Preparation method of balosavir intermediate

An intermediate, benzyloxy technology, applied in the field of medicine, can solve the problems of high synthesis cost, long steps, and the need for splitting, etc., and achieve the effect of high yield and low cost

Active Publication Date: 2020-05-29
南京法恩化学有限公司
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Problems solved by technology

[0004] (1) "Substituted Polycyclic Carbamoyl Pyridone Derivatives and Prodrugs Thereof" was disclosed in the invention of Patent Publication No. CN108440564A, which disclosed the synthesis method of baloxavir intermediate, and the specific synthesis route is as follows figure 2 , however, this method has the disadvantages of long steps, high synthesis cost, and the need for splitting;
[0005] (2) At the same time, the synthetic method of another baloxavir intermediate is also disclosed in the prior art, and the specific synthetic route is as follows: image 3 , however, the problem with this method is that the racemate needs to be resolved, causing waste of another configuration compound and increasing the cost

Method used

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  • Preparation method of balosavir intermediate
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  • Preparation method of balosavir intermediate

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Experimental program
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Effect test

Embodiment 1

[0026] see figure 1 , a baloxavir intermediate (R)-7-(benzyloxy)-3,4,12,12a-tetrahydro-1H-[1,4]oxazin[3,4-c]pyrido The preparation method of [2,1-f][1,2,4]-triazine-6,8-dione comprises the following steps:

[0027] Step 1: Add 1kg of 3-benzyloxy-1-Bocamino-4-carbonyl-1,4-dihydropyridine-2-carboxylate methyl ester, 400g of L-serine ester, 600g of DCC, 10g of DMAP, and 700g of triethyl in the reaction flask The amine and 10L of dichloromethane were reacted at 30°C. After the reaction, filtered, the filtrate was concentrated, cooled, crystallized and filtered to obtain 935g of intermediate A with a yield of 73%.

[0028] Step 2: Add 900g of intermediate A, 5LDMF and 56g of sodium hydride into the reaction flask, dropwise add 396g of bromoacetal dimethanol, heat up to 60°C for reaction, after the reaction, pour solvent C into 30L of ice water, filter and wash with water , dried to obtain 860g of intermediate B, yield 80%.

[0029] Step 3: Nitrogen protection, first add 850g of...

Embodiment 2

[0031] A preparation method of baloxavir intermediate, comprising the following steps:

[0032] Step 1: Add 1.5kg of 3-benzyloxy-1-Bocamino-4-carbonyl-1,4-dihydropyridine-2-carboxylate methyl ester, 410g of L-serine ester, 600g of EDCI, 10g of DMAP, 700g of three Ethylamine and 10L dichloroethane were reacted at 40°C. After the reaction was completed, filtered, the filtrate was concentrated, cooled, crystallized and filtered to obtain 945g of intermediate A with a yield of 75%.

[0033] Step 2: Add 900g of intermediate A, 5LTHF and 50g of sodium hydride into the reaction flask, dropwise add 395g of bromoacetal dimethanol, heat up to 60°C for reaction, after the reaction, pour solvent C into 40L of ice water, filter and wash with water , and dried to obtain 850g of intermediate B with a yield of 85%.

[0034] Step 3: Nitrogen protection, first add 850g of intermediate B, 4L of ethylene glycol and 1L of water into the reaction bottle, then add 200g of hydrochloric acid, heat up...

Embodiment 3

[0036] A preparation method of baloxavir intermediate, comprising the following steps:

[0037]Step 1: Add 1kg 3-benzyloxy-1-Bocamino-4-carbonyl-1,4-dihydropyridine-2-carboxylate methyl ester, 400g L-serine ester, 600g DIC, 15g HOBT, 700g diiso Propylethylamine and 10L of dichloromethane were reacted at 30°C. After the reaction, filtered, the filtrate was concentrated, cooled, crystallized and filtered to obtain 930g of intermediate A with a yield of 78%.

[0038] Step 2: Add 1000g of intermediate A, 5LDMSO and 56g of sodium hydride into the reaction flask, dropwise add 400g of bromoacetal dimethanol, and heat up to 60°C for reaction. After the reaction, pour solvent C into 30L of ice water, filter and wash with water , dried to obtain 860g of intermediate B, yield 82%.

[0039] Step 3: Nitrogen protection, first add 850g of intermediate B, 4L of tetrahydrofuran and 1L of water into the reaction bottle, then add 220g of sulfuric acid, heat up for 2 hours, then add 20gPt / C, he...

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Abstract

The invention discloses a preparation method of a baloxavir intermediate (R)-7-(benzyloxy)-3, 4, 12, 12a-tetrahydro-1H-[1, 4]oxazine[3, 4-c]pyrido[2, 1-f][1, 2, 4]-triazine-6, 8-diketone, and belongsto the field of drugs. According to the method, 3-benzyloxy-1-Boc amino-4-carbonyl-1, 4-dihydropyridine-2-carboxylic acid methyl ester and a chiral substrate L-serine ester are taken as raw materialsto carry out condensation reaction, substitution reaction and cyclization decarboxylation reaction to synthesize a baloxavir key intermediate (R)-7-(benzyloxy)-3, 4, 12, 12a-tetrahydro-1H-[1, 4]oxazine[3, 4-c]pyrido[2, 1-f][1, 2, 4]-triazine-6, 8-diketone and creatively develop the synthetic route for synthesizing the baloxavir intermediate (R)-7-(benzyloxy)-3, 4, 12, 12a-tetrahydro-1H-[1, 4]oxazine[3, 4-c]pyrido[2, 1-f][1, 2, 4]-triazine-6, 8-diketone. Compared to the traditional route, the preparation method has the advantages of the high yield, low cost, no need of resolution, the high chiral purity, convenience in industrialization and the like.

Description

technical field [0001] The present invention relates to the field of medicines, more specifically, to a baloxavir intermediate (R)-7-(benzyloxy)-3,4,12,12a-tetrahydro-1H-[1,4] A preparation method of oxazin[3,4-c]pyrido[2,1-f][1,2,4]-triazine-6,8-dione. Background technique [0002] Baloxavir was discovered and developed by Shionogi Pharmaceutical. Its new mechanism of drug action is to inhibit the key enzyme of virus replication - CAP-dependent endonuclease. Baloxavir is an oral single-dose antiviral drug for the treatment of uncomplicated influenza, which is different from all current antiviral treatments. In nonclinical studies, baloxavir was effective against most influenza viruses including oseltamivir Drug-resistant strains and avian strains (H7N9, H5N1) showed good antiviral effects. At present, baloxavir has been listed in Japan, and the product name is It is used to treat influenza A and B in adults and children. [0003] The key intermediate of baloxavir curre...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D498/14
CPCC07D498/14
Inventor 王坤鹏
Owner 南京法恩化学有限公司
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