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Preparation method of trans-2-[(3R)-3-benzyloxy-1-pyrrolidinyl]-1-cyclohexanol

A technology of benzyloxypyrrolidinyl salt and pyrrolidinyl, which is applied in the field of preparation of trans-2-[(3R)-3-benzyloxy-1-pyrrolidinyl]-1-cyclohexanol, capable of Solve the problems of shortened reaction time, long reaction time, and low yield, and achieve the effects of low price, high synthesis efficiency, and high yield

Inactive Publication Date: 2015-05-13
CHINA PHARM UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0015] The object of the present invention is to aim at the long reaction time, low purity, Low yield and other problems, a preparation method of trans-2-[(3R)-3-benzyloxy-1-pyrrolidinyl]-1-cyclohexanol (I) is provided, the method has mild reaction conditions and easy operation Simple, high yield, stable quality, shortened reaction time, suitable for industrial production

Method used

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  • Preparation method of trans-2-[(3R)-3-benzyloxy-1-pyrrolidinyl]-1-cyclohexanol
  • Preparation method of trans-2-[(3R)-3-benzyloxy-1-pyrrolidinyl]-1-cyclohexanol
  • Preparation method of trans-2-[(3R)-3-benzyloxy-1-pyrrolidinyl]-1-cyclohexanol

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Effect test

Embodiment 1

[0028] Embodiment 1, the preparation of trans-2-[(3R)-3-benzyloxy-1-pyrrolidinyl]-1-cyclohexanol (I)

[0029] Add 5.0g (R)-3-benzyloxypyrrolidine oxalate (II), toluene 100ml, water 100ml, epoxy cyclohexane 1.9g, potassium hydroxide 2.1g, tetrabutyl bromide to the reaction flask Ammonium 0.6g, heated at 80°C for 4.5h, separated, the organic layer was dried over anhydrous sodium sulfate, filtered with suction, and the filtrate was concentrated under reduced pressure to obtain 4.9g of a light yellow oil with a yield of 95.1% and a purity of 98.0%.

[0030] 1 H-NMR (CDCl 3 , 300M) δ: 7.34~7.27 (m, 5H, Ar-H); 4.50 (s, 2H, CHOC H 2 Ph); 4.13~4.07(m, 1H, C H OH); 3.37~3.32(m, 1H, C H OCH 2 Ph); 2.94~2.68(m, 4H, C H 2 NC H 2 ); 2.48~2.46 (m, 1H, C H N); 2.13~2.00(m, 2H, NCH 2 C H 2 ); 1.80~1.73(m, 4H, C H 2 CH 2 CH 2 C H 2 ); 1.27~1.16(m, 4H, CH 2 C H 2 C H 2 CH 2 ).

[0031] MS (m / z): 276 ([M+H] + ).

Embodiment 2

[0032] Embodiment 2, the preparation of trans-2-[(3R)-3-benzyloxy-1-pyrrolidinyl]-1-cyclohexanol (I)

[0033] Add 5.0g (R)-3-benzyloxypyrrolidine hydrochloride (II), toluene 100ml, water 100ml, epoxycyclohexane 2.4g, potassium hydroxide 2.6g, tetrabutyl bromide to the reaction flask Ammonium 0.7g, heated at 80°C for 4.5h, separated into layers, the organic layer was dried over anhydrous sodium sulfate, filtered with suction, and the filtrate was concentrated under reduced pressure to obtain 6.1g of light yellow oil with a yield of 94.7% and a purity of 98.2%.

Embodiment 3

[0034] Embodiment 3, the preparation of trans-2-[(3R)-3-benzyloxy-1-pyrrolidinyl]-1-cyclohexanol (I)

[0035] Add 5.0g (R)-3-benzyloxypyrrolidine p-toluenesulfonate (II) to the reaction flask, toluene 100ml, water 100ml, epoxycyclohexane 1.5g, potassium hydroxide 1.6g, tetrabutyl Ammonium bromide 0.5g, heated at 80°C for 4.5h, separated into layers, the organic layer was dried over anhydrous sodium sulfate, filtered with suction, and the filtrate was concentrated under reduced pressure to obtain 3.8g of light yellow oil with a yield of 96.4% and a purity of 97.9%.

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Abstract

The invention relates to a preparation method of trans-2-[(3R)-3-benzyloxy-1-pyrrolidinyl]-1-cyclohexanol. The compound is a key intermediate for preparing vernakalant, serving as hydrochloride. The preparation method is characterized by comprising the following steps: with (R)-3-benzyloxy pyrrolidine hydrochloride (II) as a raw material, carrying out SN2 nucleophilic substitution reaction on the (R)-3-benzyloxy pyrrolidine hydrochloride (II) and cyclohexene oxide to open the ring, thus obtaining the trans-2-[(3R)-3-benzyloxy-1-pyrrolidinyl]-1-cyclohexanol (I). The preparation method is simple and convenient to operate, mild in reaction condition, stable in quality, high in yield, simple in post-processing and suitable for industrial production.

Description

technical field [0001] The preparation method of trans-2-[(3R)-3-benzyloxy-1-pyrrolidinyl]-1-cyclohexanol Background technique [0002] Vernakalant hydrochloride (vernakalant hydrochloride) has the following structural formula. It is a new type of antiarrhythmic drug jointly developed by Cardiome Pharmaceutical Company of Canada and Astellas Company of the United States. It is clinically used for the treatment of atrial fibrillation. This product was first listed in Europe in 2010. For the synthesis of Cardiome Pharmaceuticals, see WO2004099137. Trans-2-[(3R)-3-benzyloxy-1-pyrrolidinyl]-1-cyclohexanol (I) is an important intermediate in the synthesis of vernakalant hydrochloride. [0003] [0004] The key to the synthetic route of vernakalant hydrochloride currently reported is to construct the chiral center in the molecule. Because the chiral center of the hydroxyl group on the pyrrolidine in the raw material used already exists, it is necessary to carry out the synthes...

Claims

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Application Information

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IPC IPC(8): C07D207/12
CPCC07D207/12
Inventor 陈国华葛婷
Owner CHINA PHARM UNIV
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