CN104109157B - The preparation method that Ka Gelie is clean - Google Patents
The preparation method that Ka Gelie is clean Download PDFInfo
- Publication number
- CN104109157B CN104109157B CN201410377806.2A CN201410377806A CN104109157B CN 104109157 B CN104109157 B CN 104109157B CN 201410377806 A CN201410377806 A CN 201410377806A CN 104109157 B CN104109157 B CN 104109157B
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- CN
- China
- Prior art keywords
- methyl
- gelie
- fluorophenyl
- aminomethyl phenyl
- clean
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- 238000002360 preparation method Methods 0.000 title claims abstract description 25
- 238000006243 chemical reaction Methods 0.000 claims abstract description 41
- 150000001875 compounds Chemical class 0.000 claims abstract description 29
- -1 iodo-2-aminomethyl phenyl Chemical group 0.000 claims abstract description 28
- ZZPNDIHOQDQVNU-UHFFFAOYSA-N 2-hydroxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane Chemical compound CC1(C)OB(O)OC1(C)C ZZPNDIHOQDQVNU-UHFFFAOYSA-N 0.000 claims abstract description 19
- YTPLMLYBLZKORZ-UHFFFAOYSA-N Thiophene Chemical compound C=1C=CSC=1 YTPLMLYBLZKORZ-UHFFFAOYSA-N 0.000 claims abstract description 16
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims abstract description 13
- YQTCQNIPQMJNTI-UHFFFAOYSA-N 2,2-dimethylpropan-1-one Chemical group CC(C)(C)[C]=O YQTCQNIPQMJNTI-UHFFFAOYSA-N 0.000 claims abstract description 11
- 238000012805 post-processing Methods 0.000 claims abstract description 10
- 238000011084 recovery Methods 0.000 claims abstract description 8
- 229930192474 thiophene Natural products 0.000 claims abstract description 8
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 claims description 38
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 30
- 229910052763 palladium Inorganic materials 0.000 claims description 19
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 claims description 16
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 15
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims description 14
- SCVFZCLFOSHCOH-UHFFFAOYSA-M potassium acetate Chemical compound [K+].CC([O-])=O SCVFZCLFOSHCOH-UHFFFAOYSA-M 0.000 claims description 14
- LENZDBCJOHFCAS-UHFFFAOYSA-N tris Chemical class OCC(N)(CO)CO LENZDBCJOHFCAS-UHFFFAOYSA-N 0.000 claims description 13
- 239000002253 acid Substances 0.000 claims description 11
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 10
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 8
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 8
- 238000003756 stirring Methods 0.000 claims description 8
- 235000011056 potassium acetate Nutrition 0.000 claims description 7
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 6
- RIOQSEWOXXDEQQ-UHFFFAOYSA-N triphenylphosphine Chemical compound C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-N 0.000 claims description 6
- PIBWKRNGBLPSSY-UHFFFAOYSA-L palladium(II) chloride Chemical compound Cl[Pd]Cl PIBWKRNGBLPSSY-UHFFFAOYSA-L 0.000 claims description 5
- 229940072033 potash Drugs 0.000 claims description 5
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Substances [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 5
- 235000015320 potassium carbonate Nutrition 0.000 claims description 5
- 239000013078 crystal Substances 0.000 claims description 4
- GCUVBACNBHGZRS-UHFFFAOYSA-N cyclopenta-1,3-diene cyclopenta-2,4-dien-1-yl(diphenyl)phosphane iron(2+) Chemical compound [Fe++].c1cc[cH-]c1.c1cc[c-](c1)P(c1ccccc1)c1ccccc1 GCUVBACNBHGZRS-UHFFFAOYSA-N 0.000 claims description 4
- 238000001035 drying Methods 0.000 claims description 4
- 238000001914 filtration Methods 0.000 claims description 4
- 239000010410 layer Substances 0.000 claims description 4
- 229910052757 nitrogen Inorganic materials 0.000 claims description 4
- 239000012044 organic layer Substances 0.000 claims description 4
- 239000000376 reactant Substances 0.000 claims description 4
- 239000012141 concentrate Substances 0.000 claims description 3
- KTWOOEGAPBSYNW-UHFFFAOYSA-N ferrocene Chemical compound [Fe+2].C=1C=C[CH-]C=1.C=1C=C[CH-]C=1 KTWOOEGAPBSYNW-UHFFFAOYSA-N 0.000 claims description 3
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 claims description 2
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 claims description 2
- 238000000605 extraction Methods 0.000 claims 2
- 238000004519 manufacturing process Methods 0.000 abstract description 10
- 238000000034 method Methods 0.000 abstract description 9
- 239000003054 catalyst Substances 0.000 abstract description 6
- 239000002994 raw material Substances 0.000 abstract description 4
- 239000003513 alkali Substances 0.000 abstract description 3
- 238000010511 deprotection reaction Methods 0.000 abstract description 3
- 238000011017 operating method Methods 0.000 abstract description 3
- 230000009471 action Effects 0.000 abstract description 2
- 238000007336 electrophilic substitution reaction Methods 0.000 abstract description 2
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 12
- 239000003153 chemical reaction reagent Substances 0.000 description 12
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 9
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 9
- YXFVVABEGXRONW-UHFFFAOYSA-N toluene Substances CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 7
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 6
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 6
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 6
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 6
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 6
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 6
- GETQZCLCWQTVFV-UHFFFAOYSA-N trimethylamine Chemical compound CN(C)C GETQZCLCWQTVFV-UHFFFAOYSA-N 0.000 description 6
- YFTHZRPMJXBUME-UHFFFAOYSA-N tripropylamine Chemical compound CCCN(CCC)CCC YFTHZRPMJXBUME-UHFFFAOYSA-N 0.000 description 6
- OKKJLVBELUTLKV-MZCSYVLQSA-N Deuterated methanol Chemical compound [2H]OC([2H])([2H])[2H] OKKJLVBELUTLKV-MZCSYVLQSA-N 0.000 description 4
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 4
- 239000011734 sodium Substances 0.000 description 4
- 229910052708 sodium Inorganic materials 0.000 description 4
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 3
- XTNGUQKDFGDXSJ-ZXGKGEBGSA-N Canagliflozin Chemical compound CC1=CC=C([C@H]2[C@@H]([C@@H](O)[C@H](O)[C@@H](CO)O2)O)C=C1CC(S1)=CC=C1C1=CC=C(F)C=C1 XTNGUQKDFGDXSJ-ZXGKGEBGSA-N 0.000 description 3
- 239000004215 Carbon black (E152) Substances 0.000 description 3
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 3
- 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 3
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 3
- 108091006269 SLC5A2 Proteins 0.000 description 3
- VMHLLURERBWHNL-UHFFFAOYSA-M Sodium acetate Chemical compound [Na+].CC([O-])=O VMHLLURERBWHNL-UHFFFAOYSA-M 0.000 description 3
- 102000058081 Sodium-Glucose Transporter 2 Human genes 0.000 description 3
- DKGAVHZHDRPRBM-UHFFFAOYSA-N Tert-Butanol Chemical compound CC(C)(C)O DKGAVHZHDRPRBM-UHFFFAOYSA-N 0.000 description 3
- JFDZBHWFFUWGJE-UHFFFAOYSA-N benzonitrile Chemical compound N#CC1=CC=CC=C1 JFDZBHWFFUWGJE-UHFFFAOYSA-N 0.000 description 3
- 239000008103 glucose Substances 0.000 description 3
- 229930195733 hydrocarbon Natural products 0.000 description 3
- 150000007529 inorganic bases Chemical class 0.000 description 3
- 239000012046 mixed solvent Substances 0.000 description 3
- 150000007530 organic bases Chemical class 0.000 description 3
- 150000003053 piperidines Chemical class 0.000 description 3
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 description 3
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 3
- 230000035484 reaction time Effects 0.000 description 3
- 239000001632 sodium acetate Substances 0.000 description 3
- 235000017281 sodium acetate Nutrition 0.000 description 3
- ODZPKZBBUMBTMG-UHFFFAOYSA-N sodium amide Chemical compound [NH2-].[Na+] ODZPKZBBUMBTMG-UHFFFAOYSA-N 0.000 description 3
- 229910000029 sodium carbonate Inorganic materials 0.000 description 3
- QDRKDTQENPPHOJ-UHFFFAOYSA-N sodium ethoxide Chemical compound [Na+].CC[O-] QDRKDTQENPPHOJ-UHFFFAOYSA-N 0.000 description 3
- YKXCWZVUWWQSAV-BTVCFUMJSA-N (2r,3s,4r,5r)-2,3,4,5,6-pentahydroxyhexanal;sodium Chemical compound [Na].OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)C=O YKXCWZVUWWQSAV-BTVCFUMJSA-N 0.000 description 2
- KZPYGQFFRCFCPP-UHFFFAOYSA-N 1,1'-bis(diphenylphosphino)ferrocene Chemical compound [Fe+2].C1=CC=C[C-]1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=C[C-]1P(C=1C=CC=CC=1)C1=CC=CC=C1 KZPYGQFFRCFCPP-UHFFFAOYSA-N 0.000 description 2
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 2
- 238000005160 1H NMR spectroscopy Methods 0.000 description 2
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 description 2
- 229910002666 PdCl2 Inorganic materials 0.000 description 2
- XYFCBTPGUUZFHI-UHFFFAOYSA-N Phosphine Chemical compound P XYFCBTPGUUZFHI-UHFFFAOYSA-N 0.000 description 2
- 229940123518 Sodium/glucose cotransporter 2 inhibitor Drugs 0.000 description 2
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 2
- 239000008280 blood Substances 0.000 description 2
- 210000004369 blood Anatomy 0.000 description 2
- WTEOIRVLGSZEPR-UHFFFAOYSA-N boron trifluoride Chemical compound FB(F)F WTEOIRVLGSZEPR-UHFFFAOYSA-N 0.000 description 2
- 229960001713 canagliflozin Drugs 0.000 description 2
- VHOFTEAWFCUTOS-TUGBYPPCSA-N canagliflozin hydrate Chemical compound O.CC1=CC=C([C@H]2[C@@H]([C@@H](O)[C@H](O)[C@@H](CO)O2)O)C=C1CC(S1)=CC=C1C1=CC=C(F)C=C1.CC1=CC=C([C@H]2[C@@H]([C@@H](O)[C@H](O)[C@@H](CO)O2)O)C=C1CC(S1)=CC=C1C1=CC=C(F)C=C1 VHOFTEAWFCUTOS-TUGBYPPCSA-N 0.000 description 2
- 206010012601 diabetes mellitus Diseases 0.000 description 2
- WMKGGPCROCCUDY-PHEQNACWSA-N dibenzylideneacetone Chemical compound C=1C=CC=CC=1\C=C\C(=O)\C=C\C1=CC=CC=C1 WMKGGPCROCCUDY-PHEQNACWSA-N 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- 238000002330 electrospray ionisation mass spectrometry Methods 0.000 description 2
- 239000003112 inhibitor Substances 0.000 description 2
- 230000000977 initiatory effect Effects 0.000 description 2
- 229940121068 invokana Drugs 0.000 description 2
- 239000000463 material Substances 0.000 description 2
- 210000005239 tubule Anatomy 0.000 description 2
- 208000001072 type 2 diabetes mellitus Diseases 0.000 description 2
- 238000003809 water extraction Methods 0.000 description 2
- VYXHVRARDIDEHS-UHFFFAOYSA-N 1,5-cyclooctadiene Chemical compound C1CC=CCCC=C1 VYXHVRARDIDEHS-UHFFFAOYSA-N 0.000 description 1
- 239000004912 1,5-cyclooctadiene Substances 0.000 description 1
- PURJRGMZIKXDMW-UHFFFAOYSA-N 2-(4-fluorophenyl)thiophene Chemical compound C1=CC(F)=CC=C1C1=CC=CS1 PURJRGMZIKXDMW-UHFFFAOYSA-N 0.000 description 1
- TUCRZHGAIRVWTI-UHFFFAOYSA-N 2-bromothiophene Chemical compound BrC1=CC=CS1 TUCRZHGAIRVWTI-UHFFFAOYSA-N 0.000 description 1
- GSFNQBFZFXUTBN-UHFFFAOYSA-N 2-chlorothiophene Chemical compound ClC1=CC=CS1 GSFNQBFZFXUTBN-UHFFFAOYSA-N 0.000 description 1
- BUBVLQDEIIUIQG-UHFFFAOYSA-N 3,4,5-tris(phenylmethoxy)-6-(phenylmethoxymethyl)oxan-2-one Chemical compound C=1C=CC=CC=1COC1C(OCC=2C=CC=CC=2)C(OCC=2C=CC=CC=2)C(=O)OC1COCC1=CC=CC=C1 BUBVLQDEIIUIQG-UHFFFAOYSA-N 0.000 description 1
- PWTUNOWHNRYMOB-UHFFFAOYSA-N 3-iodo-2-methylbenzoyl chloride Chemical compound CC1=C(I)C=CC=C1C(Cl)=O PWTUNOWHNRYMOB-UHFFFAOYSA-N 0.000 description 1
- 229910015900 BF3 Inorganic materials 0.000 description 1
- ZOXJGFHDIHLPTG-UHFFFAOYSA-N Boron Chemical compound [B] ZOXJGFHDIHLPTG-UHFFFAOYSA-N 0.000 description 1
- CPELXLSAUQHCOX-UHFFFAOYSA-M Bromide Chemical compound [Br-] CPELXLSAUQHCOX-UHFFFAOYSA-M 0.000 description 1
- DKPFZGUDAPQIHT-UHFFFAOYSA-N Butyl acetate Natural products CCCCOC(C)=O DKPFZGUDAPQIHT-UHFFFAOYSA-N 0.000 description 1
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 1
- 101100393023 Crocus sativus GLT2 gene Proteins 0.000 description 1
- ZAFNJMIOTHYJRJ-UHFFFAOYSA-N Diisopropyl ether Chemical compound CC(C)OC(C)C ZAFNJMIOTHYJRJ-UHFFFAOYSA-N 0.000 description 1
- LCGLNKUTAGEVQW-UHFFFAOYSA-N Dimethyl ether Chemical group COC LCGLNKUTAGEVQW-UHFFFAOYSA-N 0.000 description 1
- 206010013710 Drug interaction Diseases 0.000 description 1
- 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 1
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical group [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 description 1
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- TWKVUTXHANJYGH-UHFFFAOYSA-L allyl palladium chloride Chemical class Cl[Pd]CC=C.Cl[Pd]CC=C TWKVUTXHANJYGH-UHFFFAOYSA-L 0.000 description 1
- 230000008901 benefit Effects 0.000 description 1
- 229910052796 boron Inorganic materials 0.000 description 1
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 1
- 230000003197 catalytic effect Effects 0.000 description 1
- 230000008859 change Effects 0.000 description 1
- 239000000460 chlorine Substances 0.000 description 1
- 229910052801 chlorine Inorganic materials 0.000 description 1
- 230000003247 decreasing effect Effects 0.000 description 1
- 125000003963 dichloro group Chemical group Cl* 0.000 description 1
- FSRXIRGQJIHEFB-UHFFFAOYSA-N diphenylphosphane;ethane Chemical compound CC.C=1C=CC=CC=1PC1=CC=CC=C1 FSRXIRGQJIHEFB-UHFFFAOYSA-N 0.000 description 1
- ONDPGJBEBGWAKI-UHFFFAOYSA-N diphenylphosphane;propane Chemical compound CCC.C=1C=CC=CC=1PC1=CC=CC=C1 ONDPGJBEBGWAKI-UHFFFAOYSA-N 0.000 description 1
- 238000001647 drug administration Methods 0.000 description 1
- 229940000406 drug candidate Drugs 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- 238000003810 ethyl acetate extraction Methods 0.000 description 1
- FUZZWVXGSFPDMH-UHFFFAOYSA-N hexanoic acid Chemical compound CCCCCC(O)=O FUZZWVXGSFPDMH-UHFFFAOYSA-N 0.000 description 1
- 230000007062 hydrolysis Effects 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- 230000006872 improvement Effects 0.000 description 1
- 210000003734 kidney Anatomy 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- GPNDARIEYHPYAY-UHFFFAOYSA-N palladium(ii) nitrate Chemical compound [Pd+2].[O-][N+]([O-])=O.[O-][N+]([O-])=O GPNDARIEYHPYAY-UHFFFAOYSA-N 0.000 description 1
- UQPUONNXJVWHRM-UHFFFAOYSA-N palladium;triphenylphosphane Chemical compound [Pd].C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 UQPUONNXJVWHRM-UHFFFAOYSA-N 0.000 description 1
- NFHFRUOZVGFOOS-UHFFFAOYSA-N palladium;triphenylphosphane Chemical compound [Pd].C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 NFHFRUOZVGFOOS-UHFFFAOYSA-N 0.000 description 1
- 229910000073 phosphorus hydride Inorganic materials 0.000 description 1
- 230000008569 process Effects 0.000 description 1
- 230000009467 reduction Effects 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 238000010189 synthetic method Methods 0.000 description 1
- PQDJYEQOELDLCP-UHFFFAOYSA-N trimethylsilane Chemical compound C[SiH](C)C PQDJYEQOELDLCP-UHFFFAOYSA-N 0.000 description 1
- 229940094989 trimethylsilane Drugs 0.000 description 1
- 238000007039 two-step reaction Methods 0.000 description 1
Classifications
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
Abstract
The present invention relates to the clean preparing technical field of Ka Gelie, particularly the clean preparation method of a kind of Ka Gelie<b>:</b>Generate compounds Ⅳ taking four pivaloyl groups-alpha-D-bromo glucopyranose as raw material with connection boric acid pinacol ester generation electrophilic substitution reaction; Taking the iodo-2-aminomethyl phenyl of 2-(4-fluorophenyl)-5-[(5-) methyl] thiophene as raw material under catalyst action with compounds Ⅳ reacting generating compound VI; Compound VI is hydrolyzed under alkali condition, and it is clean that Deprotection obtains Ka Gelie. The clean method of Ka Gelie of preparing of the present invention, synthetic route shortens dramatically, only have three steps, simplified operating procedure, reaction condition is comparatively gentle, post processing is simple and easy to do, be more suitable for industrialization production requirements, not only save production time and labour cost, and reduced production cost, the yield that has increased substantially reaction, this route total recovery reaches more than 60%.
Description
Technical field
The present invention relates to the clean preparing technical field of Ka Gelie, particularly the clean preparation method of a kind of Ka Gelie.
Background technology
Ka Gelie clean (canagliflozin), commodity are called Invokana, the New type of S GLT2 inhibitor of being researched and developed by Johson & Johnson, be used for the treatment of type II diabetes, on March 29th, 2013, U.S. FDA has been ratified the Invokana of Johnson & Johnson sheet (canagliflozin) and has been used for the treatment of diabetes B adult patient; In September, 2013, Ka Gelie has only obtained European drug administration (EMA) approval and has been used for the treatment of adult's diabetes B. In addition, Ka Gelie has also obtained Australian approval only. Ka Gelie Jing Shi Johson & Johnson is one of the most promising drug candidate person. Under Johson & Johnson Yang Sen department have this medicine in North America, the power of sale of South America, Europe, the Middle East, Africa, Australia, New Zealand and some Asian countries.
The clean chemical name of Ka Gelie is (1S)-1,5-dehydrogenation-1-C-[3-[[5-(4-fluorophenyl)-2-thienyl] methyl]-4-aminomethyl phenyl]-D-Glucose alcohol, No. CAS is 842133-18-0, structural formula is as shown in I.
（Ⅰ）
First SGLT2 inhibitor that Ka Gelie ratifies for FDA only, belong to selective sodium-glucose body 2(SGLT2 that cotransports) kind new medicine of inhibitor, sodium-glucose body that cotransports is that a kind of GLUT has two kinds of hypotypes, SGLT2 is one of them hypotype, express at nearly renal tubule, participate in the heavily absorption of the glucose filtering in most tube chamber, Ka Gelie net energy suppresses SGLT2, make the glucose in renal tubule can not suction smoothly receipts, reduce kidney glucose threshold (RTG), thereby reduce blood sugar concentration. Clinical in type II diabetes. Ka Gelie is first SGLT2 inhibitor of listing only, and day clothes once, can reach blood sugar decreasing effect and have good tolerance, and drug interaction is low, has wide potential applicability in clinical practice. At present in the listing of multiple countries.
At present, to the clean preparation method's existing bibliographical information both at home and abroad of Ka Gelie, WO2005012326 discloses, taking the bromo-2-tolyl aldehyde of 5-as initiation material, through reacting with 2-chlorothiophene, with 2,3,4,6-tetra--O-TMS-maltonic acid-1,5-lactone reaction, then react and obtain thick methyl ether compound with the methanol solution of pyrovinic acid, react and obtain target product I with trimethyl silane and boron trifluoride ether solution again
Concrete synthetic route is as follows:
WO2009035969 and WO2012140120 disclose, taking fluorobromobenzene as initiation material, with magnesium powder form format reagent; react with 2-bromothiophene again and obtain 2-(4-fluorophenyl)-thiophene; the latter reacts with the iodo-2-methyl benzoyl chloride of 5-, and the product obtaining removes carbonyl through reduction; with 2; the reaction of 3,4,6-O-, tetra-pivaloyl groups-alpha-D-glucopyranose bromide; hydrolysis Deprotection obtains target product I, and concrete synthetic route is as follows:
The clean equal more complicated of synthetic method of above prior art disclosed preparation Ka Gelie, step is longer, has extended the production cycle, and reaction condition is comparatively harsh, and post processing is comparatively loaded down with trivial details, and route total recovery is not high.
Summary of the invention
In above prior art, prepare in order to solve that Ka Gelie the accounts show a surplus of reactions steps is long, technique is loaded down with trivial details, severe reaction conditions, post processing complexity, problem that route total recovery is not high, the invention provides a kind of reactions steps shorter, the clean new method of preparation Ka Gelie that yield is high.
The present invention is achieved by the following measures:
The preparation method that Ka Gelie is clean, comprises the following steps
(1) there is electrophilic substitution reaction taking four pivaloyl groups-alpha-D-bromo glucopyranose (II) as raw material with connection boric acid pinacol ester (III) and generate compound (IV);
(2) taking the iodo-2-aminomethyl phenyl of 2-(4-fluorophenyl)-5-[(5-) methyl] compound (IV) reacting generating compound (VI) that obtains with step (1) under catalyst action as raw material of thiophene (V);
(3) get the compound (VI) that step (2) obtains and be hydrolyzed under alkali condition, it is that Ka Gelie is clean that Deprotection obtains compound (I).
Whole course of reaction as shown in the formula:
The clean new method of preparation Ka Gelie provided by the invention, the palladium catalyst wherein using in step (1) can be one of following reagent: palladium bichloride, palladium dydroxide, palladium, palladium nitrate, allyl palladium chloride dimer, two (benzonitrile) palladium bichloride, two (dibenzalacetones) close palladium, 1, two (diphenylphosphino) ferrocene of 1'-] close palladium bichloride, two (triphenylphosphine) ferrocene closes palladium bichloride, four (triphen phosphino-) palladium, three (dibenzalacetone) two palladiums, two (1, two (diphenylphosphine) ethane of 2-) palladium, dichloro two (thricyclohexyl is seen) palladium, two (three-O-toluene phosphine) palladiums of trans-dichloro, (1, 5-cyclo-octadiene) palladium chloride, chlorine palladium acid sodium, three (dibenzalacetone) two palladiums-chloroform adducts, triphenylphosphine palladium acetate, two (acetonitrile) palladium bichloride, [1, the two diphenylphosphine propane of 3-] palladium bichloride, tetrakis triphenylphosphine palladium etc. preferably 1, two (diphenylphosphino) ferrocene of 1'-] close palladium bichloride (PdCl2 (dppf)). wherein the consumption mol ratio of halogenated aryl hydrocarbon, that acid esters of connection boron frequency is 1:1-1:2, and the consumption mol ratio of halogenated aryl hydrocarbon and palladium catalyst is 20:1-100:1.
Wherein step (1) reaction dissolvent is the mixed solvent of one or both and multiple mentioned reagent for DMF, dioxane, oxolane, DMSO, carrene, chloroform (chloroform), toluene, acetone. Reaction temperature can, at 0 DEG C-160 DEG C, be 20 DEG C-60 DEG C as preferable reaction temperature, and the reaction time is as the criterion to react completely, and can be 30 minutes to 24 hours. Wherein the alkaline reagent of the use of step (1) one of is following reagent: organic base, as sodium methoxide, caustic alcohol, sodium acetate, potassium acetate, Sodamide, trityl sodium, potassium tert-butoxide, pyridine, piperidines, trimethylamine, triethylamine, tripropyl amine (TPA) or diisopropyl ethyl amine etc.; Inorganic base, as potash, sodium carbonate, saleratus, sodium acid carbonate, NaOH, potassium hydroxide, preferably alkaline reagent is potassium acetate, the consumption mol ratio of halogenated aryl hydrocarbon and potassium acetate is 1:1-1:3.
The clean method of Ka Gelie of preparing provided by the invention, wherein step (2) starting compound used (V) can be one of following: the iodo-2-aminomethyl phenyl of 2-(4-fluorophenyl)-5-[(5-) methyl] thiophene, the bromo-2-aminomethyl phenyl of 2-(4-fluorophenyl)-5-[(5-) methyl] thiophene.
Wherein the alkaline reagent of the use of step (2) one of is following reagent: organic base, as sodium methoxide, caustic alcohol, sodium acetate, potassium acetate, Sodamide, trityl sodium, potassium tert-butoxide, pyridine, piperidines, trimethylamine, triethylamine, tripropyl amine (TPA) or diisopropyl ethyl amine etc.; Inorganic base, as potash, sodium carbonate, saleratus, sodium acid carbonate, NaOH, potassium hydroxide, compound (V) is 1:1-1:3 with the consumption mol ratio of alkali.
Wherein the reaction dissolvent of step (2) is the mixed solvent of one or both and multiple mentioned reagent of DMF, dioxane, oxolane, DMSO, carrene, chloroform (chloroform), toluene, acetone. Reaction temperature can, at 0 DEG C-200 DEG C, be 0 DEG C-60 DEG C as preferable reaction temperature, and the reaction time is as the criterion to react completely, and can be 30 minutes to 24 hours.
The clean preparation method of a kind of Ka Gelie provided by the invention, wherein step (3) alkaline reagent used is one of following: organic base, as sodium methoxide, caustic alcohol, sodium acetate, potassium acetate, Sodamide, trityl sodium, potassium tert-butoxide, pyridine, piperidines, trimethylamine, triethylamine, tripropyl amine (TPA) or diisopropyl ethyl amine etc.; Inorganic base, as potash, sodium carbonate, saleratus, sodium acid carbonate, NaOH, potassium hydroxide, preferably alkaline reagent is sodium methoxide.
Wherein the reaction dissolvent of step (3) is the mixed solvent of one or both and multiple mentioned reagent of methyl alcohol, ethanol, isopropyl alcohol, n-butanol, the tert-butyl alcohol, carrene, ethyl acetate, butyl acetate, ether, methyl tertiary butyl ether(MTBE), isopropyl ether, chloroform (chloroform), acetone etc. Reaction temperature can, at 0 DEG C-200 DEG C, be 20 DEG C-80 DEG C as preferable reaction temperature, and the reaction time is as the criterion to react completely, and can be 30 minutes to 24 hours.
Advantage of the present invention:
(1) the clean method of Ka Gelie of preparing of the present invention, adopt palladium catalyst catalytic synthetic techniques, synthetic route shortens dramatically, and only has three steps, simplify operating procedure, reaction condition is comparatively gentle, and post processing is simple and easy to do, is more suitable for industrialization production requirements, not only save production time and labour cost, and reduced production cost, and increasing substantially the yield of reaction, this route total recovery reaches more than 60%;
(2) in the time preparing compound (VI), this route is taked first by compound (II) four pivaloyl groups-alpha-D-bromo glucopyranose and connection boric acid pinacol ester generation substitution reaction, boric acid pinacol ester group in the compound (IV) obtaining is more easily left away, and has improved reaction yield;
(3) being obtained in the process of compound (VI) by compound (II), this route adopts the method for carrying out two-step reaction in same reaction system, at compound (II) through reacting and obtain after compounds Ⅳ with connection boric acid pinacol ester, without post processing, directly in former reaction system, add compound (V) to react and obtain compound (VI), simplify operating procedure, shorten the production cycle, post processing is simple and easy to do, improve the yield of reaction, reduce production cost, after the catalyst reaction using in route, be easy to remove, be more suitable for industrialized production.
Detailed description of the invention:
Following examples are to further illustrate of the present invention, include but not limited to following examples. Elaborate the present invention below with reference to embodiment, but it will be appreciated by those skilled in the art that the present invention is not limited to the preparation method of these embodiment and use. And those skilled in the art can be equal to replacement, combination, improvement or modify the present invention according to description of the invention, but these all will comprise within the scope of the invention.
Embodiment 1
The preparation of (1) four pivaloyl groups-alpha-D-glucopyranose boric acid pinacol ester (IV)
Under nitrogen protection, in 50ml reaction bulb, by [1, two (diphenylphosphino) ferrocene of 1'-] palladium chloride (PdCl2 (dppf)) (0.22g, 0.3mmol), potassium acetate (3.0g, 30mmol) and connection boric acid pinacol ester (2.8g, 10mmol) be dissolved in 12mlDMSO, separately add four pivaloyl groups-alpha-D-bromo glucopyranose (5.8g, 10mmol), temperature control, in 80 DEG C, reacts 8 hours, reacts complete, without post processing, directly carry out next step reaction;
(2) three (2,2-neopentanoic acid)-(2S, 3S, 4R, 5R, 6R)-2-(3-((5-(4-fluorophenyl) thiophene-2-yl) methyl)-4-aminomethyl phenyl)-6-(oxy acid methyl neopentyl) tetrahydrochysene-2H-pyrans-3, the preparation of 4,5-, tri-base esters (VI)
In the reactant liquor of above-mentioned reaction, add the iodo-2-aminomethyl phenyl of compound (V) 2-(4-fluorophenyl)-5-[(5-) methyl] thiophene (4.9g, 12mmol), temperature control, in 15 DEG C, reacts 4 hours, react complete, with ethyl acetate/water extraction (V/V=1:1), water layer, with ethyl acetate washed twice, merges organic layer, anhydrous sodium sulfate drying, concentrated (7.7g) total recovery of compound (VI) that obtains: 85%;
(3) (1S)-1,5-dehydrogenation-1-C-[3-[[5-(4-fluorophenyl)-2-thienyl] methyl]-4-aminomethyl phenyl] preparation of-D-Glucose alcohol (Ka Gelie is clean)
In 50ml reaction bulb, add compound VI (4.0g, 5mmol) and 20ml methyl alcohol, stirring at room temperature, dissolves, and adds sodium methoxide (28% methanol solution), temperature control is in 60 DEG C, react 16 hours, be cooled to room temperature, the yellow solution obtaining adds 7ml water and crystal seed, stir 1 hour in-5 DEG C, filtration obtains target compound Ka Gelie clean (1.8g), yield 88%, purity 94%. M.p:105-107 DEG C; ESI-MS:445 (MH+).1HNMR(CD3OD)δ7.5(m,2H),7.3(m,1H),7.25(d,1H,J=7.8Hz),7.15(d,1H,J=7.8Hz),7.0(m,3H),6.7(m,1H),4.9(s,4H),4.2(s,2H),4.1(m,1H),3.9(d,1H,J=12.0Hz),3.7(d,1H,J=12.0Hz),3.45(m,4H),2.3(s,3H)。
Embodiment 2
The preparation of (1) four pivaloyl groups-alpha-D-glucopyranose boric acid pinacol ester (IV)
Under nitrogen protection, in 50ml reaction bulb, two (triphenylphosphine) ferrocene are closed to palladium bichloride (0.21g, 0.3mmol), potash (4.1g, 30mmol) and connection boric acid pinacol ester (2.8g, 10mmol) be dissolved in 12mlDMF, separately add four pivaloyl groups-alpha-D-bromo glucopyranose (5.8g, 10mmol), temperature control is in 80 DEG C, react 10 hours, react complete, without post processing, directly carry out next step reaction;
(2) three (2,2-neopentanoic acid)-(2S, 3S, 4R, 5R, 6R)-2-(3-((5-(4-fluorophenyl) thiophene-2-yl) methyl)-4-aminomethyl phenyl)-6-(oxy acid methyl neopentyl) tetrahydrochysene-2H-pyrans-3, the preparation of 4,5-, tri-base esters (VI)
In the reactant liquor of above-mentioned reaction, add the bromo-2-aminomethyl phenyl of compound (V) 2-(4-fluorophenyl)-5-[(5-) methyl] thiophene (4.9g, 12mmol), temperature control is in 20 DEG C, react 8 hours, react complete, with carrene/water extraction (V/V=1:1), water layer is with twice of washed with dichloromethane, merge organic layer, anhydrous magnesium sulfate drying, concentrates and obtains compound (VI) (7.0g), total recovery: 75%;
(3) (1S)-1,5-dehydrogenation-1-C-[3-[[5-(4-fluorophenyl)-2-thienyl] methyl]-4-aminomethyl phenyl] preparation of-D-Glucose alcohol (Ka Gelie is clean)
In 50ml reaction bulb, add in compound VI (4.0g, 5mmol) and 20ml methyl alcohol, stirring at room temperature makes it to dissolve, add sodium methoxide (28% methanol solution), temperature control, in 60 DEG C, reacts 16 hours, be cooled to room temperature, the yellow solution obtaining adds 7ml water and crystal seed, in-5 DEG C of stirrings 1 hour, filters and obtains target compound Ka Gelie clean (1.7g), yield 85%, purity 90%. M.p:105-107 DEG C; ESI-MS:445 (MH+).1HNMR(CD3OD)δ7.5(m,2H),7.3(m,1H),7.25(d,1H,J=7.8Hz),7.15(d,1H,J=7.8Hz),7.0(m,3H),6.7(m,1H),4.9(s,4H),4.2(s,2H),4.1(m,1H),3.9(d,1H,J=12.0Hz),3.7(d,1H,J=12.0Hz),3.45(m,4H),2.3(s,3H)。
Above-described embodiment is preferably embodiment of the present invention; but embodiments of the present invention are not subject to the restriction of embodiment; other is any does not deviate from change, modification, the combination made under Spirit Essence of the present invention and principle, substitute, simplify and all should be equivalent substitute mode, within being included in protection scope of the present invention.
Claims (2)
1. the clean preparation method of Yi Zhong Ka Gelie, is characterized in that comprising the following steps:
The preparation of (1) four pivaloyl groups-alpha-D-glucopyranose boric acid pinacol ester
Under nitrogen protection, in 50ml reaction bulb, be 0.3mmol by [two (diphenylphosphino) ferrocene of 1,1'-] palladium chloride 0.22g, potassium acetate 3.0g is that 30mmol and connection boric acid pinacol ester 2.8g are that 10mmol is dissolved in 12mlDMSO, separately adding four pivaloyl groups-alpha-D-bromo glucopyranose 5.8g is 10mmol, temperature control, in 80 DEG C, reacts 8 hours, reacts complete, without post processing, directly carry out next step reaction;
(2) three (PAs)-(2S, 3S, 4R, 5R, 6R)-2-(3-((5-(4-fluorophenyl) thiophene-2-yl) methyl)-4-aminomethyl phenyl)-6-(oxy acid methyl neopentyl) tetrahydrochysene-2H-pyrans-3, the preparation of 4,5-, tri-base esters
In the reactant liquor of step (1) reaction, add the iodo-2-aminomethyl phenyl of 2-(4-fluorophenyl)-5-[(5-) methyl] thiophene 4.9g is 12mmol, temperature control is in 15 DEG C, react 4 hours, react complete, with ethyl acetate and water V/V=1:1 extraction, water layer is with ethyl acetate washed twice, merge organic layer, anhydrous sodium sulfate drying, concentrate and obtain three (2, 2-neopentanoic acid)-(2S, 3S, 4R, 5R, 6R)-2-(3-((5-(4-fluorophenyl) thiophene-2-yl) methyl)-4-aminomethyl phenyl)-6-(oxy acid methyl neopentyl) tetrahydrochysene-2H-pyrans-3, 4, 5-tri-base ester 7.7g, total recovery: 85%,
(3) (1S)-1,5-dehydrogenation-1-C-[3-[[5-(4-fluorophenyl)-2-thienyl] methyl]-4-aminomethyl phenyl] preparation of-D-Glucose alcohol
In 50ml reaction bulb, add three (2, 2-neopentanoic acid)-(2S, 3S, 4R, 5R, 6R)-2-(3-((5-(4-fluorophenyl) thiophene-2-yl) methyl)-4-aminomethyl phenyl)-6-(oxy acid methyl neopentyl) tetrahydrochysene-2H-pyrans-3, 4, 5-tri-base ester 4.0g are 5mmol and 20ml methyl alcohol, stirring at room temperature, dissolve, add the methanol solution of sodium methoxide 28%, temperature control is in 60 DEG C, react 16 hours, be cooled to room temperature, the yellow solution obtaining adds 7ml water and crystal seed, stir 1 hour in-5 DEG C, filtration obtains the clean 1.8g of target compound Ka Gelie, yield 88%, purity 94%.
2. the clean preparation method of Yi Zhong Ka Gelie, is characterized in that comprising the following steps:
The preparation of (1) four pivaloyl groups-alpha-D-glucopyranose boric acid pinacol ester
Under nitrogen protection, in 50ml reaction bulb, it is 0.3mmol that two (triphenylphosphine) ferrocene are closed to palladium bichloride 0.21g, potash 4.1g is that 30mmol and connection boric acid pinacol ester 2.8g are that 10mmol is dissolved in 12mlDMF, and separately adding four pivaloyl groups-alpha-D-bromo glucopyranose 5.8g is 10mmol, and temperature control is in 80 DEG C, react 10 hours, react complete, without post processing, directly carry out next step reaction;
(2) three (PAs)-(2S, 3S, 4R, 5R, 6R)-2-(3-((5-(4-fluorophenyl) thiophene-2-yl) methyl)-4-aminomethyl phenyl)-6-(oxy acid methyl neopentyl) tetrahydrochysene-2H-pyrans-3, the preparation of 4,5-, tri-base esters
In the reactant liquor of step (1) reaction, add the bromo-2-aminomethyl phenyl of 2-(4-fluorophenyl)-5-[(5-) methyl] thiophene 4.9g is 12mmol, temperature control is in 20 DEG C, react 8 hours, react complete, with carrene and water V/V=1:1 extraction, water layer is with twice of washed with dichloromethane, merge organic layer, anhydrous magnesium sulfate drying, concentrate and obtain three (2, 2-neopentanoic acid)-(2S, 3S, 4R, 5R, 6R)-2-(3-((5-(4-fluorophenyl) thiophene-2-yl) methyl)-4-aminomethyl phenyl)-6-(oxy acid methyl neopentyl) tetrahydrochysene-2H-pyrans-3, 4, 5-tri-base ester 7.0g, total recovery: 75%,
(3) (1S)-1,5-dehydrogenation-1-C-[3-[[5-(4-fluorophenyl)-2-thienyl] methyl]-4-aminomethyl phenyl] preparation of-D-Glucose alcohol
In 50ml reaction bulb, add three (2, 2-neopentanoic acid)-(2S, 3S, 4R, 5R, 6R)-2-(3-((5-(4-fluorophenyl) thiophene-2-yl) methyl)-4-aminomethyl phenyl)-6-(oxy acid methyl neopentyl) tetrahydrochysene-2H-pyrans-3, 4, 5-tri-base ester 4.0g are in 5mmol and 20ml methyl alcohol, stirring at room temperature makes it to dissolve, add the methanol solution of sodium methoxide 28%, temperature control is in 60 DEG C, react 16 hours, be cooled to room temperature, the yellow solution obtaining adds 7ml water and crystal seed, stir 1 hour in-5 DEG C, filtration obtains the clean 1.7g of target compound Ka Gelie, yield 85%, purity 90%.
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