CN111362852A - Preparation method of drug intermediate 1-tert-butyloxycarbonyl-3-azetidinone - Google Patents
Preparation method of drug intermediate 1-tert-butyloxycarbonyl-3-azetidinone Download PDFInfo
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- CN111362852A CN111362852A CN201811588971.7A CN201811588971A CN111362852A CN 111362852 A CN111362852 A CN 111362852A CN 201811588971 A CN201811588971 A CN 201811588971A CN 111362852 A CN111362852 A CN 111362852A
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- 238000002360 preparation method Methods 0.000 title claims abstract description 20
- VMKIXWAFFVLJCK-UHFFFAOYSA-N tert-butyl 3-oxoazetidine-1-carboxylate Chemical compound CC(C)(C)OC(=O)N1CC(=O)C1 VMKIXWAFFVLJCK-UHFFFAOYSA-N 0.000 title abstract description 19
- 239000003814 drug Substances 0.000 title description 7
- 229940079593 drug Drugs 0.000 title description 4
- 238000006243 chemical reaction Methods 0.000 claims abstract description 16
- 238000000034 method Methods 0.000 claims abstract description 16
- 239000002253 acid Substances 0.000 claims abstract description 14
- 150000007522 mineralic acids Chemical class 0.000 claims abstract description 11
- 150000007524 organic acids Chemical class 0.000 claims abstract description 11
- 238000004519 manufacturing process Methods 0.000 claims abstract description 6
- 150000001875 compounds Chemical class 0.000 claims description 49
- -1 diazabicyclo Natural products 0.000 claims description 24
- DYHSDKLCOJIUFX-UHFFFAOYSA-N tert-butoxycarbonyl anhydride Chemical compound CC(C)(C)OC(=O)OC(=O)OC(C)(C)C DYHSDKLCOJIUFX-UHFFFAOYSA-N 0.000 claims description 22
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical group CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 21
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 claims description 18
- WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 claims description 12
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 claims description 12
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims description 12
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 12
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 12
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 claims description 12
- NLKNQRATVPKPDG-UHFFFAOYSA-M potassium iodide Chemical compound [K+].[I-] NLKNQRATVPKPDG-UHFFFAOYSA-M 0.000 claims description 12
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 10
- 150000007529 inorganic bases Chemical class 0.000 claims description 9
- 150000007530 organic bases Chemical group 0.000 claims description 9
- FVAUCKIRQBBSSJ-UHFFFAOYSA-M sodium iodide Chemical compound [Na+].[I-] FVAUCKIRQBBSSJ-UHFFFAOYSA-M 0.000 claims description 9
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 8
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 claims description 8
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 claims description 8
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 8
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims description 8
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 claims description 8
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical group [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 8
- YGSDEFSMJLZEOE-UHFFFAOYSA-N salicylic acid Chemical compound OC(=O)C1=CC=CC=C1O YGSDEFSMJLZEOE-UHFFFAOYSA-N 0.000 claims description 8
- MFRIHAYPQRLWNB-UHFFFAOYSA-N sodium tert-butoxide Chemical compound [Na+].CC(C)(C)[O-] MFRIHAYPQRLWNB-UHFFFAOYSA-N 0.000 claims description 8
- QAIPRVGONGVQAS-DUXPYHPUSA-N trans-caffeic acid Chemical compound OC(=O)\C=C\C1=CC=C(O)C(O)=C1 QAIPRVGONGVQAS-DUXPYHPUSA-N 0.000 claims description 8
- GETQZCLCWQTVFV-UHFFFAOYSA-N trimethylamine Chemical compound CN(C)C GETQZCLCWQTVFV-UHFFFAOYSA-N 0.000 claims description 8
- 235000015165 citric acid Nutrition 0.000 claims description 6
- IOLCXVTUBQKXJR-UHFFFAOYSA-M potassium bromide Chemical compound [K+].[Br-] IOLCXVTUBQKXJR-UHFFFAOYSA-M 0.000 claims description 6
- JHJLBTNAGRQEKS-UHFFFAOYSA-M sodium bromide Chemical compound [Na+].[Br-] JHJLBTNAGRQEKS-UHFFFAOYSA-M 0.000 claims description 6
- UKVIEHSSVKSQBA-UHFFFAOYSA-N methane;palladium Chemical compound C.[Pd] UKVIEHSSVKSQBA-UHFFFAOYSA-N 0.000 claims description 5
- 238000007363 ring formation reaction Methods 0.000 claims description 5
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 5
- ACEAELOMUCBPJP-UHFFFAOYSA-N (E)-3,4,5-trihydroxycinnamic acid Natural products OC(=O)C=CC1=CC(O)=C(O)C(O)=C1 ACEAELOMUCBPJP-UHFFFAOYSA-N 0.000 claims description 4
- BJEPYKJPYRNKOW-REOHCLBHSA-N (S)-malic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O BJEPYKJPYRNKOW-REOHCLBHSA-N 0.000 claims description 4
- 239000005711 Benzoic acid Substances 0.000 claims description 4
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 claims description 4
- FEWJPZIEWOKRBE-UHFFFAOYSA-N Tartaric acid Natural products [H+].[H+].[O-]C(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-N 0.000 claims description 4
- BJEPYKJPYRNKOW-UHFFFAOYSA-N alpha-hydroxysuccinic acid Natural products OC(=O)C(O)CC(O)=O BJEPYKJPYRNKOW-UHFFFAOYSA-N 0.000 claims description 4
- 229910000147 aluminium phosphate Inorganic materials 0.000 claims description 4
- 150000003863 ammonium salts Chemical class 0.000 claims description 4
- 235000010233 benzoic acid Nutrition 0.000 claims description 4
- FJDQFPXHSGXQBY-UHFFFAOYSA-L caesium carbonate Chemical compound [Cs+].[Cs+].[O-]C([O-])=O FJDQFPXHSGXQBY-UHFFFAOYSA-L 0.000 claims description 4
- 229910000024 caesium carbonate Inorganic materials 0.000 claims description 4
- 229940074360 caffeic acid Drugs 0.000 claims description 4
- 235000004883 caffeic acid Nutrition 0.000 claims description 4
- 239000003054 catalyst Substances 0.000 claims description 4
- QAIPRVGONGVQAS-UHFFFAOYSA-N cis-caffeic acid Natural products OC(=O)C=CC1=CC=C(O)C(O)=C1 QAIPRVGONGVQAS-UHFFFAOYSA-N 0.000 claims description 4
- 229910052736 halogen Inorganic materials 0.000 claims description 4
- 150000002367 halogens Chemical class 0.000 claims description 4
- 239000001630 malic acid Substances 0.000 claims description 4
- 235000011090 malic acid Nutrition 0.000 claims description 4
- 235000006408 oxalic acid Nutrition 0.000 claims description 4
- FJKROLUGYXJWQN-UHFFFAOYSA-N papa-hydroxy-benzoic acid Natural products OC(=O)C1=CC=C(O)C=C1 FJKROLUGYXJWQN-UHFFFAOYSA-N 0.000 claims description 4
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 4
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 claims description 4
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 4
- 229960004889 salicylic acid Drugs 0.000 claims description 4
- 239000011975 tartaric acid Substances 0.000 claims description 4
- 235000002906 tartaric acid Nutrition 0.000 claims description 4
- 235000009518 sodium iodide Nutrition 0.000 claims description 3
- 239000002585 base Substances 0.000 claims 6
- 239000003513 alkali Substances 0.000 claims 3
- 238000013341 scale-up Methods 0.000 abstract 1
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 21
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 15
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 15
- 238000003756 stirring Methods 0.000 description 12
- 239000010410 layer Substances 0.000 description 11
- VMENWOKQWSVFKS-UHFFFAOYSA-N 3,3-dimethoxyazetidine Chemical compound COC1(OC)CNC1 VMENWOKQWSVFKS-UHFFFAOYSA-N 0.000 description 10
- 239000000203 mixture Substances 0.000 description 8
- 239000012044 organic layer Substances 0.000 description 7
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 6
- XPRVSYXHPUYSGF-UHFFFAOYSA-N azetidin-3-one Chemical compound O=C1CNC1 XPRVSYXHPUYSGF-UHFFFAOYSA-N 0.000 description 6
- 239000000706 filtrate Substances 0.000 description 6
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 6
- 238000005160 1H NMR spectroscopy Methods 0.000 description 5
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 5
- 239000000243 solution Substances 0.000 description 5
- 230000015572 biosynthetic process Effects 0.000 description 4
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 4
- 229910052739 hydrogen Inorganic materials 0.000 description 4
- 238000003786 synthesis reaction Methods 0.000 description 4
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 4
- 201000010099 disease Diseases 0.000 description 3
- 239000003651 drinking water Substances 0.000 description 3
- 235000020188 drinking water Nutrition 0.000 description 3
- 238000001035 drying Methods 0.000 description 3
- 238000010438 heat treatment Methods 0.000 description 3
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 3
- 235000017557 sodium bicarbonate Nutrition 0.000 description 3
- KTWNITKLQPCZSL-UHFFFAOYSA-N 1,3-dichloro-2,2-dimethylpropane Chemical compound ClCC(C)(C)CCl KTWNITKLQPCZSL-UHFFFAOYSA-N 0.000 description 2
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 2
- 208000004476 Acute Coronary Syndrome Diseases 0.000 description 2
- 241000218236 Cannabis Species 0.000 description 2
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 2
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 2
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 2
- 206010028980 Neoplasm Diseases 0.000 description 2
- 102000032626 PAR-1 Receptor Human genes 0.000 description 2
- 108010070519 PAR-1 Receptor Proteins 0.000 description 2
- 230000003321 amplification Effects 0.000 description 2
- 230000008901 benefit Effects 0.000 description 2
- WGQKYBSKWIADBV-UHFFFAOYSA-N benzylamine Chemical compound NCC1=CC=CC=C1 WGQKYBSKWIADBV-UHFFFAOYSA-N 0.000 description 2
- 125000002619 bicyclic group Chemical group 0.000 description 2
- 201000011510 cancer Diseases 0.000 description 2
- 239000000460 chlorine Substances 0.000 description 2
- 229910052801 chlorine Inorganic materials 0.000 description 2
- 238000001816 cooling Methods 0.000 description 2
- 238000002425 crystallisation Methods 0.000 description 2
- 230000008025 crystallization Effects 0.000 description 2
- 238000004090 dissolution Methods 0.000 description 2
- FMPNFDSPHNUFOS-LPJDIUFZSA-N himbacine Chemical compound C(/[C@@H]1[C@H]2CCCC[C@@H]2C[C@@H]2C(=O)O[C@H]([C@H]12)C)=C\[C@H]1CCC[C@H](C)N1C FMPNFDSPHNUFOS-LPJDIUFZSA-N 0.000 description 2
- 239000001257 hydrogen Substances 0.000 description 2
- 208000027866 inflammatory disease Diseases 0.000 description 2
- 238000003199 nucleic acid amplification method Methods 0.000 description 2
- 238000004321 preservation Methods 0.000 description 2
- 238000000746 purification Methods 0.000 description 2
- 239000011541 reaction mixture Substances 0.000 description 2
- 229920006395 saturated elastomer Polymers 0.000 description 2
- 238000000926 separation method Methods 0.000 description 2
- 239000002904 solvent Substances 0.000 description 2
- 238000000967 suction filtration Methods 0.000 description 2
- SNBYDHCSBZIOQL-UHFFFAOYSA-N 3-hydroxyazetidine-1-carboxylic acid Chemical compound OC1CN(C(O)=O)C1 SNBYDHCSBZIOQL-UHFFFAOYSA-N 0.000 description 1
- 208000023275 Autoimmune disease Diseases 0.000 description 1
- FMPNFDSPHNUFOS-HQEQRHKESA-N Himbacine Natural products C(/[C@@H]1[C@H]2CCCC[C@@H]2C[C@@H]2C(=O)O[C@H]([C@H]12)C)=C\[C@@H]1CCC[C@H](C)N1C FMPNFDSPHNUFOS-HQEQRHKESA-N 0.000 description 1
- 206010062016 Immunosuppression Diseases 0.000 description 1
- 102000006500 Janus Kinase 3 Human genes 0.000 description 1
- 108010019421 Janus Kinase 3 Proteins 0.000 description 1
- FMPNFDSPHNUFOS-UHFFFAOYSA-N N-Methyl-himandravin Natural products C12C(C)OC(=O)C2CC2CCCCC2C1C=CC1CCCC(C)N1C FMPNFDSPHNUFOS-UHFFFAOYSA-N 0.000 description 1
- 208000005764 Peripheral Arterial Disease Diseases 0.000 description 1
- 208000030831 Peripheral arterial occlusive disease Diseases 0.000 description 1
- 206010043647 Thrombotic Stroke Diseases 0.000 description 1
- 206010052779 Transplant rejections Diseases 0.000 description 1
- 229940126575 aminoglycoside Drugs 0.000 description 1
- 239000005557 antagonist Substances 0.000 description 1
- 230000000844 anti-bacterial effect Effects 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 239000006227 byproduct Substances 0.000 description 1
- MGHPNCMVUAKAIE-UHFFFAOYSA-N diphenylmethanamine Chemical compound C=1C=CC=CC=1C(N)C1=CC=CC=C1 MGHPNCMVUAKAIE-UHFFFAOYSA-N 0.000 description 1
- 229940042399 direct acting antivirals protease inhibitors Drugs 0.000 description 1
- 208000035475 disorder Diseases 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 230000007613 environmental effect Effects 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 1
- 230000001506 immunosuppresive effect Effects 0.000 description 1
- 239000012535 impurity Substances 0.000 description 1
- 208000015181 infectious disease Diseases 0.000 description 1
- 229960000367 inositol Drugs 0.000 description 1
- 150000002576 ketones Chemical class 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 208000010125 myocardial infarction Diseases 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- IJGRMHOSHXDMSA-UHFFFAOYSA-N nitrogen Substances N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 1
- CTSLXHKWHWQRSH-UHFFFAOYSA-N oxalyl chloride Chemical compound ClC(=O)C(Cl)=O CTSLXHKWHWQRSH-UHFFFAOYSA-N 0.000 description 1
- 238000007254 oxidation reaction Methods 0.000 description 1
- 239000000137 peptide hydrolase inhibitor Substances 0.000 description 1
- 150000008518 pyridopyrimidines Chemical class 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 108091006082 receptor inhibitors Proteins 0.000 description 1
- 238000007789 sealing Methods 0.000 description 1
- 230000009863 secondary prevention Effects 0.000 description 1
- XRRXRQJQQKMFBC-UHFFFAOYSA-N tert-butyl 3-hydroxyazetidine-1-carboxylate Chemical compound CC(C)(C)OC(=O)N1CC(O)C1 XRRXRQJQQKMFBC-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D205/00—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom
- C07D205/02—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings
- C07D205/06—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D205/00—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom
- C07D205/02—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings
- C07D205/04—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings having no double bonds between ring members or between ring members and non-ring members
-
- 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)
- Plural Heterocyclic Compounds (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention relates to the technical field of organic chemistry, in particular to a preparation method of 1-tert-butyloxycarbonyl-3-azetidinone and derivatives thereof, which has the following reaction formula:
wherein R is1Is C1‑C6Alkyl radical, R2And R3Is H or C1‑C6And the acid is organic acid or inorganic acid. The method has high relative yield and strong applicability in industrial scale-up production.
Description
Technical Field
The invention relates to the field of medicine synthesis, in particular to a preparation method of a medicine intermediate 1-tert-butyloxycarbonyl-3-azacyclobutanone.
Background
1-Boc-3-azetidinone is a currently common organic intermediate (CAS: 398489-26-4). It is a key intermediate for preparing various medicaments. It can be used for preparing Janus kinase 3(JAKS), which is a useful target for immunosuppression and transplant rejection, and can be used for treating inflammatory disorders, autoimmune disorders, cancer and other diseases; also useful in the preparation of a second class of HCV protease inhibitors useful in the treatment of HCV genotype 1 infection; can also be used for preparing novel aminoglycoside compounds with antibacterial activity; bicyclic himbacine (himbacine) derivatives can be prepared which are useful as antagonists of the protease activated receptor-1 (PAR-1) and are predicted to be cannabis (CB2) receptor inhibitors, useful for the treatment of secondary prevention of Acute Coronary Syndrome (ACS), myocardial infarction or thrombotic stroke or peripheral arterial disease; bicyclic azacyclobenzylamine derivatives, such as pyridopyrimidines, can be prepared that modulate the activity of phospho-inositol 3-kinase (P13K) and are useful in the treatment of diseases associated with P13K, including, for example, inflammatory disorders, immune-based disorders, cancer, and other diseases. For example, WO2013134012, merck, filed on day 27, 2.2013, discloses a route to a new class of bicyclobacine derivatives from 1-tert-butoxycarbonyl-3-azetidinone.
The traditional preparation method of 1-tert-butyloxycarbonyl-3-azetidinone is mainly to oxidize the hydroxyl on an aza ring into ketone. For example, the chinese patent CN103524392(P165) filed by eckeli hiss gmbh on 5/10/2006 discloses the following route: 3-azetidinium alkoxide, di-tert-butyl dicarbonate and sodium bicarbonate in dioxane: stirring the mixture of water for 15 hours to obtain 3-hydroxyazetidine-1-carboxylic acid-1, 1-dimethylethyl ester; dissolving 3-hydroxyazetidine-1-carboxylic acid-1, 1-dimethyl ethyl ester in ethanedioyl chloride and dichloromethane, adding DMSO and triethylamine, stirring at room temperature for 15 hours to obtain 1-tert-butyloxycarbonyl-3-azetidinone.
The reaction is easy to generate impurities, so that the yield is not high, and the solvents of dioxane and DMSO are not environment-friendly.
Patent CN102026999, filed on 3.10.2009 by the company nesota, discloses the following route:
in the reaction, the cost of the raw material of the benzhydrylamine is high, and a plurality of byproducts are generated; the oxidation reaction has higher requirements on the treatment of three wastes in environmental protection.
The report of the preparation method for obtaining the 1-tert-butoxycarbonyl-3-azetidinone by removing the bismethoxy on the nitrogen heterocycle is basically in a blank state, and the method has the advantages of simple operation, relatively higher yield and strong applicability in industrial amplification production. The method brings great help to the economic benefit of the drug synthesis and the operation process.
Disclosure of Invention
In order to solve the technical problems that the preparation of a key drug intermediate 1-tert-butyloxycarbonyl-3-azetidinone is complex and difficult to industrialize and the like, the invention provides a preparation method of a compound shown in a formula III, the compound is prepared by a cyclization reaction of a compound shown in a formula II and ammonium salt, and the technical scheme is as follows;
wherein R is1Is C1-C6Alkyl radical, R1Methyl groups may be preferred.
Wherein R is2And R3Is H or C1-C6Alkyl radical, R2And R3H may be preferred.
Wherein R is4Is benzyl or substituted benzyl, R4Benzyl may be preferred.
R5And R6Is halogen, R5And R6Chlorine may be preferred.
The cyclization reaction is carried out in the presence of a catalyst,
the catalyst is selected from sodium bromide, potassium bromide, sodium iodide and potassium iodide.
In a second aspect, the invention provides a method for preparing a compound of formula IV, which is prepared from a compound of formula III under palladium-carbon conditions,
wherein R is1Is C1-C6Alkyl radical, R1Methyl groups may be preferred.
Wherein R is2And R3Is H or C1-C6Alkyl radical, R2And R3H may be preferred.
Wherein R is4Is benzyl or substituted benzyl, R4Benzyl may be preferred.
In a third aspect, the invention provides a process for preparing a compound of formula V by reacting a compound of formula IV with Boc anhydride in the presence of a base,
wherein R is1Is C1-C6Alkyl radical, R1Methyl groups may be preferred.
Wherein R is2And R3Is H or C1-C6Alkyl radical, R2And R3H may be preferred.
The base is organic base or inorganic base, the organic base is selected from triethylamine, trimethylamine, diisopropylethylamine, diazabicyclo, pyridine and imidazole, and the inorganic base is selected from potassium carbonate, sodium carbonate, cesium carbonate, potassium hydroxide, sodium hydroxide, lithium hydroxide, potassium tert-butoxide and sodium tert-butoxide.
In a fourth aspect, the present invention provides a process for the preparation of a compound of formula VI from a compound of formula IV in the presence of an acid,
wherein R is1Is C1-C6Alkyl radical, R1Methyl groups may be preferred.
Wherein R is2And R3Is H or C1-C6Alkyl radical, R2And R3H may be preferred.
The acid is organic acid or inorganic acid, the organic acid is selected from tartaric acid, oxalic acid, malic acid, citric acid, benzoic acid, salicylic acid and caffeic acid, and the inorganic acid is selected from hydrochloric acid, sulfuric acid and phosphoric acid.
In a fifth aspect, the present invention provides a process for the preparation of a compound of formula I, prepared from a compound of formula V:
wherein R is1Is C1-C6Alkyl radical, R1Methyl groups may be preferred.
Wherein R is2And R3Is H or C1-C6Alkyl radical, R2And R3H may be preferred.
The acid is organic acid or inorganic acid, the organic acid is selected from tartaric acid, oxalic acid, malic acid, citric acid, benzoic acid, salicylic acid and caffeic acid, and the inorganic acid is selected from hydrochloric acid, sulfuric acid and phosphoric acid.
In a sixth aspect, the present invention provides a process for preparing a compound of formula I, prepared by reacting a compound of formula VI with Boc anhydride in the presence of a base:
wherein R is2And R3Is H or C1-C6Alkyl radical, R2And R3H may be preferred.
The base is organic base or inorganic base, the organic base is selected from triethylamine, trimethylamine, diisopropylethylamine, diazabicyclo, pyridine and imidazole, and the inorganic base is selected from potassium carbonate, sodium carbonate, cesium carbonate, potassium hydroxide, sodium hydroxide, lithium hydroxide, potassium tert-butoxide and sodium tert-butoxide.
In a seventh aspect, the present invention provides a process for the preparation of a compound of formula I, comprising the steps of: 1) preparing a compound shown in a formula III by a cyclization reaction of a compound shown in a formula II and ammonium salt; 2) preparing a compound of formula IV from a compound of formula III under palladium-carbon conditions, 3) reacting the compound of formula IV with Boc anhydride in the presence of a base to prepare a compound of formula V, and then preparing the compound of formula V under the presence of an acid, or preparing a compound of formula VI from a compound of formula IV under the presence of an acid, and then reacting the compound of formula VI with Boc anhydride in the presence of a base, wherein the reaction formula is as follows:
wherein R is1Is C1-C6Alkyl radical, R1Methyl groups may be preferred.
Wherein R is2And R3Is H or C1-C6Alkyl radical, R2And R3H may be preferred.
Wherein R is4Is benzyl or substituted benzyl, R4Benzyl may be preferred.
R5And R6Is halogen, R5And R6Chlorine may be preferred.
The acid is organic acid or inorganic acid, the organic acid is selected from tartaric acid, oxalic acid, malic acid, citric acid, benzoic acid, salicylic acid and caffeic acid, and the inorganic acid is selected from hydrochloric acid, sulfuric acid and phosphoric acid.
The base is organic base or inorganic base, the organic base is selected from triethylamine, trimethylamine, diisopropylethylamine, diazabicyclo, pyridine and imidazole, and the inorganic base is selected from potassium carbonate, sodium carbonate, cesium carbonate, potassium hydroxide, sodium hydroxide, lithium hydroxide, potassium tert-butoxide and sodium tert-butoxide.
The catalyst is selected from sodium bromide, potassium bromide, sodium iodide and potassium iodide.
The 1-tert-butoxycarbonyl-3-azetidinone prepared by the method has relatively high yield and strong applicability in industrial amplification production.
Detailed Description
For better understanding of the present invention, the following description is given with reference to specific examples, but the present invention is not limited to the specific embodiments.
Example 1: preparation of 1-benzyl-3, 3-dimethoxy-azetidine (IIIa)
DMF50ml was put into a 250ml dry and clean four-necked flask A, 1, 3-dichloro-2, 2-dimethylpropane (IIa) (20g, 115.6mmol), potassium iodide (1g, 6mmol) and sodium carbonate (9.9g, 93mmol) were put into the flask with stirring, and after stirring for 30 minutes, a mixture of DMF50ml and benzylamine (12.4g, 116mmol) was added dropwise, and the mixture was heated to 50-100 ℃ and incubated for 6-12 hours to terminate the control reaction.
Adding 100ml of domestic drinking water into 500ml of dry and clean four-mouth bottle B, dropwise adding the reaction solution in the four-mouth bottle A, stirring for 20-30 minutes after dropwise adding, extracting the water layer for 3 times by using 50ml of ethyl acetate x 3, combining the organic layers, drying by using anhydrous sodium sulfate (20g), filtering, and concentrating the filtrate to obtain 13.9g of 1-benzyl-3, 3-dimethoxy-azetidine (IIIa) with the yield of 58%.
The 1-benzyl-3, 3-dimethoxy-azetidine (IIIa) was used in the next synthesis without purification.
Example 2: preparation of 3, 3-dimethoxy-azetidine (IVa)
Putting 1-benzyl-3, 3-dimethoxy-azetidine (IIIa) (10g, 48.2mmol), ethanol (50ml) and palladium carbon (0.1g) into a 150ml autoclave, sealing the autoclave, replacing with hydrogen for 3 times, pressurizing the autoclave with hydrogen at 0.1-0.5MPa, stirring, heating to 60-80 ℃, keeping the temperature for reaction for 6-10 hours, and finishing the central control reaction.
The reaction was filtered and the filtrate was concentrated to give 3, 3-dimethoxy-azetidine (IVa) as an oil, 5.0g, yield: 89 percent.
3, 3-dimethoxy-azetidine (IVa) was used in the next synthesis without purification.
1H NMR(400MHz，DMSO):δ3.16(s，6H)，3.98[t(J＝6.4Hz)，4H]，8.93 (br,H)。
Example 3: preparation of 1-tert-Butoxycarbonyl-3, 3-dimethoxy-azetidine (Va)
Into a 250ml four-necked flask were charged 3, 3-dimethoxy-azetidine (IVa) (10g, 85.4mmol) and 50ml of methylene chloride, and triethylamine (12.9g, 128.1mmol) was added under stirring, and di-tert-butyl dicarbonate (22.3g, 102.5mmol) was added dropwise at an internal temperature of 10 to 40 ℃ to terminate the dropwise addition, followed by stirring at 10 to 40 ℃ for 3 to 4 hours. And finishing the control reaction.
To the reaction mixture was added 20ml of water, and the mixture was stirred for 5 minutes, followed by separation of layers, and the upper aqueous layer was extracted once with methylene chloride (20 ml). The organic layers were combined and washed once with 30ml of drinking water. The layers were separated and the lower organic layer was dried over anhydrous sodium sulfate (20g) for 0.5 h, filtered and the filtrate was concentrated to give 16.9g of 1-tert-butoxycarbonyl-3, 3-dimethoxy-azetidine (Va) at 91% yield.
1H NMR(400MHz，DMSO):δ3.13(s，6H)，3.78(s，4H),1.38(s,9H)。
Example 4: preparation of azetidin-3-one (VIa)
Into a 250ml four-necked flask was charged 3, 3-dimethoxy-azetidine (IVa) (10g, 85.4mmol), 50ml of ethyl acetate was added, and a 10% aqueous solution of citric acid (24.6g,128mmol) was added under stirring and stirred at 20 to 40 ℃ for 3 to 4 hours. And finishing the control reaction.
Saturated aqueous sodium bicarbonate solution was added dropwise to the reaction solution, the pH was adjusted to 7 to 8, and the mixture was stirred for 10 minutes. The layers were separated by standing, and the upper aqueous layer was extracted once with ethyl acetate (50 ml). The combined organic layers were dried over anhydrous sodium sulfate (30g), filtered, and the filtrate was concentrated to give azetidin-3-one (VIa)4.8g, 79.1% yield
1H NMR(400MHz，DMSO):δ5.00(s，4H)，9.88(br，H)。
Example 5: preparation of 1-tert-butoxycarbonyl-3-azetidinone (Ia)
A100 ml four-necked flask was charged with 1-tert-butoxycarbonyl-3, 3-dimethoxy-azetidine (Va) (10.4g, 47.9mmol) dissolved in ethyl acetate (50ml), and 10% aqueous citric acid (12g, 62.5mmol) was added thereto under stirring and stirred at 20 to 40 ℃ for 3 to 4 hours. And finishing the control reaction.
Saturated aqueous sodium bicarbonate solution was added dropwise to the reaction solution, the pH was adjusted to 7 to 8, and the mixture was stirred for 10 minutes. The layers were separated by standing, and the upper aqueous layer was extracted once with ethyl acetate (50 ml). The combined organic layers were dried over anhydrous sodium sulfate (20g), filtered, and the filtrate was concentrated until no liquid flowed out.
Adding 52ml of hexane into the concentrated residue, stirring and heating to 40-50 ℃ for dissolution, cooling to 5-10 ℃ for crystallization and heat preservation for 1-2 hours, performing suction filtration and drying to obtain 7.0g of 1-tert-butoxycarbonyl-3-azetidinone (Ia) with the yield of 85.4%.
1H NMR(400MHz，DMSO)：δ4.67(s，4H)，1.42(s，9H)。
Example 6: preparation of 1-tert-butoxycarbonyl-3-azetidinone (Ia)
A100 ml four-necked flask was charged with azetidin-3-one (VIa) (4.5g, 63.3mmol) dissolved in dichloromethane (40ml), triethylamine (9.6g, 95mmol) was charged, BOC anhydride (15.2g, 69.6mmol) was added dropwise at 10-40 ℃ and the mixture was stirred for 3-5 hours. And finishing the control reaction.
To the reaction mixture was added 20ml of water, and the mixture was stirred for 5 minutes, followed by separation of layers, and the upper aqueous layer was extracted once with methylene chloride (20 ml). The organic layers were combined and washed once with 30ml of drinking water. The layers were separated and the lower organic layer was dried over anhydrous sodium sulfate (20g) for 0.5 h, filtered and the filtrate was concentrated to no solvent run-off.
Adding 45ml of hexane into the concentrated residue, stirring and heating to 40-50 ℃ for dissolution, cooling to 5-10 ℃ for crystallization and heat preservation for 1-2 hours, performing suction filtration and drying to obtain 8.7g of 1-tert-butoxycarbonyl-3-azetidinone (Ia) with the yield of 80.2%.
1H NMR(400MHz，DMSO):δ4.67(s，4H)，1.42(s，9H)。
Claims (10)
1. A preparation method of a compound shown in formula III is characterized in that the compound is prepared by cyclization reaction of a compound shown in formula II and ammonium salt,
wherein R is1Is C1-C6Alkyl radical, R2And R3Is H or C1-C6Alkyl radical, R4Is benzyl or substituted benzyl, R5And R6Is halogen.
2. The method of claim 1, wherein the compound of formula III prepared in claim 1 is further prepared under palladium-carbon conditions to obtain a compound of formula IV,
wherein R is1Is C1-C6Alkyl radical, R2And R3Is H or C1-C6Alkyl radical, R4Is benzyl or substituted benzyl.
3. The method of claim 1 or 2, wherein the compound of formula IV prepared in claim 2 is further reacted with Boc anhydride in the presence of a base to prepare a compound of formula V,
wherein R is1Is C1-C6Alkyl radical, R2And R3Is H or C1-C6And the base is organic base or inorganic base.
4. A process according to claim 1 or 2, wherein the compound of formula IV obtained in claim 2 is further subjected to an acid to prepare a compound of formula VI,
wherein R is1Is C1-C6Alkyl radical, R2And R3Is H or C1-C6And the acid is organic acid or inorganic acid.
5. A process according to claim 1, 2 or 3, wherein the compound of formula V obtained in claim 3 is further processed in the presence of an acid to obtain a compound of formula I,
wherein R is1Is C1-C6Alkyl radical, R2And R3Is H or C1-C6And the acid is organic acid or inorganic acid.
6. The process of claim 1, 2 or 4, wherein the compound of formula VI obtained in claim 4 is further reacted with Boc anhydride in the presence of a base to obtain the compound of formula I,
wherein R is2And R3Is H or C1-C6And the base is organic base or inorganic base.
7. A process for preparing a compound of formula 1, comprising the steps of: 1) preparing a compound shown in a formula III by a cyclization reaction of a compound shown in a formula II and ammonium salt; 2) preparing a compound of formula IV from a compound of formula III under palladium-carbon conditions, 3) reacting the compound of formula IV with Boc anhydride in the presence of a base to prepare a compound of formula V, and then preparing the compound of formula V under the presence of an acid, or preparing a compound of formula VI from a compound of formula IV under the presence of an acid, and then reacting the compound of formula VI with Boc anhydride in the presence of a base, wherein the reaction formula is as follows:
wherein R is1Is C1-C6Alkyl radical, R2And R3Is H or C1-C6Alkyl radical, R4Is benzyl or substituted benzyl, R5And R6Is halogen, the acid is organic acid or inorganic acid, and the alkali is organic alkali or inorganic alkali.
8. A preparation process according to claim 3, 6 or 7, characterized in that the organic base is selected from triethylamine, trimethylamine, diisopropylethylamine, diazabicyclo, pyridine, imidazole and the inorganic base is selected from potassium carbonate, sodium carbonate, cesium carbonate, potassium hydroxide, sodium hydroxide, lithium hydroxide, potassium tert-butoxide, sodium tert-butoxide.
9. A process according to claim 4, 5 or 7, wherein the organic acid is selected from tartaric acid, oxalic acid, malic acid, citric acid, benzoic acid, salicylic acid, caffeic acid and the inorganic acid is selected from hydrochloric acid, sulfuric acid, phosphoric acid.
10. The method of claim 1 or 7, wherein the catalyst is selected from the group consisting of sodium bromide, potassium bromide, sodium iodide, and potassium iodide.
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Non-Patent Citations (4)
| Title |
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| DIRK DE SMAELE等: "A new entry towards the synthesis of 1-substituted 3-azetidinones", 《TETRAHEDRON LETTERS》 * |
| MASATOSHI ASAMI等: "Enantioselective addition of diethylzinc to aldehydes catalyzed by (R)-1-phenylethylamine-derived 1,4-amino alcohols", 《TETRAHEDRON》 * |
| 王杰等: "合成1-(1,3-噻唑啉-2-基) -3-巯基氮杂环丁烷盐酸盐的工艺改进", 《合成化学》 * |
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