JPWO2008143342A1 - Method for producing 3-amino-2,5-dioxopyrrolidine derivative - Google Patents

Abstract

A method for efficiently producing a 3-amino-2,5-dioxopyrrolidine derivative useful as a pharmaceutical intermediate without protecting an amino group, which is represented by the following reaction formula: A method for producing a 2,5-dioxopyrrolidine derivative.

Description

  The present invention relates to a method for producing a 3-amino-2,5-dioxopyrrolidine derivative useful as a synthetic intermediate for pharmaceutical products.

（式中、Ｒ³は置換基を有していてもよい低級アルキルを表す）で表される化合物は医薬品の合成中間体として有用な化合物である［特開平６−１９２２２２号公報、ジャーナル・オブ・メディシナル・ケミストリー（Ｊ．Ｍｅｄ．Ｃｈｅｍ．）、１９９８年、第４１巻、ｐ．４１１８］。これらの化合物を製造する方法としては、アミノ基を保護した２−アミノマロン酸ジエステル、またはアミノ基を保護した２−アミノ−２−シアノ酢酸エステルを出発物質として、数工程を経て一般式（ＩＶ）

（式中、Ｒ⁴は、カルボキシル基の保護基を表し、Ｒ⁵は、加水素分解により脱離しうる基で保護されたアミノ基、またはｔｅｒｔ-ブトキシカルボニルアミノ基を表す）で表される化合物を得、続いて脱保護することにより、製造する方法（特許文献１および２、非特許文献１参照）が知られている。Formula (III)

A compound represented by the formula (wherein R ³ represents a lower alkyl which may have a substituent) is a compound useful as a synthetic intermediate of a pharmaceutical product [JP-A-6-192222, Journal of Medicinal chemistry (J. Med. Chem.), 1998, Vol. 41, p. 4118]. As a method for producing these compounds, 2-aminomalonic acid diester having an amino group protected, or 2-amino-2-cyanoacetic acid ester having an amino group protected is used as a starting material, and the general formula (IV )

Wherein R ⁴ represents a protecting group for a carboxyl group, and R ⁵ represents an amino group protected by a group capable of leaving by hydrogenolysis or a tert-butoxycarbonylamino group. And subsequent deprotection to produce the compound (see Patent Documents 1 and 2, Non-Patent Document 1).

However, these methods are complicated and require many steps such as protection of amino groups and deprotection reactions. For example, expensive reagents such as di-tert-butyl dicarbonate and benzyl chloroformate are used for protecting the amino group, which is not necessarily suitable for industrialization.
Japanese Patent No. 2516147 Japanese Patent No. 3158128 Journal of Medicinal Chemistry (J. Med. Chem.), 1998, vol. 41, p. 4118

  An object of the present invention is to provide a method for efficiently producing a 3-amino-2,5-dioxopyrrolidine derivative useful as a pharmaceutical intermediate without protecting the amino group.

（式中、Ｒ¹およびＲ²は同一または異なって、置換基を有していてもよい低級アルキルを表す）で表される２−アミノマロン酸ジエステルまたはその塩と、一般式（ＩＩ）

（式中、Ｘはハロゲンを表す）で表される２−置換酢酸アミドとを、塩基の存在下で反応させることを特徴とする一般式（ＩＩＩ）

（式中、Ｒ³は置換基を有していてもよい低級アルキルを表す）で表される３−アミノ−２，５−ジオキソピロリジン誘導体の製造方法。The present invention relates to the following (1) to (5).
(1) General formula (I)

(Wherein R ¹ and R ² are the same or different and each represents a lower alkyl which may have a substituent) 2-aminomalonic acid diester represented by the general formula (II)

(Wherein X represents a halogen) and a 2-substituted acetic acid amide represented by the general formula (III)

(Wherein R ³ represents a lower alkyl which may have a substituent), a method for producing a 3-amino-2,5-dioxopyrrolidine derivative represented by:

(2) The production method according to (1), wherein R ¹ and R ² are both methyl or ethyl.
(3) The production method according to (1) or (2), wherein X is chloro, bromo, or iodo.
(4) The production method according to any one of (1) to (3), wherein a salt is present during the reaction.
(5) The production method according to (4), wherein the salt is sodium bromide, potassium bromide, ammonium bromide, sodium iodide, or potassium iodide.

  The present invention provides a method for efficiently producing a 3-amino-2,5-dioxopyrrolidine derivative useful as a synthetic intermediate of a pharmaceutical product without protecting the amino group.

Hereinafter, the compound represented by formula (I) is referred to as compound (I). The same applies to the compounds of other formula numbers.
In the definition of each group of general formulas (I), (II) and (III):
Examples of the lower alkyl include linear or branched alkyl having 1 to 10 carbon atoms, and more specifically, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, Examples include isopentyl, neopentyl, hexyl, heptyl, octyl, nonyl, decyl and the like.
Halogen means each atom of fluorine, chlorine, bromine and iodine.

The substituents in the lower alkyl which may have a substituent are the same or different, for example, those having 1 to 3 substituents,
Halogen, hydroxy, sulfanyl, nitro, cyano, carboxy, carbamoyl, C _3-8 cycloalkyl, C _6-14 aryl, aliphatic heterocyclic group, aromatic heterocyclic group,
C _1-10 alkoxy, C _3-8 cycloalkoxy, C _6-14 aryloxy, C _7-16 aralkyloxy, C _2-11 alkanoyloxy, C _7-15 aroyloxy,
C _1-10 alkylsulfanyl,
-NR ^X R ^Y (wherein R ^X and R ^Y are the same or different and are a hydrogen atom, C _1-10 alkyl, C _3-8 cycloalkyl, C _6-14 aryl, aromatic heterocyclic group, C _{7 -16} aralkyl, C _2-11 alkanoyl, C _7-15 aroyl, C _1-10 alkoxycarbonyl or C _7-16 aralkyloxycarbonyl)
A substituent selected from the group consisting of C _2-11 alkanoyl, C _7-15 aroyl, C _1-10 alkoxycarbonyl, C _6-14 aryloxycarbonyl, C _1-10 alkylcarbamoyl and di-C _1-10 alkylcarbamoyl; can give.

The halogen shown here is as defined above, and C _1-10 alkyl and C _1-10 alkoxy, C _2-11 alkanoyloxy, C _1-10 alkylsulfanyl, C _2-11 alkanoyl, C _1-10 alkoxycarbonyl as the C _1-10 alkyl moiety of the C _1-10 alkylcarbamoyl, and di-C _1-10 alkylcarbamoyl, for example, the groups listed illustrative of the lower alkyl are exemplified. The two C _1-10 alkyls in the diC _1-10 alkylcarbamoyl may be the same or different.

C _3-8 The cycloalkyl moiety of the cycloalkyl and C _3-8 cycloalkoxy, for example, an cycloalkyl having 3 to 8 carbon atoms, more specifically, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, And cyclooctyl.

Examples of the aryl moiety of C _6-14 aryl and C _6-14 aryloxy, C _7-15 aroyl, C _7-15 aroyloxy and C _6-14 aryloxycarbonyl include aryl having 6 to 14 carbon atoms, More specifically, phenyl, naphthyl, azulenyl, anthryl and the like can be mentioned.

Examples of the aryl moiety of C _7-16 aralkyloxy, C _7-16 aralkyl and C _7-16 aralkyloxycarbonyl include the groups exemplified in the above-mentioned aryl, and examples of the alkyl moiety include, for example, C _1-10 Examples include alkylene, and more specifically, methylene, ethylene, trimethylene, propylene, tetramethylene, pentamethylene, hexamethylene, heptamethylene, octamethylene, nonamethylene, decamethylene and the like.

  As the aliphatic heterocyclic group, for example, a 5-membered or 6-membered monocyclic aliphatic heterocyclic group containing at least one atom selected from a nitrogen atom, an oxygen atom and a sulfur atom, and a 3- to 8-membered ring are condensed. A bicyclic or tricyclic condensed ring aliphatic heterocyclic group containing at least one atom selected from a nitrogen atom, an oxygen atom and a sulfur atom, and more specifically, aziridinyl, azetidinyl, pyrrolidinyl, Piperidino, piperidinyl, azepanyl, 1,2,5,6-tetrahydropyridyl, imidazolidinyl, pyrazolidinyl, piperazinyl, homopiperazinyl, pyrazolinyl, oxiranyl, tetrahydrofuranyl, tetrahydro-2H-pyranyl, 5,6-dihydro-2H-pyranyl, oxazolidinyl, Morpholino, morpholinyl, thioxazolidinyl, thiomo Folinyl, 2H-oxazolyl, 2H-thioxazolyl, dihydroindolyl, dihydroisoindolyl, dihydrobenzofuranyl, benzimidazolidinyl, dihydrobenzoxazolyl, dihydrobenzothioxazolyl, benzodioxolinyl, tetrahydroquino Ril, tetrahydroisoquinolyl, dihydro-2H-chromanyl, dihydro-1H-chromanyl, dihydro-2H-thiochromanyl, dihydro-1H-thiochromanyl, tetrahydroquinoxalinyl, tetrahydroquinazolinyl, dihydrobenzodioxanyl, etc. It is done.

  As the aromatic heterocyclic group, for example, a 5- or 6-membered monocyclic aromatic heterocyclic group containing at least one atom selected from a nitrogen atom, an oxygen atom and a sulfur atom, and a 3- to 8-membered ring are condensed. A bicyclic or tricyclic fused ring aromatic heterocyclic group containing at least one atom selected from a nitrogen atom, an oxygen atom and a sulfur atom, and more specifically furyl, thienyl, pyrrolyl, Imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, isothiazolyl, thiadiazolyl, triazolyl, tetrazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, benzofuranyl, benzothiophenyl, benzoxazolyl, benzothiazolyl, isoindolyl, indolyl, indazolyl Lil, benzotriazolyl, oxazolopyridyl pyrimidinyl, thiazolopyrimidinyl, pyrrolopyridinyl, pyrrolopyrimidinyl, imidazopyridinyl, purinyl, quinolinyl, isoquinolinyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, etc. naphthyridinyl and the like.

  Salts of compound (I) include, for example, acid addition salts, metal salts, ammonium salts, organic amine addition salts, amino acid addition salts and the like. Examples of acid addition salts include inorganic acid salts such as hydrochloride, hydrobromide, nitrate, sulfate, and phosphate, acetate, oxalate, maleate, fumarate, citrate, and benzoate. Acid salts, organic acid salts such as methanesulfonate, and the like. Examples of metal salts include alkali metal salts such as sodium salts and potassium salts, alkaline earth metal salts such as magnesium salts and calcium salts, aluminum salts, Examples of the ammonium salt include ammonium salts and tetramethylammonium salts. Examples of the organic amine addition salts include addition salts such as morpholine and piperidine. Examples of amino acid addition salts include: For example, addition salts such as lysine, glycine, phenylalanine, aspartic acid and glutamic acid can be mentioned.

Next, the manufacturing method of compound (III) is demonstrated concretely.
Compound (III) can be obtained by reacting compound (I) and compound (II) in the presence of a base, preferably in a solvent.
Compound (II) is preferably used in an amount of 0.5 to 3 equivalents, more preferably 0.9 to 1.5 equivalents, relative to compound (I).
Examples of compound (I) include diethyl 2-aminomalonate and dimethyl 2-aminomalonate.
Examples of the compound (II) include 2-chloroacetamide, 2-bromoacetamide, 2-iodoacetamide and the like.

  The reaction of compound (I) and compound (II) can also be carried out in the presence of a salt. The salt is preferably used in an amount of 0.5 to 3.5 equivalents, more preferably 1.5 to 2.5 equivalents, relative to compound (II). Examples of the salt include bromides such as sodium bromide, potassium bromide and ammonium bromide, iodides such as sodium iodide and potassium iodide, preferably potassium iodide.

  The amount of the base to be used is preferably 0.5 to 3.5 equivalents, more preferably 1.5 to 2.5 equivalents, relative to compound (I). The type of the base is not particularly limited, and preferred examples include metal alkoxides such as sodium methoxide, sodium ethoxide and potassium tert-butoxide, and carbonates such as sodium carbonate, potassium carbonate and calcium carbonate. Further, when the compound (I) is an acidic salt, a base for neutralizing the acid is separately required, but those skilled in the art can easily set the necessary amount of base.

  Although there is no restriction | limiting in particular in the kind of solvent used by this invention, Preferably, a highly polar water-soluble solvent is mention | raise | lifted, For example, methanol, ethanol, 1-propanol, 2-propanol, acetone, acetonitrile, tetrahydrofuran, N, N -Dimethylformamide, dimethylsulfoxide and the like are preferable. The amount of the solvent used is not particularly limited, but is preferably in the range of 3 to 20 times by weight with respect to Compound (I).

The reaction is usually carried out at a temperature between −50 ° C. and the boiling point of the solvent used, preferably 0 ° C. to 60 ° C. and is completed in 5 minutes to 72 hours.
The target compound (III) in the above production method is isolated and purified by separation and purification methods commonly used in organic synthetic chemistry, such as filtration, extraction, washing, drying, concentration, recrystallization, and various chromatography. Can do.

Although compound (III) has stereoisomers such as optical isomers, all possible isomers and mixtures thereof are also included in the compound obtained by the present invention.
Compound (III) may be obtained as a salt or in the form of an adduct with water or various solvents, and these salts and adducts are also included in the compound obtained by the present invention.
Hereinafter, the present invention will be described more specifically by way of examples. However, the present invention is not limited to these examples.

[Example 1]
2-Aminomalonic acid diethyl hydrochloride 52.9 g and 2-bromoacetamide 34.5 g were dissolved in 150 mL of ethanol, and 294 mL of a 20% ethanol solution of sodium ethoxide was added under ice cooling, followed by stirring for 1 hour. . Here, as a result of analyzing a part of the reaction solution by HPLC, the production rate of 3-amino-3-ethoxycarbonyl-2,5-dioxopyrrolidine was 70%. After adding hydrochloric acid to the reaction solution to make it acidic, the solvent was distilled off, and the concentrated residue was extracted with ethyl acetate and then crystallized with 2-propanol to give 3-amino-3-ethoxycarbonyl-2,5- Dioxopyrrolidine (21.1 g, yield 45.4%) was obtained.
Melting point 105-110 ° C.
¹ H NMR (300 MHz, CDCl ₃ ) δ 1.30 (t, J = 7.2 Hz, 3H), 2.21 (br s, 2H), 2.75 (d, J = 18.0 Hz, 1H), 3.19 (d, J = 18.0 Hz, 1H), 4.28 (q, J = 7.2 Hz, 2H), 8.42 (br s, 1H).

HPLC conditions Instrument: Hitachi, Ltd. Column: YMC-Pack ODS AM-313, 250 x 6.0 mm (manufactured by YMC Corporation)
Mobile phase: methanol / phosphate buffer = 7/23 (phosphate buffer was prepared by dissolving 1.87 g of K ₂ HPO ₄ and 3.74 g of KH ₂ PO _{4 in} 2.3 L of water)
Temperature: 40 ° C
Flow rate: 1.3 mL / min Detection: UV (218 nm)
Measurement time: 30 minutes Quantitative method: Absolute quantitative method

[Example 2]
11.2 g of 2-chloroacetamide and 19.9 g of potassium iodide were dissolved in 60 mL of ethanol, stirred at 60 ° C. for 4 hours, allowed to cool to room temperature, and 21.2 g of 2-aminomalonic acid diethyl hydrochloride was added. . To the obtained suspension, 118 mL of a 20% ethanol solution of sodium ethoxide was added under ice cooling, and the mixture was stirred as it was for 1 hour. Here, as a result of analyzing a part of the reaction solution by HPLC in the same manner as in Example 1, the production rate of 3-amino-3-ethoxycarbonyl-2,5-dioxopyrrolidine was 85%. After adding hydrochloric acid to the reaction solution to make it acidic, the solvent was distilled off, and the concentrated residue was extracted with ethyl acetate and then crystallized with 2-propanol to give 3-amino-3-ethoxycarbonyl-2,5- Dioxopyrrolidine (11.7 g, yield 63.0%) was obtained.

Claims (5)

Formula (I)

(Wherein R ¹ and R ² are the same or different and each represents a lower alkyl which may have a substituent) 2-aminomalonic acid diester represented by the general formula (II)

(Wherein X represents a halogen) and a 2-substituted acetic acid amide represented by the general formula (III)

(Wherein R ³ represents a lower alkyl which may have a substituent), a method for producing a 3-amino-2,5-dioxopyrrolidine derivative represented by: The process according to claim 1, wherein R ¹ and R ² are both methyl or ethyl. The method according to claim 1 or 2, wherein X is chloro, bromo, or iodo. The production method according to claim 1, wherein a salt is present during the reaction. The process according to claim 4, wherein the salt is sodium bromide, potassium bromide, ammonium bromide, sodium iodide, or potassium iodide.