CN107954998A - The preparation method of fosaprepitant intermediate - Google Patents
The preparation method of fosaprepitant intermediate Download PDFInfo
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- CN107954998A CN107954998A CN201610900158.3A CN201610900158A CN107954998A CN 107954998 A CN107954998 A CN 107954998A CN 201610900158 A CN201610900158 A CN 201610900158A CN 107954998 A CN107954998 A CN 107954998A
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- 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
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- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
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Abstract
The present invention discloses the preparation method of fosaprepitant intermediate, more particularly to 5 [[(2R of medicine, 3S) 2 [(1R) 1 [3,5 pairs of (trifluoromethyl) phenyl] ethyoxyl] 3 (4 fluorophenyl) 4 morpholinyls] methyl] 1,2 dihydro 3H 1,2, the new preparation process of 4 triazole, 3 ketone (i.e. Aprepitant), this method is included in the presence of condensation system, compound (IV) is synthesized, then target product compound (I) is made in cyclization compound (IV) below 139 DEG C.Preparation method provided by the present invention is green, environmentally friendly, efficient, easily industrialization.
Description
Technical field
The invention belongs to technical field of medicine synthesis, and in particular to 5- [[(2R, 3S) -2- [(1R) -1- [3,5- double (trifluoros
Methyl) phenyl] ethyoxyl] -3- (4- fluorophenyls) -4- morpholinyls] methyl] and -1,2- dihydro -3H-1,2,4- triazole -3- ketone system
Preparation Method.
Background technology
Aprepitant is the key intermediate of Fosaprepitant, its chemical name for 5- [[(2R, 3S) -2- [(1R) -1- [3,
Double (trifluoromethyl) phenyl of 5-] ethyoxyl] -3- (4- fluorophenyls) -4- morpholinyls] methyl] -1,2- dihydros -3H-1,2,4- three
Azoles -3- ketone, is first Arg-Pro-Lys-Pro-Gln-Gln-Phe-Phe-Gly-Leu-Met-NH2/neurokinin 1 (NK1) receptor antagonist pharmaceuticals of Merck ＆ Co., Inc.'s exploitation, has to NK1 acceptors
Selective and high affinity, but there is no affinity to 5-HT3 acceptors, dopamine receptor, corticosteroid receptors.A Rui
It is smooth to ratify to list in the U.S. first by FDA in 2003, then listed successively in global other countries, be mainly used for being directed to chemotherapy
The treatment of the Nausea and vomiting of induction, is also used for post-operative nausea, the treatment of vomiting.
The structural formula of Aprepitant is：
The Aprepitant preparation method of existing literature report includes following two methods,
Method one：
Document Terahedron Lett., 2000,41,8661-8664, it was recently reported that using compound ii and 3- chloromethyls-
1,2,4- triazoline -5- ketone (compound (V)) direct polycondensation obtains Aprepitant (compound (I)).Wherein compound (V) is no
Easily it is made, yield is low, production cost is high.Therefore, this method is unfavorable for the industrialized production of Aprepitant.
Method two：
Patent CN1293077C, it was recently reported that compound (II) and compound (III) are condensed to yield compounds Ⅳ first, should
Intermediate needs not move through separation and purifying, directly carries out cyclisation in next step and obtains Aprepitant (compound (I)).Wherein it is condensed
Step is emphasized to use inorganic base, toluene and polarity, aprotic solvent, needs to concentrate higher boiling after simultaneous reactions
Toluene, follow-up cyclization temperature could be caused to reach 140 DEG C~150 DEG C, but concentration step high energy consumption, add operation difficulty and
Production cost；Cyclization step is completed at 140 DEG C~150 DEG C, risk of the high temperature there are accessory substance increase, product racemization；This side
Method yield only has 85%, and yield is relatively low；Therefore, this method is unfavorable for the implementation of the industrialized production of Aprepitant.
Accordingly, it is desirable to provide a kind of new method of Aprepitant, to overcome above-mentioned problems of the prior art.
The content of the invention
It is an object of the invention to solve above-mentioned problems of the prior art, there is provided it is a kind of it is inexpensive, environmentally protective,
It is easy to industrialized production, the method for the formula of high income (I) compound.
The technical scheme is that be accomplished in the following manner：
In the presence of inorganic base, organic solvent, compound (II) is reacted with compound (III), obtains compound (IV), then
It it is less than 139 DEG C in reaction temperature, cyclizing compounds (IV), are prepared compound (I).
Specific reaction scheme is as follows：
Wherein, the molar ratio of compound (II) and compound (III) is 1:1.0~1.5, preferably 1:1.1~1.3, more preferably
1:1.1~1.2.
The reaction temperature of compound (II) and compound (III) is less than 20 DEG C, preferably 0 DEG C~10 DEG C.
Compound (II) and the molar ratio of inorganic base are 1:3.0~5.0, preferably 1:3.5~4.0, more preferably 1:3.5.
The mass volume ratio of compound (II) and organic solvent is 1:2~10, preferably 1:3~4.
The organic solvent is dimethylbenzene, dimethyl sulfoxide or the mixed solution of the two, and preferably dimethylbenzene-dimethyl sulfoxide is mixed
Close solution, more preferably volume ratio VDimethylbenzene：VDimethyl sulfoxideFor 1:0.1~1:10 dimethylbenzene-dimethyl sulfoxide mixed solution, more preferably volume
Compare VDimethylbenzene：VDimethyl sulfoxideFor 1:1~1:5 dimethylbenzene-dimethyl sulfoxide mixed solution, most preferably volume ratio VDimethylbenzene：VDimethyl sulfoxideFor 1:1 diformazan
Benzene-dimethyl sulfoxide mixed solution.
The cyclization temperature is 100 DEG C~139 DEG C, preferably 120 DEG C~139 DEG C, more preferably 130 DEG C~139 DEG C.
The inorganic base is selected from potassium carbonate, sodium carbonate, sodium acid carbonate, preferably cesium carbonate, potassium carbonate.
After reaction, filtering, washing, drying steps are generally further included.It is preferred that washed using dimethylbenzene.
The beneficial effects of the invention are as follows：Compared with prior art, the problem of present invention overcomes raw material to be not easy to be made；In chemical combination
Toluene being substituted using dimethylbenzene in thing (IV) preparation process and making solvent, then direct cyclization obtains compound (I), and it is high to solve concentration
The problem of toluene of boiling point, energy consumption is reduced, enormously simplify operation, be easy to industrialized production；Production technology reduces molten
The use of agent toluene, reduces while using the production risk of a variety of high-risk solvents；Cyclization step reaction temperature 139 DEG C with
Under, reducing high temperature causes accessory substance increase, the risk of product racemization, makes the process recovery ratio for preparing Aprepitant (compound (I))
More than 97% can be increased to, yield is improved while reducing production cost.
Brief description of the drawings
Fig. 1 is Aprepitant1H nuclear magnetic resoance spectrums.
Fig. 2 is Aprepitant13C nuclear magnetic resoance spectrums.
Embodiment
Content for a better understanding of the present invention, is described further with reference to specific embodiment, but the present invention
Protection domain is not limited to specific embodiment.
Embodiment 1：
Compound (II) (100.0g), Anhydrous potassium carbonate (102.0g), dimethyl sulfoxide (200ml), two are added in reaction bulb
Toluene (200ml), stirs 10~15 minutes at 0~10 DEG C, adds compound (III) (39.0g), when stir about 16 is small, add dimethylbenzene
And water, stirring 10 minutes, stratification, organic layer is washed with water, and anhydrous sodium sulfate drying, filtering, filter cake is washed with dimethylbenzene,
When 130 DEG C~139 DEG C reactions 4 of filtrate are small.Stirring is cooled to 0 DEG C~10 DEG C, and filtering, filter cake is washed with dimethylbenzene.Solid vacuum
When drying 20 is small, compound (I) 109.0g, molar yield 97.7% are obtained.HPLC：99.97%, total isomers 0.017%.LC/
MS(m/c)535.25(M+H+)。
Embodiment 2：
Compound (II) (10.0g), Anhydrous potassium carbonate (10.2g), dimethylbenzene (5ml), dimethyl sulfoxide are added in reaction bulb
(25ml), stirs 10~15 minutes at 0~10 DEG C, adds compound (III) (3.90g), when stir about 16 is small, add dimethylbenzene and water,
Stirring 10 minutes, stratification, organic layer is washed with water, and anhydrous sodium sulfate drying, filtering, filter cake, filtrate are washed with dimethylbenzene
When 130 DEG C~139 DEG C reactions 4 are small.Stirring is cooled to 0~10 DEG C, and filtering, filter cake is washed with dimethylbenzene.Solid vacuum drying 20
Hour, obtain compound (I) 10.81g, molar yield 95.8%, HPLC：99.95%, total isomers 0.015%.
Embodiment 3：
Compound (II) (10.0g), Anhydrous potassium carbonate (10.2g), dimethyl sulfoxide (20ml), dimethylbenzene are added in reaction bulb
(20ml), stirs 10~15 minutes at 0~10 DEG C, adds compound (III) (3.90g), when stir about 16 is small, add dimethylbenzene and water,
Stirring 10 minutes, stratification, organic layer is washed with water, and anhydrous sodium sulfate drying, filtering, filter cake, filtrate are washed with dimethylbenzene
When 120 DEG C~130 DEG C reactions 9 are small.Stirring is cooled to 0~10 DEG C, and filtering, filter cake is washed with dimethylbenzene.Solid vacuum drying 20
Hour, obtain compound (I) 10.94g, molar yield 97.0%, HPLC：99.93%, total isomers 0.019%.
Embodiment 4：
Addition compound (II) (10.0g), Anhydrous potassium carbonate (10.2g), dimethylbenzene (30ml) in reaction bulb, 0~10 DEG C
Lower stirring 10~15 minutes, adds compound (III) (3.90g), when stir about 16 is small, adds water, stirs 10 minutes, stratification, has
Machine layer is washed with water, anhydrous sodium sulfate drying, filtering, filter cake is washed with dimethylbenzene, when 130~139 DEG C of reactions 4 of filtrate are small.Stir
Mix and be cooled to 0~10 DEG C, filtering, filter cake is washed with dimethylbenzene.When solid vacuum drying 20 is small, compound (I) 10.26g is obtained, is rubbed
That yield 91.0%, HPLC：99.92%, total isomers 0.020%.
Embodiment 5：
Compound (II) (10.0g), natrium carbonicum calcinatum (8.9g), dimethyl sulfoxide (20ml), dimethylbenzene are added in reaction bulb
(20ml), stirs 10~15 minutes at 0~10 DEG C, adds compound (III) (3.90g), when stir about 15 is small, add dimethylbenzene and water,
Stirring 10 minutes, stratification, organic layer is washed with water, and anhydrous sodium sulfate drying, filtering, filter cake, filtrate are washed with dimethylbenzene
When 120 DEG C~130 DEG C reactions 9 are small.Stirring is cooled to 0~10 DEG C, and filtering, filter cake is washed with dimethylbenzene.Solid vacuum drying 20
Hour, obtain compound (I) 10.54g, molar yield 93.5%, HPLC：99.90%, total isomers 0.018%.
Claims (9)
1. a kind of method of formula (I) compound,
This method is included in the presence of inorganic base, organic solvent, compound (II)
Reacted with compound (III)：
Obtain compound (IV)
In the case where reaction temperature is 100 DEG C~139 DEG C, cyclizing compounds (IV), are prepared compound (I), it is characterised in that institute
It is dimethylbenzene, dimethyl sulfoxide or the mixed solution of the two to state organic solvent.
2. the method for formula (I) compound according to claim 1, it is characterised in that compound (II) and compound (III)
Molar ratio be 1:1.0~1.5, preferably 1:1.1~1.3, more preferably 1:1.1~1.2.
3. the method for formula (I) compound according to claim 1, it is characterised in that compound (II) and compound (III)
Reaction temperature be less than 20 DEG C, preferably 0 DEG C~10 DEG C.
4. the method for formula (I) compound according to claim 1, it is characterised in that compound (II) is rubbed with inorganic base
You are than being 1:3.0~5.0, preferably 1:3.5~4.0, more preferably 1:3.5.
5. the method for formula (I) compound according to claim 1, it is characterised in that compound (II) and organic solvent
Mass volume ratio is 1:2~10, preferably 1:3~4.
6. the method for formula (I) compound according to claim 1, it is characterised in that the organic solvent for dimethylbenzene-
The mixed solution of dimethyl sulfoxide.
7. the method for formula (I) compound according to claim 6, it is characterised in that the mixing of dimethylbenzene-dimethyl sulfoxide
Solution, volume ratio VDimethylbenzene：VDimethyl sulfoxideFor 1:0.1~1:10, preferred volume ratio VDimethylbenzene：VDimethyl sulfoxideFor 1:1~1:5, more preferably volume
Compare VDimethylbenzene：VDimethyl sulfoxideFor 1:1.
8. the method for formula (I) compound according to claim 1, it is characterised in that cyclizing compounds (IV), reaction
Temperature is 120 DEG C~139 DEG C, preferably 130 DEG C~139 DEG C.
9. the method for formula (I) compound according to claim 1, it is characterised in that the inorganic base be selected from potassium carbonate,
Sodium carbonate, sodium acid carbonate, cesium carbonate, preferably potassium carbonate.
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Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1293077C (en) * | 2002-04-18 | 2007-01-03 | 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 |
| CN103030668A (en) * | 2011-10-09 | 2013-04-10 | 江苏豪森药业股份有限公司 | Method for preparing fosaprepitant |
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- 2016-10-14 CN CN201610900158.3A patent/CN107954998B/en active Active
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1293077C (en) * | 2002-04-18 | 2007-01-03 | 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 |
| CN103030668A (en) * | 2011-10-09 | 2013-04-10 | 江苏豪森药业股份有限公司 | Method for preparing fosaprepitant |
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