Synthetic telaprevir intermediate and preparation method thereof

A suitable and compound technology, which is applied in the field of synthetic telaprevir intermediates and its preparation, can solve the problems of cumbersome operation and expensive preparation

Active Publication Date: 2018-03-23
SHANGHAI INST OF PHARMA IND CO LTD +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0005] Patent WO02 / 18369 discloses protease inhibitors for the treatment of HCV infection, especially a series of compounds of serine protease inhibitors and intermediates for the synthesis of these compounds, wherein (1S, aR, 6aS)-octahydrocyclopentadiene [c]pyrrole-1-carboxylic acid [(1S,3aR,6aS)-octahydrocyclopenta[c]pyrrole-carboxylic acid, compound 1] is a key intermediate for the synthesis of telaprevir and its analogues, the patent disclosure There are multiple deficiencies in the preparation method: the operation is loaded down with trivial details and used dangerous reagent explosive sodium hydrogen (NaH), hypertoxic reagent carbon disulfide and methyl iodide in key preparation steps; 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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  • Synthetic telaprevir intermediate and preparation method thereof
  • Synthetic telaprevir intermediate and preparation method thereof
  • Synthetic telaprevir intermediate and preparation method thereof

Examples

Experimental program
Comparison scheme
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, suction filtered, and spin-dried to obtain 4g of the 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) of compound 12, 76.2g (10 times the mass fraction) of Raney nickel, 700mL of tert-butanol into the four-neck flask, protect with nitrogen, reflux for 8 hours to stop the reaction, filter with suction, and spin dry to obtain 3.8g of the target Compound (65% yield), MS(m / z): 317.16[M+H] + .

Embodiment 3

[0036]

[0037] Add 10.4g (35mmol) ethyl racemic-2-(tert-butoxycarbonyl)-4-(carbonyl)octahydrocyclopentadieno[c]pyrrole-1-carboxylate into a four-neck flask, 3.5g (38.5mmol) 1,2-ethanedithiol, 10g (70mmol) boron trifluoride ether, 100mL dichloromethane, stirred at room temperature for 30min to stop the reaction, washed twice with saturated sodium bicarbonate solution (100ml*2), Wash once with water (100ml*1), dry the organic phase with anhydrous magnesium sulfate, and spin dry. Obtain 9.1g of the target compound (95% yield) MS (m / z): 274.09[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),8.1-8.12(s,1H,D 2 O exchange disappears).

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Abstract

The present invention provides a (1S, 3aR, 6aS)-octahydro-cyclopenta [c] pyrrole-1-carboxylic acid synthesis intermediate-compound c and a preparation method thereof, the method is as follows: a compound b is reduced in an alcohol solvent in the presence of raney nickel to obtain the compound c; the reaction conditions are as follows: reaction temperature is 70-90 DEG C, the alcohol solvent is selected from one or a plurality of methanol, ethanol, propanol, n-butyl alcohol, isopropyl alcohol, and tertiary butyl alcohol, the route VI shown in the specification; R1 in the chemical formula is selected from benzyl oxy carbonyl acyl group or tert-butyl oxy carbonyl group, R2 in the chemical formula is selected from C1-C4 alkyl groups. 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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Patent Type & AuthorityPatents(China)
IPC IPC(8): C07D209/52
CPCC07D209/52
Inventor薛燕王哲烽益兵王圣利袁博韩璐时惠麟
OwnerSHANGHAI INST OF PHARMA IND CO LTD