PREPARATION METHOD OF L-NICOTINE

Abstract

A preparation method for L-nicotine involves multiple steps. The resulting L-nicotine can have an optical purity of more than 99.9%, much higher than that of similar products in the current market. The total yield of synthesis reaches 50-60%.

Claims

1. A preparation method for L-nicotine, having the following synthetic route: ##STR00010## wherein the preparation method comprises the following steps: (1) subjecting a compound of formula I to a substitution reaction with N-vinylpyrrolidone, and performing decarboxylation to obtain a compound of formula II; (2) subjecting the compound of formula II to a cyclization reaction to obtain myosmine; and (3) subjecting myosmine to reduction and methylation to obtain L-nicotine; in the compound of formula I, R is selected from C.sub.1-C.sub.8 alkyl, phenyl, and benzyl.

2. The preparation method for L-nicotine according to claim 1, wherein in the step (1), the compound of formula I is subjected to the substitution reaction with N-vinylpyrrolidone under the action of a base; the base is selected from one or more of potassium hydroxide, sodium hydroxide, potassium tert-butoxide, sodium ethoxide, potassium carbonate, sodium hydride, butyl lithium, and methylmagnesium bromide.

3. The preparation method for L-nicotine according to claim 1, wherein in the substitution reaction of the step (1), one or more of the following reagents are used as a reaction solvent: toluene, xylene, tetrahydrofuran, ethanol, 2-methyltetrahydrofuran, and n-hexane.

4. The preparation method for L-nicotine according to claim 1, wherein in the step (1), an acid is added for the decarboxylation reaction; the acid is selected from one or more of hydrochloric acid, phosphoric acid, sulfuric acid, formic acid, and acetic acid.

5. The preparation method for L-nicotine according to claim 1, wherein in the step (2), the compound of formula II is subjected to the cyclization reaction under the action of a base; the base is selected from one or more of potassium hydroxide, sodium hydroxide, potassium tert-butoxide, sodium ethoxide, potassium carbonate, sodium hydride, triethylamine, butyl lithium, and methylmagnesium bromide; in the step (2), one or more of the following reagents are used as a reaction solvent: water, ethyl acetate, dichloromethane, N,N-dimethylformamide, tetrahydrofuran, ethanol, 2-methyltetrahydrofuran, n-hexane, and methyl tert-butyl ether.

6. The preparation method for L-nicotine according to claim 5, wherein in the step (2), the reaction solvent and the compound of formula II are in a feeding mass ratio of 20:1-2:1; the base and the compound of formula II are in a feeding mass ratio of 1:1-1:20.

7. The preparation method for L-nicotine according to claim 1, wherein in the step (3), the reduction is performed in the presence of a ligand and a metal catalyst; in the step (3), the metal catalyst is selected from Rh(COD)Cl.sub.2, Ir(COD)Cl.sub.2, Ru(COD)Cl.sub.2, PdCl(PPh.sub.3).sub.3, PdCl.sub.2(PPh.sub.3).sub.2, Ni(acac).sub.2, NiCl.sub.2, and Ni(COD).sub.2; in the step (3), the ligand is selected from the following structures: ##STR00011##

8. The preparation method for L-nicotine according to claim 7, wherein in the step (3), a reagent for the methylation is selected from one or more of formaldehyde (e.g., an aqueous formaldehyde solution), paraformaldehyde, iodomethane, and dimethyl sulfate; preferably, in the step (3), a reagent system for the methylation is used, and the reagent system for the methylation further comprises formic acid in addition to one or more of formaldehyde (e.g., an aqueous formaldehyde solution), paraformaldehyde, iodomethane, and dimethyl sulfate.

9. A catalyst generated in situ from a ligand and a metal catalyst, wherein the metal catalyst is selected from Rh(COD)Cl.sub.2, Ir(COD)Cl.sub.2, Ru(COD)Cl.sub.2, PdCl(PPh.sub.3).sub.3, PdCl.sub.2(PPh.sub.3).sub.2, Ni(acac).sub.2, NiCl.sub.2, and Ni(COD).sub.2; the ligand is selected from the following structures: ##STR00012##

10. Use of the catalyst according to claim 9 in a reduction reaction, wherein preferably, the catalyst is used in a carbonyl reduction reaction.

Description

BRIEF DESCRIPTION OF THE DRAWINGS

[0049] FIG. 1 is a mass spectrum of L-nicotine according to the present disclosure;

[0050] FIG. 2 is a nuclear magnetic resonance spectrum of L-nicotine according to the present disclosure;

[0051] FIG. 3 is an optical purity diagram of L-nicotine according to the present disclosure.

DETAILED DESCRIPTION

[0052] The technical solutions of the present disclosure will be further illustrated in detail with reference to the following specific examples. It should be understood that the following examples are merely exemplary illustrations and explanations of the present disclosure, and should not be construed as limiting the protection scope of the present disclosure. All techniques implemented based on the content of the present disclosure described above are included within the protection scope of the present disclosure.

[0053] Unless otherwise stated, the starting materials and reagents used in the following examples are all commercially available products or can be prepared using known methods.

[0054] Optical detection instrument and method: detection instrument A (ultraviolet detector); a chiral chromatography column Daicel OD-H is used, the mobile phase is isopropanol/n-heptane=5:95, the flow rate is 0.9 mL/min, the sample injection volume is 10 ?L, the detection wavelength is 254 nm, and the column temperature is 25? C.

General Reaction Route:

[0055] ##STR00009##

Example 1: Preparation of Intermediate Compound of Formula II

[0056] To a 50 L three-necked flask were added 20 kg of xylene, 5 kg of ethyl nicotinate (i.e., R=ethyl), 2.5 kg of potassium tert-butoxide, and 4 kg of N-vinylpyrrolidone at 30? C. The system was heated to 100? C. for a reaction for 4 h, and then 3 kg of 15% hydrochloric acid was added dropwise over 3 h with the temperature controlled at 50? C. After the dropwise addition, the system was heated to 90 ?C for a reaction for 2 h, and then cooled to 30? C. The system was adjusted to pH 7 with 10% sodium hydroxide, and then extracted with ethyl acetate (20 kg?2). The organic phases were combined, dried, and concentrated under reduced pressure at 40? C. to obtain 4.11 kg of the compound of formula II with a liquid phase purity of 97.3% and a yield of 76.7%, which was used directly in the next step. 1HNMR (CDCl.sub.3, 400M) ?: 8.91 (d, J=7.8 Hz, 1H), 8.51 (d, J=8.0 Hz, 1H), 8.35 (d, J=7.8 Hz, 1H), 7.68 (d, J=8.0 Hz, 1H), 3.03 (t, J=8.0 Hz, 2H), 2.81 (t, J=8.0 Hz, 2H), 2.22-2.20 (m, 2H), 1.90-1.88 (br, 2H), LC-MS Calc: 164.21, Detec. M+1:167.2.

Example 2: Preparation of Myosmine

[0057] To a 50 L three-necked flask were added 15 kg of tetrahydrofuran, 5 kg of water, and 5 kg of the compound of formula II at 20? ? C. 1.5 kg of sodium hydroxide was added with the temperature of the system controlled at 40? C. The reaction was performed at 40? C. until the compound of formula II was completely consumed. The system was extracted with dichloromethane (10 kg?2). The organic phases were combined and concentrated under reduced pressure at 30? C. to obtain 4.35 kg of myosmine with a liquid phase purity of 97.1% and a yield of 97.8%, which was used directly in the next step. 1HNMR (CDCl.sub.3, 400M) ?: 8.58 (d, J=8.0 Hz, 1H), 8.45 (d, J=7.8 Hz, 1H), 7.68 (d, J=8.0 Hz, 1H), 7.24-7.20 (m, 1H), 4.13 (t, J=4.0 Hz, 1H), 3.20-3.17 (m, 1H), 3.06-3.01 (m, 1H), 2.22-2.20 (m, 1H), 1.90-1.88 (m, 1H), 1.80-1.60 (m, 1H); LC-MS Calc: 146.19, Detec. M+1: 147.2.

Example 3: Preparation of L-Nicotine

[0058] To a 50 L autoclave were added 20 kg of tetrahydrofuran, 3 kg of myosmine, 1.5 g of ligand L2, and 1 g of Ir(COD)Cl.sub.2 at 25? C. The system was purged with nitrogen at a pressure of 0.3 MPa for three times, and then charged with hydrogen at a pressure of 1.2 MPa. The system was reacted at 30? C. for 4 h. After the system was emptied and purged with nitrogen at a pressure of 0.2 MPa for 2 times, 500 g of paraformaldehyde and 1 kg of formic acid were added for a reflux reaction at 95? C. for 5 h. The system was concentrated to remove the organic solvent, adjusted to pH 11 with an aqueous sodium hydroxide solution, and extracted with ethyl acetate (9 kg?3). The organic phases were combined and concentrated to give a nicotine crude product, which was then distilled under reduced pressure to obtain a pure L-nicotine product as a colorless transparent liquid, with an optical purity of more than 99.9% ee. The pure product had a fraction weight of 2.46 and a yield of 73.9%. .sup.1HNMR (400 MHZ, CDCl.sub.3) ?: 8.47-8.44 (br, 2H), 7.61 (d, J=8.0 Hz, 1H), 7.20-7.16 (m, 1H), 3.18 (t, J=8.0 Hz, 1H), 3.11 (t, J=8.0 Hz, 1H), 2.25-2.19 (m, 1H), 2.13-2.09 (m, 1H), 2.08 (s, 3H), 1.89-1.87 (m, 1H), 1.76-1.66 (m, 2H); LC-MS Calc: 162.24, Detec. M+1: 163.20.

[0059] The resulting pure L-nicotine was subjected to optical detection. The results are shown in FIG. 3 and the table below:

TABLE-US-00001 Serial Peak Peak Peak Symmetry Peak number Time area height width factor area % 1 3.849 4435.1 546.6 0.1194 0.342 100.00

[0060] The embodiments of the present disclosure have been described above. However, the present disclosure is not limited to the embodiments described above. Any modification, equivalent, improvement, and the like made without departing from the spirit and principle of the present disclosure shall fall within the protection scope of the present disclosure.