JPH0948778A - 2-substituted-3-alkoxy-5-(pyrrol-2-yl)furan derivative - Google Patents

Abstract

PROBLEM TO BE SOLVED: To obtain the subject new compound having a specific chemical structure, exhibiting strong cytotoxicity and expected to be useful as a carcinostatic agent. SOLUTION: This compound is expressed by formula I R<1> is H, a group of formula: SO2 R<3> [R<3> is a 1-5C (branched)alkyl, a (substituted) aralkyl, a (substituted) aryl], a group of formula: CO2 R<4> (R<4> is R<3> ); R<2> is R<3> ; X is a halogen; A is a group of formula II (n is 0-3), a group of formula III, etc.,}, e.g. 5-(3-chloro-2-pyrrolyl)-2-(cyclohexylhydroxylmethyl)-3-methoxyfuran. The compound of formula I wherein R<1> is H, and A is a group of formula II is obtained by removing an amino-protecting group from a compound of formula IV, and subsequently reacting the reaction product with a compound of formula V without isolating the reaction product.

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention exhibits a novel cytotoxicity and is expected to be used as an anticancer agent.
It relates to 3-alkoxy-5- (pyrrol-2-yl) furan derivatives.

[0002]

2. Description of the Related Art There is a strong demand from society for the development of excellent anticancer agents, and the creation of new compounds having strong cytotoxicity occupies a very important position in the development of excellent anticancer agents. In general, the antitumor activity and antitumor spectrum of a compound largely depend on its chemical structure, and therefore, from a cytotoxic compound having a novel structure different from the known one,
There is a great possibility that an anticancer drug having characteristics superior to those currently put to practical use will be developed.

[0003]

The object of the present invention is to create a new anticancer agent having a novel chemical structure and having strong cytotoxicity.

[0004]

Means for Solving the Problems As a result of intensive investigations by the present inventors, the following general formulas [I] and [II] were identified as compounds having a novel chemical structure and having strong cytotoxicity.
The present invention was completed by finding a 2-substituted-3-alkoxy-5- (pyrrol-2-yl) furan derivative represented by

That is, the present invention has the following general formula

[0006]

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[In the formula, R ¹ is a hydrogen atom or a group represented by SO ₂ R ³ or CO ₂ R ⁴ (provided that R ³ and R ⁴ are each linear or branched having 1 to 5 carbon atoms) An alkyl group, a substituted or unsubstituted aralkyl group, or a substituted or unsubstituted aryl group), R ² is a linear or branched alkyl group having 1 to 5 carbon atoms, a substituted or unsubstituted Represents an aralkyl group or a substituted or unsubstituted aryl group, and X represents a halogen atom. A is the following general formula

[0008]

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(Wherein n represents an integer of 0 to 3) or the following general formula

[0010]

[Chemical 12]

(Wherein n represents an integer of 0 to 3) or the following general formula

[0012]

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(Wherein n represents an integer of 0 to 3) or the following general formula

[0014]

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(In the formula, R ⁵ is a hydrogen atom or a group represented by SO ₂ R ⁶ or CO ₂ R ⁷ (provided that R ⁶ and R ⁷ are each linear or branched having 1 to 5 carbon atoms). An alkyl group, a substituted or unsubstituted aralkyl group, or a substituted or unsubstituted aryl group)), or the following general formula

[0016]

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(Wherein R ⁵ is as defined above), or a 2-substituted-3-alkoxy-5- (pyrrol-2-yl) furan derivative represented by the formula:

[0018]

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[In the formula, R ² represents a linear or branched alkyl group having 1 to 5 carbon atoms, a substituted or unsubstituted aralkyl group, or a substituted or unsubstituted aryl group,
X represents a halogen atom. A is below

[0020]

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1- (2H-pyrrole-2-ylidene) ethyl group represented by:

[0022]

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2,6-dihydro-4H-indol-7-yl group represented by: 2-substituted-3-alkoxy-5- (pyrrol-2-yl) furan derivative represented by: To provide an acceptable salt.

[0024]

BEST MODE FOR CARRYING OUT THE INVENTION The above-mentioned compounds [I] and [II]
The substituents R ² , R ³ , R ⁴ , R ⁶ and R ⁷ are alkyl such as methyl group, ethyl group, propyl group, isopropyl group, butyl group, sec-butyl group, tert-butyl group and pentyl group. Groups, phenylmethyl groups, phenylethyl groups, aralkyl groups such as naphthylmethyl groups, phenyl groups, naphthyl groups, aryl groups such as pyridyl groups,
These aralkyl groups and aryl groups are nitro groups,
It may be substituted with a lower alkyl group, a halogen atom, a lower alkoxy group or the like. Therefore, as the substituted aryl group, p-chlorophenyl group, p-methoxyphenyl group, p-nitrophenyl group, p-tolyl group, 2,5-
Dichlorophenyl group, 2,4-dimethylphenyl group,
2,4-dinitrophenyl group, 2-mesityryl group, 4-
Examples thereof include a tert-butylphenyl group and 2,4,6-triisopropylphenyl group, and examples of the substituted aralkyl group include lower alkyl groups substituted with these substituted aryl groups. The lower alkyl group is, for example, a linear or branched alkyl group having 1 to 5 carbon atoms, and specific examples thereof include the above alkyl groups. Moreover, as the halogen atom represented by X, a chlorine atom, a bromine atom, or an iodine atom is particularly exemplified.

The 2-substituted-3-alkoxy-5- (pyrrol-2-yl) furan derivatives represented by the above general formulas [I] and [II] can be produced by the following synthetic steps.

[0026]

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[0027]

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[0028]

[Chemical 21]

[0029]

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[In the formula, n represents an integer of 0 to 3, R ² ,
R ³ and R ⁴ each represent a linear or branched alkyl group having 1 to 5 carbon atoms, a substituted or unsubstituted aralkyl group, or a substituted or unsubstituted aryl group, R 3
⁵ is a group represented by SO ₂ R ⁶ or CO ₂ R ⁷ (provided that R ⁶
And R ⁷ each represents a linear or branched alkyl group having 1 to 5 carbon atoms, a substituted or unsubstituted aralkyl group, or a substituted or unsubstituted aryl group),
X represents a halogen atom]

First Step In this step, a sulfonyl group which is a protecting group for an amino group of a 3-alkoxy-5- (pyrrol-2-yl) furan derivative represented by the general formula [III] (see Reference Example) is added. Removed,
The resulting 3-alkoxy-5 represented by the general formula [IV]
-(Pyrrol-2-yl) furan derivative (see Reference Example)
Is reacted with an aldehyde represented by the general formula [V] without isolation to give a 2-substituted-3-alkoxy-5- (pyrrole-2 represented by the general formula [Ia] which is a compound of the present invention.
-Yl) to produce a furan derivative.

Removal of the sulfonyl group is the condition usually applied [T. W. Greene and P.P. G. FIG. M. Wut
s, "Protective groups in O
organic Synthesis ”, 2nd E
d. , Wiley Interscience Pub
license, John-Wiley & Son
s, New York, 1991, pp315-40
5] and the reaction with the aldehyde proceeds smoothly under the same conditions.

Step 2 In this step, the amino group of pyrrole of the 2-substituted-3-alkoxy-5- (pyrrol-2-yl) furan derivative represented by the general formula [Ia] is alkyloxycarbonylated to form It is intended to produce a 2-substituted-3-alkoxy-5- (pyrrol-2-yl) furan derivative represented by the general formula [Ib] which is a compound of the invention.

Alkyloxycarbonylation is carried out by methyl chloroformate, ethyl chloroformate, vinyl chloroformate, propyl chloroformate, isopropyl chloroformate, chloroformate 2
-Propenyl, butyl chloroformate, isobutyl chloroformate, phenylethyl chloroformate, 2,2,2 chloroformate
-Trichloroethyl, 2-trimethylsilylethyl chloroformate, cinnamyl chloroformate, cinnamyloxycarbonyloxybenzotriazoyl, 4-nitrocinnamyl chloroformate, phenyl chloroformate, benzyl chloroformate,
P-Methoxybenzyl chloroformate, p-nitrobenzyl chloroformate, di-tert-butyl dicarbonate, 2
-(Tert-Butoxycarbonyloxyimino) -2-
It is carried out using an alkyloxycarbonylating agent such as phenylacetonitrile, 9-fluorenylmethyl chloride, 1-benzotriazoyl 9-fluorenylmethylcarbamate.

The reaction may be carried out in the presence of a base.
Examples of the coexisting base include triethylamine, ethyldiisopropylamine, pyridine, piperidine, pyrrolidine, imidazole, 4- (dimethylamino) pyridine,
N, N-diethylaniline, 1,5-diazabicyclo [4.3.0] non-5-ene, 1,4-diazabicyclo [2.2.2] octane, 1,8-diazabicyclo [5.4.0] ] Undec-7-ene, potassium carbonate, sodium carbonate, sodium hydrogen carbonate, potassium hydroxide,
Sodium hydroxide or the like is used.

The reaction is usually carried out in a solvent, and any solvent which does not participate in the reaction can be used, but hydrocarbon solvents such as pentane, hexane, cyclohexane, benzene, toluene and xylene, Halogenated hydrocarbon solvents such as dichloromethane, 1,2-dichloroethane, chloroform and carbon tetrachloride,
Ether-type solvents such as diethyl ether, diisopropyl ether, tetrahydrofuran, 1,4-dioxane, methanol, ethanol, 1-propanol, 2-
Propanol, 1-butanol, 2-butanol, 2-
Methyl-1-propanol, alcohol solvents such as 2-methyl-2-propanol, acetonitrile, propionitrile, acetone, nitromethane, nitroethane,
An aprotic polar solvent such as N, N-dimethylformamide or dimethylsulfoxide is used. When the base is a liquid, the base can also be used as a solvent.
The reaction proceeds smoothly at -50 ° C to 50 ° C.

Third Step In this step, the hydroxyl group of the 2-substituted-3-alkoxy-5- (pyrrol-2-yl) furan derivative represented by the general formula [Ib] is sulfonylated and, at the same time, the sulfonate formed is removed. 2-substituted-3-alkoxy-5- (pyrrole-, represented by the general formula [Ic], which is a compound of the present invention.
2-yl) furan derivative is produced.

Sulfonylation is carried out by methanesulfonyl chloride, ethanesulfonyl chloride, 1-propanesulfonyl chloride, isopropylsulfonyl chloride, 1-butanesulfonyl chloride, benzenesulfonyl chloride, p-chlorobenzenesulfonyl chloride, p-methoxybenzenesulfonyl chloride, p-nitrobenzene. Sulfonyl chloride, α-toluenesulfonyl chloride, p-toluenesulfonyl chloride, 2,5-dichlorobenzenesulfonyl chloride, 2,4-dimethylbenzenesulfonyl chloride, 2,4-dinitrobenzenesulfonyl chloride, 2-nitro-α-toluenesulfonyl Chloride, 2-mesitylene sulfonyl chloride, 4-
tert-butylbenzenesulfonyl chloride, 2,
It is carried out using a sulfonylating agent such as 4,6-triisopropylbenzenesulfonyl chloride, methanesulfonic anhydride, p-toluenesulfonic anhydride.

The reaction is carried out in the presence of a base, and as the base, triethylamine, ethyldiisopropylamine, pyridine, 4- (dimethylamino) pyridine, N, N-diethylaniline, 1,5-diazabicyclo [4.3.
0] non-5-ene, 1,4-diazabicyclo [2.
2.2] Octane, 1,8-diazabicyclo [5.4.
0] Undeca-7-ene or the like is used.

The reaction is usually carried out in a solvent, and any solvent that does not participate in the reaction can be used, but hydrocarbon solvents such as pentane, hexane, cyclohexane, benzene, toluene and xylene, Halogenated hydrocarbon solvents such as dichloromethane, 1,2-dichloroethane, chloroform and carbon tetrachloride,
An ether solvent such as diethyl ether, diisopropyl ether, tetrahydrofuran, 1,4-dioxane, or acetonitrile is preferably used. When pyridine is used as the base, pyridine can also be used as a solvent. The reaction is from -20 ° C to 50
Proceed smoothly at ℃.

Fourth Step In this step, a 2-substituted-3-alkoxy-5- (pyrrol-2-yl) furan derivative represented by the general formula [Ic] is alkyloxycarbonyl which is a protecting group for the amino group of pyrrole. The group is removed to give a compound of the invention of the general formula [Id]
A 2-substituted-3-alkoxy-5- (pyrrol-2-yl) furan derivative represented by

Removal of the protecting group is subject to conditions normally applied to the protecting group used [T. W. Greene and
P. G. FIG. M. Wuts, "Protective gr
oops in Organic Synthesi
s ", 2nd Ed., Wiley Intersci
ence Publication, John-Wil
ey & Sons, New York, 1991, p
p315-405].

Fifth Step This step was produced by removing the sulfonyl group, which is a protecting group for the amino group of the 3-alkoxy-5- (pyrrol-2-yl) furan derivative represented by the general formula [III]. 3-alkoxy-5- (pyrrole-represented by the general formula [IV]
The 2-yl) furan derivative can be isolated by the general formula [V
II] is condensed with a ketone represented by the formula [II] to produce a 2-substituted-3-alkoxy-5- (pyrrol-2-yl) furan derivative represented by the general formula [Ie] of the present invention. is there.

Removal of the sulfonyl group is the condition usually applied [T. W. Greene and P.P. G. FIG. M. Wut
s, "Protective groups in O
organic Synthesis ”, 2nd E
d. , Wiley Interscience Pub
license, John-Wiley & Son
s, New York, 1991, pp315-40
5] and the reaction with the ketone proceeds smoothly under the same conditions.

Sixth Step In this step, a 3-alkoxy-5- (pyrrol-2-yl) furan derivative represented by the general formula [III] and a 2-acetylpyrrole derivative represented by the general formula [VIII] are prepared. The 2-substituted-3 represented by the general formula [If], which is a compound of the present invention, is condensed with trimethyl orthoformate in the presence of an acid.
-Alkoxy-5- (pyrrol-2-yl) furan derivative.

Acids used include hydrogen fluoride, hydrogen chloride, hydrogen bromide, hydrogen iodide, chloric acid, bromic acid, perchloric acid, periodic acid, nitric acid, sulfuric acid, phosphoric acid, boric acid, trifluoride. Inorganic acids such as boron, or acetic acid, trifluoroacetic acid, formic acid, benzoic acid, citric acid, tartaric acid, malic acid, camphorsulfonic acid, methanesulfonic acid, trifluoromethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, An organic acid such as pyridinium p-toluenesulfonate is used, and camphorsulfonic acid is preferably used.

The reaction is usually carried out in a solvent, and any solvent which does not participate in the reaction can be used, but hydrocarbon solvents such as pentane, hexane, cyclohexane, benzene, toluene and xylene, Halogenated hydrocarbon solvents such as dichloromethane, 1,2-dichloroethane, chloroform and carbon tetrachloride,
Ether-type solvents such as diethyl ether, diisopropyl ether, tetrahydrofuran, 1,4-dioxane, methanol, ethanol, 1-propanol, 2-
Propanol, 1-butanol, 2-butanol, 2-
Methyl-1-propanol, alcohol solvents such as 2-methyl-2-propanol, acetonitrile, propionitrile, acetone, nitromethane, nitroethane,
An aprotic polar solvent such as N, N-dimethylformamide or dimethylsulfoxide is used, and preferably methanol is used. In addition, trimethyl orthoformate can also be used as a solvent. The reaction proceeds smoothly at -50 ° C to 50 ° C.

Seventh Step In this step, the protecting group for the amino group of one pyrrole of the 2-substituted-3-alkoxy-5- (pyrrol-2-yl) furan derivative represented by the general formula [If] is removed. 2-substituted-3-, represented by the general formula [Ig], which is a compound of the present invention.
It is intended to produce an alkoxy-5- (pyrrol-2-yl) furan derivative.

Removal of the protecting group is subject to conditions normally applied to the protecting group used [T. W. Greene and P.M.
G. FIG. M. Wuts, "Protective group
psin Organic Synthesis ”, 2
nd Ed. , WileyInterscience
Publication, John-Wiley & S
ons, New York, 1991, pp315-4
05].

Eighth Step This step is a protecting group for the amino group of one pyrrole of the 2-substituted-3-alkoxy-5- (pyrrol-2-yl) furan derivative represented by the general formula [If]. The sulfonyl group is removed, and 2-substituted-3-alkoxy-5- (pyrrole-2-one represented by the general formula [Ih], which is a compound of the present invention, is removed.
Il) to produce a furan derivative.

Removal of the sulfonyl group is the condition usually applied [T. W. Greene and P.P. G. FIG. M. Wut
s, "Protective groups in O
organic Synthesis ”, 2nd E
d. , Wiley Interscience Pub
license, John-Wiley & Son
s, New York, 1991, pp315-40
5].

Ninth Step In this step, the protecting group of pyrrole of the 2-substituted-3-alkoxy-5- (pyrrol-2-yl) furan derivative represented by the general formula [Ih] is removed to obtain the compound of the present invention. 2-Substituted-3-alkoxy-5 represented by the general formula [IIa], which is a compound
A-(pyrrol-2-yl) furan derivative or a salt thereof is produced.

Removal of the protecting group is a condition commonly applied to the protecting group used [T. W. Greene and P.M.
G. FIG. M. Wuts, "Protective group
psin Organic Synthesis ”, 2
nd Ed. , WileyInterscience
Publication, John-Wiley & S
ons, New York, 1991, pp315-4
05].

Step 10 In this step, the 3-alkoxy-5- (pyrrol-2-yl) furan derivative represented by the general formula [III] and the tetrahydroindole derivative represented by the general formula [IX] are treated with orthoformic acid. 2-Substitution-3-3 represented by the general formula [Ii], which is a compound of the present invention, by condensation with trimethyl in the presence of an acid.
It is intended to produce an alkoxy-5- (pyrrol-2-yl) furan derivative.

Acids used include hydrogen fluoride, hydrogen chloride, hydrogen bromide, hydrogen iodide, chloric acid, bromic acid, perchloric acid, periodic acid, nitric acid, sulfuric acid, phosphoric acid, boric acid, trifluoride. Inorganic acids such as boron, or acetic acid, trifluoroacetic acid, formic acid, benzoic acid, citric acid, tartaric acid, malic acid, camphorsulfonic acid, methanesulfonic acid, trifluoromethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, An organic acid such as pyridinium p-toluenesulfonate is used, and camphorsulfonic acid is preferably used.

The reaction is usually carried out in a solvent, and any solvent which does not participate in the reaction can be used, but hydrocarbon solvents such as pentane, hexane, cyclohexane, benzene, toluene and xylene, Halogenated hydrocarbon solvents such as dichloromethane, 1,2-dichloroethane, chloroform and carbon tetrachloride,
Ether-type solvents such as diethyl ether, diisopropyl ether, tetrahydrofuran, 1,4-dioxane, methanol, ethanol, 1-propanol, 2-
Propanol, 1-butanol, 2-butanol, 2-
Methyl-1-propanol, alcohol solvents such as 2-methyl-2-propanol, acetonitrile, propionitrile, acetone, nitromethane, nitroethane,
An aprotic polar solvent such as N, N-dimethylformamide or dimethylsulfoxide is used, and preferably methanol is used. In addition, trimethyl orthoformate can also be used as a solvent. The reaction proceeds smoothly at -50 ° C to 50 ° C.

Eleventh step In this step, the protecting group for the amino group of dihydroindole of the 2-substituted-3-alkoxy-5- (pyrrol-2-yl) furan derivative represented by the general formula [Ii] is removed. A 2-substituted- represented by the general formula [Ij], which is a compound of the present invention:
A 3-alkoxy-5- (pyrrol-2-yl) furan derivative is produced.

Removal of the protecting group is subject to conditions normally applied to the protecting group used [T. W. Greene and P.M.
G. FIG. M. Wuts, "Protective group
psin Organic Synthesis ”, 2
nd Ed. , WileyInterscience
Publication, John-Wiley & S
ons, New York, 1991, pp315-4
05].

Twelfth Step This step is a sulfonyl group which is a protecting group for the amino group of the pyrrole of the 2-substituted-3-alkoxy-5- (pyrrol-2-yl) furan derivative represented by the general formula [Ii]. And is represented by the formula [Ik] which is a compound of the present invention.
-Substituted-3-alkoxy-5- (pyrrol-2-yl)
A furan derivative is produced.

Removal of the sulfonyl group is the condition usually applied [T. W. Greene and P.P. G. FIG. M. Wut
s, "Protective groups in O
organic Synthesis ”, 2nd E
d. , Wiley Interscience Pub
license, John-Wiley & Son
s, New York, 1991, pp315-40
5].

Thirteenth Step In this step, the protecting group for the amino group of dihydroindole of the 2-substituted-3-alkoxy-5- (pyrrol-2-yl) furan derivative represented by the general formula [Ik] is removed. , A 2-substituted-3-alkoxy-5- (pyrrol-2-yl) furan derivative represented by the general formula [IIb], which is a compound of the present invention, or a salt thereof.

Removal of the protecting group is subject to conditions normally applied to the protecting group used [T. W. Greene and P.M.
G. FIG. M. Wuts, "Protective group
psin Organic Synthesis ”, 2
nd Ed. , WileyInterscience
Publication, John-Wiley & S
ons, New York, 1991, pp315-4
05].

When the compound of the present invention is used as an anticancer agent, the compound of the present invention is also used as a pharmaceutically acceptable salt. Typical examples of pharmaceutically acceptable salts include salts with inorganic acids such as carbonic acid, phosphoric acid, hydrochloric acid, sulfuric acid, acetic acid,
Examples thereof include salts with organic acids such as propionic acid, fumaric acid, citric acid, trifluoroacetic acid, paratoluenesulfonic acid and trifluoromethanesulfonic acid.

The 2-substituted-3-alkoxy-5- (pyrrol-2-yl) furan derivatives represented by the above general formulas [I] and [II], obtained as described above, inhibit the growth of malignant tumor cells. An activity test was carried out and it was confirmed that these compounds showed strong cytotoxicity and had use as anticancer agents.

Hereinafter, the present invention will be described in detail with reference to Reference Examples, Examples and Test Examples, but the present invention is not limited thereto.

[0066]

【Example】

 Reference example 1

[0067]

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Reference [F. Bel
lamy and J. Street J. Che
m. Res. (S) 18 (1979) and J. Che
m. Res. (M) 0101 (1979)], a mixture of 3-chloro-2-formylpyrrole (130 mg, 1.00 mmol) and triethylamine (0.42 mL, 3.0 mmol) in acetonitrile (10 mL) was added with p chloride. -Toluenesulfonyl (28
7 mg, 1.50 mmol) was added and the mixture was stirred at room temperature for 20 hours. The reaction mixture is poured into saturated saline and the mixture is washed with ether.
Extracted times. The organic layers were collected, dried over magnesium sulfate, and then concentrated with an evaporator. The residue was subjected to silica gel thin layer chromatography (hexane / ethyl acetate 9: 1-4:
1-) and purified by 3-chloro-2-formyl-1-p-toluenesulfonylpyrrole (278 mg, 0.979 m
mol) was obtained with a yield of 98%.

TLC R _f 0.33 (hexane / ethyl acetate 4: 1). Melting point 74-75 [deg.] C. ¹ H NMR spectrum (200 MHz, CDCl ₃ ) δ
2.43 (s, 3H), 6.39 (d, J = 3.3H
z, 1H), 7.34 (br d, J = 8.1 Hz, 2
H), 7.68 (d, J = 3.2 Hz, 1H), 7.8
6 (br d, J = 8.4 Hz, 2H), 9.89
(S, 1H). IR spectrum (neat) 3430 (br,
m), 2920 (m), 1720 (s), 1680
(S), 1380 (s), 1175 (s), 1120
(W), 1035 (m), 810 (m), 665 (m)
cm ^-1 . Low resolution MS m / e (relative ratio) 285 (M,
1), 283 (M, 2), 221 (4), 219 (1
1), 155 (31), 91 (100). Elemental analysis (C ₁₂ H ₁₀ ClNO ₃ S) calculated: C;
50.80, H; 3.55, N; 4.94, S; 11.
30, Cl; 12.50, found: C; 50.8
0, H; 3.35, N; 4.98, S; 11.15, C
1; 12.50.

Reference Example 2

[0071]

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3-chloro-at -78 ° C in an argon stream.
2-Formyl-1-p-toluenesulfonylpyrrole (709 mg, 2.50 mmol) in THF (25 m
L) To the solution was added a 3.0 M solution of methylmagnesium bromide in ethyl ether (1.00 mL, 3.0 mmol)-
The mixture was stirred at 78 ° C. for 2 hours and at room temperature for 16 hours. The reaction mixture was poured into saturated ammonium chloride water and extracted with ether three times. The organic layers were collected, dried over magnesium sulfate, and then concentrated with an evaporator. The residue was flash chromatographed on silica gel (hexane / ethyl acetate 9:
1) and purified by 3-chloro-2- (1-hydroxyethyl) -1-p-toluenesulfonylpyrrole (632m
g, 2.11 mmol) was obtained with a yield of 84%.

TLC R _f 0.49 (hexane / ethyl acetate 4: 1). ¹ H NMR spectrum (200 MHz, CDCl ₃ ) δ
1.56 (d, J = 6.7 Hz, 3H), 2.42
(S, 3H), 2.74 (d, J = 8.4Hz, 1
H), 5.28 (dq, Jd = 8.3, Jq = 6.8H
z, 1H), 6.21 (d, J = 3.5Hz, 1H),
7.20 (d, J = 3.5 Hz, 1H), 7.32
(D, J = 8.1 Hz, 2H), 7.69 (d, J =
8.5 Hz, 2H). IR spectrum (neat) 3555 (w), 34
30 (br w), 3154 (w), 2978 (w),
2932 (w), 1582 (m), 1370 (s), 1
208 (m), 1177 (vs), 1138 (m), 1
086 (m), 1034 (w), 999 (w), 920
(Br w), 814 (w), 714 (m), 673
(S) cm ^-1 . Low resolution MS m / e (relative ratio) 301 (M,
3), 299 (M, 10), 286 (9), 284 (2
4), 291 (6), 155 (29), 128 (3
3), 91 (100).

Reference Example 3

[0075]

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3-chloro-2- at room temperature in an argon stream.
A solution of (1-hydroxyethyl) -1-p-toluenesulfonylpyrrole (116 mg, 0.386 mmol) in dichloromethane (4 mL) was added to 1,1,1-triacetoxy-1,1-dihydro-1,2-benzyo. -Doxole-3 (1H) -one (327 mg, 0.771 mmo
1) was added and the mixture was stirred at room temperature for 30 minutes. After 10% aqueous sodium thiosulfate was added and the mixture was vigorously stirred, the reaction mixture was poured into saturated saline and extracted three times with ether. The organic layers were collected, dried over magnesium sulfate, and then concentrated with an evaporator. The residue was purified by silica gel flash chromatography (hexane / ethyl acetate 9: 1) to give 2-acetyl-3-chloro-1-p-toluenesulfonylpyrrole (109 mg, 0.365 mmol) in 95% yield. It was

TLC R _f 0.40 (hexane / ethyl acetate 4: 1). Melting point 117 [deg.] C. ¹ H NMR spectrum (200 MHz, CDCl ₃ ) δ
2.42 (s, 3H), 2.54 (s, 3H), 6.
32 (d, J = 3.5 Hz, 1 H), 7.33 (d, J
= 8.1 Hz, 2H), 7.70 (d, J = 3.5H)
z, 1H), 7.86 (d, J = 8.5Hz, 2H). IR spectrum (neat) 3145 (w), 29
20 (s), 2850 (m), 1670 (s), 159
0 (w), 1520 (w), 1435 (m), 1400
(S), 1360 (s), 1310 (m), 1230
(M), 1205 (m), 1170 (s), 1130
(S), 1080 (m), 1010 (m), 920
(W), 815 (m) cm ^-1 . Low resolution MS m / e (relative ratio) 299 (M,
2), 297 (M, 4), 282 (0.6), 235
(7), 233 (19), 220 (3), 218
(8), 155 (38), 91 (100). Elemental analysis (C ₁₃ H ₁₂ ClNO ₃ S) calculated: C;
52.44, H; 4.06, N; 4.70, S; 10.
77, Cl; 11.91, found: C; 52.4.
7, H; 4.06, N; 4.60, S; 10.61, C
1; 11.89.

Reference Example 4

[0079]

[Chemical formula 26]

Diisopropylamine (1.05 mL, 7.14 mmol) in THF at −78 ° C. in an argon stream.
To the solution (35 mL) was added a 1.7 M hexane solution of n-butyllithium (4.1 mL, 7.0 mmol), and -78 was added.
The mixture was stirred at 0 ° C for 5 minutes and at 0 ° C for another 20 minutes. -78
After cooling to ℃, 2-acetyl-3-chloro-1-p-
Toluenesulfonyl pyrrole (1.06g, 3.56m
THF solution (2 mL) of (mol) was added and stirred at -78 ° C for 1 hour. (Tetrahydro-2-pyranyloxy)
A solution of acetaldehyde (1.01 g, 7.01 mmol) in THF (2 mL) was added, and the mixture was further stirred at -78 ° C for 1.5 hr. The cold reaction mixture was poured into saturated ammonium chloride water and extracted three times with ether. The organic layers were collected, dried over magnesium sulfate, and then concentrated with an evaporator. The residue was purified by silica gel flash chromatography (hexane / ethyl acetate 2: 1) to give 3-chloro-2-
[3-hydroxy-1-oxo-4- (tetrahydro-
2-pyranyloxy) butyl] -1-p-toluenesulfonylpyrrole (851 mg, 1.93 mmol) was added to 5
Starting material 2-acetyl-3-chloro-1-p with a yield of 4%
-Toluenesulfonylpyrrole (0.15 g, 0.50
mmol).

TLC R _f 0.59 (hexane / ethyl acetate 1: 1). ¹ H NMR spectrum (200 MHz, CDCl ₃ ) δ
1.46-1.80 (m, 6H), 2.43 (s, 3
H), 3.12 to 3.19 (m, 2H), 3.46 to
3.93 (m, 4H), 4.26 to 4.38 (m, 1
H), 4.56 to 4.64 (m, 1H), 6.31
(D, J = 3.4 Hz, 1H), 7.33 (d, J =
8.2Hz, 2H), 7.66 (d, J = 3.4Hz,
1H), 7.86 (d, J = 8.3 Hz, 2H). IR spectrum (neat) 3420 (br
m), 3145 (w), 2930 (s), 2860
(W), 1670 (s), 1590 (w), 1520
(M), 1415 (m), 1400 (m), 1365
(S), 1170 (vs), 1125 (s), 1030
(S), 970 (m), 900 (w), 810 (m) c
m ^-1 . Low resolution MS m / e (relative ratio) 357 (M-DH
P, 1), 340 (3), 322 (5), 286
(4), 284 (4), 256 (4), 202 (5),
186 (6), 155 (19), 91 (57), 85
(100). CI-MS m / e 442 (M + 1).

Reference Example 5

[0083]

Embedded image

3-chloro-2- at room temperature in an argon stream.
[3-hydroxy-1-oxo-4- (tetrahydro-
2-Pyranyloxy) butyl] -1-p-toluenesulfonylpyrrole (176 mg, 0.398 mmol) in dichloromethane (8 mL) solution was added to 1,1,1-triacetoxy-1,1-dihydro-1,2-benzyo. -Doxole-3 (1H) -one (212 mg, 0.500 mm
ol) was added little by little over 1 hour, and the mixture was stirred at room temperature for 1 hour. After 10% aqueous sodium thiosulfate was added and the mixture was vigorously stirred, the reaction mixture was poured into saturated saline and air-cooled.
Extracted 3 times with tel. The organic layers were collected, dried over magnesium sulfate, and then concentrated with an evaporator. The residue was subjected to silica gel thin layer chromatography (hexane / ethyl acetate 2:
After purification in 1), 3-chloro-2- [1,3-dioxo-
4- (tetrahydro-2-pyranyloxy) butyl]-
1-p-toluenesulfonylpyrrole (106 mg,
0.240 mmol) was obtained in a yield of 60%.

TLC R _f 0.50 (hexane / ethyl acetate 2: 1). ¹ H NMR spectrum (200 MHz, CDCl ₃ ) δ
1.46-1.93 (m, 6H), 2.44 (s, 3
H), 3.49 to 3.59 (m, 1H), 3.79 to
3.90 (m, 1H), 4.16 (d, J = 17.0H
z, 1H), 4.35 (d, J = 16.6 Hz, 1
H), 4.71 to 4.73 (brs, 1H), 6.3.
2 (d, J = 3.5Hz, 1H), 6.41 (s, 1
H), 7.33 (d, J = 8.1 Hz, 2H), 7.5
8 (d, J = 3.5 Hz, 1 H), 7.86 (d, J =
8.4 Hz, 2H). IR spectrum (neat) 3150 (br
w), 2940 (m), 1735 (w), 1595 (b
rs), 1370 (m), 1175 (s), 1125
(S), 1080 (s), 1035 (m), 810
(M) cm ^-1 . Low resolution MS m / e (relative ratio) 355 (M-DH
P, 4), 324 (16), 320 (10), 297.
(3), 282 (4), 184 (7), 155 (4
0), 128 (13), 91 (62), 85 (10
0). CI-MS m / e 440 (M + 1).

Reference Example 6

[0087]

Embedded image

3-chloro-2- at room temperature in an argon stream.
Methanol of [1,3-dioxo-4- (tetrahydro-2-pyranyloxy) butyl] -1-p-toluenesulfonylpyrrole (93.9 mg, 0.213 mmol)
Solution (2.1 mL) with camphorsulfonic acid (9.9
(mg, 0.043 mmol) was added and the mixture was stirred at room temperature for 13 hours. The reaction mixture was poured into saturated sodium hydrogen carbonate water and extracted with ether three times. The organic layers were collected, dried over magnesium sulfate, and then concentrated with an evaporator. The residue was purified by silica gel thin layer chromatography (hexane / ethyl acetate 2: 1, 1% triethylamine) to give 5- (3
-Chloro-1-p-toluenesulfonyl-2-pyrrolyl) -3-methoxyfuran (56.7 mg, 0.161
mmol) was obtained in a yield of 76%.

TLC R _f 0.62 (hexane / ethyl acetate 2: 1). ¹ H NMR spectrum (200 MHz, C ₆ D ₆ ) δ
1.72 (s, 3H), 3.16 (s, 3H), 5.9
0 (d, J = 3.5 Hz, 1 H), 6.43 (br
s, 1H), 6.53 (d, J = 8.2Hz, 2H),
6.83 (d, J = 0.9 Hz, 1H), 7.21
(D, J = 3.6 Hz, 1H), 7.45 (d, J =
8.4 Hz, 2H). IR spectrum (neat) 3680-3230
(Br w), 2920 (m), 2360 (w), 17
20 (w), 1635 (m), 1570 (m), 145
5 (m), 1380 (s), 1300 (w), 1265
(M), 1205 (w), 1170 (s), 1130
(S), 1080 (w), 1050 (m), 1025
(S), 980 (w), 890 (m), 800 (m) c
m ^-1 . Low resolution MS m / e (relative ratio) 353 (M, 1
1), 351 (M, 28), 198 (34), 196.
(100), 155 (9), 153 (19), 125
(8), 91 (23). High resolution MS (C ₁₆ H ₁₄ ClNO ₄ S) Calculated value:
351.0331, measured value: 351.0317.
^{_{(C 16 H 14 Cl * NO}} 4 S) Calculated: 353.030
1, measured value: 353.0280.

Reference Example 7

[0091]

[Chemical 29]

5- (3-chloro-1-p-toluenesulfonyl-2-pyrrolyl) -3- at room temperature in an argon stream.
Methoxyfuran (26.9 mg, 0.0765 mmo
To a solution of 1) in methanol (0.8 mL) was added potassium carbonate (106 mg, 0.767 mmol), and the mixture was stirred at room temperature for 23 hours.
Stir the time. The reaction mixture was poured into saturated saline and extracted 3 times with ether. The organic layers were collected, dried over magnesium sulfate, and then concentrated with an evaporator. The residue was subjected to silica gel thin layer chromatography (hexane / ethyl acetate 2:
Purification with 1,1% triethylamine) and 5- (3-chloro-2-pyrrolyl) -3-methoxyfuran (10.8m
g, 0.0547 mmol) was obtained in a yield of 71%.

TLC R _f 0.51 (hexane / ethyl acetate 2: 1). ¹ H NMR spectrum (200 MHz, C ₆ D ₆ ) δ
3.25 (s, 3H), 5.92 (t, J = 3.0H
z, 1H), 6.08 (t, J = 3.0Hz, 1H),
6.78 (d, J = 0.9 Hz, 1H), 6.81
(D, J = 0.8 Hz, 1H), 7.28 to 7.62
(Br, 1H). IR spectrum (neat) 3420 (br
m), 2920 (w), 2350 (w), 2330
(W), 1625 (m), 1575 (m), 1530
(W), 1380 (m), 1250 (w), 1100
(W), 1060 (w), 1030 (m), 960
(W), 880 (w) cm ^-1 . Low resolution MS m / e (relative ratio) 199 (M, 3
4), 197 (M, 100), 156 (22), 154
(68), 128 (11), 126 (34), 91 (2
0). High resolution MS (C ₉ H ₈ ClNO ₂ ) Calculated value: 1
97.0243, found: 197.0231.
^{_{(C 9 H 8 Cl * NO}} 2) Calculated: 199.0213,
Found: 199.0216.

Example 1

[0095]

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5- (3-chloro-1-p-toluenesulfonyl-2-pyrrolyl) -3- at room temperature in an argon stream.
Methoxyfuran (17.8mg, 0.0506mmo
potassium carbonate (35.0 mg, 0.253 mmol) was added to a methanol (0.5 mL) solution of 1) at room temperature.
Stir for 7 hours. After confirming the formation of 5- (3-chloro-2-pyrrolyl) -3-methoxyfuran by TLC, cyclohexanecarboxaldehyde (30.6 μL,
0.253 mmol) was added and the mixture was stirred at room temperature for 11 hours. The reaction mixture was concentrated under reduced pressure and the residue was purified by silica gel thin layer chromatography (hexane / ethyl acetate 2:
Purification with 1,1% triethylamine) and 5- (3-chloro-2-pyrrolyl) -2- (cyclohexylhydroxymethyl) -3-methoxyfuran (8.1 mg, 0.02
6 mmol) was obtained with a yield of 52%.

TLC R _f 0.43 (hexane / ethyl acetate 2: 1). ¹ H NMR spectrum (200 MHz, C ₆ D ₆ ) δ
0.97 to 2.10 (m, 11H), 2.29 (br,
1H), 3.31 (s, 3H), 4.59 (d, J =
8.4 Hz, 1 H), 6.10 (t, J = 2.9 Hz,
1H), 6.15 (t, J = 2.9 Hz, 1H), 6.
73 (s, 1H), 8.37 (br, 1H). IR spectrum (neat) 3650-3070
(Br m), 2920 (vs), 2850 (m), 1
715 (w), 1635 (s), 1600 (w), 15
25 (m), 1445 (m), 1385 (m), 123
0 (m), 1100 (m), 1050 (s), 985
(M), 880 (m), 780 (m), 720 (m) c
m ^-1 . Low resolution MS m / e (relative ratio) 311 (M,
1), 309 (M, 4), 293 (34), 291 (1
00), 228 (20), 226 (57), 212 (1
3), 210 (32), 197 (12), 163 (1
9), 128 (43). High resolution MS (C ₁₆ H ₂₀ ClNO ₃ ) Calculated value:
309.1130, Found: 309.1111.
^{_{(C 16 H 20 Cl * NO}} 3) Calculated: 311.110
0, found: 311.1092.

Example 2

[0099]

[Chemical 31]

5- (3-chloro-2-pyrrolyl) -2- (cyclohexylhydroxymethyl) -3-methoxyfuran (12.4 mg, 0.04) at room temperature in a stream of argon.
(00 mmol) in acetonitrile (0.4 mL) was added with di-tert-butyl dicarbonate (16.8 mg,
0.0770 mmol) and 4-dimethylaminopyridine (4.3 mg, 0.038 mmol) were added and the mixture was stirred at room temperature for 30
Stir for a minute. The reaction mixture was concentrated under reduced pressure and the residue was purified by silica gel thin layer chromatography (hexane / ethyl acetate 4: 1,1% triethylamine) to give 5-
(1-tert-butoxycarbonyl-3-chloro-2
-Pyrrolyl) -2- (cyclohexylhydroxymethyl) -3-methoxyfuran (8.9 mg, 0.022 m
mol) was obtained with a yield of 54%.

TLC R _f 0.40 (hexane / ethyl acetate 4: 1). ¹ H NMR spectrum (200 MHz, C ₆ D ₆ ) δ
0.97 to 2.23 (m, 11H), 1.25 (s, 9
H), 3.33 (s, 3H), 4.26 (brd, J =
8.0 Hz, 1 H), 6.01 (d, J = 3.5 Hz,
1H), 6.30 (s, 1H), 7.15 (d, J =
3.5 Hz, 1H). IR spectrum (neat) 3670-3040
(Br m), 2920 (s), 2850 (w), 17
40 (s), 1640 (m), 1455 (m), 138
0 (m), 1365 (m), 1310 (vs), 125
0 (m), 1140 (s), 1060 (w), 1015
(M), 950 (w), 840 (w), 735 (w) c
m ^-1 . Low resolution MS m / e (relative ratio) 411 (M,
1), 409 (M, 3), 393 (4), 391 (1
0), 337 (21), 335 (62), 291 (1
9), 272 (12), 270 (38), 228 (1
0), 226 (33), 128 (15), 57 (10
0). High resolution MS (C ₂₁ H ₂₈ ClNO ₅ ) Calculated value:
409.1655, found: 409.1660.
(C ₂₁ H ₂₈ Cl ^* NO ₅ ) calculated: 411.162
5, measured value: 411.1647.

Example 3

[0103]

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5- (1-ter) at 0 ° C. in an argon stream.
t-butoxycarbonyl-3-chloro-2-pyrrolyl)
Triethylamine (7.5 μL, 0.054 mmol) was added to a solution of 2- (cyclohexylhydroxymethyl) -3-methoxyfuran (4.4 mg, 0.0107 mmol) in dichloromethane (0.5 mL), followed by methanesulfonyl chloride ( 2.0 μL, 0.026 mm
ol) was added and the mixture was stirred at 0 ° C. for 20 minutes and at room temperature for 40 minutes. The reaction mixture was concentrated under reduced pressure and the residue was subjected to silica gel thin layer chromatography (hexane / ethyl acetate).
Purify with 4: 1, 1% triethylamine) to give 5- (1-
tert-Butoxycarbonyl-3-chloro-2-pyrrolyl) -2- (cyclohexylidenemethyl) -3-methoxyfuran (3.4 mg, 0.0087 mmol) was added to 8
Obtained in a yield of 1%.

TLC R _f 0.57 (hexane / ethyl acetate 4: 1). ¹ H NMR spectrum (200 MHz, C ₆ D ₆ ) δ
1.27 (s, 9H), 1.30 to 1.55 (m, 6
H), 2.15 (brt, J = 6 Hz, 2H), 2.
74 (br t, J = 6 Hz, 2H), 3.35 (s,
3H), 5.99 (d, J = 3.5Hz, 1H), 6.
31 (br s, 1H), 6.32 (s, 1H), 7.
25 (d, J = 3.5 Hz, 1H). IR spectrum (neat) 2920 (m), 17
40 (s), 1560 (w), 1455 (w), 136
5 (w), 1310 (vs), 1250 (w), 114
0 (s), 1105 (w), 1055 (w), 1015
(W), 950 (w) cm ^-1 . Low resolution MS m / e (relative ratio) 393 (M,
6), 391 (M, 17), 337 (34), 335.
(100), 293 (9), 291 (26), 212
(5), 210 (15), 128 (22), 57 (9
6). High resolution MS (C ₂₁ H ₂₆ ClNO ₄ ) Calculated value:
391.1548, Found: 391.1537.
^{_{(C 21 H 26 Cl * NO}} 4) Calculated: 393.151
9, measured value: 393.1547.

Example 4

[0107]

[Chemical 33]

5- (1-ter) at room temperature in an argon stream.
t-butoxycarbonyl-3-chloro-2-pyrrolyl)
2- (Cyclohexylidenemethyl) -3-methoxyfuran (3.4 mg, 0.0087 mmol) in methanol (0.2 mL) solution was added with potassium carbonate (12.0 mg,
0.087 mmol) was added and the mixture was stirred at room temperature for 1.5 hours. The reaction mixture was concentrated under reduced pressure and the residue was purified by silica gel thin layer chromatography (hexane / ethyl acetate 4: 1,
Purified with 1% triethylamine) and 5- (3-chloro-
2-pyrrolyl) -2- (cyclohexylidenemethyl)-
3-Methoxyfuran (1.92 mg, 0.0066 mm
was obtained in a yield of 76%.

TLC R _f 0.46 (hexane / ethyl acetate 4: 1). ¹ H NMR spectrum (200 MHz, C ₆ D ₆ ) δ
1.44-1.73 (m, 6H), 2.23 (br
t, J = 6 Hz, 2H), 2.76 (br t, J = 6)
Hz, 2H), 3.33 (s, 3H), 5.88 (t,
J = 3.0Hz, 1H), 6.13 (t, J = 3.0H
z, 1H), 6.31 (br s, 1H), 6.74
(S, 1H), 7.56 (br s, 1H). IR spectrum (neat) 3650-3050
(Br m), 2920 (s), 2850 (w), 16
15 (m), 1565 (m), 1455 (m), 138
0 (m), 1105 (m), 1060 (m), 1015
(M), 880 (w) cm ^-1 . Low resolution MS m / e (relative ratio) 293 (M,
4), 291 (M, 12), 238 (3), 236
(7), 212 (6), 210 (14), 199
(3), 197 (8), 163 (11), 128 (2
0). High resolution MS (C ₁₆ H ₁₈ ClNO ₂ ) Calculated value:
291.1024, measured value: 291.0992.

Example 5

[0111]

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5- (3-chloro-1-p-toluenesulfonyl-2-pyrrolyl) -3-methoxyfuran (14.
2 mg, 0.0404 mmol), cyclohexanone (0.084 mL, 0.81 mmol), potassium carbonate (27.9 mg, 0.20 mmol), and methanol (0.4 mL) in a sealed tube at 100 ° C. for 17 hours. did. The reaction mixture was concentrated under reduced pressure and the residue was subjected to silica gel thin layer chromatography (hexane / ethyl acetate).
Purify with 2: 1, 1% triethylamine) to give 5- (3-
Chloro-2-pyrrolyl) -2- (1-cyclohexenyl) -3-methoxyfuran (3.8 mg, 0.0136
mmol) was obtained in a yield of 34%.

TLC R _f 0.61 (hexane / ethyl acetate 2: 1). ¹ H NMR spectrum (200 MHz, C ₆ D ₆ ) δ
1.54 to 1.76 (m, 4H), 2.17 to 2.28
(M, 2H), 2.54 to 2.67 (m, 2H), 3.
30 (s, 3H), 5.99 (t, J = 3.0Hz, 1
H), 6.15 (t, J = 3.0 Hz, 1H), 6.4
6 (tt, J = 4.2, 1.8 Hz, 1H), 6.79
(S, 1H), 7.56 (br, 1H). IR spectrum (neat) 3700 to 3050
(Br m), 2925 (m), 2850 (w), 16
15 (m), 1570 (m), 1380 (s), 114
0 (w), 1095 (m), 1065 (m), 1020
(S) cm ^-1 . Low resolution MS m / e (relative ratio) 279 (M, 3
4), 277 (M, 100), 264 (3), 262
(9), 251 (7), 249 (21), 210 (8)
197 (8), 81 (26). High resolution MS (C ₁₅ H ₁₆ ClNO ₂ ) Calculated value:
277.0868, Found: 277.0846.
^{_{(C 15 H 16 Cl * NO}} 2) Calculated: 279.083
9, measured value: 279.0846.

Example 6

[0115]

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5- (3-chloro-1-p-toluenesulfonyl-2-pyrrolyl) -3-methoxyfuran (12.
5 mg, 0.0355 mmol), cycloheptanone (0.084 mL, 0.71 mmol), potassium carbonate (24.6 mg, 0.178 mmol), and methanol (0.4 mL) in a sealed tube at 100 ° C.
Heated for hours. The reaction mixture was concentrated under reduced pressure and the residue was purified by silica gel thin layer chromatography (hexane / ethyl acetate 2: 1, 1% triethylamine) to give 5- (3
-Chloro-2-pyrrolyl) -2- (1-cycloheptenyl) -3-methoxyfuran (6.4 mg, 0.022 m
mol) was obtained in a yield of 62%.

TLC R _f 0.68 (hexane / ethyl acetate 2: 1). ¹ H NMR spectrum (200 MHz, C ₆ D ₆ ) δ
1.51 to 1.80 (m, 6H), 2.35 (dd, J
= 10.9, 7.0 Hz, 2H), 2.87 to 2.92
(M, 2H), 3.29 (s, 3H), 5.96 (t,
J = 3.0Hz, 1H), 6.14 (t, J = 3.0H
z, 1H), 6.69 (t, J = 7.0Hz, 1H),
6.78 (s, 1H), 7.56 (br, 1H). IR spectrum (neat) 3720-3300
(Br m), 2920 (m), 2850 (w), 16
25 (m), 1600 (m), 1560 (m), 144
5 (w), 1380 (m), 1100 (w), 1060
(M), 1015 (m) cm ^-1 . Low resolution MS m / e (relative ratio) 293 (M, 3
3), 291 (M, 100), 278 (4), 276.
(10), 265 (15), 263 (44), 250
(2), 248 (4), 239 (6), 237 (1
5), 224 (4), 222 (5), 212 (3), 2
10 (6), 199 (3), 197 (6), 163 (1
7), 130 (8), 128 (21), 95 (10). High resolution MS (C ₁₆ H ₁₈ ClNO ₂ ) Calculated value:
291.125, measured value: 291.1013.
^{_{(C 16 H 18 Cl * NO}} 2) Calculated: 293.099
5, measured value: 293.1014.

Example 7

[0119]

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5- (3-chloro-1-p-toluenesulfonyl-2-pyrrolyl) -3-methoxyfuran (11.
5 mg, 0.0327 mmol), cyclooctanone (82.6 mg, 0.654 mmol), potassium carbonate (22.6 mg, 0.164 mmol), and methanol (0.3 mL) in a sealed tube at 120 ° C. Heated for days. The reaction mixture was concentrated under reduced pressure and the residue was subjected to silica gel thin layer chromatography (hexane / ethyl acetate).
Purify with 2: 1, 1% triethylamine) to give 5- (3-
Chloro-2-pyrrolyl) -2- (1-cyclooctenyl) -3-methoxyfuran (3.7 mg, 0.0121
mmol) was obtained in a yield of 37%.

TLC R _f 0.67 (hexane / ethyl acetate 2: 1). ¹ H NMR spectrum (200 MHz, C ₆ D ₆ ) δ
1.50 to 1.67 (m, 6H), 1.71 to 1.85
(M, 2H), 2.28 to 2.40 (m, 2H), 2.
83 (dd, J = 6.4, 6.0 Hz, 2H), 3.2
9 (s, 3H), 5.95 (t, J = 3.0Hz, 1
H), 6.15 (dd, J = 3.0, 2.8 Hz, 1
H), 6.49 (t, J = 8.5 Hz, 1H), 6.7.
7 (s, 1H), 7.56 (br, 1H). IR spectrum (neat) 3430 (br
m), 2920 (s), 2850 (m), 1625
(M), 1570 (m), 1460 (m), 1380
(M), 1235 (w), 1095 (m), 1025
(M) cm ^-1 . Low resolution MS m / e (relative ratio) 307 (M, 1
9), 305 (M, 54), 279 (34), 277.
(100), 264 (11), 262 (22), 239
(11), 237 (32), 130 (10), 128
(27). High resolution MS (C ₁₇ H ₂₀ ClNO ₂ ) Calculated value:
305.1181, measured value: 305.1162.
^{_{(C 17 H 20 Cl * NO}} 2) Calculated: 307.115
2, measured value: 307.1170.

Embodiment 8

[0123]

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5- (3-chloro-1-p-toluenesulfonyl-2-pyrrolyl) -3- at room temperature in an argon stream.
Methoxyfuran (12.7mg, 0.0361mmo
1), 2-acetyl-1-p-toluenesulfonylpyrrole (19.0 mg, 0.0722 mmol), and trimethyl orthoformate (0.050 mL, 0.46 mmo).
Camphorsulfonic acid (4.2 mg, 0.018 mmol) was added to a solution of 1) in methanol (0.36 mL), and the mixture was stirred at room temperature for 4 hours. The reaction mixture was purified by silica gel thin layer chromatography (hexane / ethyl acetate 2: 1) to give 5- (3-chloro-1-p-toluenesulfonyl-2-pyrrolyl) -3-methoxy-2- [1- (1 -P
-Toluenesulfonyl-2-pyrrolyl) ethenyl] furan (7.1 mg, 0.0119 mmol) was obtained in 33% yield.

TLC R _f 0.37 (hexane / ethyl acetate 2: 1). ¹ H NMR spectrum (200 MHz, C ₆ D ₆ ) δ
1.77 (s, 3H), 1.79 (s, 3H), 3.1
0 (s, 3H), 4.95 (d, J = 1.8Hz, 1
H), 5.87 (d, J = 1.8Hz, 1H), 5.9
5 (d, J = 3.5 Hz, 1 H), 6.07 (dd, J
= 3.4, 3.2 Hz, 1H), 6.18 (dd, J =
3.2, 1.8 Hz, 1H), 6.34 (s, 1H),
6.65 (d, J = 8.0 Hz, 2H), 6.83
(D, J = 8.2 Hz, 2H), 7.30 (d, J =
3.5 Hz, 1 H), 7.47 (dd, J = 3.4,
1.8 Hz, 1 H), 7.70 (d, J = 8.4 Hz,
2H), 7.75 (d, J = 8.3 Hz, 2H). IR spectrum (neat) 2970 (w), 29
40 (m), 2870 (w), 1740 (w), 146
5 (w), 1390 (m), 1075 (m), 810
(W) cm ^-1 . Low resolution MS m / e (relative ratio) 598 (M,
2), 596 (M, 5), 531 (3), 441
(5), 379 (5), 377 (14), 364
(2), 362 (4), 286 (9), 245 (3),
243 (8), 91 (100). High resolution _{MS (C 29 H 25 ClN 2} O 6 S 2) Calculated: 596.0840, Found: 596.082
6. ^{_{(C 29 H 25 Cl * N}} 2 O 6 S 2) Calculated: 59
8.0811, Found: 598.0797.

Example 9

[0127]

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5- (3-chloro-1-p-toluenesulfonyl-2-pyrrolyl) -3- at room temperature in an argon stream.
Methoxyfuran (17.9 mg, 0.0509 mmo
l), 2-acetyl-1-tert-butoxycarbonylpyrrole (21.3 mg, 0.102 mmol), and trimethyl orthoformate (0.050 mL, 0.46 m).
camphorsulfonic acid (2.4 mg, 0.010 mmol) was added to a methanol (0.5 mL) solution of (mol) and stirred at room temperature for 4 hours. The reaction mixture was concentrated under reduced pressure,
The residue was purified by silica gel thin layer chromatography (hexane / ethyl acetate 2: 1) to give 2- [1- (1-ter
t-butoxycarbonyl-2-pyrrolyl) ethenyl]-
5- (3-chloro-1-p-toluenesulfonyl-2-
Pyrrolyl) -3-methoxyfuran (12.1 mg, 0.
0223 mmol) was obtained in a yield of 44%.

TLC R _f 0.73 (hexane / ethyl acetate 2: 1). ¹ H NMR spectrum (200 MHz, C ₆ D ₆ ) δ
1.31 (s, 9H), 1.79 (s, 3H), 3.1
5 (s, 3H), 5.23 (d, J = 2.1Hz, 1
H), 5.73 (d, J = 2.1 Hz, 1H), 5.9
6 (d, J = 3.5 Hz, 1 H), 6.12 (t, J =
3.2 Hz, 1 H), 6.29 (dd, J = 3.2,
2.0 Hz, 1H), 6.32 (s, 1H), 6.67
(D, J = 8.1 Hz, 2H), 7.25 (d, J =
3.5 Hz, 1 H), 7.50 (d, J = 8.4 Hz,
2H), 7.59 (dd, J = 7.2, 2.0 Hz, 1
H). IR spectrum (neat) 2940 (w), 17
40 (s), 1405 (w), 1380 (m), 134
5 (m), 1325 (s), 1260 (w), 1220
(W), 1180 (m), 1155 (m), 1140
(M), 1120 (m), 1090 (w), 1065
(W), 1015 (w) cm ^-1 . Low resolution MS m / e (relative ratio) 544 (M,
5), 542 (M, 12), 487 (27), 486.
(32), 485 (55), 332 (11), 331
(17), 330 (18), 289 (17), 287
(51), 252 (10), 162 (17), 128
(11), 91 (37), 57 (100) High resolution MS (C ₂₇ H ₂₇ ClN ₂ O ₆ S) Calculated value:
542.1276, measured value: 542.1251.
^{_{(C 27 H 27 Cl * N}} 2 O 6 S) Calculated: 544.12
46, found: 544.1238.

Example 10

[0131]

Embedded image

5- (3-chloro-1-p-toluenesulfonyl-2-pyrrolyl) -3- at room temperature in a stream of argon.
Methoxy-2- [1- (1-p-toluenesulfonyl-
2-pyrrolyl) ethenyl] furan (3.0 mg, 0.0
050 mmol) of tetrahydrofuran (0.1 mL)
/ Methanol (0.1 mL) solution was added with sodium methoxide (27 mg, 0.50 mmol) and stirred at room temperature for 5 hours. The reaction mixture was concentrated under reduced pressure, and the residue was subjected to silica gel thin layer chromatography (hexane / ethyl acetate).
Purify with 2: 1, 1% triethylamine) to give 5- (3-
Chloro-2-pyrrolyl) -3-methoxy-2- [1-
7- (1-p-toluenesulfonyl-2-pyrrolyl) ethenyl] furan (1.6 mg, 0.0036 mmol)
Obtained in a yield of 2%.

TLC R _f 0.47 (hexane / ethyl acetate 2: 1). ¹ H NMR spectrum (200 MHz, C ₆ D ₆ ) δ
1.73 (s, 3H), 3.23 (s, 3H), 5.2
5 (d, J = 1.8 Hz, 1H), 5.80 (t, J =
3.0 Hz, 1 H), 6.05 (t, J = 3.0 Hz,
1H), 6.08 (d, J = 1.7HZ, 1H), 6.
10 (t, J = 3.3 Hz, 1 H), 6.24 (dd,
J = 3.2, 1.8 Hz, 1H), 6.54 (d, J =
8.1Hz, 2H), 6.65 (s, 1H), 7.50
(Dd, J = 3.4, 1.8 Hz, 1H), 7.62
(D, J = 8.3 Hz, 2H). IR spectrum (neat) 3500-3200
(Br w), 2940 (w), 1660 (w), 16
30 (m), 1575 (m), 1550 (m), 146
5 (w), 1370 (m), 1250 (w), 1220
(W), 1180 (m), 1155 (m), 1100
(W), 1060 (w), 895 (w), 820 (w)
cm ^-1 . Low resolution MS m / e (relative ratio) 444 (M, 2
5), 442 (M, 60), 379 (12), 377
(29), 365 (3), 363 (6), 311 (1
8), 289 (14), 287 (32), 162 (3
3), 91 (100). High resolution MS (C ₂₂ H ₁₉ ClN ₂ O ₄ S) Calculated value:
442.0773, measured value: 442.0763.
^{_{(C 22 H 19 Cl * N}} 2 O 4 S) Calculated: 444.07
23, measured value: 444.0717.

Example 11

[0135]

Embedded image

2- [1- (1-
tert-Butoxycarbonyl-2-pyrrolyl) ethenyl] -5- (3-chloro-1-p-toluenesulfonyl-2-pyrrolyl) -3-methoxyfuran (13.6m
g, 0.0250 mmol) to trifluoroacetic acid (0.
1 mL) and stirred at room temperature for 4 hours. The reaction mixture is poured into saturated sodium hydrogencarbonate water and washed with ether.
Extracted times. The organic layers were collected, dried over magnesium sulfate, and then concentrated by an evaporator. The residue was purified by silica gel thin layer chromatography (hexane / ethyl acetate 2: 1, 1% triethylamine) to give 5- (3-chloro-1-p.
-Toluenesulfonyl-2-pyrrolyl) -3-methoxy-2- [1- (2-pyrrolyl) ethenyl] furan (8.
0 mg, 0.018 mmol) was obtained with a yield of 72%.

TLC R _f 0.50 (hexane / ethyl acetate 2: 1). ¹ H NMR spectrum (200 MHz, C ₆ D ₆ ) δ
1.70 (s, 3H), 3.21 (s, 3H), 5.6
5 (d, J = 1.2 Hz, 1H), 5.82 (d, J =
1.2Hz, 1H), 5.94 (d, J = 3.5Hz,
1H), 6.28 to 6.32 (m, 1H), 6.29
(S, 1H), 6.48 (d, J = 8.0 Hz, 2
H), 6.50 to 6.55 (m, 1H), 6.71
6.75 (m, 1H), 7.23 (d, J = 3.5H
z, 1H), 7.36 (d, J = 8.5Hz, 2H),
9.09 (br, 1H). IR spectrum (neat) 3430 (m), 31
60 (w), 2950 (m), 2870 (w), 164
0 (w), 1600 (m), 1530 (w), 1465
(W), 1380 (s), 1300 (w), 1215
(W), 1195 (w), 1180 (vs), 1140
(S), 1095 (w), 1070 (w), 1020
(W), 940 (w), 915 (w), 820 (m) c
m ^-1 . Low resolution MS m / e (relative ratio) 444 (M,
6), 442 (M, 10), 353 (5), 351 (1
2), 289 (10), 287 (22), 139 (2
2), 124 (24), 91 (100). High resolution MS (C ₂₂ H ₁₉ ClN ₂ O ₄ S) Calculated value:
442.0753, measured value: 442.0776.
^{_{(C 22 H 19 Cl * N}} 2 O 4 S) Calculated: 444.07
22, measured value: 444.0693.

Example 12

[0139]

Embedded image

2- [1- (1-
tert-Butoxycarbonyl-2-pyrrolyl) ethenyl] -5- (3-chloro-1-p-toluenesulfonyl-2-pyrrolyl) -3-methoxyfuran (14.3m
g, 0.0263 mmol) of methanol (0.5 m
L) solution into potassium carbonate (36.3 mg, 0.263 m)
mol) was added and the mixture was stirred at room temperature for 17 hours. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel thin layer chromatography (hexane / ethyl acetate 2: 1, 1% triethylamine) to give 2- [1- (1-tert-butoxycarbonyl-2-pyrrolyl) ethenyl]. -5- (3-
Chloro-2-pyrrolyl) -3-methoxyfuran (5.2
mg, 0.0134 mmol) was obtained in a yield of 51%.

TLC R _f 0.67 (hexane / ethyl acetate 2: 1). ¹ H NMR spectrum (200 MHz, C ₆ D ₆ ) δ
1.17 (s, 9H), 3.23 (s, 3H), 5.4
1 (d, J = 2.0 Hz, 1H), 5.86 (t, J =
3.0 Hz, 1 H), 5.97 (d, J = 2.0 Hz,
1H), 6.06 (t, J = 2.9 Hz, 1H), 6.
16 (t, J = 3.3 Hz, 1H), 6.39 (dd,
J = 3.3, 1.9 Hz, 1H), 6.74 (s, 1
H), 7.60 (dd, J = 3.3, 1.8 Hz, 1
H), 7.86 (br, 1H). IR spectrum (neat) 3550-3180
(Br m), 2940 (m), 2870 (w), 17
40 (s), 1640 (m), 1470 (w), 141
0 (m), 1380 (w), 1330 (s), 1155
(M), 1125 (m), 1065 (w), 1025
(W), 895 (w) cm ^-1 . Low resolution MS m / e (relative ratio) 390 (M, 1
1), 388 (M, 31), 333 (34), 331
(79), 289 (4), 287 (10), 273 (1
8), 271 (19), 92 (18), 57 (10)
0). High resolution _{MS (C 20 H 21 ClN 2} O 4) Calculated:
388.1187, Found: 388.1158.
^{_{(C 20 H 21 Cl * N}} 2 O 4) Calculated: 390.115
9, measured value: 390.1184.

Example 13

[0143]

Embedded image

2- [1- (1-
A solution of tert-butoxycarbonyl-2-pyrrolyl) ethenyl] -5- (3-chloro-2-pyrrolyl) -3-methoxyfuran (5.2 mg, 0.013 mmol) in deuterated chloroform (0.40 mL) was placed in an NMR tube. Transferred and trifluoroacetic acid (0.10 mL) was added. Thirteen
After hours, after confirming disappearance of raw materials by NMR, the reaction mixture was concentrated under reduced pressure to give 5- (3-chloro-2-pyrrolyl)-
Trimethoxyacetic acid salt of 3-methoxy-2- [1- (2H-pyrrole-2-ylidene) ethyl] furan (4.4 m
g, 0.011 mmol) was obtained with a yield of 82%.

TLC R _f 0.30 (chloroform /
Methanol 9: 1, 1% trifluoroacetic acid). Melting point 174 to 176 ° C. ¹ H NMR spectrum (200 MHz, CDCl ₃ ) δ
2.68 (s, 3H), 4.22 (s, 3H), 6.
43 (brt, J = 2.2 Hz, 1H), 6.53
(Quint, J = 2.1 Hz, 1H), 7.10
(S, 1H), 7.23 to 7.28 (m, 1H), 7.
49 (brt, J = 3.0 Hz, 1H), 8.04 to
8.09 (m, 1H), 12.40 (br, 1H), 1
4.57 (br, 1H). IR spectrum (neat) 3620-3030
(Br m), 2930 (w), 1700 (m), 16
85 (m), 1590 (s), 1550 (s), 147
0 (w), 1430 (m), 1390 (m), 1370
(W), 1300 (m), 1260 (w), 1235
(W), 1210 (s), 1170 (m), 1130
(Vs), 1060 (m), 1010 (w), 930
(W), 880 (m), 800 (m), 765 (m),
730 (m) cm ^-1 . Low resolution MS m / e (relative ratio) 290 (M-CF
₃ CO ₂ H, 36), 288 (M-CF ₃ CO ₂ H, 10
0), 275 (10), 273 (23), 271 (2
3), 259 (5), 243 (9), 209 (10),
182 (10), 144 (10), 125 (28), 9
2 (76). High resolution _{MS (C 15 H 13 ClN 2} O 2, M-CF 3 C
O ₂ H) Calculated: 288.0664, Found:
288.0656. ^{_{(C 15 H 13 Cl * N}} 2 O 2, M-C
F ₃ CO ₂ H) Calculated value: 290.0635, Measured value: 290.0656. Elemental analysis _{(C 17 H 14 ClF 3 N} 2 O 4) Calculated:
C; 50.70, H; 3.50, N; 6.96, found: C; 50.56, H; 3.44, N; 6.74.

Example 14

[0147]

Embedded image

5- (3-chloro-1-p-toluenesulfonyl-2-pyrrolyl) -3- at room temperature in a stream of argon.
Methoxyfuran (12.3mg, 0.0350mmo
l), 7-oxo-1-p-toluenesulfonyl-4,
5,6,7-Tetrahydroindole [Reference: J.
Org. Chem. 48, 3214 (1983)] (2
0.2 mg, 0.0698 mmol) and trimethyl orthoformate (0.10 mL, 0.92 mmol) in methanol (0.35 mL) were added with camphorsulfonic acid (1.6 mg, 0.0068 mmol) at room temperature.
Stir the time. The reaction mixture was concentrated under reduced pressure and the residue was purified by silica gel thin layer chromatography (hexane / ethyl acetate 2: 1, 1% triethylamine) to give 5- (3
-Chloro-1-p-toluenesulfonyl-2-pyrrolyl) -3-methoxy-2- (1-p-toluenesulfonyl-4,5-dihydroindol-7-yl) furan (1.55 mg, 0.00249 mmol) Was obtained in a yield of 7%.

TLC R _f 0.45 (hexane / ethyl acetate 2: 1). ¹ H NMR spectrum (200 MHz, C ₆ D ₆ ) δ
1.72 (s, 3H), 1.74 (s, 3H), 1.7
8 to 2.01 (m, 4H), 3.52 (s, 3H),
5.84 (d, J = 3.3 Hz, 1H), 5.98
(D, J = 3.6 Hz, 1 H), 6.32 (t, J =
5.1 Hz, 1 H), 6.59 (d, J = 8.2 Hz,
2H), 6.61 (s, 1H), 6.70 (d, J =
8.1Hz, 2H), 7.20 (d, J = 3.3Hz,
1H), 7.31 (d, J = 3.5Hz, 1H), 7.
62 (d, J = 8.3 Hz, 2H), 7.71 (d, J
= 8.4 Hz, 2H). IR spectrum (neat) 2930 (m), 28
60 (w), 1740 (w), 1730 (w), 160
0 (w), 1480 (w), 1380 (m), 1180
(S), 1135 (m), 815 (m) cm ^-1 . Low resolution MS m / e (relative ratio) 624 (M, 1
5), 622 (M, 30), 469 (18), 467
(43), 314 (8), 313 (14), 312 (2
0), 144 (26), 91 (100). High resolution MS (C ₃₁ H ₂₇ ClN ₂ O ₆ S ₂ ) Calculated value: 622.0996, Found value: 622.097
2.

Example 15

[0151]

Embedded image

5- (3-chloro-1-p-toluenesulfonyl-2-pyrrolyl) -3- at room temperature in an argon stream.
Methoxyfuran (15.6mg, 0.0443mmo
l), 1-tert-butoxycarbonyl-7-oxo-4,5,6,7-tetrahydroindole [Reference: J. Org. Chem. 48, 3214 (198
3)] (20.9 mg, 0.0833 mmol), and trimethyl orthoformate (0.050 mL, 0.46 mm)
ol) in methanol (0.35 mL) was added camphorsulfonic acid (2.1 mg, 0.0090 mmol), and the mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated under reduced pressure, the residue was purified by silica gel thin layer chromatography (hexane / ethyl acetate 2: 1, 1% triethylamine), and 2- (1-tert-butoxycarbonyl-4,5).
-Dihydroindol-7-yl) -5- (3-chloro-1-p-toluenesulfonyl-2-pyrrolyl) -3-
Methoxyfuran (6.4 mg, 0.011 mmol) was obtained in 25% yield.

TLC R _f 0.70 (hexane / ethyl acetate 2: 1). ¹ H NMR spectrum (200 MHz, C ₆ D ₆ ) δ
1.26 (s, 9H), 1.78 (s, 3H), 2.0
5 to 2.17 (m, 2H), 2.28 to 2.36 (m,
2H), 3.26 (s, 3H), 6.01 (d, J =
3.5 Hz, 1 H), 6.04 (d, J = 3.2 Hz,
1H), 6.33 (t, J = 5.4Hz, 1H), 6.
44 (s, 1H), 6.65 (d, J = 8.2Hz, 2
H), 7.32 (d, J = 3.6Hz, 1H), 7.3
5 (d, J = 3.2 Hz, 1H), 7.56 (d, J =
8.4 Hz, 2H). IR spectrum (neat) 2940 (m), 17
45 (s), 1730 (w), 1715 (w), 163
5 (w), 1600 (w), 1565 (w), 1470
(W), 1375 (vs), 1335 (m), 1310
(M), 1260 (m), 1215 (w), 1180
(S), 1160 (s), 1140 (m), 1100
(W), 1070 (w), 1030 (m), 910
(W), 850 (w), 820 (m) cm ^-1 . Low resolution MS m / e (relative ratio) 570 (M, 1
2), 568 (M, 30), 470 (13), 468
(35), 315 (34), 313 (99), 144
(33), 91 (48), 57 (100). High resolution MS (C ₂₉ H ₂₉ ClN ₂ O ₆ S) calculated:
568.1432, Found: 568.1423.
^{_{(C 29 H 29 Cl * N}} 2 O 6 S) Calculated: 570.14
03, measured value: 570.1402.

Example 16

[0155]

Embedded image

2- (1-ter) at room temperature in an argon stream.
t-Butoxycarbonyl-4,5-dihydroindol-7-yl) -5- (3-chloro-1-p-toluenesulfonyl-2-pyrrolyl) -3-methoxyfuran (2.
6 mg, 0.0046 mmol) was dissolved in trifluoroacetic acid (0.1 mL) and stirred at room temperature for 3.5 hours. Pour the reaction mixture into saturated sodium hydrogen carbonate water,
Extracted three times with ether. The organic layers were collected, dried over magnesium sulfate, and then concentrated by an evaporator. The residue was subjected to silica gel thin layer chromatography (hexane / ethyl acetate).
2: 1) and 5- (3-chloro-1-p-toluenesulfonyl-2-pyrrolyl) -2- (4,5-dihydroindol-7-yl) -3-methoxyfuran (1.
6 mg, 0.0034 mmol) was obtained with a yield of 74%.

TLC R _f 0.55 (hexane / ethyl acetate 2: 1). ¹ H NMR spectrum (200 MHz, C ₆ D ₆ ) δ
2.42 to 2.51 (m, 2H), 2.74 (t, J =
8.3 Hz, 2H), 3.20 (s, 3H), 5.96
(D, J = 3.5 Hz, 1 H), 6.22 (t, J =
2.5Hz, 1H), 6.27 (s, 1H), 6.44
(D, J = 8.4 Hz, 2H), 6.48 (t, J =
5.3 Hz, 1 H), 6.54 (t, J = 2.6 Hz,
1H), 7.31 (d, J = 3.4Hz, 1H), 7.
32 (d, J = 8.5 Hz, 2H). IR spectrum (neat) 3680-3100
(Br m), 2940 (m), 2860 (w), 15
65 (m), 1465 (w), 1380 (s), 130
0 (m), 1180 (s), 1140 (s), 1095
(W), 1070 (w), 1030 (w), 900
(W), 820 (m) cm ^-1 . Low resolution MS m / e (relative ratio) 470 (M, 2
0), 468 (M, 54), 466 (15), 315
(26), 314 (32), 313 (79), 311
(36), 144 (50), 91 (100).

Example 17

[0159]

Embedded image

2- (1-ter) at room temperature in an argon stream.
t-Butoxycarbonyl-4,5-dihydroindol-7-yl) -5- (3-chloro-1-p-toluenesulfonyl-2-pyrrolyl) -3-methoxyfuran (2.
3 mg, 0.0040 mmol) of methanol (0.1
mL) solution to potassium carbonate (11.2 mg, 0.081
mmol) was added and the mixture was stirred at room temperature for 5 hours. The reaction mixture was concentrated under reduced pressure, the residue was purified by silica gel thin layer chromatography (hexane / ethyl acetate 2: 1, 1% triethylamine), and 2- (1-tert-butoxycarbonyl-4,5-dihydroindole-7-). Ill) -5
-(3-Chloro-2-pyrrolyl) -3-methoxyfuran (0.75 mg, 0.0018 mmol) was obtained with a yield of 45%.

TLC R _f 0.70 (hexane / ethyl acetate 2: 1). ¹ H NMR spectrum (200 MHz, C ₆ D ₆ ) δ
1.12 (s, 9H), 2.12 to 2.43 (m, 4
H), 3.38 (s, 3H), 5.97 (t, J = 3.
0Hz, 1H), 6.09 (d, J = 3.2Hz, 1
H), 6.10 (t, J = 3.0 Hz, 1H), 6.5
6 (t, J = 5.4 Hz, 1H), 6.87 (s, 1
H), 7.38 (d, J = 3.1 Hz, 1H), 8.1
6 (br, 1H). IR spectrum (neat) 3100 (m), 29
30 (m), 2860 (w), 1740 (w), 172
5 (w), 1675 (vs), 1630 (m), 156
5 (m), 1530 (w), 1465 (m), 1375
(S), 1345 (m), 1260 (m), 1160
(S), 1035 (m), 1020 (m), 890
(W) cm ^-1 . Low resolution MS m / e (relative ratio) 416 (M,
9), 414 (M, 25), 358 (6), 316 (1
5), 314 (44), 301 (5), 299 (1
4), 57 (100). High resolution _{MS (C 22 H 23 ClN 2} O 4) Calculated:
414.1345, Found: 414.1348.

Example 18

[0163]

Embedded image

2- (1-ter) at room temperature in an argon stream.
t-Butoxycarbonyl-4,5-dihydroindol-7-yl) -5- (3-chloro-2-pyrrolyl) -3
-Methoxyfuran (6.3 mg, 0.015 mmol)
The deuterochloroform (0.40 mL) solution was transferred to an NMR tube, and trifluoroacetic acid (0.050 mL) was added. After 23 hours, the disappearance of the starting materials was confirmed by NMR, and the reaction mixture was concentrated under reduced pressure to give 5- (3-chloro-2-pyrrolyl) -2- (5,6-dihydro-4H-indole-
The trifluoroacetic acid salt of 7-yl) -3-methoxyfuran (0.83 mg, 0.0019 mmol) was obtained in a yield of 13%.

TLC R _f 0.25 (chloroform /
Methanol 9: 1, 1% trifluoroacetic acid). ¹ H NMR spectrum (200 MHz, CDCl ₃ ) δ
2.04 (quint, J = 6.3 Hz, 2H),
2.85 (t, J = 6.3 Hz, 2H), 3.13
(T, J = 6.1 Hz, 2H), 4.19 (s, 3
H), 6.33 (br s, 1H), 6.40 (t, J
= 2.4 Hz, 1H), 7.06 (s, 1H), 7.3
8 to 7.42 (m, 1H), 8.15 to 8.18 (m,
1H), 12.79 (br, 1H), 14.30 (b
r, 1H). IR spectrum (neat) 3600 to 3050
(Br m), 2940 (m), 2870 (w), 16
90 (m), 1565 (w), 1550 (m), 153
0 (w), 1515 (w), 1465 (m), 1430
(W), 1390 (w), 1370 (w), 1300
(W), 1265 (w), 1210 (w), 1180
(W), 1130 (m), 1075 (w), 1030
(W), 1000 (w), 890 (w) cm ⁻¹ . Low resolution MS m / e (relative ratio) 316 (M-CF
₃ CO ₂ H, 37), 314 (M-CF ₃ CO ₂ H, 10
0), 312 (50), 301 (7), 299 (2
0), 297 (14), 144 (75). High resolution MS (C ₁₇ H ₁₅ ClN ₂ O ₂ , M-CF ₃ C
O ₂ H) Calculated: 314.0820, Found:
314.0817. ^{_{(C 17 H 15 Cl * N}} 2 O 2, M-C
F ₃ CO ₂ H) Calculated: 316.0791, Found: 316.0825.

Test Example (Malignant Tumor Cell Growth Inhibition Test) Mouse lymphocytic leukemia cells (P388) were treated with 2-hydroxyethyl disulfide 5 μM and kanamycin sulfate 100.
RPMI containing 10% fetal bovine serum supplemented with μg / mL
Add 1 × 10 ⁴ cells / mL to -1640 medium
Adjusted to. In addition, the compound of the general formula [I]
And 2-substituted-3-alkoxy-represented by [II]
A 5- (pyrrol-2-yl) furan derivative was added to a predetermined concentration, and a CO ₂ incubator (CO ₂ 5%, humidity 1) was added.
The cells were cultured at 00%, 37 ° C for 4 days. The number of surviving cells was counted by the MTT colorimetric method, and the 50% cell growth inhibitory concentration (IC ₅₀ ) was determined from the growth inhibition rate with respect to the control group. The results are shown in Tables 1 and 2.

Table 1. Mouse lymphocytic leukemia cell (P38
50% growth inhibitory concentration against

[0168]

[Table 1]

Table 2. Mouse lymphocytic leukemia cell (P38
50% growth inhibitory concentration against

[0170]

[Table 2]

─────────────────────────────────────────────────── ───

[Procedure amendment]

[Submission date] May 24, 1996

[Procedure amendment 1]

[Document name to be amended] Statement

[Correction target item name] 0028

[Correction method] Change

[Correction contents]

[0028]

[Chemical 21]

[Procedure amendment 2]

[Document name to be amended] Statement

[Correction target item name] 0031

[Correction method] Change

[Correction contents]

[0031] 4 first step This step is represented by the general formula [III] - alkoxy - 2 - (pyrrol-2-yl) furan derivatives sulfonyl group which is a protecting group of the amino groups of (reference example see) Removed,
The resulting 4 -alkoxy- 2 represented by the general formula [IV]
-(Pyrrol-2-yl) furan derivative (see Reference Example)
Is reacted with an aldehyde represented by the general formula [V] without isolation to give a 2-substituted-3-alkoxy-5- (pyrrole-2 represented by the general formula [Ia] which is a compound of the present invention.
-Yl) to produce a furan derivative.

[Procedure 3]

[Document name to be amended] Statement

[Correction target item name] 0043

[Correction method] Change

[Correction contents]

[0043] Fifth Step This formula 4 is represented by [III] - alkoxy - 2 - (pyrrol-2-yl) sulfonyl group is a protective group of the amino group of furan derivatives was removed to yield 4 -alkoxy- 2- (pyrrole-represented by the general formula [IV]
The 2-yl) furan derivative can be isolated by the general formula [V
II] is condensed with a ketone represented by the formula [II] to produce a 2-substituted-3-alkoxy-5- (pyrrol-2-yl) furan derivative represented by the general formula [Ie] of the present invention. is there.

[Procedure amendment 4]

[Document name to be amended] Statement

[Name of item to be corrected] 0045

[Correction method] Change

[Correction contents]

[0045] Sixth Step This 4 represented by the general formula [III] - alkoxy - 2 - (pyrrol-2-yl) 2-acetyl pyrrole derivative represented by furan derivatives of the general formula [VIII] The 2-substituted-3 represented by the general formula [If], which is a compound of the present invention, is condensed with trimethyl orthoformate in the presence of an acid.
-Alkoxy-5- (pyrrol-2-yl) furan derivative.

[Procedure Amendment 5]

[Document name to be amended] Statement

[Correction target item name] 0054

[Correction method] Change

[Correction contents]

[0054] Tenth Step This formula 4 is represented by [III] - alkoxy - 2 - (pyrrol-2-yl) furan derivative with the general formula orthoformate tetrahydroindole derivative represented by [IX] 2-Substitution-3-3 represented by the general formula [Ii], which is a compound of the present invention, by condensation with trimethyl in the presence of an acid.
It is intended to produce an alkoxy-5- (pyrrol-2-yl) furan derivative.

[Procedure correction 6]

[Document name to be amended] Statement

[Correction target item name] 0088

[Correction method] Change

[Correction contents]

3-chloro-2- at room temperature in an argon stream.
Methanol of [1,3-dioxo-4- (tetrahydro-2-pyranyloxy) butyl] -1-p-toluenesulfonylpyrrole (93.9 mg, 0.213 mmol)
Solution (2.1 mL) with camphorsulfonic acid (9.9
(mg, 0.043 mmol) was added and the mixture was stirred at room temperature for 13 hours. The reaction mixture was poured into saturated sodium hydrogen carbonate water and extracted with ether three times. The organic layers were collected, dried over magnesium sulfate, and then concentrated with an evaporator. The residue was purified by silica gel thin layer chromatography (hexane / ethyl acetate 2: 1, 1% triethylamine) to give 2- (3
- chloro -1-p-toluenesulfonyl-2-pyrrolyl) - 4 - methoxy furan (56.7 mg, 0.161
mmol) was obtained in a yield of 76%.

[Procedure amendment 7]

[Document name to be amended] Statement

[Correction target item name] 0092

[Correction method] Change

[Correction contents]

[0092] In an argon gas stream at room temperature for 2 - (3-chloro -1-p-toluenesulfonyl-2-pyrrolyl) - 4 -
Methoxyfuran (26.9 mg, 0.0765 mmo
To a solution of 1) in methanol (0.8 mL) was added potassium carbonate (106 mg, 0.767 mmol), and the mixture was stirred at room temperature for 23 hours.
Stir the time. The reaction mixture was poured into saturated saline and extracted 3 times with ether. The organic layers were collected, dried over magnesium sulfate, and then concentrated with an evaporator. The residue was subjected to silica gel thin layer chromatography (hexane / ethyl acetate 2:
Purification by 1,1% triethylamine) 2 - (3-chloro-2-pyrrolyl) - 4 - methoxy furan (10.8 m
g, 0.0547 mmol) was obtained in a yield of 71%.

[Procedure amendment 8]

[Document name to be amended] Statement

[Correction target item name] 0096

[Correction method] Change

[Correction contents]

[0096] In an argon gas stream at room temperature for 2 - (3-chloro -1-p-toluenesulfonyl-2-pyrrolyl) - 4 -
Methoxyfuran (17.8mg, 0.0506mmo
potassium carbonate (35.0 mg, 0.253 mmol) was added to a methanol (0.5 mL) solution of 1) at room temperature.
Stir for 7 hours. (3-chloro-2-pyrrolyl) - - 2 TLC 4 - After confirming the formation of methoxy furan, cyclohexane carboxaldehyde (30.6MyuL,
0.253 mmol) was added and the mixture was stirred at room temperature for 11 hours. The reaction mixture was concentrated under reduced pressure and the residue was purified by silica gel thin layer chromatography (hexane / ethyl acetate 2:
Purification with 1,1% triethylamine) and 5- (3-chloro-2-pyrrolyl) -2- (cyclohexylhydroxymethyl) -3-methoxyfuran (8.1 mg, 0.02
6 mmol) was obtained with a yield of 52%.

[Procedure amendment 9]

[Document name to be amended] Statement

[Correction target item name] 0112

[Correction method] Change

[Correction contents]

[0112] 2 - (3-chloro -1-p-toluenesulfonyl-2-pyrrolyl) - 4 - methoxy furan (14.
2 mg, 0.0404 mmol), cyclohexanone (0.084 mL, 0.81 mmol), potassium carbonate (27.9 mg, 0.20 mmol), and methanol (0.4 mL) in a sealed tube at 100 ° C. for 17 hours. did. The reaction mixture was concentrated under reduced pressure and the residue was subjected to silica gel thin layer chromatography (hexane / ethyl acetate).
Purify with 2: 1, 1% triethylamine) to give 5- (3-
Chloro-2-pyrrolyl) -2- (1-cyclohexenyl) -3-methoxyfuran (3.8 mg, 0.0136
mmol) was obtained in a yield of 34%.

[Procedure amendment 10]

[Document name to be amended] Statement

[Correction target item name]

[Correction method] Change

[Correction contents]

[0116] 2 - (3-chloro -1-p-toluenesulfonyl-2-pyrrolyl) - 4 - methoxy furan (12.
5 mg, 0.0355 mmol), cycloheptanone (0.084 mL, 0.71 mmol), potassium carbonate (24.6 mg, 0.178 mmol), and methanol (0.4 mL) in a sealed tube at 100 ° C.
Heated for hours. The reaction mixture was concentrated under reduced pressure and the residue was purified by silica gel thin layer chromatography (hexane / ethyl acetate 2: 1, 1% triethylamine) to give 5- (3
-Chloro-2-pyrrolyl) -2- (1-cycloheptenyl) -3-methoxyfuran (6.4 mg, 0.022 m
mol) was obtained in a yield of 62%.

[Procedure amendment 11]

[Document name to be amended] Statement

[Correction target item name]

[Correction method] Change

[Correction contents]

[0120] 2 - (3-chloro -1-p-toluenesulfonyl-2-pyrrolyl) - 4 - methoxy furan (11.
5 mg, 0.0327 mmol), cyclooctanone (82.6 mg, 0.654 mmol), potassium carbonate (22.6 mg, 0.164 mmol), and methanol (0.3 mL) in a sealed tube at 120 ° C. Heated for days. The reaction mixture was concentrated under reduced pressure and the residue was subjected to silica gel thin layer chromatography (hexane / ethyl acetate).
Purify with 2: 1, 1% triethylamine) to give 5- (3-
Chloro-2-pyrrolyl) -2- (1-cyclooctenyl) -3-methoxyfuran (3.7 mg, 0.0121
mmol) was obtained in a yield of 37%.

[Procedure amendment 12]

[Document name to be amended] Statement

[Correction target item name] 0124

[Correction method] Change

[Correction contents]

[0124] In an argon gas stream at room temperature for 2 - (3-chloro -1-p-toluenesulfonyl-2-pyrrolyl) - 4 -
Methoxyfuran (12.7mg, 0.0361mmo
1), 2-acetyl-1-p-toluenesulfonylpyrrole (19.0 mg, 0.0722 mmol), and trimethyl orthoformate (0.050 mL, 0.46 mmo).
Camphorsulfonic acid (4.2 mg, 0.018 mmol) was added to a solution of 1) in methanol (0.36 mL), and the mixture was stirred at room temperature for 4 hours. The reaction mixture was purified by silica gel thin layer chromatography (hexane / ethyl acetate 2: 1) to give 5- (3-chloro-1-p-toluenesulfonyl-2-pyrrolyl) -3-methoxy-2- [1- (1 -P
-Toluenesulfonyl-2-pyrrolyl) ethenyl] furan (7.1 mg, 0.0119 mmol) was obtained in 33% yield.

[Procedure amendment 13]

[Document name to be amended] Statement

[Correction target item name] 0128

[Correction method] Change

[Correction contents]

[0128] In an argon gas stream at room temperature for 2 - (3-chloro -1-p-toluenesulfonyl-2-pyrrolyl) - 4 -
Methoxyfuran (17.9 mg, 0.0509 mmo
l), 2-acetyl-1-tert-butoxycarbonylpyrrole (21.3 mg, 0.102 mmol), and trimethyl orthoformate (0.050 mL, 0.46 m).
camphorsulfonic acid (2.4 mg, 0.010 mmol) was added to a methanol (0.5 mL) solution of (mol) and stirred at room temperature for 4 hours. The reaction mixture was concentrated under reduced pressure,
The residue was purified by silica gel thin layer chromatography (hexane / ethyl acetate 2: 1) to give 2- [1- (1-ter
t-butoxycarbonyl-2-pyrrolyl) ethenyl]-
5- (3-chloro-1-p-toluenesulfonyl-2-
Pyrrolyl) -3-methoxyfuran (12.1 mg, 0.
0223 mmol) was obtained in a yield of 44%.

[Procedure Amendment 14]

[Document name to be amended] Statement

[Correction target item name] 0148

[Correction method] Change

[Correction contents]

[0148] In an argon gas stream at room temperature for 2 - (3-chloro -1-p-toluenesulfonyl-2-pyrrolyl) - 4 -
Methoxyfuran (12.3mg, 0.0350mmo
l), 7-oxo-1-p-toluenesulfonyl-4,
5,6,7-Tetrahydroindole [Reference: J.
Org. Chem. 48, 3214 (1983)] (2
0.2 mg, 0.0698 mmol) and trimethyl orthoformate (0.10 mL, 0.92 mmol) in methanol (0.35 mL) were added with camphorsulfonic acid (1.6 mg, 0.0068 mmol) at room temperature.
Stir the time. The reaction mixture was concentrated under reduced pressure and the residue was purified by silica gel thin layer chromatography (hexane / ethyl acetate 2: 1, 1% triethylamine) to give 5- (3
-Chloro-1-p-toluenesulfonyl-2-pyrrolyl) -3-methoxy-2- (1-p-toluenesulfonyl-4,5-dihydroindol-7-yl) furan (1.55 mg, 0.00249 mmol) Was obtained in a yield of 7%.

[Procedure Amendment 15]

[Document name to be amended] Statement

[Correction target item name]

[Correction method] Change

[Correction contents]

[0152] In an argon gas stream at room temperature for 2 - (3-chloro -1-p-toluenesulfonyl-2-pyrrolyl) - 4 -
Methoxyfuran (15.6mg, 0.0443mmo
l), 1-tert-butoxycarbonyl-7-oxo-4,5,6,7-tetrahydroindole [Reference: J. Org. Chem. 48, 3214 (198
3)] (20.9 mg, 0.0833 mmol), and trimethyl orthoformate (0.050 mL, 0.46 mm)
ol) in methanol (0.35 mL) was added camphorsulfonic acid (2.1 mg, 0.0090 mmol), and the mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated under reduced pressure, the residue was purified by silica gel thin layer chromatography (hexane / ethyl acetate 2: 1, 1% triethylamine), and 2- (1-tert-butoxycarbonyl-4,5).
-Dihydroindol-7-yl) -5- (3-chloro-1-p-toluenesulfonyl-2-pyrrolyl) -3-
Methoxyfuran (6.4 mg, 0.011 mmol) was obtained in 25% yield.

Claims (2)

[Claims] 1. The following general formula: [Wherein R ¹ is a hydrogen atom or SO ₂ R ³ or CO ₂ R
A group represented by ⁴ (provided that R ³ and R ⁴ are each a linear or branched alkyl group having 1 to 5 carbon atoms, a substituted or unsubstituted aralkyl group, or a substituted or unsubstituted aryl group; R ² represents a linear or branched alkyl group having 1 to 5 carbon atoms, a substituted or unsubstituted aralkyl group, or a substituted or unsubstituted aryl group, and X represents a halogen atom. Represent A is the following general formula: (In the formula, n represents an integer of 0 to 3), or the following general formula: (In the formula, n represents an integer of 0 to 3), or the following general formula: (In the formula, n represents an integer of 0 to 3), or the following general formula: (In the formula, R ⁵ is a hydrogen atom or SO ₂ R ⁶ or CO ₂ R
A group represented by ⁷ (provided that R ⁶ and R ⁷ are each a linear or branched alkyl group having 1 to 5 carbon atoms, a substituted or unsubstituted aralkyl group, or a substituted or unsubstituted aryl group; Represents)) or the following general formula: (In the formula, R ⁵ is the same as defined above), and is a 2-substituted-3-alkoxy-5- (pyrrol-2-yl) furan derivative. 2. The following general formula: [In the formula, R ² represents a linear or branched alkyl group having 1 to 5 carbon atoms, a substituted or unsubstituted aralkyl group, or a substituted or unsubstituted aryl group, and X represents a halogen atom. A is the following 1- (2H-pyrrole-2-ylidene) ethyl group represented by: or the following: 5,6-dihydro-4H-indole-7- represented by
2-substituted-3-alkoxy-5-
(Pyrrol-2-yl) furan derivative, or a pharmaceutically acceptable salt thereof.