CN104341422A - Tofacitinib intermediate and preparation method thereof - Google Patents
Tofacitinib intermediate and preparation method thereof Download PDFInfo
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- CN104341422A CN104341422A CN201310319405.7A CN201310319405A CN104341422A CN 104341422 A CN104341422 A CN 104341422A CN 201310319405 A CN201310319405 A CN 201310319405A CN 104341422 A CN104341422 A CN 104341422A
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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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- 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
- C07B2200/13—Crystalline forms, e.g. polymorphs
Abstract
The invention discloses a tofacitinib intermediate, a crystal form and a preparation method thereof, the tofacitinib intermediate is a compound shown as a formula VI. The positions of characteristic diffraction peaks of the intermediate in an X-ray powder diffraction pattern when the reflection angle 2theta is about 7.4 DEG, 10.0 DEG, 11.8 DEG, 14.6 DEG, 16.3 DEG, 19.0 DEG, 19.3 DEG, 20.5 DEG, 23.8 DEG, 24.2 DEG, 25.2 DEG, 25.8 DEG, 26.0 DEG, 27.0 DEG, 28.0 DEG, 28.3 DEG, 28.9 DEG, 29.3 DEG, 31.2 DEG, 31.7 DEG, 32.1 DEG, 34.4 DEG and 38.2 DEG. The formula VI compound is stable and easy to store and transport.
Description
Technical field
The invention belongs to field of pharmaceutical chemistry technology, be specifically related to hold in the palm the luxuriant and rich with fragrance midbody compound for Buddhist nun and crystal formation and its preparation method.
Technical background
Tuo Fei replaces Buddhist nun, general tofacitinib by name, and its chemistry is by name: 3-[(3R, 4R) [(7H-pyrroles [2 for methyl for-4-methyl-3-, 3-d] pyrimidine-4-yl) amino] piperidin-1-yl]-3-oxypropionitrile, its chemical structural formula is formula II compound
。
Tuo Fei, for Buddhist nun and the following type I compound of single Citrate trianion thereof, is a kind of selectivity Janus kinases (JAK) 1/3 tyrosine protein kinase inhibitor developed by Pfizer.At present, for the listing of Buddhist nun's Citrate trianion, (commodity are called the multinational approval holder such as the U.S., Japan, Switzerland, Argentina, Kuwait phenanthrene: Xeljanz), be used for the treatment of adult rheumatoid joint.Meanwhile, self can be used as the treatment that immunosuppressor also can be used for the Other diseases such as such as psoriatic, ulcerative colitis, psoriatic arthritis, mandatory spondylitis, Crohn's disease, renal transplant rejection, its clinical study well afoot.
。
Tuo Fei has many sections of documents to report for work for the preparation technology of Buddhist nun.CN1729192 discloses a kind of preparation method: formula IV is at Pd (OH)
2after removing benzyl protecting group under the catalytic hydrogenation conditions of/C, the method through silica gel column chromatography obtains formula III; Formula III and the amination of cyano group-acetic acid 2,5-dioxo-pvrrolidin-1-base ester generation cyano-acetamide are obtained by reacting formula II (namely holder is luxuriant and rich with fragrance for Buddhist nun).2009, the people such as Price, K.E. adopted ethyl cyanacetate to improve as the preparation technology of cyano-acetamide amination reaction reagent to formula II.CN101233138, CN1325498, CN102459270 disclose the preparation method of holder phenanthrene for Buddhist nun's Citrate trianion of formula I: formula II and citric acid reactions can obtain formula I.
CN101233138 also discloses the another kind of method of preparation formula I: formula V is at Pd (OH)
2formula III is obtained by reacting under the catalytic hydrogenation conditions of/C; There is cyano-acetamide amination and be obtained by reacting the holder phenanthrene of formula II for Buddhist nun in formula III; Formula II and citric acid generation salt-forming reaction can obtain the holder phenanthrene of formula I for Buddhist nun's Citrate trianion.
The present inventor is through finding the research of existing Technology, and the holder phenanthrene of preparation formula II, for the method for Buddhist nun, all adopts formula III that the method for cyano-acetamide amination reaction occurs.Formula III is converted into the final step chemical reaction that molecular structure change occurs when formula II is preparation Xeljanz, so formula III belongs to the luxuriant and rich with fragrance important advanced intermediate for Buddhist nun of preparation holder, and its quality is particularly important to the quality control of finished product.Formula III compound contains a secondary amine and a tertiary amine group, and have and be easy to the moisture absorption, the easily feature such as oxidized, poor stability, quality is restive, is being quality control in storage and transport especially, thus is increasing the quality control difficulty of type I compound.The stability of solution formula III compound and a quality control difficult problem replace the quality control of Buddhist nun significant to holder is luxuriant and rich with fragrance.
Summary of the invention
The object of the present invention is to provide and a kind ofly hold in the palm the luxuriant and rich with fragrance intermediate for Buddhist nun's Citrate trianion and formula VI compound.This intermediate is easily prepared, quality controllable, stable in properties, nonhygroscopic, not easily oxidized, be easy to storage and transport, the luxuriant and rich with fragrance preparation for Buddhist nun's Citrate trianion of holder and quality control are had great importance.
For realizing object of the present invention, provide a kind of embodiment, a kind of formula VI compound:
。
Described VI compound is the dihydrochloride of formula III compound.
The object of the present invention is to provide a kind of monohydrate crystal form of formula VI compound.This crystal formation is defined as crystal form A.
In the monohydrate of the formula VI compound of the invention described above, the number of crystal water is by Karl-Fischer method and TGA(thermogravimetric analysis) method determines.
The monohydrate crystal form of the formula VI compound of the invention described above, i.e. crystal form A, is characterized in that its X-ray powder diffraction is about position its characteristic diffraction peak corresponding of 7.4 °, 10.0 °, 11.8 °, 14.6 °, 16.3 °, 19.0 °, 19.3 °, 20.5 °, 23.8 °, 24.2 °, 25.2 °, 25.8 °, 26.0 °, 27.0 °, 28.0 °, 28.3 °, 28.9 °, 29.3 °, 31.2 °, 31.7 °, 32.1 °, 34.4 °, 38.2 ° in 2 θ values.
The crystal form A of the invention described above, its X-ray powder diffraction is about position its characteristic diffraction peak corresponding of 14.8 °, 17.3 °, 17.5 °, 21.5 °, 22.6 °, 22.9 °, 32.9 °, 33.0 °, 38.4 ° 35.6 °, 36.1 ° in 2 θ values.
The X-ray powder diffraction test of formula VI monohydrate crystal form A of the present invention is under envrionment temperature and ambient moisture, has measured through the CuK α source (α=1.5406) of Japanese Shimadzu XRD-6000 type x-ray diffractometer." envrionment temperature " is generally 0 ~ 40 DEG C; " ambient moisture " is generally the relative humidity of 30% ~ 80%.
The representational X-ray powder diffraction of formula VI monohydrate crystal form A of the present invention is listed in Fig. 1." representational X-ray powder diffraction " refers to that the X-ray powder diffraction feature of this crystal formation meets the overall pattern of this collection of illustrative plates display, be understandable that in test process, owing to being subject to the impact of many factors, as test sample granularity, test time sample treatment process, instrument, test parameter, test operation etc., the X-ray powder diffraction measured by same crystal formation go out peak position or peak intensity has certain difference.Therefore, above-mentioned " term " about " in the corresponding 2 θ values of X-ray powder diffraction (XRPD) charateristic avsorption band should be defined as ± and 0.2 °, represent 2 above-mentioned got θ values and allowed necessarily rational limit of error, its limit of error is ± 0.2 °.
The DSC(dsc of formula VI monohydrate crystal form A of the present invention) collection of illustrative plates display, crystal form A has from about room temperature to endothermic thermal event within the scope of about 125 DEG C, and Fig. 2 is shown in by its DSC collection of illustrative plates.
The study on the stability experiment of crystal form A of the present invention: by crystal form A under room temperature preservation 3 months, investigate its chemistry and optical purity, crystal formation and hygroscopic change, the results are shown in Table 1
The study on the stability result of table 1 formula VI crystal form A
the result of upper table 1 shows, crystal form A of the present invention have not easily the moisture absorption, comparatively stablize, be easy to the advantages such as preservation.
Formula VII compound is a hydrochloride of III compound, at room temperature carries out stability test research to formula VII compound solid, investigates its water absorbability, chemical pure and optically pure change.Its experimental result data is in table 2.
Table 2 formula VII compound solid study on the stability result
* water content adopts Karl-Fischer method to measure
Table 2 result shows, formula VII is the moisture absorption, instability very easily, is difficult to store.
Another object of the present invention is to a kind of method providing preparation formula VI compound.
In one embodiment, the method for preparation formula VI compound of the present invention, comprises the following steps:
(1) formula III compound is dissolved in solvent forms solution;
(2) solution of step (1) and hydrochloric acid soln mixing, reaction;
(3) isolate solid, obtain formula VI compound.
In above-mentioned specific embodiments, method of the present invention, wherein, described solvent is ethyl acetate, methyl acetate, isopropyl acetate, methyl alcohol, ethanol, Virahol or their mixture in step (1), particular methanol, ethanol or their mixture; Described in step (2), hydrochloric acid soln is methanol hydrochloride solution or ethanol solution hydrochloride, and hydrochloric acid is 2.0 ~ 3.0 with the ratio of the amount of substance of formula III compound.
Preferably, the method for preparation formula VI of the present invention, comprises the following steps:
(1) N-methyl-N-((3R, 4R)-4-methyl piperidine-3-base)-7H-pyrrolo-[2, the 3-D] pyrimidine-4-amine solvent of formula III is formed solution in solvent;
(2) hydrochloric acid soln is prepared: at room temperature, appropriate concentrated hydrochloric acid is dissolved in solvent, is mixed with hydrochloric acid soln;
(3) solution of the hydrochloric acid soln of step (2) and step (1) is mixed, reaction;
(4) from reaction solution, product is isolated.
The method of the invention described above, step (1) described solvent refers to ethyl acetate, methyl acetate, isopropyl acetate, methyl alcohol, ethanol, Virahol or their mixture, particular methanol, ethanol or their mixture; Step (2) described solvent refers to ethyl acetate, methyl acetate, isopropyl acetate, methyl alcohol, ethanol, Virahol or their mixture, particular methanol, ethanol or their mixture.
The method of the invention described above, step (2) described concentrated hydrochloric acid refers to that commercial concentration is the hydrochloric acid of 36% ~ 38%; Step (2) described hydrochloric acid soln, its concentration is 1 mol/L ~ 6 mol/L, preferably 2 mol/L ~ 3 mol/L.
The method of the invention described above, the temperature of reaction of step (2) is 10 DEG C ~ 50 DEG C, preferably 20 DEG C ~ 40 DEG C; In step (3), hydrochloric acid is 1.5 ~ 5.0 with the ratio of the amount of substance of formula III compound, preferably 2.0 ~ 3.0.
In a preferred specific embodiments, the method for preparation formula VI compound of the present invention, comprises the following steps:
(1) formula III compound is dissolved in solvent methanol or ethanol;
(2) concentrated hydrochloric acid is dissolved in ethanol or methyl alcohol, forms acidic alcohol or methanol solution, then joins reaction in step (1);
(3) isolate solid product, obtain formula VI compound.
In step (2), hydrochloric acid is 2.0 ~ 3.0 with the ratio of the amount of substance of formula III compound, and temperature of reaction is 10 DEG C ~ 50 DEG C, preferably 20 DEG C ~ 40 DEG C.
The method of preparation formula VI compound of the present invention.The method has simple to operate, mild condition, yield advantages of higher.
Another object of the present invention there is provided a kind of method preparing crystal form A, comprises the following steps:
(1) formula III compound is dissolved in solvent forms solution;
(2) solution of step (1) and hydrochloric acid soln mixing, reaction;
(3) crystallization, isolates solid.
In above-mentioned specific embodiments, method of the present invention, wherein, described solvent is ethyl acetate, methyl acetate, isopropyl acetate, methyl alcohol, ethanol, Virahol or their mixture in step (1), particular methanol, ethanol or their mixture; Described in step (2), hydrochloric acid soln is methanol hydrochloride solution or ethanol solution hydrochloride, and hydrochloric acid is 2.0 ~ 3.0 with the amount of substance ratio of formula III compound.
Preferably, the method preparing crystal form A of the present invention, comprises the following steps:
(1) N-methyl-N-((3R, 4R)-4-methyl piperidine-3-base)-7H-pyrrolo-[2, the 3-D] pyrimidine-4-amine solvent of formula III is formed solution in solvent;
(2) hydrochloric acid soln is prepared: at room temperature, appropriate concentrated hydrochloric acid is dissolved in solvent, is mixed with hydrochloric acid soln;
(3) solution of the hydrochloric acid soln of step (2) and step (1) is mixed, reaction;
(4) crystallization, isolates solid.
The method of the invention described above, step (1) described solvent refers to ethyl acetate, methyl acetate, isopropyl acetate, methyl alcohol, ethanol, Virahol or their mixture, particular methanol, ethanol or their mixture; Step (2) described solvent refers to ethyl acetate, methyl acetate, isopropyl acetate, methyl alcohol, ethanol, Virahol or their mixture, particular methanol, ethanol or their mixture.
The method of the invention described above, step (2) described concentrated hydrochloric acid refers to that commercial concentration is the hydrochloric acid of 36% ~ 38%; Step (2) described hydrochloric acid soln, its concentration is 1 mol/L ~ 6 mol/L, preferably 2 mol/L ~ 3 mol/L.
The method of the invention described above, the temperature of reaction of step (2) is 10 DEG C ~ 50 DEG C, preferably 20 DEG C ~ 40 DEG C; In step (3), the mol ratio of hydrochloric acid and formula III compound is 1.5 ~ 5.0, preferably 2.0 ~ 3.0.
In a preferred specific embodiments, the method preparing crystal form A of the present invention, comprises the following steps:
(1) formula III compound is dissolved in solvent methanol or ethanol;
(2) concentrated hydrochloric acid is dissolved in ethanol or methyl alcohol, forms acidic alcohol or methanol solution, then joins reaction in step (1);
(3) crystallization, isolates solid product.
Wherein, in step (2), hydrochloric acid is 2.0 ~ 3.0 with the ratio of the amount of substance of formula III compound, and temperature of reaction is 10 DEG C ~ 50 DEG C, preferably 20 DEG C ~ 40 DEG C.
The holder phenanthrene that another object of the present invention is to provide a kind of preparation formula I replaces the method for Buddhist nun's Citrate trianion.
In one embodiment, of the present invention preparation holds in the palm the luxuriant and rich with fragrance method for Buddhist nun's Citrate trianion, and comprise formula VI compound and alkali reaction, products therefrom reacts with ethyl cyanacetate under DBU exists, and then adds citric acid salify and obtains holder phenanthrene for Buddhist nun's Citrate trianion.
Specific embodiments is as follows:
Tuo Fei is for the method for Buddhist nun's Citrate trianion, formula IV compound is dissolved in alcohol/water mixed solvent, at hydrogen and catalyzer as under the palladium hydroxide supported on carbon or the palladium effect supported on carbon, formula IV compound removes benzyl and is converted into formula III compound, described alcohol is selected from methyl alcohol, ethanol, propyl alcohol, Virahol, butanols and their mixed solvent, particular methanol, ethanol or their mixed solvent, after formula III compound is dissolved in alcohol, described alcohol is selected from methyl alcohol, ethanol, Virahol and their mixed solvent, at 0 DEG C ~ 60 DEG C, at preferably 10 DEG C ~ 40 DEG C temperature, drip ethanol solution hydrochloride or methanol hydrochloride solution, stir 1 hour ~ 10 hours, preferably 3 hours ~ 5 hours, solid-liquid separation, collects solid and obtains formula VI compound, formula VI compound reacts at the mixed solvent of methylene dichloride/water and alkali such as sodium hydroxide or potassium hydroxide, then with methylene dichloride or toluene or extraction into ethyl acetate, residue is obtained after extraction liquid solvent evaporated, by residue under propyl carbinol and DBU exist with ethyl cyanacetate at 20 DEG C ~ 60 DEG C, preferably react 5 hours ~ 30 hours under 40 DEG C of temperature condition, preferably 15 hours ~ 20 hours, add citric acid, at 20 DEG C ~ 60 DEG C, preferably react 1 hour ~ 6 hours under 40 DEG C of temperature condition, preferably 2 hours ~ 4 hours, isolate solid, prepare the holder phenanthrene of formula I for Buddhist nun's Citrate trianion.
Reaction formula is as follows:
In another embodiment, the present invention prepares the luxuriant and rich with fragrance method for Buddhist nun's Citrate trianion of holder, comprise and be dissolved in alcohol/water mixed solvent by formula V compound, at hydrogen and catalyzer as under the palladium hydroxide supported on carbon or the palladium effect supported on carbon, formula V converting compounds is formula III compound, described alcohol is selected from methyl alcohol, ethanol, propyl alcohol, Virahol, butanols and their mixed solvent, particular methanol, ethanol or their mixed good, after formula III compound is dissolved in alcohol, described alcohol is selected from methyl alcohol, ethanol, Virahol and their mixed solvent, at 0 DEG C ~ 60 DEG C, at preferably 10 DEG C ~ 40 DEG C temperature, drip ethanol solution hydrochloride or methanol hydrochloride solution, stir 1 hour ~ 10 hours, preferably 3 hours ~ 5 hours, solid-liquid separation, collects solid and obtains formula VI compound, formula VI compound reacts at the mixed solvent of methylene dichloride/water and alkali such as sodium hydroxide or potassium hydroxide, then with methylene dichloride or toluene or extraction into ethyl acetate, residue is obtained after extraction liquid solvent evaporated, by residue in propyl carbinol and DBU exist under with ethyl cyanacetate at 20 DEG C ~ 60 DEG C, preferably react 5 hours ~ 30 hours under 40 DEG C of temperature condition, preferably 15 hours ~ 20 hours, add citric acid, at 20 DEG C ~ 60 DEG C, preferably react 1 hour ~ 6 hours under 40 DEG C of temperature condition, preferably 2 hours ~ 4 hours, isolate solid, prepare the holder phenanthrene of formula I for Buddhist nun's Citrate trianion.
Reaction formula is as follows:
Embodiment
The invention will be further described in conjunction with the embodiments, and professional and technical personnel in the field can be made better to understand the present invention, but the scope do not limited the present invention in any way.
embodiment 1
The preparation of methyl-((3R, 4R)-4-methyl-pi-3-base)-(7H-pyrido [2,3-d] pyrimidine-4-yl)-amine (formula III)
Method 1: by the method for formula IV preparation formula III
The preparation method of (3R, 4R)-(1-benzyl-4-methyl-pi-3-base)-methyl-(7H-pyrido [2,3-d] pyrimidine-4-yl)-amine (formula IV) is with reference to CN1729192.Under room temperature, by 8g (3R, 4R)-(1-benzyl-4-methyl-pi-3-base)-methyl-(7H-pyrido [2,3-d] pyrimidine-4-yl)-amine joins in 200ml hydrogenation reaction cauldron, measures 32ml ethanol, 8ml water adds in reactor.Taking 1.43g acetic acid adds in solution, and stir, solid is entirely molten.Take 1.6g 20% palladium hydroxide carbon to add wherein.Interior temperature 50 DEG C is heated under stirring after hydrogenation gas reactor adds hydrogen to 0.7MPa successively after nitrogen, hydrogen exchange.To exit stripping assembly after reaction 5h, thin-layer chromatography send out detection reaction completely after, filter, the aqueous sodium hydroxide solution of filtrate 2Mol/L regulates PH to 8.Methylene dichloride (3 × 40ml) extracts, the organic phase 2g anhydrous sodium sulfate drying of merging.Filter, be evaporated to dry, obtain the title product (5.3g, yield is 91%, HPLC purity is 96.2%) of pale solid.
Method 2: by the method for formula V preparation formula III
The preparation method of N-[(3R, 4R)-1-benzyl-4-methyl piperidine-3-base] the chloro-N-methyl of-2--7H-pyrido [2,3-d] pyrimidine-4-amine (formula V) is with reference to CN101233138.Under room temperature, measure 40ml ethanol and 10ml water joins in 200ml hydriding reactor, take 10g N-[(3R successively, 4R)-1-benzyl-4-methyl piperidine-3-base] the chloro-N-methyl of-2--7H-pyrido [2,3-d] pyrimidine-4-amine, 2g 20% palladium hydroxide carbon joins in hydriding reactor.Interior temperature 70 DEG C is heated under stirring after hydrogenation gas reactor adds hydrogen to 0.7MPa successively after nitrogen, hydrogen exchange.Thin-layer chromatography sends out detection reaction, after reacting completely, filters, and the aqueous sodium hydroxide solution of filtrate 2Mol/L regulates PH to 8.Methylene dichloride (3 × 60ml) extracts, the organic phase 2g anhydrous sodium sulfate drying of merging.Filter, be evaporated to dry, obtain the title product (6.1g, yield is 90%, HPLC purity is 95.5%) of pale solid.
embodiment 2
Methyl-((3R, 4R)-4-methyl-pi-3-base)-(7H-pyrido [2,3-d] pyrimidine-4-yl)-amine. the preparation of dihydrochloride (formula VI)
Method A:
5.0g methyl-((3R, 4R)-4-methyl-pi-3-base)-(7H-pyrido [2,3-d] pyrimidine-4-yl)-amine is dissolved in 20ml methyl alcohol, stirs.Under room temperature, the solution that 6ml concentrated hydrochloric acid is dissolved in 40ml ethanol is added drop-wise in above-mentioned solution, there is crystal to separate out, drip and finish, stir 5h, suction filtration, filter cake 10ml washing with alcohol, 50 DEG C of drying under reduced pressure, to constant weight, obtain pale solid title product (5.8g, yield is 85%, HPLC purity is 99.2%).
Measure the X-ray powder diffraction pattern (XRPD) of gained solid, the results are shown in Figure 1, be crystal form A.The X-ray powder diffraction pattern surveyed, its 2 θ angle, d value and relative intensity I value, as following table 3, get the peak that relative intensity value is more than or equal to 7%.Adopt Karl-Fischer method and TGA(thermogravimetric analysis) method mensuration, crystal form A contains a crystal water.
The XRPD data of table 3 crystal form A of the present invention
Method B:
5.0g methyl-((3R, 4R)-4-methyl-pi-3-base)-(7H-pyrido [2,3-d] pyrimidine-4-yl)-amine is dissolved in 20ml methyl alcohol, stirs, adds 20ml alcohol dilution.Under room temperature, the solution that 6ml concentrated hydrochloric acid is dissolved in 20ml ethanol is added drop-wise in above-mentioned solution, there is crystal to separate out, drip and finish, stir 5h, suction filtration, filter cake 10ml washing with alcohol, 50 DEG C of drying under reduced pressure, to constant weight, obtain pale solid title product (5.7g, yield is 83%, HPLC purity is 99.1%).Measure the XRPD of solid, Fig. 1 of its characteristic peak and method A gained crystal formation is basically identical, shows that this solid is also crystal form A.
embodiment 3
Tuo Fei is for the preparation of Buddhist nun's Citrate trianion
By 5g methyl-((3R, 4R)-4-methyl-pi-3-base)-(7H-pyrido [2,3-d] pyrimidine-4-yl)-amine. dihydrochloride is suspended in 25ml methylene dichloride, with 2mol/L aqueous sodium hydroxide solution regulator solution about PH to 8.0, system extracting and separating, aqueous phase 50ml methylene dichloride extracts at twice, combined dichloromethane phase, wash with saturated aqueous common salt 30ml, 1.0g anhydrous sodium sulfate drying methylene dichloride phase 2h.Filter, filtrate reduced in volume, to dry, obtains foaming solid.This solid joins in 100ml there-necked flask, adds 15ml propyl carbinol, 3.3g ethyl cyanacetate, 2.2g DBU successively, and stirring, nitrogen protection, be warming up to interior temperature 40 DEG C, stirring reaction liquid.Take 5.6g citric acid to be dissolved in 30ml acetone and to be mixed with solution.Thin layer analyses detection, and after reacting completely, citric acid-acetone soln is added drop-wise in reaction solution, keeps temperature 40 DEG C during dropping, drips after finishing, stirs 2h.Reaction solution decompress filter, filter cake is with 50 DEG C of drying under reduced pressure after 100ml washing with acetone to constant weight, and obtain white solid holder phenanthrene for Buddhist nun's Citrate trianion 6.9g, yield is 92%, HPLC purity is 99.0%.
reference example 1
The preparation of methyl-((3R, 4R)-4-methyl-pi-3-base)-(7H-pyrido [2,3-d] pyrimidine-4-yl)-amine one hydrochloride (formula VII)
5.0g methyl-((3R, 4R)-4-methyl-pi-3-base)-(7H-pyrido [2,3-d] pyrimidine-4-yl)-amine is dissolved in 20ml methyl alcohol, stirs.Under room temperature, 1.7ml concentrated hydrochloric acid is added drop-wise in solution, stirs 30 minutes.Solution decompression adds the making beating of 20ml ethyl acetate after being concentrated into and doing.After 3 hours, suction filtration, filter cake to constant weight, obtains grey title product (5.4g, yield is 94%) at 50 DEG C of drying under reduced pressure.
accompanying drawing explanation
The X-powder x ray diffration pattern x of Fig. 1 formula VI monohydrate and crystal form A.
The means of differential scanning calorimetry figure of Fig. 2 formula VI monohydrate and crystal form A.
Claims (11)
1. formula VI compound
。
2. a method for preparation formula VI compound, comprises the following steps:
(1) formula III compound is dissolved in solvent forms solution;
(2) by the solution of step (1) and hydrochloric acid soln mixing, reaction;
(3) solid is isolated.
3. method as claimed in claim 2, wherein, the solvent in step (1) is selected from ethyl acetate, methyl acetate, isopropyl acetate, methyl alcohol, ethanol, Virahol or their mixture; Described in step (2), hydrochloric acid soln is methanol hydrochloride solution or ethanol solution hydrochloride.
4. method as claimed in claim 3, described solvent is methyl alcohol, ethanol or their mixture.
5. method as claimed in claim 3, hydrochloric acid is 2.0 ~ 3.0 with the ratio of the amount of substance of formula III compound.
6. prepare the luxuriant and rich with fragrance method for Buddhist nun's Citrate trianion of holder, comprise the following steps:
(1) by formula VI chemical combination and alkali reaction, obtained formula III compound;
(2) step (1) gained formula III compound is reacted with ethyl cyanacetate under propyl carbinol and DBU exist;
(3) citric acid is joined in the reaction solution of step (2);
(4) solid is isolated.
7. the monohydrate crystal form of a formula VI compound.
8. crystal formation as claimed in claim 7, is characterized in that its X-ray powder diffraction is about position its characteristic diffraction peak corresponding of 7.4 °, 10.0 °, 11.8 °, 14.6 °, 16.3 °, 19.0 °, 19.3 °, 20.5 °, 23.8 °, 24.2 °, 25.2 °, 25.8 °, 26.0 °, 27.0 °, 28.0 °, 28.3 °, 28.9 °, 29.3 °, 31.2 °, 31.7 °, 32.1 °, 34.4 °, 38.2 ° in 2 θ values.
9. crystal formation as claimed in claim 8, is characterized in that its X-ray powder diffraction is about position its characteristic diffraction peak corresponding of 14.8 °, 17.3 °, 17.5 °, 21.5 °, 22.6 °, 22.9 °, 32.9 °, 33.0 °, 38.4 ° 35.6 °, 36.1 ° in 2 θ values.
10. a method for the monohydrate crystal form of preparation formula VI compound, comprises the following steps:
(1) formula III compound is dissolved in solvent forms solution;
(2) solution of step (1) and hydrochloric acid soln mixing, reaction;
(3) crystallization, isolates solid.
11. formula VI compounds are for the preparation of the luxuriant and rich with fragrance purposes replacing Buddhist nun or its salt of holder.
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| EP3078665A1 (en) * | 2015-04-10 | 2016-10-12 | OLON S.p.A. | Efficient method for the preparation of tofacitinib citrate |
| 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 |
| CN109293682A (en) * | 2017-07-25 | 2019-02-01 | 重庆医药工业研究院有限责任公司 | A kind of support method is for cloth impurity and preparation method thereof |
| CN110003220A (en) * | 2019-05-07 | 2019-07-12 | 江苏永安制药有限公司 | Preparation method of tofacitinib citrate |
| CN112679505A (en) * | 2020-12-25 | 2021-04-20 | 杭州澳赛诺生物科技有限公司 | Synthesis method of 4-methyl-7H-pyrrolo [2,3-d ] pyrimidine |
| CN113248509A (en) * | 2021-05-17 | 2021-08-13 | 上海中西三维药业有限公司 | Preparation method of tofacitinib citrate intermediate |
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| EP3078665A1 (en) * | 2015-04-10 | 2016-10-12 | OLON S.p.A. | Efficient method for the preparation of tofacitinib citrate |
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| 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 |
| CN110003220A (en) * | 2019-05-07 | 2019-07-12 | 江苏永安制药有限公司 | Preparation method of tofacitinib citrate |
| CN112679505A (en) * | 2020-12-25 | 2021-04-20 | 杭州澳赛诺生物科技有限公司 | Synthesis method of 4-methyl-7H-pyrrolo [2,3-d ] pyrimidine |
| CN113248509A (en) * | 2021-05-17 | 2021-08-13 | 上海中西三维药业有限公司 | Preparation method of tofacitinib citrate intermediate |
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