CN113583001A - Preparation of ibrutinib - Google Patents
Preparation of ibrutinib Download PDFInfo
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- CN113583001A CN113583001A CN202110793515.1A CN202110793515A CN113583001A CN 113583001 A CN113583001 A CN 113583001A CN 202110793515 A CN202110793515 A CN 202110793515A CN 113583001 A CN113583001 A CN 113583001A
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- phenoxyphenyl
- ibrutinib
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- XYFPWWZEPKGCCK-GOSISDBHSA-N ibrutinib Chemical compound C1=2C(N)=NC=NC=2N([C@H]2CN(CCC2)C(=O)C=C)N=C1C(C=C1)=CC=C1OC1=CC=CC=C1 XYFPWWZEPKGCCK-GOSISDBHSA-N 0.000 title claims abstract description 26
- 239000002177 L01XE27 - Ibrutinib Substances 0.000 title claims abstract description 25
- 229960001507 ibrutinib Drugs 0.000 title claims abstract description 25
- 238000002360 preparation method Methods 0.000 title abstract description 8
- 150000001875 compounds Chemical class 0.000 claims abstract description 18
- HNIMEQCLCNSCGH-UHFFFAOYSA-N 3-amino-5-(4-phenoxyphenyl)-1h-pyrazole-4-carbonitrile Chemical compound NC1=NNC(C=2C=CC(OC=3C=CC=CC=3)=CC=2)=C1C#N HNIMEQCLCNSCGH-UHFFFAOYSA-N 0.000 claims abstract description 7
- ZIYCMWSAXJKKHX-GOSISDBHSA-N 5-amino-3-(4-phenoxyphenyl)-1-[(3R)-1-prop-2-enoylpiperidin-3-yl]pyrazole-4-carbonitrile Chemical compound Nc1c(C#N)c(nn1[C@@H]1CCCN(C1)C(=O)C=C)-c1ccc(Oc2ccccc2)cc1 ZIYCMWSAXJKKHX-GOSISDBHSA-N 0.000 claims abstract description 7
- 238000006482 condensation reaction Methods 0.000 claims abstract description 7
- GEXJGXKSILFZQH-ZETCQYMHSA-N 1-[(3S)-3-hydroxypiperidin-1-yl]prop-2-en-1-one Chemical compound O[C@@H]1CN(CCC1)C(C=C)=O GEXJGXKSILFZQH-ZETCQYMHSA-N 0.000 claims abstract description 4
- 238000006243 chemical reaction Methods 0.000 claims description 13
- 239000002904 solvent Substances 0.000 claims description 5
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 claims description 4
- RIOQSEWOXXDEQQ-UHFFFAOYSA-N triphenylphosphine Substances C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-N 0.000 claims description 4
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 3
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 3
- VVWRJUBEIPHGQF-MDZDMXLPSA-N propan-2-yl (ne)-n-propan-2-yloxycarbonyliminocarbamate Chemical compound CC(C)OC(=O)\N=N\C(=O)OC(C)C VVWRJUBEIPHGQF-MDZDMXLPSA-N 0.000 claims description 3
- LMDZBCPBFSXMTL-UHFFFAOYSA-N 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide Substances CCN=C=NCCCN(C)C LMDZBCPBFSXMTL-UHFFFAOYSA-N 0.000 claims description 2
- YEDUAINPPJYDJZ-UHFFFAOYSA-N 2-hydroxybenzothiazole Chemical compound C1=CC=C2SC(O)=NC2=C1 YEDUAINPPJYDJZ-UHFFFAOYSA-N 0.000 claims description 2
- FPQQSJJWHUJYPU-UHFFFAOYSA-N 3-(dimethylamino)propyliminomethylidene-ethylazanium;chloride Chemical compound Cl.CCN=C=NCCCN(C)C FPQQSJJWHUJYPU-UHFFFAOYSA-N 0.000 claims description 2
- 239000003795 chemical substances by application Substances 0.000 claims description 2
- FAMRKDQNMBBFBR-BQYQJAHWSA-N diethyl azodicarboxylate Substances CCOC(=O)\N=N\C(=O)OCC FAMRKDQNMBBFBR-BQYQJAHWSA-N 0.000 claims description 2
- NPZTUJOABDZTLV-UHFFFAOYSA-N hydroxybenzotriazole Substances O=C1C=CC=C2NNN=C12 NPZTUJOABDZTLV-UHFFFAOYSA-N 0.000 claims description 2
- 238000000034 method Methods 0.000 claims 3
- 238000006751 Mitsunobu reaction Methods 0.000 claims 1
- ZHNUHDYFZUAESO-UHFFFAOYSA-N Formamide Chemical compound NC=O ZHNUHDYFZUAESO-UHFFFAOYSA-N 0.000 abstract description 8
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 6
- 208000010839 B-cell chronic lymphocytic leukemia Diseases 0.000 description 6
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 6
- 208000025205 Mantle-Cell Lymphoma Diseases 0.000 description 5
- 239000003814 drug Substances 0.000 description 5
- 208000031422 Lymphocytic Chronic B-Cell Leukemia Diseases 0.000 description 4
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 4
- 208000016025 Waldenstroem macroglobulinemia Diseases 0.000 description 4
- 208000033559 Waldenström macroglobulinemia Diseases 0.000 description 4
- 208000032852 chronic lymphocytic leukemia Diseases 0.000 description 4
- ONDSBJMLAHVLMI-UHFFFAOYSA-N trimethylsilyldiazomethane Chemical compound C[Si](C)(C)[CH-][N+]#N ONDSBJMLAHVLMI-UHFFFAOYSA-N 0.000 description 4
- -1 4-phenoxyphenyl Chemical group 0.000 description 3
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 3
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 3
- 229940079593 drug Drugs 0.000 description 3
- 229910052757 nitrogen Inorganic materials 0.000 description 3
- 239000000126 substance Substances 0.000 description 3
- NTSAEGNFPKKRLX-LJQANCHMSA-N tert-butyl (3r)-3-[4-amino-3-(4-phenoxyphenyl)pyrazolo[3,4-d]pyrimidin-1-yl]piperidine-1-carboxylate Chemical compound C1N(C(=O)OC(C)(C)C)CCC[C@H]1N1C2=NC=NC(N)=C2C(C=2C=CC(OC=3C=CC=CC=3)=CC=2)=N1 NTSAEGNFPKKRLX-LJQANCHMSA-N 0.000 description 3
- CYPYTURSJDMMMP-WVCUSYJESA-N (1e,4e)-1,5-diphenylpenta-1,4-dien-3-one;palladium Chemical compound [Pd].[Pd].C=1C=CC=CC=1\C=C\C(=O)\C=C\C1=CC=CC=C1.C=1C=CC=CC=1\C=C\C(=O)\C=C\C1=CC=CC=C1.C=1C=CC=CC=1\C=C\C(=O)\C=C\C1=CC=CC=C1 CYPYTURSJDMMMP-WVCUSYJESA-N 0.000 description 2
- QUKPALAWEPMWOS-UHFFFAOYSA-N 1h-pyrazolo[3,4-d]pyrimidine Chemical group C1=NC=C2C=NNC2=N1 QUKPALAWEPMWOS-UHFFFAOYSA-N 0.000 description 2
- IRVRZQLHMPWLLY-UHFFFAOYSA-N 2-[methoxy-(4-phenoxyphenyl)methylidene]propanedinitrile Chemical compound C1=CC(C(=C(C#N)C#N)OC)=CC=C1OC1=CC=CC=C1 IRVRZQLHMPWLLY-UHFFFAOYSA-N 0.000 description 2
- YYVUOZULIDAKRN-UHFFFAOYSA-N 3-(4-phenoxyphenyl)-2h-pyrazolo[3,4-d]pyrimidin-4-amine Chemical compound C=12C(N)=NC=NC2=NNC=1C(C=C1)=CC=C1OC1=CC=CC=C1 YYVUOZULIDAKRN-UHFFFAOYSA-N 0.000 description 2
- HQAIUXZORKJOJY-UHFFFAOYSA-N 3-iodo-2h-pyrazolo[3,4-d]pyrimidin-4-amine Chemical compound NC1=NC=NC2=NNC(I)=C12 HQAIUXZORKJOJY-UHFFFAOYSA-N 0.000 description 2
- RYAQFHLUEMJOMF-UHFFFAOYSA-N 4-phenoxybenzoic acid Chemical compound C1=CC(C(=O)O)=CC=C1OC1=CC=CC=C1 RYAQFHLUEMJOMF-UHFFFAOYSA-N 0.000 description 2
- 102000001714 Agammaglobulinaemia Tyrosine Kinase Human genes 0.000 description 2
- 108010029445 Agammaglobulinaemia Tyrosine Kinase Proteins 0.000 description 2
- 206010035226 Plasma cell myeloma Diseases 0.000 description 2
- 210000003719 b-lymphocyte Anatomy 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- 239000007859 condensation product Substances 0.000 description 2
- 238000005859 coupling reaction Methods 0.000 description 2
- 201000003444 follicular lymphoma Diseases 0.000 description 2
- 201000007924 marginal zone B-cell lymphoma Diseases 0.000 description 2
- 208000021937 marginal zone lymphoma Diseases 0.000 description 2
- 230000035772 mutation Effects 0.000 description 2
- 238000007363 ring formation reaction Methods 0.000 description 2
- 238000003786 synthesis reaction Methods 0.000 description 2
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 2
- NWZSZGALRFJKBT-KNIFDHDWSA-N (2s)-2,6-diaminohexanoic acid;(2s)-2-hydroxybutanedioic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O.NCCCC[C@H](N)C(O)=O NWZSZGALRFJKBT-KNIFDHDWSA-N 0.000 description 1
- LHCPRYRLDOSKHK-UHFFFAOYSA-N 7-deaza-8-aza-adenine Chemical compound NC1=NC=NC2=C1C=NN2 LHCPRYRLDOSKHK-UHFFFAOYSA-N 0.000 description 1
- 229940125814 BTK kinase inhibitor Drugs 0.000 description 1
- 208000002250 Hematologic Neoplasms Diseases 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 1
- 238000005577 Kumada cross-coupling reaction Methods 0.000 description 1
- 208000031671 Large B-Cell Diffuse Lymphoma Diseases 0.000 description 1
- 208000034578 Multiple myelomas Diseases 0.000 description 1
- 206010028980 Neoplasm Diseases 0.000 description 1
- 101100030361 Neurospora crassa (strain ATCC 24698 / 74-OR23-1A / CBS 708.71 / DSM 1257 / FGSC 987) pph-3 gene Proteins 0.000 description 1
- WTKZEGDFNFYCGP-UHFFFAOYSA-N Pyrazole Chemical compound C=1C=NNC=1 WTKZEGDFNFYCGP-UHFFFAOYSA-N 0.000 description 1
- CZPWVGJYEJSRLH-UHFFFAOYSA-N Pyrimidine Chemical compound C1=CN=CN=C1 CZPWVGJYEJSRLH-UHFFFAOYSA-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
- 102000015098 Tumor Suppressor Protein p53 Human genes 0.000 description 1
- 108010078814 Tumor Suppressor Protein p53 Proteins 0.000 description 1
- HFBMWMNUJJDEQZ-UHFFFAOYSA-N acryloyl chloride Chemical compound ClC(=O)C=C HFBMWMNUJJDEQZ-UHFFFAOYSA-N 0.000 description 1
- 230000009471 action Effects 0.000 description 1
- 230000004913 activation Effects 0.000 description 1
- 230000006907 apoptotic process Effects 0.000 description 1
- 230000004888 barrier function Effects 0.000 description 1
- 230000008901 benefit Effects 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 239000003054 catalyst Substances 0.000 description 1
- 210000004027 cell Anatomy 0.000 description 1
- 238000004440 column chromatography Methods 0.000 description 1
- 238000002648 combination therapy Methods 0.000 description 1
- 125000000151 cysteine group Chemical group N[C@@H](CS)C(=O)* 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 230000037430 deletion Effects 0.000 description 1
- 238000012217 deletion Methods 0.000 description 1
- 206010012818 diffuse large B-cell lymphoma Diseases 0.000 description 1
- 239000002552 dosage form Substances 0.000 description 1
- 238000002651 drug therapy Methods 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 239000002360 explosive Substances 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- ANSXAPJVJOKRDJ-UHFFFAOYSA-N furo[3,4-f][2]benzofuran-1,3,5,7-tetrone Chemical compound C1=C2C(=O)OC(=O)C2=CC2=C1C(=O)OC2=O ANSXAPJVJOKRDJ-UHFFFAOYSA-N 0.000 description 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 1
- 239000012456 homogeneous solution Substances 0.000 description 1
- IKDUDTNKRLTJSI-UHFFFAOYSA-N hydrazine monohydrate Substances O.NN IKDUDTNKRLTJSI-UHFFFAOYSA-N 0.000 description 1
- 230000026045 iodination Effects 0.000 description 1
- 238000006192 iodination reaction Methods 0.000 description 1
- 210000003563 lymphoid tissue Anatomy 0.000 description 1
- 238000003760 magnetic stirring Methods 0.000 description 1
- 230000003211 malignant effect Effects 0.000 description 1
- CUONGYYJJVDODC-UHFFFAOYSA-N malononitrile Chemical compound N#CCC#N CUONGYYJJVDODC-UHFFFAOYSA-N 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 238000003541 multi-stage reaction Methods 0.000 description 1
- 201000000050 myeloid neoplasm Diseases 0.000 description 1
- 239000002547 new drug Substances 0.000 description 1
- 229910000510 noble metal Inorganic materials 0.000 description 1
- 239000012074 organic phase Substances 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- BIWOSRSKDCZIFM-UHFFFAOYSA-N piperidin-3-ol Chemical compound OC1CCCNC1 BIWOSRSKDCZIFM-UHFFFAOYSA-N 0.000 description 1
- 125000003386 piperidinyl group Chemical group 0.000 description 1
- 230000003389 potentiating effect Effects 0.000 description 1
- 230000035755 proliferation Effects 0.000 description 1
- 125000006239 protecting group Chemical group 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 238000011125 single therapy Methods 0.000 description 1
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 238000001308 synthesis method Methods 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
- 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 description 1
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 230000004614 tumor growth Effects 0.000 description 1
- 239000011592 zinc chloride Substances 0.000 description 1
- 235000005074 zinc chloride Nutrition 0.000 description 1
- JIAARYAFYJHUJI-UHFFFAOYSA-L zinc dichloride Chemical compound [Cl-].[Cl-].[Zn+2] JIAARYAFYJHUJI-UHFFFAOYSA-L 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 invention relates to a preparation process of ibrutinib. Specifically, the compound shown in the formula I (5-amino-3- (4-phenoxyphenyl) -1H-pyrazole-4-carbonitrile) and the compound shown in the formula II ((S) -1- (3-hydroxypiperidin-1-yl) prop-2-en-1-one) are subjected to Mitsunobu condensation reaction to obtain a compound shown in the formula III ((R) -1- (1-acryloylpiperidin-3-yl) -5-amino-3- (4-phenoxyphenyl) -1H-pyrazole-4-carbonitrile), and the compound shown in the formula III is reacted with formamide to prepare ibrutinib.
Description
Technical Field
The invention belongs to the fields of medicine technology and medicine synthesis, and particularly relates to a preparation method of ibrutinib.
Background
Ibrutinib is an oral Bruton Tyrosine Kinase (BTK) inhibitor, and has the chemical name of 1- [ (3R) -3- [ 4-amino-3- (4-phenoxyphenyl) 1H-pyrazolo [3,4-d ] pyrimidin-1-yl ] -1-piperidyl ] -2-propen-1-one. Ibrutinib can be selectively and covalently combined with cysteine residue (Cys-481) on the BTK active site, irreversibly inhibits the activity of BTK, further inhibits the activation of a BCR signal path, effectively prevents tumors from migrating from B cells to lymphoid tissues suitable for tumor growth, reduces the malignant proliferation of the B cells and induces the apoptosis of the cells, thereby playing a role in treating CLL and MCL. In addition, ibrutinib single and combination therapies exhibit potent therapeutic efficacy against a wide variety of hematologic malignancies, including Chronic Lymphocytic Leukemia (CLL), Mantle Cell Lymphoma (MCL), Waldenstrom Macroglobulinemia (WM), diffuse large B-cell lymphoma (CLBCL), Follicular Lymphoma (FL), Multiple Myeloma (MM), and Marginal Zone Lymphoma (MZL), among others. The united states Food and Drug Administration (FDA) has accelerated approval and approval of the marketed application for ibrutinib at 2013, 11/13/d in the dosage form of 140mg capsule, under the trade name of Imbruvica, for the treatment of mantle cell lymphoma. The FDA granted ibrutinib breakthrough medication eligibility on 12/2/2014 for Chronic Lymphocytic Leukemia (CLL) patients who had previously received at least one drug therapy, since the FDA introduced new drug breakthrough, the 2 nd drug approved for such treatment. Since 10 months 2014, ibrutinib was three times approved on the market by EMA of the european union for the treatment of relapsed or refractory MCL, for the concurrent treatment of CLL, CLL carrying a del17p deletion mutation or a TP53 mutation, Waldenstrom Macroglobulinemia (WM). Ibrutinib was approved in 2015 by japanese PMDA to treat relapsed or refractory CLL.
The chemical name of ibrutinib is 1- [ (3R) -3- [ 4-amino-3- (4-phenoxyphenyl) -1H-pyrazolo [3,4-D ] pyrimidine-1-yl ] -1-piperidyl ] -2-propylene-1-ketone, and the molecular structure of ibrutinib contains a pyrazolo [3,4-D ] pyrimidine group and a piperidine group and also contains a chiral center. The chemical structural formula of ibrutinib is as follows:
the original synthesis route of ibrutinib (WO2013003629) starts from 4-phenoxybenzoic acid, and the preparation of ibrutinib is realized through multi-step reaction. 4-phenoxybenzoic acid reacts with thionyl chloride and malononitrile in sequence to obtain an intermediate 2- (hydroxy 4-phenoxyphenyl) methylene malononitrile; reacting the 2- (hydroxy 4-phenoxyphenyl) methylene malononitrile with trimethylsilyldiazomethane under the protection of nitrogen to obtain an intermediate 2- (methoxy (4-phenoxyphenyl) methylene) malononitrile; 2- (methoxyl (4-phenoxyphenyl) methylene) malononitrile and hydrazine hydrate are subjected to pyrazole cyclization reaction to obtain an intermediate 5-amino-3- (4-phenoxyphenyl) -1H-pyrazole-4-carbonitrile; carrying out pyrimidine cyclization reaction on 5-amino-3- (4-phenoxyphenyl) -1H-pyrazole-4-carbonitrile and formamide under the protection of nitrogen to obtain an intermediate 3- (4-phenoxyphenyl) -1H-pyrazolo [3,4-d ] pyrimidine-4-amine; carrying out Mitsunobu coupling reaction on 3- (4-phenoxyphenyl) -1H-pyrazolo [3,4-d ] pyrimidine-4-amine and Boc protected 3-hydroxypiperidine to obtain a condensation product, namely (R) -3- (4-amino-3- (4-phenoxyphenyl) -1H-pyrazolo [3,4-d ] pyrimidin-1-yl) piperidine-1-carboxylic acid tert-butyl ester; and removing the Boc protecting group from the condensation product, and reacting with acryloyl chloride to obtain ibrutinib. The relevant synthetic route is as follows:
patent CN104557945 describes another synthetic route for (R) -3- (4-amino-3- (4-phenoxyphenyl) -1H-pyrazolo [3,4-d ] pyrimidin-1-yl) piperidine-1-carboxylic acid tert-butyl ester. The route takes 1H-pyrazolo [3,4-d ] pyrimidine-4-amine as a starting material, and 3-iodo-1H-pyrazolo [3,4-d ] pyrimidine-4-amine is prepared by iodination; carrying out Mitsunobu condensation reaction on 3-iodo-1H-pyrazolo [3,4-d ] pyrimidine-4-amine and Boc-protected 3-hydroxypiperidine to prepare (R) -3- (4-amino-3-iodo-1H-pyrazolo [3,4-d ] pyrimidin-1-yl) piperidine-1-tert-butyl formate; the preparation of the tert-butyl (R) -3- (4-amino-3-iodo-1H-pyrazolo [3,4-d ] pyrimidin-1-yl) piperidine-1-carboxylate is realized by coupling reaction (Kumada coupling reaction) of tert-butyl (R) -3- (4-amino-3- (4-phenoxyphenyl) -1H-pyrazolo [3,4-d ] pyrimidin-1-yl) piperidine-1-carboxylate with 4-PhOPhMgBr under the action of ZnCl2/Pd2(dba) 3. This route, while circumventing the use of trimethylsilyldiazomethane, which is sensitive to water/air and potentially explosive, involves the use of the expensive noble metal catalyst Pd2(dba) 3. The relevant synthetic route is as follows:
disclosure of Invention
The invention aims to provide a synthesis method for preparing ibrutinib, aiming at overcoming the barriers and defects of the existing patent for synthesizing ibrutinib.
The technical scheme of the invention is that the compound formula I (5-amino-3- (4-phenoxyphenyl) -1H-pyrazole-4-carbonitrile) and the compound formula II ((S) -1- (3-hydroxypiperidin-1-yl) prop-2-en-1-one) are subjected to Mitsunobu condensation reaction to obtain the compound formula III ((R) -1- (1-acryloylpiperidin-3-yl) -5-amino-3- (4-phenoxyphenyl) -1H-pyrazole-4-carbonitrile), and then the compound formula III is reacted with formamide to prepare ibrutinib. The specific reaction formula is as follows:
step 1 involves a Mitsunobu condensation reaction under conditions wherein the compound of formula I and the compound of formula III are condensed in the presence of PPh3 and in the presence of condensing agents including DEAD, EDCI, HOBT, DIAD to produce the compound of formula III.
The solvent of the Mitsunobu condensation reaction related to the step 1 comprises THF, Dioxane, CH3CN, 2-Me-THF.
The solvent used in the reaction for constructing the pyrazolo [3,4-D ] pyrimidine ring in the step 1 comprises DMF, Dioxane, DMSO, CH3CN, toluene and the like.
Detailed Description
It will be understood by those skilled in the art, given the benefit of this disclosure, that various modifications and improvements may be made to the invention without departing from the spirit and scope of the invention. They are intended to fall within the scope of protection of the patent as defined by the claims of the present application. Furthermore, it should be understood that the examples provided herein are for illustrative purposes only and are not to be construed as limiting the invention.
The present invention will be described in further detail with reference to specific examples.
EXAMPLE 1 preparation of (R) -1- (1-acryloylpiperidin-3-yl) -5-amino-3- (4-phenoxyphenyl) -1H-pyrazole-4-carbonitrile
A5L reaction flask equipped with magnetic stirring and a thermometer. Under the protection of nitrogen, compound of formula I (5-amino-3- (4-phenoxyphenyl) -1H-pyrazole-4-carbonitrile) (120g,434.3mmol) and anhydrous Dioxane (1.5L) were added to a reaction flask, and stirred to give a completely homogeneous solution. The compound of formula II ((S) -1- (3-hydroxypiperidin-1-yl) prop-2-en-1-one) (80.9g,521.3mmol) and Ph3P (284.8g,1.086mol) were then added to the system. After the addition was complete the system was cooled to <0 ℃ and then DIAD (220g,1.088mmol) was added to the reaction via the addition funnel. After the addition is finished, the system is naturally heated to room temperature for reaction, and the reaction is followed by HPLC until the 5-amino-3- (4-phenoxyphenyl) -1H-pyrazole-4-carbonitrile is basically reacted completely. After the reaction is finished, the organic solvent is removed from the system under the condition of high vacuum, then H2O (1.0L) is added into the reaction system, and then the pH value of the system is adjusted to 6.0-7.0 by dilute hydrochloric acid. The system was extracted with dichloromethane (3X 1.5L), the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, the filtrate was freed of the solvent under reduced pressure, and the residue was purified by column chromatography to give the compound of formula III ((R) -1- (1-acryloylpiperidin-3-yl) -5-amino-3- (4-phenoxyphenyl) -1H-pyrazole-4-carbonitrile) (152.9g, 85.3%).
Example 2 preparation of ibrutinib
The reaction flask was charged with the compound of formula III ((R) -1- (1-acryloylpiperidin-3-yl) -5-amino-3- (4-phenoxyphenyl) -1H-pyrazole-4-carbonitrile) (16.54g,40mmol), formamide (2.70g,59.95mmol), and DMF (150mL) in that order. After the addition, the system is heated to 110 ℃ for reflux, a solvent (50mL) containing DMF is separated out through a water separator, the system is naturally cooled to 0 ℃, and the filtration is carried out, and the obtained solid is recrystallized by using toluene to obtain ibrutinib (14.66g, 83.2%).
Claims (3)
1. A method for preparing an ibrutinib intermediate (R) -1- (1-acryloylpiperidin-3-yl) -5-amino-3- (4-phenoxyphenyl) -1H-pyrazole-4-carbonitrile, in particular to a Mitsunobu condensation reaction between a compound shown as a formula I (5-amino-3- (4-phenoxyphenyl) -1H-pyrazole-4-carbonitrile) and a compound shown as a formula II ((S) -1- (3-hydroxypiperidin-1-yl) prop-2-en-1-one) to obtain a compound shown as a formula III ((R) -1- (1-acryloylpiperidin-3-yl) -5-amino-3- (4-phenoxyphenyl) -1H-pyrazole-4-carbonitrile) ). The reaction formula is as follows:
2. the process of claim 1 wherein the reaction involves a Mitsunobu condensation reaction under conditions such that the reaction is carried out at PPh3Condensing the compounds of formula I and formula III in the presence of a condensing agent comprising DEAD, EDCI, HOBT, DIAD.
3. The method of claim 1, wherein the Mitsunobu reaction involves a solvent selected from the group consisting of THF, Dioxane, and CH3CN,2-Me-THF。
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| CN105859728A (en) * | 2016-05-26 | 2016-08-17 | 江苏中邦制药有限公司 | Preparation method for ibrutinib |
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| WO2013003629A2 (en) * | 2011-06-28 | 2013-01-03 | Pharmacyclics, Inc. | Methods and compositions for inhibition of bone resorption |
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