JP2001089447A - Production of n-alkoxycarbonyl cyclic ketone containing nitrogen - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a new method for producing N-alkoxycarbonyl cyclic ketones containing nitrogen by a simple method in a high yield. SOLUTION: This method for producing N-alkoxycarbonyl cyclic ketones containing nitrogen is provided by reacting an N-benzyl cyclic ketones containing nitrogen with dicarbonate in the presence of a hydrogen-donating compound to obtain the N-alkoxycarbonyl cyclic ketones containing nitrogen expressed by a general formula (3) (A is a nitrogen-containing cyclic ketone residue; R is an alkyl).

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

The present invention relates to a method for producing N-alkoxycarbonyl-containing cyclic ketones, which are compounds useful as raw materials or intermediates of pharmaceuticals and agricultural chemicals. Specifically, N-alkoxycarbonyl-4-piperidone, N-alkoxycarbonyl-3-piperidone or N-alkoxycarbonyl-3-piperidone
-Alkoxycarbonyl-3-pyrrolidone. The compound is used, for example, as a main raw material of a 4-heterocyclic piperidine derivative which functions to promote the release of growth hormone in humans and animals.
506914).

[0002]

2. Description of the Prior Art N-Alkoxycarbonyl-4-piperidone can be produced by the following methods: (1) 4-piperidone hydrochloride hydrate and di-t-t-dimethyldiamide (DMF).
There is a method in which butyl dicarbonate is charged, an amine is added thereto, reacted, and alkoxycarbonylated to obtain an intended product (Japanese Patent Application Laid-Open No. 10-506914).

As a method for producing N-alkoxycarbonyl-3-piperidone, (2) 3-piperidone hydrobromide hydrate is prepared by adding di-piperidone hydrobromide hydrate in the presence of a large excess of triethylamine.
A method of obtaining the desired product by reacting with t-butyl dicarbonate (J. Med. Chem., Vol. 29, 224-229)
1986).

As a method for producing N-alkoxycarbonyl-3-pyrrolidone, (3) freed 3-pyrrolidinol is converted to di-t-pyrrolidinol in the presence of a large excess of triethylamine.
-Butyl dicarbonate to give N-alkoxycarbonyl-3-pyrrolidinol, which is oxidized with methylene chloride with pyridinium chlorochromate (PCC) to give the desired product (Synth. Com.
mun. 15, Vol. 587-598 (1985)).

However, N-alkoxycarbonyl-4-piperidone and N-alkoxycarbonyl-3-
In the methods (1) and (2) relating to the method for producing piperidone, 4-piperidone hydrochloride and 3-piperidone hydrobromide easily become hydrates because of their hygroscopicity, and are alkoxycarbonylating agents. An excess amount of dicarbonate is required. Furthermore, since a base is required for freeing the nitrogen atom of the piperidine ring, steps such as neutralization and washing are required at the time of purification, and the operation is complicated.

The method (3) relating to the method for producing N-alkoxycarbonyl-3-pyrrolidone uses toxic pyridinium chlorochromate (PCC), which may deteriorate the working environment. Is not satisfactory for industrialization.

[0007]

SUMMARY OF THE INVENTION An object of the present invention is to provide an N-
It is an object of the present invention to provide a novel production method for producing an alkoxycarbonyl nitrogen-containing cyclic ketone by a simple method in a high yield.

[0008]

The present inventors have made intensive studies to solve the above problems, and as a result, have found that N-benzyl nitrogen-containing cyclic ketones and dicarbonate are reacted in the presence of a hydrogen donor. As a result, a novel method for obtaining the corresponding N-alkoxycarbonyl nitrogen-containing cyclic ketones was found, and the present invention was completed.

That is, the present invention provides a compound represented by the general formula (1):

Embedded image N-benzyl-containing cyclic ketones represented by the general formula (2)

Embedded image (Wherein R represents an alkyl group) by reacting with dicarbonate represented by the formula (3) in the presence of a hydrogen donor and optionally a catalyst, particularly a catalyst containing palladium.

Embedded image (Wherein, A and R are the same as defined above), wherein the N-alkoxycarbonyl nitrogen-containing cyclic ketone is obtained.

[0010]

DESCRIPTION OF THE PREFERRED EMBODIMENTS The present invention will be described below in detail. R in the formulas of the dicarbonate and the target compound of the present invention is an alkyl group, which may be linear or branched, and is not particularly limited. For example, methyl group, ethyl group, n-propyl group, isopropyl group, n-butyl group, isobutyl group,
Examples include a t-butyl group and a t-amyl group.

Specific examples of the target compound in the present invention include N-methoxycarbonyl-4-piperidone,
Methoxycarbonyl-3-piperidone, N-methoxycarbonyl-3-pyrrolidone, N-ethoxycarbonyl-
4-piperidone, N-ethoxycarbonyl-3-piperidone, N-ethoxycarbonyl-3-pyrrolidone, N-
Propoxycarbonyl-4-piperidone, N-propoxycarbonyl-3-piperidone, N-propoxycarbonyl-3-pyrrolidone, N-isopropoxycarbonyl-4-piperidone, N-isopropoxycarbonyl-3
-Piperidone, N-isopropoxycarbonyl-3-pyrrolidone, N-butoxycarbonyl-4-piperidone,
N-butoxycarbonyl-3-piperidone, N-butoxycarbonyl-3-pyrrolidone, N-isobutoxycarbonyl-4-piperidone, N-isobutoxycarbonyl-3-piperidone, N-isobutoxycarbonyl-3-
Pyrrolidone, Nt-butoxycarbonyl-4-piperidone, Nt-butoxycarbonyl-3-piperidone,
Nt-butoxycarbonyl-3-pyrrolidone, Nt
-Amyl-4-piperidone, Nt-amyl-3-piperidone, Nt-amyl-3-pyrrolidone and the like.

Examples of the dicarbonate include dimethyl dicarbonate, diethyl dicarbonate, dipropyl dicarbonate, diisopropyl dicarbonate, dibutyl dicarbonate, diisobutyl dicarbonate, di-t-carbonate.
Butyl dicarbonate, di-t-amyl dicarbonate and the like can be mentioned. The amount of the dicarbonate used may be an equimolar amount or more with respect to the N-benzyl nitrogen-containing cyclic ketone, but is preferably 1 to 1.5 times the molar amount.

Examples of the catalyst include a palladium-containing catalyst, a rhodium-containing catalyst, a nickel-containing catalyst and the like, and a palladium-containing catalyst is particularly preferable. These catalysts can be used as heterogeneous catalysts or homogeneous catalysts. As the heterogeneous catalyst, a catalyst in which palladium, rhodium or nickel is supported on a carrier such as activated carbon, alumina, silica and barium sulfate can be used. Specifically, when palladium is used as an example, palladium carbon, palladium alumina, palladium silica, palladium barium sulfate and the like can be mentioned. Examples of the homogeneous catalyst include palladium oxide, inorganic salts of palladium such as palladium chloride and palladium bromide, organic acid salts such as palladium acetate and palladium benzoate, and di-μ-chlorobis [(η-allyl) palladium ( I
I)], dichlorobis (acetonitrile) palladium (I
And palladium complexes such as I). palladium,
The use amount of palladium, rhodium or nickel in a catalyst containing rhodium or nickel will be described taking the case of palladium as an example, but the use amount is the same as that of palladium. Taking the amount of palladium used (as palladium atoms) as an example, in the case of a heterogeneous catalyst, the amount of palladium is usually 0.1 to 0.1% with respect to N-benzyl nitrogen-containing cyclic ketones.
It is 0.5 to 1% by weight, preferably 0.12 to 1.0% by weight. In the case of a homogeneous catalyst, the content is 0.5 to 10% by weight, preferably 1.2 to 3% by weight, based on the N-benzyl nitrogen-containing cyclic ketone. A preferred palladium-containing catalyst is palladium carbon in view of ease of recovery of the catalyst, amount of the catalyst used, and the like.

Examples of the hydrogen donor include hydrogen, formic acid, cyclohexene, and isopropanol, and a typical one is hydrogen. The pressure of hydrogen is not particularly limited, but is preferably in the range of normal pressure to 1.0 MPa. If the hydrogen pressure is too high, decomposition and excessive reduction of the raw materials and products proceed, and the yield of the target product decreases.

Although the reaction proceeds even without a solvent, the absence of a solvent increases the viscosity of the reaction system, slowing the progress of the reaction and complicating the operability of the post-treatment. Become. When a solvent is used, there is no particular limitation as long as it does not affect the reaction. For example, toluene, ethyl acetate, tetrahydrofuran, an organic acid, or a mixture thereof can be used.

The reaction of the present invention is an exothermic reaction, and proceeds favorably at a reaction temperature in the range of 10 to 60 ° C. If the temperature is lower than 10 ° C., a sufficient reaction rate cannot be obtained, which is not preferable. If the temperature is too high, the catalyst is deactivated and the yield of the desired product is reduced.

After completion of the reaction, the desired product can be purified according to a conventional method. For example, after filtering the catalyst and distilling off the solvent from the reaction mixture under reduced pressure, the target product is purified by distillation, recrystallization, column chromatography and the like.

[0018]

EXAMPLES The present invention will be described below with reference to examples.
The present invention is not limited thereby.

Example 1 N-benzyl-4- was added to a 1-L electromagnetic stirring type autoclave.
50 g (264 mmol) of piperidone, 61 g (277 mmol) of di-t-butyl dicarbonate, toluene 2
23g, 2.5g of 5wt% palladium carbon catalyst was added,
The reaction was performed at a hydrogen pressure of 0.5 MPa and 60 ° C. It took 7 hours to stop hydrogen absorption. After cooling the reaction solution, the catalyst was filtered off, the solvent was distilled off with an evaporator, and the residue was recrystallized with hexane to give 50 g of the target compound, Nt-butoxycarbonyl-4-piperidone (251 mmol, yield 95%).
%, Melting point 73.7 ° C).

NMR spectrum (CDCl ₃ ) δpp
m: 1.50 (9H, s), 2.45 (4H, t),
3.72 (4H, t) mass spectrum m / e: 199 (M ⁺ ), 114, 1
26, 56 (base)

Example 2 In a 200 mL autoclave, 1.0 g (5.3 mmol) of N-benzyl-4-piperidone, 1.3 g (5.8 mmol) of di-t-butyl dicarbonate, 4.4 g of toluene and 5 wt. 67% of a palladium-alumina catalyst was added, and the mixture was reacted at a hydrogen pressure of 1.0 MPa and 50 ° C. It took one hour to stop hydrogen absorption. Thereafter, the same treatment as in Example 1 was performed, and Nt-butoxycarbonyl-4-piperidone 0.88 g (4.42 mmol, yield 83.6) was obtained.
%).

Example 3 In a 200 mL autoclave, 1.0 g (5.3 mmol) of N-benzyl-4-piperidone, 1.3 g (5.8 mmol) of di-t-butyl dicarbonate, 4.4 g of toluene, oxidation 65 mg of a palladium catalyst was added, and the mixture was reacted at a hydrogen pressure of 0.5 MPa and 50 ° C. It took 3 hours to stop hydrogen absorption. Thereafter, the same treatment as in Example 1 was performed, and Nt-butoxycarbonyl-4-piperidone 0.1.
99 g (4.95 mmol, 93.6% yield) were obtained.

Example 4 In a 200 mL autoclave, 1.0 g (5.3 mmol) of N-benzyl-4-piperidone, 1.3 g (5.8 mmol) of di-tert-butyl dicarbonate, 4.4 g of toluene, and acetic acid 140 mg of a palladium catalyst was added, and the mixture was reacted at a hydrogen pressure of 1.0 MPa and 50 ° C. It took 3 hours to stop hydrogen absorption. Thereafter, the same treatment as in Example 1 was performed, and Nt-butoxycarbonyl-4-piperidone 0.1.
93 g (4.67 mmol, yield 88.3%) were obtained.

Example 5 In a 200 mL autoclave, 3.1 g (16.6 mmol) of N-benzyl-4-piperidone, 4.5 g (18.3 mmol) of di-t-amyl dicarbonate, 8.1 g of toluene and 5 wt. Then, 220 mg of a palladium on carbon catalyst was added and reacted at 45 ° C. under a hydrogen pressure of 0.5 MPa. It took one hour to stop hydrogen absorption. After cooling the reaction solution, the catalyst was filtered off, the solvent was distilled off with an evaporator, and the residue was purified by column chromatography [silica gel, hexane / ethyl acetate = 5/1 (v / v)] to give Nt- 3.5 g of amyloxycarbonyl-4-piperidone (1
6.4 mmol, yield 98.9%).

NMR spectrum (CDCl ₃ ) δpp
m: 0.92 (3H, t), 1.47 (6H, s),
1.82 (2H, q), 2.44 (4H, t), 3.7
3 (4H, t) mass spectrum m / e: 213 (M ⁺ ), 198, 1
84, 144, 126, 71 (base)

Example 6 In a 200 mL autoclave, 4.0 g (21.1 mmol) of N-benzyl-3-piperidone, 5.4 g (24.7 mmol) of di-t-butyl dicarbonate, 17.3 g of toluene and 5 wt. 0.6 g of a palladium on carbon catalyst was added, and the mixture was reacted at 55 ° C. under a hydrogen pressure of 1.0 MPa. It took 5 hours to stop hydrogen absorption. After cooling the reaction solution, the catalyst was filtered, the solvent was distilled off by an evaporator, and the residue was purified by distillation to obtain 4.0 g of Nt-butoxycarbonyl-3-piperidone (20.0 mmol, yield 94. 7%, boiling point 115 / 2.0 mmHg).

NMR spectrum (CDCl ₃ ) δpp
m: 1.49 (9H, s), 1.98 (2H, tt),
2.47 (2H, t), 3.59 (2H, t), 4.0
1 (2H, s) mass spectrum m / e: 199 (M ⁺ ), 143, 1
26, 57 (base)

Example 7 N-benzyl-3- was added to a 1-L electromagnetically stirred autoclave.
Pyrrolidone 30 g (171 mmol), di-t-butyl dicarbonate 44 g (200 mmol), toluene 2
26 g, 10 g (171 mmol) of acetic acid, 6.0 g of 5 wt% palladium carbon catalyst were added, and the hydrogen pressure was 0.5 MPa.
The reaction was performed at 40 ° C. It took 27 hours to stop hydrogen absorption. After cooling the reaction solution, the catalyst was filtered, the solvent was distilled off by an evaporator, and the residue was purified by distillation to obtain 57 g of Nt-butoxycarbonyl-3-pyrrolidone (146 mmol, yield 85.2%, boiling point 104-109 / 0.3mm
Hg).

NMR spectrum (CDCl ₃ ) δpp
m: 1.49 (9H, s), 2.59 (2H, t),
3.75 (2H, s), 3.78 (2H, t) Mass spectrum m / e: 185 (M ⁺ ), 170, 1
30, 112, 57 (base)

[0030]

According to the present invention, N-alkoxycarbonyl-4-piperidone, N-alkoxycarbonyl-3-piperidone or N-alkoxycarbonyl-3-pyrrolidone, which is useful as a raw material or intermediate of pharmaceuticals and agricultural chemicals, has a corresponding N-alkoxycarbonyl-3-pyrrolidone. -It can be easily and efficiently produced from a benzyl form.

Claims (2)

[Claims] 1. A compound of the general formula (1) N-benzyl nitrogen-containing cyclic ketones represented by the general formula (2) (Wherein R represents an alkyl group) by reacting with a dicarbonate represented by the following general formula (3): (Wherein A and R are the same as defined above), wherein the N-alkoxycarbonyl nitrogen-containing cyclic ketone is obtained. 2. A compound of the general formula (1) N-benzyl nitrogen-containing cyclic ketones represented by the general formula (2) (Wherein R represents an alkyl group) in the presence of a catalyst containing hydrogen and palladium by reacting with a dicarbonate represented by the following general formula (3): (Wherein A and R are the same as defined above), wherein the N-alkoxycarbonyl nitrogen-containing cyclic ketone is obtained.