PROCESS FOR UNPROTECTED ASYMMETRIC PREPARATION OF NICOTINE

Abstract

The present disclosure relates to an asymmetric process for preparing nicotine without protection, in particular to a process for preparing optically pure nicotine by taking nicotinate as a starting material and carrying out four-step reaction. The process comprises the following steps: nicotinate and -butyrolactone are subjected to condensation reaction, asymmetric catalytic reduction reaction, activation, and reaction with methylamine to give optically pure nicotine. The asymmetric catalytic reduction for preparing the chiral alcohol intermediate compound with high optical activity is a key step of the method. The method of the present disclosure has the characteristics of high atom economy, very high reaction activity, capability of keeping excellent stereocontrol, capability of obtaining a chiral product with very high enantioselectivity, short reaction steps, low cost of raw materials, green and pollution-free, capability of greatly reducing the quantity of three wastes, and easiness in realizing industrial amplification production.

Claims

1. A method for preparing a compound of formula (3), ##STR00043## the compound having an R or S configuration at the stereoisomer center labeled with *; an enantiomer excess of at least 70% relative to the opposite enantiomer, wherein the method comprises the following steps: asymmetrically reducing the intermediate compound represented by formula (2): ##STR00044## the asymmetric reduction is carried out in a suitable organic solvent in the presence of a chiral metal catalyst, a chiral ligand, a transition metal, an additive, and a hydrogen source, wherein the hydrogen source is selected from at least one of hydrogen, formic acid, a mixture of formic acid and formate, and a mixture of formic acid and organic amine, and the transition metal is selected from at least one of ruthenium, rhodium, iridium, palladium, manganese, copper, and iron.

2. The method for preparing the compound of formula (3) according to claim 1, wherein the chiral catalyst has the structure of formula I: ##STR00045## wherein X and Y are each independently halogen, acetate, or hydrogen; ##STR00046## represents a diphosphine ligand; ##STR00047## represents a diamine structure.

3. The method according to claim 2, wherein the diamine structure is selected from any one of the following structures or corresponding isomers thereof: ##STR00048##

4. The method according to claim 2, wherein the diphosphine ligand is selected from at least one of Binap, H8-Binap, MeO-Biphep, C3*-Tunephos, Segphos, Synphos, SunPhos, Difluophos, P-Phos, BPE, DIPAMP, DIOP, Duphos, SDP, and O-SDP, and corresponding isomers thereof or derivatives thereof.

5. The method according to claim 4, wherein the diphosphine ligand is: at least one of ##STR00049## ##STR00050## ##STR00051##

6. The method according to claim 1, wherein the chiral catalyst is selected from: ##STR00052## ##STR00053## ##STR00054## wherein the Ar group in the diphosphine ligand represents aryl and is selected from at least one of phenyl, 4-methylphenyl, 3,5-dimethylphenyl, 3,5-di-tert-butylphenyl, or 3,5-di-tert-butyl 4-rethoxyphenyl.

7. The method according to claim 1, wherein the chiral catalyst is obtained by complexing a metal precursor and a chiral ligand, wherein the metal is selected from ruthenium, rhodium, iridium, or palladium, and the chiral ligand is selected from at least one of L1-L27: ##STR00055## ##STR00056## ##STR00057##

8. The method according to claim 1, wherein the hydrogen source is hydrogen; and/or the organic solvent is selected from at least one of methanol, ethanol, isopropanol, tetrahydrofuran, dichloromethane, and toluene; and/or the additive is a base, and is selected from at least one of potassium tert-butoxide, sodium tert-butoxide, lithium tert-butoxide, potassium hydroxide, sodium hydroxide, sodium carbonate, potassium carbonate, and cesium carbonate.

9. The method according to claim 1, wherein the chiral catalyst is selected from: at least one of ##STR00058## ##STR00059##

10. The method according to claim 1, wherein the organic solvent is selected from at least one of EtOAc, CH.sub.2Cl.sub.2, ClCH.sub.2CH.sub.2Cl, MeOH, EtOH, iPrOH, (HOCH.sub.2).sub.2, THF, and PhMe; and/or the hydrogen source is selected from at least one of HCOOH/Et.sub.3N, HCOOH/DIPEA, HCOOH/iPr.sub.2NH, HCOOH/Et.sub.2NH, HCOOH/DBU, HCOOH/HCOOK, and HCOOH/HCOONa.

11. A compound, having the structure of the following formula (3): ##STR00060## and specifically comprising two configurations (R) and (S), wherein the structures thereof are shown below, ##STR00061## wherein R-(3) and S-(3) can be prepared by any one of the methods according to claim 1.

12. An asymmetric process for preparing nicotine, wherein the synthetic route is as follows: ##STR00062## wherein R in compound (1) represents alkyl, and the leaving group LG in compound (4) represents halogen or sulfonate, wherein the sulfonate is selected from at least one of methanesulfonate, trifluoromethanesulfonate, p-toluenesulfonate, and nitrosulfonate, and intermediate (3) is prepared by the synthesis method according to claim 1.

Description

BRIEF DESCRIPTION OF DRAWINGS

[0053] FIG. 1 is a schematic diagram of a nicotine asymmetric synthesis process.

[0054] FIG. 2 is a .sup.1H NMR spectrum of compound (2).

[0055] FIG. 3 is a .sup.13C NMR spectrum of compound (2).

[0056] FIG. 4 is a .sup.1H NMR spectrum of compound (3).

[0057] FIG. 5 is a .sup.13C NMR spectrum of compound (3).

[0058] FIG. 6 is a .sup.1H NMR spectrum of compound (5).

[0059] FIG. 7 is a 13C NMR spectrum of compound (5).

[0060] FIG. 8 is an HPLC chromatogram of racemic compound (3).

[0061] FIG. 9 is an HPLC chromatogram of chiral compound (3).

[0062] FIG. 10 is an HPLC chromatogram of racemic compound (5).

[0063] FIG. 11 is an HPLC chromatogram of chiral compound (5).

DETAILED DESCRIPTION OF THE EMBODIMENTS

[0064] The present disclosure will be further described with reference to the specific examples and figures, but the present disclosure is not limited thereto.

[0065] The experimental methods in the examples, in which specific conditions are not specified, are generally performed under the conventional conditions and the conditions described in the manual or under the conditions recommended by the manufacturer; the materials, reagents, and the like used are commercially available unless otherwise specified.

[0066] The asymmetric synthesis process schematic diagram referring to FIG. 1:

Example 1 Synthesis of Intermediate (2) (reference: Journal of Heterocyclic Chemistry, 2006, 49, 1252-1258.)

##STR00028##

[0067] 3-Bromopyridine (15.8 g, 100 mmol) was added to a three-necked round-bottom flask under argon atmosphere, dissolved with 250 mL of methyl tert-butyl ether (MTBE), and stirred and cooled to 78 C. in a low-temperature tank. 48 mL of a solution of n-butyl lithium (2.4 M, 120 mmol) in n-hexane was then slowly added dropwise, and the temperature was maintained at 78 C. during the dropwise addition. After the dropwise addition, the temperature was maintained at 78 C., and the mixture was stirred for 30 min. -Butyrolactone (8.46 mL, 110 mmol) was dissolved with 50 mL of methyl tert-butyl ether (MTBE) and then added dropwise to the reaction mixture. The temperature was maintained at 78 C., and the mixture was stirred for 2 h, slowly warmed to room temperature, and reacted for 1 h. The reaction was quenched with 50 mL of dilute hydrochloric acid (2 M), and the mixture was extracted with ethyl acetate. The organic phase was washed with saturated sodium bicarbonate and saturated brine, dried over anhydrous sodium sulfate, and concentrated to dryness by rotary evaporation to give a crude product, which was separated by column chromatography to give pure intermediate (2), 69% yield.

[0068] .sup.1H NMR (600 MHz, Chloroform-d) 9.18 (s, 1H), 8.80-8.72 (m, 1H), 8.25 (d, J=7.7 Hz, 1H), 7.47-7.41 (m, 1H), 3.76 (t, J=5.7 Hz, 2H), 3.16 (t, J=6.9 Hz, 2H), 2.78 (s, 1H), 2.04 (q, J=6.2 Hz, 2H). .sup.13C NMR (151 MHz, CDCl.sub.3) 199.11, 153.25, 149.43, 135.41, 132.08, 123.63, 61.61, 35.38, 26.56.

[0069] FIG. 2 is a .sup.1H NMR spectrum of compound (2), and FIG. 3 is a .sup.13C NMR spectrum of compound (2).

Example 2 Synthesis of Intermediate (2)

##STR00029##

Example 2-1 Condensation Reaction

[0070] A base (198.5 mmol) and nicotinate (132.3 mmol) were dissolved in 200 mL of a corresponding solvent at room temperature, and -butyrolactone (185.2 mmol) was diluted with 50 mL of the reaction solvent and added dropwise to the reaction system. After the addition was completed, the mixture was reacted at 75-100 C. overnight. After the reaction was completed, the mixture was returned to the room temperature and quenched with water. The pH of the system was neutralized to 71. The system was precipitated. The aqueous phase was extracted three times with DCM, dried over anhydrous sodium sulfate, filtered and concentrated to dryness by rotary evaporation to give a condensation product, which was directly used in the next reaction. In this reaction, the effect of the starting materials nicotinate, base, and reaction solvent was investigated. The results are shown in Table 1 below.

TABLE-US-00001 TABLE 1 No. Nicotinate Base Reaction solvent Yield (%) 1 Ethyl nicotinate Sodium tert- Tetrahydrofuran 88 butoxide 2 Ethyl nicotinate Potassium tert- Tetrahydrofuran 86 butoxide 3 Ethyl nicotinate Sodium Tetrahydrofuran 74 methoxide 4 Ethyl nicotinate Sodium ethoxide Tetrahydrofuran 78 5 Ethyl nicotinate Sodium hydride Tetrahydrofuran 82 6 Ethyl nicotinate Sodium tert- 2-Methyltetrahydrofuran 89 butoxide 7 Ethyl nicotinate Sodium tert- Diethylene 90 butoxide glycol dimethyl ether 8 Ethyl nicotinate Sodium tert- Ethylene glycol dimethyl 85 butoxide ether 9 Ethyl nicotinate Sodium tert- Toluene 85 butoxide 10 Ethyl nicotinate Sodium tert- Xylene 82 butoxide 11 Methyl nicotinate Sodium tert- Tetrahydrofuran 84 butoxide

Example 2-2 Hydrolytic Decarboxylation Reaction

[0071] The condensation product (8.12 g, 42.5 mmol) prepared in Example 2-1 described above was added to a diluted acid solution, and the mixture was refluxed at 100-110 C. for 24 h. After the reaction was completed, the system was cooled to 0 C., and the pH of the system was adjusted to greater than 11 with 6 M sodium hydroxide solution. The system was extracted three times with DCM (3100 mL), dried over anhydrous sodium sulfate, filtered and concentrated to dryness by rotary evaporation to give intermediate (2). In this reaction, the effect of different acids on this reaction was investigated. The results are shown in Table 2 below.

TABLE-US-00002 TABLE 2 No. Acid + water Yield (%) 1 HCl (36%, 20 mL) + H.sub.2O (20 mL) 60 2 H.sub.2SO.sub.4 (98%, 5 mL) + H.sub.2O (30 mL) 78 3 H.sub.3PO.sub.4 (85%, 6.4 mL) + H.sub.2O (30 mL) 75 4 HOAc (30 mL) + H.sub.2O (0 mL) 52 5 H.sub.2SO.sub.4 (98%, 5 mL) + HOAc (10 mL) + H.sub.2O (20 mL) 86

Example 3 Preparation of Chiral Alcohol Intermediate Compound (3) (Ruthenium-Diphosphine-Diamine Catalytic System Investigation)

##STR00030## ##STR00031## ##STR00032##

[0072] 0.63 g of intermediate 2 (3.8 mmol), 2 mL of isopropanol, and 4.3 mg of potassium tert-butoxide (0.038 mmol) were added to a 50 mL reaction kettle under argon atmosphere, and 0.0002 mmol of the catalyst Cat. was finally added. The gas in the autoclave was purged with hydrogen three times, and finally 50 atm of hydrogen was introduced, and the mixture was reacted at 25 C. for 16 h. After the reaction was completed, the gas in the autoclave was slowly released, and the mixture was concentrated under reduced pressure to give 0.63 g of a yellow oily liquid, which was hydrogenation product (3).

[0073] R-(3) characterization data: [].sup.25.sub.D=+45.8 (c=1.0, CHCl.sub.3); .sup.1H NMR (600 MHz, Chloroform-d) 8.42 (s, 1H), 8.34-8.28 (m, 1H), 7.69 (d, J=7.8 Hz, 1H), 7.26-7.17 (m, 1H), 4.89 (br, 2H), 4.69 (t, J=5.9 Hz, 1H), 3.60 (ddt, J=18.4, 13.8, 7.0 Hz, 2H), 1.80 (q, J=6.3 Hz, 2H), 1.62 (ddq, J=26.8, 13.3, 6.6 Hz, 2H). .sup.13C NMR (151 MHz, CDCl.sub.3) 147.70, 147.08, 140.85, 134.08, 123.52, 71.24, 61.97, 36.23, 28.81.

[0074] FIG. 4 is a .sup.1H NMR spectrum of compound (3), and FIG. 5 is a .sup.13C NMR spectrum of compound (3). FIG. 8 is an HPLC chromatogram of racemic compound (3); FIG. 9 is an HPLC chromatogram of chiral compound (3); the conversion rate and ee value were determined by HPLC, and the results are shown in Table 3 below.

TABLE-US-00003 TABLE 3 Catalyst Conversion No. (S/C = 5000) rate (%) ee (%) 1 Cat. 1a >99 57 2 Cat. 1b >99 65 3 Cat. 1c >99 80 4 Cat. 2a >99 93 5 Cat. 2b >99 97 6 Cat. 2c >99 99 7 Cat. 3a >99 34 8 Cat. 3b >99 45 9 Cat. 3c >99 50 10 Cat. 4 >99 95 11 Cat. 5 >99 97 12 Cat. 6 >99 98 13 Cat. 7 >99 92 14 Cat. 8 >99 84 15 Cat. 9 >99 96

[0075] Example 4 To further investigate the effect of the solvent in the reaction system on the reaction, the asymmetric hydrogenation reaction was catalyzed by Cat. 2c on the basis of Example 2, and the solvent .sup.iPrOH was sequentially replaced by MeOH, EtOH, DCM, THF, hexane, toluene, etc. The reaction time was 16 h, S/C=5000. The results of the effect of different solvents on the conversion rate and ee value of the reduction of compound (2) are shown in Table 4 below. The conversion rate (cony.) and the enantioselectivity (ee) were determined by HPLC.

TABLE-US-00004 TABLE 4 Reaction Conversion No. Catalyst (n mol %) solvent rate (%) ee (%) 1 Cat. 2c (0.02 mol %) .sup.iPrOH >99 99 2 Cat. 2c (0.02 mol %) MeOH >99 98 3 Cat. 2c (0.02 mol %) EtOH >99 99 4 Cat. 2c (0.02 mol %) DCM 97 96 5 Cat. 2c (0.02 mol %) THF 91 98 6 Cat. 2c (0.02 mol %) Hexane 80 96 7 Cat. 2c (0.02 mol %) Toluene 95 98

[0076] Example 5 To investigate the effect of the base added to the reaction system on the reaction, the asymmetric hydrogenation reaction was similarly catalyzed by Cat. 2c on the basis of Example 2 and Example 3 using isopropanol as the solvent, and potassium tert-butoxide was sequentially replaced by potassium carbonate, cesium carbonate, potassium hydroxide, sodium hydroxide, sodium methoxide, potassium methoxide, sodium tert-butoxide, and lithium tert-butoxide. The reaction time was 16 h, S/C=5000. The following experiment was performed. The results are shown in Table 5 below.

TABLE-US-00005 TABLE 5 Reaction Conversion No. Base solvent rate (%) ee (%) 1 .sup.tBuOK .sup.iPrOH >99 99 2 K.sub.2CO.sub.3 .sup.iPrOH 23 3 Cs.sub.2CO.sub.3 .sup.iPrOH 30 4 KOH .sup.iPrOH 50 5 NaOH .sup.iPrOH 41 6 NaOMe .sup.iPrOH 67 98 7 KOMe .sup.iPrOH 70 97 8 .sup.tBuONa .sup.iPrOH >99 98 9 .sup.tBuOLi .sup.iPrOH 93 96

Example 6 Preparation of Chiral Alcohol Intermediate Compound (3) (Ir-ligand Catalyst Investigation, S/C=10000)

##STR00033## ##STR00034## ##STR00035##

[0077] [Ir(COD)Cl].sub.2 (2.6 mg, 3.810.sup.3 mmol) and a chiral ligand (8.410.sup.3 mmol) were dissolved in 4 mL of isopropanol and stirred at room temperature for 3 h under argon atmosphere to give an orange clear catalyst solution. 200 L of this orange solution was taken with a microsyringe and added to a mixed system of intermediate (2) (0.63 g, 3.82 mmol), isopropanol (4 mL) and potassium tert-butoxide (4.3 mg, 0.038 mmol). The reaction system was placed in an autoclave. The gas in the autoclave was purged with hydrogen three times, and finally 50 atm of hydrogen was introduced, and the mixture was reacted at 60 C. for 24 h. After the reaction was completed, the gas in the autoclave was slowly released, and the mixture was concentrated under reduced pressure to give 0.63 g of a yellow oily liquid, which was hydrogenation product (3). The conversion rate and ee value were determined by HPLC. The results are shown in Table 6 below.

TABLE-US-00006 TABLE 6 Conversion No. Ligand S/C rate (%) ee (%) 1 L3 10000 >99 99 2 L7 10000 >99 98 3 L8 10000 >99 98 4 L9 10000 >99 >99 5 L10 10000 >99 96 6 L12 10000 85 95 7 L14 10000 >99 98 8 L16 10000 98 97 9 L19 10000 95 92 10 L20 10000 >99 86 11 L21 10000 >99 95 12 L22 10000 >99 91 13 L24 10000 >99 93 14 L25 10000 >99 97 15 L27 10000 98 96

[0078] Example 7 To investigate the effect of the solvent in the reaction system on the reaction, on the basis of Example 6, L9 was used as the catalyst, potassium tert-butoxide was used as the base, and the solvent was sequentially replaced by MeOH, EtOH, EtOAc, DCM, THF, hexane, toluene, etc. The reaction time was 2 h, S/C=10000. The results of the effect of different solvents on the conversion rate and ee value of the reduction of compound (2) are shown in Table 7 below. The conversion rate (cony.) and the enantioselectivity (ee) were determined by HPLC.

TABLE-US-00007 TABLE 7 Reaction Conversion No. Catalyst (n mol %) solvent rate (%) ee (%) 1 f-phamidol-L9 (0.01 mol %) .sup.iPrOH >99 >99 2 f-phamidol-L9 (0.01 mol %) MeOH NR 3 f-phamidol-L9 (0.01 mol %) EtOH 67 98 4 f-phamidol-L9 (0.01 mol %) EtOAc 20 5 f-phamidol-L9 (0.01 mol %) DCM 97 99 6 f-phamidol-L9 (0.01 mol %) THF 98 >99 7 f-phamidol-L9 (0.01 mol %) Hexane 99 >99 8 f-phamidol-L9 (0.01 mol %) Toluene 99 >99

[0079] Example 8 To investigate the effect of the base added to the reaction system on the reaction, on the basis of Example 7, L9 was used as the catalyst, isopropanol was used as the solvent, and potassium tert-butoxide was sequentially replaced by potassium carbonate, cesium carbonate, potassium hydroxide, sodium hydroxide, sodium methoxide, potassium methoxide, sodium tert-butoxide, and lithium tert-butoxide. The reaction time was 12 h, S/C=10000. The hydrogenation experiment was performed. The results are shown in Table 8 below.

TABLE-US-00008 TABLE 8 Reaction Conversion No. Base solvent rate (%) ee (%) 1 .sup.tBuOK .sup.iPrOH >99 99 2 K.sub.2CO.sub.3 .sup.iPrOH >99 99 3 Cs.sub.2CO.sub.3 .sup.iPrOH 90 95 4 KOH .sup.iPrOH >99 99 5 NaOH .sup.iPrOH >99 98 6 NaOMe .sup.iPrOH >99 98 7 KOMe .sup.iPrOH >99 99 8 .sup.tBuONa .sup.iPrOH >99 99 9 .sup.tBuOLi .sup.iPrOH >99 97

[0080] Example 9 Further, the catalyst f-phamidol-L9 was used as the catalyst, and isopropanol, a green solvent, was used as the solvent. The amount of the catalyst, the reaction time, and the like were separately changed. The results are shown in Table 9 below.

TABLE-US-00009 TABLE 9 Reaction Reaction Conversion No. S/C temperature ( C.) time rate (%) ee (%) 1 10000 25 12 h >99 >99 2 20000 25 12 h >99 >99 3 50000 25 24 h >99 >99 4 100000 25 24 h >99 >99 5 200000 25 48 h 97 99 6 500000 25 72 h 36 99

Example 10 Preparation of Chiral Alcohol Intermediate Compound (R)-(3) (Hectogram Scale, S/C=100000)

##STR00036##

[0081] [Ir(COD)Cl].sub.2 (2.6 mg, 3.810.sup.3 mmol) and the chiral ligand f-phamidol-L9 (4.8 mg, 8.410.sup.3 mmol) were dissolved in 4 mL of isopropanol and stirred for well complexing at room temperature for 3 h under argon atmosphere to give an orange clear catalyst solution. Intermediate (2) (126 g, 0.763 mol), isopropanol (500 mL) and potassium tert-butoxide (853 mg, 7.6 mmol) were added to a hydrogenation kettle, and the catalyst solution described above was added to the reaction solution described above. The hydrogenation kettle was sealed. The gas in the autoclave was purged with hydrogen three times, and finally 50 atm of hydrogen was introduced, and the mixture was reacted at 25-30 C. for 48 h. After the reaction was completed, the gas in the autoclave was slowly released in a fume hood, and the mixture was concentrated under reduced pressure to give 126.9 g of a yellow oily liquid, which was hydrogenation product (R)-(3). The yield was quantified, and the ee value was determined 99% by chiral HPLC analysis. [].sup.25.sub.D=+45.8 (c=1.0, CHCl.sub.3); .sup.1H NMR (600 MHz, Chloroform-d) 8.42 (s, 1H), 8.34-8.28 (m, 1H), 7.69 (d, J=7.8 Hz, 1H), 7.26-7.17 (m, 1H), 4.89 (br, 2H), 4.69 (t, J=5.9 Hz, 1H), 3.60 (ddt, J=18.4, 13.8, 7.0 Hz, 2H), 1.80 (q, J=6.3 Hz, 2H), 1.62 (ddq, J=26.8, 13.3, 6.6 Hz, 2H). .sup.13C NMR (151 MHz, CDCl.sub.3) 147.70, 147.08, 140.85, 134.08, 123.52, 71.24, 61.97, 36.23, 28.81.

Example 11 Preparation of Chiral Alcohol Intermediate Compound (3) (Transfer Hydrogenation Catalyst Investigation)

##STR00037##

[0082] Compound 2 (0.2 mmol) was in ethanol (1 mL), and a mixture of the catalyst cat. (S/C=1000) and 50 L of formic acid-triethylamine (HCOOH/Et.sub.3N, 5:2) (3.0 equivalents of [H], calculated by formic acid) were added at a temperature of 30 C. under argon or nitrogen atmosphere (the catalyst was 0.002 M ethanol solution, and 100 L was used). Asymmetric transfer hydrogenation reaction was performed for 3 h tracked by TLC to give intermediate (3). The conversion rate and ee value were determined by HPLC. The results are shown in Table 10 below.

TABLE-US-00010 TABLE 10 Reaction Conversion No. Catalyst (n mol %) time (h) rate (%) ee (%) 1 cat. a (0.1 mol %) 24 36 34 2 cat. b (0.1 mol %) 24 60 60 3 cat. c (0.1 mol %) 24 80 80 4 cat. d (0.1 mol %) 24 62 78 5 cat. e (0.1 mol %) 24 46 43 6 cat. f (0.1 mol %) 6 99 91 7 cat. g (0.1 mol %) 6 99 92 8 cat. h (0.1 mol %) 6 99 93 9 cat. i (0.1 mol %) 6 99 92 10 cat. j (0.1 mol %) 6 99 90

[0083] Example 12 To further investigate the effect of the base added to the reaction system on the reaction, the following experiment was performed using cat. h as the catalyst (S/C=1000) and ethanol as the solvent, and sequentially replacing triethylamine with diisopropylethylamine (DIPEA), diisopropylamine (.sup.iPr.sub.2NH), diethylamine (Et.sub.2NH), DBU, and no base added on the basis of Example 11. The reaction time was 3 h, S/C=1000. The results are shown in Table 11 below.

TABLE-US-00011 TABLE 11 Reaction Conversion No. Hydrogen source (5:2) solvent rate (%) ee (%) 1 HCOOH/Et.sub.3N EtOH 99 93 2 HCOOH/DIPEA EtOH 99 93 3 HCOOH/iPr.sub.2NH EtOH 99 93 4 HCOOH/Et.sub.2NH EtOH 99 93 5 HCOOH/DBU EtOH 99 94 6 HCOOH/no base EtOH 70 93

[0084] Example 13 On the basis of Example 12, the hydrogen source formic acid-triethylamine (5:2) was further replaced with formic acid-sodium formate (3:1), formic acid-potassium formate (3:1), sodium formate, and potassium formate (3.0 equivalents of [H]). The reaction time was determined by TLC tracking, S/C=1000. The reaction solvent was methanol, ethanol, or a mixed solution of methanol and water, and ethanol and water in a volume ratio of 1:1, and the following experiment was performed. The results of the effect on the conversion rate and ee value of the reduction of compound (2) are shown in Table 12 below. The results show that the reaction can be carried out even in aqueous solvents, and that the conversion rate and the enantioselectivity can both achieve very good results (>90% conv., 98% ee).

TABLE-US-00012 TABLE 12 Reaction Conversion No. Hydrogen source solvent rate (%) ee (%) 1 HCOOH/HCOONa (3:1) EtOH 98 93 2 HCOOH/HCOOK (3:1) EtOH 99 93 3 HCOONa EtOH/H.sub.2O 93 93 4 HCOOK EtOH/H.sub.2O 91 93

[0085] Example 14 Further, the catalyst cat. h was used as the catalyst, and ethanol (EtOH), a green solvent, was used as the reaction solvent, and formic acid triethylamine (5:2) was used as the hydrogen source. The amount of the hydrogen source was 3.0 equivalents (calculated by formic acid). The reaction concentration was 0.5 M. The catalyst, the reaction time, the reaction temperature, and the like were separately changed. The results are shown in Table 13 below.

TABLE-US-00013 TABLE 13 Reaction Reaction Conversion No. S/C temperature ( C.) time rate (%) ee (%) 1 1000 30 6 h 99 93 2 2000 30 30 h 99 93 3 5000 30 30 h 77 93 4 5000 60 30 h >99 90

[0086] Example 15 On the basis of Example 11, the catalyst cat. h was used as the catalyst, and the solvent was sequentially replaced with MeOH, THF, EtOAc, DCM, MeCN, etc. The reaction was performed for 6 h. The results of the effect of different solvents on the conversion rate and ee value of the reduction of compound (2) are shown in Table 14 below.

TABLE-US-00014 TABLE 14 Reaction Conversion No. Hydrogen source solvent rate (%) ee (%) 1 HCOOH/Et.sub.3N(5:2) EtOH 99 93 2 HCOOH/Et.sub.3N(5:2) MeOH 99 93 3 HCOOH/Et.sub.3N(5:2) THF 95 92 4 HCOOH/Et.sub.3N(5:2) EtOAc 80 91 5 HCOOH/Et.sub.3N(5:2) DCM 89 93 6 HCOOH/Et.sub.3N(5:2) MeCN 75 92

Example 16 Synthesis of (S)-Nicotine (Leaving Group LG Was OMs, Methylamine Alcohol Solution)

##STR00038##

[0087] 33.4 g (0.2 mol) of chiral alcohol intermediate (R)-(3) was weighed out. 200 mL of dichloromethane and 83.4 mL of triethylamine (0.6 mol) were added. The reaction system was placed in a 10 C. low-temperature cold bath. 38.8 mL of methanesulfonyl chloride (0.5 mol) was dissolved in 100 mL of dichloromethane and slowly added dropwise to the reaction system. After the dropwise addition was completed, the mixture was reacted at 10 C. for 1 h. After the reaction was completed, the reaction was quenched with 100 mL of water. The aqueous phase was extracted three times with dichloromethane (100 mL3), and the organic phases were combined, washed once with 20 mL of saturated sodium bicarbonate solution, dried over anhydrous sodium sulfate, filtered, and concentrated to one fourth for later use. In a 10 C. low-temperature cold bath, 66 mL of methylamine alcohol solution (33 wt % in EtOH) was added dropwise to the concentrated solution obtained above, and the mixture was stirred at 10 C. for 24 h. After the reaction was completed, excess methylamine was directly removed by rotary evaporation, and the residue was diluted with water and extracted 3 times with DCM. The organic phase was dried and concentrated to give 30.8 g of (S)-nicotine crude product. The ee value was determined 99% by HPLC, and the purity was 97% by GC analysis. Compound (5) was obtained after distillation, namely 26.6 g of (S)-nicotine pure product, 82% yield. The ee value was determined 99% by HPLC, and the purity was 99.7% by GC analysis.

[0088] [].sup.25.sub.D=98.5 (c=1.0, CHCl.sub.3); .sup.1H NMR (400 MHz, Chloroform-d) 8.59 (d, J=1.8 Hz, 1H), 8.54 (dd, J=4.8, 1.6 Hz, 1H), 7.76 (dt, J=7.8, 1.8 Hz, 1H), 7.31 (dd, J=7.8, 4.8 Hz, 1H), 3.33-3.25 (m, 1H), 3.14 (t, J=8.3 Hz, 1H), 2.36 (q, J=9.2 Hz, 1H), 2.26 (ddt, J=12.7, 5.1, 2.1 Hz, 1H), 2.21 (s, 3H), 2.09-1.96 (m, 1H), 1.92-1.83 (m, 1H), 1.78 (dddd, J=12.4, 11.1, 8.9, 5.6 Hz, 1H); .sup.13C NMR (101 MHz, CDCl.sub.3) 149.38, 148.47, 138.59, 134.78, 123.49, 68.74, 56.87, 40.24, 35.06, 22.47.

[0089] FIG. 6 is a .sup.1H NMR spectrum of compound (5), and FIG. 7 is a .sup.13C NMR spectrum of compound (5). FIG. 10 is an HPLC chromatogram of racemic compound (5), and FIG. 11 is an HPLC chromatogram of chiral compound (5).

Example 17 Synthesis of (S)-Nicotine (Leaving Group LG Was OTs, Methylamine Alcohol Solution)

##STR00039##

[0090] 33.4 g (0.2 mol) of chiral alcohol intermediate (R)-(3) was weighed out and dissolved with 200 mL of dichloromethane, and 83.4 mL of triethylamine (0.6 mol) was added dropwise. The reaction system was placed in a 10 C. low-temperature cold bath. 95.3 g of p-toluenesulfonyl chloride (0.5 mol) was dissolved in 100 mL of dichloromethane and slowly added dropwise to the reaction system. After the dropwise addition was completed, the mixture was reacted at 10 C. for 3 h. After the reaction was completed, the reaction was quenched with 100 mL of water. The aqueous phase was extracted three times with dichloromethane (100 mL3), and the organic phases were combined, washed once with 20 mL of saturated sodium bicarbonate solution, dried over anhydrous sodium sulfate, filtered, and concentrated to one fourth for later use. In a 10 C. low-temperature cold bath, 66 mL of methylamine alcohol solution (33 wt % in EtOH) was added dropwise to the concentrated solution obtained above, and the mixture was stirred at 10 C. for 24 h. After the reaction was completed, excess methylamine was directly removed by rotary evaporation, and the residue was diluted with water and extracted 3 times with DCM. The organic phase was dried and concentrated to give 31.2 g of (S)-nicotine crude product. The ee value was determined 99% by HPLC, and the purity was 94% by GC analysis. 26.0 g of (S)-nicotine pure product was obtained after distillation, 82% yield. The ee value was determined 99% by HPLC, and the purity was 99.6% by GC analysis.

Example 18 Synthesis of (S)-Nicotine (Leaving Group LG Was OMs, Methylamine Aqueous Solution)

##STR00040##

[0091] 33.4 g (0.2 mol) of chiral alcohol intermediate (R)-(3) was weighed out. 200 mL of dichloromethane and 83.4 mL of triethylamine (0.6 mol) were added. The reaction system was placed in a 10 C. low-temperature cold bath. 38.8 mL of methanesulfonyl chloride (0.5 mol) was dissolved in 100 mL of dichloromethane and slowly added dropwise to the reaction system. After the dropwise addition was completed, the mixture was reacted at 10 C. for 1 h. After the reaction was completed, the reaction was quenched with 100 mL of water. The aqueous phase was extracted three times with dichloromethane (100 mL3), and the organic phases were combined, washed once with 20 mL of saturated sodium bicarbonate solution, dried over anhydrous sodium sulfate, filtered, and concentrated to one fourth for later use. In a 10 C. low-temperature cold bath, 40 mL of methylamine alcohol solution (40 wt % in H.sub.2O) was added dropwise to the concentrated solution obtained above, and the mixture was stirred at 10 C. for 24 h. After the reaction was completed, excess methylamine was directly removed by rotary evaporation, and the residue was diluted with water and extracted 3 times with DCM. The organic phase was dried and concentrated to give 31.6 g of (S)-nicotine crude product. The ee value was determined 99% by HPLC, and the purity was 95% by GC analysis. 26.9 g of (S)-nicotine pure product was obtained after distillation, 83% yield. The ee value was determined 99% by HPLC, and the purity was 99.6% by GC analysis.

Example 19 Preparation of Chiral Alcohol Intermediate Compound (S)-(3) (S/C=100000)

##STR00041##

[0092] [Ir(COD)Cl].sub.2 (2.6 mg, 3.810.sup.3 mmol) and the chiral ligand ent-f-phamidol-L9 (4.8 mg, 8.410.sup.3 mmol) with the opposite configuration to Example 10 were dissolved in 4 mL of isopropanol and stirred for well complexing at room temperature for 3 h under argon atmosphere to give an orange clear catalyst solution. Intermediate (2) (63 g, 0.382 mol), isopropanol (250 mL), and potassium tert-butoxide (427 mg, 3.8 mmol) were added to a hydrogenation kettle, and 2 mL of the catalyst solution described above was added to the reaction solution described above. The hydrogenation kettle was sealed. The gas in the autoclave was purged with hydrogen three times, and finally 50 atm of hydrogen was introduced, and the mixture was reacted at 25-30 C. for 48 h. After the reaction was completed, the gas in the autoclave was slowly released in a fume hood, and the mixture was concentrated under reduced pressure to give 63.8 g of a yellow oily liquid, which was hydrogenation product (S)-(3). The yield was quantified, and the ee value was determined 99% by chiral HPLC analysis. The configuration of the product was the opposite to that of Example 10. The NMR characterization data of (S)-(3) was consistent with that of (R)-(3), and the optical rotation value was [].sup.25.sub.D=45.0 (c=1.0, CHCl.sub.3).

Example 20 Synthesis of (R)-Nicotine (Leaving Group LG Was OMs, Methylamine Alcohol Solution)

##STR00042##

[0093] 16.7 g of chiral alcohol intermediate (S)-(3) (0.1 mol) was weighed out. 100 mL of dichloromethane and 41.7 mL of triethylamine (0.3 mol) were added. The reaction system was placed in a 10 C. low-temperature cold bath. 19.4 mL of methanesulfonyl chloride (0.25 mol) was dissolved in 50 mL of dichloromethane and slowly added dropwise to the reaction system. After the dropwise addition was completed, the mixture was reacted at 10 C. for 1 h. After the reaction was completed, the reaction was quenched with 50 mL of water. The aqueous phase was extracted three times with dichloromethane (50 mL3), and the organic phases were combined, washed once with 10 mL of saturated sodium bicarbonate solution, dried over anhydrous sodium sulfate, filtered, and concentrated to one fourth for later use. In a 10 C. low-temperature cold bath, 15 mL of methylamine alcohol solution (33 wt % in EtOH) was added dropwise to the concentrated solution obtained above, and the mixture was stirred at 10 C. for 24 h. After the reaction was completed, excess methylamine was directly removed by rotary evaporation, and the residue was diluted with water and extracted 3 times with DCM. The organic phase was dried and concentrated to give 15.8 g of (R)-nicotine crude product. The ee value was determined 99% by HPLC, and the purity was 94% by GC analysis. 13.0 g of (R)-nicotine pure product was obtained after distillation, 80% yield. The ee value was determined 99% by HPLC, and the purity was 99.7% by GC analysis.

[0094] The examples described above are preferred embodiments of the present disclosure, which, however, are not intended to limit the embodiments of the present disclosure. Any other changes, modifications, substitutions, combinations, and simplifications can be made without departing from the spirit and principle of the present disclosure, and should be construed as equivalent replacements and included in the protection scope of the present disclosure.