HK1075659B - A process for producing phenserine and its analog - Google Patents

Description

Process for preparing phenylserines and analogues thereof

Background

Phenylserine and phenylserine analogues are well known acetylcholinesterase inhibitors and are useful in the treatment of alzheimer's syndrome and as anti-inflammatory agents. See US5,306,825 and US5,734,062. Phenylserines have been prepared by converting physostigmine salts, such as physostigmine salicylate, to oxidostigmine and then reacting with isocyanates, such as phenyl isocyanate, in an organic solvent in the presence of a base catalyst at basic pH to form phenylserines and the like. This method has a number of drawbacks due to the number of processing steps involved in the production of phenylserine or its analogs from physostigmine salts. This results in very low yields and relatively low purity of phenylserine.

In the first step of the reaction, physostigmine salt is converted to physostigmine free base, which is then hydrolyzed to oxidostigmine by treatment with a base in an organic solvent. The physostigmine produced by this process requires numerous work-up steps, as disclosed in US5,498,726, such as the separation of the physostigmine from the reaction mixture, so that it can be subsequently converted to phenylserine. In another process, physostigmine oxide is prepared by reacting physostigmine with a metal alkoxide in an alcohol, as disclosed in U.S. patent No. 5,306,825; also, physostigmine is hydrolyzed in an organic solvent miscible with water, using aqueous sodium or potassium hydroxide, as disclosed in US 4,978,673, European patent EP 0,298,202, or by oxidizing physostigmine fumarate (Heterocycles 1987, 26: 5pages 1271-1275). In these processes, it is necessary to neutralize the crude reaction mixture with mineral or organic acids, as disclosed in US 4,978,673 and US5,498,726. In addition, as disclosed in US5,306,825 and US5,498,726, it is desirable to prevent oxidation of physostigmine in solution by applying vacuum to the reaction mixture or by conducting the reaction under an inert atmosphere. These processes require the isolation of the physostigmine from the reaction mixture; unless strict measures are taken to exclude air, the resulting physostigmine can degrade significantly. Thus, there has long been a need to provide a simple method for converting physostigmine salts to oxidized physostigmine followed by conversion of oxidized physostigmine to phenylserine.

In a subsequent step of the reaction, the physostigmine reacts with the isocyanate to form phenylserine or its derivatives. The reaction is generally carried out in a water-immiscible organic solvent, such as diethyl ether, diisopropyl ether, benzene, toluene or petroleum ether, in the presence of traces of basic substances, such as alkali metal hydroxides. See US 4,978,673, US5,306,828 and US5,498,726. Other U.S. patents, such as US5,705,657 and US5,726,323, disclose methods for preparing phenylserines using quaternary * salts and quaternary ammonium salts containing metal cyanate or bicyclic amidine catalysts. This method has many drawbacks, particularly with respect to the difficulty involved in isolating and purifying phenylserine or its derivatives.

Summary of The Invention

According to the invention, phenylserines and phenylserine analogues of the formula III,

wherein R is lower alkyl, R¹Is lower alkyl, phenyl lower alkyl, cycloalkyl or cycloalkyl lower alkyl;

can be prepared from the physostigmine compounds of formula I or salts thereof under uniquely selected reaction conditions, solvents and processing conditions that yield high yields and high purification of the phenylserine compounds of formula III in an economical manner,

wherein R is as defined above, and wherein,

by reacting a physostigmine compound of formula II,

wherein R is as defined above, and wherein,

with an isocyanate of the formula V,

R¹-N＝C＝O V

wherein R is¹As defined above. The reaction can be accomplished without the need to use numerous processing steps. Thus, the process is ideally suited for the large-scale production of phenylserine and its analogs in an efficient and economical manner.

Detailed Description

The method of the invention is carried out according to the following reaction flow:

wherein R and R¹Lower alkyl and phenyl, phenyl lower alkyl or cycloalkyl, lower alkyl.

According to the process of the present invention, a physostigmine compound of formula I or a salt thereof is reacted in a hydration reaction medium by hydrolyzing the physostigmine compound of formula I with an alkali metal hydroxide to produce a physostigmine compound of formula II. The compound of physostigmine of formula II is then isolated in pure form from the reaction medium.

The purified physostigmine is then treated with a strong organic base in an anhydrous reaction medium containing a water-miscible organic solvent. The treated oxtoxin lablab base compound is then reacted with an isocyanate of formula V without isolation from the reaction medium. Reacting said isocyanate compound of formula V with said physostigmine compound in said reaction medium to produce said phenylserine compound of formula III. The phenylserine compounds of formula III can be easily isolated in pure form by terminating the reaction by addition of water. During this addition, either water or the reaction mixture may be added to the reaction mixture. It is generally preferred to add the reaction mixture to water.

The process can be used to form compounds of formula III in any enantiomeric form, such as the (+) or (-) enantiomer, and racemates thereof. Depending on the particular enantiomer of formula I used as starting material, compounds of formulae II and III will be obtained having the same stereoconfiguration as the quaternary chiral center of the compound of formula I. Alternatively, the compounds of formula I may be used as racemates, thereby producing the compounds of formulae II and III as racemates.

In the first reaction step of the present invention, step (a), the physostigmine compound of formula I or a salt thereof is converted to the oxidostigmine compound of formula II. The reaction is a hydrolysis reaction carried out in the presence of an alkali metal hydroxide. Physostigmine is a compound that has undergone extensive degradation and can therefore be used in the form of an acid addition salt. According to the previous procedure for the hydrolysis of physostigmine salts of formula I to oxidized physostigmine compounds of formula II, physostigmine salts are first converted to the free base and then hydrolyzed.

According to the invention, physostigmine salts of formula I are hydrolyzed in a step where conversion to its free base is not necessary. The reaction is accomplished by hydrolysis with an alkali metal hydroxide in a hydration medium. In carrying out this reaction, any alkali metal hydroxide may be used. If desired, the aqueous solution may comprise a compound of formula I, or more preferably a compound in the form of a salt thereof. The hydrate may also contain an organic solvent immiscible with water, if desired. Any conventional water-immiscible organic solvent that is inert in the hydrolysis reaction can be used. Among the preferred solvents are lower alkyl ethers such as diethyl ether, tert-butyl methyl ether and diisopropyl ether. The temperature and pressure are not critical in carrying out the reaction. The reaction of step (a) may be carried out at room temperature. However, temperatures of about 20 to 25 ℃ are generally employed in carrying out the reaction. In carrying out step (a), the hydrolysis reaction does not use an organic solvent miscible with water. According to this method, the hydrolysis reaction and recovery of the compound of formula II can be accomplished in the absence of any water-miscible organic solvent. By this means, the acid addition salts of formula I can be converted directly into the Oxycotigmine compound of formula II without the need to convert the salts of formula I into the free base of formula I. In addition, the compound of formula II oxidostigmine can be easily isolated in pure form from the reaction medium.

The presence of water and the absence of water-miscible organic solvents in reaction step (a) produces physostigmine of formula II in the hydration medium, which product is soluble in the hydration medium. In this way, the physostigmine compound of formula II can be easily recovered from the aqueous medium in a high yield of pure form, wherein the product can be simply produced in a straightforward manner. The purity of the physostigmine of formula II can be up to 90% or more, in many cases 98-99.9%.

Although the recovery reaction may preferably be carried out at any basic pH level, according to the present invention, the reaction is generally carried out at a pH in the range of 8.0 to 9.5, which minimizes the loss of physostigmine. The reaction step (a) is carried out at a higher pH, generally from 12 to 14. In this way, the physostigmine compound of formula II is dissolved in the hydration reaction medium and can therefore be easily recovered. After the compound of formula II is generated in the hydration medium, the pH value can be adjusted to 8.0-9.5, and the pure compound of formula II is extracted. For this purpose, any conventional form of extraction method may be used. As described above, the pH is adjusted to 8.0 to 9.5, thereby reducing the loss of the physostigmine compound of formula II.

In adjusting the pH to 8.0-9.5, we have found that excellent results can be obtained by adding an alkali metal bisulfite in place of the inorganic acid. According to the present invention, we have found that mineral acids can adversely affect the yield of the compound of formula II. When the extraction pH is less than 8.0 to 9.5 when an alkali metal bisulfite is used, this adverse effect is eliminated.

The term "pharmaceutically acceptable salts" refers to acid addition salts. The expression "pharmaceutically acceptable acid addition salts" refers to any non-toxic organic or inorganic acid addition salt applied to the compounds of formulae I and III. Any pharmaceutically acceptable salt of the compound of formula I may be used as starting material according to the present invention, the preferred salt being the salicylate salt. Examples of inorganic acids which form suitable salts include hydrochloric, hydrobromic, sulfuric and phosphoric acids, and acid metal salts such as sodium monohydrogen orthophosphate and potassium hydrogen sulfate. Examples of organic acids that form suitable salts include mono-, di-, and tricarboxylic acids. Examples of such acids are acetic, glycolic, lactic, pyruvic, malonic, succinic, glutaric, fumaric, malic, tartaric, citric, ascorbic, maleic, hydroxymaleic, benzoic, hydroxycycybenzoic, phenylacetic, cinnamic, salicylic, 2-phenoxybenzoic and sulfonic acids, such as p-toluenesulfonic, methanesulfonic and 2-hydroxyethanesulfonic acids. Such salts may be present in either a hydrated or substantially anhydrous form.

In the next step of the present invention (step (b)), the physostigmine compound of formula II is converted to the phenylserine compound of formula III by reaction with an isocyanate of formula V. The reaction is carried out by treating the purified compound of formula II oxepin with a strong organic base in an anhydrous reaction medium containing an inert aprotic water-miscible organic solvent after separation from the resulting reaction medium. Deprotonating a compound of formula II by treating the compound with an organic base in an inert aprotic, water miscible organic solvent to yield the compound in reactive form. According to this way, the hydrogen of the hydroxyl group is removed from the compound of formula II, which is in a state of reaction with the isocyanate of formula V. The formation of the reactive form of the compound of formula II is carried out in an anhydrous medium using an inert aprotic organic solvent containing a catalytic amount of an organic base miscible with water. Any conventional strong organic base may be used, such as alkyl lithium, e.g., N-butyl lithium. Any aprotic organic solvent miscible with water may be used, such as dimethoxyethane, tetrahydrofuran, and the like. It must be borne in mind that the solvent is inert both to the deprotonating reaction medium and to the reaction medium in which the isocyanate of formula V is used, including the isocyanate itself.

In the next step of the process after the deprotonation reaction has occurred, the deprotonated compound of formula II is reacted with an isocyanate of formula V to give the compound of formula III. The isocyanate of the formula III is mixed with the reaction mixture in which the deprotonation takes place by adding to the isocyanate of the formula V the reaction mixture containing the deprotonated compound of the formula V or by adding to this reaction mixture the isocyanate of the formula V.

In carrying out the reaction step (b) comprising the isocyanate of formula V, one may use the same reaction medium as that used in the deprotonation reaction. In carrying out the deprotonation reaction and the subsequent condensation reaction with the isocyanate of the formula V, the temperature and pressure are not particularly required, and the reaction can be carried out at room temperature and atmospheric pressure. On the other hand, temperatures of from 15 to 30 ℃ are generally used. After mixing with the isocyanate of formula V, the reaction can be quenched by the addition of water. After addition of water, the compound of formula III precipitates from the resulting reaction medium, allowing easy isolation and purification of the compound. In this way, the reaction mixture can be added to water and vice versa. In this process, the phenylserine compound of the formula III in the form of a free base can be isolated from the reaction medium as a solid precipitate without any distillation or drying step by adding water or by injecting it into water. According to this manner, phenylserine base can be produced, and the product can be recovered in high yield and high purity.

If it is desired to form a phenylserine salt for administration, the phenylserine compounds of formula III may be converted into their phenylserine acid addition salts by suitable means, for example by reaction with a pharmaceutically acceptable acid such as the one described above. A preferred salt for administration of the phenylserine compounds of formula III is the tartrate or succinate salt of phenylserine.

The term "lower alkyl" includes all lower alkyl groups containing 1 to 6 carbon atoms, such as methyl, ethyl, propyl, butyl, isobutyl, and the like. The term "lower alkanolates" includes alkanolates of lower alkyl groups, such as methanolate, ethanolate, isopropanolate and butanolate. The term "cycloalkyl" includes cycloalkyl groups containing from 3 to 7 carbon atoms, such as cyclopropyl, cyclobutyl, cyclohexyl.

The invention is further illustrated by the following examples, which are intended to be illustrative only and not limiting.

Examples

Example 1: synthesis of Oxidophysostigmine

50% by weight sodium hydroxide solution (67.7g, 0.8462mol) was added dropwise to physostigmine salicylate (100g, 0.2418mol) in degassed DI water (300ml) at 45 ℃ under an argon atmosphere. During the addition, the temperature was maintained between 45 and 55 ℃. After about 3 hours at 45 ℃ the yellow solution was cooled to 25 to 30 ℃ and tert-butyl methyl ether (300ml) was added. Using sodium metabisulfite (54g, Na)₂S₂O₅250ml of water) to adjust the pH of the aqueous phase to 9.1. The mixture was stirred for 30 minutes, allowed to stand, and then separated. The aqueous phase was extracted twice with tert-butyl methyl ether (300ml each) over 30 minutes. The organic phases were combined, washed three times with 20% by weight sodium chloride solution (200ml each) and then dried over magnesium sulphate (150g) overnight. The slurry was filtered through celite and the filter cake was washed with tert-butyl methyl ether. The filtrate was concentrated to 300ml in vacuo at 25 to 29in and the residue co-distilled twice with diethoxymethane (300ml each). The residue was diluted with diethoxymethane (300ml) and heated to 50 ℃. The resulting clear slurry was cooled to 5 ℃, stirred for 45 minutes, and then concentrated to about 300 ml. Cold heptane (300ml) was added dropwise, the slurry stirred for 20 minutes and the volume increased by the addition of cold heptane (125 ml). After stirring for about 2 hours, the slurry was filtered through a Buchner funnel. By using cold airThe collected solid was washed with an alkane (200ml) and then dried overnight under vacuum to give physostigmine oxide (35.6g) as a white solid in 67.4% yield and 98.3% purity.

Example 2: synthesis of phenylserine base

Oxidophysostigmine (50g, 0.229mol) was dissolved in 400ml of anhydrous dimethoxyethane under an argon atmosphere. A catalytic amount of 2.5M n-butyllithium in hexane (6.4ml, 16mmol) was added over 1 minute and the solution was stirred for 10 minutes. Phenyl isocyanate (27.269g, 0.2286mmol) was added over 32 minutes, maintaining the temperature between 20 and 23 ℃. The reaction solution was stirred at room temperature for 2 hours and 20 minutes, and then transferred to an addition funnel. The reaction solution was added to a mixture of DI water (630ml) and dimethoxyethane (42ml) over 49 minutes with vigorous stirring. The resulting slurry was stirred for 30 minutes and then filtered through a Buchner funnel (Whatman #3 filter paper). The solid residue was washed four times with DI water (100ml each) and once with heptane (100ml) and then dried at 45 ℃ under 29in vacuum for 9 hours to give phenylserine base (74.4g) as a reddish solid in 96.2% yield and 95.1% purity.

Example 3: synthesis of phenyl serine tartrate

Tartaric acid solution (17.12g, 0.114mol) in a mixture of absolute ethanol (131ml) and DI water (3.3ml) was added over 32 minutes to a slurry of phenylserine base (35g, 0.1037mol) in a mixture of absolute ethanol (126ml) and DI water (3.1ml) under a hydrogen atmosphere. After addition of approximately 60 to 75% tartaric acid solution, the reaction solution was seeded with phenylserine tartrate (72 mg). The reaction mixture was stirred at room temperature for 19 hours 15 minutes, then a mixture of isopropanol (490ml) and water (12ml) was added over 30 minutes. The slurry was stirred for 3.5 hours and filtered through a Buchner funnel (Whatman #3 filter paper). The white residue was washed twice with isopropanol (100ml) and then dried at 45 ℃ under 29in vacuum for 19 hours to give phenylserine tartrate (38.62g) as a white solid in 76% yield and 99.4% purity.

Claims (24)

1. A process for the preparation of an oxidostigmine compound of the formula,

wherein R is independently C_1-6An alkyl group, which process comprises treating a compound of formula I or a salt thereof with an alkali metal hydroxide in a hydration reaction medium in the absence of a water-miscible solvent at a pH of from 12 to 14,

wherein R is independently C_1-6Alkyl radical

Hydrolyzing the compound of formula I or a salt thereof to form the oxepin compound.

2. The process according to claim 1, wherein the reaction medium comprises an inert organic solvent immiscible with water.

3. The method according to claim 2, wherein R is methyl.

4. The method according to claim 3, wherein the compound of formula I is a salt.

5. The method of claim 4 wherein the salt is a salicylate salt.

6. The process according to claim 5, wherein the alkali metal hydroxide is sodium hydroxide.

7. The process according to claim 2, wherein the water-immiscible solvent is C_1-6An alkyl ether.

8. The process according to claim 1, wherein said oxypsostigmine compound is a purified oxypsostigmine compound, said process comprising adjusting said reaction medium to a pH of from 8 to 9.5 and extracting said oxypsostigmine compound in pure form from said adjusted reaction medium.

9. The process according to claim 8, wherein the adjustment is carried out by adding an alkali metal bisulfite.

10. A process according to claim 9 wherein the hydration medium comprises an inert organic solvent which is immiscible with water.

11. The process according to claim 10, wherein the organic solvent is C_1-6An alkyl ether.

12. The method according to claim 11, wherein the physostigmine compound is an acid addition salt.

13. The method of claim 12, wherein the salt is a salicylate.

14. A process for the preparation of a phenylserine compound of formula III,

wherein R is independently C_1-6Alkyl radical, R¹Is C_3-7Cycloalkyl, phenyl C_1-6Alkyl or C_3-7Cycloalkyl radical C_1-6An alkyl group, the method comprising:

a) treating the purified physostigmine compound of formula II with an organic base in an anhydrous reaction medium comprising an inert aprotic organic solvent miscible with water,

wherein R is independently C_1-6An alkyl group; and

b) mixing in said reaction medium an isocyanate IV with said reaction medium,

R-N＝C＝O IV

wherein R is C_1-6Alkyl, phenyl C_1-6Alkyl radical, C_3-7Cycloalkyl or C_3-7Ring C_1-6An alkyl group, reacting said treated physostigmine compound with said isocyanate to produce said phenylserine compound.

15. The process according to claim 14, wherein the water miscible solvent is dimethoxyethane.

16. The process according to claim 15, wherein the organic base is butyllithium.

17. The process of claim 15 wherein R is methyl and the isocyanate is phenyl isocyanate.

18. The process according to claim 14, which comprises the further step, after the formation of the phenylserine compound, of adding water to the reaction medium and precipitating the formed phenylserine compound in the reaction medium.

19. A process for the preparation of a phenylserine compound of formula III,

wherein R is independently C_1-6Alkyl radical, R¹Is C_3-7Cycloalkyl, phenyl C_1-6Alkyl or C_3-7Ring C_1-6An alkyl group, a carboxyl group,

the method comprises the following steps:

a) hydrolysing a physostigmine compound of formula I or a salt thereof with an alkoxide metal hydroxide in a hydration reaction medium in the absence of a water miscible solvent at a pH of from 12 to 14,

wherein R is as defined above, in said hydration reaction medium to produce the compound of formula II Oxycotigmine,

wherein R is as defined above, and wherein,

b) adjusting said reaction medium containing said oxypsostigmine compound to a pH of 8 to 9.5, and extracting said oxypsostigmine compound in pure form from said adjusted hydration reaction medium;

c) treating said purified physostigmine compound with an organic base in an anhydrous reaction medium comprising an inert aprotic organic solvent miscible with water;

d) by mixing the IV isocyanate with the anhydrous reaction medium,

R-N＝C＝0 IV

wherein R is C_1-6Alkyl, phenyl C_1-6Alkyl radical, C_3-7Cycloalkyl or C_3-7Ring C_1-6An alkyl group, a carboxyl group,

reacting said treated oxypotaxine compound with said isocyanate to produce said phenylserine compound.

20. The process according to claim 19, wherein the organic base is n-butyllithium.

21. The process according to claim 19, wherein the water miscible solvent is dimethoxyethane.

22. The method of claim 21 wherein R is methyl and the isocyanate is phenyl isocyanate.

23. The process according to claim 19, comprising the additional step of adding water to said anhydrous reaction medium after the formation of the phenylserine compound, to precipitate said phenylserine compound.

24. The method according to claim 19, said adjusting being carried out by adding an alkali metal bisulfite.