WO1994013627A1

WO1994013627A1 - Method of preparing iodoalkinyl carbamates

Info

Publication number: WO1994013627A1
Application number: PCT/EP1993/003442
Authority: WO
Inventors: Wolfgang Ritter; Harald Kluschanzoff; Gerhard Schachtlbauer
Original assignee: Henkel Kommanditgesellschaft Auf Aktien
Priority date: 1992-12-16
Filing date: 1993-12-07
Publication date: 1994-06-23
Also published as: DE4242483A1; CN1094032A; TW237443B

Abstract

The invention concerns iodoalkinyl carbamates of general formula (I) I-C = C-C(R1R2)-O-[C(R?3R4)-C(R5R6)-O]¿n-CONHR7, in which R?1 and R2¿, independently of each other, are hydrogen or straight-chain or branched-chain alkyl groups with 1 to 6 C-atoms; R3 to R6, independently of each other, are hydrogen or straight-chain or branched-chain alkyl groups with 1 to 4 C-atoms; R7 is hydrogen, a straight-chain or branched-chain alkyl group with 1 to 12 C-atoms, a cyclohexyl group, a substituted or unsubstituted phenyl group, a benzyl group or a p-toluenesulphonyl group and n is 0 or 1. Such carbamates are obtained in high yields and in pale-colour quality, without the need for additional purification procedures, by reacting the appropriate alkinyl alcohol with the appropriate isocyanate to give a carbamate. The carbamate produced is subsequently iodinated, the alkaline reaction mixture neutralized with carbon dioxide and the iodoalkinyl carbamate filtered off.

Description

"Process for the preparation of iodoalkynyl carbamates"

Field of the Invention

The invention relates to an improved process for the preparation of iodine alkynyl carbamates.

State of the art

Iodine alkynyl carbamates have long been known as antimicrobial agents. For example, EP-PS-93 962 describes substituted 2- (3-iodo-2-propynyloxy) ethanol carbamates and a process for their preparation in which equimolar amounts of iodoalkynyl alcohols are reacted with isocyanates. Since the use of iodoalkynyl alcohols is problematic because of their explosive properties, alternative methods have been proposed in which this intermediate is avoided.

For example, EP-PS-14 032 describes a process for the preparation of iodoalkynylcarbamates, in which an alkynyl alcohol is first reacted with an isocyanate to give the corresponding carbamate and this carbamate is then iodinated in aqueous alkaline solution to give the corresponding iodoalkynyl carbamate. However, this process has the disadvantage that additional cleaning measures such as extraction with water-insoluble organic solvents such as toluene are required. Such additional cleaning measures are on the one hand complex, on the other hand further measures are required to free the iodoalkynyl carbamate from the organic solvent.

The object was therefore to develop an improved process for the preparation of iodoalkynylcarbamates which avoids the disadvantages of the known prior art and in which, in particular, light-colored products are obtained without complex cleaning operations such as extraction with organic solvents being carried out have to.

Description of the invention

This object was achieved according to the invention by a process for the preparation of iodoalkynyl carbamates of the general formula (I)

IO ^ -CtRiR- ^ JO-LCCRSR ^ J-CCRδR ^β j-oj ^ CO HR ^ (I)

wherein the radicals Rl and R2 independently of one another are hydrogen or linear or branched alkyl radicals having 1 to 6 C atoms, the radicals R ^* * - ^* to R6 independently of one another are hydrogen or linear or branched alkyl radicals with 1 to 4 C atoms, the radical R ? Hydrogen, a linear or branched alkyl radical

1 to 12 carbon atoms, a cyclohexyl radical, a substituted or unsubstituted phenyl radical, a benzyl radical or a p-toluenesulfonyl radical and n denote the number 0 or 1, with the corresponding alkynyl alcohol being first reacted with the corresponding isocyanate to give the carbamate, this carbamate in alkaline solution iodized, the alkaline reaction mixture neutralized with carbon dioxide and the iodoalkynyl carbonate then filtered off.

The present invention thus relates to a process for the preparation of iodoalkynyl carbamates of the general formula (I)

IC≡CC (R ¹ R ² ) -0- [C (R3R4) -C (R5R6) _o] _n -CONHR ⁷ (I)

wherein the radicals R ** - and R- independently of one another are hydrogen or linear or branched alkyl radicals having 1 to 6 C atoms, the radicals R3 to R ^ independently of one another are hydrogen or linear or branched alkyl radicals with 1 to 4 C atoms, the rest R7 is hydrogen, a linear or branched alkyl radical

1 to 12 carbon atoms, a cyclohexyl radical, a substituted or unsubstituted phenyl radical, a benzyl radical or a p-toluenesulfonyl radical and n represent the number 0 or 1, with firstly an alkynyl alcohol of the general formula

(II)

HC≡CC (RlR2) -0- [C (R3R4) -C (R5R6). ₀ ] _n -H (II)

in which the radicals Rl to R- have the abovementioned meaning, with an isocyanate of the formula (III)

R? NC0 (III)

wherein R- ^{7 has} the meaning given above, to a carbamate of the general formula (IV) HC≡CC (RlR) -0- [C (R ³ R) -C (R5R ⁶ ) -0] _n -C0NHR7 (IV)

in which the radicals R * to R? have the abovementioned meaning, the carbamate (IV) is iodized in alkaline solution, the alkaline reaction mixture is neutralized and the iodoalkynyl carbamate (I) is then filtered off, and the neutralization is carried out using carbon dioxide.

The process according to the invention has the advantage that light-colored iodalkynylcarbamates are obtained directly without additional cleaning operations having to be carried out.

In a preferred embodiment, the process according to the invention relates to the production of iodoalkynyloxyalkylcarbamates, ie. H. to compounds of the general formula (I) in which n denotes the number 1.

The alkynyl alcohols of the general formula (II) are known compounds. For example, prop-2-yn-1-ol (propargyl alcohol) is mentioned in "Beil¬stein's Handbuch der Organischen Chemie" (see, inter alia, 4th supplementary work, first volume, fourth part, pages 2214-2215; Berlin 1974). By adding ethylene oxide (EO) to propinols, corresponding propinol-EO adducts are accessible. T. are commercially available. From the homolog mixtures of these EO adducts, the individual indivi dues can be obtained by enrichment processes, e.g. B. fractional distillation, in pure form.

Examples of suitable isocyanates of the general formula (III) are: a) alkyl isocyanates, e.g. B. dodecyl, octyl, hexyl isocyanates and especially lower alkyl isocyanates such as butyl, propyl, ethyl and methyl isocyanate and a wide variety of structural isomers thereof; b) cycloalkyl isocyanates, e.g. B. cyclohexyl isocyanate; c) onocyclic aryl isocyanates such as phenyl, 4-chlorophenyl and 3,4-dichlorophenyl, benzyl and p-toluenesulfonyl isocyanate

The first stage of the process according to the invention, the reaction of the alkynyl alcohol (II) with an isocyanate (III), is carried out by means of methods which are well known to those skilled in urethane chemistry. For example, the isocyanate can be added to the alkynyl alcohol in a controlled manner in such a way that the reaction temperature can easily be kept constant; if required, external cooling can be used. The reaction can be carried out in the absence of a solvent; however, it is also possible to use a solvent which is inert to isocyanates. Examples of suitable solvents are esters such as ethyl acetate, butyl acetate and 2-ethoxyethyl acetate, ketones such as methyl ethyl ketone, methyl isobutyl ketone and cyclohexanone, hydrocarbons such as toluene or xylene, halogenated hydrocarbons such as trichlorethylene, methylene chloride, 1,1,1-trichloroethane and tetrachloroethane and polar aprotic solvents such as dimethylformamide and dimethylacetamide.

It may also be desirable to use a catalyst that accelerates the reaction of isocyanates and alcohols. Examples of such catalysts are organic or inorganic bases and soluble metal compounds, eg. B. iron and manganese acetylacetonate, dibutyltin dilaurate and zinc octanoate, lead tetraacetate, basic lead acetate and lead 2-ethylhexanoate.

The second stage of the process according to the invention, the iodination of the carbamate (IV), is carried out in an alkaline medium. The choice of the iodination agent used is not subject to any particular restrictions. For example, elemental iodine in the form of powder or pellets can be used, but it is also possible, among other things, to use a mixture of sodium hypochlorite and an alkali metal iodide or a mixture of use of sodium hypochlorite, an alkali metal hydroxide and iodine. The iodinating agent is usually used in approximately equimolar amounts, based on the carbamate (IV); it may be desirable to use the iodination agent in a slight deficit or a slight excess.

The second stage of the process according to the invention is generally carried out in the presence of an organic solvent; polar, water-miscible solvents are preferred. Alcohols such as methanol, ethanol, propanol or i-propanol are particularly advantageous. It is particularly preferred to use methanol and to work under largely or completely anhydrous conditions. If the latter mode of operation is selected, the reaction mixture is added after the iodination reaction has ended, ie. H. before the neutralization, water to (see Example 1).

However, it may also be desirable to carry out the iodination of the carbamate (IV) in an aqueous medium. In this case, it is advisable to add further auxiliaries to the reaction mixture in order to facilitate the reaction. One possibility is e.g. B. adding a surfactant to the aqueous alkaline system; the effect of this is that the carbamate (IV) is emulsified or dispersed and is therefore in a finely divided state throughout the reaction time and is more susceptible to attack by the iodinating agent.

The temperature is preferably kept below 30 ° C. during the second stage of the process according to the invention. The reaction mixture can be kept at the desired temperature by any known device that allows appropriate heat transfer and temperature control. The carbon dioxide used in the course of the inventive method for neutralization can be used in the solid or gaseous state. For example, it is possible to carry out the neutralization by adding dry ice in portions; for practical reasons, however, it is preferred to effect the neutralization by introducing CO 2 gas into the alkaline reaction mixture.

The process is usually carried out at atmospheric pressure, for example in a simple stirring vessel with a corresponding heating / cooling and stirring device. A conventional type of motor-driven agitator can be used, but it is sometimes desirable, especially when working in large vessels, to use high-speed shear agitators at a few thousand revolutions per minute in order to ensure appropriate mixing and a uniform temperature in the to maintain the entire reaction mixture.

The process according to the invention has the advantage that the intermediate carbamate (IV) does not have to be isolated. Rather, a preferred embodiment of the present invention is to carry out the entire process in the same container without isolating intermediate products.

It has also been found that it has no effect on the result of the process whether the iodinating agent used to iodine the carbamate (IV) is added to the reaction mixture in portions or in its total amount, ie. H. dosed all at once. A further preferred embodiment of the present invention therefore consists in metering the total amount of the iodinating agent used into the reaction mixture.

The following examples serve to illustrate the invention and are not to be understood as restrictive. Examples

1. General

Propinyloxyethanol was obtained by fractional distillation from "Golpanol PME" (from BASF), an adduct of ethylene oxide with propinol (propargyl alcohol).

embodiments

example 1

Propynyloxyethanol (50.05 g = 0.5 mol) and dibutyltin dilaurate (approx. 0.2 ml) were placed in a three-necked flask equipped with a stirrer, internal thermometer and dropping funnel. 59.56 g (0.5 mol) of phenyl isocyanate were added to the mixture with stirring over a period of about 2 hours. Due to the exothermic nature of the reaction and the external supply of temperature, the product was kept in the melt (approx. 80-90 ° C.) after metering in the isocyanate and stirred for a further 30 minutes.

About 250 g of methanol were added to the melt present and the reaction mixture was then cooled to 15 ° C. After 99 g (0.55 mol) of 30% sodium methylate solution had been added, the mixture was cooled again to 15 ° C. and 126.9 g (0.5 mol) of iodine (powder or pellets) were added to the alkaline dispersion. After stirring for 2 hours at 15-20 ° C (only slight water cooling required), about 230 ml of methanol were suctioned off at 25-30 ° C in a slight vacuum. After cooling to a temperature below 20 ° C, the remaining suspension was slowly mixed with 300 ml of deionized water and stirred for a further 15 minutes. The highly alkaline reaction mixture was neutralized by introducing CO 2 gas (pH = 7), the product was filtered off, washed with 300 ml of deionized water and then dried.

The yield of 2- (3-iodo-2-propynyloxy) -ethyl-N-phenylcarbamate was 160.5 g or 93% of the theoretical amount; the product had a melting point of 98-101 ° C. The color of the product was dazzling white.

Example 2

Example 1 was repeated. For the iodination, 120.55 g (0.475 mol)

Iodine (= 5% deficit) used. The yield was 92.6% of the theoretical amount. The color of the product was dazzling white.

Example 3

Propynyloxyethanol (50.05 g = 0.5 mol) and dibutyltin dilaurate (approx. 0.2 ml) were placed in a three-necked flask equipped with a stirrer, internal thermometer and dropping funnel. 59.56 g (0.5 mol) of phenyl isocyanate were added to the mixture with stirring over a period of about 2 hours. The product was kept in the melt (approx. 80-90.degree. C.) after the isocyanate had been metered in, and the mixture was stirred for a further 30 minutes by the exotherm of the reaction and by external temperature supply.

About 400 g of methanol were added to the melt present and the reaction mixture was then cooled to 15 ° C. A solution of 83.1 g (0.5 mol) of potassium iodide and 40 g (0.5 mol) of 50% NaOH (in 100 ml of deionized water) was added to the crystal slurry and the mixture was cooled again to 15 ° C. 278 g (0.5 mol) of an aqueous sodium hypochlorite solution (12.8% active chlorine) were then metered in with stirring at 18-19 ° C. (intensive cooling required) and the suspension was stirred for a further 30 minutes. The highly alkaline reaction mixture was neutralized by introducing CO 2 gas (pH = 7), the product was filtered off, washed with 300 ml of deionized water and then dried. The yield of 2- (3-iodo-2-propynyloxy) ethyl N-phenyl carbamate was 155 g or 90% of the theoretical amount; the product had a melting point of 97-100 ° C. The color of the product was dazzling white.

Example 4

Example 3 was repeated. 77.3 g (0.465 mol) of potassium iodide (= 7% deficit) and 37.2 g (0.465 mol) NaOH (= 7% deficit) were used for the iodination. The yield was 90% of the theoretical amount. The color of the product was dazzling white.

Comparative Example 1

Example 1 was repeated, except that 50% sulfuric acid was added dropwise to neutralize the highly alkaline reaction mixture until a pH of 8 was reached. The yield was as in Example 1, but the color of the product was dark brown.

Comparative Example 2

Example 1 was repeated, but 18% hydrochloric acid was added dropwise to neutralize the highly alkaline reaction mixture until a pH of 8 was reached. The yield was as in Example 1, but the color of the product was dark brown.

Claims

Patent claims

1. Process for the preparation of iodoalkynylcarbamates of the general formula (I)

IC≡CC (R ¹ R) -0- [C (R3R ⁴ ) -C (R5R6) -0] _n -CONHR7 (I)

wherein

the radicals R * - * and R- independently of one another are hydrogen or linear or branched alkyl radicals having 1 to 6 carbon atoms,

the radicals R3 to R ~ independently of one another are hydrogen or linear or branched alkyl radicals having 1 to 4 carbon atoms,

- The radical hydrogen, a linear or branched alkyl radical having 1 to 12 carbon atoms, a cyclohexyl radical, a substituted or unsubstituted phenyl radical, a benzyl radical or a p-toluenesulfonyl radical and

- n is the number 0 or 1, where first an alkynyl alcohol of the general formula (II)

HC≡CC (R ¹ R2) -0- [C (R3R4) -C (R5R6) _o] _n -H (II)

in which the radicals R to R6 have the meaning given above,

with an isocyanate of the formula (III)

R ⁷ NC0 (III)

where R ^{7 has} the meaning given above, to a carbamate of the general formula (IV)

HC≡CC (R ¹ R ² ) -0- [C (R3R4) -C (R ⁵ R6) -0] _n -C0NHR7 (IV)

in which the radicals R ¹ to R? have the meaning given above,

reacted, the carbamate (IV) iodized in alkaline solution, the alkali reaction mixture neutralized and the iodoalkynyl carbamate (I) subsequently filtered off, characterized in that the neutralization was carried out with carbon dioxide.

2. The method according to claim 1, wherein the entire process is carried out without isolation of the intermediate carbamate (IV) in the same container.

3. The method according to claim 1 or 2, wherein the iodination of the carbamate (IV) is carried out under largely anhydrous conditions in an alcohol.

4. The method according to any one of claims 1 to 3, wherein the iodination agent used to iodine the carbamate (IV) is not added to the reaction mixture in portions, but in its total amount.

5. The method according to any one of claims 1 to 4, wherein the carbon dioxide used for neutralization is used in the gaseous state.

6. The method according to any one of claims 1 to 5, wherein n denotes the number 1.