DE1200799B - Process for the preparation of 2-halo-alkyl-2-alkyl-1,3-propanediol dicarbamates - Google Patents

Description

FEDERAL REPUBLIC OF GERMANY

GERMAN

PATENT OFFICE

EDITORIAL

Int. α .:

C07c

German KL: 12 ο -17/01

Number: 1200 799

File number: A 42759IV b / 12 ο

Filing date: March 29, 1963

Opening day: September 16, 1965

The invention relates to a process for the preparation of 2-haloalkyl-2-alkyl-1,3-propanediol dicarbamates, which is characterized in that 2-haloalkyl-2-alkyl-l, 3-propanediol a) with Reacts phosgene and the dichlorocarbonate derivative obtained is then treated with aqueous ammonia or b) with a low molecular weight alkyl urethane with the possible addition of an anhydrous one Solvent and heated by aluminum isopropylate.

Dicarbamates of 2,2-dialkyl-substituted 1,3-propanediols are known to have muscle-relaxing and antispasmodic effects and are largely used as a sedative. However, an essential feature of the invention was found to be that by introducing a chlorine substituent into the propyl side chain of 2-methyl-2-n-propyl-1,3-propanediol dicarbamate (Meprobamat) creates a connection that relaxes the muscles when it is preserved and antispasmodic effect has surprisingly lower toxicity. In addition, owns the new compound in contrast to dicarbamates which are unsubstituted or not halogenated on the nitrogen atom a valuable, analgesic effect. So, surprisingly, there are two in one molecule extremely desirable effects combined with minimal side effects at the same time.

Test report

The 2- (3'-chloropropyl> 2-methyl-1,3-propanediol dicarbamate was treated with meprobamate with regard to toxicity as well as analgesic and muscle-relaxing effect, the following values were obtained:

Process for the preparation of 2-haloalkyl-2-alkyl-1,3-propanediol dicarbamates

Applicant:

American Home Products Corporation, New York, N.Y. (V. St. A.)

Representative:

Dr. phil. G. Henkel

and Dr. rer. nat. W.-D. Henkel, patent attorneys, Munich 9, Eduard-Schmid-Str. 2

Named as inventor:

Joseph Seifter, Berwyn, Pa .;

Cathryn Helen Gudmundsen, Narberth, Pa.

(V. St. A.)

Claimed priority:

V. St. v. America March 29, 1962 (183 348)

Muscle relaxing effect

a) Effect on the polysynaptic flexor muscle reflex in cats anesthetized with chloralosis

toxicity

In mice, when administered intraperitoneally, the

LD ₅₀ of meprobamate 800 mg / kg,

LD ₅₀ of the compound prepared according to Example 1> 1000 mg / kg without occurrence of deaths at 800 mg / kg.

Analgesic effect

In the modified D'Amour-Smith test, thermally induced pain was found with no visible change in behavior by 2- (3'-chloropropyl) -2-methyl-1,3-propanediol dicarbamate suppressed by 32 to 100 mg / kg doses, while meprobamate, on the other hand, is suppressed proved to be inactive.

2- (3'-Chloropropyl) -2-methyl-1,3-propanediol dicarbamate showed maximum reflex prevention at a dose of 50 mg / kg at minutes while it occurred after just 30 minutes with meprobamate at a dose of 40 mg / kg. So stopped at the compound prepared according to the invention the effect longer.

b) Influence of meprobamate (I) or 2- (3'-chloropropyl) -2-methyl-1,3-propanediol dicarbamate (II) on the duration of the tolerance of the lateral position in mice treated with pentobarbital sodium in% of the mice not treated with I or II

dose

10 mg / kg
mg / kg
mg / kg

39% 38% 30%

90% 138% 169%

509 687/465

In this test, too, the product of the invention is many times more effective than meprobamate.

As already stated above, the inventive alkyl haloalkylpropanediol dicarbamates can also by ester exchange of a 2-haloalkyl-2-alkyl-1,3-propanediol be made with a low molecular weight alkyl urethane. In this reaction, the urethane becomes anhydrous in a Solvent such as toluene dissolved. A small amount of aluminum isopropoxide is added and the mixture to remove that formed upon condensation of the alkyl urethane with the diol Distilled alcohol. The alcohol distills off azeotropically with the toluene. The distillation will continued until the theoretical amount of alcohol has been removed. The solvent is then removed from the The mixture is removed under reduced pressure and the residue is dissolved in a hot aqueous solvent, like isopropanol, dissolved. The hot solution is filtered and then separates on cooling the corresponding dicarbamate.

The 2-alkyl-2-haloalkyl-1,3-propanediols used as starting compounds can be prepared by selective reduction of the dialkyl ester of the corresponding alkyl haloalkylmalonic acid. Included it must be ensured that the halogen substituent is not removed during the reduction of the ester groups will. Aluminum hydride complexes such as lithium aluminum hydride and aluminum chloride aluminum hydride are used for this purpose suitable.

The compounds that can be prepared according to the invention are preferably in the form of oral medicaments administered by tablets or capsules, although solutions, suspensions or syrups are also used can be.

The following examples serve to illustrate the invention.

example 1

Preparation of 2- (3-chloropropyl) -2-methyl-1,3-propanediol dicarbamate

a) The sodium salt of diethylmethylmalonate is added in portions of 4.6 g (0.2 mol) Sodium prepared to a solution of 34.8 g (0.2 mol) of ester in 150 ml of benzene. After the addition the solution is stirred with heating for 1 hour. The reaction mixture is allowed to cool and then added 40.8 g (0.2 mol) of 1-chloro-3-iodopropane are added and heating continues. The mixture is refluxed for 9 hours boiled, cooled and shaken with water to remove the sodium iodide. After that, the Separated benzene layer and dried over anhydrous sodium sulfate.

After removal of the benzene and fractionation of the residue, about 20.5 g of diethyl 2- (3'-chloropropyl) -2-methylmalonate, Κρ, are obtained. _{0) 111) ΐΒ0> 16} = 79 to 81 ⁰ C, which corresponds to a yield of 41%.

b) In a 250 ml three-necked flask equipped with a stirrer, reflux condenser with attached calcium chloride tube and dropping funnel, 20 g (0.08 mol) of diethyl 2- (3'-chloropropyl) -2-methylmalonate are gradually added to a cooled suspension of 3 , 4 g (0.09 mol) of lithium aluminum hydride in 100 ml of anhydrous ether. After the ester has been added, the mixture is stirred at room temperature for 1 hour. The complex is hydrolyzed with a mixture of 10% aqueous sulfuric acid and ice, the ether is separated off and the aqueous layer is repeatedly extracted with ether. The combined ether solutions are washed with water and dried _{over anhydrous MgSO 4.}

After the drying agent has been separated off and the solvent has been removed, 2- (3'-chloropropyl) -2-methyl-1,3-propanediol is obtained obtained as a white solid substance. After a single recrystallization from ether Petroleum ether will yield about 9.5 g (72%)

ίο obtained from melting point 59 to 62 ° C. The Beilstein trial this substance on halogen is positive.

c) 13 g (0.13 mol) of phosgene are condensed and placed in 40 ml of -10 ° C cold tetrahydrofuran, which is located in a 150 ml three-necked flask with stirrer, dry ice condenser with attached calcium chloride tube and dropping funnel. In the course of half an hour, 9 g of 2- (3'-chloropropyl) -2-methyl-1,3-propanediol (0.06 mol) in 30 ml of tetrahydrofuran are added. The solution is stirred at -5 to -10 ° C for 2 hours and then warmed to 8 ° C. The conversion of the chlorocarbonate into the carbamate is carried out by pouring the reaction mixture into 30 ml of cold, concentrated aqueous ammonia to which a little ice has been added. The solution is stirred for 10 minutes, mixed with 25 ml of water and then heated on the steam bath. After most of the tetrahydrofuran has been removed, a further 25 ml of water are added. The product crystallizes out of the cold aqueous solution. After recrystallizing once from water, a yield of about 9 g (67%) of vacuum-dried 2- (3'-chloropropyl) -2-methyl-1,3-propanediol dicarbamate with a melting point of 127 to 128 ^° C. is obtained.

Analysis for C ₉ H ₁₇ O ₄ N ₂ Cl:

Calculated ... C 42.78, H 6.78, N 11.08, C 14.03%; Found ... C 42.83, H 6.85, N 10.90, Cl 14.07%.

Example 2

Production of 2- (2'-chloroethyl) -2-methyl-1,3-propanediol dicarbamate

a) 85.8 g (0.6 Mol) 1-bromo-2-chloroethane added. The reaction mixture is ^{stirred for 2 days at 70 °} C., cooled to room temperature and its pH value is adjusted to 5 with a few drops of glacial acetic acid. Water is added to the contents of the flask, the resulting mixture is transferred to a separating funnel, the benzene layer is separated off and the organic phase is washed again with water. The benzene solution

is dried over anhydrous Na ₂ SO _4. An ether extract of the aqueous washing solution is also dried _{over anhydrous Na 2} SO _4. When the combined residues of benzene and ether solution are fractionated, 36 g of diethyl 2- (2'-chloroethyl) -2-methylmalonate with a boiling point of _{0> 3} = 74 to 78 ° C. are obtained.

b) The reduction of the chloroalkylmalonic _{acid ester into the corresponding diol using LiAlH 4} as reducing agent is carried out in the usual way: 22 g of ester are added through a dropping funnel to a cold, stirred suspension of 3.7 g of LiAlH ₄ in 150 ml of anhydrous ether . When the addition is complete, stirring is continued for two hours, during which time the mixture is boiled up

5 6

Room temperature cools down. Unreacted LiAlH ₄ extracted equal parts by volume of ether. The united

is decomposed by carefully adding water. Ether solution is mixed with some NaHCO ₃ solution

The mixture is then carefully washed into a mixture of and dried _{over anhydrous Na 2} SO _4.

Stir in ice and 10% sulfuric acid. The aqueous, after evaporation of the ether remains an oily,

acidic phase is separated off and repeated with 5 slowly crystallizing residue, which consists of ether

Ether extracted. The ether extracts are recrystallized with the petroleum ether. That's how you get it

original ether solution combined and over water- 2 - chloromethyl - 2 - η - propyl -1,3 - propanediol from

dried free MgSO _4. After removing the melting point 50 to 52 ° C.

Ether and recrystallization of the residue from c) The diol is, as already described, converted into the dicarbamate via the ether-petroleum ether (1:10). 2 - (2 '- chloroethyl) - 2 - methyl -1,3 - propanediol vom A solution of 2.5 g (0.015 mol) diol in about 10 ml melting point 53 ° C. Again Ig product from tetrahydrofuran is added dropwise with stirring Melting point 51 to 52 ° C can be isolated from the mother liquor of a solution of (slightly excess) phosgene. The overall yield is 26%. in cold -1O ⁰ C tetrahydrofuran. In c) a 300 cm ³ two-necked flask with a magnetic stirrer, * 5 over the course of 2 hours, the temperature is slowly increased to 8 ° C. in a condenser cooled by dry ice-acetone. The reaction mixture is then, together with an attached calcium chloride tube and one ml ice cold in about 15 ^{28%, it} ig ammonia cast, pressure equalizing dropping funnel is in a cold, the mixture is further kept cold and bad of - 15 ° C immersed with 30 ml tetrahydro- about 15 Minutes stirred. The tetrahydrofuran and 4 ml of phosgene are then charged. The diol solution, ²⁰ furan removed by heating on the steam bath, namely 4.25 g of 2- (2'-chloroethyl) -2-methyl-1,3-propane The product that results from the aqueous solution of diol in 20 ml of tetrahydrofuran , is initially deposited dropwise as an oil, crystallized when added. The reaction mixture is allowed to cool for 2 hours. When recrystallizing several times, this was stirred and the temperature was gradually increased to 0 ° C. until the crude product obtained from 18% aqueous alcohol. When 8 ° C. is reached, the mixture becomes 2-chloromethyl-2-n-propyl-1,3-propanediol dicarb mixture in 25 ml of 28% ice-cold ammonia with a melting point of 119 to 120 ° C.
poured to which some ice was added. The mixture

is stirred for 10 minutes and then to remove analysis for C ₉ H ₁₇ ClN ₂ O ₄ :

of tetrahydrofuran heated on a steam bath. Calculated ... C 42.78, H 6.78, N 11.08, Cl 14.03%; The crude product solidifies on cooling the aqueous 30 ... C 43.16, H 6.67, N 11.10, Cl 13.63%. Solution. After recrystallization from 15% strength aqueous ethanol, about 2.5 g (36%) 2- (2'-chlorine- Example 4) are obtained
ethyl) -2-methyl-1,3-propanediol dicarbamate with a

Melting point from 105 to 106.5 ⁰ C. In a flask with a device for

35 Far from the ethanol-toluene azeotrope, ethyl analysis for C ₈ H ₁₅ ClN ₂ O ₄ : carbamate, 2- (3'-chloropropyl) -2-methyl-1,3-pro-calculated ... C 40, 27, H 6.29, N 11.75, Cl 14.85%; introduced pandiol and anhydrous toluene. These found ... .C 40.35, H 6.36, N 11.66, Cl 14.95%. Mixture then becomes a catalytic amount of

Aluminum isopropylate added and

B is ρ ie 1 3 ⁴ ° distill the theoretically calculated amount of ethanol

heated. The toluene is then

a) The sodium salt of diethyl n-propylmalonate is distilled off under reduced pressure and the 2- (3'-chlorine becomes by adding 2.3 g (0.1 mol) of small pieces of propyl) - 2 - methyl -1,3 - propanediol carbamate from Sodium with stirring to a solution of 20.2 g melting point 127 to 128 ° C from the residue through (0.001 moles) of ester in approximately 150 ml of benzene. 45 Extraction obtained with ether.

The solution is refluxed until all of it has dissolved. The same compound can also be refluxed from an amount of sodium. After the diol, n-butyl carbamate and aluminum have been cooled to room temperature, the mixture is prepared with isopropylate, the tempe-26 g (0.2 mol) of methylene chlorobromide are added and the temperature is adjusted so that the n-butyl alcohol is then continuously heated overnight and stirred. The cooled 5 ° borrowed distilled off.
The reaction mixture is neutralized with acetic acid, B is η ie 1 5
Added water and separated the benzene layer.

The aqueous phase is extracted with ether. The in one with a device for removing the

Combined benzene-ether solution is over a water-ethanol-toluene azeotrope provided reaction vessel

dried free Na ₂ SO _4. After removing the 55 ethyl carbamate, 2- (2'-chloroethyl) -2-methyl-

An oil remains in the solvent, which is introduced with under-1,3-propanediol and anhydrous toluene,

pressure is fractionated. The diethyl mixture obtained becomes a catalytic amount

2-chloromethyl-2-n-propylmaIonat distilled at bp _{0> 05} aluminum isopropylate added. Then until

= 70 to 73 ° C. Distilling off the theoretically calculated ethanol

b) 10 g of diethyl 2-chloromethyl-2-n-propylmalonate are heated 60 amount and then the toluene im (0.04 mol) are distilled off dropwise while stirring under vacuum. The 2- (2'-chloroethyl) -2-methyl is added to a cooled suspension of 1.6 g of LiAlH ₄ (0.04 mol) of 1,3-propanediol dicarbamate with a melting point of 105 to 75 ml of anhydrous ether. After completion of 106.5 ⁰ C is obtained from the residue by extracting addition, the mixture obtained to room temperature with ether.

heated and stirred for 1 hour. The complex turns 65

by pouring into a mixture of ice and 10% analysis for C ₈ H ₁₅ UN ₂ O ₄ :

Sulfuric acid decomposes. The ethereal layer is calculated ... C 40.27, H 6.29, N 11.75, Cl 14.85%;

separated and the aqueous layer found twice with ... C 40.25, H 6.30, N 11.65, Cl 14.90%.

Claims (1)

7th 8th ^Claim : unc * the dichlorocarbonate derivative obtained is then treated with aqueous ammonia Process for the preparation of 2-haloalkyl- or b) with a low molecular weight alkyl urethane I-alkyl-l ^ -propandioldicarbamaten, thereby with the possible addition of an anhydrous solvent characterized in that 2-haloalkyl 5 solvent and aluminum isopropylate are 2-alkyl-l, 3-propanediol a) reacts with phosgene heats. 509 687/465 9.65 © Bundesdruckerei Berlin