DE1243668B - Process for the preparation of N-isopropyl-2-methyl-2-sec.-butyl-1,3-propanediol dicarbamate - Google Patents

Description

GERMAN

PATENT OFFICE

EDITORIAL

German class: 12 ο -17/01

Number: 1 243 668

File number: C 20044 IV b / 12 ο

Filing date: October 27, 1959

Opened on: July 6, 1967

The invention relates to the preparation of a new organic compound with strong muscle relaxant Effect.

Many medicines are already known which are used for the purpose of relieving muscle spasms, which by various diseases and disorders, such as B. rheumatic and related Illnesses, cerebral palsy and various neurological disorders can be used will. For many years salicylates have been used for this purpose, but they are not generally effective as they relieve pain for a short period of time. Later 3-o-toloxy-1,2-propanediol Used on a larger scale in various cases when muscle paralysis has occurred. The main disadvantage of this compound is its short duration of action. The newest drug, which 2-methyl-2-n-propyl-1,3-propanediol dicarbamate is widely used for the relief of muscle cramps. The muscle relaxing effect of this agent is similar to that of S-o-Toloxy-l ^ -propanediol, but of greater strength and longer duration.

The subject of patent 1,068,242 is a process for the preparation of N-monosubstituted propanediol diccarbamates the general formula

CH ₃

η -C ₃ H ₇

CH ₂ OCONHR

CH ₂ OCONH ₂

where R is a saturated aliphatic hydrocarbon radical having 2 to 4 carbon atoms, the consists in either using a monocarbamate of the general formula

CH ₃ CH ₂ O-CO-NHR

nC ₃ H ₇

CH ₉ OH

where R has the above meaning,

a) with cyanic acid or

b) with the carbamic acid ester of a low-boiling alcohol or

c) first reacts with phosgene and then the chlorocarbonate formed with ammonia lets react

or that one is a monocarbamate of the general formula

CH ₃ CH ₂ -OCONH ₂

nC ₃ H ₇

CHoOH

Process for the preparation of N-isopropyl-2-methyl-2-sec.-butyl-1,3-propanediol dicarbamate

Addendum to the patent: 1,068,242

Applicant:

Carter Products, Inc.,

New York, N.Y. (V. St. A.)

Representative:

Dr. H. H. Willrath, patent attorney,

Wiesbaden, Hildastr. 18th

Named as inventor:

Frank MiIa Berger, Princeton, N. J .;

Bernard John Ludwig,

North Brunswick, N. J. (V. St. A.)

Claimed priority:

V. St. v. America June 11, 1959 (819 552)

a) first reacting with phosgene and then _{allowing the chlorocarbonate formed thereby to react with an amine RNH 2} , where R has the meaning given above, or

b) with an isocyanate of the general formula

R-N = C = O

implements.

A further development of this process has now been found in that one is known per se Way either a monocarbamate of the formula

CH;

³ \

sec.-CHn

, CH ₂ O - CO - NH-ISO-C ₃ H ₇

CH ₂ OH

a) with cyanic acid or

b) with the carbamic acid ester of a low-boiling alcohol or

709 609/451

c) first reacts with phosgene and allows the resulting chlorocarbonate to react with ammonia,
or that one is a monocarbamate of the formula

CH ₃

sec.-C ₄ H "

CHo-OCONH ₂

CH ₂ OH

a) initially
arise

reacts with phosgene and the ^ chlorocarbonate then with isopropyl

lets or

with isopropyl acrylate
implements.

The new compound which can be prepared by the method of the invention has unexpected muscle relaxing activity. For comparison, the mean paralyzing dose (PD ₆₀ ) and the mean lethal dose (LD ₆₀ ) in mice after intraperetoneal administration were determined. While the well-known 2-methyl-2-n-propyl-1,3-propanediol dicarbamate (meprobamate) has a PD ₅₀ value of 235 mg / kg and an LD ₅₀ value of 800 mg / kg, the PD ₅₀ value lies of the compound prepared according to the invention at 90 mg / kg and the LD ₅₀ value at 55 mg / kg. As could be shown by further comparative experiments, this improved muscle-relaxing effectiveness is apparently based at least in part on the substitution of one and not more than one of the four hydrogen atoms of the carbamate nitrogen by the aliphatic group. However, the type of alkyl groups in the 2-position also influences the effectiveness of the agent. Also compared to the Nn-butyl-2-methyl-2-n-propyl-1,3-propanediol dicarbamate known from Belgian patent specification 567 079 with a PD ₅₀ value of 94 mg / kg and an LD ₅₀ value of 514 mg / kg, the compound prepared according to the invention has improved efficacy, since the paralyzing dose is even smaller, while the lethal dose is considerably larger.

The compound which can be prepared by the process of the invention is a colorless substance with a melting point of 78 to 89 ^° C. It is soluble in most organic solvents, but only sparingly soluble in water at room temperature. It is easily hydrolyzed by hot alkali or strongly acidic solutions.

In the following, the method of making the connection is explained by means of some exemplary embodiments, which describe different procedures which can be used alternately. Unless otherwise stated, parts are to be understood as parts by weight.

example 1

55

Preparation of N-isopropyl-2-methyl-2-secbutyl-1,3-propanediol dicarbamate after the urethane

method

To remove all traces of residual water, 24.6 parts of N-isopropyl-2-methyl-2-sec.-butyl-3-hydroxypropylcarbamate, 10.7 parts of urethane and 200 parts of xylene distilled. The mixture is cooled and 1 part of aluminum isopropoxide is added. The mixture is then distilled for so long to almost or substantially the theoretical amount of ethanol in the form of its azeotropic mixture is distilled off with xylene. The xylene is removed by distillation under reduced pressure, and 100 parts of water are added. The water is distilled off under reduced pressure and the residue dissolved in 150 parts of isopropanol.

The insoluble compounds are removed by filtration and the isopropanol is passed through Distillation removed. After cooling, 15 g of a purified product with a melting point are obtained = 78 to 80 ° C obtained.

Example 2

Production of N-isopropyl-2-methyl-2-sec-

butyl-1,3-propanediol dicarbamate from the mono-

carbamate using the phosgene process

A cooled 10 ° / ₀ solution of 0.1 mole of phosgene in toluene is added with stirring to a cooled solution of 0.1 mol of 2-methyl-2-sec-butyl-3-hydroxypropylcarbamate and 0.11 mol of pyridine in toluene added at such a rate as to maintain the temperature of the reaction mixture at about 0-5 ° C. The mixture is then warmed to 25 ° C. and then stirred for several hours. The pyridine hydrochloride is removed by filtration, the toluene is distilled off under reduced pressure and the residue is dissolved in dry ether. 0.2 mol of isopropylamine, dissolved in dry ether, is added to this solution, and the mixture is warmed to room temperature, the reaction taking place. The excess amine is removed by extraction with dilute hydrochloric acid and the ether layer is concentrated by evaporation of the solvent. The desired compound is deposited in the form of crystals. F. = 78 to 8O ⁰ C. The yield is about 70 ° / ₀ of theory.

Example 3

Production of N-isopropyl-2-methyl-2-sec-

butyl l, 3-propanediol dicarbamate with isopropyl

isocyanate

189 parts of 2-methyl-2-sec.-butyl-3-hydroxyρroρylcarbamate and 100 parts of isopropyl isocyanate are added to 1,250 parts of dry benzene and the mixture is heated under reflux conditions for 8 hours. The solvent is removed by distillation under reduced pressure and the residue is dissolved in approximately 1,800 parts of warm trichlorethylene hexane solvent. On cooling, the compound separates out in the form of colorless crystals, which are separated off and dried. The yield of the purified compound is about 75 ° / ₀ of the theoretical amount. The purified compound has a melting point = 78 to 8O ⁰ C.

Example 4

Production of N-isopropyl-2-methyl-2-sec-

butyl-1,3-propanediol dicarbamate with sodium

cyanate

0.1 mol of N-isopropyl ^ -methyl ^ -sec.-butyl-S-hydroxypropylcarbamate and 0.11 mol of dry sodium cyanate are ^{stirred in 200 cm 3 of} dry chloroform. While cooling, dry hydrogen chloride is bubbled into the stirred mixture for 5 hours while the temperature is maintained at 0 to 5 ° C. After standing overnight, the

solid compounds are removed by filtration, and the chloroform solution is removed by evaporation of the Concentrated solvent. The residue is purified by crystallization from a toluene solution. 18 g of the compound are obtained.

Example 5

Preparation of N-isopropyl-2-methyl-2-secbutyl-1,3-propanediol dicarbamate with isopropylamine

To 18.9 g of 2-methyl-2-sec-butyl-3-hydroxypropyl carbamate and 9.5 g of pyridine in 150 cm ^{3 of} dichloromethane, 17.1 g of phenyl chlorocarbonate in 50 cm ^{3 of} dichloromethane are slowly added with stirring. After a reaction time of 2 hours at room temperature, the solvent is removed under reduced pressure. The liquid residue is cm heated under reflux for 6 hours with 52 ³ 50 ° / ₀ aqueous Isopropylamins. The reaction mixture obtained is concentrated under reduced pressure, the residue, dissolved in ether, is extracted with dilute hydrochloric acid and then with an aqueous potassium carbonate solution and dried over dry potassium carbonate. The solvent is then removed and the residue is made to crystallize by adding a hexane-ether mixture. There are 12 g of a purified product with a melting point = 78 to 8O ⁰ C. were obtained.

The N - isopropyl - 2 - methyl - 2 -sec produced by the process of the invention. - butyl -1,3 - propanediol dicarbamate is preferably taken orally in the form of pills, tablets, capsules or solutions, which after known methods can be administered. If the active ingredient is in the form of a solid compound is present, a characteristic tablet composition has 0.5 g of the active Compound that comes as a dry powder with gelatin, starch, magnesium stearate and alginic acid in tablet form is pressed. If the active compound is in the form of a liquid, it becomes a suitable solvent dissolved. In general, the effective dose of the active ingredient will be within Range from about 0.05 to 2 g.

Claims (1)

Claim: Further development of the process for the preparation of N-monosubstituted propanediol dicarbamates the general formula CH _a nC ₃ H, CH ₂ OCONHR CHoOCONH, where R is a saturated aliphatic hydrocarbon radical with 2 to 4 carbon atoms, according to patent 1,068,242, characterized in that in a manner known per se either a monocarbamate of the formula CH ₃ CH ₂ O - CO - NH-ISO-C ₃ H ₇ sec-C ₄ H ₉ CH ₂ OH a) with cyanic acid or b) with the carbamic acid ester of a low-boiling alcohol or c) initially reacted with phosgene and the resulting chlorocarbonate then with ammonia lets react or that one is a monocarbamate of the formula CH ₃ sec.-C ₄ H ₉ CH ₂ - OCONH ₂ CH.OH a) initially reacted with phosgene and the resulting chlorocarbonate then with isopropylamine lets react or b) with isopropyl isocyanate
implements. Considered publications:
Opened documents of Belgian patent No. 567 079. 709 609/451 6 67 © Bundesdruckerei Berlin