JP2003012647A - Method for producing 2,3-diaminopyridine - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide an industrially advantageous method for 2,3- diaminopyridine production. SOLUTION: In this method for 2,3-diaminopyridine production, 2,3- diaminopyridine production is reduced in the presence of a Pd-C catalyst.

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention relates to a method for producing 2,3-diaminopyridine or a synthetic intermediate thereof, which is useful as a cephem antibacterial agent, a synthetic intermediate such as imidazopyridine, or a medicinal raw material for a ligand of an organometallic complex. Regarding

[0002]

2. Description of the Prior Art 2,3-Diaminopyridine is, for example, W
O00 / 32606, Reference Example 29 and the like are described as a starting material for the 3rd side chain of the cephem antibacterial agent. A typical method for producing 2,3-diaminopyridine is Org. Syn., Coll. Vo.
I. V, 346 (1973) describes a method of synthesizing 2-aminopyridine as a starting material in four steps. But,
In the production method, a metal such as bromine or iron is used as a reaction reagent, which is not desirable in terms of environment and safety, and the yield is as low as 26%, which is not a satisfactory industrial production method. J.
Chem. Soc. Perkin Trans. I, 2995 (1982) includes 3-
A method for producing 2,3-diaminopyridine by reducing 3-amino-2-nitropyridine obtained from ethoxycarbonylamino-2-nitropyridine with Ni / hydrogen is described, but nickel metal which may cause carcinogenicity is described. Is used, it is not preferable as an industrial production method.

[0003]

Therefore, there has been a demand for the development of a novel process for producing 2,3-diaminopyridine, which is more preferable for industrial implementation.

[0004]

Means for Solving the Problems As a result of intensive studies by the present inventors, 2,3-diaminopyridine can be efficiently obtained by reducing 3-amino-2-nitropyridine in the presence of a Pd-C catalyst. Then, the present invention shown below was completed. (1) As shown in the following reaction scheme, 3-amino-2-
2,3-diaminopyridine (V), which is characterized by reducing nitropyridine (IV) in the presence of a Pd-C catalyst.
Manufacturing method.

[Chemical 3] (2) As shown in the following reaction scheme, after protecting the amino group of 3-aminopyridine (I) to give 3-protected aminopyridine (II) (in the formula, R ¹ is an amino protecting group), nitro A method for producing 3-amino-2-nitropyridine (IV), which comprises reacting an agent to obtain compound (III) and deprotecting it.

[Chemical 4] (3) The production method according to (1) above, wherein 3-amino-2-nitropyridine (IV) is obtained by the production method according to (2) above. (4) A method for producing a compound having an optionally substituted imidazo [4,5-b] pyridinium group, which comprises the step described in any of (1) to (3) above. (5) A cephem having an imidazo [4,5-b] pyridiniummethyl group optionally substituted at the 3-position, characterized by including the step described in any of (1) to (3) above. Method for producing compound.

The 2,3-diaminopyridine (V) is
Obtained by reducing 3-amino-2-nitropyridine (IV). Examples of the reducing conditions include reduction with sodium hydrosulfite and reduction under a hydrogen atmosphere in the presence of a Pd—C catalyst. However, the latter reduction is preferable from the viewpoint of easy isolation of the target product. Further, as a hydrogen source for the reduction reaction, ammonium formate, cyclohexene, hydrazine and the like may be used. Pd-
The amount of C catalyst used is about 0.01 to 0.1 with respect to compound (IV).
It is 0 mol equivalent, preferably about 0.05 mol equivalent. As the reaction solvent, alcohol (eg, methanol, ethanol, etc.), tetrahydrofuran, 1,2-dichloroethane, water,
Ethyl acetate etc. are illustrated. The amount of the reaction solvent is usually about 15 ml to 1000 ml per 1 g of compound (IV). The reaction temperature is usually about 10-40 ° C, preferably about 25 ° C.
℃. The reaction time is several tens of minutes to several tens of hours. Two
3-diaminopyridine (V) is obtained by diluting the concentrated solution of the reaction solution with, for example, ethers (eg, diisopropyl ether, methyl t-butyl ether), ethyl acetate, toluene, acetonitrile, acetone, or methyl isobutyl ketone. Thus, in any case, it can be preferably isolated as crystals.

The above 3-amino-2-nitropyridine (I
V) is preferably obtained by the following method. (Step 1) The amino group of the 3-aminopyridine (I) is protected to obtain the 3-protected aminopyridine (II) (in the formula, R ¹ is an amino protecting group). The reaction may be performed under reaction conditions known as amino protection reaction. Examples of the amino protecting reagent include methyl chlorocarbonate, ethyl chlorocarbonate, 9-fluorenylmethyl chlorocarbonate, ethyl trifluoroacetate and the like, but methyl chlorocarbonate is preferable. Examples of the amino protecting group represented by R ¹ include lower alkoxycarbonyl (eg, methoxycarbonyl),
Aralkyl (eg: triphenylmethyl), aralkyloxycarbonyl (eg: benzyloxycarbonyl), lower alkanoyl (eg: acetyl), halogenated lower alkoxycarbonyl (eg: trichloroethoxycarbonyl), halogenated lower alkanoyl (eg: trifluoro) Acetyl), phthaloyl, urea-type protecting groups (eg: phenothiazinylcarbonyl group), phosphoric acid-type protecting groups (eg: diphenylphosphoryl group), silyl-type protecting groups (eg: t-butyldiphenylsilyl group), sulfur-type protecting groups (Example: benzenesulfenyl group), imine type protecting group (salicylidene group) and the like are exemplified, but methoxycarbonyl is preferable. Examples of the reaction solvent include acetone, water, alcohol, acetonitrile, tetrahydrofuran, dimethylformamide and the like. The reaction temperature is usually about 10-
It is 40 ° C, preferably about 25 ° C. The reaction is carried out in the presence of a base, if necessary, and examples of the base include alkali metal hydrogen carbonate (eg sodium hydrogen carbonate) and alkali metal carbonate (eg:
Examples thereof include potassium carbonate).

(Step 2) The compound (III) is obtained by reacting the 3-protected aminopyridine (II) with a nitrating agent to nitrate the 2-position. Examples of the nitrating agent include nitric acid (eg fuming nitric acid, hydrous nitric acid, etc.), potassium nitrite, nitrogen dioxide / ozone, etc., but fuming nitric acid is preferred. Examples of the reaction solvent include concentrated sulfuric acid, acetic acid, dimethyl sulfoxide, hexamethylphosphoric triamide, nitromethane and the like. The reaction temperature is generally about 10-60 ° C, preferably about 40 ° C. The reaction time is several tens of minutes to several tens of hours. (Third step) 3-amino-2-nitropyridine (IV) is obtained by deprotecting the protected amino group portion of the compound (III). The deprotection reaction is carried out by hydrolysis or the like, but preferably an alkali metal hydroxide (eg NaO
H, KOH, etc.) and alkaline earth metal hydroxides (eg Ba (OH)
_It may be hydrolyzed in the presence of a base such as ₂ ). The reaction temperature is generally about 10-60 ° C, preferably about 40 ° C. The reaction time is several tens of minutes to several tens of hours.

According to the manufacturing method of the present invention, the above-mentioned 2,3-
Diaminopyridine (V), preferably 3-aminopyridine (I), can be produced as a starting material in a safer and more convenient and higher yield than conventional methods. 3-amino-2-nitropyridine (I
V) and 2,3-diaminopyridine (V) can be derived into, for example, the following compound (VI). Furthermore, the compound (V
By subjecting (I) to a cyclization reaction, the following compound (VI
Optionally substituted imidazo [4,5-b] such as I)
Can be induced to pyridine. The substituent is imidazo [4,5-
b] On the 1st N atom of pyridine is preferred. The optionally substituted imidazo [4,5-b] pyridine can be used for producing a compound having an optionally substituted imidazo [4,5-b] pyridinium group. Preferably W
O00 / 32606, a cephem compound having an imidazo [4,5-b] pyridinium group which may be substituted at the 3-position (Example: Compound (IXI) below) or a salt thereof (Example: hydrochloride, It is used as a raw material for the production of sulfates, etc.).

[0009]

[Chemical 5] In the above formula, R ⁴ is hydrogen or an organic residue, and preferably an optionally substituted lower alkyl (substituent: amino, hydroxy, lower alkyl (protected) amino (eg, methylamino, Nt-butoxycarbonyl- N-methylamino etc.) etc.), heterocycle etc.). Particularly preferred R ⁴ is
3-methylamino-propyl _{(- (CH 2) 3 NHCH} 3)
And Nt-butoxycarbonyl-N-methylaminopropyl. In order to introduce the substituent R ⁴ into the 3-amino group of the compound (IV) or (V), it is preferable to carry out the condensation reaction using an aldehyde or the like corresponding to R ⁴ . Compound (I
To obtain the compound (VI) directly from V), Pd-C / H
The reducing agent such as ₂ may be used together to reduce the nitro group. The reaction of compound (VI) to compound (VII) can be carried out by using orthoformate HC (OR) ₃ (eg R
= Et, Me) is preferably reacted in the presence of an acid (eg, paratoluenesulfonic acid, etc.). Reaction temperature is 6
The temperature is 0 ° C to 100 ° C, preferably 100 ° C. In compound (VIII), R ₆ is a leaving group (eg, halogen,
Hydroxy, acetyloxy, etc.). Acyl is not particularly limited as long as it is used as the 7-position acyl group of the cephem compound, but is preferably the acyl group shown below.

[Chemical 6] In the formula, R ⁷ is hydrogen, lower alkyl (eg, methyl, ethyl, etc.), halogenated lower alkyl (eg, fluoromethyl,
2-fluoroethyl etc.) and the like, and particularly preferably ethyl.

Reference examples and examples will be shown below. Example 1

[Chemical 7] (1) Compound 2 3-methoxycarbonylaminopyridine 3-aminopyridine 72 g (760 mmol) is dissolved in acetone (360 ml), and sodium hydrogencarbonate 77 g (912 mmol) is added. 71 ml (912 mmol) of methyl chlorocarbonate was added dropwise to this solution over about 10 minutes (with vigorous foaming). Stir at room temperature for about 1 hour,
Dilute to 435 ml water. The reaction mixture was concentrated under reduced pressure to remove acetone, and the mixture was stirred in an ice-water bath for about 90 minutes under cooling, and the precipitated crystals were collected by filtration. After washing with cold water, it was dried to obtain compound 2. Yield 107g, 92% yield. (2) Compound 3 3-methoxycarbonylamino-2-
Compound 2 91 g (600 mmol) was added to concentrated sulfuric acid 2 under concentrated heating in a nitropyridine oil bath at 45 ° C.
Dissolve in 00 ml and add 30 ml of fuming nitric acid (d = 1.52) dropwise over about 2 hours. Keep the internal temperature near 45 ° C. After the completion of dropping, stir at this temperature for about 3 hours. After cooling to room temperature, water with crushed ice added 16
When the reaction solution was diluted to 00 ml, yellow solid 3 was precipitated. It was filtered with a glass filter, washed with cold water, and dried by aeration for about 1 hour to obtain Compound 3. Yield 94.5g, 80% yield. (3) Compound 4 3-amino-2-nitropyridine Compound 3 12 g (60.9 mmol) of 2.5 N-sodium hydroxide 125 ml
Dissolve in (becomes a red transparent solution). Stir at room temperature for 2 days. The color of the solution changed to orange and yellow with stirring, and the number of precipitates increased. After the reaction was completed, the precipitate 4 was collected by filtration. It was washed with a small amount of water and dried in a heating dryer under reduced pressure at about 40 ° C. for 2 hours to obtain compound 4. Yield 8.1g, 96% yield. (4) Compound 5 2,3-Diaminopyridine Compound 4 To 300 mg (2.16 mmol) of methanol was added methanol (9 ml), and 10% Pd-C catalyst (M type wet) 49 mg (0.022 mmol) was added in a suspension state. Stir at room temperature in a hydrogen atmosphere. After 1 hour, the reaction solution was filtered and the filtrate was concentrated to about 1 ml. The concentrated liquid was diluted with 5 ml of diisopropyl ether to obtain crystals of compound 5. Yield 177 mg, 75% yield. (5) Compound 5 2,3-Diaminopyridine In the above (4), methyl tert-butyl ether, ethyl acetate, toluene, acetonitrile, acetone, or methyl isobutyl ketone is used as the crystallization solvent instead of diisopropyl ether. Thus, in any case, Compound 5 was obtained as crystals in good yield.

Reference Example 1 Synthesis of compound 6

[Chemical 8] Compound 278 mg (2 mmol) is dissolved in methanol (18 ml). To this solution was added Nt-butoxycarbonyl-N-methylaminopropionaldehyde 450 mg (2.4 mmol), acetic acid (2 ml), 1
130 mg of 0% Pd-C catalyst is added, and the mixture is stirred at room temperature under a hydrogen atmosphere at atmospheric pressure for about 4 hours. The formation of compound 6 (Me = methyl, Boc = t-butoxycarbonyl) was confirmed by high performance liquid chromatography (production rate 73%). Compound 6 is WO00
As described in Reference Example 29 of / 32606, it is a raw material for synthesizing the 3-position side chain of a cephem compound, and is also compound 5 to 10
It can be synthesized using a% Pd-C catalyst or the like.

Reference example 2

[Chemical 9] (1) Compound 9 3-Aminomethylpropione aldehyde diethyl acetal 3-chloropropione aldehyde diethyl acetal (8) 30 g (0.18 mol) 4
Add to 309 ml (3.6 mol) of 0% aqueous methylamine solution. Initially, it has a two-layered structure, but when heated and stirred in an oil bath at 50 degrees, it gradually dissolves and becomes a uniform solution. After stirring for 8 hours, the mixture was cooled to room temperature and the aqueous methylamine solution was distilled off under reduced pressure to obtain a pale yellow oily compound 9.
Yield 34.2 g, 96% yield (2) Compound 10 3-Bock aminopropione aldehyde diethyl acetal compound 9 To 32 g (162 mmol) of water was added water (160 ml), and 17 g (162 mmol) of sodium hydrogen carbonate was added to the solution to completely Dissolve. Dicarbonic acid-di-t-butyl 33.5 ml (146 mmol) in acetone (3
2 ml) is added dropwise at room temperature, and the mixture is stirred for 4 hours. After standing overnight at room temperature, it is diluted with 150 ml of ethyl acetate and the two layers are separated. The water layer was back-extracted with 150 ml of ethyl acetate, and then the organic layers were combined to form 150 ml of water.
Wash with and concentrate under reduced pressure to give compound 10 as a yellow oil. Yield 38 g Yield 100% (3) Compound 7 Bock Amino Aldehytate Compound 10 38 g (146 mmol) in water (200 ml), acetic acid (100 m
Addition of l) results in a bilayer solution. Stir at room temperature for 1 hour, then stir in an oil bath at 40 degrees for 1.5 hours.
A homogeneous solution is formed by stirring. After cooling to room temperature, in an ice bath 8N
Add 175 ml of sodium hydroxide aqueous solution to adjust the pH to 5-6. After extracting twice with 150 ml of ethyl acetate, the organic layer is concentrated under reduced pressure to give a mixture of compound 7 and acetic acid (purity of 7 by NMR: 72%). Yield 37g (including 27g of compound 7), yield (converted) 98%.

Reference Example 3

[Chemical 10] Compound 6 33 g (118 mmol) and triethyl orthoformate 26 g (177
(mmol) to make a suspension. p-toluenesulfonic acid
Add 0.22 g (1.2 mmol) of monohydrate, heat to 100 ° C. in an oil bath and stir. After heating for 4 hours, confirm the disappearance of raw materials by TLC,
After cooling to room temperature, triethyl orthoformate and by-produced ethanol are distilled off under reduced pressure to obtain a slurry of compound 11 described in Reference Example 8 of WO00 / 32606. The reaction proceeds almost quantitatively.

Industrial Applicability The present invention provides an industrially advantageous process for producing 2,3-diaminopyridine and its synthetic intermediate, 3-amino-2-nitropyridine. By using this production method, for example, a cephem antibacterial agent can be industrially efficiently produced.

   ─────────────────────────────────────────────────── ─── Continued front page    (72) Inventor Yukinori Sumino             Salt, 2-3-1, Kiserejima, Amagasaki City, Hyogo Prefecture             Nogi Pharmaceutical Co., Ltd. F-term (reference) 4C055 AA01 BA02 BA51 BA52 BB15                       BB17 CA02 CA52 CB17 DA01                       FA01 FA15                 4C065 AA04 BB01 CC01 DD03 EE02                       HH01 JJ01 KK09 LL01 PP01                       QQ02                 4G069 AA03 AA08 BA08A BA08B                       BC72A BC72B CB02 DA05

Claims (5)

[Claims] 1. A method shown in the following reaction scheme, wherein 3-amino-2-nitropyridine (IV) is added in the presence of a Pd-C catalyst.
A method for producing 2,3-diaminopyridine (V), which comprises reducing. [Chemical 1] 2. After the amino group of 3-aminopyridine (I) is protected by the following reaction scheme to give 3-protected aminopyridine (II) (wherein R ¹ is an amino-protecting group): A method for producing 3-amino-2-nitropyridine (IV), which comprises reacting a nitrating agent to obtain compound (III) and deprotecting it. [Chemical 2] 3. 3-Amino-2-nitropyridine (IV)
Is obtained by the manufacturing method according to claim 2,
The manufacturing method according to claim 1. 4. A method for producing a compound having an optionally substituted imidazo [4,5-b] pyridinium group, which comprises the step according to any one of claims 1 to 3. 5. A cephem compound having an optionally substituted imidazo [4,5-b] pyridiniummethyl group at the 3-position, which comprises the step according to any one of claims 1 to 3. Manufacturing method.