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ChemSpider 2D Image | firibastat | C8H20N2O6S4
26188 - Firibastat ( QGC-001 ) | CAS 648927-86-0

Firibastat

  • Molecular FormulaC8H20N2O6S4
  • Average mass368.514 Da

C8H20N2O6S4

368.5

RB 150

Qgc-001(racemate)

UNII-PD5EII1F9A

Firibastat, (+/-)-

PD5EII1F9A

3-amino-4-[(2-amino-4-sulfobutyl)disulfanyl]butane-1-sulfonic acid

(+/-)-QGC-001

1-Butanesulfonic acid, 4,4′-dithiobis(3-amino-

3-Amino-4-((2-amino-4-sulfo-butyl)disulfanyl)butane-1-sulfonic acid

cas 721392-96-7, RACEMIC

CAS 648927-86-0, (S)-3-amino-4-(((S)-2-amino-4-sulfobutyl)disulfaneyl)butane-1-sulfonic acid

фирибастат[Russian][INN]

فيريباستات[Arabic][INN]

(3S,3’S)-4,4′-Disulfanediylbis(3-aminobutane-1-sulfonic acid)

firibastatum

фирибастат

فيريباستات

非立巴司他[Chinese]

PAPER

Journal of Labelled Compounds & Radiopharmaceuticals (2004), 47(13), 997-1005

PATENT

https://patents.google.com/patent/WO2020084131A1/en

PATENT

WO2012045849

WO2012045849

EXAMPLES

Example 1: Synthesis of compound I from (S) ethyl 2-(benzyloxycarbonylamino) 4-(neopentyloxysulfonyl)butanoate

Step (a): (S) neopentyl 3-(benzylox carbonylamino) 4-hydroxybutane 1-sulfonate B

B

(S) ethyl 2-(benzyloxycarbonylamino) 4-(neopentyloxysulfonyl)butanoate A (41.55g, 100.0 mmol, 1.0 eq.) is added dropwise onto a 2M solution of LiBH4 in THF (50 mL, 44.8 g, 100.0 mmol, 1.0 eq.). The addition is performed at room temperature over a 3 hrs period. At the end of the addition, the mixture is stirred at room temperature until conversion is complete (A<1%). Addition of toluene, followed by hydrolysis with HC1, washings of the organic layer with NaHC03 and water, and concentration under vacuum lead to the desired product as a pale yellow oil in quantitative yield (ee = 98%), which slowly crystallises at room temperature in 4 or 5 days.

As B was found to have a very low melting point by DSC analysis, it was not possible to isolate it as a solid by simple crystallisation. It was decided to let it in solution and use it without further purification in the following step.

Step (b): (S) neopentyl 3-(benzyloxycarbonylamino) 4-(methylsulfonyloxy)butane 1-sulfonate

C

C

A solution of B (57.64 g, 154.34 mmol, 1.0 eq.) in toluene (115 mL, 2.0 vol.) is diluted with MTBE (173 mL, 3.0 vol.) at room temperature. Mesyl chloride (17.9 mL, 26.5 g, 231.50 mmol, 1.5 eq.) is then added at room temperature and the homogeneous mixture is cooled to 10°C. The addition of triethylamine (43.0 mL, 31.2 g, 308.67 mmol, 2.0 eq.) is performed at T<20°C. At the end of the addition, the mixture is stirred at 10°C until conversion is complete (B<1%). After hydrolysis with diluted HCl, the organic layer is washed with NaHC03, water and brine, followed by a partial concentration under reduced pressure. The corresponding mesylate is then crystallised by addition of heptanes (5.0 vol.) at 40°C. After cooling, filtration and drying, the expected product is isolated as a whitish solid in 92.5% yield and with a very high chemical purity (98%).

Step (c): (S) 2-(benzyloxycarbonylamino) 4-(neopentyloxysulfonyl)butyl thioacetate D

D

A solution of mesylate C (81.3 g, 180.05 mmol, 1.0 eq.) in acetone (203 mL, 2.5 vol.) is added dropwise to a suspension of potassium thioacetate (41.1 g, 360.1 mmol, 2.0 eq.) in acetone (203 mL, 2.5 vol.) at room temperature and over a period of 2 hrs. The reaction mixture is stirred at room temperature until conversion is complete (C<1%). After filtration of the salts and addition of toluene (4.0 vol.), acetone is removed by distillation under reduced pressure at 25°C. The solution is then treated with active charcoal and concentrated to 2.0 volumes. Slow addition of heptane (5.0 vol.) at room temperature, followed by cooling at 0°C, filtration and drying at 45°C, provides the expected product as a whitish solid in 78.2% yield and with a very high chemical purity (98%).

Step (d): (3S,3S’) neopentyl 4,4′-disulfanediylbis(3-(benzyloxycarbonylamino)butane 1-sulfonate) E

E

A solution of D (59.16 g, 137.1 mmol, 1.0 eq.) suspended in ethanol (203 mL, 2.5 vol.) is cooled to 0°C. 20% sodium hydroxide (25.1 mL, 150.8 mmol, 1.1 eq.) diluted with water

(16.9 mL, 0.285 vol.) is then added dropwise to the suspension by keeping the temperature below 10°C. The reaction mixture is warmed to room temperature and stirred until conversion is complete (D<1%). The intermediate thiol reacts at room temperature with a solution of iodine (20.9 g, 82.3 mmol, 0.6 eq.) in ethanol (118 mL, 2.0 vol.). The reaction is complete at the end of the addition of the oxidizing agent. After addition of a Na2S205 (13.0 g, 68.5 mmol, 0.5 eq.) aqueous solution (118 mL, 2.0 vol.) to reduce the excess of residual iodine, ethanol is removed by distillation under reduced pressure at 40°C. Addition of water (3.0 vol.) at room temperature, followed by cooling at 0°C, filtration and drying at 45-50°C, provides the expected dimer as a white solid in 98.3% yield and with a very high chemical purity (97.0%). The amount of iodide ions, coming from the reduction of iodine, is checked in the sample by potentiometric assay.

E°(Ag+/Ag(s))=0.80V

KsAgi=1.5.10“16

[AgNO3]=0.1N

Electrode: E=E°(Ag+/Ag(s))+0.061og[Ag+]

E=E°(Ag+/Ag(s))+0.061og (Ksi/[L])

Assay: [T] decreases and E increases

LOD=l mg

Four further washings with water are performed until no more iodide ions are detected. The results are presented in table 2.

Table 2.

Step (e): (3S,3S’) 4,4′-disulfanediylbis(3-aminobutane 1-sulfonic acid) compound I

4

Compound I

A solution of E (44.0 g, 56.6 mmol, 1.0 eq.) in TFA (220 mL, 5.0 vol.) and anisole (44 mL, 1.0 vol.) is heated to reflux (75°C) and the reaction mixture is stirred in these conditions until conversion is complete (E<1%). TFA is removed by distillation under reduced pressure at 50°C. Slow addition of MTBE (5.0 vol.) at room temperature makes the expected product precipitate. After trituration, filtration and washing with MTBE (1.0 vol.), the crude solid is suspended in methanol (220 mL, 5.0 vol.). New trituration, filtration and washing with MTBE (1.0 vol.), followed by drying under reduced pressure, provides compound I as a white solid in 92.5% yield.

NMR: 1H (solvent D20, 400 MHz, ppm): 4.70 (s, 6H, ¾); 3.77 (m, 2H, H2); 3.14 (dd, 2H, Hi); 2.98 (dd, 4H, H4); 2.86 (dd, 2H, Hi); 2.13 (m, 4H, H3). 13C (solvent D20, 100 MHz, ppm): 49.4 (2C, C2); 46.6 (2C, C4); 38.3 (2C, C ; 26.9 (2C, C3).

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/////////////////////////////////////////////////////////////////////////////

  • OriginatorCNRS; INSERM; University Paris Descartes
  • DeveloperQuantum Genomics
  • ClassAmines; Aminopeptidases; Antihypertensives; Cardiovascular therapies; Disulfides; Heart failure therapies; Metalloexopeptidases; Small molecules; Sulfonic acids
  • Mechanism of ActionGlutamyl aminopeptidase inhibitors
  • Orphan Drug StatusNo
  • New Molecular EntityYes
  • Phase IIIHypertension
  • Phase IIChronic heart failure; Left ventricular dysfunction
  • 28 Mar 2022No recent reports of development identified for phase-I development in Hypertension(In volunteers) in United Kingdom (PO, Tablet)
  • 25 Nov 2021Firibastat licensed to Teva in Israel
  • 11 Oct 2021Quantum Genomics plans a phase III trial for Heart failure

////////Firibastat, фирибастат , فيريباستات , firibastatum, фирибастат ,فيريباستات ,非立巴司他 , rb 150, (+/-)-QGC-001, qgc 001, 

C(CS(=O)(=O)O)C(CSSCC(CCS(=O)(=O)O)N)N


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DR ANTHONY CRASTO

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DR ANTHONY MELVIN CRASTO Ph.D

DR ANTHONY MELVIN CRASTO Ph.D

DR ANTHONY MELVIN CRASTO, Born in Mumbai in 1964 and graduated from Mumbai University, Completed his Ph.D from ICT, 1991,Matunga, Mumbai, India, in Organic Chemistry, The thesis topic was Synthesis of Novel Pyrethroid Analogues, Currently he is working with GLENMARK LIFE SCIENCES LTD, Research Centre as Principal Scientist, Process Research (bulk actives) at Mahape, Navi Mumbai, India. Total Industry exp 30 plus yrs, Prior to joining Glenmark, he has worked with major multinationals like Hoechst Marion Roussel, now Sanofi, Searle India Ltd, now RPG lifesciences, etc. He has worked with notable scientists like Dr K Nagarajan, Dr Ralph Stapel, Prof S Seshadri, Dr T.V. Radhakrishnan and Dr B. K. Kulkarni, etc, He did custom synthesis for major multinationals in his career like BASF, Novartis, Sanofi, etc., He has worked in Discovery, Natural products, Bulk drugs, Generics, Intermediates, Fine chemicals, Neutraceuticals, GMP, Scaleups, etc, he is now helping millions, has 9 million plus hits on Google on all Organic chemistry websites. His friends call him Open superstar worlddrugtracker. His New Drug Approvals, Green Chemistry International, All about drugs, Eurekamoments, Organic spectroscopy international, etc in organic chemistry are some most read blogs He has hands on experience in initiation and developing novel routes for drug molecules and implementation them on commercial scale over a 30 PLUS year tenure till date June 2021, Around 35 plus products in his career. He has good knowledge of IPM, GMP, Regulatory aspects, he has several International patents published worldwide . He has good proficiency in Technology transfer, Spectroscopy, Stereochemistry, Synthesis, Polymorphism etc., He suffered a paralytic stroke/ Acute Transverse mylitis in Dec 2007 and is 90 %Paralysed, He is bound to a wheelchair, this seems to have injected feul in him to help chemists all around the world, he is more active than before and is pushing boundaries, He has 9 million plus hits on Google, 2.5 lakh plus connections on all networking sites, 90 Lakh plus views on dozen plus blogs, 233 countries, 7 continents, He makes himself available to all, contact him on +91 9323115463, email amcrasto@gmail.com, Twitter, @amcrasto , He lives and will die for his family, 90% paralysis cannot kill his soul., Notably he has 33 lakh plus views on New Drug Approvals Blog in 233 countries......https://newdrugapprovals.wordpress.com/ , He appreciates the help he gets from one and all, Friends, Family, Glenmark, Readers, Wellwishers, Doctors, Drug authorities, His Contacts, Physiotherapist, etc

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