PREPARATION METHOD FOR SYNTHESIZING CHIRAL NICOTINE FROM CHIRAL TERT-BUTYLSULFENAMIDE

Abstract

The present application provides a preparation method for synthesizing a chiral nicotine from a chiral tert-butylsulfenamide, which includes steps as follows: condensating 3-pyridinecarboxaldehyde with tert-butylsulfenamide at the presence of a titanate; and then reacting (1,3-dioxane-2-yl ethyl) magnesium bromide; cyclizing under an acidic condition; finally obtaining chiral nicotine after reduction and amine methylation.

Claims

1. A preparation method for synthesizing a chiral nicotine from a chiral tert-butylsulfenamide, comprising steps as follow: step S1: condensing 3-pyridinecarboxaldehyde with the chiral tert-butylsulfenamide at the presence of a titanate to obtain a chiral 2-methyl-N-(pyridine-3-yl methylene) propane-2-sulfenamide; step S2: reacting the chiral 2-methyl-N-(pyridine-3-yl methylene) propane-2-sulfenamide with (1,3-dioxane-2-yl ethyl) magnesium bromide to obtain a chiral N-(3-(1,3-dioxane-2-yl)-1-(pyridine-3-yl) propylidene)-2-methyl propane-2-sulfenamide; step S3: cyclizing the chiral N-(3-(1,3-dioxane-2-yl)-1-(pyridine-3-yl) propylidene)-2-methyl propane-2-sulfenamide under an acidic condition to obtain a chiral 3-(3,4-dihydro-2H-pyrrol-2-yl) pyridine; and step S4: reducing and amine methylating the chiral 3-(3,4-dihydro-2H-pyrrol-2-yl) pyridine to obtain the chiral nicotine.

2. The preparation method for synthesizing the chiral nicotine from the chiral tert-butylsulfenamide according to claim 1, wherein, in the step S1, a mole ratio of 3-pyridinecarboxaldehyde, the chiral tert-butylsulfenamide and the titanate is 1:1:(1-3).

3. The preparation method for synthesizing the chiral nicotine from the chiral tert-butylsulfenamide according to claim 2, wherein, in the step S1, the mole ratio of 3-pyridinecarboxaldehyde, the chiral tert-butylsulfenamide and the titanate is 1:1:2.

4. The preparation method for synthesizing the chiral nicotine from the chiral tert-butylsulfenamide according to claim 1, wherein, in the step S1, the titanate is one or more selected from the group consisting of tetraethyl titanate, tetrapropyl titanate and tetrabutyl titanate.

5. The preparation method for synthesizing the chiral nicotine from the chiral tert-butylsulfenamide according to claim 1, wherein, a temperature of the step S1 is 30-70° C.

6. The preparation method for synthesizing the chiral nicotine from the chiral tert-butylsulfenamide according to claim 1, wherein, a solvent used in the step S1 is one selected from a group consisting of anhydrous tetrahydrofuran and dimethyl tetrahydrofuran.

7. The preparation method for synthesizing the chiral nicotine from the chiral tert-butylsulfenamide according to claim 1, wherein, in the step S2, a mole ratio of the chiral 2-methyl-N-(pyridine-3-yl methylene) propane-2-sulfenamide and (1,3-dioxane-2-yl ethyl) magnesium bromide is 1:(1.1-1.3).

8. The preparation method for synthesizing the chiral nicotine from the chiral tert-butylsulfenamide according to claim 7, wherein, in the step S2, the mole ratio of the chiral 2-methyl-N-(pyridine-3-yl methylene) propane-2-sulfenamide and (1,3-dioxane-2-yl ethyl) magnesium bromide is 1:1.225.

9. The preparation method for synthesizing the chiral nicotine from the chiral tert-butylsulfenamide according to claim 1, wherein, in the step S4, a reducing agent used for the reducing is sodium borohydride.

10. The preparation method for synthesizing the chiral nicotine from the chiral tert-butylsulfenamide according to claim 9, wherein a mole ratio of sodium borohydride and the chiral 3-(3,4-dihydro-2H-pyrrol-2-yl) pyridine is (1.5-2.5):1.

Description

DESCRIPTION OF THE EMBODIMENTS

[0042] The present application is further described in detail below in combination with examples.

[0043] Raw materials used in the present application can be obtained through commercial sale. The raw materials not mentioned in the present application are purchased from Sinopharm Chemical Reagent Co., Ltd., unless otherwise stated.

[0044] Examples 1-15 provide a preparation method for synthesizing chiral nicotine from a chiral tert-butylsulfenamide. Example 1 is described below as an example.

[0045] Example 1 provides a preparation method for synthesizing chiral nicotine from chiral tert-butylsulfenamide, in which the chiral tert-butylsulfenamide is S-tert-butylsulfenamide, and the chiral nicotine is S-chiral nicotine, and a synthetic route is shown as reaction formula 1:

##STR00001##

[0046] The specific preparation steps are shown as follows.

[0047] Step S1: in a nitrogen atmosphere, 106.7 g (1 mol, 1 eq) 3-pyridinecarboxaldehyde, 121.7 g (1 mol, 1 eq) (S)-tert-butylsulfenamide and 455.5 g (2 mol, 2 eq) tetraethyl titanate were dissolved in 6 L anhydrous tetrahydrofuran, and reacted at 70° C. for 2 h. After the reaction, a reaction solution was poured into 10 L saturated salt water solution, stirred at 1000 rpm for 15 min, and filtered to obtain a filtrate and a filter cake. The filter cake was washed with 3 L ethyl acetate, and the filtrate was collected, and separated to obtain a water layer. The water layer was extracted with 6 L ethyl acetate-water (volume ratio of ethyl acetate to water is 2:1) for 3 times to obtain organic layers. The organic layers were combined, washed with 3 L saturated salt water solution, dried by anhydrous Na.sub.2SO.sub.4 and vacuum concentrated to remove solvent to obtain a light yellow oily liquid of (S,E)-2-methyl-N-(pyridine-3-yl methylene) propane-2-sulfenamide.

[0048] Step S2: 8 L tetrahydrofuran was added into (S,E)-2-methyl-N-(pyridine-3-yl methylene) propane-2-sulfenamide prepared by Step S1, and mixed uniformly. In the nitrogen atmosphere at −30° C., 2.45 L 0.5 mol/L solution of (1,3-dioxane-2-yl ethyl) magnesium bromide in tetrahydrofuran was added dropwise (in which, (1,3-dioxane-2-yl ethyl) magnesium bromide is 1.225 mol, 1.225 eq), stirred and reacted at −30° C., 400 rpm for 30 min. Then, nitrogen was removed, and the reaction vessel was sealed, the reaction solution was stirred and performed at 0° C., 400 rpm for 3 h. After the reaction, the reaction solution was heated to 25° C., and a mixed solution of 0.5 L saturated NH.sub.4Cl water solution and 0.3 L ethyl acetate were added for a quenching reaction. After the quenching reaction, the reaction solution was separated to obtain an organic layer and a water layer. The water layer was extracted with 10 L ethyl acetate for 3 times, and separated. All the organic layers in the water layer were collected, combined, washed with 15 L saturated salt water, dried with anhydrous magnesium sulfate, filtered and vacuum concentrated to obtain (S,E)-N-(3-(1,3-dioxane-2-yl)-1-(pyridine-3-yl) propylidene)-2-methyl propane-2-sulfenamide.

[0049] Step S3: 8 L tetrahydrofuran was added into (S,E)-N-(3-(1,3-dioxane-2-yl)-1-(pyridine-3-yl) propylidene)-2-methyl propane-2- sulfenamide prepared by Step S2, and the system was adjusted to a pH of 3 by adding hydrochloric acid methanol solution with HCl content of 20 wt % and reacted at 25° C. for 2 h to obtain a mixture containing (S)-3-(3,4-dihydro-2H-pyrrol-2-yl) pyridine.

[0050] Step S4: 75.66 g (2 mol, 2 eq) sodium borohydride was added into the mixture containing (S)-3-(3,4-dihydro-2H-pyrrol-2-yl) pyridine prepared by Step S3, reacted at 0° C. for 3 h. (S)-3-(3,4-dihydro-2H-pyrrol-2-yl) pyridine is reduced to (S)-demethylnicotine, so as to obtain a mixing solution containing (S)-demethylnicotine. The pH of the mixing solution containing (S)-demethylnicotine to 9 with 4 mol/L NaOH, and then 488.3 g (1.5 mol. 1.5 eq) cesium carbonate and 170 g (1.2 mmol, 1.2 eq) methyl iodide were added and reacted at 25° C. for 3 h, and the pH of the system was adjusted to 7 with 5 mol/L HCl, and then the reaction solution was extracted with 15 L saturated salt water and 15 L dichloromethane to obtain an organic phase, which is collected and dried by adding anhydrous Na.sub.2SO.sub.4. The solvent was vacuum concentrated and evaporated to obtain a crude product of (S)-nicotine, which was atmospheric distillation purified to obtain (S)-nicotine, of which a yield is 72%, an ee value is 98%, and a purity is 98%.

[0051] Examples 2-3 differ from Example 1 only in that: in Step S1, an amount of the titanate is varied, as specifically shown in table 1.

TABLE-US-00001 TABLE 1 Effect of the amount of the titanate on the yield of (S)-nicotine Equivalence quantity No. of titanate(eq) Yield of (S)-nicotine (%) Example 1 2 72 Example 2 1 43 Example 3 3 68

[0052] Example 4 differs from Example 1 only in that: in Step S1, the type of titanate is varied, as specifically shown in table 2.

TABLE-US-00002 TABLE 2 Effect of the selection of titanate on the yield of (S)-nicotine No. Selected titanate Yield of (S)-nicotine (%) Example 1 tetraethyl titanate 72 Example 4 tetrabutyl titanate 70

[0053] Examples 5-7 differ from Example 1 only in that: in Step S1, a reaction temperature is varied, as specifically shown in table 3.

TABLE-US-00003 TABLE 3 Effect of the reaction temperature on the yield of (S)-nicotine No. Reaction temperature (° C.) Yield of (S)-nicotine (%) Example 1 70 72 Example 5 90 65 Example 6 80 68 Example 7 50 54

[0054] Example 8-9 differ from Example 1 only in that: in Step S1, the type of the solvent is varied, as specifically shown in table 4.

TABLE-US-00004 TABLE 4 Effect of the solvent on the yield of (S)-nicotine No. Selection of the solvent Yield of (S)-nicotine (%) Example 1 anhydrous tetrahydrofuran 72 Example 8 dimethyl tetrahydrofuran 70 Example 9 dichloromethane 53

[0055] Examples 10-11 differ from Example 1 only in that: in Step S2, the amount of (1,3-dioxane-2-yl ethyl) magnesium bromide is varied, as specifically shown in table 5.

TABLE-US-00005 TABLE 5 Effect of the amount of (1,3-dioxane-2-yl ethyl) magnesium bromide on the yield of (S)-nicotine Equivalence quantity of (1,3-dioxane-2-yl ethyl) No. magnesium bromide (eq) the yield of (S)-nicotine (%) Example 1 1.225 72 Example 10 1.1 65 Example 11 1.3 70

[0056] Example 12 differs from the Example 1 only in that: in Step S3, acid condition is varied, as specifically shown in table 6.

TABLE-US-00006 TABLE 6 Effect of the acid conditions on the yield of (S)-nicotine No. the acid conditions the yield of (S)-nicotine (%) Example 1 hydrochloric acid 72 methanol solution with HCl content of 20 wt % Example 12 90 wt % trifluoroacetic 68 acid aqueous solution

[0057] Examples 13-14 differ from the Example 1 only in that: in Step S4, reduction condition is varied, as specifically shown in table 7.

TABLE-US-00007 TABLE 7 Effect of the reduction conditions on the yield of (S)-nicotine No. the reduction conditions the yield of (S)-nicotine (%) Example 1 sodium borohydride 72 Example 13 sodium triacetyl 30 borohydride Example 14 sodium dithionite 50

[0058] The Example 15 differs from the Example 1 only in that: in Step S1, (S)-tert-butylsulfenamide is replaced by (R)-tert-butylsulfenamide in equimolar. The yield of (R)-nicotine is 71%, the ee value is 98%, the purity is 98%.

Comparative Example

[0059] The comparative Example 1 differs from the Example 1 only in that: in Step S1, the titanate is replaced by cesium carbonate in equimolar amount. The yield of (S)-nicotine is 28%, the ee value is 97%, the purity is 92%.

[0060] What is provided above is merely the preferred embodiments according to the present application, and the protection scope of the present application is not limited to the above embodiments. On the contrary, all the technical solutions obtained based on the concepts of the present application should fall in the protection scope of the present application. It should be noted that, for those skilled in the art, some improvements and modifications can be made without departing from the principles of the present applications, which should be also considered as falling within the protection scope of the present application.