1H NMR (500 MHz, CDCl3) δ = 1.85 (s, 2H), 2.39 (s, 2H), 2.56 (s, 2H), 4.05 (m, 4H), 4.81 (d, J = 25.02 Hz, 2H), 6.76 (s, 1H), 6.93 (s, 1H).
13C NMR (125 MHz, CDCl3) δ = 24.7, 27.5, 31.9, 37.9, 42.2, 43.3, 105.2, 117.8, 124.6, 145.4, 147.7, 149.9, 150.8, 154.6, 156.9, 171.3.
Compound Name:
1,3-dichloro-2-fluorobenzene
Molecular Formula: C6H3Cl2F
Molecular Weight: 165.0
CAS Registry No.:
2268-05-5
1H NMR CDCL3
| 399.65 MHz | |
| C6 H3 Cl2 F | 0.040 g : 0.5 ml CDCl3 |
| 1,3-dichloro-2-fluorobenzene | |
Hz ppm Int.
2926.51 7.323 808 2919.92 7.307 846 2918.33 7.303 1000 2911.87 7.287 952 2905.15 7.270 25 2817.26 7.050 318 2815.67 7.046 313 2809.45 7.030 388 2808.84 7.029 347 2807.74 7.026 400 2801.03 7.009 244 2799.44 7.005 236
13C NMR
| 100.53 MHz | |
| 0.040 g : 0.5 ml CDCl3 |
MASS
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ZY 19489, MMV 253
C24 H32 FN9, 465.5
CAS 1821293-40-6
MMV253, GTPL10024, MMV674253
N-(4-cyclopropyl-5-fluoro-6-methylpyridin-2-yl)-5-((3R)-2-((1,5-dimethyl-1H-pyrazol-3-yl)amino)-3,4-dimethylpiperazin-1-yl)pyrimidin-2-amine
2-N-(4-cyclopropyl-5-fluoro-6-methylpyridin-2-yl)-5-[(3R)-3,4-dimethylpiperazin-1-yl]-4-N-(1,5-dimethylpyrazol-3-yl)pyrimidine-2,4-diamine
Nature Communications (2015), 6, 6715.
https://www.nature.com/articles/ncomms7715
Hameed P., S., Solapure, S., Patil, V. et al. Triaminopyrimidine is a fast-killing and long-acting antimalarial clinical candidate. Nat Commun 6, 6715 (2015). https://doi.org/10.1038/ncomms7715
Synthesis of (R)-N2-(4-cyclopropyl-5-fluoro-6-methylpyridin-2-yl)-N4-(1, 5-dimethyl-1H-pyrazol-3-yl)-5-(3, 4-dimethylpiperazin-1-yl)pyrimidine-2,4-diamine (12). (R)-N2-(4-cyclopropyl-5-fluoro-6-methylpyridin-2-yl)-N4-(1,5-dimethyl-1H-pyrazol-3-yl)-5-(3-methylpiperazin-1-yl)pyrimidine-2,4-diamine hydrochloride (compound 9, 190 mg, 0.42 mmol) was taken in dichloromethane (2 ml) to give a yellow suspension. To this Hunig’s Base (0.184 ml, 1.05 mmol) was added and the suspension turned clear. After 10 min of stirring, reaction mixture turned into a white suspension and then it was concentrated to dryness. Resultant residue was dissolved in ethanol (absolute, 99.5%) (3 ml), and formaldehyde (0.042 ml, 0.63 mmol) was added and stirred for 10 min. To this clear solution, sodium cyanoborohydride (26.4 mg, 0.42 mmol) was added in one portion to get a white suspension. The reaction mixture was concentrated and the crude product was purified through reverse-phase chromatography to get the pure off-white solid of (R)-N2-(4-cyclopropyl-5-fluoro-6-methylpyridin-2-yl)-N4-(1, 5-dimethyl-1H-pyrazol-3-yl)-5-(3,4-dimethylpiperazin-1-yl)pyrimidine-2,4-diamine (80 mg, 40.8%). Yield: 40.8%, purity: >95% by HPLC (ultraviolet at 220 and 254 nm). 1H NMR (300 MHz, DMSO-d6) δ 9.26 (s,1H), 8.03 (s, 1H) 8.00 (s, 1H) 7.67 (d, J=5.1 Hz, 1H) 6.83 (s, 1H) 3.33 (s, 3H) 2.96–2.73 (m, 4H) 2.75–2.50 (m, 1H) 2.38–2.30 (m, 4H) 2.23 (s, 7H) 2.10–1.96 (m, 1H),1.08–1.02 (m, 2H) 1.00 (d, J=6.2 Hz, 3H) 0.78–0.67 (m, 2H). 13C-NMR (126 MHz, DMO-d6) δ 155.30, 154.67, 152.10, 150.93, 148.98, 146.81. 145.29, 141.95, 140.31, 138.81, 124.91, 106.20, 97.07, 58.78, 51.87, 42.16, 35.28, 17.23. 10.99 and 8.77, HRMS (ESI): m/z calculated for C24H32FN9+H [M+H]: 466.2765. Found: 466. 2838. Traces of LC-MS, HRMS, 1H NMR and 13C-NMR of compound 12 are shown in Supplementary Figs 1–3.
THIAMINE
3595616 [Beilstein]
3-[(4-Amino-2-methy
thiamin hydrochloride
Vitamin B1 hydrochloride
thiamine hydrochloride
aneurin hydrochloride
3-(4-amino-2-methyl-5-pyrimidinyl)methyl-5-(2-hydroxyethyl)-4-methylthiazolium chloride hydrochloride
3. 3-1 (4-Amino-2-methylpyrimidin-5-yl)methyl]-5-(2-hydroxyethyl)-4-methylthiazolium Chloride Hydrochloride (Thiamine Hydrochloride, la). Compound 4 (7.4 g, 0.05 mol) was dissolved in 100 ml of HCOOH. To this slightly yellow soh, 5a (9.25 g, 0.052 mol) was immediately added at such a rate so that the temp. did not exceed 3540". The mixture was further stirred for 30 min at r.t. and then 25 ml of a freshly prepared sat. soh. of HCI in abs. EtOH was added dropwise. The temp. rose to 35-36O, and the mixture was further stirred for 30 min at r.t.''), The crude mixture was then poured into a 500-ml flask and evaporated at 50" under reduced pressure to give 26.07 g of a green-yellow solid residue, which was taken up in 100 ml of ahs. EtOH. Aq. HCI soh. (25%, 30 ml) was then added and the crude mixture heated on a steam-bath, until a clear soln. was obtained. The soln. was cooled to r.t. and placed overnight in the refrigerator. The resulting white crystals were collected and dried in vucuo to yield 14.56 g (86.3%) of la. M.p. 245-246' (dec.). The mother-liquor was then evaporated at 50O under reduced pressure and the residue taken up in 50 ml of H,O. The aq. phase was then washed twice with 25 ml of CH2C1, and evaporated under reduced pressure to give 3.29 g of a still slightly greenish residue, which was again taken up in 20 ml of abs. EtOH. Aq. HCI soln. (25%, 5 ml) was added and the mixture heated on a steam-bath, until a clear soln. was obtained. It was then cooled to r.t. and kept overnight in the refrigerator. The white crystals were filtered to give 1.42 g (8.4%) of la. M.p. 244-24So(dec.) (combined yieldI2) of la: 94.7% based on 4).
Recrystallization. The two crops of la were combined and dissolved in 100 ml of warm abs. EtOH. Aq. HCI soh (25 %, 40 ml) was added. The soln. was then allowed to cool slowly to r.t. and kept at Oo overnight. The white crystals were filtered and dried in vucuo at 50" to give 13.6 g (0.04 mol, 80.6 %) of la.
M.p. 243-244" (dec.). UV: 234 (4.1), 266 (3.9).
IR (KBr): 3500m, 3430m. 3340m. 3240m. 3065s. 2615m. 1660s, 1607m, 1380m.
'H-NMR (D,O): 2.54(s,Me);2.62(s,Me);3.19(t,J= 5.8,CH2);3.88(t,J= 5.8,CH20);5.56(s,1H,CH2N);8.02(s,1arom.H); proton of thiazole ring is exchanged with deuterium of D,O.
FAB-MS: 265 (100, M+), 181 (18), 144 (30), 123 (65), 122 (65), 91 (78).
Anal. calc. for C,2H18C1,N40S (337.27): C 42.74, H 5.38, N 16.61, S 9.51, CI 21.02; found: C 42.93, H 5.28, N 16.70, S 9.61, C121.17.
Dibenzoate5-(ethylsulfone)-2-(naphthalen-2- yl)benzo[d]oxazole (Ezotrumid) 5a:
5- (ethylthio)-2-(naphthalen-2-yl)Benzo[d]oxazole (30.5 mg, 0.1 mmol), UO2(OAc)2 . 2H2O (0.8 mg, 0.002 mol), H2O (10 equiv., 36 μL), o-xylene (8.3 equiv., 0.2 mL), CH3CN (1 mL) were stirred under oxygen atmosphere (1 atm, balloon) at room temperature until the total consumption of sulfide and sulfoxide under the irradiation of three 2 w blue LEDs in a paralleled reactor. 5a (27.3 mg, 81%) was obtained through column chromatography (PE/EA = 20/1-5/1) as a white solid, Rf = 0.6 (PE/EA = 2/1);
1H NMR (500 MHz, Chloroform-d) δ 8.82 (s, 1H), 8.37 (s, 1H), 8.32 (d, J = 8.5 Hz, 1H), 8.02 (d, J = 8.0 Hz, 2H), 7.99 – 7.89 (m, 2H), 7.84 – 7.76 (m, 1H), 7.61 (t, J = 7.3 Hz, 2H), 3.28 – 3.08 (m, 2H), 1.32 (dt, J = 7.3, 3.6 Hz, 3H)..
13C NMR (126 MHz, Chloroform-d) δ 165.57, 153.87, 142.86, 135.26, 135.14, 132.86, 129.09, 128.97, 128.37, 127.99, 127.19, 125.35, 123.87, 123.34, 121.00, 111.36, 51.04, 7.62.
IR (KBr) 2933, 1507, 1498, 1258, 1064, 1046, 756, 474 cm-1 .
HRMS (ESI) Calcd for C19H16NO3S 338.0851 (M+H), Found 338.0865.
DEXMETHYLPHENIDATE
SynonymsDexmethylphenidate HCl, UNII1678OK0E08, CAS Number19262-68-1, WeightAverage: 269.77
Chemical FormulaC14H20ClNO2
methyl (2R)-2-phenyl-2-[(2R)-piperidin-2-yl]acetate hydrochloride
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CLIP
An Improved and Efficient Process for the Production of Highly Pure Dexmethylphenidate Hydrochloride
Long-Xuan Xing, Cheng-Wu Shen, Yuan-Yuan Sun, Lei Huang, Yong-Yong Zheng,* Jian-Qi Li*
https://onlinelibrary.wiley.com/doi/abs/10.1002/jhet.2705
The present work describes an efficient and commercially viable process for the synthesis of dexmethylphenidate hydrochloride (1), a mild nervous system stimulant. The overall yield is 23% with ~99.9% purity (including seven chemical steps). Formation and control of possible impurities are also described in this report.
(R)-methyl 2-phenyl-2-((R)-piperidin-2-yl)acetate hydrochloride (1). ............ afford 1 as a white solid (107.6 g, 87.3% yield) with 99.50% purity and 99.70% ee. The crude product (107.6 g, 0.4 mol) was further purified by recrystallization from pure water (100 mL) to obtain the qualified product 1 (98.3 g, 91.4% yield) with 99.92 purity and 99.98% ee.
[α] 25 D +85.6 (MeOH, c 1) (lit [4b]. [α] 25 D +84 (MeOH, c 1));
Mp 222-223 C (lit [4b]. Mp 222– 224°C); MS m/z 234 [M + H]+ .
1 H NMR (400Hz, DMSO-d6) δ 1 H NMR (400 MHz, DMSO-d6) δ 9.64 (br, 1H), 8.97 (br, 1H), 7.41-7.26 (m, 5H), 4.18-4.16 (d, J = 9.2Hz, 1H), 3.77-3.75 (m, 1H), 3.66 (s, 3H), 3.25 (m, 1H), 2.94 (m, 1H), 1.67-1.64 (m, 3H), 1.41-1.25 (m, 3H).
13C NMR (100.6 MHz, DMSO-d6) δ 171.3, 134.2, 129.1, 128.6, 128.2, 56.8, 53.3, 52.6, 44.5, 25.7, 21.5, 21.4.
1H-NMR, and 13C-NMR of compound 1......................................... 10-11
DEPT,
COSY, NOESY, GHMBC, and HMQC of compound 1.................. 12-14
COSY
NOESY
GHMBC
![2-N-(4-cyclopropyl-5-fluoro-6-methylpyridin-2-yl)-5-[(3R)-3,4-dimethylpiperazin-1-yl]-4-N-(1,5-dimethylpyrazol-3-yl)pyrimidine-2,4-diamine.png](https://pubchem.ncbi.nlm.nih.gov/image/imgsrv.fcgi?cid=92045019&t=l)
