CN114891005B - Preparation process of Wupalision p-toluenesulfonate - Google Patents
Preparation process of Wupalision p-toluenesulfonate Download PDFInfo
- Publication number
- CN114891005B CN114891005B CN202210332644.5A CN202210332644A CN114891005B CN 114891005 B CN114891005 B CN 114891005B CN 202210332644 A CN202210332644 A CN 202210332644A CN 114891005 B CN114891005 B CN 114891005B
- Authority
- CN
- China
- Prior art keywords
- formula
- reaction
- compound
- compound represented
- compound shown
- 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.)
- Active
Links
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 title claims abstract description 51
- 238000002360 preparation method Methods 0.000 title abstract description 17
- 150000001875 compounds Chemical class 0.000 claims abstract description 307
- 238000006243 chemical reaction Methods 0.000 claims abstract description 269
- 238000004519 manufacturing process Methods 0.000 claims abstract description 17
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 99
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 90
- 238000003756 stirring Methods 0.000 claims description 76
- 238000010992 reflux Methods 0.000 claims description 71
- 238000000034 method Methods 0.000 claims description 67
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 60
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 55
- 239000012074 organic phase Substances 0.000 claims description 51
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 48
- 239000000243 solution Substances 0.000 claims description 45
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 40
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 38
- WTDHULULXKLSOZ-UHFFFAOYSA-N Hydroxylamine hydrochloride Chemical compound Cl.ON WTDHULULXKLSOZ-UHFFFAOYSA-N 0.000 claims description 38
- 238000001035 drying Methods 0.000 claims description 36
- 238000001914 filtration Methods 0.000 claims description 27
- 239000002904 solvent Substances 0.000 claims description 26
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 21
- 238000010438 heat treatment Methods 0.000 claims description 21
- 239000002585 base Substances 0.000 claims description 20
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 20
- 239000000047 product Substances 0.000 claims description 19
- NWZSZGALRFJKBT-KNIFDHDWSA-N (2s)-2,6-diaminohexanoic acid;(2s)-2-hydroxybutanedioic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O.NCCCC[C@H](N)C(O)=O NWZSZGALRFJKBT-KNIFDHDWSA-N 0.000 claims description 18
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 18
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 18
- 239000003513 alkali Substances 0.000 claims description 18
- IKDUDTNKRLTJSI-UHFFFAOYSA-N hydrazine monohydrate Substances O.NN IKDUDTNKRLTJSI-UHFFFAOYSA-N 0.000 claims description 18
- 239000011259 mixed solution Substances 0.000 claims description 18
- 238000001816 cooling Methods 0.000 claims description 17
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 claims description 16
- 239000012359 Methanesulfonyl chloride Substances 0.000 claims description 16
- 239000011777 magnesium Substances 0.000 claims description 16
- 229910052749 magnesium Inorganic materials 0.000 claims description 16
- QARBMVPHQWIHKH-UHFFFAOYSA-N methanesulfonyl chloride Chemical compound CS(Cl)(=O)=O QARBMVPHQWIHKH-UHFFFAOYSA-N 0.000 claims description 16
- 238000001953 recrystallisation Methods 0.000 claims description 16
- 238000004128 high performance liquid chromatography Methods 0.000 claims description 15
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 14
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 14
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 14
- 238000005406 washing Methods 0.000 claims description 14
- LGRFSURHDFAFJT-UHFFFAOYSA-N Phthalic anhydride Natural products C1=CC=C2C(=O)OC(=O)C2=C1 LGRFSURHDFAFJT-UHFFFAOYSA-N 0.000 claims description 12
- JHIWVOJDXOSYLW-UHFFFAOYSA-N butyl 2,2-difluorocyclopropane-1-carboxylate Chemical compound CCCCOC(=O)C1CC1(F)F JHIWVOJDXOSYLW-UHFFFAOYSA-N 0.000 claims description 12
- 239000007864 aqueous solution Substances 0.000 claims description 11
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 11
- 239000003223 protective agent Substances 0.000 claims description 11
- XTHFKEDIFFGKHM-UHFFFAOYSA-N Dimethoxyethane Chemical compound COCCOC XTHFKEDIFFGKHM-UHFFFAOYSA-N 0.000 claims description 10
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 9
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 9
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims description 9
- 238000000605 extraction Methods 0.000 claims description 9
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-dimethylformamide Substances CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 8
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 claims description 8
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 claims description 7
- 238000002425 crystallisation Methods 0.000 claims description 7
- 230000008025 crystallization Effects 0.000 claims description 7
- 239000012065 filter cake Substances 0.000 claims description 7
- 239000007788 liquid Substances 0.000 claims description 7
- 229910052757 nitrogen Inorganic materials 0.000 claims description 7
- 239000003208 petroleum Substances 0.000 claims description 7
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 7
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 claims description 6
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 6
- 239000012295 chemical reaction liquid Substances 0.000 claims description 6
- CDBYLPFSWZWCQE-UHFFFAOYSA-L sodium carbonate Substances [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 6
- MFRIHAYPQRLWNB-UHFFFAOYSA-N sodium tert-butoxide Chemical compound [Na+].CC(C)(C)[O-] MFRIHAYPQRLWNB-UHFFFAOYSA-N 0.000 claims description 6
- JWUJQDFVADABEY-UHFFFAOYSA-N 2-methyltetrahydrofuran Chemical compound CC1CCCO1 JWUJQDFVADABEY-UHFFFAOYSA-N 0.000 claims description 5
- VMHLLURERBWHNL-UHFFFAOYSA-M Sodium acetate Chemical compound [Na+].CC([O-])=O VMHLLURERBWHNL-UHFFFAOYSA-M 0.000 claims description 3
- 238000012544 monitoring process Methods 0.000 claims description 3
- 238000000746 purification Methods 0.000 claims description 3
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 3
- 239000001632 sodium acetate Substances 0.000 claims description 3
- 235000017281 sodium acetate Nutrition 0.000 claims description 3
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 3
- 238000004321 preservation Methods 0.000 claims description 2
- 230000035484 reaction time Effects 0.000 claims description 2
- GSNUFIFRDBKVIE-UHFFFAOYSA-N DMF Natural products CC1=CC=C(C)O1 GSNUFIFRDBKVIE-UHFFFAOYSA-N 0.000 claims 1
- MHABMANUFPZXEB-UHFFFAOYSA-N O-demethyl-aloesaponarin I Natural products O=C1C2=CC=CC(O)=C2C(=O)C2=C1C=C(O)C(C(O)=O)=C2C MHABMANUFPZXEB-UHFFFAOYSA-N 0.000 claims 1
- 238000000926 separation method Methods 0.000 claims 1
- 239000007858 starting material Substances 0.000 abstract description 10
- 238000007126 N-alkylation reaction Methods 0.000 abstract description 7
- 238000007363 ring formation reaction Methods 0.000 abstract description 7
- 238000005810 carbonylation reaction Methods 0.000 abstract description 5
- 150000001412 amines Chemical class 0.000 abstract description 3
- 230000006315 carbonylation Effects 0.000 abstract description 3
- 238000010511 deprotection reaction Methods 0.000 abstract description 3
- 238000006146 oximation reaction Methods 0.000 abstract description 3
- 238000003786 synthesis reaction Methods 0.000 description 27
- 230000015572 biosynthetic process Effects 0.000 description 25
- 239000000203 mixture Substances 0.000 description 13
- 230000036632 reaction speed Effects 0.000 description 12
- 230000009471 action Effects 0.000 description 7
- 239000003153 chemical reaction reagent Substances 0.000 description 6
- 239000012458 free base Substances 0.000 description 6
- 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 6
- 230000008569 process Effects 0.000 description 5
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 description 4
- 235000003205 Smilax rotundifolia Nutrition 0.000 description 4
- 240000009022 Smilax rotundifolia Species 0.000 description 4
- 150000003141 primary amines Chemical class 0.000 description 4
- 208000027418 Wounds and injury Diseases 0.000 description 3
- 239000007795 chemical reaction product Substances 0.000 description 3
- 230000006378 damage Effects 0.000 description 3
- 239000003814 drug Substances 0.000 description 3
- 208000014674 injury Diseases 0.000 description 3
- 239000000376 reactant Substances 0.000 description 3
- KYJWUPZPSXZEPG-NTISSMGPSA-N 2-[(1s)-1-[4-amino-3-(3-fluoro-4-propan-2-yloxyphenyl)pyrazolo[3,4-d]pyrimidin-1-yl]ethyl]-6-fluoro-3-(3-fluorophenyl)chromen-4-one;4-methylbenzenesulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1.C1=C(F)C(OC(C)C)=CC=C1C(C1=C(N)N=CN=C11)=NN1[C@@H](C)C1=C(C=2C=C(F)C=CC=2)C(=O)C2=CC(F)=CC=C2O1 KYJWUPZPSXZEPG-NTISSMGPSA-N 0.000 description 2
- 125000004180 3-fluorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C(F)=C1[H] 0.000 description 2
- RYVOZMPTISNBDB-UHFFFAOYSA-N 4-bromo-2-fluorophenol Chemical compound OC1=CC=C(Br)C=C1F RYVOZMPTISNBDB-UHFFFAOYSA-N 0.000 description 2
- -1 5-fluoro-2-hydroxyphenyl Chemical group 0.000 description 2
- 239000007818 Grignard reagent Substances 0.000 description 2
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 2
- 238000006069 Suzuki reaction reaction Methods 0.000 description 2
- 239000002253 acid Substances 0.000 description 2
- 230000009286 beneficial effect Effects 0.000 description 2
- 239000011230 binding agent Substances 0.000 description 2
- 238000006266 etherification reaction Methods 0.000 description 2
- 150000004795 grignard reagents Chemical class 0.000 description 2
- 239000003112 inhibitor Substances 0.000 description 2
- 239000000463 material Substances 0.000 description 2
- CTSLXHKWHWQRSH-UHFFFAOYSA-N oxalyl chloride Chemical compound ClC(=O)C(Cl)=O CTSLXHKWHWQRSH-UHFFFAOYSA-N 0.000 description 2
- 150000002923 oximes Chemical class 0.000 description 2
- 230000000306 recurrent effect Effects 0.000 description 2
- 238000011160 research Methods 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- YBBRCQOCSYXUOC-UHFFFAOYSA-N sulfuryl dichloride Chemical compound ClS(Cl)(=O)=O YBBRCQOCSYXUOC-UHFFFAOYSA-N 0.000 description 2
- 231100000331 toxic Toxicity 0.000 description 2
- 230000002588 toxic effect Effects 0.000 description 2
- RIOQSEWOXXDEQQ-UHFFFAOYSA-N triphenylphosphine Chemical compound C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-N 0.000 description 2
- LLAPDLPYIYKTGQ-UHFFFAOYSA-N 1-aminoethyl Chemical group C[CH]N LLAPDLPYIYKTGQ-UHFFFAOYSA-N 0.000 description 1
- YEAUYVGUXSZCFI-UHFFFAOYSA-N 2-(3-fluorophenyl)acetic acid Chemical compound OC(=O)CC1=CC=CC(F)=C1 YEAUYVGUXSZCFI-UHFFFAOYSA-N 0.000 description 1
- IUVCFHHAEHNCFT-INIZCTEOSA-N 2-[(1s)-1-[4-amino-3-(3-fluoro-4-propan-2-yloxyphenyl)pyrazolo[3,4-d]pyrimidin-1-yl]ethyl]-6-fluoro-3-(3-fluorophenyl)chromen-4-one Chemical compound C1=C(F)C(OC(C)C)=CC=C1C(C1=C(N)N=CN=C11)=NN1[C@@H](C)C1=C(C=2C=C(F)C=CC=2)C(=O)C2=CC(F)=CC=C2O1 IUVCFHHAEHNCFT-INIZCTEOSA-N 0.000 description 1
- 229940124292 CD20 monoclonal antibody Drugs 0.000 description 1
- 208000002250 Hematologic Neoplasms Diseases 0.000 description 1
- 239000008186 active pharmaceutical agent Substances 0.000 description 1
- 230000029936 alkylation Effects 0.000 description 1
- 238000005804 alkylation reaction Methods 0.000 description 1
- 230000000259 anti-tumor effect Effects 0.000 description 1
- 210000003719 b-lymphocyte Anatomy 0.000 description 1
- 230000031709 bromination Effects 0.000 description 1
- 238000005893 bromination reaction Methods 0.000 description 1
- 238000006757 chemical reactions by type Methods 0.000 description 1
- 238000005660 chlorination reaction Methods 0.000 description 1
- 238000004440 column chromatography Methods 0.000 description 1
- 239000012141 concentrate Substances 0.000 description 1
- 230000006837 decompression Effects 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 230000017858 demethylation Effects 0.000 description 1
- 238000010520 demethylation reaction Methods 0.000 description 1
- 238000013461 design Methods 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 238000001647 drug administration Methods 0.000 description 1
- 230000009977 dual effect Effects 0.000 description 1
- 230000007613 environmental effect Effects 0.000 description 1
- 238000003912 environmental pollution Methods 0.000 description 1
- 238000000227 grinding Methods 0.000 description 1
- 230000006872 improvement Effects 0.000 description 1
- 238000010907 mechanical stirring Methods 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000003647 oxidation Effects 0.000 description 1
- 238000007254 oxidation reaction Methods 0.000 description 1
- 229910052763 palladium Inorganic materials 0.000 description 1
- 231100000614 poison Toxicity 0.000 description 1
- 238000007867 post-reaction treatment Methods 0.000 description 1
- 230000009467 reduction Effects 0.000 description 1
- 238000012827 research and development Methods 0.000 description 1
- 230000009885 systemic effect Effects 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- 239000003440 toxic substance Substances 0.000 description 1
- 230000009466 transformation Effects 0.000 description 1
- 238000011282 treatment Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
- C07D487/04—Ortho-condensed systems
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C303/00—Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides
- C07C303/32—Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides of salts of sulfonic acids
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C303/00—Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides
- C07C303/42—Separation; Purification; Stabilisation; Use of additives
- C07C303/44—Separation; Purification
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C309/00—Sulfonic acids; Halides, esters, or anhydrides thereof
- C07C309/01—Sulfonic acids
- C07C309/28—Sulfonic acids having sulfo groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton
- C07C309/29—Sulfonic acids having sulfo groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton of non-condensed six-membered aromatic rings
- C07C309/30—Sulfonic acids having sulfo groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton of non-condensed six-membered aromatic rings of six-membered aromatic rings substituted by alkyl groups
-
- 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
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention provides a preparation process of Wupalis p-toluenesulfonate, which takes a compound shown in a formula 2 as a starting material, and synthesizes a target product through 6 steps of reactions such as N-alkylation, carbonylation, amine protection, oximation, cyclization, deprotection, salification and the like. Compared with the prior art, the synthetic route and the preparation process have the advantages of short steps, mild conditions and easiness in operation, shorten the reaction process, reduce the production period and the production cost of a single batch, and are suitable for the operability of industrial mass production. The synthetic route and the preparation process of the invention are brand new and are not reported in the literature.
Description
Technical Field
The invention relates to the technical field of biological medicine, in particular to a preparation process of Wupalis p-toluenesulfonate.
Background
The Umbralinib (alias: wu Pali S, research and development code RP5264 or TGR-1202) is an oral, P13K delta and CK 1-epsilon dual-targeting inhibitor, which is first developed by Rhizen pharmaceutical company, which is developed before anti-tumor medicine is applied in Switzerland, and is signed by the company on 8 and 16 days 2012 with the company of TG therautics, which is focused on developing innovative therapies for B cell related diseases, in the United states, and the company of TG is granted to develop Wupalies for treating hematological malignancies exclusively, to develop clinical trial studies, to strive for marketing permissions by the drug administration, and to realize commercialization. Accelerated FDA approval of Wu Pali S p-toluenesulfonate (umbralisib tosylate) on month 2 and 5 of 2021 was marketed under the trade name It is a first marketed P13K delta/CK 1-epsilon dual targeted inhibitor orally administered once daily as a recurrent or refractory MZL adult patient previously receiving at least 1 treatment with an anti-CD 20 monoclonal antibody and a recurrent or refractory F previously receiving ≡3 systemic treatmentsL adult patients are treated with drugs.
Wu Pali the active pharmaceutical ingredient is Wu Pali s p-toluenesulfonate, formula C 38 H 32 F 3 N 5 O 6 S, the molecular weight is 743.75g/mol, and the chemical structure of the S is a compound shown in a formula 1:
formula 1.
Wu Pali S's original research corporation's Lisen pharmaceutical in patent CN201080060611.5, two synthetic routes were designed:
route one: 3-fluorophenylacetic acid is used as a starting material, and a key intermediate a is obtained after chlorination, alkylation, demethylation, cyclocondensation, bromination, style oxidation, asymmetric reduction and chiral inversion; 4-bromo-2-fluorophenol is used as a starting material, and key intermediate b is obtained through etherification, miyaura boride and Suzuki coupling; and (3) carrying out N-alkylation reaction on the key intermediate a and the key intermediate b to obtain the free base of the target product 1, and then carrying out para-toluenesulfonic acid salt to obtain the compound shown in the target product formula 1.
Route two: taking 1- (5-fluoro-2-hydroxyphenyl) -2- (3-fluorophenyl) ethyl-1-ketone as a starting material, and obtaining a key intermediate a through ring condensation and dehydroxy protection; 4-bromo-2-fluorophenol is used as a starting material, and key intermediate b is obtained through etherification, miyaura boride and Suzuki coupling; and (3) carrying out N-alkylation reaction on the key intermediate a and the key intermediate b to obtain the free base of the target product 1, and then carrying out para-toluenesulfonic acid salt to obtain the compound shown in the target product formula 1.
The two routes adopt triphenylphosphine which is a high-risk chemical substance in the reaction process; high-risk and highly toxic substances oxalyl chloride are also used; expensive palladium reagent is used; a deep cooling reaction occurs in the reaction process; column chromatography means are often used in post-reaction treatments to purify the reaction products. These operations all lead to great difficulty in industrial transformation of the synthetic route disclosed by the original research enterprise, and also lead to serious environmental protection and safety risks after industrialization of the route, thereby leading to various cost multiplication of the product.
Thus, there is still a need for improvement in the preparation process of the compound represented by formula 1.
Disclosure of Invention
The present invention aims to solve at least one of the technical problems in the related art to some extent. To this end, an object of the present invention is to propose a novel process for the preparation of Wu Pali s p-toluenesulfonate. Compared with the prior art, the inventor innovatively uses the new starting material as the starting point of the synthetic process route, the whole synthetic route avoids the use of toxic and harmful reagents, reduces the injury of dangerous processes and dangerous reagents to personnel and the pollution to the environment, and reduces the possibility of safety accidents; the purification means with high efficiency and simple operation are adopted, the production time is reduced, the yield of the reaction product is improved, and the HPLC purity of the target product can reach more than 99.4 percent; compared with the prior art, the synthetic route and the preparation process have the advantages of short steps, mild conditions and easiness in operation, shorten the reaction process, reduce the production period and the production cost of a single batch, and are suitable for the operability of industrial mass production.
In one aspect of the invention, the invention provides a process for preparing a compound Wu Pali s p-toluenesulfonate represented by formula 1. According to an embodiment of the invention, the preparation process comprises:
(1) Contacting a compound represented by formula 2 with a compound represented by formula 3 to obtain a compound represented by formula 4;
(2) Contacting a compound represented by formula 4 with a compound represented by formula 5 to obtain a compound represented by formula 6;
(3) Contacting a compound represented by formula 6 with phthalic anhydride to obtain a compound represented by formula 7;
(4) Contacting a compound represented by formula 7 with hydroxylamine hydrochloride to obtain a compound represented by formula 8;
(5) Contacting a compound represented by formula 8 with methanesulfonyl chloride to obtain a compound represented by formula 9;
(6) Contacting the compound shown in the formula 9 with hydrazine hydrate and p-toluenesulfonic acid in sequence to obtain a compound Wu Pali s-toluenesulfonate shown in the formula 1,
the inventor discovers that the preparation process takes (R) -2- (1-aminoethyl) -6-fluoro-3- (3-fluorophenyl) -4H-benzopyran-4-one (a compound shown in a formula 2) as a starting material, and synthesizes a target product, namely a compound Wu Pali S-p-toluenesulfonate shown in the formula 1 through the steps of N-alkylation, carbonylation, amine protection, oximation, cyclization, deprotection, salification and the like, wherein the total reaction process comprises six steps: firstly, carrying out N-alkylation reaction on a halogenide and primary amine under the action of alkali to generate a compound shown in a formula 4; step two, the compound shown in the formula 4 and the Grignard reagent are subjected to carbonylation reaction to generate a compound shown in the formula 6; thirdly, protecting primary amine in the compound shown in the formula 6 by phthalic anhydride to generate a compound shown in the formula 7; fourthly, carrying out oxime synthesis reaction on the compound shown in the formula 7 and hydroxylamine hydrochloride to generate a compound shown in the formula 8; fifthly, carrying out cyclization reaction on the compound shown in the formula 8 under the action of sulfonyl chloride and an acid binding agent to generate a compound shown in the formula 9; and sixthly, deprotecting the compound shown in the formula 9 under the action of hydrazine hydrate to obtain the glabrous greenbrier rhizome free base, and salifying the glabrous greenbrier rhizome free base with p-toluenesulfonic acid to generate p-toluenesulfonic acid salt, thereby obtaining a target product, namely the compound Wu Pali s-toluenesulfonic acid shown in the formula 1.
The term "contacting" as used herein is to be understood in a broad sense and may be any manner that enables at least two reactants to react chemically, for example by mixing the two reactants under appropriate conditions. The reactants to be contacted may be mixed under stirring as needed, and thus the type of stirring is not particularly limited, and for example, mechanical stirring, that is, stirring under the action of mechanical force, may be used.
The terms "first," "second," and the like herein are used for descriptive purposes only and are not to be construed as indicating or implying relative importance or implicitly indicating the number of technical features indicated. Thus, a feature defining "a first" or "a second" may explicitly or implicitly include one or more such feature. In the description of the present invention, the meaning of "a plurality" is two or more, unless explicitly defined otherwise.
According to embodiments of the present invention, the above-described method for preparing the compound represented by formula 4, the compound represented by formula 6, the compound represented by formula 7, the compound represented by formula 8, the compound represented by formula 9, and the compound represented by formula 1 may further have at least one of the following additional technical features:
According to embodiments of the present invention, the chemical reactions described herein may be performed according to any method known in the art. The source of the starting materials for preparing the compound represented by formula 4, the compound represented by formula 6, the compound represented by formula 7, the compound represented by formula 8, the compound represented by formula 9, and the compound represented by formula 1 is not particularly limited, and they may be prepared by any known method or commercially available.
According to the embodiment of the present invention, in the step (1), the compound represented by formula 2, the compound represented by formula 3, and the manner of contact with the base are not particularly limited. Therefore, the efficiency of the contact reaction of the compound shown in the formula 2, the compound shown in the formula 3 and the alkali can be improved, the reaction speed is increased, and the efficiency of preparing the compound shown in the formula 4 by using the method is further improved.
According to an embodiment of the present invention, in step (1), the steps of: adding a solvent A into a reaction container, adding a compound shown in a formula 2, a compound shown in a formula 3 and alkali under stirring, heating a reaction system to 90-120 ℃ after the addition, carrying out heat preservation reaction for 9-14 h, cooling to room temperature after the reaction is finished, slowly adding water into the reaction system, continuously stirring for 1h, filtering, recrystallizing a filter cake with ethyl acetate, purifying, and drying under reduced pressure to obtain the compound shown in the formula 4. Thus, the efficiency of the contact reaction between the compound shown in the formula 2, the compound shown in the formula 3 and the alkali can be improved, the reaction speed can be increased, and the efficiency of preparing the compound shown in the formula 4 by using the method can be further improved.
According to an embodiment of the present invention, in step (1), the solvent a is at least one selected from DMF, DMAC, or DMSO.
According to an embodiment of the present invention, in step (1), the base is at least one selected from potassium carbonate, potassium hydroxide, sodium tert-butoxide, or sodium hydroxide.
According to the embodiment of the invention, in the step (1), the molar ratio of the compound shown in the formula 2, the compound shown in the formula 3 and the alkali is 1 (1.2-1.7): (1.5-2.5), and preferably the molar ratio of the compound shown in the formula 2, the compound shown in the formula 3 and the alkali is 1:1.5:2.0. Thereby, the efficiency of preparing the compound represented by formula 4 using this method can be further improved.
According to an embodiment of the present invention, in the step (1), the mass-to-volume ratio of the compound represented by formula 2 to the solvent A is 1 (8-15) (W/V), preferably the mass-to-volume ratio of the compound represented by formula 2 to the solvent A is 1:10. Thereby, the efficiency of preparing the compound represented by formula 4 using this method can be further improved.
According to an embodiment of the present invention, in step (1), the reaction temperature of the contact stirring of the compound represented by formula 2, the compound represented by formula 3, and the base is preferably 100℃and the reaction time is preferably 10 hours. Thus, the efficiency of the contact reaction of the compound represented by formula 2, the compound represented by formula 3 and the base can be improved, and the efficiency of the preparation of the compound represented by formula 4 by the method can be further improved.
According to a specific embodiment of the present invention, in step (1), the steps of: DMF (300 ml) was added to a reaction flask, the compound of formula 2 (30.1 g,0.1 mol), the compound of formula 3 (23.2 g,0.15 mol) and potassium carbonate (27.6 g,0.2 mol) were added with stirring, after the addition was completed, the reaction system was warmed to 100℃and reacted at a constant temperature for 10 hours, after the reaction was completed, cooled to room temperature, water (600 ml) was slowly added to the reaction system, stirring was continued for 1 hour, filtration was carried out, and the cake was recrystallized and purified with ethyl acetate and dried under reduced pressure to give the compound of formula 4 (33.1 g), yield 78.9%.
According to the embodiment of the present invention, in the step (2), the contact manner of the compound represented by formula 4 with the compound represented by formula 5 and magnesium is not particularly limited. Therefore, the efficiency of the contact reaction of the compound shown in the formula 4, the compound shown in the formula 5 and magnesium can be improved, the reaction speed is increased, and the efficiency of preparing the compound shown in the formula 6 by using the method is further improved.
According to an embodiment of the present invention, in step (2), the steps of: adding a dry solvent B into a reaction vessel, adding magnesium under stirring, heating to a reflux state, adding a mixed solution of a compound shown in a formula 5 and the solvent B into a reaction system, keeping reflux for 3 hours, dropwise adding the mixed solution of the compound shown in the formula 4 and the solvent B, continuing reflux reaction for 6-9 hours, adding a hydrochloric acid solution into the reaction system, keeping the temperature of 73-77 ℃ for stirring reaction for 8-12 hours, cooling the reaction system to room temperature, separating the liquid, washing an organic phase with water, concentrating the organic phase to dryness under reduced pressure, recrystallizing with dichloromethane, and drying under reduced pressure to obtain the compound shown in the formula 6. Therefore, the efficiency of the contact reaction of the compound shown in the formula 4, the compound shown in the formula 5 and magnesium can be improved, the reaction speed is increased, and the efficiency of preparing the compound shown in the formula 6 by using the method is further improved.
According to an embodiment of the present invention, in step (2), the solvent B is at least one selected from tetrahydrofuran, methyltetrahydrofuran, or ethylene glycol dimethyl ether.
According to the embodiment of the invention, in the step (2), the molar ratio of the compound shown in the formula 4 to the compound shown in the formula 5 and magnesium is 1 (0.95-1.1): 1.2, and preferably the molar ratio of the compound shown in the formula 4 to the compound shown in the formula 5 and magnesium is 1:1:1.2. Thereby, the efficiency of preparing the compound represented by formula 6 using this method can be further improved.
According to a specific embodiment of the present invention, in step (2), the steps of: under the protection of nitrogen, dry tetrahydrofuran (20 ml) is added into a reaction bottle, magnesium (2.23 g,91.61 mmol) is added under stirring, heating is carried out until a reflux state, a mixed solution of a compound (17.80 g,76.35 mmol) shown in a formula 5 and tetrahydrofuran (150 ml) is added into a reaction system, after keeping reflux for 3 hours, a mixed solution of a compound (32.02 g,76.35 mmol) shown in a formula 4 and tetrahydrofuran (150 ml) is dropwise added, reflux reaction is continued for 7 hours, 1mol/L hydrochloric acid (300 ml) is added into the reaction system, stirring is carried out at 73-77 ℃ for 10 hours, the reaction system is cooled to room temperature, the organic phase is separated, washed with water, the organic phase is concentrated to dryness under reduced pressure, dichloromethane is recrystallized, and the compound (32.02 g) shown in a formula 6 is obtained after reduced pressure drying, and the yield is 73.0%.
According to an embodiment of the present invention, in step (3), the contact manner of the compound represented by formula 6, the amino protecting agent and the base is not particularly limited. Thus, the efficiency of the contact reaction of the compound shown in the formula 6, the amino protective agent and the alkali can be improved, the reaction speed is increased, and the efficiency of preparing the compound shown in the formula 7 by using the method is further improved.
According to an embodiment of the present invention, in step (3), the steps of: adding a solvent C into a reaction bottle, adding a compound shown in a formula 6, an amino protective agent and alkali under stirring, heating to reflux, stirring and reacting for 6-10 h, cooling to room temperature after the reaction is finished, adding water, stirring and crystallizing for 1h, filtering, and drying to obtain a filter cake which is the compound shown in a formula 7. Thus, the efficiency of the contact reaction of the compound shown in the formula 6, the amino protective agent and the alkali can be improved, the reaction speed is increased, and the efficiency of preparing the compound shown in the formula 7 by using the method is further improved.
According to an embodiment of the present invention, in step (3), the solvent C is at least one selected from acetonitrile, ethanol or tetrahydrofuran.
According to the embodiment of the invention, in the step (3), the molar ratio of the compound shown in the formula 6, the amino protective agent and the alkali is 1 (1.0-1.5): (1.0-1.5), and preferably the molar ratio of the compound shown in the formula 6, the amino protective agent and the alkali is 1:1.2:1.2. Thereby, the efficiency of preparing the compound represented by formula 7 using this method can be further improved.
According to an embodiment of the invention, in step (3), the amino protecting agent is selected from phthalic anhydride.
According to an embodiment of the present invention, in step (3), the base is at least one selected from triethylamine, DIPEA, or pyridine.
According to a specific embodiment of the present invention, in step (3), the steps of: acetonitrile (450 ml) was added to the reaction flask, while stirring, a compound of formula 6 (31.02 g,53.99 mmol), phthalic anhydride (9.59 g,64.75 mmol) and triethylamine (6.55 g,64.75 mmol) were added, the mixture was warmed to reflux and stirred for 8 hours, after the reaction was completed, cooled to room temperature, water (500 ml) was added, stirred and crystallized for 1 hour, filtered and dried, and the obtained cake was a compound of formula 7 (35.36 g), yield 91.0%, and the compound of formula 7 was directly put into the next reaction.
According to an embodiment of the present invention, in step (4), the contact manner of the compound represented by formula 7, hydroxylamine hydrochloride, and base is not particularly limited. Thus, the efficiency of the contact reaction of the compound shown in the formula 7, hydroxylamine hydrochloride and alkali can be improved, the reaction speed can be increased, and the efficiency of preparing the compound shown in the formula 8 by using the method can be further improved.
According to an embodiment of the present invention, in step (4), the steps of: putting the compound shown in the formula 7 into a reaction bottle, adding hydroxylamine hydrochloride, alkali, water and ethanol into the reaction bottle, reacting under reflux of a reaction system, monitoring the reaction until the reaction is basically complete by HPLC, concentrating the reaction solution under reduced pressure until the reaction solution is dry, adding ethyl acetate for extraction, washing an organic phase by water and saturated sodium chloride aqueous solution, concentrating the organic phase under reduced pressure until the organic phase is dry, adding ethyl acetate for recrystallization, and drying under reduced pressure to obtain the compound shown in the formula 8. Thus, the efficiency of the contact reaction of the compound shown in the formula 7, hydroxylamine hydrochloride and alkali can be improved, the reaction speed can be increased, and the efficiency of preparing the compound shown in the formula 8 by using the method can be further improved.
According to an embodiment of the present invention, in step (4), the base is at least one selected from sodium hydroxide, sodium acetate, or sodium carbonate.
According to an embodiment of the present invention, in the step (4), the molar ratio of the compound represented by formula 7, hydroxylamine hydrochloride, and the base is 1 (1.0 to 1.5): (1.0 to 1.5), preferably the molar ratio of the compound represented by formula 7, hydroxylamine hydrochloride, and the base is 1:1.3:1.3. Thereby, the efficiency of preparing the compound represented by formula 8 using this method can be further improved.
According to a specific embodiment of the present invention, in step (4), the method comprises the steps of: the compound represented by formula 7 (35.36 g,49.14 mmol) was put into a reaction flask, and hydroxylamine hydrochloride (4.44 g,63.87 mmol), sodium hydroxide (2.55 g,63.87 mmol), water (20 ml) and ethanol (350 ml) were added to the reaction flask, the reaction was monitored by HPLC under reflux, the reaction was substantially complete, then the reaction solution was concentrated to dryness under reduced pressure, ethyl acetate (200 ml) was added for extraction, the organic phase was washed with water and saturated sodium chloride aqueous solution, the organic phase was concentrated to dryness under reduced pressure, ethyl acetate (100 ml) was added for recrystallization, and dried under reduced pressure to give the compound represented by formula 8 (26.40 g), yield 71.7%.
According to an embodiment of the present invention, in step (5), the contact manner of the compound represented by formula 8, triethylamine, and methanesulfonyl chloride is not particularly limited. Thus, the efficiency of the contact reaction of the compound shown in the formula 8, triethylamine and methanesulfonyl chloride can be improved, the reaction speed can be increased, and the efficiency of preparing the compound shown in the formula 9 by using the method can be further improved.
According to an embodiment of the present invention, in step (5), the steps of: adding dichloromethane and a compound shown in a formula 8 into a reaction bottle, adding triethylamine, stirring the reaction system at room temperature for 15min, cooling to-5 ℃, controlling the reaction temperature at-5 ℃, dropwise adding a dichloromethane solution containing methanesulfonyl chloride, controlling the reaction temperature at-5 ℃ after the dropwise addition is finished, stirring and reacting for 2-5 h, adding water after the reaction is finished, stirring and separating liquid, drying an organic phase with a proper amount of anhydrous sodium sulfate, concentrating under reduced pressure to dryness, adding ethyl acetate into a concentrated solution for recrystallization, filtering, and drying under reduced pressure to obtain the compound shown in the formula 9. Thus, the efficiency of the contact reaction of the compound shown in the formula 8, triethylamine and methanesulfonyl chloride can be improved, the reaction speed can be increased, and the efficiency of preparing the compound shown in the formula 9 by using the method can be further improved.
According to an embodiment of the present invention, in the step (5), the molar ratio of the compound represented by formula 8, triethylamine, and methanesulfonyl chloride is 1 (1.0 to 1.5): (1.5 to 2.5), and preferably the molar ratio of the compound represented by formula 8, triethylamine, and methanesulfonyl chloride is 1:1.2:2. Thereby, the efficiency of preparing the compound represented by formula 9 using this method can be further improved.
According to a specific embodiment of the present invention, in step (5), the steps of: dichloromethane (500 ml) was added to the reaction flask, the compound represented by formula 8 (26.0 g,36.15 mmol), triethylamine (7.32 g,72.30 mmol) was further added, the reaction system was stirred at room temperature for 15min, the temperature was lowered to-2 to 2 ℃, a solution of methanesulfonyl chloride (4.97 g,43.38 mmol) in dichloromethane (70 ml) was added dropwise at a reaction temperature of-2 to 2 ℃, the reaction was stirred at a reaction temperature of-2 to 2 ℃ for 3h after the completion of the dropwise addition, water (200 ml) was added after the completion of the reaction, the mixture was stirred and separated, the organic phase was dried over a suitable amount of anhydrous sodium sulfate, concentrated under reduced pressure to dryness, ethyl acetate (200 ml) was added to the concentrated solution for recrystallization, and the mixture was filtered and dried under reduced pressure to give the compound represented by formula 9 (21.04 g), the yield was 83.0%.
According to the embodiment of the present invention, in step (6), the contact manner of the compound represented by formula 9 with hydrazine hydrate and p-toluenesulfonic acid is not particularly limited. Therefore, the efficiency of the contact reaction of the compound shown in the formula 9, hydrazine hydrate and p-toluenesulfonic acid can be improved, the reaction speed is increased, and the efficiency of preparing the compound shown in the formula 1 by using the method is further improved.
According to an embodiment of the present invention, in step (6), the steps of: adding a solvent D into a reaction bottle, adding a compound shown in a formula 9 and hydrazine hydrate under stirring, heating to reflux, keeping the reflux reaction for 15-24 hours, cooling to room temperature after the reaction is finished, slowly adding a sodium hydroxide aqueous solution, extracting the reaction liquid with dichloromethane, concentrating the obtained organic phase under reduced pressure to dryness, dissolving the concentrated solution with isopropanol, adding p-toluenesulfonic acid, heating to reflux, keeping the reflux reaction for 1 hour, concentrating the reaction liquid to dryness after the reaction is finished, adding water, stirring for crystallization for 30 minutes, filtering, washing with petroleum ether, and drying under reduced pressure to obtain the compound shown in the target product formula 1. Therefore, the efficiency of the contact reaction of the compound shown in the formula 9, hydrazine hydrate and p-toluenesulfonic acid can be improved, the reaction speed is increased, and the efficiency of preparing the compound shown in the formula 1 by using the method is further improved.
According to an embodiment of the present invention, in step (3), the solvent D is an alcohol selected from C1 to C6, preferably the solvent D is at least one selected from ethanol, methanol, or isopropanol.
According to the embodiment of the invention, in the step (6), the molar ratio of the compound shown in the formula 9 to the hydrazine hydrate to the p-toluenesulfonic acid is 1 (1.3-1.8): (1.05-1.25), and preferably the molar ratio of the compound shown in the formula 9 to the hydrazine hydrate to the p-toluenesulfonic acid is 1:1.5:1.1. Thereby, the efficiency of preparing the compound represented by formula 1 using this method can be further improved.
According to a specific embodiment of the present invention, in step (6), the steps of: ethanol (250 ml) was added to a reaction flask, the compound of formula 9 (21 g,29.95 mmol) and hydrazine hydrate (2.25 g,44.92 mmol) were added with stirring, the temperature was raised to reflux and kept for 18h of reflux reaction, after the reaction was completed, the temperature was lowered to room temperature, 0.1mol/L aqueous sodium hydroxide solution (100 ml) was slowly added, the reaction solution was extracted with methylene chloride (300 ml), the obtained organic phase was concentrated to dryness under reduced pressure, the concentrated solution was dissolved with isopropanol (500 ml), p-toluenesulfonic acid (5.68 g,32.98 mmol) was added, the temperature was raised to reflux and kept for 1h of reflux reaction, the reaction solution was concentrated to dryness after the reaction was completed, water (250 ml) was added, stirred for 30min of crystallization, filtration, petroleum ether washing, and drying under reduced pressure to obtain the compound of formula 1 (18.42 g) as the target product, yield 82.7%, and HPLC purity 99.7%.
According to an embodiment of the present invention, the synthetic route of the compound represented by formula 1 may be as follows:
compared with the prior art, the preparation process of the Wupalis p-toluenesulfonate has at least the following beneficial effects:
(1) The synthetic route and the preparation process disclosed by the invention are a brand-new synthetic route and a brand-new preparation method developed by the applicant, and the novel route is not reported in the literature.
(2) The preparation process of the invention takes (R) -2- (1-amino ethyl) -6-fluoro-3- (3-fluorophenyl) -4H-benzopyran-4-ketone as a starting material, and synthesizes a target product, namely a compound Wu Pali S-toluenesulfonate shown in formula 1 through the steps of N-alkylation, carbonylation, amine protection, oximation, cyclization, deprotection, salification and the like, wherein the total reaction process comprises six steps: firstly, carrying out N-alkylation reaction on a halogenide and primary amine under the action of alkali to generate a compound shown in a formula 4; step two, the compound shown in the formula 4 and the Grignard reagent are subjected to carbonylation reaction to generate a compound shown in the formula 6; thirdly, protecting primary amine in the compound shown in the formula 6 by phthalic anhydride to generate a compound shown in the formula 7; fourthly, carrying out oxime synthesis reaction on the compound shown in the formula 7 and hydroxylamine hydrochloride to generate a compound shown in the formula 8; fifthly, carrying out cyclization reaction on the compound shown in the formula 8 under the action of sulfonyl chloride and an acid binding agent to generate a compound shown in the formula 9; and sixthly, deprotecting the compound shown in the formula 9 under the action of hydrazine hydrate to obtain the glabrous greenbrier rhizome free base, and salifying the glabrous greenbrier rhizome free base with p-toluenesulfonic acid to generate p-toluenesulfonic acid salt, thereby obtaining a target product, namely the compound Wu Pali s-toluenesulfonic acid shown in the formula 1.
(3) In order to cope with the defects of the original enterprise design route, the synthetic route innovatively uses a new starting material as the starting point of the route, the whole synthetic route selects the conventional reaction type and the conventional reaction condition, and the use of toxic and harmful reagents is avoided, so that the injury of dangerous processes and dangerous reagents to personnel and the pollution to the environment are reduced, and the possibility of safety accidents is reduced; the purification means of recrystallization and extraction with high efficiency and simple operation are adopted, the production time is reduced, the yield of the reaction product is improved, and the HPLC purity of the target product can reach more than 99.4 percent; compared with the original grinding process, the method shortens the reaction process and reduces the production period and the production cost of a single batch.
(4) The above advantages of the route are all beneficial to the conversion of the synthetic route to a mass production stage, and the route is used for mass production, so that the cost of production can be reduced, and the possibility of risk occurrence such as personnel injury, environmental pollution, production safety and the like can be reduced. Compared with the prior art, the synthetic route and the preparation process have the advantages of short steps, mild conditions and easiness in operation, and can be suitable for the operability of industrial mass production.
Detailed Description
Embodiments of the present invention are described in detail below. The following examples are illustrative only and are not to be construed as limiting the invention. The examples are not to be construed as limiting the specific techniques or conditions described in the literature in this field or as per the specifications of the product. The reagents or apparatus used were conventional products commercially available without the manufacturer's attention.
EXAMPLE 1 Synthesis of Compound of formula 4
DMF (300 ml) was added to a reaction flask, the compound of formula 2 (30.1 g,0.1 mol), the compound of formula 3 (23.2 g,0.15 mol) and potassium carbonate (27.6 g,0.2 mol) were added with stirring, after the addition was completed, the reaction system was warmed to 100℃and reacted at a constant temperature for 10 hours, after the reaction was completed, cooled to room temperature, water (600 ml) was slowly added to the reaction system, stirring was continued for 1 hour, filtration was carried out, and the cake was recrystallized and purified with ethyl acetate and dried under reduced pressure to give the compound of formula 4 (33.1 g), yield 78.9%.
LC-MS(ESI):m/z＝420.12(M+1) +
EXAMPLE 2 Synthesis of Compound of formula 4
DMF (300 ml) was added to a reaction flask, the compound of formula 2 (30.1 g,0.1 mol), the compound of formula 3 (18.5 g,0.12 mol) and potassium carbonate (20.7 g,0.15 mol) were added with stirring, after the addition was completed, the reaction system was warmed to 90℃and reacted at a constant temperature for 14 hours, after the reaction was completed, cooled to room temperature, water (600 ml) was slowly added to the reaction system, stirring was continued for 1 hour, filtration was carried out, and the cake was recrystallized and purified with ethyl acetate and dried under reduced pressure to give the compound of formula 4 (31.9 g), yield 76.1%.
EXAMPLE 3 Synthesis of Compound of formula 4
DMF (450 ml) was added to a reaction flask, the compound of formula 2 (30.1 g,0.1 mol), the compound of formula 3 (26.3 g,0.17 mol) and potassium carbonate (34.6 g,0.25 mol) were added with stirring, after the addition was completed, the reaction system was warmed to 120℃and reacted at a temperature of 9 hours, after the completion of the reaction, cooled to room temperature, water (600 ml) was slowly added to the reaction system, stirring was continued for 1 hour, filtration was carried out, and the cake was recrystallized and purified with ethyl acetate and dried under reduced pressure to give the compound of formula 4 (32.3 g), yield 77.0%.
EXAMPLE 4 Synthesis of Compound of formula 4
Dimethylacetamide (DMAC) (240 ml) was added to the reaction flask, the compound of formula 2 (30.1 g,0.1 mol), the compound of formula 3 (21.6 g,0.14 mol) and sodium tert-butoxide (19.2 g,0.2 mol) were added with stirring, after the addition was completed, the reaction system was warmed to 110℃and allowed to react at a constant temperature for 10 hours, after the completion of the reaction, cooled to room temperature, water (600 ml) was slowly added to the reaction system, stirring was continued for 1 hour, filtration was performed, and the cake was recrystallized and purified with ethyl acetate and dried under reduced pressure to give the compound of formula 4 (32.0 g), yield 76.3%.
EXAMPLE 5 Synthesis of Compound of formula 4
DMAC (300 ml) was added to a reaction flask, and after the addition of the compound represented by formula 2 (30.1 g,0.1 mol), the compound represented by formula 3 (23.2 g,0.15 mol) and potassium hydroxide (10.1 g,0.18 mol) with stirring, the reaction system was warmed to 100℃and allowed to react for 11 hours at a constant temperature, after the completion of the reaction, cooled to room temperature, water (600 ml) was slowly added to the reaction system, stirring was continued for 1 hour, filtration was performed, and the cake was recrystallized and purified with ethyl acetate and dried under reduced pressure to give the compound represented by formula 4 (32.1 g), yield 76.5%.
EXAMPLE 6 Synthesis of Compound of formula 4
DMSO (350 ml) is added into a reaction bottle, a compound (30.1 g,0.1 mol) shown in a formula 2, a compound (24.7 g,0.16 mol) shown in a formula 3 and sodium hydroxide (8.8 g,0.22 mol) are added into the reaction bottle under stirring, after the addition, the reaction system is heated to 110 ℃, the reaction is kept at the temperature for 10 hours, the temperature is reduced to room temperature after the reaction is finished, water (600 ml) is slowly added into the reaction system, the stirring is continued for 1 hour, the filtration is carried out, the filter cake is recrystallized and purified by ethyl acetate, the compound (31.4 g) shown in the formula 4 is obtained by decompression and drying, and the yield is 74.9%.
EXAMPLE 7 Synthesis of Compound of formula 6
Under the protection of nitrogen, dry tetrahydrofuran (20 ml) is added into a reaction bottle, magnesium (2.23 g,91.61 mmol) is added under stirring, heating is carried out until a reflux state, a mixed solution of a compound (17.80 g,76.35 mmol) shown in a formula 5 and tetrahydrofuran (150 ml) is added into a reaction system, after keeping reflux for 3 hours, a mixed solution of a compound (32.02 g,76.35 mmol) shown in a formula 4 and tetrahydrofuran (150 ml) is dropwise added, reflux reaction is continued for 7 hours, 1mol/L hydrochloric acid (300 ml) is added into the reaction system, stirring is carried out at 73-77 ℃ for 10 hours, the reaction system is cooled to room temperature, the organic phase is separated, washed with water, the organic phase is concentrated to dryness under reduced pressure, dichloromethane is recrystallized, and the compound (32.02 g) shown in a formula 6 is obtained after reduced pressure drying, and the yield is 73.0%.
LC-MS(ESI):m/z＝575.18(M+1) +
EXAMPLE 8 Synthesis of Compound of formula 6
Under the protection of nitrogen, dry tetrahydrofuran (20 ml) is added into a reaction bottle, magnesium (2.23 g,91.61 mmol) is added under stirring, heating is carried out until a reflux state, a mixed solution of a compound (16.91 g,72.53 mmol) shown in a formula 5 and tetrahydrofuran (150 ml) is added into a reaction system, after the reflux is maintained for 3 hours, a mixed solution of a compound (32.02 g,76.35 mmol) shown in a formula 4 and tetrahydrofuran (150 ml) is dropwise added, reflux reaction is continued for 6 hours, 1mol/L hydrochloric acid (300 ml) is added into the reaction system, stirring reaction is carried out for 8 hours at 73-77 ℃, the reaction system is cooled to room temperature, the organic phase is separated, washed by water, the organic phase is concentrated to dryness under reduced pressure, dichloromethane is recrystallized, and the reduced pressure drying is carried out to obtain the compound (31.13 g) shown in a formula 6, and the yield is 69.6%.
EXAMPLE 9 Synthesis of Compound of formula 6
Under the protection of nitrogen, dry tetrahydrofuran (20 ml) is added into a reaction bottle, magnesium (2.23 g,91.61 mmol) is added under stirring, heating is carried out until a reflux state, a mixed solution of a compound (19.58 g,83.99 mmol) shown in a formula 5 and tetrahydrofuran (150 ml) is added into a reaction system, after keeping reflux for 3 hours, a mixed solution of a compound (32.02 g,76.35 mmol) shown in a formula 4 and tetrahydrofuran (150 ml) is dropwise added, and reflux reaction is continued for 9 hours, 1mol/L hydrochloric acid (300 ml) is added into the reaction system, stirring reaction is carried out for 12 hours at 73-77 ℃, the reaction system is cooled to room temperature, the organic phase is separated, washed with water, the organic phase is concentrated to dryness under reduced pressure, dichloromethane is recrystallized, and reduced pressure drying is carried out to obtain the compound (31.13 g) shown in a formula 6, and the yield is 71.0%.
EXAMPLE 10 Synthesis of Compound of formula 6
Under the protection of nitrogen, dry methyltetrahydrofuran (20 ml) is added into a reaction bottle, magnesium (2.23 g,91.61 mmol) is added under stirring, heating is carried out to a reflux state, a mixed solution of a compound (17.80 g,76.35 mmol) shown in a formula 5 and methyltetrahydrofuran (150 ml) is added into a reaction system, after the mixture is kept at reflux for 3 hours, a mixed solution of a compound (32.02 g,76.35 mmol) shown in a formula 4 and methyltetrahydrofuran (150 ml) is dropwise added, reflux reaction is continued for 7 hours, 1mol/L hydrochloric acid (300 ml) is added into the reaction system, the mixture is stirred and reacted for 10 hours at 73-77 ℃, the reaction system is cooled to room temperature, the organic phase is washed by water, the organic phase is concentrated to dryness under reduced pressure, dichloromethane is recrystallized, and the reduced pressure is dried to obtain a compound (31.85 g) shown in a formula 6, and the yield is 72.6%.
EXAMPLE 11 Synthesis of Compound of formula 6
Under the protection of nitrogen, adding dry ethylene glycol dimethyl ether (20 ml), adding magnesium (2.23 g,91.61 mmol) under stirring, heating to reflux state, adding a mixed solution of a compound (17.80 g,76.35 mmol) shown in a formula 5 and ethylene glycol dimethyl ether (150 ml) into a reaction system, keeping reflux for 3 hours, dropwise adding a mixed solution of a compound (32.02 g,76.35 mmol) shown in a formula 4 and ethylene glycol dimethyl ether (150 ml), continuing reflux reaction for 7 hours, adding 1mol/L hydrochloric acid (300 ml) into the reaction system, keeping stirring at 73-77 ℃ for reaction for 10 hours, cooling the reaction system to room temperature, separating the liquid, washing an organic phase, concentrating the organic phase to dryness under reduced pressure, recrystallizing with dichloromethane, and drying under reduced pressure to obtain the compound (30.80 g) shown in a formula 6, wherein the yield is 70.2%.
EXAMPLE 12 Synthesis of Compound of formula 7
Acetonitrile (450 ml) was added to the reaction flask, while stirring, a compound of formula 6 (31.02 g,53.99 mmol), phthalic anhydride (9.59 g,64.75 mmol) and triethylamine (6.55 g,64.75 mmol) were added, the mixture was warmed to reflux and stirred for 8 hours, after the reaction was completed, cooled to room temperature, water (500 ml) was added, stirred and crystallized for 1 hour, filtered and dried, and the obtained cake was a compound of formula 7 (35.36 g), yield 91.0%, and the compound of formula 7 was directly put into the next reaction.
LC-MS(ESI):m/z＝705.19(M+1) +
EXAMPLE 13 Synthesis of Compound of formula 7
Tetrahydrofuran (360 ml) was added to the reaction flask, and while stirring, the compound of formula 6 (31.02 g,53.99 mmol), phthalic anhydride (8.00 g,53.99 mmol) and triethylamine (5.46 g,53.99 mmol) were added, the temperature was raised to reflux and stirred for 10 hours, after the reaction was completed, the temperature was lowered to room temperature, water (500 ml) was added, stirred and crystallized for 1 hour, filtration and drying were carried out, and the obtained cake was the compound of formula 7 (33.92 g), yield 87.3%, and the compound of formula 7 was directly put into the next reaction.
EXAMPLE 14 Synthesis of Compound of formula 7
Ethanol (500 ml) was added to the reaction flask, and while stirring, the compound of formula 6 (31.02 g,53.99 mmol), phthalic anhydride (12.00 g,80.99 mmol) and DIPEA (10.47 g,80.99 mmol) were added, the temperature was raised to reflux and the reaction was stirred for 6 hours, after the reaction was completed, the temperature was lowered to room temperature, water (500 ml) was added, stirred and crystallized for 1 hour, filtration and drying were carried out, and the obtained cake was the compound of formula 7 (34.78 g), yield 89.5%, and the compound of formula 7 was directly put into the next reaction.
EXAMPLE 15 Synthesis of Compound of formula 7
Acetonitrile (450 ml) was added to the reaction flask, while stirring, the compound of formula 6 (31.02 g,53.99 mmol), phthalic anhydride (9.59 g,64.75 mmol) and pyridine (5.12 g,64.75 mmol) were added, the reaction flask was warmed to reflux and stirred for 8 hours, after the reaction was completed, cooled to room temperature, water (500 ml) was added, stirred and crystallized for 1 hour, filtered and dried, the obtained cake was the compound of formula 7 (35.01 g), the yield was 90.1%, and the compound of formula 7 was directly put into the next reaction.
EXAMPLE 16 Synthesis of Compound of formula 8
The compound represented by formula 7 (35.36 g,49.14 mmol) was put into a reaction flask, and hydroxylamine hydrochloride (4.44 g,63.87 mmol), sodium hydroxide (2.55 g,63.87 mmol), water (20 ml) and ethanol (350 ml) were added to the reaction flask, the reaction was monitored by HPLC under reflux, the reaction was substantially complete, then the reaction solution was concentrated to dryness under reduced pressure, ethyl acetate (200 ml) was added for extraction, the organic phase was washed with water and saturated sodium chloride aqueous solution, the organic phase was concentrated to dryness under reduced pressure, ethyl acetate (100 ml) was added for recrystallization, and dried under reduced pressure to give the compound represented by formula 8 (26.40 g), yield 71.7%.
LC-MS(ESI):m/z＝720.20(M+1) +
EXAMPLE 17 Synthesis of Compound of formula 8
The compound represented by formula 7 (35.36 g,49.14 mmol) was put into a reaction flask, and hydroxylamine hydrochloride (3.41 g,49.14 mmol), sodium hydroxide (1.97 g,49.14 mmol), water (20 ml) and ethanol (300 ml) were added to the reaction flask, the reaction was monitored by HPLC under reflux, the reaction was substantially complete, then the reaction solution was concentrated to dryness under reduced pressure, ethyl acetate (200 ml) was added for extraction, the organic phase was washed with water and saturated sodium chloride aqueous solution, the organic phase was concentrated to dryness under reduced pressure, ethyl acetate (100 ml) was added for recrystallization, and drying under reduced pressure was carried out to obtain the compound represented by formula 8 (25.33 g), yield 68.8%.
EXAMPLE 18 Synthesis of Compound of formula 8
The compound represented by formula 7 (35.36 g,49.14 mmol) was put into a reaction flask, and hydroxylamine hydrochloride (5.12 g,73.71 mmol), sodium acetate (2.55 g,73.71 mmol), water (20 ml) and ethanol (400 ml) were added to the reaction flask, the reaction was monitored by HPLC under reflux, the reaction was substantially complete, then the reaction solution was concentrated to dryness under reduced pressure, ethyl acetate (200 ml) was added for extraction, the organic phase was washed with water and saturated sodium chloride aqueous solution, the organic phase was concentrated to dryness under reduced pressure, ethyl acetate (100 ml) was added for recrystallization, and dried under reduced pressure to give the compound represented by formula 8 (25.77 g), yield 70.0%.
EXAMPLE 19 Synthesis of Compound of formula 8
The compound represented by formula 7 (35.36 g,49.14 mmol) was put into a reaction flask, and hydroxylamine hydrochloride (4.44 g,63.87 mmol), sodium carbonate (2.55 g,63.87 mmol), water (20 ml) and ethanol (360 ml) were added to the reaction flask, the reaction was monitored by HPLC under reflux, the reaction was substantially complete, then the reaction solution was concentrated to dryness under reduced pressure, ethyl acetate (200 ml) was added for extraction, the organic phase was washed with water and saturated sodium chloride aqueous solution, the organic phase was concentrated to dryness under reduced pressure, ethyl acetate (100 ml) was added for recrystallization, and dried under reduced pressure to give the compound represented by formula 8 (26.18 g), yield 71.1%.
EXAMPLE 20 Synthesis of Compound of formula 9
Dichloromethane (500 ml) was added to the reaction flask, the compound represented by formula 8 (26.0 g,36.15 mmol), triethylamine (7.32 g,72.30 mmol) was further added, the reaction system was stirred at room temperature for 15min, the temperature was lowered to-2 to 2 ℃, a solution of methanesulfonyl chloride (4.97 g,43.38 mmol) in dichloromethane (70 ml) was added dropwise at a reaction temperature of-2 to 2 ℃, the reaction was stirred at a reaction temperature of-2 to 2 ℃ for 3h after the completion of the dropwise addition, water (200 ml) was added after the completion of the reaction, the mixture was stirred and separated, the organic phase was dried over a suitable amount of anhydrous sodium sulfate, concentrated under reduced pressure to dryness, ethyl acetate (200 ml) was added to the concentrated solution for recrystallization, and the mixture was filtered and dried under reduced pressure to give the compound represented by formula 9 (21.04 g), the yield was 83.0%.
LC-MS(ESI):m/z＝702.19(M+1) +
EXAMPLE 21 Synthesis of Compound of formula 9
Dichloromethane (500 ml) was added to the reaction flask, the compound (26 g,36.15 mmol) represented by formula 8 was further added to triethylamine (5.49 g,54.23 mmol), the reaction system was stirred at room temperature for 15min, the temperature was lowered to-5 to 0 ℃, a solution of methanesulfonyl chloride (4.14 g,36.15 mmol) in dichloromethane (70 ml) was added dropwise at a reaction temperature controlled at-5 to 0 ℃, the reaction was stirred at-5 to 0 ℃ for 5h after the completion of the dropwise addition, water (200 ml) was added after the completion of the reaction, the mixture was separated by stirring, the organic phase was dried over a suitable amount of anhydrous sodium sulfate, and concentrated to dryness under reduced pressure, ethyl acetate (200 ml) was added to the concentrated solution for recrystallization, filtration and drying under reduced pressure to give the compound (20.58 g) represented by formula 9, the yield of 80.2%.
EXAMPLE 22 Synthesis of Compound of formula 9
Dichloromethane (500 ml) was added to a reaction flask, a compound (26 g,36.15 mmol) represented by formula 8 was further added to triethylamine (9.15 g,90.38 mmol), the reaction system was stirred at room temperature for 15min, the temperature was lowered to 2 to 5 ℃, a solution of methanesulfonyl chloride (6.21 g,54.23 mmol) in dichloromethane (70 ml) was added dropwise at 2 to 5 ℃, after the completion of the dropwise addition, the reaction was stirred at 2 to 5 ℃ for 2 hours, water (200 ml) was added after the completion of the reaction, the mixture was stirred and separated, the organic phase was dried over a suitable amount of anhydrous sodium sulfate, concentrated to dryness under reduced pressure, ethyl acetate (200 ml) was added to the concentrated solution for recrystallization, filtration and drying under reduced pressure to give a compound (20.81 g) represented by formula 9 in 82.1% yield.
EXAMPLE 23 Synthesis of Compound of formula 1
Ethanol (250 ml) was added to a reaction flask, the compound of formula 9 (21 g,29.95 mmol) and hydrazine hydrate (2.25 g,44.92 mmol) were added with stirring, the temperature was raised to reflux and kept for 18h of reflux reaction, after the reaction was completed, the temperature was lowered to room temperature, 0.1mol/L aqueous sodium hydroxide solution (100 ml) was slowly added, the reaction solution was extracted with methylene chloride (300 ml), the obtained organic phase was concentrated to dryness under reduced pressure, the concentrated solution was dissolved with isopropanol (500 ml), p-toluenesulfonic acid (5.68 g,32.98 mmol) was added, the temperature was raised to reflux and kept for 1h of reflux reaction, the reaction solution was concentrated to dryness after the reaction was completed, water (250 ml) was added, stirred for 30min of crystallization, filtration, petroleum ether washing, and drying under reduced pressure to obtain the compound of formula 1 (18.42 g) as the target product, yield 82.7%, and HPLC purity 99.7%.
LC-MS(ESI):m/z＝572.19(M+1-PTSA) +
EXAMPLE 24 Synthesis of Compound of formula 1
Methanol (250 ml) was added to a reaction flask, a compound of formula 9 (21 g,29.95 mmol) and hydrazine hydrate (1.95 g,38.94 mmol) were added with stirring, the temperature was raised to reflux and kept for 15h of reflux reaction, after the reaction was completed, the temperature was lowered to room temperature, 0.1mol/L aqueous sodium hydroxide solution (100 ml) was slowly added, the reaction solution was extracted with methylene chloride (300 ml), the obtained organic phase was concentrated to dryness under reduced pressure, the concentrated solution was dissolved with isopropyl alcohol (500 ml), p-toluenesulfonic acid (5.42 g,31.45 mmol) was added, the temperature was raised to reflux and kept for 1h of reflux reaction, the reaction solution was concentrated to dryness after the reaction was completed, water (250 ml) was added, stirred for 30min of crystallization, filtration, petroleum ether washing, and drying under reduced pressure to obtain the compound of formula 1 (18.03 g) as the target product, yield 81.0%, and HPLC purity 99.5%.
EXAMPLE 25 Synthesis of Compound of formula 1
Isopropanol (250 ml) was added to a reaction flask, the mixture of the compound represented by formula 9 (21 g,29.95 mmol) and hydrazine hydrate (2.70 g,53.91 mmol) was added with stirring, the mixture was warmed to reflux and kept for 24 hours at reflux, the temperature was lowered to room temperature after the completion of the reaction, 0.1mol/L aqueous sodium hydroxide solution (100 ml) was slowly added, the reaction solution was extracted with methylene chloride (300 ml), the obtained organic phase was concentrated to dryness under reduced pressure, the concentrate was dissolved with isopropanol (500 ml), p-toluenesulfonic acid (6.45 g,37.43 mmol) was added, the mixture was warmed to reflux and kept for 1 hour at reflux, the reaction solution was concentrated to dryness after the completion of the reaction, water (250 ml) was added, stirred for 30 minutes for crystallization, filtration, petroleum ether washing, and drying under reduced pressure to obtain the compound represented by the objective formula 1 (18.27 g) in 82.1% yield and 99.4% HPLC purity.
In the description of the present specification, a description referring to terms "one embodiment," "some embodiments," "examples," "specific examples," or "some examples," etc., means that a particular feature, structure, material, or characteristic described in connection with the embodiment or example is included in at least one embodiment or example of the present invention. In this specification, schematic representations of the above terms are not necessarily directed to the same embodiment or example. Furthermore, the particular features, structures, materials, or characteristics described may be combined in any suitable manner in any one or more embodiments or examples. Furthermore, the different embodiments or examples described in this specification and the features of the different embodiments or examples may be combined and combined by those skilled in the art without contradiction.
While embodiments of the present invention have been shown and described above, it will be understood that the above embodiments are illustrative and not to be construed as limiting the invention, and that variations, modifications, alternatives and variations may be made to the above embodiments by one of ordinary skill in the art within the scope of the invention.
Claims (32)
1. A process for preparing a compound Wu Pali s p-toluenesulfonate of formula 1, comprising:
(1) Contacting a compound represented by formula 2 with a compound represented by formula 3 to obtain a compound represented by formula 4;
(2) Contacting a compound represented by formula 4 with a compound represented by formula 5 to obtain a compound represented by formula 6;
(3) Contacting a compound represented by formula 6 with phthalic anhydride to obtain a compound represented by formula 7;
(4) Contacting a compound represented by formula 7 with hydroxylamine hydrochloride to obtain a compound represented by formula 8;
(5) Contacting a compound represented by formula 8 with methanesulfonyl chloride to obtain a compound represented by formula 9;
(6) Contacting the compound shown in the formula 9 with hydrazine hydrate and p-toluenesulfonic acid in sequence to obtain a compound Wu Pali s-toluenesulfonate shown in the formula 1,
2. the method according to claim 1, characterized in that in step (1), it comprises the steps of: adding a solvent A into a reaction container, adding a compound shown in a formula 2, a compound shown in a formula 3 and alkali under stirring, heating a reaction system to 90-120 ℃ after the addition, carrying out heat preservation reaction for 9-14 h, cooling to room temperature after the reaction is finished, slowly adding water into the reaction system, continuously stirring for 1h, filtering, recrystallizing a filter cake with ethyl acetate, purifying, and drying under reduced pressure to obtain the compound shown in the formula 4.
3. The method according to claim 2, wherein in step (1), the solvent a is at least one selected from DMF, DMAC, or DMSO.
4. The method according to claim 2, wherein in step (1), the base is at least one selected from potassium carbonate, potassium hydroxide, sodium tert-butoxide, or sodium hydroxide.
5. The method according to claim 2, wherein in the step (1), the molar ratio of the compound represented by the formula 2, the compound represented by the formula 3, and the base is 1 (1.2 to 1.7): 1.5 to 2.5.
6. The method according to claim 5, wherein in the step (1), the molar ratio of the compound represented by formula 2, the compound represented by formula 3, and the base is 1:1.5:2.0.
7. The method according to claim 2, wherein in the step (1), the mass to volume ratio of the compound represented by formula 2 to the solvent A is 1 (8 to 15).
8. The method according to claim 7, wherein in the step (1), the mass to volume ratio of the compound represented by formula 2 to the solvent A is 1:10.
9. The method according to claim 2, wherein in the step (1), the reaction temperature of the contacting and stirring of the compound represented by formula 2, the compound represented by formula 3, and the base is 100℃and the reaction time is 10 hours.
10. The method according to claim 1, characterized in that in step (2), it comprises the steps of: adding a dry solvent B into a reaction vessel, adding magnesium under stirring, heating to a reflux state, adding a mixed solution of a compound shown in a formula 5 and the solvent B into a reaction system, keeping reflux for 3 hours, dropwise adding the mixed solution of the compound shown in the formula 4 and the solvent B, continuing reflux reaction for 6-9 hours, adding a hydrochloric acid solution into the reaction system, keeping the temperature of 73-77 ℃ for stirring reaction for 8-12 hours, cooling the reaction system to room temperature, separating the liquid, washing an organic phase with water, concentrating the organic phase to dryness under reduced pressure, recrystallizing with dichloromethane, and drying under reduced pressure to obtain the compound shown in the formula 6.
11. The method according to claim 10, wherein in step (2), the solvent B is at least one selected from tetrahydrofuran, methyltetrahydrofuran, or ethylene glycol dimethyl ether.
12. The method according to claim 10, wherein in the step (2), the molar ratio of the compound represented by the formula 4 to the compound represented by the formula 5 and magnesium is 1 (0.95 to 1.1): 1.2.
13. The method according to claim 12, wherein in the step (2), the molar ratio of the compound represented by formula 4 to the compound represented by formula 5, magnesium is 1:1:1.2.
14. The method according to claim 1, characterized in that in step (3), it comprises the steps of: adding a solvent C into a reaction bottle, adding a compound shown in a formula 6, an amino protective agent and alkali under stirring, heating to reflux, stirring and reacting for 6-10 h, cooling to room temperature after the reaction is finished, adding water, stirring and crystallizing for 1h, filtering, and drying to obtain a filter cake which is the compound shown in a formula 7.
15. The method according to claim 14, wherein in step (3), the solvent C is at least one selected from acetonitrile, ethanol or tetrahydrofuran.
16. The method according to claim 14, wherein in the step (3), the molar ratio of the compound represented by formula 6, the amino protecting agent, and the base is 1 (1.0 to 1.5): 1.0 to 1.5.
17. The method according to claim 16, wherein in the step (3), the molar ratio of the compound represented by formula 6, the amino protecting agent, and the base is 1:1.2:1.2.
18. The method of claim 14, wherein in step (3), the amino protecting agent is selected from phthalic anhydride.
19. The method according to claim 14, wherein in step (3), the base is at least one selected from triethylamine, DIPEA, or pyridine.
20. The method according to claim 1, characterized in that in step (4) it comprises the steps of: putting the compound shown in the formula 7 into a reaction bottle, adding hydroxylamine hydrochloride, alkali, water and ethanol into the reaction bottle, reacting under reflux of a reaction system, monitoring the reaction until the reaction is basically complete by HPLC, concentrating the reaction solution under reduced pressure until the reaction solution is dry, adding ethyl acetate for extraction, washing an organic phase by water and saturated sodium chloride aqueous solution, concentrating the organic phase under reduced pressure until the organic phase is dry, adding ethyl acetate for recrystallization, and drying under reduced pressure to obtain the compound shown in the formula 8.
21. The method of claim 20, wherein in step (4), the base is at least one selected from sodium hydroxide, sodium acetate, or sodium carbonate.
22. The method according to claim 20, wherein in the step (4), the molar ratio of the compound represented by formula 7, hydroxylamine hydrochloride, and the base is 1 (1.0 to 1.5): 1.0 to 1.5.
23. The method according to claim 22, wherein in step (4), the molar ratio of the compound represented by formula 7, hydroxylamine hydrochloride, and the base is 1:1.3:1.3.
24. The method according to claim 1, characterized in that in step (5) it comprises the steps of: adding dichloromethane and a compound shown in a formula 8 into a reaction bottle, adding triethylamine, stirring the reaction system at room temperature for 15min, cooling to-5 ℃, controlling the reaction temperature at-5 ℃, dropwise adding a dichloromethane solution containing methanesulfonyl chloride, controlling the reaction temperature at-5 ℃ after the dropwise addition is finished, stirring and reacting for 2-5 h, adding water after the reaction is finished, stirring and separating liquid, drying an organic phase with a proper amount of anhydrous sodium sulfate, concentrating under reduced pressure to dryness, adding ethyl acetate into a concentrated solution for recrystallization, filtering, and drying under reduced pressure to obtain the compound shown in the formula 9.
25. The method according to claim 24, wherein in the step (5), the molar ratio of the compound represented by formula 8, triethylamine, and methanesulfonyl chloride is 1 (1.0 to 1.5): 1.5 to 2.5.
26. The method according to claim 25, wherein in step (5), the molar ratio of the compound of formula 8, triethylamine, and methanesulfonyl chloride is 1:1.2:2.
27. The method according to claim 1, characterized in that in step (6), it comprises the steps of: adding a solvent D into a reaction bottle, adding a compound shown in a formula 9 and hydrazine hydrate under stirring, heating to reflux, keeping the reflux reaction for 15-24 hours, cooling to room temperature after the reaction is finished, slowly adding a sodium hydroxide aqueous solution, extracting the reaction liquid with dichloromethane, concentrating the obtained organic phase under reduced pressure to dryness, dissolving the concentrated solution with isopropanol, adding p-toluenesulfonic acid, heating to reflux, keeping the reflux reaction for 1 hour, concentrating the reaction liquid to dryness after the reaction is finished, adding water, stirring for crystallization for 30 minutes, filtering, washing with petroleum ether, and drying under reduced pressure to obtain the compound shown in the target product formula 1.
28. The method according to claim 27, wherein in step (6), the solvent D is an alcohol selected from C1-C6.
29. The method according to claim 28, wherein in step (6), the solvent D is at least one selected from ethanol, methanol, or isopropanol.
30. The method according to claim 27, wherein in the step (6), the molar ratio of the compound represented by the formula 9 to hydrazine hydrate to p-toluenesulfonic acid is 1 (1.3 to 1.8): 1.05 to 1.25.
31. The method according to claim 30, wherein in the step (6), the molar ratio of the compound represented by formula 9 to hydrazine hydrate to p-toluenesulfonic acid is 1:1.5:1.1.
32. The method according to claim 1, characterized in that in step (1), it comprises the steps of: adding 300ml of DMF into a reaction bottle, adding 30.1g of a compound shown in a formula 2, 23.2g of a compound shown in a formula 3 and 27.6g of potassium carbonate under stirring, heating a reaction system to 100 ℃ after the addition, preserving heat for reaction for 10 hours, cooling to room temperature after the reaction is finished, slowly adding 600ml of water into the reaction system, continuously stirring for 1 hour, filtering, recrystallizing a filter cake with ethyl acetate for purification, and drying under reduced pressure to obtain 33.1g of the compound shown in the formula 4, wherein the yield is 78.9%;
in step (2), the method comprises the following steps: under the protection of nitrogen, adding dry 20ml of tetrahydrofuran into a reaction bottle, adding 2.23g of magnesium under stirring, heating to a reflux state, adding 17.80g of a mixed solution of a compound shown in a formula 5 and 150ml of tetrahydrofuran into a reaction system, keeping reflux for 3 hours, dropwise adding 32.02g of a mixed solution of a compound shown in a formula 4 and 150ml of tetrahydrofuran, continuing reflux reaction for 7 hours, adding 300ml of 1mol/L hydrochloric acid into the reaction system, keeping the temperature of 73-77 ℃ for stirring and reacting for 10 hours, cooling the reaction system to room temperature, separating the liquid, washing an organic phase, concentrating the organic phase to dryness under reduced pressure, recrystallizing dichloromethane, and drying under reduced pressure to obtain 32.02g of the compound shown in the formula 6, wherein the yield is 73.0%;
In step (3), the method comprises the following steps: adding 450ml of acetonitrile into a reaction bottle, adding 31.02g of a compound shown in a formula 6, 9.59g of phthalic anhydride and 6.55g of triethylamine under stirring, heating to reflux, stirring for reaction for 8 hours, cooling to room temperature after the reaction is finished, adding 500ml of water, stirring, crystallizing for 1 hour, filtering, and drying to obtain a filter cake which is 35.36g of the compound shown in a formula 7, wherein the yield is 91.0%, and directly adding the compound shown in the formula 7 into the next reaction;
in step (4), the method comprises the following steps: adding 35.36g of a compound shown in a formula 7 into a reaction bottle, adding 4.44g of hydroxylamine hydrochloride, 2.55g of sodium hydroxide, 20ml of water and 350ml of ethanol into the reaction bottle, reacting under reflux of a reaction system, monitoring the reaction until the reaction is basically complete by HPLC, concentrating the reaction solution under reduced pressure until the reaction solution is dry, adding 200ml of ethyl acetate for extraction, washing an organic phase with water and a saturated sodium chloride aqueous solution, concentrating the organic phase under reduced pressure until the organic phase is dry, adding 100ml of ethyl acetate for recrystallization, and drying under reduced pressure to obtain 26.40g of the compound shown in the formula 8, wherein the yield is 71.7%;
in step (5), the method comprises the following steps: adding 500ml of dichloromethane and 26.0g of a compound shown in formula 8 into a reaction bottle, adding 7.32g of triethylamine, stirring the reaction system at room temperature for 15min, cooling to-2 ℃, controlling the reaction temperature to-2 ℃, dropwise adding 70ml of dichloromethane solution of 4.97g of methanesulfonyl chloride, controlling the reaction temperature to-2 ℃ after the dropwise addition, stirring for 3h, adding 200ml of water after the reaction, stirring for liquid separation, drying an organic phase by using a proper amount of anhydrous sodium sulfate, concentrating to dryness under reduced pressure, adding 200ml of ethyl acetate into the concentrated solution for recrystallization, filtering, and drying under reduced pressure to obtain 21.04g of the compound shown in formula 9, wherein the yield is 83.0%;
In step (6), the method comprises the following steps: adding 250ml of ethanol into a reaction bottle, adding 21g of a compound shown in a formula 9 and 2.25g of hydrazine hydrate under stirring, heating to reflux, keeping reflux reaction for 18h, cooling to room temperature after the reaction is finished, slowly adding 100ml of 0.1mol/L sodium hydroxide aqueous solution, extracting the reaction liquid with 300ml of dichloromethane, concentrating the obtained organic phase under reduced pressure to dryness, dissolving the concentrated solution with 500ml of isopropanol, adding 5.68g of p-toluenesulfonic acid, heating to reflux, keeping reflux reaction for 1h, concentrating the reaction liquid to dryness after the reaction is finished, adding 250ml of water, stirring for crystallization for 30min, filtering, washing with petroleum ether, and drying under reduced pressure to obtain 18.42g of a compound shown in a target product formula 1, wherein the yield is 82.7% and the HPLC purity is 99.7%.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202210332644.5A CN114891005B (en) | 2022-03-30 | 2022-03-30 | Preparation process of Wupalision p-toluenesulfonate |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202210332644.5A CN114891005B (en) | 2022-03-30 | 2022-03-30 | Preparation process of Wupalision p-toluenesulfonate |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN114891005A CN114891005A (en) | 2022-08-12 |
| CN114891005B true CN114891005B (en) | 2024-01-19 |
Family
ID=82716041
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN202210332644.5A Active CN114891005B (en) | 2022-03-30 | 2022-03-30 | Preparation process of Wupalision p-toluenesulfonate |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN114891005B (en) |
Citations (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102812013A (en) * | 2009-11-05 | 2012-12-05 | 理森制药股份公司 | Novel Kinase Modulators |
| CN103702989A (en) * | 2011-05-04 | 2014-04-02 | 理森制药股份公司 | Novel compounds as modulators of protein kinases |
| WO2014071125A1 (en) * | 2012-11-02 | 2014-05-08 | Tg Therapeutics, Inc. | Combination of anti-cd20 antibody and pi3 kinase selective inhibitor |
| CN104470923A (en) * | 2012-07-04 | 2015-03-25 | 理森制药股份公司 | Selective PI3K delta inhibitors |
| CN106661029A (en) * | 2014-06-27 | 2017-05-10 | 理森制药股份公司 | Substituted chromene derivatives as selective dual inhibitors of PI3 delta and gamma protein kinases |
| CN107454902A (en) * | 2015-04-16 | 2017-12-08 | 奇斯药制品公司 | Chromene derivative as the kinase inhibitor of phosphoinositide 3 |
Family Cites Families (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US10130635B2 (en) * | 2012-05-04 | 2018-11-20 | Rhizen Pharmaceuticals Sa | Process for preparation of optically pure and optionally substituted 2-(1-hydroxy-alkyl)-chromen-4-one derivatives and their use in preparing pharmaceuticals |
-
2022
- 2022-03-30 CN CN202210332644.5A patent/CN114891005B/en active Active
Patent Citations (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102812013A (en) * | 2009-11-05 | 2012-12-05 | 理森制药股份公司 | Novel Kinase Modulators |
| CN103702989A (en) * | 2011-05-04 | 2014-04-02 | 理森制药股份公司 | Novel compounds as modulators of protein kinases |
| CN104470923A (en) * | 2012-07-04 | 2015-03-25 | 理森制药股份公司 | Selective PI3K delta inhibitors |
| WO2014071125A1 (en) * | 2012-11-02 | 2014-05-08 | Tg Therapeutics, Inc. | Combination of anti-cd20 antibody and pi3 kinase selective inhibitor |
| CN106661029A (en) * | 2014-06-27 | 2017-05-10 | 理森制药股份公司 | Substituted chromene derivatives as selective dual inhibitors of PI3 delta and gamma protein kinases |
| CN107454902A (en) * | 2015-04-16 | 2017-12-08 | 奇斯药制品公司 | Chromene derivative as the kinase inhibitor of phosphoinositide 3 |
Also Published As
| Publication number | Publication date |
|---|---|
| CN114891005A (en) | 2022-08-12 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| EP2534131B1 (en) | Methods of synthesizing and isolating n-(bromoacetyl)-3,3-dinitroazetidine and a composition including the same | |
| ES2208265T3 (en) | TELMISARTAN POLYMORPHES, PROCEDURE FOR PREPARATION AND USE FOR THE PREPARATION OF A MEDICINAL PRODUCT. | |
| CN111875517A (en) | Intermediate for synthesizing camptothecin derivative and preparation method and application thereof | |
| CN112010817A (en) | Method for preparing tetrazine compound and application thereof | |
| CN114891005B (en) | Preparation process of Wupalision p-toluenesulfonate | |
| CN111217791B (en) | Ibrutin intermediate and preparation method thereof | |
| CN113620868A (en) | Torasemide new impurity and preparation method thereof | |
| CN111440181B (en) | Dipyrazolo seven-membered oxygen heterocyclic compound containing quinoline structure and synthetic method thereof | |
| CN114195739A (en) | High-purity roxatidine acetate hydrochloride, intermediate thereof and preparation methods thereof | |
| CN113956198A (en) | Impurity of roxasistat, preparation method and application thereof | |
| JPS5949217B2 (en) | Method for producing substituted diphenyl ether | |
| CN111116477A (en) | Synthesis process of doramelamine | |
| CN110845504A (en) | Novel method for synthesizing pratinib | |
| CN115894303B (en) | Preparation method of (3-amino bicyclo [1.1.1] pentane-1-yl) carbamic acid tert-butyl ester and intermediate thereof | |
| CN115536571B (en) | Preparation method of indole derivative | |
| CN118026935A (en) | Synthesis method of 1H-arylpyrazole compound | |
| CN109384734B (en) | Preparation method of Selsemipa intermediate | |
| CN114671869A (en) | Novel synthesis method of compound Tomivosertib | |
| CN117024485A (en) | Synthesis method of 2' -OMe adenosine | |
| CN113754715A (en) | Optical selectivity process synthesis method of (5R) -5-hydroxyl triptolide | |
| WO2023217058A1 (en) | Method for preparing glucopyranosyl-containing compound | |
| CN117551038A (en) | Synthesis method for promoting preparation of 4-bromo-7-methyl-1H-indazole ring by boric acid | |
| CN114195694A (en) | Preparation method of pyrrole compound | |
| CN112341468A (en) | 1, 4-benzodiazepine compound and preparation and functionalization method thereof | |
| KR820001122B1 (en) | Process for preparing n-alkenyl moranoline derivatives |
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 | ||
| GR01 | Patent grant | ||
| GR01 | Patent grant |