CN106967057A - A kind of efficient preparation technology of Aprepitant - Google Patents
A kind of efficient preparation technology of Aprepitant Download PDFInfo
- Publication number
- CN106967057A CN106967057A CN201710402988.8A CN201710402988A CN106967057A CN 106967057 A CN106967057 A CN 106967057A CN 201710402988 A CN201710402988 A CN 201710402988A CN 106967057 A CN106967057 A CN 106967057A
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- Prior art keywords
- aprepitant
- stirring
- ethyoxyl
- phenyl
- trifluoromethyl
- Prior art date
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- 0 CC(c1ccc([C@](CC2CC2)C(O)O[C@@](c2cc(*)cc(*)c2)N*)cc1)=C Chemical compound CC(c1ccc([C@](CC2CC2)C(O)O[C@@](c2cc(*)cc(*)c2)N*)cc1)=C 0.000 description 2
- XYLMUPLGERFSHI-UHFFFAOYSA-N CC(c1ccccc1)=C Chemical compound CC(c1ccccc1)=C XYLMUPLGERFSHI-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
- C07D413/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
Abstract
The invention discloses a kind of efficient preparation technology of Aprepitant, comprise the following steps that：First, with (2R, 3S) 2 [(1R) 1 [3,5 pairs of (trifluoromethyl) phenyl] ethyoxyl] 3 (4 fluorophenyl) morpholine hydrochlorides be raw material prepare 2R [1R [3,5 two (trifluoromethyl) phenyl] ethyoxyl] 3S (4 fluorophenyl) 4 (the amino second hydrazone group of N methoxycarbonyl groups 2) morpholine；Aprepitant crude product is prepared using 2R [1R [3,5 2 (trifluoromethyl) phenyl] ethyoxyl] 3S (4 fluorophenyl) 4 (the amino second hydrazone group of N methoxycarbonyl groups 2) morpholine；Aprepitant crude product refining is obtained into Aprepitant finished product again.Aprepitant high income, the good drug efficacy prepared using the technique, and whole process costs are low, safety non-pollution.
Description
Technical field
The present invention relates to medicine preparation field, and in particular to a kind of efficient preparation technology of Aprepitant.
Background technology
Aprepitant (Aprepitant, trade name：Emend), chemical name：5- [[2- (R)-[1 (R)-[double (trifluoros of 3,5-
Methyl) phenyl] ethyoxyl] -3 (S)-(4- fluorophenyls) -4- morpholinyls] methyl] -1,2- dihydros -3H-1,2,4- triazole -3- ketone,
Structural formula is as follows：
Aprepitant is first NK1 receptor antagonist that U.S. FDA is ratified, and its brand-new mechanism of action is different from
Conventional 5-hydroxytryptamine receptor retarding agent, with more excellent antiemetic drug effect, brings glad tidings to patients undergoing chemotherapy.
Aprepitant synthetic method head sees Publication No. WO9516679A1 patent application, and this method uses rare
To fluorine, this glycine is raw material to alpha-non-natural amino acid L-, and with violent in toxicity 1,2- Bromofume high temperature cyclizations, reaction is depressurized after terminating
Unnecessary Bromofume is distilled off.The extremely difficult purifying of grease finished product obtained by the route, reaction scheme is long, and yield is low, very not
Beneficial to environmental protection.
JOrg Chem,2002,67(19):Report one kind using chiral induction method synthesis Aprepitant in 6743-6747
Method, but this method need to use that to be difficult to the chiral alcohol that obtains be raw material, and chiral alcohol ee values are required more than 99%, are thus made
Into with high costs, it is unfavorable for industry chemical conversion production.Due to having three chiral centres, respectively 1R, 2R in Aprepitant molecule,
3S, thus, sizable difficulty is brought to high optics pure raw material medicine is synthesized.At present, the synthetic method of Aprepitant turns into and ground
The focus studied carefully.
The content of the invention
In order to solve the above-mentioned technical problem, the present invention discloses a kind of efficient preparation technology of Aprepitant, utilizes the technique system
For the Aprepitant high income, good drug efficacy gone out, and whole process costs are low, safety non-pollution.
The present invention is achieved through the following technical solutions：
A kind of efficient preparation technology of Aprepitant, is comprised the following steps that：
(1) with (2R, 3S) -2- [(1R) -1- [3,5- double (trifluoromethyl) phenyl] ethyoxyl] -3- (4- fluorophenyls) -
Quinoline hydrochloride is that raw material prepares 2R- [1R- [3,5- bis- (trifluoromethyl) phenyl] ethyoxyl] -3S- (4- fluorophenyls) -4- (N-
Methoxycarbonyl group -2- amino second hydrazone group)-morpholine；
(2) 2R- [1R- [3,5- bis- (trifluoromethyl) phenyl] ethyoxyl] -3S- (4- fluorophenyls) -4- (N- methoxy carbonyls are utilized
Base -2- amino second hydrazone group)-morpholine prepares Aprepitant crude product；
(3) Aprepitant crude product refining is obtained into Aprepitant finished product.
Wherein, the concrete technology of the step (1) is：
1) nitrogen will be full of in 100L reactors, adds dimethyl sulfoxide (DMSO), (2R, 3S) -2- [(1R) -1- [3,5- double (three
Methyl fluoride) phenyl] ethyoxyl] -3- (4- fluorophenyls)-morpholine hydrochlorides and dimethylbenzene, potassium carbonate, 20- are added after stirring and dissolving
25 DEG C of stirrings, add (AR-3) 2- (the chloro- 1- imido ethyls of 2-) methyl carbazate, benzyltriethylammoinium chloride reaction 18-
22h；
2) step 1 is treated) after completion of the reaction, added toward reaction system is interior at dimethylbenzene and water, 37-43 DEG C after stirring 30min
Stand, separate and separate water after 5min, standing are stirred at 32-38 DEG C after addition saturated brine in water layer collection, upper organic layer
Layer, which is collected, to be merged, and releases organic phase, the aqueous phase of merging is transferred in kettle, adds dimethylbenzene and 5min is stirred at 32-38 DEG C, stand
Aqueous phase is separated, merges organic phase, anhydrous magnesium sulfate stirring is added and dries 30min, be filtered to remove drier, drenched using dimethylbenzene
Wash, obtain pale yellow filtrate, obtain 2R- [1R- [3,5- bis- (trifluoromethyl) phenyl] ethyoxyl] -3S- (4- fluorophenyls) -4-
The xylene solution of (N- methoxycarbonyl group -2- amino second hydrazone group)-morpholine.
The concrete technology of the step (2) is：
1) by 2R- [1R- [3,5- bis- (trifluoromethyl) phenyl] ethyoxyl] -3S- (4- fluorophenyls) -4- (N- methoxycarbonyl groups -
2- amino second hydrazone group) xylene solution of-morpholine is transferred in 50L reactors, the lower heating stirring of nitrogen protection and in 135-141
Reflux water-dividing 2 hours at DEG C, slow cooling is to 2-8 DEG C after completion of the reaction and stirs 60min；
2) filter, wash filter cake with dimethylbenzene, drain, again with methanol and purified water are mixed, and wash filter cake, obtain white extremely
The crystalline powder of off-white color；
3) gained crystalline powder is transferred in vacuum drying chamber and be dried, vacuum≤- 0.08Mp, temperature 52-
58 DEG C, 8-10h is dried under reduced pressure to constant weight, timing stirring, 2h records temperature, a vacuum, receives to obtain Aprepitant crude product.
The concrete technology of the step (3) is：
1) methanol and Aprepitant crude product are added into 50L reactors, 60-66 DEG C of backflow is heated to, then adds activity
Charcoal backflow decolouring 30min, filtering is washed using methanol；
2) filtrate obtained is transferred to stirring in 100L reactors, and temperature control is added dropwise to purified water at 60-66 DEG C, separates out
Solid, is slowly cooled to 19-25 DEG C, and stirring and crystallizing 12h, then filters, and using methanol and purifying water washing filter cake, obtains white
Color or off-white powder；
3) filter cake is transferred in vacuum drying chamber and is dried, vacuum≤- 0.08Mp, and temperature is at 52-58 DEG C, and decompression is dry
Dry 8-10h is to constant weight, and stirring, 2h record temperature, a vacuum, after drying, are crushed, packaging is obtained Aprepitant per hour
Finished product.
The present invention compared with prior art, has the following advantages and advantages：
A kind of efficient preparation technology of Aprepitant of the present invention, compared to existing preparation technology, its manufacturing cost is lower, and with
(2R, 3S) -2- [(1R) -1- [double (trifluoromethyl) phenyl of 3,5-] ethyoxyl] -3- (4- fluorophenyls)-morpholine hydrochloride is original
Material, the reaction condition through strict control each operation, obtained Aprepitant product yield is high, and good drug efficacy is suitably pushed away in this area
Extensively use.
Embodiment
For the object, technical solutions and advantages of the present invention are more clearly understood, with reference to embodiment, to present invention work
Further to describe in detail, exemplary embodiment and its explanation of the invention is only used for explaining the present invention, is not intended as to this
The restriction of invention.
Embodiment
A kind of efficient preparation technology of Aprepitant of the present invention, is comprised the following steps that：
(1) with (2R, 3S) -2- [(1R) -1- [3,5- double (trifluoromethyl) phenyl] ethyoxyl] -3- (4- fluorophenyls) -
Quinoline hydrochloride is that raw material prepares 2R- [1R- [3,5- bis- (trifluoromethyl) phenyl] ethyoxyl] -3S- (4- fluorophenyls) -4- (N-
Methoxycarbonyl group -2- amino second hydrazone group)-morpholine；
(2) 2R- [1R- [3,5- bis- (trifluoromethyl) phenyl] ethyoxyl] -3S- (4- fluorophenyls) -4- (N- methoxy carbonyls are utilized
Base -2- amino second hydrazone group)-morpholine prepares Aprepitant crude product；
(3) Aprepitant crude product refining is obtained into Aprepitant finished product.
Wherein, the concrete technology of the step (1) is：
1) nitrogen will be full of in 100L reactors, adds dimethyl sulfoxide (DMSO), (2R, 3S) -2- [(1R) -1- [3,5- double (three
Methyl fluoride) phenyl] ethyoxyl] -3- (4- fluorophenyls)-morpholine hydrochlorides and dimethylbenzene, potassium carbonate, 20- are added after stirring and dissolving
25 DEG C of stirrings, add (AR-3) 2- (the chloro- 1- imido ethyls of 2-) methyl carbazate, benzyltriethylammoinium chloride reaction 18-
22h；
2) step 1 is treated) after completion of the reaction, added toward reaction system is interior at dimethylbenzene and water, 37-43 DEG C after stirring 30min
Stand, separate and separate water after 5min, standing are stirred at 32-38 DEG C after addition saturated brine in water layer collection, upper organic layer
Layer, which is collected, to be merged, and releases organic phase, the aqueous phase of merging is transferred in kettle, adds dimethylbenzene and 5min is stirred at 32-38 DEG C, stand
Aqueous phase is separated, merges organic phase, anhydrous magnesium sulfate stirring is added and dries 30min, be filtered to remove drier, drenched using dimethylbenzene
Wash, obtain pale yellow filtrate, obtain 2R- [1R- [3,5- bis- (trifluoromethyl) phenyl] ethyoxyl] -3S- (4- fluorophenyls) -4-
The xylene solution of (N- methoxycarbonyl group -2- amino second hydrazone group)-morpholine.
The concrete technology of the step (2) is：
1) by 2R- [1R- [3,5- bis- (trifluoromethyl) phenyl] ethyoxyl] -3S- (4- fluorophenyls) -4- (N- methoxycarbonyl groups -
2- amino second hydrazone group) xylene solution of-morpholine is transferred in 50L reactors, the lower heating stirring of nitrogen protection and in 135-141
Reflux water-dividing 2 hours at DEG C, slow cooling is to 2-8 DEG C after completion of the reaction and stirs 60min；
2) filter, wash filter cake with dimethylbenzene, drain, again with methanol and purified water are mixed, and wash filter cake, obtain white extremely
The crystalline powder of off-white color；
3) gained crystalline powder is transferred in vacuum drying chamber and be dried, vacuum≤- 0.08Mp, temperature 52-
58 DEG C, 8-10h is dried under reduced pressure to constant weight, timing stirring, 2h records temperature, a vacuum, receives to obtain Aprepitant crude product.
The concrete technology of the step (3) is：
1) methanol and Aprepitant crude product are added into 50L reactors, 60-66 DEG C of backflow is heated to, then adds activity
Charcoal backflow decolouring 30min, filtering is washed using methanol；
2) filtrate obtained is transferred to stirring in 100L reactors, and temperature control is added dropwise to purified water at 60-66 DEG C, separates out
Solid, is slowly cooled to 19-25 DEG C, and stirring and crystallizing 12h, then filters, and using methanol and purifying water washing filter cake, obtains white
Color or off-white powder；
3) filter cake is transferred in vacuum drying chamber and is dried, vacuum≤- 0.08Mp, and temperature is at 52-58 DEG C, and decompression is dry
Dry 8-10h is to constant weight, and stirring, 2h record temperature, a vacuum, after drying, are crushed, packaging is obtained Aprepitant per hour
Finished product.
The technological process of specific raw material, intermediate and product is as follows：
Above-described embodiment, has been carried out further to the purpose of the present invention, technical scheme and beneficial effect
Describe in detail, should be understood that the embodiment that the foregoing is only the present invention, be not intended to limit the present invention
Protection domain, within the spirit and principles of the invention, any modification, equivalent substitution and improvements done etc. all should be included
Within protection scope of the present invention.
Claims (4)
1. a kind of efficient preparation technology of Aprepitant, it is characterised in that comprise the following steps that：
(1) with (2R, 3S) -2- [(1R) -1- [double (trifluoromethyl) phenyl of 3,5-] ethyoxyl] -3- (4- fluorophenyls)-alkylbenzyldimethylasaltsum saltsum
Hydrochlorate is that raw material prepares 2R- [1R- [3,5- bis- (trifluoromethyl) phenyl] ethyoxyl] -3S- (4- fluorophenyls) -4- (N- methoxies
Carbonyl -2- amino second hydrazone group)-morpholine；
(2) using 2R- [1R- [3,5- bis- (trifluoromethyl) phenyl] ethyoxyl] -3S- (4- fluorophenyls) -4- (N- methoxycarbonyl groups -
2- amino second hydrazone group)-morpholine prepares Aprepitant crude product；
(3) Aprepitant crude product refining is obtained into Aprepitant finished product.
2. a kind of efficient preparation technology of Aprepitant according to claim 1, it is characterised in that the tool of the step (1)
Body technology is：
1) nitrogen will be full of in 100L reactors, adds dimethyl sulfoxide (DMSO), (2R, 3S) -2- [(1R) -1- [3,5- double (fluoroforms
Base) phenyl] ethyoxyl] -3- (4- fluorophenyls)-morpholine hydrochlorides and dimethylbenzene, potassium carbonate, 20-25 DEG C are added after stirring and dissolving
Stirring, adds (AR-3) 2- (the chloro- 1- imido ethyls of 2-) methyl carbazate, benzyltriethylammoinium chloride reaction 18-22h；
2) step 1 is treated) after completion of the reaction, stood toward reaction system interior add at dimethylbenzene and water, 37-43 DEG C after stirring 30min,
Separate to add to stir at 32-38 DEG C after saturated brine in water layer collection, upper organic layer and water layer collection is separated after 5min, standing
Merge, release organic phase, the aqueous phase of merging is transferred in kettle, add dimethylbenzene and 5min is stirred at 32-38 DEG C, standing separates water
Phase, merges organic phase, adds anhydrous magnesium sulfate stirring and dries 30min, is filtered to remove drier, is eluted using dimethylbenzene, obtained
To pale yellow filtrate, 2R- [1R- [3,5- bis- (trifluoromethyl) phenyl] ethyoxyl] -3S- (4- fluorophenyls) -4- (N- methoxies are obtained
Carbonyl -2- amino second hydrazone group)-morpholine xylene solution.
3. a kind of efficient preparation technology of Aprepitant according to claim 1, it is characterised in that the tool of the step (2)
Body technology is：
1) by 2R- [1R- [3,5- bis- (trifluoromethyl) phenyl] ethyoxyl] -3S- (4- fluorophenyls) -4- (N- methoxycarbonyl group -2- ammonia
Base second hydrazone group) xylene solution of-morpholine is transferred in 50L reactors, the lower heating stirring of nitrogen protection and at 135-141 DEG C
Reflux water-dividing 2 hours, slow cooling is to 2-8 DEG C after completion of the reaction and stirs 60min；
2) filter, wash filter cake with dimethylbenzene, drain, again with methanol and purified water are mixed, and wash filter cake, obtain white white to class
The crystalline powder of color；
3) gained crystalline powder is transferred in vacuum drying chamber and be dried, vacuum≤- 0.08Mp, 52-58 DEG C of temperature,
8-10h is dried under reduced pressure to constant weight, timing stirring, 2h records temperature, a vacuum, receives to obtain Aprepitant crude product.
4. a kind of efficient preparation technology of Aprepitant according to claim 1, it is characterised in that the tool of the step (3)
Body technology is：
1) methanol and Aprepitant crude product are added into 50L reactors, 60-66 DEG C of backflow is heated to, activated carbon is then added and returns
Decolouring 30min is flowed, filtering is washed using methanol；
2) filtrate obtained is transferred to stirring in 100L reactors, and temperature control is added dropwise to purified water at 60-66 DEG C, separates out solid,
Be slowly cooled to 19-25 DEG C, and stirring and crystallizing 12h, then filter, using methanol and purifying water washing filter cake, obtain white or
Off-white powder；
3) filter cake is transferred in vacuum drying chamber and is dried, vacuum≤- 0.08Mp, and temperature is dried under reduced pressure 8- at 52-58 DEG C
10h is to constant weight, stirring per hour, and 2h records temperature, a vacuum, after drying, crush, packaging be made Aprepitant into
Product.
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201710402988.8A CN106967057A (en) | 2017-06-01 | 2017-06-01 | A kind of efficient preparation technology of Aprepitant |
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| Application Number | Priority Date | Filing Date | Title |
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| CN201710402988.8A CN106967057A (en) | 2017-06-01 | 2017-06-01 | A kind of efficient preparation technology of Aprepitant |
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| CN106967057A true CN106967057A (en) | 2017-07-21 |
Family
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN109467552A (en) * | 2019-01-14 | 2019-03-15 | 成都晶富医药科技有限公司 | The preparation process of Aprepitant |
| CN110655515A (en) * | 2018-06-29 | 2020-01-07 | 江苏海悦康医药科技有限公司 | Preparation method of high-purity aprepitant |
| CN110746371A (en) * | 2019-11-20 | 2020-02-04 | 山东鲁抗医药股份有限公司 | Intermediate for preparing aprepitant and preparation method and application thereof |
Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1646525A (en) * | 2002-04-18 | 2005-07-27 | 麦克公司 | Process for 5-[[2(R)-[1(R)-[3,5-bis(trifluoromethyl)phenyl]ethoxy]-3(S)-(4-fluorophenyl)-4-morpholinyl]methyl]-1,2-dihydro-3H-1,2,4-triazol-3-one |
| WO2007039883A2 (en) * | 2005-10-05 | 2007-04-12 | Ranbaxy Laboratories Limited | Process for preparation of aprepitant |
| CN103030668A (en) * | 2011-10-09 | 2013-04-10 | 江苏豪森药业股份有限公司 | Method for preparing fosaprepitant |
| WO2013124823A1 (en) * | 2012-02-23 | 2013-08-29 | Piramal Enterprises Limited | An improved process for the preparation of aprepitant |
-
2017
- 2017-06-01 CN CN201710402988.8A patent/CN106967057A/en active Pending
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1646525A (en) * | 2002-04-18 | 2005-07-27 | 麦克公司 | Process for 5-[[2(R)-[1(R)-[3,5-bis(trifluoromethyl)phenyl]ethoxy]-3(S)-(4-fluorophenyl)-4-morpholinyl]methyl]-1,2-dihydro-3H-1,2,4-triazol-3-one |
| WO2007039883A2 (en) * | 2005-10-05 | 2007-04-12 | Ranbaxy Laboratories Limited | Process for preparation of aprepitant |
| CN103030668A (en) * | 2011-10-09 | 2013-04-10 | 江苏豪森药业股份有限公司 | Method for preparing fosaprepitant |
| WO2013124823A1 (en) * | 2012-02-23 | 2013-08-29 | Piramal Enterprises Limited | An improved process for the preparation of aprepitant |
Non-Patent Citations (1)
| Title |
|---|
| BRANDS KM，等: "Efficient synthesis of NK(1) receptor antagonist aprepitant using a crystallization-induced diastereoselective transformation.", 《JOURNAL OF THE AMERICAN CHEMICAL SOCIETY》 * |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN110655515A (en) * | 2018-06-29 | 2020-01-07 | 江苏海悦康医药科技有限公司 | Preparation method of high-purity aprepitant |
| CN109467552A (en) * | 2019-01-14 | 2019-03-15 | 成都晶富医药科技有限公司 | The preparation process of Aprepitant |
| CN110746371A (en) * | 2019-11-20 | 2020-02-04 | 山东鲁抗医药股份有限公司 | Intermediate for preparing aprepitant and preparation method and application thereof |
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