CN105017260A - Preparation method of sitagliptin intermediate triazolopyrazine derivative - Google Patents
Preparation method of sitagliptin intermediate triazolopyrazine derivative Download PDFInfo
- Publication number
- CN105017260A CN105017260A CN201510458441.0A CN201510458441A CN105017260A CN 105017260 A CN105017260 A CN 105017260A CN 201510458441 A CN201510458441 A CN 201510458441A CN 105017260 A CN105017260 A CN 105017260A
- Authority
- CN
- China
- Prior art keywords
- hydrochloride
- reaction
- preparation
- compound
- formula
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
- 238000002360 preparation method Methods 0.000 title claims abstract description 28
- -1 sitagliptin intermediate triazolopyrazine derivative Chemical class 0.000 title abstract description 17
- 238000006243 chemical reaction Methods 0.000 claims abstract description 55
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims abstract description 49
- 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 claims abstract description 23
- IKDUDTNKRLTJSI-UHFFFAOYSA-N hydrazine monohydrate Substances O.NN IKDUDTNKRLTJSI-UHFFFAOYSA-N 0.000 claims abstract description 23
- DTQVDTLACAAQTR-UHFFFAOYSA-M Trifluoroacetate Chemical compound [O-]C(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-M 0.000 claims abstract description 15
- 150000001875 compounds Chemical class 0.000 claims abstract description 12
- 150000007857 hydrazones Chemical class 0.000 claims abstract description 10
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 claims abstract description 6
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 57
- DHMQDGOQFOQNFH-UHFFFAOYSA-N Glycine Chemical compound NCC(O)=O DHMQDGOQFOQNFH-UHFFFAOYSA-N 0.000 claims description 34
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 26
- HYHBKLWDTGTBME-UHFFFAOYSA-N pyrazin-1-ium;chloride Chemical compound Cl.C1=CN=CC=N1 HYHBKLWDTGTBME-UHFFFAOYSA-N 0.000 claims description 23
- 239000004471 Glycine Substances 0.000 claims description 21
- 238000003756 stirring Methods 0.000 claims description 18
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 18
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 14
- 150000002148 esters Chemical class 0.000 claims description 13
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 12
- 239000003513 alkali Substances 0.000 claims description 11
- 239000000706 filtrate Substances 0.000 claims description 11
- 229910052500 inorganic mineral Inorganic materials 0.000 claims description 11
- 239000011707 mineral Substances 0.000 claims description 11
- 235000010755 mineral Nutrition 0.000 claims description 11
- 229910052799 carbon Chemical group 0.000 claims description 10
- 239000007787 solid Substances 0.000 claims description 9
- 239000002904 solvent Substances 0.000 claims description 9
- 238000009835 boiling Methods 0.000 claims description 8
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Substances [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 7
- 230000035484 reaction time Effects 0.000 claims description 7
- 239000012065 filter cake Substances 0.000 claims description 6
- 239000007795 chemical reaction product Substances 0.000 claims description 5
- VTYYLEPIZMXCLO-UHFFFAOYSA-L Calcium carbonate Chemical compound [Ca+2].[O-]C([O-])=O VTYYLEPIZMXCLO-UHFFFAOYSA-L 0.000 claims description 4
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical group [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 4
- AYJRCSIUFZENHW-UHFFFAOYSA-L barium carbonate Chemical compound [Ba+2].[O-]C([O-])=O AYJRCSIUFZENHW-UHFFFAOYSA-L 0.000 claims description 4
- 150000003839 salts Chemical class 0.000 claims description 4
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 3
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 3
- 235000015320 potassium carbonate Nutrition 0.000 claims description 3
- 239000000376 reactant Substances 0.000 claims description 3
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 3
- 125000004044 trifluoroacetyl group Chemical group FC(C(=O)*)(F)F 0.000 claims description 3
- 125000000217 alkyl group Chemical group 0.000 claims description 2
- 229910000019 calcium carbonate Inorganic materials 0.000 claims description 2
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 claims description 2
- 229910000041 hydrogen chloride Inorganic materials 0.000 claims description 2
- 239000000203 mixture Substances 0.000 claims description 2
- 238000010992 reflux Methods 0.000 claims description 2
- VKPPFDPXZWFDFA-UHFFFAOYSA-N 2-chloroethanamine Chemical compound NCCCl VKPPFDPXZWFDFA-UHFFFAOYSA-N 0.000 claims 9
- 238000000034 method Methods 0.000 abstract description 14
- 239000002994 raw material Substances 0.000 abstract description 6
- 238000009833 condensation Methods 0.000 abstract description 5
- 230000005494 condensation Effects 0.000 abstract description 5
- 230000018044 dehydration Effects 0.000 abstract description 5
- 238000006297 dehydration reaction Methods 0.000 abstract description 5
- 230000000694 effects Effects 0.000 abstract description 5
- 230000008569 process Effects 0.000 abstract description 3
- WJPYOCIWVYDFDT-UHFFFAOYSA-N ethyl 3-oxo-4-(2,4,5-trifluorophenyl)butanoate Chemical compound CCOC(=O)CC(=O)CC1=CC(F)=C(F)C=C1F WJPYOCIWVYDFDT-UHFFFAOYSA-N 0.000 abstract description 2
- 238000007363 ring formation reaction Methods 0.000 abstract description 2
- 238000000926 separation method Methods 0.000 abstract description 2
- KYQCOXFCLRTKLS-UHFFFAOYSA-N Pyrazine Chemical compound C1=CN=CC=N1 KYQCOXFCLRTKLS-UHFFFAOYSA-N 0.000 abstract 2
- IVLXQGJVBGMLRR-UHFFFAOYSA-N 2-aminoacetic acid;hydron;chloride Chemical compound Cl.NCC(O)=O IVLXQGJVBGMLRR-UHFFFAOYSA-N 0.000 abstract 1
- PCNDJXKNXGMECE-UHFFFAOYSA-N Phenazine Natural products C1=CC=CC2=NC3=CC=CC=C3N=C21 PCNDJXKNXGMECE-UHFFFAOYSA-N 0.000 abstract 1
- SKOLWUPSYHWYAM-UHFFFAOYSA-N carbonodithioic O,S-acid Chemical compound SC(S)=O SKOLWUPSYHWYAM-UHFFFAOYSA-N 0.000 abstract 1
- 125000001425 triazolyl group Chemical group 0.000 abstract 1
- ONRREFWJTRBDRA-UHFFFAOYSA-N 2-chloroethanamine;hydron;chloride Chemical compound [Cl-].[NH3+]CCCl ONRREFWJTRBDRA-UHFFFAOYSA-N 0.000 description 14
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 12
- MFFMDFFZMYYVKS-SECBINFHSA-N sitagliptin Chemical compound C([C@H](CC(=O)N1CC=2N(C(=NN=2)C(F)(F)F)CC1)N)C1=CC(F)=C(F)C=C1F MFFMDFFZMYYVKS-SECBINFHSA-N 0.000 description 12
- 229960004034 sitagliptin Drugs 0.000 description 11
- 206010012601 diabetes mellitus Diseases 0.000 description 7
- STSCVKRWJPWALQ-UHFFFAOYSA-N TRIFLUOROACETIC ACID ETHYL ESTER Chemical compound CCOC(=O)C(F)(F)F STSCVKRWJPWALQ-UHFFFAOYSA-N 0.000 description 5
- 239000003814 drug Substances 0.000 description 5
- 238000004519 manufacturing process Methods 0.000 description 5
- OFUCCBIWEUKISP-UHFFFAOYSA-N 2,2,2-trifluoroacetohydrazide Chemical compound NNC(=O)C(F)(F)F OFUCCBIWEUKISP-UHFFFAOYSA-N 0.000 description 4
- 235000011182 sodium carbonates Nutrition 0.000 description 4
- QAEDZJGFFMLHHQ-UHFFFAOYSA-N trifluoroacetic anhydride Chemical compound FC(F)(F)C(=O)OC(=O)C(F)(F)F QAEDZJGFFMLHHQ-UHFFFAOYSA-N 0.000 description 4
- GELVZYOEQVJIRR-UHFFFAOYSA-N 2-chloropyrazine Chemical compound ClC1=CN=CC=N1 GELVZYOEQVJIRR-UHFFFAOYSA-N 0.000 description 3
- 230000009435 amidation Effects 0.000 description 3
- 238000007112 amidation reaction Methods 0.000 description 3
- 230000007613 environmental effect Effects 0.000 description 3
- UKVIEHSSVKSQBA-UHFFFAOYSA-N methane;palladium Chemical compound C.[Pd] UKVIEHSSVKSQBA-UHFFFAOYSA-N 0.000 description 3
- MPNNOLHYOHFJKL-UHFFFAOYSA-N peroxyphosphoric acid Chemical compound OOP(O)(O)=O MPNNOLHYOHFJKL-UHFFFAOYSA-N 0.000 description 3
- XHXFXVLFKHQFAL-UHFFFAOYSA-N phosphoryl chloride Substances ClP(Cl)(Cl)=O XHXFXVLFKHQFAL-UHFFFAOYSA-N 0.000 description 3
- 238000011084 recovery Methods 0.000 description 3
- 238000006467 substitution reaction Methods 0.000 description 3
- 125000005323 thioketone group Chemical group 0.000 description 3
- TXTWXQXDMWILOF-UHFFFAOYSA-N (2-ethoxy-2-oxoethyl)azanium;chloride Chemical compound [Cl-].CCOC(=O)C[NH3+] TXTWXQXDMWILOF-UHFFFAOYSA-N 0.000 description 2
- SNTWKPAKVQFCCF-UHFFFAOYSA-N 2,3-dihydro-1h-triazole Chemical compound N1NC=CN1 SNTWKPAKVQFCCF-UHFFFAOYSA-N 0.000 description 2
- RWSOTUBLDIXVET-UHFFFAOYSA-N Dihydrogen sulfide Chemical compound S RWSOTUBLDIXVET-UHFFFAOYSA-N 0.000 description 2
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 2
- NSOXQYCFHDMMGV-UHFFFAOYSA-N Tetrakis(2-hydroxypropyl)ethylenediamine Chemical compound CC(O)CN(CC(C)O)CCN(CC(C)O)CC(C)O NSOXQYCFHDMMGV-UHFFFAOYSA-N 0.000 description 2
- 239000002253 acid Substances 0.000 description 2
- 239000008280 blood Substances 0.000 description 2
- 210000004369 blood Anatomy 0.000 description 2
- 239000012043 crude product Substances 0.000 description 2
- 238000005516 engineering process Methods 0.000 description 2
- 239000007789 gas Substances 0.000 description 2
- COQRGFWWJBEXRC-UHFFFAOYSA-N hydron;methyl 2-aminoacetate;chloride Chemical group Cl.COC(=O)CN COQRGFWWJBEXRC-UHFFFAOYSA-N 0.000 description 2
- 239000003112 inhibitor Substances 0.000 description 2
- 229910052757 nitrogen Inorganic materials 0.000 description 2
- HYAFETHFCAUJAY-UHFFFAOYSA-N pioglitazone Chemical compound N1=CC(CC)=CC=C1CCOC(C=C1)=CC=C1CC1C(=O)NC(=O)S1 HYAFETHFCAUJAY-UHFFFAOYSA-N 0.000 description 2
- IWELDVXSEVIIGI-UHFFFAOYSA-N piperazin-2-one Chemical class O=C1CNCCN1 IWELDVXSEVIIGI-UHFFFAOYSA-N 0.000 description 2
- 229910000027 potassium carbonate Inorganic materials 0.000 description 2
- 235000011181 potassium carbonates Nutrition 0.000 description 2
- 239000000843 powder Substances 0.000 description 2
- 230000009467 reduction Effects 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- 238000010189 synthetic method Methods 0.000 description 2
- 150000003852 triazoles Chemical group 0.000 description 2
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 description 2
- 239000002351 wastewater Substances 0.000 description 2
- VEUMBMHMMCOFAG-UHFFFAOYSA-N 2,3-dihydrooxadiazole Chemical compound N1NC=CO1 VEUMBMHMMCOFAG-UHFFFAOYSA-N 0.000 description 1
- CDMJONZJGWIFJA-MLPAPPSSSA-N C=C(CNCC1)N1/C(/C(F)(F)F)=N\N Chemical compound C=C(CNCC1)N1/C(/C(F)(F)F)=N\N CDMJONZJGWIFJA-MLPAPPSSSA-N 0.000 description 1
- VGCXGMAHQTYDJK-UHFFFAOYSA-N Chloroacetyl chloride Chemical compound ClCC(Cl)=O VGCXGMAHQTYDJK-UHFFFAOYSA-N 0.000 description 1
- PIICEJLVQHRZGT-UHFFFAOYSA-N Ethylenediamine Chemical compound NCCN PIICEJLVQHRZGT-UHFFFAOYSA-N 0.000 description 1
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 1
- 102000004877 Insulin Human genes 0.000 description 1
- 108090001061 Insulin Proteins 0.000 description 1
- 101500016415 Lophius americanus Glucagon-like peptide 1 Proteins 0.000 description 1
- RXWOVONXAGAKIB-UHFFFAOYSA-N O=C(C(F)(F)F)N(CCNC1)C1=O Chemical compound O=C(C(F)(F)F)N(CCNC1)C1=O RXWOVONXAGAKIB-UHFFFAOYSA-N 0.000 description 1
- OAICVXFJPJFONN-UHFFFAOYSA-N Phosphorus Chemical compound [P] OAICVXFJPJFONN-UHFFFAOYSA-N 0.000 description 1
- 150000008065 acid anhydrides Chemical class 0.000 description 1
- 230000009471 action Effects 0.000 description 1
- 230000004913 activation Effects 0.000 description 1
- 229940059260 amidate Drugs 0.000 description 1
- 125000003368 amide group Chemical group 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 239000002585 base Substances 0.000 description 1
- 210000000227 basophil cell of anterior lobe of hypophysis Anatomy 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 239000006227 byproduct Substances 0.000 description 1
- 239000003054 catalyst Substances 0.000 description 1
- 230000003197 catalytic effect Effects 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- DRWMGJONTCWKES-UHFFFAOYSA-N chloroform;hydrochloride Chemical compound Cl.ClC(Cl)Cl DRWMGJONTCWKES-UHFFFAOYSA-N 0.000 description 1
- 230000007812 deficiency Effects 0.000 description 1
- 238000007033 dehydrochlorination reaction Methods 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 239000000890 drug combination Substances 0.000 description 1
- NLFBCYMMUAKCPC-KQQUZDAGSA-N ethyl (e)-3-[3-amino-2-cyano-1-[(e)-3-ethoxy-3-oxoprop-1-enyl]sulfanyl-3-oxoprop-1-enyl]sulfanylprop-2-enoate Chemical class CCOC(=O)\C=C\SC(=C(C#N)C(N)=O)S\C=C\C(=O)OCC NLFBCYMMUAKCPC-KQQUZDAGSA-N 0.000 description 1
- VEUUMBGHMNQHGO-UHFFFAOYSA-N ethyl chloroacetate Chemical compound CCOC(=O)CCl VEUUMBGHMNQHGO-UHFFFAOYSA-N 0.000 description 1
- NPUKDXXFDDZOKR-LLVKDONJSA-N etomidate Chemical compound CCOC(=O)C1=CN=CN1[C@H](C)C1=CC=CC=C1 NPUKDXXFDDZOKR-LLVKDONJSA-N 0.000 description 1
- 230000003203 everyday effect Effects 0.000 description 1
- 125000000524 functional group Chemical group 0.000 description 1
- 208000021302 gastroesophageal reflux disease Diseases 0.000 description 1
- 239000008103 glucose Substances 0.000 description 1
- 229910000037 hydrogen sulfide Inorganic materials 0.000 description 1
- 238000005984 hydrogenation reaction Methods 0.000 description 1
- 230000002218 hypoglycaemic effect Effects 0.000 description 1
- 150000002500 ions Chemical class 0.000 description 1
- 238000004811 liquid chromatography Methods 0.000 description 1
- 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 1
- 230000010534 mechanism of action Effects 0.000 description 1
- OETHQSJEHLVLGH-UHFFFAOYSA-N metformin hydrochloride Chemical compound Cl.CN(C)C(=N)N=C(N)N OETHQSJEHLVLGH-UHFFFAOYSA-N 0.000 description 1
- KQSSATDQUYCRGS-UHFFFAOYSA-N methyl glycinate Chemical compound COC(=O)CN KQSSATDQUYCRGS-UHFFFAOYSA-N 0.000 description 1
- 238000012544 monitoring process Methods 0.000 description 1
- 230000005311 nuclear magnetism Effects 0.000 description 1
- 125000001151 peptidyl group Chemical group 0.000 description 1
- 229910052698 phosphorus Inorganic materials 0.000 description 1
- 239000011574 phosphorus Substances 0.000 description 1
- CYQAYERJWZKYML-UHFFFAOYSA-N phosphorus pentasulfide Chemical compound S1P(S2)(=S)SP3(=S)SP1(=S)SP2(=S)S3 CYQAYERJWZKYML-UHFFFAOYSA-N 0.000 description 1
- 229960005095 pioglitazone Drugs 0.000 description 1
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 238000012827 research and development Methods 0.000 description 1
- 230000000192 social effect Effects 0.000 description 1
- CMQCNTNASCDNGR-UHFFFAOYSA-N toluene;hydrate Chemical group O.CC1=CC=CC=C1 CMQCNTNASCDNGR-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
- C07D487/04—Ortho-condensed systems
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention relates to a preparation method of a sitagliptin intermediate triazolopyrazine derivative. The method comprises the following steps: by using 2-chlorethamin hydrochloride as an initial raw material, reacting the 2-chlorethamin hydrochloride with trifluoroacetate and aminoacetate hydrochloride to generate 1-trifluoroacetyl-2-piperazino ketone (III), and carrying out condensation ring formation on the compound (III), hydrazine hydrate and hydrochloric acid to obtain the sitagliptin intermediate 3-trifluoromethyl-5,6,7,8-tetrahydro-1,2,4-triazolyl[4,3-a]pyrazine hydrochloride (II). The high-activity triluoroacetyl carbonyl functional group and hydrazine hydrate are dehydrated into hydrazone, and the hydrochloric acid is directly added without separation, thereby performing intramolecular dehydration to generate the triazole ring. The method can avoid using thioketone, has the advantages of cheap and accessible raw materials, high reaction selectivity, short process, simple technical operation, high safety and environment friendliness.
Description
Technical field
The present invention relates to a kind of preparation method of sitagliptin intermediate, be specifically related to a kind of preparation method of Triazolopyridine oxazine derivative, this intermediate, for the preparation of diabetes B medicine sitagliptin, belongs to medicine bioengineering chemical field.
Background technology
Sitagliptin, chemical name is (3R)-3-amino-1-[3-(trifluoromethyl)-5,6,7,8-tetrahydrochysene-1,2,4-triazolo [4,3-a] pyrazine-7-base]-4-(2,4,5-trifluorophenyl) fourth-1-ketone, No. CAS is 486460-32-6, English sitagliptin by name, be dipeptidyl peptidase-1V (DPP-1V) inhibitor of MSD Corp. of U.S. research and development, structural formula is such as formula shown in I.
In October, 2006, the listing of U.S. FDA approval sitagliptin.Sitagliptin is first two peptidyl enzyme-4 (DPP-4) inhibitor class diabetes B medicine, its mechanism of action is different from orally-taken blood sugar reducing medicine in the past, the degraded of sitagliptin by suppressing DPP-4 to reduce glucagon-like peptide-I, improve the ability that diabetic subject self beta Cell of islet produces Regular Insulin, control the glucose level of diabetic subject, significantly improve the hypoglycemic ability of patient self.Sitagliptin has high selectivity, its to the selectivity of DPP-4 comparatively DPP-8 and DPP-9 exceed 2500 times, therefore cause side effect without because DPP-8 and DPP-9 is suppressed.Sitagliptin opens a kind of new way for the treatment of diabetes B, every day, oral once i.e. sustainable reductions DPP-4 activity, oral safe and effective, alone or all significantly can reduce blood sugar with Walaphage, pioglitazone drug combination, use safety is effective, in 2009 in Discussion on Chinese Listed.
WO03004498, WO2004085378A, WO2005020920A, WO2005097733A, CN1832949 and CN101863891 etc. describe the preparation technology of sitagliptin and salt thereof or acid salt, subsalt, wherein 3-trifluoromethyl-5,6,7,8-tetrahydrochysene-1,2,4-triazole [4,3-a] pyrazine hydrochloride (II) is wherein key intermediate, its synthetic method is divided into following several according to starting raw material difference: glycine methyl ester route, 2-chloropyrazine route, 1-benzyl-3-sulfo-piperazine route, hydrazine hydrate-Trifluoroacetic Acid Ethyl Ester-chloroacetyl chloride route.
Document Organic Process Research & Development 2005; 9; 634-639 utilizes 2-chloropyrazine to generate N '-trifluoroacetyl group-N '-2-pyrazinyl trifluoroacetyl hydrazine with hydrazine hydrate, trifluoroacetic acid anhydride reactant successively; ring, palladium carbon catalytic hydrogenating reduction is dehydrated into again through peroxophosphoric acid; hydrochloric acid salify preparation formula II compound; total recovery only has 25%, and its reaction method is shown in chemical reaction route 1.
The method raw materials used 2-chloropyrazine, 2 equivalent trifluoroacetic anhydrides, peroxophosphoric acid, 10% palladium-carbon catalyst price are higher, are unfavorable for cost control; Use trifluoroacetic anhydride simultaneously, peroxophosphoric acid produces a large amount of acid waste water, be unfavorable for environmental protection; Palladium carbon hydrogenation pressure is high, and operation hidden danger is large.
Chinese Journal of Pharmaceuticals; o. 11th in 2010; 805-806. reports and utilizes hydrazine hydrate and Trifluoroacetic Acid Ethyl Ester, chloroacetyl chloride reaction to generate N '-trifluoroacetyl group cianazide; 2-chloromethyl-5-Trifluoromethyl-1 is prepared again through phosphorus oxychloride cyclic condensation; 3; 4-oxadiazole; reset with quadrol again and obtain N-[(2Z)-piperazine-2-subunit] trifluoroacetyl hydrazine; ring preparation formula II compound is refluxed into finally by concentrated hydrochloric acid-chloroform; total recovery is 54%, and its reaction method is shown in chemical reaction route 2:
When the method Trifluoroacetic Acid Ethyl Ester and hydrazine hydrate reaction, two amino of hydrazine hydrate all easily react with active stronger Trifluoroacetic Acid Ethyl Ester, and reaction preference is poor, produces a large amount of N, N '-two (trifluoroacetyl) hydrazine; Use phosphorus oxychloride to produce a large amount of phosphorus-containing wastewater, the feature of environmental protection is poor.
Chemical reagent; 3rd phase in 2015; 270-272. reports with quadrol, ethyl chloroacetate as raw material; be substituted, condensation prepares 2-piperazinones; after 2-piperazinones utilizes Boc acid anhydrides to carry out amido protecting, prepare 4-(N-tertbutyloxycarbonyl)-2-piperazine thioketones through thiophosphoric anhydride thio reaction, the latter be substituted with trifluoroacetyl hydrazine again react, ring-closure reaction, de-tertbutyloxycarbonyl salify preparation formula II compound; total recovery is 54%, and its reaction method is shown in chemical reaction route 3:
There is the drawback of reaction preference difference in the method, utilize thiophosphoric anhydride to produce active stronger thioketones simultaneously, then in trifluoroacetyl hydrazine reaction, produce hypertoxic hydrogen sulphide by-product, smell is large, and potential safety hazard is high simultaneously.
Above method is all unfavorable for that the cost of II reduces and green safety suitability for industrialized production.And China is one of diabetes big country at present, estimate that patient has reached 6,000 ten thousand people, wherein about 95% is diabetes B patient.Therefore in order to optimize the production line of sitagliptin, reducing production cost, the synthetic method of the intermediate of exploitation sitagliptin, has important productive value and social effect.
Summary of the invention
For the deficiencies in the prior art, the invention provides a kind of preparation method of sitagliptin intermediate Triazolopyridine oxazine derivative, described Triazolopyridine oxazine derivative is formula II compound 3-trifluoromethyl-5,6,7,8-tetrahydrochysene-1,2,4-triazole [4,3-a] pyrazine hydrochloride.Also namely, the invention provides the preparation method of 3-trifluoromethyl-5,6,7,8-tetrahydrochysene-1,2,4-triazole [4,3-a] pyrazine hydrochloride (II) of a kind of green safety, low cost.
Clear in order to be concise in expression, the formula II compound mentioned by the present invention and 3-trifluoromethyl-5,6,7,8-tetrahydrochysene-1,2,4-triazolo [4,3-a] pyrazine hydrochloride (II) synonym, all refers to 3-trifluoromethyl-5,6,7,8-tetrahydrochysene-1,2,4-triazolo [4,3-a] pyrazine hydrochloride is target compound of the present invention.
Technical scheme of the present invention is as follows:
A preparation method for formula II compound, comprises step as follows:
(1) under solvent and mineral alkali exist, 2-chloroethyl amine hydrochloride generates 1-trifluoroacetyl group-2-piperazinones (III) with trifluoro-acetate, glycine ester hydrochloride reaction successively, adopts " one kettle way " to complete;
(2) reactant of step (1) is cooled to 20-25 DEG C, filters, use toluene wash filter cake; Merging filtrate, goes in the reactor with water trap, adds hydrazine hydrate, make the carbonyl of trifluoroacetyl group and hydrazine hydrate be dehydrated into hydrazone, then add hydrochloric acid, reflux azeotropic water removing, until point water is thorough, 3-trifluoromethyl-5,6,7 is obtained after reclaim under reduced pressure toluene, 8-tetrahydrochysene-1,2,4-triazolo [4,3-a] pyrazine hydrochloride (II);
Reaction scheme is as follows:
Wherein, R is methyl, ethyl or carbon four and other carbon less than four alkyl.
Above method gained 3-trifluoromethyl-5,6,7,8-tetrahydrochysene-1,2,4-triazolo [4,3-a] pyrazine hydrochloride (II) is through the decolouring of ethanol-gac recrystallization, obtain white solid 3-trifluoromethyl-5,6,7,8-tetrahydrochysene-1,2,4-triazolo [4,3-a] pyrazine hydrochloride (II).
In above step (1), 2-chloroethyl amine hydrochloride and trifluoroacetic acid amidation generate N-TFA base-2-chloroethyl amine, and N-TFA base-2-chloroethyl amine and glycine ester hydrochloride carry out SN under mineral alkali effect
2substitution reaction, dehydrochlorination condensation generates 2 '-trifluoroacetyl amido ethyl glycine ester; Then there is dealcoholysis in molecule in 80-110 DEG C in 2 '-trifluoroacetyl amido ethyl glycine ester, and amidation generates 1-trifluoroacetyl group-2-piperazinones, and above each reaction " one kettle way " completes.
Preferred according to the present invention, a kind of preparation method of 3-trifluoromethyl-5,6,7,8-tetrahydrochysene-1,2,4-triazolo [4,3-a] pyrazine hydrochloride (II), step is as follows:
(1) in four-hole boiling flask, add solvent, mineral alkali, 2-chloroethyl amine hydrochloride, trifluoro-acetate successively, after 20-40 DEG C of stirring reaction 1-3 hour, reaction product is N-TFA base-2-chloroethyl amine; Then glycine ester hydrochloride is added, in 40-60 DEG C of reaction 1-3 hour, generate 2 '-trifluoroacetyl amido ethyl glycine ester, then in 80-110 DEG C of stirring reaction 2-5 hour dealcoholysis, generate 1-trifluoroacetyl group-2-piperazinones (III), reclaim the ethanol steamed simultaneously;
(2) 20-25 DEG C is cooled to, filter, filter cake toluene wash 1-3 time, the filtrate merged, be transferred in the four-hole boiling flask with water trap, between 20-25 DEG C, drip hydrazine hydrate, in 40-60 DEG C of temperature stirring reaction 1-3 hour after dropwising, make the carbonyl of 1-trifluoroacetyl group-2-piperazinones be dehydrated into hydrazone; Add hydrochloric acid again, backflow azeotropic water removing, until point water is thorough, reclaim under reduced pressure toluene, obtains 3-trifluoromethyl-5,6,7,8-tetrahydrochysene-1,2,4-triazole [4,3-a] pyrazine hydrochloride.
In above-mentioned steps (1) specifically, reaction formula is as follows:
Above gained 3-trifluoromethyl-5,6,7,8-tetrahydrochysene-1,2,4-triazolo [4,3-a] pyrazine hydrochloride is crude product, and proceeding aftertreatment can by prior art.The present invention preferably provides the post-treating method of following steps (3):
(3) in above gained 3-trifluoromethyl-5,6,7,8-tetrahydrochysene-1,2,4-triazolo [4,3-a] pyrazine hydrochloride crude product, add gac and ethanol, stir at 50-65 DEG C of temperature, then filtered while hot; Filtrate is cooled to 0-5 DEG C, filters, dry, obtains white solid 3-trifluoromethyl-5,6,7,8-tetrahydrochysene-1,2,4-triazolo [4,3-a] pyrazine hydrochloride (II).
According to the present invention, preferably, the mass ratio of described solvent and 2-chloroethyl amine hydrochloride is 10:1 to 20:1; Described solvent is C1-C4 low-carbon alcohol and toluene mixture; The mass ratio of preferred C1-C4 low-carbon alcohol and toluene is 1:(1-3); Preferably C1-C4 low-carbon alcohol is methyl alcohol or ethanol further.
According to the present invention, preferably, the mol ratio of described mineral alkali and 2-chloroethyl amine hydrochloride is (1.5-2.5): 1; Described mineral alkali is sodium carbonate, salt of wormwood, calcium carbonate, barium carbonate or volatile salt, and preferably mineral alkali is sodium carbonate or salt of wormwood further.
According to the present invention, preferably, described trifluoro-acetate is trifluoro-acetate or Trifluoroacetic Acid Ethyl Ester; Described glycine ester hydrochloride is glycine methyl ester hydrochloride or glycine ethyl ester hydrochloride; Namely, in reaction formula, R is methyl or ethyl.
According to the present invention, preferably, described 2-chloroethyl amine hydrochloride and trifluoro-acetate, glycine ester hydrochloride mol ratio be 1:(1.0-1.2): (1.0-1.2);
According to the present invention, preferably, 2-chloroethyl amine hydrochloride and trifluoro-acetate temperature of reaction are 20-40 DEG C; Further preferable reaction temperature is 30-35 DEG C, and the reaction times is 1.5-2 hour;
According to the present invention, preferably, the reaction product N-TFA base-2-chloroethyl amine of 2-chloroethyl amine hydrochloride and trifluoro-acetate and the temperature of reaction of glycine ester hydrochloride are 50-55 DEG C, and the reaction times is 1.5-2 hour;
According to the present invention, preferably, the temperature of reaction of the reaction product 2-trifluoroacetyl amido ethyl glycine ester dealcoholysis generation 1-trifluoroacetyl group-2-piperazinones of N-TFA base-2-chloroethyl amine and glycine ester hydrochloride is 90-95 DEG C, stirring reaction 3-4 hour;
According to the present invention, preferably, the mol ratio of hydrazine hydrate and 2-chloroethyl amine hydrochloride is (1.0-1.5); 1-trifluoroacetyl group-2-piperazinones and toluene to mix the temperature of reaction that filtrate and hydrazine hydrate be dehydrated into hydrazone be 50-55 DEG C, the reaction times is 1.5-2 hour.
According to the present invention, preferably, the hydrazone that 1-trifluoroacetyl group-2-piperazinones and hydrazine hydrate dehydration generate, without being separated, directly adds hydrochloric acid; dehydration generates triazole ring, i.e. 3-trifluoromethyl-5,6, and 7; 8-tetrahydrochysene-1,2,4-triazole [4,3-a] pyrazine hydrochloride (II).Described hydrochloric acid, amounts to hydrogenchloride meter, is (1.2-2.0): 1 with the mol ratio of 2-chloroethyl amine hydrochloride, and back flow reaction temperature is toluene-water azeotropic temperature, and the reaction times is 2-5 hour;
Preferred according to the present invention, the mass concentration of hydrochloric acid used is 30-35%; The concentration of hydrazine hydrate used is 75-80% hydrazine hydrate.
Beneficial effect of the present invention:
The present invention with 2-chloroethyl amine hydrochloride for initial feed; 2-chloroethyl amine hydrochloride and trifluoro-acetate, glycine ester hydrochloride reaction is utilized to generate 1-trifluoroacetyl group-2-piperazinones (III); this compound III again with hydrazine hydrate, hydrochloric acid cyclic condensation 3-trifluoromethyl-5; 6; 7,8-tetrahydrochysene-1,2; 4-triazole [4,3-a] pyrazine hydrochloride (II).The present inventor studies discovery, and active stronger trifluoroacetyl group and hydrazine hydrate are dehydrated into hydrazone, without separation, directly add hydrochloric acid, and intramolecular dehydration generates triazole ring, can avoid using thioketones.
Under solvent and mineral alkali exist, " one kettle way " carries out following reaction successively: 2-chloroethyl amine hydrochloride and trifluoroacetic acid amidation generate N-TFA base-2-chloroethyl amine, N-TFA base-2-chloroethyl amine and glycine ester hydrochloride through SN
2substitution reaction generates 2 '-trifluoroacetyl amido ethyl glycine ester, 2 '-trifluoroacetyl amido ethyl glycine ester intramolecular amideization under high temperature generates 1-trifluoroacetyl group-2-piperazinones.Use 2-chloroethyl amine hydrochloride to replace document 1,2-diaminoethane used and trifluoro-acetate reaction, relate to functional group reactions single; And carry out described amidate action, SN successively by controlling temperature of reaction
2substitution reaction and intramolecular amideization reaction, selectivity is good, and yield is high.The present invention does not use thioketones described in document, but utilizes the activation effect of trifluoromethyl, to make in 1-trifluoroacetyl group-2-piperazinones and be connected carbonyl and hydrazine hydrate of trifluoromethyl is dehydrated into hydrazone; then with hydrochloric acid reflux azeotropic, intramolecular dehydration is impelled to form 1,2; 4-triazole ring, i.e. 3-trifluoromethyl-5,6; 7; 8-tetrahydrochysene-1,2,4-triazolo [4; 3-a] pyrazine hydrochloride (II), do not relate to the emission problem of hypertoxic hydrogen sulfide.
The present invention uses raw material cheap and easy to get, and reaction preference is high, and flow process is short, and technological operation is easy, and the environmental protection of production process green safety, is conducive to suitability for industrialized production.
Embodiment
Describe the present invention in detail below in conjunction with embodiment, but the present invention is not only confined to this.
In embodiment, the monitoring of step of reaction and the purity of each intermediate are by gas chromatographic detection, and gas chromatograph is Shimadzu GC-2010PLUS.Concentration % in embodiment is mass percent.
The preparation of embodiment 1:3-trifluoromethyl-5,6,7,8-tetrahydrochysene-1,2,4-triazolo [4,3-a] pyrazine hydrochloride (II)
50 grams of ethanol are added successively in 250 milliliters of four-hole boiling flasks, 100 grams of toluene, 17 grams of powdered sodium carbonates, 11.6 grams of (0.1 mole) 2-chloroethyl amine hydrochlorides, 14.5 grams of (0.10 mole) Trifluoroacetic Acid Ethyl Esters, between 30-35 DEG C, stirring reaction is after 2 hours, add 14.5 grams of (0.10 mole) glycine ethyl ester hydrochlorides, react 2 hours between 50-55 DEG C, between 90-95 DEG C, stirring reaction 3 hours, reclaims the ethanol steamed simultaneously.Be cooled to 20-25 DEG C, filter, filter cake 30 grams of toluene wash, the filtrate of merging is transferred in 250 milliliters of four-hole boiling flasks with water trap, 6.5 gram of 80% hydrazine hydrate is dripped between 20-25 DEG C, within about 1 hour, drip and finish, after this stirring reaction 2 hours between 50-55 DEG C, adding 15 grams of concentration is the hydrochloric acid of 35%, backflow azeotropic water removing, until point water is thorough, about 3 hours, reclaim under reduced pressure toluene, 0.5 gram of gac is added in gained faint yellow solid, 25 grams of ethanol, stirring reaction 1 hour at 60 DEG C, filtered while hot, filtrate is cooled to 0-5 DEG C, filter, dry white solid 3-trifluoromethyl-5, 6, 7, 8-tetrahydrochysene-1, 2, 4-triazolo [4, 3-a] pyrazine hydrochloride (II) 19.7 gram, yield 86.2%, fusing point: 264 DEG C.
Product analysis data are as follows:
Infrared V (cm
-1): 3014,2975,1499,1267,1165.
Nuclear-magnetism
1hNMR (deuterated DMSO, 400MHz) δ (ppm): 3.51 (triplet, 2H), 4.43 (triplet, 2H), 4.71 (unimodal, 2H), 9.82 (broad peak, 2H).
Liquid chromatography mass spectrometric result LC-MS positive ion scans: [M+1] 229.
The preparation of embodiment 2:3-trifluoromethyl-5,6,7,8-tetrahydrochysene-1,2,4-triazolo [4,3-a] pyrazine hydrochloride (II)
50 grams of methyl alcohol are added successively in 250 milliliters of four-hole boiling flasks, 100 grams of toluene, 17 grams of powdered sodium carbonates, 11.6 grams of (0.1 mole) 2-chloroethyl amine hydrochlorides, 13.0 grams of (0.1 mole) trifluoro-acetates, between 30-35 DEG C, stirring reaction is after 2 hours, add 13.1 grams of (0.10 mole) glycine methyl ester hydrochlorides, react 2 hours between 50-55 DEG C, between 90-95 DEG C, stirring reaction 3 hours, reclaims the methyl alcohol steamed simultaneously.Be cooled to 20-25 DEG C, filter, filter cake 30 grams of toluene wash, the filtrate of merging is transferred in 250 milliliters of four-hole boiling flasks with water trap, the hydrazine hydrate of 6.5 gram 80% is dripped between 20-25 DEG C, within about 1 hour, drip and finish, after this stirring reaction 2 hours between 50-55 DEG C, add 15 gram of 35% hydrochloric acid, backflow azeotropic water removing, until point water is thorough, about 3 hours, reclaim under reduced pressure toluene, 0.5 gram of gac is added in gained faint yellow solid, 25 grams of ethanol, stirring reaction 1 hour at 60 DEG C, filtered while hot, filtrate is cooled to 0-5 DEG C, filter, dry white solid 3-trifluoromethyl-5, 6, 7, 8-tetrahydrochysene-1, 2, 4-triazolo [4, 3-a] pyrazine hydrochloride (II) 18.7 gram, yield 81.5%.
The preparation of embodiment 3:3-trifluoromethyl-5,6,7,8-tetrahydrochysene-1,2,4-triazolo [4,3-a] pyrazine hydrochloride (II)
Replace 17 grams of powdered sodium carbonates of embodiment 1 by 22 grams of potassium carbonate powder, all the other are with embodiment 1, obtain white solid 3-trifluoromethyl-5,6,7,8-tetrahydrochysene-1,2,4-triazolo [4,3-a] pyrazine hydrochloride (II) 19.1 gram, yield 83.6%.
The preparation of embodiment 4:3-trifluoromethyl-5,6,7,8-tetrahydrochysene-1,2,4-triazolo [4,3-a] pyrazine hydrochloride (II)
Replace 17 grams of powdered sodium carbonates of embodiment 2 by 22 grams of potassium carbonate powder, all the other are with embodiment 2, obtain white solid 3-trifluoromethyl-5,6,7,8-tetrahydrochysene-1,2,4-triazolo [4,3-a] pyrazine hydrochloride (II) 19.0 gram, yield 83.2%.
Claims (10)
1. a preparation method for formula II compound, is characterized in that comprising step as follows:
(1) under solvent and mineral alkali exist, 2-chloroethyl amine hydrochloride generates 1-trifluoroacetyl group-2-piperazinones (III) with trifluoro-acetate, glycine ester hydrochloride reaction successively, adopts " one kettle way " to complete;
(2) reactant of step (1) is cooled to 20-25 DEG C, filters, use toluene wash filter cake; Merging filtrate, goes in the reactor with water trap, adds hydrazine hydrate, make the carbonyl of trifluoroacetyl group and hydrazine hydrate be dehydrated into hydrazone, then add hydrochloric acid, reflux azeotropic water removing, until point water is thorough, 3-trifluoromethyl-5,6,7 is obtained after reclaim under reduced pressure toluene, 8-tetrahydrochysene-1,2,4-triazolo [4,3-a] pyrazine hydrochloride (II);
Reaction scheme is as follows:
Wherein, R is methyl, ethyl or carbon four and other carbon less than four alkyl.
2. the preparation method of formula II compound as claimed in claim 1, is characterized in that comprising step as follows:
(1) in four-hole boiling flask, add solvent, mineral alkali, 2-chloroethyl amine hydrochloride, trifluoro-acetate successively, after 20-40 DEG C of stirring reaction 1-3 hour, reaction product is N-TFA base-2-chloroethyl amine; Then glycine ester hydrochloride is added, in 40-60 DEG C of reaction 1-3 hour, generate 2 '-trifluoroacetyl amido ethyl glycine ester, then in 80-110 DEG C of stirring reaction 2-5 hour dealcoholysis, generate 1-trifluoroacetyl group-2-piperazinones (III), reclaim the ethanol steamed simultaneously;
(2) 20-25 DEG C is cooled to, filter, filter cake toluene wash 1-3 time, the filtrate merged, be transferred in the four-hole boiling flask with water trap, between 20-25 DEG C, drip hydrazine hydrate, in 40-70 DEG C of temperature stirring reaction 1-3 hour after dropwising, make the carbonyl of 1-trifluoroacetyl group-2-piperazinones be dehydrated into hydrazone; Add hydrochloric acid again, backflow azeotropic water removing, until point water is thorough, reclaim under reduced pressure toluene, obtains 3-trifluoromethyl-5,6,7,8-tetrahydrochysene-1,2,4-triazolo [4,3-a] pyrazine hydrochloride.
3. the preparation method of formula II compound as claimed in claim 1 or 2, it is characterized in that the 3-trifluoromethyl-5 to step (2) gained, 6,7,8-tetrahydrochysene-1,2,4-triazolo [4,3-a] add gac and ethanol in pyrazine hydrochloride, stir at 50-65 DEG C of temperature, then filtered while hot; Filtrate is cooled to 0-5 DEG C, filters, dry, obtains white solid 3-trifluoromethyl-5,6,7,8-tetrahydrochysene-1,2,4-triazolo [4,3-a] pyrazine hydrochloride (II).
4. the preparation method of formula II compound as claimed in claim 1 or 2, is characterized in that the mass ratio of described solvent and 2-chloroethyl amine hydrochloride is 10:1 to 20:1; Described solvent is C1-C4 low-carbon alcohol and toluene mixture; The mass ratio of preferred C1-C4 low-carbon alcohol and toluene is 1:(1-3); Preferably C1-C4 low-carbon alcohol is methyl alcohol or ethanol further.
5. the preparation method of formula II compound as claimed in claim 1 or 2, it is characterized in that, the mol ratio of described mineral alkali and 2-chloroethyl amine hydrochloride is (1.5-2.5): 1; Preferred described mineral alkali is sodium carbonate, salt of wormwood, calcium carbonate, barium carbonate or volatile salt.
6. the preparation method of formula II compound as claimed in claim 1 or 2, it is characterized in that described 2-chloroethyl amine hydrochloride and trifluoro-acetate, glycine ester hydrochloride mol ratio be 1:(1.0-1.2): (1.0-1.2).
7. the preparation method of formula II compound as claimed in claim 1 or 2, it is characterized in that, 2-chloroethyl amine hydrochloride and trifluoro-acetate temperature of reaction are 25-35 DEG C; Reaction times is 1-2 hour; The reaction product N-TFA base-2-chloroethyl amine of 2-chloroethyl amine hydrochloride and trifluoro-acetate and the temperature of reaction of glycine ester hydrochloride are 50-55 DEG C, and the reaction times is 1-3 hour.
8. the preparation method of formula II compound as claimed in claim 1 or 2, it is characterized in that, in step (1), 2 '-trifluoroacetyl amido ethyl glycine ester dealcoholization temperature is 80-110 DEG C, stirring reaction 2-4 hour.
9. the preparation method of formula II compound as claimed in claim 1 or 2, it is characterized in that, the mol ratio of described hydrazine hydrate and 2-chloroethyl amine hydrochloride is (1.0-1.5); The temperature of reaction that step (2) is dehydrated into hydrazone is 40-60 DEG C, and the reaction times is 1-3 hour.
10. the preparation method of formula II compound as claimed in claim 1 or 2, it is characterized in that described hydrochloric acid amounts to hydrogenchloride meter, is (1.2-2.0) with the mol ratio of 2-chloroethyl amine hydrochloride: 1.
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN201510458441.0A CN105017260B (en) | 2015-07-30 | 2015-07-30 | Preparation method of sitagliptin intermediate triazolopyrazine derivative |
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN201510458441.0A CN105017260B (en) | 2015-07-30 | 2015-07-30 | Preparation method of sitagliptin intermediate triazolopyrazine derivative |
Publications (2)
Publication Number | Publication Date |
---|---|
CN105017260A true CN105017260A (en) | 2015-11-04 |
CN105017260B CN105017260B (en) | 2017-04-19 |
Family
ID=54407607
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CN201510458441.0A Active CN105017260B (en) | 2015-07-30 | 2015-07-30 | Preparation method of sitagliptin intermediate triazolopyrazine derivative |
Country Status (1)
Country | Link |
---|---|
CN (1) | CN105017260B (en) |
Cited By (6)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN106117153A (en) * | 2016-07-05 | 2016-11-16 | 淮阴师范学院 | The preparation method of 2 piperazinones |
CN113527312A (en) * | 2021-08-24 | 2021-10-22 | 江苏八巨药业有限公司 | Green synthesis method of sitagliptin intermediate |
CN114853674A (en) * | 2022-04-26 | 2022-08-05 | 浙江安贝特药业有限公司 | Production method of medical intermediate 1,4,5, 6-tetrahydro-3-cyclopentapyrazole formonitrile |
CN115260200A (en) * | 2022-08-30 | 2022-11-01 | 宿迁阿尔法科技有限公司 | Preparation method of sitagliptin intermediate |
CN115650987A (en) * | 2022-10-26 | 2023-01-31 | 长沙创新药物工业技术研究院有限公司 | Method for preparing sitagliptin intermediate substituted pyrazine hydrochloride |
WO2023175492A1 (en) * | 2022-03-14 | 2023-09-21 | Hikal Limited | Novel intermediates and its use in manufacturing of sitagliptin |
Citations (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN1524082A (en) * | 2001-07-06 | 2004-08-25 | Beta-amino tetrahydroimidazo (1,2-a) pyrazines and ahydrotrioazolo (4,3-a) pyrazines as dipeptidyl idase inhibitors for the treatment or prevention of diabetes | |
WO2004087650A2 (en) * | 2003-03-27 | 2004-10-14 | Merck & Co. Inc. | Process and intermediates for the preparation of beta-amino acid amide dipeptidyl peptidase-iv inhibitors |
WO2004103276A2 (en) * | 2003-05-14 | 2004-12-02 | Merck & Co., Inc. | 3-amino-4-phenylbutanoic acid derivatives as dipeptidyl peptidase inhibitors for the treatment or prevention of diabetes |
CN1832949A (en) * | 2003-06-24 | 2006-09-13 | 麦克公司 | Phosphoric acid salt of a dipeptidyl peptidase-iv inhibitor |
WO2007050485A2 (en) * | 2005-10-25 | 2007-05-03 | Merck & Co., Inc. | Combination of a dipeptidyl peptidase-4 inhibitor and an anti-hypertensive agent for the treatment of diabetes and hypertension |
-
2015
- 2015-07-30 CN CN201510458441.0A patent/CN105017260B/en active Active
Patent Citations (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN1524082A (en) * | 2001-07-06 | 2004-08-25 | Beta-amino tetrahydroimidazo (1,2-a) pyrazines and ahydrotrioazolo (4,3-a) pyrazines as dipeptidyl idase inhibitors for the treatment or prevention of diabetes | |
WO2004087650A2 (en) * | 2003-03-27 | 2004-10-14 | Merck & Co. Inc. | Process and intermediates for the preparation of beta-amino acid amide dipeptidyl peptidase-iv inhibitors |
WO2004103276A2 (en) * | 2003-05-14 | 2004-12-02 | Merck & Co., Inc. | 3-amino-4-phenylbutanoic acid derivatives as dipeptidyl peptidase inhibitors for the treatment or prevention of diabetes |
CN1832949A (en) * | 2003-06-24 | 2006-09-13 | 麦克公司 | Phosphoric acid salt of a dipeptidyl peptidase-iv inhibitor |
WO2007050485A2 (en) * | 2005-10-25 | 2007-05-03 | Merck & Co., Inc. | Combination of a dipeptidyl peptidase-4 inhibitor and an anti-hypertensive agent for the treatment of diabetes and hypertension |
Non-Patent Citations (4)
Title |
---|
ELLI SMAKULA HAND 等: "A definitive synthesis of 2-[(5-methyl-s-triazolo[4,3-c]quinazolin-3-yl)thio]-N-benzylacetanilide and other reactions of its precursors", 《CANADIAN JOURNAL OF CHEMISTRY》 * |
MANCILLA, TERESA 等: "Synthesis and characterization of piperazine-2,6-dione", 《ORGANIC PREPARATIONS AND PROCEDURES INTERNATIONAL》 * |
叶飞 等: "西他列汀外消旋体的合成及拆分", 《合成化学》 * |
孙桂芳 等: "西他列汀合成路线图解", 《中国医药工业杂志》 * |
Cited By (9)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN106117153A (en) * | 2016-07-05 | 2016-11-16 | 淮阴师范学院 | The preparation method of 2 piperazinones |
CN113527312A (en) * | 2021-08-24 | 2021-10-22 | 江苏八巨药业有限公司 | Green synthesis method of sitagliptin intermediate |
CN113527312B (en) * | 2021-08-24 | 2022-06-07 | 江苏八巨药业有限公司 | Green synthesis method of sitagliptin intermediate |
WO2023175492A1 (en) * | 2022-03-14 | 2023-09-21 | Hikal Limited | Novel intermediates and its use in manufacturing of sitagliptin |
CN114853674A (en) * | 2022-04-26 | 2022-08-05 | 浙江安贝特药业有限公司 | Production method of medical intermediate 1,4,5, 6-tetrahydro-3-cyclopentapyrazole formonitrile |
CN114853674B (en) * | 2022-04-26 | 2024-02-02 | 浙江安贝特药业有限公司 | Production method of medical intermediate 1,4,5, 6-tetrahydro-3-cyclopentapyrazole carbonitrile |
CN115260200A (en) * | 2022-08-30 | 2022-11-01 | 宿迁阿尔法科技有限公司 | Preparation method of sitagliptin intermediate |
CN115260200B (en) * | 2022-08-30 | 2024-03-26 | 宿迁阿尔法科技有限公司 | Preparation method of sitagliptin intermediate |
CN115650987A (en) * | 2022-10-26 | 2023-01-31 | 长沙创新药物工业技术研究院有限公司 | Method for preparing sitagliptin intermediate substituted pyrazine hydrochloride |
Also Published As
Publication number | Publication date |
---|---|
CN105017260B (en) | 2017-04-19 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
CN105017260A (en) | Preparation method of sitagliptin intermediate triazolopyrazine derivative | |
CN107915738B (en) | For synthesizing Ba Rui for the preparation method of the key intermediate 2 of Buddhist nun | |
CN102712637A (en) | Method for producing methyl-{4,6-diamino-2-[1-(2-fluorobenzyl)-1h-pyrazolo[3,4-b]pyridino-3-yl]pyrimidino-5-yl} carbamate and its purification for use thereof as pharmaceutical substance | |
CN104059023B (en) | The environment-friendly preparation method of VITMAIN B1 key intermediate 2-methyl-4-amino-5-amino methylpyrimidine | |
US10189760B2 (en) | Method for preparing sitagliptin intermediate via asymmetrical reduction method | |
CN101830891A (en) | Synthesizing method of piribedil | |
CN102126976B (en) | Intermediates of Sitagliptin and preparation method thereof | |
CN114599650A (en) | DCN 1/2-mediated cullin ubiquitination-modified pharmaceutically active pyrazolo-pyridone modulators | |
CN103319487A (en) | Preparation method of sitagliptin and intermediate of sitagliptin | |
CN104987338A (en) | Low cost method for preparing sitagliptin phosphate salt key intermediate | |
CN102491953A (en) | Method for synthesizing florfenicol midbody RT0131 | |
CN102503829B (en) | Preparation methods for sitagliptin intermediates | |
CN104151253A (en) | Synthesis method of Alogliptin intermediate | |
CN109608468A (en) | Tofacitinib citrate impurity, and synthesis method and application thereof | |
CN113527312A (en) | Green synthesis method of sitagliptin intermediate | |
CN101698664B (en) | Preparation method of pharmaceutical intermediate 2-amine methylpyrazine hydrochloride | |
CN103739545B (en) | Simple preparation method of vitamin B6 | |
CN110759914A (en) | Preparation method of medicine for treating diabetes | |
CN102363599B (en) | A kind of sitagliptin intermediate chiral separation method | |
CN114685349B (en) | Process for preparing cis-exo-bicyclo [2.2.1] heptane-2, 3-dicarboximide | |
CN103551144A (en) | Bimetallic composite catalyst for preparing afloqualone and method for preparing afloqualone | |
CN106966940B (en) | A kind of preparation method of Sitagliptin phosphate intermediate N arylmethyl -2S- cyano methyl acridine | |
CN105330664A (en) | Synthetic method Sitagliptin impurity | |
CN102030757B (en) | Synthesis process of methoxsalen | |
CN105418507A (en) | Preparation method for 1-(3-methyl-1-phenyl-1H-pyrazole-5-yl)piperazine |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
C06 | Publication | ||
PB01 | Publication | ||
C10 | Entry into substantive examination | ||
SE01 | Entry into force of request for substantive examination | ||
GR01 | Patent grant | ||
GR01 | Patent grant | ||
PE01 | Entry into force of the registration of the contract for pledge of patent right |
Denomination of invention: Preparation method of triazole pyrazine derivative as an intermediate of sitagliptin Effective date of registration: 20231205 Granted publication date: 20170419 Pledgee: Hengfeng bank Limited by Share Ltd. Dongying branch Pledgor: Xinfa pharmaceutical Co.,Ltd. Registration number: Y2023980069314 |
|
PE01 | Entry into force of the registration of the contract for pledge of patent right |