PROCESS FOR PRODUCTION OF NEW SULFOLENIC INTERMEDIATES

Abstract

The present invention relates to a new process for the production of new specific intermediates, which are preferably used in the production of vitamin A, vitamin A acetate, or β-carotene and derivatives thereof, e.g. canthaxanthin, astaxanthin or zeaxanthin.

Claims

1. Process of the production of compounds of formula (I) ##STR00018## 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, wherein the compound of formula (II) ##STR00019## is reacted with the compound of formula (III) ##STR00020## wherein R has the same meanings as defined for the compound of formula (I).

2. Process according to claim 1, wherein R is R is H, or —(CO)—(CH.sub.2).sub.nCH.sub.3, wherein n has a value of 0 or 1, 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.

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

4. Process according to claim 3, 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.

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

6. Process according to claim 5, wherein the solvent is a polar aprotic solvent.

7. Process according to claim 5, wherein the at least one solvent is chosen from the group consisting of pyridine, toluene, xylene, THF, methyl THF, and ethers (such as diethylether, 1,4-dioxane, 1,2-dimethoxyethane and crown ethers.

8. Process according to claim 1, wherein the process is carried out at a temperature range of from −100° C. to 25° C.

9. Process according to claim 1, wherein the molar ratio of the compound of formula (II) to the compound of formula (III) goes from 1:2 to 2:1.

10. Compounds of formula (I) ##STR00021## 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.

11. Compounds according to claim 10, wherein R is —(CO)—(CH.sub.2).sub.nCH.sub.3 and n has a value of 0-10.

12. Compounds according to claim 10, wherein R is —(CO)—(CH.sub.2).sub.nCH.sub.3 and n has a value of 0 or 1.

Description

EXAMPLES

Example 1: Synthesis of the Intermediate

[0075] 3-Methyl-2-((2,6,6-trimethylcyclohex-1-en-1-yl)methyl)-2,5-dihydrothiophene 1,1-dioxide (5.65 g, 20.1 mmol; 1.0 eq), (E)-3-methyl-4-oxobut-2-en-1-yl acetate (2.95 g, 20.8 mmol; 1.03 eq) and dry tetrahydrofuran (40.0 mL) were placed in a dried four necked round bottom flask equipped with a magnetic stirrer, thermometer and condenser under an argon atmosphere. The reaction mixture was cooled to −76° C. Lithium diisopropylamide (20.0 mL, 20.0 mmol, 0.99 eq, 1 M in tetrahydrofuran/hexane, d=0.719 g/mL) was added dropwise over a period of 40 min. The reaction was stirred at −76° C. for 2 h. Subsequently, the cooling bath was removed and half saturated ammonium chloride solution (100 mL) was added. The reaction mixture was diluted with diethylether (150 mL). The aqueous layer was separated and extracted with diethylether (150 mL). The organic layers were washed with half saturated ammonium chloride solution (100 mL), water (2×100 mL) and saturated sodium chloride solution (100 mL). The combined organic layers were filtered over a plug of cotton wool. All volatiles were evaporated at 40° C. (5 mbar).

[0076] The crude was purified with a column chromatography (SiO2) to obtain the products in 45% yield.

Example 2: Synthesis of Compound IV

[0077] (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 (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 in 82% yield

Example 3: Synthesis of Vitamin A Acetate from Compound I

[0078] (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 4: Preparation of Retinyl Propionate

[0079] 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) until a clear yellow oil remained.

[0080] The oil was 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 5: Preparation of Retinyl Acetate

[0081] 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 (1×10 mL). The combined organic layers were filtered over a plug of cotton wool. All volatiles were evaporated at 40° C. (5 mbar).

[0082] The oil 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.