Summary of the invention:
Main purpose of the present invention is the synthetic method by the improvement ranimustine, and the consumption of side chain N-skatole is reduced, and total recovery improves, and simplifies the operation, and reduces cost, and makes it to be easier to suitability for industrialized production.Major technique characteristics of the present invention are: " splitting after earlier ".
Be about to 4 of racemization; 5,6, the vitriol (or hydrochloride) of 7-tetrahydrochysene-1H-benzoglyoxaline-5-formic acid through chlorination, with the indoline acidylate make 5-formyl indoline-4; 5; 6,7-tetrahydrochysene-1H-benzoglyoxaline splits with D-dibenzoyl tartaric acid or tartrate again; obtain R-5-formic acid-4 after the hydrolysis; 5,6,7-tetrahydrochysene-1H-benzoglyoxaline hydrochloride (structural formula II I).It makes R-5-formylpyrrole alkane-4 through chlorination, acidylate again; 5; 6,7-tetrahydrochysene-1H-benzoglyoxaline hydrochloride (active amide, structural formula II); with the reaction of N-skatole, the free R-5-[(1-Methyl-1H-indole-3-yl that generates) carbonyl]-4; 5,6,7-tetrahydrochysene-1H-benzoglyoxaline (ranimustine; structural formula I), last salify obtains ramosetron hydrochloride.
Specifically, preparation process can be divided into two portions:
(1) R-5-formic acid-4,5,6, the preparation of 7-tetrahydrochysene-1H-benzoglyoxaline hydrochloride
This compound can be with reference to disclosed document (Mitsuaki Ohta etc., Chem.Pharm.Bull., 44 (9): 1707~1716; U.S 5677326) be prepared.
1. 5-formyl chloride-4,5,6, the preparation of the vitriol (or hydrochloride) of 7-tetrahydrochysene-1H-benzoglyoxaline.
With 4 of racemization, 5,6, the vitriol (or hydrochloride) of 7-tetrahydrochysene-1H-benzoglyoxaline-5-formic acid is (as: ethylene dichloride, acetonitrile etc.) or direct and excessive sulfur oxychloride reaction in appropriate solvent, generate 5-formyl chloride-4,5,6, the vitriol (or hydrochloride) of 7-tetrahydrochysene-1H-benzoglyoxaline.
2. 5-formyl indoline-4,5,6, the preparation of 7-tetrahydrochysene-1H-benzoglyoxaline
Selecting indoline as acylating agent, is because it can be introduced than macoradical near the chiral centre in molecule, is convenient to split.Concrete grammar is with 5-formyl chloride-4,5,6, the vitriol (or hydrochloride) of 7-tetrahydrochysene-1H-benzoglyoxaline and indoline (as: triethylamine, salt of wormwood etc.) or direct and excessive indoline condensation reaction under alkaline condition generate 5-formyl indoline-4,5,6,7-tetrahydrochysene-1H-benzoglyoxaline.
3. R-5-formyl indoline-4,5,6, the preparation of 7-tetrahydrochysene-1H-benzoglyoxaline hydrochloride
With the 5-formyl indoline-4,5 of racemization, 6,7-tetrahydrochysene-1H-benzoglyoxaline and resolving agent D-dibenzoyl tartaric acid or tartrate is (as: methyl alcohol etc.) periodic crystallisation in alcoholic solvent, until obtaining the sufficiently high R-5-formyl of optical purity indoline-4,5,6, the D-dibenzoyl tartaric acid or the tartrate of 7-tetrahydrochysene-1H-benzoglyoxaline, free through alkalizing again, salify get R-5-formyl indoline-4,5,6,7-tetrahydrochysene-1H-benzoglyoxaline hydrochloride.
4. R-5-formic acid-4,5,6, the preparation of 7-tetrahydrochysene-1H-benzoglyoxaline hydrochloride (structural formula I)
With R-5-formyl indoline-4,5,6, the reaction that under acid (as: hydrochloric acid, sulfuric acid etc.) or alkalescence (sodium hydroxide, yellow soda ash etc.) condition, is hydrolyzed of 7-tetrahydrochysene-1H-benzoglyoxaline hydrochloride, generation R-5-formic acid-4,5,6,7-tetrahydrochysene-1H-benzoglyoxaline.
(2) carbonyl R-5-[(1-Methyl-1H-indole-3-yl)]-4,5,6,7-tetrahydrochysene-1H-benzoglyoxaline (ranimustine)
By R-5-formic acid-4,5,6,7-tetrahydrochysene-1H-benzoglyoxaline prepares R-5-[(1-Methyl-1H-indole-3-yl) carbonyl]-4,5,6,7-tetrahydrochysene-1H-benzoglyoxaline (ranimustine) though method from unexposed mistake, but still can be with reference to open source literature (Mitsuaki Ohta etc., Chem.Pharm.Bull., 45 (5): 1000~1008) be prepared.
1. R-5-formyl chloride-4,5,6, the preparation of 7-tetrahydrochysene-1H-benzoglyoxaline hydrochloride
With R-5-formic acid-4,5,6,7-tetrahydrochysene-1H-benzoglyoxaline hydrochloride is (as: ethylene dichloride, acetonitrile etc.) or direct and excessive sulfur oxychloride reaction in appropriate solvent, generates R-5-formyl chloride-4,5,6,7-tetrahydrochysene-1H-benzoglyoxaline hydrochloride.
2. R-5-formylpyrrole alkane-4,5,6, the preparation of 7-tetrahydrochysene-1H-benzoglyoxaline hydrochloride (active amide, structural formula II)
With R-5-formyl chloride-4,5,6,7-tetrahydrochysene-1H-benzoglyoxaline hydrochloride and tetramethyleneimine be (as: triethylamine, salt of wormwood etc.) or direct and excessive tetramethyleneimine condensation reaction under alkaline condition, generates R-5-formylpyrrole alkane-4,5,6,7-tetrahydrochysene-1H-benzoglyoxaline hydrochloride.
Experiment showed, that by R-5-formyl chloride-4,5,6 7-tetrahydrochysene-1H-benzoglyoxaline hydrochloride prepares ranimustine, must at first prepare this intermediate (active amide), otherwise can't generate target product.
3. carbonyl R-5-[(1-Methyl-1H-indole-3-yl)]-4,5,6, the preparation of 7-tetrahydrochysene-1H-benzoglyoxaline (ranimustine, structural formula II I)
With R-5-formylpyrrole alkane-4,5,6,7-tetrahydrochysene-1H-benzoglyoxaline hydrochloride (active amide) reacts with the N-skatole under the phosphorus oxychloride effect, after alkali is free, generate target product R-5-[(1-Methyl-1H-indole-3-yl) carbonyl]-4,5,6,7-tetrahydrochysene-1H-benzoglyoxaline (ranimustine) can make ramosetron hydrochloride behind its salify.
In sum, with " split earlier after " of the present invention though that method prepares the ranimustine reaction scheme is longer, but total recovery higher (experiment shows that comparable original " splitting after the first condensation " the method total recovery of employing " splitting after earlier " method of the present invention improves 4%), especially resolution yield significantly high (experiment show adopt " splitting after earlier " of the present invention method to split comparable original " splitting after the first condensation " method yield improve nearly a times), the consumption of side chain N-skatole lowers significantly that (experiment shows " splitting after earlier " the of the present invention method that adopts, original " splitting after the first condensation " method of N-skatole consumption rate reduces more than 60%), solvent is convenient to recycling, easy and simple to handle, cost is lower.Especially can realize " cooking all things in one pot " operate continuously after splitting, be convenient to suitability for industrialized production.
Embodiment:
Embodiment 1:5-formyl chloride-4,5,6, the preparation (method A) of 7-tetrahydrochysene-1H-benzoglyoxaline vitriol
With 5-formic acid-4,5,6,7-tetrahydrochysene-1H-benzoglyoxaline vitriol 43.4g (0.20mol) suspends in the 500ml ethylene dichloride, adds sulfur oxychloride 47.6g (0.40mol), stirs, heat temperature raising to 60 ℃, insulation reaction 2 hours removes solvent under reduced pressure, get 5-formyl chloride-4,5,6, the crude product 36.6g of 7-tetrahydrochysene-1H-benzoglyoxaline vitriol, yield: 77.7%, it need not further refining, can be directly used in following reaction.
Embodiment 2:5-formyl chloride-4,5,6, the preparation (method B) of 7-tetrahydrochysene-1H-benzoglyoxaline vitriol
5-formyl chloride-4,5,6,7-tetrahydrochysene-1H-benzoglyoxaline vitriol also can directly make with big excessive sulfur oxychloride reaction, and concrete method is with 5-formic acid-4,5,6,7-tetrahydrochysene-1H-benzoglyoxaline vitriol 43.4g (0.20mol) is suspended among the sulfur oxychloride 238g (2.0mol), stirs, heat temperature raising is to refluxing, reacted 2 hours, concentrating under reduced pressure reclaims excessive sulfur oxychloride, gets 5-formyl chloride-4,5,6,7-tetrahydrochysene-1H-benzoglyoxaline vitriol crude product 42.8g, yield: 90.9%, it also need not further refining, can be directly used in following reaction.
Embodiment 3:5-formyl chloride-4,5,6, the preparation of 7-tetrahydrochysene-1H-benzoglyoxaline hydrochloride
With reference to embodiment 1 or 2, with 5-formic acid-4,5,6,7-tetrahydrochysene-1H-benzoglyoxaline hydrochloride replaces 5-formic acid-4,5,6, and 7-tetrahydrochysene-1H-benzoglyoxaline vitriol, gained crude product need not further refining, can be directly used in following reaction.
Embodiment 4:5-formyl indoline-4,5,6, the preparation (method C) of 7-tetrahydrochysene-1H-benzoglyoxaline
Will be by the 5-formyl chloride-4 of embodiment 2 preparations, 5,6, the crude product 35.3g (0.15mol) of 7-tetrahydrochysene-1H-benzoglyoxaline vitriol is suspended in the 200ml acetonitrile, is cooled to below 5 ℃, dropping contains the 200ml acetonitrile solution of indoline 178g (1.5mol), the control rate of addition makes temperature of reaction between 5~10 ℃, drips and finishes, be warming up to 25 ℃, insulation reaction 2 hours.Be evaporated to driedly, resistates is with ethylene dichloride 500ml dissolving, and washes with water to neutrality, is evaporated to driedly again, and resistates ethyl acetate crystallization is filtered, and dries.5-formyl indoline-4,5,6,7-tetrahydrochysene-1H-benzoglyoxaline 32.8g, yield: 81.3%, M.p:182~186 ℃.
Embodiment 5:5-formyl indoline-4,5,6, the preparation (method D) of 7-tetrahydrochysene-1H-benzoglyoxaline
5-formyl indoline-4,5,6,7-tetrahydrochysene-1H-benzoglyoxaline also can be prepared with alkaline de-acidying agent in solvent.Concrete method is with the 5-formyl chloride-4 by embodiment 2 preparations, 5,6, the crude product 35.3g (0.15mol) of 7-tetrahydrochysene-1H-benzoglyoxaline vitriol is suspended in the 200ml ethylene dichloride, is cooled to below 5 ℃, dropping contains the 200ml dichloroethane solution of indoline 21.4g (0.18mol) and triethylamine 45.5g (0.45mol), the control rate of addition makes temperature of reaction between 5~10 ℃, drips and finishes, be warming up to 25 ℃, insulation reaction 2 hours.In the about 500ml water of its impouring, stirring at room is after 10 minutes, and separatory, organic layer wash with water to neutrality, is evaporated to driedly, and resistates adds ethyl acetate 200ml and stirs and to spend the night, and filters the solid of being separated out, oven dry.5-formyl indoline-4,5,6,7-tetrahydrochysene-1H-benzoglyoxaline 36.2g, yield: 89.7%, M.p:218~220 ℃.
Embodiment 6:5-formyl indoline-4,5,6, the preparation (method E) of 7-tetrahydrochysene-1H-benzoglyoxaline
With reference to embodiment 4 or 5, with 5-formyl chloride-4,5,6, the hydrochloride of 7-tetrahydrochysene-1H-benzoglyoxaline replaces 5-formyl chloride-4,5,6, and the vitriol of 7-tetrahydrochysene-1H-benzoglyoxaline reacts.
Embodiment 7:R-5-formyl indoline-4,5,6, the preparation (method F) of 7-tetrahydrochysene-1H-benzoglyoxaline hydrochloride
Will be by the 5-formyl indoline-4,5,6 of embodiment 5 preparation, 7-tetrahydrochysene-1H-benzoglyoxaline 26.9g (0.10mol) is dissolved in the 300ml methyl alcohol, adds (+)-tartrate 15g (0.10mol), and heating reflux reaction 4 hours, is chilled to room temperature, filters.Filter cake refluxed 4 hours with methyl alcohol 300ml once more, and cooling is filtered, oven dry.R-5-formyl indoline-4,5,6, (+)-tartrate 15.8g of 7-tetrahydrochysene-1H-benzoglyoxaline, M.p:228~230 ℃, [α]
D=+1.7 ° (C=0.7, DMF).
With above-mentioned R-5-formyl indoline-4,5,6, (+)-tartrate of 7-tetrahydrochysene-1H-benzoglyoxaline is dissolved in the mixture of being made up of 100ml ethylene dichloride and 100ml water, sodium hydroxide with 20% is transferred pH=9~10, separatory, and organic layer is washed to neutrality, be evaporated to dried again, resistates adds dissolve with ethanol, and the acidic alcohol with 30% is transferred pH=1~2, crystallization, filter oven dry.R-5-formyl indoline-4,5,6, the hydrochloride 11.8g of 7-tetrahydrochysene-1H-benzoglyoxaline, yield: 38.5%, M.p:240~242 ℃, [α]
D=-19.5 ° (C=1.0, methyl alcohol).
Embodiment 8:R-5-formyl indoline-4,5,6, the preparation (method G) of 7-tetrahydrochysene-1H-benzoglyoxaline hydrochloride
R-5-formyl indoline-4,5,6,7-tetrahydrochysene-1H-benzoglyoxaline hydrochloride also can obtain by splitting with the D-dibenzoyl tartaric acid, concrete method is with the 5-formyl indoline-4 by embodiment 5 preparations, 5,6,7-tetrahydrochysene-1H-benzoglyoxaline 26.9g (0.10mol) and D-dibenzoyl tartaric acid monohydrate 37.6g (0.1mol) are dissolved in the 500ml methyl alcohol in the lump, and reflux, reacted 1 hour, and be chilled to room temperature, filter.Gained filter cake, salify free with embodiment 7 similar methods, R-5-formyl indoline-4,5,6, the hydrochloride 12.6g of 7-tetrahydrochysene-1H-benzoglyoxaline, yield: 41.2%, M.p:240~242 ℃, [α]
D=-19.2 ° (C=1.0, methyl alcohol).
Embodiment 9:R-5-formic acid-4,5,6, the preparation (structural formula I, method H) of 7-tetrahydrochysene-1H-benzoglyoxaline hydrochloride
Will be by the R-5-formyl indoline-4,5 of embodiment 7 preparations, 6,7-tetrahydrochysene-1H-benzoglyoxaline hydrochloride 61.1g (0.2mol) is dissolved in the 300ml methyl alcohol, add sodium hydroxide 20g (0.5mol), stir, and be heated to backflow, react after 3 hours, be evaporated to driedly, resistates adds ethylene dichloride 100ml and water 200ml dissolving, separatory, water layer is transferred pH=1~2 with hydrochloric acid, is evaporated to dried again.Get R-5-formic acid-4,5,6, the mixture of 7-tetrahydrochysene-1H-benzoglyoxaline hydrochloride and sodium-chlor, it need not further refining, can be directly used in following reaction.
Embodiment 10:R-5-formic acid-4,5,6, the preparation (method I) of 7-tetrahydrochysene-1H-benzoglyoxaline hydrochloride
R-5-formic acid-4,5,6,7-tetrahydrochysene-1H-benzoglyoxaline hydrochloride also can be by making R-5-formyl indoline-4,5,6, the hydrolysis and making under acidic conditions of 7-tetrahydrochysene-1H-benzoglyoxaline hydrochloride.Its concrete method is, will be by the R-5-formyl indoline-4,5 of embodiment 7 preparations, 6,7-tetrahydrochysene-1H-benzoglyoxaline hydrochloride 61.1g (0.2mol) is dissolved in the hydrochloric acid (0.6mol) of 300ml 2N, is heated to backflow, reacts after 3 hours, be evaporated to dried, resistates is dissolved in the 300ml water, and the sodium hydroxide solution with 20% is transferred pH=9~10, adds ethylene dichloride 100ml and extracts, water layer is transferred pH=1~2 with hydrochloric acid again, is evaporated to dried.Get R-5-formic acid-4,5,6, the mixture of 7-tetrahydrochysene-1H-benzoglyoxaline hydrochloride and sodium-chlor, it need not further refining, can be directly used in following reaction.
Embodiment 11:R-5-formyl chloride-4,5,6, the preparation of 7-tetrahydrochysene-1H-benzoglyoxaline hydrochloride
With reference to embodiment 1 or 2, use R-5-formic acid-4 by embodiment 10 preparations, 5,6, the 7-tetrahydrochysene-hydrochloride of 1H-benzoglyoxaline and the mixture of sodium-chlor replace 5-formic acid-4,5,6, the vitriol of 7-tetrahydrochysene-1H-benzoglyoxaline, yield are respectively 81% (method A) and 92% (method B), the gained crude product need not further refining, can be directly used in following reaction.
Embodiment 12:R-5-formylpyrrole alkane-4,5,6, the preparation of 7-tetrahydrochysene-1H-benzoglyoxaline hydrochloride (structural formula II, active amide)
With reference to embodiment 4 or 5, use R-5-formyl chloride-4,5,6 by embodiment 11 preparations, the hydrochloride of 7-tetrahydrochysene-1H-benzoglyoxaline replaces 5-formyl chloride-4,5,6, the vitriol of 7-tetrahydrochysene-1H-benzoglyoxaline, replace indoline to react with tetramethyleneimine simultaneously, yield is respectively 82% (method C) and 93% (method D), M.p:>250 ℃, [α]
D=-5.8 ° (C=1.12, methyl alcohol).
Embodiment 13:R-5-[(1-Methyl-1H-indole-3-yl) carbonyl]-4,5,6, the preparation of 7-tetrahydrochysene-1H-benzoglyoxaline (structural formula II I, ranimustine)
Will be by the R-5-formylpyrrole alkane-4 of embodiment 12 preparations, 5,6,7-tetrahydrochysene-1H-benzoglyoxaline hydrochloride (active amide) 25.8g (0.10mol), N-skatole 19.7g (0.15mol), phosphorus oxychloride 45.9g (0.30mol) and 1,2-ethylene dichloride 300ml mixes, heating reflux reaction 7 hours.Be chilled to room temperature, in the about 500g frozen water of its impouring, separatory, water layer is transferred pH=9~10 with 20% sodium hydroxide, and solid filters after separating out fully, washing, oven dry.Get R-5-[(1-Methyl-1H-indole-3-yl) carbonyl]-4,5,6,7-tetrahydrochysene-1H-benzoglyoxaline (ranimustine) 26.2g, yield: 93.2%, M.p:>200 ℃ (decomposition).
Embodiment 14:R-5-[(1-Methyl-1H-indole-3-yl) carbonyl]-4,5,6, the preparation of 7-tetrahydrochysene-1H-benzoglyoxaline (ranimustine) (" cooking all things in one pot " method)
Will be by the R-5-formyl indoline-4,5 of embodiment 7 preparations, 6,7-tetrahydrochysene-1H-benzoglyoxaline hydrochloride 61.1g (0.2mol) is dissolved in the 300ml methyl alcohol, add sodium hydroxide 20g (0.5mol), stir, and be heated to backflow, react after 3 hours, be evaporated to driedly, resistates adds ethylene dichloride 100ml and water 200ml dissolving, separatory, water layer is transferred pH=1~2 with hydrochloric acid, is evaporated to dried again.
The gained resistates is suspended among the sulfur oxychloride 238g (2.0mol), stirs, heat temperature raising is to refluxing, reacted 2 hours, concentrating under reduced pressure reclaims excessive sulfur oxychloride, and the gained resistates is suspended in 300ml 1, in the 2-ethylene dichloride, be cooled to below 5 ℃, drip the 100ml 1 that contains tetramethyleneimine 21.3g (0.30mol) and triethylamine 40.4g (0.40mol), the 2-dichloroethane solution, the control rate of addition makes temperature of reaction between 5~10 ℃, drips and finishes, be warming up to 25 ℃, insulation reaction 2 hours.In the about 400ml saturated sodium-chloride water solution of its impouring, separatory, organic phase is stand-by.
With N-skatole 39.3g (0.30mol), phosphorus oxychloride 91.8g (0.60mol) and above-mentioned 1, the 2-dichloroethane solution mixes, heating reflux reaction 7 hours.Be cooled to room temperature, in the about 1Kg frozen water of its impouring, separatory, water layer is transferred pH=9~10 with 20% sodium hydroxide, and solid filters after separating out fully, washing, oven dry.Get R-5-[(1-Methyl-1H-indole-3-yl) carbonyl]-4,5,6,7-tetrahydrochysene-1H-benzoglyoxaline (ranimustine) 41.2g, yield: 73.3%, M.p:>200 ℃ (decomposition).
Embodiment 15:R-5-[(1-Methyl-1H-indole-3-yl) carbonyl]-4,5,6, the preparation of 7-tetrahydrochysene-1H-benzoglyoxaline hydrochloride (ramosetron hydrochloride)
Will by embodiment 13 or 14 the preparation R-5-[(1-Methyl-1H-indole-3-yls) carbonyl]-4,5,6,7-tetrahydrochysene-1H-benzoglyoxaline (ranimustine) 28.1g (0.10mol) is dissolved in the 150ml dehydrated alcohol, acidic alcohol with 30% is transferred pH=1~2, solid filters after separating out fully, oven dry.Get R-5-[(1-Methyl-1H-indole-3-yl) carbonyl]-4,5,6,7-tetrahydrochysene-1H-benzoglyoxaline hydrochloride (ramosetron hydrochloride) 28.8g, yield: 90.7%, M.p:>220 ℃ (decomposition), [α]
D=-42.8 ° (C=1.0, methyl alcohol).