CN111574497A - Method for preparing chiral sulfoxide drugs in water phase - Google Patents
Method for preparing chiral sulfoxide drugs in water phase Download PDFInfo
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- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 title claims abstract description 37
- 150000003462 sulfoxides Chemical class 0.000 title claims abstract description 29
- 239000003814 drug Substances 0.000 title claims abstract description 27
- 229940079593 drug Drugs 0.000 title claims abstract description 26
- 238000000034 method Methods 0.000 title claims abstract description 24
- 239000003054 catalyst Substances 0.000 claims abstract description 44
- 239000010936 titanium Substances 0.000 claims abstract description 32
- 150000001413 amino acids Chemical class 0.000 claims abstract description 30
- 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 abstract description 29
- 239000012071 phase Substances 0.000 claims abstract description 27
- MHAJPDPJQMAIIY-UHFFFAOYSA-N Hydrogen peroxide Chemical compound OO MHAJPDPJQMAIIY-UHFFFAOYSA-N 0.000 claims abstract description 24
- 150000003568 thioethers Chemical class 0.000 claims abstract description 24
- 229910052719 titanium Inorganic materials 0.000 claims abstract description 19
- RTAQQCXQSZGOHL-UHFFFAOYSA-N Titanium Chemical compound [Ti] RTAQQCXQSZGOHL-UHFFFAOYSA-N 0.000 claims abstract description 18
- 238000007254 oxidation reaction Methods 0.000 claims abstract description 13
- 238000002360 preparation method Methods 0.000 claims abstract description 12
- 239000000758 substrate Substances 0.000 claims abstract description 11
- 230000001590 oxidative effect Effects 0.000 claims abstract description 8
- 239000007800 oxidant agent Substances 0.000 claims abstract description 7
- 239000008346 aqueous phase Substances 0.000 claims abstract description 5
- 238000006243 chemical reaction Methods 0.000 claims description 32
- -1 amino acid compound Chemical class 0.000 claims description 22
- 229960000381 omeprazole Drugs 0.000 claims description 14
- 150000003254 radicals Chemical class 0.000 claims description 12
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 claims description 10
- 229910052717 sulfur Inorganic materials 0.000 claims description 10
- 239000011593 sulfur Substances 0.000 claims description 10
- 239000011203 carbon fibre reinforced carbon Substances 0.000 claims description 9
- 229910052739 hydrogen Inorganic materials 0.000 claims description 8
- 229920000642 polymer Polymers 0.000 claims description 8
- 229960003174 lansoprazole Drugs 0.000 claims description 6
- 229960004157 rabeprazole Drugs 0.000 claims description 6
- IQPSEEYGBUAQFF-SANMLTNESA-N 6-(difluoromethoxy)-2-[(s)-(3,4-dimethoxypyridin-2-yl)methylsulfinyl]-1h-benzimidazole Chemical compound COC1=CC=NC(C[S@](=O)C=2NC3=CC=C(OC(F)F)C=C3N=2)=C1OC IQPSEEYGBUAQFF-SANMLTNESA-N 0.000 claims description 5
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 5
- 125000000475 sulfinyl group Chemical group [*:2]S([*:1])=O 0.000 claims description 5
- 125000000217 alkyl group Chemical group 0.000 claims description 4
- 125000003118 aryl group Chemical group 0.000 claims description 4
- 239000001257 hydrogen Substances 0.000 claims description 4
- YHWCPXVTRSHPNY-UHFFFAOYSA-N butan-1-olate;titanium(4+) Chemical compound [Ti+4].CCCC[O-].CCCC[O-].CCCC[O-].CCCC[O-] YHWCPXVTRSHPNY-UHFFFAOYSA-N 0.000 claims description 3
- QNILTEGFHQSKFF-UHFFFAOYSA-N n-propan-2-ylprop-2-enamide Chemical compound CC(C)NC(=O)C=C QNILTEGFHQSKFF-UHFFFAOYSA-N 0.000 claims description 3
- 238000006116 polymerization reaction Methods 0.000 claims description 3
- DSQMTXJDRNDSKN-UHFFFAOYSA-N 4-ethyl-3-(furan-2-yl)-5-[[3-(trifluoromethyl)phenyl]methylsulfanyl]-1,2,4-triazole Chemical compound N=1N=C(C=2OC=CC=2)N(CC)C=1SCC1=CC=CC(C(F)(F)F)=C1 DSQMTXJDRNDSKN-UHFFFAOYSA-N 0.000 claims description 2
- 125000003545 alkoxy group Chemical group 0.000 claims description 2
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 2
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 claims description 2
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 2
- 125000003107 substituted aryl group Chemical group 0.000 claims description 2
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 2
- 125000004793 2,2,2-trifluoroethoxy group Chemical group FC(CO*)(F)F 0.000 claims 1
- 150000001263 acyl chlorides Chemical class 0.000 claims 1
- 125000004435 hydrogen atom Chemical class [H]* 0.000 claims 1
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 32
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 18
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 14
- 238000001035 drying Methods 0.000 description 10
- 230000002209 hydrophobic effect Effects 0.000 description 10
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 8
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 8
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 8
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 6
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 6
- 238000004440 column chromatography Methods 0.000 description 6
- 238000012512 characterization method Methods 0.000 description 5
- 238000004128 high performance liquid chromatography Methods 0.000 description 5
- 239000000047 product Substances 0.000 description 5
- 239000002904 solvent Substances 0.000 description 5
- 238000005406 washing Methods 0.000 description 5
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 4
- 238000005160 1H NMR spectroscopy Methods 0.000 description 4
- 238000004458 analytical method Methods 0.000 description 4
- 238000004811 liquid chromatography Methods 0.000 description 4
- 239000000843 powder Substances 0.000 description 4
- 238000000926 separation method Methods 0.000 description 4
- 238000001228 spectrum Methods 0.000 description 4
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 4
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 3
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 3
- 230000000694 effects Effects 0.000 description 3
- 230000003647 oxidation Effects 0.000 description 3
- 238000011084 recovery Methods 0.000 description 3
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 2
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 2
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 2
- 229910052799 carbon Inorganic materials 0.000 description 2
- 230000003197 catalytic effect Effects 0.000 description 2
- 150000001875 compounds Chemical class 0.000 description 2
- 238000003912 environmental pollution Methods 0.000 description 2
- SBQLYHNEIUGQKH-UHFFFAOYSA-N omeprazole Chemical compound N1=C2[CH]C(OC)=CC=C2N=C1S(=O)CC1=NC=C(C)C(OC)=C1C SBQLYHNEIUGQKH-UHFFFAOYSA-N 0.000 description 2
- 239000003960 organic solvent Substances 0.000 description 2
- 239000000741 silica gel Substances 0.000 description 2
- 229910002027 silica gel Inorganic materials 0.000 description 2
- 238000010898 silica gel chromatography Methods 0.000 description 2
- PPTXVXKCQZKFBN-UHFFFAOYSA-N (S)-(-)-1,1'-Bi-2-naphthol Chemical compound C1=CC=C2C(C3=C4C=CC=CC4=CC=C3O)=C(O)C=CC2=C1 PPTXVXKCQZKFBN-UHFFFAOYSA-N 0.000 description 1
- HBAQYPYDRFILMT-UHFFFAOYSA-N 8-[3-(1-cyclopropylpyrazol-4-yl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl]-3-methyl-3,8-diazabicyclo[3.2.1]octan-2-one Chemical class C1(CC1)N1N=CC(=C1)C1=NNC2=C1N=C(N=C2)N1C2C(N(CC1CC2)C)=O HBAQYPYDRFILMT-UHFFFAOYSA-N 0.000 description 1
- 102000004190 Enzymes Human genes 0.000 description 1
- 108090000790 Enzymes Proteins 0.000 description 1
- 238000005033 Fourier transform infrared spectroscopy Methods 0.000 description 1
- 208000008469 Peptic Ulcer Diseases 0.000 description 1
- 102100021904 Potassium-transporting ATPase alpha chain 1 Human genes 0.000 description 1
- 108010083204 Proton Pumps Proteins 0.000 description 1
- 239000003513 alkali Substances 0.000 description 1
- 238000003556 assay Methods 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 238000006555 catalytic reaction Methods 0.000 description 1
- 239000007809 chemical reaction catalyst Substances 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- YSAVZVORKRDODB-WDSKDSINSA-N diethyl tartrate Chemical compound CCOC(=O)[C@@H](O)[C@H](O)C(=O)OCC YSAVZVORKRDODB-WDSKDSINSA-N 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 210000004211 gastric acid Anatomy 0.000 description 1
- 230000027119 gastric acid secretion Effects 0.000 description 1
- 150000002431 hydrogen Chemical class 0.000 description 1
- 238000009776 industrial production Methods 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 239000003446 ligand Substances 0.000 description 1
- 229910052751 metal Inorganic materials 0.000 description 1
- 239000002184 metal Substances 0.000 description 1
- WCYWZMWISLQXQU-UHFFFAOYSA-N methyl Chemical compound [CH3] WCYWZMWISLQXQU-UHFFFAOYSA-N 0.000 description 1
- 244000005700 microbiome Species 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 230000003287 optical effect Effects 0.000 description 1
- 239000012074 organic phase Substances 0.000 description 1
- 208000011906 peptic ulcer disease Diseases 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- 230000001376 precipitating effect Effects 0.000 description 1
- 238000001338 self-assembly Methods 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 150000003457 sulfones Chemical class 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 238000001291 vacuum drying Methods 0.000 description 1
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
- B01J31/00—Catalysts comprising hydrides, coordination complexes or organic compounds
- B01J31/16—Catalysts comprising hydrides, coordination complexes or organic compounds containing coordination complexes
- B01J31/22—Organic complexes
- B01J31/2204—Organic complexes the ligands containing oxygen or sulfur as complexing atoms
- B01J31/2208—Oxygen, e.g. acetylacetonates
- B01J31/2217—At least one oxygen and one nitrogen atom present as complexing atoms in an at least bidentate or bridging ligand
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- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
- B01J2231/00—Catalytic reactions performed with catalysts classified in B01J31/00
- B01J2231/70—Oxidation reactions, e.g. epoxidation, (di)hydroxylation, dehydrogenation and analogues
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- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
- B01J2531/00—Additional information regarding catalytic systems classified in B01J31/00
- B01J2531/02—Compositional aspects of complexes used, e.g. polynuclearity
- B01J2531/0202—Polynuclearity
- B01J2531/0205—Bi- or polynuclear complexes, i.e. comprising two or more metal coordination centres, without metal-metal bonds, e.g. Cp(Lx)Zr-imidazole-Zr(Lx)Cp
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- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
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- B01J2531/00—Additional information regarding catalytic systems classified in B01J31/00
- B01J2531/40—Complexes comprising metals of Group IV (IVA or IVB) as the central metal
- B01J2531/46—Titanium
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- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
- B01J2531/00—Additional information regarding catalytic systems classified in B01J31/00
- B01J2531/80—Complexes comprising metals of Group VIII as the central metal
- B01J2531/84—Metals of the iron group
- B01J2531/842—Iron
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- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
- B01J2531/00—Additional information regarding catalytic systems classified in B01J31/00
- B01J2531/90—Catalytic systems characterized by the solvent or solvent system used
- B01J2531/96—Water
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Abstract
The invention relates to the field of chiral drug preparation, in particular to a method for preparing chiral sulfoxide drugs in an aqueous phase. The method for preparing the chiral sulfoxide drugs in the water phase comprises the following steps: in a pure water phase, hydrogen peroxide solution is used as an oxidant, a temperature-sensitive ferrocene chiral amino acid titanium complex is used as a catalyst, prochiral thioether is used as a substrate, and asymmetric oxidation reaction is carried out to synthesize the chiral sulfoxide drug.
Description
Technical Field
The invention relates to the field of chiral drug preparation, in particular to a method for preparing chiral sulfoxide drugs in an aqueous phase.
Background
Chiral sulfoxide drugs with H-inhibiting effect+/K+The activity of ATP enzyme (also called proton pump) can effectively inhibit gastric acid secretion, and is widely used for treating peptic ulcer related diseases caused by gastric acid hypersecretion. At present, two methods are mainly used for preparing chiral sulfoxide drugs: one is a resolution method, as described in international patent W091/12221, which directly resolves omeprazole as racemate into single enantiomers. Chinese patent CN1087739 describes the resolution of omeprazole with (S) -binaphthol to obtain an inclusion complex of levo-omeprazole. However, the resolution method wastes half of chiral drugs, which causes environmental pollution and economic loss, and the resolving agent with optical activity is expensive; secondly, an asymmetric oxidation method, for example, international patent W096/02535 discloses a method for preparing S-omeprazole by oxidizing omeprazole thioether with a hydrogen peroxide derivative in the presence of a chiral bidentate ligand diethyl tartrate, a titanium metal complex and an alkali. International patent W02004/052881 describes a process for the preparation of S-pantoprazole using chiral pickaxel complexes. International patents W096/17076 and W096/17077 describe methods of selective oxidation of thioethers using microorganisms to obtain single enantiomeric sulfoxides; however, the prior asymmetric oxidation methods are all carried out in organic solvents, and have the problems of environmental pollution, low yield, difficult catalyst recovery and the like.
The temperature-sensitive ferrocene polymer can be self-assembled in water to form a nano reactor with a hydrophilic shell and a hydrophobic core, and the active center amino acid titanium is wrapped and gathered by a hydrophobic cavity of the ferrocene. The thioether substrate is enriched in the hydrophobic cavity and fully contacts with the active center, so that the effective collision times are increased, and the asymmetric thioether oxidation reaction of the water phase is accelerated. After the reaction is finished, the temperature of the reaction system is raised, so that the catalyst is conveniently recovered and effectively reused.
Disclosure of Invention
In order to solve the problems, the invention aims to provide a method for preparing chiral sulfoxide drugs in a water phase, and the method utilizes a temperature-sensitive ferrocene chiral amino acid titanium complex catalyst to catalyze the asymmetric oxidation reaction of thioether in the pure water phase and has the characteristics of high catalytic efficiency and easiness in recovery of the catalyst.
In order to achieve the purpose, the method for preparing the chiral sulfoxide drugs in the water phase comprises the following steps: in a pure water phase, performing asymmetric oxidation reaction to synthesize a chiral sulfoxide drug by using a hydrogen peroxide solution as an oxidant, a temperature-sensitive ferrocene chiral amino acid titanium complex as a catalyst and prochiral thioether as a substrate, wherein the temperature-sensitive ferrocene chiral amino acid titanium complex has a structure of a general formula (1);
wherein, represents R configuration or S configuration;
R1、R2independently selected from hydrogen, alkyl, aryl-substituted alkyl;
R3is selected from alkyl, alkoxy, aryl and aryl substituent groups;
R4is selected from C1～C16Alkyl, isopropyl, isobutyl, tert-butyl, benzyl or substituted aryl of (a);
x, Y is (1-100): 1.
preferably, the ratio of X to Y is (5-50): 1.
as a preferred scheme, the preparation process of the temperature-sensitive ferrocene chiral amino acid titanium complex comprises the following steps:
(1) reacting R-configured or S-configured chiral amino acid with ferrocenyl chloride containing carbon-carbon double bonds, thereby introducing unsaturated carbon-carbon double bonds into the chiral amino acid to obtain a ferrocene chiral amino acid compound containing the carbon-carbon double bonds;
(2) then carrying out polymerization reaction on a ferrocene chiral amino acid compound containing carbon-carbon double bonds and N-isopropyl acrylamide to obtain a temperature-sensitive ferrocene chiral amino acid block polymer;
(3) the temperature-sensitive type ferrocene chiral amino acid block polymer is subjected to self-folding under the action of tetrabutyl titanate through coordination to form a temperature-sensitive type ferrocene chiral amino acid titanium complex.
Preferably, the prochiral thioether is 5-methoxy-2- [ [ (4-methoxy-3, 5-dimethyl-2-pyridyl) methyl]Sulfur based radicals]-1H-benzimidazole of formula C17H19N3O3S, the structural formula of which is shown as formula 2,2- [ [ [3 methyl-4- (2,2, 2-trifluoroethoxy) -2-pyridyl]Methyl radical]Sulfur based radicals]-1H-benzimidazole of formula C16H14F3N3OS, its structural formula is shown as formula 3, 5-difluoro methoxy-2- [ [ (3, 4-dimethoxy-2-pyridyl)]Methyl radical]Sulfur based radicals]-1H-benzimidazole of formula C16H15F2N3O3S, the structural formula of which is shown in formula 4, 2- [ [ [ (3 methyl-4- (3-methoxy-1-propoxy) -2-pyridyl)]Methyl radical]Sulfur based radicals]-1H-benzimidazole of formula C19H23N3O2S, the structural formula is shown as formula 5:
as a preferable scheme, the generated chiral sulfoxide drug is S-5-methoxy-2- [ [ (4-methoxy-3, 5-dimethyl-2-pyridyl) methyl ] sulfinyl ] -1H-benzimidazole (S-omeprazole), the molecular formula of which is C17H19N3O4S, the corresponding structural formula is shown in formula 6, S-2- [ [ [3 methyl-4- (2,2, 2-trifluoroethoxy) -2-pyridyl ] methyl ] sulfinyl ] -1H-benzimidazole (S-lansoprazole), the molecular formula of which is C16H14F3N3O2S, the corresponding structural formula is shown in formula 7, S-5-difluoromethoxy-2- [ [ (3, 4-dimethoxy-2-pyridyl ] methyl ] sulfinyl ] -1H-benzimidazole (S-pantoprazole), the molecular formula of the compound is C16H15F2N3O4S, the corresponding structural formula is shown in formula 8, and the molecular formula of the compound is C19H23N3O3S, S-2- [ [ [ (3 methyl-4- (3-methoxy-1-propoxy) -2-pyridyl ] methyl ] sulfinyl ] -1H-benzimidazole (S-rabeprazole), and the corresponding structural formula is shown in formula 9;
preferably, the molar ratio of the catalyst to the prochiral thioether is 1: 50-1: 1000, the mass concentration of the hydrogen peroxide solution is 15 wt% -70 wt%, the molar ratio of hydrogen peroxide to the prochiral thioether in the hydrogen peroxide solution is 1: 1-2: 1, and the reaction temperature is 0-40 ℃.
Preferably, the molar ratio of the catalyst to the prochiral thioether is 1: 100-1: 300; the mass concentration of the hydrogen peroxide solution is 25 wt% -35 wt%, and the molar ratio of hydrogen peroxide to the prochiral thioether in the hydrogen peroxide solution is 1-1.2: 1; the reaction temperature is 20-30 ℃.
The principle of improving the efficiency of the asymmetric thioether oxidation reaction in the water phase by using the temperature-sensitive ferrocene chiral amino acid titanium complex catalyst is as follows: the temperature-sensitive ferrocene chiral amino acid titanium complex catalyst is dissolved in water, self-assembly is carried out under the hydrophobic effect and the metal coordination effect to form a nano reactor, a reaction substrate thioether enters the nano reactor to be concentrated, and an oxidant hydrogen peroxide slowly enters a hydrophobic cavity to carry out oxidation reaction, so that the reaction rate is greatly accelerated, and thioether asymmetric oxidation reaction is efficiently carried out.
The invention has the advantages that:
(1) compared with the traditional catalyst of chiral sulfoxide drugs, the temperature-sensitive ferrocene chiral amino acid titanium complex catalyst can efficiently catalyze thioether asymmetric oxidation reaction in a pure water phase, and the problems of difficult mass transfer and low catalytic efficiency of the traditional thioether oxidation reaction catalyst in water are solved.
(2) Compared with the traditional catalyst of chiral sulfoxide drugs, the temperature-sensitive ferrocene chiral amino acid titanium complex catalyst disclosed by the invention can realize hydrophilic and hydrophobic conversion by controlling the reaction temperature, and realize temperature-controlled recovery and reuse of the catalyst.
(3) Compared with the traditional preparation method of the chiral sulfoxide drug, the chiral sulfoxide drug synthesized by the method has the advantages of high conversion rate, good enantioselectivity of the product, safe operation, mild process conditions and contribution to large-scale industrial production.
Drawings
FIG. 1 is nuclear magnetic hydrogen spectrum of S-omeprazole;
FIG. 2 is a nuclear magnetic carbon spectrum of S-omeprazole;
FIG. 3 is a nuclear magnetic hydrogen spectrum of S-rabeprazole;
FIG. 4 is a nuclear magnetic carbon spectrum of S-rabeprazole;
FIG. 5 shows a catalyst TiIVPNxAy reuse Performance map.
Detailed Description
For a better understanding of the present invention, reference will now be made in detail to the present invention, examples of which are illustrated in the accompanying drawings.
Example 1 temperature-sensitive ferrocene chiral amino acid titanium Complex (Ti)IV-PNxAy) preparation:
(1) firstly, preparing a temperature-sensitive ferrocene chiral amino acid block polymer (PNxAy), wherein the preparation reaction formula is as follows:
reacting chiral amino acid with ferrocenyl chloride containing carbon-carbon double bonds, thereby introducing unsaturated carbon-carbon double bonds into the chiral amino acid to obtain a ferrocene chiral amino acid compound containing the carbon-carbon double bonds; then carrying out polymerization reaction on a ferrocene chiral amino acid compound containing carbon-carbon double bonds and N-isopropyl acrylamide to obtain a temperature-sensitive type ferrocene chiral amino acid block polymer PNxAy;
(2) dissolving 2mmol of block polymer PNxAy in 30mL of dichloromethane, adding 1mmol of tetrabutyl titanate, reacting for 8 hours at room temperature, adding two drops of water into the reaction solution, oscillating for a moment, spin-drying the solvent, adding 2mL of THF, repeatedly precipitating with 3 × 50mL of diethyl ether to obtain yellow solid precipitate, and vacuum drying at 30 ℃ to obtain the temperature-sensitive ferrocene chiral amino acid titanium complex (Ti chiral amino acid titanium complex)IVPNxAy), for TiIVPNxAy for corresponding characterization FT-IR(KBr):γmax/cm-13423,3062,2930,2875,1728,1614,1556,1336,1272,1135,1105,924,836,704,617,558,511,452cm-1。
EXAMPLE 2 preparation of S-omeprazole
The reaction formula for preparing the S-omeprazole is as follows:
to a 10mL reaction flask was added 1mmol of the substrate (5-methoxy-2- [ [ (4-methoxy-3, 5-dimethyl-2-pyridinyl) methyl)]Sulfur based radicals]-1H-benzimidazole), 1.0 mmol% of catalyst TiIV-PNxAy, 1mL solvent, placing the reaction bottle at the constant temperature of 25 ℃, and slowly dropwise adding 1.2mmol of 30% H within 15min2O2The reaction was continued for 3 h. Raising the temperature of the reaction system to 40 ℃, and using the catalyst TiIVAnd (3) automatically separating out the-PNxAy, separating a water phase, washing the catalyst with n-hexane, drying and reusing the catalyst, extracting the water phase with dichloromethane, carrying out spin drying, carrying out column chromatography separation to obtain the chiral sulfoxide compound-S-omeprazole, calculating the yield, carrying out liquid chromatography analysis to obtain an ee value, and carrying out nuclear magnetic characterization to determine the product structure.
As shown in fig. 1 to 4, S-omeprazole, white powder, was separated by silica gel column chromatography (methanol: dichloromethane ═ 20:80 (volume ratio)).1H NMR(CDCl3,500MHz):(ppm):2.06～2.16(s,6H),3.54(s,3H),3.78(s,3H),4.73～4.76(AB-system,2H),6.87～6.90(dd,2H),7.48(d,1H),8.14(s,1H)；13C NMR(125MHz,CDCl3)164.2,157.2,151.5,149.5,148.6,126.8,126.2,113.9,60.5,59.7,55.6,13.2, 11.3; the ee value is determined by chiral high performance liquid chromatography (column: Daicel chiralpak AD, mobile phase: isopropanol/n-hexane: 15:85 (volume ratio), flow rate: 1.0mL/min, wavelength: 254nm, temperature 25 ℃ C.).
The solvent respectively adopts dichloromethane, methanol, acetonitrile, ethyl acetate, tetrahydrofuran and water, and the yield and the enantioselectivity of S-omeprazole obtained by the synthesis are shown in the table 1:
TABLE 1
| Serial number | Solvent(s) | Yield (%)a | Enantioselectivity (%)b |
| 1 | Methylene dichloride | 76 | 79 |
| 2 | Methanol | 69 | 68 |
| 3 | Acetonitrile | 64 | 71 |
| 4 | Ethyl acetate | 75 | 64 |
| 5 | Tetrahydrofuran (THF) | 10 | / |
| 6 | Water (W) | 95 | 98 |
[a] Separating and calculating yield; [b] chiral high performance liquid chromatography assay
As can be seen from Table 1, the catalyst works best when the solvent is water. In water solution, the catalyst has good solubility, and because one end of the catalyst is hydrophobic and the other end is hydrophilic, the catalyst can be folded automatically under the action of intramolecular hydrophobic force in water to form a nano reactor, and a hydrophobic active center is wrapped inside the nano reactor. After adding the organic phase reaction substrate thioether, the substrate enters the interior of the nano reactor under the hydrophobic force and is greatly concentrated. Hydrogen peroxide serving as an aqueous phase oxidant slowly enters the nano reactor, and the oxidant violently collides with enough thioether to accelerate the reaction and prevent the excessive oxidant from forming sulfone. Thus, the catalyst can achieve higher yields and enantioselectivities in water compared to organic solvents.
Catalyst Ti capable of automatically precipitatingIVAfter filtering, washing and drying PNxAy, the catalyst is used in the next catalytic reaction system, the repeated use effect is shown in figure 5, and the catalyst can be obtained from figure 5, and the reusability of the catalyst is good.
Example 3 preparation of S-Lansoprazole
To a 10mL reaction flask was added 1mmol of substrate (2- [ [ [3 methyl-4- (2,2, 2-trifluoroethoxy) -2-pyridinyl)]Methyl radical]Sulfur based radicals]-1H-benzimidazole), 1.0 mmol% of catalyst TiIV-PNxAy, 1mL water, the reaction flask is placed at the constant temperature of 25 ℃, and 1.2mmol of 30% H is slowly dropped in within 15min2O2The reaction was continued for 3 h. Raising the temperature of the reaction system to 40 ℃, and using the catalyst TiIVAnd (3) automatically separating out the-PNxAy, separating a water phase, washing the catalyst with n-hexane, drying and reusing the catalyst, extracting the water phase with dichloromethane, carrying out spin drying and column chromatography separation to obtain the chiral sulfoxide compound-S-lansoprazole, calculating the yield, carrying out liquid chromatography analysis to obtain an ee value, and carrying out nuclear magnetic characterization to determine the structure of the product.
S-lansoprazole, white powder, silica gel column chromatography(methanol: dichloromethane: 20:80 (vol.)) (yield 92%, ee 97%).1H NMR(CDCl3,500MHz):(ppm):2.36～2.39(s,3H),4.13～4.16(AB-system,2H),4.46(dd,2H),7.21(dd,2H),7.38(s,1H),7.54(dd,2H),8.48(d,1H),12.54(s,1H)；13C NMR(125MHz,CDCl3)165.3,160.2,147.2,141.5,138.6,123.2,122.4,115.9,111.8,104.7,82.8,57.7, 11.3; the ee value was determined by chiral high performance liquid chromatography (column: Daicel chiralpakAD, mobile phase: isopropanol/n-hexane/acetic acid/triethylamine ═ 10: 90: 0.1: 0.2 (volume ratio), flow rate: 1.5mL/min, wavelength: 284nm, temperature 25 ℃ C.)
Example 4 preparation of S-pantoprazole
To a 10mL reaction flask was added 1mmol of substrate (5-difluoromethoxy-2- [ [ (3, 4-dimethoxy-2-pyridinyl)]Methyl radical]Sulfur based radicals]-1H-benzimidazole), 1.0 mmol% of catalyst TiIV-PNxAy, 1mL water, the reaction flask is placed at the constant temperature of 25 ℃, and 1.2mmol of 30% H is slowly dropped in within 15min2O2The reaction was continued for 3 h. Raising the temperature of the reaction system to 40 ℃, and using the catalyst TiIVAnd (3) automatically separating out PNxAy, separating a water phase, washing the catalyst with n-hexane, drying and reusing the catalyst, extracting the water phase with dichloromethane, carrying out spin drying and column chromatography separation to obtain the chiral sulfoxide compound-S-pantoprazole, calculating the yield, carrying out liquid chromatography analysis to obtain an ee value, and carrying out nuclear magnetic characterization to determine the product structure.
S-pantoprazole, white powder, isolated by column chromatography on silica gel (methanol: dichloromethane: 20:80 (vol.)) (yield 87%, ee 92%).1H NMR(CDCl3,500MHz):(ppm):3.81～3.83(s,6H),4.78～4.83(s,2H),6.77(s,1H),7.06(s,1H),7.11(s,1H),7.37(s,1H),7.05(s,1H),8.14(s,1H),12.67(s,1H)；13C NMR(125MHz,CDCl3)158.7,145.9,145.5,143.6,118.4,116.4,114.3,108.0,61.3,57.6, 55.7; the ee value was determined by chiral high performance liquid chromatography (column: Daicel chiralpak AD, mobile phase: isopropanol/n-hexane: 15:95 (volume ratio), flow rate: 1.0mL/min, wavelength: 254nm, temperature 25 ℃ C.)
EXAMPLE 5 preparation of S-rabeprazole
To a 10mL reaction flask was added 1mmol of substrate: (2- [ [ [ (3 methyl-4- (3-methoxy-1-propoxy) -2-pyridinyl)]Methyl radical]Sulfur based radicals]-1H-benzimidazole), 1.0 mmol% of catalyst TiIV-PNxAy, 1mL water, the reaction flask is placed at the constant temperature of 25 ℃, and 1.2mmol of 30% H is slowly dropped in within 15min2O2The reaction was continued for 3 h. Raising the temperature of the reaction system to 40 ℃, and using the catalyst TiIVAnd (3) automatically separating out PNxAy, separating a water phase, washing the catalyst with n-hexane, drying and reusing the catalyst, extracting the water phase with dichloromethane, carrying out spin drying and column chromatography separation to obtain the chiral sulfoxide compound-S-pantoprazole, calculating the yield, carrying out liquid chromatography analysis to obtain an ee value, and carrying out nuclear magnetic characterization to determine the product structure.
S-rabeprazole, pale yellow powder, was isolated by column chromatography on silica gel (methanol: dichloromethane ═ 20:80 (vol.)) (89% yield, 94% ee).1H NMR(CDCl3,500MHz):(ppm):2.00～2.02(s,2H),2.03～2.11(s,3H),3.33(s,3H),3.51(s,2H),4.01～4.04(s,2H),4.80(s,2H),6.67(s,1H),7.24(s,2H),7.35～7.84(s,2H),8.25(s,1H)；13C NMR(125MHz,CDCl3)163.6,153.2,149.3,148.2,122.8,106.2,68.8,65.1,60.8,58.7,29.2, 11.0; the ee value was determined by chiral high performance liquid chromatography (column: Daicel chiralpak AD, mobile phase: isopropanol, flow rate: 0.6mL/min, wavelength: 292nm, temperature: 25 ℃).
The above-mentioned embodiments only express several embodiments of the present invention, and the description thereof is more specific and detailed, but not construed as limiting the scope of the present invention. It should be noted that, for a person skilled in the art, several variations and modifications can be made without departing from the inventive concept, which falls within the scope of the present invention. Therefore, the protection scope of the present patent shall be subject to the appended claims.
Claims (6)
1. A method for preparing chiral sulfoxide drugs in a water phase is characterized in that in a pure water phase, hydrogen peroxide solution is used as an oxidant, a temperature-sensitive ferrocene chiral amino acid titanium complex is used as a catalyst, and a former chiral thioether is used as a substrate to carry out asymmetric oxidation reaction to synthesize the chiral sulfoxide drugs, wherein the temperature-sensitive ferrocene chiral amino acid titanium complex has a structure of a general formula (1);
wherein, represents R configuration or S configuration;
R1、R2independently selected from hydrogen, alkyl, aryl-substituted alkyl;
R3is selected from alkyl, alkoxy, aryl and aryl substituent groups;
R4is selected from C1～C16Alkyl, isopropyl, isobutyl, tert-butyl, benzyl or substituted aryl of (a);
x, Y is (1-100): 1.
2. the method for preparing the chiral sulfoxide medicine in the water phase according to claim 1, wherein the preparation process of the temperature-sensitive ferrocene chiral amino acid titanium complex comprises the following steps:
(1) reacting chiral amino acid with R configuration or S configuration with acyl chloride containing carbon-carbon double bond, thereby introducing unsaturated carbon-carbon double bond into the chiral amino acid to obtain ferrocene chiral amino acid compound containing carbon-carbon double bond;
(2) then carrying out polymerization reaction on a chiral amino acid compound containing carbon-carbon double bonds and N-isopropyl acrylamide to obtain a temperature-sensitive ferrocene chiral amino acid block polymer;
(3) the temperature-sensitive type ferrocene chiral amino acid block polymer is subjected to self-folding under the action of tetrabutyl titanate through coordination to form a temperature-sensitive type ferrocene chiral amino acid titanium complex.
3. The method for preparing chiral sulfoxide drugs in aqueous phase according to claim 1, wherein the prochiral thioether is 5-methoxy-2- [ [ (4-methoxy-3, 5-dimethyl-2-pyridyl) methyl]Sulfur based radicals]-1H-benzimidazole of formula C17H19N3O3S, the structural formula is shown as formula 2,2- [ [ [3 methyl-4- (2,2, 2-trifluoroethoxy) -2-pyridinyl]Methyl radical]Sulfur based radicals]-1H-benzimidazole of formula C16H14F3N3OS, its structural formula is shown as formula 3, 5-difluoro methoxy-2- [ [ (3, 4-dimethoxy-2-pyridyl)]Methyl radical]Sulfur based radicals]-1H-benzimidazole of formula C16H15F2N3O3S, the structural formula of which is shown in formula 4, 2- [ [ [ (3 methyl-4- (3-methoxy-1-propoxy) -2-pyridyl)]Methyl radical]Sulfur based radicals]-1H-benzimidazole of formula C19H23N3O2S, the structural formula is shown as a formula 5;
4. the method for preparing chiral sulfoxide drugs in aqueous phase according to claim 3, wherein the chiral sulfoxide drug is S-5-methoxy-2- [ [ (4-methoxy-3, 5-dimethyl-2-pyridyl) methyl ] sulfinyl ] -1H-benzimidazole (S-omeprazole) with a molecular formula of C17H19N3O4S, a corresponding structural formula of C16H14F3N3O2S, a corresponding structural formula of S-5-difluoromethoxy-2- [ [ (3-methoxy-3, 5-dimethyl-2-pyridyl) methyl ] sulfinyl ] -1H-benzimidazole (S-lansoprazole) with a molecular formula of C17H19N3O4S, a corresponding structural formula of S-2- [ [ (2,2, 2-trifluoroethoxy) -2-pyridyl ] methyl ] sulfinyl ] -1H-benzimidazole (S-lansoprazole) with a molecular formula of C16H14F3N3O2S, 4-dimethoxy-2-pyridyl ] methyl ] sulfinyl ] -1H-benzimidazole (S-pantoprazole) having a molecular formula of C16H15F2N3O4S, the corresponding structural formula is represented by formula 8, and S-2- [ [ [ (3 methyl-4- (3-methoxy-1-propoxy) -2-pyridyl ] methyl ] sulfinyl ] -1H-benzimidazole (S-rabeprazole) having a molecular formula of C19H23N3O3S, the corresponding structural formula is represented by formula 9;
5. the method for preparing the chiral sulfoxide drugs in the water phase according to claim 4, wherein the molar ratio of the catalyst to the prochiral thioether is 1: 50-1: 1000, the mass concentration of the hydrogen peroxide solution is 15 wt% -70 wt%, the molar ratio of hydrogen peroxide to the prochiral thioether in the hydrogen peroxide solution is 1: 1-2: 1, and the reaction temperature is 0-40 ℃.
6. The method for preparing the chiral sulfoxide drugs in the water phase according to claim 5, wherein the molar ratio of the catalyst to the prochiral thioether is 1: 100-1: 300; the mass concentration of the hydrogen peroxide solution is 25 wt% -35 wt%, and the molar ratio of hydrogen peroxide to the prochiral thioether in the hydrogen peroxide solution is 1-1.2: 1; the reaction temperature is 20-30 ℃.
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