CN112574195A - Preparation method of intermediate - Google Patents
Preparation method of intermediate Download PDFInfo
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- CN112574195A CN112574195A CN201910937878.0A CN201910937878A CN112574195A CN 112574195 A CN112574195 A CN 112574195A CN 201910937878 A CN201910937878 A CN 201910937878A CN 112574195 A CN112574195 A CN 112574195A
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- 238000002360 preparation method Methods 0.000 title claims abstract description 23
- 238000006243 chemical reaction Methods 0.000 claims abstract description 61
- 238000007363 ring formation reaction Methods 0.000 claims abstract description 19
- 238000000034 method Methods 0.000 claims abstract description 18
- 238000006722 reduction reaction Methods 0.000 claims abstract description 17
- 238000005984 hydrogenation reaction Methods 0.000 claims abstract description 16
- 238000003379 elimination reaction Methods 0.000 claims abstract description 14
- 238000006114 decarboxylation reaction Methods 0.000 claims abstract description 12
- 150000001875 compounds Chemical class 0.000 claims description 112
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 36
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 29
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 23
- JNGZXGGOCLZBFB-IVCQMTBJSA-N compound E Chemical compound N([C@@H](C)C(=O)N[C@@H]1C(N(C)C2=CC=CC=C2C(C=2C=CC=CC=2)=N1)=O)C(=O)CC1=CC(F)=CC(F)=C1 JNGZXGGOCLZBFB-IVCQMTBJSA-N 0.000 claims description 20
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 18
- LVTJOONKWUXEFR-FZRMHRINSA-N protoneodioscin Natural products O(C[C@@H](CC[C@]1(O)[C@H](C)[C@@H]2[C@]3(C)[C@H]([C@H]4[C@@H]([C@]5(C)C(=CC4)C[C@@H](O[C@@H]4[C@H](O[C@H]6[C@@H](O)[C@@H](O)[C@@H](O)[C@H](C)O6)[C@@H](O)[C@H](O[C@H]6[C@@H](O)[C@@H](O)[C@@H](O)[C@H](C)O6)[C@H](CO)O4)CC5)CC3)C[C@@H]2O1)C)[C@H]1[C@H](O)[C@H](O)[C@H](O)[C@@H](CO)O1 LVTJOONKWUXEFR-FZRMHRINSA-N 0.000 claims description 17
- 239000002904 solvent Substances 0.000 claims description 17
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 16
- 239000012074 organic phase Substances 0.000 claims description 16
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 15
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 12
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 12
- JHIVVAPYMSGYDF-UHFFFAOYSA-N cyclohexanone Chemical compound O=C1CCCCC1 JHIVVAPYMSGYDF-UHFFFAOYSA-N 0.000 claims description 12
- 239000001257 hydrogen Substances 0.000 claims description 12
- 229910052739 hydrogen Inorganic materials 0.000 claims description 12
- 239000007810 chemical reaction solvent Substances 0.000 claims description 11
- 125000001584 benzyloxycarbonyl group Chemical group C(=O)(OCC1=CC=CC=C1)* 0.000 claims description 10
- 238000001914 filtration Methods 0.000 claims description 10
- -1 p-methylbenzyl Chemical group 0.000 claims description 10
- UYWQUFXKFGHYNT-UHFFFAOYSA-N phenylmethyl ester of formic acid Natural products O=COCC1=CC=CC=C1 UYWQUFXKFGHYNT-UHFFFAOYSA-N 0.000 claims description 10
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 10
- 239000002585 base Substances 0.000 claims description 9
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 9
- 239000003153 chemical reaction reagent Substances 0.000 claims description 9
- 238000000605 extraction Methods 0.000 claims description 8
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 8
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 8
- 238000001035 drying Methods 0.000 claims description 7
- JWUJQDFVADABEY-UHFFFAOYSA-N 2-methyltetrahydrofuran Chemical compound CC1CCCO1 JWUJQDFVADABEY-UHFFFAOYSA-N 0.000 claims description 6
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 6
- 239000003638 chemical reducing agent Substances 0.000 claims description 6
- 239000012280 lithium aluminium hydride Substances 0.000 claims description 6
- 230000008569 process Effects 0.000 claims description 6
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 6
- 229940126062 Compound A Drugs 0.000 claims description 5
- NLDMNSXOCDLTTB-UHFFFAOYSA-N Heterophylliin A Natural products O1C2COC(=O)C3=CC(O)=C(O)C(O)=C3C3=C(O)C(O)=C(O)C=C3C(=O)OC2C(OC(=O)C=2C=C(O)C(O)=C(O)C=2)C(O)C1OC(=O)C1=CC(O)=C(O)C(O)=C1 NLDMNSXOCDLTTB-UHFFFAOYSA-N 0.000 claims description 5
- 239000003810 Jones reagent Substances 0.000 claims description 5
- 125000004172 4-methoxyphenyl group Chemical group [H]C1=C([H])C(OC([H])([H])[H])=C([H])C([H])=C1* 0.000 claims description 4
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-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
- 239000003513 alkali Substances 0.000 claims description 4
- 125000003277 amino group Chemical group 0.000 claims description 4
- UORVGPXVDQYIDP-UHFFFAOYSA-N borane Chemical compound B UORVGPXVDQYIDP-UHFFFAOYSA-N 0.000 claims description 4
- 238000001816 cooling Methods 0.000 claims description 4
- 238000004519 manufacturing process Methods 0.000 claims description 4
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 claims description 4
- 125000006239 protecting group Chemical group 0.000 claims description 4
- 239000012295 chemical reaction liquid Substances 0.000 claims description 3
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical group [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 2
- XDTMQSROBMDMFD-UHFFFAOYSA-N Cyclohexane Chemical compound C1CCCCC1 XDTMQSROBMDMFD-UHFFFAOYSA-N 0.000 claims description 2
- 239000012448 Lithium borohydride Substances 0.000 claims description 2
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-diisopropylethylamine Substances CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 claims description 2
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 claims description 2
- 239000002253 acid Substances 0.000 claims description 2
- 229910000085 borane Inorganic materials 0.000 claims description 2
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Chemical group BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 2
- 229910052794 bromium Chemical group 0.000 claims description 2
- 239000000460 chlorine Substances 0.000 claims description 2
- 229910052801 chlorine Inorganic materials 0.000 claims description 2
- 125000001309 chloro group Chemical group Cl* 0.000 claims description 2
- 239000012279 sodium borohydride Substances 0.000 claims description 2
- 229910000033 sodium borohydride Inorganic materials 0.000 claims description 2
- 239000008096 xylene Substances 0.000 claims description 2
- 125000004435 hydrogen atom Chemical class [H]* 0.000 claims 1
- 230000009286 beneficial effect Effects 0.000 abstract description 2
- 238000009776 industrial production Methods 0.000 abstract description 2
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 27
- 238000004128 high performance liquid chromatography Methods 0.000 description 18
- 230000002829 reductive effect Effects 0.000 description 10
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 9
- 239000000706 filtrate Substances 0.000 description 7
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 6
- 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 6
- 238000005160 1H NMR spectroscopy Methods 0.000 description 5
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 5
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 5
- 150000002431 hydrogen Chemical class 0.000 description 5
- 239000000203 mixture Substances 0.000 description 5
- 239000000047 product Substances 0.000 description 5
- 239000000243 solution Substances 0.000 description 5
- 239000007868 Raney catalyst Substances 0.000 description 4
- NPXOKRUENSOPAO-UHFFFAOYSA-N Raney nickel Chemical compound [Al].[Ni] NPXOKRUENSOPAO-UHFFFAOYSA-N 0.000 description 4
- 229910000564 Raney nickel Inorganic materials 0.000 description 4
- 230000009471 action Effects 0.000 description 4
- 239000003054 catalyst Substances 0.000 description 4
- FABPRXSRWADJSP-MEDUHNTESA-N moxifloxacin Chemical compound COC1=C(N2C[C@H]3NCCC[C@H]3C2)C(F)=CC(C(C(C(O)=O)=C2)=O)=C1N2C1CC1 FABPRXSRWADJSP-MEDUHNTESA-N 0.000 description 4
- 229960003702 moxifloxacin Drugs 0.000 description 4
- KSCPLKVBWDOSAI-NKWVEPMBSA-N (4as,7as)-2,3,4,4a,5,6,7,7a-octahydro-1h-pyrrolo[3,4-b]pyridine Chemical compound N1CCC[C@H]2CNC[C@H]21 KSCPLKVBWDOSAI-NKWVEPMBSA-N 0.000 description 3
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 3
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 3
- 238000003756 stirring Methods 0.000 description 3
- 238000005406 washing Methods 0.000 description 3
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 2
- XBDQKXXYIPTUBI-UHFFFAOYSA-M Propionate Chemical compound CCC([O-])=O XBDQKXXYIPTUBI-UHFFFAOYSA-M 0.000 description 2
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- KXKVLQRXCPHEJC-UHFFFAOYSA-N acetic acid trimethyl ester Natural products COC(C)=O KXKVLQRXCPHEJC-UHFFFAOYSA-N 0.000 description 2
- 238000009835 boiling Methods 0.000 description 2
- 239000003759 ester based solvent Substances 0.000 description 2
- JMMWKPVZQRWMSS-UHFFFAOYSA-N isopropanol acetate Natural products CC(C)OC(C)=O JMMWKPVZQRWMSS-UHFFFAOYSA-N 0.000 description 2
- 229940011051 isopropyl acetate Drugs 0.000 description 2
- GWYFCOCPABKNJV-UHFFFAOYSA-N isovaleric acid Chemical compound CC(C)CC(O)=O GWYFCOCPABKNJV-UHFFFAOYSA-N 0.000 description 2
- 239000000463 material Substances 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- 229910052757 nitrogen Inorganic materials 0.000 description 2
- IJGRMHOSHXDMSA-UHFFFAOYSA-N nitrogen Substances N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 description 2
- 239000011541 reaction mixture Substances 0.000 description 2
- 230000009467 reduction Effects 0.000 description 2
- 238000010992 reflux Methods 0.000 description 2
- VSTXCZGEEVFJES-UHFFFAOYSA-N 1-cycloundecyl-1,5-diazacycloundec-5-ene Chemical compound C1CCCCCC(CCCC1)N1CCCCCC=NCCC1 VSTXCZGEEVFJES-UHFFFAOYSA-N 0.000 description 1
- 206010001076 Acute sinusitis Diseases 0.000 description 1
- 206010006458 Bronchitis chronic Diseases 0.000 description 1
- PMMYEEVYMWASQN-DMTCNVIQSA-N Hydroxyproline Chemical compound O[C@H]1CN[C@H](C(O)=O)C1 PMMYEEVYMWASQN-DMTCNVIQSA-N 0.000 description 1
- 206010035664 Pneumonia Diseases 0.000 description 1
- 206010062255 Soft tissue infection Diseases 0.000 description 1
- HFBMWMNUJJDEQZ-UHFFFAOYSA-N acryloyl chloride Chemical compound ClC(=O)C=C HFBMWMNUJJDEQZ-UHFFFAOYSA-N 0.000 description 1
- 230000001154 acute effect Effects 0.000 description 1
- 230000000844 anti-bacterial effect Effects 0.000 description 1
- 229940124350 antibacterial drug Drugs 0.000 description 1
- 239000008346 aqueous phase Substances 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- AGEZXYOZHKGVCM-UHFFFAOYSA-N benzyl bromide Chemical compound BrCC1=CC=CC=C1 AGEZXYOZHKGVCM-UHFFFAOYSA-N 0.000 description 1
- HSDAJNMJOMSNEV-UHFFFAOYSA-N benzyl chloroformate Chemical compound ClC(=O)OCC1=CC=CC=C1 HSDAJNMJOMSNEV-UHFFFAOYSA-N 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 206010006451 bronchitis Diseases 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 229940117975 chromium trioxide Drugs 0.000 description 1
- WGLPBDUCMAPZCE-UHFFFAOYSA-N chromium trioxide Inorganic materials O=[Cr](=O)=O WGLPBDUCMAPZCE-UHFFFAOYSA-N 0.000 description 1
- GAMDZJFZMJECOS-UHFFFAOYSA-N chromium(6+);oxygen(2-) Chemical compound [O-2].[O-2].[O-2].[Cr+6] GAMDZJFZMJECOS-UHFFFAOYSA-N 0.000 description 1
- 208000007451 chronic bronchitis Diseases 0.000 description 1
- 239000012141 concentrate Substances 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 238000004949 mass spectrometry Methods 0.000 description 1
- UKVIEHSSVKSQBA-UHFFFAOYSA-N methane;palladium Chemical compound C.[Pd] UKVIEHSSVKSQBA-UHFFFAOYSA-N 0.000 description 1
- NXJCBFBQEVOTOW-UHFFFAOYSA-L palladium(2+);dihydroxide Chemical compound O[Pd]O NXJCBFBQEVOTOW-UHFFFAOYSA-L 0.000 description 1
- 244000052769 pathogen Species 0.000 description 1
- BASFCYQUMIYNBI-UHFFFAOYSA-N platinum Chemical compound [Pt] BASFCYQUMIYNBI-UHFFFAOYSA-N 0.000 description 1
- 238000004321 preservation Methods 0.000 description 1
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 1
- 229940072132 quinolone antibacterials Drugs 0.000 description 1
- 239000000376 reactant Substances 0.000 description 1
- 230000000241 respiratory effect Effects 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- 125000003944 tolyl group Chemical group 0.000 description 1
- FGMPLJWBKKVCDB-UHFFFAOYSA-N trans-L-hydroxy-proline Natural products ON1CCCC1C(O)=O FGMPLJWBKKVCDB-UHFFFAOYSA-N 0.000 description 1
- 238000010626 work up procedure Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
- C07D471/04—Ortho-condensed systems
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/07—Optical isomers
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention relates to a preparation method of an intermediate, belonging to the field of pharmaceutical chemistry. The preparation method comprises at least one reaction step of addition elimination reaction, cyclization reaction, reduction reaction, decarboxylation reaction and hydrogenation reaction; the method can simply and conveniently obtain the target intermediate with a single configuration, effectively avoids chiral resolution, improves the yield, reduces the cost and is beneficial to industrial production.
Description
Technical Field
The invention relates to the field of pharmaceutical chemistry, in particular to a preparation method of an intermediate.
Background
Moxifloxacin is an antibacterial drug with a broad quinolone antibacterial spectrum, has strong antibacterial activity on common respiratory pathogens, and is clinically used for treating acute sinusitis, acute attack of chronic bronchitis, community-acquired pneumonia, skin and skin soft tissue infection and the like; the structure is shown as the following formula:
the (S, S) -2, 8-diazabicyclo- (4,3,0) -nonane exists in the structure of moxifloxacin, and 2 chiral centers exist in the structure, so that a single form of moxifloxacin is difficult to obtain. Therefore, the single configuration of (S, S) -2, 8-diazabicyclo- (4,3,0) -nonane is obtained simply, and the bond and important influence on the preparation of moxifloxacin are realized; the research on the preparation method of (S, S) -2, 8-diazabicyclo- (4,3,0) -nonane or the amino protection product thereof is needed to obtain the method which has the advantages of simple operation, easy implementation, high yield, high purity and low cost and can obtain the target product with single configuration.
Disclosure of Invention
In one aspect, the present invention provides a preparation method, which can be used for preparing a compound, comprising at least one of the following reaction steps:
the compound C and the compound 01 are subjected to addition elimination reaction to prepare a compound D
The compound D and the compound 02 are subjected to cyclization reaction to prepare a compound E
The compound E is subjected to reduction reaction to prepare a compound F
The compound F is subjected to decarboxylation reaction to prepare a compound G
the compound G is subjected to hydrogenation reaction to obtain a compound H
Wherein R is1Is hydrogen, or R1A protecting group for amino group selected from: optionally substituted phenyl, optionally substituted benzyl, phenyl, p-methoxyphenyl, benzyl, p-methylbenzyl, benzyloxycarbonyl, or optionally substituted benzyloxycarbonyl.
On the other hand, the invention provides a preparation method of an intermediate compound H shown as a formula H,
wherein R is1Is hydrogen, or R1A protecting group for amino group, which may be selected from: optionally substituted phenyl, optionally substituted benzyl, phenyl, p-methoxyphenyl, benzyl, p-methylbenzyl, benzyloxycarbonyl, optionally substituted benzyloxycarbonyl, and the like.
A process for the preparation of compound H comprising at least one of the preceding reaction steps. In some embodiments, a method of preparing compound H comprises two or three or four or five of the aforementioned reaction steps.
In some embodiments, a method of making compound H comprises: carrying out addition elimination reaction on the compound C and the compound 01 to prepare a compound D; carrying out cyclization reaction on the compound D and a compound 02 to prepare a compound E; carrying out reduction reaction on the compound E to prepare a compound F; performing decarboxylation reaction on the compound F to prepare a compound G; carrying out hydrogenation reaction on the compound G to obtain a compound H; the reaction scheme is as follows:
wherein R is1Is hydrogen, or R1A protecting group for amino group, which may be selected from: optionally substituted phenyl, optionally substituted benzyl, phenyl, p-methoxyphenyl, benzyl, p-methylbenzyl, benzyloxycarbonyl, optionally substituted benzyloxycarbonyl, and the like.
In the addition elimination reaction of the compound C and the compound 01, the reaction solvent may be at least one of toluene, xylene, tetrahydrofuran, methyltetrahydrofuran, dichloromethane, chloroform, cyclohexane and n-hexane. In some embodiments, the reaction solvent is toluene during the elimination reaction, which is more advantageous for the reaction operation and the work-up. The amount of reaction solvent used may be 3mL to 50mL, or 5mL to 50mL, or 10mL to 35mL per gram of compound C.
The molar ratio of compound C to compound 01 can be 1:1 to 1:2 or 1:1.01 to 1: 1.5.
In the addition elimination reaction, the reaction temperature is 20-140 ℃. In some embodiments, the reaction temperature in the addition elimination reaction is from 50 ℃ to 140 ℃. In some embodiments, the reaction temperature in the addition elimination reaction is from 70 ℃ to 140 ℃. In some embodiments, the reaction temperature in the addition elimination reaction is from 100 ℃ to 140 ℃.
After the completion of the addition elimination reaction, the reaction system may be subjected to a post-treatment to obtain compound D, the post-treatment including: and cooling the reaction liquid to room temperature, and removing the solvent to obtain a compound D.
In some embodiments, compound C and compound 01 are subjected to an addition elimination reaction in toluene at 90 ℃ to 140 ℃, after the reaction is completed, the reaction system is cooled to room temperature, and the solvent is removed by concentration to obtain compound D.
In the cyclization reaction of the compound D with the compound 02, the reaction solvent may be THF, methyltetrahydrofuran, chloroform, dichloromethane, toluene or the like. In some embodiments, during the cyclization reaction, the reaction solvent is THF, methyltetrahydrofuran, or toluene.
The amount of the reaction solvent used in the cyclization reaction may be 1ml to 30ml, or 3ml to 30ml, or 5ml to 20ml per gram of the compound D.
The molar ratio of compound D to compound 02 charged may be 1:1 to 1:5, or 1:1 to 1: 3.
In the cyclization reaction, a base reagent may be added, and the base reagent may be at least one of pyridine, triethylamine, N-diisopropylethylamine, DBU (1, 8-diazabicycloundec-7-ene), and the like. In some embodiments, a base reagent is added during the cyclization reaction, the base reagent being pyridine or triethylamine.
The charging molar ratio of the compound D and the alkali agent may be 1:1 to 1:20, or 1:1 to 1:15, or 1:1 to 1:10, or 1:1 to 1:5, and may be adjusted as appropriate according to the amount of the compound 02.
The reaction temperature of the cyclization reaction is 20-120 ℃. In some embodiments, the reaction temperature of the cyclization reaction is from 30 ℃ to 100 ℃. In some embodiments, the reaction temperature for the cyclization reaction is from 50 ℃ to 90 ℃. In some embodiments, the reaction temperature for the cyclization reaction is from 60 ℃ to 80 ℃.
After the cyclization reaction is finished, performing post-treatment to obtain a compound E, wherein the post-treatment comprises the following steps: concentrating the reaction system to dryness, adding an extraction solvent, and adjusting the pH to 3-4 with an acid; then drying the organic phase, filtering and concentrating to obtain a compound E; the extraction solvent can be ethyl acetate, isopropyl acetate, methyl acetate and other ester solvents or other suitable solvents.
In some embodiments, compound D is reacted with compound 02 in tetrahydrofuran in the presence of pyridine at 50 ℃ to 100 ℃, after completion of the reaction, the reaction is concentrated to dryness, ethyl acetate is added, and pH is adjusted to 3 to 4 with hydrochloric acid; the organic phase is then dried, filtered and concentrated to afford compound E.
In the process of preparing the compound F by the reduction reaction of the compound E, the reducing agent can be any suitable reducing agent such as lithium aluminum hydride, sodium borohydride, lithium borohydride, borane and the like. In some embodiments, the reducing agent is lithium aluminum hydride. The molar ratio of compound E to reducing agent may be 1:0.1 to 1:20, or 1:0.5 to 1:10, or 1:1 to 1:5, or 1:2 to 1: 3.
The temperature of the reduction reaction may be-5 ℃ to 80 ℃. In some embodiments, the temperature of the reduction reaction is from-5 ℃ to 60 ℃. In some embodiments, the temperature of the reduction reaction is from 20 ℃ to 60 ℃. In some embodiments, the temperature of the reduction reaction is from 40 ℃ to 60 ℃.
The reaction solvent for the reduction reaction may be any suitable solvent, such as tetrahydrofuran, 2-methyltetrahydrofuran, and the like.
After the reduction reaction is finished, the compound F can be prepared by post-treatment, wherein the post-treatment comprises the following steps: cooling the reaction liquid to-5-25 ℃, or-5-10 ℃ or-5 ℃, adding water, then adjusting the pH to 9-14 by using sodium hydroxide, extracting by using an extraction solvent, drying the organic phase, filtering and concentrating to obtain a compound F; the extraction solvent can be ethyl acetate, isopropyl acetate, methyl acetate and other ester solvents or other suitable solvents.
In some embodiments, compound E is subjected to a reduction reaction in tetrahydrofuran at 40 ℃ to 60 ℃ under the action of lithium aluminum hydride, after the reaction is completed, the reaction solution is cooled to-5 ℃ to 25 ℃, water is added, then the pH is adjusted to 9 to 14 by sodium hydroxide, ethyl acetate is used for extraction, and the organic phase is dried, filtered and concentrated to obtain compound F.
In the process of preparing the compound G by the decarboxylation reaction of the compound F, the decarboxylation reaction can be carried out under the condition of adding high boiling point solvent such as cyclohexanone or the like or without solvent. The high boiling solvent, such as cyclohexanone, may be used in an amount of 1mL to 50mL, alternatively 3mL to 30mL, alternatively 5mL to 25mL, per gram of compound F.
The reaction temperature of the decarboxylation reaction may be 60 ℃ to 180 ℃. In some embodiments, the reaction temperature of the decarboxylation reaction is from 80 ℃ to 160 ℃. In some embodiments, the reaction temperature of the decarboxylation reaction is from 100 ℃ to 160 ℃.
After the decarboxylation reaction is completed, the reaction system can be concentrated to dryness to obtain a compound G.
In some embodiments, compound F is reacted in cyclohexanone at 130 ℃ to 160 ℃, and after completion of the reaction, the reaction system is concentrated under reduced pressure to remove the solvent to obtain compound G.
And (3) carrying out hydrogen reduction hydrogenation reaction on the compound G in the presence of a catalyst, filtering after the reaction is finished, and concentrating the filtrate to be dry to prepare the compound H.
The reaction temperature of the hydrogenation reaction may be 20 ℃ to 100 ℃. In some embodiments, the hydrogenation reaction is carried out at a reaction temperature of 50 ℃ to 100 ℃ to facilitate the formation of the product.
The reaction solvent for the hydrogenation reaction may be at least one of ethanol, isopropanol, methanol, tert-butanol, and THF.
The catalyst for the hydrogenation reaction may be palladium carbon, Raney nickel, Pt/C, palladium hydroxide or other suitable catalyst. In some embodiments, the catalyst for the hydrogenation reaction is palladium on carbon.
The pressure of the hydrogen in the hydrogenation reaction may be in the range of from 0.5MPa to 2MPa or any other suitable pressure.
In some embodiments, compound G is subjected to hydrogen reduction hydrogenation in ethanol at 70 ℃ to 80 ℃ under the action of raney nickel, and after the reaction is completed, the compound G is optionally filtered and concentrated to obtain compound H.
The compound H can be subjected to hydrogenation reaction to prepare a compound I, and the reaction is as follows:
the invention also provides a preparation method of the compound C. A method of making compound C comprising: compound 00 and R1-X reaction to produce compound a; reacting the compound A with a Jones reagent to prepare a compound B; reacting the compound B with Bn-X to prepare a compound C; the reaction scheme is shown as follows, wherein R1As defined above, X is chlorine or bromine:
in some embodiments, compound 00 and R1Reacting the-X in the presence of alkali, and after the reaction is finished, carrying out post-treatment to obtain a compound A.
In some embodiments, compound a is oxidized with Jones reagent, after the reaction is complete, concentrated, and the resulting concentrate is dissolved in a solvent such as chloroform, washed with water, the organic phase dried, filtered, and concentrated to provide compound B.
In some embodiments, compound B is reacted with Bn-X in tetrahydrofuran in the presence of a base such as triethylamine, and after the reaction is completed, the reaction is concentrated to dryness, and then a solvent such as dichloromethane is added to dissolve, and the solution is washed once with hydrochloric acid, and the organic phase is dried, filtered, and concentrated to obtain compound C.
In some embodiments, compound C is reacted with compound 01 in toluene at 105 ℃ to 140 ℃, after the reaction is completed, cooled to room temperature, and concentrated to dryness under reduced pressure to obtain compound D.
In some embodiments, compound D is reacted with compound 02 in tetrahydrofuran in the presence of a base such as pyridine, triethylamine or other bases at 50-80 ℃, after the reaction is completed, concentrated to dryness, dissolved in ethyl acetate, washed with dilute hydrochloric acid, and the organic phase is dried, filtered, and concentrated to obtain compound E.
In some embodiments, compound E is reduced in tetrahydrofuran by lithium aluminum hydride at 30 ℃ to 60 ℃, after the reaction is completed, the temperature is reduced to-5 ℃ to 10 ℃, a sodium hydroxide solution is added, extraction is performed with ethyl acetate, and the organic phase is dried, filtered and concentrated to obtain compound F.
In some embodiments, compound F is decarboxylated in cyclohexanone at 130 ℃ to 160 ℃, and after completion of the reaction, it is concentrated to dryness under reduced pressure to give compound G.
In some embodiments, compound G is hydrogenated in ethanol under the action of raney nickel and hydrogen, and after the reaction is completed, it is filtered and concentrated to obtain compound H.
In some embodiments, compound H is subjected to reductive hydrogenation in ethanol under the action of palladium on carbon and hydrogen, and after the reaction is completed, the compound H is filtered and concentrated to obtain compound I.
In some embodiments, in the above method, R1Is benzyloxycarbonyl.
The method of the invention can simply and conveniently obtain the target product with single configuration, effectively avoid chiral resolution, improve the yield, reduce the cost and be beneficial to industrial production.
In the description herein, references to the description of the term "one embodiment," "some embodiments," "an example," "a specific example," or "some examples," etc., mean that a particular feature, structure, material, or characteristic described in connection with the embodiment or example is included in at least one embodiment or example of the invention. In this specification, the schematic representations of the terms used above are not necessarily intended to refer to the same embodiment or example. Furthermore, the particular features, structures, materials, or characteristics described may be combined in any suitable manner in any one or more embodiments or examples. Furthermore, various embodiments or examples and features of different embodiments or examples described in this specification can be combined and combined by one skilled in the art without contradiction.
In the present invention, the expression "compound a" and "compound represented by formula a" means the same compound.
In the invention, the room temperature refers to the ambient temperature and is 15-35 ℃, or 20-30 ℃, or 25-28 ℃.
In the present invention, the Jones reagent refers to a mixture of chromium trioxide, sulfuric acid and water, and may have any suitable concentration.
Detailed Description
In order to make the technical solutions of the present invention better understood by those skilled in the art, some non-limiting examples are further disclosed below, and the present invention is further described in detail.
The reagents used in the present invention are either commercially available or can be prepared by the methods described herein.
In the present invention, mmol means mmol, h means hour, min means minute, g means g, ml means ml, DMF means N, N-dimethylformamide, THF means tetrahydrofuran, DCM means dichloromethane, EA means ethyl acetate, Bn means benzyl.
ee: enantiomeric excess (enantiomeric excess).
LC-MS: liquid phase-mass spectrometry.
In the present invention, when the remaining amount of the reactant is less than 5%, or 2%, or 1%, or 0.5%, or 0.1% of the charged amount thereof, the reaction is considered to be completed, and the remaining amount can be detected by High Performance Liquid Chromatography (HPLC) or other suitable method.
EXAMPLE 1 preparation of Compound C
20.0g L-hydroxyproline, 32.0g of sodium bicarbonate and 300.0mL of water are added into a 500mL single-neck flask and stirred uniformly at room temperature; a solution of 30.0g of benzyl chloroformate in 60.0mL of toluene was added dropwise, and the mixture was stirred at room temperature for 16 hours after the addition. Stopping the reaction, standing for layering, separating out an organic phase, washing an aqueous phase twice with 50mL of diethyl ether, adjusting the pH of the system to 2 with concentrated hydrochloric acid, extracting with 250mL of EA for three times, combining the organic phases, drying with anhydrous sodium sulfate, filtering, and concentrating under reduced pressure to obtain an oily compound A: 37.3g, HPLC content: 97.8 percent; the yield thereof was found to be 90.2%.
7.82g of Compound A (HPLC content: 97.8%) is dissolved in 420mL of acetone, 12mL of prepared 2mol/L Jones reagent is added dropwise, the mixture is stirred at room temperature for 0.5h, after the reaction is finished, the mixture is concentrated to dryness under reduced pressure, 200mL of chloroform is added into the obtained product to be dissolved, an organic phase is washed 4 times with water, the organic phase is dried and filtered, and the filtrate is concentrated to dryness to obtain an oily compound B: 7.56g, HPLC content: 93.2 percent; the yield thereof was found to be 92.8%.
4.18g of Compound B (HPLC content: 93.2%) is dissolved in 40mL of THF, 7.82g of benzyl bromide and 1.35g of triethylamine are added dropwise and stirred at room temperature for 18h, the reaction mixture is concentrated to dryness, 100mL of dichloromethane are added and dissolved, 20mL of 4mol/L dilute hydrochloric acid is used for washing once, then anhydrous sodium sulfate is used for drying, filtration is carried out, and the filtrate is concentrated to obtain oily compound C: 5.21g, HPLC content: 98.4 percent; the yield thereof was found to be 98.2%.
EXAMPLE 2 preparation of Compound D
3.83g of Compound C (HPLC content: 98.4%) are dissolved in 100mL of toluene, 1.76g S-methylbenzylamine is added dropwise, after the addition is complete, the temperature is raised to 110 ℃ and stirring is carried out with heat preservation for 18 h. Cooling to room temperature, and then concentrating the reaction system under reduced pressure to obtain an oily compound D: 4.89g, HPLC content: 96.7% and a yield of 96.9%.
LC-MS:[M+1]＝457.1；1H-NMR(400MHZ):δ7.37-7.23(m,15H),5.31(s,2H),5.13(s,2H),4.43-4.53(m,1H),3.52-3.69(m,5H),1.32(m,3H)。
EXAMPLE 3 preparation of Compound E
3.97g of Compound D (HPLC content: 96.7%) was dissolved in 40mL of THF, 7.50g of pyridine was added, and after stirring at room temperature for 30min, 2.26g of acryloyl chloride was added dropwise, and after the addition, the system was warmed to 70 ℃ and stirred at the same temperature for 2 hours. Concentrating the reaction system under reduced pressure to dryness, then adding 100mL of ethyl acetate to dissolve, washing with 1mol/L diluted hydrochloric acid (100mL multiplied by 4), drying the organic phase, filtering, and concentrating the filtrate to obtain an oily compound E: 4.02g, HPLC content: 96.3 percent; yield: 90.2 percent.
LC-MS:[M+1]＝511.2；1H-NMR(400MHZ):δ7.39-7.21(m,15H),5.3(s,2H),5.1(s,2H),4.63(s,1H),4.53-4.48(m,1H),3.69(s,2H),2.34-2.23(m,4H),1.31(m,3H)。
EXAMPLE 4 preparation of Compound F
3.0g of Compound E (HPLC content: 96.3%) are dissolved in 50mL of tetrahydrofuran, 0.61g of lithium aluminum hydride is added, the system is warmed to 50 ℃ and stirred for 10h with constant temperature. After the reaction, the reaction mixture was cooled to 0 ℃ and slowly quenched with 5mL of water. 20mL of a 2mol/L aqueous solution of sodium hydroxide was added, the system was extracted with ethyl acetate (50 mL. times.3), the combined organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to give an oil F: 2.67g, HPLC content: 93.5 percent; yield: 88.8 percent.
LC-MS:[M+1]＝497.1；1H-NMR(400MHZ):δ7.36-7.17(m,15H),5.32(s,2H),5.13(s,2H),4.63(s,1H),4.53-4.43(m,1H),3.69(s,2H),2.34-2.00(m,6H),1.31(m,3H)。
EXAMPLE 5 preparation of Compound G
2.0g of Compound F (HPLC content: 93.5%) are dissolved in 50mL of cyclohexanone, and the system is warmed to 150 ℃ and stirred for 10h with constant temperature. After the reaction was complete, the system was decompressed to give oil G: 1.31g, HPLC content: 96.1 percent; yield: 92.6 percent.
LC-MS:[M+1]＝363.1；1H-NMR(400MHZ):δ7.36-7.17(m,10H),5.32(s,2H),4.53-4.43(m,1H),3.69-3.50(m,4H),2.34-2.00(m,6H),1.31(m,3H)。
EXAMPLE 6 preparation of Compound H
2.0G of Compound G (HPLC content: 95.8%) was dissolved in 50mL of ethanol, 0.2G of Raney nickel was added, the air in the system was replaced with nitrogen, then with hydrogen for 3 times, and then, under a hydrogen atmosphere of 1MPa, the mixture was heated under reflux and stirred for about 24 hours. After the reaction was complete, filtration was carried out and the filtrate was concentrated to give oil H: 1.96g, HPLC content: 97.3%, e.e. 99.4%; yield: 99.3 percent.
LC-MS:[M+1]＝365.2；1H-NMR(400MHZ):δ7.36-7.17(m,10H),5.32(s,2H),4.53-4.43(m,1H),3.69-3.50(m,4H),2.73-2.64(m,1H),2.34-2.00(m,6H),1.71-1.64(m,1H),1.31(m,3H)。
EXAMPLE 7 preparation of Compound I
2.0g of Compound H (HPLC content: 97.0%) was dissolved in 50mL of ethanol, 0.2g of 10% Pd/C was added, the air in the system was replaced with nitrogen, and then with hydrogen for 3 times, followed by heating under reflux and stirring under 1MPa for about 16 hours. After the reaction was complete, filtration was carried out and the filtrate was concentrated to give oil I: 0.66g, HPLC content: 99.1%, ee ═ 99.92%; yield: 97.6 percent.
While the methods of the present invention have been described in terms of preferred embodiments, it will be apparent to those of ordinary skill in the art that variations and modifications of the methods and applications described herein, as well as other suitable variations and combinations, may be made to implement and use the techniques of the present invention within the context, spirit and scope of the invention. Those skilled in the art can modify the process parameters appropriately to achieve the desired results with reference to the disclosure herein. It is expressly intended that all such similar substitutes and modifications which would be obvious to those skilled in the art are deemed to be included within the invention.
Claims (10)
1. A method of preparation comprising at least one of the following reaction steps:
the compound C and the compound 01 are subjected to addition elimination reaction to prepare a compound D
The compound D and the compound 02 are subjected to cyclization reaction to prepare a compound E
The compound E is subjected to reduction reaction to prepare a compound F
The compound F is subjected to decarboxylation reaction to prepare a compound G
The compound G is subjected to hydrogenation reaction to obtain a compound H
Wherein R is1Is hydrogen, or R1A protecting group for amino group selected from: optionally substituted phenyl, optionally substituted benzyl, phenyl, p-methoxyphenyl, benzyl, p-methylbenzyl, benzyloxycarbonyl, or optionally substituted benzyloxycarbonyl.
2. The production method according to claim 1, wherein in the addition elimination reaction, the reaction solvent is at least one of toluene, xylene, tetrahydrofuran, methyltetrahydrofuran, dichloromethane, chloroform, cyclohexane, and n-hexane; or in the cyclization reaction, the reaction solvent is at least one of THF, methyltetrahydrofuran, chloroform, dichloromethane and toluene; or the reaction solvent of the hydrogenation reaction is at least one of ethanol, isopropanol, methanol, tert-butanol and THF.
3. The production method according to claim 1, wherein, in the addition elimination reaction, the reaction temperature is 20 ℃ to 140 ℃; or the reaction temperature of the cyclization reaction is 20-120 ℃; or the temperature of the reduction reaction is-5 ℃ to 80 ℃; or the reaction temperature of the decarboxylation reaction is 60-180 ℃; or the reaction temperature of the hydrogenation reaction is 20-100 ℃.
4. The preparation method according to claim 1, wherein the feeding molar ratio of the compound C to the compound 01 is 1:1-1: 2; or the feeding molar ratio of the compound D to the compound 02 is 1:1-1: 5; or the molar ratio of the compound E to the reducing agent is 1:0.1-1: 20.
5. The preparation method according to claim 1, wherein in the cyclization reaction, a base reagent is added, and the base reagent is at least one of pyridine, triethylamine, N-diisopropylethylamine and DBU; or adding an alkali reagent in the cyclization reaction, wherein the feeding molar ratio of the compound D to the alkali reagent is 1:1-1: 20.
6. The preparation method according to claim 1, wherein the reducing agent in the reduction reaction is at least one of lithium aluminum hydride, sodium borohydride, lithium borohydride and borane.
7. The preparation method according to claim 1, wherein after the cyclization reaction is completed, a post-treatment is performed to obtain a compound E, and the post-treatment comprises: concentrating the reaction system to dryness, adding an extraction solvent, and adjusting the pH to 3-4 with an acid; then drying the organic phase, filtering and concentrating to obtain a compound E; or after the reduction reaction is finished, performing post-treatment to obtain a compound F, wherein the post-treatment comprises the following steps: cooling the reaction liquid to-5-25 ℃, adding water, then adjusting the pH value to 9-14 by using sodium hydroxide, extracting by using an extraction solvent, drying the organic phase, filtering and concentrating to obtain a compound F.
8. The process according to claim 1, wherein cyclohexanone is added in the decarboxylation in an amount of 1 to 50mL per gram of the compound F.
9. The method of any one of claims 1-8, further comprising: compound 00 and R1-X reaction to produce compound a; reacting the compound A with a Jones reagent to prepare a compound B; the compound B reacts with Bn-X to prepare a compound C
wherein R is1As defined in claim 1; x is chlorine or bromine.
10. The process according to any one of claims 1 to 9, wherein R is1Is benzyloxycarbonyl.
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| CN107793414A (en) * | 2016-09-06 | 2018-03-13 | 上虞京新药业有限公司 | The synthetic method of (S, S) 2,8 diazabicyclo [4.3.0] nonane |
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| US4296113A (en) * | 1980-01-14 | 1981-10-20 | E. R. Squibb & Sons, Inc. | Mercaptoacyl derivatives of keto substituted proline and pipecolic acid |
| US4734508A (en) * | 1987-05-01 | 1988-03-29 | E. R. Squibb & Sons, Inc. | Process and intermediates for preparing 4-substituted proline derivatives |
| CN103044418A (en) * | 2011-10-14 | 2013-04-17 | 上海朴颐化学科技有限公司 | Asymmetric synthesis method, relevant raw materials and preparation method of (S,S)-2,8-diazabicyclo[4,3,0] nonane |
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