Structure of 177947-67-0
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CAS No. : | 177947-67-0 |
Formula : | C16H23NO3 |
M.W : | 277.36 |
SMILES Code : | O=C(N1C[C@H](OCC2=CC=CC=C2)CC1)OC(C)(C)C |
MDL No. : | MFCD16556310 |
* All experimental methods are cited from the reference, please refer to the original source for details. We do not guarantee the accuracy of the content in the reference.
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
96.5% | In a 10L dry reactor,Add 60% sodium hydride (133g, 0.55mol) and dry THF (5400ml),Cool to 0 C ~ 5 C, at this temperature,A solution of (R)-N-tert-butoxycarbonyl-3-hydroxypyrrolidine (467 g, 2.5 mol) in anhydrous THF (1800 ml) was added dropwise, and the mixture was stirred for 1 h, and the absence of benzyl bromide (500 g, 2.9 mol) was added. Water THF (360 ml) solutionTetrabutylammonium bromide (90 g, 0.29 mol) was stirred at room temperature for 20 h. TLC was used to identify the end point of the reaction [developer:Ethyl acetate (v):methanol (v):dichloromethane (v)=5:2:5]. After completion of the reaction, water (2800 ml) was added, stirred for 10 min, and extracted with ethyl acetate (2200 ml×3). The organic layer was successively watered (1500 mL x 3)Wash with saturated sodium chloride solution (1500mL x 3),Anhydrous Na2SO4 is dried, filtered, and the filtrate is concentrated under reduced pressure.A yellow oil (R)-N-tert-butoxycarbonyl-3-benzyloxypyrrolidine 663 g, 96.5%,The HPLC normalized content was 95.8% and was directly used in the next step reaction. | |
76% | In tetrahydrofuran; water; | b (3R)-N-tert-Butyloxycarbonyl-3-benzyloxypyrrolidine A solution of (3R)-N-tert-butyloxycarbonylpyrrolidin-3-ol (2.25 g, 12.0 mmol), in anhydrous THF (10 ml) was added portionwise to a slurry of sodium hydride (60% dispersion in oil, 0.63 g, 13.8 mmol) in THF (35 ml) and the mixture stirred for 0.3 h at 0 C. A solution of benzyl bromide (2.37 g, 13.8 mmol) in dry THF (2 ml) was added and the mixture warmed to room temperature and stirred for 18 h. Water (70 ml) was added and the mixture extracted with ethyl acetate (3*100 ml). The combined extracts were washed with brine, dried (MgSO4) and evaporated. The crude product was chromatographed on silica gel eluding with CH2 Cl2 /MeOH (100:0→97:3) to give the desired product (2.53 g, 76%), δ (250 MHz, CDCl3) 1.46 (9H, s, OC(Me)3), 1.87-2.11 (2H, m, CH2), 3.42-3.50 (4H, m, 2 of CH2), 4.10-4.16 (1H, m, CH--OBn), 4.53 (2H, s, OCH2 Ar), 7.26-7.39 (5H, m, Ar). |
68% | To the stirred solution of tert-butyl (R)-3-hydroxypyrrolidine-l-carboxylate (Intermediate 8-step 1, 3 g, 16.04 mmol, 1.0 eq) in DMF (30 mL), then the reaction mixture was cooled at 0 C and added NaH (1.9 g, 80.2 mmol, 5.0 eq) followed by benzyl bromide (3.13 mL, 19.24 mmol, 1.2 eq). The reaction mixture was stirred at room temperature for about 3 hours. The reaction mixture was diluted with water and extracted with CH2C12. The combined organic extracts were dried over Na2S04, filtered and evaporated under reduced pressure. The residue was purified by column chromatography by using 10% ethylacetate and hexane as an eluent to afford the desired product (3.0 g, yield: 68.0%) as a white solid. |
55.9% | With sodium ethanolate; In tetrahydrofuran; at 30 - 70℃; for 7h;Product distribution / selectivity; | Comparative examples 1 to 8 In Example 1, the solvent was variously changed for doing studies and the results are shown in Table 6. Additionally, there were used pellet for KOH and powder for sodium methylate. |
32.8% | With sodium methylate; In tetrahydrofuran; at 30 - 70℃; for 7h;Product distribution / selectivity; | Comparative examples 1 to 8 In Example 1, the solvent was variously changed for doing studies and the results are shown in Table 6. Additionally, there were used pellet for KOH and powder for sodium methylate. |
5.6% | With sodium hydroxide; In tetrahydrofuran; water; at 30 - 70℃; for 7h;Product distribution / selectivity; | Comparative examples 1 to 8 In Example 1, the solvent was variously changed for doing studies and the results are shown in Table 6. Additionally, there were used pellet for KOH and powder for sodium methylate. |
With sodium hydride; In N,N-dimethyl-formamide; at 20℃; | To a solution of <strong>[109431-87-0](R)-tert-butyl 3-hydroxypyrrolidine-1-carboxylate</strong> (3.2 mmol) in dimethyl formamide (10 mL) was added sodium hydride (3.2 mmol) and benzyl bromide (3.2 mmol) at 0 C. and the resulting mixture was stirred at room temperature. After stirring overnight, distilled water (50 mL) was added and the resulting precipitate was collected by filtration to afford D1. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
98% | (Example 26) N-tert-butoxycarbonyl-(R)-3-benzyloxypyrrolidine Dimethyl sulfoxide (50 g) was added to about 60 % toluene solution of N-tert-butoxycarbonyl-(R)-3-hydroxypyrrolidine (20 g) which had been obtained separately, and potassium iodide (5.32 g) and a solid of 85 % potassium hydroxide (14.1 g) were added thereto. | |
96 - 97.7% | With sodium hydroxide; In dimethyl sulfoxide; at 30 - 70℃; for 7h;Product distribution / selectivity; | Examples 2 to 4 (Form of NaOH) In Example 1, the used amount of each component was set to the following and the form of sodium hydroxide was changed variously for doing studies and the results are shown in Table 1. In the table, the used amount of solvent represents times by weight based on R-BocHP.From the above table, it is known that sodium hydroxide may be used either in the form of aqueous solution or solid. |
92 - 97% | With sodium hydroxide; tetrabutylammomium bromide;potassium iodide; In water; toluene; at 50 - 72℃;Product distribution / selectivity; | 180 g of N-tert-butoxycarbonyl-(R)-3-hydroxypyrrolidine was dissolved into 725 g of toluene, followed by adding 31 g of tetra-n-butyl ammonium bromide and 16g of potassium iodide as a catalyst. Further, after 1924g of 10 % aqueous solution of sodium hydroxide was added and the mixture was heated to 50 C, 158g of benzyl chloride was dropped. After the reaction finished, the mixture was cooled to 25 C and an organic layer was washed with water. The resultant organic layer was concentrated, thereby obtaining 244 g of N-tert-butoxycarbonyl-(R)-3-benzyloxypyrrolidine (yield of 92 %). A residual quantity of N-tert-butoxycarbonyl-(R)-3-hydroxypyrrolidine with respect to N-tert-butoxycarbonyl-(R)-3-benzyloxypyrrolidine was 1.1 wt %. |
88.9% | With sodium hydroxide; In water; N,N-dimethyl-formamide; at 30 - 70℃; for 7h;Product distribution / selectivity; | Comparative examples 1 to 8 In Example 1, the solvent was variously changed for doing studies and the results are shown in Table 6. Additionally, there were used pellet for KOH and powder for sodium methylate. |
86.7 - 100% | With sodium hydroxide; In water; dimethyl sulfoxide; at 30 - 70℃; for 7h;Product distribution / selectivity; | In a four-neck flask of 1 L equipped with a thermometer and a dropping funnel, 182. 0 g of dimethylsulfoxide was charged, 121. 3 g (0. 65 moles) of R-BocHP obtained above was added thereto and stirred to dissolve. Next, 48% sodium hydroxide of 162.0 g (1.94 moles) (3.0 equivalent amount to R-BocHP) was added, and while stirring, benzyl chloride of 106.6 g (0.84 moles) (1.3 equivalent amount to R-BocHP) was added dropwise for the inner temperature to be from 30 to 40C in a water bath. After aging of 7 hours, the reaction liquid was quantitatively analyzed using the above-described HPLC analysis method, as a result, the production amount of R-BocBHP was 171 g (reaction yield: 95%). Examples 2 to 4 (Form of NaOH) In Example 1, the used amount of each component was set to the following and the form of sodium hydroxide was changed variously for doing studies and the results are shown in Table 1. In the table, the used amount of solvent represents times by weight based on R-BocHP. From the above table, it is known that sodium hydroxide may be used either in the form of aqueous solution or solid.Examples 5 to 7 (Used amount of NaOH) In Example 1, the used amount of 48% sodium hydroxide aqueous solution (hereinafter, sometimes abbreviated as "48% NaOH") was variously changed for doing studies and the results are shown in Table 2.From the above table, to progress the reaction efficiently, the more the used amount of base is, the better.Examples 8 to 10 (Used amount of benzyl chloride) In Example 1, the used amount of benzyl chloride was variously changed for doing studies and the results are shown in Table 3. From the above table, to progress the reaction efficiently, the more the used amount of benzyl chloride is, the better. In the table, being quantitatively means that the calculated result based on analytical results by a predetermined HPLC analysis was 99% or more.Examples 11 to 14 (Used amount of DMSO) In Example 1, the used amount of solvent was changed for doing studies of benzylation reaction and the results are shown in Table 4. From the above table, to progress the reaction efficiently, it is particularly good that the used amount of dimethylsulfoxide (DMSO) is 1.3 times by weight or more based on R-BocHP.Examples 15 to 18 (Reaction temperature) In Example 1, the reaction temperature was changed for doing studies of benzylation reaction and the results are shown in Table 5. From the above table, to progress the reaction efficiently, it is particularly good that the reaction temperature is from 30 to 70C. |
47.2% | With sodium hydroxide; In water; acetonitrile; at 30 - 70℃; for 7h;Product distribution / selectivity; | Comparative examples 1 to 8 In Example 1, the solvent was variously changed for doing studies and the results are shown in Table 6. Additionally, there were used pellet for KOH and powder for sodium methylate. |
10.2% | With potassium hydroxide; In ethanol; at 30 - 70℃; for 7h;Product distribution / selectivity; | Comparative examples 1 to 8 In Example 1, the solvent was variously changed for doing studies and the results are shown in Table 6. Additionally, there were used pellet for KOH and powder for sodium methylate. |
With sodium hydroxide; tetrabutylammomium bromide; sodium iodide; In water; toluene; at 25 - 50℃; | (Example 25) N-tert-butoxycarbonyl-(R)-3-benzyloxypyrrolidine 187 mg of N-tert-butoxycarbonyl-(R)-3-hydroxypyrrolidine prepared separately was dissolved in 748 mg of toluene followed by adding 16 mg of tetra-n-butyl ammonium bromide and 9 mg of sodium iodide. Further, after 666 mg of 30 % aqueous solution of sodium hydroxide was added and the mixture was heated to 50 C, 164 mg of benzyl chloride was dropped. A reaction temperature was cooled to 25 C to stop the reaction at the stage where a remaining N-tert-butoxycarbonyl-(R)-3-hydroxypyrrolidine became 6.4 wt % with respect to N-tert-butoxycarbonyl-(R)-3-benzyloxypyrrolidine. | |
98.6 - 99.1%Chromat. | With sodium hydroxide;tetrabutylammonium sulfate; In tetrahydrofuran; water; at 50℃; for 7h;Product distribution / selectivity; | To a mixed liquid of R-BocHP of 1.02 g (5.45 mmol), tetrahydrofuran of 1.50 g, tetra-n-butylammonium sulfate of 92.1 mg (0.27 mmol, 0.05 equivalent amount to R-BocHP) and 48% sodium hydroxide aqueous solution of 1.39 g (16.68 mmol, 3.06 equivalent amount to R-BocHP), benzyl chloride of 0.88 g (6.95 mmol, 1.28 equivalent amount to R-BocHP) was added and stirred, raised to 50C and heated for 7 hours. As a result of analysis by liquid chromatography, the yield of R-BocBHP was 98.6% on the basis of R-BocHP standard. Example 24 To a mixed liquid of R-BocHP, of 15.13 g (81.77 mmol), tetrahydrofuran of 22.60 g, tetra-n-butylammonium sulfate of 1.40 g (4.12 mmol, 0.05 equivalent amount to R-BocHP) and 48% sodium hydroxide aqueous solution of 20.00 g (240. 00 mmol, 2.94 equivalent amount to R-BocHP), benzyl chloride of 13.76 g (108.71 mmol, 1.33 equivalent amount to R-BocHP) was added and stirred, raised to 50C and heated for 7 hours. As a result of analysis by liquid chromatography, the yield of R-BocBHP was 99.1% on the basis of R-BocHP standard. While maintaining the obtained reaction liquid at a temperature in the range from 25C to 35C, 35% HCl was added dropwise thereto. After completion of dropping, while maintaining 50C, it was heated for 7 hours. As a result of analysis of the resulting reaction liquid by liquid chromatography, the yield of R-3BHP was 93.8% on the basis of R-BocHP standard. |
81.1%Chromat. | With sodium hydroxide;tetrabutyl-ammonium chloride; In tetrahydrofuran; water; at 50℃; for 7h;Product distribution / selectivity; | To a mixed liquid of R-BocHP of 1.00 g (5.34 mmol), tetrahydrofuran of 1.50 g, tri-n-butylbenzylammonium chloride of 84.5 mg (0.27 mmol, 0.05 equivalent amount to R-BocHP) and 48% sodium hydroxide aqueous solution of 1.38 g (16.56 mmol, 3.10 equivalent amount to R-BocHP), benzyl chloride of 0.88 g (6.95 mmol, 1.30 equivalent amount to R-BocHP) was added and stirred, raised to 50C and heated for 7 hours. As a result of analysis by liquid chromatography, the yield of R-BocBHP was 81.1% on the basis of R-BocHP standard. |
98%Chromat. | With sodium hydroxide;trimethyldodecylammonium chloride; In tetrahydrofuran; water; at 50℃; for 7h;Product distribution / selectivity; | To a mixed liquid of R-BocHP of 1.02 g (5.45 mmol), tetrahydrofuran of 1.50 g, n-dodecyltrimethylammonium chloride of 77.5 mg (0.29 mmol, 0.05 equivalent amount to R-BocHP) and 48% sodium hydroxide aqueous solution of 1.37 g (16.44 mmol, 3.02 equivalent amount to R-BocHP), benzyl chloride of 0.88 g (6.95 mmol, 1.28 equivalent amount to R-BocHP) was added and stirred, raised to 50C and heated for 7 hours. As a result of analysis by liquid chromatography, the yield of R-BocBHP was 98.0% on the basis of R-BocHP standard. |
100%Chromat. | With sodium hydroxide;tetrabutylammomium bromide; In tetrahydrofuran; water; at 50℃; for 7h;Product distribution / selectivity; | In a 50 mL flask equipped with a thermometer and a dropping funnel, to a mixed liquid of R-BocHP of 1.01 g (5.39 mmol), tetrahydrofuran of 1.50 g, tetra-n-butylammonium bromide of 90.3 mg (0.28 mmol, 0.05 equivalent amount to R-BocHP) and 48% sodium hydroxide aqueous solution of 1.37 g (16.44 mmol, 3.05 equivalent amount to R-BocHP), benzyl chloride of 0.88 g (6.95 mmol, 1.29 equivalent amount to R-BocHP) was added and stirred, raised to 50C and heated for 7 hours. As a result of analysis by liquid chromatography, the yield of R-BocBHP was 100% on the basis of R-BocHP standard. |
5.6%Chromat. | With sodium hydroxide; In tetrahydrofuran; water; at 50℃; for 8h;Product distribution / selectivity; | To a mixed liquid of R-BocHP (3.06 g, 16.34 mmol), tetrahydrofuran (18.89 g) and 48% sodium hydroxide aqueous solution (1. 62 g, 19. 44 mmol, 3.05 equivalent amount to R-BocHP), benzyl chloride (3.16 g, 18.47 mmol, 1.13 equivalent amount to R-BocHP) was added and stirred, raised to 50C and heated for 8 hours. As a result of analysis by liquid chromatography, the yield of R-BocBHP was 5.6% on the basis of R-BocHP standard. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
98% | In toluene; at 80℃; for 72h; | (Examples 27 to 28) A similar reaction operation was carried out except that toluene and dimethyl sulfoxide which were solvents of Example 26 were replaced by a single solvent described below and that a reaction temperature and a reaction time were changed. Results are shown in Table 4. |
93% | In acetonitrile; at 70℃; for 42h; | (Examples 27 to 28) A similar reaction operation was carried out except that toluene and dimethyl sulfoxide which were solvents of Example 26 were replaced by a single solvent described below and that a reaction temperature and a reaction time were changed. Results are shown in Table 4. |