DE1064942B - Process for the preparation of carbamates of tertiary acetylene carbinols - Google Patents

Description

C07C

GERMAN

kl. 12 ο

INTERNAT. KL. C 07 C

PATENT OFFICE

P 14029 IVb / 12 ο

REGISTRATION DATE: APRIL 28, 1955

NOTICE
DEK REGISTRATION
AND ISSUE OF THE
EDITORIAL. SEPTEMBER 10, 1959

The invention relates to a process for the preparation of carbamates of tertiary acetylene carbinols, which are Narcotics for animals and / or agents for preventing cramps are suitable for animals.

The compounds obtainable according to the invention have the following formula:

R "/

R '

O = C-NH ₂

wherein R '"is hydrogen or an alkyl group with 1 to

6 carbon atoms, R 'is an alkyl group with 1 to

7 carbon atoms, preferably an ethyl group, R "hydrogen, an alkyl group with 1 to 6 carbon atoms or a halogen, preferably chlorine or bromine, and X is hydrogen or a halogen, preferably chlorine or bromine.

It is known that a group of tertiary vinylethinyl carbinols represent highly effective anesthetics and / or anticonvulsant agents. These connections are mostly liquid and are therefore administered in capsule form. However, the encapsulation is more fluid pharmaceutical products are expensive and are therefore avoided as far as possible.

It has now been found that the carbamates of the abovementioned tertiary vinylethinyl carbinols also have the high Have the efficiency of the carbinols, but are obtained in a solid state, so that they are good for tabletting suitable and do not need to be encapsulated. Furthermore, these carbamates proved to be few in animal experiments poisonous. This makes them particularly suitable as anesthetics and anticonvulsants.

The presence of a halogen atom (X) on the terminal vinyl carbon atom appears to these compounds to impart unusually strong stunning power. The derivatives of this class, in the R 'is a methyl group, usable for this purpose, but such compounds have been found in which R' is ethyl, as particularly suitable.

If you try the Vinyläthinylcarbamate in a known manner, for. B. by implementing excess To produce methyl vinyl ethinyl carbinol with cyanic acid (from cyanuric acid), this is mainly the result Allophanate. Although a small amount of carbamate may have been formed, it was not possible to separate the carbamate from the less soluble allophanate. Implementation of the same carbinol with Potassium cyanate and acetic acid apparently led to extensive elimination of water or to rearrangement, procedure

for the production of carbamates
tertiary acetylene carbinols

Applicant:

Chas. Pfizer & Co., Inc.,
Brooklyn, NY (V. St. A.)

Representative: Dr. W. Beil, lawyer,
Frankfurt / M.-Höchst, Antoniterstr. 36

Claimed priority:
V. St. v. America April 29 and September 23, 1954

Abraham Bavley, Brooklyn, NY,
and William Merrill McLamore, Kew Gardens, NY

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

whereby carbamate could not be isolated. The transesterification of ethyl carbamate (urethane) with methyl vinyl ethinyl carbinol in the presence of sodium ethylate proceeded slowly and incompletely, and in the recovered No carbamate of carbinol was found in ethyl carbamate. It also carried out the conversion this carbinol with ethyl chloroformate in pyridine to form a mixed carbonate, and the treatment of this Carbonate with ammonia (gaseous or in aqueous alcoholic solution) or with lithium amide led to Obtaining the carbonate. The infrared spectrum of the mixed carbonate obtained did not indicate any Carbamate formation.

Two of the synthetic methods given in the literature were considered to be particularly useful for implementation of the tertiary carbinols. In one such method, the addition of carbamyl chloride resulted in a solution of the Methyl vinyl äthinylcarbinols in pyridine to a lively conversion and precipitation of pyridine hydrochloride. However, in several attempts of this type, only the carbinol could ever be recovered. In addition, the amount of carbinol recovered was small and the infrared spectrum showed no trace of Carbamate. In one of the experiments a very small amount of a solid was isolated, but it turned out to be proved the allophanate of the treated carbinol.

909 627/418

The other method which, starting from simple tertiary alcohols, supposedly gives good results can achieve is based on the reaction of the alcohol with phosgene to form its chloroformic acid ester low temperature and in the presence of a tertiary amine and the subsequent treatment of the chloroformate with ammonia. This method has been used in numerous experiments on methylvinylethinylcarbinol and related carbinols are used. Not in any pallethylchloroformate. Implementation is preferred carried out under anhydrous conditions and with cooling, with a reaction time in most cases from about 2 to 5 hours is sufficient. After adding water, the tertiary acrylic carbonate Carbinols with a water-immiscible solvent such as ether, chloroform, cyclohexane, Benzene and the like. After extracting the carbonate several times with the solvent verii i

However, there was a major precipitation of hydro- ίο one agrees the solvent extracts and washes them with it Chlorides of the amines, not even when using a mineral acid such as hydrochloric or sulfuric acid

considerably higher temperatures than those recommended in literature. Only a small amount of carbinol was recovered and after treatment with ammonia only traces of the carbamates were found.

It has now been found that the above class of carbamates can easily be prepared by using a tertiary carbinol of the general formula

.C = CH - C - C - = CR "

OH

35

wherein R ', R ", R'" and X are as defined above, with an aromatic chloroformic acid ester reacts in the presence of a tertiary base, forming the corresponding aromatic carbonate, which one then subsequently treated with ammonia. The tertiary ethynyl carbinols can in turn by treatment the corresponding ketone, d. H. an alkenyl or haloalkenyl ketone, with an alkali salt of a Acetylene compound can be produced.

Examples of such carbinols are:
Methyl - ^ - chlorovinyl-ethinylcarbinol
Ethyl ^ -chlorovinyl-ethinylcarbmol
Propyl- ^ chlorovinyl-ethmylcarbmol
Hexyl ^ -chlorovmyl-ethmylcarbmol
Hepty - ^ - ch orvmyl-äthmylcarbmol
Methyl ^ -chloropropenyl-ethmylcarbmol
Ethyl ^ -c-morooctenyl-ethmylcarbmol
Propyl - ^ - chlorheptenyl-ethmylcarbinol
Butyl- ^ bromobutenyl-ethinylcarbinol
Hexyl - /? - brompenteny -äthmy carbinol
Hepty ^ -bromohexenyl-ethinylcarbmol
Methyl 1-chloromyl propmyl carbinol
Ethyl ^ -chlorovinyl-butmylcarbmol
Propyl- ^ chloro-vinyl-octmylcarbinol
Methylvmyl-ethmylcarbinol
Ethylvinyl-ethmylcarbrnol
Isopropylhexenyl-ethmylcarbinol
n-propyloctenyl-ethmylcarbmol

to remove any remaining bases from the solution, which is followed by a treatment with a saturated Saline solution, e.g. B. of sodium chloride or sulphate with an additional content of sodium bicarbonate, followed by, to neutralize the combined extracts and partially drain them. The [the aryl carbonate of tertiary Äthinylcarbinols containing solution is then expediently with a conventional drying agent, such as anhydrous magnesium sulfate, dried and finally filtered. The solution obtained can be used immediately Serve production of the carbamate, or they are concentrated to obtain the crude aromatic carbonate of the tertiary carbinols. This carbonate intermediate can be represented by the following structural formula will:

= CH C

C - 0 - R "

_R , _R " _{R /} "

_R ""

_{a bene Be} _ _{aromatic or}

_{represents substituted aromatic} group.

_{The undesired} carbamates are preferably produced by treating the aromatic carbonates with ammonia directly, ie without prior isolation of the carbonate. Here you can _hen in different ways. _{For at Ie} i _{can be> to the} aromatic carbonates into the corresponding carbamates convert _ases gaseous ammonia slowly through the _{solution,% B in Äth bd room} temperature _durchb within about _{10 to 2Q hours} i. But the ethereal solution of the _{crude aromatic} carbonate can be added also to the liquid ammonia and _{reacted for} 10 to _{24 hours} j _who the while the ammo _{nia lan on Rückflußküh he} i det _them and finally

is evaporated. According to the invention, aromatic chlorine is preferred to this process in order to achieve the best results. With a different deformate slowly drive to a solution of the tertiary carbinol one concentrates the above stated essential in the presence of a tertiary organic base, preferred solution of the aromatic carbonate, treats them with wise one that also acts as a solvent. saturated ethanolic ammonia and leaves that Suitable bases for this are triethylamine, dimethyl mixture obtained at room temperature about the same aniline and coal tar bases, such as pyridine, picolines, colli-60 long, as stated above, until complete umdine, Lutidines, quinolines and substituted quinolines and settlement are available.

their mixtures. The base is used in such an amount. that they expediently the carbamate standing by the reaction between water and ether tertiary carbinol and the chloroformate released and added with further ether to separate the Binding hydrogen chloride, with one to achieve the best 65 desired product of by-products and results preferably at least 1 mole of base is extracted per mole of impurities. The essential extract can Uses carbinol. Examples of the one to be used only then with caustic soda to remove the aromatic chloroformates are the following: phenylchlorophenolic reaction by-products and then with formate, alkylated phenylchloroformates, chlorophenyl-saturated saline solution, whereupon you wash it chloroformates, nitrophenyl chloroformates, α- and / J-Naph- 7 ° dries and concentrates to a smaller volume. Thereon

the carbamate is precipitated as a solid white body by adding petroleum ether. The cleaning succeeds easily by recrystallization from a mixture of ether and petroleum ether.

example 1

a) 39 g of phenyl chloroformate (0.249 mol) were added dropwise with stirring to an ice-cooled solution of 39.6 g of ethyl-ß-chlorovinyl-ethinylcarbinol (0.274 mol) in 100 ecm of anhydrous pyridine. The suspension of the solid substances was then stirred with cooling for 2 to 3 hours, 150 ecm of water and 150 ecm of ether were added and the aqueous layer was extracted with several fresh portions of ether. Dried the combined ethereal extracts were washed twice with 300 cc of cold, 18 ° / _o hydrochloric acid and finally with saturated sodium chloride containing solution, the excess sodium bicarbonate, and then with anhydrous magnesium sulfate, and nitrided. The ethereal solution can then be used directly for the preparation of the carbamate or it can also be concentrated in order to first obtain the crude phenyl carbonate of ethyl - ^ - chlorovinyl-ethinylcarbinol.

b) Ammonia was blown slowly for 8 hours through an ethereal solution of the phenyl carbonate of ethyl-ß-chlorovinyl-äthinylcarbinol prepared according to a) from 6.6 g of carbinol. Although a cooler was used here, most of the ether was lost during the treatment. The reddish semi-solid residue was taken up in water and more ether, and the aqueous layer was extracted with further portions of ether. The combined ethereal extracts were washed twice with 50 cc of 2.5 ° / _o aqueous sodium hydroxide solution and finally with saturated sodium chloride solution, then dried with anhydrous magnesium sulfate, concentrated to a smaller volume and finally diluted with petroleum ether. The carbonate which precipitated out as a solid white precipitate was recrystallized from an ether-petroleum ether mixture and consisted of 5.2 g of colorless flakes with a melting point of 98.5 to 99.5 ° C. A further 0.3 g were still obtained from the filtrate won; So the total yield was 5.5 g (64 ° / ₀ of the carbinol). An analytical sample was purified by recrystallization from a methanol-water mixture to form heavier crystals of mp. 98.5 to 99.5 C ^0.

Analysis: C ₈ H ₁₀ O ₂ NCl.

Calculated C 51.21, H 5.37, N 7.47 ° / ₀ ;

Found C 51.43, H 5.40, N 7.42 ° / ₀ .

Example 2

1700 ecm of an ethereal solution of the crude phenyl carbonate, prepared from 390 g of ethyl - ^ - chlorovinyl-äthinylcarbinol according to Example 1, a), to 2500 ecm of liquid ammonia and kept the mixture at the reflux temperature of the mixture for 6.5 hours. The ammonia was then allowed to evaporate overnight with stirring. The remaining solution was treated as in Example 1, b) and the carbamate in the form of 3389 g (65.8 ° / _o yield) of colorless flakes of mp. Gained from 100 to 101.2 ⁰ C.

Example 3

The crude phenyl carbonate prepared from 19.8 g of ethyl-ß-chlorovinyl-äthinylcarbinol according to Example 1, a) and obtained by careful concentration of the ethereal solution was taken up in 100 ecm of a saturated ethanolic ammonia solution and the mixture was left to stand overnight at room temperature. The resulting red solution was concentrated under mild conditions and, as in Example 1, b), gave the carbamate during work-up. The yellowish crystals weighed 10.9 g (42.4% yield) and melted at 97 to 98 ^° C.

Example 4

From 13.1 g of methyl-ß-chlorovinyl-äthinylcarbinol (0.10 mol) were prepared by following the procedure of Example 1, a) the corresponding carbonate of the methyl homologue

ίο and gave the resulting crude phenyl carbonate, such as described in Example 2, to liquid ammonia to obtain the mixed carbonate obtained as an intermediate to convert to carbamate. After treating the remaining solution as in Example 1, b), the desired Carbamate was obtained in an amount of 8.38 g (48.3% yield) with a melting point of 92.9 to 93 ° C.

Analysis: C ₇ H ₈ O ₂ NCl.

Calculated C 48.43, H 4.65, N 8.07%;

found C 48.25, H 4.70, N 8.07%.

Example 5

15 g n-propyl-ß-chlorovinyl-ethinylcarbinol (0.10 mol) were treated as in Example 4 and gave 5.86 g (29.1% yield) of the corresponding carbamate, Mp 63.9-64.8 ° C.

Analysis: C ₉ H ₁₂ O ₂ NCl.

Calculated C 53.60, H 6.00, N 6.95%;

found C 53.62, H 6.11, N 6.93%.

Example 6

Following the procedure of Example 4, 15.9 g of i-propyl-β-chlorovinyl-ethinylcarbinol (0.10 mol) were used to prepare 1.3 g of the corresponding carbamate (6.5% yield, mp 91-92 ⁰ C).

Analysis: C ₉ H ₁₂ O ₂ NCl.

Calculated C 53.60, H 6.00, N 6.95%;

found C 53.61, H 5.90, N 7.17%.

Example 7

By treating 19.2 g of methyl vinyl ethinyl carbinol (0.20 mol) according to Example 4 resulted in 19.9 g (71.6% yield) of the corresponding carbamate the m.p. 56.6 to 57.4 ° C.

Analysis: C ₇ H ₉ O ₂ N.

Calculated C 60.42, H 6.52, N 10.07%;

found C 60.41, H 6.60, N 10.16%.

Example 8

The treatment of 16.5 g of ethylvinyl-äthinylcarbinol (0.15 mol) according to Example 4 gave 12.7 g (55.2% yield) of the corresponding carbamate with the melting point 39.2 to 40 ° C.

Analysis: C ₈ H ₁₁ O ₂ N.

Calculated C 62.72, H 7.24, N 9.15%;

found C 62.46, H 7.12, N 9.16%.

Example 9

10.1 g Isopropylvinyl-äthinylcarbinol (0.081 mol) were treated according to Example 4 to give 3.4 g (25.0% yield) of the corresponding carbamate; mp. 44.5 to 45.5 ⁰ C.

Analysis: C ₉ H ₁₃ O ₂ N.

Calculated C 64.65, H 7.83, N 8.38%;

found C 64.41, H 7.72, N 8.43%.

Example 10

14.35 g of methyl- β- chloropropenyl-äthinylcarbinol (0.1 mol), dissolved in 50 ecm of anhydrous pyridine, were treated with 15.65 g of phenyl chloroformate (0.1 mol) according to the procedure of Example 1, a), whereby the phenyl carbonate of methyl-ß-chloropropenyl-äthinylcarbinol was obtained. By treatment of an ethereal solution of this material with liquid ammonia as described in Example 2, 9.57 g (51.3 ° / ₀₎ receives the corresponding carbamate.

Example 11

active substances in the form of tablets, capsules, elixirs, injectable solutions and the like Are substances, they are particularly suitable for the manufacture of tablets for oral administration. In general the preparation forms intended for oral administration can also be sweetened and with different the usual substances are seasoned for this.

In medicinal doses, the compounds can be used in concentrations of from about 0.5 to about 90 percent by weight the preparation mixtures must be present. Lower concentrations are usually not recommended, otherwise the total amount of preparation to be administered would be too large.

22.85 g of η-propyl-ß-chlorheptenyl-äthinylcarbinol (0.1 mol), dissolved in 50 ecm of anhydrous pyridine, were treated with 15.65 g of phenyl chloroformate (0.1 mol) according to the procedure of Example 1, a) , the phenyl carbonate of n-propyl-jS-chlorheptenyl-äthinylcarbinol was obtained. By treatment of an ethereal solution of this material with liquid ammonia as described in Example 2, 10.34 g (38.1 ° / ₀₎ receives the corresponding carbamate.

In general, the carbamates of the invention are solid white bodies that are easily used in therapeutic applications Let purposes use.

Pronounced anesthesia was observed when administered to animals, and the compounds also gave effective protection against seizures in animals. This enables it to be used in animals certain types of treatment that would be impossible without the use of anesthetic. As already stated, the compounds were low in toxicity and their administration had no harmful pharmacological effects Effects.

The new compounds can be administered in various forms; H. along with various inert pharmaceutical carriers, e.g. B. solid diluents or oils, or with biological

Claims (1)

Claim: Process for the preparation of carbamates of tertiary acetylene carbinols, characterized in that one a carbinol of the general formula R '" R ' : C = CH —C-C = CR " I.
OH wherein R '"is hydrogen or an alkyl group having 1 to 6 carbon atoms, R' is an alkyl group having 1 to 7 carbon atoms and R ″ hydrogen, an alkyl group with 1 to 6 carbon atoms or halogen and X hydrogen or means a halogen, with an aromatic chloroformic acid ester in the presence of a tertiary one Reacts base and the carbonate obtained in this way with ammonia to give the corresponding carbamate implements. Considered publications:
Arch. Exp. Path. Pharmakol., 219, 130 [1953]. ® 909 627/418 9.