US2878158A - Carbamic acid ester of phenyl isopropyl carbinol - Google Patents

Carbamic acid ester of phenyl isopropyl carbinol Download PDF

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US2878158A
US2878158A US660479A US66047957A US2878158A US 2878158 A US2878158 A US 2878158A US 660479 A US660479 A US 660479A US 66047957 A US66047957 A US 66047957A US 2878158 A US2878158 A US 2878158A
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carbamic acid
ester
phenyl isopropyl
isopropyl carbinol
carbinol
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US660479A
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Stuehmer Werner
Funke Siegfried
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Kali Chemie AG
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Kali Chemie AG
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C271/00—Derivatives of carbamic acids, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups
    • C07C271/06—Esters of carbamic acids

Definitions

  • the present invention relates to a carbamic acid ester and more particularly to a carbamic acid ester of high sedative and analgetic activity and to a process of making same.
  • Carbamic acid esters of the formula wherein R is the ethyl, n-propyl, or n-butyl radical, i. e. a straight-chain alkyi radical, are known. Such esters, however, do not possess sedative or analgetic activity when orally administered to white mice in a dose of 200 mg. per kg.
  • Another object of the present invention is to provide a simple and effective process of making such a new and valuable carbamic acid ester of high sedative and analgetic activity.
  • Still another object of the present invention is to provide a therapeutically useful composition which not only possesses a high sedative activity but also produces surprising analgetic effects when administered orally.
  • the new and valuable carbamic acid ester of the present invention is the carbamic acid phenyl isopropyl carbinol ester of Formula II CeHs-CH-O O O .NH:
  • this compound in contrast to the known esters, is characterized by a branched alkyl radical R, namely, the isopropyl radical.
  • R branched alkyl radical
  • the sedative activity of this compound is surprisingly high so that it is significantly antagonistic to the stimulating activity of l-phenyl-Z-N-methylamino propane which is known to be a highly eifective arousal amine.
  • the new compound difiers in this respect essentially from the known carbamic acid esters as is evident from the following table wherein the sedative activity of the new compound is compared with that of the known compounds:
  • the new compound has a surprisingly high sedative activity on oral administration in contrast to the known compounds with straight chain alkyl radicals.
  • esters and the new compound exhibits a high analgetic acivity when administered to white mice in the dose of 200 milligram per kg. only, the .known straight-chain compounds mentioned hereinabove do not possess such an activity when administered in such a dose nor do they show any analgetic properties even when administered in an increased dose of 300 mg. per kg.
  • the new sedative ester is especially suitable for therapeutic purposes on account of its additional analgetic activity which is completely lacking in the known compounds.
  • carbamic acid phenyl isopropyl carbinol ester of Formula II is about 400 mg. daily while the maximum oral dose is as high as 3.6 g. daily.
  • the maximum single dose should preferably not exceed about 1.2 g.
  • the preferred dose in humans is about 1.2 g. daily given in three subdivided doses of 400 mg. each.
  • the new carbamic acid phenyl isopropyl carbinol ester may be prepared according to one of the following methods:
  • Phenyl isopropyl carbinol is reacted with cyanic acid according to the following equation whereby preferably an alkali cyanate is used as the one reaction component and the reaction is carried out in an inert organic solvent, especially methylene chloride, with the addition of an acid, such as trichloro acetic acid, at a temperature of about 50 C.
  • an alkali cyanate is used as the one reaction component and the reaction is carried out in an inert organic solvent, especially methylene chloride, with the addition of an acid, such as trichloro acetic acid, at a temperature of about 50 C.
  • Still another method of producing the new compound consists in heating phenyl isopropyl carbinol with urea or, respectively, with salts of urea such as urea nitrate,
  • Another method of producing the ester according to the present invention consists in first converting phenyl isopropyl carbinol by means of phosgene into the chloro carbonic acid ester of phenyl isopropyl carbinol and reacting said ester with ammonia. This reaction is illustrated by the following equations:
  • Example 1 A solution of 32.6 g. of trichloro acetic acid in 60 cc. of methylene chloride is added to 16.2 g. of potassium cyanate and 30 g. of phenyl isopropyl carbinol having a boiling point of 99-103 C./mm. The mixture is heated to boiling and is diluted by the addition of 90 cc. of methylene chloride. The precipitate is filtered off by suction. The filtrate is neutralized by the addition of alkali hydroxide solution and is evaporated to dryness in a vacuum on the water bath. The oily residue is purified by distillation. It boils at 126-140 C./3 mm. After recrystallization from cyclohexane, the resulting carbamic acid phenyl isopropyl carbinol ester of Formula II has a melting point of 82-84 C.
  • Example 2 4 g. of carbamyl chloride are added to g. of isopropyl carbinol while stirring and cooling. The reaction mixture is diluted with water and extracted with ether. After drying and distilling off the ether and excess phenyl isopropyl cabinol, the residue is dissolved in cyclohexane and is allowed to crystallize. The resulting crystalline carbamic acid phenyl isopropyl carbinol ester of Formula II has a melting point of 83-85 C. It is difficultly soluble in water.
  • Example 3 6 g. of urea and 0.4 g. of zinc acetate are added to 30 g. of phenyl isopropyl carbinol. The mixture is heated to 155 C. for 8 hours while stirring. Water is added. The separated oil is extracted with ether, and the ethereal solution is dried over sodium sulfate. After distilling ofi the ether, the residue is dissolved in hot ligroine and the solution is filtered and cooled. The precipitated carbamic acid phenyl isopropyl carbinol ester of Formula II is dissolved in cyclohexane and allowed to crystallize. It has a melting point of 8284 C.
  • Example 4 17.8 g. of carbamic acid ethyl ester are heated with 30 g. of phenyl isopropyl carbinol in a reaction vessel connected with a descending cooler to 210 C. for 8 hours. Thereby, the ethanol, split off during the reaction, is distilled oil. Water is then added to the reaction mixture. The precipitated oil is extracted with ether. The ethereal solution is dried over sodium sulfate and the ether is distilled off. The crude ester has a boiling point of 127-140 C./3 mm. On dissolving the crude product in lig-roine and allowing the solution to crystallize, the resulting carbamic acid phenyl isopropyl carbinol ester has a melting point of 82-84 C.
  • Example 5 15 g. of phenyl isopropyl carbinol of the boiling point of 99102 C./10 mm. are gradually added, while stirring, to an ice-cooled solution of 10 g. of phosgene in g. of water-free toluene. The reaction mixture is stirred until a clear solution is obtained. Thereafter, a suitable acid binding agent, for instance, 18.8 g. of 1,5-dimethyl 2-phenyl-3-pyrazolone, known as antipyrine, dissolved in as little chloroform as possible, is added to the reaction mixture in order to accelerate reaction between phosgene and the carbinol and stirring of the mixture is continued at room temperature until the reaction is completed.
  • a suitable acid binding agent for instance, 18.8 g. of 1,5-dimethyl 2-phenyl-3-pyrazolone, known as antipyrine, dissolved in as little chloroform as possible
  • Nitrogen is then passed through the apparatus and the precipitated antipyrine hydrochloride is filtered 01f by suction.
  • the filtrate is saturated with ammonia gas while stirring and cooling.
  • the precipitate which is readily soluble in water is filtered 01f and the toluene is removed by evaporation in a vacuum on a water bath. The residue is distilled. It boils at 132-136 C./3 mm.
  • the resulting carbamic acid phenyl isopropyl carbinol ester of Formula II is dissolved in cyclohexane and allowed to crystallize. It has a melting point of 83-84 C.
  • the new carbamic acid phenyl isopropyl carbinol ester of Formula II is preferably administered orally.
  • the preferred mode of administration is in the form of solid preparations such as tablets, pills, dragees, powders, capsules, or the like.
  • the commonly used carriers and diluting agents, binders, lubricants, and the like tableting adjuvants are employed, such as sugar, lactose, starch, pectin, bolus alba, as lubricants, stearic acid, magnesium stearate, and as binders, gelatin, gum arabic, methyl cellulose, carboxy ethyl cellulose, yeast extract, agar, tragacanth, and others. It is, of course, understood that any of the tableting materials conventionally used in pharmaceutical practice can be employed provided there is no incompatibility with the new sedative and analgetic agent.
  • compositions according to the present invention may vary. Ordinarily, capsules are administered which contain 400 mg. of the new ester. Tablets may also contain 400 mg. each of the active compound and in addition thereto the usual tableting adjuvants.
  • compositions in dosage unit form, said composition comprising about 400 mg. of the carbamic acid phenyl isopropyl carbinol ester of the formula CsHs-GH-O 0 C.NH2 CH-CH: CHs

Description

United CARBAMIC ACID ESTER F PHENYL ISGPROPYL CINOL Werner Stuehmer, Eidagsen, near Hannover, and Siegfried Funke, Hannover, Germany, assignors to Kali- Chemie Aktiengesellschaft, Hannover, Germany, a German stock company No Drawing. Application May 21, 1957 Serial No. 660,479
Claims priority, application Germany June 1, 1956 3 Claims. (Cl. 167-52) The present invention relates to a carbamic acid ester and more particularly to a carbamic acid ester of high sedative and analgetic activity and to a process of making same.
Carbamic acid esters of the formula wherein R is the ethyl, n-propyl, or n-butyl radical, i. e. a straight-chain alkyi radical, are known. Such esters, however, do not possess sedative or analgetic activity when orally administered to white mice in a dose of 200 mg. per kg.
It is one object of the present invention to provide a new and valuable carbamic acid ester which possesses high sedative activity and has a surprising analgetic effect which is not observed in the known carbamic acid esters.
Another object of the present invention is to provide a simple and effective process of making such a new and valuable carbamic acid ester of high sedative and analgetic activity.
Still another object of the present invention is to provide a therapeutically useful composition which not only possesses a high sedative activity but also produces surprising analgetic effects when administered orally.
Other objects of the present invention and advantageous features thereof will become apparent as the de scription proceeds.
The new and valuable carbamic acid ester of the present invention is the carbamic acid phenyl isopropyl carbinol ester of Formula II CeHs-CH-O O O .NH:
H-C H3 CH2 II It is evident that this compound, in contrast to the known esters, is characterized by a branched alkyl radical R, namely, the isopropyl radical. The sedative activity of this compound is surprisingly high so that it is significantly antagonistic to the stimulating activity of l-phenyl-Z-N-methylamino propane which is known to be a highly eifective arousal amine.
The new compound difiers in this respect essentially from the known carbamic acid esters as is evident from the following table wherein the sedative activity of the new compound is compared with that of the known compounds:
2,878,158 Patented Mar. 17, 195 9 ice sedative activity Oom- N 0. pound, R= white mice, rabbits, white mice, 300
200 mg./kg. 200 rug/kg. mgJkg. orally orally orally 1 Isopropyl- 10(t) efiec- 10%){75 efiec- 100% effective.
we. ve. 2 Ethyl inefiectivenot tested-" 503 11 to 60% eflccve. n-PropyL. do inefiective'. Do. n-Butyl-.. do -do Do.
It is evident that the new compound has a surprisingly high sedative activity on oral administration in contrast to the known compounds with straight chain alkyl radicals.
A further very important difference between the known esters and the new compound is to be seen in the high analgetic activity of the new ester. While said ester of Formula II exhibits a high analgetic acivity when administered to white mice in the dose of 200 milligram per kg. only, the .known straight-chain compounds mentioned hereinabove do not possess such an activity when administered in such a dose nor do they show any analgetic properties even when administered in an increased dose of 300 mg. per kg.
Thus, the new sedative ester is especially suitable for therapeutic purposes on account of its additional analgetic activity which is completely lacking in the known compounds.
The above mentioned pharmacological tests have been confirmed by clinical tests with humans. The minimum does of carbamic acid phenyl isopropyl carbinol ester of Formula II is about 400 mg. daily while the maximum oral dose is as high as 3.6 g. daily. The maximum single dose should preferably not exceed about 1.2 g. The preferred dose in humans is about 1.2 g. daily given in three subdivided doses of 400 mg. each.
The new carbamic acid phenyl isopropyl carbinol ester may be prepared according to one of the following methods:
Phenyl isopropyl carbinol is reacted with cyanic acid according to the following equation whereby preferably an alkali cyanate is used as the one reaction component and the reaction is carried out in an inert organic solvent, especially methylene chloride, with the addition of an acid, such as trichloro acetic acid, at a temperature of about 50 C.
C1a.C.COOH KNOO HO.CH.CaHs
CHzCiz lSO-CaH7 CUHs-CH-OOC.NH2 CI3.C.COOK
iSo-GzHr Another method of producing the new ester consists in reacting an excess of phenyl isopropyl carbinol with carbamyl chloride, while stirring and cooling. The reaction proceeds according to the following equations:
NH2.C 001+ HO.CH.C5H5
Still another method of producing the new compound consists in heating phenyl isopropyl carbinol with urea or, respectively, with salts of urea such as urea nitrate,
This re- CsH-CH-OOC.NH: 02 35011 Another method of producing the ester according to the present invention consists in first converting phenyl isopropyl carbinol by means of phosgene into the chloro carbonic acid ester of phenyl isopropyl carbinol and reacting said ester with ammonia. This reaction is illustrated by the following equations:
01.60.01 HO.Cl-I.CsHs Cl.CO0.CH.CsH H0 The following examples serve to illustrate the present invention and the method of producing the new ester without, however, limiting the same thereto.
Example 1 A solution of 32.6 g. of trichloro acetic acid in 60 cc. of methylene chloride is added to 16.2 g. of potassium cyanate and 30 g. of phenyl isopropyl carbinol having a boiling point of 99-103 C./mm. The mixture is heated to boiling and is diluted by the addition of 90 cc. of methylene chloride. The precipitate is filtered off by suction. The filtrate is neutralized by the addition of alkali hydroxide solution and is evaporated to dryness in a vacuum on the water bath. The oily residue is purified by distillation. It boils at 126-140 C./3 mm. After recrystallization from cyclohexane, the resulting carbamic acid phenyl isopropyl carbinol ester of Formula II has a melting point of 82-84 C.
Example 2 4 g. of carbamyl chloride are added to g. of isopropyl carbinol while stirring and cooling. The reaction mixture is diluted with water and extracted with ether. After drying and distilling off the ether and excess phenyl isopropyl cabinol, the residue is dissolved in cyclohexane and is allowed to crystallize. The resulting crystalline carbamic acid phenyl isopropyl carbinol ester of Formula II has a melting point of 83-85 C. It is difficultly soluble in water.
Example 3 6 g. of urea and 0.4 g. of zinc acetate are added to 30 g. of phenyl isopropyl carbinol. The mixture is heated to 155 C. for 8 hours while stirring. Water is added. The separated oil is extracted with ether, and the ethereal solution is dried over sodium sulfate. After distilling ofi the ether, the residue is dissolved in hot ligroine and the solution is filtered and cooled. The precipitated carbamic acid phenyl isopropyl carbinol ester of Formula II is dissolved in cyclohexane and allowed to crystallize. It has a melting point of 8284 C.
Example 4 17.8 g. of carbamic acid ethyl ester are heated with 30 g. of phenyl isopropyl carbinol in a reaction vessel connected with a descending cooler to 210 C. for 8 hours. Thereby, the ethanol, split off during the reaction, is distilled oil. Water is then added to the reaction mixture. The precipitated oil is extracted with ether. The ethereal solution is dried over sodium sulfate and the ether is distilled off. The crude ester has a boiling point of 127-140 C./3 mm. On dissolving the crude product in lig-roine and allowing the solution to crystallize, the resulting carbamic acid phenyl isopropyl carbinol ester has a melting point of 82-84 C.
Example 5 15 g. of phenyl isopropyl carbinol of the boiling point of 99102 C./10 mm. are gradually added, while stirring, to an ice-cooled solution of 10 g. of phosgene in g. of water-free toluene. The reaction mixture is stirred until a clear solution is obtained. Thereafter, a suitable acid binding agent, for instance, 18.8 g. of 1,5-dimethyl 2-phenyl-3-pyrazolone, known as antipyrine, dissolved in as little chloroform as possible, is added to the reaction mixture in order to accelerate reaction between phosgene and the carbinol and stirring of the mixture is continued at room temperature until the reaction is completed. Nitrogen is then passed through the apparatus and the precipitated antipyrine hydrochloride is filtered 01f by suction. The filtrate is saturated with ammonia gas while stirring and cooling. The precipitate which is readily soluble in water, is filtered 01f and the toluene is removed by evaporation in a vacuum on a water bath. The residue is distilled. It boils at 132-136 C./3 mm. The resulting carbamic acid phenyl isopropyl carbinol ester of Formula II is dissolved in cyclohexane and allowed to crystallize. It has a melting point of 83-84 C.
As stated above, the new carbamic acid phenyl isopropyl carbinol ester of Formula II is preferably administered orally. The preferred mode of administration is in the form of solid preparations such as tablets, pills, dragees, powders, capsules, or the like.
When preparing such tablets, pills, powders, and the like shaped solid preparations, the commonly used carriers and diluting agents, binders, lubricants, and the like tableting adjuvants are employed, such as sugar, lactose, starch, pectin, bolus alba, as lubricants, stearic acid, magnesium stearate, and as binders, gelatin, gum arabic, methyl cellulose, carboxy ethyl cellulose, yeast extract, agar, tragacanth, and others. It is, of course, understood that any of the tableting materials conventionally used in pharmaceutical practice can be employed provided there is no incompatibility with the new sedative and analgetic agent.
The content of the active compound in compositions according to the present invention may vary. Ordinarily, capsules are administered which contain 400 mg. of the new ester. Tablets may also contain 400 mg. each of the active compound and in addition thereto the usual tableting adjuvants.
Of course, many changes and variations in the method of preparing the new ester, in the methods of isolating and purifying said ester, in the dosage and mode of administration, and the like, may be made by those skilled in the art in accordance with the principles set forth herein and in the claims annexed hereto.
We claim:
1. An orally effective sedative and analgetic composition in dosage unit form, said composition comprising about 400 mg. of the carbamic acid phenyl isopropyl carbinol ester of the formula CsHs-GH-O 0 C.NH2 CH-CH: CHs
per dosage unit and a pharmaceutical carrier.
2. The carbamic acid phenyl isopropyl carbinol ester of the formula 5 6 from the reaction mixture the resulting carbamic acid ester.
CH3 References Cited in the file of this patent 3. In a process of producing the carbamic acid phenyl 5 UNITED STATES PATENTS isopropyl carbinol ester of the formula 2,197,479 Meigs p 1940 CuH5OHOOC.NHz
511-0113 FOREIGN PATENTS (5H; 10 532,464 France Sept. 22, 1920 $321? viiifi iii fik iif iiiiie ifififiififie$523 53; OTHER REFERENCES with the addition of trichloro acetic acid and recovering Beilstein, vol. 6, 2nd supp. (1944), p. 446.

Claims (1)

1. AN ORALLY EFFECTIVE SEDATIVE AND ANALGETIC COMPOSITION IN DOSAGE UNIT FORM, SAID COMPOSITION COMPRISING ABOUT 400 MG. OF THE CARBAMIC ACID PHENYL ISOPROPYL CARBINOL ESTER OF THE FORMULA
US660479A 1956-06-01 1957-05-21 Carbamic acid ester of phenyl isopropyl carbinol Expired - Lifetime US2878158A (en)

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Cited By (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3072710A (en) * 1960-12-15 1963-01-08 Smith Kline French Lab Process for the preparation of carbamates
US3098012A (en) * 1962-09-04 1963-07-16 Frosst & Co Charles E 1, 3-diphenylpropyl carbamate derivatives
US3161567A (en) * 1963-05-29 1964-12-15 Upjohn Co Process for relieving pain with 3-p-chlorophenoxy-2-hydroxy-propyl carbamate
US3265728A (en) * 1962-07-18 1966-08-09 Armour Pharma Substituted phenethyl carbamates
US3313692A (en) * 1958-04-21 1967-04-11 Armour Pharma Method of inducing calming and muscle relaxation with carbamates
US3450710A (en) * 1967-01-06 1969-06-17 Merck & Co Inc Process for the preparation of nitroimidazole carbamates
US4145557A (en) * 1975-08-28 1979-03-20 Eli Lilly And Company (Phenoxyphenyl) alkyl acetates, propionates, and carbamates
CN102060735A (en) * 2011-01-18 2011-05-18 杭州澳赛诺化工有限公司 Synthesis method of carbamic acid tertiary alkyl ester

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
FR532464A (en) * 1920-09-22 1922-02-04 Ets Poulenc Freres Preparation of urethanes of secondary alcohols with an aromatic nucleus
US2197479A (en) * 1936-01-04 1940-04-16 Du Pont Carbamic acid esters of monoalkyl ethers of polyalkylene glycols

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
FR532464A (en) * 1920-09-22 1922-02-04 Ets Poulenc Freres Preparation of urethanes of secondary alcohols with an aromatic nucleus
US2197479A (en) * 1936-01-04 1940-04-16 Du Pont Carbamic acid esters of monoalkyl ethers of polyalkylene glycols

Cited By (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3313692A (en) * 1958-04-21 1967-04-11 Armour Pharma Method of inducing calming and muscle relaxation with carbamates
US3072710A (en) * 1960-12-15 1963-01-08 Smith Kline French Lab Process for the preparation of carbamates
US3265728A (en) * 1962-07-18 1966-08-09 Armour Pharma Substituted phenethyl carbamates
US3098012A (en) * 1962-09-04 1963-07-16 Frosst & Co Charles E 1, 3-diphenylpropyl carbamate derivatives
US3161567A (en) * 1963-05-29 1964-12-15 Upjohn Co Process for relieving pain with 3-p-chlorophenoxy-2-hydroxy-propyl carbamate
US3450710A (en) * 1967-01-06 1969-06-17 Merck & Co Inc Process for the preparation of nitroimidazole carbamates
US4145557A (en) * 1975-08-28 1979-03-20 Eli Lilly And Company (Phenoxyphenyl) alkyl acetates, propionates, and carbamates
CN102060735A (en) * 2011-01-18 2011-05-18 杭州澳赛诺化工有限公司 Synthesis method of carbamic acid tertiary alkyl ester

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