Bemfivastatin, PPD 10558, RBx 10558

Bemfivastatin, PPD 10558, RBx 10558

cas 805241-79-6

• PPD-10558 calcium salt
• Ppd-10558(calcium salt)
• 805241-64-9
• ppd-10558 calcium
• 3I8G750MW3
• calcium;(3R,5R)-7-[2-(4-fluorophenyl)-4-[[4-(hydroxymethyl)phenyl]carbamoyl]-3-phenyl-5-propan-2-ylpyrrol-1-yl]-3,5-dihydroxyheptanoate
• C₆₈H₇₂CaF₂N₄O₁₂

• 1H-PYRROLE-1-HEPTANOIC ACID, 2-(4-FLUOROPHENYL)-.BETA.,.DELTA.-DIHYDROXY-4-(((4-(HYDROXYMETHYL)PHENYL)AMINO)CARBONYL)-5-(1-METHYLETHYL)-3-PHENYL-, CALCIUM SALT (2:1), (.BETA.R,.DELTA.R)-
• calcium;(3R,5R)-7-[2-(4-fluorophenyl)-4-[[4-(hydroxymethyl)phenyl]carbamoyl]-3-phenyl-5-propan-2-ylpyrrol-1-yl]-3,5-dihydroxyheptanoate

• UNII-3I8G750MW3
• 1H-Pyrrole-1-heptanoic acid, 2-(4-fluorophenyl)-beta,delta-dihydroxy-4-(((4-(hydroxymethyl)phenyl)amino)carbonyl)-5-(1-methylethyl)-3-phenyl-, calcium salt (2:1), (betaR,deltaR)-
• Bemfivastatin calcium
• Bemfivastatin hemicalcium

Bemfivastatin (PPD 10558) is an orally active, HMG-CoA Reductase (HMGCR) inhibitor, also known as Statin. Bemfivastatin enhances the activity of liver extraction. Bemfivastatin exhibits little developmental toxicity effects in pregnant rats and rabbits via daily oral doses during organogenesis period. The no observed adverse effect level (NOAEL) are ≥320 mg/kg/day for rats developmental toxicity, 12.5 mg/kg/day for rabbits maternal toxicity, and 25 mg/kg/day for rabbits developmental toxicity, respectively. Bemfivastatin can be used for research on Statin-related hypercholesterolemic myalgia with inability to tolerate statins.

Korean Patent No. 10-1329113 describes a method for preparing (3R,5R)-7-[2-(4-fluorophenyl)-5-isopropyl-3-phenyl-4-[(4-hydroxymethylphenylamino)carbonyl]-pyrrol-1-yl]-3,5-dihydroxy-heptanoic acid hemicalcium salt, as shown in the following reaction scheme.

SCHEME

MAIN

PATENT

WO2020040614

https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2020040614&_cid=P11-M8VDBE-14315-1

Step 3: Preparation of tert-butyl (3R,5R)-7-(2-(4-fluorophenyl)-4-((4-(hydroxymethyl)phenyl)carbamoyl)-5-isopropyl-3-phenyl-1H-pyrrol-1-yl)-3,5-dihydroxyheptanoate

[499]In step 2, tert-butyl 2-((4R,6R)-6-(2-(3-((4-(((tert-butyldimethylsilyl)oxy)methyl)phenyl)carbamoyl)-5-(4-fluorophenyl)-2-isopropyl-4-phenyl-1H-pyrrol-1-yl)ethyl)-2,2-dimethyl-1,3-dioxan-4-yl)acetate (5 g) was dissolved in methanol (37 ml) and THF (37 ml), 1 N HCl aqueous solution (37 ml) was added, and the mixture was stirred at room temperature for 2 hours. EA was added to the reaction solution, diluted, and washed several times with distilled water and brine. The extracted organic layer was dried over Na 

₂ SO 

₄ and filtered under reduced pressure. The filtrate was concentrated under reduced pressure, EA and hexane were added, and the mixture was purified by recrystallization to obtain the title compound. 

[500]White solid 4.6 g (yield quantitative); 

[501]

¹H NMR (500 MHz, CDCl ₃): 7.24-7.14 (m, 9H), 7.06 (d, J = 8.5 Hz, 2H), 6.99 (t, J = 8.5 Hz, 2H), 6.87 (br s, 1H), 4.57 (s, 2H), 4.45-4.08 (m, 2H), 3.96-3.90 (m, 1H), 3.75-3.71 (m, 1H), 3.58 (sep, J = 7.0 Hz, 1H), 2.32 (d, J = 6.5 Hz, 2H), 1.73-1.65 (m, 1H), 1.64-1.58 (m, 1H), 1.54 (d, J = 7.0 Hz, 6H), 1.45 (s, 9H), 1.27-1.22 (m, 2H), MH+ 645.

Step 4: Preparation of (3R,5R)-7-(2-(4-fluorophenyl)-5-isopropyl-3-phenyl-4-((4-hydroxymethylphenylamino)carbonyl)-pyrrol-1-yl)-3,5-dihydroxyheptanoic acid hemicalcium salt

[503]In step 3, tert-butyl (3R,5R)-7-(2-(4-fluorophenyl)-4-((4-(hydroxymethyl)phenyl)carbamoyl)-5-isopropyl-3-phenyl-1H-pyrrol-1-yl)-3,5-dihydroxyheptanoate (4.19 g) obtained was dissolved in MeOH (65 ml) and THF (65 ml), and stirred in an ice bath. NaOH pellets (5 eq, 1.3 g) were added, and the mixture was stirred for 1 more hour at room temperature. After concentrating the reaction solution under reduced pressure, distilled water (44 ml) was added until the formed solid was completely dissolved. After concentrating the reaction solution under reduced pressure, distilled water (430 ml) was added until the solid was completely dissolved. 1 M Ca(OAc) 

₂ aqueous solution (3.6 ml) was slowly added dropwise, and the mixture was stirred for 15.5 hours at room temperature. After the generated solid was filtered under reduced pressure, it was washed several times with distilled water and the filtered solid was dried in an oven. 

[504]2.98 g of white solid (yield 76%); 

[505]

¹H NMR (500 MHz, DMSO-d ₆) δ 9.78 (br s, 1H), 7.46 (d, J = 8.5 Hz, 2H), 7.26-7.23 (m, 2H), 7.19 (t, J = 9.0 Hz, 2H), 7.15 (d, J = 8.5 Hz, 2H), 7.09-7.05 (m, 4H), 7.02-6.98 (m, 1H), 6.41 (br s, 1H), 5.04 (t, J = 5.5 Hz, 1H), 4.75 (br s, 1H), 4.39 (d, J = 5.5 Hz, 2H), 3.98-3.91 (m, 1H), 3.79-3.69 (m, 2H), 3.55-3.50 (m, 1H), 3.22 (sep, J = 7.0 Hz, 1H), 2.03 (dd, J = 15.0 Hz, 4.0 Hz, 1H), 1.90 (dd, J = 15.0 Hz, 8.0 Hz, 1H), 1.63-1.57 (m, 1H), 1.54-1.47 (m, 1H), 1.41-1.36 (m, 1H), 1.37 (d, J = 7.0 Hz, 6H), 1.23-1.16 (m, 1H), MH+ (acid+1) 589.

Step 5: Preparation of (3R,5R)-7-(2-(4-fluorophenyl)-5-isopropyl-3-phenyl-4-((4-hydroxymethylphenylamino)carbonyl)-pyrrol-1-yl)-3,5-dihydroxyheptanoic acid hemicalcium salt

[540]The title compound was prepared in the same manner as in step 4 of Example 15. 

[541]

¹H NMR (500 MHz, DMSO-d ₆) δ 9.78 (br s, 1H), 7.46 (d, J = 8.5 Hz, 2H), 7.26-7.23 (m, 2H), 7.19 (t, J = 9.0 Hz, 2H), 7.15 (d, J = 8.5 Hz, 2H), 7.09-7.05 (m, 4H), 7.02-6.98 (m, 1H), 6.41 (br s, 1H), 5.04 (t, J = 5.5 Hz, 1H), 4.75 (br s, 1H), 4.39 (d, J = 5.5 Hz, 2H), 3.98-3.91 (m, 1H), 3.79-3.69 (m, 2H), 3.55-3.50 (m, 1H), 3.22 (sep, J = 7.0 Hz, 1H), 2.03 (dd, J = 15.0 Hz, 4.0 Hz, 1H), 1.90 (dd, J = 15.0 Hz, 8.0 Hz, 1H), 1.63-1.57 (m, 1H), 1.54-1.47 (m, 1H), 1.41-1.36 (m, 1H), 1.37 (d, J = 7.0 Hz, 6H), 1.23-1.16 (m, 1H), MH+ (acid+1) 589.

KR2001835  63%

KR2016103248

• [1]. Faqi AS, et al. Developmental toxicity of the HMG-CoA reductase inhibitor (PPD10558) in rats and rabbits. Birth Defects Res B Dev Reprod Toxicol. 2012 Feb;95(1):23-37.  [Content Brief][2]. Wierzbicki A, et al. Drugs in development for the management of dyslipidaemia[J]. Future Prescriber, 2012, 13(2): 12-15.

/////////Bemfivastatin, PPD 10558,  PPD-10558, RBx-10558; PPD10558, RBx10558, PPD 10558, RBx 10558, bemfivastatin CA, RBx 10558