GB1580352A

GB1580352A - Optically active isomers of 1,4-disubstituted imidazolidin-2-ones and thiones and their use in the non-asymmetric synthesis of levamisoles

Info

Publication number: GB1580352A
Application number: GB10270/77A
Authority: GB
Original assignee: American Cyanamid Co
Current assignee: Wyeth Holdings LLC
Priority date: 1976-04-26
Filing date: 1977-03-17
Publication date: 1980-12-03
Also published as: NZ183577A; ES458163A1; IL51639A0; AU2341177A; DD131170A5; IT1086594B; NL7704251A; SE7704744L; DK181077A; DE2718058A1; AR214311A1; FR2371433A1; JPS52131579A; SU791231A3; NO771421L

Description

(54) OPTICALLY ACTIVE ISOMERS OF 1,4-DISUBSTITUTED IMIDAZOLIDIN-2-ONES AND THIONES AND THEIR USE IN THE NON-ASYMMETRIC SYNTHESIS OF LEVAMISOLES (71) We, AMERICAN CYANAMID COMPANY, a Corporation organized and existing under the laws of the State of Maine, United States of America, of Berdan Avenue, Township of Wayne, State of New Jersey, United States of America, do hereby declare the invention for which we pray that a patent may be granted to us, and the method by which it is to be performed, to be particularly described in and by the following statement: This invention relates to novel 1 ,4-disubstituted imidazolidine-2-ones and thiones, and is a modification of, or improvement in, the invention forming the subject of our co-pending application No. 11485/77 (Serial No. 1579861) The main application, inter alia, describes and claims 1,4-disubstituted imidazolidine-2ones and thiones of the formula:

wherein R is hydrogen, alkyl C1-C6, phenyl optionally substituted with up to three atoms or groups consisting of alkyl C1-C, halo and alkoxy Cl-C6 or R is a moiety of the formula COR3, wherein R3 is hydrogen, alkyl C1-C6, halo alkyl C1-C6, alkoxy C1-C6, phenoxy, phenyl, or phenyl or phenoxy substituted with up to four atoms or groups consisting of alkyl C1-C6, halo, trifluoromethyl or alkoxy Cl-C6; R1 is hydrogen or a moiety of the formula COR4, wherein R4 is alkyl Cl-C6, alkoxy C1-C6, cycloalkyl C5-C10, or phenyl or phenoxy optionally substituted with up to four atoms or groups consisting of alkyl C1-C6, alkoxy C1-C6, halo or trifluoromethyl; R2 is phenyl optionally substituted with up to two atoms or groups consisting of alkyl Cl-C6, alkoxy C1-C6, halo or trifluoromethyl and Z is oxygen or sulfur, with the proviso that when Z is sulfur then Rl must be hydrogen and R cannot be hydrogen.

The conversion of thiones within the scope of formula (I) above into tetramisole and substituted tetramisoles is also disclosed in said main application.

The present invention is concerned with the optically active isomers of the compounds of formula (I), and the conversion thereof into levamisoles.

The optically active isomers of the present invention may be prepared by reducing an imidazoline of the formula:

wherein R, R2 and R4 are defined above, by hydrogenating in the presence of a chiral catalyst in a suitable organic solvent (e.g. an alcohol, aromatic hydrocarbon, ketone or ethyl acid ester), at a temperature of from 25 to 80"C and suitably a pressure of from 15 to 1500 psig of hydrogen, to obtain an optically active isomer of imidazolidine of the formula:

The optically active isomer thus obtained may then be converted into an optically active isomer of a thione of the formula:

wherein R and R2 are as defined above except R is not hydrogen, by first hydrolyzing the imidazolidine in the presence of a hydroxide source in either water or alcohol at a temperature of from 70" to 100" C to yield an optically active isomer of a compound of the formula:

and then refluxing the optically active isomer of formula (IV) with phosphorus pentasulfide or phosphorus trisulfide in a suitable solvent at a temperature of from 80" to 200 C.

A process for the preparation of the starting imidazolidine of formula (II) is described in the specification of the main patent.

The preferred chiral catalyst for the homogeneous reduction of the optically inactive imidazolidine of formula (II) to the optically active isomer of the imidazolidine of formula (III) is (+ )2 ,3-isopropylidene-2,3-dihydroxy-1 ,4-bis-(diphenylphosphino)butane cyclooctadiene rhodium chloride.

The optically active isomer of the thione of formula (V) may be converted into levamisole or substituted levamisole of the formula:

wherein R2 is as defined above and Y is a pharmaceutically acceptable anion, by heating said imidazolidine thione with a compound of the formula HY in a solvent at a temperature of from 0 to 200"C. Suitable solvents for this reaction include water, alkanols C,-C6, ketones, ethers and hydrocarbons (including halogenated hydrocarbons).

If desired, the acid addition salt of the 2,3.5,6-tetrahydroimidazo [2,1-b] thiazole i.e. the compound of formula (VII), may be neutralized to provide the free base.

A preferred embodiment of the reactions of the present invention are illustrated by the Flowsheet below:

p Alooil or a arornatic solvent FNI 25 Oû C [H R2AN [H p1 (It) PPh2 /I CH2 0 PPh2 b S (Elill) Chral Catalyst R2aN/L R1 (m) 70"-100"C water ar alcohol UH sulfuratjng agent solvent l Op R2Th*%-s L & r-3O[rL (V) h (N) and(V)as the optically active free base HV solvent l 0 -2ûOOC R2 < N The compound of formula (II) undergoes homogeneous reduction, as shown in the flowsheet, with a chiral catalyst such as compound VIII, when hydrogenated at from 15 to 1500 psig of hydrogen in a suitable organic solvent such as an alcohol, aromatic hydrocarbon, ketone or ethyl acid ester at a temperature from 25 to 80 C. Compound (III) is hydrolyzed, when heated from 25 to 80 C. Compound (III) is hydrolyzed, when heated from 70" to 100"C. in the presence of a hydroxide source in water or alcohol, to optically active isomer (IV). Optically active isomer (IV) is converted to optically active isomer (V), along with some optically active (VI), on treatment with a reagent capable of substituting sulfur for oxygen (e.g. phosphorouspentasulfide or phosphorus trisulfide) in refluxing hydrocarbon solvents at a temperature from 80" to 2000C. The compounds of formula (V) are converted to optically active isomer (VI) on heating with HY, wherein Y is a pharmaceutically acceptable anion (such as chloride, fluoride, iodide, bisulfate orp-toluene sulfonate), in a suitable solvent at a temperature from 0 to 200"C.

In the case of formula (IV) compounds wherein R is hydrogen, reaction with phosphorus pentasulfide also affects the free hydroxyl group, altering it to form a sulfur-containing group which may or may not also contain phosphorus. This altered group is nonetheless capable of undergoing ring closure in the final step to form compounds of formula VI. In the case of formula IV compounds wherein R is the COR3 moiety, it is frequently found that the COR3 group reacts with the thiating reagent (e.g. phosphorus pentasulfide) to form the CSR3 group. This does not affect the ability of the formula V compounds in which this change has occurred to ring close to the desired compounds of formula VI. Accordingly; both these variants are within the scope of the present invention It will thus be seen that the present invention, in one of its aspects, relates to a novel process using novel intermediates, for the production of levamisole. It involves simpler and fewer steps, and avoids the use of expensive reducing agents. For the first time a catalytic assymetric synthesis of levamisole has been achieved through the reduction of a prochiral intermediate. All other known processes proceed through the expensive resolution of tetramisole or intermediates. This invention is capable of producing the appropriate acid-addition salts of tetramisole of levamisole directly, and is applicable to the production of analogs of tetramisole and levamisole.

There are several procedures for the production of the anthelmintic tetramisole reported in the literature (Raemaekers et al., J. Med. Chem. 9, 545 (1966), Bakelien et al., Aust. J.

Chem. 21 1557 (1968), T. R. Roy U.S. Patent No. 3,855,234, M. E. McMenin, U.S. Patent No. 3,854,070). These procedures yield tetramisole, a racemic compound, which is then resolved to give its physiologically active levorotatory enantiomer levamisole. None of these procedures is adaptable to a direct synthesis of levamisole without resolution.

A method for making tetramisole from 1-(2-hydroxyethyl)--4-phenyl-4-imidazolin-2thione and thionyl chloride is disclosed in U.S. Patent No. 3,726,894. This compound is made by the hydroboration reaction on 1-vinyl-4-phenyl-4--imidazolin-2-thione, which is obtained as a by-product in the racemization of physiologically inactive d-tetramisole to the physiologically active dl-compound, tetramisole.

The instant invention overcomes the drawbacks of the prior art in that it is regioselective (no iso-levamisole can be formed); all the steps can occur in good yields; it involves for the first time in levamisole synthesis a catalytic reduction step, capable of introducing chirality, using catalytic amounts of a chiral reagent such as the rhodium chloride complex of (+) or (-), DIOP (see Formula (VIII) above). (The property of nonidentity of an object with its mirror image is termed chirality. An object such as a molecule is given configuration or conformation, is termed chiral when it is not identical with its mirror image; it is termed achiral when it is identical with its mirror image. J. Org. Chem. Vol. 35 No. 9 Sept. 1970.) The present synthesis is even expected to be more economical than the current routes for tetramisole; and it is applicable to the synthesis of other analogs.

One class of compounds of this invention are optically active compounds of formula (I) wherein R is hydrogen, alkyl C1-C6, phenyl or halophenyl, or R is COR3 wherein R3 is hydrogen, alkyl C1-C6, halo-C1-C6 alkyl, phenyl or halophenyl; R1 is hydrogen or COR4 wherein R4 is alkyl C1-C6, cycloalkyl C5-C10 or phenyl optionally substituted with halo, dihalo, alkyl C1-C6, alkoxy C1-C6 or trifluoromethyl; and R2 is phenyl optionally substituted with trifluoromethyl, halo or dihalo.

Specific compounds of this invention include the optically active isomers of: 1-(2-methoxyethyl)-4-phenyl-2-imidazolidone, 1-(2-hydroxyethyl)-4-phenyl-2imidazolidone, 1-(2-acetoxyethyl)-4--phenyl-2-imidazolidone, 1-(2-methoxyethyl)-4-(3methoxyphenyl--2-imidazolidone, 1-(2-methoxyethyl)-3-acetyl-4-phenyl-2--imidazolidone, 1-(2-methoxyethyl)-3-benzoyl-4-phenyl-2-imidazolidone, 1-(2-methoxyethyl)-3-(2 methoxybenzoyl)-4--phenyl-2-imidazolidone, 1-(2-methoxyethyl)-3-(4trifluoromethylbenzoyl-4-phenyl-2-imidazolidone, 1-(2-methoxyethyl)--3-(1 adamantanecarbonyl)-4-phenyl-2-imidazolidone, 1-(2--methoxyethyl)-3cyclohexanecarbonyl-4-phenyl-2-imidazolidone, 1-(2-butoxyethyl)-4-phenyl-2- imidazolidone, 1-(2-methoxyethyl)-4-(3-trifluoromethyl)phenyl-2-imidazolidone, 1-(2-- methoxyethyl).4-(3-methyphenyl)-2-imidazolidone, 1-(2--methoxyethyl)-4-(4trifluoromethylphenyl)-2-imidazolidone, 1-(2-benzoyloxyethyl)-4-phenyl-2-imidazolidone, 1-(2--methoxyethyl)-4-phenylimidazolidone-2-thione and 1-(2-phenoxyethyl)-4phenylimidazolidone-2-thione .

The invention is illustrated by the Examples which follows.

EXAMPLE 1 Hydrogenation of N-acyl derivatives of 1 - (2-methoxyethyl) -4-phenyl-4-imidazolin-2-one using (+) DIOP RhCODCI Catalyst and Hydrogen The hydrogenations are carried out in a Parr Shaker apparatus or in a high pressure laboratory in glass lined autoclaves. The products are extracted with ether or etherbenzene, concentrated and hydrolyzed by refluxing in a 10 percent sodium hydroxide solution. The crude 1-(2--methoxyethyl)-4-phenyl-2-imidazolidone generated is extracted with methylene chloride, concentrated, and analyzed for the ratio of enantiomers by Nuclear Magnetic Resonance (NMR) using the chiral shift reagent tris-[-3 trifluoromethylhydroxymethylene)-d-camphorato], europium (III) derivative, Eu(tfc)3.

The results of the hydrogenations are summarized in the following table.

The catalyst is prepared from (-) tartaric acid as described by H.B. Kagan and T.P.

Dang. J. Am. Chem. Soc. 94, 6429 (1972). The (+) DIOP can also be bought from Strem Chemicals, Inc. Benerly, Mass.

The starting 4-imidazolidone-2-ones are prepared in Example 20 of the main patent.

TABLE I Reduction of N-Acyl Imidazolinones with (+)DIOP-RhCODCl Catalyst and Hydrogen Enantiomeric Temp. Pressure Time Selectivity Excess or Substrate Solvent 0 C. Psig Hours S/R Optical Yields 1-(2-methoxyethyl)-3-benzoyl -4-phenyl-4-imidazolin-2-one #H-ETOH (1:1) 40 55 18 1.65:1.0 25% 1-(2-methoxyethyl)-3-benzoyl -4-phenyl-4-imidazolin-2-one #H-ETOH (3:1) 60 1000 6 1.25:1.0 11.1% 1-(2-methoxyethyl)-3-cyclohexanecarbonyl-4-phenyl-4 -imidazolin-2-one #H-ETOH (1:1) 25 45 20 2.0:1.0 33% 1-(2-methoxyethyl)-3-p-trifluoromethylbenzoyl-4-phenyl -4-imidazolin-2-one #H-ETOH (3:1) 60 1000 4 1.7:1.0 26% 1-(2-methoxyethyl-3-(1-adamantanecarbonyl)-4-phenyl-4 -imidazolin-2-one #H-ETOH 60 1000 4 1.2:1.0 9.1% 1-(2-methoxyethyl)-3-o-anisoyl -4-phenyl-4-imidazolin-2-one #HETOH (3:1) 60 1000 4 1.5:1.0 20.0% 1-(2-methoxyethyl)-3-acetyl -4-phenyl-4-imidazolin-2-one #H-PriOH(3:1) 60 500 6 2.0:1.0 33% EXAMPLE 2 Optically Active Levamisole from 1-(2-methoxyethyl)-4--phenyl-3-acetyl-4-imidazolin-2-one Approximately 5.2 g. of 1-(2-methoxyethyl)--4-acetyl-4-phenyl-4-imidazolin-2-one, 250 mg. of cyclo-octadiene rhodium chloride dimer and 600 mg. of (+)DIOP dissolved under nitrogen in 30 ml. of ethanol and 30 ml of benzene is hydrogenated in a Parr Shaker apparatus at 40"C. and 35 psig hydrogen for 11 hours. The solution is concentrated to dryness under reduced pressure, the residue dissolved in ether (100 ml.) and filtered. The filtrate is concentrated under reduced pressure, the residue dissolved in ether (100 ml.) and filtered. The filtrate is concentrated under reduced pressure to give a brown oil. This oil is dissolved in 20 ml of ethanol and 40 ml. of 10 percent sodium hydroxide is added. The mixture is refluxed for 1 hour, cooled and extracted with methylenechloride (2us0 ml.) The combined organic layer is washed, dried and the solvent removed to give optically active 1-(2-methoxyethyl)-4-phenyl-2-imidazolidone as a waxy solid. This material is estimated to contain 24 percent excess of one enantiomer using the chiral shift reagent Eu(tfc)3 mentioned in Example 1. The solid is refluxed with 2 g of phosphorous pentasulfide in toluene for 20 hours. Toluene is removed under reduced pressure, the residue taken up in 100 ml of chloroform and 100 ml. of 20 percent sodium hydroxide. The organic layer is separated, washed and concentrated to give an oil. This oil is taken in 20 ml of concentrated hydrochloric acid and the solution is refluxed for 1 hour. The solution is cooled, filtered and filtrate made basic with ammonium hydroxide. The mixture is extracted with 2 2x50 50 ml of methylene chloride. The combined organic layer is washed, dried and the solvent removed to give an oil which crystallizes on standing. The spectral characteristics are identical to that of tetramisole and the material had a specific rotation []D20 = 17.70 (c7 in chloroform) corresponding to a 21% enantiomeric excess of levamisole.

EXAMPLE 3 Optically Active Levamisole from 1-(2-methoxyethyl)-3--benzoyl-4-phenyl-4-imidazolin-2one Approximately 6.4 g of 1-(2-methoxyethyl)-3-benzoyl-4-phenyl-4-imidazolin-2-one, 250 mg. of cyclooctadiene rhodium chloride dimer and 550 gm of (+) DIOP dissolved in 30 ml of ethanol and 30 ml of benzene is hydrogenated in a Parr Shaker apparatus at 400C. and 45 psig of hydrogen for 18 hours. The solution is then concentrated under reduced pressure and the residue extracted with ether (3x75 ml.). The ether extracts are combined and concentrated to give 6.3 g of an oil. This oil is hydrolyzed by refluxing with 10 percent sodium hydroxide solution and optically active 1-(2-methoxy-ethyl)-4-phenyl-2imidazolidone is obtained as described in Example 2. The material is estimated to contain a 26 percent excess of one enantiomer. Further conversion of this material to levamisole as described in Example 2 gives optically active levamisole with a specific rotation [a]20 -17.9 (C 10, chloroform), corresponding to a 22 percent excess of levamisole.

Claims

WHAT WE CLAIM IS:

1. An optically active isomer of a compound of the formula:

wherein R is hydrogen, alkyl C1-C6, phenyl optionally substituted with up to three atoms or groups consisting of alkyl C1-C6, halo and alkoxy C1-C6 or R is a moiety of the formula COR3, wherein R3 is hydrogen, alkyl Cl-C6, alkoxy C1-C6, phenoxy, halo-C1-C6 alkyl, phenyl, or phenyl or phenoxy substituted with up to four atoms or groups consisting of alkyl C1-C6, halo, trifluoromethyl or alkoxy C1-C6; R1 is hydrogen or a moiety of the formula COR4, wherein R4 is alkyl C1-C6, alkoxy C1-C6, phenoxy, cycloalkyl Cs-C1oS phenyl, or phenyl or phenoxy substituted with up to four atoms or groups consisting of alkyl C1-C6, alkoxy C1-C6, halo or trifluoromethyl; R2 is phenyl optionally substituted with up to two atoms or groups consisting of alkyl C1 -C6, alkoxy C1-C6, halo or trifluoromethyl; and Z is oxygen or sulfur, with the proviso that when Z is sulfur R1, must be hydrogen and R cannot be hydrogen.

2. An optically active isomer according to Claim 1, 1-(2-methoxyethyl)-4-phenyl-2imidazolidone, 1-(2-hydroxyethyl)-4-phenyl-2-imidazolidone, 1-(2-acetoxyethyl)-4-phenyl2-imidazolidone, 1-(2-methoxyethyl)-4-(3-methoxyphenyl)-2-imidazolidone, 1-(2 methoxyethyl)-3--acetyl-4-phenyl-2-imidazolidone, 1-(2-methoxyethyl)-3--benzoyl-4phenyl-2-imidazolidone, 1-(2-methoxyethyl)--3-(2-methoxybenzoyl)-4-phenyl-2 imidazolidone, 1-(2--methoxyethyl)-3-(4-trifluoromethylbenzoyl)-4-phenyl--2- imidazolidone, 1-(2-methoxyethyl)-3-( 1-adamantane-carbonyl)-4-phenyl-2-imidazolidone, 1-(2-methoxyethyl)--3-cyclohexanecarbonyl-4-phenyl-2-imidazolidone, 1-(2--butoxyethyl)4-phenyl-2-imidazolidone, 1-(2-methoxyethyl)-4-(3-trifluoromethyl)phenyl-2imidazolidone, 1-(2-methoxyethyl)-4-(3-methylphenyl)-2-imidazolidone, 1-(2 methoxyethyl)-4-(4-trifluoromethylphenyl)-2-imidazolidone, 1-(2-benzoyloxyethyl)-4- phenyl-2-imidazolidone, 1-(2--methoxyethyl)-4-phenylimidazolidone-2-thione or phenoxyethyl)-4.phenylimidazolidine-2-thione.

3. An optically active isomer according to Claim 1, wherein R is hydrogen, alkyl C1-C6, phenyl or halophenyl or R is COR3 wherein R3 is hydrogen, alkyl C1-C6, halo-C1-C6 alkyl, phenyl or halophenyl; R1 is hydrogen or COR4 wherein R4 is alkyl C1-C6, cycloalkyl C5-C10, or phenyl optionally substituted with halo, dihalo, alkyl C1-C6, alkoxy C1-C6 or trifluoromethyl; and R2 is phenyl optionally substituted with trifluoromethyl, halo or dihalo.

4. A method for the preparation of an optically active isomer of a compound of the formula:

wherein R, R2 and R4 are as defined in Claim 1 characterized by reducing an imidazolinone of the formula:

wherein R, R2 and R4 are as defined above, by hydrogenating in the presence of a chiral catalyst in a suitable organic solvent at a temperature from 25 to 800C. to obtain an optically active isomer of an imidazolidone of the formula:

wherein R, R2 and R4 are as defined above.

5. A method according to Claim 4, wherein said suitable organic solvent is an alcohol, aromatic hydrocarbon, ketone or ethyl acid ester.

6. A method according to Claim 4 or Claim 5, wherein said chiral catalyst is (+ )2,3-isopropylidene-2,3--dihydroxy-1 ,4-bis(diphenylphosphino) butane cyclooctadiene rhodium chloride.

7. A method for the preparation of a compound of the formula:

wherein R and R2 are as defined in Claim 1, characterized by hydrolyzing a compound of the formula:

wherein R, R2 and R4 are as defined in Claim 1, in the presence of a hydroxide source in either water or alcohol at a temperature from 70" to 1000C. to yield an optically active isomer of a compound of the following formula:

wherein R and R2 are as defined above, and refluxing said optically active isomer with phosphorous pentasulfide or phosphoroustrisulfide in a suitable solvent at a temperature from 80" to 2000C.

8. A method for the preparation of an optically active isomer of a compound of the. formula:

wherein R2 is as defined in Claim 1 and Y is a pharmaceutically acceptable anion, which comprises reacting a substituted optically active imidazolidinethione of the formula:

wherein R2 is as defined in Claim 1 and R is as defined in Claim 1 except that it is not hydrogen, with a compound of the formula HY, wherein Y is as defined above, in a solvent at a temperature from 0 to 200"C., and recovering the substituted optically active 2,3,5,6-tetrahydroimidazo-[2,1-b] thiazole acid addition salt of the free base.

9. A method according to Claim 8, wherein said solvent is water, alkanol C1-C6, ketone, ether, hydrocarbon or halogenated hydrocarbon.

10. A method according to Claim 8 or 9, wherein said acid addition salt is neutralized to provide the free base.

11. A method for the preparation of an optically active isomer of a compound of the formula:

wherein R2 and Y are as defined in Claim 8, which comprises refluxing a compound of the formula:

wherein R and R2 are as defined in Claim 1; with phosphorus pentasulfide or phosphorus trisulfide in a suitable solvent at a temperature from 80" to 200"C.; reacting the product of this reaction with a compound of the formula HY, wherein Y is as defined above, in a solvent at a temperature from 0 to 200"C.; and recovering the substituted optically active 2,3,5,6-tetrahydroimidazo [2,1-b] thiazole acid addition salt of the free base.

12. An optically active isomer as defined in Claim 1, substantially as described in Example 1 herein.

13. A method of preparing an optically active isomer as defined in Claim 1, substantially as described in Example 1 herein,.

14. A method of preparing optically active levamisole, substantially as described in Example 2 or Example 3 herein.