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New preparation method of 4-aminoindan compound

A technology of aminoindane and compound, which is applied in the field of drug synthesis, can solve problems such as low yield of nitration reaction, poor regioselectivity, and difficulty in separation and purification of final products, and achieve the effects of avoiding separation difficulties, high yield, and good industrialization prospects

Inactive Publication Date: 2019-08-09
NANKAI UNIV
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  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0006] The biggest problem of this method is that the yield of the nitration reaction is low and the regioselectivity is poor, which makes the separation and purification of the final product very difficult. Since the products are isomers of each other, the two often exist in the sample as impurities. Quality Control in API Manufacturing Creates Challenges

Method used

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  • New preparation method of 4-aminoindan compound
  • New preparation method of 4-aminoindan compound
  • New preparation method of 4-aminoindan compound

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0027] Preparation of Intermediate 2:

[0028] Dissolve 1.5g (10mmol) of compound 1 (o-carboxybenzaldehyde) in 10mL of thionyl chloride, slowly add 10.0mL of anhydrous methanol dropwise to the system in an ice bath, stir for 10min after the dropwise addition, and then move to room temperature After stirring for about 0.5 h, TLC monitored that the reaction was complete. After the solvent was removed under reduced pressure, the solvent was quickly purified on a silica gel column to obtain 1.31 g of a colorless oily liquid 2 with a yield of 82%.

Embodiment 2

[0030] Preparation of intermediate 3:

[0031] Preparation of triethylamine formic acid solution: Take a 25.0mL round bottom flask and add 0.98g (3.5eq) of formic acid, add 0.91g (1.4eq) of triethylamine dropwise under ice-bath conditions, and stir for ten minutes after the addition is complete.

[0032] Add 3.0mL DMF to a 50.0mL round-bottom flask to dissolve 1.0g of compound 2, then add 0.97g (1.1eq) of McFarlandic acid and stir, the system is yellow and transparent, then add dropwise the triethylamine formic acid solution prepared above, after the addition is complete Move to an oil bath at 100°C and heat to react for 6 hours. TLC monitors that the reaction of the raw materials is complete, and proceed to the reaction treatment: use an oil pump to dry up the solvent, add water to dilute, and then use 1M dilute hydrochloric acid to adjust the pH of the system to 2. At this time, a yellow solid will precipitate and be filtered by suction , it was subjected to flash silica gel...

Embodiment 3

[0034] Preparation of Intermediate 4:

[0035] Add 20.0mL 1,2-dichloroethane to a 50.0mL round-bottom flask to dissolve 1.5g of compound 3, then add 1.7g (2.0eq) of thionyl chloride dropwise, then heat the reaction in an oil bath at 80°C for 3h, then concentrate under reduced pressure to remove the solvent , and the obtained oil was dissolved in 5.0 mL 1,2-dichloroethane for later use. In addition, take a 50.0mL round bottom flask and add 20.0mL 1,2-dichloroethane, then add 1.9g (2.0eq) of aluminum trichloride and stir, the system is cooled in an ice bath, and then the acid chloride solution prepared above is added dropwise, the system Turn into a brown transparent oil bath, then heat the reaction at 80°C for 6h, monitor the reaction by TLC, and carry out post-processing: quench the reaction with saturated sodium bicarbonate solution, then filter the precipitated solid with diatomaceous earth, and concentrate the filtrate under reduced pressure to remove the solvent. Add wate...

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Abstract

The invention relates to a new preparation method of a 4-aminoindan compound. 4-Aminoindan is an important medical intermediate. With carboxybenzaldehyde as an initial raw material, through esterification, condensation, cyclization, reduction elimination, Curtius rearrangement, an amidogen deprotection reaction and a hydrogenation reaction in sequence, the 4-aminoindan is prepared. According to the method, the problems of difficult generation of isomers, difficult separation of substitution products and the like in a traditional method are solved, the whole preparation method is convenient toimplement, the yield is high, and the method has great industrial prospects.

Description

[0001] Technical field: [0002] The invention relates to the field of drug synthesis, and relates to a novel preparation method of 4-aminoindan compounds, which are a class of important pharmaceutical intermediates. [0003] Background technique: [0004] 4-Aminoindan is an important class of pharmaceutical intermediates, which can be used to synthesize a variety of raw drug compounds. Its molecular structure is as follows: figure 1 It has the functions of anti-tumor, anti-hypertension, regulation of endocrine and metabolic disorders, and improvement of abnormal heart rate. In 2015, Vincent Gasparik found that a compound containing an indane structure can be used as an I 1 The receptor of RS, thus participates in the regulation of the biological system of the human body, and is used as a new antihypertensive drug for suppressing sympathetic nerves in metabolic syndrome, thereby reducing high blood pressure and improving metabolic disorders; it synthesizes such as figure 2 T...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07C209/70C07C209/62C07C211/60C07C27/02C07C63/49C07C67/317C07C67/313C07C67/343C07C67/14C07C69/76C07C269/04C07C271/30
CPCC07C51/09C07C67/14C07C67/313C07C67/317C07C67/343C07C209/62C07C209/70C07C211/60C07C269/04C07C2602/08C07C63/49C07C69/76C07C271/30
Inventor 苗志伟张海坤蔡岩
Owner NANKAI UNIV
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