KR20080008223A - Benzoxazine compound having crystal structure and preparing method thereof - Google Patents

Abstract

A (±)-6-chloro-3,4-dihydro-4-methyl-3-oxo-N-(3-quinuclidinyl)-2H-1,4-benzoxazine-8-carboxamide hydrochloride(benzoxazine) compound is provided which shows stabilized quality and has a novel crystalline structure, thereby being optimally used for medicines. A method for preparing the benzoxazine is provided to obtain the compound through a simple process. A benzoxazine has the crystalline structure having characteristic peaks at 2theta of 7.1°, 13.5°, 14.2°, 16.5°, 21.5°, 22.4°, and 23.2° by X-ray diffraction using Cu-K alpha-ray. A method for preparing the benzoxazine comprises the steps of: (a) contacting a C1-5 alcohol solution of (±)-6-chloro-3,4-dihydro-4-methyl-3-oxo-N-(3-quinuclidinyl)-2H-1,4-benzoxazine-8-carboxamide with HCl-dissolved ether; and (b) educing the benzoxazine from the mixture solution obtained from the step(a) by maintaining the temperature at more than 20 deg.C.

Description

A benzoxazine compound having a crystal structure and a manufacturing method thereof {BENZOXAZINE COMPOUND HAVING CRYSTAL STRUCTURE AND PREPARING METHOD THEREOF}

1 is an X-ray diffraction chart of a benzoxazine compound of the present invention prepared in Example 1. FIG.

2 is an infrared absorption spectrum of the benzoxazine compound of the present invention prepared in Example 1. FIG.

3 is a TG-DTA curve of the benzoxazine compound of the present invention prepared in Example 1. FIG.

4 is an X-ray diffraction chart of the I-form benzoxazine compound prepared in Comparative Example 1. FIG.

5 is an infrared absorption spectrum of the I-form benzoxazine compound prepared in Comparative Example 1. FIG.

6 is a TG-DTA curve of the I-form benzoxazine compound prepared in Comparative Example 1. FIG.

7 is an X-ray diffraction chart of a type II benzoxazine compound prepared in Comparative Example 7. FIG.

8 is an infrared absorption spectrum of the type II benzoxazine compound prepared in Comparative Example 7.

9 is a TG-DTA curve of a type II benzoxazine compound prepared in Comparative Example 7. FIG.

10 is an X-ray diffraction chart of a benzoxazine compound of the present invention prepared in Example 8. FIG.

11 is an infrared absorption spectrum of the benzoxazine compound of the present invention prepared in Example 8. FIG.

Patent Document 1: Japanese Patent No. 3726291

The present invention provides (±) -6-chloro-3,4-dihydro-4-methyl-3-oxo-N- (3-quinucridinyl) -2H-1,4-benzjade having a novel crystal structure. Photo-8-carboxamide ((±) -6-chloro-3, 4-dihydro-4-methyl-3-oxo-N- (3-quinucridinyl) -2H-1, 4-benzoxazine-8-carboxamide) Hydrochloride and a method for producing the same. The compound has excellent serotonin-3 receptor antagonism. Therefore, it is useful as an agent for suppressing symptoms such as vomiting caused by the administration of an anti-malignant tumor agent such as cisplatin, or as a therapeutic agent for digestive system diseases such as chronic gastritis and irritable enteritis syndrome.

(±) -6-chloro-3,4-dihydro-4-methyl-3-oxo-N- (3-quinucridinyl) -2H-1,4-benzoxazine-8-carboxamide hydrochloride (Hereinafter sometimes abbreviated as benzoxazine compound) has several crystal structures. As the benzoxazine compound having a stable crystal structure, a benzoxazine compound having a crystal structure giving a characteristic peak at 2θ = 15.76 °, 16.464 °, and 20.639 ° by X-ray diffraction using Cu-K α-rays. (According to Patent Document 1, there is a crystal structure described as an I-type crystal).

The manufacturing method of the benzoxazine compound which has an I-form crystal structure described in the said patent document 1 is a method described below. First, this production method is (±) -6-chloro-3, 4-dihydro-4-methyl-3-oxo-N- (3-quinucridinyl) -2H-1,4-benzoxazine-8 Hydrochloric acid is added to a hydrous ethanol suspension of -carboxamide (hereinafter sometimes abbreviated as benzoxazine compound precursor) to dissolve the benzoxazine compound precursor. Thereafter, the pH of the solution is adjusted to 3.8 to 4.2 using dilute hydrochloric acid or dilute alkali. Next, ethanol is added to the solution which adjusted the said pH, maintaining liquid temperature at 40-50 degreeC, and precipitate the Form I crystal of the benzoxazine compound.

Patent Document 1 also describes a production method using seed crystals. In the case of the method using a seed crystal, ethanol is added to the solution which adjusted pH, maintaining liquid temperature at 30-40 degreeC, and precipitate the Form I crystal of the benzoxazine compound.

Moreover, the method of crystal-precipitating a Form I crystal at 50-60 degreeC comparatively high temperature from ethanol hydrochloric acid solution is also described (patent document 1).

In the above method, the benzoxazine compound having a crystal structure of Form I is stable in crystal structure. In the case of treating the compound as a medicine, it is particularly preferable that the crystal structure is more stable in pharmaceutical manufacture. From this point of view, a benzoxazine compound having a crystal structure of this I type is useful.

The present inventors examined the precipitation method of the benzoxazine compound using hydrous ethanol and hydrochloric acid which were described in the said patent document 1. As a result, when dissolving the benzoxazine compound which has the crystal structure of Form I manufactured by the method described in the said patent document 1 in water, the value of pH of the aqueous solution of the benzoxazine compound obtained becomes the production lot of the said compound ( We noticed a big change between lots. It has also turned out to be very difficult to control this imbalance.

In addition, it was found that the same tendency was observed even when the benzoxazine compound of I-form crystal structure precipitated from the ethanol hydrochloric acid solution described in Patent Document 1 was dissolved in water. That is, the pH of each aqueous solution obtained by dissolving the same compound of different production lots was varied and unstable for each production lot.

In addition, as described in Patent Document 1, the benzoxazine compound of the I-form crystal structure produced by the method of crystallization from the ethanol hydrochloric acid solution is about 5% ethanol when dried by the usual drying method. It was confirmed by the inventors to remain in the crystal.

The said patent document 1 describes the method of precipitating a benzoxazine compound by adding ethanol to the hydrous ethanol solution of the benzoxazine compound which adjusted pH with hydrochloric acid at 10 degrees C or less low temperature. According to this method, it is described that Form II crystals, which are crystals described in Example 15 of JP-A-28182, can be obtained. Japanese Patent Application Laid-Open No. 228182 discloses treating benzoxazine compound precursor crystals with etheric hydrochloric acid to obtain type II crystals.

In addition, Patent Literature 1 describes that when a benzoxazine compound is crystallized from an ethanol hydrochloric acid solution at about room temperature, type III crystals are obtained.

According to the studies by the present inventors, even in the case of type II crystals, it was found that the pH of the aqueous solution varies greatly from production lot to production lot.

Regarding the type III crystals, reproducibility of manufacture was poor and a type III crystal could not be obtained.

When preparing the aqueous solution of benzoxazine compound, it is expected that a variation occurs in the dissolution rate if a gap occurs in the pH value of the aqueous solution. Variation in the rate of dissolution is undesirable from the standpoint of bioavailability when administered to humans.

The present inventors thought that the reason why the pH value fluctuates is that water or an organic solvent remains in the crystal and the amount of the trace amount of HCl to be accepted in the crystal varies. In addition, it was thought that the cause of water or an organic solvent remaining in a crystal | crystallization has a problem with a crystal structure.

Thus, the present invention further examined the method for producing the benzoxazine compound. As a result, a benzoxazine compound having a new crystal structure was found. When the benzoxazine compound of this crystal structure dissolves this compound in water, the pH of the aqueous solution obtained is hard to fluctuate for every lot of manufacture.

Therefore, an object of the present invention is (±) -6-chloro-3, 4-dihydro-4-methyl-3-oxo-N- having a novel crystal structure in which pH control of the aqueous solution is easy. (3-quinukridinyl) -H-1, 4-benzoxazine-8-carboxamide hydrochloride, and its manufacturing method are provided.

The 1st crystalline benzoxazine compound (Hereinafter, it may be described as an alpha benzoxazine compound.) Of this invention which solves the said subject is at least 2 (theta) by X-ray diffraction using Cu-K (alpha) ray. (±) -6-chloro-3, 4-dihydro-4-methyl-3 of a crystalline structure having peaks characteristic of = 7.1 °, 13.6 °, 14.2 °, 16.5 °, 21.5 °, 22.4 °, 23.2 ° -Oxo-N- (3-quinukridinyl) -2H-1,4-benzoxazine-8-carboxamide ((±) -6-chloro-3,4-dihydro-4-methyl-3-) oxo-N- (3-quinucridinyl) -2H-1, 4-benzoxazine-8-carboxamide) hydrochloride.

In addition, the present invention is (±) -6-chloro-3,4-dihydro-4-methyl-3-oxo-N- (3-quinucridinyl) -2H-1,4-benzoxazine-8 (±) -6-chloro-3,4-dihydro-4-methyl-3-oxo- from a mixed solution obtained by contacting an alcohol solution having 1 to 5 carbon atoms of a carboxamide with an ether in which hydrogen chloride is dissolved. Cu which comprises the process of depositing N- (3-quinukridinyl) -2H-1 and 4-benzoxazine-8-carboxamide hydrochloride, maintaining the mixed liquid temperature at 20 degreeC or more. (±) -6 having a crystal structure giving characteristic peaks at least 2θ = 7.1 °, 13.6 °, 14.2 °, 16.5 °, 21.5 °, 22.4 °, 23.2 ° by X-ray diffraction using -K α-rays -Chloro-3, 4-dihydro-4-methyl-3-oxo-N- (3-quinucridinyl) -2H-1, 4-benzoxazine-8-carboxamide hydrochloride (α type benzox) Photo compound) It is the law.

The benzoxazine compound of the second crystalline form of the present invention (hereinafter sometimes referred to as a β-type benzoxazine compound) is at least 2θ = 6.7 ° and 9.9 by X-ray diffraction using Cu-K α-rays. (±) -6-chloro-3, 4-dihydro-4-methyl-3-oxo-N- (3) with crystal structures giving characteristic peaks at °, 14.5 °, 15.2 °, 22.7 °, and 23.6 ° -Quinukridinyl) -2H-1 and 4-benzoxazine-8-carboxamide hydrochloride.

In addition, the present invention is (±) -6-chloro-3,4-dihydro-4-methyl-3-oxo-N- (3-quinucridinyl) -2H-1,4-benzoxazine-8 (±) -6-chloro-3,4-dihydro-4-methyl-3-oxo-N- from a mixed solution obtained by bringing an alcohol solution having 1 to 5 carbon atoms of a carboxamide into contact with an ether containing hydrogen chloride dissolved therein; (3-quinukridinyl) -2H-1, 4-benzoxazine-8-carboxamide hydrochloride, The process of depositing, maintaining mixed liquid temperature at -20 degreeC or more and less than 20 degreeC, It characterized by the above-mentioned. (±) -6-chloro-3 having a crystal structure giving characteristic peaks at least 6.7 °, 9.9 °, 14.5 °, 15.2 °, 22.7 °, and 23.6 ° by X-ray diffraction using Cu-K α-rays , 4-dihydro-4-methyl-3-oxo-N- (3-quinucridinyl) -2H-1,4-benzoxazine-8-carboxamide hydrochloride (β-type benzoxazine compound) Manufacturing method to be.

Moreover, this invention is (±) -6-chloro-3, 4-dihydro- 4-methyl-3-oxo-N- (3-quinukridinyl) -2H-1, 4-benzoxazine-8- (±) -6-chloro-3,4-dihydro-4-methyl-3-oxo- from a mixed solution obtained by contacting an alcohol solution having 3 to 5 carbon atoms of a carboxamide with an ester in which hydrogen chloride is dissolved. By X-ray diffraction using Cu-K α-ray, comprising the step of depositing N- (3-quinucridinyl) -2H-1,4-benzoxazine-8-carboxamide hydrochloride. (±) -6-chloro-3,4-dihydro-4-methyl- with a crystal structure giving a characteristic peak at at least 2θ = 6.7 °, 9.9 °, 14.5 °, 15.2 °, 22.7 °, 23.6 ° 3-Oxo-N- (3-quinucridinyl) -2H-1, 4-benzoxazine-8-carboxamide hydrochloride ((beta-type benzoxazine compound)) is a manufacturing method of the said carbon number 1- 5 Carr It includes the case of ester of a carboxylic acid and alcohol of 1 to 5 carbon atoms.

First crystal compound (α type Mercedes-Benz Photo  compound)

(±) -6-chloro-3,4-dihydro-4-methyl-3-oxo-N- (3-quinucridinyl) -2H-1,4-benz which is the first crystal compound of the present invention Oxazine-8-carboxamide hydrochloride (benzoxazine compound) has a predetermined crystal structure (hereinafter, may be described as an α-type crystal structure). That is, it is a compound which has the crystal structure which gives the characteristic peak at least 2 (theta) = 7.1 degrees, 13.5 degrees, 14.2 degrees, 16.5 degrees, 21.5 degrees, 22.4 degrees, and 23.2 degrees by X-ray diffraction using Cu-K (alpha) rays. . In this case, the measurement error of the X-ray diffraction angle is allowed to about 0.2 degrees.

This alpha benzoxazine compound shows the infrared absorption spectrum shown in FIG. In addition, the benzoxazine compound gives thermal balance (TG) and differential thermal analysis (DTA) results shown in FIG. 3.

The α-type benzoxazine compound has a specific crystal structure and therefore has little content of a solvent and water. As a result, when the compound is dissolved in water (concentration 5% by mass), the pH value of the solution falls within a narrow range of 5.0 to 5.2.

(Method for producing α-type benzoxazine compound)

(±) -6-chloro-3,4-dihydro-4-methyl-3-oxo-N- (3-quinucridinyl) used as a starting material in the production method of the α-type benzoxazine compound -2H-1 and 4-benzoxazine-8-carboxamide (also called a benzoxazine compound precursor) may be manufactured by any method. For example, the benzoxazine compound precursor manufactured by the method of Unexamined-Japanese-Patent No. 2-28182 can be used.

In the method for producing an α-type benzoxazine compound of the present invention, an alcohol solution of a benzoxazine compound precursor and an ether in which hydrogen chloride is dissolved are contacted to form a mixed solution thereof, and then benzox which is crystallized from the mixed solution. The photographic compound is isolated.

The alcohol in which the benzoxazine compound precursor is dissolved is an alcohol having 1 to 5 carbon atoms. Since the alcohol having more than 6 carbon atoms has a high boiling point, the alcohol easily remains in the crystal of the benzoxazine compound obtained. Alcohol can be used without limitation, such as reagents or industrial raw materials.

Examples of the alcohol used include methyl alcohol, ethyl alcohol, 1-propyl alcohol, 2-propyl alcohol, 1-butyl alcohol, 2-butyl alcohol, and 2-methyl-1-propyl alcohol. (2-methyl-1-propyl alcohol), 2-methyl-2-propanol, 1-pentanol, 1-pentanol, 3-pentanol, 2-methyl-1-butanol, 3-methyl -1-butanol, 2-methyl-2-butanol, 3-methyl-1-butanol, 3-methyl-2-butanol, 2,2-dimethyl-1-propanol (2, 2-dimethyl-1-propanol) and the like Monovalent alcohols are exemplified.

Among them, methanol, ethanol, 1-propanol, 2-propanol, 1-butanol, 2-butanol, and 2-methyl have low toxicity, relatively low boiling point, and are difficult to remain in the resulting α-type benzoxazine compound. -1-propanol, 1-pentanol, and 3-methyl- 1-butanol are preferable.

The amount of these alcohols used depends on the solubility of each benzoxazine compound precursor in each alcohol. Usually, the usage-amount of 0.5-100 ml of alcohol is preferable with respect to 1 g of benzoxazine compounds, and 1-50 ml is more preferable. When the amount of alcohol used is less than 0.5 ml, operation becomes difficult. Moreover, when the usage-amount of alcohol exceeds 100 ml, the yield of a benzoxazine compound falls.

The ether used in the production method of the present invention is diethyl ether, dipropyl ether, diisopropyl ether, dibutyl ether, dihexyl ether, tert-butyl methyl ether (tert-butyl methyl and alkyl ethers having 4 to 12 carbon atoms such as ether), anisole, tetrahydrofuran, 1,2-dimethoxyethane and the like. Among these, diethyl ether, tert-butyl methyl ether, anisole, tetrahydrofuran, and 1,2-dimethoxyethane are preferable because of their low toxicity and relatively low boiling point, and are difficult to remain in the product obtained.

Hydrogen chloride-dissolved ethers (also referred to as hydrogen chloride ether solutions) used in the method for producing the α-type benzoxazine compound of the present invention may be produced by absorbing hydrogen chloride gas in the ether as described below. good. That is, ether is added and cooled in a four-necked flask equipped with a hydrogen chloride gas and a nitrogen gas supply pipe. Thereafter, hydrogen chloride gas is slowly supplied in a bubbling state in the cooled and low temperature ether. As a result, an ether in which a predetermined amount of hydrogen chloride is dissolved is obtained. In addition, an ether in which hydrogen chloride is dissolved, which is commercially available as a reagent or an industrial raw material, can be used without any limitation.

The concentration of hydrogen chloride dissolved in these ethers depends on the solubility of the hydrogen chloride gas in each ether. Usually, the concentration of hydrogen chloride in ether is preferably in the range of 0.01 mol / L to 10 mol / L. When the concentration of hydrogen chloride is low, since the amount of ether used is relatively large, the concentration of hydrogen chloride is more preferably 0.02 mol / L to 8 mol / L.

In the manufacturing method of this invention, the said benzoxazine compound precursor solution and the hydrogen chloride ether solution are made to contact. There is no restriction | limiting in particular as a contact method, The method of mixing both is illustrated. The mixing method is not particularly limited, and a hydrogen chloride ether solution may be added to the alcohol solution of the benzoxazine compound precursor, or an alcohol solution of the benzoxazine compound precursor may be added to the hydrogen chloride ether solution.

The benzoxazine compound precursor and hydrogen chloride react almost quantitatively. When mixing both solutions, the amount of hydrogen chloride contained in the hydrogen chloride ether solution used is 0.8-2.0 mol, in particular 0.9-1.5 mol, with respect to 1 mol of the benzoxazine compound precursor contained in the alcohol solution of the benzoxazine compound precursor. It is preferable that the amount of solution be adjusted. The temperature at the time of mixing both liquids is 20 degreeC or more, 20-60 degreeC is preferable and 22-55 degreeC is more preferable. When the two liquids are mixed, the heat of reaction is generated, and the rise of the liquid temperature is recognized, but the liquid temperature can be controlled by controlling the mixing speed of the two liquids during mixing. You may control liquid temperature by heating or cooling suitably.

By contacting both solutions, X-ray diffraction using an α-type benzoxazine compound having a crystal structure giving a peak characteristic to 2θ of the present invention, i.e., Cu-K α-ray, from a mixed solution of 20 ° C or higher (±) -6-chloro-3,4-dihydro- having a crystal structure giving a characteristic peak at least 2θ = 7.1 °, 13.5 °, 14.2 °, 16.5 °, 21.5 °, 22.4 °, 23.2 ° 4-Methyl-3-oxo-N- (3-quinucridinyl) -2H-1, 4-benzoxazine-8-carboxamide ((±) -6-chloro-3, 4-dihydro-4 Crystals of -methyl-3-oxo-N- (3-quinucridinyl) -2H-1,4-benzoxazine-8-carboxamide) hydrochloride are crystallized out. The mixture liquid temperature in crystal precipitation is 20 degreeC or more, 20-60 degreeC is preferable and 22-55 degreeC is more preferable.

When crystal precipitation temperature is less than 20 degreeC, the beta benzoxazine compound mentioned later is obtained. In addition, when crystal | crystallization precipitates simultaneously with mixing of the said both solutions, it is necessary to maintain the mixed liquid temperature at the time of mixing at 20 degreeC or more.

The benzoxazine compound to be precipitated is separated by a solid-liquid separation method such as filtration or centrifugation, and further dried through a drying step such as natural drying, blowing drying, vacuum drying, and the like, as necessary.

The α-type benzoxazine compound produced as described above and isolated is extremely uniform in quality and, when the compound is dissolved in water (concentration 5% by mass), the pH of the aqueous solution of the benzoxazine compound obtained. Values fall within a narrow range of 5.0 to 5.2.

Second crystal compound (β type Mercedes-Benz Photo  compound)

(±) -6-chloro-3,4-dihydro-4-methyl-3-oxo-N- (3-quinucridinyl) -2H-1,4-benz which is a second crystal compound of the present invention Oxazine-8-carboxamide ((±) -6-chloro-3, 4-dihydro-4-methyl-3-oxo-N- (3-quinucridinyl) -2H-1,4-benzoxazine-8-carboxamide) The hydrochloride (benzoxazine compound) has a predetermined crystal structure (hereinafter, may be described as a β-type crystal structure). That is, it is a compound which has a crystal structure which gives the characteristic peak at least 2 (theta) = 6.7 degrees, 9.9 degrees, 14.5 degrees, 15.2 degrees, 22.7 degrees, and 23.6 degrees by X-ray diffraction using Cu-K (alpha) rays.

The measurement error of the X-ray diffraction angle is allowed up to about 0.2 degrees. This β-type benzoxazine compound shows an X-ray diffraction chart shown in FIG. 10.

Moreover, the said benzoxazine compound shows the infrared absorption spectrum shown in FIG.

Since the benzoxazine compound has a specific crystal structure and there is little content of water or an organic solvent in the crystal, when the compound is dissolved in water (concentration 5% by mass), the pH value of the solution is in a narrow range of 5.0 to 5.2. Enter

(Method for producing β-type benzoxazine compound)

The β-type benzoxazine compound of the present invention has two production methods. In these production methods, (±) -6-chloro-3, 4-dihydro-4-methyl-3-oxo-N- (3-quinucridinyl) -2H-1, 4 used as starting materials. The benzoxazine-8-carboxamide (also called a benzoxazine compound precursor) may be produced by any method. For example, the benzoxazine compound precursor manufactured by the method of Unexamined-Japanese-Patent No. 2-28182 can be used.

(1) Method of producing first β-type benzoxazine compound

In the first production method of the β-type benzoxazine compound, first, an alcohol solution of the benzoxazine compound precursor and an ether in which hydrogen chloride is dissolved are contacted to form a mixed solution thereof. Next, the benzoxazine compound precipitated from the mixed solution is separated.

As the alcohol in which the benzoxazine compound precursor is dissolved, the same alcohol as that used in the method for producing the α-type benzoxazine compound is used.

The usage-amount of these alcohols is also the same usage-amount as the manufacturing method of the said alpha-type benzoxazine compound.

The ether used in this manufacturing method can use the ether used in the manufacturing method of the said alpha type benzoxazine compound.

Hydrogen chloride-dissolved ether (also called hydrogen chloride ether solution) used in the production method of the present invention can be obtained by the production method described in the production method of the α-type benzoxazine compound. In addition, an ether in which hydrogen chloride is dissolved, which is commercially available as a reagent or an industrial raw material, can be used without any limitation.

Moreover, the density | concentration described in the manufacturing method of the said alpha type benzoxazine compound is also preferable for the density | concentration of the hydrogen chloride dissolved in such an ether.

In the first production method of the present invention, the alcohol solution of the benzoxazine compound precursor and the hydrogen chloride ether solution are brought into contact with each other. Although there is no restriction | limiting in particular as a contact method, The method of mixing both is illustrated. The mixing method is not particularly limited, and a hydrogen chloride ether solution may be added to the alcohol solution of the benzoxazine compound precursor, or an alcohol solution of the benzoxazine compound precursor may be added to the hydrogen chloride ether solution.

The benzoxazine compound precursor and hydrogen chloride react almost quantitatively. When mixing both solutions, the amount of hydrogen chloride contained in the hydrogen chloride ether solution used is 0.8-2.0 mol, in particular 0.9-1.5 mol, with respect to 1 mol of the benzoxazine compound precursor contained in the alcohol solution of the benzoxazine compound precursor. It is preferable that the amount of solution be adjusted.

When both solutions are mixed, the benzoxazine compound precipitates. On the occasion of this mixing, the temperature of both of these solutions is adjusted and mixed so that the temperature of the mixed solution is within the range of -20 to 20 ° C, preferably -15 to 15 ° C. Usually, there is a slight exotherm at the time of mixing, but the mixture liquid temperature can be controlled within the above range by appropriately adjusting the temperature of the alcohol solution and the hydrogen chloride ether solution of the benzoxazine compound precursor. For example, the temperature of both solutions before mixing is adjusted to a range of -20 to 18 ° C, preferably -15 to 15 ° C, and the mixing rate at the time of mixing the solutions is controlled to easily control the mixture liquid temperature within the above range. can do. Depending on the environmental temperature to be mixed, the crystal precipitation temperature can be controlled by heating or cooling the mixed liquid as necessary.

When both solutions are brought into contact, a β-benzoxazine compound having a crystal structure giving a peak characteristic to 2θ of the present invention from a mixed solution having a temperature of less than -20 to 20 ° C, that is, X using Cu-K α-rays (±) -6-chloro-3,4-dihydro- having a crystal structure giving characteristic peaks by at least 2θ = 6.7 °, 9.9 °, 14.5 °, 15.2 °, 22.7 °, 23.6 ° by line diffraction Β-type crystals of 4-methyl-3-oxo-N- (3-quinucridinyl) -2H-1 and 4-benzoxazine-8-carboxamide hydrochloride are crystallized. The mixed liquid temperature during crystal precipitation is in the range of -20 to 20 ° C, preferably -15 to 15 ° C.

In addition, when crystal | crystallization precipitates simultaneously with mixing of the said both solutions, it is necessary to hold the mixed liquid temperature at the time of mixing at less than -20-20 degreeC.

When crystal precipitation temperature is 20 degreeC or more, the said alpha benzoxazine compound is obtained.

The benzoxazine compound to be precipitated is isolated by solid-liquid separation means such as filtration or centrifugation, and further dried through a drying step such as natural drying, blowing drying, or vacuum drying, if necessary.

The benzoxazine compound produced and isolated as described above is extremely uniform in quality, and when the compound is dissolved in water (concentration 5% by mass), the pH value of the aqueous solution of the benzoxazine compound obtained is 5.0 to 5.2. Go into range

(2) Manufacturing Method of Second β-Benzoxazine Compound

In the second production method of the β-type benzoxazine compound of the present invention, an alcohol solution of the benzoxazine compound precursor and an ester in which hydrogen chloride is dissolved are brought into contact with each other to form a mixture thereof, and then the mixed solution. The benzoxazine compound precipitated from the crystals is separated.

The alcohol in which the benzoxazine compound precursor is dissolved is an alcohol having 3 to 5 carbon atoms. The alcohol with more than 6 carbon atoms has a high boiling point, and alcohol easily remains in the benzoxazine compound crystal obtained. Therefore, it is preferable that alcohol is in the range of the said carbon number.

Alcohol may be used without any restriction as a reagent or alcohol of industrial raw materials.

As alcohol used, it is 1-propyl alcohol (1-propyl alcohol), 2-propyl alcohol, 1-butyl alcohol (1-butyl alcohol), 2-butyl alcohol, 2-methyl- 1-propyl alcohol (2-methyl- 1-propyl alcohol), 2-methyl-2-propanol (2-methyl-2-propanol), 1-pentanol (1-pentanol), 2-pentanol, 3-pentanol, and 2-methyl-1-butanol (2-methyl-1-butanol), 3-methyl-1-butanol, 2-methyl-2-butanol, 3-methyl-1-butanol, 3-methyl-2-butanol, 2,2-dimethyl-1- Monovalent alcohols, such as propanol (2, 2-dimethyl- 1-propanol), are illustrated.

Among them, 1-propanol, 2-propanol, 1-butanol, 2-butanol, and 2-methyl-1-propanol, because of low toxicity and relatively low boiling point, and are difficult to remain in the β-type benzoxazine crystal obtained. And 1-pentanol and 3-methyl-1-butanol are preferable.

Although the usage-amount of these alcohols changes with solubility with respect to each alcohol of a benzoxazine compound precursor, 0.5-100 ml is preferable with respect to 1 g of benzoxazine compounds, and 1-50 ml is more preferable. If the amount of alcohol is less than 0.5 ml, the operation becomes difficult. Moreover, when the amount of alcohol exceeds 100 ml, there exists a tendency for the yield of a benzoxazine compound to fall.

As ester used as a solvent in the manufacturing method of a 2nd (beta) type benzoxazine compound, ester of a C1-C5 carboxylic acid and a C1-C5 alcohol is preferable.

When the molecular weight of an ester becomes too large, a boiling point will become high and ester will likely remain in the (beta) -type benzoxazine compound crystal obtained. Therefore, the ester is preferably an ester of a carboxylic acid and an alcohol within the above carbon number range.

As ester, methyl acetate, ethyl acetate, 1-propyl acetate, ethyl methyl acetate, 1-butyl acetate, 1-methylpropyl acetate, 2-methylpropyl acetate, 1, 1-dimethylethyl acetate, 1-pentyl acetate, 1-methylbutyl acetate, 2-methylbutyl acetate, 3-methylbutyl acetate, 1-ethylpropyl acetate, 2-ethylpropyl acetate, acetic acid 1, 1-dimethylpropyl, acetic acid 1, 2-dimethylpropyl, acetic acid 2, 2-dimethylpropyl, methyl propionate, ethyl propionate, propionic acid 1-propyl, ethyl propionate, 1-butyl propionate, propionic acid 1- Methylpropyl, propionic acid 2-methylpropyl, propionic acid 1, 1-dimethylethyl, propionic acid 1-pentyl, propionic acid 1-methylbutyl, propionic acid 2-methylbutyl, propionic acid 3-methylbutyl, propionic acid 1-ethylpropyl, propionic acid 2-ethyl Lofil, propionic acid 1, 1-dimethylpropyl, propionic acid 1, 2-dimethylpropyl, propionic acid 2, 2-dimethylpropyl (2, 2-dimethylpropyl propionate), methyl butyrate, ethyl butyrate, butyric acid 1-propyl, butyric acid Ethyl methyl, butyric acid 1-butyl, butyric acid 1-methylpropyl, butyric acid 2-methylpropyl, butyric acid 1,1-dimethylethyl, butyric acid 1-pentyl, butyric acid 1-methylbutyl, butyric acid 2-methylbutyl, butyric acid 3-methylbutyl , Butyric acid 1-ethylpropyl, butyric acid 2-ethylpropyl, butyric acid 1, 1-dimethylpropyl, butyric acid 1, 2-dimethylpropyl, butyric acid 2, 2-dimethylpropyl (2, 2-dimethylpropyl butyrate), methyl pentane (methyl pentanoate), ethyl pentanate, 1-propyl pentanate, ethyl methyl pentanate, 1-butyl pentanate, 1-methylpropyl pentanate, 2-methylpropyl pentanate, 1,1-dimethylethyl, pentanic acid 1 -To pentyl, pentanoic acid 1-methylbutyl, pentanoic acid 2-methylbutyl, pentanoic acid 3-methylbutyl, pentanoic acid 1- Include propyl, 2-ethyl pentanoic acid propyl pentanoic acid 1, 1-dimethylpropyl, pentanoic acid 1,2-dimethylpropyl, pentanoic acid 2, 2-dimethylpropyl (2, 2-dimethylpropyl pentanoate) and the like.

Among these, methyl acetate, ethyl acetate, 1-butyl acetate, 2-methylpropyl acetate, ethylmethyl acetate, and 1-propyl acetate are preferable from a viewpoint of toxicity.

Hydrogen chloride-dissolved ester (also called hydrogen chloride ester solution) used in the method for producing the second β-type benzoxazine may be produced by absorbing hydrogen chloride gas into the ester. The manufacturing method is the same as the manufacturing method of the hydrogen chloride ether solution described in the manufacturing method of the said 1st type benzoxazine compound.

Moreover, hydrogen chloride-dissolved ester marketed as a reagent or an industrial raw material can also be used without a restriction | limiting at all.

The concentration of hydrogen chloride dissolved in these esters depends on the solubility of the hydrogen chloride gas in the ester. Usually, the concentration of hydrogen chloride in the ester is preferably in the range of 0.01 mol / L to 10 mol / L. When the concentration of hydrogen chloride is low, the amount of hydrogen chloride ester solution used is relatively large. Therefore, the concentration of hydrogen chloride is more preferably 0.02 mol / L to 8 mol / L.

In the method for producing the second β-type benzoxazine compound, the alcohol solution of the benzoxazine compound precursor and the hydrogen chloride ester solution are brought into contact with each other. Although there is no restriction | limiting in particular as a contact method, The method of mixing both is illustrated. The mixing method is not particularly limited, and a hydrogen chloride ester solution may be added to the alcohol solution of the benzoxazine compound precursor, or an alcohol solution of the benzoxazine compound precursor may be added to the hydrogen chloride ether solution.

The benzoxazine compound precursor and hydrogen chloride react almost quantitatively as in the first production method. When mixing both solutions, the amount of hydrogen chloride contained in the hydrogen chloride ester solution used is 0.8-2.0 mol, particularly 0.9-1.5 mol, with respect to 1 mol of the benzoxazine compound precursor contained in the alcohol solution of the benzoxazine compound precursor. It is preferable that the amount of solution be adjusted.

There is no restriction | limiting in particular if the temperature at the time of mixing both liquids is below the boiling point of the solvent used. Generally -20-60 degreeC is preferable and -15-55 degreeC is more preferable. Mixing both solutions produces heat of reaction and an increase in solution temperature is noted. Liquid temperature can be controlled by controlling the mixing speed at the time of mixing both liquids. You may control liquid temperature by heating or cooling a mixture liquid suitably.

By contacting both solutions, at least 2θ = 6.7 ° by X-ray diffraction using a β-type benzoxazine compound having a crystal structure giving a characteristic peak to 2θ of the present invention from the mixed solution, that is, Cu-K α-ray. (±) -6-chloro-3,4-dihydro-4-methyl-3-oxo-N- having a crystal structure giving characteristic peaks at 9.9, 14.5, 15.2, 22.7 and 23.6 degrees Crystals of (3-quinucridinyl) -2H-1 and 4-benzoxazine-8-carboxamide hydrochloride are crystallized out. Although the temperature in crystal precipitation does not have a restriction | limiting in particular, Usually, -20-60 degreeC is preferable and -15-55 degreeC is more preferable.

The benzoxazine compound precipitated by crystals is isolated by a known solid-liquid separation method such as filtration or centrifugation, and further dried by a drying step such as natural drying, blowing drying, or vacuum drying, if necessary.

The benzoxazine compound prepared and isolated as described above is extremely uniform in quality. When dissolving this compound in water (concentration 5 mass%), the pH value of the aqueous solution of the benzoxazine compound obtained falls in the narrow range of 5.0-5.2.

Example

Hereinafter, although an Example is given and this invention is demonstrated further more concretely, this invention is not restrict | limited at all by these Examples.

(Production of α-type benzoxazine compound)

Example  One

(±) -6-chloro-3,4-dihydro-4-methyl-3-oxo-N- (3-quinucridinyl) -2H-1,4-benzoxazine-8-carboxamide ( 2 g of (±) -6-chloro-3, 4-dihydro-4-methyl-3-oxo-N- (3-quinucridinyl) -2H-1,4-benzoxazine-8-carboxamide) are placed in a flask, and 25 mL of 1-butanol was added and dissolved. After adjusting the liquid temperature of the 1-butanol solution to 25 degreeC, crystal | crystallization precipitated when 8 mL (1.4 mol with respect to 1 mol of substrates) of 1 mol / L hydrogen chloride / diethyl ether was dripped slowly. At that time, the temperature rose to 40 degreeC. The temperature of the liquid mixture was 25 degreeC, and it stirred at 25 degreeC for 30 minutes. Then, the obtained crystal | crystallization is filtrated and it is made to dry for 12 hours on 60 degreeC and the conditions of 0.67 kPa, (±) -6-chloro-3, 4-dihydro- 4-methyl- 3-oxo-N- (3-qui) Nucrisdinyl) -2H-1, and 4-10-benzoxazine-8-carboxamide hydrochloride 2.10 g (yield 95.1%) were obtained.

When powder X-ray diffraction (hereinafter referred to as XRD) was measured using this crystal as a sample, an X-ray diffraction chart shown in FIG. 1 was obtained. From this result, it was found that this crystal was a compound having a crystal structure giving a characteristic peak at 2θ = 7.08 °, 13.54 °, 14.24 °, 16.52 °, 21.46 °, 22.40 °, 23.22 °. In addition, the infrared absorption spectrum (IR spectrum) is shown in FIG. 2, and the TG-DTA curve is shown in FIG. From these results, it was found that this crystal was an α-type benzoxazine compound having a novel crystal form.

It was 5.0 when the pH of the 5 mass% aqueous solution of this crystal was measured with the temperature correction type pH meter. In addition, the residual solvent amount of the obtained salt (dry salt) after drying was analyzed by gas chromatography (hereinafter, referred to as GC). Content of diethyl ether was 120 mass ppm (0.0120 mass%), and content of 1-butanol (1-butanol) was 3210 mass ppm (0.3210 mass%).

Example  2

2 g of (±) -6-chloro-3,4-dihydro-4-methyl-3-oxo-N- (3-quinucridinyl) -2H-1,4-benzoxazine-8-carboxamide The flask was placed in a flask, and 25 mL of 1-butanol was added to dissolve it. The liquid temperature of 1-butanol solution was adjusted to 25 degreeC. Temperature adjustment was performed by immersing a flask in the water bath of temperature control. Thereafter, 8 mL of 1 mol / L hydrogen chloride / diethyl ether (1.4 mol relative to 1 mol of the benzoxazine compound precursor) was slowly added dropwise to precipitate crystals. At that time, the temperature rose to 28 degreeC. The liquid mixture temperature was 25 degreeC, and it stirred at 25 degreeC for 30 minutes. Then, the obtained crystal | crystallization is filtrated, and it is made to dry for 12 hours on 60 degreeC and the conditions of 0.67 kPa, (±) -6-chloro-3, 4-dihydro- 4-methyl- 3-oxo-N- (3- Quinukridinyl) -2H-1 and 4-11 benzoxazine-8-carboxamide hydrochloride 2.11g (yield 95.5%) were obtained.

XRD measurement results in the same results as in Fig. 1, and α-benz having a novel crystal structure giving characteristic peaks at 2θ = 7.08 °, 13.54 °, 14.24 °, 16.52 °, 21.46 °, 22.40 °, 23.22 ° It was found to be an oxazine compound.

It was 5.2 when the pH of 5 mass% aqueous solution was measured with the temperature correction type pH meter similarly to Example 1. Moreover, when the residual solvent amount was analyzed by GC about the obtained dry salt, content of diethyl ether was 310 mass ppm (0.0310 mass%), and content of 1-butanol (1-butanol) was 3310 mass ppm (0.3310 mass%).

Example  3

The same operation as in Example 1 was carried out except that 1-butanol of Example 1 was replaced with ethanol. As a result, (±) -6-chloro-3,4-dihydro-4-methyl-3-oxo-N- (3-quinucridinyl) -2H-1,4-benzoxazine-8-car 2.11 g (95.5% yield) of boxamide hydrochloride was obtained. XRD measurement results in the same results as in Fig. 1, and α-benz having a novel crystal structure having peaks characteristic at 2θ = 7.08 °, 13.54 °, 14.24 °, 16.52 °, 21.46 °, 22.40 °, 23.22 ° It was found to be an oxazine compound.

It was 5.1 when the pH of 5 mass% aqueous solution was measured with the temperature correction type pH meter like Example 1. Moreover, the residual solvent amount of the obtained dry salt was analyzed by GC. Content of diethyl ether was 180 mass ppm (0.0180 mass%), and content of ethanol was 2650 mass ppm (0.2650 mass%).

Example  4

The same operation as in Example 1 was performed except that 1-butanol of Example 1 was replaced with 2-propanol. As a result, (±) -6-chloro-3,4-dihydro-4-methyl-3-oxo-N- (3-quinucridinyl) -2H-1,4-benzoxazine-8-car 2.11 g (95.5% yield) of boxamide hydrochloride was obtained. XRD measurement results in the same results as in Fig. 1, and α-benz having a novel crystal structure having peaks characteristic at 2θ = 7.08 °, 13.54 °, 14.24 °, 16.52 °, 21.46 °, 22.40 °, 23.22 ° It was found to be an oxazine compound.

It was 5.2 when the pH of 5 mass% aqueous solution was measured with the temperature correction type pH meter similarly to Example 1. Moreover, the residual solvent amount of the obtained dry salt was analyzed by GC. Content of diethyl ether was 150 mass ppm (0.0150 mass%), and content of 2-propanol (2-propanol) was 2770 mass ppm (0.2770 mass%).

Example  5

The same operation as in Example 1 was carried out except that 8 mL of 1 mol / L hydrogen chloride / diethyl ether of Example 1 was replaced with 4 mL of 2 mol / L hydrogen chloride / tetrahydrofuran. As a result, (±) -6-chloro-3,4-dihydro-4-methyl-3-oxo-N- (3-quinucridinyl) -2H-1,4-benzoxazine-8-car 2.16 g (97.8% yield) of boxamide hydrochloride were obtained. XRD measurement results in the same results as in Fig. 1, and α-benz having a novel crystal structure having peaks characteristic at 2θ = 7.08 °, 13.54 °, 14.24 °, 16.52 °, 21.46 °, 22.40 °, 23.22 ° It was found to be an oxazine compound.

It was 5.2 when the pH of 5 mass% aqueous solution was measured with the temperature correction type pH meter similarly to Example 1. Moreover, the residual solvent amount of the obtained dry salt was analyzed by GC. Content of tetrahydrofuran was 1010 mass ppm (0.1010 mass%), and content of 1-butanol (1-butanol) was 3120 mass ppm (0.3120 mass%).

Example  6

The same operation as in Example 1 was carried out except that 8 mL of 1 mol / L hydrogen chloride / diethyl ether of Example 1 was replaced with 8 mL of 1 mol / L hydrogen chloride / tert-butyl methyl ether. As a result, (±) -6-chloro-3,4-dihydro-4-methyl-3-oxo-N- (3-quinucridinyl) -2H-1,4-benzoxazine-8-car 2.15 g (97.4% of yield) of boxamide hydrochloride were obtained. XRD measurement results in the same results as in Fig. 1, and α-benz having a novel crystal structure having peaks characteristic at 2θ = 7.08 °, 13.54 °, 14.24 °, 16.52 °, 21.46 °, 22.40 °, 23.22 ° It was found to be an oxazine compound.

It was 5.1 when the pH of 5 mass% aqueous solution was measured with the temperature correction type pH meter like Example 1. Moreover, when the residual solvent amount of the obtained dry salt was analyzed by GC, content of tert- butyl methyl ether is 1250 mass ppm (0.1250 mass%), and content of 1-butanol (1-butanol) is It was 3180 mass ppm (0.3180 mass%).

Example  7

The same operation as in Example 1 was carried out except that the mixed liquid temperature during the dropwise addition was kept at 25 ° C from the beginning to the end, and stirred at 25 ° C for 30 minutes after completion of dropping. As a result, (±) -6-chloro-3,4-dihydro-4-methyl-3-oxo-N- (3-quinucridinyl) -2H-1,4-benzoxazine-8-car 2.14 g (96.9% yield) of boxamide hydrochloride was obtained. XRD measurement results in the same results as in Fig. 1, and α-benz having a novel crystal structure having peaks characteristic at 2θ = 7.08 °, 13.54 °, 14.24 °, 16.52 °, 21.46 °, 22.40 °, 23.22 ° It turned out to be an oxazine.

In the same manner as in Example 1, the pH of the 5% aqueous solution was 5.0 when measured with a temperature calibrated pH meter. Moreover, the residual solvent amount of the obtained dry salt was analyzed by GC. Content of diethyl ether was 150 mass ppm (0.0150 mass%), and content of 1-butanol (1-butanol) was 3090 mass ppm (0.3090 mass%).

Example  8

The same operation as in Example 1 was carried out except that the mixed liquid temperature during the dropwise addition was kept at 50 ° C from the beginning to the end, and the mixed liquid temperature after the completion of dropping was 25 ° C and stirred at 25 ° C for 30 minutes. As a result, (±) -6-chloro-3,4-dihydro-4-methyl-3-oxo-N- (3-quinucridinyl) -2H-1,4-benzoxazine-8-car 2.14 g (96.9% yield) of boxamide hydrochloride was obtained. XRD measurement results in the same results as in Fig. 1, and α-benz having a novel crystal structure having peaks characteristic at 2θ = 7.08 °, 13.54 °, 14.24 °, 16.52 °, 21.46 °, 22.40 °, 23.22 ° It was found to be an oxazine compound.

In the same manner as in Example 1, the pH of the 5% aqueous solution was 5.2 when measured with a temperature calibrated pH meter. Moreover, when the residual solvent amount of the obtained dry salt was analyzed by GC, content of diethyl ether was 160 mass ppm (0.0160 mass%), and content of 1-butanol was 2990 mass ppm (0.2990 mass%).

(Preparation of β-type benzoxazine compound)

(1st manufacturing method)

Example  9

2 g of (±) -6-chloro-3,4-dihydro-4-methyl-3-oxo-N- (3-quinucridinyl) -2H-1,4-benzoxazine-8-carboxamide Was added to a flask, and 25 mL of ethanol was added thereto to dissolve it. The flask was immersed in a temperature-controlled water bath, and after adjusting the liquid temperature of the ethanol solution to 10 ° C., 8 mL of 1 mol / L hydrogen chloride / diethyl ether (1.4 mol relative to 1 mol of the benzoxazine compound precursor) was slowly added to the crystal. Was precipitated. At that time, the temperature was rising to 12 ° C. After stirring at 12 ° C. for 30 minutes, the obtained crystals were filtered, dried at 60 ° C. under a condition of 0.67 kPa for 12 hours, and (±) -6-chloro-3,4-dihydro-4-methyl-3-oxo- 2.2 g (yield 99.6%) of N- (3-quinukridinyl) -2H-1 and 4-benzoxazine-8-carboxamide hydrochloride were obtained.

When XRD was measured using this crystal as a sample, the X-ray diffraction chart shown in FIG. 10 was obtained. From this result, it was found that this crystal had a crystal structure giving a characteristic peak at 2θ = 6.7 °, 9.9 °, 14.5 °, 15.2 °, 22.7 °, and 23.6 °. Moreover, the infrared absorption spectrum (IR spectrum) shown in FIG. 11 was obtained. From these results, it was found that this crystal was a beta benzoxazine compound having a novel crystal form.

It was 5.1 when the pH of the 5 mass% aqueous solution of this crystal was measured by the temperature correction type pH meter. In addition, when the residual solvent amount of the obtained dried salt (dry salt) was analyzed by gas chromatography (hereinafter referred to as GC), the content of diethyl ether was 360 mass ppm (0.0360 mass%), and ethanol The content of was 2850 mass ppm (0.2850 mass%).

Example  10

It operated in the same manner as in Example 9 except that the liquid temperature of the ethanol solution of the benzoxazine compound precursor was changed from 10 ° C to 18 ° C. In addition, at this time, the temperature of the mixed solution rose to 19 degreeC at maximum, and stirred at 19 degreeC for 30 minutes. As a result, (±) -6-chloro-3,4-dihydro-4-methyl-3-oxo-N- (3-quinucridinyl) -2H-1,4-benzoxazine-8-car 2.1 g (95.1%) of boxamide hydrochloride was obtained. XRD measurement results in the same results as in FIG. 10 and is a β-type benzoxazine compound having a novel crystal structure having peaks characteristic at 2θ = 6.7 °, 9.9 °, 14.5 °, 15.2 °, 22.7 °, and 23.6 °. Turned out.

It was 5.1 when the pH of the 5 mass% aqueous solution of this crystal was measured by the temperature correction type pH meter. When the residual solvent amount of the obtained dry salt was analyzed by GC, content of diethyl ether was 380 mass ppm (0.0380 mass%), and content of ethanol was 2670 mass ppm (0.2670 mass%).

Example  11

Operation was carried out in the same manner as in Example 9, except that the liquid temperature of the ethanol solution of the benzoxazine compound precursor was changed from 10 ° C to -15 ° C. In addition, at this time, the temperature of the mixed solution rose up to -13 degreeC and stirred for 30 minutes at -13 degreeC. As a result, (±) -6-chloro-3,4-dihydro-4-methyl-3-oxo-N- (3-quinucridinyl) -2H-1,4-benzoxazine-8-car 2.1 g (95.1%) of boxamide hydrochloride was obtained. XRD measurement results in the same results as in FIG. 10 and is a β-type benzoxazine compound having a novel crystal structure having peaks characteristic at 2θ = 6.7 °, 9.9 °, 14.5 °, 15.2 °, 22.7 °, and 23.6 °. It turned out.

It was 5.1 when the pH of the 5 mass% aqueous solution of this crystal was measured by the temperature correction type pH meter. Moreover, when the residual solvent amount of the obtained dry salt was analyzed by GC, content of diethyl ether was 350 mass ppm (0.0350 mass%), and content of ethanol was 2510 mass ppm (0.2510 mass%).

Example  12

2 g of (±) -6-chloro-3,4-dihydro-4-methyl-3-oxo-N- (3-quinucridinyl) -2H-1,4-benzoxazine-8-carboxamide Was added to a flask, and 25 mL of 1-pentanol was added thereto to dissolve the compound. The flask was immersed in a temperature-controlled water bath, the liquid temperature of the 1-pentanol solution was adjusted to 5 ° C., and then slowly added dropwise 0.8 mol / L hydrogen chloride / THF 10 mL (1.4 mol relative to 1 mol of the benzoxazine compound precursor). , A crystal was precipitated. At that time, the temperature rose to 8 degreeC. The crystal obtained after stirring at 8 degreeC for 30 minutes was filtered, and it dried for 12 hours on 60 degreeC and the conditions of 0.67 kPa, (±) -6-chloro-3, 4-dihydro- 4-methyl- 3-oxo-N 2.2 g of-(3-quinucridinyl) -2H-1 and 4-benzoxazine-8-carboxamide hydrochloride were obtained (yield 99.6%). XRD measurement results in the same results as in FIG. 10 and is a β-type benzoxazine compound having a novel crystal structure having peaks characteristic at 2θ = 6.7 °, 9.9 °, 14.5 °, 15.2 °, 22.7 °, and 23.6 °. It turned out.

It was 5.1 when the pH of the 5 mass% aqueous solution of this crystal was measured by the temperature correction type pH meter. Moreover, when the residual solvent amount of the obtained dry salt was analyzed by GC, content of THF was 1130 mass ppm (0.1130 mass%), and content of 1-pentanol was 4370 mass ppm (0.4370 mass%).

(Second manufacturing method)

Example  13

2 g of (±) -6-chloro-3,4-dihydro-4-methyl-3-oxo-N- (3-quinucridinyl) -2H-1,4-benzoxazine-8-carboxamide Was added to a flask, and 25 mL of 1-butanol was added thereto to dissolve the compound. The flask was immersed in a temperature-controlled water bath and the liquid temperature of the 1-butanol solution was adjusted to 40 ° C., followed by 2 mL of 4 mol / L hydrogen chloride / ethyl acetate (1.4 mol relative to 1 mol of the benzoxazine compound precursor). When dripping slowly, a crystal precipitated. At that time, the temperature was rising to 45 degreeC. The liquid mixture temperature was 25 degreeC, and it stirred at 25 degreeC for 30 minutes. Then, the obtained crystal | crystallization is filtrated, and it is made to dry for 12 hours on 60 degreeC and the conditions of 0.67 kPa, (±) -6-chloro-3, 4-dihydro- 4-methyl- 3-oxo-N- (3- Quinokridinyl) -2H-1, and 4-benzoxazine-8-carboxamide hydrochloride 2.10g (yield 95.1%) were obtained.

When powder X-ray diffraction was measured using this crystal as a sample, the chart similar to the XRD chart of Example 9 was obtained. From this result, it was found that this crystal had a crystal structure giving a characteristic peak at 2θ = 6.7 °, 9.9 °, 14.5 °, 15.2 °, 22.7 °, and 23.6 °. Moreover, IR spectrum was also the same as FIG. From these results, it was found that this crystal was a beta benzoxazine compound having a novel crystal form.

It was 5.0 when the pH of the 5 mass% aqueous solution of this crystal was measured with the temperature correction type pH meter. Moreover, when the residual solvent amount of the obtained dry salt was analyzed by GC, content of ethyl acetate was 210 mass ppm (0.0210 mass%), and content of 1-butanol (1-butanol) was 1490 mass ppm (0.1490 mass). %).

Example  14

2 g of (±) -6-chloro-3,4-dihydro-4-methyl-3-oxo-N- (3-quinucridinyl) -2H-1,4-benzoxazine-8-carboxamide Was added to a flask, and 25 mL of 1-butanol was added thereto to dissolve the compound. The flask was immersed in a temperature-controlled water bath, the liquid temperature of the 1-butanol solution was adjusted to -15 ° C, and then slowly dropwise added 2 mL of 4 mol / L hydrogen chloride / ethyl acetate (1.4 mol relative to 1 mol of the benzoxazine compound precursor). Crystals precipitated out. At that time, liquid temperature rose to -12 degreeC. It stirred at -12 degreeC for 30 minutes. Then, the obtained crystal | crystallization is filtrated and it is made to dry for 12 hours on 60 degreeC and the conditions of 0.67 kPa, (±) -6-chloro-3, 4-dihydro- 4-methyl- 3-oxo-N- (3-qui) Nuclidinyl) -2H-1 and 2.10 g (yield 95.1%) of 4-benzoxazine-8-carboxamide hydrochlorides were obtained.

When XRD was measured using this crystal as a sample, the X-ray diffraction chart similar to FIG. 10 was obtained. From this result, it was found that this crystal had a crystal structure giving a characteristic peak at 2θ = 6.7 °, 9.9 °, 14.5 °, 15.2 °, 22.7 °, and 23.6 °. Moreover, it was an IR spectrum similar to the case of Example 9. From these results, it was found that this crystal was a beta benzoxazine compound having a novel crystal form.

It was 5.0 when the pH of the 5 mass% aqueous solution of this crystal was measured with the temperature correction type pH meter. Moreover, when the residual solvent amount of the obtained dry salt was analyzed by GC, content of ethyl acetate was 230 mass ppm (0.0230 mass%), and content of 1-butanol was 1630 mass ppm (0.1630 mass%).

Example  15

The same operation as in Example 13 was carried out except that 2 mL of 4 mol / L hydrogen chloride / ethyl acetate was replaced with 2.5 mL of 4 mol / L hydrogen chloride / ethyl acetate (1.75 mol with respect to 1 mol of the benzoxazine compound precursor). The temperature after dripping was rising to 45 degreeC. The liquid mixture temperature was 25 degreeC, and it stirred at 25 degreeC for 30 minutes. The obtained crystals were filtered and dried under conditions of 60 ° C and 0.67 kPa for 12 hours, and (±) -6-chloro-3,4-dihydro-4-methyl-3-oxo-N- (3-quinucridinyl ) -2H-1 and 4-06-benzoxazine-8-carboxamide hydrochloride 2.06g (yield 93.3%) were obtained.

When XRD was measured using this crystal as a sample, the X-ray diffraction chart similar to what is shown in FIG. 10 was obtained. From this result, it was found that this crystal had a crystal structure giving a characteristic peak at 2θ = 6.7 °, 9.9 °, 14.5 °, 15.2 °, 22.7 °, and 23.6 °. Moreover, IR spectrum was also the same as the case of Example 9. From these results, it was found that this crystal was a beta benzoxazine compound having a novel crystal form.

It was 5.0 when the pH of the 5 mass% aqueous solution of this crystal was measured with the temperature correction type pH meter. Moreover, when the residual solvent amount of the obtained dry salt was analyzed by GC, content of ethyl acetate was 210 mass ppm (0.0210 mass%), and content of 1-butanol was 1550 mass ppm (0.1550 mass%).

Example  16

The same operation as in Example 13 was performed except that 2 mL of 4 mol / L hydrogen chloride / ethyl acetate was replaced with 1.55 mL of 4 mol / L hydrogen chloride / ethyl acetate (1.09 mol with respect to 1 mol of the benzoxazine compound precursor). The temperature after dripping was rising to 45 degreeC. The liquid mixture temperature was 25 degreeC, and it stirred at 25 degreeC for 30 minutes. Then, the obtained crystal | crystallization is filtrated and it is made to dry for 12 hours on 60 degreeC and the conditions of 0.67 kPa, (±) -6-chloro-3, 4-dihydro- 4-methyl- 3-oxo-N- (3-qui) Nucridinyl) -2H-1 and 2.06 g (yield 93.3%) of 4-benzoxazine-8-carboxamide hydrochloride were obtained.

Using this crystal as a sample, when XRD was measured, an X-ray diffraction chart similar to that shown in FIG. 10 was obtained. From this result, it was found that this crystal had a crystal structure giving a characteristic peak at 2θ = 6.7 °, 9.9 °, 14.5 °, 15.2 °, 22.7 °, and 23.6 °. Moreover, IR spectrum was also the same as the case of Example 9. From these results, it was found that this crystal was a beta benzoxazine compound having a novel crystal form.

It was 5.2 when the pH of the 5 mass% aqueous solution of this crystal was measured by the temperature correction type pH meter. Moreover, when the residual solvent amount of the obtained dry salt was analyzed by GC, content of ethyl acetate was 250 mass ppm (0.0250 mass%), and content of 1-butanol was 1660 mass ppm (0.1660 mass%).

Example  17

2 g of (±) -6-chloro-3,4-dihydro-4-methyl-3-oxo-N- (3-quinucridinyl) -2H-1,4-benzoxazine-8-carboxamide Was added to a flask, and 25 mL of propanol was added thereto to dissolve the compound. The flask was immersed in a temperature-controlled bath to adjust the liquid temperature of the propanol solution to 40 ° C., followed by 4.0 mL of 2 mol / L hydrogen chloride / ethyl propionate (1.4 mol per 1 mol of benzoxazine precursor). When slowly added dropwise, crystals were precipitated. At that time, the temperature rose to 43 degreeC. The liquid mixture temperature was 25 degreeC, and it stirred at 25 degreeC for 30 minutes. Then, the obtained crystal | crystallization is filtrated and it is made to dry for 12 hours on 60 degreeC and the conditions of 0.67 kPa, (±) -6-chloro-3, 4-dihydro- 4-methyl- 3-oxo-N- (3-qui Nuclidinyl) -2H-1 and 2.01 g (yield 91.0%) of 4-benzoxazine-8-carboxamide hydrochloride were obtained.

When XRD was measured using this crystal as a sample, the X-ray diffraction chart similar to what is shown in FIG. 10 was obtained. From this result, it was found that this crystal had a crystal structure giving a characteristic peak at 2θ = 6.7 °, 9.9 °, 14.5 °, 15.2 °, 22.7 °, and 23.6 °. Moreover, IR spectrum was also the same as the case of Example 9. From these results, it was found that this crystal was a beta benzoxazine compound having a novel crystal form.

It was 5.1 when the pH of the 5 mass% aqueous solution of this crystal was measured by the temperature correction type pH meter. When the residual solvent amount was analyzed by GC for the obtained dried salt, the content of ethyl propionate was 760 mass ppm (0.0760 mass%), and the content of propanol was 1240 mass ppm (0.1240 mass%). It was.

Example  18

2 g of (±) -6-chloro-3,4-dihydro-4-methyl-3-oxo-N- (3-quinucridinyl) -2H-1,4-benzoxazine-8-carboxamide Was added to a flask, and 25 mL of 1-pentanol was added thereto to dissolve the compound. The flask was immersed in a temperature-controlled water bath, and the liquid temperature of the 1-pentanol solution was adjusted to 40 ° C., followed by 3.2 mL of 2.5 mol / L hydrogen chloride / l-pentyl butyrate (benzoxazine compound precursor When 1.4 mol) was slowly added dropwise to 1 mol, crystals were precipitated. At that time, the temperature rose to 44 degreeC. The liquid mixture temperature was 25 degreeC, and it stirred at 25 degreeC for 30 minutes. Then, the obtained crystal | crystallization is filtrated and it is made to dry for 12 hours on 60 degreeC and the conditions of 0.67 kPa, (±) -6-chloro-3, 4-dihydro- 4-methyl- 3-oxo-N- (3-qui) Nuclidinyl) -2H-1 and 2.03 g (yield 91.9%) of 4-benzoxazine-8-carboxamide hydrochloride were obtained.

When XRD was measured using this crystal as a sample, the X-ray diffraction chart similar to what is shown in FIG. 10 was obtained. From this result, it was found that this crystal had a crystal structure giving a characteristic peak at 2θ = 6.7 °, 9.9 °, 14.5 °, 15.2 °, 22.7 °, and 23.6 °. Moreover, IR spectrum was also the same as the case of Example 9. From these results, it was found that this crystal was a beta benzoxazine compound having a novel crystal form.

It was 5.1 when the pH of the 5 mass% aqueous solution of this crystal was measured by the temperature correction type pH meter. When the residual solvent amount of the obtained dried salt was analyzed by GC, the content of pentyl butyrate was 3200 mass ppm (0.3200 mass%), and the content of 1-pentanol (1 -pentanol) was 4470 mass ppm (0.4470). Mass%).

Example  19

Operation was carried out in the same manner as in Example 13, except that the liquid temperature of the 1-butanol solution of the benzoxazine compound precursor was changed from 40 ° C to 55 ° C. In addition, at this time, the liquid mixture temperature rose to 58 degreeC. The liquid mixture temperature was 25 degreeC, and it stirred at 25 degreeC for 30 minutes. Then, the obtained crystal | crystallization is filtrated and it is made to dry for 12 hours on 60 degreeC and the conditions of 0.67 kPa, (±) -6-chloro-3, 4-dihydro- 4-methyl- 3-oxo-N- (3-qui Nuclidinyl) -2H-1 and 2.11 g (yield 95.5%) of 4-benzoxazine-8-carboxamide hydrochloride were obtained.

When powder X-ray diffraction was measured using this crystal as a sample, the chart similar to the XRD chart of FIG. 10 was obtained. From this result, it was found that this crystal had a crystal structure giving a characteristic peak at 2θ = 6.7 °, 9.9 °, 14.5 °, 15.2 °, 22.7 °, and 23.6 °. Moreover, IR spectrum was also the same as Example 9. From these results, it was found that this crystal was a beta benzoxazine compound having a novel crystal form.

It was 5.0 when the pH of the 5 mass% aqueous solution of this crystal was measured with the temperature correction type pH meter. The residual solvent amount of the obtained dried salt was analyzed by GC. The content of ethyl acetate was 250 mass ppm (0.0250 mass%), and the content of 1-butanol (1-butanol) was 1370 mass ppm (0.1370 mass%). It was.

Comparative example  One

(Production of Form I Form by the Method of Patent Document 1)

(±) -6-chloro-3,4-dihydro-4-methyl-3-oxo-N- (3-quinucridinyl) -2H-1,4-benzoxazine-8-carboxamide 10.5 g was placed in a flask and suspended therein by adding 21 mL of 50% water-containing ethanol. To this was added 3 g of concentrated hydrochloric acid to dissolve the compound. 0.1 mol / L hydrochloric acid was added to this solution to adjust the pH to about 4. Thereafter, 105 mL of ethanol was added and the mixture was kept at 40 to 50 ° C to precipitate crystals. The flask was immersed in a temperature-controlled water bath to adjust the precipitation temperature. The reaction mixture was cooled to 25 ° C. and stirred for 30 minutes. After that, the decision was filtered. The filtered crystals were dried at 60 ° C. under conditions of 0.67 kPa for 12 hours, and (±) -6-chloro-3,4-dihydro-4-methyl-3-oxo-N- (3-quinucridinyl) 9.62 g (yield 83.1%) of -2H-1 and 4-benzoxazine-8-carboxamide hydrochloride were obtained.

The result of measuring XRD is shown in FIG. From this result, it was found that the obtained crystal is an I crystal of Patent Document 1. The IR spectrum is shown in FIG. 5, and the measurement result of TG-DTA is shown in FIG. In the same manner as in Example 1, the pH of the 5% by mass aqueous solution of the crystal was measured by a temperature calibrated pH meter.

Comparative example  2

(Reproducibility examination 1 of manufacture -pH of crystalline Form I by the method of patent document 1)

The same operation as in Comparative Example 1 is repeated, and (±) -6-chloro-3,4-dihydro-4-methyl-3-oxo-N- (3-quinucridinyl) -2H-1,4- 9.72 g (yield 83.8%) of benzoxazine-8-carboxamide hydrochloride was obtained.

When XRD was measured, the result similar to FIG. 4 was obtained and it turned out that it is an I-type crystal | crystallization of the said patent document 1. In the same manner as in Example 1, the pH of the 5 mass% aqueous solution was 6.0 when measured with a temperature calibrated pH meter.

Comparative example  3

(Reproducibility study 2 of pH of manufacture-input amount of crystalline Form I by the method of patent document 1 is changed)

(±) -6-chloro-3,4-dihydro-4-methyl-3-oxo-N- (3-quinucridinyl) -2H-1,4-benzoxazine-8-carboxamide The operation was carried out in the same manner as in Comparative Example 1 except that the charged amount was 2 g, and the other reagents were increased in proportion to the charged amount. As a result, (±) -6-chloro-3,4-dihydro-4-methyl-3-oxo-N- (3-quinucridinyl) -2H-1,4-benzoxazine-8-car 1.82 g (82.6% yield) of boxamide hydrochloride were obtained.

When XRD was measured, it turned out as a result similar to FIG. 4, and it turned out that it is an I type crystal | crystallization of the said patent document 1. It was 3.3 when the pH of 5 mass% aqueous solution was measured with the temperature correction type pH meter like Example 1.

Comparative example  4

(Production of Form I Form by Other Methods of Patent Document 1)

5 g of (±) -6-chloro-3,4-dihydro-4-methyl-3-oxo-N- (3-quinucridinyl) -2H-1,4-benzoxazine-8-carboxamide Was added to a flask, and 21 mL of ethanol was added thereto to suspend the compound. Then, it heated to 50 degreeC and dissolved. The flask was immersed in a temperature-controlled water bath to adjust the precipitation temperature. 9.6 mL of 2 mol / L hydrogen chloride / ethanol was added to the solution to precipitate crystals. After stirring for 2 hours ice cooled and the crystals were filtered off. The filtered crystal | crystallization was dried for 12 hours on 60 degreeC and the conditions of 0.67 kPa, (±) -6-chloro-3, 4-dihydro- 4-methyl- 3-oxo-N- (3-quinukridinyl)- 5.31 g (yield 96.2%) of 2H-1 and 4-benzoxazine-8-carboxamide hydrochloride were obtained.

When XRD was measured, it turned out as a result similar to FIG. 4, and it turned out that it is an I type crystal | crystallization of the said patent document 1. It was 4.6 when the pH of 5 mass% aqueous solution was measured with the temperature correction type pH meter like Example 1. Moreover, when the residual solvent amount of the obtained dry salt was analyzed by GC, it was found that it is 49010 mass ppm (4.9010 mass%) of ethanol, and the residual amount of ethanol is very high.

Comparative example  5

(Reproducibility study 1 of pH of production of crystalline form I by the other method described in Patent Literature 1-input amount changed)

(±) -6-chloro-3,4-dihydro-4-methyl-3-oxo-N- (3-quinucridinyl) -2H-1,4-benzoxazine-8-carboxamide The same operation as in Comparative Example 4 was performed except that the input amount was 2 g and the other reagents were proportional to the input amount. As a result, (±) -6-chloro-3,4-dihydro-4-methyl-3-oxo-N- (3-quinucridinyl) -2H-1,4-benzoxazine-8-car 2.11 g (95.5% yield) of boxamide hydrochloride was obtained.

When XRD was measured, it turned out as a result similar to FIG. 4, and it turned out that it is an I crystal of the said patent document 1. It was 5.8 when the pH of 5 mass% aqueous solution was measured with the temperature correction type pH meter like Example 1. Moreover, when the residual solvent amount of the obtained dry salt was analyzed by GC, it turned out that 48520 mass ppm (4.852 mass%) of ethanol is very high.

Comparative example  6

(Reproducibility study 2 of pH of manufacture-dosage of crystalline form I form by the other method of patent document 1 is changed)

The same operation as in Comparative Example 5 is repeated, and (±) -6-chloro-3 and 4-dihydro-4-methyl-3-oxo-N- (3-quinucridinyl) -2H-1,4- 2.11 g (yield 95.5%) of benzoxazine-8-carboxamide hydrochloride were obtained.

When XRD was measured, it turned out as a result similar to FIG. 4, and it turned out that it is an I type crystal | crystallization of the said patent document 1. It was 4.0 when the pH of 5 mass% aqueous solution was measured with the temperature correction type pH meter like Example 1. Moreover, when analyzing the residual solvent amount of the obtained dry salt by GC, it turned out that 48750 mass ppm (4.8750 mass%) of ethanol is very high.

Comparative example  7

(Production of Crystalline Form II by the Method of Patent Document 1)

2 g of (±) -6-chloro-3,4-dihydro-4-methyl-3-oxo-N- (3-quinucridinyl) -2H-1,4-benzoxazine-8-carboxamide Was added to a flask, and 4 mL of 50% hydrous ethanol was added thereto to suspend the compound. 0.57 g of concentrated hydrochloric acid was added thereto and dissolved. 0.1 mol / L hydrochloric acid was added to this solution to adjust the pH to about 4. After that, 20 mL of ethanol was added to precipitate crystals at 3 ° C. The flask was immersed in a temperature-controlled water bath to adjust the precipitation temperature. The crystals were filtered off and dried at 60 ° C. under a condition of 0.67 kPa for 12 hours to give (±) -6-chloro-3,4-dihydro-4-methyl-3-oxo-N- (3-quinucridinyl). 1.89 g (yield 85.6%) of -2H-1 and 4-benzoxazine-8-carboxamide hydrochloride were obtained.

When XRD was measured, it became the result of FIG. 7, and it turned out that it is a type II crystal | crystallization of the said patent document 1. Moreover, IR spectrum is shown in FIG. 8, and TG-DTA is shown in FIG. It was 3.7 when the pH of 5 mass% aqueous solution was measured with the temperature correction type pH meter like Example 1.

Moreover, when the amount of residual solvent of the obtained dried salt was analyzed by GC, content of ethyl acetate was 12270 mass ppm (1.2270 mass%), and content of ethanol was 23290 mass ppm (2.3290 mass%).

Comparative example  8

(Production of Form II Form by the Method of Japanese Patent Application Laid-Open No. 2-218614)

2 g of (±) -6-chloro-3,4-dihydro-4-methyl-3-oxo-N- (3-quinucridinyl) -2H-1,4-benzoxazine-8-carboxamide Was added to a flask, and 4 mL of 2 mol / L hydrogen chloride / diethyl ether was added thereto. The precipitated crystals were filtered out and dried for 12 hours under the conditions of 60 ° C and 0.67 kPa, and (±) -6-chloro-3,4-dihydro-4-methyl-3-oxo-N- (3-quinucridy 2.11 g (yield 95.5%) of 2-)-1H, 4-benzoxazine-8-carboxamide hydrochlorides were obtained.

When XRD was measured, it became a result similar to FIG. 7, and it turned out that it is a type II crystal | crystallization of the said patent document 1. In addition, IR spectrum and TG-DTA were the same as what is shown to FIG. 8, FIG. 9, respectively.

It was 5.7 when the pH of 5 mass% aqueous solution was measured with the temperature correction type pH meter like Example 1.

Comparative example  9

(Reproducibility examination 3 of manufacture-dosage of crystal form I form by the method of patent document 1 is changed)

(±) -6-chloro-3,4-dihydro-4-methyl-3-oxo-N- (3-quinucridinyl) -2H-1,4-benzoxazine-8-carboxamide The operation amount was 3.5 g, and the same operation as in Comparative Example 1 was performed except that each other reagent was increased in proportion to the injection amount of the benzoxazine compound precursor. As a result, (±) -6-chloro-3,4-dihydro-4-methyl-3-oxo-N- (3-quinucridinyl) -2H-1,4-benzoxazine-8-car 4.20 g (99.9% yield) of boxamide hydrochloride were obtained.

When XRD was measured, it turned out as a result similar to FIG. 4, and it turned out that it is an I crystal of the said patent document 1. It was 4.1 when it measured the pH of 5 mass% aqueous solution by the temperature correction type pH meter like Example 1.

Reference Example  One

2 g of (±) -6-chloro-3,4-dihydro-4-methyl-3-oxo-N- (3-quinucridinyl) -2H-1,4-benzoxazine-8-carboxamide Was added to a flask, and 25 mL of 1-hexanol was added to dissolve it. The liquid temperature of 1-hexanol solution was adjusted to 5 degreeC. Temperature adjustment was performed by immersing the flask in the temperature-controlled water tank. Thereafter, 8 mL of 1 mol / L hydrogen chloride / diethyl ether (1.4 mol relative to 1 mol of the benzoxazine compound precursor) was slowly added dropwise to precipitate crystals. At that time, the temperature rose to 8 degreeC. Stirred at 8 ° C. for 30 minutes. The obtained crystal | crystallization was filtrated, and it dried under conditions of 60 degreeC and 0.67 kPa for 12 hours, and (±) -6- chloro- 3, 4-dihydro- 4-methyl- 3-oxo-N- (3-quinukridy Neil) -2H-1 and 4-gbenzoxazine-8-carboxamide hydrochloride 2.2g (yield 99.6%) were obtained.

When XRD was measured using this crystal as a sample, the chart similar to the X-ray diffraction chart shown in FIG. 10 was obtained. From this result, it was found that this crystal had a crystal structure giving a characteristic peak at 2θ = 6.7 °, 9.9 °, 14.5 °, 15.2 °, 22.7 °, and 23.6 °. Moreover, the IR spectrum shown in FIG. 11 was obtained. From these results, it was found that this crystal was a beta benzoxazine compound having a novel crystal form.

The pH of the 5 mass% aqueous solution of this crystal was measured by a temperature calibrated pH meter to 5.1. Moreover, when the residual solvent amount was analyzed by GC about the obtained dry salt, content of diethyl ether was 380 mass ppm (0.0380 mass%), and content of 1-hexanol (11-hexanol) was 11780 mass. ppm (1.1780 mass%).

This result shows that in the first manufacturing method of the beta benzoxazine compound, when alcohol having 6 or more carbon atoms is used, a large amount of solvent remains, which is not suitable for industrial production.

Reference Example  2

2 g of (±) -6-chloro-3,4-dihydro-4-methyl-3-oxo-N- (3-quinucridinyl) -2H-1,4-benzoxazine-8-carboxamide Was added to a flask and 25 mL of ethanol was added to dissolve it. The liquid temperature of the ethanol solution was adjusted to 50 ° C. Temperature adjustment was performed by immersing the flask in the temperature-controlled water tank. Thereafter, 2 mL of 4 mol / L hydrogen chloride / ethyl acetate (1.4 mol relative to 1 mol of the benzoxazine compound precursor) was slowly added dropwise to precipitate crystals. At that time, the temperature rose to 53 degreeC. The liquid mixture temperature was 25 degreeC, and it stirred at 25 degreeC for 30 minutes. The obtained crystal | crystallization was filtrated, and it dried under conditions of 60 degreeC and 0.67 kPa for 12 hours, and (±) -6- chloro- 3, 4-dihydro- 4-methyl- 3-oxo-N- (3-quinukridy Nil) -2g-1, 4-benzoxazine-8-carboxamide hydrochloride 2.1g (yield 95.1%) were obtained.

When XRD was measured using this crystal as a sample, the chart similar to the X-ray diffraction chart shown in FIG. 10 was obtained. From this result, it was found that this crystal had a crystal structure giving a characteristic peak at 2θ = 6.7 °, 9.9 °, 14.5 °, 15.2 °, 22.7 °, and 23.6 °. Moreover, the chart similar to the IR spectrum shown in FIG. 11 was obtained. From these results, it was found that this crystal was a beta benzoxazine compound having a novel crystal form.

It was 5.0 when the pH of the 5 mass% aqueous solution of this crystal was measured with the temperature correction type pH meter. Moreover, when the amount of residual solvent was analyzed with GC about the obtained dry salt, content of ethyl acetate was 3420 mass ppm (0.3420 mass%), and content of ethanol was 41520 mass ppm (4.1520 mass%).

This result shows that in the second manufacturing method of the β-type benzoxazine compound, when an alcohol having 2 or less carbon atoms is used, a large amount of solvent remains and is not suitable for an industrial production method.

Reference Example  3

2 g of (±) -6-chloro-3,4-dihydro-4-methyl-3-oxo-N- (3-quinucridinyl) -2H-1,4-benzoxazine-8-carboxamide Was added to a flask, and 25 mL of 1-hexanol was added to dissolve it. The liquid temperature of 1-hexanol solution was adjusted to 25 degreeC. Temperature adjustment was performed by immersing the flask in the temperature-controlled water tank. Thereafter, 8 mL of 1 mol / L hydrogen chloride / ethyl acetate (1.4 mol relative to 1 mol of the benzoxazine compound precursor) was slowly added dropwise to precipitate crystals. At that time, the temperature rose to 28 degreeC. The liquid mixture temperature was 25 degreeC, and it stirred at 25 degreeC for 30 minutes. The obtained crystal | crystallization was filtrated, and it dried for 12 hours on 60 degreeC and the conditions of 0.67 kPa, (±) -6-chloro-3, 4-dihydro- 4-methyl- 3-oxo-N- (3-quinook) 2.2 g (yield 99.6%) of ridinyl) -2H-1 and 4-benzoxazine-8-carboxamide hydrochloride were obtained.

When XRD was measured using this crystal as a sample, the chart similar to the X-ray-diffraction chart shown in FIG. 10 was obtained. From this result, it was found that this crystal had a crystal structure giving a characteristic peak at 2θ = 6.7 °, 9.9 °, 14.5 °, 15.2 °, 22.7 °, and 23.6 °. Moreover, the spectrum similar to the IR spectrum shown in FIG. 11 was obtained. From these results, it was found that this crystal was a beta benzoxazine compound having a novel crystal form.

It was 5.1 when the pH of the 5 mass% aqueous solution of this crystal was measured by the temperature correction type pH meter. When the residual solvent amount was analyzed by GC for the obtained dried salt, the content of ethyl acetate was 2080 mass ppm (0.2080 mass%), and the content of hexanol was 12180 mass ppm (1.2180 mass%). Was.

This result shows that in the second manufacturing method of the β-type benzoxazine compound, when an alcohol having 6 or more carbon atoms is used, a large amount of solvent remains, which is not suitable as an industrial production method.

Analytical Method

X-ray powder diffraction analysis was performed on a rigaku RINT 1200 X-ray powder diffractometer using Cu-K alpha radiation having a wavelength of 1.5406 angstroms. The voltage was set to 40 kV and the current to 40 mA. The sampling width was set at 0.020 and the scan speed was set at 2.0 ° / min. The starting angle was measured at 5 ° and the ending angle at 35 °. Samples were prepared for analysis by pushing them evenly into the holder.

TG / DTA measurements were performed using the SIIEXSTAR 6000. Approximately 10 mg of sample was accurately weighed and inserted into the furnace. Each sample was heated to a final temperature of 30 ° C. to 300 ° C. at a rate of 10 ° C./min to obtain a TG-DTA curve.

Infrared spectroscopic analysis was performed on a PerkinElmer SpectrumOne FT-IR Spectrometer. Each spectrum was measured on the conditions of 4 scan counts and the spectrometer resolution 4.00 cm- ^{1 in} the range of 4000-400 cm- ¹ . The ATR method was used for the measurement.

PH of the aqueous solution of the benzoxazine compound was measured using the temperature correction type pH meter (Dongkei Kay HM-60G). As a measurement sample, the 5 mass% aqueous solution which melt | dissolved the benzoxazine compound in water was used.

The residual solvent amount of the dried salt was measured using head space gas chromatography (apparatus: GC14A + HSS-2B (manufactured by Shimadzu Corporation), column): DB-624 (30 mX 0.53 mm film thickness: 3 µm manufactured by J & W Scientific). After the sample was dissolved in water, the residual solvent was evaporated and measured by the GC.

The benzoxazine compound of the present invention has a novel crystal structure. This compound is stable in quality, and when it is dissolved in water, the pH of the aqueous solution obtained is small and stable between production lots. Therefore, it is especially suitable for the use of medicines.

According to the manufacturing method of the benzoxazine compound of this invention, the benzoxazine compound which has a novel crystal structure can be manufactured easily.

Claims (6)

(±)-having a crystal structure giving characteristic peaks at least 2θ = 7.1 °, 13.5 °, 14.2 °, 16.5 °, 21.5 °, 22.4 °, 23.2 ° by X-ray diffraction using Cu-K α-rays 6-chloro-3, 4-dihydro-4-methyl-3-oxo-N- (3-quinucridinyl) -2H-1,4-benzoxazine-8-carboxamide hydrochloride. (±) -6-chloro-3,4-dihydro-4-methyl-3-oxo-N- (3-quinucridinyl) -2H-1,4-benzoxazine-8-carboxamide (±) -6-chloro-3,4-dihydro-4-methyl-3-oxo-N- (3-quinok) from a mixed solution obtained by bringing an alcohol solution having 1 to 5 carbon atoms into contact with an ether in which hydrogen chloride is dissolved. X-rays using Cu-K α-ray, comprising the step of precipitating aridinyl) -2H-1 and 4-benzoxazine-8-carboxamide hydrochloride while maintaining the mixed solution temperature at 20 ° C or higher. (±) -6-chloro-3,4-di having a crystal structure giving characteristic peaks by at least 2θ = 7.1 °, 13.6 °, 14.2 °, 16.5 °, 21.5 °, 22.4 °, 23.2 ° by diffraction The method for producing hydro-4-methyl-3-oxo-N- (3-quinucridinyl) -2H-1,4-benzoxazine-8-carboxamide hydrochloride. (±) -6-cle having a crystal structure giving characteristic peaks at least 2θ = 6.7 °, 9.9 °, 14.5 °, 15.2 °, 22.7 °, and 23.6 ° by X-ray diffraction using Cu-K α-rays Loro-3, 4-dihydro-4-methyl-3-oxo-N- (3-quinucridinyl) -2H-1, 4-benzoxazine-8-carboxamide hydrochloride. (±) -6-chloro-3,4-dihydro-4-methyl-3-oxo-N- (3-quinucridinyl) -2H-1,4-benzoxazine-8-carboxamide (±) -6-chloro-3,4-dihydro-4-methyl-3-oxo-N- (3-quinok) from a mixed solution obtained by bringing an alcohol solution having 1 to 5 carbon atoms into contact with an ether in which hydrogen chloride is dissolved. Cu-K alpha ray, comprising the step of precipitating aridinyl) -2H-1 and 4-benzoxazine-8-carboxamide hydrochloride while maintaining the mixed liquid temperature at -20 ° C or more and less than 20 ° C. X-ray diffraction using (±) -6-chloro-3,4- with a crystal structure giving a characteristic peak at least 2θ = 6.7 °, 9.9 °, 14.5 °, 15.2 °, 22.7 °, and 23.6 °. Method for producing dihydro-4-methyl-3-oxo-N- (3-quinucridinyl) -2H-1,4-benzoxazine-8-carboxamide hydrochloride. (±) -6-chloro-3,4-dihydro-4-methyl-3-oxo-N- (3-quinucridinyl) -2H-1,4-benzoxazine-8-carboxamide (±) -6-chloro-3,4-dihydro-4-methyl-3-oxo-N- (3-quinok) from a liquid mixture obtained by bringing an alcohol solution having 3 to 5 carbon atoms into contact with an ester in which hydrogen chloride is dissolved. At least 2θ = 6.7 °, by X-ray diffraction using Cu-K α-ray, comprising the step of precipitating lidinyl) -2H-1 and 4-benzoxazine-8-carboxamide hydrochloride. (±) -6-chloro-3, 4-dihydro-4-methyl-3-oxo-N- (having a crystal structure giving characteristic peaks at 9.9 °, 14.5 °, 15.2 °, 22.7 ° and 23.6 ° 3-quinukridinyl) -2H-1, the manufacturing method of 4-benzoxazine-8-carboxamide hydrochloride. The method of claim 5, The said ester is ester of a C1-C5 carboxylic acid and C1-C5 alcohol, It is characterized by the above-mentioned (±) -6-chloro-3, 4-dihydro- 4 -methyl- 3-oxo-N- ( 3-quinukridinyl) -2H-1, the manufacturing method of 4-benzoxazine-8-carboxamide hydrochloride.

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