CN86107840A - The improvement of synthesis of citric acid triphenylamine oxide - Google Patents

Abstract

A kind ofly be used for synthetic anti-breast cancer medicine---the method for citric acid triphenylamine oxide, present method is to be starting raw material with p bromophenol and acetate, and five step unit processes just can make qualified product through ether condensation, (chlorination, condensation) alkylation, Ge Liweiya reaction, dehydration, salify etc.This method than previous methods have reactions steps lack, easy and simple to handle, overall yield is high, low cost and other advantages.Being more suitable for medicine industry produces in batches.

Description

The present invention belongs to a kind of anti-breast cancer medicine-tamoxifen citrate (chemical name: (Z)-2-(4-(1,2-phenylbenzene-1-butylene base)-phenoxy group)-N, N-dimethyl amine citrate 1: 1) improvement of synthetic method.

In 1984, the meter will loyalty people such as (1) of Shenyang Pharmacy College reported the method for the synthetic ulcer peace Citrate trianion that looses of their designs, and this method is that they are self-designed on three synthetic route bases analyzing foreign patent (2) (3) (4) report.Be to be starting raw material with phenyl aldehyde and phenol, as follows by its reaction formula of nine steps reaction such as benzoic condensation, reduction, ethylization, bromination, etherificate, amination, grignard reaction, dehydration, separation and salify:

Tamoxifen citrate

(ulcer of loosing peace Citrate trianion)

The main drawback that this synthetic route exists has: two main intermediate (1 in the reaction, 2-two phenyl propyl ketones and 2-(4-bromine phenoxy group)-N, the preparation method of N-dimethyl amine falls behind, to compound tamoxifen (Z, E xenogenesis body mixture) therefore inferior separating effect causes the synthetic route total recovery 2.7%(only to be arranged in phenyl aldehyde).

The objective of the invention is to propose that a step is short, easy to operate, cost is lower, be suitable for the synthetic method that medicine industry is in batches produced.

It is starting raw material that the present invention adopts p bromophenol and toluylic acid, through five step unit processes such as ether condensation, (chlorination, condensation) alkylation, grignard reaction, dehydration, separation and salify, just makes qualified tamoxifen citrate.Its reaction formula is as follows:

When carrying out the ether condensation reaction by p bromophenol, we are starting raw material with commercial goods p bromophenol and β-dimethylamino-chloroethane hydrochloride directly, just can generate 2-(4-bromine phenoxy group through single step reaction)-N, the N-dimethyl amine.In reaction, we have for example successfully used quaternary ammonium salts such as four fourth brometo de amonios, tetraethyl ammonium iodide and benzyltriethylammoinium chloride as phase-transfer catalyst, make solvent with dioxane, ethylene dichloride, methylene dichloride, acetone.Make the condensing agent temperature of reaction with sodium hydroxide (50% aqueous solution) and can remain between 50-80 ℃, suitable temperature of reaction is 60-70 ℃, and reaction yield is about 60%.

Be feedstock production 1 by toluylic acid, during 2-two phenyl propyl ketones, we have adopted chlorination, condensation, the operate continuously of ethylization three-step reaction, one step completed method, and with sulfur oxychloride as chlorizating agent, the overall yield of three-step reaction is stabilized in about 78%, compare with substep operation, the not only high 5-10% of productive rate, and operation saving of time about 40%.

By chemical compounds I and compound ii during through grignard reaction synthetic compound III, be 1 as the compound of reaction raw materials and the mole ratio of compound ii: (1～1.2), preferably mole ratio is 1: 1.After question response is finished, steam earlier and remove tetrahydrofuran (THF), add ether then.Handle again.Crude product after the processing can carry out next step dehydration reaction.

By the compound III when dehydration reaction prepares the compound VI, used ethanol is to adopt 95% commercially available ethanol reagent.Reacting reflux time is 6-8 hour, and the crude product yield is about 98%, and the ratio of gained Z, E two isomer is 7: 3.

When two kinds of isomer of Z, E of separating and dehydrating reaction gained, we adopt hexane, heptane, methyl alcohol equal solvent to carry out the way of substep recrystallization, and the rate of recovery of triphen oxygen ammonium reaches about 80%, and the content of E-isomer is lower than 0.4%.

Synthetic method after the improvement has following advantage:

1, successfully introduces in the ether condensation reaction of this route owing to phase-transfer catalyst, therefore can directly make condensing agent with aqueous sodium hydroxide solution, this has just not only been avoided in the classical way (5), the a large amount of sodium Metal 99.5s of required use, make easy and simple to handle, safely, be beneficial to medicine industry production, and saved man-hour, improved productive rate, reduced cost.We had once carried out simultaneous test to two kinds of methods, now relevant data were listed in table one.

The effect that table one or two kind of method prepares the bromine Atenolol compares

(using the 10L reactor)-N to produce 1 kilogram of 2-(4-bromine phenoxy group, N-2 methyl ethyl-amine meter)

* dioxane is recyclable, and the rate of recovery is more than 90%.

2, because our employing is a raw material with the toluylic acid, and chlorination, condensation, the stagewise operation of ethylization three-step reaction change operate continuously into and once finish, and not only improve work efficiency 40%, and productive rate improves 5～10%.

3, after finishing, steams grignard reaction except that tetrahydrofuran (THF), and with substituted ether it, not only reclaimed valuable tetrahydrofuran (THF) effectively, in order to repeated use, and help aftertreatment, reduce operational losses, again in addition, in hydrolysis reaction, replace dehydrated alcohol and increased reacting reflux time, make from synthetic method in the past 1: 1 of the ratio of Z, E isomer improve 7: 3, increased the content of effective ingredient-Z type isomer as medicine with 95% ethanol.

4, when separating Z, E isomer, owing to utilized aforementioned three kinds of solvents to carry out the substep recrystallization method, yield is increased to 56.1% from 27.8% of Shenyang medicine institute.

In general, through improved synthetic method, synthetic method has shortened reactions steps and man-hour than before, has improved total yield greatly.People's such as Shenyang Pharmacy College meter will loyalty synthetic method tamoxifen citrate needs nine step operating units as previously mentioned, and only needs for five steps through our improved method.In the total yield of phenylformic acid is 34%, and the synthetic method of Shenyang Pharmacy College only is 2.5% in phenylformic acid, and this just must reduce the cost of product.

Embodiment one

1, the preparation of 2-phenylbenzene butanone: under 30～50 ℃ of temperature of reaction conditions, the 620ml sulfur oxychloride is splashed in the 900g toluylic acid, stirring and refluxing is till interior temperature rise to 120 ℃.The water pump decompression extracts the residue sulfur oxychloride.Add the 5.3L dry-out benzene.The 1kg aluminum trichloride (anhydrous) is added in the 10L reaction flask, and careful, gradation adds freshly prepd phenyllacetyl chloride benzole soln.Backflow 4hrs.Reaction solution gradation adding is filled in the container of 7kg trash ice and 2.1L hydrochloric acid (36%).After the hydrolysis, tell organic phase, water is used the 1L benzene extraction once, united extraction liquid.Till benzole soln is concentrated into remaining 4L.With the 15g Tetrabutyl amonium bromide, the 1.6kg50% aqueous sodium hydroxide solution adds in the residue benzole soln, and temperature is 30～40 ℃ in keeping, Dropwise 5 15ml monobromethane.Stirring and refluxing 6 hours.Add 0.5L water, make the solid dissolving.Tell organic phase, water 1L benzene extraction, combined benzene solution is with saturated sodium-chloride water solution washing three times, anhydrous magnesium sulfate drying.Steaming desolventizes back residuum vacuum distilling, collects 114～120 ℃/0.3～0.4mmHg cut.Must measure 1070～1170g, productive rate 72～79%(is that theoretical value is calculated with the toluylic acid).

Embodiment two

2-(4-bromine phenoxy group)-N, the preparation of N-dimethyl amine: p bromophenol (1384g), dioxane (3.2L), sodium hydroxide (640g), water (640ml) and benzyltriethylammoinium chloride (53g) are added in the 10L reaction flask, keep 60～70 ℃ of agitation and dropping β-dimethylin monochloroethane (isolating free β-dimethylin monochloroethane after by 40% sodium hydroxide solution alkaliization), dropwise the back and continue stirring reaction 5hrs by the saturated aqueous solution of 1.5kg β-dimethylamino-chloroethane hydrochloride.Steaming removes, reclaims dioxane, adds 3L ether and an amount of water in residuum, makes the solid dissolving, separation organic phase, water ether extraction secondary, united extraction liquid.Ether solution dilute hydrochloric acid extraction three times, hydrochloric acid extraction liquid washs secondary with ether, uses strong caustic alkaliization then, separates the organic liquor of separating out, water ether extraction three times.Merge organic liquor, wash secondary with saturated nacl aqueous solution, dried over anhydrous sodium carbonate.Steaming desolventizes, and 106～110 ℃/0.5～0.7mmHg cut is collected in residual solution vacuum distilling, gets product 1180～1235g, n ²⁵ _D: 1.5400～1.5410, productive rate 57.9～63.3%(is that theoretical basis is calculated with the p bromophenol).

Embodiment three

1-((4-β-dimethylamino ethoxy) phenyl)-1,2-phenylbenzene 1-butanols: 122.5g magnesium and 1220g2-(4-bromine phenoxy group) N, the N-dimethyl amine is made Grignard reagent in the 3.5L tetrahydrofuran (THF), at room temperature add 1120g1 then, tetrahydrofuran (THF) (3.5L) solution of 2-phenylbenzene butanone, stirring and refluxing 6hrs steams then and removes, reclaims tetrahydrofuran (THF), and the 7L ether is added in the residuum.Ammonium chloride solution (4kg ammonium chloride and 8L water) is added in the ether solution, after the hydrolysis, tell ether layer, divide the second extraction water with the 5L ether.Merge ether extracted liquid, steam and remove ether.Residuum 5% acetic acid extraction.Acetic acid extraction liquid is used concentrated sodium hydroxide alkaliization, benzene extraction after the ether washing.Steam except that the 1-((4-β-dimethylamino ethoxy) phenyl)-1 that promptly obtains about 1750g behind the benzene, 2-phenylbenzene 1-butanols crude product.Heavy Xie Jingke obtains pure product with methyl alcohol, mp120～121 ℃.

Embodiment four

The preparation of tamoxifen Z, E isomer mixture: the 1750g1-((4-β-dimethylamino ethoxy) phenyl)-1 that embodiment three is made, 2-phenylbenzene 1-butanols crude product is dissolved in 16L95% ethanol and 550ml hydrochloric acid (36%) mixing solutions, backflow 7hrs, be chilled to room temperature then, with strong caustic alkaliization, filtering sodium-chlor.Filtrate is concentrated into dried, the residuum ether dissolution, wash with water, steam and remove ether, get 1610g tamoxifen Z, E isomer crude mixture, through high pressure liquid chromatographic analysis, Z, E isomer mixture content are 98.4%, and impurity 1.6%, crude product productive rate are that 85.1%(is with 1,2-phenylbenzene butanone is that theoretical basis is calculated), wherein the Z-configuration is promptly:

Embodiment five

The separation and purification of tamoxifen (Z-configuration): with 1610g tamoxifen Z, twice in hexane recrystallization of E isomer mixture (wherein the Z-configuration contains 1120.6g) of embodiment four preparations, use the heptane recrystallization again three times, can get tamoxifen (Z-configuration) the about 700g of purity more than 99.2%.Wherein E-configuration content is lower than 0.4%, and the hexane mother liquor is concentrated into dried, uses recrystallizing methanol twice then, and the crystallization main component is the E-configuration.Methanol mother liquor and heptane mother liquor are concentrated into dried respectively, and residuum merges, and uses hexane recrystallization in heptan again, can obtain the pure Z-configuration product of a part again, twice of repetitive operation.Altogether pure Z-configuration product 903g, the rate of recovery is 80%.

Embodiment six

The preparation of tamoxifen citrate: according to a conventional method, 1kg tamoxifen (Z-configuration) is dissolved in 3.5L acetone, the 1kg anhydrous citric acid is dissolved in 3.5L acetone, mix then, stirred 1 hour fast, behind the salify, filter, solid once gets 1450～1500g tamoxifen citrate with acetone recrystallization again.Mp143～145 ℃ E-configuration content is lower than 0.4%, productive rate 96～99%.

Reference

(1) meter will loyalty etc. " research (bulletin) of the anti-breast cancer new drug-ulcer of loosing peace (Tamoxifon) Citrate trianion "

Participate in 1984 national synthetic drugs experience exchangement meeting paper in October, 1984

〔2〕U.K.Pat.1，031，907

〔3〕U.K.Pat.1，354，939

〔4〕JaPan KoKai 77，122，351

〔5〕David W.Robertson J.Org.Chem.1982，47，2390

Claims (6)

1, a kind of synthetic citric acid triphenylamine oxide (chemical name: the method for (Z-2-(4-(1,2-phenylbenzene-1-butylene base)-phenoxy group)-N, N-dimethyl amine citrate salt 1: 1), comprising:

-in the presence of phase-transfer catalyst, make p bromophenol and β-dimethylin monochloroethane play the ether condensation reaction, sodium hydroxide is made condensing agent, generates chemical compounds I;

-generate compound ii by toluylic acid through chlorination, condensation and three step of alkylation successive reaction;

-compound ii and I are carried out grignard reaction and are generated the compound III;

-compound III generates the compound IV through dehydration reaction;

-compound IV generates V through the organic solvent recrystallization;

-press well-established law compound V and citric acid to generate the tamoxifen citrate salt.

Its reaction formula is as follows:

2, tamoxifen citrate synthetic method according to claim 1 when being played ether condensation reaction generation chemical compounds I by p bromophenol and β-dimethylin monochloroethane, is characterized in that having used phase-transfer catalyst in the reaction.For example Tetrabutyl amonium bromide, tetraethyl ammonium iodide, quaternary ammonium salts such as benzyltriethylammoinium chloride, solvent for use can be any one in dioxane, ethylene dichloride, methylene dichloride, the acetone equal solvent, temperature of reaction can be 50-80 ℃, β-dimethylin monochloroethane and p bromophenol mole ratio are (1.1～1.5): 1, the mole ratio of sodium hydroxide and p bromophenol is (1.5～4): 1, and the mol amount ratio that is more suitable for is 2: 1.

3, the synthetic method of tamoxifen citrate according to claim 1, by toluylic acid when chlorination, condensation and alkylation successive reaction prepare compound ii, it is characterized in that it is chlorizating agent that chlorination reaction adopts sulfur oxychloride, the alkylated reaction that carries out phase-transfer catalysis is with for example, quaternary ammonium salts such as Tetrabutyl amonium bromide, tetraethyl ammonium iodide, benzyltriethylammoinium chloride are made catalyzer, and the equivalence ratio scope of sodium hydroxide 50% aqueous solution and toluylic acid is 2-4.

4, the synthetic method of tamoxifen citrate according to claim 1 when compound ii and I are carried out Ge Liweiya reacting generating compound III, is characterized in that the mole ratio of compound ii and I is 1: (1～1.2).

5, the synthetic method of tamoxifen citrate according to claim 1 is carried out dehydration reaction when preparing the compound IV in the compound III, and raw materials used compound III is that ethanol is 95% commercial goods without the crude product of purifying, and the reaction times is backflow 6-8 hour.

6, the synthetic method of tamoxifen citrate according to claim 1 with substep recrystallization method separating compound IV the time, is characterized in that solvent for use is respectively hexane, heptane, methyl alcohol.