JPH0160469B2 - - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION (Field of Industrial Application) The present invention relates to a new and useful 4-aminonicotine and a method for producing the same.

(Prior Art) In recent years, research on artificial antigens has been actively conducted in the medical and biological research fields, such as treatment with the human body or drugs. It is well known that these methods greatly contribute to the progress of research. Regarding nicotine, research has continued for many years on its effects on the human body from the medical perspective of smoking, and these artificial antigens have also been synthesized, and their application to radioimmunoquantification of trace amounts of nicotine is also being carried out. .

(Problem to be solved by the invention) However, since all the nicotine that exists in natural leaf tobacco exists in one form, the normally required artificial antigen antibody reacts specifically to only one form. However, many conventional methods for synthesizing artificial antigens result in racemization during the synthesis process. Therefore, the drawback was that the normally required single-body antibody production ability of artificial antigens was halved. An optically active nicotine derivative similar to the compound of the present invention has been proposed as a nicotine derivative that improves this drawback (Japanese Patent Publication, 1982-914). However, this nicotine derivative is complicated to isolate and purify, and is an extremely hygroscopic compound.
Storage and handling are inconvenient.

The present invention aims to provide a nicotine derivative that does not have the drawbacks associated with conventionally known nicotine derivatives, can be synthesized and isolated by extremely easy methods, and can be produced while maintaining optical purity. This is the purpose.

(Means for Solving the Problems) That is, the present invention is 4-aminonicotine represented by the following formula and a method for producing the same.

This compound is a new compound that has not been published in any literature, and its physical properties are shown below.

4-Aminicotine properties; white crystal melting point; 125-126°C ^1H NMR (solvent CDCL ₃ , internal standard TMS);
(ppm) 1.86 (m, 2H), 1.98 (m, 1H), 2.02 (m, 1H),
2.18 (s, 3H), 2.22 (t, J=8.7Hz, 1H),
3.12 (t, J = 8.7Hz, 1H), 3.16 (t, J = 9.4
Hz, 1H), 5.60 (bs, 2H), 6.41 (d, J = 5.4
Hz, 1H), 8.00 (s, 1H), 8.07 (d, J=5.4
Hz, 1H) C NMR (solvent CDCL ₃ , internal standard TMS);
(ppm) 22.61 (t), 30.15 (t), 40.09 (q), 56.58 (t)
，
70.00(d), 110.09(d), 119.27(s), 148.86
(d), 149.83 (d), 152.45 (s) MASS; (M/Z) 177 (M+; 22), 84 (54), 119 (14), 121 (42),
134 (20), 148 (40), 162 (100), 176 (11) Optical rotation; [α] ²⁵ _d = -95.2° (c = 0.7, MeOH) 4-Aminonicotine oxidizes cotinine with peracid After converting to cotinine-N-oxide, concentrated sulfuric acid,
It can be easily obtained by nitration with fuming nitric acid, reduction with iron in acetic acid, and subsequent reduction with diborane. The manufacturing method will be described in detail below based on manufacturing examples described later.

Cotinine is dissolved in 2 to 5 times the amount of cotinine, preferably 3 times the amount of acetic acid, and 0.2 times the amount of cotinine is dissolved in acetic acid.
Add twice the amount of 30% hydrogen peroxide solution and react at 70°C for 1 to 10 hours, preferably 5 hours. After the reaction, the solvent is distilled off under reduced pressure, an appropriate amount of alcohol such as ethyl alcohol or methyl alcohol is added to decompose excess hydrogen peroxide, water is added, and the solvent is distilled off under reduced pressure. The obtained oily substance is neutralized by adding an alkali such as potassium carbonate or sodium carbonate, and extracted with an organic solvent such as chloroform or dichloromethane.
After drying with sodium sulfate, magnesium sulfate, etc. and distilling off the solvent under reduced pressure, cotinine-N-
The oxide is obtained as white crystals with a yield of 95-99%.

The obtained cotinine-N-oxide was dissolved in 10 to 20 times its amount, preferably 12 times its amount, of concentrated sulfuric acid and the same amount of fuming nitric acid, and then heated at 130°C for 3 to 10 hours.
Preferably, the reaction is allowed to proceed for 5 hours. After the reaction, carefully pour the reaction solution onto ice with an amount twice as much as the amount of concentrated sulfuric acid added. Next, an alkali such as potassium carbonate or sodium carbonate is added to neutralize the mixture, and the mixture is extracted with an organic solvent such as chloroform or dichloromethane. After drying the extract with sodium sulfate, magnesium sulfate, etc.
The solvent is distilled off under reduced pressure and recrystallized from a small amount of chloroform to obtain 4-nitrocotinine-N-oxide as pale yellow crystals in a yield of 30-45%.

The obtained 4-nitrocotinine-N-oxide is dissolved in 5 to 20 times the amount of acetic acid, preferably 8 times the amount of 4-nitrocotinine-N-oxide. Add twice the amount of iron powder and reflux at the boiling point of acetic acid for 2 to 10 hours, preferably 3 hours. After the reaction, unreacted iron powder is filtered, acetic acid is distilled off under reduced pressure, neutralized with an alkali such as potassium carbonate or sodium carbonate, extracted with an organic solvent such as chloroform dichloromethane, and extracted with sodium sulfate or magnesium sulfate. 4-aminocotinine was obtained in a yield of 40.
Obtained as white crystals at ~65%. Next, the obtained 4-aminocotinine and sodium borohydride in an amount 4 to 8 times, preferably 5 times the amount of 4-aminocotinine, are added in an amount of 8 to 20 times, preferably 10 times the amount of 4-aminocotinine. of the boron trifluoride/ether complex is slowly added dropwise to the solution in an amount of 1.25 times the amount of sodium borohydride. After dropping, the mixture is stirred at room temperature for 3 to 5 hours, preferably 4 hours.
Thereafter, the reaction solution was poured into 10% hydrochloric acid in an amount of 5 to 20 times, preferably 10 times, the amount of 4-aminocotinine added at the beginning, and neutralized with an alkali such as potassium carbonate or sodium hydroxide. - Extract with 30 times the amount of chloroform compared to aminocotinine. When the solvent is distilled off under reduced pressure, 4-aminonicotine can be obtained as white crystals in a yield of 50 to 70%.

As explained in detail above, the production method according to the present invention allows the amino group to be introduced into the 4-position regioselectively, and can be produced without losing optical purity. It has the advantage of maintaining the pyridine ring and pyrrolidine ring, which are extremely important features for an artificial nicotine antigen, as well as optical activity.

(Example) In a 100 ml eggplant flask, 3.4 g (20 mmol) of cotinine was dissolved in 12 ml of acetic acid.
Add 2.4 ml of 30% hydrogen peroxide and react at 70°C for 5 hours. After the reaction, acetic acid was distilled off under reduced pressure, ethyl alcohol was added to remove excess hydrogen peroxide, water was added and the solvent was distilled off under reduced pressure, neutralized with potassium carbonate, extracted with chloroform, and dried over sodium sulfate. The solvent was distilled off to obtain 3.7 g (yield 98%) of cotinine-N-oxide as white crystals.

3.7 g of cotinine-N-oxide obtained
(19 mmol) in a 100 ml eggplant flask, concentrated sulfuric acid 40
ml, dissolved in 40 ml of fuming nitric acid and reacted at 130°C for 5 hours. After the reaction, the reaction solution was poured into 100 ml of ice, neutralized with potassium carbonate, extracted with chloroform, dried over sodium sulfate, the solvent was distilled off, recrystallized with a small amount of chloroform, and 4-nitrocotinine-N-oxide was obtained. 1.8 as light yellow needle-shaped crystals
g (yield 40%) was obtained.

Obtained 4-nitrocotinine-N-oxide
1.8g (7.6mmol) of acetic acid in a 100ml eggplant flask
Dissolve in 20 ml, add 4 g of iron powder, and reflux for 3 hours. After the reaction, unreacted iron powder is filtered, acetic acid is distilled off under reduced pressure, neutralized with potassium carbonate, iron hydroxide is filtered off, extracted with chloroform, dried over sodium sulfate, and the solvent is removed under reduced pressure. After evaporation, the residue was recrystallized from a small amount of chloroform to obtain 1.0 g (yield: 62%) of 4-aminocotinine.

Obtained 4-aminocochinini 1.9g (10mmol)
and 1.9 g (50 mmol) of sodium borohydride,
Dissolve in 20ml of diglyme in a 50ml eggplant flask,
8.8 g (63 mmol) of BF ₃ .Et ₂ O is added dropwise. After the dropwise addition, the mixture was stirred at room temperature for 4 hours, poured into 20 ml of 10% hydrochloric acid, neutralized with sodium hydroxide, and extracted with chloroform. After drying with sodium sulfate, the solvent was distilled off under reduced pressure and subjected to vacuum distillation.
1.0 g (yield: 56%) of 4-aminonicotine was obtained as a 160°C (2 mmHg) fraction.

(Effect of the invention) As mentioned above, 4-aminonicotine can be produced by bonding it to a polymer compound such as a protein having a carboxyl group using a peptide synthesis reagent.
Can be used as an artificial antigen for nicotine,
These artificial antigens have the ability to produce antibodies with high titers. That is, as is clear from the structural formula of the compound of the present invention, these artificial antigens are bonded to a polymer compound at the primary amino group of the compound of the present invention. This contributes to the production of highly specific antibodies without making any changes to the N-methylpyrrolidine ring.

Furthermore, the antibodies produced in the animal body by the artificial antigen obtained from the compound of the present invention react specifically with nicotine and have a small cross-reactivity with d-nicotine, which is similar to the previously known artificial antigen of nicotine. There are significant advantages compared to this.

Claims (1)

[Claims] 4-aminonicotine represented by the linear formula 2 Cotinine is treated with peracid to form cotinine-N-oxide, and then reacted with concentrated sulfuric acid and fuming nitric acid to form 4-
A method for producing 4-aminonicotine, which comprises preparing nitrocotinine-N-oxide, reducing it with iron in acetic acid, and then reducing it with diborane.