CN105315184A - Preparation method and intermediate of vortioxetine - Google Patents
Preparation method and intermediate of vortioxetine Download PDFInfo
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- AMNLXDDJGGTIPL-UHFFFAOYSA-N Cc(cc1)cc(C)c1S Chemical compound Cc(cc1)cc(C)c1S AMNLXDDJGGTIPL-UHFFFAOYSA-N 0.000 description 1
- TTYGYMLSPHRTOD-UHFFFAOYSA-N Cc(cc1C)ccc1Sc(cccc1)c1C#N Chemical compound Cc(cc1C)ccc1Sc(cccc1)c1C#N TTYGYMLSPHRTOD-UHFFFAOYSA-N 0.000 description 1
- MMZYCBHLNZVROM-UHFFFAOYSA-N Cc1ccccc1F Chemical compound Cc1ccccc1F MMZYCBHLNZVROM-UHFFFAOYSA-N 0.000 description 1
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Abstract
The invention discloses a preparation method and intermediate of vortioxetine. The preparation method of vortioxetine includes the following steps that 1, a compound V is prepared according to a preparation method of the compound V; 2, the compound V and dichloro ethylamine or salt of dichloro ethylamine are subjected to a cyclization reaction in a high-boiling-point solvent to prepare vortioxetine, wherein the boiling point of the high-boiling-point solvent is above 120 DEG C at normal pressure. The preparation method is low in cost, easy to implement, safe, environmentally friendly, high in yield and suitable for industrial production, and reaction conditions are mild.
Description
Technical field
The present invention relates to a kind of fertile Preparation Method And Their Intermediate for Xi Ting.
Background technology
Fertile is a kind of thymoleptic developed jointly by Ling Bei (Lundbeck) and military field (Takeda) for Xi Ting, commodity are called Brintellix, FDA approval listing is obtained on September 30th, 2013, the clinical treatment for major depressive disorder (MDD) and generalized anxiety disorder adult patient, the molecular structure of its main active ingredient is 1-[2-(2,4-methylphenyl-sulfanyl) phenyl] piperazine, structural formula is as follows:
The initial preparation method (WO2003/029232A1) of this compound carries out nucleophilic substitution reaction with the piperazine of resin protection and the ferrocene complex compound of orthodichlorobenzene; subsequently with 2; 4-thiophenol dimethyl benzene carries out nucleophilic substitution; crude product is obtained again through the complexing of visible ray illumination solution, resin fracture; finally be prepared purifying with LC-MS and ion exchange resin; total recovery is only 4%, complex operation and employ the dangerous toxic reagents such as ferrocene.
(the WO2007/144005A1 that improves one's methods subsequently; J.Med.Chem, 2011,54 (9), 3206-3221) be the linked reaction of catalyzing by metal palladium, C-S key and C-N key is constructed respectively under the effect of metal palladium catalyst, these methods all need to use expensive palladium catalyst and Phosphine ligands, and the residue problem of metal is dealt with improperly and will be had a strong impact on the quality of finished product.
The problem of carrying out suitability for industrialized production is all not suitable for for above several method, Zupancic (WO2014161976A1) and Cen Junda (Chinese Journal of Pharmaceuticals, 2014,45 (4), 301-303) in succession reported in 2014, with 2,4-thiophenol dimethyl benzene and 2-chloronitrobenzene (or 2-fluoronitrobenzene) are raw material, first obtain 2-(2 through substitution reaction, 4-thiophenol dimethyl benzene) oil of mirbane, restore and obtain 2-(2,4-thiophenol dimethyl benzene) aniline, generate with two (2-chloroethyl) amine hydrochlorate cyclization fertile for Xi Ting subsequently.But in the reduction step of nitro, Zupancic uses iron/acetate system, and Cen Junda uses hydrogen/palladium carbon system, and the former aftertreatment is loaded down with trivial details, and the latter's potential safety hazard is larger.In addition, starting raw material 2-chloronitrobenzene (or 2-fluoronitrobenzene) and 2,4-thiophenol dimethyl benzene price higher.
In addition, synthesis, 2010,21,3602 ~ 3608. describe above-mentioned reaction, and it use copper catalyst and part, condition is comparatively harsh, and yield is only 57%.
Therefore, this area is needed that a kind of cost is low, reaction conditions is gentle, simple to operate, safety and environmental protection, yield are high badly, is applicable to the fertile preparation method for Xi Ting of suitability for industrialized production.
Summary of the invention
Defects such as technical problem to be solved by this invention is that existing fertile preparation method's cost for Xi Ting is high in order to overcome, severe reaction conditions, complex operation, danger, contaminate environment, yield are low and provide a kind of fertile Preparation Method And Their Intermediate for Xi Ting, preparation method's cost of the present invention is low, reaction conditions is gentle, simple to operate, safety and environmental protection, yield are high, be applicable to suitability for industrialized production.
The invention provides the preparation method of a kind of compound V, it comprises the steps: compound IV to carry out hoffman degradation reaction, obtained compound V;
The condition of described hoffman degradation reaction can be the condition of this area hoffman degradation reaction routine, the present invention is following condition particularly preferably: in water, under the existence of alkali and hypohalite, compound IV is carried out hoffman degradation reaction, obtained compound V.
In described hoffman degradation reaction, than can be this area, such reacts conventional Molar ratio to the Molar of described water and described compound IV, is preferably 3L/mol ~ 4L/mol, such as 3.5L/mol.
In described hoffman degradation reaction, described alkali can be the conventional alkali of such reaction of this area, being preferably mineral alkali, is more preferably one or more in potassium hydroxide, sodium hydroxide, salt of wormwood and sodium carbonate, best for the mol ratio of sodium hydroxide and sodium carbonate composition is the alkali of 1.2.
In described hoffman degradation reaction, the mol ratio of described alkali and described compound IV can be this area, and such reacts conventional mol ratio, and being preferably 15 ~ 25, is 16 ~ 22 best.
In described hoffman degradation reaction, described hypohalite can be the conventional hypohalite of such reaction of this area, be preferably hypobromite or hypochlorite, being more preferably one or more in sodium hypobromite, potassium hypobromite, clorox and potassium hypochlorite, is clorox best.
In described hoffman degradation reaction, the mol ratio of described hypohalite and described compound IV can be this area, and such reacts conventional mol ratio, and being preferably 1.5 ~ 3.0, is more preferably 1.8 ~ 2.5.
In described hoffman degradation reaction, preferably, the water described in described clorox, part and the sodium hydroxide described in part add reaction system with the form of antiformin; The parameter of described antiformin is preferably: every 100ml contains 5.68g reactive chlorine, 7.8g sodium hydroxide and 32g sodium carbonate.
In described hoffman degradation reaction, preferably, the water described in part and the sodium hydroxide described in part add reaction system with the form of aqueous sodium hydroxide solution.
In described hoffman degradation reaction, the temperature of described DeR can be the conventional temperature of such reaction of this area, and being preferably 25 DEG C ~ 100 DEG C, is more preferably 80 DEG C ~ 100 DEG C.
In described hoffman degradation reaction, time of described DeR can be such reaction of this area conventional time, generally no longer reacts with compound IV or till (such as TLC) reacts completely after testing; Be preferably 2h ~ 6h, such as 4h.
The preparation method of described compound V also can comprise the steps: at C
2~ C
6alcoholic solvent in, in the presence of base, be hydrolyzed compound III reaction, obtains described compound IV;
In described hydrolysis reaction, described C
2~ C
6alcoholic solvent can be the conventional C of such reaction of this area
2~ C
6alcoholic solvent, be preferably Virahol or the trimethyl carbinol.
Preferably, not moisture in described hydrolysis reaction.
In described hydrolysis reaction, than can be this area, such reacts conventional Molar ratio to the Molar of described alcoholic solvent and described compound III, is preferably 0.5L/mol ~ 1.5L/mol, such as 1.0L/mol.
In described hydrolysis reaction, described alkali can be the conventional alkali of such reaction of this area, such as organic bases and/or mineral alkali; Described organic bases can be the conventional organic bases of such reaction of this area, is preferably potassium tert.-butoxide; Described mineral alkali can be the conventional mineral alkali of such reaction of this area, and being preferably sodium hydroxide and/or potassium hydroxide, is potassium hydroxide best.
In described hydrolysis reaction, the mol ratio of described alkali and described compound III can be this area, and such reacts conventional mol ratio, is preferably 2.0 ~ 5.0, such as 3.0 ~ 4.0.
In described hydrolysis reaction, the temperature of described reaction can be the conventional temperature of such reaction of this area; Being preferably 50 DEG C ~ 120 DEG C, is more preferably 65 DEG C ~ 85 DEG C, such as 80 DEG C.
In described hydrolysis reaction, time of described reaction can be such reaction of this area conventional time, generally no longer reacts with compound III or till (such as TLC) reacts completely after testing; Be at least 1h, such as 2h, 6h.
In the preparation method of described compound V, preferably, after described hydrolysis reaction completes, without separation, (namely not by compound IV separation and purification, or acquisition contains the mixture of compound IV to compound IV; The reaction solution of such as hydrolysis reaction carries out simple aftertreatment etc. without the reaction solution of aftertreatment, hydrolysis reaction, obtains the mixture containing compound IV; Described simple aftertreatment can be removing solvent, concentrated, filtration etc.), then carry out described hoffman degradation reaction.
Described " described hydrolysis reaction complete after, compound IV without separation, then carries out described hoffman degradation reaction " preferably for " after described hydrolysis reaction completes, the C in the reaction solution of removing hydrolysis reaction
2~ C
6alcoholic solvent obtain residuum; Described residuum is carried out described hoffman degradation reaction ", more preferably for " after described hydrolysis reaction completes, the C in the reaction solution of removing hydrolysis reaction
2~ C
6alcoholic solvent obtain residuum; In water, under the existence of alkali and hypohalite, described residuum is carried out described hoffman degradation reaction ".
The preparation method of described compound V also can comprise the steps: in organic solvent, in the presence of base, Compound I and Compound II per is carried out substitution reaction, obtains described compound III; Described organic solvent is alcoholic solvent and/or polar aprotic solvent; Wherein, LG is leavings group, R
1for hydrogen or metal ion;
In described substitution reaction, described leavings group can be the leavings group of such aromatic nucleophilic substitution reaction routine of this area, is preferably fluorine, chlorine, bromine, OTf or OTs, is more preferably fluorine or chlorine.Described aromatic nucleophilic substitution reaction is the reaction that a group on aromatic ring is replaced by a nucleophilic reagent.
In described substitution reaction, described metal ion can be the conventional metal ion of such reaction of this area, and being preferably alkalimetal ion, is more preferably sodium ion or potassium ion.
In described substitution reaction, described alcoholic solvent can be the conventional alcoholic solvent of such reaction of this area, is preferably C
1~ C
6alcoholic solvent; Described polar aprotic solvent can be the conventional polar aprotic solvent of such reaction of this area, and being preferably methyl-sulphoxide and/or DMF, is more preferably DMF.
In described substitution reaction, than can be this area, such reacts conventional Molar ratio to the Molar of described organic solvent and described Compound I, is preferably 0.5L/mol ~ 1.5L/mol, such as 1.0L/mol.
In described substitution reaction, the mol ratio of described Compound II per and described Compound I can be this area, and such reacts conventional mol ratio, is preferably 1.0 ~ 1.2, such as 1.05.
In described substitution reaction, described alkali can be the conventional alkali of such reaction of this area, is preferably organic bases and/or mineral alkali; Described mineral alkali can be the conventional mineral alkali of such reaction of this area, and being preferably salt of wormwood and/or sodium carbonate, is more preferably salt of wormwood.
In described substitution reaction, the mol ratio of described alkali and described Compound I can be this area, and such reacts conventional mol ratio, is preferably 1.0 ~ 1.5, such as 1.2.
In described substitution reaction, the temperature of described reaction can be the conventional temperature of such reaction of this area; Being preferably 0 DEG C ~ 120 DEG C, is more preferably 100 DEG C ~ 120 DEG C.
In described substitution reaction, time of described reaction can be such reaction of this area conventional time, generally no longer reacts with Compound I or till (such as TLC) reacts completely after testing; Be preferably 2h ~ 6h, such as 4h.
In the present invention, the preparation method of described compound V can be shown below:
Present invention also offers a kind of preparation method of compound IV, it comprises the steps: at C
2~ C
6alcoholic solvent in, in the presence of base, be hydrolyzed compound III reaction, obtains described compound IV;
The parameter of described hydrolysis reaction is all described above.
The preparation method of described compound IV also can comprise the steps: in organic solvent, in the presence of base, Compound I and Compound II per is carried out substitution reaction, obtains described compound III; Described organic solvent is alcoholic solvent and/or polar aprotic solvent; Wherein, LG is leavings group, R
1for hydrogen or metal ion;
The parameter of described substitution reaction is all described above.
In the present invention, the preparation method of described compound IV can be shown below:
Present invention also offers a kind of preparation method of compound III, it comprises the steps: in organic solvent, in the presence of base, Compound I and Compound II per is carried out substitution reaction, obtains described compound III; Described organic solvent is alcoholic solvent and/or polar aprotic solvent; Wherein, LG is leavings group, R
1for hydrogen or metal ion;
The parameter of described substitution reaction is all described above.
Present invention also offers a kind of fertile preparation method for Xi Ting, it comprises the steps,
(1) according to the preparation method of above-mentioned compound V, obtained compound V;
(2) in high boiling solvent, by described compound V, ring-closure reaction is carried out with Dichloroethyl amine or its salt, obtained fertile for Xi Ting; Described high boiling solvent is the solvent of boiling point more than 120 DEG C under normal pressure;
In described ring-closure reaction, described high boiling solvent is preferably diethylene glycol monomethyl ether and/or sym-trimethylbenzene.
In described ring-closure reaction, than can be this area, such reacts conventional Molar ratio to the Molar of described high boiling solvent and described compound V, is preferably 0.5L/mol ~ 1.5L/mol, such as 1.0L/mol.
In described ring-closure reaction, described salt can be the salt of this area routine, is preferably hydrochloride and/or vitriol.
In described ring-closure reaction, described Dichloroethyl amine or its salt, such reacts conventional mol ratio to can be this area with the mol ratio of described compound V, is preferably 1.0 ~ 1.5.
In described ring-closure reaction, the temperature of described ring-closure reaction can be the conventional temperature of such reaction of this area; When described solvent is diethylene glycol monomethyl ether, described temperature is preferably 120 DEG C ~ 140 DEG C, such as 130 DEG C; When described solvent is sym-trimethylbenzene, described temperature is preferably 160 DEG C ~ 165 DEG C.
In described ring-closure reaction, time of described ring-closure reaction can be such reaction of this area conventional time, generally no longer reacts with compound V or till (such as TLC) reacts completely after testing.
In the present invention, the described fertile preparation method for Xi Ting can be shown below:
Present invention also offers a kind of compound III or its salt (can be the salt of this area routine, such as hydrochloride, vitriol etc.), its structure is as follows:
Present invention also offers a kind of compound IV or its salt (can be the salt of this area routine, such as hydrochloride, vitriol etc.), its structure is as follows:
Without prejudice to the field on the basis of common sense, above-mentioned each optimum condition, can arbitrary combination, obtains the preferred embodiments of the invention.
Agents useful for same of the present invention and raw material are all commercially.
Positive progressive effect of the present invention is: preparation method's cost of the present invention is low, reaction conditions is gentle, simple to operate, safety and environmental protection, yield are high, be applicable to suitability for industrialized production.
Embodiment
Mode below by embodiment further illustrates the present invention, but does not therefore limit the present invention among described scope of embodiments.The experimental technique of unreceipted actual conditions in the following example, conventionally and condition, or selects according to catalogue.
Antiformin used in the present invention is purchased from traditional Chinese medicines reagent, and design parameter is: every 100ml contains 5.68g reactive chlorine, 7.8g sodium hydroxide and 32g sodium carbonate, oxidizing and corrodibility.
Embodiment 1 prepares intermediate 2-(2,4-thiophenol dimethyl benzene) cyanophenyl (III) by 2-fluorobenzonitrile (Ia)
2-fluorobenzonitrile (compound such as formula shown in Ia) (12.1g is added in 250ml reaction flask, 100mmol), salt of wormwood (16.6g, 120mmol), DMF (100ml), then add 2,4-thiophenol dimethyl benzene (compound such as formula shown in II) (14.5g, 105mmol), be warming up to 100 DEG C of reaction 4h, TLC point plate detection reaction to complete.Reaction system is down to room temperature, add frozen water (200ml), stirring at room temperature one hour, slow precipitation white solid, filter, 20ml frozen water washing leaching cake, 50 DEG C of vacuum-dryings obtain 2-(2,4-thiophenol dimethyl benzene) cyanophenyl (compound as shown in formula III) crude product 24g, yield 100%.
mp＝58.9-60.2℃；MS(m/z):240[M+H]+；1HNMR(400MHz,CDCl
3,TMS)δ：7.70(dd,J＝8.2、1.2Hz,1H),7.48(d,J＝7.8Hz,1H),7.36-7.40(m,1H),7.20-7.25(m,2H),7.15(d,J＝7.8Hz,1H),6.80(dd,J＝8.2、1.2Hz,1H),2.42(s,3H)，2.35(s,3H)。
Embodiment 2 prepares intermediate 2-(2,4-thiophenol dimethyl benzene) cyanophenyl (III) by 2-6-chlorophenyl nitrile (Ib)
2-6-chlorophenyl nitrile (compound such as formula shown in Ib) (13.7g is added in 250ml reaction flask, 100mmol), salt of wormwood (16.6g, 120mmol), DMF (100ml), then add 2,4-thiophenol dimethyl benzene (compound such as formula shown in II) (14.5g, 105mmol), be warming up to 100 DEG C of reaction 4h, TLC point plate detection reaction to complete.Reaction system is down to room temperature, add frozen water (200ml), stirring at room temperature one hour, slow precipitation white solid, filter, 20ml frozen water washing leaching cake, 50 DEG C of vacuum-dryings obtain 2-(2,4-thiophenol dimethyl benzene) cyanophenyl (compound as shown in formula III) (23.5g, yield 98%).
mp＝58.9-60.2℃；MS(m/z):240[M+H]
+；
1HNMR(400MHz,CDCl
3,TMS)δ：7.70(dd,J＝8.2、1.2Hz,1H),7.48(d,J＝7.8Hz,1H),7.36-7.40(m,1H),7.20-7.25(m,2H),7.15(d,J＝7.8Hz,1H),6.80(dd,J＝8.2、1.2Hz,1H),2.42(s,3H)，2.35(s,3H)。
The preparation of embodiment 3a intermediate 2-(2,4-thiophenol dimethyl benzene) benzamide (IV)
2-(2 is added in 250ml reaction flask, 4-thiophenol dimethyl benzene) cyanophenyl (compound as shown in formula III) (12.0g, 50mmol), potassium hydroxide (11.2g, 200mmol), Virahol (50ml), be warming up to 80 DEG C of reaction 2h, reaction completes.Reaction system is down to room temperature, and concentrating under reduced pressure, except desolventizing, obtains white paste, and silica gel column chromatography is crossed post separation (PE/EA=2/1) and obtained white solid, and 50 DEG C of vacuum-dryings obtain 12g product (compound such as formula shown in IV), yield 93%.
mp＝148.5-150.0℃；MS(m/z):258[M+H]
+；
1HNMR(400MHz,CDCl
3,TMS)δ：7.75(dd,J＝8.2、1.2Hz,1H),7.36(d,J＝8.0Hz,1H),7.18-7.25(m,3H),7.12(d,J＝7.8Hz,1H),6.82(dd,J＝8.5、1.2Hz,1H),6.30(brs,2H)，2.42(s,3H)，2.35(s,3H)。
The preparation of embodiment 3b intermediate 2-(2,4-thiophenol dimethyl benzene) benzamide (IV)
2-(2 is added in 250ml reaction flask, 4-thiophenol dimethyl benzene) cyanophenyl (compound as shown in formula III) (12.0g, 50mmol), potassium hydroxide (11.2g, 200mmol), the trimethyl carbinol (50ml), 80 DEG C of reactions, TLC monitoring is to having reacted.Reaction system is down to room temperature, concentrating under reduced pressure, except desolventizing, obtains white paste, and silica gel column chromatography is crossed post separation (PE/EA=2/1) and obtained white solid, 50 DEG C of vacuum-dryings obtain 11.6g product (compound such as formula shown in IV), yield 90%.
The preparation of embodiment 3c intermediate 2-(2,4-thiophenol dimethyl benzene) benzamide (IV)
2-(2 is added in 250ml reaction flask, 4-thiophenol dimethyl benzene) cyanophenyl (compound as shown in formula III) (12.0g, 50mmol), potassium tert.-butoxide (22.4g, 200mmol), Virahol (50ml), be warming up to 80 DEG C of reaction 2h, reaction completes.Reaction system is down to room temperature, and concentrating under reduced pressure, except desolventizing, obtains white paste, and silica gel column chromatography is crossed post separation (PE/EA=2/1) and obtained white solid, and 50 DEG C of vacuum-dryings obtain 9.7g product (compound such as formula shown in IV), yield 75%.
The preparation of embodiment 4 intermediate 2-(2,4-thiophenol dimethyl benzene) aniline (V)
2-(2 is added in 250ml reaction flask, 4-thiophenol dimethyl benzene) benzamide (compound such as formula shown in IV) (3.8g, 15mmol), antiformin (50ml, reactive chlorine containing 38mmol), add the sodium hydroxide solution (3.2g sodium hydroxide is dissolved in 3.2ml water) that massfraction is 50% again, be warming up to 80 DEG C of reaction 6h, reaction completes.Reaction system is down to room temperature, extraction into ethyl acetate, washing, anhydrous sodium sulfate drying, concentrating under reduced pressure removes desolventizing and obtains brown oil 3g, and structure determines that it is 2-(2,4-thiophenol dimethyl benzene) aniline (compound such as formula shown in V), yield 87%.
MS(m/z):230[M+H]
+；
1HNMR(400MHz,CDCl
3,TMS)δ：7.35(dd,J＝7.2、1.3Hz,1H),7.23(m,1H),7.01(m,1H),6.76-6.83(m,3H),6.72(d,J＝8.5Hz,1H),4.30(brs,2H)，2.40(s,3H)，2.28(s,3H)。
Embodiment 5 prepares intermediate 2-(2,4-thiophenol dimethyl benzene) aniline (V) by 2-(2,4-thiophenol dimethyl benzene) cyanophenyl (III)
2-(2 is added in 250ml reaction flask, 4-thiophenol dimethyl benzene) cyanophenyl (compound as shown in formula III) (12.0g, 50mmol), potassium hydroxide (11.2g, 200mmol), Virahol (50ml), be warming up to 80 DEG C of reaction 2h, reaction completes.Reaction system is down to room temperature, and concentrating under reduced pressure, except desolventizing, obtains white paste.
In white paste obtained above, add antiformin (120ml, the reactive chlorine containing 91mmol), be warming up to 80 DEG C of reaction 6h, reaction completes.Reaction system is down to room temperature, extraction into ethyl acetate, and saturated common salt is washed, washing, anhydrous sodium sulfate drying, and concentrating under reduced pressure removes desolventizing and obtains brown oil 9g, two step yields 78%.
MS(m/z):230[M+H]
+；
1HNMR(400MHz,CDCl
3,TMS)δ：7.35(dd,J＝7.2、1.3Hz,1H),7.23(m,1H),7.01(m,1H),6.76-6.83(m,3H),6.72(d,J＝8.5Hz,1H),4.30(brs,2H)，2.40(s,3H)，2.28(s,3H)。
The preparation of embodiment 61-[2-(2,4-methylphenyl-sulfanyl) phenyl] piperazine (VI, fertile for Xi Ting)
2-(2 is added in 250ml reaction flask, 4-thiophenol dimethyl benzene) aniline (compound such as formula shown in V) (9.2g, 40mmol), two (2-chloroethyl) amine hydrochlorate (7.1g, 40mmol), diethylene glycol monomethyl ether (40ml), is warming up to 130 DEG C of reactions, complete to TLC point plate detection reaction.Be cooled to room temperature, add frozen water (80ml), ice bath stirs one hour, filtering precipitate, 20ml frozen water washing leaching cake.The throw out collected is dissolved in methyltetrahydrofuran (40ml), 1M sodium hydroxide (40ml) is added during room temperature, collect organic phase, aqueous phase uses methyltetrahydrofuran (20ml) to extract again, merge organic phase, anhydrous sodium sulfate drying, concentrating under reduced pressure is except desolventizing, obtain colorless solid 5.8g, yield is 48.6%.
mp＝224-226℃；MS(m/z):299[M+H]
+；
1HNMR(400MHz,CDCl
3,TMS)δ：7.35(d,J＝7.2Hz,1H),7.21(m,1H),7.06-7.12(m,3H),6.86(m,1H),6.43(m,1H),3.12-3.18(m,8H),2.38(s,3H)，2.25(s,3H),1.65(brs,1H)。
The preparation of embodiment 71-[2-(2,4-methylphenyl-sulfanyl) phenyl] piperazine (VI, fertile for Xi Ting)
2-(2 is added in 250ml reaction flask, 4-thiophenol dimethyl benzene) aniline (compound such as formula shown in V) (9.2g, 40mmol), two (2-chloroethyl) amine hydrochlorate (7.1g, 40mmol), sym-trimethylbenzene (40ml), is warming up to 165 DEG C of reactions, complete to TLC point plate detection reaction.Be cooled to room temperature, add frozen water (80ml), ice bath stirs one hour, collected by filtration thing.In filtrate, pass into HCl gas, have throw out to separate out, collecting by filtration.Merge throw out, add methyltetrahydrofuran (40ml), 1M sodium hydroxide (40ml) is added during room temperature, collect organic phase, aqueous phase uses methyltetrahydrofuran (20ml) to extract again, merges organic phase, anhydrous sodium sulfate drying, concentrating under reduced pressure is except desolventizing, and obtain colorless solid 6.2g, yield is 52%.
mp＝224-226℃；MS(m/z):299[M+H]
+；
1HNMR(400MHz,CDCl
3,TMS)δ：7.35(d,J＝7.2Hz,1H),7.21(m,1H),7.06-7.12(m,3H),6.86(m,1H),6.43(m,1H),3.12-3.18(m,8H),2.38(s,3H)，2.25(s,3H),1.65(brs,1H)。
Comparative example 1
2-(2 is added in 25ml reaction flask, 4-thiophenol dimethyl benzene) cyanophenyl (compound as shown in formula III) (1.2g, 5mmol), concentrated hydrochloric acid (10ml), 80 DEG C of stirring reaction 2h, TLC monitoring generates without product, and time expand also generates without product to 24h.
Comparative example 2
2-(2 is added in 25ml reaction flask, 4-thiophenol dimethyl benzene) cyanophenyl (compound as shown in formula III) (1.2g, 5mmol), the sulfuric acid (10ml) of 5mol/L, 80 DEG C of stirring reaction 2h, TLC monitoring generates without product, and time expand also generates without product to 24h.
Comparative example 3
2-(2 is added in 50ml reaction flask, 4-thiophenol dimethyl benzene) cyanophenyl (compound as shown in formula III) (2.4g, 10mmol), potassium hydroxide (2.2g, 40mmol), hydrogen peroxide (2ml), Virahol (10ml), be warming up to 80 DEG C of reaction 2h, TLC detection reaction completes, except generating target product (compound such as formula shown in IV), assorted point is had to produce (be speculated as thioether bond and be oxidized to the corresponding sulfoxide of product and sulfone).Reaction system is down to room temperature, and concentrating under reduced pressure, except desolventizing, obtains white paste, and silica gel column chromatography is crossed post separation (PE/EA=2/1) and obtained white solid, and 50 DEG C of vacuum-dryings obtain 1.3g product (compound such as formula shown in IV), yield 50%.
Comparative example 4
2-(2 is added in 50ml reaction flask, 4-thiophenol dimethyl benzene) cyanophenyl (compound as shown in formula III) (2.4g, 10mmol), potassium hydroxide (2.2g, 40mmol), water (2ml), Virahol (10ml), be warming up to 80 DEG C of reaction 2h, TLC detection reaction completes, except generating target product (compound such as formula shown in IV), assorted point is had to produce (through TLC contrast, being speculated as corresponding carboxylic acid product).Reaction system is down to room temperature, and concentrating under reduced pressure, except desolventizing, obtains white paste, and silica gel column chromatography is crossed post separation (PE/EA=2/1) and obtained white solid, and 50 DEG C of vacuum-dryings obtain 0.7g product (compound such as formula shown in IV), yield 28%.
Comparative example 5
2-(2 is added in 50ml reaction flask, 4-thiophenol dimethyl benzene) cyanophenyl (compound as shown in formula III) (2.4g, 10mmol), potassium hydroxide (2.2g, 40mmol), methyl alcohol (10ml), is warming up to 60 DEG C of reaction 2h, TLC detects and generates without product, extends the reaction times to 24h still driftlessness product generation.
Claims (16)
1. a preparation method of compound V, it comprises the steps: compound IV to carry out hoffman degradation reaction, obtained compound V;
2. preparation method as claimed in claim 1, it is characterized in that, the condition of described hoffman degradation reaction is: in water, under the existence of alkali and hypohalite, compound IV is carried out hoffman degradation reaction, obtained compound V.
3. preparation method as claimed in claim 2, is characterized in that, in described hoffman degradation reaction, described water is 3L/mol ~ 4L/mol with the Molar ratio of described compound IV;
And/or in described hoffman degradation reaction, described alkali is one or more in potassium hydroxide, sodium hydroxide, salt of wormwood and sodium carbonate;
And/or in described hoffman degradation reaction, the mol ratio of described alkali and described compound IV is 15 ~ 25;
And/or in described hoffman degradation reaction, described hypohalite is one or more in sodium hypobromite, potassium hypobromite, clorox and potassium hypochlorite;
And/or in described hoffman degradation reaction, the mol ratio of described hypohalite and described compound IV is 1.5 ~ 3.0;
And/or in described hoffman degradation reaction, the temperature of described DeR is 25 DEG C ~ 100 DEG C;
And/or in described hoffman degradation reaction, the time of described DeR is 2h ~ 6h.
4. preparation method as claimed in claim 1, is characterized in that, also comprise the steps: at C
2~ C
6alcoholic solvent in, in the presence of base, be hydrolyzed compound III reaction, obtains described compound IV;
5. preparation method as claimed in claim 4, is characterized in that, in described hydrolysis reaction, and described C
2~ C
6alcoholic solvent be Virahol or the trimethyl carbinol;
And/or, not moisture in described hydrolysis reaction;
And/or in described hydrolysis reaction, described alcoholic solvent is 0.5L/mol ~ 1.5L/mol with the Molar ratio of described compound III;
And/or in described hydrolysis reaction, described alkali is one or more in potassium tert.-butoxide, sodium hydroxide and potassium hydroxide;
And/or in described hydrolysis reaction, the mol ratio of described alkali and described compound III is 2.0 ~ 5.0;
And/or in described hydrolysis reaction, the temperature of described reaction is 50 DEG C ~ 120 DEG C;
And/or in described hydrolysis reaction, the time of described reaction is at least 1h.
6. preparation method as claimed in claim 4, it is characterized in that, after described hydrolysis reaction completes, compound IV without separation, then carries out described hoffman degradation reaction.
7. preparation method as claimed in claim 6, is characterized in that, " described hydrolysis reaction complete after, compound IV without separation, then carries out described hoffman degradation reaction " be " after described hydrolysis reaction completes, remove the C in the reaction solution of hydrolysis reaction
2~ C
6alcoholic solvent obtain residuum; Described residuum is carried out described hoffman degradation reaction ".
8. preparation method as claimed in claim 7, is characterized in that, " after described hydrolysis reaction completes, the C in the reaction solution of removing hydrolysis reaction
2~ C
6alcoholic solvent obtain residuum; Described residuum is carried out described hoffman degradation reaction " be " after described hydrolysis reaction completes, the C in the reaction solution of removing hydrolysis reaction
2~ C
6alcoholic solvent obtain residuum; In water, under the existence of alkali and hypohalite, described residuum is carried out described hoffman degradation reaction ".
9. preparation method as claimed in claim 4, is characterized in that, also comprise the steps: in organic solvent, in the presence of base, Compound I and Compound II per are carried out substitution reaction, obtains described compound III; Described organic solvent is alcoholic solvent and/or polar aprotic solvent;
Wherein, LG is the leavings group of aromatic nucleophilic substitution reaction, R
1for hydrogen or metal ion.
10. preparation method as claimed in claim 9, it is characterized in that, in described substitution reaction, described leavings group is fluorine, chlorine, bromine, OTf or OTs;
And/or in described substitution reaction, described metal ion is sodium ion or potassium ion;
And/or in described substitution reaction, described alcoholic solvent is C
1~ C
6alcoholic solvent;
And/or in described substitution reaction, described polar aprotic solvent is methyl-sulphoxide and/or DMF;
And/or in described substitution reaction, described organic solvent is 0.5L/mol ~ 1.5L/mol with the Molar ratio of described Compound I;
And/or in described substitution reaction, the mol ratio of described Compound II per and described Compound I is 1.0 ~ 1.2;
And/or in described substitution reaction, described alkali is salt of wormwood and/or sodium carbonate;
And/or in described substitution reaction, the mol ratio of described alkali and described Compound I is 1.0 ~ 1.5;
And/or in described substitution reaction, the temperature of described reaction is 0 DEG C ~ 120 DEG C;
And/or in described substitution reaction, the time of described reaction is 2h ~ 6h.
The preparation method of 11. 1 kinds of compound IV, it comprises the steps: at C
2~ C
6alcoholic solvent in, in the presence of base, be hydrolyzed compound III reaction, obtains described compound IV;
The condition of described hydrolysis reaction is according to any one of claim 4 ~ 5.
12. preparation methods as claimed in claim 11, is characterized in that, also comprise the steps: in organic solvent, in the presence of base, Compound I and Compound II per are carried out substitution reaction, obtains described compound III; Described organic solvent is alcoholic solvent and/or polar aprotic solvent;
Wherein, LG is the leavings group of aromatic nucleophilic substitution reaction, R
1for hydrogen or metal ion; The condition of described substitution reaction is according to any one of claim 9 ~ 10.
The preparation method of 13. 1 kinds of compound III, it comprises the steps: in organic solvent, in the presence of base, Compound I and Compound II per is carried out substitution reaction, obtains described compound III; Described organic solvent is alcoholic solvent and/or polar aprotic solvent;
Wherein, LG is the leavings group of aromatic nucleophilic substitution reaction, R
1for hydrogen or metal ion; The condition of described substitution reaction is according to any one of claim 9 ~ 10.
14. 1 kinds of fertile preparation methods for Xi Ting, it comprises the steps:
(1) according to the preparation method of the compound V according to any one of claim 1 ~ 10, obtained compound V;
(2) in high boiling solvent, by described compound V, ring-closure reaction is carried out with Dichloroethyl amine or its salt, obtained fertile for Xi Ting; Described high boiling solvent is the solvent of boiling point more than 120 DEG C under normal pressure;
15. 1 kinds of compound III or its salt, its structure is as follows:
16. 1 kinds of compound IV or its salt, its structure is as follows:
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| CN110078626A (en) * | 2019-06-10 | 2019-08-02 | 成家钢 | A kind of preparation method of neighbour's diaminodiphenylmethane |
| EP4247802A4 (en) * | 2021-05-31 | 2024-06-19 | R L Fine Chem Private Limited | A method for preparation of 1-(2-((2,4-dimethylphenyl)thio)phenyl) piperazine and its salts |
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| CN105315184B (en) | 2017-03-29 |
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