Prolinol

2-(Hydroxymethyl)pyrrolidine is an amino alcohol formed by reduction of the amino acid proline.

Prolinol is an amino alcohol formed by reduction of the amino acid proline.

DL-Proline (6.0 g, 52.0 mmol) was added slowly and portion wise to a stirred suspension of LiAIHTo a solution of DL-proline (10Og, 869 mmol) in MeOH (1500 mL) was slowly added SOClas a metal-supported catalyst, ruthenium carbon having a dispersity of 17.46percent, a metal surface area of 63.78 (m 2 / g), a particle diameter of 7.73 (nm), and a metal loading of 5percent A catalyst was prepared.In a pressure vessel, 100 g of water, 3.2 g of glutamic acid, 2.86 g of phosphoric acid and 0.16 g of ruthenium carbon catalyst were mixed. The mixture was stirred for 16 hours while pressurizing at 180 ° C. to a hydrogen pressure of 8 MPa. After completion of the reaction, the reaction mixture was filtered. When the components contained in the filtrate were analyzed by LC (liquid chromatography), prolinol was obtained in a yield of 35percent. Prolinol was synthesized under the same conditions as in Example 1. However, instead of glutamic acid, 2.8 g of pyroglutamic acid was used as a raw material. The reaction temperature was 150 ° C., and the reaction time was 21 hours. The yield of prolinol was 35percent.The substrate (1 equiv) was added to a solution of CAN (20 mol percent) in minimum amount of water (roughly 15 equiv). The reaction mixture was dissolved in dichloromethane and stirred magnetically. Acetic acid (10 equiv) was added to the solution and left to stir at rt for the required time mentioned in Table 2. Upon completion of the reaction, the solvent was evaporated under reduced pressure and worked up in the following methods. Method A: The solid residue was washed twice with petroleum ether to remove the by product trityl alcohol. The residue was then dissolved in methanol and filtered through a short pad of celite. Removal of the solvent under reduced pressure yielded the free amine. Method B: Water and acetic acid were removed from the reaction mixture in vacuo. The residue was dissolved in dry dichloromethane, followed by the addition of triethylamine (2.5 equiv) and acetic anhydride or benzoyl chloride (1.5 equiv). After the completion of the reaction, the solvent was evaporated. The residue was extracted with ethyl acetate twice. The combined organic layer was washed with water and brine and finally dried (Na2SO4). Solvent was removed under reduced pressure and the residue obtained was purified by silica gel column chromatography to afford the acylated amine.as a metal-supported catalyst, ruthenium carbon having a dispersity of 17.46percent, a metal surface area of 63.78 (m 2 / g), a particle diameter of 7.73 (nm), and a metal loading of 5percent A catalyst was prepared.In a pressure vessel, 100 g of water, 3.2 g of glutamic acid, 2.86 g of phosphoric acid and 0.16 g of ruthenium carbon catalyst were mixed. The mixture was stirred for 16 hours while pressurizing at 180 ° C. to a hydrogen pressure of 8 MPa. After completion of the reaction, the reaction mixture was filtered. When the components contained in the filtrate were analyzed by LC (liquid chromatography), prolinol was obtained in a yield of 35percent. Prolinol was synthesized under the same conditions as in Example 1. However, the reaction time was 24 hours. The yield of prolinol was 36percent.Step 1. Synthesis of tert-butyl 2-(hydroxymethyl)pyrrolidine-1-carboxylate A solution of 2-pyrrolidinemethanol (0.300 g, 1.98 mmol) in CH2Cl2 (5.0 mL) and di-tert-butyl dicarbonate (0.650 g, 1.98 mmol) were used to carry out the reaction. After the reaction was stirred at room temperature for 16 h and work-up, the residue was purified by Isco Combi-Flash Companion column chromatography (0-10percent MeOH in CH2Cl2) to give tert-butyl 2-(hydroxymethyl)pyrrolidine-1-carboxylate (0.590 g, 98percent). 1H NMR (CDCl3, 300 MHz) delta 4.78 (br d, 1H), 4.05-3.90 (br, 1H), 3.67-3.53 (m, 2H), 3.49-3.41 (m, 1H), 3.34-3.26 (m, 1H), 2.00 (dddd, 1H), 1.85-1.72 (m, 2H), 1.60-1.50 (m, 1H), 1.46 (s, 9H).Step 1 Preparation of tert-butyl 2-(hydroxymethyl) pyrrolidine-1-carboxylate To a stirred mixture of pyrrolidin-2-ylmethanol (0.500 g, 4.95 mmol) and di-tert-butyl dicarbonate (2.16 g, 9.89 mmol) in DCM (10 mL) was added triethylamine (0.751 g, 7.42 mmol). The system was stirred at room temperature overnight. The reaction was quenched with water (10 mL) and extracted with EtOAc (20 mL*3). The combined organic layer was washed with brine (10 mL), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to afford tert-butyl 2-(hydroxymethyl)pyrrolidine-1-carboxylate (0.900 g, 90percent) as light yellow oil.To a solution of pyrrolidin-2-ylmethanol (505 mg, 4.99 mmol) and TEA (1.0 g, 9.9 mmol) in CH2Cl2 (5 mL) was added a solution of BoC2O (1.31 g, 6 mmol) in CH2Cl2 (10 mL). The reaction mixture was stirred for 3 h at room temperature. The reaction mixture was quenched with water (100 mL) and extracted with CH2Cl2, The organic layer was washed with brine, dried over Na2Spsi4, filtered, and concentrated under reduced pressure to give the crude material that was purified by silica gel flash column chromatography (MeOHiCH2Cl2 = 1: 100) to afford 14.2 g (48percent) of tert-butyl 2- (hydroxymethyl)pyrrolidine-l-carboxylate. LCMS ESI (+) m/z 202 (M+ 1) detected.To a solution of DL-proline (10.0 g, 86.9 mmol) in THF (20 mL) were added boron trifluoride etherate complex (12.9 g, 91.2 mmol) and borane-tetrahydrofuran (1.0 mol/L THF solution, 100 mL) at 0°C, and the mixture was stirred at room temperature for 16 hr. After completion of the reaction, the mixture was further heated under reflux for 1 hr and cooled to room temperature. THF-water (1:1, 2.5 mL) and 6N sodium hydroxide were successively added to the reaction solution, and the mixture was heated under reflux for 2 hr. The reaction solution was cooled to room temperature, and concentrated under reduced pressure. The residue was washed with diethyl ether. The remaining residue, di-tert-butyl dicarbonate (19.9 g, 91.2 mmol) and potassium carbonate (36.0 g, 260 mmol) were dissolved in diethyl ether-water (100 mL-150 mL), and the mixture was stirred at room temperature for 16 hr. The diethyl ether layer was separated and washed with saturated brine, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane-ethyl acetate 95:5 - 60:40 - 50:50) to give the title compound (13.6 g, 76percent) as a colorless oil. 1H NMR (300 MHz, CDCl3) delta 4.74 (d like, 1H), 3.96 (br s, 1H), 3.74-3.21 (m, 4H), 2.13-1.67 (m, 4H), 1.49 (s, 9H).Maleic acid (2.86g, 24.72 mmol) was added to pyrrolidin-2-ylmethanol(2.5g, 24.72 mmol) (A.170) in ethyl acetate (10 mL). The resultant mixture was stirred at room temperature for 2 hrs. After concentration, NaHCO3(10.38g, 123.6 mmol) in water (16 mL) was added to the residue. (BOC)2O (6.47 g, 29.66 mmol) was then added. The mixture was stirred at room temperature for 16 hrs. After removing solid by filtration, the aqueous solution was extracted with ethyl acetate. The organics were dried and concentrated, gave crude N-BOC protected pyrrolidin-2-ylmethanol. To the crude N-BOC protected pyrrolidin-2-ylmethanol(2.5g, 12.43mmol) and triethylamine (4.16ml, 29.82 mmol) in ethyl acetate at O0C, MsCl(1.16 mL, 14.91 mmol) was added and the mixture was stirred at 0°C for 2 hrs. The reaction was quenched with water and extracted with ethyl acetate. The organics were washed with 2N HCl, water, Sat. aq. NaHCO3, and brine, dried and concentrated. A portion of the residue(257.6 mg, 0.924mmol) was added to a mixture Of Cs2CO3 ( 301.1 mg, 0.924 mmol) and 4-(5-bromo-lH-indol-3-yl)-5-chloropyrimidin-2-amine A.170 (100 mg, 0.308 mmol) in DMF (1 mL) and DMSO(I mL). The mixture was heated at 110 0C for 16 hrs. After cooling to room temperature, the mixture was diluted with ether, washed with water and brine, dried and concentrated. A portion of the residue (68.5mg, 0.135 mmol) was dissolved in dichloromethane (8 mL) and TFA (2mL) then was added. The mixture was stirred at room temperature for 1 hr, concentrated and diluted with methanol-dichloromethane (1 :9). The solution was washed with Sat. aq. NaHCO3, and brine, dried and concentrated to afford 4-(5- bromo-l-(pyrrolidin-2-ylmethyl)-lH-indol-3-yl)-5-chloropyrimidin-2-amine (A.178) (32.0 mg, 58percent): 1H NMR (methanol- d4) b 8.78(s, 1 H), 8.43(s, 1 H), 8.15(s, 1 H), 7.42 (d, J= 8.0 Hz, 1

2-(Hydroxymethyl)pyrrolidine is an intermediate in the synthesis of Physostigmine and Physostigmine derivative used for treatment of Alzheimer's disease.

Molecular Weight:101.15
XLogP3:-0.3
Hydrogen Bond Donor Count:2
Hydrogen Bond Acceptor Count:2
Rotatable Bond Count:1
Exact Mass:101.084063974
Monoisotopic Mass:101.084063974
Topological Polar Surface Area:32.3
Heavy Atom Count:7
Complexity:56
Undefined Atom Stereocenter Count:1
Covalently-Bonded Unit Count:1
Compound Is Canonicalized:Yes