Preparation method of 2-amino-4,6-dichloro-5-formamine pyrimidine

A technology of formamide and pyrimidine, which is applied in the field of pharmaceutical preparation, can solve problems such as unresolved inherent drawbacks, inability to recycle, difficult process control, etc., and achieve the effects of fast production cycle, short time consumption, and reduction of three wastes pollution

Active Publication Date: 2016-06-08
INSIGHT FINECHEM +1
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Problems solved by technology

[0007] The preparation method (1) of FADCP is more complicated to operate, especially the process of the step-by-step hydrolysis step is not easy to control, it is easy to generate by-products, and the cost is high; the preparation method (2) of FADCP is an expansion of the preparation method (1) of FADCP , the raw materials used are relatively basic, but the process steps are longer, and the inherent disadvantages of the preparation method (1) of FADCP are not overcome; the preparation method (3) of FADCP can be regarded as an improvement of the preparation method (2) of FADCP, and the route is summarized The rate is relatively high (74%), which is a new emerging technology at present, but it involves the use of a large amount of zinc powder, the amount of waste residue is relatively large, and the price of the catalyst used is relatively high, which cannot be recycled and needs further optimization

Method used

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  • Preparation method of 2-amino-4,6-dichloro-5-formamine pyrimidine
  • Preparation method of 2-amino-4,6-dichloro-5-formamine pyrimidine

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preparation example Construction

[0031] In order to solve the above technical problems, the embodiment of the present invention provides a preparation method of 2-amino-4,6-dichloro-5-carboxamidopyrimidine, comprising the following steps:

[0032] Step S1: In the case of using an organic solvent, ADMP undergoes nitrosation reaction with sodium nitrite to obtain 2-amino-4,6-dimethoxy-5-isonitrosopyrimidine:

[0033]

[0034] Step S2: In the case of using methanol and palladium on carbon as a catalyst, pass hydrogen gas into the 2-amino-4,6-dimethoxy-5-isonitrosopyrimidine obtained in step S1 to undergo a hydrogenation reduction reaction, and remove it by filtration palladium carbon catalyst, concentrated hydrochloric acid was added to the filtrate to obtain 2,5-diamino-4,6-dimethoxypyrimidine hydrochloride:

[0035]

[0036] Step S3: In the case of using the catalyst Cat-1, the 2,5-diamino-4,6-dimethoxypyrimidine hydrochloride obtained in step S2 is subjected to a formylation reaction with a formylation ...

Embodiment 1

[0051] 1. Preparation of 2-amino-4,6-dimethoxy-5-isonitrosopyrimidine

[0052] Add 2-amino-4,6-dimethoxypyrimidine (31.0g, 0.2mol), methanol (200ml) and 40% aqueous sodium nitrite solution (38.0g, 0.22mol) successively in a 500ml three-necked flask, stir and mix Evenly, heat to 70-75°C, slowly add concentrated hydrochloric acid dropwise to system pH=2.5-3.0, consume concentrated hydrochloric acid (51.0g, 0.51mol) in total, continue to keep warm for 1 hour, take samples and monitor until the raw material content is <1% (HPLC- Area%), down to room temperature suction filtration to obtain a filter cake, the filter cake was washed twice with 50ml water, and dried at 50°C to obtain the crude product of 2-amino-4,6-dimethoxy-5-isonitrosopyrimidine 37.4g, content 94.5%, yield 96.1%, the product was confirmed by hydrogen nuclear magnetic resonance spectrum (1HNMR for short) and mass spectrometry (MS for short): 1HNMR (400Hz, DMSO-d6) 3.88(s, 6H), 7.85(s, 2H); MS (HPLC, ESI) 185 (M+H)...

Embodiment 2

[0064] 1. Preparation of 2-amino-4,6-dimethoxy-5-isonitrosopyrimidine

[0065] Add 2-amino-4,6-dimethoxypyrimidine (31.0g, 0.2mol), tetrahydrofuran (200ml) and 40% sodium nitrite aqueous solution (38.0g, 0.22mol) successively in a 500ml three-necked flask, stir and mix Evenly, heat to 60-65°C, slowly add concentrated hydrochloric acid dropwise to system pH=2.5-3.0, consume concentrated hydrochloric acid (51.0g, 0.51mol) in total, continue to keep warm for 3 hours, take samples and monitor until the raw material content is <1% (HPLC- Area%), down to room temperature suction filtration to obtain a filter cake, the filter cake was washed twice with 50ml water, and dried at 50°C to obtain the crude product of 2-amino-4,6-dimethoxy-5-isonitrosopyrimidine 35.6g, content 97.0%, yield 93.8%, the product was confirmed by 1HNMR and MS: 1HNMR (400Hz, DMSO-d6) 3.88 (s, 6H), 7.85 (s, 2H); MS (HPLC, ESI) 185 (M +H).

[0066] 2. Preparation of 2,5-diamino-4,6-dimethoxypyrimidine hydrochlor...

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Abstract

The invention provides a preparation method of 2-amino-4,6-dichloro-5-formamine pyrimidine. According to the preparation method of the 2-amino-4,6-dichloro-5-formamine pyrimidine, 2-amino-4,6-dimethoxy pyrimidine is used as a basic raw material, and the 2-amino-4,6-dichloro-5-formamine pyrimidine is synthesized through reactions of nitrosation, hydrogenation reduction, formylation, alkaline hydrolysis, chlorination and the like. By using the method provided by the invention, a new process route for preparing the FADCP (2-amino-4,6-dichloro-5-formamine pyrimidine) is established; the preparation method has innovative significance and a utility value; in addition, the preparation method provided by the invention has the characteristics that a process is smooth, a reaction condition is mild, a productive cycle is quick, the consumed time is shorter, three wastes are easily treated, the pollution by the three wastes are reduced, and the like; moreover, product purity is more than 98 percent; a total yield is up to above 79 percent; the preparation method is suitably applied to industrial production.

Description

technical field [0001] The invention relates to the field of medicine preparation, in particular to a preparation method of 2-amino-4,6-dichloro-5-carboxamidopyrimidine. Background technique [0002] Abacavir (Abacavir, referred to as ABC) is a new anti-AIDS drug. It is a new carbocyclic 2'-deoxyguanosine nucleoside drug. Its oral bioavailability is high and it can easily penetrate into the central nervous system. Like other nucleoside reverse transcriptase inhibitors, ABC is an inactive prodrug, which is metabolized into an active triphosphate through 4 steps in the body, and has been clinically proven to be effective against Human Immunodeficiency Virus (HIV). Replication has a strong inhibitory effect. Since the U.S. Food and Drug Administration (Food and Drug Administration, FDA) approved the listing of ABC in 1998, the market performance of the drug has become increasingly strong. 2-Amino-4,6-dichloro-5-carboxamidopyrimidine (FADCP for short) is an important intermedi...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D239/48
CPCC07D239/48
Inventor 凌云殷巍黄碧波
Owner INSIGHT FINECHEM
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