CN114933536A - Synthetic method of chiral intermediate of SOS1 pan KRAS inhibitor - Google Patents
Synthetic method of chiral intermediate of SOS1 pan KRAS inhibitor Download PDFInfo
- Publication number
- CN114933536A CN114933536A CN202210276336.5A CN202210276336A CN114933536A CN 114933536 A CN114933536 A CN 114933536A CN 202210276336 A CN202210276336 A CN 202210276336A CN 114933536 A CN114933536 A CN 114933536A
- Authority
- CN
- China
- Prior art keywords
- formula
- reaction
- compound shown
- compound
- sos1
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
- 101100404726 Arabidopsis thaliana NHX7 gene Proteins 0.000 title claims abstract description 25
- 102000057028 SOS1 Human genes 0.000 title claims abstract description 25
- 108700022176 SOS1 Proteins 0.000 title claims abstract description 25
- 101100197320 Saccharomyces cerevisiae (strain ATCC 204508 / S288c) RPL35A gene Proteins 0.000 title claims abstract description 25
- 101150100839 Sos1 gene Proteins 0.000 title claims abstract description 25
- 229940124785 KRAS inhibitor Drugs 0.000 title claims abstract description 22
- 238000010189 synthetic method Methods 0.000 title claims description 3
- 150000001875 compounds Chemical class 0.000 claims abstract description 114
- 238000006243 chemical reaction Methods 0.000 claims abstract description 78
- MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 claims abstract description 22
- 238000000034 method Methods 0.000 claims abstract description 22
- 230000015572 biosynthetic process Effects 0.000 claims abstract description 15
- 238000010791 quenching Methods 0.000 claims abstract description 14
- 238000003786 synthesis reaction Methods 0.000 claims abstract description 14
- 230000000171 quenching effect Effects 0.000 claims abstract description 13
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 claims abstract description 11
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims abstract description 11
- NXPHGHWWQRMDIA-UHFFFAOYSA-M magnesium;carbanide;bromide Chemical compound [CH3-].[Mg+2].[Br-] NXPHGHWWQRMDIA-UHFFFAOYSA-M 0.000 claims abstract description 11
- 239000003153 chemical reaction reagent Substances 0.000 claims abstract description 10
- 230000018044 dehydration Effects 0.000 claims abstract description 8
- 238000006297 dehydration reaction Methods 0.000 claims abstract description 8
- 238000006482 condensation reaction Methods 0.000 claims abstract description 7
- 239000007795 chemical reaction product Substances 0.000 claims abstract description 6
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 claims description 48
- 239000000243 solution Substances 0.000 claims description 31
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 24
- 238000001035 drying Methods 0.000 claims description 21
- 239000012074 organic phase Substances 0.000 claims description 20
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 claims description 14
- 239000008346 aqueous phase Substances 0.000 claims description 13
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 claims description 12
- 239000007864 aqueous solution Substances 0.000 claims description 12
- 229910052757 nitrogen Inorganic materials 0.000 claims description 12
- 239000000741 silica gel Substances 0.000 claims description 12
- 229910002027 silica gel Inorganic materials 0.000 claims description 12
- 238000005406 washing Methods 0.000 claims description 12
- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical compound ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 claims description 11
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 claims description 11
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 claims description 8
- 230000035484 reaction time Effects 0.000 claims description 8
- 238000000605 extraction Methods 0.000 claims description 7
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical class [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 claims description 6
- 229910000147 aluminium phosphate Inorganic materials 0.000 claims description 6
- 239000012065 filter cake Substances 0.000 claims description 6
- 230000001939 inductive effect Effects 0.000 claims description 6
- CESUXLKAADQNTB-UHFFFAOYSA-N tert-butanesulfinamide Chemical compound CC(C)(C)S(N)=O CESUXLKAADQNTB-UHFFFAOYSA-N 0.000 claims description 5
- 239000012043 crude product Substances 0.000 claims description 4
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 abstract description 31
- 239000000543 intermediate Substances 0.000 abstract description 25
- 238000001308 synthesis method Methods 0.000 abstract description 16
- 230000008569 process Effects 0.000 abstract description 9
- 239000002994 raw material Substances 0.000 abstract description 9
- -1 -tert-butyl sulfenamide Chemical compound 0.000 abstract description 6
- 239000003814 drug Substances 0.000 abstract description 6
- 229940079593 drug Drugs 0.000 abstract description 4
- 238000011031 large-scale manufacturing process Methods 0.000 abstract description 4
- 230000003287 optical effect Effects 0.000 abstract description 3
- 238000000926 separation method Methods 0.000 abstract description 3
- 230000006698 induction Effects 0.000 abstract description 2
- 230000002194 synthesizing effect Effects 0.000 abstract 1
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 36
- 238000004128 high performance liquid chromatography Methods 0.000 description 25
- CSJLBAMHHLJAAS-UHFFFAOYSA-N diethylaminosulfur trifluoride Chemical compound CCN(CC)S(F)(F)F CSJLBAMHHLJAAS-UHFFFAOYSA-N 0.000 description 16
- 102100030708 GTPase KRas Human genes 0.000 description 13
- 101000584612 Homo sapiens GTPase KRas Proteins 0.000 description 13
- 206010028980 Neoplasm Diseases 0.000 description 11
- 238000001816 cooling Methods 0.000 description 11
- 238000003756 stirring Methods 0.000 description 11
- 238000004140 cleaning Methods 0.000 description 10
- 238000001514 detection method Methods 0.000 description 10
- 238000001914 filtration Methods 0.000 description 9
- SCYULBFZEHDVBN-UHFFFAOYSA-N 1,1-Dichloroethane Chemical compound CC(Cl)Cl SCYULBFZEHDVBN-UHFFFAOYSA-N 0.000 description 8
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 8
- HUMNYLRZRPPJDN-UHFFFAOYSA-N benzaldehyde Chemical compound O=CC1=CC=CC=C1 HUMNYLRZRPPJDN-UHFFFAOYSA-N 0.000 description 6
- 201000011510 cancer Diseases 0.000 description 6
- 238000010438 heat treatment Methods 0.000 description 6
- 239000000203 mixture Substances 0.000 description 6
- 102200006538 rs121913530 Human genes 0.000 description 6
- 230000008901 benefit Effects 0.000 description 5
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 5
- 101100272976 Panax ginseng CYP716A53v2 gene Proteins 0.000 description 4
- QARVLSVVCXYDNA-UHFFFAOYSA-N bromobenzene Chemical compound BrC1=CC=CC=C1 QARVLSVVCXYDNA-UHFFFAOYSA-N 0.000 description 4
- ARUVKPQLZAKDPS-UHFFFAOYSA-L copper(II) sulfate Chemical compound [Cu+2].[O-][S+2]([O-])([O-])[O-] ARUVKPQLZAKDPS-UHFFFAOYSA-L 0.000 description 4
- 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 4
- 238000000746 purification Methods 0.000 description 4
- ZDYVRSLAEXCVBX-UHFFFAOYSA-N pyridinium p-toluenesulfonate Chemical compound C1=CC=[NH+]C=C1.CC1=CC=C(S([O-])(=O)=O)C=C1 ZDYVRSLAEXCVBX-UHFFFAOYSA-N 0.000 description 4
- VKJVXYWGRYQADR-UHFFFAOYSA-N s-tert-butylthiohydroxylamine Chemical compound CC(C)(C)SN VKJVXYWGRYQADR-UHFFFAOYSA-N 0.000 description 4
- 239000007787 solid Substances 0.000 description 4
- 239000000126 substance Substances 0.000 description 4
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 4
- GQLJZDHBPFJQCF-OGFXRTJISA-N (1R)-1-[2-methyl-3-(trifluoromethyl)phenyl]ethanamine hydrochloride Chemical compound CC1=C(C=CC=C1C(F)(F)F)[C@@H](C)N.Cl GQLJZDHBPFJQCF-OGFXRTJISA-N 0.000 description 3
- 238000005160 1H NMR spectroscopy Methods 0.000 description 3
- KWOLFJPFCHCOCG-UHFFFAOYSA-N Acetophenone Natural products CC(=O)C1=CC=CC=C1 KWOLFJPFCHCOCG-UHFFFAOYSA-N 0.000 description 3
- OWBHILUDLKIQEF-NUBCRITNSA-N C[C@H](C1=C(C(=CC=C1)C(F)(F)F)F)N.Cl Chemical compound C[C@H](C1=C(C(=CC=C1)C(F)(F)F)F)N.Cl OWBHILUDLKIQEF-NUBCRITNSA-N 0.000 description 3
- LMVWLMYIWIMIAX-NUBCRITNSA-N Cl.FC(C=1C(=C(C=CC=1)[C@@H](C)N)F)F Chemical compound Cl.FC(C=1C(=C(C=CC=1)[C@@H](C)N)F)F LMVWLMYIWIMIAX-NUBCRITNSA-N 0.000 description 3
- 206010009944 Colon cancer Diseases 0.000 description 3
- 208000001333 Colorectal Neoplasms Diseases 0.000 description 3
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 3
- 239000002262 Schiff base Substances 0.000 description 3
- 229910000365 copper sulfate Inorganic materials 0.000 description 3
- 238000010586 diagram Methods 0.000 description 3
- 239000001257 hydrogen Substances 0.000 description 3
- 229910052739 hydrogen Inorganic materials 0.000 description 3
- 238000009776 industrial production Methods 0.000 description 3
- 239000003112 inhibitor Substances 0.000 description 3
- 230000004048 modification Effects 0.000 description 3
- 238000012986 modification Methods 0.000 description 3
- 230000035772 mutation Effects 0.000 description 3
- 238000000643 oven drying Methods 0.000 description 3
- QNGNSVIICDLXHT-UHFFFAOYSA-N para-ethylbenzaldehyde Natural products CCC1=CC=C(C=O)C=C1 QNGNSVIICDLXHT-UHFFFAOYSA-N 0.000 description 3
- 230000011664 signaling Effects 0.000 description 3
- 238000001228 spectrum Methods 0.000 description 3
- OZBLIJWTPQRCAS-OGFXRTJISA-N CC1=C(C=CC=C1C(F)F)[C@@H](C)N.Cl Chemical compound CC1=C(C=CC=C1C(F)F)[C@@H](C)N.Cl OZBLIJWTPQRCAS-OGFXRTJISA-N 0.000 description 2
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 2
- 206010069755 K-ras gene mutation Diseases 0.000 description 2
- 206010058467 Lung neoplasm malignant Diseases 0.000 description 2
- 238000005481 NMR spectroscopy Methods 0.000 description 2
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 2
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 2
- 150000004753 Schiff bases Chemical class 0.000 description 2
- 230000000903 blocking effect Effects 0.000 description 2
- 210000004027 cell Anatomy 0.000 description 2
- 239000003795 chemical substances by application Substances 0.000 description 2
- 230000032798 delamination Effects 0.000 description 2
- 239000005457 ice water Substances 0.000 description 2
- 201000005249 lung adenocarcinoma Diseases 0.000 description 2
- 201000005202 lung cancer Diseases 0.000 description 2
- 208000020816 lung neoplasm Diseases 0.000 description 2
- 239000002829 mitogen activated protein kinase inhibitor Substances 0.000 description 2
- 230000003285 pharmacodynamic effect Effects 0.000 description 2
- 239000012071 phase Substances 0.000 description 2
- 238000011160 research Methods 0.000 description 2
- CESUXLKAADQNTB-ZETCQYMHSA-N 2-methylpropane-2-sulfinamide Chemical compound CC(C)(C)[S@@](N)=O CESUXLKAADQNTB-ZETCQYMHSA-N 0.000 description 1
- OUAZPCKRSSEQKB-UHFFFAOYSA-N 3-bromo-2-fluorobenzaldehyde Chemical compound FC1=C(Br)C=CC=C1C=O OUAZPCKRSSEQKB-UHFFFAOYSA-N 0.000 description 1
- HHVUFPUWPWOWOA-UHFFFAOYSA-N 3-bromo-2-methylbenzaldehyde Chemical compound CC1=C(Br)C=CC=C1C=O HHVUFPUWPWOWOA-UHFFFAOYSA-N 0.000 description 1
- 108700028369 Alleles Proteins 0.000 description 1
- 101100421901 Caenorhabditis elegans sos-1 gene Proteins 0.000 description 1
- 239000007818 Grignard reagent Substances 0.000 description 1
- 101150105104 Kras gene Proteins 0.000 description 1
- WHXSMMKQMYFTQS-UHFFFAOYSA-N Lithium Chemical compound [Li] WHXSMMKQMYFTQS-UHFFFAOYSA-N 0.000 description 1
- 102000043136 MAP kinase family Human genes 0.000 description 1
- 108091054455 MAP kinase family Proteins 0.000 description 1
- 206010061902 Pancreatic neoplasm Diseases 0.000 description 1
- 208000005718 Stomach Neoplasms Diseases 0.000 description 1
- ATJFFYVFTNAWJD-UHFFFAOYSA-N Tin Chemical compound [Sn] ATJFFYVFTNAWJD-UHFFFAOYSA-N 0.000 description 1
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 1
- 230000004913 activation Effects 0.000 description 1
- 238000007259 addition reaction Methods 0.000 description 1
- 208000037844 advanced solid tumor Diseases 0.000 description 1
- 230000000259 anti-tumor effect Effects 0.000 description 1
- 238000013459 approach Methods 0.000 description 1
- 238000003556 assay Methods 0.000 description 1
- 238000011914 asymmetric synthesis Methods 0.000 description 1
- 238000010009 beating Methods 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 239000003054 catalyst Substances 0.000 description 1
- 230000003197 catalytic effect Effects 0.000 description 1
- 230000005754 cellular signaling Effects 0.000 description 1
- 239000012295 chemical reaction liquid Substances 0.000 description 1
- 238000009833 condensation Methods 0.000 description 1
- 230000005494 condensation Effects 0.000 description 1
- 229910000366 copper(II) sulfate Inorganic materials 0.000 description 1
- 230000006837 decompression Effects 0.000 description 1
- 230000001419 dependent effect Effects 0.000 description 1
- 230000004069 differentiation Effects 0.000 description 1
- 206010017758 gastric cancer Diseases 0.000 description 1
- 150000004795 grignard reagents Chemical class 0.000 description 1
- 230000012010 growth Effects 0.000 description 1
- 230000005764 inhibitory process Effects 0.000 description 1
- 230000003993 interaction Effects 0.000 description 1
- 229910052744 lithium Inorganic materials 0.000 description 1
- 208000015486 malignant pancreatic neoplasm Diseases 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 229910052751 metal Inorganic materials 0.000 description 1
- 239000002184 metal Substances 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 229910000510 noble metal Inorganic materials 0.000 description 1
- 229910052763 palladium Inorganic materials 0.000 description 1
- 201000002528 pancreatic cancer Diseases 0.000 description 1
- 208000008443 pancreatic carcinoma Diseases 0.000 description 1
- 230000037361 pathway Effects 0.000 description 1
- 238000009520 phase I clinical trial Methods 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- 238000011946 reduction process Methods 0.000 description 1
- 230000004044 response Effects 0.000 description 1
- 102200006532 rs112445441 Human genes 0.000 description 1
- 102200006539 rs121913529 Human genes 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- 229920006395 saturated elastomer Polymers 0.000 description 1
- 238000013341 scale-up Methods 0.000 description 1
- 229940126586 small molecule drug Drugs 0.000 description 1
- 150000003384 small molecules Chemical class 0.000 description 1
- 235000002639 sodium chloride Nutrition 0.000 description 1
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 1
- 201000011549 stomach cancer Diseases 0.000 description 1
- 238000013517 stratification Methods 0.000 description 1
- 230000004083 survival effect Effects 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- JMXKSZRRTHPKDL-UHFFFAOYSA-N titanium ethoxide Chemical compound [Ti+4].CC[O-].CC[O-].CC[O-].CC[O-] JMXKSZRRTHPKDL-UHFFFAOYSA-N 0.000 description 1
- VXUYXOFXAQZZMF-UHFFFAOYSA-N titanium(IV) isopropoxide Chemical compound CC(C)O[Ti](OC(C)C)(OC(C)C)OC(C)C VXUYXOFXAQZZMF-UHFFFAOYSA-N 0.000 description 1
Images
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C17/00—Preparation of halogenated hydrocarbons
- C07C17/093—Preparation of halogenated hydrocarbons by replacement by halogens
- C07C17/18—Preparation of halogenated hydrocarbons by replacement by halogens of oxygen atoms of carbonyl groups
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C209/00—Preparation of compounds containing amino groups bound to a carbon skeleton
- C07C209/62—Preparation of compounds containing amino groups bound to a carbon skeleton by cleaving carbon-to-nitrogen, sulfur-to-nitrogen, or phosphorus-to-nitrogen bonds, e.g. hydrolysis of amides, N-dealkylation of amines or quaternary ammonium compounds
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C381/00—Compounds containing carbon and sulfur and having functional groups not covered by groups C07C301/00 - C07C337/00
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C45/00—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
Abstract
The invention belongs to the technical field of drug synthesis, and relates to a synthesis method of a chiral intermediate of a SOS1 pan KRAS inhibitor. The synthesis method comprises the following steps: (1) reacting a compound shown in a formula 6 with n-butyllithium, and quenching the reaction product through DMF (dimethyl formamide) to obtain a compound shown in a formula 7, (2) carrying out dehydration condensation reaction on the compound shown in the formula 7 and a chiral induction reagent (S) -tert-butyl sulfenamide to obtain a compound shown in a formula 8, (3) carrying out reaction on the compound shown in the formula 8 and methyl magnesium bromide to obtain a compound shown in a formula 9, and (4) carrying out hydrochloric acid gas/dioxane solution on the compound shown in the formula 9 to obtain a compound shown in the formula 1, namely a SOS1 pan KRAS inhibitor chiral intermediate. The synthesis method disclosed by the invention can be used for synthesizing important intermediates in the synthetic process of the BI 1701963, wherein the intermediates are easy to obtain raw materials, low in cost, mild in process conditions, high in yield and optical purity, simple in subsequent separation and suitable for large-scale production.
Description
Technical Field
The invention belongs to the technical field of drug synthesis, and relates to a synthesis method of a chiral intermediate of SOS1 pan KRAS inhibitor.
Background
According to 2019 national cancer reports issued by the national cancer center, lung cancer, gastric cancer and colorectal cancer are the top three malignant tumors of the Chinese incidence rate, and KRAS mutation occurs in about 25% of cancer cases, and is commonly seen in lung cancer (10-20%), pancreatic cancer (80-90%) and colorectal cancer (40-50%).
KRAS is one of the targets of the frontline signaling response, and triggers activation of a series of signaling molecules that link the cell surface to the nucleus, thereby controlling the growth, survival and differentiation of normal cells. KRAS plays a central role in cell signaling in a range of common cancers, coupled with its cardioid structure, so it is called a "tumor-beating heart". Thus, blocking KRAS has great potential to benefit many tumor patients, but finding and developing effective therapies for this major target is extremely challenging.
The advent of class BI 1701963 (structure shown below) as a SOS1: KRAS small molecule inhibitor broke the dilemma that no inhibitors specifically directed to the KRAS gene have been available for many years.
Preclinical data indicate that KARS G12C and SOS1 pan KRAS inhibitors can increase antitumor activity. SOS1 pan KRAS inhibitors may make KRAS G12C mutant tumors more sensitive to covalent KRAS G12C inhibitors binding to KRAS (off state) by shifting KRAS equilibrium from the activated to the inactivated state.
The KRAS G12C mutation is present in about 14% of non-small cell lung adenocarcinoma (NSCLC) patients, 3-4% of colorectal cancer patients, and in patients branching from other types of cancer. Tumors characterized by mutations in KRAS G12C are often poorly prognostic and resistant to treatment, and patients carrying these mutations have few treatment options. The treatment of patients with molecular-identified KRAS G12C positive advanced solid tumors is currently being evaluated in a phase I/II clinical trial to assess the safety, tolerability, pharmacokinetic and pharmacodynamic properties and preliminary efficacy of single drug use and use in combination with MEK inhibitors.
BI 1701963 is an orally available small molecule drug in research that binds to the catalytic domain of SOS1, thereby preventing interaction with KRAS (turning off) and simultaneously blocking SOS 1-driven feedback. This can reduce KRAS (open) formation and thus inhibit MAPK pathway signaling in KRAS-dependent cancers. Selective inhibition of SOS1 is a therapeutic concept that can block KRAS independently of the type of KRAS mutation (pan KRAS approach). A recent paper published by Hofmann MH et al in the American Association for Cancer Research (AACR) journal Cancer Discovery reports that SOS1: KRAS inhibitors are active against a wide range of KRAS alleles, including all major G12D/V/C and G13D oncoproteins. BI 1701963 is currently being evaluated in a phase I clinical trial for treatment of patients with advanced KRAS mutant cancer to assess the safety, tolerability, pharmacokinetic and pharmacodynamic properties and preliminary efficacy of BI 1701963 single drug and in combination with MEK inhibitors.
Disclosure of Invention
The invention aims to provide a synthesis method of a chiral intermediate of an SOS1 pan KRAS inhibitor, which is an important intermediate in a synthetic BI 1701963 synthetic process, and has the advantages of readily available raw materials, low cost, mild process conditions, high yield and optical purity, simple subsequent separation and suitability for large-scale production.
To achieve this object, in a basic embodiment, the present invention provides a synthesis method of a chiral intermediate of SOS1 pan KRAS inhibitor, said synthesis method comprising the steps of:
(1) reacting the compound shown in the formula 6 with n-butyllithium, and quenching the reaction product by using DMF to obtain a compound shown in a formula 7,
(2) the compound shown in the formula 7 and a chiral inducing reagent (S) -tert-butyl sulfinamide are subjected to dehydration condensation reaction to obtain a compound shown in a formula 8,
(3) the compound of formula 8 reacts with methyl magnesium bromide to obtain a compound of formula 9,
(4) the compound of the formula 9 is subjected to hydrochloric acid gas/dioxane solution to obtain the compound of the formula 1, namely SOS1 pan KRAS inhibitor chiral intermediate,
wherein: r 4 Is CHF 2 Or CF 3 ，R 6 Is F or CH 3 。
The SOS1 pan KRAS inhibitor chiral intermediate synthesized by the invention is the most important intermediate in the synthetic process of BI 1701963 and is also the intermediate with the highest cost ratio, and the structures of the intermediates are as follows:
formula 2(R) -1- (3- (difluoromethyl) -2-fluorophenyl) ethylamine hydrochloride
Formula 3(R) -1- (2-methyl-3- (trifluoromethyl) phenyl) ethylamine hydrochloride
Formula 4(R) -1- (3- (difluoromethyl) -2-methylphenyl) ethylamine hydrochloride
Formula 5(R) -1- (2-fluoro-3- (trifluoromethyl) phenyl) ethylamine hydrochloride
In the prior art, the four compounds have the following synthetic routes, and all have the following problems:
(1) through the reaction of the acetophenone compound and tert-butyl sulfenamide, a shrinking agent isopropyl titanate/ethyl titanate is needed, the price of the shrinking agent is high, the post-treatment is troublesome, a large amount of suspended precipitates are generated, the filtration treatment is difficult, and the industrial production difficulty is high. Meanwhile, raw materials of the acetophenone are all realized by exchanging bromobenzene with a noble metal catalyst palladium or organic tin reagent/Grignard reagent, so that the method has high cost and low yield.
(2) Lithium tri-sec-butyl borohydride is used in the chiral reduction process of the Schiff base compound, deep cooling is needed for the reaction at-78 ℃, anhydrous and oxygen-free operation is needed, the industrial production cost is high, and the operation is difficult.
(3) The process route has low total yield and high cost, and is not beneficial to industrial production.
In a preferred embodiment, the invention provides a synthesis method of chiral intermediate of SOS1 pan KRAS inhibitor, wherein in the step (1), the reaction temperature is-100 ℃ to-50 ℃, and the reaction time is 0.1 hour to 2 hours.
In a preferred embodiment, the invention provides a synthesis method of SOS1 pan KRAS inhibitor chiral intermediate, wherein in step (1), after the reaction is completed, the reaction solution is poured into a phosphoric acid aqueous solution for quenching, methyl tert-butyl ether is added for extraction, layers are separated, after the aqueous phase is extracted by methyl tert-butyl ether, all organic phases are combined, anhydrous sodium sulfate is dried overnight, and reduced pressure concentration is carried out to obtain the compound of formula 7.
In a preferred embodiment, the invention provides a synthesis method of SOS1 pan KRAS inhibitor chiral intermediate, wherein in the step (2), the reaction temperature is 25-85 ℃ and the reaction time is 4-10 hours.
In a preferred embodiment, the invention provides a synthesis method of SOS1 pan KRAS inhibitor chiral intermediate, wherein in step (2), after the reaction is completed, the reaction solution is filtered, the filter cake is washed by 1, 2-dichloroethane, the organic phases are combined and concentrated under reduced pressure, a crude product is obtained and passes through a 200-mesh and 300-mesh silica gel column, and the compound shown in the formula 8 is obtained after concentration under reduced pressure.
In a preferred embodiment, the invention provides a synthesis method of SOS1 pan KRAS inhibitor chiral intermediate, wherein in the step (3), the reaction temperature is-50 ℃ to 25 ℃, and the reaction time is 2 hours to 8 hours.
In a preferred embodiment, the invention provides a synthesis method of a chiral intermediate of SOS1 pan KRAS inhibitor, wherein in step (3), after the reaction is completed, the reaction solution is poured into saturated ammonium chloride aqueous solution to be quenched, methyl tert-butyl ether is added to extract layers, the aqueous phase is extracted by methyl tert-butyl ether, all organic phases are combined, washed by saturated saline solution, dried by anhydrous sodium sulfate overnight, and concentrated under reduced pressure to obtain the compound of formula 9.
In a preferred embodiment, the invention provides a synthesis method of SOS1 pan KRAS inhibitor chiral intermediate, wherein in the step (4), the reaction temperature is 0-50 ℃, and the reaction time is 0.5-2 hours.
In a preferred embodiment, the invention provides a synthesis method of a chiral intermediate of a SOS1 pan KRAS inhibitor, wherein the reactions of the steps (1) and (3) are carried out under the protection of nitrogen.
The method has the advantages that the method can obtain important intermediates in the synthetic process of the synthetic BI 1701963 in large-scale production, and has the advantages of easily available raw materials, low cost, mild process conditions, high yield and optical purity, simple subsequent separation and suitability for large-scale production.
The important chiral intermediate in the synthetic process of BI 1701963 is synthesized by a high-selectivity asymmetric synthesis method, bromobenzene raw materials are made into benzaldehyde, then the benzaldehyde and a chiral induction reagent tert-butyl sulfinamide are subjected to dehydration condensation to generate Schiff base, and then the Schiff base and a metal organic reagent are subjected to addition reaction to obtain the high-selectivity chiral intermediate. Compared with the existing reported synthesis method, the method has the advantages of simple and easily obtained raw materials, better yield and chiral selectivity, and is more suitable for industrial scale-up production.
Drawings
FIG. 1 is a Nuclear Magnetic Resonance (NMR) result chart of (R) -1- (3- (difluoromethyl) -2-fluorophenyl) ethylamine hydrochloride prepared in example 1.
FIG. 2 is a diagram showing the results of HPLC analysis of (R) -1- (3- (difluoromethyl) -2-fluorophenyl) ethylamine hydrochloride prepared in example 1.
FIG. 3 is a graph showing the results of nuclear magnetic detection of (R) -1- (2-methyl-3- (trifluoromethyl) phenyl) ethylamine hydrochloride prepared in example 2.
FIG. 4 is a diagram showing the results of HPLC analysis of (R) -1- (2-methyl-3- (trifluoromethyl) phenyl) ethylamine hydrochloride prepared in example 2.
FIG. 5 is a diagram showing the results of HPLC analysis of (R) -1- (3- (difluoromethyl) -2-methylphenyl) ethylamine hydrochloride prepared in example 3.
FIG. 6 is a graph showing the results of nuclear magnetic assay of (R) -1- (2-fluoro-3- (trifluoromethyl) phenyl) ethylamine hydrochloride prepared in example 4.
FIG. 7 is a high performance liquid chromatography result chart of (R) -1- (2-fluoro-3- (trifluoromethyl) phenyl) ethylamine hydrochloride prepared in example 4.
Detailed Description
The following examples further illustrate embodiments of the present invention.
Example 1: synthesis and detection of (R) -1- (3- (difluoromethyl) -2-fluorophenyl) ethylamine hydrochloride
1) Reaction of a compound of formula 10 with diethylaminosulfur trifluoride (DAST) to give a compound of formula 11
Cleaning and drying a three-neck flask, putting 10g of formula 10 raw material 3-bromo-2-fluorobenzaldehyde (purchased from Shanghai Biao medical science) into the three-neck flask under the protection of nitrogen, dissolving the 10g raw material in 50ml dichloromethane, cooling to 0 ℃, slowly dripping 12g diethylamino sulfur trifluoride (DAST), controlling the temperature to 0 ℃, slowly heating to room temperature after finishing addition, stirring for 1-2 hours, and finishing TLC detection reaction. After the reaction is finished, pouring the reaction liquid into ice water, layering, extracting the water phase with 25ml dichloromethane twice, combining all organic phases, drying over night by anhydrous sodium sulfate, concentrating under reduced pressure to obtain 14.5g of a crude product compound, passing through a 200-mesh silica gel column with 300 meshes, concentrating under reduced pressure to obtain 9.2g of the compound shown in the formula 11, wherein the purity is 95 percent, and the yield is 83 percent.
2) Reacting the compound of the formula 11 with n-butyllithium, and quenching the reaction product by using Dimethylformamide (DMF) to obtain the compound aldehyde of the formula 12
Cleaning and drying a three-neck flask, putting 5g of compound of formula 11 into the three-neck flask under the protection of nitrogen, adding 50ml of tetrahydrofuran, cooling to-78 ℃, slowly dripping 10.5ml of 2.5N N-butyllithium, stirring for 1 hour at-78 ℃, detecting the completion of the reaction, slowly dripping 5g of DMF at-78 ℃, stirring for 30 minutes, and detecting the completion of the reaction. After the reaction is finished, the reaction solution is poured into a dilute phosphoric acid aqueous solution for quenching, 50ml of methyl tert-butyl ether is added for extraction, layering is carried out, the aqueous phase is extracted twice by 50ml of methyl tert-butyl ether respectively, all organic phases are combined, 50ml of saturated salt is used for washing once, anhydrous sodium sulfate is used for drying overnight, and reduced pressure concentration is carried out to obtain 4.7g of the compound of the formula 12, so that the next reaction can be directly carried out without further purification.
3) The compound shown in the formula 12 and a chiral inducing reagent (S) -tert-butyl sulfenamide are subjected to dehydration condensation reaction to obtain a compound shown in the formula 13
Washing and drying the mixture in a three-neck flask, adding 4.7g of the compound of formula 12 and 1, 2-dichloroEthane (DCE)23.5ml, anhydrous cupric sulfate (CuSO) 4 )10.5g, 260mg of 4-methyl benzene sulfonic pyridine (PPTS) and 3.9g of S-tertiary butyl sulfenamide, slowly raising the temperature to 50 ℃, stirring for reacting for 6-8 hours, and detecting by TLC that the reaction is finished. Filtering the reaction solution, washing the filter cake with 1, 2-Dichloroethane (DCE) for 1-2 times, combining the organic phases, concentrating under reduced pressure to obtain 7.8g of crude compound, passing through a 200-mesh and 300-mesh silica gel column, and concentrating under reduced pressure to obtain 4.3g of compound in formula 13.
4) Reacting the compound of formula 13 with methyl magnesium bromide to obtain a compound of formula 14
Cleaning and drying a three-neck flask, adding 4.0g of a compound shown in the formula 13 and 20ml of Dichloromethane (DCM) under the protection of nitrogen, cooling to-30 ℃, slowly dropwise adding 7.0ml of 3N methyl magnesium bromide solution, slowly heating to 0 ℃ after dropwise adding is finished, keeping the temperature for reaction for 3-4 hours, and detecting the reaction completion by TLC. The reaction solution is poured into saturated ammonium chloride aqueous solution to quench, 20ml of methyl tert-butyl ether is added to extract and separate layers, the aqueous phase is extracted for 2 times by 10ml of methyl tert-butyl ether respectively, all organic phases are combined, washed for 1 time by 25ml of saturated saline, dried overnight by anhydrous sodium sulfate, and concentrated under reduced pressure to obtain 5.5g of crude compound, and the crude compound passes through a 200-mesh 300-mesh silica gel column and concentrated under reduced pressure to obtain 2.5g of the compound shown in the formula 14 with the yield of 59.1% (HPLC > 97% DE > 98%).
5) Subjecting the compound of formula 14 to hydrochloric acid gas/dioxane solution to obtain the compound of formula 2
After washing and drying, 2.5g of the compound of formula 14 and 25ml of 4N hydrochloric acid gas/dioxane solution were added to the flask, and the mixture was stirred for 1 hour to precipitate a white solid, which was then detected by HPLC to be complete. Filtering and drying to obtain 1.7g of the compound shown in the formula 2, wherein the yield is 89%, the total yield of the five-step reaction is 30.4%, and the total yield of the latter four-step reaction is 36.6% (HPLC > 98% EE > 98%). H-NMR (400MHz, D2O) delta 7.537-7.611(m,2H), 7.279-7.318(m,1H), 6.810-7.082(m,1H), 4.696-4.773(m,1H), 1.562-1.579(D, 3H); LCMS (M/z,190.1, M + 1); chemical purity HPLC 98.9% (Agilent 1100, YMC ODS-AQ 3UM 120A 4.6X 50MM, 210nm, ACN/H2O/buffer). The nuclear magnetic hydrogen spectrum and the high performance liquid chromatography detection spectrogram are shown in figures 1-2.
Example 2: synthesis and detection of (R) -1- (2-methyl-3- (trifluoromethyl) phenyl) ethylamine hydrochloride
1) Reacting the compound shown in the formula 16 with n-butyllithium, and quenching the reaction product through DMF to obtain the compound shown in the formula 17
Cleaning and drying a three-neck flask, adding 20g of a compound (purchased from Shanghai Biao medicine) shown in the formula 16 under the protection of nitrogen, adding 200ml of tetrahydrofuran, cooling to-78 ℃, slowly dropwise adding 36ml of 2.5N N-butyl lithium, controlling the temperature to-78 ℃, stirring for 1 hour, and detecting the completion of the reaction. 20g of DMF is slowly added dropwise at the temperature of minus 78 ℃, the reaction is stirred for 30 minutes, and the completion of the reaction is detected. The reaction solution was quenched into dilute phosphoric acid aqueous solution, extracted with 200ml of methyl tert-butyl ether for layering, the aqueous phase was extracted 2 times with 100ml of methyl tert-butyl ether, the organic phases were combined, washed once with 200ml of saturated common salt, dried over anhydrous sodium sulfate overnight, and concentrated under reduced pressure to give 15g of the compound of formula 17, which was directly subjected to the next reaction without further purification.
2) The compound shown in the formula 17 and a chiral inducing reagent (S) -tert-butyl sulfinamide are subjected to dehydration condensation reaction to obtain a compound shown in the formula 18
Washing and oven drying in a three-neck flask, adding 5g of compound of formula 17, adding 100ml of 1,2 Dichloroethane (DCE), adding anhydrous copper sulfate (CuSO) 4 )8.5g, 125mg PPTS is added, 3.8g of S-tert-butylsulfinamide is added, the mixture is heated to 50 ℃, the reaction is stirred for 6 to 8 hours, and the reaction is detected by TLC to be finished. Filtering, washing the filter cake with 1, 2-Dichloroethane (DCE) for 1-2 times, combining the organic phases, concentrating under reduced pressure to obtain 8.2g of crude compound, passing through 200-300-Silica gel column, vacuum concentration to obtain compound of formula 18 6.1 g.
3) Reacting the compound of formula 18 with methyl magnesium bromide to obtain a compound of formula 19
Cleaning and drying a three-neck flask, adding 32.8g of a compound shown in formula 18 under the protection of nitrogen, adding 165ml of Dichloromethane (DCM), cooling to-30 ℃, slowly dropwise adding 57ml of 3N methyl magnesium bromide solution, slowly heating to 0 ℃ after dropwise adding, keeping the temperature for reaction for 3-4 hours, and detecting the reaction completion by TLC. The reaction solution is poured into saturated ammonium chloride aqueous solution for quenching, 165ml of methyl tert-butyl ether is added for extraction and delamination, the aqueous phase is respectively extracted for 2 times by 90ml of methyl tert-butyl ether, the organic phases are combined, 200ml of saturated common salt is used for washing for 1 time, anhydrous sodium sulfate is used for drying overnight, 35g of crude compound is obtained by decompression and concentration, 21g of the compound of the formula 19 is obtained by passing through a 200-mesh 300-mesh silica gel column, and the yield is 60.7% (HPLC > 97% DE > 98%).
4) Subjecting the compound of formula 19 to hydrochloric acid gas/dioxane solution to obtain the compound of formula 3
The compound of formula 19 (21 g) is added into a washed and dried three-neck flask, 210ml of 4N hydrochloric acid gas/dioxane solution is added, the mixture is stirred and reacted for 1 hour, white solid is separated out, and the reaction is detected to be finished by HPLC. Filtering and drying to obtain 15.0g of the compound in the formula 3 with the yield of 92 percent and the total yield of 41.8 percent of four-step reaction (HPLC >98 percent EE >98 percent). H-NMR (600MHz, DMSO-d6) delta 8.60(s,3H), 7.93(d,1H), 7.71(dd,1H), 7.52(t,1H), 4.72(q,1H), 2.45(d,3H), 1.51(d, 3H); LCMS (M/z,204.3, M + 1); chemical purity HPLC 98.6% (Agilent 1100, YMC ODS-AQ 3UM 120A 4.6X 50MM, 210nm, ACN/H2O/buffer). The nuclear magnetic hydrogen spectrum and the high performance liquid chromatography detection spectrogram are shown in figures 3-4.
Example 3: synthesis and detection of (R) -1- (3- (difluoromethyl) -2-methylphenyl) ethylamine hydrochloride
1) Reaction of a compound of formula 21 with diethylaminosulfur trifluoride (DAST) to give a compound of formula 22
Cleaning and drying a three-neck flask, putting 20g of a 21-raw material 2-methyl-3-bromo-benzaldehyde (purchased from Shanghai Bian medical science) into the three-neck flask under the protection of nitrogen, dissolving the benzaldehyde into 200ml of dichloromethane, cooling to 0 ℃, slowly dripping 32.3g of diethylamino sulfur trifluoride (DAST), controlling the temperature to be 0 ℃, slowly heating to room temperature after the dripping is finished, stirring for 1-2 hours, and completing TLC detection reaction. After the reaction, the reaction solution was poured into ice water, and the layers were separated, and the aqueous phase was extracted twice with 100ml of dichloromethane, and the organic phases were combined, dried over anhydrous sodium sulfate overnight, and concentrated under reduced pressure to obtain 22g of a crude compound. Passing through 200-mesh 300-mesh silica gel column, concentrating under reduced pressure to obtain 19g of the compound of formula 22 with the yield of 85.5% (HPLC > 95%).
2) Reacting the compound of the formula 22 with n-butyllithium, and quenching with DMF to obtain the compound of the formula 23
Cleaning and drying a three-neck flask, adding 19g of a compound shown in a formula 22 under the protection of nitrogen, adding 190ml of tetrahydrofuran, cooling to-78 ℃, slowly dropwise adding 41.5ml of 2.5N N-butyllithium, controlling the temperature to-78 ℃, stirring for 1 hour, detecting the completion of the reaction, slowly dropwise adding 19g of DMF at-78 ℃, stirring for 30 minutes, and detecting the completion of the reaction. The reaction solution was quenched into dilute phosphoric acid aqueous solution, 200ml of methyl tert-butyl ether was added for extraction and stratification, the aqueous phase was extracted 2 times with 100ml of methyl tert-butyl ether, the organic phases were combined, washed once with 200ml of saturated saline, dried over anhydrous sodium sulfate overnight, and concentrated under reduced pressure to give 14.7g of the compound of formula 23, which was directly subjected to the next reaction without further purification.
3) The compound shown in the formula 23 and a chiral inducing reagent (S) -tert-butyl sulfenamide are subjected to dehydration condensation reaction to obtain a compound shown in the formula 24
Washing and oven drying three-neck flask, adding 5g of formula 23 compound, adding 50ml of 1,2 Dichloroethane (DCE), and adding anhydrous copper sulfate (CuSO) 4 )9.5g, 125mg of PPTS is added, 4.3g of S-tert-butyl sulfenamide is added, the temperature is heated to 50 ℃, the reaction is stirred for 6 to 8 hours, and the reaction is detected by TLC to be finished. Filtering, washing the filter cake with 1, 2-Dichloroethane (DCE) for 1-2 times, combining the organic phases, concentrating under reduced pressure to obtain 8.5g of crude compound, passing through 200-mesh silica gel column of 300 meshes, and concentrating under reduced pressure to obtain 6.2g of compound of formula 24.
4) Reacting the compound of formula 24 with methyl magnesium bromide to obtain a compound of formula 25
Cleaning and drying a three-neck flask, adding 27g of a compound shown in a formula 24 under the protection of nitrogen, adding 135ml of Dichloromethane (DCM), cooling to-30 ℃, slowly dropwise adding 50ml of 3N methyl magnesium bromide solution, slowly heating to 0 ℃ after dropwise adding, preserving heat for reacting for 3-4 hours, and detecting by TLC to complete the reaction. The reaction solution is poured into saturated ammonium chloride aqueous solution to be quenched, 135ml of methyl tert-butyl ether is added to extract and separate layers, the aqueous phase is extracted for 2 times by 70ml of methyl tert-butyl ether respectively, the organic phases are combined, washed for 1 time by 150ml of saturated common salt solution, dried overnight by anhydrous sodium sulfate, and concentrated under reduced pressure to obtain 30g of crude compound, and the crude compound passes through a 200-mesh 300-mesh silica gel column to obtain 18.5g of the compound of the formula 25, and the yield is 64.7% (HPLC > 97% DE > 98%).
5) Subjecting the compound of formula 25 to hydrochloric acid gas/dioxane solution to obtain the compound of formula 4
The compound of formula 25 (18.5 g) was added to a washed and dried three-necked flask, 185ml of a 4N hydrochloric acid gas/dioxane solution was added thereto, and the mixture was stirred for 1 hour to precipitate a white solid, and the reaction was detected by HPLC to be completed. Filtering and drying to obtain 12.5g of the compound of the formula 4, wherein the yield is 88.6 percent, the total yield of the five-step reaction is 37.9 percent, and the total yield of the latter four-step reaction is 44.3 percent (HPLC >98 percent EE >98 percent). LCMS (M/z,186.4, M + 1); chemical purity HPLC ═ 98.5% (Agilent 1100, YMC ODS-AQ 3UM 120A 4.6X 50MM, 210nm, ACN/H2O/buffer), and its HPLC chromatogram is shown in FIG. 5.
Example 4: synthesis and detection of (R) -1- (2-fluoro-3- (trifluoromethyl) phenyl) ethylamine hydrochloride
1) Reacting the compound shown in the formula 27 with n-butyllithium, and quenching the reaction product through DMF to obtain a compound shown in a formula 28
Cleaning and drying a three-neck flask, adding 25g of a compound (purchased from Shanghai Biao medicine) in a formula 27 under the protection of nitrogen, adding 250ml of tetrahydrofuran, cooling to-78 ℃, slowly dropwise adding 53ml of 2.5N N-butyllithium, controlling the temperature to-78 ℃, stirring for 1 hour, detecting the completion of the reaction, slowly dropwise adding 25g of DMF at-78 ℃, stirring for 30 minutes, and detecting the completion of the reaction. The reaction solution was quenched into dilute phosphoric acid aqueous solution, 250ml of methyl tert-butyl ether was added to extract the layers, the aqueous phase was extracted 2 times with 100ml of methyl tert-butyl ether, the organic phases were combined, washed once with 250ml of saturated brine, dried over anhydrous sodium sulfate overnight, and concentrated under reduced pressure to give 19.5g of the compound of formula 28, which was directly subjected to the next reaction without further purification.
2) The compound shown in the formula 28 and a chiral inducing reagent (S) -tert-butyl sulfinamide are subjected to dehydration condensation reaction to obtain a compound shown in the formula 29
Washing and oven drying three-neck flask, adding 19.5g of formula 28 compound, adding 200ml of 1, 2-Dichloroethane (DCE), and adding anhydrous copper sulfate (CuSO) 4 )32.5g, 487mg of PPTS is added, 14.7g of S-tert-butyl sulfenamide is added, the temperature is slowly raised to 50 ℃, the reaction is stirred for 6-8 hours, and the reaction is detected by TLC to be finished. Filtering, washing the filter cake with 1, 2-Dichloroethane (DCE) for 1-2 times, mixing the organic phases, and concentrating under reduced pressure32g of crude compound is obtained, and the crude compound is filtered through a 200-mesh 300-mesh silica gel column and concentrated under reduced pressure to obtain 22.6g of the compound shown in the formula 29.
3) Reacting the compound of formula 29 with methyl magnesium bromide to obtain a compound of formula 30
Cleaning and drying a three-neck flask, adding 13.2g of a compound in the formula 29 under the protection of nitrogen, adding 135ml of Dichloromethane (DCM), cooling to-30 ℃, slowly dropwise adding 22.4ml of 3N methyl magnesium bromide solution, slowly heating to 0 ℃ after dropwise adding is finished, keeping the temperature for reaction for 3-4 hours, and detecting the reaction completion by TLC. The reaction solution is poured into saturated ammonium chloride aqueous solution for quenching, 135ml of methyl tert-butyl ether is added for extraction and delamination, the aqueous phase is extracted for 2 times by 90ml of methyl tert-butyl ether respectively, the organic phases are combined, washed for 1 time by 100ml of saturated common salt, dried over anhydrous sodium sulfate overnight, and concentrated under reduced pressure to obtain 18g of crude compound, and the crude compound passes through a 200-mesh 300-mesh silica gel column to obtain 8.4g of the compound with the formula 30, and the yield is 60.4% (HPLC > 97% DE > 98%).
4) Subjecting the compound of formula 30 to hydrochloric acid gas/dioxane solution to obtain the compound of formula 5
The mixture was washed and dried in a three-necked flask, and 8.4g of the compound of formula 30 was added thereto, and 84ml of a 4N hydrochloric acid gas/dioxane solution was added thereto, followed by stirring and reaction for 1 hour to precipitate a white solid, which was then detected by HPLC to be complete. Filtration and drying gave 5.9g of the compound of formula 1 in 89.9% yield, 40.2% overall yield from the four-step reaction (HPLC > 98% EE > 98%). H-NMR (400MHz, D2O) delta: 7.68-7.76(m,2H), 7.36-7.41(m,1H), 4.68-4.84(m,1H), 1.62-1.64(D, 3H); LCMS (M/z,208.3, M + 1); chemical purity HPLC ═ 99.5% (Agilent 1100, YMC ODS-AQ 3UM 120A 4.6X 50MM, 210nm, ACN/H2O/buffer). The nuclear magnetic hydrogen spectrum and the high performance liquid chromatography detection spectrogram are shown in figures 6-7.
It will be apparent to those skilled in the art that various changes and modifications may be made in the present invention without departing from the spirit and scope of the invention. Thus, if such modifications and variations of the present invention fall within the scope of the claims of the present invention and their equivalents, the present invention is intended to include such modifications and variations. The foregoing examples or embodiments are merely illustrative of the present invention, which may be embodied in other specific forms or in other specific forms without departing from the spirit or essential characteristics thereof. The described embodiments are, therefore, to be considered in all respects as illustrative and not restrictive. The scope of the invention should be indicated by the appended claims, and any changes that are equivalent to the intent and scope of the claims should be construed to be included therein.
Claims (9)
1. A synthetic method of a chiral intermediate of SOS1 pan KRAS inhibitor is characterized by comprising the following steps:
(1) reacting the compound shown in the formula 6 with n-butyllithium, and quenching the reaction product by DMF to obtain a compound shown in a formula 7,
(2) the compound shown in the formula 7 and a chiral inducing reagent (S) -tert-butyl sulfinamide are subjected to dehydration condensation reaction to obtain a compound shown in a formula 8,
(3) reacting the compound of the formula 8 with methyl magnesium bromide to obtain a compound of a formula 9,
(4) the compound of the formula 9 is subjected to hydrochloric acid gas/dioxane solution to obtain the compound of the formula 1, namely SOS1 pan KRAS inhibitor chiral intermediate,
wherein: r 4 Is CHF 2 Or CF 3 ，R 6 Is F or CH 3 。
2. The method of synthesis according to claim 1, characterized in that: in the step (1), the reaction temperature is-100 ℃ to-50 ℃, and the reaction time is 0.1 hour to 2 hours.
3. The method of synthesis according to claim 1, characterized in that: in the step (1), after the reaction is finished, pouring the reaction solution into a phosphoric acid aqueous solution for quenching, adding methyl tert-butyl ether for extraction, demixing, extracting an aqueous phase by using the methyl tert-butyl ether, combining all organic phases, drying over night by using anhydrous sodium sulfate, and concentrating under reduced pressure to obtain the compound shown in the formula 7.
4. The method of synthesis according to claim 1, characterized in that: in the step (2), the reaction temperature is 25-85 ℃, and the reaction time is 4-10 hours.
5. The method of synthesis according to claim 1, characterized in that: in the step (2), after the reaction is finished, the reaction solution is filtered, a filter cake is washed by 1, 2-dichloroethane, organic phases are combined, the pressure is reduced and concentrated to obtain a crude product, the crude product passes through a 200-mesh and 300-mesh silica gel column, and the compound shown in the formula 8 is obtained by the pressure reduction and concentration.
6. The method of synthesis according to claim 1, characterized in that: in the step (3), the reaction temperature is-50 ℃ to 25 ℃, and the reaction time is 2 hours to 8 hours.
7. The method of synthesis according to claim 1, characterized in that: in the step (3), after the reaction is finished, pouring the reaction solution into a saturated ammonium chloride aqueous solution for quenching, adding methyl tert-butyl ether for extraction and demixing, extracting an aqueous phase by using the methyl tert-butyl ether, combining all organic phases, washing by using saturated saline solution, drying overnight by using anhydrous sodium sulfate, and concentrating under reduced pressure to obtain the compound shown in the formula 9.
8. The method of synthesis according to claim 1, characterized in that: in the step (4), the reaction temperature is 0-50 ℃, and the reaction time is 0.5-2 hours.
9. The method of synthesis according to claim 1, characterized in that: and (3) carrying out the reactions in the steps (1) and (3) under the protection of nitrogen.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202210276336.5A CN114933536A (en) | 2022-03-21 | 2022-03-21 | Synthetic method of chiral intermediate of SOS1 pan KRAS inhibitor |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202210276336.5A CN114933536A (en) | 2022-03-21 | 2022-03-21 | Synthetic method of chiral intermediate of SOS1 pan KRAS inhibitor |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN114933536A true CN114933536A (en) | 2022-08-23 |
Family
ID=82863015
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN202210276336.5A Pending CN114933536A (en) | 2022-03-21 | 2022-03-21 | Synthetic method of chiral intermediate of SOS1 pan KRAS inhibitor |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN114933536A (en) |
Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN112624950A (en) * | 2020-12-10 | 2021-04-09 | 北京蓝博特科技有限公司 | Synthesis method of (R) -2- (2, 5-difluorophenyl) pyrrolidine |
| CN112679421A (en) * | 2021-01-04 | 2021-04-20 | 都创(上海)医药科技股份有限公司 | Synthesis method of (R) -3-chloropyridyl-2-trifluoroethylamine hydrochloride |
| WO2021127429A1 (en) * | 2019-12-20 | 2021-06-24 | Mirati Therapeutics, Inc. | Sos1 inhibitors |
| WO2021173524A1 (en) * | 2020-02-24 | 2021-09-02 | Mirati Therapeutics, Inc. | Sos1 inhibitors |
| WO2022017519A1 (en) * | 2020-07-24 | 2022-01-27 | 南京明德新药研发有限公司 | Quinazoline compound |
-
2022
- 2022-03-21 CN CN202210276336.5A patent/CN114933536A/en active Pending
Patent Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2021127429A1 (en) * | 2019-12-20 | 2021-06-24 | Mirati Therapeutics, Inc. | Sos1 inhibitors |
| WO2021173524A1 (en) * | 2020-02-24 | 2021-09-02 | Mirati Therapeutics, Inc. | Sos1 inhibitors |
| WO2022017519A1 (en) * | 2020-07-24 | 2022-01-27 | 南京明德新药研发有限公司 | Quinazoline compound |
| CN112624950A (en) * | 2020-12-10 | 2021-04-09 | 北京蓝博特科技有限公司 | Synthesis method of (R) -2- (2, 5-difluorophenyl) pyrrolidine |
| CN112679421A (en) * | 2021-01-04 | 2021-04-20 | 都创(上海)医药科技股份有限公司 | Synthesis method of (R) -3-chloropyridyl-2-trifluoroethylamine hydrochloride |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| KR102604876B1 (en) | Synthesis of MCL-1 inhibitors | |
| CN106243031B (en) | A kind of Ah handkerchief replaces the preparation method of Buddhist nun | |
| Sarkar et al. | Luminescent anticancer ruthenium (II)-p-cymene complexes of extended imidazophenanthroline ligands: synthesis, structure, reactivity, biomolecular interactions and live cell imaging | |
| CN106632271A (en) | Erlotinib derivative with antitumor activity, and preparation method and application thereof | |
| CN113024508A (en) | Nitrogen heterocyclic ring derivative and preparation method and application thereof | |
| JP2022508494A (en) | Method for Producing Morpholine Quinazoline Compound and its Intermediate | |
| Zhai et al. | Effective laboratory-scale preparation of axitinib by two CuI-catalyzed coupling reactions | |
| CN114933536A (en) | Synthetic method of chiral intermediate of SOS1 pan KRAS inhibitor | |
| CN111943885A (en) | Synthetic method of Laolatinib intermediate 2-amino-5-bromo-3-hydroxypyridine | |
| CN110483387B (en) | Method for synthesizing nicotinamide amide derivative by one-pot method | |
| CN111646974A (en) | N-methyl gatifloxacin propenone derivative and preparation method and application thereof | |
| CN111825678A (en) | Preparation method of carbamatinib | |
| CN111875601A (en) | Synthetic method and application of indolizine compound | |
| CN107118215A (en) | A kind of preparation method for treating breast cancer medicines Rui Boxini intermediates | |
| JP6530807B2 (en) | Process for the preparation of indenoisoquinoline derivatives | |
| Yue et al. | First synthesis of novel 3, 3′-bipyridazine derivatives as new potent antihepatocellular carcinoma agents | |
| CN110041338A (en) | One kind double indoles maleic amide class compounds with anti-tumor activity and its application | |
| CN111646937B (en) | Propenone derivative of N-acetyl ciprofloxacin and preparation method and application thereof | |
| CN109651241B (en) | Synthesis method of 4-bromo-6-chloronicotinaldehyde | |
| CN109535087A (en) | A kind of synthetic method of -2 C-3 aroyl compounds of (1H) -one of quinoxaline | |
| CN109912556B (en) | Benzopyrone skeleton derivative and preparation method and application thereof | |
| Reis et al. | Synthesis, spectroscopic characterization and X-ray structure of novel 7-methoxy-4-oxo-N-phenyl-4H-chromene-2-carboxamides | |
| CN108530445A (en) | A kind of synthetic method of 3- cyanoimidazoles simultaneously [1,5-a] quinoline compound | |
| CN113387797B (en) | Preparation method of key intermediate of erlotinib | |
| CN108409648A (en) | A kind of preparation method of Sorafenib Tosylate correlation intermediate |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination |