Crystalline methyl carbamate compound

A technology of compounds and compositions, applied in the fields of organic chemistry, organic active ingredients, organic chemistry methods, etc., can solve the problems of patient treatment failure, patients without treatment alternatives, etc., and achieve the effect of low hygroscopicity

Active Publication Date: 2018-10-19
BEIJING KAWINGREEN BIOTECH CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, even with combination therapy with pegylated IFN-α plus ribavirin, 40% to 50% of patients fail treatment, ie, they are non-responders or relapsers
There are currently no effective treatment alternatives for these patients

Method used

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  • Crystalline methyl carbamate compound
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  • Crystalline methyl carbamate compound

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0041] Embodiment 1 formula (I) compound N-[(2S)-1-[(2S)-2-{4-[7-(4-{2-[(2S)-1-[(2S)-2- [(Methoxycarbonyl)amino]-3-methylbutyryl]pyrrolidin-2-yl]-1H-imidazol-4-yl}phenyl)-2H-1,3-benzodioxol-4 -yl]-1H-imidazol-2-yl}pyrrolidin-1-yl]-3-methyl-1-oxobutane-2-yl]preparation of methyl carbamate (according to the method disclosed in CN102791687B )

[0042]

[0043] step 1

[0044]

[0045] To a solution of ethyl 4-bromo-2,3-dihydroxybenzoate (I-VIh, 1.3 g, 5.0 mmol) in DMF (10.0 mL) was added Cs2CO3 (3.5 g, 11.0 mmol), and the mixture was stirred at room temperature for 1 Hour. To the mixture was added CH2I2 (2.2 g, 8.1 mmol) and the mixture was stirred at 70 °C for 12 hours. The reaction mixture was diluted with ethyl acetate and washed with water and brine. The solvent was removed and the residue was purified by column chromatography on silica gel (eluent: PE:EtOAc=4:1) to provide compound I-IXa (700 mg, yield 52%) as a yellow solid. 1H NMR (400MHz, CDCl3) δ7.31(d, 1H), ...

Embodiment 2

[0064] Embodiment 2 formula (I) compound N-[(2S)-1-[(2S)-2-{4-[7-(4-{2-[(2S)-1-[(2S)-2- [(Methoxycarbonyl)amino]-3-methylbutyryl]pyrrolidin-2-yl]-1H-imidazol-4-yl}phenyl)-2H-1,3-benzodioxol-4 Preparation of -yl]-1H-imidazol-2-yl}pyrrolidin-1-yl]-3-methyl-1-oxobutane-2-yl]carbamate dihydrochloride

[0065] At room temperature, a solution of the pure product of formula II (800 g, 1.0 eq) and ethyl acetate (8 L) was successively added into a 20 L bottle and stirred. Add dropwise HCl / ethyl acetate solution (839g) with a concentration of about 11.2% into the system, control the temperature of the system at 15°C to 25°C, stir for more than 3 hours, stop the reaction, filter with suction, and filter the cake with ethyl acetate (2L) Wash, control the temperature of the filter cake and dry it at 40-60°C, take a sample and test until the residue of ethyl acetate <0.5%, (about 73 hours after drying), the compound of structural formula I is obtained, off-white solid powder or granule, 77...

Embodiment 3

[0066] Embodiment 3 carries out crystal form screening to formula (I) compound with different crystallization methods

[0067] 1. Slow volatile crystallization

[0068] Weigh about 10 mg of the pure product with structural formula I into a 3 mL glass bottle, respectively add about 0.5-1.25 mL of the following solvents to ensure that the samples are completely dissolved to obtain a clear solution, and the obtained solution is slowly volatilized at room temperature. Solid test XRPD, the results are shown in Table 1. The solids obtained in the volatile crystallization experiment were all amorphous, and no other new crystal forms were obtained.

[0069] Experiment number

Solvent used

temperature

get solid

805301-14-A1

H2O

RT

amorphous

805301-14-A2

MeOH

RT

amorphous

805301-14-A3

EtOH

RT

amorphous

805301-14-A4

IPA

RT

N / A*

805301-14-A5

Acetic acid

RT

amorphous

805301-...

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Abstract

The invention relates to a crystalline methyl carbamate compound, namely a crystal form of N-[(2S)-1-[(2S)-2-{4-[7-(4-{2-[(2S)-1-[(2S)-2-[(methoxycarbonyl)amino]-3-methylbutyryl]pyrrolidin-2-yl]-1H-imidazol-4-yl}phenyl)-2H-1,3-benzodioxan-4-yl]-1H-imidazol-2-yl}pyrrolidin-1-yl]-3-methyl-1-oxybutan-2-yl]methyl carbamate dihydrochloride, a pharmaceutical composition containing the crystal form, anda use of the crystal form in preparation of drugs in treatment of hepatitis C virus.

Description

technical field [0001] The invention relates to a crystalline methyl carbamate compound, namely: N-[(2S)-1-[(2S)-2-{4-[7-(4-{2-[(2S)-1 -[(2S)-2-[(Methoxycarbonyl)amino]-3-methylbutyryl]pyrrolidin-2-yl]-1H-imidazol-4-yl}phenyl)-2H-1,3 -Benzodioxol-4-yl]-1H-imidazol-2-yl}pyrrolidin-1-yl]-3-methyl-1-oxobutan-2-yl]carbamate methyl ester disalt The crystal form of the acid salt, the pharmaceutical composition comprising the crystal form, and the application of the crystal form in medicine for treating hepatitis C virus belong to the field of medicinal chemistry. Background technique [0002] Hepatitis C virus (HCV) infection is the most common chronic blood-borne infection in the United States. Although the number of new infections has declined, the burden of chronic infection remains substantial, with the Centers for Disease Control estimating that there are 3.9 million infected people (1.8%) in the United States. Chronic liver disease is the tenth leading cause of death amon...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D405/14A61K31/4178A61P31/14
CPCA61P31/14C07B2200/13C07D405/14
Inventor 熊国裕杨健周德胜潘海闫甫昆
Owner BEIJING KAWINGREEN BIOTECH CO LTD
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