ZY 19489, MMV 253

 

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

• N2-(4-Cyclopropyl-5-fluoro-6-methyl-2-pyridinyl)-5-[(3R)-3,4-dimethyl-1-piperazinyl]-N4-(1,5-dimethyl-1H-pyrazol-3-yl)-2,4-pyrimidinediamine
• (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

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, VIT B1

 

THIAMINE

• Molecular FormulaC12H17N4OS
• Average mass265.354 Da

• 59-43-8    has cl atom
• 70-16-6 [RN]  no cl atom

• Thiazolium, 3-[(4-amino-2-methyl-5-pyrimidinyl)methyl]-5-(2-hydroxyethyl)-4-methyl-, chloride, hydrochloride (1:1:1), Thiamine CL  hcl, 67-03-8, (Component: 70-16-6) 1;1;1,
• C12 H17 N4 O S . Cl H . Cl

3595616 [Beilstein]

3-[(4-Amino-2-methyl-5-pyrimidinyl)methyl]-5-(2-hydroxyethyl)-4-methylthiazolium

thiamin hydrochloride
Vitamin B1 hydrochloride
thiamine hydrochloride
aneurin hydrochloride
3-(4-amino-2-methyl-5-pyrimidinyl)methyl-5-(2-hydroxyethyl)-4-methylthiazolium chloride hydrochloride

SPECTROSCOPY

Compound Name:
Thiamin hydrochlorideMolecular Formula: C12H17ClN4OSMolecular Weight: 300.8CAS Registry No.:
67-03-8

 MASS

13C NMR D2O

 

1H NMR : 400 MHz in DMSO-d6

 

 

IR

 

Syn

HELVETICA CHIMICA ACTA ~ Vol. 73 (1990)

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.

Ezutromid

 

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.

https://onlinelibrary.wiley.com/doi/10.1002/anie.201906080

DEXMETHYLPHENIDATE

 

DEXMETHYLPHENIDATE

SynonymsDexmethylphenidate HCl, UNII1678OK0E08, CAS Number19262-68-1, WeightAverage: 269.77
Chemical FormulaC14H20ClNO2

methyl (2R)-2-phenyl-2-[(2R)-piperidin-2-yl]acetate hydrochloride

CAS Number	40431-64-9  as HCl: 19262-68-1
PubChem CID	154101 as HCl: 154100
IUPHAR/BPS	7554
DrugBank	DB06701  as HCl: DBSALT001458
ChemSpider	135807  as HCl: 135806
UNII	M32RH9MFGP as HCl: 1678OK0E08

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

HMQC

Medical uses

Buspirone

 

Buspirone

• Molecular FormulaC21H31N5O2
• Average mass385.503 Da
• буспирон
  بوسبيرون
  丁螺酮

251-489-4 [EINECS]

253-072-2 [EINECS]

36505-84-7 [RN]

8-[4-(4-Pyrimidin-2-yl-piperazin-1-yl)-butyl]-8-aza-spiro[4.5]decane-7,9-dione

8-[4-[4-(2-Pyrimidinyl)-1-piperazinyl]butyl]-8-azaspiro[4.5]decane-7,9-dione

• 8-[4-[4-(2-Pyrimidinyl)-1-piperazinyl]butyl]-8-azaspiro[4.5]decane-7,9-dione
• Buspin
• Buspirone
• Spitomin

Buspirone

PAPER

https://pubs.rsc.org/en/content/articlelanding/2019/GC/C8GC03328E#!divAbstract

1. Green Chemistry, 21(1), 59-63; 2019

Abstract

A continuous flow method for the direct conversion of alcohols to amines via a hydrogen borrowing approach is reported. The method utilises a low loading (0.5%) of a commercial catalyst system ([Ru(p-cymene)Cl2]2 and DPEPhos), reagent grade solvent and is selective for primary alcohols. Successful methylation of amines using methanol and the direct dimethylamination of alcohols using commercial dimethylamine solution are reported. The synthesis of two pharmaceutical agents Piribedil (5) and Buspirone (25) were accomplished in good yields employing these new methods.

http://www.rsc.org/suppdata/c8/gc/c8gc03328e/c8gc03328e2.pdf

 

8-(4-hydroxybutyl)-8-azaspiro[4.5]decane-7,9-dione (23): A solution of 3,3-tetramethyleneglutaric anhydride (0.25 mol/L in THF) was combined in a tee piece with a solution of 4-amino-1-butanol (0.25 mol/L in THF) and reacted in a 20 mL reactor coil (stainless steel, 20 min residence time) heated at 250 °C. The output was concentrated in vacuo and the residue purified by column chromatography on silica gel to afford the product in 84% yield (Rf = 0.31, 63% DCM/AcOEt). 1H NMR (400 MHz, CDCl3) δ = 3.78 (t, J = 7.2 Hz, 2H), 3.65 (t, J = 6.0 Hz, 2H), 2.58 (s, 4H), 1.77 – 1.64 (m, 4H), 1.64 – 1.53 (m, 4H), 1.53 – 1.43 (m, 4H). 13C NMR (100 MHz, CDCl3) δ = 172.33, 62.28, 44.87, 39.47, 39.14, 37.54, 29.81, 24.35, 24.17. HRMS for [C13H22NO3] + calculated 240.1594 found 240.1605.

 

 

 

8-(4-(4-(pyrimidin-2-yl)piperazin-1-yl)butyl)-8-azaspiro[4.5]decane-7,9-dione (Buspirone, 25): The flow system was flushed with THF, the back-pressure regulator was set to 50 bar, and the coil reactor heated to 250 °C. Then a solution (10 mL overall volume) containing 1-(2-pyrimidyl)piperazine (2 mmol), 8-(4-hydroxybutyl)- 8-azaspiro[4.5]decane-7,9-dione (23) (2 mmol), dichloro(p-cymene)ruthenium(II) dimer (0.08 mmol) and bis[(2- diphenylphosphino)phenyl] ether (DPEPhos, 0.17 mmol) was pumped at 0.8 ml/min through a heated coil (8 mL, Phoenix reactor). The output solution obtained in steady state (monitored using the FlowUV) was concentrated in vacuo and purified by column chromatography on silica gel to afford the desired product in 76% yield (Rf = 0.29, 5% MeOH/DCM). 1H NMR (400 MHz, CDCl3) δ = 8.31 (d, J = 4.7 Hz, 2H), 6.48 (t, J = 4.7 Hz, 1H), 3.84 (t, J = 5.1 Hz, 4H), 3.79 (t, J = 6.8 Hz, 2H), 2.60 (s, 4H), 2.50 (t, J = 5.1 Hz, 4H), 2.40 (t, J = 6.8 Hz, 2H), 1.79 – 1.65 (m, 4H), 1.65 – 1.42 (m, 8H). 13C NMR (100 MHz, CDCl3) δ = 172.19, 161.63, 157.68, 109.77, 58.31, 53.06, 44.92, 43.60, 39.48, 39.35, 37.56, 26.04, 24.19, 24.19. HRMS for [C21H32N5O2] + calculated 386.2551 found 386.2570.

CAS Registry Number: 36505-84-7

CAS Name: 8-[4-[4-(2-Pyrimidinyl)-1-piperazinyl]butyl]-8-azaspiro[4.5]decane-7,9-dione

Molecular Formula: C21H31N5O2

Molecular Weight: 385.50

Percent Composition: C 65.43%, H 8.11%, N 18.17%, O 8.30%

Literature References: Non-benzodiazepine anxiolytic; 5-hydroxytryptamine (5-HT1) receptor agonist. Prepn: Y. H. Wu et al., J. Med. Chem. 15, 477 (1972); Y. H. Wu, J. W. Rayburn, DE 2057845 (1971 to Bristol-Myers); eidem, US 3717634 (1973 to Mead-Johnson). Pharmacology: L. E. Allen et al., Arzneim.-Forsch. 24, 917 (1974). Comparison with diazepam in treatment of anxiety: H. L. Goldberg, R. J. Finnerty, Am. J. Psychiatry 136, 1184 (1979); A. F. Jacobson et al., Pharmacotherapy 5, 290 (1985). Nonsynergistic effect with alcohol: T. Seppala et al., Clin. Pharmacol. Ther. 32, 201 (1982). Disposition and metabolism: S. Caccia et al., Xenobiotica 13, 147 (1983). Series of articles on chemistry, pharmacology, addictive potential, and clinical trials: J. Clin. Psychiatry 43, pp 1-116 (1982); on pharmacology, safety and clinical comparison with clorazepate: Am. J. Med. 80, Suppl. 3B, 1-51 (1986). Review of pharmacology and therapeutic efficacy: K. L. Goa, A. Ward, Drugs 32, 114-129 (1986). Review: M. W. Jann, Pharmacotherapy 8, 100-116 (1988); D. P. Taylor, FASEB J. 2, 2445-2452 (1988).

 

Derivative Type: Hydrochloride

CAS Registry Number: 33386-08-2

Trademarks: Ansial (Vita); Ansiced (Abello); Axoren (Glaxo Wellcome); Bespar (BMS); Buspar (BMS); Buspimen (Menarini); Buspinol (Zdravlje); Buspisal (Lesvi); Narol (Almirall)

Molecular Formula: C21H31N5O2.HCl

Molecular Weight: 421.96

Percent Composition: C 59.77%, H 7.64%, N 16.60%, O 7.58%, Cl 8.40%

Properties: Crystals from abs ethanol, mp 201.5-202.5°. LD50 i.p. in rats: 136 mg/kg (Allen).

Melting point: mp 201.5-202.5°

Toxicity data: LD50 i.p. in rats: 136 mg/kg (Allen)

 

Therap-Cat: Anxiolytic.

Keywords: Anxiolytic; Arylpiperazines; Serotonin Receptor Agonist.

AMIODARONE

AMIODARONE

 

PATENT

CN109053652-PREPARATION METHOD OF AMIODARONE HYDROCHLORIDE INTERMITTENT

https://patentscope.wipo.int/search/en/detail.jsf?docId=CN235615504&_cid=P11-KL0AU0-06410-1

Description of the drawings

Figure 3 shows the proton nuclear magnetic resonance spectrum of compound 9;

Figure 4 shows the carbon nuclear magnetic resonance spectrum of compound 9.

compound 9 as an off-white crystalline powder with a yield of about 86.9%.

1 HNMR(400MHz,d DMSO )δ: 0.81～0.85(t,3H,-CH 3 ), 1.24～1.29(m,2H,-CH 2 CH 3 ),1.68～1.70(m,2H,-CH 2 CH 2 CH 3 ), 2.82～2.85(t,2H,Ar-CH 2 -CH 2 ), 6.91～7.72(m,8H,ArH), 10.46(m,1H,-OH).  13 CNMR(400 Hz,DMSO)δ:189.72,163.49,162.69,153.48,132.08, 130.16,127.28,124.87,123.98 ,121.16,116.90,11 5.78, 111.51,29.94,27.51,22.09,13.84. See attached drawings 3～4.

FTIR spectra of Amiodarone, Pluronic F68 and their solid dispersion formulations.  ...https://www.japsonline.com/admin/php/uploads/2119_pdf.pdf

CLIP

MAGNETIC RESONANCE IN CHEMISTRY, VOL. 29, 482493 (1991) 'H and 13C NMR Analyses of Amiodarone, Desethylamiodarone and Desoxoamiodarone 

Amiodarone (AMIO) is an antianginal and antiarrhythmic drug used clinically to treat a wide range of cardiac arrhythmias.',' Desethylamiodarone (DEA) is the major metabolite of amiodarone,' and desoxoamiodarone (DOA) is reported to be a less toxic form of ami~daro

Figure 1. !%O-MHz 'H NMR spectra of (top) AMIO, (middle) DEA and (bottom) DOA in their HCI forms in CDCI, at 27°C. Note the presence of the 3-CH2 resonance and the upfield shift of the aromatic singlet of DOA and the upfield shift of the HCI signal and the half-intensity of the ethyl resonances of DEA. See text for details. 

Figure 2. 500-MHz ‘H 2D COSY NMR spectra showing the spin connectivities in (A) the aliphatic region of AMIO, (B) the aliphatic region of DEA, (C) the aliphatic region of DOA and (D) the aromatic region of AMIO. Note the similarity of the COSY patterns of AMIO, DEA and DOA.

Figure 6. 75-MHz 1D 13C NMR spectrum of AM10 in CDCI, at 27°C (bottom) and selective INEPT spectra transferring from proton multiplet positions indicated. 

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