N-[(1R,2R)-2-(2,3-Dihydro-1,4-benzodioxin-6-yl)-2-hydroxy-1-(1-pyrrolidinylmethyl)ethyl]octanamide

Eliglustat is an specific, potent and orally active glucocerebroside synthase inhibitor with an IC50 of 24 nM.

Eliglustat is a carboxamide obtained by formal condensation of the carboxy group of octanoic acid with the primary amino group of (1R,2R)-2-amino-1-(2,3-dihydro-1,4-benzodioxin-6-yl)-3-(pyrrolidin-1-yl)propan-1-ol. A ceramide glucosyltransferase inhibitor used (as its tartrate salt) for treatment of Gaucher's disease. It has a role as an EC 2.4.1.80 (ceramide glucosyltransferase) inhibitor. It is a benzodioxine, a N-alkylpyrrolidine, a secondary alcohol and a carboxamide. It is a conjugate base of an eliglustat(1+).|Eliglustat, marketed by Genzyme as CERDELGA, is a glucosylceramide synthase inhibitor indicated for the long-term treatment of type 1 Gaucher disease. Patients selected for treatment with Eliglustat undergo an FDA approved genotype test to establish if they are CYP2D6 EM (extensive metabolizers), IM (intermediate metabolizers), or PM (poor metabolizers), as the results of this test dictate the dosage of Eliglustat recommended. There are no recommended dosing guidelines for CYP2D6 ultra-rapid or indeterminate metabolizers. Eliglustat was approved for use by the FDA in August 2014.|Eliglustat is a Glucosylceramide Synthase Inhibitor. The mechanism of action of eliglustat is as a Glucosylceramide Synthase Inhibitor, and P-Glycoprotein Inhibitor, and Cytochrome P450 2D6 Inhibitor.|Eliglustat is an oral inhibitor of glucosylceramide synthase which is used in the therapy of type 1 Gaucher disease. Clinical experience with eliglustat is limited, but it not been linked to serum enzyme elevations during therapy or to instances of clinically apparent acute liver injury.|Eliglustat is a ceramide analog and an orally bioavailable inhibitor of glucosylceramide synthase (GCS; ceramide glucosyltransferase), that may be used to decrease the production of glycosphingolipids (GSLs) including glucosylceramide, also known as glucocerebroside. Upon oral administration, eliglustat inhibits GCS, which catalyzes the initial step in the synthesis of glucosylceramide and other GSLs. This decreases the production of glucosylceramide and other GSLs, which have important roles in various diseases and cellular processes, including immune processes and functions. Eliglustat may be used in substrate reduction therapy in diseases in which the enzyme glucocerebrosidase (GCase), responsible for the breakdown of glucocerebroside, is deficient.

A compound of formula (VII) (60 mg, 0.22 mmol) in 5 mL of N, N dimethylformamide, Add DIPEA (0.065 mL, 0.38 mmol), Then intermediate A (60 mg, 0.24 mmol), Room temperature 18h, After the TLC is displayed completely, Extracted with 20 mL of ethyl acetate and washed with water.Wash with saturated sodium chloride and dry over anhydrous sodium sulfate.Filtration, evaporation of the solvent, and column chromatography (PE: EA = 10: 1-DCM: MeOH = 10:1) afforded product 65mg, yield 75percent.(1 R, 2R)-2-Amino-1 -(2', 3'-dihydro-benzo [1 , 4] dioxin-6'-yl)-3-pyrrolidin-1 -yl-propan- 1 -ol (15g) obtained from above stage 5 was dissolved in dry dichloromethane (150ml) at room temperature under nitrogen atmosphere and cooled to 10-15At 25 ~ 30 °C, the raw material EGS-SMA2.5g (1 eq) was dissolved in 50 ml of anhydrous DCM and the raw material EGS-SMB2.2g (1 eq) was dissolved in 25 ml of anhydrous DCM and replaced with nitrogen twice. Under nitrogen, the EGS-SMA solution was slowly added dropwise to the EGS-SMB solution at room temperature for 30 min. After the addition was completed, the reaction was continued for 20 hours at room temperature. 35 ml of 1 M NaOH was added to the reaction system and stirred for 45 min. After the completion of the reaction, the reaction system was separated, the organic phase was washed twice with 20 ml of 1 M NaOH, washed twice, and dried to dryness to obtain a viscous yellow liquid. And further adding 100 ml of a 5percent EA n-hexane solution to the reaction system, heating and refluxing to dissolve most of the crude product, cooling to 40 ° C, and pouring the liquid into another reaction flask. The remaining yellow viscous yellow liquid was further added to 20 ml of a 5percent EA solution of n-hexane, heated to reflux to dissolve most of the crude product, cooled to 40 ° C, poured out and repeated. The resulting n-hexane solution was stirred at room temperature for 4 h, filtered, and 10 ml of 5percent EA of n-hexane was washed twice to give 2 g of a white product as EGS-API in 55percent yield.Compound 6 (1R, 2R)-Octanoic acid [2-(2', 3'-dihydro-benzo[1, 4]dioxin-6'-yl)-2-hydroxy-1-pyrrolidin-1-ylmethyl-ethyl]-amide 1 mmol of compound VIII (wherein R5 is a hydrogen atom) was dissolved in 30 ml of DMF, 1.5 mmol of DIPEA was added1.2 mmol of compound IX (wherein R6 is succinimidoyl). Plus 25, 24 hours under the reaction. After the reaction, add water quenchingAnd extracted twice with ethyl acetate. The combined organic phase was washed and dried and concentrated to give 0.3g of etilogluzideWithout furher purification, 7 (150 mg, 0.55 mmol) was dissolved in DMF (5 mL), DIPEA (0.16 mL, 0.95 mmol) was added to the mixture. The reaction was stirred for 5 min, then 2, 5-dioxopyrrolidin-1-yl octanoate (150 mg, 0.6 mmol) was added and the mixture was stirred at room temperature for 18 h. Water was added to the reaction (15 mL) and extracted with EtOAc (3×30 mL). The combined organics were washed with brine, dried over NaAdd to the reaction flask(2R, 3'-dihydro-1, 4-benzodioxin-6-yl) -3- (pyrrolidin-1-yl) - Propane-1-ol (V) (1.39 g, 5 mmol), octanoyl chloride (0.89 g, 5.5 mmol) and dichloromethaneAfter stirring and stirring, N, N-diisopropylethylamine (0.71 g, 5.5 mmol) was added dropwise, and the mixture was stirred for 4-5 hours, TLC detection reaction ends. Concentrated under reduced pressure, and the residue was partitioned with ethyl acetate and sodium bicarbonate solution, The aqueous phase was extracted twice with ethyl acetate and the combined organic phases were dried over anhydrous sodium sulfate. concentrate, The residue was recrystallized from ethyl acetate and n-hexane, To obtain the white solid Irubs he 1.24g, the yield of 61.4percent

Molecular Weight:404.5
XLogP3:3.7
Hydrogen Bond Donor Count:2
Hydrogen Bond Acceptor Count:5
Rotatable Bond Count:11
Exact Mass:404.26750763
Monoisotopic Mass:404.26750763
Topological Polar Surface Area:71
Heavy Atom Count:29
Complexity:484
Defined Atom Stereocenter Count:2
Covalently-Bonded Unit Count:1
Compound Is Canonicalized:Yes