CN109336892B - Preparation method of tofacitinib impurity - Google Patents
Preparation method of tofacitinib impurity Download PDFInfo
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- CN109336892B CN109336892B CN201811435907.5A CN201811435907A CN109336892B CN 109336892 B CN109336892 B CN 109336892B CN 201811435907 A CN201811435907 A CN 201811435907A CN 109336892 B CN109336892 B CN 109336892B
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- 239000004012 Tofacitinib Substances 0.000 title claims abstract description 64
- UJLAWZDWDVHWOW-YPMHNXCESA-N tofacitinib Chemical compound C[C@@H]1CCN(C(=O)CC#N)C[C@@H]1N(C)C1=NC=NC2=C1C=CN2 UJLAWZDWDVHWOW-YPMHNXCESA-N 0.000 title claims abstract description 64
- 229960001350 tofacitinib Drugs 0.000 title claims abstract description 63
- 238000002360 preparation method Methods 0.000 title claims abstract description 59
- 239000012535 impurity Substances 0.000 title abstract description 10
- 150000001875 compounds Chemical class 0.000 claims abstract description 49
- 238000000034 method Methods 0.000 claims abstract description 24
- 238000006243 chemical reaction Methods 0.000 claims description 81
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 57
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims description 37
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 claims description 33
- 238000000605 extraction Methods 0.000 claims description 28
- 239000002253 acid Substances 0.000 claims description 25
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 claims description 24
- 238000010438 heat treatment Methods 0.000 claims description 23
- 239000000126 substance Substances 0.000 claims description 18
- 230000003472 neutralizing effect Effects 0.000 claims description 15
- 239000003960 organic solvent Substances 0.000 claims description 14
- 229940098779 methanesulfonic acid Drugs 0.000 claims description 12
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 10
- 238000002425 crystallisation Methods 0.000 claims description 10
- 230000008025 crystallization Effects 0.000 claims description 10
- 229960001701 chloroform Drugs 0.000 claims description 9
- 239000007788 liquid Substances 0.000 claims description 9
- 239000008346 aqueous phase Substances 0.000 claims description 8
- ZAFNJMIOTHYJRJ-UHFFFAOYSA-N Diisopropyl ether Chemical compound CC(C)OC(C)C ZAFNJMIOTHYJRJ-UHFFFAOYSA-N 0.000 claims description 6
- 239000012074 organic phase Substances 0.000 claims description 6
- LMBFAGIMSUYTBN-MPZNNTNKSA-N teixobactin Chemical compound C([C@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H](CCC(N)=O)C(=O)N[C@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H]1C(N[C@@H](C)C(=O)N[C@@H](C[C@@H]2NC(=N)NC2)C(=O)N[C@H](C(=O)O[C@H]1C)[C@@H](C)CC)=O)NC)C1=CC=CC=C1 LMBFAGIMSUYTBN-MPZNNTNKSA-N 0.000 claims description 6
- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical group ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 claims description 5
- 230000015572 biosynthetic process Effects 0.000 claims description 5
- 238000003786 synthesis reaction Methods 0.000 claims description 5
- 239000002904 solvent Substances 0.000 claims description 4
- 238000004519 manufacturing process Methods 0.000 claims description 2
- 238000000638 solvent extraction Methods 0.000 claims 1
- 230000008569 process Effects 0.000 abstract description 7
- 239000003814 drug Substances 0.000 abstract description 6
- 229940079593 drug Drugs 0.000 abstract description 5
- 239000013558 reference substance Substances 0.000 abstract description 4
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 42
- 238000003756 stirring Methods 0.000 description 33
- 239000007787 solid Substances 0.000 description 27
- 238000004128 high performance liquid chromatography Methods 0.000 description 24
- HTSGKJQDMSTCGS-UHFFFAOYSA-N 1,4-bis(4-chlorophenyl)-2-(4-methylphenyl)sulfonylbutane-1,4-dione Chemical compound C1=CC(C)=CC=C1S(=O)(=O)C(C(=O)C=1C=CC(Cl)=CC=1)CC(=O)C1=CC=C(Cl)C=C1 HTSGKJQDMSTCGS-UHFFFAOYSA-N 0.000 description 21
- 230000006872 improvement Effects 0.000 description 19
- 238000001816 cooling Methods 0.000 description 14
- 238000001914 filtration Methods 0.000 description 14
- 238000001035 drying Methods 0.000 description 13
- 238000006386 neutralization reaction Methods 0.000 description 11
- 239000000047 product Substances 0.000 description 10
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 8
- 230000000052 comparative effect Effects 0.000 description 8
- 238000001514 detection method Methods 0.000 description 8
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 7
- 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 6
- 239000012071 phase Substances 0.000 description 6
- 238000006460 hydrolysis reaction Methods 0.000 description 5
- 238000000926 separation method Methods 0.000 description 5
- NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 description 4
- 230000021736 acetylation Effects 0.000 description 4
- 238000006640 acetylation reaction Methods 0.000 description 4
- 239000002274 desiccant Substances 0.000 description 4
- 239000002994 raw material Substances 0.000 description 4
- 238000005406 washing Methods 0.000 description 4
- 230000000694 effects Effects 0.000 description 3
- 230000020477 pH reduction Effects 0.000 description 3
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 2
- 238000005160 1H NMR spectroscopy Methods 0.000 description 2
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 2
- 238000007126 N-alkylation reaction Methods 0.000 description 2
- 238000003763 carbonization Methods 0.000 description 2
- MLIREBYILWEBDM-UHFFFAOYSA-N cyanoacetic acid Chemical compound OC(=O)CC#N MLIREBYILWEBDM-UHFFFAOYSA-N 0.000 description 2
- 238000006264 debenzylation reaction Methods 0.000 description 2
- 230000018044 dehydration Effects 0.000 description 2
- 238000006297 dehydration reaction Methods 0.000 description 2
- 238000002330 electrospray ionisation mass spectrometry Methods 0.000 description 2
- 238000007327 hydrogenolysis reaction Methods 0.000 description 2
- 230000007062 hydrolysis Effects 0.000 description 2
- 238000001819 mass spectrum Methods 0.000 description 2
- 150000002825 nitriles Chemical class 0.000 description 2
- 125000003386 piperidinyl group Chemical group 0.000 description 2
- 238000000746 purification Methods 0.000 description 2
- 239000007858 starting material Substances 0.000 description 2
- SYIKUFDOYJFGBQ-YLAFAASESA-N tofacitinib citrate Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O.C[C@@H]1CCN(C(=O)CC#N)C[C@@H]1N(C)C1=NC=NC2=C1C=CN2 SYIKUFDOYJFGBQ-YLAFAASESA-N 0.000 description 2
- UXVMQQNJUSDDNG-UHFFFAOYSA-L Calcium chloride Chemical compound [Cl-].[Cl-].[Ca+2] UXVMQQNJUSDDNG-UHFFFAOYSA-L 0.000 description 1
- KRKNYBCHXYNGOX-UHFFFAOYSA-K Citrate Chemical compound [O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O KRKNYBCHXYNGOX-UHFFFAOYSA-K 0.000 description 1
- 229940123241 Janus kinase 3 inhibitor Drugs 0.000 description 1
- FBOZXECLQNJBKD-ZDUSSCGKSA-N L-methotrexate Chemical compound C=1N=C2N=C(N)N=C(N)C2=NC=1CN(C)C1=CC=C(C(=O)N[C@@H](CCC(O)=O)C(O)=O)C=C1 FBOZXECLQNJBKD-ZDUSSCGKSA-N 0.000 description 1
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 1
- 239000006227 byproduct Substances 0.000 description 1
- 239000001110 calcium chloride Substances 0.000 description 1
- 229910001628 calcium chloride Inorganic materials 0.000 description 1
- 235000011148 calcium chloride Nutrition 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 238000009833 condensation Methods 0.000 description 1
- 230000005494 condensation Effects 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 150000002576 ketones Chemical class 0.000 description 1
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 1
- 235000019341 magnesium sulphate Nutrition 0.000 description 1
- 229960000485 methotrexate Drugs 0.000 description 1
- 125000000250 methylamino group Chemical group [H]N(*)C([H])([H])[H] 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- XRIARWQZLGCQDM-KOLCDFICSA-N n-methyl-n-[(3r,4r)-4-methylpiperidin-3-yl]-7h-pyrrolo[2,3-d]pyrimidin-4-amine Chemical compound C[C@@H]1CCNC[C@@H]1N(C)C1=NC=NC2=C1C=CN2 XRIARWQZLGCQDM-KOLCDFICSA-N 0.000 description 1
- 125000002560 nitrile group Chemical group 0.000 description 1
- 230000003647 oxidation Effects 0.000 description 1
- 238000007254 oxidation reaction Methods 0.000 description 1
- 150000003053 piperidines Chemical group 0.000 description 1
- 230000009467 reduction Effects 0.000 description 1
- 230000004044 response Effects 0.000 description 1
- 206010039073 rheumatoid arthritis Diseases 0.000 description 1
- 238000007086 side reaction Methods 0.000 description 1
- 229910052938 sodium sulfate Inorganic materials 0.000 description 1
- 235000011152 sodium sulphate Nutrition 0.000 description 1
- 238000003860 storage Methods 0.000 description 1
- 229960004247 tofacitinib citrate Drugs 0.000 description 1
- FUSNMLFNXJSCDI-UHFFFAOYSA-N tolnaftate Chemical compound C=1C=C2C=CC=CC2=CC=1OC(=S)N(C)C1=CC=CC(C)=C1 FUSNMLFNXJSCDI-UHFFFAOYSA-N 0.000 description 1
- 229960004880 tolnaftate Drugs 0.000 description 1
- 238000010626 work up procedure Methods 0.000 description 1
- 229940039916 xeljanz Drugs 0.000 description 1
Classifications
-
- 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
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention discloses a preparation method of tofacitinib impurity, which comprises the following synthetic route
Description
Technical Field
The invention relates to a preparation method of chemicals for researching the quality of chemical bulk drugs, in particular to a preparation method of related substances of tofacitinib (chemical name: 3- { (3R,4R) -4-methyl-3- [ methyl (7H-pyrrolo [2,3-d ] pyrimidin-4-yl) amino ] piperidin-1-yl } -3-oxopropanenitrile).
Background
Tofacitinib (pharmaceutical citrate, trade name: Xeljanz) has a structural formula of
Is a novel oral JAK3 inhibitor developed by American fevere pharmacy, is approved by FDA to be marketed in 11 months of 2012, and can be used for medium and severe active rheumatoid arthritis adult patients with insufficient or intolerant response to methotrexate treatment.
Acetylation of the N-nitrile on the piperidine ring is an essential step in the preparation of tofacitinib. In view of efficiency and cost control in practical production, a strategy of preparing its intermediate ((3R,4R) -4-methyl-3- [ methyl (7H-pyrrolo [2,3-d ] pyrimidin-4-yl) amino ] piperidine) and then conducting N-nitrile acetylation on the piperidine ring is frequently employed. The prior published reports of the tofacitinib synthesis process are mainly as follows:
method one (US6627754, CN1409712C)
The method takes benzyl-protected 4-methyl-piperidine-3-ketone as an initial raw material, firstly performs reduction and ammoniation reaction on methylamino through ketone, and then performs resolution after N-alkylation, hydrogenolysis debenzylation and piperidine N-nitrile acetylation to obtain tofacitinib.
Method two (WO2007012953, CN101233138A)
The method takes 3-amido-4-methylpyridine as a raw material, obtains a substituted piperidine fragment protected by benzyl through 4 steps of reaction and 1 time of resolution, and then obtains tofacitinib through N-alkylation, hydrogenolysis debenzylation and piperidine N-nitrile acetylation.
There are also many publications (CN1195755C, CN106146517A, CN105440039A, CN101233138A, Chem Med Chem,2014:9(11),2516-2527, Tetrahedron Letters,2013:54(37),5096-5098, Journal of Medicinal Chemistry 2010:53(24),8468-8484) which use this synthesis strategy to prepare tofacitinib by dehydration condensation using cyanoacetic acid as acylating agent.
According to the published reports, the preparation process of tofacitinib is difficult to avoid strong acid environment, and hydrolysis to compound I exists
Compound II
The risk of (c). In addition, the stability research data of the raw material medicaments show that the tofacitinib citrate can be slowly degraded in the storage process to cause the compounds I and IIContinues to increase. Therefore, the two compounds belong to key related substances in the tofacitinib bulk drug, and it is necessary to provide a preparation method of the compound I, II so as to obtain a high-purity impurity research reference substance and use the high-purity impurity research reference substance for quality research of the tofacitinib bulk drug.
The process of preparing the compound I and the compound II by using tofacitinib relates to the hydrolysis reaction of a nitrile group of tofacitinib, but the reaction has strict requirements on reaction conditions, is easy to generate other impurities, and is difficult to effectively obtain the compound I and the compound II. How to simply and efficiently obtain the high-purity tolnaftate related substance compound I and compound II is a technical problem to be solved.
Disclosure of Invention
The invention aims to overcome the defects of the prior art and provides a method for preparing related impurities, namely compound I and compound II by utilizing tofacitinib.
The technical scheme adopted by the invention is as follows:
a method for preparing tofacitinib substances, the structural formula of the tofacitinib substances is shown as a formula I and a formula II,
the synthetic route is as follows:
the method comprises the following steps:
1) dissolving tofacitinib in an acid solution with the mass concentration of 50-60% or 80-90%, wherein the acid is one of sulfuric acid and methanesulfonic acid;
2) heating to 40-50 ℃ or 90-100 ℃ for reaction;
3) and (3) finishing the reaction, neutralizing, extracting and crystallizing to obtain the tofacitinib shown in the formula I and/or the formula II.
As a further improvement of the preparation method, the mass concentration of the acid used in the preparation process of the compound of the formula I is 50-60 percent; the mass concentration of the acid used in the preparation process of the compound of the formula II is 80-90%.
As a further improvement of the preparation method, the mass concentration of the acid used in the preparation process of the compound of the formula I is 55 percent; the mass concentration of the acid used in the preparation of the compound of formula II was 85%.
As a further improvement of the preparation method, the reaction temperature in the preparation process of the compound of the formula I is 40-50 ℃; the reaction temperature in the preparation process of the compound of the formula II is 90-100 ℃.
As a further improvement of the preparation method, the reaction temperature in the preparation process of the compound of the formula I is 50 ℃; the reaction temperature during the preparation of the compound of formula II is 90 ℃.
As a further improvement of the preparation method, neutralizing the reaction system of the compound shown in the formula I to pH 8-9, extracting by using an organic solvent, and taking an organic phase extraction liquid; or
Adding an organic solvent into a compound reaction system shown in the formula II, neutralizing to pH 8-9, and taking a water phase extraction liquid; and acidifying the aqueous phase extraction liquid to pH 3-4, and then extracting with an organic solvent.
As a further improvement of the preparation method, the organic solvent used in the extraction operation is selected from one of dichloromethane, trichloromethane and dichloroethylene; preferably dichloromethane.
As a further improvement of the preparation method, the crystallization solvent is selected from one of isopropyl ether and methyl tert-butyl ether; methyl tert-butyl ether is preferred.
The invention has the beneficial effects that:
the preparation method provided by the invention has the advantages of simple synthesis process, easy separation and purification of the product, high purity (purity is more than 98.0%) of the obtained product and the like. The compound I, II obtained by the preparation method can be used as an impurity reference substance of tofacitinib bulk drug and preparation for quality research and process research of related products.
Detailed Description
A method for preparing tofacitinib substance, the structural formula of tofacitinib substance is shown as formula I,
the synthetic route is as follows:
the method comprises the following steps:
1) dissolving tofacitinib in an acid solution with the mass concentration of 50-60%, wherein the acid is one of sulfuric acid and methanesulfonic acid;
2) heating to 40-50 ℃ for reaction;
3) and (4) finishing the reaction, neutralizing, extracting and crystallizing to obtain the tofacitinib substance shown in the formula I.
As a further improvement of the preparation method, the mass concentration of the acid used in the preparation process of the compound of the formula I is 50-60%.
As a further improvement of the above preparation process, the mass concentration of the acid used in the preparation of the compound of formula I is 55%.
As a further improvement of the preparation method, the reaction temperature in the preparation process of the compound of the formula I is 40-50 ℃.
As a further improvement of the above preparation process, the reaction temperature during the preparation of the compound of formula I is 50 ℃.
As a further improvement of the preparation method, after the reaction system of the compound shown in the formula I is neutralized to pH 8-9, an organic solvent is used for extraction, and an organic phase extraction liquid is taken.
A method for preparing tofacitinib substance, the structural formula of the tofacitinib substance is shown as a formula II,
the method comprises the following steps:
1) dissolving tofacitinib in an acid solution with the mass concentration of 80-90%, wherein the acid is one of sulfuric acid and methanesulfonic acid;
2) heating to 90-100 ℃ for reaction;
3) and (3) finishing the reaction, neutralizing, extracting and crystallizing to obtain the tofacitinib substance shown in the formula II.
As a further improvement of the preparation method, the mass concentration of the acid used in the preparation process of the compound of the formula II is 80-90%.
As a further improvement of the above preparation process, the mass concentration of the acid used in the preparation of the compound of formula II is 85%.
As a further improvement of the preparation method, the reaction temperature in the preparation process of the compound shown in the formula II is 90-100 ℃.
As a further improvement of the above preparation process, the reaction temperature during the preparation of the compound of formula II is 90 ℃.
As a further improvement of the preparation method, adding an organic solvent into a compound reaction system shown in the formula II, neutralizing to pH 8-9, and taking a water phase extraction liquid; and acidifying the aqueous phase extraction liquid to pH 3-4, and then extracting with an organic solvent.
The purpose of the neutralization is to increase the degree of separation of the product in the aqueous and organic phases. The pH does not significantly affect the purity of the product and can be appropriately adjusted as needed.
As a further improvement of the preparation method, the organic solvent used in the extraction operation is selected from one of dichloromethane, trichloromethane and dichloroethylene; preferably dichloromethane. The organic solvent used in the extraction operation has no significant effect on the purity of the product.
As a further improvement of the preparation method, the crystallization solvent is selected from one of isopropyl ether and methyl tert-butyl ether; methyl tert-butyl ether is preferred.
The present invention will be further described with reference to the following examples.
In the following examples, the concentration of the acid is a mass concentration unless otherwise specified. The added solid desiccant is removed by filtration by adding the solid desiccant to the extract to remove residual water therefrom. Solid desiccants are solid desiccants commonly used in the art and include, but are not limited to, sodium sulfate, magnesium sulfate, calcium chloride, and the like.
Preparation of Compound I
Example 1
1) Adding 3.12g (10mmol) of tofacitinib and 55% of sulfuric acid (75 ml) into a reaction bottle, heating to 50 ℃, and stirring for reaction for 7-8 hours;
2) confirming the reaction is complete by HPLC, cooling to 5-10 ℃, adding a sodium hydroxide solution (10%) for neutralization until the pH value is 8-9;
3) extracted three times with dichloromethane (50ml × 3);
4) the extract was dried, filtered, concentrated and then added with methyl t-butyl ether (25ml), and an off-white solid (compound I, 1.34g) was precipitated with slow stirring in a yield of 40.5%.
The detection shows that the purity of the white-like solid is 99.0 percent; mass spectra and nuclear magnetic data were as follows:
ESI-MS：m/z(M+H+)＝331.2；
1HNMR(500MHz，DMSO-d6)，δ(ppm)：1.00～1.02(d,5H)，1.53～1.84(m,2H)，2.34～2.43(m,1H)，3.21～3.32(m,5H)，3.50～3.52(t,1H)，3.62～3.71(m,1H)，3.77～3.92(d,1H)，6.55(s,1H)，6.95～7.02(d,1H)，7.13～7.14(d,1H)，7.42～7.49(d,1H)，8.10～8.12(d,1H)，11.64～11.70(d,1H)；
13CNMR(125MHz，DMSO-d6)，δ(ppm)：168.61，165.65，156.95，151.68，150.49，120.66，102.16，101.71，66.59，45.68，42.88，41.69，40.65，31.20，23.27，13.94。
example 2
Adding 3.12g (10mmol) of tofacitinib and 50% of methanesulfonic acid (80 ml) into a reaction bottle, heating to 50 ℃, stirring for reaction for 12 hours, cooling to 5-10 ℃ after confirming the reaction is complete by HPLC, adding a sodium hydroxide solution (10%) for neutralization to pH 8-9, extracting with dichloromethane (50ml × 3) for three times, drying, filtering and concentrating an extract, adding methyl tert-butyl ether (25ml), slowly stirring to separate out a white-like solid (compound I, 1.00g, purity 98.2%) and yield of 30.2%.
Example 3
Adding 3.12g (10mmol) of tofacitinib and 60-80 ml of sulfuric acid into a reaction bottle, heating to 40 ℃, stirring and reacting for 6-7 hours, cooling to 5-10 ℃ after confirming complete reaction by HPLC, adding 10% of sodium hydroxide solution to neutralize to pH 8-9, extracting for three times by trichloromethane (50ml × 3), drying, filtering and concentrating an extract, adding 25ml of methyl tert-butyl ether, slowly stirring to separate out a white-like solid (compound I, 0.85g, purity of 98.0%) and yield of 25.7%.
Example 4
Adding 1.60g (5mmol) of tofacitinib and 60% of methanesulfonic acid (40 ml) into a reaction bottle, heating to 50 ℃, stirring for reaction for 3-4 hours, cooling to 5-10 ℃ after HPLC (high performance liquid chromatography) confirms that the reaction is complete, adding a sodium hydroxide solution (10%) for neutralization to pH 8-9, extracting with dichloromethane (30ml × 3) for three times, drying, filtering and concentrating an extract, adding isopropyl ether (15ml), slowly stirring to separate out a white-like solid (compound I, 0.50g, purity of 98.0%), and yield of 30.2%.
Example 5
Adding 1.60g (5mmol) of tofacitinib and 50% of sulfuric acid (35 ml) into a reaction bottle, heating to 40 ℃, stirring for reaction for 12 hours, cooling to 5-10 ℃ after confirming the reaction is complete by HPLC, adding a sodium hydroxide solution (10%) for neutralization to pH 8-9, extracting with dichloromethane (20ml × 3) for three times, drying, filtering and concentrating an extract, adding methyl tert-butyl ether (20ml), slowly stirring to separate out an off-white solid (compound I, 0.60g, purity 98.5%) with yield of 36.2%.
Example 6
Adding 6.24g (20mmol) of tofacitinib and 50% of methanesulfonic acid (150 ml) into a reaction bottle, heating to 40 ℃, stirring for reaction for 7-8 hours, cooling to 5-10 ℃ after confirming the reaction is complete by HPLC, adding a sodium hydroxide solution (10%) for neutralization to pH 8-9, extracting with dichloromethane (100ml × 3) for three times, drying, filtering and concentrating an extract, adding methyl tert-butyl ether (50ml), slowly stirring to separate out a white-like solid (compound I, 1.95g, purity 98.9%) and yield 29.6%.
Example 7
Adding 6.24g (20mmol) of tofacitinib and 60-150 ml of sulfuric acid into a reaction bottle, heating to 50 ℃, stirring and reacting for 4-5 hours, cooling to 5-10 ℃ after confirming complete reaction by HPLC, adding 10% of sodium hydroxide solution to neutralize to pH 8-9, extracting for three times by dichloroethylene (100ml × 3), drying, filtering and concentrating an extract, adding 50ml of methyl tert-butyl ether, slowly stirring to separate out a white-like solid (compound I, 1.55g, purity of 98.3%) and yield of 23.5%.
Preparation of Compound II
Example 8
1) Adding 3.12g (10mmol) of tofacitinib and 85% of sulfuric acid (75 ml) into a reaction bottle, heating to 90 ℃, and stirring for reacting for 3-4 hours;
2) confirming the reaction is complete by HPLC, cooling to 5-10 ℃, adding 50ml of dichloromethane, and neutralizing with a sodium hydroxide solution (10%) until the pH value is 8-9;
3) acidifying the aqueous phase extract to pH 3-4, adding chloroform (50ml × 3) for extraction three times, drying the extract, filtering, concentrating, adding methyl tert-butyl ether (25ml), slowly stirring to separate out a white-like solid (compound II, 1.05 g) with a yield of 31.7%.
The purity of the white-like solid is 99.0% through detection, and the mass spectrum data and the nuclear magnetic data are respectively as follows:
ESI-MS：m/z(M+H+)＝332.2；
1HNMR(500MHz，DMSO-d6)，δ(ppm)：0.96～0.99(t,3H)，1.51～1.83(m,2H)，2.29～2.37(m,1H)，3.11～3.14(m,2H)，3.27～3.33(t,3H)，3.42～3.61(m,2H)，3.69～3.82(m,2H)，4.87～4.95(d,1H)，6.54(s,1H)，7.12(s,2H)，8.09～8.10(d,1H)，11.77(s,1H)。
13CNMR(125MHz，DMSO-d6)，δ(ppm)：170.11，167.92，157.08，151.67，150.46，120.63，102.16，101.72，55.99，46.32，45.86，43.14，41.36，31.63，30.95，14.32。
example 9
Adding 3.12g (10mmol) of tofacitinib and 80% of methanesulfonic acid (80% and 80ml) into a reaction bottle, heating to 100 ℃, stirring and reacting for 4-5 hours, cooling to 5-10 ℃ after HPLC (high performance liquid chromatography) confirms complete reaction, adding 50ml of dichloromethane, neutralizing to pH 8-9 with a sodium hydroxide solution (10%), taking a water phase extract, acidifying to pH 3-4, adding trichloromethane (50ml × 3) for extraction for three times, drying, filtering and concentrating the extract, adding 25ml of methyl tert-butyl ether (25ml), slowly stirring to separate out a white-like solid (a compound II, 0.83g and 98.2% purity), and obtaining the yield of 25.0%.
Example 10
Adding 3.12g (10mmol) of tofacitinib and 90-80 ml of methanesulfonic acid into a reaction bottle, heating to 90 ℃, stirring for reaction for 5-6 hours, cooling to 5-10 ℃ after confirming the reaction is complete by HPLC, adding 50ml of dichloromethane, neutralizing to pH 8-9 by using a sodium hydroxide solution (10%), taking a water phase extract, acidifying to pH 3-4, adding dichloromethane (50ml of × 3) for extraction for three times, drying, filtering and concentrating the extract, adding 25ml of methyl tert-butyl ether, slowly stirring to separate out a white-like solid (a compound II, 1.05g, the purity of 99.0%) and the yield of 31.8%.
Example 11
Adding 1.60g (5mmol) of tofacitinib and 80-35 ml of sulfuric acid into a reaction bottle, heating to 90 ℃, stirring and reacting for 8-9 hours, cooling to 5-10 ℃ after HPLC (high performance liquid chromatography) confirms that the reaction is complete, adding 25ml of dichloromethane, neutralizing to pH 8-9 with a sodium hydroxide solution (10%), taking an aqueous phase extract, acidifying to pH 3-4, adding trichloromethane (20ml × 3) for extraction for three times, drying, filtering and concentrating the extract, adding 20ml of methyl tert-butyl ether (20ml), slowly stirring to separate out a white-like solid (a compound II, 0.75g, the purity is 98.1%) and the yield is 42.4%.
Example 12
Adding 1.60g (5mmol) of tofacitinib and 90-35 ml of sulfuric acid into a reaction bottle, heating to 100 ℃, stirring and reacting for 2-3 hours, cooling to 5-10 ℃ after confirming complete reaction by HPLC, adding 25ml of dichloromethane, neutralizing to pH 8-9 by using a sodium hydroxide solution (10%), taking a water phase extract, acidifying to pH 3-4, adding dichloroethylene (25ml × 3) for extraction for three times, drying, filtering and concentrating the extract, adding 20ml of isopropyl ether, slowly stirring to separate out a light gray solid (compound II, 0.72g, purity of 98.2%) and yield of 43.7%.
Example 13
Adding 6.24g (20mmol) of tofacitinib and 80-150 ml of methanesulfonic acid into a reaction bottle, heating to 90 ℃, stirring for reaction for 5-6 hours, cooling to 5-10 ℃ after HPLC (high performance liquid chromatography) confirms that the reaction is complete, adding 100ml of dichloromethane, neutralizing to pH 8-9 with a sodium hydroxide solution (10%), taking a water phase extract, acidifying to pH 3-4, adding trichloromethane (100ml × 3) for extraction for three times, drying, filtering and concentrating the extract, adding 50ml of methyl tert-butyl ether, slowly stirring to separate out a white-like solid (a compound II, 1.82g, the purity is 99.1%) and the yield is 27.6%.
Example 14
Adding 6.24g (20mmol) of tofacitinib and 90-150 ml of methanesulfonic acid into a reaction bottle, heating to 100 ℃, stirring for reaction for 3-4 hours, cooling to 5-10 ℃ after HPLC (high performance liquid chromatography) confirms that the reaction is complete, adding 100ml of dichloromethane, neutralizing to pH 8-9 with a sodium hydroxide solution (10%), taking an aqueous phase extract, acidifying to pH 3-4, adding trichloromethane (100ml × 3) for extraction for three times, drying, filtering and concentrating the extract, adding 55ml of isopropyl ether, slowly stirring to separate out a light gray solid (compound II, 1.82g, purity 98.7%) and yield 24.3%.
Comparative example 1:
after tofacitinib 3.12g (10mmol) and sulfuric acid (40%, 75ml) were added to a reaction flask and stirred at room temperature (20-25 ℃) for reaction for 48 hours, no compound I/compound II was detected by LC-MS.
Comparative example 2:
adding 3.12g (10mmol) of tofacitinib and sulfuric acid (40%, 75ml) into a reaction bottle, heating to 40 ℃, stirring for reacting for 24 hours, and confirming a large amount of starting materials (tofacitinib) remained by HPLC detection; and (3) continuing to react for 24 hours, and performing post-treatment operations such as neutralization, extraction, concentration, crystallization and the like to obtain a white-like solid, wherein the white-like solid is identified as an impure compound I (the main component is tofacitinib) by LC-MS detection.
Comparative example 3:
adding 3.12g (10mmol) of tofacitinib and 50% of sulfuric acid (75 ml) into a reaction bottle, stirring and reacting for 24 hours at room temperature (20-25 ℃), and confirming that a large amount of starting raw materials (tofacitinib) remain by HPLC detection; and (3) continuing to react for 24 hours, and performing post-treatment operations such as neutralization, extraction, concentration, crystallization and the like to obtain a white-like solid, wherein the white-like solid is identified as an impure compound I (the main component is tofacitinib) by LC-MS detection.
Comparative example 4
Adding 3.12g (10mmol) of tofacitinib and 70% of sulfuric acid (75 ml) into a reaction bottle, heating to 80 ℃, stirring and reacting for 3-4 hours, confirming the mixture as a compound I, II by HPLC, continuously reacting for 2 hours, and carrying out post-treatment operations such as neutralization, washing, acidification, extraction, concentration (washing the used organic phase and re-acidification, and respectively concentrating the extracted organic phase), crystallization and the like to obtain a white-like solid, wherein the low-purity compound I (about 50%) and the low-purity compound II (about 60%) are confirmed by LC-MS detection, and the separation difficulty of the compound II from other impurities is large.
Comparative example 5
Adding 3.12g (10mmol) of tofacitinib and 70% of sulfuric acid (75 ml) into a reaction bottle, heating to 100 ℃, stirring and reacting for 2-3 hours, confirming that a main product is a compound II (part of the compound I in addition) by HPLC (high performance liquid chromatography), continuously reacting for 1 hour, and carrying out post-treatment operations such as neutralization, washing, acidification, extraction, concentration, crystallization and the like to obtain a white-like solid, wherein the compound II with low purity (60%) is confirmed by LC-MS detection.
Comparative example 6
Adding 3.12g (10mmol) of tofacitinib and 98% of sulfuric acid (75 ml) into a reaction bottle, heating to 90 ℃, stirring and reacting for 2-3 hours, and enabling a reaction solution to turn black to generate a carbonization byproduct; the reaction was stopped and after work-up operations such as neutralization, washing, acidification, extraction, concentration, crystallization, etc., a small amount of grey solid was obtained, which was confirmed by LC-MS to be a less pure compound II (-50%).
As can be seen from the comparative examples and comparative examples:
1) in the preparation process of the compound I, when the reaction conditions can not meet the conditions that the acid concentration is 50-60% and the reaction temperature is 40-50 ℃, the incomplete hydrolysis reaction of nitrile can not be carried out or can not be completely carried out, the effective separation of the starting material (tofacitinib) and the compound I can not be realized in the existing post-treatment process, and the high-purity compound I can not be obtained;
2) in the preparation process of the compound II, when the reaction conditions can not meet the conditions that the acid concentration is more than 80% and the reaction temperature is more than 90 ℃, the complete hydrolysis reaction of nitrile can not be completely carried out, so that partial incomplete hydrolysis products (namely the compound I) can not be completely reacted, the purification effect of the existing acid-base extraction separation process is limited, and only the compound I and the compound II with lower purity can be respectively obtained;
3) in the preparation process of the compound II, when the commercially available concentrated sulfuric acid is directly used and the reaction temperature is higher than 90 ℃, side reactions such as oxidation and carbonization are easy to occur in the reaction due to the strong dehydration effect of the high-concentration acid, so that the post-treatment is difficult, the color of the obtained product is deepened, the purity is greatly reduced, and even the product cannot be obtained.
Claims (7)
1. A method for preparing tofacitinib substances, the structural formula of the tofacitinib substances is shown as a formula I and a formula II,
the synthesis of the tofacitinib shown in the formula I comprises the following steps:
1) dissolving tofacitinib in an acid solution with the mass concentration of 50-60%, wherein the acid is one of sulfuric acid and methanesulfonic acid;
2) heating to 40-50 ℃ for reaction;
3) after the reaction is finished, neutralizing the reaction system of the compound shown in the formula I to pH 8-9, extracting by using an organic solvent, taking an organic phase extraction liquid, and crystallizing to obtain the tofacitinib related substance shown in the formula I;
the synthesis of the tofacitinib shown in the formula II comprises the following steps:
1) dissolving tofacitinib in an acid solution with the mass concentration of 80-90%, wherein the acid is one of sulfuric acid and methanesulfonic acid;
2) heating to 90-100 ℃ for reaction;
3) finishing the reaction, adding an organic solvent into a compound reaction system shown in the formula II, neutralizing until the pH value is 8-9, and taking the aqueous phase extraction liquid; and acidifying the aqueous phase extraction liquid to pH 3-4, and then performing organic solvent extraction and crystallization to obtain the tofacitinib related substance shown in the formula II.
2. The method of claim 1, wherein: the mass concentration of the acid used in the preparation process of the compound of formula I is 55%; the mass concentration of the acid used in the preparation of the compound of formula II was 85%.
3. The method of claim 1, wherein: the reaction temperature in the preparation process of the compound of the formula I is 50 ℃; the reaction temperature during the preparation of the compound of formula II is 90 ℃.
4. The method of claim 1, wherein: the organic solvent used in the extraction operation is selected from one of dichloromethane, trichloromethane and dichloroethylene.
5. The production method according to any one of claims 1 to 4, characterized in that: the crystallization solvent is selected from one of isopropyl ether and methyl tert-butyl ether.
6. The method of claim 4, wherein: the organic solvent used for the extraction was dichloromethane.
7. The method of claim 5, wherein: the crystallization solvent is methyl tert-butyl ether.
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