TW200533672A - Crystal of oxacephem - Google Patents

Abstract

The present invention relates to a novel crystal of the flomoxef advantage in environment and preparation. A methyl acetate solvate crystal or a hydrate crystal of the flomoxef.

Description

'200533672 IX. Description of the invention: [Technical field to which the invention belongs] The present invention relates to a crystal of stilbene which is useful as an antibacterial agent. [Prior art] The following formula is known as flomoxef: h〇ch3 f2ch "

Useful as a phenphene-based antibacterial agent. A freeze-dried preparation containing its sodium salt is commercially available as an injection (trade name: Flumabell, Shiono Pharmaceutical Co., Ltd.). This lyophilized preparation is produced by using flumochif as a main raw material and sodium chloride and a stabilizer (refer to Patent Document 1). The crystals of flumochif are also known. For example, the protective body of the corresponding 4-carboxylic acid is methylene chloride and methoxybenzene, treated with a Lewis acid (TiCl4 or A1C13), and then crystallized from ethyl acetate ( Reference: Patent Document 2, Example 3). The other method is to make the intermediate protected by the 4-carboxylic acid and the 3-terminal hydroxyl group also be treated with Lewis acid (SnCl4) and crystallized from dichloromethane and acetone in the presence of methoxybenzene. Non-Patent Document 1). Although these crystal forms are not described in detail, according to the method of the inventor's retrospective examination ', the crystal containing dichloromethane was obtained. [Patent Document 1] JP-A Sho 6 0-4 5 5 1 4 [Patent Document 2] JP-A Sho 59-139385 [Non-Patent Document 1] * 200533672

The Journal of Antibiotics (Apr. P466-476, 1 985) [Contents of the Invention] (Questions to be Solved by the Invention)

It is not easy to degas methylene chloride containing crystals of flumochief according to the usual drying method. In the past, the formulation method used in actual production was lyophilized as described in Patent Document 1 and sterilized, so that no sodium salt containing dichloromethane was obtained. However, the freeze-drying method generally has high manufacturing costs and is also very burdensome in terms of equipment maintenance. Therefore, as a more effective industrial preparation method for sterile preparations for injection, it has recently been desired to use a method other than the lyophilization method. As long as Flumochif does not contain dichloromethane, there is also a possibility of using it as a medicinal active ingredient. Therefore, flimoxicif is required to contain no dichloromethane, and it is more advantageous to formulate new crystals. (Means for Solving the Problems) As a result of an intensive review conducted by the present inventors in view of the above-mentioned problems, they discovered that the novel solvate crystals containing flumochisef have finally completed the following inventions:

1) Hydrate or hydrate crystal of compound f2ch

S \ ^ N OH (|) (2) The hydrate or hydrate crystal described in 1 above, which is a monohydrate (3) The hydrate crystal described in 1 or 2 above, and its powder X-ray diffraction pattern is on the surface The interval d = 8.31, 7.00, 6.11, 5.43, 4.47, 4 35, 4,19 4.15, 3.95, 3.81, 3.50, 3.32, 2.96 (unit: A) have main peaks. (4) Methyl acetate compound or methyl acetate compound of the compound (I) of the formula 200533672 Crystal: h〇3

(5) The methyl acetate compound or methyl acetate compound crystal according to the above 4, is a methyl acetate compound of 0.5.

(6) The crystals of the methyl acetate compound described in 4 or 5 above, whose powder X-ray diffraction mode is at an interval d = 10.42, 6.32, 4.96, 4.62, 4.56, 4.36, 4.23, 3.97, 3.93, 3.79, 3.47 There is a main peak at 2.7 9 (unit: A). (Effects of the Invention) The novel solvate of flumochif according to the present invention should preferably be crystallized, and it is also advantageous for formulation because of its excellent stability and handling properties. In particular, since the hydrate crystals do not contain organic solvents such as dichloromethane, there is a possibility that the hydrate crystals can be formulated as an injection by the powder filling method. Furthermore, the methyl acetate crystallization is more advantageous than the crystals containing dichloromethane in terms of safety and environmental aspects, so that femochicil can be efficiently produced industrially. That is, these crystals can be used as pharmaceutical active ingredients or their manufacturing intermediates. [Embodiment] (Best Mode for Carrying Out the Invention) Each solvate and its crystals of the present invention will be described below. (1) Hydrate The 1-molecule of flumochif hydrate should contain 1 molecule of water. The hydrate is preferably crystalline. The crystal X-ray diffraction pattern should have a main peak at an interplanar interval d = 8.31, 7.00, 6.11, 5.43, 4.47, 4.35, 4.19, 4.15, 3.95, 3.81, 3.50, 3.32, 2.96 (unit: A), etc. It is more preferable to present the model shown in Table 1 and Figure 1 described later in 200533672. (X-ray diffraction measurement conditions · Tube CuKa line, tube voltage 40 Kv, tube current 30 mA, dsin 0 = η λ (η is an integer, 0 is the diffraction angle)

In the present specification, although the interplanar interval d 以 is selected from the X-ray peaks as a main peak for convenience, a peak having a relatively strong intensity is selected, but the crystal structure is not necessarily limited to these 値. It can also include peaks other than these. In general, when crystals are measured by X-ray analysis, the peaks of the crystals may vary depending on the measurement equipment, measurement conditions, and presence of adhesion solvents. Therefore, more or less errors must also be taken into account in the identification of the crystal structure. Essentially, crystals specialized by the same X-ray pattern as described above are within the scope of the present invention. The above-mentioned hydrate can make, for example, flumochiv or its dichloromethane hydrate obtained by the method of JP-A-Sho 59- 1 3 93 85 or The Journal of Antibiotics (Apr. P466-476, 1985) at room temperature or After heating (preferably about 20 ~ 40 ° C), dissolve in a small amount of soluble solvent, and then put more water than the soluble solvent at room temperature or under ice cooling, then at 0 ° C ~ room temperature, preferably about 5 ~ 25 It is obtained by stirring or standing at ° C for several hours to 1 day. The amount of soluble solvent is 0.1 g to 10 g of flumochif, preferably 0.5 to 5 mL, and more preferably 1 to 3 mL. The amount of water used is 1 to 100 mL, preferably 5 to 50 mL, and more preferably 10 to 30 mL. As the soluble solvent, alcohols such as methanol, ethanol, 2-propanol, 2-methoxyethanol, ethylene glycol, methoxyethanol, glycerol, propylene glycol, dioxane, tetrahydrofuran, dimethoxyethane, and diethyl alcohol can be used. Ethers such as glycol dimethyl ether, ketones such as acetone, methyl ethyl ketone, methyl pentanone, methyl formate, ethyl acetate, propyl formate, methyl acetate, ethyl acetate, propyl acetate, butyl acetate Esters, methyl propionate 200533672 esters, esters such as ethyl propionate, methylene chloride, chloroform, carbon tetrachloride, 1,2-dichloroethane, trichloroethane, chlorobenzene, dichlorobenzene, etc. Hydrocarbons, nitriles such as acetonitrile, propionitrile, dimethylformamide, dimethylmethane, dimethylacetamide, N-methylpyrididone, quinoline, pyridine, triethylamine, etc. . These solvents may be used alone or in combination of two or more. The obtained crystals can be separated from the solvent by ordinary separation means (for example: filtration, centrifugation, etc.), and then separated by ordinary purification means (for example, washing, air drying, and drying under reduced pressure).

In addition, the above hydrate can also dissolve the extraction residue containing flumochisif or its organic solvate obtained in the reaction solution of the demoprotection of flumochisif intermediate, and then dissolve it in water at a temperature of 0 to 10 ° C. Stir for several hours to several days. (2) Methyl acetate compound The methyl acetate compound of flumochisif is 1 molecule of p-flomochisif, preferably containing 0.5 to 1.0 molecules of methyl acetate, more preferably 0.5 molecules. The methyl acetate compound is preferably crystalline. The crystal should have main peaks in the powder X-ray diffraction mode at a plane interval d = 10.42, 6.32, 4.96, 4.62, 4.56, 4.36, 4.23, 3.97, 3.93, 3.79, 3.47, 2.79 (unit: A), etc. It should be in the mode shown in Table 3 or Figure 2 described later. The said methyl acetate compound can be obtained as follows, for example. Flumochif or its dichloromethane compound is dissolved in methyl acetate by heating (preferably about 20-40 ° C), and then the solvent is distilled off. After the residue is dissolved in methyl acetate by heating (preferably about 20 to 40 ° C), it is stirred at 0 ° C to room temperature for several hours to several days. The precipitated crystals are collected by filtration, washed with cold methyl acetate and air-dried. The amount of methyl acetate used for the first and second times is flumochicil lg 0.1 to 20 mL, preferably 0.5 to 15 mL, more preferably 200533672 1 to 10 mL. The amount of water used is 1 to 100 mL of Flumochif lg, preferably 5 to 50 mL, and more preferably 10 to 30 mL. The above-mentioned methyl acetate compound can also be obtained by using the extraction residue of the reaction solution for deprotecting the intermediate of femochicil as a raw material.

The hydrate or methyl acetate hydrate may be converted into another solvate or crystal as desired. It can also be formulated with the p (R) adjusting agent, stabilizer, etc. alone or as desired by lyophilization, powder filling, or the like. In particular, hydrates should be formulated by the powder filling method, which is conducive to formulation. Reference example

(In the formula, Me = methyl; BΗ = diphenylmethyl)

Blend the intermediates of flumochisif (non-patent document 1 (The Journal of Antibiotics (Apr. P466-476, 1 985))) (flumochisif has diphenylmethyl at the 4-position and tetrazole at the 3-position The hydroxy group is a compound protected by p-methylbenzyloxycarbonyl) (405mg), dichloromethane (2.5ml) and nitromethane (0.5ml) and cooled to -3 01: Add methoxybenzene (0.11ml) And a solution of SnCl4 (0.17 ml) in dichloromethane (2 ml). After stirring, the temperature was gradually raised to -10 ° C over 3 hours and a half. After the reaction solution was poured into a mixed solution of 1N hydrochloric acid, ethyl acetate and methyl ethyl ketone, the separated organic layer was mixed with an aqueous solution of sodium bicarbonate. The aqueous layer was made acidic with concentrated hydrochloric acid, and mixed with ethyl acetate and methyl ethyl ketone-10- 200533672 Liquid extraction. The extract was washed with saturated brine, dried over magnesium sulfate, and dried under reduced pressure to obtain a bubble-like reaction extraction residue containing flumochif methylene chloride. Example 1

1,000 mg of the reaction extraction residue obtained in Reference Example 1 was dissolved in 20 mL of water with heating, and then stirred at 5 ° C. for 1 day. The precipitated crystals were filtered and washed with 10 mL of cold water. Air drying and drying under reduced pressure (condition: 50 Pa, 5 to 10 hours), 803 mg (77%) of the crystals of flumochif 1 hydrate were obtained. IR (Nujol): 35 39, 3198, 2924, 28 54, 1776, 1711, 1 685, 1 645, 1 5 34, 1450, 1 3 87, 1267, 1130, 1062, 1 039, 997, 861, 6 6 5 cm'1] H NMR (DMSO-i / 6); δ 3 · 3 6 (3 Η, s), 3 · 5 9 (1 Η, d, /=15.3 Hz), 3.66 (1H, d, / = 15 · 3 Hz), 3.73 (2H, t, /=5.1 Hz), 4.18 (1H, d, /=13.5 Hz), 4.23 (1H, d, "7 = 13.5 Hz), 4.31 ( 2H, t, /=5.1 Hz), 4.52 (2H, s), 5.06 (2H, brs), 7.30 (1H, t, / = 5 6.4 Hz), 9.25 (1H, s) Elemental analysis: c15h18n6o7f2s2. h2o theory 値: C3 5.02, H3.92, N16.33, F7.39, S12.46 Measured 値: C35.05, H3.93, N16.39, F7.22, S12.32 Water content theory 値 (1 Hydrate): 3.50% Car Fisher Moisture Meter (KF) Determination 値: 3.52%

Melting point: 9 4 ° C The powder X-ray diffraction mode is shown in Table i, Figure 1. -11- 200533672 [Table 1]. Γ ~ 2θ m Relative strength 10.64 8.30 12.64 7.00 14.48 6.11 16.30 5.43 16.56 5.34 19.04 4.66 19.86 4.47 20.40 4.35 21.18 4.19 21.38 4.15 22.48 3.95 23.30 3.81 23.88 3.72 24.62 3.61 25.46 3.50 25.64 3.47 26.86 3.31 27.24 3.27 28.36 3.14 29.62 3.01 30.20 2.96 31.24 2.86 32.36 2.76 33.50 2.67 33.66 2.66 33.84 2.65 35.04 2.56 35.78 2.51 36.20 2.48 30424647333355380 11 11 11 1x 1M 11 1X 11 Ίχ 85637567655 6 Example 2 Refer to the reaction extraction residue below Table 2 After dissolving in a soluble solvent at room temperature or heating, water is added at room temperature or under ice cooling. Stir or stand at 5 ~ 2 5 ° C for several hours to 1 day. All the obtained crystals were confirmed to contain no organic solvent by NMR, and were confirmed to be monohydrate by elemental analysis. It also showed the same X-ray powder recrystallization mode as in Example 1. -12- 200533672

im 2] Soluble crystals of raw materials, ml water (ml) 1 1 100 mg methanol 0.2 1.3 1 100 mg ethanol 0.2 0.3 1 OOmg ethanol 0.3 0.2 4 r 1 OOmg acetone 0.2 1.3 D 1 OOmg--1.5 6 1 OOOmg methanol 2 18 1 OOOmg ethanol 2 18 V 1T 1 OOOmg 2-propanol 2 18 1 OOOmg 2-methoxyethanol 2 18 1 OOOmg ethylene glycol 2 18 11 1 OOOmg methyl acetate 2 18 1 2 Ττ 1 OOOmg ethyl acetate 2 18 A 3 1 OOOmg Tetrahydrofuran 2 18 14 Ττ 1 OOOmg _Pane 2 18 1 5 Tr- 1 OOOmg Monomethoxyethane 2 18 1 6 ττ 1 OOOmg Monoethylene glycol monomethyl ether 2 18 1 OOOmg Acetone 2 18 1 8 1 OOOmg Methyl ethyl ketone 2 18 1 9 1 OOOmg Acetonitrile 2 18 2〇1 OOOmg Dimethan® 2 18 2 1 2T 1 OOOmg Dimethylformamide 2 18 1 OOOmg Dimethylacetamide 2 18 2 3 — 1 OOOmg N -Methylpyrrolidone 2 18 Example 3 The reaction extraction residue 1000 mg obtained in Reference Example 1 was dissolved in methyl acetate 5 mL under warming, and then the solvent was distilled off. The residue was dissolved in 2 mL of methyl acetate under heating, and then stirred at 5 ° C for 1 day. The precipitated crystals were filtered and washed with 2 mL of cold methyl acetate. Air-drying gave 784 mg (82%) of 0.5 methyl acetate crystalline. W (Nujol) · 3493, 3249, 3 04 1, 2925, 28 5 3, 1 765, 1 737, -13- 200533672 1711, 1 66 8, 1 643, 1 543, 1 45 7, 1441, 1420, 1 392, 1 3 76, 1 248, 1231, 1 080, 1062, 1042, 1 030, 805, 751 NMR (DMSO-J6); δ 3 · 3 6 (3 Η, s), 3 · 5 9 (1 Η, d, /=15.3 Hz), 3.66 (1H, d, "7 = 15.3 Hz), 3.73 (2H, t, /=5.1 Hz), 4.18 (1H, d, J = 13.5 Hz), 4.23 (1H, d, /=13.5 Hz), 4.31 (2H, t, /=5.1 Hz), 4.51 (2H, s), 5.06 (2H, brs), 7.30 (1H, t, /=56.4 Hz), 9.25 (1H, s)

The peak of methyl acetate 0.5-5 (π, s), 3.55 (3H, s) was observed by NMR. Elemental analysis: C15H18N607F2S2 · l / 2AcOMe Theoretical 値: C37.15, H3.97, N15.75, F7.12, S12.02 Measured 値: C36.96, H3.92, N15.55, F6.98, S11 .96

Melting point: 7 8 ° C The powder X-ray diffraction mode is shown in Table 3 and Figure 2.

-14- '200533672 [Table 3] 2 Θ d 値 Relative strength 8.48 10.42 38 11.34 7.80 6 11.70 7.56 5 14.00 6.32 10 16.94 5.23 7 17.86 4.96 15 19.20 4.62 14 19.46 4.56 23 20.00 4.44 8 20.36 4.36 33 21.00 4.23 17 22.36 3.97 15 22.62 3.93 12 23.48 3.79 12 24.50 3.63 6 25.66 3.47 18 26.78 3.32 7 27.02 3.30 9 27.42 3.25 6 27.82 3.20 9 30.80 2.90 9 31.70 2.82 8 32.04 2.79 10

Example 4 After 1,000 mg of the reaction extraction residue obtained in Reference Example 1 was dissolved in 5 mL of methyl acetate under heating, the solvent was distilled off. The residue was dissolved in 2 mL of methyl acetate under heating, and then stirred at 5 ° C for 1 day. The precipitated crystals were filtered and washed with 2 mL of cold methyl acetate. It was air-dried and the same as Example 3 was obtained, and 8 0.5 mg (78%) of 0.5 methyl acetate crystalline was obtained. [Simplified illustration of the drawing] [Figure 1] Flumochief monohydrate obtained in Example 1 Crystal powder X-ray diffraction mode. [Fig. 2] A powder X-ray diffraction pattern of crystals of a fumacisif 0.5 methyl acetate compound obtained in Example 3. 15-

Claims (1)

200533672 10. Scope of patent application: 1. A hydrate or hydrate crystal of the compound (1) VnOH (,) crystals, which are water 2 · Hydrate or hydrate hydrate as in item 1 of the scope of patent application. 3 · If the hydrate crystal of item 丨 or 2 of the scope of the patent application, the powder x-ray diffraction mode, the surface interval d = 8.3 1,7.0 0, 6.1 1,5.4 3, 4 4 7 4.35, 4.19, 4.15, 3.95, 3.81, 3.50, 3.32, 2.96 (unit: A) have main peaks. 4. A crystal of methyl acetate or methyl acetate of compound (I) 5. If the methyl acetate compound or methyl acetate compound crystallized in item 4 of the patent application scope, it is 0.5 methyl acetate compound. 6. If the methyl acetate compound crystal of item 4 or 5 of the scope of patent application, the powder X-ray diffraction mode 'at the plane interval d = 1 0.4.6.3 2, 4.9 6, 4 6 2 4.56, 4.36 , 4.23, 3.97, 3.93, 3.79, 3.47, 2.79 (unit: A) have main peaks. -16-