863513-91-1

Basic information

• Product Name: GRT6005
• Synonyms: GRT6005;GRT-6005;(1alpha,4beta)-6'-Fluoro-4',9'-dihydro-N,N-dimethyl-4-phenylspiro[cyclohexane-1,1'(3'H)-pyrano[3,4-b]indol]-4-amine;(1r,4r)-6'-Fluoro-N,N-dimethyl-4-phenyl-4',9'-dihydro-3'H-spiro[cyclohexane-1,1'-pyrano[3,4-b]indol]-4-amine;Cebranopadol(GRT-6005);Spiro[cyclohexane-1,1'(3'H)-pyrano[3,4-b]indol]-4-amine, 6'-fluoro-4',9'-dihydro-N,N-dimethyl-4-phenyl-, trans-;Cebranopadol;GRT 6005
• CAS NO: 863513-91-1
• Molecular Formula: C₂₄H₂₇FN₂O
• Molecular Weight: 378.4823832
• Mol File: 863513-91-1.mol
• Article Data: 9

Chemical Properties

• Boiling Point: 547.5±50.0 °C(Predicted)
• Appearance: /
• Density: 1.23±0.1 g/cm3(Predicted)
• Storage Temp.: Refrigerator
• Solubility: Chloroform (Slightly), DMSO (Slightly)
• PKA: 16.79±0.40(Predicted)
• CAS DataBase Reference: GRT6005(CAS DataBase Reference)
• NIST Chemistry Reference: GRT6005(863513-91-1)
• EPA Substance Registry System: GRT6005(863513-91-1)

Safety Data

• Hazardous Substances Data: 863513-91-1(Hazardous Substances Data)

Usage

Description

GRT6005 is a high-quality, pure glycerol product derived from renewable resources. It is a colorless, odorless, and viscous liquid with a sweet taste. Glycerol is a versatile and essential chemical compound with a wide range of applications across various industries due to its unique properties, such as its hygroscopic nature, solubility in water, and ability to act as a humectant, solvent, and emulsifier.

Uses

Used in the Pharmaceutical Industry:
GRT6005 is used as a pharmaceutical excipient for its humectant properties, which helps maintain the moisture content in medications and ensures their stability and effectiveness. It is also used as a solvent for various active pharmaceutical ingredients (APIs) and in the production of suppositories, elixirs, and liquid medications.
Used in the Food and Beverage Industry:
Glycerol is used as a humectant to retain moisture in food products, preventing them from drying out and extending their shelf life. It is also used as a sweetener and flavor enhancer in various food and beverage products, such as candies, baked goods, and soft drinks.
Used in the Cosmetics and Personal Care Industry:
Glycerol is used as a humectant in cosmetics and personal care products, such as lotions, creams, and shampoos, to help retain moisture and improve skin hydration. It also acts as an emulsifier, helping to blend oil and water-based ingredients, and as a solvent for various cosmetic ingredients.
Used in the Agriculture Industry:
Glycerol is used in the agriculture industry as a foliar spray to improve plant growth and health. It helps in the absorption of nutrients and water, leading to increased crop yields and better resistance to environmental stress.
Used in the Chemical Industry:
GRT6005 is used as a raw material in the production of various chemicals, such as nitroglycerin, which is used in the manufacture of explosives, and as a building block in the synthesis of other complex organic compounds.
Used in the Energy Industry:
Glycerol can be used as a feedstock for the production of biofuels, such as biodiesel and bioethanol, contributing to the development of sustainable and renewable energy sources.
Used in the Textile Industry:
Glycerol is used in the textile industry as a humectant and lubricant in the manufacturing process, improving the softness, flexibility, and durability of fabrics.
Used in the Paper and Pulp Industry:
Glycerol is used in the paper and pulp industry as a plasticizer to improve the flexibility and strength of paper products, as well as a retention aid to enhance the retention of fillers and fibers during the papermaking process.
Used in the Automotive Industry:
Glycerol is used in the automotive industry as a component in antifreeze and coolant formulations, helping to prevent freezing and corrosion in engine cooling systems.
Used in the Fine Chemicals Industry:
GRT6005 is used as a starting material or intermediate in the synthesis of various fine chemicals, such as tritium-labeled probes for autoradiography studies, which are used in research and diagnostic applications.

Synthetic route

4-dimethylamino-4-phenylcyclohexanone (65619-20-7) + 2-(5-fluoro-1H-indol-3-yl)ethanol (101349-12-6) → (1r,4r)-6'-fluoro-N,N-dimethyl-4-phenyl-4',9'-dihydro-3'H-spiro[cyclohexane-1,1'-pyrano[3,4-b]indole]-4-amine (863513-91-1)

Conditions	Yield
With trimethylsilyl trifluoromethanesulfonate In dichloromethane at 22 - 40℃; for 65h; Inert atmosphere;	91%
Stage #1: 4-dimethylamino-4-phenylcyclohexanone; 2-(5-fluoro-1H-indol-3-yl)ethanol With trimethylsilyl trifluoromethanesulfonate In dichloromethane at 20 - 45℃; for 65h; Inert atmosphere; Stage #2: With sodium hydroxide In dichloromethane; water at 21 - 22℃;	91%
With sulfuric acid In acetic acid at 45 - 60℃;	60%

cyclohexanedione monoethylene ketal (4746-97-8) → (1r,4r)-6'-fluoro-N,N-dimethyl-4-phenyl-4',9'-dihydro-3'H-spiro[cyclohexane-1,1'-pyrano[3,4-b]indole]-4-amine (863513-91-1)

Conditions	Yield
Multi-step reaction with 4 steps 1.1: hydrogenchloride / water; methanol / 0 - 20 °C 2.1: tetrahydrofuran / 0 - 20 °C 2.2: 0 - 20 °C 3.1: water; hydrogenchloride / diethyl ether 4.1: trimethylsilyl trifluoromethanesulfonate / dichloromethane / 20 h / 20 °C / Inert atmosphere View Scheme

8-(dimethylamino)-1,4-dioxaspiro-[4.5]-decane-8-carbonitrile (65619-92-3) → (1r,4r)-6'-fluoro-N,N-dimethyl-4-phenyl-4',9'-dihydro-3'H-spiro[cyclohexane-1,1'-pyrano[3,4-b]indole]-4-amine (863513-91-1)

Conditions	Yield
Multi-step reaction with 3 steps 1.1: tetrahydrofuran / 0 - 20 °C 1.2: 0 - 20 °C 2.1: water; hydrogenchloride / diethyl ether 3.1: trimethylsilyl trifluoromethanesulfonate / dichloromethane / 20 h / 20 °C / Inert atmosphere View Scheme

4-dimethylamino-4-phenylcyclohexanone, ethylene ketal hydrochloride (65619-19-4) → (1r,4r)-6'-fluoro-N,N-dimethyl-4-phenyl-4',9'-dihydro-3'H-spiro[cyclohexane-1,1'-pyrano[3,4-b]indole]-4-amine (863513-91-1)

Conditions	Yield
Multi-step reaction with 2 steps 1: water; hydrogenchloride / diethyl ether 2: trimethylsilyl trifluoromethanesulfonate / dichloromethane / 20 h / 20 °C / Inert atmosphere View Scheme

formaldehyd (50-00-0) + C22H23FN2O → (1r,4r)-6'-fluoro-N,N-dimethyl-4-phenyl-4',9'-dihydro-3'H-spiro[cyclohexane-1,1'-pyrano[3,4-b]indole]-4-amine (863513-91-1)

Conditions	Yield
With formic acid In water at 70℃; for 16h; Eschweiler-Clark Amine Methylation;	280 mg

(1r,4r)-6'-fluoro-N,N-dimethyl-4-phenyl-4',9'-dihydro-3'H-spiro[cyclohexane-1,1'-pyrano[3,4-b]indole]-4-amine (863513-91-1) → (1r,4r)-6'-fluoro-N,N-dimethyl-4-phenyl-4',9'-dihydro-3'H-spiro[cyclohexane-1,1'-pyrano[3,4-b]indole]-4-amine hydrochloride (1443039-98-2)

Conditions	Yield
With hydrogenchloride In tetrahydrofuran; water; acetone at 20℃; for 120h; Concentration; Solvent; Time;
With hydrogenchloride In tetrahydrofuran; water; acetone at 20℃; for 24h;

(1r,4r)-6'-fluoro-N,N-dimethyl-4-phenyl-4',9'-dihydro-3'H-spiro[cyclohexane-1,1'-pyrano[3,4-b]indole]-4-amine (863513-91-1) → (1r,4r)-6'-fluoro-N,N-dimethyl-4-phenyl-4',9'-dihydro-3'H-spiro[cyclohexane-1,1'-pyrano[3,4-b]indole]-4-amine sulfate (1443050-72-3)

Conditions	Yield
With sulfuric acid In tetrahydrofuran; water; acetone at 20℃; for 24h; Solvent; Time; Temperature; Reagent/catalyst;

(1r,4r)-6'-fluoro-N,N-dimethyl-4-phenyl-4',9'-dihydro-3'H-spiro[cyclohexane-1,1'-pyrano[3,4-b]indole]-4-amine (863513-91-1) + citric acid (77-92-9) → trans-6'-fluoro-4',9'-dihydro-N,N-dimethyl-4-phenyl-spiro[cyclohexane-1,1'(3'H)-pyrano[3,4-b]indol]-4-amine hemicitrate

Conditions	Yield
In ethanol at 5℃; Heating;	640 mg

Upstream product

• 50-00-0 formaldehyd 
• 65619-20-7 4-dimethylamino-4-phenylcyclohexanone 
• 101349-12-6 2-(5-fluoro-1H-indol-3-yl)ethanol 
• 65619-19-4 4-dimethylamino-4-phenylcyclohexanone, ethylene ketal hydrochloride 
• 65619-92-3 8-(dimethylamino)-1,4-dioxaspiro-[4.5]-decane-8-carbonitrile 
• 4746-97-8 cyclohexanedione monoethylene ketal 

Downstream Products

• 863513-92-2 trans-6'-fluoro-4',9'-dihydro-N,N-dimethyl-4-phenyl-spiro[cyclohexane-1,1'(3'H)-pyrano[3,4-b]indol]-4-amine hemicitrate 
• 1443050-72-3 (1r,4r)-6'-fluoro-N,N-dimethyl-4-phenyl-4',9'-dihydro-3'H-spiro[cyclohexane-1,1'-pyrano[3,4-b]indole]-4-amine sulfate 
• 1443039-98-2 (1r,4r)-6'-fluoro-N,N-dimethyl-4-phenyl-4',9'-dihydro-3'H-spiro[cyclohexane-1,1'-pyrano[3,4-b]indole]-4-amine hydrochloride 

Relevant articles and documents

Improved and Flexible Synthetic Access to the Spiroindole Backbone of Cebranopadol

By changing the dimethylamino to a nitro group, a novel synthetic access to the spirocyclic opioid analgesic cebranopadol was developed that is much more efficient compared with the established route. On the basis of the α-acidity of α-nitrotoluene, the two-fold Michael addition to acrylate gave an acyclic precursor compound, which was easily transformed by Dieckmann condensation and decarboxylation to the cyclohexanone derivative needed for the annulation of the indole ring by an oxa-Pictet-Spengler reaction. As an additional benefit, the reduction of the nitro group furnished an amine, which could be late-stage-diversified to carboxamides, sulfonamides, ureas, and N-alkyl congeners. The transformation of the nitro group at the spirocyclic scaffold to the dimethylamino function of the actual title compound was achieved in one step with zinc/formic acid/formaldehyde in 83% yield.

CRYSTALLINE (1R,4R)-6'-FLUORO-N,N-DIMETHYL-4-PHENYL-4',9'-DIHYDRO-3'H-SPIRO[CYCLOHEXANE-1,1'-PYRANO[3,4,B]INDOL]-4-AMINE

Crystalline forms of (1r,4r)-6′-fluoro-N,N-dimethyl-4-phenyl-4′,9′-dihydro-3′H-spiro[cyclohexane-1,1′-pyrano[3,4,b]indol]-4-amine, pharmaceutical compositions and medicaments comprising these crystalline modifications, the use of these modifications as well as a process for the enrichment of such crystalline modifications.

Process for the preparation of (1r,4r)-6'-fluoro-(N,N-dimethyl- and N-methyl)-4-phenyl-4',9'-dihydro-3'H-spiro[cyclohexane-1,1'-pyrano-[3,4,b]indol]-4-amine

A process for the preparation of (1r,4r)-6′-fluoro-N,N-dimethyl-4-phenyl-4′,9′-dihydro-3′H-spiro[cyclohexane-1,1′-pyrano[3,4b]indol]-4-amine and (1r,4r)-6′-fluoro-N-methyl-4-phenyl-4′,9′-dihydro-3′H-spiro[cyclohexane-1,1′-pyrano[3,4b]-indol]-4-amine or physiologically acceptable acid addition salts thereof.