PL236430B1 - Derivative of thiophene and method for obtaining it - Google Patents
Derivative of thiophene and method for obtaining it Download PDFInfo
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- PL236430B1 PL236430B1 PL422237A PL42223717A PL236430B1 PL 236430 B1 PL236430 B1 PL 236430B1 PL 422237 A PL422237 A PL 422237A PL 42223717 A PL42223717 A PL 42223717A PL 236430 B1 PL236430 B1 PL 236430B1
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- butan
- methylthiophen
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- 150000003577 thiophenes Chemical class 0.000 title claims abstract description 12
- 238000000034 method Methods 0.000 title claims abstract description 6
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims abstract description 39
- OAKJQQAXSVQMHS-UHFFFAOYSA-N Hydrazine Chemical compound NN OAKJQQAXSVQMHS-UHFFFAOYSA-N 0.000 claims abstract description 26
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims abstract description 21
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims abstract description 18
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 claims abstract description 18
- FUSUHKVFWTUUBE-UHFFFAOYSA-N buten-2-one Chemical compound CC(=O)C=C FUSUHKVFWTUUBE-UHFFFAOYSA-N 0.000 claims abstract description 16
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 12
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims abstract description 10
- KZMGYPLQYOPHEL-UHFFFAOYSA-N Boron trifluoride etherate Chemical compound FB(F)F.CCOCC KZMGYPLQYOPHEL-UHFFFAOYSA-N 0.000 claims abstract description 10
- LSSRGAPUBFMBRJ-UHFFFAOYSA-N C(C)(=O)OC(CCC=1SC(=CC=1C)CCCC)C Chemical compound C(C)(=O)OC(CCC=1SC(=CC=1C)CCCC)C LSSRGAPUBFMBRJ-UHFFFAOYSA-N 0.000 claims abstract description 10
- 238000005886 esterification reaction Methods 0.000 claims abstract description 9
- 230000032050 esterification Effects 0.000 claims abstract description 8
- 238000002955 isolation Methods 0.000 claims abstract description 8
- JVFWKWMSTLLUGZ-UHFFFAOYSA-N 4-(3-methylthiophen-2-yl)butan-2-ol Chemical compound CC(O)CCC=1SC=CC=1C JVFWKWMSTLLUGZ-UHFFFAOYSA-N 0.000 claims abstract description 7
- 238000005804 alkylation reaction Methods 0.000 claims abstract description 7
- 239000012429 reaction media Substances 0.000 claims abstract description 7
- 239000007864 aqueous solution Substances 0.000 claims abstract description 5
- 238000006243 chemical reaction Methods 0.000 claims abstract description 5
- 229910052757 nitrogen Inorganic materials 0.000 claims abstract description 5
- 239000012279 sodium borohydride Substances 0.000 claims abstract description 5
- 229910000033 sodium borohydride Inorganic materials 0.000 claims abstract description 5
- 238000004587 chromatography analysis Methods 0.000 claims abstract description 4
- XVMSFILGAMDHEY-UHFFFAOYSA-N 6-(4-aminophenyl)sulfonylpyridin-3-amine Chemical compound C1=CC(N)=CC=C1S(=O)(=O)C1=CC=C(N)C=N1 XVMSFILGAMDHEY-UHFFFAOYSA-N 0.000 claims abstract description 3
- 238000006722 reduction reaction Methods 0.000 claims abstract 9
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 claims description 21
- -1 4- [3- methyl-5- (3-oxo-butyl) thiophen-2-yl] -butan-2-ol Chemical compound 0.000 claims description 6
- RRPGYRVBJIODMO-UHFFFAOYSA-N C(CCC)C1=CC(=C(S1)CCC(C)O)C Chemical compound C(CCC)C1=CC(=C(S1)CCC(C)O)C RRPGYRVBJIODMO-UHFFFAOYSA-N 0.000 claims description 6
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 6
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 6
- 150000002576 ketones Chemical class 0.000 claims description 6
- WJOQKGDEHMJAJV-UHFFFAOYSA-N 4-(3-methylthiophen-2-yl)butan-2-one Chemical compound CC(=O)CCC=1SC=CC=1C WJOQKGDEHMJAJV-UHFFFAOYSA-N 0.000 claims description 5
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 3
- 239000003377 acid catalyst Substances 0.000 claims description 2
- 150000002009 diols Chemical class 0.000 claims description 2
- 241000243251 Hydra Species 0.000 claims 1
- 239000001257 hydrogen Substances 0.000 claims 1
- 229910052739 hydrogen Inorganic materials 0.000 claims 1
- QRXWMOHMRWLFEY-UHFFFAOYSA-N isoniazide Chemical compound NNC(=O)C1=CC=NC=C1 QRXWMOHMRWLFEY-UHFFFAOYSA-N 0.000 claims 1
- 229910001950 potassium oxide Inorganic materials 0.000 claims 1
- 238000000926 separation method Methods 0.000 claims 1
- 150000001875 compounds Chemical class 0.000 abstract description 8
- AUWLPLYJNSYPMW-UHFFFAOYSA-N C(CCC)C1=C(C=C(S1)CCC(C)=O)C Chemical compound C(CCC)C1=C(C=C(S1)CCC(C)=O)C AUWLPLYJNSYPMW-UHFFFAOYSA-N 0.000 abstract 1
- 150000008064 anhydrides Chemical class 0.000 abstract 1
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 12
- 239000000047 product Substances 0.000 description 7
- 239000000243 solution Substances 0.000 description 6
- 239000000203 mixture Substances 0.000 description 4
- 239000002904 solvent Substances 0.000 description 4
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 3
- 238000005160 1H NMR spectroscopy Methods 0.000 description 3
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 3
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 description 3
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 3
- YTPLMLYBLZKORZ-UHFFFAOYSA-N Thiophene Chemical compound C=1C=CSC=1 YTPLMLYBLZKORZ-UHFFFAOYSA-N 0.000 description 3
- 230000029936 alkylation Effects 0.000 description 3
- 238000002290 gas chromatography-mass spectrometry Methods 0.000 description 3
- 238000002360 preparation method Methods 0.000 description 3
- HGINCPLSRVDWNT-UHFFFAOYSA-N Acrolein Chemical compound C=CC=O HGINCPLSRVDWNT-UHFFFAOYSA-N 0.000 description 2
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- 239000012044 organic layer Substances 0.000 description 2
- 230000003595 spectral effect Effects 0.000 description 2
- 238000001228 spectrum Methods 0.000 description 2
- 229930192474 thiophene Natural products 0.000 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 description 2
- NWZSZGALRFJKBT-KNIFDHDWSA-N (2s)-2,6-diaminohexanoic acid;(2s)-2-hydroxybutanedioic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O.NCCCC[C@H](N)C(O)=O NWZSZGALRFJKBT-KNIFDHDWSA-N 0.000 description 1
- LOXBELRNKUFSRD-UHFFFAOYSA-N 2-propan-2-ylthiophene Chemical compound CC(C)C1=CC=CS1 LOXBELRNKUFSRD-UHFFFAOYSA-N 0.000 description 1
- MNUCWNIDIHCBOU-UHFFFAOYSA-N 4-[4-methyl-5-(3-oxobutyl)thiophen-2-yl]butan-2-one Chemical compound CC(=O)CCC1=CC(C)=C(CCC(C)=O)S1 MNUCWNIDIHCBOU-UHFFFAOYSA-N 0.000 description 1
- HBAQYPYDRFILMT-UHFFFAOYSA-N 8-[3-(1-cyclopropylpyrazol-4-yl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl]-3-methyl-3,8-diazabicyclo[3.2.1]octan-2-one Chemical class C1(CC1)N1N=CC(=C1)C1=NNC2=C1N=C(N=C2)N1C2C(N(CC1CC2)C)=O HBAQYPYDRFILMT-UHFFFAOYSA-N 0.000 description 1
- JQYVTJBTJNNYQC-UHFFFAOYSA-N C(CCC)C=1SC(=CC=1C)CCCC Chemical compound C(CCC)C=1SC(=CC=1C)CCCC JQYVTJBTJNNYQC-UHFFFAOYSA-N 0.000 description 1
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 1
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical class [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 1
- 125000003118 aryl group Chemical group 0.000 description 1
- 239000003054 catalyst Substances 0.000 description 1
- 239000007795 chemical reaction product Substances 0.000 description 1
- 235000020971 citrus fruits Nutrition 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 229940019836 cyclamen aldehyde Drugs 0.000 description 1
- 125000005594 diketone group Chemical group 0.000 description 1
- 238000004821 distillation Methods 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- 238000001704 evaporation Methods 0.000 description 1
- 235000013305 food Nutrition 0.000 description 1
- 239000012634 fragment Substances 0.000 description 1
- 239000003205 fragrance Substances 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- IKDUDTNKRLTJSI-UHFFFAOYSA-N hydrazine monohydrate Substances O.NN IKDUDTNKRLTJSI-UHFFFAOYSA-N 0.000 description 1
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 1
- 239000004615 ingredient Substances 0.000 description 1
- 239000010410 layer Substances 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 230000007935 neutral effect Effects 0.000 description 1
- 230000002085 persistent effect Effects 0.000 description 1
- 239000000376 reactant Substances 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 230000001953 sensory effect Effects 0.000 description 1
- 239000000741 silica gel Substances 0.000 description 1
- 229910002027 silica gel Inorganic materials 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 231100000027 toxicology Toxicity 0.000 description 1
- ZFNVDHOSLNRHNN-UHFFFAOYSA-N xi-3-(4-Isopropylphenyl)-2-methylpropanal Chemical compound O=CC(C)CC1=CC=C(C(C)C)C=C1 ZFNVDHOSLNRHNN-UHFFFAOYSA-N 0.000 description 1
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- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Oxygen Or Sulfur (AREA)
Abstract
Przedmiotem zgłoszenia jest nowy związek, pochodna tiofenu, którą stanowi octan 3-(5-butylo-3-metylotiofen-2-ylo)-1-metylopropylu o wzorze 1. Zgłoszenie dotyczy także sposobu otrzymywania tego związku, który polega na tym, że 4-(3-metylotiofen-2-ylo)-butan-2-on poddaje się reakcji redukcji borowodorkiem sodu w środowisku metanolu, otrzymany w tej reakcji 4-(3-metylo-tiofen-2-ylo)-butan-2-ol, po wyodrębnieniu ze środowiska reakcji, poddaje się reakcji alkilowania metylowinyloketonem w obecności eteratu trifluorku boru w środowisku dichlorometanu, po czym otrzymany w tej reakcji 4-[3-metylo-5-(3-okso-butylo)tiofen-2-ylo]-butan-2-ol, po wyodrębnieniu ze środowiska reakcji, poddaje się redukcji roztworem wodnym hydrazyny w obecności wodorotlenku potasu w środowisku glikolu propylenowego, produkt redukcji, po oddestylowaniu nadmiaru wody i hydrazyny, oraz wydzieleniu się azotu, wyodrębnia się ze środowiska redukcji i poddaje estryfikacji bezwodnikiem octowym w obecności pirydyny w środowisku dichlorometanu, a produkt estryfikacji, po wyodrębnieniu ze środowiska, oczyszcza się chromatograficznie.The subject of the application is a new compound, a thiophene derivative, which is 3-(5-butyl-3-methylthiophen-2-yl)-1-methylpropyl acetate of the formula 1. The application also concerns the method of obtaining this compound, which consists in -(3-methylthiophen-2-yl)-butan-2-one is subjected to a reduction reaction with sodium borohydride in methanol medium, 4-(3-methyl-thiophen-2-yl)-butan-2-ol obtained in this reaction, after isolation from the reaction medium, it is subjected to an alkylation reaction with methyl vinyl ketone in the presence of boron trifluoride etherate in a dichloromethane medium, and then the 4-[3-methyl-5-(3-oxo-butyl)thiophen-2-yl]-butane obtained in this reaction -2-ol, after isolation from the reaction medium, is subjected to reduction with an aqueous solution of hydrazine in the presence of potassium hydroxide in a propylene glycol environment, the reduction product, after distilling off excess water and hydrazine, and releasing nitrogen, is isolated from the reduction medium and subjected to esterification with anhydride in the presence of pyridine in environments in dichloromethane, and the esterification product, after isolation from the medium, is purified by chromatography.
Description
Opis wynalazkuDescription of the invention
Przedmiotem wynalazku jest nowy związek, pochodna tiofenu oraz sposób jej otrzymywania.The subject of the invention is a new compound, a thiophene derivative and the method of its preparation.
Tiofen stanowi fragment strukturalny licznych związków aktywnych sensorycznie, zarówno pochodzenia naturalnego jak i syntetycznego (Safety evolution of substituted thiophene used as flavoring ingredients., Food and Chemical Toxicology, 99, s 40-59, 2016).Thiophene is a structural fragment of numerous sensory active compounds, both of natural and synthetic origin (Safety evolution of substituted thiophene used as flavoring ingredients., Food and Chemical Toxicology, 99, pp. 40-59, 2016).
Z opisu zgłoszenia patentowego P. 412803 jest znana pochodna tiofenu, którą stanowi 2,5-dibutylo-3-metylotiofen o wzorze AFrom the patent application P. 412803 there is known a thiophene derivative, which is 2,5-dibutyl-3-methylthiophene of formula A
AAFyAA wzór AAAFyAA pattern A
Z opisu tego zgłoszenia znany jest także sposób otrzymywania pochodnej tiofenu o wzorze A, polegający na redukcji diketonu, 4-[3-metylo-5-(3-oksobutylo)tiofen-2-ylo]-butan-2-onu przy użyciu hydrazyny w postaci roztworu wodnego o stężeniu 60-85%, wodorotlenku potasowego oraz glikolu etylenowego, w temperaturze 115-180°C w czasie do 2 godzin, a po oddestylowaniu wody i nadmiaru hydrazyny oraz wydzieleniu się azotu, produkt reakcji schładza się, dodaje do niego wodę i oddestylowuje się z parą wodną związek o wzorze A.The description of this application also describes a method for the preparation of a thiophene derivative of the formula A, which consists in reducing the diketone, 4- [3-methyl-5- (3-oxobutyl) thiophen-2-yl] -butan-2-one with hydrazine in in the form of an aqueous solution with a concentration of 60-85%, potassium hydroxide and ethylene glycol, at a temperature of 115-180 ° C for up to 2 hours, and after the distillation of water and excess hydrazine and the evolution of nitrogen, the reaction product is cooled and water is added to it and distilling off with steam the compound of formula A.
Z opisu patentowego EP 1458705 B1 znany jest tiofenowy analog aldehydu cyklamenowego o wzorze B, który otrzymuje się przez alkilowanie 2-izopropylotiofenu akroleiną w obecności kwasu p-toluenosulfonowego jako katalizatoraEP 1458705 B1 describes a thiophene analog of cyclamenaldehyde of formula B, which is obtained by alkylation of 2-isopropylthiophene with acrolein in the presence of p-toluenesulfonic acid as a catalyst
wzór Bpattern B
Przedmiotem wynalazku jest nowa pochodna tiofenu, którą stanowi racemiczny octan 3-(5-butylo-3-metylotiofen-2-ylo)-1-metylopropylu o wzorze 1The subject of the invention is a new thiophene derivative, which is racemic 3- (5-butyl-3-methylthiophen-2-yl) -1-methylpropyl acetate of formula 1
wzór 1pattern 1
Nowa pochodna tiofenu o wzorze 1, stanowiąca mieszaninę dwóch enancjomerów, jest cieczą o barwie jasnozielonej, charakteryzującą się bardzo przyjemnym, czystym, cytrusowo-owocowym zapachem, przy czym zapach ten jest bardzo trwały i jest wyczuwalny z paska bibuły nawet po 30 dniach. Dane spektralne nowego związku, octanu 3-(5-butylo-3-metylotiofen-2-ylo)-1-metylopropylu są następujące:The new thiophene derivative of the formula I, which is a mixture of two enantiomers, is a light green liquid, characterized by a very pleasant, pure, citrus-fruit smell, the smell is very persistent and can be felt from the blotting paper strip even after 30 days. The spectral data of the new compound, 3- (5-butyl-3-methylthiophen-2-yl) -1-methylpropyl acetate, is as follows:
1H-NMR (CDCb), 6.44 ppm (s 1 H-2), 4.92 (m 1 H-8), 2.70 ppm (m 4 H-6,12), 2.14 ppm (s 3 H-5) 2.05 ppm (d 3 H-11) 1.88 ppm (m 2 H-7), 1.61 ppm (m 2 H-13), 1.38 ppm (m 2 H-14) 1.25 ppm (d 3 H-9) 0.93 ppm (t 3 H-15); 1 H-NMR (CDClb), 6.44 ppm (s 1 H-2), 4.92 (m 1 H-8), 2.70 ppm (m 4 H-6.12), 2.14 ppm (s 3 H-5) 2.05 ppm (d 3 H-11) 1.88 ppm (m 2 H-7), 1.61 ppm (m 2 H-13), 1.38 ppm (m 2 H-14) 1.25 ppm (d 3 H-9) 0.93 ppm (t 3 H-15);
13C-NMR (CDCb), 170.70 ppm (s C-10), 141.34 ppm (s C-11), 134.20 ppm (s-4), 132.15 ppm (s C-3), 126.98 ppm (s C-2), 70.39 ppm (s C-8), 37.60 ppm (s C-7), 33.83 ppm (s C-12), 29.71 ppm 13 C-NMR (CDCb), 170.70 ppm (s C-10), 141.34 ppm (s C-11), 134.20 ppm (s-4), 132.15 ppm (s C-3), 126.98 ppm (s C-2 ), 70.39 ppm (s C-8), 37.60 ppm (s C-7), 33.83 ppm (s C-12), 29.71 ppm
PL 236 430 Β1 (s C-13), 23.90 ppm (s C-6), 22.27 ppm (s C-14), 21.35 ppm (s C-11), 20.04 (s C-9), 13.86 ppm (s C-15), 13.51 ppm (s C-5);PL 236 430 Β1 (s C-13), 23.90 ppm (s C-6), 22.27 ppm (s C-14), 21.35 ppm (s C-11), 20.04 (s C-9), 13.86 ppm (s C-15), 13.51 ppm (s C-5);
IR (cm1): 2957.59, 29277.77, 1736.46, 1371.49, 1237.78;IR (cm 1 ): 2957.59, 29277.77, 1736.46, 1371.49, 1237.78;
GC-MS (m/z): 43(19), 77(5), 91(12), 111(17), 124(11), 137(17), 151(12), 165(100), 167(50), 193(29), 208(50), 268(M+ 18).GC-MS (m / z): 43 (19), 77 (5), 91 (12), 111 (17), 124 (11), 137 (17), 151 (12), 165 (100), 167 (50), 193 (29), 208 (50), 268 (M + 18).
Nowy związek, octan 3-(5-butylo-3-metylotiofen-2-ylo)-1-metylopropylu ze względu na bardzo cenne walory zapachowe i trwałość, może znaleźć zastosowanie jako składnik kompozycji zapachowych różnego przeznaczenia.The new compound, 3- (5-butyl-3-methylthiophen-2-yl) -1-methylpropyl acetate, due to its very valuable aromatic qualities and durability, can be used as a component of fragrance compositions for various purposes.
Sposób otrzymywania pochodnej tiofenu, octanu 3-(5-butylo-3-metylotiofen-2-ylo)-1-metylopropylu o wzorze 1, z wykorzystaniem reakcji redukcji ketonu borowodorkiem sodu w środowisku alkoholu, reakcji alkilowania alkoholu metylowinyloketonem w środowisku katalizatora kwasowego, reakcji redukcji ketonu roztworem wodnym hydrazyny w środowisku zasadowym w obecności diolu oraz reakcji estryfikacji alkoholu bezwodnikiem octowym w środowisku zasadowym, według wynalazku polega na tym, że reakcji redukcji borowodorkiem sodu poddaje się 4-(3-metylotiofen-2-ylo)-butan-2-on w środowisku metanolu w temperaturze 0-5°C w czasie 2 godzin, stosując 0,13 g borowodorku i 5 ml metanolu na 1 g 4-(3-metylotiofen-2-ylo)-butan-2-onu. Otrzymany w tej reakcji 4-(3-metylotiofen-2-ylo)-butan-2-ol, po wyodrębnieniu ze środowiska reakcji, poddaje się reakcji alkilowania metylowinyloketonem w obecności eteratu trifluorku boru w środowisku dichlorometanu w temperaturze 10-25°C w czasie 3 godzin, stosując 0,5 g metylowinyloketonu, 0,2 ml eteratu trifluorku boru i 15 ml dichlorometanu na 1 g 4-(3-metylotiofen-2-ylo)-butan-2-olu. Produkt alkilowania, 4-[3-metylo-5-(3-oksobutylo)tiofen-2-ylo]-butan-2-ol, po wyodrębnieniu ze środowiska reakcji, poddaje się redukcji roztworem wodnym hydrazyny o stężeniu 80-85% w obecności wodorotlenku potasu w środowisku glikolu propylenowego w temperaturze 110-190°C w czasie 1-3 godzin, stosując 3,75 ml hydrazyny, 2 g wodorotlenku potasu i 5,6 ml glikolu propylenowego na 1 g 4-[3-metylo-5-(3-oksobutylo)tiofen-2-ylo]-butan-2-olu. Produkt redukcji, 4-(5-butylo-3-metylotiofen-2-ylo)-butan-2-ol, po oddestylowaniu nadmiaru wody i hydrazyny oraz wydzieleniu się azotu, wyodrębnia się ze środowiska i poddaje estryfikacji bezwodnikiem octowym w obecności pirydyny w środowisku dichlorometanu w temperaturze 40°C w czasie 1,5 godziny, stosując 1,75 g bezwodnika octowego, 1,2 ml pirydyny, 3 ml dichlorometanu na 1 g 4-(5-butylo-3-metylotiofen-2-ylo)-butan-2-olu. Produkt estryfikacji, po wyodrębnieniu ze środowiska reakcji, oczyszcza się chromatograficznie.The method of obtaining the thiophene derivative, 3- (5-butyl-3-methylthiophen-2-yl) -1-methylpropyl acetate, formula 1, using the reduction of the ketone with sodium borohydride in an alcohol medium, the alkylation of the alcohol with methyl vinyl ketone in an acid catalyst, the reaction the reduction of the ketone with an aqueous solution of hydrazine in a basic medium in the presence of a diol and the esterification of the alcohol with acetic anhydride in a basic medium, according to the invention, consists in subjecting 4- (3-methylthiophen-2-yl) -butan-2- on in methanol at 0-5 ° C for 2 hours, using 0.13 g of borohydride and 5 ml of methanol per 1 g of 4- (3-methylthiophen-2-yl) -butan-2-one. The 4- (3-methylthiophen-2-yl) -butan-2-ol obtained in this reaction, after isolation from the reaction medium, is subjected to a methyl vinyl ketone alkylation reaction in the presence of boron trifluoride etherate in a dichloromethane medium at a temperature of 10-25 ° C during 3 hours, using 0.5 g of methylvinylketone, 0.2 ml of boron trifluoride etherate and 15 ml of dichloromethane per 1 g of 4- (3-methylthiophen-2-yl) -butan-2-ol. The alkylation product, 4- [3-methyl-5- (3-oxobutyl) thiophen-2-yl] -butan-2-ol, after isolation from the reaction medium, is reduced with an 80-85% aqueous hydrazine solution in the presence of potassium hydroxide in propylene glycol medium at 110-190 ° C for 1-3 hours, using 3.75 ml of hydrazine, 2 g of potassium hydroxide and 5.6 ml of propylene glycol per 1 g of 4- [3-methyl-5- (3-oxobutyl) thiophen-2-yl] -butan-2-ol. The reduction product, 4- (5-butyl-3-methylthiophen-2-yl) -butan-2-ol, after distilling off the excess water and hydrazine and the evolution of nitrogen, is separated from the medium and subjected to esterification with acetic anhydride in the presence of pyridine in the medium of dichloromethane at 40 ° C for 1.5 hours using 1.75 g of acetic anhydride, 1.2 ml of pyridine, 3 ml of dichloromethane per 1 g of 4- (5-butyl-3-methylthiophen-2-yl) -butane -2-ol. The esterification product, after isolation from the reaction medium, is purified by chromatography.
Przebieg procesu otrzymywania octan 3-(5-butylo-3-metylotiofen-2-ylo)-1-metylopropylu ilustruje poniższy schemat:The course of the preparation of 3- (5-butyl-3-methylthiophen-2-yl) -1-methylpropyl acetate is illustrated by the following scheme:
Przedmiot wynalazku ilustruje poniższy przykład.The following example illustrates the subject of the invention.
PrzykładExample
W zlewce sporządzono roztwór 11,02 g (0,066 mola) 4-(3-metylotiofen-2-ylo)-butan-2-onu w 50 ml alkoholu metylowego, po czym roztwór ten umieszczono w łaźni lodowej i podczas mieszania dodano do niego 1,46 g (0,038 mola) borowodorku sodu. Następnie odparowano na wyparce rotacyjnej alkohol metylowy, pozostałość zakwaszono kwasem solnym do pH ok. 2 i ekstrahowano heksanem (2 porcjami x 50 ml), a następnie przemyto wodą do odczynu obojętnego. Po odparowaniu rozpuszczalnika na wyparce próżniowej otrzymano 9,0 g 4-(3-metylotiofen-2-ylo)-butan-2-olu o czystości chromatograficznej 99%, co stanowiło 81% wydajności teoretycznej. Strukturę związku potwierdziły widma:A solution of 11.02 g (0.066 mol) of 4- (3-methylthiophen-2-yl) -butan-2-one in 50 ml of methyl alcohol was prepared in a beaker, then this solution was placed in an ice bath and 1 was added with stirring. 46 g (0.038 mol) of sodium borohydride. Then, the methyl alcohol was evaporated on a rotary evaporator, the residue was acidified with hydrochloric acid to a pH of about 2 and extracted with hexane (2 portions x 50 ml), and then washed with water until neutral. After evaporating the solvent in a vacuum evaporator, 9.0 g of 4- (3-methylthiophen-2-yl) -butan-2-ol were obtained with a chromatographic purity of 99%, which was 81% of theory. The structure of the compound was confirmed by the spectra:
1H-NMR (CDCh), 7.04- 6.82 ppm (dd 2 H-1,2), 3.86 ppm (m 1 H-8), 2.85 ppm (m 2 CH2-łańcuch), 2.21 ppm (s 3 H-5), 1.82 ppm (m 2 CH2-łańcuch), 1.28 ppm (dd 3 H-9); 1 H-NMR (CDCl 3), 7.04- 6.82 ppm (dd 2 H-1.2), 3.86 ppm (m 1 H-8), 2.85 ppm (m 2 CH 2 -chain), 2.21 ppm (s 3 H- 5), 1.82 ppm (m 2 CH 2 -chain), 1.28 ppm (dd 3 H-9);
13C-NMR (CDCh), 137.70 ppm (s C-4), 132.40 ppm (s C-3), 129.77 ppm (s C-2), 120.77 ppm (s C-1), 66.99 ppm (s C-8), 40.39 ppm (s C-7), 23.98 ppm (s C-6), 23.32 ppm (s C-9), 13.37 ppm (s C-5); 13 C-NMR (CDCl 3), 137.70 ppm (s C-4), 132.40 ppm (s C-3), 129.77 ppm (s C-2), 120.77 ppm (s C-1), 66.99 ppm (s C- 8), 40.39 ppm (s C-7), 23.98 ppm (s C-6), 23.32 ppm (s C-9), 13.37 ppm (s C-5);
IR (cm1), 3349.26, 2965.86, 2925.02, 2859.43, 1450.65, 1374.05, 1328.02;IR (cm 1 ), 3349.26, 2965.86, 2925.02, 2859.43, 1450.65, 1374.05, 1328.02;
GC-MS (m/z), 45(19), 77(12), 97(26), 111(100), 112(31), 137(81), 152(14), 170 (M+ 29).GC-MS (m / z), 45 (19), 77 (12), 97 (26), 111 (100), 112 (31), 137 (81), 152 (14), 170 (M + 29) .
W kolbie okrągłodennej, dwuszyjnej, zaopatrzonej w termometr i wkraplacz umieszczono 4 g (0,024 mola) 4-(3-metylotiofen-2-ylo)-butan-2-olu, 0,8 ml eteratu trifluoroborku, 55 ml dichlorometanu. Kolbę umieszczono w łaźni lodowej i wkraplano do niej roztwór 2 g (0,029 mola) metylowinyloketonu4 g (0.024 mol) of 4- (3-methylthiophen-2-yl) -butan-2-ol, 0.8 ml of trifluoroboride etherate, 55 ml of dichloromethane were placed in a round bottom two-necked flask equipped with a thermometer and dropping funnel. The flask was placed in an ice bath and a solution of 2 g (0.029 mol) of methyl vinyl ketone was added dropwise to it.
PL 236 430 Β1 w 5 ml dichlorometanu, tak aby temperatura nie przekraczała 25°C. Po całkowitym wkropleniu ketonu zawartość kolby mieszano jeszcze przez 3 godziny, a następnie dodano 15 ml nasyconego roztworu węglanu sodu i całość mieszano 15 minut. Produkt ekstrahowano eterem, przemyto wodą, osuszono nad bezwodnym siarczanem magnezu i odparowano rozpuszczalnik. Otrzymano 5,6 g surowego 4-[3-metylo-5-(3-oksobutylo)tiofen-2-ylo]-butan-2-olu o czystości chromatograficznej 83% z wydajnością 81%. Otrzymany produkt poddano redukcji hydrazyną. W tym celu umieszczono w kolbie 5,6 g (0,023 mola) ketonu, roztwór 11 g KOH (0,2 mola) w 30 ml glikolu propylenowego, 20 ml 85% wodzianu hydrazyny i całość ogrzewano utrzymując w stanie wrzenia przez około 1,5 godziny. Następnie oddestylowano nadmiar wody i hydrazyny zbierając frakcję o temperaturze 118-125°C, po czym reagenty ogrzewano pod chłodnicą zwrotną do momentu zakończenia wydzielania się azotu. Po ostudzeniu dodano 30 ml wody, oddzielono warstwę organiczną a warstwę wodną ekstrahowano 3 porcjami po 25 ml heksanu. Połączone warstwy organiczne przemyto wodą i suszono nad bezwodnym siarczanem magnezu. Rozpuszczalnik odparowano na wyparce rotacyjnej, w wyniku czego otrzymano 4,23 g (wydajność 85%) 4-(5-butylo-3-metylotiofen-2-ylo)-butan-2-olu o czystości 92%. Strukturę otrzymanego produktu potwierdziły widma:PL 236 430 Β1 in 5 ml of dichloromethane so that the temperature does not exceed 25 ° C. After complete dropwise addition of the ketone, the contents of the flask were stirred for an additional 3 hours, then 15 ml of saturated sodium carbonate solution was added and the mixture was stirred for 15 minutes. The product was extracted with ether, washed with water, dried over anhydrous magnesium sulfate and the solvent was evaporated. 5.6 g of crude 4- [3-methyl-5- (3-oxobutyl) thiophen-2-yl] -butan-2-ol were obtained with a chromatographic purity of 83% with a yield of 81%. The obtained product was reduced with hydrazine. To this end, 5.6 g (0.023 mol) of ketone, a solution of 11 g of KOH (0.2 mol) in 30 ml of propylene glycol, 20 ml of 85% hydrazine hydrate, were placed in the flask and the mixture was heated under reflux for about 1.5 hours. Then excess water and hydrazine were distilled off, collecting the fraction at 118-125 ° C, and the reactants were refluxed until nitrogen evolution ceased. After cooling, 30 ml of water was added, the organic layer was separated and the aqueous layer was extracted with 3 portions of 25 ml of hexane. The combined organic layers were washed with water and dried over anhydrous magnesium sulfate. The solvent was evaporated on a rotary evaporator to obtain 4.23 g (85% yield) of 4- (5-butyl-3-methylthiophen-2-yl) -butan-2-ol with a purity of 92%. The structure of the obtained product was confirmed by the spectra:
1H-NMR (CDCh), 6.46 ppm (s 1 H-2), 3.85 ppm (m 1 H-8, hydroksyl), 2.91-2.66 ppm (m 4 H-6,12), 2.11 ppm (s 3 H-5), 1.78-1.38 ppm (m 4 H-13,7) 1.39 ppm (m 2 H-14), 1.24 ppm (d 3 H-9), 0.94 ppm (t 3 H-15); 1 H-NMR (CDCl 3), 6.46 ppm (s 1 H-2), 3.85 ppm (m 1 H-8, hydroxyl), 2.91-2.66 ppm (m 4 H-6.12), 2.11 ppm (s 3 H -5), 1.78-1.38 ppm (m 4 H-13.7) 1.39 ppm (m 2 H-14), 1.24 ppm (d 3 H-9), 0.94 ppm (t 3 H-15);
13C-NMR (CDCh), 140.99 ppm (s C-1), 135.12 ppm (s C-4), 132.05 ppm (s C-3), 126.45 ppm (s C-2), 67.46 ppm (s C-8), 40.61 ppm (s C-7), 33.72 (s C-12), 29.61 ppm (s C-13), 24.18 (s C-6), 23.52 ppm (s C-9), 22.19 ppm (s C-14), 13.80 ppm (s C-15), 13.51 (s C-5); 13 C-NMR (CDCl 3), 140.99 ppm (s C-1), 135.12 ppm (s C-4), 132.05 ppm (s C-3), 126.45 ppm (s C-2), 67.46 ppm (s C- 8), 40.61 ppm (s C-7), 33.72 (s C-12), 29.61 ppm (s C-13), 24.18 (s C-6), 23.52 ppm (s C-9), 22.19 ppm (s C-14), 13.80 ppm (s C-15), 13.51 (s C-5);
IR (cm-1): 3347.82, 2957.54,2925.17, 2859.41, 1456.53, 1376.69;IR (cm- 1 ): 3347.82, 2957.54, 2925.17, 2859.41, 1456.53, 1376.69;
GC-MS (m/z): 45(12), 91(22), 111(38), 125(27), 137(21), 165(95), 167(100), 168(32), 193(21), 208(13), 226(M+ 46).GC-MS (m / z): 45 (12), 91 (22), 111 (38), 125 (27), 137 (21), 165 (95), 167 (100), 168 (32), 193 (21), 208 (13), 226 (M + 46).
4,22 g (0,019 mola) 4-(5-butylo-3-metylotiofen-2-ylo)-butan-2-olu poddano estryfikacji przez ogrzewanie z 3,57 g (0,035 mola) bezwodnika octowego, 2,4 ml (0,03 mola) pirydyny i 5 ml dichlorometanu w ciągu 1,5 godziny w temperaturze 40°C. Po zakończeniu estryfikacji produkt rozcieńczono wodą i ekstrahowano heksanem (3 porcje po 10 ml), przemyto wodą i osuszono nad bezwodnym siarczanem magnezu. Następnie usunięto rozpuszczalnik pod próżnią (8 kPa) uzyskując 4,21 g (0,015 mola) surowego octanu 3-(5-butylo-3-metylotiofen-2-ylo)-1-metylopropylu o czystości 91% (GC), który oczyszczono na kolumnie chromatograficznej wypełnionej silikażelem, stosując jako eluent heksan/octan etylu (95:5).4.22 g (0.019 mol) 4- (5-butyl-3-methylthiophen-2-yl) -butan-2-ol was esterified by heating with 3.57 g (0.035 mol) acetic anhydride, 2.4 ml ( 0.03 mol) of pyridine and 5 ml of dichloromethane during 1.5 hours at the temperature of 40 ° C. After esterification was complete, the product was diluted with water and extracted with hexane (3 portions of 10 ml), washed with water and dried over anhydrous magnesium sulfate. Then the solvent was removed in vacuo (8 kPa) to give 4.21 g (0.015 mol) of crude 3- (5-butyl-3-methylthiophen-2-yl) -1-methylpropyl acetate, 91% pure (GC), which was purified chromatography column packed with silica gel, eluting with hexane / ethyl acetate (95: 5).
Otrzymano 3,75 g octanu 3-(5-butylo-3-metylotiofen-2-ylo)-1-metylopropylu o czystości 98% (GC). Budowę otrzymanego estru potwierdziły jego dane spektralne.3.75 g of 3- (5-butyl-3-methylthiophen-2-yl) -1-methylpropyl acetate with a purity of 98% (GC) was obtained. The structure of the obtained ester was confirmed by its spectral data.
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