CN107325020A - The preparation method of Ao Gelieting intermediates - Google Patents
The preparation method of Ao Gelieting intermediates Download PDFInfo
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- CN107325020A CN107325020A CN201710482625.XA CN201710482625A CN107325020A CN 107325020 A CN107325020 A CN 107325020A CN 201710482625 A CN201710482625 A CN 201710482625A CN 107325020 A CN107325020 A CN 107325020A
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- gelieting
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- 238000002360 preparation method Methods 0.000 title claims abstract description 23
- 239000000543 intermediate Substances 0.000 title claims abstract description 22
- 150000001875 compounds Chemical class 0.000 claims abstract description 74
- -1 propargyl compound Chemical class 0.000 claims abstract description 13
- 239000000463 material Substances 0.000 claims abstract description 10
- 150000001345 alkine derivatives Chemical class 0.000 claims abstract description 9
- 230000004224 protection Effects 0.000 claims abstract description 9
- 230000000977 initiatory effect Effects 0.000 claims abstract description 8
- ZHDORMMHAKXTPT-UHFFFAOYSA-N n-benzoylbenzamide Chemical compound C=1C=CC=CC=1C(=O)NC(=O)C1=CC=CC=C1 ZHDORMMHAKXTPT-UHFFFAOYSA-N 0.000 claims abstract description 8
- 238000006467 substitution reaction Methods 0.000 claims abstract description 6
- XBXCNNQPRYLIDE-UHFFFAOYSA-N tert-butylcarbamic acid Chemical compound CC(C)(C)NC(O)=O XBXCNNQPRYLIDE-UHFFFAOYSA-N 0.000 claims abstract description 6
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 60
- 238000006243 chemical reaction Methods 0.000 claims description 40
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 34
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 claims description 33
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 30
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 24
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 20
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 20
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 18
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 18
- 239000002904 solvent Substances 0.000 claims description 18
- 239000003960 organic solvent Substances 0.000 claims description 17
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 10
- LWIHDJKSTIGBAC-UHFFFAOYSA-K tripotassium phosphate Chemical compound [K+].[K+].[K+].[O-]P([O-])([O-])=O LWIHDJKSTIGBAC-UHFFFAOYSA-K 0.000 claims description 10
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 claims description 8
- SUAKHGWARZSWIH-UHFFFAOYSA-N N,N‐diethylformamide Chemical class CCN(CC)C=O SUAKHGWARZSWIH-UHFFFAOYSA-N 0.000 claims description 6
- SJRJJKPEHAURKC-UHFFFAOYSA-N N-Methylmorpholine Chemical compound CN1CCOCC1 SJRJJKPEHAURKC-UHFFFAOYSA-N 0.000 claims description 6
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 claims description 6
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims description 6
- QOSMNYMQXIVWKY-UHFFFAOYSA-N Propyl levulinate Chemical compound CCCOC(=O)CCC(C)=O QOSMNYMQXIVWKY-UHFFFAOYSA-N 0.000 claims description 6
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 6
- 239000002253 acid Substances 0.000 claims description 6
- 239000002585 base Substances 0.000 claims description 6
- 229940092714 benzenesulfonic acid Drugs 0.000 claims description 6
- 150000007530 organic bases Chemical class 0.000 claims description 6
- YORCIIVHUBAYBQ-UHFFFAOYSA-N propargyl bromide Chemical compound BrCC#C YORCIIVHUBAYBQ-UHFFFAOYSA-N 0.000 claims description 6
- 239000003513 alkali Substances 0.000 claims description 5
- SRSXLGNVWSONIS-UHFFFAOYSA-N benzenesulfonic acid Chemical compound OS(=O)(=O)C1=CC=CC=C1 SRSXLGNVWSONIS-UHFFFAOYSA-N 0.000 claims description 5
- 229910000160 potassium phosphate Inorganic materials 0.000 claims description 5
- 235000011009 potassium phosphates Nutrition 0.000 claims description 5
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 claims description 5
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-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
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 4
- MFRIHAYPQRLWNB-UHFFFAOYSA-N sodium tert-butoxide Chemical compound [Na+].CC(C)(C)[O-] MFRIHAYPQRLWNB-UHFFFAOYSA-N 0.000 claims description 4
- 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 4
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 claims description 3
- 125000000532 dioxanyl group Chemical group 0.000 claims description 3
- QUGUFLJIAFISSW-UHFFFAOYSA-N 1,4-difluorobenzene Chemical class FC1=CC=C(F)C=C1 QUGUFLJIAFISSW-UHFFFAOYSA-N 0.000 claims description 2
- 229960000549 4-dimethylaminophenol Drugs 0.000 claims description 2
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 claims description 2
- 238000006555 catalytic reaction Methods 0.000 claims description 2
- 229910017604 nitric acid Inorganic materials 0.000 claims description 2
- 235000006408 oxalic acid Nutrition 0.000 claims description 2
- 229910000027 potassium carbonate Inorganic materials 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
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims 2
- 229910052760 oxygen Inorganic materials 0.000 claims 1
- 239000001301 oxygen Substances 0.000 claims 1
- CVHZOJJKTDOEJC-UHFFFAOYSA-N saccharin Chemical compound C1=CC=C2C(=O)NS(=O)(=O)C2=C1 CVHZOJJKTDOEJC-UHFFFAOYSA-N 0.000 claims 1
- 229940081974 saccharin Drugs 0.000 claims 1
- 235000019204 saccharin Nutrition 0.000 claims 1
- 239000000901 saccharin and its Na,K and Ca salt Substances 0.000 claims 1
- 238000000034 method Methods 0.000 abstract description 7
- 230000015572 biosynthetic process Effects 0.000 abstract description 4
- 230000007812 deficiency Effects 0.000 abstract description 4
- 238000003786 synthesis reaction Methods 0.000 abstract description 4
- 150000001408 amides Chemical class 0.000 abstract description 3
- 230000008901 benefit Effects 0.000 abstract description 3
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 abstract description 3
- 229910052794 bromium Inorganic materials 0.000 abstract description 2
- 238000004519 manufacturing process Methods 0.000 abstract description 2
- GOYDNIKZWGIXJT-UHFFFAOYSA-N 1,2-difluorobenzene Chemical compound FC1=CC=CC=C1F GOYDNIKZWGIXJT-UHFFFAOYSA-N 0.000 abstract 2
- WDBAXYQUOZDFOJ-UHFFFAOYSA-N 2,3-difluorobenzaldehyde Chemical class FC1=CC=CC(C=O)=C1F WDBAXYQUOZDFOJ-UHFFFAOYSA-N 0.000 abstract 1
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 abstract 1
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 abstract 1
- 125000004212 difluorophenyl group Chemical group 0.000 abstract 1
- 239000012074 organic phase Substances 0.000 description 23
- 238000003756 stirring Methods 0.000 description 22
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 16
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 13
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 12
- QUSNBJAOOMFDIB-UHFFFAOYSA-N Ethylamine Chemical compound CCN QUSNBJAOOMFDIB-UHFFFAOYSA-N 0.000 description 6
- DKGAVHZHDRPRBM-UHFFFAOYSA-N Tert-Butanol Chemical compound CC(C)(C)O DKGAVHZHDRPRBM-UHFFFAOYSA-N 0.000 description 6
- 238000001035 drying Methods 0.000 description 6
- 230000000694 effects Effects 0.000 description 6
- 238000002474 experimental method Methods 0.000 description 6
- 239000007788 liquid Substances 0.000 description 6
- 238000005406 washing Methods 0.000 description 5
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical class [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 4
- 238000007796 conventional method Methods 0.000 description 4
- 229940124213 Dipeptidyl peptidase 4 (DPP IV) inhibitor Drugs 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- 239000003603 dipeptidyl peptidase IV inhibitor Substances 0.000 description 3
- 239000010410 layer Substances 0.000 description 3
- 239000002994 raw material Substances 0.000 description 3
- 239000000376 reactant Substances 0.000 description 3
- 230000035484 reaction time Effects 0.000 description 3
- FVAUCKIRQBBSSJ-UHFFFAOYSA-M sodium iodide Chemical compound [Na+].[I-] FVAUCKIRQBBSSJ-UHFFFAOYSA-M 0.000 description 3
- VVVOJODFBWBNBI-UHFFFAOYSA-N 2,5-difluorobenzaldehyde Chemical class FC1=CC=C(F)C(C=O)=C1 VVVOJODFBWBNBI-UHFFFAOYSA-N 0.000 description 2
- XCRCSPKQEDMVBO-UHFFFAOYSA-N 2-bromo-1,4-difluorobenzene Chemical class FC1=CC=C(F)C(Br)=C1 XCRCSPKQEDMVBO-UHFFFAOYSA-N 0.000 description 2
- 108010067722 Dipeptidyl Peptidase 4 Proteins 0.000 description 2
- 102100025012 Dipeptidyl peptidase 4 Human genes 0.000 description 2
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 2
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 2
- YKYMGFHOJJOSEB-UHFFFAOYSA-N butan-1-ol;potassium Chemical compound [K].CCCCO YKYMGFHOJJOSEB-UHFFFAOYSA-N 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- 239000003112 inhibitor Substances 0.000 description 2
- 229910052700 potassium Inorganic materials 0.000 description 2
- 239000011591 potassium Substances 0.000 description 2
- 238000011160 research Methods 0.000 description 2
- 229910052708 sodium Inorganic materials 0.000 description 2
- 239000011734 sodium Substances 0.000 description 2
- 235000002639 sodium chloride Nutrition 0.000 description 2
- 229910052938 sodium sulfate Inorganic materials 0.000 description 2
- 235000011152 sodium sulphate Nutrition 0.000 description 2
- 208000001072 type 2 diabetes mellitus Diseases 0.000 description 2
- 238000010792 warming Methods 0.000 description 2
- 208000013016 Hypoglycemia Diseases 0.000 description 1
- ATHHXGZTWNVVOU-UHFFFAOYSA-N N-methylformamide Chemical compound CNC=O ATHHXGZTWNVVOU-UHFFFAOYSA-N 0.000 description 1
- 206010030113 Oedema Diseases 0.000 description 1
- 241000255964 Pieridae Species 0.000 description 1
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 1
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 description 1
- 239000005864 Sulphur Substances 0.000 description 1
- 150000008065 acid anhydrides Chemical class 0.000 description 1
- 125000002252 acyl group Chemical group 0.000 description 1
- 238000005917 acylation reaction Methods 0.000 description 1
- 150000001335 aliphatic alkanes Chemical class 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- AQEFLFZSWDEAIP-UHFFFAOYSA-N di-tert-butyl ether Chemical compound CC(C)(C)OC(C)(C)C AQEFLFZSWDEAIP-UHFFFAOYSA-N 0.000 description 1
- MJEMIOXXNCZZFK-UHFFFAOYSA-N ethylone Chemical compound CCNC(C)C(=O)C1=CC=C2OCOC2=C1 MJEMIOXXNCZZFK-UHFFFAOYSA-N 0.000 description 1
- 239000002360 explosive Substances 0.000 description 1
- 125000005843 halogen group Chemical group 0.000 description 1
- 230000002218 hypoglycaemic effect Effects 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 230000002045 lasting effect Effects 0.000 description 1
- 239000007791 liquid phase Substances 0.000 description 1
- 230000007246 mechanism Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 239000012044 organic layer Substances 0.000 description 1
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 1
- 230000003389 potentiating effect Effects 0.000 description 1
- 230000008569 process Effects 0.000 description 1
- 238000012545 processing Methods 0.000 description 1
- 150000003217 pyrazoles Chemical class 0.000 description 1
- 238000012113 quantitative test Methods 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- 229920006395 saturated elastomer Polymers 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- 239000012312 sodium hydride Substances 0.000 description 1
- 229910000104 sodium hydride Inorganic materials 0.000 description 1
- 235000009518 sodium iodide Nutrition 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 230000003442 weekly effect Effects 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C249/00—Preparation of compounds containing nitrogen atoms doubly-bound to a carbon skeleton
- C07C249/02—Preparation of compounds containing nitrogen atoms doubly-bound to a carbon skeleton of compounds containing imino groups
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C269/00—Preparation of derivatives of carbamic acid, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups
- C07C269/04—Preparation of derivatives of carbamic acid, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups from amines with formation of carbamate groups
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
Abstract
The present invention relates to a kind of preparation method of Ao Gelieting intermediates, Ao Gelieting intermediates are [1 (2,5 difluorophenyls) 1 oxo, penta 4 base of alkynes 2] t-butyl carbamate, this method prepares formula (III) compound by initiation material of Isosorbide-5-Nitrae difluorobenzene；Then reacted with dibenzimide, obtain formula (IV) compound；Occur substitution reaction with propargyl compound again, obtain formula (V) compound；Acidolysis and Boc protections are carried out again, obtain formula (II) compound, i.e. Ao Gelieting intermediates.The preparation method that the present invention is provided, got rid of in the prior art synthesis step length, using fairly expensive initiation material such as 2, the technological deficiency such as 5 difluorobenzaldehydes or 2 bromine Isosorbide-5-Nitrae difluorobenzenes, preparation Weinreb acid amides and use carbonyl dimidazoles (CDI)；And have the advantages that simple to operate, high income, cost of material are low and it is wide to originate, it is suitably applied industrialized production.
Description
Technical field
The present invention relates to technical field of medicine synthesis, and in particular to a kind of preparation method of Ao Gelieting intermediate.
Background technology
The present invention relates to the facility side for preparing the important intermediate for being used to synthesize dipeptidyl peptidase-iv inhibitor (DP-IV)
Method.Specifically, with following structure entitled Ao Gelieting or (2R, 3S, 5R) -2- (2,5- difluorophenyl) -5- [2- (first sulphurs
Acyl group) -2,6- pyrrolin simultaneously [3,4-c] pyrazoles -5 (4H)-yl] tetrahydrochysene -2H- pyrans -3- amine compound, formula (I)：
Ao Gelieting researches and develops for Merck ＆ Co., Inc., the medicine of the treatment type ii diabetes in Japan's approval on the 30th of September in 2015,
It is the long-acting DPP-IV inhibitor of a class, only needs to take once (25mg) weekly, lasting DPP-IV inhibitory action can be produced, has
There is brand-new hypoglycemic mechanism, do not put on weight while having, hypoglycemic reaction will not be caused, oedema etc. will not be caused superior
Property.Patent document WO2010/056708 discloses the potent inhibitor as DP-IV and therefore can be used for treatment type ii diabetes
A class amino tetrahydro pyran compound, the compound is specifically disclosed for the first time.
Formula (II) compound [the amyl- 4- alkynes -2- bases of 1- (2,5- difluorophenyls) -1- oxos] t-butyl carbamate is synthesis
One of Ao Gelieting important intermediate, the preparation method of formula (II) compound is in US2009/0187028 and Organic
Process Research&Development,2015,19(11)：Had been reported that in 1760-1768.
In the technology of preparation formula (II) compound disclosed above, there is synthesis step length, using expensive initiation material
Lack such as 2,5- difluorobenzaldehydes or the bromo- 1,4- difluorobenzenes of 2-, preparation Weinreb acid amides and using carbonyl dimidazoles (CDI)
Fall into, and complex operation, yield are low.
Patent document CN 105392772 discloses one kind using Isosorbide-5-Nitrae-difluorobenzene as initiation material, prepares formula (II) compound
Method, the method reaction condition is simple, the cost of raw material is relatively low, but reaction in use inflammable and explosive chemicals sodium hydride, exist
The difficult control of reaction, the low shortcoming of yield.
For above-mentioned technical problem, invent a kind of safe and reliable method and prepare formula (II) compound, with particularly significant
Meaning.
The content of the invention
In view of the above-mentioned deficiencies in the prior art, it is an object of the present invention to which solving prior art prepares Ao Gelieting intermediate (formulas
(II) compound) the novel processing step that technological deficiency is there is provided a kind of cost is low, safe operation, yield are higher.
The invention provides a kind of preparation method of Ao Gelieting intermediates, Ao Gelieting intermediates are [1- (2,5- difluoros
Phenyl) the amyl- 4- alkynes -2- bases of -1- oxos] t-butyl carbamate, this method is using Isosorbide-5-Nitrae-difluorobenzene as initiation material, synthetic route
It is as follows：
；
Preparation method comprises the following steps：S1：Formula (III) compound is prepared by initiation material of 1,4- difluorobenzenes；
S2：Formula (III) compound and dibenzimide are reacted, formula (IV) compound is obtained；S3：By formula (IV) compound and alkynes third
Substitution reaction occurs for based compound, obtains formula (V) compound；S4：Formula (V) compound is subjected to acidolysis and Boc protections, formula is obtained
(II) compound, i.e. [the amyl- 4- alkynes -2- bases of 1- (2,5- difluorophenyl) -1- oxos] t-butyl carbamate.Need explanation
Be, in formula (III) compound X be halogen atom Cl or Br, its preparation method can by disclosed report technology, through pay-
Gram acylation reaction is prepared.
In the further embodiment of the present invention, in S2, reaction is specifically included：In organic solvent, in organic base
Under catalysis, formula (III) compound is reacted with dibenzimide, obtains formula (IV) compound.
The present invention further embodiment in, in S2, organic base be selected from triethylamine, diisopropyl ethyl amine, pyridine,
One or more in N-methylmorpholine and DMAP；Organic solvent is selected from dioxane, tetrahydrofuran, acetonitrile, acetone, dichloromethane
One in alkane, ethyl acetate, methyl tertiary butyl ether(MTBE), N,N-dimethylformamide, N, N- diethylformamides and dimethyl sulfoxide (DMSO)
Plant or a variety of.It should be noted that in view of cost and using effect, the preferred diisopropyl ethyl amine of organic base；Organic base
Consumption is preferably 1.0~2.0 times of the molal quantity of formula (III) compound；According to many experiments result, in dichloromethane, acetonitrile
With reaction effect in acetone more preferably, therefore, the preferred dichloromethane of organic solvent, acetonitrile and acetone, the consumption of organic solvent are general
For 3.0~9.0 times of the molal quantity of formula (III) compound.
In the further embodiment of the present invention, in S2, the temperature of reaction is -20~80 DEG C, is preferably -10~60
DEG C, the time of reaction is 1~24h.It should be noted that the reaction time is untill detecting that reactant consumption is complete, generally 1~
24h；After reaction terminates, it can be post-processed by this area conventional method.
In the further embodiment of the present invention, in S3, substitution reaction is specifically included：In organic solvent, formula (IV)
Compound is reacted in the presence of alkali with propargyl compound, obtains formula (V) compound.
In the further embodiment of the present invention in S3, propargyl compound includes propargyl bromide and/or benzene sulfonic acid alkynes
Propyl ester；One kind in potassium tert-butoxide, sodium tert-butoxide, sodium methoxide, caustic alcohol, potassium carbonate, potassium phosphate and potassium hydroxide of alkali or
It is a variety of；Organic solvent is selected from dioxane, tetrahydrofuran, acetonitrile, dichloromethane, ethyl acetate, methyl tertiary butyl ether(MTBE), N, N- bis-
One or more in NMF, N, N- diethylformamides, dimethyl sulfoxide (DMSO) and acetone.It should be noted that alkynes third
Based compound consumption is preferably 1.0~3.0 times of the molal quantity of formula (IV) compound；In view of cost and using effect, alkali is excellent
Elect potassium tert-butoxide or potassium phosphate as, consumption is preferably 1.0~5.0 times of the molal quantity of formula (IV) compound；According to many experiments
As a result, reaction effect is more preferable in DMF, methyl tertiary butyl ether(MTBE) and tetrahydrofuran, and therefore, organic solvent is excellent
DMF, methyl tertiary butyl ether(MTBE) or tetrahydrofuran are selected, the consumption of organic solvent is generally formula (IV) compound
3.0~9.0 times.
In the further embodiment of the present invention, in S3, the temperature of reaction is -20~60 DEG C, is preferably -10~50
DEG C, the time of reaction is 1~36h.It should be noted that the reaction time is untill detecting that reactant consumption is complete, generally 1~
36h；After reaction terminates, it can be post-processed by this area conventional method.
In the further embodiment of the present invention, S4 is specifically included：In organic solvent, by formula (V) compound with it is dilute
Acid reaction, sloughs protection group；With Boc anhydride reactions after alkalization, upper protection group obtains formula (II) compound.
In the further embodiment of the present invention, in S4, the one kind of diluted acid in hydrochloric acid, sulfuric acid, nitric acid and oxalic acid
Or it is a variety of；Organic solvent is selected from C1-C4Alcohols solvent, dioxane, tetrahydrofuran, acetonitrile, dichloromethane, ethyl acetate, first
One or more in base tertbutyl ether, N,N-dimethylformamide, N, N- diethylformamides, dimethyl sulfoxide (DMSO) and acetone.
It should be noted that cost and using effect are considered, and the preferred hydrochloric acid of diluted acid, the consumption of hydrochloric acid is preferably formula (V)
1.0~2.0 times of the molal quantity of compound；According to many experiments result, reaction effect is more preferable in methyl tertiary butyl ether(MTBE), because
This, organic preferred methyl tertiary butyl ether(MTBE)；The consumption of organic solvent is preferably 3.0~9.0 times of the molal quantity of formula (V) compound.
In the further embodiment of the present invention in S4, the temperature of reaction is -20~60 DEG C, is preferably -10~40 DEG C,
The time of reaction is 1~24h.It should be noted that the reaction time is untill detecting that reactant consumption is complete, generally 1~24h；
After reaction terminates, it can be post-processed by this area conventional method.
Agents useful for same and raw material of the present invention are unless otherwise indicated, commercially available.
The technical scheme that the present invention is provided, with following beneficial effect：The present invention has got rid of in existing literature report and closed
Into step length, using the bromo- 1,4- difluorobenzenes of fairly expensive initiation material such as 2,5- difluorobenzaldehydes or 2-, prepare
The technological deficiency such as Weinreb acid amides and use carbonyl dimidazoles (CDI)；In addition, the technical scheme that the present invention is provided, with operation
Simply, high income, raw materials used price is low, the advantages of originating wide, is suitably applied industrialized production.
The additional aspect and advantage of the present invention will be set forth in part in the description, and will partly become from the following description
Obtain substantially, or recognized by the practice of the present invention.
Embodiment
Below in conjunction with the embodiment of the present invention, technical scheme is clearly and completely described.Implement below
Example is only used for clearly illustrating technical scheme, therefore is intended only as example, and can not limit this hair with this
Bright protection domain.
Experimental method in following embodiments, is conventional method unless otherwise specified.Examination used in following embodiments
Material is tested, is to be commercially available from conventional reagent shop unless otherwise specified.Quantitative test in following examples, is all provided with
Three repetition experiments are put, data are the average value or mean+SD of three repetition experiments.
Embodiment 1
Formula (III) compound (X=Br) (23.5g, 0.10mol) is dissolved in dichloromethane (100mL), added at room temperature
Diisopropyl ethyl amine (21mL, 0.15mol), stir 10min, be slowly dropped into dissolved with dibenzimide (21.7g,
Dichloromethane solution (100mL) 0.12mol), stirs 5h.After reaction terminates, 100mL water stirring point liquid, organic phase warp are added
Watery hydrochloric acid is washed, and saturated sodium bicarbonate solution is washed, and saturated common salt washing, anhydrous sodium sulfate drying is recovered under reduced pressure solvent, obtains formula (IV)
Compound.Yield is 93%.
Embodiment 2
Formula (III) compound (X=Br) (23.5g, 0.10mol) is dissolved in acetonitrile (100mL), two are added at room temperature different
Ethylamine (21mL, 0.15mol), stirs 10min, is slowly dropped into dissolved with dibenzimide (21.7g, 0.12mol)
Acetonitrile solution (100mL), stirs 5h.After reaction terminates, removal of solvent under reduced pressure, residue adds dichloromethane (100mL)/water
(100mL) stirring point liquid, organic phase is washed through watery hydrochloric acid, and saturated sodium bicarbonate solution is washed, and saturated common salt washing, anhydrous sodium sulfate is done
It is dry, solvent is recovered under reduced pressure, formula (IV) compound is obtained.Yield is 93%.
Embodiment 3
Formula (III) compound (X=Cl) (19.1g, 0.10mol) is dissolved in acetone (100mL), two are added at room temperature different
Ethylamine (21mL, 0.15mol), stirs 10min, is slowly dropped into dissolved with dibenzimide (21.7g, 0.12mol)
Acetone soln (100mL), stirs 5h.After reaction terminates, removal of solvent under reduced pressure, residue adds dichloromethane (100mL)/water
(100mL) stirring point liquid, organic phase is washed through watery hydrochloric acid, and saturated sodium bicarbonate solution is washed, and saturated common salt washing, anhydrous sodium sulfate is done
It is dry, solvent is recovered under reduced pressure, formula (IV) compound is obtained.Yield is 89%.
Embodiment 4
Formula (III) compound (X=Cl) (19.1g, 0.10mol) is dissolved in acetone (100mL), two are added at room temperature different
Ethylamine (21mL, 0.15mol), stirs 10min, is slowly dropped into dissolved with dibenzimide (21.7g, 0.12mol)
Acetone soln (100mL), adds sodium iodide (9.3g, 0.05mol), stirs 5h.After reaction terminates, removal of solvent under reduced pressure is residual
Excess adds dichloromethane (100mL)/water (100mL) stirring point liquid, and organic phase is washed through watery hydrochloric acid, saturated sodium bicarbonate solution
Wash, saturated common salt washing, anhydrous sodium sulfate drying is recovered under reduced pressure solvent, obtains formula (IV) compound.Yield is 94%.
Embodiment 5
Formula (IV) compound (33.5g, 0.10mol) is dissolved in DMF (200mL), uncle is slowly added to
Butanol potassium (22.4g, 0.20mol), stirs 2h, adds propargyl bromide (15.5g, 0.13mol), reacts 5h.After reaction terminates, delay
It is slow to add 200mL water, then extracted with dichloromethane (200mL × 2), merge organic phase, organic phase is washed through saturated common salt, anhydrous
Sodium sulphate is dried, and solvent is recovered under reduced pressure, formula (V) compound is obtained.Yield is 91%.
Embodiment 6
Formula (IV) compound (33.5g, 0.10mol) is dissolved in tetrahydrofuran (200mL), potassium tert-butoxide is slowly added to
(22.4g, 0.20mol), stirs 2h, adds propargyl bromide (15.5g, 0.13mol), reacts 5h.After reaction terminates, it is slowly added to
100mL water, then extracted with dichloromethane (100mL × 2), merge organic phase, organic phase is washed through saturated common salt, anhydrous sodium sulfate
Dry, solvent is recovered under reduced pressure, formula (V) compound is obtained.Yield is 90%.
Embodiment 7
Formula (IV) compound (33.5g, 0.10mol) is dissolved in tetrahydrofuran (200mL), potassium tert-butoxide is slowly added to
(22.4g, 0.20mol), stirs 2h, adds benzene sulfonic acid alkynes propyl ester (25.5g, 0.13mol), reacts 5h.After reaction terminates, slowly
100mL water is added, then is extracted with dichloromethane (100mL × 2), merges organic phase, organic phase is washed through saturated common salt, anhydrous sulphur
Sour sodium is dried, and solvent is recovered under reduced pressure, formula (V) compound is obtained.Yield is 93%.
Embodiment 8
Formula (IV) compound (33.5g, 0.10mol) is dissolved in DMF (200mL), uncle is slowly added to
Butanol potassium (22.4g, 0.20mol), stirs 2h, adds benzene sulfonic acid alkynes propyl ester (25.5g, 0.13mol), reacts 5h.Reaction terminates
Afterwards, 200mL water is slowly added to, then is extracted with dichloromethane (200mL × 2), merges organic phase, organic phase is through saturated aqueous common salt
Wash, solvent is recovered under reduced pressure in anhydrous sodium sulfate drying, obtain formula (V) compound.Yield is 92%.
Embodiment 9
Formula (IV) compound (33.5g, 0.10mol) is dissolved in methyl tertiary butyl ether(MTBE) (200mL), the tert-butyl alcohol is slowly added to
Potassium (22.4g, 0.20mol), stirs 2h, adds propargyl bromide (15.5g, 0.13mol), reacts 5h.It is slow to add after reaction terminates
Enter 100mL water, then extracted with dichloromethane (100mL × 2), merge organic phase, organic phase is washed through saturated common salt, anhydrous slufuric acid
Sodium is dried, and solvent is recovered under reduced pressure, formula (V) compound is obtained.Yield is 91%.
Embodiment 10
Formula (IV) compound (33.5g, 0.10mol) is dissolved in methyl tertiary butyl ether(MTBE) (200mL), the tert-butyl alcohol is slowly added to
Potassium (22.4g, 0.20mol), stirs 2h, adds benzene sulfonic acid alkynes propyl ester (15.5g, 0.13mol), reacts 5h.After reaction terminates, delay
It is slow to add 200mL water, then extracted with dichloromethane (200mL × 2), merge organic phase, organic phase is washed through saturated common salt, anhydrous
Sodium sulphate is dried, and solvent is recovered under reduced pressure, formula (V) compound is obtained.Yield is 92%.
Embodiment 11
Formula (IV) compound (33.5g, 0.10mol) is dissolved in methyl tertiary butyl ether(MTBE) (200mL), potassium phosphate is added
(106g, 0.50mol), is warming up to 50 DEG C, adds propargyl bromide (15.5g, 0.13mol), stirs 10h.After reaction terminates, cooling
To room temperature, 100mL water is added, point liquid, water layer is extracted with methyl tertiary butyl ether(MTBE) (100mL) again, merge organic phase, organic phase is through full
With salt washing, anhydrous sodium sulfate drying is recovered under reduced pressure solvent, obtains formula (V) compound.Yield is 92%.
Embodiment 12
Formula (IV) compound (33.5g, 0.10mol) is dissolved in methyl tertiary butyl ether(MTBE) (200mL), potassium phosphate is added
(106g, 0.50mol), is warming up to 50 DEG C, adds benzene sulfonic acid alkynes propyl ester (25.5g, 0.13mol), stirs 10h.After reaction terminates,
Room temperature is cooled to, 100mL water is added, point liquid, water layer is extracted with methyl tertiary butyl ether(MTBE) (100mL) again, merges organic phase, organic phase
Washed through saturated common salt, solvent is recovered under reduced pressure in anhydrous sodium sulfate drying, obtain formula (V) compound.Yield is 93%.
Embodiment 13
Formula (V) compound (37.3g, 0.10mol) is dissolved in methyl tertiary butyl ether(MTBE) (200mL), temperature 10~20 is controlled
DEG C, 1N hydrochloric acid solutions (110mL, 0.11mol) are slowly dropped into, 5h is stirred, discards and 30% sodium hydroxide is added in organic layer, water layer
Solution, regulation pH value is 10~11, is slowly dropped into acid anhydrides containing Boc (24.0g, 0.11mol) t-butyl methyl ether solution
(20mL), stirs 6h at room temperature.After reaction terminates, methyl tertiary butyl ether(MTBE) (150mL × 2) point liquid is added, merges organic phase, stirring
It is lower that reaction solution is poured into frozen water (300g), add dichloromethane (200mL × 2) and extracted, merge organic phase, organic phase warp
Saturated common salt is washed, and anhydrous sodium sulfate drying, removal of solvent under reduced pressure obtains white formula (II) compound solid.Yield is 94%.
It should be noted that unless otherwise indicated, technical term or scientific terminology used in this application should be this hair
The ordinary meaning that bright one of ordinary skill in the art are understood.Unless specifically stated otherwise, otherwise illustrate in these embodiments
Part and relative step, numerical expression and the numerical value of step are not limit the scope of the invention.It is illustrated and described herein
In all examples, unless otherwise prescribed, any occurrence should be construed as merely exemplary, not as limitation, because
This, other examples of exemplary embodiment can have different values.
Finally it should be noted that：Various embodiments above is merely illustrative of the technical solution of the present invention, rather than its limitations；To the greatest extent
The present invention is described in detail with reference to foregoing embodiments for pipe, it will be understood by those within the art that：Its according to
The technical scheme described in foregoing embodiments can so be modified, or which part or all technical characteristic are entered
Row equivalent substitution；And these modifications or replacement, the essence of appropriate technical solution is departed from various embodiments of the present invention technology
The scope of scheme, it all should cover among protection scope of the present invention.
Claims (10)
1. a kind of preparation method of Ao Gelieting intermediates, the Ao Gelieting intermediates are [1- (2,5- difluorophenyl) -1- oxygen
For amyl- 4- alkynes -2- bases] t-butyl carbamate, it is characterised in that
Synthetic route is as follows：
；
The preparation method comprises the following steps：
S1：Formula (III) compound is prepared by initiation material of 1,4- difluorobenzenes；
S2：Formula (III) compound and dibenzimide are reacted, formula (IV) compound is obtained；
S3：Substitution reaction is occurred into for formula (IV) compound and propargyl compound, formula (V) compound is obtained；
S4：Formula (V) compound is subjected to acidolysis and Boc protections, formula (II) compound is obtained, i.e. [1- (2,5- difluorophenyl) -1-
The amyl- 4- alkynes -2- bases of oxo] t-butyl carbamate.
2. the preparation method of Ao Gelieting intermediates according to claim 1, it is characterised in that：
In the S2, the reaction is specifically included：In organic solvent, under the catalysis of organic base, formula (III) compound and two
Saccharin reacts, and obtains formula (IV) compound.
3. the preparation method of Ao Gelieting intermediates according to claim 2, it is characterised in that
In the S2, the organic base in triethylamine, diisopropyl ethyl amine, pyridine, N-methylmorpholine and DMAP one
Plant or a variety of；
The organic solvent is selected from dioxane, tetrahydrofuran, acetonitrile, acetone, dichloromethane, ethyl acetate, methyl tertbutyl
One or more in ether, N,N-dimethylformamide, N, N- diethylformamides and dimethyl sulfoxide (DMSO).
4. the preparation method of Ao Gelieting intermediates according to claim 2, it is characterised in that：
In the S2, the temperature of reaction is -20~80 DEG C, is preferably -10~60 DEG C, and the time of reaction is 1~24h.
5. the preparation method of Ao Gelieting intermediates according to claim 1, it is characterised in that：
In the S3, the substitution reaction is specifically included：In organic solvent, formula (IV) compound in the presence of alkali with alkynes third
Based compound reacts, and obtains formula (V) compound.
6. the preparation method of Ao Gelieting intermediates according to claim 5, it is characterised in that：
In the S3, the propargyl compound includes propargyl bromide and/or benzene sulfonic acid alkynes propyl ester；
The one kind of the alkali in potassium tert-butoxide, sodium tert-butoxide, sodium methoxide, caustic alcohol, potassium carbonate, potassium phosphate and potassium hydroxide
Or it is a variety of；
The organic solvent be selected from dioxane, tetrahydrofuran, acetonitrile, dichloromethane, ethyl acetate, methyl tertiary butyl ether(MTBE), N,
One or more in dinethylformamide, N, N- diethylformamides, dimethyl sulfoxide (DMSO) and acetone.
7. the preparation method of Ao Gelieting intermediates according to claim 5, it is characterised in that：
In the S3, the temperature of reaction is -20~60 DEG C, is preferably -10~50 DEG C, and the time of reaction is 1~36h.
8. the preparation method of Ao Gelieting intermediates according to claim 1, it is characterised in that：
The S4 is specifically included：In organic solvent, formula (V) compound and diluted acid are reacted, sloughs protection group；After alkalization with
Boc anhydride reactions, upper protection group obtains formula (II) compound.
9. the preparation method of Ao Gelieting intermediates according to claim 8, it is characterised in that：
In the S4, one or more of the diluted acid in hydrochloric acid, sulfuric acid, nitric acid and oxalic acid；
The organic solvent is selected from C1-C4Alcohols solvent, dioxane, tetrahydrofuran, acetonitrile, dichloromethane, ethyl acetate,
One kind or many in methyl tertiary butyl ether(MTBE), N,N-dimethylformamide, N, N- diethylformamides, dimethyl sulfoxide (DMSO) and acetone
Kind.
10. the preparation method of Ao Gelieting intermediates according to claim 8, it is characterised in that：
In the S4, the temperature of reaction is -20~60 DEG C, is preferably -10~40 DEG C, and the time of reaction is 1~24h.
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| CN113831266A (en) * | 2019-01-22 | 2021-12-24 | 河南医学高等专科学校 | Synthesis of alkyl 1- (2, 5-difluorophenyl) -1-oxopent-4-yn-2-ylcarbamate |
| CN113831266B (en) * | 2019-01-22 | 2024-04-05 | 河南医学高等专科学校 | Synthesis of alkyl 1- (2, 5-difluorophenyl) -1-oxopent-4-yn-2-ylcarbamate |
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