CN104230880A - Simple preparation method of 2-((4R,6R)-6-aminoethyl-2,2-dimethyl-1,3-dioxyhexacyclo-4-yl)acetate - Google Patents
Simple preparation method of 2-((4R,6R)-6-aminoethyl-2,2-dimethyl-1,3-dioxyhexacyclo-4-yl)acetate Download PDFInfo
- Publication number
- CN104230880A CN104230880A CN201410404491.6A CN201410404491A CN104230880A CN 104230880 A CN104230880 A CN 104230880A CN 201410404491 A CN201410404491 A CN 201410404491A CN 104230880 A CN104230880 A CN 104230880A
- Authority
- CN
- China
- Prior art keywords
- dimethyl
- dioxane
- ester
- base
- aminoethyl
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
- 238000002360 preparation method Methods 0.000 title claims abstract description 34
- 238000006243 chemical reaction Methods 0.000 claims abstract description 22
- 239000002994 raw material Substances 0.000 claims abstract description 10
- NPXOKRUENSOPAO-UHFFFAOYSA-N Raney nickel Chemical compound [Al].[Ni] NPXOKRUENSOPAO-UHFFFAOYSA-N 0.000 claims abstract description 7
- 239000002904 solvent Substances 0.000 claims abstract description 7
- 239000002841 Lewis acid Substances 0.000 claims abstract description 5
- 150000007517 lewis acids Chemical class 0.000 claims abstract description 5
- 229910000564 Raney nickel Inorganic materials 0.000 claims abstract description 3
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 109
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 78
- 235000019439 ethyl acetate Nutrition 0.000 claims description 36
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 21
- 239000000243 solution Substances 0.000 claims description 20
- FKRCODPIKNYEAC-UHFFFAOYSA-N ethyl propionate Chemical compound CCOC(=O)CC FKRCODPIKNYEAC-UHFFFAOYSA-N 0.000 claims description 19
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 18
- 239000010410 layer Substances 0.000 claims description 15
- KAIHOCOWYAMXQY-UHFFFAOYSA-N 3-cyanoprop-2-enoic acid Chemical compound OC(=O)C=CC#N KAIHOCOWYAMXQY-UHFFFAOYSA-N 0.000 claims description 14
- 150000001875 compounds Chemical class 0.000 claims description 13
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical class N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 claims description 12
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical group [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 10
- 229910052799 carbon Inorganic materials 0.000 claims description 10
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 10
- 230000015572 biosynthetic process Effects 0.000 claims description 9
- 239000012044 organic layer Substances 0.000 claims description 9
- 238000003786 synthesis reaction Methods 0.000 claims description 9
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 8
- 239000007848 Bronsted acid Substances 0.000 claims description 6
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 6
- SRSXLGNVWSONIS-UHFFFAOYSA-N benzenesulfonic acid Chemical compound OS(=O)(=O)C1=CC=CC=C1 SRSXLGNVWSONIS-UHFFFAOYSA-N 0.000 claims description 6
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 6
- 239000003054 catalyst Substances 0.000 claims description 6
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 6
- 239000001257 hydrogen Substances 0.000 claims description 6
- 229910052739 hydrogen Inorganic materials 0.000 claims description 6
- 238000004519 manufacturing process Methods 0.000 claims description 6
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 6
- 230000035484 reaction time Effects 0.000 claims description 6
- 239000000126 substance Substances 0.000 claims description 6
- 238000005406 washing Methods 0.000 claims description 6
- 230000000694 effects Effects 0.000 claims description 5
- -1 sec.-propyl Chemical group 0.000 claims description 5
- ATUOYWHBWRKTHZ-UHFFFAOYSA-N Propane Chemical compound CCC ATUOYWHBWRKTHZ-UHFFFAOYSA-N 0.000 claims description 4
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims description 4
- 230000001476 alcoholic effect Effects 0.000 claims description 4
- 125000000217 alkyl group Chemical group 0.000 claims description 4
- 229910021529 ammonia Inorganic materials 0.000 claims description 4
- 239000007864 aqueous solution Substances 0.000 claims description 4
- 238000006555 catalytic reaction Methods 0.000 claims description 4
- 230000007062 hydrolysis Effects 0.000 claims description 4
- 238000006460 hydrolysis reaction Methods 0.000 claims description 4
- GEHJYWRUCIMESM-UHFFFAOYSA-L sodium sulfite Chemical compound [Na+].[Na+].[O-]S([O-])=O GEHJYWRUCIMESM-UHFFFAOYSA-L 0.000 claims description 4
- LRDPYMPHDKBQQJ-UHFFFAOYSA-N tert-butyl 3,3-diethoxypropanoate Chemical compound CCOC(OCC)CC(=O)OC(C)(C)C LRDPYMPHDKBQQJ-UHFFFAOYSA-N 0.000 claims description 4
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 3
- 239000002253 acid Substances 0.000 claims description 3
- 238000007171 acid catalysis Methods 0.000 claims description 3
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 3
- 150000002148 esters Chemical class 0.000 claims description 3
- 150000002431 hydrogen Chemical class 0.000 claims description 3
- 239000011968 lewis acid catalyst Substances 0.000 claims description 3
- 229940017219 methyl propionate Drugs 0.000 claims description 3
- 229920006395 saturated elastomer Polymers 0.000 claims description 3
- JWUJQDFVADABEY-UHFFFAOYSA-N 2-methyltetrahydrofuran Chemical compound CC1CCCO1 JWUJQDFVADABEY-UHFFFAOYSA-N 0.000 claims description 2
- 238000010719 annulation reaction Methods 0.000 claims description 2
- 238000010511 deprotection reaction Methods 0.000 claims description 2
- UNONUCVWBGLFIO-UHFFFAOYSA-N ethyl 3-methoxyprop-2-enoate Chemical group CCOC(=O)C=COC UNONUCVWBGLFIO-UHFFFAOYSA-N 0.000 claims description 2
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 2
- RGSFGYAAUTVSQA-UHFFFAOYSA-N pentamethylene Natural products C1CCCC1 RGSFGYAAUTVSQA-UHFFFAOYSA-N 0.000 claims description 2
- 239000001294 propane Substances 0.000 claims description 2
- 235000010265 sodium sulphite Nutrition 0.000 claims description 2
- OHWGCWUIQFALOJ-UHFFFAOYSA-N tert-butyl 3-methoxyprop-2-enoate Chemical compound COC=CC(=O)OC(C)(C)C OHWGCWUIQFALOJ-UHFFFAOYSA-N 0.000 claims description 2
- 239000012485 toluene extract Substances 0.000 claims description 2
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 claims description 2
- 238000000034 method Methods 0.000 abstract description 7
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 abstract description 2
- 239000007868 Raney catalyst Substances 0.000 abstract 1
- SJNALLRHIVGIBI-UHFFFAOYSA-N allyl cyanide Chemical group C=CCC#N SJNALLRHIVGIBI-UHFFFAOYSA-N 0.000 abstract 1
- 230000000903 blocking effect Effects 0.000 abstract 1
- 230000003197 catalytic effect Effects 0.000 abstract 1
- 238000009903 catalytic hydrogenation reaction Methods 0.000 abstract 1
- 238000009776 industrial production Methods 0.000 abstract 1
- 238000007039 two-step reaction Methods 0.000 abstract 1
- 239000002585 base Substances 0.000 description 37
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 16
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 14
- WTEOIRVLGSZEPR-UHFFFAOYSA-N boron trifluoride Chemical compound FB(F)F WTEOIRVLGSZEPR-UHFFFAOYSA-N 0.000 description 12
- WMOVHXAZOJBABW-UHFFFAOYSA-N tert-butyl acetate Chemical compound CC(=O)OC(C)(C)C WMOVHXAZOJBABW-UHFFFAOYSA-N 0.000 description 12
- 238000004128 high performance liquid chromatography Methods 0.000 description 10
- 238000006722 reduction reaction Methods 0.000 description 9
- 239000007787 solid Substances 0.000 description 9
- 238000010792 warming Methods 0.000 description 9
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 8
- 229910015900 BF3 Inorganic materials 0.000 description 6
- 239000007788 liquid Substances 0.000 description 6
- 238000004064 recycling Methods 0.000 description 6
- JIAARYAFYJHUJI-UHFFFAOYSA-L zinc dichloride Chemical compound [Cl-].[Cl-].[Zn+2] JIAARYAFYJHUJI-UHFFFAOYSA-L 0.000 description 6
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 5
- 238000009833 condensation Methods 0.000 description 5
- 230000005494 condensation Effects 0.000 description 5
- 238000004821 distillation Methods 0.000 description 5
- 238000001035 drying Methods 0.000 description 5
- 239000000543 intermediate Substances 0.000 description 5
- 239000012074 organic phase Substances 0.000 description 5
- 206010013786 Dry skin Diseases 0.000 description 4
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 4
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 4
- KXZJHVJKXJLBKO-UHFFFAOYSA-N chembl1408157 Chemical compound N=1C2=CC=CC=C2C(C(=O)O)=CC=1C1=CC=C(O)C=C1 KXZJHVJKXJLBKO-UHFFFAOYSA-N 0.000 description 4
- 229910052757 nitrogen Inorganic materials 0.000 description 4
- 238000003756 stirring Methods 0.000 description 4
- 238000010189 synthetic method Methods 0.000 description 4
- OSDWBNJEKMUWAV-UHFFFAOYSA-N Allyl chloride Chemical group ClCC=C OSDWBNJEKMUWAV-UHFFFAOYSA-N 0.000 description 3
- 229920001651 Cyanoacrylate Polymers 0.000 description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- 238000006086 Paal-Knorr synthesis reaction Methods 0.000 description 3
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 3
- BHELZAPQIKSEDF-UHFFFAOYSA-N allyl bromide Chemical group BrCC=C BHELZAPQIKSEDF-UHFFFAOYSA-N 0.000 description 3
- CBHOOMGKXCMKIR-UHFFFAOYSA-N azane;methanol Chemical class N.OC CBHOOMGKXCMKIR-UHFFFAOYSA-N 0.000 description 3
- 238000000605 extraction Methods 0.000 description 3
- SUOFREPYJDSUTJ-UHFFFAOYSA-N iron sulfurous acid Chemical compound [Fe].S(O)(O)=O SUOFREPYJDSUTJ-UHFFFAOYSA-N 0.000 description 3
- OVEHNNQXLPJPPL-UHFFFAOYSA-N lithium;n-propan-2-ylpropan-2-amine Chemical compound [Li].CC(C)NC(C)C OVEHNNQXLPJPPL-UHFFFAOYSA-N 0.000 description 3
- 238000011084 recovery Methods 0.000 description 3
- 238000001953 recrystallisation Methods 0.000 description 3
- 235000005074 zinc chloride Nutrition 0.000 description 3
- 239000011592 zinc chloride Substances 0.000 description 3
- HEWZVZIVELJPQZ-UHFFFAOYSA-N 2,2-dimethoxypropane Chemical class COC(C)(C)OC HEWZVZIVELJPQZ-UHFFFAOYSA-N 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical class COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 description 2
- XBDQKXXYIPTUBI-UHFFFAOYSA-M Propionate Chemical compound CCC([O-])=O XBDQKXXYIPTUBI-UHFFFAOYSA-M 0.000 description 2
- DWAQJAXMDSEUJJ-UHFFFAOYSA-M Sodium bisulfite Chemical compound [Na+].OS([O-])=O DWAQJAXMDSEUJJ-UHFFFAOYSA-M 0.000 description 2
- KXKVLQRXCPHEJC-UHFFFAOYSA-N acetic acid trimethyl ester Natural products COC(C)=O KXKVLQRXCPHEJC-UHFFFAOYSA-N 0.000 description 2
- VSCWAEJMTAWNJL-UHFFFAOYSA-K aluminium trichloride Chemical compound Cl[Al](Cl)Cl VSCWAEJMTAWNJL-UHFFFAOYSA-K 0.000 description 2
- 150000001649 bromium compounds Chemical class 0.000 description 2
- 239000012295 chemical reaction liquid Substances 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- 229940079593 drug Drugs 0.000 description 2
- 239000012065 filter cake Substances 0.000 description 2
- 238000001914 filtration Methods 0.000 description 2
- 239000007789 gas Substances 0.000 description 2
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 2
- 229910000041 hydrogen chloride Inorganic materials 0.000 description 2
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 2
- 239000000203 mixture Substances 0.000 description 2
- LYGJENNIWJXYER-UHFFFAOYSA-N nitromethane Chemical compound C[N+]([O-])=O LYGJENNIWJXYER-UHFFFAOYSA-N 0.000 description 2
- 239000000047 product Substances 0.000 description 2
- 235000017557 sodium bicarbonate Nutrition 0.000 description 2
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 2
- 229910000029 sodium carbonate Inorganic materials 0.000 description 2
- 235000010267 sodium hydrogen sulphite Nutrition 0.000 description 2
- AIDLAEPHWROGFI-UHFFFAOYSA-N 2-methylbenzene-1,3-dicarboxylic acid Chemical compound CC1=C(C(O)=O)C=CC=C1C(O)=O AIDLAEPHWROGFI-UHFFFAOYSA-N 0.000 description 1
- OUCSEDFVYPBLLF-KAYWLYCHSA-N 5-(4-fluorophenyl)-1-[2-[(2r,4r)-4-hydroxy-6-oxooxan-2-yl]ethyl]-n,4-diphenyl-2-propan-2-ylpyrrole-3-carboxamide Chemical compound C=1C=CC=CC=1C1=C(C=2C=CC(F)=CC=2)N(CC[C@H]2OC(=O)C[C@H](O)C2)C(C(C)C)=C1C(=O)NC1=CC=CC=C1 OUCSEDFVYPBLLF-KAYWLYCHSA-N 0.000 description 1
- 208000024172 Cardiovascular disease Diseases 0.000 description 1
- 206010008190 Cerebrovascular accident Diseases 0.000 description 1
- 208000031288 Combined hyperlipidaemia Diseases 0.000 description 1
- 229910021589 Copper(I) bromide Inorganic materials 0.000 description 1
- 229940121710 HMGCoA reductase inhibitor Drugs 0.000 description 1
- 208000035150 Hypercholesterolemia Diseases 0.000 description 1
- WHPVJAUHUINSHD-UHFFFAOYSA-N OC(CC(=O)OCCBr)C Chemical compound OC(CC(=O)OCCBr)C WHPVJAUHUINSHD-UHFFFAOYSA-N 0.000 description 1
- 208000006011 Stroke Diseases 0.000 description 1
- JAQAFPOLKCZORL-UHFFFAOYSA-N [Na].C(C)B(OC)CC Chemical compound [Na].C(C)B(OC)CC JAQAFPOLKCZORL-UHFFFAOYSA-N 0.000 description 1
- 239000002671 adjuvant Substances 0.000 description 1
- 230000003321 amplification Effects 0.000 description 1
- FQCKMBLVYCEXJB-MNSAWQCASA-L atorvastatin calcium Chemical compound [Ca+2].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.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 FQCKMBLVYCEXJB-MNSAWQCASA-L 0.000 description 1
- 230000002210 biocatalytic effect Effects 0.000 description 1
- JHXKRIRFYBPWGE-UHFFFAOYSA-K bismuth chloride Chemical compound Cl[Bi](Cl)Cl JHXKRIRFYBPWGE-UHFFFAOYSA-K 0.000 description 1
- OBNCKNCVKJNDBV-UHFFFAOYSA-N butanoic acid ethyl ester Natural products CCCC(=O)OCC OBNCKNCVKJNDBV-UHFFFAOYSA-N 0.000 description 1
- 159000000007 calcium salts Chemical class 0.000 description 1
- 230000002490 cerebral effect Effects 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- NKNDPYCGAZPOFS-UHFFFAOYSA-M copper(i) bromide Chemical compound Br[Cu] NKNDPYCGAZPOFS-UHFFFAOYSA-M 0.000 description 1
- 208000029078 coronary artery disease Diseases 0.000 description 1
- 230000007812 deficiency Effects 0.000 description 1
- 238000004807 desolvation Methods 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 230000007613 environmental effect Effects 0.000 description 1
- 125000004494 ethyl ester group Chemical group 0.000 description 1
- 125000003187 heptyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 239000002471 hydroxymethylglutaryl coenzyme A reductase inhibitor Substances 0.000 description 1
- RBTARNINKXHZNM-UHFFFAOYSA-K iron trichloride Chemical compound Cl[Fe](Cl)Cl RBTARNINKXHZNM-UHFFFAOYSA-K 0.000 description 1
- 229940002661 lipitor Drugs 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 150000004702 methyl esters Chemical class 0.000 description 1
- 230000005311 nuclear magnetism Effects 0.000 description 1
- 238000003199 nucleic acid amplification method Methods 0.000 description 1
- 238000005457 optimization Methods 0.000 description 1
- 239000003880 polar aprotic solvent Substances 0.000 description 1
- 238000012827 research and development Methods 0.000 description 1
- 239000012047 saturated solution Substances 0.000 description 1
- 238000004904 shortening Methods 0.000 description 1
- 239000012279 sodium borohydride Substances 0.000 description 1
- 229910000033 sodium borohydride Inorganic materials 0.000 description 1
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- JRMUNVKIHCOMHV-UHFFFAOYSA-M tetrabutylammonium bromide Chemical compound [Br-].CCCC[N+](CCCC)(CCCC)CCCC JRMUNVKIHCOMHV-UHFFFAOYSA-M 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D319/00—Heterocyclic compounds containing six-membered rings having two oxygen atoms as the only ring hetero atoms
- C07D319/04—1,3-Dioxanes; Hydrogenated 1,3-dioxanes
- C07D319/06—1,3-Dioxanes; Hydrogenated 1,3-dioxanes not condensed with other rings
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention relates to a simple preparation method of 2-((4R,6R)-6-aminoethyl-2,2-dimethyl-1,3-dioxyhexacyclo-4-yl)acetate (I). The method comprises the following steps: reacting 3-cyanopropylene (II) and 3,3-dialkoxypropionate (III) or 3-alkoxyacrylate (IV) under the catalytic action of Lewis acid to prepare 2-((4R,6R)-6-cyanomethyl-2-ester-methyl-1,3-dioxyhexacyclo-4-yl)acetate (V), removing the solvent, directly carrying out blocking group conversion to prepare 2-((4R,6R)-6-cyanomethyl-2,2-dimethyl-1,3-dioxyhexacyclo-4-yl)acetate (VI), and carrying out Raney nickel catalytic hydrogenation two-step reaction to prepare (I). The stable form of the hexatomic ring chair-structure equatorial bond is utilized to construct the chiral center without using any additional chiral assistant. The method has the advantages of accessible raw materials, short reaction procedure and low cost, avoids carbonyl asymmetric reduction, is simple and environment-friendly, and is industrial production.
Description
Technical field
The present invention relates to a kind of 2-((4R, 6R)-6-aminoethyl-2,2-dimethyl-1,3-dioxane-4-base) synthetic method of acetic ester, this compound is the important side chain preparing atorvastatincalcuim, belongs to atorvastatincalcuim intermediate synthesis technical field.
Background technology
Cardiovascular diseases is the principal disease of a class serious harm human health, and atorvastatincalcuim is the choice drug being used for the treatment of hypercholesterolemia and combined hyperlipidemia familial, coronary heart disease and cerebral apoplexy.Atorvastatincalcuim; Chinese commodity is called " Lipitor ", chemistry (3R, 5R)-7-[2-(4-fluorophenyl)-5-sec.-propyl-3-phenyl-4-(carbaniloyl,phenylcarbamoyl) pyrroles-1-base]-3 by name; 5-dihydroxy heptyl acid calcium salt, its chemical structure is as follows:
It is the first that atorvastatincalcuim since two thousand occupies global best-selling drugs always, and the optimization of its synthesis technique is always doubly for paying close attention to.
The synthetic method more employing Paal-Knorr synthesis method of atorvastatincalcuim, the core of Paal-Knorr synthesis method is important intermediate 2-(2-(4-fluorophenyl)-2-oxo-1-styroyl)-4-methyl-3-oxo-N-phenyl-pentanamide (VII) and 2-(4R, 6R)-6-aminoethyl-2, 2-dimethyl-1, the preparation of 3-dioxane-4-acetic ester (I), and utilize these two kinds of intermediates to be obtained by reacting atorvastatin lactone through Paal-Knorr, atorvastatincalcuim is obtained again through hydrolysis, and the synthesis of formula I side chain compound is the key of atorvastatincalcuim.
At present; the synthetic method relatively with I of industrial value is for raw material with (3S)-4-cyano-3-hydroxy butyric ester; proton condensation is taken off by LDA (lithium diisopropylamine)-tert.-butyl acetate; cis-diol compound is generated again through diethylmethoxyborane-sodium borohydride selective reduction; after two hydroxyl protection, reduction cyano group and obtaining.Reactions steps is loaded down with trivial details, and starting raw material not easily obtains, and use LDA-tert.-butyl acetate potential safety hazard large, asymmetric reduction reaction requires very low temperature, operation inconvenience, and cost of material is high, is difficult to scale operation.CN103614430A discloses a kind of synthetic method of atorvastatincalcuim intermediate, by the bromo-ethyl 3-hydroxybutanoate of (3S)-4-through condensation, asymmetric biocatalytic reduction, hydroxyl protection obtains [(4R, 6S)-6-brooethyl-2, 2-dimethyl-1, 3-dioxane-4-base] tert.-butyl acetate, then under cuprous bromide and the effect of nitrogenous compound part with Nitromethane 99Min. condensation after, atorvastatincalcuim intermediate [(4R is obtained through raney ni catalysis hydro-reduction, 6R)-6-(2-amino-ethyl)-2, 2-dimethyl-1, 3-dioxane-4-base] tert.-butyl acetate.The method uses chiral raw material (3S)-4-bromo-3-aldehyde radical ethyl butyrate to be starting raw material, and price is higher, not easily obtains; During condensation, operational requirement is high, and LDA price is high; Asymmetric biocatalysis industrialization amplification circulation ratio is low; And Nitromethane 99Min. condensation yield is lower, need 5 step reactions altogether, reaction process is loaded down with trivial details.
Above-mentioned prior art problems cause formula I side chain compound to become the bottleneck of restriction atorvastatincalcuim synthesis, therefore need research and development a kind of easy low consumption, green safety and be easy to industrialized novel synthesis, for the industrialization of statins lays the foundation.
Summary of the invention
For the deficiencies in the prior art, the invention provides a kind of preparation method of easy formula I side chain compound, i.e. a kind of 2-((4R, 6R)-6-aminoethyl-2,2-dimethyl-1,3-dioxane-4-base) simple and convenient process for preparing of acetic ester (I)." acetic ester " wherein comprises the ester of methyl esters, ethyl ester and the tert-butyl ester and other carbon four and carbon less than four.
Technical scheme of the present invention is as follows:
A kind of preparation method of formula I 2-((4R, 6R)-6-aminoethyl-2,2-dimethyl-1,3-dioxane-4-base) acetic ester,
Wherein, R2 is methyl, ethyl, the tertiary butyl, carbon tetraalkyl or other carbon less than four alkyl;
Comprise step as follows:
(1) synthesis of 2-((4R, 6R)-6-cyanogen methyl-2,2-dimethyl-1,3-dioxane-4-base) acetic ester (VI)
With 3-cyanoacrylate (II) for starting raw material, with 3,3-dialkoxy propionic ester (III) or 3-alkoxy acrylic ester (IV), in solvent, under Louis acid catalysis effect, in 10-100 DEG C of reaction production V compound, again through hydrolysis deprotection, with the 2-malonaldehydic acid ester that sodium sulfite aqueous solution washing removing is free, water layer toluene extracts, gained organic layer under bronsted acid catalyst effect with acetone or 2,2-dialkoxy propane annulation preparation formula VI compound;
(2) synthesis of formula I
Formula VI compound, in saturated ammonia alcoholic solution, under raney nickel catalyst exists, passes into hydrogen, through hydrogenating reduction cyano group, and obtained formula I;
Reaction formula is as follows:
Wherein: R
1for methyl, ethyl, sec.-propyl, n-propyl, the tertiary butyl, isobutyl-
R
2for methyl, ethyl, the tertiary butyl, carbon tetraalkyl or other carbon less than four alkyl
Preferred according to the present invention, described in step (1) 3,3-dialkoxy propionic ester is selected from 3,3-diethoxy ethyl propionate, 3,3-dimethoxy methyl propionate or 3,3-diethoxy propanoic acid tert-butyl ester, described 3-alkoxy acrylic ester is selected from 3-methoxy acrylic acid ethyl ester, 3-ethoxy ethyl acrylate, the 3-methoxy acrylic acid tert-butyl ester or 3-ethoxy-c enoic acid ter-butyl ester.
Preferred according to the present invention, lewis acid catalyst used in step (1) is conventional Lewis acid, can be selected from any one in boron trifluoride, boron trifluoride ether solution, Trichlorobismuthine, Zinc Chloride Anhydrous, aluminum chloride, FERRIC CHLORIDE ANHYDROUS, wherein preferred mass mark is boron trifluoride ether solution or the Zinc Chloride Anhydrous of 40-50%.
Preferred according to the present invention, in step (1), described lewis acid catalyst, 3,3-dialkoxy propionic esters or 3-alkoxy acrylic ester are (0.05-0.5) with the amount of substance ratio of 3-cyanoacrylate: (2.0-2.5): 1.
Preferred according to the present invention, solvent described in step (1) is tetrahydrofuran (THF), 2-methyltetrahydrofuran, methoxyl group pentamethylene or toluene polar aprotic solvent.
Preferred according to the present invention, in step (1), the temperature of Lewis acid catalyzed reaction is 20-90 DEG C, and further preferable reaction temperature is 40-75 DEG C.
Preferred according to the present invention, in step (1), the Lewis acid catalyzed reaction time is 1-10 hour.The further preferred reaction time is 4-6 hour.
Preferred according to the present invention, the bronsted acid catalyst described in step (1) is the sulfuric acid of massfraction 98%, Phenylsulfonic acid or p-methyl benzenesulfonic acid.
Preferred according to the present invention, described in step (1), hydrolysising reacting temperature is 10-80 DEG C, and further preferable reaction temperature is 20-50 DEG C.
Preferred according to the present invention, the hydrolysis time 0.5-8 hour of step (1).Preferred 4-6 hour further.
Preferred according to the present invention, step (1) bronsted acid catalyst is (0.005-0.1) with the amount of substance ratio of 3-cyanoacrylate: 1.Further preferably (0.01-0.05): 1.
Preferred according to the present invention, the saturated ammonia alcoholic solution described in step (2) passes into ammonia to saturated in C1-C4 alcohol under referring to normal temperature; Wherein C1-C4 alcohol more preferably methyl alcohol or ethanol.The preparation of alcohol ammonia saturated solution by prior art, such as, can directly pass into ammonia to constant weight at normal temperatures and pressures.Conventional saturated ammonia methanol solution, saturated rear mass concentration about 35%.
Preferred according to the present invention, in step (2), in formula VI compound, described catalyzer Raney Ni consumption is 5-30% mass ratio.
Preferred according to the present invention, the hydrogenating reduction temperature of step (2) is 20-80 DEG C, reaction times 1-12 hour.Preferably hydrogenating reduction temperature is 40-60 DEG C further, reaction times 5-8 hour.Hydrogen pressure is 10-20 normal atmosphere.
Initial feed 3-cyanoacrylate of the present invention can be commercial, also can prepare by prior art.The invention provides the preparation method of following preferred 3-cyanoacrylate:
In toluene solvant, under the existence of Tetrabutyl amonium bromide catalyzer, chlorallylene or 3-bromopropylene are mixed with the sodium cyanide solution of 25-35wt%, chlorallylene or 3-bromopropylene are 1:(1.0-1.1 with sodium cyanide amount of substance ratio); Be warming up to 50-60 DEG C of reaction 5-6 hour.React complete, be cooled to room temperature.Layering, water layer with toluene extraction 2-3 time, merge organic phase, successively with the sulfurous acid iron of 2wt% wash, saturated sodium-chloride water solution wash, gained organic layer uses anhydrous sodium sulfate drying again, filtration, recovery toluene, namely underpressure distillation obtains 3-cyanoacrylate.
According to the present invention, a most preferred technical scheme, the preparation method of a kind of formula I 2-((4R, 6R)-6-aminoethyl-2,2-dimethyl-1,3-dioxane-4-base) acetic ester, step is as follows:
The preparation of step 1:3-cyanoacrylate
In 1000 ml flasks, add 300 grams of toluene, 76.5 grams of (1.0 moles) chlorallylenes, 1.0 grams of Tetrabutyl amonium bromides, the sodium cyanide solution of 170 gram 30%, be warming up to 60 DEG C of reactions 6 hours.React complete, be cooled to room temperature.Layering, water layer toluene extracting twice (each 80 grams of toluene), merge organic phase, the sulfurous acid iron washing of 50 gram 2%, the washing of 50 grams of saturated sodium-chloride water solutions, organic layer 15 grams of anhydrous sodium sulfate dryings 4 hours, filtration, reclaim toluene, underpressure distillation (45-55 DEG C/10 mmhg) obtains colourless transparent liquid 61.8 grams.Purity 99.5% (GC), yield 91.3%.
The preparation of step 2:2-((4R, 6R)-6-cyanogen methyl-2,2-dimethyl-1,3-dioxane-4-base) tert.-butyl acetate
50 grams of tetrahydrofuran (THF)s are added in 250 ml flasks, 6.7 grams of (0.1 mole) 3-cyanoacrylate, 48.0 grams of (0.22 moles) 3,3-diethoxy propanoic acid tert-butyl ester, the boron trifluoride ether solution of 3.4 grams of (20 mmole) massfractions 47%, nitrogen replacement 3 times, is warming up to 60 DEG C of reactions, 6 hours (recovery ether).React complete, slightly cool (30-40 DEG C), recycling design, adds 100 grams of toluene in resistates, 10 grams of water, 0.03 gram of Phenylsulfonic acid, is warming up to 35 DEG C of reactions 4 hours.React complete, be cooled to 10 DEG C, add 120 gram of 10% aqueous solution of sodium bisulfite, stir 1 hour, layering, water layer toluene extracting twice (each 30 grams of toluene reclaim 2-formyl radical ethyl acetate by the water layer after extracting), merges organic layer.Gone in dry flask by organic layer, add 12.5 grams of 2,2-dimethoxypropanes, 0.03 gram of Phenylsulfonic acid, 40 DEG C are reacted 4 hours.Be cooled to room temperature, reaction liquid is added in the aqueous sodium carbonate of 50 gram 2%, stir 1 hour, layering, water layer toluene extracting twice (each 20 grams of toluene), merges organic phase, 5 grams of anhydrous sodium sulfate dryings 4 hours, filter, after toluene distillation, resistates 80 grams of methyl tert-butyl ethers and 1.0 grams of gac recrystallizations, obtain 21.3 grams of white solid 2-((4R, 6R)-6-cyanogen methyl-2,2-dimethyl-1,3-dioxane-4-base) ethyl acetate, fusing point 67-70 DEG C, purity 99.5% (HPLC), yield 79.3%.
The preparation of step 3:2-((4R, 6R)-6-aminoethyl-2,2-dimethyl-1,3-dioxane-4-base) tert.-butyl acetate
4.0 grams of (15 mmole) 2-((4R are added in 250 milliliters of autoclave pressures, 6R)-6-cyanogen methyl-2,2-dimethyl-1,3-dioxane-4-base) tert.-butyl acetate, 80 grams of saturated ammonia methanol solutions, 1.0 grams of Raney Nis, nitrogen replacement 2 times, pass into hydrogen, a pressure 12-15 normal atmosphere, be warming up to 45 DEG C of reactions 6 hours.React complete, be cooled to 20 DEG C, filter, recycling design, 20 grams of acetone solutions are added in residuum, pass into dry hydrogen chloride gas until solid is thoroughly separated out, filter, filter cake is added in 30 grams of methylene dichloride and 30 gram of 5% sodium bicarbonate mixture, 20 DEG C are stirred 1 hour, layering, water layer dichloromethane extraction 2 times, combined dichloromethane layer, 4.0 grams of colourless oil liquid 2-((4R are obtained after recycling design, 6R)-6-aminoethyl-2,2-dimethyl-1,3-dioxane-4-base) tert.-butyl acetate.Purity 99.4% (HPLC), yield 97.6%.
Technical characterstic of the present invention and excellent results:
The invention provides the simple and convenient process for preparing of a kind of 2-((4R, 6R)-6-aminoethyl-2,2-dimethyl-1,3-dioxane-4-base) acetic ester (I).Without chiral raw material; with 3-cyanoacrylate for initial feed and 3; 3-dialkoxy propionic ester or 3-alkoxy acrylic ester; 2-((4R is prepared under Louis acid catalysis; 6R)-6-cyanogen methyl-2-ester group methyl isophthalic acid; 3-dioxane-4-base) acetic ester (V); transform through overprotection group after desolvation and directly prepare 2-((4R; 6R)-6-cyanogen methyl-2; 2-dimethyl-1; 3-dioxane-4-base) acetic ester (VI), then through Raney Ni shortening preparation formula I side chain compound, reaction process shortens to two steps.The equatorial bond stable form of six-ring chair structure is utilized to build chiral centre, product is easy to recrystallization purifying feature, obtains 2-((4R, 6R)-6-aminoethyl-2 of high-optical-purity, 2-dimethyl-1,3-dioxane-4-base) acetic ester.
The present invention does not use chiral adjuvant in addition, and raw material is easy to get, and reaction process is short, avoids the asymmetric reduction of carbonyl, easy and environmental protection, significantly reduces production cost, is suitable for large-scale industrial and produces.
Embodiment
The embodiment of the following stated describes the present invention in detail, but the present invention is not limited only to following examples.The concentration " % " of the various raw materials in embodiment, reagent is mass percent, has except special instruction.
The preparation of embodiment 1:3-cyanoacrylate
In 1000 ml flasks, add 300 grams of toluene, 76.5 grams of (1.0 moles) chlorallylenes, 1.0 grams of Tetrabutyl amonium bromides, the sodium cyanide solution of 170 gram 30%, be warming up to 60 DEG C of reactions 6 hours.React complete, be cooled to room temperature.Layering, water layer toluene extracting twice (each 80 grams of toluene), merge organic phase, the sulfurous acid iron washing of 50 gram 2%, 50 grams of saturated sodium-chloride water solution washings, organic layer 15 grams of anhydrous sodium sulfate dryings 4 hours, filter, reclaim toluene, underpressure distillation (45-55 DEG C/10 mmhg) obtains colourless transparent liquid 61.8 grams, purity 99.5% (GC), yield 91.3%.
The preparation of embodiment 2:3-cyanoacrylate
Replace the chlorallylene of embodiment 1 with 121 grams of 3-bromopropylenes, all the other are with embodiment 1, obtain colourless transparent liquid 62.6 grams, purity 99.6% (GC), yield 93.5%.
The preparation of embodiment 3:2-((4R, 6R)-6-cyanogen methyl-2,2-dimethyl-1,3-dioxane-4-base) ethyl acetate
50 grams of tetrahydrofuran (THF)s are added in 250 ml flasks, 6.7 grams of (0.1 mole) 3-cyanoacrylate, 41.8 grams of (0.22 moles) 3,3-diethoxy ethyl propionate, the boron trifluoride ether solution of 3.4 grams of (20 mmole) massfractions 47%, nitrogen replacement 3 times, is warming up to 60 DEG C of reactions, 6 hours (recovery ether).React complete, slightly cool (30-40 DEG C), recycling design, adds 100 grams of toluene in resistates, 10 grams of water, 0.03 gram of Phenylsulfonic acid, is warming up to 35 DEG C of reactions 4 hours.React complete, be cooled to 10 DEG C, add 120 gram of 10% aqueous solution of sodium bisulfite, stir 1 hour, layering, water layer toluene extracting twice (each 30 grams of toluene reclaim 2-formyl radical ethyl acetate by the water layer after extracting), merges organic layer.Gone in dry flask by organic layer, add 12.5 grams of 2,2-dimethoxypropanes, 0.03 gram of Phenylsulfonic acid, 40 DEG C are reacted 4 hours.
Be cooled to room temperature, reaction liquid is added in the aqueous sodium carbonate of 50 gram 2%, stir 1 hour, layering, water layer toluene extracting twice (each 20 grams of toluene), merges organic phase, 5 grams of anhydrous sodium sulfate dryings 4 hours, filter, after toluene distillation, resistates 80 grams of methyl tert-butyl ethers and 1.0 grams of gac recrystallizations, obtain 18.7 grams of white solid 2-((4R, 6R)-6-cyanogen methyl-2,2-dimethyl-1,3-dioxane-4-base) ethyl acetate, fusing point 65-68 DEG C, purity 99.6% (HPLC), yield 77.6%.
The preparation of embodiment 4:2-((4R, 6R)-6-cyanogen methyl-2,2-dimethyl-1,3-dioxane-4-base) ethyl acetate
3 of embodiment 3 are replaced with 31.5 grams of (0.22 mole) 3-ethoxy ethyl acrylates, 3-diethoxy ethyl propionate, all the other are identical, obtain 18.2 grams of white solid 2-((4R, 6R)-6-cyanogen methyl-2,2-dimethyl-1,3-dioxane-4-base) ethyl acetate, purity 99.4% (HPLC), yield 75.5%.
The preparation of embodiment 5:2-((4R, 6R)-6-cyanogen methyl-2,2-dimethyl-1,3-dioxane-4-base) ethyl acetate
The tetrahydrofuran (THF) of embodiments 2 is replaced with 25 grams of toluene and 25 grams of tetrahydrofuran compounds, all the other are with embodiment 3, obtain 17.6 grams of white solid 2-((4R, 6R)-6-cyanogen methyl-2,2-dimethyl-1,3-dioxane-4-base) ethyl acetate, purity 99.5% (HPLC), yield 73.0%.
The preparation of embodiment 6:2-((4R, 6R)-6-cyanogen methyl-2,2-dimethyl-1,3-dioxane-4-base) ethyl acetate
The boron trifluoride ether solution of embodiment 3 is replaced with 3.0 grams of Zinc Chloride Anhydrouss, all the other are with embodiment 3, obtain 17.9 grams of white solid 2-((4R, 6R)-6-cyanogen methyl-2,2-dimethyl-1,3-dioxane-4-base) ethyl acetate, purity 99.2% (HPLC), yield 74.3%.
The preparation of embodiment 7:2-((4R, 6R)-6-cyanogen methyl-2,2-dimethyl-1,3-dioxane-4-base) methyl acetate
With 32.5 grams of (0.22 moles) 3,3-dimethoxy methyl propionate replaces 3 of embodiment 3,3-diethoxy ethyl propionate, all the other are identical, obtain 17.8 grams of white solid 2-((4R, 6R)-6-cyanogen methyl-2,2-dimethyl-1,3-dioxane-4-base) methyl acetate, fusing point 59-61 DEG C, purity 99.7% (HPLC), yield 78.5%.
The preparation of embodiment 8:2-((4R, 6R)-6-cyanogen methyl-2,2-dimethyl-1,3-dioxane-4-base) tert.-butyl acetate
With 48.0 grams of (0.22 moles) 3,3-diethoxy propanoic acid tert-butyl ester replaces 3 of embodiment 3,3-diethoxy ethyl propionate, all the other are identical, obtain 21.3 grams of white solid 2-((4R, 6R)-6-cyanogen methyl-2,2-dimethyl-1,3-dioxane-4-base) tert.-butyl acetate, fusing point 67-70 DEG C, purity 99.5% (HPLC), yield 79.3%.
The preparation of embodiment 9:2-((4R, 6R)-6-aminoethyl-2,2-dimethyl-1,3-dioxane-4-base) tert.-butyl acetate
4.0 grams of (15 mmole) 2-((4R are added in 250 milliliters of autoclave pressures, 6R)-6-cyanogen methyl-2,2-dimethyl-1,3-dioxane-4-base) tert.-butyl acetate (embodiment 8 obtains), 80 grams of saturated ammonia methanol solutions, 1.0 grams of Raney Nis, nitrogen replacement 2 times, pass into hydrogen (pressure is about 12-15 normal atmosphere), be warming up to 45 DEG C of reactions 6 hours.React complete, be cooled to 20 DEG C, filter, recycling design, 20 grams of acetone solutions are added in residuum, pass into dry hydrogen chloride gas until solid is thoroughly separated out, filter, filter cake is added in 30 grams of methylene dichloride and 30 gram of 5% sodium bicarbonate mixture, 20 DEG C are stirred 1 hour, layering, water layer dichloromethane extraction 2 times (each 10 grams), combined dichloromethane layer, 4.0 grams of colourless oil liquid 2-((4R are obtained after recycling design, 6R)-6-aminoethyl-2, 2-dimethyl-1, 3-dioxane-4-base) tert.-butyl acetate, purity 99.4% (HPLC), yield 97.6%.
Product confirms through nuclear-magnetism, and data are as follows:
1hNMR (solvent C DCl
3, 400MHz) and δ: ppm
1.29 (unimodal, 9H), 1.41 (triplet, 3H), 1.52 (triplet, 3H), 2.1 (broad peak, 2H), 2.83 (multiplet, 2H), 2.92 (multiplets, 2H), 3.22 (doublet, 2H), 4.13 (multiplet, 1H), 4.31 (quartets, 2H), 4.45 (multiplet, 1H).
The preparation of embodiment 10:2-((4R, 6R)-6-aminoethyl-2,2-dimethyl-1,3-dioxane-4-base) ethyl acetate
As described in Example 9, difference is: with 3.6 grams of (15 mmole) 2-((4R, 6R)-6-cyanogen methyl-2,2-dimethyl-1,3-dioxane-4-base) ethyl acetate replaces the 2-((4R of embodiment 9,6R)-6-cyanogen methyl-2,2-dimethyl-1,3-dioxane-4-base) tert.-butyl acetate, all the other are with embodiment 9, obtain 3.6 grams of colourless oil liquid 2-((4R, 6R)-6-aminoethyl-2,2-dimethyl-1,3-dioxane-4-base) ethyl acetate, purity 99.6% (HPLC), yield 97.3%.
1hNMR (solvent C DCl
3, 400MHz) and δ: ppm
1.30 (triplet, 3H), 1.42 (triplet, 3H), 1.51 (triplet, 3H), 2.6 (broad peak, 2H), 2.80 (multiplet, 2H), 2.93 (multiplet, 2H), 3.19 (doublet, 2H), 3.71 (quartet, 2H), 4.11 (multiplet, 1H), 4.29 (quartets, 2H), 4.41 (multiplet, 1H).
Claims (10)
1. the preparation method of formula I 2-((4R, 6R)-6-aminoethyl-2, a 2-dimethyl-1,3-dioxane-4-base) acetic ester,
Wherein, R2 is methyl, ethyl, the tertiary butyl, carbon tetraalkyl or other carbon less than four alkyl;
Comprise step as follows:
(1) synthesis of 2-((4R, 6R)-6-cyanogen methyl-2,2-dimethyl-1,3-dioxane-4-base) acetic ester (VI)
With 3-cyanoacrylate (II) for starting raw material; with 3; 3-dialkoxy propionic ester (III) or 3-alkoxy acrylic ester (IV); in solvent, under Louis acid catalysis effect; in 10-100 DEG C of reaction production V compound; again through hydrolysis deprotection; with the 2-malonaldehydic acid ester that sodium sulfite aqueous solution washing removing is free; water layer toluene extracts; gained organic layer under bronsted acid catalyst effect with acetone or 2,2-dialkoxy propane annulation preparation formula VI compound.
(2) synthesis of formula I
Formula VI compound, in saturated ammonia alcoholic solution, under raney nickel catalyst exists, passes into hydrogen, through hydrogenating reduction cyano group, and obtained formula I;
Reaction formula is as follows:
Wherein: R
1for methyl, ethyl, sec.-propyl, n-propyl, the tertiary butyl, isobutyl-
R
2for methyl, ethyl, the tertiary butyl, carbon tetraalkyl or other carbon less than four alkyl.
2. 2-((4R as claimed in claim 1,6R)-6-aminoethyl-2,2-dimethyl-1,3-dioxane-4-base) preparation method of acetic ester, it is characterized in that 3 described in step (1), 3-dialkoxy propionic ester is selected from 3,3-diethoxy ethyl propionate, 3,3-dimethoxy methyl propionate or 3,3-diethoxy propanoic acid tert-butyl ester, described 3-alkoxy acrylic ester is selected from 3-methoxy acrylic acid ethyl ester, 3-ethoxy ethyl acrylate, the 3-methoxy acrylic acid tert-butyl ester or 3-ethoxy-c enoic acid ter-butyl ester.
3. 2-((4R as claimed in claim 1,6R)-6-aminoethyl-2,2-dimethyl-1,3-dioxane-4-base) preparation method of acetic ester, it is characterized in that in step (1), described lewis acid catalyst, 3,3-dialkoxy propionic esters or 3-alkoxy acrylic ester are (0.05-0.5) with the amount of substance ratio of 3-cyanoacrylate: (2.0-2.5): 1.
4. 2-((4R as claimed in claim 1,6R)-6-aminoethyl-2,2-dimethyl-1,3-dioxane-4-base) preparation method of acetic ester, it is characterized in that solvent described in step (1) is tetrahydrofuran (THF), 2-methyltetrahydrofuran, methoxyl group pentamethylene or toluene.
5. 2-((4R as claimed in claim 1,6R)-6-aminoethyl-2,2-dimethyl-1,3-dioxane-4-base) preparation method of acetic ester, it is characterized in that the temperature of Lewis acid catalyzed reaction in step (1) is 40-75 DEG C; The preferred reaction time is 4-6 hour.
6. 2-((4R as claimed in claim 1,6R)-6-aminoethyl-2,2-dimethyl-1,3-dioxane-4-base) preparation method of acetic ester, it is characterized in that the bronsted acid catalyst described in step (1) is the sulfuric acid of massfraction 98%, Phenylsulfonic acid or p-methyl benzenesulfonic acid.
7. 2-((4R as claimed in claim 1,6R)-6-aminoethyl-2,2-dimethyl-1,3-dioxane-4-base) preparation method of acetic ester, it is characterized in that the amount of substance of step (1) bronsted acid catalyst and 3-cyanoacrylate is than being (0.005-0.1): 1.
8. 2-((4R as claimed in claim 1,6R)-6-aminoethyl-2,2-dimethyl-1,3-dioxane-4-base) preparation method of acetic ester, it is characterized in that in C1-C4 alcohol, passing into ammonia under the saturated ammonia alcoholic solution described in step (2) refers to normal temperature to saturated.
9. 2-((4R as claimed in claim 1,6R)-6-aminoethyl-2,2-dimethyl-1,3-dioxane-4-base) preparation method of acetic ester, it is characterized in that in step (2), in formula VI compound, described catalyzer Raney Ni consumption is 5-30% mass ratio.
10. 2-((4R as claimed in claim 1,6R)-6-aminoethyl-2,2-dimethyl-1,3-dioxane-4-base) preparation method of acetic ester, it is characterized in that the hydrogenating reduction temperature of step (2) is 20-80 DEG C, reaction times 1-12 hour, hydrogen pressure is 10-20 normal atmosphere.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201410404491.6A CN104230880B (en) | 2014-08-15 | 2014-08-15 | The simple and convenient process for preparing of 2-((4R, 6R)-6-aminoethyl-2,2-dimethyl-1,3-dioxane-4-yl) acetic acid esters |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201410404491.6A CN104230880B (en) | 2014-08-15 | 2014-08-15 | The simple and convenient process for preparing of 2-((4R, 6R)-6-aminoethyl-2,2-dimethyl-1,3-dioxane-4-yl) acetic acid esters |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN104230880A true CN104230880A (en) | 2014-12-24 |
| CN104230880B CN104230880B (en) | 2016-05-04 |
Family
ID=52219883
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201410404491.6A Active CN104230880B (en) | 2014-08-15 | 2014-08-15 | The simple and convenient process for preparing of 2-((4R, 6R)-6-aminoethyl-2,2-dimethyl-1,3-dioxane-4-yl) acetic acid esters |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN104230880B (en) |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105153110A (en) * | 2015-09-23 | 2015-12-16 | 河南师范大学 | Synthesis method for chiral intermediate of atorvastatin calcium |
| CN114181188A (en) * | 2021-12-08 | 2022-03-15 | 江苏阿尔法药业股份有限公司 | Non-solvation synthesis method of atorvastatin calcium intermediate |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20050148784A1 (en) * | 2001-12-20 | 2005-07-07 | Inhee Lee | Process for the preparation of optically active 2-[6-substituted alkyl)-1,3-dioxan-4-yl]acetic acid derivatives |
| CN103387560A (en) * | 2013-07-04 | 2013-11-13 | 复旦大学 | Preparation method of 2-[(4R, 6S)-6-substitued methyl-2, 2-dimethyl-1, 3-dioxan]-acetate |
| CN103614430A (en) * | 2013-11-22 | 2014-03-05 | 苏州卫生职业技术学院 | Synthetic method of atorvastatin calcium intermediate |
-
2014
- 2014-08-15 CN CN201410404491.6A patent/CN104230880B/en active Active
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20050148784A1 (en) * | 2001-12-20 | 2005-07-07 | Inhee Lee | Process for the preparation of optically active 2-[6-substituted alkyl)-1,3-dioxan-4-yl]acetic acid derivatives |
| CN103387560A (en) * | 2013-07-04 | 2013-11-13 | 复旦大学 | Preparation method of 2-[(4R, 6S)-6-substitued methyl-2, 2-dimethyl-1, 3-dioxan]-acetate |
| CN103614430A (en) * | 2013-11-22 | 2014-03-05 | 苏州卫生职业技术学院 | Synthetic method of atorvastatin calcium intermediate |
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105153110A (en) * | 2015-09-23 | 2015-12-16 | 河南师范大学 | Synthesis method for chiral intermediate of atorvastatin calcium |
| CN107011314A (en) * | 2015-09-23 | 2017-08-04 | 葛云龙 | The synthetic method of Atorvastatin calcium chiral intermediate |
| CN107011315A (en) * | 2015-09-23 | 2017-08-04 | 葛云龙 | A kind of Atorvastatin calcium chiral intermediate |
| CN114181188A (en) * | 2021-12-08 | 2022-03-15 | 江苏阿尔法药业股份有限公司 | Non-solvation synthesis method of atorvastatin calcium intermediate |
Also Published As
| Publication number | Publication date |
|---|---|
| CN104230880B (en) | 2016-05-04 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN101613341B (en) | Synthetic method of key intermediate of rosuvastatin calcium side chain | |
| CN101624390B (en) | Preparation method of key intermediate of rosuvastatin calcium side chain | |
| CN104370755B (en) | Preparation method for optical activity active 3-amino butanol and optical activity 3-amino butyric acid | |
| JP6487568B2 (en) | Kinetic resolution by catalytic asymmetric hydrogenation of racemic δ-hydroxy ester and its application | |
| CN106365986B (en) | Compound and preparation method thereof and the purposes in synthesis Bu Waxitan | |
| WO2022199378A1 (en) | Synthetic method of bempedoic acid active pharmaceutical ingredient | |
| CN103613498B (en) | The synthetic method of Win-35833 | |
| CN113105319A (en) | Preparation method of biparidic acid | |
| CN110937985B (en) | Synthesis method of paradol | |
| US8912345B2 (en) | Method for preparing optically pure (−)-clausenamide compound | |
| CN103180325B (en) | Prepare the method for β-Artemether | |
| CN104230880A (en) | Simple preparation method of 2-((4R,6R)-6-aminoethyl-2,2-dimethyl-1,3-dioxyhexacyclo-4-yl)acetate | |
| CN107602399B (en) | Preparation method of enkephalinase inhibitor intermediate | |
| CN102557967A (en) | Preparation method of ambroxol hydrochloride | |
| CN103265428B (en) | Method for preparing 4-[(3-halogenate-4-oxo) butyl] benzoic acid | |
| CN102286036A (en) | Synthesis method of rhodioside | |
| CN104909994A (en) | Method for synthesizing ciprofibrate intermediate and the intermediate | |
| CN109265385B (en) | Synthesis process of chiral catalyst | |
| CN108659086A (en) | A kind of synthetic method of Austria's shellfish cholic acid | |
| CN101891716B (en) | Synthesis method of S-beta-hydroxy-gamma-butyrolactone | |
| CN105237340A (en) | Novel synthesis method for 4,4,4-trifluorobutanol | |
| CN107163049B (en) | A kind of preparation method of Entecavir | |
| CN111018928A (en) | Synthetic method and application of gastrodin hemihydrate | |
| CN102153475A (en) | Preparation method for mint derivatives | |
| CN102127061A (en) | Improvement method for preparing 6-fluorin-3,4-dihydro-2H-1-benzopyranyl-2-epoxy ethane |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| C14 | Grant of patent or utility model | ||
| GR01 | Patent grant | ||
| PE01 | Entry into force of the registration of the contract for pledge of patent right | ||
| PE01 | Entry into force of the registration of the contract for pledge of patent right |
Denomination of invention: A simple preparation method of 2 - ((4R, 6R) - 6-aminoethyl-2,2-dimethyl-1,3-dioxane-4-yl) acetate Effective date of registration: 20211130 Granted publication date: 20160504 Pledgee: Zhejiang Commercial Bank Co.,Ltd. Dongying Branch Pledgor: Xinfa pharmaceutical Co.,Ltd. Registration number: Y2021980013546 |