CN110590649A - Preparation method of vismodegib and intermediate thereof - Google Patents
Preparation method of vismodegib and intermediate thereof Download PDFInfo
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- CN110590649A CN110590649A CN201810607627.1A CN201810607627A CN110590649A CN 110590649 A CN110590649 A CN 110590649A CN 201810607627 A CN201810607627 A CN 201810607627A CN 110590649 A CN110590649 A CN 110590649A
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- chloro
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- pyridyl
- methylsulfonyl
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- 238000002360 preparation method Methods 0.000 title claims abstract description 30
- BPQMGSKTAYIVFO-UHFFFAOYSA-N vismodegib Chemical compound ClC1=CC(S(=O)(=O)C)=CC=C1C(=O)NC1=CC=C(Cl)C(C=2N=CC=CC=2)=C1 BPQMGSKTAYIVFO-UHFFFAOYSA-N 0.000 title claims abstract description 23
- 229960004449 vismodegib Drugs 0.000 title claims abstract description 22
- 238000006243 chemical reaction Methods 0.000 claims abstract description 35
- 238000000034 method Methods 0.000 claims abstract description 23
- -1 4-chloro-3- (2-pyridyl) phenyl Chemical group 0.000 claims abstract description 20
- 239000003153 chemical reaction reagent Substances 0.000 claims abstract description 9
- 239000002994 raw material Substances 0.000 claims abstract description 5
- 238000004519 manufacturing process Methods 0.000 claims abstract 3
- 239000002904 solvent Substances 0.000 claims description 54
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical group ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 38
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 36
- 150000001875 compounds Chemical class 0.000 claims description 32
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 26
- 239000000243 solution Substances 0.000 claims description 25
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 24
- 238000001914 filtration Methods 0.000 claims description 22
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 22
- YLNMGMIEOWFPRX-UHFFFAOYSA-N 3-pyridin-2-ylaniline Chemical compound NC1=CC=CC(C=2N=CC=CC=2)=C1 YLNMGMIEOWFPRX-UHFFFAOYSA-N 0.000 claims description 18
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical group CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 18
- XFNJVJPLKCPIBV-UHFFFAOYSA-N trimethylenediamine Chemical compound NCCCN XFNJVJPLKCPIBV-UHFFFAOYSA-N 0.000 claims description 18
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 16
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 claims description 16
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical class [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 16
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 16
- CTTWSFIIFMWHLQ-UHFFFAOYSA-N 2-chloro-4-methylsulfonylbenzoic acid Chemical compound CS(=O)(=O)C1=CC=C(C(O)=O)C(Cl)=C1 CTTWSFIIFMWHLQ-UHFFFAOYSA-N 0.000 claims description 15
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 15
- 238000001035 drying Methods 0.000 claims description 15
- CKQHAYFOPRIUOM-UHFFFAOYSA-N 3'-Aminoacetophenone Chemical compound CC(=O)C1=CC=CC(N)=C1 CKQHAYFOPRIUOM-UHFFFAOYSA-N 0.000 claims description 14
- JRNVZBWKYDBUCA-UHFFFAOYSA-N N-chlorosuccinimide Chemical compound ClN1C(=O)CCC1=O JRNVZBWKYDBUCA-UHFFFAOYSA-N 0.000 claims description 14
- 239000003513 alkali Substances 0.000 claims description 13
- 239000007864 aqueous solution Substances 0.000 claims description 13
- 239000003054 catalyst Substances 0.000 claims description 13
- 239000010949 copper Substances 0.000 claims description 13
- 239000007787 solid Substances 0.000 claims description 13
- RYGMFSIKBFXOCR-UHFFFAOYSA-N Copper Chemical compound [Cu] RYGMFSIKBFXOCR-UHFFFAOYSA-N 0.000 claims description 12
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 12
- 229910052802 copper Inorganic materials 0.000 claims description 12
- 239000012153 distilled water Substances 0.000 claims description 12
- 238000010438 heat treatment Methods 0.000 claims description 12
- 239000012044 organic layer Substances 0.000 claims description 12
- 239000012046 mixed solvent Substances 0.000 claims description 11
- 239000003795 chemical substances by application Substances 0.000 claims description 10
- CLCPHXRHYYEUME-UHFFFAOYSA-N 2-chloro-4-methylsulfonylbenzoyl chloride Chemical compound CS(=O)(=O)C1=CC=C(C(Cl)=O)C(Cl)=C1 CLCPHXRHYYEUME-UHFFFAOYSA-N 0.000 claims description 9
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 9
- 230000008569 process Effects 0.000 claims description 9
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 claims description 9
- 238000005406 washing Methods 0.000 claims description 9
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 claims description 8
- 238000001816 cooling Methods 0.000 claims description 8
- 239000000203 mixture Substances 0.000 claims description 8
- CTSLXHKWHWQRSH-UHFFFAOYSA-N oxalyl chloride Chemical group ClC(=O)C(Cl)=O CTSLXHKWHWQRSH-UHFFFAOYSA-N 0.000 claims description 8
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 8
- 238000007363 ring formation reaction Methods 0.000 claims description 8
- 239000007858 starting material Substances 0.000 claims description 8
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 8
- IDXKTTNFXPPXJY-UHFFFAOYSA-N pyrimidin-1-ium;chloride Chemical compound Cl.C1=CN=CN=C1 IDXKTTNFXPPXJY-UHFFFAOYSA-N 0.000 claims description 7
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 6
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 6
- 239000002253 acid Substances 0.000 claims description 6
- OPQARKPSCNTWTJ-UHFFFAOYSA-L copper(ii) acetate Chemical compound [Cu+2].CC([O-])=O.CC([O-])=O OPQARKPSCNTWTJ-UHFFFAOYSA-L 0.000 claims description 6
- 239000012074 organic phase Substances 0.000 claims description 6
- 230000001376 precipitating effect Effects 0.000 claims description 6
- 239000000047 product Substances 0.000 claims description 6
- 239000000376 reactant Substances 0.000 claims description 6
- 238000010992 reflux Methods 0.000 claims description 6
- 239000000126 substance Substances 0.000 claims description 6
- 238000005303 weighing Methods 0.000 claims description 6
- USFZMSVCRYTOJT-UHFFFAOYSA-N Ammonium acetate Chemical compound N.CC(O)=O USFZMSVCRYTOJT-UHFFFAOYSA-N 0.000 claims description 5
- 239000005695 Ammonium acetate Substances 0.000 claims description 5
- 235000019257 ammonium acetate Nutrition 0.000 claims description 5
- 229940043376 ammonium acetate Drugs 0.000 claims description 5
- ORTQZVOHEJQUHG-UHFFFAOYSA-L copper(II) chloride Chemical group Cl[Cu]Cl ORTQZVOHEJQUHG-UHFFFAOYSA-L 0.000 claims description 5
- 238000000605 extraction Methods 0.000 claims description 5
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 claims description 5
- SCYULBFZEHDVBN-UHFFFAOYSA-N 1,1-Dichloroethane Chemical compound CC(Cl)Cl SCYULBFZEHDVBN-UHFFFAOYSA-N 0.000 claims description 4
- 229910021589 Copper(I) bromide Inorganic materials 0.000 claims description 4
- 229910021595 Copper(I) iodide Inorganic materials 0.000 claims description 4
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 4
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 claims description 4
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 claims description 4
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 claims description 4
- 238000004440 column chromatography Methods 0.000 claims description 4
- NKNDPYCGAZPOFS-UHFFFAOYSA-M copper(i) bromide Chemical compound Br[Cu] NKNDPYCGAZPOFS-UHFFFAOYSA-M 0.000 claims description 4
- LSXDOTMGLUJQCM-UHFFFAOYSA-M copper(i) iodide Chemical compound I[Cu] LSXDOTMGLUJQCM-UHFFFAOYSA-M 0.000 claims description 4
- 239000003960 organic solvent Substances 0.000 claims description 4
- 239000011736 potassium bicarbonate Substances 0.000 claims description 4
- 229910000028 potassium bicarbonate Inorganic materials 0.000 claims description 4
- 235000015497 potassium bicarbonate Nutrition 0.000 claims description 4
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 4
- 235000011181 potassium carbonates Nutrition 0.000 claims description 4
- TYJJADVDDVDEDZ-UHFFFAOYSA-M potassium hydrogencarbonate Chemical compound [K+].OC([O-])=O TYJJADVDDVDEDZ-UHFFFAOYSA-M 0.000 claims description 4
- 229910000030 sodium bicarbonate Inorganic materials 0.000 claims description 4
- 235000017557 sodium bicarbonate Nutrition 0.000 claims description 4
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 4
- 235000017550 sodium carbonate Nutrition 0.000 claims description 4
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 3
- 239000013078 crystal Substances 0.000 claims description 3
- 239000000706 filtrate Substances 0.000 claims description 3
- 229910052760 oxygen Inorganic materials 0.000 claims description 3
- 239000001301 oxygen Substances 0.000 claims description 3
- 238000000926 separation method Methods 0.000 claims description 3
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 claims description 2
- 239000005711 Benzoic acid Substances 0.000 claims description 2
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 claims description 2
- SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 claims description 2
- 235000010233 benzoic acid Nutrition 0.000 claims description 2
- XTVVROIMIGLXTD-UHFFFAOYSA-N copper(II) nitrate Chemical compound [Cu+2].[O-][N+]([O-])=O.[O-][N+]([O-])=O XTVVROIMIGLXTD-UHFFFAOYSA-N 0.000 claims description 2
- SBTSVTLGWRLWOD-UHFFFAOYSA-L copper(ii) triflate Chemical compound [Cu+2].[O-]S(=O)(=O)C(F)(F)F.[O-]S(=O)(=O)C(F)(F)F SBTSVTLGWRLWOD-UHFFFAOYSA-L 0.000 claims description 2
- 229940076286 cupric acetate Drugs 0.000 claims description 2
- 229940098779 methanesulfonic acid Drugs 0.000 claims description 2
- 230000001590 oxidative effect Effects 0.000 claims description 2
- 238000000746 purification Methods 0.000 claims description 2
- ITMCEJHCFYSIIV-UHFFFAOYSA-N triflic acid Chemical compound OS(=O)(=O)C(F)(F)F ITMCEJHCFYSIIV-UHFFFAOYSA-N 0.000 claims description 2
- 239000002585 base Substances 0.000 claims 1
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 abstract description 6
- 229910052763 palladium Inorganic materials 0.000 abstract description 3
- 238000005660 chlorination reaction Methods 0.000 abstract 1
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 16
- 206010004146 Basal cell carcinoma Diseases 0.000 description 8
- 230000008410 smoothened signaling pathway Effects 0.000 description 7
- MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 description 6
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 5
- 238000005160 1H NMR spectroscopy Methods 0.000 description 5
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 4
- 238000002390 rotary evaporation Methods 0.000 description 4
- 238000006482 condensation reaction Methods 0.000 description 3
- KWOLFJPFCHCOCG-UHFFFAOYSA-N Acetophenone Chemical compound CC(=O)C1=CC=CC=C1 KWOLFJPFCHCOCG-UHFFFAOYSA-N 0.000 description 2
- KXDAEFPNCMNJSK-UHFFFAOYSA-N Benzamide Chemical compound NC(=O)C1=CC=CC=C1 KXDAEFPNCMNJSK-UHFFFAOYSA-N 0.000 description 2
- 108010016200 Zinc Finger Protein GLI1 Proteins 0.000 description 2
- 230000001594 aberrant effect Effects 0.000 description 2
- 230000004913 activation Effects 0.000 description 2
- 239000012295 chemical reaction liquid Substances 0.000 description 2
- 229940079593 drug Drugs 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- 239000005457 ice water Substances 0.000 description 2
- 238000009776 industrial production Methods 0.000 description 2
- 239000003112 inhibitor Substances 0.000 description 2
- 239000004973 liquid crystal related substance Substances 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- 230000017423 tissue regeneration Effects 0.000 description 2
- 229940121827 Hedgehog pathway inhibitor Drugs 0.000 description 1
- NTIZESTWPVYFNL-UHFFFAOYSA-N Methyl isobutyl ketone Chemical compound CC(C)CC(C)=O NTIZESTWPVYFNL-UHFFFAOYSA-N 0.000 description 1
- UIHCLUNTQKBZGK-UHFFFAOYSA-N Methyl isobutyl ketone Natural products CCC(C)C(C)=O UIHCLUNTQKBZGK-UHFFFAOYSA-N 0.000 description 1
- 238000006411 Negishi coupling reaction Methods 0.000 description 1
- 206010028980 Neoplasm Diseases 0.000 description 1
- 101710158727 Protein smoothened Proteins 0.000 description 1
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical group C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 1
- 229910006124 SOCl2 Inorganic materials 0.000 description 1
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 1
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 1
- 241000251539 Vertebrata <Metazoa> Species 0.000 description 1
- 238000005273 aeration Methods 0.000 description 1
- 238000013459 approach Methods 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 239000012267 brine Substances 0.000 description 1
- 230000008859 change Effects 0.000 description 1
- 238000005859 coupling reaction Methods 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 230000018109 developmental process Effects 0.000 description 1
- 230000013020 embryo development Effects 0.000 description 1
- 239000002360 explosive Substances 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 239000010410 layer Substances 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 238000012423 maintenance Methods 0.000 description 1
- 108020004999 messenger RNA Proteins 0.000 description 1
- 230000001394 metastastic effect Effects 0.000 description 1
- 206010061289 metastatic neoplasm Diseases 0.000 description 1
- 238000012544 monitoring process Methods 0.000 description 1
- 230000003647 oxidation Effects 0.000 description 1
- 238000007254 oxidation reaction Methods 0.000 description 1
- 230000035790 physiological processes and functions Effects 0.000 description 1
- 230000005855 radiation Effects 0.000 description 1
- 230000035484 reaction time Effects 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 230000000306 recurrent effect Effects 0.000 description 1
- 238000007670 refining Methods 0.000 description 1
- 238000011069 regeneration method Methods 0.000 description 1
- 230000019491 signal transduction Effects 0.000 description 1
- 230000011664 signaling Effects 0.000 description 1
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 1
- 239000012265 solid product Substances 0.000 description 1
- 210000000130 stem cell Anatomy 0.000 description 1
- 238000001356 surgical procedure Methods 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
- 230000009772 tissue formation Effects 0.000 description 1
- 230000030968 tissue homeostasis Effects 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- 230000003827 upregulation Effects 0.000 description 1
- 238000001291 vacuum drying Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
- C07D213/36—Radicals substituted by singly-bound nitrogen atoms
- C07D213/40—Acylated substituent nitrogen atom
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pyridine Compounds (AREA)
Abstract
The invention provides a preparation method of vismodegib and an intermediate thereof, namely a preparation method of 2-chloro-N- (4-chloro-3- (2-pyridyl) phenyl) -4- (methylsulfonyl) benzamide and an intermediate thereof. The method comprises the steps of firstly preparing an intermediate 2-chloro-4-methylsulfonyl-N- (3- (2-pyridyl) phenyl) benzamide, and then carrying out chlorination reaction to obtain the 2-chloro-N- (4-chloro-3- (2-pyridyl) phenyl) -4- (methylsulfonyl) benzamide. The method has the characteristics of short steps, simple operation, cheap and easily obtained starting raw materials, no use of palladium reagent, low requirement of reaction conditions on anhydrous and anaerobic conditions and the like, and can effectively reduce the production cost.
Description
Technical Field
The invention relates to the field of organic synthesis and pharmaceutical chemistry, in particular to a preparation method of vismodegib and an intermediate thereof, namely a preparation method of 2-chloro-N- (4-chloro-3- (2-pyridyl) phenyl) -4- (methylsulfonyl) benzamide and an intermediate thereof.
Background
The Hh signaling pathway plays an important role in numerous physiological processes such as vertebrate embryonic development, tissue formation, and maintenance, tissue repair, and regeneration of mature individual stem cells.
The Hh signaling pathway is briefly summarized as the Hh-Ptch-Smo-Gli signaling axis, and in general, the Hh signaling pathway is not expressed and active in adults. Aberrant activation of the Hh signaling pathway is closely associated with the development of a variety of tumors, including basal cell carcinoma. The results of the study showed that upregulation of Ptch1mRNA, gli mRNA and gli protein levels was involved in almost all basal cell carcinomas, confirming that the occurrence of human basal cell carcinomas is closely associated with aberrant activation of the Hedgehog signaling pathway. The discovery of Hh signaling pathway inhibitors provides a new approach to the treatment of basal cell carcinoma. The Hh signaling pathway inhibitors currently on the market, Vismodegib (Vismodegib) and sonbigbib (Sondegib), are both used in the treatment of basal cell carcinoma.
Vismodegib (Vismodegib), chemically known as 2-chloro-N- (4-chloro-3- (2-pyridyl) phenyl) -4- (methylsulfonyl) benzamide, is a Hedgehog pathway inhibitor developed by Genetech, roche, which is capable of preventing signal transduction by binding to and inhibiting the 7-transmembrane protein smoothened (smo).
In 2012, the U.S. food and drug administration approved it to be marketed in advance for the treatment of recurrent locally advanced basal cell carcinoma or metastatic basal cell carcinoma that could not be treated with surgery or radiation. This was the first approved drug for the treatment of basal cell carcinoma since history.
For the preparation of Vismodegib (Vismodegib), the relevant routes disclosed in the original patent WO 2006028958 are shown below. The route is short, but requires key steps of a Negishi coupling reaction, n-butyllithium preparation is required, and strict anhydrous and oxygen-free conditions are required for preparing the n-butyllithium. The n-butyl lithium is flammable and explosive, and the industrial production is dangerous. In addition, the coupling reaction uses an expensive palladium catalyst, resulting in higher costs.
In the prior art, a method suitable for industrially synthesizing the vismodegib and the intermediate thereof, which has the advantages of low cost, high yield, mild reaction conditions and simple post-treatment, is not available.
Disclosure of Invention
Aiming at the defects of the prior art, the invention aims to provide a preparation method of vismodegib and an intermediate thereof, namely a preparation method of 2-chloro-N- (4-chloro-3- (2-pyridyl) phenyl) -4- (methylsulfonyl) benzamide and an intermediate thereof.
The technical scheme of the invention is as follows:
the preparation method of the 2-chloro-N- (4-chloro-3- (2-pyridyl) phenyl) -4- (methylsulfonyl) benzamide intermediate compound shown in the formula IV comprises one of the following methods:
the method comprises the following steps:
oxidizing the compound of the formula I and 1, 3-propane diamine to perform cyclization reaction to prepare a compound of a formula II;
then, condensing the compound shown in the formula II and the compound shown in the formula III to obtain a compound shown in the formula IV;
or the second method:
taking a compound of formula I as a raw material, and reacting the compound of formula I with a compound of formula III to prepare a compound of formula VI;
then, cyclizing the compound of formula VI to obtain a compound of formula IV;
a preferable method for preparing the intermediate (the compound shown in the formula IV) of the vismodegib comprises the steps of taking m-aminoacetophenone as a starting material, carrying out oxidation cyclization reaction with 1, 3-propane diamine, and then carrying out condensation reaction with 2-chloro-4-methylsulfonylbenzoic acid.
According to the invention, the preferable preparation method of the vismodegib intermediate (compound shown as formula IV) 2-chloro-4-methylsulfonyl-N- (3- (2-pyridyl) phenyl) benzamide comprises the following steps:
dissolving m-aminoacetophenone (I) in a first solvent, adding a first copper catalyst, acid and 1, 3-propane diamine, heating to 80-100 ℃, reacting for 24-48 hours in an oxygen environment, performing alkali washing, extraction, water washing, drying, and performing column chromatography separation and purification to obtain 3- (2-pyridyl) aniline (II);
dissolving 2-chloro-4-methylsulfonylbenzoic acid (III) in a second solvent, dropwise adding an acylating agent and a small amount of N, N-dimethylformamide at room temperature, and heating for reflux reaction for 4-8 hours; removing excess acylating agent and solvent; then dissolving the product 2-chloro-4-methylsulfonylbenzoyl chloride in a third solvent;
dissolving 3- (2-pyridyl) aniline (II) in a third solvent, adding alkali, and cooling to 0 ℃; and slowly dripping the prepared solution of the 2-chloro-4-methylsulfonylbenzoyl chloride into a 3- (2-pyridyl) aniline (II) solution, reacting at room temperature for 6-12 hours, adding a small amount of distilled water after the reaction is finished, separating the solution to obtain an organic layer, washing the organic layer with saturated sodium carbonate, slowly adding the organic layer into a large amount of distilled water, filtering and drying to obtain the 2-chloro-4-methylsulfonyl-N- (3- (2-pyridyl) phenyl) benzamide (IV).
It is further preferred that the first and second liquid crystal compositions,
the acid is selected from p-toluenesulfonic acid, trifluoroacetic acid, trifluoromethanesulfonic acid, methanesulfonic acid or benzoic acid.
The first solvent is selected from ethanol, isopropanol, 1, 4-dioxane, N-methyl pyrrolidone, acetonitrile, toluene or ethyl acetate.
The first copper catalyst is selected from copper chloride, cuprous bromide, cuprous iodide, copper acetate, copper nitrate or copper trifluoromethanesulfonate.
The molar ratio of the starting material I, the 1, 3-propane diamine, the first copper catalyst and the acid is 1: 3-5: 0.05-0.2: 0.2 to 1.0; the mass volume ratio of the starting material I to the first solvent is 1:20 to 50.
The acylating agent is oxalyl chloride or thionyl chloride.
The second solvent is selected from dichloromethane, chloroform, tetrahydrofuran or a mixed solvent of more than two of the solvents.
The third solvent is selected from dichloromethane, dichloroethane, chloroform, tetrahydrofuran or a mixed solvent of more than two of the solvents.
The alkali is selected from triethylamine, Diisopropylethylamine (DIPEA), potassium carbonate, sodium carbonate, potassium bicarbonate or sodium bicarbonate.
The molar ratio of the reactant III, the acylating reagent, the intermediate II and the alkali is 1: 2-10: 0.80-1.0: 1.0 to 3.0; the mass-volume ratio of the reactant III to the second solvent and the third solvent is 1: 30-50: 30-60.
Another preferred method for preparing the intermediate (the compound shown in the formula IV) of the vismodegib comprises the steps of taking m-aminoacetophenone and 2-chloro-4-methylsulfonylbenzoic acid as starting materials, carrying out a condensation reaction, and then carrying out a ring formation reaction with pyrimidine chloride salt.
According to the invention, the preferable preparation method of the vismodegib intermediate (compound shown as formula IV) 2-chloro-4-methylsulfonyl-N- (3- (2-pyridyl) phenyl) benzamide comprises the following steps:
dissolving 2-chloro-4-methylsulfonylbenzoic acid (III) in a second solvent, dropwise adding an acylating agent and a small amount of N, N-dimethylformamide at room temperature, and heating for reflux reaction for 4-8 hours; removing excess acylating agent and solvent; then dissolving the product 2-chloro-4-methylsulfonylbenzoyl chloride in a third solvent;
weighing m-aminoacetophenone (I), dissolving in a third solvent, adding alkali, and cooling to 0 deg.C; slowly dripping the prepared solution of the 2-chloro-4-methylsulfonylbenzoyl chloride into a m-aminoacetophenone (I) solution, reacting at room temperature for 6-12 hours, adding a small amount of distilled water after the reaction is finished, separating the solution to obtain an organic layer, washing the organic layer with saturated sodium carbonate, slowly adding the organic layer into a large amount of distilled water, filtering and drying to obtain N- (3-phenylacetyl) -2-chloro-4-methylsulfonylbenzoyl formamide (VI);
weighing N- (3-phenylacetyl) -2-chloro-4-methylsulfonylbenzamide, dissolving in acetic acid, adding pyrimidine chloride and ammonium acetate, heating to 100-; after the reaction is finished, cooling, adding ethanol, slowly dropwise adding 0.3M NaOH aqueous solution into the mixture, adjusting the pH to 5-6, and dropwise adding 1.0M NaOH aqueous solution until the pH is 12-14; precipitating a large amount of solid, filtering and drying, dissolving in 1MHCl aqueous solution, filtering to remove insoluble substances, adjusting the 1M NaOH aqueous solution to be alkaline, precipitating the solid, filtering and drying in vacuum, and recrystallizing with methanol/water mixed solvent to obtain light yellow crystal.
It is further preferred that the first and second liquid crystal compositions,
the acylating agent is oxalyl chloride or thionyl chloride.
The second solvent is selected from dichloromethane, chloroform, tetrahydrofuran or a mixed solvent of more than two of the solvents.
The third solvent is selected from dichloromethane, dichloroethane, chloroform, tetrahydrofuran or a mixed solvent of more than two of the solvents.
The alkali is selected from triethylamine, Diisopropylethylamine (DIPEA), potassium carbonate, sodium carbonate, potassium bicarbonate or sodium bicarbonate.
The molar ratio of the 2-chloro-4-methylsulfonylbenzoic acid (III), the acylating reagent, the reactant I and the alkali is 1: 2-10: 0.80-1.0: 1.0 to 3.0; the mass volume ratio of the 2-chloro-4-methylsulfonylbenzoic acid (III) to the second solvent and the third solvent is 1: 30-50: 30-60.
The molar ratio of the intermediate VI to the pyrimidine chloride salt to the ammonium acetate is 1: 1.0-2.0: 5-10; the mass-volume ratio of the intermediate VI to the acetic acid solvent is 1: 10 to 20.
A process for the further preparation of vismodegib (formula v) using the intermediate prepared above (formula iv) 2-chloro-N- (4-chloro-3- (2-pyridyl) phenyl) -4- (methylsulfonyl) benzamide (formula v) comprising the steps of:
dissolving 2-chloro-4-methylsulfonyl-N- (3- (2-pyridyl) phenyl) benzamide (IV) in a fourth solvent, adding a second copper catalyst and N-chlorosuccinimide (NCS), heating to 100-120 ℃, and reacting for 6-12 hours. After the reaction is finished, adding an organic solvent and water, adjusting the reaction solution to be alkaline, and filtering to obtain a filtrate; adding organic solvent for extraction, combining the organic phases and concentrating; dissolving in 1M HCl aqueous solution, and filtering to remove insoluble substances; adjusting the pH value of 1M NaOH aqueous solution to be alkaline, filtering and drying to obtain 2-chloro-N- (4-chloro-3- (2-pyridyl) phenyl) -4- (methylsulfonyl) benzamide (V).
The second copper catalyst is selected from copper chloride, cuprous bromide, cuprous iodide and cupric acetate.
The fourth solvent is selected from N, N-dimethylformamide or N, N-dimethylacetamide.
The molar ratio of the intermediate IV to the N-chlorosuccinimide to the second copper catalyst is 1: 1-3: 0.1 to 0.5; the mass-volume ratio of the intermediate IV to the fourth solvent is 1: 10 to 30.
The room temperature is 15-25 ℃.
Technical characteristics and beneficial effects of the invention
1. The invention takes the m-aminoacetophenone as the starting material, the prior art mostly uses 3-halogen-4-chloronitrobenzene, and the m-aminoacetophenone with the same purity is about 1/3 of the 3-halogen-4-chloronitrobenzene; m-aminoacetophenone is used as a starting material, and is condensed with 2-chloro-4-methylsulfonylbenzoic acid after ring formation. Compared with the cyclization reaction, the yield of the cyclization reaction is lower, and the m-aminoacetophenone with the same purity is about 1/2 of 2-chloro-4-methylsulfonylbenzoic acid, so that the cost can be greatly reduced by the post-condensation reaction.
2. Compared with the prior art, the second method has the advantages that the acetophenone is subjected to pyridine ring formation reaction with 1, 3-propane diamine by adopting pyrimidine chloride salt, the yield is higher, the reaction temperature is lower, the reaction time is shorter, column chromatography is not needed in post-treatment, and the method is more suitable for large-scale preparation.
3. Expensive palladium reagent, highly toxic or dangerous reagent are not used, reaction raw materials are cheap and easy to obtain, reaction conditions are mild, and the method is more suitable for industrial production.
4. According to the invention, through selection of specific reaction conditions, dosage and proportion and the like, the yield of the target product of the vismodegib is high and reaches 58.2%, and the purity is 99.8974%.
In conclusion, the method has the advantages of cheap and easily obtained raw materials, simple post-treatment, low cost, high yield, high purity and the like.
Detailed Description
The present invention will be further illustrated by the following specific examples. The following examples are intended to provide those skilled in the art with a better understanding of the present invention, and are not intended to limit the present invention in any way.
Example 1: preparation of vismodegib intermediate (compound shown as formula IV) 2-chloro-4-methylsulfonyl-N- (3- (2-pyridyl) phenyl) benzamide
Preparation of 3- (2-pyridyl) aniline (II):
weighing m-aminoacetophenone (100.0mg,0.74mmol) and dissolving in ethanol (3mL), adding Cu (OTf)2(26.8mg,0.074mmol)、TsOH·H2O (84.4mg,0.44mmol) and 1, 3-propanediamine (185. mu.L, 2.22mmol) were reacted at 80 ℃ for 72 hours with aeration and oxygen. After the reaction is finished, the reaction liquid is cooled to room temperature, rotary evaporation and concentration are carried out, and ethyl acetate, water and saturated sodium carbonate are added to adjust the alkalinity. Extracted with ethyl acetate (25mL x 3), washed with brine (30mL x 2), and dried over anhydrous sodium sulfate. Column chromatography (EA: PE 1:3) is carried out, thus obtaining 62.3mg of product with 49.5 percent of yield.
1H NMR(600MHz,CDCl3)δ8.68(ddd,J＝4.8,1.6,0.9Hz,1H),7.78–7.73(m,1H),7.73–7.69(m,1H),7.42–7.38(m,1H),7.35–7.30(m,1H),7.26(t,J＝7.8Hz,1H),7.23(ddd,J＝7.3,4.9,1.2Hz,1H),6.75(ddd,J＝7.8,2.3,0.9Hz,1H),3.24(s,2H).
13C NMR(600MHz,CDCl3)δ157.50,149.45,146.95,140.39,136.79,129.68,122.14,120.71,117.21,115.83,113.61,77.42,77.10,76.78.
m/z[M+H]+171.3。
Preparation of 2-chloro-4-methylsulfonyl-N- (3- (2-pyridyl) phenyl) benzamide (IV):
2-chloro-4-methylsulfonylbenzoic acid (165.5mg,0.71mmol) was weighed out, dissolved in DCM (10mL), added 4 drops of DMF and heated to reflux. The solution was gradually clarified and the end of the reaction was monitored by TLC. After the reaction is finished, performing rotary evaporation and concentration to remove excessive SOCl2And DCM, dissolved in anhydrous THF (10 mL).
The 3- (2-pyridyl) aniline (100mg,0.59mmol) prepared above was dissolved in anhydrous THF (5ml), TEA (164. mu.L, 1.18mmol) was added, and cooled to 0 ℃ in an ice-water bath. Slowly dropwise adding the prepared anhydrous THF solution of the 2-chloro-4-methylsulfonylbenzoyl chloride into the solution, slowly heating to room temperature after dropwise adding is finished, reacting for 5 hours, and monitoring the reaction end point by TLC. After the reaction was completed, the solution was in the form of a suspension, 0.5mL of distilled water was added, and the solution gradually clarified. The solution was washed with saturated sodium carbonate solution (2 mL. times.2) and the solution was partitioned. The organic phase was slowly added dropwise to 50mL of distilled water, and a white solid precipitated, filtered, and dried under vacuum to give 204.7mg of a white solid with a yield of 90.1%.
1H NMR(400MHz,DMSO-d6)δ10.84(s,1H),8.69(d,J＝4.7Hz,1H),8.52(s,1H),8.15(d,J＝1.4Hz,1H),8.02(dd,J＝8.0,1.5Hz,1H),7.92(dd,J＝10.6,6.3Hz,3H),7.84(d,J＝7.8Hz,1H),7.75(d,J＝8.8Hz,1H),7.50(t,J＝7.9Hz,1H),7.43–7.35(m,1H),3.36(s,3H).
13C NMR(400MHz,DMSO-d6)δ164.29,156.07,150.06,143.46,141.68,139.87,139.54,137.83,131.47,130.43,129.83,128.57,126.40,123.33,122.79,120.76,120.73,118.35,43.59.
HRMS-ESI:m/z[M+H]+calcd for C19H15ClN2O3S:386.0492；found:387.0605Mp 198-199℃。
Example 2: preparation of vismodegib intermediate (compound shown as formula IV) 2-chloro-4-methylsulfonyl-N- (3- (2-pyridyl) phenyl) benzamide
Preparation of N- (3-phenylacetyl) -2-chloro-4-methylsulfonylbenzamide (VI)
2-chloro-4-methylsulfonylbenzoic acid (5.00g,21.31mmol) was weighed out and dissolved in DCM (120mL) and SOCl was added2(6.5mL,88.78mmol), DMF (0.5mL) was added dropwise and the reaction was heated to reflux. After the reaction is finished, the reaction liquid is cooled to room temperature, and excess SOCl is removed by rotary evaporation2And DCM to give a white solid.
Weighing m-aminoacetophenone (2.40g,17.76mmol) and dissolving in anhydrous THF, adding TEA (5mL,35.51mmol), and cooling to 0 deg.C in ice-water bath. Then, the anhydrous THF solution of 2-chloro-4-methylsulfonylbenzoic acid prepared above was slowly added dropwise thereto, and a solid precipitated. After the completion of the dropwise addition, the temperature was slowly raised to room temperature, and the reaction was carried out at room temperature. After the reaction is finished, 8mL of distilled water is added, the reaction solution becomes clear from turbidity, liquid separation is carried out, an organic phase is taken, saturated sodium carbonate is used for washing (15mL x 2), then the organic phase is slowly added into 700mL of distilled water, a large amount of solid is separated out, filtration and drying are carried out, 5.90g of brown yellow solid is obtained, and the yield is 94.4%.
1H NMR(400MHz,DMSO-d6)10.90(s,1H),8.31(t,J＝1.8Hz,1H),8.14(d,J＝1.6Hz,1H),8.02(dd,J＝8.0,1.7Hz,1H),7.95–7.89(m,2H),7.79–7.74(d,J＝7.9Hz,1H),7.54(t,J＝7.9Hz,1H),3.36(s,3H),2.59(s,3H).
13C NMR(400MHz,DMSO-d6)δ198.04,164.41,143.57,141.43,139.37,137.92,131.45,130.43,129.88,128.59,126.41,124.75,124.54,119.22,43.57,27.25.
m/z[M+H]+352.3
Mp 201-202℃。
Preparation of 2-chloro-4-methylsulfonyl-N- (3- (2-pyridyl) phenyl) benzamide (IV)
N- (3-Phenylacetyl) -2-chloro-4-methylsulfonylbenzamide (0.50g,1.42mmol) was dissolved in acetic acid (6mL), and pyrimidine chloride (342.4mg,2.13mmol) and ammonium acetate (1.29g,16.74mmol) were added, followed by heating to 110 ℃ for 10 h. After the reaction is finished, cooling, adding 6mL of ethanol, slowly dropwise adding a NaOH (0.3M) solution into the mixture, adjusting the pH to 5-6, and dropwise adding a NaOH (1.0M) aqueous solution until the pH is 12-14. Precipitating a large amount of solid, filtering and drying, dissolving HCl (1M), filtering to remove insoluble substances, adjusting NaOH (1M) to be alkaline, precipitating the solid, filtering and drying in vacuum, and recrystallizing with methanol/water (1:2) mixed solvent to obtain light yellow crystal 0.42g, wherein the yield is 76.4%.
1H NMR(600MHz,DMSO-d6)δ10.86(s,1H),8.69(d,J＝4.6Hz,1H),8.53(t,J＝1.7Hz,1H),8.15(d,J＝1.6Hz,1H),8.03(dd,J＝7.9,1.6Hz,1H),7.97–7.88(m,3H),7.84(d,J＝7.8Hz,1H),7.76(dd,J＝7.9,1.4Hz,1H),7.51(t,J＝7.9Hz,1H),7.39(ddd,J＝6.7,4.8,1.7Hz,1H),3.37(s,3H).
13C NMR(600MHz,DMSO-d6)δ164.28,156.06,150.06,143.45,141.67,139.86,139.54,137.84,131.46,130.43,129.83,128.57,126.40,123.34,122.78,120.74,118.33,43.57.
m/z[M+H]+387.3。
Example 3: preparation of vismodegib (formula V) 2-chloro-N- (4-chloro-3- (2-pyridyl) phenyl) -4- (methylsulfonyl) benzamide
2-chloro-4-methylsulfonyl-N- (3- (2-pyridylphenyl)) benzamide (1.00g,2.58mmol) was dissolved in DMF (20mL), NCS (0.69g,5.17mmol) and copper chloride (69.5mg,0.52mmol) were added, and the mixture was heated to 120 ℃ for reaction. The reaction was monitored by TLC and after completion of the reaction, the reaction was cooled to room temperature. Dichloromethane (50mL), water (100mL) and saturated sodium carbonate were added to make the mixture basic, and the mixture was filtered through celite. The filtrate is separated into layers, dichloromethane is used for extraction (30mL x 2), organic phases are combined, rotary evaporation and concentration are carried out, HCl (1M) is dissolved, insoluble substances are removed by filtration, NaOH (1M) is adjusted to be alkaline, a large amount of white solid is separated out, filtration and vacuum drying are carried out to obtain 0.88g of white solid product, the yield is 80.7%, and then methyl isobutyl ketone is adopted for recrystallization and refining.
1H NMR(600MHz,DMSO-d6)δ10.93(s,1H),8.71(s,1H),8.13(s,1H),8.01(d,J＝8.1Hz,2H),7.92(dd,J＝13.7,7.4Hz,2H),7.74(d,J＝9.8Hz,1H),7.70(d,J＝7.8Hz,1H),7.59(d,J＝8.7Hz,1H),7.45(m,1H),3.35(s,3H).
13C NMR(600MHz,DMSO-d6)δ164.35,156.26,150.01,143.61,141.34,139.73,138.11,136.94,131.44,130.90,130.43,128.59,126.42,126.29,125.01,123.52,122.87,121.42,43.57.
HRMS-ESI:m/z[M+H]+calcd for C19H15Cl2N2O3S:420.0102；found:421.0245
Mp 187-189 ℃; purity: 99.8974 percent.
The above description is only exemplary of the present invention, and is not intended to limit the present invention in any way, and any simple modification, equivalent change and modification made to the above exemplary embodiments according to the technical spirit of the present invention are all included in the scope of the present invention.
Claims (10)
- A process for the preparation of 2-chloro-N- (4-chloro-3- (2-pyridyl) phenyl) -4- (methylsulfonyl) benzamide intermediate of formula IV, characterized by one of the following:the method comprises the following steps:oxidizing the compound of the formula I and 1, 3-propane diamine to perform cyclization reaction to prepare a compound of a formula II;then, condensing the compound shown in the formula II and the compound shown in the formula III to obtain a compound shown in the formula IV;or the second method:taking a compound of formula I as a raw material, and reacting the compound of formula I with a compound of formula III to prepare a compound of formula VI;then, cyclizing the compound of formula VI to obtain a compound of formula IV;
- 2. a process for the preparation of 2-chloro-N- (4-chloro-3- (2-pyridyl) phenyl) -4- (methylsulfonyl) benzamide intermediate of formula IV according to claim 1 comprising the steps of:dissolving m-aminoacetophenone (I) in a first solvent, adding a first copper catalyst, acid and 1, 3-propane diamine, heating to 80-100 ℃, reacting for 24-48 hours in an oxygen environment, performing alkali washing, extraction, water washing, drying, and performing column chromatography separation and purification to obtain 3- (2-pyridyl) aniline (II);dissolving 2-chloro-4-methylsulfonylbenzoic acid (III) in a second solvent, dropwise adding an acylating agent and a small amount of N, N-dimethylformamide at room temperature, and heating for reflux reaction for 4-8 hours; removing excess acylating agent and solvent; then dissolving the product 2-chloro-4-methylsulfonylbenzoyl chloride in a third solvent;dissolving 3- (2-pyridyl) aniline (II) in a third solvent, adding alkali, and cooling to 0 ℃; and slowly dripping the prepared solution of the 2-chloro-4-methylsulfonylbenzoyl chloride into a 3- (2-pyridyl) aniline (II) solution, reacting at room temperature for 6-12 hours, adding a small amount of distilled water after the reaction is finished, separating the solution to obtain an organic layer, washing the organic layer with saturated sodium carbonate, slowly adding the organic layer into a large amount of distilled water, filtering and drying to obtain the 2-chloro-4-methylsulfonyl-N- (3- (2-pyridyl) phenyl) benzamide (IV).
- 3. A process for the preparation of 2-chloro-N- (4-chloro-3- (2-pyridyl) phenyl) -4- (methylsulfonyl) benzamide intermediate of formula IV according to claim 2, comprising any one or more of the following conditions:A1) the acid is selected from p-toluenesulfonic acid, trifluoroacetic acid, trifluoromethanesulfonic acid, methanesulfonic acid or benzoic acid;A2) the first solvent is selected from ethanol, isopropanol, 1, 4-dioxane, N-methyl pyrrolidone, acetonitrile, toluene or ethyl acetate;A3) the first copper catalyst is selected from copper chloride, cuprous bromide, cuprous iodide, copper acetate, copper nitrate or copper trifluoromethanesulfonate;A4) the acylating reagent is oxalyl chloride or thionyl chloride;A5) the second solvent is selected from dichloromethane, chloroform, tetrahydrofuran or a mixed solvent of more than two of the solvents;A6) the third solvent is selected from dichloromethane, dichloroethane, chloroform, tetrahydrofuran or a mixed solvent of more than two of the solvents;A7) the alkali is selected from triethylamine, Diisopropylethylamine (DIPEA), potassium carbonate, sodium carbonate, potassium bicarbonate or sodium bicarbonate.
- 4. The process for preparing 2-chloro-N- (4-chloro-3- (2-pyridyl) phenyl) -4- (methylsulfonyl) benzamide intermediate compound of formula IV according to claim 2, wherein the molar ratio of starting material I, 1, 3-propanediamine, first copper catalyst, and acid is 1: 3-5: 0.05-0.2: 0.2 to 1.0; the mass volume ratio of the starting material I to the first solvent is 1: 20-50.
- 5. The process for preparing 2-chloro-N- (4-chloro-3- (2-pyridyl) phenyl) -4- (methylsulfonyl) benzamide intermediate of formula IV according to claim 2, wherein the molar ratio of reactant III, acylating reagent, intermediate II, and base is 1: 2-10: 0.80-1.0: 1.0 to 3.0; the mass-volume ratio of the reactant III to the second solvent and the third solvent is 1: 30-50: 30-60.
- 6. A process for the preparation of 2-chloro-N- (4-chloro-3- (2-pyridyl) phenyl) -4- (methylsulfonyl) benzamide intermediate of formula IV according to claim 1 comprising the steps of:dissolving 2-chloro-4-methylsulfonylbenzoic acid (III) in a second solvent, dropwise adding an acylating agent and a small amount of N, N-dimethylformamide at room temperature, and heating for reflux reaction for 4-8 hours; removing excess acylating agent and solvent; then dissolving the product 2-chloro-4-methylsulfonylbenzoyl chloride in a third solvent;weighing m-aminoacetophenone (I), dissolving in a third solvent, adding alkali, and cooling to 0 deg.C; slowly dripping the prepared solution of the 2-chloro-4-methylsulfonylbenzoyl chloride into a m-aminoacetophenone (I) solution, reacting at room temperature for 6-12 hours, adding a small amount of distilled water after the reaction is finished, separating the solution to obtain an organic layer, washing the organic layer with saturated sodium carbonate, slowly adding the organic layer into a large amount of distilled water, filtering and drying to obtain N- (3-phenylacetyl) -2-chloro-4-methylsulfonylbenzoyl formamide (VI);weighing N- (3-phenylacetyl) -2-chloro-4-methylsulfonylbenzamide (VI), dissolving in acetic acid, adding pyrimidine chloride and ammonium acetate, heating to 100-118 ℃, and reacting for 6-12 h; after the reaction is finished, cooling, adding ethanol, slowly dropwise adding 0.3M NaOH aqueous solution into the mixture, adjusting the pH to 5-6, and dropwise adding 1.0M NaOH aqueous solution until the pH is 12-14; precipitating a large amount of solid, filtering and drying, dissolving with 1M HCl aqueous solution, filtering to remove insoluble substances, adjusting 1M NaOH aqueous solution to be alkaline, precipitating the solid, filtering and drying in vacuum, and recrystallizing with methanol/water mixed solvent to obtain light yellow crystal.
- 7. A process for the preparation of 2-chloro-N- (4-chloro-3- (2-pyridyl) phenyl) -4- (methylsulfonyl) benzamide intermediate of formula IV according to claim 6, comprising any one or more of the following conditions:B1) the acylating reagent is oxalyl chloride or thionyl chloride;B2) the second solvent is selected from dichloromethane, chloroform, tetrahydrofuran or a mixed solvent of more than two of the solvents;B3) the third solvent is selected from dichloromethane, dichloroethane, chloroform, tetrahydrofuran or a mixed solvent of more than two of the solvents;B4) the alkali is selected from triethylamine, Diisopropylethylamine (DIPEA), potassium carbonate, sodium carbonate, potassium bicarbonate or sodium bicarbonate.
- 8. A process for the preparation of 2-chloro-N- (4-chloro-3- (2-pyridyl) phenyl) -4- (methylsulfonyl) benzamide intermediate of formula IV according to claim 6, comprising any one or more of the following conditions:C1) the molar ratio of the 2-chloro-4-methylsulfonylbenzoic acid (III), the acylating reagent, the reactant I and the alkali is 1: 2-10: 0.80-1.0: 1.0 to 3.0; the mass volume ratio of the 2-chloro-4-methylsulfonylbenzoic acid (III) to the second solvent and the third solvent is 1: 30-50: 30-60 parts of;C2) the molar ratio of the intermediate VI to the pyrimidine chloride salt to the ammonium acetate is 1: 1.0-2.0: 5-10; the mass-to-volume ratio of the compound of formula VI to the acetic acid solvent is 1: 10 to 20.
- 9. A process for the further preparation of vismodegib (formula v) 2-chloro-N- (4-chloro-3- (2-pyridyl) phenyl) -4- (methylsulfonyl) benzamide using the intermediate compound of formula IV prepared according to claim 1, comprising the steps of:dissolving 2-chloro-4-methylsulfonyl-N- (3- (2-pyridyl) phenyl) benzamide (IV) in a fourth solvent, adding a second copper catalyst and N-chlorosuccinimide (NCS), heating to 100-120 ℃, and reacting for 6-12 hours; after the reaction is finished, adding an organic solvent and water, adjusting the reaction solution to be alkaline, and filtering to obtain a filtrate; adding organic solvent for extraction, combining the organic phases and concentrating; dissolving in 1M HCl aqueous solution, and filtering to remove insoluble substances; adjusting the pH value of 1M NaOH aqueous solution to be alkaline, filtering and drying to obtain 2-chloro-N- (4-chloro-3- (2-pyridyl) phenyl) -4- (methylsulfonyl) benzamide (V).
- 10. A process as claimed in claim 9 for the preparation of 2-chloro-N- (4-chloro-3- (2-pyridinyl) phenyl) -4- (methylsulfonyl) benzamide (formula v) which comprises any one or more of the following conditions:D1) the second copper catalyst is selected from copper chloride, cuprous bromide, cuprous iodide and cupric acetate;D2) the fourth solvent is selected from N, N-dimethylformamide or N, N-dimethylacetamide;D3) the molar ratio of the intermediate IV to the N-chlorosuccinimide to the second copper catalyst is 1: 1-3: 0.1 to 0.5; the mass-volume ratio of the intermediate IV to the fourth solvent is 1: 10 to 30.
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Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103910672A (en) * | 2013-01-08 | 2014-07-09 | 连云港润众制药有限公司 | Preparation method for vismodegib |
| CN106892863A (en) * | 2017-03-09 | 2017-06-27 | 山东大学 | The preparation method of vismodegib and its intermediate |
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Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103910672A (en) * | 2013-01-08 | 2014-07-09 | 连云港润众制药有限公司 | Preparation method for vismodegib |
| CN106892863A (en) * | 2017-03-09 | 2017-06-27 | 山东大学 | The preparation method of vismodegib and its intermediate |
Non-Patent Citations (2)
| Title |
|---|
| LONG-YI XI等: "《Copper-Catalyzed Aerobic Synthesis of 2‑Arylpyridines from Acetophenones and 1,3-Diaminopropane》", 《ORG. LETT.》 * |
| REMY ANGELAUD 等: "《Manufacturing Development and Genotoxic Impurity Control Strategy of the Hedgehog Pathway Inhibitor Vismodegib》", 《ORG. PROCESS RES. DEV.》 * |
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