JPH0859611A - Production of heterocyclic derivative - Google Patents

Abstract

PURPOSE: To obtain a heterocyclic derivative having an electron-attracting group at 3-site easily is high yield and industrially advantageous way by two- stage reaction comprising conducting a simplified synthesis of a precursor before cyclization using readily available raw materials and then carrying out cyclization. CONSTITUTION: A reaction is first conducted between a compound of formula II (R<1> is an alkyl, an alkenyl, an alkynyl, an aryl, a heterocycle, etc.; R<2> is an electron-attracting group; R<3> and R are each H or an alkyl) and a compound of formula III [X' is NR<5> ' (R<5> ' is H or an alkyl, etc.), 0 or S; Y' is COOM (M is an alkali metal), cyano, etc.] to form a compound of formula IV. Subsequently, the compound of formula IV' (Y" is carboxyl or Y') as one of compounds of formula IV is cyclized in the presence of a base or a compound of formula V (R<7> is an alkyl) to obtain the objective derivative of formula I. By this method, the objective heterocyclic derivative such as pyrrole, furan or thiophene each having an electron-attracting group at 3-site can be easily obtained in high yield by introducing the electron-attracting group at the α-site of a α, β-unsaturated ketone.

Description

Detailed Description of the Invention

[0001]

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to a method for producing a heterocyclic derivative having an electron-withdrawing group at the 3-position such as pyrrole, furan and thiophene in a simple and high yield.

[0002]

2. Description of the Related Art Among the methods for synthesizing pyrrole, furan and thiophene, the cyclization method consisting of a unit of (3 + 2) is a unit of "2", and a hetero atom (N,
Acetic acid derivatives with O, S) (ie glycine, glyco-
Acid, thioglycolic acid derivative),
These derivatives are extremely effective methods because they are easily and inexpensively available. There are many known reports that follow this method, Comprehensive Heterocyclic Chemistry, vol.
4., Part 3. (1984) p123−125; CA., 80 , 59815; CA., 87 , 2
2933; J. Chem. Soc., Chem. Commun., 472, 1976; EP. 18273.
8; Helv.Chim.Acta. 65 , 1694,1982; J.Med.Chem., 23 , 48
1,1980; Heterocycles, 31 , 1049,1990; Synthesis, 389,19
90. In these reports, the unit of "3" was synthesized so as to meet a special purpose such as physiological activity and lacks generality. It is not convenient to synthesize a precursor until cyclization, and cyclization yield is low. It has problems such as a low rate.

[0003]

DISCLOSURE OF THE INVENTION The present invention provides a pyrrole, a furan and a thiophene having an electron-withdrawing group at the 3-position by introducing an electron-withdrawing group at the α-position of an α, β-unsaturated ketone. It is an object of the present invention to provide a method by which the production of a heterocyclic derivative such as can be carried out conveniently in a high yield and industrially advantageously.

[0004]

[Means for Solving the Problems]

1. The invention is characterized in that the following steps a and b are performed,
Formula [I]

[Chemical 11] Is a method for producing a heterocyclic derivative. Where R ¹
Is an alkyl group which may have a substituent, an alkenyl group which may have a substituent, an alkynyl group which may have a substituent, an aryl group which may have a substituent, and a substituent Optionally represents a heterocycle or COOR ⁴ . R ² represents an electron-withdrawing group. R ³ represents a hydrogen atom or an alkyl group which may have a substituent. X represents NR ⁵ , O or S. Y is a hydrogen atom,
Represents a carboxy group, COOR ⁶ or cyano group. R ⁵ is a hydrogen atom, an alkyl group which may have a substituent, an alkenyl group which may have a substituent, an alkynyl group which may have a substituent, an aryl group which may have a substituent, It represents a heterocycle optionally having a substituent or COR ⁷ . R ⁴ and R ⁶ are an alkyl group which may have a substituent, an alkenyl group which may have a substituent, an alkynyl group which may have a substituent, an aryl group which may have a substituent, or It represents a heterocycle which may have a substituent. R ⁷ represents an alkyl group which may have a substituent. Step a: Formula [II]

Embedded image R ¹ COC (= CR ³ —OR ⁸ ) R ² [II] [In the formula, R ¹ , R ² and R ³ have the same meanings as described above. R ⁸ represents a hydrogen atom or an alkyl group which may have a substituent. ] A compound represented by the formula [III]

Embedded image HX′CH ₂ Y ′ [III] [wherein, X ′ represents NR ⁴ ′, O or S 2. R ⁴ 'is a hydrogen atom,
An alkyl group which may have a substituent, an alkenyl group which may have a substituent, an alkynyl group which may have a substituent,
It represents an aryl group which may have a substituent or a heterocycle which may have a substituent. Y'represents COOM, COOR ⁶ or a cyano group. M represents an alkali metal. R ⁶ has the same meaning as described above. ] By reacting with a compound represented by the formula [IV]

Embedded image R ¹ COC (= CR ³ —X′CH ₂ Y ′) R ² [IV] [In the formula, R ¹ , R ² , R ³ , X ′, and Y ′ have the same meanings as described above. ] The process of manufacturing the compound represented by these. Step b: Formula [IV ']

Embedded image R ¹ COC (= CR ³ —X′CH ₂ Y ″) R ² [IV ′] [In the formula, Y ″ represents a carboxy group, COOM, COOR ⁶ or a cyano group. M and R ⁶ have the same meanings as described above. ] The compound represented by the base or formula [V]

Embedded image R ⁷ COOCOR ⁷ [V] [In the formula, R ⁷ represents the same meaning as described above. ] The compound of formula [I]

[Chemical 17] [In the formula, R ¹ , R ² , R ³ , X and Y have the same meanings as described above. ] The process of manufacturing the compound represented by these. However, step b
Is carried out in the presence of a compound represented by the formula [V], X ′ is
In the case of NH, X is NCOR ⁷ (R ⁷ has the same meaning as described above), and when Y ″ is a carboxy group or COOM (M has the same meaning as described above), Y 2 is a hydrogen atom.

[0005] 2. Detailed Description The substituent of the alkyl group, alkenyl group and alkynyl group for R ¹ , R ⁴ , R ⁵ , R ⁶ and R ⁷ includes, for example, halogen, alkoxy, alkenyloxy, alkynyloxy group, phenoxy group and alkylthio group. , An alkenylthio group, an alkynylthio group, a phenylthio group, a cyano group, an alkoxycarbonyl group, a nitro group, a dialkylamino group, and a substituent (such as an aryl which may have a substituent such as alkyl or alkyl). Examples thereof include sulfonyl and the like. R ¹ ,
R ⁴ , R ⁵ and R ⁶ are aryl, and the substituent of the heterocycle is C ₁
~ C ₁₀ alkyl group, alkyl group, alkenyl group, alkynyl group, halogen, alkoxy, alkenyloxy,
Alkynyloxy group, phenoxy group, alkylthio group,
Alkenylthio group, alkynylthio group, phenylthio group, cyano, alkoxycarbonyl, acyl, nitro,
And dialkylamino, sulfonyl which may have a substituent (such as alkyl or aryl which may have a substituent such as alkyl), and the like. R ² is alkoxycarbonyl, acyl, cyano, nitro, sulfonyl which may have a substituent (such as alkyl or aryl which may have a substituent such as alkyl), trifluoromethyl and tetrafluoro. Electron withdrawing groups such as haloalkyl such as ethyl. R ³ is a hydrogen atom,
Examples thereof include C _{1 to} C ₆ alkyl groups. R ⁷ is usually a C ₁ -C ₆ alkyl group, a haloalkyl group such as trichloromethyl, trifluoromethyl, or the like. R ⁸ is usually a hydrogen atom, a C ₁ -C ₆ alkyl group, or the like.
In the present invention, the alkyl group is usually C _{1 to} C ₁₀ ,
C ₁₁ or higher is acceptable. When X is S, Y is preferably a hydrogen atom, a carboxy group or a cyano group.

Description of step a

Embedded image Formula [II] [In the formula, R ¹ , R ² , R ³ and R ⁸ have the same meanings as described above. ] And a compound represented by the formula [III] [wherein X'and
Y'has the same meaning as described above. ] It is carried out by reacting a compound represented by The compound represented by the formula [II] is, for example, J. Org. Chem., 49 , 140, 1984 or J. Heterocycl
It can be easily synthesized by the method described in ic Chem., 13 , 973, 1976. As the compound represented by the formula [III], for example, a commercially available product may be used as it is, and in some cases, glycine, glycolic acid or thioglycolic acid and an alkali metal hydroxide are mixed with alcohol such as ethanol. Manufactured by mixing and dissolving in a solvent. Next, the formula [III
] An alcohol solution of the compound represented by
The compound represented by I] is mixed. The amount of alcohol used at this time is arbitrary. Further, an aprotic polar solvent such as DMF or DMSO may be used. In particular, in the formula [III], X'is
In the case of O or S, a base is used in the reaction with [II]. Examples of the base include inorganic bases such as potassium hydroxide, and organic bases such as alcoholates and amines. Preferred is 1 equivalent of an inorganic base such as potassium hydroxide or sodium hydroxide. The reaction is carried out at room temperature to 100 ° C for 10 minutes to 5 hours, preferably at 50 to 80 ° C for 30 minutes.
After stirring for 2 hours and evaporating the solvent, a crude compound of the formula [IV] can be obtained. When Y ′ in the formula [IV] is an alkali metal salt of a carboxylic acid, it may be used by adding an acid such as hydrochloric acid to form a carboxylic acid. These crude compounds may be used as they are in the next step, or may be subjected to ordinary purification (recrystallization, column chromatography, etc.).

Description of step b

[Chemical 19] A compound represented by the formula [IV ′] [wherein R ¹ , R ² , R ³ , X ′ and Y ″ have the same meanings as described above] is a base or a formula [V]
[In the formula, R ⁷ represents the same meaning as described above. ] It is performed by carrying out a ring closure reaction in the presence of a compound represented by

B-1) When carried out in the presence of a base The compound of the formula [IV '] is subjected to a ring closure reaction in the presence of a base. Examples of the base include inorganic bases such as potassium hydroxide, sodium hydroxide, metallic sodium or sodium hydride, and organic bases such as sodium alcoholate and potassium tert-butoxide. Preferred is 1 equivalent of sodium alcoholate. Examples of the solvent include alcohols, BTX-based hydrocarbons, ethers, DMF, and a mixture thereof. Among them, alcohols such as methanol and ethanol are preferable. The reaction is carried out by stirring at room temperature to 100 ° C for 10 minutes to 10 hours, preferably at 50 to 80 ° C for 1 hour to 3 hours. Y'is preferably a carboxy group, COOR ⁶ or a cyano group, more preferably
It is COOR ⁶ or a cyano group.

B-2) When carried out in the presence of the compound represented by the formula [V] The compound represented by the formula [IV '] and the compound represented by the formula [V] are present in the presence or absence of a solvent. React to. Examples of the solvent include BTX hydrocarbons, ethers, acetic acid and the like. As the compound represented by the formula [V],
Although various carboxylic acid anhydrides can be used, acetic anhydride is most preferable because it is industrially very inexpensive and easy to handle in large quantities. The amount used is 1 to 50 equivalents, preferably 10 to 25 equivalents, relative to the compound represented by the formula [IV ′]. The reaction is
50 to 200 ° C, 10 minutes to 24 hours, preferably 100 to 140 ° C,
Perform by stirring for 30 minutes to 2 hours. Y "is preferably a carboxy group or an alkali metal salt thereof. In this reaction, when X'is NH, X becomes NCOR ⁷ (R ⁷ has the same meaning as described above), and Y" is a carboxy group or COOM. (M has the same meaning as above.) When decarboxylated, Y becomes a hydrogen atom.

After carrying out the above reaction, a usual post-treatment is carried out. When purification is required, the compound represented by the formula [I] can be obtained by a conventional method, for example, distillation, recrystallization or column chromatography. The structure of the compound in the present invention was confirmed by measuring NMR, IR, MASS, melting point and the like.

[0011]

EXAMPLES The present invention will be described more specifically with reference to representative examples.

Example 1 Synthesis of diethyl 3-methylpyrrole-2,4-dicarboxylate:

[Chemical 20] MeCOC (= CHOEt) COOEt + EtOCOCH ₂ NH ₂ · HCL
→ MeCOC (= CHNHCH ₂ COOEt) COOEt 37g of (ethoxymethylene) ethyl acetoacetate and 28g
Of glycine ethyl ester hydrochloride was added to 500 mL of ethanol and to this mixture was added 21 g of triethylamine. After heating and stirring at 50 to 60 ° C. for about 1 hour, ethanol was distilled off under reduced pressure, water was added to the residue, and the mixture was extracted with methylene chloride. The organic layer was washed with water and dried over anhydrous sodium sulfate, then the solvent was distilled off to give crude N- (2-ethoxycarbonyl).
-3-Oxo-1-butenyl) glycine ethyl ester (39.
8g) was obtained. MS (CI); 244 (M + 1,100%), 198 (M-OEt, 20%), ¹ H-NMR (CDC
l ₃ ) δ1.3 (t, 6H), 2.46 (s, 3H), 4.15 (m, 6H), 7.86 (d, 1H), 1
1.1 (br s, 1H)

[0013]

[Chemical 21] Then 49 g of N- (2-ethoxycarbonyl-3-oxo-1
-Butenyl) glycine ethyl ester was added to an ethanol solution (500 mL) in which 1.4 g of sodium ethylate was dissolved, and the mixture was stirred with heating under reflux for about 1 hour. After cooling, ethanol was distilled off under reduced pressure, water was added to the residue, and the mixture was extracted with ethyl acetate. The organic layer was washed with water, dried over anhydrous sodium sulfate, the solvent was distilled off, and the residue was subjected to silica gel column chromatography (developing solvent: hexane-ethyl acetate v / v = 7/3).
Purification was carried out to obtain a white powder of diethyl 3-methylpyrrole-2,4-dicarboxylate (31.6 g). mp.91-91.5 ℃ (Lit.90-91 ℃, JACS., 64 , 1267, 1942)

Example 2 Synthesis of ethyl 3-methylthiophene-4-carboxylate:

[Chemical formula 22] MeCOC (= CHOEt) COOEt + HSCH ₂ COONa → Me
COC (= CHSCH ₂ COOH) COOEt 34.3 g of sodium thioglycolate was added to 500 mL of ethanol in which 20 g of potassium hydroxide was dissolved, and the mixture was stirred under heating under reflux for 30 minutes, and then 55 g of (ethoxymethylene)
Ethyl acetoacetate was added. This mixture was stirred under heating under reflux for about 3 hours, and then ethanol was distilled off under reduced pressure.
Water was added to the residue and 2N hydrochloric acid was added dropwise until pH 1-2. The resulting crystals were filtered, washed with water and dried to give crude S-
(2-Ethoxycarbonyl-3-oxo-1-butenyl) thioglycolic acid (54.3 g) was obtained.

[0015]

[Chemical 23] Next, 54.3 g of S- (2-ethoxycarbonyl-3-oxo-1-butenyl) thioglycolic acid was added to 300 mL of acetic anhydride, and the mixture was stirred at 130 to 135 ° C. for about 1 hour. After allowing to cool, acetic anhydride was distilled off, ethyl acetate (1 L) was added to the residue, and the mixture was washed twice with saturated aqueous sodium hydrogen carbonate solution and once with saturated brine. The organic layer was dried over anhydrous sodium sulfate, the solvent was evaporated, and the residue was purified by distillation under reduced pressure to give ethyl 3-methylthiophene-4-carboxylate (32 g). bp. 90-100 ℃ /
0.5 mm

Example 3 Synthesis of 3-ethoxycarbonyl-4-methylpyrrole;

[Chemical formula 24] Glycine (75g, 1mol) and 85% potassium hydroxide (66g, 1mo)
l) was added to 700 mL of ethanol and dissolved by stirring at 40 to 50 ° C. Ethyl (ethoxymethylene) acetoacetate (185 g, 1 mol) was added to this solution, and the mixture was stirred with heating under reflux for about 1 hr. After allowing to cool, ethanol was distilled off under reduced pressure, and water (400 mL) was added to the residue to dissolve it. The crystals formed by adding 35% hydrochloric acid (80 mL) to this were filtered, washed with water, and then dried to give 154.8 g of N- (2-acetyl-2-
Ethoxycarbonylethylene) glycine was obtained.

[0017]

[Chemical 25] Next, N- (2-acetyl-2-ethoxycarbonylethylene) glycine (50 g, 0.23 mol) was added to acetic anhydride (50 mL, 5 mol), and the mixture was stirred at 130 to 135 ° C for 1 hr. After cooling, excess acetic anhydride was distilled off under reduced pressure, ethyl acetate (1 L) was added to the residue, and the mixture was washed twice with saturated aqueous sodium hydrogen carbonate solution (300 mL) and once with saturated brine (300 mL). did. The separated organic layer was dried over anhydrous sodium sulfate, the solvent was distilled off, and the residue was purified by silica gel column chromatography (developing solvent: hexane-ethyl acetate v / v = 7/3) to give 35.6 g.
1-Acetyl-3-ethoxycarbonyl-4-methylpyrrole was obtained. Yield 78.7% .mp.41-44 ℃ As the fraction after this, 1.4 g of 3-ethoxycarbonyl-4-
Methylpyrrole was obtained. Yield 4%.

Reactions were carried out according to the method of Example 3 using various compounds. The results are shown in Table 1.

[0019]

[Table 1]

[0020]

The pyrrole having an electron-withdrawing group at the 3-position,
A method has been realized in which the production of a heterocyclic derivative such as furan and thiophene can be carried out more simply and with higher yield than in the prior art and industrially advantageous.

Claims (2)

[Claims] 1. A compound represented by the formula [I]: wherein the following steps a and b are performed. [In the formula, R ¹ is an alkyl group which may have a substituent, an alkenyl group which may have a substituent, an alkynyl group which may have a substituent, and an aryl group which may have a substituent. Represents a heterocycle which may have a substituent or CO0R ⁴ . R ² represents an electron-withdrawing group. R ³ represents a hydrogen atom or an alkyl group which may have a substituent. X represents NR ⁵ , O or S. Y represents a hydrogen atom, a carboxy group, CO0R ⁶ or a cyano group.
R ⁴ and R ⁶ are an alkyl group which may have a substituent, an alkenyl group which may have a substituent, an alkynyl group which may have a substituent, an aryl group which may have a substituent, or It represents a heterocycle which may have a substituent. R ⁵ is a hydrogen atom, an alkyl group which may have a substituent, an alkenyl group which may have a substituent, an alkynyl group which may have a substituent, an aryl group which may have a substituent, It represents a heterocycle optionally having a substituent or COR ⁷ . R ⁷ represents an alkyl group which may have a substituent. However, when X is S, Y represents a hydrogen atom, a carboxy group, or a cyano group, and the step b is represented by the formula [V].
When performing in the presence of the compound represented by, when X'is NH, X
Is NCOR ⁷ (R ⁷ has the same meaning as described above), and Y "is a carboxy group or COOM (M represents an alkali metal).
Y represents a hydrogen atom. ] The manufacturing method of the heterocyclic derivative represented by these. Step a: Formula [II] embedded image R ¹ COC (= CR ³ —OR ⁸ ) R ² [II] [In the formula, R ¹ , R ² and R ³ have the same meanings as described above. R ⁸ represents a hydrogen atom or an alkyl group which may have a substituent. ] And a compound represented by the formula [III]: HX'CH ₂ Y '[III] [In the formula, X'represents NR ⁵ ', O or S 2. R ⁵ 'is a hydrogen atom,
An alkyl group which may have a substituent, an alkenyl group which may have a substituent, an alkynyl group which may have a substituent,
It represents an aryl group which may have a substituent or a heterocycle which may have a substituent. Y 'represents a COOM, CO0R ⁶ or a cyano group. R ⁶ and M have the same meanings as described above. ] The compound represented by the formula] is reacted to give a compound of the formula [IV] R ¹ COC (= CR ³ -X'CH ₂ Y ') R ² [IV] [wherein R ¹ , R ² , R ³ , X ′, and Y ′ have the same meanings as described above. ] The process of manufacturing the compound represented by these. Step b: Formula [IV ′] embedded image R ¹ COC (= CR ³ —X′CH ₂ Y ″) R ² [IV ′] [In the formula, Y ″ is a carboxy group, COOM, COOR ⁶ or a cyano group. Represents R ¹ , R ² , R ³ , R ⁶ , X ′ and M have the same meanings as described above. A compound represented by the formula: a base or a compound of the formula [V] embedded image R ⁷ COOCOR ⁷ [V] [wherein R ⁷ has the same meaning as described above. ] The compound represented by the formula [I] [In the formula, R ¹ , R ² , R ³ , X and Y have the same meanings as described above. ] The process of manufacturing the compound represented by these. 2. A compound represented by the formula [IV ']: embedded image R ¹ COC (= CR ³ -X'CH ₂ Y ") R ² [IV'] [wherein R ¹ , R ² , R ³ and X ' And Y "have the same meanings as described above. A compound represented by the formula: a base or a compound of the formula [V] embedded image R ⁷ COOCOR ⁷ [V] [wherein R ⁷ has the same meaning as described above. ] The compound represented by the formula [I] [In the formula, R ¹ , R ² , R ³ , X and Y have the same meanings as described above. ] The manufacturing method of the heterocyclic derivative represented by these.