CN115181103B - Preparation method of barytinib - Google Patents
Preparation method of barytinib Download PDFInfo
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- CN115181103B CN115181103B CN202210982899.6A CN202210982899A CN115181103B CN 115181103 B CN115181103 B CN 115181103B CN 202210982899 A CN202210982899 A CN 202210982899A CN 115181103 B CN115181103 B CN 115181103B
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- 238000002360 preparation method Methods 0.000 title claims abstract description 20
- 238000000034 method Methods 0.000 claims abstract description 15
- 238000007670 refining Methods 0.000 claims abstract description 5
- 238000005904 alkaline hydrolysis reaction Methods 0.000 claims abstract description 4
- 238000007259 addition reaction Methods 0.000 claims abstract description 3
- 150000001875 compounds Chemical class 0.000 claims description 43
- 238000006243 chemical reaction Methods 0.000 claims description 32
- 238000003756 stirring Methods 0.000 claims description 27
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 19
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 18
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 15
- 238000002425 crystallisation Methods 0.000 claims description 13
- 230000008025 crystallization Effects 0.000 claims description 13
- 238000001914 filtration Methods 0.000 claims description 11
- 239000000243 solution Substances 0.000 claims description 11
- 239000002904 solvent Substances 0.000 claims description 11
- WYURNTSHIVDZCO-UHFFFAOYSA-N tetrahydrofuran Substances C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 11
- 239000012043 crude product Substances 0.000 claims description 10
- 238000010992 reflux Methods 0.000 claims description 9
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 8
- 150000007530 organic bases Chemical class 0.000 claims description 8
- LVTJOONKWUXEFR-FZRMHRINSA-N protoneodioscin Natural products O(C[C@@H](CC[C@]1(O)[C@H](C)[C@@H]2[C@]3(C)[C@H]([C@H]4[C@@H]([C@]5(C)C(=CC4)C[C@@H](O[C@@H]4[C@H](O[C@H]6[C@@H](O)[C@@H](O)[C@@H](O)[C@H](C)O6)[C@@H](O)[C@H](O[C@H]6[C@@H](O)[C@@H](O)[C@@H](O)[C@H](C)O6)[C@H](CO)O4)CC5)CC3)C[C@@H]2O1)C)[C@H]1[C@H](O)[C@H](O)[C@H](O)[C@@H](CO)O1 LVTJOONKWUXEFR-FZRMHRINSA-N 0.000 claims description 8
- 238000010791 quenching Methods 0.000 claims description 8
- 230000000171 quenching effect Effects 0.000 claims description 8
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 claims description 6
- 239000007864 aqueous solution Substances 0.000 claims description 6
- 238000001035 drying Methods 0.000 claims description 6
- 239000003054 catalyst Substances 0.000 claims description 5
- 239000007810 chemical reaction solvent Substances 0.000 claims description 5
- JNGZXGGOCLZBFB-IVCQMTBJSA-N compound E Chemical compound N([C@@H](C)C(=O)N[C@@H]1C(N(C)C2=CC=CC=C2C(C=2C=CC=CC=2)=N1)=O)C(=O)CC1=CC(F)=CC(F)=C1 JNGZXGGOCLZBFB-IVCQMTBJSA-N 0.000 claims description 4
- 238000001953 recrystallisation Methods 0.000 claims description 4
- 239000000047 product Substances 0.000 claims description 3
- 238000005859 coupling reaction Methods 0.000 claims description 2
- 230000008878 coupling Effects 0.000 claims 1
- 238000010168 coupling process Methods 0.000 claims 1
- 239000012535 impurity Substances 0.000 abstract description 12
- -1 methyl (4-chloro-7H-pyrrolo [2,3-d ] pyrimidin-7-yl) pivalate Chemical compound 0.000 abstract description 12
- 229950010765 pivalate Drugs 0.000 abstract description 5
- 238000010511 deprotection reaction Methods 0.000 abstract description 4
- 239000003814 drug Substances 0.000 abstract description 4
- 125000004029 hydroxymethyl group Chemical group [H]OC([H])([H])* 0.000 abstract description 4
- 238000009776 industrial production Methods 0.000 abstract description 4
- 239000003513 alkali Substances 0.000 abstract description 3
- 229940079593 drug Drugs 0.000 abstract description 3
- 230000007062 hydrolysis Effects 0.000 abstract description 3
- 238000006460 hydrolysis reaction Methods 0.000 abstract description 3
- 239000007858 starting material Substances 0.000 abstract description 2
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 12
- 238000004128 high performance liquid chromatography Methods 0.000 description 12
- 239000012065 filter cake Substances 0.000 description 11
- 239000000543 intermediate Substances 0.000 description 10
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 8
- BPXKZEMBEZGUAH-UHFFFAOYSA-N 2-(chloromethoxy)ethyl-trimethylsilane Chemical compound C[Si](C)(C)CCOCCl BPXKZEMBEZGUAH-UHFFFAOYSA-N 0.000 description 7
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 6
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 6
- 238000010438 heat treatment Methods 0.000 description 6
- CZPWVGJYEJSRLH-UHFFFAOYSA-N Pyrimidine Chemical compound C1=CN=CN=C1 CZPWVGJYEJSRLH-UHFFFAOYSA-N 0.000 description 5
- 238000001816 cooling Methods 0.000 description 5
- 239000000203 mixture Substances 0.000 description 5
- 239000007787 solid Substances 0.000 description 5
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 4
- 230000000052 comparative effect Effects 0.000 description 4
- 238000001514 detection method Methods 0.000 description 4
- 239000006185 dispersion Substances 0.000 description 4
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 4
- 206010039073 rheumatoid arthritis Diseases 0.000 description 4
- 238000001291 vacuum drying Methods 0.000 description 4
- 229940126062 Compound A Drugs 0.000 description 3
- NLDMNSXOCDLTTB-UHFFFAOYSA-N Heterophylliin A Natural products O1C2COC(=O)C3=CC(O)=C(O)C(O)=C3C3=C(O)C(O)=C(O)C=C3C(=O)OC2C(OC(=O)C=2C=C(O)C(O)=C(O)C=2)C(O)C1OC(=O)C1=CC(O)=C(O)C(O)=C1 NLDMNSXOCDLTTB-UHFFFAOYSA-N 0.000 description 3
- WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical group [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 description 3
- 230000000694 effects Effects 0.000 description 3
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- XUZMWHLSFXCVMG-UHFFFAOYSA-N baricitinib Chemical compound C1N(S(=O)(=O)CC)CC1(CC#N)N1N=CC(C=2C=3C=CNC=3N=CN=2)=C1 XUZMWHLSFXCVMG-UHFFFAOYSA-N 0.000 description 2
- 230000009286 beneficial effect Effects 0.000 description 2
- GGRHYQCXXYLUTL-UHFFFAOYSA-N chloromethyl 2,2-dimethylpropanoate Chemical compound CC(C)(C)C(=O)OCCl GGRHYQCXXYLUTL-UHFFFAOYSA-N 0.000 description 2
- 230000007547 defect Effects 0.000 description 2
- 239000012467 final product Substances 0.000 description 2
- 238000002386 leaching Methods 0.000 description 2
- 238000004519 manufacturing process Methods 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- 229910052763 palladium Inorganic materials 0.000 description 2
- 229910000027 potassium carbonate Inorganic materials 0.000 description 2
- 125000006239 protecting group Chemical group 0.000 description 2
- 239000008213 purified water Substances 0.000 description 2
- 239000002994 raw material Substances 0.000 description 2
- 238000001228 spectrum Methods 0.000 description 2
- 239000000725 suspension Substances 0.000 description 2
- SFMNHCLLSKRLRN-UHFFFAOYSA-N 1-ethylsulfonylazetidine Chemical compound CCS(=O)(=O)N1CCC1 SFMNHCLLSKRLRN-UHFFFAOYSA-N 0.000 description 1
- BPTCCCTWWAUJRK-UHFFFAOYSA-N 4-chloro-7h-pyrrolo[2,3-d]pyrimidine Chemical compound ClC1=NC=NC2=C1C=CN2 BPTCCCTWWAUJRK-UHFFFAOYSA-N 0.000 description 1
- JJTNLWSCFYERCK-UHFFFAOYSA-N 7h-pyrrolo[2,3-d]pyrimidine Chemical compound N1=CN=C2NC=CC2=C1 JJTNLWSCFYERCK-UHFFFAOYSA-N 0.000 description 1
- 206010067484 Adverse reaction Diseases 0.000 description 1
- 101000997835 Homo sapiens Tyrosine-protein kinase JAK1 Proteins 0.000 description 1
- 101000997832 Homo sapiens Tyrosine-protein kinase JAK2 Proteins 0.000 description 1
- 229940122245 Janus kinase 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
- 229910013063 LiBF 4 Inorganic materials 0.000 description 1
- 238000006845 Michael addition reaction Methods 0.000 description 1
- 201000004681 Psoriasis Diseases 0.000 description 1
- XUIMIQQOPSSXEZ-UHFFFAOYSA-N Silicon Chemical compound [Si] XUIMIQQOPSSXEZ-UHFFFAOYSA-N 0.000 description 1
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 1
- 238000006069 Suzuki reaction reaction Methods 0.000 description 1
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 1
- 102100033438 Tyrosine-protein kinase JAK1 Human genes 0.000 description 1
- 102100033444 Tyrosine-protein kinase JAK2 Human genes 0.000 description 1
- 230000006838 adverse reaction Effects 0.000 description 1
- 239000005456 alcohol based solvent Substances 0.000 description 1
- 229950000971 baricitinib Drugs 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 238000007664 blowing Methods 0.000 description 1
- 239000004327 boric acid Substances 0.000 description 1
- 229940126600 bulk drug product Drugs 0.000 description 1
- 238000006555 catalytic reaction Methods 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 238000004090 dissolution Methods 0.000 description 1
- 125000006125 ethylsulfonyl group Chemical group 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 230000005764 inhibitory process Effects 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 229960000485 methotrexate Drugs 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 239000011259 mixed solution Substances 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- 238000005580 one pot reaction Methods 0.000 description 1
- BSCHIACBONPEOB-UHFFFAOYSA-N oxolane;hydrate Chemical compound O.C1CCOC1 BSCHIACBONPEOB-UHFFFAOYSA-N 0.000 description 1
- IUGYQRQAERSCNH-UHFFFAOYSA-N pivalic acid Chemical compound CC(C)(C)C(O)=O IUGYQRQAERSCNH-UHFFFAOYSA-N 0.000 description 1
- 238000003908 quality control method Methods 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 229910052710 silicon Inorganic materials 0.000 description 1
- 239000010703 silicon Substances 0.000 description 1
- 239000012312 sodium hydride Substances 0.000 description 1
- 229910000104 sodium hydride Inorganic materials 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 1
- USFPINLPPFWTJW-UHFFFAOYSA-N tetraphenylphosphonium Chemical compound C1=CC=CC=C1[P+](C=1C=CC=CC=1)(C=1C=CC=CC=1)C1=CC=CC=C1 USFPINLPPFWTJW-UHFFFAOYSA-N 0.000 description 1
- RIOQSEWOXXDEQQ-UHFFFAOYSA-N triphenylphosphine Substances C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-N 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
Abstract
The application discloses a preparation method of barytanib; methyl (4-chloro-7H-pyrrolo [2,3-d ] pyrimidin-7-yl) pivalate is used as a starting material, and is coupled with 1- (1-ethoxyethyl) -4- (4, 5-tetramethyl-1, 3, 2-dioxaborane-2-yl) -1H-pyrazole, acidolysis is carried out, and addition reaction is carried out to obtain the methyl (4- (1- (3- (cyanomethyl) -1- (ethylsulfonyl) azetidin-3-yl) -1H-pyrazol-4-yl) -7H-pyrrolo [2,3-d ] pyrimidin-7-yl) pivalate; and then refining to obtain the barytinib through alkaline hydrolysis reaction. The alkaline hydrolysis reaction adopts DBU and other organic alkali to carry out hydrolysis deprotection reaction, the obtained baratinib has high purity and good yield, wherein the hydroxymethyl intermediate impurity G is reduced to below 0.15 percent, and the purity of the obtained baratinib bulk drug can reach 99.9 percent after the refining process, thus being easy for industrial production.
Description
Technical Field
The application belongs to the technical field of drug synthesis, relates to a preparation method of baratinib, and particularly relates to a preparation method of high-purity baratinib.
Background
Baratinib (Baricitinib, trade name ol @) chemical name 1- (ethylsulfonyl) -3- [4- (7H-pyrrolo [2,3-d ] pyrimidin-4-yl) -1H-pyrazol-1-yl ] -3-azetidine acetonitrile, a Janus kinase inhibitor, developed by the company gidder and antique pharmaceutical, and available from the company oer at 13 months 2, 2017, alone or in combination with methotrexate, is useful in the treatment of Rheumatoid Arthritis (RA) patients who are poorly or intolerably treated with DMARDs. The baratinib has a strong inhibition effect on JAK1 and JAK2, has a good curative effect on rheumatoid arthritis, has slight adverse reaction and is easy to be tolerated by patients. The baratinib can treat rheumatoid arthritis, and has the experiment that the baratinib can also be used for treating psoriasis and other diseases.
Patent CN102026999B by siet corporation discloses a method for preparing barytanib, the reaction scheme is as follows:
the route is as 4-chloropyrrolo [2,3-d ]]Pyrimidine (1) is used as raw material, and SEM protected pyrrolo [2,3-d ] is obtained through 2- (trimethylsilyl) ethoxymethyl chloride (SEMCl) protection]Pyrimidine (2), 3 and boric acid ester (3) are subjected to Suzuki coupling reaction to obtain an intermediate (4), 4 is subjected to 1-ethoxyethyl removal protection by hydrochloric acid aqueous solution to obtain a pyrazole compound (5), 1- (ethylsulfonyl) azetidine and the intermediate 5 are subjected to Michael addition reaction under DBU catalysis to obtain an intermediate (6), and the intermediate (6) is subjected to LiBF 4 Deprotection gives the hydroxymethyl intermediate (compound 7), finally with NH 4 OH further converts compound 7 to the final product baratinib.
The preparation method of the barytinib has the main defects that: 1) When 2- (trimethylsilyl) ethoxymethyl chloride (SEMCl) is used for SEM protection of the 4-chloropyrrolo [2,3-d ] pyrimidine (2), sodium hydride is needed to be used as alkali for reaction, the operation is more complicated, the subsequent operation is more troublesome and the SEMCl is high in price, and meanwhile, silicon element is introduced, so that the quality control is not facilitated; 2) The SEM protecting group is used for protecting pyrrolo [2,3-d ] pyrimidine, the subsequent removal is troublesome, and the removal can be realized only by two steps of operation procedures; 3) In this literature route, the overall yield of the reaction is low. Is not beneficial to the industrialized production of the medicine.
Meanwhile, CN102026999B discloses a method of using chloromethyl Pivalate (POM) instead of 2- (trimethylsilyl) ethoxymethyl chloride (SEMCl) as a protecting group, but in the final step of hydrolysis deprotection, hydroxymethyl intermediate impurity G (i.e., compound 7) is easily generated in the process of preparing baratinib, and the impurity is difficult to remove in baratinib, thereby affecting the quality of the bulk drug product.
Therefore, there is a need to develop a process for preparing baratinib suitable for industrial production.
Disclosure of Invention
Aiming at the defects existing in the prior art, the application aims to provide a preparation method of baratinib suitable for industrial production.
In order to achieve the above object of the present application, the present application provides the following technical solutions:
the application provides a preparation method of baratinib, which comprises the following steps:
s1, taking methyl (4-chloro-7H-pyrrolo [2,3-d ] pyrimidine-7-yl) pivalate (compound B) as a starting material, and carrying out one-step coupling reaction on the methyl (4- (1- (1-ethoxyethyl) -1H-pyrazolo-4-yl) -7H-pyrrolo [2,3-d ] pyrimidine-7-yl) pivalate (compound C) with 1- (1-ethoxyethyl) -4- (4, 5-tetramethyl-1, 3, 2-dioxaborane-2-yl) -1H-pyrazole (compound A);
s2, carrying out acidolysis reaction on the compound C to obtain methyl (4- (1H-pyrazol-4-yl) -7H-pyrrolo [2,3-D ] pyrimidine-7-yl) pivalate (compound D);
s3, carrying out addition reaction on the compound D and 2- (1- (ethylsulfonyl) azetidin-3-alkylene) acetonitrile (compound E) to obtain (4- (1- (3- (cyanomethyl) -1- (ethylsulfonyl) azetidin-3-yl) -1H-pyrazol-4-yl) -7H-pyrrolo [2,3-D ] pyrimidin-7-yl) pivalate (compound F);
s4, carrying out alkaline hydrolysis reaction on the compound F by using an organic base to obtain a barytanib crude product, and finally refining to obtain the target product barytanib.
As one embodiment, compound D and compound E are reacted in DMF solution in the presence of DBU at room temperature for 2-5 hours, then solvent is added into the reaction system for quenching, stirring and crystallization are carried out at a certain temperature, and then the compound F is obtained after filtration and drying.
As an embodiment, the quenching solvent is preferably THF and water in a volume ratio of 1:1, and the total volume thereof is 12 to 20 times, more preferably 16 times, the weight of the compound D.
As an embodiment, THF and water mixed solution may be added to the system.
As another embodiment, THF in the quenching solvent may be added to the system first, followed by slow addition of water.
As one embodiment, the crystallization temperature is 0-30 ℃; more preferably 20-30 ℃.
As one embodiment, the drying temperature is 50-60 ℃.
As an embodiment, the molar equivalent of DBU is 0.03-0.1 times, more preferably 0.05 times that of compound D.
As one embodiment, compound F is dispersed in a reaction solvent, then an organic base catalyst is added, the temperature is raised to reflux, after the reaction, the temperature is naturally lowered, stirring crystallization is carried out, and the barytanib crude product is obtained by filtration. And recrystallizing by using a recrystallization solvent to obtain the high-purity baratinib.
As one embodiment, the organic base catalyst is selected from any one or two of organic bases such as DBU, TEA, DIPEA.
As an embodiment, the molar equivalent of the organic base catalyst is 0.01 to 0.1 times, more preferably 0.03 to 0.04 times that of compound F.
As one embodiment, the reaction solvent is one or more of alcohol solvents such as methanol, ethanol and isopropanol; the volume of the compound is 8-12 times of the weight of the compound F.
As one embodiment, the solvent for recrystallization is 50% thf in water.
In some embodiments, compound B and compound A are reacted at 85-95℃for 1.5-3 hours in the presence of 1, 4-dioxane, potassium carbonate, and palladium tetra-triphenylphosphine to give a 1, 4-dioxane solution containing compound C.
In some embodiments, the 1, 4-dioxane solution of the compound C is cooled to 0 ℃, hydrochloric acid aqueous solution is added, then the reaction is carried out for 4 to 6 hours at room temperature, after the reaction is completed, sodium hydroxide water is used for dissolving and adjusting the pH=7 to 8 of the system, the mixture is stirred for 1 to 3 hours and then filtered, purified water is used for leaching filter cakes, absolute ethanol solution is added and heated to reflux, the mixture is stirred for 1 to 3 hours, and the mixture is filtered to obtain the compound D.
Compared with the prior art, the application has the following beneficial effects:
the application discloses a preparation method of high-purity barytinib; the raw materials are easy to obtain, the operation is continuous and simple, the intermediate D is prepared by adopting a one-pot synthesis method, and the product purity and the yield are high; in the process of preparing the baratinib from the intermediate F, organic alkali such as DBU and the like is adopted for hydrolysis deprotection reaction, the obtained baratinib has high purity and good yield, wherein the hydroxymethyl intermediate impurity G is reduced to below 0.15%, and the purity of the obtained baratinib bulk drug can reach 99.9% after the refining process, so that the industrial production is easy.
Drawings
Other features, objects and advantages of the present application will become more apparent upon reading of the detailed description of non-limiting embodiments, given with reference to the accompanying drawings in which:
FIG. 1 is a HPLC detection spectrum of baratinib obtained in example 4;
FIG. 2 is a HPLC detection spectrum of baratinib obtained in comparative example 1;
Detailed Description
The following examples will assist those skilled in the art in further understanding the present application, but are not intended to limit the application in any way. It will be apparent to those skilled in the art that various changes and modifications can be made without departing from the spirit of the application. The application will be described in detail with reference to specific examples below:
example 1 preparation of Compound C
100g of compound B (0.37 mol) and 119.6g of compound A (0.45 mol) are weighed into a 3L three-port reaction flask, and 1L of 1, 4-dioxane is added for stirring and dissolving; 154.3g of anhydrous potassium carbonate (1.11 mol) were dissolved in 500ml of water and charged into a 3L reaction flask, followed by rapid addition of 4.3g of tetraphenylphosphine palladium. Stir and displace 3 nitrogen times. After heating to 90 ℃ for 2 hours, the reaction system is cooled to room temperature, and the mixture is stood for liquid separation, and the water layer is separated to obtain a 1, 4-dioxane solution (HPLC 93.6%) containing the compound C.
MS:m/z＝372.1[M+H] +
1 H NMR(400MHz,Chloroform-d)δ8.88(s,1H),8.39(s,1H),8.24(s,1H),7.48(d,J＝4.0Hz,1H),6.76(d,J＝3.6Hz,1H),6.25(s,2H),5.60(dd,J 1 ＝6.0Hz,J 2 ＝12.0Hz,1H),3.56–3.38(m,2H),1.74(d,J＝6.0Hz,3H),1.18(d,J＝7.2Hz,3H),1.15(s,9H)。
EXAMPLE 2 preparation of Compound D
Transferring the 1, 4-dioxane solution containing the compound C into a 5L three-port reaction bottle, adding 2L of water, cooling to 0 ℃, and slowly adding 270g of 20% hydrochloric acid aqueous solution. And after the addition, removing the cooling equipment, naturally heating to room temperature, and stirring for reaction for 5 hours. After completion of the reaction, the ph=7 to 8 of the system was adjusted by dissolution with 6M sodium hydroxide water, and at this time, a large amount of white solid was precipitated from the reaction solution. After stirring for 2h, the filter cake was filtered and rinsed with purified water. Transferring the water-containing filter cake into a 2L three-port reaction bottle, adding 1L absolute ethanol solution, heating to reflux, stirring for 2h, and naturally cooling to room temperature. The suspension was filtered and the filter cake was rinsed with ethanol and dried under vacuum at 50 ℃ to constant weight to give 93.6g of compound D as a white solid. (HPLC 99.3%, overall yield in two steps 84.6%)
MS:m/z＝300.1[M+H] +
1 H NMR(400MHz,DMSO-d)δ13.41(s,1H),8.76(s,1H),8.66(s,1H),8.33(s,1H),7.69(d,J＝3.6Hz,1H),7.11(d,J＝3.6Hz,1H),6.22(s,2H),1.06(s,9H)。
Example 3 preparation of Compound F
30g of Compound D (0.1 mol) was weighed into a 1L reaction flask, 120ml of DMF was added and stirred, followed by addition of 22.3g of Compound E (0.12 mol) and 0.8g of DBU, stirring at room temperature and reaction for 3 hours, followed by addition of 240ml of THF and 240ml of water to the reaction system and quenching, a large amount of white solid precipitated with the addition of water, stirring at room temperature and crystallization for 2 hours, then filtration was carried out, and after rinsing the cake with water, drying by air blast at 60℃until the weight became constant, 46.2g of Compound F as a white solid was obtained. (HPLC 99.6% yield 95.1%). The effect of different quenching solvents and crystallization temperatures on the purity and yield of the intermediates are shown in table 1 below:
MS:m/z＝486.1[M+H] +
1 H NMR(400MHz,DMSO-d)δ8.96(s,1H),8.80(s,1H),8.49(s,2H),7.76(d,J＝3.6,1H),7.20(d,J＝4.0Hz,1H),6.23(s,2H),4.59(d,J＝9.2Hz,2H),4.23(d,J＝8.8Hz,2H),3.68(s,2H),3.22(q,J 1 ＝7.6Hz,J 2 ＝14.8Hz,2H),1.225(t,J＝7.2Hz 3H),1.06(s,9H)。
TABLE 1
Example 4 preparation of baratinib
40g of compound F is weighed and put into a 1L three-port reaction bottle, 400ml of ethanol is added for stirring and dispersion, then 0.4g of DBU is added, the temperature is raised to reflux, after stirring and reaction for 3 hours, the temperature is naturally reduced to room temperature, stirring and crystallization are carried out for 2 hours, then filtration is carried out, filter cakes are leached by ethanol, and the filter cakes are dried to constant weight in vacuum at 50 ℃ to obtain 28.6g of baratinib crude products. (HPLC detection, RT16.225 baratinib main peak purity 98.83%, RT15.244 impurity G0.12%, yield 93.6%; see FIG. 1 for details).
10g of the crude product is taken, the crude product is filled into a 100ml three-port reaction bottle, 40ml of 50% THF-water solution is added, and the mixture is stirred and heated to reflux, and white suspension is dissolved. Cooling to room temperature after the system is dissolved, stirring and crystallizing for 2 hours, filtering, leaching a filter cake by water, and drying by blowing at 60 ℃ to obtain 9.3G of white crystalline baratinib, (HPLC 99.90%, impurity G content 0.02% and other impurities below 0.1%).
MS:m/z＝372.1[M+H] +
1 H NMR(600MHz,DMSO-d)δ12.15(s,1H),8.94(s,1H),8.72(s,1H),8.49(s,1H),7.63(d,J＝6.0Hz,1H),7.09(d,J＝1.2Hz,1H),4.62(d,J＝12.0Hz,2H),4.26(d,J＝6.0Hz,2H),3.71(s,2H),3.27(q,J 1 ＝6.0Hz,J 2 ＝12.0Hz 2H),1.25(t,J＝6.0Hz,3H)。
Example 5 preparation of baratinib
40G of compound F is weighed and put into a 1L three-port reaction bottle, 400ml of isopropanol is added for stirring and dispersion, then 1.0G of DBU is added, the temperature is raised to reflux, after stirring and reaction for 2 hours, the temperature is naturally reduced to room temperature, stirring and crystallization are carried out for 2 hours, filtration is carried out, a filter cake is leached by isopropanol, and vacuum drying is carried out at 50 ℃ until the constant weight is achieved, thus obtaining 27.1G of baratinib crude product, (HPLC 98.41 percent of impurity G content is 0.15 percent, and yield is 88.5 percent).
Example 6 preparation of baratinib
40G of compound F is weighed and put into a 1L three-port reaction bottle, 400ml of methanol is added for stirring and dispersion, then 1.2G of DBU is added for heating to reflux, after stirring and reaction for 3 hours, the temperature is naturally reduced to room temperature, stirring and crystallization are carried out for 2 hours, filtration is carried out, a filter cake is leached by methanol, the temperature is 50 ℃ and vacuum drying is carried out until the constant weight is achieved, 27.5G of baratinib crude product is obtained, the main peak of the baratinib crude product is 98.72% by detecting HPLC, the content of impurity G is 0.13%, and the yield is 90%).
Example 7 preparation of baratinib
40G of compound F is weighed and put into a 1L three-port reaction bottle, 400ml of ethanol is added for stirring and dispersion, then 0.34G of DIPEA is added for heating to reflux, after stirring and reaction for 3 hours, the temperature is naturally reduced to room temperature, stirring and crystallization are carried out for 2 hours, filtration is carried out, filter cakes are leached by ethanol, the temperature is 50 ℃ and vacuum drying is carried out until the constant weight is achieved, and the baratinib crude product is obtained, the content of impurity G is 0.36% by detecting HPLC 98.12%, and the yield is 87.6%.
Comparative example 1
10g of Compound F (0.02 mol) was weighed into a 250ml three-port reaction flask, and 50ml of absolute methanol and 200ml of tetrahydrofuran were added thereto to disperse with stirring. Cooling to 0 ℃, slowly dropwise adding 23ml of 1M sodium hydroxide aqueous solution, naturally heating to room temperature, stirring and reacting for 3h, and adjusting the pH of the system to 7.0-7.5 by using 100ml of water and 2ml of 1N hydrochloric acid aqueous solution. After stirring and crystallization for 2h, filtration is carried out, and the filter cake is washed 2 times with 40ml of acetonitrile and water (mixed according to the volume ratio of 2:3). Vacuum drying at 45℃to constant weight gives 6.5g of baratinib as a white solid. ( HPLC detection: the purity of the baratinib in the period of 13.823min is 97.67 percent, the impurity G in the period of 12.905 percent is 1.0 percent, and the yield is 85 percent; see fig. 2. )
Comparative example 2
Similarly, the sodium hydroxide in comparative example 1 was replaced with lithium hydroxide, and the final product was baratinib with an HPLC purity of 97.0%, impurity G of 1.8% and a yield of 78%.
The foregoing describes specific embodiments of the present application. It is to be understood that the application is not limited to the particular embodiments described above, and that various changes or modifications may be made by those skilled in the art within the scope of the appended claims without affecting the spirit of the application. The embodiments of the application and the features of the embodiments may be combined with each other arbitrarily without conflict.
Claims (8)
1. A process for the preparation of baratinib, the process comprising the steps of:
s1, compound BAnd Compound A->Coupling to give the compound->
S2, carrying out acidolysis reaction on the compound C to obtain a compound D
S3, compound D and Compound EThe addition reaction gives the compound F->
S4, carrying out organic alkaline hydrolysis on the compound F to obtain a barytanib crude product, and refining to obtain barytanib; the organic base is selected from any one or two of DBU, TEA, DIPEA; the molar equivalent of the organic base catalyst is 0.01-0.1 times of that of the compound F.
2. The preparation method of the baratinib as claimed in claim 1, wherein in the step S3, the compound D and the compound E are stirred and reacted in DMF solution in the presence of DBU at room temperature for 2-5 hours, then solvent quenching is added into a reaction system, stirring and crystallization are carried out at a certain temperature, and the compound F is obtained after filtration and drying.
3. The preparation method of baratinib according to claim 2, wherein the quenching solvent is THF and water in a volume ratio of 1:1, and the total volume of the quenching solvent is 12-20 times the weight of the compound D.
4. The method for preparing baratinib according to claim 2, wherein the crystallization temperature is 0-30 ℃; the drying temperature is 50-60 ℃.
5. The process for the preparation of baratinib according to claim 2, characterized in that the molar equivalent of DBU is 0.03-0.1 times that of compound D.
6. The method for preparing the baratinib according to claim 1, wherein in the step S4, the compound F is dispersed in a reaction solvent, then an organic base catalyst is added, the temperature is raised to reflux, after the reaction, the natural temperature is reduced, stirring crystallization is carried out, and a crude baratinib product is obtained through filtration.
7. The method for preparing baratinib according to claim 6, wherein the reaction solvent is one or more of methanol, ethanol and isopropanol; the volume of the reaction solvent is 8-12 times of the weight of the compound F.
8. The method for preparing the baratinib according to claim 1, wherein in the step S4, the crude baratinib is recrystallized by adopting a recrystallization solvent to obtain the high-purity baratinib; the solvent for the recrystallization was 50% thf aqueous solution.
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