JPH11246552A - Production of amine derivative - Google Patents

Abstract

PROBLEM TO BE SOLVED: To safely and easily obtain an amine derivative useful as a medicine, a perfume, etc., in a high yield at a low cost by reducing a nitrile derivative under specific conditions. SOLUTION: This method for producing an amine derivative of the formula: R<1> CH2 NH2 comprises reducing (A) a nitrile derivative of the formula: R<1> CN R<1> is a group of formula I [a group of formula II is a single bond or a double bond; R<2> is H, a lower alkyl, a lower alkoxy or a halogen; (n) is 0, 1-3] or the like) with (B) sodium borohydride in the presence of (C) sulfuric acid. Therein, the component A is preferably 1-[1-(4-fluoropphenetyl)pyridin-4-yl]-6- cyanoindoline, etc., and the components B and C are preferably used in amounts of 1.0-5.0 equivalents and 1.0-5.0 equivalents, respectively. The used solvent is preferably ethylene glycol dimethyl ether, etc.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to a novel method for industrially and economically producing a pharmaceutical, a perfume, a dye or the like, or an amine derivative useful as an intermediate for producing the same.

[0002]

2. Description of the Related Art Conventionally, many methods for producing amine derivatives have been known, but a method for reducing a nitrile derivative is often used. For example, J. Am. Chem. Soc., 70 , 3738, 1
948. discloses a method of reducing o-tolunitrile using lithium aluminum hydride to obtain 0-methylbenzylamine. Helv. Chim. Acta., 53 , 47, 1970.
Discloses a method of reducing benzonitrile with sodium borohydride / Raney Ni to obtain benzylamine. Further, Tetrahedron Lett., 1969 , 4555. states that phenylhydroxyacetonitrile [C ₆ H ₅ CH (OH) CN] is reduced using sodium borohydride / cobalt chloride to obtain β-hydroxyphenethylamine [C ₆ H ₅ CH]. (OH) CH ₂ N
How to obtain H _2] is disclosed.

[0003]

[Problems to be solved by the present invention] However, since lithium aluminum hydride, which has been conventionally used, is easily absorbed and deactivated, the solvent or the reaction apparatus is limited, and it is difficult to industrially store and use it in large quantities. There were difficult problems.
In addition, sodium borohydride is relatively stable to water, but Raney Ni has ignitability, and there is also a problem that it is difficult to store and use it industrially in large quantities. Further, cobalt chloride is expensive, and it has been difficult to use it industrially in large quantities.

As described above, at present, no industrially superior method for producing an amine derivative has been established.
A new and superior method was required.

[0005]

Means for Solving the Problems The present inventors have intensively studied to improve the above problems. as a result,
The present inventors have found that by reducing a nitrile derivative in the presence of sodium borohydride and sulfuric acid, the desired amine derivative can be produced in a high yield, safely, easily, and inexpensively, and the present invention has been completed.

Next, the present invention will be described in detail. The present invention relates to a nitrile derivative (I) represented by the general formula R ¹ CN, wherein R ¹ is a group represented by the following general formula:

[0007]

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(Wherein the bond represented by the following general formula means a single bond (—CH ₂ —CH ₂ —) or a double bond (—CH = CH—).

[0009]

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R ² represents a hydrogen atom, a lower alkyl group, a lower alkoxy group or a halogen atom, and n represents 0 or an integer of 1-3. ), A group represented by the following general formula

[0011]

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(Wherein R ³ represents a hydrogen atom, a lower alkyl group, a lower alkoxy group or a halogen atom), a group represented by the following general formula:

[0013]

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(Wherein R ⁴ represents a hydrogen atom, a lower alkyl group, a lower alkoxy group or a halogen atom) or a group represented by the following general formula:

[0015]

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(Wherein, R ⁵ represents a hydrogen atom, a lower alkyl group, a lower alkoxy group or a halogen atom, and A represents a sulfur atom, an oxygen atom or an NH group). Is reduced in the presence of sodium borohydride and sulfuric acid, wherein the amine represented by the general formula R ¹ CH ₂ NH ₂ (wherein R ¹ has the same meaning as described above). This is a method for producing derivative (II).

Here, the lower alkyl group in the definition of R ² , R ³ , R ⁴ or R ⁵ in the above general formula is a methyl group, an ethyl group, an n-propyl group, an i-propyl group, an n-butyl group. A linear or branched alkyl group having 1 to 6 carbon atoms such as a group, i-butyl group, t-butyl group, n-pentyl group, i-pentyl group, t-pentyl group, neopentyl group, hexyl group, etc. Means Next, a lower alkoxy group is a methoxy group, an ethoxy group, an n-propoxy group, an i-propoxy group, an n-butoxy group, an i-butoxy group, a t-butoxy group, a pentyloxy group,
It means a group in which an oxygen atom is bonded to a lower alkyl group having 1 to 6 carbon atoms such as a hexyloxy group. Further, a halogen atom means a chlorine atom, a bromine atom, a fluorine atom or an iodine atom.

More specifically, examples of the nitrile derivative (I) include the following compounds. (1) 1- [1- (4-fluorophenethyl) piperidin-4-yl]-
6-cyanoindoline, (2) 1- [1- (4-chlorophenethyl)
Piperidin-4-yl] -6-cyanoindoline, (3) 1- [1- (4
-Bromophenethyl) piperidin-4-yl] -6-cyanoindoline, (4) 1- [1- (4-methylphenethyl) piperidine-4-
Yl] -6-cyanoindoline, (5) 1- [1- (4-methoxyphenethyl) piperidin-4-yl] -6-cyanoindoline, (6)
1- [1- (4-fluorophenethyl) piperidin-4-yl] -6-cyanoindole, (7) 1- [1- (4-chlorophenethyl) piperidin-4-yl] -6-cyanoindole, ( 8) 1- [1- (4-bromophenethyl) piperidin-4-yl] -6-cyanoindole, (9) 1- [1- (4-methylphenethyl) piperidin-4-yl] -6-cyanoindole , (10) 1- [1- (4-methoxyphenethyl) piperidin-4-yl] -6-cyanoindole, (11)
Benzonitrile, (12) 4-tolunitrile, (13) 3-anisnitrile (3-methoxybenzonitrile), (14) 2-chlorobenzonitrile, (15) 4-fluorobenzonitrile,
(16) 4-cyanopyridine, (17) 2-methyl-4-cyanopyridine, (18) 3-methoxy-2-cyanopyridine, (19) 4-chloro-3-cyanopyridine, (20) 2-fluoro -4-cyanopyridine, (21) (2-thienyl) acetonitrile, (22) (2-
Methyl-3-thienyl) acetonitrile, (23) (5-methoxy
-2-) cyanothiophene, (24) (3-chloro-4-thienyl) acetonitrile, (25) (2-fluoro-5-thienyl) acetonitrile.

Next, more specific examples of the amine derivative (II) include the following compounds. (1) 1- [1- (4-fluorophenethyl) piperidin-4-yl]-
6-aminoindoline, (2) 1- [1- (4-chlorophenethyl)
Piperidin-4-yl] -6-aminoindoline, (3) 1- [1- (4
-Bromophenethyl) piperidin-4-yl] -6-aminoindoline, (4) 1- [1- (4-methylphenethyl) piperidine-4-
Yl] -6-aminoindoline, (5) 1- [1- (4-methoxyphenethyl) piperidin-4-yl] -6-aminoindoline, (6)
1- [1- (4-fluorophenethyl) piperidin-4-yl] -6-aminoindole, (7) 1- [1- (4-chlorophenethyl) piperidin-4-yl] -6-aminoindole, ( 8) 1- [1- (4-bromophenethyl) piperidin-4-yl] -6-aminoindole, (9) 1- [1- (4-methylphenethyl) piperidin-4-yl] -6-aminoindole , (10) 1- [1- (4-methoxyphenethyl) piperidin-4-yl] -6-aminoindole, (11)
Benzylamine, (12) 4-methylbenzylamine, (13)
3-methoxybenzylamine, (14) 2-chlorobenzylamine, (15) 4-fluorobenzylamine, (16) 4-aminopyridine, (17) 2-methyl-4-aminopyridine, (18) 3-
Methoxy-2-aminopyridine, (19) 4-chloro-3-aminopyridine, (20) 2-fluoro-4-aminopyridine, (21) 2
-(Aminoethyl) thiophene, (22) 2-methyl-3- (aminoethyl) thiophene, (23) 5-methoxy-2- (aminoethyl) thiophene, (24) 3-chloro-4- (aminoethyl) Thiophene, (25) 2-fluoro-5- (aminoethyl) thiophene.

The 1- [1- (4-fluorophenethyl) piperidin-4-yl] -6-cyanoindoline and the like according to the present invention can be produced according to Example 124 of Japanese Patent Application No. 9-98433. Can be. Other nitrile derivatives are known compounds and can be obtained or manufactured as reagents, industrial raw materials, and the like.

Next, the present invention will be described in detail. The present invention is characterized in that the nitrile derivative (I) is reduced in the presence of sodium borohydride and sulfuric acid, an amine derivative
The production method of (II). Here, the amount of sodium borohydride used is not limited, but is usually preferably 1.0 to 5.0 equivalents, more preferably 2.0 to 5.0 equivalents to the nitrile derivative (I).
4.0 equivalents, and more preferably 3.0 equivalents.

The amount of sulfuric acid to be used is also not limited, but is usually preferably 1.0 to 5.0 equivalents, more preferably 2.0 to 4.0 equivalents, and still more preferably 3.0 equivalents, based on the nitrile derivative (I). Sulfuric acid may be added at once, or may be added in two portions. At that time, 2.0 equivalents are initially charged, and then, while checking the progress of the reaction, the remaining 1.0 equivalent is added to obtain more preferable results.

The reaction solvent is not limited, and may be any solvent that is inert to sodium borohydride or sulfuric acid. More specifically, ether solvents such as ethylene glycol dimethyl ether, diethylene glycol dimethyl ether, tetrahydrofuran (THF), 1,4-dioxane, diisopropyl ether, diethyl ether, t-butyl methyl ether, and alcohols such as methanol, ethanol, and propanol Solvent, acetonitrile, ethyl acetate, butyl acetate, N, N-dimethylformamide (DM
F), 1-methyl-2-pyrrolidone, dimethyl sulfoxide (DM
SO), hexamethylphosphonamide (HMPA) and the like can be used. Among them, ethylene glycol dimethyl ether or diethylene glycol dimethyl ether gives more preferable results.

Although the amount of the solvent used is not limited, it is usually 0 to 100 ml, more preferably 0.5 to 50 ml, and still more preferably 1 to 20 ml, based on 1 g of the nitrile derivative (I).

The reaction temperature is not limited, and is usually from -78 ° C.
It can be carried out at the heating reflux temperature of the solvent. However,
Depending on the reactivity of the starting material, it can be usually selected from the range of -78 to 150 ° C, preferably -30 to 100 ° C, more preferably -10 to 70 ° C.

The reaction time varies depending on the amount of the solvent used, the reaction temperature and the like, but is usually completed within 24 hours. After completion of the reaction, alcohols and / or water are added, and the organic layer is appropriately washed with water, dried and concentrated, and then purified by a conventional method such as recrystallization, various column chromatography, or distillation. The amine derivative (II) obtained by the practice of the present invention has high purity even if it is unpurified, and can be used as a raw material in the next step as it is.

Next, the present invention will be described in more detail with reference to the following examples. However, it goes without saying that the present invention is not limited to these examples.

EXAMPLES Example 1 1- [1- (4-Fluorophenethyl) pi
Synthesis of Peridin-4-yl] -6-acetamidoindoline

[0028]

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3.24 g (85.8 mmol) of sodium borohydride
1- [1] obtained according to Example 124 of Japanese Patent Application No. 9-98433 in a 120 ml suspension of ethylene glycol dimethyl ether.
10.0 g (28.6 mmol) of-(4-fluorophenethyl) piperidin-4-yl] -6-cyanoindoline was dissolved. Under ice cooling and stirring, 3.18 ml (57.2 mmol) of sulfuric acid was added dropwise. After heating and stirring this reaction solution at 60 ° C. for 30 minutes, the progress of the reaction was checked by HPLC (see FIGS. 1 and 2), and 0.80 ml of sulfuric acid was further added.
(14.3 mmol) were added dropwise five times.

HPLC analysis conditions ──────────────────────── Column; 15 cm, ID; 6.0 mm, Packing YMC AM312 ODS Mobile phase; MeCN: H ₂ O: HClO ₄ = 500: 500: 1 Oven Temp; 30 ℃ Flow rate; 1.0ml / min Detector; UV254nm ────────────────────────

After diluting with 100 ml of t-butyl methyl ether under ice cooling and quenching with 20 ml of methanol, 100 ml of 4N-aqueous sodium hydroxide solution was added, and 1- [1- (4-fluorophenethyl) piperidine-4-l was added. A solution containing [yl] -6-aminoindoline was obtained. 3.0 ml of acetic anhydride (3
1.8 mmol) was added dropwise. After stirring for 10 minutes, the layers were separated, and the organic layer was washed three times with 100 ml of water and concentrated under reduced pressure to obtain 11.4 g of crystals. This was recrystallized from a mixed solution of methanol / water = 1/1 to obtain 9.60 g of the title compound as white crystals. (Yield; 85
%) ¹ H-NMR (400 MHz, CDCl ₃ ); δ (ppm) 7.14-7.18 (2H, m), 6.9
5-7.00 (3H, m), 6.50 (1H, dd, J = 1.2,7.6Hz), 6.31 (1H, d, J =
0.8Hz), 5.61 (1H, br), 4.33 (2H, d, J = 5.6Hz), 3.42 (2H, t, J =
8.4Hz), 3.35-3.44 (1H, m), 3.11 (2H, d, J = 12.0Hz), 2.93 (2
(H, t, J = 8.4Hz), 2.77-2.81 (2H, m), 2.57-2.61 (2H, m), 2.14
(2H, dt, J = 3.6,14.8Hz), 2.00 (3H, s), 1.71-1.82 (4H, m).

Example 2 Synthesis of benzylamine

[0033]

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Sodium borohydride 2.22 g (58.8 mmol)
2.0 ml (19.6 mmol) of benzonitrile was added to a suspension of ethylene glycol dimethyl ether (24 ml). Under ice cooling and stirring, 2.10 ml (39.4 mmol) of sulfuric acid was added dropwise. After stirring at room temperature for 40 minutes, further add 1.0 ml of sulfuric acid (18.
8 mmol) was added dropwise three times. The mixture was diluted with 20 ml of t-butyl methyl ether under ice-cooling, quenched with 4 ml of methanol, and added with 27 ml of a 4N aqueous sodium hydroxide solution. After the precipitated sodium sulfate was filtered, liquid separation was performed. The aqueous layer was washed twice with 40 ml of t-butyl methyl ether, and the title compound was quantified from the HPLC area value. [Yield (quantitative value); 71%] ¹ H-NMR (400 MHz, CDCl ₃ ); δ (ppm) 7.28-7.36 (3H, m), 7.2
2-7.26 (2H, m), 3.86 (2H, s), 1.42 (2H, br) .IRnmax (neat); 3372, 3026, 2858, 1604, 1494, 1452, 1385c
m ^-1 .

Example 3 Synthesis of 4-picolylamine

[0036]

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1.09 g (28.8 mmol) of sodium borohydride
1.00 g (9.61 mmol) of 4-cyanopyridine was added to a 15 ml suspension of ethylene glycol dimethyl ether. 1.00 ml (18.8 mmol) of sulfuric acid was added dropwise with stirring under ice cooling. After stirring at room temperature for 30 minutes, further add 0.5 ml of sulfuric acid (9.4
(mmol). Under ice cooling, dilute with 60 ml of t-butyl methyl ether, quench with 6 ml of methanol,
40 ml of a 4N aqueous sodium hydroxide solution was added. After the precipitated sodium sulfate was filtered, liquid separation was performed. The title compound was quantified from the HPLC area value. [Yield (quantitative value); 75%] ¹ H-NMR (400 MHz, CDCl ₃ ); δ (ppm) 8.55 (2H, dd, J = 1.6,4.
4Hz), 7.26 (2H, dd, J = 4.4,1.6Hz), 3.91 (2H, s), 1.46 (2H, b
r). IRnmax (neat); 3363, 3027, 2900, 2360, 1600, 1558, 1495,
1414, 1220cm ^-1 .

Example 4 N- (2-thienylethyl) acetami
Compound

[0039]

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1.07 g (28.3 mmol) of sodium borohydride
1.00 ml (9.42 mmol) of 2-thienylacetonitrile was added to a suspension of 15 ml of ethylene glycol dimethyl ether. 1.00 ml (18.8 mmol) of sulfuric acid while stirring under ice cooling
Was added dropwise. After stirring at room temperature for 30 minutes,
0.5 ml (9.4 mmol) was added dropwise twice. Under ice cooling, the mixture was diluted with 20 ml of t-butyl methyl ether, quenched with 4 ml of methanol, and then added with 25 ml of 2N-sodium hydroxide solution.
The precipitated sodium sulfate was filtered to obtain a solution containing 2-thienylethylamine. Under stirring, 0.9 ml (31.8 mmol) of acetic anhydride was added dropwise. After stirring for 10 minutes, the layers were separated and the organic layer was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane /
Ethyl acetate) to give the title compound as a pale yellow oil (528m)
g was obtained. (Yield; 33%) ¹ H-NMR (400 MHz, CDCl ₃ ); δ (ppm) 7.17 (1 H, dd, J = 1.2,5.
2Hz), 6.96 (1H, dd, J = 3.6,5.2Hz), 6.84 (1H, dd, J = 1.2,3.6H
z), 5.57 (1H, br), 3.53 (2H, dd, J = 6.4, 12.8 Hz), 3.04 (2H, d
d, 12.8, 6.4 Hz), 1.97 (3H, s). IRnmax (neat); 3285, 3079, 2929, 2360, 1651, 1556, 1435,
1366, 1296cm ^-1 .

[Brief description of the drawings]

FIG. 1. Starting material (1- [1- (4-fluorophenethyl) piperidin-4-yl] -6-cyanoindoline, retention time: 6.59
2) is an HPLC chart for (min).

FIG. 2 is an HPLC chart confirming the completion of the reaction by disappearance of the peak of the raw material.

──────────────────────────────────────────────────続 き Continued on the front page (51) Int.Cl. ⁶ Identification symbol FI C07C 217/48 C07C 217/48 // C07D 207/335 C07D 207/335

Claims (7)

[Claims] 1. A nitrile derivative (I) represented by the general formula R ¹ CN wherein R ¹ is a group represented by the following general formula: (Wherein, a bond represented by the following general formula: Represents a single bond or a double bond. R ² is a hydrogen atom,
A lower alkyl group, a lower alkoxy group or a halogen atom, and n means 0 or an integer of 1-3. ), A group represented by the following general formula: (Wherein R ³ represents a hydrogen atom, a lower alkyl group, a lower alkoxy group or a halogen atom), a group represented by the following general formula: (In the formula, R ⁴ represents a hydrogen atom, a lower alkyl group, a lower alkoxy group or a halogen atom.) Or a group represented by the following general formula: (In the formula, R ⁵ represents a hydrogen atom, a lower alkyl group, a lower alkoxy group or a halogen atom, and A represents a sulfur atom, an oxygen atom or an NH group.) Is reduced in the presence of sodium borohydride and sulfuric acid, wherein the amine represented by the general formula R ¹ CH ₂ NH ₂ (wherein R ¹ has the same meaning as described above). Method for producing derivative (II). 2. The method according to claim 1, wherein the nitrile derivative (I) is 1- [1- (4-fluorophenethyl) piperidin-4-yl] -6-cyanoindoline, benzonitrile, cyanopyridine or thienylacetonitrile. Amine derivatives (II)
Manufacturing method. 3. The use amount of sodium borohydride is 1.0
The method for producing an amine derivative (II) according to claim 1 or 2, wherein the amount is from -5.0 equivalents. 4. The process for producing an amine derivative (II) according to claim 1, wherein the amount of sulfuric acid used is 1.0 to 5.0 equivalents. 5. After reacting using 2.0 equivalents of sulfuric acid,
5. The process for producing an amine derivative (II) according to claim 1, wherein 1.0 equivalent is further added. 6. The amount of sodium borohydride used is 3.0
The method for producing an amine derivative (II) according to any one of claims 1 to 5, wherein the reaction is carried out by using 2.0 equivalents of sulfuric acid and then adding 1.0 equivalent. 7. The method for producing an amine derivative (II) according to claim 1, wherein the solvent is ethylene glycol dimethyl ether or diethylene glycol dimethyl ether.