SK4202001A3 - Method for producing 6,6-dialkoxy-5-hydroxy-3-oxo-hexanoic acid esters - Google Patents
Method for producing 6,6-dialkoxy-5-hydroxy-3-oxo-hexanoic acid esters Download PDFInfo
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- SK4202001A3 SK4202001A3 SK420-2001A SK4202001A SK4202001A3 SK 4202001 A3 SK4202001 A3 SK 4202001A3 SK 4202001 A SK4202001 A SK 4202001A SK 4202001 A3 SK4202001 A3 SK 4202001A3
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- hydroxy
- dialkoxy
- acid esters
- alkyl
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- 238000004519 manufacturing process Methods 0.000 title abstract 2
- 230000015572 biosynthetic process Effects 0.000 claims abstract description 7
- 125000002485 formyl group Chemical class [H]C(*)=O 0.000 claims abstract 2
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 17
- 238000000034 method Methods 0.000 claims description 12
- 238000002360 preparation method Methods 0.000 claims description 6
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 6
- 125000005907 alkyl ester group Chemical group 0.000 claims description 4
- 125000000217 alkyl group Chemical group 0.000 claims description 4
- 150000002081 enamines Chemical class 0.000 claims description 4
- 238000006243 chemical reaction Methods 0.000 claims description 3
- 239000003960 organic solvent Substances 0.000 claims description 3
- 125000000129 anionic group Chemical group 0.000 claims description 2
- 230000007717 exclusion Effects 0.000 claims description 2
- 230000005595 deprotonation Effects 0.000 claims 1
- 238000010537 deprotonation reaction Methods 0.000 claims 1
- 125000003923 ethanoic acid ester group Chemical group 0.000 claims 1
- 238000003786 synthesis reaction Methods 0.000 abstract description 4
- 229940121710 HMGCoA reductase inhibitor Drugs 0.000 abstract description 2
- 239000002471 hydroxymethylglutaryl coenzyme A reductase inhibitor Substances 0.000 abstract description 2
- 229940096701 plain lipid modifying drug hmg coa reductase inhibitors Drugs 0.000 abstract description 2
- WDJHALXBUFZDSR-UHFFFAOYSA-N Acetoacetic acid Natural products CC(=O)CC(O)=O WDJHALXBUFZDSR-UHFFFAOYSA-N 0.000 abstract 1
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 9
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 9
- 239000002585 base Substances 0.000 description 8
- RWRDLPDLKQPQOW-UHFFFAOYSA-N Pyrrolidine Chemical compound C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 description 6
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 6
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 6
- 239000000203 mixture Substances 0.000 description 6
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 5
- 239000012312 sodium hydride Substances 0.000 description 5
- 229910000104 sodium hydride Inorganic materials 0.000 description 5
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 4
- MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 description 4
- 150000001875 compounds Chemical class 0.000 description 4
- OGFKTAMJLKHRAZ-UHFFFAOYSA-N 2,2-dimethoxyacetaldehyde Chemical compound COC(OC)C=O OGFKTAMJLKHRAZ-UHFFFAOYSA-N 0.000 description 3
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 3
- 150000001299 aldehydes Chemical class 0.000 description 3
- -1 alkyl acetic acid esters Chemical class 0.000 description 3
- 239000011541 reaction mixture Substances 0.000 description 3
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 3
- 238000005160 1H NMR spectroscopy Methods 0.000 description 2
- HOOZGORFVSQKLE-UHFFFAOYSA-N 2-tert-butyl-5-hydroxy-6,6-dimethoxy-3-oxohexanoic acid Chemical compound COC(OC)C(O)CC(=O)C(C(O)=O)C(C)(C)C HOOZGORFVSQKLE-UHFFFAOYSA-N 0.000 description 2
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 2
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 description 2
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 2
- 238000004440 column chromatography Methods 0.000 description 2
- 239000012043 crude product Substances 0.000 description 2
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 2
- 229910052739 hydrogen Inorganic materials 0.000 description 2
- 239000001257 hydrogen Substances 0.000 description 2
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 2
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 2
- ZCSHNCUQKCANBX-UHFFFAOYSA-N lithium diisopropylamide Chemical compound [Li+].CC(C)[N-]C(C)C ZCSHNCUQKCANBX-UHFFFAOYSA-N 0.000 description 2
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 2
- 239000002480 mineral oil Substances 0.000 description 2
- 235000010446 mineral oil Nutrition 0.000 description 2
- 239000012074 organic phase Substances 0.000 description 2
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 2
- 239000002904 solvent Substances 0.000 description 2
- 239000000725 suspension Substances 0.000 description 2
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 2
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 description 1
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 1
- WHNQTHDJEZTVHS-UHFFFAOYSA-N 3-(1,3-benzothiazol-2-yl)propanoic acid Chemical compound C1=CC=C2SC(CCC(=O)O)=NC2=C1 WHNQTHDJEZTVHS-UHFFFAOYSA-N 0.000 description 1
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 1
- QQIRAVWVGBTHMJ-UHFFFAOYSA-N [dimethyl-(trimethylsilylamino)silyl]methane;lithium Chemical compound [Li].C[Si](C)(C)N[Si](C)(C)C QQIRAVWVGBTHMJ-UHFFFAOYSA-N 0.000 description 1
- 229910052783 alkali metal Inorganic materials 0.000 description 1
- 150000001340 alkali metals Chemical class 0.000 description 1
- 229910052784 alkaline earth metal Inorganic materials 0.000 description 1
- 150000001342 alkaline earth metals Chemical class 0.000 description 1
- 150000001450 anions Chemical class 0.000 description 1
- 125000004432 carbon atom Chemical group C* 0.000 description 1
- WASQWSOJHCZDFK-UHFFFAOYSA-N diketene Chemical compound C=C1CC(=O)O1 WASQWSOJHCZDFK-UHFFFAOYSA-N 0.000 description 1
- 125000005594 diketone group Chemical group 0.000 description 1
- 150000002170 ethers Chemical class 0.000 description 1
- 235000019439 ethyl acetate Nutrition 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 125000004051 hexyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 229930195733 hydrocarbon Natural products 0.000 description 1
- 150000002430 hydrocarbons Chemical class 0.000 description 1
- 238000011065 in-situ storage Methods 0.000 description 1
- 229910052987 metal hydride Inorganic materials 0.000 description 1
- 150000004681 metal hydrides Chemical class 0.000 description 1
- DVSDBMFJEQPWNO-UHFFFAOYSA-N methyllithium Chemical compound C[Li] DVSDBMFJEQPWNO-UHFFFAOYSA-N 0.000 description 1
- 238000006386 neutralization reaction Methods 0.000 description 1
- 239000003921 oil Substances 0.000 description 1
- 125000001147 pentyl group Chemical group C(CCCC)* 0.000 description 1
- NHKJPPKXDNZFBJ-UHFFFAOYSA-N phenyllithium Chemical compound [Li]C1=CC=CC=C1 NHKJPPKXDNZFBJ-UHFFFAOYSA-N 0.000 description 1
- 150000003335 secondary amines Chemical class 0.000 description 1
- ODZPKZBBUMBTMG-UHFFFAOYSA-N sodium amide Chemical compound [NH2-].[Na+] ODZPKZBBUMBTMG-UHFFFAOYSA-N 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- JKUYRAMKJLMYLO-UHFFFAOYSA-N tert-butyl 3-oxobutanoate Chemical compound CC(=O)CC(=O)OC(C)(C)C JKUYRAMKJLMYLO-UHFFFAOYSA-N 0.000 description 1
- WMOVHXAZOJBABW-UHFFFAOYSA-N tert-butyl acetate Chemical compound CC(=O)OC(C)(C)C WMOVHXAZOJBABW-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C67/00—Preparation of carboxylic acid esters
- C07C67/30—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group
- C07C67/333—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group by isomerisation; by change of size of the carbon skeleton
- C07C67/343—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group by isomerisation; by change of size of the carbon skeleton by increase in the number of carbon atoms
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
Abstract
Description
Oblasť technikyTechnical field
Vynález sa týka spôsobu výroby esterov kyseliny 6,6-dialkoxy-5-hydroxy-3-oxohexánovej. Uvedené zlúčeniny sú dôležité základné látky na syntézu mnohých inhibítorov HMG-CoA-reduktázy (WO-A-92/10503).The invention relates to a process for the preparation of 6,6-dialkoxy-5-hydroxy-3-oxohexanoic acid esters. These compounds are important bases for the synthesis of many HMG-CoA reductase inhibitors (WO-A-92/10503).
Doterajší stav technikyBACKGROUND OF THE INVENTION
Podľa WO-A-92/10503 sa tieto zlúčeniny získajú reakciou esterú kyseliny octovej s T-dialkoxy-p-hydroxyesterom. Táto syntéza je nevýhodná v tom, že posledný edukt sa ťažko získava a preto je drahý.According to WO-A-92/10503, these compounds are obtained by reacting acetic esters with T-dialkoxy-p-hydroxyester. This synthesis is disadvantageous in that the last starting material is difficult to obtain and therefore expensive.
Úlohou predloženého vynálezu je vyvinúť jednoduchý a finančne výhodnejší prístup k menovaným základným látkam syntézy.It is an object of the present invention to provide a simple and more cost-effective approach to the aforementioned synthesis bases.
Úlohu sa podarilo vyriešiť spôsobom podľa patentového nároku 1.The problem was solved by the method of claim 1.
Podstata vynálezuSUMMARY OF THE INVENTION
Spôsob výroby esterov kyseliny 6,6-dialkoxy-5-hydroxy-3-oxohexánovej všeobecného vzorca IA process for the preparation of 6,6-dialkoxy-5-hydroxy-3-oxohexanoic acid esters of the formula I
R2OR 2 O
OR1 (O, kde R1 a R2 sú rovnaké alebo rôzne a znamenajú Ci.6alkyl, spočíva podľa vynálezu v tom, že sa nechá reagovať alkylester kyseliny acetoctovej všeobecného vzorca II ·· ·· ο οOR 1 (O, where R 1 and R 2 are the same or different and represent C 1-6 alkyl, according to the invention, consists in reacting an alkyl ester of acetic acid of the general formula II
XAor. co.XA or . what.
kde R1 má uvedený význam, v prítomnosti zásady s aldehydom všeobecného vzorca IIIwherein R 1 is as defined above, in the presence of a base with an aldehyde of formula III
OABOUT
kde R2 má uvedený význam.wherein R 2 is as described above.
Pod pojmom Ci.6alkylová skupina sa rozumie alkylová skupina s rovným alebo rozvetveným reťazcom s 1—6 atómami uhlíka, menovite metyl, etyl, izopropyl, propyl, butyl, izobutyl, terc.-butyl, pentyl a jeho izoméry, ako aj hexyl a jeho izoméry. Výhodné sú vymenované Ci^alkylskupiny.The term Ci. 6 alkyl is understood to mean a straight or branched chain alkyl group having 1-6 carbon atoms, namely methyl, ethyl, isopropyl, propyl, butyl, isobutyl, tert-butyl, pentyl and its isomers as well as hexyl and its isomers. C 1-4 alkyl groups are preferred.
Výhodou spôsobu podľa vynálezu je to, že alkylestery kyseliny acetoctovej všeobecného vzorca II sú priemyselne dostupné.An advantage of the process according to the invention is that the alkyl esters of acetic acid of the formula II are commercially available.
Alkylestery kyseliny acetoctovej všeobecného vzorca II sa získajú reakciou diketónu so zodpovedajúcim alkoholom. Alkylester kyseliny acetoctovej všeobecného vzorca II sa môže tiež pripraviť in situ z diketenu. Výhodnými alkylestermi kyseliny acetoctovej všeobecného vzorca II sú metylester, etylester, propylester, izopropylester, butylester, izobutylester alebo terc.-butylester. Obzvlášť výhodný je terc.-butylester.The alkyl acetic acid esters of formula II are obtained by reacting the diketone with the corresponding alcohol. The acetyl acetic acid alkyl ester of formula II can also be prepared in situ from diketene. Preferred alkyl acetic acid esters of formula II are methyl, ethyl, propyl, isopropyl, butyl, isobutyl or tert-butyl. Particularly preferred is the tert-butyl ester.
Aldehydy všeobecného vzorca III sú spravidla komerčne dostupné. Výhodným aldehydom všeobecného vzorca III je glyoxal-1,1 -dimetylacetál.The aldehydes of formula III are generally commercially available. A preferred aldehyde of formula III is glyoxal-1,1-dimethylacetal.
·· ·· ·· • · • · · • · · • ··· • · ···· ·· • · ··· • · · · · • · · · ·· ·····················································
Účelne sa spôsob podľa vynálezu uskutočňuje v organickom rozpúšťadle za významného vylúčenia vody. Vhodnými rozpúšťadlami sú étery, ako napr. tetrahydrofurán, dioxán, dietyléter alebo terc.-butylmetyléter, aromáty ako benzén alebo toluén alebo uhľovodíky ako hexán a tiež zmesi menovaných organických rozpúšťadiel.Suitably, the process according to the invention is carried out in an organic solvent with significant water exclusion. Suitable solvents are ethers such as e.g. tetrahydrofuran, dioxane, diethyl ether or tert-butyl methyl ether, aromatics such as benzene or toluene or hydrocarbons such as hexane and also mixtures of the said organic solvents.
Reakčná teplota sa zvyčajne volí v rozmedzí od -80 do 130 °C, výhodne v rozmedzí od -40 do 20 °C.The reaction temperature is usually chosen in the range of -80 to 130 ° C, preferably in the range of -40 to 20 ° C.
Zásada sa použije preto, aby sa vytvoril di-anión alkylesteru kyseliny acetoctovej všeobecného vzorca II. V podstate sa môže táto tvorba di-aniónu uskutočniť priamo so silnou zásadou, ako napr. s butyllítiom, metyllítiom, fenyllítiom alebo nátriumamidom, lítiumdiizopropylamidom alebo lítiumhexametyldisilazánom.The base is used to form the di-anion of the alkyl acetic acid ester of formula II. In principle, this formation of the di-anion can be carried out directly with a strong base, such as e.g. with butyllithium, methyllithium, phenyllithium or sodium amide, lithium diisopropylamide or lithium hexamethyldisilazane.
Zvyčajne sa postupuje v dvoch stupňoch, kedy sa najprv deprotonuje skupina —CH2— slabšou a tiež lacnejšou zásadou a až v druhom stupni sa uskutoční tvorba di-aniónu s menovanou silnou zásadou. Ako slabé zásady sú vhodné hydridy kovov, ako napr. hydridy alkalických kovov alebo kovy alkalických zemín, výhodne nátriumhydrid, ale tiež sekundárne amíny (výhodne pyrolidín), ktorý s alkylesterom kyseliny acetoctovej vytvára enamín ako aniónový ekvivalent. V poslednom prípade sa pod pojmom di-anión rozumie anión zodpovedajúci enamínu.Usually, the procedure in two steps, where first a -CH 2 - weak and also cost base and in a second stage, the dianion formation with the abovementioned strong base. Suitable weak bases are metal hydrides, such as e.g. alkali metal or alkaline earth metal hydrides, preferably sodium hydride, but also secondary amines (preferably pyrrolidine), which form the enamine as an anionic equivalent with the acetic acid alkyl ester. In the latter case, di-anion means an anion corresponding to an enamine.
Požadovaný ester kyseliny 6,6-dialkoxy-5-hydroxy-3-oxohexánovej sa môže získať v odbore známym spôsobom, napr. neutralizáciou reakčnej zmesi s nasledujúcou extrakciou vhodným rozpúšťadlom.The desired 6,6-dialkoxy-5-hydroxy-3-oxohexanoic acid ester can be obtained by a method known in the art, e.g. by neutralization of the reaction mixture followed by extraction with a suitable solvent.
Príklady uskutočnenia vynálezuDETAILED DESCRIPTION OF THE INVENTION
Príklad 1:Example 1:
Výroba 6,6-dimetoxy-5-hydroxy-3-oxo-terc.-butylhexanoátuPreparation of 6,6-dimethoxy-5-hydroxy-3-oxo-tert-butylhexanoate
Do 250 ml guľatej banky sa dalo 0,88 g (22 mmol) nátriumhydridu (55—60 % v minerálnom oleji) v 50 ml tetrahydrofuránu pri 0 eC. Potom sa pomocou striekačky • · pridalo 3,16 g (20 mmol) terc.-butylesteru kyseliny acetoctovej k suspenzii nátriumhydridu v priebehu 5—10 minút (vývin vodíka). Miešalo sa 5 minút, potom sa v priebehu cca 10 minút k reakčnej zmesi prikvapkalo 13,1 ml roztoku BuLi (1,6 M v hexáne) pri 0 °C. Zmes sa cca 1 hodinu miešala a potom sa k reakčnej zmesi prikvapkalo 5,7 g (22 mmol) roztoku glyoxal-1,1-dimetylacetálu v priebehu 5 minút. Potom sa pri 0 °C 3 hodiny miešalo. Pri 0 °C sa pridalo 5 ml koncentrovanej kyseliny chlorovodíkovej (-> pH 8). Zmes sa zriedila s 30 ml vody a 2-krát extrahovala zakaždým s 50 ml dietyléteru. Surový produkt, ktorý sa získal zahustením organických fáz sa čistil pomocou stĺpcovej chromatografie. Tak sa získala požadovaná zlúčenina vo forme ľahko viskózneho, mierne nažltlého oleja. (Výťažok: 11 %).To a 250 mL round-bottomed flask afford 0.88 g (22 mmol) of sodium hydride (55-60% in mineral oil) in 50 ml of THF at 0 C. The much by syringe • · added 3.16 g (20 mmol) of tert butyl acetate of acetic acid to a suspension of sodium hydride over 5-10 minutes (evolution of hydrogen). The mixture was stirred for 5 minutes, then 13.1 ml BuLi solution (1.6 M in hexane) was added dropwise over about 10 minutes at 0 ° C. The mixture was stirred for about 1 hour and then 5.7 g (22 mmol) of glyoxal-1,1-dimethylacetal solution was added dropwise over 5 minutes. It was then stirred at 0 ° C for 3 hours. At 0 ° C, 5 ml of concentrated hydrochloric acid (-> pH 8) was added. The mixture was diluted with 30 mL of water and extracted twice with 50 mL of diethyl ether each time. The crude product obtained by concentrating the organic phases was purified by column chromatography. This gave the title compound as a slightly viscous, slightly yellowish oil. (Yield: 11%).
1H-NMR (400 MHz, CDCI3): 1,47 (s, 9H) 1 H-NMR (400 MHz, CDCl 3 ): 1.47 (s, 9H)
2,73 (dd, 1H)2.73 (dd, IH)
2,75 (br. s, 1H)2.75 (br. S, 1H)
2.82 (dd, 1H)2.82 (dd, 1 H)
3,41 (s, 2H)3.41 (s, 2H).
3.44 (s, 3H)3.43 (s, 3H)
3.45 (s, 3H)3.44 (s, 3H)
4,13 (m, 1H)4.13 (m, IH)
4,25 (d, 1H)4.25 (d, IH)
Príklad 2Example 2
Výroba 6,6-dimetoxy-5-hydroxy-3-oxo-terc.-butylhexanoátuPreparation of 6,6-dimethoxy-5-hydroxy-3-oxo-tert-butylhexanoate
Do 1000 ml banky s dvojitým plášťom sa dalo 6,6 g (165 mmol) nátriumhydridu (55— 60 % v minerálnom oleji) a 400 ml tetrahydrofuránu pri 0 °C. K suspenzii nátriumhydridu sa pomocou lievika s ventilom prikvapkalo v priebehu 15 minút 23,75 g (150 mmol) terc.-butylesteru kyseliny acetoctovej (vývin vodíka). Miešalo sa 60 minút, potom sa k reakčnej zmesi prikvapkalo počas cca 40 minút pri 0 °C 100 ml roztoku ·· ·· • · · · • · · • ··· • · ···· ·· ·· ·· • · · • · ··· • · · · • · · · ·· ·· • · • · · • · • · · • · ·· ·To a 1000 mL double-jacketed flask was charged 6.6 g (165 mmol) of sodium hydride (55-60% in mineral oil) and 400 mL of tetrahydrofuran at 0 ° C. 23.75 g (150 mmol) of acetic acetic acid tert-butyl ester (hydrogen evolution) was added dropwise to the sodium hydride suspension via a valve funnel over 15 minutes. Stir for 60 minutes, then add 100 ml of solution dropwise to the reaction mixture over about 40 minutes at 0 ° C. · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · ·
BuLi (1,6 M roztok v hexáne, 160 mmol). Zmes sa miešala cca 25 minút a potom sa prikvapkalo 34,7 g (150 mmol) glyoxal-1,1 -dimetylacetálu (45% roztok v TBME) v priebehu 30 minút. Potom sa 20 minút miešalo pri 0 °C a 1 hodinu pri 20 °C. Pri 0 °C sa pridalo 37 ml koncentrovanej kyseliny chlorovodíkovej a 250 ml vody (-> pH 8).BuLi (1.6 M solution in hexane, 160 mmol). The mixture was stirred for about 25 minutes and then 34.7 g (150 mmol) of glyoxal-1,1-dimethylacetal (45% solution in TBME) was added dropwise over 30 minutes. Then it was stirred at 0 ° C for 20 minutes and at 20 ° C for 1 hour. At 0 ° C, 37 ml of concentrated hydrochloric acid and 250 ml of water (-> pH 8) were added.
• Zmes sa 2-krát extrahovala zakaždým s 250 ml dietyléteru. Surový produkt, ktorý sa získal zahustením organických fáz sa čistil pomocou stĺpcovej chromatografie. Tak sa získala požadovaná zlúčenina v čistej forme. Výťažok: 17,3 g (44 %).The mixture was extracted twice with 250 ml of diethyl ether each time. The crude product obtained by concentrating the organic phases was purified by column chromatography. This gave the title compound in pure form. Yield: 17.3 g (44%).
Príklad 3Example 3
Výroba 3-N-pyrolidino-terc.-butyl-but-2-enoátuPreparation of 3-N-pyrrolidino-tert-butyl-but-2-enoate
Roztok terc.-butylesteru kyseliny acetoctovej (7,91 g, 50 mmol) v 50 ml toluénu sa pridal k 3,75 g pyrolidínu (52,5 mmol) a refluxovalo sa 1,5 hodiny na oddelovači vody. Po tomto čase sa oddelilo teoretické množstvo vody. Enamín sa môže prakticky získať v kvantitatívnom výťažku zahustením reakčnej zmesi.A solution of acetoacetic acid tert-butyl ester (7.91 g, 50 mmol) in 50 mL of toluene was added to 3.75 g of pyrrolidine (52.5 mmol) and refluxed for 1.5 hours on a water separator. After this time, the theoretical amount of water was separated. Enamine can be practically obtained in quantitative yield by concentrating the reaction mixture.
1H-NMR (400 MHz, CDCI3): 1,46 (s, 9H) 1 H-NMR (400 MHz, CDCl 3 ): 1.46 (s, 9H)
1,91 (m, 4H)1.91 (m, 4H)
2,43 (s, 3H)2.43 (s, 3H)
3,27 (br. s, 4H)3.27 (br. S, 4H)
4,41 (s, 1H)4.41 (s, 1 H)
Claims (5)
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| EP98118191 | 1998-09-25 | ||
| US14704199P | 1999-08-03 | 1999-08-03 | |
| PCT/EP1999/007100 WO2000018718A1 (en) | 1998-09-25 | 1999-09-23 | Method for producing 6,6-dialkoxy-5-hydroxy-3-oxo-hexanoic acid esters |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| SK4202001A3 true SK4202001A3 (en) | 2001-12-03 |
Family
ID=56289947
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| SK420-2001A SK4202001A3 (en) | 1998-09-25 | 1999-09-23 | Method for producing 6,6-dialkoxy-5-hydroxy-3-oxo-hexanoic acid esters |
Country Status (11)
| Country | Link |
|---|---|
| EP (1) | EP1115689B1 (en) |
| JP (1) | JP2002525345A (en) |
| CN (1) | CN1209339C (en) |
| AT (1) | ATE259774T1 (en) |
| AU (1) | AU6087299A (en) |
| CA (1) | CA2345134A1 (en) |
| CZ (1) | CZ20011044A3 (en) |
| HU (1) | HUP0103515A3 (en) |
| PL (1) | PL346899A1 (en) |
| SK (1) | SK4202001A3 (en) |
| WO (1) | WO2000018718A1 (en) |
Family Cites Families (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| FR2670206B1 (en) * | 1990-12-11 | 1993-01-22 | Rhone Poulenc Sante | PROCESS FOR THE PREPARATION OF DERIVATIVES OF 3,5-DIHYDROXY ACID PENTANOUIC. |
-
1999
- 1999-09-23 AT AT99947416T patent/ATE259774T1/en not_active IP Right Cessation
- 1999-09-23 AU AU60872/99A patent/AU6087299A/en not_active Abandoned
- 1999-09-23 PL PL99346899A patent/PL346899A1/en unknown
- 1999-09-23 CZ CZ20011044A patent/CZ20011044A3/en unknown
- 1999-09-23 EP EP99947416A patent/EP1115689B1/en not_active Expired - Lifetime
- 1999-09-23 SK SK420-2001A patent/SK4202001A3/en unknown
- 1999-09-23 CA CA002345134A patent/CA2345134A1/en not_active Abandoned
- 1999-09-23 CN CNB998113530A patent/CN1209339C/en not_active Expired - Fee Related
- 1999-09-23 HU HU0103515A patent/HUP0103515A3/en unknown
- 1999-09-23 WO PCT/EP1999/007100 patent/WO2000018718A1/en active IP Right Grant
- 1999-09-23 JP JP2000572180A patent/JP2002525345A/en active Pending
Also Published As
| Publication number | Publication date |
|---|---|
| ATE259774T1 (en) | 2004-03-15 |
| CN1320112A (en) | 2001-10-31 |
| AU6087299A (en) | 2000-04-17 |
| JP2002525345A (en) | 2002-08-13 |
| WO2000018718A1 (en) | 2000-04-06 |
| EP1115689A1 (en) | 2001-07-18 |
| PL346899A1 (en) | 2002-03-11 |
| CN1209339C (en) | 2005-07-06 |
| CZ20011044A3 (en) | 2001-09-12 |
| CA2345134A1 (en) | 2000-04-06 |
| HUP0103515A2 (en) | 2003-08-28 |
| EP1115689B1 (en) | 2004-02-18 |
| HUP0103515A3 (en) | 2003-10-28 |
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