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

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

Used in Pharmaceutical Industry:
Anamorelin is used as a therapeutic agent for the treatment of cachexia and sarcopenia, particularly in patients with cancer. It helps to improve muscle mass, strength, and overall quality of life in these patients by stimulating the release of growth hormone.
Used in Cancer Cachexia Treatment:
Anamorelin is used as a treatment option for cancer cachexia, a severe wasting syndrome that affects many cancer patients. It helps to counteract the muscle wasting and weight loss associated with this condition, improving the patient's physical function and overall well-being.
Used in Clinical Therapeutic Interventions:
Anamorelin is also used in various clinical therapeutic interventions aimed at addressing the muscle wasting and cachexia associated with chronic diseases, including cancer. Its role in these interventions is to support the patient's body in maintaining muscle mass and strength, which can be crucial for their recovery and ability to withstand various treatments.

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.

CRYSTAL FORMS OF (3R)-1-(2-METHYLALANYL-D-TRYPTOPHYL)-3-(PHENYLMETHYL)-3-PIPERIDINECARBOXYLIC ACID 1,2,2-TRIMETHYLHYDRAZIDE

Crystalline polymorphs of (3 R)-1-(2-methylalanyl-D-tryptophyl)-3- (phenylmethyl)-3-piperidinecarboxylic acid 1,2,2-trimethylhydrazide which are useful as pharmaceutical agents are disclosed. Methods of production and isolation of these polymorphs and pharmaceutical compositions which include these polymorphs and pharmaceutical methods of treatment are also disclosed. The crystalline polymorphs of the present invention are useful as they act directly on the pituitary gland cells to release growth hormone.