JPH0565506B2 - - Google Patents

Description

[Detailed description of the invention]

[0001] The present invention is based on the following formula (A)-1

[0002]

[Chemical 2]

[ka]

[0003] 2,6,6-trimethyl-(10'-carboxy-3',7'-dimethyldec-E
-1',3',5',7'-Z-9'-pentaenyl)cyclohex-1-ene.

[0004] The compound of the above formula (A)-1 has the following formula (1)

[0005]

[Chemical formula 3]

[ka]

[0006] In the formula, R represents a hydrogen atom or a COCH ₃ group. Retinol or retinyl acetate represented by the following is combined with triphenylphosphine and hydrogen halide water or triphenylphosphonium salt [P(C ₆ H ₅ ) ₃・HX] and the above formula
Forming a phosphonium salt of the compound of (1), then contacting the phosphonium salt with glyoxylic acid (OHCCOOH) in the presence of an alkali, and converting the resulting compound of formula (A) to the compound of (A)-1. (Hereinafter, this manufacturing method will be referred to as the method of the present invention for convenience.

[0007] 2,6,6-trimethyl-(10'-carboxy-
3′,7′-dimethyldeca-1′,3′,5′,7′-9′-
Pentaenyl)cyclohex-1-ene [the compound of formula (A)-2 in Reaction Scheme 2 below] is an important synthetic intermediate of carotenoids. In addition, 2,6,6-trimethyl-(10'-carboxy-3',7'-dimethyldec-
E-1',3',5',7'-Z-9'-pentaenyl)cyclohex-1-ene is a new compound previously described at the end of the literature, and is an important synthetic intermediate for carotenoids. , is a useful compound expected to have anticancer effects for medicinal purposes, for example.

[0008] Conventionally, the known substance included in the above formula (A) 2,6,6-trimethyl-(10'-carboxy-
3′,7′-dimethyldeca-1′,3′,5′,7′-9′-
As a method for synthesizing (pentaenyl)-cyclohex-1-ene, for example, as shown in Reaction Formula 1 below, retinyl acetate as a starting material is hydrolyzed with an alkali to synthesize retinol, and the compound is oxidized with manganese dioxide. to form retinal, and then convert the retinal into dimethoxycarbonylmethylenephosphine oxide [

2,6,6-trimethyl-
Synthesize (10′-methoxycarbonyl-3′,7-′dimethyldeca-1′,3′,5′,7′-9′-pentaenyl)-cyclohex-1-ene, and further hydrate the compound with alkali. A method has been proposed in which synthesis is performed by decomposing and then acidifying [Journal of
Pharmaceutical Sciences, 62(6)859-898
(1973)].

【0009】 Reaction formula 1

【0010】

[C4]

[ka]

[ka]

[ka]

[ka]

[0011] However, this method has many drawbacks, such as long steps, complicated reaction operations, and the need for an expensive reagent (dimethoxymethoxycarbonylmethylenephosphine oxide), making it unsuitable for industrial use.

[0012] The present inventors have conducted extensive research in order to overcome the drawbacks of the conventional methods and develop a method for industrially easily and efficiently synthesizing the compound of formula (A). As a result, it has been found that the compound of formula (A) above can be synthesized with high yield in two steps from retinyl acetate, which is easily available on the market.

[0013] Furthermore, in the structural formula of the compound included in the above formula (A), the double bond at the 9-position of the side chain has a cis-bond. Trimethyl-(10′-carboxy-3′,7′-dimethyldec-E-1′,3′,5′,7′-Z-9′-pentaenyl)cyclohex-1-ene is simultaneously produced and easily We found that it is possible to separate

[0014] Furthermore, the compound of formula (A)-1 in the form of cis-form included in formula (A) is a new compound that has not been previously described in the literature, and is a synthetic intermediate of carotenoids. , was found to be a useful compound expected to have anticancer effects for medicinal purposes, for example.

[0015] Therefore, the object of the present invention is to provide a new synthetic method that includes the novel compound of formula (A)-1 and can produce the above compound of formula (A) with industrially easy operations at low cost and in good yield. The present invention also provides a novel compound of formula (A)-1, which is useful as a synthetic intermediate for carotenoids and for pharmaceutical purposes.

[0016] According to the method of the present invention, 2 from easily available retinol or retinyl acetate of the above formula (1)
In the step, the compound of the above formula (A) can be synthesized at low cost with easy industrial operations. For example, the method of the present invention can be represented by the following reaction formula.

【0017】 Reaction formula 2

【0018】

[C5]

[ka]

[ka]

[ka]

[0019] In the above embodiment, the triphenylphosphonium salt used [P(C ₆ H ₅ ) ₃ ·HX] (in the formula,
X represents a halogen atom) can be easily synthesized, for example, from triphenylphosphine [P(C ₆ H ₅ ) ₃ ] and HX (wherein X represents a halogen atom) by a conventional method.

[0020] The reaction between the triphenylphosphonium salt and retinol or retinyl acetate represented by the above formula (1) can be carried out in the presence of an organic solvent. Examples of such organic solvents include methanol, ethanol, propanol, isopropanol, butanol, chloroform, dichloromethane, 1,2-dichloroethane, tetrahydrofuran, DME, DMF, and DMSO.

[0021] These organic solvents can be used alone or in combination. Further, there is no particular restriction on the amount used, but for example, about 1 to about 50 times the weight of retinol or retinyl acetate of formula (1), preferably about 2 to about 10 times the weight of retinol or retinyl acetate.
An example of the usage amount is about twice the weight.

[0022] The phosphonium salt type reaction of the above formula (1) is
For example, the temperature can be suitably selected from a wide temperature range of about -20° to about 100°C, and preferably for about 1 to about 24 hours. or,
The reaction is preferably carried out, for example, under an atmosphere of nitrogen, argon or other inert gas. In the above phosphonium salt formation reaction, triphenylphosphine and hydrogen halide HX (in the formula, X represents a halogen atom) are used instead of triphenylphosphonium salt.
The reaction can be carried out in the same manner as described above by making it exist in the reaction system. The preferred amount of the triphenylphosphonium salt to be used is, for example, about 1 to about 10 times the amount of the compound (A) by mole.

[0023] The compound of the above formula (A) can be obtained, for example, by reacting a phosphonium salt solution of retinol or retinyl acetate represented by the above formula (2), which can be synthesized as described above, with glyoxylic acid in the presence of an alkali. It can be easily synthesized by The above reaction can be carried out, for example, at an appropriately selected temperature in the range of about -20° to about 100°C. In addition, the reaction time is, for example, about 10 minutes to
A range of about 6 hours can be exemplified, and can be selected as appropriate.

[0024] Examples of the alkali used in the above reaction include caustic soda, caustic potash, sodium methoxide, sodium ethoxide, potassium-
Preferred examples include t-butoxide and sodium hydride.

[0025] Furthermore, the amount of glyoxylic acid used in the above reaction is, for example, about 0.5 to about 5 mol, more preferably about 0.9 to about 5 mol, relative to the compound of formula (2) above. The usage amount can be exemplified. At this time, glyoxylic acid can be used after being neutralized with an alkali such as potassium carbonate. After the reaction is completed, the organic solvent used is distilled off, the residue is extracted with an organic solvent such as petroleum ether, the neutral part is removed, and the mixture is acidified with hydrochloric acid.
For example, by extracting with an organic solvent such as petroleum ether, washing the extraction station with an alcohol-containing aqueous solution and water, and drying to distill off the organic solvent, the compound of the above formula (A) in the form of red and colored crystals is obtained. be able to. 2,6,6-trimethyl-(10'-carboxy-
3′,7′-dimethyldeca-E-1′,3′,5′,7′-Z
−
9′-Pentaenyl)cyclohex-1-ene can be easily separated from the compound of formula (A) obtained above by, for example, treating the compound of formula (A) above with silica gel column chromatography. can.

[0026] Hereinafter, the present invention will be explained in more detail with reference to Examples.

【0027】

【Example】

Example 1 0.3 ml of concentrated hydrochloric acid or 0.34 ml of concentrated hydrobromic acid is added to 0.87 g of retinol, 0.8 g of triphenylphosphine and 20 ml of methanol, and the mixture is reacted overnight at room temperature under an argon or nitrogen atmosphere. Next, 0.5 g of glyoxylic acid monohydrate was added, and after stirring for 10 minutes, a caustic potassium aqueous solution (caustic potassium 1.4 g, water 2.5 g) was added, and the reaction was carried out at room temperature for 0.5 hours. The reaction solution was extracted with petroleum ether. (25ml x 3) and remove the neutral part. The methanol layer is acidified with dilute hydrochloric acid and then extracted with petroleum ether (25 ml x 3). The organic layer is washed with a 90% aqueous methanol solution and water, and then dried with MgSO ₄ . Next, the solvent was recovered and 0.68 g of the target compound of formula (A) was obtained (yield 68
%) was obtained. Melting point 145-148℃. This crystal is TLC
(dichloromethane:ethyl acetate=4:1)
-9' position Z-form [formula (A)-1] and E-form [formula (A)-2]
It turned out to be a mixture (2:1) of

Example 2 1 g of retinyl acetate, 1 g of triphenylphosphine hydrobromide and methanol
Using 20 ml and using caustic soda instead of caustic potash, the reaction was carried out in the same manner as in Example 1 to obtain a compound of formula (A).
0.7 g (yield 70%) was obtained.

Example 3 Using 1 g of retinyl acetate instead of retinol, the reaction was carried out in the same manner as in Example 1 to obtain the formula (A).
0.72 g (yield 72%) of the compound was obtained. By purifying this compound of formula (A) using silica gel column chromatography and using dichloromethane as a developing solvent, the compound of formula (A)-1, which is a cis-form, was obtained.
0.32g, trans-form [compound of formula (A)-2]
0.16g was obtained.

[0030] Furthermore, each was recrystallized from acetonitrile to obtain a pure compound. The trans-isomer [compound of formula (A)-2] gave the same physical properties (melting point 179-180°C) as the literature values. Moreover, the cis-form [compound of formula (A)-1] showed the following physical property values.

[0031] Melting point 155.5-157.0°C UV ethanol λ max nm (ε) = 379 (80900) IRKBr λ max cm ^-1 = 3425 (ω), 2920 (s), 1680 (s), 1655 (s), 1605
(m), 1580(s), 1570(s), 1545(s), 1430(s), 1380(m),
1290(m), 1235(s), 1210(s), 1160(s), 960(s), 950
(s), 820(s), 745(m), 700(m), 625(m).

[0032] PMR _CDCl3 δ ^ppm = 1.04 (6H, s, C-6DiMe), 1.72 (3H, s, C
-2Me), 1.98 (3H, s, C-3'Me), 2.03 (3H,
s, C-7'Me), 5.65 (1H, d, J=10Hz, C-
10'H), 6.88 (1H, dd, J=11Hz, 15Hz, C
-5'H), 7.05 (1H, dd, J=10Hz, 12Hz, C
−9′H), 7.43 (1H, d, J=12Hz, C−8′H).

[0033] MS m / z : 328 (M ⁺ , 23%), 327 (93), 312 (16), 145 (38),
133 (38), 119 (52), 105 (68), 91 (55), 69 (60
),
55 (58), 43 (100), 41 (84).

Claims (1)

[Claims] [Claim 1] 2,6,6-trimethyl-(10'-carboxy-3',7'-dimethyldec-E-1', 3',
5′,7′-Z-9′-pentaenyl)cyclohexane
1-En.