CN108997199A - A kind of synthetic method of tropsch imatinib intermediate (3R, 4R) -1- benzyl-N, 4- lupetidine -3- amine - Google Patents
A kind of synthetic method of tropsch imatinib intermediate (3R, 4R) -1- benzyl-N, 4- lupetidine -3- amine Download PDFInfo
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- CN108997199A CN108997199A CN201810917629.0A CN201810917629A CN108997199A CN 108997199 A CN108997199 A CN 108997199A CN 201810917629 A CN201810917629 A CN 201810917629A CN 108997199 A CN108997199 A CN 108997199A
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
- C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
- C07D211/36—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D211/56—Nitrogen atoms
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B53/00—Asymmetric syntheses
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/07—Optical isomers
Abstract
The invention discloses a kind of tropsch imatinib intermediate (3R, 4R) -1- benzyl-N, the synthetic method of 4- lupetidine -3- amine, 3- chlorobutyraldehyde (II) is used to react for raw material with Cymag, Leuckart-Wallach reaction and Thorpe-Ziegler reaction are carried out again, react with 30% methylamine methanol solution generate enamine later, obtain finished product (3R by catalytic asymmetric hydrogenation, 4R) -1- benzyl-N, 4- lupetidine -3- amine (I).In this synthetic method, the synthesis of compound VI is reacted using Thorpe-Ziegler, and yield is high, and catalytic asymmetric hydrogenation makes final products not need to carry out chiral resolution, and total recovery and purity is high, by-product are few.
Description
Technical field
The invention belongs to field of medicine preparing technology, are related to a kind of tropsch imatinib intermediate (3R, 4R) -1- benzyl-N, 4-
The synthetic method of lupetidine -3- amine.
Background technique
(3R, 4R) -1- benzyl-N, 4- lupetidine -3- amine is to prepare citric acid tropsch imatinib (tofacitinib
Citrate a kind of intermediate), chemical structural formula are as follows:
[[(7H- pyrrolo- [2,3-d] is phonetic for methyl-by (3R, 4R) -4- methyl -3- by the entitled 3- of citric acid tropsch imatinib chemistry
Pyridine -4- base) amino] piperidin-1-yl] -3- oxo propionitrile citrate is a kind for the treatment of developed by Pfizer drugmaker
Rheumatoid arthritis drug, trade name Xeljanz.Xeljanz can be used as single therapy or with methotrexate or other are abiotic
Disease-modifying antirheumatic (DMARD) is used in combination.The medicine should not be with biological DMARD or strong immunosuppressor (such as sulphur
Azoles purine and cyclosporin) it is used in combination.
On November 6th, 2012, Food and Drug Adminstration of the US (FDA) and Pfizer's joint announce that citric acid support method is replaced
Buddhist nun it is granted for it is insufficient to methotrexate for treatment response or in not tolerating to severe active rheumatoid arthritis (RA)
Adult patient.Rheumatoid arthritis is a kind of chronic disease that the course of disease is extremely long and extremely painful, is caused to the physical and mental health of patient
Great harm, is a kind of unknown systemic disease chronic, based on inflammatory synovitis of cause of disease, it is characterized in that hand, foot
Multi-joint, symmetry, the aggressive arthritis of Minor articulus, are often accompanied by organ outside joint and are involved serum rheumatoid factor (SRF) sun
Property, joint deformity and function can be caused to lose, endangered with organ harm such as interstitial lung lesion, peripheral nerve outside joint,
It is one of most common rheumatism immunological disease.Most RA patients serum rheumatoid factor, antiCCP antibody are positive, and RA can lead to joint
Deformation and function loss.
Other RA therapeutic agents mainly act on unlike extracellular target spot from Most current, and Tofacitinib is with thin
Intracellular signal transduction access is target spot, acts on the core of cytokine network.Tofacitinib is strong to the inhibition of JAK3
Degree is 5~100 times to JAK1 and JAK2, and Tofacitinib is the pioneering medicine that exploitation is used for rheumatoid arthritis treatment
Object.
Currently, associated documents report tropsch imatinib intermediate synthetic route have it is following several:
1) synthetic route of 106831538 A of patent CN report is as follows:
With 1- benzyl -4- methyl-1,2,3,6- tetrahydropyridines are oxidized to ketone, Zhi Houyu as starting material, by alkylene
After amine forms imines, amine is formed with asymmetric reduction imines, transisomer is removed by recrystallization and obtains cis-isomer,
Finally final product (3R, 4R) -1- benzyl-N, 4- lupetidine -3- amine dihydrochloride is obtained with chiral resolution.This method
Expensive reducing agent 3-sec-butyl lithium borohydride and raw material are not used only, and reacts by splitting, reduces ultimate yield.
2) D.H.Brown et al., Org.Proc.Res.Dev.2003,7, the 115-120 pages discloses by using methyl
The method that amine prepares 3- amino-piperadine structural unit D to the reduction amination of ketone C as reagent.The combination of tetrahydropyridine A is passed through
Hydroboration/oxidation process reuses the SO of excessive valuableness3Gained compound B is carried out the toluene of piperidine alcohols by pyridine complex
Sulfonate aoxidizes to obtain ketone C.Whole process includes using hydroborating agents and strong oxidizer these hazardous agents, is extensive raw
Production brings security risk.
3) synthetic route of patent WO2010123919A2 report is as follows:
The patent is raw material by 3- amino-4-methylpyridine, by amine ester exchange reaction, forms pyridine with Bian bromine
Salt, the salt first use sodium borohydride reduction, are then reduced into piperidine ring with platinum oxide, finally produced being restored by Lithium Aluminium Hydride
Object.Costly metallic reducing agent is not used only for this method, while there are also the use of Lithium Aluminium Hydride, undoubtedly increasing big industrial production
In security risk.This method does not refer to chiral synthesis, and final result generates four kinds of isomers, reduces light reaction purity,
Reduce end reaction yield.
Summary of the invention
It is an object of the invention to overcome the deficiencies of existing technologies, a kind of tropsch imatinib intermediate (3R, 4R) -1- is provided
The synthetic method of benzyl-N, 4- lupetidine -3- amine, this method starting material are easy to get, and process route is simple, using 3- chlorine
Butyraldehyde (II) is that raw material is reacted with Cymag, then carries out Leuckart-Wallach reaction and Thorpe-Ziegler reaction, it
It is reacted afterwards with 30% methylamine methanol solution and generates enamine, obtain finished product (3R, 4R) -1- benzyl by catalytic asymmetric hydrogenation
Base-N, 4- lupetidine -3- amine (I).In this synthetic method, the synthesis of compound VI is reacted using Thorpe-Ziegler,
Yield is high, and catalytic asymmetric hydrogenation makes final products not need to carry out chiral resolution, total recovery and purity is high, by-product
It is few.
Synthetic route of the present invention is as follows:
A kind of synthetic method of tropsch imatinib intermediate (3R, 4R) -1- benzyl-N, 4- lupetidine -3- amine, step is such as
Under:
A, 3- chlorobutyraldehyde (II) reacts synthesis compound III with Cymag；
B, Leuckart-Wallach reaction synthesis compound V occurs under formic acid effect for compound III and compound IV；
C, Thorpe-Ziegler reaction occurs under basic conditions for compound V, and hydrolysis later, decarboxylation synthesize compound
VI；
D, compound VI is reacted with 30% methylamine methanol solution generates compound VII；
E, catalytic asymmetric hydrogenation synthesis (3R, 4R)-occurs under the conditions of metallic catalyst and ligand for compound VII
1- benzyl-N, 4- lupetidine -3- amine (I)；
Wherein, 3- chlorobutyraldehyde (II) used in step a and Cymag molar ratio 1:1~1.1；Reaction dissolvent is second alcohol and water；
70~80 DEG C of reaction temperature；2~3h of reaction time.
Leuckart-Wallach compound of reaction III, compound IV used in step b, formic acid molar ratio be 1:1.0~
1.1:1.1~1.5；Reaction dissolvent is ethyl alcohol；8~12h of reaction time.
Highly basic used in step c is sodium ethoxide；Compound V and highly basic molar ratio 1:1.05~1.5；Reaction dissolvent is second
Alcohol.
The compound VI that states used in step d, 30% methylamine methanol solution molar ratio are 1:1.5；Catalyst is acetic acid, pH=
4~5；Reaction time 12~16 hours.
Metallic catalyst used in step e is two (acetate) ruthenium [Ru (OAc)2], ligand is R- (+) -1,1 '-dinaphthalene -
2,2 '-diphenyl phosphines [(R)-BINAP]；Compound VII, metallic catalyst and ligand molar ratio=1:0.001~0.004:0.002
~0.008；The pressure of hydrogen is 2.0~3.5Mpa, preferably pressure 3.0Mpa；Reaction dissolvent is N,N-dimethylformamide or different
Propyl alcohol.
Compared with the prior art, the beneficial effects of the present invention are:
(1) the invention discloses a kind of tropsch imatinib intermediate (3R, 4R) -1- benzyl-N, 4- lupetidine -3- amine salt
The synthetic method of hydrochlorate, wherein step c utilizes Thorpe-Ziegler reaction synthesis 1- benzyl -4- methyl piperidine -3- ketone, phase
Than the synthetic route of 106831538 A of patent CN report, which is overcome in the past using expensive initial feed, and
Thorpe-Ziegler reaction is the effective ways for synthesizing cyclic ketones, high income easy to operate.
(2) step d passes through control pH value in reaction and methylamine solution solvent in reaction process selection synthesis 1- benzyl-N, 4-
Dimethyl -1,2,5,6- tetrahydropyridine -3- amine (VII) avoid the fractionation of reaction final products.
(3) step e uses asymmetric catalytic hydrogenation technology in reaction process, does not need to carry out chiral resolution, shortens anti-
Route is answered to solve the problems, such as low using traditional product total recovery in the prior art.
(4) present invention solves the problems, such as that fractionation product yield is low in the prior art, and preparation is convenient, and reaction does not need to tear open
Point, and overall yield of reaction and purity is high, by-product are few.
Specific embodiment
Summary of the invention of the invention is described in further detail below by specific embodiment, but is not therefore limited
Determine the contents of the present invention.
Embodiment 1
The synthesis of compound III
In 250ml there-necked flask, 3- chlorobutyraldehyde (II) 10.65g and Cymag 4.9g, 50ml second alcohol and water are sequentially added
(VEthyl alcohol:VWater=1:1) mixed solution, it is heated with stirring to 70~80 DEG C of 2~3h of reaction and steams etoh solvent after reaction, use
Ethyl acetate extraction, stratification separate organic phase, wash, and anhydrous sodium sulfate dries, filters, and decompression boils off ethyl acetate, obtain
Compound III 9.12g, yield 94.3%, HPLC purity 98.76%.
Embodiment 2
The synthesis of compound III
In 250ml there-necked flask, 3- chlorobutyraldehyde (II) 10.65g and Cymag 5.39g, 50ml second alcohol and water are sequentially added
(V Ethyl alcohol:VWater=1:1) mixed solution, it is heated with stirring to 70~80 DEG C of 2~3h of reaction and steams etoh solvent after reaction, use
Ethyl acetate extraction, stratification separate organic phase, wash, and anhydrous sodium sulfate dries, filters, and decompression boils off ethyl acetate, obtain
Compound III 9.32g, yield 96.7%, HPLC purity 98.21%.
Embodiment 3
The synthesis of compound V
In 250ml there-necked flask, 2- (benzylamino) acetonitrile (IV) 13.9g, 2- methyl -4- oxo butyronitrile is sequentially added
(III) 9.2g and formic acid 4.6g, 60ml ethyl alcohol, stirring, are warming up to reflux, reaction 10h, after reaction, with alkali neutralization to weak
Alkalinity steams solvent, and chloroform and water is added, and extraction merges organic phase, and anhydrous sodium sulfate dries, filters, boils off solvent chloroform and obtain
Compound V19.37g, yield 89.7%, HPLC purity 98.33%.
Embodiment 4
The synthesis of compound V
In 250ml there-necked flask, 2- (benzylamino) acetonitrile (IV) 13.2g, 2- methyl -4- oxo butyronitrile is sequentially added
(III) 9.6g and formic acid 6.2g, 60ml ethyl alcohol, stirring, are warming up to reflux, reaction 12h, after reaction, with alkali neutralization to weak
Alkalinity steams solvent, and chloroform and water is added, and extraction merges organic phase, and anhydrous sodium sulfate dries, filters, and decompression boils off solvent chlorine
Imitate to obtain compound V 18.51g, yield 90.5%, HPLC purity 98.88%.
Embodiment 5
The synthesis of compound V
In 250ml there-necked flask, 2- (benzylamino) acetonitrile (IV) 13.2g, 2- methyl -4- oxo butyronitrile is sequentially added
(III) 9.6g and formic acid 20.7g, 60ml ethyl alcohol, stirring are warming up to 100 DEG C, react 11h, after reaction, extremely with alkali neutralization
Alkalescent steams solvent, and chloroform and water is added, and extraction merges organic phase, and anhydrous sodium sulfate dries, filters, and boils off solvent chloroform
Obtain compound V 14.36g, yield 70.2%, HPLC purity 95.31%.
Embodiment 6
The synthesis of compound VI
In 250ml there-necked flask, compound V 19.32g, sodium ethoxide 6.07g and 60ml ethyl alcohol are sequentially added, is warming up to back
Stream is stirred to react 3h, after reaction, is cooled to room temperature, and adjusts pH=3~4 with hydrochloric acid, heating continues back flow reaction 4h, reaction
After, etoh solvent is steamed, is extracted with ethyl acetate, organic phase is separated, anhydrous sodium sulfate dries, filters, and decompression boils off molten
Agent obtains colourless liquid 16.5g, yield 95.5%, HPLC purity 98.34%.
Embodiment 7
The synthesis of compound VI
In 250ml there-necked flask, compound V 18.63g and sodium ethoxide 8.2g, 60ml ethyl alcohol are sequentially added, is warming up to back
Stream is stirred to react 3h, is cooled to room temperature, and adjusts pH=3~4 with hydrochloric acid, and heating continues 3~4h of back flow reaction, after reaction,
Steam etoh solvent, be extracted with ethyl acetate, separate organic phase, anhydrous sodium sulfate dries, filters, decompression boil off solvent obtain it is colourless
Liquid 115.4g, yield 92.1%, HPLC purity 97.21%.
Embodiment 8
The synthesis of compound VI
In 250ml there-necked flask, compound V 18.63g, sodium methoxide 4.64g and 60ml ethyl alcohol, stirring heating are sequentially added
To reflux, reaction time 3h is cooled to room temperature after reaction, adjusts pH=3~4 with hydrochloric acid, and the continuation back flow reaction 3 that heats up~
4h steams etoh solvent after reaction, is extracted with ethyl acetate, and separates organic phase, and anhydrous sodium sulfate dries, filters, decompression
Solvent is boiled off, colourless liquid 11.86g, yield 71.2%, HPLC purity 95.37% are obtained.
Embodiment 9
The synthesis of compound VII
Weigh Compound VI 16.2g and 30% methylamine methanol solution 12.4g is added in there-necked flask, dry glacial acetic acid tune
PH=4~5 are saved, under nitrogen protection, 25~30 DEG C of room temperature are reacted about 12 hours, and TLC tracks fully reacting, solvent evaporated
Obtain compound VII 16.35g, yield 94.5%, HPLC purity 97.22%.
Embodiment 10
The synthesis of compound VII
Weigh Compound VI 16.2g and 30% methylamine methanol solution 12.4g is added in there-necked flask, dry glacial acetic acid tune
PH=2~3 are saved, under nitrogen protection, 25~30 DEG C of room temperature are reacted about 16 hours, and TLC tracks fully reacting, solvent evaporated
Obtain compound VII 11.8g, yield 68.3%, HPLC purity 95.69%.
Embodiment 11
The synthesis of compound VII
Weigh Compound VI 16.2g and 30% methylethylolamine solution 12.4g is added in there-necked flask, dry glacial acetic acid tune
PH=4~5 are saved, under nitrogen protection, 25~30 DEG C of room temperature are reacted about 14 hours, and TLC tracks fully reacting, solvent evaporated
Obtain compound VII 12.11g, yield 70.4%, HPLC purity 95.33%.
Embodiment 12
The synthesis of compound I
In 250ml there-necked flask, compound VII 15.8g, 27.9mg Ru (OAc) is sequentially added2With 0.27g (R)-
BINAP is dissolved in 50ml n,N-Dimethylformamide, successively replaces nitrogen three times, and hydrogen three times, is passed through hydrogen 3.5MPa, and 20
~25 DEG C are stirred to react 12h, filter, steam solvent concentration and obtain compound I 15.3g, yield 96.1%, HPLC purity
98.89%, ee value 98%.
Embodiment 13
The synthesis of compound I
In 250ml there-necked flask, compound VII 15.1g, 53.4mg Ru (OAc) is sequentially added2With 0.34g (R)-
BINAP is dissolved in 50ml isopropanol, successively replaces nitrogen three times, and hydrogen three times, is passed through hydrogen 2.5MPa, 20~25 DEG C of stirrings
12h is reacted, is filtered, is steamed solvent concentration and obtain compound I 14.46g (0.066mol, molecular weight 218.28), yield 94.7%,
HPLC purity 96.21%, ee value 97%.
Embodiment 14
The synthesis of compound I
In 250ml there-necked flask, compound VII 15.57g, 27.51mg Ru (OAc) is sequentially added2With 0.87g (R)-
BINAP is dissolved in 50ml dichloromethane solution, successively replaces nitrogen three times, and hydrogen three times, is passed through hydrogen 2.0MPa, and 20~25
DEG C it is stirred to react 12h, filters, steam solvent concentration and obtain compound I 11.35g, yield 73.4%, HPLC purity 92.97%, ee
Value 90%.
Embodiment 15
The synthesis of compound I
In 250ml there-necked flask, compound VII 15.35g, 81.4mg Ru (OAc) is sequentially added2With 44mg (R)-
BINAP is dissolved in 50ml n,N-Dimethylformamide, successively replaces nitrogen three times, and hydrogen three times, is passed through hydrogen 3.0MPa, and 20
~25 DEG C are stirred to react 12h, filter, steam solvent, be concentrated to give compound I 10.25g, yield 67.3%, HPLC purity
91.31%, ee value 84%.
Claims (10)
1. a kind of synthetic method of tropsch imatinib intermediate (3R, 4R) -1- benzyl-N, 4- lupetidine -3- amine, feature exist
Include the following steps: in the synthetic method
A, 3- chlorobutyraldehyde (II) reacts synthesis compound III with Cymag；
B, Leuckart-Wallach reaction synthesis compound V occurs under formic acid effect for compound III and compound IV；
C, Thorpe-Ziegler reaction occurs under basic conditions for compound V, and hydrolysis later, decarboxylation synthesize compound VI；
D, compound VI reacts synthesis compound VII with 30% methylamine methanol solution；
E, catalytic asymmetric hydrogenation synthesis (3R, 4R) -1- benzyl occurs under the conditions of metallic catalyst and ligand for compound VII
Base-N, 4- lupetidine -3- amine (I)；
Its synthetic route is as follows:
2. the method according to claim 1, wherein 3- chlorobutyraldehyde (II) described in step a and Cymag molar ratio
1:1~1.1, reaction dissolvent are second alcohol and water.
3. the method according to claim 1, wherein chemical combination in the reaction of Leuckart-Wallach described in step b
Object III, compound IV, formic acid molar ratio be 1:1.0~1.1:1.1~1.5, reaction dissolvent is ethyl alcohol.
4. the method according to claim 1, wherein highly basic described in step c is sodium ethoxide.
5. the method according to claim 1, wherein compound V described in step c and highly basic molar ratio 1:1.05
~1.5, reaction dissolvent is ethyl alcohol.
6. the method according to claim 1, wherein compound VI, 30% methylamine methanol solution described in step d
Molar ratio is 1:1.5.
7. the method according to claim 1, wherein catalyst used in step d is acetic acid, pH=4~5.
8. the method according to claim 1, wherein metallic catalyst described in step e be two (acetate) rutheniums,
Ligand be R- (+) -1,1 '-dinaphthalene -2,2 '-diphenyl phosphines, compound VII, metallic catalyst and ligand molar ratio 1:0.001~
0.004:0.002~0.008.
9. the method according to claim 1, wherein the pressure of hydrogen described in step e is 2.0~3.5Mpa.
10. the method according to claim 1, wherein reaction dissolvent used in step e is N, N- dimethyl formyl
Amine or isopropanol.
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| CN201810917629.0A CN108997199B (en) | 2018-08-13 | 2018-08-13 | Synthesis method of tofacitinib intermediate (3R,4R) -1-benzyl-N, 4-dimethylpiperidine-3-amine |
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| CN201810917629.0A CN108997199B (en) | 2018-08-13 | 2018-08-13 | Synthesis method of tofacitinib intermediate (3R,4R) -1-benzyl-N, 4-dimethylpiperidine-3-amine |
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN110204549A (en) * | 2019-06-05 | 2019-09-06 | 南京焕然生物科技有限公司 | A kind of preparation method of N- methyl-N- (4- methyl piperidine) -3- base -7H- pyrrolopyrimidine -4- amine |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2018060512A1 (en) * | 2016-09-30 | 2018-04-05 | Patheon Austria Gmbh & Co Kg | Process for preparing chiral amines |
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2018
- 2018-08-13 CN CN201810917629.0A patent/CN108997199B/en active Active
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2018060512A1 (en) * | 2016-09-30 | 2018-04-05 | Patheon Austria Gmbh & Co Kg | Process for preparing chiral amines |
Non-Patent Citations (1)
| Title |
|---|
| 万惠霖等: "《固体表面物理化学若干研究前沿》", 31 December 2006 * |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN110204549A (en) * | 2019-06-05 | 2019-09-06 | 南京焕然生物科技有限公司 | A kind of preparation method of N- methyl-N- (4- methyl piperidine) -3- base -7H- pyrrolopyrimidine -4- amine |
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Inventor after: Li Minghua Inventor after: Dong Xueju Inventor after: Zhang Jiwen Inventor after: Wang Xiutian Inventor before: Dong Xueju Inventor before: Zhang Jiwen Inventor before: Wang Xiutian |