JPH0770120A - Benzoxazine compound having stable crystal structure and its production - Google Patents

Abstract

PURPOSE:To produce a crystalline compound having a new crystal structure different from the conventional crystal, excellent in temperature stability and moisture stability, capable of mass-production and, therefore, having a secured uniformity as an original drug for an antiemetic or a therapeutic medicine for chlonic gastritis. CONSTITUTION:(+ or -)-6-Chloro-3,4-dihydro-4-methyl-3-oxo-N-(3-quinuclidinyl)-2H-1,4- benzoxanzine-8-carboxamide hydrochloride having a stable crystal structure giving characteristic peaks at 2theta=15.76 deg., 16.464 deg. and 20.639 deg. in X-ray diffraction by Cu-Kalpha ray.

Description

Detailed Description of the Invention

[0001]

The present invention relates to an excellent serotonin-3.
Useful as an antiemetic agent that has a receptor antagonistic effect and suppresses vomiting due to administration of antineoplastic agents such as cisplatin, or 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-quinuclidinyl) -2H-1,
The present invention relates to a stable crystal of 4-benzoxazine-8-carboxamide hydrochloride and a method for producing the same.

[0002]

2. Description of the Related Art Japanese Unexamined Patent Publication (Kokai) No. 2-28182 discloses an antiemetic agent or irritable enteritis syndrome which has an excellent serotonin-3 receptor antagonistic effect and suppresses vomiting and the like caused by administration of antineoplastic agents such as cisplatin. (±) -6-chloro-3,4-dihydro-4-methyl-3-oxo-N- (3-quinuclidinyl) -2H useful as a therapeutic agent for digestive system diseases
-1,4-Benzoxazine-8-carboxamide hydrochloride (hereinafter sometimes referred to as Compound A) is described. According to the same publication, compound A is (±) -6-chloro-3,4-dihydro-4-methyl-3-oxo-2H.
-1,4-benzoxazine-8-carboxylic acid chloride and 3-aminoquinuclidine were reacted in the presence of N-methylmorpholine, and the reaction product was recrystallized from ethanol-isopropyl ether and treated with ethereal hydrochloric acid. It is disclosed that the melting point is 281 ° C. (decomposition).

[0003]

By the way, the subsequent industrial synthesis research of the compound A revealed that the crystal form of the compound A changes with temperature and humidity, that is, that the compound A has polymorphism. In the case of developing as a pharmaceutical product, it has been desired to provide Compound A having a more stable crystal structure particularly in the production of pharmaceutical preparations.

[0004]

Therefore, the present inventors have
As a result of repeated intensive research to solve the above problems, by crystallizing by a specific method, against temperature and humidity,
It was found that a compound A having a novel crystal structure that is stable and suitable for large-scale synthesis can be obtained, and has completed the present invention.

That is, according to the present invention, (1) 2θ = 15.76 °, 16.4 by X-ray diffraction using Cu-Kα rays.
(±) -6-Chloro-3,4-dihydro-4-methyl-3-oxo-N- (3-quinuclidinyl)-having a stable crystal structure showing characteristic peaks at 64 ° and 20.639 °. 2H-1,4-benzoxazine-8-carboxamide hydrochloride (hereinafter sometimes referred to as type I crystal), (2) (±) -6-chloro-3,4-dihydro-
4-Methyl-3-oxo-N- (3-quinuclidinyl)
-2H-1,4-benzoxazine-8-carboxamide was added to a water-containing ethanol suspension with hydrochloric acid to adjust the pH of the resulting solution to about 3.8 to about 4.2 with diluted hydrochloric acid or diluted alkali, and then ethanol. 2 by X-ray diffraction using Cu-Kα rays characterized by precipitating crystals from
θ = 15.76 °, 16.464 ° and 20.639
(±) -6-chloro-3,4-dihydro-4-methyl- having a stable crystal structure showing a characteristic peak at
3-oxo-N- (3-quinuclidinyl) -2H-1,
Process for producing 4-benzoxazine-8-carboxamide hydrochloride, and (3) (±) -6-chloro-3,4-dihydro-4-methyl-3-oxo-N- (3-quinuclidinyl) -2H-. The aqueous solution of 1,4-benzoxazine-8-carboxamide hydrochloride in ethanol is adjusted to pH 3.8 to 4.2 with dilute hydrochloric acid or dilute alkali, and then crystals are precipitated from ethanol.
2θ = 15.76 by X-ray diffraction using u-Kα ray
(±) -6-chloro-3,4-dihydro-4-methyl-3-oxo-N- having a stable crystal structure with characteristic peaks at deg., 16.464 ° and 20.639 °.
It relates to a method for producing (3-quinuclidinyl) -2H-1,4-benzoxazine-8-carboxamide hydrochloride.

The hydrous ethanol used in the production of the type I crystal of the compound A of the present invention has a concentration of about 1%.
To about 70%, which is used in about 1.5 to about 3 times the amount of (±) -6-chloro-3,4-dihydro-4-methyl-.
3-oxo-N- (3-quinuclidinyl) -2H-1,
4-Benzoxazine-8-carboxamide can be suspended or its hydrochloride salt, Compound A, can be dissolved. (±) -6-chloro-3,4 in the above suspension
-Dihydro-4-methyl-3-oxo-N- (3-quinuclidinyl) -2H-1,4-benzoxazine-8-
The carboxamide needs to be salified with hydrochloric acid, and the hydrochloric acid used may be concentrated hydrochloric acid in an amount capable of forming the desired compound A which is a monohydrochloride. These benzoxazine compounds can be produced by the method described in JP-A-2-28182.

The aqueous ethanol solution of the compound A thus obtained was diluted with dilute hydrochloric acid or dilute alkali to obtain its p
The H is adjusted to about 3.8 to about 4.2, and the dilute hydrochloric acid used is preferably 0.1 to 0.3 N, and the dilute alkali has a pH of the solution of about 3.8. ~ About 4.2
Those which can be adjusted to 10 are preferable, and dilute sodium hydroxide, dilute potassium hydroxide, dilute sodium carbonate, dilute potassium carbonate, dilute ammonium hydroxide and the like are exemplified.

For crystallization, methanol or isopropyl alcohol may be used as a solvent, but ethanol is preferably used. The crystallization temperature is preferably 40 to 50 ° C or 30 to 40 ° C when a seed crystal is used. In addition,
When compound A is crystallized at a relatively low temperature of 10 ° C. or lower,
A crystal having a melting point of 281 ° C. (decomposition) described in Example 15 of JP-A-2-28182 (hereinafter referred to as type II crystal) was obtained, and this type II crystal was an X-ray using Cu-Kα ray. It shows a characteristic peak at 2θ = 11.494 ° by diffraction. The type II crystal is converted to the type I crystal by heating and humidification, but the obtained crystal is not a pure product and the solvent ethanol remains, which requires a further step for removal and is not industrial. . When compound A is crystallized from ethanolic hydrochloric acid at a relatively high temperature of 50 to 60 ° C,
Form I crystals are formed, but there is a problem that these crystals contain 4 to 5% of ethanol which cannot be removed by usual means such as drying under reduced pressure, heating and humidification. On the other hand, when compound A is crystallized from ethanolic hydrochloric acid at about room temperature, a crystal showing a melting point of 305 to 307 ° C. (decomposition) (hereinafter referred to as III
Type crystal) is generated. This type III crystal is Cu-
X-ray diffraction using Kα ray shows a characteristic peak at 2θ = 7.303 °. The type III crystal is also converted to the type I crystal by heating, humidification, etc., but there is a problem that its selectivity and reproducibility are poor, and it is not industrial because it requires treatment of the residual solvent. .

The type I crystal of the compound A of the present invention thus crystallized can be easily isolated and obtained by an ordinary simple means such as cooling, filtration, drying or by an appropriate combination. .

The type I crystal obtained by the present invention has a melting point of 307 ° C. (decomposition), and its infrared spectrum and powder X-ray diffraction pattern are as shown in FIGS. Table 1 shows the diffraction angles and the relative intensities from the powder X-ray diffraction pattern of the type I crystal.

Table 1 ──────────────────────────────────── Folding angle Relative strength ──── ─────────────────────────────────────── No. 2θ (°) d (A) I / I ₁ (%) ─ ─────────────────────────────────── 1 28.553 3.1235 47 2 26.819 3.3214 55 3 26.493 3.3615 62 4 24.759 3.5929 48 5 23.945 3.7131 55 6 22.970 3.8685 66 7 7 20.639 4.2999 86 8 16.464 5.3794 73 9 15.760 5.6184 100 10 13.266 6.6683 59 ───────────────────────── ───────────

On the other hand, the melting points of the type II crystal and the type III crystal are 281 ° C. (decomposition) and 305 to 307, respectively.
In addition, the infrared absorption spectrum and the powder X-ray diffraction pattern are shown in FIGS. 3 to 6, and the diffraction angle and the relative intensity from the powder X-ray diffraction pattern are shown in Tables 2 and 3.

Table 2 ──────────────────────────────────── Folding angle Relative strength ──── ─────────────────────────────────────── No. 2θ (°) d (A) I / I ₁ (%) ─ ─────────────────────────────────── 1 24.715 3.5991 20 2 23.271 3.8191 29 3 21.914 4.0525 21 4 18.017 4.9192 52 5 11.494 7.6921 100 6 7.948 11.1145 28 ─────────────────────────────────────

Table 3 ──────────────────────────────────── Folding angle Relative strength ──── ─────────────────────────────────────── No. 2θ (°) d (A) I / I ₁ (%) ─ ─────────────────────────────────── 1 24.867 3.5775 64 2 24.000 3.7048 36 3 22.156 4.0086 36 4 21.235 4.1805 51 5 20.801 4.2666 43 6 19.880 4.4623 36 7 12.507 7.0712 32 8 7.303 12.0944 100 ────────────────────────────────── ───

[0015]

The present invention will be described in detail below with reference to Examples, Reference Examples and Test Examples, but the present invention is not limited to these.

Example 1 (±) -6-chloro-3,4-
Dihydro-4-methyl-3-oxo-N- (3-quinuclidinyl) -2H-1,4-benzoxazine-8-carboxamide 886 g of 50% hydrous ethanol 1780
Suspend in ml and add 253 g of concentrated hydrochloric acid to dissolve. After adjusting the pH to about 4 by adding 0.1N hydrochloric acid to this solution, 8900 ml of ethanol was added to precipitate crystals at 40 to 50 ° C, and the crystals were cooled, filtered and dried to give a melting point of 307 ° C ( (I) of (±) -6-chloro-3,4-dihydro-4-methyl-3-oxo-N- (3-quinuclidinyl) -2H-1,4-benzoxazine-8-carboxamide hydrochloride Crystals are obtained.

Example 2 (±) -6-chloro-3,4-
Dihydro-4-methyl-3-oxo-N- (3-quinuclidinyl) -2H-1,4-benzoxazine-8-carboxamide hydrochloride (ethanol-containing type I crystal, type II crystal or type III crystal, or their 1160 g of 50% hydrous ethanol 20
Dissolve in 100 ml and add 0.1N hydrochloric acid to the solution to adjust pH to about 4, then add 100,000 m of ethanol.
l was added to precipitate crystals at 40 to 50 ° C., and the crystals were cooled, collected by filtration, and dried to give (±) -6-chloro-3,4-dihydro-4-methyl- (mp) mp 307 ° C.
3-oxo-N- (3-quinuclidinyl) -2H-1,
I of 4-benzoxazine-8-carboxamide hydrochloride
Mold crystals are obtained.

Reference Example 1 (±) -6-chloro-3,4-
1600 g of dihydro-4-methyl-3-oxo-N- (3-quinuclidinyl) -2H-1,4-benzoxazine-8-carboxamide is dissolved by heating in 6600 ml of ethanol. 21% ethanolic hydrochloric acid 10 at 50 ° C
When 66 g is added, the internal temperature rises to 57 ° C. After stirring for 2 hours, the mixture was cooled with ice and the precipitated crystals were collected by filtration and dried to give 4
(±) -6-chloro-3,4 containing% ethanol
-Dihydro-4-methyl-3-oxo-N- (3-quinuclidinyl) -2H-1,4-benzoxazine-8-
Form I crystals of carboxamide hydrochloride are obtained. This residual solvent could not be removed by heating and humidification.

Reference Example 2 (±) -6-chloro-3,4-
1251 g of dihydro-4-methyl-3-oxo-N- (3-quinuclidinyl) -2H-1,4-benzoxazine-8-carboxamide is dissolved by heating in 5000 ml of ethanol. After cooling to 25 ° C. and adding 804 g of 21% ethanolic hydrochloric acid, the internal temperature rises to 44 ° C. Two
After stirring for an hour, the mixture was cooled with ice and the precipitated crystals were collected by filtration and dried to give (±) -6-chloro-3,4-dihydro-4-methyl-3-oxo-N- (3-quinuclidinyl) -2H. −
Form III crystals of 1,4-benzoxazine-8-carboxamide hydrochloride are obtained. This III crystal changes to a type I crystal by heating and humidification. The Form I crystal thus obtained contained ethanol as a residual solvent.

Test Example for Crystallographic Stability A sample of type I crystal stored at 40 ° C. and 75% relative humidity for 6 months, I
Powder X-ray diffraction was measured for each of the sample in which the type I crystal was stored for 1 day at 35 ° C. and 75% relative humidity and the sample for which the type III crystal was stored for 3 days at 35 ° C. and 75% relative humidity.
The results are shown in FIGS. As shown in FIG. 7, it was confirmed that the powdery X-ray diffraction pattern of the I-type crystal did not change before and after storage, and was stable. On the other hand, II
The type III crystal and the type III crystal are shown in FIG. 8 and FIG. 9, respectively.
As shown in, the change to the type I crystal was observed upon storage, and it was confirmed that these crystals were easily transformed into the type I crystal.

[0021]

INDUSTRIAL APPLICABILITY The type I crystal of the compound A of the present invention is novel, unlike the type II crystal obtained hitherto.
Compared to type I crystal and type III crystal, it has good stability against temperature and humidity and can be manufactured in large quantities. Therefore, homogeneity as a drug substance of an antiemetic agent or a therapeutic agent such as chronic gastritis is established.

[Brief description of drawings]

FIG. 1 is an infrared spectrum of a type I crystal obtained according to the present invention.

FIG. 2 is a powder X-ray diffraction pattern of the type I crystal obtained according to the present invention.

FIG. 3 is an infrared spectrum of the type II crystal of compound A.

FIG. 4 is a powder X-ray diffraction pattern of a type II crystal of compound A.

FIG. 5 is an infrared spectrum of the type III crystal of compound A.

FIG. 6 is a powder X-ray diffraction pattern of a Form III crystal of Compound A.

FIG. 7 shows powder X-ray diffraction measurement results for a sample in which the type I crystal was stored at 40 ° C. and 75% relative humidity for 6 months.

FIG. 8 shows powder X-ray diffraction measurement results for a sample in which the type II crystal was stored for 1 day at 35 ° C. and 75% relative humidity.

FIG. 9: Form III crystal at 35 ° C. and 75% relative humidity 3
The powder X-ray-diffraction measurement result about the sample preserve | saved day is shown.

 ─────────────────────────────────────────────────── ─── Continuation of the front page (72) Takeshi Kawakita, Address 955, Ozai, Yoshitomi-cho, Tsukigami-gun, Fukuoka Prefecture, Yoshitomi Pharmaceutical Co., Ltd.

Claims (3)

[Claims] 1. An X-ray diffraction analysis using Cu-Kα rays
θ = 15.76 °, 16.464 ° and 20.639
(±) -6-chloro-3,4-dihydro-4-methyl- having a stable crystal structure showing a characteristic peak at
3-oxo-N- (3-quinuclidinyl) -2H-1,
4-benzoxazine-8-carboxamide hydrochloride. 2. Water-containing ethanol of (±) -6-chloro-3,4-dihydro-4-methyl-3-oxo-N- (3-quinuclidinyl) -2H-1,4-benzoxazine-8-carboxamide. Hydrochloric acid was added to the suspension, and the pH of the resulting solution was adjusted to about 3.8 with diluted hydrochloric acid or diluted alkali.
˜about 4.2, and then crystals are precipitated from ethanol, and 2θ = 15.76 °, 16.464 ° and 20.6 by X-ray diffraction using Cu-Kα ray.
(±) -6-Chloro-3,4-dihydro-4-methyl- having a stable crystal structure showing a characteristic peak at 39 °
3-oxo-N- (3-quinuclidinyl) -2H-1,
Process for producing 4-benzoxazine-8-carboxamide hydrochloride. 3. A (±) -6-chloro-3,4-dihydro-4-methyl-3-oxo-N- (3-quinuclidinyl) -2H-1,4-benzoxazine-8-carboxamide hydrochloride salt. The pH of the water-containing ethanol solution is adjusted to about 3.8 to about 4.2 with diluted hydrochloric acid or diluted alkali, and then crystals are precipitated from ethanol.
By X-ray diffraction using -Kα ray, 2θ = 15.76 °,
(±) -6-Chloro-, which has a stable crystal structure with characteristic peaks at 16.464 ° and 20.639 °.
3,4-dihydro-4-methyl-3-oxo-N- (3
-Quinuclidinyl) -2H-1,4-benzoxazine-8-carboxamide hydrochloride.