* 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.
With bis(1,5-cyclooctadiene)diiridium(I) dichloride; hydrogen; (R)-(+)-2,2’-bis(diphenylphosphino)6,6’-dimethoxy-1,1’biphenyl In tetrahydrofuran at 45℃; for 2 h;
Firstly the [Ir (COD) Cl]2(0.7g, 1mmol) and (R)-MEO-BiPhep (0.7g, 1 . 2mmol) suspended 200 ml of tetrahydrofuran, the reaction 2 hours, then added with 1-benzyl-4-methyl -2,6-dihydro-3-ketone piperidine (20.1g, 100mmol), temperature control 45 °C, hydrogen gas to the reaction solution, the control pressure is 5atm, thin layer monitoring after the reaction is complete. Adding saturated salt water washing, anhydrous sulfuric acid drying the organic phase, the organic phase concentrating, the residue is recrystallized with ethyl acetate, to obtain 1-benzyl-4-methyl-3-ketone piperidine 19.3g, yield 95.0percent, optical purity 99.5percent (HPLC method).
Reference：
[1] Patent: CN105884781, 2016, A, . Location in patent: Paragraph 0056; 0057
2
[ 32018-56-7 ]
[ 32018-96-5 ]
Yield
Reaction Conditions
Operation in experiment
89%
With trimethylsilyl trifluoromethanesulfonate; cyclohexanone In dichloromethane at -20℃; Inert atmosphere
The starting material 1-benzyl-4-methyl-1,2,3,6-tetrahydropyridine (187 mg) was dissolved in methylene chloride(10 mL) was added. A solution of trimethylsilyl trifluorosulfonate (1.1 g) in methylene chloride was added under a nitrogen atmosphere at -20 ° C. and a catalytic amount of cyclohexanone was added. The reaction was stirred and controlled to complete the reaction. Column chromatography gave Compound II. (89percent yield).
Reference：
[1] Patent: CN106831538, 2017, A, . Location in patent: Paragraph 0033; 0034
[2] Organic Process Research and Development, 2003, vol. 7, # 1, p. 115 - 120
[3] Patent: CN107337676, 2017, A,
3
[ 23662-66-0 ]
[ 32018-96-5 ]
Reference：
[1] Organic Process Research and Development, 2003, vol. 7, # 1, p. 115 - 120
[2] Patent: CN107337676, 2017, A,
4
[ 108-89-4 ]
[ 32018-96-5 ]
Reference：
[1] Organic Process Research and Development, 2003, vol. 7, # 1, p. 115 - 120
[2] Patent: CN107337676, 2017, A,
5
[ 100-44-7 ]
[ 32018-96-5 ]
Reference：
[1] Organic Process Research and Development, 2003, vol. 7, # 1, p. 115 - 120
[2] Patent: CN107337676, 2017, A,
With bis(1,5-cyclooctadiene)diiridium(I) dichloride; (S)-3,5-di-tert-butyl-4-methoxyphenyl-(6,6’-dimethoxybiphenyl-2,2’-diyl)-bis(diphenylphosphine); hydrogen In methanol; dichloromethane at 20℃; for 18 h;
Procedure: MeNH3.OAc was formed by slowly adding MeNH2 (33 wtpercent EtOH) to a solution of dry acetic acid in toluene. Upon removal of the volatile components, a white hygroscopic salt was obtained. MeNH3.OAc was used as a reagent to convert ketone 2 into imine 3 in presence of the hydrogenation catalysts, acetic acid, and hydrogen. (1 .4eq/substrate 2) Same catalysts as described above tested with/without l2 in MeOH and in IPA. Hydrogenation conditions: Ir (0.001 mmol), I2 (0 or 0.002mmol), substrate 2 (0.05mmol), IPA or MeOH = 1 ml_, 50 bar H2, R.T., 18h.
Method E 1-Benzyl-4-methyl-piperidin-3-one To a solution of the product from Method D (9.8 grams/0.026 mol) and 31.7 mL of diisopropylethylamine dissolved in 250 mL of dichloromethane and cooled to 0 C. was added (dropwise) 12.4 grams of SO3pyridine complex dissolved in 153 mL of dimethylsulfoxide over a 40 minute period. Once added, the reaction stirred for 1.5 hours at room temperature and was then quenched upon addition of 200 mL of saturated NaHCO3 (aq). The dichloromethane was removed in vacuo and the remaining aqueous residue extracted four times with diisopropyl ether (150 mL). The combined ether layers were washed four times with water (100 mL), dried over Na2SO4 and concentrated to dryness in vacuo affording 3.81 grams (72.97%) of the title compound as yellow oil. LRMS: 204 (M+1).
2
[ 32018-96-5 ]
[ 74-89-5 ]
cis-N-benzyl-3-methoxycarbonylamino-4-methylpiperidine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
80%
With Ir*C36H28P2; hydrogen; In methanol; water; under 7500.75 Torr;Reflux;
Step 2: Add 190 g of intermediate 1, 362 g of monomethylamine aqueous solution, 600 ml of methanol and 10 g of Ir/Biphep (2,2'-bis(diphenylphosphino)biphenyl) to the reaction flask, and pass hydrogen gas to 1 Mpa.The reaction was refluxed, and after the reaction was completed, the mixture was filtered, and the filtrate was concentrated, and then adjusted to pH = 8 with aqueous acetic acid.Dichloromethane extraction and concentration gave 163 g of Intermediate 2, yield: 80%.
69%
To a stirred solution of <strong>[32018-96-5]1-benzyl-4-methyl-piperidin-3-one</strong> (2.3 grams, 11.5 mmol), prepared by the methods of lorio, M.A. and Damia, G., Tetrahedron, 26, 5519 (1970) and Grieco et aL, Journal of the American Chemical Society, 107. 1768 (1985), (modified using 5% methanol as a co-solvent), both references are incorporated by reference in their entirety, dissolved in 23 mL of 2 M methylamine in tetrahydrofuran was added 1.4 mL (23 mmol) of acetic acid and the resulting mixture stirred in a sealed tube for 16 hours at room temperature. Triacetoxy sodium borohydride (4.9 grams, 23 mmol) was added and the new mixture stirred at room temperature in a sealed tube for 24 h, at which time, the reaction was quenched upon addition of 1 N sodium hydroxide (50 mL). The reaction mixture was then extracted 3 x <n="47"/>80 ml_ with ether, the combined ether layers dried over sodium sulfate (Na2SO4) and concentrated to dryness in vacuo affording 1.7 grams (69%) of the title compound as a white solid. LRMS: 219.1 (M+1 ).
(RS)-10-methyl-7-(phenylmethyl)-1,4-dioxa-7-azaspiro[4,5]decane hydrochloride[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
35%
p-Toluenesulfonic acid (31 mg) was added to a solution of (RS)-4-methyl-1-phenylmethyl)-3-piperidinone (Tetrahedron 1970, 26, 5519-5527, 1.55 g, 7.6 mmol) and ethylene glycol (20 mL, 0.35 mol) in toluene (76 mL) and the mixture was heated under reflux with azeotropic removal of water overnight. The mixture was cooled, poured into saturated aqueous potassium carbonate (150 mL) and extracted with dichloromethane (3×100 mL). The combined organic fractions were washed with water, dried (MgSO4) and the solvent was evaporated under reduced pressure. The residue was purified by flash column chromatography on silica gel, eluting with CH2Cl2/MeOH/NH3(Aq.) (96.5:3.5:1). The residue was suspended in diethyl ether (50 mL) and ethereal hydrogen chloride (1M, 3 mL) was added. The solid was collected and dried in vacuo to give the title compound (750 mg, 35%). m/z (ES+) 248 (M+1).
(1-Benzvl-4-methvl-piperidin-3-vl)-methvl-amine To a stirred solution of <strong>[32018-96-5]1-benzyl-4-methyl-piperidin-3-one</strong> (2.3 grams, 11.5 mmol), prepared by the methods of lorio, M. A. and Damia, G. , Tetrahedron, 26, 5519 (1970) and Grieco et al., Journal of the American Chemical Society, 107, 1768 (1985), (modified using 5% methanol as a co-solvent), both references are incorporated by reference in their entirety, dissolved in 23 mL of 2 M methylamine in tetrahydrofuran was added 1.4 mL (23 mmol) of acetic acid and the resulting mixture stirred in a sealed tube for 16 hours at room temperature. Triacetoxy sodium borohydride (4.9 grams, 23 mmol) was added and the new mixture stirred at room temperature in a sealed tube for 24 h, at which time, the reaction was quenched upon addition of 1 N sodium hydroxide (50 mL). The reaction mixture was then extracted 3 x 80 mL with ether, the combined ether layers dried over sodium sulfate (Na2SO4) and concentrated to dryness in vacuo affording 1.7 grams (69%) of the title compound as a white solid
69%
Method A: (1-Benzyl-4-methyl-piperidin-3-yl)-methyl-amine To a stirred solution of <strong>[32018-96-5]1-benzyl-4-methyl-piperidin-3-one</strong> (2.3 grams, 11.5 mmol), prepared by the methods of Iorio, M. A. and Damia, G., Tetrahedron, 26, 5519 (1970) and Grieco et al., Journal of the American Chemical Society, 107, 1768 (1985), (modified using 5% methanol as a co-solvent), both references are incorporated by reference in their entirety, dissolved in 23 mL of 2 M methylamine in tetrahydrofuran was added 1.4 mL (23 mmol) of acetic acid and the resulting mixture stirred in a sealed tube for 16 hours at room temperature. Triacetoxy sodium borohydride (4.9 grams, 23 mmol) was added and the new mixture stirred at room temperature in a sealed tube for 24 h, at which time, the reaction was quenched upon addition of 1 N sodium hydroxide (50 mL). The reaction mixture was then extracted 3×80 mL with ether, the combined ether layers dried over sodium sulfate (Na2SO4) and concentrated to dryness in vacuo affording 1.7 grams (69%) of the title compound as a white solid. LRMS: 219.1 (M+1).
50%
Method A (1-Benzyl-4-methyl-piperidin-3-yl)-methyl-amine To a stirred solution of <strong>[32018-96-5]1-benzyl-4-methyl-piperidin-3-one</strong> (2.3 grams, 11.5 mmol), prepared by the methods of lorio, M. A. and Damia, G., Tetrahedron, 26, 5519 (1970) and Grieco et al., Journal of the American Chemical Society, 107, 1768 (1985), (modified using 5% methanol as a co-solvent), both references are incorporated by reference in their entirety, dissolved in 23 mL of 2 M methylamine in tetrahydrofuran was added 1.4 mL (23 mmol) of acetic acid and the resulting mixture stirred in a sealed tube for 16 hours at room temperature. Triacetoxy sodium borohydride (4.9 grams, 23 mmol) was added and the new mixture stirred at room temperature in a sealed tube for 24 h, at which time, the reaction was quenched upon addition of 1 N sodium hydroxide (50 mL). The reaction mixture was then extracted 3*80 mL with ether, the combined ether layers dried over sodium sulfate (Na2SO4) and concentrated to dryness in vacuo affording 1.7 grams (69%) of the title compound as a white solid. LRMS: 219.1 (M+1).
Methanol (500 mL) and N-Benzyl-4-methylpiperid-3-one (100 gm) were charged in a 2L 4-neck round bottom flask with an overhead stirrer. Stirred for 15 minutes at RT. The reaction mass was cooled to 0C to 5C and Titanium(IV) tetraisopropoxide solution (175 mL) was added drop wise within 30-45 minutes. The reaction mass was stirred at 0C to 5 C for 30 minutes and Methylamine hydrochloride (66 gm) was added at 0 C to 5 C within 30-45 minutes. The reaction mass was stirred for 2-3 h at 0C to 5C. Sodium borohydride (22 gm) was added to the reaction mass within 30-45 minutes at 0C to 5C and stirred for 2-3 h. After the completion of the reaction as monitored by TLC, HPLC; water (500 mL) was added to the reaction mass and stirred for 30-45 minutes at RT. The product was extracted by using MDC (500 mL) to get the pure product. Yield: 95%; HPLC: 90%.
A. Add 2.2 kg of 3-amino-4-methyl-pyridine to 15 kg of dichloromethane and 22 kg of toluene, reduce the temperature to 0-10 C, dropwise add 1.7 kg of acetyl chloride, and react at 20-25 C for 10 hours; Add a sodium hydroxide aqueous solution dropwise below , adjust the pH to 8-9, and separate the lower aqueous phase; concentrate the organic phase under reduced pressure to a volume of 23-25L; B. Add 1.9 kg of benzyl chloride to the product obtained in the previous step, and raise the temperature to 70-80 C for reaction. The dichloromethane distilled off is separated during the temperature rise; after the reaction is completed, the temperature is reduced to 0-10 C. C. The temperature is controlled below 10 C, and at the same time, 1.5 kg of sodium borohydride and 60 g of sodium hydroxide in 10 kg of aqueous solution are added dropwise; the temperature is maintained for 14 hours after the dropwise addition is completed; D. Filter to obtain N- (1-benzyl-4-methyl-1,2,5,6-tetrahydropiperidin-3-yl) acetamide wet product as an off-white solid. After drying, 4.5 kg N- (1-benzyl-4-methyl-1,2,5,6-tetrahydropiperidin-3-yl) acetamide, with a purity of 94-97%;
With trimethylsilyl trifluoromethanesulfonate; cyclohexanone; In dichloromethane; at -20℃;Inert atmosphere;
The starting material 1-benzyl-4-methyl-1,2,3,6-tetrahydropyridine (187 mg) was dissolved in methylene chloride(10 mL) was added. A solution of trimethylsilyl trifluorosulfonate (1.1 g) in methylene chloride was added under a nitrogen atmosphere at -20 C. and a catalytic amount of cyclohexanone was added. The reaction was stirred and controlled to complete the reaction. Column chromatography gave Compound II. (89% yield).
Methanol (500 mL) and N-Benzyl-4-methylpiperid-3-one (100 gm) were charged in a 2L 4-neck round bottom flask with an overhead stirrer and stirred for 15 minutes at RT. The reaction mass was cooled to 0C to 5C and Titanium(IV) tetraisopropoxide solution (175 mL) was added drop wise within 30-45 minutes. The reaction mass was stirred at 0C to 5C for 30 minutes and Methanolic methylamine solution (30%) (100 mL) was added drop wise at 0C to 5C within 30-45 minutes. The reaction mass was stirred for 2-3 h at 0C to 5C. Sodium borohydride (22 gm) was then added to the reaction mass within 30-45 minutes at 0C to 5C and stirred for 2-3 h. After the completion of the reaction as monitored by TLC, HPLC; water (500 mL) was added to the reaction mixture and stirred for 30-45 minutes at RT. The product was extracted using MDC (500 mL) to get the pure product. Yield: 90%; HPLC: 90%.
N-(1-benzyl-4-methyl-1,2,5,6-tetrahydropyridine-3-yl)acetylamine[ No CAS ]
[ 32018-96-5 ]
Yield
Reaction Conditions
Operation in experiment
95%
With hydrogenchloride; water; acetic acid; at 20 - 90℃;
Acetic acid (50 mL), Cone. HCl 35% (100 mL) were charged in a 2L 4-neck round bottom flask with an overhead stirrer and stirred for 10 minutes at RT. l-Benzyl-4-methyl-l, 2,5,6- tetrahydropyridin-3-yl-acetylamine (100 gm) was then added into the reaction mass at that temperature. Temperature of the reaction mixture was raised slowly to 85C to 90C and stirred for 3-4 h at that temperature as required to complete the reaction (monitored by TLC, HPLC). The reaction mixture was cooled to 25C to 30C and extracted with Toluene (500 mL) to get the pure product. Yield: 95%; HPLC: 95%
A. Add 2.2 kg of 3-amino-4-methyl-pyridine to 15 kg of dichloromethane and 22 kg of toluene, reduce the temperature to 0-10 C, dropwise add 1.7 kg of acetyl chloride, and react at 20-25 C for 10 hours; Add a sodium hydroxide aqueous solution dropwise below , adjust the pH to 8-9, and separate the lower aqueous phase; concentrate the organic phase under reduced pressure to a volume of 23-25L; B. Add 1.9 kg of benzyl chloride to the product obtained in the previous step, and raise the temperature to 70-80 C for reaction. The dichloromethane distilled off is separated during the temperature rise; after the reaction is completed, the temperature is reduced to 0-10 C. C. The temperature is controlled below 10 C, and at the same time, 1.5 kg of sodium borohydride and 60 g of sodium hydroxide in 10 kg of aqueous solution are added dropwise; the temperature is maintained for 14 hours after the dropwise addition is completed; D. Filter to obtain N- (1-benzyl-4-methyl-1,2,5,6-tetrahydropiperidin-3-yl) acetamide wet product as an off-white solid. After drying, 4.5 kg N- (1-benzyl-4-methyl-1,2,5,6-tetrahydropiperidin-3-yl) acetamide, with a purity of 94-97%;
With 5%-palladium/activated carbon; hydrogen; In tetrahydrofuran; at 20℃; for 12h;
<strong>[32018-96-5]1-benzyl-4-methyl-piperidin-3-one</strong> (2-1) 5.0g was dissolved in 50mL of tetrahydrofuran, and added 0.5g of Pd / C (5%) and 5.9g of di-tert-butyl ester, the reaction mixture was reacted at room temperature for 12 hours to atmospheric hydrogenation. End of the reaction, the Celite pad with frit funnel filtration, the filtrate was spin-dried to give a pale yellow viscous liquid 1-tert-butoxycarbonyl-4-methyl-piperidin-3-one (3-1) 5.2g, yield: 99.9%.
1-benzyl-3-oxo-4-methylpiperidin-4 carboxylic acid methyl ester[ No CAS ]
[ 32018-96-5 ]
Yield
Reaction Conditions
Operation in experiment
87.5%
With hydrogenchloride; In water; at 100℃; for 5h;
1-benzyl-4-methyl-3-oxo-piperidine-4-carboxylic acid methyl ester (1-2) 10.0g was added to 50mL of 6mol / L hydrochloric acid, the reaction was heated to reflux for 5 100 hour. End of the reaction cooled to room temperature, the solvent was distilled off under reduced pressure, the residue was dissolved in 50mL of water and adjusted with aqueous sodium hydroxide 2mol / L of PH = 10, was added ethyl acetate three times, the combined organic phases washed with a small amount of salt, dried over anhydrous sodium sulfate, the organic solvent is spin-dried to give a viscous yellow liquid 1-benzyl-4-methylpiperidin-3-one (2-1) 6.8g, yield: 87.5%.
The TiCl4(0.2g, 1mmol), NEt3(0.15g, 1 . 5mmol) suspended 200 ml in toluene, then add 1-benzyl-4-methyl-3-ketone piperidine (20.3g, 100mmol), temperature control 35 C methylamine solution is added to the reaction solution (9.32g, 120mmol) reaction 4 hours, adding NaBH (OAC) 3 (0.32g, 1 . 5mmol), glacial acetic acid 2 ml, temperature control 35 C reaction, thin layer monitoring after the reaction is complete. Adding saturated salt water washing, anhydrous sodium sulfate for drying the organic phase, the organic phase concentrated, with residues 35% hydrochloric acid ethanol re-crystallization, to obtain (3R, 4R)-cis-1-benzyl-4-methyl-3-methylamino-piperidine dihydrochloride 17.2g, yield 85.0%, optical purity 99.0% (HPLC method).
With bis(1,5-cyclooctadiene)diiridium(I) dichloride; hydrogen; (R)-(6,6?-dimethoxy-[1,1?-biphenyl]-2,2?-diyl)bis(diphenylphosphine); In tetrahydrofuran; at 45℃; under 3800.26 Torr; for 2h;
Firstly the [Ir (COD) Cl]2(0.7g, 1mmol) and (R)-MEO-BiPhep (0.7g, 1 . 2mmol) suspended 200 ml of tetrahydrofuran, the reaction 2 hours, then added with 1-benzyl-4-methyl -2,6-dihydro-3-ketone piperidine (20.1g, 100mmol), temperature control 45 C, hydrogen gas to the reaction solution, the control pressure is 5atm, thin layer monitoring after the reaction is complete. Adding saturated salt water washing, anhydrous sulfuric acid drying the organic phase, the organic phase concentrating, the residue is recrystallized with ethyl acetate, to obtain 1-benzyl-4-methyl-3-ketone piperidine 19.3g, yield 95.0%, optical purity 99.5% (HPLC method).
To a three-necked flask were added Compound II (17.6g) and 50ml of tetrahydrofuran, nitrogen protection, cooling To 15 C, methylamine hydrochloride (7g) was added dropwise, the reaction temperature was controlled at 15-20 C, and the reaction was completed until the reaction was completed. Directly into the next step.
To a 1 L reaction flask was added Intermediate III 30 g (1.0 eq)Methylamine 6.87 g (1.5 eq), acetic acid 10.6 g and ethanol 150 mL and stirred for 3 h at 25 C;TLC monitoring reaction was basically completed, and then to the reaction system was added NaBH4 8.37g (1.5eq), at 25 C conditions,Stirring 4h; TLC monitoring reaction is basically completed,To the reaction solution was slowly added 150 mL of water, filtered,The filter cake was washed with dichloromethane and the filtrate was extracted twice with 100 mL of dichloromethane. The organic phases were combined,In the external temperature 40 ~ 45 C conditions, concentrated to dryness under reduced pressure,To obtain a crude product; to the crude product isopropanol 240mL and methanol 60mL, L-di-p-methyl27.2 g (1.1 eq) of benzoyl tartaric acid aqueous solution,The mixture was heated to reflux 3h, slowly cooled to room temperature,Filtration gave a white solid which was dried in vacuo at 40-50 C to give (3R, 4R) -1-benzyl-N, 4-dimethylpiperidin-3-amine L-p-toluyltartrate 43.7 g, yield 36%.
With sulfur trioxide pyridine complex; triethylamine; In dimethyl sulfoxide; at 25℃; for 5h;
Into a 1 L reaction flask was charged 50 g (1.0 eq) of Intermediate IV, 250 mL of DMSO and 49.3 g (2.0 eq) of triethylamine,Open the stirring, at 25 C conditions,SO3 / py 77.5 g (2.0 eq) was slowly added dropwise,At this temperature, stirring 5h;TLC monitoring reaction is basically completed, to the reaction solution was added 300mL of water, extracted with DCM 100mL twice,The organic phases are combined and the organic phase is washed with brine,In the external temperature 40 ~ 45 C conditions, concentrated to dryness under reduced pressure,37.1 g of the intermediate III as a yellow oil were obtained,Yield 75%.
(3R,4R)-1-benzyl-N,4-dimethylpiperidine-3-amine dihydrochloride[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
74%
Preparative experiments were performed using only 1 .25 eq. N-MeOAc. 10 identical reaction mixtures containing 0.2 mmol starting material 2 were hydrogenated at 70C, in IPA, under 50 bar of H2 at S/C=1000 during 18h. All samples are combined in a round-bottom flask of 100 mL. To the IPA solution, 6N HCI(aq) (1 mL) was added. The solvent IPA is removed under vacuum leaving a yellow solid residue. The residue is dissolved in water (10 mL) and acidified with 6 N HCI (1 mL). The mixture was extracted with toluene (3 x 10 mL). The remaining water layer was basified with NaOH(aq) (32 % (wt)) to pH ~ 13 in the presence of CH2CI2 (10 mL) while maintaining the temperature to 25C. The DCM layer was separated after extraction of the product. The remaining water layer was further extracted with DCM (2 x 10 mL). The combined DCM layers were dried over Na2SO4 anhydrous. Removal of DCM under vacuum gives a yellow oily residue (Mass: 406.7mg). The residue is dissolved in dry acetone (10 mL) and while stirring, 1 N HCI in ether (5 mL) is added. The mixture was allowed to stir for 1 hour. A white solid forms and is filtered off, washed with minimum amounts of acetone. The solid is dried at open air (not hygroscopic) giving the product (4a and 4b as bis-HCI salts) in 498 mg (1 .72 mmol, Yield: 86 %) yield. The purity was determined to be 97 % according to GC. The ee was determined to be 72%. The isolated yield of 4b is 74%.
(3S,4S)-1-benzyl-N,4-dimethylpiperidin-3-amine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
61%; 29%
With bis(1,5-cyclooctadiene)diiridium(I) dichloride; (S)-3,5-di-tert-butyl-4-methoxyphenyl-(6,6?-dimethoxybiphenyl-2,2?-diyl)-bis(diphenylphosphine); hydrogen; In methanol; dichloromethane; at 20℃; under 37503.8 Torr; for 18h;
Procedure: MeNH3.OAc was formed by slowly adding MeNH2 (33 wt% EtOH) to a solution of dry acetic acid in toluene. Upon removal of the volatile components, a white hygroscopic salt was obtained. MeNH3.OAc was used as a reagent to convert ketone 2 into imine 3 in presence of the hydrogenation catalysts, acetic acid, and hydrogen. (1 .4eq/substrate 2) Same catalysts as described above tested with/without l2 in MeOH and in IPA. Hydrogenation conditions: Ir (0.001 mmol), I2 (0 or 0.002mmol), substrate 2 (0.05mmol), IPA or MeOH = 1 ml_, 50 bar H2, R.T., 18h.
Ketone 2 (20.4mg, 0.1 mmol) is placed into a vial and 1 ml_ of dry isopropanol is added. 33 wt% MeNH2 in EtOH (124 muIota_, 1 mmol, 10eq) is added and stirred at 50C. Analysis is done by GC (HP-5, isotherm at 150C, 12min). After 17h, the yield of imine 3 is 97% area. The same reaction was conducted neat - i.e. without adding isopropanol (IPA) - at room temperature. After 5h, the yield of imine 3 is 98% area.
In a 250 mL three-necked flask, 4-methylpiperidin-3-one hydrochloride (II) 14.96 g, 50 mL of distilled water and 50mL of toluene, cooled to 0 ~ 5 C under ice bath conditions, stirred, weighed 16.8g of sodium hydroxide, added to the reaction bottle in batches, anti After 2 hours, remove the ice bath conditions, slowly increase the temperature to room temperature, add 19g of benzyl chloride, add 30min, continue to stir Mix, heat to reflux reaction for 6h, after the reaction is finished, leave the layer, separate the organic phase, wash with water, anhydrous sodium sulfate, filter, decompression The solvent toluene was distilled off to obtain 19.81 g of a colorless liquid, yield 97.23%, and HPLC purity 98.37%.
Weighing Compound III 19.72g, N-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-amine (IV) 15.09g and HClO4-SiO2 solid 31mg was added to a 250mL three-necked bottle at room temperature 20 ~ 25 C. The reaction was stirred for 20 min under the conditions, and the reaction was completed by TLC, diluted with dichloromethane and filtered to remove solids. The organic layer was dried over anhydrous sodium sulfate and filtered and evaporated, and the compound V was concentrated, and the yield was 96.98%, and the HPLC purity was 97.33%.
1-benzyl-N,4-dimethyl-1,2,5,6-tetrahydropyridine-3-amine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
94.5%
With acetic acid; at 25 - 30℃; for 12h;pH 4 - 5;Inert atmosphere;
Weigh 16.2g of compound VI and 12.4g of 30% methylamine methanol solution into a three-necked bottle, and adjust the pH to 4~5 with dry glacial acetic acid under nitrogen protection. Reactive at room temperature 25 ~ 30 C for about 12 hours, TLC tracking reaction is complete, Evaporation of the solvent gave 16.35 g of Compound VII, yield 94.5%, HPLC purity 97.22%.
In a 250ml three-necked bottle, Compound V 19.32 g, sodium ethoxide 6.07 g and 60 ml of ethanol were added in sequence. The temperature was raised to reflux and stirred for 3 hours. After the reaction was completed, the mixture was cooled to room temperature, adjusted to pH 3-4 with hydrochloric acid, and refluxed for 4 hours. After the reaction was completed, the solvent was evaporated, and then ethyl acetate was evaporated. Filtration and evaporation of the solvent under reduced pressure afforded 16.5 g of colorless liquid, yield 95.5%, HPLC purity 98.34%.
Step 1: Add 113 g of 4-methyl-3-piperidone, 350 ml of water and 350 ml of methanol to the reaction flask, and stir at 0 to 5 C.60 g of potassium hydroxide was added in portions, and the reaction was carried out for 2 hours. 171 g of benzyl bromide was added dropwise at room temperature, and the reaction was refluxed for 6 hours.The reaction was controlled, and after completion of the reaction, the solvent was distilled under reduced pressure and washed with water to give 197 g of Intermediate 1, yield: 97%.
91.3%
With potassium carbonate; In tetrahydrofuran; at 60 - 65℃; for 5h;Green chemistry;
To the agitator, thermometer, A 500 ml four-necked flask with a reflux condenser, Add 150 grams of tetrahydrofuran, 22.6 g (0.2 mol) of 4-methylpiperidin-3-one, 36.0 g (0.21 mol) of benzyl bromide, 30.0 grams of potassium carbonate, Stir the reaction at 60-65 C for 5 hours. After the gas phase detection reaction is completed, filter, Wash the filter cake twice with tetrahydrofuran, 20 grams each time, Combined filtrates, Solvent recovery by distillation, Distillate under reduced pressure to collect 90-110 C / 2-3mmHg fractions, 37.1 g of N-benzyl-4-methylpiperidin-3-one are obtained, Yield 91.3 %%, The gas phase purity was 99.5%.
With potassium carbonate; In N,N-dimethyl-formamide; at 85 - 90℃; for 4h;Green chemistry;
To the agitator, thermometer, A 500 ml four-necked flask with a reflux condenser, Add 150 g of N, N-dimethylformamide, 22.6 g (0.2 mol) of 4-methylpiperidin-3-one, 27.8 grams (0.22 moles) of Benzyl chloride, 30.0 grams of potassium carbonate, The reaction was stirred at 85-90 C for 4 hours. After the gas phase detection reaction is completed, filter, Wash the filter cake twice with N, N-dimethylformamide, 20 grams each time, Combined filtrates, Solvent recovery by distillation, Distillate under reduced pressure to collect 90-110 C / 2-3mmHg fractions, 36.9 g of N-benzyl-4-methylpiperidin-3-one are obtained, Yield 90.9 %%, The gas phase purity was 99.3%.
A. Dissolve the pale yellow oily liquid in 14kg of methanol, and dissolve at a temperature of 50-55 C, then add 3.6kg of L-tartaric acid p-toluoyl ester, and maintain the temperature at 50-55 C for 1 hour, then add 17kg of purified water dropwise After the addition is completed, the temperature is lowered to 10-15 C for crystallization; B. The precipitated crystals are obtained by filtration, and the crystals are washed with a mixed solution of methanol and water; then the crystals are added to a mixed solution of 20L of methanol and water in a volume ratio of 1: 1, and the pH is adjusted to 30% with sodium hydroxide 8.6-9.0; then add 30kg of purified water, lower the temperature to 0-5 C, separate the insolubles, and wash the insolubles with purified water; C. Add the insoluble matter obtained in the previous step to 15 kg of methanol, adjust the pH to about 3.0 with concentrated hydrochloric acid, add seed crystals, continue stirring for 2 hours, and re-measure the pH; filter, wash with a small amount of methanol, and dry at 45 C under vacuum to obtain (3R , 4R) -1-Benzyl-N, 4-dimethylpiperidine-3-amine dihydrochloride 1.7 kg.
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