JP2015020973A - Crystalline form of chroman compound hydrochloric acid salt and method for producing the same - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a crystalline form of N-{(3R,4S)-3-hydroxy-6-methoxy-2,2-dimethyl-4-(phenetylamino)chroman-7-yl}methanesulfonamide which has antiarrhythmic action and is useful as a pharmaceutical raw material and to provide an industrial production method thereof which is stable and safe.SOLUTION: There are provided: a method for producing N-{(3R,4S)-3-hydroxy-6-methoxy-2,2-dimethyl-4-(phenetylamino)chroman-7-yl}methanesulfonamide which comprises a step of reacting a compound represented by the following formula with hydrochloric acid in an ester-alcohol mixed solvent or a nitrile solvent to crystallize; and a crystalline form obtained by the production method.

Description

The present invention relates to N-{(3R ^* , 4S ^* )-3-hydroxy-6-methoxy-2,2-dimethyl-4- (phenethylamino) chroman-7-yl} methanesulfonamide hydrochloride, its crystalline form And its manufacturing method.

（＊は相対配置を表す）
で示されるＮ−｛（３Ｒ^＊，４Ｓ^＊）−３−ヒドロキシ−６−メトキシ−２，２−ジメチル−４−（フェネチルアミノ）クロマン−７−イル｝メタンスルホンアミド（以下、化合物（１））は、抗不整脈作用を有し、医薬品としての使用の可能性が知られている（特許文献１）。 Formula (1)

(* Indicates relative arrangement)
N-{(3R ^* , 4S ^* )-3-hydroxy-6-methoxy-2,2-dimethyl-4- (phenethylamino) chroman-7-yl} methanesulfonamide (hereinafter referred to as Compound (1)) ) Has an antiarrhythmic action and is known for its potential use as a pharmaceutical (Patent Document 1).

  On the other hand, the solubility of a drug is an important physical property that affects oral absorption and drug efficacy. The solubility is composed of a dissolution rate and a solubility, and the former is one of the important characteristics of the drug because it is faster and expresses higher pharmacological activity (Non-patent Document 1).

  As factors that influence the dissolution rate, the salt and crystal form of the compound are known. Many drugs have basic or acidic functional groups, and in order to improve solubility, many drugs are used as their salts. In addition, even if crystals have the same chemical composition, the existence of crystal polymorphs having different crystal structures is known. Since these salts and crystal polymorphs usually have different dissolution rates and the like, it is necessary to select a more suitable salt and crystal form when developing as a pharmaceutical (Non-patent Document 2).

  However, with regard to compound (1), Patent Document 1 describes that “if a salt can be formed, a pharmaceutically acceptable salt thereof can also be used as an active ingredient.” "Hydrochloride, hydrobromide, sulfate, methanesulfonate, acetate, benzoate, tartrate, phosphate, lactate, maleate, fumarate, malate, gluconate And salicylate, etc. ", and there is no specific disclosure of salts and crystal forms thereof. Therefore, in developing Compound (1) as a pharmaceutical product, it was necessary to find the presence of a crystalline form of the salt of this compound.

  In addition, in the manufacture of pharmaceuticals, it is necessary to obtain crystals of the same quality and the same crystal form so that a constant action and effect can always be expected. A method that takes into account the safety aspects of the system is desired.

International Publication No. 2005/080368

Nagai Tsuneji, “Pharmaceutical Textbook Series“ Hybrid Pharmacology ””, Maruzen Co., Ltd., March 31, 1998, p38, 111 Written by Kazuhide Serizawa, “Crystal Polymorphism and Crystallization of Pharmaceuticals”, Maruzen Planet, September 20, 2002, p310

  The object of the present invention is to find a salt of compound (1) and a novel crystal form that the salt can take, and to produce a salt having these crystal forms with the same quality and the same crystal polymorph and safely. It is to provide an industrial manufacturing method that can be used.

As a result of intensive studies, the present inventors have found that there are novel crystal forms referred to as A-form crystals and C-form crystals in the hydrochloride of compound (1), and a method for producing these crystal forms. The present invention was completed.
That is, the present invention is characterized by the following.

(I)
N-{(3R ^* , 4S ^* )-3-hydroxy-6-methoxy-2,2-dimethyl-4- (phenethylamino) chroman-7-yl} methanesulfonamide hydrochloride crystals.
(II)
In the powder described in (I), in a powder X-ray diffraction diagram, diffraction angles: 2θ = 6.7, 10.6, 15.9, 16.3, 16.7, 17.7, 21.1, 21. N-{(3R ^* , 4S ^* )-3-hydroxy-6-methoxy-2,2-dimethyl-4- (phenethylamino) chroman-7 having characteristic peaks at 5, 22.5 and 25.4 -Yl} methanesulfonamide hydrochloride Form A crystals.
(III)
In the powder X-ray diffraction diagram, diffraction angles: 2θ = 5.2, 9.0, 9.3, 15.5, 15.9, 18.6, 18.8, 19. N-{(3R ^* , 4S ^* )-3-hydroxy-6-methoxy-2,2-dimethyl-4- (phenethylamino) having characteristic peaks at 3, 19.9, 20.3, 24.4 C) Form 7 crystals of chroman-7-yl} methanesulfonamide hydrochloride.
(IV)
N-{(3R ^* , 4S ^* )-3-hydroxy-6-methoxy-2,2-dimethyl-4- (phenethylamino) chroman-7-yl} methanesulfonamide is mixed with hydrochloric acid in an ester-alcohol mixed solvent. And N-{(3R ^* , 4S ^* )-3-hydroxy-6-methoxy-2,2-dimethyl-4- (phenethylamino) according to (I) above Chroman-7-yl} methanesulfonamide hydrochloride production method.
(V)
Among the production methods shown in (IV), N-{(3R ^* , 4S ^* )-3-hydroxy-6- (6) described in (II) above, wherein crystallization is carried out at 25 ° C. to 55 ° C. A method for producing methoxy-2,2-dimethyl-4- (phenethylamino) chroman-7-yl} methanesulfonamide hydrochloride Form A crystals.
(VI)
Of the production methods shown in (IV), N-{(3R ^* , 4S ^* )-3-hydroxy-6- (6) described in (III) above, wherein crystallization is carried out at 0 to 10 ° C. Process for producing methoxy-2,2-dimethyl-4- (phenethylamino) chroman-7-yl} methanesulfonamide hydrochloride C-form crystals.
(VII)
The production method according to any one of (IV) to (VI) above, wherein the ester solvent is ethyl acetate and the alcohol solvent is ethanol.
(VIII)
N-{(3R ^* , 4S ^* )-3-hydroxy-6-methoxy-2,2-dimethyl-4- (phenethylamino) chroman-7-yl} methanesulfonamide was added hydrochloric acid in a nitrile solvent, N-{(3R ^* , 4S ^* )-3-hydroxy-6-methoxy-2,2-dimethyl-4- (phenethylamino) chroman-7 as described in (III) above, which is crystallized -Il} methanesulfonamide hydrochloride C-form crystal production method.
(IX)
The production method according to (VIII) above, wherein the nitrile solvent is acetonitrile.

According to the present invention, N-{(3R ^* , 4S ^* )-3-hydroxy-6-methoxy-2,2-dimethyl-4- () has a novel crystalline form called Form A and Form C useful as pharmaceuticals. Phenethylamino) chroman-7-yl} methanesulfonamide hydrochloride is provided.

  The present invention also provides a novel production method for stably and safely obtaining these crystalline forms of hydrochloride with the same quality.

N-{(3R ^* , 4S ^* )-3-hydroxy-6-methoxy-2,2-dimethyl-4- (phenethylamino) chroman-7-yl} methanesulfonamide hydrochloride of the present invention 1 shows a powder X-ray diffraction pattern. The vertical axis represents the diffraction intensity (count), which means the count number of X-ray photons. The horizontal axis represents the diffraction angle: 2θ (°). N-{(3R ^* , 4S ^* )-3-hydroxy-6-methoxy-2,2-dimethyl-4- (phenethylamino) chroman-7-yl} methanesulfonamide hydrochloride C-form crystals of the present invention A powder X-ray diffraction pattern is shown (ethyl acetate-ethanol mixed solvent conditions). The vertical axis represents the diffraction intensity (count), which means the count number of X-ray photons. The horizontal axis represents the diffraction angle: 2θ (°). N-{(3R ^* , 4S ^* )-3-hydroxy-6-methoxy-2,2-dimethyl-4- (phenethylamino) chroman-7-yl} methanesulfonamide hydrochloride C-form crystals of the present invention A powder X-ray diffraction pattern is shown (acetonitrile solvent conditions). The vertical axis represents the diffraction intensity (count), which means the count number of X-ray photons. The horizontal axis represents the diffraction angle: 2θ (°). The result of the dissolution test of the A form crystal and the C form crystal in the first solution (pH 1.2) of the dissolution test measured in Test Example 1 is shown. The vertical axis represents the dissolution rate (%), and the horizontal axis represents time (minutes). The result of the dissolution test of the A form crystal | crystallization and the C form crystal | crystallization in the 2nd liquid (pH 6.8) of the dissolution test measured in Test Example 1 is shown. The vertical axis represents the dissolution rate (%), and the horizontal axis represents time (minutes). In the drawings, “vertical axis” means an axis in which numerical values are arranged in the vertical direction, and “horizontal axis” means an axis in which numerical values are arranged in the horizontal direction.

Hereinafter, the present invention will be described in more detail.
In this specification, "n-" is normal, "i-" is iso, "s-" and "sec-" are secondary, "t-" and "tert-" are tertiary, and "o-" is Ortho, “m-” means meta, “p-” means para.

で表され、粉末Ｘ線回折図において回折角：２θ＝６．７、１０．６、１５．９、１６．３、１６．７、１７．７、２１．１、２１．５、２２．５、２５．４に特徴的なピークを有する、Ｎ−｛（３Ｒ^＊，４Ｓ^＊）−３−ヒドロキシ−６−メトキシ−２，２−ジメチル−４−（フェネチルアミノ）クロマン−７−イル｝メタンスルホンアミド塩酸塩の結晶を、「Ａ形結晶」と呼ぶ。 In the present invention, the following formula (2)

In the powder X-ray diffraction diagram, diffraction angles: 2θ = 6.7, 10.6, 15.9, 16.3, 16.7, 17.7, 21.1, 21.5, 22.5 N-{(3R ^* , 4S ^* )-3-hydroxy-6-methoxy-2,2-dimethyl-4- (phenethylamino) chroman-7-yl} methane having a characteristic peak at 25.4 The crystals of sulfonamide hydrochloride are referred to as “A-form crystals”.

Moreover, it is represented by the above formula (2), and in the powder X-ray diffraction diagram, diffraction angles: 2θ = 5.2, 9.0, 9.3, 15.5, 15.9, 18.6, 18.8, N-{(3R ^* , 4S ^* )-3-hydroxy-6-methoxy-2,2-dimethyl-4-, having characteristic peaks at 19.3, 19.9, 20.3, 24.4 The crystals of (phenethylamino) chroman-7-yl} methanesulfonamide hydrochloride are referred to as “C crystals”.

  The solvent that can be used in the production method of the present invention is not particularly limited as long as the reaction is not hindered, but water, ester solvents (for example, methyl formate, ethyl formate, n-propyl formate, methyl acetate, ethyl acetate, acetic acid) n-propyl, i-propyl acetate, n-butyl acetate, i-butyl acetate, t-butyl acetate), alcohol solvent (means alcohol having 1 to 4 carbon atoms, such as methanol, ethanol, n-propanol, i-propanol, n-butanol, s-butanol, t-butanol), ketone solvents (eg, acetone, methyl ethyl ketone), aromatic hydrocarbon solvents (eg, p-xylene, toluene), aliphatic hydrocarbon solvents (eg, Cyclohexane, heptane), ether solvent (eg cyclopentyl methyl ether) or halogen-containing Medium (e.g., chloroform, 1,2-dichlorobenzene) can be used.

  The solvent to be used may be used singly or in combination of two or more. If these solvents are contained, other solvents can be added.

Then, the manufacturing method of A-type crystal is demonstrated.
The ester solvent used is preferably a formic acid ester having 1 to 3 carbon atoms of an alkoxy group such as methyl formate, ethyl formate, n-propyl formate, or methyl acetate, ethyl acetate, n-propyl acetate, i-propyl acetate, Acetic acid esters having 1 to 4 carbon atoms of alkoxy groups such as n-butyl acetate, i-butyl acetate, and t-butyl acetate, and more preferably ethyl acetate, n-propyl acetate, and i-propyl acetate.

  The alcohol solvent used is preferably an alcohol having 1 to 4 carbon atoms, such as methanol, ethanol, n-propanol, i-propanol, n-butanol, s-butanol, t-butanol, more preferably ethanol, n -Propanol.

The amount of solvent used is based on 1 g of N-{(3R ^* , 4S ^* )-3-hydroxy-6-methoxy-2,2-dimethyl-4- (phenethylamino) chroman-7-yl} methanesulfonamide. Thus, it is preferably 1 to 50 times by weight, more preferably 5 to 20 times by weight.

Hydrochloric acid is N-{(3R ^* , 4S ^* )-3-hydroxy-6-methoxy-2,2-dimethyl-4- (phenethylamino) chroman-7-yl} methanesulfonamide, Preferably it is 1 molar equivalent or more, More preferably, it is 1 to 2 molar equivalent, More preferably, it is 1 to 1.5 molar equivalent.

As a method of mixing hydrochloric acid and N-{(3R ^* , 4S ^* )-3-hydroxy-6-methoxy-2,2-dimethyl-4- (phenethylamino) chroman-7-yl} methanesulfonamide, N- Hydrochloric acid may be added to a solution or suspension of {(3R ^* , 4S ^* )-3-hydroxy-6-methoxy-2,2-dimethyl-4- (phenethylamino) chroman-7-yl} methanesulfonamide. A solution or suspension of N-{(3R ^* , 4S ^* )-3-hydroxy-6-methoxy-2,2-dimethyl-4- (phenethylamino) chroman-7-yl} methanesulfonamide in hydrochloric acid. Liquid may be added.

  The crystallization temperature is preferably in the range of 20 ° C to 60 ° C, more preferably 25 ° C to 55 ° C.

  A seed crystal can be used for crystallization. The seed crystal can be obtained by a method well known to those skilled in the art, such as rubbing the wall of a container containing a solution for crystallization with a spatula.

Next, a method for producing a C-type crystal will be described.
The ester solvent used is preferably a formic acid ester having 1 to 3 carbon atoms of an alkoxy group such as methyl formate, ethyl formate, n-propyl formate, or methyl acetate, ethyl acetate, n-propyl acetate, i-propyl acetate, Acetic acid esters having 1 to 4 carbon atoms of alkoxy groups such as n-butyl acetate, i-butyl acetate, and t-butyl acetate, and more preferably ethyl acetate, n-propyl acetate, and i-propyl acetate.

  The alcohol solvent used is preferably an alcohol having 1 to 4 carbon atoms, such as methanol, ethanol, n-propanol, i-propanol, n-butanol, s-butanol, t-butanol, more preferably ethanol, n -Propanol.

  The nitrile solvent used is preferably acetonitrile or propionitrile, more preferably acetonitrile.

The amount of solvent used is based on 1 g of N-{(3R ^* , 4S ^* )-3-hydroxy-6-methoxy-2,2-dimethyl-4- (phenethylamino) chroman-7-yl} methanesulfonamide. Thus, it is preferably 1 to 50 times by weight, more preferably 5 to 20 times by weight.

Hydrochloric acid is N-{(3R ^* , 4S ^* )-3-hydroxy-6-methoxy-2,2-dimethyl-4- (phenethylamino) chroman-7-yl} methanesulfonamide, Preferably it is 1 molar equivalent or more, More preferably, it is 1 to 2 molar equivalent, More preferably, it is 1 to 1.5 molar equivalent.

As a method of mixing hydrochloric acid and N-{(3R ^* , 4S ^* )-3-hydroxy-6-methoxy-2,2-dimethyl-4- (phenethylamino) chroman-7-yl} methanesulfonamide, N- Hydrochloric acid may be added to a solution or suspension of {(3R ^* , 4S ^* )-3-hydroxy-6-methoxy-2,2-dimethyl-4- (phenethylamino) chroman-7-yl} methanesulfonamide. A solution or suspension of N-{(3R ^* , 4S ^* )-3-hydroxy-6-methoxy-2,2-dimethyl-4- (phenethylamino) chroman-7-yl} methanesulfonamide in hydrochloric acid. Liquid may be added.

  The crystallization temperature is preferably in the range of -5 ° C to 20 ° C, more preferably 0 ° C to 10 ° C.

  A seed crystal can be used for crystallization. The seed crystal can be obtained by a method well known to those skilled in the art, such as rubbing the wall of a container containing a solution for crystallization with a spatula.

  EXAMPLES The present invention will be specifically described below with reference to examples, but the scope of the present invention is not limited to these examples.

  The hydrochloric acid content in the examples was measured by neutralization titration with a 0.1 mol / l sodium hydroxide aqueous solution using a potentiometric automatic titrator AT-510 manufactured by Kyoto Electronics Industry Co., Ltd. The powder X-ray diffraction measurement was carried out using X'Pert PRO (radiation source: Cu · Kα, wavelength: 1.54060 (10-10 m)) manufactured by Panalytical Co., Ltd. A photometer UV-2400PC was used.

  A commercial product (manufactured by Kanto Chemical Co., Inc .: specific gravity 1.18 g / mL) was used as the 35% hydrochloric acid described in the examples.

Example 1
Preparation of N-{(3R ^* , 4S ^* )-3-hydroxy-6-methoxy-2,2-dimethyl-4- (phenethylamino) chroman-7-yl} methanesulfonamide hydrochloride Form A ethyl acetate 16 .50 g, ethanol 13.52 g, water 2.99 g, 35% hydrochloric acid 1.38 g (13.2 mmol) were mixed and heated to 30 ° C. To this solution, separately prepared ethyl acetate of N-{(3R ^* , 4S ^* )-3-hydroxy-6-methoxy-2,2-dimethyl-4- (phenethylamino) chroman-7-yl} methanesulfonamide A 2/3 amount of 25.00 g of solution (containing 5.57 g, 13.2 mmol) was added dropwise at 30 ° C. over 1 hour. After stirring at 30 ° C. for 1 hour, the remaining 1/3 amount was added dropwise over 1 hour. After washing with 5.02 g of ethanol, the mixture was stirred at 30 ° C. for 3.5 hours, and the precipitated crystals were filtered, washed with a mixed solution of 7.30 g of ethyl acetate and 3.70 g of ethanol, and 7.29 g of ethyl acetate, Washed with a mixture of 3.68 g of ethanol. The obtained crystals were dried at 50 ° C. under reduced pressure for 3 hours, and N-{(3R ^* , 4S ^* )-3-hydroxy-6-methoxy-2,2-dimethyl-4- (phenethylamino) chroman- Thus, 3.71 g (8.12 mmol, 61% yield) of Form A crystals of 7-yl} methanesulfonamide hydrochloride was obtained as white crystals.
The obtained crystal was 1.02 hydrochloride, and diffraction angles of this powder X-ray diffraction diagram: 2θ = 6.7, 10.6, 15.9, 16.3, 16.7, 17.7, Characteristic peaks were observed at 21.1, 21.5, 22.5, and 25.4. The results are shown in FIG.

Example 2
Production of N-{(3R ^* , 4S ^* )-3-hydroxy-6-methoxy-2,2-dimethyl-4- (phenethylamino) chroman-7-yl} methanesulfonamide hydrochloride C-form crystals (ethyl acetate -Ethanol mixed solvent conditions)
A solution obtained by mixing 20.02 g of ethyl acetate, 10.03 g of ethanol and 2.50 g of water was cooled to 1 ° C., and then 1.38 g (13.2 mmol) of 35% hydrochloric acid was added. Separately, 15.00 g of an ethyl acetate solution of N-{(3R ^* , 4S ^* )-3-hydroxy-6-methoxy-2,2-dimethyl-4- (phenethylamino) chroman-7-yl} methanesulfonamide ( 5.57 g containing, 13.2 mmol) was prepared, insoluble matter was filtered and washed with 10.03 g of ethyl acetate. The filtrate was added dropwise to the hydrochloric acid mixture at 1 ° C. over 1 hour. Wash with 5.02 g of ethanol and stir at 1 ° C. to 2 ° C. for 4 hours to precipitate crystals. Filter, wash with a mixture of 8.02 g of ethyl acetate and 2.97 g of ethanol, and further 8.00 g of ethyl acetate and ethanol 3 Washed with 0.04 g of mixture. The obtained crystals were dried under reduced pressure at 50 ° C. for 4 hours, and N-{(3R ^* , 4S ^* )-3-hydroxy-6-methoxy-2,2-dimethyl-4- (phenethylamino) chroman- 7.39 g (7.42 mmol, yield 56%) of C-form crystals of 7-yl} methanesulfonamide hydrochloride were obtained as white crystals.
The obtained crystal is 0.99 hydrochloride, and diffraction angles of this powder X-ray diffraction diagram: 2θ = 5.2, 9.0, 9.3, 15.5, 15.9, 18.6, Characteristic peaks were observed at 18.8, 19.3, 19.9, 20.3, and 24.4. The results are shown in FIG.

Example 3
Production of N-{(3R ^* , 4S ^* )-3-hydroxy-6-methoxy-2,2-dimethyl-4- (phenethylamino) chroman-7-yl} methanesulfonamide hydrochloride C-form crystals (acetonitrile solvent conditions)
N-{(3R ^* , 4S ^* )-3-hydroxy-6-methoxy-2,2-dimethyl-4- (phenethylamino) chroman-7-yl} methanesulfonamide 0.505 g (1.20 mmol) in acetonitrile It melt | dissolved in 5.03g, 35% hydrochloric acid 0.116mL (1.31mmol) was added at 3 degreeC, and it stirred at 2 to 3 degreeC for 3 hours, and the precipitated crystal | crystallization was filtered. The obtained crystals were dried under reduced pressure at 50 ° C. for 2 hours, and N-{(3R ^* , 4S ^* )-3-hydroxy-6-methoxy-2,2-dimethyl-4- (phenethylamino) chroman- 7-yl} methanesulfonamide hydrochloride C-form crystals 0.512 g (1.12 mmol, 93% yield) were obtained as white crystals.
The obtained crystal was 0.98 hydrochloride, and this powder X-ray diffraction diagram showed the same peak as the crystal obtained in Example 2. The results are shown in FIG.

Test Examples Hereinafter, test examples using A-type crystals and C-type crystals obtained by the methods of Examples 1 and 2 described above are shown.

Test example 1
N-{(3R ^* , 4S ^* )-3-hydroxy-6-methoxy-2,2-dimethyl-4- (phenethylamino) chroman-7-yl} methanesulfonamide hydrochloride A-form crystal, C-form crystal And the elution test of the free body (compound (1)) was conducted. About 50 mg of A-form crystals, C-form crystals, and free form were precisely weighed, 10 mL each of Japanese Pharmacopoeia dissolution test first solution (pH 1.2) was added, stirred for 30 seconds, and then kept at 37 ° C. for 480 mL Was added to the first solution of the dissolution test. Further, washing was performed using 10 mL of the first dissolution test solution. The test was performed by the paddle method (paddle rotation speed: 100 rpm), and 10 mL was sampled over time (5, 15, 30, 60 minutes) (same volume as a replacement solution), passed through a filter, and an equal amount of methanol was added. The sample solution was diluted by use. On the other hand, about 10 mg each of hydrochloride A-form crystals and free form were precisely weighed, and 20 mL of methanol was added and dissolved completely. A part of these solutions was diluted 5, 25, and 250 times with methanol, and then diluted with the same amount of the first dissolution test solution as a calibration curve solution. Using an ultraviolet-visible absorptiometer (measurement wavelength: 302 nm), the absorbance of each of the obtained sample solution and calibration curve solution was measured, and after preparing a calibration curve, the elution rate ( %) Was calculated.
The results are shown in FIG. There was no big difference in any elution rate, and it became 90% in 60 minutes.

Test example 2
N-{(3R ^* , 4S ^* )-3-hydroxy-6-methoxy-2,2-dimethyl-4- (phenethylamino) chroman-7-yl} methanesulfonamide hydrochloride A-form crystal, C-form crystal And the elution test of the free body was conducted. About 50 mg of A-form crystals, C-form crystals, and free form were weighed, 10 mL each of Japanese Pharmacopoeia dissolution test solution 2 (pH 6.8) was added, stirred for 30 seconds, and then kept at 37 ° C. for 480 mL Was added to the second solution of the dissolution test. Further, washing was performed using 10 mL of the second dissolution test solution. The test was performed by the paddle method (paddle rotation speed: 100 rpm), and 10 mL was sampled over time (5, 15, 30, 60, 120 minutes) (same volume as replacement fluid), passed through a filter, Diluted with methanol to obtain a sample solution. On the other hand, about 10 mg of each of the hydrochloride A-form crystals and the free form was precisely weighed, and 20 mL of methanol was added and dissolved completely. A part of these solutions was diluted 5, 25, and 250 times with methanol, and then diluted with an equal amount of the second dissolution test solution to obtain a calibration curve solution. Using an ultraviolet-visible absorptiometer (measurement wavelength: 302 nm), the absorbance of each of the obtained sample solution and calibration curve solution was measured, and after preparing a calibration curve, the elution rate ( %) Was calculated.
The results are shown in FIG. The elution rate of the free form is about 65% after 120 minutes, whereas the hydrochloride A form crystal and the C form crystal are about 80%, and both the hydrochloride form crystals have better elution ratio than the free form. Indicated.

According to the present invention, N-{(3R ^* , 4S ^* )-3-hydroxy-6-methoxy-2,2-dimethyl-4- (phenethylamino) chroman- having novel crystalline forms referred to as Form A and Form C 7-yl} methanesulfonamide hydrochloride is useful in that it can be stably produced in the same crystal form and can be produced safely with the same quality.

Claims (9)

N-{(3R ^* , 4S ^* )-3-hydroxy-6-methoxy-2,2-dimethyl-4- (phenethylamino) chroman-7-yl} methanesulfonamide hydrochloride crystals. The crystal according to claim 1, wherein a diffraction angle in a powder X-ray diffraction diagram is 2θ = 6.7, 10.6, 15.9, 16.3, 16.7, 17.7, 21.1, 21. N-{(3R ^* , 4S ^* )-3-hydroxy-6-methoxy-2,2-dimethyl-4- (phenethylamino) chroman-7 having characteristic peaks at 5, 22.5 and 25.4 -Yl} methanesulfonamide hydrochloride Form A crystals. The crystal according to claim 1, wherein in the powder X-ray diffraction diagram, diffraction angles: 2θ = 5.2, 9.0, 9.3, 15.5, 15.9, 18.6, 18.8, 19. N-{(3R ^* , 4S ^* )-3-hydroxy-6-methoxy-2,2-dimethyl-4- (phenethylamino) having characteristic peaks at 3, 19.9, 20.3, 24.4 C) Form 7 crystals of chroman-7-yl} methanesulfonamide hydrochloride. N-{(3R ^* , 4S ^* )-3-hydroxy-6-methoxy-2,2-dimethyl-4- (phenethylamino) chroman-7-yl} methanesulfonamide is mixed with hydrochloric acid in an ester-alcohol mixed solvent. The N-{(3R ^* , 4S ^* )-3-hydroxy-6-methoxy-2,2-dimethyl-4- (phenethylamino) chroman according to claim 1, characterized in that -7-yl} methanesulfonamide hydrochloride production method. N-{(3R ^* , 4S ^* )-3-hydroxy-6-methoxy according to claim 2, characterized in that, in the production method shown in claim 4, crystallization is carried out at 25 ° C to 55 ° C. A process for producing -2,2-dimethyl-4- (phenethylamino) chroman-7-yl} methanesulfonamide hydrochloride Form A crystals. N-{(3R ^* , 4S ^* )-3-hydroxy-6-methoxy according to claim 3, characterized in that, in the production method shown in claim 4, crystallization is carried out at 0 to 10 ° C. A method for producing a -2,2-dimethyl-4- (phenethylamino) chroman-7-yl} methanesulfonamide hydrochloride C-form crystal.   The production method according to any one of claims 4 to 6, wherein the ester solvent is ethyl acetate and the alcohol solvent is ethanol. N-{(3R ^* , 4S ^* )-3-hydroxy-6-methoxy-2,2-dimethyl-4- (phenethylamino) chroman-7-yl} methanesulfonamide was added hydrochloric acid in a nitrile solvent, N-{(3R ^* , 4S ^* )-3-hydroxy-6-methoxy-2,2-dimethyl-4- (phenethylamino) chroman-7- according to claim 3, characterized in that it is crystallized. Yl} methanesulfonamide hydrochloride C-type crystal production method.   The production method according to claim 8, wherein the nitrile solvent is acetonitrile.

Images