JP3348401B2 - Vindrin synthesis intermediate and method for synthesizing vindrin synthesis intermediate - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

TECHNICAL FIELD The present invention relates to a compound useful as an intermediate in the total synthesis of vindoline, a compound of the general formula A, and an acrylic acid represented by the general formula B, which is an important intermediate in the total synthesis of vindoline. The present invention relates to a method for efficiently and reproducibly producing an indole derivative having an alkyl group, particularly a methyl acrylate group, which is particularly suitable for mass synthesis.

[0002]

BACKGROUND OF THE INVENTION Vinblastine (1), a natural product extracted from plants of the family Apocynaceae, is an antitumor agent currently used in clinical practice. However, new analogs have been widely developed in Japan and overseas because they also show relatively strong side effects.

[0003]

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The present inventors have already reported on the total synthesis of vindoline which constitutes a half (lower) portion of vinblastine (1) used for the synthesis of vinblastine. However, the total synthesis of vindoline requires the synthesis of many intermediates, and it is also important to improve the reproducibility and yield of each of these steps and to improve the steps suitable for production on a commercial basis. Conventionally, a compound represented by the above general formula B, which is an important intermediate in the synthesis of vindoline, uses a 2-iodide indole in which the 2-position of the compound of the above general formula A is substituted with iodine, and uses a palladium catalyst and tin It was synthesized by the following coupling reaction using a compound (S. Kobayashi, T. Ueda, T. Fukuyam
a, Synlett., 883-886 (2000)].

[0005]

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However, in the above reaction, it is difficult to realize a reproducible reaction with a good yield, and in this reaction, as shown in the above reaction formula, a highly toxic arsenic compound or a carcinogenic hexane compound. Methyl phosphate triamide (HMP
There is a problem that a reagent such as A) needs to be used. Accordingly, it has been desired to establish a method for synthesizing the intermediate B, which eliminates the problems of the prior art.

[0007]

SUMMARY OF THE INVENTION Accordingly, an object of the present invention is to improve the problems of the prior art, to improve the yield and reproducibility, and to adopt the above-mentioned general formula B which can be employed in a production process on a commercial basis. To provide a method for producing an intermediate. The present inventors have studied a method for producing a compound of the general formula B without passing through the conventional 2-iodide indole compound, and by establishing a synthesis method via the compound of the general formula A, It has been found that the object of the present invention can be solved.

[0008]

A first aspect of the present invention is a compound represented by the general formula A, which is useful as an intermediate in the total synthesis of vindoline. The second aspect of the present invention is the above-mentioned general formula A
Is hydrogenated to convert a benzyl ester to a carboxylic acid, and then represented by the general formula B having an acrylic acid alkyl ester unit by a Mannich reaction accompanied by decarboxylation under Mannich reaction conditions. This is a method for synthesizing an indole derivative useful for synthesizing vindoline.
Preferably, there is provided a method for synthesizing an indole derivative useful for synthesizing the vindoline and the derivative represented by the general formula B, wherein a palladium carbon catalyst having palladium supported on activated carbon is used as the hydrogenation catalyst.

[0009]

BEST MODE FOR CARRYING OUT THE INVENTION The present invention will be described in more detail.
First, a production example of the starting compound of the general formula A will be described. In the general formula A, R ¹ = MsO, R ² = Boc, R ³ = Me, R ⁴
= Bn, R ⁵ = THP can be efficiently synthesized using a quinoline derivative in which hydrogen at the 7-position hydroxy group is substituted with an alkylsulfonyl group, an arylsulfonyl group, or the like as a raw material. For example, 7-mesyloxyquinoline is subjected to a ring-opening reaction (Na ₂ CO ₃ ) with thiophosgene (CSCl ₂ ).
Α by ₃ of THF / H ₂ O mixed solution), beta-unsaturated aldehyde phenyl isothiocyanate with, following protection reduction to the aldehyde alcohols, nucleophilic addition of malonic acid derivative (malonic acid benzyl methyl The diester was reacted in a tetrahydrofuran solution of NaH under ice-cooling) to synthesize a thioamide compound, which was then treated with tri-n-butyltin hydride (n-Bu ₃ SnH) and 2,2′-azobisisobutylnitrile (AIBN). The mixture was allowed to react in a toluene solution at 80 ° C. (under argon), cooled to room temperature, added with a saturated KF solution, stirred at room temperature, diluted with ethyl acetate, washed with saturated saline, and dried over an organic layer. After drying over magnesium sulfate, the solvent was concentrated under reduced pressure, the residue was subjected to silica gel chromatography, and n-hexane: ethyl acetate = 2: Obtaining an indole derivative compound C in elution to.

[0010]

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A solution of this compound, di-tert-butyl dicarbonate (di-tert-butyl dicarbonate) and triethylamine in dichloromethane was added under ice-cooling with 4-
(Dimethylamino) pyridine was added, the temperature was raised to room temperature, and the mixture was stirred for 1 hour. The reaction solution was diluted with ethyl acetate, washed with saturated saline, and the organic layer was dried over anhydrous magnesium sulfate. The solvent was concentrated under reduced pressure, the residue was subjected to silica gel chromatography, and n-hexane: ethyl acetate = 2. : 1 and eluted at 1: 1 in the general formula A of the present invention, particularly in the general formula A, R ¹ = MsO, R ² = Boc, R ³ = Me, R ⁴ = Bn, R ⁵
= THP can be obtained. Other compounds represented by the general formula A can be similarly synthesized.
The present inventors have also applied for an efficient method for synthesizing a starting material for synthesizing the compound of the general formula A (Japanese Patent Application No. 2000-372508).

As a hydrogen source for the synthesis of the compound of the general formula B from the compound of the general formula A, ammonium formate, cyclohexene, 1,4-cyclohexadiene or the like can be used instead of hydrogen. In addition, a lower alcohol such as methanol or ethanol or ethyl acetate can be used as the solvent. As the hydrogenation catalyst, a palladium carbon catalyst, palladium hydroxide, Raney nickel or the like can be used, and a palladium carbon catalyst can be mentioned as a preferable one. The Mannich reaction is based on a combination of formalin, dimethylamine hydrochloride, acetic acid, sodium acetate, a combination of formalin and dimethylamine hydrochloride, a combination of formalin, diethylamine and acetic acid, or a secondary amine such as pyrrolidine or an inorganic acid such as formalin or hydrochloric acid. It can be carried out using a combination or the like, but a combination of formalin, dimethylamine hydrochloride, acetic acid and sodium acetate can be mentioned as a preferable example.

[0013]

Embodiment 1

[0014]

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As shown in the above reaction formula, palladium carbon (10 wt.% On activated carbon) (280 mg) was added to an ethanol solution (35 ml) of the compound of formula D (2.79 g, 4.32 mmol), and the mixture was added under a hydrogen atmosphere for 6 hours. Stirred. The reaction solution was filtered using a celite column, and further washed with ethanol. The reaction solution was not concentrated and was cooled under ice-cooling with formalin (5.2 ml,
65 mmol), dimethylamine hydrochloride (3.6 g, 43 mmol), sodium acetate (3.8 g, 45 mmol), and acetic acid (1.4 ml, 24 mmol) were sequentially added, followed by heating to room temperature and stirring overnight at that temperature. After completion of the reaction, the reaction solution was diluted with diethyl ether,
The extract was washed sequentially with saturated aqueous sodium hydrogen carbonate and saturated saline. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was concentrated under reduced pressure. The residue was subjected to silica gel column chromatography, and using a mixed solution of hexane: ethyl acetate = 5: 1, 1.93 g (85%) of the desired compound of the formula E was obtained from the eluate.

Physical properties: IR (film, cm ^-1 ): 3554,2952,1730,1613,1475,1442,1364,1
^{330,1184,1153,1097,967,835,758,529. 1 H NMR (400MHz,} C
DCl ₃ ): d1.37-1.69 (6H, m), 1.53 (9H, s), 2.89 (2H, m), 3.09
(3H, s), 3.37 (1H, m), 3.51 (1H, q, J = 6.8Hz), 3.66 (3H, s), 3.
62-3.68 (1H, m), 3.86 (1H, m), 4.50 (1H, s), 5.87 (1H, s), 6.5
7 (1H, d, J = 2.0Hz), 7.11 (1H, dd, J = 2.0,7.6Hz), 7.55 (1H,
d, J = 8.8Hz), 8.06 (1H, d, J = 1.6Hz). 13 C NMR (100MHz, CDCl
₃ ): d14.2,19.5,25.2,25.3,27.8,30.5,37.2,52.1,62.2,6
7.1,85.1,99.0,109.8,116.8,118.5,120.4,128.6,128.8,
133.3, 134.0, 135.6, 146.8, 149.7, 166.2.In the measurement, JASCO manufactured by JASCO Corporation as an infrared spectrometer
FT / IR-410, JEOL-LA manufactured by JEOL Ltd.
400 was used.

Reference Example: An explanation of the usefulness of the intermediate obtained in the present invention. Here, a method for synthesizing a vindoline compound, which is a useful use of the compound obtained by the synthesis method of the present invention, will be described. (1S)-(+)-Camphorsulfonic acid (7.3 g, 28.2 mmol) was added to a methanol solution (200 ml) of the compound of the above formula E (7.4 g, 14 mmol) under ice cooling, and the mixture was stirred for 2 hours. The reaction solution was diluted with ethyl acetate, and washed sequentially with saturated aqueous sodium hydrogen carbonate and saturated brine. The organic layer was dried over anhydrous magnesium sulfate, filtered, and the solvent was concentrated under reduced pressure. The residue was recrystallized from ethyl acetate to give the following compound F. Compound F (6.
67 g, 15.2 mmol), a chiral amine represented by the following formula G (DNs = 2,4-dinitrobenzenesulfonyl) and triphenylphosphine (6.30, 22.8 mmol) in a benzene solution (132 ml) were added with diethyl azodiamine under ice cooling. Carboxylate (DEAD, 10.3 ml, 22.8 mol) (40% toluene solution) was added dropwise, and the mixture was heated to room temperature and stirred for 1 hour. The reaction solution was diluted with ethyl acetate, and the organic layer was dried over anhydrous magnesium sulfate. After doing so, the solution was concentrated under reduced pressure. The residue was subjected to silica gel column chromatography, and n-hexane:
The mixture was eluted with a mixture of ethyl ether = 1: 2 to obtain compound H as a yellow powder. Dimethyl sulfide (Me ₂ S) is added dropwise to a dichloromethane solution of the compound H at room temperature, and the mixture is stirred at the same temperature for 5 minutes, and then trifluoroacetic acid (TFA) is added dropwise. The mixture was stirred at this temperature for 5 minutes, and the reaction solution was added dropwise to ice-cooled saturated aqueous sodium hydrogen carbonate. The aqueous layer was extracted twice with ethyl acetate and twice with dichloromethane, and the extracts were combined. After drying over anhydrous magnesium sulfate, the mixture was filtered and concentrated under reduced pressure. The obtained residue is dissolved in acetonitrile and methanol, and pyrrolidine is added dropwise under ice cooling. After stirring at room temperature for 5 minutes,
The temperature was raised to 70 ° C., and the mixture was stirred for 3 hours. The reaction solution was cooled to room temperature, diluted with diethyl ether, and washed twice with a saturated saline solution. After the organic layer was dried over anhydrous magnesium sulfate, the solution was concentrated under reduced pressure, the residue was subjected to silica gel column chromatography, and eluted with a mixture of n-hexane: ethyl acetate: methanol = 100: 50: 3 to give a white powder. [14β-hydroxyvincadiformin: a precursor compound of (−)-vindrin].

[0018]

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[0019]

As described above, according to the synthesis route of the compound of the general formula B of the present invention, not only the yield is improved to 85%, but also the reagent used in the synthesis is the same as that of the prior art. An excellent effect that toxicity and the like are small as compared with those of the present invention is brought about.

Claims (3)

(57) [Claims] 1. A compound of the general formula A wherein R ¹ is H, OH, an alkoxy group, a substituted or unsubstituted benzenesulfonyloxy group or an alkylsulfonyloxy group,
² is 1,1-dimethylethoxycarbonyl [(1,1-Dim
ethylethoxy) carbonyl, Boc] group or acetyl group, R ³ represents an alkyl group, and R ⁴ represents a benzyl or substituted benzyl group. R ⁵ is H, tetrahydropyranyl group (T
HP), an ethoxyethyl group, a methoxymethyl group, an acetyl group, a benzoyl group, a trialkylsilyl group, or an alkyldiarylsilyl group. A) a compound useful as an intermediate in the total synthesis of vindulin represented by Embedded image 2. The hydrogenation of the compound of the general formula A,
After converting the ester to carboxylic acid, the Mannich
By the Mannich reaction with decarboxylation under the reaction conditions
The above general formula having an alkyl acrylate unit
B (where R ¹Is H, OH, an alkoxy group, substituted and
Unsubstituted benzenesulfonyloxy group or alkyl sulf
One of the honyloxy groups is represented by R^TwoIs 1,1-di
Methylethoxycarbonyl [(1,1-Dimethylethoxy) car
bonyl, Boc) group or acetyl group, R^ThreeIs alkyl
Represents a group. R^FiveIs H, tetrahydropyranyl group (THP)
Ethoxyethyl, methoxymethyl, acetyl,
Azoyl group, trialkylsilyl group, alkyldiary
Represents a lucylyl group. Useful for the synthesis of vindoline represented by)
For synthesizing indole derivatives. Embedded image 3. A method for synthesizing an indole derivative useful for synthesizing the vindoline represented by the general formula B according to claim 2, wherein a palladium carbon catalyst having palladium supported on activated carbon is used as a hydrogenation catalyst. .