TW200404807A - Method for preparing Cephem compound - Google Patents

Abstract

This present invention is related to provide a method for preparing the compound of formula (I), (wherein R1 and R2 are defined as below) or pharmaceutical acceptable salt thereof or solvate thereof, which is characterized in deprotecting the compound of formula (II), (wherein R1 and R2 are each independent hydrogen, optionally substituted lower alkyl; R3 is amino protecting group; R is anion, hydrogen or carboxy protecting group) or pharmaceutical acceptable salt thereof or solvate thereof, and provides the crystal of compound of formula (II).

Description

200404807 (1) Description of the invention: [Technical Field of the Invention] The present invention relates to an intermediate of a Cephem compound having a wide range of antibacterial activity against various susceptible bacteria, a crystal thereof, and a manufacturing method using the same. [Previous technology] As a wide range of Saifen compounds with strong antibacterial power against Gram-positive bacteria and Gram-negative bacteria, in recent years, the 7th position of the Saifen backbone is aminothiadiazole, and the 3rd position is Compounds of cyclic type 4 ammonium methyl group have attracted attention. For example, it is known that a Saifen compound in which imidazo [4,5-b] pyridiniummethyl is introduced at the third position of a Saifen compound (for example, refer to Patent Document 1). In addition, there have been reported methods for producing other saphene compounds using a method in which the amine group at position 7 is an unprotected intermediate (for example, refer to Patent Documents 2, 3, and 4). (Patent Document 1) International Publication No. 00/32606 (Patent Document 2) International Publication No. 9 8/25 93 5 (Patent Document 3) International Publication No. 86/03204 (Patent Document 4) JP 10 In the above-mentioned WO00 / 32606 in -291993, for example, Example 6-2 is used as an example, which uses an amino group containing the 7th position (aminothiadiazolylethoxyimine acetamido), and 3rd Intermediate of amine group (aminoalkylimidazolidinemethyl) and carboxyl group at position 4, deprotection of amine group and carboxyl group at the two positions with aluminum chloride, but it is produced as an industrial method The rate cannot be satisfied (31% yield). In order to remove isomers of by-products, a column processing step is necessary. [Summary of the Invention] 200404807 The invention discloses that the present invention provides an improved method for preparing the above-mentioned saifen compound, which uses a method in which the amino group of the 7th aminothiathiazolyl group is an unprotected intermediate, and further, at the 3rd side In the deprotection step of the amine group on the chain and / or the carboxyl group at the 4th position, a novel combination of deprotection reagents was used, and it was found that the safin compound was obtained in good yield, and the intermediate was also successfully crystallized. The present invention is as follows: 1. A compound represented by formula (II),

C00R

(ID (wherein R1 and R2 are each independently a lower alkyl group which may be substituted; R3 is an amine-protecting group; R is an anion, hydrogen or money-protecting group), and pharmaceutically acceptable salts or solvates thereof. 2 · such The compound according to the above 1, which is represented by formula (II-1),

(Wherein R ^ R2 and R3 have the same meanings as above; R4 is a hydrogen or carboxy protecting group; X · is a counter ion). 3. The compound according to the above 2, wherein R1 is ethyl; R2 is methyl; R3 is tertiary butoxycarbonyl; R4 is P-methoxybenzyl, diphenylmethyl or trimethylsilane base. 4. The compound according to the above 1, which is represented by formula (II-2), 200404807

(IH) (wherein R1, V, and r3 have the same meanings as described above). 5. The compound according to the above 4, wherein R1 is an ethyl group; R2 is a methyl group; and R3 is a tertiary butoxycarbonyl group. 6 · —A method for producing a compound represented by formula (I) or a pharmaceutically acceptable salt or solvate thereof,

(Wherein R1 and R2 have the same meaning as described above) It is characterized in that the compound described in any one of 1 to 5 above or a pharmaceutically acceptable salt or solvate thereof is deprotected.

7. The production method according to 6 above, which is deprotected in the presence of formic acid and sulfuric acid. 8. · A method for producing a compound represented by the formula (II-1) described in the above 2 or a pharmaceutically acceptable salt or solvate thereof, characterized by the formula (III)

(Where R1 is a lower alkyl group which may be substituted; R4 is a hydrogen or carboxy protecting group; Y 200404807 is a leaving group), and the compound shown by the formula (IV) mr αν) N ^ N \ ^ \ / Nvr3 (where R2 is a lower alkyl group which may be substituted; R3 is an amine protecting group) or a salt thereof to react to obtain a compound of formula (I1-1). 9. The method for producing a compound represented by formula (I) or a pharmaceutically acceptable salt or solvate thereof according to the above 6, characterized in that the compound (II-1) obtained from the production method according to the above 8 is deprotected.

1 0 · —A method for producing a compound represented by the formula (11-2) described in the above 4 or a pharmaceutically acceptable salt or solvate thereof, characterized in that the formula (V)

(Wherein R4 is a hydrogen or carboxy protecting group; R5 is a hydrogen or amine protecting group; Y is a leaving group), and the compound represented by the formula (IV) 2 · W? (IV) NVN \ ^ \ / N, R3 ( Where R2 is a lower alkyl group which may be substituted; R3 is an amine protecting group) or a salt thereof to obtain a formula (VI) -10-(VI) 200404807

Is a counter ion) (wherein R2, R3, R4, and R5 are the same as the aforementioned synonymous compound or a salt thereof, and the formula (VII) S-N 〇 2NΆΛν ^ 0Η (vii)

The compound represented by NK 1 OR (wherein the lower alkyl group may be substituted) or a reactive derivative thereof is reacted. 1 1. The method for producing a compound represented by the formula (I) or a pharmaceutically acceptable salt or solvate thereof according to the above 6, characterized in that the compound (Π-2) obtained from the above-mentioned production method according to i 0 is deprotected. ^ ^ Γ (ΙΙ-3)] The compound described in 1 above

12. $ | h2n (III-1) (wherein R1 and R2 are each independently substituted lower alkyl groups; r3 is an amine protecting group; X · is a counter ion). 13. The compound according to the above 12, wherein R1 is ethyl; R2 is methyl; R3 is tertiary butoxycarbonyl. 14 · A method for producing a compound represented by formula (I) or a pharmaceutically acceptable salt or solvate thereof according to the above 6, characterized in that the compound obtained from the above-mentioned production method according to 12 is -11 · 200404807 (Π-3) To protect. 15. The production method according to 14 above, which is deprotected in the presence of sulfuric acid, water, and acetonitrile. 1 6 · * —A method for producing a compound represented by the formula (11-3) described in 1 2 above, characterized in that-· · · · is the reaction of the compound (V) described in 10 above with a compound (IV) or a salt thereof , Got

To formula (VI)

(In the formula, R is a substitutable lower radical; R3 is an amine-protecting group; R4 is a hydrogen or an end-protecting group; R5 is a hydrogen or an amine-protecting group; χ • is a counter ion) After salt, it reacts with compound (VII) or its reactive derivative.

(Wherein R1 is ethyl; R2 is methyl; R3 is tertiary butoxycarbonyl). 18. The crystal according to 17 above, which contains one or more solvents selected from the group consisting of water, acetonitrile, tetrahydrofuran, dimethylformamide, and acetone. -12- 1 7 · —A crystal of a compound or a solvate thereof as described in 5 §5 above, which has the formula (Π-2-a) 200404807

1 9. One type (I) H.N

法 (Method in which R1 is ethyl; R2 is methyl) or a method for producing a pharmaceutically acceptable salt or solvate thereof 'is characterized by deprotecting the crystals described in 17 or 18 above. 20. The method according to 6 or 19 above, which is a method for producing a sulfate or a solvate of the compound (I). Best Mode for Carrying Out the Invention The present invention will be described in further detail. The definitions of the respective groups of the compounds (I) to (VII) of the present invention are described below. (Definition of R1) The lower radical includes straight or branched C i -C 6 fluorenyl, such as methyl, ethyl, η-propyl, tertiary butyl, n-pentyl, η-hexyl, etc. , But Ci_c3 alkyl is preferred, and ethyl is particularly preferred. The substituents of the above lower alkyl are halogen (for example, F, Cl, Br, etc.), hydroxyl, residue, cyano, amine, carbamoyloxy, sulfamoyl, and lower alkoxy group (for example, Methoxycarbonyl, ethoxycarbonyl, etc.), lower alkylthio (such as methylthio, etc.), preferably halogen, and particularly preferably F. R1 is preferably hydrogen, methyl, CH2F, ethyl, CH2CH2F, etc., and particularly preferably ethyl. (Definition of R2) A lower alkyl group having the same definition as the aforementioned R1, but preferably a Cl-C3 alkyl group, and particularly 200404807 is preferably a methyl group. Examples of the above-mentioned lower substituents include a bond group, a substituted aminomethyl group (substituents: methyl, ethyl, etc.), a halogen (such as F, C1, etc.), and a substituted amino group ( Substituents: lower alkyl (such as methyl, ethyl, etc.), lower cannyl (such as: 2, propane, etc.), lower oxo group (such as: tertiary butoxycarbonyl group, etc.), warp group Lower academic group (for example: 1-Ethyl group, 2-Ethyl group, etc.), lower alkoxy group (such as methoxy group, ethoxy group, etc.), lower academic oxycarbonyl group (such as methoxycarbonyl group) , Ethoxycarbonyl, etc.). R2 is preferably methyl, ethyl, hydroxyethyl, or the like, and particularly preferably methyl. (Definition of R3) The amine-based protecting group may suitably use a protecting group known in the art, such as Ci-Ce alcohol (such as methyl ethyl, ethyl ethyl, etc.), c3-C5 alkyl (such as: acrylic acid) Base, crotonyl, etc.), C6-C1Q arylcarbonyl (eg, benzylfluorenyl, naphthol, P-toluenyl, p-hydroxybenzyl, etc.), heterocyclic carbonyl (example of the heterocycle: 4- Imidazolyl, ι, 2,3-triazolyl, 1H-tetrazolyl, 4-oxazolyl, 3 · pyridyl, etc.), CrC6 alkylsulfonyl (for example: methanesulfonyl, ethanesulfonyl Base, etc.),. Arylsulfonyl (such as benzenesulfonyl, naphthylsulfonyl, p-toluenesulfonyl, etc.), substituted oxycarbonyl (eg: methoxymethyloxy, ethoxymethyl) Oxymine group, 2-dimethylmethsalinoethoxy group, 2-methanesulfonylethoxycarbonyl group, 2,2,2-trichloroethoxycarbonyl group, 2-cyanoethoxy group Carbonyl, p-methylphenoxycarbonyl, p-methoxyphenoxycarbonyl, P-chlorophenoxycarbonyl, benzyloxycarbonyl, p-methylbenzyloxycarbonyl, P-methoxy Benzyloxycarbonyl, p-chlorobenzyloxycarbonyl, p-nitrobenzyloxymine, tertiary butoxycarbonyl, 2-propenyloxycarbonyl, etc.), substituted -14 200404807 Silyl groups (such as: trimethylsilyl, tertiary butyldimethylmethyl, Shixiyuan, etc.). R3 is preferably a substituted oxycarbonyl group, and particularly preferably a tertiary butoxycarbonyl group. (Definition of R) R means an anion, hydrogen or carboxy protecting group, but the carboxy protecting group has the same meaning as R4. When R is an anion, COOR is COO ·; Moreover, the fourth-order ammonium cation on the side chain at the third position of the compound is opposite to the COCT at the fourth position to form an intramolecular salt, but the fourth position is COOH or COOR ( When R is a carboxy protecting group), there is a counter ion (X ·), and the counter ion of COOH at the 4th position (XI can form an HX salt. (Definition of R4) R4 means hydrogen or a carboxy protecting group, However, a substituted C ^ -C ^ alkyl, a C2-C6 dilute group, a C3-C1 () cyclofluorenyl group, a cyclodyne group C, a C6 alkyl group, a substituted c6-c1Q aryl group, A substituted c7-cl2 aralkyl group, a di-C6-Cio arylmethyl group, a tris-arylmethyl group, a substituted silyl group, etc. The substituted c ^ -c ^ alkyl group, For example, a methyl group, an ethyl group, an isopropyl group, a tertiary butyl group, and the like are used. Examples of the groups include a benzyloxy group and a Cl-C4 alkylsulfenylsulfonyl group (eg, methylsulfonyl group, etc.) , Halogen (for example: F, C1, etc.), ethenyl, nitrobenzyl, benzenesulfonyl, alkylsulfinyl (for example: methylsulfinyl, etc.), cyano, etc. Examples of substituted groups include benzyloxymethyl 2-methylsulfonylethyl, 2,2,2-trichloroethyl, ethynylmethyl, P-nitrobenzylfluorenylmethyl, p-methanesulfonylbenzylmethyl, benzene Sulfonylmethyl, etc. The C2-C6 alkenyl groups used are ethylene, dipropyl, propyl, and butanyl-15-200404807. Cycloalkyl is cyclopropyl, cyclopentyl , Cyclohexyl, adamantyl 'alkyl, etc. The c3-c1Q cycloalkyl CrC6 alkyl used is cyclopropylmethyl, cyclohexylmethyl and the like.

CfCi. As the aryl group, a phenyl group, a naphthyl group, etc. may be used. These groups may also be substituted with, for example, a nitro group, a halogen (for example, F, Cl, Br, etc.), and such substituted groups may be exemplified by using p-nitrobenzene. And p-chlorophenyl. Examples of the C7-C12 aralkyl group which may be substituted include the use of benzyl, naphthylmethyl φ, etc., which may be, for example, via a nitro group, an alkoxy group (for example, methoxy group, etc.), a C / C4 alkyl group (for example, methyl group) And the like, and hydroxyl groups. Such substituted groups can be, for example, P-nitrobenzyl, P-methoxybenzyl, 3,5-di-tertiary butyl-4-hydroxybenzyl, and the like. Two CfCi. Examples of the arylmethyl group include trityl and the like. Arylmethyl is trityl and the like, or substituted silyl is trimethylsilyl, tertiary butyldimethylsilyl and the like. R4 is preferably P-nitrobenzyl, P-methoxybenzyl, 3,5-di-tertiary butyl φ-4-hydroxybenzyl, benzyl, trityl, trimethyl The silyl group and the tertiary butyldimethylsilyl group are preferably a p-methoxy group; a methyl group, a benzyl group, and a trimethylsilyl group. (Definition of Y) The leaving group Y used is a methyl group, a halogen (Cl, Br, I, etc.), a carbamoyl group, a substituted carbamoyloxy group (such as methylaminocarbamoyloxy, N, N-dimethylamine formamyloxy), fluorenyloxy (for example, acetamyloxy, chloroethanyloxy 16-200404807, trimethylacetamyloxy) and the like. Y is preferably a hydroxyl group, a halogen group, or a fluorenyloxy group, and particularly a hydroxyl group, ci, Br, I, or ethoxyl. (Definition of χ_) X · is a counter ion, preferably halogen, particularly Cl, Br, and I. (Definition of R5) R5 means hydrogen or an amine protecting group. The amine protecting group has the same definition as the aforementioned R3. R5 is preferably a substituted silyl group, especially a trimethylsilyl group. Examples of the pharmaceutically acceptable salts of the compound (I), (II: II-1, II-2, II-3), (IV) or (VI) include inorganic bases, ammonia, organic bases, inorganic acids, organic Salts or intramolecular salts formed by acids, basic amino acids, halogen ions, etc. For example, the inorganic base is an alkali metal (Na, K, etc.), an alkaline earth metal (Mg, etc.), and the organic test group is 2-phenylethylbenzylamine, benzylethylenediamine, ethanolamine, diethanolamine, trihydroxy Methylamine methane, polyhydroxyalkylamine, N-methylglucamine and the like. 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. Basic amino acids are, for example, lysine, arginine, ornithine, histidine, and the like. [Embodiment] The production method of the present invention will be described below. The compound (II) contains a novel intermediate of a wide range of Saifen compound (I), its salt and solvate, and preferably contains compound (II-1) and compound (II-2). ), And compound (II-3). The amine group at the terminal of the side chain at the 3rd position of the compound (Π) or a salt thereof is protected. 200404807 The carboxyl position at the 4th position is protected, or contains a free or anion. In the conventional method, in order to produce the compound (I), it is necessary to protect the amine group end of the amine thiadiazole ring of the side chain at the 7th position of the compound (II). However, in the method of the present invention, the conversion to the compound (I) which does not protect the amine group can improve the yield of the deprotection step. Further discussing the reaction conditions for deprotection can also suppress the isomerization of the oxime moiety at the 7th position. The compound (II) or (I) may be a solvate such as a salt or a hydrate. The present invention is described in detail below. (Manufacturing Law 1)

0 COOR ^

(IV)

(In the formula, R1 and R2 are each independently a lower alkyl group which may be substituted; R3 is an amine protecting group, R is a gas or residue protecting group, Y is a leaving group; X. is a counter ion) Compound (III) Compound (II-i) is obtained after reacting with compound (IV). Compound (III) can be synthesized according to the method described in the literature (for example, W09 8/25 935, JP 042 702 90, JP58041887, JP 59076088, etc.). 200404807 The solvents used in this reaction (reaction of compounds III and IV) are, for example, ethers (eg, dioxane, tetrahydrofuran, diethyl ether, tertiary butyl methyl ether, diisopropyl ether), and esters. (Example: ethyl formate, ethyl acetate, n-butyl acetate), halogenated hydrocarbons (example: dichloromethane, chloroform, carbon tetrachloride, 1,2-dichloroethane), ammonium (example: Formamidine, N, N-dimethylformamide (DMF), N, N-dimethylacetamide, N-methylpyrrolidone, n, N-dimethylimidazolidone (DM I)) Ketones (example: acetone, methyl ethyl ketone, methyl isobutyl ketone), nitriles (example · acetonitrile, propane), alcohols (methanol, ethanol, isopropanol, tertiary butanol ), Dimethylimine, water, etc. Alternatively, the compound (IV) may be used as a solvent. The amount of the compound (IV) to be used is usually about i to 5 times mole, preferably 1 to 3 times mole, relative to the compound (III). The reaction is usually carried out at a temperature in the range of -30 to 100 ° C, preferably -20 to 50 ° C. The reaction time ranges from tens of minutes to several + hours. Adding a halide (e.g., NaBr, KBτ, Nal, KI) or a thiocyanate (e.g., sodium thiocyanate, potassium thiocyanate) as a reaction accelerator to obtain a desired product of the reaction. When Y is a hydroxy group, for example, it is described in Japanese Patent Application Laid-Open No. 58-43979, and it is carried out in the presence of various organic phosphorus compounds, and the halogen is converted to thionyl chloride, phosphorus oxychloride, or phosphorus tribromide (examples: Cl, Br). Etc.), you can also perform the desired reaction. The compound (Π-1) having the amine group at the 3rd terminal and / or the 4th carboxyl group protected is treated with a deprotecting agent to obtain the compound (I) of the present invention. The deprotection reaction is carried out by the usual method of removing the protecting group. When the acidic conditions are deprotected, the organic acid (such as trifluoroacetic acid, acetic acid, formic acid, etc.), inorganic acid (such as hydrochloric acid, sulfuric acid, etc.), and Lewis acid In the presence of deprotection, -19-200404807 uses aluminum chloride, titanium tetrachloride, and the like. Anisole may also be added to the above deprotection reaction. And different from usual, it can also be inorganic acid-water-organic solvent (such as inorganic acid, hydrochloric acid, sulfuric acid, phosphoric acid, nitric acid, etc .; organic solvent, acetonitrile, acetone, methanol, ethanol, dioxane, dimethylformamide , Dimethylacetamide, etc.) or an organic acid-inorganic acid (such as acetic acid-sulfuric acid, formic acid, sulfuric acid, etc.) for deprotection. When the protection is performed under reducing conditions, various catalytic enzymes using metal reducing agents such as zinc are contacted for reduction. The preferred deprotection agent is a combination of organic acid-inorganic acid, especially a combination of formic acid and sulfuric acid. The yield of the deprotection step is preferably more than 40%, more preferably 60%. Compound (π-οκ is added to a formic acid solvent containing sulfuric acid to obtain compound (I). The preferred temperature range for this reaction is -10-50 ° C, more preferably 0-3 (TC temperature range, compared to formic acid, sulfuric acid is preferred). In order to use 0.1-3 times the amount, more preferably 0.3-1.5 times, the concentration of the sulfuric acid used is usually 10-9 8%, preferably 50-70%, and the reaction time is tens of minutes to A range of tens of hours. (Manufacturing Method 2)

(In the formula, R1 and R2 are each independently a substituted lower alkyl group; R3 is an amine protecting group; R4 is a hydrogen or carboxy protecting group; R5 is a hydrogen or amine protecting group; X · is a counter ion) • 20 -200404807 The compound (II) or a salt thereof (hereinafter collectively referred to as the compound (VI)) is reacted with the compound (VII) to obtain the present compound (II-2). The salts of the compound (VI) are the same as those of the compound (II). In the above reaction, it is desirable to use an appropriate condensing agent. For the condensing agent, for example, N, N'-dicyclohexylcarbodiimide, N, N '· carbonyldiimidazole, N, N, thiocarbonyldiimidazole, N-ethoxy Carbonyl-2-ethoxy-1,2-dihydroquinoline, phosphorus oxychloride, chloramphonium chloride, alkoxyacetylene, 2-chloropyridyl iron methyl iodide, 2-fluoropyridyl methyl iodide, methanesulfonic acid Rhenium chloride, trifluoromethanesulfonyl chloride, p-toluenesulfonyl chloride and the like. Examples of the reactive derivative of the compound (VII) include an inorganic base, an organic base, an acid halide, an acid azide, an acid anhydride, a mixed acid anhydride, an active amidine, an active ester, and an active thioester. For example, the inorganic base is an alkali metal (for example, Na, K, etc.), an alkaline earth metal (for example, Ca, Mg, etc.), and the organic base is trimethylamine, triethylamine, tributylamine, or tertiary butyl. Dimethylamine, dibenzylmethylamine, benzyldimethylamine, etc., acid halide is acid chloride, acid bromide, etc., mixed acid anhydride is monoalkyl carbonic acid mixed acid anhydride, aliphatic carboxylic acid mixed acid anhydride , Aromatic carboxylic acid mixed acid anhydride, organic sulfonic acid mixed acid anhydride, etc., the active amidine is a nitrogen-containing heterocyclic compound amidine. Active esters are organic phosphates (e.g. diethoxy phosphate, diphenoxy phosphate, etc.), p-nitrophenyl, 2,4-dinitrophenyl ester, cyanomethyl ester, and the like. The active thioester is, for example, an ester of an aromatic heterocyclic hydrogenthio compound (for example, 2-pyridinethioester, benzothiazolethioester, etc.). The solvent used in this reaction is the same solvent as listed in the aforementioned production method (1), and a solvent using the compound (VII) is more preferable. The amount of the compound (VII) to be used is usually about 1 to 5 moles, preferably about 1 to 2 moles relative to 1 mole of the compound (VI). The reaction is carried out at about -8 to 80 ° C, preferably in the range of about -20 to 40 ° C compared to 200404807. The reaction time ranges from tens of minutes to tens of hours. Compound (VI) is synthesized by reacting compound (V) with imidazo [4,5-b] pyridine (IV) or a salt thereof (hereinafter collectively referred to as compound (IV)). Compound (V) can be synthesized by a method described in a literature (for example, W08 6/03204, Japanese Patent Application Laid-Open No. 10-291993, etc.), and compound (IV) can be synthesized by a method described in a literature (WO00 / 32606, etc.). Examples of the salt of the compound (IV) include inorganic acid addition salts (eg, hydrochloride, hydrobromide, sulfate, nitrate, phosphate, etc.) or organic acid addition salts (formate, acetate) , Trifluoroacetate, methanesulfonate, etc.). The solvent used in this reaction is the same solvent as listed in the above-mentioned production method (1) ', and the compound (IV) may be used as a solvent. The compound (IV) is used in an amount of about 1 to 5 moles, preferably about 1 to 2 moles, relative to 1 mole of the compound (V). The reaction is carried out at a temperature 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-2) is the same as that of the aforementioned production method (1). (Manufacturing Law 3)

(VII)

C00R " (VI)

(I 3) 200404807 (wherein R1 and R2 are each independently a lower alkyl group which may be substituted; R3 is an amine protecting group; R4 is a hydrogen or carboxy protecting group; R5 is a hydrogen or amine protecting group; Ion) The compound (VI) or a salt thereof (hereinafter collectively referred to as the compound (VI)) is reacted with the compound (VII) to obtain the present compound (III-3). The salts of the compound (VI) are the same as those of the compound (II). In the above reaction, it is desirable to use a suitable condensing agent or a reactive derivative of the compound (VII). The solvent used in this reaction is the same solvent as that exemplified in the aforementioned production method (1), and the compound (VII) may be used as a solvent. The compound (VII) or a reactive derivative thereof is usually used in an amount of about 1 to 5 moles, preferably about 1 to 2 moles, with respect to the mole compound (VI) '. The reaction is carried out at a temperature 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 ammonium amination reaction is expected to proceed in the presence of bases. When using bases, it is better to use weak nucleophilic bases or bases without nucleophilicity. Is the particularly good base N-methyl? Porphyrinyl. The amount of the base used is usually about 1 to 5 moles, preferably about 1 to 3 moles, relative to 1 mole of the compound (VI). The amine group-protected compound (II-3) is treated with a deprotecting agent to obtain the present compound (I). The present compound (I) contains the same pharmaceutically acceptable salt or its solvate of the above production methods 1 and 2. The deprotection reaction is generally performed using a method (described in Production Method 1) to remove the existing protecting group, and an organic acid is used for deprotection under acidic conditions (for example, -23-200404807 trisacetic acid, acetic acid, formic acid, etc.), Inorganic acids (for example: hydrochloric acid, sulfuric acid, phosphoric acid, nitric acid, etc.), but different from usual, organic acids-water-organic solvents (such as organic acids, trifluoroacetic acid, acetic acid, formic acid, etc.); organic solvents, acetonitrile, acetone , Methanol, ethanol, isopropanol, dioxane, dimethylformamide, dimethylacetamide, etc.), inorganic acid-water-organic solvents (such as inorganic acid, hydrochloric acid, sulfuric acid, phosphoric acid, nitric acid, etc.); Organic solvent, acetonitrile, acetone, methanol, ethanol, isopropanol, dioxane, dimethylformamide, dimethylacetamide, etc.) or organic acid-inorganic acid (such as acetic acid-sulfuric acid, formic acid-sulfuric acid, etc.) ) For deprotection. Furthermore, a combination of organic acid-inorganic acid-water, organic acid-inorganic acid-water-organic solvent, or organic acid-inorganic acid-organic solvent may be used for deprotection. In the above deprotection reaction, a combination of an inorganic acid-water-organic solvent is particularly preferred. The inorganic acid is preferably hydrochloric acid and sulfuric acid, the organic acid is preferably dimethylacetamide, and the particularly preferred inorganic acid is sulfuric acid and organic. The solvent was acetonitrile. The yield of the deprotection step using the combination of the inorganic acid-water-organic solvent is preferably 40% or more, and more preferably 60% or more. It also has the effect of inhibiting the formation of isomers of compound VII. The suppression is preferably several% or less. For example, compound (II-3) is added with sulfuric acid in a water-acetonitrile solvent to obtain compound (I). Compared with lg compound (II-3), water is preferably 0.1 to 100 ml, and acetonitrile is preferably 0.1 to 100. ml, preferably 1 to 10 ml with individual solvents. 0.1 to 100 m of acetonitrile is used with respect to 1 m of water, and Inil acetonitrile is preferably used with respect to 1 ml of water. Relative to 1 equivalent of compound (11-3), the preferred sulfuric acid is 1 to 100 equivalents, more preferably 5 to 50 equivalents, and the concentration of sulfuric acid is usually in the range of 10 to 98%, preferably 50 to 70%. The concentration of sulfuric acid 200404807 used in the deprotection reaction varies depending on the amount of water-acetonitrile solvent. This reaction is preferably performed in a temperature range of -10 to 50 ° C ', more preferably 0 to 30 ° C, and the reaction time is tens of minutes to tens of hours. The present invention further provides a crystal of a compound represented by the following formula (Π-2-a) or a solvate thereof ^

OR

COO (II-2-a)

(Wherein R1 is ethyl; R2 is methyl; R3 is tertiary butoxycarbonyl).

The solvent contained in the crystal of the compound (Π-2-a) is, for example, water or an organic solvent (for example, acetonitrile, tetrahydrofuran (THF), dimethylformamide (DMF), acetone, acetic acid, methanol, ethanol, isopropanol, Methyl acetate, ethyl acetate, methyl ethyl ketone, diethyl ether, diisopropyl ether, di-alkane, toluene, dimethylacetamide (DMA), dimethyl sulfene (DMSO), etc.) . Water, acetonitrile, tetrahydrofuran, dimethylformamide, acetone and the like are preferable, and an arbitrary ratio containing these solvents is obtained. The solvent and number will vary depending on the type of solvent and cannot be specified overnight, but it is preferably 1 to 10 molecules. A particularly preferred combination containing a solvent is, for example, crystalline ①: THF-water, crystallization ②: only water , Crystallization ③: acetamidine-acetone, crystallization ④: water-acetone, others such as DMF-acetonitrile, DMF-acetone, water-acetonitrile, etc., but in terms of crystallization degree, crystallinity, handling and / or stability, etc. , Preferably crystalline ① or ②. Various crystal structures are characterized by, for example, a powder X-ray diffraction pattern (for example, a diffraction angle of 20 and a d between the plane lattice d). Among the crystals ① to ③ described above, each of the crystals is preferably -25- 200404807 from Example 1 3 to The X-ray diffraction patterns shown in Tables 2 to 4 of 1 5 or the present invention also provides crystals characterized by the X-ray diffraction patterns shown in Table 5. However, the measurement of the crystal structure may of course be subject to errors, and the present invention includes substantially the same X-ray pattern characteristics as described above. The method for producing the crystal of the compound (II-2-a) is not particularly limited. It is preferred that the non-crystalline form or crystal of the compound (II-2-a) is dissolved in water, an organic solvent, or a mixed solution thereof, and the desired compound is added. The preferred seed crystals are cooled from ice to room temperature, preferably from 0 to 10 ° C, and more preferably from about 5 ° C. After a few minutes to several hours of stirring, the precipitated crystals are filtered. It is preferably washed with ice-cold water, an organic solvent φ or a mixture thereof, and dried. The obtained crystals are further dried, for example, under reduced pressure or heating conditions, and it is possible to change crystals containing different solvents. In the case where a compound (II-2-a) is produced together with an isomer as a by-product, there is also a concern that the compound (I) may be mixed. However, in order to separate the crystals of (Π-2-a) ', it is preferable to perform complicated purification means such as column treatment to obtain the compound (I) with high purity. In addition, the preferred crystals of compound (Π-2-a) or its solvate are more stable than those without crystals. Therefore, deprotection of the compound according to the aforementioned reaction conditions can produce a high-yield, high-purity corresponding saphene compound (1 ), Its salts or solvates, which are very useful as intermediates in industrial production. Examples of the pharmaceutically acceptable salt of the compound (I) include salts formed from inorganic bases, ammonia, organic bases, inorganic acids, organic acids, basic amino acids, halide ions, or intramolecular salts. The inorganic base is an alkali metal (Na, K, etc.) and an alkaline earth metal (Mg, etc.). Examples of the organic base include procaine, 2-phenylethylbenzylamine, dibenzylethylenediamine, Ethanolamine, diethanolamine, trihydroxymethylamine methane, polyamines, N-methylglucosamine, etc. Inorganic acids are, for example, hydrochloric acid, hydrobromic acid, -26-200404807 sulfuric acid, nitric acid, phosphoric acid, and the like, and organic acids are, for example, P-toluenesulfonic acid, methanesulfonic acid, formic acid, trifluoroacetic acid, maleic acid, and the like. Examples of the basic amino acid include lysine, arginine, ornithine, and histidine. It is preferable to deprotect the compound (Π) in the presence of sulfuric acid to obtain a sulfate salt of the compound (e.g., 0.5 sulfate salt, 1 sulfate salt), and the sulfate salt may also be converted into other salts. (Abbreviation) HP-20SS = DIAION exchange resin (Mitsubishi Chemical); Me = methyl; Et = ethyl; Boc = tertiary butylcarbonyl; PMB = ρ · methoxymethyl; DMF = dimethylformamidine Amine; DMI = 1,3-dimethyl-2-imidazolidinone; HPLC = high-efficiency liquid chromatography; BH = benzhydryl; DMA = dimethylacetamide; TMS = trimethylsandamine ; TMSI = Iodine Trimethyl Shi Xi Yuan; HMDS = Hexamethyl Disarza Nitrogen; THF = Tetrahydrofuran. Example 1

(A) To 4.0 g (18.5 mmol) of (5-amino [1,2,4] thiadiazol-3-yl) ethoxyiminoacetic acid (1) was added 16 ml of DMI and 64 ml of acetic acid. Ethyl acetate and 7.9 g (19.6 mmol) of 7々 · amino-3-chloromethyl isomer. 3. · Fen-4-carboxylic acid-P-methoxybenzyl ester hydrochloride (2) under nitrogen Flow down and stir with -10 mol. Add 1.9 ml (21 mmol) of phosphorus oxychloride to this suspension, and then dropwise add 8. 2 m 1 (7 4 · 5 mmol) of N-methyl The morpholine was stirred for 1 hour. -27- 200404807 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 a 5% sodium hydrogen carbonate aqueous solution and 1 5 · 7 m 1 of water, and then washed with 39.4 ml of ethyl acetate. Each aqueous layer was extracted, and the organic layer was combined, and the solvent was distilled off under reduced pressure. The concentrated solution was crystallized from a mixed solution of acetonitrile and tertiary butyl methyl ether, and the crystals were collected by filtration and dried to obtain 9.9 g (yield 94.3%) of the compound (3). Melting point: 100 ° C, 1H-NMR (CDC13): (5 1.33 (t, 3H, J = 7Hz, Et), 3.47, 3.67 (dd, 2H, J = 18Hz, -SCH2-), 3.8 1 (s, 3H, -OCH3), 4.3-4.6 (m54H, -CH2Cl, Et), 5.07 (s, 1H, C6-H), 5.22 (s, 2H, -CH2Ar), 6.10 (m, 1H, C7- H), 6.50 (s, 2H, -NH2), 6.8-7.4 (m54H, Ar), 7.93 (d, 1H, J = 9Hz, -CONH-) 〇 (B) Will be obtained by (A) 23.65g ( 41 mmol) compound (3) was dissolved in 26.9 ml of DMF, 6.97 g (67.7 mmol) sodium bromide was added at room temperature, and 12.82 g (44.2 mmol) (3- Imidazolo [4,5-b] pyridin-1-yl-propyl) methylcarbamic acid tert-butyl ester (4), stirred at 5 ° C for 21 hours. To this reaction solution was added 6 7 · 2ml After acetonitrile, it was dropped into 45 9.6 ml of methyl isobutyl ketone cooled at 5 ° C, and the slurry was liquefied. After stirring at 5 ° C for 30 minutes, the precipitate was filtered and dried under reduced pressure to obtain 3 7 · 8 3 g of crude solid (5). Example 2 200404807

1 / 2H2S04 3 7 · 8 g (4 1 · 9 mmol) of the compound (5) obtained in Example 1 was dissolved in 6 1.1 ml of HCOOH, and ice-cold 77.8 g (491.9 mmol) of 62% H2S04 was added. After stirring at the same temperature for 2 hours, the reaction solution was dropped into 768 ml of ice-based isopropyl alcohol, and the precipitate was filtered and dried to obtain 33.2 g of a crude solid (6) (HPCL purity 82%). This crude solid was dissolved in 66.4 ml of distilled water, adjusted to pH 4 to 5 with an aqueous sodium hydroxide solution, and subjected to column chromatography of 3 68 ml of synthetic adsorption resin HP-2 OSS. After washing and eluting with 5% acetonitrile / water, the effective area was concentrated under reduced pressure to 15.5 g. This concentrated liquid was dropped into 480 ml of cold isopropyl alcohol. The precipitate was filtered and dried to obtain 18.1 g. Compound (6) (yield, 66.5% from (3)). HPLC purity 980 / 〇 (Shimadzu LC-10CLASS-VP, column Waters-COSMOSIL-5C18-AR: 4.6xl50mm). 1H-NMR (DMSO-d6): δ 1.1.1 (15 3 H 5 J = 7 Η z 5 E t), 2.1 5-2.3 0 (m, 2H, -CH2-) 52.8-2.9 (m, 2H , -CH2-), 4.10 (q, 2H, J = 7Hz, Et) 5 4.55-4.65 (m, 2H, SCH2-), 5.04 (d, lH, J = 5Hz, C6-H), 5.55-5.75 ( m, 3H, C7-H, NCH2-), 8.12 (s52H5NH2) 59.45 (S, lHrCONH-), 7.86, 8.96, 9.15, 9.45 (4Η). Example 3 -29- 200404807 h2n-41 0 κοι

Et

C00R 7a: Z = NH2 Y = OH R = H 7b: Z = NH2 · HC1 Y = C1 R = BH Η2Ν ^ > ^ Λ

COOBH OH Cl 8 -► 9 Q --1 〇 Y = OH Y = C1 Y = 〇H Y = Br

(A) Dissolve 2.27 g (10.5 mmol) of compound (i) in a DMI solution of 141111, and sequentially drop i 64 g (l5.6 mmol) of methylsulfonium chloride and 1.97 g (19.5 Mmol) triethylamine, and stirred under ice-cooling for 1 hour. In a separate container, pour 2 · 3 0 g (1 0 · 0 mmol) of 7 cold-amino-3 -hydroxymethylsai-3-fen-4-carboxylic acid (7a) and 9.9 ml of acetonitrile. 13.1 η] of water, was added to 〇c cold 2.23 g (22.0 millimoles) triethylamine, and stirred at the same temperature. In 30 minutes, the mesylate salt solution of (1) was dropped into the previously prepared mixture, and the mixture was stirred under ice-cooling for 1 hour, and then 2.9 5 g (1 5.7 5 mmol) of diphenyl was added under ice-cooling. A solution of diazomethane in 25 ml of ethyl acetate, followed by the dropwise addition of a 2N-HC1 aqueous solution, adjusting the pH to 4 to 5 and stirring under ice-cooling for 2 days. The reaction solution was extracted with a mixture of ethyl acetate and water, in order The ethyl acetate layer was washed with dilute hydrochloric acid and water, dried under anhydrous sulfuric acid, and the solvent was distilled off under reduced pressure. Diisopropyl ether was added to the residue, and the precipitated slurry was filtered to obtain 4.85 g of compound (8) ( Yield: 81.5%). iH-NMIUCDCls): ^ 1.33 (t, 3H, J = 7Hz), 3.59 (s, 2H), 3.98-4.44 -30- 200404807 (m, 4H), 5.06 (d, lH5J = 5Hz), 6.14 (dd, lH, J = 5,9Hz), 6.42 (s, 2H), 6.92 (s, lH), 7.2-7.4 (m, 10H), 7.92 (d, lH, J = 9Hz) IR (N ujol): 3414, 3261, 3 171, 1 790, 171 7, 1676, 1 377, 1066cnr] FABMS (m / z): [M + H] + 5955 [2M + H] + 1189 (B) 2.0 g of compound (A) will be obtained from (A) ( 8) After cooling 26 ml of tetrahydrofuran solution at -30 ° C, 52 // 1 (0.67 mmol) of DMF and 3 89 // 1 (5.04 mmol) of thionyl chloride were sequentially added dropwise, and the reaction solution was dropped. After stirring at -30-3 ° C for 4 hours, the mixture was extracted with a mixture of ethyl acetate and water. The ethyl acetate layer was washed with dilute hydrochloric acid and water in that order, 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 the compound (9). Melting point: 1 111: iH-NMRCCDCl,): ^ 1.34 (t, 3H, J = 7Hz5Et), 3.49, 3.66 (dd, 2H, J = 18Hz, -SCH2-), 4.3-4.5 (m, 4H,- CH2Cl, Et), 5.11 (d, 1H5J = 5Hz, C6-H), 6.1-1.26 (m, 1H, C, 7-H), 6.48 (s, 2H, -NH2), 6.97 (s5lH, -CH- ), 7.2-7.4 (m, l OH, Phx2), 7.96 (d, lH, J = 9Hz, -CONH-) IR (Nujol): 33 1 5, 3206, 1780, 1 726, 1679, 1377, 1040cm · 1. FABMS (m / z): [M + H] + 6 13, [2M + H] + 1 225. (C) 38 ml of DMI, 153 ml of ethyl acetate and 20 g (44.3 mmol) of 70 -Amino-3-chloromethylsai-3-fen-4-carboxylic acid benzotoluate hydrochloride (7b) was added to 9.58 g (44.3 mmol) of compound (1) under nitrogen flow_ Stir at 10 ° C. Add 4.5 ml (48.7 mmol) of phosphorus oxychloride to this suspension, and then dropwise drop in 19.5 ml of N · methylmorpholine at -15 ° C to -5 ° C over 1 hour, and stir at the same temperature for 1 · After 5 hours, the reaction solution was cooled and extracted with 60 ml of water and 2 ml of 200404807 concentrated sulfuric acid. The organic layer was washed with 40 m 1 5% aqueous sodium hydrogen carbonate solution and 40 m 1 water, and the aqueous layers were extracted with 100 ml of ethyl acetate. The organic layer was distilled to remove the solvent under reduced pressure. The concentrated solution was crystallized with a mixed solution of ethyl acetate and toluene, filtered and dried to obtain 28.8 g of the compound (9). (D) After cooling 16 ml of a tetrahydrofuran solution of compound (8) obtained in 2.0 g (3.36 mmol) of (A) at -5 1 ° C, drop in 144 at -51 to -38 ° C over 16 minutes // 1 (1.51 millimolar) phosphorus tribromide in 1 ml of tetrahydrofuran solution. The temperature was raised to -2.5 ° C over 1 hour, and the mixture was stirred under ice cooling for 19 hours and 49 minutes. The reaction solution was extracted with ethyl acetate and ice water. 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 acetonitrile and water. This slurry was filtered to obtain 1.91 g. (Yield: 86%) of the compound (10). ln ^ UR (COC \ 3): δ 1.34 (t53H5J = 7Hz, Et) 53.46-3.74 (m52H5-SCH2-), 4.24-4.44 (m, 4H, -CH2Br, Et), 5.12 (d, lH, J = 5Hz, C6-H), 6.12 (dd, 1H, J = 5,9Hz, C7-H) 56.47 (s, 2H, -NH2), 6.99 (s, 1H, -CH-), 7.2-7.4 (m, 10H, Phx 2), 7.95 (d, lH, J = 9Hz, -CONH-) FABMS (m / z): [M + H] + 657, [2M + H] + 1313 (E) will be 5g (8.16 millimeters) Mol) in compound (9) obtained in (C) was dissolved in 7 ml of DMF '. At room temperature, i.68 g (16.3 mmol) of sodium bromide was added, and 2.29 dissolved in 4.2 ml of DMF was added under ice-cooling. g (8.16 mmol) of compound (4), and stirred at 5 ° C for 20 hours and 30 minutes. 19 ml of ethyl acetate was added to the reaction solution, and 1 1 4 ml of ethyl acetate cooled at 5 ° C was added dropwise while stirring at high speed to make a slurry. After stirring at 5 ° C for 30 minutes, the precipitate was collected by filtration and dried under reduced pressure to obtain 7.5 g (yield 97%) of a crude solid (1 1). 1H-NMR (DMSO-d6): δ 1.19 (t, 3H, J = 4.2Hz, Et), 1.31 (s, 9H, t_ -32- 200404807

Bu), 2.02-2 "0 (m, 2H, -CH2-), 2.87 (s, 3H, N-CH3), 4.13 (q, 2H, J = 4.2Hz, Et), 4.3 8-4.50 (m, 2H, S-CH2), 5.12 (d, 1H, J = 4.8Hz, C6-H), 5.55 (m, 1H, C7-H), 5.90-6.10 (m, 4H, N-CH2x2), 6.95 (s , 1H, -CH-), 7.20-7.52 (m, 10H, Phx2), 8.1 3 (m, 2H, -NΗ2), 7.93, 8.83, 8.98, 9.60 (4Η) · Implementation Example 4

C00BH N ^ N ^^^ v ^ NMeBoc

COO " N ^ N > ^^ NHMe 1 / 2H2S04 5 g (5. 27 mmol) of the compound (1 1) obtained in Example 3 was dissolved in 10 ml HCOOH, and 8.34 g (52.7 mmol) was added under ice cooling. ) 62% H2S04, stirred at the same temperature for 2 hours, this reaction solution was dropped into i 50 ml of isopropyl alcohol, and the precipitate was filtered and dried to obtain 2.0 g of purified solid of compound (6) (yield 58%). HPLC purity 92% 1H-NMR (DMSO-d6): 5 1. 1 8 (t, 3 H, J = 7 Η z 5 E t) 5 2. 1 5-2.3 (m52H5-CH2-), 2.8-2.9 (m, 2H, -CH2-), 4.10 (q, 2H, J = 7Hz, Et), 4.5 5-4.65 (m, 2H, -SCHr), 5.04 (d, 1H, J = 5Hz, C6 -H), 5.55-5.75 (m, 3H, C7-H, -NCH2-), 8.12 (s, 2H, -NH2), 9.45 (s, 1H,-CONH-), 7.86, 8.96, 9 · 15,9 · 45 (4Η) 200404807 Example 5

(A) In 42 ml of 1,2-dichloroethane and 6.0 g (22 mmol) of -amino-3 -ethoxymethylmethyl-3 -fen-4 -carboxylic acid (Compound 1 2 ) Suspension was added with 10.68 g (66 millimoles) of hexamethyldisilazane and 43 mg (0. 02 equivalent) of sulfuric acid, and stirred at room temperature for 30 minutes, then the temperature was increased, and refluxed 2 hour. Cool at 5 ° C, drop 5.64 ml (39.6 mmol) of iodotrimethylsilane in 10 ml of 1,2-dichloroethane.ane solution over 10 minutes, and stir at the same temperature for 5 hours. A dark reddish brown suspension solution was obtained. After the suspension was left at -20 ° C for 15 hours, the solvent was distilled off under reduced pressure to obtain Compound (1 3) 2 4 g. (B) To 24 g of compound (13) obtained from (A), add 40 ml of acetonitrile and 11.7 g (3 9.6 mmol) of compound (4), and stir at 5 ° C for 5 hours. 100 ml of isopropyl alcohol cooled at ° C was dropped into the reaction solution, and after stirring at 5 ° C for 30 minutes, the precipitate was filtered and dried under reduced pressure to obtain 11.3 g (yield from (12) of 82 %) Of crude solid. 'H-NMRiDMSO-dJ: ^ 1.35 (s59H? -C (CH3) 3) 52.05-2.20 (m52H? -CH2-), 2.80 (s.3H, -NCH3), 3.2-3.3 (m, 2H, -CH2 -), 4.48 (s, 2H, -SCH2-), 4.81 (d, lH, J = 5Hz, C6-H), 4.92 (d, lH, J = 5Hz, C7-Η), 5.60, 5.97 ( dd, 2H, J = 14Hz,--34- 200404807 NCH2-), 7.98, 9.03, 9.1 0, 9.14 (4H) (C) 3.15 g (5 mmol) of the compound (B) was dissolved in (14) Ice-cold 9.5 ml of methanol and 2.63 ml (11 mmol) of tributylamine. In another reaction vessel, 1.3 g (6 mmol) of the compound (1) was dissolved in 13 ml of dimethylacetamidine. In amine, add 0.56 ml (7.2 mmol) of methanesulfonyl chloride and 2.15 ml (9 mmol) of tributylamine under ice cooling, stir under ice cooling for 1 hour, and cool this under ice cooling for 20 minutes. The solution was dropped into a previously prepared raw material solution, and after stirring for 1 hour under ice-cooling, 150 ml of ethyl acetate was added dropwise at room temperature to precipitate a precipitate. The precipitate was filtered off and dried to obtain 4.47 g of a crude solid (1 5 ). ^ -NMRCDMSO-d,): 5 1. 1 8 (t? 3 H 5 J = 7 Η z 5 E t)? 1. 3 3 (s 5 9 Η 5 -C (CH3) 3), 2.05-2 , 20 (m52H, -CH2-), 2.78 (s, 3H, -NCH3), 2.9 5-3.05 (m, 2H5-CH2-), 4.10 (q, 2H, J = 7Hz, Et), 4.46 (s, 2H, -SCH2-), 5.03 (d, 1H, J = 5Hz, C6-H), 5.6-5.8 (m, 3H, C7-H, -NCH2-), 8.11 (s, 2H, -NH2), 9.56 (s, 1H, -NΗ-), 7.98, 9.03, 9.10, 9.14 (4Η) Example 6

N ^ N ^ x ^ NHMe 1 / 2H.S0, dissolve L92g of the compound (15) obtained in Example 5 in 3.75ml of HC00H, and add 1.64g (10,7 mmol) of 62% H2S04 under ice cooling. Fang Ling stomach? Stir for 1 hour on a pan. This reaction solution was dropped into 75 ml of ice-cold isopropyl alcohol ', and the deposited precipitate was filtered and dried to obtain 1.5 9 g of a crude solid. -35- 200404807 This crude solid was dissolved in 4.5 ml of distilled water, the pH was adjusted to about 4 with an aqueous solution of sodium hydroxide, and column chromatography was performed with 25 ml of HP-2 0SS, and washed with 3% acetonitrile / water to 3.8 g. The effective zone was concentrated under reduced pressure. The concentrated solution was dropped into 45 ml of cold isopropyl alcohol, and the precipitate was filtered and dried to obtain 0.68 g (yield, from (14)) of a pure solid of compound (6). 49%). HPLC purity 92%.

'H-NMRCDMSO.dJ:^ 1.18 (t53H5J = 7Hz, Et) 52.15-2.30 (m, 2H, -CH2-), 2.8-2.9 (m, 2H, -CH2-), 4.10 (q, 2H, J = 7Hz, Et), 4.55-4.65 (m, 2H, -SCH2-), 5.04 (d, 1H, J = 5Hz, C6-H), 5.55-5.75 (m, 3H, C7-H, -NCH2-), 8.12 (s, 2H, -NH2), 9.45 (s, 1H,-CONH,), 7.86, 8.96, 9.1 5,9.45 (4H).--. Example 7

NMeBoc (A) in 3.24 g (15.0 mmol) of compound (1) in 14.2 ml of DMI solution was sequentially dropped into 1.40 ml (18.0 mmol) of ice-cold methanesulfonyl chloride and 3.14ιη1 (18 · 0 Millimoles) of triethylamine. The reaction solution was stirred with (5-amino- [1,2,4] thiadiazol-3-yl) ethoxyimine methanesulfonate solution under ice-cooling for 1 hour -36-200404807. To an aqueous solution of 2.72 g (1.0 mmol) of compound (12) in a suspension of 17.0 water and 11.0 acetonitrile was added ice-cooled an aqueous solution of sodium carbonate (0.64 to 6.0 mmol). 10% sodium carbonate aqueous solution 1 Inil and the sulfonate solution prepared above were added dropwise to the suspension at the same time. 60 ml of ethyl acetate and concentrated sulfuric acid were added to the reaction for extraction, and the extract was washed twice with water. It was dried and concentrated under reduced pressure to obtain 4.43 g (94.0%) of the compound (16). Compound (16) was recrystallized from ethyl acetate-DMI to obtain crystals of 1,3-dimethyl-4-imidazolidinone solvate. C14H1807N6S2 2DMI (FW 6 9 8.78)

Mp.l25-131 ° C 'H-NMRiDMSO-dJ: ^ 1.25 (t53H5J = 6.8Hz) 52.03 (s53H), 2.63 (s, 12H) 53.20 (s, 8H), 3.44-3.66 (m52H), 4.18 (q , 2H, J = 6.8Hz), 4.65-5.00 (m, 2H), 5.15 (d, lH, J = 4.8Hz), 5.83 (dd, lH, J = 4.8.8.7Hz), 8.13 (s, 2H), 9.54 (d, lH, J = 8.7Hz)

Compound (16) was recrystallized from acetonitrile-sodium bicarbonate water to obtain 1.5 H20 sodium 〇 Elemental analysis ChHuCMSaNai * 1.5H20 (FW.519.49)

Calculate 値 C: 36.99, H: 3.88, N: 16.18, S: 12.34, Na: 4.43, Η20: 5 · 20 Measured 値 C: 36.79, H: 3.88, N: 16.48, S: 12.47, Na: 4.44, H20 : 5.38 mp.> 230 ° C (B) At room temperature, 1.0 g of the compound (16) obtained in 10 ml of 2-37-200404807 chloroform institute suspension was dropped at room temperature. Into 1.22ml (6.58 millimoles) of methyl trimethyl sand ik-based difluoroacetamidine, and stir at the same temperature as the drip for 丨 hours, then add 0.70ηι1 (4.494 millimoles) of iodine After trimethylsilane was stirred at the same temperature for 1 hour, the solvent was removed under reduced pressure to obtain 2.8 g of an oily compound (17). 2.8 g of the obtained crude (17) was dissolved in 5.0 ml of acetonitrile and 0.58 ml of tetrahydrofuran, and stirred under ice-cooling, '95 6 mg (3.29 mmol) of compound (4) was added, and stirred at the same temperature for i night '. The precipitate precipitated from the ethyl acetate-methanol mixed solution was filtered and dried under reduced pressure to obtain 1.26 g of the compound (15) ΗI salt (yield, from (1 2) 92 2%). Example 8

6 COO '1 / 2H2S04 Dissolve 1.2 g of the compound (15) obtained in Example 7 in 2.4 ml of HCOOH, add 62.40% H2SO40.92 g (5.8 mmol) under ice cooling, and stir at the same temperature for 1 hour. This reaction solution was dropped into 48 ml of ice-cold isopropyl alcohol, and the precipitate was filtered and dried to obtain 1.2 g of a crude solid. This crude solid was dissolved in 3.0 ml of distilled water, and the pH was adjusted with an aqueous sodium hydroxide solution.値 is about 4, and concentrated to 2.3 g under reduced pressure. This concentrated solution was dropped into 28 ml of cold isopropyl alcohol, and the precipitate was filtered and dried to obtain 0.46 g of a purified solid (yield, 36% from (12): HPLC quantification 値). 'H-NMRCD ^): ^ 1.30 (t53H? J = 7.0Hz)? 2.41 (m? 2H)? 2.73 (s, 3H), 3.17 (t.2H, J = 8.0Hz), 3.33 (d, lH, J = 18.2Hz), 3.65 (d, lH, J = 18.2Hz), 4.33 (q, 2H, J = 7.0Hz), 4.64 (t, 2H, J = 7.3Hz -38- 200404807), 5.25 (d, lH, J = 4.8 Hz), 5.70 (d, lH, J = 14.8 Hz), 5.88 (d, lH, J: = 4.8 Hz), 5.93 (d, l H, J = 14.8 Hz), 7.89 (dd, lH, J = 6,4Hz, 8.2Hz), 8.82 (d, lH, J = 8.2Hz), 8.85 (d, lH, J = 6.4Hz), 8.89 (s, lH) Reference example 1 a

nh2 18

To 106.5 g (38.0 mmol) of compound (18) at room temperature was added 1.4 g of p-toluenesulfonic acid monohydrate, and at this temperature, 100 · 8 g (9 5 · 0 mmol) was added. Ear) Trimethyl orthoformate. After the temperature was raised to 90 ° C and stirred for 3.5 hours, it was cooled to room temperature and concentrated under reduced pressure. 120 ml of ethyl acetate was added to the concentrate, and 72 ml of the solution was dropped into the solution under room overflow. Hexane was vigorously stirred for 30 minutes, and the precipitated crystals were collected by filtration and dried to obtain 103.8 g (yield 94.1%) of a white crystalline compound ⑷.

'H-NMRCCDC ^) ^ 8.59 ((1, J = 4.5? 1H) 38.20 (s51H)? 7.73 (dd5 J = 8.1, 1.5, lH), 7.25 (dd, J = 8.7, 5.1, lH), 4.22 ( t, J = 7.2, 2H), 3.3 2 (brs, 2H), 2.85 (s, 3H), 2.12 (tt, J = 13.8, 6.9), 1.44 (s, 9H) Elemental analysis c15h22n4o2 Calculate 値 C, 62.05; H, 7.64; N, 19.30; O, 11.02 Measured 値 C, 61 · 96; Η, 7.49; Ν, 19 · 42 The powder X-ray diffraction pattern of compound (4) is shown in Figure 1, Its representative high-39- 200404807 peak is described in Table 1. X-ray measurement conditions: tube bulb Cu (wavelength λ = 1.5405 1 A), tube voltage 30Kv tube current 15mA, dsin0 λ (η is an integer, 0 is around Shooting Angle) (Table 1 -0 85315733609067499503434 16 15557288530428694694148264 -θ-1 3456788901223345891147 8 j OQ ~ · * ~ J t—ii—ir—l-^^ 1 ± 1 ± oxw 00 00 00 oo 00 d

A 2 18069517272722133651294 670 7 39874310987641088633 -7 66554444444333333322222% _ / fv degree strong opposite phase 18 90818995200909266667667 wide] lx w—x 1x 1x i »x 1x Hi

Reference example 2 S-N Η

Nk 1 COOH (COCI) 2 OEt

43.2 g (0.2 mole) of compound (1), 200 ml of dichloromethane, 0.8 ml (l -40-200404807 pen; 旲 ear) of DMF were stirred at -10C for 40 minutes at the same temperature. 2 0.91111 (0.24 moles) chloramphenicol. After stirring the reaction solution at the same temperature for 1 hour, the precipitated crystals were filtered and dried under reduced pressure to obtain 43.3 g of compound (19) (yield 80%) ° Elemental analysis C6H702SC1 HC1 (FW. 271.12) Calculate 値 C: 26.58, H: 2.97, N: 20.66, S: 11.83, C1: 26.15 Measured 値 C: 26.50, H: 2.96, N: 20.13, S: 11.23, C1: 25.49, H2〇: 0.8 8 Example 9

5 In a suspension of 6 ml of 1,2-dichloroethane and 7.0 g (24.9 mmol) of compound (12), force D into 10.4 ml (49.8 mmol) of HMDS and 49 mg (0.02 equivalent) of sulfuric acid. After flowing for 2 hours, after cooling, 6.41111 (44.8 millimoles) TMSI was added dropwise within 10 minutes, and the temperature was changed from 10 to 1 hour. (: Raise to 20 t: After that, 2.4 ml (29.9 mmol) of ice-cold tetrahydrofuran was added dropwise at 5 ° C for 5 minutes, and then 8 · 6 g (2 9 · 9 mmol) obtained in Reference Example 1 was added dropwise. Mol) Compound (4) was added, and after stirring at 5 ° C for 4 hours, it was left to stand at the same temperature for 16 hours. Put 1, 2-dichloroethane 4 0 m 1 and methanol 1 4 in other containers. Cool at -30 ° C. Then add the reaction solution, and add 7.4 g (2 7.4 mmol) of compound -41- 200404807 (19) at the same temperature, followed by 5 minutes at the same temperature. 6.8 ml (62.2 mmol) of N-methylmorpholine was added dropwise over time, and the mixture was stirred at the same temperature for 1.5 hours, and then stirred at 0 ° C for 1 hour. The precipitate was filtered and dried under reduced pressure to obtain compound (15) HI. 25.8g of salt powder, 72% purity by HPLC. Example 1 〇

10 g of the compound (15) HI salt obtained in Example 9 was dissolved in a mixed solution of 40 ml of water and 40 ml of acetonitrile, and 62% 1123〇42 8.6§ (0.18 mol) was added under ice cooling, and the mixture was stirred at room temperature for 4 hours. 90 ml of 4N-NaOH aqueous solution was added dropwise to the reaction solution under ice-cooling within 1 hour, the pH was adjusted to 4 and concentrated under reduced pressure. The column was subjected to column chromatography analysis, washed with water, 4% acetonitrile / water, and concentrated under reduced pressure to 19.4 g. The concentrated solution was dropped into 240 ml of cold isopropyl alcohol, and the precipitate was filtered out. And dried to obtain 4.4 g of purified solid of compound (6) (yield 55% from compound (12)). HPLC purity 92%. iH-NMR ^ O): ^ 1.30 (t, 3H, J = 10Hz, Et), 2.3-2.5 (m, 2H, -CH2-), 2.73 (s, 3H, -NMe), 3.1-3.2 (m, 2H, -CH2-), 3.3, 3.65 (Abq, 2H, J = 18Hz, -SCH2-), 4.32 -42- 200404807 (q, 2H, J = 7Hz, Et), 4.6_4.66 (m, 2H5- CH2-), 5.24 (d, lH, J = 5Hz, C6-H), 5.63, 5.90 (Abq, 2H, -CH2N-), 5.85 (d? LH5C7-H)? 7.9, 8.7-8.9 (m? 4H) Example 1 1

14

Boc (A) was charged with 8-9 g (55.1 mmol) of HMDS and 72 mg (0.02 equivalent) of sulfuric acid in a suspension of 80 ml of 1,2-dichloroethane and 10.0 g (36.7 mmol) of compound (12). After 4 hours of reflux, cool and drip 9.4ml (66.1 millimoles) of TMSI in 3 minutes of TC. Increase the temperature from 10 in 1 hour (: increase to 20 ° C, and then, 5 ° C for 5 minutes 8.9 ml (110 millimoles) of tetrahydrofuran was added dropwise, and after stirring at 5.0 for 6 hours, it was allowed to stand at the same temperature for 16 hours. This reaction solution was dropped into 500 ml of ethyl acetate over 2 minutes. In a mixed solution with 25 ml of methanol, stir for 30 minutes at the same temperature, filter out the precipitated precipitate, and dry under reduced pressure to obtain 23.2 g of compound (14) (100% yield from compound (12)). 43- 200404807 HPLC purity 70%. ^ -NMFUDMSO-ddJlJSOJH, -C (CH3) 3)? 2.05 -2.20 (m? 2H? -CH2-)? 2.8 0 (s53H? -NCH3)? 3.2-3.3 (m, 2H, -CH2-), 4.47 (s52H, -SCH2-) 54.8 1 (d, 1H, J = 5Hz 5C6-H), 4.92 (d, 1H, J = 5Hz, C7-H), 5.60, 5.97 (dd, 2H, J = 14Hz, -NCH2-), 7.98, 9.03, 9.1 0, 9.14 (m, 4H) (B) 10 g (46 mmol) of compound (1) and 50 ml of two The suspension of methane was cooled, 4.8 ml (55 mmol) of chloramphenicol and 0.34 g (0.1 equivalent) of DMF were added, and the mixture was stirred at 0 ° C for 1 hour. 7.7 g (46 mmol) of 2-hydrothiothiobenzene The solution of benzothiazole (21) and 40 ml of dichloroformamidine and 12.6 ml (115 mmol) of N-methylmorpholine was cooled, and the reaction solution adjusted in advance was dropped at 0 ° C for 30 minutes. At the same temperature for 1 hour After stirring for a while, 500 ml of ethyl acetate and 150 ml of water were added for washing. The organic layer was washed with 100 ml of water, and the aqueous layer was extracted with 100 ml of ethyl acetate. The organic layer was combined, dried over magnesium sulfate, and concentrated under reduced pressure. 50 ml of acetamidine was added to 18.3 g of the crystalline residue, and the crystals were filtered and dried to obtain 1 3.6 g (yield 81%) of the compound (2 2). OH-NMR (CDC13): (5 1 .38 ( t53H? J = 7Hz? Et)? 4.41 (q52H5 J = 7Hz, Et), 6.59 (s, 2H, NH2), 7.4-8.1 (m, 4H) (C) 3.1 5g (5) obtained by (A) To the solution of compound (14) with 20 ml of dichloromethane and 0.55 ml (5 mmol) of N-methylmorpholine, add the compound (22) obtained in (B) 1.83 under ice cooling. g (5 millimolar) and stirred at the same temperature for 4.5 hours. The reaction solution was added to 100 ml of ethyl acetate and stirred at room temperature for 1 hour. The precipitated precipitate was filtered and dried to obtain 4.23 g of the HI salt of the compound (15) as a powder. HPLC purity 69%. 200404807 Example 1 2 1.66 g (2 mmol) of the compound (i 5) H i obtained in Example 11 was dissolved in a mixed solution of 6.6 ml of water and 6.6 ml of acetonitrile, and under ice-cooling, 4.74 was added. g (30 mmol) 6 2% H 2 S 0 4, and stirred at room temperature for 3 hours. Under water cooling, this reaction solution was dropped into a 4N-NaOH aqueous solution, adjusted to pH 4 and concentrated under reduced pressure. This 40g concentrated solution was packed in a 20ml synthetic sorption resin HP-2 OSS 塡 packed column for column chromatography, washed with water, 4% acetonitrile / water, and concentrated under reduced pressure to 3g. The liquid was dropped into 40 ml of cold isopropyl alcohol, and the precipitate was collected by filtration and dried to obtain a purified solid of compound (6) (K71 g (yield: 5 6% from compound (12)). 1 ^! ^ (: Purity 92%.] 1 ^ 1 ^ 11 (01 ^ 30-(! 6): 5 1.1 8 (153 H? J = 7 H z 5 Et) 5 2.1 5-2.3 0 (m? 2H? -CH2-) 52.8-2.9 (m? 2H? -CH2-) 54.10 (q? 2H, J = 7Hz, Et), 4.55-4.65 (m, 2H, -SCH2-), 5.04 (d, lH, J = 5Hz, C6- H)? 5.55-5.75 (m? 3H? C7.H? -NCH2-), 8.12 (s52H, -NH2) 5 9.45 (s, 1H5-CONH-), 7.86, 8.96, 9.15, 9.45 (m, 4H)

Reference example 3

(II-2-a) Boc = -COOC (CH3) 3 -45- 200404807 According to the following method, Compound 15 (Compound 11-2-a) described in Example 5 with high purity was obtained. 30g of compound (Ia) synthesized according to the method described in WO00 / 3 2606 or the 41st ICAAC Proceedings (December 16-19, 2001, Chicago, USA, Lecture No. F-3 70) (39.8 millimoles, 1 sulfate and 3 crystals) In a suspension of 150ml of water, 5.23g (62.1 millimoles) of sodium bicarbonate was added to dissolve. To this aqueous solution, a solution of 10.42 g (47.8 mmol) of di-tertiary-butyl dicarbonate in 300 ml of acetonitrile was added at 25 ° C. At the same temperature for 5 hours, the mixed solution was kept at pH 7.0-7.5 and stirred vigorously. After the reaction was completed, the reaction solution was concentrated under reduced pressure to remove acetonitrile and water. The decanted water layer was removed and 60 ml of 10% acetonitrile water was added to dissolve. This solution was subjected to column chromatography with 400 ml of HP-20SS synthetic absorbent resin, washed with 1 L 5% acetonitrile / water and 1 L 30% acetonitrile / water, and the effective area was distilled off under reduced pressure to obtain 3 3 g of foamy residue. 30 ml of acetonitrile and 3 ml of water were added to the residue to dissolve, and the solution was dropped into 500 ml of acetonitrile at room temperature. The precipitated powder was stirred for 5 minutes, then filtered, washed with acetone, and dried to obtain 22.3 g of the compound (II-2- a) powder. ^ -NMRCDMSO-dJ: δ 1. 1 5 (13 3 H 3 J = 7 Η z? E t)? 1.3 2 (br 5 9 Η? Β 〇c)? 2.0-2.1 (m, 2H,- CH2-), 2.76 (s, 3H, -NCH3), 2.9-3.5 (m54H, -CH2- x2), 4.07 (q, 2H, J = 7Hz5Et), 4.4-4.5 (m, -CH2-), 5.00 ( d5lH5J = 5Hz, C6-H) 55.6-5.7 (m53H, C7-H, -CH2-), 8.10 (s, 2H,-NH2) 59.72, 1H, J = 6Hz, -NH-), 7.95, 8.93, 9.1 1.9.41 (4H) FABMS (m / z): [M + H] + 70 1, [2M + H] + 1401 Below, the crystallization of the compound (Π-2-a) will be discussed. (Powder X-ray measurement conditions) X-ray: CuK α, tube voltage: 30 mA, scanning rate: 4 ° / min, sampling 200404807 frame: 〇. 〇 2 °, operating axis: 20 / e, scanning range: 5. ~ 4 0. . The powder X-ray and the simultaneous measurement of TG / E) TA were used to determine the crystallizing solvent by NMR, FNMR, and the like. Example 13 (crystals containing THF and H20) 500 mg of the compound (Π-2-a) was dissolved in a mixture of 0.5 ml 2H20 and 0.5 ml CH3CN, 2.5 ml of THF seed crystals were added, and the mixture was stirred at 5 ° C overnight. , The precipitated crystals were filtered, washed with cold H20-CH3CN-THF (l-: l-5), cold 1 ^ 20-CH3CN-THF (1-1-10), and air-dried to obtain 3 20mg of the compound ( II-2-a) Crystal (1). ^ -NMRCDMSO-dJ: ά 1 .1 7 (15 3 H? J = 7 Η z? E t)? 1. 3 5 (br? 9H? -C (CH3) 3) 51.7-1.8 (m, 4H, THF), 2.05-2.20 (m52H, -CH2-), 2,79 (s, 3H, -NCH3), 2.9-3.5 (m, 4H, (-CH2-) 2), 3.55 · 3.65 (m? 4H? THF) 54.10 (q52H5J = 7Hz? Et) 54.46 (br? 2H9-SCH2-), 5.02 (d, 1H, J = 5Hz, C6-H), 5.6-5.7 (m, 3H, C7-H, -CH2- 58.12 (s52H5-NH2)? 9.7 7 (d5lH5J = 6Hz5-NΗ-), 7.98, 8.96, 9.1 4, 9.43 (4Η)

K F Moisture measurement 6: 6.87% crystallization solvent THF = 1 molecule, H2O = 5 molecules. The representative peaks of the powder X-ray diffraction pattern in the second figure are shown in Table 2. -47- 200404807 Table 2 2 Θ d 値 Relative strength 5.90 14.97 3 6.64 13.30 4 10.48 8.43 3 12.08 7.32 4 13.52 6.54 3 14.22 6.22 7 14.52 6.10 3 18.18 4.88 5 19.60 4.53 4 20.18 4.40 3 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 14 (H20-containing crystals) 150 mg of the crystals obtained in Example 13 were dried under reduced pressure (15 mmHg) for 2 hours to obtain 130 mg of crystals (2).

1H-NMR (DMSO-d6): ά 1 .1 7 (t? 3 H? J = 7Hz5Et)? 1. 3 5 (br5 9H? -C (CH3) 3) 52.05-2.20 (m, 2H, -CH2 -), 2.79 (8,3H, -NCH3), 2.9-3.5 (m, 4H, (-CH2-) 2) 54.10 (q, 2H, J = 7Hz, Et), 4.46 (br52H, -SCH2-), 5.02 (d, lH, J = 5Hz, C6-H), 5.6-5.7 (m, 3H, C7-H, -CH2-) 58.12 (s, 2H, -NH2), 9.72 (d, lH, J = 6Hz , -NΗ-), 7.97, 8.96, 9.13, 9.45 (4Η). KF moisture measurement 値: 8.11% crystallization solvent Η 2 〇 = 4.5 molecules The representative peaks of the powder X-ray diffraction pattern in Figure 3 are shown in Table 3. -48- 200404807 Table 3 2 Θ (HU relative intensity 6.16 14.34 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 20.16 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 38.18 2.36 100

Example 15 (CH3CN, crystal containing acetonitrile) Dissolve 250 mg of the compound (II-2-a) selected from Reference Example 3 in 2.5 ml of DMF, add 0.5 ml of seed crystals, and stir at 5 ° C for 60 hours. The precipitated crystals were filtered, followed by cold DHF-CH3CN-acetone (5-1-1), cold DMF-CH3CN-acetone (2-1-1), and cold 〇1 ^-(: 113 ^ acetone ( Bu 1.5-1.5) was washed and air-dried to obtain 240 mg of crystals (3).

'H-NMRCDMSO-dJ: ά 1. 1 8 (15 3 H? J = 7 Η z? E t) 5 1. 3 5 (br 5 9H? -C (CH2) 2), 2.07 (s, 3H, CH3CN), 2.09 (s, 6H, acetone), 2.05--2.20 (m52H, -CH2-), 2.79 (s53H, -NCH3) 52.9-3.5 (m, 4H, (-CH2〇2), 4.07 ( q.2H, J = 7Hz, Et), 4.46 (br, 2H, -SCH2-), 5.02 (d, 1H, J = 5Hz, C6-H), 5.6-5.7 (m, 3H, C7-H,- CH2-) 58.12 (s52H5-NH 2) 5 9.7 5 (br5lH, -NH〇, 7.9 7,8.96,9.14, 9.45 (4H) -49 · 200404807 Crystallization solvent CH3CN = 1 molecule, acetone = 1 molecule Figure 4 The representative peaks of powder X-ray diffraction patterns are shown in Table 4. Table 4 2 Θ d 値 Relative intensity 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 27.84 3.20 4 28.26 3.16 4 29.22 3.05 4 38.42 2.34 100

Example 16 1.0 g of compound (II-2-a) was dissolved in a mixed solution of 1.02 H10 and 1.0 ml acetone, 4.0 ml of acetone seed crystals were added, and the mixture was stirred at 5 ° C for one hour. . The precipitated crystals were filtered, washed with cold H20-acetone (1-5), cold hO-acetone (1-10), acetone and air-dried in order to obtain 24 mg of crystals (4). No agent was identified. The representative peaks of the powder X-ray diffraction pattern in Figure 5 are shown in Table 5 ° -50- 200404807 Table 5 2 0 d 値 Relative intensity 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 26.16 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 (Stability of Crystallization) The change over time (10 days) between the crystal (1) of the compound (li-2-a) obtained in Example 13 and no crystal at room temperature by HPLC (peak area)% . Table 6 HPLC PA (%) Initial 1st 2nd 3rd 5th 6th 10th Crystallized 1 1 1 99.6 99.2 .- 99.2 Amorphous 97.0 96.6 95.5 92.9 1 91.4 1

Due to crystallization, it improves the stability of leaps and bounds. Industrial Applicability The present invention provides industrially advantageous deprotection reactions and intermediates. Because of the use of the present invention, it is possible to produce industrially effective antifungal antibacterial agents. -51- 200404807 [Brief description of the figure] Figure 1 shows the results of powder X-ray measurement of the crystal of the compound (4) obtained in Reference Example 1. Fig. 2 is a result of powder X-ray measurement of the crystal (1) of the compound (II-2-a) obtained in Example 13. Fig. 3 is a result of powder X-ray measurement of the crystal (2) of the compound (II-2-a) obtained in Example 14. Fig. 4 is a result of powder X-ray measurement of the crystal (3) of the compound (II_2_a) obtained in Example 15. Fig. 5 is a result of powder X-ray measurement of the crystal (4) of the compound (II_2_a) obtained in Example 16.

-52-

Claims (1)

200404807 Scope of patent application: 1. A compound represented by formula (II), C00R (ID (Wherein R1 and R2 are each independently a lower alkyl group which may be substituted; R3 is an amine protecting group; R is an anion, hydrogen or residue protecting group), and pharmaceutically acceptable salts or solvates thereof. 2 · The compound shown in item 1 of the scope of patent application, which is represented by the formula _ 丨), COOR ^ K 1 OR! (Where R1, R2, and R3 have the same meaning as in item 1 of the scope of patent application; R4 is a hydrogen or carboxy protecting group; X · is a counter ion). 3. As the compound in the second item of the patent application, wherein R1 is ethyl; R2 is methyl; R3 is third-order butoxycarbonyl; R4 is p-methoxybenzyl, diphenylmethyl or trimethyl Silyl. 4. The compound shown in item 1 of the scope of patent application, which is represented by formula (II-2), (Where R1, R2 and R3 have the same meaning as the first item in the scope of patent application). -53- 200404807 5 · Compound No. 4 in the scope of patent application, wherein R1 is ethyl; R2 is methyl; R3 is tertiary butoxycarbonyl. 6 · —A method for producing a compound represented by formula (I) or a pharmaceutically acceptable salt or solvate thereof, (Wherein R1 and R have the same meaning as in item 1 of the scope of patent application), it is characterized by deprotecting the compound of any one of the scope of patent applications 1 or 5 or a pharmaceutically acceptable salt or solvate thereof. 7. If the method of applying for the scope of patent application No. 6 is used, it is protected in the presence of formic acid and sulfuric acid. 8. A method for preparing a compound represented by formula (II-1) as described in item 2 of the scope of patent application, characterized in that formula (III) (III) (Where R1 is a lower alkyl group which may be substituted; R4 is a hydrogen or carboxy protecting group; Y is a leaving group), and the compound shown by the formula (IV) -54- 200404807 // (IV) (wherein R2 is a lower alkyl group which may be substituted; r3 is an amine protecting group) or a salt thereof is reacted. 9 · A method for preparing a compound represented by formula (I) or a pharmaceutically acceptable salt or solvate thereof according to item 6 of the application for a patent, characterized in that the compound (II-1) obtained by the method for application of the 8th application for a patent is removed protection. 10 · —A method for preparing a compound of formula (11-2) as shown in item 4 of the scope of patent application, which is characterized by combining formula (V) (Wherein R4 is a hydrogen or carboxy protecting group; R5 is a hydrogen or amine protecting group; γ is a leaving group); (IV) (wherein R2 is a substituted lower alkyl group; R3 is an amine protecting group) or a salt thereof is reacted to obtain formula (VI) -55200404807 And R, R, and R5 are synonymous with the foregoing; are counterions), or a salt thereof, and the formula (νπ) S—N 〇 h2n_Si ^ tT ^ 〇h (VII) NM, OR1 (Wherein R1 is a lower alkyl group which may be substituted) or a reactive derivative thereof. 1 1 · The method for preparing a compound shown in formula (6) of the scope of patent application or a pharmaceutically acceptable salt or solvate thereof is characterized in that the compound (II-2) obtained by the method of scope of patent application (10) is removed. protection. 12. If the compound in the scope of patent application No. 1 has the following formula (11-3) (II-3) (In the formula, R1 and R2 are each independently substitutable lower radical; R3 is an amine protecting group; X · is a counter ion). 13. The compound according to item 12 of the application, wherein R1 is ethyl; R2 is methyl; R3 is tertiary butoxycarbonyl. 14. A method for preparing a compound represented by formula (I) or a pharmaceutically acceptable salt or solvate thereof according to item 6 of the scope of patent application, which is characterized in that the compound obtained by the method of preparation of the scope of patent application No. 12-56-200404807 (11 -3) Deprotection. 15 · If the method of claim 14 in the scope of the patent of if is applied, it is deprotected in the presence of sulfuric acid, water and ethyl acetate. 16. · A method for preparing a compound represented by formula (11-3) according to item 12 of the scope of patent application, which is characterized by reacting compound (v) of item 10 of patent scope with compound (IV) or a salt thereof Get formula (VI) COOir φ (where R2 is a substituted lower alkyl group; R3 is an amine protecting group; r4 is a hydrogen or carboxy protecting group; R5 is a hydrogen or amine protecting group; χ • is a counter ion) After the salt, it is reacted with the compound. (V) [U or its reactive derivative. 1 7 · —A crystal such as the compound or solvate of item 5 in the patent application, which is represented by the formula (II-2-a ) (Π-2-a) represents an oxygen-based group) 18. The crystal according to item 17 of the scope of patent application, which contains more than one solvent selected from water, acetonitrile, tetrahydrofuran, dimethylformamide and acetone. -57- 200404807 19 · One formula (I) S-N (I) A method for preparing a compound represented by COO N ^ Nv ^-^ NhR2 (wherein R1 is ethyl; R2 is methyl) or a pharmaceutically acceptable salt or solvate thereof is characterized in that 7 ^ 18 Crystal deprotection. 20 · If the preparation method of the patent application scope item 6 or 19, it is the preparation method of the sulfur salt of the compound (I) or its solvate. -58-