WO2010002075A1 - Methods for preparing amide derivatives - Google Patents

Methods for preparing amide derivatives Download PDF

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WO2010002075A1
WO2010002075A1 PCT/KR2008/006838 KR2008006838W WO2010002075A1 WO 2010002075 A1 WO2010002075 A1 WO 2010002075A1 KR 2008006838 W KR2008006838 W KR 2008006838W WO 2010002075 A1 WO2010002075 A1 WO 2010002075A1
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derivative
substituted
branched
alkyl
straight
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PCT/KR2008/006838
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French (fr)
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Jae Won Kim
Young Gwan Cha
Hyung Chul Ryu
Sun Joo Kim
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Pharmacostech Co., Ltd.
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/04—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A61P11/02—Nasal agents, e.g. decongestants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A61P11/06—Antiasthmatics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/08—Antiallergic agents

Definitions

  • the present invention relates to a method for preparing amide derivatives.
  • Leukotriene as a biological metabolite of arachidonic acid is liberated from mast cells or eosinophils. There are leukotriene B 4 (LTB 4 ), leukotriene C 4 (LTC 4 ), leukotriene D 4 (LTD 4 ) and leukotriene E 4 (LTE 4 ) as a major leukotriene.
  • LTB 4 leukotriene B 4
  • LTC 4 leukotriene C 4
  • LTD 4 leukotriene D 4
  • LTE 4 leukotriene E 4
  • Biosynthesis of these leukotrienes is as follows: (a) production of an unstable epoxide known as leukotriene A 4 (LTA 4 ) produced from arachidonic acid by 5-lipoxigenase; and (b) conversion to other leukotrienes according to serial enzymatic reactions ⁇ Leukotrienes and Lipoxygenases, J. Rokach, Elsevier, Amsterdam, 1989).
  • Pranlukast and its hydrates represented by the following formula 1 are a compound having a strong antagonist activity to a leukotriene C 4 (LTC 4 ), leukotriene D 4 (LTD 4 ) and leukotriene E 4 (LTE 4 ) receptor, and have been used as a therapeutic agent for asthma and allergic rhinitis.
  • Pranlukast and its hydrates come into the market as a capsule of Onon® Cap. (112.5 mg pranlukast hydrates/capsule, Dong-A Pharmaceutical).
  • the acid chloride represented by formula 11 is obtained by reacting the benzoic derivative of formula 10 with the thionyl chloride. The resulting compound is reacted with the compound represented by formula 4.
  • the preparation method according to the reaction formula I has quite a few problems: (a) difficult manipulation due to utilizing excess amounts of toxic thionyl chlorides around a reflux temperature when the acid chloride represented by formula 11 is obtained by reacting the benzoic derivative of formula 10 with the thionyl chloride; (b) hard elimination of thionyl chlorides toxic in a body after terminating the reactions; (c) requirement of base in an equivalent ratio of above 4 to collect the compound represented by formula 7; (d) unsuitability of massive production in a economical area because the compound is modified into a form of natrium salt and then purified for removal of contaminants after preparing pranlukart.
  • the preparation method according to the reaction formula II has also the following difficulties: (a) it is difficult to perform the method due to utilizing excess amounts of toxic thionyl chlorides around a reflux temperature to obtain the acid chloride derivative in the preparation of the compounds represented by formula 8; (b) it is very difficult and toxic in body to eliminate thionyl chlorides after terminating the reactions; (c) it is not easy to massively produce the compounds of interest in an industrial-scale because much hydrazine toxic in body and nitrogen oxides harmful in environment are generated and unstable nitrous acids are used during the reactions.
  • Oxalyl chlorides are massively used because the preparation method according to the reaction formula III is very expensive cost and has highly hygroscopic characteristics. In addition, the method has to be carried out under violent conditions that the temperature is increased up to around reflux temperature using 1,2- dichloroethanol as a solvent and further reacted for 1 hr. It is also difficult to remove harmful carbon monoxide and chlorine gases massively generated in elimination of oxalyl chloride after terminating the reactions, and it is not feasible to be applied into an industrial mass-production because the reaction is carried out under conditions of anhydrous and inactive gases.
  • the present inventors have made intensive studies to develop a method for industrially producing pranlukart having a strong antagonistic activity to a leukotriene receptor in a stable and massive manner by an organic synthesis.
  • a novel method for economically preparing various amide derivatives containing pranlukart by reacting a carboxylic acid derivative and an amine derivative through a brief procedure compared with a conventional technology. Accordingly, it is an object of this invention to provide a method for preparing amide derivatives.
  • a method for preparing amide derivatives comprising the steps of: (a) obtaining an acid halide derivative by reacting a carboxylic acid derivative and a halogenating agent in a dimethylacetamide (DMAC) or N-methylpyrrolidine (NMP) solvent; and (b) producing an amide derivative by reacting the acid halide derivative with an amine derivative.
  • DMAC dimethylacetamide
  • NMP N-methylpyrrolidine
  • the present inventors have made intensive studies to develop a method for industrially producing pranlukart having a strong antagonistic activity to a leukotriene receptor in a stable and massive manner by an organic synthesis.
  • a novel method for economically preparing various amide derivatives containing pranlukart by reacting a carboxylic acid derivative and an amine derivative through a brief procedure compared with a conventional technology.
  • the preparation method of the present invention is to obtain an acid halide derivative by reacting a carboxylic acid derivative and a halogenating agent in a dimethylacetamide (DMAC) or N-methylpyrrolidine (NMP) solvent as an initial step.
  • DMAC dimethylacetamide
  • NMP N-methylpyrrolidine
  • dimethylacetamide (DMAC) or N- methylpyrrolidine (NMP) solvent is used as a reaction solvent.
  • the amount of the halogenating agent ⁇ e.g., chlorinating agent may be minimized.
  • the amount of dimethylacetamide (DMAC) or N- methylpyrrolidine (NMP) has a volume ratio of from 2 to 5-fold in respect to a starting material, and most preferably 3-fold.
  • the carboxylic acid used is the compound represented by the following formula 22: R 1 -A-COOH (22) wherein A represents a single bond, Ci -4 alkylene, vinylene, propenylene, butenylene or butadienylene; R 1 represents straight or branched, substituted or non- substituted Ci -I0 alkyl, alkenyl or alkynyl, or substituted or non-substituted aryl, alkaryl, aralkyl or heteroaryl.
  • A represents a single bond and Ri represents straight or branched, substituted or non-substituted Ci -I0 alkyl, or a group represented by the following formula 23:
  • X represents a carbon or nitrogen atom and R 2 and R 3 independently represents H, hydroxy, halogen, nitro, straight or branched, substituted or non- substituted Ci-I 0 alkyl, or substituted or non-substituted arylalkoxy.
  • alkylene used in the present invention refers to be straight or branched hydrocarbon radical of 1 to 4 carbon atoms, including, for example, methylene, ethylene and a structural isomer of propylene and butylene.
  • the alkylene group may be substituted with one or more substituents, including, for example, alkyl, halo, hydroxy, carbroxyl, amino, alkylamino, alkoxy, nitro, cyano, sulfuric acid or phosphoric acid.
  • substituents including, for example, alkyl, halo, hydroxy, carbroxyl, amino, alkylamino, alkoxy, nitro, cyano, sulfuric acid or phosphoric acid.
  • Ci-C 10 alkyl used in the present invention refers to a straight or branched saturated hydrocarbon group of 1 to 10 carbon atoms, and includes, for example, methyl, ethyl, propyl, isobutyl, pentyl, hexyl, octyl, nonyl and decil, but not limited to.
  • alkenyl used in the present invention means a straight or branched saturated hydrocarbon chain containing a designated number of carbon atoms and includes a hydrocarbon group containing one or more carbon-carbon double bonds.
  • a straight or branched C 2 -C 6 alkenyl hydrocarbon includes 2 to 6 carbon atoms containing one or more carbon-carbon double bonds, and includes the substituent such as ethenyl, propenyl, iso-propenyl, butenyl, iso-butenyl, tert-butenyl, n-pentenyl and n-hexenyl, but is not limited to.
  • alkynyl used in the present invention refers to a hydrocarbon radical containing optionally substituted (containing multiple substitutions) carbon atoms of 2 to 10 and one or more carbon-carbon triple bonds, including, for example, 4-hex-l inyl and 3,3-dimethyl-but-l inyl, but not limited to.
  • aryl used in the present invention refers to a saturated monocyclic or polycyclic carbon ring which can be substituted or unsubstituted wholly or partially, and preferably monoaryl or biaryl.
  • monoaryl includes the number of 5 to 6 carbon atoms
  • biaryl includes the number of 9 to 10 carbon atoms.
  • Monoaryl replaced with phenyl may be substituted with various substituents in a variety of positions, and preferably may be substituted with halo, hydroxy, nitro, cyano, substituted or unsubstituted straight or branched Ci-C 4 alkyl, straight or branched C 1 - C 4 alkoxy, alkyl-substituted sulfanyl, phenoxy, C 3 -C 6 cycloheteroalkyl, or substituted or unsubstituted amino group.
  • alkaryl (alkylaryl) used in the present invention refers to an alkyl that is covalently jointed to an aryl group.
  • aralkyl (arylalkyl) used in the present invention refers to an aryl that is substituted with one or more alkyl groups.
  • heteroaryl used in the present invention refers to a heterocyclic aromatic group which carries N, O or S atom as a heteroatom.
  • arylalkoxy used in the present invention refers to an arylalkyl group
  • arylalkyl-O ⁇ i.e., arylalkyl-O
  • the arylalkoxy includes 2-phenylethoxy, 3-napht-2-ylpropoxy and 5-phenylpentaoxy, but not limited to.
  • nitro used in the present invention means -NO 2 and the term “halogen” includes fluorine, chorine, bromine and iodine.
  • an amide bond between reaction compounds has to be formed.
  • the methods to form an amide bond are as follows: (a) a method using a mixed acid anhydride; (b) a method using an acid halide; and (c) a method using a dicydohexylcarbodimide (DCC).
  • DCC dicydohexylcarbodimide
  • the halogenating agent used in the present invention may include a fluorinating agent, a chlorinating agent, a brominating agent or an iodinating agent, preferably a chlorinating agent or a iodinating agent, more preferably a chlorinating agent, much more preferably the chlorinating agent selected from the group consisting of thionyl chloride, oxalyl chloride, phosphorous pentachloride and phosphorous oxytrichloride, and most preferably thionyl chloride or oxalyl chloride.
  • the utilization of the chlorinating agent may be minimized.
  • the chlorinating agent used in the reaction is used at an equivalent ratio of from 1 to 3, more preferably from 1 to 2, and most preferably from 1 to 1.2.
  • the reaction temperature is used in a range of -5°C to 10 0 C, and most preferably -1°C to 2°C.
  • the reaction time is used in a range of 10 min to 1 hr.
  • the acid halide derivative obtained from the reaction directly reacts with an amine derivative without an isolation process to produce the amide bond.
  • the amine derivative used in the present invention is represented by the following formula 24:
  • R 4 independently represents H, halogen, hydroxy, nitro or -COOR 6 (Re represents hydrogen or straight or branched CM 0 alkyl); B represents a 4-8 membered carbocyclic ring and one or more atoms of the 4-8 members may be an oxygen, nitrogen or sulfur atom, wherein the carbocyclic ring may be substituted with oxo, thioxo or hydroxy group; and R 5 exists with a proviso that B is the carbocyclic ring, and
  • R 5 represents or
  • B represents hydrogen, halogen, hydroxy, nitro, -COOR 7 (R 7 represents a hydrogen, or straight or branched C 1-I0 alkyl), -COR 8 (R 8 represents a hydrogen, or straight or branched Ci -I0 alkyl), or -X-CH 2 -R 9 (X represents an oxygen or sulfur atom, and R 9 represents proviso that B is not the carbocyclic ring;
  • U represents an oxygen or sulfur atom;
  • m and n represents an integer of 1-10;
  • p and q represent an integer of 0-10; and
  • R i0 represents a hydrogen or straight or branched Ci -6 alkyl.
  • R 4 represents H, hydroxy or -COOR 6 (R 6 represents hydrogen or straight or branched C 1-10 alkyl); B represents a 4-8 membered carbocyclic ring and one or more atoms of the 4-8 members may be an oxygen, nitrogen or sulfur atom, wherein the carbocyclic ring may be substituted with oxo or hydroxy group; and R 5 exists with a proviso that B is the carbocyclic ring, and R 5 represents
  • R 9 represents hydrogen, hydroxy, -COOR 7 (R 7 represents a hydrogen, or straight or branched Ci -10 alkyl), -COR 8 (R 8 represents a hydrogen, or straight or branched Ci -I0 alkyl), or -X-CH 2 -R 9 (X represents an oxygen or sulfur atom, and R 9 represents
  • R 4 represents H; B represents a 4-8 membered carbocyclic ring and one or more atoms of the 4-8 members may be an oxygen, wherein the carbocyclic ring may be substituted with oxo; and R 5 exists with a proviso that B is the carbocyclic ring, and R 5 represents
  • ⁇ X carbocycle refers to a non-aromatic hydrocarbon radical ring of 4 to 8 carbon atoms and the ring containing 5 to 8 carbon atoms may include a double bond in a structure, or form two rings in a structure.
  • the ring includes, but not limited to, cydopropyl, cyclobutyl, cydopentyl, cyclopentenyl, cyclohexyl and cycloheptyl.
  • ⁇ oxo refers to an oxygen atom as a substituent jointed to a carbon atom by a double bond
  • thioxo means a sulfur atom as a substituent jointed to a carbon atom by a double bond
  • the step (b) occurring the amide bond reaction is carried out under a base condition.
  • the base used in the step (b) may be any one of based utilized in the organochemistry conventionally, and includes, preferably triethylamine, pyridine, A- (dimethylamino)pyridine, 1-methyimidazol, imidazol or tertiary C 1 -C 5 alkylamine, more preferably triethylamine, pyridine or 4-(dimethylamino)pyridine, and most preferably triethylamine or pyridine.
  • the amount of base used in the preparation method of this invention is not particularly limited, and is preferably used at an equivalent ratio of from 1 to 10, more preferably from 1 to 5, and most preferably from 1 to 1.1.
  • reaction temperature and time may be varied depending on organic solvents or bases.
  • the reaction temperature may be used in a range of 0 0 C to 100 0 C, and most preferably 2O 0 C to 5O 0 C.
  • the reaction time is selected in a range of 2 hr to 7 hrs, preferably 3 hrs to 6 hrs, and most preferably 5 hrs.
  • the reaction temperature and time may be not limited to the above-described range, and variously applied depending on conditions.
  • the present method further includes the step, after the step reacting the acid halide derivative with the amine derivative, purifying a precipitate produced by adding the solvent to the resulting amide derivative.
  • the amide derivative synthesized by the preparation method of this invention is a final precipitate produced by adding the solvent.
  • the solvent used to form the precipitate may be selected from the group consisting of water, Ci-C 4 alcohol, acetonitrile, acetone, ethylacetate, tetahydrofuran, dioxane, toluene, xylene and a mixture thereof, and most preferably water or C x -C 4 alcohol.
  • the amide derivative with a high purity may be obtained by a purification process in which the precipitates are isolated by adding the solvent and then filtered.
  • the present method may further include the step performing a thermal reflux by adding the solvent to the precipitated reaction products.
  • the solvent selected from the group consisting of water, Ci-C 4 alcohol, acetonitrile, acetone and a mixture thereof or the mixed solvent of the above-described solvent and water may be added to the precipitates obtained in the purification process to obtain much more pure amide derivatives.
  • the amide derivatives obtained may be kept to stand on air to produce their hydrates.
  • the production of hydrates may be carried out at various temperatures, and most preferably at room temperature in respect to convenience.
  • the process to produce the hydride of the amide derivatives on air at room temperature may be varied depending on the compounds, and preferably be kept to stand on air for 0.5-20 hrs, more preferably 2-15 hrs, and most preferably 3-7 hrs.
  • the carboxylic acid derivative is a benzoic acid derivative represented by the following formula 10;
  • the amine derivative is a benzopyran amine derivative represented by the following formula 12; and
  • the resulting amide derivative is a compound represented by a formula 1:
  • n an integer of 0-4;
  • n an integer of 0-4;
  • the amine derivative of formula 12 may be used as a form of its base.
  • 8-amino-4-oxo-tetrazol-5-yl-4H-l-benzopyran acid addition salt may be used.
  • the compound represented by formula 12 may be a conventional acid addition salt and
  • an inorganic acid such as hydrochloric acid, sulfuric acid, nitric acid and
  • phenylbutoxy)benzamide may be obtained by reacting the above-described
  • reaction materials may be prepared according to the method disclosed in
  • the reaction product of formula 1, particularly pranlukart perse has a property
  • Pranlukart prepared is kept to stand on air at room temperature for 1-20 hrs, preferably 2-15 hrs and most preferably 3-7 hrs.
  • the method for preparing an amide derivative according to the present invention has some advantages capable of: (a) shortening production and purification process of contaminants by minimizing the amount of a toxic solvent difficult to be manipulated because the acid halide derivative as an intermediate compound is directly reacted with the amine derivative using a dimethylacetamide (DMAC) or N- methylpyrrolidine (NMP) solvent; (b) being quite suitable for massive production because the reaction time is short; and (c) obtaining amide derivatives at a high yield rate.
  • DMAC dimethylacetamide
  • NMP N- methylpyrrolidine
  • EXAMPLE 1 Preparation of Pranlukart Hemihydrates 4-(4-phenylbutoxy)benzoic acid (29.1 g; 1.1 equivalent ratio; prepared according to the method disclosed in US Pat. No. 4,780,469) was dissolved in 80 ml dimethylacetamide (DMAC, Aldrich) at 0 0 C and then thionyl chloride (14.2 g, 1.2 equivalent ratio, Aldrich) was gradually added to the solution.
  • DMAC dimethylacetamide
  • m-toluic acid (1.98 g, 1.1 equivalent ratio, Aldrich) was dissolved in 15 ml dimethylacetamide (DMAC, Aldrich) at 0 0 C and then thionyl chloride (1.81 g, 1.15 equivalent ratio) was gradually added to the solution. After the mixture solution was stirred for 10 min at 0 0 C, the mixture of l-(3-amino-2-hydroxy-phenyl)-ethanone (2 g, 1 equivalent ratio) dissolved in 15 ml dimethylacetamide (DMAC, Aldrich) was slowly added to the mixture solution, and thermally stirred for 5 hrs at 25°C.
  • DMAC dimethylacetamide
  • Picolic acid (1.79 g, 1.1 equivalent ratio, Aldrich) was dissolved in 15 ml dimethylacetamide (DMAC, Aldrich) at 0 0 C and then thionyl chloride (1.81 g, 1.15 equivalent ratio) was gradually added to the solution. After the mixture solution was stirred for 10 min at 0 0 C, the mixture of l-(3-amino-2-hydroxy-phenyl)-ethanone (2 g, 1 equivalent ratio) dissolved in 15 ml dimethylacetamide (DMAC, Aldrich) was slowly added to the mixture solution, and thermally stirred for 5 hrs at 25°C. The reaction mixture was mixed with 40 ml H 2 O and stirred for 1 hr at 25°C.
  • 2-nitrobenzoic acid (2.43 g, 1.1 equivalent ratio, Aldrich) was dissolved in 15 ml dimethylacetamide (DMAC, Aldrich) at 0 0 C and then thionyl chloride (1.81 g, 1.15 equivalent ratio) was gradually added to the solution. After the mixture solution was stirred for 10 min at O 0 C, the mixture of l-(3-amino-2-hydroxy-phenyl)-ethanone (2 g, 1 equivalent ratio) dissolved in 15 ml dimethylacetamide (DMAC, Aldrich) was slowly added to the mixture solution, and thermally stirred for 5 hrs at 25 0 C. The reaction mixture was mixed with 40 ml H 2 O and stirred for 1 hr at 25°C.
  • 3-nitrobenzoic acid (2.43 g, 1.1 equivalent ratio, Aldrich) was dissolved in 15 ml dimethylacetamide (DMAC, Aldrich) at 0 0 C and then thionyl chloride (1.81 g, 1.15 equivalent ratio) was gradually added to the solution. After the mixture solution was stirred for 10 min at 0 0 C, the mixture of l-(3-amino-2-hydroxy-phenyl)-ethanone (2 g, 1 equivalent ratio) dissolved in 15 ml dimethylacetamide (DMAC, Aldrich) was slowly added to the mixture solution, and thermally stirred for 5 hrs at 25°C. The reaction mixture was mixed with 40 ml H 2 O and stirred for 1 hr at 25°C.
  • Nitrobenzoic acid (6.1 g, 1.1 equivalent ratio, Aldrich) was dissolved in 15 ml dimethylacetamide (DMAC, Aldrich) at 0 0 C and then thionyl chloride (6.21 g, 1.15 equivalent ratio) was gradually added to the solution. After the mixture solution was stirred for 10 min at 0 0 C, the mixture of l-(3-amino-2-hydroxy-phenyl)-ethanone (6.86 g, 1 equivalent ratio) dissolved in 15 ml dimethylacetamide (DMAC, Aldrich) was slowly added to the mixture solution, and thermally stirred for 5 hrs at 25°C.
  • DMAC dimethylacetamide

Abstract

The present invention provides a novel method for preparing an amide derivative. The method of the present invention enables to economically prepare various amide derivatives containing pranlukart by reacting a carboxylic acid derivative 5 and an amine derivative through a brief procedure compared with a conventional technology, and permits to obtain a final product at a high yield rate because it is feasible to eliminate by-products after termination of reactions. Accordingly, the present method is to be quite suitable for massive production.

Description

METHODS FOR PREPARING AMIDE DERIVATIVES
BACKGROUND OF THE INVENTION FIELD OF THE INVENTION The present invention relates to a method for preparing amide derivatives.
BACKGROUND OF TECHNIQUE
Leukotriene as a biological metabolite of arachidonic acid is liberated from mast cells or eosinophils. There are leukotriene B4 (LTB4), leukotriene C4 (LTC4), leukotriene D4 (LTD4) and leukotriene E4 (LTE4) as a major leukotriene. Biosynthesis of these leukotrienes is as follows: (a) production of an unstable epoxide known as leukotriene A4 (LTA4) produced from arachidonic acid by 5-lipoxigenase; and (b) conversion to other leukotrienes according to serial enzymatic reactions {Leukotrienes and Lipoxygenases, J. Rokach, Elsevier, Amsterdam, 1989). Pranlukast and its hydrates represented by the following formula 1 are a compound having a strong antagonist activity to a leukotriene C4 (LTC4), leukotriene D4 (LTD4) and leukotriene E4 (LTE4) receptor, and have been used as a therapeutic agent for asthma and allergic rhinitis. Pranlukast and its hydrates come into the market as a capsule of Onon® Cap. (112.5 mg pranlukast hydrates/capsule, Dong-A Pharmaceutical).
Figure imgf000003_0001
The conventional method for preparing pranlukast was disclosed in US Pat. No. 5,587,483 and pranlukart is prepared by the following reaction formula I.
Reaction Formula I
Figure imgf000003_0002
As described in the reaction formula I, the acid chloride represented by formula 11 is obtained by reacting the benzoic derivative of formula 10 with the thionyl chloride. The resulting compound is reacted with the compound represented by formula 4. The compound (n = 4) represented by formula 5 is reacted with the tetrazol derivative represented by formula 6 to introduce tetrazol group and then benzopyran ring is formed, preparing pranlukast. However, the preparation method according to the reaction formula I has quite a few problems: (a) difficult manipulation due to utilizing excess amounts of toxic thionyl chlorides around a reflux temperature when the acid chloride represented by formula 11 is obtained by reacting the benzoic derivative of formula 10 with the thionyl chloride; (b) hard elimination of thionyl chlorides toxic in a body after terminating the reactions; (c) requirement of base in an equivalent ratio of above 4 to collect the compound represented by formula 7; (d) unsuitability of massive production in a economical area because the compound is modified into a form of natrium salt and then purified for removal of contaminants after preparing pranlukart.
On the other hand, as described in the following reaction formula II in US Pat. No. 5,874,593, nitril compounds of formula 8 are reacted with hydrazine to prepare amidrazone compounds of formula 9a and 9b, and then pranlukart is fabricated by performing a tetrazol ring reaction using nitrous acids.
Reaction Formula II
Figure imgf000004_0001
However, the preparation method according to the reaction formula II has also the following difficulties: (a) it is difficult to perform the method due to utilizing excess amounts of toxic thionyl chlorides around a reflux temperature to obtain the acid chloride derivative in the preparation of the compounds represented by formula 8; (b) it is very difficult and toxic in body to eliminate thionyl chlorides after terminating the reactions; (c) it is not easy to massively produce the compounds of interest in an industrial-scale because much hydrazine toxic in body and nitrogen oxides harmful in environment are generated and unstable nitrous acids are used during the reactions.
Likewise, US Pat. No. 5,874,593, as described in the following reaction formula III, discloses that benzoic derivatives of formula 10' are reacted with oxalyl chlorides to isolate acid chlorides represented by formula 11', and the resulting acid chlorides are reacted with benzopyran amine derivatives containing tetrazol of formula 12, producing various derivatives containing pranlukart.
Reaction Formula III
Figure imgf000005_0001
( I D' ] (H ' )
Figure imgf000005_0002
Oxalyl chlorides are massively used because the preparation method according to the reaction formula III is very expensive cost and has highly hygroscopic characteristics. In addition, the method has to be carried out under violent conditions that the temperature is increased up to around reflux temperature using 1,2- dichloroethanol as a solvent and further reacted for 1 hr. It is also difficult to remove harmful carbon monoxide and chlorine gases massively generated in elimination of oxalyl chloride after terminating the reactions, and it is not feasible to be applied into an industrial mass-production because the reaction is carried out under conditions of anhydrous and inactive gases.
The above-described problems are generated in the synthesis of various amide derivatives containing pranlukart described in the present invention. Hence, the present inventors developed a method for preparing a novel amide derivative to overcome problems of conventional methods.
Throughout this application, various publications and patents are referred and citations are provided in parentheses. The disclosures of these publications and patents in their entities are hereby incorporated by references into this application in order to fully describe this invention and the state of the art to which this invention pertains.
DETAILED DESCRIPTION OF THE INVENTION
The present inventors have made intensive studies to develop a method for industrially producing pranlukart having a strong antagonistic activity to a leukotriene receptor in a stable and massive manner by an organic synthesis. As results, we have discovered a novel method for economically preparing various amide derivatives containing pranlukart by reacting a carboxylic acid derivative and an amine derivative through a brief procedure compared with a conventional technology. Accordingly, it is an object of this invention to provide a method for preparing amide derivatives. Other objects and advantages of the present invention will become apparent from the following detailed description together with the appended claims and drawings.
In one aspect of this invention, there is provided a method for preparing amide derivatives, comprising the steps of: (a) obtaining an acid halide derivative by reacting a carboxylic acid derivative and a halogenating agent in a dimethylacetamide (DMAC) or N-methylpyrrolidine (NMP) solvent; and (b) producing an amide derivative by reacting the acid halide derivative with an amine derivative.
The present inventors have made intensive studies to develop a method for industrially producing pranlukart having a strong antagonistic activity to a leukotriene receptor in a stable and massive manner by an organic synthesis. As results, we have discovered a novel method for economically preparing various amide derivatives containing pranlukart by reacting a carboxylic acid derivative and an amine derivative through a brief procedure compared with a conventional technology.
The preparation method of the present invention is to obtain an acid halide derivative by reacting a carboxylic acid derivative and a halogenating agent in a dimethylacetamide (DMAC) or N-methylpyrrolidine (NMP) solvent as an initial step.
It is one of most features of this invention that dimethylacetamide (DMAC) or N- methylpyrrolidine (NMP) solvent is used as a reaction solvent. In reaction of the present invention in the presence of dimethylacetamide (DMAC) or N-methylpyrrolidine (NMP), the amount of the halogenating agent {e.g., chlorinating agent) may be minimized. Preferably, the amount of dimethylacetamide (DMAC) or N- methylpyrrolidine (NMP) has a volume ratio of from 2 to 5-fold in respect to a starting material, and most preferably 3-fold.
According to a preferable embodiment, the carboxylic acid used is the compound represented by the following formula 22: R1-A-COOH (22) wherein A represents a single bond, Ci-4 alkylene, vinylene, propenylene, butenylene or butadienylene; R1 represents straight or branched, substituted or non- substituted Ci-I0 alkyl, alkenyl or alkynyl, or substituted or non-substituted aryl, alkaryl, aralkyl or heteroaryl.
According to a preferable embodiment, A represents a single bond and Ri represents straight or branched, substituted or non-substituted Ci-I0 alkyl, or a group represented by the following formula 23:
Figure imgf000008_0001
wherein X represents a carbon or nitrogen atom and R2 and R3 independently represents H, hydroxy, halogen, nitro, straight or branched, substituted or non- substituted Ci-I0 alkyl, or substituted or non-substituted arylalkoxy. The term "aikylene" used in the present invention refers to be straight or branched hydrocarbon radical of 1 to 4 carbon atoms, including, for example, methylene, ethylene and a structural isomer of propylene and butylene. The alkylene group may be substituted with one or more substituents, including, for example, alkyl, halo, hydroxy, carbroxyl, amino, alkylamino, alkoxy, nitro, cyano, sulfuric acid or phosphoric acid.
The term "Ci-C10 alkyl" used in the present invention refers to a straight or branched saturated hydrocarbon group of 1 to 10 carbon atoms, and includes, for example, methyl, ethyl, propyl, isobutyl, pentyl, hexyl, octyl, nonyl and decil, but not limited to.
The term "alkenyl" used in the present invention means a straight or branched saturated hydrocarbon chain containing a designated number of carbon atoms and includes a hydrocarbon group containing one or more carbon-carbon double bonds. For example, a straight or branched C2-C6 alkenyl hydrocarbon includes 2 to 6 carbon atoms containing one or more carbon-carbon double bonds, and includes the substituent such as ethenyl, propenyl, iso-propenyl, butenyl, iso-butenyl, tert-butenyl, n-pentenyl and n-hexenyl, but is not limited to.
The term "alkynyl" used in the present invention refers to a hydrocarbon radical containing optionally substituted (containing multiple substitutions) carbon atoms of 2 to 10 and one or more carbon-carbon triple bonds, including, for example, 4-hex-l inyl and 3,3-dimethyl-but-l inyl, but not limited to. The term "aryl" used in the present invention refers to a saturated monocyclic or polycyclic carbon ring which can be substituted or unsubstituted wholly or partially, and preferably monoaryl or biaryl. Preferably, monoaryl includes the number of 5 to 6 carbon atoms, and biaryl includes the number of 9 to 10 carbon atoms. Monoaryl replaced with phenyl may be substituted with various substituents in a variety of positions, and preferably may be substituted with halo, hydroxy, nitro, cyano, substituted or unsubstituted straight or branched Ci-C4 alkyl, straight or branched C1- C4 alkoxy, alkyl-substituted sulfanyl, phenoxy, C3-C6 cycloheteroalkyl, or substituted or unsubstituted amino group. The term "alkaryl (alkylaryl)" used in the present invention refers to an alkyl that is covalently jointed to an aryl group. The term "aralkyl (arylalkyl)" used in the present invention refers to an aryl that is substituted with one or more alkyl groups. The term "heteroaryl" used in the present invention refers to a heterocyclic aromatic group which carries N, O or S atom as a heteroatom. The term "arylalkoxy" used in the present invention refers to an arylalkyl group
{i.e., arylalkyl-O) that is covalently jointed to the residue of parent molecule via oxy residue. For example, the arylalkoxy includes 2-phenylethoxy, 3-napht-2-ylpropoxy and 5-phenylpentaoxy, but not limited to.
The term "nitro" used in the present invention means -NO2 and the term "halogen" includes fluorine, chorine, bromine and iodine.
Illustrative examples of the compounds used in the present invention are described in the Examples below. To obtain final products in the present invention, an amide bond between reaction compounds has to be formed. The methods to form an amide bond are as follows: (a) a method using a mixed acid anhydride; (b) a method using an acid halide; and (c) a method using a dicydohexylcarbodimide (DCC). The present method is carried out according to the acid halide method, and its detailed description is disclosed in US Pat. No. 4,780,469.
To synthesize the amide bond using the acid halide in the present invention the carboxylic acid derivative as a starting material has to be reacted with the halogenating agent. The halogenating agent used in the present invention may include a fluorinating agent, a chlorinating agent, a brominating agent or an iodinating agent, preferably a chlorinating agent or a iodinating agent, more preferably a chlorinating agent, much more preferably the chlorinating agent selected from the group consisting of thionyl chloride, oxalyl chloride, phosphorous pentachloride and phosphorous oxytrichloride, and most preferably thionyl chloride or oxalyl chloride. According to the preparation method of this invention, the utilization of the chlorinating agent may be minimized. Preferably, the chlorinating agent used in the reaction is used at an equivalent ratio of from 1 to 3, more preferably from 1 to 2, and most preferably from 1 to 1.2.
According to the preparation method of this invention, it is preferable to perform the reaction at a temperature between -5°C and 25°C. More preferably, the reaction temperature is used in a range of -5°C to 100C, and most preferably -1°C to 2°C. The reaction time is used in a range of 10 min to 1 hr. According to a preferable embodiment, the acid halide derivative obtained from the reaction directly reacts with an amine derivative without an isolation process to produce the amide bond.
According to a preferable embodiment, the amine derivative used in the present invention is represented by the following formula 24:
Figure imgf000012_0001
wherein R4 independently represents H, halogen, hydroxy, nitro or -COOR6 (Re represents hydrogen or straight or branched CM0 alkyl); B represents a 4-8 membered carbocyclic ring and one or more atoms of the 4-8 members may be an oxygen, nitrogen or sulfur atom, wherein the carbocyclic ring may be substituted with oxo, thioxo or hydroxy group; and R5 exists with a proviso that B is the carbocyclic ring, and
— U— (CH2)OT— ~(CH2)p— COOR10
R5 represents
Figure imgf000012_0002
or
Figure imgf000012_0003
; and B represents hydrogen, halogen, hydroxy, nitro, -COOR7 (R7 represents a hydrogen, or straight or branched C1-I0 alkyl), -COR8 (R8 represents a hydrogen, or straight or branched Ci-I0 alkyl), or -X-CH2-R9 (X represents an oxygen or sulfur atom, and R9 represents
Figure imgf000013_0001
proviso that B is not the carbocyclic ring; U represents an oxygen or sulfur atom; m and n represents an integer of 1-10; p and q represent an integer of 0-10; and Ri0 represents a hydrogen or straight or branched Ci-6 alkyl. Preferably, R4 represents H, hydroxy or -COOR6 (R6 represents hydrogen or straight or branched C1-10 alkyl); B represents a 4-8 membered carbocyclic ring and one or more atoms of the 4-8 members may be an oxygen, nitrogen or sulfur atom, wherein the carbocyclic ring may be substituted with oxo or hydroxy group; and R5 exists with a proviso that B is the carbocyclic ring, and R5 represents
Figure imgf000013_0002
represents hydrogen, hydroxy, -COOR7 (R7 represents a hydrogen, or straight or branched Ci-10 alkyl), -COR8 (R8 represents a hydrogen, or straight or branched Ci-I0 alkyl), or -X-CH2-R9 (X represents an oxygen or sulfur atom, and R9 represents
Figure imgf000013_0003
proviso that B is not the carbocyclic ring; U represents an oxygen or sulfur atom; m and n represents an integer of 1-5; p and q represent zero or an integer of 1-5; and Ri0 represents a hydrogen or straight or branched Ci-4 alkyl. Most preferably, R4 represents H; B represents a 4-8 membered carbocyclic ring and one or more atoms of the 4-8 members may be an oxygen, wherein the carbocyclic ring may be substituted with oxo; and R5 exists with a proviso that B is the carbocyclic ring, and R5 represents
Figure imgf000014_0001
; q represent zero; and B is represented by -COR8 (Rs represents hydrogen or straight or branched Ci-3 alkyl) with a proviso that B is not the carbocyclic ring. The term λXcarbocycle" used in the present invention refers to a non-aromatic hydrocarbon radical ring of 4 to 8 carbon atoms and the ring containing 5 to 8 carbon atoms may include a double bond in a structure, or form two rings in a structure. For example, the ring includes, but not limited to, cydopropyl, cyclobutyl, cydopentyl, cyclopentenyl, cyclohexyl and cycloheptyl. The term λΛoxo" used in the present invention refers to an oxygen atom as a substituent jointed to a carbon atom by a double bond, and the term "thioxo" means a sulfur atom as a substituent jointed to a carbon atom by a double bond.
Illustrative examples of the compounds used in the present invention are described in the Examples below. According to a preferable embodiment, the step (b) occurring the amide bond reaction is carried out under a base condition.
The base used in the step (b) may be any one of based utilized in the organochemistry conventionally, and includes, preferably triethylamine, pyridine, A- (dimethylamino)pyridine, 1-methyimidazol, imidazol or tertiary C1-C5 alkylamine, more preferably triethylamine, pyridine or 4-(dimethylamino)pyridine, and most preferably triethylamine or pyridine. The amount of base used in the preparation method of this invention is not particularly limited, and is preferably used at an equivalent ratio of from 1 to 10, more preferably from 1 to 5, and most preferably from 1 to 1.1.
In reaction of the acid halide derivative compounds and amine derivative, the reaction temperature and time may be varied depending on organic solvents or bases.
Preferably, the reaction temperature may be used in a range of 00C to 1000C, and most preferably 2O0C to 5O0C. In addition, the reaction time is selected in a range of 2 hr to 7 hrs, preferably 3 hrs to 6 hrs, and most preferably 5 hrs. The reaction temperature and time may be not limited to the above-described range, and variously applied depending on conditions.
According to a preferable embodiment, the present method further includes the step, after the step reacting the acid halide derivative with the amine derivative, purifying a precipitate produced by adding the solvent to the resulting amide derivative.
The amide derivative synthesized by the preparation method of this invention is a final precipitate produced by adding the solvent. The solvent used to form the precipitate may be selected from the group consisting of water, Ci-C4 alcohol, acetonitrile, acetone, ethylacetate, tetahydrofuran, dioxane, toluene, xylene and a mixture thereof, and most preferably water or Cx-C4 alcohol. The amide derivative with a high purity may be obtained by a purification process in which the precipitates are isolated by adding the solvent and then filtered.
According to a preferable embodiment, the present method may further include the step performing a thermal reflux by adding the solvent to the precipitated reaction products. The solvent selected from the group consisting of water, Ci-C4 alcohol, acetonitrile, acetone and a mixture thereof or the mixed solvent of the above-described solvent and water may be added to the precipitates obtained in the purification process to obtain much more pure amide derivatives. On the other hand, the amide derivatives obtained may be kept to stand on air to produce their hydrates. The production of hydrates may be carried out at various temperatures, and most preferably at room temperature in respect to convenience. The process to produce the hydride of the amide derivatives on air at room temperature may be varied depending on the compounds, and preferably be kept to stand on air for 0.5-20 hrs, more preferably 2-15 hrs, and most preferably 3-7 hrs.
According to a preferable embodiment, the carboxylic acid derivative is a benzoic acid derivative represented by the following formula 10; the amine derivative is a benzopyran amine derivative represented by the following formula 12; and the resulting amide derivative is a compound represented by a formula 1:
Figure imgf000016_0001
n represents an integer of 0-4;
Figure imgf000016_0002
n represents an integer of 0-4;
Figure imgf000017_0001
(12) Where n represents 4, the compound represented by formula 10 is 4-(4-
phenylbutoxy)benxoic acid, and the compound represented by formula 12 is 8-amino-
4-oxo-tetrazol-5-yl-4H-l-benzopyran.
The amine derivative of formula 12 may be used as a form of its base. For
example, 8-amino-4-oxo-tetrazol-5-yl-4H-l-benzopyran acid addition salt may be used.
The compound represented by formula 12 may be a conventional acid addition salt and
preferably an inorganic acid such as hydrochloric acid, sulfuric acid, nitric acid and
phosphoric acid or acetic acid, or an organic acid such as citric acid and oxalic acid,
and most preferably, 8-amino-4-oxo-tetrazol-5-yl-4H-l-benzopyran hydrochloride salt.
Pranlukast (N-[4-oxo-2-(lH-tetrazol-5-yl)-4H-l-benzopyran-8-yl]-4-(4-
phenylbutoxy)benzamide) may be obtained by reacting the above-described
compounds according to the preparation method of this invention. The derivatives
used as the reaction materials may be prepared according to the method disclosed in
US Pat. No. 4,780,469.
The reaction product of formula 1, particularly pranlukart perse has a property
to form a hemihydrate (1/2 hydrate) by absorbing a moisture on air. Pranlukart prepared is kept to stand on air at room temperature for 1-20 hrs, preferably 2-15 hrs and most preferably 3-7 hrs.
The method for preparing an amide derivative according to the present invention has some advantages capable of: (a) shortening production and purification process of contaminants by minimizing the amount of a toxic solvent difficult to be manipulated because the acid halide derivative as an intermediate compound is directly reacted with the amine derivative using a dimethylacetamide (DMAC) or N- methylpyrrolidine (NMP) solvent; (b) being quite suitable for massive production because the reaction time is short; and (c) obtaining amide derivatives at a high yield rate.
The present invention will now be described in further detail by examples. It would be obvious to those skilled in the art that these examples are intended to be more concretely illustrative and the scope of the present invention as set forth in the appended claims is not limited to or by the examples.
EXAMPLES EXAMPLE 1: Preparation of Pranlukart Hemihydrates 4-(4-phenylbutoxy)benzoic acid (29.1 g; 1.1 equivalent ratio; prepared according to the method disclosed in US Pat. No. 4,780,469) was dissolved in 80 ml dimethylacetamide (DMAC, Aldrich) at 00C and then thionyl chloride (14.2 g, 1.2 equivalent ratio, Aldrich) was gradually added to the solution. After the mixture solution was stirred for 10 min at 00C, the mixture of 8-amino-4-oxo-tetrazol-5-yl-4H- 1-benzopyran hydrochloride salt (26.7 g; 1 equivalent ratio; prepared according to the method disclosed in US Pat. No. 4,780,469) and triethylamine (TEA, 10.1 g, 1 equivalent ratio, Aldrich) dissolved in 80 ml dimethylacetamide (DMAC, Aldrich) was slowly added to the mixture solution, and thermally stirred for 5 hrs at 25°C. The reaction mixture was mixed with 300 ml H2O and stirred for 1 hr at 250C. The solid material obtained by filtering the solid material produced was washed with 100 ml H2O. 200 ml 50% acetone aqueous solution was added to the solid material and then refluxed for 1 hr. After the reaction mixture was cooled to room temperature, filtered and air-dried, the mixture was kept to stand on air for 5 hrs, obtaining 47.0 g pranlukart hemihydrates (yield rate: 98%): melting point 231-233°C (decomposition); 1H-NMR (DMSO-d6, 300 MHz) δ 1.9 (m, 4H), 2,7 (m, 2H), 4.0 (t, 2H), 7.0 (s, 2H), 7.1 (s, IH), 7.2-7.3 (m, 5H), 7.6 (t, IH), 7.9 (t, IH), 8.0 (m, 2H), 8.3 (t, IH), 10.0 (bs, IH).
EXAMPLE 2: Preparation of Pranlukart Hemihydrates - Substitution of the Chlorinating Agent
4-(4-phenylbutoxy)benzoic acid (29.1 g, 1.1 equivalent ratio) was dissolved in 80 ml dimethylacetamide (DMAC) at 00C and then oxalyl chloride (15.2 g, 1.2 equivalent ratio, Aldrich) was gradually added to the solution. After the mixture solution was stirred for 10 min at 00C, the mixture of 8-amino-4-oxo-tetrazol-5-yl-4H- 1-benzopyran hydrochloride salt (26.7 g; 1 equivalent ratio) and triethylamine (TEA, 10.1 g, 1 equivalent ratio) dissolved in 80 ml dimethylacetamide (DMAC) solution was slowly added to the mixture solution, and thermally stirred for 5 hrs at 25°C. The reaction mixture was mixed with 300 ml H2O and stirred for 1 hr at 25°C. The solid material obtained by filtering the solid material produced was washed with 100 ml H2O. 200 ml 50% acetone aqueous solution was added to the solid material and then refluxed for 1 hr. After the reaction mixture was cooled to room temperature, filtered and air-dried, the mixture was kept to stand on air for 5 hrs, obtaining 43.3 g pranlukart hemihydrates (yield rate: 92%).
EXAMPLE 3: Preparation of Pranlukart Hemihydrates - Change of Base Condition
4-(4-phenylbutoxy)benzoic acid (29.1 g, 1.1 equivalent ratio) was dissolved in 80 ml dimethylacetamide (DMAC) at 00C and then thionyl chloride (14.2 g, 1.2 equivalent ratio) was gradually added to the solution. After the mixture solution was stirred for 10 min at 00C, the mixture of 8-amino-4-oxo-tetrazol-5-yl-4H-l-benzopyran hydrochloride salt (26.7 g; 1 equivalent ratio) and pyridine (7.9 g, 1 equivalent ratio, Aldrich) dissolved in 80 ml dimethylacetamide (DMAC) solution was slowly added to the mixture solution, and thermally stirred for 5 hrs at 25°C. The reaction mixture was mixed with 300 ml H2O and stirred for 1 hr at 25°C. The solid material obtained by filtering the solid material produced was washed with 100 ml H2O. 200 ml 50% acetone aqueous solution was added to the solid material and then refluxed for 1 hr. After the reaction mixture was cooled to room temperature, filtered and air-dried, the mixture was kept to stand on air for 5 hrs, obtaining 45.6 g pranlukart hemihydrates (yield rate: 95%).
EXAMPLE 4: Preparation of Pranlukart Hemihydrates - Change of Reaction Temperature Condition
4-(4-phenylbutoxy)benzoic acid (29.1 g, 1.1 equivalent ratio) was dissolved in 80 ml dimethylacetamide (DMAC) at 00C and then thionyl chloride (14.2 g, 1.2 equivalent ratio) was gradually added to the solution. After the mixture solution was stirred for 10 min at O0C, the mixture of 8-amino-4-oxo-tetrazol-5-yl-4H-l-benzopyran hydrochloride salt (26.7 g; 1 equivalent ratio) and triethylamine (TEZ, 10.1 g, 1 equivalent ratio) dissolved in 80 ml dimethylacetamide (DMAC) solution was slowly added to the mixture solution, and thermally stirred for 4 hrs at 500C. The reaction mixture was mixed with 300 ml H2O and stirred for 1 hr at 500C. The solid material obtained by filtering the solid material produced was washed with 100 ml H2O. 200 ml 50% acetone aqueous solution was added to the solid material and then refluxed for 1 hr. After the reaction mixture was cooled to room temperature, filtered and air-dried, the mixture was kept to stand on air for 5 hrs, obtaining 45.6 g pranlukart hemihydrates (yield rate: 95%).
EXAMPLE 5: Preparation of Pranlukart Hemihydrates - Substitution of Reaction Solvent 4-(4-phenylbutoxy)benzoic acid (29.1 g, 1.1 equivalent ratio) was dissolved in 80 ml N-methylpyrrolidine (NMP, Aldrich) at O0C and then thionyl chloride (14.2 g, 1.2 equivalent ratio) was gradually added to the solution. After the mixture solution was stirred for 10 min at 00C, the mixture of 8-amino-4-oxo-tetrazol-5-yl-4H-l-benzopyran hydrochloride salt (26.7 g; 1 equivalent ratio) and triethylamine (TEZ, 10.1 g, 1 equivalent ratio) dissolved in 80 ml N-methylpyrrolidine (NMP) solution was slowly added to the mixture solution, and thermally stirred for 4 hrs at 250C. The reaction mixture was mixed with 300 ml H2O and stirred for 1 hr at 25°C. The solid material obtained by filtering the solid material produced was washed with 100 ml H2O. 200 ml 50% acetone aqueous solution was added to the solid material and then refluxed for 1 hr. After the reaction mixture was cooled to room temperature, filtered and air-dried, the mixture was kept to stand on air for 5 hrs, obtaining 43.3 g pranlukart hemihydrates (yield rate: 90%).
EXAMPLE 6: Preparation of Pranlukart Hemihydrates - Equivalent Ratio Change of the Chlorinating Agent
4-(4-phenylbutoxy)benzoic acid (29.1 g, 1.1 equivalent ratio) was dissolved in 80 ml dimethylacetamide (DMAC) at 00C and then thionyl chloride (14.2 g, 1 equivalent ratio) was gradually added to the solution. After the mixture solution was stirred for 10 min at 00C, the mixture of 8-amino-4-oxo-tetrazol-5-yl-4H-l-benzopyran hydrochloride salt (26.7 g, 1 equivalent ratio) and triethylamine (TEZ, 10.1 g, 1 equivalent ratio) dissolved in 80 ml dimethylacetamide (DMAC) solution was slowly added to the mixture solution, and thermally stirred for 4 hrs at 25°C. The reaction mixture was mixed with 300 ml H2O and stirred for 1 hr at 25°C. The solid material obtained by filtering the solid material produced was washed with 100 ml H2O. 200 ml 50% acetone aqueous solution was added to the solid material and then refluxed for 1 hr. After the reaction mixture was cooled to room temperature, filtered and air-dried, the mixture was kept to stand on air for 5 hrs, obtaining 44.6 g pranlukart hemihydrates (yield rate: 93%).
EXAMPLE 7: Preparation of (N-(3-acetyl-2-hydroxyphenyl)-3-methy-
Figure imgf000023_0001
m-toluic acid (1.98 g, 1.1 equivalent ratio, Aldrich) was dissolved in 15 ml dimethylacetamide (DMAC, Aldrich) at 00C and then thionyl chloride (1.81 g, 1.15 equivalent ratio) was gradually added to the solution. After the mixture solution was stirred for 10 min at 00C, the mixture of l-(3-amino-2-hydroxy-phenyl)-ethanone (2 g, 1 equivalent ratio) dissolved in 15 ml dimethylacetamide (DMAC, Aldrich) was slowly added to the mixture solution, and thermally stirred for 5 hrs at 25°C. The reaction mixture was mixed with 40 ml H2O and stirred for 1 hr at 25°C. The solid material obtained by filtering the solid material produced was washed with 20 ml H2O and then dried at 600C with hot-wind, obtaining 3.31 g (yield rate: 93%): 1H NMR (400 MHz, DMSO) δ 12.62 (s, IH) 9.58 (s, IH) 7.98 (d, IH7 J = 6.2 Hz) 7.77 (m, 3H) 7.41 (d, 2H, J = 3.8 Hz) 7.01 (t, IH, J= 6.3 Hz) 2.71 (s, 3H) 2.39 (s, 3H).
EXAMPLE 8: Preparation of (Pyridine-2-carboxylic acid(3-acetyl-2- hydroxyphenyl)-amide)
Figure imgf000024_0001
Picolic acid (1.79 g, 1.1 equivalent ratio, Aldrich) was dissolved in 15 ml dimethylacetamide (DMAC, Aldrich) at 00C and then thionyl chloride (1.81 g, 1.15 equivalent ratio) was gradually added to the solution. After the mixture solution was stirred for 10 min at 00C, the mixture of l-(3-amino-2-hydroxy-phenyl)-ethanone (2 g, 1 equivalent ratio) dissolved in 15 ml dimethylacetamide (DMAC, Aldrich) was slowly added to the mixture solution, and thermally stirred for 5 hrs at 25°C. The reaction mixture was mixed with 40 ml H2O and stirred for 1 hr at 25°C. The solid material obtained by filtering the solid material produced was washed with 20 ml H2O and then dried at 600C with hot-wind, obtaining 3.38 g (yield rate: 95%): 1H NMR (400 MHz, DMSO) δ 12.89 (bs, IH) 10.56 (s, IH) 8.75 (d, IH, J = 3.6 Hz) 8.67 (d, IH, J = 5.4 Hz) 8.19 (d, IH, J = 6.2 Hz) 8.10 (t, IH, J = 6.2 Hz) 7.72 (m, 2H) 7.06 (t, IH, J = 6.4 Hz) 2.69 (s, 3H). EXAMPLE 9: Preparation of (N-(3-acetyl-2-hydiOxyphenyl)-4-nitro- benzamide)
Figure imgf000025_0001
4-nitrobenzoic acid (24.32 g, 1.1 equivalent ratio, Aldrich) was dissolved in 50 ml dimethylacetamide (DMAC, Aldrich) at 00C and then thionyl chloride (1.81 g, 1.15 equivalent ratio) was gradually added to the solution. After the mixture solution was stirred for 10 min at 00C, the mixture of l-(3-amino-2-hydroxy-phenyl)-ethanone (20 g, 1 equivalent ratio) dissolved in 50 ml dimethylacetamide (DMAC, Aldrich) was slowly added to the mixture solution, and thermally stirred for 5 hrs at 25°C. The reaction mixture was mixed with 40 ml H2O and stirred for 1 hr at 25°C. The solid material obtained by filtering the solid material produced was washed with 20 ml H2O and then dried at 600C with hot-wind, obtaining 36.9 g (yield rate: 93%): 1H NMR (400 MHz, DMSO) δ 12.61 (bs, IH) 10.09 (bs, IH) 8.37 (d, IH, J = 7.0 Hz) 8.20 (d, 2H, J = 6.96 Hz) 7.89 (m, 2H) 7.03 (t, IH, J= 6.3 Hz) 2.70 (s, 3H).
EXAMPLE 10: Preparation of (N-(3-acetyl-2-hydroxyphenyl)-4-chloro- benzamide)
Figure imgf000026_0001
4-chlorobenzoic acid (2.28 g, 1.1 equivalent ratio, Aldrich) was dissolved in 15 ml dimethylacetamide (DMAC, Aldrich) at 00C and then thionyl chloride (1.81 g, 1.15 equivalent ratio) was gradually added to the solution. After the mixture solution was stirred for 10 min at 00C, the mixture of l-(3-amino-2-hydroxy-phenyl)-ethanone (2 g, 1 equivalent ratio) dissolved in 15 ml dimethylacetamide (DMAC, Aldrich) was slowly added to the mixture solution, and thermally stirred for 5 hrs at 25°C. The reaction mixture was mixed with 40 ml H2O and stirred for 1 hr at 25°C. The solid material obtained by filtering the solid material produced was washed with 20 ml H2O and then dried at 600C with hot-wind, obtaining 3.8 g (yield rate: 99%): 1H NMR (300 MHz, DMSO) δ 12.60 (bs, IH) 9.79 (bs, IH) 7.82-8.01 (m, 4H) 7.60 (d, 2H, J = 8.67 Hz) 7.01 (t, IH, J= 7.89 Hz) 2.70 (s, 3H).
EXAMPLE 11: Preparation of (N-(3-acetyl-2-hydroxyphenyl)-propionamide)
Figure imgf000026_0002
4-propionic acid (1.08 g, 1.1 equivalent ratio, Aldrich) was dissolved in 15 ml dimethylacetamide (DMAC, Aldrich) at 00C and then thionyl chloride (1.81 g, 1.15 equivalent ratio) was gradually added to the solution. After the mixture solution was stirred for 10 min at 00C, the mixture of l-(3-amino-2-hydroxy-phenyl)-ethanone (2 g, 1 equivalent ratio) dissolved in 15 ml dimethylacetamide (DMAC, Aldrich) was slowly added to the mixture solution, and thermally stirred for 5 hrs at 25°C. The reaction mixture was mixed with 40 ml H2O and stirred for 1 hr at 25°C. The solid material obtained by filtering the solid material produced was washed with 20 ml H2O and then dried at 600C with hot-wind, obtaining 2.60 g (yield rate: 95%): 1H NMR (300 MHz, DMSO) δ 12.70 (bs, IH) 9.26 (bs, IH) 8.16 (d, IH, J = 7.68 Hz) 7.68 (d, IH, J = 6.78 Hz) 6.94 (t, IH, 7= 8.04 Hz) 2.66 (s, 3H) 2.42 (q, 2H, J= 7.5 Hz) 1.07 (t, 3H, J = 7.5 Hz).
EXAMPLE 12: Preparation of (N-(3-acetyl-2-hydroxyphenyl)-2-nitro- benzamide)
Figure imgf000027_0001
2-nitrobenzoic acid (2.43 g, 1.1 equivalent ratio, Aldrich) was dissolved in 15 ml dimethylacetamide (DMAC, Aldrich) at 00C and then thionyl chloride (1.81 g, 1.15 equivalent ratio) was gradually added to the solution. After the mixture solution was stirred for 10 min at O0C, the mixture of l-(3-amino-2-hydroxy-phenyl)-ethanone (2 g, 1 equivalent ratio) dissolved in 15 ml dimethylacetamide (DMAC, Aldrich) was slowly added to the mixture solution, and thermally stirred for 5 hrs at 250C. The reaction mixture was mixed with 40 ml H2O and stirred for 1 hr at 25°C. The solid material obtained by filtering the solid material produced was washed with 20 ml H2O and then dried at 6O0C with hot-wind, obtaining 3.85 g (yield rate: 97%): 1H NMR (300 MHz, DMSO) δ 12.65 (bs, IH) 10.46 (bs, IH) 8.14 (d, IH, J = 9.0 Hz) 7.71-8.02 (m, 4H) 7.04 (t, IH, J= 7.8 Hz) 2.69 (s, 3H).
EXAMPLE 13: Preparation of (N-(3-acetyl-2-hydroxyphenyl)-3-nitro- benzamide)
Figure imgf000028_0001
3-nitrobenzoic acid (2.43 g, 1.1 equivalent ratio, Aldrich) was dissolved in 15 ml dimethylacetamide (DMAC, Aldrich) at 00C and then thionyl chloride (1.81 g, 1.15 equivalent ratio) was gradually added to the solution. After the mixture solution was stirred for 10 min at 00C, the mixture of l-(3-amino-2-hydroxy-phenyl)-ethanone (2 g, 1 equivalent ratio) dissolved in 15 ml dimethylacetamide (DMAC, Aldrich) was slowly added to the mixture solution, and thermally stirred for 5 hrs at 25°C. The reaction mixture was mixed with 40 ml H2O and stirred for 1 hr at 25°C. The solid material obtained by filtering the solid material produced was washed with 20 ml H2O and then dried at 6O0C with hot-wind, obtaining 3.77 g (yield rate: 95%): 1H NMR (300 MHz, DMSO) δ 12.61 (bs, IH) 10.19 (bs, IH) 8.80 (s, IH) 8.37-8.59 (m, 2H) 7.56-7.56 (m, 4H) 2.71 (s, 3H).
EXAMPLE 14: Preparation of (N-(3-acetyl-2-hydroxyphenyl)-benzamide)
Figure imgf000029_0001
Nitrobenzoic acid (6.1 g, 1.1 equivalent ratio, Aldrich) was dissolved in 15 ml dimethylacetamide (DMAC, Aldrich) at 00C and then thionyl chloride (6.21 g, 1.15 equivalent ratio) was gradually added to the solution. After the mixture solution was stirred for 10 min at 00C, the mixture of l-(3-amino-2-hydroxy-phenyl)-ethanone (6.86 g, 1 equivalent ratio) dissolved in 15 ml dimethylacetamide (DMAC, Aldrich) was slowly added to the mixture solution, and thermally stirred for 5 hrs at 25°C. The reaction mixture was mixed with 40 ml H2O and stirred for 1 hr at 250C. The solid material obtained by filtering the solid material produced was washed with 20 ml H2O and then dried at 600C with hot-wind, obtaining 11.24 g (yield rate: 97%): 1H NMR (300 MHz, DMSO) δ 10.13 (bs, IH) 9.64 (bs, IH) 7.75-7.85 (m, 4H) 2.47 (s, 3H). EXAMPLE 15: Preparation of (N-(3-acetyl-2-hydroxyρhenyl)-4-(4- phenylbutoxy)-benzamide)
Figure imgf000030_0001
4-(4-phenylbutoxy)benzoic acid (31.70 g, 1.1 equivalent ratio) was dissolved in 60 ml dimethylacetamide (DMAC, Aldrich) at 00C and then thionyl chloride (14.58 g,
1.15 equivalent ratio) was gradually added to the solution. After the mixture solution was stirred for 10 min at O0C, the mixture of l-(3-amino-2-hydroxy-phenyl)-ethanone
(20 g, 1 equivalent ratio) dissolved in 60 ml dimethylacetamide (DMAC, Aldrich) was slowly added to the mixture solution, and thermally stirred for 5 hrs at 25°C. The reaction mixture was mixed with 40 ml H2O and stirred for 1 hr at 250C. The solid material obtained by filtering the solid material produced was washed with 20 ml H2O and then dried at 600C with hot-wind, obtaining 40.86 g (yield rate: 95%): 1H NMR
(300 MHz, DMSO) δ 12.61 (bs,lH) 9.47 (bs,lH) 7.92-7.98 (m, 3H) 7.85 (d, IH, J =
8.79) 7.14-7.30 (m, 5H) 6.97-7.04 (m, 3H) 4.05 (m,2H) 2.62-2.66 (m,4H) 2.47-2.50 (m, 3H) 1.73-1.74 (m, 2H)
Having described a preferred embodiment of the present invention, it is to be understood that variants and modifications thereof falling within the spirit of the invention may become apparent to those skilled in this art, and the scope of this invention is to be determined by appended claims and their equivalents.

Claims

What is claimed is:
1. A method for preparing amide derivatives, comprising the steps of:
(a) obtaining an acid halide derivative by reacting a carboxylic acid derivative and a halogenating agent in a dimethylacetamide (DMAC) or N-methylpyrrolidine (NMP) solvent; and
(b) producing an amide derivative by reacting the acid halide derivative with an amine derivative.
2. The method according to claim 1, wherein the carboxylic acid derivative is represented by the following formula 22:
R1-A-COOH (22) wherein A represents a single bond, Ci-4 alkylene, vinylene, propenylene, butenylene or butadienylene; Ri represents straight or branched, substituted or non- substituted Ci-io alkyl, alkenyl or alkynyl, or substituted or non-substituted aryl, alkaryl, aralkyl or heteroaryl.
3. The method according to claim 1, wherein A represents a single bond and Ri represents straight or branched, substituted or non-substituted CMO alkyl, or a group represented by the following formula 23:
Figure imgf000033_0001
wherein X represents a carbon or nitrogen atom and R2 and R3 independently represents H, hydroxy, halogen, nitro, straight or branched, substituted or non- substituted Ci-io alkyl, or substituted or non-substituted arylalkoxy.
4. The method according to claim 1, wherein the halogenating agent comprises a fluorinating agent, a chlorinating agent, a brominating agent or an iodinating agent.
5. The method according to claim 4, wherein the halogenating agent is the chlorinating agent selected from the group consisting of thionyl chloride, oxalyl chloride, phosphorous pentachloride and phosphorous oxytrichloride.
6. The method according to claim 5, wherein the chlorinating agent is used at an equivalent ratio of from 1.0 to 1.2.
7. The method according to claim 1, wherein the step (b) is performed without isolation of the acid halide derivative obtained from the step (a).
8. The method according to claim 1, wherein the amine derivative is represented by the following formula 24:
Figure imgf000034_0001
wherein R4 represents H, halogen, hydroxy, nitro or -COOR6 (Re represents hydrogen or straight or branched Ci-I0 alkyl); B represents a 4-8 membered carbocyclic ring and one or more atoms of the 4-8 members may be an oxygen, nitrogen or sulfur atom, wherein the carbocyclic ring may be substituted with oxo, thioxo or hydroxy group; and R5 exists with a proviso that B is the carbocyclic ring, and R5 represents
- U — (PHd1S- COOR10 , — -(CH2V-- COOR10 -(CH2),
Figure imgf000034_0002
represents hydrogen, halogen, hydroxy, nitro, -COOR7 (R7 represents a hydrogen, or straight or branched CM0 alkyl), -COR8 (R8 represents a hydrogen, or straight or branched CM0 alkyl), or -X-CH2-Rg (X represents an oxygen or sulfur atom, and R9
represents
Figure imgf000034_0003
or
Figure imgf000034_0004
) with a proviso that B is not the carbocyclic ring; U represents an oxygen or sulfur atom; m and n represents an integer of 0-10; p and q represent an integer of 0-10; and Ri0 represents a hydrogen or straight or branched Ci-6 alkyl.
9. The method according to claim 8, wherein R4 represents H; B represents a 4-8 membered carbocydic ring and one or more atoms of the 4-8 members may be an oxygen, wherein the carbocydic ring may be substituted with oxo; and R5 exists with a
proviso that B is the carbocydic ring, and R5 represents
Figure imgf000035_0001
; q represent zero; and B is represented by -COR8 (R8 represents hydrogen or straight or branched Ci-3 alkyl) with a proviso that B is not the carbocydic ring.
10. The method according to claim 1, wherein the step (b) is carried out under a base condition.
11. The method according to claim 10, wherein the base comprises triethylamine, pyridine, 4-(dimethylamino)pyridine, 1-methyimidazol, imidazol or tertiary CrC5 alkylamine.
12. The method according to claim 1, further comprising the step, after the step reacting the acid halide derivative with the amine derivative, purifying a precipitate produced by adding the solvent to the resulting amide derivative.
13. The method according to claim 12, wherein the solvent is selected from the group consisting of water, Ci-C4 alcohol, acetonitrile, acetone, ethylacetate, tetahydrofuran, dioxane, toluene, xylene and a mixture thereof.
14. The method according to claim 12, further comprising the step performing a thermal reflux by adding the solvent to the resulting amide derivative.
15. The method according to claim 14, wherein the solvent is selected from the group consisting of water, Ci-C4 alcohol, acetonitrile, acetone and a mixture thereof.
16. The method according to claim 1, wherein the carboxylic acid derivative is a benzoic acid derivative represented by the following formula 10; the amine derivative is a benzopyran amine derivative represented by the following formula 12; and the resulting amide derivative is a compound represented by the formula 1:
Figure imgf000036_0001
n represents an integer of 0-4;
Figure imgf000036_0002
n represents an integer of 0-4;
Figure imgf000037_0001
(12)
17. The method according to claim 16, wherein n represents 4.
18. The method according to claim 16, further comprising the step in which the amine derivative of formula 1 is kept to stand on air to produce its hydrate.
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