Vitamin a related compounds and process for producing the same

Details Vitamin a related compounds and process for producing the same Vitamin a related compounds and process for producing the same

2000-02-09

2002-02-19

Richter, Johann (Department: 1621)

Organic compounds -- part of the class 532-570 series

Organic compounds

Carboxylic acid esters

C560S231000, C560S232000, C560S129000, C560S226000, C560S227000, C560S228000, C560S249000, C560S254000, C560S261000, C560S262000, C560S265000, C560S266000, C568S824000, C568S825000, C568S826000, C568S827000, C568S034000, C568S031000, C568S028000, C568S027000

Reexamination Certificate

active

06348622

ABSTRACT:

FIELD OF THE INVENTION
The present invention provides novel halohydrin compounds, sulfone compounds and triene compounds which are useful intermediates for producing Vitamin A and processes for producing the intermediate compounds and Vitamin A.
SUMMARY OF THE INVENTION
The present invention provides:
1. A compound of the formula[I]:
wherein R represents a hydrogen atom or a protective group for a hydroxyl group; and
A represents a hydrogen atom, a halogen atom or a group of the formula A1:
 wherein Ar represents an aryl group which may be substituted; and
when A represents A1, Q represents Q3:
 wherein R
1
represents a hydrogen atom or a protective group for a hydroxyl group;
when A represents a halogen atom, Q represents Q3 as defined above or Q4:
 wherein R
2
represents a hydrogen atom or a protective group for a hydroxyl group;
when A represents a hydrogen atom, Q is Q2:
2. A process for producing retinol of the formula [X]
which comprises the steps of:
(a) subjecting a compound of the formula [III]:
 wherein R′ represents a protective group for a hydroxyl group, to a reaction in the presence of a titanium tetrachloride, and
(b) reacting the resulting compound in step (a) with a base(hereinafter referred to as “Process A”);
3. A process for producing a compound of the formula [III]:
wherein Ar is an aryl group which may be substituted and R′ is a protective group for a hydroxyl group, which comprises reacting a compound of the formula [IV]:
wherein Ar is the same as defined above, with a protective agent in the presence of a base and a phase transfer catalyst(hereinafter referred to as “Process B”);
4. A process for producing a compound of the formula [V]:
wherein Ar represents an aryl group which may be substituted, R
10
and R′ are the same or different and represent a protective group for a hydroxyl group, which comprises reacting a sulfone compound of the formula[VI]:
wherein Ar is the same as defined above, with a halohydrin compound of the formula [VII]:
wherein R
10
and R′ are as defined above, and X represents a halogen atom, in the presence of a base (hereinafter referred to as “Process C”);
5. A process for producing a halohydrin compound of the formula [VII′]:
wherein R
12
represents an acyl group and R′ represent a protective group for a hydroxyl group, and X represents a halogen atom, which comprises reacting at least one halohydrin compound selected from the group consisting of a compound of the formula [VII′a]:
and a compound of the formula [VII′b]:
wherein R
11
represents an acyl group or a hydrogen atom and R′ represents a protective group for a hydroxyl group, with a carboxylic acid of the formula:
R
12
OH
wherein R
12
is the same as defined above, in the presence of a strong acidic catalyst(hereinafter referred to as “Process D”);
6. A process for producing at least one halohydrin compound selected from the group consisting of the formula [VII′a]:
a compound of the formula [VII′b]:
wherein R
11
represents an acyl group or a hydrogen atom and R′ represents a protective group for a hydroxyl group, which comprises reacting a triene compound of the formula [VIII]:
wherein R′ is the same as defined above, with a halogenating agent and a compound of the formula:
R
11
OH
wherein R
11
is is the same as defined above (hereinafter referred to as “Process E”); and
7. A process for producing the triene compound of the formula [VIII] as defined above, which comprises reacting a compound of the formula [IX]:
wherein X is a halogen atom and R′ is a protective group for a hydroxyl group, with a base in the presence of a palladium catalyst, a phosphine ligand and a phase transfer catalyst(hereinafter referred to as “Process F”).
DESCRIPTION OF THE PREFERRED EMBODIMENT
First a description will be made to the compound of the formula I.
The compound of the formula I above includes:
Compound [V]:
Compound [VII]:
Compound [VII′a]:
Compound [VIII]:
wherein R′, R
10
, R
11
, X and Ar are the same as defined above.
In the present specification, a chemical bond indicated by
means that the compound having the bond includes E isomer or Z isomer or both isomers with respect to a double bond connected to the said bond, and Compound [I] above has an optically active isomer and racemate thereof resulting from an asymmetric carbon atom present in the compound, which can be used in the following processes.
Examples of Ar group which may be substituted in the above formulas include a phenyl and naphthyl group which may be substituted.
Examples of the substituent include at least one substituent selected from a (C
1-C
5
)alkyl group (e.g., methyl, ethyl, n-propyl, i-propyl, n-butyl, t-butyl, s-butyl, n-pentyl), a (C
1
-C
5
)alkoxy group (e.g., methoxy, ethoxy, n-propoxy, i-propoxy, n-butoxy, t-butoxy, s-butoxy, n-pentoxy), a halogen atom(e.g., a fluorine, chlorine, bromine, or iodine atom), and a nitro group and the like.
Specific examples of Ar group which may be substituted include phenyl, naphthyl, o-tolyl, m-tolyl, p-tolyl, o-methoxyphenyl, m-methoxyphenyl, p-methoxyphenyl, o-chlorophenyl, m-chlorophenyl, p-chlorophenyl, o-bromophenyl, m-bromophenyl, p-bromophenyl, o-iodophenyl, m-iodophenyl, p-iodophenyl, o-fluorophenyl, m-fluorophenyl, p-fluorophenyl, o-nitrophenyl, m-nitrophenyl, p-nitrophenyl and the like.
Examples of the protective group for a hydroxyl group for R, R′, R
1
, R
2
and R
10
include:
an acyl group (an aliphatic or aromatic acyl group which may be substituted) such as acetyl, pivaloyl, benzoyl and p-nitrobenzoyl;
a silyl group such as trimethylsilyl, t-butyldimethylsilyl and t-butyldiphenylsilyl;
an alkoxymethyl group such as tetrahydrofuranyl, tetrahydropyranyl, methoxymethyl, methoxyethoxymethyl and 1-ethoxyethyl;
a benzyl group which may be substituted such as a benzyl group, a p-methoxybenzyl group and a trityl group;
a (C1-C6)lower alkyl group such as a t-butyl group, a methyl group;
a 2,2,2-trichloroethoxycarbonyl group;
an allyloxycarbonyl group and the like.
The acyl group described above may also includes those groups as defined for R
11
and R
12
below. The silyl group, alkoxymethyl group and a benzyl group described above may also include those defined for R
12
below.
Next description will be made to each Process A to F for producing Compound [I] and Vitamin A.
Process A
Retinol of the formula [X] can be industrially advantageously produced by a process which comprises the steps of:
(a) reacting a compound of the formula [III] as defined above to a reaction in the presence of titanium tetrachloride, and
(b) reacting the resulting compound in step (a) with abase.
In step (a) an amount of titanium tetrachloride to be used is preferably 0.3-1.5 mol per mol of Compound [III].
In the above reaction, an organic solvent is usually used. Examples of the solvent include an ether solvent such as diethyl ether, tetrahydrofuran, dimethoxyethane and anisole; a hydrocarbon solvent such as n-hexane, cyclohexane, n-pentane, toluene and xylene;
a halogenated solvent such as chloroform, dichloromethane, 1,2-dichloroethane, monochlorobenzene and o-dichlorobenzene; and an aprotic polar solvent such as N,N-dimethyl formamide, dimethyl sulfoxide, N,N-dimethyl acetamide, hexamethylphosphoric triamide.
A reaction temperature usually ranges from −78° C. to a boiling point of the solvent used, and preferably ranges from −10° C. to 50° C.
Next a description will be made to step (b).
Examples of the base used in this step include alkali metal hydroxide, alkaline earth metal hydroxide, alkali metal hydride, alkaline earth metal hydride, alkali metal alkoxide and alkaline earth metal alkoxide, and specific examples thereof include sodium hydroxide, potassium hydroxide, sodi

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