CN115594689A - Ruuggol intermediate and synthesis method of Ruuggol - Google Patents
Ruuggol intermediate and synthesis method of Ruuggol Download PDFInfo
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- CN115594689A CN115594689A CN202210831588.XA CN202210831588A CN115594689A CN 115594689 A CN115594689 A CN 115594689A CN 202210831588 A CN202210831588 A CN 202210831588A CN 115594689 A CN115594689 A CN 115594689A
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- 238000001308 synthesis method Methods 0.000 title description 3
- 150000001875 compounds Chemical class 0.000 claims abstract description 132
- 238000002360 preparation method Methods 0.000 claims abstract description 24
- 239000001257 hydrogen Substances 0.000 claims abstract description 10
- 229910052739 hydrogen Inorganic materials 0.000 claims abstract description 10
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims abstract description 7
- 239000007858 starting material Substances 0.000 claims abstract description 6
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims abstract description 3
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims abstract description 3
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 51
- 238000006243 chemical reaction Methods 0.000 claims description 49
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 36
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 31
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 30
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 30
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 30
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 27
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 27
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 18
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 18
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical group CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 18
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical group [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 18
- WSFSSNUMVMOOMR-UHFFFAOYSA-N Formaldehyde Chemical compound O=C WSFSSNUMVMOOMR-UHFFFAOYSA-N 0.000 claims description 16
- 238000000034 method Methods 0.000 claims description 16
- 101100132433 Arabidopsis thaliana VIII-1 gene Proteins 0.000 claims description 15
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 15
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 14
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 12
- ROSDSFDQCJNGOL-UHFFFAOYSA-N Dimethylamine Chemical compound CNC ROSDSFDQCJNGOL-UHFFFAOYSA-N 0.000 claims description 12
- YNAVUWVOSKDBBP-UHFFFAOYSA-N Morpholine Chemical group C1COCCN1 YNAVUWVOSKDBBP-UHFFFAOYSA-N 0.000 claims description 12
- 239000002585 base Substances 0.000 claims description 12
- 239000007810 chemical reaction solvent Substances 0.000 claims description 12
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 claims description 12
- ZSXGLVDWWRXATF-UHFFFAOYSA-N N,N-dimethylformamide dimethyl acetal Chemical compound COC(OC)N(C)C ZSXGLVDWWRXATF-UHFFFAOYSA-N 0.000 claims description 10
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 claims description 10
- 239000003513 alkali Substances 0.000 claims description 10
- PFKFTWBEEFSNDU-UHFFFAOYSA-N 1,1'-Carbonyldiimidazole Substances C1=CN=CN1C(=O)N1C=CN=C1 PFKFTWBEEFSNDU-UHFFFAOYSA-N 0.000 claims description 9
- 239000002253 acid Substances 0.000 claims description 9
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 9
- GSNUFIFRDBKVIE-UHFFFAOYSA-N DMF Natural products CC1=CC=C(C)O1 GSNUFIFRDBKVIE-UHFFFAOYSA-N 0.000 claims description 8
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 claims description 8
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 8
- 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 8
- 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 6
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 claims description 6
- SJRJJKPEHAURKC-UHFFFAOYSA-N N-Methylmorpholine Chemical compound CN1CCOCC1 SJRJJKPEHAURKC-UHFFFAOYSA-N 0.000 claims description 6
- NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 claims description 6
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims description 6
- RWRDLPDLKQPQOW-UHFFFAOYSA-N Pyrrolidine Chemical compound C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 claims description 6
- 239000003054 catalyst Substances 0.000 claims description 6
- 235000019253 formic acid Nutrition 0.000 claims description 6
- XNXVOSBNFZWHBV-UHFFFAOYSA-N hydron;o-methylhydroxylamine;chloride Chemical compound Cl.CON XNXVOSBNFZWHBV-UHFFFAOYSA-N 0.000 claims description 6
- UCPYLLCMEDAXFR-UHFFFAOYSA-N triphosgene Chemical compound ClC(Cl)(Cl)OC(=O)OC(Cl)(Cl)Cl UCPYLLCMEDAXFR-UHFFFAOYSA-N 0.000 claims description 6
- ZPTVNYMJQHSSEA-UHFFFAOYSA-N 4-nitrotoluene Chemical compound CC1=CC=C([N+]([O-])=O)C=C1 ZPTVNYMJQHSSEA-UHFFFAOYSA-N 0.000 claims description 5
- VZTDIZULWFCMLS-UHFFFAOYSA-N ammonium formate Chemical compound [NH4+].[O-]C=O VZTDIZULWFCMLS-UHFFFAOYSA-N 0.000 claims description 5
- 238000006482 condensation reaction Methods 0.000 claims description 5
- MJXRENZUAQXZGJ-UHFFFAOYSA-N 2-(chloromethyl)-1,3-difluorobenzene Chemical compound FC1=CC=CC(F)=C1CCl MJXRENZUAQXZGJ-UHFFFAOYSA-N 0.000 claims description 4
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 4
- SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 claims description 4
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 4
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 claims description 4
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims description 4
- DKGAVHZHDRPRBM-UHFFFAOYSA-N Tert-Butanol Chemical compound CC(C)(C)O DKGAVHZHDRPRBM-UHFFFAOYSA-N 0.000 claims description 4
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 4
- 239000000126 substance Substances 0.000 claims description 4
- 238000006467 substitution reaction Methods 0.000 claims description 4
- 229910052717 sulfur Inorganic materials 0.000 claims description 4
- 239000011593 sulfur Substances 0.000 claims description 4
- IMNIMPAHZVJRPE-UHFFFAOYSA-N triethylenediamine Chemical compound C1CN2CCN1CC2 IMNIMPAHZVJRPE-UHFFFAOYSA-N 0.000 claims description 4
- 150000002431 hydrogen Chemical class 0.000 claims description 3
- 239000000463 material Substances 0.000 claims description 3
- AVFZOVWCLRSYKC-UHFFFAOYSA-N 1-methylpyrrolidine Chemical compound CN1CCCC1 AVFZOVWCLRSYKC-UHFFFAOYSA-N 0.000 claims description 2
- 238000006683 Mannich reaction Methods 0.000 claims description 2
- AHVYPIQETPWLSZ-UHFFFAOYSA-N N-methyl-pyrrolidine Natural products CN1CC=CC1 AHVYPIQETPWLSZ-UHFFFAOYSA-N 0.000 claims description 2
- 239000007868 Raney catalyst Substances 0.000 claims description 2
- NPXOKRUENSOPAO-UHFFFAOYSA-N Raney nickel Chemical compound [Al].[Ni] NPXOKRUENSOPAO-UHFFFAOYSA-N 0.000 claims description 2
- 229910000564 Raney nickel Inorganic materials 0.000 claims description 2
- 239000003638 chemical reducing agent Substances 0.000 claims description 2
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 2
- BASFCYQUMIYNBI-UHFFFAOYSA-N platinum Chemical compound [Pt] BASFCYQUMIYNBI-UHFFFAOYSA-N 0.000 claims description 2
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 claims description 2
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 2
- QDRKDTQENPPHOJ-UHFFFAOYSA-N sodium ethoxide Chemical compound [Na+].CC[O-] QDRKDTQENPPHOJ-UHFFFAOYSA-N 0.000 claims description 2
- 125000006273 (C1-C3) alkyl group Chemical group 0.000 claims 1
- SPEUIVXLLWOEMJ-UHFFFAOYSA-N acetaldehyde dimethyl acetal Natural products COC(C)OC SPEUIVXLLWOEMJ-UHFFFAOYSA-N 0.000 claims 1
- 125000000217 alkyl group Chemical group 0.000 abstract description 2
- 238000004128 high performance liquid chromatography Methods 0.000 description 21
- 238000003756 stirring Methods 0.000 description 16
- 238000001914 filtration Methods 0.000 description 15
- 239000007787 solid Substances 0.000 description 14
- 239000000243 solution Substances 0.000 description 14
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 14
- 239000012065 filter cake Substances 0.000 description 13
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 12
- 238000001816 cooling Methods 0.000 description 11
- 238000001035 drying Methods 0.000 description 11
- 239000012074 organic phase Substances 0.000 description 10
- 239000005457 ice water Substances 0.000 description 9
- 238000010438 heat treatment Methods 0.000 description 8
- 238000005160 1H NMR spectroscopy Methods 0.000 description 7
- 238000005406 washing Methods 0.000 description 7
- 238000004519 manufacturing process Methods 0.000 description 6
- 239000002904 solvent Substances 0.000 description 5
- 150000003254 radicals Chemical class 0.000 description 4
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 4
- 229960000583 acetic acid Drugs 0.000 description 3
- 238000007348 radical reaction Methods 0.000 description 3
- 239000002994 raw material Substances 0.000 description 3
- XPGHWBDZNQUUQD-UHFFFAOYSA-N 1-(chloromethyl)-2,4-difluorobenzene Chemical compound FC1=CC=C(CCl)C(F)=C1 XPGHWBDZNQUUQD-UHFFFAOYSA-N 0.000 description 2
- PAQZWJGSJMLPMG-UHFFFAOYSA-N 2,4,6-tripropyl-1,3,5,2$l^{5},4$l^{5},6$l^{5}-trioxatriphosphinane 2,4,6-trioxide Chemical compound CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1 PAQZWJGSJMLPMG-UHFFFAOYSA-N 0.000 description 2
- 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 2
- 239000000579 Gonadotropin-Releasing Hormone Substances 0.000 description 2
- 101000857870 Squalus acanthias Gonadoliberin Proteins 0.000 description 2
- MUMGGOZAMZWBJJ-DYKIIFRCSA-N Testostosterone Chemical compound O=C1CC[C@]2(C)[C@H]3CC[C@](C)([C@H](CC4)O)[C@@H]4[C@@H]3CCC2=C1 MUMGGOZAMZWBJJ-DYKIIFRCSA-N 0.000 description 2
- 230000009286 beneficial effect Effects 0.000 description 2
- 230000007613 environmental effect Effects 0.000 description 2
- 239000000706 filtrate Substances 0.000 description 2
- XLXSAKCOAKORKW-AQJXLSMYSA-N gonadorelin Chemical compound C([C@@H](C(=O)NCC(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N1[C@@H](CCC1)C(=O)NCC(N)=O)NC(=O)[C@H](CO)NC(=O)[C@H](CC=1C2=CC=CC=C2NC=1)NC(=O)[C@H](CC=1N=CNC=1)NC(=O)[C@H]1NC(=O)CC1)C1=CC=C(O)C=C1 XLXSAKCOAKORKW-AQJXLSMYSA-N 0.000 description 2
- 229940035638 gonadotropin-releasing hormone Drugs 0.000 description 2
- 230000003301 hydrolyzing effect Effects 0.000 description 2
- UKVIEHSSVKSQBA-UHFFFAOYSA-N methane;palladium Chemical compound C.[Pd] UKVIEHSSVKSQBA-UHFFFAOYSA-N 0.000 description 2
- 238000002156 mixing Methods 0.000 description 2
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 2
- 239000012071 phase Substances 0.000 description 2
- 239000000843 powder Substances 0.000 description 2
- 231100000331 toxic Toxicity 0.000 description 2
- 230000002588 toxic effect Effects 0.000 description 2
- YBADLXQNJCMBKR-UHFFFAOYSA-N (4-nitrophenyl)acetic acid Chemical compound OC(=O)CC1=CC=C([N+]([O-])=O)C=C1 YBADLXQNJCMBKR-UHFFFAOYSA-N 0.000 description 1
- FTBSGSZZESQDBM-UHFFFAOYSA-N 1-(bromomethyl)-2,3-difluorobenzene Chemical compound FC1=CC=CC(CBr)=C1F FTBSGSZZESQDBM-UHFFFAOYSA-N 0.000 description 1
- COXCGWKSEPPDAA-UHFFFAOYSA-N 2,4-dimethylpentanenitrile Chemical compound CC(C)CC(C)C#N COXCGWKSEPPDAA-UHFFFAOYSA-N 0.000 description 1
- YPWBPONDYDVMLX-UHFFFAOYSA-N 6-methoxypyridazin-3-amine Chemical compound COC1=CC=C(N)N=N1 YPWBPONDYDVMLX-UHFFFAOYSA-N 0.000 description 1
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 1
- 201000009273 Endometriosis Diseases 0.000 description 1
- 102000012673 Follicle Stimulating Hormone Human genes 0.000 description 1
- 108010079345 Follicle Stimulating Hormone Proteins 0.000 description 1
- 102000006771 Gonadotropins Human genes 0.000 description 1
- 108010086677 Gonadotropins Proteins 0.000 description 1
- 102000008238 LHRH Receptors Human genes 0.000 description 1
- 108010021290 LHRH Receptors Proteins 0.000 description 1
- 102000009151 Luteinizing Hormone Human genes 0.000 description 1
- 108010073521 Luteinizing Hormone Proteins 0.000 description 1
- OFOBLEOULBTSOW-UHFFFAOYSA-L Malonate Chemical compound [O-]C(=O)CC([O-])=O OFOBLEOULBTSOW-UHFFFAOYSA-L 0.000 description 1
- GMPKIPWJBDOURN-UHFFFAOYSA-N Methoxyamine Chemical compound CON GMPKIPWJBDOURN-UHFFFAOYSA-N 0.000 description 1
- RJKFOVLPORLFTN-LEKSSAKUSA-N Progesterone Chemical class C1CC2=CC(=O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@H](C(=O)C)[C@@]1(C)CC2 RJKFOVLPORLFTN-LEKSSAKUSA-N 0.000 description 1
- 206010060862 Prostate cancer Diseases 0.000 description 1
- 208000000236 Prostatic Neoplasms Diseases 0.000 description 1
- 206010046798 Uterine leiomyoma Diseases 0.000 description 1
- 230000002378 acidificating effect Effects 0.000 description 1
- 230000004913 activation Effects 0.000 description 1
- 150000001263 acyl chlorides Chemical class 0.000 description 1
- 150000001408 amides Chemical class 0.000 description 1
- 210000004198 anterior pituitary gland Anatomy 0.000 description 1
- 239000012267 brine Substances 0.000 description 1
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 1
- 229910052794 bromium Inorganic materials 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 238000009833 condensation Methods 0.000 description 1
- 230000005494 condensation Effects 0.000 description 1
- 239000013078 crystal Substances 0.000 description 1
- 230000000911 decarboxylating effect Effects 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 150000004656 dimethylamines Chemical class 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 229940011871 estrogen Drugs 0.000 description 1
- 239000000262 estrogen Substances 0.000 description 1
- ZIUSEGSNTOUIPT-UHFFFAOYSA-N ethyl 2-cyanoacetate Chemical compound CCOC(=O)CC#N ZIUSEGSNTOUIPT-UHFFFAOYSA-N 0.000 description 1
- RIFGWPKJUGCATF-UHFFFAOYSA-N ethyl chloroformate Chemical compound CCOC(Cl)=O RIFGWPKJUGCATF-UHFFFAOYSA-N 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 229940028334 follicle stimulating hormone Drugs 0.000 description 1
- 239000008098 formaldehyde solution Substances 0.000 description 1
- 239000012362 glacial acetic acid Substances 0.000 description 1
- 239000002622 gonadotropin Substances 0.000 description 1
- 229940094892 gonadotropins Drugs 0.000 description 1
- 239000003999 initiator Substances 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 229940040129 luteinizing hormone Drugs 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- QYZFTMMPKCOTAN-UHFFFAOYSA-N n-[2-(2-hydroxyethylamino)ethyl]-2-[[1-[2-(2-hydroxyethylamino)ethylamino]-2-methyl-1-oxopropan-2-yl]diazenyl]-2-methylpropanamide Chemical compound OCCNCCNC(=O)C(C)(C)N=NC(C)(C)C(=O)NCCNCCO QYZFTMMPKCOTAN-UHFFFAOYSA-N 0.000 description 1
- 210000001672 ovary Anatomy 0.000 description 1
- 238000000643 oven drying Methods 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 239000000583 progesterone congener Substances 0.000 description 1
- 239000002464 receptor antagonist Substances 0.000 description 1
- 229940044551 receptor antagonist Drugs 0.000 description 1
- 238000007363 ring formation reaction Methods 0.000 description 1
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 1
- 239000012453 solvate Substances 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
- 238000012360 testing method Methods 0.000 description 1
- 210000001550 testis Anatomy 0.000 description 1
- 229960003604 testosterone Drugs 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 239000002699 waste material Substances 0.000 description 1
Images
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D495/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
- C07D495/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
- C07D495/04—Ortho-condensed systems
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
- C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
- C07D409/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The present invention provides compounds of structural formula VI wherein R 1 、R 2 、R 3 、R 4 、R 5 、R 6 And R 7 Each independently selected from hydrogen and C 1 ‑C 3 Alkyl of (C) 1 ‑C 3 Alkoxy, amino or hydroxy of R 8 Selected from hydrogen or C 1 ‑C 3 The alkyl group of (1). The invention also provides a compound with a preferable structural formula VI and application of the compound as a starting material in preparation of Ruogeli. In addition, the invention also provides a novel preparation method of Ruogeli.
Description
Technical Field
The invention belongs to the field of organic chemistry, and particularly relates to a new Ruugeli intermediate and a Ruugeli synthesis method.
Background
Ruuggoli (CAS: 737789-87-6) was the first orally administered gonadotropin releasing hormone (GnRH) receptor antagonist to bind to and block GnRH receptors in the anterior pituitary gland, thereby reducing the release of gonadotropins, luteinizing hormone and follicle stimulating hormone, which in turn reduces estrogen and progestin production in the female ovaries and testosterone production in the male testes. Ruogeli was developed by Wutian, japan pharmaceutical industry Co., ltd, and is currently used clinically for the treatment of uterine myoma and endometriosis and advanced prostate cancer.
The molecular structure of Ruugeli is shown as formula I:
chinese patent application publication No. CN104703992A (published 2015, 6-10) discloses a method of synthesizing rilogeli:
first, p-nitrophenylacetic acid of formula A and SOCl 2 Reacting to prepare acyl chloride with a structural formula B; secondly, condensing, hydrolyzing and decarboxylating the compound with the structural formula B and malonate to obtain a compound with a structural formula C; thirdly, the compound with the structural formula C, the elemental sulfur and ethyl cyanoacetate are subjected to condensation and cyclization to prepare the compound with the structural formula D, and the yield of the three steps is 79.8 percent; step four, reacting the compound with the structural formula D with ethyl chloroformate to obtain a compound with a structural formula F, wherein the yield is 96.1%; fifthly, the compound of the structural formula E and 2, 3-difluorobenzyl bromide are subjected to substitution reaction in the presence of alkali to prepare the compound of the structural formula F, wherein the yield is 95.5%; sixthly, taking 2,2' -azobis (2, 4-dimethylvaleronitrile as a free radical initiator, reacting a compound with a structural formula F and NBS to generate bromine through a free radical reaction to obtain a compound with a structural formula G, wherein the yield is 92.1 percent and the purity is 93 percent, seventhly, carrying out a substitution reaction on the compound with the structural formula G and dimethylamine salt to obtain a compound with a structural formula H, wherein the yield is 89.6 percent, eighthly, hydrolyzing the compound with the structural formula F to prepare a compound with a structural formula J, wherein the yield is 89.9 percent, and ninthly, carrying out an amide condensation reaction on the compound with the structural formula J and 3-amino-6-methoxypyridazine in the presence of propylphosphonic anhydride and alkali to obtain a compound with a structural formula KCompound, yield 97%; step ten, cyclizing the compound with the structural formula K under an alkaline condition to prepare a compound with a structural formula L, wherein the yield is 98%; step ten, reducing the compound with the structural formula L to obtain a compound with a structural formula M, wherein the yield is 84.1%; in the twelfth step, the compound of formula M reacts with methoxyamine under the activation of 1,1' -Carbonyldiimidazole (CDI), and then is crystallized in tetrahydrofuran to obtain the compound of formula I, i.e., tetrahydrofuran solvate crystal of rilogeli, with a yield of 91%.
The above preparation method has problems that:
firstly, the price of the starting material, namely p-nitroacetoacetic acid is expensive, which is not beneficial to reducing the cost; second, the preparation of compounds of formula B requires the use of large amounts of SOCl 2 The odor is big and toxic, which is not beneficial to environmental protection and safe production; thirdly, a large amount of acid is added when the compound of the structural formula C is prepared, and a larger amount of waste liquid is generated by washing with brine; fourthly, in the sixth step, the compound of the structural formula F is synthesized into the compound of the structural formula G through a free radical reaction, which is difficult to control, so that the compound of the structural formula G has low purity (the purity is 93%); finally, the whole route has 12 steps, which is complicated.
Therefore, the development of a novel method for preparing Ruugeli, which has the advantages of short steps, simple control, low cost and environmental friendliness, is necessary to ensure safe production and reduce the medication cost of the public.
Disclosure of Invention
In order to overcome the defects of the prior art, the invention provides a Ruugeli intermediate with a structural formula VI, a preparation method thereof and a method for preparing Ruugeli through the Ruugeli intermediate. The novel method for preparing Ruogeli provided by the invention has a short route; compared with 12 steps disclosed in the prior art CN104703992A, the preparation method of relugar provided by the present invention only requires 7 steps. In addition, the preparation method has low price of the starting raw materials; free radical reaction is not adopted, and the control is easy; in addition, the use of thionyl chloride which has large odor and is toxic and a large amount of acid is avoided, so that the production is safer and more environment-friendly.
In order to realize the technical effects, the invention adopts the following technical scheme:
a compound of the formula VI,
wherein R is 1 、R 2 、R 3 、R 4 、R 5 、R 6 And R7 is each independently selected from hydrogen, C 1 -C 3 Alkyl of (C) 1 -C 3 Alkoxy, amino or hydroxy of R 8 Selected from hydrogen or C 1 -C 3 The alkyl group of (1).
As a preferred embodiment, R 1 、R 2 、R 3 、R 4 、R 5 、R 6 And R 7 Are all hydrogen, R 8 Is methyl, which is a compound of structural formula VI-1,
the present invention also provides a process for the preparation of the compound of structural formula VI above comprising the steps of:
step A: taking a compound with a structural formula IX as a starting material, and carrying out condensation reaction with N, N-dimethylformamide dimethyl acetal to obtain a compound with a structural formula VIII;
and B, step B: reacting the compound of the structural formula VIII with a sulfur simple substance and the compound of the structural formula VII in the presence of alkali to obtain a compound of a structural formula VI;
wherein R is 1 -R 8 As previously defined.
As a preferred embodiment, the present invention provides a process for the preparation of a compound of formula VI-1, comprising the steps of:
step A-1: taking p-nitrotoluene with a structural formula IX-1 as a starting material, and carrying out condensation reaction with N, N-dimethylformamide dimethyl acetal to obtain a compound with a structural formula VIII-1;
step B-1: reacting the compound with the structural formula VIII-1 with sulfur simple substance and the compound with the structural formula VII-1 in the presence of alkali to obtain the compound with the structural formula VI-1.
Preferably, in the step A-1, the molar ratio of the p-nitrotoluene of the structural formula IX-1 to the N, N-dimethylformamide dimethyl acetal is 1: 1 to 1: 10; more preferably 1: 1 to 1: 3.
Also preferably, in said step A-1, N, N-dimethylformamide dimethyl acetal is added in 2 to 3 portions.
Preferably, the reaction solvent of step A-1 is selected from DMF, DMAc (N, N-dimethylacetamide), N-methylpyrrolidone, DMSO or toluene; more preferably DMF.
Preferably, the reaction temperature of the step A-1 is 50 to 200 ℃, more preferably 80 to 160 ℃.
Preferably, in the step B-1, the molar ratio of the compound with the structural formula VIII-1 to the elemental sulfur is 1: 1-1: 2, and more preferably 1: 1-1: 1.2.
Preferably, in step B-1, the molar ratio of the compound of formula VIII-1 to the compound of formula VII-1 is from 1: 1 to 1: 2, more preferably from 1: 1 to 1: 1.2.
Preferably, in step B-1, the base is selected from morpholine, piperidine or tetrahydropyrrole; more preferably morpholine.
Preferably, in the step B-1, the molar ratio of the compound with the structural formula VIII-1 to the base is 1: 0.5-1: 5; more preferably 1: 0.5 to 1: 3.
Preferably, the reaction solvent of step B-1 is selected from methanol, ethanol, isopropanol, tert-butanol, dichloromethane, ethyl acetate, acetone or tetrahydrofuran; more preferably methanol, ethanol or isopropanol.
Preferably, the reaction temperature of step B-1 is 30 to 100 ℃, more preferably 50 to 80 ℃.
The invention also provides application of the compound with the structural formula VI-1 in preparation of Ruugeli.
Therefore, the invention also provides a preparation method of Ruogeli, which takes the compound with the structural formula VI-1 as a starting material and comprises the following steps:
step 1, reacting a compound with a structural formula VI-1 with triphosgene to generate a compound with a structural formula V;
step 2, carrying out substitution reaction on the compound with the structural formula V and 2, 6-difluorobenzyl chloride in the presence of alkali to generate a compound with a structural formula IV;
step 3, reducing the compound with the structural formula IV by using a catalyst to obtain a compound with a structural formula III;
step 4, reacting the compound with the structural formula III and 1,1' -Carbonyl Diimidazole (CDI) with methoxyamine hydrochloride in the presence of alkali to prepare a compound with a structural formula II;
and 5, carrying out Mannich reaction on the compound with the structural formula II, dimethylamine and formaldehyde in the presence of acid to generate the compound with the structural formula I.
Preferably, in the step 1, the molar ratio of the compound with the structural formula VI-1 to the triphosgene is 1: 0.35-1: 3; more preferably 1: 0.35 to 1: 1.
Preferably, the reaction solvent of step 1 is selected from tetrahydrofuran, ethyl acetate, dichloromethane, acetonitrile, toluene, DMF or DMSO; more preferably tetrahydrofuran.
Preferably, the reaction temperature of step 1 is 0 to 100 ℃, more preferably 30 to 80 ℃.
Preferably, in the step 2, the molar ratio of the compound with the structural formula V to the 2, 6-difluorobenzyl chloride is 1: 1-1.5: 1; more preferably 1: 1 to 1.2: 1.
Preferably, in the step 2, the base is selected from potassium carbonate, sodium carbonate, potassium hydroxide, sodium methoxide, sodium ethoxide or potassium tert-butoxide; more preferably potassium carbonate or sodium carbonate.
Preferably, in step 2, the molar ratio of the compound of formula V to the base is 1: 0.5 to 1: 2; more preferably 1: 0.8 to 1: 1.5.
Preferably, the reaction solvent of step 2 is selected from DMF, N-dimethylacetamide, N-methylpyrrolidone, DMSO, acetonitrile or tetrahydrofuran; more preferably DMF.
Preferably, the reaction temperature of step 2 is 30 to 120 ℃, more preferably 50 to 100 ℃.
Preferably, the catalyst of step 3 is selected from palladium on carbon, platinum on carbon or raney nickel; more preferably palladium on carbon.
Preferably, in the step 3, the mass ratio of the catalyst to the compound of the structural formula IV is 0.05: 1-0.5: 1, and more preferably 0.1: 1-0.3: 1.
Preferably, the reducing agent of step 3 is ammonium formate, formic acid or hydrogen; more preferably ammonium formate.
Preferably, the reaction solvent of step 3 is selected from one or more of dichloromethane, methanol, ethanol, isopropanol, ethyl acetate, tetrahydrofuran, acetonitrile, DMF and DMSO.
Preferably, the reaction temperature of step 3 is 10 to 60 ℃, more preferably 20 to 50 ℃.
Preferably, in step 4, the molar ratio of 1,1' -carbonyldiimidazole to the compound of formula III is from 1: 1 to 4: 1, more preferably from 1.1: 1 to 2.5: 1.
Preferably, in the step 4, the molar ratio of the methoxylamine hydrochloride to the compound of the structural formula III is 1: 1 to 4: 1, and more preferably 1.1: 1 to 2.5: 1.
Preferably, in the step 4, the base is selected from triethylamine, N-methylmorpholine, N-methylpyrrolidine, pyridine or triethylenediamine; more preferably triethylamine.
Preferably, in step 4, the molar ratio of the base to the compound of formula III is 1: 1 to 4: 1, more preferably 1.1: 1 to 2.5: 1.
Preferably, the reaction solvent of step 4 is selected from dichloromethane, tetrahydrofuran, ethyl acetate, acetone, methanol, ethanol, isopropanol, acetonitrile or toluene; more preferably dichloromethane.
Preferably, the reaction temperature of step 4 is 10 to 80 ℃, more preferably 30 to 60 ℃.
Preferably, in step 5, the molar ratio of the compound of formula II to formaldehyde is from 1: 1 to 1: 100, more preferably from 1: 2 to 1: 30.
Preferably, in step 5, the molar ratio of the compound of formula II to dimethylamine is from 1: 1 to 1: 100, more preferably from 1: 2 to 1: 30.
Preferably, in the step 5, the acid exists under the condition that the pH of the reaction system is 3-4; the acid is selected from acetic acid, formic acid, hydrochloric acid, sulfuric acid, more preferably acetic acid.
Preferably, the reaction temperature of step 5 is 20 to 80 ℃, more preferably 30 to 60 ℃.
Drawings
The invention is further described below with reference to the accompanying drawings.
FIG. 1 shows an HPLC chromatogram of the compound of structural formula VI-1 prepared in example 1, in which the peaks labeled "1-31.345" are the chromatographic peaks of said compound of structural formula VI-1.
Figure 2 shows the HPLC profile of rilogeli prepared in example 6, with the peak labeled "31.708-ridl" being the chromatographic peak of rilogeli.
Detailed Description
The invention is illustrated below with reference to specific examples. It will be understood by those skilled in the art that these examples are merely illustrative of the present invention and do not limit the scope of the present invention in any way.
The experimental procedures in the following examples are all conventional ones unless otherwise specified. The raw materials, reagent materials and the like used in the following examples are all commercially available products unless otherwise specified.
EXAMPLE 1 preparation of Compound of formula VI-1
Step A, preparation of Compound of structural formula VIII-1
Adding 60.0g (0.438 mol) of p-nitrotoluene with the structural formula IX-1, 57.4g (0.482 mol) of N, N-dimethylformamide dimethyl acetal and 200ml of DMF into a reaction bottle, and heating to 140 ℃ for reaction for 7 hours; adding 14.4g (0.12 mol) of N, N-dimethylformamide dimethyl acetal, and continuing to react for 3 hours at 140 ℃; then, 14.4g (0.12 mol) of N, N-dimethylformamide dimethyl acetal is added again, and the reaction is kept at 140 ℃ for 3 hours; cooling to room temperature, pouring the reaction solution into 1200ml of ice water, washing the reaction bottle with 50ml of DMF, and pouring the washing solution into the ice water; stirring for 30min, and filtering; the filter cake was washed successively with 400ml of water and 400ml of n-hexane and dried to give 78.2g of a brick-red solid of the formula VIII-1 in a yield of 93% and a purity of 98% by HPLC.
1 H-NMR(400M，DMSO-d 6 )∶8.11(2H，d)，7.50(1H，d)，7.27(2H，d)， 5.19(1H，d)，2.92(6H，s)。
Step 2, preparation of Compound of structural formula VI-1
The method comprises the following steps: adding 14.3g (74.4 mmol) of the compound of the structural formula VIII-1, 14.4g (75 mmol) of the compound of the structural formula VII-1, 2.4g (75 mmol) of elemental sulfur, 150ml of methanol and 15.0ml (173 mmol) of morpholine into a reaction bottle, and heating to 70 ℃ for reacting for 6 hours; distilling until the reaction solution is about 50ml, adding 100ml ice water, stirring at 0-10 deg.C for 1h, filtering, and oven drying the filter cake to obtain 23.5g red solid of structural formula VI-1 with yield of 85% and HPLC purity of 99.8% (HPLC chromatogram shown in figure 1).
The method 2 comprises the following steps: adding 14.3g (74.4 mmol) of the compound of the structural formula VIII-1, 15.4g (80 mmol) of the compound of the structural formula VII-1, 2.6g (80 mmol) of elemental sulfur, 150ml of ethanol and 17.3g (200 mmol) of piperidine into a reaction bottle, and heating to 60 ℃ for reaction for 10 hours; distilling until the reaction solution is about 50ml, adding 100ml ice water, keeping the temperature at 0-10 ℃, stirring for 1h, filtering, and drying the filter cake to obtain 24.3g of red solid of the structural formula VI-1, wherein the yield is 88%, and the HPLC purity is 98% (HPLC chromatogram is not shown).
The method 3 comprises the following steps: adding 14.3g (74.4 mmol) of the compound of the structural formula VIII-1, 14.4g (75 mmol) of the compound of the structural formula VII-1, 2.4g (75 mmol) of elemental sulfur, 150ml of isopropanol and 17.4g (200 mmol) of morpholine into a reaction bottle, and heating to 70 ℃ for reacting for 8 hours; distilling until the reaction solution is about 50ml, adding 100ml of ice water, keeping the temperature at 0-10 ℃, stirring for 1h, filtering, and drying a filter cake to obtain 23.8g of red solid of the structural formula VI-1, wherein the yield is 86 percent, and the HPLC purity is 99 percent (a HPLC map is not shown).
MS(m/z)：[M+1] + 372.1。
1 H-NMR(400M，CDCl 3 )：12.32(1H，br)，8.15(2H，d)，7.57-7.51 (4H，m)，7.43(1H，s)，6.25(2H，s)，4.18(3H，s)。
EXAMPLE 2 preparation of Compound of formula V
Example 2a
15.0g (40.4 mmol) of the compound of the structural formula VI-1, 4.81g (16.2 mmol) of triphosgene and 200ml of tetrahydrofuran are added into a reaction bottle, and the temperature is raised to 60 ℃ for reaction for 3 hours; distilling to remove all solvents, adding 100ml of ice water, adjusting pH to 10 with potassium carbonate, and stirring for 1h at 0-10 ℃; filtration and washing of the filter cake with 20ml of water and drying gave 15.2g of a yellow solid of formula V in 95% yield and 99% HPLC purity.
Example 2b
15.0g (40.4 mmol) of the compound of the structural formula VI-1, 5.94g (20.0 mmol) of triphosgene and 200ml of acetonitrile are added into a reaction bottle, and the temperature is increased to 50 ℃ for reaction for 6 hours; distilling to remove all solvents, adding 100ml of ice water, adjusting pH to 10 with potassium carbonate, and stirring for 1h at 0-10 ℃; filtration and washing of the filter cake with 20ml of water and drying gave 14.8g of a yellow solid of formula V in 92% yield and 99% HPLC purity.
1 H-NMR(400M，CDCl 3 )：11.85(1H，br)，8.22(2H，d)，7.63-7.56 (5H，m)，4.21(3H，s)。
EXAMPLE 3 preparation of Compound of formula IV
Example 3a
10.0g (25.2 mmol) of the compound of formula V, 3.8g (27.7 mmol) of potassium carbonate powder, 50ml of DMF and 4.5g (27.7 mmol) of 2, 4-difluorobenzyl chloride are added into a reaction flask and heated to 70 ℃ for reaction for 2h; pouring the reaction solution into 150ml of ice water, extracting with ethyl acetate for three times, each time 70ml, combining organic phases, and distilling until the volume of the solution is about 30ml; cooling to 0-10 deg.C, slowly adding 120ml heptane, and stirring for 60min; filtration and drying of the filter cake gave 12.6g of compound IV as a yellow solid in 96% yield and 99% HPLC purity.
Example 3b
10.0g (25.2 mmol) of the compound of formula V, 4.14g (30.0 mmol) of potassium carbonate powder, 50ml of DMSO and 4.87g (30.0 mmol) of 2, 4-difluorobenzyl chloride are added into a reaction flask, and the temperature is raised to 60 ℃ for reaction for 5 hours; pouring the reaction solution into 150ml of ice water, extracting with ethyl acetate for three times, each time 70ml, combining organic phases, and distilling until the volume of the solution is about 30ml; cooling to 0-10 deg.C, slowly adding 120ml heptane, and stirring for 60min; filtration and drying of the filter cake gave 12.1g of compound IV as a yellow solid in 92% yield and 99% purity by HPLC.
1 H-NMR(400M，CDCl 3 )：8.25(2H，d)，7.67-7.57(5H，m)，7.25(2H， t)，6.88(1H，d)，5.31(2H，s)，4.23(3H，s)。
EXAMPLE 4 preparation of Compounds of formula III
Example 4a
Adding 10.0g (19.1 mmol) of the compound with the structural formula IV, 50ml of dichloromethane, 50ml of methanol and 1.3g of palladium-carbon (10 percent of content and 50 percent of water) into a reaction bottle, heating to 30 ℃, adding 4.8g (76.4 mmol) of ammonium formate in batches, and keeping the temperature at 30 ℃ for reacting for 5 hours after the addition is finished; cooling to 0-10 deg.c, adding 50ml of dichloromethane, stirring for 30min, filtering, distilling the filtrate to remove all solvent to obtain 9.14g of the compound of formula III as a white solid with a yield of 97% and an HPLC purity of 98%.
Example 4b
Adding 10.0g (19.1 mmol) of the compound with the structural formula IV, 50ml of dichloromethane, 50ml of ethanol and 1.8g of palladium-carbon (10 percent of content and 50 percent of water) into a reaction bottle, heating to 45 ℃, adding 4.6g (100 mmol) of formic acid in batches, and keeping the temperature at 45 ℃ for reacting for 6 hours after the addition is finished; adding 100ml of water, and adjusting the pH value to 9 by using potassium carbonate; filtering, distilling the filtrate, removing the solvent, cooling to 0-10 ℃, stirring for 30min, filtering, and drying the filter cake to obtain 8.6g of a white solid compound of the structural formula III, wherein the yield is 91 percent, and the HPLC purity is 97 percent.
1 H-NMR(400M，CDCl 3 )：7.58-7.56(2H，m)，7.30-7.24(4H，m)，6.86 (2H，d)，6.63(2H，d)，5.24(2H，s)，4.15(3H，s)，3.62(2H，br)。
EXAMPLE 5 preparation of Compound of formula II
Example 5a
Adding 100ml of dichloromethane, 7.0g (43.26 mmol) of 1,1' -Carbonyldiimidazole (CDI) and 2.63g (26.0 mmol) of triethylamine into a reaction bottle, cooling to 10 ℃, adding 4.0g (47.6 mmol) of methoxylamine hydrochloride in batches, heating to 30 ℃ after the addition is finished, reacting for 30min, adding 10.7g (21.63 mmol) of a compound with a structural formula III, and keeping the temperature at 40 ℃ after the addition is finished, and reacting for 6h; adding 100ml water, keeping 20-30 deg.C, stirring for 30min, separating, and extracting the water phase with 50ml dichloromethane once; mixing the organic phases, distilling until about 30ml of solution remains, cooling to 0-10 ℃, dropwise adding 80ml of heptane, and stirring for 2h after the addition is finished; filtration and drying of the filter cake gave 11.67g of the white solid compound of formula II in 95% yield and 99% HPLC purity.
Example 5b
Adding 100ml of ethyl acetate, 6.47g (40.0 mmol) of 1,1' -Carbonyldiimidazole (CDI) and 3.03g (30.0 mmol) of triethylamine into a reaction bottle, cooling to 10 ℃, adding 3.36g (40.0 mmol) of methoxylamine hydrochloride in batches, heating to 40 ℃ after the addition is finished, reacting for 30min, adding 10.7g (21.63 mmol) of the compound of the structural formula III, and keeping the temperature at 50 ℃ after the addition is finished, and reacting for 5h; adding 100ml water, keeping 20-30 deg.C, stirring for 30min, separating, and extracting the water phase with 100ml ethyl acetate once; mixing the organic phases, distilling until about 50ml of solution remains, cooling to 0-10 ℃, dropwise adding 100ml of heptane, and stirring for 2h after the addition is finished; filtration and drying of the filter cake gave 11.42g of the white solid compound of formula II in 93% yield and 99% HPLC purity.
1 H-NMR(400M，CDCl 3 )：7.73(1H，s)，7.65(1H，s)，7.59-7.57(2H， m)，7.44-7.36(5H，m)，7.29(1H，t)，6.89(2H，d)，5.28(2H，s)，4.17 (3H，s)，3.82(3H，s)。
EXAMPLE 6 preparation of Compound of structural formula I (Rulugol)
Example 6a
9.22g (16.28 mmol) of the compound of formula II, 100ml of glacial acetic acid, 6.6g of aqueous formaldehyde (81.4 mmol,37% (w/w)), 7.3g of aqueous dimethylamine (81.4 mmol, 50% (w/w)) were charged into a reaction flask and heated to 50 ℃ for reaction for 4h; pouring the reaction solution into 150ml of water, extracting with dichloromethane for three times, each time with the volume of 100ml, and combining organic phases; washing the organic phase with water twice, 50ml each time, distilling the organic phase until the residual volume is 30ml, cooling to 10-15 deg.C, and dripping 60ml heptane; stirring for 2h after the addition is finished; filtration and drying of the filter cake gave 9.24g of the compound of formula I as a white solid in 91% yield and 99% HPLC purity (see FIG. 2 for HPLC).
Example 6b
A reaction flask was charged with 9.22g (16.28 mmol) of the compound of formula II, 100ml of formic acid, 13.2g of an aqueous formaldehyde solution (162.8mmol, 37% (w/w)), 14.6g of an aqueous dimethylamine solution (162.8 mmol, 50% (w/w)), and the mixture was heated to 70 ℃ for reaction for 2 hours; pouring the reaction solution into 150ml of water, extracting with dichloromethane for three times, each time with the volume of 100ml, and combining organic phases; washing the organic phase with water twice, 50ml each time, distilling the organic phase until about 30ml remains, cooling to 10-15 ℃, and dropwise adding 60ml heptane; stirring for 2h after the addition is finished; filtration and drying of the filter cake gave 9.04g of the compound of formula I as a white solid in 89% yield and 98% HPLC purity (slight HPLC pattern).
1 H-NMR(400M，CDCl 3 )：7.64-7.12(8H，m)，6.91(2H，t)，6.80(1H， br)，5.33(2H，br)，4.17(3H，s)，3.81(3H，s)，3.69(2H，s)，2.13(6H， s)。
In summary, the present invention provides a novel method for preparing Ruugeli. Compared with the prior art, the preparation method has the advantages of short and simple route, low raw material price, easy control of reaction, avoidance of use of thionyl chloride with strong odor and toxicity, great reduction of the dosage of the acidic solvent, and safer and more environment-friendly production.
Claims (10)
1. A compound of the formula VI,
wherein R is 1 、R 2 、R 3 、R 4 、R 5 、R 6 And R 7 Each independently selected from hydrogen and C 1 -C 3 Alkyl of (C) 1 -C 3 Alkoxy, amino or hydroxy of R 8 Selected from hydrogen or C 1 -C 3 Alkyl group of (1).
2. The compound of formula VI as claimed in claim 1, wherein when R is 1 、R 2 、R 3 、R 4 、R 5 、R 6 And R 7 Are all hydrogen, and R 8 When methyl, the compound of formula VI is a compound of formula VI-1,
3. a process for the preparation of a compound of structural formula VI as claimed in claim 1, comprising the steps of:
step A: taking a compound with a structural formula IX as an initial material, and carrying out condensation reaction with N, N-dimethylformamide dimethyl acetal to obtain a compound with a structural formula VIII;
and B, step B: reacting a compound with a structural formula VIII with a sulfur simple substance and a compound with a structural formula VII in the presence of alkali to obtain a compound with a structural formula VI;
wherein R is 1 -R 8 As previously defined.
4. A process for the preparation of a compound of structural formula VI-1 comprising the steps of:
step A-1: taking p-nitrotoluene with a structural formula IX-1 as an initial material, and carrying out condensation reaction with N, N-dimethylformamide dimethyl acetal to obtain a compound with a structural formula VIII-1;
step B-1: reacting the compound with the structural formula VIII-1 with sulfur simple substance and the compound with the structural formula VII-1 in the presence of alkali to obtain the compound with the structural formula VI-1.
5. The method according to claim 4, wherein in the step A-1, the molar ratio of p-nitrotoluene of formula IX-1 to N, N-dimethylformamide dimethyl acetal is 1: 1 to 1: 10; more preferably 1: 1 to 1: 3;
also preferably, in said step a-1, N-dimethylformamide dimethyl acetal is added in 2 to 3 portions;
preferably, the reaction solvent of step A-1 is selected from DMF, DMAc (N, N-dimethylacetamide), N-methylpyrrolidone, DMSO or toluene; more preferably DMF.
6. The method according to claim 4, wherein the reaction temperature of step A-1 is 50 to 200 ℃, more preferably 80 to 160 ℃;
preferably, in the step B-1, the molar ratio of the compound with the structural formula VIII-1 to the elemental sulfur is 1: 1-1: 2, and more preferably 1: 1-1: 1.2;
preferably, in step B-1, the molar ratio of the compound of formula VIII-1 to the compound of formula VII-1 is from 1: 1 to 1: 2, more preferably from 1: 1 to 1: 1.2;
preferably, in step B-1, the base is selected from morpholine, piperidine or tetrahydropyrrole; more preferably morpholine;
preferably, in the step B-1, the molar ratio of the compound of the structural formula VIII-1 to the base is 1: 0.5-1: 5; more preferably 1: 0.5-1: 3;
preferably, the reaction solvent of step B-1 is selected from methanol, ethanol, isopropanol, tert-butanol, dichloromethane, ethyl acetate, acetone or tetrahydrofuran; more preferably methanol, ethanol or isopropanol;
preferably, the reaction temperature of the step B-1 is 30 to 100 ℃, more preferably 50 to 80 ℃.
7. Application of a compound with a structural formula VI-1 in preparation of Ruogeli.
8. A preparation method of Ruogeli takes a compound with a structural formula VI-1 as a starting material and comprises the following steps:
step 1, reacting a compound with a structural formula VI-1 with triphosgene to generate a compound with a structural formula V;
step 2, carrying out substitution reaction on the compound with the structural formula V and 2, 6-difluorobenzyl chloride in the presence of alkali to generate a compound with a structural formula IV;
step 3, reducing the compound with the structural formula IV by using a catalyst to obtain a compound with a structural formula III;
step 4, reacting the compound with the structural formula III and 1,1' -Carbonyl Diimidazole (CDI) with methoxyamine hydrochloride in the presence of alkali to prepare a compound with a structural formula II;
and 5, carrying out Mannich reaction on the compound with the structural formula II, dimethylamine and formaldehyde in the presence of acid to generate the compound with the structural formula I.
9. The method of claim 8, wherein in step 1, the compound of formula VI-1 is used in a molar ratio to triphosgene of 1: 0.35 to 1: 3; preferably 1: 0.35-1: 1;
preferably, the reaction solvent of step 1 is selected from tetrahydrofuran, ethyl acetate, dichloromethane, acetonitrile, toluene, DMF or DMSO; more preferably tetrahydrofuran;
preferably, the reaction temperature of the step 1 is 0-100 ℃, more preferably 30-80 ℃;
preferably, in the step 2, the molar ratio of the compound with the structural formula V to the 2, 6-difluorobenzyl chloride is 1: 1-1.5: 1; more preferably 1: 1 to 1.2: 1;
preferably, in the step 2, the base is selected from potassium carbonate, sodium carbonate, potassium hydroxide, sodium methoxide, sodium ethoxide or potassium tert-butoxide; more preferably potassium carbonate or sodium carbonate;
preferably, in step 2, the molar ratio of the compound of formula V to the base is 1: 0.5 to 1: 2; more preferably 1: 0.8-1: 1.5;
preferably, the reaction solvent of step 2 is selected from DMF, N-dimethylacetamide, N-methylpyrrolidone, DMSO, acetonitrile or tetrahydrofuran; more preferably DMF;
preferably, the reaction temperature of the step 2 is 30-120 ℃, more preferably 50-100 ℃;
preferably, the catalyst of step 3 is selected from palladium on carbon, platinum on carbon or raney nickel; more preferably palladium on carbon;
preferably, in the step 3, the mass ratio of the catalyst to the compound with the structural formula IV is 0.05: 1-0.5: 1, and more preferably 0.1: 1-0.3: 1;
preferably, the reducing agent of step 3 is ammonium formate, formic acid or hydrogen; more preferably ammonium formate;
preferably, the reaction solvent of step 3 is selected from one or more of dichloromethane, methanol, ethanol, isopropanol, ethyl acetate, tetrahydrofuran, acetonitrile, DMF and DMSO;
preferably, the reaction temperature of step 3 is 10 to 60 ℃, more preferably 20 to 50 ℃.
10. The process according to claim 8, wherein in step 4, the molar ratio of 1,1' -carbonyldiimidazole to compound of formula III is 1: 1 to 4: 1, more preferably 1.1: 1 to 2.5: 1;
preferably, in the step 4, the molar ratio of the methoxylamine hydrochloride to the compound of the structural formula III is 1: 1-4: 1, and more preferably 1.1: 1-2.5: 1;
preferably, in the step 4, the base is selected from triethylamine, N-methylmorpholine, N-methylpyrrolidine, pyridine or triethylenediamine; more preferably triethylamine;
preferably, in step 4, the molar ratio of the base to the compound of formula III is 1: 1 to 4: 1, more preferably 1.1: 1 to 2.5: 1;
preferably, the reaction solvent of step 4 is selected from dichloromethane, tetrahydrofuran, ethyl acetate, acetone, methanol, ethanol, isopropanol, acetonitrile or toluene; more preferably dichloromethane;
preferably, the reaction temperature of the step 4 is 10-80 ℃, more preferably 30-60 ℃;
preferably, in the step 5, the molar ratio of the compound of the structural formula II to formaldehyde is 1: 1 to 1: 100, more preferably 1: 2 to 1: 30;
preferably, in step 5, the molar ratio of the compound of formula II to dimethylamine is from 1: 1 to 1: 100, more preferably from 1: 2 to 1: 30;
preferably, in the step 5, the acid exists under the condition that the pH of the reaction system is 3-4; the acid is selected from acetic acid, formic acid, hydrochloric acid, sulfuric acid, more preferably acetic acid;
preferably, the reaction temperature of step 5 is 20 to 80 ℃, more preferably 30 to 60 ℃.
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| Publication number | Priority date | Publication date | Assignee | Title |
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| US20170210753A1 (en) * | 2012-09-28 | 2017-07-27 | Takeda Pharmaceutical Company Limited | Production method of thienopyrimidine derivative |
| CN112552312A (en) * | 2020-12-07 | 2021-03-26 | 杭州科巢生物科技有限公司 | Synthetic method of Ruogeli or salt thereof |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20170210753A1 (en) * | 2012-09-28 | 2017-07-27 | Takeda Pharmaceutical Company Limited | Production method of thienopyrimidine derivative |
| CN112552312A (en) * | 2020-12-07 | 2021-03-26 | 杭州科巢生物科技有限公司 | Synthetic method of Ruogeli or salt thereof |
Non-Patent Citations (1)
| Title |
|---|
| 李 敏: "瑞卢戈利的合成工艺", 《中国医药工业杂志》, vol. 53, no. 7, pages 962 - 968 * |
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