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Preparation method of 3-azabicyclo[3.1.0]hexane hydrochloride

A technology of hexane hydrochloride and azabicycle is applied in the field of pharmaceutical synthesis and achieves the effects of simple operation, stable process and short reaction steps

Active Publication Date: 2018-07-31
PHARMABLOCK SCIENCES (NANJING) INC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0011] Solvents and reagents: (a) CHBr 3 , aq NaOH, CH 2 Cl 2 , BnEt 3 NCl, the reported yield of this step reaction is only 50%

Method used

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  • Preparation method of 3-azabicyclo[3.1.0]hexane hydrochloride
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  • Preparation method of 3-azabicyclo[3.1.0]hexane hydrochloride

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Experimental program
Comparison scheme
Effect test

Embodiment 1

[0039]

[0040] Preparation of Compound II:

[0041] Compound VI (650g, 3.84mol, 1eq.) was placed in a reaction flask, added n-heptane (13L) and potassium tert-pentoxide (3394g, 26.89mol, 7eq.), stirred, cooled to -15°C, N 2 Under protection, tribromomethane (2912g, 11.52mol, 3eq.) was slowly added dropwise, and the temperature was controlled at -15~-5°C. During the reaction, the reaction solution became viscous. Stir for 3 hours after dropping, sampling and monitoring. After the reaction is over, the reaction solution is washed with water, and the organic phase is dried and concentrated to obtain a brownish black oil. Petroleum ether is added for freezing and crystallization to obtain 1192 g of a brown solid, yield: 91%. 1 HNMR (CDCl 3 , 400MHz) δ (ppm) 3.58 (m, 4H), 2.40 (m, 2H), 1.52 (s, 9H).

[0042] Preparation of compound I:

[0043] Put compound II (1800g, 5.28mol, 1eq.) in a reaction flask, add toluene (2.5L), acetic acid (2218g, 36.95mol, 7eq.), stir, heat up to...

Embodiment 2

[0047]

[0048]Preparation of Compound II:

[0049] Compound VI (1000g, 5.91mol, 1eq.) was placed in a reaction flask, n-heptane (20L) and potassium tert-amyloxide (4476g, 35.45mol, 6eq.) were added, stirred, cooled to -5°C, N 2 Under protection, tribromomethane (4480g, 17.73mol, 3eq.) was slowly added dropwise, and the temperature was controlled at -5-10°C. During the reaction, the reaction solution became viscous. After dropping, stirred for 4 hours, sampling and monitoring, the reaction was completed, the reaction solution was washed with water, the organic phase was dried and concentrated to obtain a brownish black oil, added petroleum ether, and freeze crystallized to obtain 1874 g of a brown solid, yield: 93%. 1 HNMR (CDCl 3 , 400MHz) δ (ppm) 3.58 (m, 4H), 2.40 (m, 2H), 1.52 (s, 9H).

[0050] Preparation of compound I:

[0051] Put compound II (682g, 2.00mol, 1eq.) in a reaction flask, add toluene (1L), acetic acid (360g, 6.00mol, 3eq.), stir, heat up to 70-85°C an...

Embodiment 3

[0055]

[0056] Preparation of Compound II:

[0057] Compound VI (1500g, 8.86mol, 1eq.) was placed in a reaction flask, added n-heptane (30L) and sodium tert-amyloxide (6833g, 62.05mol, 7eq.), stirred, cooled to -10°C, N 2 Under protection, tribromomethane (6720g, 26.59mol, 3eq.) was slowly added dropwise, and the temperature was controlled at -10-0°C. During the reaction, the reaction solution became viscous. After dropping, stirred for 6 hours, sampling and monitoring, the reaction was completed, the reaction solution was washed with water, and the organic phase was dried and concentrated to obtain a brownish black oil, which was added with petroleum ether and frozen for crystallization to obtain 2872 g of a brown solid, yield: 95%. 1 HNMR (CDCl 3 ,400MHz)δ(ppm)3.58(m,4H),2.40(m,2H),1.52(s,9H).

[0058] Preparation of compound I:

[0059] Compound II (341g, 1.00mol, 1eq.) was placed in a reaction flask, toluene (0.6L) and acetic acid (600g, 10.00mol, 10eq.) were added,...

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PUM

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Abstract

The invention discloses a preparation method of 3-azabicyclo[3.1.0]hexane hydrochloride, compound II as a raw material is reacted with an acetic acid solution and zinc powder under heating to obtain areaction liquid containing compound III, the reaction liquid containing the compound III is further treated with a base to obtain a treatment liquid containing compound IV, the treatment liquid containing the compound IV is then reacted with hydrogen chloride gas to obtain the 3-azabicyclo[3.1.0]hexane hydrochloride. Compared with the prior art, the preparation process is simple, the reaction condition is mild, and the cost is low. At the same time, the total yield of the preparation process can reach 71%.

Description

technical field [0001] The invention belongs to the field of medicine synthesis, and in particular relates to a preparation method of 3-azabicyclo[3.1.0]hexane hydrochloride. Background technique [0002] Overactive bladder is one of the most common causes of bladder control problems. It arises from the uncontrolled spontaneous activity of the detrusor muscle when the bladder is full, leading to symptoms of frequent urination, urgency and incontinence, and increased frequency of urination. Although there are some treatment options, at present most still choose antimuscarinic drugs to treat overactive bladder. Muscarinic receptors are widely distributed in the human body, and five different subtypes (M1-M5) are currently known. Human bladder smooth muscle contains M2- and M3-muscarinic receptor subtypes, and although M2-receptors are predominantly present in the bladder, it appears that the M3-receptors present in small amounts are functionally most important because they d...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D209/52
CPCC07D209/52
Inventor 黄孟炜姜伟蒋爱民
Owner PHARMABLOCK SCIENCES (NANJING) INC
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