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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Diquafosol

READ
https://newdrugapprovals.org/2020/07/30/diquafosol/

Favipiravir

• Molecular FormulaC5H4FN3O2
• Average mass157.103 Da

SYNTHESIS AT https://newdrugapprovals.org/2015/08/18/filgotinib/

259793-96-9 [RN]

2-Pyrazinecarboxamide, 6-fluoro-3,4-dihydro-3-oxo-

 

6-Fluoro-3-hydroxypyrazine-2-carboxamide

6-Fluoro-3-oxo-3,4-dihydro-2-pyrazinecarboxamide

 

8916

Avigan

ファビピラビル
Favipiravir

SYN

https://link.springer.com/article/10.1007/s11696-018-0654-9

Electronic supplementary material

 

Below is the link to the electronic supplementary material.

Supplementary material 1 (DOCX 1315 kb)

Ref

https://pdfs.semanticscholar.org/be8e/cb882b99204983d2f60077c7ab8b53f4d62c.pdf

Drug Discoveries & Therapeutics. 2014; 8(3):117-120.

 mp = 178-180°C. 1 H-NMR (600 MHz, DMSO): δ 12.34 (brs, 1H, OH), 8.31 (d, 1H, pyrazine H, J = 8.0 Hz), 7.44 (s, 1H, CONH2), 5.92 (s, 1H, CONH2). 13C-NMR (75 MHz, DMSO): δ 168.66, 159.69, 153.98, 150.76, 135.68. HRMS (ESI): m/z [M + H]+ calcd for C5H5FN3O2 + : 158.0366; found: 158.0360.

PAPER

Chemical Papers (2017), 71(11), 2153-2158.

https://link.springer.com/article/10.1007%2Fs11696-017-0208-6

Below is the link to the electronic supplementary material.

Supplementary material 1 (DOCX 514 kb)

Take a tour

Kerkennah Islands

Kerkennah Islands seen from space
Kerkennah Islands
Geography
Coordinates	34°42′N 11°11′ECoordinates: 34°42′N 11°11′E
Area	160 km2 (62 sq mi)
Administration
Tunisia

Kerkennah Islands (Tunisian Arabic: قرقنة‎ qarqna) are a group of islands lying off the east coast of Tunisia in the Gulf of Gabès, at 34°42′N 11°11′E. The Islands are low-lying, being no more than 13 metres (43 feet) above sea level. The main islands are Chergui and Gharbi. The archipelago has an area of 160 square kilometres (62 sq mi) and a population of 15,501 (2014).^[2]

Kerkennah's main town, Remla (on Chergui), has a population of 2,000. The population of the islands significantly decreased during the 1980s due to drought. The islands were unable to provide suitable irrigation systems and, with clean water rapidly running out, many islanders were forced to leave for mainland Tunisia, the nearest town being Sfax.

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NIDUFEXOR

NIDUFEXOR

LMB763

4-[[benzyl-(8-chloro-1-methyl-4H-chromeno[4,3-c]pyrazole-3-carbonyl)amino]methyl]benzoic acid

Nidufexor is a farnesoid X receptor (FXR) agonist.

Molecular Weight	487.93
Formula	C₂₇H₂₂ClN₃O₄
CAS No.	1773489-72-7

PHASE 2 Treatment of Liver and Biliary Tract Disorders,
Agents for Diabetic Nephropathy, NOVARTIS

Nidufexor

1773489-72-7, LMB-763, UNII-CJ1PL0TE6J, CJ1PL0TE6J, BCP28929, EX-A1854

Nidufexor pound LMB-763 pound(c)

ZINC584641402

4-((N-benzyl-8-chloro-1-methyl-1,4-dihydrochromeno[4,3-c]pyrazole-3-carboxamido)methyl)benzoic acid

HY-109096

CS-0039398

https://pubs.acs.org/doi/pdf/10.1021/acs.jmedchem.9b01621

1 (7.6 g, 89% yield) as a white solid. Melting point: 232.6 °C.

1 H NMR (400 MHz, DMSO): δ 12.93 (s, 1H), 7.96−7.85 (m, 2H), 7.71 (dd, J = 7.1, 2.5 Hz, 1H), 7.42−7.20 (m, 8H), 7.06 (dd, J = 8.7, 1.9 Hz, 1H), 5.45 (d, J = 3.9 Hz, 2H), 5.25 (d, J = 9.2 Hz, 2H), 4.58 (d, J = 12.1 Hz, 2H), 4.12 (d, J = 16.6 Hz, 3H).

13C NMR (101 MHz, DMSO-d6): δ 167.07, 162.21, 151.98, 142.65, 139.18, 132.20, 132.67, 129.70, 129.50, 129.50, 128.53, 128.53, 127.43, 127.43, 127.43, 127.43, 127.43, 125.53, 122.24, 119.0, 117.09, 116.64, 64.51, 50.68, 48.24. LC-MS m/z: 488.2/490.2 (M +H)+ ; chlorine pattern; method 3; RT = 1.41 min.

Elemental Analysis calcd for C27H22ClN3O4: C 66.46, H 4.54, N 8.61; found: C 66.43, H 4.56, N 8.62.

TRIS Salt Formation. Methanol (400 mL) was added to a mixture of 1 (4.0 g, 8.2 mmol) and 2-amino-2-hydroxymethylpropane-1,3-diol (TRIS, 1.0 g, 8.2 mmol). The mixture was heated to 70 °C for 0.5 h. After cooling to room temperature, the solvent was removed in vacuum. The residue was sonicated in dichloromethane (10 mL) and concentrated again. The resulting white solid was dried under vacuum overnight. The crude material was crystallized by slurring the solid residue in a 4:1 mixture of acetonitrile and methanol (5 mL). The mixture was stirred at room temperature for 24 h to give 4-((N-benzyl-8-chloro-1-methyl-1,4-dihydrochromeno- [4,3-c]pyrazole-3-carboxamido)methyl)benzoic acid TRIS salt as a white salt (3.7 g, 73% yield). Melting point: 195.6 °C. 1 H NMR (400 MHz, DMSO): δ 7.92−7.80 (m, 2H), 7.78−7.64 (m, 1H), 7.41− 7.19 (m, 8H), 7.13−7.00 (m, 1H), 5.44 (s, 2H), 5.25−5.14 (m, 2H), 4.61−4.48 (m, 2H), 4.18−4.03 (m, 3H), 3.39 (s, 7H). TRIS OH masked by water peak. LC-MS m/z: 488.0/490.0 (M+H)+ ; chlorine pattern, method 3. RT = 1.58 min. Elemental Analysis calc for C31H33ClN4O7: C 61.00, H 5.36, N 9.15; found: C 60.84, H 5.34, N 9.13.

https://pubs.acs.org/doi/suppl/10.1021/acs.jmedchem.9b01621/suppl_file/jm9b01621_si_001.pdf

Patent

WO 2015069666

https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2015069666&tab=PCTDESCRIPTION

///////NIDUFEXOR, LMB 763, Phase II, PHASE 2, Liver and Biliary Tract Disorders,  Diabetic Nephropathy, NOVARTIS

CN1C(C2=CC(Cl)=CC=C2OC3)=C3C(C(N(CC4=CC=CC=C4)CC5=CC=C(C(O)=O)C=C5)=O)=N1