CN1349522A - Salts of 2,2-dimethyl-1,3-dioxide intermediates and process for the prepn. thereof - Google Patents
Salts of 2,2-dimethyl-1,3-dioxide intermediates and process for the prepn. thereof Download PDFInfo
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- CN1349522A CN1349522A CN00807159A CN00807159A CN1349522A CN 1349522 A CN1349522 A CN 1349522A CN 00807159 A CN00807159 A CN 00807159A CN 00807159 A CN00807159 A CN 00807159A CN 1349522 A CN1349522 A CN 1349522A
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- 150000003839 salts Chemical class 0.000 title claims abstract description 25
- 238000000034 method Methods 0.000 title claims description 36
- 239000000543 intermediate Substances 0.000 title description 2
- 150000001875 compounds Chemical class 0.000 claims abstract description 20
- 150000007524 organic acids Chemical class 0.000 claims abstract description 16
- 238000002360 preparation method Methods 0.000 claims abstract description 11
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 69
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 claims description 57
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 39
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 36
- 150000002148 esters Chemical class 0.000 claims description 34
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 32
- 239000000203 mixture Substances 0.000 claims description 23
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 claims description 22
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 18
- IUGYQRQAERSCNH-UHFFFAOYSA-N pivalic acid Chemical compound CC(C)(C)C(O)=O IUGYQRQAERSCNH-UHFFFAOYSA-N 0.000 claims description 14
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 claims description 13
- 239000012043 crude product Substances 0.000 claims description 12
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 10
- 238000006243 chemical reaction Methods 0.000 claims description 10
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 9
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 claims description 9
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 claims description 9
- 125000001931 aliphatic group Chemical group 0.000 claims description 8
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 claims description 8
- 239000002253 acid Substances 0.000 claims description 7
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 6
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 claims description 6
- FERIUCNNQQJTOY-UHFFFAOYSA-N Butyric acid Chemical compound CCCC(O)=O FERIUCNNQQJTOY-UHFFFAOYSA-N 0.000 claims description 6
- OFOBLEOULBTSOW-UHFFFAOYSA-N Malonic acid Chemical compound OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 claims description 6
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 6
- PVNIIMVLHYAWGP-UHFFFAOYSA-N Niacin Chemical compound OC(=O)C1=CC=CN=C1 PVNIIMVLHYAWGP-UHFFFAOYSA-N 0.000 claims description 6
- 150000001732 carboxylic acid derivatives Chemical class 0.000 claims description 6
- -1 cycloalkanes carboxylic acid Chemical class 0.000 claims description 6
- JBDSSBMEKXHSJF-UHFFFAOYSA-N cyclopentanecarboxylic acid Chemical compound OC(=O)C1CCCC1 JBDSSBMEKXHSJF-UHFFFAOYSA-N 0.000 claims description 6
- 239000003960 organic solvent Substances 0.000 claims description 6
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 claims description 6
- NQPDZGIKBAWPEJ-UHFFFAOYSA-N valeric acid Chemical compound CCCCC(O)=O NQPDZGIKBAWPEJ-UHFFFAOYSA-N 0.000 claims description 6
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 claims description 5
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 claims description 5
- 239000012429 reaction media Substances 0.000 claims description 5
- 239000002904 solvent Substances 0.000 claims description 5
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 4
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 4
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 claims description 4
- SRSXLGNVWSONIS-UHFFFAOYSA-N benzenesulfonic acid Chemical compound OS(=O)(=O)C1=CC=CC=C1 SRSXLGNVWSONIS-UHFFFAOYSA-N 0.000 claims description 4
- 239000001530 fumaric acid Substances 0.000 claims description 4
- 235000006408 oxalic acid Nutrition 0.000 claims description 4
- XYHKNCXZYYTLRG-UHFFFAOYSA-N 1h-imidazole-2-carbaldehyde Chemical compound O=CC1=NC=CN1 XYHKNCXZYYTLRG-UHFFFAOYSA-N 0.000 claims description 3
- JUSXLWAFYVKNLT-UHFFFAOYSA-N 2-bromobenzenesulfonic acid Chemical compound OS(=O)(=O)C1=CC=CC=C1Br JUSXLWAFYVKNLT-UHFFFAOYSA-N 0.000 claims description 3
- HNNQYHFROJDYHQ-UHFFFAOYSA-N 3-(4-ethylcyclohexyl)propanoic acid 3-(3-ethylcyclopentyl)propanoic acid Chemical compound CCC1CCC(CCC(O)=O)C1.CCC1CCC(CCC(O)=O)CC1 HNNQYHFROJDYHQ-UHFFFAOYSA-N 0.000 claims description 3
- GWYFCOCPABKNJV-UHFFFAOYSA-M 3-Methylbutanoic acid Natural products CC(C)CC([O-])=O GWYFCOCPABKNJV-UHFFFAOYSA-M 0.000 claims description 3
- TUXYZHVUPGXXQG-UHFFFAOYSA-N 4-bromobenzoic acid Chemical compound OC(=O)C1=CC=C(Br)C=C1 TUXYZHVUPGXXQG-UHFFFAOYSA-N 0.000 claims description 3
- KDVYCTOWXSLNNI-UHFFFAOYSA-N 4-t-Butylbenzoic acid Chemical compound CC(C)(C)C1=CC=C(C(O)=O)C=C1 KDVYCTOWXSLNNI-UHFFFAOYSA-N 0.000 claims description 3
- LSNNMFCWUKXFEE-UHFFFAOYSA-M Bisulfite Chemical compound OS([O-])=O LSNNMFCWUKXFEE-UHFFFAOYSA-M 0.000 claims description 3
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 3
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 claims description 3
- KDYFGRWQOYBRFD-UHFFFAOYSA-N Succinic acid Natural products OC(=O)CCC(O)=O KDYFGRWQOYBRFD-UHFFFAOYSA-N 0.000 claims description 3
- GWYFCOCPABKNJV-UHFFFAOYSA-N beta-methyl-butyric acid Natural products CC(C)CC(O)=O GWYFCOCPABKNJV-UHFFFAOYSA-N 0.000 claims description 3
- KDYFGRWQOYBRFD-NUQCWPJISA-N butanedioic acid Chemical compound O[14C](=O)CC[14C](O)=O KDYFGRWQOYBRFD-NUQCWPJISA-N 0.000 claims description 3
- NPPVRRHAPWWXME-UHFFFAOYSA-N cyclobutane formic acid Chemical compound C(=O)O.C1CCC1 NPPVRRHAPWWXME-UHFFFAOYSA-N 0.000 claims description 3
- YMGUBTXCNDTFJI-UHFFFAOYSA-N cyclopropanecarboxylic acid Chemical compound OC(=O)C1CC1 YMGUBTXCNDTFJI-UHFFFAOYSA-N 0.000 claims description 3
- HCPOCMMGKBZWSJ-UHFFFAOYSA-N ethyl 3-hydrazinyl-3-oxopropanoate Chemical compound CCOC(=O)CC(=O)NN HCPOCMMGKBZWSJ-UHFFFAOYSA-N 0.000 claims description 3
- BDAGIHXWWSANSR-UHFFFAOYSA-N formic acid Substances OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 claims description 3
- 238000010438 heat treatment Methods 0.000 claims description 3
- 150000002762 monocarboxylic acid derivatives Chemical class 0.000 claims description 3
- 239000011664 nicotinic acid Substances 0.000 claims description 3
- 229960003512 nicotinic acid Drugs 0.000 claims description 3
- 235000001968 nicotinic acid Nutrition 0.000 claims description 3
- YNVOMSDITJMNET-UHFFFAOYSA-N thiophene-3-carboxylic acid Chemical group OC(=O)C=1C=CSC=1 YNVOMSDITJMNET-UHFFFAOYSA-N 0.000 claims description 3
- 229940005605 valeric acid Drugs 0.000 claims description 3
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 claims description 2
- 150000004945 aromatic hydrocarbons Chemical class 0.000 claims description 2
- 150000005826 halohydrocarbons Chemical class 0.000 claims description 2
- 150000002825 nitriles Chemical class 0.000 claims description 2
- 239000003921 oil Substances 0.000 claims description 2
- 239000002994 raw material Substances 0.000 claims description 2
- 239000011877 solvent mixture Substances 0.000 claims description 2
- LBLYYCQCTBFVLH-UHFFFAOYSA-N 2-Methylbenzenesulfonic acid Chemical compound CC1=CC=CC=C1S(O)(=O)=O LBLYYCQCTBFVLH-UHFFFAOYSA-N 0.000 claims 1
- 238000006053 organic reaction Methods 0.000 claims 1
- 238000001953 recrystallisation Methods 0.000 abstract description 11
- 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 abstract description 4
- 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 abstract description 4
- 229960005370 atorvastatin Drugs 0.000 abstract description 4
- 239000012450 pharmaceutical intermediate Substances 0.000 abstract description 3
- 239000003524 antilipemic agent Substances 0.000 abstract 1
- 235000005985 organic acids Nutrition 0.000 abstract 1
- HWSHVKNLMBMKSR-GHMZBOCLSA-N tert-butyl 2-[(4r,6r)-6-(2-aminoethyl)-2,2-dimethyl-1,3-dioxan-4-yl]acetate Chemical class CC(C)(C)OC(=O)C[C@H]1C[C@@H](CCN)OC(C)(C)O1 HWSHVKNLMBMKSR-GHMZBOCLSA-N 0.000 abstract 1
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 16
- 239000000047 product Substances 0.000 description 16
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 description 16
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 12
- 229910021529 ammonia Inorganic materials 0.000 description 8
- 238000004458 analytical method Methods 0.000 description 8
- 239000013078 crystal Substances 0.000 description 8
- 239000011541 reaction mixture Substances 0.000 description 8
- 238000001816 cooling Methods 0.000 description 7
- 238000003756 stirring Methods 0.000 description 7
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 6
- 238000004440 column chromatography Methods 0.000 description 6
- 238000004519 manufacturing process Methods 0.000 description 6
- 238000001914 filtration Methods 0.000 description 5
- 238000005194 fractionation Methods 0.000 description 5
- 229950010765 pivalate Drugs 0.000 description 5
- 238000005406 washing Methods 0.000 description 5
- 238000013019 agitation Methods 0.000 description 4
- 238000010992 reflux Methods 0.000 description 4
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 4
- 238000002425 crystallisation Methods 0.000 description 3
- 230000008025 crystallization Effects 0.000 description 3
- 238000000746 purification Methods 0.000 description 3
- 230000008901 benefit Effects 0.000 description 2
- 229960000935 dehydrated alcohol Drugs 0.000 description 2
- 238000001035 drying Methods 0.000 description 2
- 238000001704 evaporation Methods 0.000 description 2
- 230000008020 evaporation Effects 0.000 description 2
- 239000012535 impurity Substances 0.000 description 2
- QPJVMBTYPHYUOC-UHFFFAOYSA-N methyl benzoate Chemical compound COC(=O)C1=CC=CC=C1 QPJVMBTYPHYUOC-UHFFFAOYSA-N 0.000 description 2
- 238000001291 vacuum drying Methods 0.000 description 2
- 238000007738 vacuum evaporation Methods 0.000 description 2
- 125000000022 2-aminoethyl group Chemical group [H]C([*])([H])C([H])([H])N([H])[H] 0.000 description 1
- 230000003321 amplification Effects 0.000 description 1
- 239000000010 aprotic solvent Substances 0.000 description 1
- SRSXLGNVWSONIS-UHFFFAOYSA-M benzenesulfonate Chemical compound [O-]S(=O)(=O)C1=CC=CC=C1 SRSXLGNVWSONIS-UHFFFAOYSA-M 0.000 description 1
- 229940077388 benzenesulfonate Drugs 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 238000009835 boiling Methods 0.000 description 1
- 238000005119 centrifugation Methods 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 229960004756 ethanol Drugs 0.000 description 1
- 238000004817 gas chromatography Methods 0.000 description 1
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 1
- 150000002632 lipids Chemical class 0.000 description 1
- 229940095102 methyl benzoate Drugs 0.000 description 1
- 239000012454 non-polar solvent Substances 0.000 description 1
- 238000003199 nucleic acid amplification method Methods 0.000 description 1
- 239000002798 polar solvent Substances 0.000 description 1
- 238000004321 preservation Methods 0.000 description 1
- 230000002035 prolonged effect Effects 0.000 description 1
- 239000003586 protic polar solvent Substances 0.000 description 1
- 238000011403 purification operation Methods 0.000 description 1
- 210000002966 serum Anatomy 0.000 description 1
- 229940124530 sulfonamide Drugs 0.000 description 1
- 150000003456 sulfonamides Chemical class 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)
- Heterocyclic Compounds That Contain Two Or More Ring Oxygen Atoms (AREA)
- Plural Heterocyclic Compounds (AREA)
- Pyrrole Compounds (AREA)
Abstract
The invention relates to salts of (4R-cis) -(1,1-dimethyl -ethyl) -6-(2-aminoethyl) -2,2-dimethyl -1,3-dioxane -4-acetate of formula (I) formed with organic acids. The new salts according to the invention are stable and can be easily purified by recrystallization. The new salts of the invention are valuable pharmaceutical intermediates which can be used e.g. in the preparation of the hypolipidemic agent having the generic (INN) name atorvastatin. The invention further relates to the preparation of the new salts of the compound of formula (I).
Description
Invention field
The present invention relates to new pharmaceutical intermediate and preparation method thereof.
More particularly, the present invention relates to (4R-is suitable)-6-(2-amino-ethyl)-2,2-dimethyl-1, the salt that 3-dioxane-4-acetate (1,1-dimethyl-ethyl) ester and organic acid form.
Background technology
Formula I's
(4R-is suitable)-6-(2-amino-ethyl)-2,2-dimethyl-1,3-dioxane-4-acetate (1,1-dimethyl-ethyl) ester is important pharmaceutical intermediate, it can be used for preparation example suc as formula shown in the II
International generic name (INN) is that the short serum lipid of atorvastatin reduces reagent.
According to the prior art of preparation I compound, two kinds of methods are known.USP5155251 discloses the described preparation method of reaction scheme A
Reaction scheme A
According to this patent, come the amino-ethyl derivative of preparation formula I by under the condition of 125-135 ℃/0.05Hgmm, carrying out fractionation.Degree of purity of production is not higher than 96%.The shortcoming of this method is that high-vacuum fractionation is a kind of method of purification of complexity, and it just is applicable to industrial-scale production once in a while.
USP5,103,024 and corresponding hungarian patent 213,731 in the method that proposes shown in reaction scheme B.
Reaction scheme B
According to this patent, with the compound of column chromatography purification formula I.The shortcoming of this method is that the investment of column chromatography is big, and difficulty is applicable to plant-scale production especially.The purity of products therefrom is no more than 98.2%.
The shortcoming of above-mentioned two kinds of currently known methodss is, is with fractionated method or all can not make purity with column chromatography is higher than 99% product.
Summary of the invention
The objective of the invention is to overcome the shortcoming of currently known methods, and work out a kind of preparation (4R-is suitable)-6-(2-amino-ethyl)-2,2-dimethyl-1,3-dioxane-4-acetate (1,1-dimethyl-ethyl) short-cut method of ester, this method also more preferably are used for industrial-scale production and can provide purity to be higher than 99% product.
The present invention has realized above-mentioned purpose.
Have now found that, formula I (4R-is suitable)-6-(2-amino-ethyl)-2,2-dimethyl-1, the salt (this salt crystal property excellence) that 3-dioxane-4-acetate (1,1-dimethyl-ethyl) ester and organic acid form is stable and have a high purity.The formula I compound purity of the present invention that exists with salt form is very high, and can change into the atorvastatin shown in the formula II with the purity that meets the pharmacopeia requirement expediently.Advantage of the present invention is to have avoided using high-vacuum fractionation and the column chromatography of using in art methods.
One aspect of the present invention provides (4R-is suitable)-6-(2-amino-ethyl)-2,2-dimethyl-1, the salt that 3-dioxane-4-acetate (1,1-dimethyl-ethyl) ester and organic acid form.
The present invention provides (4R-is suitable)-6-(2-amino-ethyl)-2 on the other hand, 2-dimethyl-1, the preparation method of the salt that 3-dioxane-4-acetate (1,1-dimethyl-ethyl) ester and organic acid form, this method is included in and makes formula I compound and organic acid reaction in the organic solvent.
Detailed Description Of The Invention
The present invention is based on following understanding, that is, formula I compound and organic acid form stable salt.It is particularly startled that this understanding is made us.As everyone knows, according to prior art, ketal is unsettled in the presence of acid.Two hydroxyls of the sulfonamide derivatives of formula I are by the ketal ring protection.Unexpectedly, described ketal group has stability to organic acid under employed reaction conditions.Especially surprisingly, salt of the present invention is not only at room temperature stable, even and still keep stable under comparatively high temps in the process of recrystallization from organic solvent.
The method according to this invention, following acid can be used for the formation of salt: mono carboxylic acid of aliphatic series, dicarboxylic acid or poly carboxylic acid, cycloalkanes carboxylic acid, aliphatic unsaturated carboxylic acid, aromatic carboxylic acid, heterocyclic carboxylic acid or sulfonic acid.
According to the preferred embodiments of the invention, can use following acid: acetate, butyric acid, valeric acid, isovaleric acid, PIVALIC ACID CRUDE (25), oxalic acid, oxysuccinic acid, Succinic Acid, propanedioic acid, citric acid, cyclopropane-carboxylic acid, cyclobutane formate, cyclopentane-carboxylic acid, naphthenic acid, fumaric acid, toxilic acid, phenylformic acid ,-methyl-phenylformic acid, 4-methoxyl group-phenylformic acid, 4-bromo-phenylformic acid, the 4-tertiary butyl-phenylformic acid, Phenylsulfonic acid, methylsulfonic acid, right-methyl-Phenylsulfonic acid, right-the bromo-Phenylsulfonic acid, nicotinic acid (nicotic acid), tetrahydrofuran (THF)-2-formic acid or thiophene-3-formic acid.
The particularly preferred embodiment according to the present invention is used PIVALIC ACID CRUDE (25).
Reaction can be carried out in nonpolar, aprotic, polar or protic solvent.Aliphatic hydrocrbon, aromatic hydrocarbons, halohydrocarbon, ester, nitrile, alcohol or ether can be used as reaction medium.The preferred a kind of solvent that uses in the following solvents: hexane, heptane, sherwood oil, toluene, benzene, dimethylbenzene, methylene dichloride, chloroform, ethyl acetate, acetonitrile, methyl alcohol, ethanol, Virahol, tetrahydrofuran (THF), dioxane or ether.
Solvent mixture also can be used as reaction medium.The preferred mixture that uses heptane and toluene, the mixture of hexane and toluene, the mixture of hexane, toluene and tetrahydrofuran (THF), the mixture of the mixture of heptane, toluene and tetrahydrofuran (THF) or hexane and ether.
The particularly preferred embodiment according to the present invention, formula I compound and organic acid react with the form of solution, and described solution is the solution that forms with same solvent.
Formula I compound and organic acid mol ratio are preferably 0.5-5, and more preferably 0.5-2 is preferably 0.5-1.2 especially.
Preferably at room temperature formula I compound is mixed with organic acid, and reaction can be carried out under heating or room temperature condition.Can be preferably react at the boiling point of reaction mixture.
Reaction mixture can carry out aftertreatment with simple method.Can preferably pass through reaction mixture, after filtration or the salt of the sedimentary formula I compound of centrifugation, come the aftertreatment reaction mixture with organic solvent washing gained salt and drying.Salt can be purified by recrystallization.
According to the inventive method preferred embodiment, with the crude product of formula I compound as reaction raw materials.In this case, avoided formula I compound is carried out expensive and complicated purification operations.
Summary of benefits of the present invention is as follows:
According to the present invention, use the compound of simple recrystallization method purification formula I, to compare with high-vacuum fractionation and column chromatography that currently known methods uses, recrystallization method very easily carries out.
The invention provides the product that purity is higher than art methods.Behind the recrystallization, degree of purity of production＞99% (according to gas-chromatography), behind twice recrystallization, purity＞99.95%.The product purity that obtains with currently known methods is lower than 98%.
Method of the present invention also is easy to carry out with technical scale.The amplification scale can not cause any problem.On the other hand, high-vacuum fractionation and column chromatography need sizable investment, and are difficult to be applicable to plant-scale production.
Formula I compound is stable, and itself and organic acid form after the salt can prolonged preservation and can not decompose.
By the high purity salt of formula I compound of the present invention, can make the atorvastatin that meets the pharmacopeia requirement.
Be described in further detail the present invention with following embodiment, but described embodiment does not limit protection scope of the present invention.
Embodiment 1
(4R-is suitable)-6-(2-amino-ethyl)-2,2-dimethyl-1, the Pivalate of 3-dioxane-4-acetate (1,1-dimethyl-ethyl) ester
With 55g (4R-is suitable)-6-(2-amino-ethyl)-2,2-dimethyl-1, the oily crude product of 3-dioxane-4-acetate (1,1-dimethyl-ethyl) ester are dissolved in 500ml by in 4: 1 blended heptane and the toluene mixture.With 20.6g (201mmol) PIVALIC ACID CRUDE (25) be dissolved in 190ml by in 4: 1 blended heptane and the toluene mixture.Two kinds of solution are mixed and reflux 1 hour.Filtering heat solution is used the frozen water cooling mixture under agitation condition.Leach sedimentary crystal, with the cold mixt washing of heptane and toluene, and dry.Obtain 64.9g (172mmol) target product, yield 86%, fusing point: 131 ℃.
Ultimate analysis: C% H% N%
Theoretical value: 60.77 9.93 3.73
Measured value: 60.77 9.88 3.81
TLC propyl alcohol/ammonia=7: 3, R
f=0.63.
IR(KBr)：2949，1725，1520，1173.
HNMR(DMSO，i400)：4.17(m，1H)，3.98(m，1H)，2.66(m，
2H)，2.36(dd，J1＝4.9Hz，J2＝15.0Hz，1H)，2.22(dd，J1＝8.1
Hz，J2＝15.0Hz，1H)，1.54(m，3H)，1.39(s，12H)，1.24(s，3H)，
1.05(s，9H)，1.03(～t，J＝12.0Hz，1H).
CNMR：180.87，169.77，98.22，79.85，66.50，66.12，42.34，
38.26，37.05，36.44，35.97，30.11，28.03，27.92，19.88.
MS：274(3)，202(57)，200(47)，173(44)，158(50)，57(100)，
41(48)，30(96).
GC content＞99%, diastereomer impurity＜0.7%.
Embodiment 2
(4R-is suitable)-6-(2-amino-ethyl)-2,2-dimethyl-1, the Pivalate of 3-dioxane-4-acetate (1,1-dimethyl-ethyl) ester
With 23.3g through (4R-the is suitable)-6-of primary crystallization (2-amino-ethyl)-2,2-dimethyl-1, the Pivalate of 3-dioxane-4-acetate (1,1-dimethyl-ethyl) ester be dissolved in 220ml by in 4: 1 blended hexanes and the toluene mixture.Heating gained solution is to refluxing, and filtering heat solution is also used the frozen water cooling mixture under agitation condition.Sedimentary crystal is filtered, with cold diethyl ether washing, drying.Obtain the required product of 20.7g, yield 89%, fusing point: 132-133 ℃.
GC content＞99.95%, total impurities＜0.05%.
Embodiment 3
(4R-is suitable)-6-(2-amino-ethyl)-2,2-dimethyl-1, the Pivalate of 3-dioxane-4-acetate (1,1-dimethyl-ethyl) ester
With 21g (4R-is suitable)-6-(2-amino-ethyl)-2,2-dimethyl-1, the oily crude product of 3-dioxane-4-acetate (1,1-dimethyl-ethyl) ester be dissolved in 116ml by in 2: 2: 1 blended hexanes, toluene and the tetrahydrofuran compounds.The PIVALIC ACID CRUDE (25) of 7.6g (201mmol) is dissolved in the mixture of 53ml by 1: 1 blended hexane and toluene.Two kinds of solution are mixed and reflux.Filtering heat solution is used the frozen water cooling mixture under agitation condition.Leach sedimentary crystal, with the cold diethyl ether washing, and dry.Obtain the 21.1g target product, yield 73%, fusing point: 131 ℃.
Embodiment 4
(4R-is suitable)-6-(2-amino-ethyl)-2,2-dimethyl-1, the Pivalate of 3-dioxane-4-acetate (1,1-dimethyl-ethyl) ester
With 24g (87.8mmol) (4R-is suitable)-6-(2-amino-ethyl)-2,2-dimethyl-1, the oily crude product of 3-dioxane-4-acetate (1,1-dimethyl-ethyl) ester be dissolved in 200ml by in 4: 1: 1 blended heptane, toluene and the tetrahydrofuran compounds.With the PIVALIC ACID CRUDE (25) of 9.0g (88mmol) be dissolved in 100ml by in 4: 1: 1 blended heptane, toluene and the tetrahydrofuran compounds.Two kinds of solution are mixed and reflux.Filtering heat solution is used the frozen water cooling mixture under agitation condition.Leach sedimentary crystal, with the cold diethyl ether washing, and dry.Obtain the 29.0g target product, yield 88%, fusing point: 131 ℃.
Embodiment 5
(4R-is suitable)-6-(2-amino-ethyl)-2,2-dimethyl-1, the benzoate of 3-dioxane-4-acetate (1,1-dimethyl-ethyl) ester
With (4R-is suitable)-6-(2-amino-ethyl)-2 of 0.6g (219mmol), 2-dimethyl-1,3-dioxane-4-acetate (1,1-dimethyl-ethyl) ester crude product is dissolved in the 4ml ethyl acetate.With the 0.26g phenylformic acid be dissolved in 8ml by in 1: 1 blended hexane and the ether mixture.Two kinds of solution are mixed and stirring at room 1 hour.The vacuum-evaporation reaction mixture.Resistates from 5ml by recrystallization the mixture of 4: 1 blended hexanes and toluene.After the cooling, leach sedimentary crystal, with cold hexane wash and dry.Obtain the 0.71g target product, yield 82%, fusing point: 113-114 ℃.
Molecular formula: C
21H
33NO
6
Molecular weight: 395.500.
Ultimate analysis: C% H% N%
Theoretical value: 63.78 8.41 3.54
Measured value: 63.74 8.38 3.55
TLC propyl alcohol/ammonia=7: 3, R
f=0.63.
IR(KBr)：2979，1722，1519，1370.
HNMR(CDCl3，g200)：8.39(b，3H)，7.98(～d，J＝7.0Hz，2H)，
7.39(m，3H)，4.13(m，1H)，3.79(m，1H)，2.97(m，2H)，2.23
(m，2H)，1.70(m，2H)，1.43(s，9H)，1.32(s，3H)，1.27(s，3H)，
1.00(m，2H).
Embodiment 6
(4R-is suitable)-6-(2-amino-ethyl)-2,2-dimethyl-1, the maleate of 3-dioxane-4-acetate (1,1-dimethyl-ethyl) ester
With (4R-is suitable)-6-(2-amino-ethyl)-2 of 0.6g (219mmol), 2-dimethyl-1, the oily crude product of 3-dioxane-4-acetate (1,1-dimethyl-ethyl) ester is dissolved in the 6ml ether.0.25g (219mmol) toxilic acid is dissolved in the 4ml ether.Two kinds of solution are mixed and stirring at room.Leach sedimentary crystal after the cooling, with cold hexane wash and dry.Obtain the 0.80g target product, yield 93%, molten point: 87-89 ℃.
Molecular formula: C
18H
31NO
8
Molecular weight: 389.450.
Ultimate analysis: C% H% N%
Theoretical value: 55.51 8.02 3.60
Measured value: 54.70 8.12 3.52
TLC propyl alcohol/ammonia=7: 3, R
f=0.63.
IR(KBr)：3430，2980，1722.
HNMR(CDCl3，i400)：7.97(b，3H)，6.25(s，2H)，4.28(m，1H)，
4.10(m，1H)，3.21(m，2H)，2.40(m，1H)，2.31(m，1H)，1.89
(m，2H)，1.57(m，1H)，1.46(s，3H)，1.44(s，9H)，1.35(s，3H)，
1.27(m，1H).
Embodiment 7
(4R-is suitable)-6-(2-amino-ethyl)-2,2-dimethyl-1, the fumarate of 3-dioxane-4-acetate (1,1-dimethyl-ethyl) ester
With 0.6g (219mmol) (4R-is suitable)-6-(2-amino-ethyl)-2,2-dimethyl-1, the oily crude product of 3-dioxane-4-acetate (1,1-dimethyl-ethyl) ester is dissolved in the 4ml dehydrated alcohol.0.25g (219mmol) fumaric acid is dissolved in the dehydrated alcohol of 10ml.Two kinds of solution are mixed and stirring at room.Evaporation reaction mixture is suspended in resistates in the hexane.After the cooling, leach sedimentary crystal, and from the 2-propyl alcohol recrystallization.Obtain the 0.75g target product, yield 85%, fusing point: 145-148 ℃.
Molecular formula: C
18H
31NO
8
Molecular weight: 389.450.
Ultimate analysis: C% H% N%
Theoretical value: 55.51 8.02 3.60
Measured value: 55.31 8.04 3.55
TLC propyl alcohol/ammonia=7: 3, R
f=0.63.
IR(KBr)：3430，2988，1736，1157.
HNMR(DMSO，g200)：8.52(b，3H)，6.44(s，2H)，4.17(m，1H)，
3.98(m，1H)，2.80(m，2H)，2.36(m，1H)，2.19(m，1H)，1.68
(m，2H)，1.58(m，1H)，1.38(m，12H)，1.24(m，3H)，1.09(m，
1H).
Embodiment 8
(4R-is suitable)-6-(2-amino-ethyl)-2,2-dimethyl-1, methyl-benzoate between 3-dioxane-4-acetate (1,1-dimethyl-ethyl) ester
With (4R-is suitable)-6-(2-amino-ethyl)-2 of 0.6g (219mmol), 2-dimethyl-1, the oily crude product of 3-dioxane-4-acetate (1,1-dimethyl-ethyl) ester is dissolved in the 6ml ether.Methyl-phenylformic acid between 0.3g (219mmol) is dissolved in the 3ml ether.Two kinds of solution are mixed and stirring at room.Evaporation reaction mixture.Resistates is from by recrystallization 5: 1 blended hexanes and the toluene mixture.Obtain the 0.84g target product, yield 92%, fusing point 95-96 ℃.
Molecular formula: C
22H
35NO
6
Molecular weight: 409.527.
Ultimate analysis: C% H% N%
Theoretical value: 64.52 8.61 3.42
Measured value: 64.23 8.64 3.45
TLC propyl alcohol/ammonia=7: 3, R
f=0.63.
IR(KBr)：2977，2200，1722，1367.
HNMR(CDCl3，i400)：8.86(b，3H)，7.79(m，1H)，7.77(m，1H)，
7.24(m，2H)，4.13(m，1H)，3.79(m，1H)，3.02(m，1H)，2.93
(m，1H)，2.37(s，3H)，2.31(m，1H)，2.18(m，1H)，1.71(m，
2H)，1.50(m，1H)，1.43(s，9H)，1.33(s，3H)，1.26(s，3H)，1.00
(m，1H).
Embodiment 9
(4R-is suitable)-6-(2-amino-ethyl)-2,2-dimethyl-1, the benzene sulfonate of 3-dioxane-4-acetate (1,1-dimethyl-ethyl) ester
With 0.6g (219mmol) (4R-is suitable)-6-(2-amino-ethyl)-2,2-dimethyl-1, the oily crude product of 3-dioxane-4-acetate (1,1-dimethyl-ethyl) ester be dissolved in 5ml by in 4: 1 blended hexanes and the toluene mixture.0.34g (219mmol) Phenylsulfonic acid is dissolved in the toluene of 5ml.Two kinds of solution are mixed and stirring at room.The vacuum-evaporation reaction mixture.Resistates is from by recrystallization 5: 1 blended hexanes and the toluene mixture.Obtain the 0.76g target product, yield 80%, fusing point: 96-98 ℃.
Molecular formula: C
20H
33NO
7S.
Molecular weight: 431.553.
Ultimate analysis: C% H% S% N%
Theoretical value: 55.66 7.71 7.43 3.25
Measured value: 54.79 7.73 7.32 3.28
TLC propyl alcohol/ammonia=7: 3, R
f=0.63.
IR(KBr)：3430，2976，1737，1719，1165.
HNMR(CDCl3，i400)：7.90(m，1H)，7.63(m，2H)，7.40(m，
2H)，4.13(m，1H)，3.82(m，1H)，2.98(m，2H)，2.33(m，1H)，
3.21(m，1H)，1.68(m，2H)，1.50(m，1H)，1.44(s，9H)，1.33(s，
3H)，1.27(s，3H)，1.03(m，1H).
Embodiment 10
(4R-is suitable)-6-(2-amino-ethyl)-2,2-dimethyl-1, the acetate of 3-dioxane-4-acetate (1,1-dimethyl-ethyl) ester
With 0.6g (219mmol) (4R-is suitable)-6-(2-amino-ethyl)-2,2-dimethyl-1, the oily crude product of 3-dioxane-4-acetate (1,1-dimethyl-ethyl) ester is dissolved in the 6ml ether.0.131g (219mmol) acetate is dissolved in the ether of 5ml.Two kinds of solution are mixed and stirring at room.Filter out crystallization, use hexane wash, and in room temperature vacuum-drying.Obtain the 0.56g target product, yield 76%, fusing point: 76-77 ℃.
Molecular formula: C
16H
31NO
6
Molecular weight: 333.429.
Ultimate analysis: C% H% N%
Theoretical value: 57.64 9.37 4.20
Measured value: 57.80 9.40 4.09
TLC propyl alcohol/ammonia=7: 3, R
f=0.63.
IR(KBr)：3430，2986，1731，1157.
HNMR(CDCl3，i400)：8.18(b，3H)，4.26(m，1H)，3.97(m，1H)，
2.93(m，2H)，2.43(m，1H)，2.29(m，1H)，1.96(s，3H)，1.80
(m，2H)，1.56(m，1H)，1.44(s，9H)，1.44(s，3H)，1.34(s，3H)，
1.22(m，1H).
Embodiment 11
Two-(4R-is suitable)-6-(2-amino-ethyls)-2,2-dimethyl-1, the oxalate of 3-dioxane-4-acetate (1,1-dimethyl-ethyl) ester
With 0.6g (219mmol) (4R-is suitable)-6-(2-amino-ethyl)-2,2-dimethyl-1, the oily crude product of 3-dioxane-4-acetate (1,1-dimethyl-ethyl) ester is dissolved in the 6ml ether.0.19g (219mmol) oxalic acid is dissolved in the ether of 3ml.Two kinds of solution are mixed and stirring at room.Filter out sedimentary crystallization, use cold hexane wash, and in room temperature vacuum-drying.Obtain the 0.56g target product, yield 80%, fusing point: 76-77 ℃.
Molecular formula: C
30H
56N
2O
12
Molecular weight: 333.429.
Ultimate analysis: C% H% N%
Theoretical value: 56.59 8.86 4.40
Measured value: 56.21 8.38 4.36
TLC propyl alcohol/ammonia=7: 3, R
f=0.63.
IR(KBr)：3430，2982，1739，1575，1161.
HNMR(CDCl3，i400)：8.60(b，3H)，4.24(m，1H)，3.99(m，1H)，
3.00(m，2H)，2.32(m，2H)，1.90(m，2H)，1.54(m，1H)，1.44 (s，9H)，1.41(s，3H)，1.32(s，3H)，1.21(m，1H).
Claims (17)
1. (4R-the is suitable)-6-shown in the formula I (2-amino-ethyl)-2,2-dimethyl-1, the salt that 3-dioxane-4-acetate (1,1-dimethyl-ethyl) ester and organic acid form.
2. the salt that forms of the formula I compound of claim 1 and mono carboxylic acid of aliphatic series, dicarboxylic acid or poly carboxylic acid, cycloalkanes carboxylic acid, aliphatic unsaturated carboxylic acid, aromatic carboxylic acid, heterocyclic carboxylic acid or sulfonic acid.
3. the formula I compound and the acetate of claim 2, butyric acid, valeric acid, isovaleric acid, PIVALIC ACID CRUDE (25), oxalic acid, oxysuccinic acid, Succinic Acid, propanedioic acid, citric acid, cyclopropane-carboxylic acid, cyclobutane formate, cyclopentane-carboxylic acid, naphthenic acid, fumaric acid, toxilic acid, phenylformic acid, between-methyl-phenylformic acid, 4-methoxyl group-phenylformic acid, 4-bromo-phenylformic acid, the 4-tertiary butyl-phenylformic acid, Phenylsulfonic acid, methylsulfonic acid, right-methyl-Phenylsulfonic acid, right-the bromo-Phenylsulfonic acid, nicotinic acid, the salt that tetrahydrofuran (THF)-2-formic acid or thiophene-3-formic acid forms.
4. the salt that forms of the formula I compound of claim 1 and PIVALIC ACID CRUDE (25).
5. (4R-the is suitable)-6-shown in the preparation formula I (2-amino-ethyl)-2,2-dimethyl-1,3 dioxanes-4-acetate (1,1-dimethyl-ethyl) method of the salt of ester, it is included in the organic solvent (4R-the is suitable)-6-(2-amino-ethyl)-2 with formula I, 2-dimethyl-1,3 dioxane-4-acetate (1,1-dimethyl-ethyl) ester and organic reaction.
6. the method for claim 5, it comprises and uses mono carboxylic acid of aliphatic series, dicarboxylic acid or poly carboxylic acid, cycloalkanes carboxylic acid, aliphatic unsaturated carboxylic acid, aromatic carboxylic acid, heterocyclic carboxylic acid or sulfonic acid as organic acid.
7. the method for claim 6, it comprise use acetate, butyric acid, valeric acid, isovaleric acid, PIVALIC ACID CRUDE (25), oxalic acid, oxysuccinic acid, Succinic Acid, propanedioic acid, citric acid, cyclopropane-carboxylic acid, cyclobutane formate, cyclopentane-carboxylic acid, naphthenic acid, fumaric acid, toxilic acid, phenylformic acid ,-methyl-phenylformic acid, 4-methoxyl group-phenylformic acid, 4-bromo-phenylformic acid, the 4-tertiary butyl-phenylformic acid, Phenylsulfonic acid, methylsulfonic acid, to methyl-Phenylsulfonic acid, to bromo-Phenylsulfonic acid, nicotinic acid, tetrahydrofuran (THF)-2-formic acid or thiophene-3-formic acid.
8. the method for claim 7, it comprises the use PIVALIC ACID CRUDE (25).
9. each described method of claim 6-8, it comprises and uses nonpolar, polarity, non-proton or protonic solvent as reaction medium.
10. the method for claim 9, it comprises and uses aliphatic hydrocrbon, aromatic hydrocarbons, halohydrocarbon, ester, nitrile, alcohol or ether as organic solvent.
11. the method for claim 10, it comprises that use hexane, heptane, sherwood oil, toluene, benzene, dimethylbenzene, methylene dichloride, chloroform, ethyl acetate, acetonitrile, methyl alcohol, ethanol, Virahol, tetrahydrofuran (THF), dioxane or ether are as organic solvent.
12. each described method of claim 9-11, it comprises that the use solvent mixture is as reaction medium.
13. the method for claim 12, it mixture that comprises the mixture of mixture, heptane, toluene and tetrahydrofuran (THF) of mixture, hexane, toluene and tetrahydrofuran (THF) of the mixture, hexane and the toluene that use heptane and toluene or hexane and ether is as reaction medium.
14. each described method of claim 5-13, it comprises formula I compound is dissolved in the identical solvent with organic acid, and two kinds of solution are mixed.
15. each described method of claim 5-14, its Chinese style I compound and organic acid mol ratio are 0.5-5, are preferably 0.5-2, are preferably 0.5-1.2 especially.
16. each described method of claim 5-15, it is included under room temperature or the heating condition, preferably reacts at 20-90 ℃.
17. each described method of claim 5-16 is wherein used (4R-is suitable)-6-(2-amino-ethyl)-2,2-dimethyl-1, and 3-dioxane-4-acetate (1,1-dimethyl-ethyl) ester crude product is as reaction raw materials.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| HUP9901526 | 1999-05-06 | ||
| HU9901526A HU227840B1 (en) | 1999-05-06 | 1999-05-06 | Intermediates of atorvastatin synthesis and process for producing them |
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| JP (1) | JP2002544207A (en) |
| KR (1) | KR20020033617A (en) |
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| CA (1) | CA2373077A1 (en) |
| CZ (1) | CZ20013965A3 (en) |
| HK (1) | HK1046271A1 (en) |
| HR (1) | HRP20010846A2 (en) |
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| GB0011120D0 (en) | 2000-05-09 | 2000-06-28 | Avecia Ltd | Process |
| NL1015744C2 (en) | 2000-07-19 | 2002-01-22 | Dsm Nv | Process for the preparation of 2- (6-substituted-1,3-dioxan-4-yl) acetic acid derivatives. |
| WO2002057229A1 (en) * | 2001-01-19 | 2002-07-25 | Biocon India Limited | FORM V CRYSTALLINE [R-(R*,R*)]-2-(4-FLUOROPHENYL)-ß,$G(D)-DIHYDROXY-5-(1-METHYLETHYL)-3-PHENYL-4-[(PHENYLAMINO)CARBONYL]-1H-PYRROLE-1- HEPTANOIC ACID HEMI CALCIUM SALT. (ATORVASTATIN) |
| US7199261B2 (en) | 2001-07-06 | 2007-04-03 | Teva Pharmaceutical Industries Ltd | Process for the preparation of 7-amino syn 3,5-dihydroxy heptanoic acid derivatives via 6-cyano syn 3,5-dihydroxy hexanoic acid derivatives |
| EP1323717A1 (en) | 2001-12-27 | 2003-07-02 | Dsm N.V. | Process for the preparation of 2-(6-Substituted-1,3-Dioxane-4-yL) acetic acid derivatives |
| EP1375493A1 (en) * | 2002-06-17 | 2004-01-02 | Dsm N.V. | Process for the preparation of an dioxane acetic acid ester |
| JP2008533128A (en) | 2005-03-14 | 2008-08-21 | ファイザー・サイエンス・アンド・テクノロジー・アイルランド・リミテッド | Preparation of atorvastatin intermediate using Paal-Knorr condensation |
| WO2007034909A1 (en) * | 2005-09-22 | 2007-03-29 | Kaneka Corporation | Process for production of (3r,5r)-7-amino-3,5-dihydroxyheptanoic acid derivative |
| MX2013002674A (en) | 2010-09-09 | 2013-06-13 | Dsm Sinochem Pharm Bv | Salts of 7-amino-3,5-dihydroxyheptanoic acid esters. |
| CN107949556B (en) | 2015-08-05 | 2021-12-07 | 株式会社Api | Method for producing pitavastatin calcium |
| CN108191813B (en) * | 2017-12-20 | 2020-01-17 | 帕潘纳(北京)科技有限公司 | Preparation method of ketal |
| CN109232354A (en) * | 2018-10-09 | 2019-01-18 | 河南师范大学 | A kind of preparation method of high purity atorvastatin calcium raw material drug |
| CN109232353A (en) * | 2018-10-09 | 2019-01-18 | 河南师范大学 | A kind of preparation method of Atorvastatin calcium condensation product |
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| US5003080A (en) * | 1988-02-22 | 1991-03-26 | Warner-Lambert Company | Process for trans-6-(2-(substituted-pyrrol-1-yl)alkyl)pryan-2-one inhibitors of cholesterol synthesis |
| US5103024A (en) * | 1990-10-17 | 1992-04-07 | Warner-Lambert Company | Process for the synthesis of (4r-cis)-1,1-dimethylethyl 6-cyanomethyl-2,2-dimethyl-1,3-dioxane-4-acetate |
| US5155251A (en) * | 1991-10-11 | 1992-10-13 | Warner-Lambert Company | Process for the synthesis of (5R)-1,1-dimethylethyl-6-cyano-5-hydroxy-3-oxo-hexanoate |
| US5278313A (en) * | 1992-03-27 | 1994-01-11 | E. R. Squibb & Sons, Inc. | Process for the preparation of 1,3-dioxane derivatives useful in the preparation of HMG-COA reductase inhibitors |
| JP3652394B2 (en) * | 1995-01-27 | 2005-05-25 | 高砂香料工業株式会社 | N-substituted-7-amino-5-hydroxy-3-oxoheptanoic acid derivative and process for producing the same |
| HU226465B1 (en) * | 1996-07-29 | 2008-12-29 | Warner Lambert Co | Improved process for the synthesis of protected esters of (s)-3,4-dihydroxybutyric acid |
| DE69910562T2 (en) * | 1998-04-30 | 2004-06-17 | Kaneka Corp. | METHOD FOR PRODUCING DERIVATIVES OF 6-CYANOMETHYL-1,3-DIOXANE-4-ACETIC ACID |
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| EP1178980A1 (en) | 2002-02-13 |
| PL351145A1 (en) | 2003-03-24 |
| HU227840B1 (en) | 2012-05-02 |
| SK15842001A3 (en) | 2002-04-04 |
| CZ20013965A3 (en) | 2002-04-17 |
| AU4600200A (en) | 2000-11-21 |
| HK1046271A1 (en) | 2003-01-03 |
| HU9901526D0 (en) | 1999-07-28 |
| JP2002544207A (en) | 2002-12-24 |
| HUP9901526A2 (en) | 2001-04-28 |
| WO2000068221A1 (en) | 2000-11-16 |
| KR20020033617A (en) | 2002-05-07 |
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