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A kind of deuterated telaprevir key intermediate and preparation method thereof

An intermediate and deuterated technology, applied in the field of deuterated compounds, can solve problems such as unreported preparation methods, and achieve the effects of simplified operation, easy availability of reaction raw materials, and simple and convenient preparation steps.

Active Publication Date: 2020-05-19
安徽诺全药业有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

And deuterated telaprevir is the compound after telaprevir isotope replacement, has isotope effect, and the key intermediate of preparation deuterated telaprevir and its preparation method are also not reported at present

Method used

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  • A kind of deuterated telaprevir key intermediate and preparation method thereof
  • A kind of deuterated telaprevir key intermediate and preparation method thereof
  • A kind of deuterated telaprevir key intermediate and preparation method thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0032] The synthesis process is as follows:

[0033]

[0034] (1) Preparation of deuterated cyclopropanecarboxylic acid as shown in formula (III)

[0035] Add 30mL of methanol to the reaction flask, add 5.5g of sodium metal in batches, stir until the sodium block disappears to obtain sodium methylate (NaOMe), then add 28g of hexadeuterio ethyl 4-chlorobutyrate shown in formula (II) , heated and refluxed for 12 hours, lowered to 20-30 ° C, added 50 g of 30% sodium hydroxide aqueous solution, reacted for 6 hours, concentrated, adjusted pH to 3 with concentrated hydrochloric acid, extracted twice with dichloromethane, concentrated to dryness, and obtained yellow The liquid was 13.5 g of deuterated cyclopropanecarboxylic acid represented by formula (III), and the yield was 83%. Detect above-mentioned yellow liquid with mass spectrometry and nuclear magnetic resonance, the result is as follows: 1 H NMR (DMSO-d 6 ,400MHz,ppm)δ13.05(s,br,1H).MS(ESI):m / z=92[M+H] + . Because in...

Embodiment 2

[0041] (1) Preparation of deuterated cyclopropanecarboxylic acid as shown in formula (III)

[0042] In reaction bottle, add 30mL methyl alcohol, add 3g sodium metal in batches, stir until sodium block disappears and make sodium methylate (NaOMe), then add 24g hexadeuterio ethyl 4-chlorobutyrate shown in formula (II), Heat up and reflux for 10 hours, drop to 20-30°C, add 50g of 30% sodium hydroxide aqueous solution, react for 4 hours, concentrate, adjust pH to 3 with concentrated hydrochloric acid, extract twice with dichloromethane, concentrate to dryness, and obtain a yellow liquid 10.1 g of deuterated cyclopropanecarboxylic acid represented by formula (III), the yield is 75%. Detect above-mentioned yellow liquid with mass spectrometry and nuclear magnetic resonance, the result is as follows: 1 H NMR (DMSO-d 6,400MHz,ppm)δ13.05(s,br,1H).MS(ESI):m / z=92[M+H] + . Because in the deuterated cyclopropyl formic acid shown in formula (III), 5 hydrogen atoms on the cyclopropyl gro...

Embodiment 3

[0048] (1) Preparation of deuterated cyclopropanecarboxylic acid as shown in formula (III)

[0049] In reaction bottle, add 30mL methyl alcohol, add 9g metal sodium in batches, stir until sodium block disappears and make sodium methylate (NaOMe), then add 36g hexadeuterio ethyl 4-chlorobutyrate shown in formula (II), Heat up and reflux for 14 hours, drop to 20-30°C, add 50g of 30% sodium hydroxide aqueous solution, react for 8 hours, concentrate, adjust the pH to 3 with concentrated hydrochloric acid, extract twice with dichloromethane, concentrate to dryness, and obtain a yellow liquid 12g of deuterated cyclopropanecarboxylic acid as shown in formula (III), the yield is 78%. Detect above-mentioned yellow liquid with mass spectrometry and nuclear magnetic resonance, the result is as follows: 1 H NMR (DMSO-d 6 ,400MHz,ppm)δ13.05(s,br,1H).MS(ESI):m / z=92[M+H] + . Because in the deuterated cyclopropyl formic acid shown in formula (III), 5 hydrogen atoms on the cyclopropyl grou...

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Abstract

The invention discloses a deuterotelaprevir key intermediate which has a structure shown by formula (VII): FORMULA shown in the description. The invention also discloses a preparation method of the deuterotelaprevir key intermediate, wherein the preparation method comprises the following steps: with hexadeutero 4-ethyl chlorobutyrate and sodium hydroxide as reaction raw materials, performing a cyclization and hydrolysis reaction, a rearrangement reaction, a reduction reaction and a condensation reaction to obtain a deutero compound shown by the formula (VII). The deuterotelaprevir key intermediate disclosed by the invention has the advantages of reasonable design of reaction route, easiness and convenience in operation of the preparation steps and easily available reaction raw materials.

Description

technical field [0001] The invention relates to the technical field of deuterated compounds, and more specifically relates to a key intermediate of deuterated telaprevir and a preparation method thereof. Background technique [0002] Telaprevir, chemical name (1S,3aR,6aS)-(2S)-2-cyclohexyl-N-(carbonylpyrazine)-glycyl-3-methyl-L-valyl -N-(1S)-1-[(cyclopropylamino)-oxoacetyl]butyl-octahydrocyclopenta[c]pyrrole-1-carboxamide, the molecular formula is C 36 h 53 N 7 o 6 , the molecular weight is 679.85, and the structure is shown in the following formula. [0003] [0004] Telaprevir is a drug used to treat chronic hepatitis C. Deuterium is a hydrogen isotope that exists in nature, which means that common medicines contain trace amounts of deuterium isotope. Deuterium is non-toxic, non-radioactive, and safe to the human body, and the C-D bond is more stable (6-9 times) than the C-H bond. In other words, after replacing hydrogen with deuterium, it may close the metabolic ...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07C231/02C07C237/04C07K7/06
CPCC07B2200/05C07C51/09C07C209/50C07C231/02C07C269/04C07K7/06C07C237/04C07C211/35C07C271/24C07C61/04
Inventor 何大荣许良志胡志刚杜小鹏钱祝进何勇刘庄子
Owner 安徽诺全药业有限公司
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