CN115819412B - A synthetic method of N-heterocyclic BET bromodomain inhibitor and its intermediates - Google Patents
A synthetic method of N-heterocyclic BET bromodomain inhibitor and its intermediates Download PDFInfo
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- CN115819412B CN115819412B CN202211482870.8A CN202211482870A CN115819412B CN 115819412 B CN115819412 B CN 115819412B CN 202211482870 A CN202211482870 A CN 202211482870A CN 115819412 B CN115819412 B CN 115819412B
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- 229940125763 bromodomain inhibitor Drugs 0.000 title abstract description 4
- 239000000543 intermediate Substances 0.000 title 1
- 238000010189 synthetic method Methods 0.000 title 1
- 150000001875 compounds Chemical class 0.000 claims abstract description 89
- 238000006243 chemical reaction Methods 0.000 claims abstract description 84
- FKLJPTJMIBLJAV-UHFFFAOYSA-N Compound IV Chemical compound O1N=C(C)C=C1CCCCCCCOC1=CC=C(C=2OCCN=2)C=C1 FKLJPTJMIBLJAV-UHFFFAOYSA-N 0.000 claims abstract description 52
- NLFBCYMMUAKCPC-KQQUZDAGSA-N ethyl (e)-3-[3-amino-2-cyano-1-[(e)-3-ethoxy-3-oxoprop-1-enyl]sulfanyl-3-oxoprop-1-enyl]sulfanylprop-2-enoate Chemical compound CCOC(=O)\C=C\SC(=C(C#N)C(N)=O)S\C=C\C(=O)OCC NLFBCYMMUAKCPC-KQQUZDAGSA-N 0.000 claims abstract description 47
- FCSKOFQQCWLGMV-UHFFFAOYSA-N 5-{5-[2-chloro-4-(4,5-dihydro-1,3-oxazol-2-yl)phenoxy]pentyl}-3-methylisoxazole Chemical compound O1N=C(C)C=C1CCCCCOC1=CC=C(C=2OCCN=2)C=C1Cl FCSKOFQQCWLGMV-UHFFFAOYSA-N 0.000 claims abstract description 28
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 96
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 63
- 239000003054 catalyst Substances 0.000 claims description 48
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 47
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 40
- -1 (diphenylphosphine) dicyclopentadienyl iron nickel dichloride Chemical compound 0.000 claims description 39
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- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 36
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 36
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- 239000003153 chemical reaction reagent Substances 0.000 claims description 28
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 27
- 239000003446 ligand Substances 0.000 claims description 26
- NFHFRUOZVGFOOS-UHFFFAOYSA-N palladium;triphenylphosphane Chemical group [Pd].C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 NFHFRUOZVGFOOS-UHFFFAOYSA-N 0.000 claims description 26
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 claims description 23
- 238000000034 method Methods 0.000 claims description 22
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 20
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 18
- RIOQSEWOXXDEQQ-UHFFFAOYSA-N triphenylphosphine Chemical compound C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-N 0.000 claims description 18
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 17
- FJDQFPXHSGXQBY-UHFFFAOYSA-L caesium carbonate Chemical compound [Cs+].[Cs+].[O-]C([O-])=O FJDQFPXHSGXQBY-UHFFFAOYSA-L 0.000 claims description 17
- 229910000024 caesium carbonate Inorganic materials 0.000 claims description 17
- VNFWTIYUKDMAOP-UHFFFAOYSA-N sphos Chemical compound COC1=CC=CC(OC)=C1C1=CC=CC=C1P(C1CCCCC1)C1CCCCC1 VNFWTIYUKDMAOP-UHFFFAOYSA-N 0.000 claims description 17
- 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 claims description 16
- PCLIMKBDDGJMGD-UHFFFAOYSA-N N-bromosuccinimide Chemical compound BrN1C(=O)CCC1=O PCLIMKBDDGJMGD-UHFFFAOYSA-N 0.000 claims description 16
- 239000003513 alkali Substances 0.000 claims description 15
- 229910052751 metal Inorganic materials 0.000 claims description 15
- 239000002184 metal Substances 0.000 claims description 15
- LVEYOSJUKRVCCF-UHFFFAOYSA-N 1,3-Bis(diphenylphosphino)propane Substances C=1C=CC=CC=1P(C=1C=CC=CC=1)CCCP(C=1C=CC=CC=1)C1=CC=CC=C1 LVEYOSJUKRVCCF-UHFFFAOYSA-N 0.000 claims description 14
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 14
- DVSDBMFJEQPWNO-UHFFFAOYSA-N methyllithium Chemical group C[Li] DVSDBMFJEQPWNO-UHFFFAOYSA-N 0.000 claims description 14
- LWIHDJKSTIGBAC-UHFFFAOYSA-K tripotassium phosphate Chemical compound [K+].[K+].[K+].[O-]P([O-])([O-])=O LWIHDJKSTIGBAC-UHFFFAOYSA-K 0.000 claims description 14
- 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 claims description 11
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 claims description 11
- YJVFFLUZDVXJQI-UHFFFAOYSA-L palladium(ii) acetate Chemical group [Pd+2].CC([O-])=O.CC([O-])=O YJVFFLUZDVXJQI-UHFFFAOYSA-L 0.000 claims description 11
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 10
- NXPHGHWWQRMDIA-UHFFFAOYSA-M magnesium;carbanide;bromide Chemical compound [CH3-].[Mg+2].[Br-] NXPHGHWWQRMDIA-UHFFFAOYSA-M 0.000 claims description 10
- MFRIHAYPQRLWNB-UHFFFAOYSA-N sodium tert-butoxide Chemical compound [Na+].CC(C)(C)[O-] MFRIHAYPQRLWNB-UHFFFAOYSA-N 0.000 claims description 10
- JWUJQDFVADABEY-UHFFFAOYSA-N 2-methyltetrahydrofuran Chemical compound CC1CCCO1 JWUJQDFVADABEY-UHFFFAOYSA-N 0.000 claims description 9
- 101100030361 Neurospora crassa (strain ATCC 24698 / 74-OR23-1A / CBS 708.71 / DSM 1257 / FGSC 987) pph-3 gene Proteins 0.000 claims description 8
- 230000009471 action Effects 0.000 claims description 8
- 239000012046 mixed solvent Substances 0.000 claims description 8
- QFMZQPDHXULLKC-UHFFFAOYSA-N 1,2-bis(diphenylphosphino)ethane Chemical compound C=1C=CC=CC=1P(C=1C=CC=CC=1)CCP(C=1C=CC=CC=1)C1=CC=CC=C1 QFMZQPDHXULLKC-UHFFFAOYSA-N 0.000 claims description 7
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 7
- SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 claims description 7
- 229910000160 potassium phosphate Inorganic materials 0.000 claims description 7
- 235000011009 potassium phosphates Nutrition 0.000 claims description 7
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 7
- UGOMMVLRQDMAQQ-UHFFFAOYSA-N xphos Chemical compound CC(C)C1=CC(C(C)C)=CC(C(C)C)=C1C1=CC=CC=C1P(C1CCCCC1)C1CCCCC1 UGOMMVLRQDMAQQ-UHFFFAOYSA-N 0.000 claims description 7
- MENYRYNFSIBDQN-UHFFFAOYSA-N 5,5-dibromoimidazolidine-2,4-dione Chemical compound BrC1(Br)NC(=O)NC1=O MENYRYNFSIBDQN-UHFFFAOYSA-N 0.000 claims description 6
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims description 6
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 6
- 239000002585 base Substances 0.000 claims description 6
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 6
- CXNIUSPIQKWYAI-UHFFFAOYSA-N xantphos Chemical compound C=12OC3=C(P(C=4C=CC=CC=4)C=4C=CC=CC=4)C=CC=C3C(C)(C)C2=CC=CC=1P(C=1C=CC=CC=1)C1=CC=CC=C1 CXNIUSPIQKWYAI-UHFFFAOYSA-N 0.000 claims description 6
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 claims description 5
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims description 5
- MUALRAIOVNYAIW-UHFFFAOYSA-N binap Chemical compound C1=CC=CC=C1P(C=1C(=C2C=CC=CC2=CC=1)C=1C2=CC=CC=C2C=CC=1P(C=1C=CC=CC=1)C=1C=CC=CC=1)C1=CC=CC=C1 MUALRAIOVNYAIW-UHFFFAOYSA-N 0.000 claims description 5
- 239000007810 chemical reaction solvent Substances 0.000 claims description 5
- AXAZMDOAUQTMOW-UHFFFAOYSA-N dimethylzinc Chemical compound C[Zn]C AXAZMDOAUQTMOW-UHFFFAOYSA-N 0.000 claims description 5
- CCERQOYLJJULMD-UHFFFAOYSA-M magnesium;carbanide;chloride Chemical compound [CH3-].[Mg+2].[Cl-] CCERQOYLJJULMD-UHFFFAOYSA-M 0.000 claims description 5
- VXWPONVCMVLXBW-UHFFFAOYSA-M magnesium;carbanide;iodide Chemical compound [CH3-].[Mg+2].[I-] VXWPONVCMVLXBW-UHFFFAOYSA-M 0.000 claims description 5
- NRQNMMBQPIGPTB-UHFFFAOYSA-N methylaluminum Chemical compound [CH3].[Al] NRQNMMBQPIGPTB-UHFFFAOYSA-N 0.000 claims description 5
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 4
- 229910052794 bromium Inorganic materials 0.000 claims description 4
- YNHIGQDRGKUECZ-UHFFFAOYSA-N dichloropalladium;triphenylphosphanium Chemical group Cl[Pd]Cl.C1=CC=CC=C1[PH+](C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1[PH+](C=1C=CC=CC=1)C1=CC=CC=C1 YNHIGQDRGKUECZ-UHFFFAOYSA-N 0.000 claims description 4
- TUQOTMZNTHZOKS-UHFFFAOYSA-N tributylphosphine Chemical compound CCCCP(CCCC)CCCC TUQOTMZNTHZOKS-UHFFFAOYSA-N 0.000 claims description 4
- USXXIRQDHZXYHX-UHFFFAOYSA-N 2,3,4-tribromopyridine Chemical compound BrC1=CC=NC(Br)=C1Br USXXIRQDHZXYHX-UHFFFAOYSA-N 0.000 claims description 3
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- 125000001246 bromo group Chemical group Br* 0.000 claims description 3
- WDVGNXKCFBOKDF-UHFFFAOYSA-N dicyclohexyl-[3,6-dimethoxy-2-[2,4,6-tri(propan-2-yl)phenyl]phenyl]phosphane Chemical compound COC1=CC=C(OC)C(C=2C(=CC(=CC=2C(C)C)C(C)C)C(C)C)=C1P(C1CCCCC1)C1CCCCC1 WDVGNXKCFBOKDF-UHFFFAOYSA-N 0.000 claims description 3
- XGZVUEUWXADBQD-UHFFFAOYSA-L lithium carbonate Chemical compound [Li+].[Li+].[O-]C([O-])=O XGZVUEUWXADBQD-UHFFFAOYSA-L 0.000 claims description 3
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- 238000001727 in vivo Methods 0.000 description 1
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 231100000053 low toxicity Toxicity 0.000 description 1
- 238000001819 mass spectrum Methods 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000001280 n-hexyl group Chemical group C(CCCCC)* 0.000 description 1
- 125000000740 n-pentyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 230000017074 necrotic cell death Effects 0.000 description 1
- 125000001147 pentyl group Chemical group C(CCCC)* 0.000 description 1
- 230000035755 proliferation Effects 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 238000004537 pulping Methods 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 230000001105 regulatory effect Effects 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 150000003384 small molecules Chemical class 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 238000001308 synthesis method Methods 0.000 description 1
- 238000003786 synthesis reaction Methods 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
- CZDYPVPMEAXLPK-UHFFFAOYSA-N tetramethylsilane Chemical compound C[Si](C)(C)C CZDYPVPMEAXLPK-UHFFFAOYSA-N 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
Landscapes
- Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
Abstract
本申请提供了化合物III、化合物IV和化合物VI及其在制备一种N‑杂环BET溴结构域抑制剂(化合物VII)方面的用途，反应的起始原料简单易购，成本较低，每步反应条件温和，操作简单，收率高，利于工业化生产。The present application provides compound III, compound IV and compound VI and their use in preparing an N-heterocyclic BET bromodomain inhibitor (compound VII). The starting materials for the reaction are simple and easy to purchase, the cost is low, the reaction conditions for each step are mild, the operation is simple, the yield is high, and it is conducive to industrial production.
Description
Technical Field
The invention belongs to the technical field of pharmaceutical chemistry synthesis, and particularly relates to a compound III, a compound IV and a compound VI and application thereof in preparing an N-heterocycle BET bromodomain inhibitor (compound VII).
Background
Histone acetylation is an important component of epigenetic studies, and acetylated histones can activate gene transcription by DNA polymerase, RNA polymerase and transcription factors. The bromodomain and super-terminal domain (BET) families belong to the bromodomain protein family (bromodomain proteins, BRDs), an evolutionarily highly conserved class of proteins that recognize and bind acetylated lysine residues at the tail of histones, recruit chromatin-regulating related proteins, transcription factors, chromatin remodeling factors, etc., thereby playing an important role in regulating gene transcription and chromatin remodeling, which are associated with a variety of biological processes such as cell growth, proliferation differentiation, apoptotic necrosis, etc., and are important epigenetic "readers".
So far, the human genome has been found to encode 61 bromodomains in total, distributed among 46 different proteins. The BRDs family consists of BRD2, BRD3, BRD4, BRDT 4 subtypes, each of which contains two bromodomains (BD 1, BD 2) in tandem and one super terminal (ET) domain. The two bromodomains are mainly responsible for recognizing and binding to acetylated lysine residues, and the ET domain interacts with cofactors. Abnormal expression of BET proteins has been associated with various diseases, and although 4 members of the BET family have similar structures, there are still differences in biological functions, and in particular BRD4 is closely related to various diseases such as cancer and inflammation (Jung M et al, epigenomics,2015,7 (3): 487-501).
Targeting BET proteins is beneficial for developing new therapeutic strategies targeting cancers, inflammation and viruses. Small molecule inhibitors against BET proteins have been introduced into preclinical and clinical research stages, primarily for the treatment of cancer and autoimmune diseases.
In summary, the BET protein inhibitor has a good application prospect as drug development, the applicant develops a related bromine binding domain protein BRD4 inhibitor of epigenetic science in the form of N-ethyl-4- (5- (2-hydroxypropyl-2-yl) -3- (indoline-1-yl) thiophene-2-yl) -6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2,3-c ] pyridine-2-carboxamide, the structural formula of the BET protein inhibitor is shown as a formula VII, and the applicant reports that the compound has good BET protein inhibition activity and good pharmacokinetic property in PCT/CN2021/134454 (application date 2021.11.30, domestic application number 202180005165.6) of the prior application, and simultaneously can show good in vivo tumor inhibition activity and low risk of hERG heart toxicity, and is a new generation of high-efficiency low-toxicity BET protein inhibitor.
Therefore, the development of a preparation method which is simple in process, low in production cost and small in environmental pollution and is suitable for industrial production has important practical significance.
Disclosure of Invention
A first object of the present invention is to provide a compound III having the following structure:
wherein R is selected from C1-C6 alkyl;
Preferably, R is selected from C1-C4 alkyl;
Further preferably, R is selected from methyl or ethyl;
still more preferably, R is selected from methyl.
A second object of the present invention is to provide a compound IV having the following structure:
wherein R is selected from C1-C6 alkyl;
Preferably, R is selected from C1-C4 alkyl;
Further preferably, R is selected from methyl or ethyl;
still more preferably, R is selected from methyl.
A third object of the present invention is to provide a compound VI having the following structure:
wherein R is selected from C1-C6 alkyl;
Preferably, R is selected from C1-C4 alkyl;
Further preferably, R is selected from methyl or ethyl;
still more preferably, R is selected from methyl.
A fourth object of the present invention is to provide a process for preparing compound VII, which comprises the steps of reacting compound VI with a methyl metal reagent in a solvent D to prepare compound VII
Wherein the methyl metal reagent is selected from methyl lithium, methyl magnesium bromide, methyl magnesium chloride, methyl magnesium iodide, methyl zinc or methyl aluminum, preferably methyl lithium or methyl magnesium bromide;
wherein the molar ratio of the compound VI to the methyl metal reagent is 1:4.0-4.5;
wherein the solvent D is selected from tetrahydrofuran, 2-methyltetrahydrofuran, preferably tetrahydrofuran;
wherein the reaction temperature is 0-30 ℃, preferably 10-20 ℃.
In some specific embodiments, the process of the present invention for preparing compound VII comprises the steps of:
(1) The compound IV reacts with the compound V under the action of a catalyst B, alkali 2 and a solvent C to prepare a compound VI
In some specific embodiments, the reaction further comprises a ligand for catalyst B, wherein the ligand for catalyst B is selected from the group consisting of X-Phos, S-Phos, asPh 3、n-Bu3P、(MeO)3 P, PPh, and a bidentate ligand Ph 2P(CH2)2PPh2 (dppe) or Ph 2P(CH2)3PPh2 (dppp), preferably PPh3, asPh 3, or a bidentate ligand Ph2P(CH2)2PPh2(dppe)、Ph2P(CH2)3PPh2(dppp),, more preferably PPh3;
wherein the molar ratio of the catalyst B to the catalyst B ligand is 1:1.0-4.0, preferably 1:1.0-1.5;
wherein the molar ratio of the compound IV to the compound V is 1.0:0.9-1.2, preferably 1.0:1.0;
Wherein, the catalyst B is selected from palladium catalyst tetra (triphenylphosphine) palladium, palladium acetate, bis (triphenylphosphine) palladium dichloride or 1, 1-bis (triphenylphosphine) dicyclopentadienyl iron nickel dichloride, preferably tetra (triphenylphosphine) palladium, palladium acetate, more preferably tetra (triphenylphosphine) palladium;
Wherein the molar ratio of the compound IV to the catalyst B is 1:0.05-0.3, preferably 1:0.05-0.10;
Wherein the base 2 is selected from potassium carbonate, sodium carbonate, cesium carbonate, potassium phosphate, preferably potassium carbonate;
wherein the molar ratio of the compound IV to the alkali 2 is 1:2.0-3.5;
Wherein the reaction solvent C is a mixed solvent composed of an organic solvent and water, and the organic solvent is selected from 1, 4-dioxane, N-dimethylformamide, N-dimethylacetamide, dimethyl sulfoxide and N-methylpyrrolidone, preferably 1, 4-dioxane, N-dimethylacetamide, more preferably 1, 4-dioxane;
Wherein the mass ratio of the organic solvent to water in the mixed solvent is 1:0.05-0.20;
wherein the reaction temperature is 60-120 ℃, preferably 80-120 ℃, more preferably 80-90 ℃;
(2) Preparation of Compound VII by reacting Compound VI with methyl Metallium reagent in solvent D
Wherein the methyl metal reagent is selected from methyl lithium, methyl magnesium bromide, methyl magnesium chloride, methyl magnesium iodide, methyl zinc or methyl aluminum, preferably methyl lithium or methyl magnesium bromide;
wherein the molar ratio of the compound VI to the methyl metal reagent is 1:4.0-4.5;
wherein the solvent D is selected from tetrahydrofuran, 2-methyltetrahydrofuran, preferably tetrahydrofuran;
wherein the reaction temperature is 0-30 ℃, preferably 10-20 ℃.
In some specific embodiments, the process of the present invention for preparing compound VII comprises the steps of:
(1) Preparation of Compound IV by reacting Compound III with brominating reagent in solvent B
Wherein the brominating reagent is selected from bromine, NBS, tribromopyridine or dibromohydantoin, preferably NBS or dibromohydantoin, more preferably NBS;
wherein the molar ratio of the compound III to the brominating reagent is 1.0:0.9-1.2, preferably 1.0:1.0;
wherein the solvent B is an organic solvent selected from acetonitrile, ethyl acetate, acetone, N-dimethylformamide, N-dimethylacetamide or N-methylpyrrolidone, preferably acetonitrile, acetone, more preferably acetonitrile;
Wherein the reaction temperature is-10 to 30 ℃, preferably 0to 20 ℃, more preferably 0to 10 ℃;
(2) The compound IV reacts with the compound V under the action of a catalyst B, alkali 2 and a solvent C to prepare a compound VI
In some specific embodiments, the reaction further comprises a ligand for catalyst B, wherein the ligand for catalyst B is selected from the group consisting of X-Phos, S-Phos, asPh 3、n-Bu3P、(MeO)3 P, PPh, and a bidentate ligand Ph 2P(CH2)2PPh2 (dppe) or Ph 2P(CH2)3PPh2 (dppp), preferably PPh3, asPh 3, or a bidentate ligand Ph2P(CH2)2PPh2(dppe)、Ph2P(CH2)3PPh2(dppp),, more preferably PPh3;
wherein the molar ratio of the catalyst B to the catalyst B ligand is 1:1.0-4.0, preferably 1:1.0-1.5;
wherein the molar ratio of the compound IV to the compound V is 1.0:0.9-1.2, preferably 1.0:1.0;
Wherein, the catalyst B is selected from palladium catalyst tetra (triphenylphosphine) palladium, palladium acetate, bis (triphenylphosphine) palladium dichloride or 1, 1-bis (triphenylphosphine) dicyclopentadienyl iron nickel dichloride, preferably tetra (triphenylphosphine) palladium, palladium acetate, more preferably tetra (triphenylphosphine) palladium;
Wherein the molar ratio of the compound IV to the catalyst B is 1:0.05-0.3, preferably 1:0.05-0.10;
Wherein the base 2 is selected from potassium carbonate, sodium carbonate, cesium carbonate, potassium phosphate, preferably potassium carbonate;
wherein the molar ratio of the compound IV to the alkali 2 is 1:2.0-3.5;
Wherein the reaction solvent C is a mixed solvent composed of an organic solvent and water, and the organic solvent is selected from 1, 4-dioxane, N-dimethylformamide, N-dimethylacetamide, dimethyl sulfoxide and N-methylpyrrolidone, preferably 1, 4-dioxane, N-dimethylacetamide, more preferably 1, 4-dioxane;
Wherein the mass ratio of the organic solvent to water in the mixed solvent is 1:0.05-0.20;
wherein the reaction temperature is 60-120 ℃, preferably 80-120 ℃, more preferably 80-90 ℃;
(3) Preparation of Compound VII by reacting Compound VI with methyl Metallium reagent in solvent D
Wherein the methyl metal reagent is selected from methyl lithium, methyl magnesium bromide, methyl magnesium chloride, methyl magnesium iodide, methyl zinc or methyl aluminum, preferably methyl lithium or methyl magnesium bromide;
wherein the molar ratio of the compound VI to the methyl metal reagent is 1:4.0-4.5;
wherein the solvent D is selected from tetrahydrofuran, 2-methyltetrahydrofuran, preferably tetrahydrofuran;
wherein the reaction temperature is 0-30 ℃, preferably 10-20 ℃.
In some specific embodiments, the process of the present invention for preparing compound VII comprises the steps of:
(1) The compound I and the compound II react under the action of a catalyst A, alkali 1 and a solvent A to prepare a compound III
X is Cl, br or I;
in some specific embodiments, the reaction further comprises a ligand for catalyst a;
Wherein the ligand of the catalyst A is selected from P(o-tolyl)3、P(t-Bu)3、CyPF-t-Bu、JosiPhos、Binap、XantPhos、DPPF、Brett-Phos、Ru-Phos、X-Phos、S-Phos、Bippy-Phos,, preferably JosiPhos, xantPhos, brett-Phos, ru-Phos, X-Phos, S-Phos, bippy-Phos or Binap, more preferably S-Phos, binap;
wherein the molar ratio of the compound I to the compound II is 1:1.0-2.0, preferably 1:1.2;
Wherein, the catalyst A is selected from one of tetra (triphenylphosphine) palladium, tri (dibenzylideneacetone) dipalladium, palladium acetate and 1, 1-bis (diphenylphosphine) dipalladium dichloride, preferably tri (dibenzylideneacetone) dipalladium and palladium acetate, more preferably tri (dibenzylideneacetone) dipalladium;
wherein the molar ratio of the compound I to the catalyst A is 1:0.025-0.05;
Wherein the molar ratio of the catalyst A to the catalyst A ligand is 1:1.0-1.5;
wherein the base 1 is selected from potassium tert-butoxide, sodium tert-butoxide, potassium carbonate, sodium carbonate, cesium carbonate, lithium carbonate, potassium phosphate, potassium hydroxide, sodium hydroxide, preferably potassium tert-butoxide, sodium tert-butoxide, potassium carbonate, sodium carbonate, cesium carbonate, lithium carbonate, potassium phosphate, more preferably sodium tert-butoxide, cesium carbonate;
Wherein the molar ratio of the compound I to the alkali 1 is 1:2.0-3.5, preferably 1:2.0;
Wherein the reaction solvent A is an organic solvent selected from toluene, xylene, tetrahydrofuran, 2-methyltetrahydrofuran or 1, 4-dioxane, preferably toluene, xylene, tetrahydrofuran or 2-methyltetrahydrofuran, more preferably toluene or tetrahydrofuran;
wherein the reaction temperature is 60-120 ℃, preferably 60-80 ℃, more preferably 60-75 ℃;
(2) Preparation of Compound IV by reacting Compound III with brominating reagent in solvent B
Wherein the brominating reagent is selected from bromine, NBS, tribromopyridine or dibromohydantoin, preferably NBS or dibromohydantoin, more preferably NBS;
wherein the molar ratio of the compound III to the brominating reagent is 1.0:0.9-1.2, preferably 1.0:1.0;
wherein the solvent B is an organic solvent selected from acetonitrile, ethyl acetate, acetone, N-dimethylformamide, N-dimethylacetamide or N-methylpyrrolidone, preferably acetonitrile, acetone, more preferably acetonitrile;
Wherein the reaction temperature is-10 to 30 ℃, preferably 0to 20 ℃, more preferably 0to 10 ℃;
(3) The compound IV reacts with the compound V under the action of a catalyst B, alkali 2 and a solvent C to prepare a compound VI
In some specific embodiments, the reaction further comprises a ligand for catalyst B, wherein the ligand for catalyst B is selected from the group consisting of X-Phos, S-Phos, asPh 3、n-Bu3P、(MeO)3 P, PPh, and a bidentate ligand Ph 2P(CH2)2PPh2 (dppe) or Ph 2P(CH2)3PPh2 (dppp), preferably PPh3, asPh 3, or a bidentate ligand Ph2P(CH2)2PPh2(dppe)、Ph2P(CH2)3PPh2(dppp),, more preferably PPh3;
wherein the molar ratio of the catalyst B to the catalyst B ligand is 1:1.0-4.0, preferably 1:1.0-1.5;
wherein the molar ratio of the compound IV to the compound V is 1.0:0.9-1.2, preferably 1.0:1.0;
Wherein, the catalyst B is selected from palladium catalyst tetra (triphenylphosphine) palladium, palladium acetate, bis (triphenylphosphine) palladium dichloride or 1, 1-bis (triphenylphosphine) dicyclopentadienyl iron nickel dichloride, preferably tetra (triphenylphosphine) palladium, palladium acetate, more preferably tetra (triphenylphosphine) palladium;
Wherein the molar ratio of the compound IV to the catalyst B is 1:0.05-0.3, preferably 1:0.05-0.10;
Wherein the base 2 is selected from potassium carbonate, sodium carbonate, cesium carbonate, potassium phosphate, preferably potassium carbonate;
wherein the molar ratio of the compound IV to the alkali 2 is 1:2.0-3.5;
Wherein the reaction solvent C is a mixed solvent composed of an organic solvent and water, and the organic solvent is selected from 1, 4-dioxane, N-dimethylformamide, N-dimethylacetamide, dimethyl sulfoxide and N-methylpyrrolidone, preferably 1, 4-dioxane, N-dimethylacetamide, more preferably 1, 4-dioxane;
Wherein the mass ratio of the organic solvent to water in the mixed solvent is 1:0.05-0.20;
wherein the reaction temperature is 60-120 ℃, preferably 80-120 ℃, more preferably 80-90 ℃;
(4) Preparation of Compound VII by reacting Compound VI with methyl Metallium reagent in solvent D
Wherein the methyl metal reagent is selected from methyl lithium, methyl magnesium bromide, methyl magnesium chloride, methyl magnesium iodide, methyl zinc or methyl aluminum, preferably methyl lithium or methyl magnesium bromide;
wherein the molar ratio of the compound VI to the methyl metal reagent is 1:4.0-4.5;
wherein the solvent D is selected from tetrahydrofuran, 2-methyltetrahydrofuran, preferably tetrahydrofuran;
wherein the reaction temperature is 0-30 ℃, preferably 10-20 ℃.
In some specific embodiments, the process of the present invention for preparing compound VII comprises the steps of:
(1) Compound I, compound II, cesium carbonate, tris (dibenzylideneacetone) dipalladium, S-Phos in toluene at 75 ℃ to produce compound III;
(2) Reacting the compound III with NBS at 0-10 ℃ in acetonitrile to generate a compound IV;
(3) Carrying out Suzuki reaction on the compound IV and the compound V to obtain a compound VI;
(4) And (3) reacting the compound VI with methyl lithium in tetrahydrofuran at a temperature of 10-20 ℃ to generate a compound VII.
The invention has the beneficial effects that:
The method adopts the compound I (4-bromothiophene-2-methyl formate), the compound II (indoline) and the compound V (2- (ethylaminocarbonyl) -6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2,3-c ] pyridine-4-boric acid pinacol ester) as raw materials, and obtains the target compound VII through 4 steps of reactions.
Detailed Description
The present invention is described in further detail below with reference to examples, but is not limited to the following examples, and any equivalents in the art, which are in accordance with the present disclosure, are intended to fall within the scope of the present invention.
The structure of the compounds was determined by Mass Spectrometry (MS) or nuclear magnetic resonance (1HNMR、13 C NMR).
Nuclear magnetic resonance (1HNMR、13 C NMR) shift (. Delta.) is given in parts per million (ppm) and nuclear magnetic resonance (1 HNMR) is measured using a BrukerAVANCE-400 nuclear magnetic resonance apparatus with deuterated dimethyl sulfoxide (DMSO) as the solvent, tetramethylsilane (TMS) as the internal standard, and chemical shift is given in 10 -6 (ppm).
The Mass Spectrum (MS) was measured using FINNIGAN LCQAD (ESI) mass spectrometer (manufacturer: therm, model: FINNIGAN LCQ ADVANTAGE MAX).
In the case where no specific explanation is given to the present invention, the solution mentioned in the reaction of the present invention is an aqueous solution.
The term "room temperature" in the present invention means that the temperature is between 10 ℃ and 25 ℃.
In the present invention, unless otherwise indicated, the term "Cm-Cn" is used to refer to the moiety modified by the term having m-n carbon atoms (n is greater than m and both are integers). For example, C1-C6 means having 1-6 carbon atoms in its modified moiety, such as 1 carbon atom, 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms, or 6 carbon atoms.
In the present invention, the term "alkyl" is used to refer to a saturated hydrocarbon group consisting of only carbon atoms and hydrogen atoms, including, but not limited to, C1-C6 alkyl, C1-C5 alkyl, C1-C4 alkyl, C1-C3 alkyl, C1-C2 alkyl, and C1 alkyl, unless otherwise indicated. As non-limiting examples of alkyl groups, there may be mentioned straight or branched saturated hydrocarbon groups such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl and the other seven isomers, n-hexyl and the other sixteen isomers. For example, C1-C7 alkyl includes methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, and all isomers thereof.
The words "comprise", "comprising" and "include" and their equivalents are to be construed in an open, non-exclusive sense, i.e. "including but not limited to", meaning that other unspecified elements, components and steps are contemplated in addition to those listed.
EXAMPLE 1 preparation of Compound III 4- (indolin-1-yl) thiophene-2-carboxylic acid methyl ester
Toluene 1L, compound I100 g, compound II 64.5g, cesium carbonate 221.15g were added to a reaction flask at room temperature, replaced with nitrogen, and then 9.25g of S-Phos and 10.35g of tris (dibenzylideneacetone) dipalladium were added thereto, replaced with nitrogen again, and the temperature was raised to 75℃for 20 hours. Cooling to room temperature, adding water 1L, suction filtering, and separating. The organic phase was washed twice with 1.2L of 1M hydrochloric acid, then with saturated brine, separated, and concentrated under reduced pressure to remove the organic solvent. 400ml of methanol was added to the residue, which was stirred at room temperature for 2 hours, followed by suction filtration to obtain a crude product of Compound III. Recrystallization from acetonitrile, purification and drying gave 74.8g of pure compound III (HPLC purity 99.50%, yield 64%).
MS+[M+1]260.2。
1H NMR(400MHz,DMSO-d6)δ7.77(d,J＝1.9Hz,1H),7.31(d,J＝1.9Hz,1H),7.16(dd,J＝7.2,1.4Hz,1H),7.09(td,J＝7.6,1.4Hz,1H),7.05–6.97(m,1H),6.74(td,J＝7.3,1.1Hz,1H),3.92(t,J＝8.5Hz,2H),3.84(s,3H),3.09(t,J＝8.5Hz,2H).
13C NMR(101MHz,DMSO-d6)δ161.80,146.10,142.88,131.42,130.51,127.29,125.26,124.95,119.05,110.93,110.89,107.73,52.30,51.98,27.35.
EXAMPLE 2 preparation of Compound III 4- (indolin-1-yl) thiophene-2-carboxylic acid methyl ester
100ML of tetrahydrofuran, 10g of compound I, 6.45g of compound II and 22.12g of cesium carbonate are added to a reaction flask at room temperature, the mixture is replaced by nitrogen, 0.93g of S-Phos and 1.04g of tris (dibenzylideneacetone) dipalladium are added, the mixture is replaced by nitrogen again, and the temperature is raised to 75 ℃ for reaction for 20 hours. Cooling to room temperature, adding 100mL of ethyl acetate and 100mL of water, filtering, and separating. The organic phase was washed twice with 120mL of 1M hydrochloric acid, then with saturated brine, separated, and the organic solvent was concentrated under reduced pressure. 40ml of methanol was added to the residue, which was stirred at room temperature for 2 hours, followed by suction filtration to obtain a crude product of Compound III. Recrystallization from acetonitrile, purification and drying gave 6.25g (HPLC purity 99.17%, yield 53.3%) of pure compound III.
EXAMPLE 3 preparation of Compound III 4- (indolin-1-yl) thiophene-2-carboxylic acid methyl ester
100ML of toluene, 10g of compound I, 10.78g of compound II and 22.12g of cesium carbonate are added to a reaction flask at room temperature, the mixture is replaced by nitrogen, 0.93g of S-Phos and 1.04g of tris (dibenzylideneacetone) dipalladium are added, the mixture is replaced by nitrogen again, and the temperature is raised to 75 ℃ for reaction for 20 hours. Cooling to room temperature, adding 100mL of water, suction filtering, and separating. The organic phase was washed twice with 120mL of 1M hydrochloric acid, then with saturated brine, separated, and the organic solvent was concentrated under reduced pressure. 40ml of methanol was added to the residue, which was stirred at room temperature for 2 hours, followed by suction filtration to obtain a crude product of Compound III. Recrystallization from acetonitrile, purification and drying gave 7.54g (HPLC purity 99.68%, yield 64.3%) of pure compound III.
EXAMPLE 4 preparation of Compound III 4- (indolin-1-yl) thiophene-2-carboxylic acid methyl ester
100ML of tetrahydrofuran, 10g of compound I, 6.45g of compound II and 22.12g of cesium carbonate are added into a reaction flask at room temperature, the mixture is replaced by nitrogen, 1.42g of Binap and 1.04g of tris (dibenzylideneacetone) dipalladium are added, the mixture is replaced by nitrogen again, and the temperature is raised to 75 ℃ for reaction for 20 hours. Cooling to room temperature, adding 100mL of ethyl acetate and 100mL of water, filtering, and separating. The organic phase was washed twice with 120mL of 1M hydrochloric acid, then with saturated brine, separated, and the organic solvent was concentrated under reduced pressure. 40ml of methanol was added to the residue, which was stirred at room temperature for 2 hours, followed by suction filtration to obtain a crude product of Compound III. Recrystallization from acetonitrile, purification and drying gave 4.32g (HPLC purity 99.36%, yield 36.9%) of pure compound III.
EXAMPLE 5 preparation of Compound III 4- (indolin-1-yl) thiophene-2-carboxylic acid methyl ester
100ML of toluene, 10g of compound I, 10.78g of compound II and 6.5g of sodium tert-butoxide are added to a reaction flask at room temperature, the mixture is replaced by nitrogen, 0.93g of S-Phos and 1.04g of tris (dibenzylideneacetone) dipalladium are added, the mixture is replaced by nitrogen again, and the temperature is raised to 75 ℃ for reaction for 20 hours. Cooling to room temperature, adding 100mL of water, suction filtering, and separating. The organic phase was washed twice with 120mL of 1M hydrochloric acid, then with saturated brine, separated, and the organic solvent was concentrated under reduced pressure. Column chromatography purification gave 4.17g of pure compound III (HPLC purity 98.57%, yield 35.6%).
EXAMPLE 6 preparation of Compound III 4- (indolin-1-yl) thiophene-2-carboxylic acid methyl ester
100ML of toluene, 10g of compound I, 6.45g of compound II and 22.12g of cesium carbonate are added to a reaction flask at room temperature, the mixture is replaced by nitrogen, 1.85g of S-Phos and 2.07g of tris (dibenzylideneacetone) dipalladium are added, the mixture is replaced by nitrogen again, and the temperature is raised to 75 ℃ for reaction for 14 hours. Cooling to room temperature, adding 100mL of water, suction filtering, and separating. The organic phase was washed twice with 120mL of 1M hydrochloric acid, then with saturated brine, separated, and the organic solvent was concentrated under reduced pressure. 40ml of methanol was added to the residue, which was stirred at room temperature for 2 hours, followed by suction filtration to obtain a crude product of Compound III. Recrystallization from acetonitrile, purification and drying gave 7.31g (HPLC purity 99.08%, yield 62.3%) of pure compound III.
EXAMPLE 7 preparation of Compound III 4- (indolin-1-yl) thiophene-2-carboxylic acid methyl ester
100ML of toluene, 10g of compound I, 6.45g of compound II and 38.70g of cesium carbonate are added to a reaction flask at room temperature, the mixture is replaced by nitrogen, 0.93g of S-Phos and 1.04g of tris (dibenzylideneacetone) dipalladium are added, the mixture is replaced by nitrogen again, and the temperature is raised to 75 ℃ for reaction for 20 hours. Cooling to room temperature, adding 100mL of water, suction filtering, and separating. The organic phase was washed twice with 120mL of 1M hydrochloric acid, then with saturated brine, separated, and the organic solvent was concentrated under reduced pressure. 40ml of methanol was added to the residue, which was stirred at room temperature for 2 hours, followed by suction filtration to obtain a crude product of Compound III. Recrystallization from acetonitrile, purification and drying gave 7.68g (HPLC purity 99.34%, yield 65.4%) of pure compound III.
EXAMPLE 8 preparation of Compound III 4- (indolin-1-yl) thiophene-2-carboxylic acid methyl ester
100ML of toluene, 10g of compound I, 6.45g of compound II and 22.12g of cesium carbonate are added to a reaction flask at room temperature, the mixture is replaced by nitrogen, 0.93g of S-Phos and 1.04g of tris (dibenzylideneacetone) dipalladium are added, the mixture is replaced by nitrogen again, and the temperature is raised to 60 ℃ for reaction for 41 hours. Cooling to room temperature, adding 100mL of water, suction filtering, and separating. The organic phase was washed twice with 120mL of 1M hydrochloric acid, then with saturated brine, separated, and the organic solvent was concentrated under reduced pressure. 40ml of methanol was added to the residue, which was stirred at room temperature for 2 hours, followed by suction filtration to obtain a crude product of Compound III. Recrystallization from acetonitrile, purification and drying gave 5.83g of pure compound III (HPLC purity 99.42%, yield 49.7%).
EXAMPLE 9 preparation of Compound III 4- (indolin-1-yl) thiophene-2-carboxylic acid methyl ester
100ML of toluene, 10g of compound I, 6.45g of compound II and 22.12g of cesium carbonate are added to a reaction flask at room temperature, the mixture is replaced by nitrogen, 0.93g of S-Phos and 1.04g of tris (dibenzylideneacetone) dipalladium are added, the mixture is replaced by nitrogen again, and the temperature is raised to 120 ℃ for reaction for 10 hours. Cooling to room temperature, adding 100mL of water, suction filtering, and separating. The organic phase was washed twice with 120mL of 1M hydrochloric acid, then with saturated brine, separated, and the organic solvent was concentrated under reduced pressure. 40ml of methanol was added to the residue, which was stirred at room temperature for 2 hours, followed by suction filtration to obtain a crude product of Compound III. Recrystallization from acetonitrile, purification and drying gave 6.17g (HPLC purity 98.93%, yield 52.6%) of pure compound III.
EXAMPLE 10 preparation of Compound IV 4- (indolin-1-yl) -5-bromothiophene-2-carboxylic acid methyl ester
675Ml of acetonitrile and 45g of compound III were added to the reaction flask at room temperature, stirring was started, the temperature was lowered to 5℃and a solution of 29.2g of NBS dissolved in 450ml of acetonitrile was further added to react at 5℃for 1 hour. Suction filtration, drying at 30℃under reduced pressure for 4h and recrystallisation from acetonitrile gave pure compound IV 45.6g (HPLC purity 99.21%, yield 77.6%).
MS+[M+1]338.0/340.0。
1H NMR(400MHz,DMSO-d6)δ7.76(s,1H),7.17(dd,J＝7.2,1.3Hz,1H),7.01(td,J＝7.7,1.3Hz,1H),6.73(t,J＝7.5Hz,1H),6.37(d,J＝7.8Hz,1H),3.87(t,J＝8.4Hz,2H),3.82(s,3H),3.10(t,J＝8.4Hz,2H).
13C NMR(101MHz,DMSO-d6)δ160.65,148.12,143.60,131.93,129.63,129.13,126.98,124.84,119.15,111.76,108.51,53.16,52.58,28.18.
EXAMPLE 11 preparation of Compound IV 4- (indolin-1-yl) -5-bromothiophene-2-carboxylic acid methyl ester
675Ml of acetonitrile and 45g of compound III were added to a reaction flask at room temperature, stirring was started, the temperature was lowered to 5℃and a solution of 49.6g of dibromohydantoin dissolved in 450ml of acetonitrile was further added to react at 5℃for 1 hour. Suction filtration, drying at 30℃under reduced pressure for 4h and recrystallisation from acetonitrile gave 32.6g of pure compound IV (HPLC purity 98.43%, yield 55.5%).
EXAMPLE 12 preparation of Compound IV 4- (indolin-1-yl) -5-bromothiophene-2-carboxylic acid methyl ester
675Ml of acetonitrile and 45g of compound III were added to the reaction flask at room temperature, stirring was started, the temperature was lowered to 5℃and a solution of 35.04g of NBS dissolved in 450ml of acetonitrile was further added to react at 5℃for 1 hour. Suction filtration, drying at 30℃under reduced pressure for 4h and recrystallisation from acetonitrile gave pure compound IV 40.08g (HPLC purity 98.67%, yield 68.3%).
EXAMPLE 13 preparation of Compound IV 4- (indolin-1-yl) -5-bromothiophene-2-carboxylic acid methyl ester
675Ml of acetone and 45g of compound III were added to the reaction flask at room temperature, stirring was started, the temperature was lowered to 5℃and a solution of 29.2g of NBS dissolved in 450ml of acetone was further added to react at 5℃for 1 hour. 100ml of water was added, stirred for 30min, suction filtered, dried at 30℃under reduced pressure for 4h and recrystallized from acetonitrile to give 43.9g of pure compound IV (HPLC purity 99.17%, yield 74.8%).
EXAMPLE 14 preparation of Compound IV 4- (indolin-1-yl) -5-bromothiophene-2-carboxylic acid methyl ester
675Ml of acetonitrile and 45g of compound III were added to the reaction flask at room temperature, stirring was started, the temperature was lowered to 0℃and a solution of 29.2g of NBS dissolved in 450ml of acetonitrile was further added to react at 0℃for 1 hour. Suction filtration, drying at 30℃under reduced pressure for 4h and recrystallisation from acetonitrile gave 44.6g of pure compound IV (HPLC purity 99.59%, yield 76.0%).
EXAMPLE 15 preparation of Compound IV 4- (indolin-1-yl) -5-bromothiophene-2-carboxylic acid methyl ester
675Ml of acetonitrile and 45g of compound III were added to the reaction flask at room temperature, stirring was started, the temperature was lowered to 10℃and a solution of 29.2g of NBS dissolved in 450ml of acetonitrile was further added to react at 10℃for 1 hour. Suction filtration, drying at 30℃under reduced pressure for 4h and recrystallisation from acetonitrile gave 46.1g of pure compound IV (HPLC purity 98.86%, yield 78.5%).
EXAMPLE 16 preparation of Compound VI N-ethyl-4- [ 5-methoxycarbonyl-3- (indolin-1-yl) thiophen-2-yl ] -6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2,3-c ] pyridine-2-carboxamide
1, 4-Dioxahexacyclic ring 405ml, water 45ml, compound IV 15.0g, compound V18.3g, potassium carbonate 18.3g and tetrakis (triphenylphosphine) palladium 3.06 were added to a reaction flask at room temperature, nitrogen substitution and the temperature was raised to 80℃for reaction for 8 hours. Cooling to room temperature, adding 300ml of ethyl acetate, extracting with 300ml of water, separating liquid, extracting water phase with 300ml of ethyl acetate once, mixing organic phases, washing with saturated saline, concentrating under reduced pressure to remove organic solvent, adding 100ml of methanol into the residue, heating to 65deg.C, pulping for 1 hr, cooling to room temperature, filtering, and drying to obtain 17.32g of compound VI (HPLC purity 99.36%, yield 82.0%). MS + [ M+1]477.2.
1H NMR(400MHz,DMSO-d6)δ12.39(s,1H),8.38(t,J＝5.4Hz,1H),7.90(s,1H),7.54(s,1H),7.06(dd,J＝7.2,1.2Hz,1H),6.99(d,J＝1.7Hz,1H),6.86(td,J＝7.7,1.3Hz,1H),6.60(td,J＝7.4,1.0Hz,1H),6.31(d,J＝7.8Hz,1H),3.85(s,3H),3.76(t,J＝8.5Hz,2H),3.47(s,3H),3.26(qd,J＝7.3,5.3Hz,2H),2.98(t,J＝8.4Hz,2H),1.14–1.06(m,3H).
13C NMR(101MHz,DMSO-d6)δ161.49,159.16,154.02,147.82,139.79,133.90,131.99,130.76,129.66,129.09,127.79,126.79,124.60,124.15,118.53,107.93,106.14,104.64,52.99,52.39,35.88,33.73,28.07,14.52.
EXAMPLE 17 preparation of Compound VI N-ethyl-4- [ 5-methoxycarbonyl-3- (indolin-1-yl) thiophen-2-yl ] -6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2,3-c ] pyridine-2-carboxamide
40.5Ml of 1, 4-dioxane, 4.5ml of water, 1.5g of compound IV, 2.2g of compound V, 1.83g of potassium carbonate and 0.31g of tetrakis (triphenylphosphine) palladium were added to a reaction flask at room temperature, nitrogen substitution was performed, and the temperature was raised to 80℃for reaction for 8 hours. Cooling to room temperature, adding 30ml of ethyl acetate, extracting and separating liquid with 30ml of water, and extracting the water phase with 30ml of ethyl acetate once. The organic phases were combined, washed with saturated brine, concentrated under reduced pressure to remove the organic solvent, 10ml of methanol was added to the residue, the mixture was slurried at 65℃for 1 hour, cooled to room temperature, filtered and dried to give 1.80g of Compound VI (HPLC purity: 99.68%, yield: 85.4%). EXAMPLE 18 preparation of Compound VI N-ethyl-4- [ 5-methoxycarbonyl-3- (indolin-1-yl) thiophen-2-yl ] -6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2,3-c ] pyridine-2-carboxamide
40.5Ml of 1, 4-dioxane, 4.5ml of water, 1.5g of compound IV, 2.2g of compound V, 1.83g of potassium carbonate, 0.06g of palladium acetate and 0.28g of triphenylphosphine are added to a reaction flask at room temperature, nitrogen substitution is performed, and the temperature is raised to 80 ℃ for reaction for 8 hours. Cooling to room temperature, adding 30ml of ethyl acetate, extracting and separating liquid with 30ml of water, and extracting the water phase with 30ml of ethyl acetate once. The organic phases were combined, washed with saturated brine, concentrated under reduced pressure to remove the organic solvent, 10ml of methanol was added to the residue, the mixture was slurried at 65℃for 1 hour, cooled to room temperature, filtered and dried to give 1.72g of Compound VI (HPLC purity 98.74%, yield 81.5%). EXAMPLE 19 preparation of Compound VI N-ethyl-4- [ 5-methoxycarbonyl-3- (indolin-1-yl) thiophen-2-yl ] -6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2,3-c ] pyridine-2-carboxamide
40.5Ml of 1, 4-dioxane, 4.5ml of water, 1.5g of compound IV, 2.2g of compound V, 1.22g of potassium carbonate and 0.31g of tetrakis (triphenylphosphine) palladium were added to a reaction flask at room temperature, nitrogen substitution was performed, and the temperature was raised to 80℃for reaction for 8 hours. Cooling to room temperature, adding 30ml of ethyl acetate, extracting and separating liquid with 30ml of water, and extracting the water phase with 30ml of ethyl acetate once. The organic phases were combined, washed with saturated brine, concentrated under reduced pressure to remove the organic solvent, 10ml of methanol was added to the residue, the mixture was slurried at 65℃for 1 hour, cooled to room temperature, filtered and dried to give 1.62g of Compound VI (purity of 99.15% by HPLC, yield 76.8%). EXAMPLE 20 preparation of Compound VI N-ethyl-4- [ 5-methoxycarbonyl-3- (indolin-1-yl) thiophen-2-yl ] -6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2,3-c ] pyridine-2-carboxamide
40.5Ml of 1, 4-dioxane, 4.5ml of water, 1.5g of compound IV, 2.2g of compound V, 2.14g of potassium carbonate and 0.31g of tetrakis (triphenylphosphine) palladium were added to a reaction flask at room temperature, nitrogen substitution was performed, and the temperature was raised to 80℃for reaction for 8 hours. Cooling to room temperature, adding 30ml of ethyl acetate, extracting and separating liquid with 30ml of water, and extracting the water phase with 30ml of ethyl acetate once. The organic phases were combined, washed with saturated brine, concentrated under reduced pressure to remove the organic solvent, 10ml of methanol was added to the residue, the mixture was slurried at 65℃for 1 hour, cooled to room temperature, filtered and dried to give 1.82g of Compound VI (HPLC purity 99.03%, yield 86.3%). EXAMPLE 21 preparation of Compound VI N-ethyl-4- [ 5-methoxycarbonyl-3- (indolin-1-yl) thiophen-2-yl ] -6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2,3-c ] pyridine-2-carboxamide
40.5Ml of N, N-dimethylacetamide, 4.5ml of water, 1.5g of compound IV, 2.2g of compound V, 1.83g of potassium carbonate and 0.31g of tetrakis (triphenylphosphine) palladium were added to a reaction flask at room temperature, nitrogen substitution was performed, and the temperature was raised to 80℃for reaction for 8 hours. Cooling to room temperature, adding 30ml of ethyl acetate, extracting and separating liquid with 30ml of water, and extracting the water phase with 30ml of ethyl acetate once. The organic phases were combined, washed with saturated brine, concentrated under reduced pressure to remove the organic solvent, 10ml of methanol was added to the residue, the mixture was slurried at 65℃for 1 hour, cooled to room temperature, filtered and dried to give 1.57g of Compound VI (HPLC purity 99.72%, yield 74.4%). EXAMPLE 22 preparation of Compound VI N-ethyl-4- [ 5-methoxycarbonyl-3- (indolin-1-yl) thiophen-2-yl ] -6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2,3-c ] pyridine-2-carboxamide
40.5Ml of 1, 4-dioxane, 4.5ml of water, 1.5g of compound IV, 2.2g of compound V, 1.83g of potassium carbonate and 0.31g of tetrakis (triphenylphosphine) palladium were added to a reaction flask at room temperature, nitrogen substitution was performed, and the temperature was raised to 60℃for reaction for 24 hours. Cooling to room temperature, adding 30ml of ethyl acetate, extracting and separating liquid with 30ml of water, and extracting the water phase with 30ml of ethyl acetate once. The organic phases were combined, washed with saturated brine, concentrated under reduced pressure to remove the organic solvent, 10ml of methanol was added to the residue, the mixture was slurried at 65℃for 1 hour, cooled to room temperature, filtered and dried to give 1.42g of Compound VI (purity of 98.77% by HPLC, yield 67.3%). EXAMPLE 23 preparation of Compound VI N-ethyl-4- [ 5-methoxycarbonyl-3- (indolin-1-yl) thiophen-2-yl ] -6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2,3-c ] pyridine-2-carboxamide
40.5Ml of 1, 4-dioxane, 4.5ml of water, 1.5g of compound IV, 2.2g of compound V, 1.83g of potassium carbonate and 0.31g of tetrakis (triphenylphosphine) palladium were added to a reaction flask at room temperature, nitrogen substitution was performed, and the temperature was raised to 120℃for reaction for 4 hours. Cooling to room temperature, adding 30ml of ethyl acetate, extracting and separating liquid with 30ml of water, and extracting the water phase with 30ml of ethyl acetate once. The organic phases were combined, washed with saturated brine, concentrated under reduced pressure to remove the organic solvent, 10ml of methanol was added to the residue, the mixture was slurried at 65℃for 1 hour, cooled to room temperature, filtered and dried to give 1.79g of Compound VI (HPLC purity 99.16%, yield 84.8%). EXAMPLE 24 preparation of Compound VII (N-ethyl-4- (5- (2-hydroxypropyl-2-yl) -3- (indolin-1-yl) thiophen-2-yl) -6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2,3-c ] pyridine-2-carboxamide)
Under the protection of inert gas at room temperature, 600ml of tetrahydrofuran and 20g of compound VI are added into a reaction bottle, the temperature is reduced to 10 ℃, 11.1ml of 1.6M methyl lithium is added dropwise, and the reaction is carried out for 30min. The reaction was quenched by adding saturated ammonium chloride, adjusting pH to 8-9, further adding 120ml of water, separating the solution, washing the organic phase with saturated brine, drying over anhydrous sodium sulfate, filtering, concentrating the organic solvent under reduced pressure, adding 160ml of methylene chloride and 30ml of 1, 4-dioxane, crystallizing at 20℃for 6 hours, filtering, and drying to give 15.2g of Compound VII (HPLC purity 99.18%, yield 76.0%).
MS+[M+1]477.3,
1H NMR(400MHz,DMSO-d6)δ12.28(s,1H),8.36(t,J＝5.4Hz,1H),7.34(s,1H),7.05(s,1H),7.01(dd,J＝7.2,1.2Hz,1H),6.92(d,J＝1.2Hz,1H),6.90–6.79(m,1H),6.54(td,J＝7.4,1.0Hz,1H),6.34(d,J＝7.7Hz,1H),5.53(s,1H),4.02(q,J＝7.1Hz,1H),3.70(t,J＝8.5Hz,2H),3.47(s,3H),3.25(qd,J＝7.2,5.3Hz,2H),3.02–2.83(m,2H),1.99(s,1H),1.53(s,6H),1.17(t,J＝7.1Hz,1H),1.11(t,J＝7.2Hz,3H).
13C NMR(101MHz,DMSO-d6)δ170.33,159.27,154.00,153.91,148.56,138.11,133.59,129.65,129.27,128.75,126.84,124.39,124.16,121.69,117.73,117.25,107.66,107.50,105.12,105.07,69.93,52.87,35.75,33.72,32.16,28.01,14.50.
EXAMPLE 25 preparation of Compound VII (N-ethyl-4- (5- (2-hydroxypropyl-2-yl) -3- (indolin-1-yl) thiophen-2-yl) -6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2,3-c ] pyridine-2-carboxamide)
Under the protection of inert gas at room temperature, 60ml of tetrahydrofuran and 2.0g of compound VI are added into a reaction bottle, the temperature is reduced to 10 ℃, 5.9ml of 3M methyl magnesium bromide is added dropwise, and the reaction is carried out for 30min. The reaction was quenched by adding saturated ammonium chloride, adjusting pH to 8-9, adding 12ml of water, separating the solution, washing the organic phase with saturated brine, drying over anhydrous sodium sulfate, filtering, concentrating the organic solvent under reduced pressure, adding 16ml of methylene chloride and 3ml of 1, 4-dioxane at 20℃for crystallization for 6 hours, filtering, and drying to give 1.48g of Compound VII (HPLC purity 98.56%, yield 74.0%).
EXAMPLE 26 preparation of Compound VII (N-ethyl-4- (5- (2-hydroxypropyl-2-yl) -3- (indolin-1-yl) thiophen-2-yl) -6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2,3-c ] pyridine-2-carboxamide)
Under the protection of inert gas at room temperature, 60ml of tetrahydrofuran and 2.0g of compound VI are added into a reaction bottle, the temperature is reduced to 10 ℃, 11.8ml of 1.6M methyl lithium is added dropwise, and the reaction is carried out for 30min. The reaction was quenched by adding saturated ammonium chloride, adjusting pH to 8-9, adding 12ml of water, separating the solution, washing the organic phase with saturated brine, drying over anhydrous sodium sulfate, filtering, concentrating the organic solvent under reduced pressure, adding 16ml of methylene chloride and 3ml of 1, 4-dioxane at 20℃for crystallization for 6 hours, filtering, and drying to give 1.46g of Compound VII (HPLC purity 97.21%, yield 73.0%).
EXAMPLE 27 preparation of Compound VII (N-ethyl-4- (5- (2-hydroxypropyl-2-yl) -3- (indolin-1-yl) thiophen-2-yl) -6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2,3-c ] pyridine-2-carboxamide)
Under the protection of inert gas at room temperature, 60ml of 2-methyltetrahydrofuran and 2.0g of compound VI are added into a reaction bottle, the temperature is reduced to 10 ℃, 11.1ml of 1.6M methyl lithium is added dropwise, and the reaction is carried out for 30min. The reaction was quenched by adding saturated ammonium chloride, adjusting pH to 8-9, adding 12ml of water, separating the solution, washing the organic phase with saturated brine, drying over anhydrous sodium sulfate, filtering, concentrating the organic solvent under reduced pressure, adding 16ml of methylene chloride and 3ml of 1, 4-dioxane at 20℃for crystallization for 6 hours, filtering, and drying to give 1.55g of Compound VII (HPLC purity: 97.94%, yield: 77.5%).
EXAMPLE 28 preparation of Compound VII (N-ethyl-4- (5- (2-hydroxypropyl-2-yl) -3- (indolin-1-yl) thiophen-2-yl) -6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2,3-c ] pyridine-2-carboxamide)
Under the protection of inert gas at room temperature, 60ml of tetrahydrofuran and 2.0g of compound VI are added into a reaction bottle, the temperature is reduced to 20 ℃, 11.1ml of 1.6M methyl lithium is added dropwise, and the reaction is carried out for 30min. The reaction was quenched by adding saturated ammonium chloride, adjusting pH to 8-9, adding 120ml of water, separating the solution, washing the organic phase with saturated brine, drying over anhydrous sodium sulfate, filtering, concentrating the organic solvent under reduced pressure, adding 16ml of methylene chloride and 3ml of 1, 4-dioxane at 20℃for crystallization for 6 hours, filtering, and drying to give 1.49g of Compound VII (HPLC purity 98.99%, yield 74.5%).
Claims (20)
1. A compound IV having the structure:
wherein R is C1-C6 alkyl.
2. Compound IV according to claim 1, characterized in that R is a C1-C4 alkyl group.
3. Compound IV according to claim 2, characterized in that R is methyl or ethyl.
4. A process for preparing compound VII features that compound VI is reacted with methyl metal reagent in solvent D to obtain compound VII
Wherein R is as defined in any one of claims 1 to 3.
5. The method according to claim 4, comprising the steps of:
(1) The compound IV reacts with the compound V under the action of a catalyst B, alkali 2 and a solvent C to prepare a compound VI;
(2) Reacting the compound VI with a methyl metal reagent in a solvent D to obtain a compound VII
6. The method according to claim 4, comprising the steps of:
(1) Preparation of Compound IV by reacting Compound III with brominating reagent in solvent B
(2) The compound IV reacts with the compound V under the action of a catalyst B, alkali 2 and a solvent C to prepare a compound VI
(3) Reacting the compound VI with a methyl metal reagent in a solvent D to obtain a compound VII
7. The method according to claim 4, comprising the steps of:
wherein X is Cl, br or I;
(1) The compound I and the compound II react under the action of a catalyst A, alkali 1 and a solvent A to prepare a compound III;
(2) Reacting the compound III with a brominating reagent in a solvent B to obtain a compound IV;
(3) The compound IV reacts with the compound V under the action of a catalyst B, alkali 2 and a solvent C to prepare a compound VI;
(4) Compound VI is reacted with a methyl metal reagent in solvent D to produce compound VII.
8. The method according to any one of claims 4-7, wherein:
The methyl metal reagent is selected from methyl lithium, methyl magnesium bromide, methyl magnesium chloride, methyl magnesium iodide, methyl zinc or methyl aluminum, and the solvent D is selected from tetrahydrofuran or 2-methyltetrahydrofuran.
9. The method according to any one of claims 5-7, wherein:
The catalyst B is selected from tetra (triphenylphosphine) palladium, palladium acetate, bis (triphenylphosphine) palladium dichloride or 1, 1-bis (diphenylphosphine) dicyclopentadienyl iron nickel dichloride;
The base 2 is selected from potassium carbonate, sodium carbonate, cesium carbonate or potassium phosphate;
the solvent C is a mixed solvent composed of an organic solvent and water, wherein the organic solvent is one or more selected from 1, 4-dioxane, N-dimethylformamide, N-dimethylacetamide, dimethyl sulfoxide or N-methylpyrrolidone, and the mass ratio of the organic solvent to the water in the mixed solvent is 1:0.05-0.20.
10. The method according to any one of claims 6-7, wherein:
the brominating reagent is selected from bromine, NBS, tribromopyridine or dibromohydantoin;
the solvent B is an organic solvent selected from acetonitrile, ethyl acetate, acetone, N-dimethylformamide, N-dimethylacetamide or N-methylpyrrolidone.
11. The method according to claim 7, wherein:
The catalyst A is selected from tetra (triphenylphosphine) palladium, tris (dibenzylideneacetone) dipalladium, palladium acetate or 1, 1-bis (diphenylphosphine) dicyclopentadienyl iron;
The alkali 1 is selected from potassium tert-butoxide, sodium tert-butoxide, potassium carbonate, sodium carbonate, cesium carbonate, lithium carbonate, potassium phosphate, potassium hydroxide or sodium hydroxide;
The reaction solvent A is an organic solvent selected from toluene, xylene, tetrahydrofuran, 2-methyltetrahydrofuran or 1, 4-dioxane.
12. The method according to claim 7, wherein:
In the step (1), a catalyst A ligand is also contained in the reaction, wherein the ligand is PPh3、P(o-tolyl)3、P(t-Bu)3、CyPF-t-Bu、JosiPhos、Binap、XantPhos、DPPF、Brett-Phos、Ru-Phos、X-Phos、S-Phos or Bippy-Phos, the molar ratio of the catalyst A to the catalyst A ligand is 1:1.0-1.5, the molar ratio of the compound I to the catalyst A is 1:0.025-0.05, the molar ratio of the compound I to the compound II is 1:1.0-2.0, the molar ratio of the compound I to alkali is 1:2.0-3.5, and the reaction temperature is 60-120 ℃;
in the step (2), the mol ratio of the compound III to the brominating reagent is 1.0:0.90-1.2, and the reaction temperature is-10-30 ℃;
in the step (3), a catalyst B ligand is also contained in the reaction, wherein the ligand is selected from X-Phos, S-Phos, asPh 3、n-Bu3P、(MeO)3 P, PPh3, bidentate ligand Ph 2P(CH2)2PPh2 (dppe) or Ph 2P(CH2)3PPh2 (dppp), the molar ratio of the catalyst B to the catalyst B ligand is 1:1.0-4.0, the molar ratio of the compound IV to the compound V is 1:0.9-1.2, the molar ratio of the compound IV to the catalyst B is 1:0.05-0.30, the molar ratio of the compound IV to the alkali 2 is 1:2.0-3.5, and the reaction temperature is 60-120 ℃;
In the step (4), the molar ratio of the compound VI to the methyl metal reagent is 1:4.0-4.5, and the reaction temperature is 0-30 ℃.
13. The method according to claim 12, wherein the molar ratio of compound I to compound II in step (1) is 1:1.2.
14. The method according to claim 12, wherein the molar ratio of the compound I to the base in the step (1) is 1:2.0.
15. The method of claim 12, wherein the reaction temperature in the step (1) is 60-80 ℃.
16. The method of claim 12, wherein the molar ratio of the compound III to the brominating agent in the step (2) is 1.0:1.0, and the reaction temperature is 0-20 ℃.
17. The method of claim 16, wherein the reaction temperature is 0-10 ℃.
18. The method according to claim 12, wherein the molar ratio of the catalyst B to the ligand of the catalyst B in the step (3) is 1:1.0-1.5, the molar ratio of the compound IV to the compound V is 1.0:1.0, the molar ratio of the compound IV to the catalyst B is 1:0.05-0.10, and the reaction temperature is 80-120 ℃.
19. The method of claim 18, wherein the reaction temperature is 80-90 ℃.
20. The method according to claim 12, wherein the reaction temperature in the step (4) is 10 to 20 ℃.
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