KR790001073B1 - Process for preparing aminocyclols - Google Patents

Abstract

Aminocyclos (I; R = C1-5 alkyl, Particulary methyl or isopropyl) which have 2-methyl and 5-secbutyl, useful as antihypnotics, was prepd. by condensation of acid added salts-type II with III in the pressence of solvent and condensing agent or by hydrogenation of IV in the pressence of catalyst.

Description

Manufacturing method of amino cyclos

The present invention relates to a method for producing aminocyclones having a methyl group at 2-position and a secondary butyl group at 5-position of the novel compound of formula (I).

(Wherein R is an alkyl group of 1-5c)

In particular, R is an alkyl group, i.e., isopropyl, linked to a nitrogen atom to which R is bonded at the methyl or α position.

The process for preparing the compound of formula (I) according to the present invention comprises (a) condensing a reactive functional derivative of the acid of formula (II) with a compound of formula (III) in the form of an acid addition salt in the presence of a solvent and a condensing agent

(Wherein R is the same as described above)

(B) Hydrogen impregnation of the following compound of formula (IV) in the presence of a catalyst:

(Wherein R is the same as described above)

The reaction in step (a) is a condensation reaction for amides.

Reactive functional derivatives of 9,10-dihydroglyceric acid that can be used in such reactions and the reaction conditions thereof are known in the ergot chemistry.

For example, acidified hydrochlorides, acid azides or mixed anhydrides of acids of formula (II) with sulfuric acid or triholoacetinic acid may be used as reactive functional derivatives of acids of formula (II).

Preference is given to using reactive functional derivatives which can be obtained by reaction of an amidochloride formed from an N-di (lower) alkyl-substituted acid amide of 1-3c aliphatic carboxylic acid with an acid of formula (II) formed with a chloroating agent. Examples of croroating agents that can be used include thionyl chloride, phosgene or oxylyl chloride and the like. Suitable acid amides for the preparation of the desired amido chlorides are, for example, dimethyl formamide or dimethylacetamide.

Suitable solvents for this reaction are, for example, chloroform, methylene chloride, dimethylformamide and acetonitrile.

Examples of condensing agents are tertiary organic bases, ie triethylamine, in particular pyridine.

The reaction is effectively carried out at temperatures between -30- and + 20 ° C. and under atmospheric pressure. The reactive functional derivative of the acid of formula (II) is preferably used at 1.2-2.4 moles per mole of the compound of formula (III) in the form of acid addition salt.

The preferred acid form of the compound of formula III is hydrochloride.

The hydrogenation reaction (step (B)) according to the present invention is carried out according to a known method used for hydrogenation of ergotin I compounds of ergot alkaloids.

For example, the riserynic acid derivative of formula (IV) is taken in an inert solvent or solvent mixture to add a catalyst, such as palladium chloride or palladium in activated carbon.

Examples of suitable inert solvents include neutral solvents such as dioxane, amides of aliphatic carboxylic acids such as dimethylformamide or lower alkanols.

The present hydrogenation reaction is effectively carried out at room temperature or slightly elevated temperature. The pressure is not limited and varies from atmospheric pressure to about 81 atmospheres, and atmospheric pressure is generally effective.

It is convenient to filter the catalyst after taking hydrogen.

The free base form of the compound of formula (I) can be converted to the acid addition salt form in the usual manner and vice versa. Suitable acids for acid addition salt formation are hydrochloric acid.

Among the compounds of formula (II) used as starting materials, compounds in which R is methyl and ethyl are known. The novel compounds of formula (II) are prepared in a similar manner to that used for the preparation of 6-note-6-ethyl-9, 10-dihydroglyceric acid.

The compound of formula III, hereinafter referred to as aminocyclo, is a novel compound.

This amino cyclo is obtained by removing the R ₁ group from the compound of formula (V).

Wherein R ₁ is a protecting group that can be selectively separated.

The selective removal of the protecting group, ie the benzyloxycarbonyl group, is carried out in a similar manner to that known in the art of peptide chemistry.

When R ₁ is a benzyloxycarbonyl group, for example, it may be removed as follows.

The protecting group is separated by hydrocracking in an acidic catalyst. The hydrogenation reaction is effectively carried out in the presence of a noble metal catalyst. Palladium is particularly suitable for this reaction. Activated charcoal can be used as a carrier for palladium. The catalytic hydrocracking reaction is effectively carried out under acidic conditions, i.e. in the presence of 1.2-1.5 moles of acid. Suitable reaction media are, for example, inert organic solvents such as dioxane and dimethylformamide or mixtures of tetrahydrofuran and hydrochloric acid of methanol. This hydrogenation reaction is effectively performed at room temperature and atmospheric pressure.

The compound of formula (V) is obtained from known methods, ie, the acid azide of the corresponding structure (VI).

The acid azide of formula VI can also be converted to aminocyclones by treatment with theoretical amounts of water and acid, i.e. hydrochloric acid, in an inert solvent.

In principle, the above-mentioned method for synthesizing aminocyclones is a part of the Curtis method or a modified method thereof, and it is effective to use the compound of formula (VII) as starting material.

Wherein R ₂ is lower alkyl such as ethyl.

The ester of formula (VII) can be converted to the corresponding free acid by known methods and the aminocyclo is obtained by converting the carboxylic acid chloride to the acid azide of formula (VI).

The compound of formula (VII) is prepared by known methods using L-isoleucine-L-proline lactam and S-(+)-methyl-benzyloxymalonic acid monoethyl ester chloride as starting materials.

The compound of formula (IV) is obtained by reacting the aminocyclo of structure (III) with the reactive functional derivative of the corresponding resetginic acid according to known methods.

The compound of formula (IV) can be obtained by a method similar to that described in the above method (A).

The following examples are provided to illustrate the present invention in detail, and the present invention is not limited thereto, and the temperature in the present embodiments means degrees Celsius.

Example 1

2'β-methyl-5'α-tert-butyl-9, 10-dihydroergotin

(Hereinafter referred to as dihydro-β-ergosin)

에 부어넣고 염화메틸렌으로 3회 추출시킨다. 염화메틸렌용액을 700cc의 물로 세척하여 황산나트륨으로 탈수시키고 회전증발기로 증발건조시킨다. 기포성 수지를 수득하며 산화알루미늄의 15배의 양으로 크로마토그래피 한다. 생성되는 순수한 디하이드로-β-에르고신을 염화메틸렌과 메탄올로부터 재결정시킨다.300 cc of anhydrous dimethylformamide is placed in a sulfonated hulsk cooled to -20 ° C- and added dropwise within 20 minutes at this temperature while stirring oxalyl chloride distilled clean from 66cc of anhydrous acetonitrile. The resulting yellow suspension is stirred for a further 15 minutes and 38.6 g (0.143 mole) of vacuum dried finely divided dihydrol-setginic acid is whisked at -20 ° C. If the reaction mixture is further stirred for 30 minutes, the temperature is raised to 0 ° C. Again cool to + 20 ° C. and add 143 cc of dry pyridine as soon as possible. 31.6 g (0.0713 moles) of crystalline aminocyclohydrochloride (containing 1 mole of dimethylformamide and 0.5 mole of tetrahydrofuran [molecular weight 442.9] per mole of preparation as described below) is then whisked into the half-and-half mixture. The temperature is then raised to -10 ° C and stirred for an hour more to give an orange search suspension. Cool back to −20 ° C. and add 200 cc of phosphate buffer pH4. The reaction mixture was dissolved in 2 normal sodium carbonate solution 2.6

Pour into and extract three times with methylene chloride. The methylene chloride solution is washed with 700cc of water, dehydrated with sodium sulfate and evaporated to dryness using a rotary evaporator. A foamable resin is obtained and chromatographed in 15 times the amount of aluminum oxide. The resulting pure dihydro-β-ergosine is recrystallized from methylene chloride and methanol.

=-44℃Melting Point: 180-180 ° C (Decomposition),

= -44 ℃

(C = 1, pyridine)

Aminocyclos are obtained as follows.

17.2 g of the compound of formula (V) (R═C ₆ H ₅ —CH ₂ O—CO) (40 mmol) is dissolved in 90 cc of anhydrous dimethyl formamide and poured into a nitrogen-washed Widmer Hulask.

6 g of palladium catalyst (10% of palladium in charcoal) is continuously immersed and rinsed with 80 cc of anhydrous tetrahydrofuran. 8 cc of 6.5 normal hydrogen chloride and tetrahydrofuran (52 mmol) are added and then hydrogenated immediately. After hydrogenation (25 minutes) the catalyst is filtered off and the tetrahydrofuran and dimethylformamide are evaporated off with a vacuum rotary evaporator at a maximum temperature of 25c. The residue is dissolved in 100 cc of dimethyl formamide and the solution is rubbed with a snow blower. The aminocyclol crystallized as hydrochloride and contained 1 mole of dimethylformamide and 0.5 mole tetrahydrofuran per mole and the melting point after filtration and washing with tetrahydrofuran was 122-123 ° C.

During the synthesis of the compound of formula (V) (melting point 188-189 ° C.) the following intermediate product is formed.

Ester of formula (VII) R ₂ = C ₂ H ₅ , melting point 124-125 ° C.

Acid melting point corresponding to this ester: 168 ° C. (decomposition)

Sanazide of Structural Formula (VI) used in the next step

Example 2

6-nor-6-isopropyl-2'β-methyl 5'α-tert-butyl-9, 10-dihydro-ergopeptin

(6-Nor-6-isopropyl-dihydro-β-ergosine)

A method similar to Example 1, except that 13.4 g of dry 6-nor-6-isopropyl-dihydro-resetginic acid was used instead of dihydrolyseric acid, and the compound of the title was Obtained.

=-15.5℃ (C=1, 염화메틸렌)

= -15.5 ° C (C = 1, methylene chloride)

6-Nor-6-isofurophyll-9, 10-dihydro-resetginic acid, used as starting material, is obtained as follows.

A) 6-Nor-9-Isopropyl- with a melting point of 194 ° C in the form of colorless crystals by alkylating 6-nor-9, 10-dihydro-resetginic acid methyl ester with isopurophyll bromide; 9,10-dihydro-resetginic acid methyl ester is obtained.

= -80.2℃ (C=0.582 염화메틸렌)

= -80.2 ° C (C = 0.582 methylene chloride)

B) The ester obtained in a) is saponified with a caustic soda solution in methanol / methylene chloride to give 6-nor-6-isopropyl-9 and 10-dihydro-resetginic acid having a melting point of 290 ° C (decomposition). To obtain.

= -101℃ (메탄올에서 C=0.6)

= -101 ° C (C = 0.6 in methanol)

Example 3

Dihydro-β-ergosine

= -140.2℃ (C=1, 클로로포름)]5.48 g (0.01 mol) β-ergosin [melting point 203-205 ° C. (decomposition)

= -140.2 ° C. (C = 1, chloroform)]

Was dissolved in 100 cc of anhydrous ethanol and 100 cc of dimethylformamide, and hydrogen immersion was carried out at room temperature with 2 g of palladium / activated carbon catalyst (5% of palladium). After taking 2.5 liters of hydrogen, the reaction is considerably slowed and the hydrogenation reaction is terminated to leave the catalyst free to evaporate the filtrate in vacuo. The residue is crystallized twice from methylene chloride methanol to give a compound of the title having a melting point of 181-183 ° C. (decomposition) as a single layer chromatography homogeneous material.

= -45℃ (C=2, 피리딘)

= -45 ° C (C = 2, pyridine)

β-ergosine is obtained as follows.

24.1 g of Riserginic acid are suspended in 270 cc of acetonitrile and cooled to -20 ° C. A mixture of 12.5 cc of trifluoroacetinic anhydride, 6.88 cc of triholoacetinic acid and 100 cc of acetonitrile is added dropwise at this temperature in about 4 minutes.

The mixture is stirred for 5 minutes and 26.6 g of amino cyclohydrochloride is sprinkled on the reaction mixture at -20 ° C and immediately added 90cc of pyridine at -20 ° C dropwise to raise the temperature to 0 ° C. Stir at 0 ° C. for 1 hour 30 minutes, cool to −20 ° C. and add 270 cc of phosphate buffer (pH-4) dropwise. The reaction mixture is poured into 1 L of 2N soda solution and purified with 30 times the amount of aluminum oxide with methylene chloride / 0.4-0.6% methanol. β-ergosine is washed from the column with methylene chloride / 0.6-1% methanol to crystallize from methylene chloride / ethylacetate.

After recrystallization, β-ergosine is dried in high vacuum.

+ 11.1℃ (피리딘중 C=3.5)Melting point 203-205 ° C,

+ 11.1 ° C. (C = 3.5 in pyridine)

Example 4

6-nor-6-isopropyl-2'β-methyl-5'α-tert-butyl-9, 10-dihydro-ergopeptin

(6-Nor-6-isopropyl-dihydro-β-ergosine) Hydrolysis of 6-nor-6-isoprocle-β-ergosine in the same manner as in Example 3, melting point 182-183 ℃ ( Compound) is obtained.

=15.5℃ (C=1, 염화메틸렌) 구조식(I)화합물은 약리학적 특성을 갖는다. 구조식(I)화합물은 특히 후술할 테스트에 나타낸 약리학적 작용을 나타낸다. 특히 이 화합물은 동물 테시트에 지적된 바와같이 각성작용을 나타낸다. 예를들어 표준테스트에서 본 화합물을쥐에 피하주사한다. 쥐의 흥분도를 2시간에 걸쳐 관찰한다. 또 하나의 테스트에서 본 화합물을 뇌에 장기적으로 설치된 전극을 갖는 쥐에 투여한다. 각성상태의 증가 및 숙면상태의 감소를 전자뇌파기를 사용하여 통상의 방법으로 측정한다.

= 15.5 ° C. (C = 1, methylene chloride) The compound of formula (I) has pharmacological properties. Structural formula (I) compounds particularly exhibit the pharmacological action shown in the tests described below. In particular this compound exhibits awakening as indicated in the animal tecit. For example, in a standard test, the compound is injected subcutaneously in rats. The excitability of the rat is observed over 2 hours. In another test, the compound is administered to rats with electrodes that are installed in the brain long term. The increase in the arousal state and the decrease in the sound sleep state are measured by a conventional method using an electroencephalogram.

The P.G.O spike test is also carried out according to the methods of Deprter Ech and Deproter and Matesec. In this test method, P.G.O.spikes decreased after intraperitoneal injection of reserpin at 0.5 mg / kg body weight. After administration of this compound, the decrease in the number of P.G.O.spikes was observed. This test shows profound triphthaminal neurostimulation. Therefore, this compound is used as an arousal increasing agent.

In application, the daily dose is about 5-6omg and the dosage of sweet milk containing about 1-30mg is administered 2-4 times a day. Structural formula (I) compounds can be administered in the form of pharmacologically useful acid addition salts. This form of acid addition salt has the same effect as that of free base. The present invention also provides a composition containing the compound of formula (I) together with a carrier or a diluent in the form of a free base or in the form of a pharmacologically useful acid addition salt. Such compositions can be made into solutions or tablets in conventional manner.

Claims (1)

In the presence of a solvent and a condensing agent, the reactive functional derivative of the following structural formula (II) acid is condensed with the following structural formula (III) Process for producing aminocyclos of the following formula (I) by hydrogenation of the following formula (IV) compound in the presence of a catalyst

R in the above formulas is 1-5 alkyl