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New impurity and preparation method thereof

A technology of impurities and pyrrolidinyl, which is applied in the field of new impurities and its preparation, can solve the problems affecting the quality level of finished products, and achieve the effects of short synthesis route, high product purity and simple operation

Pending Publication Date: 2021-05-21
CHONGQING HUABANGSHENGKAI PHARM
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

At the same time, because of the presence of the aromatic bromine substituent, which is consistent with the structural characteristics of the intermediate formula III, it will participate in the next heck reaction and subsequent reaction steps. If it is not effectively controlled, it will greatly affect the quality of the finished product.

Method used

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  • New impurity and preparation method thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0059] Example 1 Preparation of 6-bromo-3-methyl-10-(2-(1-pyrrolidinyl)ethyl)pyrido[1,2-α]indole (recovery crystallization method from mother liquor)

[0060]Concentrate about 4.5L (E)-2-bromo-6-(3-(1-pyrrolidinyl)-1-p-tolyl-1-propenyl)pyridine (Formula III) mother liquor at 50-60°C under reduced pressure to about 200-300ml, then add about 5L of drinking water and 1L of ethyl acetate to the concentrated residue, add ammonia water under stirring to adjust the pH to 8-10, after the adjustment is completed, let it stand for stratification, separate the organic layer and then use 500ml The aqueous layer was extracted once with ethyl acetate; the combined organic layers were washed three times with saturated aqueous sodium chloride solution. Add 20g of activated carbon and 180g of anhydrous sodium sulfate to the organic layer, dry for 30 minutes, filter with suction, concentrate the mother liquor to dryness under reduced pressure, add about 600g of n-hexane, stir and dissolve at 60...

Embodiment 2

[0062] HPLC, IR, m / z, Proton spectrum and carbon spectrum identification, its result is as follows:

[0063] HPLC: 99.0% (with figure 1 ).

[0064] The integral result of HPLC is shown in the following table:

[0065]

[0066] IR: 1699cm-1, 1674cm-1, 1625cm-1, 1606cm-1, 1484cm-1, 2964cm-1, 2873cm-1, 1375cm-1 (with figure 2 ).

[0067] m / z: 357.3, 359.3[M+H]+ (with image 3 ).

[0068] 1HNMR (600MHz, CD3OD): 8.816(s,1H); 7.684-7.698(d,1H); 7.478-7.494(dd,1H); 7.245-7.259; 6.707-6.720; 2H); 2.729-2.756(m, 2H); 2.674-2.683(m, 4H); 2.541(s, 3H); 1.846-1.868(m, 4H) (attached Figure 4 ).

[0069] 13CNMR (600MHz, CD3OD): 136.514; 132.314; 130.145; 128.221; 125.347; 120.657; 118.396; 116.932; Figure 5 ).

Embodiment 3

[0070] Example 3 Preparation of bromo-3-methyl-10-(2-(1-pyrrolidinyl)ethyl)pyrido[1,2-α]indole (directed synthesis method)

[0071] Add 20g of water to a 500ml three-necked flask, slowly add 184g of sulfuric acid, and control the temperature below 90°C; add 50g of (E)-2-bromo-6-(3-(1-pyrrolidinyl)-1-p-tolyl- 1-propenyl)pyridine (Formula III), react at 108-120° C. for 4 hours at a temperature of 108 to 120° C., take a sample and carry out central control until the reaction meets the requirements. Cool down to 15-20°C, add ammonia water dropwise to adjust the pH value to 8-10, extract with 200ml×3 ethyl acetate, combine the organic layers, wash with 200ml×3 water, and concentrate to dryness. To obtain an oily substance, add 10ml of ethyl acetate and 50ml of n-hexane, heat up and reflux to dissolve, add dropwise 150ml of n-hexane, slowly cool down to crystallize, crystallize at 0-10°C for 1-2 hours, filter, wash with 20ml of refrigerated n-hexane, pump Dry; send solid samples fo...

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Abstract

The invention belongs to the technical field of chemical synthesis, and particularly relates to a new impurity related to acrivastine and a preparation method thereof. The new impurity is generated in a process of preparing (E)-2-bromo-6-(3-(1-pyrrolidinyl)-1-p-tolyl-1-propenyl) pyridine by heating 1-(6-bromo-2-pyridyl)-3-(1-pyrrolidinyl)-1-p-methylphenyl-1-propanol in sulfuric acid in a synthetic route of acrivastine and carrying out an elimination reaction, the new impurity is 6-bromo-3-methyl-10-(2-(1-pyrrolidinyl) ethyl) pyrido [1, 2-alpha] indole, is an important impurity in synthesis of acrivastine, and is beneficial to quality control of acrivastine bulk drugs. A mother liquor recovery crystallization method and a directional synthesis method are adopted for preparation, the synthesis route is short, operation is easy, the obtained product is high in purity, and the method can be applied to reference substance research and atrivastine intermediate product quality control.

Description

technical field [0001] The invention belongs to the technical field of chemical synthesis, and in particular relates to a new impurity and a preparation method thereof. Background technique [0002] Aclastine is a strong competitive histamine H1 receptor antagonist without obvious anticholinergic effect. It is indicated for the relief of symptoms of allergic rhinitis, including hay fever, chronic spontaneous urticaria, dermatophytosis, cholinergic urticaria and idiopathic acquired cold urticaria. In April 2003, SFDA approved its listing in China. [0003] The chemical name of Avastin is: (E)-3-[6-[(E)-1-(4-methylphenyl)-3-pyrrolidin-1-yl-1-propenyl]pyridine- 2-yl]-2-acrylic acid, its structural formula is as follows: [0004] [0005] Chinese patents CN200910086187.0, CN200910086870.4 and CN201510597158.6 successively disclose the preparation method of Avastatin, and the specific synthetic route is as follows: [0006] [0007] In the synthesis process of Avastin, ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D471/04
CPCC07D471/04
Inventor 王绍辉李红强
Owner CHONGQING HUABANGSHENGKAI PHARM
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