CN105218392B - D winestone acid monoester monoamides class compounds - Google Patents
D winestone acid monoester monoamides class compounds Download PDFInfo
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- 150000001875 compounds Chemical class 0.000 title claims abstract description 31
- 239000002253 acid Substances 0.000 title claims abstract description 30
- 229960004770 esomeprazole Drugs 0.000 claims abstract description 15
- 239000003960 organic solvent Substances 0.000 claims abstract description 15
- 238000000034 method Methods 0.000 claims abstract description 13
- SUBDBMMJDZJVOS-DEOSSOPVSA-N esomeprazole Chemical compound C([S@](=O)C1=NC2=CC=C(C=C2N1)OC)C1=NC=C(C)C(OC)=C1C SUBDBMMJDZJVOS-DEOSSOPVSA-N 0.000 claims abstract description 11
- 229940126409 proton pump inhibitor Drugs 0.000 claims abstract description 5
- 239000000612 proton pump inhibitor Substances 0.000 claims abstract description 5
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 claims description 73
- 229960001270 d- tartaric acid Drugs 0.000 claims description 71
- -1 benzyl ester Chemical class 0.000 claims description 62
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 54
- UHOVQNZJYSORNB-UHFFFAOYSA-N monobenzene Natural products C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 claims description 41
- 229910052739 hydrogen Inorganic materials 0.000 claims description 37
- 150000001412 amines Chemical class 0.000 claims description 26
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 claims description 22
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 21
- 125000002252 acyl group Chemical group 0.000 claims description 20
- 238000006243 chemical reaction Methods 0.000 claims description 17
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 15
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical group CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 12
- 239000002904 solvent Substances 0.000 claims description 11
- 238000003756 stirring Methods 0.000 claims description 11
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 10
- VXUYXOFXAQZZMF-UHFFFAOYSA-N titanium(IV) isopropoxide Chemical compound CC(C)O[Ti](OC(C)C)(OC(C)C)OC(C)C VXUYXOFXAQZZMF-UHFFFAOYSA-N 0.000 claims description 10
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 claims description 9
- DRSHXJFUUPIBHX-UHFFFAOYSA-N COc1ccc(cc1)N1N=CC2C=NC(Nc3cc(OC)c(OC)c(OCCCN4CCN(C)CC4)c3)=NC12 Chemical compound COc1ccc(cc1)N1N=CC2C=NC(Nc3cc(OC)c(OC)c(OCCCN4CCN(C)CC4)c3)=NC12 DRSHXJFUUPIBHX-UHFFFAOYSA-N 0.000 claims description 8
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 claims description 8
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-diisopropylethylamine Substances CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 claims description 7
- 239000007787 solid Substances 0.000 claims description 7
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 claims description 6
- 230000003287 optical effect Effects 0.000 claims description 6
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 5
- 230000003197 catalytic effect Effects 0.000 claims description 5
- 238000001816 cooling Methods 0.000 claims description 5
- 238000001953 recrystallisation Methods 0.000 claims description 5
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 5
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 4
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 4
- 239000001257 hydrogen Substances 0.000 claims description 4
- 239000001301 oxygen Substances 0.000 claims description 4
- 150000002978 peroxides Chemical class 0.000 claims description 4
- 125000001637 1-naphthyl group Chemical group [H]C1=C([H])C([H])=C2C(*)=C([H])C([H])=C([H])C2=C1[H] 0.000 claims description 3
- 230000001476 alcoholic effect Effects 0.000 claims description 3
- YQHLDYVWEZKEOX-UHFFFAOYSA-N cumene hydroperoxide Chemical compound OOC(C)(C)C1=CC=CC=C1 YQHLDYVWEZKEOX-UHFFFAOYSA-N 0.000 claims description 3
- 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 compound CCOC(=O)\C=C\SC(=C(C#N)C(N)=O)S\C=C\C(=O)OCC NLFBCYMMUAKCPC-KQQUZDAGSA-N 0.000 claims description 3
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 claims description 3
- 229910000041 hydrogen chloride Inorganic materials 0.000 claims description 3
- 229910052760 oxygen Inorganic materials 0.000 claims description 3
- 238000010992 reflux Methods 0.000 claims description 3
- 150000003851 azoles Chemical class 0.000 claims description 2
- 125000004786 difluoromethoxy group Chemical group [H]C(F)(F)O* 0.000 claims description 2
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 2
- TXTHKGMZDDTZFD-UHFFFAOYSA-N n-cyclohexylaniline Chemical class C1CCCCC1NC1=CC=CC=C1 TXTHKGMZDDTZFD-UHFFFAOYSA-N 0.000 claims description 2
- 239000012074 organic phase Substances 0.000 claims description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N sulfuric acid Substances OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims description 2
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims 5
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 claims 4
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims 3
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims 2
- 150000001408 amides Chemical class 0.000 claims 2
- 102100021904 Potassium-transporting ATPase alpha chain 1 Human genes 0.000 claims 1
- 108010083204 Proton Pumps Proteins 0.000 claims 1
- 125000000217 alkyl group Chemical group 0.000 claims 1
- 239000003795 chemical substances by application Substances 0.000 claims 1
- HPNMFZURTQLUMO-UHFFFAOYSA-N diethylamine Chemical compound CCNCC HPNMFZURTQLUMO-UHFFFAOYSA-N 0.000 claims 1
- 239000000126 substance Substances 0.000 claims 1
- 238000003786 synthesis reaction Methods 0.000 abstract description 7
- 230000015572 biosynthetic process Effects 0.000 abstract description 6
- 238000006555 catalytic reaction Methods 0.000 abstract description 5
- 239000003446 ligand Substances 0.000 abstract description 5
- 238000010189 synthetic method Methods 0.000 abstract description 4
- 238000010438 heat treatment Methods 0.000 abstract description 2
- HTSGKJQDMSTCGS-UHFFFAOYSA-N 1,4-bis(4-chlorophenyl)-2-(4-methylphenyl)sulfonylbutane-1,4-dione Chemical compound C1=CC(C)=CC=C1S(=O)(=O)C(C(=O)C=1C=CC(Cl)=CC=1)CC(=O)C1=CC=C(Cl)C=C1 HTSGKJQDMSTCGS-UHFFFAOYSA-N 0.000 abstract 1
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 136
- 238000005160 1H NMR spectroscopy Methods 0.000 description 68
- 238000004896 high resolution mass spectrometry Methods 0.000 description 62
- 239000003814 drug Substances 0.000 description 6
- 239000002243 precursor Substances 0.000 description 5
- PAFZNILMFXTMIY-UHFFFAOYSA-N Cyclohexylamine Natural products NC1CCCCC1 PAFZNILMFXTMIY-UHFFFAOYSA-N 0.000 description 4
- HQABUPZFAYXKJW-UHFFFAOYSA-N N-butylamine Natural products CCCCN HQABUPZFAYXKJW-UHFFFAOYSA-N 0.000 description 4
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 4
- QARVLSVVCXYDNA-UHFFFAOYSA-N bromobenzene Chemical compound BrC1=CC=CC=C1 QARVLSVVCXYDNA-UHFFFAOYSA-N 0.000 description 4
- 150000003983 crown ethers Chemical class 0.000 description 4
- WGYKZJWCGVVSQN-UHFFFAOYSA-N mono-n-propyl amine Natural products CCCN WGYKZJWCGVVSQN-UHFFFAOYSA-N 0.000 description 4
- 239000007800 oxidant agent Substances 0.000 description 4
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 4
- 239000000047 product Substances 0.000 description 4
- 239000002994 raw material Substances 0.000 description 4
- 150000003462 sulfoxides Chemical group 0.000 description 4
- WVDDGKGOMKODPV-UHFFFAOYSA-N Benzyl alcohol Chemical compound OCC1=CC=CC=C1 WVDDGKGOMKODPV-UHFFFAOYSA-N 0.000 description 3
- 0 CC(OC([C@@](*=C)C(O1)=O)C1=O)=O Chemical compound CC(OC([C@@](*=C)C(O1)=O)C1=O)=O 0.000 description 3
- FEWJPZIEWOKRBE-UHFFFAOYSA-N Tartaric acid Natural products [H+].[H+].[O-]C(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-N 0.000 description 3
- 239000003054 catalyst Substances 0.000 description 3
- 238000013461 design Methods 0.000 description 3
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 3
- 238000001035 drying Methods 0.000 description 3
- 230000003647 oxidation Effects 0.000 description 3
- 238000007254 oxidation reaction Methods 0.000 description 3
- 230000001590 oxidative effect Effects 0.000 description 3
- 238000002360 preparation method Methods 0.000 description 3
- 229960001367 tartaric acid Drugs 0.000 description 3
- 235000002906 tartaric acid Nutrition 0.000 description 3
- 239000011975 tartaric acid Substances 0.000 description 3
- 150000003568 thioethers Chemical class 0.000 description 3
- NHOWDZOIZKMVAI-UHFFFAOYSA-N (2-chlorophenyl)(4-chlorophenyl)pyrimidin-5-ylmethanol Chemical compound C=1N=CN=CC=1C(C=1C(=CC=CC=1)Cl)(O)C1=CC=C(Cl)C=C1 NHOWDZOIZKMVAI-UHFFFAOYSA-N 0.000 description 2
- 125000000590 4-methylphenyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1*)C([H])([H])[H] 0.000 description 2
- SUBDBMMJDZJVOS-UHFFFAOYSA-N 5-methoxy-2-{[(4-methoxy-3,5-dimethylpyridin-2-yl)methyl]sulfinyl}-1H-benzimidazole Chemical compound N=1C2=CC(OC)=CC=C2NC=1S(=O)CC1=NC=C(C)C(OC)=C1C SUBDBMMJDZJVOS-UHFFFAOYSA-N 0.000 description 2
- IQPSEEYGBUAQFF-UHFFFAOYSA-N Pantoprazole Chemical compound COC1=CC=NC(CS(=O)C=2NC3=CC=C(OC(F)F)C=C3N=2)=C1OC IQPSEEYGBUAQFF-UHFFFAOYSA-N 0.000 description 2
- ATTZFSUZZUNHBP-UHFFFAOYSA-N Piperonyl sulfoxide Chemical compound CCCCCCCCS(=O)C(C)CC1=CC=C2OCOC2=C1 ATTZFSUZZUNHBP-UHFFFAOYSA-N 0.000 description 2
- KAESVJOAVNADME-UHFFFAOYSA-N Pyrrole Chemical compound C=1C=CNC=1 KAESVJOAVNADME-UHFFFAOYSA-N 0.000 description 2
- 235000002597 Solanum melongena Nutrition 0.000 description 2
- 244000061458 Solanum melongena Species 0.000 description 2
- RTAQQCXQSZGOHL-UHFFFAOYSA-N Titanium Chemical compound [Ti] RTAQQCXQSZGOHL-UHFFFAOYSA-N 0.000 description 2
- 150000001335 aliphatic alkanes Chemical group 0.000 description 2
- 201000010099 disease Diseases 0.000 description 2
- 238000004090 dissolution Methods 0.000 description 2
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 2
- 238000002474 experimental method Methods 0.000 description 2
- 239000012065 filter cake Substances 0.000 description 2
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 2
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 description 2
- 229960000381 omeprazole Drugs 0.000 description 2
- 125000000636 p-nitrophenyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1*)[N+]([O-])=O 0.000 description 2
- 229960005019 pantoprazole Drugs 0.000 description 2
- 229910052708 sodium Inorganic materials 0.000 description 2
- 239000011734 sodium Substances 0.000 description 2
- 238000000967 suction filtration Methods 0.000 description 2
- 230000002194 synthesizing effect Effects 0.000 description 2
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 2
- 229910052719 titanium Inorganic materials 0.000 description 2
- 239000010936 titanium Substances 0.000 description 2
- 229910052720 vanadium Inorganic materials 0.000 description 2
- LEONUFNNVUYDNQ-UHFFFAOYSA-N vanadium atom Chemical compound [V] LEONUFNNVUYDNQ-UHFFFAOYSA-N 0.000 description 2
- DVWQNBIUTWDZMW-UHFFFAOYSA-N 1-naphthalen-1-ylnaphthalen-2-ol Chemical compound C1=CC=C2C(C3=C4C=CC=CC4=CC=C3O)=CC=CC2=C1 DVWQNBIUTWDZMW-UHFFFAOYSA-N 0.000 description 1
- ZUDZWKJBYZAGBS-UHFFFAOYSA-N 4-ethoxy-2,3-dihydroxy-4-oxobutanoic acid Chemical compound CCOC(=O)C(O)C(O)C(O)=O ZUDZWKJBYZAGBS-UHFFFAOYSA-N 0.000 description 1
- QOSMNYMQXIVWKY-UHFFFAOYSA-N Propyl levulinate Chemical compound CCCOC(=O)CCC(C)=O QOSMNYMQXIVWKY-UHFFFAOYSA-N 0.000 description 1
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 1
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical class [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 1
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 1
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 description 1
- 239000005864 Sulphur Substances 0.000 description 1
- WGQKYBSKWIADBV-UHFFFAOYSA-N aminomethyl benzene Natural products NCC1=CC=CC=C1 WGQKYBSKWIADBV-UHFFFAOYSA-N 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 125000003118 aryl group Chemical group 0.000 description 1
- SRDSFKAPZJYPGA-UHFFFAOYSA-N benzene N-methylaniline Chemical class CNC1=CC=CC=C1.C1=CC=CC=C1 SRDSFKAPZJYPGA-UHFFFAOYSA-N 0.000 description 1
- 235000019445 benzyl alcohol Nutrition 0.000 description 1
- 150000003939 benzylamines Chemical class 0.000 description 1
- 230000000903 blocking effect Effects 0.000 description 1
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 208000010643 digestive system disease Diseases 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 125000004185 ester group Chemical group 0.000 description 1
- DQYBDCGIPTYXML-UHFFFAOYSA-N ethoxyethane;hydrate Chemical compound O.CCOCC DQYBDCGIPTYXML-UHFFFAOYSA-N 0.000 description 1
- 125000000623 heterocyclic group Chemical group 0.000 description 1
- 229960003174 lansoprazole Drugs 0.000 description 1
- SIXIIKVOZAGHPV-UHFFFAOYSA-N lansoprazole Chemical compound CC1=C(OCC(F)(F)F)C=CN=C1CS(=O)C1=NC2=CC=C[CH]C2=N1 SIXIIKVOZAGHPV-UHFFFAOYSA-N 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 1
- 229960004157 rabeprazole Drugs 0.000 description 1
- YREYEVIYCVEVJK-UHFFFAOYSA-N rabeprazole Chemical compound COCCCOC1=CC=NC(CS(=O)C=2NC3=CC=CC=C3N=2)=C1C YREYEVIYCVEVJK-UHFFFAOYSA-N 0.000 description 1
- 238000009666 routine test Methods 0.000 description 1
- 150000003457 sulfones Chemical class 0.000 description 1
- 238000010792 warming Methods 0.000 description 1
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- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The present invention relates to D winestone acid monoester monoamides class compounds, and it can be used as the S type chiral proton pump inhibitors such as ligand catalysis synthesis esomeprazole.The synthetic method includes compound II and the D winestones acid monoester monoamides class compound being dissolved in organic solvent, and heating response obtains the S type chiral proton pump inhibitors such as esomeprazole.Methods described has higher yield and e.e values.
Description
Technical field
The present invention relates to synthetic pharmacochemistry technical field, is related to optically active tartaric acid structure, is related to one kind
The synthesis of chiral sulfoxide compounds.
Background technology
Acid-related disease is a kind of disease most commonly seen in disease of digestive system, and proton pump inhibitor is to treat at present
The maximally effective medicine of acid related disorder.The proton pump inhibitor listed mainly has Omeprazole, esomeprazole, Lan Suola
Azoles, Rabeprazole, Pantoprazole etc., and it is chiral sulfoxide structure that these, which draw the primary structure of azole drug,.It has been reported that hand
Property sulfoxide synthesis chiral catalytic system have a lot, but report that more, more ripe is mainly the catalysis of titanium and vanadium complex
System, but for the precursor thioether containing heterocycle or the sulfoxide type medicine of amino structure, vanadium or other complex-catalyzed systems are extremely
The present can not obtain high corresponding selection, and titanium catalyst system can obtain high corresponding selection.
The key of asymmetry catalysis oxidation is the selection of chiral catalyst, and the design key of novel chiral catalyst is hand
Property part.The chiral catalytic system now reported also is mainly the difference of chiral ligand, for example Liao Jian etc. is by titanium-tartaric acid diamides
Class compound is used for the pure Omeprazole of asymmetry catalysis synthesizing optical, Lansoprazole, Pantoprazole as part, and Uemura is small
Group makees chiral ligand etc. using optically pure binaphthol.
Tartaric acid mono-methyl monoamides class compound, tartaric acid mono ethyl ester list are mentioned in the A of Chinese patent CN 103113351
Amides compound, tartaric acid list propyl ester monoamides class compound and tartaric acid list isopropyl ester monoamides class compound are chiral sub-
Application in sulfone class medicine, the Ester groups in such compound are the fat alkane side chain of small group, and are protected in this patent
The aryl side chains of shield are involved in yield in being actually catalyzed and the e.e values A of even better than patent CN 103113351 similar with its
And compound.Winestone acid monoester monoamides class compound and isopropyl titanate are dissolved in organic solvent by the patent, add catalytic amount
Water, heating stirring, add thioether precursor, after dissolving cooling add organic amine and oxidant, start to aoxidize.This method yield
More than 60%, e.e values are up to 98%.However, finding the part of the Patent design in an experiment and what isopropyl titanate was formed matches somebody with somebody
Solubility of the compound in solvent (such as toluene) is unsatisfactory, and situation in a solvent can not be completely dissolved by having part, and this is specially
The solubility of designed ligand compound in organic solvent, which is significantly better than in the A of patent CN 103113351, in profit is previously mentioned
Ligand compound.
Be found through experiments that, when winestone acid monoester monoamides class compound both sides in succession compared with macoradical when, thus it is speculated that
Because steric hindrance causes the e.e values of chiral catalysis slightly elevated blocking for reactive site.
The content of the invention
It is an object of the invention to provide with optically active chiral monoester monoamides class compound, also provide simultaneously
Its corresponding asymmetric syntheses preparation method and its application in catalytically synthesizing chiral sulfoxide type medicine.The present invention relates to
General structure compound as follows.
In above formula, R1For benzyl, phenyl, normal-butyl, cyclohexyl.R2For methyl, ethyl, n-propyl, isopropyl, positive fourth
Base, the tert-butyl group, cyclohexyl, benzyl, phenyl, rubigan, p-nitrophenyl, p-methylphenyl, o-methyl-phenyl, to bromobenzene
Base, 1- naphthyls, R-1- phenethyls, S-1- phenethyls.
In order to synthesize above-claimed cpd, the present invention adopts the following technical scheme that：
A kind of method for preparing a kind of D- tartaric acid mono-methyl monoamides class compound that formula is I, its reaction equation
It is as follows：
In above-mentioned formula, R1For benzyl, phenyl, normal-butyl, cyclohexyl.R2For methyl, ethyl, n-propyl, isopropyl, just
Butyl, the tert-butyl group, cyclohexyl, benzyl, phenyl, rubigan, p-nitrophenyl, p-methylphenyl, o-methyl-phenyl, to bromobenzene
Base, 1- naphthyls, R-1- phenethyls, S-1- phenethyls.
Described method is implemented as follows：
D- tartaric acid is added in acetic anhydride, adds the concentrated sulfuric acid, 5~30min is stirred at reflux, ice bath cooling, filters, use
Cold ether, the solid of gained is dissolved in organic solvent, the amine for being dissolved in organic solvent is added dropwise thereto, react 0.5~2h,
Solvent is spin-dried for, adds the alcoholic solution of hydrogen chloride, is stirred at 15~45 DEG C, reacts 10~72h.Product is separated out, filters and uses nothing
Water ether washs, and the compound that formula is I is made.
According to the present invention, the preferred dichloromethane of organic solvent.
According to the present invention, the preferred 10min of described return time.
According to the present invention, the time preferred 1h with amine reaction.
According to the present invention, the time preferred 60h with the reaction of the alcoholic solution of hydrogen chloride.
Present invention could apply to the synthesis of chiral sulphoxide medicine such as esomeprazole, concrete scheme are as follows：
The reaction equation of such reaction is：
Wherein, R3For hydrogen or methyl, R4For the C for being interrupted or be not interrupted by oxygen by oxygen1~C6Alkyl, R5For methyl or methoxy
Base, R6For hydrogen or difluoro-methoxy or methoxyl group.
Described method is implemented as follows：
Any one compound described in compound II and claim 1 is dissolved in organic solvent, is heated to 40~80 DEG C
0.5~2h of stirring reaction, adds the pure water of isopropyl titanate and catalytic amounts, after 0.5~2h of stirring reaction, is cooled to 10~30
DEG C, organic amine is added, after stirring 0.25~2h, -10~5 DEG C is cooled to, peroxide oxidant is added dropwise, is progressively warmed to room temperature anti-
1~5h is answered, reaction terminates, and adds 30% hypo solution, is extracted with organic solvent, merges organic phase, is evaporated under reduced pressure
Solvent is removed, recrystallization purifying obtains compound III.Wherein compound II, isopropyl titanate, any one described in claim 1
The mol ratio of compound and peroxide oxidant is 1: 0.2~0.8: 0.5~1.5: 0.8~2, the quality of described organic amine
For the 50%~100% of compound II mass.
According to the present invention, the preferred toluene of described organic solvent.
According to the present invention, preferably 60 DEG C of described heating-up temperature, preferably 0 DEG C of the temperature of cooling.
According to the present invention, described compound II, isopropyl titanate, any one compound and mistake described in claim 1
The mol ratio of oxide oxidizing agent is 1: 0.3: 0.6: 2.
According to the present invention, the preferred DIPEA of described organic amine and quality used is compound II mass
80%.
According to the present invention, described recrystallization solvent preferred volume ratio is 1: 1 normal heptane-methyl tertiary butyl ether(MTBE), positive heptan
Toluene-methyl tertiary butyl ether(MTBE) of alkane, volume ratio 1: 4.
Compared with prior art compared with one kind that the present invention designs carries the D- winestone acid monoester monoamides compared with large-substituent
Compound forms sound response intermediate as part and isopropyl titanate, thioether precursor, can obtain that yield is higher, e.e values are higher
Chiral sulphoxide product, reached the purpose of the present invention.
Embodiment
Below by embodiment, the invention will be further described.It should be understood that methods described of the embodiment of the present invention
It is only used for the explanation present invention, rather than limitation of the present invention, to preparation side of the invention under the concept thereof of the present invention
The simple modifications of method belong to the scope of protection of present invention.The implementation condition used in embodiment can be according to specific requirement
Further adjustment is done, unreceipted implementation condition is usually the condition in routine test.All raw materials for being used in embodiment and
Solvent is that commercially available analysis is pure.
Embodiment 1：
The synthesis of D- tartaric acid list benzene methyl list acyl benzene methanamines
In 50ml eggplant type bottles, D- tartaric acid 5.0g (0.056mol), acetic anhydride 10ml are sequentially added, is slowly added into dense sulphur
Sour 0.2ml, under stirring, 10min is heated to reflux, ice bath cooling, filters, is washed with cold absolute ether, obtain off-white powder
10.1g, yield 83.5%.In 50ml eggplant type bottles, product 4.2g (0.019mol), dichloromethane 20ml, ice bath are walked in addition
Under stirring, the 3.7ml benzylamines for being dissolved in 5ml dichloromethane are added dropwise, 0 DEG C of reaction 1h, are warming up to room temperature reaction 1h.Solvent is spin-dried for, is added
Enter ethyl acetate 20ml, washed successively with 5% hydrochloric acid 20ml × 4, saturated sodium bicarbonate solution 15ml × 3 are washed, saturated common salt
Water 15ml × 3 are washed, and anhydrous sodium sulfate drying, suction filtration is spin-dried for, adds 20mlHCl benzyl alcohol solution, 60h is stirred at room temperature, and are analysed
Go out white solid, suction filtration is washed with absolute ether, obtains product 5.46g, yield 87.2%.
1H-NMR (400MHz, CDCl3)δ：3.23 (2H, brs, OH), 4.16 (2H, d, NCH2), 4.93 (2H, s, OCH2),
5.89 (1H, d, OCH), 6.06 (1H, d, OCH), 7.26 (2H, d, ArH), 7.33 (2H, d, ArH), 7.35 (1H, t, ArH),
7.37 (1H, t, ArH), 7.40 (2H, t, ArH), 7.43 (2H, t, ArH), 8.03 (1H, s, NH) .HR-MS：Calcd for
C18H19NO5329.35 found 329.3.
According to the synthetic method similar to embodiment 1, appropriate reaction raw materials and intermediate are selected, you can be made real respectively
Apply the compound of an I-02~I-68.
I-02：D- tartaric acid monophenyl list acyl benzene methanamines
1H-NMR (400MHz, CDCl3)δ：3.22 (1H, brs, OH), 3.25 (1H, brs, OH), 4.17 (2H, d, NCH2),
5.67 (1H, s, OCH), 5.92 (1H, d, OCH), 7.23 (2H, d, ArH), 7.29 (1H, t, ArH), 7.31 (2H, t, ArH),
7.34 (1H, t, ArH), 7.39 (2H, d, ArH), 7.43 (2H, t, ArH), 8.10 (1H, s, NH) .HR-MS：Calcd for
C19H19NO5315.32 found 315.2.
I-03：D- monobutyl tartalic acid list acyl benzene methanamines
1H-NMR (400MHz, CDCl3)δ：1.03 (3H, t, CH3), 1.26 (2H, m, CH2), 1.52 (2H, m, CH2), 3.23
(1H, brs, OH), 3.31 (1H, brs, OH), 3.75 (2H, t, OCH2), 4.96 (2H, s, NCH2), 5.48 (1H, d, OCH),
5.83 (1H, d, OCH), 7.34 (1H, t, ArH), 7.37 (2H, t, ArH), 7.43 (2H, d, ArH), 8.09 (1H, s, NH) .HR-
MS：Calcd for C15H21NO5295.33 found 295.1.
I-04：D- tartaric acid list cyclohexyl list acyl benzene methanamines
1H-NMR (400MHz, CDCl3)δ：1.21-1.43 (10H, m, CH2), 3.03 (1H, m, NCH), 3.21 (1H, brs,
OH), 3.29 (1H, brs, OH), 5.02 (2H, s, NCH2), 5.52 (1H, d, OCH), 5.79 (1H, d, OCH), 7.26 (1H, t,
ArH), 7.29 (2H, t, ArH), 7.35 (2H, t, ArH), 8.23 (1H, s, NH) .HR-MS：Calcd for
C17H23NO5321.37 found 321.2.
I-05：D- tartaric acid list benzene methyl list acyl methylamines
1H-NMR (400MHz, CDCl3)δ：3.21 (1H, brs, OH), 3.31 (1H, brs, OH), 3.61 (3H, d, NCH3),
4.91 (2H, s, OCH2), 5.78 (1H, d, OCH), 6.13 (1H, d, OCH), 7.31 (1H, t, ArH), 7.33 (2H, t, ArH),
7.38 (2H, d, ArH), 8.43 (1H, s, NH) .HR-MS：Calcd for C12H15NO5253.25 found 253.1.
I-06：D- tartaric acid monophenyl list acyl methylamines
1H-NMR (400MHz, CDCl3)δ：3.22 (1H, brs, OH), 3.34 (1H, brs, OH), 3.58 (3H, d, NCH3),
5.91 (1H, d, OCH), 6.08 (1H, d, OCH), 7.46 (1H, t, ArH), 7.50 (2H, d, ArH), 7.64 (2H, t, ArH),
8.03 (1H, s, NH) .HR-MS：Calcd for C11H13NO5239.22 found 239.1.
I-07：D- monobutyl tartalic acid list acyl methylamines
1H-NMR (400MHz, CDCl3)δ：1.02 (3H, t, CH3), 1.23 (2H, m, CH2), 1.26 (2H, m, CH2), 3.21
(1H, brs, OH), 3.26 (1H, brs, OH), 3.27 (3H, s, NCH3), 4.18 (2H, t, OCH2), 5.75 (1H, d, OCH),
5.97 (1H, d, OCH), 8.01 (1H, s, NH) .HR-MS：Calcd for C9H17NO5219.23 found 219.0.
I-08：D- tartaric acid list cyclohexyl list acyl methylamines
1H-NMR (400MHz, CDCl3)δ：1.48 (2H, m, CH2), 1.57 (4H, m, CH2), 1.60 (4H, m, CH2), 3.16
(3H, s, NCH3), 3.20 (1H, brs, OH), 3.28 (1H, brs, OH), 3.93 (1H, m, OCH), 5.89 (1H, d, OCH),
6.06 (1H, d, OCH), 8.07 (1H, s, NH) .HR-MS：Calcd for C11H19NO5245.27 found 245.1.
I-09：D- tartaric acid list benzene methyl list acyl ethamine
1H-NMR (400MHz, CDCl3)δ：1.04 (3H, t, CH3), 3.24 (1H, brs, OH), 3.32 (1H, brs, OH),
3.46 (2H, q, NCH2), 4.93 (2H, s, OCH2), 5.88 (1H, d, OCH), 6.04 (1H, d, OCH), 7.26 (1H, t, ArH),
7.29 (2H, d, ArH), 7.33 (2H, t, ArH), 8.45 (H, s, NH) .HR-MS：Calcd for C13H17NO5267.28
found 267.1。
I-10：D- tartaric acid monophenyl list acyl ethamine
1H-NMR (400MHz, CDCl3)δ：1.18 (3H, t, CH3), 3.16 (2H, q, NCH2), 3.20 (1H, brs, OH),
3.31 (1H, brs, OH), 5.79 (1H, d, OCH), 5.96 (1H, d, OCH), 7.35 (1H, t, ArH), 7.42 (2H, d, ArH),
7.49 (2H, t, ArH), 8.31 (H, s, NH) .HR-MS：Calcd for C12H15NO5253.25 found 253.1.
I-11：D- monobutyl tartalic acid list acyl ethamine
1H-NMR (400MHz, CDCl3)δ：1.02 (3H, t, CH3), 1.12 (3H, t, CH3), 1.45 (2H, m, CH2), 1.62
(2H, m, CH2), 3.35 (2H, brs, OH), 3,49 (2H, q, NCH2), 4.17 (2H, t, OCH2), 5.71 (1H, d, OCH), 6.09
(1H, d, OCH), 8.70 (1H, s, NH) .HR-MS：Calcd for C10H19NO5233.26 found 233.2.
I-12：D- tartaric acid list cyclohexyl list acyl ethamine
1H-NMR (400MHz, CDCl3)δ：1.02 (3H, t, CH3), 1.47 (2H, m, CH2), 1.58 (4H, m, CH2), 1.60
(4H, m, CH2), 3.19 (2H, q, NCH3), 3.25 (1H, brs, OH), 3.33 (1H, brs, OH), 3.98 (1H, m, OCH), 5.81
(1H, d, OCH), 6.01 (1H, d, OCH), 8.13 (1H, s, NH) .HR-MS：Calcd for C12H21NO5259.30, found
259.2。
I-13：D- tartaric acid list benzene methyl list acyl propylamine
1H-NMR (400MHz, CDCl3)δ：0.94 (3H, t, CH3), 1.41 (2H, q, CH2), 3.20 (1H, brs, OH),
3.37 (1H, brs, OH), 3.66 (2H, q, NCH2), 5.13 (2H, s, OCH2), 5.89 (1H, d, OCH), 6.01 (1H, d, OCH),
7.29 (1H, t, ArH), 7.34 (2H, d, ArH), 7.40 (2H, t, ArH), 8.15 (H, s, NH) .HR-MS：Calcd for
C14H19NO5281.30 found 281.2.
I-14：D- tartaric acid monophenyl list acyl propylamine
1H-NMR (400MHz, CDCl3)δ：1.08 (3H, t, CH3), 1.34 (2H, q, CH2), 3.21 (1H, brs, OH),
3.39 (1H, brs, OH), 3.66 (2H, q, NCH2), 5.78 (1H, d, OCH), 5.98 (1H, d, OCH), 7.25 (1H, t, ArH),
7.32 (2H, d, ArH), 7.41 (2H, t, ArH), 8.10 (H, s, NH) .HR-MS：Calcd for C13H17NO5267.28
found 267.2。
I-15：D- monobutyl tartalic acid list acyl propylamine
1H-NMR (400MHz, CDCl3)δ：1.02 (3H, t, CH3), 1.12 (3H, t, CH3), 1.36 (2H, m, CH2), 1.45
(2H, m, CH2), 1.62 (2H, m, CH2), 3.26 (2H, brs, OH), 3,49 (2H, q, NCH2), 4.17 (2H, t, OCH2), 5.71
(1H, d, OCH), 6.09 (1H, d, OCH), 8.70 (1H, s, NH) .HR-MS：Calcd for C11H21NO5247.29, found
247.2。
I-16：D- tartaric acid list cyclohexyl list acyl propylamine
1H-NMR (400MHz, CDCl3)δ：1.01 (3H, t, CH3), 1.43-1.60 (8H, m, CH2), 1.76 (4H, m,
CH2), 3.23 (1H, brs, OH), 3.26 (1H, brs, OH), 3,51 (2H, q, NCH2), 4.37 (1H, m, OCH), 5.71 (1H, d,
OCH), 6.09 (1H, d, OCH), 8.20 (1H, s, NH) .HR-MS：Calcd for C13H23NO5273.33 found 273.2.
I-17：D- tartaric acid list benzene methyl list acyl isopropylamines
1H-NMR (400MHz, CDCl3)δ：1.04 (6H, d, CH3), 3.21 (1H, brs, OH), 3.30 (1H, brs, OH),
3.81 (1H, m, NCH), 4.96 (2H, s, OCH2), 5.88 (1H, d, OCH), 6.04 (1H, d, OCH), 7.26 (1H, t, ArH),
7.29 (2H, d, ArH), 7.33 (2H, t, ArH), 8.45 (H, s, NH) .HR-MS：Calcd for C14H19NO5281.30
found 281.2。
I-18：D- tartaric acid monophenyl list acyl isopropylamines
1H-NMR (400MHz, CDCl3)δ：1.18 (6H, d, CH3), 3.22 (1H, brs, OH), 3.36 (1H, brs, OH),
3.66 (2H, q, NCH2), 5.79 (1H, d, OCH), 5.96 (1H, d, OCH), 7.35 (1H, t, ArH), 7.42 (2H, d, ArH),
7.49 (2H, t, ArH), 8.31 (H, s, NH) .HR-MS：Calcd for C13H17NO5267.28 found 267.2.
I-19：D- monobutyl tartalic acid list acyl isopropylamines
1H-NMR (400MHz, CDCl3)δ：0.97 (3H, t, CH3), 1.12 (6H, d, CH3), 1.46 (2H, m, CH2), 1.64
(2H, m, CH2), 3.23 (2H, brs, OH), 3,87 (1H, m, NCH), 4.20 (2H, t, OCH2), 5.76 (1H, d, OCH), 6.11
(1H, d, OCH), 8.20 (1H, s, NH) .HR-MS：Calcd for C11H21NO5247.29 found 247.2.
I-20：D- tartaric acid list cyclohexyl list acyl isopropylamines
1H-NMR (400MHz, CDCl3)δ：1.05 (6H, d, CH3), 1.47 (2H, m, CH2), 1.58 (4H, m, CH2), 1.60
(4H, m, CH2), 3.33 (2H, brs, OH), 3.89 (1H, m, NCH), 4.08 (1H, m, OCH), 5.81 (1H, d, OCH), 6.01
(1H, d, OCH), 8.13 (1H, s, NH) .HR-MS：Calcd for C13H23NO5273.33 found 273.3.
I-21：D- tartaric acid list benzene methyl list acyl butylamine
1H-NMR (400MHz, CDCl3)δ：1.04 (3H, t, CH3), 1.32 (2H, m, CH2), 1.45 (2H, m, CH2), 3.24
(1H, brs, OH), 3.29 (1H, brs, OH), 3.37 (2H, t, NCH2), 4.93 (2H, s, OCH2), 5.88 (1H, d, OCH),
6.04 (1H, d, OCH), 7.26 (1H, t, ArH), 7.29 (2H, d, ArH), 7.33 (2H, t, ArH), 8.25 (H, s, NH) .HR-
MS：Calcd for C15H21NO5296.33 found 297.3.
I-22：D- tartaric acid monophenyl list acyl butylamine
1H-NMR (400MHz, CDCl3)δ：1.12 (3H, t, CH3), 1.33 (2H, m, CH2), 1.56 (2H, m, CH2), 3.26
(1H, brs, OH), 3.36 (1H, brs, OH), 3.76 (2H, t, NCH2), 5.83 (1H, d, OCH), 5.92 (1H, d, OCH),
7.35 (1H, t, ArH), 7.42 (2H, d, ArH), 7.50 (2H, t, ArH), 8.31 (H, s, NH) .HR-MS：Calcd for
C14H19NO5281.30 found 281.2.
I-23：D- monobutyl tartalic acid list acyl butylamine
1H-NMR (400MHz, CDCl3)δ：0.97-1.02 (6H, m, CH3), 1.29 (2H, m, CH2), 1.45 (2H, m,
CH2), 1.57 (2H, m, CH2), 1.62 (2H, m, CH2), 3.27 (2H, brs, OH), 3,49 (2H, t, NCH2), 4.28 (2H, t,
OCH2), 5.71 (1H, d, OCH), 6.09 (1H, d, OCH), 7.90 (1H, s, NH) .HR-MS：Calcd for
C12H23NO5261.31 found 262.3.
I-24：D- tartaric acid list cyclohexyl list acyl butylamine
1H-NMR (400MHz, CDCl3)δ：1.15 (3H, t, CH3), 1.29 (2H, m, CH2), 1.37 (2H, m, CH2), 1.58
(4H, m, CH2), 1.60 (4H, m, CH2), 3.28 (2H, brd, OH), 3.29 (2H, t, NCH2), 4.28 (1H, m, OCH), 5.81
(1H, d, OCH), 6.08 (1H, d, OCH), 8.23 (1H, s, NH) .HR-MS：Calcd for C14H25NO5287.35, found
287.2。
I-25：D- tartaric acid list benzene methyl list acyl tert-butylamines
1H-NMR (400MHz, CDCl3)δ：1.34 (9H, s, CH3), 3.22 (1H, brs, OH), 3.31 (1H, brs, OH),
5.23 (2H, s, OCH2), 5.88 (1H, d, OCH), 6.12 (1H, d, OCH), 7.36 (1H, t, ArH), 7.41 (2H, d, ArH),
7.46 (2H, t, ArH), 8.25 (H, s, NH) .HR-MS：Calcd for C15H21NO5295.33 found 295.3.
I-26：D- tartaric acid monophenyl list acyl tert-butylamines
1H-NMR (400MHz, CDCl3)δ：1.35 (9H, s, CH3), 3.23 (1H, brs, OH), 3.34 (1H, brs, OH),
5.68 (1H, d, OCH), 5.89 (1H, d, OCH), 7.25 (1H, t, ArH), 7.32 (2H, d, ArH), 7.39 (2H, t, ArH),
8.10 (H, s, NH) .HR-MS：Calcd forC14H19NO5281.30 found 281.2.
I-27：D- monobutyl tartalic acid list acyl tert-butylamines
1H-NMR (400MHz, CDCl3)δ：0.94 (3H, t, CH3), 1.38 (9H, s, CH3), 1.45 (2H, m, CH2), 1.63
(2H, m, CH2), 3.23 (2H, brs, OH), 4.17 (2H, t, OCH2), 5.91 (1H, d, OCH), 6.14 (1H, d, OCH), 8.39
(1H, s, NH) .HR-MS：Calcd for C12H23NO5261.31 found 261.2.
I-28：D- tartaric acid list cyclohexyl list acyl tert-butylamines
1H-NMR (400MHz, CDCl3)δ：1.36 (9H, s, CH3), 1.45 (2H, m, CH2), 1.59 (4H, m, CH2), 1.62
(4H, m, CH2), 3.22 (2H, brd, OH), 4.79 (1H, m, OCH), 5.82 (1H, d, OCH), 6.01 (1H, d, OCH), 8.18
(1H, s, NH) .HR-MS：Calcd for C14H23NO5287.35 found 287.3.
I-29：D- tartaric acid list benzene methyl list acyl cyclohexylamine
1H-NMR (400MHz, CDCl3)δ：1.39 (4H, m, CH2), 1.46 (2H, m, CH2), 1.60 (4H, q, CH2), 3.24
(1H, brs, OH), 3.31 (1H, brs, OH), 3.47 (1H, m, NCH), 4.97 (2H, s, OCH2), 5.84 (1H, d, OCH),
6.01 (1H, d, OCH), 7.31 (1H, t, ArH), 7.35 (2H, d, ArH), 7.40 (2H, t, ArH), 8.49 (H, s, NH) .HR-
MS：Calcd forC17H23NO5321.37 found 321.3.
I-30：D- tartaric acid monophenyl list acyl cyclohexylamine
1H-NMR (400MHz, CDCl3)δ：1.33 (4H, m, CH2), 1.44 (2H, m, CH2), 1.56 (4H, q, CH2), 3.22
(1H, brs, OH), 3.36 (1H, brs, OH), 3.58 (1H, m, NCH), 5.82 (1H, d, OCH), 5.97 (1H, d, OCH), 7.38
(1H, t, ArH), 7.43 (2H, d, ArH), 7.50 (2H, t, ArH), 8.29 (H, s, NH) .HR-MS：Calcd for
C16H21NO5307.34 found 307.2.
I-31：D- monobutyl tartalic acid list acyl cyclohexylamine
1H-NMR (400MHz, CDCl3)δ：1.02 (3H, t, CH3), 1.27-1.54 (14H, m, CH2), 1.62 (2H, m,
CH2), 3.24 (2H, brs, OH), 3,67 (1H, q, NCH), 4.26 (2H, t, OCH2), 5.82 (1H, d, OCH), 6.01 (1H, d,
OCH), 8.40 (1H, s, NH) .HR-MS：Calcd for C14H25NO5287.35 found 287.2.
I-32：D- tartaric acid list cyclohexyl list acyl cyclohexylamine
1H-NMR (400MHz, CDCl3)δ：1.27 (4H, m, CH2), 1.38-1.56 (8H, m, CH2), 1.66 (4H, m,
CH2), 1.78 (4H, m, CH2), 3.22 (2H, brs, OH), 3.69 (1H, s, NCH), 4.38 (1H, m, OCH), 5.81 (1H, d,
OCH), 6.01 (1H, d, OCH), 8.24 (1H, s, NH) .HR-MS：Calcd for C16H27NO5313.39 found 313.3.
I-33：D- tartaric acid list benzene methyl mono-anilines
1H-NMR (400MHz, CDCl3)δ：3.33 (2H, brs, OH), 4.97 (2H, s, OCH2), 5.84 (1H, d, OCH),
6.03 (1H, d, OCH), 7.21 (1H, t, ArH), 7.25 (2H, d, ArH), 7.29 (1H, t, ArH), 7.36 (2H, t, ArH),
7.45 (2H, d, ArH), 7.49 (2H, t, ArH), 8.29 (H, s, NH) .HR-MS：Calcd for C17H17NO5315.32
found 315.2。
I-34：D- tartaric acid monophenyl mono-anilines
1H-NMR (400MHz, CDCl3)δ：3.35 (2H, brs, OH), 5.86 (1H, d, OCH), 5.99 (1H, d, OCH),
7.24 (1H, t, ArH), 7.27 (2H, d, ArH), 7.33 (1H, t, ArH), 7.39 (2H, t, ArH), 7.46 (2H, d, ArH),
7.51 (2H, t, ArH), 8.21 (H, s, NH) .HR-MS：Calcd for C16H15NO5301.29 found 301.2.
I-35：D- monobutyl tartalic acid mono-anilines
1H-NMR (400MHz, CDCl3)δ：1.02 (3H, t, CH3), 1.37 (2H, m, CH2), 1.62 (2H, m, CH2), 3.26
(1H, brs, OH), 3.35 (1H, brs, OH), 4.29 (2H, t, OCH2), 5.81 (1H, d, OCH), 6.12 (1H, d, OCH),
7.31 (2H, t, ArH), 7.36 (2H, d, ArH), 7.42 (2H, t, ArH), 8.23 (1H, s, NH) .HR-MS：Calcd for
C14H17NO581.30 found 281.2.
I-36：D- tartaric acid list cyclohexyl mono-anilines
1H-NMR (400MHz, CDCl3)δ：1.45 (4H, m, CH2), 1.53 (2H, m, CH2), 1.76 (4H, m, CH2), 3.26
(1H, brs, OH), 3.34 (1H, brs, OH), 4.78 (1H, m, OCH), 5.82 (1H, d, OCH), 6.03 (1H, d, OCH), 7.28
(2H, t, ArH), 7.33 (2H, d, ArH), 7.42 (2H, t, ArH), 8.14 (1H, s, NH) .HR-MS：Calcd for
C16H21NO5307.34 found 307.2.
I-37：D- tartaric acid monophenyl list acyl parachloroanilinum
1H-NMR (400MHz, CDCl3)δ：3.35 (1H, brs, OH), 3.39 (1H, brs, OH), 5.86 (1H, d, OCH),
5.99 (1H, d, OCH), 7.24 (1H, t, ArH), 7.34 (2H, d, ArH), 7.43 (2H, t, ArH), 7.48 (2H, d, ArH),
7.68 (2H, d, ArH), 7.91 (H, s, NH) .HR-MS：Calcd for C16H14ClNO5335.74 found 336.7.
I-38：D- monobutyl tartalic acid list acyl parachloroanilinum
1H-NMR (400MHz, CDCl3)δ：1.12 (3H, t, CH3), 1.41 (2H, m, CH2), 1.78 (2H, m, CH2), 3.23
(1H, brs, OH), 3.39 (1H, brs, OH), 4.29 (2H, t, OCH2), 5.83 (1H, d, OCH), 6.11 (1H, d, OCH),
7.42 (2H, d, ArH), 7.76 (2H, d, ArH), 7.96 (1H, s, NH) .HR-MS：Calcd for C14H18ClNO5315.75
found315.6。
I-39：D- tartaric acid list cyclohexyl list acyl parachloroanilinum
1H-NMR (400MHz, CDCl3)δ：1.46 (4H, m, CH2), 1.52 (2H, m, CH2), 1.78 (4H, m, CH2), 3.26
(1H, brs, OH), 3.38 (1H, brs, OH), 4.84 (1H, m, OCH), 5.83 (1H, d, OCH), 6.11 (1H, d, OCH), 7.48
(2H, d, ArH), 7.79 (2H, d, ArH), 7.94 (1H, s, NH) .HR-MS：Calcd for C16H20ClNO5341.79, found
342.7。
I-40：D- tartaric acid list benzene methyl list acyl parachloroanilinum
1H-NMR (400MHz, CDCl3)δ：3.29 (1H, brs, OH), 3.38 (1H, brs, OH), 4.97 (2H, s, OCH2),
5.86 (1H, d, OCH), 6.08 (1H, d, OCH), 7.21 (1H, t, ArH), 7.28 (2H, d, ArH), 7.37 (2H, t, ArH),
7.49 (2H, d, ArH), 7.82 (2H, d, ArH), 7.89 (H, s, NH) .HR-MS：Calcd for C17H16ClNO5349.77
found 349.7。
I-41：D- tartaric acid monophenyl list acyl paranitroanilinum
1H-NMR (400MHz, CDCl3)δ：3.40 (2H, brd, OH), 5.85 (1H, d, COCH), 5.97 (1H, d, COCH),
7.24 (1H, t, ArH), 7.34 (2H, d, ArH), 7.43 (2H, t, ArH), 7.84 (2H, d, ArH), 8.19 (2H, d, ArH),
7.21 (H, s, NH) .HR-MS：Calcd for C16H14N2O7346.29 found 346.2.
I-42：D- monobutyl tartalic acid list acyl paranitroanilinum
1H-NMR (400MHz, CDCl3)δ：1.14 (3H, t, CH3), 1.43 (2H, m, CH2), 1.79 (2H, m, CH2), 3.23
(1H, brs, OH), 3.39 (1H, brs, OH), 4.29 (2H, t, OCH2), 5.88 (1H, d, OCH), 6.10 (1H, d, OCH),
7.82 (2H, d, ArH), 8.16 (2H, d, ArH), 7.26 (1H, s, NH) .HR-MS：Calcd for C14H18N2O7326.30
found 326.2。
I-43：D- tartaric acid list cyclohexyl list acyl paranitroanilinum
1H-NMR (400MHz, CDCl3)δ：1.46 (4H, m, CH2), 1.53 (2H, m, CH2), 1.79 (4H, m, CH2), 3.26
(1H, brs, OH), 3.39 (1H, brs, OH), 4.88 (1H, m, OCH), 5.84 (1H, d, OCH), 6.13 (1H, d, OCH), 7.81
(2H, d, ArH), 8.19 (2H, d, ArH), 7.34 (1H, s, NH) .HR-MS：Calcd for C16H20N2O7352.34, found
352.34。
I-44：D- tartaric acid list benzene methyl list acyl paranitroanilinum
1H-NMR (400MHz, CDCl3)δ：3.28 (1H, brs, OH), 3.39 (1H, brs, OH), 5.02 (2H, s, OCH2),
5.88 (1H, d, OCH), 6.10 (1H, d, OCH), 7.21 (1H, t, ArH), 7.29 (2H, d, ArH), 7.38 (2H, t, ArH),
7.82 (2H, d, ArH), 8.26 (2H, d, ArH), 7.29 (H, s, NH) .HR-MS：Calcd for C17H16N2O7360.32
found 360.32。
I-45：D- tartaric acid monophenyl list acyl open-chain crown ethers
1H-NMR (400MHz, CDCl3)δ：3.32 (2H, brs, OH), 2.29 (3H, s, COCH3), 5.86 (1H, d, OCH),
5.99 (1H, d, OCH), 7.24 (1H, t, ArH), 7.31 (2H, d, ArH), 7.34 (2H, d, ArH), 7.48 (2H, t, ArH),
7.54 (2H, d, ArH), 7.56 (H, s, NH) .HR-MS：Calcd for C17H17NO5315.32 found 315.2.
I-46：D- monobutyl tartalic acid list acyl open-chain crown ethers
1H-NMR (400MHz, CDCl3)δ：1.10 (3H, t, CH3), 1.39 (2H, m, CH2), 1.77 (2H, m, CH2), 3.23
(1H, brs, OH), 3.31 (1H, brs, OH), 2.31 (3H, s, COCH3), 4.27 (2H, t, OCH2), 5.84 (1H, d, OCH),
6.10 (1H, d, OCH), 7.27 (2H, d, ArH), 7.51 (2H, d, ArH), 7.58 (1H, s, NH) .HR-MS：Calcd for
C14H18ClNO5295.33 found 295.2.
I-47：D- tartaric acid list cyclohexyl list acyl open-chain crown ethers
1H-NMR (400MHz, CDCl3)δ：1.47 (4H, m, CH2), 1.53 (2H, m, CH2), 1.80 (4H, m, CH2), 2.26
(3H, s, CH3), 3.27 (1H, brs, OH), 3.32 (1H, brs, OH), 4.84 (1H, m, OCH), 5.83 (1H, d, OCH), 6.11
(1H, d, OCH), 7.48 (2H, d, ArH), 7.79 (2H, d, ArH), 7.64 (1H, s, NH) .HR-MS：Calcd for
C17H23NO5321.37 found 321.3.
I-48：D- tartaric acid list benzene methyl list acyl open-chain crown ethers
1H-NMR (400MHz, CDCl3)δ：2.10 (3H, s, CH3), 3.29 (2H, brd, OH), 4.98 (2H, s, OCH2),
5.89 (1H, d, OCH), 6.07 (1H, d, OCH), 7.21 (1H, t, ArH), 7.28 (2H, d, ArH), 7.34 (2H, d, ArH),
7.40 (2H, t, ArH), 7.72 (2H, d, ArH), 7.69 (H, s, NH) .HR-MS：Calcd for C18H19NO5329.35
found 329.35。
I-49：D- tartaric acid monophenyl list acyl o-toluidines
1H-NMR (400MHz, CDCl3)δ：2.12 (3H, s, CH3), 3.30 (2H, brs, OH), 5.87 (1H, d, OCH),
6.01 (1H, d, OCH), 7.13 (1H, t, ArH), 7.23 (1H, t, ArH), 7.27 (1H, t, ArH), 7.31 (2H, d, ArH),
7.35 (1H, d, ArH), 7.41 (1H, d, ArH), 7.48 (2H, t, ArH), 7.79 (H, s, NH) .HR-MS：Calcd for
C17H17NO5315.32 found 315.2.
I-50：D- monobutyl tartalic acid list acyl o-toluidines
1H-NMR (400MHz, CDCl3)δ：0.98 (3H, t, CH3), 1.37 (2H, m, CH2), 1.74 (2H, m, CH2), 2.14
(3H, s, CH3), 3.25 (1H, brs, OH), 3.31 (1H, brs, OH), 4.21 (2H, t, OCH2), 5.86 (1H, d, OCH), 6.06
(1H, d, OCH), 7.16 (H, t, ArH), 7.25 (1H, t, ArH), 7.31 (1H, d, ArH), 7.40 (1H, d, ArH), 7.81
(1H, s, NH) .HR-MS：Calcd for C14H18ClNO5295.33 found 296.3.
I-51：D- tartaric acid list cyclohexyl list acyl o-toluidines
1H-NMR (400MHz, CDCl3)δ：1.49 (4H, m, CH2), 1.56 (2H, m, CH2), 1.81 (4H, m, CH2), 2.17
(3H, s, CH3), 3.26 (1H, brs, OH), 3.31 (1H, brs, OH), 4.86 (1H, m, OCH), 5.87 (1H, d, OCH), 6.14
(1H, d, OCH), 7.18 (1H, t, ArH), 7.22 (1H, t, ArH), 7.32 (1H, d, ArH), 7.39 (1H, d, ArH), 7.80
(1H, s, NH) .HR-MS：Calcd for C17H23NO5321.37 found 321.3.
I-52：D- tartaric acid list benzene methyl list acyl o-toluidines
1H-NMR (400MHz, CDCl3)δ：2.21 (3H, s, CH3), 3.29 (2H, brd, OH), 5.12 (2H, s, OCH2),
5.79 (1H, d, OCH), 6.05 (1H, d, OCH), 7.11 (1H, t, ArH), 7.23 (1H, t, ArH), 7.30 (1H, d, ArH),
7.36 (3H, t, ArH), 7.39 (1H, t, ArH), 7.46 (2H, d, ArH), 7.57 (2H, d, ArH), 7.68 (H, s, NH) .HR-
MS：Calcd for C18H19NO5329.35 found 329.3.
I-53：D- tartaric acid monophenyl list acyl para-bromoaniline
1H-NMR (400MHz, CDCl3)δ：3.33 (2H, brs, OH), 5.86 (1H, d, OCH), 6.01 (1H, d, OCH),
7.25 (1H, t, ArH), 7.36 (2H, d, ArH), 7.44 (2H, t, ArH), 7.49 (2H, d, ArH), 7.71 (2H, d, ArH),
8.21 (H, s, NH) .HR-MS：Calcd for C16H14BrNO5380.19 found 380.1.
I-54：D- monobutyl tartalic acid list acyl para-bromoaniline
1H-NMR (400MHz, CDCl3)δ：1.11 (3H, t, CH3), 1.41 (2H, m, CH2), 1.77 (2H, m, CH2), 3.25
(1H, brs, OH), 3.33 (1H, brs, OH), 4.30 (2H, t, OCH2), 5.84 (1H, d, OCH), 6.10 (1H, d, OCH),
7.42 (2H, d, ArH), 7.78 (2H, d, ArH), 7.83 (1H, s, NH) .HR-MS：Calcd for C14H18BrNO5360.20
found 360.1。
I-55：D- tartaric acid list cyclohexyl list acyl para-bromoaniline
1H-NMR (400MHz, CDCl3)δ：1.45 (4H, m, CH2), 1.53 (2H, m, CH2), 1.79 (4H, m, CH2), 3.27
(1H, brs, OH), 3.33 (1H, brs, OH), 4.86 (1H, m, OCH), 5.85 (1H, d, OCH), 6.13 (1H, d, OCH), 7.47
(2H, d, ArH), 7.81 (2H, d, ArH), 7.84 (1H, s, NH) .HR-MS：Calcd for C16H20BrNO5386.24, found
386.2。
I-56：D- tartaric acid list benzene methyl list acyl para-bromoaniline
1H-NMR (400MHz, CDCl3)δ：3.28 (1H, brs, OH), 3.32 (1H, brs, OH), 4.98 (2H, s, OCH2),
5.89 (1H, d, OCH), 6.10 (1H, d, OCH), 7.22 (1H, t, ArH), 7.29 (2H, d, ArH), 7.38 (2H, t, ArH),
7.49 (2H, d, ArH), 7.81 (2H, d, ArH), 7.83 (H, s, NH) .HR-MS：Calcd for C17H16BrNO5394.22
found 395.2。
I-57：D- tartaric acid monophenyl lists acyl-(1- naphthyls) amine
1H-NMR (400MHz, CDCl3)δ：3.32 (1H, brs, OH), 3.36 (1H, brs, OH), 5.74 (1H, d, OCH),
5.85 (1H, d, OCH), 7.04 (1H, d, ArH), 7.24 (1H, t, ArH), 7.29 (2H, d, ArH), 7.38 (1H, d, ArH),
7.42 (2H, t, ArH), 7.51 (1H, d, ArH), 7.53 (2H, d, ArH), 8.02 (1H, d, ArH), 8.07 (1H, d, ArH),
8.10 (H, s, NH) .HR-MS：Calcd for C20H17NO5351.35 found 351.2.
I-58：D- monobutyl tartalic acid lists acyl-(1- naphthyls) amine
1H-NMR (400MHz, CDCl3)δ：1.13 (3H, t, CH3), 1.42 (2H, m, CH2), 1.71 (2H, m, CH2), 3.24
(1H, brs, OH), 3.34 (1H, brs, OH), 4.27 (2H, t, OCH2), 5.83 (1H, d, OCH), 6.12 (1H, d, OCH),
7.04 (1H, d, ArH), 7.38 (1H, d, ArH), 7.51 (1H, d, ArH), 7.53 (2H, d, ArH), 8.02 (1H, d, ArH),
8.07 (1H, d, ArH), 8.10 (H, s, NH) .HR-MS：Calcd for C18H21NO5331.36 found 331.3.
I-59：D- tartaric acid list cyclohexyl lists acyl-(1- naphthyls) amine
1H-NMR (400MHz, CDCl3)δ：1.46 (4H, m, CH2), 1.52 (2H, m, CH2), 1.78 (4H, m, CH2), 3.23
(1H, brs, OH), 3.32 (1H, brs, OH), 4.86 (1H, m, OCH), 5.82 (1H, d, OCH), 6.13 (1H, d, OCH), 7.04
(1H, d, ArH), 7.38 (1H, d, ArH), 7.51 (1H, d, ArH), 7.53 (2H, d, ArH), 8.02 (1H, d, ArH), 8.07
(1H, d, ArH), 8.12 (H, s, NH) .HR-MS：Calcd for C20H23NO5357.40 found 357.3.
I-60：D- tartaric acid list benzene methyl lists acyl-(1- naphthyls) amine
1H-NMR (400MHz, CDCl3)δ：3.29 (1H, brs, OH), 3.34 (1H, brs, OH), 4.99 (2H, s, OCH2),
5.87 (1H, d, OCH), 6.07 (1H, d, OCH), 7.21 (1H, t, ArH), 7.28 (2H, d, ArH), 7.37 (2H, t, ArH),
7.49 (2H, d, ArH), 7.82 (2H, d, ArH), 8.14 (H, s, NH) .HR-MS：Calcd for C21H19NO5365.31
found 366.3。
I-61：D- tartaric acid monophenyl lists acyl-((R) -1- phenethyls) amine
1H-NMR (400MHz, CDCl3)δ：1.36 (3H, d, CH3), 3.34 (2H, brs, OH), 5.18 (1H, q, NCH),
5.87 (1H, d, OCH), 5.96 (1H, d, OCH), 7.24 (1H, t, ArH), 7.26 (1H, t, ArH), 7.29-7.31 (4H, q,
ArH), 7.40-7.42 (4H, m, ArH), 7.89 (H, s, NH) .HR-MS：Calcd for C18H19NO5329.35, found
329.3。
I-62：D- monobutyl tartalic acid lists acyl-((R) -1- phenethyls) amine
1H-NMR (400MHz, CDCl3)δ：1.08 (3H, t, CH3), 1.43 (2H, m, CH2), 1.74 (2H, m, CH2), 3.26
(1H, brs, OH), 3.32 (1H, brs, OH), 4.32 (2H, t, OCH2), 5.16 (1H, q, NCH), 5.87 (1H, d, OCH),
6.11 (1H, d, OCH), 7.23 (1H, t, ArH), 7.31 (2H, d, ArH), 7.47 (2H, t, ArH), 7.93 (1H, s, NH) .HR-
MS：Calcd for C16H23NO5309.39 found 309.3.
I-63：D- tartaric acid list cyclohexyl lists acyl-((R) -1- phenethyls) amine
1H-NMR (400MHz, CDCl3)δ：1.46-1.48 (7H, m, CH3&CH2), 1.51 (2H, m, CH2), 1.76 (4H, m,
CH2), 3.29 (2H, brd, OH), 4.88 (1H, m, OCH), 5.16 (1H, q, NCH), 5.84 (1H, d, OCH), 6.06 (1H, d,
OCH), 7.21 (1H, t, ArH), 7.33 (2H, d, ArH), 7.47 (2H, t, ArH), 7.93 (1H, s, NH) .HR-MS：Calcd
for C18H25NO5335.39 found 335.3.
I-64：D- tartaric acid list benzene methyl lists acyl-((R) -1- phenethyls) amine
1H-NMR (400MHz, CDCl3)δ：1.48 (3H, d, CH3), 3.32 (2H, brs, OH), 4.97 (2H, s, OCH2),
5.19 (1H, q, NCH), 5.86 (1H, d, OCH), 6.09 (1H, d, OCH), 7.21 (1H, t, ArH), 7.23 (1H, t, ArH),
7.28-7.29 (4H, t, ArH), 7.37 (2H, t, ArH), 7.39 (2H, t, ArH), 7.82 (H, s, NH) .HR-MS：Calcd
for C19H21NO5343.37 found 343.3.
I-65：D- tartaric acid monophenyl lists acyl-((S) -1- phenethyls) amine
1H-NMR (400MHz, CDCl3)δ：1.36 (3H, d, CH3), 3.34 (2H, brs, OH), 5.18 (1H, q, NCH),
5.87 (1H, d, OCH), 5.96 (1H, d, OCH), 7.23 (1H, t, ArH), 7.26 (1H, t, ArH), 7.29-7.31 (4H, q,
ArH), 7.40-7.41 (4H, m, ArH), 7.88 (H, s, NH) .HR-MS：Calcd for C18H19NO5329.35, found
330.3。
I-66：D- monobutyl tartalic acid lists acyl-((S) -1- phenethyls) amine
1H-NMR (400MHz, CDCl3)δ：1.08 (3H, t, CH3), 1.43 (2H, m, CH2), 1.74 (2H, m, CH2), 3.26
(1H, brs, OH), 3.32 (1H, brs, OH), 4.32 (2H, t, OCH2), 5.16 (1H, q, NCH), 5.87 (1H, d, OCH),
6.11 (1H, d, OCH), 7.23 (1H, t, ArH), 7.31 (2H, d, ArH), 7.47 (2H, t, ArH), 7.93 (1H, s, NH) .HR-
MS：Calcd for C16H23NO5309.36 found 309.3.
I-67：D- tartaric acid list cyclohexyl lists acyl-((S) -1- phenethyls) amine
1H-NMR (400MHz, CDCl3)δ：1.46-1.48 (7H, m, CH3&CH2), 1.51 (2H, m, CH2), 1.76 (4H, m,
CH2), 3.29 (2H, brd, OH), 4.88 (1H, m, OCH), 5.16 (1H, q, NCH), 5.84 (1H, d, OCH), 6.06 (1H, d,
OCH), 7.21 (1H, t, ArH), 7.33 (2H, d, ArH), 7.47 (2H, t, ArH), 7.93 (1H, s, NH) .HR-MS：Calcd
for C18H25NO5335.39 found 335.3.
I-68：D- tartaric acid list benzene methyl lists acyl-((S) -1- phenethyls) amine
1H-NMR (400MHz, CDCl3)δ：1.48 (3H, d, CH3), 3.32 (2H, brs, OH), 4.97 (2H, s, OCH2),
5.19 (1H, q, NCH), 5.86 (1H, d, OCH), 6.09 (1H, d, OCH), 7.21 (1H, t, ArH), 7.23 (1H, t, ArH),
7.28-7.29 (4H, t, ArH), 7.37 (2H, t, ArH), 7.39 (2H, t, ArH), 7.82 (H, s, NH) .HR-MS：Calcd
for C19H21NO5343.37 found 343.3.
Embodiment 2：
Wherein, I-01 represents the D- tartaric acid list benzene methyl list acyl benzene methanamines of the preparation of embodiment 1.
Wherein, [O] represents cumyl hydroperoxide.
Esomeprazole thioether precursor 3.53g and D- tartaric acid list benzene methyl list acyl benzene methanamine 2.0g is mixed, added
35ml toluene, 60 DEG C are heated to, treat dissolution of raw material, add H2O0.03ml, 30min is reacted, add isopropyl titanate 0.81g, continued
1h is reacted, is cooled to 20 DEG C, adds diisopropylethylamine 0.80ml, reacts 30min, ice bath is cooled to 0 DEG C, and temperature control is 0~5
DEG C add 80% CHP6.0ml, react 5h under conditions of 0~5 DEG C.After reaction completely, 10m130%Na is added2S2O3, stir
10min is mixed, 20ml heptane-methyl tertiary butyl ether(MTBE) (V=1: 1) is added dropwise under the conditions of 0~10 DEG C, then 33ml heptane is added dropwise, is separated out
White solid, 1h is stirred, filtered.Filter cake is washed with 8ml toluene-methyl tertiary butyl ether(MTBE) (V=1: 4), and white solid is obtained after drying
2.51g, as esomeprazole, yield 68.1%, enantiomeric excess 99.7%.
According to the synthetic method similar to embodiment 2, with I-02~I-36 come before selective oxidation esomeprazole thioether
Body generates esomeprazole, and its yield and optical purity are as shown in table 1
Table 1 uses I-2~I-36 synthesis esomeprazole yields and optical purity table
Embodiment 3：
Wherein, I-37 represents D- tartaric acid monophenyl list acyl parachloroanilinum
Wherein, [O] represents cumyl hydroperoxide.
Esomeprazole thioether precursor 3.30g and D- tartaric acid monophenyl list acyl parachloroanilinum 2.0g is mixed, added
35ml toluene, 60 DEG C are heated to, treat dissolution of raw material, add H2O0.03ml, 30min is reacted, add isopropyl titanate 0.81g, continued
1h is reacted, is cooled to 20 DEG C, adds diisopropylethylamine 0.80ml, reacts 30min, ice bath is cooled to 0 DEG C, and temperature control is 0~5
DEG C add 80% CHP6.0ml, react 5h under conditions of 0~5 DEG C.After reaction completely, 10ml30%Na is added2S2O3, stir
10min is mixed, 20ml heptane-methyl tertiary butyl ether(MTBE) (V=1: 1) is added dropwise under the conditions of 0~10 DEG C, then 33ml heptane is added dropwise, is separated out
White solid, 1h is stirred, filtered.Filter cake is washed with 8ml toluene-methyl tertiary butyl ether(MTBE) (V=1: 4), and white solid is obtained after drying
Esomeprazole 2.30g, yield 66.8%, enantiomeric excess 98.9%.
According to the synthetic method similar to embodiment 4, with I-38~I-68 come before selective oxidation esomeprazole thioether
Body generates esomeprazole, and its yield and optical purity are as shown in table 2
Table 2 synthesizes the yield and optical purity table of esomeprazole using I-38~I-68
Claims (8)
1. a kind of D- winestones acid monoester monoamides class compound, it is characterised in that the compound is any one following chemical combination
Thing：
I-01:D- tartaric acid list benzyl ester list acyl benzylamines；
I-02:D- tartaric acid monophenyl mono-anilines；
I-03:D- monobutyl tartalic acid mono-anilines；
I-04:D- tartaric acid list cyclohexyl mono-anilines；
I-33:D- tartaric acid list benzyl ester mono-anilines；
I-35:D- monobutyl tartalic acid mono-anilines；
I-37:D- tartaric acid monophenyl list acyl parachloroanilinum；
I-41:D- tartaric acid monophenyl list acyl paranitroanilinum；
I-54:D- monobutyl tartalic acid list acyl para-bromoaniline；
I-57:D- tartaric acid monophenyl list acyl (1- naphthyls) amine；
I-61:D- tartaric acid monophenyl lists acyl ((R) -1- phenethyls) amine；
I-63:D- tartaric acid list cyclohexyl list acyl ((R) -1- phenethyls) amine；
I-65:D- tartaric acid monophenyl lists acyl ((S) -1- phenethyls) amine；
I-67:D- tartaric acid list cyclohexyls list-((S) -1- phenethyls) acid amides；
I-68:D- tartaric acid list benzene methyls list-((S) -1- phenethyls) acid amides.
A kind of 2. method for preparing compound described in claim 1, it is characterised in that：D- tartaric acid is added in acetic anhydride, is added
Enter the concentrated sulfuric acid, be stirred at reflux 5~30min, ice bath cooling, filter, with cold ether, the solid of gained is dissolved in organic solvent
In, it is added dropwise is dissolved in the amine of organic solvent thereto, reacts 0.5~2h, be spin-dried for solvent, add the alcoholic solution of hydrogen chloride, in 15~
Stirred at 45 DEG C, react 10~72h, separate out product, filtered and washed with absolute ether, compound described in claim 1 is made.
3. according to the method for claim 2, it is characterised in that：The organic solvent is selected from ethyl acetate, dichloromethane, first
One or more in benzene and chloroform；Also include re-crystallization step, recrystallize solvent used be selected from acetone, n-hexane, toluene,
One or more in ethyl acetate.
4. with any described compound of claim 1, the method for preparing optical homochiral sulfoxide compound, its reactional equation
Formula is as follows：
Wherein, R3For hydrogen or methyl, R4For the alkyl for the C1~C6 for being interrupted or be not interrupted by oxygen by oxygen, R5For methyl or methoxy,
R6For hydrogen or difluoro-methoxy or methoxyl group；
Wherein any described compound of compound II and claim 1 is dissolved in organic solvent, 40~80 DEG C is heated to and stirs
Mix 0.5~2h of reaction, add the pure water of isopropyl titanate and catalytic amounts, after 0.5~2h of stirring reaction, be cooled to 10~30 DEG C,
Organic amine is added, after stirring 0.25~2h, -10~5 DEG C is cooled to, peroxide is added dropwise, is progressively warmed to room temperature 1~5h of reaction,
Reaction terminates, and adds 30% hypo solution, is extracted with organic solvent, merges organic phase, is evaporated under reduced pressure and removes solvent,
Recrystallization purifying obtains compound III；The wherein any described compound of compound II, isopropyl titanate, claim 1 and peroxide
The mol ratio of compound is 1：0.2~0.8:0.5~1.5:0.8~2, the quality of the organic amine is the 50% of compound II mass
~100%.
5. according to the method for claim 4, it is characterised in that：The compound III is esomeprazole.
6. according to the method for claim 4, it is characterised in that：Organic solvent is in dichloromethane, ethyl acetate, toluene
One or more；Organic amine is selected from N, the one or more in N- diisopropylethylamine, diethylamine, triethylamine；The peroxide
Compound is cumyl hydroperoxide；Used recrystallization solvent be selected from acetone, toluene, water, methyl tertiary butyl ether(MTBE), normal heptane,
One or more in n-hexane.
7. claim 1 any described compound or any methods describeds of claim 2-6, suppress preparing chiral proton pump
Application in terms of agent.
8. application according to claim 7, it is characterised in that：The chiral proton pump inhibitor, which is specially that Esso is beautiful, to be drawn
Azoles.
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