JP2672939B2 - Process for producing N-allyl-2,5-dimethyl-piperidinol-4-benzoyl ester - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

FIELD OF THE INVENTION The present invention relates to a piperidine derivative, more specifically, N-allyl-2,5-dimethyl-piperidinol-4-benzoyl ester of the following structural formula (I) (hereinafter referred to as "piperidine derivative (I)"). Sometimes called)
And a method for producing the same.

[0002]

Embedded image

[0003]

2. Description of the Related Art Piperidine derivative (I), which is mainly used as a local anesthetic, has an excellent continuous anesthetic effect and low toxicity as compared with other local anesthetics such as novocaine, cocaine and lidocaine. . As the method for synthesizing the piperidine derivative (I), for example, the following three methods are known.

The first method is the following formula

[0005]

Embedded image

According to the method, 2,3,5-trimethyl-4-piperidinol and ethyl chloroformate are reacted in a benzene solution. The second method is

[0007]

Embedded image

According to the method, 2-methyl-1,4-cyclohexanedione is reacted with liquid ammonia. And the third method is

[0009]

Embedded image

According to the method, a propenyl isopropenyl ketone (or its methoxy derivative) is reacted with ammonia. However, in the above-mentioned conventional method, it is not easy to synthesize a basic raw material, and a synthetic route of a desired compound is difficult and complicated.

[0011]

SUMMARY OF THE INVENTION An object of the present invention is to provide a method capable of producing a piperidine derivative (I) with a relatively easy method and a low production cost by using a raw material that is easily purchased. Especially.

[0012]

The method for producing N-allyl-2,5-dimethyl-piperidinol-4-benzoyl ester according to the present invention comprises (a) an α, β-unsubstituted compound of the following general formula (II): A step of producing a secondary amine of the following general formula (IV) by a Michael addition reaction between a saturated compound and a primary amine of the following general formula (III),

[0013]

Embedded image

(In the formula, R ¹ is --CN, --COOCH ₃ , --COOC.
₂ H _5, -COO- (p- nitrobenzyl), -COO- (p-methoxybenzyl), a -CO-O-COCH ₃ or -COOH. ) (B) generating a piperidinone derivative of the following formula (V) by Dieckmann condensation reaction of the secondary amine (IV),

[0015]

Embedded image

(C) a step of introducing an alcohol functional group and a methyl group by a reduction reaction of the piperidinone derivative (V) to produce 2,5-dimethyl-4-piperidinol of the following formula (VI) or a derivative thereof. ,

[0017]

Embedded image

(In the formula, R ² is a hydrogen atom, --COOCH ₃ , --COO
C ₂ H _5, -COO- (p- nitrobenzyl), -COO- (p-methoxybenzyl), a -CO-O-COCH ₃ or -COOH. ) (D) The 2,5-dimethyl-4-piperidinol or its derivative (VI) is reacted with an allylating reagent to form N-allyl-2,5-dimethyl-4-piperidinol of the following formula (VII) or its Generating a derivative,

[0019]

Embedded image

(In the formula, R ³ is a hydrogen atom, --COOCH ₃ , --COO
C ₂ H _5, -COO- (p- nitrobenzyl), -COO- (p-methoxybenzyl), a -CO-O-COCH ₃ or -COOH. ) (E) The N-allyl-2,5-dimethyl-4-piperidinol or its derivative (VII) is reacted with a benzoylating reagent to give a target compound, N-allyl-2, of the following formula (I): Forming a 5-dimethyl-piperidinol-4-benzoyl ester;

[0021]

Embedded image

Including In the production method of the present invention, 2,5-dimethyl-4-produced in the step (c) is used.
Piperidinol or its derivative (VI) is treated in the step (d)
Alternatively, the reaction product may be reacted with the benzoylating reagent by the step (e), but the order of the reaction is reversed and the reaction product produced in the step (c) is 5-Dimethyl-4-piperidinol or its derivative (VI) may be reacted first with a benzoylating reagent and then the reaction product thereof with an allylating reagent. That is, the production method of the present invention comprises the step (d)
Instead of (e), (f) 2,5-dimethyl-4-piperidinol or its derivative (VI) is reacted with a benzoylating reagent to react with 2,5-dimethyl-piperidinol-4 of the following formula (VIII). -Producing a benzoyl ester or derivative thereof,

[0023]

Embedded image

(In the formula, R ³ is a hydrogen atom, -COOCH ₃ , -COO.
C ₂ H _5, -COO- (p- nitrobenzyl), -COO- (p-methoxybenzyl), a -CO-O-COCH ₃ or -COOH. ) (G) The 2,5-dimethyl-piperidinol-4-benzoyl ester or its derivative (VIII) is reacted with an allylation reagent to give the target compound N-of the following formula (I):
Forming allyl-2,5-dimethyl-piperidinol-4-benzoyl ester;

[0025]

Embedded image

May be included. A basic catalyst is preferably used in the Michael addition reaction of the step (a). When a basic catalyst is used, the basic catalyst desorbs a proton (H ⁺ ) from the primary amine (III), and the amine group left behind becomes an active unsaturated group of the α, β-unsaturated compound (II). Addition produces a secondary amine (IV). The basic catalyst that can be used in this step is not particularly limited, but for example, sodium amide, sodium hydride, sodium methoxide, etc. can be used. Also,
As the reaction solvent, for example, ether, toluene,
An aromatic organic solvent such as xylene can be used.

It is preferable to use a basic catalyst also in the Dieckmann condensation reaction in the step (b). When a basic catalyst is used, the Dieckmann condensation reaction causes the active α-hydrogen of the secondary amine (IV) to be captured by the basic catalyst, whereby the activated α-carbon of the secondary amine (IV) is removed. The secondary amine (IV) is cyclized and hydrolyzed by an intramolecular nucleophilic reaction that attacks the carbonyl carbon to produce a piperidinone derivative (V). The basic catalyst that can be used in this step is not particularly limited, but for example, sodium amide, sodium hydride, sodium methoxide, etc. can be used. Moreover, as the reaction solvent, for example, an aromatic organic solvent such as toluene or xylene can be used in addition to ether.

Next, in the step (c), the alcohol functional group and the methyl group are introduced by the reduction reaction of the piperidinone derivative (V), and then the 2,5-dimethyl-4 produced.
-Piperidinol or its derivative (VI) is reacted first with an allylation reagent and then with a benzoylation reagent (steps (d), (e)) or vice versa, first with a benzoylation reagent and then with a benzoylation reagent. The desired N-allyl-2,5-dimethyl-piperidinol-4-benzoyl ester (I) is obtained by reacting with an allylating reagent (steps (f) and (g)).

R ¹ is -COOCH ₃ , -COOC ₂ H ₅ , -COO- (p-
Nitrobenzyl), -COO- (p-methoxybenzyl), -CO-
In the case of O-COCH ₃ or —COOH, a step (h) of substituting a hydrogen atom for R ² or R ³ after introducing a methyl group in the step (c) may be further included. This step (h) may be performed at any time after the introduction of the methyl group in step (c). The step (h) is, for example, a step of adding the reaction product obtained in the previous steps to a solution obtained by dissolving lithium iodide dihydrate in anhydrous 2,6-lutidine, and then heating and refluxing. Can be included. Note that R ¹ is
In the case of -CN, since R ² and R ³ are hydrogen atoms,
It is not necessary to perform step (h).

The allylation reagent used in the present invention is not particularly limited, and examples thereof include allyl bromide, allyl chloride, allyl iodide, allyl mesylate, allyl tosylate, allyl triflate and the like. Alternatively, two or more kinds can be used. The benzoylating reagent used in the present invention is not particularly limited, and examples thereof include benzoyl bromide, benzoyl chloride, benzoyl iodide, benzoyl mesylate, benzoyl tosylate, benzoyl triflate, and benzoic anhydride. One kind or two or more kinds can be used.

[0031]

EXAMPLES The present invention will be described below with reference to specific examples, but the present invention is not limited to the following examples. Example 1-1 N- (2-cyanoethyl) -1-methyl-2-ethoxy
Preparation of carbonylethylamine Ethyl-3-aminobutyrate (1.44 g, 10.9
acrylonitrile (0.53 g, 10.0 m) to a solution of 1.5 ml of ethyl alcohol and 1.5 ml of ethyl alcohol under stirring.
mol) was added slowly. After standing at room temperature for 48 hours, the solvent was removed to obtain N- (2-cyanoethyl) -1-methyl-2-ethoxycarbonylethylamine. The yield (yield) and NMR spectrum of this compound were as follows.

Yield (yield): 1.66 g (91%) NMR (CDCl ₃ ): δ0.8 (d, 3H); 1.1
(T, 3H); 1.5 (s, 1H); 2.7 (q, 2)
H); 2.2 (t, 1H); 2.3 (t, 2H); 2.
9 (q, 1H); 4.0 (q, 2H) Example 1-2 Preparation of 5-cyano-2-methyl-4-piperidinone Sodium (0.2g, 8.7) in 15 ml of anhydrous toluene.
mmol) was added, and the mixture was heated to a temperature of 100 to 120 ° C. and refluxed. Continue heating at this temperature and continue refluxing until the sodium becomes a small silver bead. N-
1- (2-cyanoethyl) -1-methyl-2-ethoxycarbonylethylamine (1.6 g, 8.7 mmol)
Slowly added dropwise over 0 minutes. After dropping, about 1
After radiating heat for about 0 minutes, the mixture was heated again at 100 to 120 ° C. for 7 hours and refluxed. After a brown solid was produced and the reaction was completed, the reaction solution was poured into water and extracted with a large amount of water.

After the extracted aqueous layer was neutralized with concentrated hydrochloric acid, the product was extracted with ethyl acetate. By removing the solvent and purifying by chromatography, 5-cyano-
2-Methyl-4-piperidinone was obtained. The yield (yield) and NMR spectrum of this compound were as follows. Yield (yield): 0.84 g (70%) NMR (DMSO): δ1.0 (d, 3H); 1.8
(D, 2H); 2.1 (d, 2H); 2.5 (d, 1
H); 3.2 (t, 1H) Example 1-3 Preparation of 2,5-dimethyl-4-piperidinol 5-cyano-2-methyl-4-piperidinone (1.5 g, 10. 9 mmol)
Was dissolved and 0.5 g of a palladium carbon catalyst was slowly added. This solution was shaken under hydrogen pressure at room temperature for 7 hours.
After completion of the reaction, filtration was performed using Celite and the solvent was removed to obtain 2,5-dimethyl-4-piperidinol. The yield (yield) and NMR spectrum of this compound were as follows.

Yield (yield): 1.1 g (78%) NMR (DMSO): δ1.2 (d, 3H); 1.3
(D, 3H); 2.3 (d, 2H); 2.5 (d, 2)
H); 2.6 (m, 1H); 2.9 (t, 1H);
2 (t, 1H) Example 1-4 of N-allyl-2,5-dimethyl-4-piperidinol
Preparation 2,5-dimethyl-4-piperidinol (1.5 g, 1
1.7 mmol) was dissolved in 20 ml of acetone and potassium carbonate (0.8 g, 5.85 mmol) was added. Allyl bromide (1.42g, 11.7mm) in this solution
ol) was added slowly at 0 ° C. After reacting for 2 hours,
The reaction solution was washed with water and sodium carbonate solution. afterwards,
Purification by chromatography gave N-allyl-2,5-dimethyl-4-piperidinol. The yield (yield) and NMR spectrum of this compound were as follows.

Yield (yield): 1.57 g (80%) NMR (DMSO): δ1.0 (d, 3H); 1.5
(D, 3H); 2.6 (t, 2H); 2.3 (t, 2)
H); 2.6 (m, 1H); 3.7 (m, 1H);
0 (m, 1H); 4.2 (d, 2H); 5.2 (d, 2)
H); 6.0 (m, 1H) Example 1-5 N-allyl-2,5-dimethyl-piperidinol-4-
Preparation of benzoyl ester N-allyl-2,5-dimethyl-4-piperidinol (1.5 g, 8.9 mmol) was added to anhydrous pyridine (10 ml).
Dissolved in benzoyl chloride (1.25 g,
8.9 mmol) was added dropwise. After heating at 60 to 70 ° C. for 1 hour, the solution was poured into water and extracted with benzene. Remove the solvent from the extracted benzene solution,
The residue was recrystallized to obtain N-allyl-2,5-dimethyl-piperidinol-4-benzoyl ester as a white solid. Yield (Yield) and N of this compound
The MR spectrum was as follows:

Yield (yield): 2.1 g (82%) NMR (DMSO): δ1.0 (d, 3H); 1.5
(D, 3H); 2.4 (m, 2H); 2.6 (d, 2)
H); 2.9 (m, 1H); 3.9 (m, 1H);
7 (m, 2H); 5.6 (d, 2H); 6.1 (m, 1
H); 7.4 (t, 2H); 7.6 (t, 1H);
0 (d, 2H) Example 2-1 N- (2-methoxycarbonylethyl) -1-methyl-
Preparation of 2-ethoxycarbonylethylamine Ethyl-3-aminobutyrate (1.44 g, 10.9
mmol) and methyl acrylate (1 g, 9.98 mm
ol) and 10 ml of anhydrous ethyl alcohol were thoroughly mixed and then left at room temperature for 4 days. After completion of the reaction, N- (2-methoxycarbonylethyl) -1-
Methyl-2-ethoxycarbonylethylamine was obtained.
The yield (yield) and NMR spectrum of this compound were as follows.

Yield (yield): 1.5 g (83.3%) NMR (CDCl ₃ ): δ 0.9 (d, 3H); 1.1
(T, 3H); 1.4 (s, 1H); 2.2 (t, 2)
H); 2.4 (t, 2H); 2.5 (q, 2H);
9 (m, 1H); 3.5 (s, 3H); 4.0 (q, 2)
H) Example 2-2 5-methoxycarbonyl-2-methyl-4-piperidino
Manufacture of sodium in anhydrous toluene 25 ml (0.6 g, 6.9
mmol) and heated at a temperature of 100 to 120 ° C.,
Refluxed. When sodium was broken into small balls, N- (2-methoxycarbonylethyl) -1-methyl-2-ethoxycarbonylethylamine (1.5
g, 6.9 mmol) was added slowly. After radiating heat for about 10 minutes, heat at 100-120 ° C for 7 hours,
Refluxed. After the yellow solid was formed and the reaction was completed, the reaction solution was poured into water. The aqueous layer was acidified and extracted with ethyl acetate, then the solvent was removed. Then, the residue was recrystallized to obtain 5-methoxycarbonyl-2-methyl-4-piperidinone. The yield (yield) and NMR spectrum of this compound were as follows. Yield (yield): 0.83 g (70%) NMR (DMSO): δ1.0 (d, 3H); 1.8
(T, 2H); 2.1 (d, 2H); 2.5 (d, 1
H); 3.4 (t, 1H); 3.7 (s, 3H) Example 2-3 5-methoxycarbonyl-2,5-dimethyl-4-pipet.
Preparation of Lidinone Lithium diisopropylamide (0.93 g, 8.76 mmol) was added to 10 ml of anhydrous tetrahydrofuran at −30.
After the temperature was further lowered to -70 ° C, 5-methoxycarbonyl-2-methyl-4-piperidinone (1.56 g, 8.76 mmol) was slowly added.
After about 30 minutes, methyl iodide (1.42 g, 10 mmo
l) was added slowly. The temperature of the reaction mixture was gradually returned to room temperature over 3 hours. After the reaction was completed, 5 ml of water was added. The aqueous layer was extracted with ethyl acetate to give 5-methoxycarbonyl-2,5-dimethyl-4-
I got piperidinone. The yield (yield) and NMR spectrum of this compound were as follows.

Yield (yield): 1.13 g (70%) NMR (DMSO): δ1.2 (d, 3H); 1.8
(D, 3H); 2.3 (d, 2H); 2.5 (d, 2)
H); 2.9 (t, 1H); 3.3 (t, 1H);
7 (s, 3H) Example 2-4 5-methoxycarbonyl-2,5-dimethyl-4-pipet
Preparation of Lidinol 5-Methoxycarbonyl-2,5-dimethyl-4-piperidinone (0.5 g, 8.1 mmol) was dissolved in 20 ml of anhydrous ethyl alcohol and sodium borohydride (0.15 g, 4.05 mmol) was added at 0 ° C. I added it slowly. The mixture was allowed to react for 2 hours while gradually raising the temperature to 25 ° C, and after completion of the reaction, 10 ml of water was added,
By extracting the aqueous layer with ethyl acetate, 5
-Methoxycarbonyl-2,5-dimethyl-4-piperidinol was obtained. Yield (Yield) and NM of this compound
The R spectrum was as follows:

Yield (yield): 0.99 g (65%) NMR (DMSO): δ1.0 (d, 3H); 1.4
(D, 3H); 2.2 (d, 2H); 2.7 (m, 1
H); 3.0 (t, 1H); 3.3 (t, 1H);
7 (s, 3H) Example 2-5 5-methoxycarbonyl-2,5-dimethyl-piperidi
Preparation of ol- 4-benzoyl ester 5-Methoxycarbonyl-2,5-dimethyl-4-piperidinol (1.5 g, 8.01 mmol) was dissolved in 20 ml of anhydrous pyridine, and benzoyl chloride (1.4
8 g, 8.01 mmol) was slowly added dropwise. 60 ~
After heating at 70 ° C. for 1 hour, this solution was poured into water and extracted with diethyl ether. After removing the extraction solvent, purification by chromatography gave 5-methoxycarbonyl-2,5-dimethyl-piperidinol-4-benzoyl ester. The yield (yield) and NMR spectrum of this compound were as follows.

Yield (Yield): 1.92 g (82%) NMR (DMSO): δ1.1 (d, 3H); 1.4
(D, 3H); 2.3 (d, 2H); 2.5 (d, 2)
H); 2.7 (m, 1H); 3.0 (t, 1H);
2 (t, 1H); 3.7 (s, 3H); 7.4 (t, 2)
H); 7.6 (t, 1H); 8.0 (d, 2H) Example 2-6 N-allyl-5-methoxycarbonyl-2,5-dimethyl.
Preparation of lu-piperidinol-4-benzoyl ester 5-methoxycarbonyl-2,5-dimethyl-piperidinol-4-benzoyl ester (1.5 g, 5.15
(mmol) was dissolved in 20 ml of acetone, and potassium carbonate (0.36 g, 2.6 mmol) was added. Allyl bromide (0.62 g, 5.15 mmo) was added to this solution at 0 ° C.
l) was added slowly. After reacting for 2 hours to complete the reaction, the reaction mixture was washed with water and a sodium carbonate solution, and the solvent was removed. Then, it was purified by chromatography to obtain N-allyl-5-methoxycarbonyl-2,5-dimethyl-piperidinol-4-benzoyl ester. Yield (Yield) and N of this compound
The MR spectrum was as follows:

Yield (yield): 1.36 g (80%) NMR (DMSO): δ1.1 (d, 3H); 1.5
(D, 3H); 2.3 (d, 2H); 2.5 (d, 2)
H); 2.7 (m, 1H); 3.0 (t, 1H);
3 (t, 1H); 3.6 (s, 3H); 4.2 (d, 2)
H); 5.2 (d, 2H); 6.0 (m, 1H);
4 (t, 2H); 7.6 (t, 1H); 8.0 (d, 2)
H) Example 2-7 N-allyl-2,5-dimethyl-piperidinol-4-
Preparation of benzoyl ester Lithium iodide dihydrate (1.16 g, 6.13 mmol) was dissolved in 20 ml of anhydrous 2,6-lutidine, heated and refluxed. To this solution was added N-allyl-5-methoxycarbonyl-2,5-dimethyl-piperidinol-4-
Benzoyl ester (1.5 g, 4.5 mmol) was added slowly. After carbon dioxide gas began to evolve from the solution, the solution was heated to reflux for 10 hours. After the reaction is completed
The mixture was neutralized with 6N hydrochloric acid and extracted with ether. The extracted ether layer was washed with brine, dried and the solvent was removed, and the residue was recrystallized to give N-allyl-
2,5-Dimethyl-piperidinol-4-benzoyl ester was obtained. Yield (yield) and NMR of this compound
The spectrum was as follows:

Yield (yield): 0.93 g (72%) NMR (DMSO): δ1.0 (d, 3H); 1.5
(D, 3H); 2.4 (m, 2H); 2.6 (d, 2)
H); 2.9 (m, 1H); 3.9 (m, 1H);
7 (m, 2H); 5.6 (d, 2H); 6.1 (m, 1
H); 7.4 (t, 2H); 7.6 (t, 1H);
0 (d, 2H)

[0043]

INDUSTRIAL APPLICABILITY According to the present invention, as compared with the conventional method using expensive piperidine derivative, N-allyl-2, 5-Dimethyl-piperidinol-4-benzoyl ester can be produced in high yield and at low cost.

Claims (6)

(57) [Claims] 1. A secondary amine of the following general formula (IV) is formed by a Michael addition reaction between an α, β-unsaturated compound of the following general formula (II) and a primary amine of the following general formula (III). The step of generating, and (In the formula, R ¹ is -CN, -COOCH ₃ , -COOC ₂ H ₅ , -COO- (p-nitrobenzyl), -COO- (p-methoxybenzyl), -CO-O-
COCH ₃ or -COOH. ) (B) generating a piperidinone derivative of the following formula (V) by a Dieckmann condensation reaction of the secondary amine (IV): (c) a step of introducing an alcohol functional group and a methyl group by a reduction reaction of the piperidinone derivative (V) to produce 2,5-dimethyl-4-piperidinol of the following formula (VI) or a derivative thereof: 3] (In the formula, R ² is a hydrogen atom, -COOCH ₃ , -COOC ₂ H ₅ , -COO-
(p-nitrobenzyl), -COO- (p-methoxybenzyl),-
CO-O-COCH ₃ or -COOH. ) (D) The 2,5-dimethyl-4-piperidinol or its derivative (VI) is reacted with an allylating reagent to form N-allyl-2,5-dimethyl-4-piperidinol of the following formula (VII) or its A step of forming a derivative, and (In the formula, R ³ is a hydrogen atom, -COOCH ₃ , -COOC ₂ H ₅ , -COO-
(p-nitrobenzyl), -COO- (p-methoxybenzyl),-
CO-O-COCH ₃ or -COOH. ) (E) The N-allyl-2,5-dimethyl-4-piperidinol or its derivative (VII) is reacted with a benzoylating reagent to give a target compound, N-allyl-2, of the following formula (I): A step of forming 5-dimethyl-piperidinol-4-benzoyl ester and A method for producing an N-allyl-2,5-dimethyl-piperidinol-4-benzoyl ester containing: 2. Instead of the steps (d) and (e), (f) the 2,5-dimethyl-4-piperidinol or its derivative (VI) is reacted with a benzoylating reagent to give the following formula (VIII): ) 2,5-Dimethyl-piperidinol-4-
Forming a benzoyl ester or derivative thereof, and (In the formula, R ³ is a hydrogen atom, -COOCH ₃ , -COOC ₂ H ₅ , -COO-
(p-nitrobenzyl), -COO- (p-methoxybenzyl),-
CO-O-COCH ₃ or -COOH. ) (G) The 2,5-dimethyl-piperidinol-4-benzoyl ester or its derivative (VIII) is reacted with an allylation reagent to give the target compound N-of the following formula (I):
A step of forming allyl-2,5-dimethyl-piperidinol-4-benzoyl ester and The manufacturing method according to claim 1, further comprising: 3. R ¹ is -COOCH ₃ , -COOC ₂ H ₅ , -COO- (p-nitrobenzyl), -COO- (p-methoxybenzyl), -CO-O-COCH.
₃ or -COOH, and the step of substituting R ² or R ³ with a hydrogen atom after introducing the methyl group in the step (c).
The manufacturing method according to claim 1, further comprising (h). 4. In the step (h), the reaction product obtained in the previous steps is added to a solution prepared by dissolving lithium iodide dihydrate in anhydrous 2,6-lutidine, and then heated. The manufacturing method according to claim 3, comprising a step of refluxing. 5. The allylating reagent is allyl bromide,
The method according to any one of claims 1 to 4, which is at least one selected from the group consisting of allyl chloride, allyl iodide, allyl mesylate, allyl tosylate, and allyl triflate. 6. The benzoylating reagent is at least one selected from the group consisting of benzoyl bromide, benzoyl chloride, benzoyl iodide, benzoyl mesylate, benzoyl tosylate, benzoyl triflate and benzoic anhydride. Claims 1 to 5
The manufacturing method according to any one of 1 to.