JPH04117383A - 2-alkoxycarbonyl-2-methyl-1-oxo-1,2,3,6,7,8-hexahydro-benzo(1,2-b;4,3-b')dipyrrole derivative - Google Patents

Abstract

NEW MATERIAL:A compound of formula I (R<1> is H, 1-6C chain-like alkyl, R<2>, R<4> are H, amino-protecting group; R<3>, R<5> are H, OH-protecting group). EXAMPLE:8-Acetoxymethyl-4-benzyloxy-6-t-butoxycarbonyl-1,2-dioxo-1,2,3 ,6,7,8-hexahydro- benzo[1,2-b;4,3-b']dipyrrole. USE:A raw material for preparing duocarmycin A hopeful as an anti-cancer drug. PREPARATION:A compound of formula II is first protected and sulfonated. After reduced, the reaction product is subjected to an intramolecular ring-closing reaction and further to the introduction of an amino group to form a compound of formula III (R<8> is amino-protecting group; R<10> is OH-protecting group). The compound of formula III is nitrated and reduced and a compound of formula IV is obtained from the reaction product. The compound of formula IV is subjected to a protecting group- removing reaction, to a protecting reaction and subsequently to an oxidation reaction to prepare a compound of formula V. Finally, a compound of formula VI obtained from the compound of formula V is subjected to a protecting group-removing reaction and to an intramolecular ring-closing reaction. The compounds of formula IV, V and VI are new materials.

Description

DETAILED DESCRIPTION OF THE INVENTION [Industrial Application Field] The present invention relates to -linear formula (1) (where ill is a hydrogen atom or a linear or branched lower alkyl group having 1 to 6 carbon atoms, 1rg and R4 are each independently a hydrogen atom or the same or different amino group protecting group, R
3 and y% each independently represent a hydrogen atom or the same or different hydroxyl protecting group.
7,8-hexahydro-benzo(1,2-b,4.3-
b') General formula () used as a dipyrole derivative and its production intermediate (in the formula, R3 and R9 are each independently a hydrogen atom or the same or different hydroxyl group protecting group, R- is a hydrogen atom or the number of carbon atoms 1 to 6 linear or branched lower alkyl groups, R7
is an unsubstituted or substituted amino group, R@ represents a protecting group for the amino group, 4-alkoxycarbonyl-2
, 3-dihydro-IH-indole derivative and -wire formula (
1,2-dioxo1.2. 3,
6.7.8-hexahydro-benzo(1,2-b;4.
3-b') Regarding dipyrole derivatives. The above general formula (
nI) and C11), the general formula (
2-alkoxycarbonyl-2-methyl-1-oxo-1,2,3,6,7,8-hexahydro-benzo(1,2-b,4.3-b') divirol represented by 1) The derivative is derived from duocarmycin A1, which is expressed by the formula () and is expected to be used as an anticancer agent due to its strong cytotoxicity.It is expected to be used as an antitumor agent due to its strong cytotoxicity. Duocarmidino C3, (bilindamycin A) or B represented by the general formula (V) (wherein, X represents a chlorine or bromine atom)
1, and the general formula (
Vl) Duocarmycin C1, (pyridamycin B) or B (wherein, X represents a chlorine or bromine atom)
+ (Che-, Pharm, Bull, , 36
．． 3728 (1988).

J, Antibiot, 42.1299.1515.
1713 (1989), Natural Organic Compounds Discussion Group,
Fukuoka, country, abstract collection p300. ) can be used as a raw material for manufacturing (see reference examples below).

In addition, 2-alcokynecarbonyl-2-methyl-1-oxo-1,2,36,7, represented by the general formula (1), which is produced via the compound of the -line formula (111) and (II), 8
-hexahydro-benzo(1,2-b;4.3-b')
From dipyrole derivatives, the formula (rl/)-linear formula [■],
The 2-position epimer of duocarmycins represented by the and -line formulas (VI) can also be produced (see reference examples below). We can expect many uses.

[Conventional technology]

Conventionally, duocarmycin A, C, C1B, and B2
was extracted and isolated from the culture solution of actinomycetes. In addition, duocarmycin C3 and C! is duocarmycin A
with hydrochloric acid, and duocarmycin B1 and B,
It was also obtained by treating duocarmycin A with potassium bromide in aqueous acetone (Che*, Ph
arm, Bull, 363728 (1988), J
, Antibiot, , 42.1299. (1989
), Natural Organic Compounds Discussion Group, Fukuoka, ■ Suzu, Abstract Collection ρ3
00. ).

However, the production efficiency of duocarmycins by vAw is low, and in order to efficiently obtain duocarmycins, including their 2-position epimer, which are highly expected to be used as anticancer drugs due to their strong cytotoxicity, chemical synthesis is required. Development of a law is strongly desired.

[NM that the invention attempts to solve]

An object of the present invention is to provide raw materials for producing duocarmycin A and its 2-position epimer, which is the most important duocarmycin among the duocarmycins expected to be used as anticancer agents.

[Means to solve the problem]

The present invention relates to the linear formula (1) (wherein R1 is a hydrogen atom or a linear or branched lower alkyl group having 1 to 6 carbon atoms, and R4 are each independently a hydrogen atom or the same or different amino protecting group, R3
as well as? 2-alkoxycarbonyl-2-methyl-1-oxo-1,2゜3.6.7.8-hexahydro-benzo [where each S independently represents a hydrogen atom or a hydroxyl group aS] 1,2b;4.3-b') dipyrole derivatives and their 4- represented by a linear or branched lower alkyl group, R7 is an unsubstituted or substituted amino group, and R8 is a hydrogen atom or a protecting group for the amino group.
Alcoquinecarbonyl-2,3-dihydro-IH-indole derivatives and -linear (I[[) where R1 and R
IG is each independently a hydrogen atom or the same or different hydroxyl group protecting group, R@ is a hydrogen atom or an amino group protecting group, R
1,2-dioxo-1,2,3,6,7,8-hexahydrogenzo (1,2-b, 4.3 -b') Regarding divirol derivatives. 2- represented by the above-wire formula [1]
alkoxycarbonyl-2-methyl-1-oxo-1,
2,3,6,7,8-hexahydrobendoC1,2-
b; 4.3-b'l divirol derivative is synthesized by the synthesis process shown below to produce 1,2 divirol derivatives represented by the above-mentioned -linear formula (I
-Dioxo-1,2,3,6゜78-hexahydro-benzo(1,z-b;4.3-b') dipyrole derivative and 4-alkoxycarbonyl-2 represented by the above-mentioned -linear formula CI =dihydro-IH-indole derivative.

R30No□ 3O OR R”O Ox [Step 11] ■ (Ia) −(I a ′) −(T b) −(I b ′) (in the formula, 1171.1i13. R1, R”, [+” Haf
jl Note M represents the meaning, R represents a protecting group for the amino group,
R1@l represents a hydroxyl protecting group, R11 represents a linear or branched lower alkyl group having 1 to 6 carbon atoms, or a substituted or unsubstituted aryl group).

Note that the protective groups for hydroxyl groups and amino groups used in this manufacturing process can be appropriately removed by methods commonly used for these protective groups.

Furthermore, esters having R1 and P, which are the same or different linear or branched lower alkyl groups having 1 to 6 carbon atoms, can be hydrolyzed by known methods to yield free carboxylic acids. Needless to say.

[First step] This step is performed to prepare 2-(2nitrophenyl) having a hydroxyl group protected at the 4-position on the benzene ring represented by the -line formula [■].
A hydroxyl protecting group is introduced into one of the two primary alcohols of a propane-1,3-diol derivative to produce a 2-(2nitrophenyl)propanol derivative represented by the -line formula [■]. be. As the hydroxyl protecting group that can be introduced into the 4-position of the benzene ring, from the first step to the first step described below,
A compound that stably exists up to 8 steps and can be removed in the 19th and 20th steps without damaging other parts of the compound is selected. Hydroxyl group retention that satisfies these requirements
I groups include benzyl group, pmethoxybenzyl group, 2
．． Examples include substituted or unsubstituted allylmethyl groups such as 4-dimethoxybenzyl group, benzhydryl group, di(p-methoxyphenyl)methyl group, and trityl group, with benzyl group being preferably used. 4 on these Heyn rings
2-(2-nitrophenyl)propane-1,3-diol derivatives having a protected hydroxyl group can be produced according to known methods (J, A Sono, Chem.

Soc, 103 5622 (1981), J
,Med,Chem,, 31. 590 (1988
),).

The 11 hydroxyl groups introduced into the 2-(2-nitrophenyl)propane-1,3-diol derivative represented by the general formula [■] are stable from the second step to the sixth step. Those that are present and can be removed in the seventh step without damaging other parts of the compound are selected. Protecting groups for hydroxyl groups that meet this strict requirement include formyl group, acetyl group, propionyl group, butyryl group, pentanoyl group, 2-
1 or more carbon atoms such as methylpropionyl group and pivaloyl group
Examples include substituted or unsubstituted aryloyl groups such as linear or branched lower alkanoyl groups, benzoyl groups, p-methoxyhendiyl groups, p-nitrobenzyl groups, and 2,4-dimethoxybenzuyl groups. Acetyl group is preferably used. These hydroxyl-protecting groups can be introduced into the 2-(2-nitrophenyl)propane-1,3-diol derivative represented by the -line formula [■] according to a known method (@Protective Groups in
Organic Synthesis,” Jobn
Wjley & 5ons, Ne@York+u+pp50-72).

[Second step] This step is to sulfonylate 2-(2-nitrophenyl) propazole IFeUl represented by the -line formula [■] to produce a sulfonic acid ester represented by the -line formula CI. be.

On the sulfonyl side, sulfonyl halides such as methanesulfonyl chloride, methanesulfonyl bromide, ethanesulfonyl chloride, ethanesulfonyl bromide, benzenesulfonyl chloride, p-toluenesulfonyl chloride, methanesulfonic anhydride, trifluoromethanesulfonic anhydride, anhydride Sulfonic acid anhydrides such as benzenesulfonic acid and p-)luenesulfonic anhydride are exemplified, and methanesulfonyl chloride is preferably used. Sulfonylation can be carried out according to known methods.
tional Group Preparations
,” 2nd Ed,.

Academic Press+ New York+
1983+ Vol, 1+ pp619-639,)
.

[Third step] In this step, the nitro group on the heyn ring of the sulfonic acid ester represented by the -line formula CIX) is reduced to an amino group, the ring is intramolecularly closed, and a protecting group for the amino group is further introduced. In this way, a 2,3 dihydro-IH-indole derivative represented by the -line formula (X) is produced.

The reduction of a nitro group to an amino group is carried out according to a known method (Organic Functional Gr.
oupPreparations,” 2nd E
d, +Academic Press+New Yo
R.K., 1983. Vol.1. pp377-43
3. ), the 0 reaction is preferably carried out by hydrogenation using platinum, palladium supported on charcoal powder, or the like as a catalyst in the presence of a tertiary amine such as triethylamine or diisopropylethylamine in a solvent under a hydrogen pressure of 1 to 10 atmospheres. As the v# medium, any solvent can be used as long as it does not participate in the reaction, but ether solvents such as diethyl ether, tetrahydrofuran, dioxane, and 1,2-dimethoxyethane are preferably used. Hydrogenation proceeds smoothly between 0°C and 50°C.

The amino group generated by hydrogenation immediately reacts with an intramolecular sulfonyloxy group in the presence of a tertiary amine such as triethylamine or diisopropylethylamine to undergo an intramolecular ring-closing reaction.The generated 2,3-dihydro-IH-
The protecting group for the amino group introduced into the 1-position amino group of the indole derivative exists stably from the 4th step to the 12th step, and is removed in the 13th and 14th steps without damaging other parts of the compound. Those that are possible are selected.

As protecting groups for amino groups that meet these requirements, straight-chain or branched groups having 1 to 6 carbon atoms such as methoxycarbonyl group, ethoxycarbonyl group, impropoxycarbonyl group, and t-butoxycarbonyl group are used. Substituted or unsubstituted aralkyloxycarbonyl groups such as lower alkoxycarbonyl group, hennyloxycarbonyl group, p-methoxybenzyloxycarbonyl group, benzhydryloxycarbonyl group, di(p-methoxyphenyl)methoxycarbonyl group, trityloxycarbonyl group, etc. Among these groups, a t-butoxycarbonyl group is preferably used.

These protecting groups can be introduced by known methods. (”Protect i veGroups
in Organic 5yntheais,' J
ohn Wiley 1Sons, New York
, 1981+ρp226-248. ).

[Fourth step] In this step, 2,3-dihydro-
A nitro group is introduced into the 5-position of the IH-indole derivative, and -
A 5-nitro-2,3-dihydro-IH-indole derivative represented by the linear formula (XI) is produced.

The introduction of the nitro group is carried out according to the known method of nitrating a benzene ring ("Organic Functi").
onalGroup Preparatons,'
2nd, fid, Academic Press198
3, Vol, 1 pp49B-548,) Preferably, the reaction carried out using acetyl nitrate is carried out in a solvent, and as a solvent, any solvent can be used as long as it does not participate in the reaction, but preferably For this purpose, halogenated hydrogen solvents such as chloroform, dichloromethane and carbon tetrachloride, and nitrated hydrocarbon solvents such as nitromethane and nitrobenzene are used.

The reaction proceeds smoothly at -40°C to 20°C.

[Fifth step] In this step, 5-nitro-2, represented by -wire formula (XI),
The nitro group at the 5-position of the 3-dihydro-IH-indole derivative is reduced to form 5-amino-2 represented by the -line formula (Xll).
, 3-dihydro-IH-indole derivatives.

The reduction of a nitro group to an amino group is carried out according to known methods ("Organic Functional
GroupPreparations,” 2ndJd
, Academic Press+ New York
1983, Vol. 1. pp377-433. ),
Preferably, one reaction carried out by hydrogenation using platinum, palladium supported on charcoal powder, or the like as a catalyst is carried out in a solvent under a hydrogen pressure of 1 to 10 atmospheres. Any solvent can be used as long as it does not participate in the reaction, but
Ether solvents such as diethyl ether, tetrahydrofuran, dioxane, and 1,2-dimethoxyethane are preferably used. Hydrogenation proceeds smoothly between 0°C and 50°C.

[Sixth step] In this step, 5-ami/-2, represented by the -wire formula (Xu),
Methylthio! to the 3-dihydro-IH-indole derivative! 4-(1-methylthio-1-alkoxycarbonyl)methyl was produced by reacting the alkyl chloride and sulfuryl chloride with the thus prepared S-chloro-8-methyl-3-alkoxycarbonylmethylsulfonium chlorosulfinate in the presence of a base. -5-amino-2,3-dihydro-IH
The -indole derivative is further treated with a carboxylic acid and separated by internal ring closure to produce 1-methylthio-2-oxo 1,2.
3. 6. 7. 8-benzo[1,2-b; 4.1
-b') Dipyrrole derivative and further oxidize the 1-position to obtain the compound of the present invention, 1 represented by the general formula (lla).
, 2-dioxo-1,2,3,67,8-hexahydrogenzo(1,2-b;4.3-b') divirol derivative.

The preparation of S-chloro-8-methyl-3-alkoxycarbonylmethylsulfonium chlorosulfinate from alkyl methylthioacetate and sulfuryl chloride is carried out according to literature methods (J, Med, Ches+,.
31, 590 (1988), ), examples of the alkyl methylthioacetate used include straight or branched lower alkyl esters of methylthioacetic acid having 1 to 6 carbon atoms, such as methyl methylthioacetate, ethyl methylthioacetate, and isopropyl methylthioacetate. However, methyl methylthioacetate is preferably used.

The obtained chlorosulfinate and 5-amino-2,3-
The reaction with the dihydro-IH-indole derivative is carried out in the presence of a tertiary amine. The tertiary amine used is
Triethylamine, diisopropylethylamine, 4-
Examples include dimethylaminopyridine, 1.8-bisdimethylaminonaphthalene (proton sponge), 1.4-diazabicyclo[2.2.2]octane, and 1.8-diazabicyclo(5,4,0)undec-7-ene. However, 1,8-bisdimethylaminonaphthalene (proton sponge) is preferably used.

4-(1
-methylthio-1-alkoxycarbonyl)methyl-5
The -amino-2,3-dihydro-IH-indole derivative undergoes ring closure by treatment with carboxylic acid, resulting in 1-methylthio-2oxo-1,2,3,6,7,8-hexahydro-benzo[1, 2-b; 4.3-b') giving a divirol derivative. The carboxylic acids that can be used include formic acid, acetic acid, propionic acid, butyric acid, isobutyric acid, etc.
-6 straight or branched lower fatty acids are exemplified, and acetic acid is preferably used.

Preparation of chlorosulfinate, reaction of chlorosulfinate with 5-amino-2,3-dihydro-IH zeynol derivatives, and ■-methylthio 2-oxo 1.
2.3,6.7.8-hexahydro-benzo(1,2-
b, 4.3-b') Ring closure to dipyrole derivatives is the same as -
Alternatively, the reaction can be carried out in a different solvent, and any solvent can be used as long as it does not participate in the reaction, but preferably ether solvents such as diethyl ether, tetrahydrofuran, dioxane, and 1,2-dimethoxyethane, Halogenated hydrocarbon solvents such as chloroform, dichloromethane, and carbon tetrachloride are used.

The preparation of chlorosulfinate and the reaction of chlorosulfinate with 5-amino-2,3-dihydro IH-indole derivatives proceed smoothly at temperatures ranging from 100°C to -20°C. -2-oxo-1,2
,3,6°7.8-hexahydro-benzoC1,2-b
.

4.3-b') Ring closure to divirol derivatives proceeds smoothly from 0°C to 50°C.

1-methylthio-2-oxo-], 2. 37.8
-hexahydro-benzo(1,2-bi4.3-b')
By oxidizing the divirol derivative, the compound of the present invention, 1,2-dioxo-1,2,3,6,78-hexahydro-benzo(1
, 2-b; 4,3b') dipyrole derivatives are obtained.

On the oxidation side, a combination of copper chloride (■) and copper oxide (I[) is preferably used. Oxidation is carried out in a solvent,
Any solvent that does not participate in the reaction and has a 6°C temperature can be used, but diethyl ether, tetrahydrofuran, dioxane, and 12°C are preferably used.
The reaction using an ether solvent such as dimethoxyethane, or a ketone solvent such as acetone, methyl ethyl ketone, diethyl ketone, or cyclohexanone proceeds smoothly at a temperature of -20°C to 50°C.

[Seventh step] This step is performed to convert 1,2-dioxo-1,2,3,6,7,8-hexahydro-benzo(1
, 2-b, 4.3-b') The protecting group of the protected hydroxymethyl group present at the 8-position of the dipyrole derivative is removed to form 8-hydroxymethyl- represented by the linear formula (II[b)]. A 1,2-dioxo-1,2,3,6,7,8-hexahydro-benzo(1,2-b;4.3-b') divirol derivative is produced.

Removal of the protecting group is carried out according to a known method depending on the type of protecting group introduced in the first step.
tive Groups in Organic
5 synthesis.

John Wiley 5ons, New Yo
rk, 1981. pp 50-72. ).

[Eighth Step] This step is a process in which 8-hydroxymethyl-1,2-dioxo-1,2,36,7,8-
At the 8-position hydroxymethyl group of the hexahydro-benzo(1,2-b;4.3-b') divirol derivative, -linear C
1,2-dioxo-1,2,3, represented by n[a:l
6,7,8-hexahydro-benzo(1,2-b,4
3-b') Re-introducing a hydroxyl protecting group different from the protecting group possessed by the divirol derivative to obtain 1,2-dioxo-1,2,3,6,ma,8 represented by the -line formula (Illc) -hexahydro-benzo(1,2-b; 4+ 3-b')
This is to produce divirol derivatives.

As the protecting group to be introduced, one is selected that exists stably from the 9th step to the 12th step and can be removed in the 13th and 14th steps without damaging other parts of the compound. Examples of hydroxyl-protecting groups that meet these requirements include silyl groups such as triethylsilyl, isopropyldimethylsilyl, t-butyldimethylsilyl, and t-butyldiphenylsilyl.
Butyldimethylsilyl group is used. These protecting groups are converted into 8-hydroxymethyl-1,2-dioxo-12,3,6,7 represented by the general formula (mb) according to known methods.
,8-hexahydro-benzo(1,2-b;4.3-b
') Introduced into divirol derivatives ("Protect
ive Groups in Organic Synt
hesis,” John-Wiley i 5ons,
New York, 1981pp 39-50. )
.

[Ninth step] This step is a 1,2-dioxo-
1,2,3,6,7,8-hexahydro-benzo(1,
2-b; 4+ 3-b') The divirol derivative is oxidized to give an anhydrous isatone # derivative, and the anhydrous indole derivative is further alcoholized to give 5 represented by the general formula (Ila), which is a compound of the present invention. -Amino-4-alkoxycarbonyl 2,3-dihydro-IH-indole derivative is produced.

The oxidation is carried out in the presence of a base using a peroxide such as hydrogen peroxide, peracetic acid, perbenzoic acid, m-chloroperbenzoic acid, and monoperphthalic acid, preferably m-chloroperbenzoic acid. is used. Examples of bases include alkali metal acid carbonates such as lithium hydrogen carbonate, sodium hydrogen carbonate, and potassium hydrogen carbonate, alkali metal carbonates such as #2# lithium, sodium carbonate, and potassium carbonate, lithium hydroxide, sodium hydroxide, and hydroxide. An alkali metal hydroxide such as potassium is used, but preferably the reaction in which sodium bicarbonate is used is carried out in a solvent, and the solvent used can be any solvent that does not take part in the reaction. However, the reaction, which preferably uses a halogenated hydrocarbon solvent such as chloroform, dichloromethane, or carbon tetrachloride, proceeds smoothly at a temperature of -20°C to 50°C.

Alcoholysis of the isatonic anhydride derivative obtained by oxidation is carried out using alcohol in the presence of a base. Alcohols used include methanol, ethanol, propatool, isoproptool, butanol,
Examples include linear or branched lower aliphatic alcohols having 1 to 6 carbon atoms such as isobutanol and pentanol, but methanol is preferably used. Examples of bases include alkali metal carbonates such as lithium carbonate and potassium carbonate, alkali metal hydroxides such as sodium hydroxide and potassium hydroxide, triethylamine, diisopropylethylamine, 4-dimethylaminopyridine, and 1.8-bisdimethylaminonaphthalene. (proton sponge), 1.
4-Diazabicyclo[2,2,2)octane, 1.8-
Examples include tertiary amines such as diazabicyclo(5,4,0)undec-7-ene, but preferably, the reaction using potassium carbonate proceeds smoothly at a temperature of -20°C to 50°C.

[Step 10] In this step, 5-amino-4- represented by -wire formula [■a]
By introducing a (1-alkoxycarbonyl)ethyl group into the 5-position amino group of the alkoxycarbonyl-2,3-dihydro-IH-indole derivative, 5-((( 1-alkoxycarbonyl)ethyl]amino-4-alkoxycarbonyl-2,3
-dihydro-IH-indole derivatives are produced.

The (1-alkoxycarbonyl)ethyl group is introduced using a 2-halopropionic acid ester in the presence of a base. The 2-halopropionic acid esters used include methyl, ethyl, propyl, isopropyl, 2-bromopropionic acid or 2-iodopropionic acid.
Examples include linear or branched lower alkyl esters of 2-halopropionic acid having 1 to 6 carbon atoms, such as butyl, isobutyl, pentyl, and esters, and methyl 2-bromopropionate is preferably used. As chlorine,
Examples include alkali metal carbonates such as sodium carbonate, calcium carbonate, and cesium carbonate, and alkali metal carbonates such as magnesium carbonate, calcium carbonate, and barium carbonate. Preferably, the reaction using cesium carbonate is carried out in a solvent. Any solvent can be used as long as it does not participate in the reaction, but preferably,
Aprotic polar solvents such as N,N-dimethylformamide, N,N-dimethylacetamide, hexamethylphosphorustriamide are used, and more preferably N,
N-dimethylformamide is used. Reaction at 30℃
The process progresses smoothly from 120°C to 120°C.

[Step 11] This step is carried out at the 5-((1alkoxycarbonylethyl))]amino-4-alkoxycarbonyl 2,3-dihydro-LH-indole derivative represented by the -linear formula CI[b) ( A protecting group is introduced into the nitrogen atom of the (1-alkoxycarbonylethyl)amino group, and the compound of the present invention has a protected (1-alkoxycarbonylethyl)amino group at the 5-position represented by the general formula JU c ). 5-(1-
(alkoxycarbonylethyl)amino-4-alkoxycarbonyl-2,3-dihydro-IH-indole derivative.

The protecting group to be introduced is one that exists stably in the 12th step and can be removed in the 13th and 14th steps without damaging other parts of the compound.

The retention of (1-alkoxycarbonylethyl) amino group that meets these requirements! Examples of the group include a linear or branched lower alkanoyl group having 1 to 6 carbon atoms, such as a formyl group, an acetyl group, a propionyl group, a 2-methylpropionyl group, a butyryl group, and a 3-methylbutyryl group; a metquine carbonyl group; 1 carbon number such as ethoxocarbonyl group, isopropoxycarbonyl group, t-butoxycarbonyl group, etc.
-6 III-like or branched lower alkoxycarbonyl groups, silyl groups such as triethylsilyl group, triethylsilyl group, isopropyldimethylsilyl group, t-butyldimethylsilyl group, t-butyldiphenylsilyl group, etc. A formyl group or a t-butoxycarbonyl group is preferably used, and a formyl group is more preferably used. These protecting groups are introduced into the 5-(1-alkoxycarbonylethyl)amino-4alkoxycarbonyl-2,3-dihydro IH-indole derivative represented by the general formula (II cal) by a known method (“Protective Groups tn O
rganic Syntbes1g+” John-W
iley & 5ons, New Work, 198
1+ pH+ 223-257 and p 283. ).

[Step 12] In this step, 5-(1-alkoxycarbonylethyl)amino- having a protected (l-alkoxycarbonylethyl)amino group at the 5-position represented by the -line formula (Ilc:) 4-Alkoxycarbonyl-2,3-dihydro-IH
- The indole derivative is intramolecularly closed using a base, and the compound of the present invention is (2R'', 83'')-2-alkoxycarbonyl-2, which is represented by the linear formula [1a) and (Iai).
-Methyl-1-oxo-1,2,3,6,7°8-heshydrobenzo(L,2-b;4,3=b')dipyrrol derivative and its (2R'').

83”)-isomer.

Bases used in the intramolecular ring-closing reaction include alkali metal hydrides such as lithium hydride, sodium hydride, and potassium hydride, lithium methoxide, sodium methoxide, potassium methoxide, lithium methoxy, sodium ethoxide, and potassium ethoxy. Sodium t
Examples include alkali metal alkoxides such as -butoxide, potassium t-butoxide, sodium phenoxide, and potassium phenoxide, and alkali metal amides such as lithium amide, sodium amide, potassium amide, lithium diisopropylamide, and lithium hexamethyldisilazide. However, lithium diisopropylamide is preferably used. The reaction is carried out in a solvent, and any solvent can be used as long as it does not participate in the reaction, but ether solvents such as diethyl ether, tetrahydrofuran, dioxane, and 12-dimethoxyethane are preferably used. It will be done. The reaction proceeds smoothly at a temperature of -100°C to -20°C.

[13th and 14th steps] This step is performed using the -wire formula CTa] and (Ia') (
2R", 8S") - and (2S").

8S”) 2-alkoxycarbonyl-2-methyl-1-oxo-
1,2,3,6,7,8-hexahydrogenzo C1,
2-b; 4.3-b') The protecting groups of the 3-position, 6-position, and 7Ii hydroxynotyl group of the dipyrole derivative are removed at once, and the product is expressed by the -linear formula [from] and (Ib') The compounds of the present invention (2R", 8S")- and (2S", 8
3'')-2-Alkoxycarbonyl-8-hydroxymethyl-2-methyl-1-oxo-1,2,3,6,7°8-hexahydro-benzoCI, 2-b; 4,3-b'
] Divirol derivatives are produced.

Removal of the protective groups is carried out according to known methods depending on the type of protective groups used for the 3-, 6-, and 7-position hydroxymethyl
oup3in Organic 5 synthesis,
” Job-1+Ijley &5ons, New
York, 1981. pp223-257 and p.
283. ), preferably using methanol saturated with hydrogen chloride, the reaction proceeds smoothly at 0°C to 50°C.
A compound of the present invention represented by C) and (Ic') (
2R", 8S")- and (2S", 8S")-8-hydroxymethyl-2-methoxycarbonyl-2-methyl-
1-Oxo-1,2,3,67,8-hexahydro-benzo[1,2-b;4.3-b') divirol derivative is produced as an anticancer agent due to its strong cytotoxicity through the following synthesis process. Duocarmycin A (I
V) and its 2-epimer (■'), respectively.

(Ib) -(Ib') Me -(XIV) (XV) -(XIV') (XV') (XVI) -(XVl〔■〕 □〔■〕 (In the formula, R1'' has 1 to (6) represents a linear or branched lower alkyl group or a substituted or unsubstituted allyl group.

[Steps 15 and 16] This step is carried out to prepare (2R", 8S")- and (2S") represented by the general formulas (Ic) and (Ic'), which are the compounds of the present invention.
", BS")-hydroxymethyl-2-medoxycarbonyl-2-methyl-1-oxo-1,2,3,6,7,
8-hexahydro-benzo (1,2-b, 4.3-b'
) dipyrole derivatives represented by the formula (Xn[) 5, 6.
7-1-rimethoxy IH-condensed with indole-2-carboxylic acid, (2R18S")- and (23",8S")-8- represented by -wire formulas (XIV) and (XIV')
Hydroxymethyl-2-methoxycarbonyl-6-(5
゜6, 7-) Rimethoxy IH-indole-2-carbonyl)-2-methyl-1-oxo-1,23,6,
7,8-hexahydro-benzo[1,2-b,4.3-
b') A divirol derivative is produced.

The 567-drimethoxy IH-indole dicarboxylic acid represented by formula (XI) used in this reaction is 3.4
．． 54 It is a compound that can be easily produced from rimethoxyhenzaldehyde (see the reference side below). The reaction is carried out using the condensation side, and the condensation side is a compound that can be easily produced from rimethoxyhenzaldehyde. Those commonly used to prepare the corresponding amide derivatives are used ("
Advanced OrganlcCbemlstr
y: Reactions Mechanisms,
and 5structure,” MuGraw-
Old 11Kogakusha, Tokyo, 1977+
pp384-385. ), preferably a carbodiimide derivative such as 1,3-dicyclohexylcarbodiimide, 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride. The reaction is carried out in a solvent, and the solvent used Any substance can be used as long as it does not participate in the reaction, but preferably N,N-dimethylformamide, N,N-dimethylacetamide,
The 0 reaction, which uses an aprotic polar solvent such as hexamethylphosphorustriamide or acetonitrile, proceeds smoothly between 0°C and 50°C.

[19th and 20th Steps] This step is performed to form (2R", 83")- and (23", 8S")-8- represented by -wire formulas (XIV) and (XIV').
Hydroxymethyl-2-methoxycarbonyl-6-(5
,6,7-)rimethoxyIH-indole-2-carbonyl)-2-methyl-1-oxo-1,2,3,6,
7,8-hexahydro-benzo(1,2-b;4,3-
b') The 8-position hydroxymethyl group of the divirol derivative is sulfonylated to produce (2R", 83")- and (23", BS")-2 represented by the linear formulas (XV) and (XV').
Methoxycarbonyl-6-(5,6,7-drimethoxyIH-indole-2-carbonyl)2-methyl-1
-oxo-8-sulfonyloxymethyl-1,2,3,
6,7,8-hexahydrobenzo (1,2-b; 4,3
-b') A dipyrole derivative is produced.

Sulfonylating agents include sulfonyl halides such as methanesulfonyl chloride, methanesulfonyl bromide, ethanesulfonyl chloride, ethanesulfonyl bromide, heynesulfonyl chloride, p-)luenesulfonyl chloride, methanesulfonic anhydride, and trifluoromethanesulfone anhydride. Examples include sulfonic acid anhydrides such as benzenesulfonic anhydride and P-)toluenesulfonic anhydride, and methanesulfonyl chloride is preferably used. Sulfonylation can be carried out according to known methods (“OrganicFun
ctional Group Preparati
ons,” 2nd, Ed.

Academic Press+ New York+
Business, Vol1. l, pp 619 [19th and 20th
Process] This process is represented by -wire formulas (XV) and (XV') (
2R", BS")- and (2S", 83")2-methoxycarbonyl-6-(5,6,7trimethoxyIH-
indole-2-carbonyl)-2-methyl-1-oxo-8-sulfonyloxymethyl-1,2,3,6,7
,8-hexahydro-benzo(1,2-b;4,3-b
') removing the protecting group of the 4-position hydroxyl group of the divirol derivative,
- Linear formula (XVI) and (XV!') represented by (2R”
.

8S")- and (23", 83")-4-hydroxy-
2-Methoxycarbonyl-6-(5,6-trimethoxyIH-indole-2-carbonyl-2-methyl-
1-oxo-8-sulfonyloxymethyl-1,2,3
,67,8-hexahydro-benzo(1,2-bi4,
3-b') Dipyrrole derivatives are produced.

Removal of the protecting group is carried out according to known methods depending on the type of protecting group used ("Protective").
e Groups in Organic 5ynt
hesis.

John-Wiley & 5ons, New Y
ork, 1981. +1p14-39. ) [21st and 22nd steps] This step is performed to prepare (2R", 8S")- and (23", 8S') 4-hydroxy-2-methoxy represented by the -wire formula CXVI) and (XVT'). Carbonyl-6 (5,6,7-
) Rimethoxy IH-indole-2-carbonyl)-
2-Methyl-1-oxo-8-sulfonyloxymethyl-1,2,3,67,8-hexahydro-benzo(1,
2-b4.3-b') The divirol derivative is treated with a base to undergo intramolecular ring closure, and the wax semiform duocarmycin A represented by formulas (IV) and [■'] and its 2-position epimer (
2-eviduocarmycin A) is produced.

Bases used in the reaction include alkali metal hydrides such as lithium hydride, sodium hydride, and potassium hydride, alkali metal hydroxides such as lithium hydroxide, sodium hydroxide, and potassium hydroxide, lithium carbonate, and sodium carbonate. , alkali metal carbonates such as potassium carbonate,
Triethylamine, diisopropylethylamine, pyridine, 4-dimethylaminopyridine, 1.8-bisdimethylaminonaphthalene (proton sponge), 1.4-
3 such as diazabicyclo(2,2,2)octane, 1,8-diazabicyclo(5,4,0)undec=7-ene, etc.
Preferred examples include alkali metal hydrides, more preferably sodium hydride.
The reaction is carried out in a solvent, and any solvent can be used as long as it does not participate in the reaction, but diethyl ether, tetrahydrofuran,
The reaction using an ether solvent such as dioxane or 1,2-dimethoxyethane proceeds smoothly at a temperature of -20°C to 50°C.

Hereinafter, the present invention will be explained in detail with reference to Examples and Reference Examples.
The present invention is not limited to these, but the following abbreviations are used in Examples and Reference Examples.

Bn: benzyl group Ac + acetyl group M3: methanesulfonyl group TBDMS: t-butyldimethylsilyl group Boc:
t-Butoxycarbonyl group Reference example Method described in literature (J, Med, Chem, 11,5
90 (1988), ) and 2-(4-benzyloxy-2-nitrophenyl)propane-1,3-diol (1,82g + 6.0wmol) and triethylamine (0.84ml゜6.0ml゜ol) in dichloromethane. (20 ml) and water-cooled acetic anhydride (0,8
The reaction solution was stirred for 2.5 hours and washed sequentially with water, 1χ aqueous sodium bicarbonate solution, and saturated brine, dried over anhydrous magnesium sulfate, and then the solvent was distilled off. . The obtained residue was subjected to column chromatography (silica gel: dichloromethane-ethyl acetate-
20:1) to give 3-acetoxy-2-(4-benzyloxy-2-nitrophenyl)propatol as an oil (1.54 g, 741).

111'1R (CDC1*): δ: 7.19-
7.45 (8HIIll, C6■a, Cs-H.

CS-■, and C1-H), 5.09 (2B, s, Ph
CH*O), 4.49 (IO, dd, J-11,1,6
, 8Hz, HCl10^c), 4.32 (IB, dd.

J = 11.1, 6.2Hz, CHO^c), 3.90
(IH, dd, J-11, 3° 5.8Hz, 1CBOB
), 3.87 (III, dd, J-11, 3, 5, 5
Hz.

[IC31011), 3.65 (IH, -, cEIcB
sOB)-2,04(311,s.

C0CHs).

Reference Example 2 3-acetoxy-2-(4-benzyloxy-2-nitrophenyl) propatool (1,53 g, 4.4 mmo
1) and triethylamine (0.68ml, 4.9m5o
l) Dissolved in cyclomethane (15 ml) and added methanesulfonyl chloride (0.3f3ml1.4.9s+5o
1) was added dropwise and the mixture was stirred for 30 minutes. The reaction solution was washed successively with water and saturated brine, dried over anhydrous magnesium sulfate, and then the solvent was distilled off.

The obtained residue was purified by column chromatography (silica gel: dichloromethane-ethyl acetate-50:1) to convert 3-acetoxy-2-(4-benzyloxy-2-nitrophenyl)propyl methanesulfonate into an oily substance ( Obtained as 1.86 g, 100 ml.

NMR (CDCIs): δ: 7.19-7.4
9 (8H,m, CJs+C*-11tCs-El, and C,-H), 5.11 (2H,s, PhCl1
sO), 4.53 (111,dd, J-11,5,
5,911z, IcHOMg), 4.50 (IH, dd
.

J-11, 4, 5, 7Hz, IIC! LOMs), 4
．． 45 (ILdd, J-11, 2°6.9Hz, JIC
HOAc), 4.36 (IB, dd, J-11, 3, 6
,0Hz.

ncio^c) + 3-94 (181l, CICH
*0M5) 12.95 (3FI + s +SO*
CHs), 2.04 (3H,!, COCll5).

Reference Example 2-Nitrophenyl)brobylmethacysulfone) (
1.85 g, 4.4 mmol) and triethylamine (0.61 ml, 4.4 m5 ol) were dissolved in tetrahydrofuran (20 mmol), and platinum oxide (139 mmol, 0.6 mmol) was dissolved in tetrahydrofuran (20 mmol).
Hydrogenation was carried out for 20 minutes at room temperature under a hydrogen pressure of 3 atm. The catalyst was filtered off and the filtrate was diluted with dichloromethane. After washing successively with water and saturated brine, it was dried over anhydrous magnesium sulfate and the solvent was distilled off. Crude 3-acetoxymethyl-6-benzyloxy- obtained as a residue
2,3-dihydro-IH-indole was dissolved in dichloromethane (5 Kasumi) and mono-t-butyl carbonate anhydride (1,0
5 g, 4.8 mmol) was added. After stirring at room temperature for 12 hours, the solvent was distilled off. The obtained residue was subjected to column chromatography (silica gel: benzene-ethyl acetate-2
11), 3-acetoxymethyl-6-benzyloxy-1-t-butoxycarbonyl-2,3-dihydro-IH-indole was purified as an oily substance (1,65 g, 95
) was obtained.

NMR (CDCIs) i δ: 7.66 (IB, br
s, Cy-B), 7.28-7.45 (511, m, C
Ji) +7.06 (IB, dd, J-8, 2, 0, 5H
z, Go-B).

6.57 (IB, dd, J-8, 2, 2, 41 [z, C
m-B), 5.06 (2B, s.

PhCH*O), 3.51-4.27 (511, PengtC
*-a proverb, and CBC11 snow0^c), 2.08(
38,s, C0CHs), 1.56 (9B.

C00C(CEs)s).

Reference Example 3 - Acetoxymethyl-6-benzyloxy 1-t-butoxycarbonyl-2,3-dihydro-1H-indole (1,65 g + 4.2 mmol) was added to nitromethane (8
0 ml) and acetic anhydride (2.35 ml, 25 mm
Acetyl nitrate prepared from fuming nitric acid (0.26 ml, 1.6.2 m-ol) was added dropwise at -20°C, and then
Stir for hours.

The reaction solution was diluted with benzene and washed successively with 1% aqueous sodium hydrogen carbonate solution and saturated brine. After drying over anhydrous magnesium sulfate, the solvent was distilled off and the resulting residue was subjected to column chromatography (silica gel: benzene-ethyl acetate-20:
1) to give 3-acetoxymethyl-6-benzyloxy-1-t-butoxycarbonyl-5-nitro2.
3-dihydro-IH-indole as pale yellow crystals (1,4
1g, 77χ).

NMR (CDCIs): δ: 7.88 (111, d
, J-1,0Hz, Co-H)+7.81(111,b
rs, Ct-fl) +7.30-7.56 (5H, m,
CJa).

5.25 (2I1.8.PbC11m0), 3.58-
4.26 (5H, m, Cm-11m.

and CBClltOAc), 2.10(3H,s,C
0CHs) 1.58 (COOC(CEIs)s).

Reference example 5 3-acetoxymethyl-6-benzyloxy-1-t-
Butoxycarbonyl-5-nitro-2゜3-dihydro-
Dissolve IH-indole (443 μ, 1.0-10 l) in tetrahydrofuran (5 Kasumi I) and dissolve platinum oxide (22,
Hydrogenation was carried out for 15 minutes at room temperature under a hydrogen pressure of 3 atm. After filtering off the catalyst, the solvent was distilled off. The obtained residue was purified by column chromatography (silica gel: benzene-ethyl acetate-5:l),
3-acetoxymethyl-5-amino-6-benzyloxy-1-t-butoxycarbonyl-2,3-dihydro-
IH-indole was obtained as an oil (390μ, 95χ).

NMR (CDCIs): δ: 7.64 (1B, b
rs, Ct-El), 7.31-7.47 (ll16H
1c4-11 and C&Hs), 5.09(2
H,brs,-0CfltPh).

3.504.60(-,5fl,Ct-211and
-CHCHtO-), 2.09(s 311.-CO
CBs), 1.56(s, 91.(C1ls)sccO
-).

Example 1 Methyl methylthioacetate (137 μ, 1.1 m5 ol) was dissolved in dichloromethane (91), and sulfuryl chloride (8
4,0/j 1 , 1.1s o1) was added dropwise at -78°C and stirred at the same temperature for 20 minutes to prepare S-chloro-8-methyl-8-methoxycarbonylmethylsulfonium chlorosulfinate in dichloromethane. A solution was prepared. To this solution was added 3-acetoxymethyl-5-amino-6-pendinioxy-1-t-butoxycarbonyl-2,3-dihydro-IH-indole (390 m +
A dichloromethane solution (6 ml) of 1,0+uiol) and 1,8-bisdimethylaminonaphthalene (224+1.1 mmol) was added dropwise over 20 minutes.

After stirring at 78°C for 3.5 hours, triethylamine (146
p 1 , 1. l++nol) was added dropwise. Then -
After stirring at 78°C for 2 hours, acetic acid (3 x 1) was added to the reaction mixture, which was stirred at room temperature for 21 hours, and after stirring at room temperature for 1 hour,
It was washed successively with water and saturated brine, and dried over anhydrous magnesium sulfate. Crude 8-acetoxy obtained by distilling off the solvent
4-benzyloxy-6-t-butoxycarbonyl-1
-Methylthio-2-oxo-1゜2.3,6.7.8-
Hexahydro-benzo(1,2-b;4,3-b')dipyrrole was dissolved in acetone (20 µl) and cooled with copper(n) chloride (128 µl).

1.0ms+ol) and copper(II) oxide (113m, 1
．． The reaction mixture was stirred at room temperature for 1.5 hours, diluted with dichloromethane, and washed with a saturated aqueous ammonium chloride solution. After drying over anhydrous magnesium sulfate, the solvent was distilled off and the resulting residue was subjected to column chromatography (silica gel: dichloromethane: ethyl acetate (1 ol)).
) and purified with 8-acetoxymethyl-4-benzyloxy-6-t-butoxycarbonyl-1,2-dioxo-
1,2,3,6,7,8-hexahydro-benzo(1,
2-b, 4.3-b') Dipyrrole as purple crystal (3
40■, 77ri.

This product was recrystallized from ethanol to obtain an analytical sample.

178-179℃ IR (KBr): 3550.3200.1740.17
00 cs-District NMR (CDCIs): δ: 8
．． 00 (1B, brsJEI), 7.63 (IH, br
s.

Cs-■), 7.40 (5f1.Il, CJs), 5.
14 (2H13, PhClatO).

3.82-4.42 (5H,m, C1-FIm and CH
CHtOAc), 2.03 (3B, s, COCl1s)
, 1.56 (9H,s, C00C(CHs)s).

MS: m/e: 466 (M”), 350.306, 24
9.2Q5,91゜Elemental analysis: True value FC, 64,37$ as Cs5B*aOJt; B, 5.62K,
11,6.01χ.

Analysis value: C, 64, 37X: B, 5.51! ;N+
5.9618-acetoxymethyl-4-benzyloxy-6-t-butoxycarbonyl-1,2-dioxo1.
2.3.6,7.8-hexahydro-benzo(1,2-
b; 4.3-b') dipyrole (163 mg, 0.35
smol) was dissolved in methanol (7s+1), potassium carbonate (96.7 mol, 0.70 mol) was added under water cooling, and the mixture was stirred at room temperature for 2.5 hours. Acetic acid (50μ) was added, stirred for 15 minutes, and diluted with dichloromethane. After washing with saturated brine, it was dried over anhydrous sodium sulfate.

The solvent was distilled off to give crude 4-benzyloxy-6-t-butoxycarbonyl-8-hydroxymethyl-1,2-dioxo-1,2,3,6,7,8-hexahydro-benzo(1,2 -b, 4.3-b') Divirol was obtained as purple crystals (129■, 87χ).

This product was immediately used in the next silylation.

NMR (DMSO-dh): δ: 11.11 (
s, In, -Nfl-), 7.82 (brs, 11
1. cv-B), 7.30-7.60 (m, 6B, Cs
-11and-CJm), 5.18(s, 211.-0
Cfl*Ph), 4.84(t, In, J-5,7Hz
, -011), 3.95 (d, 2H, J-6, 5Hz)
, 3.38-3.74(s, 3H, Ct-2Hand
C5-H)+1.50(8,9B.

(CBs) *CC0-).

1'1si -/@: 420 (M'), 368,324,249
, 147,91°crude 4-benzyloxy-6-t-
Butoxycarbonyl-8-hydroxymethyl-1,2-
Dioxo-1,2,3,6,7,8-hexahydro-benzo(1,2-bi4.3-b') divirol (149
m, 0.35 smol) was dissolved in N,N-dimethylformamide (1.5 ml), and t-butyldimethylchlorosilane (106 w, 0.70 maol) and imidazole (47.7 dens, 0°7 mol) were dissolved. The mixture was added and stirred at room temperature for 8 hours.

The reaction solution was diluted with benzene and washed successively with saturated ammonium chloride aqueous solution and saturated brine. After drying over anhydrous magnesium sulfate, the solvent was distilled off. The obtained residue was purified by column chromatography (silica gel: benzene-ethyl acetate-8:1) to give 4-benzyloxy-6-t-butoxycarbonyl-8-(t-butyldimethylsilyloxy)methyl-1, 2-dioxo-1,2,3,6,7
8-hexahydro-benzo (1,2-b; 4.3-b'
] Dipyrrole was obtained as reddish-purple crystals (169cm, 90χ). This product was recrystallized from ethanol to obtain an analytical sample.

mp, 197-198℃ IR (KBr): 3200.1740.1715cm-
'NMR (CDCIs): δ: 7.9B (11
1, s, JIH-), 7.61 (1B, s.

C5-H), 7.40 (5Lbrs, -CJs)
+5.13 (2B, s.

0CBxPb), 3.85-4.15 (5H, m, Ct
-28, Cs-11andCBsO-), 1.55 (9
El, s, (CHs)scco-), 0.82 (9B
.

s, (CE[5)ssl-), 0.04 (3B, s,
5iC111s)+-0,06(3B.

s+5iCHs).

MS: m/e: 538 (M”), 482, 425, 3
81,304,260,91゜Elemental analysis: C Unshizuku Bs5
Calculated value as OJsSi +C, 64, 66Z ill,
7.11! , N, 5.20! .

Analysis value: C, 64,611; II, 7.17X; N+
5.19X.

4-benzyloxy-6-t-butoxycarbonyl-8
-(t-butyldimethylsilyloxy)methyl-1,2
-dioxo-1,2,3,6,7゜8,-hexahydro-benzo(1,2-1z4.3-b') divirol (5
3,9■, 0.10++nol) in dichloromethane (i
ll) and at -15°C m-black perbenzoin #(3
1,1■, 0.18-Kuo1) and sodium hydrogen carbonate (16.8m, 0.20smol) were added sequentially and stirred at the same temperature for 2 hours. The 0 reaction solution was diluted with dichloromethane,
After sequentially washing with a 1% aqueous sodium bisulfite solution, a 1% aqueous sodium bicarbonate solution, and saturated brine, it was dried over anhydrous sodium sulfate. The crude isatonic anhydride derivative obtained by distilling off the solvent was dissolved in methanol (ill), and water-cooled potassium carbonate (16.6w + 0.12m5ol) was added to the mixture.
Stir for hours. After adding acetic acid (70 pl>), it was diluted with saturated brine and extracted with benzene. After drying the benzene solution over anhydrous sodium sulfate, the solvent was distilled off and the resulting residue was subjected to column chromatography (silica gel: benzene-ethyl acetate). -50: 1-30: Purified by 1) to give 5-amino-6-benzyloxy-1-t-butoxycarbonyl-3-(t-butyldimethylsilyloxy)methyl-
4-Methoxycarbonyl-2,3-dihydro-IH-indole as pale yellow crystals (50.9mm).

94χ) was obtained. This product was recrystallized from methanol to obtain an analytical sample.

mp, 120.5-121℃ IR (KBr): 355G, 3545.1700c
*-'NMR (CI); δ: 7.80 (I
B, a, cv-B), 7.27-7.54 (5H,, m
, CJs), 5.70<2H,brd,NBx),5.
16 (2B.

s, PhCHtO), 3.90 (3H, s, cote
llx), 3.15-4.25 (5B+m+Ct-1
1m and C ■ C1 [l0TB Kano S), 1.54 (9 [
1°s, C00C(CTo)s), 0.90(911,
! , 5tC(CHi)s), 0.15(3B, a,
5iCB*) , 0.01 (3B, s, 5iCI
ls).

MS: s/e: 542 (M'), 486, 231° Elemental analysis: CmJ < 0. N, calculated value: C, 64,
18X +F1.7.80χ; N, 5.16χ.

Analysis value: C, 64,08χ; ■, 7.85χ; N+5.
04χ.

5-Amino-6-benzyloxy-1-t-butoxycarbonyl-3-(t-butyldimethylsilyloxy)methyl-4-methoxycarbonyl-2,3-dihydro-I
H-indole (32,5■.

60μmol1), methyl 2-bromopropionate (10
0μ4゜0.9QII@01), cesium llate (3
9m, 0.12 snol) was added to N,N-dimethylformamide (1,2s+1) and heated at 70°C for 48 hours. After cooling, the reaction solution was diluted with water and extracted with benzene.

The benzene layer was washed successively with water and saturated brine, dried over anhydrous sodium sulfate, and then the solvent was distilled off. The obtained residue was purified by preparative thin layer chromatography (silica gel: benzene-ethyl acetate-201) to obtain a mixture of diastereomers, 6-benzyloxy-1-t-butoxycarbonyl-3-(t- Butyldimethylsilyloxy)methyl-4-methoxycarbonyl-5-(1-methoxycarbonylethyl)amino-2,3-dihydro-IH-indole was obtained as a pale yellow caramel (21,4■, 57X). This solidified when left alone.

N'llR<CDC15>: δ: 7.86 (1
11, brs, Cy-B), 7.30-7.48 (5H
, m, -CJs), 5.09 (2B, brs, -0CI
11Ph), 4.29-4.41 (IH+ qXL-N
CH<, eacb diastereoisossrL
3.30-4.12(5H,m,Cm-28,-Cll
CEIm-0-, each diastereoisome
er) +3.92.3.94 (3H+s, ^r-CO
Je.

each dtatereosomer)+3.
58.3.55 (3B+s+-COJe, each
diastersoisoser)+1.54(9
Ls+(CBs)scco), 1.28.1.36(3
B, dx2. J-7,0,7,2tlz.

each diaster soiser)+0.8
4+0.86(9LsX2゜(CEIs)sSll e
ach dtatereosomer)+-0,
08~-0,40 (6, ■, 5t(CRs)s).

MS: m/e: 628 (M”), 572, 527,
481,349.289,245° formic acid (5B/J l
, 0.15 snol) and acetic anhydride (132 μl.

6-benzyloxy-1-t-butoxycarbonyl-
3-(t-butyldimethylsilyloxy)methyl-4-
Methoxycarbonyl-5-(1-methoxycarbonylethyl)amino-2,3-dihydro-IH-indole (
43.9m, 70+u+nol) was added and stirred at room temperature for 9 hours. The reaction solution was diluted with benzene, washed with a 10% aqueous sodium bicarbonate solution, and then dried over anhydrous sodium sulfate. The residue obtained by distilling off the solvent was subjected to preparative thin layer chromatography (silica gel: benzene: methanol - 20:1
) to produce a mixture of diastereomers, 6-benzyloxy-1-t-butoxycarbonyl-3(t-butyldimethylsilyloxy)methyl-5-(N-formyl-N-(1-methoxycarbonylethyl )amino)−
2,3-dihydro-LH-indole in colorless caramel (
42.7m, 93X).

NMR (CDC1*): δ near, 96-8.1
0(IB, m, C110, two rotemers
for each dlastersoisower)
+7.66 (111brs+Cv-11), 7.36
(5111, brs, CJs), 5.12 (2E1.b
rs.

QCI [mPh) + 4.96-5.16 (IO+
m, -Nll-, two rotemersfor
@ach diastsreoisom@r)+3.
36-4.26 (5B.

-1cl-2I[and -CHCEIsO-)+3
-84-4-01 (311+LArCO, Me+two
rotemers for each dlayer
eoisomer), 3.53+3.72 (3B, br
s, C0tCBs.

two rotewers for 5ach
dlastereoiaomerLl, 42-1.6
6(9H,brd,(CHs)sC-, two ro
temers foreach diastere
oisomsr) 4.06-1.49 (3H, m, (j
lstwo rotemsrs for eac
h diastereoisomer) 0.69-0
．． 96 (9E14.5lc(CBs)s), -0,20
~0.12 (6■, seagull, 5i (CHs)).

MS knee/e: 656(M”), 599,543,
499,367.323,245゜91゜6-benzyloxy-1-t-butoxycarbonyl-3
-(t-butyldimethylsilyloxy)methyl-5-(
N-formyl-N-(1-methoxycarbonylethyl)
amino)-2,3-dihydro-IH-indole (38
, 5*, 59 um-ol) in tetrahydrofuran (2
ml) and a solution of lithium diisopropylamide in tetrahydrofuran (0.88 M solution, 10
0 μm +88 μsmol) was added dropwise and stirred for 5.5 hours. After adding acetic acid (2 drops), the mixture was diluted with benzene and washed with saturated ammonium chloride aqueous solution. After drying over anhydrous sodium sulfate, the solvent was distilled off and the resulting residue was subjected to preparative thin layer chromatography (silica gel:hexene:ether-2
:1) and purified with less polar methyl (2R”, B
S”)-4-benzyloxy-6-t-butoxycarbonyl-8-(t-butyldimethylsilyloxy)methyl-3-formyl-2-methyl-1-oxo-1,2,3
,6,7,8-hexahydro-benzo(1,2-b,4
．． 3-b') Tavirol-2-carboxylate (10
, 3■, 28ri, which has a higher polarity (Z>(2S”)
, 83'')-isomers (10,4w, 28'') were obtained as pale yellow caramels, respectively.

(2R”, 83”) Integral NMR (CDCIs): δ: 9.46 (IH, a
, CHO), 8.18 (IH, brs.

C, - ■), 7.36-7.46 (SR, -, CJs)
, 5.22 (2Fl, ABtype q, J-16,
4Hz, PhCBtO), 4.20 (1B, brd.

Jdl, 3flz, DanCf10TBDMS), 4.00
(IH,brd,J=10.IBz,BCIIOTBD
MS), 3.87 (1■, dd, J = 12.3, 6.0
Hz.

Cm-B)+3.67-3.76(211,m,Ct-
Bi)+3.71 (311+s+C00CHs), 1.
80 (311,s, Cl1sCCO), 1.57 (9B
, s.

C00C(CHa)s), 0.79(9)I,s,5i
C(CIls)s), O,0O(311,s+5iC1
ls), -0-15 (3H1s, 5iCHs).

MS: s/e: 62401”), 568,511,
483,379,273,91゜(23", 83")
Integral NMR (CDCIs): δ: 9.47 (1B, s
, cBo), 8.18 (IR, brs.

Cs-11), 7.36-7.46 (511,-, cJ
s), 5.23 (2B, ABtype q, PbCBt
O), 4.19 (1 day +brd, J-10,9Hz [1
, 80 BDNS), 3.99 (IB, brd, J-1
0.3Hz.

MS: IC Dan OTMDMs), 3.86 (IEI, dd, J=
9.0.5.7Hz, Ca-H).

3.66-3.77 (2114, Cv-Flg), 3
．． 72 (3EI, s, C00CHz) 1.81 (311
, s, CHsCCO) , 1.57 (9B, s, C00
C (CBs) s) 0.79 (9EI, s, 5ic (C
11s)s), 0.01(3E[,s,5ICFIs)
.

-0,13 (3H,s, 5iCBs).

m/a: 624 (M”), 568, 524, 483,
379,273.91, male side 8 oc methyl (2R", 83")-4-benzyloxy-6-
t-Butoxycarbonyl-8-(t-butyldimethylsilyloxy)methyl-3-formyl-2-methyl-1-
Oxo-1,2,3,6゜7.8-hexahydro-benzo(1,2-tz4.3-b') divirole-2-carboxylene) (10,3■, 17μmol1) was saturated with hydrogen chloride. Methanol (2 ml) was added and the mixture was left at room temperature for 11 hours. When the solvent is distilled off, crude methyl (2R”
, 8S”)-4-benzyloxy-8-hydroxymethyl-2methyl-1-oxo-1,2,3,6,7,8-
Hexahydro-benzo(1,2-b;4.3b') divirol-2-carboxylate hydrochloride as pale yellow crystals (6
, 9 h, 100 χ).

NMR (DMSO-di): δ near, 80 (311
1+brsJi-11Ji-2B).

7.20-7.60 (6H, m, C1-H, -CJs)
, 3.40-3.95 (58, m, Cy-2II, CH
CHmO), 3.65 (3Ls, C0tCHs).

! , 45 (3B, s, CBs).

Example 9 Methyl (2S", BS")-4-benzyloxy-6-
t-Butoxycarbonyl-8-(t-butyldimethylsilyloxy)methyl-3-formyl-2-methyl-1-
Same as Example 8 for oxo-1,2,3,6゜7.8-hexahydro-benzo(1,2-bit, 3-b') divirole-2-carboxylene) (10,4■, 17μmol1) The crude methyl (23”, 83
”) -4-benzyloxy-8-hydroxymethyl-
2-Methyl-1-oxo-1,2,3,6,7,8-hexahydro-benzo(1,2-bB4.3-b')dipyrrole-2-carboxylate hydrochloride as pale yellow crystals (7
, 0■, 100χ).

NMR (DMSO-d,): δ near 79 (3B+
brs+N5-11+Ni-29)+7.20-7.6
0 (6H1, Cs-1f, -Ca11m), 3.40-
3.95 (5II+IIICv-28and-CB
CBgo-)+3-62(3B+s.

COtMe), 1.47 (3EI,s,Me).

Reference example 3.4.5-trimethoxybenzaldehyde (98fg
, 5w + 5ol) and methyl azidoacetate (2.30g, 2
A methanol solution (1.0M solution, 1.0M solution,
5.0 wL, 5.0-eal) and stirred overnight at room temperature. Ice water was added and the precipitated crystals were collected by filtration. After washing with water and drying, methyl 1-azido-2-(3,4,5-)
Rimethoxyphenyl)etheno-1-carboxylate was obtained as pale yellow crystals (502 µm, 34K). This product was immediately used for the next reaction.

NMR (CDCIs): δ: 7.10 (211
, s, Ar-El), 6.85 (111, s.

-CB-C), 3.29-3.93 (12B, s, 0
CHsX3 and COJe).

San, p, 100.5-101.5℃.

Elemental analysis: Calculated value as C+sH+JsOs: C, 5
3,24X, R, 5,16X; N, 14.33%.

Analysis value: C, 53, 58X; H, 5, IQX; N,
13.25X.

MS: ale: 293(M”), 256,20
6,160° Reference Example Methyl 1-azido-2-(3,4,5-)rimethoxyphenyl)etheno-2-carboxylate (293■,
1-ugly o1) was dissolved in xylene (5 ml) and heated at 150°C.
The mixture was added dropwise to xylene (5 ml) boiling at 500 ml and refluxed for 1 hour. The residue obtained by distilling off the solvent was subjected to column chromatography (silica gel: benzene: ethyl acetate - 15:1).
) and purified with methyl 5.6゜7-drimethoxy IH
-Indole-2-carboxylate as colorless crystals (25
0w, 94X).

This product was recrystallized from methanol to obtain an analytical sample.

mp, 106-107°C NMR (CDCIs): δ: 8.87 (10,
brs, Nu), 7.18 (18, d.

J-2, 3H! , C5-fl), 6.82 (IEI, s
, Co-[1), 4.07 (3Hs, 0CRs), 3.
929 (3H, s, 0CHs), 3.926 (3B, s
.

0CBs) 13.90 (3B, s, C00CBs).

MS; ale: Elemental analysis: Calculated value: Analytical value: 265 (M, 218,160°C + J + JOs as C, 58,861L II, 5.70X; C, 58,
95Xi B, 5.59X; N, 5°28x.

N, 5.19X.

Reference example Methyl 5.6.7-)rimethoxy IH-indole-2-carboxylate (50,2■, 0.2-of
) was added to a mixture of 40% potassium hydroxide aqueous solution (0.5 ml) and methanol (0.5 ml) and stirred at 50°C for 30 minutes. The mixture was neutralized with concentrated hydrochloric acid, and the precipitated crystals were collected by filtration. After washing with water and drying, 5,6.7-drimethoxy IH-
Colorless crystals of indole-2-carboxylic acid (45.5g,
96χ).

mp, 215.5-216℃ NFIR (DMSO-dh>: δ: 7.00(
IB, d, J-1,511z, C5-H) 6.91 (I
H,s, Co-tl), 3.89 (3F1.s, OMe
), 3.79 (3Rg, OMe), 3.77 (38,s
, OMe), 3.25 (28, brs, N1 (and
C0J).

MS; ale: 251 (M, 218.160° Elemental analysis: Calculated value as CoJ + 5OsN: C, 57,37X, B, 5.22X, N
, 5.58! .

Analysis value: C, 57, 21X, B, 5. IQX, N
, 5.43X.

OMe methyl(2R”,83”)-4-benzyloxy-8-
hydroxymethyl-2-methyl-1-oxo 1.2,
3.6,7.8-hexahydro-benzo(1,2-tz
4.3-b') Dissolve divirole-2-carboxylate hydrochloride (6,9*, 16μ5ol) in N,N-dimethyJreformamide (0,18ml), 5.6.7-)
Rimethoxy IH-indole-2-force J levon acid 4
．． 2■, 17 μ theory o1), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (9,6 curve, 50 μ theory o1), and sodium hydrogen carbonate (7,0 m
, 83μ5ol) and stirred at room temperature for 20 hours.
The reaction solution was diluted with ethyl acetate, washed with water, and then dried over anhydrous sodium sulfate. The residue obtained by distilling off the solvent was purified by preparative thin layer chromatography (silica gel: chloroform: acetone-4:l), and methyl (2R", 8S-4
-benzyloxy-8-hydroxymethyl-6 (5,6
,7-drimethoxylH-indole-2-carbonyl)-1,2,3,5,6,7-hexahydro-benzo(1,2-b,4.3-b') di-role-2-carboxylate was obtained as yellow caramethyl (5,8■, 57χ).

NMR (CDCIs): δ: 9.35 (I
H, brs, C'+4), 8.45 (IH.

s+C5-El), 7.36-7.5H5H1i++P
h-■), 6.95 (IH, sC;-El), 6.85
(11!, s, Cm-El), 5.25 (1B, a, c
s-H).

5.20 (2B, s, OCI [*Ph), 4.61 (I
B, t, J-9, 27) lz.

BCHOB), 4.48 (18,brd,d,J□10
．． 3Hz, IIC and 0FF) 4.07 (3B, s,
OMe), 3.942 (3H,s, 0CRs), 3.9
37 (311,s, OMe), 3.91 (311,s,
0CRs), 3.78 (3B, s.

CO*C11s), 3.86-4.38 (214, Ct
-L), 3.73-3.86 (IR, m, Cs-11)
, 2.52 (1B, brt, OB), 1.67 (3B
.

s, CRs).

MS; m8: 615(P), 525,49
4.382,291,234゜201.91゜Methyl (23", 83")-4-benzyloxy-8-
hydroxymethyl-2-methyl-1-oxo-1,2,
3,6,7,8-hexahydro-benzo(1,2-b:
4+ 3-b') Dipyrrole-2-carboxylate hydrochloride (7.0 yen, 17μ theory o1) was treated in the same manner as in Reference Example 9 to obtain methyl (2S”).

8S”)-4-benzyloxy-8-hydroxy-6-
(5,6,7-dorimethoxyIH-indole-2-
carbonyl'')-1,2,3,6,7°8-hexahydro-benzo(1,2-b;4.3-b')dipyrrole-2-carboxylate in yellow caramel (6,2■,6
2χ).

! fMR (CDCIs): δ: 9.40 (IB
, brs, C'+-1f), 8.45 (ill.

a, c--11), 7.35-7.54 (5B,
et al. L), 6.95 (111, d.

J-2,3B! , C5-H), 6.85 (IH,s,C
5-H), 5.28 (IFI.

s, C5-B), 5.21 (2■, s, PbCHlO)
, 4.61 (IB, t, J-9, 8Hz, 1lC110
11), 4.46 (111, dd, J-10, 4, 4,
OBx.

nc and 0 noise), (111, e+, Cs-11), 4.0
7 (3R,s, 0cB3).

3.88-4.02 (2111, ugly, Ct-DI), 3
．． 94 (3B, s, 0cH3).

3.91 (3B, s, 0CBs) + 3.7B - 3,86
(IH, w*, Cm-W).

3.77 (311,a, C00CEIs), 2.73
(111,brt,0tl), 1.69(3B,
s lCB 5cco).

Precedent 11 Methyl (2R”.

83")-4-benzyloxy-8-hydroxymethyl-6-(5,6,7-trimethoxy-IH-indole-2-carbonyl)-2-methyl-1-oxo-1,2,3,6° 7.8-Hexahydro-benzo (1,2-b.

4.3-b') Dipyrrole-2-carboxylene) (
3,4uw, 5.6+umol) in dichloromethane (0
, 6 Sono 1) and cooled with methanesulfonyl chloride (0
,7μ! .

8.4 μmol) and triethylamine (1,6 u j
, 11.2 μmof) was added dropwise and stirred for 30 minutes. 1
The mixture was washed successively with an aqueous χ sodium bicarbonate solution and saturated brine, dried over anhydrous sodium sulfate, and then the solvent was distilled off. The obtained residue was subjected to preparative thin layer chromatography (silica gel:
Purified with dichloromethane:ethyl acetate (7:2) to give methyl (2R”,83”)-4-benzyloxy-8-methanesulfonyloxymethyl-6-(5,6,7-)rimethoxyIH-indole-2 -carbonyl)-2-
Methyl-1-oxo-1,2,3,6,7,8-hexahydro-benzo(1,2-b,4.3-b') divirol-2-carboxylate in yellow caramel (3,8■,
99χ).

NMR (CDCIs): δ: 9.34 (IF
I, brs, C+'-[1), 8.43(1)1°a,
Cs-11), 7.36-7.52 (5El, m, CJ
s), 6.95 (18°d, J-2,3Hz, C5-B
), 6.87 (1B, s, C; -8), 5.25 (1B
, brs, C5-B), 5.21 (2El, s, PhC
BtO), 4.74 (IH, dd, J=10.0, 3.
4Hz, CHOMg), 4.56-4.68 (2HJ
, Cy-Hm), 4.46 (1B, dd, J-10,
0,8,0IlzEICLOMs)14.12-4.2
1 (1B, m, Ct-B), 4.08 (3El.

a, 0CRs), 3.94 (311,s, 0cJ)
, 3.92 (31(,s,0CRs).

3.78 (31+, s, C00CHs), 2.97 (3
R,s, 5OiCFls), 1.67(3H,s, C
BsCC0).

MS: */e: 693 (M″), 597,506
,364,303,234.91゜Reference Example 2 Methyl (2S'', 83'')-4-benzyloxy-8-
Hydroxymethyl-6-(5,6,7-drimethoxyIH-indole-2-carbonyl)-2-methyl-1
-oxo-1,2,3,6°7.8-hexahydro-benzo(1,2-b.

4.3-b') Dipyrrole-2-carboxylate (6
.
7-) RimethoxyIH-indole-2-carbonyl)-1,2,3,6,7,8-hexahydro-benzo(
1,2-b; 4,3-b'] divirole-2-carboxylate was obtained as a yellow caramel (6,9, 992).

NMR (CDCIs): δ: 9.35 (IHlb
rs, Cm-H), 8.42 (1B.

s, ci-B), 7.35-7.53 (5B, m, CJ
s), 6.95 (Ill.

d, J-2,3Hz, C5-El)+6.87(ill
, s, Cm-) 1) + 5.21 (2H, s, PhCBt
O), 4.80 (1B, dd, J・9.9.3.4EI
z11c110MS) 14.57-4.67 (2fl,
Peng, Cy-fls), 4.39 (II(.

dd, JP9.8, 8.6FIz, HCE101'ls
), 4.12-4.19 (IH, m.

Cm-H), 4.07 (3B, s, 0CRs), 3.9
4 (3El, s, 0CHs).

3.91 (3H, s, OCl [s), 3.77 (3H,
s, C00CRs), 3.03 (3H, s, 5OsC1
1s), 1.68 (3B, s, CBsCC0), 1.6
5 (IH.

brs+Cs-11).

MS: m/e: 693 (M, 597.538,
506.364,303,234゜91゜Reference Example 3 Methyl (2R", 85")-4-benzyloxy-8-
Methanesulfonyloxymethyl-6-(5,6,7-)
Rimethoxy IH-indole-2-carbonyl)-2
-Methyl-1-oxo-1,2,3,6,7,8-hexahydro-benzo(1,2-b;4,3-b')dipyrrole-2-carboxylate (3,8■, 5.4μmo
Dissolve 1) in tetrahydrofuran (0.5 μl) and add 1
Hydrogenation was carried out under a hydrogen pressure of 1 atmosphere in the presence of 0x palladium on carbon (2■). After the catalyst was filtered off, the solvent was distilled off and the resulting residue was purified by preparative thin layer chromatography (silica gel: chloroform; acetone-2=1) to give methyl (2R'').

$3”)-4-hydroxy-8-methanesulfonyloxymethyl-6-(5,6,7-)rimethoxyIH-indole-2-carbonyl)-2-methyl-1-oxo-1,2,3, 6,7,8-hexahydro-benzo(1
, 2-b; 4,3-b') Novirol-2-carboxylate was obtained as yellow crystals.

1BMR (CDCIs): δ: 9.50 (IB,
brs, (:+-11), 9.30 (1■ bra C5
-El), 8.46 (1B, s, C5-H), 6.99
(1B, d.

J-2,3■z,cs-11), 6.85(IH,s,
C knee H), 4.74 (IH.

dd, J-10,0,3,4Hz4C110,Ms),
4.56-4.67 (2H.

m, ct-Bm), 4.46 (IB, dd, J-10,
0,8,0Hz,EICdanOMg).

4.10-4.19 (ILm, Co-E[)+4.13
(3B+s, 0C1ls).

3.95 (3B, s, OCl [1s), 3.91 (31
1,a,0CHs) ,3.77(38s,C00C1
1s), 2.97 (311,s, 5OxCHs), 1.
68 (3B, s.

Reference example 4 Methyl (23”, 83”)-4-benzyloxy-8-
Methanesulfonyloxymethyl-6-(6,7,8-)
RimethoxyIH-indole=2-carbonyl)-2
-Methyl-1-oxo 1.2,3.6,7.8-hexahydro-benzo(1,2-b,4.3-b') novirol-2-carboxylate (6,9*, 9.9 μmol
) was treated in the same manner as in Reference Example 13, and methyl (23”
, 83”)-4-hydroxy-8-methanesulfonyloxymethyl-6-(5,6,7-1rimethoxy-IH-
indole-2-carbonyl)-2-methyl-1-oxo-1,2,3,6,7,8-hexahydro-benzo(
1,2-bi4.3-b') divirole-2-carboxylate as yellow crystals (5,0.

83χ).

NMR (CDCIs): δ: 9.52 (111,
brs, C'+-H), 8.52 (IH.

brs, CB-■), 6.99 (LH, d, J-2, 3
11z, C5-El), 6.85 (1B, a, Co-E
), 4.79 (IN, dd, J-10,0,3,5Hz
.

BCHOMs) +4-56-4.65 (2tl9m, C
y-Et)+4.39(IB.

■, HC Dan QMs), 4.14 (311,s, 0C11
s), 3.96 (311, s.

o'c■s), 3.91 (3EI, s, 0CRs) +3
．． 74 (3H, s, C00Ctl.

3.03 (311,a, 5QsCtls), 1.
69 (3tl, a, cHsccQ).

MS: m/e: 603 (!'!'), 507,44
8,368,313,213° Reference Example 15 Methyl (2R”, BS”)-4-hydroxy-8-methanesulfonyloxymethyl-6-(5°6.7-)rimethoxyIH-indole-2-carbonyl) -2-Methyl-1-oxo-1,23,6,7,8-hexahydro-benzo[1,2bi4,3-b')dipyrrole-2
-Dissolve carboxylate (2,8 mol, 4.6 μmol) in tetrahydrofuran (1,5 ml) and add sodium hydride (5oz oil version) (0,8w
, 20 usol) and stirred at room temperature for 3.5 hours.
The reaction solution was diluted with ethyl acetate and washed successively with 0.5M aqueous potassium dihydrogen phosphate solution and saturated brine. After drying over anhydrous sodium sulfate, the solvent was distilled off. The resulting residue was purified by column chromatography (alumina:chloroform:acetone - 5:1) to obtain a-duocarmycin A as pale yellow crystals (1.4 cm, 60 x).

Nl'1R (CDC1s): δ: 9.23 (IR,
brs, 1'-NB), 7.17 (IFI, a,
lt-11)+6.94(11,d, J-2,3Hz,
C'5-B).

6.78 (IHla, Ca4) + 6.01 (IH+s,
1-NH), 4.37-4.48 (2H, plow + C5-L
), 4.08 (3H, s + 0CHs), 3.94 (3 days, s, 0C)ls), 3.89 (3)l,s, 0CHs
), 3.75 (30131COtCBs), 3.03-
3.09 (IR1s+, Caa-B), 2.25 (IE
Idd, J-4, 0+7.6Hz, Ca-■), 1.2
5-1.32 (111, m.

C, - ■), 1.67 (3tl, s, 2-CI(s).

This NMR spectrum completely matched that of the standard (+)-duocarmycin A (Natural Organic Compounds Forum, Fukuoka, Tsu, Abstracts p300).

MS: m/e: 507 (M”), 448,274,
234° Reference Example 16 Methyl (2S”.

8S”) 4-hydroxy-8-methanesulfonyloxymethyl-6-(5°6.7
-) Rimethoxy IH-indole-2-carbonyl)
-2-methyl-1-oxo-1,2゜3.6.7.8-
hexahydro-benzo[1,2-b,4.3-b') divirol-2-carboxylene) (6,0■, 9.9
μ5ol) was treated in the same manner as Reference Example 15, and dl
-2-evideocarmycin A as pale yellow crystals (2,4
■, 561).

NMR (CDCIs): δ: 9-21 (18,
bra, 1′-Nu), 7.16(111,s,
cy-H), 6.94 (111, d, J・2.3Hz,
C', -■).

6.78 (111, a, C'e-8) + 6.01 (11
1, s, 1-N11) + 4.38-4.47 (211,
嘗、CsCs-1l+4.08(3B、a、0CBs)
, 3.94 (3H1s, 0CHs), 3.89 (3B,
s, 0CBs), 3.78 (3B, s.

C05CBs), 3.06-3.11 (11,m,
Ca-B), 2.23 (IFI.

dd, J-3,9,7,6Hz, CeJLl, 27(I
O, m, Ca-11) + 1.65 (31, s, 2-CH
s).

NS: m/e: 507 (M"), 448, 27
4,234゜Procedure Principal Ho Seisho Hat) In March 1991, Toshiaki Ueda, Commissioner of the Japanese Patent Office, 1, Display of the Case, Patent Application No. 159828, 1990, Name of the Invention, Alkoxycarbonyl-2-methyloxohexahydro Person making the amendment Relationship to the case Patent applicant Postal code 00 Contents of the amendment (1) "Low polarity" on page 77, line 12 of the specification of the present application is corrected to "high polarity."

(2) In the first line of page 78 of the same specification, "large" is corrected to "f small."

(3) Structural formula % Formula % on the right of page 79, line 8 of the same specification (4) The structural formula “ "of jnt133゜ (5) 3rd line from the bottom of page 86 of the same specification Structural formula on the left %formula% (6) The structural formula on the left on page 89, line 2 of the same specification is “ "of (Mi′T=18° Below Up

Claims (4)

[Claims] (1) General formula ▲ Numerical formula, chemical formula, table, etc. ▼ (In the formula, R^1 is a hydrogen atom or a linear or branched lower alkyl group having 1 to 6 carbon atoms, R^2 and R^4 2-alkoxycarbonyl-2, each independently representing a hydrogen atom or the same or different protecting group for an amino group, and R^3 and R^5 each independently representing a hydrogen atom or a protecting group for the same or different hydroxyl group. -methyl-1-oxo-1,2
,3,6,7,8-hexahydro-benzo[1,2-b
;4,3-b']dipyrrole derivative. (2) In the compound described in item (1), the 2nd position is (
R^*)-configuration and the 8th position is the (S^*)-configuration, or the 2nd position is the (S^*)-configuration and the 8th position is the (S^*)-configuration, 2-alkoxycarbonyl-2- Methyl-1-oxo-1,2,3,6,7,8-hexahydro-benzo[1,2-b;4,3-b']dipyrrole derivative. (3) General formula ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ (In the formula, R^3 and R^9 are each independently a hydrogen atom or the same or different hydroxyl group protecting group, and R^6 is a hydrogen atom or the number of carbon atoms. 4-alkoxycarbonyl represented by 1 to 6 linear or branched lower alkyl groups, R^7 is an unsubstituted or substituted amino group, and R^8 is a hydrogen atom or a protecting group for the amino group. -2,3-dihydro-1H-indole derivative. (4) General formula ▲ Numerical formula, chemical formula, table, etc. ▼ (In the formula, R^8 is a hydrogen atom or a protecting group for an amino group, R^
3 and R^1^0 each independently represent a hydrogen atom or the same or different hydroxyl group-protecting group. ) 1,2-
Dioxo-1,2,3,6,7,8-hexahydro-benzo[1,2-b;4,3-b']dipyrrole derivative.