CN104761555A - Tofacitinib intermediate preparation method and method for preparing tofacitinib or its salt by using tofacitinib intermediate preparation method - Google Patents
Tofacitinib intermediate preparation method and method for preparing tofacitinib or its salt by using tofacitinib intermediate preparation method Download PDFInfo
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- CN104761555A CN104761555A CN201510124536.9A CN201510124536A CN104761555A CN 104761555 A CN104761555 A CN 104761555A CN 201510124536 A CN201510124536 A CN 201510124536A CN 104761555 A CN104761555 A CN 104761555A
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- QWHNJUXXYKPLQM-UHFFFAOYSA-N CC1(C)CCCC1 Chemical compound CC1(C)CCCC1 QWHNJUXXYKPLQM-UHFFFAOYSA-N 0.000 description 1
- PWZKIZAHIAGUMK-UHFFFAOYSA-N CC1CCN(Cc2ccccc2)CC1 Chemical compound CC1CCN(Cc2ccccc2)CC1 PWZKIZAHIAGUMK-UHFFFAOYSA-N 0.000 description 1
- UZOFELREXGAFOI-UHFFFAOYSA-N CC1CCNCC1 Chemical compound CC1CCNCC1 UZOFELREXGAFOI-UHFFFAOYSA-N 0.000 description 1
- ZGRADWKJDNWYCQ-UHFFFAOYSA-N CNc1c(cc[nH]2)c2nc(Cl)n1 Chemical compound CNc1c(cc[nH]2)c2nc(Cl)n1 ZGRADWKJDNWYCQ-UHFFFAOYSA-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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Abstract
The invention provides a N-methyl-N((3R,4R)-4-methyl piperidine-3-group)-7H-pyrrolo[2,3-D]pyrimidine-4-amine (tofacitinib intermediate)preparation method and a method for preparing tofacitinib or its salt by using the tofacitinib intermediate preparation method. The tofacitinib intermediate preparation method can dissolve a compound in a formula (II) in a mixed solvent system of an acidic solvent and an organic solvent, and then a hydrogenation reaction is carried out under existence of palladium carbon or platinum carbon catalyst, thereby a compound in a formula (1) can be obtained. The method is simple to operate, and the tofacitinib intermediate yield is high. The invention also relates to the compound in the formula (1) prepared by the method and tofacitinib or its medicinal salt prepared by the compound.
Description
Technical field
The present invention relates to pharmaceutical synthesis field, particularly relate to the preparation method of N-methyl-N-((3R, 4R)-4-methyl piperidine-3-base)-7H-pyrrolo-[2,3-D] pyrimidine-4-amine and utilize it to prepare the method for holder method for cloth or its salt.
Background technology
Rheumatoid arthritis any age all can fall ill, and be mainly in 30-60 year, one's mid-40s is the most common, and also increases with age growth sickness rate, and women is apparently higher than the male sex.Be 0.32%-0.36% at the sickness rate of China, global incidence is 0.5%-1.0%.Calculate by this, the patient of rheumatoid arthritis suffers from more than 4,000,000 in China.The harm of rheumatoid arthritis is very large, and as treated not in time, rheumatoid arthritis (RA) patient of 75% can occur osteoclasia in two years in morbidity, and the patient up to 80% occurred deformity after ill 20 years; Having in work capacity patient, have an appointment 1/3 RA patient's disability in 2 years after morbidity.
Holder method is for cloth (tofacitinib), i.e. 3-((3R, 4R)-4-methyl-3-(methyl (7H-pyrrolo-[2,3-d] pyrimidine-4-yl) amino send pyridine-1-base)-3-oxypropionitrile, be Pfizer research and development a kind of new oral JAK pathway inhibitor, for methotrexate for treatment response insufficient or in not tolerating to the treatment of the adult patient of severe active rheumatoid arthritis.With other RA medicines of Most current mainly act on extracellular target spot unlike, holder method for cloth with intracellular signal transduction path for target spot, act on the core of cytokine network.Holder method is 5 ~ 100 times to JAK1 and JAK2 for the inhibition strength of cloth to JAK3.Under dose therapeutically effective, holder method suppresses, to JAK2 without obvious restraining effect JAK1 part for cloth.On November 6th, 2012, the holder method developed by Pfizer Inc. is gone on the market by FDA (Food and Drug Adminstration) (FDA) approval for cloth Citrate trianion (trade(brand)name: Xeljanz).
Describe in such as Chinese patent CN1195755A, CN101233138A and CN1729192A about the preparation method of Citric Acid holder method for cloth in prior art, the full text of above-mentioned patent (patent application) is incorporated into herein as a reference.The method disclosed in above-mentioned patent documentation is all generate holder method for cloth by the derivatives reaction of N-methyl-N-((3R, 4R)-4-methyl piperidine-3-base)-7H-pyrrolo-[2,3-D] pyrimidine-4-amine and cyanoacetic acid.Visible, N-methyl-N-((3R, 4R)-4-methyl piperidine-3-base)-7H-pyrrolo-[2,3-D] pyrimidine-4-amine compound is the key intermediate of synthesis holder method for cloth, its purity directly can affect quality and the productive rate that Citric Acid holder method replaces cloth.
The preparation of N-methyl-N-((3R, 4R)-4-methyl piperidine-3-base)-7H-pyrrolo-[2,3-D] pyrimidine-4-amine (formula A compound) is normally prepared by hydrogenation.The preparation method of the compd A reported in the patent CN1195755C that Pfizer has obtained the authorization in China and pending application application CN1729192A is identical.The method disclosed in above-mentioned patent (patent application) is all obtained by compd B hydrogenation debenzylation.
Specifically, Chinese patent CN1195755C discloses and is dissolved in 15ml ethanol by 0.7g compd B, adds 1.5ml 2M hydrochloric acid, and then adds 0.5g 20% palladium hydroxide carbon.Under 50psi (0.35MPa) hydrogen pressure, at room temperature by mixture vibration (Parr-vibrator) 2 days, filter, filter vacuum is concentrated into dry.Utilize column chromatography (SiO
2, CH
2cl
2: CH
3oH=95:5) purifying obtains 0.48g target product, and yield is 90%.This reaction conditions is gentle, but the reaction times is long, and just will can obtain target product by column chromatography, is not suitable for suitability for industrialized production.
In addition, report two kinds of hydrogenation conditions in the patent family application CN101233138A that Pfizer applies in China, it is incorporated into herein as a reference in full.In the two kinds of hydrogenation conditions disclosed in CN101233138A, wherein a kind of sloughs pyrimidine chlorine in ring atom by Compound C by hydrogenation debenzylation simultaneously and obtain the compound of formula A.
Specifically, in CN101233138A, the concrete a kind of hydrogenation conditions disclosed is in 500ml hydrogenation reaction cauldron, add 5g palladium hydroxide carbon (20%), 200ml water and 50g Compound C, hydrogen exchange, heat up heating, under 50psi (0.35MPa) pressure, react at 70-75 DEG C, detect absorption of hydrogen situation, until 1h no hydrogen consumes, by reactor cooling to 20-30 DEG C, Filtration of catalyst, filtrate carries out subsequent processes.This hydrogenation conditions take water as reaction solvent, and reaction terminates rear Filtration of catalyst, but needs steaming to dewater to obtain target compound, and water not easily evaporate to dryness, make product purity lower.
In CN101233138A, the concrete another kind of hydrogenation conditions disclosed first is sloughed by the benzenesulfonyl on pyrrole ring in the basic conditions by Compound D, again with palladium hydroxide carbon for catalyzer, the acetic acid of amount such as to add, with water: Virahol (V:V=1:4) solution is reaction solvent, under 50psi (0.35MPa) hydrogen pressure, react at 45-55 DEG C, detect absorption of hydrogen situation, until 1h no hydrogen consumes, by reactor cooling to 20-30 DEG C, Filtration of catalyst, add alkali lye, heating is steamed except Virahol, add 2-methyltetrahydrofuran again, heating and separating water layer, steam except 2-methyltetrahydrofuran, add toluene, concentrated, cooling leaves standstill, separate out solid, filtration obtains compd A, yield is 83.7%.But this post-reaction treatment process is loaded down with trivial details, but also introduces solvent toluene.
In above-mentioned method for hydrogenation, relative to compd B and Compound D, the preparation of chlorine-containing compound C is more easy, and yield is higher (can reach 95%-100%) also.But prepare in the hydrogenation of compd A above-mentioned by Compound C, utilize water for reaction solvent.Thus after the completion of reaction, after Filtration of catalyst, also need steaming to dewater and obtain target compound.But water is evaporate to dryness not easily, thus make product purity lower.Therefore, also needing to provide a kind of is that starting material replaces the simple and easy to do of cloth midbody compound A and the method that productive rate is high to prepare holder method by Compound C.
Summary of the invention
Main purpose of the present invention is to provide a kind of N-methyl-N-((3R, 4R)-4-methyl piperidine-3-base)-7H-pyrrolo-[2,3-D] pyrimidine-4-amine (holder method for cloth intermediate) preparation method and utilize it to prepare the method for holder method for cloth or its salt, to provide a kind of simple and holder method that productive rate is high for the preparation method of cloth intermediate.
For this reason, provide the method for a kind of preparation formula (I) compound in the present invention,
The method comprises the compound making formula (II)
Be dissolved in the mixed solvent system of acid solvent and organic solvent, and carry out hydrogenation under the existence of palladium carbon or platinum C catalyst, thus obtain formula (I) compound.Wherein, relative to the molar weight of formula (II) compound, the relative molecular weight of described catalyzer is 0.03 ~ 0.08.
As described above, in the method for hydrogenation of prior art, hydrogen pressure is at 50psi (0.35MPa) pressure.The present inventor finds, in the preparation of formula (I) compound, utilize palladium carbon or platinum carbon to replace palladium hydroxide carbon to be catalyzer, reaction also can normally be carried out.
The present inventor also finds, in certain embodiments of the present invention, hydrogenation pressure can react in the scope of 0.1MPa ~ 0.3MPa.In other words, in the method for the invention, hydrogen pressure does not need to reach 50psi (0.35MPa), and the reaction times can complete at 12-24h.Compared to the hydrogenation conditions of patent prior art (such as CN1195755C and CN101233138A), reduce reaction cost to a certain extent.
The present inventor also finds, adds acid solvent and contribute to improving reaction efficiency in the preparation of formula (I) compound.In certain embodiments of the present invention, relative to the molar weight of formula (II) compound, this acid solvent is with H
+the relative molecular weight of meter is 1 ~ 3, preferably 1.5 ~ 2.This acid solvent is mineral acid or organic acid.In a particular embodiment, mineral acid is selected from hydrochloric acid, sulfuric acid, or their combination, preferred hydrochloric acid; Organic acid is selected from Glacial acetic acid, formic acid, trifluoroacetic acid, or their combination.
In a kind of preferred implementation of the method for the invention, mineral acid is hydrochloric acid or sulfuric acid, and organic acid is Glacial acetic acid, formic acid, trifluoroacetic acid.
The present inventor also finds, utilizes organic solvent, and such as ethylene glycol, Virahol, propyl alcohol, acetonitrile, methyl alcohol, acetone etc. replace water as reaction solvent, and this hydrogenation can carry out better.Wherein, relative to the quality of formula (II) compound, this consumption of organic solvent is 5ml/g ~ 10ml/g.Not containing water in the reaction solvent of the application, make follow-up treatment step easier.Such as, after completion of the reaction, by heat filtering removing catalyzer, steam except partial solvent, at room temperature leave standstill, separate out solid, after filtration, can target product be obtained.Method of the present invention can not need to steam the additional step dewatered, and both improves reaction efficiency, turn improves the purity of product.
In a kind of preferred implementation of the method for the invention, organic solvent is ethanol, methyl alcohol, propyl alcohol, ethylene glycol, Virahol, acetonitrile, acetone.In the especially preferred embodiment of one, organic solvent is acetonitrile.
In a kind of embodiment of the method for the invention, formula (I) compound utilizing method of the present invention to prepare is separated out from reaction soln, and its purity is greater than 97.5%.
Present invention also offers utilization and prepare according to formula (I) compound prepared by claim method of the present invention the method that holder method replaces cloth or its pharmacologically acceptable salt.In a kind of embodiment of the method for the invention, holder method is that holder method is for cloth citrate for the salt of cloth.The holder method utilizing method of the present invention to prepare can be used for treating moderate that is insufficient to methotrexate for treatment response or that do not tolerate to severe active rheumatoid arthritis (RA) adult patient for cloth or its pharmacologically acceptable salt.
Compared with the preparation method of the compd A disclosed in prior art, method of the present invention in lower reaction pressure condition, such as, can be reacted under (being low to moderate the hydrogen pressure of 0.1MPa).And it is simple and easy to do to have reacted the rear process to product.Such as, after heat filtering removing catalyzer, filtrate at room temperature leaves standstill and separates out solid, and filtration can obtain target product.The preparation process that method of the present invention overcomes compd A in prior art is complicated, and the defect that the production cycle is long reduces production cost, is suitable for large-scale industrial production.And replace in preparation holder method in the subsequent treatment process of cloth pharmacologically acceptable salt (if Citric Acid holder method is for cloth), the midbody compound utilizing the method for the invention to prepare can reduce the introducing of impurity to a certain extent.
Accompanying drawing explanation
The Figure of description forming a application's part is used to provide a further understanding of the present invention, and schematic description and description of the present invention, for explaining the present invention, does not form inappropriate limitation of the present invention.In the accompanying drawings:
Fig. 1 is the mass spectrum of formula I prepared by a kind of embodiment of the inventive method;
Fig. 2 is the hydrogen nuclear magnetic resonance spectrogram of formula I prepared by a kind of embodiment of the inventive method;
Fig. 3 is the carbon-13 nmr spectra figure of formula I prepared by a kind of embodiment of the inventive method.
Embodiment
It should be noted that, when not conflicting, the embodiment in the application and the feature in embodiment can combine mutually.Below with reference to the accompanying drawings and describe the present invention in detail in conjunction with the embodiments.Unless otherwise expressly defined, those skilled in the art should think that the technical term of chemistry used during full text herein describes have the usual implication used in this area.
In the method disclosed by Chinese patent CN1195755C, use ethanol as organic solvent, and use palladium hydroxide carbon as catalyzer, under the hydrogen pressure of 0.35Mpa, carry out hydrogenation.Although compared to other technologies scheme of the prior art, this reaction conditions is gentleer, and the yield of product can reach 90%, the reaction times long (such as, needing at room temperature oscillatory reaction 2 days).And just to can obtain target product by column chromatography, be not suitable for suitability for industrialized production.In the technical scheme of the application, have adjusted the consumption of organic solvent and catalyzer, make it possible under lower reaction pressure, obtain with the shorter reaction times target product that purity is greater than 97.5%, thus more economically, be suitable for the needs of large-scale industrial production.
In the method disclosed by Chinese patent application CN101233138A, use water as solvent, this makes the step also needing additionally to remove water after completion of the reaction.This extra step not only time and effort consuming, and water is not easy evaporate to dryness, thus make the purity of product lower.By contrast, the application adopts and does not use water as solvent, thus avoids the extra step removing water, while enhancing productivity, obtains higher product purity.
According to method provided by the present invention, in the hydrogenation reaction cauldron of drying, add the mixed solvent system of formula (II) compound and acid solvent and organic solvent.Be stirred to after dissolving completely, then add palladium carbon or platinum C catalyst.First by the air in nitrogen replacement reactor at least three times, then use nitrogen in hydrogen exchange reactor at least three times.Under the hydrogen pressure of about 0.1MPa to about 0.3MPa, reactor is heated to 70 DEG C-75 DEG C, and sustained reaction 8-9h.
Then, in Büchner funnel, add about diatomite, and soak with organic solvent.After reaction terminates, reaction soln is transferred to Büchner funnel while hot, vacuum is revolved and is steamed filtrate, residue about 1/2 solvent.Be cooled to room temperature afterwards, and hold over night.Filtration obtains solid, and with organic solvent washing, obtains light yellow solid.Then carry out vacuum-drying 4-5h, namely obtain the compound of title formula (I).
Following examples are only make for illustrational object, instead of limit the scope of the invention by any way, in the following example, relative molecular weight about catalyzer and acid solvent all refers to the relative molecular weight of the molar weight based on formula (II) compound, and its unit is mol/mol.
Embodiment 1
The preparation of N-methyl-N-((3R, 4R)-4-methyl piperidine-3-base)-7H-pyrrolo-[2,3-D] pyrimidine-4-amine (formula I)
35g Compound II per, 175ml acetonitrile, 142ml hydrochloric acid (1mol/L, relative molecular weight is 1.5) is added in the hydrogenation reaction cauldron of the 500ml of drying.Be stirred to after dissolving completely, then add 3.98g Pd (OH)
2/ C (commodity are called palladium hydroxide/carbon, and purchased from Beijing lark prestige Science and Technology Ltd., wherein palladium content is 20%, and moisture 50%, relative molecular weight is 0.03).First by the air in nitrogen replacement reactor three times, then use nitrogen in hydrogen exchange reactor three times, under 0.1MPa hydrogen pressure, reactor is heated to 70 DEG C-75 DEG C, and sustained reaction 9h.
In Büchner funnel, add the diatomite that about 3cm is high, and soak with acetonitrile.After reaction terminates, reaction soln is transferred to Büchner funnel while hot, vacuum is revolved and is steamed filtrate, and residue about 1/2 solvent, is cooled to room temperature, and hold over night.Filtration obtains solid, and with acetonitrile wash twice, obtains light yellow solid.Vacuum-drying 4-5h at 50 DEG C, obtains 22g title compound, and HPLC purity is 99.30%, and yield is 90%.
The mensuration of N-methyl-N-((3R, 4R)-4-methyl piperidine-3-base)-7H-pyrrolo-[2,3-D] pyrimidine-4-amine (formula I) prepared by embodiment 1.
The mass spectrum of formula I prepared by a kind of embodiment that Fig. 1 shows the inventive method.Fig. 2 is the hydrogen nuclear magnetic resonance spectrogram of formula I prepared by a kind of embodiment of the inventive method.Fig. 3 is the carbon-13 nmr spectra of formula I prepared by a kind of embodiment of the inventive method.
Provide compound with reference to the accompanying drawings to confirm: Compound I: HNMR (400HMZ, DMSO) δ (ppm): 12.97 (s,
1h, NH), 9.99 (s,
1h, NH), 8.46 (s,
1h, CH), 7.48 (s,
1h, CH), 6.91 (s,
1h, CH), 5., 21 (s,
1h, CH), 3.65-3.67 (m, 1H, CH
2), 3.38 (s,
3h, CH
3), 3.16 (m,
1h, CH
2), 2.99 (m,
1h, CH
2), 2.46 (m,
1h, CH), 2.28 (m,
1h, CH
2), 1.69,1.66 (d,
1h, CH
2), 1.13 (s,
3h, CH
3); CNMR (400HMZ, DMSO) δ (ppm): 156.72,151.59,150.51,120.68,102.12,101.61,53.67,43.57,40.30,33.95,30.92,30.74,13.27.ESI-MS：m/z 245。
Embodiment 2
The preparation of N-methyl-N-((3R, 4R)-4-methyl piperidine-3-base)-7H-pyrrolo-[2,3-D] pyrimidine-4-amine (formula I): with reference to embodiment 1 is wherein that 1mol/L sulfuric acid is (with H by 95ml concentration
+meter, relative molecular weight is 2) replace hydrochloric acid as mineral acid, replace 175ml acetonitrile as organic solvent with 350ml ethanol, and hydrogen pressure is 0.3MPa.Reaction times is 9h, and the HPLC purity of product is 98.98%, and yield is 83%.
Embodiment 3
N-methyl-N-((3R, 4R)-4-methyl piperidine-3-base)-7H-pyrrolo-[2,3-D] preparation of pyrimidine-4-amine (formula I): with reference to embodiment 1, (commodity are called platinum carbon wherein to use 11.05g platinum carbon, purchased from Beijing lark prestige reagent company limited, platinum content is 5%, and relative molecular weight is 0.03) replace palladium carbon as catalyzer.Reaction times is 8h, HPLC purity is 99.32%, and yield is 92%.
Embodiment 4
The preparation of N-methyl-N-((3R, 4R)-4-methyl piperidine-3-base)-7H-pyrrolo-[2,3-D] pyrimidine-4-amine (formula I): with reference to embodiment 1 is wherein that 3mol/L sulfuric acid is (with H by 47ml concentration
+meter, relative molecular weight is 3) replace hydrochloric acid as mineral acid, replace 175ml acetonitrile as organic solvent with 250ml ethylene glycol, use 10.61g palladium-carbon catalyst (relative molecular weight is 0.08), and hydrogen pressure is 0.2MPa.Reaction times is 8.5h, HPLC purity is 98.89%, and yield is 82%.
Embodiment 5
N-methyl-N-((3R, 4R)-4-methyl piperidine-3-base)-7H-pyrrolo-[2,3-D] preparation of pyrimidine-4-amine (formula I): with reference to embodiment 1, wherein use 19ml concentration for 5mol/L Glacial acetic acid is (with H
+meter, relative molecular weight is 1) as organic acid.With 5.30g palladium carbon (relative molecular weight is 0.04) as catalyzer, replace 175ml acetonitrile as organic solvent with 175ml acetone, and hydrogen pressure is the 0.2MPa reaction times be 8h, HPLC purity is 97.68%, yield is 82%.
Embodiment 6
The preparation of N-methyl-N-((3R, 4R)-4-methyl piperidine-3-base)-7H-pyrrolo-[2,3-D] pyrimidine-4-amine (formula I): with reference to embodiment 1, wherein uses 95ml concentration for 2mol/L formic acid is (with H
+meter, relative molecular weight is 2), as organic acid, replace 175ml acetonitrile as organic solvent with 210ml methyl alcohol, use 4.38g palladium-carbon catalyst (relative molecular weight is 0.033), and hydrogen pressure is outside 0.3MPa.Reaction times is 8.5h, HPLC purity is 97.93%, and yield is 80%.
Embodiment 7
The preparation of N-methyl-N-((3R, 4R)-4-methyl piperidine-3-base)-7H-pyrrolo-[2,3-D] pyrimidine-4-amine (formula I): with reference to embodiment 1, wherein uses 32ml concentration for 3mol/L formic acid is (with H
+meter, relative molecular weight is 1) as organic acid, wherein use 18.48g platinum carbon (relative molecular weight is 0.05), replace 175ml acetonitrile as organic solvent with 175ml acetone, and hydrogen pressure is 0.2MPa.Reaction times is 7h, HPLC purity is 97.89%, and yield is 83%.
Embodiment 8
The preparation of N-methyl-N-((3R, 4R)-4-methyl piperidine-3-base)-7H-pyrrolo-[2,3-D] pyrimidine-4-amine (formula I): with reference to embodiment 1, wherein uses 95ml concentration for 3mol/L hydrochloric acid is (with H
+meter, relative molecular weight is 3) as organic acid, with wherein using 10.60g palladium carbon (relative molecular weight is 0.08) as catalyzer, replace 175ml acetonitrile as organic solvent with 210ml acetone, and hydrogen pressure is 0.3MPa.Reaction times is 9h, HPLC purity is 98.72%, and yield is 85%.
Productive rate and the purity of hydrogenation condition in embodiment 1-7 and product have been shown in following table 1.
The productive rate of table 1 hydrogenation condition and product and purity
Can find out from the result of above-described embodiment, utilize the compound of method preparation formula I of the present invention simple and easy to do, and reaction efficiency is high and productive rate is high.Such as, using 1M hydrochloric acid as mineral acid and using palladium carbon as in the embodiment 1 of catalyzer, the pressure of hydrogenation is only 0.1MPa, and the reaction times is under the reaction conditions only 9 hours, the yield of product can reach 90%, and product purity can reach 99.30%.And as described above, art methods needs at room temperature oscillatory reaction about 2 days usually, and method of the present invention significantly improves reaction efficiency.The holder method that method of the present invention overcomes prior art is complicated for the preparation process in cloth preparation method, and the defect that the production cycle is long is suitable for large-scale industrial production.And preparing Citric Acid holder method in cloth subsequent treatment process, the midbody compound utilizing the method for the invention to prepare in the introducing reducing impurity, can be conducive to the application at pharmaceutical field.
The foregoing is only the preferred embodiments of the present invention, be not limited to the present invention, for a person skilled in the art, the present invention can have various modifications and variations.Within the spirit and principles in the present invention all, any amendment done, equivalent replacement, improvement etc., all should be included within protection scope of the present invention.
Claims (9)
1. for the preparation of a method for formula (I) compound,
It is characterized in that, said method comprising the steps of:
Make the compound of formula (II)
Be dissolved in the mixed solvent system of acid solvent and organic solvent, under the existence of palladium carbon or platinum C catalyst, carry out hydrogenation, thus obtain described formula (I) compound, the pressure of described hydrogenation is in the scope of 0.1Mpa-0.3Mpa.
2. method according to claim 1, is characterized in that, relative to the molar weight of formula (II) compound, the relative molecular weight of described catalyzer is 0.03 ~ 0.08, and described acid solvent is with H
+the relative molecular weight of meter is 1 ~ 3.
3. method according to claim 2, is characterized in that, relative to the quality of formula (II) compound, described consumption of organic solvent is 5ml/g ~ 10ml/g.
4. method according to claim 1, is characterized in that, described acid solvent is organic acid or mineral acid or their combination; Described organic solvent is selected from ethanol, ethylene glycol, Virahol, propyl alcohol, acetonitrile, methyl alcohol, acetone, or their combination.
5. method according to claim 4, is characterized in that, described mineral acid is selected from hydrochloric acid or sulfuric acid, or their combination; Described organic acid is selected from Glacial acetic acid, formic acid or trifluoroacetic acid, or their combination.
6. method according to any one of claim 1 to 5, is characterized in that, purity >=97.5% of described formula (I) compound.
7. formula (I) compound utilizing method according to any one of claim 1 to 6 to prepare.
8. holder method prepared by formula (I) compound utilizing method according to any one of claim 1 to 6 to prepare is for cloth or its pharmacologically acceptable salt.
9. the holder method utilizing method according to claim 8 to prepare is for cloth or its pharmacologically acceptable salt, and wherein, described holder method is that holder method is for cloth citrate for the salt of cloth.
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Cited By (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104987339A (en) * | 2015-07-29 | 2015-10-21 | 张燕梅 | Synthesis method of tofacitinib citrate |
| CN105732641A (en) * | 2016-03-28 | 2016-07-06 | 南通常佑药业科技有限公司 | Preparation method of JAKs inhibitor drug tofacitinib |
| CN106188064A (en) * | 2016-07-07 | 2016-12-07 | 国药集团容生制药有限公司 | A kind of preparation method of N methyl N ((3R, 4R) 4 picoline 3 base) 7H pyrrolo-[2,3 d] pyrimidine 4 amine |
| CN106366076A (en) * | 2016-08-29 | 2017-02-01 | 河北国龙制药有限公司 | Posaconazole synthesis method |
| CN110343113A (en) * | 2019-08-07 | 2019-10-18 | 山东鲁抗医药股份有限公司 | Preparation method of tofacitinib intermediate |
| CN111995627A (en) * | 2020-09-15 | 2020-11-27 | 山东金城昆仑药业有限公司 | Tofacitinib citrate intermediate and preparation method and application thereof |
-
2015
- 2015-03-21 CN CN201510124536.9A patent/CN104761555A/en active Pending
Non-Patent Citations (2)
| Title |
|---|
| 王铁英: "托法替尼柠檬酸盐(Tofacitinib)", 《中国药物化学杂志》 * |
| 赵方露等，: "枸橼酸托法替尼的合成", 《中国医药工业杂志》 * |
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| CN105732641A (en) * | 2016-03-28 | 2016-07-06 | 南通常佑药业科技有限公司 | Preparation method of JAKs inhibitor drug tofacitinib |
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