KR100250335B1 - A process for preparing 4-aminobenzamide derivatives - Google Patents

Abstract

PURPOSE: Provided are 4-aminobenzamide derivatives, which have an effect on the activation of the stomach, and also can be used as an irritating agent for the stomach movement, a curing and analgesic agent for a gastric ulcer, a mental disorder, and a migraine. CONSTITUTION: The 4-aminobenzamide derivatives (formula 1) are produced by a process comprising the steps of: reacting a 4-amino benzoyl acid derivative and a phosphate compound in a solvent selected from the group consisting of dichloromethane, 1,2-dichloroethane, chloroform, or acetonitrile in the presence of a base to form a 4-phosphor amino benzoyl acid phosphate derivative (formula 4); reacting the 4-phosphor amino benzoyl acid phosphate derivative (formula 4) and an amine derivative (NHR2R3) to form a 4-phosphor amino benzamide derivative (formula 6); separating and recovering by adding an acid. In the formula, R1 is C1-C3 straight or branched alkoxy, R2 is hydrogen, or C1-C3 straight or branched alkyl, R3 is hydrogen, or -(CH2)n-Z, n is 0 or 1, Z is hydrogen, or di(C1-C3 alkyl)amino, R4 is hydrogen, or C1-C3 straight or branched alkyl, R5 is C1-C3 straight or branched alkyl, X is hydrogen, halogen, or nitro, and L is oxygen atom.

Description

Method for preparing 4-aminobenzamide derivative

The present invention relates to a method for producing 4-aminobenzamide derivatives, and more particularly, 4-aminobenzoyl acid derivatives are reacted with phosphate compounds to synthesize novel phosphoaminobenzoyl acid phosphates as intermediates, which are then reacted with amine derivatives. The present invention relates to a method for producing a 4-aminobenzamide derivative represented by the following Chemical Formula 1 by suppressing the production of dimers and polymer by-products to the maximum and having a high yield of 90% or more.

[Formula 1]

In Formula 1 above:

R ¹ is an alkoxy group of a linear or branched C ₁ ~C _3;

R ² represents a hydrogen atom or a C _{1 to} C ₃ straight or pulverized alkyl group;

R ³ represents a hydrogen atom or-(CH ₂ ) _n -Z; n is 0 or 1, wherein Z is a hydrogen atom, a di (C ₁ -C ₃ alkyl) amino group, or Represents; and m is 0 or 1, Q is an alkoxy group of a linear or branched C ₁ ~C _3, E is a phenoxy hydrogen atom, a straight-chain or alkyloxy carbonyl group, p- fluoro-milling of the C ₁ ~C ₃ Profile Group or benzyl group;

R ⁴ represents a hydrogen atom or a C ₁ to C ₃ straight or pulverized alkyl group;

X represents a hydrogen atom, a halogen atom or a nitro group.

As a representative compound of the 4-aminobenzamide derivative represented by Chemical Formula 1, cisapride represented by the following Chemical Formula 10 is well known to be particularly effective for gastrointestinal activation. In addition, N-piperidinyl benzamide derivatives It is known to be useful as a stimulant, gastric ulcer, mental disorders and migraines in gastrointestinal system exercise.

[Formula 10]

Methods of preparing some derivatives represented by Formula 1 have been disclosed in several patents.

For example, European Patent No.76530 and Korean Patent Publication No.86-1584 disclose the reaction of 3-aminobenzoyl acid in the form of anhydride to react with 3-alkoxy-4-piperidinylamine derivatives, as shown in Scheme 1 below. The preparation method is described.

In the conventional acylation method according to Scheme 1, after activating the carboxyl group in the form of anhydride at a low temperature of 10 ° C or less, the acylation reaction is performed at room temperature for 18 hours. The yield was 80% for the compound in which R is an ethoxycarbonyl group, and the yield was not specified for the compound in which R is p-fluorophenoxypropyl group, but the inventors performed the acylation reaction in the same manner. Yield was low at 20-30% (HPLC and NMR analysis results).

In the case of the preparation method according to Scheme 1, the production of by-products is almost inevitable due to the structural characteristics of 4-aminobenzoyl acid used as a raw material. That is, since the amine group and the carboxyl group exist in one molecule, there is a problem in that the formation of the polymer or the dimer is easy, and as the acylation reaction time becomes longer, other side reactions occur such as the anhydride of the activated carboxyl group is broken.

In addition, the inventors of the present invention synthesized various reaction conditions such as increasing the reaction time or increasing the reaction temperature in order to determine the optimum conditions in the preparation method according to Scheme 1, but the yield was not greatly improved. Side reactions were still produced. When the acylation reaction temperature was maintained at 40 ° C. or higher, it was confirmed that the formation rate of dimers generated by side reaction was 17% or more with respect to the target compound (see Comparative Example in the specification).

As another acylation method for the preparation of some derivatives represented by the formula (1) using 4-aminobenzoyl acid as a raw material and using a coupling reagent such as 1,3-dicyclohexyl carbodiimide (DCC) Conventional acylation methods are known, such as the production method [Spanish Patent No. 2002640] or the method of making it activate by halogen (Spanish Patent No. 550123). These two reactions also do not fundamentally prevent the formation of dimers or polymers that may occur due to the structural properties of 4-aminobenzoyl acid used as raw material.

In the case of compounds in which an amine group and a carboxyl group are present in the molecule at the same time as in a 4-aminobenzoyl acid derivative, ie, a structure such as a peptide or an aminobenzoyl acid derivative, a side reaction such as a polymer or a dimer is produced as in the above-mentioned prior arts. It has been pointed out that the problem is easy and takes a long time to react. In order to prevent such side reactions, generally, after introducing a protecting group into an amine group, a carboxyl group activation and acylation reaction are performed, and a method of deprotecting the amine as necessary is used. However, these methods have a problem in that the reaction is complicated and the yield is reduced since the introduction of the amine protecting group and the deprotection process are added.

Therefore, there is an urgent need for the development of new methods that can minimize intermolecular polymerization while activating 4-aminobenzoyl acid.

The present inventors have tried to find a substance that can inhibit side reactions in the acylation reaction of 4-aminobenzoyl acid derivatives as much as possible, and is capable of simultaneously activating carboxyl groups while facilitating amine protecting group introduction and deprotection reactions. It has been found that phosphate-based compounds are very suitable.

Therefore, the present invention synthesized 4-phosphoaminobenzoyl acid phosphate by introducing a phosphate-based compound capable of simultaneously performing amine group protection function and carboxyl group activation function to 4-aminobenzoyl acid derivative. The present invention was completed by preparing a compound represented by Chemical Formula 1 to a high yield within a quick reaction time by reacting with various amines.

In other words, the present invention is distinguished from other prior arts in that the acylation reaction of the 4-aminobenzoyl acid derivative including the amine group and the carboxyl group in one molecule is suppressed to the maximum.

Accordingly, an object of the present invention is to provide a novel preparation method capable of industrial production of 4-aminobenzamides and compounds having various peptide structures useful as medicinal substances.

The present invention is reacted with a carboxyl compound by reacting a 4-aminobenzoylic acid derivative represented by the following formula (2) with a phosphate compound represented by the following formula (3) in a solvent selected from dichloromethane, 1,2-dichloroethane, chloroform or acetonitrile in the presence of a base. Preparing a 4-phosphoaminobenzoic acid phosphate derivative represented by the following formula (4) having an activation of a group and an amine protecting group simultaneously; By reacting the 4-phosphoaminobenzoyl acid phosphate derivative represented by the formula (4) with the amine derivative represented by the following formula (5) to prepare a 4-phosphoaminobenzamide derivative represented by the following formula (6), and then added an acid ( acid) is added and then a conventional separation process is characterized by a method for producing the 4-amino benzamide derivative represented by the following formula (1).

[Formula 2]

[Formula 3]

[Formula 4]

[Formula 5]

[Formula 6]

[Formula 1]

In the above formula; R ¹ is an alkoxy group of a linear or branched C ₁ ~C _3;

R ² represents a hydrogen atom or a C _{1 to} C ₃ straight or pulverized alkyl group;

R ³ represents a hydrogen atom or ;-( CH ₂ ) _n -Z; n is 0 or 1, wherein Z is a hydrogen atom, a di (C ₁ -C ₃ alkyl) amino group, or Represents; and m is 0 or 1, Q is an alkoxy group of a linear or branched C ₁ ~C _3, E is a phenoxy hydrogen atom, a straight-chain or alkyloxy carbonyl group, p- fluoro-milling of the C ₁ ~C ₃ Profile Group or benzyl group;

R ⁴ represents a hydrogen atom or a C _{1 to} C ₃ straight or pulverized alkyl group;

R ⁵ is a C ₁ -C ₃ linear or pulverized alkyl group;

X represents a hydrogen atom, a halogen atom or a nitro group;

Y represents a halogen atom;

L represents an oxygen atom.

Referring to the present invention in more detail as follows.

The present invention is to minimize the production of side reactions such as polymers and dimers that can be generated in the acylation reaction by activating the carboxyl group of the 4-aminobenzoyl acid derivative containing the amine group and the carboxyl group in one molecule As a preparation method, a novel intermediate having both an amine group protecting ability and a carboxyl group activating ability is produced to overcome the inconvenience of having to go through a multi-step manufacturing process and to prepare a desired 4-aminobenzamide derivative in high yield. will be.

Throughout the specification of the present invention, the term “halogen atom” used by itself or in various groups includes, for example, fluorine (F), chlorine (Cl), bromine (Br), iodine (I), and the like. . The "C ₁ -C ₃ linear or pulverized alkyl group" used by itself or in various groups includes, for example, methyl group, ethyl group, propyl group, isopropyl group and the like. The term “C _{1 to} C ₃ straight chain or pulverized alkoxy group” used by itself or in various groups includes, for example, methoxy group, ethoxy group, propoxy group, isopropoxy group and the like.

The preparation process of the 4-aminobenzamide derivative represented by Chemical Formula 1 according to the present invention is briefly shown in Scheme 2 below.

In Scheme 2: R ¹ , R ² , R ³ , R ⁴ , R ⁵ , X, Y and L are as defined above, respectively.

The present invention has the greatest feature in preparing the 4-phosphoaminobenzoyl acid phosphate compound represented by Chemical Formula 4, which is a novel compound, as an intermediate by simultaneously activating a carboxyl group and introducing an amine protecting group as shown in Scheme 2. .

Although the novel intermediate represented by the general formula (4) of the present invention has an activated structure, almost no dimer or polymer is produced upon reaction with the amine derivative represented by the general formula (5). The reason for this is that when phosphate reacts with the carboxyl group and the amine group, phosphate bonds are first formed in the amine group rather than the carboxyl group due to the difference in reactivity, thereby fundamentally preventing the formation of dimers. Regarding the fact that reacting the 4-aminobenzoyl acid derivative represented by the formula (2) with the phosphate compound represented by the formula (3) selectively attaches the phosphate protecting group to the amine group first, the ¹⁵ N-NMR and ³¹ P-NMR analyzes in the following reference examples It was identified through.

In addition, in the present invention, the phosphate compound represented by Formula 3 used for amine protecting group and carboxyl group activation is a conventional phosphate compound. For example, dimethylchlorophosphate, diethylchlorophosphate, diethylchlorothiophosphate, diphenylchlorophosphate, bis (2,4-dichlorophenyl) chlorophosphate, bis (3,5-dimethylphenyl) chlorophosphate, bis ( 2-methylphenyl) chlorophosphate, diethylbromophosphate, diisopropylfluorophosphate, diethylcyanophosphate, bis (2,2,2-trichloro) phosphoride and the like. Especially preferred are dimethylchlorophosphate, diethylchlorophosphate, diethylbromophosphate and the like.

In the reaction of the 4-aminobenzoyl acid derivative represented by the formula (2) with the phosphate compound represented by the formula (3), it is preferable to use a base, and the base that can be used is not particularly limited, and a wide range is appropriately determined. As a base, both the organic and inorganic bases containing amines and metals generally used can be used, and 2 or more types of bases can also be mixed and used. The phosphate compound represented by the general formula (3) is used in an amount of at least about 2 moles or more, preferably about 2 to 3 molar ratios in molar ratio with respect to the 4-aminobenzoyl acid derivative represented by the general formula (2).

In addition, the reaction solvent is an inert solvent which is commonly used, and it is particularly preferable to use an aprotic polar solvent. For example, dichloromethane, 1,2-dichloroethane, chloroform, acetonitrile, dimethylformamide, dimethylacetamide, hexamethylphosphoamide, etc. Among them, dichloromethane and 1,2-dichloro which are low boiling point solvents Preference is given to using ethane, chloroform or acetonitrile or the like.

By preparing a novel intermediate represented by the formula (4) having both the protection of the amine group and the activating action of the carboxyl group through the above operation, it is possible to perform the acylation reaction to be carried out in a high yield.

In addition, the intermediate compound represented by the formula (4) may be separated from the reactant and reacted with the amine derivative represented by the formula (5), or may be directly reacted with the amine derivative without separation to perform an acylation reaction.

The acylation reaction according to the present invention is particularly faster than the acylation reaction described in the prior art, and the reaction is also carried out almost quantitatively.

The 4-phosphoaminobenzamide derivative represented by the above formula (6), which is an intermediate compound resulting from the acylation reaction according to the present invention, is also a novel compound. In addition, the intermediate compound represented by Chemical Formula 6 may be easily separated from the reactants by simple extraction using an organic solvent, or may be deprotected by adding acid directly without separating from the reaction solution. A desired aminobenzamide derivative represented by the formula (1) can also be obtained.

The deprotection reaction according to the invention is not carried out in a separate additional process but by the addition of acid in the work up to separate the desired product from the reactants. The acid used at this time can use the acid generally used. Inorganic acids including, for example, hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid and perchloric acid; Lower alkanoic acids such as formic acid, acetic acid and propionic acid; Organic acids, including benzoic acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, and 4-methyl- benzenesulfonic acid, etc., Preferably, strong acids, such as hydrochloric acid and a sulfuric acid, are used.

In the above, as shown in Scheme 2, it was described as a three-step manufacturing process including the intermediate that can be produced in the present invention, in the actual synthesis without the separation process of the compound represented by Formula 4 and Formula 6 generated as an intermediate It may also be carried out by a one-pot reaction.

As described above, the production method according to the present invention can prepare the target compound in a high yield of 90% or more, can prevent side reactions such as the formation of polymers and dimers, and the process is very easy for industrial application. Have

When the present invention is described in more detail as follows, the present invention is not limited thereto.

[Reference Example]

[Preparation of 5-chloro-2-methoxy-4- (diethoxyphosphonylamino) -benzoic acid]

To 5-chloro-2-methoxy-4-aminobenzoic acid (1 g, 5 mmol), potassium monohydrogen carbonate (1 g, 10 mmol) and potassium carbonate (1.4 g, 10 mmol) were added to dichloromethane (30 mL), and slowly Diethylchlorophosphate (0.8 mL, 5.5 mmol) was added and stirred for 6 hours. The reaction mixture was briefly filtered and the filtrate was concentrated under reduced pressure, and the oily substance thus obtained was vacuum dried and subjected to NMR analysis.

¹ H-NMR (CDCl ₃ , ppm): δ 1.17 (6H, t), 3.60 (3H, s), 4.08 (4H, m), 6.43 (1H, s), 7.51 (1H, s)

¹⁵ N-NMR (CDCl ₃ , ppm): δ 91.40

³¹ P-NMR (CDCl ₃ , ppm): δ -11.89

Example 1

[Preparation of 5-chloro-2-methoxy-4- (diethoxyphosphonylamino) -benzoyldiethoxyphosphate]

To 5-chloro-2-methoxy-4-aminobenzoic acid (1 g, 5 mmol), potassium monohydrogen carbonate (2 g, 20 mmol) and potassium carbonate (2.7 g, 20 mmol) were added to dichloromethane (30 mL), and slowly Diethyl chlorophosphate (1.6 mL, 11 mmol) was added and stirred for 4 hours. The reaction mixture was briefly filtered and the filtrate was concentrated under reduced pressure and dried under vacuum to yield 2.32 g (yield 98%) of the title compound.

¹ H-NMR (CDCl ₃ , ppm): δ 1.30 (12H, txt), 3.80 (3H, s), 4.17 (8H, m), 6.38 (1H, s), 7.66 (1H, s)

¹³ C-NMR (CDCl ₃ , ppm): δ 16.42, 56.30, 65.37, 65.59, 97.98, 109.99, 134.46, 151.34, 158.25, 162,39

¹⁵ N-NMR (CDCl ₃ , ppm): δ 91.40

³¹ P-NMR (CDCl ₃ , ppm): δ -11.89, 1.53

Example 2

[Preparation of 5-chloro-2-methoxy-4- (diethoxyphosphonylamino) -benzoyldiethoxyphosphate]

2.32 g (yield 98%) of the title compound was obtained in the same manner as in Example 1 using diethylbromophosphate (2.4 g, 11 mmol).

Example 3

[Preparation of 5-chloro-2-methoxy-4- (dimethoxyphosphonylamino) -benzoyldimethoxyphosphate]

2.0 g (yield 98%) of the title compound was obtained in the same manner as in Example 1 using dimethylchlorophosphate (1.2 ml, 11 mmol).

¹ H-NMR (CDCl ₃ , ppm): δ 3.82 (3H, s), 4.01 (12H, m), 6.35 (1H, s), 7.68 (1H, s)

Example 4

[Cis-4-amino-5-chloro-N- [1- [3- (4-fluorophenoxy) propyl] -3-isopropoxy-4-piperidinyl] -2-methoxybenzamide Produce]

To 5-chloro-2-methoxy-4-aminobenzoic acid (1 g, 5 mmol), potassium monohydrogen carbonate (2 g, 20 mmol) and potassium carbonate (2.7 g, 20 mmol) were added to dichloromethane (30 mL), and slowly Diethylchlorophosphate (1.6 mL, 11 mmol) was added and stirred for 4 hours. Cis-1- [3- (4-fluorophenoxy) propyl] -4-amino-3-isopropoxypiperidine (1.55 g, 5 mmol) was added to the reaction solution, and the mixture was stirred for 2 hours. The reaction solution was filtered, the solvent was concentrated under reduced pressure, and concentrated hydrochloric acid (30 ml) was added to the residue, followed by stirring at 60 ° C for about 1 hour, followed by neutralization with sodium hydroxide solution. The mixture was extracted with dichloromethane (30 mL × 3), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the dried oily residue was crystallized in 2-propanol to give 2.22 g (yield 90%) of the title compound.

¹ H-NMR (CDCl ₃ , ppm): δ 1.15 (6H, s), 1.21 (2H, m), 1.91 (2H, m), 2.17 (2H, m), 2.58 (2H, m), 2.91 (1H , m), 3,05 (1H, m), 3.44 (1H, s), 3.71 (1H, m) 3.90 (3H, s), 3.94 (2H, t), 4.21 (1H, m), 4.41 (2H , s), 6.31 (1H, s), 6.82 (2H, m), 6.98 (2H, m), 8.13 (1H, s), 8.21 (1H, d)

Example 5

Preparation of [cis-4-amino-5-chloro-N- [1- [3- (4-fluorophenoxy) propyl] -3-methoxy-4-piperidinyl] -2-methoxybenzamide ]

To 5-chloro-2-methoxy-4-aminobenzoic acid (1 g, 5 mmol), potassium monohydrogen carbonate (2 g, 20 mmol) and potassium carbonate (2.7 g, 20 mmol) were added to dichloromethane (30 mL), and slowly Diethyl chlorophosphate (1.6 mL, 11 mmol) was added and stirred for 4 hours. Cis-1- [3- (4-fluorophenoxy) propyl] -4-amino-3-methoxypiperidine (1.4 g, 5 mmol) was added to the filtrate, and the reaction mixture was stirred for 2 hours. . The solvent was concentrated under reduced pressure, and concentrated hydrochloric acid (30 ml) was added to the residue, followed by stirring at 60 ° C. for about 1 hour, followed by neutralization with sodium hydroxide solution. Extract with dichloromethane (30 mL × 3), remove water with anhydrous sodium sulfate, and filter. The filtrate was concentrated under reduced pressure, and the dried oily residue was crystallized in 2-propanol to give 2.21 g (yield 95%) of the title compound.

m, p. : 120-130 degreeC

¹ H-NMR (CDCl ₃ , ppm): δ 1.20 (2H, m), 1.86 (2H, m), 2.19 (2H, m), 2.56 (2H, m), 2.88 (1H, m), 3.08 (1H) , m), 3.44 (4H, s), 3.89 (3H, s), 3.96 (2H, t), 4.19 (1H, m), 4.42 (2H, s), 6.30 (1H, s), 6.84 (2H, m), 6.96 (2H, m), 8.11 (1H, s), 8.24 (1H, d)

¹³ C-NMR (CDCl ₃ , ppm): δ 26.81, 27.80, 48.08, 51.90, 53.55, 55.13, 55.91, 56.96, 66.88, 97.84, 111.46, 112.60, 115.32, 115,43, 115.54, 115.84, 132.93, 146.58, 155.00, 155.52, 157,52, 158.68, 163.70

Example 6

Preparation of [cis-4-amino-5-chloro-N- [1- [3- (4-fluorophenoxy) propyl] -3-methoxy-4-piperidinyl] -2-methoxybenzamide ]

To 5-chloro-2-methoxy-4-aminobenzoic acid (1 g, 5 mmol), potassium monohydrogen carbonate (2 g, 20 mmol) and potassium carbonate (2.7 g, 20 mmol) were added to dichloromethane (30 mL), and slowly Diethyl chlorophosphate (1.6 mL, 11 mmol) was added and stirred for 4 hours. Cis-1- [3- (4-fluorophenoxy) propyl] -4-amino-3-methoxy piperidine (1.4 g, 5 mmol) was added to this solution, which was stirred for 2 hours and filtered. 2.20 g (yield 95%) of the title compound was obtained through the same operation as in Example 5.

Example 7

Preparation of [cis-4-amino-5-chloro-N- [1- [3- (4-fluorophenoxy) propyl] -3-methoxy-4-piperidinyl] -2-methoxybenzamide ]

To 5-chloro-2-methoxy-4-aminobenzoic acid (1 g, 5 mmol), potassium monohydrogen carbonate (2 g, 20 mmol) and potassium carbonate (2.7 g, 20 mmol) were added to dichloromethane (30 mL), and slowly Diethyl bromophosphate (2.4 g, 11 mmol) was added and stirred for 4 hours. Cis-1- [3- (4-fluorophenoxy) propyl] -4-amino-3-methoxypiperidine (1.4 g, 5 mmol) was added to the filtrate of the reaction mixture, which was stirred for 2 hours. Thereafter, 2.26 g (yield 97%) of the title compound was obtained through the same operation as in Example 5.

Example 8

Preparation of [cis-4-amino-5-chloro-N- [1- [3- (4-fluorophenoxy) propyl] -3-methoxy-4-piperidinyl] -2-methoxybenzamide ]

To 5-chloro-2-methoxy-4-aminobenzoic acid (1 g, 5 mmol), potassium monohydrogen carbonate (2 g, 20 mmol) and potassium carbonate (2.7 g, 20 mmol) were added to dichloromethane (30 mL), and slowly Dimethyl chlorophosphate (1.2 ml, 11 mmol) was added and stirred for 4 hours. Cis-1- [3- (4-fluorophenoxy) propyl] -4-amino-3-methoxypiperidine (1.4 g, 5 mmol) was added to the filtrate of the reaction mixture, which was stirred for 2 hours. Thereafter, 2.14 g (yield 92%) of the title compound was obtained in the same manner as in Example 5.

Example 9

[Preparation of 4-amino-5-chloro-N- [1-benzyl-3-methoxy-4-piperidinyl] -2-methoxybenzamide]

To 5-chloro-2-methoxy-4-aminobenzoic acid (1 g, 5 mmol), potassium monohydrogen carbonate (2 g, 20 mmol) and potassium carbonate (2.7 g, 20 mmol) were added to dichloromethane (30 mL), and slowly Diethyl chlorophosphate (1.6 mL, 11 mmol) was added and stirred for 4 hours. 1-benzyl-3-methoxy-4-piperidinylamine (1.1 g, 5 mmol) was added to the reaction solution, and 2.0 g (yield 98%) of the target compound was obtained in the same manner as in Example 5.

m.p. : 180 to 190 ° C

¹ H-NMR (CDCl ₃ , ppm): δ 1.81 (2H, m), 2.02 (1H, m), 2.17 (2H, m), 2.61 (2H, m), 2.77 (1H, m), 3.17 (1H) , m), 3.46 (3H, s), 3.91 (3H, s), 4.15 (1H, m), 4.46 (2H, s), 6.28 (1H, s), 7.35 (5H, m), 8.10 (1H, s), 8.22 (1 H, d)

Example 10

[Production of 4-diethylphosphoamino-5-chloro-N-methyl-2-methoxybenzamide]

5-chloro-2-methoxy-4-aminobenzoyl acid (1 g, 5 mmol), potassium monohydrogen carbonate (2 g, 20 mmol) and potassium carbonate (2.7 g, 20 mmol) were added to acetonitrile (30 mL) slowly. Diethyl chlorophosphate (1.6 mL, 11 mmol) was added and stirred for 4 hours. The reaction mixture was added 2M methanol methylamine solution (2.5 mL, 5 mmol) to the filtrate, and stirred for 2 hours. The solvent was concentrated under reduced pressure to obtain 1.68 g (96% yield) of the title compound.

¹ H-NMR (CDCl ₃ , ppm): δ 1.21 (6H, t), 2.77 (3H, d), 3.84 (3H, s), 3.93 (4H, q), 4.69 (1H, broad), 6.45 (1H , s), 6.84 (2H, m), 7.69 (1H, s)

Example 11

[Preparation of cis-4-diethylphosphoamino-5-chloro-N- [1-carbetoxy-3-methoxy-4-piperidinyl] -2-methoxybenzamide]

To 5-chloro-2-methoxy-4-aminobenzoic acid (1 g, 5 mmol), potassium monohydrogen carbonate (2 g, 20 mmol) and potassium carbonate (2.7 g, 20 mmol) were added to dichloromethane (30 mL), and slowly Diethyl chlorophosphate (1.6 mL, 11 mmol) was added and stirred for 4 hours. Cis-4-amino-N-carbetoxy-3-methoxypiperidine (1.0 g, 5 mmol) was added to the reaction solution, stirred for 1 hour, filtered, the solvent was concentrated under reduced pressure, and ethyl acetate (30 mL × Extracted with 3), filtered with anhydrous sodium sulfate. The filtrate was concentrated under reduced pressure, and the oily substance thus obtained was vacuum dried to obtain 2.5 g (yield 96%) of the title compound.

m.p. : 136-144 ℃

¹ H-NMR (CDCl ₃ , ppm): δ 1.22 (3H, t), 1.34 (6H, t), 1.72 (2H, s), 2.81 (2H, m), 3.41 (4H, s), 3.83 (3H , s), 4.16 (8H, m), 4.61 (2H, s), 6.29 (1H, s), 8.09 (1H, s), 8.17 (1H, broad)

¹³ C-NMR (CDCl ₃ , ppm): δ 13.95, 14.44, 15.76, 26.70, 42.52, 43.79, 48.74, 55.68, 56.63, 60.11, 61.12, 65.06, 75.68, 97.58, 110.71, 111.09, 132.29, 147.57, 155.70, 157.51, 163.60

[Comparative Example]

Preparation of [cis-4-amino-5-chloro-N- [1- [3- (4-fluorophenoxy) propyl] -3-methoxy-4-piperidinyl] -2-methoxybenzamide ]

5-chloro-2-methoxy-4-aminobenzoyl acid (1 g, 5 mmol) and triethylamine (0.7 mL, 6 mmol) were dissolved in dichloromethane (30 mL), and ethylchloroformate (0.57 mL, 6 mmol) was dissolved. ) Was added dropwise at 10 ° C. and stirred for 45 minutes. Cis-1- [3- (4-fluorophenoxy) propyl] -4-amino-3-methoxypiperidine (1.4 g, 5 mmol) was added to the reaction solution, and the mixture was stirred under reflux for 18 hours. The reaction mixture was separated by HPLC to obtain 0.58 g (yield 25%) of the target compound and 0.08 g (yield 4.25%) of 5-chloro-2-methoxy-4-aminobenzoylic acid dimer. It can be seen that this remains. From this test result, the production rate of dimer for the target compound was obtained.

The reaction mixture was washed with water (30 mL × 3), dried over anhydrous sodium sulfate, concentrated under reduced pressure, purified by silica gel column chromatography, and concentrated under reduced pressure for each compound. At this time, 5-chloro-2-methoxy-4-aminobenzoyl acid dimer produced by side reaction was separated and subjected to NMR and elemental analysis. Production rate of dimer for target compound (HPLC analysis): 17%

¹ H-NMR for dimers: CDCl ₃ , ppm: δ 3.83 (3H, s), 4.00 (3H, s), 4.60 (2H, broad), 6.58 (1H, s), 7.81 (1H, s) , 7.87 (1H, s), 8.51 (1H, s), 10.59 (1H, s)

Elemental Analysis of Dimers (C ₁₆ H ₁₄ C ₁₂ N ₂ O ₅ : 385.20)

Theoretical Values: C 49.9%, H 3.7%, N 7.3%

Experimental value: C 49.874%, H 3.706%, N 7.255%

As described above, the present invention relates to the preparation of a conventional prior art involving side reactions of polymers and dimers due to structural properties when 4-aminobenzoyl acid derivatives in which an amine group and a carboxyl group are present in one molecule are reacted with an amine derivative. Overcome the method. In other words, by using the phosphate compound to activate 4-aminobenzoic acid and at the same time to prepare a new compound incorporating a protecting group into an amine group as an intermediate, a high yield of acylation reaction without side reactions was made possible. Even in the time required for the reaction, while the prior art takes a long time of 18 hours or more, the present invention has the effect of greatly reducing the total reaction time to 5 to 7 hours.

In addition, the amine group protection and the carboxyl group activation process are simultaneously performed through a one-pot reaction without undergoing a multi-step manufacturing process including an N-protecting group introduction process and a deprotecting group process. Industrial mass production of 4-aminobenzamide derivatives represented by the formula (1) and industrially useful peptides was made possible.

Claims (8)

The 4-aminobenzoyl acid derivative represented by the following formula (2) is reacted with a phosphate compound represented by the following formula (3) in a solvent selected from dichloromethane, 1,2-dichloroethane, chloroform or acetonitrile in the presence of a base to activate the carboxyl group and Preparing a 4-phosphoaminobenzoyl acid phosphate derivative represented by the following formula (4) having an amine protecting group simultaneously; By reacting the 4-phosphoaminobenzoyl acid phosphate derivative represented by the formula (4) with the amine derivative represented by the following formula (5) to prepare a 4-phosphoaminobenzamide derivative represented by the following formula (6), and then added an acid ( acid) is added and then recovered separately by a conventional method for producing a 4-aminobenzamide derivative represented by the following formula (1). [Formula 2] [Formula 3] [Formula 4] [Formula 5] [Formula 6] [Formula 1] In the above formula; R ¹ is an alkoxy group of a linear or branched C ₁ ~C _3; R ² represents a hydrogen atom or a C _{1 to} C ₃ straight or pulverized alkyl group; R ³ represents a hydrogen atom or-(CH ₂ ) _n -Z; n is 0 or 1, wherein Z is a hydrogen atom, a di (C ₁ -C ₃ alkyl) amino group, or Represents; and m is 0 or 1, Q is an alkoxy group of a linear or branched C ₁ ~C _3, E is a phenoxy hydrogen atom, a straight-chain or alkyloxy carbonyl group, p- fluoro-milling of the C ₁ ~C ₃ Profile Group or benzyl group; R ⁴ represents a hydrogen atom or a C ₁ to C ₃ straight or pulverized alkyl group; R ⁵ is a C ₁ to C ₃ linear or pulverized alkyl group; X represents a hydrogen atom, a halogen atom or a nitro group; Y represents a halogen atom; L represents an oxygen atom. The method for preparing 4-aminobenzamide derivatives according to claim 1, wherein the following reaction is performed immediately without separating and recovering the intermediate represented by Formula 4 or Formula 6. The compound of claim 1, wherein the compound represented by Formula 1 is cis-4-amino-5-chloro-N- [1- [3- (4-fluorophenoxy) propyl] -3-methoxy-4- Piperidinyl] -2-methoxybenzamide. A process for producing 4-aminobenzamide derivatives. The method according to claim 1, wherein dichloromethane or acetonitrile is used as the reaction solvent. The method of claim 1, wherein dialkyl halophosphate is used as an activator. The 4-phosphoaminobenzoyl acid phosphate derivative represented by the following formula (4), characterized in that it is useful as an intermediate for the preparation of the 4-aminobenzamide derivative represented by the following formula (1). [Formula 4] [Formula 1] In the formula: R ¹ , R ² , R ³ , R ⁴ , R ⁵ , L and X are as defined in claim 1, respectively. According to claim 6, wherein the compound represented by Formula 4 is 5-chloro-2-methoxy-4-phosphoaminobenzoyl acid phosphate. The 4-phosphoaminobenzamide derivative represented by the following formula (6), characterized in that it is useful as an intermediate for the preparation of the 4-aminobenzamide derivative represented by the following formula (1). [Formula 6] [Formula 1] In the formula: R ¹ , R ² , R ³ , R ⁴ , R ⁵ , L and X are as defined in claim 1, respectively.