CN1453264A

CN1453264A - Prepn of cis-N-methyl-4-(3,4-dichlorophenyl)-1, 2, 3, 4-tetrahydro-1-naphthylamine and its derivative

Info

Publication number: CN1453264A
Application number: CN 02117189
Authority: CN
Inventors: 朗福双
Original assignee: WANQUAN SUNLIGHT MEDICINE SCIENCE AND TECHNOLOGY Co Ltd BEIJING
Current assignee: WANQUAN SUNLIGHT MEDICINE SCIENCE AND TECHNOLOGY Co Ltd BEIJING
Priority date: 2002-04-25
Filing date: 2002-04-25
Publication date: 2003-11-05

Abstract

The present invention discloses the one-step reaction process of preparing cis-N-methyl-4-(dichloro, phenyl)-1, 2, 3, 4-tetrahydro-1-naphthylamine and its derivative by using 4-(substituted phenyl)-3, 4-dihydro-naphthyl-1-ketone and its derivative as material. The said process has easy operation and high yield, and is one new method of synthesizing intermediate for Sertraline hydrochloride.

Description

Preparation cis-N-methyl-4-(3, the 4-dichlorophenyl)-1,2,3, the novel method of 4-tetrahydrochysene-naphthalidine and derivative thereof

Invention field

The present invention relates to prepare the method for following compound:

The invention discloses with 4-(substituted-phenyl)-3,4-dihydro-naphthalene-1-ketone and derivative thereof are raw material, obtain N-methyl-4-(substituted-phenyl)-1,2,3, the method for 4-tetrahydrochysene-naphthalidine and derivative thereof, wherein R through single step reaction ₁And R ₂Be hydrogen, halogen or alkane substituting group, R ₃Be hydrogen or alkane substituting group, R ₄Be alkyl substituent.This compound can be used for preparing sertraline hydrochloride and derivative thereof.

Background of invention

U.S. Pat 4536518 and Journal of Medicinal Chemistry, 1984, vol27, all reported among the 1508-1515 with 4-(substituted-phenyl)-3,4-dihydro-naphthalene-1-ketone is raw material, with the titanium tetrachloride is catalyzer, generate N-methyl-4-(substituted-phenyl)-1,2,3 with the methylamine effect, 4-tetrahydrochysene-1-naphthalene imines, this imines obtains N-methyl-4-(substituted-phenyl)-1,2,3 through sodium borohydride or catalytic hydrogenation reduction, 4-tetrahydrochysene-naphthalidine, this method products therefrom cis-trans ratio is 7: 3.

These existing technology all do not relate to or advise of the present inventionly with 4-(substituted-phenyl)-3, and 4-dihydro-naphthalene-1-ketone is raw material, obtains N-methyl-4-(substituted-phenyl)-1,2,3, the method for 4-tetrahydrochysene-naphthalidine through single step reaction.

Goal of the invention

The purpose of this invention is to provide a kind of easy preparation sertraline hydrochloride and the key intermediate N-methyl-4-(substituted-phenyl)-1,2,3 of derivative thereof, the method for 4-tetrahydrochysene-naphthalidine.

Summary of the invention

The invention provides a kind of new preparation method of following compound: Flow process is as follows:

R wherein ₁And R ₂Be hydrogen, halogen or alkane substituting group, R ₃Be hydrogen or alkane substituting group, R ₄Be alkyl substituent.

Content of the present invention has following advantage:

1. do not need to use titanium tetrachloride in this law, avoided because of the operation of adopting titanium tetrachloride to bring problems such as loaded down with trivial details and environmental pollution; Solvent for use needn't make simplified control through no water treatment simultaneously.

2. this law only needs single step reaction, and solvent for use and palladium catalyst carbon are all recyclable to be applied mechanically, and aftertreatment is simple, is easier to suitability for industrialized production.

3. present method stereoselectivity is strong, the product cis-isomeride ratio of gained can reach more than 90%, and U.S. Pat 4536518 and Journal of Medicinal Chemistry, 1984, vol 27, method cis-isomeride ratio described in the 1508-1515 is 70%, make to adopt this law prepare that the hydrochloric acid house is got woods and the derivative yield is higher.

Embodiment Embodiment 1

1L hydrogenation reaction steel cylinder adds 200 milliliters of methylamine alcohol solutions, 200 milliliters of anhydrous methanols, and 4-(3, the 4-dichlorophenyl)-3, (20g 0.074mol), stirs palladium carbon 1 gram of adding 10% down to 4-dihydro-naphthalene-1-ketone, feeds hydrogen, catalytic hydrogenation under the room temperature.To the disappearance of thin layer point plate analysis raw material point, stopped reaction.Elimination palladium carbon, the filtrate decompression solvent evaporated, the off-white color solid, be N-methyl-4-(substituted-phenyl)-1,2,3,4-tetrahydrochysene-naphthalidine, claim 19.8 the gram, yield 93.8%.The proton nmr spectra data are as follows: ¹H-NMR (300MHz, DMSO-d ₆) δ: 1.97-2.13 (4H, m ,-CH ₂-CH ₂-), 2.63 (3H, s ,-CH ₃), 4.10 (1H, t ,-CH-), 4.33 (1H, t ,-CH-), 6.73 (1H, d ,-Ar), 7.24-7.35 (4H, m ,-Ar), 7.49-7.53 (2H, m ,-Ar). Embodiment 2

To purify with column chromatography by example 1 operation gained off-white color solid, sorbent material is a 300-400 order silica gel, and eluent is a sherwood oil: ethyl acetate: triethylamine=40: 20: 1.Going out component earlier is cis-isomeride, and gained cis and trans-isomer(ide) are collected respectively, weighs, and calculating the two weight ratio is cis: trans=9: 1. Embodiment 3

To add isopropyl ether by example 1 operation gained white solid, and stir and feed hydrogen chloride gas down, to pH value be about 2, stop ventilation, stirring half an hour.Suction filtration, filter cake adds the 200ml anhydrous methanol, is heated to dissolving.Cooling adds the 150ml tetrahydrofuran (THF), and refrigerator and cooled is frozen and spent the night, white solid.The gained solid is separated salt, get light yellow oil 15.6 grams.Method by example 2 is collected cis and trans-isomer(ide) respectively, and calculating the cis-isomeride proportion is about 97%. Embodiment 4

As expect cis N-methyl-4-(substituted-phenyl)-1,2,3 that ratio is higher, 4-tetrahydrochysene-naphthalidine can repeat the operation of example 3.

Claims

1. the preparation method of general formula (1) compound:

General formula (1)

This method comprises:

With general formula (2) and alkylamine alcoholic solution is raw material, is catalyzer with palladium carbon, carries out hydrogenation reaction, and temperature range is 10 ℃-80 ℃, and pressure range is a 1-50 normal atmosphere, through single step reaction, obtains general formula (1) compounds.

General formula (2)

R in general formula (1) and the general formula (2) ₁And R ₂Be hydrogen, halogen or alkane substituting group, R ₃Be hydrogen or alkane substituting group.

2. the process of claim 1 wherein that used alkylamine alcoholic solution is a methylamine alcohol solution, commercially available or self-control, concentration is 10%-30%.

3. the method for claim 1 can add anhydrous methanol (or dehydrated alcohol) and make solvent, increases reactant solubility, improves the mixing effect in the reaction process, and wherein anhydrous methanol (or dehydrated alcohol) is 0-10 with the volume ratio scope of methylamine alcohol solution.

4. the method for claim 1, can obtain along reverse proportionality is N-methyl-4-(substituted-phenyl)-1,2 of 9: 1,3,4-tetrahydrochysene-naphthalidine, product can separate cis and trans-isomer(ide) by column chromatography method, obtain purified cis N-methyl-4-(3, the 4-dichlorophenyl)-1,2,3,4-tetrahydrochysene-naphthalidine, and then obtain (the 4S)-N-methyl-4-(3 of cis-(1S) by fractionation, the 4-dichlorophenyl)-1,2,3,4-tetrahydrochysene-naphthalidine (Sertraline).

5. the method for claim 1, products therefrom also can obtain purified cis N-methyl-4-(3, the 4-dichlorophenyl)-1,2 by the method for recrystallization behind the salify, 3,4-tetrahydrochysene-naphthalidine, and then obtain (the 4S)-N-methyl-4-(3, the 4-dichlorophenyl)-1 of cis-(1S) by fractionation, 2,3,4-tetrahydrochysene-naphthalidine (Sertraline), the solvent of recrystallization are the mixed solvent of methyl alcohol and tetrahydrofuran (THF).