JP2002179680A - Optically active fr-900482, its analogue compound and synthetic intermediate compound, and method for producing the same - Google Patents

Abstract

PROBLEM TO BE SOLVED: To obtain FR900482 expectable of new development of a new antitumor antibiotic and its application and its analogue and to provide a method for synthesizing a synthetic intermediate. SOLUTION: The FR900482 and its analogue or its enantiomer or diastereomer is synthesized by starting from a coupling reaction of a triflate compound with an optically active acetylene compound.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

[0001] The invention of this application relates to FR90
The present invention relates to a method for synthesizing 0482, its analog compounds and synthetic intermediates. More specifically, the invention of this application relates to a method for synthesizing FR900482, an analog compound thereof, which is an antitumor substance having a mechanism of action similar to Mytomycin C, and a synthetic intermediate therefor.

[0002]

2. Description of the Related Art Conventionally,

[0003]

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[0004] FR900482 represented by
It is known as an antitumor active substance having a mechanism of action similar to that of omycin C, and the inventors of this application have established a total synthesis method of its racemic form.

[0005] However, with regard to FR900482, its analogs and methods for synthesizing them have not been studied much.

[0006] Therefore, it is extremely important to search for and establish a new method for synthesizing FR900482 and its analogs, which are expected to be developed and applied to antitumor antibiotics.

[0007]

SUMMARY OF THE INVENTION The invention of this application is based on the first aspect of the present invention, which solves the above-mentioned problems.
New technical means as described in ~ 11 are provided. These technical means relate to a method of synthesizing FR900482, analog compounds thereof, and synthetic intermediates thereof.

In the invention described in the claims, the symbols Ra and Rb and R ₁ and R ₂ shown in the chemical formula each represent
The same or different, a hydrogen atom or an organic group. Examples of the organic group in this case include a hydrocarbon group such as an alkyl group, a cycloalkyl group, and an aryl group, an alkoxy group, an aryloxy group, an amino group, a (di) alkylamino group, an arylamino group, an ester group, and an alkylcarbonyl group. , An arylcarbonyl group, an alkylcarbonyloxy group, a halogen atom and the like.

[0009] As for the protecting groups for Rc, Rd, Re, Rf, and Rg, various types of conventionally known benzyl group, p-methylphenyl group, TBS, acyl group and the like are considered.

[0010] In particular, in the invention of this application, FR9
For the synthesis of 00482, a practical synthesis method with excellent applicability to reactions on a large scale will be provided. According to this method, not only both enantiomers of the optically active substance but also various analogous substances such as diastereochoses can be widely synthesized. New drug development using FR900482 as a lead compound becomes possible.

[0011]

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS Therefore, FR9 will be described below as an example.
The synthesis of 00482 is shown, and embodiments of the invention are described in more detail.

The synthesis of FR90082 is realized as the following reaction steps.

[0013]

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[0014]

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[0015]

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[0016]

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[0017]

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[0018]

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[0019]

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[0020]

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By using the above method, FR-9
Not only 00482, but also its enantiomers and diastereomers, and various analogs can be prepared as optically active substances.

That is, if L-tartaric acid is used as a starting material of acetylene 13, an enantiomer can be synthesized by the same route. Further, since the two secondary hydroxyl groups of the compound 41 are distinguishable, the synthesis of a stereoisomer (β-epoxide) of the compound 45 is also easy, and thus FR-90048
Synthesis of two stereoisomers (α-aziridine) is also possible.

Further, instead of the triflate 6, an aromatic compound having an alkyl group, an alkoxyl group, an amino group, an acyl group, a halogen or the like on an aromatic ring is used, or the compound 55 is decomposed with various amines. Thereby, synthesis of each type of analog is also possible. <Example 1> Synthesis of compound 3

[0024]

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Vanillic acid (150 g, 0.89 mol)
Concentrated methanol (1 L) was added to concentrated sulfuric acid (5 mL), and the mixture was heated under reflux for 2 days. The solvent was distilled off, and the obtained residue was dissolved in chloroform and washed with a saturated aqueous sodium hydrogen carbonate solution. The organic layer was separated, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure.

The obtained residue (173 g) was treated with acetic acid (50 g).
(0 mL) solution, concentrated nitric acid (78 mL) was added over 20 minutes under ice cooling, and the mixture was further stirred for 30 minutes. Water (1
L) was added, and the mixture was stirred for 1 hour under ice-cooling. The precipitated crude crystals were collected by filtration and washed with water. The crude crystals were mixed with chloroform (2
L) and washed with water, and the organic layer was dried over anhydrous magnesium sulfate. Hexane (400 mL) was added to the crude product (300 g) obtained by concentration under reduced pressure, and the precipitated crystals were collected by filtration and dried under reduced pressure to obtain Compound 3 (148 g).

[0027]

[Table 1]

Example 2 Synthesis of Compound 4

[0029]

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Compound 3 (51.9 g, 0.23 mol)
In a 1,2-dichloroethane (1 L) solution was added boron tribromide / dimethylsulfide complex (75.0 g, 0.24 mol
l) was added and the mixture was heated under reflux for 20 minutes. After cooling the reaction solution to room temperature, water (500 mL) was added, and the mixture was vigorously stirred for 3 minutes. The organic layer was separated, washed with saturated saline, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained residue was recrystallized from hexane-ethyl acetate to give Compound 4 (30.
3 g) was obtained.

[0031]

[Table 2]

Example 3 Synthesis of Compound 5

[0033]

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Sodium hydride (60% oil diffusion,
6.7 g, 0.28 mol) of tetrahydrofuran (4
Compound 4 (30.0 g, 0.14
mol) of N, N-dimethylformamide (130 m
L) The solution was added dropwise at room temperature over 30 minutes and stirred for another 30 minutes. The reaction solution was cooled on ice, and benzyl bromide (16.6 m
L, 23.9 g, 0.14 mol) was added dropwise over 5 minutes, followed by stirring at room temperature for 5 hours. 1N Hydrochloric acid (300 mL) was added to the reaction solution, and the mixture was vigorously stirred and extracted with ethyl acetate (500 mL). The organic layer was washed with saturated saline and concentrated under reduced pressure. The precipitated crystals were collected by filtration, washed with hexane, and dried under reduced pressure to obtain Compound 5 (25.0 g).

[0035]

[Table 3]

Example 4 Synthesis of Compound 6

[0037]

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Compound 5 (37.9 g, 0.13 mol)
And pyridine (25 mL, 0.31 mol) in dichloromethane (1 L) under ice-cooling in a trifluoromethanesulfonic anhydride (22 mL, 37, 0.13 mol)
Was added dropwise over 15 minutes, and the mixture was further stirred for 1 hour. The reaction solution was washed sequentially with 1 N hydrochloric acid, saturated saline, saturated aqueous sodium hydrogen carbonate solution and saturated saline, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to obtain compound 6 (53.5 g).

[0039]

[Table 4]

Example 5 Synthesis of Compound 11

[0041]

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Ice-cooled sodium hydride (30.0 g,
1.25 mol) in tetrahydrofuran (1 L) was suspended in 2,3-di-O-isopropylidene-D-threitol (Organic Synthesis Coll).
active Volume VIII, 1993, 15
A solution of 87.5 g, 0.54 mol) in tetrahydrofuran (150 mL) was added dropwise over 1 hour. After the reaction solution was stirred at room temperature for 1 hour, it was cooled on ice and t
tert-butyldimethylchlorosilane (97.6 g,
(0.65 mol) in dichloromethane (200 mL) was added dropwise over 1 hour, and the mixture was further stirred under ice-cooling for 30 minutes. The reaction solution was poured into crushed ice and extracted with diethyl ether. The organic layer was washed with saturated saline, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent; hexane: ethyl acetate = 90: 10 to 50:50) to give Compound 1.
1 (113 g) was obtained.

[0043]

[Table 5]

Example 6 Synthesis of Compound 13

[0045]

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Oxalyl dichloride (36.8 g, 0.29 mol) cooled to −78 ° C. in dichloromethane (1
L) The solution was added to dimethyl sulfoxide (34.1 mL, 3
7.5 g (0.48 mol) of dichloromethane (50 m
L) Solution and Compound 11 (67.3 g, 0.24 mo
l) A dichloromethane (70 mL) solution was sequentially added dropwise.
After further stirring at the same temperature for 30 minutes, triethylamine (1
00 mL, 72.6 g, 0.72 mol).
The temperature was raised to room temperature over time. The reaction solution was washed with a 10% aqueous citric acid solution, a saturated aqueous sodium hydrogen carbonate solution, and a saturated saline solution, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure.

The obtained residue (57.3 g) was dissolved in methanol (50 mL), and ice-cooled anhydrous potassium carbonate (58.0 g, 0.42 mol) in methanol (1 L) was used.
It was dropped into the suspension. Subsequently, dimethyl-1-
Diazo-2-oxopropylphosphonate (Synth
etic Communications, 1984,
Prepared according to 14,155, 48.4 g, 0.25 mo
l) was added dropwise over 15 minutes, and the mixture was further stirred at room temperature for 2 hours. The reaction solution was filtered through celite, and the filtrate was concentrated under reduced pressure.
The residue was dissolved in ethyl acetate, washed with saturated saline, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained residue is subjected to silica gel column chromatography (developing solution; hexane: ethyl acetate = 90: 10 to 50:50).
The compound 13 (31.6 g) was obtained.

[0048]

[Table 6]

Example 7 Synthesis of Compound 14

[0050]

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Compound 6 (39.2 g, 88.7 mmol)
1), triphenylphosphine (4.65 g, 17.7)
mmol) and palladium acetate (1.99 g, 8.8).
To a solution of 7 mmol) in tetrahydrofuran (200 mL) and triethylamine (200 mL), a solution of compound 13 (27.5 g, 0.129 mol) in tetrahydrofuran (200 mL) was added dropwise over 1 hour and 30 minutes under vulcanization reflux. After the addition, the reaction solution was cooled to room temperature and concentrated under reduced pressure. The obtained residue was dissolved in ethyl acetate, washed with a 10% aqueous citric acid solution, a saturated sodium hydrogencarbonate solution, and a saturated saline solution, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained residue is subjected to silica gel column chromatography (developing solution; hexane: ethyl acetate = 95: 5-9).
0:10) to give compound 14 (40.9 g).

[0052]

[Table 7]

Example 8 Synthesis of Compound 16

[0054]

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Compound 14 (104 g, 0.19 mol)
In a benzene (1 L) solution at room temperature with piperidine (30 L).
mL, 25.7 g, 0.36 mol) was added dropwise and stirred for 1 hour. The reaction solution was cooled on ice, and a 50% acetic acid aqueous solution (600%
mL) over 20 minutes, followed by vigorous stirring at room temperature for 2 hours. The organic layer was separated, washed successively with a saturated aqueous solution of sodium bicarbonate, a 10% aqueous solution of citric acid, and a saturated saline solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain Compound 16 (110 g).

[0056]

[Table 8]

Example 9 Synthesis of Compound 17

[0058]

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Compound 16 (110) cooled to -25.degree.
g, 0.19 mol) of diethyl ether (500 m
L) The solution was added to a 0.13 M zinc borohydride diethyl ether solution (Chem, Pharm, Bull., 198).
Prepared according to 4,32,1141, 1 L) was added dropwise over 2 hours, dried for 15 minutes, and 10% aqueous citric acid solution (1 L) was added. The organic layer was separated, washed successively with a saturated aqueous solution of sodium hydrogen carbonate and a saturated saline solution, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent; hexane: ethyl acetate = 95: 5 to 90:10) to obtain Compound 17 (86.3 g).

[0060]

[Table 9]

Example 10 Synthesis of Compound 18

[0062]

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Compound 17 (86.1 g, 0.15 mol
l) and 4-dimethylaminopyridine (1.8 g, 1
Acetic anhydride (28 mL, 0.30 mol) was added dropwise to a solution of 5 mmol) in pyridine (200 mL) over 15 minutes under ice-cooling, followed by stirring at room temperature for 2 hours. The reaction solution was concentrated under reduced pressure, the obtained residue was dissolved in ethyl acetate, washed sequentially with 1N hydrochloric acid, saturated saline, saturated aqueous sodium hydrogen carbonate solution and saturated saline, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. This gave compound 18 (103 g).

[0064]

[Table 10]

Example 11 Synthesis of Compound 19

[0066]

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Compound 18 (47.2 g, 76.4 mmol)
To a solution of 1) in methanol (1 L) was added 5% platinum-activated carbon (10 g), and the mixture was stirred at room temperature for 14 hours under a hydrogen atmosphere. The reaction solution was filtered, and the filtrate was 5% platinum-activated carbon (5%).
g) was added, and the mixture was stirred at room temperature under a hydrogen atmosphere for 5 hours. The reaction solution was filtered and concentrated under reduced pressure, and the obtained residue was subjected to silica gel column chromatography (developing solution; chloroform).
Then, compound 19 (42.3 g) was obtained.

[0068]

[Table 11]

Example 12 Synthesis of Compound 20

[0070]

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Compound 19 (42.2 g, 71.8 mol)
1), 2-nitrobenzenesulfonyl chloride (23.
Pyridine (23.1) was added to a solution of 9 g, 0.108 mol) and 4-dimethylaminopyridine (0.88 g, 7.2 mmol) in dichloromethane (150 mL) under ice-cooling.
mL, 0.287 mol) was added dropwise over 5 minutes, and the mixture was stirred at room temperature for 3 hours. Dilute the reaction solution with chloroform and add 1
The extract was washed sequentially with normal hydrochloric acid, a saturated saline solution, a saturated aqueous solution of sodium hydrogen carbonate and a saturated saline solution, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent; hexane: ethyl acetate = 95: 5-75: 25) to give Compound 20 (3
5.5 g).

[0072]

[Table 12]

Example 13 Synthesis of Compound 22

[0074]

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Compound 20 (35.3 g, 45.9 mmol)
l) and acetic acid (17 mL, 0.30 mol) in tetrahydrofuran (120 mL) were added dropwise over 30 minutes under ice-cooling with tetrabutylammonium fluoride (1 M in tetrahydrofuran, 275 mL, 0.275 mol). Stirred for hours. The reaction solution was diluted with ethyl acetate, washed successively with a 10% aqueous citric acid solution, a saturated aqueous sodium hydrogen carbonate solution and a saturated saline solution, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure.

The obtained residue (29.4 g) and triphenylphosphine (17.5 g, 66.9 mmol)
In a benzene (1.5 L) solution at room temperature with diethyl azodicarboxylate (40% toluene solution, 24 mL, 5 mL).
2.8 mmol) was added dropwise over 20 minutes. The reaction solution was further stirred for 30 minutes, concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (eluent; hexane: ethyl acetate = 70: 30 to 60:40) to give Compound 22 (35. 0 g).

[0077]

[Table 13]

Example 14 Synthesis of Compound 24

[0079]

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Compound 22 (34.5) cooled to -78 ° C.
g) in dichloromethane (150 mL) was added to diisobutylaluminum hydride (1 M toluene solution, 270 m 2).
L, 0.27 mol) was added dropwise over 1 hour. After stirring the reaction solution at the same temperature for 15 minutes, anhydrous methanol (190
mL) was added dropwise over 30 minutes, and the mixture was further stirred at room temperature for 1 hour. Chloroform (2 L) and 1 N hydrochloric acid (1 L) were added to the reaction solution, the organic layer was separated, and the aqueous layer was extracted with chloroform. The organic layers were combined, washed successively with a saturated saline solution, a saturated aqueous solution of sodium hydrogen carbonate, and a saturated saline solution, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure.

The obtained residue (31.5 g), 4-methoxyphenol (6.64 g, 53.5 mmol) and triphenylphosphine (14.0 g, 53.5 mm)
ol) in benzene (250 mL) at room temperature in diethyl azodicarboxylate (40% toluene solution, 2
4.3 mL, 53.5 mmol) was added dropwise over 10 minutes. After stirring the reaction solution for 10 minutes, it was concentrated under reduced pressure, chloroform (100 mL) was added to the obtained residue, and the mixture was stirred under ice-cooling. The precipitated insoluble material was separated by filtration, and the filtrate was concentrated under reduced pressure. The obtained residue is subjected to silica gel column chromatography (developing solution; benzene: ethyl acetate = 90: 1).
Purification by 0) gave compound 24 (21.2 g).

[0082]

[Table 14]

Example 15 Synthesis of Compound 25

[0084]

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To a solution of oxalyl dichloride (3.6 mL, 5.2 g, 41.7 mmol) in dichloromethane (150 mL) cooled to -78 ° C. was added dimethyl sulfoxide (3.9 mL, 4.3 g, 55.6 mmol) in dichloromethane (150 mL). 10 mL) solution and compound 24 (21.0
g, 31.0 mmol) in dichloromethane (200 m
L) The solution was sequentially added dropwise, and after stirring at the same temperature for 30 minutes, triethylamine (11.6 mL, 8.4 g, 8
3.4 mmol) was added dropwise, and the temperature was raised to room temperature over 1 hour. The reaction solution was washed with a 10% aqueous citric acid solution, a saturated aqueous sodium hydrogen carbonate solution, and a saturated saline solution, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. Ethyl acetate (50 mL) and hexane (50 mL) were added to the obtained residue, and the mixture was stirred under ice cooling for 1 hour. The precipitated crystals were collected by filtration, washed with hexane-ethyl acetate (2: 1), and dried under reduced pressure to obtain Compound 25 (15.1 g).

[0086]

[Table 15]

Example 16 Synthesis of Compound 28

[0088]

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Compound 25 (15.1) was placed in a stainless steel reaction tube.
g, 22.4 mmol), 2-propanol (150 m
L), dimethylamine hydrochloride (2.19 g, 26.9 m)
mol), 37% formalin (8.5 mL, 0.11 m
ol), triethylamine (0.94 mL, 0.68
g, 6.72 mmol) and water (15 mL) were added sequentially, and the mixture was sealed and stirred at 90 ° C. for 4 hours and 30 minutes. The reaction solution was concentrated under reduced pressure, and the obtained residue was dissolved in chloroform, washed successively with a 10% aqueous citric acid solution, a saturated aqueous sodium hydrogen carbonate solution and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure.

The obtained residue (18.8 g) was dissolved in tetrahydrofuran (50 mL) -methanol (50 mL), and triethylamine (1.2 mL, 0.87 g) was added at room temperature.
g, 8.96 mmol) and thiophenol (3.4).
mL, 3.6 g, 33.6 mmol) were successively added, followed by stirring for 3 hours. The reaction solution was ice-cooled, sodium borohydride (0.85 g, 22.4 mmol) was added over 15 minutes, and the mixture was further stirred at the same temperature for 15 minutes. The reaction solution was diluted with chloroform (1 L), washed sequentially with a 10% aqueous citric acid solution, a saturated aqueous sodium hydrogen carbonate solution and a saturated saline solution, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent; benzene: ethyl acetate = 98: 2 to 95: 5) to obtain Compound 28 (15.0 g).

[0091]

[Table 16]

Example 17 Synthesis of Compound 29

[0093]

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Compound 28 (14.9 g, 18.7 mmol)
l) and 4-dimethylaminopyridine (0.27 g,
Acetic anhydride (10.5 mL, 11.4 g, 0.11 mL) was added to a solution of 2.24 mmol) in pyridine (30 mL) under ice cooling.
mol) was added dropwise over 5 minutes and then at room temperature for 2 hours 30 minutes.
Minutes. The reaction solution was diluted with ethyl acetate (500 mL), washed sequentially with 1 N hydrochloric acid, saturated saline, saturated aqueous sodium hydrogen carbonate, and saturated saline, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent: hexane: dichloromethane = 30: 70) to give compound 29 (1
2.5 g) were obtained.

[0095]

[Table 17]

Example 18 Synthesis of Compound 32

[0097]

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Compound 29 (6.0) cooled to -13 ° C.
g, 7.13 mmol) in dichloromethane (30 m
L) To the solution was added m-chloroperbenzoic acid (1.70 g, 6.
90 mmol) in 50 mL of dichloromethane
After dropwise addition over time, the mixture was stirred at the same temperature for 15 minutes. The reaction solution was poured into an ice-cooled saturated aqueous sodium hydrogen solution, the organic layer was separated, and the aqueous layer was extracted with dichloromethane. The organic layers were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure.

The obtained residue (7.14 g) was dissolved in toluene (30 mL), and triethylamine (4.0 mL, 5.5 g, 28.5 mmol) and trifluoroacetic anhydride (2.0 mL) were cooled with ice. , 3.0 g, 14.
3 mmol) and stirred for 30 minutes. The reaction solution was -7
Sodium borohydride cooled to 8 ° C (2.7 g, 7
1 mmol) in methanol (150 mL) suspension.
After dropping over 0 minutes, the temperature was gradually raised to room temperature. The reaction solution was diluted with ethyl acetate (1 L), washed successively with a 10% aqueous citric acid solution and saturated saline, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent; hexane: ethyl acetate = 70: 30-0: 100) to give Compound 32.
(3.90 g) was obtained.

[0100]

[Table 18]

Example 19 Synthesis of Compound 35

[0102]

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Compound 32 (7.9) cooled to -78 ° C.
g, 10.5 mmol) of dichloromethane (40 mL)
Diisobutylaluminum hydride (1 M toluene solution, 32 mL, 32 mmol) was added dropwise to the solution over 10 minutes. After the reaction solution was stirred at the same temperature for 1 hour, anhydrous methanol (22.4 mL) was added dropwise over 10 minutes, and further stirred at room temperature for 1 hour. Chloroform and 1N hydrochloric acid were added to the reaction solution, the organic layer was separated, and the aqueous layer was extracted with chloroform. The organic layers were combined, washed successively with a saturated saline solution, a saturated aqueous solution of sodium hydrogen carbonate, and a saturated saline solution, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure.

The obtained residue (8.4 g) was dissolved in dichloromethane (40 mL), and at room temperature, 4-dimethylaminopyridine (120 mg, 1.0 mmol) and triethylamine (4.4 mL, 3.2 g, 31.6 mmol). ) And tert-butyldimethylchlorosilane (2.70)
g, 17.9 mol), and the mixture was further stirred for 1 hour. The reaction solution was diluted with chloroform, washed sequentially with a 10% aqueous citric acid solution, a saturated aqueous sodium hydrogen carbonate solution, and a saturated saline solution, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure.

The obtained residue (9.0 g) was dissolved in acetonitrile (40 mL), and thiophenol (2.0 mL, 2.2 g, 20 mmol) and cesium carbonate (7.0 g, 20 mmol) were sequentially added at room temperature. And stirred for 1 hour. The reaction solution was diluted with ethyl acetate, washed successively with a 10% aqueous citric acid solution and saturated saline, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent; hexane: dichloromethane = 65: 35 to 25: 75 → hexane: ethyl acetate = 75: 25) to give Compound 35 (4.9).
0 g).

[0106]

[Table 19]

Example 20 Synthesis of Compound 38

[0108]

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Compound 35 (4.76 g, 7.49 mmol)
l) in dichloromethane (50 mL) solution at room temperature
A dichloromethane solution (60 mL) of chloroperbenzoic acid (2.06 g, 8.37 mmol) was added dropwise over 20 minutes, and the mixture was further stirred for 10 minutes. The reaction solution was washed successively with a saturated aqueous solution of sodium hydrogen carbonate and a saturated saline solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure.

Acetic anhydride (20 mL) was added to the obtained residue (4.24 g), and the mixture was stirred at room temperature for 12 hours. The reaction solution was concentrated under reduced pressure, and the obtained residue was dissolved in ethyl acetate.
The extract was washed successively with a 10% aqueous citric acid solution, a saturated aqueous sodium hydrogen carbonate solution and a saturated saline solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure.

The obtained residue (5.88 g) was dissolved in dichloromethane (10 mL), and cooled to −78 ° C. oxalyl dichloride (1.3 mL, 1.9 g, 15.3 m).
mol) and dimethyl sulfoxide (2.1 mL,
2.3 g (30.0 mmol) of dichloromethane (40
After stirring for 30 minutes at the same temperature, triethylamine (5.3 mL, 3.8 g, 38. mL) was added.
3 mmol) was added dropwise, and the temperature was raised to room temperature over 1 hour. The reaction solution was diluted with dichloromethane, washed with a 10% aqueous citric acid solution, a saturated aqueous sodium hydrogen carbonate solution, and a saturated saline solution, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained residue is subjected to silica gel column chromatography (developing solution; diethyl ether: hexane = 50: 5).
Purification by 0) afforded compound 38 (3.70 g).

[0112]

[Table 20]

Example 21 Synthesis of Compound 39

[0114]

[Of 60]

Compound 38 (3.67 g, 5.30 mmol)
l) methanol (10 mL) -dichloromethane (10 mL)
hydrazine-hydrate (2.6 m
L, 27 g, 53.0 mmol), stirred for 1 hour, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (developing solution; hexane: ethyl acetate = 80: 20) to obtain Compound 39 (1.09 g).

[0116]

[Table 21]

Example 22 Synthesis of Compound 41

[0118]

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Compound 39 (0.15 g, 0.23 mmol)
To a solution of 1) in methanol (2.5 mL) -dichloromethane (2.5 mL) was added trifluoroacetic acid (1 M dichloromethane solution, 0.5 mL, 0.5 mmol), and the mixture was stirred at room temperature for 2 hours and at 50 ° C. for 1 hour. The reaction solution was concentrated under reduced pressure, and acetone (2.5 mL), acetone dimethyl acetal (2.5 mL), 2-methoxypropene (110 μL, 0.11 mmol) and p-
Pyridinium toluenesulfonate (25 mg, 0.10
mmol), and the mixture was stirred at room temperature for 1 hour. The reaction solution was purified by silica gel column chromatography (developing solution; chloroform: methanol = 10: 1) to give Compound 4.
1 (70 mg) was obtained.

[0120]

[Table 22]

Example 23 Synthesis of Compound 44

[0122]

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Compound 41 (0.34 g, 0.63 mmol)
l), 4-dimethylaminopyridine (12 mg, 0.1
0 mmol) and triethylamine (0.21 mL,
1.5 mmol) in dichloromethane (3 mL)
Under ice cooling, triethylchlorosilane (0.15 mL, 0.1 mL) was added.
13g, 0.89 mmol) and stirred at the same temperature for 3 hours. The reaction solution was saturated aqueous sodium hydrogen carbonate solution, 10%
The extract was washed sequentially with a citric acid aqueous solution and a saturated saline solution, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure.

The obtained residue (0.43 g) was dissolved in dichloromethane (3 mL), and triethylamine (0.53 mL, 0.38 g, 3.8 mmol) and methanesulfonic acid chloride (0.16 mL, 0.1 mL) were dissolved at room temperature. 23
g, 2.0 mmol) and stirred for 3 hours. The reaction solution was washed sequentially with a saturated aqueous solution of sodium hydrogencarbonate, a 10% aqueous solution of citric acid, and a saturated saline solution, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure.

The obtained residue (0.45 g) was dissolved in tetrahydrofuran (3 mL), and tetrabutylammonium fluoride (1M solution in tetrahydrofuran,
(1.2 mL, 1.2 mol) and stirred for 1 hour.
The reaction solution was diluted with ethyl acetate, washed successively with a 10% aqueous citric acid solution and saturated saline, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent; hexane: ethyl acetate = 70: 30-65: 35) to give Compound 44.
(0.31 g) was obtained.

[0126]

[Table 23]

Example 24 Synthesis of Compound 46

[0128]

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Compound 44 (234 mg, 0.38 mmol)
l) in N, N-dimethylformamide (2 mL) solution was added to sodium hydride (60% oil nucleic acid, 40 mg,
1.0 mmol) and stirred at room temperature for 10 minutes and at 120 ° C. for 10 minutes. The reaction solution was ice-cooled, a saturated aqueous solution of ammonium chloride was added, and the aqueous layer was extracted with ethyl acetate. The organic layer was washed with saturated saline, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure.

The obtained residue (226 mg) was treated with N, N-
Dimethylformamide (3.5 mL)-water (0.35 m
L) and dissolved in lithium azide (450 mg, 9.19
mmol) and stirred at 120 ° C. for 3 hours 30 minutes.
After the reaction solution was cooled to room temperature, it was poured into ice water and extracted with ethyl acetate. The organic layer was washed with saturated saline, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent; hexane: ethyl acetate = 80: 20) to give Compound 46 (158).
mg).

[0131]

[Table 24]

Example 25 Synthesis of Compound 47

[0133]

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Compound 46 (174 mg, 0.31 mmol)
To a solution of 1) in dichloromethane (1 mL) were added triethylamine (136 μL, 0.98 mmol) and methanesulfonic acid chloride (51 μL, 0.66 mmol), and the mixture was stirred at room temperature for 3 hours. The reaction solution was poured into a saturated aqueous solution of sodium hydrogen carbonate and extracted with chloroform. The organic layer was washed sequentially with a 10% aqueous citric acid solution and a saturated saline solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue is subjected to silica gel column chromatography (developing solution;
Hexane: ethyl acetate = 80: 20-70: 30) to give Compound 47 (157 mg).

[0135]

[Table 25]

Example 26 Synthesis of Compound 49

[0137]

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Compound 47 (147 mg, 0.23 mmol)
To a solution of 1) in dichloromethane (3 mL) was added trifluoroacetic acid (140 μL, 1.84 mmol), and the mixture was stirred at room temperature for 3 hours. The reaction solution was diluted with dichloromethane, washed with a saturated aqueous solution of sodium hydrogen carbonate, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure.

The obtained residue (145 mg) was dissolved in dichloromethane (0.5 mL), and ice-cooled triphosgene (297 mg, 1.00 mol) and pyridine (97 mg) were dissolved.
μL, 1.20 mmol) of dichloromethane (1 mL)
The solution was added dropwise over 10 minutes, and the mixture was further stirred at the same temperature for 20 minutes. The reaction solution was diluted with chloroform, washed sequentially with a saturated aqueous solution of sodium hydrogencarbonate, a 10% aqueous solution of citric acid, and a saturated saline solution, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained residue is subjected to silica gel column chromatography (developing solution; dichloromethane: hexane = 75:
Purification by 25) afforded compound 49 (132 mg).

[0140]

[Table 26]

Example 27 Synthesis of Compound 50

[0142]

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Compound 49 (132 mg, 0.21 mmol)
l) in acetonitrile (4 mL) -water (1 mL) solution, cerium (IV) diammonium nitrate (290 m
g, 0.53 mmol) and stirred at room temperature for 10 minutes. The reaction solution was poured into saturated saline and extracted with ethyl acetate. The organic layer was washed with saturated saline, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent; hexane: ethyl acetate = 70: 30-50: 50) to give Compound 5
0 (92 mg) was obtained.

[0144]

[Table 27]

Example 28 Synthesis of Compound 52

[0146]

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Compound 50 (90 mg, 0.17 mmol)
l) in dichloromethane (3 mL) solution, anhydrous magnesium sulfate (84 mg, 0.70 mmol) and pyridinium chlorochromate (75 mg, 0.35 mmol)
, And the mixture was stirred at room temperature for 1 hour and 30 minutes. After adding diethyl ether (5 mL) to the reaction solution and stirring for 3 minutes,
Celite filtration. The filtrate was concentrated under reduced pressure, the obtained residue (81 mg) was dissolved in methanol (4 mL), and methyl orthoformate (1 mL) and camphorsulfonic acid (3 mL) were dissolved.
mg, 13 μmol) and stirred at room temperature for 1 hour.
The reaction solution was poured into saturated saline and extracted with dichloromethane. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (eluent; hexane: ethyl acetate = 70: 30) to obtain Compound 52 (77 mg).

[0148]

[Table 28]

Example 29 Synthesis of Compound 53

[0150]

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To a solution of compound 52 (35 mg, 62 μmol) in tetrahydrofuran (1 mL) -water (0.1 mL) was added diisopropylethylamine (13 μL, 75 μm).
ol) and triphenylphosphine (31 mg, 0.1 mg).
12 mmol), and the mixture was stirred at 60 ° C. for 1 hour and 30 minutes. After the reaction solution was cooled to room temperature, it was poured into saturated saline and extracted with dichloromethane. The organic layer was dried over anhydrous magnesium sulfate, concentrated under reduced pressure, and the obtained residue was purified by preparative thin-layer chromatography (developing solution, benzene: ethyl acetate = 50: 50) to obtain Compound 53 (23 mg). Was.

[0152]

[Table 29]

Example 30 Synthesis of Compound 56

[0154]

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To a solution of compound 53 (20 mg, 45 μmol) in ethanol (1.5 mL) was added 10 palladium activated carbon (7 mg), and the mixture was stirred under a hydrogen atmosphere at room temperature for 1 hour. The reaction solution was filtered and concentrated under reduced pressure. The obtained residue (16 mg) was dissolved in tetrahydrofuran (2.5 mL) -water (0.25 mL), and a 1% aqueous solution of perchloric acid (0.
1 mL) and stirred for 3 hours 30 minutes. The reaction solution was poured into saturated saline and extracted with diethyl ether. The organic layer was washed with saturated saline, dried over anhydrous magnesium sulfate,
It was concentrated under reduced pressure. The obtained residue (20 mg) was dissolved in tetrahydrofuran (3 mL), and ammonia gas was blown therein for 13 minutes while stirring at room temperature. After further stirring for 2 hours, the mixture was concentrated under reduced pressure, and the obtained residue (17 mg) was separated by preparative thin-layer chromatography (developing solution; dichloromethane:
Purification was performed using methanol = 85:15, and Compound 56 (7.
1 mg).

[0156]

[Table 30]

[0157]

According to the invention of this application, novel development of antitumor antibiotics and application of FR9004 are expected.
Practical methods for the synthesis of 82 and its analogs and their synthetic intermediates are provided.

Claims (11)

[Claims] 1. The following formula: (Ra and Rb in the formula are each the same or different;
A hydrogen atom or an organic group, and Tf represents a triflate group) is represented by the following formula: (Rc represents a protecting group) by a coupling reaction with an optically active acetylene compound represented by the following formula: (Ra, Rb, and Rc are as defined above). A method for synthesizing an optically active acetylene compound, comprising synthesizing an optically active compound represented by the formula: 2. Conversion to an optically active ketone compound represented by the following formula (Ra, Rb, Rc is as defined above), reduction of the carbonyl group, and the following formula: (Ra, Rb, Rc are as defined above). A method for synthesizing an optically active hydroxyl compound, comprising synthesizing an optically active compound represented by the formula: 3. The following formula: (Where Ra and Rb in the formula are the same or different and each represent a hydrogen atom or an organic group, and Rc represents a protecting group). Reduction to an amino group gives the following formula: (Ra, Rb, and Rc are as described above, and Rd is a protecting group.) A method for synthesizing an optically active aniline compound represented by the formula: 4. The following formula: (Ra and Rb in the formula are each the same or different;
Rd represents a hydrogen atom or an organic group, and Rd represents a protecting group. )) Wherein the amino group of the optically active aniline compound is protected. (Ra, Rb, Rc, and Rd are as described above, and Re is a protecting group).
Is eliminated to form a hydroxyl group, and then subjected to a reduction reaction, whereby the following formula is obtained. (Ra, Rb, Rd and Re are as defined above). A method for synthesizing an optically active 8-membered ring compound represented by the formula: 5. The following formula: (Ra and Rb in the formula are each the same or different;
It represents a hydrogen atom or an organic group, and Rd and Re each represent a protecting group. )), The carbonylation of the optically active 8-membered ring compound represented by the following formula: (Wherein Ra, Rb, and Re are as defined above), and then converted to a ketone compound of the following formula: (Wherein Ra, Rb, and Re represent the above, Rf represents a hydrocarbon group, and Rg represents a protecting group.) An optically active 8-membered ring sulfide compound represented by the formula: A method for synthesizing an 8-membered ring sulfide compound. 6. The following formula: Wherein Ra and Rb in the formula are the same or different and each represent a hydrogen atom or an organic group, Re and Rg each represent a protecting group, and Rf represents a hydrocarbon group. The compound is represented by the following formula: (Ra, Rb, Re, and Rg are as defined above) or a compound obtained by removing the protecting group Rg from a compound having an optically active 8-membered ring hydroxy compound. . 7. The following formula: (Ra and Rb in the formula are each the same or different;
It represents a hydrogen atom or an organic group, and Re and Rg each represent a protecting group. ) Or an optically active 8-membered hydroxy compound from which the protecting group Rg has been eliminated is represented by the following formula: (Ra and Rb are as described above, and Rh is a protecting group). A method for synthesizing an optically active secondary amine compound represented by the formula: 8. The following formula: (Ra and Rb are the same or different and each represents a hydrogen atom or an organic group, and Rh represents a protecting group.) The optically active secondary amine compound represented by After a ring reaction, the following formula: (Ra, Rb, and Rh are as defined above). A method for synthesizing an optically active tetracyclic compound represented by the formula: 9. The following formula: (Ra and Rb are the same or different and each represents a hydrogen atom or an organic group, and Rh represents a protecting group.) An optically active tetracyclic compound represented by the following formula: (Ra and Rb are the same as those described above.), And after epoxidation, azide is formed to give the following formula: A method for synthesizing an optically active azide compound, comprising synthesizing an optically active azide compound represented by the formula (Ra and Rb are as defined above). 10. The following formula: (Wherein Ra and Rb are the same or different and each represent a hydrogen atom or an organic group). The optically active azide compound represented by the formula is converted into an optically active aziridine compound. (R ₁ and R ₂ are the same or different and represent a hydrogen atom or an organic group, and R ₃ and R ₄ are the same or different and represent a hydrogen atom or a hydrocarbon group.) FR90048 characterized by synthesizing
2 or a method for synthesizing an analog compound thereof. 11. The optically active FR9 according to claim 10,
A method for synthesizing 00482, comprising: The azide compound of the formula is converted into a methanesulfonyl (MS) carbonate by the following formula: To remove the p-methoxyphenyl group (MP),
After oxidation to an aldehyde, it is converted to dimethyl acetal to give the following formula: And the azide group is reduced to give the following formula: After the aziridine compound of formula (I), a deprotection reaction and ammonolysis of the carbonate group are carried out to give the following formula: A method for synthesizing optically active FR900482, wherein the optically active FR900482 is used.