WO2004026882A1

WO2004026882A1 - Process for the preparation of cephems

Info

Publication number: WO2004026882A1
Application number: PCT/JP2003/011825
Authority: WO
Inventors: Makoto Hajima; Koji Ishikura; Teruo Sakata
Original assignee: Shionogi & Co., Ltd.
Priority date: 2002-09-20
Filing date: 2003-09-17
Publication date: 2004-04-01
Also published as: AU2003264462A1; JPWO2004026882A1; TW200404807A

Abstract

The invention provides both a process for the preparation of compounds represented by the general formula (I), pharmaceutically acceptable salts thereof, or solvates of both: (I) [wherein R1 and R2 are each independently optionally substituted lower alkyl], characterized by deblocking a compound represented by the general formula (II), a pharmaceutically acceptable salt thereof, or a solvate of either: (II) [wherein R1 and R2 are each as defined above; R3 is an amino-protecting group; and R is an anion, hydrogen, or a carboxyl-protecting group]; and crystals of compounds (II).

Description

Specification

'' Manufacturing technology of septum

The present invention relates to an intermediate of a broad-range cefm compound exhibiting a broad antibacterial spectrum against various susceptible bacteria, a crystal thereof, and a method for producing a cefm compound using the same. Background art

In recent years, as a wide-ranging cefm compound with strong antibacterial activity against gram-positive and gram-negative bacteria, amino thiadiazole is located at position 7 of the cef skeleton and cyclic quaternary ammonium methyl group at position 3 Compounds are receiving attention. For example, a cefm compound in which an imidazo [4,5-] pyridiniummethyl group is introduced at the 3-position of the cefm compound is known (for example, see Patent Document 1). In addition, as a method for producing other cefm compounds, a method using an intermediate in which the 7-amino group is not protected has been reported (for example, see Patent Documents 2, 3, and 4).

(Patent Literature 1) International Publication No. 0/3 26 06 Pamphlet

(Patent Literature 2) International Patent Publication No. 98/25953 Pamphlet

(Patent Document 3) International Publication No. 86/0 320 04 pamphlet

(Patent Document 4) Japanese Patent Application Laid-Open No. 10-291933 In the above-mentioned WO 00/3266, for example, in Example 6-2, the 7-position (aminothiadiazole ethoxyiminoacetamide group ), An amino group having a 3-position (aminoalkylimidazopyridiniummethyl group) and a 4-position ethoxy group, and the deprotection of the amino and carboxyl groups at the two positions was carried out by using aluminum chloride. However, the yield was not satisfactory for an industrial process (yield 31%). In addition, a column treatment step is essential to remove the by-product isomer Met. Disclosure of the invention

The present invention provides, as an improved process for producing the above septum compound, a process using an intermediate in which the amino group of 7-aminothiadiazole is not protected. Furthermore, in the deprotection step of the amino group on the 3-position side chain and / or the carboxy group at the 4-position, the use of a novel combination of deprotection reagents showed that a Cefm compound could be obtained in good yield. I found it. The intermediate was also successfully crystallized. The present invention is described below. Expression

(Wherein, R ¹ and R ² are independently lower alkyl which may be substituted; R ³ is an amino protecting group; R is an anion, hydrogen or a carboxy protecting group) or a compound represented by the formula: Pharmaceutically acceptable salts or solvates thereof.

2. Formula:

(Wherein, R ¹ R ² and R ³ are as defined above; R ⁴ is hydrogen or a carboxy protecting group; X is a counter ion).

3. The compound according to the above 2, wherein R ¹ is ethyl; R ² is methyl; R ³ is tertiary butoxycarbonyl; R ⁴ is P-methoxybenzyl, benzhydryl or trimethylsilyl.

(Wherein, R ¹ R ² and R ³ are the same meaning as defined) _of Compound _c of claim 1, wherein represented by

5. The compound according to the above 4, wherein R ¹ is ethyl; R ² is methyl; R ³ is tertiary butoxycarbonyl.

6. The compound according to any one of the above 1 to 5, or a pharmaceutically acceptable salt thereof, or a solvate thereof, wherein the compound has the formula:

(Wherein, R ¹ and R ² are as defined above) or a pharmaceutically acceptable salt thereof or a solvate thereof.

7. The method according to the above item 6, wherein the deprotection is carried out in the presence of formic acid and sulfuric acid.

8. Formula:

(Wherein R ¹ is lower alkyl which may be substituted; R ⁴ is hydrogen or a carboxy protecting group; Y is a leaving group).

(Wherein, R ² is lower alkyl which may be substituted, R ³ is an amino protecting group) or a salt thereof, wherein the compound is represented by the following formula: (11-1) 3. A method for producing the compound according to the above 2, wherein

9-A compound (I A1) is obtained by the production method described in 8 above, and then deprotected, and the compound represented by the formula 6 described in 6 above: Preparation of acceptable salts or solvates thereof.

1 0. Formula:

(Wherein R ⁴ is a hydrogen or carboxyl protecting group; R ⁵ is a hydrogen or amino protecting group; Y is a leaving group).

, R

(Wherein R ² is lower alkyl which may be substituted; R ³ is an amino protecting group) or a salt thereof.

Expression:

(Wherein R ² , R ³ , R ⁴ and R ⁵ are as defined above; X— is a counter ion) or a salt thereof.

(Wherein, R ¹ is lower alkyl which may be substituted)

A method for producing a compound represented by the formula: (II-12) according to the above item 4, wherein the compound represented by the formula: or a reactive derivative thereof is reacted.

1 1. Compound (II-12) obtained by the production method described in 10 above, and then deprotected, the compound represented by the above formula 6: (I) or a drug thereof. Of salts or solvates thereof which are acceptable above.

1 2. Formula:

(Wherein, R ¹ and R ² are each independently a lower alkyl which may be substituted; R ³ is an amino protecting group; and X— is a counter ion).

13. The compound according to claim 12, wherein R ¹ is ethyl; R ² is methyl; R ³ is tertiary butoxycarbonyl.

1 4. A method for producing the compound (I) according to the above 6, or a pharmaceutically acceptable salt thereof, or a solvate thereof, wherein the compound (II-13) according to the above 12 is deprotected.

1 5. The process according to 14 above, wherein the deprotection is carried out in the presence of sulfuric acid, water and acetonitrile.

1 6. The compound (V) described in the above 10 is reacted with the compound (IV) or a salt thereof to obtain a compound represented by the formula:

(In the formula, R ² is a lower alkyl which may be substituted; R ³ is an amino protecting group; R ⁴ is a hydrogen or carboxy protecting group; R ⁵ is a hydrogen or amino protecting group; and X— is a counter ion.) 12. A method for producing a compound represented by the formula: (II-13) according to the above item 12, wherein the compound (VII) or a reactive derivative thereof is reacted after obtaining the compound or a salt thereof.

1 7. Expression:

(II-1 2-a)

(Wherein, ¹ is ethyl; R ² is methyl; R ³ is tertiary butoxycarbonyl), or a solvate thereof.

1 8. A crystal of the solvate according to the above item 17, comprising one or more solvents selected from the group consisting of water, acetonitrile, tetrahydrofuran, dimethylformamide and acetone.

1 9. Deprotecting the crystal according to the above 17 or 18;

(Wherein, R ¹ is ethyl; R ² is methyl) or a pharmaceutically acceptable salt thereof, or a solvate thereof.

20. The method described in 6 or 1 above, which is a method for producing a sulfate of compound (I) or a solvate thereof. 9. Manufacturing method according to 9.

(Brief description of drawings)

(FIG. 1) X-ray powder measurement results of the crystal of compound (4) obtained in Reference Example 1.

(FIG. 2) X-ray powder measurement results of crystal (1) of compound (II-2-a) obtained in Example 13

(FIG. 3) This is the result of powder X-ray measurement of the crystal (2) of the compound (II-1-a) obtained in Example 14.

(FIG. 4) Powder of crystal (3) of compound (II-1-a) obtained in Example 15

It is an X-ray measurement result.

. (FIG. 5) X-ray powder measurement results of crystal (4) of compound (II-2-a) obtained in Example 16. BEST MODE FOR CARRYING OUT THE INVENTION

The present invention will be described in more detail.

The definition of each group of the compounds (I) to (V I I) will be described below.

(Definition of R ¹⁾

Lower alkyl includes straight or branched C 1 -C 6 alkyl, for example, methyl, ethyl, n-propyl, tertiary butyl, n-pentyl, n-hexyl and the like. And preferably C 1 -C 3 alkyl, especially ethyl.

Examples of the substituent of the lower alkyl include halogen (eg, F, Cl, Br, etc.), hydroxy, carboxy, cyano, amino, carbamoyloxy, sulfamoyl, lower alkoxycarbonyl (eg, methoxycarbonyl, ethoxy) Examples thereof include carbonyl, etc.), lower alkylthio (eg, methylthio, etc.) and the like, preferably halogen, especially F.

R ¹ is preferably hydrogen, methyl, CH ₂ F, ethyl, CH ₂ CH ₂ F, etc. Especially ethyl.

(Definition of R ²⁾

Lower alkyl is as defined for R ¹ above, but is preferably C 1 -C 3 alkyl, especially methyl.

Examples of the substituent of the lower alkyl include hydroxy, optionally substituted rubamoyl (substituent: methyl, ethyl, etc.), halogen (eg, F, C1, etc.), and optionally substituted amino ( Substituents: lower alkyl (eg, methyl, ethyl, etc.), lower alkenyl (eg, 2-propenyl, etc.), lower alkoxycarbonyl (eg, t-butoxycarbonyl, etc.), hydroxy lower alkyl (eg, 1— Etc.), lower alkoxy (eg, methoxy, ethoxy, etc.), lower alkoxycarbonyl (eg, methoxycarbonyl, ethoxycarbonyl, etc.).

R ² is preferably methyl, ethyl, hydroxethyl or the like, particularly methyl.

(Definition of R ³⁾

As the amino protecting group, a protecting group known in the art is appropriately used, and examples thereof include C 1 -C 6 alkanoyl (eg, formyl, acetyl, etc.) and C 3 -C 5 alkenoyl (eg, acryloyl, crotonyl, etc.). , C 6 -C 10 arylcarbonyl (eg, benzoyl, naphthyl, p-toluoyl, p-hydroxybenzoyl, etc.), heterocyclic carbonyl group (example of the heterocyclic ring: 4-imidazolyl, 1,2,3-triazolyl, 1H-tetrazolyl, 4-oxazolyl, 3-pyridyl, etc., C1-C6 alkylsulfonyl (eg: methanesulfonyl, ethanesulfonyl, etc.), C6-C10aryl Sulfonyl (eg, benzenesulfonyl, naphthyl lensulfonyl, p-toluenesulfonyl, etc.), substituted oxycarbonyl (eg, methoxymethyloxycarbonyl, acetyl) Methyloxycarbonyl, 2-trimethylsilylethoxycarbonyl, 2-methanesulfonylethoxycarbonyl, 2,2,2-trichloroethoxy Carbonyl, 2-cyanoethoxycarbonyl, p-methylphenoxycarbonyl, P-methoxyphenoxycarbonyl, p-chlorophenoxycarbonyl, benzyloxycarbonyl, p-methylbenzyloxycarbonyl, p-methoxybenzyl Oxycarbonyl, p-chlorobenzyloxycarbonyl, p-nitrobenzyloxycarbonyl, tert-butoxycarbonyl, 2-propenyloxycarbonyl, etc.), substituted silyls (eg, trimethylsilyl, tertiary butyldimethylsilyl) Etc.) are used.

R ³ is preferably substituted oxycarbonyl, especially tertiary butoxycarbonyl.

(Definition of R)

R represents an anion, hydrogen or a carboxy protecting group, wherein the carboxy protecting group is as defined for R ⁴ . If R is an anion, COOR is CO CK. The quaternary ammonium cation on the side chain at the 3-position of the compound forms an internal salt with the C 00 at the 4-position, but the C 4-OH or C 00 R (R is In the case of (carboxy protecting group), it has a counter ion (X). If the 4-position is COOH and has a counter ion (X—), it may form an HX salt.

(Definition of R ⁴⁾

R ⁴ represents hydrogen or a carboxy protecting group, but may be substituted C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 3 -C 10 cycloalkyl, C 3 -C 10 cycloalkyl C1-C6 alkyl, optionally substituted C6-C10 aryl, optionally substituted C7-C12 aralkyl, di-C6-C10 arylmethyl, tri-C6 ~ C 10 arylmethyl, substituted silyl and the like are used.

As the optionally substituted C 1 -C 6 alkyl, for example, methyl, ethyl, isopropyl, tertiary butyl and the like are used, and for example, benzyloxy,

C1-C4 alkylsulfonyl (eg: methylsulfonyl, etc.), halogen (eg: F, C 1, etc.), acetyl, nitrobenzoyl, benzenesulfonyl, C 1 -C 4 alkylsulfinyl (eg, methylsulfinyl, etc.), cyano, etc., and such groups include, for example, benzyl Oxymethyl, 2-methylsulfonylethyl, 2,2,2-trichloroethyl, acetylmethyl, p-nitrobenzoylmethyl, p-mesylbenzoylmethyl, benzenesulfonylmethyl, and the like.

As C 2 -C 6 alkenyl, vinyl, aryl, isopropyl, butenyl and the like are used.

As C3-C10 cycloalkyl, cyclopropyl, cyclopentyl, cyclohexyl, adamantyl and the like are used.

C 3 -C 10 cycloalkyl As C 1 -C 6 alkyl, cyclopropylmethyl, cyclohexylmethyl and the like are used.

As C 6 -C 10 aryl, phenyl, naphthyl and the like are used, which may be substituted with, for example, nitro, halogen (eg, F, C 1, Br, etc.). Examples thereof include p-nitrophenyl, p-chlorophenyl, and the like.

As the optionally substituted C 7 -C 12 aralkyl, for example, benzyl, naphthylmethyl and the like are used, and for example, nitro, C 1 -C 4 alkoxy (eg, methoxy and the like), C 1 -C 2 It may be substituted by alkyl (eg, methyl, etc.), hydroxy, etc. Examples of such a group include p-nitropentyl, p-methoxybenzyl, 3,5-di-tert-butyl butyl. -Hydroxybenzyl is used.

Benzhydryl and the like are used as di-C 6 -C 10 arylmethyl, trityl and the like are used as tri-C 6 -C 10 arylmethyl, and trimethylsilyl and tertiary butyldimethylsilyl are used as substituted silyls. Can be

R ⁴ is preferably p-nitropentyl, p-methoxybenzyl, 3,5-ditert-butyl-4-hydroxybenzyl, benzhydryl, trityl, trimethylsilyl, tert-butyldimethylsilyl, Particularly preferred is p-methoxybenzyl, Benzhydryl, trimethylsilyl.

(Definition of Y). Y is a leaving group such as hydroxy, halogen (C1, Br, I, etc.), carpamoyloxy, substituted carpamoyloxy (eg, methylcarbamoyloxy, N, N-dimethylcarbamoyl) Xy), asiloxy (eg, acetoxy, chloroacetoxy, vivaloyloxy) and the like are used.

Preferred as Y are hydroxy, halogen, and acyloxy, especially hydroxy, Cl, Br, I, and acetoxy.

(Definition of X—)

X is a counter ion, preferably halogen, especially Cl, Br, I. (Definition of R ⁵⁾

R ⁵ is a hydrogen or an amino protecting group, but Amino protecting groups are the same meanings as defined in the R ^3. R ⁵ is preferably a substituted silyl, particularly trimethylsilyl. The pharmaceutically acceptable salt of the compound (1), (11: 1-11-1, II-12, 11-3), (IV) or (VI) includes an inorganic base, ammonia, an organic base, Examples thereof include salts formed by inorganic acids, organic acids, basic amino acids, and halogen ions, and internal salts. Examples of the inorganic base include alkali metals (Na, K, etc.), alkaline earth metals (Mg, etc.), and examples of the organic bases include 2-phenylethylpentylamine, dibenzylethylenediamine, Ethanolamine, diethanolamine, trishydroxymethylamino methane, polyhydroxyalkylamine, N-methylglucosamine and the like are exemplified. Examples of the inorganic acid include hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, and phosphoric acid. Examples of the organic acid include p-toluenesulfonic acid, methanesulfonic acid, formic acid, trifluoroacetic acid, and maleic acid. Examples of basic amino acids include lysine, arginine, orditin, and histidine. It is. The production method of the present invention will be described below.

The present compound (II) is a novel intermediate of the compound (I), which is a wide-area cephem, a salt thereof, and a solvate, and is preferably a compound (11-1), a compound (II-2), or a compound (II-2). (II-3). In the compound (II) or a salt thereof, the amino group at the terminal of the 3-position side chain is protected. The carboxyl group at the 4-position is protected or free or has an anion. According to the conventional method, in order to produce the compound (I), it was necessary to protect one end of the amino group of the aminothiadiazole ring on the 7-position side chain of the compound (II). However, according to the method of the present invention, the amino group can be converted to the compound (I) without protection, and the yield in the deprotection step can be improved. Furthermore, by examining the deprotection reaction conditions, it was possible to suppress the isomerization of the 7-position oxime moiety and the like.

Compounds (II) and (I) may be solvates such as salts or hydrates. This will be described in more detail below.

(III)

(Wherein, R ¹ and R ² are independently lower alkyl which may be substituted R ³ is an amino protecting group; R ⁴ is a hydrogen or carboxy protecting group; Y is a leaving group; X— is a ion) By reacting compound (III) with compound (IV), the compound (II— 1) is obtained. Compound (III) is described in the literature (eg, W09 8/259 935, JP0427,290, JP580,4,887, JP590,760,88, etc.) It can be synthesized according to the method described in The compound (IV) can be synthesized according to a method described in a literature (eg, WO0Z32606).

Solvents in this reaction (reaction between compounds III and IV) include, for example, ethers (eg, dioxane, tetrahydrofuran, getyl ether, tertiary butyl methyl ether, diisopropyl ether), esters (eg, formic acid) Ethyl, ethyl acetate, n-butyl acetate), halogenated hydrocarbons (eg, dichloromethane, chloroform, carbon tetrachloride, 1,2-dichloroethane), amides (eg, formamide, Ν, Ν-dimethylformamide (DMF), Ν, Ν-dimethylacetamide, Ν-methylpyrrolidone, Ν, Ν'-dimethylimidazolidinone (DMI)), ketones (eg, acetone, methylethyl) Ketone, methyl isobutyl ketone), nitriles (eg, acetonitrile, propionitrile), alcohols (eg, : Methanol, ethanol, isopropanol, tertiary butyl alcohol), dimethyl sulfoxide, water and the like. Compound (IV) may be used as a solvent. The amount of compound (IV) to be used is generally about 1 to 5 moles, preferably about 1 to 3 moles, per 1 mole of compound (III). The reaction is usually carried out at a temperature in the range of about -30 to 100 ° C, preferably about -20 to 50 ° C, and the reaction time is in the range of tens of minutes to tens of hours. If desired, a halide (eg, NaBr, KBr, NaI, KI) or a thiocyanate (eg, thiocyanic acid Na, thiocyanic acid K) or the like is added to the reaction as a reaction accelerator. obtain.

When Y is hydroxy, the reaction is carried out in the presence of various organic phosphorus compounds, as described in JP-A-58-43979, for example, or in the presence of thionyl chloride, oxychlorine phosphate, or the like. Alternatively, the desired reaction may be performed after conversion to halogen (eg, Cl, Br, etc.) with phosphorus tribromide.

The compound (I1-1) in which the 3-position terminal amino group and / or 4-position carboxy group is protected is treated with a deprotection reagent to obtain the present compound (I).

The deprotection reaction is performed according to a method usually used for removing an existing protecting group. When deprotection is performed under acidic conditions, an organic acid (eg, trifluoroacetic acid, acetic acid, formic acid, etc.), an inorganic acid (eg, hydrochloric acid, sulfuric acid, etc.), aluminum chloride is used when deprotection is performed in the presence of a Lewis acid, For example, titanium tetrachloride is used. In the above deprotection reaction, anisol may be added, or unusually, an inorganic acid-water-organic solvent (eg, inorganic acid; organic solvent such as hydrochloric acid, sulfuric acid, phosphoric acid, nitric acid, etc.); Deprotection is achieved by a combination of acetonitrile, acetone, methanol, ethanol, dioxane, dimethylformamide, dimethylacetamide, etc. or an organic acid-inorganic acid (eg, acetic acid monosulfate, formic acid monosulfate, etc.) May be. When deprotection can be performed under reducing conditions, corrosion reduction using various catalysts or a metal reducing agent such as zinc is used.

Preferably, the deprotection reagent is a combination of an organic acid and an inorganic acid, particularly a combination of formic acid and monosulfuric acid. The yield of the deprotection step is preferably at least 40%, more preferably at least 60%. . Compound (I) can be obtained by adding sulfuric acid to compound (II-11) in a formic acid solvent. This reaction is preferably carried out in a temperature range of -10 to 50 ° C, more preferably in a temperature range of 0 to 30 ° C, for 0.1 to 3 times, more preferably 0.1 to 3 times the amount of sulfuric acid with respect to formic acid. Use 3 to 1.5 times the amount. The concentration of sulfuric acid used is usually in the range of 10 to 98%, preferably 50 to 70%. The reaction time ranges from tens of minutes to tens of hours. (Method 2)

Wherein, ¹ and R ² are independently independently substituted lower alkyl; R ³ is an amino protecting group; R ⁴ is a hydrogen or carboxyl protecting group; R ⁵ is a hydrogen or amino protecting group; Is a counter ion) The compound (II-2) can be obtained by reacting the compound (VI) or a salt thereof (hereinafter collectively referred to as compound (VI)) with the compound (VII). . As the salt of compound (VI), those similar to the compound (II) are exemplified.

In the above reaction, a suitable condensing agent is used if desired. Examples of the condensing agent include Ν, Ν'-dicyclohexylcarbodiimide, Ν, Ν'-carbonyldiimidazole, Ν, Ν'-thiocarberdiimidazole, Ν-ethoxycarbodilu-2-ethoxy-1, 2-dihydroquinoline, phosphorus oxychloride, oxalyl chloride, alkoxyacetylene, 2-chloropyridinium methyl iodide, 2-fluoropyridinium methyl iodide, methanesulfonyl Chloride, trifluoromethanesulfonyl chloride, paratoluenesulfonyl chloride and the like are used.

Examples of the reactive derivative of the compound (VII) include inorganic base salts, organic base salts, and acid halides. Examples thereof include amides, acid azides, acid anhydrides, mixed acid anhydrides, active amides, active esters, active thioesters, and the like. Examples of the inorganic base include alkali metals (eg, Na, K, etc.) and alkaline earth metals (eg, Ca, Mg), etc., and examples of the organic bases include trimethylamine, triethylamine, triptylamine, and tertiary amine. Grade butyldimethylamine, dibenzylmethylamine, benzyldimethylamine, etc., acid halides such as acid chloride, acid bromide, etc., mixed acid anhydrides are monoalkyl carbonic acid mixed acid anhydrides, aliphatic carboxylic acid mixed Acid anhydrides, mixed acid anhydrides of aromatic carboxylic acids, mixed acid anhydrides of organic sulfonic acids, and the like, and examples of active amides include amides with nitrogen-containing heterocyclic compounds. Examples of the active ester include organic phosphates (eg, ethoxy phosphate ester, diphenoxy phosphate ester, etc.), p-ditrophenyl ester, 2,4-dinitrophenyl ester, cyanomethyl ester, and the like. Examples of the activated polyester include esters with an aromatic heterocyclic thiol compound (eg, 2-pyridylthioester, benzothiazolthioester, and the like).

Examples of the solvent used in this reaction include the same solvents as in the above-mentioned production method (1). Further, the compound (VII) may be used as a solvent.

The amount of compound (VII) to be used is generally about 1-5 mol, preferably about 1-2 mol, per 1 mol of compound (VI). The reaction is carried out at a temperature in the range of about -80 to 80 ° C, preferably about -20 to 40 ° C. The reaction time ranges from tens of minutes to tens of hours. Compound (VI) can be synthesized by reacting compound (V) with imidazo [4,5-b] pyridine (IV) or a salt thereof (hereinafter, these are collectively referred to as compound (IV)). . Compound (V) can be synthesized according to the method described in the literature (eg, WO86 / 03204, JP-A-10-291933, etc.). Compound (IV) can be synthesized by a method described in a literature (eg, WO 00/32606). Examples of the salt of the compound (IV) include inorganic acid addition salts (eg, hydrochloride, hydrobromide, sulfate, nitrate, phosphate, etc.) and organic acid addition salts (formate, acetate, trifluoride) Acetate, methanesulfonate, etc.). Examples of the solvent used in this reaction include the same solvents as in the above-mentioned production method (1). Compound (IV) may be used as a solvent.

The amount of compound (IV) to be used is generally about 1-5 mol, preferably about 1-2 mol, per 1 mol of compound (V). The reaction is carried out in a temperature range of about -80 to 70 ° C, preferably about -20 to 40 ° C. The reaction time ranges from tens of minutes to tens of hours. The deprotection reaction of the compound (II-12) is exemplified in the same manner as in the above-mentioned production method (1).

(Method 3)

(Π-3)

(Wherein R ¹ and R ² are independently lower alkyl which may be substituted; R ³ is an amino protecting group; R ⁴ is a hydrogen or carboxy protecting group; R ⁵ is a hydrogen or amino protecting group; X — Is a counter ion)

This compound (II-13) is obtained by reacting compound (VI) or a salt thereof (hereinafter, these are collectively referred to as compound (VI)) with compound (VII). As the salt of the compound (VI), those similar to the salt of the present compound (II) are exemplified.

In the above reaction, an appropriate condensing agent or compound (VI The reactive derivative of I) is used.

The amount of compound (VI) or a reactive derivative thereof to be used is generally about 1-5 mol, preferably about 1-2 mol, per 1 mol of compound (VI). The reaction is carried out in a temperature range of about -80 to 80 ° C, preferably about -20 to 40 ° C. The reaction time ranges from tens of minutes to tens of hours.

This amidation reaction is carried out in the presence of a base, if desired. When a base is used, it is preferable to use a base having weak nucleophilicity or a base having no nucleophilicity. Particularly preferred as the base is N-methylmorpholine.

The amount of the base to be used is generally about 1-5 mol, preferably about 1-3 mol, per 1 mol of compound (VI). The compound (II-13) in which the amino group is protected is treated with a deprotection reagent to obtain the present compound (I). The present compound (I) includes a pharmaceutically acceptable salt or a solvate thereof as in Production methods 1 and 2 above.

The deprotection reaction is carried out according to a method usually used for removing an existing protecting group (described in Production Method 1). In the case of deprotection under acidic conditions, organic acids (eg, trifluoroacetic acid, acetic acid, formic acid, etc.), inorganic acids (eg, hydrochloric acid, sulfuric acid, phosphoric acid, nitric acid, etc.) are used. In the above deprotection reaction, unusually, organic acid-water-organic solvent

(Example: organic acid; trifluoroacetic acid, acetic acid, formic acid, etc., organic solvent; acetonitril, acetone, methanol, ethanol, isopropanol, dioxane, dimethylformamide, dimethylacetamide, etc.), inorganic acid / water / organic Solvents (eg, inorganic acids; hydrochloric acid, sulfuric acid, phosphoric acid, nitric acid, etc., organic solvents; acetonitrile, acetone, methanol, ethanol, isopropanol, dioxane, dimethylformamide, dimethylacetamide, etc.) Alternatively, deprotection may be performed using a combination of an organic acid and an inorganic acid (eg, acetic acid monosulfuric acid, formic acid monosulfuric acid, etc.). Furthermore, organic acids-inorganic acids-water, organic acids The deprotection may be performed by a combination of an inorganic acid / water / organic solvent or an organic acid / inorganic acid / organic solvent. Deprotection may be performed with a combination of an inorganic acid and an organic solvent if desired.o

As the above deprotection reaction, a combination of an inorganic acid-water-organic solvent is particularly preferred, and the inorganic acid is preferably hydrochloric acid or sulfuric acid, and the organic solvent is preferably dimethylacetamide or acetatenitrile. Particularly preferred are sulfuric acid as the inorganic acid and acetonitril as the organic solvent.

The yield of the deprotection step is preferably at least 40%, more preferably at least 60%, by the combination of the inorganic acid / water / organic solvent. It also has the effect of suppressing the formation of isomers of compound (1). Preferably, it is suppressed to several percent or less.

For example, compound (I) can be obtained by adding sulfuric acid to compound (II-3) in a water-acetonitrile solvent. For 1 g of the compound (II-13), water is preferably 0.1 to 100 ml, and acetonitrile is preferably 0 .; 100 to 100 ml, and more preferably each solvent is 1 to 100 ml. Use 10 ml. 0.1 to 100 ml of acetate is used for 1 ml of water. Preferably, 1 ml of acetonitrile is used for 1 ml of water. Sulfuric acid is preferably used in an amount of 1 to 100 times, more preferably 5 to 50 equivalents, per equivalent of the compound (II-13). The concentration of sulfuric acid used usually ranges from 10 to 98%, preferably from 50 to 70%. The concentration of sulfuric acid in the deprotection reaction varies depending on the amount of water-acetonitrile solvent used. This reaction is carried out preferably at a temperature in the range of -10 to 50 ° C, more preferably 0 to 30 ° C, and the reaction time is in the range of tens of minutes to tens of hours. The present invention further provides the formula:

(Wherein R ¹ is ethyl; R ² is methyl; R ³ is tertiary butoxycarbonyl) or a solvate of the compound (II-2-a).

Examples of the solvent containing the compound (a-2-a) crystals include water and organic solvents (eg, acetonitril, tetrahydrofuran (THF), dimethylformamide (DMF), acetone, acetic acid, methanol, ethanol, Isopropanol, methyl acetate, ethyl acetate, methyl ethyl ketone, getyl ether, diisopropyl ether, dioxane, toluene, dimethylacetamide (DMA), dimethyl sulfoxide (DMSO), and the like. Examples include cetonitrile, tetrahydrofuran (THF), dimethylformamide, and acetone, which may be contained in any proportion. The solvation number varies depending on the type of the solvent and cannot be unconditionally specified, but is preferably 1 to 10 molecules. Particularly preferred combinations of the contained solvents are, for example, crystal 1: THF-water, crystal 2: water alone, crystal 3: acetonitrile-acetone, crystal 2: water-acetone, DMF-acetonitrile, DMF Examples thereof include -acetone and water-acetonitrile, but from the viewpoints of crystallinity, crystallinity, handleability, and / or stability, etc. are preferably crystalline.

Each crystal structure is characterized by, for example, a powder X-ray diffraction pattern (eg, a value of the diffraction angle 20 and a spacing d). Each of the crystals (1) to (3) preferably has a powder X-ray diffraction pattern shown in Tables 2 to 4 of Examples 13 to 15 respectively. The invention also provides a crystal characterized by the powder X-ray diffraction pattern shown in Table 5.

It should be noted that some errors should be taken into account in identifying the crystal structure, and any crystal characterized by an X-ray pattern substantially similar to the above is within the scope of the present invention.

The method for producing the crystal of the compound () -2-a) is not particularly limited, but is preferably a compound

The amorphous or crystal of (II-2-a) is dissolved in water, an organic solvent or a mixture thereof, and if necessary, a seed crystal is preferably added, and the mixture is ice-cooled to room temperature, preferably 0 ° C to 10 ° C. It can be precipitated by stirring at C, more preferably around 5 ° C. for several hours to several tens of hours. The precipitated crystals are then filtered and preferably cooled water, organic solvent or Is washed with the mixture and dried. The obtained crystals can be further converted to crystals having different contained solvents by, for example, drying under reduced pressure or heating conditions.

Compound (II-2-a) may be accompanied by isomers and the like as by-products depending on the production conditions, and it may be mixed into compound (I). However, since (II-2-a) could be isolated as crystals, in a more preferred embodiment, compound (I) can be obtained with high purity without complicated purification means such as column treatment. Now you can do it. Preferred crystals of the compound (II-2-a) or a solvate thereof have better stability than an amorphous form. Therefore, by deprotecting the crystals according to the above reaction conditions, the corresponding septum compound (I), a salt thereof, or a solvate can be produced in high yield and high purity. Very useful as a body.

Examples of the pharmaceutically acceptable salt of compound (I) include salts formed with inorganic bases, ammonia, organic bases, inorganic acids, organic acids, basic amino acids, halogen ions, and the like, or internal salts. . Examples of the inorganic base include alkali metals (Na, K, etc.), alkaline earth metals (Mg, etc.), and examples of the organic base include proforcein, 2-phenylethylbenzylamine, dibenzylethylenediamine, ethanolamine, Examples include genoaluminamine, trihydroxymethylaminoaminomethane, polyhydroxyalkylamine, and N-methyldarcosamine. Examples of the inorganic acid include hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid and the like. Examples of the organic acid include p-toluenesulfonic acid, methanesulfonic acid, formic acid, trifluoroacetic acid, and maleic acid. Examples of the basic amino acid include lysine, argin, orditin, histidine and the like. Compound (II) is preferably deprotected in the presence of sulfuric acid to obtain a sulfate of compound (I) (eg, 0.5 sulfate, 1 sulfate). The sulfate can be converted to another salt.

(Abbreviation)

H P—20 S S = Diamond ion exchange resin (Mitsubishi Chemical); Me = Methyl; Et

= Ethyl; B 0 c tertiary butoxycarbonyl; PMB p-methoxypentyl; D MF didimethylformamide; DMI2,3-dimethyl-2-imidazolidinone; HPLC = high-performance liquid chromatography; BH =: benzhydryl; DMA = dimethylacetamide; TMS = trimethylsilane; TMSI = odo Trimethylsilane; HMD S = hexamethyldisilazane; THF (tetrahydrofuran)

(A) (5-Amino [1,2,4] thiadiazole-3-yl) ethoxyminoacetic acid (1) 4.0 g (18.5 mmol) in 16 ml of DMI, 64 ml of ethyl acetate and 7-amino-3-chloro Mouth methylsef-3-em-4-carbonic acid-: 7.9 g (19.6 mmol) of P-methoxybenzyl ester hydrochloride (2) was added, and the mixture was stirred at -10 ° C under a nitrogen stream. To this suspension was added 1.9 ml of oxychlorinated chloride (21 mmol) followed by 8.2 ml of N-methylmorpholine.

(74.5 mimol) was added dropwise at -5 ° C or lower, and the mixture was stirred at -10 ° C for 1 hour. After the reaction was completed, 21.4 ml of water and 4.6 ml of 2N-hydrochloric acid were added for extraction. The organic layer was washed with 15.7 ml of 5% aqueous sodium bicarbonate and 15.7 ml of water, and each aqueous layer was re-extracted with 39.4 ml of ethyl acetate. The organic layers were combined and the solvent was distilled off under reduced pressure. The concentrate was crystallized from a mixture of acetonitrile and tertiary butyl methyl ether. The crystals are collected by filtration and dried to give 9.9 g (yield 94.3%) of the compound.

(3) was obtained.

Melting point: 100 °

_{Ή-NMR (CDC1 3):} δ 1.33 (t, 3H, J = 7Hz, Et), 3.47,3.67 (dd, 2H, J = 18Hz, -

SCH), 3.81 (s, 3H , - 0CH 3), 4.3-4.6 (m, 4H, - CH 2 C1, Et), 5.07 (s, 1H, C r H), _{5.22 (s, 2H, -CH 2} Ar), 6.10 (m, 1H, C 7 - H), 6.50 (s, 2H, - NH 2), 6.8-7.4 (m, 4H, Ar), 7.93 (d, 1H, J = 9Hz, -C0NH-).

(B) 23.65 g (41.7 mmol) of the compound (3) obtained in (A) was dissolved in 26.9 ml of MF, and 6.97 g (67.7 mmol) of sodium bromide was added at room temperature. Under ice-cooling, add tert-butyl (3-imidazo [4,5-b] pyridine-1-yl-propyl) methylcarbamate (4) 12.82 g (44.2 mimol) and add 5 ° C. For 21 hours. After 67.2 ml of acetonitrile was added to this reaction solution, it was dropped into 459.6 ml of methyl isobutyl ketone cooled to 5 ° C. to form a slurry. After stirring at 5 ° C. for 30 minutes, the precipitate was filtered and dried under reduced pressure to obtain 37.83 g of a crude solid (5). Example 2

37.8 g (41.9 mimol) of the compound (5) obtained in Example 1 was dissolved in 61.1 ml of HC00H, and under ice cooling, δΖ ^ Η ^ Ο ^ 77.8 g (491.9 mimol) was added thereto. Stirred. This reaction solution was added dropwise to 768 l of ice-cooled isopropyl alcohol, and the deposited precipitate was filtered and dried to obtain 33.2 g of a crude solid (6) (HPLC purity 82%). . This crude solid is dissolved in 66.4 ml of distilled water, and the pH is adjusted to 4 to 4 with sodium hydroxide ice solution.

After adjustment to 5, column chromatography was performed with 368 ml of synthetic adsorption resin HP-20SS. Elution was performed with 5% acetate nitrile / water, and the effective fraction was concentrated under reduced pressure to 15.5 g. This concentrate was added dropwise to 480 ml of cold isopropyl alcohol, and the deposited precipitate was collected by filtration and dried. 18.1 g (yield, 66.5% from (3)) of the compound (6) was obtained.

HPLC purity 98% (Shimadzu LG-10CLASS-VP, column Waters- C0SM0SIL-5C18-AR: 4.6x150mm), Ή-NMR (DMS0-d ₍ ): δ 1.18 (t, 3H, J = 7Hz, Et), 2.15 -2.30 (m, 2H, -CH Factory): 2.8-2.9 (m, 2H, -CH), 4.10 (q, 2H, J = 7Hz, Et), 4.55-4.65 (m, 2H, SCH _2- ), 5.04 (d, 1H, J = 5Hz, C "H), 5.55-5.75 (m, 3H , C 7 -H, NCH 2 -), 8.12 (s, 2H, NH 2), 9.45 (s, 1H, - CONH-), 7.86, 8.96, 9.15, 9.45 (4H).

Example 3

= NH ₂ Y = 0H R = HY = OH

7b Z = NH, ■ HC1 Y = C1 R = BH Y = CI

9-1 0

Y = 0H Y = C1 Y = 0H Y = Br

(A) To a solution of 2.27 g (10.5 mmol) of compound (1) in 14 ml of DMI was added 1.64 g (15.6 mmol) of methanesulfonyl chloride and 1.97 g (19.5 mmol) of triethylamine under ice-cooling. After slowly and sequentially dropping, the mixture was stirred for 1 hour under ice cooling. In another container

Add 7.30 g (10.0 mimol) of 7 amino-3-hydroxymethylcef-3-em-4-carboxylic acid (7a), 9.9 ml of acetonitrile, and 13.1 ml of water, and cool to 0 ° C. Then, 2.23 g (22.0 mimol) of triethylamine was added, and the mixture was stirred at the same temperature. In this mixture The mesylate solution of (1) prepared above was added dropwise over 30 minutes. After stirring under water cooling for 1 hour, a solution of 2.95 g (15.75 mimol) of diphenyldiazomethane in 25 ml of ethyl acetate was added under ice cooling. Further, a 2N-HC1 aqueous solution was added dropwise, and the mixture was stirred for 2 days under water cooling while adjusting the pH to 4 to 5. The reaction solution was poured into a mixture of ethyl acetate and water and extracted. The ethyl acetate layer was washed successively with dilute hydrochloric acid and water, dried over ice-free sodium sulfate, and the solvent was distilled off under reduced pressure. Diisopropyl ether was added to the residue, and the precipitated slurry was collected by filtration to obtain 4.85 g of compound (8) (yield: 81.5%).

Ή-NMR (CDClj): δ 1.33 (t, 3H, J = 7Hz), 3.59 (s, 2H), 3.98-4.44 (m, 4H), 5.06 (d, 1H, J = 5Hz), 6.14 (dd, 1H, J = 5, 9Hz), 6.42 (s, 2H), 6.92 (s, 1H), 7.2-7.4 (m, 10H), 7.92 (d-, 1H, J = 9Hz).

IR (Nujol): 3414, 3261, 3171, 1790, 1717, 1676, 1377, 1066 cm- ¹ .

FABMS (m / z): [阔 + 595, [2M + H] ⁺ 1189.

(B) A solution of 2.0 g of the compound obtained in (A) in 26 ml of tetrahydrofuran was cooled to -30 ° C, and then DMF 52 n \ (0.67 mimol) and thionyl chloride 389〃1 (5.04 mi) ) Was sequentially added dropwise. The reaction solution was stirred at −30 ° C. to 3 ° C. for 4 hours, then poured into a mixture of ethyl acetate and water and extracted. The ethyl acetate layer was washed successively with dilute hydrochloric acid and water, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was slurried with ethyl acetate and diisopropyl ether, and the slurry was collected by filtration to obtain 2.23 g of compound (9).

Melting point 111 ° C.

_{Ή-NMR (CDC1 3):} d 1.34 (t, 3H, J = 7Hz, Et), 3.49,3.66 (dd, 2H, J = 18Hz, -

SCH _2- ), 4.3-4.5 (m, 4H,-CH ₂ C1, Et), 5.11 (d, 1H, J = 5Hz, C _f -H), 6.1-6.2 (m,

1H, C ₇ -H), 6.48 (s, 2H,-NH ₂ ), 6.97 (s, 1H, -CH-), 7.2-7.4 (m, 10H, Phx

2), 7.96 (d, 1H, J = 9Hz, -C0NH-).

IR (Nujol): 3315, 3206, 1780, 1726, 1679, 1377, 1040 cm- ¹ .

FABMS (m / z): [M + H] ⁺ 613, [2M + H] ⁺ 1225.

(C) 38 ml of MI and 153 ml of ethyl acetate were added to 9.58 g (44.3 mimol) of compound (1). And 70 g (44.3 mimol) of benzhydrylester hydrochloride (compound 7b) were added to the mixture, and the mixture was stirred at -1 CTC under a nitrogen stream. . To this suspension was added 4.5 ml (48.7 mimol) of phosphorus oxychloride, followed by the dropwise addition of 19.5 ml (177.2 mimol) of N-methylmorpholine at -15 ° C to -5 ° C over 1 hour. The mixture was stirred at the same temperature for 1.5 hours. The reaction mixture was poured into cooled water (60 ml) and concentrated hydrochloric acid (2 ml) and extracted.The organic layer was washed with 5% aqueous sodium bicarbonate (40 inl) and water (40 mi), and each aqueous layer was extracted again with ethyl acetate (100 ml). The layers were combined and the solvent was distilled off under reduced pressure. The concentrate was crystallized from a mixture of ethyl acetate and toluene, filtered and dried to obtain 28.8 g of compound (9). (D) A solution of 2.0 g (3.36 mmol) of the compound (8) obtained in (A) in 16 ml of tetrahydrofuran was cooled to -51 ° C, and 4 l (1.51 mmol) of phosphorus tribromide was added. A 1 ml solution of tetrahydrofuran was added dropwise at -51 ° C to -38 ° C over 16 minutes. After the temperature was raised to -2.5 ° C over 1 hour, the mixture was stirred under ice cooling for 19 hours and 49 minutes. The reaction solution was poured into ethyl acetate and permanent water and extracted. The ethyl acetate layer was washed with water, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was slurried with acetone and water, and the slurry was collected by filtration to obtain 1.91 (yield 86) of compound (10).

_{Ή-NMR (CDC1 3):} δ 1.34 (t, 3H, J = 7Hz, Et), 3.46-3.74 (m, 2H, -SCH), 4.24-4.44 (m, 4H, -G¾Br, Et), 5.12 ( d, 1H, J = 5Hz, C "H), 6.12 (dd, 1H , J = 5, 9Hz, C, -H), 6.47 (s, 2H, -NH 2), 6.99 (s, 1H, -CH -), 7.2-7.4 (m, 10H , PhX 2), 7.95 (d, 1H 5 J = 9Hz, -C0NH-).

FABMS (m / z): mentor] + 657, [2謹] ⁺ 1313.

(E) 5 g (8.16 mimol) of the compound (9) obtained in (C) was dissolved in 7 ml of MF, and 1.68 g (16.3 mimol) of sodium bromide was added at room temperature. Under ice cooling, 2.29 g (8.16 mmol) of the compound (4) dissolved in 4.2 ml was added, and the mixture was stirred at 5 ° C for 20 hours and 30 minutes. After adding 19 ml of ethyl acetate to this reaction solution, it was dropped into 114 ml of ethyl acetate cooled to 5 ° C. while stirring at a high speed to form a slurry. After stirring at 5 ° C for 30 minutes, the precipitate was filtered and dried under reduced pressure to obtain 7.5 g of a crude solid (11) (yield 97%).

Ή-NMR (DMS0-d _t ): δ 1.19 (t, 3H, J = 4.2Hz, Et), 1.31 (s, 9H, t-Bu), 2.02-2.10 (m, 2H,-CH _2- ), 2.87 (s, 3H, N-CH ₃ ), 4.13 (q, 2H, J = 4.2Hz, Et), 4.38-4.50

(m, 2H, S-CH 2), 5.12 (d, 1H, J = 4.8Hz, C r H), 5.55 (m, 1H, C 7 - H), 5.90-6.10

(m, 4H, N-CH _! X2), 6.95 (s, 1H,-CH-), 7.20-7.52 (m, 10H, Phx2), 8.13 (m,

2H,-NH ₂ ), 7.93, 8.83, 8.98, 9.60 (4H).

5 g (5.27 mimol) of the compound (11) obtained in Example 3 was dissolved in 10 ml of HC00H, and 62% H ₂ SO ₍ 8.34 g (52.7 mimol) was added under ice-cooling, followed by 2 hours at the same temperature. The reaction mixture was added dropwise to 150 ml of ice-cooled isopropyl alcohol, and the precipitated precipitate was filtered and dried to obtain 4.42 g of a crude solid. solution, adjust the pH to 4 to 5 with aqueous sodium hydroxide solution, perform chromatographic chromatography with 80 nil of HP-20SS, elute with 5% acetonitrile / water, and reduce the effective area to 15.5 g. The concentrate was added dropwise to 170 ml of cold isopropyl alcohol, and the deposited precipitate was filtered and dried to obtain 2.0 g (yield: 58%) of a purified solid of the compound (.6). HPLC purity 92%.

! H-NMR (MS0-): 1.18 (t, 3H, J = 7Hz, Et), 2.15-2.30 (m, 2H, -GH) ₃

2.8-2.9 (m, 2H, - CH 2 -), 4.10 (q, 2H, J = 7Hz, Et), 4.55-4.65 (m, 2H, - SCH 2 -),

5.04 (d, 1H, J = 5Hz, CH), 5.55-5.75 (m, 3H, C 7 -H, - NCH 2 -), 8.12 (s, 2H, -Ν¾), 9.45 (s, 1H, -C0NH -), 7.86, 8.96, 9.15, 9.45 (4H). Example 5

(A) A suspension of 42 g of 1,2-dichloroethane and 6.0 g (22 mmol) of 75-amino-3-acetoxymethylcef-3-em-4-carboxylic acid (compound 12) was added to Xametyldisilazane (10.68 g, 66 mmol) and sulfuric acid (43 mg, 0.02 equivalent) were added, and the mixture was stirred at room temperature for 30 minutes, heated, and refluxed for 2 hours. After cooling to 5 ° C, a solution of 5.64 ml (39.6 millimoles) of o-trimethylsilane in 10 ml of 1,2-dichloromethane was added dropwise over 10 minutes and stirred at the same temperature for 5 hours to give a dark reddish brown suspension. was gotten. After the suspension was allowed to stand at -20 ° C for 15 hours, the solvent was distilled off under reduced pressure to obtain 24 g of compound (13).

(B) To 24 g of the compound (13) obtained in (A) were added 40 ml of acetonitrile and 11.7 g (39.6 mmol) of the compound (4), and the mixture was stirred at 5 ° C for 5 hours. It was added dropwise to 100 ml of isopropyl alcohol cooled to C over 10 minutes. After stirring at 5 ° C for 30 minutes, the deposited precipitate was filtered and dried under reduced pressure to obtain 11.3 g of a crude solid (14) (yield,

(82% from (12)).

Ή-NMR (also MS0-): δ 1.35 (s, 9H, -C (CH ₃ ) ₃ ), 2.05-2.20 (m, 2H,-(¾-), 2.80 (s, 3H, -NCH ₃ ), 3.2-3.3 (m, 2H, -CH), 4.48 (s, 2H, -SCH _2- ), 4.81 (d, 1H,

J = 5Hz, CH), 4.92 (d, 1H, J = 5Hz, C _v -H), 5.60, 5.97 (dd, 2H, J = 14Hz, -NCH _2- ), 7.98, 9.03, 9.10, 9.14 (4H).

(C) 3.15 g (5 mimol) of the compound (14) obtained in (B) was dissolved in 9.5 ml of methanol and 2.63 ml (11 mimol) of triptylamine and cooled with water. In a separate reactor, 1.3 g (6 mmol) of compound (1) was dissolved in 13 ml of dimethylacetamide, and 0.56 ml (7.2 mmol) of methyl sulfonyl chloride and 2.15 ml of tributylamine were added under ice-cooling. ml (9 mmol) was added, and the mixture was stirred under ice cooling for 1 hour. This solution was added dropwise to the previously prepared raw material solution over 20 minutes under ice cooling. After 1 hour of ice-cooling and stirring, the temperature was raised to room temperature, and 150 ml of ethyl acetate was added dropwise, whereby a precipitate was deposited. The precipitate was filtered and dried to obtain 4.47 g of a crude solid (15).

Ή-NMR (DMS0-d _t ): δ 1.18 (t, 3H, J = 7 Hz, Et), 1.33 (s, 9H, -C (CH ₃ ) ₃ ), 2.05-2.20 (m, 2H, -CH) , 2.78 (s, 3H, -NCH ₃ ), 2.95-3.05 (m, 2H, -CH Factory), .10 (q, 2H, J = 7Hz, Et), 4.46 (s, 2H, -SCH,-) , 5.03 (d, 1H, J = 5Hz, C _t -H), 5.6-5.8 (m, 3H, CH, -NGH), 8.11 (s, 2H, -N), 9.56 (s, 1H, -NH- ), 7.98, 9.03, 9.10, 9.14 (4H).

1.92 g of the compound (15) obtained in Example 5 was dissolved in 3.75 ml of HC00H, and under ice-cooling, 62% H ₂ S0 <

1.64 g (10.7 mmol) was added, and the mixture was stirred at the same temperature for 1 hour. The reaction solution was dropped into 75 ml of ice-cooled isopropyl alcohol, and the deposited precipitate was filtered and dried to obtain 1.59 g of a crude solid. Dissolve the crude solid in 4.5 ml of distilled water, adjust the pH to about 4 with aqueous sodium hydroxide solution, perform column chromatography with 25 ml of HP-20SS, elute with 3% acetonitril / water, Was concentrated under reduced pressure to 3.8 g. This concentrate is added dropwise to 45 ml of cold isopropyl alcohol, and the deposited precipitate is filtered. Drying yielded 0.68 g (yield, 49% from (14)) of a pure solid of compound (6), HPLC purity 92¾.

_{Ή-NMR (DMS0-d s} ): δ 1.18 (t, 3H, J = 7Hz, Et), 2.15-2.30 (m, 2H, -CH 2 -): 2.8-2.9 (m, 2H, -CH广) , 4.10 (q, 2H, J = 7Hz, Et), 4.55-4.65 (m, 2H, -SCH广), 5.04 (d, 1H, J = 5Hz, C 5 - H), 5.55-5.75 (m, 3H , C, -H, -. NCH厂), 8.12 (s, 2H, -NH Z), 9.45 (s, 1H, -C0NH-), 7.86, 8.96, 9.15, 9.45 (4H) · example 7

(A) Compound (1) 1.24 nil (18.0 mimol) and 3.14 ml (18.0 mimol) of methanesulfonyl chloride were added to a solution of 3.24 g (15.0 mimol) of MI in 14.2 ml of MI under ice-cooling. Lmol) was slowly added dropwise slowly. The reaction solution was stirred for 1 hour under ice-cooling to obtain a solution of (5-amino- [1,2,4] thiadiazole-3-yl) ethoxyminomethanesulfonate. To a suspension of 2.72 g (10.0 mimol) of compound (12) in 17.0 ml of water and 11.0 ml of acetone, an aqueous solution of 0.64 g (6.0 mimol) of sodium carbonate in 10 ml of water was added dropwise under ice cooling. did. To the suspension, 11 ml of a 10% aqueous sodium carbonate solution and the sulfonate solution prepared above were slowly and simultaneously added dropwise, and the reaction solution was stirred for 1 hour and 40 minutes under ice-cooling. The reaction mixture was extracted with 60 ml of ethyl acetate and concentrated hydrochloric acid. The extract was washed twice with water, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain 4.43 g (94.0%) of a crude solid of compound (16).

Compound (16) was recrystallized from ethyl acetate-DMI to give 1,3-dimethyl-4-imidazolyl. Crystals of the dinone solvate were obtained.

CnHnOiNtS, 2DMI (FW. 698.78).

mp.l25-131 ° C.

'Η-Awake (DMS0-d _t ): δ 1.25 (t, 3H, J = 6.8Hz), 2.03 (s, 3H), 2.63 (s, 12H), 3.20 (s, 8H), 3.44-3.66 (m , 2H), 4.18 (q, 2H, J = 6.8Hz), 4.65-5.00 (m, 2H), 5.15 (d, 1H, J = 4.8Hz), 5.83 (dd, 1H, J = 4.8, 8.7Hz) , 8.13 (s, 2H), 9.54 (d, 1H, J = 8.7Hz).

Compound (1 6) § Se Tonito Lil - and recrystallized from bicarbonate isocyanatomethyl Riumu water to obtain a sodium salt of 1.5 H ₂ 0.

Elemental analysis

1.5¾0 (FW.519.49).

Calcd, C:. 36.99, H : 3.88, N: 16.18, S: 12.34, Na: 4.43, H 2 0: 5.20.

Found, C: 36.79, H: 3.88, N: 16.48, S: 12.47, Na: 4.44, H 2 0: 5.38.

mp.> 230 ° C.

(B) To a suspension of the compound obtained in (A) (16) l.OOg in 10 ml of dichloromethane at room temperature, N-methyl-N-trimethylsilyl trifluoroacetamide 1.22 ml (6.58 mimol) Was slowly dropped. After the addition, the mixture was stirred at the same temperature for 1 hour, and then 0.70 nil (4.94 mimol) of lodotrimethylsilane was slowly added dropwise. After stirring at the same temperature for 1 hour, the solvent was distilled off under reduced pressure to obtain an oily compound (17) 2.8. 2.8 g of the obtained crude (17) was dissolved in 5.0 ml of acetonitrile and 0.57 ml of tetrahydrofuran, and while stirring under ice-cooling, 956 mg (3.29 mimol) of compound (4) was added.晚 Stirred. The reaction solution was poured into a mixed solution of ethyl acetate-methanol, and the deposited precipitate was filtered and dried under reduced pressure to obtain 1.26 g of compound (15) HI salt (yield, 92% from (12)). Was done. Example 8

1.20 g of the compound (15) HI salt obtained in Example 7 was dissolved in 2.4 ml of HC00H, and under ice-cooling, δΖ Η ^ Ο ^ 0.92 g (5.8 mimol) was added thereto, followed by stirring at the same temperature for 1 hour. did. The reaction solution was added dropwise to 48 ml of ice-cooled isopropyl alcohol, and the deposited precipitate was filtered and dried to obtain 1.12 g of a crude solid. Dissolve the crude solid in 3.0 ml of distilled water, adjust the pH to about 4 with aqueous sodium hydroxide solution, perform chromatographic chromatography with 15 ml of HP-20SS, elute with 3% acetonitrile / ice, and elute 2.3 g It concentrated under reduced pressure until. This concentrated solution was added dropwise to 28 ml of cold isopropyl alcohol, and the deposited precipitate was filtered and dried. 0.46 g (yield, 36% from (12)) of the purified solid compound (6) was obtained by HPLC. (Quantitative value) was obtained.

Ή-NMR (D ₂₀ ): δ 1.30 (t, 3H, J = 7.0 Hz), 2.41 (m, 2H), 2.73 (s, 3H), 3.17 (t, 2H, J = 8.0 Hz), 3.33 ( d, 1H, J = 18.2Hz), 3.65 (d, 1H, J = 18.2Hz), 4.33 (q, 2H, J = 7.0Hz), 4.64 (t, 2H, J = 7.3Hz), 5.25 (d, 1H, J = 4.8Hz), 5.70 (d, 1H, J = 14.8Hz), 5.88 (d, 1H, J = 4.8Hz), 5.93 (d, 1H, J = 14.8Hz) _} 7.89 (dd, 1H, J = 6.4, 8.2Hz), 8.82 (d, 1H, J = 8.2Hz), 8.85 (d, 1H, J = 6.4Hz), 8.89 (s, 1H).

To 106.5 g (38.0 mimol) of the compound (18) was added 1.4 g (7.4 mimol) of paratoluenesulfonic acid monohydrate. At room temperature, 100.8 g (95.0 g) of trimethyl orthoformate was added at room temperature. (Millimol) was added. After heating to 90 ° C and stirring for 3.5 hours, the mixture was cooled to room temperature and concentrated under reduced pressure. To this concentrated solution, 120 mL of ethyl acetate was added, and this solution was added dropwise to 720 mL of hexane at room temperature, followed by vigorous stirring for 30 minutes. The precipitated crystals were collected by filtration and dried to obtain 103.8 g (yield, 94.1%) of compound (4) as white crystals.

79-81 ° C (decomposition).

'H-MRiGDCla) ^ 8.59 (d, J = 4.5, 1H), 8.20 (s, 1H), 7.73 (dd, J = 8.1, 1.5, 1H), 7.25 (dd, J = 8.7, 5.1, 1H), 4.22 (t, J = 7.2, 2H), 3.32 (brs, 2H), 2.85 (s, 3H), 2.12 (tt, J = 13.8, 6.9), 1.44 (s, 9H).

Elemental analysis C _1S H „N ₄ 0 ₂ Calcd., C, 62.05; H, 7.64; N, 19.30; 0, 11.02.

Found, C, 61.96; H, 7.49; N, 19.42.

The powder X-ray diffraction pattern of the compound (4) is shown in FIG. 1, and the typical peaks are shown in Table 1.

X-ray measurement conditions: tube Cu (wavelength = 1.540 51 A), tube voltage 30 Kv, tube current 15 mA, d sin0 = ηλ (n is an integer, 0 is the diffraction angle).

(table 1 )

C7 (°

V) U- (A) Today vs. 5 (% / 0)

丄 1.00 (.6 2 O Q

a

丄 3 • 1 80 .7 1 y Q

1 4 • 5 5 D .0 8 丄 U U

1 5.5 3 b .7 0 o o

1 6 5 1 5 .3 6 丄丄

1 7 .7 5 4 .9 9 1 丄 8 Q

1 8.2 .7 4 .8 5 y

1 8 .8 3 4.7 .1 A a

1 9 .8 3 4 • 4 7 I 0

2 0 .5 6 4 .3 2 1 2

2 1 .3 0 4 .1 7 1 0

2 2 .0 9 4 .0 2 1 U

2 2 .4 0 3 .9 7 9

Q

D .8 2 1 n u

2 3 .8 7 3.7 .2 9

2 4 .6 4 3 .6 1 2 2

2 5.9 9 3 .4 3 6

2 8 .4 9 3 .1 3 6

2 9.1 5 3 .0 6 6

3 1 .4 0 2 .8 5 6

3 1 .8 3 2 .8 1 7

3 4 .2 4 2 .6 2 6

3 7 .6 3 2 • 3 9 6

3 8.4 2 .3 4 7 Reference example 2

While stirring compound (1) 43.2 g (0.2 mol) and dichloromethane 200 ml DMF 0.8 ml (1 mmol) at 110 ° C, 20.9 ml (0.24 mol) of oxalyl chloride is required at the same temperature for 40 minutes. And dropped. The reaction solution was stirred at the same temperature for 1 hour, 216 ml of isopropyl ether was added, and the mixture was further stirred at the same temperature for 1 hour, and the precipitated crystals were collected by filtration and dried under reduced pressure to obtain 43.3 g of compound (19) (yield Rate 80%). Elemental analysis CAN ₄ 0 ₂ SC physician HC1 (FW. 271.12).

Calcd., C: 26.58, H: 2.97, N: 20.66, S: 11.83, Cl: 26.15.

Found, C: 26.50, H: 2.96, N: 20.13, S: 11.23, Cl: 25.49, H 2 0: 0.89, Example 9

15

To a suspension of 56 ml of 1,2-dichloroethane and 7.0 g (24.9 mmol) of compound (12), 10.4 ml (49.8 mmol) of HMDS and 49 mg (0.02 equivalent) of sulfuric acid were added, and the mixture was refluxed for 2 hours. . After cooling, 6.4 ml (44.8 mmol) of TMSI was added dropwise at 10 ° C for 3 minutes. After heating for 1 hour from 10 ° C to 20 ° C, the mixture was cooled on ice and 2.4 ml (29.9 mimol) of tetrahydrofuran was added dropwise at 5 ° C for 5 minutes. Next, 8.6 g (29.9 mmol) of the compound (4) obtained in Reference Example 1 was added, and the mixture was stirred at 5 ° C. for 4 hours and left still at the same temperature for 16 hours. In another container, 40 ml of 1,2-dichloroethane and 14 ml of methanol were put and cooled to 130 ° C. Next, after the reaction solution was added, 7.4 g (27. millimol) of the compound (19) obtained in Reference Example 2 was added at the same temperature, and 6.8 ml (62.2 millimol) of N-methylmorpholine was further added at the same temperature. Dropping took 5 minutes. Subsequently, after stirring at the same temperature for 1.5 hours, stirring at 0 ° C for 1 hour, the reaction solution was added dropwise to 480 ml of ethyl acetate at 20 ° C for 10 minutes, and after stirring at the same temperature for 1 hour, the precipitate was filtered. I took it. Drying under reduced pressure gave 25.8 g of powder of the compound (15) HI salt. HPLC purity Ί%. Example 10

10 g of the compound (15) HI salt obtained in Example 9 was dissolved in a mixture of 40 ml of water and 40 ml of acetonitrile, and the mixture was cooled under ice-cooling.

g (0.18 mol) was added and the mixture was stirred at room temperature for 4 hours. To this reaction solution, 90 ml of an aqueous solution of 4-NaOH was added dropwise over 1 hour under ice cooling, adjusted to pH 4, and concentrated under reduced pressure. 185 g of this concentrated solution was packed in 130 ml of synthetic adsorption resin HP-20SS, subjected to column chromatography, eluted with water and 4% acetonitrile / water, and the effective fraction was concentrated under reduced pressure to 19.4 g. This concentrated liquid was dropped into 240 ml of cold isopropyl alcohol, and the deposited precipitate was collected by filtration and dried to obtain 4.4 g of a purified solid of compound (6) (a yield of 55% from compound (12)). .

. HPLC purity _{92% Ή-NMR (D ¾} 0): δ 1.30 (t, 3H, J = 10Hz, Et), 2.3-2.5 (m, 2H, -CHj-), 2.73 (s, 3H, -NMe) , 3.1-3.2 (m, 2H, -CH 2 -), 3.3, 3.65 (ABq, 2H, J = 18Hz, - SCH 2 -), 4.32 (q, 2H, J = 7Hz, Et), 4.6-4.66 ( m, 2H,-CH _2- ), 5.24 (d, 1H, J = 5Hz, CH), 5.63, 5.90 (ABq, 2H,-CN-), 5.85 (d, 1H, C ₇ -H), 7.9, 8.7-8.9 (m, 4H).

(A) To a suspension of 80 ml of 1,2-dichloroethane and 10.0 g (36.7 mmol) of compound (12), 8.9 g (55.1 mmol) of HMDS and 72 mg (0.0 equivalent) of sulfuric acid were added, and the mixture was refluxed. After 4 hours, the mixture was cooled and 9.4 ml (66.1 mimol) of TMSI was added dropwise at 10 ° C for 3 minutes. After heating for 1 hour from 10 ° C to 20 ° C, the mixture was cooled on ice and 8.9 ml (110 mimol) of tetrahydrofuran was added dropwise at 5 ° C for 5 minutes. Next, 12.8 g (44.0 mimol) of the compound (4) was added, and the mixture was stirred at 5 ° C for 6 hours, and allowed to stand at the same temperature for 16 hours. The reaction solution was mixed with 500 ml of ethyl acetate and 25 ml of methanol. The mixture was added dropwise at 20 ° C for 30 minutes. After stirring at the same temperature for 30 minutes, the deposited precipitate was collected by filtration and dried under reduced pressure to obtain 23.2 g of compound (14) (100% yield from compound (12)).

HPLC purity 70%. 'Η- 丽 R (dish S0-): 5 1.35 (s, 9H, -C (CH ₃ ) ₃ ), 2.05- 2.20 (m,

2H, -CHj-), 2.80 (s , 3H, - NCH 3), 3.2-3.3 (m, 2H, -CH), 4.47 (s, 2H, - SCH厂), 4.81 (d, 1H, J = 5Hz , CH), 4.92 (d, 1H, J = 5Hz, C Factory H), 5.60, 5.97 (dd, 2H,

J = 14Hz, -NCH), 7.98, 9.03, 9.10, 9.14 (m, 4H).

(B) Compound (1) Cool a suspension of lOg (46 mmol) and dichloromethane (50 ml), 4.8 ml (55 mmol) of ogizarilk D-ride and 0.34 g (0.1 equivalent) of DMF were added, and the mixture was stirred at 0 ° C for 1 hour. A solution of 7.7 g (46 mimol) of 2-mercaptobenzothiazole (21), 40 ml of dichloromethane and 12.6 ml (115 mimol) of N-methylmorpholine was cooled, and the reaction solution prepared above was cooled at 0 ° C for 30 minutes. It was dropped when necessary. After stirring at the same temperature for 1 hour, the mixture was poured into 500 ml of ethyl acetate and 150 ml of water for extraction. The organic layer was washed with 100 ml of water, and the ice layer was extracted with 100 ml of ethyl acetate. The organic layer was collected, dried over magnesium sulfate, and concentrated under reduced pressure. To 18.3 g of the crystalline residue was added 50 nil of acetonitrile, and the crystals were collected by filtration and dried to obtain 13.6 g (yield 81%) of compound (22) as crystals.

_{Ή-NMR (CDC1 3):} δ 1.38 (t, 3H, J = 7Hz, Et), 4.41 (q, 2H, J = 7Hz, Et), 6.59 (s, 2H, NH 2), 7.4-8.1 (m , 4H).

(C) A solution of 3.15 g (5 mmol) of the compound (14) obtained in (A), 20 ml of dichloromethane and 0.55 ml (5 mmol) of N-methylmorpholine was obtained in (B) under ice-cooling. 1.83 g (5 mmol) of the compound (22) was added, and the mixture was stirred at the same temperature for 4.5 hours. The reaction solution was poured into 100 ml of ethyl acetate, stirred at room temperature for 1 hour, and the deposited precipitate was collected by filtration and dried to obtain 4.23 g of a powdery HI salt of compound (15).

HPLC purity 69%. Example 1 2

Compound obtained in Example 1 1 (1 5) HI salt 1.66 g (2 Mi Rimoru) was dissolved in a mixture of water 6.6 ml and § cell Tonito Lil 6.6 ml, under ice-cooling, 62¾¾S0 ₄ 4.74 g (30 Mi Rimoru ) Was added and the mixture was stirred at room temperature for 3 hours. Under ice-cooling, a 4N-NaOH aqueous solution was added dropwise to the reaction solution, adjusted to pH 4, and concentrated under reduced pressure. 40 g of this concentrated solution was packed in 20 ml of synthetic adsorption resin HP-20SS, subjected to column chromatography, eluted with water and 4-acetonitrile / water, and the effective fraction was concentrated under reduced pressure to 3 g. This concentrated solution was dropped into 40 ml of cold isopropyl alcohol, and the deposited precipitate was collected by filtration and dried to obtain 0.71 g of a purified solid of compound (6) (yield: 56% from compound (12)). . HPLC purity 92% Ή-NMR (DMS0- d s): δ 1.18 (t, 3H, J = 7Hz, Et), 2.15-2.30 (m 3 2H, - (¾-), 2.8-2.9 (m, 2H , -CH _2- ), 4.10 (q, 2H, J = 7Hz, Et), 4.55-4.65 (m, 2H, -SGH Factory), 5.04 (d, 1H, J = 5Hz, CH), 5.55-5.75 ( m, 3H, C, -H, - NCH r), 8.12 (s, 2H, -. NH 2), 9.45 (s, 1H, -CONH-), 7.86, 8.96, 9.15, 9.45 (m, 4H) reference Example 3

B. c =-COOC (CH ₃ ) ₃

Compound 15 described in Example 5 was obtained with high purity (Compound II-2-a) by the following method. WO 0/3 2 6 0 6 and the 4th ICAAC Program Collection (February 16th to 19th, 2001, Chicago, USA, Lecture No. F — To a suspension of 30 g (39.8 mimol, monosulfate trihydrate crystals) of compound (I-a) synthesized according to the method described in 370) and 150ffll of water, add sodium hydrogen carbonate 5.23. g (62.1 millimoles) was added and dissolved. A solution of 10.42 g (47.8 mmol) of di-tert-butyl dicarbonate in 300 ml of acetonitrile was added to the aqueous solution at 25 ° C. This mixture was vigorously stirred at the same temperature for 5 hours while maintaining the pH at 7.0 to 7.5. After the reaction was completed, the reaction solution was concentrated under reduced pressure to remove acetonitrile, whereby the candy portion was separated from water. The aqueous layer was decanted, and 60 ml of 10% aqueous acetonitrile was added to and dissolved in the aqueous portion. The solution was subjected to column chromatography using 400 ml of synthetic adsorption resin HP-20SS. 5% acetate nitrile / water 1 L,

Elution was carried out with 1 L of 30% acetonitril / water, and the effective zone was removed under reduced pressure to obtain 33 g of a foamy residue. 30 ml of acetonitrile and 3 ml of water are added to the residue to dissolve it. The mixture was dropped slowly at room temperature, and the precipitated powder was collected by filtration after 5 minutes of stirring, washed with acetone, and dried to obtain 22.3 g of a powder (amorphous) of the compound (II-2-a).

-丽 (MS0-): δ 1.15 (t, 3H, J = 7Hz, Et), 1.32 (br, 9H, Boc), 2.0-2.l (m, 2H, -CH), 2.76 (s, 3H, -NCH ₃ ), 2.9- 3.5 (m, 4H, -CH Factory X2), 4.07 (q, 2H, J = 7Hz, Et), 4.4-4.5 (m, -CH Factory), 5.00 (d, 1H, J _{= 5Hz, C 8 -H),} 5.6-5.7 (m, 3H, C 7 - H, - CH厂), 8.10 (s, 2H, - NH 2), 9.72 (d, 1H, J = 6Hz, -NH -), 7.95, 8.93, 9.11, 9.4K4H).

FABMS (m / z): [M + H] ⁺ 701, [2M + H] ⁺ 1401. The crystallization of the compound (II-2-a) was examined below.

(Powder X-ray measurement conditions)

X-ray: CuK, tube voltage: 40 Kv, tube current: 30 mA, scan speed: 4 ° / iain, sampling width: 0.02 °, operation axis: 2θ / Θ scanning range: 5. ~ 40 °

The identification of the crystallization solvent was carried out based on the TG / DTA measurement results measured simultaneously with the powder X-ray, NMR, KF value, etc. Example 1 3 (THF, H ₂ 0 containing crystals)

500 mg of the compound (II-2-a) was dissolved in a mixture of 00.5 ml and 0.5 ml of CH ₃ CN, 2.5 ml of THF was added, seed crystals were added, and the mixture was stirred at 5 ° C. overnight. The precipitated crystals were filtered, washed with cold _{_{H 2 0- CH 3 CN- THF (}} 1- 1- 5), cold _{_{H 2 0- GH 3 CN-THF}} (1- 1- 10), and washed sequentially with THF, air drying As a result, 320 nig of the crystal (1) of the compound (Π-2-a) was obtained.

ΐ-丽 R (MS0- d _t ): ά 1.17 (t, 3H, J = 7Hz, Et), 1.35 (¾r, 9H, -C (C¾) ₃ ), 1.7-1.8 (m,

4H, THF), 2.05-2.20 (m , 2H, - CH广), 2.79 (s, 3H, - NCH 3), 2.9-3.5 (m, 4H, (-

_{CH) 2), 3.55-3.65 (m} , 4H, THF), 4.10 (q, 2H, J = 7Hz, Et), 4.46 (br, 2H, - SCH 2 -),

5.02 (d, 1H, J = 5Hz, CH), 5.6-5.7 (m 3 3H, CH, - CH "), 8.12 (s, 2H, -NHj),

9.77 (d, 1H, J = 6Hz, -NH-), 7.98, 8.96, 9.14, 9.43 (4H). F Moisture measurement value: 6.87%

Crystal solvent THF = 1 molecule, H ₂ 0 = 5 molecules

The X-ray powder diffraction pattern is shown in Fig. 2, and typical peaks are shown in Table 2.

Table 2

d value fcR Sfc

Afraid ^ r 5m

D. Y o un

14.97 0 Q

0,04 13.30

21.20 4.19 3

22.70 3.91 3

23.96 3.71 4

24.12 3.69 3

24.88 3.58 4

25.56 3.48 5

26.28 3.39 3

38.06 2.36 83

38.22 2.35 100 Example 1 4 (H ₂ 0 containing crystals)

After drying 150 mg of the crystals obtained in Example 13 under reduced pressure (15 mniHg) for 2 hours, 130 mg of crystals (2) were obtained.

'H-NMR (DMSO-dt ): 6 1.17 (t, 3H, J = 7Hz, Et), 1.35 (br, 9H, - G (CH 3) 3), 2.05- 2.20 (m, 2H, - C - ), 2.79 (s, 3H, -NCH 3), 2.9- 3.5 (m, 4H, (-CH r) 2), 4.10 (q, 2H, J = 7Hz, Et), 4.46 (br, 2H, -SCH _{2 -), 5.02 (d,} 1H, J = 5Hz, C r H), 5.6-5.7 (m, 3H, C, -H, -CH), 8.12 (s, 2H, -NH 2), 9.72 (d , 1H, J = 6Hz, -NH-), 7.97, 8.96, 9.13, 9.45 (4H). KF moisture content: 8.11% Crystal solvent H ₂ 0 = 4.5 molecule

The powder X-ray diffraction pattern is shown in Fig. 3, and typical peaks are shown in Table 3.

Table 3

2 Θ d value Relative strength

6.16 2

6.90 12.80 2

10.44 8.47 2

12.12 7.30 2

12.58 7.03 2

14.56 6.08 4

18.20 4.87 3

18.64 4.76 2

19.64 4.52 3

4.40 3

21.20 4.19 2

21.62 4.11 2

24.94 3.57 3

25.08 3.55 3

25.60 3.48 3

26.14 3.41 2

2.36 100 Example 15 (CH ₃ CN, acetone-containing crystal)

Dissolve 250m of the compound (a-2-a) selected in Reference Example 3 in 2.5ml of DMF, add 0.5ml of CH ₃ CN and 0.5ml of acetone, add seed crystals, and stir at 5 ° C for 60 hours. . The precipitated crystals were filtered, and cold MF-CH ₃ CN-acetone (5-1-1), cold MF-G CN-acetone (2-1-1), cold MF-CH ₃ CN-acetone (1 -1.5-1.5), washed successively with cold CH ₃ CN-acetone (Table 1) and air-dried to obtain 240 mg of crystals (3).

'H-NMRCDMSO-dj): δ 1.18 (t, 3H, J = 7Hz, Et), 1.35 (br, 9H, - C (CH 3) 3), 2.07 (s, 3H, CH 3 CN), 2.09 ( s, 6H, Aceton), 2.05- 2.20 (m, 2H,-CH Factory), 2.79 (s, 3H,

-NCH ₃ ), 2.9-3.5 (m, 4H, (-CH) j), 4.07 (q, 2H, J = 7Hz, Et), 4.46 (br, 2H,-

SCH Guang), 5.02 (d, 1H, J = 5Hz, C H), 5.6-5.7 (m, 3H, C, -H, -CH), 8.12 (s, 2H,

-NHj), 9.75 (br, 1H, -NH-), 7.97, 8.96, 9.14, 9.45 (4H) Crystal solvent CH ₃ CN = 1 molecule, acetone = 1 molecule

The powder X-ray diffraction pattern is shown in Fig. 4 and the typical peaks are shown in Table 4.

o o

Table 4 dimensions

2 Θ d value Relative strength

6.20 14.24 6

7.94 11.23 3

10.68 8.28 5

11.98 7.38 4

14.56 6.08 7

14.90 5.94 4

17.30 5.12 3

18.02 4.92 6

18.34 4.83 4

19.42 4.57 3

19.78 4.49 4

20.46 4.34 4

20.90 4.27 4

21.08 4.21 5

21.58 4.11 4

22.40 3.97 5

24.00 3.70 5

24.26 3.67 6

24.80 3.59 4

25.38 3.51 7

26.44 3.37 4

3.20 4

28.26 3.16 4

29.22 3.05 4

38.42 2.34 100 Example 16

Compound (II-2-a) 1. Og was dissolved in a mixture of 1.0 ml of H ₂ 0 and l.Oml of acetone, 4.0 nil of acetone was added, seed crystals were added, and the mixture was stirred at 5 ° C for 48 hours. did. The precipitated crystals were collected by filtration, washed successively with cold 0-acetone (1-5), cold 0-acetone (1-10), and acetone, and air-dried to obtain 24 nig crystals (4). The presence or absence of the solvent has not been confirmed. X-ray powder diffraction Figure 5 shows an example and Table 5 shows typical peaks.

O C

o t

Table 5

2 Θ d value Relative strength

6.14 14.38 3

7.88 11.21 2

10.64 8.31 3

11.90 7.43 2

14.48 6.11 4

17.90 4.95 3

19.72 4.50 2

20.28 4.38 2

21.04 4.22 3

21.48 4.13 2

22.32 3.98 3

23.88 3.72 3

24.20 3.67 3

25.30 3.52 3

3.40 3

27.74 3.21 3

28.16 3.17 2

29.12 3.06 2

38.34 2.35 100 Test Example 1 (Crystal stability)

The crystal (1) of the compound (II-2-a) obtained in Example 13 and the amorphous were allowed to stand at room temperature, and their temporal changes (10 days) were compared by HPLC (peak area)%.

Table 6

Crystallization has dramatically improved stability, Industrial applicability

The present invention provides industrially advantageous deprotection reactions and intermediates. By using the present invention, a septum antibacterial agent can be industrially and efficiently produced.

Claims

The scope of the claims

Expression

(Wherein R ¹ and R ² are independently lower alkyl which may be substituted; R ³ is an amino protecting group; R is an anion, hydrogen or a carboxy protecting group) or a compound represented by the following formula: Pharmaceutically acceptable salts or solvates thereof.

2. Formula:

(Wherein R ¹ R ² and R ³ are as defined above; R ⁴ is hydrogen or a carboxy protecting group; X is a counter ion).

^3.1 is Echiru; R ² is methyl; R ³ is a tertiary butoxycarbonyl; 1 ⁴ - main Tokishipenjiru a Benzuhi drill or trimethylsilyl compound of claim 2, wherein.

4. Formula:

(Wherein, RR ² and R ³ are the same defined above) The compound of claim 1, wherein represented by ₍

5. The compound according to claim 4, wherein R ¹ is ethyl; R ² is methyl; R ³ is tertiary butoxycarbonyl.

6. The compound according to any one of claims 1 to 5, or a pharmaceutically acceptable salt thereof, or a solvate thereof, wherein the compound is deprotected.

(Wherein, R ¹ and R ² are as defined above), or a pharmaceutically acceptable salt thereof, or a solvate thereof.

7. The method according to claim 6, wherein the deprotection is performed in the presence of formic acid and sulfuric acid.

8. Expression:

(Wherein, R ¹ is lower alkyl which may be substituted; R ⁴ is hydrogen or a carbonyl protecting group; Y is a leaving group).

Wherein R ² is lower alkyl which may be substituted; R ³ is an amino-protecting group; or a salt thereof is reacted with the compound represented by the formula: (II-11) Item 3. A method for producing the compound according to Item 2.

9. After the compound (II-11) is obtained by the production method according to claim 8, it is deprotected. 7. A method for producing a compound represented by the formula: (I) according to claim 6, or a pharmaceutically acceptable salt thereof or a solvate thereof.

1 0. Formula:

(Wherein, R ⁴ is a hydrogen or carboxy protecting group; R ⁵ is a hydrogen or amino protecting group; Y is a leaving group).

N

Expression

(Wherein R ² , R ³ , R ⁴ and R ⁵ have the same meanings as above; X − is a counter ion) or a salt thereof.

(Wherein, R ¹ is lower alkyl which may be substituted)

Wherein the compound represented by the formula (1) or a reactive derivative thereof is reacted. A method for producing a compound represented by the formula: (II-12).

1 1. After obtaining the compound (II-12) by the production method according to claim 10, the compound is deprotected, and the compound represented by the formula: (I) according to claim 6, A method for producing a pharmaceutically acceptable salt thereof or a solvate thereof.

1 2. Formula:

Wherein R ¹ and R ² are independently lower alkyl which may be independently substituted; R ³ is an amino protecting group; and X- is a counter ion.

1 4. The compound (I) according to claim 6, or a pharmaceutically acceptable salt or a solvate thereof, wherein the compound (II-3) according to claim 12 is deprotected. Recipe.

15. The method according to claim 14, wherein the deprotection is performed in the presence of sulfuric acid, water and acetonitrile.

1 6. The compound (V) according to claim 10 is reacted with the compound (IV) or a salt thereof to obtain a compound represented by the formula:

(Wherein, H ² is lower alkyl which may be substituted; R ³ is an amino protecting group; R ⁴ is a hydrogen or carboxy protecting group; R ⁵ is a hydrogen or amino protecting group; X— is a counter ion) After obtaining the compound or a salt thereof, the compound (VII) or a reactive derivative thereof is reacted. The compound represented by the formula: (3) according to claim 12, wherein

7 Expression

(Wherein: ¹ is ethyl; R ² is methyl; R ³ is tert-butoxycarbonyl). A crystal of the compound or a solvate thereof according to claim 5, wherein

18. The solvate crystal according to claim 17, comprising one or more solvents selected from the group consisting of water, acetonitrile, tetrahydrofuran, dimethylformamide and acetone.

19. The formula: characterized in that the crystal according to claim 17 or 18 is deprotected.

20. The process according to claim 6 or 19, which is a process for producing a sulfate of compound (I) or a solvate thereof.