Procedure for the production of new n (1-Aryloxy-2-hydroxypropyl) - amino acids and their derivatives

The subject of the invention is a procedure for the production of new n (1-Aryloxy-2-hydroxypropyl) - - amino acids and their derivatives of the general formula OH l acre --0 -- CHzCH --CHz -- A -- CO -- R2 g 1 (i) in which acres a Naphthyloder Indenylgmppe or one if necessary by halogens, Hydmxy, Alkoxy, Alkenyt, Alkenyloxy, alkyl, Alkoxyalkyl, TrifluoralkyI, Alkylmereapto, A, hydrogenated if necessary, lkenylmetca o, A mino, A of lkylsulfonylaminooder Acylarninogruppen substituted Phenylgruppe, RI hydrogen, a low Alkyloder Aralkylgmppe, RZ a hydraulic XY, a Alkoxy, Amino, AlkyIamino, DialkyIaminooder one if necessary by a group of aryls of N' - substituted Piperazinogruppe, A or a arylierte low alkyl chain alkylated if necessary, which one widened Carboxyoder Carbalkoxygruppe if necessary carries, means, as well as their salts. One pure one of stmktureI1 is of course become known to similarly built adrenergen substances (Prolxanolol; see also Belgian Patentsehrift No. 716088; ), However available the according to invention connections (I) are characterised Netherlands laying out writing No. 68,01661 opposite well-known 3-Rezeptorbloekem by an unexpectedly low Iokalanästheti effect and a surprisingly high protective effect in relation to hypoxic loads (Glykolyse inhibition) with otherwise excellent compatibility. Those connections (I) are particularly well effective, in which acre substituted a Naphthylgruppe or a one if necessary with 1 or 2 halogens and/or AIkyl, Alkoxy, alkenyl, Alkenyloxygruppen substitttierte Phenylgtuppe, blank hydrogen, a Alkyloder group of benzyles, RZ a hydraulic XY, a Alkoxy, Amino, Alkylamino, Dialkylaminooder one N' N-Piperazylgruppe and A an alkylated or a arylierte never that AIkylenkette, which carries a further Carbox7oder Carbalkoxygruppe if necessary, means. The new connections (I) according to invention by the fact it is manufactured that one a 1-Aryloxy-2, 3-epoxyptopan of the general formula acre--OCHz--C “/CHz O (II) in that acre the meaning indicated above has, with a amino acid derivative dex general formula HN--A -- CO - Kj f RI, (III) into soft g 1 and The meaning indicated above have and R with exception of the hydroxy group the same meaning as R2 have or with a salt of these Aiiänosäure convert, whereby one if blank hydrogen represents, if necessary a received secondary amine N-aIkyliert or if a group of benzyles represents to RI, these hydrogenolytisch split off, gewünschtenfalls a received ester into the free acid, into another ester, into an amide and/or into a salt, a received amide into the free acid, into an ester and/or into a salt and a received salt transfers into the free acid, an ester, an amide and/or into another salt. The soaping of the connections (1), in those RZ a Alkoxy, Amino, Alkylamino, Dialkylaminooder Piperazylgrnppe means and/or the remainder of A a Carbalkoxygruppe carries, effected in well-known way with aqueous acids or bases, whereby one can arrive in the latter case directly at the salts. The Veresterung of connections, in which RZ means a hydroxyl group and/or for which remainder of A carries a Catboxylgtuppe, lets itself under dehydratisterenden conditions with a surplus betreffendenA lkohols would drive through. The Dehydratisierung Reaktiomgemi can either by azeotrope distillation with a solvent serving as tractors (e.g. Methylenehlorid or benzene) or by an additive dehydratisierendet substances (e.g. konz. Sulfuric acid, hydrogen chloride or Borfluoridätherat) to be reached. It is also in principle possible, the free group of carboxyls with Diazoalkanen too alkylieren.DieUmestetung vonVetbindungen (I), in which RZ means an alkoxy group, e.g. becomes in a surplus aIs of the Estertomponente of water-free alcohol under additive of catalytic quantities, which can be introduced, Minetalsäute, like hydrogen chloride or konz. Sulfuric acid, accomplished. Substances, in which RZ means a Alkoxygmppe, can be transferred by means of ammonia and/or amines in simple way into amides. To the N-Alkyliertmg of connections (I), in which g 1 hydrogen means, sees in particular alkyl - 3 - is suitable Nx.302273 or Atalkylhalogenide and/or, - sulfates or - tosylate, which one appropriately in a höhe1 simmering inert solvents, how Dimethylsulfoxyd or dimethylformamide brings, to the reaction. A hspaltung the benzyle remainder of g 1 takes place in simple way via catalytic Hydriemng, whereby usual hydrogenation catalysts, how Raney nickel or palladium coal is used, in polar solvents. For the transfer of free acids (IlI) into salts one uses preferably strongly basic MetaUhydroxyde, like alkali hydroxides or alkaline-earth hydroxides; however also organic bases, like e.g. tri alkyl amines, let themselves be begun. The conversion is preferably accomplished in a polar solvent. As solvents are particularly suitable hiefür Dimethylformarnid and tetrahydrofurane as well as isopropanol, n-Ptopanol among other things low A1kohole; since however both the intermediate products and the final products are a little sensitive, most conversions without solvents in the melt leave themselves would drive through. There the connections (I) at least an asymmetrical carbon atom possess, exist the possibility, the 13oder wished in each case L-lsomeren and/or the Diastereomeren by Racematenspalttmg with OF " table active auxiliary materials or by fractionated crystallization of diastereomerer forms to win. From the beginning of course it is also possible to direct the synthesis e.g. by employment of optically active amino acid derivatives of the Forme1 (II1) into a certain stereospezifische direction. One places the pharmakologisch compatible salts for example by neutralization of the free amino group of the connections (I) with not-toxic, inorganic or organic acids ago. Hiezu are e.g. suitable hydrochloric acid, sulfuric acid, phosphoric acid, hydrobromic acid, acetic acid, Milchsättre, Zitronensänre, oxalic acid, apple acid, Salieylsäure, Malonsäme, maleic acid or Bemsteimäure; f {l the case that Rreine represents hydroxyl group and/or the remainder of A carries a group of carboxyls, receives manpharmakologisch compatible salts by conversion with a strong base, preferably to a Alkalioder alkaline-earth hydroxide. Available the according to invention new connections and their salts can be appliziert in liquid or firm form duck ral and parenterally. As Injektiommedium water is preferably used, which the additives, how Stabilisiemngsmittel, usual with injection solutions, solution mediator or buffer contain. Such additives are e.g. Tartratund CIT advice buffer, ethanol, complexing agent (like ethylen diamine - tetraessigsäure and their not-toxic salts), high-molecular Polymemn (like liquid PL oxide) for viscosity adjustment. Firm one of carrier materials are e.g. strength, lactose, Maunit, methyl cellulose, talcum powder, hochdisperse flint-sour, höheimolekulare fatty acids (like stearic acid), Geiatine, agar agar, Calcinmphosphat, magnesium stearate, animal and vegetable fats, firm high-molecular polymers (like PL glycols); for oral applications suitable Zubeieitungen knows gewünschtenfalls taste and sweet material containing. In the following examples the new connections and the procedure according to invention for the production of the same are more near described. Example 1: N-Ll (2 ', 4 ' - Dichlorphenoxy) - 2-hydmxyprepyl] - L-A-alanine: 13.35 g (0, 15 mol) L-A-alanine and 6, 0 g (0.15 mol) Natriurnhydroxyd are warmed up together in 125 ml dimethylformamide, until everything went into solution. Then 32, 8 g 2, is course-dripped 4-Dichlorphenoxyglyceiidäther on which one warms up the Reaktionsgemiseh 4 h to 120oc. The reaction mixture is then restricted, the solitary Natriurmalz is solved in water and the solution in-hydrochloric acid is neutralized. Hiebei the formed precipitation is sucked off, dried, boiled up and filtered off with 75 ml Merhanol. One receives 35 g (75, 8% D. Th.) N [1 (2 ', 4 ' - Dichlorphenoxy) - 2-hydrexypropyl] - La alanine; F p, 224oc (zers.). In similar way receipt one the connections specified in the following table 1: Chemical designation Fp. degrees of yield % N [1 (3 ' - Methylphenoxy) - 2-hydroxypmpyl] - - D, La alanine n [1 (3 ' - Methylphenoxy) - 2-hydroxypropyl] - - La alanine n [1 (3 ' - Methylphenoxy) - 2-hydroxypmpyl] - - D, La-leuein n [1 (3 ' - Metläylphenoxy) - 2-hydroxypropyl] - - D, L-isoleuein n [1 - (3 ' - Methylphenoxy) - 2h ydroxypro pyl] - - D, La valin 208 (Zers.) 218 - 220,216 - 217,208 - 210,218 - 219 58 69 chemical designation n [i (3 ' -Methylphenoxy) - 2-hydtoxypropyl] - - La phenylalanin n [i (2 ' - A llyloxyphenoxy) - 2-hydroxypropyl] - - D, La alanine n [i (2 ' - A llylphenoxy) - 2hydroxypropyl] - - D, La alanine n [i (2 ' - Bromphenoxy) - 2-hydmxypropyl] - - D, La alanine n [i (2 ', - Dichlorphenoxy) - 2-hydroxypropyl] - - D, L-aalanin n [i (2 ' - Bromph enoxy) - 9. - hydroxypropyl] - - La phenylalanin n [i (2 ', 3 ' - Dichlorphenoxy) - 9. - hydroxypropyl] - - D, Lalanin n [l (A - Naphthyloxy) - 2-hydroxypro pyl] - - D, La alanine n [l (A - Naphthyloxy) - 2-hydroxypmpyl] - - L-aalanin n [i (aNaphthyloxy) - 2-hydroxypro pyl] - - there - alanine n [l (A - Naphthyloxy) - 2-hy& oxypmpyl] - - D, La-phenylalanin n [l (A-Naphthyloxy) - 2-hydroxypropyl] - - D, La - valin n [1 (A-Naphthyloxy) - 2-hydroxypro pyl] - - D, Lleucin n [l (A - Naphthyloxy) - 2-hydroxypzopyl] - - D, Liso len cin n [l (A-Naphthyloxy) - 2-hydroxypro pyl] - - glycine n [l (A-Naphthyloxy) - 2-hydroxypropyl] - - D, La aminobuttersänre n [i (aNaphthyloxy) - g-hydroxypm pyl] - - sarkosin n [i (A - Naphthyloxy) - 2-hydroxypropyl] - - Nisopropylglycin n [i (A-Naphthyloxy) - 2-hydmxypropyl] - - D, LS aminobuttersäum NMethyl n [l (A-naphthyloxy) - 2-hydroxypropyl] - - D, La alanine N-Isopropyl-n [l (A naphthyloxy) - 2-hydroxypropyl] - - D, La alanine n [l (A - Naphthyloxy) - 2-hydroxypropyl] - - A aminoßobut [ersgum n [2 ' - (A llylphenoxy) - 2-hydro xypropyl] - - A aminoisob ttersäure Fp. °C 208 - 209,198,190,203 - 204 201202 206 - 208,202,189 - 190,202 - 203 17q - lq8 201 - 203,215 - 217,202 - 204 213215 Ii0 amorphously 211 - 212,180 amorphously 169171 (oxalate) amorphously (Natrinmsalz) amorphously (sodium salt) 243 - 244 202203 Nr.302273 Ambeute% 53 48 52 ql 91 68 58 74 77 48 52 58 63 43 84 52 61 53 66.7 67 - 5 - N 802278 B e i s pi e 1 2: N [1 (3 ' - Methylphenoxy) - 2-hydroxypmpyl] - sarkosin isopropylester: 9, 8 g (0.075 mol) Sarkosin more isopropylester are heated up with 13, i g (0.08 mol) 3-Methylphenoxyglycidäther 4 h on i00 to 120oc and distilled afterwards in the Hochvaktmm. One receives A US of the parliamentary group ilbergehenden with a vacuum of 0.2 mm Hg with 160 to 164°C in a yield from 65,3% d.Th. 15.4 g n [i (3 ' - Methylphenoxy) - 2-hydroxypropyl] - sarkosin isopropylester. In analogcr way one receives the connections specified in the following table 9. Table 2 chemical designation kp. °C mm Hg Fp. °C yield % N [! - (2 '. 3 ' - Dichlorphenoxy) - 2-hydroxypropyI] - - D, La - alaninisopropylester n [1 (2 ' - Bromphenoxy) - 2-hydroxypropyl] - - D, La - alanine ISO per pyle ster n [i (2 ', 3 “- Dich.lo phenoxy) - 2 - hydroxypropyl] - - La of alanine isopropylester n [1 (2” - Bromphenoxy) - 2-hydroxypro pyl] - - La - alaninisopmpylester n [l (3 ' - Methoxyphenoxy) - 2-hydroxypropyl] - - D, La - alaninisopropylester N - [i (3 ' - Methylpheno XY) - 2-hydro xypropyl] - - D, L-A - phenylalaninEthylester n [1(3 ' - Methylphenoxy) - 2-hy droxypropyl] - - Lasparaginsäure diäthylester n [1 (3 ' - Methylphenoxy) - 2-hydmxypropyl] - 190 - 193,170 - 180 192194 177180 181 - 182 0.01 0.01 0,05 O, Ol 0.1,104 126128 Hydmchlorid 127128 hydrochloride - D, La - of alanine isopropylester n [1 (A - N aphthyloxy) - 2hydroxypropyl] - - D, L-A - alanine isopropylester n [! - (A - N aphthyloxy) - 2hydroxypmpyl] - - D, La - phen ylalaninäth yleste r N - [1 (A - N aphthylo XY) - 2hydroxypropyl] - - L-leucinethylester n [1 (A - Naphthylo XY) - 2hydmxypropyl] - - Lasparagins of äure diäthylester n [1 (A - Naphthyloxy) - 2hydroxypropy1] - - La - alanine isopropylester N - [! - (A N aphthylo XY) - 2hydroxypropyl] - - gly cinisopropylester n [1 (A - N aphthyloxy) - 2-hydroxypmpyl] - - D, La - alanine methyl ester n [1 (2-A llylpheno XY) - 2hydroxypropyl3] - - D, La - more alaninisopropylester 159161 210 - 220,205 - 210,163 - 166 0.01 O, Ol 0.05 0.01 168170 Hydroehlorid 152153 hydrochloride 125127 Hydrochl rid 163164 Hydmchlorid amorphously hydrochloride 53 57 68 55.6 59 63 54 66 60,6 63 47 66 63 48 53 62 B e is p i e 1 3: N [! - (2 ', 3 ' - Dichlorphenoxy) - 2-hydroxypmpyl] - D, L-A - alanine methyl ester: 6, 16 g (0, 02 mol) n [1 (2 ', 3 ' - Dichlorphenoxy) - 2-hydroxypropyl] - D, L-A-alanine are cooked for methanolic hydrochloric acid at the Rüekfluß during 10 to 14 h in 50 ml. After taking the solvent off one rubs the arrears with ethyl acetate and receives after the Abffltrieren 3, 58 g (50% D. Th. ) N [1 (2 ', 3 ' - Dichlorphenoxy) - 2-hydroxypropyl] - D, La-alanine-methylester; Fp. 144 to 146°C. In similar way one receives n [1 (A-Naphthyloxy) - 2-hydroxypmpyl] - D, L-A-alanin'methylesterin amorphet form and in a yield of 58%. - 6 - Nr.3022q3 B e is pi e! 4: N [! - (3 ' - Methylphenoxy) - 2-hydroxypropyl] - glycine amide: 18 g n [1 (3 ' - MethyIphenoxy) - 2-hydroxypropyl] - N-benzylglycinamid in 150 ml methanol and ml water are solved and acidified after addition from 1 g palladium coal (10%ig) with methanoltscher hydrochloric acid. Within l0 min becomes the Benzylgmppe catalytic hydrogenolytisch abgespalten. The Reaktiomlösung is then sucked off by the catalyst and the F is iltrat restricted. After the Umkristallisiemn of the arrears from methanol one receives to 8, 1 g (74, 6% D. Th.) N [1 (3 ' - Methylphenoxy) - 2hydroxypropyl] - glycine amide in form of the hydrochloride; Fp. 189oc. The output product is manufactured as follows: 20 g (0.1 times) Benzylaminoacetamid hydrochlodd (manufactured after CH. K.Bradsher, C.F. Brown and E.F. Sinclair: J. To. Chem. seconds. 78, P. 6189 to 92) is solved in l0 100 ml water and shifted with 100 ml n-NaOH. One restricts the solution in the vacuum to dry ones and takes up the arrears with 100 ml dimethylformamide. After the addition of 24, 6 g (0! 5 times) 3-Methylphcnoxy-glycidäther one heats up 4 h on 120oC. Afterwards one evaporates methanol in the vacuum as far as possible, takes up the arrears with 100 ml, filtered and evaporates. One receives 31 g (95% d.Th.) as arrears N [1 (3 ' - Methoxyphenoxy) - 2-hydroxypropyl] - N-benzylglycinamid as viscous oil. In similar way one erhtflt the connections aufgefllhrten in the following table 8: Table 3 chemical designation solvent yield % methanol 89, 9 N [! - (A - Naphthyloxy) - 2-hydmxypropy! ] - - glycine dimethylamid n [l (A Naphthyloxy) - 2-hydroxypropyl] - - glycinmehhylamid N - [1 (3 “- Methy 1pheno XY) - 2-hy DM xypropyl] - - glycine isopropylamid N - [1 (A Naphthylo XY) - 2-hydro xypropyl] - - glycine amide n [1 (Te - Naphthyloxy) - 2-hydroxypropyl] - - gly cin - N - 4me the xyphenylpipe RA zid n [1 (2”, 3 ' - Dichlorphenoxy) - 2 - hydroxypro pyl] - - ly cinamid n [i (2 '; 3 ' - Dichlorphenoxy) - 2-hydmxypmpyl] - - glycinisopropylamid n [1 (2 ' - n-Propylphenoxy) - 2hydroxypropyl] - - glycine amide n [! - (2n Propylphenoxy) - 2-hydroxypropyl] - - glycine isopropylamid n [1 (A - Naphthyloxy) - 2-hydmxypropyl] - - glycine isopropy] amide methanol methanol methanol methanol methanol methanol methanol methanol methanol Fp. °C 190 - 191 Hydroch! orid 136 - 137 base 74,180 hydrochloride 115116 base 121 - 124 base 125126 98 92 251253 hydrochloride 69, 2 76, 6 69 87, I 94 98 87 (Rohprod.) 81, 7 (isopropanol) 98 (Rohprod.) 71, 5 (ethyl acetates) 98 (Rohprod.) 77, 4 (Isopmpanol) in similar way is manufactured: N- [! - (A - Naphthyloxy) - 2-hydroxypropyl] - N-impropyl-glycine (sodium salt); N [1 (3 ' - Methylphenoxy) - 2-hydmxypmpyl] - Nisopropylglycin isopropylamid; Fp. 82 to 84°C1 n [1 (3 ' - Methylphenoxy) - 2-hydroxypropyl] - glycine N phenylpiperazid; Fp. 104 to 105°C (base); N [! - (3 ' - Methylphenoxy) - 2-hydroxypropyl] - glycine amide; Pp. 91 to 92°C (base); N [1 (2 ', - Dinhlorphenoxy) - 2-hydmxypropyl] - glyeinamid; Fp. ! 5! °C (base); N [1 (2 ', 3 ' - Dichlorphenoxy) - 2-hydmxypropyl] - sarkosin isopropylamid; Fp. 109oc (hydrochloride); N [1 (2 ', 3 ' - Dichlorphenoxy) - 2-hydmxypropyl] - NisopropyIglyeinisopropylamid; Fp. 161 to! 83°C (Hydroehlorid); N [1 (3 ' - Methoxyphenoxy) - 2-hydroxypropyl] - N-isopropylglycinamid; Pp. 77 to 790C (base); N [! - (8 ' - Methoxyphenaxy) - 2-hydroxypropyl] - N-isopropylglycinisoprapylamid; Fp. ! 10oC chlorine; d); N [l (A - Naphthyloxy) - 2-hydroxypmpyl] - N-isopmpyl-glycinamid; Fp. 116 to I17°C (base); (HydmN [1 (A - Naphthyloxy) - 2-hydroxypropyl] - N-isopropyl-glycine-isopmpylamid; Fp. 92 to 98°C (base); N [l (A - Naphthyloxy) - 2-hydroxypropyl] - N-isopropyl-glycine-phenylpiperazid; Fp. 177°C (oxalate); N [l (A - Naphthyloxy) - 2-hydroxypropyl] - D, Lc - alanine methyl amide; Fp. 211 to 218°C (hydrochloride); N [l (A - Naphthyloxy) - 2-hydroxypropyl-3] - D, L-A-alaninamid; Fp. 200 to 20! degrees (Hydroehlodd); N-Isoprepyl-n [l (A - naphthyloxy) - 2-hydroxypropyl] - D, Lalanin isopropylamid; Fp. 177 to 178°C (hydrochloride); N [1 (8 ' - Methylphenoxy) - 2hydmxypropyl] - Nbenzylglycinamid (not crystallizing öI); N [1 (, 9 - Methylphenoxy) - 2-hydroxypropyl] - N-benzyle-glycine-isopropylamid; Fp. 76 to 80Oc (base); N [1 (A ~Naphthyloxy) - 2-hydroxypropyl] - N-benzyle-glycinamid; Fp. 108 to! 09°C; D, LN [! - (A - Naphthyloxy) - 2-hydroxypropyl] - alanine dimethylamid; Fp. ] 95 to 196°C; D, LN [! - (A - Naphthyloxy) - 2-hydmxypropyl] - alanine isopropylamid; Fp. 187 to 188°C.