Process for producing retinal and intermediates for producing the same

There are disclosed: PA1 a hydroxyaldehyde derivative of formula (1): ##STR1## wherein the wavy line depicted by {character pullout} indicates a single bond and the compound having a double bond to which said single bond is attached represents E or Z isomer or a mixture thereof, PA1 a methoxy alcohol derivative of formula (2): ##STR2## wherein the wavy line depicted by {character pullout} indicates a single bond and the compound having a double bond to which said single bond is attached represents E or Z isomer or a mixture thereof, processes for producing the same, and a process for producing a retinal using the same.

BACKGROUND OF THE INVENTION
 1. Field of the Invention
 The present invention relates to a process for producing retinal which is a
 basic starting material for producing carotenoids that is important in the
 fields of medicines, feed additives and food additives and it also relates
 to intermediates for producing retinal.
 2. Description of Related Art
 Retinal is an important basic starting material for producing carotenoids,
 e.g., .beta.-carotene. As a method for the production of retinal, a method
 has been known, in which retinal is produced by oxidizing retinol (e.g.,
 J. Chem. Soc. 411 (1944), JP63-233943A, Helv. Chim. Acta 40, 265 (1957)
 and JP7-103095B). However, this method has a problem in that it has
 required handling of retinol, which is sensitive to heat, light and
 oxygen. In addition to the above methods, the following methods are known,
 a method in which a carbon-increment reaction is conducted in the side
 chain of .beta.-ionone which is a C13 compound (e.g., Bull. Soc. Chim. Fr.
 132, 696 (1995)) and a method in which a carbon-increment reaction is
 conducted in a side chain of cyclocitral which is a C10 compound (Chem.
 Lett. 1201 (1975)). These methods, however, require, as a starting
 material, .beta.-ionone or cyclocitral which is expensive on the market
 and produced by multistage processes. Hence, these methods are not always
 industrially satisfactory.
 SUMMARY OF THE INVENTION
 An object of the invention is to provide a process for producing retinal
 from relatively inexpensive starting material through an intermediate
 which is easy to handle, instead of labile retinol.
 It is also an object of the invention to provide a novel intermediate
 compounds of formula (1) and (2) as well as processes for producing said
 intermediates from a diol derivative (3).
 As shown in Scheme 1 said diol derivative (3) can be synthesized by
 treating a sulfone (8) with a base;
 said sulfone (8) can be obtained by coupling a cyclic sulfone derivative
 (6) with an allyl halide derivative (7); and
 said cyclic sulfone derivative (6) and said allylhalide derivative (7) can
 be derivatized from linalool or geraniol which is a relatively inexpensive
 C10 compound.
 ##STR3##
 The method for producing the diol derivative (3) as shown in the scheme 1
 is described in Chem. Lett. 479 (1975), JP11-130709A, JP11-130730A,
 JP11-222479A, JP11-236356A and JP11-236357A.
 The present invention provides:
 1. a hydroxyaldehyde derivative of formula (1):
 ##STR4##
 wherein the wavy line depicted by {character pullout} indicates a single
 bond and the compound having a double bond to which said single bond is
 attached represents E or Z isomer or a mixture thereof,
 2. a process for producing the hydroxyaldehyde derivative of formula (1) as
 defined above, which comprises oxidizing a diol derivative of formula (3):
 ##STR5##
 wherein the wavy line depicted by {character pullout} indicates a single
 bond and the compound having a double bond to which said single bond is
 attached represents E or Z isomer or a mixture thereof,
 3. a process for producing retinal of formula (4):
 ##STR6##
 wherein the wavy line depicted by {character pullout} indicates a single
 bond and the compound having a double bond to which said single bond is
 attached represents E or Z isomer or a mixture thereof,
 which comprises subjecting the hydroxyaldehyde derivative of formula (1) as
 defined above to a dehydrating reaction,
 4. a methoxy alcohol derivative of formula (2):
 ##STR7##
 wherein the wavy line depicted by {character pullout} indicates a single
 bond and the compound having a double bond to which said single bond is
 attached represents E or Z isomer or a mixture thereof.
 5. a process for producing the methoxy alcohol derivative of formula (2) as
 defined above, which comprises selectively methylating a diol derivative
 of formula (3) as defined above,
 6. a process for producing a methoxyaldehyde derivative of formula (5):
 ##STR8##
 wherein the wavy line depicted by {character pullout} indicates a single
 bond and the compound having a double bond to which said single bond is
 attached represents E or Z isomer or a mixture thereof,
 which comprises oxidizing a methoxy alcohol derivative of formula (2) as
 defined above, and
 7. a process as defined in item 6 above, which further comprises the step
 of eliminating a methoxy group of the methoxyaldehyde derivative (5) to
 produce a retinal of formula (4) as defined above.
 DESCRIPTION OF THE PREFERRED EMBODIMENTS
 In the present invention, the wavy line depicted by {character pullout} in
 formulae (1) to (8) indicates a single bond and the compound having a
 double bond to which said single bond is attached represents E or Z isomer
 or a mixture thereof. The hydroxyaldehyde derivative of formula (1) or the
 methoxy alcohol derivative of formula (2), for example, may represent a
 single geometrical isomer of all the possible isomers resulting from
 geometrical isomerism of each double bond to which a wavy line is attached
 or an optional mixture thereof.
 The hydroxyaldehyde derivative (1) can be obtained by a process which
 comprises oxidizing the diol derivative (3) as defined above. In a similar
 manner, the methoxyaldehyde derivative of formula (5) also can be obtained
 by a process which comprises oxidizing the methoxy alcohol derivative of
 formula (2) and the following description refers to both the processes.
 Oxidation of the diol derivative of formula (3) or the methoxy alcohol
 derivative of formula (2) is usually conducted with an oxidizing agent.
 Examples of the oxidizing agent to be used include salts or oxides of
 metals such as chromium and manganese or a metal oxide of selenium.
 Specific examples thereof include pyridinium chlorochromate, pyridinium
 dichromate, manganese dioxide and selenium dioxide. The amount of the
 oxidizing agent is usually about 1 to 10 moles and preferably 1 to 3 moles
 per mol of the diol derivative (3) or the methoxy alcohol derivative of
 formula (2), respectively.
 In the above reaction, an organic solvent is usually used. Examples of such
 a solvent include
 a hydrocarbon solvent such as n-hexane, cyclohexane, n-pentane, n-heptane,
 toluene or xylene,
 a halogenated solvent such as chloroform, dichloromethane,
 1,2-dichloroethane, monochlorobenzene or o-dichlorobenzene,
 an aprotic solvent such as N,N-dimethylformamide, dimethyl sulfoxide,
 acetonitrile, N,N-dimethylacetamide or hexamethylphosphoric triamide, and
 an ether solvent such as 1,4-dioxane, tetrahydrofuran or anisole.
 The oxidation reaction is usually conducted in a range from 0.degree. C. to
 the boiling point of the solvent used.
 After the reaction, the hydroxyaldehyde derivative (1) or the
 methoxyaldehyde derivative (5) can be obtained by a usual post-treatment
 such as filtration, extraction, evaporation or the like and may be further
 purified, for example, by silica gel chromatography, if necessary.
 The hydroxyaldehyde derivative (1) can be derivatized to retinal (4) by a
 process which comprises dehydrating the hydroxyaldehyde derivative (1) in
 the presence of an acid catalyst.
 Examples of the acid catalyst include triphenylphosphine hydrobromide,
 pyridine hydrochloride, pyridine hydrobromide, aniline hydrochloride,
 aniline hydrobromide, lutidine hydrochloride, lutidine hydrobromide,
 picoline hydrochloride, picoline hydrobromide, 2-pyridineethansulfonic
 acid, 4-pyridineethansulfonic acid, thionyl chloride-pyridine and
 paratoluenesulfonic acid-pyridine.
 The amount of the acid catalyst to be used is preferably 0.05 to 2 moles
 per mol of the hydroxyaldehyde derivative (1).
 In the above reaction, an organic solvent is usually used.
 Examples of the solvent include
 a hydrocarbon solvent such as n-hexane, cyclohexane, n-pentane, n-heptane,
 toluene or xylene,
 an ether solvent such as diethyl ether, tetrahydrofuran or anisole,
 a halogenated solvent such as chloroform, dichloromethane,
 1,2-dichloroethane, monochlorobenzene or o-dichlorobenzene, and
 an aprotic solvent such as N,N-dimethylformamide, dimethyl sulfoxide,
 acetonitrile, N,N-dimethylacetamide or hexamethylphosphoric triamide.
 The dehydration is usually conducted in a range from -10.degree. C. to the
 boiling point of the solvent used and preferably in a range from about
 0.degree. C. to 100.degree. C. After completion of the reaction, the
 desired product can be obtained by a usual post-treatment such as
 extraction, distillation and the like or may be further purified, for
 example by silica gel chromatography or the like, if necessary.
 Next descriptions will be made to a process for producing the methoxy
 alcohol derivative (2), and a process for producing retinal of formula (4)
 from the methoxy alcohol derivative of formula (2) through the
 methoxyaldehyde derivative of formula (5).
 The methoxy alcohol derivative (2) used in the present invention may be
 produced by a process which comprises reacting the diol derivative (3)
 with methanol in the presence of an acid catalyst, whereby selectively
 methylating a secondary alcoholic OH group of the diol derivative of
 formula (3).
 Examples of the acid catalyst include a Lewis acid, Bronsted acid,
 heteropolyacid, acidic ion-exchange resin and acid chloride. More
 specifically, examples of Lewis acid include tin (II) chloride, tin (IV)
 chloride, zinc chloride, iron (III) chloride, boron trifluoride ether
 complex and rare earth metal triflate. Examples of Bronsted acid include
 hydrobromic acid, hydrochloric acid, sulfuric acid, paratoluenesulfonic
 acid, benzenesulfonic acid, methanesulfonic acid, benzoic acid,
 triphenylphosphine hydrobromide and pyridine hydrochloride. Examples of
 the acidic ion-exchange resin include a strong acid type having a sulfonic
 acid group at the terminal thereof
 The amount of the acid catalyst is preferably about 0.01 to 1 mol per mol
 of the diol derivative (3).
 The reaction is usually conducted in a range of from -78.degree. C. to the
 boiling point of the solvent to be used and preferably from -10.degree. C.
 to 50.degree. C.
 After completion of the reaction, the methoxy alcohol derivative (2) can be
 obtained by a usual post-treatment such as extraction or the like, and may
 be further purified, for example, by silica gel chromatography, if
 necessary.
 The methoxy alcohol derivative of formula (2) can be further oxidized to a
 corresponding methoxyaldehyde derivative of formula (5) by a process as
 described above.
 The process for producing retinal of formula (4) from the methoxyaldehyde
 derivative (5) will be described below. The methoxyaldehyde derivative (5)
 is subjected to an elimination reaction to produce retinal (4). Said
 elimination reaction is usually conducted by a process which comprises
 contacting the methoxyaldehyde derivative of formula (5) with a base. The
 reaction can also be conducted by a method of Mukaiyama et al. in which
 DBU(1,8-diazabicyclo[5,4,0]undec-7-ene) is used as the base (Chem. Lett.
 1201 (1975)). The base include a bicyclo tertiary amines such as DBU or
 DBN, which are preferably used. The amount of the amine is usually about
 0.1 to 5 moles per mol of the methoxyaldehyde derivative of formula (5).
 Catalytic amount of the amine may be used, preferably in the co-presence
 of an alkali metal carbonate of which amount is 1 mol or more per mol of
 the methoxyaldehyde derivative of formula (5). Examples of the alkali
 metal carbonate include potassium carbonate and sodium carbonate.
 In the above reaction, an organic solvent is usually used.
 Examples of the solvent include
 an ether solvent such as 1,4-dioxane, tetrahydrofuran and anisole,
 a hydrocarbon solvent such as n-hexane, cyclohexane, n-heptane, n-pentane,
 toluene or xylene,
 a halogenated solvent such as chloroform, dichloromethane,
 1,2-dichloroethane, monochlorobenzene or o-dichlorobenzene,
 an aprotic solvent such as acetonitrile, N,N-dimethylformamide, dimethyl
 sulfoxide, N,N-dimethylacetamide or hexamethylphosphoric triamide.
 The reaction is usually conducted in a range from -30.degree. C. to the
 boiling point of the solvent used and preferably in a range from
 20.degree. C. to 100.degree. C.
 Thus, retinal of formula (4) can be obtained by the dehydration reaction of
 the hydroxyaldehyde derivative (1) using an acid catalyst or by the
 eliminating reaction of the methoxyaldehyde derivative (5) using a base,
 followed by a usual post-treatment.
 According to the process of the present invention, retinal can be produced
 from the diol derivative (3) as starting material, which can be
 synthesized from the sulfones (8) obtained by coupling of the cyclic
 sulfone derivative (6) with the allyl halide derivative (7), both of which
 can be derived from a relatively inexpensive C10 compound such as linalool
 or geraniol without using retinol which is sensitive to heat, light and
 oxygen.

EXAMPLES
 The present invention will be explained in more detail by way of examples,
 which are not to be construed to limit the invention thereto. Chemical
 formulae of the compounds (I), (II), (III), (IV) and (V) in the following
 Examples are shown below.
 Example 1
 1.22 g (4 mmol) of
 1,5-dihydroxy-3,7-dimethyl-9-(2,6,6-trimethylcyclohexene-1-yl)-2,6,8-nonat
 riene (I) was dissolved in 30 ml of methylene chloride, to which was then
 added 3.48 g (40 mmol) of manganese dioxide and the mixture was stirred at
 an ambient temperature for 24 hours. After the resulting mixture was
 diluted with ether, it is dried over anhydrous magnesium sulfate and
 filtered, followed by evaporation of ether to obtain
 5-hydroxy-3,7-dimethyl-9-(2,6,6-trimethylcyclohexene-1-yl)-nona-2,6,8-trie
 nal (II) as a mixture of E and Z isomers in a yield of 90%.
 Isomer (1)
 1H-NMR .delta.(CDCl3) 1.00 (6H, s), 1.40-1.50 (2H, br), 1.50-1.75 (2H, br),
 1.68 (3H, s), 1.88 (3H, s), 1.95-2.10 (2H, br), 2.24 (3H, s), 2.30-2.60
 (2H, m), 4.70-4.90 (1H, m), 5.41 (1H, d, J=8Hz), 5.90-6.10 (2H, m), 6.16
 (1H, d, J=16Hz), 10.00 (1H, d, J=8Hz).
 Isomer (2)
 1H-NMR .delta.(CDCl3) 1.00 (6H, s), 1.40-1.50 (2H, br), 1.50-1.75 (2H, br),
 1.68 (3H, s), 1.90 (3H, s), 1.95-2.10 (2H, br), 2.22 (3H, s), 2.30-2.60
 (2H, m), 4.70-4.90 (1H, m), 5.31 (1H, d, J=9Hz), 5.99 (1H, d, J=16Hz),
 6.22 (1H, d, J=16Hz), 6.37 (1H, d, J=16Hz), 9.98 (1H, d, J=8Hz).
 Example 2
 605 mg (2 mmol) of
 5-hydroxy-3,7-dimethyl-9-(2,6,6-trimethylcyclohexene-1-yl)-nona-2,6,8-trie
 nal (II) was dissolved in 20 ml of toluene, to which were then added 57.8
 mg (0.5 mmol) of pyridine hydrochloride and 39.5 mg (0.5 mmol) of pyridine
 and the mixture was stirred at 70.degree. C. for 2 hours. After the
 mixture was cooled to an ambient temperature, water was added to the
 mixture. The resulting mixture was subjected to extraction with ether and
 the extract was dried over anhydrous magnesium sulfate, followed by
 evaporation of the solvent to obtain crude retinal. The resulting crude
 product was purified by neutral alumina column chromatography to obtain
 retinal (III) as a mixture of E and Z isomers in a yield of 46%.
 Example 3
 605 mg (2 mmol) of
 5-hydroxy-3,7-dimethyl-9-(2,6,6-trimethylcyclohexene-1-yl)-nona-2,6,8-trie
 nal (II) was dissolved in 6 ml of tetrahydrofuran, to which was then added
 23.1 mg (0.2 mmol) of pyridine hydrochloride and the mixture was heated
 under reflux for 1 hour. After the mixture was cooled to an ambient
 temperature, water was added to the mixture. The resulting mixture was
 subjected to extraction with ether and the extract was dried over
 anhydrous magnesium sulfate, followed by evaporation of the solvent to
 obtain crude retinal. The resulting crude product was purified by neutral
 alumina column chromatography to obtain retinal (III) as a mixture of E
 and Z isomers in a yield of 48%.
 Example 4
 1.52 g (5 mmol) of
 1,5-dihydroxy-3,7-dimethyl-9-(2,6,6-trimethylcyclohexene-1-yl)-2,6,8-nonat
 riene (I) was dissolved in 20 ml of methanol and the mixture was cooled to
 0.degree. C. To the mixture was then added 47.6 mg (0.25 mmol) of
 paratoluenesulfonic acid hydrate. After the mixture was stirred at
 0.degree. C. for 3 hours, a saturated aqueous sodium bicarbonate solution
 was added to the mixture and the resulting mixture was subjected to
 extraction with ether, followed by washing with a saturated brine. The
 resulting product was dried over anhydrous magnesium sulfate and the
 solvent was evaporated to obtain
 1-hydroxy-5-methoxy-3,7-dimethyl-9-(2,6,6-trimethylcyclohexene- 1-yl)
 -2,6,8-nonatriene (IV) as a mixture of E and Z isomers in a yield of 85%.
 1H-NMR .delta.(CDCl3) 1.01 (6H, s), 1.45-1.48 (2H, br), 1.60-1.72 (2H, br),
 1.69 (3H, s), 1.72 (3H, s), 1.84 (3H, s), 1.98-2.05 (2H, br), 2.05-2.44
 (2H, m), 3.25 (3H, m), 4.12-4.21 (3H, m), 5.13-5.26 (1H, m), 5.44-5.49
 (1H, m), 6.05-6.67 (2H, m).
 Example 5
 1.34 g (4.2 mmol) of
 1-hydroxy-5-methoxy-3,7-dimethyl-9-(2,6,6-trimethylcyclohexene-1-yl)-2,6,8
 -nonatriene (IV) was dissolved in 40 ml of methylene chloride, to which was
 then added 3.66 g (42 mmol) of manganese dioxide and the mixture was
 stirred at an ambient temperature for 24 hours. After the resulting
 mixture was diluted with an ether, it was dried over anhydrous magnesium
 sulfate and filtered, followed by evaporation of the solvent to obtain
 5-methoxy-3,7-dimethyl-9-(2,6,6-trimethylcyclohexene-1-yl)-nona-2,6,8-trie
 nal (V) as a mixture of E and Z isomers in a yield of 91%.
 1H-NMR .delta.(CDCl3) 1.01 (6H, s), 1.41-1.50 (2H, br), 1.50-1.75 (2H, br),
 1.69 (3H, s), 1.86 (3Hx 72/100, s), 1.93 (3Hx 28/100, s), 1.95-2.10 (2H,
 br), 2.18 (3Hx 28/100, s), 2.21 (3Hx 72/100, s), 2.31-2.56 (2H, m), 3.24
 (3Hx 28/100, s), 3.26 (3Hx 72/100, s), 4.23-4.35 (1H, m), 5.12-5.30 (1H,
 m), 5.92-6.40 (3H, m), 9.99 (1Hx 28/100, d, J=7Hz), 10.02 (1Hx 72/100, d,
 J=7Hz).
 Example 6
 633 mg (2 mmol) of
 5-methoxy-3,7-dimethyl-9-(2,6,6-trimethylcyclohexene-1-yl)-nona-2,6,8-trie
 nal (V) was dissolved in 6 ml of tetrahydrofuran, to which was then added
 152 mg (1 mmol) of 1,8-diazabicyclo[5,4,0]undecene-7-ene (DBU) and the
 mixture was heated under reflux for 6 hours. After the reaction, the
 solvent was evaporated to give a crude product. The resulting crude
 product was purified by silica gel chromatography to obtain retinal (III)
 as a mixture of E and Z isomers in a yield of 55%.
 ##STR9##