PROCESS FOR PRODUCTION OF VITAMIN A

Abstract

The present invention relates to a new process for the production of vitamin A and/or its derivatives.

Claims

1. Process for the production of the compound of formula (III) ##STR00016## R is H, or —(CO)—(CH.sub.2).sub.nCH.sub.3, wherein n has a value of 0-14, or R is —X(C.sub.1-4alkyl).sub.3 or —X(C.sub.6H.sub.5).sub.3, wherein X is Si or Ge or R is tetrahydro pyrane, isopropylmethyl ether or 2-methoxy-butylether, characterized in that in a first step (step (i)) a compound of formula (I) ##STR00017## wherein R has the same as defined for the compound of formula (III) is treated with heat to form a compound of formula (II) ##STR00018## wherein R has the same as defined for the compound of formula (III), which is then converted into compound of formula (III) by an elimination reaction (step (ii)).

2. Process according to claim 1, wherein the reaction temperature in step (i) is up to 200° C.

3. Process according to claim 1, wherein the reaction temperature range in step (i) goes from 50° C.-200° C.

4. Process according to claim 1, wherein the reaction temperature range in step (i) goes from 60° C.-150° C.

5. Process according to claim 1, wherein the reaction in step (i) is carried out in at least one inert solvent.

6. Process according to claim 5, wherein the solvent chosen from the group consisting of pyridine, toluene, xylene, THF, methyl THF, and ethers.

7. Process according to claim 1, wherein the process of step (i) can be carried at atmospheric pressure.

8. Process according to claim 1, wherein the reaction temperature in step (ii) is up to 200° C.

9. Process according to claim 1, wherein the reaction temperature range in step (ii) goes from 50° C.-200° C.

10. Process according to claim 1, wherein the reaction temperature range in step (ii) goes from 60° C.-150° C.

11. Process according to claim 1, wherein the reaction in step (ii) is carried out in at least one inert solvent.

12. Process according to claim 11, wherein the solvent is chosen from the group consisting of pyridine, toluene, xylene, THF, methyl THF, and ether.

13. Process according to claim 1, wherein the reaction in step (i) is carried out at atmospheric pressure.

14. Process according to claim 1, wherein step (i) and (step (ii) are carried as a one pot reaction using the same reaction conditions without isolating the reaction of step (i).

15. Compound of formula (II) ##STR00019## wherein R is H, or —(CO)—(CH.sub.2).sub.nCH.sub.3, wherein n has a value of 0-14, or R is —X(C.sub.1-4alkyl).sub.3 or —X(C.sub.6H.sub.5).sub.3, wherein X is Si or Ge or R is tetrahydro pyrane, isopropylmethyl ether or 2-methoxy-butylether.

Description

EXAMPLES

Example 1: Preparation of (2E,5E,7E)-4-hydroxy-3,7-dimethyl-9-(2,6,6-trimethylcyclohex-1-en-1-yl)nona-2,5,7-trien-1-yl acetate (Compound of Formula (II))

[0069] (E)-4-hydroxy-3-methyl-4-(4-methyl-1,1-dioxido-5-((2,6,6-trimethylcyclohex-1-en-1-yl)methyl)-2,5-dihydrothiophen-2-yl)but-2-en-1-yl acetate [I] (55 mg, 0.13 mmol; 1.0 eq) and pyridine (3.0 mL) were placed in a dried two necked round bottom flask equipped with a magnetic stirrer and condenser under an argon atmosphere. The reaction mixture was heated to 100° C. for 5 h. All volatiles were evaporated under reduced pressure (50° C., 5 mbar) to obtain the product (43 mg), yield=82%.

Example 2: Synthesis of Vitamin a Derivate Retinyl Acetate

[0070] (E)-4-hydroxy-3-methyl-4-(4-methyl-1,1-dioxido-5-((2,6,6-trimethylcyclohex-1-en-1-yl)methyl)-2,5-dihydrothiophen-2-yl)but-2-en-1-yl acetate (product obtained from Example 1) (263 mg, 0.6 mmol; 1.0 eq) and dry toluene (5.0 mL) were placed in a dried two necked round bottom flask equipped with a magnetic stirrer and condenser under an argon atmosphere. The reaction mixture was heated to reflux for 2 h. All volatiles were evaporated under reduced pressure (40° C., 5 mbar) to obtain the product in a yield of 71%.

Example 3: Preparation of Retinyl Propionate

[0071] 3-Methyl-2-((2,6,6-trimethylcyclohex-1-en-1-yl)methyl)-2,5-dihydrothiophene 1,1-dioxide (310 mg, 1.1 mmol; 1.0 eq), (E)-3-methyl-4-oxobut-2-en-1-yl propionate (190 mg, 1.2 mmol; 1.1 eq) and dry toluene (2.0 mL) were placed in a dried two necked round bottom flask under an argon atmosphere. The reaction mixture was cooled to −76° C. Lithium diidopropylamide (1.2 mL, 1.2 mmol, 1.1 eq, 1 M in tetrahydrofuran/hexane, d=0.719 g/mL) was added over a period of 7 min. The reaction mixture was stirred at −76° C. for 7 min. Subsequently the cooling bath was removed and half saturated ammonium chloride solution (5 mL) was added. The reaction mixture was diluted and extracted with toluene (10 mL). The aqueous layer was separated and extracted with toluene (10 mL). The organic layers were washed with water (2×10 mL) and saturated sodium chloride solution (1×10 mL). The combined organic layers were filtered over a plug of cotton wool. All volatiles were evaporated at 40° C. (5 mbar).

[0072] The residue placed in a dried two necked round bottom flask and dissolved in toluene (5 mL) with a magnetic stirrer, condenser under an argon atmosphere. The reaction mixture was heated to reflux for 2 h. All volatiles were evaporated under reduced pressure (50° C., 5 mbar) to obtain the product (399 mg), yield=52%.

Example 4

[0073] 3-Methyl-2-((2,6,6-trimethylcyclohex-1-en-1-yl)methyl)-2,5-dihydrothiophene 1,1-dioxide (308 mg, 1.1 mmol; 1.0 eq), (E)-3-methyl-4-oxobut-2-en-1-yl acetate (161 mg, 1.1 mmol; 1.0 eq) and dry toluene (2.0 mL) were placed in a dried two necked round bottom flask equipped with a magnetic stirrer under an argon atmosphere. The reaction mixture was cooled to −76° C. Lithium diidopropylamide (1.2 mL, 1.2 mmol, 1.1 eq, 1 M in tetrahydrofuran/hexane, d=0.719 g/mL) was added dropwise over a period of 8 min. The reaction was stirred at −76° C. for 7 min. Subsequently the cooling bath was removed and half saturated ammonium chloride solution (5 mL) was added. The reaction mixture was diluted with toluene (10 mL). The aqueous layer was separated and extracted with toluene

(10 mL). The organic layers were washed with water (2×10 mL) and saturated sodium chloride solution (10 mL). The combined organic layers were filtered over a plug of cotton wool. All volatiles were evaporated at 40° C. (5 mbar).

[0074] The residue was placed in a dried two necked round bottom flask and dissolved in toluene (5 mL) with a magnetic stirrer under an argon atmosphere. The reaction mixture was heated to reflux for 1 h. All volatiles were evaporated under reduced pressure (40° C., 5 mbar) purification afforded the product in 34% yield.