CN106632358A - Method for preparing lurasidone hydrochloride intermediate - Google Patents
Method for preparing lurasidone hydrochloride intermediate Download PDFInfo
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- CN106632358A CN106632358A CN201610967424.4A CN201610967424A CN106632358A CN 106632358 A CN106632358 A CN 106632358A CN 201610967424 A CN201610967424 A CN 201610967424A CN 106632358 A CN106632358 A CN 106632358A
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
- C07D487/10—Spiro-condensed systems
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Abstract
The invention discloses a method for preparing a lurasidone hydrochloride intermediate (formula I). (S,R)-p-toluene sulfonic acid cyclohexane dimethyl ester (formula II) and benzisothiazole piperazine (formula III) are dissolved in an aprotic polar solvent, a basic catalyst is used to serve as an acid binding agent, and heating reaction is performed for 10-24 h. The proper aprotic polar solvent is adopted to serve as a reaction medium for substitution reaction, a mixed feeding method is adopted, so that the reaction is performed quickly, the content of chiral impurities is low, and a postprocessing process is simple and convenient.
Description
Technical field
The invention belongs to pharmaceutical technology field, relates generally to medicine Lurasidone HCl precursor（S, R）- ring N, N- hexamethylene
Dimethylene-（N- benzisothia oxazolyls）The technical study of-piperazine tosilate.
Background technology
Lurasidone HCl, trade name Latuda, chemical name is（3aR, 4S, 7R, 7aS）-2-[（1R, 2R）-2-
[4-（1,2 benzisothiazole -3- bases）Piperazine -1- ylmethyls] cyclohexyl methyl] hexahydro -1H-4,7- methyl iso-indoles -1,3- bis-
Ketone, it has higher affinity to 5-HT2 acceptors and d2 dopamine receptor, has aobvious to the positive and negative symptoms of mental patient
Curative effect is write, for treating schizophrenia.In the food and medicine Surveillance Authority of the Huo U.S. of October 28 in 2010（FDA）Approval exists
It is listed within the border.（S, R）- ring N, N- cyclohexanedimethyleterephthalate-（N- benzisothia oxazolyls）- piperazine tosilate is SARS
Type antipsychotics Lurasidone HCl（lurasidone）Important intermediate, its structural formula is：
。
Chinese patent CN 102731512B are adopted（S, R）- methanesulfonic acid cyclohexane dicarboxylates and benzisothia oxazolyl piperazine exist
K2CO3With（n-Bu)4N+Br-In the presence of, in being added to toluene, a point water being heated to reflux, Jing is filtered, reduced pressure concentration and acetonitrile refining are obtained
Arrive（S, R）- ring N, N- cyclohexanedimethyleterephthalate-（N- benzisothia oxazolyls）- piperazine methanesulfonate.The meeting in technical process of this method
A large amount of extremely toxic substance methanesulfonic acids are produced, to the process of the three wastes greatly challenge are brought, can virtually increase many production costs,
So as to and be unfavorable for industrialized production.
The content of the invention
In view of demand of the environmental protection to synthesis technique, the invention provides a kind of reaction condition is gentle, economic and environment-friendly, receive
Rate is higher and is easy to industrialized（S, R）- ring N, N- cyclohexanedimethyleterephthalate-（N- benzisothia oxazolyls）- piperazine is to toluene sulphur
The synthetic method of hydrochlorate.
The present invention is adopted（S, R）- p-methyl benzenesulfonic acid cyclohexane dicarboxylates（Formula II）With benzisothia oxazolyl piperazine（Formula III）
For raw material, using aprotic polar solvent as reaction medium, using base catalyst as acid binding agent, heating response 10-24 h, Jing
Cooling, crystallization, filtration and inorganic base aqueous solution wash to obtain product（Formula I）.From the point of view of reaction mechanism angle, the present invention is using to first
Used as reaction substrate, its cation is easy to strong solvating by aprotic polar solvent to benzene sulfonic acid hydrocarbyl carbonate, under alkaline environment,
Substitution reaction can rapidly occur with benzisothiazole piperazine.Its reaction equation is as follows：
。
The alternative aprotic polar solvent of the present invention has N,N-dimethylformamide, DMAC N,N' dimethyl acetamide, N-
Methyl pyrrolidone, dimethyl sulfoxide, hexamethyl phosphoramide, Isosorbide-5-Nitrae-dioxane, nitromethane, quinoline, MEK, acetonitrile, it is molten
Agent consumption with（S,R）- p-methyl benzenesulfonic acid cyclohexane dicarboxylates（Formula II）It is calculated as 5-20 mL/g；
Used as acid binding agent, alternative base catalyst has sodium carbonate, hydroxide to course of reaction neutral and alkali catalyst of the present invention
Sodium, potassium hydroxide, triethylamine, caustic alcohol, sodium tert-butoxide or potassium tert-butoxide, sodium hydride, N, N- diisopropylethylamine, pyridine, carbon
Sour hydrogen sodium, sodium acetate, triphenyl sodium, DBU, Sodamide, potassium carbonate；Base catalyst with（S, R）- p-methyl benzenesulfonic acid hexamethylene two
Methyl esters（Formula II）With benzisothia oxazolyl piperazine（Formula III）Rate of charge be 2:1:1-1.1:1:1.
Reaction temperature of the present invention be reflux temperature, reaction time 10-24 h.
The crystallization mode that the present invention is adopted naturally cools to room temperature, stirring and crystallizing 2-10 h for gradient crystallization.
The product separate mode that the present invention is adopted is filtration.
The removal of impurities mode that the present invention is adopted is filtered to be beaten 2-4 h with inorganic base aqueous solution；Alternative inorganic base has
Sodium carbonate, NaOH, sodium acid carbonate, and with（S, R）- ring N, N- cyclohexanedimethyleterephthalate-（N- benzisothia oxazolyls）- piperazine
Tosilate（Formula I）It is calculated as 5-10 mL/g.
The present invention innovative point be：
（1）Using aprotic polar solvent as the reaction medium of substitution reaction, solvation is greatly promoted, so as to protect
Being smoothed out for substitution reaction is demonstrate,proved.
（2）Using p-methyl benzenesulfonic acid hydrocarbyl carbonate as effective hydrocarbylating agent.
（3）Using mixing charging method so that being swift in response is carried out, and chiral impurity content is low.
It is embodied as example
With reference to instantiation, the present invention is further illustrated, but should not be construed as limiting the invention.
Embodiment 1
By 200.0 g（0.4419 mol）（S,R）- p-methyl benzenesulfonic acid cyclohexane dicarboxylates, 48.5g (0.2210mol) benzisoxa
Thiazolyl piperazine and 30.5 g（0.2210mol）Potassium carbonate is dissolved in 2000.0 ml acetonitriles, is warming up to reaction system backflow, instead
Answer 14 h.Naturally cool to room temperature, the h of stirring and crystallizing 4.Filter, a small amount of acetonitrile drip washing filter cake.Filter cake is with 800.0 ml saturated carbons
Sour hydrogen sodium water solution washs 2 h.Filter again, collect filter cake.Filter cake is placed in into 40 DEG C of air dry ovens and is dried 14 h, obtain cream-coloured
The g of color pulverulent solids 80.8, yield 73.1%.
Embodiment 2
By 200.0 g（0.4419mol）（S,R）- p-methyl benzenesulfonic acid cyclohexane dicarboxylates, 53.8g (0.2455mol) benzisothia
Oxazolyl piperazine and 33.9 g（0.2455mol）Potassium carbonate is dissolved in 2000.0 ml acetonitriles, is warming up to reaction system backflow, reaction
14 h.Naturally cool to room temperature, the h of stirring and crystallizing 4.Filter, a small amount of acetonitrile drip washing filter cake.Filter cake is with 1120.0 ml unsaturated carbonates
Hydrogen sodium water solution washs 2 h.Filter again, collect filter cake.Filter cake is placed in into 40 DEG C of air dry ovens and is dried 16 h, obtain ecru
Pulverulent solids 90.7g, yield 74.0%.
Embodiment 3
By 200.0 g（0.4419mol）（S,R）- p-methyl benzenesulfonic acid cyclohexane dicarboxylates, 53.8g (0.2455mol) benzisoxa
Thiazolyl piperazine and 33.9 g（0.2455mol）Potassium carbonate is dissolved in 2000.0 ml acetonitriles, is warming up to reaction system backflow, instead
Answer 14 h.Naturally cool to room temperature, the h of stirring and crystallizing 6.Filter, a small amount of acetonitrile drip washing filter cake.Filter cake is with 1120.0 ml saturated carbons
Sour hydrogen sodium water solution washs 2 h.Filter again, collect filter cake.Filter cake is placed in into 40 DEG C of air dry ovens and is dried 19 h, obtain cream-coloured
Color pulverulent solids 98.7g, yield 80.5%.
Embodiment 4
By 200.0 g（0.4419mol）（S,R）- p-methyl benzenesulfonic acid cyclohexane dicarboxylates, 64.6g (0.2946mol) benzisothia
Oxazolyl piperazine and 40.7 g（0.2946mol）Potassium carbonate is dissolved in 2000.0 ml acetonitriles, is warming up to reaction system backflow, reaction
14 h.Naturally cool to room temperature, the h of stirring and crystallizing 8.Filter, a small amount of acetonitrile drip washing filter cake.Filter cake is with 1350.0 ml unsaturated carbonates
Hydrogen sodium water solution washs 2 h.Filter again, collect filter cake.Filter cake is placed in into 40 DEG C of air dry ovens and is dried 13 h, obtain ecru
Pulverulent solids 117.2g, yield 79.6%.
Embodiment 5
By 200.0 g（0.4419mol）（S,R）- p-methyl benzenesulfonic acid cyclohexane dicarboxylates, 64.6g (0.2946mol) benzisothia
Oxazolyl piperazine and 40.7 g（0.2946mol）Potassium carbonate is dissolved in 2000.0 ml acetonitriles, is warming up to reaction system backflow, reaction
14 h.Naturally cool to room temperature, the h of stirring and crystallizing 8.Filter, a small amount of acetonitrile drip washing filter cake.Filter cake is with 1080.0 ml unsaturated carbonates
Hydrogen sodium water solution washs 2 h.Filter again, collect filter cake.Filter cake is placed in into 40 DEG C of air dry ovens and is dried 13 h, obtain ecru
Pulverulent solids 119.7g, yield 81.3%.
Embodiment 6
By 200.0 g（0.4419mol）（S,R）- p-methyl benzenesulfonic acid cyclohexane dicarboxylates, 64.6g (0.2946mol) benzisoxa
Thiazolyl piperazine and 40.7 g（0.2946mol）Potassium carbonate is dissolved in 3000.0 ml acetonitriles, is warming up to reaction system backflow, instead
Answer 14 h.Naturally cool to room temperature, stirring and crystallizing 4h.Filter, a small amount of acetonitrile drip washing filter cake.Filter cake is with 1080.0 ml saturated carbons
Sour hydrogen sodium water solution washs 2 h.Filter again, collect filter cake.Filter cake is placed in into 40 DEG C of air dry ovens and is dried 11 h, obtain cream-coloured
Color pulverulent solids 120.8g, yield 82.1%.
Embodiment 7
By 200.0 g（0.4419mol）（S,R）- p-methyl benzenesulfonic acid cyclohexane dicarboxylates, 88.1g (0.4017mol) benzisoxa
Thiazolyl piperazine and 55.5 g（0.4017mol）Potassium carbonate is dissolved in 2000.0 ml acetonitriles, is warming up to reaction system backflow, instead
Answer 14 h.Naturally cool to room temperature, the h of stirring and crystallizing 4.Filter, a small amount of acetonitrile drip washing filter cake.Filter cake is with 1080.0 ml saturated carbons
Sour hydrogen sodium water solution washs 2 h.Filter again, collect filter cake.Filter cake is placed in into 40 DEG C of air dry ovens and is dried 12.6h, obtain rice
Yellow powdery solid 167.8g, yield 83.6%.
Embodiment 8
By 200.0 g（0.4419mol）（S,R）- p-methyl benzenesulfonic acid cyclohexane dicarboxylates, 88.1g（0.4017mol）Benzisoxa
Thiazolyl piperazine and 55.5 g（0.4017mol）Potassium carbonate is dissolved in 1600.0 ml acetonitriles, is warming up to reaction system backflow, instead
Answer 14 h.Naturally cool to room temperature, the h of stirring and crystallizing 6.Filter, a small amount of acetonitrile drip washing filter cake.Filter cake is with 1004.0 ml saturated carbons
Sour hydrogen sodium water solution washs 2 h.Filter again, collect filter cake.Filter cake is placed in into 40 DEG C of air dry ovens and is dried 14.8h, obtain rice
Yellow powdery solid 168.4g, yield 83.9%.
Embodiment 9
By 200.0 g（0.4419mol）（S,R）- p-methyl benzenesulfonic acid cyclohexane dicarboxylates, 88.1g（0.4017mol）Benzisoxa
Thiazolyl piperazine and 55.5 g（0.4017mol）Potassium carbonate is dissolved in 1600.0 ml acetonitriles, is warming up to reaction system backflow, instead
Answer 14 h.Naturally cool to room temperature, the h of stirring and crystallizing 4.Filter, a small amount of acetonitrile drip washing filter cake.Filter cake is with 1600.0 ml saturated carbons
Sour hydrogen sodium water solution washs 2 h.Filter again, collect filter cake.Filter cake is placed in into 40 DEG C of air dry ovens and is dried 14.8h, obtain rice
Yellow powdery solid 165.4g, yield 82.4%.
Embodiment 10
By 200.0 g（0.4419mol）（S,R）- p-methyl benzenesulfonic acid cyclohexane dicarboxylates, 74.6g（0.3399mol）Benzisoxa
Thiazolyl piperazine and 47.0 g（0.3399mol）Potassium carbonate is dissolved in 2000.0 ml acetonitriles, is warming up to reaction system backflow, instead
Answer 14 h.Naturally cool to room temperature, the h of stirring and crystallizing 4.Filter, a small amount of acetonitrile drip washing filter cake.Filter cake is with 1360.0 ml saturated carbons
Sour hydrogen sodium water solution washs 2 h.Filter again, collect filter cake.Filter cake is placed in into 40 DEG C of air dry ovens and is dried 16.1h, obtain rice
Yellow powdery solid 136.9g, yield 80.6%.
Embodiment 11
By 200.0 g（0.4419mol）（S,R）- p-methyl benzenesulfonic acid cyclohexane dicarboxylates, 74.6g（0.3399mol）Benzisoxa
Thiazolyl piperazine and 47.0 g（0.3399mol）Potassium carbonate is dissolved in 1600.0 ml acetonitriles, is warming up to reaction system backflow, instead
Answer 14 h.Naturally cool to room temperature, the h of stirring and crystallizing 2.Filter, a small amount of acetonitrile drip washing filter cake.Filter cake is with 1360.0 ml saturated carbons
Sour hydrogen sodium water solution washs 2 h.Filter again, collect filter cake.Filter cake is placed in into 40 DEG C of air dry ovens and is dried 16.1h, obtain rice
Yellow powdery solid 123.4g, yield 72.6%.
Embodiment 12
By 200.0 g（0.4419mol）（S,R）- p-methyl benzenesulfonic acid cyclohexane dicarboxylates, 74.6g（0.3399mol）Benzisoxa
Thiazolyl piperazine and 47.0 g（0.3399mol）Potassium carbonate is dissolved in 1600.0 ml acetonitriles, is warming up to reaction system backflow, instead
Answer 14 h.Naturally cool to room temperature, the h of stirring and crystallizing 4.Filter, a small amount of acetonitrile drip washing filter cake.Filter cake is with 850.0 ml saturated carbons
Sour hydrogen sodium water solution washs 2 h.Filter again, collect filter cake.Filter cake is placed in into 40 DEG C of air dry ovens and is dried 16.1h, obtain rice
Yellow powdery solid 129.7g, yield 76.3%.
Claims (7)
1. Lurasidone HCl intermediate is prepared（S, R）- ring N, N- cyclohexanedimethyleterephthalate-（N- benzisothia oxazolyls）- piperazine
Tosilate（Formula I）A kind of method, it is characterised in that comprise the following steps：Will（S, R）- p-methyl benzenesulfonic acid hexamethylene two
Methyl esters（Formula II）With benzisothia oxazolyl piperazine（Formula III）In being dissolved in aprotic polar solvent, with base catalyst as tiing up acid
Agent, heating response 10-24h, crystallization of lowering the temperature is filtered, and filter cake Jing inorganic base aqueous solutions washing 2-4 h, filtration drying obtains target product
Thing（Formula I）；Reaction equation is as follows：
。
2. preparation method according to claim 1, it is characterised in that alternative aprotic polar solvent has N, N- bis-
NMF, DMAC N,N' dimethyl acetamide, 1-METHYLPYRROLIDONE, dimethyl sulfoxide, hexamethyl phosphoramide, 1,4- dioxies six
Ring, nitromethane, quinoline, MEK, acetonitrile；Solvent load with（S,R）- p-methyl benzenesulfonic acid cyclohexane dicarboxylates（Formula II）It is calculated as
5-20 mL/g。
3. preparation method according to claim 1, it is characterised in that base catalyst as acid binding agent, alternative alkalescence
Catalyst has sodium carbonate, NaOH, potassium hydroxide, triethylamine, caustic alcohol, sodium tert-butoxide or potassium tert-butoxide, sodium hydride, N, N-
Diisopropylethylamine, pyridine, sodium acid carbonate, sodium acetate, triphenyl sodium, DBU, Sodamide, potassium carbonate；Base catalyst with（S,
R）- p-methyl benzenesulfonic acid cyclohexane dicarboxylates（Formula II）With benzisothia oxazolyl piperazine（Formula III）Rate of charge be 2:1:1-1.1:1:
1。
4. preparation method according to claim 1, it is characterised in that reaction temperature is reflux temperature, reaction time 10-24 h.
5. preparation method according to claim 1, it is characterised in that the crystallization mode for adopting is for gradient crystallization, i.e. natural cooling
To room temperature, stirring and crystallizing 2-10 h.
6. preparation method according to claim 1, it is characterised in that the product separate mode for adopting is to filter.
7. preparation method according to claim 1, it is characterised in that the removal of impurities mode for adopting with inorganic base aqueous solution to be beaten
2-4 h, filter；Alternative inorganic base has sodium carbonate, NaOH, a sodium acid carbonate, and with（S, R）- ring N, N- hexamethylene
Dimethylene-（N- benzisothia oxazolyls）- piperazine tosilate（Formula I）It is calculated as 5-10 mL/.
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN109553614A (en) * | 2017-09-27 | 2019-04-02 | 北京万全德众医药生物技术有限公司 | The preparation of Lurasidone isomer impurities |
Citations (5)
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|---|---|---|---|---|
| CN102731512A (en) * | 2011-04-12 | 2012-10-17 | 天津药物研究院 | Preparation method of lurasidone intermediate and lurasidone |
| CN103724238A (en) * | 2013-12-31 | 2014-04-16 | 无锡万全医药技术有限公司 | Preparation method of (1R, 2R)-1, 2-cyclohexanedimethanol diaryl sulphonate |
| CN103864774A (en) * | 2012-12-14 | 2014-06-18 | 成都弘达药业有限公司 | Method for preparing lurasidone |
| CN104513182A (en) * | 2013-10-08 | 2015-04-15 | 无锡万全医药技术有限公司 | Method for preparing (1R,2R)-1,2-cyclohexanedimethanol disulfonate |
| CN105732644A (en) * | 2014-12-10 | 2016-07-06 | 苏州二叶制药有限公司 | Lurasidone hydrochloride intermediate preparation method |
-
2016
- 2016-10-31 CN CN201610967424.4A patent/CN106632358A/en active Pending
Patent Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102731512A (en) * | 2011-04-12 | 2012-10-17 | 天津药物研究院 | Preparation method of lurasidone intermediate and lurasidone |
| CN103864774A (en) * | 2012-12-14 | 2014-06-18 | 成都弘达药业有限公司 | Method for preparing lurasidone |
| CN104513182A (en) * | 2013-10-08 | 2015-04-15 | 无锡万全医药技术有限公司 | Method for preparing (1R,2R)-1,2-cyclohexanedimethanol disulfonate |
| CN103724238A (en) * | 2013-12-31 | 2014-04-16 | 无锡万全医药技术有限公司 | Preparation method of (1R, 2R)-1, 2-cyclohexanedimethanol diaryl sulphonate |
| CN105732644A (en) * | 2014-12-10 | 2016-07-06 | 苏州二叶制药有限公司 | Lurasidone hydrochloride intermediate preparation method |
Non-Patent Citations (1)
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| 柳 青，等: "盐酸鲁拉西酮的合成", 《中国医药工业杂志》 * |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN109553614A (en) * | 2017-09-27 | 2019-04-02 | 北京万全德众医药生物技术有限公司 | The preparation of Lurasidone isomer impurities |
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