WO2000068221A1 - Salts of 2,2-dimethyl-1,3-dioxane intermediates and process for the preparation thereof - Google Patents
Salts of 2,2-dimethyl-1,3-dioxane intermediates and process for the preparation thereof Download PDFInfo
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- WO2000068221A1 WO2000068221A1 PCT/HU2000/000042 HU0000042W WO0068221A1 WO 2000068221 A1 WO2000068221 A1 WO 2000068221A1 HU 0000042 W HU0000042 W HU 0000042W WO 0068221 A1 WO0068221 A1 WO 0068221A1
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- Prior art keywords
- acid
- dimethyl
- carboxylic acid
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- 150000003839 salts Chemical class 0.000 title claims abstract description 22
- 238000002360 preparation method Methods 0.000 title claims abstract description 10
- 238000000034 method Methods 0.000 title claims description 34
- 239000000543 intermediate Substances 0.000 title description 2
- RPLSBADGISFNSI-UHFFFAOYSA-N 2,2-dimethyl-1,3-dioxane Chemical class CC1(C)OCCCO1 RPLSBADGISFNSI-UHFFFAOYSA-N 0.000 title 1
- 150000001875 compounds Chemical class 0.000 claims abstract description 29
- 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 claims abstract description 22
- 150000007524 organic acids Chemical class 0.000 claims abstract description 16
- 235000005985 organic acids Nutrition 0.000 claims abstract description 9
- 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 63
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 52
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 claims description 22
- 239000000203 mixture Substances 0.000 claims description 19
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 claims description 14
- OFOBLEOULBTSOW-UHFFFAOYSA-N Malonic acid Chemical compound OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 claims description 13
- IUGYQRQAERSCNH-UHFFFAOYSA-N pivalic acid Chemical compound CC(C)(C)C(O)=O IUGYQRQAERSCNH-UHFFFAOYSA-N 0.000 claims description 13
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 12
- -1 aliphatic monocarboxylic acid Chemical class 0.000 claims description 12
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 claims description 11
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 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
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 9
- 239000002253 acid Substances 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
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 claims description 8
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 7
- ZEYHEAKUIGZSGI-UHFFFAOYSA-N 4-methoxybenzoic acid Chemical compound COC1=CC=C(C(O)=O)C=C1 ZEYHEAKUIGZSGI-UHFFFAOYSA-N 0.000 claims description 6
- 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
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 6
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 claims description 6
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 6
- 238000006243 chemical reaction Methods 0.000 claims description 6
- JBDSSBMEKXHSJF-UHFFFAOYSA-N cyclopentanecarboxylic acid Chemical compound OC(=O)C1CCCC1 JBDSSBMEKXHSJF-UHFFFAOYSA-N 0.000 claims description 6
- GPSDUZXPYCFOSQ-UHFFFAOYSA-N m-toluic acid Chemical compound CC1=CC=CC(C(O)=O)=C1 GPSDUZXPYCFOSQ-UHFFFAOYSA-N 0.000 claims description 6
- 239000003960 organic solvent Substances 0.000 claims description 6
- NQPDZGIKBAWPEJ-UHFFFAOYSA-N valeric acid Chemical compound CCCCC(O)=O NQPDZGIKBAWPEJ-UHFFFAOYSA-N 0.000 claims description 6
- 235000006408 oxalic acid Nutrition 0.000 claims description 5
- 239000012429 reaction media Substances 0.000 claims description 5
- 239000005711 Benzoic acid Substances 0.000 claims description 4
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-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
- 229940092714 benzenesulfonic acid Drugs 0.000 claims description 4
- 235000010233 benzoic acid Nutrition 0.000 claims description 4
- 239000001530 fumaric acid Substances 0.000 claims description 4
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 claims description 4
- 239000011976 maleic acid Substances 0.000 claims description 4
- BJEPYKJPYRNKOW-REOHCLBHSA-N (S)-malic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O BJEPYKJPYRNKOW-REOHCLBHSA-N 0.000 claims description 3
- XYHKNCXZYYTLRG-UHFFFAOYSA-N 1h-imidazole-2-carbaldehyde Chemical compound O=CC1=NC=CN1 XYHKNCXZYYTLRG-UHFFFAOYSA-N 0.000 claims description 3
- SMNNDVUKAKPGDD-UHFFFAOYSA-N 2-butylbenzoic acid Chemical compound CCCCC1=CC=CC=C1C(O)=O SMNNDVUKAKPGDD-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
- PXACTUVBBMDKRW-UHFFFAOYSA-N 4-bromobenzenesulfonic acid Chemical compound OS(=O)(=O)C1=CC=C(Br)C=C1 PXACTUVBBMDKRW-UHFFFAOYSA-N 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
- KDYFGRWQOYBRFD-UHFFFAOYSA-N Succinic acid Natural products OC(=O)CCC(O)=O KDYFGRWQOYBRFD-UHFFFAOYSA-N 0.000 claims description 3
- 125000001931 aliphatic group Chemical group 0.000 claims description 3
- BJEPYKJPYRNKOW-UHFFFAOYSA-N alpha-hydroxysuccinic acid Natural products OC(=O)C(O)CC(O)=O BJEPYKJPYRNKOW-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
- 150000001732 carboxylic acid derivatives Chemical class 0.000 claims description 3
- TXWOGHSRPAYOML-UHFFFAOYSA-N cyclobutanecarboxylic acid Chemical compound OC(=O)C1CCC1 TXWOGHSRPAYOML-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
- FPIQZBQZKBKLEI-UHFFFAOYSA-N ethyl 1-[[2-chloroethyl(nitroso)carbamoyl]amino]cyclohexane-1-carboxylate Chemical compound ClCCN(N=O)C(=O)NC1(C(=O)OCC)CCCCC1 FPIQZBQZKBKLEI-UHFFFAOYSA-N 0.000 claims description 3
- 239000001630 malic acid Substances 0.000 claims description 3
- 235000011090 malic acid Nutrition 0.000 claims description 3
- 229940098779 methanesulfonic acid Drugs 0.000 claims description 3
- 239000002904 solvent Substances 0.000 claims description 3
- BDHFUVZGWQCTTF-UHFFFAOYSA-N sulfonic acid Chemical compound OS(=O)=O BDHFUVZGWQCTTF-UHFFFAOYSA-N 0.000 claims description 3
- UJJLJRQIPMGXEZ-UHFFFAOYSA-N tetrahydro-2-furoic acid Chemical compound OC(=O)C1CCCO1 UJJLJRQIPMGXEZ-UHFFFAOYSA-N 0.000 claims description 3
- 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 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
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 claims description 2
- 150000001338 aliphatic hydrocarbons Chemical class 0.000 claims description 2
- 239000000010 aprotic solvent Substances 0.000 claims description 2
- 150000004945 aromatic hydrocarbons Chemical class 0.000 claims description 2
- 150000002148 esters Chemical class 0.000 claims description 2
- 150000008282 halocarbons Chemical class 0.000 claims description 2
- 150000002825 nitriles Chemical class 0.000 claims description 2
- 239000003586 protic polar solvent Substances 0.000 claims description 2
- 239000011877 solvent mixture Substances 0.000 claims description 2
- 239000007858 starting material Substances 0.000 claims description 2
- 239000008096 xylene Substances 0.000 claims description 2
- 238000010792 warming Methods 0.000 claims 1
- 238000001953 recrystallisation Methods 0.000 abstract description 6
- 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
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 16
- 239000011541 reaction mixture Substances 0.000 description 12
- 239000013078 crystal Substances 0.000 description 9
- 229910021529 ammonia Inorganic materials 0.000 description 8
- 238000004458 analytical method Methods 0.000 description 8
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 description 8
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 6
- 238000004440 column chromatography Methods 0.000 description 6
- 238000004821 distillation Methods 0.000 description 5
- 238000001816 cooling Methods 0.000 description 4
- 238000003756 stirring Methods 0.000 description 4
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 4
- 150000007513 acids Chemical class 0.000 description 3
- 238000009835 boiling Methods 0.000 description 3
- 238000010992 reflux Methods 0.000 description 3
- 239000002050 international nonproprietary name Substances 0.000 description 2
- 229960004592 isopropanol Drugs 0.000 description 2
- 238000000746 purification Methods 0.000 description 2
- 125000000022 2-aminoethyl group Chemical group [H]C([*])([H])C([H])([H])N([H])[H] 0.000 description 1
- 150000001242 acetic acid derivatives Chemical class 0.000 description 1
- 150000001412 amines Chemical class 0.000 description 1
- 150000008107 benzenesulfonic acids Chemical class 0.000 description 1
- 150000001558 benzoic acid derivatives Chemical class 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 238000005119 centrifugation Methods 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 238000011109 contamination Methods 0.000 description 1
- 238000000354 decomposition reaction Methods 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 238000004508 fractional distillation Methods 0.000 description 1
- 238000004817 gas chromatography Methods 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 1
- 239000012535 impurity Substances 0.000 description 1
- 150000002689 maleic acids Chemical class 0.000 description 1
- 229950010765 pivalate Drugs 0.000 description 1
- KUTWWYHQRQQJSM-NDXYWBNTSA-N tert-butyl 2-[(4r,6r)-6-(2-aminoethyl)-2,2-dimethyl-1,3-dioxan-4-yl]acetate;2,2-dimethylpropanoic acid Chemical compound CC(C)(C)C(O)=O.CC(C)(C)OC(=O)C[C@H]1C[C@@H](CCN)OC(C)(C)O1 KUTWWYHQRQQJSM-NDXYWBNTSA-N 0.000 description 1
- 238000005406 washing Methods 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
Definitions
- This invention relates to new pharmaceutical intermediates and a process for the preparation thereof.
- the invention relates more particularly to salts of (4R- -cis)-(1 , 1 -dimethyl-ethyl)-6-(2-aminoethyl)-2,2-dimethyl-1 ,3- -dioxane-4-acetate formed with organic acids.
- the aminoethyl derivative of the Formula I is prepared by fractionated distillation carried out at 125-135°C/0.05 Hgmm.
- the purity of the product is not higher than 96 %.
- the disadvantage of this process is that fractionated distillation in high vacuo is a complicated purification method which is only circumstantially feasible on industrial scale.
- reaction scheme B The process set forth in US patent No. 5,103,024 and the corresponding Hungarian patent No. 213,731 is shown on reaction scheme B.
- the compound of the Formula I is purified by column chromatography.
- the drawback of this process is that column chromatography requires large investments and is but difficultly feasible, particularly on industrial scale.
- the purity of the product obtained does not exceed 98.2 %.
- the present invention is based on the recognition that the compound of the Formula I forms stable salts with organic acids. This recognition is so much the more surprising as it is known from prior art that ketales are instable in the presence of acids.
- the two hydroxy groups of the amine derivative of the Formula I are protected by a ketale ring. It was unforeseen that said ketale group would be resistant to organic acids under the reaction conditions used.
- the salts of the present invention are not only stable at room temperature but remain stable even during recrystallization from an organic solvent carried out at higher temperature.
- the following acids may be used for salt formation: an aliphatic monocarboxylic acid, dicarboxylic acid or polycarboxylic acid, cycloalkane carboxylic acid, aliphatic unsaturated carboxylic acid, aromatic carboxylic acid, heterocyclic carboxylic acid or sulphonic acid.
- the following acids are used: acetic acid, butyric acid, valeric acid, isovaleric acid, pivalic acid, oxalic acid, malic acid, succinic acid, malonic acid, citric acid, cyclopropane carboxylic acid, cyclobutane carboxylic acid, cyclopentane carboxylic acid, cyclohexane carboxylic acid, fumaric acid, maleic acid, benzoic acid, m-methyl-benzoic acid, 4-methoxy-benzoic acid, 4-bromo- -benzoic acid, 4-tert.
- butyl-benzoic acid benzenesulfonic acid, methanesulfonic acid, p-methyl-benzenesulfonic acid, p-bromo- -benzenesulfonic acid, nicotic acid, tetrahydrofurane-2- -carboxylic acid or tiophen-3-carboxylic acid.
- pivalic acid is used.
- the reaction may be carried out in an apolar, dipolar aprotic or protic solvent.
- an aliphatic hydrocarbon, aromatic hydrocarbon, halogenated hydrocarbon, ester, nitrile, alcohol or ether may be used. It is preferred to use one of the following solvents: hexane, heptane, petrolether, toluene, benzene, xylene, dichloro methane, chloroform, ethyl acetate, acetonitrile, methanol, ethanol, isopropanol, tetrahydrofurane, dioxane or diethyl ether.
- a solvent mixture may also be used as reaction medium. It is preferred to use a mixture of heptane and toluene; hexane and toluene; hexane, toluene and tetrahydrofurane; heptane, toluene and tetrahydrofurane; or hexane and diethyl ether.
- the compound of the Formula I and the organic acid are reacted in the form of solutions formed with the same solvent.
- the compound of the Formula I and the organic acid in a molar ratio of 0.5-5, preferably 0.5-2, particularly preferably 0.5-1.2.
- the compound of the Formula I and the organic acid are admixed preferably at room temperature and the reaction may be performed under heating or at room temperature. One may preferably work at the boiling point of the reaction mixture.
- the reaction mixture may be worked up by simple methods. One may proceed preferably by cooling the reaction mixture, isolating the precipitated salt of the compound of the Formula I by filtration or centrifugation, washing the salt with an organic solvent and drying.
- the salt may be purified by recrystallization.
- a crude compound of the Formula I is used as starting material. In this case the expensive and complicated purification of the compound of the Formula I is eliminated.
- the compound of the Formula I is purified by simple recrystallization which can be carried out significantly easier than fractionated distillation performed in high vacuo and column chromatography used in the known methods.
- the present invention provides a product of higher purity than the prior art methods. After a single recrystallization step the purity of the product is > 99 % (according to gas chromatography), after two-fold recrystallization the purity amounts to > 99.95 %. The purity of the product obtained by known methods is lower than 98 %.
- the process of the present invention can be easily carried out on industrial scale too.
- the scaling-up causes no problems.
- the fractionated distillation performed in high vacuo and column chromatography requires considerable investments and is but difficultly feasible on industrial scale.
- the compound of the Formula I is stable and can be stored for a long period of time without decomposition in the form of salts formed with organic acids.
- atorvastatin meeting the requirements of Pharmacopoeia can be prepared.
- Example 1 Further details of the present invention are to be found in the following Examples without limiting the scope of protection to said Examples.
- Example 1
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
WO 00/68221 PCTtHUOO/00042
SALTS OF 2 ,2-DIMETHYL-l ,3-DI0XANE INTERMEDIATES AND PROCESS FOR THE PREPARATION THEREOF
FIELD OF THE INVENTION
This invention relates to new pharmaceutical intermediates and a process for the preparation thereof.
The invention relates more particularly to salts of (4R- -cis)-(1 , 1 -dimethyl-ethyl)-6-(2-aminoethyl)-2,2-dimethyl-1 ,3- -dioxane-4-acetate formed with organic acids. TECHNICAL BACKGROUND
The (4R-cis)-(1 , 1 -dimethyl-ethyl)-6-(2-aminoethyl)-2,2- -dimethyl-1 ,3-dioxane-4-acetate of the Formula
Two methods are known from prior art for the preparation of the compound of the Formula I. The process disclosed in US patent No. 5,155,251 is disclosed on reaction scheme A.
The process set forth in US patent No. 5,103,024 and the corresponding Hungarian patent No. 213,731 is shown on reaction scheme B.
\\/
The disadvantage of the above two known processes is that a product having a purity higher than 99 % can be prepared neither by means of fractional distillation nor by column chromatography. ESSENCE OF THE INVENTION
It is the object of the present invention to overcome the drawbacks of the known processes and to elaborate a simple process for the preparation of (4R-cis)-(1 ,1-dimethyl-ethyl)-6- -(2-aminoethyl)-2,2-dimethyl-1 ,3-dioxane-4-acetate which is preferably feasible on industrial scale too and provides a product having a purity above 99 %.
The above object is solved by the present invention.
It has been found that (4R-cis)-(1 ,1-dimethyl-ethyl)-6-(2- -aminoethyl)-2,2-dimethyl-1 ,3-dioxane-4-acetate of the Formula I forms with organic acids salts which can be excellently crystallized, are stable and of high purity. The invention compound of the Formula I being in salt form is extremely pure and can be advantageously converted into atorvastatin of the Formula II having a purity which meets the requirements of Pharmacopoeia. The advantage of the present invention is that fractionated distillation carried out in high vacuo and
column chromatography used in prior art methods are eliminated.
According to an aspect of the present invention there are provided salts of (4R-cis)-(1 ,1-dimethyl-ethyl)-6-(2- -aminoethyl)-2,2-dimethyl-1 ,3-dioxane-4-acetate formed with organic acids.
According to a further aspect of the invention there is provided a process for the preparation of salts of (4R-cis)-(1 ,1- -dimethyl-ethyl)-6-(2-aminoethyl)-2,2-dimethyl-1 ,3-dioxane-4- -acetate formed with organic acids which comprises reacting the compound of the Formula I with an organic acid in an organic solvent. DETAILS OF THE INVENTION
The present invention is based on the recognition that the compound of the Formula I forms stable salts with organic acids. This recognition is so much the more surprising as it is known from prior art that ketales are instable in the presence of acids. The two hydroxy groups of the amine derivative of the Formula I are protected by a ketale ring. It was unforeseen that said ketale group would be resistant to organic acids under the reaction conditions used. It is particularly surprising that the salts of the present invention are not only stable at room temperature but remain stable even during recrystallization from an organic solvent carried out at higher temperature.
According to the process of the present invention the following acids may be used for salt formation: an aliphatic monocarboxylic acid, dicarboxylic acid or polycarboxylic acid,
cycloalkane carboxylic acid, aliphatic unsaturated carboxylic acid, aromatic carboxylic acid, heterocyclic carboxylic acid or sulphonic acid.
According to a preferred embodiment of our invention the following acids are used: acetic acid, butyric acid, valeric acid, isovaleric acid, pivalic acid, oxalic acid, malic acid, succinic acid, malonic acid, citric acid, cyclopropane carboxylic acid, cyclobutane carboxylic acid, cyclopentane carboxylic acid, cyclohexane carboxylic acid, fumaric acid, maleic acid, benzoic acid, m-methyl-benzoic acid, 4-methoxy-benzoic acid, 4-bromo- -benzoic acid, 4-tert. butyl-benzoic acid, benzenesulfonic acid, methanesulfonic acid, p-methyl-benzenesulfonic acid, p-bromo- -benzenesulfonic acid, nicotic acid, tetrahydrofurane-2- -carboxylic acid or tiophen-3-carboxylic acid.
According to a particularly preferred embodiment of our invention pivalic acid is used.
The reaction may be carried out in an apolar, dipolar aprotic or protic solvent. As reaction medium an aliphatic hydrocarbon, aromatic hydrocarbon, halogenated hydrocarbon, ester, nitrile, alcohol or ether may be used. It is preferred to use one of the following solvents: hexane, heptane, petrolether, toluene, benzene, xylene, dichloro methane, chloroform, ethyl acetate, acetonitrile, methanol, ethanol, isopropanol, tetrahydrofurane, dioxane or diethyl ether.
A solvent mixture may also be used as reaction medium. It is preferred to use a mixture of heptane and toluene; hexane
and toluene; hexane, toluene and tetrahydrofurane; heptane, toluene and tetrahydrofurane; or hexane and diethyl ether.
According to a particularly preferred embodiment of our invention the compound of the Formula I and the organic acid are reacted in the form of solutions formed with the same solvent.
It is preferred to use the compound of the Formula I and the organic acid in a molar ratio of 0.5-5, preferably 0.5-2, particularly preferably 0.5-1.2.
The compound of the Formula I and the organic acid are admixed preferably at room temperature and the reaction may be performed under heating or at room temperature. One may preferably work at the boiling point of the reaction mixture.
The reaction mixture may be worked up by simple methods. One may proceed preferably by cooling the reaction mixture, isolating the precipitated salt of the compound of the Formula I by filtration or centrifugation, washing the salt with an organic solvent and drying. The salt may be purified by recrystallization.
According to a preferred embodiment of the process according to the present invention as starting material a crude compound of the Formula I is used. In this case the expensive and complicated purification of the compound of the Formula I is eliminated.
The advantages of the present invention may be summarized as follows:
According to the present invention the compound of the Formula I is purified by simple recrystallization which can be carried out significantly easier than fractionated distillation performed in high vacuo and column chromatography used in the known methods.
The present invention provides a product of higher purity than the prior art methods. After a single recrystallization step the purity of the product is > 99 % (according to gas chromatography), after two-fold recrystallization the purity amounts to > 99.95 %. The purity of the product obtained by known methods is lower than 98 %.
The process of the present invention can be easily carried out on industrial scale too. The scaling-up causes no problems. On the other hand the fractionated distillation performed in high vacuo and column chromatography requires considerable investments and is but difficultly feasible on industrial scale.
The compound of the Formula I is stable and can be stored for a long period of time without decomposition in the form of salts formed with organic acids.
From the high purity salts of the compound of the Formula I according to the present invention atorvastatin meeting the requirements of Pharmacopoeia can be prepared.
Further details of the present invention are to be found in the following Examples without limiting the scope of protection to said Examples.
Example 1
Pivalate of (4R-cisH1 ,1-dimethyl-ethylV6-.2-aminoethyl)-2.2- -dimethyl-1 ,3-dioxane-4-acetate
55 g of crude oily (4R-cis)-(1 ,1-dimethyl-ethyl)-6-(2- -aminoethyl)-2,2-dimethyl-1 ,3-dioxane-4-acetate are dissolved in 500 ml of a 4:1 mixture of heptane and toluene. 20.6 g (201 millimoles) of pivalic acid are dissolved in 190 ml of a 4:1 mixture of heptane and toluene. The two solutions are admixed and the reaction mixture is refluxed for an hour. The hot solution is filtered and the mixture is cooled with icecold water under stirring. The precipitated crystals are filtered, washed with a cold mixture of heptane and toluene and dried. Thus 64.9 g (172 millimoles) of the desired compound are obtained, yield 86 %, mp.: 131 °C.
Elementary analysis: for C% H% N% calc: 60.77 9.93 3.73 found: 60.77 9.88 3.81
TLC propanol/ammonia = 7:3, Rf = 0.63 IR (KBr): 2949, 1725, 1520, 1173.
HNMR (DMSO, i400): 4.17 (m, 1 H), 3.98 (m, 1 H), 2.66 (m, 2H), 2.36 (dd, J1=4.9 Hz, J2=15.0 Hz, 1 H), 2.22 (dd, J1=8.1 Hz, J2=15.0 Hz, 1 H), 1.54 (m, 3H), 1.39 (s, 12H), 1.24 (s, 3H), 1.05 (s, 9H), 1.03 (~t, J=12.0 Hz, 1 H).
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 contamination < 0.7%.
Example 2
Pivalic acid salt of ,4R-cisH1.1-dimethyl-ethyl)-6-(2-
-aminoethyl)-2,2-dimethyl-1 ,3-dioxane-4-acetate
23.3 g of one recrystallized (4R-cis)-(1 ,1-dimethyl- -ethyl)-6-(2-aminoethyl)-2,2-dimethyl-1 ,3-dioxane-4-acetate pivalic acid salt are dissolved in 220 ml of a 4:1 mixture of hexane and toluene. The solution is heated to reflux, the hot solution is filtered and the mixture is cooled with icecold water under stirring. The precipitated crystals are filtered, washed with cold diethyl ether and dried. Thus 20.7 g of the desired product are obtained, yield 89 %, mp.: 132-133°C. GC content > 99.95 %; total impurities < 0.05 %. Example 3
Pivalic acid salt of (4R-cis)-(1 ,1-dimethyl-ethyl)-6-(2- -aminoethyl)-2,2-dimethyl-1 ,3-dioxane-4-acetate
21 g of crude oily (4R-cis)-(1 ,1-dimethyl-ethyl)-6-(2- -aminoethyl)-2,2-dimethyl-1 ,3-dioxane-4-acetate are dissolved in 116 ml of a 2:2:1 mixture of hexane, toluene and tetrahydrofurane. 7.6 g (201 millimoles) of pivalic acid are dissolved in 53 ml of a 1 :1 mixture of hexane and toluene. The two solutions are admixed and the reaction mixture is heated to boiling under reflux. The hot solution is filtered and the mixture is cooled with icecold water under stirring. The precipitated crystals are filtered, washed with cold diethyl ether and dried. Thus 21.1 g of the desired product are obtained. Yield 73 %, mp.: 131 °C.
Example 4
Pivalic acid salt of (4R-cisV(1 ,1-dimethyl-ethvh-6-(2- -aminoethyl)-2,2-dimethyl-1 ,3-dioxane-4-acetate
24 g (87.8 millimoles) of crude oily (4R-cis)-(1 ,1- -dimethyl-ethyl)-6-(2-aminoethyl)-2,2-dimethyl-1 ,3-dioxane-4- -acetate are dissolved in 200 ml of a 4:1 :1 mixture of heptane, toluene and tetrahydrofurane. 9.0 g (88 millimoles) of pivalic acid are dissolved in 100 ml of a 4:1 :1 mixture of heptane, toluene and tetrahydrofurane. The two solutions are admixed and the reaction mixture is heated to boiling under reflux. The hot solution is filtered and the mixture is cooled with icecold water under stirring. The precipitated crystals are filtered, washed with cold diethyl ether and dried. Thus 29.0 g of the desired compound are obtained, yield 88 %, mp.: 131°C. Example 5
Benzoic acid salt of (4R-cis)-(1.1-dimethyl-ethylV6-,2- -aminoethyl)-2,2-dimethyl-1 ,3-dioxane-4-acetate
0.6 g (219 millimoles) of crude (4R-cis)-(1 ,1-dimethyl- -ethyl)-6-(2-aminoethyl)-2,2-dimethyl-1 ,3-dioxane-4-acetate are dissolved in 4 ml of ethyl acetate. 0.26 g of benzoic acid are dissolved in 8 ml of a 1 :1 mixture of hexane and diethyl ether. The two solutions are admixed and stirred at room temperature for an hour. The reaction mixture is evaporated in vacuo. The residue is recrystallized from 5 ml of a 4:1 mixture of hexane and toluene. After cooling the precipitated crystals are filtered, washed with cold hexane and dried. Thus 0.71 g
of the desired compound are obtained, yield 82 %, mp.:
113-114°C.
Formula: C2-|H33NO6
Molecular weight: 395.500
Elementary analysis: for C% H% N% calc: 63.78 8.41 3.54 found: 63.74 8.38 3.55
TLC propanol/ammonia =7:3 Rf =0.63
IR (KBr): 2979, 1722, 1519, 1370.
HNMR (CDCI3, g200): 8.39 (b, 3H), 7.98 (~d, J=7.0 Hz, 2H),
7.39 (m, 3H), 4.13 (m, 1 H), 3.79 (m, 1 H), 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).
Example 6
Maleic acid salt of (4R-cisH1.1-dimethyl-ethyl)-6-(2-
-aminoethyl)-2,2-dimethyl-1 ,3-dioxane-4-acetate
0.6 g (219 millimoles) of crude oily (4R-cis)-(1 ,1- -dimethyl-ethyl)-6-(2-aminoethyl)-2,2-dimethyl-1 ,3-dioxane-4- -acetate are dissolved in 6 ml of diethyl ether. 0.25 g (219 millimoles) of maleic acid are dissolved in 4 ml of diethyl ether. The two solutions are admixed and stirred at room temperature. After cooling the precipitated crystals are filtered, washed with cold hexane and dried. Thus 0.80 g of the desired compound are obtained, yield 93 %, mp.: 87-89°C. Formula: Cι8H31N08 Molecular weight: 389.450
Elementary analysis: for C% H% N% calc: 55.51 8.02 3.60 found: 54.70 8.12 3.52
TLC propanol/ammonia =7:3 Rf =0.63
IR (KBr):3430, 2980, 1722.
HNMR (CDCI3, i400): 7.97 (b, 3H), 6.25 (s, 2H), 4.28 (m, 1 H),
4.10 (m, 1 H), 3.21 (m, 2H), 2.40 (m, 1 H), 2.31 (m, 1 H), 1.89
(m, 2H), 1.57 (m, 1 H), 1.46 (s, 3H), 1.44 (s, 9H), 1.35 (s, 3H),
1.27 (m, 1 H).
Example 7
Fumaric acid salt of (4R-cis)-(1 ,1-dimethyl-ethvD-6-(2-
-aminoethyl)-2,2-dimethyl-1 ,3-dioxane-4-acetate
0.6 g (219 millimoles) of crude oily (4R-cis)-(1 ,1- -dimethyl-ethyl)-6-(2-aminoethyl)-2,2-dimethyl-1 ,3-dioxane-4- -acetate are dissolved in 4 ml of anhydrous ethanol. 0.25 g (219 millimoles) of fumaric acid are dissolved in 10 ml of anhydrous ethanol. The two solutions are admixed and stirred at room temperature. The reaction mixture is evaporated and the residue is suspended in hexane. After cooling the precipitated crystals are filtered and recrystallized from 2- propanol. Thus 0.75 g of the desired compound are obtained, yield 85 %, mp.: 145-148°C. Formula: CιβH3ιNθ8 Molecular weight: 389.450
Elementary analysis: for C% H% N% calc: 55.51 8.02 3.60 found: 55.31 8.04 3.55
TLC propanol/ammonia =7:3 Rf =0.63
IR (KBr): 3430, 2988, 1736, 1157.
HNMR (DMSO, g200): 8.52 (b, 3H), 6.44 (s, 2H), 4.17 (m, 1 H),
3.98 (m, 1 H), 2.80 (m, 2H), 2.36 (m, 1 H), 2.19 (m, 1 H), 1.68
(m, 2H), 1.58 (m, 1 H), 1.38 (m, 12H), 1.24 (m, 3H), 1.09 (m,
1 H).
Example 8
Meta-methyl-benzoic acid salt of (4R-cis)-, 1 ,1-dimethyl-ethvD-
-6-(2-aminoethyl)-2l2-dimethyl-1 ,3-dioxane-4-acetate
0.6 g (219 millimoles) of crude oily (4R-cis)-(1 ,1- -dimethyl-ethyl)-6-(2-aminoethyl)-2,2-dimethyl-1 ,3-dioxane-4- -acetate are dissolved in 6 ml of diethyl ether. 0.3 g (219 millimoles) of meta-methyl-benzoic acid are dissolved in 3 ml of diethyl ether. The two solutions are admixed and stirred at room temperature. The reaction mixture is evaporated and the residue is crystallized from a 5:1 mixture of hexane and toluene. Thus 0.84 g of the desired compound are obtained, yield 92 %, mp.: 95-96°C. Formula: C22H3δN06 Molecular weight: 409.527 Elementary analysis: for C% H% N% calc: 64.52 8.61 3.42 found: 64.23 8.64 3.45
TLC propanol/ammonia =7:3 Rf =0.63 IR (KBr): 2977, 2200, 1722, 1367.
HNMR (CDCI3, i400): 8.86 (b, 3H), 7.79 (m, 1 H), 7.77 (m, 1 H), 7.24 (m, 2H), 4.13 (m, 1 H), 3.79 (m, 1 H), 3.02 (m, 1 H), 2.93
(m, 1H), 2.37 (s, 3H), 2.31 (m, 1 H), 2.18 (m, 1H), 1.71 (m,
2H), 1.50 (m, 1 H), 1.43 (s, 9H), 1.33 (s, 3H), 1.26 (s, 3H), 1.00
(m, 1H).
Example 9
Benzenesulfonic acid salt of (4R-cis)-(1 ,1-dimethyl-ethyl)-6-,2-
-aminoethyl)-2,2-dimethyl-1 ,3-dioxane-4-acetate
0.6 g (219 millimoles) of crude oily (4R-cis)-(1 ,1- -dimethyl-ethyl)-6-(2-aminoethyl)-2,2-dimethyl-1 ,3-dioxane-4- -acetate are dissolved in 5 ml of a 4:1 mixture of hexane and toluene. 0.34 g (219 millimoles) of benzenesulfonic acid are dissolved in 5 ml of toluene. The two solutions are admixed. The reaction mixture is stirred at room temperature and evaporated in vacuo. The residue is recrystallized from a 5:1 mixture of hexane and toluene. Thus 0.76 g of the desired compound are obtained, yield 80 %, mp.: 96-98°C. Formula: C2oH33NO S Molecular weight: 431.553 Elementary analysis: for C% H% s% N% calc: 55.66 7.71 7.43 3.25 found: 54.79 7.73 7.32 3.28
TLC propanol/ammonia =7:3 Rf =0.63 IR (KBr): 3430, 2976, 1737, 1719, 1165. HNMR (CDCI3, i400): 7.90 (m, 1H), 7.63 (m, 2H), 7.40 (m, 2H), 4.13 (m, 1 H), 3.82 (m, 1 H), 2.98 (m, 2H), 2.33 (m, 1 H), 3.21 (m, 1H), 1.68 (m, 2H), 1.50 (m, 1 H), 1.44 (s, 9H), 1.33 (s, 3H), 1.27 (s, 3H), 1.03 (m, 1 H).
Example 10
Acetic acid salt of .4R-cisH1 ,1-dimethyl-ethyl)-6-,2- -aminoethyl)-2,2-dimethyl-1 ,3-dioxane-4-acetate
0.6 g (219 millimoles) of crude oily (4R-cis)-(1 ,1- -dimethyl-ethyl)-6-(2-aminoethyl)-2,2-dimethyl-1 ,3-dioxane-4- -acetate are dissolved in 6 ml of diethyl ether. 0.131 g (219 millimoles) of acetic acid are dissolved in 5 ml of diethyl ether. The two solutions are admixed. The reaction mixture is stirred at room temperature. The crystals are filtered, washed with hexane and dried at room temperature in vacuo. Thus 0.56 g of the desired compound are obtained, yield 76 %, mp.: 76- 77°C.
Formula: Ci6H3ιNO6 Molecular weight: 333.429 Elementary analysis: for C% H% N% calc: 57.64 9.37 4.20 found: 57.80 9.40 4.09
TLC propanol/ammonia =7:3 Rf =0.63 IR (KBr): 3430, 2986, 1731 , 1157.
HNMR (CDCI3, i400): 8.18 (b, 3H), 4.26 (m, 1 H), 3.97 (m, 1 H), 2.93 (m, 2H), 2.43 (m, 1 H), 2.29 (m, 1 H), 1.96 (s, 3H), 1.80 (m, 2H), 1.56 (m, 1 H), 1.44 (s, 9H), 1.44 (s, 3H), 1.34 (s, 3H), 1.22 (m, 1 H).
Example 11
Bis-(4R-cis)-(1 ,1-dimethyl-ethyl)-6-(2-aminoethyl)-2,2-dimethyl- -1.3-dioxane-4-acetate oxalic acid salt
0.6 g (219 millimoles) of crude oily (4R-cis)-(1 ,1- -dimethyl-ethyl)-6-(2-aminoethyl)-2,2-dimethyl-1 ,3-dioxane-4- -acetate are dissolved in 6 ml of diethyl ether. 0.19 g (219 millimoles) of oxalic acid are dissolved in 3 ml of diethyl ether. The two solutions are admixed. The reaction mixture is stirred at room temperature. The precipitated crystals are filtered, washed with cold hexane and dried at room temperature in vacuo. Thus 0.56 g of the desired compound are obtained, yield 80 %, mp.: 76-77°C. Formula: C30H56N2O12 Molecular weight: 333.429 Elementary analysis: for C% H% N% calc: 56.59 8.86 4.40 found: 56.21 8.38 4.36
TLC propanol/ammonia =7:3 RF =0.63 IR (KBr): 3430, 2982, 1739, 1575, 1161. HNMR (CDCI3, i400): 8.60 (b, 3H), 4.24 (m, 1 H), 3.99 (m, 1 H), 3.00 (m, 2H), 2.32 (m, 2H), 1.90 (m, 2H), 1.54 (m, 1 H), 1.44 (s, 9H), 1.41 (s, 3H), 1.32 (s, 3H), 1.21 (m, 1 H).
Claims
1. Salts of (4R-cis)-(1 ,1-dimethyl-ethyl)-6-(2-amino- -ethyl)-2,2-dimethyl-1 ,3-dioxane-4-acetate of the Formula
formed with organic acids.
2. Salts of the compound of the Formula I according to Claim 1 formed with an aliphatic monocarboxylic acid, dicarboxylic acid or polycarboxylic acid, cycloalkane carboxylic acid, aliphatic unsaturated carboxylic acid, aromatic carboxylic acid, heterocyclic carboxylic acid or sulphonic acid.
3. Salts of the compound of the Formula I according to Claim 2 formed with acetic acid, butyric acid, valeric acid, isovaleric acid, pivalic acid, oxalic acid, malic acid, succinic acid, malonic acid, citric acid, cyclopropane carboxylic acid, cyclobutane carboxylic acid, cyclopentane carboxylic acid, cyclohexane carboxylic acid, fumaric acid, maleic acid, benzoic acid, m-methyl-benzoic acid, 4-methoxy-benzoic acid, 4-bromo-benzoic acid, 4-tert. butyl-benzoic acid, benzenesulfonic acid, methanesulfonic acid, p-methyl- -benzenesulfonic acid, p-bromo-benzenesulfonic acid, nicotic acid, tetrahydrofurane-2-carboxylic acid or tiophen-3- -carboxylic acid.
4. Salt of the compound of the Formula I according to Claim 1 formed with pivalic acid.
5. Process for the preparation of salts of (4R-cis)-(1 ,1- -dimethyl-ethyl)-6-(2-aminoethyl)-2,2-dimethyl-1 ,3-dioxane-4- -acetate of the Formula I which comprises reacting (4R-cis)- -(1 ,1-dimethyl-ethyl)-6-(2-aminoethyl)-2,2-dimethyl-1 ,3-dioxane-4- -acetate of the Formula I with an organic acid in an organic solvent.
6. Process according to Claim 5 which comprises using as organic acid an aliphatic monocarboxylic acid, dicarboxylic acid or polycarboxylic acid, cycloalkane carboxylic acid, aliphatic unsaturated carboxylic acid, aromatic carboxylic acid, heterocyclic carboxylic acid or sulphonic acid.
7. Process according to Claim 6 which comprises using acetic acid, butyric acid, valeric acid, isovaleric acid, pivalic acid, oxalic acid, malic acid, succinic acid, malonic acid, citric acid, cyclopropane carboxylic acid, cyclobutane carboxylic acid, cyclopentane carboxylic acid, cyclohexane carboxylic acid, fumaric acid, maleic acid, benzoic acid, m- -methyl-benzoic acid, 4-methoxy-benzoic acid, 4-bromo- -benzoic acid, 4-tert. butyl-benzoic acid, benzenesulfonic acid, methanesulfonic acid, p-methyl-benzenesulfonic acid, p- -bromo-benzenesulfonic acid, nicotic acid, tetrahydrofurane-2- -carboxylic acid or tiophen-3-carboxylic acid.
8. Process according to Claim 7 which comprises using pivalic acid.
9. Process according to any of Claims 6-8 which comprises using as reaction medium an apolar, dipolar, aprotic or protic solvent.
10. Process according to Claim 9 which comprises using as organic solvent an aliphatic hydrocarbon, aromatic hydrocarbon, halogenated hydrocarbon, ester, nitrile, alcohol or ether.
11. Process according to Claim 10 which comprises using as organic solvent hexane, heptane, petrolether, toluene, benzene, xylene, dichloro methane, chloroform, ethyl acetate, acetonitrile, methanol, ethanol, isopropanol, tetrahydrofurane, dioxane or diethyl ether.
12. Process according to any of Claims 9-11 which comprises using as reaction medium a solvent mixture.
13. Process according to Claim 12 which comprises using as reaction medium a mixture of heptane and toluene; hexane and toluene; hexane, toluene and tetrahydrofurane; heptane, toluene and tetrahydrofurane; or hexane and diethyl ether.
14. Process according to any of Claims 5-13 which comprises dissolving the compound of the Formula I and the organic acid in the same solvent and admixing the two solutions.
15. Process according to any of Claims 5-14 which comprises using the compound of the Formula I and the organic acid in a molar ratio of 0.5-5, preferably 0.5-2, particularly preferably 0.5-1.2.
16. Process according to any of Claims 5-15 which comprises carrying out the reaction at room temperature or under warming, preferably at 20-90°C.
17. Process according to any of Claims 5-16 which comprises using as starting material crude (4R-cis)-(1 ,1- -dimethyl-ethyl)-6-(2-aminoethyl)-2,2-dimethyl-1 ,3-dioxane-4- -acetate.
Priority Applications (9)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| KR1020017014104A KR20020033617A (en) | 1999-05-06 | 2000-05-05 | Salts of 2,2-dimethyl-1,3-dioxane intermediates and process for the preparation thereof |
| CA002373077A CA2373077A1 (en) | 1999-05-06 | 2000-05-05 | Salts of 2,2-dimethyl-1,3-dioxane intermediates and process for the preparation thereof |
| AU46002/00A AU4600200A (en) | 1999-05-06 | 2000-05-05 | Salts of 2,2-dimethyl-1,3-dioxane intermediates and process for the preparation thereof |
| JP2000617201A JP2002544207A (en) | 1999-05-06 | 2000-05-05 | 2,2-Dimethyl-1,3-dioxane intermediate salt and method for producing the same |
| SK1584-2001A SK15842001A3 (en) | 1999-05-06 | 2000-05-05 | Salts of 2,2-dimethyl-1,3-dioxane intermediates and process for the preparation thereof |
| PL00351145A PL351145A1 (en) | 1999-05-06 | 2000-05-05 | Salts of 2,2-dimethyl-1,3-dioxane intermediates and process for the preparation thereof |
| EP00927612A EP1178980A1 (en) | 1999-05-06 | 2000-05-05 | Salts of 2,2-dimethyl-1,3-dioxane intermediates and process for the preparation thereof |
| HR20010846A HRP20010846A2 (en) | 1999-05-06 | 2001-11-16 | Salts of 2,2-dimethyl-1,3-dioxane intermediates and process for the preparation thereof |
| HK02105736.6A HK1046271A1 (en) | 1999-05-06 | 2002-08-06 | Salts of 2,2-dimethyl-1,3-dioxane intermediates and process for the preparation thereof |
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| HU9901526A HU227840B1 (en) | 1999-05-06 | 1999-05-06 | Intermediates of atorvastatin synthesis and process for producing them |
| HUP9901526 | 1999-05-06 |
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|---|---|
| WO2000068221A1 true WO2000068221A1 (en) | 2000-11-16 |
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ID=89998261
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| PCT/HU2000/000042 WO2000068221A1 (en) | 1999-05-06 | 2000-05-05 | Salts of 2,2-dimethyl-1,3-dioxane intermediates and process for the preparation thereof |
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| Country | Link |
|---|---|
| EP (1) | EP1178980A1 (en) |
| JP (1) | JP2002544207A (en) |
| KR (1) | KR20020033617A (en) |
| CN (1) | CN1349522A (en) |
| AU (1) | AU4600200A (en) |
| CA (1) | CA2373077A1 (en) |
| CZ (1) | CZ20013965A3 (en) |
| HK (1) | HK1046271A1 (en) |
| HR (1) | HRP20010846A2 (en) |
| HU (1) | HU227840B1 (en) |
| PL (1) | PL351145A1 (en) |
| RU (1) | RU2001133066A (en) |
| SK (1) | SK15842001A3 (en) |
| WO (1) | WO2000068221A1 (en) |
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1999
- 1999-05-06 HU HU9901526A patent/HU227840B1/en not_active IP Right Cessation
-
2000
- 2000-05-05 JP JP2000617201A patent/JP2002544207A/en active Pending
- 2000-05-05 CZ CZ20013965A patent/CZ20013965A3/en unknown
- 2000-05-05 WO PCT/HU2000/000042 patent/WO2000068221A1/en active Search and Examination
- 2000-05-05 RU RU2001133066/04A patent/RU2001133066A/en unknown
- 2000-05-05 AU AU46002/00A patent/AU4600200A/en not_active Abandoned
- 2000-05-05 SK SK1584-2001A patent/SK15842001A3/en unknown
- 2000-05-05 EP EP00927612A patent/EP1178980A1/en not_active Withdrawn
- 2000-05-05 KR KR1020017014104A patent/KR20020033617A/en not_active Application Discontinuation
- 2000-05-05 CN CN00807159A patent/CN1349522A/en active Pending
- 2000-05-05 CA CA002373077A patent/CA2373077A1/en not_active Abandoned
- 2000-05-05 PL PL00351145A patent/PL351145A1/en unknown
-
2001
- 2001-11-16 HR HR20010846A patent/HRP20010846A2/en not_active Application Discontinuation
-
2002
- 2002-08-06 HK HK02105736.6A patent/HK1046271A1/en unknown
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US7157255B2 (en) | 2000-05-09 | 2007-01-02 | Astrazeneca Uk Limited | Process for the preparation of dihydroxy esters and derivatives thereof |
| US7888083B2 (en) | 2000-05-09 | 2011-02-15 | Astrazeneca Uk Limited | Process for the preparation of dihydroxy esters and derivatives thereof |
| US7732171B2 (en) | 2000-05-09 | 2010-06-08 | Astrazeneca Uk Limited | Process for the preparation of dihydroxy esters and derivatives thereof |
| US7416865B2 (en) | 2000-05-09 | 2008-08-26 | Astrazeneca Uk Limited | Process for the preparation of dihydroxy esters and derivatives thereof |
| US7989643B2 (en) | 2000-07-19 | 2011-08-02 | Astrazeneca Uk Ltd. | Process for the preparation of 2-(6-substituted-1,3-dioxane-4-yl)acetic acid derivatives |
| US6870059B2 (en) | 2000-07-19 | 2005-03-22 | Astrazeneca Uk Ltd. | Process for the preparation of 2-(6-substituted-1,-3-dioxane-4-yl)acetic acid derivatives |
| US7642363B2 (en) | 2000-07-19 | 2010-01-05 | Astrazeneca Uk Ltd. | Process for the preparation of 2-(6-substituted-1,3-dioxane-4-YL) acetic acid derivatives |
| WO2002057274A1 (en) * | 2001-01-19 | 2002-07-25 | Biocon India Limited | A process for the synthesis of atorvastatin form v and phenylboronates as intermediate compounds |
| US6867306B2 (en) | 2001-01-19 | 2005-03-15 | Biocon Limited | Process for the synthesis of atorvastatin form v and phenylboronates as intermediate compounds |
| US7692034B2 (en) | 2001-07-06 | 2010-04-06 | 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 |
| US7718812B2 (en) | 2001-12-27 | 2010-05-18 | Astrazeneca Uk Limited | Process for the preparation of 2-(6-substituted-1,3-dioxane-4-yl) acetic acid derivates |
| EP1375493A1 (en) * | 2002-06-17 | 2004-01-02 | Dsm N.V. | Process for the preparation of an dioxane acetic acid ester |
| US7442811B2 (en) | 2002-06-17 | 2008-10-28 | Astrazeneca Uk Limited | Process for the preparation of dioxane acetic acid esters |
| JP2005533065A (en) * | 2002-06-17 | 2005-11-04 | アストラゼネカ・ユーケイ・リミテッド | Process for producing dioxane acetates |
| WO2003106447A1 (en) * | 2002-06-17 | 2003-12-24 | Dsm Ip Assests B.V. | Process for the preparation of dioxane acetic acid esters |
| EP1861364A1 (en) | 2005-03-14 | 2007-12-05 | Pfizer Science and Technology Ireland Limited | Preparation of an atorvastatin intermediate using a paal-knorr condensation |
| WO2012032035A1 (en) | 2010-09-09 | 2012-03-15 | Dsm Sinochem Pharmaceuticals Netherlands B.V. | Salts of 7-amino-3,5-dihydroxyheptanoic acid esters |
| US20130197243A1 (en) * | 2010-09-09 | 2013-08-01 | Dsm Sinochem Pharmaceuticals Netherlands B.V. | Salts of 7-amino-3,5-dihydroxyheptanoic acid esters |
| US10676441B2 (en) | 2015-08-05 | 2020-06-09 | Api Corporation | Method for producing pitavastatin calcium |
| US10815201B2 (en) | 2015-08-05 | 2020-10-27 | Api Corporation | Method for producing pitavastatin calcium |
| CN109232353A (en) * | 2018-10-09 | 2019-01-18 | 河南师范大学 | A kind of preparation method of Atorvastatin calcium condensation product |
| 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 |
Also Published As
| Publication number | Publication date |
|---|---|
| CN1349522A (en) | 2002-05-15 |
| CA2373077A1 (en) | 2000-11-16 |
| KR20020033617A (en) | 2002-05-07 |
| JP2002544207A (en) | 2002-12-24 |
| PL351145A1 (en) | 2003-03-24 |
| AU4600200A (en) | 2000-11-21 |
| HU227840B1 (en) | 2012-05-02 |
| CZ20013965A3 (en) | 2002-04-17 |
| EP1178980A1 (en) | 2002-02-13 |
| SK15842001A3 (en) | 2002-04-04 |
| RU2001133066A (en) | 2004-02-27 |
| HRP20010846A2 (en) | 2003-02-28 |
| HK1046271A1 (en) | 2003-01-03 |
| HU9901526D0 (en) | 1999-07-28 |
| HUP9901526A2 (en) | 2001-04-28 |
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