249921-19-5

Basic information

• Product Name: Anamorelin
• Synonyms: anamorelin;(3R)-1-(2-Methylalanyl-D-tryptophyl)-3-(phenylmethyl)-3-piperidinecarboxylic acid 1,2,2-trimethylhydrazide;3-Piperidinecarboxylic acid, 1-(2-methylalanyl-D-tryptophyl)-3-(phenylmethyl)-, trimethylhydrazide, (3R)-;Rc 1291;Unii-dd5rba1nkf;ONO-7643;Anamorelin (RC-1291);(R)-1-((S)-2-((1H-indol-3-yl)methyl)-5-amino-5-methyl-4-oxohexanoyl)-3-benzyl-N,N',N'-trimethylpiperidine-3-carbohydrazide
• CAS NO: 249921-19-5
• Molecular Formula: C₃₁H₄₂N₆O₃
• Molecular Weight: 546.7
• Mol File: 249921-19-5.mol
• Article Data: 2

Chemical Properties

• Appearance: /
• Density: 1.214
• Storage Temp.: Refrigerator
• Solubility: DMSO (Slightly), Methanol (Slightly)
• PKA: 16.22±0.46(Predicted)
• CAS DataBase Reference: Anamorelin(CAS DataBase Reference)
• NIST Chemistry Reference: Anamorelin(249921-19-5)
• EPA Substance Registry System: Anamorelin(249921-19-5)

Safety Data

• Hazardous Substances Data: 249921-19-5(Hazardous Substances Data)

Usage

Uses

Anamorelin functions as a novel therapeutic options for cachexia and sarcopenia. Cancer cachexia and clinical therapeutic interventions.

Synthetic route

(R,R)-{1-[2-[3-benzyl-3-(N,N',N'-trimethyl-hydrazinocarbonyl)piperidin-1-yl]-1-(1H-indol-3-ylmethyl)-2-oxo-ethylcarbamoyl]-1-methylethyl}carbamic acid tert-butyl ester (339539-90-1) → Anamorelin (249921-19-5)

Conditions	Yield
Stage #1: (R,R)-{1-[2-[3-benzyl-3-(N,N',N'-trimethyl-hydrazinocarbonyl)piperidin-1-yl]-1-(1H-indol-3-ylmethyl)-2-oxo-ethylcarbamoyl]-1-methylethyl}carbamic acid tert-butyl ester With methanol; methanesulfonic acid at 50 - 70℃; for 0.75h; Stage #2: With potassium hydroxide In methanol; water at 22 - 70℃; for 43h; Stage #3: In water at 50℃; for 41h; Product distribution / selectivity;	81%
With hydrogenchloride In ethyl acetate
Stage #1: (R,R)-{1-[2-[3-benzyl-3-(N,N',N'-trimethyl-hydrazinocarbonyl)piperidin-1-yl]-1-(1H-indol-3-ylmethyl)-2-oxo-ethylcarbamoyl]-1-methylethyl}carbamic acid tert-butyl ester With methanesulfonic acid In methanol at 55 - 60℃; for 1h; Inert atmosphere; Stage #2: With potassium hydroxide In methanol; water at 20 - 70℃; Inert atmosphere;	595 g

Boc-D-Trp-OH (5241-64-5) → Anamorelin (249921-19-5)

Conditions

Yield

Multi-step reaction with 4 steps 1: 1-hydroxy-7-aza-benzotriazole; 4-methyl-morpholine; N,N-dimethyl acetamide; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride 2: hydrogenchloride / ethyl acetate 3: 1-hydroxy-7-aza-benzotriazole; 4-methyl-morpholine; N,N-dimethyl acetamide; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride 4: hydrogenchloride / ethyl acetate View Scheme

C16H25N3O*2ClH → Anamorelin (249921-19-5)

Conditions

Yield

Multi-step reaction with 4 steps 1: 1-hydroxy-7-aza-benzotriazole; 4-methyl-morpholine; N,N-dimethyl acetamide; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride 2: hydrogenchloride / ethyl acetate 3: 1-hydroxy-7-aza-benzotriazole; 4-methyl-morpholine; N,N-dimethyl acetamide; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride 4: hydrogenchloride / ethyl acetate View Scheme

D-tryptophan (153-94-6) → Anamorelin (249921-19-5)

Conditions	Yield
Multi-step reaction with 3 steps 1.1: 38 °C 2.1: 3-hydroxy-3,4-dihydrobenzotriazine-4-one; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride / dichloromethane / 20 °C 2.2: 20 °C 3.1: hydrogenchloride / ethyl acetate View Scheme
Multi-step reaction with 3 steps 1: 38 °C 2: triethylamine; 3-hydroxy-3,4-dihydrobenzotriazine-4-one; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride / dichloromethane / 20 h / 25 °C / Inert atmosphere 3: hydrogenchloride / ethyl acetate View Scheme

C32H43N5O4 → Anamorelin (249921-19-5)

Conditions	Yield
Multi-step reaction with 3 steps 1: hydrogenchloride / ethyl acetate 2: 1-hydroxy-7-aza-benzotriazole; 4-methyl-morpholine; N,N-dimethyl acetamide; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride 3: hydrogenchloride / ethyl acetate View Scheme

(R)-2-(2-tert-Butoxycarbonylamino-2-methyl-propionylamino)-3-(1H-indol-3-yl)-propionic acid methyl ester → Anamorelin (249921-19-5)

Conditions	Yield
Multi-step reaction with 3 steps 1.1: sodium hydroxide / water; tert-butyl methyl ether / 20 °C / Large scale 2.1: 3-hydroxy-3,4-dihydrobenzotriazine-4-one; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride / dichloromethane / 20 °C 2.2: 20 °C 3.1: hydrogenchloride / ethyl acetate View Scheme
Multi-step reaction with 3 steps 1: sodium hydroxide / water; tert-butyl methyl ether / 20 °C / Large scale 2: triethylamine; 3-hydroxy-3,4-dihydrobenzotriazine-4-one; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride / dichloromethane / 20 h / 25 °C / Inert atmosphere 3: hydrogenchloride / ethyl acetate View Scheme

(R)-2-(2-tert-Butoxycarbonylamino-2-methyl-propionylamino)-3-(1H-indol-3-yl)-propionic acid (159634-94-3) → Anamorelin (249921-19-5)

Conditions	Yield
Multi-step reaction with 2 steps 1.1: 3-hydroxy-3,4-dihydrobenzotriazine-4-one; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride / dichloromethane / 20 °C 1.2: 20 °C 2.1: hydrogenchloride / ethyl acetate View Scheme
Multi-step reaction with 2 steps 1: triethylamine; 3-hydroxy-3,4-dihydrobenzotriazine-4-one; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride / dichloromethane / 20 h / 25 °C / Inert atmosphere 2: hydrogenchloride / ethyl acetate View Scheme

(R)-(+)-tryptophan methyl ester hydrochloride (14907-27-8, 5619-09-0, 7524-52-9, 26988-71-6, 41222-70-2, 67557-19-1, 109492-62-8) → Anamorelin (249921-19-5)

Conditions	Yield
Multi-step reaction with 4 steps 1.1: triethylamine; 3-hydroxy-3,4-dihydrobenzotriazine-4-one; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride / dichloromethane / 3 h / 38 °C / Inert atmosphere; Large scale 2.1: sodium hydroxide / water; tert-butyl methyl ether / 20 °C / Large scale 3.1: 3-hydroxy-3,4-dihydrobenzotriazine-4-one; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride / dichloromethane / 20 °C 3.2: 20 °C 4.1: hydrogenchloride / ethyl acetate View Scheme
Multi-step reaction with 4 steps 1: triethylamine; 3-hydroxy-3,4-dihydrobenzotriazine-4-one; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride / dichloromethane / 3 h / 38 °C / Inert atmosphere; Large scale 2: sodium hydroxide / water; tert-butyl methyl ether / 20 °C / Large scale 3: triethylamine; 3-hydroxy-3,4-dihydrobenzotriazine-4-one; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride / dichloromethane / 20 h / 25 °C / Inert atmosphere 4: hydrogenchloride / ethyl acetate View Scheme

Anamorelin (249921-19-5) → Anamorelin hydrochloride

Conditions	Yield
With hydrogenchloride In Isopropyl acetate; water Concentration; Temperature; Solvent;

Anamorelin (249921-19-5) + (2E)-but-2-enedioic acid (110-17-8) → RC-1291 fumarate

Conditions	Yield
Stage #1: Anamorelin With sodium carbonate In dichloromethane Stage #2: (2E)-but-2-enedioic acid In ethyl acetate; isopropyl alcohol

Upstream product

• 14907-27-8 (R)-(+)-tryptophan methyl ester hydrochloride 
• 159634-94-3 (R)-2-(2-tert-Butoxycarbonylamino-2-methyl-propionylamino)-3-(1H-indol-3-yl)-propionic acid 
• 153-94-6 D-tryptophan 
• 883572-50-7 C₁₆H₂₅N₃O*2ClH 
• 5241-64-5 Boc-D-Trp-OH 
• 339539-90-1 (R,R)-{1-[2-[3-benzyl-3-(N,N',N'-trimethyl-hydrazinocarbonyl)piperidin-1-yl]-1-(1H-indol-3-ylmethyl)-2-oxo-ethylcarbamoyl]-1-methylethyl}carbamic acid tert-butyl ester 

Downstream Products

• 339539-92-3 RC-1291 fumarate 
• 861998-00-7 Anamorelin hydrochloride 

Relevant articles and documents

A practical synthesis of the pseudotripeptide RC-1291

The rapid process development of a scaleable synthesis of the pseudotripeptide RC-1291 for preclinical and clinical evaluation is described. By employing a nontraditional N-to-C coupling strategy, the peptide chain of RC-1291 was assembled in high yield, with minimal racemization and in an economical manner by introducing the most expensive component last. A one-pot deprotection/crystallization procedure was developed for the isolation of RC-1291 free base, which afforded the target compound in excellent yield and with a purity of >99.5% without chromatographic purification.