CN104892619A - Preparation method of drug intermediate - Google Patents
Preparation method of drug intermediate Download PDFInfo
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- CN104892619A CN104892619A CN201510359381.7A CN201510359381A CN104892619A CN 104892619 A CN104892619 A CN 104892619A CN 201510359381 A CN201510359381 A CN 201510359381A CN 104892619 A CN104892619 A CN 104892619A
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- 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
- C07D491/12—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 three hetero rings
- C07D491/20—Spiro-condensed systems
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Abstract
The invention relates to a preparation method of a drug intermediate. The method includes: dissolving or freeing quinuclidone prior to performing cyclization reaction in a solution form, and preparing a product via processes of liquid separation, salt formation, filtration, drying and the like. The preparation method is smooth and steady in reaction, low in thermal effect, simple in process operation, high in product yield, high in quality, easy for preservation and suitable for industrial production.
Description
Technical field
The present invention relates to a kind of preparation method of compound, particularly a kind of preparation method of pharmaceutical intermediate.
Background technology
The structure of cevimeline (Cevimeline) is:
Cevimeline is the development of Japanese Snow Brand drugmaker, and in March, 2000 is in U.S.'s Initial Public Offering.This product is the cholinergic agonist be combined with M-ChR.Cevimeline is a kind of second peptide cholinomimetic of rigidity, optionally exciting cholinergic M
1and M
3acceptor, causes the secretion of saliva and tears, thus alleviates xerostomia and xerophthalmia.The tension force of gi tract and bird egg unstriated muscle can be increased simultaneously.
All less to the report of cevimeline and intermediate both at home and abroad.Utilize quinuclidone or its salt to prepare pharmaceutical intermediate (epoxy hydrochloride), through Intermediate Preparation cevimeline.Operational path is as follows:
Preparation method disclosed in US Patent No. 4855290, utilizes 3-Quinuclidinone hydrochloride for raw material, and it is water-soluble, in solution, add sodium hydroxide again, in and hydrochloric acid, methylbenzene extraction, activated carbon decolorizing, the steps such as anhydrous magnesium sulfate drying, obtain 3-quinuclidone free alkali.3-quinuclidone reacts with trimethylammonium iodo sulfoxide again, after reaction terminates, with methylbenzene extraction, anhydrous magnesium sulfate drying, concentrates and obtains intermediate.
This processing disadvantages: 1) prepare 3-quinuclidone free alkali water and make solvent, in solid sodium hydroxide and time, thermal discharge is large, is unfavorable for controlling; 2) 3-quinuclidone free alkali is soluble in water, and toluene extraction times is many, and loss is large, and productive rate is low.3) will through extraction is with dry repeatedly, complex operation, is unfavorable for suitability for industrialized production.
Preparation method disclosed in Canadian Patent CA2584349 is solvent with dimethyl formamide makes 3-Quinuclidinone hydrochloride directly react with trimethylammonium iodo sulfoxide at 0 ~ 5 DEG C, reacts after terminating, with methylbenzene extraction, anhydrous sodium sulfate drying, concentrated, obtain yellow oil.
This processing disadvantages: 1) this technology utilization 3-Quinuclidinone hydrochloride is raw material, and not only potassium tert.-butoxide consumption is higher, and exothermic heat of reaction is violent, wayward.2) utilize 3-Quinuclidinone hydrochloride and trimethylammonium iodo sulfoxide ~ walked, in reaction, impurity is many, is not easy to product quality and controls.3) during methylbenzene extraction, concentrated, dry, obtain yellow oil, this product purity is low, and subsequent reactions feeds intake inaccurate, is unfavorable for the control of product quality.
Summary of the invention
The present invention take quinuclidone as raw material, through dissolving the step such as (or free), cyclisation, salify, obtained pharmaceutical intermediate (epoxy hydrochloride).Concrete steps are as follows:
(1) take quinuclidone as raw material, quinuclidone structure is:
(2) in organic solvent, add quinuclidone, mineral alkali, reflux, filter, collect filtrate A;
(3) in organic solvent, add catalyzer, then add trimethylammonium halo sulfoxide, react at a certain temperature, obtain reaction solution A;
(4) by the filtrate A in (2) and the reaction solution A in (3), react at a certain temperature, obtain reaction solution B;
(5) in reaction solution B, add solvent, separatory, collect reaction mixture layer;
(6) in reaction mixture layer, pass into hydrogen chloride gas, stir, filter, filter cake drying obtains product.
1. as described in preparation method, in step (1) and step (2), quinuclidone is at least one in 3-Quinuclidinone hydrochloride, 3-quinuclidone vitriol, 3-quinuclidone nitrate.Preferred 3-Quinuclidinone hydrochloride.
2. as described in preparation method, organic solvent is at least one in normal hexane, hexanaphthene, normal heptane in step (2).Preferred hexanaphthene or normal heptane.
3. as described in preparation method, mineral alkali is at least one in sodium bicarbonate, saleratus, sodium carbonate, salt of wormwood, sodium hydroxide, potassium hydroxide in step (2).Preferred sodium bicarbonate.
4. as described in preparation method, trimethylammonium halo sulfoxide is at least one in trimethylammonium chloro sulfoxide, trimethylammonium bromo sulfoxide, trimethylammonium iodo sulfoxide in step (3).Preferred trimethylammonium iodo sulfoxide.
5. as described in preparation method, organic solvent is at least one in DMF, N,N-dimethylacetamide, dimethyl sulfoxide (DMSO) in step (3).Preferred dimethyl sulfoxide (DMSO).
6. as described in preparation method, catalyzer is at least one in potassium tert.-butoxide, sodium tert-butoxide, potassium hydride KH, sodium hydride, sodium hydroxide, potassium hydroxide in step (3).Preferred potassium tert.-butoxide or sodium tert-butoxide
7. as described in preparation method, temperature of reaction-20 ~ 100 DEG C in step (3).Preferably 10 ~ 40 DEG C.
8. as described in preparation method, temperature of reaction-20 ~ 100 DEG C in step (4).Preferably 10 ~ 40 DEG C.
9. as described in preparation method, prepared pharmaceutical intermediate (epoxy hydrochloride), structure is:
The advantage of present method is:
1) utilize 3-quinuclidone raw material, add in organic solvent, mineral alkali dissociates, technique is simple, and yield is high.
2) utilize the solution of 3-quinuclidone free alkali to carry out cyclization, reacting balance, heat effect is little, and product quality is controlled, and suitability for industrialized production is convenient to realize.
3) in reaction mixture layer, pass into hydrogenchloride, stir, obtain pharmaceutical intermediate (epoxy hydrochloride), product purity is high, and quality is good, is easy to preserve, is more suitable for suitability for industrialized production.
Embodiment
The invention discloses a kind of method preparing cevimeline key intermediate, those skilled in the art can use for reference present disclosure, and suitably improve processing parameter.Special needs to be pointed out is, all similar replacements and change are all apparent for a person skilled in the art, and they all will be deemed to be included in the scope of the invention.Method of the present invention and application be described by preferred embodiment, related personnel obviously can not depart from content of the present invention, spirit and scope methods and applications as herein described are changed or suitably change with combination realize and apply the technology of the present invention.
Embodiment 1:
In 1L hexanaphthene, add 3-Quinuclidinone hydrochloride 100g, sodium bicarbonate 100g, stirring and refluxing reaction 4h, is cooled to room temperature, filters, obtain 3-quinuclidone cyclohexane solution.
80g potassium tert.-butoxide is added to 400mL dimethyl sulfoxide (DMSO), adds 150g trimethylammonium iodo sulfoxide 0 ~ 30 DEG C reaction 1h in batches, drip 3-quinuclidone cyclohexane solution, keep temperature to be 25 ~ 35 DEG C, add rear continuation reaction 1h, reaction system is cooled to 10 ~ 20 DEG C, drip 500mL water, stir 30min, filter, separatory, collects organic phase, in organic phase, passes into hydrogen chloride gas, stirring at room temperature, filters, and collects solid, 40 DEG C of dryings, obtain product (epoxy hydrochloride).
Yield: 87.2%.
Purity 98%.
Fusing point: 201.0 ~ 203.0 DEG C.
Mass spectrum (ESI): 140.1 (M-HCl+1), 175.5 (M+HCl).
1HNMR(d
6-DMSO)：10.67(s，1H)，5.61(s，1H)，3.89、3.91(d，1H)，3.78、3.80(d，1H)，3.09-3.21(m，4H)，2.96、2.99(d，1H)，2.02-2.15(m，2H)，1.79-1.83(m，2H)，1.63-1.68(m，1H)。
Embodiment 2:
In 1L hexanaphthene, add 3-Quinuclidinone hydrochloride 100g, sodium carbonate 100g, stirring and refluxing reaction 4h, is cooled to room temperature, filters, obtain 3-quinuclidone cyclohexane solution.
80g sodium tert-butoxide is added in 500mL dimethyl formamide, add 150g trimethylammonium iodo sulfoxide in batches, in-20 ~ 0 DEG C of reaction 1h, drip 3-quinuclidone cyclohexane solution, keep temperature to be 20 ~ 40 DEG C, add rear continuation reaction 1h, reaction system is cooled to 10 ~ 20 DEG C, drip 500mL water, stir 30min, filter, separatory, collect organic phase, in organic phase, pass into hydrogen chloride gas, stirring at room temperature, filter, collect solid, 40 DEG C of dryings, obtain product (epoxy hydrochloride).
Yield: 88.2%.
Purity 98%.
Fusing point: 201.0 ~ 203.0 DEG C.
Embodiment 3:
In 1L hexanaphthene, add 3-Quinuclidinone hydrochloride 100g, saleratus 100g, stirring and refluxing reaction 4h, is cooled to room temperature, filters, obtain 3-quinuclidone cyclohexane solution.
80g sodium hydroxide is added in 500mL dimethyl formamide, add 150g trimethylammonium iodo sulfoxide in batches, in 20 ~ 30 DEG C of reaction 1h, drip 3-quinuclidone cyclohexane solution, keep temperature to be 80 ~ 100 DEG C, add rear continuation reaction 1h, reaction system is cooled to 10 ~ 20 DEG C, drip 500mL water, stir 30min, filtration under diminished pressure, separatory, collect organic phase, in organic phase, pass into hydrogen chloride gas, stirring at room temperature, filter, 80 DEG C of dryings, collect solid, obtain product (epoxy hydrochloride).
Molar yield: 90.2%.
Purity 97%.
Fusing point: 202.0 ~ 203.5 DEG C.
Embodiment 4:
In 1L normal hexane, add 3-quinuclidone nitrate 100g, salt of wormwood 100g, stirring and refluxing reaction 4h, is cooled to room temperature, filters, obtain 3-quinuclidone hexane solution.
80g potassium hydroxide is added in 500mL dimethyl formamide, add 150g trimethylammonium iodo sulfoxide in batches, in-20 ~ 0 DEG C of reaction 1h, drip 3-quinuclidone hexane solution, keep temperature to be-20 ~ 0 DEG C, add rear continuation reaction 1h, reaction system is cooled to 10 ~ 20 DEG C, drip 500mL water, stir 30min, filter, separatory, collect organic phase, in organic phase, pass into hydrogen chloride gas, stirring at room temperature, filter, 50 DEG C of dryings, collect solid, obtain product (epoxy hydrochloride).
Molar yield: 86.2%
Purity 97%.
Fusing point: 202.0 ~ 204.0 DEG C.
Embodiment 5:
In 1L normal heptane, add 3-Quinuclidinone hydrochloride 100g, sodium hydroxide 100g, stirring and refluxing reaction 4h, is cooled to room temperature, filters, obtain 3-quinuclidone n-heptane solution.
80g sodium tert-butoxide is added in 500mL dimethyl sulfoxide (DMSO), adds 150g trimethylammonium iodo sulfoxide in batches, in 10 ~ 20 DEG C of reaction 1h, drip 3-quinuclidone n-heptane solution, keep temperature to be 20 ~ 30 DEG C, add rear continuation reaction 1h, reaction system is cooled to 10 ~ 20 DEG C, drips 500mL water, stir 30min, filter, separatory, collect organic phase, in organic phase, pass into hydrogen chloride gas, stirring at room temperature, filter, collect solid, 60 DEG C of dryings, obtain product (epoxy hydrochloride).
Molar yield: 89.5%.
Purity 97.0%.
Fusing point: 201.2 ~ 203.5 DEG C.
Embodiment 6:
In 20L normal heptane, add 3-Quinuclidinone hydrochloride 2kg, potassium hydroxide 2kg, stirring and refluxing reaction 4h, is cooled to room temperature, filters, obtain 3-quinuclidone n-heptane solution.
1.5kg potassium tert.-butoxide is added in 5L dimethyl sulfoxide (DMSO), adds 3kg trimethylammonium chloro sulfoxide in batches, in 20 ~ 30 DEG C of reaction 2h, slowly add 3-quinuclidone n-heptane solution, keep temperature to be 40 ~ 50 DEG C, add rear continuation reaction 1h, reaction system is cooled to 10 ~ 20 DEG C, slowly adds 10L water, stir 2h, filter, separatory, collect organic phase, in organic phase, pass into hydrogen chloride gas, stirring at room temperature, filter, collect solid, 20 DEG C of dryings, obtain product (epoxy hydrochloride).
Molar yield: 89.7%.
Purity 98%.
Fusing point: 200.0 ~ 203.0 DEG C.
Embodiment 7:
In 20L hexanaphthene, add 3-Quinuclidinone hydrochloride 2kg, sodium bicarbonate 2kg, stirring and refluxing reaction 4h, is cooled to room temperature, filters, obtain 3-quinuclidone cyclohexane solution.
1.0kg sodium hydride is added in 3L dimethyl sulfoxide (DMSO), add 3kg trimethylammonium iodo sulfoxide in batches, in 20 ~ 30 DEG C of reaction 2h, slowly add 3-quinuclidone cyclohexane solution, temperature is kept to be 20 ~ 30 DEG C, add rear continuation reaction 1h, reaction system is cooled to 10 ~ 20 DEG C, slowly adds 4L water, stir 2h, filter, separatory, collect organic phase.In organic phase, pass into hydrogen chloride gas, stirring at room temperature, filter, collect solid, 40 DEG C of dryings, obtain product (epoxy hydrochloride).
Molar yield: 92.0%.
Purity 97%.
Fusing point: 202 ~ 203.5 DEG C.
Embodiment 8:
In 1L hexanaphthene, add 3-quinuclidone vitriol 100g, stirring and refluxing reaction 6h, is cooled to room temperature, filters, obtain 3-quinuclidone cyclohexane solution.
80g potassium hydride KH is added in 500mL dimethyl formamide, adds 150g trimethylammonium iodo sulfoxide in batches, in-20 ~ 0 DEG C of reaction 1h, drip 3-quinuclidone cyclohexane solution, keep temperature to be 20 ~ 40 DEG C, add rear continuation reaction 1h, reaction system is cooled to 10 ~ 20 DEG C, drips 500mL water, stir 30min, filter, separatory, collect organic phase, in organic phase, pass into hydrogen chloride gas, stirring at room temperature, filter, collect solid, 40 DEG C of dryings, obtain product (epoxy hydrochloride).
Yield: 87.2%.
Purity 98%.
Fusing point: 201.5 ~ 204.0 DEG C.
Embodiment 9:
In 20L normal heptane, add 3-Quinuclidinone hydrochloride 2kg, stirring and refluxing reaction 6h, is cooled to room temperature, filters, obtain 3-quinuclidone n-heptane solution.
1.5kg sodium hydroxide is added in 5L N,N-DIMETHYLACETAMIDE, add 3kg trimethylammonium iodo sulfoxide in batches, in 20 ~ 30 DEG C of reaction 2h, slowly add 3-quinuclidone n-heptane solution, keep temperature to be 40 ~ 50 DEG C, add rear continuation reaction 1h, reaction system is cooled to 10 ~ 20 DEG C, slowly add 10L water, stir 2h, filter, separatory, collect organic phase, in organic phase, pass into hydrogen chloride gas, stirring at room temperature, filter, collect solid, 20 DEG C of dryings, obtain product (epoxy hydrochloride).
Molar yield: 90.7%.
Purity 99%.
Fusing point: 200.5 ~ 203.0 DEG C.
Claims (10)
1. a preparation method for pharmaceutical intermediate, this pharmaceutical intermediate structure is:
It is characterized in that, comprise the steps:
(1) take quinuclidone as raw material, the structure of quinuclidone is:
(2) in organic solvent, add quinuclidone, mineral alkali, reflux, filter, collect filtrate A;
(3) in organic solvent, add catalyzer, then add trimethylammonium halo sulfoxide, react at a certain temperature, obtain reaction solution A;
(4) by the filtrate A in (2) and the reaction solution A in (3), react at a certain temperature, obtain reaction solution B;
(5) in reaction solution B, add solvent, separatory, collect reaction mixture layer;
(6) in reaction mixture layer, pass into hydrogen chloride gas, stir, filter, filter cake drying obtains product.
2. preparation method as claimed in claim 1, wherein step (1) and the middle quinuclidone of step (2) are at least one in 3-Quinuclidinone hydrochloride, 3-quinuclidone vitriol, 3-quinuclidone nitrate.
3. the preparation method as described in claim 1-2, wherein in step (2), organic solvent is at least one of normal hexane, hexanaphthene, normal heptane.
4. the preparation method as described in claim 1-2, wherein in step (2), mineral alkali is at least one in sodium bicarbonate, saleratus, sodium carbonate, salt of wormwood, sodium hydroxide, potassium hydroxide.
5. the preparation method as described in claim 1-4, wherein in step (3), trimethylammonium halo sulfoxide is at least one in trimethylammonium chloro sulfoxide, trimethylammonium bromo sulfoxide, trimethylammonium iodo sulfoxide.
6. the preparation method as described in claim 1-5, wherein in step (3), organic solvent is at least one in DMF, N,N-dimethylacetamide, dimethyl sulfoxide (DMSO).
7. the preparation method as described in claim 1-5, wherein in step (3), catalyzer is at least one in potassium tert.-butoxide, sodium tert-butoxide, potassium hydride KH, sodium hydride, sodium hydroxide, potassium hydroxide.
8. the preparation method as described in claim 1-7, wherein temperature of reaction-20 ~ 100 DEG C in step (3).
9. the preparation method as described in claim 1-8, wherein temperature of reaction-20 ~ 100 DEG C in step (4).
10. the product prepared of preparation method as claimed in claim 1, purposes is for preparing cevimeline and pharmaceutical salts thereof.
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| CN201510359381.7A CN104892619A (en) | 2015-06-26 | 2015-06-26 | Preparation method of drug intermediate |
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| CN201510359381.7A CN104892619A (en) | 2015-06-26 | 2015-06-26 | Preparation method of drug intermediate |
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Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4855290A (en) * | 1985-05-10 | 1989-08-08 | State Of Israel, Represented By Prime Minister's Office, Israel Institute For Biological Research | Derivatives of quinuclidine |
| JP2001131165A (en) * | 1999-11-01 | 2001-05-15 | Sumika Fine Chemicals Co Ltd | Method for producing epoxide |
| US20130274474A1 (en) * | 2012-04-13 | 2013-10-17 | Apotex Pharmachem Inc. | 1,3-oxathiolane derivatives, process for the preparation of 1,3-oxathiolane derivatives and intermediates thereof |
-
2015
- 2015-06-26 CN CN201510359381.7A patent/CN104892619A/en active Pending
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4855290A (en) * | 1985-05-10 | 1989-08-08 | State Of Israel, Represented By Prime Minister's Office, Israel Institute For Biological Research | Derivatives of quinuclidine |
| JP2001131165A (en) * | 1999-11-01 | 2001-05-15 | Sumika Fine Chemicals Co Ltd | Method for producing epoxide |
| US20130274474A1 (en) * | 2012-04-13 | 2013-10-17 | Apotex Pharmachem Inc. | 1,3-oxathiolane derivatives, process for the preparation of 1,3-oxathiolane derivatives and intermediates thereof |
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Application publication date: 20150909 |