CN113754632A - Preparation method of cancer treatment medicine - Google Patents
Preparation method of cancer treatment medicine Download PDFInfo
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- CN113754632A CN113754632A CN202010504087.1A CN202010504087A CN113754632A CN 113754632 A CN113754632 A CN 113754632A CN 202010504087 A CN202010504087 A CN 202010504087A CN 113754632 A CN113754632 A CN 113754632A
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- 238000002360 preparation method Methods 0.000 title claims abstract description 20
- 239000003814 drug Substances 0.000 title abstract description 4
- 206010028980 Neoplasm Diseases 0.000 title abstract description 3
- 201000011510 cancer Diseases 0.000 title abstract description 3
- 150000001875 compounds Chemical class 0.000 claims abstract description 125
- 238000000034 method Methods 0.000 claims abstract description 37
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims abstract description 30
- 238000010511 deprotection reaction Methods 0.000 claims abstract description 17
- 238000005859 coupling reaction Methods 0.000 claims abstract description 13
- 230000008878 coupling Effects 0.000 claims abstract description 12
- 238000010168 coupling process Methods 0.000 claims abstract description 12
- 238000007363 ring formation reaction Methods 0.000 claims abstract description 7
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 66
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 54
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 45
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 45
- 238000006243 chemical reaction Methods 0.000 claims description 40
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 39
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 36
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 32
- 239000012442 inert solvent Substances 0.000 claims description 31
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 27
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 27
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 27
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 26
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 claims description 26
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 26
- 239000002585 base Substances 0.000 claims description 26
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 claims description 22
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 22
- 239000003153 chemical reaction reagent Substances 0.000 claims description 20
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 18
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 17
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 16
- 235000011181 potassium carbonates Nutrition 0.000 claims description 16
- DYHSDKLCOJIUFX-UHFFFAOYSA-N tert-butoxycarbonyl anhydride Chemical compound CC(C)(C)OC(=O)OC(=O)OC(C)(C)C DYHSDKLCOJIUFX-UHFFFAOYSA-N 0.000 claims description 14
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 claims description 13
- SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 claims description 13
- 230000035484 reaction time Effects 0.000 claims description 13
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 13
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 12
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 claims description 12
- 239000011736 potassium bicarbonate Substances 0.000 claims description 12
- 229910000028 potassium bicarbonate Inorganic materials 0.000 claims description 12
- 235000015497 potassium bicarbonate Nutrition 0.000 claims description 12
- TYJJADVDDVDEDZ-UHFFFAOYSA-M potassium hydrogencarbonate Chemical compound [K+].OC([O-])=O TYJJADVDDVDEDZ-UHFFFAOYSA-M 0.000 claims description 12
- 125000006239 protecting group Chemical group 0.000 claims description 12
- 229910052751 metal Inorganic materials 0.000 claims description 11
- 239000002184 metal Substances 0.000 claims description 11
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims description 10
- 239000002253 acid Substances 0.000 claims description 10
- 239000003795 chemical substances by application Substances 0.000 claims description 10
- 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 10
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 9
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 claims description 9
- VLKZOEOYAKHREP-UHFFFAOYSA-N hexane Substances CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 claims description 9
- 125000003088 (fluoren-9-ylmethoxy)carbonyl group Chemical group 0.000 claims description 8
- 229910021595 Copper(I) iodide Inorganic materials 0.000 claims description 8
- 125000001584 benzyloxycarbonyl group Chemical group C(=O)(OCC1=CC=CC=C1)* 0.000 claims description 8
- LSXDOTMGLUJQCM-UHFFFAOYSA-M copper(i) iodide Chemical compound I[Cu] LSXDOTMGLUJQCM-UHFFFAOYSA-M 0.000 claims description 8
- 238000005886 esterification reaction Methods 0.000 claims description 7
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 claims description 6
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 claims description 6
- UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical compound [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 claims description 6
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 claims description 6
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 6
- 235000017550 sodium carbonate Nutrition 0.000 claims description 6
- LMBFAGIMSUYTBN-MPZNNTNKSA-N teixobactin Chemical compound C([C@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H](CCC(N)=O)C(=O)N[C@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H]1C(N[C@@H](C)C(=O)N[C@@H](C[C@@H]2NC(=N)NC2)C(=O)N[C@H](C(=O)O[C@H]1C)[C@@H](C)CC)=O)NC)C1=CC=CC=C1 LMBFAGIMSUYTBN-MPZNNTNKSA-N 0.000 claims description 6
- 229910021589 Copper(I) bromide Inorganic materials 0.000 claims description 5
- 125000005257 alkyl acyl group Chemical group 0.000 claims description 5
- NKNDPYCGAZPOFS-UHFFFAOYSA-M copper(i) bromide Chemical compound Br[Cu] NKNDPYCGAZPOFS-UHFFFAOYSA-M 0.000 claims description 5
- 229960002089 ferrous chloride Drugs 0.000 claims description 5
- NMCUIPGRVMDVDB-UHFFFAOYSA-L iron dichloride Chemical compound Cl[Fe]Cl NMCUIPGRVMDVDB-UHFFFAOYSA-L 0.000 claims description 5
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 claims description 4
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 4
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 4
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 claims description 4
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 claims description 4
- 239000003513 alkali Substances 0.000 claims description 4
- 125000003236 benzoyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C(*)=O 0.000 claims description 4
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 4
- 229910052794 bromium Inorganic materials 0.000 claims description 4
- 239000000460 chlorine Substances 0.000 claims description 4
- 229910052801 chlorine Inorganic materials 0.000 claims description 4
- 239000011630 iodine Substances 0.000 claims description 4
- 229910052740 iodine Inorganic materials 0.000 claims description 4
- 239000012299 nitrogen atmosphere Substances 0.000 claims description 4
- UYWQUFXKFGHYNT-UHFFFAOYSA-N phenylmethyl ester of formic acid Natural products O=COCC1=CC=CC=C1 UYWQUFXKFGHYNT-UHFFFAOYSA-N 0.000 claims description 4
- 125000005931 tert-butyloxycarbonyl group Chemical group [H]C([H])([H])C(OC(*)=O)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 4
- -1 trimethylsilyloxycarbonyl Chemical group 0.000 claims description 4
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims description 3
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 claims description 3
- WETWJCDKMRHUPV-UHFFFAOYSA-N acetyl chloride Chemical compound CC(Cl)=O WETWJCDKMRHUPV-UHFFFAOYSA-N 0.000 claims description 3
- 239000012346 acetyl chloride Substances 0.000 claims description 3
- 230000032050 esterification Effects 0.000 claims description 3
- 235000019253 formic acid Nutrition 0.000 claims description 3
- 229940098779 methanesulfonic acid Drugs 0.000 claims description 3
- ITMCEJHCFYSIIV-UHFFFAOYSA-N triflic acid Chemical compound OS(=O)(=O)C(F)(F)F ITMCEJHCFYSIIV-UHFFFAOYSA-N 0.000 claims description 3
- HSDAJNMJOMSNEV-UHFFFAOYSA-N benzyl chloroformate Chemical compound ClC(=O)OCC1=CC=CC=C1 HSDAJNMJOMSNEV-UHFFFAOYSA-N 0.000 claims description 2
- HPNMFZURTQLUMO-UHFFFAOYSA-N diethylamine Chemical compound CCNCC HPNMFZURTQLUMO-UHFFFAOYSA-N 0.000 claims description 2
- 239000000203 mixture Substances 0.000 claims description 2
- 235000006408 oxalic acid Nutrition 0.000 claims description 2
- 229920000137 polyphosphoric acid Polymers 0.000 claims description 2
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 claims description 2
- RZWZRACFZGVKFM-UHFFFAOYSA-N propanoyl chloride Chemical compound CCC(Cl)=O RZWZRACFZGVKFM-UHFFFAOYSA-N 0.000 claims description 2
- 239000003223 protective agent Substances 0.000 claims description 2
- 238000004519 manufacturing process Methods 0.000 abstract description 10
- 239000002994 raw material Substances 0.000 abstract description 4
- 238000009776 industrial production Methods 0.000 abstract description 3
- FVTVMQPGKVHSEY-UHFFFAOYSA-N 1-AMINOCYCLOBUTANE CARBOXYLIC ACID Chemical compound OC(=O)C1(N)CCC1 FVTVMQPGKVHSEY-UHFFFAOYSA-N 0.000 abstract 1
- CPEKAXYCDKETEN-UHFFFAOYSA-N benzoyl isothiocyanate Chemical compound S=C=NC(=O)C1=CC=CC=C1 CPEKAXYCDKETEN-UHFFFAOYSA-N 0.000 abstract 1
- 229940079593 drug Drugs 0.000 abstract 1
- 239000007787 solid Substances 0.000 description 11
- 238000003756 stirring Methods 0.000 description 9
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 8
- 238000001914 filtration Methods 0.000 description 8
- 238000007664 blowing Methods 0.000 description 5
- 238000001035 drying Methods 0.000 description 5
- 230000001376 precipitating effect Effects 0.000 description 5
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 5
- FKLJPTJMIBLJAV-UHFFFAOYSA-N Compound IV Chemical compound O1N=C(C)C=C1CCCCCCCOC1=CC=C(C=2OCCN=2)C=C1 FKLJPTJMIBLJAV-UHFFFAOYSA-N 0.000 description 4
- 239000003054 catalyst Substances 0.000 description 4
- 239000007822 coupling agent Substances 0.000 description 4
- 229910052757 nitrogen Inorganic materials 0.000 description 4
- WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 description 3
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- 238000010438 heat treatment Methods 0.000 description 3
- 229910000510 noble metal Inorganic materials 0.000 description 3
- 239000002904 solvent Substances 0.000 description 3
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 2
- XFXPMWWXUTWYJX-UHFFFAOYSA-N Cyanide Chemical compound N#[C-] XFXPMWWXUTWYJX-UHFFFAOYSA-N 0.000 description 2
- 206010060862 Prostate cancer Diseases 0.000 description 2
- 208000000236 Prostatic Neoplasms Diseases 0.000 description 2
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 description 2
- 238000007605 air drying Methods 0.000 description 2
- 125000000217 alkyl group Chemical group 0.000 description 2
- 239000008346 aqueous phase Substances 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- 238000001816 cooling Methods 0.000 description 2
- 239000000047 product Substances 0.000 description 2
- 239000000376 reactant Substances 0.000 description 2
- 239000000243 solution Substances 0.000 description 2
- 238000003786 synthesis reaction Methods 0.000 description 2
- 230000002194 synthesizing effect Effects 0.000 description 2
- HTSGKJQDMSTCGS-UHFFFAOYSA-N 1,4-bis(4-chlorophenyl)-2-(4-methylphenyl)sulfonylbutane-1,4-dione Chemical compound C1=CC(C)=CC=C1S(=O)(=O)C(C(=O)C=1C=CC(Cl)=CC=1)CC(=O)C1=CC=C(Cl)C=C1 HTSGKJQDMSTCGS-UHFFFAOYSA-N 0.000 description 1
- FCSKOFQQCWLGMV-UHFFFAOYSA-N 5-{5-[2-chloro-4-(4,5-dihydro-1,3-oxazol-2-yl)phenoxy]pentyl}-3-methylisoxazole Chemical compound O1N=C(C)C=C1CCCCCOC1=CC=C(C=2OCCN=2)C=C1Cl FCSKOFQQCWLGMV-UHFFFAOYSA-N 0.000 description 1
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 1
- 150000007513 acids Chemical class 0.000 description 1
- 125000003277 amino group Chemical group 0.000 description 1
- 229910021529 ammonia Inorganic materials 0.000 description 1
- 102000001307 androgen receptors Human genes 0.000 description 1
- 108010080146 androgen receptors Proteins 0.000 description 1
- HJBWBFZLDZWPHF-UHFFFAOYSA-N apalutamide Chemical compound C1=C(F)C(C(=O)NC)=CC=C1N1C2(CCC2)C(=O)N(C=2C=C(C(C#N)=NC=2)C(F)(F)F)C1=S HJBWBFZLDZWPHF-UHFFFAOYSA-N 0.000 description 1
- 125000004432 carbon atom Chemical group C* 0.000 description 1
- 230000003197 catalytic effect Effects 0.000 description 1
- 239000007810 chemical reaction solvent Substances 0.000 description 1
- 239000012351 deprotecting agent Substances 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 239000007789 gas Substances 0.000 description 1
- 125000001183 hydrocarbyl group Chemical group 0.000 description 1
- 239000005457 ice water Substances 0.000 description 1
- 239000003112 inhibitor Substances 0.000 description 1
- 150000007529 inorganic bases Chemical class 0.000 description 1
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- NXPHGHWWQRMDIA-UHFFFAOYSA-M magnesium;carbanide;bromide Chemical compound [CH3-].[Mg+2].[Br-] NXPHGHWWQRMDIA-UHFFFAOYSA-M 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- DVSDBMFJEQPWNO-UHFFFAOYSA-N methyllithium Chemical compound C[Li] DVSDBMFJEQPWNO-UHFFFAOYSA-N 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 239000012452 mother liquor Substances 0.000 description 1
- 238000003541 multi-stage reaction Methods 0.000 description 1
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000001280 n-hexyl group Chemical group C(CCCCC)* 0.000 description 1
- 125000000740 n-pentyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 230000000683 nonmetastatic effect Effects 0.000 description 1
- 238000005580 one pot reaction Methods 0.000 description 1
- 150000007530 organic bases Chemical class 0.000 description 1
- 231100000614 poison Toxicity 0.000 description 1
- 238000004537 pulping Methods 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 238000002390 rotary evaporation Methods 0.000 description 1
- 229920006395 saturated elastomer Polymers 0.000 description 1
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- UIIMBOGNXHQVGW-UHFFFAOYSA-M sodium bicarbonate Substances [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 1
- QDRKDTQENPPHOJ-UHFFFAOYSA-N sodium ethoxide Chemical compound [Na+].CC[O-] QDRKDTQENPPHOJ-UHFFFAOYSA-N 0.000 description 1
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 125000001424 substituent group Chemical group 0.000 description 1
- 238000010189 synthetic method Methods 0.000 description 1
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 238000012360 testing method Methods 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- 239000003440 toxic substance Substances 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C335/00—Thioureas, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups
- C07C335/04—Derivatives of thiourea
- C07C335/24—Derivatives of thiourea containing any of the groups, X being a hetero atom, Y being any atom
- C07C335/26—Y being a hydrogen or a carbon atom, e.g. benzoylthioureas
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D235/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings
- C07D235/02—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings condensed with carbocyclic rings or ring systems
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C2601/00—Systems containing only non-condensed rings
- C07C2601/04—Systems containing only non-condensed rings with a four-membered ring
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
Abstract
The invention provides a preparation method of a cancer treatment drug. Specifically, 1-aminocyclobutanecarboxylic acid is used as a raw material to react with benzoyl isothiocyanate, and a product is subjected to cyclization, amino protection, coupling, deprotection and coupling reaction to obtain a target compound. The method disclosed by the invention is safe and environment-friendly, low in production cost, high in yield and suitable for industrial production.
Description
Technical Field
The invention belongs to the field of medicinal chemistry, and particularly relates to a preparation method of a medicament alupamide for treating prostate cancer.
Background
Apaluamide (apaluamide) is a 2 nd generation nonsteroidal androgen receptor inhibitor, useful for the treatment of non-metastatic castration resistant prostate cancer, the chemical name of apaluamide is: 4- (7- (6-cyano-5- (trifluoromethyl) pyridin-3-yl) -8-oxo-6-thioxo-5, 7-diazaspiro [3.4] oct-5-yl) -2-fluoro-N-methylbenzamide, having the formula:
WO2007126765 discloses a synthetic method of apaluramine, which comprises the following specific steps:
the method has long synthesis route, the synthesis route needs to adopt highly toxic cyanide, and a noble metal Pd catalyst is used in multi-step reaction, so the method has the disadvantages of complex process and high production cost.
Therefore, the method for synthesizing the apaluridine is safe, environment-friendly, low in production cost and high in yield.
Disclosure of Invention
The invention aims to provide a method for synthesizing the apaluramine, which is safe and environment-friendly, low in production cost and high in yield.
In a first aspect, the present invention provides a process for the preparation of a compound of formula X, characterised in that said process comprises the steps of:
(i) at R1-reacting a compound of formula I with a compound of formula II in the presence of OH and an acid to produce a compound of formula III;
(ii) the compound of the formula III is subjected to cyclization reaction to generate a compound of a formula IV;
(iii) reacting the compound shown in the formula IV with an amino protecting reagent to generate a compound shown in the formula V;
(iv) reacting the compound of formula V with the compound of formula VI to produce a compound of formula VII;
(v) in the presence of a deprotection agent, carrying out an amino deprotection reaction on a compound shown in a formula VII to generate a compound shown in a formula VIII; and
(vi) reacting a compound of formula VII with a compound of formula IX to produce a compound of formula X;
wherein each R1 is C1-C6 alkyl;
each R2 is an amino protecting group; and
r3 and R4 are each independently selected from the group consisting of: chlorine, bromine and iodine.
In another preferred embodiment, the amino protecting group is selected from the group consisting of: benzyloxycarbonyl (Cbz), tert-butoxycarbonyl (Boc), fluorenyl-methoxycarbonyl (Fmoc), allyloxycarbonyl (Alloc), trimethylsilyloxycarbonyl (Teoc), alkylacyl (preferably, C1-C6 alkylacyl, such as acetyl) and benzoyl.
In another preferred embodiment, the method comprises one or more steps selected from the group consisting of:
(I-1) in the presence of an acid, a compound of formula I and R1-OH is subjected to esterification reaction; and (i-2) reacting the esterification product obtained in the step (i-1) with a compound of formula II in an inert solvent in the presence of a base to produce a compound of formula III;
(ii) in an inert solvent, in the presence of alkali, the compound shown in the formula III undergoes a cyclization reaction to generate a compound shown in the formula IV;
(iii) reacting a compound shown in a formula IV with an amino protecting reagent in an inert solvent in the presence of alkali to generate a compound shown in a formula V;
(iv) reacting a compound of formula V with a compound of formula VI in an inert solvent in the presence of a metal coupling reagent and a base to produce a compound of formula VII;
(v) in an inert solvent, in the presence of a deprotection agent, carrying out an amino deprotection reaction on a compound shown in a formula VII to generate a compound shown in a formula VIII; and/or
(vi) The compound of formula VII is reacted with a compound of formula IX in an inert solvent in the presence of a metal coupling reagent and a base to produce a compound of formula X.
In another preferred embodiment, step (i) has one or more of the following features:
(a) the acid is selected from the group consisting of: hydrochloric acid, sulfuric acid, polyphosphoric acid, acetyl chloride, propionyl chloride, p-toluenesulfonic acid, oxalic acid, or a combination thereof; and/or
(b) The R1-OH is selected from the group consisting of: methanol, ethanol, propanol, isopropanol, butanol, or combinations thereof.
In another preferred embodiment, in step (i-1), the esterification reaction has one or more of the following characteristics:
(a) R1-OH is used as a reaction solvent;
(b) the reaction temperature is 60-100 ℃, preferably 70-90 ℃; and/or
(c) The reaction time is 1-8h, preferably 1.5-6h, more preferably 2-4 h.
In another preferred embodiment, in step (i-2), the reaction has one or more of the following characteristics:
(a) the inert solvent is selected from the group consisting of: methanol, ethanol, isopropanol, dimethyl sulfoxide, N-methylpyrrolidone, N, N-dimethylformamide, acetone, acetonitrile, N-hexane, N-heptane, toluene, tetrahydrofuran, ethyl acetate, 1, 4-dioxane, methyl tert-butyl ether, dichloromethane, chloroform, or a combination thereof;
(b) the base is selected from the group consisting of: diethylamine, triethylamine, or a combination thereof;
(c) the reaction temperature is 10-40 ℃, preferably 20-30 ℃; and/or
(d) The reaction time is 1-12h, preferably 2-8h, more preferably 3-6 h.
In another preferred embodiment, in step (ii), the reaction has one or more of the following characteristics:
(a) the inert solvent is selected from the group consisting of: methanol, ethanol, isopropanol, dimethyl sulfoxide, N-methylpyrrolidone, N, N-dimethylformamide, acetone, acetonitrile, N-hexane, N-heptane, toluene, tetrahydrofuran, ethyl acetate, 1, 4-dioxane, methyl tert-butyl ether, dichloromethane, chloroform, or a combination thereof;
(b) the base is selected from the group consisting of: sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, triethylamine, or a combination thereof; preferably triethylamine, potassium bicarbonate, more preferably potassium carbonate;
(c) the reaction temperature is 20-60 ℃, preferably 20-40 ℃; and/or
(d) The reaction time is 6-24h, preferably 10-20h, more preferably 12-18 h.
In another preferred embodiment, in step (iii), the reaction has one or more of the following characteristics:
(a) the inert solvent is selected from the group consisting of: methanol, ethanol, isopropanol, dimethyl sulfoxide, N-methylpyrrolidone, N, N-dimethylformamide, acetone, acetonitrile, N-hexane, N-heptane, toluene, tetrahydrofuran, ethyl acetate, 1, 4-dioxane, methyl tert-butyl ether, dichloromethane, chloroform, or a combination thereof;
(b) the base is selected from the group consisting of: triethylamine, 4-Dimethylaminopyridine (DMAP), or a combination thereof; preferably, the base is a mixture of triethylamine and 4-Dimethylaminopyridine (DMAP);
(c) the molar ratio of the compound of formula VI to the amino protecting reagent is 1:0.8-1.5, preferably 1:0.9-1.3, more preferably 1: 1-1.1;
(d) the amino protecting agent is selected from the group consisting of: boc anhydride, benzyloxycarbonyl chloride, or a combination thereof;
(e) the reaction temperature is 10-50 ℃, preferably 20-40 ℃; and/or
(f) The reaction time is 0.5-6h, preferably 1-4h, more preferably 1.5-3 h.
In another preferred embodiment, in step (iv), the reaction has one or more of the following characteristics:
(a) the inert solvent is selected from the group consisting of: dimethylsulfoxide, N-methylpyrrolidone, N, N-dimethylformamide, tetrahydrofuran, 1, 4-dioxane, methyl tert-butyl ether, or a combination thereof;
(b) the base is selected from the group consisting of: sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, triethylamine, or a combination thereof; preferably triethylamine, potassium bicarbonate, more preferably potassium carbonate;
(c) the molar ratio of the compound of formula V to the compound of formula VI is 1:0.8-1.5, preferably 1:0.9-1.3, more preferably 1: 1-1.1;
(d) the metal coupling reagent is selected from the group consisting of: ferrous chloride, cuprous bromide, cuprous iodide, or a combination thereof;
(e) the reaction is carried out under a nitrogen atmosphere;
(f) the reaction temperature is 80-110 ℃, preferably 90-100 ℃; and/or
(g) The reaction time is 2-24h, preferably 5-18h, more preferably 8-12 h.
In another preferred embodiment, in step (v), the reaction has one or more of the following characteristics:
(a) the inert solvent is selected from the group consisting of: methanol, ethanol, isopropanol, dimethyl sulfoxide, N-methylpyrrolidone, N, N-dimethylformamide, acetone, acetonitrile, N-hexane, N-heptane, toluene, tetrahydrofuran, ethyl acetate, 1, 4-dioxane, methyl tert-butyl ether, dichloromethane, chloroform, or a combination thereof;
(b) the deprotection agent is selected from the group consisting of; acetic acid, sulfuric acid, methanesulfonic acid, p-toluenesulfonic acid, trifluoromethanesulfonic acid, trifluoroacetic acid (TFA), formic acid, hydrochloric acid, or a combination thereof;
(c) the deprotection reaction is carried out under the condition that the pH is less than or equal to 2, preferably, the pH is less than or equal to 1, such as the pH is 0-1;
(d) the reaction temperature is-5-10 ℃, preferably 0-5 ℃; and/or
(e) The reaction time is 1-12h, preferably 2-10h, more preferably 4-8 h.
In another preferred embodiment, in step (vi), the reaction has one or more of the following characteristics:
(a) the inert solvent is selected from the group consisting of: dimethylsulfoxide, N-methylpyrrolidone, N, N-dimethylformamide, tetrahydrofuran, 1, 4-dioxane, methyl tert-butyl ether, or a combination thereof;
(b) the base is selected from the group consisting of: sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, triethylamine, or a combination thereof; preferably triethylamine, potassium bicarbonate, more preferably potassium carbonate;
(c) the molar ratio of the compound of formula V to the compound of formula VI is 1:0.8-1.5, preferably 1:0.9-1.3, more preferably 1: 1-1.1;
(d) the metal coupling reagent is selected from the group consisting of: ferrous chloride, cuprous bromide, cuprous iodide, or a combination thereof;
(e) the reaction is carried out under a nitrogen atmosphere;
(f) the reaction temperature is 80-110 ℃, preferably 90-100 ℃; and/or
(g) The reaction time is 2-24h, preferably 5-18h, more preferably 8-12 h.
It is to be understood that within the scope of the present invention, the above-described features of the present invention and those specifically described below (e.g., in the examples) may be combined with each other to form new or preferred embodiments. Not to be reiterated herein, but to the extent of space.
Detailed Description
The inventor provides a preparation method of the alupamide through extensive and intensive research and a large number of screens and tests. The preparation method disclosed by the invention is simple in reaction route, safe and environment-friendly, free of noble metal catalyst, low in production cost, mild in reaction condition and high in reaction yield. The present invention has been completed based on this finding.
Term(s) for
Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs.
As used herein, the term "about" when used in reference to a specifically recited value means that the value may vary by no more than 1% from the recited value. For example, as used herein, the expression "about 100" includes 99 and 101 and all values in between (e.g., 99.1, 99.2, 99.3, 99.4, etc.).
As used herein, the term "comprising" or "includes" can be open, semi-closed, and closed. In other words, the term also includes "consisting essentially of …," or "consisting of ….
The term "room temperature" as used herein means a temperature of 4-40 ℃, preferably 25 ± 5 ℃.
As used herein, the term "alkyl" by itself or as part of another substituent refers to a straight or branched chain hydrocarbon group having the indicated number of carbon atoms (i.e., C1-C6 represents 1-6 carbons, preferably 1-3 carbons). Examples of alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, isobutyl, sec-butyl, n-pentyl, n-hexyl, and the like.
As used herein, "amino protecting group" refers to a protecting group that can be used to protect an amino group (-NH 2). Such amino protecting groups include, but are not limited to: benzyloxycarbonyl (Cbz), tert-butoxycarbonyl (Boc), fluorenyl-methoxycarbonyl (Fmoc), allyloxycarbonyl (Alloc), trimethylsilyloxycarbonyl (Teoc), an alkylacyl group (e.g., acetyl), benzoyl, etc.
As used herein, the "deprotecting agent" refers to any suitable agent that can remove the corresponding amino protecting group on a compound, such as a base, an acid, or a combination thereof. The acids include, but are not limited to, acetic acid, sulfuric acid, methanesulfonic acid, p-toluenesulfonic acid, trifluoromethanesulfonic acid, trifluoroacetic acid (TFA), formic acid, hydrochloric acid, concentrated hydrochloric acid, and the like. The base may be an organic base, an inorganic base, or a combination thereof. Representative bases include, but are not limited to, lithium hydroxide, sodium hydroxide, potassium hydroxide, ammonia, sodium methoxide, sodium ethoxide, methyl magnesium bromide, methyl lithium, and the like.
As used herein, the term "coupling agent" refers to an agent capable of coupling two different compounds. The coupling agent may be catalytic or stoichiometric. Exemplary coupling agents include, but are not limited to, ferrous chloride, cuprous bromide, cuprous iodide, or combinations thereof.
Unless otherwise specified, the reactants of the present invention may be reacted in suitable molar ratios, such that the ratio of the amount of the compound of formula I to the particular reactant is 1:0.5 to 3, 1:0.8 to 2, or 1:1 to 1.5.
Unless otherwise specified, the term "inert solvent" refers to a solvent selected from the group consisting of: methanol, ethanol, isopropanol, dimethyl sulfoxide, N-methylpyrrolidone, N, N-dimethylformamide, acetone, acetonitrile, N-hexane, N-heptane, toluene, tetrahydrofuran, ethyl acetate, 1, 4-dioxane, methyl tert-butyl ether, dichloromethane, chloroform, or a combination thereof.
Process for the preparation of compounds of formula III
In the present invention, the process for preparing the compound of formula III comprises the steps of:
(i) at R1-reacting a compound of formula I with a compound of formula II in the presence of OH and an acid to produce a compound of formula III;
wherein R1 is C1-C6 alkyl.
More specifically, the method comprises the following steps:
(I-1) in the presence of an acid, a compound of formula I and R1-OH is subjected to esterification reaction; and (i-2) reacting the esterification product obtained in step (i-1) with a compound of formula II in an inert solvent in the presence of a base to produce a compound of formula III.
For example, when R1-OH is methanol, the following steps can be included:
preferably, the steps (i-1) and (i-2) may be performed in steps, or by a one-pot method.
Process for the preparation of compounds of formula IV
In the present invention, the process for preparing the compound of formula IV comprises the steps of:
(ii) the compound of the formula III is subjected to cyclization reaction to generate a compound of a formula IV;
wherein R1 is as defined above.
More specifically, the method comprises the following steps:
(ii) in an inert solvent, in the presence of a base, the compound of formula III undergoes a cyclization reaction to form the compound of formula IV.
Process for the preparation of compounds of formula V
(iii) Reacting the compound shown in the formula IV with an amino protecting reagent to generate a compound shown in the formula V;
wherein R2 is an amino protecting group.
More specifically, the method comprises the following steps:
(iii) reacting the compound of formula IV with an amino protecting reagent in an inert solvent in the presence of a base to produce the compound of formula V.
In another preferred embodiment, the amino protecting group is selected from the group consisting of: benzyloxycarbonyl (Cbz), tert-butoxycarbonyl (Boc), fluorenyl-methoxycarbonyl (Fmoc), allyloxycarbonyl (Alloc), trimethylsilyloxycarbonyl (Teoc), alkylacyl (e.g., acetyl) and benzoyl. Amino protecting reagents to obtain the amino protecting group are known in the art. For example, when the amino protecting group is Boc, the amino protecting reagent can be BOC anhydride (di-tert-butyl dicarbonate).
Process for the preparation of compounds of formula VII
In the present invention, the process for preparing the compound of formula VII comprises the steps of:
(iv) reacting the compound of formula V with the compound of formula VI to produce a compound of formula VII;
r2 is as defined above, and
r3 is selected from the group consisting of: chlorine, bromine and iodine.
More specifically, the method comprises the following steps:
(iv) reacting a compound of formula V with a compound of formula VI in an inert solvent in the presence of a metal coupling reagent and a base to produce a compound of formula VII.
Process for the preparation of compounds of formula VIII
In the present invention, the process for the preparation of the compound of formula VIII comprises the steps of:
(v) in the presence of a deprotection agent, carrying out an amino deprotection reaction on a compound shown in a formula VII to generate a compound shown in a formula VIII; and
r2 is as defined above.
More specifically, the method comprises the following steps:
(v) in an inert solvent, in the presence of a deprotection agent, the compound shown in the formula VII undergoes an amino deprotection reaction to generate the compound shown in the formula VIII.
Process for the preparation of compounds of formula X
In the present invention, the process for preparing the compound of formula X comprises the steps of:
(vi) reacting a compound of formula VII with a compound of formula IX to produce a compound of formula X;
wherein R4 is selected from the group consisting of: chlorine, bromine and iodine.
More specifically, the method comprises the following steps:
(vi) the compound of formula VII is reacted with a compound of formula IX in an inert solvent in the presence of a metal coupling reagent and a base to produce a compound of formula X.
In another preferred embodiment, step (iii) is the same type of metal coupling agent as used in step (vi), such as cuprous iodide.
In the present invention, each of the above steps may include a suitable purification step.
The main advantages of the invention include:
1. the invention provides a novel preparation method of apaluamide, which has short synthetic route and high yield;
2. the preparation method has the advantages of simple and easily obtained raw materials, no need of using a noble metal catalyst and low production cost;
3. the preparation method is safe and environment-friendly, does not use highly toxic substances such as cyanide and the like, and has low safety risk;
4. the preparation method of the invention has mild conditions and simple and convenient operation, and is suitable for industrial production.
The invention is further illustrated with reference to specific embodiments. It should be understood that these examples are for illustrative purposes only and are not intended to limit the scope of the present invention. The experimental procedures, in which specific conditions are not noted in the following examples, are generally carried out under conventional conditions or conditions recommended by the manufacturers. Unless otherwise indicated, percentages and parts are by weight.
Example 1
Dissolving the compound (20g, 0.173mol) of the formula I in methanol (350mL), adding acetyl chloride (1mL), heating to 80 ℃, refluxing for 2.5h, and cooling to room temperature after the reaction is finished. Removing methanol by rotary evaporation, adding dichloromethane (300ml) to dissolve, adding water (150ml) to wash once, separating dichloromethane layer, adding saturated NaHCO3The solution (150ml) was washed once, the dichloromethane layer was separated, and the solution was washed once with saturated brine (150ml), dichloromethane was separated, dried over anhydrous sodium sulfate for 8 hours, the dichloromethane layer was filtered, compound II (31.0g, 0.19mol) was added to the obtained dichloromethane filtrate, and triethylamine (8.6g, 0.085mol) was added thereto, and the reaction was carried out at controlled temperature of 20-30 ℃ for 4 hours. The solvent was removed by concentration under reduced pressure to give compound iii (49.2g, 0.168mol), yield: 97.1% (relative to formula I). Ms (esi): [ M +1]]+＝293.35。
Example 2
Reacting a compound of formula III (5)0g, 0.17mol) in methanol (500mL), adding potassium carbonate (187.9g, 8mol), controlling the temperature to be 20-30 ℃ for reaction for 15h, filtering to remove the potassium carbonate to obtain mother liquor, decompressing and concentrating to remove the solvent, adding 95% ethanol (500mL), pulping at 20-30 ℃ and stirring for 2h, filtering, blowing to be 50 ℃ for drying to obtain a white-like solid compound IV (26.2g), and obtaining the yield: 98.3% (relative to formula III). Ms (esi): [ M +1]]+＝157.21。
Example 3
Adding a compound IV (50g, 0.32mol) into dichloromethane (500ml), adding triethylamine (3g) and DMAP (0.5g), stirring and controlling the temperature to be about 30 ℃, dropwise adding Boc anhydride (76.8g, 0.35mol), gradually precipitating a solid after adding, reacting for 2 hours at about 30 ℃, filtering, and drying by blowing at 50 ℃ to obtain a compound V (75.4g), wherein the yield is as follows: 92.0% (relative to formula IV). Ms (esi): [ M +1]]+＝257.32。
Example 4
Adding a compound (30g, 0.12mol) of a formula V into N, N-dimethylformamide (150ml), adding a compound (24.8g, 0.12mol) of a formula VI, stirring, replacing three times with nitrogen, adding cuprous iodide (2.3g, 12mmol) under the protection of nitrogen, adding potassium carbonate (36.5g, 0.26mol), uniformly stirring, heating to 95 ℃, controlling the temperature to be about 95 ℃ and reacting for 10 hours, finishing the reaction, adding 300ml of water, adding 300ml of ethyl acetate, extracting and separating liquid, collecting an aqueous phase, adjusting the pH to 3-4 by using 4N hydrochloric acid, precipitating a large amount of solid, filtering, rinsing with water, collecting the solid, drying by blowing at 50 ℃ to obtain a compound VII (43.2g), wherein the yield is as follows: 86.6% (relative to formula V). Ms (esi): m +1 + 427.41.
Example 5
Adding a compound (100g, 0.23mol) in a formula VII into ethyl acetate (500ml), cooling in an ice-water bath to 5 ℃, introducing HCl gas until the pH value of the system is less than 1, separating out a large amount of solids, stirring for reacting for 6h, filtering to obtain solids, collecting the solids after washing with ethyl acetate, and carrying out forced air drying at 50 ℃ to obtain a compound (67.7g) in a formula VIII (yield): 88.7% (relative to formula VII) MS (ESI): m +1 + 327.30.
Example 6
Adding a compound (30g, 0.09mol) of a formula VIII into N, N-dimethylformamide (150ml), adding a compound (17.1g, 0.09mol) of a formula IX, stirring, replacing with nitrogen for three times, adding cuprous iodide (1.7g, 9mmol) under the protection of nitrogen, adding potassium carbonate (27.4g, 0.2mol), uniformly stirring, heating to 95 ℃, controlling the temperature to be about 95 ℃ for reaction for 10 hours, finishing the reaction, adding 300ml of water, adding 300ml of ethyl acetate, extracting, separating, collecting an aqueous phase, adjusting the pH to 3-4 by using 4N hydrochloric acid, precipitating a large amount of solids, filtering, rinsing with water, collecting the solids, and drying by blowing at 50 ℃ to obtain a compound X (36.0g) with the yield: 82.1% (relative to formula VIII). Ms (esi): m +1 + 478.43.
Example 7
Adding a compound IV (50g, 0.32mol) into dichloromethane (500ml), adding triethylamine (3g) and DMAP (0.5g), stirring and controlling the temperature to be about 30 ℃, dropwise adding Boc anhydride (90.8g, 0.41mol), gradually precipitating a solid after adding, reacting for 2h at about 30 ℃, filtering, and carrying out forced air drying at 50 ℃ to obtain a compound V (60.7g), wherein the yield is as follows: 74.1% (relative to formula IV). Ms (esi): [ M +1]]+＝257.32。
Example 8
Adding a compound IV (50g, 0.32mol) into dichloromethane (500ml), adding triethylamine (3g) and DMAP (0.5g), stirring and controlling the temperature to be about 30 ℃, dropwise adding Boc anhydride (104.8g, 0.48mol), gradually precipitating a solid after adding, reacting for 2 hours at about 30 ℃, filtering, and drying by blowing at 50 ℃ to obtain a compound V (54.4g), wherein the yield is as follows: 66.3% (relative to formula IV). Ms (esi): [ M +1]]+＝257.32。
In conclusion, the invention provides a brand-new preparation method of alutamide, the method has the advantages of short synthetic route, easily available raw materials, no need of expensive catalysts commonly used in the existing synthetic route, mild reaction conditions, low equipment requirement, simple operation and easy industrial production, the method has high single-step reaction yield, the total yield of the alutamide from the compound of the formula I as the starting raw material can reach 55.4%, and the total yield is high.
All documents referred to herein are incorporated by reference into this application as if each were individually incorporated by reference. Furthermore, it should be understood that various changes and modifications of the present invention can be made by those skilled in the art after reading the above teachings of the present invention, and these equivalents also fall within the scope of the present invention as defined by the appended claims.
Claims (10)
1. A process for the preparation of a compound of formula X, said process comprising the steps of:
(i) at R1-reacting a compound of formula I with a compound of formula II in the presence of OH and an acid to produce a compound of formula III;
(ii) the compound of the formula III is subjected to cyclization reaction to generate a compound of a formula IV;
(iii) reacting the compound shown in the formula IV with an amino protecting reagent to generate a compound shown in the formula V;
(iv) reacting the compound of formula V with the compound of formula VI to produce a compound of formula VII;
(v) in the presence of a deprotection agent, carrying out an amino deprotection reaction on a compound shown in a formula VII to generate a compound shown in a formula VIII; and
(vi) reacting a compound of formula VII with a compound of formula IX to produce a compound of formula X;
wherein each R1 is C1-C6 alkyl;
each R2 is an amino protecting group; and
r3 and R4 are each independently selected from the group consisting of: chlorine, bromine and iodine.
2. The method of claim 1, wherein the amino protecting group is selected from the group consisting of: benzyloxycarbonyl (Cbz), tert-butoxycarbonyl (Boc), fluorenyl-methoxycarbonyl (Fmoc), allyloxycarbonyl (Alloc), trimethylsilyloxycarbonyl (Teoc), alkylacyl (e.g., acetyl) and benzoyl.
3. The method of claim 1, wherein the method comprises one or more steps selected from the group consisting of:
(I-1) in the presence of an acid, a compound of formula I and R1-OH is subjected to esterification reaction; and (i-2) reacting the esterification product obtained in the step (i-1) with a compound of formula II in an inert solvent in the presence of a base to produce a compound of formula III;
(ii) in an inert solvent, in the presence of alkali, the compound shown in the formula III undergoes a cyclization reaction to generate a compound shown in the formula IV;
(iii) reacting a compound shown in a formula IV with an amino protecting reagent in an inert solvent in the presence of alkali to generate a compound shown in a formula V;
(iv) reacting a compound of formula V with a compound of formula VI in an inert solvent in the presence of a metal coupling reagent and a base to produce a compound of formula VII;
(v) in an inert solvent, in the presence of a deprotection agent, carrying out an amino deprotection reaction on a compound shown in a formula VII to generate a compound shown in a formula VIII; and/or
(vi) The compound of formula VII is reacted with a compound of formula IX in an inert solvent in the presence of a metal coupling reagent and a base to produce a compound of formula X.
4. The method of claim 3, wherein step (i) has one or more of the following characteristics:
(a) the acid is selected from the group consisting of: hydrochloric acid, sulfuric acid, polyphosphoric acid, acetyl chloride, propionyl chloride, p-toluenesulfonic acid, oxalic acid, or a combination thereof; and/or
(b) The R1-OH is selected from the group consisting of: methanol, ethanol, propanol, isopropanol, butanol, or combinations thereof.
5. The method of claim 3, wherein in step (i-2), the reaction has one or more of the following characteristics:
(a) the inert solvent is selected from the group consisting of: methanol, ethanol, isopropanol, dimethyl sulfoxide, N-methylpyrrolidone, N, N-dimethylformamide, acetone, acetonitrile, N-hexane, N-heptane, toluene, tetrahydrofuran, ethyl acetate, 1, 4-dioxane, methyl tert-butyl ether, dichloromethane, chloroform, or a combination thereof;
(b) the base is selected from the group consisting of: diethylamine, triethylamine, or a combination thereof;
(c) the reaction temperature is 10-40 ℃, preferably 20-30 ℃; and/or
(d) The reaction time is 1-12h, preferably 2-8h, more preferably 3-6 h.
6. The method of claim 3, wherein in step (ii), the reaction has one or more of the following characteristics:
(a) the inert solvent is selected from the group consisting of: methanol, ethanol, isopropanol, dimethyl sulfoxide, N-methylpyrrolidone, N, N-dimethylformamide, acetone, acetonitrile, N-hexane, N-heptane, toluene, tetrahydrofuran, ethyl acetate, 1, 4-dioxane, methyl tert-butyl ether, dichloromethane, chloroform, or a combination thereof;
(b) the base is selected from the group consisting of: sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, triethylamine, or a combination thereof; preferably triethylamine, potassium bicarbonate, more preferably potassium carbonate;
(c) the reaction temperature is 20-60 ℃, preferably 20-40 ℃; and/or
(d) The reaction time is 6-24h, preferably 10-20h, more preferably 12-18 h.
7. The method of claim 3, wherein in step (iii), the reaction has one or more of the following characteristics:
(a) the inert solvent is selected from the group consisting of: methanol, ethanol, isopropanol, dimethyl sulfoxide, N-methylpyrrolidone, N, N-dimethylformamide, acetone, acetonitrile, N-hexane, N-heptane, toluene, tetrahydrofuran, ethyl acetate, 1, 4-dioxane, methyl tert-butyl ether, dichloromethane, chloroform, or a combination thereof;
(b) the base is selected from the group consisting of: triethylamine, 4-Dimethylaminopyridine (DMAP), or a combination thereof; preferably, the base is a mixture of triethylamine and 4-Dimethylaminopyridine (DMAP);
(c) the molar ratio of the compound of formula VI to the amino protecting reagent is 1:0.8-1.5, preferably 1:0.9-1.3, more preferably 1: 1-1.1;
(d) the amino protecting agent is selected from the group consisting of: boc anhydride, benzyloxycarbonyl chloride, or a combination thereof;
(e) the reaction temperature is 10-50 ℃, preferably 20-40 ℃; and/or
(f) The reaction time is 0.5-6h, preferably 1-4h, more preferably 1.5-3 h.
8. The method of claim 3, wherein in step (iv), the reaction has one or more of the following characteristics:
(a) the inert solvent is selected from the group consisting of: dimethylsulfoxide, N-methylpyrrolidone, N, N-dimethylformamide, tetrahydrofuran, 1, 4-dioxane, methyl tert-butyl ether, or a combination thereof;
(b) the base is selected from the group consisting of: sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, triethylamine, or a combination thereof; preferably triethylamine, potassium bicarbonate, more preferably potassium carbonate;
(c) the molar ratio of the compound of formula V to the compound of formula VI is 1:0.8-1.5, preferably 1:0.9-1.3, more preferably 1: 1-1.1;
(d) the metal coupling reagent is selected from the group consisting of: ferrous chloride, cuprous bromide, cuprous iodide, or a combination thereof;
(e) the reaction is carried out under a nitrogen atmosphere;
(f) the reaction temperature is 80-110 ℃, preferably 90-100 ℃; and/or
(g) The reaction time is 2-24h, preferably 5-18h, more preferably 8-12 h.
9. The method of claim 3, wherein in step (v), the reaction has one or more of the following characteristics:
(a) the inert solvent is selected from the group consisting of: methanol, ethanol, isopropanol, dimethyl sulfoxide, N-methylpyrrolidone, N, N-dimethylformamide, acetone, acetonitrile, N-hexane, N-heptane, toluene, tetrahydrofuran, ethyl acetate, 1, 4-dioxane, methyl tert-butyl ether, dichloromethane, chloroform, or a combination thereof;
(b) the deprotection agent is selected from the group consisting of; acetic acid, sulfuric acid, methanesulfonic acid, p-toluenesulfonic acid, trifluoromethanesulfonic acid, trifluoroacetic acid (TFA), formic acid, hydrochloric acid, or a combination thereof;
(c) the deprotection reaction is carried out under the condition that the pH is less than or equal to 2, preferably, the pH is less than or equal to 1, such as the pH is 0-1;
(d) the reaction temperature is-5-10 ℃, preferably 0-5 ℃; and/or
(e) The reaction time is 1-12h, preferably 2-10h, more preferably 4-8 h.
10. The method of claim 3, wherein in step (vi), the reaction has one or more of the following characteristics:
(a) the inert solvent is selected from the group consisting of: dimethylsulfoxide, N-methylpyrrolidone, N, N-dimethylformamide, tetrahydrofuran, 1, 4-dioxane, methyl tert-butyl ether, or a combination thereof;
(b) the base is selected from the group consisting of: sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, triethylamine, or a combination thereof; preferably triethylamine, potassium bicarbonate, more preferably potassium carbonate;
(c) the molar ratio of the compound of formula V to the compound of formula VI is 1:0.8-1.5, preferably 1:0.9-1.3, more preferably 1: 1-1.1;
(d) the metal coupling reagent is selected from the group consisting of: ferrous chloride, cuprous bromide, cuprous iodide, or a combination thereof;
(e) the reaction is carried out under a nitrogen atmosphere;
(f) the reaction temperature is 80-110 ℃, preferably 90-100 ℃; and/or
(g) The reaction time is 2-24h, preferably 5-18h, more preferably 8-12 h.
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