EP1165511A2

EP1165511A2 - Method of producing heterocyclic carbamates from aza-heterocyclic compounds and carbon dioxide

Info

Publication number: EP1165511A2
Application number: EP00910713A
Authority: EP
Inventors: Hubert Barth; Hans-Jürgen BETCHE; Klaus Steiner; Simon Schneider; Ulrich Bayer; Manfred Westermayer; Ulrike Wolfsperger
Original assignee: Goedecke GmbH
Current assignee: Goedecke GmbH
Priority date: 1999-03-25
Filing date: 2000-02-25
Publication date: 2002-01-02
Also published as: US6566533B1; MXPA01009595A; WO2000058286A2; AU3282500A; DE19913483A1; BR0009195A; JP2002540192A; WO2000058286A3; CA2361019A1

Abstract

The invention relates to a method of producing heterocyclic carbamates of the general formula (I) by reacting aza-heterocyclic compounds with alkyl- or aryl-halides in the presence of carbon dioxide and alkali carbonate, and to new compounds of the general formula (I).

Description

Process for the preparation of heterocyclic carbamates from aza heterocycles and carbon dioxide

description

The present invention relates to a process for the preparation of compounds of the general formula I.

in the HETN denotes an aromatic aza heterocycle with a total of 5 or 6 ring atoms, where up to 3 ring atoms are nitrogen atoms, where up to two further aromatic carbon rings can be fused to the heterocycle and R is a straight-chain or branched alkyl group with 1 to 10 C atoms , an unsubstituted or substituted with up to three Cι_ ₄ alkyl groups, C ^ alkoxy groups, halogen atoms, with a cyano group, a nitro group, a trifluoromethyl group or an alkoxycarbonyl group with up to 4 C atoms, an aralkyl group or an alkenyl group. The term aralkyl group encompasses a lower alkyl radical having 2 to 10 carbon atoms, in which up to two H atoms are replaced by phenyl groups, which in turn may have a C ₄ alkyl group, a ₄ alkoxy group, a cyano group, a nitro group, a trifluoromethyl group , one Alkoxycarbonylgruppe can be substituted with up to 4 carbon atoms or with up to three halogen atoms. The term alkenyl denotes an unsaturated hydrocarbon radical with up to 5 carbon atoms.

Carbamates play an important role in many areas of chemistry, for example in the synthesis of pharmaceuticals (BJ Ludwig, LS Powell, FM Berger, J. Med. Chem. 12, 462, 1969) or plant protection products (E. Bocker,. Draber in : R. Wegler, Chemistry of Plant Protection and Pest Control, Vol. 1, p. 220, Springer, Berlin, Heidelberg, New York 1970; Ullmann's Encyclopedia of Industrial Che istry, 5 ^th . Ed., Vol. A5, p. 51 , VCH

Verlagsgesellschaft mbH, 1986]

Since some carbamic acid esters can be cleaved again by special reagents, depending on the ester residue, their synthesis is also an important process in protective group chemistry for the reversible blocking of amine functions, in particular in heterocycle chemistry and in peptide chemistry (PJ Kocienski, Protecting Groups, THIEME Verlag Stuttgart, 1994; Theodora W. Greene, PG.Wuts, Protective Groups in Organic Synthesis, John Wiley & Sons, New York, 1991).

Open-chain carbamic acid esters can be prepared by many processes (U. Petersen in: HOUBEN-WEYL, Methods of Organic Chemistry, Volume E4, Carbonic Acid Derivatives, p. 149ff, Georg Thieme Verlag, Stuttgart, New York 1983). A commonly used method in protecting aza heterocycles is by using a aromatic NH group of the aza heterocycle To convert chloroformate in the presence of a base into a carbamate ester of the general formula I (Scheme 1):

Scheme 1

Thus, in the production of indole-N-carboxylic acid from indole and carbon dioxide (DL Boger, J.Org.Chem. 52, 3934, 1987) or of indole-N-carbamates from indole and chloroformic acid esters (AC Weedon, B. Zhang, Synthesis 1992, 95; E. Reimann, T. Hassler, H. Lotter, Arch. Pharm. 323, 255, 1990), as base, frequently used hydrolysis-sensitive butyllithium, dissolved in an inert solvent, or else very special processes such as e.g. phase transfer catalyzed reactions application

(A.C. Weedon, B. Zhang, Synthesis 1992, 95; E. Reimann, T. Haßler, H. Lotter, Arch. Pharm. 323, 255, 1990).

Inspired by a work by Ken J. Butcher on the production of carbamate esters from amines and carbon dioxide (Ken J. Butcher, Synlett 1994, 825), we investigated whether aza heterocycles of the general formula II using carbon dioxide, alkali carbonate, in particular Cesium carbonate, and alkyl or aryl halides of the general formula III

HETN-H R-HAL where HETN and R have the meaning given above and HAL represents chlorine, bromine or iodine, can be converted into heterocyclic carbamate esters of the general formula I (Scheme 2):

Scheme 2

DMF, 23 ° C

Since the above-mentioned aza heterocycles of the general formula II are not to be counted as classic amines due to their physical and chemical properties and are generally more acidic in comparison to the amines used by Ken J. Butcher, e.g. Piperidine, benzylamine, N-methylbenzylamine and aniline, it was not to be expected that when the reaction according to Scheme 2 was carried out using aza heterocycles of the general formula II, heterocyclic carbamate esters of the general formula I would be formed. If the reaction is carried out as described by Ken J. Butcher using indole, cesium carbonate and benzyl bromide, only traces of the desired product, N-benzyloxycarbonylindole, are found.

Surprisingly, however, it was found that carbamate esters of the general formula I can nevertheless be prepared under very mild and preparative, very simple conditions if the amounts of alkali metal carbonate used, in particular cesium carbonate (2 to 4 equivalents based on the aza heterocycle) and the Amounts of alkyl or aryl halide (1.2 to 2 equivalents based on the aza heterocycle) increased and above all the reaction time extended from 24 hours to 48 to 72 hours.

The preparative procedure is very simple and happens as follows:

The aza heterocycle and a 2 to 4-fold molar excess of alkali carbonate, especially cesium carbonate, are in a suitable dipolar aprotic solvent such as e.g. Dimethylformamide, acetonitrile, dimethylacetamide or N-methylpyrrolidone at room temperature. With good stirring, it is now at room temperature with exclusion of moisture for 4 to 6 hours

Carbon dioxide gas is introduced into the reaction mixture. The carbon dioxide gas stream is generated here by evaporating dry ice at room temperature, which is located in an Erlenmeyer flask which is connected to the reaction vessel via a gas inlet tube. Now add the relevant alkyl or Aryl halide of the general formula III, dissolved in a little solvent, to the reaction mixture, passes on carbon dioxide for 1 to 2 hours, adds another 10% to 100%, preferably 30%, of the original alkyl or. Add the amount of aryl halide and then close the reaction vessel. With the reaction vessel closed, stirring is continued for 24 hours to 4 days, preferably 3 days, at room temperature. Then the reaction mixture is poured onto water, the product is extracted with ethyl acetate and the crude product obtained after removal of the extractant is purified with that in the preparative organic chemistry usual methods, for example by chromatography on silica gel or crystallization. The preferred solvent for the reaction described is dimethylformamide. The preferred alkali carbonate is cesium carbonate.

The reaction conditions are very mild, there are many functional groups, e.g. tolerates the double bond, the nitro group, the alkoxycarbonyl group, the cyano group, halogen groups and alkoxy groups on aromatics. The starting materials, aza heterocycles, and alkyl and aryl halides are available in large numbers. The conditions for working up the reaction are very simple.

Assuming that cesium carbonate can be recovered from the extracted, aqueous residue, the method is suitable for binding gaseous carbon dioxide to simple commercially available starting materials such as aza heterocycles, in particular indoles, and alkyl / aryl halides and thereby producing valuable, high-energy intermediates.

In this sense, the process mentioned is a valuable contribution to environmentally friendly chemistry.

Because of the simple practical feasibility of the reaction, the procedure is also excellently suitable for a 'high throuhput synthesis' of hetrocyclic carba aten, since by a suitable combination of aza heterocycles and alkyl or aryl halides in one A large number of the synthesis reactions can be carried out in parallel with carbon dioxide gassing apparatus.

Many of the compounds synthesized according to the described process are new, and they have not yet been tested for suitability for use in the field of pharmaceutical chemistry and crop protection chemistry.

The invention is illustrated and explained by the following exemplary embodiments.

example 1

N-benzyloxycarbonylindole from indole and benzyl bromide

Carbon dioxide gas is passed into a suspension of 0.48 g indole and 3.2 g cesium carbonate in 30 mL dry dimethylformamide, which is located in a 50 mL three-necked flask, with good stirring at room temperature. The carbon dioxide gas flow is through

Allowing solid carbon dioxide (dry ice) to evaporate, which is located in a 500 mL Erlenmeyer flask, is connected to the reaction apparatus via a gas inlet tube. 0.7 g of benzyl bromide, dissolved in a little DMF, is added, carbon dioxide gas is passed in for 1.25 hours, another 0.2 g of benzyl bromide is added, and the reaction vessel is then sealed airtight. The reaction mixture is then stirred for a further 2 days at room temperature. Then pour the reaction mixture onto 50 mL water (caution: exothermic reaction) and extract the product 3 times with 50 mL ethyl acetate each time. The combined organic phases are concentrated on a Rotavapor. That in the oily Residual dimethylformamide together with the product is removed on a Rotavapor by azeotropic distillation using toluene at 40 mbar / 50 ° C. The residue is chromatographed on 130 g silica gel (0.040-0.063 mm) with toluene as the eluent. 1.1 g of product (99%), mp. 42 ° C

The following examples were carried out in analogy to Example 1. The reaction time in hours / the eluent for chromatography / the yield and / physical properties are given

Example 2

N-tert. -Butoxycarbonylindol from indole and tert. -Butyl bromide (2 mol bromide) 64 / toluene / 6.7% / oil

Example 3

N-ethoxycarbonylindole from indole and ethyl bromide (2 mol bromide) 14 / toluene / 71% / oil

Example 4

N-Benzyloxycarbonylindol from indole and benzyl bromide using potassium carbonate as base 64 / toluene / 64% / mp 42 ° C.

Example 5 5-benzyloxy-N-benzyloxycarbonylindole from 5-hydroxyindole and benzyl bromide (3 mol bromide) 24 / Crystallization when concentrating the ethyl acetate extract / 82.9% / mp 144 ° C

Example 6 5-Hydroxy-N-benzyloxycarbonylindole from 5-hydroxyindole and benzyl bromide (2 mol bromide) 48 / toluene-ethanol 10 + 2/33% / mp 107 ° - 109 ° C

Example 7 N-allyloxycarbonylindole from indole and allyl bromide (2 mol bromide) 24 / hexane-ethyl acetate 10 + 2/98% / oil

Example 8 5-chloro-N-benzyloxycarbonylindole from 5-chloroindole and benzyl bromide (2 mol bromide)

64 / crystallization when concentrating the ethyl acetate extract /

96% / mp 68 ° C

Example 9

5-Benzyloxy-N-benzyloxycarbonylindol from 5-benzyloxyindole and benzyl bromide 64 / crystallization of the product when concentrating the ethyl acetate extract / 75% / mp 144 ° C.

The same approach using potassium carbonate: 64 / crystallization / 75.6% / mp 144 ° C

Example 10 5-Methyl-N-benzyloxycarbonylindole from 5-methylindole and benzyl bromide 64 / toluene / 98% / mp 63 ° -64 ° C. Example 11

5-fluoro-N-benzyloxycarbonylindol from 5-fluoroindole and benzyl bromide 64 / hexane-ethyl acetate 10 + 2/98% / mp 50 ° C

Example 12

5-methoxy-N-benzyloxycarbonylindole from 5-methoxyindole and benzyl bromide 64 / toluene / 97% / mp 65 ° C

Example 13

5-bromo-N-benzyloxycarbonylindol from 5-bromoindole and benzyl bromide 64 / hexane-ethyl acetate 10 + 2/98% / mp 69 ° C

Example 14

5, 6-Dimethoxy-N-benzyloxycarbonylindol from 5, 6-dimethoxyindole and benzyl bromide 64 / hexane-ethyl acetate 1 + 1/98% / mp 110 ° C.

Example 15

5-Nitro-N-benzyloxycarbonylindol from 5-nitroindole and benzyl bromide 30 / hexane-ethyl acetate 1 + 1/74% / mp 120 ° C

Example 16

5, 6-methylenedioxy-N-benzyloxycarbonylindole from 5, 6-methylenedioxyindole and benzyl bromide 30 / toluene / 96% / mp 116 ° -117 ° C.

Example 17 N-propyloxycarbonylindole from indole and n-propyl bromide (2 mol bromide)

64 / hexane-ethyl acetate 10 + 2/90% / oil

Example 18

N-4-methoxybenzyloxycarbonylindole from indole and 4-methoxybenzyl chloride

64 / hexane-ethyl acetate 10 + 2/95% / mp 80 ° C

Example 19

N-2, 4-dichlorobenzyloxycarbonylindole from indole and 2, 4-dichlorobenzyl chloride

64 / hexane-ethyl acetate 10 + 2/91% / mp 96 ° C

Example 20

N-2-phenylethyloxycarbonylindole from indole and 2-phenylethylbromide

64 / hexane-ethyl acetate 10 + 2/46% / oil

Example 21

N-4-methylbenzyloxycarbonylindole from indole and 4-methylbenzyl chloride 64 / hexane-ethyl acetate 10 + 2 / 73.5% / mp 73-76 ° C. Example 22 N-4-chlorobenzyloxycarbonylindole from indole and 4-chlorobenzyl chloride

64 / hexane-ethyl acetate 10 + 2 / mp 77 ° C

Example 23 N-isopropyloxycarbonylindole from indole and isopropyl bromide (2 mol bromide) 64 / hexane-ethyl acetate 10 + 2/36% / oil Example 24

N-benzyloxycarbonylindole from indole and benzyl bromide in acetonitrile 64 / toluene / 97% / 43 ° C

Example 25

7-Methyl -N-benzyloxycarbonylindol from 7-methylindole and benzyl bromide 64 / toluene / 64.3% / mp 20 ° C

Example 26

2-Methyl -N-benzyloxycarbonylindol from 2-methylindole and benzyl bromide 24 / toluene / 92% / mp 54 ° C

Example 27

N-methoxycarbonylindole from indole and methyl iodide (2 mol iodide) 64 / hexane-ethyl acetate 10 + 2 / 91.8% / oil

Example 28

5-Cyan-N-benzyloxycarbonylindole from 5-cyanindole and benzyl bromide 64 / toluene / 79.4% / oil

Example 29

3-Ethoxycarbonylmethyl -N-benzyloxycarbonylindol from 3 -ethoxycarbonylmethylindole and benzyl bromide 64 / toluene -ethanol 10 + 0.5 / 93.2% / oil

Example 30 3-methoxycarbonyl -N-benzyloxycarbonylindole from methyl indole-3-carboxylate and benzyl bromide 64 / hexane-ethyl acetate 1 + 1 / 37.8% / mp 88 ° C (65% 3-methoxycarbonyl-N-benzylindole)

Example 31

3-cyanomethyl-N-benzyloxycarbonylindole from 3-cyanomethyl indole and benzyl bromide

64 / toluene-ethanol 10 + 0.5 / 88.2 / mp 95 ° C

Example 32

3- (2-Benzyloxyethyl) -N-benzyloxycarbonylindole from 3- (2-hydroxyethyl) indole and benzyl bromide (2.5 mol bromide) 64 / hexane-ethyl acetate 10 + 2 / 96.5% / oil

Example 33

N-2-nitrobenzyloxycarbonylindole from indole and 2-nitrobenzyl bromide 64 / toluene / 87.2% / mp 106 ° C

Example 34

3-Ethoxycarbonylvinyl -N-benzyloxycarbonylindol from ethyl indole-3-acrylic acid and benzyl bromide 64 / hexane-ethyl acetate 10 + 2 / 34.9% / mp 96 ° C

Example 35

5-methoxycarbonyl -N-benzyloxycarbonyl indole from indole - 5-carboxylic acid methyl ester and benzyl bromide 64 / toluene / 100% / mp 88 ° C.

Example 36 (±) -N-1-phenylethyloxycarbonylindole from indole and (±) -1-phenylethylbromide 64 / toluene / 91.9% / oil

Example 37

N-benzyloxycarbonylimidazole from imidazole and benzyl bromide

60 / toluene / ethanol 10 + 2 / 8.4% / oil

Example 38

N-benzyloxycarbonylindazole from indazole and benzyl bromide

64 / hexane-ethyl acetate 10 + 2 / 74.4% / mp 84 ° C

Example 39

N-benzyloxycarbonylbenzimidazole from benzimidazole and benzyl bromide

64 / hexane-ethyl acetate 1 + 1 / 24.1% / mp 71 ° -72 ° C

Example 40

4-phenyl-N-benzyloxycarbonylimidazole from 4-phenylimidazole and benzyl bromide

64 / toluene-ethanol 10 + 2 / 21.9% / mp 28 ° C

Example 41

N-Benzyloxycarbonylpyrrole from pyrrole and benzyl bromide 64 / toluene / 96% / mp 28 ° C.

Example 42

N-benzyloxycarbonylcarbazole from carbazole and benzyl bromide / Crystallization after concentration of the ethyl acetate extract /% / mp 74 ° C

Claims

claims

1. Process for the preparation of heterocyclic carbamates of the general formula I

in the HETN denotes an aromatic aza heterocycle with a total of 5 or 6 ring atoms, where up to 3 ring atoms are nitrogen atoms, where up to two further aromatic carbon rings can be fused to the heterocycle and R is a straight-chain or branched alkyl group with 1 to 10 C atoms , an unsubstituted or substituted with up to three Cι- ₄ alkyl groups, Cι_ ₄ alkoxy groups, halogen atoms, with a cyano group, a nitro group, a trifluoromethyl group or an alkoxycarbonyl group with up to 4 carbon atoms, an aralkyl group or an alkenyl group that aza heterocycles of the general formula II using carbon dioxide, alkali carbonate and alkyl or aryl halides of the general formula III

HETN-H R-HAL

where HETN and R have the meaning given above and HAL represents chlorine, bromine or iodine, in heterocyclic carbamate esters of the general formula I transferred.

2. The method according to claim 1, characterized in that the solvent dimethylformamide, acetonitrile,

Is dimethylacetamide or N-methylpyrrolidone.

3. The method according to claim 1, characterized in that the carbon dioxide is introduced in gaseous form into the reaction mixture.

4. The method according to claim 1, characterized in that the aza heterocycle is introduced with a 2 to 4-fold excess of cesium carbonate in a dipolar aprotic solvent, for several hours

Carbon dioxide gas is introduced, then the halide (III) (1.2 equivalents) is added, the introduction of carbon dioxide is continued for some time, another 0.2 to 1 equivalent of halide (III) is added and then the reaction mixture with the flask closed for 1 to 4 days is stirred at room temperature.

5. Heterocyclic carbamates of the general formula I

namely

5-benzyloxy-N-benzyloxycarbonylindol, 5-hydroxy-N-benzyloxycarbonylindol, 5-chloro-N-benzyloxycarbonylindol, 5-benzyloxy-N-benzyloxycarbonylindol,

5-methyl-N-benzyloxycarbonylindol,

5-fluoro-N-benzyloxycarbonylindol,

5-methoxy-N-benzyloxycarbonylindol, 5-bromo-N-benzyloxycarbonylindol,

5, 6-dimethoxy-N-benzyloxycarbonylindol,

5-nitro-N-benzyloxycarbonylindol,

5, 6-methylenedioxy-N-benzyloxycarbonylindol,

N-propyloxycarbonylindol, N-4-methoxybenzyloxycarbonylindol,

N-2,4-dichlorobenzyloxycarbonylindol,

N-2-phenylethyloxycarbonylindol,

N-4-methylbenzyloxycarbonylindol,

N-4-chlorobenzyloxycarbonylindol, N-isopropyloxycarbonylindol,

N-benzyloxycarbonylindol,

7-methyl-N-benzyloxycarbonylindol,

2-methyl-N-benzyloxycarbonylindol,

5-cyan-N-benzyloxycarbonylindol, 3-ethoxycarbonylmethyl-N-benzyloxycarbonylindol,

3-cyanomethyl-N-benzyloxycarbonylindol,

3- (2-benzyloxyethyl) -N-benzyloxycarbonylindole,

N-2-nitrobenzyloxycarbonylindol,

3-ethoxycarbonylvinyl-N-benzyloxycarbonylindol, 5-methoxycarbonyl-N-benzyloxycarbonylindol, (±) -N-1-phenylethyloxycarbonylindol,

4-phenyl-N-benzyloxycarbonylimidazole and

N-benzyloxycarbonylcarbazole.