CN104098580B - A kind of preparation method of asenapine key intermediate - Google Patents
A kind of preparation method of asenapine key intermediate Download PDFInfo
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- CN104098580B CN104098580B CN201410350515.4A CN201410350515A CN104098580B CN 104098580 B CN104098580 B CN 104098580B CN 201410350515 A CN201410350515 A CN 201410350515A CN 104098580 B CN104098580 B CN 104098580B
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- C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
- C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
- C07D491/04—Ortho-condensed systems
- C07D491/044—Ortho-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring
Abstract
The present invention relates to a kind of chemical synthesis process, particularly can as the preparation method of the key intermediate of the asenapine of schizophrenia medicine (Asenapine) (III) compound.In anhydrous system, formula II midbody compound and acid anhydrides dewater and obtain intermediate formula III compound under catalyst action, and prepare the novel method of asenapine by intermediate formula III compound.Method provided by the invention has simple to operate, the advantage such as yield is high, environmental friendliness, cost are lower, process stabilizing.
Description
Technical field
The present invention relates to a kind of chemical synthesis process, particularly can as the preparation method of a kind of key intermediate of the asenapine of schizophrenia medicine (Asenapine).
Background technology
Asenapine (Asenapine) is the precursor preparing toxilic acid asenapine, it is the antagonist of a kind of serotonin of broad-spectrum high efficacy, norepinephrine and Dopamine HCL, there is stronger antipsychotic activity, therefore this medicine of broad scale research is necessary, and the research of the intermediate three of this medicine is vital.
The chemistry of asenapine is called: chloro-2,3,3a, 12b-tetrahydrochysene-2-methyl isophthalic acid H-dibenzo [2,3:6,7] oxa-Zhuo also [4, the 5-c] pyrroles of trans-5-, and its chemical structural formula is:
Have many sections of patents and the bibliographical information preparation method of asenapine both at home and abroad, wherein US2006229352, US2010152461, WO2011159903 etc. patent document discloses following method to prepare asenapine:
The shortcoming that above-mentioned preparation method exists be purity mostly 97 ~ 98%, wherein to sulfur oxychloride (SOCl
2) and adopt phosphoric acid and Vanadium Pentoxide in FLAKES when the preparation of key intermediate formula III (figure below) compound, there is temperature of reaction high, complex operation, yield lowly and do not process, causes the technical problem of environmental pollution.
Disclose a kind of preparation method of asenapine intermediate at Chinese patent 201010181602.3, the intermediate of the method is cyclization in strong acid, prepares asenapine by the method, and its reaction yield is low, there is the technical problem that impurity difficulty is removed.
Therefore, the preparation method of key intermediate formula III compound disclosed in prior art, and prepare that the reactions steps yield that exists in the operational path of asenapine is low by intermediate formula III compound, complex operation, environmental pollution is large, cost is high shortcomings.
Summary of the invention
The technical problem to be solved in the present invention overcomes the preparation method to key intermediate formula III compound in prior art, and it is high to prepare by intermediate formula III compound the temperature of reaction also existed in the operational path of asenapine, complex operation, low and the technical problem of environmental pollution of yield, for solving the problems of the technologies described above, the invention provides a kind of simple to operate, yield is high, environmental friendliness, cost is lower, the key intermediate formula III compounds process for production thereof of process stabilizing, and the method for asenapine is prepared by intermediate formula III compound.
In order to realize foregoing invention object, the present invention adopts following technical scheme:
A preparation method for asenapine key intermediate formula III, in anhydrous system, by formula II
Shown midbody compound and acid anhydrides dewater and obtain formula III midbody compound under catalyst action
Further, described acid anhydrides is one or more in formic anhydride, diacetyl oxide, propionic anhydride, oxalic acid acid anhydrides, Tetra hydro Phthalic anhydride, succinyl oxide, tert-Butyl dicarbonate (abbreviation BOC acid anhydrides), creatinine, maleic anhydride, apple acid anhydrides, carbonic acid gas, sulfurous gas, nitric anhydride.Acid anhydrides is preferably diacetyl oxide or propionic anhydride.
Further, the consumption of described acid anhydrides and the mol ratio of formula II midbody compound are 0.5 ~ 10:1.Further, described catalyzer is one or more in sodium hydroxide, potassium hydroxide, sodium carbonate, salt of wormwood, sodium bicarbonate or saleratus, triethylamine, morpholine, N-methylmorpholine, skin Courlene, sodium methylate, potassium methylate, sodium ethylate, potassium ethylate, DMAP (abbreviation DMAP), piperidines, piperazine, pyrroles, imidazoles.Catalyzer is preferably triethylamine or DMAP.
Wherein, described formula II midbody compound is by formula I compound
Obtained under potassium tert.-butoxide effect, wherein formula I compound with 2-(4-chlorophenoxy) toluylic acid for raw material, with haloformate class or acyl chloride in organic solvent, under the katalysis of alkali, obtain mixed acid anhydride, the condensation under alkali effect of the mixed acid anhydride obtained and hydrochloride methyl sarcosnate obtains.
Wherein, described haloformate class or acyl chloride are Vinyl chloroformate, bromine ethyl formate, phenyl chloroformate, chloroformic acid benzyl ester, methane sulfonyl chloride, p-methyl benzene sulfonic chloride, 4-Nitrobenzenesulfonyl chloride, phenylsulfonylchloride, to chloromethyl benzoic acid chlorides, to brooethyl Benzoyl chloride, one or more in pivaloyl chloride or Acetyl Chloride 98Min., described alkali is sodium hydroxide, potassium hydroxide, sodium carbonate, salt of wormwood, sodium bicarbonate or saleratus, triethylamine, morpholine, N-methylmorpholine, skin Courlene, sodium methylate, potassium methylate, sodium ethylate, potassium ethylate, DMAP, piperidines, piperazine, pyrroles, one or more in imidazoles.
Further, the consumption of described haloformate class or acyl chloride be 1:0.2 ~ 1 to the mol ratio of 2-(4-chlorophenoxy) toluylic acid, be preferably 1:0.5 ~ 1.
Further, the mol ratio of the consumption of described alkali and 2-(4-chlorophenoxy) toluylic acid is 1:0.5 ~ 1, is preferably 1:0.7 ~ 1.0.
Further, the consumption of described sarcosine methyl ester be 1:0.5 ~ 1 to the mol ratio of 2-(4-chlorophenoxy) toluylic acid, be preferably 1:0.8 ~ 1.
The reaction times wherein obtaining formula II midbody compound by formula I compound is 0.5 ~ 10 hour, and temperature of reaction is at-30 ~ 100 DEG C, and preferably 0 ~ 50 DEG C, reaction system is anhydrous system.
The present invention also provide a kind of newly obtain by above-mentioned preparation method the method that key intermediate formula III compound prepares asenapine.
New asenapine synthetic route provided by the invention is as follows:
The system of wherein reacting in this preparation method is anhydrous system.
Compared with asenapine preparation method disclosed in prior art, advantage of the present invention is: this invention simplifies reactions steps, and raw material is easy to get, simple to operate, and cost is low, and product yield is high, and quality is good, is adapted to scale operation.
Embodiment
Referring to specific embodiment, the present invention is described.It will be appreciated by those skilled in the art that these embodiments only for illustration of object of the present invention, its scope do not limited the present invention in any way.
Embodiment 1
Add in methylene dichloride 30ml to 100ml there-necked flask, add 5.6g starting raw material 2-(4-chlorophenoxy) toluylic acid, be cooled to 0 ~ 5 DEG C, drip pivaloyl chloride/methylene dichloride=12.1g/10ml, add hydrochloride methyl sarcosnate 5.6g in other 250ml there-necked flask, be cooled to less than 10 DEG C, add triethylamine 4.1g and stir 30 minutes, the dichloromethane solution (5.6g/20ml) of slow dropping mixed anhydride, controls less than 15 DEG C droppings; Finish, maintain stirring 3 ~ 4 hours, add 50ml purified water and stir 5 minutes, extract separatory, organic phase 50ml purified water is extracted once again, and organic phase is concentrated into constant weight, obtain brown or brown oily matter, i.e. formula I midbody compound 6.2g, yield 83.8%.
Embodiment 2
Add in methylene dichloride 30ml to 100ml there-necked flask, add 5.6g2-(4-chlorophenoxy) toluylic acid, be cooled to-30 ~ 5 DEG C, drip methane sulfonyl chloride/methylene dichloride=2.3g/10ml, add hydrochloride methyl sarcosnate 2.8g in other 250ml there-necked flask, be cooled to less than 10 DEG C, add triethylamine 2.0g and stir 30 minutes, slow dropping mixed anhydride dichloromethane solution (5.6g/20ml), control less than 15 DEG C droppings; Finish, maintain stirring 1 ~ 3 hour, add 50ml purified water and stir 5 minutes, extract separatory, organic phase 50ml purified water is extracted once again, and organic phase is concentrated into constant weight, obtain brown or brown oily matter, i.e. formula I midbody compound 6.1g, yield 82.4%.
Embodiment 3
Add 25ml toluene and 1.2g potassium tert.-butoxide in 50ml there-necked flask, the toluene solution (3.5g/25ml) of the formula I intermediate that above-described embodiment obtains is added in less than 20 DEG C, stirred overnight at room temperature, add 75ml purified water extraction, aqueous phase 25mlEA extracts three times, merge organic phase, extract again once by 25ml purified water, merge aqueous phase; Aqueous phase 1N hydrochloric acid regulates about pH=1.0 (occurring muddy), and growing the grain stirs 3 ~ 4 hours, filters, filter cake with the drip washing of 20ml purified water once, solid, in 40 DEG C of drying under reduced pressure 5 ~ 6 hours, obtains formula II midbody compound 2.3g, yield 71.8%.
Embodiment 4
Add 200ml methylene dichloride, 31.5g formula II intermediate, diacetyl oxide 102.0g and 0.5gDMAP, maintain less than 30 ~ 50 DEG C to stir 2 ~ 3 hours, add 200ml purified water, about pH=7 is regulated with sodium bicarbonate, add 250ml dichloromethane extraction, filtrate is concentrated dry, adds 100ml methyl alcohol and stirs rising temperature for dissolving, is cooled to crystallizing at room temperature and stirs 3 ~ 4 hours; Filter, filter cake, in 40 ~ 50 DEG C of drying under reduced pressure 5 ~ 6 hours, obtains the acetate 34.0g of formula III midbody compound, yield 94.9%.
Embodiment 5
Add 200ml methylene dichloride, 31.5g formula II intermediate, propionic anhydride 15.2g and 0.5g triethylamine, maintain less than-30 ~-20 DEG C to stir 2 ~ 3 hours, add 200ml purified water, about pH=7 is regulated with sodium bicarbonate, add 250ml dichloromethane extraction, filtrate is concentrated dry, adds 100ml methyl alcohol and stirs rising temperature for dissolving, is cooled to crystallizing at room temperature and stirs 3 ~ 4 hours; Filter, filter cake, in 40 ~ 50 DEG C of drying under reduced pressure 5 ~ 6 hours, obtains the propionic salt 34.9g of formula III midbody compound, yield 94.6%.
Embodiment 6
Add 80ml toluene and 1.22g magnesium chips in 250ml there-necked flask, add elemental iodine 3.0g under nitrogen protection, add formula III intermediate/methyl alcohol=16.4g/60ml in 20 minutes, add complete, maintain stirring 35 minutes; Divide and add 1.0g magnesium chips (every minor tick 1 hour) for 2 times, add 1mol/L dilute hydrochloric acid 650ml lower than less than 40 DEG C; Add 100ml toluene and stir separatory, aqueous phase toluene extracts 2 times (each 50ml) again, and organic phase is concentrated into constant weight, obtains the mixture 13.0g of formula IV R-intermediate and formula IV S-intermediate, yield 95%.
Embodiment 7
Add 140ml methyl alcohol and above-described embodiment preparation and the mixture 13.6g of formula IV R-intermediate and S-intermediate, add 43g potassium hydroxide, be warming up to backflow, maintain return stirring 18 hours, add 60ml methyl alcohol and 200ml purified water, concentrated removing methyl alcohol, aqueous phase methylbenzene extraction 2 times (each 100ml); Aqueous phase adds 100ml toluene, regulates pH=1.0 with hydrochloric acid, is warming up to 75 DEG C and stirs 30 minutes, separate aqueous phase, and the hydrochloride of crystallize out formula IV intermediate of lowering the temperature.
Add hydrochloride and the 0.55g sodium-acetate of 15ml toluene and 2.0g formula IV intermediate, intensification is stirred to backflow, maintains return stirring 2 hours, filters, filtrate is concentrated into dry, obtain red-brown oily matter, add 20ml methyl alcohol stirred crystallization, crystallization stirs 2 ~ 3 hours, filter, obtain white solid, i.e. formula (V) intermediate 4.2g, yield 30.9%.
Embodiment 8
Add 6.6g aluminum chloride and 50mlTHF, be cooled to 0 DEG C, keep stirring, maintain less than 10 DEG C and add 10% lithium aluminum hydride/THF solution (13.5ml), be cooled to 0 DEG C, maintain stirring 15 minutes; Maintain the THF solution (3.0g/40ml) that less than 15 DEG C add formula (V) intermediate, finish, maintain about 10 DEG C to stir 2 hours, maintain the sodium carbonate solution that 10 DEG C add 0.5mol/L, finish, maintain about 20 DEG C to stir 15 minutes, extract 2 times with toluene/EA=8:2, each 250ml; Organic layer is concentrated into constant weight, obtains asenapine 2.2g, yield 76.9%.
Only list the embodiment of part of representative in the above-described embodiments, acid anhydrides of the present invention only lists diacetyl oxide and propionic anhydride two kinds of acid anhydrides in an embodiment, in process of experimental, find that oxalic acid acid anhydrides, Tetra hydro Phthalic anhydride, succinyl oxide, BOC acid anhydrides, creatinine, maleic anhydride, apple acid anhydrides all have diacetyl oxide and the similar effect of propionic anhydride, equal energy solves practical problems of the present invention, but especially best with the effect of diacetyl oxide and propionic anhydride.Need keep a close eye on usage quantity when using acid anhydrides, the consumption of acid anhydrides of the present invention and the mol ratio of formula II midbody compound are 0.5 ~ 10:1.Technique effect of the present invention can be realized preferably in this molar ratio range.
Catalyzer of the present invention only lists triethylamine and DMAP two kinds in an embodiment, in process of experimental, find that sodium hydroxide, potassium hydroxide, sodium carbonate, salt of wormwood, sodium bicarbonate, saleratus, morpholine, N-methylmorpholine, sodium methylate, potassium methylate, sodium ethylate, potassium ethylate, skin Courlene, piperidines, piperazine, pyrroles, imidazoles all have diacetyl oxide and propionic anhydride similar effect, equal energy solves practical problems of the present invention, but especially best with the effect of triethylamine and DMAP.
Haloformate class of the present invention or acyl chloride only list methane sulfonyl chloride and pivaloyl chloride two kinds in an embodiment, find to drip Vinyl chloroformate, bromine ethyl formate, phenyl chloroformate, chloroformic acid benzyl ester, p-methyl benzene sulfonic chloride, 4-Nitrobenzenesulfonyl chloride, phenylsulfonylchloride, to chloromethyl benzoic acid chlorides, to brooethyl Benzoyl chloride, Acetyl Chloride 98Min., all there is similar effect in process of experimental, all can solve practical problems of the present invention.Should be noted that usage quantity when dripping mentioned reagent, the mol ratio of usage quantity of the present invention and starting raw material 2-(4-chlorophenoxy) toluylic acid controls in 1:0.2 ~ 1.Technique effect of the present invention can be realized preferably in this molar ratio range.
Alkali of the present invention is the one in sodium hydroxide, potassium hydroxide, sodium carbonate, salt of wormwood, sodium bicarbonate or saleratus, triethylamine, morpholine, N-methylmorpholine, skin Courlene, sodium methylate, potassium methylate, sodium ethylate, potassium ethylate, DMAP, piperidines, piperazine, pyrroles, imidazoles.The mol ratio of the usage quantity of alkali of the present invention and starting raw material 2-(4-chlorophenoxy) toluylic acid controls in 1:0.5 ~ 1, and the mol ratio of the consumption of described sarcosine methyl ester and starting raw material 2-(4-chlorophenoxy) toluylic acid controls in 1:0.5 ~ 1.Technique effect of the present invention can be realized preferably in this molar ratio range.
The reaction times obtaining formula II midbody compound by formula I compound is in the present invention 0.5 ~ 10 hour, temperature of reaction all has solution practical problems of the present invention-30 ~ 100 DEG C time, wherein temperature of reaction controls when 0 ~ 50 DEG C of scope, its best results.
1HNMR(DMSO-d6):10.1752(1H，s)，9.2840～9.2806(1H，s)，8.9976(1H，s)，8.6924～8.6832(1H，d)，8.5212～8.4719(2H，m)，8.0860(1H，d)，
7.9192～7.8991(2H，d)，7.5391～7.4755(2H，m)，7.4408～7.4262(3H，d)，7.2188～7.1980(1H，d)，3.5236(2H，s)，2.3685(8H，m)，2.2264(3H，s)，2.1527(3H，s)。
Claims (5)
1. the preparation method of asenapine key intermediate formula III, is characterized in that: in anhydrous system, formula II
Shown midbody compound and acid anhydrides dewater and obtain intermediate formula III compound under catalyst action
The consumption of described acid anhydrides and the mol ratio of formula II midbody compound are 0.5 ~ 10:1, described acid anhydrides is one or more in diacetyl oxide, propionic anhydride, oxalic acid acid anhydrides, Tetra hydro Phthalic anhydride, succinyl oxide, BOC acid anhydrides, creatinine, maleic anhydride or apple acid anhydrides, reaction times is 0.5 ~ 10 hour, and temperature of reaction is at-30 ~ 100 DEG C.
2. preparation method as claimed in claim 1, is characterized in that: described catalyzer is one or more in sodium hydroxide, potassium hydroxide, sodium carbonate, salt of wormwood, sodium bicarbonate or saleratus, triethylamine, morpholine, N-methylmorpholine, skin Courlene, sodium methylate, potassium methylate, sodium ethylate, potassium ethylate, DMAP, piperidines, piperazine, pyrroles, imidazoles.
3. preparation method as claimed in claim 1, is characterized in that: described formula II midbody compound is by formula I compound
Obtained under potassium tert.-butoxide effect, wherein formula I compound with 2-(4-chlorophenoxy) toluylic acid for raw material, with haloformate class or acyl chloride in organic solvent, under the katalysis of alkali, obtain mixed acid anhydride, the condensation under alkali effect of the mixed acid anhydride obtained and hydrochloride methyl sarcosnate obtains.
4. preparation method as claimed in claim 3, it is characterized in that: described haloformate class or acyl chloride are Vinyl chloroformate, bromine ethyl formate, phenyl chloroformate, chloroformic acid benzyl ester, methane sulfonyl chloride, p-methyl benzene sulfonic chloride, 4-Nitrobenzenesulfonyl chloride, phenylsulfonylchloride, to chloromethyl benzoic acid chlorides, to brooethyl Benzoyl chloride, one or more in pivaloyl chloride or Acetyl Chloride 98Min., described alkali is sodium hydroxide, potassium hydroxide, sodium carbonate, salt of wormwood, sodium bicarbonate or saleratus, triethylamine, morpholine, N-methylmorpholine, skin Courlene, sodium methylate, potassium methylate, sodium ethylate, potassium ethylate, DMAP, piperidines, piperazine, pyrroles, one or more in imidazoles.
5. preparation method as claimed in claim 3, it is characterized in that: the consumption of described haloformate class or acyl chloride be 1:0.2 ~ 1 to the mol ratio of 2-(4-chlorophenoxy) toluylic acid, the mol ratio of the consumption of described alkali and 2-(4-chlorophenoxy) toluylic acid is 1:0.5 ~ 1, the consumption of described sarcosine methyl ester be 1:0.5 ~ 1 to the mol ratio of 2-(4-chlorophenoxy) toluylic acid.
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| CN104710411B (en) * | 2015-03-13 | 2017-04-26 | 安润医药科技（苏州）有限公司 | Synthesis method of avanafil |
| WO2018115001A1 (en) | 2016-12-20 | 2018-06-28 | Lts Lohmann Therapie-Systeme Ag | Transdermal therapeutic system containing asenapine |
| WO2018115010A1 (en) | 2016-12-20 | 2018-06-28 | Lts Lohmann Therapie-Systeme Ag | Transdermal therapeutic system containing asenapine and polysiloxane or polyisobutylene |
| ES2881783T3 (en) | 2017-06-26 | 2021-11-30 | Lts Lohmann Therapie Systeme Ag | Transdermal therapeutic system containing asenapine and silicone acrylic polymer |
| MX2020014286A (en) | 2018-06-20 | 2021-03-25 | Lts Lohmann Therapie Systeme Ag | Transdermal therapeutic system containing asenapine. |
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| WO2012038975A2 (en) * | 2010-09-22 | 2012-03-29 | Msn Laboratories Limited | Process for the preparation of (3ars,12brs)-5-chloro-2-methyl-2,3,3a12b-tetrahydro-1hdibenzo[2,3:6,7] oxepino [4,5-c]pyrrole maleate and it's pharmaceutical composition thereof |
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| Title |
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| 抗精神病药阿塞那平的合成;张晓影等;《化学试剂》;20111231;第33卷(第12期);第1135-1137页 * |
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| 阿塞那平;惠子等;《中国药物化学杂志》;20100430;第20卷(第2期);第156页 * |
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