CN108948022A - A kind of support method replaces the synthetic method of cloth - Google Patents
A kind of support method replaces the synthetic method of cloth Download PDFInfo
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- C07—ORGANIC CHEMISTRY
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- 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
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Abstract
The invention discloses the synthetic methods that a kind of support method replaces cloth.The present invention, which is reacted using compound ii with methylamine, is made compound III; compound III passes through reduction reaction, acylation reaction prepare compound IV; compounds Ⅳ passes through asymmetric hydrogenation prepare compound V, and compound V prepares finished product support method using elimination reaction, substitution, asymmetric hydrogenation for cloth (I).The preparation method starting material is easy to get, and process route is simple, and total recovery and purity is high, by-product is few, is suitble to industrialized production.
Description
Technical field
The present invention relates to the synthesis fields of drug, and in particular to a kind of support method replaces the synthetic method of cloth.
Background technique
Support method is for a kind of novel Janus kinase inhibitor that cloth is that Pfizer Inc. researches and develops, trade name Xeljanz.This
The activity of JAK1 and JAK3 can be effectively suppressed in product, blocks the signal transduction of a variety of inflammatory cytokines.It is existing studies have shown that support method
There is good therapeutic effect to the inflammations related diseases such as rheumatoid arthritis, ulcerative colitis, psoriasis for Buddhist nun.
Support method is 3- [(3R, 4R) -4- methyl -3- [methyl-(7H- pyrrolo- [2,3-d] pyrimidine-for the chemical name of cloth
4- yl) amino] piperidin-1-yl] -3- oxo propionitrile, there is chemical structure shown in Formulas I:
It is as follows for the synthetic method report situation of cloth about support method at present:
1, it is as follows to grind United States Patent (USP) US6627754, Chinese patent CN1409712 report route for this product original:
Using 1- benzyl -4- methyl-pi -3- ketone as raw material, methylamino on reduction amination is substituted, hydroxide the route
Palladium/H2It is split after catalytic hydrogenation debenzylation, acylation and obtains support method for cloth.This route starting material is expensive, and final product will be through tearing open
Divide purifying, isomer impurities are more difficult to control, and it is at high cost, and this route reaction time is long, and total yield of products is low, is not suitable with industry
Metaplasia produces.
2, the patent WO2007012953 of Yuan Yan Pfizer application in 2006, the patent synthetic route of announcement are as follows:
Amido is first esterified and protects using 3- amido -4- picoline as raw material by this route, and rhodium catalysis restores pyridine ring, also
Benzyl protection in former amination, Lithium Aluminium Hydride reduction, then splits enantiomer with two toluoyl tartaric acid, with 4- chlorine Pyrrolopyrimidin
Pyridine aminolysis, finally acylation obtains tropsch imatinib, although starting material is cheap, synthetic route increases the route, in chirality
The acquisition of mesosome still passes through fractionation and obtains, and it is not high to ultimately cause total yield of products.
3, the synthetic route of patent CN201310537835.6 report is as follows:
Although the present invention solves the problems, such as expensive raw material price, final product resolving and purifying, synthetic route is long, at high cost etc. to ask
The problem of inscribing, but the reaction needs to use toxic boron trifluoride ether, and still remaining total yield of products.
4, synthetic route disclosed in patent CN201610181030.6 is as follows:
Although reaction route of the invention shortens, it is conducive to control impurity quality, recycled solvent pollutes small；But this is anti-
Answer raw material 2, bis- chloro- 7H pyrroles [2,3-D] of 4- and (3R, 4R)-N, 4- dimethyl -1- (phenyl methyl) -3- piperidines amine hydrochlorate
It is expensive, and there are competitive reactions, influence product yield, while can also separate to subsequent product and bring difficulty, still not
It is suitble to industrialized production.
Summary of the invention
It is an object of the invention to overcome the deficiencies of existing technologies, the new support method of one kind is provided for cloth synthetic method, is somebody's turn to do
Synthetic method starting material is easy to get, and process route is simple, and total recovery and purity is high, by-product is few, is suitble to industrialized production.
Synthetic route of the present invention is as follows:
A kind of support method replaces the synthetic method of cloth, it is characterised in that the synthetic method includes the following steps:
A, compound ii and methylamine flow back prepare compound III in organic solvent；
B, compound III first passes through reduction reaction, using cyanoacetyl chloride substitution reaction prepare compound IV；
C, compounds Ⅳ carries out hydrogenation under the conditions of alkali, metallic catalyst, ligand and potassium bromide and compound V is made；
D, compound V passes through elimination reaction under p-methyl benzenesulfonic acid, then reacts prepare compound VII with compound VI；
E, compound VII carries out asymmetric hydrogenation under catalysts conditions and prepares finished product support method for cloth (I)；
Wherein, organic solvent used in step a is toluene or methylene chloride, and compound ii and methylamine molar ratio are 1:1-
1.1。
Catalyst system used in reduction reaction is LiAIH in step b4-AlCl3, compound III, LiAIH4、AlCl3Molar ratio
For 1:2-3:1；Reduction reaction temperature is 20-25 DEG C.
The organic solvent that step c is used is isopropanol, the tert-butyl alcohol, tetrahydrofuran, methylene chloride, 1,4- dioxane, second
Any one of acetoacetic ester, benzene, toluene or two or more mixtures；Alkali used be sodium ethoxide, potassium tert-butoxide, triethylamine,
N, N- diisopropylethylamine, sodium hydroxide or sodium carbonate；Metallic catalyst used is [Rh (COD)2]BF4, ligand 1,1'-
Bis- (diphenylphosphine) ferrocene；The molar ratio of metallic catalyst, ligand and compounds Ⅳ is 0.001-0.002:0.001-
0.002:1；The pressure of hydrogen used is 10-100bar, and preferably Hydrogen Vapor Pressure is 30bar.
Step d elimination reaction temperature is 90-100 DEG C, and compound V and p-methyl benzenesulfonic acid molar ratio are 1:0.2-0.3.
Catalyst described in step e is bis- (diphenylphosphine) -1,1'- dinaphthalenes of (R) -2,2'-] ruthenous chloride (II), chemical combination
Object VII and catalyst molar ratio are 1:0.001-0.005；Reaction dissolvent is tetrahydrofuran, methylene chloride, N, N- dimethyl formyl
Amine or toluene；The pressure of hydrogen used is 50-100psi.
The present invention replaces the synthetic method of cloth about support method, obtain it is following the utility model has the advantages that
(1) it solves the problems, such as that prior art fractionation product yield is low using asymmetric catalytic technology herein, greatly improves
Total yield of products.
(2) starting material is easy to get, and process route is simple, easy to operate, and total recovery and purity is high, by-product is few, is suitble to work
Industry metaplasia produces.
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 preparation of compound III
In three-necked flask, it is separately added into compound ii 15.72g (0.1mol), toluene 300ml and methylamine 3.11g
(0.1mol), stirring are warming up to reflux, and control reaction 1.5h, TLC monitoring tracking reaction process stops after raw material fully reacting
Only heat.Solvent is removed under reduced pressure, obtains compound III 16.01g, product yield 94%, HPLC purity 99.96%.
Embodiment 2
The preparation of compound III
In three-necked flask, it is separately added into compound ii 15.72g (0.1mol), methylene chloride 300ml and methylamine 3.11g
(0.1mol), stirring are warming up to reflux, and control reaction 1.5h, TLC monitoring tracking reaction process stops after raw material fully reacting
Only heat.Solvent is removed under reduced pressure, obtains compound III 15.33g, product yield 90%, HPLC purity 99.91%.
Embodiment 3
The preparation of compound III
In three-necked flask, it is separately added into compound ii 15.72g (0.1mol), methylene chloride 300ml and methylamine 3.42g
(0.11mol), stirring are warming up to reflux, and control reaction 1.5h, TLC monitoring tracking reaction process stops after raw material fully reacting
Only heat.Solvent is removed under reduced pressure, obtains compound III 16.34g, product yield 96%, HPLC purity 99.98%.
Embodiment 4
The preparation of compounds Ⅳ
By LiAIH410.70g (0.282mol) 20ml anhydrous ether is added in reaction flask, is added portionwise at room temperature
AlCl312.53g (0.094mol), stir 15min, then be slowly added dropwise compound III 16.01g (0.094mol) 20ml it is anhydrous
2% ammonium carbonate solution 20ml is added in 20-30 DEG C of stirring 30min after adding in diethyl ether solution, and filtering, solid is washed with ether
It washs, separates ether layer, three times with extracted by ether, combined ether layer, anhydrous sodium sulfate is dry for water layer, and ether is evaporated off and obtains oily liquids.
It is added in 250ml 10:1 methylene chloride/pyridine solution into above-mentioned oily liquids and cyanoacetyl chloride 9.73g is added
(0.094mol), control are stirred to react 10h at 20-30 DEG C, are washed after reaction with saturated sodium bicarbonate solution, with nothing
Aqueous sodium persulfate is dry, then be concentrated in vacuo to it is dry obtain compounds Ⅳ (molecular weight: 209.24) 17.32g, product yield 88%,
HPLC is 99.92%.
Embodiment 5
The preparation of compounds Ⅳ
By LiAIH46.83g (0.18mol) 20ml anhydrous ether is added in reaction flask, is added portionwise at room temperature
AlCl312.0g (0.09mol) stirs 15min, then the anhydrous second of 20ml of compound III 15.33g (0.09mol) is slowly added dropwise
2% ammonium carbonate solution 20ml is added in 20-30 DEG C of stirring 30min after adding in ethereal solution, and filtering, solid is washed with ether
It washs, separates ether layer, three times with extracted by ether, combined ether layer, anhydrous sodium sulfate is dry for water layer, and ether is evaporated off and obtains oily liquids.
It is added in 250ml 10:1 methylene chloride/pyridine solution into above-mentioned oily liquids and cyanoacetyl chloride 9.32g is added
(0.09mol), control are stirred to react 10h at 20-30 DEG C, are washed after reaction with saturated sodium bicarbonate solution, with nothing
Aqueous sodium persulfate is dry, then is concentrated in vacuo to dry acquisition compounds Ⅳ 17.33g, product yield 92%, HPLC 99.95%.
Embodiment 6
The preparation of compounds Ⅳ
By LiAIH410.93g (0.288mol) 20ml anhydrous ether is added in reaction flask, is added portionwise at room temperature
AlCl36.40g (0.048mol), stir 15min, then be slowly added dropwise compound III 16.34g (0.096mol) 20ml it is anhydrous
2% ammonium carbonate solution 20ml is added in 20-30 DEG C of stirring 30min after adding in diethyl ether solution, and filtering, solid is washed with ether
It washs, separates ether layer, three times with extracted by ether, combined ether layer, anhydrous sodium sulfate is dry for water layer, and ether is evaporated off and obtains oily liquids.
It is added in 250ml 10:1 methylene chloride/pyridine solution into above-mentioned oily liquids and cyanoacetyl chloride 9.94g is added
(0.096mol), control are stirred to react 10h at 20-30 DEG C, are washed after reaction with saturated sodium bicarbonate solution, with nothing
Aqueous sodium persulfate is dry, then is concentrated in vacuo to dry acquisition compounds Ⅳ 15.69g, product yield 78%, HPLC 99.83%.
Embodiment 7
The preparation of compound V
Under nitrogen protection, compounds Ⅳ 17.32g (0.083mol) is added in reaction flask, it is molten that 200ml isopropanol is added
[Rh (COD) is added in solution2]BF4(0.083mmol), ligand 1, bis- (diphenylphosphine) ferrocene (0.083mmol) of 1'-, potassium bromide
(0.083mmol) is added the potassium tert-butoxide of 0.083mol, is passed through the hydrogen of 30bar, stirs 12h at 40 DEG C.It filters, revolving
It removes solvent and obtains the white solid powder of V 17.54g of compound.Product yield 95%, HPLC purity 99.96%, ee value
95%.
Embodiment 8
The preparation of compound V
Under nitrogen protection, compounds Ⅳ 17.33g (0.082mol) is added in reaction flask, 200ml Isosorbide-5-Nitrae-two is added
The dissolution of six ring of oxygen, is added [Rh (COD)2]BF4(0.164mmol), ligand 1, bis- (diphenylphosphine) ferrocene of 1'-
(0.082mmol), potassium bromide (0.082mmol), is added the sodium ethoxide of 0.082mol, is passed through the hydrogen of 100bar, at 40 DEG C
Stir 12h.It filters, revolving removes solvent and obtains the white solid powder of V 16.42g of compound.Product yield 89%, HPLC
Purity 99.91%, ee value 94%.
Embodiment 9
The preparation of compound V
Under nitrogen protection, compounds Ⅳ 15.69g (0.075mol) is added in reaction flask, 200ml tetrahydrofuran is added
[Rh (COD) is added in dissolution2]BF4(0.075mmol), ligand 1, bis- (diphenylphosphine) ferrocene (0.075mmol) of 1'-, bromination
Potassium (0.075mmol), is added the sodium hydroxide of 0.075mol, is passed through the hydrogen of 10bar, stirs 12h at 40 DEG C.It filters, rotation
Solvent is evaporated off and obtains the white solid powder of V 15.35g of compound.Product yield 92%, HPLC purity 99.93%, ee
Value 95%.
Embodiment 10
The preparation of compound V
Under nitrogen protection, compounds Ⅳ 17.32g (0.082mol) is added in reaction flask, it is molten that 200ml ethyl alcohol is added
[Rh (COD) is added in solution2]BF4(0.164mmol), ligand 1, bis- (diphenylphosphine) ferrocene (0.164mmol) of 1'-, potassium bromide
(0.082mmol) is added the sodium ethoxide of 0.082mol, is passed through the hydrogen of 100bar, stirs 12h at 40 DEG C.It filters, revolving is removed
Solvent is gone to obtain the white solid powder of V 13.90g of compound.Product yield 72%, HPLC purity 99.68%, ee value
90%.
Embodiment 11
The preparation of compound VII
In reaction flask be added V 17.54g of compound (0.079mol), be added dry toluene 120ml be stirred it is molten
Solution, adds (0.016mol) p-methyl benzenesulfonic acid, and 90 DEG C of reaction temperature of control is stirred to react 2h, 120ml carbonic acid is added after cooling
Hydrogen sodium saturated solution, separates organic layer, then with 120ml water washing, after reduced pressure by column chromatography for separation (solvent:
VEthyl acetate: VN-hexane=1:3) obtain solid.
The addition DMF 200ml into above-mentioned solid, addition VI 12.12g of compound (0.079mol, molecular weight: 153.37),
Reaction flask temperature is controlled and is stirred to react 9h at 90 DEG C by potassium carbonate (0.079mol), is cooled to room temperature after reaction, and filtering obtains
VII 21.84g of compound, product yield 89%, HPLC purity are 99.90%.
Embodiment 12
The preparation of compound VII
In reaction flask be added V 16.42g of compound (0.073mol), be added dry toluene 120ml be stirred it is molten
Solution, adds (0.022mol) p-methyl benzenesulfonic acid, and 100 DEG C of reaction temperature of control is stirred to react 2h, 120ml carbonic acid is added after cooling
Hydrogen sodium saturated solution, separates organic layer, then with 120ml water washing, after reduced pressure by column chromatography for separation (solvent:
VEthyl acetate: VN-hexane=1:3) obtain solid.
DMF 200ml is added into above-mentioned solid, is added compound VI 11.19 (0.073mol), potassium carbonate
Reaction flask temperature is controlled and is stirred to react 9h at 90 DEG C by (0.073mol), is cooled to room temperature after reaction, and filtering obtains compound
VII 20.63g, product yield 91%, HPLC purity are 99.93%.
Embodiment 13
The preparation of compound VII
V 15.35g of compound (0.069mol) is added in reaction flask, dry tetrahydrofuran 120ml is added and is stirred
Dissolution is mixed, (0.014mol) p-methyl benzenesulfonic acid is added, 80 DEG C of reaction temperature of control is stirred to react 2h, 120ml is added after cooling
Saturated solution of sodium bicarbonate, separates organic layer, then with 120ml water washing, after reduced pressure by column chromatography for separation (solvent:
VEthyl acetate: VN-hexane=1:3) obtain solid.
DMF 200ml is added into above-mentioned solid, is added VI 10.58g of compound (0.069mol), potassium carbonate
Reaction flask temperature is controlled and is stirred to react 9h at 90 DEG C by (0.069mol), is cooled to room temperature after reaction, and filtering obtains compound
VII 16.76g, product yield 78%, HPLC purity are 99.65%.
Embodiment 14
Support method replaces the preparation of cloth (I)
Under nitrogen protection, sequentially added into its reaction flask (0.35mmol) [bis- (diphenylphosphine) -1 (R) -2,2'-,
1'- dinaphthalene] ruthenous chloride (II), 150ml toluene, 20min is stirred at room temperature, adds VII 21.84g of compound (0.07mol), and
Reaction flask is put into the autoclave of a stainless steel, three times with hydrogen displacement, finally pours required Hydrogen Vapor Pressure 50psi,
After reacting at room temperature 12h, the sodium carbonate of 150mL saturation is added with 150mL methylene chloride diluting reaction system in slow release hydrogen
Solution stirs 15min, separates organic layer, then uses methylene chloride (3 × 150mL) aqueous layer extracted, uses Na after organic layer merging2SO4
It is dry, it removes solvent get Tuo Fa and replaces cloth (I) 21.65g, yield 96%, HPLC purity 99.95%, ee value 97%.
Embodiment 15
Support method replaces the preparation of cloth (I)
Under nitrogen protection, sequentially added into its reaction flask (0.33mmol) [bis- (diphenylphosphine) -1 (R) -2,2'-,
1'- dinaphthalene] ruthenous chloride (II), 150ml methylene chloride, 20min is stirred at room temperature, adds VII 20.63g of compound
(0.066mol), and reaction flask is put into the autoclave of a stainless steel, three times with hydrogen displacement, finally pour required hydrogen
Atmospheric pressure 30psi, after reacting at room temperature 12h, 150mL is added with 150mL methylene chloride diluting reaction system in slow release hydrogen
The sodium carbonate liquor of saturation stirs 15min, separates organic layer, then with methylene chloride (3 × 150mL) aqueous layer extracted, organic laminated
Na is used after and2SO4It is dry, it removes solvent get Tuo Fa and replaces cloth (I) 17.83g, yield 82%, HPLC purity 99.81%, ee value
95%.
Embodiment 16
Support method replaces the preparation of cloth (I)
Under nitrogen protection, sequentially added into its reaction flask (0.054mmol) [bis- (diphenylphosphine) -1 (R) -2,2'-,
1'- dinaphthalene] ruthenous chloride (II), 150ml n,N-Dimethylformamide, 20min is stirred at room temperature, adds compound VII
16.76g (0.054mol), and reaction flask is put into the autoclave of a stainless steel, three times with hydrogen displacement, finally pour institute
The Hydrogen Vapor Pressure 100psi needed, after reacting at room temperature 12h, slow release hydrogen is added with 150mL methylene chloride diluting reaction system
Enter the sodium carbonate liquor of 150mL saturation, stir 15min, separate organic layer, then with methylene chloride (3 × 150mL) aqueous layer extracted,
Organic layer uses Na after merging2SO4It is dry, it removes solvent get Tuo Fa and replaces cloth (I) 17.06g, yield 93%, HPLC purity 99.92%,
Ee value 92%.
Claims (10)
1. the synthetic method that a kind of support method replaces cloth, it is characterised in that the synthetic method includes the following steps:
A, compound ii and methylamine flow back prepare compound III in organic solvent；
B, compound III first passes through reduction reaction, using cyanoacetyl chloride substitution reaction prepare compound IV；
C, compounds Ⅳ carries out hydrogenation under the conditions of alkali, metallic catalyst, ligand and potassium bromide and compound V is made；
D, compound V passes through elimination reaction under p-methyl benzenesulfonic acid, then reacts prepare compound VII with compound VI；
E, compound VII carries out asymmetric hydrogenation under catalysts conditions and prepares finished product support method for cloth (I)；
Its synthetic route is as follows:
2. method according to claim 1, which is characterized in that organic solvent described in step a is toluene or dichloromethane
Alkane, compound ii and methylamine molar ratio are 1:1-1.1.
3. method according to claim 1, which is characterized in that catalyst system used in reduction reaction is in step b
LiAlH4-AlCl3；Compound III, LiAIH4、AlCl3Molar ratio is 1:2-3:1；Reduction reaction temperature is 20-25 DEG C.
4. method according to claim 1, which is characterized in that the organic solvent that step c is used is isopropanol, tertiary fourth
Any one of alcohol, tetrahydrofuran, methylene chloride, 1,4- dioxane, ethyl acetate, benzene, toluene or two or more mixing
Object.
5. method according to claim 1, which is characterized in that alkali described in step c is sodium ethoxide, potassium tert-butoxide, three
Ethamine, N, N- diisopropylethylamine, sodium hydroxide or sodium carbonate.
6. method according to claim 1, which is characterized in that metallic catalyst described in step c is [Rh (COD)2]
BF4, ligand be bis- (diphenylphosphine) ferrocene of 1,1'-；The molar ratio of metallic catalyst, ligand and compounds Ⅳ is 0.001-
0.002:0.001-0.002:1。
7. method according to claim 1, which is characterized in that the pressure of hydrogen used in step c is 10-100bar, excellent
Selecting Hydrogen Vapor Pressure is 30bar.
8. method according to claim 1, which is characterized in that step d elimination reaction temperature is 90-100 DEG C, compound
V with p-methyl benzenesulfonic acid molar ratio be 1:0.2-0.3.
9. method according to claim 1, which is characterized in that catalyst described in step e is (R) -2,2'- bis- (two
Phenyl phosphorus) -1,1'- dinaphthalene] ruthenous chloride (II), compound VII and catalyst molar ratio are 1:0.001-0.005.
10. method according to claim 1, which is characterized in that step e reaction dissolvent be tetrahydrofuran, methylene chloride,
N,N-Dimethylformamide or toluene；The pressure of hydrogen used is 50-100psi.
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| CN201810936532.4A CN108948022B (en) | 2018-08-16 | 2018-08-16 | Synthesis method of tofacitinib |
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Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2014097150A1 (en) * | 2012-12-17 | 2014-06-26 | Ranbaxy Laboratories Limited | Process for the preparation of tofacitinib and intermediates thereof |
| WO2014102826A1 (en) * | 2012-12-28 | 2014-07-03 | Glenmark Pharmaceuticals Limited; | The present invention relates to process for the preparation of tofacitinib and intermediates thereof. |
| CN105884781A (en) * | 2016-04-18 | 2016-08-24 | 山东罗欣药业集团股份有限公司 | Preparation method of tofacitinib citrate |
| CN106831538A (en) * | 2017-01-22 | 2017-06-13 | 苏州楚凯药业有限公司 | The preparation method of tropsch imatinib intermediate |
| CN108358930A (en) * | 2018-02-05 | 2018-08-03 | 南京法恩化学有限公司 | A kind of preparation method of citric acid tropsch imatinib |
-
2018
- 2018-08-16 CN CN201810936532.4A patent/CN108948022B/en active Active
Patent Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2014097150A1 (en) * | 2012-12-17 | 2014-06-26 | Ranbaxy Laboratories Limited | Process for the preparation of tofacitinib and intermediates thereof |
| WO2014102826A1 (en) * | 2012-12-28 | 2014-07-03 | Glenmark Pharmaceuticals Limited; | The present invention relates to process for the preparation of tofacitinib and intermediates thereof. |
| CN105884781A (en) * | 2016-04-18 | 2016-08-24 | 山东罗欣药业集团股份有限公司 | Preparation method of tofacitinib citrate |
| CN106831538A (en) * | 2017-01-22 | 2017-06-13 | 苏州楚凯药业有限公司 | The preparation method of tropsch imatinib intermediate |
| CN108358930A (en) * | 2018-02-05 | 2018-08-03 | 南京法恩化学有限公司 | A kind of preparation method of citric acid tropsch imatinib |
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| 曹运华等: "托法替尼合成路线图解", 《中国新药杂志》 * |
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