WO1994004534A1

WO1994004534A1 - Tetrahydropyrroloindole derivative, process for producing the same, and intermediates therefor

Info

Publication number: WO1994004534A1
Application number: PCT/JP1993/001158
Authority: WO
Inventors: Shiro Terashima; Yasumichi Fukuda
Original assignee: Kyorin Pharmaceutical Co., Ltd.; Sagami Chemical Research Center
Priority date: 1992-08-21
Filing date: 1993-08-19
Publication date: 1994-03-03
Also published as: AU4981193A; JPH06116270A

Abstract

The invention provides an intermediate for the production of a compound which is prospective as a carcinostatic agent, a process for producing the same, and a starting material therefor. Tetrahydropyrroloindole derivatives represented by general formula (1) and optically active isomers thereof. General formula (1) wherein R1 represents hydrogen or a hydroxyl-protecting group; R2 represents hydrogen or an amino-protecting group; and X represents halogen, hydroxyl, alkylcarbonyloxy, arylcarbonyloxy, alkylsulfonyloxy or arylsulfonyloxy.

Description

Description Tetrahydropyro mouth indole derivative, process for producing the same, and intermediate thereof

Technical field

The present invention relates to a compound represented by the following formula, which is expected to be used as an anticancer agent (hereinafter referred to as “KW • 21891”)

And a process for producing the same, and raw materials thereof.

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Conventionally, KW- 2 1 8 9 duo Karma Issy emissions that separated extracted isolated from culture broth of actinomycetes, C _x, C _2. And the B _l and B ₂ are produced semi-synthetically by chemical modification. However, due to the low efficiency of production of duocarmycins by actinomycetes, it cannot be said to be an efficient method for producing KW-189, and at the same time, a large amount of culture solution containing extremely strong cytotoxic compounds. Therefore, the development of a new synthetic method is desired from the viewpoint of environmental pollution.

Disclosure of the invention

The method for producing the tetrahydropyro-oral indole derivative according to the present invention is shown as follows. Is done. That is, the general formula (3)

(Wherein R ³ represents a protecting group for a hydroxyl group, R ⁴ represents a protecting group for an amino group, and X ¹ represents a protected hydroxyl group)

Is added or condensed to methyl 3-methylacetylenecarboxylate, methyl acetoacetate or substituted methyl crotonate to obtain a compound of the general formula (2) '

And an aminocrotonic acid derivative represented by Here, the protecting group for the hydroxyl group of R ³ is a lower alkyl group of C ₄ such as a methyl group or an ethyl group, a benzyl group, a 4-methoxybenzyl group, a 2,4-dimethoxybenzyl group, a benzhydryl group, a trityl group, and the like. Examples thereof include an alkyl group such as an arylmethyl group, a trimethylsilyl group, a t-butyldimethylsilyl group, and a t-butyldiphenylsilyl group, and an aryl substituted silyl group. A benzyl group is preferably used. R ⁴ of Amino protecting groups as the main butoxy carbonyl group, ethoxycarbonyl, isopropoxycarbonyl group, a linear or branched lower alkoxycarbonyl alkylsulfonyl group having 1 to 6 carbon atoms such as t one-butoxycarbonyl group A haloalkoxycarbonyl group such as a 2,2,2-trichloromouth ethoxycarbonyl group, a 2,2,2-trichloro-1,1-dimethylethoxyquincarbonyl group, A substituted or unsubstituted aralkyloxycarbonyl group such as a benzyloxycarbonyl group or a 4-methoxybenzyloxycarbonyl group is exemplified, and a t-butoxycarbonyl group is preferably used. Further, the protecting group for the protected hydroxyl group represented by X ¹ is a straight-chain or branched lower alkanoyl group having 1 to 6 carbon atoms such as an acetyl group, a ptyryl group, a bivaloyl group, a benzoyl group, a 4-methoxybenzoyl group. Or unsubstituted substituted or unsubstituted aryloyl, benzyl, 4-methoxybenzyl, 2,4-dimethoxybenzyl, benzhydryl, trityl, etc. An acetyl group is preferably used, for example, an arylmethyl group. -. Of such as 5-amino-2 of the compound represented by the general formula (3), 3-dihydro-1 H- indole ^{_{(R 3 = CH 2 C. H}} 5, R 4 = C (0) OC (CH) 3, X ¹ = 0C0CH ₃ ) can be produced according to a known method (Japanese Patent Application Laid-Open No. 4-117383).

—Compound represented by general formula (3) and methyl 3-methylacetylenecarboxylate, methyl acetate acetonate, methyl 3-crocetone crotonate, methyl 3-promocrotonate, methyl 3-methanesulfonyloxycyclotonate, 3 —Methyl trifluoromethanesulfonyloxyquinone and the like, in the presence of a base catalyst such as an organic base such as triethylamine, diazabicyclo base, pyridine and getylaniline, or an alkali metal salt such as sodium hydrogen carbonate or carbon dioxide, or acetic acid Aminocrotonic acid derivatives represented by the general formula (2) by reacting in the presence or absence of an acid catalyst such as carboxylic acid such as benzoic acid, and sulfonic acid such as p-toluenesulfonic acid and methanesulfonic acid. Can be manufactured. Such a reaction proceeds smoothly at a temperature of 110 ° to 100 ° C., and any solvent can be used as long as the solvent does not participate in the reaction.

The intramolecular ring closure of the aminocrotonic acid derivative represented by the general formula (2) gives

(Wherein, R ³ , R ⁴ and X ¹ are the same as above)

Can be produced. For intramolecular ring closure, palladium catalysts such as palladium chloride, palladium acetate, palladium trifluoroacetate, and acetyl acetonato palladium; transition metal complex catalysts such as nickel chloride and nickel acetate; heavy metal salts such as lead tetraacetate and copper acetate The catalyst is used alone or in combination, and the reaction is carried out in the presence or absence of a phosphine such as triphenylphosphine or trioctylphosphine as a ligand or an organic base such as triethylamine, N-methylmorpholine or pyridine. As the solvent, acetonitrile, benzonitrile, acetic acid, dimethylformamide, dimethylacetamide, tetrahydrofuran, dioxane, dimethoxetane, toluene and the like can be used. The reaction is 0. It proceeds smoothly at 1100 ° C. and can be easily carried out, for example, by heating for several hours in the presence of palladium acetate in N, N-dimethylacetamide.

— The compound of the general formula (1a) is led to KW-189 or a related compound through the following production steps.

la lb lc

(In the formula, X ² represents a halogen atom, a lower alkylsulfonyloxy group or an arylsulfonyloxy group, and R ³ , R ⁴ and X ¹ are the same as described above.) The production process of KW-2189 shown here is shown in the form of a racemic form. However, if an optically active form of the aminoindoline derivative represented by the general formula (3) is used as a starting material, KW- as an optically active form is obtained. 2 189 can be obtained. Here, the optically active isomer of the amino diindoline derivative represented by the general formula (3) is, for example, a diastereomer according to the method described in Journal of American Chemical Society, 112, 5230, 1990. It can be manufactured by optical splitting. Further, the diastereoisomer obtained by esterifying the alcohol represented by the general formula (1b) with an optically active carboxylic acid can be separated and used as an intermediate for producing an optically active substance. BEST MODE FOR CARRYING OUT THE INVENTION

(Example)

3-Acetoxymethyl-5-amino-6-benzyloxy 1-t-butoxycarbonyl 2,3-dihydro 1H-indole 103.1 mg (0.25 mm 01), methyl acetate acetate 32.4 μ .1 (0.3 mmo 1), ρ-toluenesulfonic acid monohydrate 4.8 mg (0.025 mmo 1) was heated to reflux in 8 ml of benzene 8 (TC for 4 hours) and the solvent was distilled off. The obtained residue was purified by silica gel column chromatography (hexane: ethyl acetate = 2: 1) to give 3- (3-acetoxymethyl-6-benzyloxy) 1-t-butoxycarbonyl 2,3-butane as a pale yellow gum. 106.1 mg (83%) of 3-dihydro-1H-indole-5-yl) aminocrotonic acid methyl ester was obtained. NMR (CDC 13) δ: 1.56 (9H, s), 1.87 (3H, s), 2.08 (3H, s), 3.56 (1H, br, πι), .68 (3H, s), 3.70-3.88 (1H , Br, m), 4.04-4.22 (3H, m), 4.68 (1H, s), 5.12 (2H, s), 6.96 (1H, s), 7.28-7.44 (5H, m), 7.72 (1H, br) , s), 10.07 (1H, br, s)

(Example 2)

[Formula 12]

3- (3-acetoxymethyl-6-benzyloxy-11-t-butoxycarbo-2,3-dihydro-1H-indole-5-yl) methyl aminocrotonate 221 mg (0.433 mmo 1), palladium drunkate 194.3 mg (0.866 mmol) were heated in anhydrous N, N-dimethylacetamide under a stream of argon at 70 ° C. for 4 hours. The reaction solution was poured into ice water, and insolubles were removed by filtration and extracted with ethyl acetate. The organic layer was washed three times with water, dried over anhydrous sodium sulfate, and the solvent was distilled off. The obtained residue was purified by silica gel column chromatography (hexane: ethyl acetate: = 2: 1) to give colorless crystals of 1-acetoxymethyl-5-benzyloxy-13-t-butoxycarbonol 7-methyl- 51.4 mg (23%) of 1,2,3,6-tetrahydropyrrolo [3,2-e] indole-8-methyl rubonate was obtained.

NMR (CDC 13) S: 1.58 (9H, s), 2.03 (3H, s), 2.65 (3H, s), 3.85 (3H, s), 3.88-4.36 (5H, m), 5.16 (2H, s), 7.36-7.46 (5H, m), 7.78 (1H, br, s), 8.62 (1H, br) (Example 3)

1-acetoxymethyl-5-benzyloxy 3-t-butoxycarbonyl

7-methyl-1,2,3,6-tetrahydropyro mouth [3,2-e] indole

8-1.4-Methyl ruvonate (51.4 mg, 0.101 mmo 1) was dissolved in methanol (0.5 ml), potassium carbonate (16.8 mg, 0.121 mmo 1) was added, and the mixture was stirred at room temperature for 5 minutes. The reaction solution was neutralized with 10% citric acid and extracted with ethyl acetate. The organic layer was washed with saturated saline and dried over anhydrous sodium sulfate. The residue obtained by evaporation of the solvent was purified by preparative thin-layer silica gel chromatography (hexane: ethyl acetate = 1: 2) to give a colorless gum, 5-benzyloxy-3-t-butoxycarbonyl-1-hydroxymethyl. Rue 7-Methyl-1,2,3,6-tetrahydropyrrolate [3,2-e] Indole-8-methyl ribonate was obtained in an amount of 42. Omg (89%).

To this was added 47.2 mg (0.18 mmol) of triphenylphosphine, dissolved in 0.5 ml of anhydrous methylene chloride, and 34.7 μ.1 (0.36 mmol) of carbon tetrachloride was added dropwise under an argon stream. For 10 minutes. The solvent was distilled off, and the residue was purified by silica gel gel chromatography (hexane: ethyl acetate = 2: 1). As a result, colorless crystals of 5-benzyloxy-3-t-butoxycarbonyl 1-1-chloromethyl-7-methyl-1, 3,9.3 mg (90%) of 2,3,6-tetrahydropyro [3,2-e] methyl indole-8-carboxylate was obtained.

NMR (CDC 13) (5: 1.59 (9H, s), 2.68 (3H, s), 3.30 (lH, t, J = 10Hz), 3.85 (1H, dd, J = 2Hz, J = 10Hz), 3.93 ( 3H, s), 3.98 (1H, dd, J = 9Hz, J = llHz), 4.18-4.32 (2H, m), 5.18 (2H, s), 7.38-7.47 (5H, m), 7.78 (1H, br, s), 8.54 (1H, br, s)

(Example 4)

5 1-benzyloxy 3-t-butyncarbone 1-chloromethyl-7-methyl-1,2,3,6-tetrahydropyrro [3,2-e] indole-8-methyl carboxylate 39.3 mg (81〃mo 1) It was dissolved in 1.1 ml of tetrahydrofuran and 23.6 mg of 10% palladium on carbon was added. 0. At 25 ° C., 268.51 of 25% ammonium formate was added dropwise and the mixture was stirred for 1.5 hours under an argon stream. The reaction solution was diluted with ethyl acetate and the catalyst was removed, followed by drying over anhydrous sodium sulfate. When the solvent is distilled off, colorless crystals of 3-t-butoxycarbone-l-chloromethyl-5-hydroxy 7-methyl-1,2,3,6-tetrahydropyrro [3,2-e] indole-1-8- The methyl rubonate was obtained.

To this was added 1.3 ml of a 3 M hydrogen chloride / ethyl acetate solution, and after stirring for 1 hour, the solvent was distilled off, and 5,6,7-trimethoxy 1 H-indole 2-hydrorubonic acid 20.3 mg (81 μπιιο Add 1) and add 1- (3-dimethylaminopropyl) -13-ethylcarposimid hydrochloride in the presence of 46.6 mg (243 / xmo 1) of anhydrous Ν, N-dimethylformamide in 0.8 ml of argon. The reaction was performed under the following conditions. The reaction solution was diluted with methylene chloride, washed successively with water, 10% sodium hydrogen carbonate and saturated saline, and dried over anhydrous sodium sulfate. The crystals obtained by distilling off the solvent were purified by silica gel chromatography (hexane: tetrahydrofuran = 1: 1), and the obtained crystals were washed with ether to give colorless crystals of 1-chloromethyl-5-hydroxy-. 7—Methyl-3— (5,6,7—Trimethoxy 1 H—Indole (1,2-ylcarbonyl) 1,1,2,3,6-tetrahydropyrro [3,2-e] Indole-8-methyl ribonate was obtained in an amount of 37.74 mg (88%, 3 steps).

NMR (CDC 13) 5: 2.65 (3H, s), 3.28 (IH, t, J = 10 Hz), 3.83-3.93 (IH, m), 3.90 (3H, s), 3.91 (3H, s), 3.96 (3H, s), 4.08 (3H, s), 4.45-4.49 (2H, m), 4.68 (IH, d, J = 10Hz), 6.82 (IH, s), 6.95 (IH, s), 8.31 ( 1H, s), 9.19 (IH, br, s), 9.82 (IH, br, s), 9.90 (1H, br, s)

(Reference example 1)

1-Chloromethyl-5-hydroxy-7-methyl-3- (5,6,7-trimethoxy 1 H-indole-1-ylcarbonyl) 1,1,3,6-tetrahydropyrro [3,2-e] indole-8 —Methyl ruvonate 35.7 4mg

(67.7 / zmo 1) was dissolved in 11 ml of anhydrous acetonitrile, and 1,8-diazabicyclo [5.4.0] —7-indene 20.21 (135.4 ββαα 1) was dissolved in an argon stream. The mixture was dropped and reacted for 3 hours. The reaction solution was neutralized with 0.5Μ aqueous solution of dihydrogen phosphate and diluted with chloroform. The organic layer was washed with water and saturated saline and dried over anhydrous sodium sulfate. The solvent was distilled off, and the resulting crystals were purified by gel chromatography on silica gel (form: methanol = 98: 2) to give pale yellow crystals of 6-methyl-2- (5,6,7-trimethoxy). 1 Η-indole 1-2-ylcarbonyl) 1 1,2,8,8 a-tetrahydrocyclobrono, ⁰ [c] Pyro-port [3,2-e] indole 4 (5H) -one-1 7-carboxylic acid Methyl is

27.9 mg (84%) were obtained. NMR (CDC 13) (5: 1.37 (1H, t, J = 4 Hz), 2.37 (1H, dd, J = 3 Hz, J = 8 Hz), 2.61 (3H, s), 3.65 (1H, br, m), 3.83 (3H, s), 3.90 (3H, s), 3.94 (3H, s), 4.08 (3H, s), 4.44 (2H, br, m), 6.81 (1H, s), 6.95 (1H, d, J = 2Hz), 7.10 (1H, s), 9.30 (1H, s), 10.72 (1H, br, s) (Reference example 2)

6-methyl-2- (5,6,7-trimethoxy 1 H-indole-2-yl carbonyl) 1 1,2,8.8 a-tetrahydrocycloprono. [C] Pyro mouth [3,2-e] Indole-4 (5H) one-one 7-methyl-rvonate 26.Omg

(52.9 ηιο 1) was dissolved in 6 ml of acetonitrile, 3 ml of 1 M aqueous hydrogen bromide was added, and the mixture was stirred for 50 minutes. 3 ml of a 0.5 M aqueous solution of potassium dihydrogen phosphate was added, and the mixture was extracted with chloroform. The organic layer was washed with water and saturated saline, and then dried over anhydrous sodium sulfate. The crystals obtained by evaporating the solvent were purified by silica gel column chromatography (hexane: ethyl acetate = 1: 2.5) to obtain pale yellow crystals of 1-bromomethyl 5-hydroxy-7-methyl-3- (5 , 6,7-Trimethoxy-1H-indole-12-ylcarbonyl) 1-1,2,3,6-tetrahydropyrrole [3,

2-e] 30-1.9 mg (99.7%) of indole-8-methyl sulfonate was obtained.

NMR (CDC 13) δ: 2.65 (3H, s), 3.15 (lH, t, J = 10 Hz), 3.73 (1H, br, m), 3.915 (3H, s), 3.917 (3H, s), 3.96 (3H, s), 4.06 (3H, s), 4.39-4.55 (2H, m), 4.64 (1H, d, J = 10Hz), 6.82 (1H, s), 6.92 (1H, s), 8.31 ( 1H, s), 9.22 (1H, br, s), 9.94 (2H, br, s) (Reference example 3)

1-Bromomethyl-1-5-hydroxy-17-methyl-3- (5,6,7-trimethoxy-1H-indole-2-ylcarbonyl) 1-1,2,3,6-tetrahydropyrro [3,2-e] Suspension of 26.5 mg (46.3 mo 1) of indole-8-methyl rubonate and 11.2 mg (55.6 // mo 1) of p-ditrophenyl chloroformate in 2 ml of anhydrous methylene chloride and cooling with ice Triethylamine 7.7a1 (55.6 imo 1) was added dropwise and stirred for 1 hour. To the reaction mixture was added 7.7 n 1 (69.4 mol 1) of N-methylbiperazine, and the mixture was further reacted at room temperature overnight.

The reaction solution was diluted with chloroform, washed successively with water, a 10% aqueous sodium hydrogen carbonate solution and water, and dried over anhydrous sodium sulfate. The residue obtained by distilling off the solvent was purified by silica gel column chromatography (form: chloroform = 15: 1) to obtain colorless crystals of 1-bromomethyl-7-methyl-5- (4-methylbiperazine-1 1 3-yl (oxycarbonyl) oxy-3- (5,6,7-trimethoxy-1H-indole-2-ylcarbonyl) 1-1,2,3,6-tetrahydropyro mouth [3,2-e] indole-8-methyl carbonyl 23. 28 mg (72%) were obtained.

NMR (CDC 13) δ: 2.37 (3H, s), 2.50 (4H, br, s), 2.68 (3H, s), 3.23 (lH, t, J = 10 Hz), 3.63 (2H, m), 3.80 ( 2H, ra), 3.81 (1H, dd, J = 3Hz, J = 8Hz), 3.92 (3H, s), 3.95 (3H, s), 3.97 (3H, s), 4.08 (3H, s), 4.54 ( 1H, in), 4.63 (1H, m), 4.75 (1H, d, J = 9Hz), 6.90 (IH, s), 7.00 (1H, d, J = 2Hz), 8.16 (IH, s), 8.85 ( IH, s), 9.35 (IH, s) (Reference Example 4)

1-bromomethyl-7-methyl-5- (4-methylbiperazine-1-ylcarbonyl) oxy-3- (5-, 6,7-trimethoxy-1H-indole-1-ylcarbonyl) -1,1,2,3,6-tetrahydro Pyro Mouth [3,2-e] Indole-Luo 8-Methyl rubonate 20.47 mg (29.3 // mo 1) was added with 3 M hydrogen chloride monoethyl acetate. The crystals obtained by distilling off the solvent were washed with ether to obtain 21.06 mg (98%) of d 1 -KW-2189 as pale yellow crystals.

NMR (DMSOdg) 5: 2.70 (3H, s), 2.86 (3H, br, s), 3.15-3.44 (2Η, m), 3.46 -3.67 (4Η, m), 3.78-3.82 (IH, m), 3.80 (3H, s), 3.83 (3H, s), 3.85 (3H, s), 3.95 (3H, s), 4.15 (IH, br, s), 4.35-4.55 (4H, m), 4.65 (1H, br) , m), 6.96 (IH, s), 7.00 (IH, s), 7.94 (1H, s) .10.73 (1H, br) .11.30 (IH, s), 12.13 (IH, s)

(Example 5)

According to the same method as in Example 1, (3S) —3-acetoxymethyl-5-amino-6-benzyloxy-111-t-butoxycarbonyl-2,3-dihydro-1H—from indole 3-((3S) 1-Acetoxymethyl-6-benzyloxy 1-t-butoxycarbonyl 2,3-dihydro-1H-indole-5-yl) Aminocrotonic acid methyl ester was obtained.

[a] _D ²⁵ = + 14 ° (c = 0.5, CHC)

(Example 6)

In the same manner as in Example 2, 3-((3S) -13-acetoxymethyl-6-benzyloxy-11-t-butoxycarbone-2,3-dihydro-1H-indole-5-yl) From amino crotonic acid methyl ester (1 S) — 1-acetoxymethyl-5-benzyloxy3-t-butoxycarbonyl 8- 8-methoxycarbonyl-7-methyl-1,2,3,6-tetrahydropyro [3,2-e] Indole was obtained.

Melting point 125-127 ° C

Elemental analysis value (%) As C ₂₈ Ho ₂ N ₂ 0 ₇

C H N

Calculated 66.13 6.34 5.51

Actual 65.95 6.32 5.40

[Na] _D ²⁵ 4. (C = 0.5, CHC 1)

(Example 7)

In the same manner as in Example 3, (1 S) —1-acetoxymethyl-5-benzyl 7-Methyl-1-, 1,2,3,6-tetrahydropyrro [3,2-e] Indole-8-Methyl rubonate (1S) — 5-Benzyloxy 3- There was obtained methyl 1-butoxycarbone 1-hydroxymethyl-7-methyl-1,2,3,6-tetrahydropyro [3,2-e] indole-18-carboxylate.

Melting point 212-214 ° C

Elemental analysis value (%) As C ₂₆ H ₃₀ N ₂ Og 1 / 2H ₂₀

C H N

Calculated 65.67 6.57 5.89

Actual 65.55 6.66 5.65

[Nana _D ²⁵ = -3 (c = 0.22, CHC ₁₉ )

(Example 8)

In the same manner as in Example 3, (1S) -5-benzyloxy 3-t-butoxycarbonyl 1-hydroxymethyl-7-methyl-1,2,3,6-tetrahydropyrro [3.2-e] indole 8—From methyl rubonate to (1 S) — 5 1-benzyloxy 3—t-butoxycarbone 1-chloromethyl-7-methyl 1,2,3,6-tetrahydropyrro [3,2-e] indole 8 —Methyl carboxylate was obtained.

Melting point 209-21 1 ° C

Elementary analysis as _{_{(%) C 26 H 29 C}} 1 N 2 0 5

C H N

Calculated 64.39 6.03 5.78 Actual 64.16 6.28 5.50

twenty three

[α] - 70 ° (c = 0. 2, CHC 1 3)

D

(Reference example 5)

In the same manner as in Example 4 and Reference Examples 1 to 4, (1S) -5-benzyloxy 3-t-butoxycarbone-l-chloromethyl-7-methyl-1,2,3,6-tetrahydropyrrolate [ 3, 2-e] Indole 8—from methyl rubonate

(S) One KW—2189 was obtained.

NMR (DMSOd ₆ ) 5: 2.70 (3H, s), 2.85 (3H, s), 3.15 to 3.70 (7H, m), 3.75 to 3.85 (IH, m), 3.80 (3H, s), 3.82 (3H, s), 3.85 (3H, s), 3.95 (3H, s), 4.10 to 4.24 (IH, m), 4.34 to 4.52 (3H, m), 4.65 (IH, t, J = 10Hz), 6.96 (IH, s), 7.01 (IH, s), 7.94 (IH, brs), 10.74 (IH, brs), 11.32 (IH, s), 12.15 (IH, s)

[a] _D ²⁵ = -26 ° (c = 0.31, Me OH)

Industrial applicability

INDUSTRIAL APPLICABILITY The present invention is useful as an intermediate for producing KW-2189, which is expected to be used as an anticancer agent, a production method thereof, and a raw material thereof.

Claims

The scope of the claims

1. — General formula (1)

(Wherein, R ¹ is a protecting group for a hydrogen atom or a hydroxyl group, R ² is a protecting group for a hydrogen atom or an amino group, X is a halogen atom, a hydroxyl group, an alkylcarbonyloxy group, an arylcarbonyloxy group, Represents an alkylsulfonyloxy group or an arylsulfonyloxy group)

And an optically active form thereof.

2. — General formula (2)

(Wherein, R ³ represents a protecting group for a hydroxyl group, R ⁴ represents a protecting group for an amino group, and X ¹ represents a protected hydroxyl group)

And an optically active form thereof.

3. —General formula (3)

With methyl 3-methylacetylenecarboxylate, methyl acetoacetate or substituted methyl crotonate

—General formula (2)

( ₂ )

(Wherein, R ³ , R ⁴ and X ¹ are the same as above)

Wherein the ring is closed in the presence of a metal catalyst after obtaining an aminocrotonic acid derivative represented by the following general formula (Ia):

(Wherein, R ³ , R ⁴ and X ¹ are the same as above) A method for producing a tetrahydropyromouth indole derivative represented by the formula: