JP3086837B2 - Method for producing 3-aminopyrrolidines - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

The present invention relates to a compound represented by the general formula (II):

[0002]

Embedded image [In the formula, Z represents NR ₁ , an oxygen atom or a sulfur atom, and R ₁ represents a hydrogen atom, a substituted or unsubstituted alkyl group, an alkenyl group, an aralkyl group, an aryl group, an alkoxycarbonyl group, an aryloxycarbonyl group. Or an acyl group, and R ₂ represents a hydrogen atom, a halogen atom, a substituted or unsubstituted alkyl group, an alkenyl group, an aralkyl group, an aryl group, a hydroxyl group, an alkoxy group, an aryloxy group, an acyloxy group, a carboxyl group, an alkoxy group. Carbonyl group, aryloxycarbonyl group,
Or an acyl group. And a process for producing 3-aminopyrrolidines represented by the formula:

[0003]

BACKGROUND OF THE INVENTION The 3-aminopyrrolidines represented by the general formula (II) of the present invention are useful compounds as raw materials for medicines, agricultural chemicals and the like. For example, as described in EP 132,845, 1-benzyl-3-aminopyrrolidine is used as a raw material for 1,8-naphthyridine antibacterial agents. As described in JP-A-57-2266, the 2,3-cis isomer of 1-benzyl-2-methyl-3-aminopyrrolidine is used as a raw material for an antipsychotic.

[0004]

2. Description of the Related Art There have been many studies on a method for synthesizing 3-aminopyrrolidines, for example, see "Journa of Medicinal Chemistry".
l of Medicinal Chemistry) ", 11 (5), 193
Page 4 (1968) and British Patent No. 1,392,194 describe a method for obtaining the corresponding aminopyrrolidine using, for example, 3-chloropyrrolidine as a raw material. However, it is difficult to synthesize 3-chloropyrrolidine as a raw material, and phthalimide must be used as an intermediate, which is not an industrially advantageous method. Also, generally, `` Journal of Medicinal Chemistry
Medicinal Chemistry), Vol. 24 (No. 10), p. 1244 (1981) and JP-A No. 55-22699, a method for reducing the corresponding 3-hydroxyiminopyrrolidine using Raney nickel as a catalyst is known. ing. However, this method is not industrially advantageous because it uses a large amount of Raney nickel as a catalyst and thus has a high risk of ignition and a low yield. Further, for example, from 1-benzyl-2-methyl-3-hydroxyiminopyrrolidine, the corresponding 2,3-cis isomer and trans isomer of 3-aminopyrrolidine are obtained only as an equal mixture, and Under the conditions, the selectivity of the cis isomer was not noticeable.

In order to obtain an isomer in which the amino group at the 3-position and the substituent at the 2-, 4- or 5-position respectively have the cis configuration, the isomer can be obtained from the corresponding 3-hydroxyiminopyrrolidine by a usual hydrogen reduction reaction. No suitable method has been found other than resolving the mixture of the cis form and the trans form into a carboxylate, for example. On the other hand, a method of stereoselectively synthesizing a compound having a limited substituent is known. That is, "Journal of Medicinal Chemistry", Vol. 24 (No. 10), p. 1244 (1981) describes 2,3-cis of 1-benzyl-2-methyl-3-aminopyrrolidine.
As a fumaric acid salt from a mixture of
Although a method for resolving the s-isomer is described, the yield is low,
There are many practical problems. When such a fractionation method is applied, the size of the cis ratio in the mixture amplifies and affects the fractionation yield.
It is important to keep the is ratio as high as possible. The method of stereoselectively synthesizing is also described in, for example, `` Journal of Medicinal Chemistry (Journal of Medicinal Chemistry)
Chemistry) 33 (5), 1344 (1990)
Describes a method for selectively obtaining a 3,4-cis form, but the reaction step is extremely long and complicated as shown by the following chemical formula, and the type of the substituent R _{2 in} the general formula (II) is described. Is limited and lacks versatility. Further, it is considered that application of the compound as an industrial synthetic method is difficult from the viewpoint of safety, for example, through a compound having an azide group as an intermediate.

[0006]

Embedded image

[0007]

As described above, the currently known methods for producing 3-aminopyrrolidines have many problems and are not satisfactory as industrial methods.

Thus, an object of the present invention is to provide an economical method for producing high-quality 3-aminopyrrolidines in a high yield under simple and mild conditions as compared with the conventional methods.

It is still another object of the present invention to provide a method for highly selectively synthesizing an isomer in which the amino group at the 3-position of the pyrrolidine ring and the substituent at the 2-, 4- or 5-position are in a cis configuration.

[0010]

Means for Solving the Problems In order to solve the above-mentioned problems, the present inventors have made intensive studies on the synthesis reaction of 3-aminopyrrolidines. As a result, metal boride was used as a reducing catalyst, and sodium was used as a reducing agent, for example. By using borohydride, high quality 3 under normal pressure and mild conditions
The present inventors have found that -aminopyrrolidines can be obtained in high yield, and have completed the present invention.

That is, the present invention provides a method for preparing a compound of the formula (I) from a 3-iminopyrrolidine derivative represented by the formula (I).
The present invention relates to a method for producing 3-aminopyrrolidines, which comprises reducing the 3-aminopyrrolidine derivative represented by I) in the presence of the metal boride represented by the general formula (III).

The following general formula (I)

[0013]

Embedded image In the compound represented by the formula, Z represents NR ₁ , an oxygen atom or a sulfur atom, and R ₁ is, for example, a hydrogen atom, an unsubstituted alkyl group (for example, a methyl group, an ethyl group, a propyl group, an isopropyl group, an octyl group) , A decyl group, a cyclohexyl group, etc.), an alkyl group having a substituent (for example, a carboxyl group, a halogen atom (eg, a fluorine atom, a chlorine atom, etc.), a hydroxyl group, an alkoxycarbonyl group (eg, methoxycarbonyl) Group, ethoxycarbonyl group, benzyloxycarbonyl group, etc.), aryloxycarbonyl group (eg, phenoxycarbonyl group, etc.), alkoxy group (eg, methoxy group, ethoxy group, benzyloxy group, phenethyloxy group, etc.), monocyclic group Aryloxy group (for example, phenoxy group, p-to A carbamoyl group (eg, carbamoyl group, N, N-dimethylcarbamoyl group, morpholinocarbonyl group, piperidinocarbonyl group, etc.), an acyloxy group (eg, acetyloxy group, propionyloxy group, capryloxy group, etc.) ), A sulfamoyl group (eg, a sulfamoyl group, an N, N-dimethylsulfamoyl group, a morpholinosulfamoyl group, etc.), an acylamino group (eg, an acetylamino group, a propionylamino group, a benzoylamino group, a mesylamino group, etc.), Examples thereof include a sulfonamide group (for example, an ethylsulfonamide group, a p-toluenesulfonamide group, etc.), an alkenyl group (for example, an allyl group, a 3-butenyl group, and the like), and an aralkyl group (for example, a benzyl group, -Chlorobenzyl group , 4
-Methylbenzyl group, 1-naphthylmethyl group, etc.), aryl group (eg, phenyl group, 4-methylphenyl group, etc.), alkoxycarbonyl group (eg, methoxycarbonyl group, ethoxycarbonyl group, benzyloxycarbonyl group, etc.), Aryloxycarbonyl group (for example, phenoxycarbonyl group etc.), acyl group (for example,
Acetyl, propionyl, benzoyl, p-toluenesulfonyl, etc.), but are not limited thereto.

R ₂ is, for example, a hydrogen atom, a halogen atom (eg, a fluorine atom, a chlorine atom, etc.), a substituted or unsubstituted alkyl group (the same substituents as R ₁ ), alkenyl Groups (eg, allyl group, 3-butenyl group, etc.), aralkyl groups (eg, benzyl group, 4-chlorobenzyl group, 4-methylbenzyl group, 1-naphthylmethyl group, etc.), aryl groups (eg, phenyl group, 4-methylphenyl group),
Alkoxy group (eg, methoxy group, ethoxy group, benzyloxy group, phenethyloxy group, etc.), aryloxy group (eg, phenoxy group, etc.), alkoxycarbonyl group (eg, methoxycarbonyl group, ethoxycarbonyl group, benzyloxycarbonyl group) ), An aryloxycarbonyl group (for example, a phenoxycarbonyl group, etc.), an acyloxy group (for example, an acetyloxy group, a propionyloxy group, a capryloxy group, etc.),
Examples include, but are not limited to, acyl groups (eg, acetyl, propionyl, benzoyl, p-toluenesulfonyl, etc.), hydroxyl, and carboxyl.

R ₃ is a hydrogen atom, a substituted or unsubstituted alkyl group (the same substituents as R ₁ can be mentioned), an alkenyl group (for example, allyl group, 3
-Butenyl group), an aralkyl group (for example, benzyl group, 4-chlorobenzyl group, 4-methylbenzyl group, 1
-Naphthylmethyl group) and an acyl group (e.g., acetyl group, propionyl group, benzoyl group, p-toluenesulfonyl group, etc.), but are not limited thereto.

The starting material of the present invention has the above general formula (I)
3-iminopyrrolidines represented by, for example, "Journal of Medicinal Chemistry (Journal o
f Medicinal Chemistry) ”Vol. 24 (No. 10), 1244
The compound can be easily synthesized according to the method described on page (1981) or according to this method.

For reducing 3-iminopyrrolidine represented by the above general formula (I) to obtain 3-aminopyrrolidine, a metal boride is used as a catalyst. As the metal, nickel or cobalt is used alone or in combination. Metal boride is described, for example, in "Industrial and Engineering Chemistry (Industr).
ial and Engineering Chemi
story) ", 44, 1006 (1952), and" Journal of Organic Chemistry ".
Chemistry) 35 (6), 1900 p.
970) can be easily prepared. The amount of the metal boride used is 0.01 to the 3-iminopyrrolidine derivative represented by the general formula (I).
It is in the range of ５０50 mole percent, with the range of 1-20 mole percent being particularly preferred.

Examples of the reducing agent include sodium borohydride, lithium borohydride, potassium borohydride and the like, and these are used alone or in combination.
The amount of the reducing agent is not particularly limited as long as it is equal to or more than an equivalent, but is preferably equal to or less than 3 equivalents.

As a reaction solvent, water, methanol, ethanol, isopropanol, diethyl ether, tetrahydrofuran, dioxane, monoglyme or a mixed solvent thereof can be used. The amount of the solvent used depends on the solubility of the 3-iminopyrrolidine used in the solvent, and is not particularly limited, but may be about 2 to 20 times the volume.

The reaction is carried out at normal pressure or under pressure,
Although the process proceeds at a temperature of from about ° C to about 120 ° C, it is preferably performed at a temperature of from about -30 ° to about 80 ° C. After the completion of the reaction, the reaction solution is cooled to, for example, near room temperature, and after removing precipitated inorganic substances, the resultant is concentrated to obtain a crude target substance. Also, for example, ethyl acetate,
The reaction product is extracted with an organic solvent such as toluene, chloroform, hexane, or ether, and then concentrated to obtain a crude target product. Next, if necessary, high-quality 3-aminopyrrolidines represented by the general formula (II) can be obtained by distillation or recrystallization.

[0021]

The present invention will be described in more detail with reference to the following Reference Examples and Examples, which should not be construed as limiting the invention. Reference Example 1 25.7 g of hydroxylamine hydrochloride was dissolved in 50 ml of water and 80 ml of methanol. 35 g of 1-benzyl-2-methyl-3-pyrrolidinone (0.185
Mol) in 20 ml of methanol and added dropwise at about 30 ° C. Add 25.8 g of potassium carbonate, and add 3 at 20-30 ° C.
After reacting for 0 minutes, 300 ml of water is gradually added dropwise.
The crystallized crystals were separated by filtration and washed with water to obtain 15.0 g of 1-benzyl-2-methyl-3-hydroxyiminopyrrolidine. (Yield 92.6%) mp. 97-99 ° C. NMR spectrum (CDCl ₃ ) δ: 1.3 (3H,
d), 2.2 (1H, q), 2.6 (2H, t), 3.
0 (2H, t), 3.7 (2H, d), 7.3 (5H,
m), 8.7 (1H, s) (Reference Example-2) 20.4 g (0.10 mol) of 1-benzyl-2-methyl-3-hydroxyiminopyrrolidine, 5 g of Raney nickel, and 200 ml of methanol 100 ml
The mixture is charged into an autoclave, and the reaction is carried out at 40 to 50 ° C. for 1 hour at a hydrogen pressure of 20 kg / cm ² . After filtering off the catalyst,
After concentration and distillation, 9.8 g of 1-benzyl-2-methyl-3-aminopyrrolidine was obtained. (Yield 52.0%) bp. 120 ° C./0.4 mmHg NMR spectrum (CDCl ₃ ) δ: 1.1 (3H,
d), 1.4 (2H, s), 1.5 (1H, m), 2.
0 (2H, m), 2.3 (1H, m), 2.8 (1H,
m), 3.1 (1H, d), 3.2 (1H, m), 3.
9 (1H, d), 7.3 (5H, s) C. (OV-22, 3%, 2m) cis isomer 50% trans isomer 50% (Example-1) 6.3 g (0.031 mol) of 1-benzyl-2-methyl-3-hydroxyiminopyrrolidine, chloride 0.37 g of nickel (II) hexahydrate is dissolved in 23 ml of ethanol and cooled to 10 ° C. A solution of 2.0 g of sodium borohydride in 7 ml of water was added to 1
The solution is added dropwise at 0 to 20 ° C., and reacted at room temperature for 1 hour. The precipitated inorganic substance was separated by filtration, concentrated and distilled to give 1-benzyl-2-
5.2 g of methyl-3-aminopyrrolidine were obtained. (Yield 88.2%) bp. 120 ° C./0.4 mmHg NMR spectrum (CDCl ₃ ) δ: 1.1 (3H,
d), 1.4 (2H, s), 1.5 (1H, m), 2.
0 (2H, m), 2.3 (1H, m), 2.8 (1H,
m), 3.1 (1H, d), 3.2 (1H, m), 3.
9 (1H, d), 7.3 (5H, s) C. (OV-22, 3%, 2m) cis isomer 88% trans isomer 12% (Example-2) 6.3 g (0.031 mol) of 1-benzyl-2-methyl-3-hydroxyiminopyrrolidine, chloride 0.37 g of nickel (II) hexahydrate is dissolved in 23 ml of methanol and cooled to -20 ° C. Sodium borohydride 2.0g dissolved in water 7ml,
The solution is added dropwise at -10 ° C or lower, and the reaction is performed for 1 hour. The reaction solution was adjusted to pH 6 by adding 5N-hydrochloric acid to dissolve the nickel boride as a catalyst, and then added with 20 ml of water and extracted with 30 ml of chloroform. After concentration, distillation to give 1-benzyl-
5.0 g of 2-methyl-3-aminopyrrolidine was obtained.
(Yield 84.8%) bp. 120 ° C./0.4 mmHg C. (OV-22, 3%, 2m) cis isomer 94% trans isomer 6% (Example-3) 27 ml of a 10% aqueous solution of sodium borohydride and 121 ml of a 5% aqueous solution of nickel (II) chloride
While stirring. The precipitated black nickel boride is filtered off without contact with air and stored in an ethanol solution.

6.3 g (0.031 mol) of 1-benzyl-2-methyl-3-hydroxyiminopyrrolidine, 0.63 g of nickel boride prepared by the above method and 23 ml of ethanol are charged. Sodium borohydride
What melt | dissolved 5 g in 5.3 ml of water was dripped at 10-20 degreeC, and it reacted at room temperature for 1 hour. The precipitated inorganic substance was separated by filtration, concentrated and distilled to give 1-benzyl-2-methyl-3-.
5.1 g of aminopyrrolidine were obtained. (Yield 86.5%) bp. 120 ° C./0.4 mmHg C. (OV-22, 3%, 2m) cis isomer 87% trans isomer 13% (Example-4) 6.3 g (0.031 mol) of 1-benzyl-2-methyl-3-hydroxyiminopyrrolidine, chloride 0.50 g of cobalt (II) hexahydrate is dissolved in 23 ml of ethanol and cooled to 10 ° C. A solution of 2.0 g of sodium borohydride in 7 ml of water was added to 1
The solution is added dropwise at 0 to 20 ° C., and reacted at room temperature for 1 hour. The precipitated inorganic substance was separated by filtration, concentrated and distilled to give 1-benzyl-2-
4.8 g of methyl-3-aminopyrrolidine were obtained. (Yield 81.4%) bp. 120 ° C./0.4 mmHg C. (OV-22, 3%, 2m) cis isomer 86% trans isomer 14% (Example-5) 6.7 g (0.031 mol) of 1-benzyl-2-methyl-3-methoxyiminopyrrolidine, chloride 0.37 g of nickel (II) hexahydrate in ethanol 2
Dissolve in 3 ml and cool to 10 ° C. A solution of 2.0 g of sodium borohydride in 7 ml of water
After dropwise addition at 20 ° C., the reaction is carried out at room temperature for 1 hour. The precipitated inorganic substance was separated by filtration, concentrated and distilled to give 1-benzyl-2-
5.1 g of methyl-3-aminopyrrolidine were obtained. (Yield 86.5%) bp. 120 ° C./0.4 mmHg C. (OV-22, 3%, 2m) cis isomer 87% trans isomer 13% (Example-6) 6.7 g (0.031 mol) of 1-benzyl-2-ethyl-3-hydroxyiminopyrrolidine, chloride 0.37 g of nickel (II) hexahydrate is dissolved in 23 ml of ethanol and cooled to 10 ° C. A solution of 2.0 g of sodium borohydride in 7 ml of water was added to 10 g
After dropwise addition at 16 ° C., the reaction is carried out at room temperature for 1 hour. The precipitated inorganic substance was separated by filtration, concentrated and distilled to give 1-benzyl-2.
5.8 g of -ethyl-3-aminopyrrolidine were obtained. (Yield 91.6%) bp. 130 ° C./0.4 mmHg C. (OV-22, 3%, 2m) cis isomer 89% trans isomer 11% (Example-7) 1-n-propyl-2-methyl-3-hydroxyiminopyrrolidine 0.78 g (0.005 mol) Then, 0.089 g of nickel (II) chloride hexahydrate was dissolved in 3 ml of ethanol and cooled to 10 ° C. A solution obtained by dissolving 0.38 g of sodium borohydride in 1.5 ml of water is added dropwise at 10 to 16 ° C, and then reacted at 40 ° C for 1 hour. After filtering off the precipitated inorganic substance, concentration and distillation,
0.46 g of 1-n-propyl-2-methyl-3-aminopyrrolidine was obtained. (Yield 64.7%) bp. 90 ° C./0.2 mmHg C. (OV-22, 3%, 2m) cis isomer 85% trans isomer 15% (Example-8) 2.1 g (0.01 mol) of 1-benzyl-5-methyl-3-hydroxyiminopyrrolidine, chloride 0.15 g of nickel (II) hexahydrate was added to ethanol 8
Dissolve in ml. A solution obtained by dissolving 0.8 g of sodium borohydride in 3 ml of water is added dropwise at 13 to 20 ° C. and reacted for 1 hour. The precipitated inorganic substance was separated by filtration, concentrated and distilled to obtain 1-benzyl-5-methyl-3-aminopyrrolidine (1.6 g). (Yield 84.1%) bp. 115 ° C./0.4 mmHg NMR spectrum (CDCl ₃ ) δ: 1.19 (3H,
d), 1.40 (1H, s) 1.5 to 2.7 (6H.
m), 3.1 (1H, d), 4.0 (1H, d), 7.
3 (5H, s) C. (OV-22, 3%, 2m) cis isomer 78% trans isomer 22% (Example-9) 0.58 g (0.005 mol) of 3-hydroxyimino-2-methyltetrahydrofuran, nickel (II) chloride 0.09 g of hexahydrate was added to ethanol 1.
Dissolve in 5 ml. Sodium borohydride 0.38
g in 1.5 ml of water was added dropwise at 10 to 14 ° C, and the reaction was carried out at 40 ° C for 1 hour. The precipitated inorganic substance was separated by filtration, concentrated and distilled to obtain 0.21 g of 3-amino-2-methyltetrahydrofuran. (Yield 41.2%) b. p. 50 ° C./0.5 mmHg NMR spectrum (CDCl ₃ ) δ: 1.2 (3H,
d), 1.5 (2H, br.s), 1.7 (2H, t)
d), 2.2 (2H, dt), 3.3 to 3.6 (1H,
m), 3.7-4.0 (2H, m). C. (OV-22, 3%, 2m) cis isomer 79% trans isomer 21% (Examples -10 to -17) The following compounds were synthesized in the same manner as in the above Examples -1 to -9. did.

[0023]

[Table 1]

[0024]

The following general formula (I)

[0025]

Embedded image [In the formula, Z represents NR ₁ , an oxygen atom or a sulfur atom, and R ₁ represents a hydrogen atom, a substituted or unsubstituted alkyl group, an alkenyl group, an aralkyl group, an aryl group, an alkoxycarbonyl group, an aryloxycarbonyl group. Or an acyl group, and R ₂ represents a hydrogen atom, a halogen atom, a substituted or unsubstituted alkyl group, an alkenyl group, an aralkyl group, an aryl group, a hydroxyl group, an alkoxy group, an aryloxy group, an acyloxy group, a carboxyl group, an alkoxy group. Carbonyl group, aryloxycarbonyl group,
R ₃ represents a hydrogen atom, a substituted or unsubstituted alkyl group, an alkenyl group, an aralkyl group, or an acyl group. Represented by 3-iminopyrrolidine acids in], M ₂ B [M represents a nickel or cobalt. Under the normal pressure and mild conditions in the presence of the metal boride represented by the formula (3) corresponding to the 3-iminopyrrolidines
In the aminopyrrolidines, isomers in which the amino group at the 3-position and the substituent at the 2-, 4-, or 5-position, respectively, have a cis configuration could be obtained with high selectivity.

──────────────────────────────────────────────────続 き Continued on the front page (51) Int.Cl. ⁷ Identification symbol FI C07D 333/38 C07D 333/38 (72) Inventor Yuji 5- 2-3 Higashi-Hachiman, Hiratsuka-shi, Kanagawa Sankyo Chemical Co., Ltd. (56) References JP-A-55-22699 (JP, A) JP-A-63-277655 (JP, A) (58) Fields investigated (Int. Cl. ⁷ , DB name) C07D 207/14 C07D 207/16 C07D 307/22 C07D 307/24 C07D 333/36 C07D 333/38 CA (STN) CAOLD (STN) REGISTRY (STN)

Claims (2)

(57) [Claims] 1. A compound represented by the following general formula (I) [In the formula, Z represents NR ₁ , an oxygen atom or a sulfur atom, and R ₁ represents a hydrogen atom, a substituted or unsubstituted alkyl group, an alkenyl group, an aralkyl group, an aryl group, an alkoxycarbonyl group, an aryloxycarbonyl group. Or an acyl group, and R ₂ represents a hydrogen atom, a halogen atom, a substituted or unsubstituted alkyl group, an alkenyl group, an aralkyl group, an aryl group, a hydroxyl group, an alkoxy group, an aryloxy group, an acyloxy group, a carboxyl group, an alkoxy group. Carbonyl group, aryloxycarbonyl group,
R ₃ represents a hydrogen atom, a substituted or unsubstituted alkyl group, an alkenyl group, an aralkyl group, or an acyl group. A 3-iminopyrrolidine represented by the general formula (III): M ₂ B wherein M represents nickel or cobalt. Wherein the reduction is carried out in the presence of a metal boride represented by the general formula (II): [Wherein, Z and R ₂ have the same meanings as in the general formula (I). ] The method for producing 3-aminopyrrolidines represented by the formula: 2. The following general formula (II): [Wherein, Z and R ₂ have the same meanings as in the general formula (I). 3-aminopyrrolidines represented by the formula:
The method according to claim 1, wherein an isomer having a cis configuration in which the amino group at the 3-position and the substituent at the 2-, 4- or 5-position, respectively, are obtained in a highly selective manner.