WO2001092254A1 - Method for replacing organic solvents contained in clathrate crystals - Google Patents

Abstract

The problem of how to replace an organic solvent contained in clathrate crystals with water without causing transition of the crystals is solved by using a fluidizing means under a humidity-conditioned atmosphere, the clathrate crystals being especially A-type crystals of 8-[3-[N-[(E)-3-(6-acetamido- pyridin-3-yl)acryloylglycyl]-N-methylamino]-2,6-dichloro- benzyloxy]-2-methylquinoline.

Description

 Description Method for replacing organic solvent contained in clathrate crystal

 The present invention relates to a method for replacing an organic solvent contained in a clathrate crystal. More specifically, the present invention relates to a method for replacing an organic solvent contained in a clathrate crystal, which comprises replacing the organic solvent contained in the clathrate crystal with water under a humidified atmosphere by using a flow means. About the method. Background art

8— [3— [N — [(E) -3- (6-acetamidopyridine-1-3_yl) ataliloylglycyl] mono-N-methylamino] -2,6-dichloroben Ndiloxy] _2-Methylquinoline (hereinafter referred to as “FR1 73657”) is a compound having several crystal forms. Of these crystal forms, Form A obtained by crystallization from an acetone-monoaqueous solvent crystals, solid stability good purity also been reported to be high (JP-a 10 3166 77 No.) ₀

 Type A crystal of FR 173657 contains a small amount of acetone used during crystallization. Acetone is harmful to the human body and needs to be removed.However, it is difficult to reduce the acetone content to less than 0.5% specified in the ICH Residual Solvent Guidelines by ordinary vacuum drying. Was.

Subsequent research has revealed that the type A crystal of FR173657 is a crystal having a clathrate structure (hereinafter referred to as “clathrate crystal”). Force A X-ray crystallography revealed that FR 173657 formed a tunnel structure in this A-type crystal, and that acetone-water was included in the tunnel. '' A clathrate structure is usually defined as the formation of a tunnel, layer or network when two molecules combine to form a crystal under appropriate conditions. (Tangent lattice) is understood to have a structure in which the other molecule enters the gap. No strong intermolecular force acts between the molecule that forms the inclusion lattice (host) and the molecule that is included in it (guest), and the size of the cavity matches the size of the molecule inside. Is said to affect the generation of the clathrate structure.

 Therefore, the “clathrate crystal” in the present invention means a crystal having a clathrate structure composed of a usual host and guest.

 In the type A crystal of FR 1 7 365 7 having a clathrate structure, FR 1 7 3 5 7 7 itself serves as a host, and the acetone-water used for crystallization serves as a guest. Since it is included in the clathrate structure of 57, it is considered that it is difficult to be desorbed by methods such as vacuum drying.

 Generally, as a method for removing acetone, which is a guest in the clathrate structure, a method in which acetone is replaced with water in the presence of water vapor is known. Using this method, it is possible to reduce the content of acetone from the type A crystal of FR1736757 to 0.5% or less.

 However, in the presence of water vapor, the method of replacing the acetone in the classmate crystals of FR 173 657 with water using a tray dryer is based on the fact that FR 173 657 is hydrophobic. It takes a long time. In addition, the type A crystal of FR 1 7 3 6 5 7 has a property that the crystal form tends to change in the presence of excess water, so the method using a shelf type dryer that takes a long time is However, there is an inconvenience that a different crystal form is mixed in the A-type crystal of FR1736757. Therefore, there has been a demand for the development of a method for efficiently replacing the organic solvent from the A-type crystal of FR1736757 without causing the crystal form transition.

 Disclosure of the invention

 Thus, the present inventor has surprisingly found that the organic solvent contained in the clathrate crystal can be efficiently replaced with ice by using a flow means under a humidity-controlled atmosphere, and completed the present invention. BRIEF DESCRIPTION OF THE FIGURES

FIG. 1 shows a vibrating fluidized bed apparatus which is one of the fluidizing means used in the method of the present invention. It is a schematic diagram. BEST MODE FOR CARRYING OUT THE INVENTION

 The clathrate crystal in the present invention may be a crystal having the above-mentioned clathrate structure. For example, a type A crystal of FR173657, 7 j8— [2 -— (2-—) described in WO 96/07659. Aminothiazole-4-yl) -1- (Z) -1- (hydroxyimino) acetamide] -1-[(Pyrazol-4-yl) methylthio] -13-cefm-14-carboxylic acid or its Salt crystals, or 4- [3- (3,5-dichlorobenzenebenzoylamino) phenyl] -12- (3-pyridylmethyl) -13-oxo-1,3,4-dihydropyride [W 000/18768] , 2,3-b] pyrazine methanesulfonate AO 9 crystal.

 The solvent contained in the clathrate crystal is a solvent used when crystallizing the produced compound. Therefore, the solvent contained in the clathrate crystal includes various forces depending on the compound to be crystallized, such as acetone, acetonitrile, methanol, ethanol, isopropyl alcohol, tetrahydrofuran, and ethyl acetate. Specifically, examples of the solvent contained in the clathrate structure of FR173657 include acetone and water used to form an A-type crystal of FR173657.

 The A-type crystal of FR173657 containing acetone as an organic solvent can be produced, for example, according to the method of Example 1 described in JP-A-10-316677.

 As the fluidizing means, for example, a vibrating fluidized bed apparatus (VD-1 type) manufactured by Chuo Kakoki Co., Ltd. can be used. Fig. 1 shows a schematic diagram of a vibrating fluidized bed apparatus.

In the method using an oscillating fluidized bed apparatus, steam is generated using a compressor, a heater and a humidifier while controlling the temperature and humidity, and the steam is blown into the oscillating fluidized bed apparatus. In the oscillating fluidized bed apparatus, clathrate crystals containing an organic solvent are fluidized by the movement of a motor provided in the lower part of the apparatus, making it easier to come into contact with the water vapor blown into the apparatus. Temperature inside the device The temperature is not particularly limited, but is usually preferably about 20 to 60 ° C.

 In the present invention, “under a humidified atmosphere” means that the humidity in the apparatus in which the method of the present invention is performed is adjusted to a predetermined range. The preferable relative humidity under the humidity-controlled atmosphere varies depending on the combination of the clathrate crystal and the organic solvent contained therein. Generally, the higher the humidity, the more the organic solvent in the clathrate crystal is water. Easy to be replaced. Thus, the method of the present invention is specifically performed at a relative humidity of 25-90%, more preferably 40-70%.

 The replacement of the organic solvent contained in the clathrate crystal with water can be confirmed by a conventional method such as a gas chromatography method or a kerfishing method. The time required for this replacement depends on the type of clathrate crystals and the solvent to be replaced, as well as the operating conditions of the apparatus, but usually about 10 to 100 hours is sufficient. Next, the present invention will be described with reference to examples, but the present invention is not limited to these examples. Example

Production Example 1

(1) One (a) 8— [3- (N-glycyl-1-N-methylamino) 1,2,6-dichlorobenzyloxy] —2-methinolequinoline (l O Omg), (E) — 3-(6— Acetamide pyridine-13-yl) A mixture of acrylic acid (56.1 mg) and N, N-dimethylformamide (2 ml) was added to 1-hydroxybenzotriazole (43.4 mg) and 1-ethyl-3- ( 3-Dimethylaminopropyl) carbodiimide hydrochloride (56.9 mg) was added at 0 ° C in a nitrogen stream, and the mixture was stirred at room temperature for 2 hours. The reaction mixture was poured into water and extracted with black-mouthed form. The organic layer was washed successively with a saturated aqueous solution of sodium hydrogen carbonate, water and brine, dried over magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by preparative thin-layer chromatography (methanol: dichloromethane = 1:10, v / v), solidified with dimethyl ether and ethyl acetate, and subjected to 8_ [3— [N — [(E) -3-1 (6-Acetamidopyridine-1-3-yl) acryloylglycyl] — N-methylamino] —2,6-dichlorobenzyloxy] 1-2-methylquinoline (F R 1 73657) (78.8 mg) was obtained as an off-white solid. FR173657 (7 g) was added to methanol (720 ml) at 60 ° C, and the mixture was stirred for 5 minutes under reflux. After cooling the mixture to 30 ° C or lower, the mixture was stirred at 20 to 30 ° C for 2 hours to be crystallized. The crystallized solution was filtered, and the crystallized product was washed with methanol (14ral), dried in vacuo at 40 ° C, and subjected to crude anhydrous crystals of FR173657 (6.3 g) (hereinafter referred to as “crude FR173657 crystals”). "). The crystals were crystals containing about 5% methanol.

 (1) I- (b) (E) I-3- (6-acetamidopyridine-13-yl) acrylic acid (12.9 kg), triethylamine (12.7 kg) and N, N-dimethyl To a mixture of formamide (97.9 kg) was added isopropyl chlorocarbonate (7.32 kg). C for about 20 minutes, and after stirring for 30 minutes at 0 ° C, 8- [3- (N-Glycyl-N-methylamino)-1,6-dichlorobenzoyloxy]-2-methylquinoline (23 O kg) in 15 portions at 15 minute intervals, wash with N, N-dimethylformamide (10.9 kg), stir at 0 ° C for 1.5 hours, and add methanol (230 L) Then, the reaction was stopped and allowed to stand overnight. The mixture was heated to about 65 ° C, stirred at the same temperature for about 30 minutes, cooled to 10 ° C or less, and crystallized at 0 to 10 ° C. The crystallization liquid was filtered with a centrifuge, and the filtered crystals were washed with methanol (46 L). The obtained crystals were suspended in methanol (805 L), heated to about 65 ° C, cooled, and stirred at 10 to 20 ° C for 1 hour or more. The crystallized solution was filtered, and the filtered crystals were washed with methanol (46 L), dried at 40 ° C under reduced pressure, and dried under a pressure of 8— [3— [N — [(E) -3- (6— Acetamide pyridine-3-yl) acryloylglycine] -N-methylamino]-2,6 _cyclopentabenzizoleoxy]-crude anhydrous crystals of 2-methinolequinoline (FR 173657) (24.6 kg) (hereinafter referred to as " Crude FR173 657 crystal ”). The crystals were crystals containing about 5% methanol.

(2) Concentrated hydrochloric acid (28. lml) was added to a mixture of the crude FR173657 crystal (100 g) and purified water (500 ml) while stirring at 10 ° C or lower to dissolve the crude FR473657 crystal. To this solution was added charcoal powder (5 g), and the mixture was stirred for 2.5 hours. The charcoal powder was removed by filtration, purified water (200 ml) and concentrated hydrochloric acid (1.4 ml). And washed. The obtained filtrate was added to a mixture of acetone (700 ml) and triethylamine (35.87 g) at 55 ° C, stirred at the same temperature for 5 minutes, and refluxed for 20 minutes. After cooling to 40 ° C, the precipitated crystals were collected by filtration. The crystals were washed with 50% acetone and dried under vacuum to obtain FR173657 hydrate crystals (A-type crystals) (88.7 g). The crystals were clathrate crystals containing acetone as a guest. Comparative Example 5.0 g of A-type crystal of FR 173657 prepared in Production Example 1 was vacuum-dried at 40 ° C. and 0.2 Torr for 9 days. Table 1 shows the content of acetone and the content of water in the crystals before and after vacuum drying.

9日間経過後でも、 0. 5%以下までアセトンを除去することはできなかった。 比較例 2

Even after 9 days, acetone could not be removed to less than 0.5%. Comparative Example 2

 (Stand and replace)

 14.0 kg of the A-type crystal of FR173657 prepared in Production Example 1 was placed in a shelf-type vacuum dryer together with a tray filled with water, reduced under a steam atmosphere, and allowed to stand at 40 ° C for 2 weeks. Table 2 shows the acetone content and the water content in the crystal.

 Table 2

 Acetone content (w / w%) Water content (w / w%) A-type crystal before substitution 8.33 Not measured

A-type crystal after substitution 0.36 7.10 Because of the large amount of crystals, it took two weeks to remove acetone to less than 0.5%. Example 1

 12.3 kg of type A crystal of FR173657 prepared in Production Example 1 was passed through a vibrating fluidized bed apparatus (manufactured by Chuo Ichiki Co., Ltd.) for 98 hours under steam at 45 ° C and relative humidity = 60%. Acetone in the crystals was replaced with water. 12.26 kg of type A crystal of FR173657 was obtained. Table 3 shows the acetone content and the water content in the crystal.

 Table 3

結晶の量が多いにもかかわらず、 98時間で 0. 5%以下までアセトン含有率 を低下させることができた。 産業上の利用の可能性

Despite the large amount of crystals, the acetone content could be reduced to less than 0.5% in 98 hours. Industrial applicability

 According to the method of the present invention, the organic solvent contained in the clathrate crystal can be efficiently replaced with water in a short period of time without accompanying crystal form transition.

Claims

The scope of the claims 1. A method for replacing an organic solvent contained in a clathrate crystal, which comprises replacing the organic solvent contained in the clathrate crystal with water in a humidified atmosphere using a fluidizing means. 2. The method according to claim 1, wherein the organic solvent is acetone, acetonitrile, methanol, ethanol, tetrahydrofuran, isopropyl alcohol or ethyl acetate. 3. The method according to claim 1, wherein the fluidizing means is a vibrating fluidized bed apparatus. 4. The method according to any one of claims 1 to 3, wherein the condition of the humidity control atmosphere is a relative humidity of 40 to 70%. 5. The method according to any one of claims 1 to 4, wherein the replacement of the organic solvent is performed at a temperature of from 20 to 60 ° C. 6. The clathrate crystal is composed of 8_ [3- [N-[(E) -3- (6-acetamidopyridine-3-yl)] atari-mouth ^^ glycyl] 1-N-methylamino] 1,2,6 The method according to any one of claims 1 to 5, which is an A-form crystal of 2-methylquinoline.