CN104788461A - Industrial production method applicable to citric acid tofacitinib - Google Patents
Industrial production method applicable to citric acid tofacitinib Download PDFInfo
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- CN104788461A CN104788461A CN201510219026.XA CN201510219026A CN104788461A CN 104788461 A CN104788461 A CN 104788461A CN 201510219026 A CN201510219026 A CN 201510219026A CN 104788461 A CN104788461 A CN 104788461A
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- 0 CC(CCN(C1)C(CC#N)=O)[C@]1N(C)c1c(C=C*2)c2ncn1 Chemical compound CC(CCN(C1)C(CC#N)=O)[C@]1N(C)c1c(C=C*2)c2ncn1 0.000 description 3
- QYMUENUCKRLOTB-UHFFFAOYSA-N CCC(CN)N(C)C Chemical compound CCC(CN)N(C)C QYMUENUCKRLOTB-UHFFFAOYSA-N 0.000 description 1
- PMFUYZHCWAHQME-WMYDLHIRSA-N C[C@H](CCN(CC1=[I]C=CC=C1)C1)C1N(C)/C(/c(cc1)c[n]1S(c1ccccc1)(=O)=O)=N/C Chemical compound C[C@H](CCN(CC1=[I]C=CC=C1)C1)C1N(C)/C(/c(cc1)c[n]1S(c1ccccc1)(=O)=O)=N/C PMFUYZHCWAHQME-WMYDLHIRSA-N 0.000 description 1
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- 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
- C07D487/04—Ortho-condensed systems
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- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
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Abstract
The invention relates to an industrial production method applicable to citric acid tofacitinib. The invention relates to a novel industrial production method of a high-purity orally taken JAK inhibitor and a medicine for treating rheumatoid arthritis. Raw materials are subjected to substitution, protecting group removal, reduction debenzylation, condensation and salifying to obtain a compound shown in a formula I, and the defects of a synthetic route reported in existing literatures that the impurity content in the prepared finished product is high, cost is high and yield is low are overcome. The novel industrial production method provided by the invention has the advantages that cost of a used reagent is low, environmental pollution is hardly caused, operation is easy, and short time is consumed, so that the novel industrial production method is applicable to industrial production; meanwhile, product quality is good, total impurity content is low, content of each individual impurity is controlled to be 0.1% or below, the finished product is controlled to be in a single stable crystal form, and medicinal-grade raw material requirements can be met.
Description
Technical field
The invention belongs to pharmaceutical production technical field, be specifically related to a kind of Citric Acid holder method that is applicable to for Buddhist nun's industrialized production method.
Background technology
Citric Acid holder method is for a kind of new oral JAK inhibitor of Ni Shi Pfizer Inc. exploitation, the listing that in November, 2012 is ratified through U.S. FDA, commodity are called Xeljanz, for insufficient to methotrexate for treatment response or not tolerate, in to the treatment of the adult patient of severe active rheumatoid arthritis, Citric Acid holder method is for one of new drug of Ni Shi Pfizer most market outlook.
Chinese patent ZL 02823587.8 (Pfizer Inc.'s original patent) discloses following synthetic route:
In this patent report hydrogenation reaction 3 days consuming time, the time was oversize, large produce in add production cost and potential safety hazard, and in the reaction of preparation formula V, drawing-in system SM
3acarry out condensation reaction, the supplier that this reagent can provide on retrieval market is few, high through ask price, and this step yield of patent report is on the low side simultaneously, therefore, from cost, the concrete preparation method that provides of this route of security consideration do not meet the demand of industrial large production.Chinese patent CN201310537835 also reports the preparation method of formula V, by formula SM
3areplace with cyanoacetyl chloride, this method can reduce reagent cost, but because cyanoacetyl chloride is very easily hydrolyzed in water, this method adds uncontrollable risk (equipment involved in reaction and material all need to carry out Non-aqueous processing) in suitability for industrialized production.China pharmaceutical chemistry magazine Vol.23No.2.p166 discloses another synthetic method:
The document reports and substitutes SM1a-b with SM1, and grope to find through lab scale, the formula I impurity that this method prepares is a lot.And single mixing obviously exceeds standard, be difficult to remove, main impurity is:
Based on the above fact, although this route can prepare finished product, quality cannot meet the bulk drug requirement of pharmaceutical grade.On the basis of the document, Chinese Journal of Pharmaceuticals 2014, mentions in 45 (3) page201 articles and uses formula SM
2substituted SM
1, but through retrieval type SM
2do not have supplier to provide on the market at present, large demand of producing cannot be adapted to.J.Med.Chem.2010,53,8468 ~ 8484 documents disclose another preparation method, use formula SM
3substituted SM
1, but be difficult to react completely through the substitution reaction of lab scale research discovery first engineering, yield very low (by changing feed ratio, raised temperature, the optimization of prolongation reaction times), this method cannot be carried out amplification and be produced., all there is larger defect, substantially cannot adapt to suitability for industrialized production in comprehensive above prior art processes.
Consider the market outlook of Citric Acid holder method for Buddhist nun, and the defect that the production technique of compound shown in its important intermediate formula IV, V exists, the technique that exploitation is applicable to suitability for industrialized production is very important.
Summary of the invention
Technical problem to be solved by this invention is to provide the method for a kind of applicable Citric Acid holder method for Buddhist nun's preparation of industrialization, and the production of the method is consuming time short, safe and reliable, and total impurities is few simultaneously, and single impurity meets medicinal requirements.
Synthetic route of the present invention is as follows:
Produce Citric Acid holder method as follows for Buddhist nun's concrete operation step:
(1) according to mol ratio 1: 0.9 ~ 0.98 by SM1a ~ b and SM
2be dissolved in polar protic solvent, under the effect of mineral alkali, substitution reaction occurs, keep temperature of reaction 65 DEG C ~ 95 DEG C, 8 ~ 12 hours consuming time, then cooled process, washing, pulls an oar, centrifugally obtains formula IIa ~ b.
(2) according to mol ratio 1:2 ~ 4 by formula II
aor II
bbe dissolved in the aqueous solution of the sodium hydroxide of 10% ~ 60% mass ratio, keep temperature of reaction 80 DEG C ~ 100 DEG C, 4 ~ 6 hours consuming time, be cooled to 40 ~ 50 DEG C, add water and stir and cooling process, washing, making beating, centrifugally obtain formula III.
(3) formula III is dissolved according to mass ratio 1:10% ~ 15% (palladium hydroxide-moisture 50% of 20%) acetic acid adding palladium hydroxide and catalytic amount in polar protic solvent, be warming up to 30 ~ 60 DEG C, certain pressure is kept to carry out hydrogenation reaction, 8 ~ 12 hours consuming time, obtain formula IV by filtering, concentrating.
(4) formula SM is added after formula IV being dissolved in polar protic solvent according to mol ratio 1:1.2 ~ 2.0
3, under the condition of organic bases, carry out condensation reaction, keep 40 ~ 90 DEG C of reactions, 8 ~ 10 hours consuming time, through centrifugal, spread to wash and obtain formula V.
(5) Citric Acid is added after formula V being dissolved in polar aprotic solvent according to mol ratio 1:1.5 ~ 2.0, keep 30 ~ 40 DEG C of reactions, 8 ~ 10 hours consuming time, through centrifugal, spread to wash and obtain formula I crude product, then through polar protic solvent recrystallization, obtain the high purity formula I of specific crystal formation, meet the requirement of medicinal rank bulk drug.
Described step (1), step (3), the polar protic solvent described in step (4) are methyl alcohol, ethanol, Virahol; Polar aprotic solvent in step (5) described in reaction is acetone, acetonitrile, tetrahydrofuran (THF), and the polar protic solvent described in recrystallization operation is methyl alcohol, ethanol, Virahol, water.
Mineral alkali described in described step (1) is salt of wormwood, sodium carbonate; Organic bases described in step (4) is triethylamine, DIPEA, 1,8-diazabicyclo [5.4.0] 11 carbon-7-alkene.
Described sodium hydroxide solution described in described step (2) is the sodium hydroxide solution of mass concentration 10% ~ 60%.
Described in described step (4), described hydrogenation pressure scope is 30 ~ 80PSI.
Advantageous Effects of the present invention:
Preparation method of the present invention greatly reduces the manufacturing cost of compound shown in formula I, simultaneously excellent product quality, and prior art adapts to suitability for industrialized production more.Step (1), (2) adopt SM
1a, SM
1bfor starting raw material, take II respectively
a, II
b, under the condition of sodium hydroxide, then slough protecting group height yield take formula III intermediate.The technology of existing bibliographical information exist reaction not exclusively, yield is low, impurity is many or the feature of starting raw material market unavailability business, although the many deprotection group steps of the present invention technology of adopting, substrate reactions is thorough, the good and high (SM of yield of intermediate purity
1nitrogen hydrogen on pyrroles's impurity ring is by protection, and formed and draw electronic effect, substitution reaction is easily carried out).Step (3) adopts the nitrogen-atoms added in the protonated formula III structure of catalytic amount acetic acid, and (heteroatoms in formula III easily makes poisoning of catalyst, heteroatoms easily occupies the empty d track of metallic palladium), then shortening under the condition of palladium hydroxide, reaction completes within a short period of time smoothly, compared with grinding patent with Pfizer Inc. former, obviously shorten the time of reaction, reduce production cost and decrease the security risk in production.In step (4), formula III introduces ethyl cyanacetate under the condition of organic bases, and obtain formula V by amine transesterify height yield, compared with prior art, working condition is not harsh, and without singularity operation and special reagent, production controllability is strong.Because the adult onset crowd of rheumatoid arthritis is in rising trend in modern society, the present invention has higher economic worth and social benefit.
Embodiment:
The present invention is further illustrated below by embodiment.Should correct understanding: the method in embodiments of the invention is only used for specification sheets invention and provides, instead of limitation of the present invention, institute all belongs to the scope of protection of present invention to simple modifications of the present invention under prerequisite with the inventive method.
Following examples Material Source used is described as follows:
SM
1derive from Suzhou Chukai Pharmaceutical Technology Co., Ltd., SM
2derive from Changzhou Jian Mao Chemical Co., Ltd., palladium hydroxide derives from Shaanxi and reaches chemical industry limited liability company, ethyl cyanacetate derives from Kangrui Chemical Co., Ltd., Changzhou City, Citric Acid derives from Shanghai Hao Hua Chemical Co., Ltd., other reagent Chemical Reagent Co., Ltd., Sinopharm Group and Xilong Chemical Co., Ltd all on sale.
Embodiment 1
Produce Citric Acid holder method as follows for the concrete operation step of Buddhist nun:
1. formula IIa compound preparation
Drop into 0.7Kg 7H-pyrroles [2,3-D] pyrimidine (formula SM
1ashown in compound), 0.6Kg (3R, 4R)-N, 4-dimethyl-1-(phenyl methyl)-3-piperylhydrazine hydrochloride (formula SM
2shown compound) to reactor, start priority vacuum after stirring and pump into 3kg methyl alcohol, drop into 0.5kg powdered potassium carbonate, be warming up to 60 ~ 65 DEG C, insulated and stirred 8hr, through engineering supervision HPLC detection SM
1aresidual 1.0%, be cooled to 40 ~ 45 DEG C, vacuum to pump into after acetonitrile 0.6kg insulated and stirred 3 hours, and centrifuge dripping obtains wet product, and wet product 1.5kg water spreads washes 2 times, again dry and obtain wet product 1.68kg, keep 40 ~ 50 DEG C of forced air dryings 12 hours, obtain 0.75kg off-white color solid type IIa, yield 75%, purity 97.2%, SM
1aresidual 0.5%, moisture entrapment 1.0%.
2. formula IIb compound preparation
Drop into 0.6Kg 7H-pyrroles [2,3-D] pyrimidine (formula SM
1bshown in compound), 0.54Kg (3R, 4R)-N, 4-dimethyl-1-(phenyl methyl)-3-piperylhydrazine hydrochloride (formula SM
2shown compound) to reactor, start priority vacuum after stirring and pump into 3kg methyl alcohol, drop into 0.52kg powdered potassium carbonate, be warming up to 60 ~ 65 DEG C, insulated and stirred 8 hours, through engineering supervision HPLC detection SM
1aresidual 1.2%, be cooled to 45 ~ 55 DEG C, vacuum to pump into after acetonitrile 0.65kg insulated and stirred 3 hours, centrifuge dripping obtains wet product, and wet product 1.6kg water spreads washes 2 times, again dries and obtains wet product 1.5kg, keep 40 ~ 50 DEG C of forced air dryings 12 hours, obtain 0.65kg off-white color solid type II
b, yield 73.7%, purity 96.2%, SM
1aresidual 1.0%, moisture entrapment 0.8%.
3. formula III compound preparation
A method: drop into 0.72KgII
a, pump into 3.6kg sodium hydroxide (mass concentration the is 50%) aqueous solution by vacuum, be warming up to 80 ~ 100 DEG C, insulated and stirred carried out engineering supervision after 6 hours, and HPLC detects II
bresidual 0.5%, be cooled to 40 ~ 50 DEG C, the purified water of fast drop 6kg, continue stir and be slowly down to room temperature 20 ~ 30 DEG C, insulated and stirred 2 hours, centrifuge dripping obtains wet product, and wet product 1.5kg water spreads washes 2 times, again dry and obtain wet product 1.2kg, keep 40 ~ 50 DEG C of forced air dryings 12 hours, obtain 0.36kg off-white color solid formula III, yield 73.4%, purity 98.0%, II
aresidual 0.5%, moisture entrapment 1.0%.
B method: drop into 0.6KgII
b, pump into 3.6kg sodium hydroxide (mass concentration the is 50%) aqueous solution by vacuum, be warming up to 80 ~ 100 DEG C, insulated and stirred carried out engineering supervision after 6 hours, and HPLC detects II
bresidual 0.5%, be cooled to 40 ~ 50 DEG C, the purified water of fast drop 6kg, continue stir and be slowly down to room temperature 20 ~ 30 DEG C, insulated and stirred 2 hours, centrifuge dripping obtains wet product, and wet product 1.5kg water spreads washes 2 times, again dry and obtain wet product 1.2kg, keep 40 ~ 50 DEG C of forced air dryings 12 hours, obtain 0.30kg off-white color solid formula III, yield 70%, purity 98.2%, II
bresidual 0.5%, moisture entrapment 1.0%.
4. formula IV compound preparation
4kg methyl alcohol is dropped in hydriding reactor, 0.6Kg water, intermediate shown in 0.6Kg formula III, drops into the palladium hydroxide of 60g 20% in batches, starts stirring, after dripping acetic acid (about 200g) installation testing, after displacement nitrogen and each 3 times of hydrogen, pressurized with hydrogen to 50PSI, temperature rise to 50 DEG C in reactor, insulated and stirred carried out engineering supervision after 12 hours, and HPLC detects formula III intermediate residual 0.5%.Dismounting hydriding reactor, shift reaction liquid is in reaction treatment device, by strainer filtering palladium hydroxide (properly preserving with water-lute), in filtrate, the sodium hydroxide solution of 10% is slowly dripped under room temperature (25 ~ 35 DEG C), regulate about pH to 13, the first alcohol and water in dry system is drawn in 55 DEG C of decompressions, be cooled to 30 DEG C of final vacuums and pump into 1.5kg ethyl acetate, after stirring and dissolving, vacuum pumps into 5kg normal heptane again, stir centrifuge dripping after 1 hour and obtain wet product 0.45kg, 50 DEG C of drying under reduced pressure 10 hours, obtain product shown in 350g off-white color product type IV, yield 80%, purity 98.0%, formula III residual 0.3%, moisture entrapment 0.3%.
5. formula V compound preparation
Add 180gDBU (1, 8-diazabicyclo [5.4.0] 11 carbon-7-alkene), 2.8kg anhydrous methanol, 266g ethyl cyanacetate, be warming up to 25 DEG C, insulated and stirred 2 hours, drop into 280g formula IV, temperature 45 DEG C in reaction system is kept to react after 9 hours, carry out engineering supervision, HPLC detects formula III residual 4.0%, after centrifuge dripping, 400g ice methyl alcohol spreads and washes, recentrifuge dries and obtains 360g off-white color wet product, 50 DEG C of drying under reduced pressure 10 hours, obtain intermediate shown in 300g formula V, yield 84%, purity 99.2%, formula IV residual 0.5%, moisture entrapment 0.5%.
6. formula I finished product preparation
Drop into 280g formula V in the reactor, vacuum pumps into 2kg acetone simultaneously, stirring and dissolving is clarified, and slowly adds 210g Citric Acid in batches, is warming up to 40 DEG C and insulated and stirred 2 hours, stop heating and slow cooling to 20 DEG C, insulated and stirred 2 hours, centrifuge dripping obtains 290g off-white color wet product, 50 DEG C of drying under reduced pressure 8 hours, obtain the crude product formula I of 200g drying, HPLC detection display purity is 99.1%.200g crude product formula I is dropped in 3.6kg methanol aqueous solution (50%), be warming up to 80 DEG C and insulated and stirred half an hour, obtain clear transparent solutions, continue insulation 1 hour, slow stirring is cooled to 20 DEG C, and be incubated 1 hour, centrifugal drying worry obtains wet product, the 1.2kg cold methanol aqueous solution (50%) spreads to be washed, recentrifuge dries and obtains 410g wet product, 50 DEG C of drying under reduced pressure 10 hours, obtain 360g off-white color solid type I, yield 79.5%, purity 99.5%, single assorted less than 0.1%, EE value more than 99.5%, specific rotation value should be+10.2, X-ray powder diffraction pattern is shown as single crystal formation.
Embodiment 2
Produce Citric Acid holder method as follows for the concrete operation step of Buddhist nun:
1. formula IIa compound preparation
Drop into 0.7Kg 7H-pyrroles [2,3-D] pyrimidine (formula SM
1ashown in compound), 0.6Kg (3R, 4R)-N, 4-dimethyl-1-(phenyl methyl)-3-piperylhydrazine hydrochloride (formula SM
2shown compound) to reactor, start priority vacuum after stirring and pump into 2.8kg methyl alcohol, drop into 0.4kg powdered sodium carbonate, be warming up to 60 ~ 65 DEG C, insulated and stirred 10 hours, through engineering supervision HPLC detection SM
1aresidual 1.2%, be cooled to 40 ~ 45 DEG C, vacuum to pump into after acetonitrile 0.56kg insulated and stirred 3 hours, and centrifuge dripping obtains wet product, and wet product 1.5kg water spreads washes 2 times, again dry and obtain wet product 1.6kg, keep 40 ~ 50 DEG C of forced air dryings 12 hours, obtain 0.71kg off-white color solid type IIa, yield 72.4%, purity 96.8%, SM
1aresidual 0.8%, moisture entrapment 1.2%.
2. formula IIb compound preparation
Drop into 0.6Kg 7H-pyrroles [2,3-D] pyrimidine (formula SM
1bshown in compound), 0.54Kg (3R, 4R)-N, 4-dimethyl-1-(phenyl methyl)-3-piperylhydrazine hydrochloride (formula SM
2shown compound) to reactor, start priority vacuum after stirring and pump into 3.5kg methyl alcohol, drop into 0.5kg powdered sodium carbonate, be warming up to 60 ~ 65 DEG C, insulated and stirred 10 hours, through engineering supervision HPLC detection SM
1aresidual 1.5%, be cooled to 45 ~ 55 DEG C, vacuum to pump into after acetonitrile 0.60kg insulated and stirred 4 hours, centrifuge dripping obtains wet product, and wet product 2.0kg water spreads washes 2 times, again dries and obtains wet product 1.4kg, keep 40 ~ 50 DEG C of forced air dryings 12 hours, obtain 0.61kg off-white color solid type II
b, yield 69.3%, purity 97.3%, SM
1aresidual 1.3%, moisture entrapment 0.9%.
3. formula III compound preparation
A method: drop into 0.7KgII
a, pump into 4.8kg sodium hydroxide (40%) aqueous solution by vacuum, be warming up to 80 ~ 100 DEG C, insulated and stirred carried out engineering supervision after 6 hours, and HPLC detects II
bresidual 0.8%, be cooled to 40 ~ 50 DEG C, the purified water of fast drop 6.5kg, continue stir and be slowly down to room temperature 20 ~ 30 DEG C, insulated and stirred 3 hours, centrifuge dripping obtains wet product, and wet product 1.8kg water spreads washes 2 times, again dry and obtain wet product 1.3kg, keep 40 ~ 50 DEG C of forced air dryings 14 hours, obtain 0.32kg off-white color solid formula III, yield 64.9%, purity 97.8%, II
aresidual 0.7%, moisture entrapment 1.4%.
B method: drop into 0.6KgII
b, pump into 3.6kg sodium hydroxide (40%) aqueous solution by vacuum, be warming up to 80 ~ 100 DEG C, insulated and stirred carried out engineering supervision after 7 hours, and HPLC detects II
bresidual 0.7%, be cooled to 40 ~ 50 DEG C, the purified water of fast drop 6kg, continue stir and be slowly down to room temperature 20 ~ 30 DEG C, insulated and stirred 2 hours, centrifuge dripping obtains wet product, and wet product 1.9kg water spreads washes 2 times, again dry and obtain wet product 1.1kg, keep 40 ~ 50 DEG C of forced air dryings 14 hours, obtain 0.3kg off-white color solid formula III, yield 70.7%, purity 98.6%, II
bresidual 0.4%, moisture entrapment 0.8%.
4. formula IV compound preparation
3.8kg ethanol is dropped in hydriding reactor, 0.5Kg water, intermediate shown in 0.6Kg formula III, drops into the palladium hydroxide of 70g 20% in batches, starts stirring, after dripping acetic acid (about 200g) installation testing, after displacement nitrogen and each 3 times of hydrogen, pressurized with hydrogen to 40PSI, temperature rise to 40 DEG C in reactor, insulated and stirred carried out engineering supervision after 18 hours, and HPLC detects formula III intermediate residual 0.85%.Dismounting hydriding reactor, shift reaction liquid is in reaction treatment device, by strainer filtering palladium hydroxide (properly preserving with water-lute), in filtrate, the sodium hydroxide solution of 10% is slowly dripped under room temperature (25 ~ 35 DEG C), regulate about pH to 13, the second alcohol and water in dry system is drawn in 55 DEG C of decompressions, be cooled to 30 DEG C of final vacuums and pump into 1.9kg ethyl acetate, after stirring and dissolving, vacuum pumps into 5.5kg normal heptane again, stir centrifuge dripping after 1 hour and obtain wet product 0.48kg, 50 DEG C of drying under reduced pressure 13 hours, obtain product shown in 364g off-white color product type IV, yield 83.1%, purity 98.3%, formula III residual 0.38%, moisture entrapment 0.31%.
5. formula V compound preparation
Add 120g triethylamine, 2.6kg dehydrated alcohol, 260g ethyl cyanacetate, be warming up to 25 DEG C, insulated and stirred 6 hours, drops into 280g formula IV, keeps temperature 70 ~ 75 DEG C in reaction system to react after 10 hours, carry out engineering supervision, HPLC detects formula III residual 8.0%, and after centrifuge dripping, 400g ice ethanol spreads and washes, and recentrifuge dries and obtains 320g off-white color wet product, 50 DEG C of drying under reduced pressure 9 hours, obtain intermediate shown in 270g formula V, yield 75.7%, purity 99.1%, formula IV residual 0.8%, moisture entrapment 0.4%.
6. formula I finished product preparation
Drop into 250g formula V in the reactor, vacuum pumps into 1.8kg acetonitrile simultaneously, stirring and dissolving is clarified, and slowly adds 200g Citric Acid in batches, is warming up to 30 DEG C and insulated and stirred 2 hours, stop heating and slow cooling to 20 DEG C, insulated and stirred 2.5 hours, centrifuge dripping obtains 260g off-white color wet product, 50 DEG C of drying under reduced pressure 9 hours, obtain the crude product formula I of 180g drying, HPLC detection display purity is 99.3%.180g crude product formula I is dropped in 3.3kg aqueous ethanolic solution (50%), be warming up to 80 DEG C and insulated and stirred half an hour, obtain clear transparent solutions, continue insulation 1.5 hours, slow stirring is cooled to 20 DEG C, and be incubated 1.5 hours, centrifugal drying worry obtains wet product, the cold aqueous ethanolic solution of 1.2kg (50%) spreads to be washed, recentrifuge dries and obtains 400g wet product, 50 DEG C of drying under reduced pressure 10 hours, obtain 300g off-white color solid type I, yield 74.3%, purity 99.6%, single assorted less than 0.1%, EE value more than 99.6%, specific rotation value should be+10.3, X-ray powder diffraction pattern is shown as single crystal formation.
Embodiment 3
Produce Citric Acid holder method as follows for the concrete operation step of Buddhist nun:
1. formula IIa compound preparation
Drop into 0.72Kg 7H-pyrroles [2,3-D] pyrimidine (formula SM
1ashown in compound), 0.6Kg (3R, 4R)-N, 4-dimethyl-1-(phenyl methyl)-3-piperylhydrazine hydrochloride (formula SM
2shown compound) to reactor, start priority vacuum after stirring and pump into 2.8kg Virahol, drop into 0.45kg powdered sodium carbonate, be warming up to 75 ~ 80 DEG C, insulated and stirred 12 hours, through engineering supervision HPLC detection SM
1aresidual 1.3%, be cooled to 40 ~ 45 DEG C, vacuum to pump into after acetonitrile 0.6kg insulated and stirred 4 hours, and centrifuge dripping obtains wet product, and wet product 1.8kg water spreads washes 2 times, again dry and obtain wet product 1.7kg, keep 40 ~ 50 DEG C of forced air dryings 14 hours, obtain 0.70kg off-white color solid type IIa, yield 70%, purity 97.3%, SM
1aresidual 1.0%, moisture entrapment 1.4%.
2. formula IIb compound preparation
Drop into 0.64Kg 7H-pyrroles [2,3-D] pyrimidine (formula SM
1bshown in compound), 0.54Kg (3R, 4R)-N, 4-dimethyl-1-(phenyl methyl)-3-piperylhydrazine hydrochloride (formula SM
2shown compound) to reactor, start priority vacuum after stirring and pump into 3.3kg Virahol, drop into 0.56kg powdered sodium carbonate, be warming up to 75 ~ 80 DEG C, insulated and stirred 12 hours, through engineering supervision HPLC detection SM
1aresidual 1.2%, be cooled to 45 ~ 60 DEG C, vacuum to pump into after acetonitrile 0.65kg insulated and stirred 4 hours, centrifuge dripping obtains wet product, and wet product 2.5kg water spreads washes 2 times, again dries and obtains wet product 1.7kg, keep 40 ~ 50 DEG C of forced air dryings 16 hours, obtain 0.64kg off-white color solid type II
b, yield 72.6%, purity 98.3%, SM
1aresidual 1.4%, moisture entrapment 0.8%.
3. formula III compound preparation
A method: drop into 0.7KgII
a, pump into 5.0kg sodium hydroxide (35%) aqueous solution by vacuum, be warming up to 80 ~ 100 DEG C, insulated and stirred carried out engineering supervision after 5.5 hours, and HPLC detects II
bresidual 1.0%, be cooled to 40 ~ 50 DEG C, the purified water of fast drop 6.2kg, continue stir and be slowly down to room temperature 20 ~ 30 DEG C, insulated and stirred 4 hours, centrifuge dripping obtains wet product, and wet product 1.9kg water spreads washes 2 times, again dry and obtain wet product 1.35kg, keep 40 ~ 50 DEG C of forced air dryings 16 hours, obtain 0.31kg off-white color solid formula III, yield 64.6%, purity 98.8%, II
aresidual 0.9%, moisture entrapment 1.3%.
B method: drop into 0.6KgII
b, pump into 4kg sodium hydroxide (45%) aqueous solution by vacuum, be warming up to 80 ~ 100 DEG C, insulated and stirred carried out engineering supervision after 5 hours, and HPLC detects II
bresidual 0.65%, be cooled to 40 ~ 50 DEG C, the purified water of fast drop 6.5kg, continue stir and be slowly down to room temperature 20 ~ 30 DEG C, insulated and stirred 2.5 hours, centrifuge dripping obtains wet product, and wet product 1.6kg water spreads washes 2 times, again dry and obtain wet product 1.2kg, keep 40 ~ 50 DEG C of forced air dryings 15 hours, obtain 0.33kg off-white color solid formula III, yield 80.5%, purity 98.3%, II
bresidual 0.5%, moisture entrapment 0.9%.
4. formula IV compound preparation
3.6kg Virahol is dropped in hydriding reactor, 0.52Kg water, intermediate shown in 0.6Kg formula III, drops into the palladium hydroxide of 65g 20% in batches, starts stirring, after dripping acetic acid (150g) installation testing, after displacement nitrogen and each 3 times of hydrogen, pressurized with hydrogen to 35PSI, temperature rise to 40 DEG C in reactor, insulated and stirred carried out engineering supervision after 20 hours, and HPLC detects formula III intermediate residual 0.85%.Dismounting hydriding reactor, shift reaction liquid is in reaction treatment device, by strainer filtering palladium hydroxide (properly preserving with water-lute), in filtrate, the sodium hydroxide solution of 10% is slowly dripped under room temperature (25 ~ 35 DEG C), regulate about pH to 12.5, the isopropyl alcohol and water in dry system is drawn in 55 DEG C of decompressions, be cooled to 30 DEG C of final vacuums and pump into 1.7kg ethyl acetate, after stirring and dissolving, vacuum pumps into 6.0kg t-butyl methyl ether again, stir centrifuge dripping after 1 hour and obtain wet product 0.49kg, 50 DEG C of drying under reduced pressure 13 hours, obtain product shown in 350g off-white color product type IV, yield 79.9%, purity 97.9%, formula III residual 0.40%, moisture entrapment 0.37%.5. formula V compound preparation
Add 125g triethylamine, 2.8kg Virahol, 265g ethyl cyanacetate, be warming up to 25 DEG C, insulated and stirred 5 hours, drops into 282g formula IV, keeps temperature 80 DEG C in reaction system to react after 11 hours, carry out engineering supervision, HPLC detects formula III residual 7.0%, and after centrifuge dripping, 450g ice Virahol spreads and washes, and recentrifuge dries and obtains 310g off-white color wet product, 50 DEG C of drying under reduced pressure 10 hours, obtain intermediate shown in 275g formula V, yield 76.6%, purity 99.3%, formula IV residual 0.5%, moisture entrapment 0.4%.
6. formula I finished product preparation
Drop into 240g formula V in the reactor, vacuum pumps into 1.9kg tetrahydrofuran (THF) simultaneously, stirring and dissolving is clarified, and slowly adds 190g Citric Acid in batches, is warming up to 30 DEG C and insulated and stirred 3 hours, stop heating and slow cooling to 20 DEG C, insulated and stirred 3 hours, centrifuge dripping obtains 256g off-white color wet product, 50 DEG C of drying under reduced pressure 10 hours, obtain the crude product formula I of 173g drying, HPLC detection display purity is 99.1%.173g crude product formula I is dropped in 3.0kg isopropanol water solution (50%), be warming up to 80 DEG C and insulated and stirred half an hour, obtain clear transparent solutions, continue insulation 2 hours, slow stirring is cooled to 20 DEG C, and be incubated 2 hours, centrifugal drying worry obtains wet product, the 1.3kg cold isopropanol aqueous solution (50%) spreads to be washed, recentrifuge dries and obtains 410g wet product, 50 DEG C of drying under reduced pressure 12 hours, obtain 290g off-white color solid type I, yield 74.7%, purity 99.5%, single assorted less than 0.1%, EE value more than 99.5%, specific rotation value should be+10.4, X-ray powder diffraction pattern is shown as single crystal formation.
Embodiment 4
Produce Citric Acid holder method as follows for the concrete operation step of Buddhist nun:
1. formula IIa compound preparation
Drop into 0.72Kg 7H-pyrroles [2,3-D] pyrimidine (formula SM
1ashown in compound), 0.64Kg (3R, 4R)-N, 4-dimethyl-1-(phenyl methyl)-3-piperylhydrazine hydrochloride (formula SM
2shown compound) to reactor, start priority vacuum after stirring and pump into 2.6kg Virahol, drop into 0.46kg powdered sodium carbonate, be warming up to 80 ~ 95 DEG C, insulated and stirred 14 hours, through engineering supervision HPLC detection SM
1aresidual 1.1%, be cooled to 40 ~ 45 DEG C, vacuum to pump into after acetonitrile 0.9kg insulated and stirred 4.5 hours, and centrifuge dripping obtains wet product, and wet product 2.0kg water spreads washes 2 times, again dry and obtain wet product 1.8kg, keep 40 ~ 50 DEG C of forced air dryings 16 hours, obtain 0.75kg off-white color solid type IIa, yield 73.5%, purity 97.5%, SM
1aresidual 1.1%, moisture entrapment 1.6%.
2. formula IIb compound preparation
Drop into 0.64Kg 7H-pyrroles [2,3-D] pyrimidine (formula SM
1bshown in compound), 0.55Kg (3R, 4R)-N, 4-dimethyl-1-(phenyl methyl)-3-piperylhydrazine hydrochloride (formula SM
2shown compound) to reactor, start priority vacuum after stirring and pump into 3.5kg Virahol, drop into 0.59kg powdered sodium carbonate, be warming up to 80 ~ 95 DEG C, insulated and stirred 10 hours, through engineering supervision HPLC detection SM
1aresidual 1.4%, be cooled to 45 ~ 60 DEG C, vacuum to pump into after acetonitrile 0.70kg insulated and stirred 4 hours, centrifuge dripping obtains wet product, and wet product 2.8kg water spreads washes 2 times, again dries and obtains wet product 1.8kg, keep 40 ~ 50 DEG C of forced air dryings 20 hours, obtain 0.66kg off-white color solid type II
b, yield 75.4%, purity 98.1%, SM
1aresidual 1.2%, moisture entrapment 0.9%.
3. formula III compound preparation
A method: drop into 0.7KgII
a, pump into 5.5kg sodium hydroxide (30%) aqueous solution by vacuum, be warming up to 80 ~ 100 DEG C, insulated and stirred carried out engineering supervision after 6 hours, and HPLC detects II
bresidual 0.9%, be cooled to 40 ~ 50 DEG C, the purified water of fast drop 6.6kg, continue stir and be slowly down to room temperature 20 ~ 30 DEG C, insulated and stirred 4.5 hours, centrifuge dripping obtains wet product, and wet product 2.0kg water spreads washes 2 times, again dry and obtain wet product 1.38kg, keep 40 ~ 50 DEG C of forced air dryings 20 hours, obtain 0.35kg off-white color solid formula III, yield 73%, purity 98.6%, II
aresidual 0.8%, moisture entrapment 1.2%.
B method: drop into 0.6KgII
b, pump into 4.5kg sodium hydroxide (50%) aqueous solution by vacuum, be warming up to 80 ~ 100 DEG C, insulated and stirred carried out engineering supervision after 5 hours, and HPLC detects II
bresidual 0.55%, be cooled to 40 ~ 50 DEG C, the purified water of fast drop 7kg, continue stir and be slowly down to room temperature 20 ~ 30 DEG C, insulated and stirred 3 hours, centrifuge dripping obtains wet product, and wet product 1.6kg water spreads washes 2 times, again dry and obtain wet product 1.4kg, keep 40 ~ 50 DEG C of forced air dryings 18 hours, obtain 0.32kg off-white color solid formula III, yield 76.2%, purity 98.5%, II
bresidual 0.7%, moisture entrapment 0.8%.
4. formula IV compound preparation
4.0kg methyl alcohol is dropped in hydriding reactor, 0.52Kg water, intermediate shown in 0.6Kg formula III, drops into the palladium hydroxide of 65g 20% in batches, starts stirring, after dripping acetic acid (170g) installation testing, after displacement nitrogen and each 3 times of hydrogen, pressurized with hydrogen to 48PSI, temperature rise to 40 DEG C in reactor, insulated and stirred carried out engineering supervision after 20 hours, and HPLC detects formula III intermediate residual 0.85%.Dismounting hydriding reactor, shift reaction liquid is in reaction treatment device, by strainer filtering palladium hydroxide (properly preserving with water-lute), in filtrate, the sodium hydroxide solution of 10% is slowly dripped under room temperature (25 ~ 35 DEG C), regulate about pH to 12, the first alcohol and water in dry system is drawn in 55 DEG C of decompressions, be cooled to 30 DEG C of final vacuums and pump into 2.0kg ethyl acetate, after stirring and dissolving, vacuum pumps into 5.0kg normal heptane again, stir centrifuge dripping after 2 hours and obtain wet product 0.52kg, 50 DEG C of drying under reduced pressure 18 hours, obtain product shown in 340g off-white color product type IV, yield 77.3%, purity 98.4%, formula III residual 0.6%, moisture entrapment 0.5%.
5. formula V compound preparation
Add 140g N successively, N-diisopropylethylamine, 2.8kg methyl alcohol, 268g ethyl cyanacetate, is warming up to 25 DEG C, insulated and stirred 4 hours, drop into 280g formula IV, keep temperature 60 ~ 65 DEG C reaction in reaction system after 13 hours, to carry out engineering supervision, HPLC detects formula III residual 7.5%, after centrifuge dripping, 500g ice methyl alcohol spreads and washes, recentrifuge dries and obtains 320g off-white color wet product, and 50 DEG C of drying under reduced pressure 12 hours, obtain intermediate shown in 280g formula V, yield 78.6%, purity 99.1%, formula IV residual 0.6%, moisture entrapment 0.3%.
6. formula I finished product preparation
Drop into 250g formula V in the reactor, vacuum pumps into 2.0kg acetone simultaneously, stirring and dissolving is clarified, and slowly adds 195g Citric Acid in batches, is warming up to 30 DEG C and insulated and stirred 3 hours, stop heating and slow cooling to 20 DEG C, insulated and stirred 3 hours, centrifuge dripping obtains 260g off-white color wet product, 50 DEG C of drying under reduced pressure 11 hours, obtain the crude product formula I of 179g drying, HPLC detection display purity is 99.2%.179g crude product formula I is dropped in 3.2kg methanol aqueous solution (50%), be warming up to 60 ~ 65 DEG C and insulated and stirred half an hour, obtain clear transparent solutions, continue insulation 2.5 hours, slow stirring is cooled to 20 DEG C, and be incubated 2 hours, centrifugal drying worry obtains wet product, the 1.2kg cold methanol aqueous solution (50%) spreads to be washed, recentrifuge dries and obtains 425g wet product, 50 DEG C of drying under reduced pressure 13 hours, obtain 295g off-white color solid type I, yield 73.1%, purity 99.6%, single assorted less than 0.1%, EE value more than 99.3%, specific rotation value should be+10.2, X-ray powder diffraction pattern is shown as single crystal formation.
Embodiment 5
Produce Citric Acid holder method as follows for the concrete operation step of Buddhist nun:
1. formula IIa compound preparation
Drop into 0.72Kg 7H-pyrroles [2,3-D] pyrimidine (formula SM
1ashown in compound), 0.66Kg (3R, 4R)-N, 4-dimethyl-1-(phenyl methyl)-3-piperylhydrazine hydrochloride (formula SM
2shown compound) to reactor, start priority vacuum after stirring and pump into 3.0kg methyl alcohol, drop into 0.56kg powdered potassium carbonate, be warming up to 60 ~ 75 DEG C, insulated and stirred 10 hours, through engineering supervision HPLC detection SM
1aresidual 1.0%, be cooled to 40 ~ 45 DEG C, vacuum to pump into after acetonitrile 0.8kg insulated and stirred 4.5 hours, and centrifuge dripping obtains wet product, and wet product 2.5kg water spreads washes 2 times, again dry and obtain wet product 1.9kg, keep 40 ~ 50 DEG C of forced air dryings 15 hours, obtain 0.79kg off-white color solid type IIa, yield 75.2%, purity 97.8%, SM
1aresidual 1.0%, moisture entrapment 1.4%.
2. formula IIb compound preparation
Drop into 0.64Kg 7H-pyrroles [2,3-D] pyrimidine (formula SM
1bshown in compound), 0.58Kg (3R, 4R)-N, 4-dimethyl-1-(phenyl methyl)-3-piperylhydrazine hydrochloride (formula SM
2shown compound) to reactor, start priority vacuum after stirring and pump into 3.8kg methyl alcohol, drop into 0.7kg powdered potassium carbonate, be warming up to 65 ~ 75 DEG C, insulated and stirred 11 hours, through engineering supervision HPLC detection SM
1aresidual 1.1%, be cooled to 45 ~ 60 DEG C, vacuum to pump into after acetonitrile 0.75kg insulated and stirred 4 hours, centrifuge dripping obtains wet product, and wet product 2.9kg water spreads washes 2 times, again dries and obtains wet product 1.8kg, keep 40 ~ 50 DEG C of forced air dryings 20 hours, obtain 0.68kg off-white color solid type II
b, yield 72.3%, purity 98.5%, SM
1aresidual 1.1%, moisture entrapment 0.7%.
3. formula III compound preparation
A method: drop into 0.7KgII
a, pump into 5.8kg sodium hydroxide (25%) aqueous solution by vacuum, be warming up to 80 ~ 100 DEG C, insulated and stirred carried out engineering supervision after 6 hours, and HPLC detects II
bresidual 0.85%, be cooled to 40 ~ 50 DEG C, the purified water of fast drop 6.9kg, continue stir and be slowly down to room temperature 20 ~ 30 DEG C, insulated and stirred 5.0 hours, centrifuge dripping obtains wet product, and wet product 2.5kg water spreads washes 2 times, again dry and obtain wet product 1.4kg, keep 40 ~ 50 DEG C of forced air dryings 15 hours, obtain 0.37kg off-white color solid formula III, yield 77%, purity 98.7%, II
aresidual 0.85%, moisture entrapment 1.1%.
B method: drop into 0.6KgII
b, pump into 4.8kg sodium hydroxide (40%) aqueous solution by vacuum, be warming up to 80 ~ 100 DEG C, insulated and stirred carried out engineering supervision after 5.5 hours, and HPLC detects II
bresidual 0.53%, be cooled to 40 ~ 50 DEG C, the purified water of fast drop 7.5kg, continue stir and be slowly down to room temperature 20 ~ 30 DEG C, insulated and stirred 3.5 hours, centrifuge dripping obtains wet product, and wet product 1.8kg water spreads washes 2 times, again dry and obtain wet product 1.5kg, keep 40 ~ 50 DEG C of forced air dryings 17 hours, obtain 0.33kg off-white color solid formula III, yield 78%, purity 98.6%, II
bresidual 0.6%, moisture entrapment 0.7%.
4. formula IV compound preparation
4.2kg Virahol is dropped in hydriding reactor, 0.50Kg water, intermediate shown in 0.6Kg formula III, drops into the palladium hydroxide of 68g 20% in batches, starts stirring, after dripping acetic acid (175g) installation testing, after displacement nitrogen and each 3 times of hydrogen, pressurized with hydrogen to 52PSI, temperature rise to 40 DEG C in reactor, insulated and stirred carried out engineering supervision after 16 hours, and HPLC detects formula III intermediate residual 0.7%.Dismounting hydriding reactor, shift reaction liquid is in reaction treatment device, by strainer filtering palladium hydroxide (properly preserving with water-lute), in filtrate, the sodium hydroxide solution of 10% is slowly dripped under room temperature (25 ~ 35 DEG C), regulate about pH to 13, the isopropyl alcohol and water in dry system is drawn in 55 DEG C of decompressions, be cooled to 30 DEG C of final vacuums and pump into 2.2kg ethyl acetate, after stirring and dissolving, vacuum pumps into 5.2kg t-butyl methyl ether again, stir centrifuge dripping after 2 hours and obtain wet product 0.50kg, 50 DEG C of drying under reduced pressure 16 hours, obtain product shown in 345g off-white color product type IV, yield 86.2%, purity 98.6%, formula III residual 0.65%, moisture entrapment 0.45%.5. formula V compound preparation
Add 140g triethylamine successively, 2.5kg methyl alcohol, 265g ethyl cyanacetate, be warming up to 25 DEG C, insulated and stirred 4.5 hours, drops into 280g formula IV, keeps temperature 60 ~ 65 DEG C in reaction system to react after 11 hours, carry out engineering supervision, HPLC detects formula III residual 6.5%, and after centrifuge dripping, 600g ice methyl alcohol spreads and washes, and recentrifuge dries and obtains 330g off-white color wet product, 50 DEG C of drying under reduced pressure 11 hours, obtain intermediate shown in 285g formula V, yield 79.9%, purity 99.2%, formula IV residual 0.8%, moisture entrapment 0.53%.
6. formula I finished product preparation
Drop into 250g formula V in the reactor, vacuum pumps into 2.2kg acetonitrile simultaneously, stirring and dissolving is clarified, and slowly adds 200g Citric Acid in batches, is warming up to 30 DEG C and insulated and stirred 3.5 hours, stop heating and slow cooling to 20 DEG C, insulated and stirred 4 hours, centrifuge dripping obtains 270g off-white color wet product, 50 DEG C of drying under reduced pressure 14 hours, obtain the crude product formula I of 185g drying, HPLC detection display purity is 99.1%.185g crude product formula I is dropped in 3.6kg methanol aqueous solution (50%), be warming up to 60 ~ 65 DEG C and insulated and stirred half an hour, obtain clear transparent solutions, continue insulation 3 hours, slow stirring is cooled to 20 DEG C, and be incubated 2 hours, centrifugal drying worry obtains wet product, the 1.5kg cold methanol aqueous solution (50%) spreads to be washed, recentrifuge dries and obtains 430g wet product, 50 DEG C of drying under reduced pressure 11 hours, obtain 300g off-white color solid type I, yield 74.3%, purity 99.5%, single assorted less than 0.1%, EE value more than 99.5%, specific rotation value should be+10.3, X-ray powder diffraction pattern is shown as single crystal formation.
Claims (5)
1. applicable Citric Acid holder method is for Buddhist nun's industrialized preparing process, it is characterized in that: concrete operation step is as follows:
(1) according to mol ratio 1:0.9 ~ 0.98 by SM1a ~ b and SM
2be dissolved in polar protic solvent, under the effect of mineral alkali, substitution reaction occurs, keep temperature of reaction 65 DEG C ~ 95 DEG C, 8 ~ 12 hours consuming time, then cooled process, washing, pulls an oar, centrifugally obtains formula IIa ~ b
(2) according to mol ratio 1:2 ~ 4 by formula II
aor II
bbe dissolved in the aqueous solution of the sodium hydroxide of 10% ~ 60% mass ratio, keep temperature of reaction 80 DEG C ~ 100 DEG C, 4 ~ 6 hours consuming time, be cooled to 40 ~ 50 DEG C, add water and stir and cooling process, washing, making beating, centrifugally obtain formula III
(3) formula III is dissolved according to 20% palladium hydroxide mass ratio 1:10% ~ 15% of formula III and water content 50% acetic acid adding palladium hydroxide, catalytic amount in polar protic solvent, be warming up to 30 ~ 60 DEG C, carry out hydrogenation reaction, 8 ~ 12 hours consuming time, obtain formula IV by filtering, concentrating
(4) formula SM is added after formula IV being dissolved in polar protic solvent according to mol ratio 1:1.2 ~ 2.0
3, under the condition of organic bases, carry out condensation reaction, keep 40 ~ 90 DEG C of reactions, 8 ~ 10 hours consuming time, through centrifugal, spread to wash and obtain formula V
(5) Citric Acid is added after formula V being dissolved in polar aprotic solvent according to mol ratio 1:1.5 ~ 2.0, keep 30 ~ 40 DEG C of reactions, 8 ~ 10 hours consuming time, through centrifugal, spread to wash and obtain formula I crude product, then through polar protic solvent recrystallization, obtain the high purity formula I of specific crystal formation, meet the requirement of medicinal rank bulk drug
2. one according to claim 1 is applicable to Citric Acid holder method for Buddhist nun's industrialized preparing process, it is characterized in that: step (1), step (3), the polar protic solvent described in step (4) are methyl alcohol, ethanol or Virahol; Polar aprotic solvent in step (5) described in reaction is acetone, acetonitrile or tetrahydrofuran (THF), and the polar protic solvent described in recrystallization operation is methyl alcohol, ethanol, Virahol or water.
3. one according to claim 1 is applicable to Citric Acid holder method for Buddhist nun's industrialized preparing process, it is characterized in that: the mineral alkali described in step (1) is salt of wormwood, sodium carbonate; Organic bases described in step (4) is triethylamine, DIPEA, 1,8-diazabicyclo [5.4.0] 11 carbon-7-alkene.
4. one according to claim 1 is applicable to Citric Acid holder method for Buddhist nun's industrialized preparing process, it is characterized in that: described in step (2), sodium hydroxide solution is mass concentration 30% ~ 50%.
5. one according to claim 1 is applicable to Citric Acid holder method for Buddhist nun's industrialized preparing process, it is characterized in that: described in step (3), hydrogenation pressure scope is 30 ~ 80PSI.
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Cited By (10)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105153166A (en) * | 2015-08-07 | 2015-12-16 | 湖北丽益医药科技有限公司 | N- [ (3R,4R) -1-benzyl-4-methylpiperidin-3-yl ] -N-methyl-7H-pyrrolo [2,3-d ] pyrimidin-4-amine crystal |
| CN105440039A (en) * | 2015-11-24 | 2016-03-30 | 山东淄博新达制药有限公司 | Synthesis method of tofacitinib citrate |
| CN106967072A (en) * | 2017-04-12 | 2017-07-21 | 山东裕欣药业有限公司 | Tofacitinib citrate crystal form compound and preparation method thereof |
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Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101233138A (en) * | 2005-07-29 | 2008-07-30 | 辉瑞产品公司 | Pyrrolo[2,3-d]pyrimidine derivatives, their intermediates and synthesis |
| CN103896946A (en) * | 2012-12-28 | 2014-07-02 | 浙江导明医药科技有限公司 | New compounds used for prevention and treatment of a plurality of autoimmune diseases |
| CN104292231A (en) * | 2013-09-17 | 2015-01-21 | 广东东阳光药业有限公司 | Preparation method of tofacitinib citrate |
-
2015
- 2015-04-30 CN CN201510219026.XA patent/CN104788461A/en active Pending
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101233138A (en) * | 2005-07-29 | 2008-07-30 | 辉瑞产品公司 | Pyrrolo[2,3-d]pyrimidine derivatives, their intermediates and synthesis |
| CN103896946A (en) * | 2012-12-28 | 2014-07-02 | 浙江导明医药科技有限公司 | New compounds used for prevention and treatment of a plurality of autoimmune diseases |
| CN104292231A (en) * | 2013-09-17 | 2015-01-21 | 广东东阳光药业有限公司 | Preparation method of tofacitinib citrate |
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|---|---|---|---|---|
| CN105153166A (en) * | 2015-08-07 | 2015-12-16 | 湖北丽益医药科技有限公司 | N- [ (3R,4R) -1-benzyl-4-methylpiperidin-3-yl ] -N-methyl-7H-pyrrolo [2,3-d ] pyrimidin-4-amine crystal |
| CN105440039A (en) * | 2015-11-24 | 2016-03-30 | 山东淄博新达制药有限公司 | Synthesis method of tofacitinib citrate |
| CN106967072B (en) * | 2017-04-12 | 2019-05-03 | 山东裕欣药业有限公司 | Tofacitinib citrate crystal form compound and preparation method thereof |
| CN106967072A (en) * | 2017-04-12 | 2017-07-21 | 山东裕欣药业有限公司 | Tofacitinib citrate crystal form compound and preparation method thereof |
| CN107793418A (en) * | 2017-10-24 | 2018-03-13 | 扬子江药业集团有限公司 | Industrial production method of tofacitinib citrate |
| CN107793418B (en) * | 2017-10-24 | 2020-08-04 | 扬子江药业集团有限公司 | Industrial production method of tofacitinib citrate |
| 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 |
| CN109053771A (en) * | 2018-08-22 | 2018-12-21 | 珠海优润医药科技有限公司 | A kind of support method replaces the related substance and its preparation method and application of cloth |
| CN109053771B (en) * | 2018-08-22 | 2020-02-28 | 珠海优润医药科技有限公司 | Related substance of tofacitinib and preparation method and application thereof |
| CN109879879A (en) * | 2019-03-25 | 2019-06-14 | 国药集团容生制药有限公司 | A kind of support method replaces the preparation process of cloth intermediate |
| CN113896730A (en) * | 2020-06-22 | 2022-01-07 | 浙江晖石药业有限公司 | Preparation method of tofacitinib citrate and intermediate thereof |
| CN112679508A (en) * | 2021-03-09 | 2021-04-20 | 正大天晴药业集团南京顺欣制药有限公司 | Preparation method of tofacitinib intermediate |
| CN112679508B (en) * | 2021-03-09 | 2021-08-10 | 正大天晴药业集团南京顺欣制药有限公司 | Preparation method of tofacitinib intermediate |
| CN113735860A (en) * | 2021-08-26 | 2021-12-03 | 安徽鼎旺医药有限公司 | Synthesis method of tofacitinib citrate |
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