CN104829644B - A kind of preparation method of (S) tertiary butyl dimethyl Si base glutaric acid list benzyl ester monoamides - Google Patents
A kind of preparation method of (S) tertiary butyl dimethyl Si base glutaric acid list benzyl ester monoamides Download PDFInfo
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- benzyl ester
- tertiary butyl
- acid list
- butyl dimethyl
- glutaric acid
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- 238000002360 preparation method Methods 0.000 title claims abstract description 20
- -1 benzyl ester Chemical class 0.000 title claims abstract description 19
- RTBFRGCFXZNCOE-UHFFFAOYSA-N 1-methylsulfonylpiperidin-4-one Chemical compound CS(=O)(=O)N1CCC(=O)CC1 RTBFRGCFXZNCOE-UHFFFAOYSA-N 0.000 title claims abstract description 6
- JFCQEDHGNNZCLN-UHFFFAOYSA-N anhydrous glutaric acid Natural products OC(=O)CCCC(O)=O JFCQEDHGNNZCLN-UHFFFAOYSA-N 0.000 title claims abstract description 6
- 239000003054 catalyst Substances 0.000 claims abstract description 12
- 238000006555 catalytic reaction Methods 0.000 claims abstract description 6
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical group OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 27
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 24
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 21
- 238000006243 chemical reaction Methods 0.000 claims description 16
- 239000002904 solvent Substances 0.000 claims description 13
- FZENGILVLUJGJX-NSCUHMNNSA-N (E)-acetaldehyde oxime Chemical compound C\C=N\O FZENGILVLUJGJX-NSCUHMNNSA-N 0.000 claims description 11
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 10
- 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 9
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 8
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 claims description 6
- 230000035484 reaction time Effects 0.000 claims description 5
- QPLDLSVMHZLSFG-UHFFFAOYSA-N Copper oxide Chemical compound [Cu]=O QPLDLSVMHZLSFG-UHFFFAOYSA-N 0.000 claims description 4
- OPQARKPSCNTWTJ-UHFFFAOYSA-L copper(ii) acetate Chemical compound [Cu+2].CC([O-])=O.CC([O-])=O OPQARKPSCNTWTJ-UHFFFAOYSA-L 0.000 claims description 3
- 229960004643 cupric oxide Drugs 0.000 claims description 2
- QAOWNCQODCNURD-UHFFFAOYSA-L Sulfate Chemical compound [O-]S([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 claims 1
- 150000002118 epoxides Chemical class 0.000 claims 1
- 239000000126 substance Substances 0.000 claims 1
- 229910021653 sulphate ion Inorganic materials 0.000 claims 1
- WVDDGKGOMKODPV-UHFFFAOYSA-N hydroxymethyl benzene Natural products OCC1=CC=CC=C1 WVDDGKGOMKODPV-UHFFFAOYSA-N 0.000 abstract description 17
- 150000001875 compounds Chemical class 0.000 abstract description 15
- MHAJPDPJQMAIIY-UHFFFAOYSA-N Hydrogen peroxide Chemical compound OO MHAJPDPJQMAIIY-UHFFFAOYSA-N 0.000 abstract description 14
- 238000000034 method Methods 0.000 abstract description 11
- 238000007254 oxidation reaction Methods 0.000 abstract description 8
- 230000003647 oxidation Effects 0.000 abstract description 7
- 235000019445 benzyl alcohol Nutrition 0.000 abstract description 6
- 229960004217 benzyl alcohol Drugs 0.000 abstract description 6
- 239000003513 alkali Substances 0.000 abstract description 5
- BCNZYOJHNLTNEZ-UHFFFAOYSA-N tert-butyldimethylsilyl chloride Chemical compound CC(C)(C)[Si](C)(C)Cl BCNZYOJHNLTNEZ-UHFFFAOYSA-N 0.000 abstract description 5
- 239000002585 base Substances 0.000 abstract description 4
- 239000003814 drug Substances 0.000 abstract description 4
- NUJOXMJBOLGQSY-UHFFFAOYSA-N manganese dioxide Chemical compound O=[Mn]=O NUJOXMJBOLGQSY-UHFFFAOYSA-N 0.000 abstract description 4
- FERIUCNNQQJTOY-UHFFFAOYSA-N Butyric acid Chemical compound CCCC(O)=O FERIUCNNQQJTOY-UHFFFAOYSA-N 0.000 abstract description 3
- 150000002148 esters Chemical group 0.000 abstract description 3
- 230000004224 protection Effects 0.000 abstract description 3
- 239000002994 raw material Substances 0.000 abstract description 3
- 239000004367 Lipase Substances 0.000 abstract description 2
- 102000004882 Lipase Human genes 0.000 abstract description 2
- 108090001060 Lipase Proteins 0.000 abstract description 2
- 150000001408 amides Chemical class 0.000 abstract description 2
- 235000019421 lipase Nutrition 0.000 abstract description 2
- 239000010970 precious metal Substances 0.000 abstract description 2
- 238000011084 recovery Methods 0.000 abstract description 2
- XJDNKRIXUMDJCW-UHFFFAOYSA-J titanium tetrachloride Chemical compound Cl[Ti](Cl)(Cl)Cl XJDNKRIXUMDJCW-UHFFFAOYSA-J 0.000 abstract description 2
- 125000004093 cyano group Chemical group *C#N 0.000 abstract 3
- HTOPVOTYQCSGNP-UHFFFAOYSA-N benzyl 2-hydroxybutanoate Chemical compound CCC(O)C(=O)OCC1=CC=CC=C1 HTOPVOTYQCSGNP-UHFFFAOYSA-N 0.000 abstract 1
- OBNCKNCVKJNDBV-UHFFFAOYSA-N ethyl butyrate Chemical compound CCCC(=O)OCC OBNCKNCVKJNDBV-UHFFFAOYSA-N 0.000 abstract 1
- 125000004469 siloxy group Chemical group [SiH3]O* 0.000 description 22
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 22
- 239000000047 product Substances 0.000 description 14
- 238000001914 filtration Methods 0.000 description 12
- 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 description 10
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 10
- 238000001514 detection method Methods 0.000 description 8
- 239000012074 organic phase Substances 0.000 description 8
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 7
- 239000000706 filtrate Substances 0.000 description 7
- 238000010792 warming Methods 0.000 description 7
- FERIUCNNQQJTOY-UHFFFAOYSA-M Butyrate Chemical compound CCCC([O-])=O FERIUCNNQQJTOY-UHFFFAOYSA-M 0.000 description 6
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 6
- MPTQRFCYZCXJFQ-UHFFFAOYSA-L copper(II) chloride dihydrate Chemical compound O.O.[Cl-].[Cl-].[Cu+2] MPTQRFCYZCXJFQ-UHFFFAOYSA-L 0.000 description 6
- 230000006837 decompression Effects 0.000 description 5
- 239000002808 molecular sieve Substances 0.000 description 5
- URGAHOPLAPQHLN-UHFFFAOYSA-N sodium aluminosilicate Chemical compound [Na+].[Al+3].[O-][Si]([O-])=O.[O-][Si]([O-])=O URGAHOPLAPQHLN-UHFFFAOYSA-N 0.000 description 5
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 4
- 229940121710 HMGCoA reductase inhibitor Drugs 0.000 description 4
- 125000004836 hexamethylene group Chemical group [H]C([H])([*:2])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[*:1] 0.000 description 4
- 150000002460 imidazoles Chemical class 0.000 description 4
- 239000000463 material Substances 0.000 description 4
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 4
- 239000007800 oxidant agent Substances 0.000 description 4
- 230000001590 oxidative effect Effects 0.000 description 4
- LALFOYNTGMUKGG-BGRFNVSISA-L rosuvastatin calcium Chemical compound [Ca+2].CC(C)C1=NC(N(C)S(C)(=O)=O)=NC(C=2C=CC(F)=CC=2)=C1\C=C\[C@@H](O)C[C@@H](O)CC([O-])=O.CC(C)C1=NC(N(C)S(C)(=O)=O)=NC(C=2C=CC(F)=CC=2)=C1\C=C\[C@@H](O)C[C@@H](O)CC([O-])=O LALFOYNTGMUKGG-BGRFNVSISA-L 0.000 description 4
- 229960004796 rosuvastatin calcium Drugs 0.000 description 4
- 238000003786 synthesis reaction Methods 0.000 description 4
- FKLJPTJMIBLJAV-UHFFFAOYSA-N Compound IV Chemical compound O1N=C(C)C=C1CCCCCCCOC1=CC=C(C=2OCCN=2)C=C1 FKLJPTJMIBLJAV-UHFFFAOYSA-N 0.000 description 3
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 description 3
- 230000015572 biosynthetic process Effects 0.000 description 3
- 229920001429 chelating resin Polymers 0.000 description 3
- 238000000605 extraction Methods 0.000 description 3
- 150000002576 ketones Chemical class 0.000 description 3
- 239000012071 phase Substances 0.000 description 3
- 229960000672 rosuvastatin Drugs 0.000 description 3
- BPRHUIZQVSMCRT-VEUZHWNKSA-N rosuvastatin Chemical compound CC(C)C1=NC(N(C)S(C)(=O)=O)=NC(C=2C=CC(F)=CC=2)=C1\C=C\[C@@H](O)C[C@@H](O)CC(O)=O BPRHUIZQVSMCRT-VEUZHWNKSA-N 0.000 description 3
- 238000003756 stirring Methods 0.000 description 3
- 0 C[C@@](CC=NC)CC(O*)=O Chemical compound C[C@@](CC=NC)CC(O*)=O 0.000 description 2
- 102000004190 Enzymes Human genes 0.000 description 2
- 108090000790 Enzymes Proteins 0.000 description 2
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-dimethylformamide Substances CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 2
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 2
- 229960000583 acetic acid Drugs 0.000 description 2
- 150000001412 amines Chemical class 0.000 description 2
- 239000008346 aqueous phase Substances 0.000 description 2
- BAXPZZQTNLZYCM-NSHDSACASA-N benzyl (3S)-4-cyano-3-hydroxybutanoate Chemical class C(C1=CC=CC=C1)OC(C[C@H](CC#N)O)=O BAXPZZQTNLZYCM-NSHDSACASA-N 0.000 description 2
- 239000012141 concentrate Substances 0.000 description 2
- ARUVKPQLZAKDPS-UHFFFAOYSA-L copper(II) sulfate Chemical compound [Cu+2].[O-][S+2]([O-])([O-])[O-] ARUVKPQLZAKDPS-UHFFFAOYSA-L 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 238000005516 engineering process Methods 0.000 description 2
- 239000012362 glacial acetic acid Substances 0.000 description 2
- JMANVNJQNLATNU-UHFFFAOYSA-N glycolonitrile Natural products N#CC#N JMANVNJQNLATNU-UHFFFAOYSA-N 0.000 description 2
- 239000000203 mixture Substances 0.000 description 2
- 150000002923 oximes Chemical group 0.000 description 2
- AKHNMLFCWUSKQB-UHFFFAOYSA-L sodium thiosulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=S AKHNMLFCWUSKQB-UHFFFAOYSA-L 0.000 description 2
- 235000019345 sodium thiosulphate Nutrition 0.000 description 2
- XHFLOLLMZOTPSM-UHFFFAOYSA-M sodium;hydrogen carbonate;hydrate Chemical compound [OH-].[Na+].OC(O)=O XHFLOLLMZOTPSM-UHFFFAOYSA-M 0.000 description 2
- FZENGILVLUJGJX-IHWYPQMZSA-N (Z)-acetaldehyde oxime Chemical compound C\C=N/O FZENGILVLUJGJX-IHWYPQMZSA-N 0.000 description 1
- 238000005160 1H NMR spectroscopy Methods 0.000 description 1
- JDIIGWSSTNUWGK-UHFFFAOYSA-N 1h-imidazol-3-ium;chloride Chemical compound [Cl-].[NH2+]1C=CN=C1 JDIIGWSSTNUWGK-UHFFFAOYSA-N 0.000 description 1
- XUKUURHRXDUEBC-KAYWLYCHSA-N Atorvastatin Chemical compound C=1C=CC=CC=1C1=C(C=2C=CC(F)=CC=2)N(CC[C@@H](O)C[C@@H](O)CC(O)=O)C(C(C)C)=C1C(=O)NC1=CC=CC=C1 XUKUURHRXDUEBC-KAYWLYCHSA-N 0.000 description 1
- XUKUURHRXDUEBC-UHFFFAOYSA-N Atorvastatin Natural products C=1C=CC=CC=1C1=C(C=2C=CC(F)=CC=2)N(CCC(O)CC(O)CC(O)=O)C(C(C)C)=C1C(=O)NC1=CC=CC=C1 XUKUURHRXDUEBC-UHFFFAOYSA-N 0.000 description 1
- RYGMFSIKBFXOCR-UHFFFAOYSA-N Copper Chemical compound [Cu] RYGMFSIKBFXOCR-UHFFFAOYSA-N 0.000 description 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 1
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 1
- RYMZZMVNJRMUDD-UHFFFAOYSA-N SJ000286063 Natural products C12C(OC(=O)C(C)(C)CC)CC(C)C=C2C=CC(C)C1CCC1CC(O)CC(=O)O1 RYMZZMVNJRMUDD-UHFFFAOYSA-N 0.000 description 1
- RTAQQCXQSZGOHL-UHFFFAOYSA-N Titanium Chemical compound [Ti] RTAQQCXQSZGOHL-UHFFFAOYSA-N 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 229960005370 atorvastatin Drugs 0.000 description 1
- 150000004648 butanoic acid derivatives Chemical class 0.000 description 1
- 238000009903 catalytic hydrogenation reaction Methods 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 229910052802 copper Inorganic materials 0.000 description 1
- 239000010949 copper Substances 0.000 description 1
- AEJIMXVJZFYIHN-UHFFFAOYSA-N copper;dihydrate Chemical compound O.O.[Cu] AEJIMXVJZFYIHN-UHFFFAOYSA-N 0.000 description 1
- 238000010828 elution Methods 0.000 description 1
- 230000002255 enzymatic effect Effects 0.000 description 1
- 125000004185 ester group Chemical group 0.000 description 1
- 238000010931 ester hydrolysis Methods 0.000 description 1
- 125000004494 ethyl ester group Chemical group 0.000 description 1
- 239000000284 extract Substances 0.000 description 1
- 229910052739 hydrogen Inorganic materials 0.000 description 1
- 239000001257 hydrogen Substances 0.000 description 1
- 239000002471 hydroxymethylglutaryl coenzyme A reductase inhibitor Substances 0.000 description 1
- 230000000055 hyoplipidemic effect Effects 0.000 description 1
- 239000003112 inhibitor Substances 0.000 description 1
- 238000006317 isomerization reaction Methods 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- YWOITFUKFOYODT-UHFFFAOYSA-N methanol;sodium Chemical compound [Na].OC YWOITFUKFOYODT-UHFFFAOYSA-N 0.000 description 1
- IBMRTYCHDPMBFN-UHFFFAOYSA-N monomethyl glutaric acid Chemical compound COC(=O)CCCC(O)=O IBMRTYCHDPMBFN-UHFFFAOYSA-N 0.000 description 1
- 235000006408 oxalic acid Nutrition 0.000 description 1
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 1
- 230000003389 potentiating effect Effects 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 229960002855 simvastatin Drugs 0.000 description 1
- RYMZZMVNJRMUDD-HGQWONQESA-N simvastatin Chemical compound C([C@H]1[C@@H](C)C=CC2=C[C@H](C)C[C@@H]([C@H]12)OC(=O)C(C)(C)CC)C[C@@H]1C[C@@H](O)CC(=O)O1 RYMZZMVNJRMUDD-HGQWONQESA-N 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 239000010936 titanium Substances 0.000 description 1
- 229910052719 titanium Inorganic materials 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
Landscapes
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention discloses one kind（S）The preparation method of tertiary butyl dimethyl Si base glutaric acid list benzyl ester monoamides, belongs to field of medicaments.This method is with compound（S) butyric ester of 4 cyano group 3 is raw material, believes that lipase 435 is catalyzed with Novi, benzylalcohol ester exchange obtains（S) the hydroxybutyrate benzyl ester of 4 cyano group 3, then combined with TBSCl, obtain TBS protections（S) the tertiary butyl dimethyl Si butyric acid list benzyl ester of 4 cyano group 3, reoxidizes to obtain S) 3 tertiary butyl dimethyl Si base glutaric acid list benzyl ester monoamides.Ester exchange is carried out using NOVO 435 and obtains that benzyl ester is higher than former process recovery ratio, and the three wastes are few, avoids the pollution of titanium tetrachloride.With hydrogen peroxide and alkali or catalysis oxidation acid amides, the three wastes are few, avoid the method for oxidation with manganese dioxide high pollution, avoid the high cost method aoxidized with Wilkinson precious metal catalyst.Make process costs lower, be more easy to industrialize.
Description
Technical field
The present invention is the field of chemical synthesis, and specifically a kind of hypolipidemic HMG inhibitor cuts down statin intermediate (S)-tertiary fourth
The preparation method of base dimethylsilyl bis-glutaryl amine mono-methyl.
Background technology
Rosuvastatin (also referred to as Rosuvastatin, English name：rosuvastatin).Rosuvastatin calcium is that Japanese salt is wild
Adopted (Osaka Shionogi companies) is developed, and 2 months 1999 I phases that the medicine is completed in the U.S., II phase, III phase clinic are tested
Card.In terms of its existing Clinical results and with the comparison two of like product, heavy dose of rosuvastatin calcium (80 millis
Gram) LDL can be reduced up to 65%, higher than Atorvastatin and Simvastatin, rosuvastatin calcium, which is deserve to be called, is referred to as " superstatin ", its
Lipid-lowering effect is very good, is the most potent fat-reducing medicament listed so far.Coming years rosuvastatin calcium pole has can
The market competition structure of current statins can be changed.The product respectively in July, 2002 and in August, 2003 pass through European medicine
The product committee and the examination ＆ approval of U.S. FDA, in succession in Europe and U.S.'s listing.
(S)-tertiary butyl dimethyl Si base-glutaryl amine list benzyl ester be easy in WO2013080219 close (R)-
Tertiary butyl dimethyl Si base-monomethyl glutarate is further easy to reference to EP0521471, EP0304063, WO03087112
Etc. the side chain important intermediate of patent synthesis statin.
The synthesis compound I reported at present：
Main literature has Enzymatic (2003), 21 (1-2), 55-58.；Tetrahedron Asymmetry,2004,
vol.15,#10p.1551-1554；Biotechnology Letters (2012), 34 (5), 901-905 and
WO2013080219.Preparation technology be all withFor raw material, fat is believed in Novi
Generated under enzyme, or Novi's letter lipase of improvementIn the presence of chiral different
Structure body, need to purify.
In WO2013080219 after enzyme process is prepared into the said goods, ethyl ester titanium tetrachloride is become benzyl ester, then upper guarantor
Shield, obtains target product.The purpose of ester group conversion is to improve ester hydrolysis into the selectivity of acid.
The content of the invention
The purpose of the present invention is to overcome prior art route to grow, and chiral photo-isomerisation be present, and separation is difficult, be not easy it is industrialized not
A kind of foot, there is provided preparation method of (S)-tertiary butyl dimethyl Si base-glutaric acid list benzyl ester monoamides.
Technical scheme is as follows：
The preparation method of one kind (S) -3- tertiary butyl dimethyl Si base glutaric acid list benzyl ester monoamides comprises the following steps：
1) (S) -4- cyanogen -3- hydroxyl protections butyrates (IV) are exchanged into benzyl ester in the presence of solvent, catalyst with benzylalcohol
(III)；(S) structural formula of -4- cyanogen -3- hydroxyl protections butyrate (IV) is：
Wherein P is H or TBS, R CH3Or C2H5；
Compound III structural formula is：
Wherein P is H or TBS；
2) when compound III substituent P is H, compound III is with t butyldimethylsilyl chloride in solvent, imidazoles
Reaction generation compound II in the presence of effect；When P is TBS, step 3) is directly carried out；
Compound II structural formula is：
3) using compound II as raw material, oxidation generation (S)-tertiary butyl dimethyl Si base-glutaric acid list benzyl under catalysis
Ester monoamides (I)；
(S) structural formula of-tertiary butyl dimethyl Si base-glutaric acid list benzyl ester monoamides (I) is：
Solvent in the step 1) is toluene or hexamethylene, and catalyst is Novi's letter 435, compound IV and catalyst
Mass ratio is 1:0.1~1：The mol ratio of 0.5, compound IV and benzylalcohol is 1:0.9~1：2.5, compound IV and solvent matter
Amount is than being 1:3~1:15, reaction temperature is 50~80 DEG C, and the reaction time is 8~30 hours.
T butyldimethylsilyl chloride in described step 2)：Compound III：The mol ratio of imidazoles is 1.0:1：1.0~
1.8:1：2.2, solvent is dichloromethane or DMF, and solvent and compound III mass ratio are 5:1~20:1, reaction temperature 15
~30 DEG C, the reaction time is 6~24 hours.
A kind of preparation method of (S)-tertiary butyl dimethyl Si base-glutaric acid monoester monoamides is using compound V as original
Material, generation is aoxidized under catalysis,
Compound V structural formula is as follows：
(S) structural formula of-tertiary butyl dimethyl Si base-glutaric acid monoester monoamides is as follows：
Wherein R1For CH3, C2H5, H, benzyl.
The catalyst of oxidation reaction is alkali under described catalysis, and oxidant is hydrogen peroxide；Or catalyst is cupric, oxidation
Agent is oxime.
The alkali is Amberlyst A-26 (OH), and cupric is the mixture of copper chloride and 4A molecular sieves composition, oxidation
Copper, copper acetate, Kocide SD or copper sulphate, oxidant oxime are acetaldoxime.
Solvent is methanol, ethanol, water or acetone when being oxidant with hydrogen peroxide, compound II or compound V：Solvent matter
Amount is than being 1:3~1:20, compound II or compound V：Hydrogen peroxide：The mol ratio of alkali is 1:3：1.5~1:10:3, reaction temperature
For 10~60 DEG C, 1~36 hour reaction time.
Solvent is methanol, ethanol, acetone, n-hexane, dichloromethane or toluene when being oxidant with acetaldoxime, compound
II or compound V：Solvent quality ratio is 1:2~1:20, compound II or compound V：Acetaldoxime mol ratio is 1:1.5~1:4,
Compound II or compound V：Catalyst quality ratio is 1:0.1~1:0.5, copper chloride is 1 with 4A molecular sieves mol ratio:0.5~
1:2,25~68 DEG C of reaction temperature.Reaction time is 5~16 hours.
The catalyst preparation need to activate 1~5 hour at 100~150 DEG C.
Product removes benzyl by catalytic hydrogenation, and again with methanol sodium and methanol can be easily converted to (R)-tert-butyl group two
Methyl siloxy monomethyl glutarate, available for synthesis statin side chain
The present invention obtains that benzyl ester is higher than former process recovery ratio, and the three wastes are few, avoid tetrachloro using NOVO-435 progress ester exchanges
Change the pollution of titanium.With hydrogen peroxide and alkali or catalysis oxidation acid amides, the three wastes are few, avoid the method for oxidation with manganese dioxide high pollution,
Avoid the high cost method aoxidized with Wilkinson precious metal catalyst.Make process costs lower, be more easy to industrialize
Embodiment
Compound III preparation：
Example 1：
(S) -3- hydroxyls -4- cyano butyric acids methyl esters (IV) 14.3g, benzylalcohol 20g toluene 250ml are dissolved, NOVO-4353g,
60 DEG C are heated to, reduced-pressure backflow 12 hours, constantly removes a small amount of toluene steamed therebetween, is cooled down, filtering, adds water 50ml washings
Twice, organic phase is concentrated, the material that decompression boils off low useless point obtains (S) -3- hydroxyl -4- cyano butyric acid benzyl esters, and yield 96.5% is (pure
Degree is 92.4%).
Example 2：
By (S) -3- hydroxyls -4- cyano butyric acids ethyl ester (IV) 15.7g, benzylalcohol 20g, hexamethylene 250ml dissolvings, NOVO-
4353g, 80 DEG C are heated to, reduced-pressure backflow 16 hours, constantly removes a small amount of hexamethylene steamed therebetween, cooled down, filtering, add water
50ml is washed twice, and concentrates organic phase, and the material that decompression boils off low useless point obtains (S) -3- hydroxyl -4- cyano butyric acid benzyl esters, yield
98.2% (purity 90.6%).
Example 3：
(S) -3- tert-butyl group siloxy -4- cyano butyric acids methyl esters (IV) 25.7g, benzylalcohol 20g, toluene 250ml are dissolved,
NOVO-435 is heated to 60 DEG C, reduced-pressure backflow 12 hours, constantly removes a small amount of hexamethylene steamed therebetween, cools down, and filters, and adds
Water 50ml is washed twice, and concentrates organic phase, and the material that decompression boils off low useless point obtains (S) -3- tert-butyl group siloxy -4- cyano butyric acids
Benzyl ester, yield 91.2% (purity 86.6%).
Example 4：Compound II preparation
(S) -3- hydroxyl -4- cyano butyric acids benzyl esters (II) (11g) are dissolved in dichloromethane (150ml), add imidazoles
(8.5g), TBSCl (17.5g) is added portionwise, 25 DEG C of stirrings, 12 hours, filtering, reclaims imidazole hydrochloride, adds water 80ml,
Neutrality is adjusted to glacial acetic acid and sodium bicarbonate water, is extracted, aqueous phase is extracted once again with dichloromethane 50ml, merges organic phase, decompression
Be concentrated to give (S) -3- tert-butyl group siloxy -4- glutaryl amine mono-methyls (II) is for colourless or pale brown oil thing, yield
100%.
Example 5：Compound II preparation
(S) -3- hydroxyl -4- cyano butyric acids benzyl esters (II) (11g) are dissolved in DMF (100ml), add imidazoles (8.5g),
TBSCl (17.5g) is added portionwise, 25 DEG C of stirrings, 8 hours, adds water 180ml, ethyl acetate 200ml extractions, organic phase is used
Glacial acetic acid and sodium bicarbonate water are adjusted to neutrality, and extraction, aqueous phase is extracted once again with ethyl acetate 50ml, merge organic phase, and decompression is dense
(the S) -3- tert-butyl group siloxy -4- cyano butyric acids benzyl esters (II) that contract are colourless or pale brown oil thing, yield 86%.
Example 6：Compound I preparation
By (S) -3- tert-butyl group siloxy -4- cyano butyric acids benzyl esters (16.6g), methanol 100ml, chlorinated ketone/4A molecular sieves
6g, acetaldoxime 12g, 65 DEG C are slowly warming up to, reacted 10 hours, after TLC detection reactions completely, filtering, filtrate concentration, obtain product
(S) -3- tert-butyl groups siloxy -4- glutaryls amine list benzyl ester (I), yield 92.6%.
1HNMR(CDCl3)δ:-0.03(3H,s)Si-CH3；0.00(3H,s)Si-CH3；0.76(9H,s)Si-C-(CH3)3；
2.3~2.54 (4H, m) CH2C(SiOTBS)CH2；4.41~4.45 (1H, h) methyl-CH (SiOTBS)-methyl；4.97~5.05
CH on (dd, 2H) benzyl2；5.73~6.12 (d, 2H) NH2；Hydrogen on 7.25 (5H, s) phenyl ring.
Example 7：Compound I preparation
By (S) -3- tert-butyl group siloxy -4- cyano butyric acids benzyl esters (16.6g), methanol 100ml, Amberlyst A-26
(OH) 6g, water 20ml, hydrogen peroxide 10g (30%) is slowly added dropwise, reacts 6 hours, after TLC detection reactions completely, filtering, use dichloro
Methane 300ml is extracted, and organic phase washes twice with 5% sodium thiosulfate, concentration, obtain product (S) -3- tert-butyl groups siloxy -
4- glutaryl amine list benzyl esters (I), yield 67.5%.
Example 8：Compound V preparation
By (S) -3- tert-butyl group siloxy -4- cyano butyric acids methyl esters (13g), toluene 50ml, add copper chloride/4A molecular sieves
1.35g, acetaldoxime 12g, 50 DEG C are slowly warming up to, reacted 16 hours, after TLC detection reactions completely, filtering, filtrate is concentrated to give production
Product (S) -3- tert-butyl group siloxy -4- glutaryl amine mono-methyls, yield 92.6%.
Example 9：Compound V preparation
By (S) -3- tert-butyl group siloxy -4- cyano butyric acids ethyl esters (13.5g), n-hexane 80ml, add copper chloride/4A points
Son sieve 1.35g, acetaldoxime 12g, are slowly warming up to 60 DEG C, react 16 hours, after TLC detection reactions completely, filtering, and filtrate concentration
Obtain product (S) -3- tert-butyl group siloxy -4- glutaryl amine mono-methyls, yield 90.5%.
Example 10：Compound V preparation
By (S) -3- tert-butyl group siloxy -4- cyano butyric acids ethyl esters (13.5g), methanol 50ml, add cupric oxide 2.6g, second
Aldoxime 12g, 55 DEG C are slowly warming up to, reacted 6 hours, after TLC detection reactions completely, filtering, filtrate is concentrated to give product (S) -3-
Tert-butyl group siloxy -4- glutaryl amine mono-methyls, yield 90.5%.
Example 11：Compound V preparation
By (S) -3- tert-butyl group siloxy -4- cyano butyric acids sodium (13g), water 50ml, 30% hydrogen peroxide 10g is slowly added into,
At 60 DEG C, Amberlyst A-26 (OH) 5g, time for adding be 2 hours, stir 1 hour, add dichloromethane 120ml, extraction
Take, organic phase is washed twice with 5% sodium thiosulfate, concentration, and it is 2~3 to adjust pH with 10% oxalic acid, extracts, concentration, obtains product
(S) -3- tert-butyl groups siloxy -4- glutaryl amine, yield 54.3%.
Example 12：The preparation of copper chloride catalyst
1g copper chloride dihydrate, water 600ml is added in reaction bulb, 4A molecular sieve 6g is added, is stirred overnight.Filtering, use
Water and acetone elution, it is put into and 1 hour blue solid for obtaining 6.3g is dried at 140 DEG C of baking oven, then is dried more than 2 hours at 140 DEG C, cooling
Chlorinated ketone catalyst is just obtained to room temperature.
Example 13：
By (R) -3- tert-butyl group siloxy -4- cyano butyric acids benzyl esters (16.6g), dichloromethane 100ml, chlorinated ketone/4A divides
Son sieve 6g, acetaldoxime 12g, are slowly warming up to 40 DEG C, react 20 hours, after TLC detection reactions completely, filtering, filtrate concentration, obtain
Product (R) -3- tert-butyl group siloxy -4- glutaryl amine list benzyl esters yield 91.8%.
Example 14：
By (R) -3- tert-butyl group siloxy -4- cyano butyric acids benzyl esters (16.6g), methanol 100ml, copper sulphate 6g, acetaldoxime
12g, 65 DEG C are slowly warming up to, reacted 18 hours, after TLC detection reactions completely, filtering, filtrate concentration, obtain product (R) -3- uncles
Butyl siloxy -4- glutaryl amine list benzyl esters yield 93.4%.
Example 15：
By (R) -3- tert-butyl group siloxy -4- cyano butyric acids benzyl esters (16.6g), methanol 100ml, copper acetate 3.2g, acetaldehyde
Oxime 12g, 65 DEG C are slowly warming up to, reacted 20 hours, after TLC detection reactions completely, filtering, filtrate concentration, obtain product (R) -3-
Tert-butyl group siloxy -4- glutaryl amine list benzyl esters yield 96.2%.
Claims (1)
1. the preparation method of one kind (S) -3- tertiary butyl dimethyl Si base glutaric acid list benzyl ester monoamides, it is characterised in that chemical combination
Thing III is oxidized to (S) -3- tert-butyldimethyl silyls with acetaldoxime in a solvent under cupric oxide, copper acetate or catalysis of cupric sulphate
Epoxide glutaric acid list benzyl ester monoamides,
Wherein P is TBS；
Solvent is methanol, ethanol, acetone, n-hexane, dichloromethane or toluene, and compound III is 1 with solvent quality ratio:2~1:
20, compound III：Acetaldoxime mol ratio is 1:1.5~1:4, compound III are 1 with catalyst quality ratio:0.1~1:0.5,
25~68 DEG C of reaction temperature, reaction time are 5~16 hours.
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN104066846A (en) * | 2011-11-28 | 2014-09-24 | 迈兰实验室有限公司 | Process for producing chiral statin side chain intermediates employing candida|antarctica lipase B |
| CN104356155A (en) * | 2014-10-20 | 2015-02-18 | 浙江新东港药业股份有限公司 | Preparation method of (S)-tert-butyldimethylsilyloxy-glutaramate |
| CN104370953A (en) * | 2014-08-24 | 2015-02-25 | 浙江新东港药业股份有限公司 | (R)-tert-butyl dimethyl siloxy-glutaric acid monoester preparation method |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104066846A (en) * | 2011-11-28 | 2014-09-24 | 迈兰实验室有限公司 | Process for producing chiral statin side chain intermediates employing candida|antarctica lipase B |
| CN104370953A (en) * | 2014-08-24 | 2015-02-25 | 浙江新东港药业股份有限公司 | (R)-tert-butyl dimethyl siloxy-glutaric acid monoester preparation method |
| CN104356155A (en) * | 2014-10-20 | 2015-02-18 | 浙江新东港药业股份有限公司 | Preparation method of (S)-tert-butyldimethylsilyloxy-glutaramate |
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| A heterogeneous catalytic method for the conversion of nitriles into amides using molecular sieves modified with copper(II);árpád Kiss等，;《Tetrahedron Letters》;20110910;第52卷;第6021–6023页，尤其是第6022页表格1 * |
| Selective conversion of nitriles of amides by Amberlysr A-26 supported hydroperoxide;M Mansour等，;《Indian Journal of Chemistry》;19990831;第38B卷;第974-975页，尤其是第947页右栏 * |
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