SUBSTITUTED DIOXANONES, METHOD FOR PREPARING SAME AND USE THEREOF

Abstract: Novel substituted dioxanones obtained from (R)-3-­ hydroxybutyric acid, for example 2,2-dimethoxy-6-methyl-1,3-­ dioxan-4-one, a method for their preparation and processes using the dioxanones as starting material. The dioxanones can be used in particular as intermediates in the preparation of (S)-4-methyl-­ β-butyrolactone.

Description: The present invention relates to chemical compounds and in particular to substituted dioxanones obtained from (R)-3-­ hydroxybutyric acid. This invention also relates to a method for the production of such dixanones and to processes using such dioxanones as starting-materials. (R)-3-Hydroxybutyric acid is a readily available, cheap, chiral starting material useful in a number of synthetic methods, see for example Seidel et Seebach, Tet. Lett. 2209 (1984) and the references contained therein. We have now discovered chemical intermediates, useful in the pharmaceutical and agrochemical industries, that can be prepared from (R)-3-hydroxybutyric acid. Accordingly the present invention provides a compound of the formula (I): wherein R¹ is C 1-4 alkylamino or di-C 1-4 alkylamino and R² is hydrogen; or R¹ is C 1-4 alkoxy and R² is hydrogen, C 1-4 alkyl or C 1-4 alkoxy. Suitably R¹ is di-C 1-4 alkylamino for example dimethyl­ amino and R² is hydrogen. More suitably R¹ is C 1-4 alkoxy for example methoxy or ethoxy and R² is hydrogen, C 1-4 alkyl for example methyl or ethyl or C 1-4 alkoxy for example methoxy or ethoxy. In particular the present invention provides the dioxanones wherein R¹ is methoxy and R² is hydrogen, methyl or methoxy; and wherein R¹ and R² are both methoxy or ethoxy. In another aspect of the present invention we provide a method for the production of a compound of the formula (I) wherein (R)-3-hydroxybutyric acid, of the formula (II), or a reactive derivative thereof is reacted with a compound of the formula (III): in which R¹ and R² are as defined hereinbefore and R³ and R⁴ are leaving groups. Conveniently R³ and R⁴ are the same and are C 1-4 alkoxy groups. Of course such alkoxy groups are the same as, or better leaving groups than, any alkoxy groups R¹ and R². Typically R¹, R², R³ and R⁴ take the same value for example they are all methoxy groups or they are all ethoxy groups. The reaction between the compounds of the formulae (II) and (III) is conveniently performed in an organic solvent, for example an aromatic hydrocarbon such as benzene or toluene, at ambient or an elevated temperature for example between 20°C and 120°C. Typically methanol or ethanol or similar volatile by-­ product is removed from the reaction mixture by azeotropic distillation with the organic solvent. As stated hereinbefore the compound of the formula (I) have utility as chemical intermediates. According to a further aspect of the invention we provide a process for the production of (S)-4-methyl-β-butyrolactone of the formula (IV): Wherein a compound of the formula (I) in which R¹ is C 1-4 alkoxy is subjected to the action of heat and low pressure. This compound is a well-known synthon in organic chemistry and is of potential utility in making polymers. Typically the compound of the formula (I) is subjected to distillation at a temperature in the range 60° to 250°C and a pressure in the range 0.1 to 75 torr. In general the higher the temperature the higher the pressure so that typical conditions, for the formation of (S)-4-methyl-b-butyrolactone from a compound of the formula (I) wherein R¹ is methoxy and R² is methyl, are 70°-75°C at 0.15 torr; 120-130°C at 10 torr; and 180-190°C at 50 torr. The product is obtained together with unreacted starting-­ material. A particular advantage of this process is that (S)-4-­ methyl-β-butyrolactone is generally obtained in an optical purity of greater than 98%. According to a further aspect of the invention we provide a process for the production of a compound of the formula (V) in which R⁵ is a hydrocarbon residue wherein a compound of the formula (I) is reacted with an amine of the formula R⁵NH₂. Preferably R⁵ contains an aromatic ring with benzylamine being especially suitable for the amine to be used in the reaction. EXAMPLE 1 To a solution of (R)-3-hydroxybutyric acid (2.04 g) in benzene (15 ml) was added tetraethylorthocarbonate (3.84 g) in benzene (5 ml) at room temperature. The mixture was heated to 80°C and the ethanol-benzene azeotrope was distilled until the heat temperature decreased to 50°C. The residue was evaporated under reduced pressure at 25°C/10 mbar to remove benzene to give a residue containing 2,2-dimethoxy-6-methyl-1,3-dioxan-4-one. This residue was then subjected to distillation at 140-­ 160°C mbar to afford (S)-4-methyl-β-butyrolactone (86%) with an optical purity of greater than 99% ([x] D ²⁵ = -27.9 (c = 3.3; CHCl₃)). EXAMPLES 2 - 6 In a manner similar to Example 1 the following transformations were effected in benzene under reflux: EXAMPLES 7 - 10 Distillation under the following conditions afforded (S)-4-methyl-b-butyrolactone; the remainder being unreacted starting-material. EXAMPLE 11 The product of Example 2, 2-methoxy-6-methyl-1,3-dioxan-­ 4-one, was reacted with benzylamine in dichloromethane at room temperature for 24 hours. This afforded optically active 3-(N-­ benzylamino) butyric acid. In a similar fashion the dioxanones of this invention can be reacted with a variety of amines.

Claims: 1. A compound of the formula (I): wherein R¹ is C1-4 alkylamino or di-C1-4 alkylamino and R² is hydrogen; or R¹ is C1-4 alkoxy and R² is hydrogen, C1-4 alkyl or C1-4 alkoxy. 2. A compound according to claim 1 wherein R¹ is dimethylamino and R² is hydrogen. 3. A compound according to claim 1 wherein R¹ is methoxy or ethoxy and R² is hydrogen, methyl, ethyl, methoxy or ethoxy. 4. A compound according to claim 1 wherein both R¹ and R² are methoxy or ethoxy. 5. A method for the production of a compound of the formula (I) in which R¹ is C1-4 alkylamino or di-C1-4 alkylamino and R² is hydrogen; or R¹ is C1-4 alkoxy and R² is hydrogen, C1-4 alkyl or C1-4 alkoxy wherein (R)-3-hydroxybutyric acid of the formula (II), or a reactive derivative thereof is reacted with a compound of the formula (III): in which R¹ and R² are as defined hereinbefore and R³ and R⁴ are leaving groups. 6. A method according to claim 5 wherein R³ and R⁴ are the same and are C1-4 alkoxy groups. 7. A method according to claim 5 or claim 6 wherein the reaction is performed in an organic solvent at a temperature in the range 20°C to 120°C. 8. A process for the production (S)-4-methyl-β-­ butyrolactone of the formula (IV): Wherein a compound of the formula (I): in which R¹ is C1-4 alkoxy and R² is hydrogen, C1-4 alkyl or C1-4 alkoxy is subjected to distillation at a temperature in the range 60° to 250°C and at a pressure in the range 0.1 to 75 torr. 9. A process according to claim 8 for the production of (S)-4-methyl-β-butyrolactone of the formula (IV) wherein the compounds of the formula (I) is one in which R¹ is methoxy and R² is methyl. 10. A process for the production of a compound of the formula (V): in which R⁵ is a hydrocarbon residue wherein a compound of the formula (I): in which R¹ is C1-4 alkylamino or di-C1-4 alkylamino and R² is hydrogen; or R¹ is C1-4 alkoxy and R² is hydrogen, C1-4 alkyl or C1-4 alkoxy, is reacted with an amine of the formula R⁵NH₂.

Inventors: GRIESBECK, AXEL, SEEBACH, DIETER
Applicants: IMPERIAL CHEMICAL INDUSTRIES PLC
Application year: 1987
Main classification: C07D319
IPC codes: C07D305, C07C227, C07D319, C07C67, C07D315, C07C229