DK156770B - CYCLIC SULPHONYLOXYMIDES USED AS INTERMEDIATES IN THE PRODUCTION OF CYCLIC AMINO ACIDS - Google Patents
CYCLIC SULPHONYLOXYMIDES USED AS INTERMEDIATES IN THE PRODUCTION OF CYCLIC AMINO ACIDS Download PDFInfo
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Opfindelsen angâr hidtil ukendte, cycliske imider med formlen .CH - CO 2 5 (CH.) ίΑ - O - SO~ - R (I) ^ch2 “ cox/ hvori R2 betyder en mættet acyclisk eller cyclisk, aliphatisk 10 gruppe med 1-10 carbonatomer eller eventuelt substitueret aryl, og n betyder 4, 5 eller 6, til anvendelse som mellemprodukter ved fremstilling af cycliske aminosyrer.The invention relates to novel cyclic imides of the formula .CH - CO 2 5 (CH.) SO O - O - SO ~ - R (I) ch CH₂ “cox / wherein R 2 represents a saturated acyclic or cyclic aliphatic group of 1- 10 carbon atoms or optionally substituted aryl, and n means 4, 5 or 6, for use as intermediates in the production of cyclic amino acids.
15 I besk'rivelsen til dansk patentansdgning nr. 5814/75 omtales de cycliske aminosyrer med den almene formel H2N - CH2 - C - CH2 - COOR4 (VI) (CH2)n 20 hvori R4 betyder hydrogen eller en lavere alkylgruppe, og n er 4, 5 eller 6, samt farmakologisk acceptable salte deraf. Endvidere beskrives forskellige fremgangsmâder til fremstilling af disse forbindelser, og disse fremgangsmâder afhænger 25 af kendte "dekomponeringsmetoder", som anvendes ved fremstil-lingen af primære aminer eller aminosyrer.In the specification of Danish patent application No. 5814/75, the cyclic amino acids of the general formula H2N - CH2 - C - CH2 - COOR4 (VI) (CH2) n 20 are mentioned wherein R4 is hydrogen or a lower alkyl group and n is 4, 5 or 6, and their pharmacologically acceptable salts. Furthermore, various processes for preparing these compounds are described and these methods depend on known "decomposition methods" used in the preparation of primary amines or amino acids.
En vigtig fremgangsmâde er den sâkaldte Lossen-omlej-ring af passende hydroxamcarboxylsyrer, men denne fremgangsmâde har imidlertid den ulempe, at mellemprodukterne er 30 vanskelige at isolere i ren form, hvorfor de 0nskede produk-ter ogsâ fâs i mindre ren form.An important method is the so-called Lossen rearrangement of suitable hydroxam carboxylic acids, but this method has the disadvantage that the intermediates are difficult to isolate in pure form, which is why the desired products are also obtained in less pure form.
Det har vist sig, at de hidtil ukendte, cycliske sulfonyloxyimider med den almene formel 35It has been found that the novel cyclic sulfonyloxyimides of general formula 35
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2 /CH - CO 2 (CHn) C Tï - O - S0o - R ,Tt n^^^ch2-co/ 2 {I) 5 hvori R2 betyder en mættet acyclisk eller cyclisk, aliphatisk gruppe med 1-10 carbonatomer eller eventuelt substitueret aryl, og 10 n betyder 4, 5 eller 6, direkte kan underkastes en Lossen--omlejring til dannelse af forbindelserne med foralen (VI) i ren fora og i særlig ho je udbytter.2 / CH - CO 2 (CHn) C T1 - O - SO0 - R, Tt n ^^^ ch2-co / 2 (I) 5 wherein R 2 represents a saturated acyclic or cyclic aliphatic group having 1-10 carbon atoms or optionally substituted aryl, and 10 n means 4, 5 or 6 can be directly subjected to a Lossen rearrangement to form the compounds with the parent (VI) in pure forums and in particularly high yields.
Nâr R2 betyder en aliphatisk gruppe, kan den eventuelt indeholde substituenter elelr carbonylfunktioner, som ikke 15 reagerer ved den videre reaktion.Where R 2 represents an aliphatic group, it may optionally contain substituents or carbonyl functions which do not react in the further reaction.
Til forskel fra hydroxamcarboxylsyrerne, som er van-skelige at isolere i ren fora, er forbindelserne med den almene formel (II), der kan anvendes til fremstilling af forbindelser med den almene formel (I), krystallinske, sta-20 bile forbindelser, der er uskadelige i modsætning til de eksplosive mellemproduktforbindelser, som dannes i tilfælde af Curtius-omlejringen. Forbindelserne med den almene formel (VI) fremstillet under anvendelse af forbindelserne med form-len (I) har en bemærkelsesværdig stor renhed, hvorimod der 25 ved de kendte fremgangsmâder dannes store mængder biproduk-ter, som skal fjernes i efterfolgende rensningstrin.Unlike the hydroxam carboxylic acids which are difficult to isolate in pure forums, the compounds of general formula (II) which can be used to prepare compounds of general formula (I) are crystalline, stable compounds which are harmless in contrast to the explosive intermediate compounds formed in the case of the Curtius rearrangement. The compounds of general formula (VI) prepared using the compounds of formula (I) have a remarkably high purity, whereas in the known processes, large amounts of by-products are formed which are to be removed in subsequent purification steps.
Forbindelserne med den almene formel (I) muliggor sâldes gennemforelse af Lossen-omlejringen pâ okonomisk mâde i stor mâlestok.The compounds of the general formula (I) allow for the implementation of the Lossen rearrangement in a large scale economically.
30 Forbindelserne med den almene formel (I), der som nævnt er hidtil ukendte forbindelser, kan fremstilles ved én af folgende fremgangsmâder.The compounds of the general formula (I), which as mentioned are novel compounds, can be prepared by one of the following methods.
Fremgangsmâde a: omsætning af en forbindelse med den almene formel 35 3Process a: reacting a compound of the general formula 3
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f .CH2 - COOHf .CH2 - COOH
^?H2*n (III)H 2 n (III)
V / \ CH - CO - NHOHV / \ CH - CO - NHOH
5 hvor n er 4, 5 eller 6, med et reaktivt dérivât af en sulfonsyre med den almene formel 10 HO - S02 - R2 (II) hvor R2 har den ovenfor angivne betydning i nærværelse af et 15 syrebindemiddël.5 wherein n is 4, 5 or 6, with a reactive derivative of a sulfonic acid of the general formula 10 HO - SO2 - R2 (II) wherein R2 has the meaning given above in the presence of an acid binder.
Fremgangsmâde (b): O-acylering af en forbindelse med den almene formelProcess (b): O-acylation of a compound of the general formula
' /CH„ - CO'/ CH' - CO
20 ^CH2>n ^ ' y ~ °H (Ib) <^/N:h2-co/ hvor n er 4, 5 eller 6, med mindst to ækvivalenter af et reaktivt 25 dérivât af en sulfonsyre med den almene formel (II).<RTIgt; 20 </RTI> CH2> n ^ y ~ ° H (Ib) <^ / N: h 2 -co / where n is 4, 5 or 6, with at least two equivalents of a reactive derivative of a sulfonic acid of the general formula ).
Naturen af gruppen R2 er ikke kritisk, da gruppen har mindre indflydelse pâ omlejringsreaktionen. R2 kan sâle-des være en methyl- eller ethylgruppe (hojere homologe ali-phatiske sulfonsyrer er for tiden vanskeligt tilgængelige 30 og kan derfor næppe anvendes i teknisk mâlestok), en cyclo-alkylgruppe, som ogsâ kan indeholde en carbonylfunktion (billige sulfonsyrer sâsom kamfersulfonsyre kan anvendes) eller arylgrupper, især phenyl- eller naphthylgrupper, som ogsâ kan være substitueret med lavere alkylgrupper, halogen-35 atomer eller nitrogrupper. Disulfonsyrer, f.eks. naphthalen-disulfonsyrer, kan ogsâ anvendes som forbindelser med den 4The nature of group R2 is not critical as the group has less influence on the rearrangement reaction. R2 can thus be a methyl or ethyl group (higher homologous aliphatic sulfonic acids are currently difficult to access and therefore hardly used on a technical scale), a cycloalkyl group which may also contain a carbonyl function (cheap sulfonic acids such as camphor sulfonic acid may be used) or aryl groups, especially phenyl or naphthyl groups, which may also be substituted by lower alkyl groups, halogen atoms or nitro groups. Disulfonic acids, e.g. naphthalene disulfonic acids, can also be used as compounds with the 4
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almene formel (II), i hvilke tilfælde et molekyle sulfonsyre esterificeres med to N-hydroxy 1 iminomoleky 1 er. Som eksempler pâ forbindelser med den almene formel (II) kan nævnes methan-sulfonsyre, ethansulfonsyre, benzensulfonsyre, p-toluensul-5 fonsyre, naphthalensulfonsyre, kamfersulfonsyre, naphthalen--1,5-disulfonsyre, o-nitrophenylsulfonsyre, p-bromphenylsul-fonsyre og p-chlorphenylsulfonsyre. Foretrukne grupper omfat-ter methyl-, ethyl- og kamforylgrupper samt phenyl- og naph-thylgrupper, der kan være substitueret med en eller flere 10 alkylgrupper, fortrinsvis methylgrupper, halogenatomer, chloratomer, eller nitrogrupper.general formula (II), in which case a molecule of sulfonic acid is esterified with two N-hydroxy 1 iminomolecy 1. Examples of compounds of general formula (II) include methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, naphthalenesulfonic acid, camphor sulfonic acid, naphthalene-1,5-disulfonic acid, o-nitrophenylsulfonic acid, p-bromophenyl acid and p-chlorophenylsulfonic acid. Preferred groups include methyl, ethyl and campforyl groups as well as phenyl and naphthyl groups which may be substituted by one or more alkyl groups, preferably methyl groups, halogen atoms, chlorine atoms, or nitro groups.
De reaktive derivater af syrerne med den almene formel (II) indbefatter halogensulfonsyrer, fortrinsvis chlorsulfon-syrerne, og sulfonsyreanhydriderne.The reactive derivatives of the acids of the general formula (II) include halogen sulfonic acids, preferably the chlorosulfonic acids, and the sulfonic acid anhydrides.
15 Forbindelser med den almene formel (Ib), der ogsâ er hidtil ukendte forbindelser, kan fremstilles ved omsætning af en forbindelse med den almene formel 20 /"T'Nr-''CH2 " C0>0 (VII> hvor n er 4, 5 eller 6, med hydroxylamin ved forhojet temperatur, 25 fortrinsvis pâ 50-100°C.Compounds of the general formula (Ib), which are also novel compounds, can be prepared by reacting a compound of the general formula 20 / "T'Nr -" "CH2" C0> 0 (VII> where n is 4, 5 or 6, with hydroxylamine at elevated temperature, preferably at 50-100 ° C.
Forbindelser med den almene formel (III) kan fremstilles ud fra syreanhydrider med den almene formel (VII) ved omsætning med hydroxylamin, fortrinsvis ved omgivelsemes temperatur. Forbindelserne med den almene formel (VII) er 30 kendt, jf. J. Chem. Soc. 115, 686/1919, 99, 446, 117, 639/-1920.Compounds of general formula (III) can be prepared from acid anhydrides of general formula (VII) by reaction with hydroxylamine, preferably at ambient temperature. The compounds of the general formula (VII) are known, cf. J. Chem. Soc. 115, 686/1919, 99, 446, 117, 639 / -1920.
O-acyleringen af N-hydroxyimiderne med den almene formel (Ib) gennemf0res fortrinsvis ved en temperatur pâ fra ca. 5 til 20°C med et chlorid eller anhydrid af en sul-35 fonsyre med den almene formel (II) enten i vandig eller vandig/alkoholisk opldsning i nærværelse af et syrebindemid-The o-acylation of the N-hydroxyimides of the general formula (Ib) is preferably carried out at a temperature of from ca. 5 to 20 ° C with a chloride or anhydride of a sulfonic acid of the general formula (II) either in aqueous or aqueous / alcoholic solution in the presence of an acid binder.
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5 del, f.eks. et alkalimetalcarbonat eller -hydrogencarbonat, fortrinsvis natriumhydrogencarbonat, eller i et aprotisk oplosningsmiddel i nærværelse af en tertiær amin7 f.eks. triethylamin eller pyridin.5 part, e.g. an alkali metal carbonate or hydrogen carbonate, preferably sodium bicarbonate, or in an aprotic solvent in the presence of a tertiary amine, e.g. triethylamine or pyridine.
5 Fremgangsmâde (a) gennemfores fortrinsvis ved omgivel- sernes temperatur eller derunder pâ en sâdan màde, at en forbindelse med den almene formel (III) omsættes med mindst to ækvivalenter af et reaktivt syrederivat med den almene formel (II) i nærværelse af et syrebindemiddel, f.eks. ka-10 liumcarbonat eller pyridin.Process (a) is preferably carried out at ambient temperature or below in such a way that a compound of general formula (III) is reacted with at least two equivalents of a reactive acid derivative of general formula (II) in the presence of an acid binder. , eg. potassium carbonate or pyridine.
Hydroxylaminen anvendes fortrinsvis i vandig oplos-ning, men imidlertid kan der ogsâ anvendes andre opldsnings-midler, f.eks. lavere aliphatiske alkoholer, ethere eller aromatiske carbonhydrider sâsom benzen eller toluen. Forbin-15 delserne med den almene formel (III) kan omdannes til forbin-delser med den almene formel (Ib) i l0bet af 0,5-2 timer ved opvarmning til en temperatur pâ fra 50 til 100°C, fortrinsvis i omrâdet 70-80°C. Det er ogsâ muligt at gâ fra forbindelser med den almene formel (IV) og omdanne disse 20 direkte til forbindelser med den almene formel (Ib) med hydroxylamin ved en temperatur over 50“C, fortrinsvis 70--80°C, i hvilke tilfælde der dannes forbindelser med den almene formel (III), som derpâ straks reagerer videre.The hydroxylamine is preferably used in aqueous solution, but other solvents, e.g. lower aliphatic alcohols, ethers or aromatic hydrocarbons such as benzene or toluene. The compounds of the general formula (III) can be converted into compounds of the general formula (Ib) over a period of 0.5-2 hours by heating to a temperature of 50 to 100 ° C, preferably in the range 70 -80. It is also possible to proceed from compounds of the general formula (IV) and convert these directly to compounds of the general formula (Ib) with hydroxylamine at a temperature above 50 ° C, preferably 70 to 80 ° C, in which case compounds of general formula (III) are formed, which then immediately react further.
For omdannelsen af forbindelserne til de cycliske 25 aminosyrer med den almene formel (VI) underkastes de cycliske N-sulfonyloxyimider med den almene formel (I) en Lossen--omlejring ved opvarmning i vandig opldsning i nærværelse af en ækvimolær mængde eller overskud af en base, fortrinsvis en 10%'s vandig natrium- eller kaliumhydroxidopldsning, i 30 0,5-2 timer ved 100°C, eller ved opvarmning i en lavere alkohol, f.eks. methanol eller éthanol i nærværelse af en tertiær amin eller et alkoholat med tilbagesvalingstempera-turen.For the conversion of the compounds to the cyclic 25 amino acids of general formula (VI), the cyclic N-sulfonyloxyimides of general formula (I) are subjected to a Lossen rearrangement by heating in aqueous solution in the presence of an equimolar amount or excess base. , preferably a 10% aqueous sodium or potassium hydroxide solution, for 0.5-2 hours at 100 ° C, or by heating in a lower alcohol, e.g. methanol or ethanol in the presence of a tertiary amine or alcoholate at the reflux temperature.
I det fdrste tilfælde syrnes reaktionsblandingen 35 efter afkdling, fortrinsvis med koncentreret saltsyre, og inddampes. For at skille de uorganiske stoffer fra ekstrahe-In the first case, the reaction mixture is acidified after cooling, preferably with concentrated hydrochloric acid, and evaporated. To separate the inorganic substances from the extract
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6 res inddampningsremanensen med absolut éthanol, og aminosyre-saltet, der udkrystalliserer fra éthanol ved koncentrering, overfores i den fri aminosyre ved anvendelse af en passende basisk ionbytter i OH-formen. Fra moderluden isoleres kun 5 smâ mængder lactam, som kan omdannes til den fri aminosyre. Lactamerne eller urethanerne, som dannes ved denne anden fremgangsmâdevariant, omdannes fortrinsvis til de tilsvarende aminosyrer ved hjælp af saltsyre.The residue is evaporated with absolute ethanol and the amino acid salt which crystallizes from ethanol by concentration is transferred into the free amino acid using a suitable basic ion exchanger in the OH form. Only 5 small amounts of lactam are isolated from the mother liquor, which can be converted to the free amino acid. The lactams or urethanes formed by this second process variant are preferably converted to the corresponding amino acids by hydrochloric acid.
Opfindelsen illustreres nærmere i de f0lgende ek-10 sempler.The invention is further illustrated in the following examples.
Eksempel 1 N-(benzensulfonvloxv)-1,1-cvclohexan-dieddikesvreimid.Example 1 N- (benzenesulfonylloxy) -1,1-cyclohexane diacetic acid.
50 g 1,1-cyclohexan-dieddikesyreanhydrid sættes por-15 tionsvis under omroring til en vandig oplpsning af hydroxyl-amin, som er fremstillet ud fra 23,4 g hydroxylamin-hydro-chlorid og 21,12 g natriumcarbonat. Efter endt tilsætning opvarmes reaktionsblandingen i 2 timer ved 70°C, og der udskilles en olie. Efter afkoling indstilles pH-værdien pâ 20 2 med 2 N saltsyre, og det krystallinske bundfald frafiltre- res under anvendelse af sugning. Bundfaldet vaskes med vand, optages i methanol, al uoplost materiale fjernes, og efter tilsætning af vand foretages inddampning i vakuum. Der fâs 45,5 g 1,1-cyclohexan-dieddikesyre-N-hydroxyimid med smp.50 g of 1,1-cyclohexane diacetic anhydride are added portionwise with stirring to an aqueous solution of hydroxylamine prepared from 23.4 g of hydroxylamine hydrochloride and 21.12 g of sodium carbonate. After the addition is complete, the reaction mixture is heated at 70 ° C for 2 hours and an oil is separated. After cooling, the pH is adjusted to 20 2 with 2N hydrochloric acid and the crystalline precipitate is filtered off using suction. The precipitate is washed with water, taken up in methanol, all undissolved material is removed and evaporation is done in vacuo. 45.5 g of 1,1-cyclohexane diacetic acid N-hydroxyimide are obtained, m.p.
25 104°C.25 104 ° C.
45,5 g 1,1-cyclohexan-dieddikesyre-hydroxyimid i 100 ml vand blandes med 225 g 10%'s vandig natriumcarbonatoplos-ning. Til denne suspension sættes drâbevis 29,6 ml (40,75 g) benzen-sulfonylchlorid, idet det omrores ved 5-10°C. Nâr 30 tilsætningen er afsluttet omrores blandingen i 1,5 timer ved stuetemperaur. Det udfældede produkt frafiltreres og vaskes derpâ med methanol. Der fâs 69 g N-(benzensulfonyl-oxy)-1,1-cyclohexan-dieddikesyreimid med smp. 167-168°C.45.5 g of 1,1-cyclohexane diacetic acid hydroxyimide in 100 ml of water are mixed with 225 g of 10% aqueous sodium carbonate solution. To this suspension is added dropwise 29.6 ml (40.75 g) of benzenesulfonyl chloride, stirring at 5-10 ° C. When the addition is complete, the mixture is stirred for 1.5 hours at room temperature. The precipitated product is filtered off and then washed with methanol. 69 g of N- (benzenesulfonyl-oxy) -1,1-cyclohexane-acetic acid imide are obtained, m.p. 167-168 ° C.
35 735 7
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Eksempel 2 N- (benzensulfonvloxv) -1.1-cvclopentan-dieddikesvreimidExample 2 N- (Benzenesulfonylloxy) -1,1-cyclopentane diacetic acid
Analogt med den i eksempel 1 beskrevne fremgangsmâde fâs ved omsætning af hydroxylamin med 1,1-cyclopentan-died-5 dikesyreanhydrid 1,1-cyclopentan-dieddikesyre-N-hydroxyimid med smp. 70-74'C, som ved acylering med benzensulfonylchlorid omdannes til N-(benzensulfonyloxy)-1,1-cyclopentan-died-dikesyreimid med smp. 133-136“C.Analogous to the process described in Example 1, the reaction of hydroxylamine with 1,1-cyclopentane-diacetic anhydride 1,1-cyclopentane-diacetic acid N-hydroxyimide is obtained by m.p. 70-74 ° C which, by acylation with benzenesulfonyl chloride, is converted to N- (benzenesulfonyloxy) -1,1-cyclopentane-diacetic acid imide with m.p. 133-136 "C.
10 Eksempel 3 N-fbenzensulfonvloxy)-1,1-cvcloheptan-dieddikesvreimidExample 3 N-Phenzenesulfonylloxy) -1,1-cycloheptane-diacetic acid
Analogt med den i eksempel 1 beskrevne fremgangsmâde fâs ved omsætning af hydroxylamin med 1,1-cycloheptan-died-dikesyreanhydrid 1,1-cycloheptan-dieddikesyre-N-hydroxylimid 15 med smp. 90-100°C, der ved acylering med benzensulfonylchlorid omdannes til N-(benzensulfonyloxy)-l,1-cycloheptan-died-dikesyreimid med smp. 130-133°C.Analogous to the process described in Example 1, the reaction of hydroxylamine with 1,1-cycloheptane-diacetic anhydride 1,1-cycloheptane-diacetic acid N-hydroxylimide 15 is obtained. 90-100 ° C which, by acylation with benzenesulfonyl chloride, is converted to N- (benzenesulfonyloxy) -1,1-cycloheptane-diacetic acid imide with m.p. 130-133 ° C.
Eksempel 4 20 N-(p-toluen-sulfonvloxv)-1,1-cvclohexan-dieddikesvreimid 2,13 g p-toluensulfonsyrechlorid sættes portionsvis ved 0'C og under omrdring til en opl0sning af 2 g 1,1-cyclo-hexan-dieddikesyre-N-hydroxyimid og 1,6 ml triethylamin i 35 ml chloroform. Reaktionsblandingen omrores natten over 25 ved stuetemperatur, hvorefter den hældes i vand, og der ekstraheres med methylenchlorid. Den organiske fase vaskes med 5%'s vandig natriumhydrogencarbonatopl0sning og derpâ med vand. Derpâ t0rres opl0sningen og inddampes i vakuum. Remanensen omkrystallisérés af en blanding af chloroform og 30 diethylether. Der fâs i to portioner t totalt udbytte pâ 2,96 g (89% af det teoretiske) N-(p-toluen-sulfonyloxy)--1,1-cyclohexan-dieddikesyreimid med smp. 133-135°C.Example 4 N- (p-toluenesulfonylloxy) -1,1-cyclohexane diacetic acid 2.13 g of p-toluenesulfonic acid chloride is added portionwise at 0 ° C and with stirring to a solution of 2 g of 1,1-cyclohexane hydrochloride. diacetic acid N-hydroxyimide and 1.6 ml of triethylamine in 35 ml of chloroform. The reaction mixture is stirred overnight at room temperature, then poured into water and extracted with methylene chloride. The organic phase is washed with 5% aqueous sodium hydrogen carbonate solution and then with water. The solution is then dried and evaporated in vacuo. The residue is recrystallized from a mixture of chloroform and diethyl ether. There are obtained in two portions t total yield of 2.96 g (89% of theory) of N- (p-toluene-sulfonyloxy) - 1,1-cyclohexane-diacetic acid imide, m.p. 133-135 ° C.
Analogt med ovenstâende fremgangsmâde fâs ved omsætning af cyclohexan-dieddikesyre-N-hydroxyimid og methan-35 sulfonylchlorid N-(methan-sulfonyloxy)-1,1-cyclohexan-died-dieksyreimid med smp. 77°c.Analogous to the above process, the reaction of cyclohexane-diacetic acid N-hydroxyimide and methane-sulfonyl chloride N- (methane-sulfonyloxy) -1,1-cyclohexane-diacetic acid imide is obtained with m.p. 77 ° C.
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gg
Analogt med den ovenfor beskrevne fremangsmâde kan endvidere nedenstâende forbindelse fremstilles: N- (methansul-fonyloxy) -1,1-cyclopentan-dieddikesyreimid, N-(p-nitrophenyl-sulfonyloxy)-1,1-cycloheptan-dieddikesyreimid, N-(ethansul-5 fonyloxy)-1,l-cyclohexan-dieddikesyreimid, N-(p-chlorphenyl-sulf onyloxy) -sulfonyloxy) -1, l-cyclohexan-dieddikesyreimid, N-(p-bromphenylsulfonyloxy) -1,1-cyclopentan-dieddikesyreimid, N- (1-naphthylsulfonyloxy) -1, l-cyclohexan-dieddikesyreimid og N- (1-kamforylsulfonyloxy) -1, l-cyclohexan-dieddikesyreimid.Further, by analogy with the procedure described above, the following compound can be prepared: N- (methanesulfonyloxy) -1,1-cyclopentane diacetic acid imide, N- (p-nitrophenylsulfonyloxy) -1,1-cycloheptane diacetic acid imide, N- (ethanesul -5-ponyloxy) -1,1-cyclohexane-diacetic acid imide, N- (p-chlorophenyl-sulfonyloxy) -sulfonyloxy) -1,1-cyclohexane-diacetic acid imide, N- (p-bromophenylsulfonyloxy) -1,1-cyclopentane-diacetic acid imide , N- (1-naphthylsulfonyloxy) -1,1-cyclohexane-diacetic acid imide and N- (1-camphorylsulfonyloxy) -1,1-cyclohexane-diacetic acid imide.
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Eksemoel 5Example 5
Lossen-omleiring af N-(benzensulfonvloxvï-1.1-cvclohexan--dieddikesvreimid.Lossen rearrangement of N- (benzenesulfonyl oxo-1,1-cyclohexane - dead dietetic acid.
Metode A; 15 68,25 g N-(benzensulfonyloxy)-1,1-cyclohexan-died- dikesyreimid blandes med 415 ml 10%'s vandig natriumhydroxid-oplesning. Reaktionsblandingen opvarmes til 100"C, hvorved der gradvis fâs en fuldstændig oplesning. Reaktionsblandingen opvarmes derpâ i 1 time under omroring ved 100°C, og opl0s-20 ningen syrnes med koncentreret saltsyre. Oplesningen inddam-pes derpâ til t0rhed i vakuum. Remanensen digereres med éthanol, det uorganiske materiale frafiltreres, og filtratet inddampes i vakuum. oplosningen filtreres igen, og filtratet henstilles natten over. Derved udkrystalliseres 1-aminome-25 thyl-l-cyclohexan-eddikesyre i form af det râ benzensulfonat med smp. 163-167°C.Method A; 68.25 g of N- (benzenesulfonyloxy) -1,1-cyclohexane-acetic acid imide are mixed with 415 ml of 10% aqueous sodium hydroxide solution. The reaction mixture is heated to 100 ° C to give a complete solution gradually. The reaction mixture is then heated for 1 hour with stirring at 100 ° C and the solution is acidified with concentrated hydrochloric acid. The solution is then evaporated to dryness in vacuo. with ethanol, the inorganic material is filtered off and the filtrate is evaporated in vacuo, the solution is filtered again and the filtrate is left overnight, thereby crystallizing 1-aminomethyl-1-cyclohexane acetic acid in the form of the crude benzenesulfonate, mp 163-167 ° C.
Analogt med ovenstâende fremgangsmâde fremstilles folgende forbindelser: 1-aminomethyl-l-cyclopentan-eddikesyre-benzensulfonat, smp.Analogous to the above process, the following compounds are prepared: 1-aminomethyl-1-cyclopentane-acetic acid benzenesulfonate, m.p.
30 171-173eC og 1-aminomethyl-l-cycloheptan-eddikesyre-benzen- sulfonat, smp. 141-143°C.301-173 ° C and 1-aminomethyl-1-cycloheptane acetic acid benzenesulfonate, m.p. 141-143 ° C.
Ved behandling med en basisk ionbytter, f.eks. "Amber-lite®" IR-45 i OH-formen, omdannes benzensulfonatet til den fri aminosyre, der ved blanding med en alkoholisk oplosning 35 af benzensulfonsyre og tilsætning af diethylether giver det analytisk rene 1-aminomethyl-l-cyclohexan-eddikesyre-benzen- 9When treated with a basic ion exchanger, e.g. "Amber-lite®" IR-45 in the OH form, the benzenesulfonate is converted to the free amino acid which, when mixed with an alcoholic solution of benzenesulfonic acid and the addition of diethyl ether gives the analytically pure 1-aminomethyl-1-cyclohexane acetic acid benzene - 9
DK 156770 BDK 156770 B
sulfonat med smp. 165-168°C.sulfonate with m.p. 165-168 ° C.
Analvsedata:Analvsedata:
C15H23NO5SC15H23NO5S
Beregnet: C 54,69%, H 7,04%, N 4,25%, S 9,73% 5 Fundet: 54,48%, 6,85%, 4,15%, 9,50%Calculated: C 54.69%, H 7.04%, N 4.25%, S 9.73% Found: 54.48%, 6.85%, 4.15%, 9.50%
Moderluden, hvorfra det râ benzensulfonat er blevet isoleret, inddampes i vakuum. Remanensen optages i methylen-chlorid og vaskes med 5%'s vandig natriumhydrogencarbonatop-losning og med vand. Efter t0rring afdrives oplosningsmidlet 10 i vakuum, og remanensen underkastes vakuumdestillation, hvorved fâs 1-aminomethyl-l-cyelohexan-eddikesyrelactam (Kp 110°C/0,1 ml Hg, bulbror). Efter omkrystallisation af diiso-propylether har forbindelsen smp. 89-90eC.The mother liquor from which the raw benzenesulfonate has been isolated is evaporated in vacuo. The residue is taken up in methylene chloride and washed with 5% aqueous sodium hydrogen carbonate solution and with water. After drying, solvent 10 is evaporated in vacuo and the residue is subjected to vacuum distillation to give 1-aminomethyl-1-cyelohexane acetic acid lactam (Kp 110 ° C / 0.1 ml Hg, bulbore). After recrystallization from diisopropyl ether, the compound has m.p. 89-90eC.
Ved kogning i flere timer i halvkoncentreret vandig 15 saltsyre fâs mere 1-aminomethyl-l-cyclohexan-eddikesyre i form af hydrochloridet med smp. 123-133°C efter omkrystallisation af acetone/vand.When boiling for several hours in semi-concentrated aqueous hydrochloric acid, more 1-aminomethyl-1-cyclohexane acetic acid was obtained in the form of the hydrochloride, m.p. 123-133 ° C after acetone / water recrystallization.
Metode B: 20 6,75 g N-(benzensulfonyloxy)-l,l-cyclohexan-died- dikesyreimid sættes portionsvis under omroring til en alko-holisk oplosning af natriumethylat fremstillet med oplosning af 460 mg natrium i 50 ml absolut éthanol, og der opvarmes under tilbagesvaling i 2 timer. Efter afkoling hældes suspen-25 sionen i vand og ekstraheres med methylenchlorid. Den or-ganiske fase torres og inddampes til en sirup, der ved kry-stallisation af diisopropylether giver 1-aminomethyl-l-cyclo-hexan-eddikesyrelactam med smp. 89-90°C, som derpà omdannes til den fri aminosyre i metode A.Method B: 6.75 g of N- (benzenesulfonyloxy) -1,1-cyclohexane-acetic acid imide are added portionwise with stirring to an alcoholic solution of sodium ethylate prepared with the solution of 460 mg of sodium in 50 ml of absolute ethanol, and heated under reflux for 2 hours. After cooling, the suspension is poured into water and extracted with methylene chloride. The organic phase is dried and evaporated to a syrup which, by crystallization of diisopropyl ether, gives 1-aminomethyl-1-cyclohexane acetic acid lactam with m.p. 89-90 ° C, which is then converted to the free amino acid of Method A.
3030
Metode C.Method C.
6,75 g N-(benzensulfonyloxy)-1,1-cyclohexan-died-dikesyreimid sættes til en oplosning af 2,02 g triethylamin i 50 ml vandfri methanol. Reaktionsblandingen opvarmes til 35 tilbagesvalingstemperaturen, hvorved det i starten uoploste materiale gâr i oplpsning. Efter 2 timer henstilles reak- 106.75 g of N- (benzenesulfonyloxy) -1,1-cyclohexane-diacetic acid imide are added to a solution of 2.02 g of triethylamine in 50 ml of anhydrous methanol. The reaction mixture is heated to the reflux temperature, whereby the undissolved material initially dissolves. After 2 hours, reaction is recommended
DK 156770 BDK 156770 B
tionsblandingen til afkeling og udrystes med en blanding af vand og methylenchlorid. Ved oparbejdning af den organiske fase pâ sædvanlig mâde og efterfelgende vakuumdestillation fâs methyl-N-carbomethoxy-l-aminomethyl-l-cyclohexan-acetat 5 i form af en farvelos sirup (kp. 120-125°C/0,01 ml Hg, bul-br0r).The reaction mixture is cooled and shaken with a mixture of water and methylene chloride. By working up the organic phase in the usual manner and subsequent vacuum distillation, methyl N-carbomethoxy-1-aminomethyl-1-cyclohexane acetate 5 is obtained in the form of a colorless syrup (bp 120-125 ° C / 0.01 ml Hg, bul-br0r).
Ved kogning i 3 timer med halvkoncentreret saltsyre, inddampning til torhed og krystallisation af acetone/vand fâs 1-aminomethyl-l-cyclohexan-eddieksyre-hydrochlorid.When boiling for 3 hours with semi-concentrated hydrochloric acid, evaporation to dryness and crystallization of acetone / water, 1-aminomethyl-1-cyclohexane-acetic acid hydrochloride was obtained.
1010
Metode D.Method D.
5,45 g N-(methansulfonyloxy)-1,1-cyclohexan-died-dikesyreimid opl0ses i 50 ml methanol og blandes med 2,1 g triethylamin. Reaktionsblandingen koges derpâ med tilbagesva-15 ling i 3 timer, hvorefter den oparbejdes som beskrevet under metode C. Bulbr0rsdestîllation giver 4,24 g (87% af det teoretiske) methyl-N-carbomethoxy-l-aminomethyl-cyclohexan-acetat i form af en farvel0s sirup (kp. 120-125°C/0,01 ml Hg), som derpâ omdannes til 1-aminomethyl-l-cyclohexan-ed-20 dikesyre-hydrochlorid.Dissolve 5.45 g of N- (methanesulfonyloxy) -1,1-cyclohexane diacetic acid imide in 50 ml of methanol and mix with 2.1 g of triethylamine. The reaction mixture is then refluxed for 3 hours and then worked up as described under Method C. Bulk distillation gives 4.24 g (87% of theory) of methyl N-carbomethoxy-1-aminomethyl-cyclohexane acetate. a colorless syrup (b.p. 120-125 ° C / 0.01 ml Hg) which is then converted to 1-aminomethyl-1-cyclohexane-ed-diacetic acid hydrochloride.
Eksemoel 6 1-Aminomethvl-l-cvcloheptan-eddikesvre-hvdrochlorid.Example 6 1-Aminomethyl-1-cycloheptane-acetic acid hydrochloride.
Analogt med den i eksempel 5 metode C angivne frem-25 gangsmâde omsættes N-(benzensulfonyloxy)-1,1-cycloheptan--dieddikesyreimid med triethylamin i methanol, hvorved fâs N-carbomethoxy-l-aminomethyl-l-cycloheptan-eddikesyre-methyl-ester i form af en farveles sirup i et udbytte pâ 83% af det teoretiske.Analogous to the procedure of Example 5 Method C, N- (benzenesulfonyloxy) -1,1-cycloheptane-acetic acid imide is reacted with triethylamine in methanol to give N-carbomethoxy-1-aminomethyl-1-cycloheptane-acetic acid methyl ester in the form of a farewell's syrup in a yield of 83% of theory.
30 Dette produkt koges i 3 timer med halvkoncentreret saltsyre, hvorefter der inddampes og omkrystallisérés af en blanding af acetone og diethylether, hvorved fâs 1-aminome-thyl-l-cycloheptaneddikesyre-hydrochlorid med smp. 70-79eC.This product is boiled for 3 hours with semi-concentrated hydrochloric acid, then evaporated and recrystallized from a mixture of acetone and diethyl ether to give 1-aminomethyl-1-cycloheptane acetic acid hydrochloride, m.p. 70-79eC.
Claims (7)
Applications Claiming Priority (4)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE19762611690 DE2611690A1 (en) | 1976-03-19 | 1976-03-19 | CYCLIC SULFONYLOXYIMIDE |
| DE2611690 | 1976-03-19 | ||
| DK120077A DK156826C (en) | 1976-03-19 | 1977-03-18 | PROCEDURE FOR THE PREPARATION OF CYCLIC AMINO ACIDS |
| DK120077 | 1977-03-18 |
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| Publication Number | Publication Date |
|---|---|
| DK87282A DK87282A (en) | 1982-02-26 |
| DK156770B true DK156770B (en) | 1989-10-02 |
| DK156770C DK156770C (en) | 1990-03-19 |
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| Application Number | Title | Priority Date | Filing Date |
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| DK087282A DK156770C (en) | 1976-03-19 | 1982-02-26 | CYCLIC SULPHONYLOXYMIDES USED AS INTERMEDIATES IN THE PRODUCTION OF CYCLIC AMINO ACIDS |
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| US3301147A (en) * | 1963-07-22 | 1967-01-31 | Harvey Aluminum Inc | Vehicle-supporting matting and plank therefor |
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| DK87282A (en) | 1982-02-26 |
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