SK15842001A3 - 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
- Publication number
- SK15842001A3 SK15842001A3 SK1584-2001A SK15842001A SK15842001A3 SK 15842001 A3 SK15842001 A3 SK 15842001A3 SK 15842001 A SK15842001 A SK 15842001A SK 15842001 A3 SK15842001 A3 SK 15842001A3
- Authority
- SK
- Slovakia
- Prior art keywords
- acid
- formula
- dimethyl
- dioxane
- acetate
- Prior art date
Links
- 150000003839 salts Chemical class 0.000 title claims abstract description 24
- 238000002360 preparation method Methods 0.000 title claims abstract description 8
- 238000000034 method Methods 0.000 title claims description 32
- RPLSBADGISFNSI-UHFFFAOYSA-N 2,2-dimethyl-1,3-dioxane Chemical class CC1(C)OCCCO1 RPLSBADGISFNSI-UHFFFAOYSA-N 0.000 title description 2
- 239000000543 intermediate Substances 0.000 title description 2
- 150000001875 compounds Chemical class 0.000 claims abstract description 28
- 150000007524 organic acids Chemical class 0.000 claims abstract description 18
- 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 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 66
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 59
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 claims description 48
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 claims description 28
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 16
- OFOBLEOULBTSOW-UHFFFAOYSA-N Malonic acid Chemical compound OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 claims description 13
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-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
- IUGYQRQAERSCNH-UHFFFAOYSA-N pivalic acid Chemical compound CC(C)(C)C(O)=O IUGYQRQAERSCNH-UHFFFAOYSA-N 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
- 239000000203 mixture Substances 0.000 claims description 11
- 125000000022 2-aminoethyl group Chemical group [H]C([*])([H])C([H])([H])N([H])[H] 0.000 claims description 10
- 239000002253 acid Substances 0.000 claims description 10
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 9
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 9
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 9
- -1 aliphatic monocarboxylic acid Chemical class 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-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 claims description 8
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 claims description 8
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 8
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 8
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 claims description 8
- 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
- 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
- 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
- SRSXLGNVWSONIS-UHFFFAOYSA-N benzenesulfonic acid Chemical compound OS(=O)(=O)C1=CC=CC=C1 SRSXLGNVWSONIS-UHFFFAOYSA-N 0.000 claims description 5
- 229940092714 benzenesulfonic acid Drugs 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
- PVNIIMVLHYAWGP-UHFFFAOYSA-N Niacin Chemical compound OC(=O)C1=CC=CN=C1 PVNIIMVLHYAWGP-UHFFFAOYSA-N 0.000 claims description 4
- 235000010233 benzoic acid Nutrition 0.000 claims description 4
- 239000001530 fumaric acid Substances 0.000 claims description 4
- GPSDUZXPYCFOSQ-UHFFFAOYSA-N m-toluic acid Chemical compound CC1=CC=CC(C(O)=O)=C1 GPSDUZXPYCFOSQ-UHFFFAOYSA-N 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
- 229940098779 methanesulfonic acid Drugs 0.000 claims description 4
- 235000006408 oxalic acid Nutrition 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
- 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
- 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
- 239000002904 solvent Substances 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
- YNVOMSDITJMNET-UHFFFAOYSA-N thiophene-3-carboxylic acid Chemical compound 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
- 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
- QARVLSVVCXYDNA-UHFFFAOYSA-N bromobenzene Chemical compound BrC1=CC=CC=C1 QARVLSVVCXYDNA-UHFFFAOYSA-N 0.000 claims description 2
- 150000002148 esters Chemical class 0.000 claims description 2
- 150000008282 halocarbons Chemical class 0.000 claims description 2
- 238000010438 heat treatment Methods 0.000 claims description 2
- 229960003512 nicotinic acid Drugs 0.000 claims description 2
- 235000001968 nicotinic acid Nutrition 0.000 claims description 2
- 239000011664 nicotinic acid Substances 0.000 claims description 2
- 239000003208 petroleum Substances 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
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 claims description 2
- 239000008096 xylene Substances 0.000 claims description 2
- ZWLPBLYKEWSWPD-UHFFFAOYSA-N o-toluic acid Chemical compound CC1=CC=CC=C1C(O)=O ZWLPBLYKEWSWPD-UHFFFAOYSA-N 0.000 claims 2
- PXACTUVBBMDKRW-UHFFFAOYSA-N 4-bromobenzenesulfonic acid Chemical compound OS(=O)(=O)C1=CC=C(Br)C=C1 PXACTUVBBMDKRW-UHFFFAOYSA-N 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 description 2
- 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
- 238000005160 1H NMR spectroscopy Methods 0.000 description 8
- 229910021529 ammonia Inorganic materials 0.000 description 8
- 238000000921 elemental analysis 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
- 238000004508 fractional distillation Methods 0.000 description 6
- 238000001816 cooling Methods 0.000 description 4
- 239000005457 ice water Substances 0.000 description 4
- 238000003756 stirring Methods 0.000 description 4
- 150000007513 acids Chemical class 0.000 description 3
- 238000010992 reflux Methods 0.000 description 3
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 2
- 238000009835 boiling Methods 0.000 description 2
- 239000002050 international nonproprietary name Substances 0.000 description 2
- 238000000746 purification Methods 0.000 description 2
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 1
- SADJNTUGQPZWKG-NDXYWBNTSA-N CC(O)=O.CC(C)(C)OC(=O)C[C@H]1C[C@@H](CCN)OC(C)(C)O1 Chemical compound CC(O)=O.CC(C)(C)OC(=O)C[C@H]1C[C@@H](CCN)OC(C)(C)O1 SADJNTUGQPZWKG-NDXYWBNTSA-N 0.000 description 1
- 150000001242 acetic acid derivatives Chemical class 0.000 description 1
- 150000001412 amines Chemical class 0.000 description 1
- 150000001558 benzoic acid derivatives Chemical class 0.000 description 1
- 238000005119 centrifugation Methods 0.000 description 1
- 238000011109 contamination Methods 0.000 description 1
- 239000010779 crude oil Substances 0.000 description 1
- 125000004122 cyclic group Chemical group 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
- 238000004817 gas chromatography Methods 0.000 description 1
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 1
- 239000012535 impurity Substances 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 150000002825 nitriles Chemical class 0.000 description 1
- ZQPPMHVWECSIRJ-KTKRTIGZSA-N oleic acid group Chemical group C(CCCCCCC\C=C/CCCCCCCC)(=O)O ZQPPMHVWECSIRJ-KTKRTIGZSA-N 0.000 description 1
- 239000002994 raw material Substances 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
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
Description
Soli 2,2-dimetyl-l,3-dioxánových medziproduktov a spôsob ich prípravySalts of 2,2-dimethyl-1,3-dioxane intermediates and process for their preparation
Oblasť technikyTechnical field
Tento vynález sa týka nových farmaceutických medziproduktov a spôso bu ich prípravy. Presnejšie sa vynález týka solí (4R-cis)-(l ,1-dimetyletyl)-6 (2-aminoetyl)-2,2-dimetyl-l ,3-dioxán-4-acetátu tvorených s organickými kyse linami.The present invention relates to novel pharmaceutical intermediates and to a process for their preparation. More specifically, the invention relates to (4R-cis) - (1,1-dimethylethyl) -6 (2-aminoethyl) -2,2-dimethyl-1,3-dioxane-4-acetate salts formed with organic acids.
Doterajší stav techniky (4R-cis)-( 1,1 -Dimetyletyl)-6-(2-aminoetyl)-2,2-dimetyl-l, 3-dioxán-4-(4R-cis) - (1,1-Dimethylethyl) -6- (2-aminoethyl) -2,2-dimethyl-1,3-dioxane-4-
je cenený farmaceutický medziprodukt, ktorý môže byť využitý napr. na pri pravú hypolipidemického prostriedku vzorcais a valuable pharmaceutical intermediate that can be utilized e.g. to the true hypolipidemic agent of the formula
r r ktorý má medzinárodný zákonom nechránený názov (INN) atorvastatín.r r, which has the International Non-proprietary Name (INN) of atorvastatin.
Sú známe dva doterajšie spôsoby prípravy zlúčeniny vzorca I. Postup publikovaný v US patente č. 5 155 251 je opísaný v reakčnej schéme A.Two prior art methods for the preparation of a compound of formula I are known. The process disclosed in U.S. Pat. No. 5,155,251 is described in Reaction Scheme A.
Podľa tohto patentu aminoetylderivát vzorca I sa pripravuje frakčnou destiláciou uskutočňovanou pri 125 - 135 °C/0,05 mm Hg. Čistota produktu nie je vyššia než 96 %. Nevýhodou tohto postupu je, že frakčná destilácia vo vysokom vákuu je komplikovaná čistiaca metóda, ktorá je v priemyselnom meradle uskutočniteľná iba za určitých podmienok.According to this patent, the aminoethyl derivative of formula I is prepared by fractional distillation performed at 125-135 ° C / 0.05 mm Hg. The purity of the product is not more than 96%. The disadvantage of this process is that fractional distillation under high vacuum is a complicated purification method which is feasible on an industrial scale only under certain conditions.
Postup vyložený v US patente č. 5 103 024 a zodpovedajúcom maďarskom patente č. 213 731 je uvedený na schéme B.The process set forth in U.S. Pat. No. 5,103,024 and the corresponding Hungarian patent no. 213 731 is shown in Scheme B.
r r ··· · , e p - r r p · r r f P P f r r ,r r ··· · e - p r r p r r f P P r r,
Podľa tohto patentu sa zlúčenina vzorca I čistí stĺpcovou chromatografiou. Nedostatkom tohto postupu je, že stĺpcová chromatografia vyžaduje veľké investície a je len ťažko uskutočniteľná, predovšetkým v priemyslovom meradle. Čistota získaného produktu neprekračuje 98,2 %.According to this patent, the compound of formula I is purified by column chromatography. The disadvantage of this procedure is that column chromatography requires large investments and is difficult to carry out, especially on an industrial scale. The purity of the product obtained does not exceed 98.2%.
Nevýhodou oboch známych, hore uvedených postupov je to, že produkt, ktorý by mal čistotu vyššiu než 99 %, nemôže byť pripravený ani pomocou frakčnej destilácie ani pomocou stĺpcovej chromatografie.A disadvantage of the two known processes mentioned above is that a product having a purity of more than 99% cannot be prepared either by fractional distillation or by column chromatography.
Podstata vynálezuSUMMARY OF THE INVENTION
Predmetom predkladaného vynálezu je prekonať nedostatky známych postupov a vypracovať jednoduchý spôsob prípravy (4R-cis)-(l, 1-dimetyletyl)-6(2-aminoetyl)-2,2-dimetyl-l,3-dioxán-4-acetátu, ktorý je tiež uskutočniteľný v priemyselnom meradle a poskytuje produkt s čistotou nad 99 %.It is an object of the present invention to overcome the shortcomings of the known processes and to provide a simple process for the preparation of (4R-cis) - (1,1-dimethylethyl) -6 (2-aminoethyl) -2,2-dimethyl-1,3-dioxane-4-acetate, which is also feasible on an industrial scale and provides a product with a purity above 99%.
Hore uvedený predmet je vyriešený predkladaným vynálezom.The above object is solved by the present invention.
Bolo zistené, že (4R-cis)-(l,l-dimetyletyl)-6-(2-aminoetyl)-2,2-dimetyl1,3-dioxán-4-acetát vzorca I tvorí s organickými kyselinami soli, ktoré môžu byť výborne kryštalizované, sú stále a majú vysokú čistotu. Zlúčenina vzorca I podľa vynálezu je vo forme soli mimoriadne čistá a môže byť výhodne konvertovaná na atorvastatín vzorca II, ktorý má čistotu vyhovujúcu požiadavkám r p eIt has been found that (4R-cis) - (1,1-dimethylethyl) -6- (2-aminoethyl) -2,2-dimethyl-1,3-dioxane-4-acetate of formula I forms salts with organic acids which may be They are perfectly crystallized, stable and of high purity. The compound of the formula I according to the invention is in the form of a salt of extremely pure form and can advantageously be converted to atorvastatin of the formula II having a purity satisfying the requirements r p e
farmakopéy. Výhoda predkladaného vynálezu je v tom, že sú eliminované v predchádzajúcej praxi používané metódy, frakčná destilácia vykonávaná vo vysokom vákuu a stĺpcová chromatografia.Pharmacopoeia. An advantage of the present invention is that the methods used in the prior art, fractional distillation under high vacuum, and column chromatography are eliminated.
Podľa jedného hľadiska sú predkladaným vynálezom poskytované soli (4R-cis)-(l,l-dimetyletyl)-6-(2-aminoetyl)-2,2-dimetyl-l,3-dioxán-4-acetátu vytvárané s organickými kyselinami.In one aspect, the present invention provides salts of (4R-cis) - (1,1-dimethylethyl) -6- (2-aminoethyl) -2,2-dimethyl-1,3-dioxane-4-acetate formed with organic acids.
Podľa ďalšieho hľadiska je vynálezom poskytovaný spôsob prípravy solí (4R-cis)-(l,l-dimetyletyl)-6-(2-aminoetyl)-2,2-dimetyl-l,3-dioxán-4-acetátu vytváraných s organickými kyselinami, ktorý zahrnuje reakciu zlúčeniny vzorca I s organickou kyselinou v organickom rozpúšťadle.In another aspect, the invention provides a process for preparing salts of (4R-cis) - (1,1-dimethylethyl) -6- (2-aminoethyl) -2,2-dimethyl-1,3-dioxane-4-acetate formed with organic acids comprising reacting a compound of formula I with an organic acid in an organic solvent.
Podrobný opis vynálezuDETAILED DESCRIPTION OF THE INVENTION
Predkladaný vynález je založený na poznatku, že zlúčenina vzorca I tvorí stabilné soli s organickými kyselinami. Tento poznatok je tým viac prekvapujúci, keď je z skoršej praxe známe, že ketály sú v prítomnosti kyselín nestále. Dve hydroxylové skupiny amínového derivátu vzorca I sú chránené v cyklickom ketály. Nedalo sa predvídať, že spomínaná ketálová skupina by bola za použitých reakčných podmienok rezistentná voči organickým kyselinám. Obzvlášť prekvapujúce je, že soli podľa predkladaného vynálezu sú stále nie len pri teplote miestnosti, ale že zostávajú stále aj pri vyššej teplote vykonávanej rekryštalizácii z organického rozpúšťadla.The present invention is based on the finding that the compound of formula I forms stable salts with organic acids. This finding is all the more surprising when it is known from earlier practice that ketals are unstable in the presence of acids. The two hydroxyl groups of the amine derivative of formula I are protected in the cyclic ketal. It was not predictable that the ketal group would be resistant to organic acids under the reaction conditions used. It is particularly surprising that the salts of the present invention are still not only at room temperature, but that they remain at a higher temperature by recrystallization from an organic solvent.
Podľa spôsobu podľa predkladaného vynálezu môžu byť na vytvorenie solí použité nasledujúce kyseliny: alifatická monokarboxylová kyselina, dikarboxylová kyselina alebo polykarboxylová kyselina, cykloalkánkarboxylová kyselina, alifatická nenasýtená karboxylová kyselina, aromatická karboxylová kyselina, heterocyklická karboxylová kyselina alebo sulfónová kyselina.According to the process of the present invention, the following acids may be used to form salts: aliphatic monocarboxylic acid, dicarboxylic acid or polycarboxylic acid, cycloalkanecarboxylic acid, aliphatic unsaturated carboxylic acid, aromatic carboxylic acid, heterocyclic carboxylic acid or sulfonic acid.
Podľa preferovaného vykonávania nášho vynálezu sa používajú nasledujúce kyseliny: kyselina octová, kyselina maslová, kyselina valérová, kyselina izovalérová, kyselina pivalová, kyselina Šťaveľová, kyselina jablčná, kyselina jantárová, kyselina malónová, kyselina citrónová, kyselina cyklopropánkarboxylová, kyselina cyklobután-karboxylová, kyselina cyklopentánkarboxylová, kyselina cyklohexánkarboxylová, kyselina fumarová, kyselina maleínová, kyselina benzoová, kyselina m-metylbenzoová, kyselina 4-metoxybenzoová, kyselina 4-brómbenzoová, kyselina 4-/erc-butylbenzoová, kyselina benzénsulfónová, kyselina metánsulfónová, kyselina p-metylbenzénsulfónová, kyselina pbrómbenzénsulfónová, kyselina nikotínová, kyselina tetrahydrofurán-2karboxylová alebo kyselina tiofén-3-karboxylová.According to a preferred embodiment of the present 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, cyclopropanecarboxylic acid, cyclobutanecarboxylic acid, cyclopentanecarboxylic acid , cyclohexanecarboxylic acid, fumaric acid, maleic acid, benzoic acid, m-methylbenzoic acid, 4-methoxybenzoic acid, 4-bromobenzoic acid, 4- tert -butylbenzoic acid, benzenesulfonic acid, methanesulfonic acid, p-methylbenzenesulfonic acid, p-bromobenzene, nicotinic acid, tetrahydrofuran-2-carboxylic acid or thiophene-3-carboxylic acid.
Podľa predovšetkým preferovaného vykonávania nášho vynálezu sa používa kyselina pivalová.According to a particularly preferred embodiment of our invention, pivalic acid is used.
Reakcia môže byť vykonávaná v apolárnom, dipolárnom aprotickom alebo protickom rozpúšťadle. Ako reakčné prostredie môže byť použitý alifatický uhľovodík, aromatický uhľovodík, halogénuhľovodík, ester, nitril, alkohol alebo éter. Prednosť sa dáva použitiu niektorého z nasledujúcich rozpúšťadiel: hexán, heptán, petroléter, toluén, benzén, xylén, dichlórmetán, chloroform, etylacetát, acetonitril, metanol, etanol, izopropylalkohol, tetrahydrofurán, dioxán alebo dietyléter.The reaction may be carried out in an apolar, dipolar aprotic or protic solvent. As the reaction medium, an aliphatic hydrocarbon, an aromatic hydrocarbon, a halogenated hydrocarbon, an ester, a nitrile, an alcohol or an ether can be used. Preference is given to using one of the following solvents: hexane, heptane, petroleum ether, toluene, benzene, xylene, dichloromethane, chloroform, ethyl acetate, acetonitrile, methanol, ethanol, isopropyl alcohol, tetrahydrofuran, dioxane or diethyl ether.
Ako reakčné prostredie môže byť použitá tiež zmes rozpúšťadiel. Prednosť sa dáva zmesi heptánu a toluénu, hexánu a toluénu, hexánu, toluénu a tetrahydrofuránu, heptánu, toluénu a tetrahydrofuránu alebo hexánu a dietyléteru.A solvent mixture may also be used as the reaction medium. A mixture of heptane and toluene, hexane and toluene, hexane, toluene and tetrahydrofuran, heptane, toluene and tetrahydrofuran or hexane and diethyl ether is preferred.
Podľa predovšetkým preferovaného uskutočnenia nášho vynálezu reagujú zlúčenina vzorca I a organická kyselina vo forme roztokov pripravených vo rovnakom rozpúšťadle.According to a particularly preferred embodiment of the invention, the compound of formula I and the organic acid are reacted in the form of solutions prepared in the same solvent.
Prednosť má používanie zlúčeniny vzorcal a organickej kyseliny v molárnom pomere 0,5 - 5, lepšie 0,5 - 2 a najvhodnejšie predovšetkým 0,5 - 1,2.Preference is given to using a compound of formula I and an organic acid in a molar ratio of 0.5-5, preferably 0.5-2, and most preferably 0.5-1.2.
Zlúčenina vzorca I a organická kyselina sú spolu miešané najvhodnejšie pri teplote miestnosti a reakcia môže byť uskutočnená pri zahrievaní alebo pri teplote miestnosti. Niekedy sa môže dávať prednosť práci pri teplote varu reakčnej zmesi.The compound of formula I and the organic acid are most preferably mixed together at room temperature, and the reaction may be carried out with heating or room temperature. Sometimes it may be preferred to work at the boiling point of the reaction mixture.
Reakčnú zmes je možné spracovávať jednoduchými spôsobmi. Je možné dávať prednosť postupu s ochladením reakčnej zmesi, s izoláciou vyzrážanej soli zlúčeniny vzorca I filtráciou alebo centrifugovaním, s premytím soli organickým rozpúšťadlom a vysušením. Soľ môže byť vyčistená rekryštalizáciou.The reaction mixture can be worked up in simple ways. It is preferred to proceed by cooling the reaction mixture, isolating the precipitated salt of the compound of formula I by filtration or centrifugation, washing the salt with an organic solvent, and drying. The salt can be purified by recrystallization.
Podľa preferovaného uskutočnenia spôsobu podľa predkladaného vynálezu sa ako východiskový materiál používa zlúčenina vzorca I v surovom stave. V tomto prípade je eliminované nákladné a zložité čistenie zlúčeniny vzorca I.According to a preferred embodiment of the process according to the invention, the raw material is a compound of formula I as starting material. In this case, expensive and difficult purification of the compound of formula I is eliminated.
Výhody predkladaného vynálezu je možné zhrnúť nasledujúcim spôsobom:The advantages of the present invention can be summarized as follows:
Podľa predkladaného vynálezu je zlúčenina vzorca I čistená jednoduchou rekryštalizáciou, ktorá môže byť vykonávaná podstatne ľahšie než frakčná dest tilácia pri vysokom vákuu a stĺpcová chromatografia používaná v už známych metódach.According to the present invention, the compound of formula I is purified by simple recrystallization, which can be carried out much more easily than fractional distillation under high vacuum and column chromatography used in already known methods.
Predkladaný vynález poskytuje produkt s vyššou čistotou než metódy podľa skoršej praxe. Po jedinom rekryštalizačnom stupni je podľa plynovej chromatografie čistota produktu > 99 %, po dvojnásobnej rekryštalizácii stúpa čistota na > 99,95 %. Čistota produktu získavaného už známymi metódami je nižšia než 98 %.The present invention provides a product of higher purity than prior art methods. After a single recrystallization step, the purity of the product is> 99% according to gas chromatography, after a double recrystallization the purity increases to> 99.95%. The purity of the product obtained by known methods is less than 98%.
Postup podľa predkladaného vynálezu môže byť tiež ľahko uskutočňovaný v priemyslovom merítku. Zvyšovanie merítka nečiní problémy. Na druhej strane frakčná destilácia vykonávaná vo vysokom vákuu a stĺpcová chromatografia vyžadujú značné investície a sú v priemyslovom merítku vykonávané len s problémami.The process of the present invention can also be easily carried out on an industrial scale. Increasing the scale does not cause problems. On the other hand, high vacuum fractional distillation and column chromatography require considerable investment and are only on an industrial scale with difficulty.
Zlúčenina vzorca I je stabilná a môže byť vo forme solí vzniknutých s organickými kyselinami uchovávaná bez rozkladu po dlhý čas.The compound of formula I is stable and can be stored without decomposition for long periods in the form of salts formed with organic acids.
Z vysoko čistých solí zlúčeniny vzorca I podľa predkladaného vynálezu môže byť pripravený atorvastatín vyhovujúci požiadavkám farmakopéy.Atorvastatin can be prepared from the highly pure salts of the compound of formula I of the present invention to meet the requirements of a pharmacopoeia.
e · f r r re · f yy r
Ďalšie podrobnosti o predkladanom vynáleze môžu byť nájdené v nasledujúcich príkladoch uskutočnenia vynálezu bez obmedzenia rozsahu ochrany na tieto príklady .Further details of the present invention can be found in the following Examples without limiting the scope of protection to these examples.
Príklady uskutočnenia vynálezuDETAILED DESCRIPTION OF THE INVENTION
Príklad 1Example 1
Pivalát (4R-cis)-( 1,1-d imety lety I)-6-(2-aminoetyI)-2,2-dimety 1-1,3-dioxán-4acetátu g surového olejovitého (4R-cis)-(l,l-dimetyletyl)-6-(2-aminoetyl)2,2-dimetyl-l,3-dioxán-4-acetátu sa rozpustí v 500 ml zmesi heptánu a toluénu 4:1. 20,6 g (201 milimol) pivalovej kyseliny sa rozpustí v 190 ml zmesi heptánu a toluénu 4:1. Tieto dva roztoky sa zmiešajú a reakčná zmes sa jednu hodinu zahrieva do varu. Horúci roztok sa filtruje a zmes sa za miešania ochladí vodou s ľadom. Vyzrážané kryštály sa odfiltrujú, premyjú studenou zmesou heptánu a toluénu a vysušia sa. Takto sa získa 64,9 g (172 milimol) požadovanej zlúčeniny, výťažok 86 %, t.t. 13l°C.(4R-cis) - (1,1-dimethylamino) -1- (2-aminoethyl) -2,2-dimethyl-1,3,3-dioxan-4-acetate acetate g crude oil (4R-cis) - ( 1,1-dimethylethyl) -6- (2-aminoethyl) 2,2-dimethyl-1,3-dioxane-4-acetate is dissolved in 500 ml of 4: 1 heptane / toluene. 20.6 g (201 millimoles) of pivalic acid are dissolved in 190 ml of 4: 1 heptane / toluene. The two solutions are mixed and the reaction mixture is heated at reflux for one hour. The hot solution was filtered and the mixture was cooled with ice-water with stirring. The precipitated crystals are filtered off, washed with a cold mixture of heptane and toluene and dried. 64.9 g (172 mmol) of the title compound are obtained, yield 86%, m.p. 13 l ° C.
TLC propanol : amoniak = 7 : 3, Rf = 0,63 IČ (KBr): 2949, 1725, 1520,TLC propanol: ammonia = 7: 3, Rf = 0.63 IR (KBr): 2949, 1725, 1520,
1173 ’H-NMR (DMSO, 400 MHz): 4,17 (m, 1H), 3,98 (m, 1H), 2,66 (m, 2H), 2,36 (dd, *J = 4,9 Hz, 2J = 15,0 Hz, 1H), 2,22 (dd, 'j = 8,1 Hz, 2J = 15,0 Hz, 1H), 1,54 (m, 3H), 1,39 (s, 12H), 1,24 (s, 3H), 1,05 (s, 9H), 1,03 (~t, J = 12,0 Hz, 1H).1173 1 H-NMR (DMSO, 400 MHz): 4.17 (m, 1H), 3.98 (m, 1H), 2.66 (m, 2H), 2.36 (dd, * J = 4, 9 Hz, 2 J = 15.0 Hz, 1H), 2.22 (dd, J = 8.1 Hz, 2 J = 15.0 Hz, 1H), 1.54 (m, 3H), 1, 39 (s, 12H), 1.24 (s, 3H), 1.05 (s, 9H), 1.03 (~ t, J = 12.0 Hz, 1H).
I3C-NMR: 180,87, 169,77, 98,22, 79,85, 66,50, 66,12, 42,34, 38,26, 37,05, 36,44, 35,97, 30,1 1, 28,03, 27,92, 19,88. 13 C-NMR: 180.87, 169.77, 98.22, 79.85, 66.50, 66.12, 42.34, 38.26, 37.05, 36.44, 35.97, 30 , 11.1, 28.03, 27.92, 19.88.
r »r »
HS: 274 (3), 202 (57), 200 (47), 173 (44), 158 (50), 57 (100), 41 (48), 30 (96).MS: 274 (3), 202 (57), 200 (47), 173 (44), 158 (50), 57 (100), 41 (48), 30 (96).
GC: obsah > 99 %, kontaminácia diastereoizomérom < 0,7 %.GC: content> 99%, diastereoisomer contamination <0.7%.
Príklad 2Example 2
Soľ (4R-cis)-(l,l-dim ety lety l)-6-(2-aminoetyl)-2,2-dimetyl-l,3-dioxán-4acetátu a kyseliny pivalovej(4R-cis) - (1,1-dimethylethyl) -6- (2-aminoethyl) -2,2-dimethyl-1,3-dioxane-4-acetate acetate and pivalic acid salt
23,3 g raz rekryštalizovanej soli (4R-cis)-(l, 1 -dimetyletyl)-6-(2aminoetyl)-2,2-dimetyl-l,3-dioxán-4-acetátu s kyselinou pivalovou sa rozpustí v 220 ml zmesi heptánu a toluénu 4:1. Zmes sa zahrieva do varu, horúci roztok sa filtruje a zmes sa za miešania ochladí vodou s ľadom. Vyzrážané kryštály sa odfiltrujú, premyjú studeným dietyléterom a vysušia. Takto sa získa 20,7 g požadovaného produktu, výťažok 89 %, t.t. 132-133 °C.Dissolve 23.3 g of pivalic acid (4R-cis) - (1,1-dimethylethyl) -6- (2-aminoethyl) -2,2-dimethyl-1,3-dioxane-4-acetate salt once recrystallized in 220 ml 4: 1 heptane / toluene. The mixture was heated to boiling, the hot solution was filtered and the mixture was cooled with ice-water with stirring. The precipitated crystals are filtered off, washed with cold diethyl ether and dried. 20.7 g of the expected product are obtained, yield 89%, m.p. 132-133 [deg.] C.
GC : obsah > 99,95 %; nečistoty celkom < 0,05 %.GC: content> 99.95%; total impurities <0.05%.
Príklad 3Example 3
Soľ (4R-cis)-( 1,1-dim ety lety l)-6-(2-am ino ety I)-2,2-dim ety l-l,3-dioxán-4acetátu a kyseliny pivalovej g surového olejovitého (4R-cis)-(l,l-dimetyletyl)-6-(2-aminoetyl)2,2-dimetyl-l,3-dioxán-4-acetátu sa rozpustí v 116 ml zmesi heptánu, toluénu a tetrahydrofuránu 2:2:1. 7,6 g (201 milimol) pivalovej kyseliny sa rozpustí v 53 ml zmesi heptánu a toluénu 1:1. Tieto dva roztoky sa zmiešajú a reakčná zmes sa jednu hodinu zahrieva do varu. Horúci roztok sa filtruje a zmes sa za miešania ochladí vodou s ľadom. Vyzrážané kryštály sa odfiltrujú, premyjú studeným dietyléterom a vysušia. Takto sa získa 21,1 g požadovaného produktu. Výťažok 73 %, t.t. 131 °C.(4R-cis) - (1,1-dimethylethyl) -6- (2-aminoethyl) -2,2-dimethylll, 3-dioxan-4-acetate and pivalic acid g oleic (4R-cis) cis - (1,1-dimethylethyl) -6- (2-aminoethyl) 2,2-dimethyl-1,3-dioxane-4-acetate was dissolved in 116 mL of 2: 2: 1 heptane, toluene and tetrahydrofuran. . 7.6 g (201 millimoles) of pivalic acid are dissolved in 53 ml of 1: 1 heptane / toluene. The two solutions are mixed and the reaction mixture is heated at reflux for one hour. The hot solution was filtered and the mixture was cooled with ice-water with stirring. The precipitated crystals are filtered off, washed with cold diethyl ether and dried. 21.1 g of the expected product are obtained. Yield 73%, m.p. 131 ° C.
r ·· r f e r r rr ·· r f e r r r
r r p·r r p ·
Príklad 4Example 4
Soľ (4R-cis)-(l, 1-dimety lety l)-6-(2-aminoetyl)-2,2-d im etyl-l,3-dioxán-4acctátu a kyseliny pivalovej g (87,8 milimol) surového olejovitého (4R-cis)-(l,l-dimetyletyl)-6(2-aminoetyl)-2,2-dimetyl-l,3-dioxán-4-acetátu sa rozpustí v 200 ml zmesi heptánu, toluénu a tetrahydrofuránu 4:1:1. 9,0 g (88 milimol) pivalovej kyseliny sa rozpustí v 100 ml zmesi heptánu, toluénu a tetrahydrofuránu 4:1:1. Tieto dva roztoky sa zmiešajú a reakčná zmes sa pod spätným tokom zahrieva do varu. Horúci roztok sa filtruje a zmes sa za miešania ochladí vodou s ľadom. Vyzrážané kryštály sa odfiltrujú, premyjú studeným dietyléterom a vysušia. Takto sa získa 29,0 g požadovaného produktu, výťažok 88 %, t.t. 131 °C.(4R-cis) - (1,1-Dimethyl-1) -6- (2-aminoethyl) -2,2-dimethyl-1,3-dioxan-4-acetate and pivalic acid g (87.8 millimoles) The crude oily (4R-cis) - (1,1-dimethylethyl) -6 (2-aminoethyl) -2,2-dimethyl-1,3-dioxane-4-acetate is dissolved in 200 ml of a mixture of heptane, toluene and tetrahydrofuran 4. 1: 1st 9.0 g (88 millimoles) of pivalic acid are dissolved in 100 ml of 4: 1: 1 heptane / toluene / tetrahydrofuran. The two solutions are mixed and the reaction mixture is heated to reflux. The hot solution was filtered and the mixture was cooled with ice-water with stirring. The precipitated crystals are filtered off, washed with cold diethyl ether and dried. Thus 29.0 g of the desired product are obtained, yield 88%, m.p. 131 ° C.
Príklad 5Example 5
Soľ (4R-cis)-(l, 1-dimety lety l)-6-(2-aminoetyl)-2,2-dimety 1-1,3-dioxán-4acetátu a kyseliny benzoovej(4R-cis) - (1,1-dimethyldi) -1- (2-aminoethyl) -2,2-dimethyl-1,3,3-dioxane-4-acetate and benzoic acid salt
0,6 g (219 milimol) surového (4R-cis)-(l,l-dimetyletyl)-6-(2-aminoetyl)2,2-dimetyl-l,3-dioxán-4-acetátu sa rozpustí v 4 ml etyl-acetátu. 0,26 g kyseliny benzoovej sa rozpustí v 8 ml zmesi hexánu a dietyletéru 1:1. Roztoky sa zmiešajú a jednu hodinu miešajú pri teplote miestnosti. Reakčná zmes sa vo vákuu odparí. Zvyšok sa rekryštalizuje z 5 ml zmesi hexánu a toluénu 4 : 1. Po ochladení sa vyzrážané kryštály odfiltrujú, premyjú studeným hexánom a vysušia. Takto sa získa 0,71 g požadovanej zlúčeniny, výťažok 82 %, t.t. 113-114 °C.Dissolve 0.6 g (219 mmol) of crude (4R-cis) - (1,1-dimethylethyl) -6- (2-aminoethyl) 2,2-dimethyl-1,3-dioxane-4-acetate in 4 ml of ethyl acetate. Dissolve 0.26 g of benzoic acid in 8 ml of a 1: 1 mixture of hexane and diethyl ether. The solutions were mixed and stirred at room temperature for one hour. The reaction mixture was evaporated in vacuo. The residue is recrystallized from 5 ml of 4: 1 hexane: toluene. After cooling, the precipitated crystals are filtered off, washed with cold hexane and dried. 0.71 g of the desired compound is obtained, yield 82%, m.p. 113-114 [deg.] C.
Sumárny vzorec : C21H33NO6Summary formula: C21H33NO6
Molekulová hmotnosť: 395,500Molecular Weight: 395,500
r rr r
TLC propanol : amoniak = 7 : 3, Rf = 0,63.TLC propanol: ammonia = 7: 3, Rf = 0.63.
IČ (KBr): 2979, 1722, 1519, 1370.IR (KBr): 2979, 1722, 1519, 1370.
’H-NMR (CDCb, 200 MHz): 8,39 (b, 3H), 7,98 (~d, J = 7,0 Hz, 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).1 H-NMR (CDCl 3, 200 MHz): 8.39 (b, 3H), 7.98 (~ d, J = 7.0 Hz, 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).
Príklad 6Example 6
Soľ (4R-cis)-( 1,1-dim ety lety l)-6-(2-aminoety I)-2,2-dimety 1-1,3-dioxán-4acetátu a kyseliny maleínovejMaleic acid (4R-cis) - (1,1-dimethylethyl) -6- (2-aminoethyl) -2,2-dimethyl-1,3-dioxan-4-acetate salt
0,6 g (219 milimol) surového, olejovitého (4R-cis)-(l,l-dimetyletyl)-6(2-aminoetyl)-2,2-dimetyl-l ,3-dioxán-4-acetátu sa rozpustí v 6 ml dietyléteru. 0,25 g (219 milimol) kyseliny maleínovej sa rozpustí v 4 ml dietyléteru. Tieto dva roztoky sa zmiešajú a miešajú pri teplote miestnosti. Po ochladení sa vyzrážané kryštály odfiltrujú, premyjú studeným hexánom a vysušia. Takto bolo získaných 0,80 g požadovanej zlúčeniny, výťažok 93 %, t.t. 87-89 °C.0.6 g (219 millimoles) of crude, oily (4R-cis) - (1,1-dimethylethyl) -6 (2-aminoethyl) -2,2-dimethyl-1,3-dioxane-4-acetate is dissolved in 6 ml diethyl ether. 0.25 g (219 mmol) of maleic acid is dissolved in 4 ml of diethyl ether. The two solutions are mixed and stirred at room temperature. After cooling, the precipitated crystals are filtered off, washed with cold hexane and dried. Thus, 0.80 g of the desired compound are obtained, yield 93%, m.p. 87-89 [deg.] C.
Sumárny vzorec: CigHsiNOsSummary formula: C 18 H 18 NO 5
Molekulová hmotnosť: 389,450Molecular Weight: 389,450
TLC propanol : amoniak = 7 : 3, Rf = 0,63.TLC propanol: ammonia = 7: 3, Rf = 0.63.
IČ (KBr): 3430, 2980, 1722.IR (KBr): 3430, 2980, 1722.
‘H-NMR (CDCh, 400 MHz): 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).1 H-NMR (CDCl 3, 400 MHz): 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).
• · · t r r f · ŕ e r · r e r r• · · t · r · f · r · · · r · e · r · e · e · r · r · r · e · r · r · r · e · e · r · e · e ·
Príklad 7Example 7
Sol* (4R-cis)-(l ,1-dimety lety l)-6-(2-aminoety l)-2,2-dimety l-l,3-dioxán-4acetátu a kyseliny filmárovejSol * (4R-cis) - (1,1-dimethylethyl) -6- (2-aminoethyl) -2,2-dimethyl-1,3-dioxane-4-acetate and filmaric acid
0,6 g (219 milimol) surového, olejovitého (4R-cis)-(l,l-dimetyletyl)-6(2-aminoetyl)-2,2-dimetyl-l,3-dioxán-4-acetátu sa rozpustí v 4 ml bezvodého etanolu. 0,25 g (219 milimol) kyseliny fumarovej sa rozpustí v 10 ml bezvodého etanolu. Tieto dva roztoky sa zmiešajú a miešajú pri teplote miestnosti. Reakčná zmes sa odparí a zvyšok sa suspenduje v hexáne. Po ochladení sa vyzrážané kryštály odfiltrujú a rekryštalizujú z 2-propanolu. Takto bolo získaných 0,75 g požadovanej zlúčeniny, výťažok 85 %, t.t. 145-148 °C.0.6 g (219 millimoles) of crude, oily (4R-cis) - (1,1-dimethylethyl) -6 (2-aminoethyl) -2,2-dimethyl-1,3-dioxane-4-acetate is dissolved in 4 ml of anhydrous ethanol. Fumaric acid (0.25 g, 219 mmol) is dissolved in 10 ml of anhydrous ethanol. The two solutions are mixed and stirred at room temperature. The reaction mixture was evaporated and the residue was suspended in hexane. After cooling, the precipitated crystals are filtered off and recrystallized from 2-propanol. 0.75 g of the desired compound is thus obtained, yield 85%, m.p. 145-148 [deg.] C.
Sumárny vzorec: CistbiNOgSummary formula: CistbiNOg
Molekulová hmotnosť: 389,450Molecular Weight: 389,450
TLC propanol : amoniak = 7 : 3, Rf = 0,63.TLC propanol: ammonia = 7: 3, Rf = 0.63.
IČ (KBr): 3430, 2988, 1736, 1 157.IR (KBr): 3430, 2988, 1736, 1157.
‘H-NMR (DMSO, 200 MHz): 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).1 H-NMR (DMSO, 200 MHz): 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).
Príklad 8Example 8
Soľ (4R-cis)-( 1,1 -dimety lety I)-6-(2-aminoetyl)-2,2-dimety 1-1,3-dioxán-4acetátu a kyseliny m-metylbenzoovej(4R-cis) - (1,1-Dimethyl-I) salt of -6- (2-aminoethyl) -2,2-dimethyl-1,3,3-dioxane-4-acetate and m-methylbenzoic acid
0,6 g (219 milimol) surového olejovitého (4R-cis)-(l,1-dimetyletyl)-6(2-aminoetyI)-2,2-dimetyI-l,3-dioxán-4-acetátu sa rozpustí v 6 ml dietyléteru. 0,3 g (219 milimol) kyseliny m-metylbenzoovej sa rozpustí v 3 ml dietyléteru.Dissolve 0.6 g (219 mmol) of crude oily (4R-cis) - (1,1-dimethylethyl) -6 (2-aminoethyl) -2,2-dimethyl-1,3-dioxane-4-acetate in 6 ml diethyl ether. 0.3 g (219 mmol) of m-methylbenzoic acid is dissolved in 3 ml of diethyl ether.
r r r · r rr r r · r r
Tieto dva roztoky sa zmiešajú a miešajú pri teplote miestnosti. Reakčná zmes sa odparí a zvyšok sa kryštalizuje zo zmesi hexánu a toluénu 5:1. Takto sa získa 0,84 g požadovanej zlúčeniny, výťažok 92 %, 1.1. 95-96 °C.The two solutions are mixed and stirred at room temperature. The reaction mixture was evaporated and the residue was crystallized from 5: 1 hexane: toluene. 0.84 g of the desired compound is obtained, yield 92%, m.p. Mp 95-96 ° C.
Sumárny vzorec : C22H35NO6Summary formula: C22H35NO6
Molekulová hmotnosť: 409,527Molecular Weight: 409,527
TLC propanol : amoniak =7 : 3, Rf = 0,63.TLC propanol: ammonia = 7: 3, Rf = 0.63.
IČ (KBr): 2977, 2200, 1722, 1367.IR (KBr): 2977, 2200, 1722, 1367.
’H-NMR (CDCI3, 400 MHz): 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 (m, 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), 1,00 (m, 1H).1 H-NMR (CDCl 3, 400 MHz): 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 (m, 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); m, 1H).
Príklad 9Example 9
Soľ (4R-cis)-( 1,1-dimety lety I)-6-(2-aminoety l)-2,2-dimety 1-1,3-dioxán-4acetátu a kyseliny benzénsulfónovej(4R-cis) - (1,1-Dimethyl-I) salt of -6- (2-aminoethyl) -2,2-dimethyl-1,3,3-dioxane-4-acetate and benzenesulfonic acid
0,6 g (219 milimol) surového olejovitého (4R-cis)-(l,1 -dimetyletyl)-6(2-aminoetyl)-2,2-dimetyl-1,3-dioxán-4-acetátu sa rozpustí v 5 ml zmesi hexánu a dietyléteru 4 : 1. 0,34 g (219 milimol) kyseliny benzénsulfónovej sa rozpustí v 5 ml toluénu. Tieto dva roztoky sa zmiešajú. Reakčná zmes sa mieša pri teplote miestnosti a odparí vo vákuu. Zvyšok sa kryštalizuje zo zmesi hexánu a toluénu 5:1. Takto sa získa 0,76 g požadovanej zlúčeniny, výťažok 80 %, 1.1. 96-98 °C.0.6 g (219 millimoles) of crude oily (4R-cis) - (1,1-dimethylethyl) -6 (2-aminoethyl) -2,2-dimethyl-1,3-dioxane-4-acetate is dissolved in 5 ml of a 4: 1 mixture of hexane and diethyl ether. 0.34 g (219 mmol) of benzenesulfonic acid was dissolved in 5 ml of toluene. The two solutions are mixed. The reaction mixture was stirred at room temperature and evaporated in vacuo. The residue was crystallized from 5: 1 hexane: toluene. 0.76 g of the desired compound is obtained, yield 80%, m.p. 96-98 [deg.] C.
Sumárny vzorec: C20H33NO7SSummary formula: C20H33NO7S
Molekulová hmotnosť: 431,553Molecular Weight: 431,553
TLC propanol : amoniak = 7 : 3, Rf = 0,63.TLC propanol: ammonia = 7: 3, Rf = 0.63.
IČ (KBr): 3340, 2976, 1737, 1719, 1165.IR (KBr): 3340, 2976, 1737, 1719, 1165.
‘H-NMR (CDCI3, 400 MHz): 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).l,03 (m, 1H).1 H-NMR (CDCl 3, 400 MHz): 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).
Príklad 10Example 10
Soľ (4R-cis)-(l, 1-dim ety lety l)-6-(2-aminoety l)-2,2-dimety 1-1,3-d ioxán-4acetátu a kyseliny octovej(4R-cis) - (1,1-dimethylethyl) -6- (2-aminoethyl) -2,2-dimethyl-1,3,3-dioxane-4-acetate acetate and acetic acid salt
0,6 g (219 milimol) surového olejovitého (4R-cis)-(l,l-dimetyletyl)-6(2-aminoetyl)-2,2-dimetyl-l,3-dioxán-4-acetátu sa rozpustí v 6 ml dietyléteru. 0,131 g (219 milimol) kyseliny octovej sa rozpustí v 5 ml dietyléteru. Tieto dva roztoky sa zmiešajú. Reakčná zmes sa mieša pri teplote miestnosti. Kryštály sa odfiltrujú, premyjú hexánom a pri teplote miestnosti sa vo vákuu vysušia. Takto sa získa 0,56 g požadovanej zlúčeniny, výťažok 76 %, t.t. 76-77 °C.Dissolve 0.6 g (219 mmol) of crude oily (4R-cis) - (1,1-dimethylethyl) -6 (2-aminoethyl) -2,2-dimethyl-1,3-dioxane-4-acetate in 6 ml diethyl ether. Dissolve 0.131 g (219 mmol) of acetic acid in 5 ml of diethyl ether. The two solutions are mixed. The reaction mixture was stirred at room temperature. The crystals were filtered off, washed with hexane and dried at room temperature in vacuo. 0.56 g of the desired compound is obtained, yield 76%, m.p. Mp 76-77 ° C.
Sumárny vzorec : C16H31NO6Summary formula: C16H31NO6
Molekulová hmotnosť: 333,429Molecular Weight: 333,429
TLC propanol : amoniak = 7 : 3, Rf = 0,63.TLC propanol: ammonia = 7: 3, Rf = 0.63.
IČ (KBr): 3430, 2986, 1731, 1 157.IR (KBr): 3430, 2986, 1731, 1157.
’H-NMR (CDC13j 400 MHz): 8,18 (b, 3H), 4,26 (m, IH), 3,97 (m, IH), 2,93 (m, 2H), 2,43 (m, IH), , 2,29 (m, IH), 1,96 (m, 3H), 1,80 (m, 2H), 1,56 (m, IH), 1,44 (s, 9H), 1,34 (s, 3H), 1,22 (m, IH).1 H-NMR (CDCl 3, 400 MHz): 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 (m, 3H), 1.80 (m, 2H), 1.56 (m, 1H), 1.44 (s, 9H) 1.34 (s, 3H), 1.22 (m, 1H).
Príklad 11Example 11
Soľ bis-[(4R-cis)-(l,l-dimetyIetyl)-6-(2-aminoetyl)-2,2-dimetyl-l,3-dioxán4-acetátu] a kyseliny šťaveľovejBis - [(4R-cis) - (1,1-dimethylethyl) -6- (2-aminoethyl) -2,2-dimethyl-1,3-dioxane-4-acetate] and oxalic acid salt
0,6 g (219 milimol) surového olejovitého (4R-cis)-(l,1 -dimetyletyl)-6(2-aminoetyl)-2,2-dimetyl-l ,3-dioxán-4-acetátu sa rozpustí v 6 ml dietyléteru. 0,19 g (219 milimol) kyseliny šťaveľovej sa rozpustí v 3 ml dietyléteru. Tieto dva roztoky sa zmiešajú. Reakčná zmes sa mieša pri teplote miestnosti. Vyzrážané kryštály sa odfiltrujú, premyjú studeným hexánom a pri teplote miestnosti sa vo vákuu vysušia. Takto sa získa 0,56 g požadovanej zlúčeniny, výťažok 80 %, 1.1. 76-77 °C.0.6 g (219 millimoles) of crude oily (4R-cis) - (1,1-dimethylethyl) -6 (2-aminoethyl) -2,2-dimethyl-1,3-dioxane-4-acetate was dissolved in 6 ml diethyl ether. 0.19 g (219 mmol) of oxalic acid are dissolved in 3 ml of diethyl ether. The two solutions are mixed. The reaction mixture was stirred at room temperature. The precipitated crystals are filtered off, washed with cold hexane and dried in vacuo at room temperature. 0.56 g of the desired compound is obtained, yield 80%, m.p. Mp 76-77 ° C.
Sumárny vzorec: C30H56NO12Summary formula: C30H56NO12
Molekulová hmotnosť: 333,429Molecular Weight: 333,429
TLC propanol : amoniak = 7 : 3, Rf = 0,63.TLC propanol: ammonia = 7: 3, Rf = 0.63.
IČ (KBr): 3430, 2982, 1739, 1575, 1 161.IR (KBr): 3430, 2982, 1739, 1575, 1161.
’H-NMR (CDCb, 400 MHz): 8,60 (b, 3H), 4,24 (m, IH), 3,99 (m, IH), 3,00 (m, 2H), 2,32 (m, 2H), 1,90 (m, 2H), 1,54 (m, IH), 1,44 (s, 9H), 1,41 (s, 3H), 1,32 (s, 3H), 1,21 (m, IH).1 H-NMR (CDCl 3, 400 MHz): 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)
Applications Claiming Priority (2)
| 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 |
| 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 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| SK15842001A3 true SK15842001A3 (en) | 2002-04-04 |
Family
ID=89998261
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| 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 |
Country Status (14)
| 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) |
Families Citing this family (14)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| 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) |
| JP2004533482A (en) | 2001-07-06 | 2004-11-04 | テバ ファーマシューティカル インダストリーズ リミティド | Method for producing 7-amino-syn-3,5-dihydroxyheptanoic acid derivative with 6-cyano-syn-3,5-dihydroxyhexanoic acid derivative |
| 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 |
| WO2006097909A1 (en) | 2005-03-14 | 2006-09-21 | Pfizer Science And Technology Ireland Limited | Preparation of an atorvastatin intermediate using a 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 |
| SI2614057T1 (en) * | 2010-09-09 | 2016-03-31 | Dsm Sinochem Pharmaceuticals Netherlands B.V. | 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 |
| 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 |
| CN110940764B (en) * | 2019-12-31 | 2022-06-28 | 湖南九典制药股份有限公司 | Separation method of statin optical isomer |
Family Cites Families (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| 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 |
| CN1093126C (en) * | 1996-07-29 | 2002-10-23 | 沃尼尔·朗伯公司 | Improved process for the synthesis of protected esters of (s)-3,4-dihydroxytubyric acid |
| HUP0103659A3 (en) * | 1998-04-30 | 2003-01-28 | Kaneka Corp | Process for producing 6-cyanomethyl-1,3-dioxane-4-acetic acid derivatives |
-
1999
- 1999-05-06 HU HU9901526A patent/HU227840B1/en not_active IP Right Cessation
-
2000
- 2000-05-05 CZ CZ20013965A patent/CZ20013965A3/en unknown
- 2000-05-05 EP EP00927612A patent/EP1178980A1/en not_active Withdrawn
- 2000-05-05 AU AU46002/00A patent/AU4600200A/en not_active Abandoned
- 2000-05-05 CA CA002373077A patent/CA2373077A1/en not_active Abandoned
- 2000-05-05 CN CN00807159A patent/CN1349522A/en active Pending
- 2000-05-05 SK SK1584-2001A patent/SK15842001A3/en unknown
- 2000-05-05 RU RU2001133066/04A patent/RU2001133066A/en unknown
- 2000-05-05 KR KR1020017014104A patent/KR20020033617A/en not_active Application Discontinuation
- 2000-05-05 WO PCT/HU2000/000042 patent/WO2000068221A1/en active Search and Examination
- 2000-05-05 JP JP2000617201A patent/JP2002544207A/en active Pending
- 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
Also Published As
| Publication number | Publication date |
|---|---|
| WO2000068221A1 (en) | 2000-11-16 |
| JP2002544207A (en) | 2002-12-24 |
| PL351145A1 (en) | 2003-03-24 |
| EP1178980A1 (en) | 2002-02-13 |
| RU2001133066A (en) | 2004-02-27 |
| HU9901526D0 (en) | 1999-07-28 |
| HUP9901526A2 (en) | 2001-04-28 |
| HK1046271A1 (en) | 2003-01-03 |
| KR20020033617A (en) | 2002-05-07 |
| CZ20013965A3 (en) | 2002-04-17 |
| CA2373077A1 (en) | 2000-11-16 |
| HU227840B1 (en) | 2012-05-02 |
| CN1349522A (en) | 2002-05-15 |
| HRP20010846A2 (en) | 2003-02-28 |
| AU4600200A (en) | 2000-11-21 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| JP3179515B2 (en) | Method for producing 2-chlorothiazoles | |
| SK15842001A3 (en) | Salts of 2,2-dimethyl-1,3-dioxane intermediates and process for the preparation thereof | |
| SK280942B6 (en) | (4r-cis)-1,1-dimethylethyl-6-iodomethyl-2,2-dimethyl-1,3- -dioxane-4-acetate and process of the synthesis thereof | |
| IE862605L (en) | Preparation of disubstituted pyridine -2,3- dicarboxylates | |
| US20090023918A1 (en) | Process for preparing 3-acylaminobenzofuran-2-carboxylic acid derivative | |
| SK128494A3 (en) | Method of production of indanylamine compounds | |
| US6333415B1 (en) | Intermediates and processes for the preparation of optically active octanoic acid derivatives | |
| EP0585014B1 (en) | Process for the preparation of 2-(un)substituted 4-alkylimidazoles | |
| JP2005507900A (en) | Citalopram manufacturing method | |
| US6538134B2 (en) | 4-Benzyl-2-hydroxy-1,4-oxazine-3-one and polymorphic forms thereof | |
| US20080269495A1 (en) | Process for Preparation of Piperidine Carboxylic Acid | |
| KR20190013554A (en) | Novel intermediates useful for the synthesis of aminopyrimidine derivatives, process for preparing the same, and process for preparing aminopyrimidine derivatives using the same | |
| EP2240442B1 (en) | Preparation process useful in synthesis of atorvastatin | |
| DE60308170T2 (en) | PROCESS FOR THE PREPARATION OF CHINOLINE DERIVATIVES | |
| HU223138B1 (en) | Novel process for producing alkyl-4,6,7,8,9,9a-hexahydro-2h,3h-pyrido[1,2-a]pyrazin-1-on-7-carboxylate esters | |
| EP0079740B1 (en) | Anthraniloyloxyalkanoates | |
| KR100421282B1 (en) | Process for preparing 1-methylhexahydro-4-azepinone hydrochloride | |
| WO2023205164A1 (en) | Processes for the preparation of finerenone | |
| WO2022218733A1 (en) | A process for preparation of substituted enamine compounds | |
| WO2015177801A1 (en) | Novel process for the preparation of a lactam-containing compound | |
| WO2022218734A1 (en) | A process for preparation of substituted enamine compounds | |
| PL189248B1 (en) | Method of obtaining 1-(p-methoxybenzooyl)-2-pyrolydone | |
| JP2003104985A (en) | Method for producing quinazoline derivative | |
| EP0743303A1 (en) | Synthesis of bezoquinolinones | |
| WO2020079541A1 (en) | Process for preparation of elafibranor |