IL28449A - Derivatives of dihydroxy propanes,processes for their preparation and compositions containing such derivatives - Google Patents

Description

23449/2 n B3 ηιττ ίή niV»iJar» hiaib ni φηΐ3π Derivativee o dihydroxy propanes, processes for thei preparation and compositions containin euoh derivatives FRITZSPH® DODOS & OLCOTT ING, Ct 26987. by one alkyl, one hydroxy, one or two alkoxy groups each containing 1 to 5 carbon atoms or one, two or three halogen atoms (e.g chlorine or bromine) or is fused to a further ..benzene ring or substituted by a methylenedioxy group. valuable pharmaceutical properties for example they exhibit sedative, hypnotic and/or tranquillising effects and/or produce ~ narcosis that emphasises relaxation,. The remaining compounds provided by the invention, namely the monoalkyl carbonates monoaryl carbonates, cyclic carbonates, monohaloformates, carboxylic acid monoesters, rnonohaloformate-carboxylic acid monoesters, and monoalkyl and monoarylcarbonate carboxylic acid monoesters of the glycols are useful intermediates in the preparation of the mono carbamates and N-substituted monocarbamateso The monocarbamates and N-substituted monocarbamates, and the carboxylic acid monoesters thereof, of the glycol of general formula (I) can be prepared' by carbamoylating or. N-substituted carbamoylating said glycol or a monoacyl derivative thereof with one or more reactants in one or more reaction steps, and optionally when a monoacyl starting material is used, the product obtained can be saponified (advisably with ammonia) so as to liberate the hydroxyl group from the ester while leaving the carbamate group intact to form the desired monocarbamate or N-substituted monocarbamate. The products are compounds of the general formulae in which ring A, R and R have the meanings defined above, R^ is a hydrogen atom, an alkyl radical containing 1 to 5 carbon atoms or an aryl radical and R is a hydrogen atom or a caorboxylic tm acyl roup. Preferably ring A is of general formula II.

If desired the free hydroxyl group can be esterified.

Any suitable method of monocarbamoylating or N-substituted-monocarbamoylating a glycol of general formula (I), or a monoacyl derivative, can be used. The methods as such are well known in · the art and the most suitable for preparing a particular desired compound can be used. One such general method comprises forming a carbonate as an intermediate, and splitting this with ammonia or an amine to yield the desired product.

Thus, a glycol of general formula (I), or a monoacyl derivative thereof, can be reacted in a first step with an alkyl-haloformate,. arylhaloformate or carbonyl halide, and the intermediate formed can be reacted with ammonia or an amine of formula 6 6 R NIL, in which R is an alkyl or aryl radical.

According to one embodiment of the invention, reaction of the glycol with an alkyl or aryl -haloformate, preferably a chloro-formate, generally yields a mixture of the 1- and 3- mono (alkyl or aryl) -carbonates and the 1,3-cyclic carbonate. If the conditions are carefully controlled, e.g if temperatures up to 25°S are used, and.the reactions -are preferably' carried out' n solution in'. an organic solvent' such as benzene, it generally; is, possible to obtain only the on 1- and 3-mono. (alkyl, or aryl) carb^ates , which on heating,, e.g to temperature of up 1 to 170°C yield the cyclic carbonate.

Desirably, the solution of the glycol in the solvent contains a tertiary amine such as a trialkylamine or pyridine. Preferably, the alkyl group in the alkyl chloroformate does not contain more than 5 carbon atoms and methyl or ethyl chloroformate is conveniently employed.

The gradual addition of the alkyl chloroformate to the glyco is conducted with agitation, and agi ation is coat inued. -"or several hours generally at about room temperature followed by warming to ½5- 0°C. for several hours. Water can be added with agitation and the reaction mixture separated into two layers, an aqueous layer and an organic solvent layer containing the desired carbonates. The organic solvent layer can be washed successively with water, with an aqueous mineral acid, with a saturated alkali metal bicarbonate solution and finally with. water until neutral to litmus. The solvent such. as benzene can if desired be distilled off to yield the monoalkyl carbonates and the cyclic carbonate of the glycol of general formula (I) To produce the monocarbamates or N-substituted monocarbamates, of the glycols of general formula (I) the mono(alkyl- or aryl-) carbonates and/or the cyclic carbonates are reacted with ammonia. 6 6 or an amine of formula R NHL, where R is an alkyl or aryl radicals Preferably an unsubstituted carbamate is prepared, in which case the carbonates can be added to ammonia water and a mutual solvent such as isopropyl alcohol or 2-ethoxyethanol (cellosolve) . The mixture is agitated at room temperature and a stream of ammonia gas is introduced into the mixture over a period of 10 to .20 hours„ The passage of ammonia gas through the solution is then terminated, the excess ammonia removed by heating the reaction mixture and the solvent removed by vacuum distillation. The residual viscous liquid is dissolved in a suitable solvent such as toluene or benzene, water is added and the monocarbamates are precipitated. Desirably, the monocarbamates, if solids, are separated on a Buchner funnel and are purified by further recrystallisation from a suitable solvent such as toluene or isopropyl alcohol. In the procedure heretofore described, a mixture of two monocarbamates of the glycol employed is produced.

One of these monocarbamates the 1-phenyl or 1-^ubstituted pheny]-2,2-dialkyl-l,3-dihydroxy-propane-3-carbamate is compound produced by the reaction of the primary hydroxyl (i.e. in the 3-position) of the glycol, while the. other mono-carbamate, the 1-phenyl or 1-Substituted phenyl-2, 2-dialkyl-1,3-dihydroxypropane-l-carbamate is a compound produced by the reaction of the secondar hydroxyl (i.e in the l-position) r of the glycol. The two monocarbamates may be separated from each other by repeated recrystallisation or other convenient procedure.

The N-substituted_jnonocarbamates can be produced in a similar manner by replacing the ammonia by the appropriate primary amine.

The course of these reactions is given below where R^ is 7 a hydrogen atom or an alkyl or aryl radical, R is an alkyl or aryl radical, Hal is a halogen atom (preferably chlorine) n _ . 1 2 and-ring. A, R and R have the meanings defined in connection with formula (I) » Alternatively, the alkyl or aryl haloformate can be replaced by a carbonyl halide of formula Hal-CO-Hal, which is preferably phosgene. The reaction preferably is carried out in an organic solvent such as toluene, and in the presence of an acceptor for the liberated hydrohalic acid (usually HCl) such as a tertiary base,' for example, pyridine or triethylamine, and advantageously at low temperatures such' as -10° to +10°C, followed by allowing the reaction mixture to rise to about room temperature while stirring, followed by application of heat to drive the cyclisation to completion. The product obtained in the case generally is only the cyclic carbonate of general formula IV c. It can be reacted with ammonia or a primary amine in a similar manner to that described above to yield the carbamates of the general formula Va and Vb. In this case the monocarbamate of the secondary hydroxyl group If it is desired to obtain solely a mo ocarbamate of general formula (V b, i.e a 3- (carbamate or N-substituted carbamate) the corresponding: glycol of general formula I preferably is reacted with phosgene in§^ the presence of an N,N-tertiary aniline, such ,as dimethylaniline .and a mutual solvent such as toluene.,, tetrahydro fu an or diethylene glycol dimethylether or a mixture of such solvents at a temperature below the cyclisation temperature of the corresponding monohaloformate. Conveniently, a molecular equivalent of the required glycol and a molecular equivalent of dimethylaniline are dissolved in a solvent such as tetrahydrofuran or diethyleneglycol dimethylether. This resulting solution is added to a solution of slightly over the molecular equivalent of phosgene dissolved in toluene or other suitable solvents. This addition advantageously is conducted with efficient agitation at a temperature of -10° to +5°C. and over a period of approximately 2 to 6 hours. The mohochloroformate of the primary hydroxyl group of the glycol (i.e of the hydroxyl group in position 3-) of formula I Cl (in which ring A,R and R have the meanings defined above) aftd~*»i»g Pr^.«£wfai^-i^^~s@»e^i- im»^-^^ is produced without isolation ant* this monochloroforraate is treated immediately with ammonia water to form the desired 1-phenyl or l- ubstituted pheny.0-1- hydroxy-2, 2-dialkyl-propane-3-carbamate.

The combining. of the reactants can also be conducted in the reversed order. In that case, the molecular equivalent of phosgene is dissolved in a suitable solvent, such as toluene, and periodically added under efficient agitation and cooling to a solution ofa molecular equivalent of the required glycol and a molecular equivalent of dimethyl aniline in a suitable solvent such as tetrahydrofuran. The ammonia can be replaced by an amine of G 6 general formula R H^ where R is an alkyl or aryl radical.

In a modification of the processes described above, the glycol of general formula (I) can be replaced by the corresponding monoacylated glycol. These are the 3-esters as the primary hydroxyl group is esterified in preference to the secondary hydroxyl group. These monoesters, preferably of carboxylic acids containr- ing not more than 5 carbon atoms, are produced by reacting the glycol of general formula (I) with a slight excess of the molecular equivalent of the acid in a solvent such as benzene or toluene.

The acid employed may be any carboxylic acid preferably having not more than 5 carbon atoms, such as acetic acid, propionic acid or pentanoic acid. A catalyst, such as _-toluene sulphonic acid, methane sulphonic acid or phosphoric acid, is desirably added.

On heating the reaction mixture with a water entrainer system, an azeotropic mixture consisting of the water of reaction, the solvent and part of the organic acid accumulates in the water trap. The progress of reaction is followed by measuring the water part and the amount of the organic acid in it. Accordingly, it is sometimes necessary to add fresh organic acid to the reaction. in order to replace the acid collected in the water trap. After completion of the reaction, the reaction product may if desired be taken up in a ; solvent, such as benzene or toluene, and washed free of acids. After removal of the solvent, the desired ester is obtained.

AHP ^293 In order to obtain solely the 1-carbamate or N-substituted carbamate of general formula Va, the 3-ester . ie then reacted with a carbonyl halide (preferably phosgene), an alkyl haloformate or an aryl haloformate. Desirably, the aryl moiety of the aryl haloformate has less than 9 carbon atoms and desirably the halogen is chlorine. For example, methyl chloroformate or phenyl chloroformate may be reacted with such a monoester. If phosgene is employed, a monochloroformate of the glycol is produced. If an alkyl chloroformate or an aryl chloroformate is used, a secondary monocarbonate is produced. The resulting monochloroformate of the glycol or the secondary monocarbonate of the glycol is reacted with ammonia or an alkyl or aryl primary amine to produce the 1-monocarbamate or N-sub-stituted carbamate. Whether phosgene is employed as a reactant-or an alkyl chloroformate or aryl chloroformate is used, the resulting product is the secondary monocarbamate of the glycol.

The reactions which take place are as follows, in which ring A, . 1 2 R and R have the meanings defined in connection with. formula I, 6 Hal is a halogen atom, R is a hydrogen atom or an alkyl or aryl 7 8 radical, R is an alkyl or aryl radical and R ( ^H is a carboxylic 8 acid in which R preferably is an alkyl radical containing 1 to 5 carbon atoms. tional ive thereof When it is desired to produce an N-alkyl or N-aryl monocarbaraate, it is preferred to react an alkyl isocyanate, such as methyl isocyanate, or an aromatic isocyanate such as phenyl isocyanate, with the glycols of general formula (I). A slight excess of the alkyl or aromatic isocyanate, such as 1.05 moles of isocyanate to 1 mole of the glycol, -is desirably used. for a prolonged period, auch as hours. The addition of a few drops of a tertiary amine, such as pyridine, as catalyst is recommended.

The glycols of general formula (I), which are used as starting materials for the processes of this invention can be prepared by reacting, in the presence of 1 mole of an alkali metal hydroxide, such as sodium potassium hydroxide, 1 mole of an aromatic aldehyde of the formula: with two moles of an aliphatic aldehyde having the following formula: R1 I H - C - CHO l2 R 1 2 dwhere ring A, R and R have the meanings defined herein) in an organic solvent, for example methanol.

The monocarbamates and N-substituted monocarbamates of the glycols of general formula (I) may be utilised as tranquillisers.

For this purpose, the monocarbamates or N-substituted monocarbamates may be mixed with a pharmaceutical carrier. For example, 40 g. of the monocarbamates or N-substituted monocarbamates may be dissolved in 1 kg. of a glyceridic oil such as peanut oil and administered to an animal such as a domestic animal in a dosage of 0.4 g. per kilogram of weight. Again, tablets of the monocarbamates of N-substituted . monocarbamates may be prepared by granulating the desired amount of monocarbamates or N-substituted monocarbamates with starch and lactose ■•^ and compressing them into tablets. Carriers, binders, lubricants and other components may be utilised in conventional manner with the monocarbamates or N-substituted monocarba-mates of this invention to produce dosage forms suitable for oral, parenteral or other form of administration., The following Examples illustrate the invention: EXAMPLE 1 Preparation of the monomethyl carbonates and cyclic carbonate of 1- (^-methoxyphenyl) -2 , 2-dimethyl-l, 3-dihydroxypropane.

A solution of 37 g. of methylchloroformate dissolved in 30 ml. of benzene was added to a well agitated mixture of 50 g. of 1-(4-methoxyphenyl) -2, 2-dimethyl-l, 3-dihydroxypropane, 70 ml. of benzene and 26 g. of pyridine . over a period of * minutes. During the addition, the reaction mixture was cooled and the temperature was maintained between 18° and 25°C. The reaction mixture was agitated at room temperature for one hour, then heated to 52° - 62°C. and agitated during the heating and for a period of about five hours thereafter. The reaction mixture was stood overnight at room temperature and then washed successively twice with 100 ml. of a >% .. aqueous hydrochloric acid solution, once with 100 ml. of an aqueous saturated sodium bicarbonate solution, and three times with 100 ml. . of warm water. The solvent was then distilled off on a steam bath at a slight vacuum. A theoretical yield of the crude reaction products was, obtained. I.R. curves indicated that the desired reaction products were produced.

The cyclic carbonate of the 1- C+-methoxyphenyl) -2, 2-dimethyl -1,3-dihydroxypropane may be separated out from the crude mixture of carbonates by dissolving this mixture in a suitable solvent such, as isopropanol or toluene and keeping this solution under refrigeration at -5° to -10°C. for approximately 2h hours.

The cyclic carbonate may be crystallised out and may be separated by filtration on a Buchner funnel. It was found to be present in the above crude mixture in an amount of -20% and had a melting point of 138-139°C The l-(½-methoxyphenyl)»2,2-dimethyl-l,3-dihydroxypropane employed as a starting material in this Example was prepared by initially adding a solution of 272 g. of anisic aldehyde and 6Ο g. of isobutyraldehyde to I O g. of 85% potassium hydroxide in 500 ml. of methanol over a period of 1^· hours.

The .mixtue was agitated and cooled during, .the addition, maintaining the temperature at k°- ^9°0. After the addition, agitation was continued for 3 hours at a temperature of 2°C.

The reaction mixture was cooled to 30°C and acidified with glacial acetic acid. 250 ml. of methanol were distilled off under agitation from a steam bath. To the residue there was added with agitation 100 ml. of water and the mixture was separated into two layers.

The organic layer was removed and washed with 500 ml. of water, and the water layer and washings were combined and extracted with 50 ml. of benzene. The benzene extract was added to the organic layer.

The benzene was removed by distillation. The reaction mixture was then fractionated without a column, as follows} Temperature Vapour Temperature Flack Vac. cc. wt. 27 - 160°C k - 186°C 6 mm 205 19^.5 178 - 193°C 187 - 193°C 6 mm 250 269.

Residue The first fraction with a vapour temperature of 27-l60°C. consisted mainly of unreacted isobutyraldehyde, anisic aldehyde and the desired glycol. The main section with a vapour temperature of 178-193°C contained the desired glycol and crystallised on standing.

- ]A - The yield was 65·5% of the theoretical. It was recrystallised from a mixture of 200 ml. of benzene and 150 ml. of hexane.

The crystals had a melting point of 71«5-72°C. The wet analysis (acetylation) was 98.9$· Other l-(alkoxyphenyl) -2, 2-dimethyl-l, 3-dihydroxypropanes can be produced in the same manner by substituting the required alkoxybenzaldehyde for the anisic aldehyde employed in this Example.

EXAMPLE 2 Preparation of the monocarbamates of l-( -methoxyphenyl)- , -dimethyl-1 , 5-dihydroxypropane.

A stream of ammonia gas was passed for a period of 17 hours below the surface of a solution containing 30 ml. of 28$ ammonia water, 80 ml. of isopropanol and 55 g» of the crude carbonates of l-(^-methoxyphenyl) -2, 2-dimethyl-l, 3-dihydroxypropane, prepared as described in Example 1. During the introduction of the ammonia gas, the solution was agitated and maintained at room temperature. After the 17 hour period, the solvent was distilled off under vacuum from a steam bath to yield about 50 g. of the crude raono- carbamates. The products were recrystallised from a solution of benzene, hexane and isopropanol and again from isopropanol and • activated carbon. The melting point was 82°C. The nitrogen determination by Kjeldahl was 5· 75$ compared with the theoretical of 5· 53%· A molecular weight determination by the Rast method was 262 as contrasted with a theoretical value of 253· An I.R. curve indicated the desired compound was obtained.

The derivatives of the corresponding dialkoxy ring substituted glycols, as well as the derivatives of the hydroxy ring substituted glycols, are produced in the same manner as the derivatives of the . monoalkoxy ring substituted glycols of the above Examples.

The procedures of these iSxamples are followed except that in the production of the monomethyl carbonates and cyclic carbonates, the molecular equivalent of the dialkoxy ring substituted glycol or the molecular equivalent of the hydroxy ring substituted glycol is employed instead of the l-(i-rnethoxyphenyl)- 2.2-dimethyl-l,3-dihydroxypropane; and in the production of the monocarbamates, the molecular equivalent of the crude carbonates of the dialkoxy ring substituted or hydroxy ring substituted glycol is employed instead of the crude carbonates of 1-( -methoxyphenyl)- ¾2-dimethyl-l ,3-dihydroxypropane .

EXAMPLE 3 Preparation of the cyclic carbonate, of l-phenyl-2,2-dimethyl- 1.3-dihydroxypropane.

A solution of phosgene was prepared by dissolving 218 g. of phosgene in 2000 ml. of toluene by adding phosgene as a gas to the toluene with slow agitation over a period of two hours and at a temperature of -2 to -5°C. A solution of ΐ8θ g. of l-phenyl~2,2-dimethyl-1,3-dihydroxypropane and l60 g„ of pyridine in 500 ml. of chloroform. was added to this phosgene solution over a period of 12-jLhours at a temperature of -1 ΐο-^Ο0. The reaction mixture was then permitted to come to room temperature and was agitated for a period of twelve hours, using an aqueous solution of sodium hydroxide to trap the. phosgene vapours escaping from the reaction mixture.

Chloroform was distilled off at atmospheric pressure from a steam bath. The. residual reaction product was washed three times with 100 ml. of water and dried in a slight vacuum from a steam bath. On standing, it crystallised and was recrystallised from isopropanol. It had a melting;-point of 112-ll °C. A yield of 175 g. representing 90 of the theoretical was obtained. Molecular weight determinations of the crystalline material (Rast method) gave the correct molecular weight of the cyclic carbonate.

Examination of the I.R. curve confirmed that the cyclic carbonate was obtained.

The l-phenyl-2,2-dimethyl-l, 3-dihydroxypropane used as a starting material in the Example may be produced by the method described herein.

EXAMPLE Preparation of the monocarbamates of l-phenyl-2, 2-dimethyl-1 , 3-dihydroxypropane The monocarbamates of l-phenyl-2,2-dimethyl-l,3-dihydroxy-propane are prepared by reacting ammonia gas with the cyclic carbonate of Example 3» i«e following the general reaction step shown for going from a compound of general formula IVc to those of general formula V(c) and V(b), but in which ring A is phenyl, 1 2 6 R and R are methyl and R is hydrogen .

A stream of ammonia gas was passed through a gas inlet tube over a period of 17 hours at room temperature into a solution containing 208 g. of the cyclic carbonate of l-phenyl-2, 2-dimethyl-1,3-dihydroxypropane of Example 3 in 600 ml. of 28 aqueous ammonium hydroxide and 600 g. of 2-ethoxyethanol. The reaction mixture was then heated on a steam bath to permit the escape of excess ammonia gas. The 2-ethoxyethanol and water were distilled off in a slight vacuum from a steam bath. 2500 ml. of water were added under agitation to the resulting reaction product. The mixture was cooled and agitated. The precipitated crystals were collected on a Buchner funnel and washed with cold hexane. The crystals were then recry-stallised from isopropanol with activated"carbon and again from xylene. The yield was 5^.2% of the theoretical. The melting point was 91-10^°C. The nitrogen by Kjeldahl was 6.08$ as contrasted with a theoretical value of 6.28%. Molecular weight deter-mination (Rast method) was 231 contrasted with a theoretical value of 223. The I.R. curve indicated the desired product.

- - + — EXAMPLE 5 Preparation of the monoethyl carbonates and cyclic carbonate ■.' of 1-(^-isopropylphenyl) -2 , 2-dimethyl-l, -dihydroxypropahe« A solution was prepared by combining in a 3-necked reaction flask 56 g. of l-(½-isopropylphenyl) -2 , 2-dimethyl-l, 3-dihydroxy- · propane, 32 g. of triethylamine and 100 ml. of benzene. To this solution was added over a period of three hours, under agitation and while maintaining the reaction mixture between 15-20°C. , a solution of 27 g. of ethylchloroformate in 38 ml. of benzene.

Agitation was continued for two hours at room temperature. The reaction mixture stood overnight at room temperature. , The. following day the mixture was heated to 50°C and was agitated at this temperature for 1-J hours. It was then cooled and 100 ml. of water were added to the cooled reaction mixture. The two layers . which formed were separated. The organic layer was washed successively with 100 ml. of water, three times with 100 ml. of an aqueous $ solution of hydrochloric acid, once with 100 ml. of water, once ."' with 100 ml. of dilute aqueous sodium bicarbonate solution, and three times with 100 ml. of water. The solution was neutral to litmus. The solvent was removed by distillation under vacuum from a steam bath. 7 g. of the crude reaction products wire obtained.

An I.R. curve indicated that the desired products were obtained.

The cyclic carbonate of the l-( -isopropylphenyl)-2,2- dimethyl-l, 3-dihydroxypropane may be separated out from the crude mixture of carbonates in the same manner as the cyclic carbonate of l-C+-methoxyphenyl) -2» 2-dimethyl-l, 3-dihydroxypropane was separated from the crude mixture of its carbonates as described in Example lf : 21$ of the cyclic carbonate having a m.p. of 10 -105°0 were obtained.

The l-( -isopropylphenyl)-2, 2-dimethyl-l, 3-dihydrqxypropane employed as. a starting material in this example was prepared by . initially adding to 212 g. of 85% potassium hydroxide in 700 ml.

AHP 3 of methanol over a period of three hours a solution of g. of cuminal (ja-isopropylbenzaldehyde) and ½8. g. of isobuty-raldehyde. During the addition, the reaction mixture became cloudy, viscous and changed to a yellow colour. After completion of the addition, agitation was continued for hours at a temperature of 12-l6°C, and overnight at room temperature.

The following day the reaction mixture was made slightly acidic by the addition of glacial acetic acid. A clear solution resulted. 65O ml. of methanol were distilled off under agitation (from a steam bath). 200 ml. of benzene were added to the residue and the resulting solution was washed twice with 500 ml. of warm 'water.

The benzene was removed from the reaction mass by distillation and the product was fractionated through an 8" Vigreau column as follows: Temperature Vapour Temperature Flask Vac-.- cc. wt. • 67-lA6-°C. 11 -165°C 2 mm 98. 95 Front Section l* 7-l6l°C. 165-202°C. 3 mm 527 527 g.Main Section Residue 672 g.

The main Section crystallised on standing. It was recrystallised o' ■( ' from hexane and had a melting point of 58-60 C. The wet analysis (acgtylation) was 99· 1$· The yield was 7 % of the theoretical.

Other l-(alkylphenyl) -2 , 2-dimethyl -2 , 2-dimethyl-l, 3-(iihydro y-propahes are produced in the same manner by substituting the. required alkylbenzaldehyde for the cuminal employed in this Example":., EXAMPLE 6 Preparation of the Monocarbamates of l-C^-isopropylphenyl) -2 , 2-dimethyl-l, 3-dihydroxypropane.

A stream of ammonia gas was passed for a period of 20 hours through, a solution containing 50 ml. of 28% ammonia water, 1 0 m}..-of. isopropanol, and 72 g. of monoethyl carbonates and cyclic ΛΗΡ i 2 3 .'"'v.: Carbonate of l-(4-isopropylphenyl)-2,2-dimethyl-l,3-dihydroxy-. propane, prepared as described in Example V. During the intro-? .. ·■ ductiori of the ammonia gas, the solution was agitated and maintained at room temperature.. After the 20 hour period, the mixture was heated for twenty minutes on a steam bath and the permitted to cool. The cooled reaction mixture was added to 500 ml. of cold water. The precipitated crystalline reactio products were dissolved in 200 ml. of isopropanol and refluxed for fifteen minutes, with 2 g* of activated carbon. The hot . solution was filtered and the resulting clear solution was placed... in a freezer (-5 to -10°C.) overnight. The precipitated crystals were collected on a Buchner funnel and recrystallised- from toluene. The products had a melting point of 132-l60°C. The nitrogen, determination by Kjeldahl was 5·22% as compared with a theoretical value of 5·28^.. I.R. curves indicated that the desired products were obtained.

■ EXAMPLE 7 '■■■·;'·. ■ Preparation of the monoethyl carbonates and cyclic carbonates of l-(methylphenyl) -2, 2-dimethyl-l,3-dihydroxypropanes.

A solution of z g. (0. 88 mole) of ethylchloroformate in 60 ml. of benzene was added over a period of three hours to an agitated mixture of 64.7 g. (0.33 mole) of l-(methylphenyl)-2,2T dimethyl-i,3-dihydroxypropanes, 3^·5 g» (0.3^· mole) of triethylapiine and 100 ml. of benzene in a 3 necked reaction flask; . During the addition, the reaction mixture was agitated and the temperature maintained between 20-25°C. After the addition, agitation was continued for four hours at room temperature (28.5°C). The reaction mixture was stood overnight and the following day was heated under agitation for three hours. The temperature being maintained at 52-65°C. The reacted mixture was cooled. 250 ml. of water were added to the cooled reaction mixture. >: AHP 293 Two layers formed and were separated. The organic layer was washed successively, twice with 100 ml. of water, once •with 100 ml. of a 5% aqueous hydrochloric acid solution, once with 100 ml. of a dilute sodium bicarbonate solution, and twice with 100 ml. of water. The organic layer was neutral to litmus. The solvent was removed by distillation under vacuum on a steam bath. The weight was 8li7.g« of crude mixed carbonates of the starting glycols. An I.R. curve indicated that, the desired products were obtained.

The cyclic carbonates of the l-(methylphenyl)-2,2-dimethyl- 1,3-dihydroxypropanes may be separated out from the crude mixture ' of carbonates by dissolving this mixture in a suitable solvent such as isopropanol or toluene and keeping this solution under refrigeration at -5° to -10°C. for approximately 2k hours... The cyclic carbonates may be crystallised out and may be separated by filtration on a Buchner funnel. The cyclic carbonates were found to be present in an amount of 12% and had a melting point of 92.5-9i+.50C. The mixture of l-(methylphenyl)-2,2÷dimethyl-l,3- dihydroxypropane employed as a starting material in this Example was prepared by initially addition to 212 g.. of 85% potassium . hydroxide in 700 ml. of methanol over a period of . hours, a solution of 368 g. (6¾ moles) of isobutyraldehyde, 200 ml. of methanol and 60 g. (3 moles) of a mixture of the three isomeric methyl benzaldehydes (the meta-methyl benzaldehyde being the predominant component). During the addition, the mixture was, agitated and maintained at a temperature of 12-l6°C. After the . addition, agitation was maintained overnight at room temperature. The next day the reaction mixture was acidified with acetic acid and 8OO ml. of methanol were distilled off, under agitation, from a steam bath. The reaction product was washed with 800 ml. of warm water and dried in vacuum (from a steam bath).

AHP ½ 3 The mixture of the glycols was heavy and viscous. The assay be wet analysis (acetylation) was 97.5%· The mixture boiled at l 6-lk9°Q. at 2 mm. The yield of the distilled mixture of glycols was 83$. Analysis by acetylation was 100?o.

EXAMPLE 8 Preparation of the monocarbamates of l-(methylphenyl) -2? 2-dimethyl-l, 3-dihydroxypropanes.

A stream of ammonia gas was passed for a period of 19 hours •through a solution of 50 mlo of 28 ammonium hydroxide solution 50 ml. of 2-ethoxyethanol and 8θ g. of the mixed ethyl carbonates of 1-(methylphenyl) -2,2-dime hyl-l,3-dihydroxypropanes prepared as described in Example 7. During the passage of the ammonia gas, the solution was agitated and maintained at room temperature. The temperature of the reaction mixture was raised to 50-60°C. and the/passage of ammonia gas was continued with agitation for *+ minutes. The solvent was removed under vacuum at steam bath teraperatures. A viscous yellow liquid weighing 71· g« remained.

This liquid was diluted with 150 ml. of toluene and the solution was refluxed for 20 minutes with activated carbon. It was filtered while still hot and the clear solution was' placed in a refrigerator (-5 to -10°C) overnight. A total of 59 g^ of crystalline material was. collected. From the collected material, 17·5 8·' were- recry stallised from isopropanol, again using the activated carbon. 10.2 g. of crystalline material was recovered having a melting point of 83° -99°C. The. nitrogen determination was 5·8ί$ compared with a theoretical value of 5..90 . The I,R. curve indicated that the desired monocarbamates were obtained.

EXAMPLE 9 Preparation' of the monoethylcarbonates and cyclic carbonate of .'■ ( 1 -■methylenedioxyphenyl) -2, 2-dimethyl-1, 5-dihydrbxypropane .

A solution of 119· ^ g. (1.10 moles) of ethyl chloroformate ΑΗΡί+293 AHP 293 dimethy1-1,3-dihydroxypropane, produced in accordance with Example 9» A00 ml. of Z8% ammonia water and 400 ml. of cello-solve (solvent) were agitated at room temperature and a stream of ammonia gas (NH^) was introduced into this solution over a period of 17 hours. The reaction temperature was then raised to 50-60°C. for two hours with continual agitation and ammonia ebullition. The ammonia gas introduction was- stopped and the excess ammonia was evaporated from the reaction mass (under agitation and heat from a steam bath) . The solvent was then removed by vacuum distillation and the residual viscous amber liquid was dissolved in OO ml. of tolueneel,150 ml. of water was added to this solution while agitating and rapid crystallisation took place. The light tan coloured crystals were filtered on a Buchner funnel and washed with 300 ml. of cold water. The weight of the crude crystals obtained was 217*2 g. (wet). On standing, the toluene and water separated yielding a total of 46.8 g. crystals. These were separated on a Buchner funnel and combined with the above crystalline part. On recrystallisation from isopropanol and again from isopropanol With carbon, a total of 103 g. was obtained (theoretical: 246 g.), representing a yield of 41.8%. The white crystals had a melting point of ll8-130°C. A nitrogen determination showed 5.28$ compared with a theoretical value of 5·2 %.. Molecular weight determination (Rast) showed 251 compared with a theoretical of 267. I.R. curves indicated the reactions had followed those shown in general terms for a mixture of carbonatee of formulae IV(a) IV(b) and IV(c) to give a mixture of carbamates of formula V(a) 'and V(b).

EXAMPLE 11 Preparation of l-(4-chlorophe.nyl)2,2-dimethyl-l<3-dihydroxy-propane-3-carbamate.

A solution of 2l4 g. (1 mole) of 1- (4-chlorophenyl)-2,2- ΛΗΡ ½3. dimethyl-l,3-dihydroxy-propane, 4θΟ ml. of tetrahydrofuran and 125 g· ( 1 « 03 moles) of dimethylaniline was added over a period of hours , under agitation to a solution of IQ g. of phosgene (I.05 moles), dissolved in 200 ml. of toluene, maintained at a temperature of -5°C. During the addition, the temperature was maintained at - ° to 0°C. to produce the S-monochloroformate of .the glycol was cooled to -7°C. and ,a solution containing 2 moles of ammonia (28-29%) dissolved irx water, was added gradually to the reaction mixture. . Agitation was continued for an additional hr. The reaction mixture was permitted to come to room temperature. 500 ml. of warm water were added under agitation and the lower aqueous layer was separated and discarded. The procedure was repeated and the solvent was distilled off.1 The remaining crude reaction product and dimethylaniline remained in the reaction flask.' The dimethyl-i aniline was removed by steam distillation. The reaction product was taken up in 300 ml. of benzene and was liberated from any moisture by reflux with a water trap. One gram of activated carbon was added, reflux was continued for approximately Ί hour and the benzene solution was filtered hot. On standing overnight at room temperature crystals formed which, after separation on a Buchner funnel, amounted to approximately 50-55% of the theoretical of l-(½~chlorophenyl)-2, 2-dimethyl-i-hydroxy-r propane-3-carbamate. The mother liquor was concentrated ,and yielded another 10-15% of the desired product havin a melting point of 134°C. and having the following formula: C = 0 I ' ■ .' .■. ...:·' · ' · ':'" NH2 The J'-roonocarbamates of the corresponding dihalogen and . ■ trihalogen ring substituted glycols can bev roduced in the same . manner as described in this Example. For instance,, the 3'-niono- carbamates of l-(2, -dichlorophenyl>2,2-dimethyl--l,3-dih.ydroxy- propane or l-(3.i'+» i5-trichlorophenyl) -2,2-dimethyl-l,3-dihyclroxy*" propane can be prepared in the same manner as the l-i^-chloro- phenyl) -2,2-dimethyl^l,3-dihydroxypropane-3^raonocarbamate, except ' that .one mole of l-(2,^dichlorophenyl) -2 2-dimethyl'ilj-dihydroxy- propane or one mole of l-(3, '+» 5-trichlorophenyl) -2,2-dimethyl-'l,3- dihydroxypropane is employed instead of one mole of l-i^-chlbro- phenylj^i^dijnethyl-l^-dihydroxypropane as heretofore described in this Example.

The other derivatives of dihalogen ring substituted glycols or trihalogen ring substituted glycols can be produced in the same manner as derivatives of the monohalogen ring substituted glycols described in Examples 12 and 15 given below, In all. cases, the procedures in these examples are followed except that instead of employing the l-C-chlorophenyl) -2 ,2-dimethyl-l,3-dihydroxypropane, the same molecular equivalent of the corresponding dihalogen or tri- halogen ring, substituted glycols is employed, In the preparation of the cyclic carbonates of the corresponding dihalogen or trihalogen ring substituted glycols, the procedure of Example 13 (see below) is followed except that a molecular equivalent of the mono-ethyl- carbonate of the corresponding dihalogen or trihalogen ring substituted glycols is used.

In the preparation of the 1-carbamates of the corresponding dihalogen and trihalogen ring substituted glycols, the procedure of Example Ik (see below) is followed except that the molecular equivalent of the cyclic carbonate of the corresponding dihalogen or trihalogen ring substituted glycols is employed.

EXAMPLE 12 . Preparation of ethylcarbonates, of l-( -chlorophenyl)-2,2-dimeth l-1, 3-dihydroxypropane 0 A solution of 60 g. of ethyl chloroformate (0.55 mole) in 100 ml. of benzene was added over a period of 3 hours with agitation to a solution of 107.2 g. (¾ mole) of l-(i-chlorophenyl)-2l2-dimethyl-1,3-dihydroxypropane and 5^·6 g. (0. ^ mole) of triethylamine in I5O ml. of benzene. During the addition the solution was maintained at 20-25°C. The agitation was continued at room temperature for 2 hours, then for 3 hours at i+0-60°C. It was then cooled to room temperature and 3OO ml. of water was added with agitation over a period of 5 minutes. The mixture separated into two layers. The aqueous part was extracted with 100 ml. of benzene and this extract was added to the main organic part. The organic part was washed twice with 20 ml. of water and then successively with 150 ml. of 5% aqueous hydrochloric acid, 50 ml. of water and 200 ml. of aqueous sodium bicarbonate solution. Finally, it was washed twice with 200 ml. of water. The solvent was removed by vacuum distillation on a steam bath. A pale, viscous oil resulted;.; weighing 137·5 g« An I.R,. examination indicated that the desired product was obtained. The resulting product comprised a mixture of the If .and.3-(ethyl carbonates) of l-(^-chlorophenyr)"-2,2-dimethyl-1,3-dihydroxypropane .

AHP ^293 solution and reflux maintained for hour. The hot solution was filtered and permitted to crystallise at room temperature. After 2 hours, the crystals formed were filtered on a Buchner funnel and recrystallised from benzene.

A k fc yield of the desired 1-monocarbamate having a melting point of 171°C. was obtained.

EXAMPLE 15 Preparation of monoacetate of l-(k-chlorophenyl)-2,2-dimethyl-1, 3-dihydroxypropane.

The following mixture was prepared and refluxed with a water trap: 53·6 g. of 1-(½-chlorophenyl)-2,2-dimethyl-l,3-hydroxy-propane, 16,5 g- of acetic acid (l/ mole plus 10$ excess), 0,25 g« of £-toluenesulphonic acid, and 1 0 ml. of toluene. After one hour, the theoretical amount of water was collected in the water trap. The reaction mixture was cooled to room temperature and washed successively with 75 ml. of dilute aqueous carbonate solution, 75 ml* of dilute aqueous sodium bicarhonate solution and 100 ml. of water. The solvent was distilled off under vacuum. 60 Ml. of hexane Were added to the remaining crude reaction mixture. On heating and then cooling under agitation, crystals formed which were collected on a Buchner funnel. These crystals were recrystallised from benzene and had a melting point of 78.5-80°C. Wet analysis indicated a purity of 99$ of the desired 3-monoacetate of the 1-( -chlorophenyl)-2,2-dimethyl-l,3-dihydroxypropahe., The yield was 80% of the theoretical. I.R. indicated the desired monoester was obtained.

EXAMPLE 16 Preparation of monomethylcarbamates of l-phenyl-2,2»dimethyl-1,3-dihydroxypropane.

A solution of 62.7 g. d mole plus 10$ excess) of methyl isocyanate in 100 ml. of tetrahydrofuran was added to a solution of l80 g. (1 mole) AHP 293 of l-phenyl-2, -dimethyl-l,3-dihydroxypropane in 20C ml. of tetrahydrofuran. 3 Drops of pyridine were added to the resulting solution as a catalyst and the reaction mixture was permitted to stand at room temperature for 2 hours. The tetrahydrofuran and excess methyl isocyanante were removed by distillation. The crude reaction product was twice recrystallised from benzene. A 70 theoretical yield was obtained. The product had a melting point of 117-ll8°C. I.R. examination and nitrogen determination by Kjeldahl indicated the desired product was obtained. The, product .was a, mixture of the :1 and 3-monomethylcarbamates of l-phenyl-2, 2-dimethyl-l,3-dihydroxypropane.

EXAMPLE 17 Preparation of monophenylcarbamates of l-phenyl-2,2-dimethyl- 3-dihydroxypropane .

A solution of 121 (1 mole plus 10% excess) of phenyl isocyanate in 200 ml. of tetrahydrofuran was added to a solution of l80 g. (1. mole) of l-phenyl-2, -dimethyl-l,3-dihydroxypropane in 200 ml. of tetrahydrofuran. 3 Drops of pyridine were added to the resulting solution as a catalyst and the reaction mixture was permitted to stand at room temperature for 24 hours. The tetrahydrofuran, and the excess phenyl isocyanate were removed by distillation. The resulting crude reaction product was twice recrystallised from benzene. An S0% theoretical yield was obtained. The product had a melting point of 106-110°C. I.R. examination and nitrogen determination by Kjeldahl indicated that the desired product was obtained. The product was a mixture of 1- and 3- monophenylcarbamates of l-phenyl-2, 2-dimethyl-l, 3-^dihydroxypropane.

AHP 293 The product was a mixture of the .1- and 3- monoethyl carbamates of l-(3i ^-methylenedioxyphenyl)-2,2-dimethyl-1, 3-dihydroxypropane.

EXAMPLE 20 Preparation of monophenylcarbamates of l-(3i ^-methylene-dioxyphenyl) -2 , 2-dimethyl-l, 3-dihydroxypropane A solution of 121 g. (1 mole plus 10$ excess) of phenyl isocyanate in 200 ml. of tetrahydrofuran was added to a solution of 22k g. (1 mole of 1-methylenedioxypheny 1-2 , -dimethyl-l, 3-dihydroxypropane in 200 ml. of tetrahydrofuran) . 3 Drops of pyridine were added to the resulting solution as a catalyst and the reaction mixture- was permitted to stand at room temperature for hours. The tetrahydrofuran and the excess phenyl isocyanate were removed by distillation. The crude reaction product was twice recrystallised from benzene, A 72% theoretical yield was obtained. The product had a melting point of 138-l +°C. I.R. examination and nitrogen determination by Kjeldahl indicated that the desired product was obtained. The product was a mixture of the 1- and 3- monophenyl carbamates of 1-(3,^*—methylenedioxyphenyl) -2, 2-dimethyl-l, 3-dihydroxypropane.

EXAMPLE 21 Preparation of monoethylcarbamates of l-(l-naphthyl) -r2,2-dimethyl-1, -dihydroxypropane A solution of 19 g. of ethyl isocyanate in.50 ml. of tetrahydro-furan was added to a solution of 57. g» (l/k mole) of l-(l-naphthyl) -2, 2-dimethyl-l,3-dihydroxypropane having a melting point of 112-.UA C. 1 Drop of pyridine was added to the resulting clear solution as a catalyst and the solution was permitted to stand at room temperature for 2 days. The tetrahydrofuran and unreacted ethyl isocyanate were removed by distillation. The remaining crude reaction product was recrystallised from a mixture of JO ml. of benzene and JO ml, of hexane. The mixture of the two ■ . isomeric monoethylcarbamates crystallised on cooling and : was collected. on a Buchner funnel. The product had a melting point of 8.5 to 105°C. and was obtained in an S0% yield of the theoretical. The product was identified by the I.R. examination and nitrogen determination by Kjeldahl as the desired mixture of 1- and 3- monoethylcarbamates of l-(l- naphthyl)-2,2-dimethy1-1,3-dihydroxypropane.

EXAMPLE 22 Preparation of the monoethylcarbamates of l-( -chloro-. phenyl)-2-methyl-2-n-propy1-1, -dihydroxypropane A solution of 18 g. of ethyl isocyanate in JO ml. of tetra- hydrofuran was added to a solution of 6lg. of 1-(*+-chlorophenyl)- : 2-methyl-2-propyl-l,3-dihydroxypropane in JO ml. of tetrahydrofuran. 1 Drop of pyridine was added to the resulting solution as a catalyst and the solution was permitted to stand at room temperature for 2 days. The excess of ethyl isocyanate and tetrahydrofuran was removed by distillation. The crude reaction product was taken up in 100 ml. of benzene. The resulting solution was washed successively with JO ml. of water, JO ml. of sodium bicarbonate solution and JO ml. of water. After removal of the benzene b distillation in vacuum, a heavy very viscous, light yellow mass resulted. I.R. and nitrogen determination by Kjeldahl indicated that the desired mixture of 1- and 3- monoethylcarbamates of l-(^- chlorophenyl)-2-methyl-2-n-propyl-l, -dihydroxypropane.

EXAMPLE 23 Preparation of the seconday monocarbamate of 1-phenyl-2,2-dimethylrl, ^dihydroxypropane» . , A solution of phosgene was prepared by dissolving 50 g. of phosgene in 00 ml. of toluene by adding to the toluene, phosgene as a gas, with slow agitation over a period of l-jjr hours and at a temperature of -2 to -5°C. To this phosgene solution there was added over a period of l-J hours at a temperature of 1 to -*+°C. , a eolution of 111 g. of the primary monoacetate of l-phenylf2,2-rdimethyl-l,3-idihydroxypropane, 53 g. of triethylr amine and 200 ml, of toluene. After completion of the addition, agitation was continued, for 15 minutes followed by gradual addition, with agitation over a period of 1 hour, 150 ml. of ammonia water. During the addition, the reaction mixture was maintained at a temperature of 0" to 15°C. The reaction mass was the heated to 50°Cf under a slight pressure and agitated for a period of hours.

After cooling to room temperature, the reaction mass was washed successively with 100 ml. of a 15# aqueous solution of sodium carbonate, 100 ml. of a # aqueous solution of sodium bicarbonate and twice with 100 ml. of water. The organic part was separated and then ref uxed with 1 g. of activated carbon and filtered while hot* On cooling, the secondary carbamate of the glycol crystallised and was collected on a Buchner funnel. On recrystallisation from 200 ml. of toluene, l-phenyl-2,2-diraethyl-l,3-dlhydroxypropahe-l-carbamate was obtained.

The primary monoacetate of l-phenyl-2,2-dimethyl-l,3-dihydroxy-propane which was used in this Example was prepared in the same manner as the monoaoetate of 1-(^-chlorophenyi)^ «2-dimethyl-l,3-dihydroxypropane as described in Example 1 i except that 1/k mole of l-phenyl-2,2-dimethyl-l,3-dihydroxypropane is employed instead of 1/ mole of lr( -chlprophenyl)-2,2-dimethyl-l,3-dihydroxypropane.

: ' AHP .4.293 The. secondary monocarbamate of l-.phenyl-2,2-diraeth.yl-»... 1 , 3-dIhydroxypropane may also be produced by the utilisation of a lpwer alkyl chloroformate or an aryl chlproformate.

A solution of ethyl chloroformate was prepared by dissolving ·. at room temperature 53 g» o ethyl chloroformate in 150 ml. of. - toluene. Over a period of l-J hours at a temperature of 1 to- °C. , a solution of 111 g, of the primary monoacetate of l-phenyl-2, - dimethyl^l,3-dihydroxypropane, 53 g» of triethylamine and 200 ml, of toluene was added while agitating. After completion of the addition, agitation was continued for 15 minutes., followed by '•the''"1' gradual addition, with agitation over' a period of 'an hcuifc, -of 1 0 ml. of ammonia water.' During the addition, . the reaction mixture was maintained at a temperature of 0 to 15°C. The reaction mass was then heated to 50°C, under a slight pressure and agitated for 5 hours. After cooling to room temperature, the reaction mass was washed successively with 100 ml. of a 15 aqueous solution of sodium carbonate, 100 ml. of a 5 aqueous sodium bicarbonate solution and twice with 100 ml. of water. The organic part was separated and then refluxed with 1 g. of activated carbon and filtered while hot. On cooling, the secondary carbamate crystallised and was collected on a Buchner funnel. On recrystallisation from 200 ml. of toluene, the secondary carbamate of l-phenyl^2,2-dlmethyl-l,3- dihydroxypropane was obtained.

If desired, the secondary carbamate of l-phenyl-2, 2-dimethyl- 1,3-dihydrpxypropane may be produced by utilising an aryl chloroformate, such as phenyl chloroformate. In such preparation, 80 g. of phenyl chloroformate was employed instead of 55 g. of ethyl chloroformate.

The secondary hydroxyl of the monoacetate ester was reacted with the phenyl chloroformate to produce the secondary phenyl carbonate of the primary acetate of l-phenyl-2 , 2-dimethyl-l, 3-dihydroxypropane. The secondary phenyl carbonate of the primary the - -

Claims (1)

1. CLAIMS A monocarbamate which the is an alkyl radical or a aryl monoester cyclic carboxyllc acid monoalkyl acid monoester or mono aryl acid monoester glycol of the general formulae which and are groups in vhioh the total number of carbon is from 2 to and ring A is of the general wherein either R R and R are the same or different and each represents alkyl containing 1 to 5 carbo hydroxy o containing 1 to 5 carbon or and R together represent the atoms necessary to complete a methylenedioxy ring or a fused benzene ring and is f 2 monocarbamate of the general NH2 1 2 in which R and R have the meanings defined in 1 Claim A monocarbamate of the general in which R and R have the meanings defined in Claim An monocarbamate of the general in which 8 and have the meanings defined Claim and R is an alkyl radical containing 1 to 5 carbon atoms or an aryl radical A monochloroformate of the general formula CI in which R R R R and the meanings defined in Claim A 2 3 in which R R R and R have the meanings defined in Claim and R is an alkyl radical containing 1 to 5 carbon cyclic carbonate of the general in which R R R R and R have the meanings defined 1 in Claim compound as claimed in any of the preceding cyclic carbonate A monocarbamate of 15 A monomethyl or cyclic carbonate of A monocarbamate monoethyl carbonate or cyclic carbonate of A monocarbamate of dihydroxypr A monoethylcarbonate or cyclic carbonate of 20 A monocarbamate of 21 carbamate of the formula 22 25 24 25 dihydroxypropane JUS A monomethylcarbamate of A monophenylcarbamate of A monomethylcarbamate of 29 A monoethylcarbamate of 30 A monophenylcarbamate of 31 A monoethylcarbamate of 32 33 Which ring R and R the meanings defined in Claim reacting a glycol of the general formula which and R have the meanings defined with an ieocyanate of the general formula R 6NCO in which has the meanings defined A process for the preparation of carbonates of the general formula and R have the meanings defined with a raonohalo formate of the general formula 0 II 7 Hal C in which Hal is a halogen atom and R 7 has the meanings defined A process for the preparation of the cyclic carbonate of the glycol of the formula given in Claim which comprises reacting the glycol with A process for the preparation of the of the glycol of formula given in Claim which comprises reacting said glycol with carbonyl halide at temperatures below the cyclisatipn temperature of the said to be produced A process as claimed in Claim wherein the carbonyl halide is 38 A process as claimed in Claim wherein the reaction is carried out in the presence of an aniline in an organic solvent 38 A process as claimed in Claim or wherein the reaction is carried ut at temperatures of to 38 A process as claimed in Claim or wherein the cyclic carbonate is formed which on treatment with ammonia gas is converted mainly to the A process for the preparation of a acid of the glycol of the formula given in Claim or a carbonate or carbonate of this which comprises monoacylating glycol and if desired reacting the monoester formed with a cairbonyl A process for the preparation of a or monocarbamate of the glycol of the formula given in Claim which comprises reacting a carbonate of the general formula monocarbamate of the glycol of formula given in Claim which comprises reacting a monohaloformate or monoacyl monohaloformate thereof with ammonia or an amine of the R which R 6 is an or and if necessary saponifying h a satarting is used thus yielding the alcohol moiety and leaving the carbamate group A process as claimed any of Claims 34 to wherein A is a halophenyl A process as claimed in Claim the phenyl ring is a A process as in Claim wherein the glycol is A process as claimed in Claim wherein the glycol is reacted with phosgene at temperatures below in the presence of on followed by reaction with A process for the preparation of the compounds claimed in Claim substantially as described with reference to any of the Compounds as claimed in Claim hen produced by the process claimed i any of Claims 34 to A pharmaceutical composition comprising a monocarbamate or monocarbamate as claimed in any of Claims 1 to 8 to to 33 and 50 and a pharmaceutical A composition comprising insufficientOCRQuality