CN102093233A

CN102093233A - Method for preparing 1-[2-amino-1-(p-methoxy phenyl) ethyl] cyclohexanol hydrochloride

Info

Publication number: CN102093233A
Application number: CN2009102002250A
Authority: CN
Inventors: 吴范宏; 赵敏; 杨兵; 王飞; 俞晓东
Original assignee: SHANGHAI HUALI BIOPHARMACEUTICAL CO Ltd
Current assignee: SHANGHAI HUALI BIOPHARMACEUTICAL CO Ltd; Shanghai Ecust Biomedicine Co Ltd
Priority date: 2009-12-09
Filing date: 2009-12-09
Publication date: 2011-06-15

Abstract

The invention discloses a method for preparing a 1-[2-amino-1-(p-methoxy phenyl) ethyl] cyclohexanol hydrochloride, which comprises the following steps of: performing hydrogenation reduction on alpha-(1-hydroxy cyclohexyl)-p-methoxy phenyl acetonitrile to obtain 1-[2-amino-1-(p-methoxy phenyl) ethyl] cyclohexanol under the action of raney nickel, and then acidifying the reduced product into hydrochloride to obtain the 1-[2-amino-1-(p-methoxy phenyl) ethyl] cyclohexanol hydrochloride of a formula I, wherein the total yield is about 85 percent.

Description

A kind of 1-[2-amino-1-(p-methoxyphenyl) ethyl for preparing] method of hexalin hydrochloride

Technical field

The present invention relates to a kind of preparation method of medicine intermediate, be specifically related to compound 1-[2-amino-1-(p-methoxyphenyl) ethyl] preparation method of hexalin hydrochloride.

Background technology

1-[2-amino-1-(p-methoxyphenyl) ethyl] the hexalin hydrochloride is important medicine intermediate, especially prepares the important source material of thymoleptic-Venlafaxine (venlafaxine), its structural formula is suc as formula shown in the I:

U.S. Pat 4535186 has been reported α-(1-hydroxy-cyclohexyl)-PARA METHOXY PHENYL ACETONITRILE under catalyst rhodium-alchlor effect, obtain target product through catalytic hydrogenation, but it has used expensive rhodium-alchlor catalyzer, and the recovery of rhodium is also relatively more difficult; Chinese patent CN1225356 has reported with sodium borohydride and boron trifluoride diethyl etherate and has reduced, and yield is 81%, and this wherein not only uses ether, and wherein also used tetrahydrofuran (THF), at first be that solvent types is more, next solvent of using is more expensive, and tetrahydrofuran (THF) reclaims also relatively difficulty; Chinese patent CN1640867 has reported with red aluminium and has reduced, but red aluminium large usage quantity, and also used tetrahydrofuran (THF) and ether; Chinese patent CN1847219 has reported with Lithium Aluminium Hydride or aluminium hydrogen reduction, wherein uses more expensive tetrahydrochysene lithium aluminium, and large usage quantity, and has used tetrahydrofuran (THF); European patent WO2006067808 has reported Raney Ni hydrogenating reduction, earlier under 10～15 ℃ in 2kg/cm ²Under react 1h, and then be warmed up under 35 ℃ in 7kg/cm ²Under react 6～8h, obtain the reduzate yield 85%, but its reaction times is longer; U.S. Pat 2004181093 has been reported Raney Ni hydrogenating reduction, reacts 20-30h under 60psi under 10-20 ℃, and obtaining reduzate is 75% at yield, though its temperature of reaction and pressure are all less, the reaction times is longer, and yield is also lower; U.S. Pat 03080560 has been reported Raney Ni hydrogenating reduction, and in 27 ℃ of following reaction 10h, its reduzate yield is 89% under 120Psi, and 11% impurity is arranged, and the reaction times is longer, and has impurity to produce.European patent WO2007049302 has reported palladium charcoal hydrogenating reduction, is in pressure 3.5～4kg/cm ²Temperature control is in 10～15 ℃ of following reaction 4.15h, and its reduzate is again through becoming hydrochloride, its yield 56%, though temperature of reaction and pressure are all lower, yield is lower, and has used expensive palladium charcoal.

Summary of the invention

The invention provides a kind of easy and simple to handle, cost is low, yield is high, reaction conditions is easy to realize that the method for being convenient to suitability for industrialized production prepares 1-[2-amino-1-(p-methoxyphenyl) ethyl] the hexalin hydrochloride.

The present invention includes following steps:

(A) reduction: in solvent, in the presence of Raney's nickel, under certain temperature and pressure condition, to obtain reduzate 1-[2-amino-1-(4-p-methoxy-phenyl) ethyl suc as formula compound α-(1-hydroxy-cyclohexyl)-PARA METHOXY PHENYL ACETONITRILE generation hydro-reduction reaction of II as formula III] the hexalin crude product.

(B) refining salify: in organic solvent, under the certain temperature condition, the reduzate as formula III is carried out the acidifying salify, obtain target product suc as formula I with the hydrochloric acid alcoholic solution.

Wherein, the described solvent of step (A) is pure ammonia mixture.Wherein alcohol is methyl alcohol, ethanol, Virahol etc., and ammonia can be ammonia, ammoniacal liquor, liquefied ammonia etc.; Wherein the concentration of ammonia is 5～30% (wt.), is preferably 10～25%; Wherein solvent load is 10～20 times of compound quality of formula II.0.08～0.3 times of the compound quality that described Raney's nickel consumption is II.Described pressure is 0.1～2MPa, is preferably 0.7～0.9MPa.Described temperature of reaction is 20～70 ℃, is preferably 30～50 ℃.The time of carrying out reduction reaction is 1～4h, is preferably 2～3h.

Wherein, the described organic solvent of step (B) is halogenated alkane, aromatic hydrocarbons and substituted arene, carboxylic acid esters.Wherein halogenated alkane is methylene dichloride, ethylene dichloride, trichloromethane, tetracol phenixin etc., and aromatic hydrocarbons and substituted arene are benzene, toluene, ethylbenzene, dimethylbenzene, diethylbenzene etc., and carboxylic acid esters is ethyl formate, ethyl acetate, propyl acetate, butylacetate etc.Alcohol is methyl alcohol, ethanol, Virahol etc. in the described hydrochloric acid alcoholic solution, and wherein content of hydrochloric acid is 10%～50% (wt.), is preferably 25～35%; It is 1～5 that adding hydrochloric acid alcoholic solution makes pH value of reaction system, is preferably 2～3.Described temperature of reaction is-20～50 ℃, is preferably-10～10 ℃.Reaction times is 0.5～4h, and being preferably is 1～2h.

The present invention has avoided using expensive rhodium catalyst, has shortened the reaction times, and the product purity that obtains simultaneously is higher, not needing to carry out recrystallization just can reach more than 99%, and the yield of reaction is higher, and the yield of two-step reaction is applicable to suitability for industrialized production about 85%.

Embodiment

Embodiment 1

1,1-[2-amino-1-(4-p-methoxy-phenyl) ethyl] preparation of hexalin

In the autoclave of 1L, add compound α-(1-hydroxy-cyclohexyl)-PARA METHOXY PHENYL ACETONITRILE 24.5g (0.1mol), 15% methanol ammonia solution (400ml), Raney's nickel (6.2g), sealed reactor, nitrogen replacement, logical hydrogen, to pressure be 0.9MPa, be heated to 35 ℃, logical hydrogen 3h, insulation reaction 2h then.Cooling, nitrogen replacement, reactant removes by filter catalyzer, concentrates, and obtains 25g oily matter.

2,1-[2-amino-1-(4-p-methoxy-phenyl) ethyl] preparation of hexalin hydrochloride

The oily matter that the last step was obtained is dissolved in the ethyl acetate of 50ml, adds 30% hydrochloric acid aqueous isopropanol under 0～5 ℃ of condition, and transfer to pH and be about 2, reaction 2h, suction filtration obtains white solid (24.6g, two step total recoverys are 86.1%), HPLC content 99.48%.

Embodiment 2

1,1-[2-amino-1-(4-p-methoxy-phenyl) ethyl] preparation of hexalin

In the autoclave of 1L, add compound α-(1-hydroxy-cyclohexyl)-PARA METHOXY PHENYL ACETONITRILE 24.5g (0.1mol), 20% methanol ammonia solution (300ml), Raney's nickel (3.7g) leads to hydrogen 2h, insulation reaction 2h then under 0.8MPa pressure, 40 ℃ of temperature condition.Cooling is filtered, and concentrates, and obtains 25.5g oily matter.

2,1-[2-amino-1-(4-p-methoxy-phenyl) ethyl] preparation of hexalin hydrochloride

The oily matter that obtains is dissolved in the methylene dichloride of 60ml, the hydrochloric acid aqueous isopropanol of temperature control-10～-5 ℃ following adding 25%, transferring to pH is 2～3, reaction 1.5h, suction filtration obtains white solid (24.3g, 85.3%), HPLC content 99.58%.

Embodiment 3

1,1-[2-amino-1-(4-p-methoxy-phenyl) ethyl] preparation of hexalin

In the autoclave of 1L, add compound α-(1-hydroxy-cyclohexyl)-PARA METHOXY PHENYL ACETONITRILE 24.5g (0.1mol), ethanol (300ml), logical ammonia to concentration is 20%, adds Raney's nickel (4.0g), leads to reaction 5h under 0.7MPa pressure, 45 ℃ of conditions.Cooling is filtered, and concentrates, and obtains 24.0g oily matter.

2,1-[2-amino-1-(4-p-methoxy-phenyl) ethyl] preparation of hexalin hydrochloride

The oily matter that obtains is dissolved in the toluene of 50ml, 2～7 ℃ of temperature controls stir the hydrochloric acid aqueous isopropanol of adding 35% down, and transfer to pH and be about 2～3, reaction 1.5h, suction filtration obtains white solid (24.1g, 84.5%).HPLC content 99.42%.

Embodiment 4

1,1-[2-amino-1-(4-p-methoxy-phenyl) ethyl] preparation of hexalin

In the autoclave of 1L, add compound α-(1-hydroxy-cyclohexyl)-PARA METHOXY PHENYL ACETONITRILE 24.5g (0.1mol), Virahol (200ml), the ammoniacal liquor (200ml) of adding 28%, add Raney's nickel (6.2g), sealed reactor, logical hydrogen to pressure is 0.8MPa, is heated to 35 ℃, reaction 5h.Cooling is filtered, and concentrates, and obtains 23.5g oily matter.

2,1-[2-amino-1-(4-p-methoxy-phenyl) ethyl] preparation of hexalin hydrochloride

The oily matter that obtains is dissolved in the chloroform of 50ml, adds 30% hydrochloric acid aqueous isopropanol under 0～5 ℃ of condition, transferring to pH is 2～3, reaction 2h, suction filtration, white solid (24.2g, 85.0%), HPLC content 99.68%.

Claims

1. one kind prepares 1-[2-amino-1-(p-methoxyphenyl) ethyl] method of hexalin hydrochloride, may further comprise the steps:

2. according to claim 1, it is characterized in that the described solvent of step (A) is pure ammonia mixture, wherein alcohol is methyl alcohol, ethanol, Virahol etc., and ammonia can be ammonia, ammoniacal liquor, liquefied ammonia etc., and the consumption of pure ammonia mixture is 10～20 times of compound quality of formula II.

3. as described in the claim 2, the concentration of ammonia is 5～30% (wt.) in the pure ammonia solution, is preferably 10～25%.

4. according to claim 1, it is characterized in that Raney's nickel consumption in the step (A) is 0.08～0.3 times of compound quality of formula II.

5. according to claim 1, it is characterized in that the pressure of step (A) is 0.1～2MPa, be preferably 0.7～0.9MPa.

6. according to claim 1, it is characterized in that the temperature of reaction of step (A) is 20～70 ℃, be preferably 30～50 ℃.

7. according to claim 1, it is characterized in that the reaction times of step (A) is 1～10h, be preferably 3～5h.

8. according to claim 1, the organic solvent that it is characterized in that step (B) is halogenated alkane, aromatic hydrocarbons and substituted arene, carboxylic acid esters, wherein halogenated alkane is methylene dichloride, ethylene dichloride, trichloromethane, tetracol phenixin etc., aromatic hydrocarbons and substituted arene are benzene, toluene, ethylbenzene, dimethylbenzene, diethylbenzene etc., and carboxylic acid esters is ethyl formate, ethyl acetate, propyl acetate, butylacetate etc.

9. according to claim 1, it is characterized in that alcohol is methyl alcohol, ethanol, Virahol etc. in step (B) the used salt acid alcohol solution, content of hydrochloric acid is 10%～50% (wt.), is preferably 25～35%.

10. according to claim 1, it is characterized in that the temperature of reaction of step (B) is-20～50 ℃, be preferably-10～10 ℃.

11. according to claim 1, it is characterized in that the reaction times of step (B) is 0.5～4h, being preferably is 1～2h.