WO2002055482A1

WO2002055482A1 - Process for preparing carboxylic acid amides

Info

Publication number: WO2002055482A1
Application number: PCT/JP2001/011580
Authority: WO
Inventors: Jo Ooyama; Hideo Tanabe; Susumu Harashima
Original assignee: Sankyo Company,Limited
Priority date: 2001-01-05
Filing date: 2001-12-27
Publication date: 2002-07-18

Abstract

A process of preparing a carboxylic acid amide by reacting a carboxylic acid with an amino compound in the presence of an alkanephosphonic anhydride and an N-alkylimidazole. This process enables efficient preparation of carboxylic acid amides useful drugs or intermediates of drugs.

Description

Description. Method for producing carboxylic acid amide compound

[Technical field]

The present invention relates to a method for producing a carboxylic acid amide compound. [Background technology]

As a method for producing a carboxylic acid amide compound by reacting a carboxylic acid compound and an amino compound, a method using a condensing agent or a method for converting a carboxylic acid into an activated form (for example, an acid halide compound or an acid anhydride) After that, a method of reacting with an amino compound is known.

Among the methods for producing a carboxylic acid amide compound, as a method related to the present invention,

A method using an alkanephosphonic anhydride is known (US Pat. No. 5,055,591). In this method, a base is used, and as the base, aliphatic and cycloaliphatic tertiary amines, specifically, methylmonorephorin, N-ethylmorpholine, and triethylamine are described.

[Disclosure of the Invention]

The present inventors have found that by using N-alkylimidazole as a base, a reaction of condensing a carboxylic acid compound and an amino compound in the presence of an alkanephosphonic anhydride can be efficiently performed. Was completed.

The production method of the present invention has a general formula

(In the formula, R ¹ represents a C—C ₆ alkyl group.)

(Wherein R ² represents a C ₆ alkyl group) in the presence of a compound represented by the formula: wherein a carboxylic acid compound is reacted with an amino compound to produce a carboxylic acid amide compound.

The "C ₆ alkyl group of R ¹ and R ² " is, for example, a methyl group, an ethyl group, a propyl group, an isopropyl group, a butyl group, an isobutyl group, a s-butyl group, a t-butyl group, a pentyl group, an isopentyl Group, 2-methylbutyl group, neopentyl group, 1-ethylpropyl group, hexyl group, isohexyl group, 4-methylpentyl group, 3-methylpentynole group, 2-methylpentyl group, 1-methylpentyl group, 3, 3- It may be a dimethylbutyl group, a 2,2-dimethylbutyl group, a 1,1-dimethylbutyl group, a 1,2-dimethylbutyl group, a 1,3-dimethylbutyl group, a 2, '3-dimethylbutyl group, or a 2-ethylbutyl group. , for R ¹ is preferably, C ₃ - a C ₆ alkyl group, more preferably a propyl or heptyl group, for R ² is preferably one C ₄ Al A group, more preferably a methyl group or Echiru group. The carboxylic acid compound is a compound having a carboxyl group and may have another functional group. However, it is desirable that the functional group be protected with an appropriate protecting group. Carboxylic acid compounds include, for example, formic acid, acetic acid, propionic acid, butyric acid, N-t-butoxycarbonyl glycine, N-t-butoxycarbonylalaen, N-benzyloxyl-ponylalanine, N-t-butoxy T-toxin such as carbonylserine, N-t-butoxycanolepo-norestin, N-t-butoxycanoleponinolevalin, N-t-butoxycarbonyl renoleucine, and N-t-butoxycarboninoleisleucine It may be substituted with an amino group protected by cicarpole or benzyloxyboel. 1 C ₇ aliphatic carboxylic acid; benzoic acid, 4-methylbenzoic acid, 4-methoxybenzoic acid, 4- Furuororu benzoic acid, 4 _ black port benzoic acid, 2-t Butoki Shikarubo - Ruamino benzoic acid, 4-Shiano benzoic acid, 4 - Toro acid, C i one C ₄ alkyl, such as naphth Rukarubon acid, C j- C ₄ alkoxy (e.g., main butoxy, ethoxy, propoxy, Isopurobokishi be a butoxy or Isobutokishi group, preferably, a main butoxy or ethoxy group, more preferably a main butoxy group.), a halogen (For example, it can be a fluorine, chlorine, bromine or iodine atom, preferably a fluorine or chlorine atom), t-butoxycarbonyl or benzyloxy - Amino protected in Le, it can be substituted by Shiano or nitro C ₆ - C _{1 0} Ariru acid; or N-t over script butoxycarbonyl proline, N- base Njiruokishikaru Ponirupurorin, N- t one butoxycarbonyl piperidine Nitrogen, Oxygen and Sulfur, such as 1,2-Rubonic acid, Oxazolidine-14-carboxylic acid, Thiazolidine-14-Rubonic acid, 2-oxothiazolidine-14-carboxylic acid, -Cotinic acid, Quinolinecarboxylic acid Having 1 to 3 heteroatoms selected from the group consisting of atoms and optionally having an imino moiety protected by t-poxycarbinole or benzyloxycarbonyl; And may be a 5- or 6-membered heterocyclic carboxylic acid which may be condensed with. Preferably, protected with t-butoxycarbonyl or benzyloxycarbonyl A C ₇ aliphatic carboxylic acid which may be substituted with an amino group; benzoic acid which may be substituted with methyl, methoxy, fluorine, chlorine or amino protected with t-toxycarbonyl or benzyloxycarbonyl. Or having one or two heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur atoms, and having an imino moiety protected by t- or benzyloxycarboel. A 5- or 6-membered heterocyclic carboxylic acid; more preferably, formic acid, acetic acid, propionic acid, butyric acid, N-t-ptoxcanoleponinoleglycine, N-t-peptoxyforce / leponinoleanine, N- Benzinoleoxycanololepoenolealanine, N-t-ptoxycanoleponinoreserin, N-t-putoxycarbinorestin, N-t-teptoxycarborubaline, N- t-butoxycarboeluleucine, N-t-toxycarbyl isoleucine, benzoic acid, 4-methylbenzoic acid, 4-methoxybenzoic acid, 4-fluorobenzoic acid, 4-chlorobenzoic acid, 2-t-butoxycarbo-laminobenzoic acid, N-t-butoxycarbolproline, N-benzyloxy Carbonylproline, N-t-butoxycarbol-piperidine-12-carboxylic acid, oxazolidine-4-carboxylic acid, thiazolidine-14-force olevonic acid, 2-oxothiazolidine-14-canoleponic acid or nicotinic acid, especially Preferably, N-t-butoxycarbo: ^-proline, N-benzyloxycarbol-proline, N-t-butoxycarbo-lpiridine-l-forcerbonic acid, oxazolidine-l-4 forcervonic acid, thiazolidine-l-41 It is rubonic acid or 2-oxothiazolidine.

The above amino compound is a compound having an amino group and may have another functional group, but it is preferable that the functional group is protected with an appropriate protecting group. The amino compounds include, for example, methinoleamine, dimethylamine, ethylamine, propylamine, ptinoleamine, hexinoleamine, O-methinoleglycine, O-methinolealanine, O-ethinolealanine, O-t-ptinolealanine, O-benzylalanine, O-t-no-le-a-yun, otino-erin, and otino-lein. , O-t-Puchinoreparin, O-t-Petit Honoré-leucine, 2-two Torokishi Echinoreamin, 2 two Torokishi 1-methyl E Chino Rare one C ₄ is protected by Al killed or Penjiru carboxyl or double bets such as Min Mono- or di-C i-C e alkylamines which may be substituted with methoxyl; phenylamine, 4-methylphenylenolamine, 4-methoxyphenylenolamine, 4-phenolylenolamine, 4-chlorophenylenolamine, 2-chlorophenylenolamine, 2 —Methoxykano Poyet Norre phenyl § Min, 2-t-butoxide deer Lupo sulfonyl phenylalanine § Min, such as Nafuchiruamin C ₁ - C ₄ alkyl, one C ₄ alkoxy (e.g., main butoxy, Etokishi, propoxy, Isopuropoki shea, butoxy or isobutoxy And preferably a methoxy or ethoxy group, more preferably a methoxy group), a halokene (for example, it can be a fluorine, chlorine, bromine or iodine atom, preferably Or a fluorine or chlorine atom.) Or C e- ^ which may be substituted by one C ₄ alkoxycarbonyl. Arylamine; or pyrrolidine, O-methylproline, O-ethylproline, O-t-butylproline, O-benzylproline, piperidine, 2- (O-t-butoxycarbol) piperidine , 2-aza-3-t-toxycarbonyldibicyclo [4.3.0] nonane, 1aza2-t-toxycarbonirubicyclo [4.4.0] decane, 4-t-butoxycarboello Kisazorijin, 4 - t-Butokishikarupo such as a two thiazolidine, having one or two heteroatoms selected from the group consisting of oxygen and sulfur atoms rather good also, C, one C ₄ alkoxycarbonyl or It may be a 5- to 10-membered cyclic amine which may be substituted by benzyloxycarbonyl, and is preferably a monomer which may be substituted by t-butyl or benzyl-protected olepoxyl or ethoxy. I C 6 alkylamine; methyl, methoxy, fluorine, chlorine, methoxycarbol, ethoxycarbol or phenylamine which may be substituted by t-butoxycarbonyl; oxygen and sulfur May have 1 or 2 heteroatoms selected from the group consisting of methoxycarbonyl, ethoxycarbol, tert-carboxycarbonyl or benzyloxycarbonyl. 5- or 6-membered cyclic amine; 2-aza ^ 3-t-butoxycarponinolecyclo [4.3.0] nonane; or 1-aza-2-t-butoxycarboerubiciclo [4.4.0] decane More preferably, methinoleamine, ethylamine, propinoleamine, ptynoleamine, O-methylglycine, O-methinolealanine, O-ethynolealanine, O-t-Ptinolealanine, O-penzinolealanine, O-t-Ptinoreserin, O-t —Ptinolevalin, O—t—Butinoleucine, 2-Ditroxicetilamine, 2-Ditroxyl-1-methylethylamine, Hue Luamine, 4-Methylphenamine, 4-Methoxyphenylamine, 4-Fluorophenylamine, 4-Monophenylamine, 2-Methoxycanole Poyulfe-Lamine, 2-t-Butoxycarboninolephenylamine Amine, pyrrolidine, O-methinoleproline, O-ethynoleproline, O-t-ptinoleproline, O-benzinoleproline, piperidine, 2- (0_t-butoxycarbonyl) piperidine, 2 other 3-t- Putoxycarborobicyclo [4.3.0] nonane, 1-other 2-t-butoxycarberbicyclo [4.4.0] decane, 4-t-ptoxica oleponinoleoxazolidine or 4-t-butoxycarbonylthiazolidine And particularly preferably, methylamine, ethylamine, propylamine, butylamine, o-methinoleg Shin, O- Mechinorearanin, O- Echinorearanin. O- t- Buchinoreara Nin, o—Penzinorearaen, o—t—Ptinoreserin, o—t—Butinolevulin, o

— T-Butylleucine, 2-nitroxicetilamine, 2-nitroxy-1-methylenoethylamine, O-methylproline, O-ethylproline, O-t-butylproline or O-benzylproline.

Also, the most preferred carboxylic acid compound is of the formula

The most preferred amino compound is represented by the formula

It is a compound represented by these.

The reaction of the production method of the present invention is carried out by reacting a carboxylic acid compound with an amino compound in an inert solvent in the presence of compound (I) and compound (II). The solvent used does not inhibit the reaction. As long as it is not particularly limited, for example, aliphatic hydrocarbons such as hexane, heptane, lignin, and petroleum ether; aromatic hydrocarbons such as benzene, toluene, and xylene; methylene chloride Halogenated hydrocarbons such as chlorophonolem, carbon tetrachloride, dichloroethane, chlorobenzene, and dichlorobenzene; esters such as ethyl formate, ethyl acetate, propyl acetate, butyl acetate, and getyl carbonate; Sopropyl ether, tetrahydrofuran, dioxane, dimethyloxetane, diethyl Ethers such as lenglycol dimethyl ether; ketones such as acetone, methyl ethyl ketone, methyl isobutynole ketone, isofolone, and hexahexanone; Nitro compounds such as nitrobenzene and nitrobenzene; nitroles such as acetonitrile and isoptyronitrile; formamide, N, N-dimethylformamide, N, N-dimethylacetamide, N-methyl- Amides such as 2-pyrrolidone, N-methylpyrrolidinone, hexamethylphosphorotriamide; or sulfoxides such as dimethylsulfoxide and sulfolane, preferably nitriles (especially acetonitrile) It is.

The molar ratio of the amino compound to the carboxylic acid compound is usually 1 to 10, preferably 2 to 10, and the molar ratio of the compound (I) to the carboxylic acid compound is usually 2 to 10. To 10 and preferably 3 to 6, and the molar ratio of the compound (II) to the carbone oxide compound is usually 2 to 15 and preferably 3 to 6.

The amount of the solvent to be used per 1 mol of the carboxylic acid compound is usually from 500 to 200 mL, and preferably from 800 to 120 OmL.

The reaction temperature varies depending on the type of the carboxylic acid compound, the amino compound, the compound (1), the compound (11) or the solvent, but is usually from −20 to 40 ° C., preferably from 0 to 40 ° C. 15 ° C.

The reaction time varies depending on the reaction temperature or the type of the carboxylic acid compound, amino compound, compound (1), compound (II) or solvent, but is usually 1 to 5 hours, and preferably 15 minutes. 3 hours.

After completion of the reaction, the desired carboxylic acid amide compound is collected according to a conventional method. For example, add water to the reaction mixture, extract with an organic solvent immiscible with water, wash the extract with saturated aqueous sodium bicarbonate, saturated saline and water, dry over anhydrous magnesium sulfate, and evaporate the solvent. Thereby, the desired carboxylic acid amide compound can be obtained. Further, if necessary, the desired carboxylic acid amide compound can be obtained by recrystallization, reprecipitation, and purification using various types of chromatography.

[Industrial applicability]

The method for producing the carboxylic acid amide compound of the present invention comprises: A carboxylic acid amide compound obtained by reacting a carboxylic acid compound with an amino compound in the presence of an alkanephosphonic anhydride using imidazole, whereby the desired carboxylic acid amide compound can be efficiently produced. Is useful as a pharmaceutical intermediate or a pharmaceutical (US Pat. No. 5,055,591 and Japanese Patent Application Laid-Open No. 5-213913).

[Best Mode for Carrying Out the Invention]

Hereinafter, the present invention will be described more specifically with reference to examples.

(Example 1)

Amidation reaction using N-methylimidazole

(4R) 14-oxothiazolidine 14-force rubonic acid (15 g, 1.0 eq), (1S) -1 -methyl-2-etroxyshetilamine 'hydrochloride (16 g), Propane phosphonic anhydride 50. /. Suspension of Chitinole acetate (74 g, 1.14 eq) and N-methylimidazole (35 g, 4.17 eq) are suspended in acetonitrile (100 mL) and reacted at 5 to 10 ° C for 1 hour. The solution was stirred.

Ethyl acetate (8 OmL) and aqueous sodium hydrogen carbonate (6 OmL) were added to the reaction solution, the layers were separated, and the obtained organic layer was washed with water (2 × 5 OmL). The obtained organic layer was evaporated under reduced pressure to 8 OmL, methanol (18 lmL) was added, and the mixture was further evaporated to 14 OmL under reduced pressure, and then decolorized with activated carbon (1.6 g). Then, water (6 OmL) is added, and the mixture is cooled, distilled under reduced pressure to about 8 OmL, further added with water (4 OmL), and cooled and stirred to obtain the desired (4R) —N — [(1 S) —1-Methyl1-2-troxicetyl] -12-oxothiazolidine-14-carboxamide (18.8 g, 94% yield) was obtained as white crystals.

Melting point: 1 12—123 ° C (decomposition). + NMR spectrum (CDCl ₃ + DMSO-d ₆ ) δ ppm: 1.27 (3H, d, J = 6.6 Hz), 3.67 (3H, d, J = 6.6 Hz), 4, 10-4.57 (4H, m), 7.57 (1H, bs), 7.78 (1H, bs).

(Reference example 1)

Amidation reaction using triethylamine (4R) —2-oxothiazolidine-1.4-forced rubonic acid (27.4 g, 1.05 eq), (IS) —1-methyl-1-2-to-mouth chychetilamine.hydrochloride (27.8 g), propanephosphonic anhydride 50% ethyl acetate solution (124.3 g, 1. leq) and triethylamine (57.4 g, 3.2 eq) were suspended in acetonitrile (355 mL). The reaction was stirred at -20 ° C for 1 hour.

Ethyl acetate (177 mL) and aqueous sodium hydrogen carbonate (266 mL) were added to the reaction solution, the layers were separated, and the obtained organic layer was washed with water (140 mLX2). The obtained organic layer was distilled off under reduced pressure to about 4 OmL, methanol (175 mL) was added, and the mixture was further distilled under reduced pressure to about 3 OmL, and then decolorized with activated carbon (2.3 g). Then, water (93 mL) is added and the mixture is cooled. The mixture is evaporated under reduced pressure to about 20 OmL, and the mixture is stirred with cooling to obtain the desired (4R) -N-[(1S) —1-methyl-1-2- [Nitroxyshetyl] -12-oxothiazolidine-14-carboxamide (27.lg, yield 75%) was obtained as white crystals.

Claims

Claims General formula

(Wherein, R ¹ represents a C ₆ alkyl group) and a general formula

(Wherein, R ² represents —C ₆ alkyl group.) A method for producing a carboxylic acid amide compound by reacting a carboxylic acid compound with an amino compound in the presence of a compound represented by the formula: .

2. A C 1 -C ₇ aliphatic carboxylic acid, wherein the carboxylic acid compound may be substituted with an amino group protected with t-butoxycarbonyl or benzyloxycarbonyl; C, 1 c ₄ -alkyl. 1 c ₄ Alkoxy, halogen, C ₆ — which may be substituted by an amino, cyano or ethoxy group protected by t-butoxycarbonyl or benzyloxycarbone. Aryl carboxylic acid; or an imino moiety having from 1 to 3 heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur atoms and protected with t-butoxycarbonyl or benzyloxycarbonyl. Phenyl ring and condensed ring The method for producing a carboxylic acid amide compound according to claim 1, which is a 5- or 6-membered heterocyclic carboxylic acid.

3. C 1 -C ₇ aliphatic carboxylic acid in which the carboxylic acid compound may be substituted by an amino group protected by t-butoxycarbonyl or benzyloxycarbonyl; methyl, methoxy, fluorine, chlorine or t-butoxycarbo. Benzoic acid which may be substituted with an amino protected with -nore or benzyloxy-carbonyl; or having 1 to 2 heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur, t-butoxycarbonyl 2. The method for producing a ureponic acid amide compound according to claim 1, which is a 5- to 6-membered heterocyclic carboxylic acid which may have an imino moiety protected with benzyloxycarbol.

4. Carboxylic acid compounds include formic acid, acetic acid, propionic acid, butyric acid, N-t-butoxycarbonylglycine, N-t-butoxycarbonylalanine, N-benzyloxycarbonylalanine, N-t-butoxycarbonylserine, N-t-butoxycarbonylcystine, N-t-butoxycarbonylvaline, N-t-butoxycarbonylleucine, N-t-butoxycarbonylisoleucine, benzoic acid, 4-methylbenzoic acid, 4-methoxybenzoic acid , 4-fluorobenzoic acid, 4-chlorobenzoic acid, 2-t-butoxycarbo-laminobenzoic acid, N-t-butoxycarbonylproline, N-benzyloxycarbonylproline, N-t-butoxycarponylpi Peridine-2-Rubonic acid, Oxazolidine-4-carboxylic acid, Thiazolidine-14 -Rubonic acid, 2-O 2. The method for producing a carboxylic acid amide compound according to claim 1, which is oxothiazolidine-14-carboxylic acid or ecotinic acid.

5. The carboxylic acid compound is N-t-butoxycarbolproline, N-benzyloxycarbonylproline, N-t-butoxycarbonylpiperidine-12-carboxylic acid, oxazolidine-14-carboxylic acid, thiazolidine-14- 2. The method for producing a carboxylic acid amide compound according to claim 1, wherein the carboxylic acid amide compound is carboxylic acid or 2-oxothiazolidine.

6. The carboxylic acid compound has the formula

A method for producing the carboxylic acid amide compound according to claim 1, which is a compound represented by the formula:

7. Mono- or di-Ci-Cs alkylamines in which the amine compound may be substituted by C 1 -C ₄ alkyl or benzyl-protected carboxyl or nitroxy; C — C ₄ alkyl, — C ₄ alkoxy, halogen or ten ₄ § Turkey carboxymethyl may be substituted with carbonyl C ₆ -. Arylamine; or one or two hetero atoms selected from the group consisting of oxygen and sulfur atoms, and may be substituted by 1 C ₄ alkoxycarbonyl or benzyloxycarboyl. 7. The method for producing a carboxylic acid amide compound according to claim 1, which is a 5- to 10-membered cyclic amine.

8. Mono-d-Cealkylamines in which the amine compound may be substituted by carboxyl or nitroxy protected with t-butyl or benzyl; methyl, methoxy, fluorine, chlorine, methoxycarboyl, ethoxycarbonyl or phenamine which may be substituted with t-butoxycarbonyl; which may have one or two heteroatoms selected from the group consisting of oxygen and sulfur atoms; methoxycarbonyl, ethoxycarbonyl, 5- or 6-membered cyclic amine which may be substituted with butoxycarboel or benzyloxycarbonyl; 2-aza-3-t-butoxycarbo-cyclo [4.3.0] nonane; or 1-aza-1 2 — T-Butoxycarborubicyclo

[4.4.0] A method for producing the carboxylic acid amide compound according to any one of claims 1 to 6, which is decane.

9. The amine compound is methylamine, ethylamine, propylamine, ptinoleamine, O-methinoleglycine, O-methinolealanine, O-ethinolealanine, O-t-one. Butynolealanine, o-benzinolealanine, o-t-Ptinoreserin, o-t-Ptinolevaline, O-t-Butylleucine, 2-Ditroxicetilamine, 2-nitroxy-1-methylethynoleamine , Phenylamine, 4-methylphenylamine, 4-methoxyphenylenoleamine, 4-phenylenoleamine, 4-phenylphenoleamine, 2-methoxyphenylamine, 2-methoxyphenylphenylamine, 2-t— Putoxycarponylphenolenoamine, pyrrolidine, O-methinolev. Mouth phosphorus, O-ethynoleproline, O-t-petinoleproline, 0-benzy.norreproline, piperidine, 2- (0-t-butoxycanoleponyl) piperidine, 2-aza-1-3-t-toxoxycarbonylbicyclo [ 4.3.0] Nonane, 1-other 2-t-toxycarbonyldibicyclo [4.4.0] decane, 4-t-butoxycarbo-norexazolidine or 4-t-butoxycanoleponylthiazolidine 7. A method for producing the carboxylic acid amide compound according to any one of items 1 to 6.

10. The amine compound is methylamine, ethylamine, propinoleamine, butylamine, o-methinoleglycine, o-methinolealanine, o-ethinolealanine, o-t-butylinolealanine, O-benzinolealanine, o-t-ptynoreserin, O- t-Ptinolelin, O-t-Ptinoleleucine, 2-ditroxechtinoleamine, 2-dithroxy-1-methylethynoleamine, O-methinoleproline, O-ethynoleproline, O-t-butylproline or 7. The method for producing a carboxylic acid amide compound according to claim 1, which is O-benzylproline.

1 1. The amine compound has the formula

A method for producing the carboxylic acid amide compound according to any one of claims 1 to 6, which is a compound represented by the formula:

12. The method for producing a carbonamide compound according to any one of claims ¹ to 11, wherein R ¹ is a C ₃ -C ₆ alkyl group.

13. The method for producing a compound of claim ¹ , wherein R ¹ is a propyl group or a butyl group.

14. The method for producing a carbonamide compound according to claim 1, wherein R ² is a C ₄ alkyl group.

1 5. The method R ² is, to produce methyl or claim 1, wherein a Echiru group to cull Bonn acid amide compound of the first three terms.