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Telaprevir synthesis intermediate and preparation method thereof

A compound and selected technology, applied in the direction of organic chemistry, can solve the problems of cumbersome operation and expensive preparation

Inactive Publication Date: 2015-09-23
SHANGHAI INST OF PHARMA IND +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The preparation method disclosed in this patent has many deficiencies: the operation is cumbersome and the dangerous reagent explosive sodium hydrogen (NaH), the highly toxic reagent carbon disulfide and methyl iodide are used in the key preparation steps; the reference route II
[0007] It is reported in the patent WO07 / 109023 that the initial raw material rac-octahydrocyclopenta[c]pyrrole (compound 2) for the preparation of compound 1 is synthesized by biological methods, so the preparation is expensive

Method used

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  • Telaprevir synthesis intermediate and preparation method thereof
  • Telaprevir synthesis intermediate and preparation method thereof
  • Telaprevir synthesis intermediate and preparation method thereof

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Experimental program
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Effect test

Embodiment 1

[0030]

[0031] Add 4g (13.4mmol) racemic-2-(benzyloxycarbonyl)-4-(carbonyl) octahydrocyclopentadieno[c]pyrrole-1-carboxylic acid ethyl ester in the four-necked flask, 1.36g ( 14.7mmol) 1,2-ethanedithiol, 3.8g (26.8mmol) boron trifluoride ether, 40ml dichloromethane, stirred at room temperature for 30min to stop the reaction, washed twice with saturated sodium bicarbonate solution (40ml*2) , washed once with water (40ml*1), dried the organic phase with anhydrous magnesium sulfate, filtered with suction, and spin-dried. Obtain 4g of target compound (yield 96%), MS (m / z): 407.12[M+H] + ; 1 HNMR (CDCl 3 .400MHz) δ: 1.1-1.2(t,3H),1.65-1.68(m,1H),2.0-2.21(m,2H),2.21-2.34(m,2H),2.85-2.852(m,1H), 3.0-3.05(m,1H),3.27-3.276(m,4H),3.5-3.8(m,2H),4.0-4.2(m,2H),5.0-5.1(m,2H),7.2-7.4(m ,5H).

Embodiment 2

[0033]

[0034] Add 7.62g (18.7mmol) compound 12, 76.2g (10 times mass fraction) Raney nickel, 700mL tert-butanol, nitrogen protection, reflux reaction for 8h to stop the reaction, suction filtration, and spin dry to obtain 3.8g target Compound (65% yield), MS(m / z): 317.16[M+H] + .

Embodiment 3

[0038] Add 12.18g (36.6mmol) of compound 13 and 120mL of ethanol into the four-neck flask, stir to dissolve it, cool the temperature to 0°C in an ice-salt bath, add 1.44g of sodium borohydride in batches, slowly rise to room temperature after adding, and continue stirring After 30 minutes, 4.5ml of acetic acid was added to terminate the reaction, the ethanol was spin-dried, and 350ml of ethyl acetate was added, washed with saturated ammonium chloride solution and saturated sodium bicarbonate solution respectively, dried, and spin-dried. 11.5 g of compound 14 was obtained (95% yield), MS (m / z): 333.14 [M+H] + .

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Abstract

The present invention provides a (1S, 3aR, 6aS)-octahydro-cyclopenta [c] pyrrole-1-carboxylic acid synthesis intermediate-compound b and a preparation method thereof, the method is as follows: a compound a is reacted with 1,2-ethanedithiol in a suitable solvent in the presence of an acid catalyst to obtain the compound b; the reaction conditions are as follows: reaction temperature is 10-50 DEG C, the suitable solvent is selected from ethyl acetate, methylene chloride, toluene, or tetrahydrofuran, the acid catalyst is selected from methyl phenylsulfonic acid or boron trifluoride diethyl etherate; and the reaction formula is shown in the specification. Through use of the new compound b, use of dangerous reagent sodium-hydrogen, and poisonousreagent carbon disulfide and methyl iodide and the like can be avoided in the subsequent synthesis method of the compound 1, the raw materials are cheap and readily available, operation is easy, and the yield of the compound 1 prepared by the method is equal to the yield of the compound 1 prepared by the method reported in original patent document WO02 / 18369.

Description

technical field [0001] The invention belongs to the field of pharmaceutical synthesis, in particular to an intermediate for synthesizing telaprevir and a preparation method thereof. Background technique [0002] Hepatitis C virus (hepatitis C virus, referred to as HCV) is one of the main pathogens causing chronic hepatitis and then developing into liver cirrhosis and hepatocellular carcinoma. The infection rate of hepatitis C virus in the world population is 0.1% to 10%. The infection rate of HCV in China is 3.2%, that is, about 38 million people are carriers of hepatitis C virus. In recent years, the diagnosis rate of hepatitis C in China has been continuously increasing and the number of new reported cases of hepatitis C has also continued to increase; after HCV infection, the condition is hidden, and 50% to 80% will turn into chronic hepatitis. If no reasonable treatment is taken, among them 10% to 30% of patients are likely to develop liver cirrhosis after 10 to 20 year...

Claims

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Application Information

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IPC IPC(8): C07D495/10C07D209/52
CPCC07D209/52C07D495/10
Inventor 薛燕王哲烽益兵王圣利袁博韩璐时惠麟
Owner SHANGHAI INST OF PHARMA IND
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