KR790001032B1 - Process for the preparation of vincanol(epivincanol) derivatives - Google Patents

Abstract

Vincanol (epivincanol) derivs. (I; X=F, C1, Br, or H, R=one among OR1,SR2, and NR3 R4, R1=R2=C1-C4 alkyl, C2-C4 aminoalkyl, etc., R3, R4=H. C1-C4 alkyl, phenyl, etc.) possesing psychostimulating activity, were prepd. by treating R5H (R5=OR1 or SR2) with III in inactive solvents in the acidic condition or treating IV (Z is groups which can be substituted as R) with MR (M=H or alk. metal) to substitute Z of IV to R.

Description

Method for preparing vincanol (epivincanol) derivatives

The present invention relates to a process for the preparation of vincanol (epivinkanol) derivatives of the following formula (I), which is a novel compound that exhibits excellent mental neurostimulatory action and arousal action.

From here

X is halogen or hydrogen having an atomic number of 9-35 at the 10- or 11-position

R is one of ORl, SR ₂ , NR ₃ R ₄ , wherein R ₁ and R ₂ are alkyl of 1-4 carbon atoms, aminoalkyl or hydroxyalkyl of 2-4 carbon atoms, phenyl or a total of 7 -10 carbon atoms of phenylalkyl, R ₃ and R ₄ are independently hydrogen, alkyl of 1-4 carbon atoms, phenyl or phenylalkyl of 7-10 carbon atoms in total; X represents fluorine or cancellation.

In the compound of the above formula (I), it is preferable that when X is fluorine, it is in the 10-position, and when X is cancellation, it is preferably in the 11-position. In addition, R is preferably SR ₂ .

When R ₁ or R ₂ is alkyl of 1-4 carbon atoms, this represents especially methyl or ethyl (preferably methyl).

When R ₁ or R ₂ is hydroxyalkyl of 2-4 carbon atoms, it preferably represents 2-hydroxyethyl.

When R ₁ or R ₂ is aminoalkyl of 2-4 carbon atoms, this preferably represents 2-aminoethyl.

When R ₁ or R ₂ is phenylalkyl of 7-10 carbon atoms, it is preferably benzyl or 2-phenylethyl.

R ₁ is particularly preferably methyl, and R ₂ is preferably methyl or 2-hydroxyethyl.

When R ₃ or R ₄ is alkyl of 1-4 carbon atoms, this represents especially methyl or ethyl, preferably methyl.

When R 3 or R 4 is petylalkyl of 7-10 carbon atoms, it is preferably benzyl or 2-phenylethyl.

In hydroxyalkyl, aminoalkyl or phenylalkyl, each hydroxy, amino or phenyl group is preferably located in the omega-position of the alkyl moiety.

The preparation method of the present invention for obtaining the compound of formula (I) as described above is as follows.

A) reacting a compound of formula (II) with a compound of formula (III) to produce a compound of formula (1a), or

B) The Z group in the compound represented by the following formula (IV) is substituted with an R group.

In the above structural formulas

R 'is OR ₁ or SR ₂ (where R ₁ and R ₂ are as described above),

X is as described above in formula (I);

Z is a group that can be exchanged with the R group.

In the production method of the present invention, the method a) is an addition reaction. This process is carried out under acidic conditions, which is convenient to carry out in the presence of water. 1.0 moles of acid such as sulfuric acid or methanesulfonic acid may be used per mole of the formula (III).

The reaction is carried out in an inert solvent such as chloroform or in the presence of excess compound of formula (II). The reaction temperature is variable; Generally at room temperature, preferably under warming such as between 40 ° C. and 80 ° C.

In the preparation method of the present invention, the method b) is a nucleophilic substitution reaction, for example, by reacting a compound of formula (IV) with a compound of formula (V).

MR (Ⅴ)

Where M is hydrogen or an alkali metal and R is as previously mentioned.

For example, Z in the above formula (IV) means halogen (eg, cancelled or chlorine). Of M in formula (V); For example, sodium, lithium, potassium or hydrogen can be mentioned.

Compounds of formula (IV) wherein Z is halogen are hydrogen halide addition products of compounds of formula (III). This is very unstable. When this compound reacts with the compound of formula (II) or with an alkali metal salt thereof, it is convenient to carry out the reaction at a temperature of -20 ° C or lower.

As long as the compound of formula II is in liquid state at the reaction temperature. The compound itself is used in excess as a solvent. Alternatively, it may be reacted with a liquid inert solvent or suspending agent at a reaction temperature such as hexane.

The reaction according to the method of the invention) or b) is a cis position with respect for the compounds (epi blank kanol derivative) and C ₃ positions of the following structural formula (Ⅱ) with R in trans position with respect to the hydrogen atom at the C ₃ position to hydrogen atom A mixture with a compound of formula (I) (vincanol derivative) in which R is present is produced. These compounds can be separated according to known methods such as fractional crystallization or chromatographic methods.

The compounds of formula (I) to be prepared according to the invention exist in free base form or in the form of acid addition salts. Acid addition salts such as hydrogen fumarate or P-toluenesulfonate can be prepared from free salt form according to conventional methods.

Starting materials are known ones or may be prepared according to known methods.

The manufacturing method of the present invention as described above will be described in detail as the following examples. However, the embodiments do not limit the scope of the invention.

All temperatures in the examples are degrees Celsius (° C.). It is also noted that when one isomer is separated, the other isomer at 14 position can be obtained from the remaining share after separation according to conventional methods.

Example 1

14-Methoxy-14- (2hydroxyethylthio) vincanol (method “A”)

To a solution of 1 mole of methanesulfonic acid in chloroform, 13.92 g (50 mmol) of (3S, 16S) -eburnamenin and 4.69 g (60 mmol) of metcaptoethanol were dissolved and the solution was allowed to stand at 20 ° for 2 hours. did. The mixture was partitioned between 2N aqueous ammonia solution and 50 cc of methylene chloride, dried and concentrated by evaporation to obtain a resinous residue. Crystallization as 2-propanol at 0 ° gave the desired product having a melting point of 175 °.

Example 2

O-methyl-vincanol and O-methyl-epivinolol

27.84 g (100 mmol) of (3S, 16S) -ebrunameenin was dissolved in 100 cc of a 1 molar solution of anhydrous ethanol sulfate, and the solution was boiled under nitrogen for 30 minutes. It was partitioned between 200 cc of 2N ammonia and methylene chloride, dried and concentrated by evaporation to yield an amorphous material of two epimer base mixtures. Performing fractional crystallization of hydrogen fumarate as 2-propanol at 0 ° first gives fractional crystallization of O-methyl-vincanolhydrogen fumarate with melting point 161 ° (decomposition) and then melting point 110 ° Crystals of O-methyl-epivincanol hanidrogen fumarate (decomposed) were obtained.

The base was liberated by partitioning between 2N aqueous ammonia solution and methylene chloride. The obtained oily residue was crystallized as 2-propanol to give O-methyl-vincanol having a melting point of 106 ° or O-methyl-ipvincanol having a melting point of 163 °.

Example 3

14-deoxy-14-methylthio-vincanol (method “I”)

(A) Formation of a hydrogen halide adduct of (3S, 16S) -ebournamenine

27.84 g of (3S, 16S) -ebrunameenine was passed through anhydrous hydrogen gas through it with stirring at -78 °, and concentrated until a clear yellow solution was about 100 cc.

The solution was concentrated in vacuo at 20 mmHg, again kneading in a dry ice bath, concentrated until a solid was obtained, and the residue was dehydrated for 16 h without stirring -78 ° / 20 mmHg. The vacuum was filled with nitrogen gas and the fragile residue was triturated at -78 °.

B) 14-deoxy-14-methylthio-vincanol

The milled residue obtained in step A) was added thereto while stirring at -78 °, and 100 cc of methanol was added thereto, and the mixture was warmed to 0 ° for 1 hour while stirring, and then stirred for another hour at 0 °. . The reaction mixture was partitioned between 500 cc of 2N-ammonia and 200 cc of methylene chloride, and the methylene chloride solution was evaporated to concentration and crystallized as methanol to obtain the above desired object having a melting point of 199 °.

Example 4-7

Using the compounds of the corresponding structural formulas (II) and (III), the compounds of the structural formula (I) set forth in the following table were obtained by following a method analogous to Example I.

Example 8-14

Correspondingly, Z was obtained according to the method analogous to Example 3 using the starting material of the formula (4), to obtain the compound of formula (1) as shown in the following table.

The compound of formula (I) prepared by the preparation method of the present invention as described above exhibits excellent pharmacological properties, in particular, exhibits psychostimulating action. For example, when the compound was administered to the horseshoe, it showed stimulation for more than 2 hours.

The compound also shows awakening application. For example, the sleep states of Depoortere H. and Loew D. (Int, Symp101-104, 1973 Fischer, Stuttgart) and the European Conference on Sleep Studies by Depoorteye H. (Basel, 1972, 360-364, In a test according to the method described in Karger Busel 1973), when the compound was administered to rats with electrode devices in the brain for a long time, the sleep state of the rats increased and normal sleep states could be measured.

Therefore, this compound can be used as a psychostimulating agent and a stimulant.

For this purpose, the daily dose is about 1-500mg, and for convenience, it is recommended that the dose contains about 0.25-250mg divided by 2-4 times a day.

The compounds of formula (I) may be administered in the form of pharmacologically acceptable acid addition salts. Such acid addition salt forms exhibit the same action as the free base form and can be readily prepared according to conventional methods.

In order to administer the compound, the compound or its pharmacologically acceptable acid addition salt may be administered alone, but it may be combined with these pharmaceutical carriers or diluents to form a conventional formulation such as a solution or a tablet.

It is to be noted that the compounds of Examples 1 and 3 exhibit particularly major functions.

In group 1 of the compounds X is hydrogen. R in the sub-group is alkoxy, alkylthio or dialkylamino. In another sub-group R is methoxy, iso-propylthio, n-butylthio or 2-hydroxyethylthio.

In group 1 of the compounds X is in the 10-position.

Claims (1)

As described above in this text, a compound of formula (II) is reacted with a compound of formula (III) to prepare a compound of formula (Ia), or the Z group in the compound of formula (VI) is substituted as an R group. A process for preparing a compound of formula (I), characterized by the following formula.

In the above structural formulas X is hydrogen or halogen having an atomic number of 9-35 at the 10-nia 11-position; R is a group of OR, SR ₂ or NR ₃ R ₄ , wherein R ₁ and R ₂ are alkyl of 1-4 carbon atoms, aminoalkyl or hydroxyalkyl of 2-4 carbon atoms, phenyl or phenylalkyl having a total of 7-10 carbon atoms, R ₃ and R ₄ are independently hydrogen, alkyl of 1-4 carbon atoms, phenyl or phenylalkyl having a total number of 7-10 carbon atoms; R 'is OR ₁ , or SR ₂ (R1 and R ₂ are as described above); Z is a group which may be substituted as an R group in the formula (I).