DE1180741B - Process for the preparation of 1-cyclohexyl-n-propyl-carbamate - Google Patents

Description

FEDERAL REPUBLIC OF GERMANY

GERMAN

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PATENT LETTERING

Boarding school Class: C 07 c

Number:

File number:

Registration date:

German class: 12 ο-25

C 21855 IVb / 12 ο

July 6, 1960

5th November 1964

June 24, 1965

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Issue date:

The patent specification corresponds to the patent specification

The invention relates to the production of l-cyclohexyl-n-propyl carbamate, the valuable pharmacological one Has properties and which are obtained if 1-cyclohexyl-1-propanol is used in a manner known per se either with an alkyl carbamate, with urea, cyanic acid or carbamyl chloride or condensed with an ester of chloroformic acid or with phosgene, the latter being in both cases a further condensation of the derivative obtained with ammonia follows.

The carbamate obtained has the formula

Process for the production of
1 -Cyclohexyl n-propyl carbamate

CH ₂

CH ₂ -CH ₂
CH ₂ - CH ₂

CH-CH-OCONH ₂ C ₂ H ₅

In one embodiment of the invention, 1-cyclohexyl-propanol-1 is reacted with an ester of carbamic acid with a lower alcohol, for example ethyl carbamate, under the action of heat, in the presence or absence of a catalyst such as sodium alcoholate, one must take care of the lower alcohol formed in the course of the reaction gradually remove. In another embodiment, 1-cyclohexyl-1-propanol is brought to the heat with urea for reaction, optionally in the form of a salt such as the nitrate or hydrochloride, optionally also in the presence of a salt of a heavy metal. Furthermore can 1-cyclohexyl-propanol-1 is condensed with cyanic acid, using an alkali metal cyanate, works in a neutral solvent at about 50 ° C and the cyanic acid by the addition of a other acid, such as B. a strong organic acid (for example trichloroacetic acid) free. In the case of the condensation with carbamyl chloride, an excess of this is preferably used Reagent and while cooling the reaction mixture.

The four methods mentioned above lead directly to the 1-cyclohexyl-n-propyl-carbamate. the The method described below leads to this goal via the chloroformate of this alcohol. Leaves namely that phosgene act on this alcohol, for example in an inert solvent and in the presence of a substance that binds the hydrochloric acid formed in the course of the reaction, such as sodium hydroxide, tertiary bases and phenyl-dimethyl-pyrazolone, then you get that 1-Cyclohexyl-1-propanol chloroformate, which, the Patented for:

Etablissements Kuhlmann, Paris

Representative:

Dr. M. owl,

Dipl.-Chem. Dr. rer. nat. W. J. Berg and

Dipl.-Ing. O. Stapf, patent attorneys,

Munich 13, Kurfürstenplatz 2

Named as inventor:
Henri Swierkot, Paris

Claimed priority:

France of July 8, 1959 (799 641)

Subjected to the action of ammonia in the form of gas or in the form of an aqueous solution, supplies the corresponding carbamate.

Finally, the action of an ester of chloroformic acid with a lower alcohol to 1-cyclohexyl-propanol-l in the presence of a substance that binds the acids, such as B. pyridine, a mixed carbonate which, when treated with ammonia, produces 1-cyclohexyl-n-propyl carbamate supplies.

1-Cyclohexyl-n-propyl-carbamate is a white crystalline product, the majority of which are organic Solvent soluble, very little soluble in water and at ordinary temperature both in one completely stable in organic medium as well as in aqueous medium; it sets the excitability of the central nervous system, is not soporific and is well tolerated; compared to similar carbamates (l-cyclopropyl-n-propyl-carbamate and 2-n-propyl-n-propylene-1,3-dicarbamate) it has the merit of a longer lasting effect.

B ei s ρ i e 1 1

In a solution of 109 parts of phosgene in 450 parts

A mixture of 200 parts of dimethylaniline is slowly introduced into dry toluene while cooling with ice and 142 parts of 1-cyclohexyl-propanol-1 (boiling point:

up to 98 ° C under 16 mm vacuum). After loading

509 593/319

3 4

At the end of the addition one continues to stir, whereby one goes over the ethanol. Further treatment

Reaction mixture the usual temperature is identical to that described in example 4,
lets take. By heating to 40 to 45 ° C

the reaction is completed. The precipitated Di- B is ρ ie 1 6
methylaniline chlorohydrate is washed out 5

eliminated with cold water. The organic layer is decanted off to a solution of 35.5 parts cooled with ice and dried over sodium sulfate gel-cyclohexyl-propanol-1 in 120 parts anhydrous. Finally, the action of pyridine is slowly added to 27.11 parts of ethyl chlorine from ammonia gas or an aqueous solution of formate. After 3 hours of stirring at room of ammonia, which is ^{slowly blown between -5 and 0} ° C temperature is introduced with cooling in the course, subjected. Vigorous stirring is essential for 6 hours of ammonia through the solution or essential. The resulting crystalline mass, however, is added to an aqueous solution of 13 filtered and initially added with dilute hydrochloric acid and parts by weight ammonia. The obtained Gedan-n washed with water. The filtrate gives mixed is taken up in with 18% dilute hydrochloric acid after concentration under partial vacuum a further 15 acidified water and. with chloro a little carbamate. form extracted. The chloroform extract is added

The combined precipitates are next with a 5% sodium hydroxide solution and then from benzene

crystallized out. Melting point: 128 to 129 ° C with a saturated solution of sodium chloride

(Maquenne block). washed. The solution in chloroform is over

20 Magnesium sulfate dried and concentrated. the

Example 2 obtained crystalline precipitate of the carb

amats is recrystallized from cyclohexane. Enamel

In a mixture of 142 parts of 1-cyclohexyl point: 128 to 129 ° C.

1-propanol, 200 parts of dimethylaniline and 600 parts. .

dry toluene is carried out by means of a pipe, 25 example /

which is immersed in the reaction mixture, 110 parts 142 parts by weight of 1-cyclohexyl-propanol-1

gaseous phosgene, slowly in a mixture of 600 parts by volume

Stirring and, while cooling the reaction mixture, dry ether and 101 parts by weight of triethyl

with ice. When the addition is complete, the amine is dissolved at 0 ° C. and treated with a solution of

Stirring for 1 hour and brings 3 ° 79.5 parts by weight of carbamyl chloride in 500 volumes

the temperature of the mixture to 45 ⁰ C. The split dry ether treated. Then one lets

Excess phosgene is then through. the temperature of the reaction mixture slowly

expelled a stream of nitrogen. After rising to room temperature and that continues

Direct stirring is continued for 1 hour after cooling to -5 to 0 ° C. The crystalline mixture

gaseous ammonia or an aqueous solution 35 is washed with water to remove the triethylamine

to remove the same up to the alkaline reaction to phenol chlorohydrate and then filtered,

phthalein a. This is done as in Example 1. The filtrate gives a after concentration

before. additional amount of l-cyclohexyl propyl carbamate. the

B e i s η i e 1 3 is the melting point of the carbamate obtained

40 after recrystallization from benzene 129 ° C (Maquenne-

A mixture of 81 parts of potassium cyanate and block).

14.2 parts of 1-cyclohexyl-propanol-1 is used with an · test report

Solution of 163 parts of trichloroacetic acid in 300 parts of ^{test solution}

Treated with chloroform. The whole thing is heated until the pharmacological properties of the

to simmer. After making the product alkaline with sodium (hereinafter referred to as C.H.P.C

hydroxyd and filtering off the precipitate is designated) were with those of the carbamate of

the solvent driven off. The one obtained from benzene 1-cyclopropyl-propanol-1 (hereinafter referred to as C.P.P.C.

recrystallized residue gives 1-cyclohexyl (designated) of the formula

n-propanol carbamate. ^. ο ^ χτυ

5 ° / CH ₂ \ ι

Example 4 CH ₂ CH-CH-C ₂ H ₅

A mixture of 71 parts of 1-cyclohexyl-propanol-1 compared.

30 parts of urea and 1 part of zinc chloride will The experiments were carried out in the following manner

Heated on an oil bath at 160 ° C for 10 hours. 55 carried out:

after cooling it is treated with water, ", · ....
extracted with chloroform and dried over

Magnesium sulfate. The concentrated solution in the animals used were mice of the breed

Chloroform crystallizes out. Melting point: 128 C 57 and in adulthood; the products

bisil29 ° C, after recrystallization from benzene. 60 were administered intraperitoneally in the form of 2% '

Solution administered in olive oil. There were

Example 5 obtained the following results:

In a device with a descending ^ur ^ -r · "· ^ ·

Cooler is heated a mixture of 71 parts 65 administered amount of mortality

1-Cyclohexyl-propanol-1 and 44.5 parts of ethyl carbide 0.3 g / kg 0 deaths in 10 mice

amat for 10 hours to a temperature of 0.4 g / kg 4 deaths in 10 mice "■

of 210 progresses reaction from 0.5 g to 22O ⁰ C. / kg 10 dead in 10 mice

5 6

For C.H.P.C. tonic crises, and it stayed that way with everyone

Amount administered mortality in further tests.

0.5 g / kg 0 deaths for 10 mice M Γ Η Ρ Γ

0.6 g / kg 0 dead for 10 mice '^ ^nrK -

1 ο g / kg 0 dead for 10 mice 5 The product was used with the following doses

1.25 g / kg '.'. ' 2 deaths for every 10 mice of 25, 50, 100, 300, 500 and 1000 mg / kg

1.50 g / kg 4 dead for 10 mice groups of ten animals tested,

was injected intraperitoneally, where

The maximum non-toxic dose for C.P.P.C. is the product was dissolved in olive oil.

accordingly 0.3 g / kg, while at C.H.P.C. 1 g / kg io at the doses of 25, 50 and 100 mg / kg

achieved. the thirty animals at the first test, 1 hour

2. Anticonvulsant properties after injection, a clonic-tonic crisis,

The test used was that of the audiogenic which indicated that no protection had taken place.

χ ■ W ^hen dose of 300 mg / kg all animals

^a ) CPPC I ₅ protected for the first, second and third hour. With

The product, dissolved in olive oil, was on intramural - the fourth hour the ten animals reacted again

peritoneal way mice of the Swiss albinos breed, normal and all made a complete crisis

of descent Rb (Science Mouse Letter), in ver through.

different doses of 25, 50, 100, 125, 150 and at the dose of 500 mg / kg were the ten

175 mg / kg administered by injection. The animals, 20 animals, were completely protected for 5 hours

the 4 days prior to the test were tested regularly and were not returned to normal until the sixth test

were again 1 hour before the injection and all went through a complete crisis,

tested for their acoustic sensitivity. At the dose of 1 g / kg, ten animals were tested

Check stimulus. This was a sound signal with perfect during the first seven test attempts

the frequency of 10 000 oscillations per second 25 protected. When the test attempts are repeated

and with a ¹⁰⁰ / io volume from the recording on the following day, be it after 22, 24 and

ability of the animal. (The animals reacted approximately 26 hours after the injection, had eight of the

above the stimulus with a clonic-tonic crisis, ten animals still no reaction to the tone stimulus,

which a latency phase, the clonic and the two animals made clonic crises in the

tonic phase included. The changes in the 3 ° 22 ". Hour through. In test attempts after 48 hours

The time required between these different phases, eight animals had only clonic crises, and two

and the disappearance or weakening of animals remained perfectly protected. At 72 hours

each of the phases was recorded.) Two animals were completely protected, two

After the injection, the mice made runs only, two clonic crises and only for 6 hours

checked every hour for a long time, then after 24, 48 and 35 two normal crises. So the product stayed

72 hours. even after 72 hours in almost all animals

Ten animals were used for the dose. effective.

The following results were obtained: In summary, C.H.P.C. effective in that

25 mg / kg none of the ten animals was protected. Attempt of the audiogenic crisis

None of the ten animals were protected at 50 mg / kg. 40 _{starting with} 3OO mg / kg, whereby its effect '

At 100mg / kg, seven out of ten animals lasted 3 hours but did not last 4 hours, first crisis at the first test, that of the injection

followed, the tonic characteristics of which disappeared at 500 mg / kg, the duration of action being 5 hours

are; one animal showed disappearance of the clonic den amounts without reaching 6 hours and

and tonic phase, two made a classic 45 ^ j _{g / k & wobd the duration of action at least}

Crisis through. 26 hours with complete protection of the animals

This first occurrence of protection has existed when _{Partial protection exists up to}

no animal found again after 2 hours; _{77 qt} . _{f t}

in the second test, all animals have normal atmospheres.

Crisis. This remained the same until the test after 72 hours. 5 ° So this results in the following: Around one

At 125 mg / kg, eight animals were tested for 3 to 4 hours in the first test; protection is required; two animals only had clonic crises. borrowed: 300mg / kg CHPC, ie 30% of the maxi- This effect was not prolonged, and the paint non-toxic dose, or 175 mg / kg CPPC, ten animals showed a normal crisis at which ie 58% of the maximum non-toxic dose,
second test after 2 hours. The result was that 55 On the other hand, at a dose of the same, CHPC protects up to 72 hours in all experiments. 500 mg / kg, i.e. from 50% of the maximum non-

At 150 mg / kg, the animals were exposed to six toxic doses for more than 5 hours in the first test,

Animals protected; four animals had only clonic while C.P.P.C in the same ratio.

Crises. In the second test, nine animals were turned (50% of the maximum non-toxic dose,

protects; one animal alone had a clonic crisis. ^6o ie with 150mg / kg) the animals only for a maximum

In the third test, all animals had a normal 2 hours and with different results

Crisis, and the results remained the same until appropriately protected the animals,

last test after 72 hours. The carbamate of 1-cyclohexyl-propanol-1 is

At 175 mg / kg, ten animals were completely protected from the pharmacological point of view during the first two tests. In the ⁶ 5 look much more interesting than the carbamate from the third test, only seven out of ten animals were full 1-cyclopropyl propanol.

come protected. The other three showed clonic The carbamate of 1-cyclohexyl-propanol-1 was

Crises. In the fourth test, all cloned - on the other hand with the dicarbamate of 2-n-propyl-

1,3-propanediol compared. The trials were performed as described above; the comparative results are as follows:

toxicity

Maximum, non-toxic dose for intraperitoneal use

C.H.P.C lg / kg

Dicarbamate 0.4 g / kg

Anticonvulsant properties

Time of protection against an audrogenic crisis when administered a with respect to the maximum non-toxic dose equal to large dose

C.H.P.C 26 to 72 hours

Dicarbamate 4 to 8 hours

Claims (1)

Claim: Process for the preparation of 1-cyclohexyln-propyl-carbamate the formula CHi CH ₂ - CH ₂ - CH ₂ ) CH - CH - OCONH ₂ characterized in that 1-cyclohexyl-propanol-1 with an alkyl carbamate, with urea, with cyanic acid or with carbamyl chloride or first with an ester of chloroformic acid or phosgene and then with ammonia. 409 710/430 10.64 © Bundesdruckerei Berlin