DK158512B - METHOD FOR PREPARING 4 '- (2-CARBOXYETHYL) PHENYL-TRANS-4-AMINOMETHYLCYCLOHEXANCARBOXYLATE OR ACID ADDITION SALTS THEREOF - Google Patents
METHOD FOR PREPARING 4 '- (2-CARBOXYETHYL) PHENYL-TRANS-4-AMINOMETHYLCYCLOHEXANCARBOXYLATE OR ACID ADDITION SALTS THEREOF Download PDFInfo
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1 DK 158512 B1 DK 158512 B
Den foreliggende opfindelse angår en særlig fremgangsmåde til fremstilling af 4'-(2-carboxyethyl)phenyl-trans-4-amino-methylcyclohexancarboxylat (i det følgende omtalt som "CEP-ester") med formlen (I) h2nch2 -0- ----coo •O CH2CH2COOH (I) eller terapeutisk anvendelige syreadditionssalte deraf, hvilken fremgangsmåde er ejendommelig ved det i kravets kendetegnende del anførte. De fremstillede forbindelser er anvendelige som anti-plasmiske midler eller anti-peptiske ulcusmidler.The present invention relates to a particular process for the preparation of 4 '- (2-carboxyethyl) phenyl-trans-4-amino-methylcyclohexane carboxylate (hereinafter referred to as "CEP ester") of formula (I) - CO 2 O 2 or CH 2 CH 2 COOH (I) or therapeutically useful acid addition salts thereof, which is characterized by the characterizing part of the claim. The compounds prepared are useful as anti-plasmic or anti-peptic ulcer agents.
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Der kendes følgende tre konventionelle fremgangsmåder til fremstilling af CEP-ester: (i) Katalytisk reduktion af 4(2-benzyloxycarbonylethyl)phenyl-trans-4-N-benzyloxycarbonylaminomethylcyclohexancarboxylat-hydro-chlorid eller 4'-(2-benzyloxycarbonylethyl)phenyl-trans-4-amino-methylcyclohexancarboxylat-hydrochlorid, der vindes ved at kondensere henholdsvis trans-4-N-benzyloxycarbonylaminomethylcyclohexan-carbonylchlorid eller trans-4-aminomethylcyclohexancarbonylchlorid med benzyl-4-hydroxyphenylpropionat og derefter fjerne beskyttelsesgruppen, dvs. en benzylgruppe, til dannelse af CEP-ester, som beskrevet i de offentliggjorte japanske patentansøgninger nr. 19950/71 og nr. 48978/77.The following three conventional methods for preparing CEP esters are known: (i) Catalytic reduction of 4 (2-benzyloxycarbonylethyl) phenyl-trans-4-N-benzyloxycarbonylaminomethylcyclohexane carboxylate hydrochloride or 4 '- (2-benzyloxycarbonylethyl) phenyl-trans -4-amino-methylcyclohexane carboxylate hydrochloride which is obtained by condensing trans-4-N-benzyloxycarbonylaminomethylcyclohexane carbonyl chloride or trans-4-aminomethylcyclohexane carbonyl chloride with benzyl-4-hydroxyphenylpropionate, respectively, and then removing a benzyl group, to form CEP esters, as disclosed in Japanese Patent Application Nos. 19950/71 and 48978/77.
(ii) Kondensation af trans-4-aminomethylcyclohexancarbonylchlorid med tert.-butyl-4-hydroxyphenylpropionat-hydrochlorid til dannelse af et mellemprodukt, 4*-(2-tert.-butoxycarbonylethyl)phenyl-trans- 4-aminomethylcyclohexancarboxylat-hydrochlorid, og derefter behandling af mellemproduktet med hydrogenhalogenid-eddikesyre med det formål at fjerne den carbonyl-beskyttende gruppe, dvs. en tert.-butyl-gruppe, til dannelse af CEP-ester, som beskrevet i den offentliggjorte, japanske patentansøgning nr. 78143/73. Årsagen til at disse specifikke beskyttelsesgrupper er væsentlige ved disse sædvanlige fremgangsmåder er, at phenylester-bindingen i CEP-ester-molekylet har en tendens til at blive hydrolyseret lettere end en almindelig esterbinding. Endvidere skal ved de ovenfor under (i) og (ii) beskrevne kondensationsreaktioner til syntesen af de anvendte mellemprodukter carboxyl-delen af ét af udgangsmaterialerne, dvs. p-hydroxyphenylpropionsyre være beskyttet med en egnet beskyttelsesgruppe .(ii) Condensation of trans-4-aminomethylcyclohexanecarbonyl chloride with tert.-butyl-4-hydroxyphenylpropionate hydrochloride to give an intermediate, 4 * - (2-tert.-butoxycarbonylethyl) phenyl-trans-4-aminomethylcyclohexane carboxylate, treatment of the intermediate with hydrogen halide acetic acid for the purpose of removing the carbonyl protecting group, i.e. a tert-butyl group, to form CEP ester, as disclosed in Japanese Patent Application Laid-Open No. 78143/73. The reason that these specific protecting groups are important in these conventional methods is that the phenyl ester bond in the CEP ester molecule tends to be hydrolyzed more readily than a normal ester bond. Furthermore, in the condensation reactions described above (i) and (ii) for the synthesis of the intermediates used, the carboxyl moiety of one of the starting materials, i.e. p-hydroxyphenylpropionic acid may be protected by a suitable protecting group.
Efter kondensationsreaktionen skal følgelig beskyttelsesgruppen på den endestillede carboxyl-del af disse resulterende mellemprodukter fjernes selektivt for at vinde den ønskede CEP-ester. Til dette formål skal den endestillede carboxyl-del følgelig være beskyttet med en temmelig specifik beskyttelsesgruppe, der let kan fjernes ved katalytisk reduktion eller under betingelser forskellige fra de, der anvendes ved en almindelig hydrolyse.Accordingly, after the condensation reaction, the protecting group on the terminated carboxyl moiety of these resulting intermediates must be selectively removed to obtain the desired CEP ester. Accordingly, for this purpose, the terminated carboxyl moiety must be protected with a fairly specific protecting group which can be readily removed by catalytic reduction or under conditions different from those used in ordinary hydrolysis.
Dette kan let ses af det ringe udbytte, der fremkommer ved den tredie sædvanlige fremgangsmåde, der er beskrevet nedenfor, ved hvilken en sådan specifik beskyttelsesgruppe ikke anvendtes som beskyttelsesgruppe for den endestillede carboxyl-del, men hvor der derimod anvendtes en sædvanlig alkylester.This can easily be seen by the poor yields obtained by the third usual method described below, in which such a specific protecting group was not used as the protecting group for the terminated carboxyl moiety but where a conventional alkyl ester was used.
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3 (iii) Et mellemprodukt, 4'-(2-alkoxycarbonylethyl)phenyl-trans-4-aminomethylcyclohexancarboxylat eller et syreadditionssalt deraf, der var vundet ved at omsætte et alkyl-4-hydroxyphenylpropionat med trans-4-aminomethylcyclohexancarbonylchlorid, blev hydrolyseret i nærværelse af en sur katalysator til dannelse af en CEP-ester, som omtalt i den offentliggjorte japanske patentansøgning nr. 17447/77.(Iii) An intermediate, 4 '- (2-alkoxycarbonylethyl) phenyl-trans-4-aminomethylcyclohexane carboxylate or an acid addition salt thereof, obtained by reacting an alkyl-4-hydroxyphenylpropionate with trans-4-aminomethylcyclohexane carbonyl chloride of an acid catalyst to form a CEP ester, as disclosed in Japanese Patent Application Laid-Open No. 17447/77.
Den ovennævnte fremgangsmåde (iii) er den simpleste kendte fremgangsmåde, der kan anvendes til fremstilling af CEP-ester under anvendelse af sædvanlige fremgangsmåder. Da imidlertid udbyttet ved denne fremgangsmåde (iii) er mindre end 35%, er fremgangsmåden ikke industrielt fordelagtig. Mellemproduktet har, som ovenfor anført, to typer af esterbindinger, dvs. en phenylester-binding og en alkyl-ester-binding, i molekylet. Ved en hydrolysereaktion er alkylester-bindingen i molekylet blot i ringe grad mindre stabil end phenyl-ester-bindingen. Da der kun er en lille forskel, kan alkylester-bindingen ikke blive hydrolyseret alene og selektivt, uden at der også sker hydrolyse af phenylester-bindingen.The above process (iii) is the simplest known method that can be used to prepare CEP esters using conventional methods. However, since the yield of this process (iii) is less than 35%, the process is not industrially advantageous. As mentioned above, the intermediate has two types of ester bonds, viz. a phenyl ester bond and an alkyl ester bond, in the molecule. In a hydrolysis reaction, the alkyl ester bond in the molecule is only slightly less stable than the phenyl ester bond. Since there is only a small difference, the alkyl ester bond cannot be hydrolyzed alone and selectively without hydrolysis of the phenyl ester bond.
Som et resultat af omfattende undersøgelser vedrørende fremgangsmåder til fremstilling af CEP-ester har det nu vist sig, at slutprodukt-CEP-esteren med ovenstående formel (I) eller terapeutisk anvendelige syreadditionssalte deraf let kan vindes ved fremgangsmåden ifølge den foreliggende opfindelse, der er ejendommelig ved at en forbindelse med den almene formel (IV): h2nch2 -G> C00—^^^-CH2CH2C00CH^^ (IV) i hvor R er en alkylgruppe med 1-6 C-atomer, en halogensubstitueret alkylgruppe med 1-6 C-atomer i alkyldelen, en phenylgruppe, en 2 alkoxygruppe med 1-6 C-atomer eller en aminogruppe, og R er et hydrogenatom, en alkylgruppe med 1-6 C-atomer, en phenylgruppe, en acetylgruppe, en alkoxycarbonylgruppe med 1-6 C-atomer i alkoxy-delen eller en cyanogruppe, eller et syreadditionssalt deraf hydrolyseres i svagt sur eller svagt alkalisk opløsning.As a result of extensive studies on processes for preparing CEP esters, it has now been found that the final product CEP ester of the above formula (I) or therapeutically useful acid addition salts thereof can be readily recovered by the process of the present invention which is peculiar by a compound of the general formula (IV): h2nch2 -G> C00 - ^^^ - CH2CH2C00CH ^^ (IV) wherein R is an alkyl group of 1-6 C atoms, a halogen-substituted alkyl group of 1-6 C atoms in the alkyl moiety, a phenyl group, a 2 alkoxy group of 1-6 C atoms or an amino group, and R is a hydrogen atom, an alkyl group of 1-6 C atoms, a phenyl group, an acetyl group, an alkoxycarbonyl group of 1-6 C atoms in the alkoxy moiety or a cyano group, or an acid addition salt thereof, are hydrolyzed in slightly acidic or slightly alkaline solution.
De som udgangsforbindelser anvendte forbindelser med formlen (IV) er hidtil ukendte og kan fremstilles ud fra et trans-4-amino-methylcyclohexancarbonylhalogenid eller et syreadditionssalt deraf som illustreret i nedenstående reaktionsskema A, hvor X er et halogenatom, og R^ og R2 er som ovenfor defineret.The starting compounds of formula (IV) are novel and can be prepared from a trans-4-amino-methylcyclohexanecarbonyl halide or an acid addition salt thereof as illustrated in Reaction Scheme A below, where X is a halogen atom and R 1 and R 2 are as defined above.
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Reaktionsskema A: h2nch ~COX + HO O- CH2CH2COOCH^'COR ->Reaction Scheme A: h2nch ~ COX + HO O- CH2CH2COOCH ^ COR ->
(II) (III) R(II) (III) R
/ \ .COR1 [H.O] H2NCH2—^JJ^--COO-^^-CH2CH2C(DOCH^ -- >/ \ .COR1 [H.O] H2NCH2 - ^ JJ ^ - COO - ^^ - CH2CH2C (DOCH ^ ->
c7E) Rc7E) R
H2NCH2 —coo CH2CH2COOHH2NCH2 - COO CH2CH2COOH
(I)(IN)
Det første trin i ovenstående reaktionsskema A omfatter reaktionen til fremstilling af en hidtil ukendt udgangsforbindelse med formlen (IV), der kan vindes ved at kondensere et trans-4-aminomethylcyclohexancarbonylhalogenid eller et syreadditionssalt deraf med formlen (II) med en forbindelse med formlen (III) under opvarmning i et egnet opløsningsmiddel. Der kan anvendes et hvilket som helst opløsningsmiddel ved den ovennævnte reaktion, forudsat at det ikke hindrer reaktionen. Der kan for eksempel anvendes dichlor-ethan, triehlorethan., chloroform, benzen, toluen eller dioxan. Reaktionen vil forløbe ved en temperatur inden for området fra ca.The first step of the above Scheme A comprises the reaction to prepare a novel starting compound of formula (IV) which can be obtained by condensing a trans-4-aminomethylcyclohexanecarbonyl halide or an acid addition salt thereof of formula (II) with a compound of formula (III) ) while heating in a suitable solvent. Any solvent may be used in the above reaction provided that it does not hinder the reaction. For example, dichloroethane, trichloroethane, chloroform, benzene, toluene or dioxane may be used. The reaction will proceed at a temperature within the range of approx.
30°C til ca. 110°C, fortrinsvis fra 50° til 80°C. Efter reaktionens fuldendelse kan den ønskede udgangsforbindelse med formlen (IV) let skilles fra reaktionsblandingen på sædvanlig måde, som beskrevet detaljeret i nedenstående eksempler.30 ° C to approx. 110 ° C, preferably from 50 ° to 80 ° C. Upon completion of the reaction, the desired starting compound of formula (IV) can be easily separated from the reaction mixture in the usual manner, as described in detail in the Examples below.
Det på ovennævnte måde vundne udgangsprodukt med formlen (IV) indebærer en bemærkelsesværdig fordel ved det påfølgende hydrolysetrin. Udgangsproduktet med formlen (IV) har nemlig to ester-bindinger i molekylet, der udviser betydelige forskelle i styrke over for hydrolysebetingelserne. Når derfor udgangsproduktet med formlen (IV) underkastes hydrolyse under milde hydrolysebetingelser, såsom i en svagt sur eller svagt alkalisk opløsning ved normal temperatur, kan acetonylester-delen let fraspaltes, mens phenylester-delen forbliver uhydrolyseret. Acetonylgruppen kan repræsenteres ved gruppen med formlen (V) 5The starting product of formula (IV) obtained in the above manner provides a remarkable advantage of the subsequent hydrolysis step. Namely, the starting product of formula (IV) has two ester bonds in the molecule that exhibit significant differences in strength over the conditions of hydrolysis. Therefore, when the starting product of formula (IV) is subjected to hydrolysis under mild hydrolysis conditions, such as in a slightly acidic or slightly alkaline solution at normal temperature, the acetonylic ester moiety can be readily decomposed while the phenyl ester moiety remains unhydrolyzed. The acetonyl group may be represented by the group of formula (V) 5
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COR1 -CH\r2 (V> 1 2 hvor R og R er som ovenfor defineret. Af nævnte grund er udgangsproduktet med formlen (IV) en meget nyttig og vigtig forbindelse ved den industrielle fremstilling af CEP-ester.COR1 -CH \ r2 (V> 1 2 where R and R are as defined above. For this reason, the starting product of formula (IV) is a very useful and important compound in the industrial preparation of CEP esters.
Udgangsmaterialet med formlen (II), dvs. et trans-4-amino-methylcyclohexancarbonylhalogenid eller et syreadditionssalt deraf, er en kendt forbindelse omtalt i den offentliggjorte japanske patentansøgning nr. 48978/77.The starting material of formula (II), i.e. a trans-4-amino-methylcyclohexanecarbonyl halide or an acid addition salt thereof, is a known compound disclosed in published Japanese Patent Application No. 48978/77.
Udgangsmaterialet med formlen (III), der anvendes i det ovennævnte første trin, kan let fremstilles i godt udbytte ved at omsætte 4-hydroxyphenylpropionsyre med en forbindelse med formlen (VI) xcHr'"'C0R (vi) \r2 1 2 hvor X, R og R er som ovenfor defineret. En detaljeret beskrivelse af fremstillingen af hydroxyphenylpropionesteren med formlen (III) findes nedenfor i referenceeksemplet.The starting material of formula (III) used in the above first step can be readily prepared in good yield by reacting 4-hydroxyphenylpropionic acid with a compound of formula (VI) xcHr R and R are as defined above A detailed description of the preparation of the hydroxyphenyl propionester of formula (III) is given below in the reference example.
Det andet trin ved fremgangsmåden i reaktionsskema A omfatter hydrolyse af forbindelsen med fomlen (IV) vundet i det første trin. Hydrolysereaktionen forløber ved simpelthen at suspendere forbindelsen med formlen (IV) i vand i nærværelse eller fraværelse af en base. Hydrolysen kan sædvanligvis gennemføres ved en pH-værdi på fra ca. 5 til ca. 12.The second step of the process of Scheme A comprises hydrolysis of the compound with the formula (IV) obtained in the first step. The hydrolysis reaction proceeds by simply suspending the compound of formula (IV) in water in the presence or absence of a base. The hydrolysis can usually be carried out at a pH of from approx. 5 to approx. 12th
Som eksempler på egnede og foretrukne baser, der kan anvendes ved hydrolysen, kan nævnes hydroxider af alkalimetaller eller jord-alkalimetaller eller alkalimetal- eller jordalkalimetalsalte af svage syrer, såsom natriumcarbonat, natriumbicarbonat, natriumacetat, natriumhydroxid, kaliumcarbonat, kaliumbicarbonat, kaliumhydroxid eller bariumhydroxid, eller organiske baser, såsom pyridin, triethyl- amin, trimethylamin, diethylamin, dimethylamin, monoethylamin eller monomethylamin, eller de svagt sure baser deraf. Den mængde af basen, der skal anvendes, er ikke af kritisk betydning. For eksempel er i tilfælde af hydrolyse af syreadditionssalte af forbindelsen med fomlen (IV) en ækvimolær mængde eller et lille molært overskud af basen i forhold til forbindelsen med formlen (IV) tilstrække 6As examples of suitable and preferred bases which may be used in the hydrolysis, mention may be made of hydroxides of alkali metals or alkaline earth metals or alkali metal or alkaline earth metal salts of weak acids such as sodium carbonate, sodium bicarbonate, sodium acetate, sodium hydroxide, potassium carbonate, potassium carbonate, potassium carbonate, potassium carbonate, potassium carbonate, potassium carbonate, potassium organic bases such as pyridine, triethylamine, trimethylamine, diethylamine, dimethylamine, monoethylamine or monomethylamine, or the weakly acidic bases thereof. The amount of base to be used is not critical. For example, in the case of hydrolysis of acid addition salts of the compound with the formula (IV), an equimolar amount or a small molar excess of the base relative to the compound of formula (IV) is sufficient 6
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lig til, at hydrolysereaktionen forløber. Som ovenfor beskrevet er et egnet opløsningsmiddel vand, og et vandigt organisk opløsningsmiddel, såsom alkoholer, acetone eller dioxan, kan også anvendes.equals the hydrolysis reaction to proceed. As described above, a suitable solvent is water and an aqueous organic solvent such as alcohols, acetone or dioxane may also be used.
Hydrolysereaktions-temperaturen vil afhænge af arten af beskyttelsesgruppe, der er anvendt til forbindelsen · med formlen (IV), eller af arten og mængden af den base, der skal anvendes, eller af pH af reaktionssysternet. Hydrolysereaktionen forløber imidlertid sædvanligvis ved en temperatur på fra ca. 0°C til ca. 100°C, fortrinsvis inden for et område fra 20° C til 70°C.The hydrolysis reaction temperature will depend on the nature of the protecting group used for the compound of formula (IV), or on the nature and amount of the base to be used, or on the pH of the reaction system. However, the hydrolysis reaction usually proceeds at a temperature of from about 0 ° C to approx. 100 ° C, preferably within a range of 20 ° C to 70 ° C.
Efter den ovenfor beskrevne hydrolysereaktion kan det ønskede produkt (CEP-ester) fraskilles i form af krystaller deraf under anvendelse af sædvanlig teknik, f.eks. som beskrevet i de nedenstående eksempler.Following the hydrolysis reaction described above, the desired product (CEP ester) can be separated into crystals thereof using conventional techniques, e.g. as described in the examples below.
Forbindelserne med formlerne (II) og (III) kan let fremstilles ved fremgangsmåden beskrevet i referenceeksemplet nedenfor.The compounds of formulas (II) and (III) can be readily prepared by the process described in the reference example below.
I referenceeksemplet '· og i de andre eksempler er alle dele, procenter, forhold og lignende efter vægt, med mindre andet er angivet.In the reference example and in the other examples all parts, percentages, ratios and the like are by weight, unless otherwise stated.
Referenceeksempe'lReferenceeksempe'l
Efter at 49,9 g 4-hydroxyphenylpropionsyre var opløst i 160 ml dimethylformamid blev 21,8 g kaliumcarbonat sat til opløsningen ved stuetemperatur (ca. 25°C). Derefter blev 29,1 g monochloracetone tilsat dråbevis til den ovennævnte opløsning ved 60°C og omsat med 4-hydroxyphenylpropionsyren ved 80-90°C i 1 time. Efter omsætningen blev dimethylformamidet afdestilleret fra reaktionsopløsningen, hvorved vandtes en inddampningsrest. Denne blev opløst i dichlorethan, og derefter blev opløsningen vasket med vand. Dichlorethan-laget blev fjernet, og opløsningsmidlet blev afdestilleret, hvorved vandtes 64,7 g (udbytte 97%) acetonyl-4-hydroxyphenylpropionat. Efter omkrystallisation af diisopropylether vandtes farveløse krystaller med smp. 64,5°C.After 49.9 g of 4-hydroxyphenylpropionic acid were dissolved in 160 ml of dimethylformamide, 21.8 g of potassium carbonate was added to the solution at room temperature (about 25 ° C). Then, 29.1 g of monochloroacetone was added dropwise to the above solution at 60 ° C and reacted with the 4-hydroxyphenylpropionic acid at 80-90 ° C for 1 hour. After the reaction, the dimethylformamide was distilled off from the reaction solution to give an evaporated residue. This was dissolved in dichloroethane and then the solution was washed with water. The dichloroethane layer was removed and the solvent was distilled off to give 64.7 g (yield 97%) of acetonyl-4-hydroxyphenyl propionate. After recrystallization from diisopropyl ether, colorless crystals were obtained with m.p. 64.5 ° C.
Elementæranalyse:Elemental analysis:
Beregnet (%) for C^2H14°4: C: 64,85, H; 6,35.Calcd. (%) For C 21 H 14 ° 4: C: 64.85, H; 6.35.
Fundet (%): C: 64,99, H; 6,39.Found (%): C: 64.99, H; 6.39.
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Andre udgangsmaterialeforbindelser med formlen (III) kan fremstilles på samme måde som beskrevet i referenceeksemplet ovenfor. Smeltepunkter og elementæranalyseværdier for repræsentative eksempler på udgangsmaterialeforbindelser med formlen (III) er anført i nedenstående tabel I.Other starting material compounds of formula (III) can be prepared in the same manner as described in the reference example above. Melting points and elemental analysis values for representative examples of starting material compounds of formula (III) are given in Table I below.
Tabel ITable I
/-\ ^cor1 HQ\0/—CH2CH2COOCH\^/ - \ ^ cor1 HQ \ 0 / —CH2CH2COOCH \ ^
Elementæranalyse (beregnet, fundet) R1 R2 Smp. (°C) C Η N Cl (eller produktform) -CH3 -CH3 (olie) 65'si 6>74 -CH3 -COCH3 (olie) 63^41 6*03 -CH3 -COOC2H5 (Olie) 6l|l5 6*25 -γη Π -η 86 5 56'15 5'10 - 13'81 CH2C1 H 8656,43 5,08 13,80 -NH ~H 149 5 59,19 5,87 6,27Elemental analysis (calculated, found) R1 R2 Mp. (° C) C Η N Cl (or product form) -CH3 -CH3 (oil) 65'si 6> 74 -CH3 -COCH3 (oil) 63 ^ 41 6 * 03 -CH3 -COOC2H5 (Oil) 6l | l5 6 * 25 -γη Π -η 86 5 56'15 5'10 - 13'81 CH2 Cl1 H 8656.43 5.08 13.80 -NH ~ H 149 5 59.19 5.87 6.27
NH2 H 149,5 59,39 5'9Q 6'3QNH2 H 149.5 59.39 5'9Q 6'3Q
-c6hs -h 78'5 VM-c6hs -h 78'5 VM
-0CH3 -H (olie) - -OC2H5 -COOC2H5 (Olie) ”,25 6,22 _-0CH3 -H (oil) - -OC2H5 -COOC2H5 (Oil) 6.25 _
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Eksempel 1 (a) 63,3 g Acetonyl-4-hydroxyphenylpropionat, fremstillet som beskrevet ovenfor, blev omsat med 60,4 g trans-4-aminomethylcyclohexan-carboxylsyrechlorid-hydrochlorid i 260 ml 1,2-dichlorethan ved 60-70°C i 2,5 timer under omrøring. Efter endt omsætning blev et krystallinsk bundfald fjernet ved filtrering og tørret, hvorved vandtes 105,5 g (udbytte 93,1%) 4'-(2-acetonyloxycarbonylethy1) phenyl-trans-4-aminomethylcyclohexancarboxylat-hydrochlorid. Dette produkt blev omkrystalliseret af 5% vandig isopropylalkohol, hvorved vandtes farveløse krystaller med smp. 199°C (dek.).Example 1 (a) 63.3 g of Acetonyl-4-hydroxyphenyl propionate prepared as described above was reacted with 60.4 g of trans-4-aminomethylcyclohexane carboxylic acid chloride hydrochloride in 260 ml of 1,2-dichloroethane at 60-70 ° C. for 2.5 hours with stirring. Upon completion of the reaction, a crystalline precipitate was removed by filtration and dried to give 105.5 g (yield 93.1%) of 4 '- (2-acetonyloxycarbonylethyl) phenyl-trans-4-aminomethylcyclohexane carboxylate hydrochloride. This product was recrystallized from 5% aqueous isopropyl alcohol to give colorless crystals with m.p. 199 ° C (dec.).
Elementæranalyse:Elemental analysis:
Beregnet (%) for C2oH28N05C1: C: 60,37, H: 7,09, N: 3,52, Cl: 8,91.Calculated (%) for C 20 H 28 NO 5 Cl: C: 60.37, H: 7.09, N: 3.52, Cl: 8.91.
Fundet (%): C: 60,45, H: 7,02, N: 3,61, Cl: 9,04.Found (%): C: 60.45, H: 7.02, N: 3.61, Cl: 9.04.
(b) 4,97 g 4'-(2-Acetonyloxycarbonylethyl)phenyl-trans-4-amino-methylcyclohexancarboxylat-hydrochlorid, vundet som beskrevet ovenfor, og en vandig opløsning (60 ml) indeholdende 2,10 g natriumbi-carbonat blev blandet og omsat ved 40°C i 40 timer under omrøring. Efter endt reaktion blev de udfældede krystaller frafiltreret og tørret, hvorved vandtes 3,56 g (udbytte 93,4%) 4'-(2-carboxyethyl)-phenyl-trans-4-aminomethylcyclohexancarboxylat (CEP-ester). Dette produkt blev identificeret ved sit NMR-spektrum og infrarøde (IR)-spektrum. Produktet blev derefter behandlet i en fortyndet vandig saltsyreopløsning, hvorved vandtes 3,84 g (udbytte 89,9%) af det tilsvarende saltsyre-additionssalt med smp. 235°C (dek.).(b) 4.97 g of 4 '- (2-Acetonyloxycarbonylethyl) phenyl-trans-4-amino-methylcyclohexane carboxylate hydrochloride, obtained as described above, and an aqueous solution (60 ml) containing 2.10 g of sodium bicarbonate was mixed and reacted at 40 ° C for 40 hours with stirring. Upon completion of the reaction, the precipitated crystals were filtered off and dried, yielding 3.56 g (yield 93.4%) of 4 '- (2-carboxyethyl) phenyl-trans-4-aminomethylcyclohexane carboxylate (CEP ester). This product was identified by its NMR spectrum and infrared (IR) spectrum. The product was then treated in a dilute aqueous hydrochloric acid solution to give 3.84 g (yield 89.9%) of the corresponding hydrochloric acid addition salt, m.p. 235 ° C (dec.).
Eksempel 2 41-(2-Acetonyloxycarbonylethyl)phenyl-trans-4-aminomethyl-cyclohexancarboxylat-hydrochloridet vundet som beskrevet i eksempel 1(a) blev opløst i vand, og den resulterende vandige opløsning blev gjort neutral med en fortyndet vandig opløsning af natriumbicarbonat ved stuetemperatur, hvorved vandtes krystaller. Krystallerne blev fjernet ved filtrering og omkrystalliseret af vandig methanol, hvorved vandtes frit 4'-(2-acetonyloxycarbonylethyl)phenyl-trans-4-ami-nomethylcyclohexancarboxylat med smp. 114°C (dek.).Example 2 The 41- (2-Acetonyloxycarbonylethyl) phenyl-trans-4-aminomethyl cyclohexane carboxylate hydrochloride obtained as described in Example 1 (a) was dissolved in water and the resulting aqueous solution neutralized with a dilute aqueous solution of sodium bicarbonate room temperature, thereby obtaining crystals. The crystals were removed by filtration and recrystallized from aqueous methanol to give freely 4 '- (2-acetonyloxycarbonylethyl) phenyl-trans-4-aminomethylcyclohexane carboxylate, m.p. 114 ° C (dec.).
99
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Elementæranalyse:Elemental analysis:
Beregnet (%) for C2oH27N05: C: 66,46, H: 7,53, N: 3,88.Calcd. (%) For C 20 H 27 NO 5: C: 66.46, H: 7.53, N: 3.88.
Fundet (%): C: 66,34, H: 7,34, N: 3,98.Found (%): C: 66.34, H: 7.34, N: 3.98.
4,52 g 41-(2-Acetonyloxycarbonylethyl)phenyl-trans-4-amino-methylcyclohexancarboxylat, vundet som beskrevet ovenfor, blev suspenderet i 60 ml vand og derefter hydrolyseret ved 40°C i 40 timer under omrøring. Efter endt reaktion blev opløsningen behandlet på samme måde, som beskrevet i eksempel 1(b), hvorved vandtes 3,25 g (udbytte 85,1%) CEP-ester. Det vundne produkt blev identificeret ved sine NMR- og IR-spektre.4.52 g of 41- (2-Acetonyloxycarbonylethyl) phenyl-trans-4-amino-methylcyclohexane carboxylate, obtained as described above, were suspended in 60 ml of water and then hydrolyzed at 40 ° C for 40 hours with stirring. Upon completion of the reaction, the solution was treated in the same manner as described in Example 1 (b) to yield 3.25 g (yield 85.1%) of CEP ester. The product obtained was identified by its NMR and IR spectra.
Eksempel 3 (a) 8,50 g a-Methylacetonyl-4-hydroxyphenylpropionat blev omsat med 6,37 g trans-4-aminomethylcyclohexancarbonylchlorid-hydrochlorid i 50 ml 1,2-dichlorethan ved 65-70°C i 3,5 timer under omrøring. Efter endt reaktion blev opløsningsmidlet fjernet fra reaktionsopløsningen ved destillation, og den herved vundne inddampningsrest blev omkrystalliseret af isopropylalkohol, hvorved vandtes 9,74 g (udbytte 78,4%) 41 —[2—(α-methyl-acetonyloxycarbonyl)ethyljphenyl-trans-4-aminomethylcyclohexancarboxylat-hydrochlorid med smp. 187°C (dek.).Example 3 (a) 8.50 g of α-Methylacetonyl-4-hydroxyphenyl propionate was reacted with 6.37 g of trans-4-aminomethylcyclohexanecarbonyl chloride hydrochloride in 50 ml of 1,2-dichloroethane at 65-70 ° C for 3.5 hours. stirring. Upon completion of the reaction, the solvent was removed from the reaction solution by distillation and the resulting evaporation residue was recrystallized from isopropyl alcohol to give 9.74 g (yield 78.4%) of 41 - [2- (α-methyl-acetonyloxycarbonyl) ethyl] phenyl-trans. 4-aminomethylcyclohexane carboxylate hydrochloride, m.p. 187 ° C (dec.).
Elementæranalyse:Elemental analysis:
Beregnet (%) for C2iH3oN05C^: C: 61,23, H: 7,43, N: 3,40, Cl: 8,61.Calcd. (%) For C 21 H 30 NO 5 Cl 2: C: 61.23, H: 7.43, N: 3.40, Cl: 8.61.
Fundet (%): C: 61,20, H: 7,29, N: 3,46, Cl: 8,64.Found (%): C: 61.20, H: 7.29, N: 3.46, Cl: 8.64.
(b) 5,15 g 4'-[2-(α-Methyl-acetonyloxycarbonyl)ethyllphenyl-trans-4-aminomethylcyclohexancarboxylat-hydrochlorid, vundet som beskrevet under (a) ovenfor, blev sat til 100 ml af en vandig 5% nat-riumbicarbonatopløsning, og blandingen blev behandlet på samme måde som beskrevet i eksempel 1(b), hvorved vandtes 3,17 g (udbytte 83,0%) CEP-ester. Dette produkt blev identificeret ved sine NMR- og IR-spektre.(b) 5.15 g of 4 '- [2- (α-Methyl-acetonyloxycarbonyl) ethyl phenyl-trans-4-aminomethylcyclohexane carboxylate hydrochloride, obtained as described under (a) above, was added to 100 ml of an aqueous 5% overnight sodium bicarbonate solution and the mixture was treated in the same manner as described in Example 1 (b) to give 3.17 g (yield 83.0%) of CEP ester. This product was identified by its NMR and IR spectra.
Eksempel 4 (a) 15,86 g a-Acetylacetonyl-4-hydroxyphenylpropionat blev omsat med 10,60 g trans-4-aminomethylcyclohexancarbonylchlorid-hydrochlo-rid i 50 ml 1,2-dichlor ethan ved 65-70°C i 3 timer under omrøring. Efter endt reaktion blev opløsningsmidlet afdestilleret, og den her- 10Example 4 (a) 15.86 g of α-Acetylacetonyl-4-hydroxyphenyl propionate was reacted with 10.60 g of trans-4-aminomethylcyclohexanecarbonyl chloride hydrochloride in 50 ml of 1,2-dichloroethane at 65-70 ° C for 3 hours. under stirring. After the reaction was complete, the solvent was distilled off and it was quenched
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ved vundne inddampningsrest blev opløst i diethylether. Det resulterende krystallinske bundfald blev fjernet ved filtrering og tørret, hvorved vandtes 21,0 g (udbytte 95,5%) 4*-[2-(a-acetylacetonyloxy-carbonyl)ethyl]phenyl-trans-4-aminomethylcyclohexancarboxylat-hydro-chlorid. Dette produkt blev omkrystalliseret af isopropylalkohol, hvorved vandtes bleggule krystaller med smp. 144°C (dek.).by evaporation residue obtained was dissolved in diethyl ether. The resulting crystalline precipitate was removed by filtration and dried to give 21.0 g (yield 95.5%) of 4 * - [2- (α-acetylacetonyloxy-carbonyl) ethyl] phenyl-trans-4-aminomethylcyclohexane carboxylate hydrochloride . This product was recrystallized from isopropyl alcohol to give pale yellow crystals with m.p. 144 ° C (dec.).
Elementæranalyse:Elemental analysis:
Beregnet (%) for C22H30N06C^: C: 60,06, H: 6,87, N: 3,18, Cl: 8,06.Calculated (%) for C 22 H 30 NO 6 Cl 2: C: 60.06, H: 6.87, N: 3.18, Cl: 8.06.
Fundet (%): C: 59,95, H: 6,80, N: 3,46, Cl: 8,09.Found (%): C: 59.95, H: 6.80, N: 3.46, Cl: 8.09.
(b) 5,50 g 4-[2-(α-Acetyl-acetonyloxycarbonyl)ethyl]phenyl-trans- 4-aminomethylcyclohexancarboxylat-hydrochlorid, vundet som beskrevet under (a) ovenfor, blev sat til 100 ml af en vandig 5% natrium-bicarbonatopløsning og hydrolyseret ved 40°C i 29 timer under omrøring. Reaktionsopløsningen blev behandlet på samme måde som beskrevet i eksempel 1(b), hvorved vandtes 2,79 g (udbytte 73,0%) CEP-es-ter. Dette produkt blev identificeret ved sine NMR- og IR-spektre.(b) 5.50 g of 4- [2- (α-Acetyl-acetonyloxycarbonyl) ethyl] phenyl-trans-4-aminomethylcyclohexane carboxylate hydrochloride, obtained as described under (a) above, was added to 100 ml of an aqueous 5% sodium bicarbonate solution and hydrolyzed at 40 ° C for 29 hours with stirring. The reaction solution was treated in the same manner as described in Example 1 (b) to give 2.79 g (yield 73.0%) of CEP esters. This product was identified by its NMR and IR spectra.
Eksempel 5 (a) 17,70 g a-Ethoxycarbonylacetonyl-4-hydroxyphenylpropionat blev omsat med 10,60 g trans-4-aminomethylcyclohexancarbonylchlorid-hydrochlorid i 50 ml ethylendichlorid ved 65-70°C i 3 timer under omrøring. Efter endt reaktion blev opløsningsmidlet afdestilleret, og den herved vundne inddampningsrest blev opløst i diethylether.Example 5 (a) 17.70 g of α-Ethoxycarbonylacetonyl-4-hydroxyphenyl propionate was reacted with 10.60 g of trans-4-aminomethylcyclohexanecarbonyl chloride hydrochloride in 50 ml of ethylene dichloride at 65-70 ° C for 3 hours with stirring. After the reaction was complete, the solvent was distilled off and the resulting residue was dissolved in diethyl ether.
Det resulterende krystallinske bundfald blev fjernet ved filtrering og omkrystalliseret af isopropylalkohol/n-hexan, hvorved vandtes 17,05 g (udbytte 72,6%) 4·—[2—(a-ethoxycarbonyl-acetonyloxycarbonyl)-ethyl]phenyl-trans-4-aminomethylcyclohexancarboxylat-hydrochlorid med smp. 140°C (dek.).The resulting crystalline precipitate was removed by filtration and recrystallized from isopropyl alcohol / n-hexane to give 17.05 g (yield 72.6%) of 4 - [2- (α-ethoxycarbonyl-acetonyloxycarbonyl) -ethyl] phenyl-trans. 4-aminomethylcyclohexane carboxylate hydrochloride, m.p. 140 ° C (dec.).
Elementæranalyse:Elemental analysis:
Beregnet (%) for 023^2^7^1 C: 58,78, H: 6,86, N: 2,98, Cl: 7,54.Calculated (%) for 023 ^ 2 ^ 7 ^ 1 C: 58.78, H: 6.86, N: 2.98, Cl: 7.54.
Fundet (%): C: 58,62, H: 6,88, N: 2,88, Cl: 7,44.Found (%): C: 58.62, H: 6.88, N: 2.88, Cl: 7.44.
(b) 5,87 g 4'-[2-(a-Ethoxycarbonyl-acetonyloxycarbonyl)ethyl]-phenyl-trans-4-aminomethylcyclohexancarboxylat-hydrochlorid, vundet som beskrevet under (a) ovenfor, blev opløst i 100 ml af en vandig 5% natriumbicarbonatopløsning, og den resulterende opløsning blev behandlet på samme måde som beskrevet i eksempel 3(b), hvorved vandtes 2,74 g (udbytte 71,9%) CEP-ester. Dette produkt blev identifi- 1 1(b) 5.87 g of 4 '- [2- (a-Ethoxycarbonyl-acetonyloxycarbonyl) ethyl] -phenyl-trans-4-aminomethylcyclohexane carboxylate hydrochloride, obtained as described under (a) above, was dissolved in 100 ml of an aqueous solution. 5% sodium bicarbonate solution and the resulting solution was treated in the same manner as described in Example 3 (b) to give 2.74 g (yield 71.9%) of CEP ester. This product was identified 1 1
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ceret ved sine NMR- og IR-spektre.by its NMR and IR spectra.
Eksempel 6 (a) 1,80 g γ-Chlor— acetonyl-4-hydroxyphenylpropionat blev omsat med 1,48 g trans-4-aminomethylcyclohexancarbonylchlorid-hydrochlorid i 10 ml ethylendichlorid ved 65-70°C i 3 timer under omrøring. Efter endt reaktion blev det krystallinske reaktionsprodukt frafiltreret og tørret, hvorved vandtes 2,62 g (udbytte 86,8%) 4[2-(γ-chlor-acetonyloxycarbonyl)ethyl]phenyl-trans-4-aminomethyIcyclohexancar-boxylat-hydrochlorid. Efter omkrystallisation af vandig isopropyl-alkohol vandtes produktet som farveløse krystaller med smp. 200°C (dek.).Example 6 (a) 1.80 g of γ-Chloro-acetonyl-4-hydroxyphenyl propionate was reacted with 1.48 g of trans-4-aminomethylcyclohexanecarbonyl chloride hydrochloride in 10 ml of ethylene dichloride at 65-70 ° C for 3 hours with stirring. After completion of the reaction, the crystalline reaction product was filtered off and dried to give 2.62 g (yield 86.8%) of 4 [2- (γ-chloro-acetonyloxycarbonyl) ethyl] phenyl-trans-4-aminomethylcyclohexane carboxylate hydrochloride. After recrystallization from aqueous isopropyl alcohol, the product was obtained as colorless crystals, m.p. 200 ° C (dec.).
Elementæranalyse:Elemental analysis:
Beregnet (%) for C2oH27N05C12: C: 55,56, H: 6,29, Ns 3,24, Cl: 16,40.Calculated (%) for C 20 H 27 NO 5 Cl 2: C: 55.56, H: 6.29, Ns 3.24, Cl: 16.40.
Fundet (%): C: 55,63, H: 6,20, N: 3,44, Cl: 16,17.Found (%): C: 55.63, H: 6.20, N: 3.44, Cl: 16.17.
(b) 5,40 g 4* — [2—(γ-Chloracetonyloxycarbonyl)ethyl]phenyl-trans-4-aminomethylcyclohexancarboxylat-hydrochlorid, vundet som beskrevet under (a) ovenfor, blev opløst i 100 ml af en vandig 5% natriumbi-carbonatopløsning. Derefter blev opløsningen behandlet på samme måde som beskrevet i eksempel 3(b), hvorved vandtes 1,98 g (udbytte 52,0%) CEP-ester. Dette produkt blev identificeret ved sine NMR- og IR-spektre .(b) 5.40 g of 4 * - [2- (γ-Chloroacetonyloxycarbonyl) ethyl] phenyl-trans-4-aminomethylcyclohexane carboxylate hydrochloride, obtained as described under (a) above, was dissolved in 100 ml of an aqueous 5% sodium bicarbonate. -carbonatopløsning. Then, the solution was treated in the same manner as described in Example 3 (b) to give 1.98 g (yield 52.0%) of CEP ester. This product was identified by its NMR and IR spectra.
Eksempel 7 (a) 12,0 g Phenacyl-4-hydroxyphenylpropionat blev omsat med 8,49 g trans-4-aminomethylcyclohexancarbonylchlorid-hydrochlorid i 50 ml ethylendichlorid. Reaktionsopløsningen blev behandlet på samme måde som beskrevet i eksempel 1(a), hvorved vandtes 16,09 g (udbytte 87,4%) 41-(2-phenacyloxycarbonylethyl)phenyl-trans-4-aminomethyl-cyclohexancarboxylat-hydrochlorid. Efter omkrystallisation af vand vandtes produktet som farveløse krystaller med et smp. 205°C (dek.). Elementæranalyse:Example 7 (a) 12.0 g of Phenacyl-4-hydroxyphenyl propionate was reacted with 8.49 g of trans-4-aminomethylcyclohexanecarbonyl chloride hydrochloride in 50 ml of ethylene dichloride. The reaction solution was treated in the same manner as described in Example 1 (a) to give 16.09 g (yield 87.4%) of 41- (2-phenacyloxycarbonylethyl) phenyl-trans-4-aminomethyl-cyclohexane carboxylate hydrochloride. After recrystallization of water, the product was obtained as colorless crystals with a m.p. 205 ° C (dec.). Elemental analysis:
Beregnet (%) for ^cjHgQNOtjCl: C: 65,28, H: 6,57, N: 3,05, Cl: 7,71.Calculated (%) for C ^HgQNO₂Cl: C: 65.28, H: 6.57, N: 3.05, Cl: 7.71.
Fundet (%): C: 65,22, H: 6,49, N: 3,00, Cl: 7,43.Found (%): C: 65.22, H: 6.49, N: 3.00, Cl: 7.43.
(b) 5,75 g 41-(2-Phenacyloxycarbonylethyl)phenyl-trans-4-amino-methylcyclohexancarboxylat-hydrochlorid, vundet som beskrevet under (a) ovenfor, og 5,3 g natriumbicarbonat blev opløst i 100 ml af en(b) 5.75 g of 41- (2-Phenacyloxycarbonylethyl) phenyl trans-4-amino-methylcyclohexanecarboxylate hydrochloride, obtained as described under (a) above, and 5.3 g of sodium bicarbonate dissolved in 100 ml of a
DK 158512 BDK 158512 B
12 50% vandig acetoneopløsning og blev omsat ved 50°C i 45 timer under omrøring. Efter endt reaktion blev reaktionsopløsningen behandlet på samme måde som beskrevet i eksempel 1(b), hvorved vandtes 1,83 g (udbytte 47,9%) CEP-ester. Dette produkt blev identificeret ved sine NMR- og IR-spektre.12 50% aqueous acetone solution and reacted at 50 ° C for 45 hours with stirring. After completion of the reaction, the reaction solution was treated in the same manner as described in Example 1 (b) to give 1.83 g (yield 47.9%) of CEP ester. This product was identified by its NMR and IR spectra.
Eksempel 8 (a) 2,23 g Carbamylmethyl-4-hydroxyphenylpropionat blev omsat med 2,11 g trans-4-aminomethylcyclohexancarbonylchlorid-hydrochlorid i 30 ml dioxan ved 75-80°C i 1,5 timer under omrøring. Efter endt reaktion blev det resulterende krystallinske bundfald fjernet ved filtrering og tørret, hvorved vandtes 2,80 g (udbytte 70,5%) 4'-(2-carba-mylmethoxycarbonylethyl)phenyl-trans-4-aminomethylcyclohexancarboxy-lat-hydrochlorid. Dette produkt blev omkrystalliseret af methanol, hvorved vandtes farveløse krystaller med smp. 242°C (dek.).Example 8 (a) 2.23 g of Carbamylmethyl-4-hydroxyphenyl propionate was reacted with 2.11 g of trans-4-aminomethylcyclohexanecarbonyl chloride hydrochloride in 30 ml of dioxane at 75-80 ° C for 1.5 hours with stirring. Upon completion of the reaction, the resulting crystalline precipitate was removed by filtration and dried to give 2.80 g (yield, 70.5%) of 4 '- (2-carbamylmethoxycarbonylethyl) phenyl-trans-4-aminomethylcyclohexane carboxylate hydrochloride. This product was recrystallized from methanol to give colorless crystals, m.p. 242 ° C (dec.).
Elementæranalyse:Elemental analysis:
Beregnet (%) for C^g^y^Oj-Cl: C: 57,21, H: 6,82, N: 7,02, Cl: 8,89.Calcd. (%) For C ^ g ^Y₂O₂-Cl: C: 57.21, H: 6.82, N: 7.02, Cl: 8.89.
Fundet (%): C: 57,02, H: 6,74, N: 7,01, Cl: 9,16.Found (%): C: 57.02, H: 6.74, N: 7.01, Cl: 9.16.
(b) 4,99 g 4'- (2-Carbamylmethyloxycarbonylethyl)phenyl-trans-4-aminomethylcyclohexancarboxylat-hydrochlorid, vundet som beskrevet under (a) ovenfor, blev opløst i 50 ml af en vandig 5% natriumbicar-bonatopløsning og hydrolyseret ved 50°C i 10 timer under omrøring. Reaktionsopløsningen blev derefter behandlet på samme måde som beskrevet i eksempel 1(b), hvorved vandtes 1,32 g (udbytte 34,6%) CEP-ester. Dette produkt blev identificeret gennem sine NMR- og IR-spektre .(b) 4.99 g of 4'- (2-Carbamylmethyloxycarbonylethyl) phenyl-trans-4-aminomethylcyclohexane carboxylate hydrochloride, obtained as described under (a) above, were dissolved in 50 ml of an aqueous 5% sodium bicarbonate solution and hydrolyzed at 50 ° C for 10 hours with stirring. The reaction solution was then treated in the same manner as described in Example 1 (b) to give 1.32 g (yield 34.6%) of CEP ester. This product was identified through its NMR and IR spectra.
Eksempel 9 4,76 g Methoxycarbonylmethyl-4-hydroxyphenylpropionat blev omsat med 4,23 g trans-4-aminomethylcyclohexancarbonylchlorid-hydro-chlorid i 30 ml 1,2-dichlorethan under de samme reaktionsbetingelser som beskrevet i eksempel 4(a), hvorved vandtes 7,30 g (udbytte 88,5%) 4'-(2-methoxycarbonylmethyloxycarbonylethyl)phenyl-trans-4-amino-methylcyclohexancarboxylat-hydrochlorid. Dette produkt blev omkrystalliseret af ethanol, hvorved vandtes farveløse krystaller med smp.Example 9 4.76 g of Methoxycarbonylmethyl-4-hydroxyphenyl propionate was reacted with 4.23 g of trans-4-aminomethylcyclohexanecarbonyl chloride hydrochloride in 30 ml of 1,2-dichloroethane under the same reaction conditions as described in Example 4 (a) 7.30 g (yield 88.5%) of 4 '- (2-methoxycarbonylmethyloxycarbonylethyl) phenyl-trans-4-amino-methylcyclohexane carboxylate hydrochloride. This product was recrystallized from ethanol to give colorless crystals, m.p.
198°C (dek.).198 ° C (dec.).
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1313
Elementæranalyse:Elemental analysis:
Beregnet (%) for C20H2gNOgCl: C: 58,04, H: 6,82, N: 3,38, Cl: 8,57.Calcd. (%) For C20 H20 NO2 Cl: C: 58.04, H: 6.82, N: 3.38, Cl: 8.57.
Fundet (%) C: 58,12, H: 6,87, N: 3,33, Cl: 8,35.Found (%) C: 58.12, H: 6.87, N: 3.33, Cl: 8.35.
Eksempel 10 10,8 g Diethoxycarbonylmethyl-4-hydroxyphenylpropionat blev omsat med 6,36 g trans-4-aminomethylcyclohexancarbonylchlorid-hydro-chlorid i 30 ml 1,2-dichlorethan under de samme betingelser som beskrevet i eksempel 4(a), hvorved vandtes 12,7 g (udbytte 84,7%) 4-(2-diethoxycarbonylmethyloxycarbonylethyl)phenyl-trans-4-aminomethyl-cyclohexancarboxylat-hydrochlorid. Ved krystallisation af isopropyl-alkohol vandtes produktet som farveløse krystaller med smp. 131°C (dek.).Example 10 10.8 g of Diethoxycarbonylmethyl-4-hydroxyphenyl propionate was reacted with 6.36 g of trans-4-aminomethylcyclohexanecarbonyl chloride hydrochloride in 30 ml of 1,2-dichloroethane under the same conditions as described in Example 4 (a) 12.7 g (yield 84.7%) of 4- (2-diethoxycarbonylmethyloxycarbonylethyl) phenyl-trans-4-aminomethyl-cyclohexane carboxylate hydrochloride. Upon crystallization of isopropyl alcohol, the product was obtained as colorless crystals, m.p. 131 ° C (dec.).
Elementæranalyse:Elemental analysis:
Beregnet (%) for C^H^NOgCl: C: 57,65, H: 6,85, N: 2,80, Cl: 7,09.Calcd. (%) For C ^H ^NOgCl: C: 57.65, H: 6.85, N: 2.80, Cl: 7.09.
Fundet (%): C: 57,35, H: 6,61, N: 2,77, Cl: 6,98.Found (%): C: 57.35, H: 6.61, N: 2.77, Cl: 6.98.
Eksempel 11 4.97 g 4'-(2-Acetonyloxycarbonylethyl)phenyl-trans-4-amino-methylcyclohexancarboxylat-hydrochlorid, vundet som beskrevet i eksempel 1(a), blev opløst i 100 ml vand, og 6,0 ml af en vandig 10% natriumhydroxidopløsning blev tilsat. Blandingen blev derefter omrørt ved 40°C i 3 timer til tilvejebringelse af hydrolyse. Reaktions-opløsningen blev behandlet på samme måde som beskrevet i eksempel 1(b), hvorved vandtes 2,32 g (udbytte 60,9%) CEP-ester. Dette produkt blev identificeret ved sine NMR- og IR-spektre.Example 11 4.97 g of 4 '- (2-Acetonyloxycarbonylethyl) phenyl-trans-4-amino-methylcyclohexane carboxylate hydrochloride, obtained as described in Example 1 (a), were dissolved in 100 ml of water and 6.0 ml of an aqueous solution. % sodium hydroxide solution was added. The mixture was then stirred at 40 ° C for 3 hours to provide hydrolysis. The reaction solution was treated in the same manner as described in Example 1 (b) to give 2.32 g (yield 60.9%) of CEP ester. This product was identified by its NMR and IR spectra.
Eksempel 12 4.97 g 41-(2-Acetonyloxycarbonylethyl)phenyl-trans-4-amino-methylcyclohexancarboxylat-hydrochlorid, vundet som beskrevet i eksempel 1(a), blev opløst i 50 ml vand, og 35 ml af en vandig 2% nat-riumcarbonatopløsning blev tilsat. Blandingen blev derefter omrørt ved stuetemperatur i 43 timer til tilvejebringelse af hydrolyse, og reaktionsopløsningen blev derefter behandlet på samme måde som beskrevet i eksempel 1(b), hvorved vandtes 3,14 g (udbytte 82,4%) CEP-ester. Dette produkt blev identificeret ved sine NMR- og IR-spektre.Example 12 4.97 g of 41- (2-Acetonyloxycarbonylethyl) phenyl-trans-4-amino-methylcyclohexane carboxylate hydrochloride, obtained as described in Example 1 (a), were dissolved in 50 ml of water and 35 ml of an aqueous 2% aqueous solution. rium carbonate solution was added. The mixture was then stirred at room temperature for 43 hours to provide hydrolysis and the reaction solution was then treated in the same manner as described in Example 1 (b) to give 3.14 g (yield 82.4%) of CEP ester. This product was identified by its NMR and IR spectra.
Claims (2)
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DK193678A DK158512C (en) | 1978-05-03 | 1978-05-03 | METHOD FOR PREPARING 4 '- (2-CARBOXYETHYL) PHENYL-TRANS-4-AMINOMETHYLCYCLOHEXANCARBOXYLATE OR ACID ADDITION SALTS THEREOF |
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DK193678A DK158512C (en) | 1978-05-03 | 1978-05-03 | METHOD FOR PREPARING 4 '- (2-CARBOXYETHYL) PHENYL-TRANS-4-AMINOMETHYLCYCLOHEXANCARBOXYLATE OR ACID ADDITION SALTS THEREOF |
| DK193678 | 1978-05-03 |
Publications (3)
| Publication Number | Publication Date |
|---|---|
| DK193678A DK193678A (en) | 1979-11-04 |
| DK158512B true DK158512B (en) | 1990-05-28 |
| DK158512C DK158512C (en) | 1990-11-05 |
Family
ID=8109038
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| DK193678A DK158512C (en) | 1978-05-03 | 1978-05-03 | METHOD FOR PREPARING 4 '- (2-CARBOXYETHYL) PHENYL-TRANS-4-AMINOMETHYLCYCLOHEXANCARBOXYLATE OR ACID ADDITION SALTS THEREOF |
Country Status (1)
| Country | Link |
|---|---|
| DK (1) | DK158512C (en) |
-
1978
- 1978-05-03 DK DK193678A patent/DK158512C/en not_active IP Right Cessation
Also Published As
| Publication number | Publication date |
|---|---|
| DK158512C (en) | 1990-11-05 |
| DK193678A (en) | 1979-11-04 |
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Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PBP | Patent lapsed |