PROCESS FOR PRODUCTION OF INTERMEDIATES

Abstract

The present invention relates to a new process for the production of specific intermediates, which are preferably used in the production of vitamin A and/or vitamin A acetate.

Claims

1. Process for the production of compounds of formula (III) ##STR00025## wherein R is one of the following formula ##STR00026## (* signifies where the moiety is attaching), characterized in that a compound of formula (I) ##STR00027## wherein R has the same definition as in formula (III) is reacted with a compound of formula (II) ##STR00028## R.sub.1 and R.sub.2 are independently of each other C.sub.1-C.sub.4 alkyl.

2. Process according to claim 1, wherein the starting material is the compound of formula (I′) ##STR00029## wherein R is one of the following formula ##STR00030## (*signifies where the moiety is attaching).

3. Process according to claim 1, wherein the starting material is the compound of formula (I″) ##STR00031## wherein R is one of the following formula ##STR00032## (* signifies where the moiety is attaching).

4. Process according to claim 1, wherein the process is carried out in the presence of at least one strong base.

5. Process according to claim 4, wherein the at least one strong base is chosen from the group consisting of Schlesinger base, 2,2,6,6-tetramethyl piperidine, lithium diisopropylamide, n-butyllithium, hexyllithium, tert.-butyl lithium, sec-butyllithium, metal amide, lithium hexamethyldisilazane, metal hydride, metal hydroxide, metal alkoxide and sodium hexamethyl-disilazane.

6. Process according to claim 1, wherein the process is carried out in at least one inert solvent.

7. Process according to claim 6, wherein the solvent is a polar aprotic solvent.

8. Process according to claim 6, wherein the at least one solvent is chosen from the group consisting of of pyridine, toluene, xylene, THF, methyl THF, and ethers.

9. Process according to claim 1, wherein the process is carried out at a temperature range of from −10° C. to 100° C.

Description

EXAMPLES

Example 1

Synthesis of Compound of formula IIIa′

[0039] In a 10 ml two-necked flask, C.sub.7-phosphonate (compound of formula (II)) (161 mg, 0.6 mmol) and dihydro-β-ionone (compound of formula (Ia′)) (108 mg, 0.5 mmol) were dissolved in anhydrous THF (3.0 ml). At 24° C., lithium diisopropylamide (0.50 ml, 2M in THF) was added dropwise within 5 min and stirred for 2 hours. Then GC measurement showed that the reaction was complete. Water (1 ml) was added carefully and the mixture was transferred into a separation funnel using 15 ml of dichloromethane and 15 ml of semi-saturated brine. The layers were separated, and the organic layer was washed with 15 ml of semi-saturated brine. The combined aqueous layers were extracted with 15 ml of dichloromethane. The combined organic layers were dried over sodium sulfate, filtered and evaporated to dryness under reduced pressure (rotavap) at 35° C. water-bath temperature. The crude product (compound of formula (IIIa′)) (231 mg, 34.45% purity by qNMR) was obtained in 58% yield and purified by column chromatography (SiO.sub.2/heptane).

Example 2

Synthesis of Compound of Formula (IIIa″)

[0040] In a 10 ml two-necked flask, C.sub.7-phosphonate (II) (161 mg, 0.6 mmol) and β-ionone (compound of formula Ia″)) (100 mg, 0.5 mmol) were dissolved in anhydrous THF (3.0 ml). At 24° C., lithium diisopropylamide (0.50 ml, 2M in THF) was added dropwise within 5 min and stirred for 2 hours. Then GC measurement showed that the reaction was complete. Water (1 ml) was added carefully and the mixture was transferred into a separation funnel using 15 ml of dichloromethane and 15 ml of semi-saturated brine. The layers were separated, and the organic layer was washed with 15 ml of semi-saturated brine. The combined aqueous layers were extracted with 15 ml of dichloromethane. The combined organic layers were dried over sodium sulfate, filtered and evaporated to dryness under reduced pressure (rotavap) at 35° C. water-bath temperature. After purification by column chromatography (SiO.sub.2/heptane) 55.3 mg of product compound of formula (IIIa″) were obtained.

Example 3

Synthesis of Compound of Formula (IIIc″)

[0041] In a 10 ml two-necked flask, C.sub.7-phosphonate (compound of formula (II)) (161 mg, 0.6 mmol) and α-ionone (compound of formula (Ic″)) (100 mg, 0.5 mmol) were dissolved in anhydrous THF (3.0 ml). At 24° C., lithium diisopropylamide (0.50 ml, 2M in THF) was added dropwise within 5 min and stirred for 2 hours. Then GC measurement showed that the reaction was complete. Water (1 ml) was added carefully and the mixture was transferred into a separation funnel using 15 ml of dichloromethane and 15 ml of semi-saturated brine. The layers were separated, and the organic layer was washed with 15 ml of semi-saturated brine. The combined aqueous layers were extracted with 15 ml of dichloromethane. The combined organic layers were dried over sodium sulfate, filtered and evaporated to dryness under reduced pressure (rotavap) at 35° C. water-bath temperature. After purification by column chromatography (SiO.sub.2/heptane) the product compound of formula (IIIc″) was obtained in 36% yield (48.7 mg).