庄万尚医药科技有限公司
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