NO752762L - - Google Patents
Info
- Publication number
- NO752762L NO752762L NO752762A NO752762A NO752762L NO 752762 L NO752762 L NO 752762L NO 752762 A NO752762 A NO 752762A NO 752762 A NO752762 A NO 752762A NO 752762 L NO752762 L NO 752762L
- Authority
- NO
- Norway
- Prior art keywords
- chlorophenoxy
- ester
- reaction
- nicotinoyl
- dimethylformamide
- Prior art date
Links
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 45
- 238000006243 chemical reaction Methods 0.000 claims description 24
- LYCAIKOWRPUZTN-UHFFFAOYSA-N ethylene glycol Natural products OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 claims description 21
- -1 glycol ester Chemical class 0.000 claims description 20
- 238000000034 method Methods 0.000 claims description 18
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 16
- WGCNASOHLSPBMP-UHFFFAOYSA-N hydroxyacetaldehyde Natural products OCC=O WGCNASOHLSPBMP-UHFFFAOYSA-N 0.000 claims description 16
- 239000011664 nicotinic acid Substances 0.000 claims description 12
- PVNIIMVLHYAWGP-UHFFFAOYSA-N Niacin Chemical compound OC(=O)C1=CC=CN=C1 PVNIIMVLHYAWGP-UHFFFAOYSA-N 0.000 claims description 11
- 238000004519 manufacturing process Methods 0.000 claims description 8
- 238000009835 boiling Methods 0.000 claims description 7
- 229960003512 nicotinic acid Drugs 0.000 claims description 5
- 235000001968 nicotinic acid Nutrition 0.000 claims description 5
- 150000001447 alkali salts Chemical class 0.000 claims description 4
- 239000002904 solvent Substances 0.000 claims description 4
- 238000002425 crystallisation Methods 0.000 claims description 3
- 230000008025 crystallization Effects 0.000 claims description 3
- 238000004821 distillation Methods 0.000 claims description 3
- 239000000825 pharmaceutical preparation Substances 0.000 claims description 3
- 239000000546 pharmaceutical excipient Substances 0.000 claims 1
- 230000007306 turnover Effects 0.000 claims 1
- 150000002148 esters Chemical class 0.000 description 7
- HVYWMOMLDIMFJA-DPAQBDIFSA-N cholesterol Chemical compound C1C=C2C[C@@H](O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@H]([C@H](C)CCCC(C)C)[C@@]1(C)CC2 HVYWMOMLDIMFJA-DPAQBDIFSA-N 0.000 description 6
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 4
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 4
- 239000000047 product Substances 0.000 description 4
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 3
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 3
- 239000007844 bleaching agent Substances 0.000 description 3
- 235000012000 cholesterol Nutrition 0.000 description 3
- 150000001875 compounds Chemical class 0.000 description 3
- 239000007903 gelatin capsule Substances 0.000 description 3
- 239000000203 mixture Substances 0.000 description 3
- SZIFAVKTNFCBPC-UHFFFAOYSA-N 2-chloroethanol Chemical compound OCCCl SZIFAVKTNFCBPC-UHFFFAOYSA-N 0.000 description 2
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 2
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 2
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 2
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 2
- 239000013543 active substance Substances 0.000 description 2
- 150000001348 alkyl chlorides Chemical class 0.000 description 2
- DLGYNVMUCSTYDQ-UHFFFAOYSA-N azane;pyridine Chemical compound N.C1=CC=NC=C1 DLGYNVMUCSTYDQ-UHFFFAOYSA-N 0.000 description 2
- 239000008280 blood Substances 0.000 description 2
- 210000004369 blood Anatomy 0.000 description 2
- WTEOIRVLGSZEPR-UHFFFAOYSA-N boron trifluoride Chemical compound FB(F)F WTEOIRVLGSZEPR-UHFFFAOYSA-N 0.000 description 2
- 230000003197 catalytic effect Effects 0.000 description 2
- TXCGAZHTZHNUAI-UHFFFAOYSA-N clofibric acid Chemical compound OC(=O)C(C)(C)OC1=CC=C(Cl)C=C1 TXCGAZHTZHNUAI-UHFFFAOYSA-N 0.000 description 2
- 239000008298 dragée Substances 0.000 description 2
- 239000012065 filter cake Substances 0.000 description 2
- 239000000706 filtrate Substances 0.000 description 2
- 235000021588 free fatty acids Nutrition 0.000 description 2
- 238000002844 melting Methods 0.000 description 2
- 230000008018 melting Effects 0.000 description 2
- 239000012452 mother liquor Substances 0.000 description 2
- 239000000843 powder Substances 0.000 description 2
- ATBIAJXSKNPHEI-UHFFFAOYSA-N pyridine-3-carbonyl chloride Chemical compound ClC(=O)C1=CC=CN=C1 ATBIAJXSKNPHEI-UHFFFAOYSA-N 0.000 description 2
- 239000011541 reaction mixture Substances 0.000 description 2
- 150000003839 salts Chemical class 0.000 description 2
- 239000011780 sodium chloride Substances 0.000 description 2
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 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
- UFTFJSFQGQCHQW-UHFFFAOYSA-N triformin Chemical compound O=COCC(OC=O)COC=O UFTFJSFQGQCHQW-UHFFFAOYSA-N 0.000 description 2
- CLWAXFZCVYJLLM-UHFFFAOYSA-N 1-chlorohexadecane Chemical compound CCCCCCCCCCCCCCCCCl CLWAXFZCVYJLLM-UHFFFAOYSA-N 0.000 description 1
- CEJKAKCQVUWNNA-UHFFFAOYSA-N 2-(4-chlorophenoxy)butanoic acid Chemical compound CCC(C(O)=O)OC1=CC=C(Cl)C=C1 CEJKAKCQVUWNNA-UHFFFAOYSA-N 0.000 description 1
- IUAXUYMFMHJWHL-UHFFFAOYSA-N 2-chloroethyl 2-(4-chlorophenoxy)-2-methylpropanoate Chemical compound ClCCOC(=O)C(C)(C)OC1=CC=C(Cl)C=C1 IUAXUYMFMHJWHL-UHFFFAOYSA-N 0.000 description 1
- 229910015900 BF3 Inorganic materials 0.000 description 1
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 1
- 206010014476 Elevated cholesterol Diseases 0.000 description 1
- 206010014486 Elevated triglycerides Diseases 0.000 description 1
- 208000035150 Hypercholesterolemia Diseases 0.000 description 1
- 208000031226 Hyperlipidaemia Diseases 0.000 description 1
- 241001465754 Metazoa Species 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 230000029936 alkylation Effects 0.000 description 1
- 238000005804 alkylation reaction Methods 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- 239000002585 base Substances 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- YMKDRGPMQRFJGP-UHFFFAOYSA-M cetylpyridinium chloride Chemical compound [Cl-].CCCCCCCCCCCCCCCC[N+]1=CC=CC=C1 YMKDRGPMQRFJGP-UHFFFAOYSA-M 0.000 description 1
- 239000007795 chemical reaction product Substances 0.000 description 1
- 238000003776 cleavage reaction Methods 0.000 description 1
- 239000000571 coke Substances 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 238000005260 corrosion Methods 0.000 description 1
- 230000007797 corrosion Effects 0.000 description 1
- 239000013078 crystal Substances 0.000 description 1
- 230000003111 delayed effect Effects 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 235000019439 ethyl acetate Nutrition 0.000 description 1
- 230000007717 exclusion Effects 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 230000007062 hydrolysis Effects 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- 239000012535 impurity Substances 0.000 description 1
- 238000011835 investigation Methods 0.000 description 1
- 229940126601 medicinal product Drugs 0.000 description 1
- 239000000155 melt Substances 0.000 description 1
- 210000002741 palatine tonsil Anatomy 0.000 description 1
- 239000002798 polar solvent Substances 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- 150000003222 pyridines Chemical class 0.000 description 1
- 238000005956 quaternization reaction Methods 0.000 description 1
- 230000035484 reaction time Effects 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 230000007017 scission Effects 0.000 description 1
- 159000000000 sodium salts Chemical class 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 238000005292 vacuum distillation Methods 0.000 description 1
- 238000001291 vacuum drying Methods 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
- C07D213/79—Acids; Esters
- C07D213/80—Acids; Esters in position 3
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pyridine Compounds (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Description
Oppfinnelsen vedrører en fremgangsmåte til fremstilling av a-/~2-(p-klorfenoksy)-isobutyryl7-3-nikotino-ylglykolester. The invention relates to a process for the production of α-β-2-(β-chlorophenoxy)-isobutyryl 7-3-nicotinyl glycol ester.
a-/_ 2- (p-klorf enoksy) - isobutyry_l7-B-nikotinoy 1-glykolester er en kjent kjemisk forbindelse' som smelter ved 47°C. Som bestanddel av farmasøytiske tilberedninger viser a-/_ 2- (p-klorf enoksy) -isobutyryl/-3-nikotinoylglykolester 'lipidsenkende virkning ved hyperlipidemier og ved forhøyet triglycerid- og kolesterolverdier.- Ved kliniske undersøkelser har det vist seg at ved inntak av hver gang 300 mg a-/_ 2-(p-klorfenoksy)-isobutyryl7-3-nikotinoylglykolester pr. pasient og dag ble innholdet av kolesterol, triglycerid, fosfatider og fri fettsyrer i pasientens blod markant senket. α-/_ 2-(p-chlorophenoxy)-isobutyry_17-B-nicotinoy 1-glycol ester is a known chemical compound' which melts at 47°C. As a component of pharmaceutical preparations, α-/_ 2-(p-chlorophenoxy)-isobutyryl/-3-nicotinoyl glycol ester shows a lipid-lowering effect in hyperlipidemias and in elevated triglyceride and cholesterol values.- In clinical investigations, it has been shown that when consuming each time 300 mg α-/_ 2-(p-chlorophenoxy)-isobutyryl7-3-nicotinoyl glycol ester per patient and day, the content of cholesterol, triglyceride, phosphatides and free fatty acids in the patient's blood was markedly lowered.
Det er allerede kjent en fremgangsmåte til fremstilling av a- £ 2-(p-klorfenoksy)-isobutyryJLZ-B-nikotinoyl-glykolester. Ifølge tysk patent nr. 1.941.217 omsettes 2-(p-klorfenoksy)-isosmørsyre med et etylenglykoloverskudd i nærvær av katalytiske mengder fosforsyre og p-toluensulfonsyre til halvester og denne halvester bringes i tetrahydrofuran under isavkjøling til reaksjon med et overskudd nikotinsyreklorid. Etter omkrystallisering fra eddikesteren fåes i 70$-ig utbytte a-_/—2-(p-klorfenoksy)-isobutyry_l7-B_nikotinoyl-glykolesterhydroklorid med et smeltepunkt på 100°C. A method for the production of α-α 2-(β-chlorophenoxy)-isobutyryl JLZ-β-nicotinoyl glycol ester is already known. According to German patent no. 1,941,217, 2-(p-chlorophenoxy)-isobutyric acid is reacted with an excess of ethylene glycol in the presence of catalytic amounts of phosphoric acid and p-toluenesulfonic acid to a half-ester and this half-ester is brought into tetrahydrofuran under ice-cooling to react with an excess of nicotinic acid chloride. After recrystallization from the acetic ester, a-_/-2-(p-chlorophenoxy)-isobutyryl_17-B_nicotinoyl glycol ester hydrochloride with a melting point of 100°C is obtained in 70% yield.
Enskjønt denne fremgangsmåte fører med brukbare resultater til ønsket forbindelse har den imidlertid for-skjellige ulemper. Det med halvesteren til reaksjon bragte nikotinsyreklorid er en hydrolysefølsom forbindelse, hvorfor reaksjonen må gjennomføres under fuktighetsutelukkelse. Deretter oppstår ved denne reaksjon fri saltsyre som stiller spesielle krav til korrosjonsbestandigheten av den benyttede apparatur. Although this method leads to the desired compound with usable results, it has various disadvantages. The nicotinic acid chloride reacted with the half-ester is a hydrolysis-sensitive compound, which is why the reaction must be carried out under exclusion of moisture. This reaction then produces free hydrochloric acid, which makes special demands on the corrosion resistance of the equipment used.
Oppfinnelsens oppgave er å tilveiebringe en forbedret fremgangsmåte til fremstilling av a-/_ 2-(p-klorfenoksy)-isobutyry!L7-3-nikotinoylglykolesterJ som unngår overnevnte ulemper og med forbedret utbytte fører til det ønskede produkt. The task of the invention is to provide an improved process for the production of α-/_ 2-(p-chlorophenoxy)-isobutyryl!L7-3-nicotinoyl glycol esterJ which avoids the above-mentioned disadvantages and with improved yield leads to the desired product.
Fremgangsmåten ifølge oppfinnelsen til fremstilling av ot-X 2-(p-klorfenoksy)-isobutyryl7-3-nikotinoyl-glykolest.er erkarakterisert vedat a-/~~2-(p-klorfenoksy)-isobutyr'yl7-3-kloretylester omsettes med et alkalisalt av nikotinsyre. Under de ifølge oppfinnelsen foreskrevne reak-sjonsbetingelser fremkommer derved den ønskede esterbase i utbytter fra 90 til 95%. The process according to the invention for the production of α-X 2-(p-chlorophenoxy)-isobutyryl7-3-nicotinoyl-glycol ester is characterized by reacting α-β-2-(p-chlorophenoxy)-isobutyryl7-3-chloroethyl ester with an alkali salt of nicotinic acid. Under the reaction conditions prescribed according to the invention, the desired ester base is thereby produced in yields of 90 to 95%.
Por fagfolk er det overraskende at ved omsetningen av det høyere alkylklorid ct-/~2-(p-klorfenoksy)-isobutyryl/-3_ kloretylester med pyridinderivåtet nikotinsyresaltet opptrer praktisk talt ingen kvaternisering av pyridinnitrogenet, da det fra håndboken SYNTHETISCHE ARZNEIMITTEL, utgitt av Dr. W. Knobloch, Akademie-Verlag, Berlin 1961, side 531 er kjent at ved omsetning av pyridin med cetylklorid eller med et annet høyere alkylklorid fåes overveiende N-cetylpyridiniumklorid. Por those skilled in the art, it is surprising that upon the reaction of the higher alkyl chloride ct-/~2-(p-chlorophenoxy)-isobutyryl/-3_ chloroethyl ester with the pyridine derivative wetted nicotinic acid salt, practically no quaternization of the pyridine nitrogen occurs, since from the handbook SYNTHETICSCHE ARZNEIMITTEL, published by Dr W. Knobloch, Akademie-Verlag, Berlin 1961, page 531, it is known that when pyridine is reacted with cetyl chloride or with another higher alkyl chloride, N-cetylpyridinium chloride is predominantly obtained.
Utgående fra denne godt kjente reaksjon er det overraskende at ved omsetningen ifølge oppfinnelsen av a-/_ 2-(p-klorfenoksy)-isobutyryl/-3-kloretylester med et alkali- Starting from this well-known reaction, it is surprising that in the reaction according to the invention of α-/_ 2-(p-chlorophenoxy)-isobutyryl/-3-chloroethyl ester with an alkali-
salt av nikotinsyre inntrer praktisk talt ingen alkylering av pyridinnitrogenet, men det fåes det ønskede a-/_ 2-(p-klorfenoksy )-isobutyry_l7-3-nikotinoyl-glykolester i utbytte fra 90 til 95%. salt of nicotinic acid practically no alkylation of the pyridine nitrogen occurs, but the desired α-/_ 2-(p-chlorophenoxy)-isobutyryl_17-3-nicotinoyl-glycol ester is obtained in a yield of from 90 to 95%.
Ved fremgangsmåten ifølge oppfinnelsen til fremstilling av a-/_ 2-(p-klorfenoksy)-isobutyry.l/-3-nikotinoyl-glykolester omsettes p-klorfenoksy-isosmørsyre-kloretylester med et alkalisalt av nikotinsyre. Fortrinnsvis anvendes derved natriumsaltet av nikotinsyre (Na-nikotinat), enskjønt også andre alkalisalter, som f.eks. Li-nikotinat eller K-nikotinat er godt egnet. Omsetningen av de to reaksjonsdeltagere gjen-nomføres hensiktsmessig i et polart, ved høyere temperatur kokende oppløsningsmiddel. Brukbare oppløsningsmidler hertil er f.eks. tetrahydrofuran, dimetylformamid og dimetylsulfoksyd, idet ifølge oppfinnelsen foretrekkes spesielt omsetningen i dimetylf ormamid, da det herved fåes de beste utbytter av a-/_ 2-(p-klorfenoksy)-isobutyryl7-3-nikotinoylglykolester. Fremgangsmåten ifølge oppfinnelsen gjennomføres ved forhøyet temperatur. In the method according to the invention for the production of α-/_ 2-(p-chlorophenoxy)-isobutyryl.l/-3-nicotinoyl glycol ester, p-chlorophenoxy-isobutyric acid chloroethyl ester is reacted with an alkali salt of nicotinic acid. Preferably, the sodium salt of nicotinic acid (Na-nicotinate) is used, although other alkali salts are also used, such as e.g. Li-nicotinate or K-nicotinate are well suited. The reaction of the two reaction participants is conveniently carried out in a polar solvent boiling at a higher temperature. Solvents that can be used for this are e.g. tetrahydrofuran, dimethylformamide and dimethylsulfoxide, the reaction in dimethylformamide being particularly preferred according to the invention, as this gives the best yields of α-/_ 2-(p-chlorophenoxy)-isobutyryl7-3-nicotinoyl glycol ester. The method according to the invention is carried out at an elevated temperature.
Godt egnet for omsetningen av de foreskrevne reaksjonsdeltagere i et molart oppløsningsmiddel er temperaturer på 120 til l80°C. Ved disse temperaturer er det nød-vendig for en omtrent fullstendig omsetning en reaksjons-varighet fra ca. 20 til 200 minutter, idet ved høyere reaksjonstemperaturer fører allerede kortere reaksjonstider til en tilfredsstillende omsetning. Well suited for the reaction of the prescribed reaction participants in a molar solvent are temperatures of 120 to 180°C. At these temperatures, a reaction duration of approx. 20 to 200 minutes, since at higher reaction temperatures shorter reaction times already lead to a satisfactory conversion.
Fremgangsmåten•ifølge oppfinnelsen til fremstilling av a-/_ 2-(p-klorfenoksy)-isobutyryl7-B-nikotinoyl-glykolester fører da til spesielt gode utbytter, når a-/_ 2-(p-klor-fenoksy)-isobutyryl7-B-kloretylester omsettes med Na-nikotinat 30 til 120 minutter i kokende dimetylformamid. Hensiktsmessig avdestilleres derved fra den kokende dimetylformamid samtidig omtrent 5% dimetylformamid for å fjerne dannede flyktige forurensninger fra reaksjonsblandingen. Etter omset-ningens avslutning avkjøles reaksjonsblandingen til værelsestemperatur og det dannede natriumklorid frafUtreres. Det frafiltrerte natriumklorid vaskes flere ganger med små mengder dimetylformamid, vaskedimetylformamidet forenes med reaksjons-oppløsningen og fra denne avdestilleres fullstendig dimetylformamid ved svakt forhøyet temperatur i vakuum. Det derved gjenblivende, omtrent dimetylformamidfrie, rå.a-/~2-(p-klorfenoksy )-isobutyryl/-B_nikotinoylglykolester opptas med isopropanol, etter tilsetning av et blekemiddel i kokende isopropanol og omrøres ca. 40 til 120 minutter og derpå frafil-treres blekemidlet fra den varme oppløsning. Et godt egnet blekemiddel er eksempelvis "Tonsil" 70 CC. Den frafiltrerte varme oppløsning med det ønskede produkt blandes deretter omtrent i forhold 1 : 1 med kald isopropanol, idet krystallisa-sjonen av den ønskede ester begynner. Etter ca. 6 til 10 timer ved 6 til 8°C er det ønskede produkt sterkt utkrystallisert og krystallgrøten avslynges, knuses og tørkes. Herved fremkommer a-/_ 2- (p-klorfenoksy) - isobutyry_l7-B-nikotinoylglykolester som hvitt, lysegult pulver i omtrent 70 til 75%-ig utbytte. Ved opparbeidelse av moderluten isoleres igjen ca. 20% ester, således at ved fremgangsmåten ifølge oppfinnelsen oppnås et samlet utbytte på ca. 90 til 95%. The process according to the invention for the production of a-/_ 2-(p-chlorophenoxy)-isobutyryl7-B-nicotinoyl glycol ester then leads to particularly good yields, when a-/_ 2-(p-chloro-phenoxy)-isobutyryl7- B-chloroethyl ester is reacted with Na-nicotinate for 30 to 120 minutes in boiling dimethylformamide. Appropriately, approximately 5% of dimethylformamide is distilled from the boiling dimethylformamide at the same time in order to remove formed volatile impurities from the reaction mixture. After completion of the reaction, the reaction mixture is cooled to room temperature and the sodium chloride formed is filtered off. The filtered sodium chloride is washed several times with small amounts of dimethylformamide, the washed dimethylformamide is combined with the reaction solution and from this the complete dimethylformamide is distilled off at a slightly elevated temperature in vacuum. The thus remaining, roughly dimethylformamide-free, crude.α-/~2-(p-chlorophenoxy)-isobutyryl/-β-nicotinoyl glycol ester is taken up with isopropanol, after adding a bleaching agent in boiling isopropanol and stirred approx. 40 to 120 minutes and then the bleaching agent is filtered from the hot solution. A suitable bleaching agent is, for example, "Tonsil" 70 CC. The filtered hot solution with the desired product is then mixed in an approximately 1:1 ratio with cold isopropanol, as the crystallization of the desired ester begins. After approx. 6 to 10 hours at 6 to 8°C, the desired product is strongly crystallized and the crystal mush is spun off, crushed and dried. In this way α-/_ 2-(p-chlorophenoxy)-isobutyry_l7-B-nicotinoylglycol ester appears as a white, pale yellow powder in approximately 70 to 75% yield. When working up the mother liquor, approx. 20% ester, so that with the method according to the invention a total yield of approx. 90 to 95%.
De ved fremgangsmåten ifølge oppfinnelsen anvendte reaksjonsdeltagere, oppløsningsmiddel og hjelpestoffer er vanligvis godt tilgjengelige utgangsmaterialer og kan betegnes handelsvanlige . Skulle a-/_~2- (p-klorfenoksy)-isobutyryl7-B-kloretylester ikke stå til disposisjon i de nødvendige mengder og/eller renhet kan denne ester lett fåes f.eks. av klor- The reaction participants, solvent and auxiliaries used in the method according to the invention are usually readily available starting materials and can be described as commercially available. Should a-/_~2-(p-chlorophenoxy)-isobutyryl7-B-chloroethyl ester not be available in the required quantities and/or purity, this ester can be easily obtained, e.g. of chlorine-
etanol og p-klorfenoksy-isosmørsyre. Eksempelvis oppvarmes 4 mol kloretanol med ett mol p-klorfenoksy-smørsyre i nærvær av katalytiske mengder bortrifluorid (ca. 5$, referert til syre) til ca. 100°C og bringes ved denne temperatur til reaksjon i løpet av 50 til 60 minutter. Deretter avdestilleres overskuddet med kloretanol, residuet opptas i kloroform og vaskes flere ganger med 10%- ig NaHCO-^-oppløsning. Deretter destilleres fraksjonert, idet a- £~2-(p-klorfenoksy)-isobutyryl7-B-kloretylester kan destilleres uten spaltning i vannstråle-vakuum; kokepunkt l8l°C/13 torr. ethanol and p-chlorophenoxy-isobutyric acid. For example, 4 mol of chloroethanol are heated with one mol of p-chlorophenoxy-butyric acid in the presence of catalytic amounts of boron trifluoride (approx. 5$, referred to acid) to approx. 100°C and brought to reaction at this temperature within 50 to 60 minutes. The excess is then distilled off with chloroethanol, the residue is taken up in chloroform and washed several times with 10% NaHCO-^ solution. It is then distilled fractionally, since α-£~2-(p-chlorophenoxy)-isobutyryl7-β-chloroethyl ester can be distilled without cleavage in a water jet vacuum; boiling point l8l°C/13 torr.
Oppfinnelsen skal forklares nærmere ved hjelp avThe invention shall be explained in more detail by means of
et eksempel.An example.
Eksempel.Example.
I en med rører og kolonne utstyrt reaksjonskolbe haes In a reaction flask equipped with a stirrer and column,
8,310 kg a-/<->2-(p-klorfenoksy)-isobutyryl7-B-kloretylester, 8.310 kg α-/<->2-(p-chlorophenoxy)-isobutyryl7-B-chloroethyl ester,
4,350 kg Na-nikotinat og4,350 kg Na-nicotinate and
60,000 liter dimetylformamid60,000 liters of dimethylformamide
og bringes under omrøring og oppvarmning ved 150-155°C til reaksjon i løpet av 60 minutter. Under reaksjonsforløpet fjernes 3 liter dimetylformamid over destillasjonskolonnen ved normalt trykk. Etter avsluttet reaksjon avkjøler man blandingen til værelsestemperatur og fjerner det utskilte koksalt ved filtrer-ing. Ettervaskning av filterkaken foregår med ca. 8 liter dimetylformamid. and brought under stirring and heating at 150-155°C to reaction within 60 minutes. During the course of the reaction, 3 liters of dimethylformamide are removed over the distillation column at normal pressure. After completion of the reaction, the mixture is cooled to room temperature and the separated coke salt is removed by filtration. Post-washing of the filter cake takes place with approx. 8 liters of dimethylformamide.
Filtratet underkaster man en vakuumdestilleringThe filtrate is subjected to vacuum distillation
ved 15-20 torr, idet det fjernes ca. 60 liter dimetylformamid. Destillasjonsresiduet omrøres med 5 liter isopropanol og 0,5 kg aktivkull i 60 minutter under tilbakeløp, filtreres deretter i et trykkfilter. Filterkaken vasker man med ca. 2 liter isopropanol. Filtratet blandes endelig med 3 liter kald isopropanol og bringes til krystallisasjon ved 10°C. Etter henstand natten over sentrifugerer man reaksjonsproduktet og tørker det ved 30°C i vakuum-tørkeskap. Moderluten anvender man ved neste blanding istedenfor isopropanol. at 15-20 torr, removing approx. 60 liters of dimethylformamide. The distillation residue is stirred with 5 liters of isopropanol and 0.5 kg of activated carbon for 60 minutes under reflux, then filtered in a pressure filter. The filter cake is washed with approx. 2 liters of isopropanol. The filtrate is finally mixed with 3 liters of cold isopropanol and brought to crystallization at 10°C. After standing overnight, the reaction product is centrifuged and dried at 30°C in a vacuum drying cabinet. The mother liquor is used in the next mixture instead of isopropanol.
Det fåes rundt 10 kg a- Z^ Z- X- p- klovfenoksy) - isobutyr'yl7-B-nikotinoylglykolester med smeltepunkt 46-48°C ( 91% av det teoretiske). Around 10 kg of a-Z^Z-X-p-chlorophenoxy)-isobutyr'yl7-B-nicotinoylglycol ester with a melting point of 46-48°C (91% of the theoretical) is obtained.
Produktet har følgende analysetall:The product has the following analysis numbers:
Den ifølge oppfinnelsen fremstilte a-/~2-(p-klorfenoksy)isobutyryl7-B-nikotinoylglykolester er et svakt gult krystallinsk pulver som kan anvendes som virksomt stoff i farmasøytiske preparater. Den orale applikasjon, f.eks. i form av tabletter, drasjeer, mykgelatinkapsler og hårdgela-tinkapsler fører hos mennesker og dyr til en klar senkning av innholdet kolesterol, triglycerid, fosfatider og fri fettsyrer i blodet. a-/_ 2-(p-klorfenoksy)-isobutyry3_7-B-nikoti-noylglykolester kan også innarbeides i slike tabletter, The a-/~2-(p-chlorophenoxy)isobutyryl7-B-nicotinoyl glycol ester produced according to the invention is a faint yellow crystalline powder that can be used as an active substance in pharmaceutical preparations. The oral application, e.g. in the form of tablets, dragees, soft-gelatin capsules and hard-gelatin capsules leads to a clear lowering of cholesterol, triglyceride, phosphatides and free fatty acids in the blood in humans and animals. α-/_ 2-(p-Chlorophenoxy)-isobutyry3_7-B-nicotinyl glycol ester can also be incorporated into such tablets,
drasjeer og kapsler som frigjør det virksomme stoff forsinket.dragees and capsules that release the active substance in a delayed manner.
Et egnet oralt anvendbart legemiddel består eksempelvis av gelatinkapsler som i 245 mg voksblanding hver gang inneholder 300 mg a-/~2-(p-klorfenoksy)-isobutyryl7-B-nikotinoylglykolester. A suitable orally applicable medicinal product consists, for example, of gelatin capsules which in 245 mg of wax mixture each contain 300 mg of a-/~2-(p-chlorophenoxy)-isobutyryl7-B-nicotinoyl glycol ester.
Claims (9)
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| GB3877874A GB1442474A (en) | 1974-09-05 | 1974-09-05 | Process for the production of beta-2-p-chlorophenoxy-isobutyryloxy -ethyl nicotinate |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| NO752762L true NO752762L (en) | 1976-03-08 |
Family
ID=10405641
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| NO752762A NO752762L (en) | 1974-09-05 | 1975-08-06 |
Country Status (17)
| Country | Link |
|---|---|
| JP (1) | JPS597702B2 (en) |
| AR (1) | AR205658A1 (en) |
| AT (1) | AT344173B (en) |
| BE (1) | BE832618R (en) |
| CA (1) | CA1054153A (en) |
| CH (1) | CH584198A5 (en) |
| DE (1) | DE2531254A1 (en) |
| DK (1) | DK145929C (en) |
| ES (1) | ES440711A1 (en) |
| FI (1) | FI60392C (en) |
| FR (1) | FR2283892A2 (en) |
| GB (1) | GB1442474A (en) |
| HU (1) | HU169891B (en) |
| NL (1) | NL7510526A (en) |
| NO (1) | NO752762L (en) |
| PL (1) | PL97697B1 (en) |
| YU (1) | YU37132B (en) |
Families Citing this family (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4375545A (en) * | 1981-06-22 | 1983-03-01 | Westwood Pharmaceuticals, Inc. | Process for the synthesis of the nicotinyl ester of 6-aminonicotinic acid |
Family Cites Families (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE2304405A1 (en) * | 1972-03-08 | 1973-09-13 | Hurka Wilhelm | 4-chlorophenoxy-isobutyric acid esters - with antiarteriosclerotic activity |
-
1974
- 1974-09-05 GB GB3877874A patent/GB1442474A/en not_active Expired
-
1975
- 1975-01-01 AR AR260267A patent/AR205658A1/en active
- 1975-07-12 DE DE19752531254 patent/DE2531254A1/en not_active Withdrawn
- 1975-07-18 FI FI752079A patent/FI60392C/en not_active IP Right Cessation
- 1975-07-28 YU YU1923/75A patent/YU37132B/en unknown
- 1975-07-30 AT AT591475A patent/AT344173B/en not_active IP Right Cessation
- 1975-08-06 NO NO752762A patent/NO752762L/no unknown
- 1975-08-21 BE BE159356A patent/BE832618R/en active
- 1975-08-25 CA CA234,142A patent/CA1054153A/en not_active Expired
- 1975-08-29 DK DK390875A patent/DK145929C/en not_active IP Right Cessation
- 1975-08-30 JP JP50105573A patent/JPS597702B2/en not_active Expired
- 1975-09-04 ES ES440711A patent/ES440711A1/en not_active Expired
- 1975-09-04 HU HUME1893A patent/HU169891B/hu not_active IP Right Cessation
- 1975-09-05 NL NL7510526A patent/NL7510526A/en unknown
- 1975-09-05 PL PL1975183136A patent/PL97697B1/en unknown
- 1975-09-05 FR FR7527367A patent/FR2283892A2/en active Granted
- 1975-09-05 CH CH1151575A patent/CH584198A5/xx not_active IP Right Cessation
Also Published As
| Publication number | Publication date |
|---|---|
| ES440711A1 (en) | 1977-03-16 |
| CH584198A5 (en) | 1977-01-31 |
| JPS5168572A (en) | 1976-06-14 |
| DE2531254A1 (en) | 1976-03-25 |
| GB1442474A (en) | 1976-07-14 |
| DK145929B (en) | 1983-04-18 |
| AR205658A1 (en) | 1976-05-21 |
| FR2283892A2 (en) | 1976-04-02 |
| ATA591475A (en) | 1977-11-15 |
| AT344173B (en) | 1978-07-10 |
| FI752079A (en) | 1976-03-06 |
| DK145929C (en) | 1983-09-26 |
| CA1054153A (en) | 1979-05-08 |
| FI60392C (en) | 1982-01-11 |
| HU169891B (en) | 1977-02-28 |
| PL97697B1 (en) | 1978-03-30 |
| NL7510526A (en) | 1976-03-09 |
| FI60392B (en) | 1981-09-30 |
| JPS597702B2 (en) | 1984-02-20 |
| BE832618R (en) | 1975-12-16 |
| DK390875A (en) | 1976-03-06 |
| FR2283892B2 (en) | 1980-08-08 |
| YU192375A (en) | 1983-04-27 |
| YU37132B (en) | 1984-08-31 |
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