DK174186B1 - Process for the preparation of carbamic acid derivatives - Google Patents

Process for the preparation of carbamic acid derivatives Download PDF

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DK174186B1
DK174186B1 DK198500701A DK70185A DK174186B1 DK 174186 B1 DK174186 B1 DK 174186B1 DK 198500701 A DK198500701 A DK 198500701A DK 70185 A DK70185 A DK 70185A DK 174186 B1 DK174186 B1 DK 174186B1
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carbonate
ppm
chloroethyl
carbon atoms
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DK198500701A
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DK70185A (en
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Jean-Pierre Senet
Gerard Barcelo
Gerard Sennyey
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Poudres & Explosifs Ste Nale
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
    • C07D295/16—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms acylated on ring nitrogen atoms
    • C07D295/20—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms acylated on ring nitrogen atoms by radicals derived from carbonic acid, or sulfur or nitrogen analogues thereof
    • C07D295/205—Radicals derived from carbonic acid
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/04—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D207/10—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D207/16—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
    • C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
    • C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D231/12—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
    • C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
    • C07D233/56—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, attached to ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D249/00—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms
    • C07D249/02—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms not condensed with other rings
    • C07D249/08—1,2,4-Triazoles; Hydrogenated 1,2,4-triazoles
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
    • C07D295/16—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms acylated on ring nitrogen atoms
    • C07D295/20—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms acylated on ring nitrogen atoms by radicals derived from carbonic acid, or sulfur or nitrogen analogues thereof
    • C07D295/21—Radicals derived from sulfur analogues of carbonic acid
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
    • C07D295/16—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms acylated on ring nitrogen atoms
    • C07D295/20—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms acylated on ring nitrogen atoms by radicals derived from carbonic acid, or sulfur or nitrogen analogues thereof
    • C07D295/215—Radicals derived from nitrogen analogues of carbonic acid
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
    • C07D307/02—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings
    • C07D307/34—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D307/38—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D307/40—Radicals substituted by oxygen atoms
    • C07D307/42—Singly bound oxygen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
    • C07D307/77—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D307/78—Benzo [b] furans; Hydrogenated benzo [b] furans
    • C07D307/86—Benzo [b] furans; Hydrogenated benzo [b] furans with an oxygen atom directly attached in position 7
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F7/00—Compounds containing elements of Groups 4 or 14 of the Periodic Table
    • C07F7/02—Silicon compounds
    • C07F7/08—Compounds having one or more C—Si linkages
    • C07F7/0803—Compounds with Si-C or Si-Si linkages
    • C07F7/081—Compounds with Si-C or Si-Si linkages comprising at least one atom selected from the elements N, O, halogen, S, Se or Te

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Description

DK 174186 B1 ' Opfindelsen angår en hidtil ukendt fremgangsmåde til fremstilling af carbaminsyrederivater.The invention relates to a novel process for the preparation of carbamic acid derivatives.

Nærmere betegnet angår den en fremgangsmåde til fremstilling af derivater med formlen ‘ R1 5 - C - y • liMore particularly, it relates to a process for the preparation of derivatives of the formula 'R1 5 - C - y • li

R OR O

hvor Y betegner en alkohol-, mercaptan- eller aminrest, hvilke derivater følgelig er carbamater, thiocarbamater eller urinstoffer.wherein Y represents an alcohol, mercaptan or amine residue, which derivatives are consequently carbamates, thiocarbamates or ureas.

1010

De mest almindeligt benyttede fremgangsmåder til fremstilling af disse forbindelser er fx i tilfælde af carbamater og thiocarbamater omsætningen af et chlorformiat eller thiochlorformiat med en amin som beskrevet i en artikel i Chemical Review, 1964, s. 656-663, eller omsætningen af et carbamylchlorid eller et isocyanat med en alkohol, phenol eller mercaptan (Grignard: Traité 15 de Chimie Organique, bind XIV, s. 20-31).The most commonly used methods for preparing these compounds are, for example, in the case of carbamates and thiocarbamates the reaction of a chloroformate or thiochloroformate with an amine as described in an article in Chemical Review, 1964, pp. 656-663, or the reaction of a carbamyl chloride or an isocyanate with an alcohol, phenol or mercaptan (Grignard: Traité 15 de Chimie Organique, Vol. XIV, pp. 20-31).

Hvad angår urinstoffer, fås disse hyppigst ved omsætning af et isocyanat eller et carbamylchlorid med en amin. Når de er symmetriske, kan de også fremstilles ved phosgenbehandling med en amin (Grignard: bind XIV, s. 85, 30).Regarding urea, these are most frequently obtained by reaction of an isocyanate or a carbamyl chloride with an amine. When symmetrical, they can also be prepared by phosgene treatment with an amine (Grignard: Vol. XIV, pp. 85, 30).

2020

Imidlertid gør disse forskellige fremgangsmåder det ikke altid muligt at fremstille de ønskede forbindelser, eller de er undertiden vanskelige at styre. Nogle udgangsmaterialer er - ustabile, således som det er tilfældet med et antal chlorformiater såsom fx furfuryl, tert.-butyl- og p-methoxybenzylchlorformiat, 25 - giftige, såsom isocyanater, phosgen og især lette carbamylchlorider, som er carcinogene, eller - forurenende, såsom lette thichlorformiater.However, these different methods do not always make the desired compounds possible or are sometimes difficult to control. Some starting materials are - unstable, as is the case with a number of chloroformates such as, for example, furfuryl, tert-butyl and p-methoxybenzyl chloroformate, - toxic such as isocyanates, phosgene and especially light carbamyl chlorides which are carcinogenic, or - contaminating, such as light thichloroformates.

Man har udført forskning for at finde nye veje.Research has been done to find new ways.

3030

Nogle få forbindelser er blevet fremstillet, idet man omsætter dimethylcarbonat eller ethylphe-nylcarbonat med anilin i nærværelse af en katalysator såsom uranylnitrat, men udbytterne er meget lave, blandingen må opvarmes til en høj temperatur (100e, US-A-3,763,217), og der fås biprodukter i betydelige mængder.A few compounds have been prepared, reacting dimethyl carbonate or ethyl phenyl carbonate with aniline in the presence of a catalyst such as uranyl nitrate, but the yields are very low, the mixture must be heated to a high temperature (100e, US-A-3,763,217), and available by-products in significant quantities.

i 35 ,. Diphenylcarbonat reagerer ikke med aminer til dannelse af et carbamat undtagen i nærværelse af en katalysator såsom 2-hydroxypyridin (Noboru Yamazaki and Todao Igudi, Fukuji Higashi,i 35,. Diphenyl carbonate does not react with amines to form a carbamate except in the presence of a catalyst such as 2-hydroxypyridine (Noboru Yamazaki and Todao Igudi, Fukuji Higashi,

Journal of Polymer Science, bind 17, s. 835-841 (1979)).Journal of Polymer Science, Vol. 17, pp. 835-841 (1979)).

2 DK 174186 B12 DK 174186 B1

Andre carbameringsmidler er blevet foreslået såsom - azider; synteser af disse udføres i adskillige trin og er ubekvem; de kan sønderdeles eksplosivt såsom BOC azid (Angew, Chem., Ind. Ed. Engl. 16 1977, nr. 2); - adskillige forsøg er blevet udført med meget specielle carbonater såsom blandede p-nitro-5 phenylcarbonater; de dannede biprodukter er vanskelige at flerne; -bicarbonater; syntese af disse er meget ubekvem og meget bekostelig; dette gælder især tert -butylbicarbonat; desuden går en beskyttelsesgruppe tabt; - fluorformiater; fremstillingen af disse er imidlertid vanskelig, fordi den kræver brugen af udgangsmaterialer, som ikke er i handelen, og som er ubekvemme at håndtere, såsom 10 CICOF eller BrCOF.Other carbamating agents have been proposed such as - azides; syntheses of these are performed in several steps and are inconvenient; they can decompose explosively such as BOC azide (Angew, Chem., Ind. Ed. Eng. 16 1977, no. 2); - several experiments have been carried out with very special carbonates such as mixed p-nitrophenyl carbonates; the by-products formed are difficult to multiply; bicarbonates; synthesis of these is very inconvenient and very costly; this is especially true for tert -butyl bicarbonate; moreover, a protection group is lost; fluorine formates; however, their manufacture is difficult because it requires the use of non-commercial starting materials which are inconvenient to handle, such as CICOF or BrCOF.

Omsætningen af nogle carbamater med aminer er blevet undersøgt. Urinstofferne fås først efter opvarmning til høje temperaturer af størrelsesordenen 100-250°C og under den forudsætning, at der benyttes en katalysator (Phillip Adams and Franck A. Baron, Chemical Review, 1965, s.The reaction of some carbamates with amines has been investigated. The urea is obtained only after heating to high temperatures of the order of 100-250 ° C and under the condition that a catalyst is used (Phillip Adams and Franck A. Baron, Chemical Review, 1965, p.

15 574).15 574).

Ved disse forskellige fremgangsmåder dannes der altid en alkohol eller en phenol, som ofte er meget vanskelig at flerne, og reaktionen er reversibel.In these various processes, an alcohol or a phenol is often formed, which is often very difficult to multiply and the reaction is reversible.

20 I nogle tilfælde er det absolut umuligt at fremstille urinstoffet. Når således ethyl-N-imidazoIcar-bamater omsættes med ethylamin, fås der ethyl-N-ethylcarbamat og imidazol, men ikke urinstoffet.20 In some cases it is absolutely impossible to make the urea. Thus, when ethyl N-imidazolcar bamates are reacted with ethylamine, ethyl N-ethyl carbamate and imidazole are obtained, but not the urea.

Denne korte oversigt viser grænserne for de konventionelle fremgangsmåder samt de ringe 25 resultater, man har opnået ved at gå nye veje.This brief overview shows the boundaries of the conventional approaches as well as the poor results obtained by taking new paths.

Det har derfor været ønskeligt at anvise en generel fremgangsmåde til fremstilling af carbamin-syrederivater, som er lettere at håndtere både i henseende til brugen af mindre farlige udgangsmaterialer og i henseende til arbejdsbetingelserne og fjernelsen af biprodukter.Therefore, it has been desirable to provide a general process for the preparation of carbamic acid derivatives which is easier to handle both with respect to the use of less hazardous starting materials and with respect to the working conditions and the removal of by-products.

3030

Fremgangsmåden ifølge opfindelsen er anvendelig på fremstillingen af en lang række carba-minsyrederivater, og den er særlig egnet, når de andre fremgangsmåder, som fører til disse derivater, er uegnede.The process of the invention is applicable to the preparation of a wide variety of carboxylic acid derivatives, and it is particularly suitable when the other processes leading to these derivatives are unsuitable.

35 Opfindelsen angår en fremgangsmåde til fremstilling af carbaminsyrederivater med den almene formel i 3 DK 174186 B1 R1The invention relates to a process for the preparation of carbamic acid derivatives of the general formula in the invention.

- C - Y- C - Y

9/ Il9 / Il

R OR O

5 hvor R1 og R2, som er ens eller forskellige, betegner: - et hydrogenatom, - en alifatisk gruppe med 1 -20 carbonatomer, - en cykloalifatisk eller aralifatisk gruppe med indtil 50 carbonatomer, eller R1 og R2 danner sammen med det nitrogenatom, hvortil de er bundet, en piperidino-, mor-10 pholino- eller imidazolylring, idet den alifatiske, cykloalifatiske og aralifatiske gruppe og ringen er usubstituteret eller substitueret med syre-, alkohol-, ester-, ether-, mercapto- eller aminogrup-per, og Y betegner-OR, -SR, -N-R3 eller 0-N=C-R65 wherein R 1 and R 2, which are the same or different, represent: - a hydrogen atom, - an aliphatic group of 1 to 20 carbon atoms, - a cycloaliphatic or araliphatic group of up to 50 carbon atoms, or R 1 and R 2 together with the nitrogen atom to which they are attached, a piperidino, morpholino or imidazolyl ring, the aliphatic, cycloaliphatic and araliphatic group and the ring being unsubstituted or substituted by acid, alcohol, ester, ether, mercapto or amino groups, and Y represents -OR, -SR, -N-R3 or O-N = C-R6

I II I

15 R4 R7 hvor (i) R betegner en alifatisk gruppe med 1-12 carbonatomer, hvilken gruppe er usubstitueret eller substitueret med halogenatomer eller med en furyl- eller trimethylsilylgruppe, 20 en benzyl- eller nitrobenzylgruppe, en phenyl-, benzofuranyl- eller fluorenylmethylgruppe, idet benzofuranylgruppen er usubstitueret eller substitueret med lavmolekylært alkyl, (il) R3 og R4, som er ens eller forskellige, betegner et hydrogenatom eller methyl eller danner sammen med det nitrogenatom, hvortil de er bundet, en imidazolylring, og (Hi) Rø og R7, som er ens eller forskellige, betegner en alifatisk gruppe med 1-12 carbonato-25 mer eller en cykloalifatisk gruppe med indtil 30 carbonatomer, som er usubstitueret eller substitueret med en lavmolekylær alkylthiogruppe, eller betegner hydrogen, en methylthio-gruppe eller en lavmolekylær alkyloxygruppe.R4 R7 wherein (i) R represents an aliphatic group of 1-12 carbon atoms which is unsubstituted or substituted by halogen atoms or with a furyl or trimethylsilyl group, a benzyl or nitrobenzyl group, a phenyl, benzofuranyl or fluorenylmethyl group, the benzofuranyl group being unsubstituted or substituted by low molecular alkyl, (ii) R 3 and R 4, which are the same or different, represent a hydrogen atom or methyl or form together with the nitrogen atom to which they are attached, an imidazolyl ring, and (Hi) R which is the same or different, represents an aliphatic group of 1-12 carbon atoms or a cycloaliphatic group of up to 30 carbon atoms which is unsubstituted or substituted by a low molecular alkylthio group, or represents hydrogen, a methylthio group or a low molecular weight alkyloxy group .

Denne fremgangsmåde består i, at en aminoforbindelse med formlen 30 NH-R1 R2This process consists of an amino compound of formula 30 NH-R1 R2

i nærværelse af et stof, som kan binde hydrogenhalogenidsyre, ved en temperatur mellem -5°C og 150eC omsættes med et α-halogeneret derivat af kulsyre med formlen 35 RS-CH-O-C-Yin the presence of a substance which can bind hydrogen halide acid, at a temperature between -5 ° C and 150 ° C is reacted with an α-halogenated derivative of carbonic acid of the formula 35 RS-CH-O-C-Y

I III II

x o 4 DK 174186 B1 hvor R1, R2 og Y har samme betydning som ovenfor, X betegner fluor, chlor eller brom, og R® betegner en alifatisk gruppe med 1-4 carbonatomer, som er usubstitueret eller substitueret med halogenatomer.x represents fluorine, chlorine or bromine, and R® represents an aliphatic group of 1-4 carbon atoms which is unsubstituted or substituted by halogen atoms.

5 Omsætningen kan udføres i nærværelse elleer fravær af et opløsningsmiddel.The reaction may be carried out in the presence or absence of a solvent.

Reaktionsskemaet kan skrives som følger: R1 D1 5 cThe reaction scheme can be written as follows: R1 D1 5 c

/NH + R -CH-O-C-Y -> /N - C - Y + R5 - CHO + HX/ NH + R -CH-O-C-Y -> / N - C - Y + R5 - CHO + HX

7r 1 I || 10 * X 0 R2 07r 1 I || 10 * X 0 R2 0

Det ses på overraskende måde, at HX elimineres, men dette ledsages ikke af en binding af aminresten --r- - — !*>«- 15 til det carbonatom, som bærer halogenet, til dannelse afIt is surprisingly seen that HX is eliminated, but this is not accompanied by a bond of the amine residue - r - - -! *> - 15 to the carbon atom bearing the halogen to form

R5 - ch o - c - YR5 - ch o - c - Y

I R1 III R1 II

N-^K o XR2N- ^ K o XR2

20 R20 R

således som man normalt måtte vente, og således som det normalt er tilfældet ved omsætningen af et α-chloreret carbonat med en syre R* -CH-O-C-O-R" + R"' COOH -> R’CH - 0 - C - 0 - R" I I πas would normally be expected, and as is usually the case with the reaction of an α-chlorinated carbonate with an acid R * -CH-OCOR "+ R" COOH -> R'CH - 0 - C - 0 - R "II π

Cl o s 25 0 - C - R"' (FR-A-2,201,870). j I modsætning hertil sker der ved fremgangsmåden ifølge opfindelsen spaltning af det a- halogenerede derivat, knytning af Y-C-gruppen 30 ||Cl o s 25 0 - C - R "'(FR-A-2,201,870). In contrast, the process of the invention decomposes the α-halogenated derivative, linking the Y-C group 30 ||

OISLAND

til aminogruppen og dannelse af aldehydet R^CHO.to the amino group and formation of the aldehyde R 2 CHO.

Som hydrogenholdig udgangsaminoforbindelse med formlen 35 „1As a hydrogen-containing starting amino compound of formula 35 "1

.>> NH. >> NH

R^ kan man benytte ammoniak og de fleste kendte primære eller sekundære aminer.R 2 can be used with ammonia and most known primary or secondary amines.

5 DK 174186 B1 Når R1 eller R2 betegner en allfatisk gruppe, indeholder den fortrinsvis 1-20 carbonatomer. R1 og R2 kan også betegne en cykloalifatisk eller aralifatisk gruppe, som kan indeholde indtil 50 carbonatomer, fx en benzylgruppe, eller R1 og R2 kan sammen danne en heterocyklisk ring, fx en piperidino-, morfolino- eller imidazolylring.B1 When R1 or R2 represents an allphatic group, it preferably contains 1-20 carbon atoms. R1 and R2 may also represent a cycloaliphatic or araliphatic group which may contain up to 50 carbon atoms, e.g., a benzyl group, or R1 and R2 may together form a heterocyclic ring, e.g., a piperidino, morpholino or imidazolyl ring.

55

Substituenteme R“* og R2 kan være forskellige grupper såsom carbonhydridgrupper eller syre-, alkohol-, ester-, ether-, mercapto- eller aminogrupper.The substituents R “and R₂ may be different groups such as hydrocarbon groups or acid, alcohol, ester, ether, mercapto or amino groups.

Som nyttige aminer kan især nævnes methylamin, diethylamin, di-n-butylamin, isobutylamin, n-10 octylamin, ethanolamin, benzylamin, N-methyl-N-benzylamin, piperidin, imidazol, hexamethylen-imin, morpholin og diethanolamin.In particular, useful amines include methylamine, diethylamine, di-n-butylamine, isobutylamine, n-octylamine, ethanolamine, benzylamine, N-methyl-N-benzylamine, piperidine, imidazole, hexamethylene-imine, morpholine and diethanolamine.

De naturlige eller syntetiske, optisk aktive eller inaktive eller racemiske aminosyrer, som benyttes til peptidsyntese, er også meget egnede.The natural or synthetic, optically active or inactive or racemic amino acids used for peptide synthesis are also very suitable.

1515

Fx kan nævnes L-phenylalanin, L-prolin, glycin, L-tyrosin, L-serin, L-asparaginsyre, prolin, ethylglycinat og phenylglydn.For example, L-phenylalanine, L-proline, glycine, L-tyrosine, L-serine, L-aspartic acid, proline, ethyl glycinate and phenylglydine may be mentioned.

Det andet benyttede udgangsmateriale kan være et α-halogeneret carbonat, thiocarbonat eller 20 carmabat. Det er fortrinsvis a-chloreret.The other starting material used may be an α-halogenated carbonate, thiocarbonate or carbabate. It is preferably α-chlorinated.

Fremstillingen af denne forbindelse kan foretages efter forskellige kendte ffemgangsmådeer, fx i tilfælde af chlorerede derivater ved omsætning af et α-chloreret chlorformiat med formlen: 25 »S - CH - 0 - C - ClThe preparation of this compound can be carried out according to various known methods, for example in the case of chlorinated derivatives by reaction of an α-chlorinated chloroformate of the formula: 25 S - CH - O - C - Cl

Cl o med en hydroxyderet forbindelse eller en mercaptan som beskrevet af M. Matzner, R. Kurkjy og R.J. Cotter (Chem. Rev. 64, s. 651-654 (1966)), eller med en amin efter en fremgangsmåde, som er beskrevet i EP-45 234 eller 83/401766.7.Cl o with a hydroxidized compound or a mercaptan as described by M. Matzner, R. Kurkjy and R.J. Cotter (Chem. Rev. 64, pp. 651-654 (1966)), or with an amine according to a procedure described in EP-45 234 or 83 / 401766.7.

30 α-chlorerede chlorformiater fremstilles selv meget simpelt ved fosgenbehandling af aldehyder som angivet i EP-40153.Thirty α-chlorinated chloroformates are themselves prepared very simply by phosgene treatment of aldehydes as disclosed in EP-40153.

Gruppen R$ er fortrinsvis en lavmolekylær gruppe såsom en alifatisk gruppe bestående af 1-4 35 carbonatomer, som kan være substitueret, fortrinsvis med halogenatomer og især chloratomer.The group R $ is preferably a low molecular weight group such as an aliphatic group consisting of 1-4 carbon atoms which may be substituted, preferably with halogen atoms and especially chlorine atoms.

Methyl- og trichlormethylgrupper er særlig ønskværdige.Methyl and trichloromethyl groups are particularly desirable.

6 DK 174186 B16 DK 174186 B1

Gruppen R i carbonatet eller thiocarbonatet er meget varieret. Den kan være - en alrfatisk gruppe, som fortrinsvis indeholder 1-12 carbonatomer, såsom methyl, ethyl eller tert.-butyl, som kan være substitueret med fx en heterocyklisk gruppe såsom furyl, - en aralifatisk gruppe som fx benzyl, 5 - en substitueret eller usubstitueret aromatisk kerne, som eventuelt kan udgøre en del af et ringsystem såsom phenyl eller 2,3-dihydro-2,2-dimethyl-7-benzofuranyl.The group R in the carbonate or thiocarbonate is very varied. It may be - an aliphatic group which preferably contains 1-12 carbon atoms, such as methyl, ethyl or tert-butyl, which may be substituted by, for example, a heterocyclic group such as furyl, - an araliphatic group such as benzyl, 5 - a substituted or unsubstituted aromatic core which may optionally form part of a ring system such as phenyl or 2,3-dihydro-2,2-dimethyl-7-benzofuranyl.

Gruppen R kan uanset sin betydning være substitueret med en eller flere grupperThe group R, whatever its meaning, may be substituted by one or more groups

10 -0-C-0-CH-R5 eller -S-C-0-CH-RS10-C-O-CH-R 5 or -S-C-O-CH-RS

il II i ok οχ.il II i ok οχ.

Navnlig når udgangsaminen er en aminosyre, er det en af de grupper, som normalt benyttes til peptidsyntese til beskyttelse af aminogruppen, såsom tert.-butyl, benzyl, p-nitrobenzyl, 9-fluor-15 enyl methyl, 2,2,2-trichlorethyl, trimethylsilylethyl eller furfuryl. α-chlorerede og tert.-butyl carbo- nater er særlig velegnede i dette tilfælde.In particular, when the starting amine is an amino acid, it is one of the groups normally used for peptide synthesis to protect the amino group such as tert-butyl, benzyl, p-nitrobenzyl, 9-fluorophenyl methyl, trichloroethyl, trimethylsilylethyl or furfuryl. α-chlorinated and tert-butyl carbonates are particularly suitable in this case.

R3 og R4 betegner i det α-chlorerede udgangscarbamat fx et hydrogenatom eller en methyl-gruppe eller danner sammen med det nitrogenatom, hvortil de er bundet, en imidazolylring.R 3 and R 4 in the α-chlorinated starting carbamate, for example, represent a hydrogen atom or a methyl group or together with the nitrogen atom to which they are attached form an imidazolyl ring.

20 Således har α-chlorethoxycarbonylimidazol og 1,2,2.2-tetrachlorethyl-N-methylcarbamat særlig stor værdi.Thus, α-chloroethoxycarbonylimidazole and 1,2,2,2-tetrachloroethyl-N-methylcarbamate are of particular value.

R6 og R7 betegner navnlig et hydrogenatom, en methylthiogruppe, en alifatisk gruppe med 1-12 carbonatomer eller en cykloalifatisk gruppe, som kan indeholde 30 carbonatomer. Substituen-25 terne og R7 kan være carbonhydridgrupper eller grupper indeholdende heteroatomer, især svovl.In particular, R6 and R7 represent a hydrogen atom, a methylthio group, an aliphatic group having 1 to 12 carbon atoms or a cycloaliphatic group which may contain 30 carbon atoms. The substituents and R7 may be hydrocarbon groups or groups containing heteroatoms, especially sulfur.

Da der foregår en frigørelse af hydrogenhalogenid HX under reaktionen, er tilstedeværelsen af et syrebindende middel nødvendigt til fjernelse af denne syre.Since hydrogen halide HX is released during the reaction, the presence of an acid binding agent is necessary to remove this acid.

3030

Det syrebindende middel kan være en organisk eller uorganisk base.The acid binding agent may be an organic or inorganic base.

Blandt de foretrukne baser skal nævnes natriumhydroxid eller kaliumhydroxid, natriumcarbonat eller -blcarbonat eller kaliumcarbonat eller bicarbonat, magnesiumoxid og natriumsulfit, som 35 normalt benyttes i form af en vandig opløsning, tert.-aminer såsom triethylamin, pyridin eller Ν,Ν-dimethylanilin og udgangsaminen selv med formlen 7 DK 174186 B1Among the preferred bases are sodium hydroxide or potassium hydroxide, sodium carbonate or bicarbonate or potassium carbonate or bicarbonate, magnesium oxide and sodium sulfite, which are normally used in the form of an aqueous solution, tertiary amines such as triethylamine, pyridine or Ν, ud-dimethylaniline. even with formula 7 DK 174186 B1

R1-NHR1-NH

R2 5 Mængden af basisk stof, som indføres i mediet, bør være tilstrækkeligt til at neutralisere al frigjort syre. Et lille overskud i forhold til den støkiometriske mængde benyttes fortrinsvis.R2 5 The amount of basic substance introduced into the medium should be sufficient to neutralize any acid released. A small excess relative to the stoichiometric amount is preferably used.

Reaktionen ifølge opfindelsen udføres fortrinsvis i et opløsningsmiddel. Der benyttes normalt et eller flere opløsningsmidler, som er indifferente over for reaktionsdeltagerne. De vælges for-10 trinsvis blandt chlorerede alifatiske opløsningsmidler såsom dichlormethan eller 1,2-dichlor-ethan, cykliske eller acykliske ethere, fx tetrahydrofuran eller dioxan, acetone, pyridin, acetoni-tril, dimethylformamid eller alkoholer såsom ethanol eller tert.-butanol. Reaktionsmediet kan indeholde en vis mængde vand, som fx er nødvendig til opløsning af uorganiske baser.The reaction of the invention is preferably carried out in a solvent. Usually one or more solvents which are inert to the reaction participants are used. They are preferably selected from chlorinated aliphatic solvents such as dichloromethane or 1,2-dichloroethane, cyclic or acyclic ethers, e.g., tetrahydrofuran or dioxane, acetone, pyridine, acetonitrile, dimethylformamide or alcohols such as ethanol or tert-butanol. The reaction medium may contain a certain amount of water which is required, for example, for dissolving inorganic bases.

15 Reaktionstemperaturen afhænger af karakteren af opløsningsmidlet og af reaktionsdygtigheden af udgangsforbindelserne. Den ligger mellem -5°C og 150eC. Den tigger hyppigst mellem 0 og 30°C i tilfælde af omsætning af carbonater og thiocarbonater med aminer og mellem 30 og 100°C til omsætning af carbamater.The reaction temperature depends on the nature of the solvent and the reactivity of the starting compounds. It is between -5 ° C and 150 ° C. It most often begs between 0 and 30 ° C in the case of reaction of carbonates and thiocarbonates with amines and between 30 and 100 ° C for reaction of carbamates.

20 Udgangsforbindelserne benyttes normalt i støkiometriske mængder. Det foretrækkes at benytte et lille overskud af den ene af de to reaktionsdeltagere.The starting compounds are usually used in stoichiometric amounts. It is preferable to use a small excess of one of the two reaction participants.

Når udgangsaminen benyttes som syrebindende middel, benyttes der mindst to ækvivalenter amin for hver gruppe 25 - c - o - CH - ft5When the starting amine is used as an acid binding agent, at least two equivalents of amine are used for each group 25 - c - o - CH - ft5

b Ib I

o x som skal omdannes.o x to be converted.

Den rækkefølge, hvori reaktionsdeltageme indføres, er ikke afgørende ifølge opfindelsen. Når 30 imidlertid aminen er primær, og når den også benyttes som syrebindende middel, foretrækkes det at indføre den efter de andre udgangsmaterialer.The order in which the reaction participants are introduced is not essential to the invention. However, when the amine is primary and when also used as an acid binding agent, it is preferred to introduce it according to the other starting materials.

Fremgangsmåden ifølge opfindelsen muliggør en let fremstilling af mange forbindelser, af hvilke nogle fremstilles med stort besvær ved de gængse metoder. Disse forbindelser er meget nyt· 35 tige som farmaceutiske produkter, som pesticider såsom carbofuran, 3-4-dimethylphenyl-N-methylcarbamat, aldicarb, carbaryl blandt carbamater, butylat, epic, molinate blandt thiocar-bamater og chlortoluron og monuron blandt urinstoffer eller som mellemprodukter ved peptidsyntesen af aspartam (Tetrahedron, bind 39. nr. 24, s. 4121-4126,1983, B-. Yde et al.).The process of the invention enables easy preparation of many compounds, some of which are made with great difficulty by the conventional methods. These compounds are very novel as pharmaceutical products, such as pesticides such as carbofuran, 3-4-dimethylphenyl-N-methylcarbamate, aldicarb, carbaryl among carbamates, butylate, epic, molinate among thiocarbamates and chlorotoluron and monuron among urea or as intermediates in the peptide synthesis of aspartame (Tetrahedron, Vol. 39. No. 24, pp. 4121-4126, 1983, B-. Yde et al.).

8 DK 174186 B18 DK 174186 B1

Opfindelsen skal forklares nærmere gennem nedenstående eksempler.The invention will be explained in more detail by the following examples.

Eksempel 1Example 1

Fremstilling af ethyl-N,N-di-n-butylcarbamat 5 ^nC H 4 9Preparation of ethyl N, N-di-n-butylcarbamate 5 ° C H 4 9

Λ a UU and U

0 ^*nC.H.0 ^^ AD.

4 94 9

En opløsning af 26 g (0,2 mol) di-n-butylamin i 20 ml vandfrit tetrahydrofuran (THF) sættes drå-10 bevis til en opløsning af 15,2 g (0,1 mol) a-chlorethylethylcarbonat CHjCH-OCO-CHp-CH* I II *A solution of 26 g (0.2 mole) of di-n-butylamine in 20 ml of anhydrous tetrahydrofuran (THF) is added dropwise to a solution of 15.2 g (0.1 mole) of a-chloroethyl ethyl carbonate CH CHp-CH * I II *

Cl 0 i 80 ml THF.ClO in 80 ml THF.

15 Tilsætningen foretages under omrøring ved 20°C. Reaktionen er svagt exoterm, og man iagttager en dannelse af en udfældning af dibutylaminhydrochlorid. Blandingen omrøres 2 timer ved 20eC, udfældningen fjernes ved filtrering, og THF afdampes.The addition is made with stirring at 20 ° C. The reaction is slightly exothermic and formation of a precipitate of dibutylamine hydrochloride is observed. The mixture is stirred for 2 hours at 20 ° C, the precipitate is removed by filtration and the THF is evaporated.

Resten optages i 200 ml dichlormethan, og opløsningen vaskes med 50 ml vandig mættet 20 KHC03-opløsnlng og derpå med 50 ml vand. Efter at opløsningen er tørret over magnesiumsulfat, fjernes opløsningsmidlet ved afdampning, og den resterende blanding destilleres under formindsket tryk.The residue is taken up in 200 ml of dichloromethane and the solution is washed with 50 ml of aqueous saturated 20 KHCO3 solution and then with 50 ml of water. After the solution is dried over magnesium sulfate, the solvent is removed by evaporation and the remaining mixture is distilled under reduced pressure.

På denne måde fås 15,1 g (75% udbytte) af det forventede carbamat.In this way, 15.1 g (75% yield) of the expected carbamate is obtained.

25 KP 78-80°C/40 Pa (0,3 mm Hg) IR: C= 0:1700 cm'1 1H NMR: 0,9-1,7 ppm (17 H) kompleks C-CH2-CH3 3,2 ppm (4 H) triplet N-CH2 30 4,1 ppm (2 H) kvartet 0-CH2KP 78-80 ° C / 40 Pa (0.3 mm Hg) IR: C = 0: 1700 cm -1 1 H NMR: 0.9-1.7 ppm (17 H) complex C-CH 2 -CH 3 2 ppm (4H) triplet N-CH2 4.1 ppm (2H) quartet O-CH2

Eksempel 2Example 2

Fremstilling af ethyl-N-n-octylcarbamat C2H5-0-C-NH nC8H17 0 9 DK 174186 B1Preparation of ethyl N-n-octylcarbamate C2H5-O-C-NH nC8H17 0 9 DK 174186 B1

En opløsning af 7,6 g (0,05 mol) α-chlorethylethylcarbonat i 10 ml THF afkølet til 5-10°C sættes til en opløsning, ligeledes afkølet til 5-10“C, af 12,9 g (0,1 mol) n-octylamin i 40 ml THF.A solution of 7.6 g (0.05 mole) of α-chloroethyl ethyl carbonate in 10 ml of THF cooled to 5-10 ° C is added to a solution, also cooled to 5-10 ° C, of 12.9 g (0.1 mole) n-octylamine in 40 ml of THF.

Efter afsluttet tilsætning under omrøring får blandingen lov at vende tilbage til stuetemperatur, 5 og den holdes på denne temperatur i 2 timer under omrøring.After completion of stirring, the mixture is allowed to return to room temperature and kept at this temperature for 2 hours with stirring.

Efter at uidfældningen er blevet fjernet ved filtrering, og opløsningsmidlet afdampet, optages resten i 50 ml ethylether, opløsningen filtreres igen, og etherfasen vaskes med 50 ml vand.After removing the precipitate by filtration and evaporating the solvent, the residue is taken up in 50 ml of ethyl ether, the solution is filtered again and the ether phase is washed with 50 ml of water.

10 Efter tørring af opløsningen over magnesiumsulfat fjernes opløsningsmidlet ved fordampning, og den resterende blanding destilleres under formindsket tryk.After drying the solution over magnesium sulfate, the solvent is removed by evaporation and the residual mixture is distilled under reduced pressure.

Oer fås 8,64 g (86% udbytte) af det forventede carbamat.Oer is obtained 8.64 g (86% yield) of the expected carbamate.

15 KP 110-C/40 Pa (0,3 mm Hg) IR: C = 0 1700 cm-1 N- H 3300 cm-1 1H NMR: 0,1-1.7 ppm (18 H) kompleks (CH2)nCH3 3.2 ppm (2 H) kvartet N-CH2 20 4,1 ppm (2 H) kvartet 0-CH2 5.2 ppm (1 H) kompleks NH-C-KP 110-C / 40 Pa (0.3 mm Hg) IR: C = 0 1700 cm-1 N-H 3300 cm-1 H NMR: 0.1-1.7 ppm (18 H) complex (CH2) nCH3 3.2 ppm (2H) quartet N-CH2 20 ppm (2H) quartet O-CH2 5.2 ppm (1H) complex NH-C

OISLAND

Eksempel 3Example 3

Fremstilling af ethyl-N-n-octylcarbamat 25 I en reaktionsbeholder indføres der 6,5 g (0,05 mol) n-octylamin, 30 ml THF, 10 ml vand og 10 g kaliumcarbonat K2C03. Idet man opretholder temperaturen på 5-10°C, tilsætter man derpå dråbevis 7,6 g (0,05 mol) α-chlorethylethylcarbonat opløst i 5 ml THF undeer omrøring.Preparation of ethyl N-n-octylcarbamate 25 In a reaction vessel, 6.5 g (0.05 mole) of n-octylamine, 30 ml of THF, 10 ml of water and 10 g of potassium carbonate K 2 CO 3 are introduced. Maintaining the temperature of 5-10 ° C is then added dropwise 7.6 g (0.05 mol) of α-chloroethyl ethyl carbonate dissolved in 5 ml of THF without stirring.

Blandingen får lov at genantage stuetemperatur og holdes under omrøring ved denne tempera-30 tur i 1 time. Der tilsættes 50 ml vand mættet med natriumchlorid, blandingen ekstraheres to gange med 40 ml ethylether, hvorpå etherfaserne slås sammen og tørres over magnesiumsulfat.The mixture is allowed to repeat at room temperature and kept under stirring at this temperature for 1 hour. 50 ml of water saturated with sodium chloride is added, the mixture is extracted twice with 40 ml of ethyl ether and the ether phases are combined and dried over magnesium sulfate.

Efter fjernelse af opløsningsmidlet ved fordampning og destillation under formindsket tryk fås 35 7,4 g (74%) af det forventede carbamat.After removal of the solvent by evaporation and distillation under reduced pressure, 7.4 g (74%) of the expected carbamate is obtained.

KP 110-112®C/40 Pa (0,3 mm Hg).KP 110-112®C / 40 Pa (0.3 mm Hg).

10 DK 174186 B110 DK 174186 B1

Eksempel 4Example 4

Fremstilling af ethyl-N-N-di-n-butylcarbamatPreparation of ethyl N-N-di-n-butylcarbamate

Til en opløsning af 6,5 g {0,05 mol) di-n-butylamin og 5,56 g (0,055 mol) triethylamin i 40 ml THF sættes dråbevis 8,4 g (0,055 mol) α-chlorethylethylcarbonat opløst i 10 ml THF under omrøring, 5 idet temperaturen holdes på 5-10"C.To a solution of 6.5 g (0.05 mole) of di-n-butylamine and 5.56 g (0.055 mole) of triethylamine in 40 ml of THF is added dropwise 8.4 g (0.055 mole) of α-chloroethyl ethyl carbonate dissolved in 10 ml. THF with stirring, keeping the temperature at 5-10 ° C.

Blandingen får lov at genantage stuetemperatur og holdes på denne temperatur under omrøring i 2 timer.The mixture is allowed to repeat at room temperature and kept at this temperature with stirring for 2 hours.

10 Efter fjernelse af udfældningen ved filtrering, afdampning af opløsningsmidlet og destillation under formindsket tryk fås 6,3 g (63% udbytte) af det forventede carbamat.After removal of the precipitate by filtration, evaporation of the solvent and distillation under reduced pressure, 6.3 g (63% yield) of the expected carbamate is obtained.

KP 76X/26.6 Pa (0,2 mm Hg).KP 76X / 26.6 Pa (0.2 mm Hg).

15 Eksempel 5Example 5

Fremstilling af tert.-butyl-N-N-octylcarbamat CH, CH,- C-0-C-NH-n-CBH,,Preparation of tert-butyl-N-N-octylcarbamate CH, CH, - C-O-C-NH-n-CBH,

I III II

20 1 ’20 1 '

ch3 Och3 O

a) Syntese af α-ch lorethyl-tert. -butylcarbonat I en reaktionsbeholder, som er afkølet til 5°C, indføres 600 ml dichlormethan, 43,7 g (0,59 mol) tert-butanol og 94,7 g (0,66 mol) a-chlorethylchlorformiat. 57 g (0.72 mol) pyridin tilsættes 25 derpå dråbevis under omrøring, medens temperaturen holdes på 10-20°C. Blandingen omrøres i 4 timer ved stuetemperatur.a) Synthesis of α-ch lorethyl tert. -butyl carbonate In a reaction vessel which is cooled to 5 ° C, 600 ml of dichloromethane, 43.7 g (0.59 mol) of tert-butanol and 94.7 g (0.66 mol) of a-chloroethyl chloroformate are introduced. 57 g (0.72 mole) of pyridine is then added dropwise with stirring while maintaining the temperature of 10-20 ° C. The mixture is stirred for 4 hours at room temperature.

Reaktionsblandingen vaskes med 100 ml 1 N saltsyre, 200 ml mættet Na2C03-opløsning og to gange med 100 ml iskoldt vand. Den organiske fase samles og tørres over magnesiumsulfat.The reaction mixture is washed with 100 ml of 1 N hydrochloric acid, 200 ml of saturated Na 2 CO 3 solution and twice with 100 ml of ice-cold water. The organic phase is collected and dried over magnesium sulfate.

3030

Efter afdampning af opløsningsmidlet og destillation under formindsket tryk fås 91,5 g (85%) a-chlorethyl-tert.-butylcarbonat.After evaporation of the solvent and distillation under reduced pressure, 91.5 g (85%) of α-chloroethyl tert-butyl carbonate is obtained.

KP 88eCf2,7 kPA (20 mm Hg) 35 IR: C = 0 1750 cm"1 1H NMR: 1,5 ppm (9 H) (CH3)3-C-singlet 11 DK 174186 B1KP 88eCf2.7 kPA (20 mm Hg) IR: C = 0 1750 cm -1 1 H NMR: 1.5 ppm (9 H) (CH 3) 3-C singlet 11 DK 174186 B1

1,8 ppm (3 H) dublet CHyC1.8 ppm (3H) doubled CH 2 Cl

Cl 6,4 ppm (1 H) kvartet :-0-pH- C1 5 b) Omsætning af α-chlorethyl-tert.-butylcarbonat med n-octylaminCl 6.4 ppm (1H) quartet: -0-pH-C1 5 b) Reaction of α-chloroethyl tert.-butyl carbonate with n-octylamine

En opløsning af 52 g (0,4 mol) n-octylamin i 60 ml vandffit THF sættes dråbevis til en opløsning af 36,2 g (0,2 mol) a-chlorethyt-tert.-butylcarbonat i 120 ml THF. Tilsætningen foretages under omrøring ved 10°C.A solution of 52 g (0.4 mole) of n-octylamine in 60 ml of anhydrous THF is added dropwise to a solution of 36.2 g (0.2 mole) of α-chloroethyl tert.-butyl carbonate in 120 ml of THF. The addition is made with stirring at 10 ° C.

1010

Blandingen omrøres i ca. 15 timer ved stuetemperatur, de uopløselige forbindelser fjernes ved filtrering, og THF afdampes. Resten optages i 400 ml dichlormethan, og opløsningen vaskes med 100 ml 1 N saltsyre, 200 ml vand, 100 ml mættet vandig KHC03-opløsning og derpå med 100 ml vand.The mixture is stirred for approx. 15 hours at room temperature, the insoluble compounds are removed by filtration and the THF is evaporated. The residue is taken up in 400 ml of dichloromethane and the solution is washed with 100 ml of 1N hydrochloric acid, 200 ml of water, 100 ml of saturated aqueous KHCO3 solution and then with 100 ml of water.

1515

Efter tørring af opløsningen over magnesiumsulfat fjernes opløsningsmidlet ved fordampning, og den resterende blanding destilleres under formindsket tryk.After drying the solution over magnesium sulfate, the solvent is removed by evaporation and the residual mixture is distilled under reduced pressure.

36,52 g (80% udbytte) af det forventede carbamat fås på denne måde.36.52 g (80% yield) of the expected carbamate are obtained in this way.

20 KP 142°C/200 Pa (1,5 mm Hg) IR: C = 0 1690 cm*1 NH 3340 cm'1 1H NMR: 0,1-1,3 ppm (15 H) kompleks C-(CH2)n-CH3KP 142 ° C / 200 Pa (1.5 mm Hg) IR: C = 0 1690 cm @ 1 NH 3340 cm -1 H NMR: 0.1-1.3 ppm (15 H) complex C- (CH 2) n -CH 3

25 1,4 ppm (9 H) singlet (CH3)3-C1.4 ppm (9 H) singlet (CH 3) 3-C

3,0 ppm (2 H) kvartet CH2-N3.0 ppm (2H) quartet CH2-N

4.7 ppm (1 H) kompleks NH-C-4.7 ppm (1H) complex NH-C

OISLAND

30 c) Fremstilling af chlormethyl-tert.-butylcarbonatC) Preparation of chloromethyl tert-butyl carbonate

Fremgangsmåden er som i eksempel 5a. Idet man går ud fra 7,4 g (0,1 mol) tert.-butanol, 15,48 g chlormethylchlorformiat og 8,1 ml pyridin, fås 9,2 g (55%) tert.-butyl-chlormethylcarbonat.The procedure is as in Example 5a. Starting with 7.4 g (0.1 mole) of tert.-butanol, 15.48 g of chloromethyl chloroformate and 8.1 ml of pyridine, 9.2 g (55%) of tert.-butyl chloromethyl carbonate is obtained.

35 KP 82*C/2 kPa (15 mm Hg) 1H NMR: 1,4 ppm (CH3)3-C singlet 5.8 ppm CH2-CI singlet IR : C = 01750 cm-1 12 DK 174186 B1 d) Omsætning af chlormethyl-tert.-butylcarbonat med n-octylamin35 KP 82 * C / 2 kPa (15 mm Hg) 1 H NMR: 1.4 ppm (CH3) 3-C singlet 5.8 ppm CH2-CI singlet IR: C = 01750 cm-1 12 d) Reaction of chloromethyl -tert.-butyl carbonate with n-octylamine

Fremgangsmåden er som i eksempel 5b, men 1-chlorethyl-tert.-butylcarbonat erstattes med chlormethyl-tert.-butylcarbonat. Idet man går ud fira 6,5 g n-octylamin og 8,5 g chlormethyl-tert.-butylcarbonat, får man 4,3 g (38%) tert.-butyl-N-n-octylcarbamat, som er identisk med den oven-5 for under 5b opnåede forbindelse.The process is as in Example 5b, but 1-chloroethyl tert-butyl carbonate is replaced by chloromethyl tert-butyl carbonate. Starting with 6.5 g of n-octylamine and 8.5 g of chloromethyl-tert.-butyl carbonate, 4.3 g (38%) of tert.-butyl-Nn-octylcarbamate, which is identical to the above, are obtained. 5 for compound obtained under 5b.

Eksempel 6Example 6

Fremstilling af furfuryl-N-n-octvlcarbamat 10 Μ- CH2 - OC - MKnCaH.,Preparation of furfuryl N-n-octylcarbamate 10 Μ-CH 2 - OC - MKnCaH.,

OISLAND

a) Syntese af a-chlorethylfurfurylcarbonata) Synthesis of α-chloroethylfurfuryl carbonate

Fremgangsmåden er som i eksempel 5a, men med 0,22 mol a-chlorethylchlorformiat sat dråbevis til en opløsning af 0,2 mol furfurylalkohol og 0,24 mol pyridin i 200 ml dichloimethan.The procedure is as in Example 5a, but with 0.22 mol of α-chloroethyl chloroformate added dropwise to a solution of 0.2 mol of furfuryl alcohol and 0.24 mol of pyridine in 200 ml of dichloromethane.

1515

Oer fås 35,55 g (87% udbytte) a-chlorethylfurfurylcarbonat.35.55 g (87% yield) of α-chloroethylfurfuryl carbonate are obtained.

KP 94-98°C/13,3 Pa (0,1 mm Hg) IR: = 0 1750 cm'1KP 94-98 ° C / 13.3 Pa (0.1 mm Hg) IR: = 0 1750 cm -1

20 1H NMR : 1,8 ppm (3H) dublet CH3-C1 H NMR: 1.8 ppm (3H) doubled CH3-C

5,2 ppm (2 H) singlet CH2O5.2 ppm (2H) singlet CH2O

6,3-6,6 ppm (3 H) kompleks H-C = og H-C-CI6.3-6.6 ppm (3H) complex H-C = and H-C-CI

7,5 ppm (1 H) kompleks7.5 ppm (1H) complex

OISLAND

25 b) Omsætning af α-chiorethylfurfurylcartoonat med n-octylaminB) Reaction of α-chiorethylfurfurylcartoonate with n-octylamine

Fremgangsmåden er som i eksempel 5b, men med 10,2 g (0,05 mol) af ovenstående carbonat i 30 ml THF og 12,9 g (0,1 mol) n-octylamin i 15 ml THF.The procedure is as in Example 5b, but with 10.2 g (0.05 mol) of the above carbonate in 30 ml of THF and 12.9 g (0.1 mol) of n-octylamine in 15 ml of THF.

30 Der fås 11,05 g (87% udbytte) af det forventede carbamat.11.05 g (87% yield) of the expected carbamate is obtained.

KP 162°C/66,6 Pa (0,5 mm Hg), smp. 29eC IR: C = 0 1700 cm'1 NH 3340 cm'1 35 1H NMR: 0,7 til 1,5 ppm (15 H) kompleks (CH2)n-CH3KP 162 ° C / 66.6 Pa (0.5 mm Hg), m.p. 29 C IR: C = 0 1700 cm -1 NH 3340 cm -1 1 H NMR: 0.7 to 1.5 ppm (15 H) complex (CH 2) n-CH 3

3,1 ppm (2 H) kvartet CH2N3.1 ppm (2H) quartet CH2N

4,9 ppm (1 H) bredt kompleks NH4.9 ppm (1H) wide complex NH

5,0 ppm (2 H) singlet CH20 13 DK 174186 B1 6.4 ppm (2 H) kompleks H-C= 7.4 ppm (1 H) kompleks H-ft o5.0 ppm (2H) singlet CH20 13 DK 174186 B1 6.4 ppm (2H) complex H-C = 7.4 ppm (1H) complex H-ft o

Eksempel 7 5 Fremstilling af furfuryl-N-n-octylcarbamat I en reaktor indføres 6,5 g (0,05 mol) n-octylamin, 30 ml THF og 20 ml 5 M vandig K2CO3-0P’ løsning. Idet temperaturen holdes på 5-10°C, indfører man derpå dråbevis 11,25 g (0,055 mol) α-chlorethylfurfurylcarbonat under omrøring.Example 7 Preparation of furfuryl-N-n-octylcarbamate In a reactor, 6.5 g (0.05 mole) of n-octylamine, 30 ml of THF and 20 ml of 5 M aqueous K2CO3-0P 'solution are introduced. Keeping the temperature at 5-10 ° C, 11.25 g (0.055 mol) of α-chloroethyl furfuryl carbonate is then introduced dropwise with stirring.

10 Blandingen får lov at vende tilbage til stuetemperatur og holdes på denne temperatur under omrøring i 18 timer. Der tilsættes 50 ml natriumchloridmættet vand, blandingen ekstraheres to gange med 40 ml ethylether. og etherfaseme slås sammen og tørres over magnesiumsulfat.The mixture is allowed to return to room temperature and kept at this temperature with stirring for 18 hours. 50 ml of sodium chloride saturated water are added, the mixture is extracted twice with 40 ml of ethyl ether. and the ether phases are combined and dried over magnesium sulfate.

Efter fjernelse af opløsningsmidlet og destillation under formindsket tryk fås 9.5 g (75%) af det 15 forventede carbamat.After removal of the solvent and distillation under reduced pressure, 9.5 g (75%) of the expected carbamate is obtained.

KP 142°C/36,6 Pa (0,2 mm Hg).KP 142 ° C / 36.6 Pa (0.2 mm Hg).

Eksempel 8 20 Fremstilling af benzyf-N-n-octylcarbamat (O/ 0 J - NH nc8H.7 '-' 0 25 a) Syntese af a-chlorethylbenzylcarbonatExample 8 Preparation of benzyf-N-n-octylcarbamate (O / O J - NH nc8H.7 '- '0 25 a) Synthesis of α-chloroethylbenzyl carbonate

Fremgangsmåden er som i eksempel 5a, men under anvendelse af 200 ml dichlormethan, 21,6 g (0,2 mol) benzylalkohol, 31,6 g (0,22 mol) α-chlorethylchlorformiat og 0,2 mol pyridin.The process is as in Example 5a but using 200 ml of dichloromethane, 21.6 g (0.2 mole) of benzyl alcohol, 31.6 g (0.22 mole) of α-chloroethyl chloroformate and 0.2 mole of pyridine.

30 Der fås således 40,5 (94% udbytte) a-chlorethylbenzylcarbonat.Thus, 40.5 (94% yield) of α-chloroethylbenzyl carbonate is obtained.

KP 100*0/66,6 Pa I R:C= 0 1760cm-1 1H NMR: 1 *8 PPm (8 H) dublet CHg.KP 100 * 0 / 66.6 Pa I R: C = 0 1760cm-1 H NMR: 1 * 8 PPm (8 H) doubled CH 2.

35 5,2 ppm (2 H) singlet CH25.2 ppm (2H) singlet CH2

6.4 ppm (1 H) kvartet O-CH-CI6.4 ppm (1H) quartet O-CH-CI

7,3 ppm (5 H) singlet, aromatiske protoner 14 DK 174186 B1 b) Omsætning af α-ch lorethy I benzyl ca rbonat med n-octylamin7.3 ppm (5 H) singlet, aromatic protons 14 b) Reaction of α-chloroethyl in benzyl ca rbonate with n-octylamine

Fremgangsmåden er som i eksempel 5b, men under anvendelse af 19,4 g (0,15 mol) n-octylamin i 30 ml THF og 16,2 g (0,075 mol) af ovennævnte carbonat i 40 ml THF.The procedure is as in Example 5b, but using 19.4 g (0.15 mol) of n-octylamine in 30 ml of THF and 16.2 g (0.075 mol) of the above carbonate in 40 ml of THF.

5 Man får 17,7 g (90% udbytte) af det forventede carbamat.17.7 g (90% yield) of expected carbamate are obtained.

KP 180°C/66,6 Pa (0.5 mm Hg) SMP. 33-34°C I R: C = 0 1680 cm'1 10 NH 3380 cm’1 1H NMR: 0,7 til 1,5 ppm (15 H) kompleks (CH2)n CH3KP 180 ° C / 66.6 Pa (0.5 mm Hg) SMP. 33-34 ° C In R: C = 0 1680 cm -1 NH 3380 cm -1 1 H NMR: 0.7 to 1.5 ppm (15 H) complex (CH 2) n CH 3

3.1 ppm (2 H) kvartet CH2N3.1 ppm (2H) quartet CH2N

4.8 ppm (1 H) singlet NH y— —> 5.1 ppm (2 H) singlet CH2 15 7,3 ppm (5 H) singlet, aromatiske protoner.4.8 ppm (1 H) singlet NH y - -> 5.1 ppm (2 H) singlet CH2 7.3 ppm (5 H) singlet, aromatic protons.

Eksempel 9Example 9

Fremstilling af phenyl-Nnsobutylcarbamat 20 /PSV /CV3 \VJ/° S KH CH2 c\ '-' 0 CKj a) Syntese af α-chlorethylphenylca rbonat 25 Fremgangsmåden er som i eksempel 5a, men under anvendelse af 500 ml dichlormethan, 47 g (0,5 mol) phenol, 79 g (0,55 mol) a-chlorethylchlorformiat og 0,5 mol pyridin.Preparation of phenyl-Nnsobutylcarbamate 20 / PSV / CV3 \ VJ / ° S KH CH2 c \ '-' 0 CKj a) Synthesis of α-chloroethylphenylcarbonate (0.5 mole) of phenol, 79 g (0.55 mole) of a-chloroethyl chloroformate and 0.5 mole of pyridine.

Der fås således 94,23 g (94%) a-chlorethylphenylcarbonat.There is thus obtained 94.23 g (94%) of α-chloroethyl phenyl carbonate.

30 KP 110*C/66,6 Pa (0,5 mm Hg) I R: C = 0 1170 cm'1 1HNMR: 1,7 ppm (3 H) dublet CH3KP 110 ° C / 66.6 Pa (0.5 mm Hg) I R: C = 0 1170 cm -1 1 HNMR: 1.7 ppm (3 H) doubled CH 3

6,35 ppm (1 H) kvartet CH-CI6.35 ppm (1H) quartet CH-CI

7,0 til 7,3 ppm (5 H) kompleks, aromatiske protoner, 15 DK 174186 B1 b) Omsætning af a-chlorethylphenylcarbonat med isobutylamin7.0 to 7.3 ppm (5 H) complex, aromatic protons, b) Reaction of α-chloroethyl phenylcarbonate with isobutylamine

Fremgangsmåden er som i eksempel 7, men under anvendelse af 7,3 g (0,1 mol) isobutylamin, 35 ml 5 M vandig )<2C03-opløsning og 20,1 g (0,1 mol) af ovennævnte carbonat.The procedure is as in Example 7, but using 7.3 g (0.1 mole) of isobutylamine, 35 ml of 5 M aqueous <2 CO 3 solution and 20.1 g (0.1 mole) of the above carbonate.

5 Efter fjernelse af opløsningsmidlet og omkrystallisation af petroleumsether fås 12,5 g (65%) af den forventede forbindelse.After removal of the solvent and recrystallization from petroleum ether, 12.5 g (65%) of the expected compound are obtained.

SMP 66-67°CSMP 66-67 ° C

I R: C = 01710 cm'1 10 NH 3400 cm'1 1H NMR: 0,9 ppm (6 H) dublet CH3 1,8 ppm (1 H) multiplet CH-MeIn R: C = 01710 cm -1 NH 3400 cm -1 1 H NMR: 0.9 ppm (6H) doubled CH3 1.8 ppm (1H) multiplied CH-Me

MeMe

15 3,1 ppm (2 H)= triplet CH2-N3.1 ppm (2H) = triplet CH 2 -N

5.3 ppm (1 H) bred singlet NH5.3 ppm (1H) wide singlet NH

7,0 til 7,3 ppm (5 H) kompleks, aromatiske protoner.7.0 to 7.3 ppm (5H) complex, aromatic protons.

Eksempel 10 20 Fremstilling af tert.-butyIoxycarbonylpiperidin CH,-C-OC-N > 3 1 II \ / CH3 o '-' 25 Fremgangsmåden er som i eksempel 7, men under anvendelse af 8,5 g (0,1 mol) piperidin, 60 ml THF, 20 ml mættet vandig l<2C03-opløsning og 0,11 mol a-chlorethyl-teit-butylcarbonat.Example 10 Preparation of tert-butyl oxycarbonylpiperidine CH, -C-OC-N> 3 1 II \ / CH 3 0 '-' The procedure is as in Example 7 but using 8.5 g (0.1 mole) piperidine, 60 ml of THF, 20 ml of saturated aqueous 1 <2 CO 3 solution and 0.11 mol of a-chloroethyl-teite-butyl carbonate.

Blandingen omrøres kun 2 timer. Man får 14,8 g (80%) af det forventede carbamat.The mixture is stirred for only 2 hours. 14.8 g (80%) of the expected carbamate is obtained.

30 KP 96-98eC/2 kPa (15 mm Hg) IR: C = 0 1690 cm-1 1H NMR: 1,3-1,6 ppm (15 H)-CH2,CH3KP 96-98 ° C / 2 kPa (15 mm Hg) IR: C = 0. 1690 cm -1. 1 H NMR: 1.3-1.6 ppm (15 H) -CH2, CH3

3.3 ppm (4 H) CH2N3.3 ppm (4 H) CH 2 N

16 DK 174186 B116 DK 174186 B1

Eksempel 11Example 11

Fremstilling af S-ethyl-N-N-octylthlocarbamat C2H5-s-C-NH-n-C8H17Preparation of S-ethyl-N-N-octylthlocarbamate C2H5-s-C-NH-n-C8H17

OISLAND

5 a) Fremstilling af a-chlorethyl-S-ethylthlocarbonat C2H5-S-9-O-CH-CH3 O i) 10 Fremgangsmåden er som i eksempel 5a, men under anvendelse af 31,5 g (0,22 mol) a-chlorethylchlorformiat i en opløsning af 12,4 g (0,2 mol) ethanthiol og 15,8 g (0,2 mol) pyridin i 200 ml dichlormethan.5 a) Preparation of α-chloroethyl-5-ethylthlocarbonate C 2 H 5 -S-9-O-CH-CH 3 0 i) The process is as in Example 5a, but using 31.5 g (0.22 mol) chloroethyl chloroformate in a solution of 12.4 g (0.2 mole) of ethanthiol and 15.8 g (0.2 mole) of pyridine in 200 ml of dichloromethane.

Der fås 21.1 g (62,5%) a-chlorethyl-S-ethylthiocarbonat.21.1 g (62.5%) of a-chloroethyl-5-ethylthiocarbonate is obtained.

15 KP 110*0/5,86 kPa (44 mm Hg) IR: C- 0 1720 cm'1 1H NMR : 1,3 ppm triplet CH3 1,75 ppm dublet CH3KP 110 * 0 / 5.86 kPa (44 mm Hg) IR: C-0 1720 cm -1 1 H NMR: 1.3 ppm triplet CH3 1.75 ppm double CH3

20 2,8 ppm kvartet CHjj-S2.8 ppm quartet CH₂j-S

6,5 ppm kvartet O-CHCI6.5 ppm quartet O-CHCl

b) Omsætning af a-chlorethyl-S-ethylthiocarbonat med n-octylaminb) Reaction of α-chloroethyl-5-ethylthiocarbonate with n-octylamine

Fremgangsmåden er som i eksempel 7, men under anvendelse af 6,5 g (0,05 mol) n-octylamin.The procedure is as in Example 7 but using 6.5 g (0.05 mole) of n-octylamine.

25 30 ml THF, 20 ml 5 M vandig ^COs-opløsning og 8,43 g (0,05 mol) af ovennævnte thiocarbo- nat.25 ml of THF, 20 ml of 5 M aqueous 3 CO 2 solution and 8.43 g (0.05 mole) of the above thiocarbonate.

Der fås således 5,3 g (49%) af det forventede thiocarbamat.Thus, 5.3 g (49%) of the expected thiocarbamate is obtained.

30 KP 146-152*0/66,6 Pa (0,5 mm Hg) I R: C = 0 1650 cm-1 HN 3300 cm'1 1H NMR: 0,7 til 1,6 ppm (18 H) kompleks (CH2)-n-CH3KP 146-152 * 0 / 66.6 Pa (0.5 mm Hg) IR: C = 0 1650 cm -1 HN 3300 cm -1 H NMR: 0.7 to 1.6 ppm (18 H) complex ( CH2) n-CH3

2,8 ppm (2 H) kvartet CH2S2.8 ppm (2H) quartet CH 2 S

35 3,1 ppm (2 H) pseudo-triplet CH2N3.1 ppm (2H) pseudo-triplet CH2N

3,2 ppm (1 H) bred singlet NH3.2 ppm (1H) wide singlet NH

17 DK 174186 B117 DK 174186 B1

Eksempel 12-19Examples 12-19

Fremstilling af forskellige benzylcarbamater I disse eksempler omsættes a-chlorethylbenzylcarbonat efter fremgangsmåden i eksempel 7 med forskellige primære eller sekundære aminer.Preparation of Various Benzyl Carbamates In these examples, α-chloroethylbenzyl carbonate is reacted according to the procedure of Example 7 with various primary or secondary amines.

55

Temperaturbetingelserne og reaktionstiden, de fysiske egenskaber af de opnåede forbindelser samt de opnåede udbytter fremgår af tabel I.The temperature conditions and reaction time, the physical properties of the compounds obtained as well as the yields obtained are shown in Table I.

18 DK 174186 B1 Π Q) *h tn18 DK 174186 B1 Π Q) * h tn

Cu i—I <DCu i-I <D

ω tu xs -P ^ »*' *.·> «* *·· ^ -P β> -H v r- S"· .t- t " *T r- ;>, t n p æ et r- tr ro *-"· r*- roω tu xs -P ^ »* '*. ·>« * * ·· ^ -P β> -H v r- S "· .t- t" * T r-;>, tnp æ et r- tr ro * - "· r * - ro

P β PP β P

Ό fl> O , ·.Ό fl> O, ·.

D P <HD P <H

"J 13 c s. C'C'tf-'i t) - c. a. c. c. l."J 13 c s. C'C'tf-'i t) - c. A. C. C. L.

·*. · t·* Τ'* r** * P* r- »___ · « · r· * »· *. · T · * Τ '* r ** * P * r- »___ ·« · r · * »

Pf Γ““\ Γ^Ι w *£ ^ -Γ wPf Γ ““ \ Γ ^ Ι w * £ ^ -Γ w

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*2 {Λ **. C S- s* “'v N* 2 {Λ **. C S- s * “'v N

^ ™ U «Τ L’ L* O U O U O^ ™ U «Τ L 'L * O U O U O

Viwi* « C 9 O C «.Viwi * «C 9 O C«.

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cl 3 p p ^ ,. ., , .. . ,' t? rit · * O vJ U w . v E -r * t* C » o eo tu ni .-„ r. -: c c. ~ n c HP n c« r·: n r*cl 3 p p ^ ,. .,, ... , isn't it? ride · * O vJ U w. v E -r * t * C »o eo tu ni .-„ r. -: c c. ~ n c HP n c «r ·: n r *

T) ·— -C -C — — — ^ XT) · - -C -C - - - ^ X

T* ιΛ *τ Γ\ί 1M ·“ 2. ιΛ "JT * ιΛ * τ Γ \ ί 1M · “2. ιΛ" J

H — C — S _ i ε ω = I Μ -j nj X = <U P = X 2 _ _ P> = is X X Λ z 5 /“\ H P(Qi(Q)i< OU“ 0 .H - C - S _ i ε ω = I Μ -j nj X = <U P = X 2 _ _ P> = is X X Λ z 5 / “\ H P (Qi (Q) i <OU“ 0.

»-} · m * ^ 2 - Z - £ E E El g I HC| I I | | I I I { 19 DK 174186 B1»-} · m * ^ 2 - Z - £ E E El g I HC | I I | | I I I {19 DK 174186 B1

Eksempel 20Example 20

Fremstilling af S-ethyl-N.N-hexamethylen-thiocarbamat (molinat) CH,-ch.-ch.Preparation of S-ethyl-N.N-hexamethylene-thiocarbamate (molinate) CH, -ch.-ch.

I 2 2 *\ I / N" 5-8^11¾ 5 CH.-CH^-CH. o t 4. £I 2 2 * \ I / N "5-8 ^ 11¾ 5 CH.-CH ^ -CH. O t 4. £

Fremgangsmåden er som i eksempel 11, idet man omsætter α-chlorethyl-thiocarbonat med hexamethytenimin.The process is as in Example 11, reacting α-chloroethyl thiocarbonate with hexamethytenimine.

10 Ved destillation fås den forventede forbindelse i et udbytte på 70%.10 Distillation gives the expected compound in a yield of 70%.

KP 141*C/1,7 kPa (13 mm Hg).KP 141 * C / 1.7 kPa (13 mm Hg).

Eksempel 21 15 Fremstilling af tert-butyl-N-benzylcarbamat vUnTt0)Example 21 Preparation of tert-butyl-N-benzylcarbamate (IIIT0)

' 0 CH0 CH

20 a) Syntese af 1,2,2,2-tetraclorethyl-tert.-butylcarbonat 9,9 g (0,04 mol) 1,2,2,2-tetrachlorethylchlorforrniat sættes på en gang til en opløsning af tert.· butanol (3 g, 0,04 mol) i dichlormethan (50 ml). Blandingen afkøles til 0°C, og der tilsættes dråbevis 3,2 g (0,04 mol) pyridin. Blandingen omrøres 4 timer ved stuetemperatur. Derpå tilsættes 20 ml iskoldt vand. Den tørres over magnesiumsulfat, og opløsningsmidlet afdamples.A) Synthesis of 1,2,2,2-tetraclorethyl-tert.-butyl carbonate 9.9 g (0.04 mole) of 1,2,2,2-tetrachlorethyl-chloroformate are added at once to a solution of tert.-butanol (3 g, 0.04 mole) in dichloromethane (50 ml). The mixture is cooled to 0 ° C and 3.2 g (0.04 mole) of pyridine is added dropwise. The mixture is stirred for 4 hours at room temperature. Then add 20 ml of ice-cold water. It is dried over magnesium sulfate and the solvent is evaporated.

25 Der fås 11,3 g af et fast hvidt stof (udbytte 99%), som omkrystalliseres af petroleumsether (87% udbytte, smp. 70eC), og der fås 9,9 g af det rensede carbonat.There is obtained 11.3 g of a solid white substance (yield 99%) which is recrystallized from petroleum ether (87% yield, mp 70 ° C) and 9.9 g of the purified carbonate is obtained.

KP 96“C/866 Pa (6,5 mm Hg) I R: C = 01770 cm1 30 1H NMR (CDCI3, TMS): 1.5 (s,CH3) 6,7 (s,CH) b) Omsætning af ovennævnte carbonat med benzylamin 1,1 9 (0,01 mol) benzylamin opløses i 20 ml THF, og der tilsættes 3 ml 5 M vandig kaliumcarbo-natopløsning.KP 96 ° C / 866 Pa (6.5 mm Hg) IR: C = 01770 cm1 30 1 H NMR (CDCl 3, TMS): 1.5 (s, CH 3) 6.7 (s, CH) b) Reaction of the above carbonate with benzylamine 1.19 (0.01 mole) of benzylamine is dissolved in 20 ml of THF and 3 ml of 5 M aqueous potassium carbonate solution is added.

3535

Derpå tilsætter man 2,9 g (0,01 mol) tert.-butyltetrachlorethylcarbonat opløst i 5 ml THF ved 5°C. Blandingen omrøres 1 time ved 20"C, og den organiske fase fradekanteres og vaskes med 10 ml vandig mættet NaCI-opløsning. Den organiske fase tørres, opløsningsmidlet afdam- 20 DK 174186 B1 pes, og den resterende blanding destilleres. Der fås 2,0 g af det forventede carbamat (udbytte 96%).Then, 2.9 g (0.01 mole) of tert.-butyl tetrachlorethyl carbonate dissolved in 5 ml of THF is added at 5 ° C. The mixture is stirred for 1 hour at 20 ° C and the organic phase is decanted off and washed with 10 ml of aqueous saturated NaCl solution. The organic phase is dried, the solvent is evaporated and the residue is distilled off. 2.0 g of expected carbamate (yield 96%).

KP 103eC/6,7 Pa (0,05 mm Hg).KP 103eC / 6.7 Pa (0.05 mm Hg).

55

Forbindelsen omkrystalliseres af petroleumsether, og der fås 1,84 g af det forventede carbamat (89%). Smp. 54“C (litteratur 53-54°C).The compound is recrystallized from petroleum ether to give 1.84 g of the expected carbamate (89%). Mp. 54 ° C (literature 53-54 ° C).

Eksempel 22 10 Fremstilling af tert.-butyloxycarbonylimidazol ?=\ N-C-0-OCH., / l! t 3 L·=/ o ch3 15 5 g (17,5 mmol) tert.-butyl-1,2,2,2-tetrachlorethylcarbonat opløst i 10 ml THF sættes ved 0°C til en opløsning af imidazol (1,2 g, 17,6 mmol) i THF (20 ml) i nærværelse af 5 M vandig kalium-carbonatopløsning (5 ml). Blandingen omrøres 1 time ved 20°C, og den organiske fase dekanteres fra og vaskes med 10 ml mættet vandig NaCI-opløsning.Example 22 Preparation of tert-butyloxycarbonylimidazole = N-C-O-OCH. t 3 L · = / o ch 3 15 g (17.5 mmol) of tert.-butyl-1,2,2,2-tetrachloroethyl carbonate dissolved in 10 ml of THF are added at 0 ° C to a solution of imidazole (1.2 g, 17.6 mmol) in THF (20 ml) in the presence of 5 M aqueous potassium carbonate solution (5 ml). The mixture is stirred for 1 hour at 20 ° C and the organic phase is decanted and washed with 10 ml of saturated aqueous NaCl solution.

20 Efter tørring af den organiske fase og afdampning af opløsningsmidlerne destilleres den fremkomne rest, og man får 2,55 g forbindelse (udbytte 86%).After drying the organic phase and evaporation of the solvents, the resulting residue is distilled off to give 2.55 g of compound (yield 86%).

KP 64Ό/133,3 Pa (1 mm Hg)KP 64Ό / 133.3 Pa (1 mm Hg)

Smp. 43°C 25Mp. 43 ° C

Eksempel 23Example 23

Fremstilling af 2,3-dihydro-2,2-dimethyl-7-benzofuranyl-N-methylcarbamat (carbofuran) a) Syntese af 1-chlorethyl-2,3-dihydro-2,2-dimethyl-7-benzofuranylcarbonat 21,5 g (0,15 mol) 1-chlorethylchlorformiat sættes på en gang til en opløsning af 2,3-dihydro-2,2-30 7-benzofuranol (24,6 g, 0,15 mol) i dichlormethan (150 ml). Blandingen afkøles til 0-5°C, og der tilsættes dråbevis 12 g (0,15 mol) pyridin. Blandingen omrøres 3 timer ved 20°C. Den organiske fase vaskes derpå med 2 x 50 ml iskoldt vand. Den tørres over magnesiumsulfat, og opløsningsmidlet afdampes Der fås en gul olie, som destilleres. Derved får man 34,1 g af det forventede carbonat (84% udbytte).Preparation of 2,3-dihydro-2,2-dimethyl-7-benzofuranyl-N-methylcarbamate (carbofuran) a) Synthesis of 1-chloroethyl-2,3-dihydro-2,2-dimethyl-7-benzofuranyl carbonate 21.5 g (0.15 mole) of 1-chloroethyl chloroformate is added at once to a solution of 2,3-dihydro-2,2-30 7-benzofuranol (24.6 g, 0.15 mole) in dichloromethane (150 ml). The mixture is cooled to 0-5 ° C and 12 g (0.15 mole) of pyridine is added dropwise. The mixture is stirred for 3 hours at 20 ° C. The organic phase is then washed with 2 x 50 ml of ice-cold water. It is dried over magnesium sulfate and the solvent is evaporated A yellow oil is obtained which is distilled. There is thus obtained 34.1 g of the expected carbonate (84% yield).

35 KP 127°C/66,6 Pa (0,5 mm Hg).KP 127 ° C / 66.6 Pa (0.5 mm Hg).

21 DK 174186 B1 b) Omsætning af ovennævnte carbonat med methyiamin 5,4 g 0,02 mol) af ovenstående carbonat opløses i THF (20 ml). Derpå tilsættes 10 ml ca. 5 M vandig K2CC>3-opløsning og 1,7 ml (0,02 mol) 40%'s opløsning af methyiamin i vand. Blandingen omrøres 15 timer ved 20‘C. Den organiske fase fradekanteres og vaskes med 5 mættet NaCI-opløsning, Opløsningsmidlet afdampes, og forbindelsen krystalliseres af methyl-cyclohexan. Der fås 3,5 g af det forventede carbamat (79% udbytte).B) Reaction of the above carbonate with methylamine 5.4 g of 0.02 mol) of the above carbonate is dissolved in THF (20 ml). Then add about 10 ml. 5 M aqueous K2CC> 3 solution and 1.7 ml (0.02 mol) 40% solution of methylamine in water. The mixture is stirred for 15 hours at 20 ° C. The organic phase is decanted off and washed with saturated NaCl solution, the solvent is evaporated and the compound is crystallized by methyl cyclohexane. 3.5 g of expected carbamate (79% yield) is obtained.

Smp. 148*C.Mp. 148 * C.

10 c) Man går frem som under a) og derefter b), men pyridinet erstattes med N.N-dimethylanilin, og det som mellemprodukt dannede carbonat destilleres ikke. Idet man går ud fra 16,4 g 2,3-dihydro-2,2-dimethyl-7-benzofuranol, får man 16,8 g (76%) carbofuran med smp. 147*C.C) Proceed as under a) and then b), but the pyridine is replaced with N.N-dimethylaniline and the intermediate carbonate is not distilled. Starting from 16.4 g of 2,3-dihydro-2,2-dimethyl-7-benzofuranol, 16.8 g (76%) of carbofuran is obtained with m.p. 147 * C.

Eksempel 24 15 a) Syntese af 1,2,2,2-tetrachlorethyl*N-methylcarbamat 34,7 ml (0,4 mmol) methyiamin (i 40%'s vandig opløsning) sættes dråbevis til en opløsning, som holdes på 0°C, af 49,4 g (0,2 mol) 1,2,2,2-tetrachlorethylchlorformiat i dichlormethan (150 ml). Blandingen omrøres derpå 2 timer ved stuetemperatur. Den organiske fase vaskes med to gange 100 ml vand og tørres over magnesiumsulfat.Example 24 a) Synthesis of 1,2,2,2-tetrachloroethyl * N-methylcarbamate 34.7 ml (0.4 mmol) of methylamine (in 40% aqueous solution) is added dropwise to a solution maintained at 0 ° C, of 49.4 g (0.2 mole) of 1,2,2,2-tetrachloroethyl chloroformate in dichloromethane (150 ml). The mixture is then stirred for 2 hours at room temperature. The organic phase is washed with twice 100 ml of water and dried over magnesium sulfate.

2020

Forbindelsen krystalliserer ved fordampning af opløsningsmidlet, og man får 42,6 g af det forventede carbamat (88% udbytte).The compound crystallizes on evaporation of the solvent to give 42.6 g of the expected carbamate (88% yield).

Smp. 105-106eCMp. 105-106eC

25 1H NMR: 2,75 (CH3-N) 5.2 (NH) 6,7 (CH-CI) I R:C= 0 1760cm-1 30 b) Syntese af N-methyl-N’-piperldylurlnstof 4,83 g (0,02 mol) af det ovenfor fremstillede carbamat opløses 130 ml THF og 5 mi vand mættet med K2CO3. 1,7 g (0,02 mol) piperidin sættes til denne opløsning, som holdes på 10°C, og blandingen omrøres 4 timer ved stuetemperatur. Den organiske fase dekanteres fra og vaskes med 50 ml vand mættet med NaCI. Den tørres over magnesiumsulfat, opløsningsmidlet afdam-35 pes, og resten destilleres. Der fås 1,8 g af det forventede urinstof (63% udbytte).1 H NMR: 2.75 (CH 3 -N) 5.2 (NH) 6.7 (CH-Cl) IR: C = 0.1760 cm -1 b) Synthesis of N-methyl-N'-piperidylurea 4.83 g ( 0.02 ml) of the carbamate prepared above is dissolved 130 ml of THF and 5 ml of water saturated with K 2 CO 3. 1.7 g (0.02 mole) of piperidine are added to this solution, which is kept at 10 ° C and the mixture is stirred for 4 hours at room temperature. The organic phase is decanted off and washed with 50 ml of water saturated with NaCl. It is dried over magnesium sulfate, the solvent is evaporated and the residue distilled off. 1.8 g of the expected urea are obtained (63% yield).

KP 110eC/6,7 Pa (0,05 mm Hg).KP 110eC / 6.7 Pa (0.05 mm Hg).

22 DK 174186 B122 DK 174186 B1

Eksempel 25Example 25

Fremstilling af imidazolylcarbonylpiperidin N=r\ ,__ «-c-,Γλ 5 !=/ o \_/ a) Syntese af a-clorethoxycarbonylimidazol 28,6 g (0,2 mol) chlorethylchlorformiat sættes dråbevis til en opløsning af 27,2 g (0,4 mol) imi-dazol i 200 ml dichlormethan, som er afkølet i vandbad. Blandingen omrøres ved stuetempera-10 tur i 4 timer, og derpå tilsætter man 50 ml iskoldt vand. Den organiske fase vaskes med to gange 50 ml vand og tørres derpå over magnesiumsulfat. Efter inddampning og destillation får man 38,1 g (73%) α-chlorethoxycarbonylimidazol (KP 80°C/66,6 Pa (0,5 mm Hg)) i form af en farveløs væske, som krystalliserer spontant ved stuetemperatur, smp. 50°C.Preparation of imidazolylcarbonylpiperidine N = r \, __ -c-, Γλ 5 = / o \ _ / a) Synthesis of α-chloroethoxycarbonylimidazole 28.6 g (0.2 mole) of chloroethyl chloroformate are added dropwise to a solution of 27.2 g (0.4 mole) of imidazole in 200 ml of dichloromethane which is cooled in a water bath. The mixture is stirred at room temperature for 4 hours, then 50 ml of ice-cold water is added. The organic phase is washed with twice 50 ml of water and then dried over magnesium sulfate. After evaporation and distillation, 38.1 g (73%) of α-chloroethoxycarbonylimidazole (KP 80 ° C / 66.6 Pa (0.5 mm Hg)) is obtained in the form of a colorless liquid which spontaneously crystallizes at room temperature, m.p. 50 ° C.

"=\ Cl 15 I N - CO CH CH, U/ » \ 3 1H NMR (60 MHz, CDCI3, TM): δ: 1,9(d, CH3) 20 6,7 (q, OCH-CI) 7,05, 7,4, 8,2 (3 pseudo singletter, imidazol) I R: C = 0 1770 cm'1 25 b) Omsætning af α-chlorethoxycarbonyllmidazol med piperidin1 H NMR (60 MHz, CDCl 3, TM): δ: 1.9 (d, CH 3) 6.7 (q, OCH-CI) 7, 05, 7.4, 8.2 (3 pseudo singlets, imidazole) IR: C = 0 1770 cm -1 b) Reaction of α-chloroethoxycarbonyllmidazole with piperidine

En opløsning af 8,5 g (0,1 ml) piperidin i 10 ml THF sættes dråbevis til en opløsning af a-chlor-ethoxycarbonylimidazol (8,75 g, 0,05 mol) i 50 ml THF. Denne opløsning afkøles til 5°C, medens tilsætningen foregår, og omrøres derefter ved stuetemperatur.A solution of 8.5 g (0.1 ml) of piperidine in 10 ml of THF is added dropwise to a solution of α-chloroethoxycarbonylimidazole (8.75 g, 0.05 mol) in 50 ml of THF. This solution is cooled to 5 ° C while the addition is taking place and then stirred at room temperature.

30 Det dannede piperidinhydrochlorid frafiltreres, og den organiske fase vaskes derpå en gang med vand. Derpå tørrer man over magnesiumsulfat, og opløsningsmidlet afdampes. Den resterende blanding destilleres, og man får 6,2 g (80% udbytte) af den forventede forbindelse. KP 134°C/26,6 Pa (0,2 mm Hg).The piperidine hydrochloride formed is filtered off and the organic phase is then washed once with water. Then, it is dried over magnesium sulfate and the solvent is evaporated. The remaining mixture is distilled off to give 6.2 g (80% yield) of the expected compound. KP 134 ° C / 26.6 Pa (0.2 mm Hg).

35 Den opnåede væske krystalliserer spontant i køleskab. Smp. 38°C.35 The liquid obtained spontaneously crystallizes in a refrigerator. Mp. 38 ° C.

DK 174186 B1 23 1H NMR: 1,5 ppm multiplet (CH2)3 3,5 ppm multiplet H2-N-CH2 7.0 ppm ^ 5 7,15 ppm imidazol 7.8 ppm I R: C = 0 1690 cm’1DK 174186 B1 23 1 H NMR: 1.5 ppm multiplet (CH2) 3 3.5 ppm multiplet H2-N-CH2 7.0 ppm δ 7.15 ppm imidazole 7.8 ppm I R: C = 0 1690 cm -1

Eksempel 26 10 Fremstilling af N.N-diethylimidazolcarboxamid L=y i \ EtExample 26 Preparation of N.N-Diethylimidazole Carboxamide L = γ in \ Et

Man går frem som i eksempel 25b, men piperidinet erstattes med diethylamin. Man får 6,5 g af 15 det forventede urinstof (78% udbytte).Proceed as in Example 25b, but the piperidine is replaced with diethylamine. You get 6.5 g of the expected urea (78% yield).

KP 106eC/26,6 Pa (0,2 mm Hg)KP 106eC / 26.6 Pa (0.2 mm Hg)

Smp. 41 °C (litteratur 38-43°C) 1HNMR: 1,2 ppm (t, CH3) 20 3,4 ppm (q, CH2N) 7.0 ppm’ 7,2 ppm > imidazol 7.8 ppm> I R : C = 0 1690 cm-1 25Mp. 41 ° C (literature 38-43 ° C) 1 H NMR: 1.2 ppm (t, CH 3) 3.4 ppm (q, CH 2 N) 7.0 ppm 7.2 ppm> imidazole 7.8 ppm> IR: C = 0 1690 cm-1 25

Eksempel 27Example 27

Fremstilling af 2-methyl-2-(methytthio)-propanal-0-((methylamin)-carbonyl)-oxim (Aldicarb) 50 ml toluen og 6,65 g (0,05 mol) 2-methyl-2-(methyIthio)-propanaloxim sættes gradvis til 5 ml 30 10 N natriumhydroxidopløsning. Blandingen omrøres et øjeblik ved stuetemperatur, hvorpå vandet fjernes ved azeotrop destillation. Blandingen afkøles derpå i isbad, og man tilsætter dråbevis 7,5 g (0,05 mol) 1-chlorethylchlorformiat. Blandingen omrøres 1 time ved 10-15°C.Preparation of 2-methyl-2- (methylthio) -propanal-0 - ((methylamine) carbonyl) oxime (Aldicarb) 50 ml of toluene and 6.65 g (0.05 mol) of 2-methyl-2- (methylthio) ) -Propanaloxime is gradually added to 5 ml of 30 N sodium hydroxide solution. The mixture is stirred for a moment at room temperature and the water is removed by azeotropic distillation. The mixture is then cooled in an ice bath and 7.5 g (0.05 mole) of 1-chloroethyl chloroformate are added dropwise. The mixture is stirred for 1 hour at 10-15 ° C.

Man tilsætter dråbevis 10 ml (ca. 0,13 mol) 40%'s vandigt methylamin, og blandingen omrøres yderligere 1 time ved samme temperatur. Den organiske fase dekanteres fra og vaskes med 10 35 ml iskoldt vand. Den organiske fase tørres over magnesiumsulfat og inddampes til tørhed. Der fås 8,7 g føst lysebrunt stof med smp. 90*C.10 ml (about 0.13 mole) of 40% aqueous methylamine are added dropwise and the mixture is stirred for an additional hour at the same temperature. The organic phase is decanted off and washed with 35 ml of ice-cold water. The organic phase is dried over magnesium sulfate and evaporated to dryness. 8.7 g of solid light brown substance are obtained with m.p. 90 * C.

24 DK 174186 B124 DK 174186 B1

Eksempel 28Example 28

Syntese af tert.-butyloxycarbonyl-L-asparaginsyreSynthesis of tert-butyloxycarbonyl-L-aspartic acid

Til en opløsning af 1,33 g (10 mmol) L-asparaginsyre i en blanding af dioxan og vand (1:1) (30 ml) sætter man 4,2 ml (30 mmol) triethylamin, og blandingen omrøres, indtil opløsningen er 5 fuldstændig (ca. 10 minutter). Derpå tilsætter man 2,95 g (10 mmol) tert.-butyl-1,2,2,2-tetra-chlorethylcarbonat, og blandingen omrøres 6 timer ved 20eC. Derefter tilsætter man 50 ml vand, og blandingen ekstraheres med 2 x 20 ml ethylacetat. Den vandige fase symes (pH 2-3) med 1 N HCI og ekstraheres derpå med 3 x 30 ml ethylacetat. Ekstrakten vaskes med mættet NaCI-opløsning, tørres over MgSC?4 og inddampes. Den opnåede forbindelse krystalliseres af 10 ethylacetat og petroleumsether. Der fås 1,4 g (60% udbytte) af den forventede syre.To a solution of 1.33 g (10 mmol) of L-aspartic acid in a mixture of dioxane and water (1: 1) (30 ml) is added 4.2 ml (30 mmol) of triethylamine and the mixture is stirred until the solution is 5 complete (about 10 minutes). Then 2.95 g (10 mmol) of tert.-butyl-1,2,2,2-tetrachloroethyl carbonate is added and the mixture is stirred for 6 hours at 20 ° C. Then 50 ml of water is added and the mixture is extracted with 2 x 20 ml of ethyl acetate. The aqueous phase is simulated (pH 2-3) with 1 N HCl and then extracted with 3 x 30 ml of ethyl acetate. The extract is washed with saturated NaCl solution, dried over MgSC4 and evaporated. The obtained compound is crystallized from 10 ethyl acetate and petroleum ether. 1.4 g (60% yield) of the expected acid are obtained.

Smp. 116-118‘C (litteratur 114-116“C).Mp. 116-118 ° C (literature 114-116 ° C).

a20 = -5 (c = 1.0, MeOH) (litteratur -6,2 (c = 1,0, MeOH)).a20 = -5 (c = 1.0, MeOH) (literature -6.2 (c = 1.0, MeOH)).

15 Eksempel 29Example 29

Fremstilling af ethylfurfuryloxycarbonylglycinat 2,05 g (10 mmol) α-clorethylfurfurylcarbonat sættes til en opløsning af 1,03 g (10 mmol) ethyl-glycinat i 6 ml THF og 4 ml 0,5 M kaliumcarbonatopløsning, som holdes ved 5-10eC. Man lader blandingen genantage stuetemperatur, og man omrører 18 timer. Man tilsætter 50 ml vand 20 mættet med NaCl, og blandingen ekstraheres med 3 x 40 ml ethylether. De organiske faser slås sammen og tørres over magnesiumsulfat. Efter fjernelse af opløsningsmidlet og destillation fås 1,5 g (66% udbytte) af den forventede forbindelse.Preparation of Ethylfurfuryloxycarbonylglycinate 2.05 g (10 mmol) of α-chloroethylfurfuryl carbonate is added to a solution of 1.03 g (10 mmol) of ethyl glycinate in 6 ml of THF and 4 ml of 0.5 M potassium carbonate solution maintained at 5-10 ° C. The mixture was allowed to re-enter room temperature and stirred for 18 hours. 50 ml of water is saturated with NaCl and the mixture is extracted with 3 x 40 ml of ethyl ether. The organic phases are combined and dried over magnesium sulfate. After removal of the solvent and distillation, 1.5 g (66% yield) of the expected compound are obtained.

KP 144°C/40 Pa (0,3 mm Hg) 25 I R: C = 0 1680 cm'1 NH 3280 cm'1 1HNMR(CDCI3,TMS): 1,3 ppm triplet CH3 0 3,95 ppm dublet N-CH2& 4.2 ppm kvartet CH2 (CH3)KP 144 ° C / 40 Pa (0.3 mm Hg) IR: C = 0 1680 cm -1 NH 3280 cm -1 H NMR (CDCl3, TMS): 1.3 ppm triplet CH3 0. 3.95 ppm doubled N CH2 & 4.2 ppm quartet CH2 (CH3)

30 5,1 ppm singlet CH2-O-C-N5.1 ppm singlet CH2-O-C-N

5.2 ppm bred singlet NH5.2 ppm wide singlet NH

6.4 ppm kompleks 7.4 ppm kompleks H-C-0 25 DK 174186 B16.4 ppm complex 7.4 ppm complex H-C-0 DK 174186 B1

Eksempel 30Example 30

Fremstilling af benzyloxycarbonyl-L-prolinPreparation of benzyloxycarbonyl-L-proline

Til en opløsning af 1.15 g (10 mmol) L-prolin i 10 ml methanol og 3 ml mættet vandig K2CO3-opløsning sætter man 2,36 g (11 mmol) benzyl-a-chlorethyfcarbonat ved 5°C. Efter 4 timers 5 reaktion tilsætter man 50 ml vand, og blandingen vaskes med 2 gange 10 ml ethylether. Blandingen syrnes til en pH-værdi på 2-3 med 6 N HCI og ekstraheres med ethylacetat.To a solution of 1.15 g (10 mmol) of L-proline in 10 ml of methanol and 3 ml of saturated aqueous K 2 CO 3 solution is added 2.36 g (11 mmol) of benzyl-α-chloroethy carbonate at 5 ° C. After 4 hours of reaction, 50 ml of water is added and the mixture is washed with 2 ml of 10 ml of ethyl ether. The mixture is acidified to a pH of 2-3 with 6N HCl and extracted with ethyl acetate.

Efter afdampning af opløsningsmidlerne og krystallisation af en blanding af ethylacetat og petro-leumsether fås 2,2 g (88% udbytte) Z-(L)-Pro.After evaporation of the solvents and crystallization of a mixture of ethyl acetate and petroleum ether, 2.2 g (88% yield) of Z- (L) -Pro are obtained.

1010

Smp. 75-76eC (litteratur 76-78‘C).Mp. 75-76 ° C (literature 76-78 ° C).

Eksempel 31Example 31

Fremstilling af 1,2,2,2-tetrachlorethyl-2-trimethylsilylethylcarbonat 15 (CH3)3Si-CH2-0-g-0-9H-CCI3Preparation of 1,2,2,2-tetrachloroethyl-2-trimethylsilylethyl carbonate (CH3) 3Si-CH2-O-g-0-9H-CCl3

Fremgangsmåden er som i eksempel 21a. Idet man går ud fra 5,91 g trimethylsilylethanol og 12,35 g tetrachlorethylchlorformiat, får man 13,6 g (83%) af den forventede forbindelse.The procedure is as in Example 21a. Starting from 5.91 g of trimethylsilyl ethanol and 12.35 g of tetrachlorethyl chloroformate, 13.6 g (83%) of the expected compound is obtained.

20 KP 92-94°C/6,6 Pa IRC» 0 1750 cm'1 1H NMR (CDCI3. eksternt TMS): 0,1 (s. CH3-S1) 1.1 (t, CH2-0) 4,35 (t, CH2-O) 25 6.7 (s, CH-C)KP 92-94 ° C / 6.6 Pa IRC 0 0 1750 cm'1 1 H NMR (CDCl3. External TMS): 0.1 (s, CH.-S1) 1.1 (t, CH₂-O) 4.35 ( t, CH 2 -O 6.7 (s, CH-C)

Eksempel 32Example 32

Fremstilling af trimethylsilylethyloxycarbonyl-L-phenylalaninPreparation of trimethylsilylethyloxycarbonyl-L-phenylalanine

(CH3)3Si-CH2-0-C-NH-CH-(pH2'CgH5 30 * Ce>aW(CH3) 3Si-CH2-O-C-NH-CH- (pH2'CgH5 30 * Ce> aW

0,83 g L-phenylalanin (5 mmol) opløses i en blanding af dioxan og vand (1:2) (12 ml) indeholdende 1,4 ml triethylamin (10 mmol). Blandingen afkøles til 0°C, og man tilsætter 1,8 g (5,5 mmol) af ovennævnte carbonat opløst i 4 ml dioxan på en gang. Efter 2 timers forløb ved 0°C tilsættes 20 ml vand, og blandingen ekstraheres 2 gange med 20 ml ether. Den vandige fase 35 syrnes derpå (pH 2-3) med 6 N HCI og ekstraheres med 3 gange 50 ml ethylacetat. Ekstrakten tørres over MgS04 og inddampes. Der fås 1,4 g (100% udbytte) af den forventede forbindelse i form afen olie.Dissolve 0.83 g of L-phenylalanine (5 mmol) in a mixture of dioxane and water (1: 2) (12 ml) containing 1.4 ml of triethylamine (10 mmol). The mixture is cooled to 0 ° C and 1.8 g (5.5 mmol) of the above carbonate dissolved in 4 ml of dioxane are added at once. After 2 hours at 0 ° C, 20 ml of water are added and the mixture is extracted twice with 20 ml of ether. The aqueous phase 35 is then acidified (pH 2-3) with 6 N HCl and extracted with 3 times 50 ml of ethyl acetate. The extract is dried over MgSO 4 and evaporated. 1.4 g (100% yield) of the expected compound in the form of an oil are obtained.

26 DK 174186 B1 1HNMR{CDCI3,TMS): 0(s,CH3-Si) 0,9 (t, CH^Si) 3.0 (CH2Ph) 4.0 (t,0-CH2-C-Si) 4,5 (m. C^H-N) 5,2 (s,NH) 7,2 (s.Ph) CO*.261 174186 B1 1 HNMR {CDCl3, TMS): 0 (s, CH3-Si) 0.9 (t, CH2 Si) 3.0 (CH2Ph) 4.0 (t, O-CH2-C-Si) 4.5 (m C (HN) 5.2 (s, NH) 7.2 (s.Ph) CO *.

5 8,7 (C-OH)8.7 (C-OH)

Man sætter 2 ml dicyclohexylamin til denne olie opløst i 5 ml ether, og efter krystallisation får man 1,93 g (78% udbytte)dicyclohexylammoniumsalt, smp. 111-112eC.2 ml of dicyclohexylamine are added to this oil dissolved in 5 ml of ether and after crystallization, 1.93 g (78% yield) of dicyclohexylammonium salt, m.p. 111-112eC.

Claims (4)

1. Fremgangsmåde til fremstilling af carbaminsyrederivater med formlen R1 5 \ N-C- y 2' fl R o hvor R"* og R2, som er ens eller forskellige, betegner: - et hydrogenatom, 10. en alifatisk gruppe med 1 *20 carbonatomer, - en cykloalifatisk eller aralifatisk gruppe med indtil 50 carbonatomer, eller R1 og R2 danner sammen med det nitrogenatom, hvortil de er bundet, en piperidino-, mor-pholino- eller imidazolylring, idet den alifatiske, cykloalifatiske og aralifatiske gruppe og ringen er usubstituteret eller substitueret med syre-, alkohol-, ester-, ether-, mercapto- eller aminogrup-15 per, og Y betegner-OR, -SR, -N-R3 eller 0-N=C-Rg I I R4 R7 hvor 20 (i) R betegner en alifatisk gruppe med 1-12 carbonatomer, hvilken gruppe er usubstitueret eller substitueret med halogenatomer eller med en furyl- eller trimethylsilylgruppe, en benzyl- eller nltrobenzylgruppe, en phenyl-, benzofuranyl- eller fluorenyimethylgruppe, idet benzofuranylgruppen er usubstitueret eller substitueret med lavmolekylært alkyl, 25 (ii) R3 og R^, som er ens eller forskellige, betegner et hydrogenatom eller methyl eller danner sammen med det nitrogenatom, hvortil de er bundet, en imidazolylring, og (iii) Rg og R7, som er ens eller forskellige, betegner en alifatisk gruppe med 1-12 carbonatomer eller en cykloalifatisk gruppe med Indtil 30 carbonatomer, som er usubstitueret eller substitueret med en lavmolekylær alkylthiogruppe, eller betegner hydrogen, en methylthio-30 gruppe eller en lavmolekylær alkyloxygruppe, kendetegnet ved, at en aminoforbindelse med formlen NH-R1 R2 35. nærværelse af et stof, som kan binde hydrogenhalogenidsyre, ved en temperatur mellem -5°C og 150°C omsættes med et α-halogeneret derivat af kulsyre med formlen R5'CH-0-C-Y I II X o DK 174186 B1 hvor R1, r2 og Y har samme betydning som ovenfor, X betegner fluor, chlor eller brom. og R® betegner en alifatisk gruppe med 1-4 carbonatomer, som er usubstitueret eller substitueret med halogenatomer.A process for the preparation of carbamic acid derivatives of formula R1 5 NC-y 2 'fl R o wherein R 2 and R 2, which are the same or different, represent: - a hydrogen atom, 10. an aliphatic group having 1 * 20 carbon atoms, a cycloaliphatic or araliphatic group having up to 50 carbon atoms, or R 1 and R 2 together with the nitrogen atom to which they are attached form a piperidino, morpholino or imidazolyl ring, the aliphatic, cycloaliphatic and araliphatic group and the ring being unsubstituted or substituted by acid, alcohol, ester, ether, mercapto or amino groups, and Y represents -OR, -SR, -N-R3 or 0-N = C-Rg II R4 R7 where 20 (i R represents an aliphatic group of 1-12 carbon atoms, which group is unsubstituted or substituted by halogen atoms or with a furyl or trimethylsilyl group, a benzyl or nitrobenzyl group, a phenyl, benzofuranyl or fluorenylmethyl substituent or the benzofuranyl group or (ii) R 3 and R 2, which are the same or different, represent a hydrogen atom or methyl or together with the nitrogen atom to which they are attached form an imidazolyl ring, and (iii) R 9 and R 7 which are the same or various, an aliphatic group having 1-12 carbon atoms or a cycloaliphatic group having up to 30 carbon atoms which is unsubstituted or substituted by a low molecular alkylthio group, or represents hydrogen, a methylthio group or a low molecular weight alkyloxy group, characterized in that the presence of a substance which can bind hydrogen halide acid at a temperature between -5 ° C and 150 ° C is reacted with an α-halogenated derivative of carbonic acid of formula R5'CH-0-CY I II X 1 DK 174186 B1 wherein R1, r2 and Y have the same meaning as above, X represents fluorine, chlorine or bromine. and R 2 represents an aliphatic group of 1-4 carbon atoms which is unsubstituted or substituted by halogen atoms. 2. Fremgangsmåde ifølge krav 1, kendetegnet ved, at X betegner et chloratom.Process according to claim 1, characterized in that X is a chlorine atom. 3. Fremgangsmåde ifølge krav 1, kendetegnet ved, at det α-halogenerede derivat er a-chlorethylethylcarbonat, a-chlorethyl-tert.-butytcarbonat, a-chlorethylfurfurylcarbonat, a-chlor-ethylbenzylcarbonat, α-chlorethylphenylcarbonat eller a-chlorethyl-2,3-dihydro-2,2-dimethyl-7-10 benzofuranylcarbonat, 1,2,2.2-tetrachlorethyl-tert.-butylcarbonat, a-chlorethyl-S-ethylthiocarbo-nat, α-chlorethoxyimidazol, 1,2,2,2-tetrachlorethyl-N-methylcarbamat, 1,2,2,2-tetrachlorethyl-2-trimethylsilylethylcarbonat eller 2-methyl-2-(methylthio)-propanal-0-(a-chlorethyloxycarbonyl)-oxim.Process according to claim 1, characterized in that the α-halogenated derivative is α-chloroethyl ethyl carbonate, α-chloroethyl tert-butyl carbonate, α-chloroethylfurfuryl carbonate, α-chloroethylbenzyl carbonate, α-chloroethyl phenylcarbonate or α-chloroethyl 2, 3-dihydro-2,2-dimethyl-7-benzofuranyl carbonate, 1,2,2,2-tetrachlorethyl-tert.-butyl carbonate, α-chloroethyl-5-ethylthiocarbonate, α-chloroethoxyimidazole, 1,2,2,2- tetrachlorethyl-N-methylcarbamate, 1,2,2,2-tetrachlorethyl-2-trimethylsilylethylcarbonate or 2-methyl-2- (methylthio) propanal-O- (α-chloroethyloxycarbonyl) oxime. 4. Fremgangsmåde ifølge krav 1, kendetegnet ved, at aminet er methylamin, diethyl- amin, di-n-butylamin, isobutylamin, n-octylamin, ethanolamin, benzylamin, imidazol, hexamethy-lenimin, morpholin, diethanolamin, N-methyl-N-benzylamin, piperidin, L-phenylalanin, L-prolin, glycin, L-tyrosin, L-serin, L-asparaginsyre, ethylglycinat, phenylglycin eller prolin. 20Process according to claim 1, characterized in that the amine is methylamine, diethylamine, di-n-butylamine, isobutylamine, n-octylamine, ethanolamine, benzylamine, imidazole, hexamethyleneimine, morpholine, diethanolamine, N-methyl-N -benzylamine, piperidine, L-phenylalanine, L-proline, glycine, L-tyrosine, L-serine, L-aspartic acid, ethyl glycinate, phenylglycine or proline. 20
DK198500701A 1984-02-16 1985-02-15 Process for the preparation of carbamic acid derivatives DK174186B1 (en)

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FR8402327 1984-02-16
FR8402326A FR2559767B1 (en) 1984-02-16 1984-02-16 PROCESS FOR THE MANUFACTURE OF AMINO ACID WITH PROTECTED AMINE FUNCTION
FR8402326 1984-02-16
FR8402327A FR2559766B1 (en) 1984-02-16 1984-02-16 PROCESS FOR THE PREPARATION OF CARBAMIC ACID DERIVATIVES

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US4599198A (en) * 1985-08-02 1986-07-08 Pfizer Inc. Intermediates in polypeptide synthesis
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MXPA05006938A (en) 2002-12-26 2005-10-26 Ihara Chemical Ind Co Process for producing benzylamine derivative.
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