WO2003092889A1

WO2003092889A1 - Process for the preparation of 2-aminopyrazine derivatives

Info

Publication number: WO2003092889A1
Application number: PCT/JP2003/005409
Authority: WO
Inventors: Takahiro Itoh; Kenji Maeda; Toshiaki Mase
Original assignee: Banyu Pharmaceutical Co., Ltd.
Priority date: 2002-05-01
Filing date: 2003-04-25
Publication date: 2003-11-13
Also published as: AU2003235951A1; JP2005320249A

Abstract

An industrially advantageous process for the preparation of 2-aminopyrazine derivatives represented by the general formula [I] or acid addition salts thereof: [I] [wherein R1 is hydrogen, alkyl having 1 to 6 carbon atoms, or aryl; R2 is hydrogen, alkyl having 1 to 6 carbon atoms, aryl, or halogeno; and R3 is hydrogen, alkyl having 1 to 6 carbon atoms, aryl, or aralkyl], characterized by using a reaction accelerator for the formation of pyrazine ring which contains an iron compound as the active ingredient.

Description

Specification

Method for producing 2-aminovirazine derivative

The present invention is useful in the field of fine chemicals such as pharmaceuticals. More specifically, the present invention relates to a novel method for producing a compound useful as a production intermediate in the field of medicine and the like, and a novel reaction accelerator useful for the production. Background art

The 2-aminopyrazine derivative produced by the production method of the present invention can be used, for example, as an intermediate for producing a compound useful as a neuropeptide Y receptor antagonist disclosed in International Patent Publication WO 01/14376, For example, it is useful as an intermediate for the production of luminescent reagents used for the analysis of trace components in living organisms such as peroxides, ATP, calcium ions and steroid hormones (Shimomu raeta 1). (Journal) Vol. 270, pp. 309-312 (1990)).

Known methods for producing the pyrazine derivative include, for example, Pharmaceutical Journal Vol. 89, pp. 1646 to 1651 (1969) and Journal of Chemo cal Soc. ociety), p. 932 (1951), but these production methods are not preferable as industrial production methods because the yield of the pyrazine derivative is low.

Further, a known method for producing the pyrazine derivative is described in Journal of the American Chemical Society (Journal of America, Chemical Society), Vol. 93, No. 2333. Pp. 2335 (1971). In this production method, the yield of the pyrazine derivative is improved by using expensive titanium tetrachloride, but it is still not at an industrially satisfactory level. It cannot be said that this is an advantageous production method. Disclosure of the invention

An object of the present invention is to improve the above-mentioned problems of a conventionally known method for producing a 2-aminopyrazine derivative, and to provide an industrially excellent method for producing a 2-aminopyrazine derivative and a reaction accelerator that can be used for the method. .

The present inventors have conducted intensive studies on a method for producing a 2-aminopyrazine derivative, and have surprisingly found that an iron compound has a reaction promoting action. The present inventors further have the advantage that the desired 2-aminovirazine derivative of the method of the present invention can be produced in a higher yield than the conventional method, and furthermore, the control of the reaction process is easy, and therefore the present invention is industrially useful. The inventor has found that this is an excellent manufacturing method, and has conducted further studies to complete the present invention.

That is, the present invention

(1) a pyrazine ring-forming reaction accelerator containing an iron compound as an active ingredient,

(2) The iron compounds are iron chloride (1 1 1), iron nitrate (1 1 1), iron sulfate (1 1 1), iron bromide (1 1 1), iron ammonium sulfate (1 1 1), The pyrazine ring-forming reaction accelerator according to the above (1), which is iron oxalate (111), iron oxalate (II) or iron fumarate (II),

(3) General formula [IV]: R ² people

OH [I v]

[In the formula, R ¹ represents a hydrogen atom, an alkyl group having 1 to 6 carbon atoms or aryl group, and R ² represents a hydrogen atom, an alkyl group having 1 to 6 carbon atoms, aryl group or halogen atom] And a compound represented by the general formula [III]:

H ₂ NR

CM [ ]

Wherein R ³ represents a hydrogen atom, an alkyl group having 1 to 6 carbon atoms, an aryl group or an aralkyl group, and an aminoacetonitrile compound or an acid addition salt thereof represented by the following formula: Reacting under the general formula [II]:

0 [wherein R ¹ R ² and R ³ have the same meanings as above], to produce an N-year-old oxide compound or an acid addition salt thereof. General formula [I] characterized by reducing

[I]

[Wherein RR ² and R ³ have the same meanings as above], a method for producing a 2-aminopyrazine derivative or an acid addition salt thereof

(4) The iron compounds are iron chloride (1 1 1), iron nitrate (1 1 1), iron sulfate (1 1 1), iron bromide (1 1 1), iron ammonium sulfate (1 1 1), (2) a method for producing a 2-aminopyrazine derivative or an acid addition salt thereof according to the above (3), which is iron (1 1 1), iron (II) oxalate or iron (II) fumarate;

(5) The method for producing a 2-aminopyrazine derivative according to the above (3) or (4), wherein the reduction is a catalytic reduction using palladium carbon or platinum carbon as a catalyst.

It is about. BEST MODE FOR CARRYING OUT THE INVENTION

The present invention will be described specifically and in detail.

"Iron compounds" include, for example, ferric chloride (111), iron nitrate (111), iron sulfate (II 1), iron bromide (1 I 1), iron ammonium sulfate (II 1) , Ferric citrate (II 1), iron oxalate (II) or iron (II) fumarate, which means a compound containing an iron atom. III) or iron sulfate (III). (II) or (II) attached to the end of the name of each iron compound exemplified as the “iron compound” indicates the oxidation number of the iron atom.

The "alkyl group having 1 to 6 carbon atoms" means, for example, methyl group, ethyl group, n-propyl group, isopropyl group, n-butyl group, isobutyl group, tert-butyl group. A linear or branched alkyl group having 1 to 6 carbon atoms such as a tyl group, sec-butyl group, n-pentyl group, isopentyl group, neopentyl group, n-hexyl group, or isohexyl group. Among them, a methyl group, an ethyl group, an n-propyl group, an n-butyl group or an n-hexyl group is preferred.

The "aryl group" is, for example, a phenyl group, an O-tolyl group, a P-tolyl group, an m-tolyl group, a 1-naphthyl group, a 2-naphthyl group or an indanyl group having 6 to 1 carbon atoms. It means two aryl groups, among which phenyl, 11-naphthyl or 2-naphthyl is preferred.

Accordingly, each group exemplified as the “aryl group” is a normal group that does not inhibit the reaction (for example, an alkyl group having 1 to 6 carbon atoms, a cycloalkyl group having 3 to 6 carbon atoms). You may have it as a substituent. Here, the alkyl group having 1 to 6 carbon atoms has the above-mentioned meaning, and the cycloalkyl group having 3 to 6 carbon atoms includes, for example, a cyclopropyl group, a cyclopentyl group, a cyclohexyl group, and the like. No.

The “aralkyl group” includes, for example, an aryl group having 7 to 12 carbon atoms, such as a benzyl group, a (1-naphthyl) methyl group, a (2-naphthyl) methyl group or a 2-phenylethyl group. Further, each group exemplified as the “aralkyl group” may have a substituent that does not inhibit the above reaction.

The “halogen atom” includes, for example, a chlorine atom, a bromine atom, a fluorine atom and an iodine atom. Next, the manufacturing method of the present invention will be described.

General formula [IV]:

^CN [ίII]

0

[Wherein, RR ² and R ³ have the same meanings as those described above], and then reducing the N-year-old oxide compound or the acid addition salt thereof. It is performed by This method can be carried out industrially advantageously by preferably performing the following processes (1) and (2) successively. (1) To a solvent, add a compound represented by the general formula [IV] or an acid addition salt thereof, an aminoacetonitrile compound or an acid addition salt thereof represented by the general formula [III], and an iron compound, and add the compound at about 50 ° C To about 100 ° (: preferably from about 70 ° C to about 100 ° C for about 1 hour to about 36 hours, preferably about 2 hours to about 21 hours, and react with N represented by the general formula [II]. —Produce an oxide compound or an acid addition salt thereof.

The amount of the compound represented by the general formula [IV] used in this step is from about 1 equivalent to about 5 equivalents to the aminoacetonitrile compound represented by the general formula [III].

When the aminoacetonitrile compound represented by the general formula [III] is an acid addition salt, for example, a base such as N-methylmorpholine, sodium hydroxide, potassium hydroxide, triethylamine, or diisopropylamine is added to the aminoacetonitrile compound. About 1 equivalent to about 6 equivalents, preferably about 1 equivalent to about 5 equivalents, to the aminoacetonitrile compound acid addition salt, and then the treatment of the above (1) is performed.

(2) The reaction solution containing the N-oxide compound represented by the general formula [II] or the acid addition salt thereof obtained in (1) is transferred to a reduction reaction vessel, and for example, a catalyst such as palladium carbon or platinum carbon is used. About 1 mol 1% to about 5 mol% of the aminoaminocetonitrile compound is added, and about 30 to about 10 ° C. under a hydrogen pressure of about 2 to about 6 atm, preferably about 2 to about 5 atm. The reaction is carried out at about 100 ° C, preferably about 30 ° C to about 80, for about 1 hour to about 24 hours, preferably for about 8 hours to about 15 hours.

Each of the reactions (1) and (2) of the present invention may be performed in the presence of a solvent. Examples of such a solvent include water, N, N-dimethylformamide, dimethyl sulfoxide, methanol, ethanol, and the like. Examples thereof include form-form, tetrahydrofuran, and isopropanol, and a mixed solvent thereof.

Examples of the iron compound used in this step include iron chloride (II 1), iron nitrate (I 11), iron sulfate (111), iron bromide (111), and ammonium sulfate (1 11). 11), iron citrate (1 1 1), iron oxalate (II) or iron (II) fumarate The used amount is about 0.5 equivalent to about 1 equivalent based on the aminoacetonitrile compound.

The product obtained in the above steps can be obtained by a method known per se, such as column chromatography using silica gel or adsorption resin, liquid chromatography, thin-layer chromatography, solvent extraction or recrystallization / reprecipitation. Purification and isolation can be performed by using a separation and purification method alone or in an appropriate combination as necessary.

Examples of the acids in the acid addition salts of the compounds represented by the general formulas [I] to [IV] include inorganic acids such as hydrochloric acid, sulfuric acid, and nitric acid, and organic acids such as oxalic acid and acetic acid. . Example

Hereinafter, the present invention will be described specifically with reference to Examples, but the present invention is not limited thereto. Example 1

Preparation of 2-amino-5-phenylavirazine:

Under a nitrogen stream, aminoacetonitrile hydrochloride (124 g, 1.34 mol), methanol (4 L), and a 12 N aqueous sodium hydroxide solution (123 mL, 1.48 mol) were added dropwise to a 10 L glass eggplant-shaped flask. And To this solution is added isonitrosoacetophenone (100 g, 0.67 mol) and iron (III) chloride (109 g, 0.67 mol) at 20 ° C or lower. The reaction solution is stirred and reacted at 50 ° C for 2 hours and at reflux for 4 hours. After confirming the disappearance of isonitrosoacetophenone by high-performance liquid chromatography (hereinafter abbreviated as “HPLC”), the reaction solution was cooled to room temperature and a stainless steel pressurized reaction vessel (Teflon (Registered trademark). Palladium carbon (10w / w%) was added to the reaction solution, Stir at 50 ° C for 18 hours under hydrogen pressure (5 atm). After confirming that 2-amino-5-phenylpyrazine = 1-oxide (the value measured by nuclear magnetic resonance (hereinafter abbreviated as “NMR”) is disappeared) by HPLC, the reaction solution was subjected to 12 N aqueous oxidation. Make alkaline (pH> 10) using aqueous sodium solution. This is passed through a cerite to remove insolubles, and the filtrate is concentrated under reduced pressure to concentrate methanol. Add ethyl acetate to the aqueous layer and extract twice. The obtained ethyl acetate solution is washed with a 7% by weight saline solution and then separated, and the ethyl acetate solution is dehydrated with anhydrous sodium sulfate. After the ethyl acetate solution is concentrated to a certain amount under reduced pressure, activated carbon (trade name: Darc-G60) is added, and the mixture is stirred at room temperature for 1 hour. After removing activated carbon through celite, the ethyl acetate solution is concentrated under reduced pressure to a certain amount, and crystals are precipitated. N-Heptane is added dropwise to the resulting suspension, and the mixture is stirred at room temperature for 1 hour, filtered using a glass filter, and the crystals are washed with ethyl acetate Zn-heptane (volume ratio, 1: 5). The obtained crystals were dried under reduced pressure at room temperature to obtain 77 g (yield 67%) of 2-amino-5-phenylpyrazine as yellow crystals.

2—Amino 5—Fenylvirazine = 1 1 year old oxide:

^ -NMR (500 MHz, DMSO) δ ppm: 8.79 (s, 1H), 8.22 (s, 1H), 7.96 (d, J = 7.5 Hz, 2H), 7.44 (dd, J = 7.3, 7.5Hz, 2H), 7.38 (dd, J = 7.3Hz, 1H), 7.11 (s, 2H)

2-amino-1 5-phenylpyrazine:

^ -NMR (500 MHz, DMSO) δ ppm: 8.53 (s, 1H), 8.01 (s, 1H), 7.94 (d, J = 7.6 Hz, 1H), 7.93 (d , J = 7.6Hz, 1H), 7.43 (dd, J = 7.4, 7.6Hz, 2H), 7.32 (dd, J-7.4Hz, 1H), 6.59 (s , 1 H) ¹³ C-NMR (125 MHz, DMSO) dp pm: 125.0, 12 7. 7, 129.0, 131.8, 137.5, 139.2, 139.4, 155.3 HP LC measurement conditions

Column: symmetry (Cymmetry) C 8,

4.6mmX 250mm

Measurement temperature: 25 ° C

Moving layer:

Kuraji end (g r ad i en t):

Flow rate: 1. OmL / min

0 minutes (A: B = 95: 5 (volume ratio))

35 minutes (A: B = 50: 50 (volume ratio))

A: 0.1% phosphoric acid; B: acetonitrile

Detection wavelength: 243 nm

Retention time (r e t e n t i on t ime):

Isonitroacetophenone: 20. 69 minutes

2-amino-5-phenylpyrazine = 1-oxide: 14.37 minutes 2-amino-5-phenylpyrazine: 16.03 minutes Examples 2 to 7

The compounds of Examples 2 to 7 were produced in the same manner as in the production method of Example 1. However, regarding the purification of the target compound, a silica gel column chromatography (silica gel: Kogel (manufactured by Wako Pure Chemical Industries, Ltd.); ). Example 2

2-Amino-3-methyl-5-phenylpyrazine: (Yield: 63%)

XH-NMR (50 OMHz, DMSO) δ ρ pm: 8.40 (s, IH), 7.94 (d, J = 7.4, 8.3 Hz, 2H), 7.43 (d, J = 7 6H z, 1H), 7.41 (d, J = 7.8Hz, 1H), 7.31 (d, 3 = 7.2Hz, IH), 6.35 (s, 2H), 2.40 (s, 3 H)

^{13 C - NMR (125MHz, CDC1} 3) δ p pm: 21. 1, 125. 1, 127. 6, 129. 0, 136. 8, 137. 6, 138. 8, 138. 9, 153. 6, 176.5 Example 3

2-Amino-3-ethyl-5-phenylpyrazine: (Yield: 67%)

XH-NMR (27 OMHz, CDC1 3) δ ρ pm: 8. 32 (s, 1H), 7. 93 (d, J = 7. 3, 8. 6Hz, 2H), 7. 45 (d, J = 7.3Hz, IH), 7.42 (d, J = 7.6Hz, IH), 7.34 (dd, J = 6.9, 7.6Hz, IH), 4.61 (s, 2H) , 2.73 (q, J = 7.3, 7.6 Hz, 2H), 1.41 (t, J = 7.3, 7.6 Hz, 3 H)

^{13 C-NMR (125MHz, -} CDC1 3) δ p pm: 11. 0, 26. 0, 125. 0, 127. 5, 129. 0, 136. 5, 137. 8, 138. 8, 142. 5 , 153.0 Example 4

2-amino-3,5-diphenylpyrazine: (Yield: 58%)

— NMR (27 OMHz, DMSO) δ p pm: 8.57 (s, 1 H), 8.00 (d, J = 7.3, 8.6 Hz, 2H), 7.82 (d, J = 6 98.3 Hz, 2H), 7.57-7.47 (m, 4H), 7.43 (d, J = 7. 6Hz, 1H), 7.34 (dd, J = 6.9, 7.6Hz, 1H), 6.31 (s, 2H)

¹³ C-NMR (67.5 MHz, DMSO) δ p pm: 124.9, 127.8, 128.1, 128.5, 128.6, 128.8, 128.9, 129.0, 136 9, 137. 5, 137. 8, 137. 9, 139. 7, 152.0 Example 5

2-amino-3-benzyl-5-phenylpyrazine: (Yield: 72%) iH-NMR (27 OMHz, DMSO) δ ppm: 8.44 (s, 1H),

7.92 (d, J = 7.3 Hz, 2H), 7.44-7.17 (m, 8H), 6.

41 (s, 2H), 4.11 (s, 2H)

¹³ C—NMR (67.5 MHz, DMSO) δ ppm: 124.7, 1

26. 1, 127. 3, 128. 2, 128. 6, 128. 9, 136. 9, 137. 1, 138. 1, 138. 7, 140. 0, 152.7 Example 6

2-Amino-5-phenyl-6-methylpyrazine: (Yield: 60%)

^ -NMR (270MHz, DMSO) δ ppm: 7.82 (s, 1H), 7.51 (d, J = 6.6Hz, 1H), 7.43 (d, J = 6.6Hz, 1H), 7.41 (d, J = 7.9 Hz, 1H), 7.34 (d, J = 6.6 Hz, 1H), 7.32 (d, J = 7.6 Hz, 1H), 6.40 (s , 2H), 2.35 (s, 3H)

¹³ C-NMR (67.5 MHz, DMSO) dpm: 22.7, 127.2, 128.2, 129.1, 129.2, 139.7, 140.1, 147.8, 154. Two Example 7

2-amino-5-methylpyrazine: (Yield: 55%)

NMR (500 MHz, DMSO) <5 ppm: 7.81 (sH) _; 7.78 (s, 1H), 6.10 (s, 2H), 2.25 (s, 3H)

^{1 3 C-NMR (125MHz,} DMSO) dp pm: 20. 0, 31 4, 139. 6, 140. 7, 154. 4, 176. 5 Comparative Example

According to the method of Example 1 and using the same molar amount of titanium tetrachloride instead of iron chloride (III), 2-amino-5-phenylpyrazine was produced, and the yield was 10%. Industrial applicability

The reaction accelerator for a pyrazine ring containing an iron compound as an active ingredient provided by the present invention can improve the yield compared with a conventionally known method for producing a 2-aminopyrazine derivative. A method for producing an aminovirazine derivative can be provided.

Claims

The scope of the claims

1. A pyrazine ring-forming reaction accelerator containing an iron compound as an active ingredient.

2. The iron compounds are iron chloride (111), iron nitrate (111), iron sulfate (II1), iron bromide (II1), ammonium ammonium sulfate (111), iron citrate (111). 11. The pyrazine ring-forming reaction accelerator according to claim 1, wherein the promoter is iron (II) oxalate or iron (II) fumarate.

3. General formula [IV]:

[Wherein, R ¹ represents a hydrogen atom, an alkyl group having 1 to 6 carbon atoms or an aryl group, and R ² represents a hydrogen atom, an alkyl group having 1 to 6 carbon atoms, an aryl group or a halogen atom. A compound represented by the general formula [III]:

0

[Wherein RR ² and R ³ have the same meanings as described above], and then the N-year-old oxide compound or an acid addition salt thereof is reduced. General formula [I] characterized by the following:

[Wherein, RR ² and R ³ have the above-mentioned meanings]

A method for producing a derivative or an acid addition salt thereof.

4. The iron compounds are iron chloride (111), iron nitrate (111), iron sulfate (II1), iron bromide (II1), ammonium sulfate ammonium (111), iron citrate (111). 11. The method for producing a 2-aminopyrazine derivative or an acid addition salt thereof according to claim 3, wherein the method is iron (II) oxalate or iron (II) fumarate.

5. The method for producing a 2-aminopyrazine derivative or an acid addition salt thereof according to claim 3 or 4, wherein the reduction is catalytic reduction using palladium carbon or platinum carbon as a catalyst.