DE1445652A1 - New glutarimides and methods of making them - Google Patents

Description

New glutarimides and process for their preparation The present invention relates to novel derivatives of glutarimide, and in particular '* substituted derivatives. The present invention relates to compounds of the formula in which R 1 is an alkyl o the substituted alkyl group with at least 3 carbon atoms and R 2 for one Alkyl or substituted alkyl group; or R 1 is a eolo & Uyl or substituted cycloalkyl group and% one, alkyl, substituted alkyl-o Cyoloalkyl- or aubeti- The tuated eclealkyl group means al or R, and form R2 zuemmen with Kohlenotoffatom the Glutariiaidringen, to whom she is bound, an alieyel or substituted on an alioyclic ring; and It 3 stands at £ around Wasseratoffatoin odor an alkyl, eubatitularte alkyl, cyclo. alkyl-, substituted cycloalkyl-9 aryl-v substituted aryl-t- Aralkyl or substituted aralkyl groups Compounds of this formula have been described below as rituted o (sc (-1) ialkylglutarimide bezololmeto where alkyl group. mentioned, both straight-chain and branched chain all-.yl group includes-his If R 1 and B 2 contain substituent groups, they are a expedient, for example, 11a10genatomoo Hydroxyl-wp Alkyl-p Alkoxy- uiad Aoyloxyf, -ruppon. Suitable substituents for It 3 are, for example, Hydroxyl-v carboxyl, ajain, AJIVJ = in- and dialW1amine groups. Beuonderu voraugto prebondings are d, -Butyl-. "- Uthylglutar- imidp G (-Dutyl-o (-äthjl-N-benzylgz £ .utarimid " glutariviid. The present invention also insists on a method ren to the Haratellun & from-aubjtituierte & peDialklIglutarlmiden the formal In which ni B2 and BJ the above mentioned Bedautunj bault..un, (Iaa by akaiinzeialinet intg that ain-substituted ildeliyd der-Pormelt R2 korylnitril hydrolysiert.und kondeneiertu the cyanide group to the products obtained, the aldehyde group is oxidized in order to prepare the corresponding aubstituierten glutaric and eubetituierte glutarsäurt by Umaatzung the Süure ihrea or anhydrides with Barnstoff, 9 aubstituiertem urea # ammonia or an amine of Yormel IR 3 NU, to cKpe-D: Lalkylglutariaid is converted. The condensation of the substituted aldehyde with koryl. nitrile is expediently carried out in the presence of a similar catalyst. nato 'o wi o 0 eg a Alkallmstallhydroxyd or Benzyltrinethyl. The hydrolysis of the cyanide group and the oxidation of the aldehyde group of the condensation products can take place in any desired manner it is preferred to first carry out the hydrolysis of the cyanide group under alkaline conditions, then to obtain the product obtained and then to oxidize the aldehyde group. Beaondeta prefers to hydrolyze the cyanide group with potassium or sodium hydroxide, to obtain the product obtained as free urine, to convert ea into a salt and to oxidize the aldehyde group with alkaline potassium permaganate » -The conversion of the aubetituietteÜ glutaroäÜre ih dlutar- imid k = n- in * every common white #success. For example, di4 Acid or its anhydride with urea a substituted urine stofi dd4r, Amäinoniäk ur # set w'erdän. Where an N-zubstiiulertee Glutari-inid gevi ## hgoht iatt can use an amine of the formula R 3 NH 2 the glutaric acid or the arihydride has been changed, whereby B 3 has the meaning given above * In die-Gela case know purpose- moderately no, first the appropriate one . substituted glutaramic acid to produce and then the connection by heating with a 1) ehydratis-Icrung.giliitt'el "'- w: Le ZB -t #, asigoäurahydrid or Avetylohloridl to effect '* - .The compounds of the formula according to the invention have as kxampfatillehden means and / or ledativa proven effective. * The present invention we (Ydurcii 'the following examples illustrates in more detail "which the production of certain new bindings. B 0 1 s T), generally 1, 1 Production of o (-Dutyl-O # -äthylglutarimid 128 g V% -] 3iityl-O (-i # thylacetaldeh-yd were with 11 j, 5 a 45-Xigen Gew./#Geiv. Potassium hydroxide lb, aung -beha . nIdelt and the mix stirred at 55-600. Within an hour were 53v0 Aerv1- nitrile eln, # c-drip-t and-die Alischt white 0 tere 4 hours at 55-60 , r-eriih: rt .. After cooling down, the mixture was diluted with Hydrochloric acid and the precipitated. Drowned in ether. The ätheriacho'-solution.vi was with Wageär'Jpväßehen, dried and the ether through 1) entillätion -untre r removed under reduced pressure. The remaining brown 31 was used to recover 2 (2-cyan Ethyl) -2-ethylhexanal fractionally distilled. Yield 100 Z; 20th 19.1.109,116.1; nj ' 194525. 100 g of the 2- (2-cyanoithyl) -2.iithyl- prepared above h xanal, were 6 hours with a solution of 32 g of sodium hydroxide heated in 320 o = water to the river Büok. After cooling it was the solution with conc. Acidified hydrochloric acid and the precipitated oil In Ilther extrahlorte The ätlierische solution was overall with water wash and dry and take the ether by distillation reduced] pressure removed. The remaining oil was in a Solution of 42 g of Kaltumhydroxyd dissolved in 420 com of water and the 14aung stirred at 40-50. In addition, a coach pension was gradually established from 95 a of potassium permanganate in 925 aam of water added, then the mixture was stirred for a further 3 hours at 40,500 and then over ] [eight admitted. Then the mixture was filtered and that ] Piltrat decolorized with diluted hydrogen peroxide. After a The filtrate was further filtered with constant hydrochloric acid. solidified nici aguert. c (-Butyl-ethylglutaric acid was precipitated and / fully- steadily after a few hours. This column was filtered off and no el # me yield of 5792 C obtained. From the mother liquor were another 79.0 g of crude * material was obtained. 21 p6 g of the e-butyl-4-äthjrlglutaraiiur4 found above Carnstoff were on an oil bath for 395 hours 160-lW under lWarm erhilsto, the mixture cooled and with Dae Ithylaottat was created by delatillation father vvr * and « removed the pressure and received * brown oil ! some Xal extracted with X * U on Petrollither (bp 60-80c) . Dietge kc "binterten extracts yielded after evaporation a white Vur- bindungg x "Lich ck-Butyl-d, -ätby] Zlutarizid, dan according Umkrietttlli- sation aim retroläther (bp * 60-800) has a melting point of 64-660 tesass * Analysis; for 01iN 1-9M2 ber.i 0 66t§5. 11 9971 X 7p10 '% found 2 C 66975 N 9968 X 7909% B e 1 a -p 1. e l ' 2- Manufacture of ayolopentan-spiro-4 (-alutarimid 21 90 g of cyclopentanaldehyde were -with 09.6 com a 40 -%. wäaarigen Benzyltrimothylammoniumhydroxvdlösvng treated and heated with stirring to 45-50 0th Within two minutes 1395 Z aatyluitril added dropwise and then the mixture for 4 hours at 45-50 0 stirred. After cooling, the mixture was dilute with acidified with hydrochloric acid and the precipitated oil in Ither extra- here. The ethereal solution was waxed with Wanser, dries and the ether by deotillation under pre-maintained pressure removed. The remaining brown 01 was used to win 1- (2-cyanoethyl) -cyclopentanaldehyde fractionally distilled. C 20 Yield 10.3 g; KP-GR, 134-140 ; m 1A685 nD 100 g of the 1- (2-cyanoethyl) -cyclopgntan- prepared above aldehyde were 4 hours with 3 "6 Z sodium hydroxide, In 36- com Vasser heated to reflux. The] solution vmrde - cooled and with COUZ * hydrochloric acid angosLuert, the precipitated 01 was in ether fxtrahlert and the ätiLeriaalle iduung with Wa96er and waxed : etroelmet. That oil was nj'Gh removal of the ethers by Da - Style ation under reduced pressure, in a solution of 505 g of potassium idroxyd in iBo lya #, iaer 0 301d3to 41i504 solution heated to 35-40 ad slowly 10.7 K .- & lj »-umpaz, .maziganat added. The kisch was Stirred by 2 hours at 40 and filtered "and that piltrat > t vOrdÜnatem Waaj3erutof £ perONrd, colored out and filtered * " The ipiltrate was abuch lastingly with conc. Acidified hydrochloric acid and abäe'k''üh'11'0'9 ', 2- # o'tr-amethylengl-Ütarsäure fell as white'r.Fent- fabric off. Volume 44 Z melting point 960. Analysis for I # - - 0 t bar. $ C 58900 H 7t57% 9 4 Gefei 0 57978 H'79.54 6 # 2 g of the 292-tetramethylene glutaric acid prepared above and 490 S were Ilarnea . heated and 4 hours at 170-1800- gerWart 9, - the'mixture cools down and - then, from # 5% strength (in the ithanol recrystallized with Koh14notof'fböhandluüg and so Cjrc'lope'ntan- spiro -. # d-Slutarimid lii'einur'Aiidbeute of 399 Z with a Sohmeli Earned point from 133-135-0 . This Postetef £ was made with a Sodium biocarbonate solution, "i3o'hlänimt, then filtered and removed" absi, 2nd ethanol uncritical # t. Yield 30g, melting point -Analysis for 9 11 NO t " bar ..- C 64v60 9 7984 N 0938% 9 13 2 0 64s62 11 7980 N 8952% Manufacture of cyclohexane spiro - 4-slutarimide 45A aor.yl nitrile (0.86 moles) to a Miaeihwig aun 90o84 g cyclohexaldehyde (9p81 mol) and 12 #, 1 9 45.95 % w / w # .. outside one hour at 550 under stirring I s admitted; the milking was heated to 55-60o for a further 4 hours, then cooled and acidified with digested Balzailure =. The blige Layer was extracted with ether. and the Utheribche Löaung Init Waaner and sodium sulphate dried. After Entfegnung.des ether, the obtained 01 'frakt * io'niert deritilled-. Pressure) and so "0. r - (, 2, Cya . Näthyl) - oyclohexaldgli, id received Auaheute .42. "9 KP5-6, f -1 mm 42 20 .1r476 ni TI, Analysis for CIOH 15 NOz ber.9 N 81.48 m # ö found g N 8 9 7 5 74 1795 g (09106 mol) of the above-mentioned 1- (2-cyano-tyllyl) - cyclohexaldeliyds were 6 hours with 6 9 (0915 mol) sodium hydroxide in 60 off cain Wanser zuta reflux for heating, the solution cools # extracted with ether and the essential extracts threw. The aqueous solution was acidified with hydrochloric acid and extracted with ether. The ether solution was washed with water, getrocknot and the ether removed by vacuum distillation. Daa obtained oil was fractionated under reduced pressure. lated and thus 3- (1-pormylo #, clohexyl) -ijropionic acid obtained »Aus. booty 9e5 g; 54-1600; '0t5 KP-21! Im 'ilD 194803 Analyae for 0 1011 160 3 calc .: C 65 920 11 8976 4, found C 65912 H af94 % 902 g (0 # 055 mol) of the 3- (1-forrlyloyelo- hexyl) - ") ropion.-jilure were in 51 cc of a 10% w / w. X-21i., -,. Mhydro-xydlü.eiu ng ga-Iigot uiicl to this Lbaurig at 40 0 lani; iiam a SuGpennion nao 10 "6 g Kaliiuitl) ormangitnat (09067 moles) in 105 cu. Water added. After the 4'Juz ", iLbo was the mixture for 3 hours 0 Gelaoi) cji stand 40 and 24 hours at Zifaniertelli.peratur. The allugeZalIone was filtered off and the filtrate After Aniiiiucrii discolored with pre-i-ii-itor wit künz. wil-i. * do get a white Niodorschlair, the '1.7 g; M.p. 124-126 (). To Ä- # tbztiiol had the acid has a Schmelzpunlit from 133 Analysis for #I AI 6 04 x calc. I C 60., 66 11 t3 '? 06 An intimate mixture of 15.55 9 (09077 times) 2,2-penta math, ylenglutaric acid (wio * prepared above) and 9.40 g (0o156 mol, Urea was stirred on an oil bath for 5 hours 1 170-1860 heated, the Feotstoff obtained with Biedenden 95-ip: Iligem Extracted ethanol and treated the solution with charcoal. After con- centering this solution #mrde received a white post. Yield 998 g; Melting point 141-1450. This pestant was whitened with a saturated sodium carbonate solution, filtered off and recrystallized from ethanol; so became Cyolo. Oxane-spiro-d, -glutarimide obtained at melting point 146-147 0 Analysis for 0 10EI5N02a calculated t 0 6692 X 8934 N 7973% found 8 C 65996 H 8 @ 16 N 7962% e is e 1 Preparation of d # -Butyl.G & .äthyl-N-Mgthylgutarimid 24914 9 e-ButY1--0 # -Uthylalutaraiureanhydride (derived from lus the corresponding acid prepared according to Beiapiol 1) Init 496 times 25 --- p41gem GGw./,Volo wäso rigoiü methylamine treated, the mixture cooled and shaken until it became homogeneous. After acidifying the mixture, a colorless oil was obtained solidified after Aufachlmmullg igit V1a83er. Recrystalline atloil out of 25% vol. / full aqueous ethanol yielded 270 gcK-iitityl- e-Uthyl-N-methylglutaraniinaic acid with a SOhmelzPunkt of 70 # 72 , Anal, Yoe for 0 1211 23 NO 31120 1 ber.i 0 58.3 H 10 * 1, 2 N 5970 found 8 0 57t9 H 10985 N 5v90 3490 Z the horgoatellen * 4-Butyl_4i #ttIly as above, glutartuftin3 # Zur0 was 2 hours with 340 oc - m A00tYlchlOrid For the back heated river and da = the Acotylohlorid under 'Before the pressure abdent "liOrt- Dau 30 formed viakoao oil was with Waauert Kali", bio carbonate solution and washed again with Wanaer. Then ditti became 01 dried with ether axtrahidrti diß ethereal solution and the Ether removed under reduced pressure. 7 fractionated distillate lation of the remaining oil. yielded 20.5 g of O (-butyl- «- ethyl-197 20th methylglutariraid; KP- 950 / 2-4x1r3mm; ni m 1 s4820 Analysis for C 121 121 NO2t red 0 68P3 K 1090 N 6965% found 4 0 6798 X 9986 N 6940 % B e i s -p --- ie 1 d, -Butyl-ethyl-N-benzylglutarimide L. A solution from 19, ß 9 that in Example 4 produced o # -Butyl - (9, -ethylglutaric anhydride in 50.0 com diethyl ether while cooling with a solution of 10.7 g of benzylamine in 50.0 oem Diethyl ether mixed. The ether was distilled off and the Residue dissolved in a potassium carbonate solution # die'Iäöuung- acidified and so precipitated an oil that was extracted in ether. The ethereal solution was dried and the ether evaporated # - whereupon a solid residue would remain, 'recrystallization from wäaarigerit ethanol was erte g5 21 g of a material according to the # -weite- rar recrystallization from aqueous ethanol N-benzyl-c4-butyl-Wo- äthylglutaramin.uäure with a melting point of 76'0 delivered " Analysis £ Ur C 11 NO t calc .: C H 8.90- N 4r60 % 18 27 3 - goro: C 7097 H 9905 N 4v65 % 21 90 g of the N-Benzyl-e4 - butyl'Fätliylglutar- The acid was refluxed for 2 hours with 210.0 com Auatylohlorid heated up the acetyl chloride then removed under reduced pressure and the remaining oil washed with potassium bicarbonate solution and in Ether extralated. The essential solution was dried and the Ether removed by distillation under reduced pressure. Dedicated distillation of the oil yielded 11.05 o , / 2.5x, 0-1.zm 20 N-benz, ylglutarimide; Kp. 138-140 - g, n # m 11.5240 Analjee for C "n2, NO2i ber-s 0 7594 N 898 N 499 % found 1 C 75.1 H 8v83 N 5900% B e 1 1 6 Production of ck-butyl-d # -ethyl-N- (3-morpholinopropyl) -glutar- imide hydrochloride A solution of 10.10 g of o (-butyl-ethylglutaric anhydric acid (manufactured as in Beiapiel 4) In 10 com diethylit.i-ther was rait a solution of 6.65 g of N- (3-aminopropyl) morpholine in 5 com di- ethyl ether treated The reaction was exothermic; the mixture was then diluted with 12090 com diethyl ether. There were two Phases on, and the mixture was made by adding ethyl acetate made homogeneous. After cooling down to 00 oin Feutstoft failed, which was filtered off; no were 11t2 g of a material with a Melting point of 94-97 0 obtained. Recrystallization from ethyl acotat liefortet4-ButY1-4räthY1-11- (3-morpholinopropyl) -glutaramine- aI:. ". ure with a Seliincl, -, point from 94-97 0 Analyce for Clail 34 1j20 4 z ber.i C 630.2 H 10901 X .8920 8 C 6292 11 10910 N 8.9 1 5 42 g of the above d, -] 3utyl - «- ätliyl-N- (3-worpho- linopropyl) glutaric acid and 3090 ec # acotyl chloride were 1 Hour back-, immen Zurn Wic) Cluss c) r.Ii: L-tzt, dio Alißchanz ,; under vormiii- derLem Di-ij ("'. z 1.1 #; i # -." -, itri # :: rt nit ether verduruit', whereupon 696 p eingi i..1 ti # iiii - 01 t of 151-153 failed. Dienes ti - Ltor.-Lr, 1 Ves.ser dissolved and sodium bicarbonate joined # bia duz (riranoiitNicklurr.,) stopped. The ao lierg ("., Telltr, Glim --.- dv-rdo In ether cztritliiert and dio jÄheri- see Lü: -, and Dau. Implementation before Chloi: .eaoxy through the Ütherinelie IGtiung delivered a white exi Kledorjahlag @ which was filtered off and washed with ether. This material -war ti-butyl-ethyl-N- (3-morpholinoproepyl) -glutarimidhydroolllorid with a melting point of 1560o Analyst for ei 035 N2 0 3 Clt ber.t 0 59A x 9r22 N 7.35 egg 9985% 0 59o3 X 91p22 X 89> 00

Claims (1)

Pa III withdrawal entitlements #lj compounds of the formula CD wherein R 1 is an alkyl or substituted alicyl group with at least 3 carbon atoms and R for - one.Alk- # rl- 2 or substituted Al! VI group; or R 1 is a cyclo Glykyl or substituted Cycloa11V1gruppe and R 2 a AllV1- or substituted alkyl, cycloalkyl or sub- mean substituted cycloalkyl group; or R and R form 1 2- together with the carbon atom of the glutarimide ring which they are bound to an alicyclic or substitute ten alicyclic. Ring; and R 3 represents hydrogen or an alkyl, substituted alkyl, cycloalkyl, substituted Cycloalkyl, aryl, substituted aryl, aralkyl or sub- stituiEWte aralkyl group. 2) c.-4 + butyl-δ # -ethylglutarimide. Cyclgpentane-spiro-O (-glutarimide. 4) Cyclohexane spiro-d "-glutarimide. 5) Ot - butyl - L-0 (-ethyl-N-benzylglutarimide .. 6) 7) ", / _- Butyl-g # -äthyl-N- (3-rnor'pholino, -iropyl) .--, -, lutari.mid. 8) Procedure, z, ur .., Fe-- stelilung- von, Vdr.bindunge.n ..de.r- where R, -for: r # A #] 4y17 "g # a- em J g- #PP (# at least R s # eas 0 -and, _k711 # 3 Z kh _ # for E # ine.Al or 2 substituted. i # lky, 1, zru pQ s # t # - "j #, ea R, bf "d et e ine- Cycloalky; 4-, p # er, § ## bs # it.uierte r ## zy alkyl # 9 uPP5 -> -.- 4ad Y, 2 Alk-yl- or substituted'-, uierte'-P-1 -, Y # .- C yQ # oa-lk Qd.p #, IZ substituted cycloalkyl group, - or and R 2 form together with the carbon gg a- # qm de ##, glutar # m r2.nges an-de n- slie . gebundQn are..a "alic q # ip.chen, tit14er #Qder ', # ubsten, ali- qnd-H stplit for - # Zia.5serstoff -.eine alkyl- substit4 # prte "AlXyl -" .., pycl, oall # "## 7", -, gubstituted Cy-cl-.oallk - ,. r1-. Aryl-, sub, #tituierte., Aryl- #, substitudeXte Aralkyl group, dady. # C # ig # 3g # e # lrizei, .Q4r # et .. that a, substituler- -ter aldehyde of the al # -common-n formula where R and R have the above ", rjiedeutun #, condensed with 1,7cryl-1 2 CD nitrile, the cyanide group is then hydrolyzed and the aldehyde group of the condensation compound obtained is oxidized, whereby the corresponding substij (- Juated glutaric acid is obtained, what this # 1-jä # ure or its anhydride in known 1, -ieise by reaction with urea, substituted urea, ammonia or an amine of the formula R 3 NT TH 22 wherein R 3 ' the above Process according to Claim 8, characterized in that the condensation of the substituted aldehyde with acrylonitrile in the presence of a basic catalyst, preferably an alkali metal hydroxide or benzyltrimethylammonium hydroxide, is carried out. 10) Process according to Claim 8 or 9, characterized in that the cyanide group des.Kondensationsproduktes ode under alkaline conditions, preferably with an alkyl hydroxide, especially tiatrium hydroxide r halium hydroxide, is hydrolyzed and the product obtained before the oxidation of the aldehyde group! will. > 11) Process according to claim 10, characterized in that the hydrolysis product is obtained as a free acid and converted into a salt before the oxidation of the aldehyde group. 12) Method according to A.nspruch 8 to 11, characterized in that the aldehyde group is oxidized with alkaline potassium permanganate. 13) remedies containing a compound according to claim 1 to