CN107459501B - Preparation method of chiral intermediate of augustine - Google Patents
Preparation method of chiral intermediate of augustine Download PDFInfo
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- CN107459501B CN107459501B CN201710738504.7A CN201710738504A CN107459501B CN 107459501 B CN107459501 B CN 107459501B CN 201710738504 A CN201710738504 A CN 201710738504A CN 107459501 B CN107459501 B CN 107459501B
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- 238000002360 preparation method Methods 0.000 title abstract description 9
- QLRRUWXMMVXORS-UHFFFAOYSA-N Augustine Natural products C12=CC=3OCOC=3C=C2CN2C3CC(OC)C4OC4C31CC2 QLRRUWXMMVXORS-UHFFFAOYSA-N 0.000 title description 3
- 239000011984 grubbs catalyst Substances 0.000 claims abstract description 4
- 238000007363 ring formation reaction Methods 0.000 claims abstract description 4
- WCJYTPVNMWIZCG-UHFFFAOYSA-N xylylcarb Chemical compound CNC(=O)OC1=CC=C(C)C(C)=C1 WCJYTPVNMWIZCG-UHFFFAOYSA-N 0.000 claims abstract description 4
- 238000010189 synthetic method Methods 0.000 claims abstract description 3
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 48
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 27
- 238000006243 chemical reaction Methods 0.000 claims description 22
- 229960001667 alogliptin Drugs 0.000 claims description 14
- ZSBOMTDTBDDKMP-OAHLLOKOSA-N alogliptin Chemical compound C=1C=CC=C(C#N)C=1CN1C(=O)N(C)C(=O)C=C1N1CCC[C@@H](N)C1 ZSBOMTDTBDDKMP-OAHLLOKOSA-N 0.000 claims description 14
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 claims description 12
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 12
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 12
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 12
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 10
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 9
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 9
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 9
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 6
- 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 6
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 6
- 238000006482 condensation reaction Methods 0.000 claims description 5
- VVVOJODFBWBNBI-UHFFFAOYSA-N 2,5-difluorobenzaldehyde Chemical compound FC1=CC=C(F)C(C=O)=C1 VVVOJODFBWBNBI-UHFFFAOYSA-N 0.000 claims description 4
- OJOFMLDBXPDXLQ-VIFPVBQESA-N (4s)-4-benzyl-1,3-oxazolidin-2-one Chemical compound C1OC(=O)N[C@H]1CC1=CC=CC=C1 OJOFMLDBXPDXLQ-VIFPVBQESA-N 0.000 claims description 3
- JKHPOPCIKQQRPU-UHFFFAOYSA-N 3-chloro-2-(methoxymethoxy)prop-1-ene Chemical compound COCOC(=C)CCl JKHPOPCIKQQRPU-UHFFFAOYSA-N 0.000 claims description 3
- PNPBGYBHLCEVMK-UHFFFAOYSA-N benzylidene(dichloro)ruthenium;tricyclohexylphosphanium Chemical compound Cl[Ru](Cl)=CC1=CC=CC=C1.C1CCCCC1[PH+](C1CCCCC1)C1CCCCC1.C1CCCCC1[PH+](C1CCCCC1)C1CCCCC1 PNPBGYBHLCEVMK-UHFFFAOYSA-N 0.000 claims description 3
- FJDQFPXHSGXQBY-UHFFFAOYSA-L caesium carbonate Chemical compound [Cs+].[Cs+].[O-]C([O-])=O FJDQFPXHSGXQBY-UHFFFAOYSA-L 0.000 claims description 3
- 229910000024 caesium carbonate Inorganic materials 0.000 claims description 3
- MVLMPMUGCWJDLE-UHFFFAOYSA-M dibutylboron trifluoromethanesulfonate Chemical compound [O-]S(=O)(=O)C(F)(F)F.CCCC[B+]CCCC MVLMPMUGCWJDLE-UHFFFAOYSA-M 0.000 claims description 3
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 claims description 3
- 229910000041 hydrogen chloride Inorganic materials 0.000 claims description 3
- XONPDZSGENTBNJ-UHFFFAOYSA-N molecular hydrogen;sodium Chemical compound [Na].[H][H] XONPDZSGENTBNJ-UHFFFAOYSA-N 0.000 claims description 3
- IOGXOCVLYRDXLW-UHFFFAOYSA-N tert-butyl nitrite Chemical compound CC(C)(C)ON=O IOGXOCVLYRDXLW-UHFFFAOYSA-N 0.000 claims description 3
- 239000012414 tert-butyl nitrite Substances 0.000 claims description 3
- XJDNKRIXUMDJCW-UHFFFAOYSA-J titanium tetrachloride Chemical compound Cl[Ti](Cl)(Cl)Cl XJDNKRIXUMDJCW-UHFFFAOYSA-J 0.000 claims description 3
- 230000003197 catalytic effect Effects 0.000 claims description 2
- 238000006555 catalytic reaction Methods 0.000 claims description 2
- 238000010534 nucleophilic substitution reaction Methods 0.000 claims description 2
- 238000006462 rearrangement reaction Methods 0.000 claims description 2
- 238000007142 ring opening reaction Methods 0.000 claims description 2
- 238000001308 synthesis method Methods 0.000 claims 9
- OAKJQQAXSVQMHS-UHFFFAOYSA-N Hydrazine Chemical compound NN OAKJQQAXSVQMHS-UHFFFAOYSA-N 0.000 claims 2
- KWYHDKDOAIKMQN-UHFFFAOYSA-N N,N,N',N'-tetramethylethylenediamine Chemical compound CN(C)CCN(C)C KWYHDKDOAIKMQN-UHFFFAOYSA-N 0.000 claims 1
- 239000000543 intermediate Substances 0.000 abstract description 71
- 239000002994 raw material Substances 0.000 abstract description 6
- NWZSZGALRFJKBT-KNIFDHDWSA-N (2s)-2,6-diaminohexanoic acid;(2s)-2-hydroxybutanedioic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O.NCCCC[C@H](N)C(O)=O NWZSZGALRFJKBT-KNIFDHDWSA-N 0.000 abstract description 3
- IKDUDTNKRLTJSI-UHFFFAOYSA-N hydrazine monohydrate Substances O.NN IKDUDTNKRLTJSI-UHFFFAOYSA-N 0.000 abstract description 3
- 238000009776 industrial production Methods 0.000 abstract description 3
- 238000009833 condensation Methods 0.000 abstract 2
- 230000005494 condensation Effects 0.000 abstract 2
- 241000219495 Betulaceae Species 0.000 abstract 1
- 230000009435 amidation Effects 0.000 abstract 1
- 238000007112 amidation reaction Methods 0.000 abstract 1
- 239000003603 dipeptidyl peptidase IV inhibitor Substances 0.000 abstract 1
- 230000007062 hydrolysis Effects 0.000 abstract 1
- 238000006460 hydrolysis reaction Methods 0.000 abstract 1
- 230000008707 rearrangement Effects 0.000 abstract 1
- 230000015572 biosynthetic process Effects 0.000 description 12
- 238000003786 synthesis reaction Methods 0.000 description 12
- 238000003756 stirring Methods 0.000 description 10
- 238000010898 silica gel chromatography Methods 0.000 description 9
- 239000012044 organic layer Substances 0.000 description 8
- 238000000034 method Methods 0.000 description 7
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 5
- 239000000203 mixture Substances 0.000 description 4
- 229910052757 nitrogen Inorganic materials 0.000 description 4
- 230000008569 process Effects 0.000 description 4
- 239000008280 blood Substances 0.000 description 3
- 210000004369 blood Anatomy 0.000 description 3
- 239000007858 starting material Substances 0.000 description 3
- 238000005406 washing Methods 0.000 description 3
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 3
- AMKHAJIFPHJYMH-ZETCQYMHSA-N (2s)-2-[(2-methylpropan-2-yl)oxycarbonylamino]pent-4-ynoic acid Chemical compound CC(C)(C)OC(=O)N[C@H](C(O)=O)CC#C AMKHAJIFPHJYMH-ZETCQYMHSA-N 0.000 description 2
- 102000016622 Dipeptidyl Peptidase 4 Human genes 0.000 description 2
- 108010067722 Dipeptidyl Peptidase 4 Proteins 0.000 description 2
- DTHNMHAUYICORS-KTKZVXAJSA-N Glucagon-like peptide 1 Chemical compound C([C@@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](C)C(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CCCCN)C(=O)NCC(=O)N[C@@H](CCCNC(N)=N)C(N)=O)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](CCCCN)NC(=O)[C@H](C)NC(=O)[C@H](C)NC(=O)[C@H](CCC(N)=O)NC(=O)CNC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CC=1C=CC(O)=CC=1)NC(=O)[C@H](CO)NC(=O)[C@H](CO)NC(=O)[C@@H](NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CO)NC(=O)[C@@H](NC(=O)[C@H](CC=1C=CC=CC=1)NC(=O)[C@@H](NC(=O)CNC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](C)NC(=O)[C@@H](N)CC=1N=CNC=1)[C@@H](C)O)[C@@H](C)O)C(C)C)C1=CC=CC=C1 DTHNMHAUYICORS-KTKZVXAJSA-N 0.000 description 2
- 101800000224 Glucagon-like peptide 1 Proteins 0.000 description 2
- MHAJPDPJQMAIIY-UHFFFAOYSA-N Hydrogen peroxide Chemical compound OO MHAJPDPJQMAIIY-UHFFFAOYSA-N 0.000 description 2
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 description 2
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 2
- 102100040918 Pro-glucagon Human genes 0.000 description 2
- UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical class [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 description 2
- 230000009471 action Effects 0.000 description 2
- 239000003054 catalyst Substances 0.000 description 2
- 238000001035 drying Methods 0.000 description 2
- 238000010438 heat treatment Methods 0.000 description 2
- 230000007246 mechanism Effects 0.000 description 2
- 229910000510 noble metal Inorganic materials 0.000 description 2
- MKMPWKUAHLTIBJ-ISTRZQFTSA-N omarigliptin Chemical compound C1([C@H]2OC[C@@H](C[C@@H]2N)N2CC3=CN(N=C3C2)S(=O)(=O)C)=CC(F)=CC=C1F MKMPWKUAHLTIBJ-ISTRZQFTSA-N 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- 229960000549 4-dimethylaminophenol Drugs 0.000 description 1
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical class [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 1
- HZZVJAQRINQKSD-UHFFFAOYSA-N Clavulanic acid Natural products OC(=O)C1C(=CCO)OC2CC(=O)N21 HZZVJAQRINQKSD-UHFFFAOYSA-N 0.000 description 1
- 208000013016 Hypoglycemia Diseases 0.000 description 1
- SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 description 1
- 206010030113 Oedema Diseases 0.000 description 1
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 1
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 1
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical class [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 1
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 1
- 229940098164 augmentin Drugs 0.000 description 1
- 230000015556 catabolic process Effects 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 150000001875 compounds Chemical class 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 238000006731 degradation reaction Methods 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- 229940090124 dipeptidyl peptidase 4 (dpp-4) inhibitors for blood glucose lowering Drugs 0.000 description 1
- 230000008034 disappearance Effects 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 239000005457 ice water Substances 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 230000005764 inhibitory process Effects 0.000 description 1
- 239000010410 layer Substances 0.000 description 1
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 description 1
- 239000003538 oral antidiabetic agent Substances 0.000 description 1
- 239000008057 potassium phosphate buffer Substances 0.000 description 1
- GCYXWQUSHADNBF-AAEALURTSA-N preproglucagon 78-108 Chemical compound C([C@@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](C)C(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CCCCN)C(=O)NCC(=O)N[C@@H](CCCNC(N)=N)C(=O)NCC(O)=O)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](CCCCN)NC(=O)[C@H](C)NC(=O)[C@H](C)NC(=O)[C@H](CCC(N)=O)NC(=O)CNC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CC=1C=CC(O)=CC=1)NC(=O)[C@H](CO)NC(=O)[C@H](CO)NC(=O)[C@@H](NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CO)NC(=O)[C@@H](NC(=O)[C@H](CC=1C=CC=CC=1)NC(=O)[C@@H](NC(=O)CNC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](C)NC(=O)[C@@H](N)CC=1N=CNC=1)[C@@H](C)O)[C@@H](C)O)C(C)C)C1=CC=CC=C1 GCYXWQUSHADNBF-AAEALURTSA-N 0.000 description 1
- 230000002035 prolonged effect Effects 0.000 description 1
- 239000011541 reaction mixture Substances 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 239000000741 silica gel Substances 0.000 description 1
- 229910002027 silica gel Inorganic materials 0.000 description 1
- AKHNMLFCWUSKQB-UHFFFAOYSA-L sodium thiosulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=S AKHNMLFCWUSKQB-UHFFFAOYSA-L 0.000 description 1
- 235000019345 sodium thiosulphate Nutrition 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D309/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings
- C07D309/16—Heterocyclic compounds containing six-membered rings having one oxygen 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
- C07D309/28—Heterocyclic compounds containing six-membered rings having one oxygen 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 with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D309/30—Oxygen atoms, e.g. delta-lactones
-
- 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
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention discloses a novel preparation method of AugerA synthetic method of chiral intermediates of gliptin comprises the steps of carrying out amidation, alder condensation, hydrazine hydrate condensation, rearrangement, Boc (Boc-Grubbs catalyst cyclization and hydrolysis on starting raw materials of crotonyl chloride and (S) -4-benzyl-2-. The preparation method has the advantages of low cost, easily obtained raw materials and high yield, and is suitable for industrial production.
Description
Technical Field
The invention particularly relates to a preparation method of a chiral intermediate of augustine.
Background
The origliptin (Omargigliptin, development code MK-3102) is an oral hypoglycemic drug developed by America Moshadong company as a super-long-acting dipeptidyl peptidase-4 (DPP-4) inhibitor, and has a chemical name: (2R, 3S, 5R) -2- (2, 5-difluorophenyl) -5- (2- (methylsulfonyl) pyrrolo [3, 4-C ] pyrazol-5 (2H, 4H, 6H) -yl) tetrahydro-2H-pyran-3-amine, having the chemical structure shown in the following formula (1):
the augmentin is orally taken once a week, can generate continuous DPP-4 inhibition effect, has a brand-new blood sugar reducing mechanism, and has the advantages of no weight increase, no hypoglycemic reaction, no edema and the like. The action mechanism is that the degradation of glucagon-like peptide-1 (GLP-1) by in vivo DPP-4 enzyme is inhibited, the action time of GLP-1 is prolonged, thus the concentration of endogenous GLP-1 and GIP in blood is increased, and finally the blood sugar control is improved.
At present, two synthetic routes are mainly used for preparing the alogliptin chiral intermediate:
the synthetic route of WO2016127916 is as follows:
the initial raw material Boc-L-propargyl glycine in the route is not easy to obtain and has high purchase price, and a noble metal catalyst is used in the cyclization reaction in the route.
II, US20090187028
The starting material Boc-L-propargyl glycine in the route needs to be prepared by three to four steps, is not easy to obtain and has high purchase price. In addition, in the route, a noble metal catalyst is used in the DRK reaction, so that a non-corresponding isomer is easily generated.
Disclosure of Invention
The invention aims to overcome the defects of difficult obtainment of raw materials, higher cost, lower yield and the like in the existing preparation method of the chiral intermediate of the alogliptin, and provides the preparation method of the chiral intermediate of the alogliptin. The preparation method has the advantages of easily obtained raw materials, higher yield and novel route, obtains a plurality of brand new intermediates in the synthesis process, has stable properties of the intermediates, and is suitable for industrial production.
In order to achieve the above object, the implementation process of the present invention is as follows:
a synthetic method for preparing chiral intermediates of alogliptin comprises the following steps:
the synthesis procedure is described in detail below:
the first step is as follows: dissolving (S) -4-benzyl-2-oxazolidinone in dichloromethane, adding triethylamine and 4-dimethylaminopyridine, slowly dropwise adding crotonyl chloride under stirring in an ice bath at 0 ℃, and carrying out condensation reaction to obtain an intermediate (I), wherein the intermediate (I) has a structure
The second step is that: dissolving the intermediate (I) in dichloromethane, reacting at-70 deg.C, and condensing with 2, 5-difluorobenzaldehyde under the catalysis of N, N-diisopropylethylamine and dibutylboron trifluoromethanesulfonate or titanium tetrachloride to obtain chiral intermediate (II) with structure of
The third step: dissolving the intermediate (II) in tetrahydrofuran, dropwise adding a hydrazine hydrate solution under stirring at 0 ℃, and carrying out condensation reaction on the intermediate (II) to obtain an intermediate (III), wherein the intermediate (III) has a structure
The fourth step: dissolving the intermediate (III) in isopropanol solution of hydrogen chloride, heating to 50 ℃, slowly dropwise adding isopropanol solution of tert-butyl nitrite for rearrangement reaction to obtain an Intermediate (IV), wherein the structure of the Intermediate (IV) is
The fifth step: dissolving the Intermediate (IV) in acetonitrile or dichloromethane, adding triethylamine and a catalytic amount of DMAP, dropwise adding Boc anhydride for reaction to obtain an intermediate (V), wherein the intermediate (V) has a structure
And a sixth step: dissolving the intermediate (V) in methanol, adding cesium carbonate for ring opening to obtain an intermediate (VI), wherein the intermediate (VI) has a structure
The seventh step: dissolving the intermediate (VI) in dry N, N-dimethylformamide or tetrahydrofuran, adding sodium hydrogen under stirring at 0 ℃, then slowly dropwise adding 2- (chloromethyl) -3, 5-dioxa-1-hexene for nucleophilic substitution reaction to obtain an intermediate (VII), wherein the structure of the intermediate (VII) is as follows
Eighth step: dissolving the intermediate (VII) in dry dichloromethane or toluene, adding Grubbs catalyst, heating and refluxing, and performing cyclization reaction to obtain an intermediate (VIII) with a structure of
The ninth step: the intermediate (VIII) was dissolved in ethyl acetate and reacted with 3mol/L hydrochloric acid to obtain an Intermediate (IX).
After the above reactions are completed, the post-treatment processes are all conventional operations, and the pure target compound can be obtained.
The above preferred conditions can be arbitrarily combined to obtain preferred embodiments of the present invention without departing from the common general knowledge in the art.
The reagents and starting materials used in the present invention are commercially available unless otherwise specified.
The preparation method has the advantages of easily obtained raw materials, higher yield and novel route, obtains a plurality of brand new intermediates in the synthesis process, has stable properties of the intermediates, and is suitable for industrial production.
Detailed Description
The invention is further illustrated by the following examples, which are not intended to limit the scope of the invention. The experimental methods without specifying specific conditions in the following examples were selected according to the conventional methods and conditions, or according to the commercial instructions.
In the following embodiments, the room temperature is 20 to 35 ℃.
EXAMPLE 1 Synthesis of intermediate (I)
20g (0.123mol) of (S) -4-benzyl-2-oxazolidinone were dissolved in 200ml of dichloromethane, and 25.6ml (0.184mol) of triethylamine and 0.45g (0.0037mol) of 4-dimethylaminopyridine were added. Crotonyl chloride (15.4g, 0.15mol) was added dropwise with stirring in an ice bath at 0 ℃. Stirring was maintained at 0 ℃ for 3h, TLC showed disappearance of starting material, dichloromethane and water were added, the organic layer was separated, dried, concentrated and chromatographed on silica gel to give intermediate (I), 26.8g, yield: 89%, [ M + H%+]：246.1。
EXAMPLE 2 Synthesis of intermediate (II)
The method comprises the following steps: after replacing the nitrogen reaction bottle, 24.5g (0.1mol) of the intermediate (I) and 163ml of anhydrous dichloromethane were added, the temperature was lowered to-5 ℃, 32.9g (0.12mol) of dibutylboron trifluoromethanesulfonate was slowly added dropwise and stirred for 10 minutes. Then 21ml (0.15mol) triethylamine are added dropwise. After the addition was complete, the temperature was reduced to-70 ℃ and a solution of 15g (0.105mol) of 2, 5-difluorobenzaldehyde in 50ml of dichloromethane was slowly added dropwise. The temperature is raised to-10 ℃ over 1 hour, and the mixture is stirred for 1 hour. TLC showed complete reaction, 102ml potassium phosphate buffer, 53ml methanol and 53ml 35% hydrogen peroxide were added successively, the organic layer was separated, washed with saturated sodium bicarbonate, washed with sodium thiosulfate, dried, and isolated by silica gel column chromatography to give 33.7g of intermediate (II) in 87% yield, [ M + H ]+]：388.2。
The second method comprises the following steps: after replacing the nitrogen reaction flask, 24.5g (0.1mol) of intermediate (I) and 400ml of anhydrous dichloromethane were added, the temperature was lowered to-50 ℃ to-60 ℃, 120ml (0.12mol) of a 1M solution of titanium tetrachloride in dichloromethane was slowly added dropwise, 46.3ml (0.24mol) of N, N-tetramethylethylenediamine and 19.4ml (0.2mol) of N-methylpyrrolidone were then added dropwise in this order, and the mixture was stirred for 30 minutes. A solution of 19.5g (0.2mol) of 2, 5-difluorobenzaldehyde in 70ml of dichloromethane was slowly added dropwise and stirred for 2 h. The reaction temperature was slowly raised to 15 ℃. TLC shows that the reaction is complete, saturated ammonium chloride is added, filtration is carried out, an organic layer is separated, saturated sodium bicarbonate is used for washing, drying and silica gel column chromatography are carried out to separate 34.8g of intermediate (II) with 90 percent of yield,
EXAMPLE 3 Synthesis of intermediate (III)
19.3g (0.05mol) of intermediate (II) are dissolved in 150ml of tetrahydrofuran and 3.6ml (0.0735mol) of hydrazine hydrate are slowly added dropwise with stirring in an ice bath at 0 ℃. Stirring was maintained at 0 ℃ for 2 h. After TLC detection indicated completion of the reaction, ethyl acetate and water were added. Separating organic layer, extracting water layer with ethyl acetateTwice, the organic layers were combined, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and separated by silica gel column chromatography to give intermediate (III)11.4g, yield 94%, [ M + H ]+]：243.1。
EXAMPLE 4 Synthesis of Intermediate (IV)
9.7g (0.04mol) of intermediate (III) were dissolved in 142ml of a 1.3M isopropanol solution of hydrogen chloride, the reaction temperature was raised to 50 ℃ and then 5.5ml (0.046mol) of a tert-butyl nitrite solution in isopropanol (10ml) were added dropwise. Stirring was maintained at 50 ℃ for 3 h. TLC showed complete reaction, and was concentrated under reduced pressure and separated by silica gel column chromatography to give Intermediate (IV)8.5g, yield 95%, [ M + H ]+]：226.1。
EXAMPLE 5 Synthesis of intermediate (V)
To a reaction flask, 3.15g (0.014mol) of Intermediate (IV), 40ml of methylene chloride and 3ml (0.021mol) of triethylamine were added, and 3.5g (0.016) of Boc anhydride and 0.18g (0.0014mol) of 4-dimethylaminopyridine were added dropwise. Stirred at room temperature for 2 hours. TLC showed complete reaction, and was concentrated under reduced pressure and separated by silica gel column chromatography to give intermediate (V)3.22g, yield 99%, [ M + H ]+]：326.1。
EXAMPLE 6 Synthesis of intermediate (VI)
To a reaction flask, 3.25g (0.01mol) of Intermediate (IV), 125ml of methanol and 0.66g (0.002mol) of cesium carbonate were added, and stirred at room temperature for 2 hours. TLC showed complete reaction, and was concentrated under reduced pressure and separated by silica gel column chromatography to give 2.75g of intermediate (VI) in 92% yield, [ M + H ]+]：300.1。
EXAMPLE 7 Synthesis of intermediate (VII)
2.99g (0.01mol) of intermediate (VI) was dissolved in 60ml of dry N, N-dimethylformamide or tetrahydrofuran, and 0.48g (0.012mol) of sodium hydrogen was added thereto with stirring at 0 ℃ and stirred for 30 minutes. Then, 1.6ml (0.012mol) of 2- (chloromethyl) -3, 5-dioxa-1-hexene was added dropwise thereto, and the mixture was stirred at 0 ℃ for 6 hours. TLC shows that the reaction is complete, ice water is added, methyl tert-butyl ether is added for extraction, an organic layer is dried, filtered, concentrated under reduced pressure and separated by silica gel column chromatography to obtain 3.34g of an intermediate (VII) with the yield of 81 percent and the product is M + H+]：414.1
EXAMPLE 8 Synthesis of intermediate (VIII)
2.1g (5mmol) of intermediate (VII) was dissolved in 80ml of dry toluene, 0.42g (0.5mmol) of Grubbs catalyst was added, nitrogen was replaced 3 times, and the mixture was heated to 80 ℃ and stirred overnight. TLC showed complete reaction, and the reaction mixture was concentrated under reduced pressure and subjected to silica gel column chromatography to give 1.66g of intermediate (VIII) in 86% yield, [ M + H ]+]：386.1
EXAMPLE 9 Synthesis of Intermediate (IX)
Dissolving 19.3g (0.05mol) of intermediate (VIII) in 200ml ethyl acetate, adding 3mol/L hydrochloric acid 300ml, stirring overnight at room temperature, separating organic layer after TLC shows reaction is complete, washing organic layer with saturated sodium bicarbonate, washing with saturated sodium chloride, drying, concentrating under reduced pressure, separating by silica gel column chromatography to obtain Intermediate (IX)15.5g, yield 95%, [ M + H ]+]：328.1。
Claims (10)
1. A synthetic method for preparing an alogliptin chiral Intermediate (IX) comprises the following steps:
2. the synthesis method for preparing the chiral Intermediate (IX) of alogliptin according to claim 1, characterized in that (S) -4-benzyl-2-oxazolidinone is dissolved in dichloromethane, triethylamine and 4-dimethylaminopyridine are added, crotonyl chloride is slowly added dropwise, the reaction temperature is 0 ℃, and condensation reaction is carried out to obtain the intermediate (I), wherein the structure of the intermediate (I) is shown as
3. The synthesis method for preparing chiral Intermediate (IX) of alogliptin according to claim 1, characterized in that intermediate (I) is dissolved in dichloromethane, and the reaction temperature is-70 ℃, and the intermediate (II) is obtained by condensation reaction with 2, 5-difluorobenzaldehyde under the catalysis of TEA (triethylamine) and dibutylboron trifluoromethanesulfonate, or TMEDA and titanium tetrachloride, and the intermediate (II) has the structure
4. The synthesis method for preparing the chiral Intermediate (IX) of alogliptin according to claim 1, characterized in that the intermediate (II) is dissolved in tetrahydrofuran, and hydrazine solution is added dropwise at 0 ℃ to perform condensation reaction on the intermediate (II) to obtain the intermediate (III), wherein the structure of the intermediate (III) is as follows
5. The synthesis method for preparing the chiral Intermediate (IX) of alogliptin according to claim 1, characterized in that the intermediate (III) is dissolved in isopropanol solution of hydrogen chloride, heated to 50 ℃, and dropwise added with tert-butyl nitrite to carry out rearrangement reaction to obtain the Intermediate (IV), wherein the Intermediate (IV) has a structure of
6. The synthesis method for preparing the chiral Intermediate (IX) of alogliptin according to claim 1, characterized in that the Intermediate (IV) is dissolved in acetonitrile or dichloromethane, triethylamine and catalytic amount of 4-dimethylaminopyridine are added, and Boc anhydride is added dropwise for reaction to obtain the intermediate (V), wherein the structure of the intermediate (V) is as follows
7. The synthesis method for preparing the chiral Intermediate (IX) of alogliptin according to claim 1, characterized in that the intermediate (V) is dissolved in methanol, cesium carbonate is added for ring opening to obtain the intermediate (VI), and the intermediate (VI) has the structure
8. The synthesis method for preparing chiral Intermediate (IX) of alogliptin according to claim 1, characterized in that intermediate (VI) is dissolved in dry N, N-dimethylformamide or tetrahydrofuran, and sodium hydrogen and 2- (chloromethyl) -3, 5-dioxa-1-hexene are added for nucleophilic substitution reaction to obtain intermediate (VII), wherein the structure of intermediate (VII) is as follows
9. The synthesis method for preparing the chiral Intermediate (IX) of alogliptin according to claim 1, characterized in that intermediate (VII) is dissolved in dry dichloromethane or toluene, Grubbs catalyst is added for cyclization reaction to obtain intermediate (VIII), and the structure of intermediate (VIII) is shown as
10. The synthesis method for preparing the chiral Intermediate (IX) of alogliptin according to claim 1, characterized in that the intermediate (VIII) is dissolved in ethyl acetate, and 3mol/L hydrochloric acid is added for reaction to obtain the Intermediate (IX).
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| CN102595897A (en) * | 2009-09-02 | 2012-07-18 | 默沙东公司 | Aminotetrahydropyrans as dipeptidyl peptidase-IV inhibitors for the treatment or prevention of diabetes |
| WO2016014324A1 (en) * | 2014-07-21 | 2016-01-28 | Merck Sharp & Dohme Corp. | Process for preparing chiral dipeptidyl peptidase-iv inhibitors |
| CN106543189A (en) * | 2015-09-18 | 2017-03-29 | 成都硕鼎科技有限公司 | A kind of dipeptidyl peptidase-iv inhibitor |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN102595897A (en) * | 2009-09-02 | 2012-07-18 | 默沙东公司 | Aminotetrahydropyrans as dipeptidyl peptidase-IV inhibitors for the treatment or prevention of diabetes |
| WO2016014324A1 (en) * | 2014-07-21 | 2016-01-28 | Merck Sharp & Dohme Corp. | Process for preparing chiral dipeptidyl peptidase-iv inhibitors |
| CN106543189A (en) * | 2015-09-18 | 2017-03-29 | 成都硕鼎科技有限公司 | A kind of dipeptidyl peptidase-iv inhibitor |
Non-Patent Citations (1)
| Title |
|---|
| Asymmetric Synthesis of Highly Functionalized Tetrahydropyran DPP‑4 Inhibitor;Feng Xu et al.;《Org. Lett.》;20140930;第16卷;5422-5425 * |
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