CN104119236A - Synthesis of Lorcaserin and preparation method of intermediate of Lorcaserin - Google Patents

Abstract

The invention relates to the field of pharmaceutical chemistry and relates to a method for preparing (R)-8-chlorine-1-methyl-2,3,4,5-tetrahydro-1H-3-benzodiazepine hydrochloride (Lorcaserin) and an intermediate of Lorcaserin. (R)-8-chlorine-1-methyl-2,3,4,5-tetrahydro-1H-3-benzodiazepine hydrochloride (Lorcaserin) which is an active material of a weight-loss drug is prepared from epoxy propane and p-chlorophenyl ethylamine serving as starting raw materials through the steps of ring opening, chlorination, cyclization, tartaric acid splitting, dissociation, salification and the like.

Description

The preparation method of the synthetic and intermediate in a kind of sieve card XiLin (Lorcaserin)

Technical field

The present invention relates to pharmacy field, specifically, the present invention relates to the chloro-1-of one (R)-8-methyl-2, the preparation method of 3,4,5-tetrahydrochysene-1H-3-benzazepine hydrochloride (Lorcaserin) and intermediate.

Background technology

Sieve card XiLin (Lorcaserin) is the diet pill (weight-loss drug) of FDA approval on June 27th, 2012.A kind of selectivity 5-HT2c receptor stimulant (5-HT2c receptor agonist) of being developed by Arena Pharmaceuti, activates the satisfaction that hypothalamic 5-HT2c acceptor can appetite, thereby appetite control reaches the object of fat-reducing.Its commodity are called Belviq.Obesity can cause various diseases, as cerebral embolism, the coronary heart disease that declines, hypertension, fatty liver, cardiorespiratory failure, internal secretion and metabolic disease etc.

The patent documentation CN03808272.1 of Yuan Yan company application, the four kinds of methods that have of CN200480016780.3 report are prepared sieve card XiLin.

It is raw material and the condensation of 2-chlorpromazine chloride that method one adopts chlorobenzene ethamine, makes intermediate 2-(4-chloro-phenyl-) ethyl-N-2-chlorine propionic acid amide; This intermediate reduces or first reduces to close to encircle again and makes racemization sieve card XiLin after the ring of pass, then makes sieve card XiLin hydrochloride through splitting salify.The shortcoming of this scheme is that 2-chlorpromazine chloride activity is too high, has pungency and corrodibility, and decomposition can produce HCl and 2-chloropropionic acid easily causes environmental pollution.Its synthetic route is as follows:

Method two taking 4-Chlorophenylacetic acid as starting raw material and 2-chlorine propylamine (or 2-bromine propylamine) condensation make intermediate 2-(4-chloro-phenyl-)-N-(2-chloropropyl); This intermediate reduces or first reduces to close to encircle again and makes racemization sieve card XiLin after the ring of pass, then makes sieve card XiLin hydrochloride through splitting salify.The shortcoming of this scheme is that reagent 2-chlorine propylamine (or 2-bromine propylamine) is difficult to commercialization, has restricted the industrialized developing of this synthesis technique.Its synthetic route is as follows:

It is that raw material reacts with 2-chlorine propionic aldehyde through reductive agent reduction that method three adopts chlorobenzene ethamine, makes intermediate 2-(4-chloro-phenyl-)-N-ethyl-N-2-chloropropane; This intermediate makes racemization sieve card XiLin through closing ring, then makes sieve card XiLin hydrochloride through splitting salify.The shortcoming of this scheme is that reagent 2-chlorine propionic aldehyde is difficult to commercialization, has restricted the industrialized developing of this synthesis technique.Its synthetic route is as follows:

Method four taking to chlorophenethylol as raw material, after halo, make haloethyl chlorobenzene, make key intermediate 1-[[2-(4-chloro-phenyl-) ethyl with α-amino isopropyl alcohol condensation again] amino]-2-hydroxy propane, it makes 1-[[2-(4-chloro-phenyl-) ethyl through chloro] amino]-2 cbloropropane isopropyl chloride hydrochloride; This intermediate makes racemization sieve card XiLin through closing ring, then makes sieve card XiLin hydrochloride through splitting salify.This scheme is the former synthetic syntheti c route grinding, but the same existent defect of this route, patent CN200980116092.7 exists two to replace by product 1-(two (4-chlorobenzene ethyl) amino) propan-2-ol.This route has good industrial advantages, and key is intermediate 1-[[2-(4-chloro-phenyl-) ethyl] amino] preparation of-2-hydroxy propane (formula I compound).Its synthetic route is as follows:

Key intermediate 1-[[2-(4-chloro-phenyl-) ethyl] amino]-2-hydroxy propane (formula I compound), patent documentation CN200780045133.9 has also reported another kind of preparation method, but the process of the method preparation I compound is loaded down with trivial details, without suitability for industrialized production advantage.Its synthetic route is as follows:

Summary of the invention

The object of this invention is to provide a kind of new chloro-1-of (R)-8-methyl-2, the preparation method of 3,4,5-tetrahydrochysene-1H-3-benzazepine hydrochloride (Lorcaserin) and intermediate.Through research, invent new easy to be industrialized 1-[[2-(4-chloro-phenyl-) ethyl] amino] preparation method of-2-hydroxy propane (formula I compound), advantage is that reaction directly makes this intermediate, operating process simple possible.Specifically, the invention provides a kind of so that chlorobenzene ethamine is prepared to key intermediate 1-[[2-(4-chloro-phenyl-) ethyl as starting raw material and propylene oxide] amino]-2-hydroxy propane (formula I compound), further prepare the method for sieve card XiLin hydrochloride, this route can obtain steady quality starting raw material from commercial channels, operating process is simple and convenient, is suitable for suitability for industrialized production.Its synthetic route chart is as follows:

Brief description of the drawings

The HNMR spectrogram of Fig. 1 formula I compound (1-[[2-(4-chloro-phenyl-) ethyl] amino]-2-hydroxy propane);

The HNMR spectrogram of Figure 21-[[2-(4-chloro-phenyl-) ethyl] amino]-2 cbloropropane isopropyl chloride hydrochloride;

The chloro-1-of Fig. 3 (R)-8-methyl-2, the HNMR spectrogram of 3,4,5-tetrahydrochysene-1H-3-benzazepine hydrochloride (sieve card XiLin);

The chloro-1-of Fig. 4 (R)-8-methyl-2, the MS spectrogram of 3,4,5-tetrahydrochysene-1H-3-benzazepine hydrochloride (sieve card XiLin);

Specific embodiments

Embodiment 1,1-[[2-(4-chloro-phenyl-) ethyl] amino] preparation of-2-hydroxy propane (formula I compound)

In 50L reactor, add 30kg water, stir, under room temperature, add propylene oxide 373.2g, stir, subsequently, slowly add 1000g to chlorobenzene ethamine, stir and be slowly warming up to 90 ± 5 DEG C, react 5 hours, be cooled to room temperature, add methylene dichloride 15L × 3 extraction three times, combined dichloromethane layer, spend the night with 1kg anhydrous sodium sulfate drying, filter, filtrate is concentrated into dry light yellow solid 1250g.Yield 91%.

¹HNMR(d6-DMSO，400Hz)δ(ppm)：8.44(br，1H)，7.39～7.41(d，2H)，7.28～7.30(d，2H)，5.33(d，1H)，3.92(m，1H)3.09～3.13(t，2H)，2.93～2.97(m，3H)，2.73～2.79(m，1H)，1.11～1.12(d，3H)。

Embodiment 2,1-[[2-(4-chloro-phenyl-) ethyl] amino] preparation of-2 cbloropropane isopropyl chloride hydrochloride

In the there-necked flask of 2L, add 500ml toluene, 1-[[2-(4-chloro-phenyl-) ethyl of 75g] amino]-2-hydroxy propane, DMF40g, thionyl chloride 250g, mixes evenly to 65 DEG C of reactions, 40 DEG C time molten clear (colourless), along with the rising of temperature, color is deepened gradually.React after three hours TLC (DCM: MeOH=10: 1) detect raw material complete reaction.Stop heating, ice-water bath cools to below 10 DEG C, suction filtration, and toluene 300ml*2 washing, filter cake spends the night with the making beating of 1000ml Virahol.Next day, suction filtration, 200ml × 2 washed with isopropyl alcohol, 40 DEG C of dry 4h of baking oven, obtain 63g white solid.Yield 73.8%.

¹HNMR(d6-DMSO，400Hz)δ(ppm)：9.58(br，1H)，9.19(br，1H)，7.39(d，2H)，7.31(d，2H)，4.54～4.59(m，1H)，3.39(m，1H)，3.24(m，1H)，3.14～3.21(m，2H)，3.00～3.04(m，2H)，1.53～1.55(d，3H)。

Embodiment 3,8-are chloro-2,3,4, the preparation of 5-tetrahydrochysene-1-methyl isophthalic acid H-3-benzazepine

In the reaction flask of 2000ml, add 1 of 600ml, 2-dichlorobenzene, adds 1-[[2-(4-chloro-phenyl-) ethyl successively] amino]-2 cbloropropane isopropyl chloride hydrochloride 60g, aluminum chloride 80g, is warmed up to 130 DEG C of reactions.60 DEG C of material dissolutions, 110 DEG C molten clear.TLC (DCM: MeOH=10: 1) detect raw material and disappear, stop heating, naturally cool to room temperature.Slowly add the HCl solution 800ml of 1N, methyl tertiary butyl ether 400ml, stirs, separatory, HCl solution 400mL × 2 extraction of 1N for organic phase.Merge water, adjust pH > 11 with 30% sodium hydroxide solution, with the extraction of methyl tertiary butyl ether 800ml × 3, merge organic phase, anhydrous sodium sulfate drying, filters, and is spin-dried for.Obtain the thick product of 64g.

Embodiment 4, the chloro-1-of (R)-8-methyl-2, the preparation (fractionation) of 3,4,5-tetrahydrochysene-1H-3-benzazepine, half L-(+)-tartrate

The thick product (64g) of example 3 gained is dissolved in the trimethyl carbinol (200mL), adds the tartaric aqueous solution of L-(+) (acid of 9.4g and the water of 14mL are formulated).At 15～25 DEG C by stirring overnight solution until separate out solid.Filter gained suspension and use washing with acetone throw out.Throw out is added in other trimethyl carbinol 200mL and water 5mL and reflux again, add water 40mL and dissolve completely to throw out, filtration, filtrate is cooled to 15～25 DEG C, and stirring is spent the night.Filter, use proper amount of acetone washing leaching cake, filter cake vacuum-drying at 60 DEG C.Obtain product 15g.

Embodiment 5, the free chloro-1-of (R)-8-methyl-2, the preparation (dissociating) of 3,4,5-tetrahydrochysene-1H-3-benzazepine

By the chloro-1-of (R)-8-methyl-2 of example 4 gained, 3,4, half L-(+)-tartrate 15g is soluble in water for 5-tetrahydrochysene-1H-3-benzazepine, and the sodium hydroxide solution with 30% is adjusted pH > 11, the extraction of methyl tertiary butyl ether 200ml × 3, merge organic phase, anhydrous sodium sulfate drying, filters, and is spin-dried for.Obtain the free chloro-1-of (R)-8-of 9.2g methyl-2,3,4,5-tetrahydrochysene-1H-3-benzazepine, yield 85%.

Embodiment 6, the chloro-1-of (R)-8-methyl-2, the preparation of 3,4,5-tetrahydrochysene-1H-3-benzazepine hydrochloride (sieve card XiLin)

In the single port bottle of 500ml, add the chloro-1-of 9.2g (R)-8-methyl-2,3,4,5-tetrahydrochysene-1H-3-benzazepine, is dissolved in second 30mL ethyl acetate, slowly passes into HCl gas, have a large amount of solids to separate out, suction filtration, with 30ml × 2 ethyl acetate solution washing leaching cake, filter cake is in 60 DEG C of vacuum-drying 4h, obtain the chloro-1-of 6.5g (R)-8-methyl-2,3,4,5-tetrahydrochysene-1H-3-benzazepine hydrochloride, yield 59.6%.

¹HNMR(d6-DMSO，400Hz)δ(ppm)：7.18～7.23(m，3H)，3.36～3.38(m，1H)，3.09～3.19(m，3H)，2.97～3.01(m，1H)，2.79～2.83(m，2H)，1.31～1.33(d，3H)。

MS (molecular formula: C ₁₁h ₁₄clNHCl): m/z=196 (M+H ⁺-HCl).

Except described herein those, those skilled in the art's apparent multiple correction of the present invention from the above description.These corrections are also intended to belong to the category of appended claims.

Claims (4)

1. sieve card XiLin (Lorcaserin) 1-[[2-(4-chloro-phenyl-) ethyl] amino] preparation method of-2-hydroxy propane (formula I compound) intermediate, its preparation process is as follows:

A. water, propylene oxide with chlorobenzene ethamine is mixed;

B. stir slowly and heat up and react;

C. react completely with dichloromethane extraction, extraction liquid is concentrated into dry light yellow solid, i.e. 1-[[2-(4-chloro-phenyl-) ethyl] amino]-2-hydroxy propane.

2. the method for claim 1, is characterized in that adopting propylene oxide and is reactant to chlorobenzene ethamine.

3. the method for claim 1, is characterized in that needing temperature reaction, and temperature range is preferably 90 ± 5 DEG C.

4. according to claim 2, propylene oxide and to mole proportioning of chlorobenzene ethamine 1: 1 to 1: 2.