2-[[(2S)-2-benzyl-3-[(3R,4R)-4-(3-hydroxyphenyl)-3,4-dimethyl-1-piperi dyl]propanoyl]amino]acetic acid dihydrate
- Product Name
- 2-[[(2S)-2-benzyl-3-[(3R,4R)-4-(3-hydroxyphenyl)-3,4-dimethyl-1-piperi dyl]propanoyl]amino]acetic acid dihydrate
- CAS No.
- 170098-38-1
- Chemical Name
- 2-[[(2S)-2-benzyl-3-[(3R,4R)-4-(3-hydroxyphenyl)-3,4-dimethyl-1-piperi dyl]propanoyl]amino]acetic acid dihydrate
- Synonyms
- Entereg;Alvimopan 2H2O;Alvimopan hydrate;Ly 246736 dihydrate;Alvimopan dihydrate;Ly 246736 2-hydrate;ADL 8-2698 dihydrate;156053-89-3 (Anhydrous);Alvimopan dihydrate, >=99%;Alvimopan Dihydrate Labeled d7
- CBNumber
- CB21261077
- Molecular Formula
- C25H36N2O6
- Formula Weight
- 460.57
- MOL File
- 170098-38-1.mol
2-[[(2S)-2-benzyl-3-[(3R,4R)-4-(3-hydroxyphenyl)-3,4-dimethyl-1-piperi dyl]propanoyl]amino]acetic acid dihydrate Property
- Melting point:
- 210-213°
- alpha
- D25 +51.8° (c = 1.0 in DMSO)
- storage temp.
- 2-8°C
- solubility
- Soluble in DMSO
- form
- Powder
Hazard and Precautionary Statements (GHS)
- Symbol(GHS)
-
- Signal word
- Warning
- Hazard statements
-
H302Harmful if swallowed
H315Causes skin irritation
H319Causes serious eye irritation
H332Harmful if inhaled
H335May cause respiratory irritation
- Precautionary statements
-
P261Avoid breathing dust/fume/gas/mist/vapours/spray.
P280Wear protective gloves/protective clothing/eye protection/face protection.
P305+P351+P338IF IN EYES: Rinse cautiously with water for several minutes. Remove contact lenses, if present and easy to do. Continuerinsing.
N-Bromosuccinimide Price
- Product number
- CS-1540
- Product name
- Alvimopan(dihydrate)
- Purity
- 98.70%
- Packaging
- 5mg
- Price
- $110
- Updated
- 2021/12/16
- Product number
- A3163
- Product name
- Alvimopandihydrate
- Packaging
- 5mg
- Price
- $159
- Updated
- 2021/12/16
- Product number
- CS-1540
- Product name
- Alvimopan(dihydrate)
- Purity
- 98.70%
- Packaging
- 10mg
- Price
- $160
- Updated
- 2021/12/16
- Product number
- A3163
- Product name
- Alvimopandihydrate
- Packaging
- 10mg
- Price
- $252
- Updated
- 2021/12/16
- Product number
- CS-1540
- Product name
- Alvimopan(dihydrate)
- Purity
- 98.70%
- Packaging
- 50mg
- Price
- $480
- Updated
- 2021/12/16
2-[[(2S)-2-benzyl-3-[(3R,4R)-4-(3-hydroxyphenyl)-3,4-dimethyl-1-piperi dyl]propanoyl]amino]acetic acid dihydrate Chemical Properties,Usage,Production
Description
Alvimopan is a μ-opioid receptor antagonist approved in the U.S. in May 2008 for the treatment of post-operative ileus (POI) – a temporary dysfunction of the gastrointestines. Alvimopan does not penetrate the central nervous system (CNS) and acts as a peripheral antagonist. The molecule inhibits the negative effects of opioids on the gastrointestinal (GI) system without inhibiting the desired analgesic effects of CNS penetrant opioids.
Uses
Treatment of opioid-induced bowel dysfunction, opioidinduced nausea and vomiting, postoperative ileus, idiopathic constipation, and irritable bowel syndrome (peripherally restricted mu opioid receptor antagonist).
Synthesis
Several synthetic routes have been disclosed, and the process route is described in the scheme. This route was performed on kilogram scale and no yields were reported beyond the generation of compound 8. 3-Bromophenol 1 was treated with isopropyl bromide and potassium carbonate at 60-65 ??C for 16 h to give 3-isopropyoxy bromobenzene 2. Bromide 2 was added to a suspension of Mg turnings in THF at 40-60 ??C generating the corresponding Grignard reagent to which a solution of 1,3-dimethylpiperidone 3 in THF was added as four separate fractions over a period of 2 h. Upon completion, the reaction mixture was quenched with aqueous ammonium chloride, the product was extracted into heptane and crystallized out of solution and was isolated by filtration to provide a cis-(?à) enriched mixture of piperidone alcohol 4 in 97% purity. This mixture was recrystallized from heptane to afford exclusively the cis-(?à) piperidone 4 in 97% purity and 66% yield. Piperidone alcohol 4 was treated with ethylchloroformate and triethyl amine at 0??C and warmed to room temperature over 3 h. The resulting ethylcarbonate was resolved via classical resolution with (+)-di-p-toluyl-Dtartaric acid and then recrystallized from ethanol to give 5 in 99% purity and 99.5% ee. The conversion of 5 to 3,4-trans dimethyl piperidine 8 followed the sequence described by Werner, et. al. as no experimental was disclosed in the process patent for this sequence. The (+)-DTTA salt 5 was treated with sodium hydroxide to liberate the free base which then underwent thermal elimination of the carbonate at 190 ??C in decalin to give the desired trisubstituted olefin 6 in 92% yield. Treatment of piperidine 6 with n-BuLi followed by addition of dimethyl sulfate at -50 ??C gave the desired 3,4-trans-dimethyl enamine 7. Due to the reactivity of the dimethyl sulfate, only one equivalent was used and the reaction had to be quenched into aqueous ammonium hydroxide to avoid N-methylation. The crude enamine 7 was reduced with sodium borohydride and purified by crystallization with (+)-DTTA, giving (+)-DTTA salt 8 in 65% overall yield from 5. Additionally, the crystallization provided 8 with less than 1% impurities and 98.8% ee. The free base of 8 was liberated upon treatment with sodium hydroxide and reacted with phenyl chloroformate at 80-85 ??C, to effectively demethylate the nitrogen. The resulting crude phenylcarbamate 9 was refluxed in HBr/acetic acid for 18 h to simultaneously cleave the isopropyl ether and carbamate protecting groups to give the aminophenol 10, which was precipitated out of solution and collected by filtration. Amine 10 was then treated with methylacrylate (11) in THF at 40-45 ??C for 18-19 h to give the intermediate 12, which was transferred directly into a solution of LDA. A solution of benzyl bromide in THF was added to the enolate of 12 at -20 ??C and upon complete benzylation, 13 was isolated as its HCl salt. Ester 13 was hydrolyzed with sodium hydroxide to give 14, which was coupled to glycine ethyl ester hydrochloride 15 in the presence of DCC, HOBT and triethylamine in THF providing crude ethyl ester 16. Finally, ester 16 was hydrolyzed with sodium hydroxide to give alvimopan (I), which was purified by crystallization from the reaction mixture in 99.2% purity and 99% ee.
2-[[(2S)-2-benzyl-3-[(3R,4R)-4-(3-hydroxyphenyl)-3,4-dimethyl-1-piperi dyl]propanoyl]amino]acetic acid dihydrate Preparation Products And Raw materials
Raw materials
Preparation Products
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View Lastest Price from 2-[[(2S)-2-benzyl-3-[(3R,4R)-4-(3-hydroxyphenyl)-3,4-dimethyl-1-piperi dyl]propanoyl]amino]acetic acid dihydrate manufacturers
- Product
- 2-[[(2S)-2-benzyl-3-[(3R,4R)-4-(3-hydroxyphenyl)-3,4-dimethyl-1-piperi dyl]propanoyl]amino]acetic acid dihydrate 170098-38-1
- Price
- US $7.00/KG
- Min. Order
- 1KG
- Purity
- 99%
- Supply Ability
- 100KG
- Release date
- 2020-02-13