CN109988071A - The preparation method of hydrochloric acid Vernakalant intermediate 1R, 2R-2- (3,4- dimethoxyphenethoxy) cyclohexylamine salt - Google Patents

The preparation method of hydrochloric acid Vernakalant intermediate 1R, 2R-2- (3,4- dimethoxyphenethoxy) cyclohexylamine salt Download PDF

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CN109988071A
CN109988071A CN201711477007.2A CN201711477007A CN109988071A CN 109988071 A CN109988071 A CN 109988071A CN 201711477007 A CN201711477007 A CN 201711477007A CN 109988071 A CN109988071 A CN 109988071A
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dimethoxyphenethoxy
preparation
acid
control system
added
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李元珍
刘津爱
宁瑞勃
王明新
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MEDISAN PHARMACEUTICAL Co Ltd HARBIN
BEIJING HARBIN MEDISAN SCIENCE AND TECHNOLOGY Co Ltd
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MEDISAN PHARMACEUTICAL Co Ltd HARBIN
BEIJING HARBIN MEDISAN SCIENCE AND TECHNOLOGY Co Ltd
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C213/00—Preparation of compounds containing amino and hydroxy, amino and etherified hydroxy or amino and esterified hydroxy groups bound to the same carbon skeleton
    • C07C213/02—Preparation of compounds containing amino and hydroxy, amino and etherified hydroxy or amino and esterified hydroxy groups bound to the same carbon skeleton by reactions involving the formation of amino groups from compounds containing hydroxy groups or etherified or esterified hydroxy groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C213/00—Preparation of compounds containing amino and hydroxy, amino and etherified hydroxy or amino and esterified hydroxy groups bound to the same carbon skeleton
    • C07C213/08—Preparation of compounds containing amino and hydroxy, amino and etherified hydroxy or amino and esterified hydroxy groups bound to the same carbon skeleton by reactions not involving the formation of amino groups, hydroxy groups or etherified or esterified hydroxy groups

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Abstract

The invention discloses a kind of preparation methods of Vernakalant intermediate (1R, 2R) -2- (3,4- dimethoxyphenethoxy) cyclohexylamine salt.This method comprises: compound (1R, 2R) -2- (3,4- dimethoxyphenethoxy) Cyclohexylamino formic acid -9- fluorenes methyl esters is added in solvent by (1), control system temperature is 0-35 DEG C；(2) deprotecting regent 1,11 carbon -7- alkene (DBU) of 8- diazabicylo is added, control system temperature is 20-35 DEG C, and stirring is to being completely dissolved；(3) acid is added, control system temperature is 20-35 DEG C, stirring and crystallizing；(4) it filters, is dried to obtain (1R, 2R) -2- (3,4- dimethoxyphenethoxy) cyclohexylamine salt.This method, as catalyst, avoids realizing higher catalytic efficiency using the biggish diethylamine of volatility using DBU, has the characteristics that short reaction time, easy to operate, mild condition, convenient post-treatment, easy to industrialized production.

Description

Hydrochloric acid Vernakalant intermediate 1R, 2R-2- (3,4- dimethoxyphenethoxy) hexamethylene The preparation method of amine salt
Technical field
The present invention relates to a kind of preparation method of compound, in particular to a kind of hydrochloric acid Vernakalant intermediate (1R, 2R)- The preparation method of 2- (3,4- dimethoxyphenethoxy) cyclohexylamine salt, belongs to the field of chemical synthesis.
Background technique
Vernakalant is a kind of Group III antiarrhythmic drug of novel atrium selectivity.By Canadian Cardionme Pharma drugmaker and Astellas Pharma drugmaker, the U.S. develop jointly, and mechanism of action is in auricular fibrillation Selectively block the sodium and potassium (IKur) ion channel in atrium stage of attack, inhibits IKur electric current that can extend the action potential in atrium Time-histories reduces the danger that arrhythmia cordis occurs.From the point of view of existing data, it is shown on turning the multiple auricular fibrillation occurred recently Good validity and safety, curative effect are better than amiodarone, clinically for treating atrial fibrillation.
(1R, 2R) -2- (3,4- dimethoxyphenethoxy) cyclohexylamine salt is the intermediate of synthetic hydrochloric acid Vernakalant, is It prevents amino to be substituted, need to be protected with protecting group in synthesis, then undergo the process of Deprotection again.Fmoc protects ammonia Base is the common means in laboratory, and the reagents such as diethylamine, piperidines, strong acid are often used in fmoc-protected removing laboratory, but these are de- The method of protection is often very restricted in amplification production, and the addition of strong acid and strong base often brings to last handling process hidden Suffer from.The patent application of my company Publication No. CN104610121 is disclosed using diethylamine (DEA) as alkali, and by being concentrated, At salt, removal of impurities, (1R, 2R) -2- (3,4- dimethoxyphenethoxy) cyclohexylamine has been prepared in the last handling process of crystallization etc. Salt.Experiment discovery, this deprotection mode and post-processing approach operation are more complicated, and the production cycle is long, and side reaction is more, for centre Weight control brings very big difficulty.
Therefore, the more more mild production technology of economy, condition is found, more easy post processing mode is all to be badly in need of It solves the problems, such as.
Summary of the invention
The purpose of the present invention is to provide a kind of hydrochloric acid Vernakalant intermediate (1R, 2R) -2- (3,4- dimethoxy benzene second Oxygroup) cyclohexylamine salt preparation method.This method, as catalyst, is avoided using the biggish diethylamine of volatility using DBU, real The spies such as short higher catalytic efficiency, reaction time, easy to operate, mild condition, convenient post-treatment, easy to industrialized production are showed Point
In order to achieve the above object, the technological means that the present invention uses are as follows:
A kind of hydrochloric acid Vernakalant intermediate (1R, 2R) -2- (3,4- dimethoxyphenethoxy) cyclohexylamine of the invention The preparation method of salt, comprising the following steps:
(1) compound (1R, 2R) -2- (3,4- dimethoxyphenethoxy) Cyclohexylamino formic acid -9- fluorenes methyl esters is added Enter into solvent, control system temperature is 0-35 DEG C；
(2) deprotecting regent 1,11 carbon -7- alkene (DBU) of 8- diazabicylo is added, control system temperature is 20-35 DEG C, stirring is to being completely dissolved；
(3) acid is added, control system temperature is 20-35 DEG C, stirring and crystallizing；
(4) it filters, is dried to obtain (1R, 2R) -2- (3,4- dimethoxyphenethoxy) cyclohexylamine salt；
In the present invention, it is preferred to, solvent described in step (1) is acetonitrile, methyl tertiary butyl ether(MTBE), ethyl acetate, four Hydrogen furans or acetone, more preferably acetonitrile.
In the present invention, it is preferred to, control system temperature is 25-35 DEG C in step (1).
In the present invention, it is preferred to, deprotecting regent described in step (2) and (1R, 2R) -2- (3,4- dimethoxys Benzene ethyoxyl) Cyclohexylamino formic acid -9- fluorenes methyl esters molar ratio are as follows: 0.1~0.4:1.
In the present invention, it is preferred to, control system reaction temperature is 30~35 DEG C in step (2).
In the present invention, it is preferred to, the time of stirring described in step (2) is 2~6 hours, preferably 2 hours.
In the present invention, it is preferred to, acid described in step (3) is anhydrous oxalic acid, oxalic acid dihydrate, fumaric acid or horse Carry out sour, more preferably anhydrous oxalic acid.
In the present invention, it is preferred to, acid and (1R, 2R) -2- (3,4- dimethoxyphenethoxy) ring are added in step (3) The molar ratio of hexylamino formic acid -9- fluorenes methyl esters are as follows: 1~2:1, more preferably 1.2:1.
In the present invention, it is preferred to, control system reaction temperature is 20-25 DEG C in step (3).
In the present invention, it is preferred to, the temperature of drying described in step (4) is 40-55 DEG C, more preferably 50 DEG C.
Compared with prior art, the beneficial effects of the present invention are embodied in:
(1) present invention selects DBU to replace diethylamine, and realizes catalytic amount, avoids volatile reagent for environment With the harm of people, production cost is reduced, is suitable for industrialized production.
(2) what the present invention used makes last handling process very easy at salt mode, and operability is extremely strong, working condition temperature With it is easy to industrialized production.
Specific embodiment
The invention will now be further described with reference to specific embodiments, the advantages and features of the present invention will be with description and It is apparent.But examples are merely exemplary, and it is not intended to limit the scope of the present invention in any way.Those skilled in the art answer It should be appreciated that without departing from the spirit and scope of the invention can details to technical solution of the present invention and form repair Change or replace, but these modifications and replacement are fallen within the protection scope of the present invention.
The preparation (DBU method) of embodiment 1 (1R, 2R) -2- (3,4- dimethoxyphenethoxy) cyclohexylamine salt
In single port bottle, (1R, 2R) -2- (3,4- dimethoxyphenethoxy) Cyclohexylamino formic acid -9- fluorenes first is added Ester (10.2g, 20mmol), 60ml acetonitrile, DBU (1.0g, 6.6mmol) are stirred 2 hours under 30 DEG C of water-baths, and two water of oxalic acid is added It closes object (5.0g, 40mmol), control system temperature is 30 DEG C, stirring and crystallizing 6 hours, a large amount of precipitatings is precipitated, filtering, 45 DEG C dry It is dry, the oxalates 5.10g of (1R, 2R) -2- (3,4- dimethoxyphenethoxy) cyclohexylamine is obtained, is white solid, yield 68%.HPLC purity 98.4%.
1H NMR (300M, CDCl3) δ 8.41 (br, 3H), 6.79-6.76 (m, 3H), 3.85 (s, 3H), 3.84 (s, 3H), 3.79-3.71 (m, 2H), 3.65-3.57 (m, 1H), 3.40-3.32 (m, 1H), 2.99-2.87 (m, 3H), 2.28-2.25 (m, 1H), 2.13-2.09 (m, 1H), 1.73-1.62 (m, 3H), 1.27-1.07 (m, 3H).13C NMR (75M, CDCl3) δ 148.55, 147.29,131.34,120.86,112.51,111.15,78.65,70.24,55.81,55.79,55.36,35.81,29.86, 28.76,23.63,23.33.
The preparation (DBU method) of embodiment 2 (1R, 2R) -2- (3,4- dimethoxyphenethoxy) cyclohexylamine salt
In single port bottle, (1R, 2R) -2- (3,4- dimethoxyphenethoxy) Cyclohexylamino formic acid -9- fluorenes first is added Ester (10.2g, 20mmol), 60ml acetonitrile, DBU (1.0g, 6.6mmol) are stirred 2 hours under 30 DEG C of water-baths, and anhydrous oxalic acid is added (3.8g, 40mmol), control system temperature are 20 DEG C, stirring and crystallizing 6 hours, a large amount of precipitatings, filtering are precipitated, 50 DEG C of dryings obtain It is white solid, yield 77% to the oxalates 5.10g of (1R, 2R) -2- (3,4- dimethoxyphenethoxy) cyclohexylamine. HPLC purity 98.2%.
1H NMR (300M, CDCl3) δ 8.41 (br, 3H), 6.79-6.76 (m, 3H), 3.85 (s, 3H), 3.84 (s, 3H), 3.79-3.71 (m, 2H), 3.65-3.57 (m, 1H), 3.40-3.32 (m, 1H), 2.99-2.87 (m, 3H), 2.28-2.25 (m, 1H), 2.13-2.09 (m, 1H), 1.73-1.62 (m, 3H), 1.27-1.07 (m, 3H).13C NMR (75M, CDCl3) δ 148.55, 147.29,131.34,120.86,112.51,111.15,78.65,70.24,55.81,55.79,55.36,35.81,29.86, 28.76,23.63,23.33.
The preparation (DBU method) of embodiment 3 (1R, 2R) -2- (3,4- dimethoxyphenethoxy) cyclohexylamine salt
In single port bottle, (1R, 2R) -2- (3,4- dimethoxyphenethoxy) Cyclohexylamino formic acid -9- fluorenes first is added Ester (10.2g, 20mmol), 60ml acetonitrile, DBU (1.0g, 6.6mmol) are stirred 2 hours under 30 DEG C of water-baths, and anhydrous oxalic acid is added (3.8g, 40mmol), control system temperature are 35 DEG C, stirring and crystallizing 16 hours, a large amount of precipitatings, filtering are precipitated, 55 DEG C of dryings obtain It is white solid, yield 88% to the oxalates 6.50g of (1R, 2R) -2- (3,4- dimethoxyphenethoxy) cyclohexylamine. HPLC purity 98.5%.
1H NMR (300M, CDCl3) δ 8.41 (br, 3H), 6.79-6.76 (m, 3H), 3.85 (s, 3H), 3.84 (s, 3H), 3.79-3.71 (m, 2H), 3.65-3.57 (m, 1H), 3.40-3.32 (m, 1H), 2.99-2.87 (m, 3H), 2.28-2.25 (m, 1H), 2.13-2.09 (m, 1H), 1.73-1.62 (m, 3H), 1.27-1.07 (m, 3H).13C NMR (75M, CDCl3) δ 148.55, 147.29,131.34,120.86,112.51,111.15,78.65,70.24,55.81,55.79,55.36,35.81,29.86, 28.76,23.63,23.33.
The preparation (DBU method) of embodiment 4 (1R, 2R) -2- (3,4- dimethoxyphenethoxy) cyclohexylamine salt
In single port bottle, (1R, 2R) -2- (3,4- dimethoxyphenethoxy) Cyclohexylamino formic acid -9- fluorenes first is added Ester (10.2g, 20mmol), 60ml acetonitrile, DBU (0.3g, 2.0mmol) are stirred 24 hours under 30 DEG C of water-baths, and anhydrous oxalic acid is added (3.8g, 40mmol), control system temperature are 25 DEG C, stirring and crystallizing 6 hours, a large amount of precipitatings, filtering are precipitated, 45 DEG C of dryings obtain It is white solid, yield 90% to the oxalates 6.65g of (1R, 2R) -2- (3,4- dimethoxyphenethoxy) cyclohexylamine. HPLC purity 98.0%.
1H NMR (300M, CDCl3) δ 8.41 (br, 3H), 6.79-6.76 (m, 3H), 3.85 (s, 3H), 3.84 (s, 3H), 3.79-3.71 (m, 2H), 3.65-3.57 (m, 1H), 3.40-3.32 (m, 1H), 2.99-2.87 (m, 3H), 2.28-2.25 (m, 1H), 2.13-2.09 (m, 1H), 1.73-1.62 (m, 3H), 1.27-1.07 (m, 3H).13C NMR (75M, CDCl3) δ 148.55, 147.29,131.34,120.86,112.51,111.15,78.65,70.24,55.81,55.79,55.36,35.81,29.86, 28.76,23.63,23.33.
The preparation (DBU method) of embodiment 5 (1R, 2R) -2- (3,4- dimethoxyphenethoxy) cyclohexylamine salt
In single port bottle, (1R, 2R) -2- (3,4- dimethoxyphenethoxy) Cyclohexylamino formic acid -9- fluorenes first is added Ester (10.2g, 20mmol), 60ml acetonitrile, DBU (1.0g, 6.6mmol) stir 2 hours, Quan Rong under 30 DEG C of water bath conditions, instead It should be added maleic acid (3.8g, 40mmol) completely, control system temperature is 30 DEG C, and stirring and crystallizing 6-16 hours, it was a large amount of heavy to be precipitated It forms sediment, filtering, 40 DEG C of dryings obtain the oxalates 5.10g of (1R, 2R) -2- (3,4- dimethoxyphenethoxy) cyclohexylamine, are white Color solid, yield 74%.HPLC purity 94.3%.
1H NMR (300M, CDCl3) δ 8.41 (br, 3H), 6.79-6.76 (m, 3H), 3.85 (s, 3H), 3.84 (s, 3H), 3.79-3.71 (m, 2H), 3.65-3.57 (m, 1H), 3.40-3.32 (m, 1H), 2.99-2.87 (m, 3H), 2.28-2.25 (m, 1H), 2.13-2.09 (m, 1H), 1.73-1.62 (m, 3H), 1.27-1.07 (m, 3H).13C NMR (75M, CDCl3) δ 148.55, 147.29,131.34,120.86,112.51,111.15,78.65,70.24,55.81,55.79,55.36,35.81,29.86, 28.76,23.63,23.33.
The preparation (DBU method) of embodiment 6 (1R, 2R) -2- (3,4- dimethoxyphenethoxy) cyclohexylamine salt
In single port bottle, (1R, 2R) -2- (3,4- dimethoxyphenethoxy) Cyclohexylamino formic acid -9- fluorenes first is added Ester (5.1kg, 10mmol), 30L acetonitrile, DBU (3kg, 2mol) are stirred 2 hours under 30 DEG C of water-baths, and anhydrous oxalic acid is added (1.5kg, 12mol), control system temperature are 25 DEG C, stirring and crystallizing 6 hours, a large amount of precipitatings, filtering are precipitated, 50 DEG C of dryings obtain It is white solid, yield 92% to the oxalates 3.39kg of (1R, 2R) -2- (3,4- dimethoxyphenethoxy) cyclohexylamine. HPLC purity 98.70%.
1H NMR (300M, CDCl3) δ 8.41 (br, 3H), 6.79-6.76 (m, 3H), 3.85 (s, 3H), 3.84 (s, 3H), 3.79-3.71 (m, 2H), 3.65-3.57 (m, 1H), 3.40-3.32 (m, 1H), 2.99-2.87 (m, 3H), 2.28-2.25 (m, 1H), 2.13-2.09 (m, 1H), 1.73-1.62 (m, 3H), 1.27-1.07 (m, 3H).13C NMR (75M, CDCl3) δ 148.55, 147.29,131.34,120.86,112.51,111.15,78.65,70.24,55.81,55.79,55.36,35.81,29.86, 28.76,23.63,23.33.
The preparation (Diethylamine method) of comparative example 1 (1R, 2R) -2- (3,4- dimethoxyphenethoxy) cyclohexylamine salt
In single port bottle, (1R, 2R) -2- (3,4- dimethoxyphenethoxy) Cyclohexylamino formic acid -9- fluorenes first is added Ester (10.2g, 20mmol), 50ml methylene chloride, 20ml diethylamine electromagnetic agitation 4 hours, steam solvent, 3M hydrochloric acid are added 20ml is extracted primary with methyl tertiary butyl ether(MTBE) 20ml.Water phase is extracted twice with methylene chloride 50ml, organic phase anhydrous sodium sulfate It is dry, solvent is boiled off under decompression and obtains the crude product of (1R, 2R) -2- (3,4- dimethoxyphenethoxy) cyclohexylamine salt, is brown Sticky mass is added acetonitrile and stirs 6-16 hours, and a large amount of precipitatings are precipitated, (1R, 2R) -2- (3,4- dimethoxys are obtained by filtration Benzene ethyoxyl) cyclohexylamine hydrochloride 4.10g, be white solid, yield 64%, HPLC purity 97.6%.1H NMR (300M, CDCl3) δ 8.41 (br, 3H), 6.79-6.76 (m, 3H), 3.85 (s, 3H), 3.84 (s, 3H), 3.79-3.71 (m, 2H), 3.65-3.57 (m, 1H), 3.40-3.32 (m, 1H), 2.99-2.87 (m, 3H), 2.28-2.25 (m, 1H), 2.13-2.09 (m, 1H), 1.73-1.62 (m, 3H), 1.27-1.07 (m, 3H).13C NMR (75M, CDCl3) δ 148.55,147.29,131.34, 120.86,112.51,111.15,78.65,70.24,55.81,55.79,55.36,35.81,29.86,28.76,23.63, 23.33。

Claims (10)

1. a kind of preparation side of hydrochloric acid Vernakalant intermediate (1R, 2R) -2- (3,4- dimethoxyphenethoxy) cyclohexylamine salt Method, which comprises the following steps:
(1) compound (1R, 2R) -2- (3,4- dimethoxyphenethoxy) Cyclohexylamino formic acid -9- fluorenes methyl esters is added to In solvent, control system temperature is 0-35 DEG C；
(2) deprotecting regent 1,11 carbon -7- alkene (DBU) of 8- diazabicylo is added, control system temperature is 20-35 DEG C, is stirred It mixes to being completely dissolved；
(3) acid is added, control system temperature is 20-35 DEG C, stirring and crystallizing；
(4) it filters, is dried to obtain (1R, 2R) -2- (3,4- dimethoxyphenethoxy) cyclohexylamine salt；
2. preparation method according to claim 1, which is characterized in that solvent described in step (1) is acetonitrile, methyl- tert Butyl ether, ethyl acetate, tetrahydrofuran or acetone, preferably acetonitrile.
3. preparation method according to claim 1, which is characterized in that control system temperature is 25-35 DEG C in step (1).
4. preparation method according to claim 1, which is characterized in that deprotecting regent described in step (2) with (1R, 2R) the molar ratio of -2- (3,4- dimethoxyphenethoxy) Cyclohexylamino formic acid -9- fluorenes methyl esters are as follows: 0.1~0.4:1.
5. preparation method according to claim 1, which is characterized in that in step (2) control system reaction temperature be 30~ 35℃。
6. preparation method according to claim 1, which is characterized in that the time of stirring described in step (2) is 2~6 Hour, preferably 2 hours.
7. preparation method according to claim 1, which is characterized in that acid described in step (3) is anhydrous oxalic acid, oxalic acid Dihydrate, fumaric acid or maleic acid, preferably anhydrous oxalic acid.
8. preparation method according to claim 1, which is characterized in that acid and (1R, 2R) -2- (3,4- are added in step (3) Dimethoxyphenethoxy) Cyclohexylamino formic acid -9- fluorenes methyl esters molar ratio are as follows: 1~2:1, preferably 1.2:1.
9. preparation method according to claim 1, which is characterized in that control system reaction temperature is 20-25 in step (3) ℃。
10. preparation method according to claim 1, which is characterized in that the temperature of drying described in step (4) is 40- 55 DEG C, preferably 50 DEG C.
CN201711477007.2A 2017-12-29 2017-12-29 The preparation method of hydrochloric acid Vernakalant intermediate 1R, 2R-2- (3,4- dimethoxyphenethoxy) cyclohexylamine salt Pending CN109988071A (en)

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WO2017044877A1 (en) * 2015-09-12 2017-03-16 Sequoia Sciences, Inc. Phenethyldihydrobenzodioxolones and methods of use
CN105294530A (en) * 2015-11-30 2016-02-03 北京哈三联科技有限责任公司 Purification method of vernakalant hydrochloride
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Application publication date: 20190709