DE1068242B - Process for the preparation of N-monosubstituted propanediol diicarbamates - Google Patents

Description

co 7c £ m4-

GERMAN

The invention relates to new organic compounds which have a muscle tensioning effect of high activity. Heretofore, many drugs have been used for the purpose of reversing muscle plasma caused by various disorders, e.g. B. rheumatic and related disorders, cerebral palsy and various neurological conditions is caused. Salicylates have been used for this purpose for many years, but they have not been universally effective; because it only cured painful discomfort for a short time. Later, (3-o-toloxy-1,2-propanediol was used extensively in a variety of conditions in which muscle plasma is a factor. The very short duration of action of this compound is its greatest disadvantage. The newest drug which has found widespread inclusion to dissolve muscle plasma , is 2-methyl-2-n-propyl-1,3-propanediol dicarbamate. Its muscle relaxing effect is similar to that of the first mentioned compound, but of greater potency and longer duration.

It has now been found that N-monosubstituted dicarbamates of the general formula

CH ₅

CH ₉ OCONHR

for the production of N-monosubstituted propanediol dicarbamates

Applicant:

Carter Products, Inc.,
New York, NY (V. St. A.)

Representative: Dr. H.-H. Willrath, patent attorney, Wiesbaden, Hildastr. 32

Claimed priority:
V. St. v. America April 24, 1957 and April 18, 1958

Frank Milan Berger, Princeton, NJ,
and Bernard John Ludwig, North Brunswick, N. J.

(V. St. A.),
have been named as inventors

η-C ₃ H ₇

CH ₉ OCONH,

where R is a saturated aliphatic hydrocarbon radical with 2 to 4 carbon atoms, a muscle relaxing one Have an effect of greater potency than any previously used muscle relaxant. According to the invention, they are prepared in such a way that either a monocarbamate of the general formula

CH, CH ₉ O-CO-NHR

η -C ₃ H ₇ CH ₂ 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 reacting with phosgene and then allowing the chlorocarbonate formed to react with ammonia;

or that one is a monocarbamate of the general formula

CH,

η-C ₃ H ₇

CH ₂ -OCONH ₂

CH ₂ OH

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

b) with an isocyanate of the general formula

35 R-N = C = O

implements.

The new N-monosubstituted dicarbamates have an unexpectedly intense muscle relaxing activity. This can be seen from the results in Table 1, which lists the mean paralyzing doses and mean leta doses obtained in mice after intraperitoneal administration of a number of related propanediol dicarbamate compounds. The PD ₆₀ and LD ₅₀ doses are expressed in millimoles (mm) of active ingredients per kilogram of mouse weight. The compounds listed in Table 1 below consist of 2,2-disubstituted N-monosubstituted 1,3-propanediol dicarbamates, including the new compounds; 2,2-disubstituted Ν, Ν-disubstituted 1,3-propanediol carbamates; 2,2-disubstituted N, N'-disubstituted 1,3-propanediol dicarbamates; 2,2-disubstituted Ν, Ν, Ν ', Ν'-tetrasubstituted 1,3-propanediol dicarbamates and, as a control, 2-methyl-2-propyl-1,3-propanediol dicarbamate.

909 647/426

Table 1

Y '

R. R ' χ H IS F χ " Y ' PD, ₀ LD ₅₀ ^ CH ₃ η - C ₃ H ₇ CH ₃ H H 235 800 t CHg η-C ₃ H, C ₂ H ₅ H H H 290 730 % CHg η - C ₃ H, η-C ₃ H, H H H 170 700 <* CH ₃ η-C ₃ H, Iso - C ₃ H, H H H 146 790 J-CH ₃ η-C ₃ H, η-C ₄ H ₉ H H H 153 790 A CH ₃ η-C ₃ H, IsO-CjH ₁₁ H H H j 94 514 j CH ₃ η - C ₃ H, Benzyl H H H ~ '620 940 / CH ₃ η-C ₃ H, C ₂ H ₅ H H H 1400 1400 * "C ₂ H ₅ C ₂ H ₅ CH ₃ H H H 530 940 'CH ₃ η - C ₃ H, C ₂ H ₅ H CH ₃ H 315 730 * 1 CH ₃ η-C ₃ H, CH ₃ H C ₂ H ₅ H 560 1020 y £ CH ₃ η-C ₃ H, C ₂ Hj CH ₃ H H 570 900 ^ $ CHg η-C ₃ H, C ₂ H ₅ C ₂ H ₅ H H 370 735 ^, / C ₂ H ₅ C ₂ H ₅ C ₂ H ₅ C ₂ H ₅ C ₂ H ₆ C ₂ H ₅ convulsive 650 , / 1 CH ₃ η-C ₃ H ₇ C ₂ H ₅ C ₂ H ₅ C ₂ H ₅ C ₂ Hj convulsive 940 - CH ₃ η - C ₃ H ₇ Iso-C ₄ H ₉ H C ₂ H ₅ H 560 1020 CH ₃ η-C ₃ H, H H H 175 940

The results compiled in Table 1 show the unexpectedly high muscle relaxing activity of the new connections. Apparently the increased activity depends on N- and / or N'-substituted dicarbamates compared to the known 2-methyl-2-propyl-1,3-propanediol dicarbamate of the substitution of one and not more than one of the 4 hydrogen atoms from the carbamate nitrogen atom with an aliphatic group are attached. Second, the nature of the aliphatic group affects the activity. It can therefore be seen that not every ^ -methyl ^ -n-propyl-N- and / or or N'-substituted 1,3-propanediol carbamate has improved activity compared to the control substance, but only one Compound according to the invention. As the results of Table 1 show, it was actually found that im generally the substitution of aliphatic groups in place of more than one of the 4 hydrogen atoms attached to the 2 carbamate nitrogen atoms of the control substance are attached, the muscle relaxation activity is rather reduced than increased. Also, the surprisingly improved muscle relaxing activity that the new Have connections, as clearly shown by the fact that other representatives of this particular class, d. H. 2,2-disubstituted N-monosubstituted propanediol dicarbamates, to which the compounds according to the Invention, have a far less muscle-relaxing effect than the control substance and this is of course even less than the unique muscle-relaxing activity of the new compounds.

These are colorless liquids with a high boiling point or low-melting solids. You are in the Soluble in most organic solvents, but only weakly in water at ordinary room temperature soluble. By hot caustic solution or strongly acidic solution they are with the formation of the corresponding diol, of Ammonia, a primary amine, and carbon dioxide are easily hydrolyzed.

A. Manufacture of raw materials
Example A.

Production of 5-methyl-5-n-propyl-2-m-dioxanone

132 parts of 2-methyl-2-n-propyl-1,3-propanediol and 113 parts of diethyl carbonate were mixed in a suitable vessel equipped with an effective distillation column. The mixture was freed from moisture by distilling a small portion of the diethyl carbonate. After cooling, approximately 1 part of sodium ethylate was added. The distillation was continued until practically the theoretical amount of ethanol at about 78 ° C had distilled off. A further 10 parts amount of diethyl carbonate was added and distillation continued until the ethanol was completely removed. The mixture was cooled and diluted with an equal volume of diethyl ether. This solution was washed with dilute hydrochloric acid saturated with sodium chloride and then with water. Using a suitable drying agent, drying was carried out and the solvent was removed. The residue was distilled under reduced pressure. The fraction distilling below 0.1 mm at 125 to 130 ° C. was collected as a clear, colorless, oily liquid n ² £ = 1.4506. A yield of 80 ° / ₀ of the theoretical amount of 5-methyl-5-n-propyl-2-m-dioxanone was obtained.

g Example B

Production of

2-methyl-2-n-propyl-3-oxypropyl carbamate
5 parts of 5-methyl-5-n-propyl-2-m-dioxanone and 7.5 parts of liquid ammonia were placed in a cooled stainless steel pressure bomb and the jar sealed.

The vessel was warmed to room temperature and at that temperature with occasional shaking Allowed to stand for 24 to 48 hours. The vessel was cooled, opened and the excess ammonia evaporated calmly. The monocarbamate obtained as a low melting point substance was crystallized out purified a toluene-ligroin mixture. About 4 parts of the purified product were in the form of a colorless obtained crystalline substance which was slightly soluble in water; Melting point 61.5 to 62.5 ° C.

Example C

Production of
Nn-propyl - ^ - methyl ^ -n-propyl-S-oxypropyl carbamate

55 parts of 5-methyl-5-n-propyl-2-m-dioxanone and 41 parts of n-propylamine were mixed in a suitable vessel equipped with a reflux condenser. The mixture was heated slowly and refluxed for 2 hours. The excess amine was removed by distillation and the residue was distilled under reduced pressure. The at 114 to 117 ⁰ C under 0.02 mm boiling fraction was collected in a yield of 80 ° / ₀ of theory. This product was a viscous, colorless oil with the physical constants and analysis shown in Table 2.

Example D

Production of N-ethyl-2-methyl-2-n-propyl-3-oxy-propylcarbamate

158 parts of 5-methyl-5-n-propyl-2-m-dioxanone were stirred at room temperature with 75 parts of a 70 ° / _o solution of ethylamine in water was, until the reaction is complete. The excess amine was removed by dissolving the mixture in ether and extracting with dilute hydrochloric acid. The ether was removed from the organic layer and the residue was purified by distillation under reduced pressure. The fraction distilling at 110 to 112 ^° C. below 0.02 mm was collected. It had the physical constants listed in Table 2 together with an analysis.

Example E.

Preparation of N-isobutyl-2-methyl-2-n-propyl-3-oxy-propyl carbamate

55 parts of 5-methyl-5-n-propyl-2-m-dioxanone, 51 parts of isobutylamine and 75 parts of ethanol were left to stand at room temperature overnight. The ethanol and excess amine were then removed by distillation under reduced pressure. The oily residue remaining was dissolved in ethyl ether and extracted with dilute hydrochloric acid to remove the residual amine, and then extracted with water. The ether solution was dried over a suitable drying agent and the solvent was removed by evaporation. The crude N-isobutyl ^ -methyl ^ -n-propyl-S-oxypropyl carbamate was purified by distillation under reduced pressure. The fraction boiling at 118 to 119 ° C under 0.06 mm pressure was collected. A yield of 50 parts of (62 ° / ₀ of theory) of purified compound with the analytical values and ίο physical constants, such as those listed in Table 2 was obtained.

Example F

Preparation of 2-methyl-2-n-propyl-3-oxypropyl chlorocarbonate

A cooled 10 ° / ₀ solution of 1 mole of phosgene in toluene was added with stirring to a cooled solution of 1 mole of 2-methyl-2-n-propyl-l, 3-propanediol and 2 moles dimethylaniline, also dissolved in toluene were added at such a rate that the temperature of the mixture was maintained at about 25 ° C. The mixture was kept at this temperature for several hours, then cooled and extracted with cold 5 ° / _o hydrochloric acid solution to the dimethylaniline to remove. The toluene layer was dried using a suitable drying agent and the chlorocarbonate was used in subsequent reactions as its solution in anhydrous toluene.

Example G

Manufacture of N-n-Butyl ^ -methyl ^ -n-propyl-3-oxypropylcarbamate

A quantity of a solution containing 0.1 mol of the chlorocarbonate obtained as described in Example F was treated with 0.2 mol of anhydrous n-butylamine and allowed to react at ordinary room temperature. The solution was cooled, extracted with dilute hydrochloric acid and the organic layer concentrated by evaporation of the solvent. The crude was purified monocarbamate mm by distillation at 107-108 ⁰ C under about 0.01. It was a clear viscous liquid with the physical constants and analytical values shown in Table 2.

Example H

Preparation of N-isopropyl-2-methyl-2-n-propyl-3-oxypropyl carbamate

This compound was made from 2-methyl-2-n-propyl-3-oxypropyl chlorocarbonate and isopropylamine prepared according to the method used in Example G. The product had the physical constants and analytical values listed in Table 2.

Table 2
N-substituted 2-methyl-2-n-propyl-3-oxypropyl carbamates

N-alkyl group

formula

Analysis-N calculated found

Refractive

Kp. In ° C (mm)

Ethyl ...
n-propyl
Isopropyl
η-butyl.
Isobutyl.

C ₁₀ H ₂₁ O ₃ N
C ₁₁ H ₂₃ O ₃ N
C ₁₁ H ₂₃ O ₃ N
C ₁₂ H ₂₅ O ₃ N
C ₁₂ H ₂₅ O ₃ N

6.89 6.45 6.45 6.06 6.06 6.83
6.76
6.21
6.06
5.96

1.4589
1.4579
1.4543
1.4579
1.4586

110 to 112 (0.02)
114 to 117 (0.02)
86 to 88 (0.01)
107 to 108 (0.01)
118 to 119 (0.06)

B. Manufacture of the new dicarbamates

example 1

Production of N-n-propyl-2-methyl-2-n-propyl-1, 3-propanediol dicarbamate

22 parts of Nn-propyl ^ -methyl ^ -n-propyl-S-oxypropylcarbamate and 10 parts of ethyl urethane were dissolved in 250 parts of anhydrous xylene in a suitable vessel equipped with an efficient distillation column. 2 parts of aluminum isopropoxide were added; then the mixture was heated to the boil and the distillation was continued until practically the theoretical amount of ethanol had been distilled off in the form of an azeotrope with xylene. Most of the solvent was removed by distillation under reduced pressure. 100 parts of water were added; then it was distilled under reduced pressure in order to remove the remaining traces of xylene. 50 parts of isopropanol were added and distilled off to remove the remaining water; the residue was taken up in 100 parts of isopropanol. The solution was clarified by filtration, concentrated by evaporating the isopropanol and the residue was distilled under reduced pressure. The fraction distilling below 0.02 mm at 144 to 147 ° C was collected. This product was viscous in a yield of 72 ° / ₀ of theory in the form of a bit obtained clear, oily liquid with the listed in Table 3.

Example 2
Production of N-isopropyl-2-methyl-

2-n-propyl-1,3-propanediol dicarbamate
1 mole of N-isopropyl ^ -methyl ^ -n-propyl-S-oxypropylcarbamate and 1.1 moles of ethyl urethane were reacted in an ester exchange reaction, which is described in Example 1. The product obtained after removal of the isopropanol solvent was obtained as a crystalline substance, which was purified by recrystallization from an aqueous isopropanol solution. It had the properties and analytical values set out in Table 3.

Example 3

Production of Nn-butyl-2-methyl-2-n-propyl-1,3-propanediol dicarbamate
This compound was prepared from Nn-butyl-2-methyl-2-n-propyl-3-oxypropylcarbamate and ethyl urethane by the method described in Example 1. The properties and analytical values of the purified product are listed in Table 3.

Example 4

Production of N-ethyl-2-methyl-2-n-propyl-1,3-propanediol dicarbamate
22 parts of N-ethyl - 2 - methyl - 2 - η - propyl - 3 - oxypropylcarbamate were reacted in an ester exchange reaction with 15 parts of ethyl urethane using aluminum isopropoxide as a catalyst in anhydrous toluene in a vessel which, as described in Example 1, was reacted with a distillation column was equipped. The product obtained had the properties and analytical values listed in Table 3.

Example 5

Production of N-isobutyl-2-methyl-

2-n-propyl-1,3-propanediol dicarbamate

22.1 parts of N-isobutyl ^ -methyl ^ -n-propyl-S-oxypropyl-

carbamate and 9.8 parts of urethane were dissolved in 300 parts of anhydrous xylene in a suitable vessel, which was equipped with an efficient distillation column. Xylene was distilled to remove traces of water from the To remove mixture. 2.3 parts of aluminum isopropoxide were added and the distillation was continued, until practically the theoretical amount of ethanol had been distilled off at about 78 ° C. The reaction mixture was then freed from xylene by distillation under reduced pressure. About 100 parts of water were added and the mixture was again removed by distillation under reduced pressure

ίο Solvent freed. 100 parts of trichlorethylene were added; then the solution was filtered to remove insoluble water and the solvent was removed by evaporation. The remaining oil was purified by molecular distillation at a pressure of about 0.01 mm. 8.7 parts (35 ° / ₀ of the theoretical yield) of purified N-isobutyl-2-methyl-2-n-propyl-1,3-propanediol were viscous in a form obtained colorless oil which physical listed in Table 3, and analytical Had constants.

Example 6

Preparation of N-n-propyl-2-methyl-2-n-propyl-1,3-propanediol dicarbamate

A cooled 10 ° / ₀ solution of 0.1 mole of phosgene in toluene was added with stirring to a cooled solution of 0.1 mol of 2-methyl-2-n-propyl-3-oxypropylcarbamat and 0.11 mol of pyridine, also dissolved in toluene, was added at a rate such that the temperature of the mixture was maintained at about 0-5 ° C. The mixture was allowed to ^{warm to 25 °} C. and stirred for several hours. The pyridine hydrochloride was filtered off, the toluene was removed by distillation under reduced pressure and the residue was dissolved in anhydrous ether. The solution was filtered and the chlorocarbonate used in the following reactions in the form of its solution in anhydrous ether. To this solution, 0.2 mol of n-propylamine was added and the mixture was allowed to react at room temperature. The excess amine was extracted by extraction with dilute hydrochloric acid solution and the ether layer was concentrated by evaporating the solvent. The residue was purified by distillation under reduced pressure and gave a product identical to that obtained in Example 1.

Example 7

Preparation of N-n-propyl-2-methyl-1,2-n-propyl-1 , 3-propanediol dicarbamate, N-n-propyl ^ -methyl ^ -n-propyl-S-oxypropylcarbamate was converted into its chlorocarbonate derivative by adding phosgene and pyridine as described in Example 6, used. A solution of this chlorocarbonate in ether was made at room temperature with an excess treated on dry ammonia gas by adding the gas to the agitated solution of the chlorocarbonate with cooling was blown in. The mixture was allowed to warm to room temperature and stirred for about 1 hour. The excess ammonia was removed by extraction with dilute hydrochloric acid; insulation and purification were carried out as described in Example 6. The product obtained was identical to that after Examples 1 and 6 obtained.

Example 8

Production of N-n-butyl-2-methyl-2-n-propyl-1,3-propanediol dicarbamate 175 parts of 2-methyl-2-n-propyl-3-oxypropyl carbamate and 108 parts of n-butyl isocyanate became 1,250 parts anhydrous benzene and the mixture under

Boiled reflux for about 8 hours. The solvent was removed by distillation under reduced pressure and the residue was dissolved in approximately 1800 parts of warm trichlorethylene-hexane solvent (ratio 1: 2). On cooling, the product separated out in the form of colorless crystals which, after removing the solvent and drying, melted ^{at 49 to 51 ° C.} The yield of the purified compound was about 80 ° / ₀ of theory. Analysis: Calculated for C ₁₃ H ₂₆ O ₄ N _2: nitrogen 10.21%, found: nitrogen 10.42 ° / _0th This compound can also be purified by distillation under reduced pressure. The compound distills at approximately 150 to 152 ° C under a pressure of 0.06 mm. The product obtained by distillation can be converted into a crystalline substance by subjecting it to the above-mentioned crystallization process.

Example 9

Preparation of N-isopropyl-2-methyl-2-n-propyl-1,3-propanediol dicarbamate
21.7 g (0.1 mol) of N-isopropyl ^ -methyl ^ -n-propyl-S-oxypropyl carbamate and 7.5 g (0.11 mol) of anhydrous sodium cyanate were ^{stirred with 200 cm 3 of} anhydrous chloroform in a suitable vessel equipped with a gas inlet pipe, a stirrer and a thermometer. While the vessel was cooling, anhydrous hydrogen chloride was slowly bubbled into the stirred mixture over a period of 5 hours while maintaining the temperature between 0 and 5 ° C. The mixture was then left to stand at room temperature overnight. The solid was removed by filtration

ίο separated and the chloroform solution concentrated to an oil under reduced pressure. The oil was dissolved in 50 cm ^{3 of} trichlorethylene, the solution treated with animal charcoal, filtered and the filtrate added to 125 cm ^{3 of} hexane. The crystalline material that formed on standing at refrigerator temperature was removed by filtration, washed with light petroleum ether and dried at about 50.degree. Approximately 20 grams of product was obtained. On recrystallization from trichlorethylene-hexane, 17.8 g of the purified compound were obtained

ao received; Bp. 89 to 91 ^° C. The product from this reaction was identical to that obtained in Example 2.

Tabel

N-substituted 2-methyl-2-n-propyl-1,3-propanediol dicarbamate

N-alkyl group

formula Anal}
calculated se-N
found refraction
index »ο ⁵ C ₁₁ H ₂₂ O ₄ N ₂ 11.38 11.06 1.4677 C ₁₂ H ₂₄ O ₄ N ₂ 10.76 10.71 1.4694 C ₁₂ H ₂₄ O ₄ N ₂ 10.76 10.76 C ₁₃ H ₂₆ O ₄ N ₂ 10.21 10.42 C ₁₃ H ₂₆ O ₄ N ₂ 10.21 10.47 1.4645

Bp. Or bp. In ° C (mm)

ethyl

n-propyl

Isopropyl

η-butyl

Isobutyl

*) Compound purified by distillation at the specified temperature and pressure.

154 to 156 (0.05)
144 to 147 (0.02)
Pp. 89 to 91
Sdp. 49 to 51
100 to 110 (0.01) *)

Aside from the presence of unique muscle relaxation effects of extreme value than Medicines for the solution of muscle plasma lay down the distinctive central depressive properties of the compounds according to the invention also suggest that some of them have further therapeutic value as sedatives, Sedatives, hypnotics and agents for influencing abnormal behavior are suitable.

The new compounds according to the invention are preferably administered orally in the form of pills, tablets or Capsules administered, which are formed by known methods. A typical composition consists from the active ingredient mixed in a dry powdery state with gelatin, starch, magnesium stearate and algal acid compressed into a tablet. The active ingredient can also be in a suitable solution. An effective dose of the active ingredient will generally be in the range from 0.05 to 2.0 g.

where R is a saturated aliphatic hydrocarbon radical with 2 to 4 carbon atoms, characterized in that either a monocarbamate of the general formula

CH,

η-C ₃ H ₇

CH ₂ O-CO-NHR

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

Claims (1)

Claim: Process for the preparation of N-monosubstituted propanediol dicarbamates of the general formula 60 CH, η-C ₃ H ₇ CH ₂ -OCONH ₂ CH ₂ OH CH, η - C ₃ H ₇ CH ₉ OCONHR CH ₂ OCONH ₂ a) first reacting with phosgene and then _{allowing the chlorocarbonate formed to react with an amine RNH 2} , where R has the meaning given above, or b) reacts with an isocyanate of the general formula R-N = C = O. © 909 647/426 10.