JP2000256264A - Production of acetylene carboxylic acid derivative - Google Patents

Abstract

PROBLEM TO BE SOLVED: To industrially advantageously produce the subject compound useful as an intermediate for synthesizing medicines or agrochemicals such as a carbapenem derivative, under a mild condition by reacting a specific acetylene derivative with carbon monoxide and a specified nucleophilic agent in the presence of a palladium compound, a base and a specific butene derivative. SOLUTION: An acetylene derivative is reacted with carbon monoxide and a nucleophilic agent of the formula Y-H Y is a group of R3O or R4R5N [R3 is a (substituted) alkyl or the like; and R4 and R5 are each a (substituted) alkylene or the like] in the presence of a palladium compound, a base and a butene derivative of formulas I (X is a halogen; and R1 and R2 are each H or an alkyl) or II preferably at 0-100 deg.C to provide the objective compound of formula III. The buten derivative of 2 equivalents, and the base of 2-4 equivalents are preferably used based on the acetylene derivative. The amount of the palladium compound is preferably 0.001-0.1 g-atom based on 1 mol acetylene derivative.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

TECHNICAL FIELD The present invention relates to a method for producing an acetylene carboxylic acid derivative. The acetylene carboxylic acid derivative produced according to the present invention is, for example, a carbapenem derivative [Tetrahedron Lett
ers), 28, 1859 (1987)], steroid derivatives [Tetrahedron, 47
Vol., P. 481 (1988)].

[0002]

2. Description of the Related Art Conventionally, methods for producing acetylene carboxylic acid derivatives include (1) a method of reacting an acetylene derivative with a chloroformic acid derivative in the presence of a strong base [Annalen, vol. 614, p. 37 (1958) )], And (2) a method of reacting carbon dioxide with an acetylene derivative in the presence of a strong base and then leading to a carboxylic acid derivative [Journal of Organic Chemistry (Jo
urnal of Organic Chemistry), 19, 1580
(1954)], and (3) a method of reacting an acetylene derivative with carbon monoxide and an alcohol in the presence of a palladium catalyst in the presence of an equimolar amount of a copper salt with the acetylene derivative. [Tetrahedron Letters, 21, 849
Pp. (1980)].

[0003]

However, (1)
The methods (2) and (3) have problems such as the necessity of equimolar use of a strong base, and the method (3) requires a large amount of copper salt which is difficult to treat with waste liquid. It is hard to say that it is industrially satisfactory. Thus, an object of the present invention is to provide a method for industrially and advantageously producing an acetylene carboxylic acid derivative under mild conditions.

[0004]

According to the present invention, the above object is achieved by providing a palladium compound, a base and a compound of the formula (II)

[0005]

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Wherein X represents a halogen atom, and R ¹ and R ² each independently represent a hydrogen atom or an alkyl group.

[0007]

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(Wherein X, R ¹ and R ² are as defined above) (hereinafter referred to as butene derivatives) in the presence of a general formula (I)

[0009]

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(Wherein R represents a hydrogen atom, an alkyl group which may have a substituent, a cycloalkyl group, an alkenyl group, an aralkyl group, an aryl group or an organic silyl group). Hereinafter, this is abbreviated as acetylene derivative (I)), carbon monoxide and general formula (IV)

[0011]

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(Wherein Y represents R ³ O— or R ⁴ R ⁵ N—, and R ³ represents an optionally substituted alkyl group, cycloalkyl group, alkenyl group, aralkyl group or aryl group. R ⁴ and R ⁵ are each independently an alkyl group which may have a substituent, a cycloalkyl group,
Represents an alkenyl group, an aralkyl group, an aryl group, an alkylene group which may have a substituent together, or — (CH ₂ ) ₂ —O— (CH ₂ ) ₂ —. ) (Hereinafter abbreviated as nucleophile (IV)).

[0013]

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(Wherein R and Y are as defined above) by providing a method for producing an acetylene carboxylic acid derivative (hereinafter abbreviated as acetylene carboxylic acid derivative (V)). Achieved.

[0015]

BEST MODE FOR CARRYING OUT THE INVENTION In the above general formula, the alkyl groups represented by R ¹ and R ² are methyl, ethyl, propyl, isopropyl, butyl, isobutyl, ter
Examples include a t-butyl group and a 2-butyl group.

The alkyl group represented by R, R ³ , R ⁴ and R ⁵ includes, for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, 2-butyl, 6-butyl -Methyl-2-heptyl group and the like. These alkyl groups may have a substituent. Examples of the substituent include a hydroxyl group; an alkoxyl group such as a methoxy group, an ethoxy group, a propoxy group, a butoxy group and a benzyloxy group; and tert-butyldimethylsilyloxy. A tri-substituted silyloxy group such as a tert-butyldiphenylsilyloxy group; a heterocyclic group such as an azetidinyl group, a pyrrolidinyl group, a piperidinyl group, a piperazinyl group, a pyridyl group, a furyl group, and a thienyl group; These substituents may have a functional group inert to the reaction.

Examples of the cycloalkyl group represented by R, R ³ , R ⁴ and R ⁵ include a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, a cyclohexyl group, a cycloheptyl group, a steroid hydrocarbon group and the like. These cycloalkyl groups may have a substituent,
Such substituents include, for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl,
alkyl groups such as tert-butyl group and 2-butyl group;
Alkenyl groups such as allyl group and prenyl group; aralkyl groups such as benzyl group, naphthylmethyl group and phenethyl group; hydroxyl groups; methoxy group, ethoxy group, propoxy group,
Alkoxyl groups such as butoxy and benzyloxy groups;
tert-butyldimethylsilyloxy group, tert-
Trisubstituted silyloxy groups such as butyldiphenylsilyloxy group; halogen atoms such as fluorine atom, chlorine atom and bromine atom; aryl groups such as phenyl group, p-methoxyphenyl group and p-chlorophenyl group; azetidinyl group, pyrrolidinyl group and piperidinyl And heterocyclic groups such as a piperazinyl group, a pyridyl group, a furyl group, and a thienyl group. These substituents may have a functional group that is inert to the reaction.

Examples of the alkenyl group represented by R, R ³ , R ⁴ and R ⁵ include a 2-propenyl group and 6-methyl-5
-Hepten-2-yl group, 6,10-dimethyl-5,9
-Undecadien-2-yl group and the like. These alkenyl groups may have a substituent, and examples of such a substituent include a methyl group, an ethyl group, a propyl group, an isopropyl group, a butyl group, an isobutyl group,
alkyl groups such as t-butyl group and 2-butyl group; alkenyl groups such as allyl group and prenyl group; aralkyl groups such as benzyl group, naphthylmethyl group and phenethyl group; hydroxyl groups; methoxy group, ethoxy group, propoxy group and butoxy group Group, alkoxyl group such as benzyloxy group; tert
Trisubstituted silyloxy groups such as -butyldimethylsilyloxy group and tert-butyldiphenylsilyloxy group;
And aryl groups such as a phenyl group, a p-methoxyphenyl group and a p-chlorophenyl group.

The aralkyl group represented by R, R ³ , R ⁴ and R ⁵ includes, for example, a benzyl group, a naphthylmethyl group and a phenethyl group. These aralkyl groups may have a substituent, and examples of the substituent include a methyl group, an ethyl group, a propyl group, an isopropyl group, a butyl group, an isobutyl group, a tert-butyl group,
Alkyl groups such as -butyl group; alkenyl groups such as allyl group and prenyl group; aralkyl groups such as benzyl group, naphthylmethyl group and phenethyl group; hydroxyl groups;
Alkoxyl groups such as ethoxy, propoxy, butoxy and benzyloxy groups; trisubstituted silyloxy groups such as tert-butyldimethylsilyloxy group and tert-butyldiphenylsilyloxy group; halogens such as fluorine atom, chlorine atom and bromine atom Atom; phenyl group, p-
And aryl groups such as a methoxyphenyl group and a p-chlorophenyl group.

The aryl group represented by R, R ³ , R ⁴ and R ⁵ includes, for example, a phenyl group, a naphthyl group and a tetrahydronaphthyl group. These aryl groups may have a substituent. Examples of the substituent include a methyl group, an ethyl group, a propyl group, an isopropyl group, a butyl group, an isobutyl group, a tert-butyl group, and a 2-butyl group. Alkyl groups such as allyl group and prenyl group; aralkyl groups such as benzyl group, naphthylmethyl group and phenethyl group; hydroxyl groups; alkoxyl groups such as methoxy group, ethoxy group, propoxy group, butoxy group and benzyloxy group A tri-substituted silyloxy group such as a tert-butyldimethylsilyloxy group and a tert-butyldiphenylsilyloxy group; a halogen atom such as a fluorine atom, a chlorine atom and a bromine atom; a phenyl group, a p-methoxyphenyl group and a p-chlorophenyl group And the like.

The alkylene group which may have a substituent represented by R ⁴ and R ⁵ together includes an ethylene group,
Methyl ethylene group, 1,1-dimethyl ethylene group, 1,
2-dimethylethylene group, trimethylene group, 1-methyltrimethylene group, 2-methyltrimethylene group, 2,2-
Dimethyl trimethylene group, 1,3-dimethyl trimethylene group, tetramethylene group, 3-hydroxytetramethylene group, 3-methoxytetramethylene group, 3-aminotetramethylene group, 2-methoxycarbonyltetramethylene group, 3-benzyl Tetramethylene group, pentamethylene group, 2-methylpentamethylene group, 2-methoxycarbonylpentamethylene group, 3-methoxycarbonylpentamethylene group, 4-methoxycarbonylpentamethylene group, 4-methylpentamethylene group, 4-benzylpentane Examples include a methylene group and a hexamethylene group.

Examples of the organic silyl group represented by R include, for example,
Examples include a trimethylsilyl group, a tert-butyldimethylsilyl group, a triethylsilyl group, and a tert-butyldiphenylsilyl group.

A halogen atom represented by X is a chlorine atom,
Examples thereof include a bromine atom and an iodine atom, and among them, a chlorine atom is preferable.

The butene derivative is an acetylene derivative (I)
Is preferably used in the range of 0.5 to 5 equivalents,
It is particularly preferred to use 2 equivalents.

As the base, for example, inorganic salts such as potassium carbonate and sodium carbonate; organic carboxylic acid salts such as sodium acetate and potassium acetate; and aliphatic or aromatic amines such as triethylamine and pyridine can be used. The base is 1 to 1 relative to the acetylene derivative (I).
It is preferably used in a range of 0 equivalents, and particularly preferably used in an amount of 2 to 4 equivalents.

As the palladium compound, either a zero-valent palladium compound or a divalent palladium compound can be used, and palladium chloride, palladium acetate, palladium acetylacetonate, bisacetonitrile palladium chloride, bisbenzonitrile palladium chloride and the like can be used. It is preferable to use a palladium compound, and particularly preferable to use palladium chloride or palladium acetate. The amount of palladium compound used is
The range of 0.0001 g atom to 0.5 g atom as palladium atom is preferable for 1 mol of the acetylene derivative (I), and the range of 0.001 g to 0.1 g atom is more preferable.

The palladium compound is used for stabilization.
It is preferable to use a secondary phosphine compound. Such tertiary phosphine compounds include, for example, triarylphosphines such as triphenylphosphine and tristriphosphine; tricycloalkylphosphines such as tricyclohexylphosphine; trialkylphosphines such as tributylphosphine, triisobutylphosphine and tritert-butylphosphine; Diphosphines such as diphenylphosphinoethane, diphenylphosphinopropane, diphenylphosphinobutane, 2,2′-bis (diphenylphosphino) -1,1′-binaphthyl (BINAP); and water-soluble functional groups or polymers thereof And particularly preferably a triarylphosphine such as triphenylphosphine.
When a tertiary phosphine compound is allowed to coexist, the amount of the tertiary phosphine compound is preferably in the range of 1 to 4 mol per gram atom of palladium as a phosphorus atom contained in the tertiary phosphine compound, and 1 gram atom of palladium as a phosphorus atom. It is particularly preferred that the amount is 2 mol per 1 mol.

Examples of the nucleophile (IV) include methanol, ethanol, propanol, isopropanol, butanol, isobutanol, 2-butanol and tert.
Alcohols such as butanol, pentanol, octanol, cyclohexanol and benzyl alcohol; phenols such as phenol, naphthol and 4-methoxyphenol; amines such as dimethylamine, diethylamine, diisopropylamine, pyrrolidine, piperidine, morpholine and the like. . The nucleophile (IV) is preferably used in a range of 1 to 500 equivalents to the acetylene derivative (I).

The reaction can be carried out in the presence or absence of a solvent. The solvent is not particularly limited as long as it is inert to the reaction, but ethers such as tetrahydrofuran, diethyl ether and dimethoxyethane; dimethyl sulfoxide, dimethylformamide, polar solvents such as N-methylpyrrolidone, and the like are preferable, and tetrahydrofuran is particularly preferable. preferable. Further, the nucleophile (IV) itself can have a role as a solvent. When a solvent is used, the amount of the solvent used is 2 to the acetylene derivative (I).
The range is preferably from 200 to 200 times by weight, more preferably from 10 to 50 times by weight.

The amount of carbon monoxide used in the present invention is not particularly limited, and the reaction can be carried out under normal pressure or under pressure, but the partial pressure of carbon monoxide is 50 kPa to 10 M.
It is preferably used in the range of Pa, 80 kPa to 80 kPa.
It is particularly preferable to use in the range of 0 kPa. In addition, a gas inert to the reaction, such as nitrogen or argon, may coexist in the reaction system.

The reaction temperature is preferably in the range of 0 to 100 ° C.

The acetylenecarboxylic acid derivative (V) thus obtained can be isolated and purified by a method generally used for isolating and purifying organic compounds. For example, the reaction mixture is poured into dilute hydrochloric acid or water, and extracted with an organic solvent such as diethyl ether, ethyl acetate, or methylene chloride.
Wash with water, saline, etc. to remove acidic and water-soluble substances, dry over anhydrous magnesium sulfate, anhydrous sodium sulfate, etc. and concentrate.The crude product obtained by distillation, chromatography, recrystallization, if necessary The purification is carried out by, for example, further purification.

[0033]

EXAMPLES The present invention will be described in more detail with reference to the following Examples, which should not be construed as limiting the present invention.

Example 1 277.3 mg (2.01 mmol) of potassium carbonate, 19.4 mg (0.11 mmol) of palladium chloride and 52.2 mg (0.20 mmol) of triphenylphosphine
l) was placed in a reactor, and the inside of the reactor was replaced with carbon monoxide. Then, a mixed solution of 3 ml (74 mmol) of methanol and 5 ml of tetrahydrofuran (THF), 0.11 ml (1.00 mmol) of phenylacetylene and 1,
0.21 ml of 4-dichloro-2-butene (1.99 mm
ol) were sequentially added, and the mixture was stirred at room temperature for 20 hours. Water was added to the obtained reaction solution, and the mixture was extracted with diethyl ether. The extract was washed with saturated saline, dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained concentrate was purified by silica gel column chromatography to obtain 144.2 mg of methyl phenylacetylenecarboxylate having the following physical properties (yield: 90%). ¹ H-NMR (300 MHz, CDCl ₃ , TMS, pp
m) δ: 3.84 (s, 3H), 7.34-7.59
(M, 5H) IR (neat, cm ^-1 ): 1492, 1715, 22
23, 2946

EXAMPLE 2 Phenylacetylene having the following physical properties was obtained by performing the same reaction and post-treatment as in Example 1 except that 3 ml (51 mmol) of ethanol was used instead of 3 ml (74 mmol) of methanol. Ethyl carboxylate was obtained (63% yield). ¹ H-NMR (300 MHz, CDCl ₃ , TMS, pp
m) δ: 1.34 (t, J = 7.1 Hz, 3H),
4.29 (q, J = 7.1 Hz, 2H), 7.32-
7.58 (m, 5H) IR (neat, cm ^-1 ): 1489, 1709, 22
11,2983

Example 3 A reaction and a post-treatment were carried out in the same manner as in Example 1 except that 3 ml (30 mmol) of piperidine was used instead of 3 ml (74 mmol) of methanol. (Phenylethynylcarbonyl) piperidine was obtained (yield 77%). ¹ H-NMR (300 MHz, CDCl ₃ , TMS, pp
m) δ: 1.56-1.66 (m, 6H), 3.61
(T, J = 5.3 Hz, 2H), 3.75 (t, J =
5.3Hz, 2H), 7.34-7.54 (m, 5H)
IR (neat, cm ^-1 ): 1435, 1634, 22
16, 2943

Example 4 A phenylacetylene having the following physical properties was obtained by carrying out the reaction and post-treatment in the same manner as in Example 1 except that 3 ml (34 mmol) of phenol was used instead of 3 ml (74 mmol) of methanol. Phenyl carboxylate was obtained (46% yield). ¹ H-NMR (300 MHz, CDCl ₃ , TMS, pp
m) δ: 6.83-6.91 (m, 5H), 7.18
−7.24 (m, 5H) IR (neat, cm ⁻¹ ): 1492, 1585, 17
31, 2215, 2869

Example 5 0.11 ml of phenylacetylene in Example 1
0.132 g (1.00 mmol) of 1-phenyl-2-propyn-1-ol instead of (1.00 mmol)
The reaction and post-treatment were carried out in the same manner as in Example 1 except that the mixture was stirred at room temperature for 18 hours to obtain methyl 4-phenyl-4-hydroxy-2-butynate having the following physical properties (yield: 20%). ¹ H-NMR (300 MHz, CDCl ₃ , TMS, pp
m) δ: 3.72 (s, 3H), 5.51 (s, 1)
H), 7.27-7.47 (m, 5H) IR (neat, cm ^-1 ): 1495, 1713, 22
27,2925,3395

Example 6 In Example 1, 0.11 ml of phenylacetylene was used.
3-phenyl-3-t instead of (1.00 mmol)
tert-butyldimethylsilyloxy-1-propyne
By using 246 mg (1.00 mmol) and performing the reaction and post-treatment in the same manner as in Example 1 except that the mixture was stirred at room temperature for 18 hours, 4-phenyl-4 having the following physical properties was obtained.
-Methyl-tert-butyldimethylsilyloxy-2-butynate was obtained (yield 66%). ¹ H-NMR (300 MHz, CDCl ₃ , ppm)
δ: 0.00 (s, 3H), 0.06 (s, 3H),
0.80 (s, 9H), 3.63 (s, 3H), 5.4
4 (s, 1H), 7.25-7.34 (m, 5H) IR (neat, cm ^-1 ): 1472, 1720, 22
37, 2954

Example 7 In Example 1, 0.11 ml of phenylacetylene was used.
(1.00 mmol) was replaced with 70.1 mg (1.00 mmol) of 3-butyn-1-ol, and 2
The reaction and post-treatment were carried out in the same manner as in Example 1 except for stirring for 2 hours to obtain methyl 5-hydroxy-2-pentynate having the following physical properties (yield: 33%). ¹ H-NMR (300 MHz, CDCl ₃ , TMS, pp
m) δ: 2.14 (brs, 1H), 2.58 (t,
J = 6.3, 2H), 3.74 (s, 3H), 3.77
-3.79 (m, 2H) IR (neat, cm ^-1 ): 1435, 1712, 22
39, 2956, 3414

Example 8 In Example 1, 0.11 ml of phenylacetylene was used.
(Benzyl) instead of 4-benzyloxy-
The reaction and post-treatment were carried out in the same manner as in Example 1 except that 160 mg (1.00 mmol) of 1-butyne was stirred at room temperature for 20 hours to give methyl 5-benzyloxy-2-pentate having the following physical properties. (Yield 65)
%). ¹ H-NMR (300 MHz, CDCl ₃ , TMS, pp
m) δ: 2.56 (t, J = 6.8 Hz, 2H),
3.56 (t, J = 6.8 Hz, 2H), 3.68
(S, 3H), 4.48 (m, 2H), 7.21-7.
31 (m, 5H) IR (neat, cm ^-1 ): 1492, 1715, 22
39, 2954

Example 9 In Example 1, 277.3 mg of potassium carbonate (2.
01 mmol) instead of triethylamine 0.28m
The reaction and post-treatment were carried out in the same manner as in Example 1 except for using 1, to obtain methyl phenylacetylenecarboxylate (yield 74%).

Examples 10-12 In Example 9, tetrahydrofuran (THF) 5 m
In the same manner as in Example 9 except that methanol, dimethylsulfoxide and 5 ml of N, N-dimethylformamide were used instead of l, methyl phenylacetylenecarboxylate was obtained in a yield of 48% and 52%, respectively. %, 59%.

Example 13 In Example 1, 277.3 mg of potassium carbonate (2.
01 mmol) instead of sodium carbonate 213mg
(2.01 mmol), except that the reaction and post-treatment were carried out in the same manner as in Example 1 to obtain methyl phenylacetylenecarboxylate (yield: 82%).

Example 14 In Example 1, 52.2 m of triphenylphosphine was used.
The reaction and post-treatment were carried out in the same manner as in Example 1 except that 42.6 mg (0.10 mmol) of diphenylphosphinobutane was used instead of g (0.20 mmol) to obtain methyl phenylacetylenecarboxylate ( Yield 65%).

Example 15 The procedure of Example 1 was repeated except that 52.2 m of triphenylphosphine was used.
The reaction and post-treatment were carried out in the same manner as in Example 1 except that 39.8 mg (0.10 mmol) of diphenylphosphinoethane was used instead of g (0.20 mmol) to obtain methyl phenylacetylenecarboxylate ( Yield 52%).

Example 16 In Example 1, 3.5 mg of palladium chloride (0.
02 mmol) and triphenylphosphine was used in 10.
The reaction and post-treatment were carried out in the same manner as in Example 1 except that 5 mg (0.04 mmol) was used, thereby obtaining methyl phenylacetylenecarboxylate (yield: 93%).

Example 17 In Example 1, 0.9 mg of palladium chloride (0.
005 mmol) using triphenylphosphine as
Except for using 6 mg (0.01 mmol), the reaction and post-treatment were carried out in the same manner as in Example 1 to obtain methyl phenylacetylenecarboxylate (yield: 91%).

Example 18 In Example 1, 19.4 mg of palladium chloride (0.
22.4 mg of palladium acetate instead of 11 mmol)
By performing the reaction and the post-treatment in the same manner as in Example 1 except that (0.1 mmol) was used, methyl phenylacetylenecarboxylate was obtained (83% yield).

[0050]

Industrial Applicability The present invention provides a method for industrially and advantageously producing an acetylene carboxylic acid derivative under mild conditions.

Claims (1)

[Claims] 1. A palladium compound, a base and a compound of the general formula (II) (Wherein X represents a halogen atom, R ¹ and R ² each independently represent a hydrogen atom or an alkyl group) or a compound of the general formula (III) (Wherein X, R ¹ and R ² are as defined above) in the presence of a butene derivative represented by the general formula (I): (Wherein R represents a hydrogen atom, an alkyl group which may have a substituent, a cycloalkyl group, an alkenyl group, an aralkyl group, an aryl group or an organic silyl group). Carbon and the general formula (I
V) embedded image (Wherein, Y represents R ³ O— or R ⁴ R ⁵ N—, and R ³ represents an optionally substituted alkyl group, cycloalkyl group, alkenyl group, aralkyl group or aryl group; R ⁴ and R ⁵ each independently represent an alkyl group, a cycloalkyl group, an alkenyl group, an aralkyl group, an aryl group which may have a substituent or an alkylene group which may have a substituent together; Or-(C
H ₂ ) ₂ —O— (CH ₂ ) ₂ —. (V) characterized by reacting with a nucleophile represented by the following formula: (Wherein, R and Y are as defined above).