119302-20-4

Basic information

• Product Name: (2b,3a,5a,16b,17b)-2-(4-Morpholinyl)-16-(1-pyrrolidinyl)androstane-3,17-diol
• Synonyms: Androstane-3,17-diol, 2-(4-morpholinyl)-16-(1-pyrrolidinyl);(2b,3a,5a,16b,17b)-2-(4-morpholinyl)-16-(1-pyrrolidinyl)androstane-3,17-diol(9CI);2-(4-MORPHOLINYL)-16-(1-PYRROLIDINYL)-5-ANDROSTANE-3,17-DIOL;3,17-DIHYDROXY-2-(4-MORPHOLINYL)-16-(1-PYRROLINYL)-ANDROSTANE;3,17-dihydroxy-2-(4-morpholinyl)-16-(1-pyrroliny)-androstane;2,3-Epoxy-1H-cyclopenta[a]phenanthrene,anddrostan-17-ol deriv;（2β，3ɑ，5ɑ，16ɑ，17β）-2-（4-morpholinyl）-16-（1-pyrrolidinyl）-androstane-3，17-diol;(2b,3a,5a,16b,17b)-2-(4-Morpholinyl)-16-(1-pyrrolidinyl)androstane-3,17-diol
• CAS NO: 119302-20-4
• Molecular Formula: C₂₇H₄₆N₂O₃
• Molecular Weight: 446.67
• EINECS: 1312995-182-4
• Product Categories: INTERMEDIATESOFROCURONIUMBROMIDE
• Mol File: 119302-20-4.mol
• Article Data: 5

Chemical Properties

• Boiling Point: 565.4 °C at 760 mmHg
• Flash Point: 295.7 °C
• Appearance: Whitish or yellowish crystalline powder
• Density: 1.163
• Vapor Pressure: 3.88E-15mmHg at 25°C
• Refractive Index: 1.574
• Storage Temp.: 2-8°C
• Solubility: Chloroform (Slightly), DMSO (Slightly, Heated), Methanol (Slightly, Heated)
• PKA: 14.69±0.70(Predicted)
• CAS DataBase Reference: (2b,3a,5a,16b,17b)-2-(4-Morpholinyl)-16-(1-pyrrolidinyl)androstane-3,17-diol(CAS DataBase Reference)
• NIST Chemistry Reference: (2b,3a,5a,16b,17b)-2-(4-Morpholinyl)-16-(1-pyrrolidinyl)androstane-3,17-diol(119302-20-4)
• EPA Substance Registry System: (2b,3a,5a,16b,17b)-2-(4-Morpholinyl)-16-(1-pyrrolidinyl)androstane-3,17-diol(119302-20-4)

Safety Data

• Hazardous Substances Data: 119302-20-4(Hazardous Substances Data)

Usage

Chemical Properties

White Solid

Uses

Different sources of media describe the Uses of 119302-20-4 differently. You can refer to the following data:
1. (2β,3α,5α,16β,17β)-2-(4-Morpholinyl)-16-(1-pyrrolidinyl)androstane-3,17-diol is used in the synthesis of the neuromuscular blocking agent rocuronium bromide.
2. This compound is used in the synthesis of the neuromuscular blocking agent rocuronium bromide.

InChI:InChI=1/C27H46N2O3/c1-26-8-7-20-19(21(26)16-22(25(26)31)28-9-3-4-10-28)6-5-18-15-24(30)23(17-27(18,20)2)29-11-13-32-14-12-29/h18-25,30-31H,3-17H2,1-2H3/t18-,19+,20-,21-,22-,23-,24-,25-,26-,27-/m0/s1

Synthetic route

3α-hydroxy-2β-(4-morpholinyl)-16β-(1-pyrrolidinyl)-5α-androstan-17-one → (2β,3α,5α,16β,17β)-2-(4-morpholinyl)-16-(1-pyrrolidinyl)androstane-3,17-diol (119302-20-4)

Conditions	Yield
With sodium tetrahydroborate In methanol at -3℃; for 2h;	92.7%

morpholine (110-91-8) + (2α,3α,5α,16β,17β)-2,3-epoxy-16-(1-pyrrolidinyl)-androstan-17-ol (119302-19-1) → (2β,3α,5α,16β,17β)-2-(4-morpholinyl)-16-(1-pyrrolidinyl)androstane-3,17-diol (119302-20-4)

Conditions	Yield
toluene-4-sulfonic acid In water at 20 - 110℃; for 40h; Product distribution / selectivity; Heating / reflux;	89.7%
methanesulfonic acid In water at 20 - 110℃; for 40h; Product distribution / selectivity; Heating / reflux;
In water for 72h; Product distribution / selectivity; Heating / reflux;

rocuronium bromide → (2β,3α,5α,16β,17β)-17-acetoxy-3-hydroxy-2-(4-morpholinyl)-16-(1-pyrrolidinyl)androstane (119302-24-8) + (2β,3α,5α,16β,17β)-2-(4-morpholinyl)-16-(1-pyrrolidinyl)androstane-3,17-diol (119302-20-4)

Conditions	Yield
In N,N-dimethyl-formamide for 5h; Product distribution / selectivity; Heating / reflux;	A 67.5% B n/a

pyrrolidine (123-75-1) + 2β-(4-morpholinyl)-3α-ol-16β-bromo-17-one-5α-androstane → (2β,3α,5α,16β,17β)-2-(4-morpholinyl)-16-(1-pyrrolidinyl)androstane-3,17-diol (119302-20-4)

Conditions	Yield
In acetonitrile Reflux;	62.1%

rocuronium bromide → (2β,3α,5α,16β,17β)-17-acetoxy-3-hydroxy-2-(4-morpholinyl)-16-(1-pyrrolidinyl)androstane (119302-24-8) + (2β,3α,5α,16β,17β)-2-(4-morpholinyl)-16-(1-pyrrolidinyl)androstane-3,17-diol (119302-20-4) + 1-[(2β, 3α, 5α, 16β, 17β)-2-(4-morpholinyl)-androstan-16-yl-]-1-(2-propenyl)-pyrrolidinium bromide-3,17-diol (119302-86-2)

Conditions	Yield
In dimethyl acetamide (DMA) for 3h; Product distribution / selectivity; Heating / reflux;
sodium thiophenolate In isopropyl alcohol for 4h; Product distribution / selectivity; Heating / reflux;
In N,N-dimethyl-formamide for 5h; Product distribution / selectivity; Heating / reflux;

(2α,3α,5α,16β,17β)2,3-epoxy-16-(1-pyrrolidinyl)-androstan-17-ol → (2β,3α,5α,16β,17β)-2-(4-morpholinyl)-16-(1-pyrrolidinyl)androstane-3,17-diol (119302-20-4)

Conditions	Yield
In morpholine; water

morpholine (110-91-8) + (2α,3α,5α,16β,17β)-2,3-epoxy-16-(1-pyrrolidinyl)-androstan-17-ol (119302-19-1) → (2β,3α,5α,16β,17β)-2-(4-morpholinyl)-16-(1-pyrrolidinyl)androstane-3,17-diol (119302-20-4) + (2β,3α,5α,16α,17β)-2-(4-morpholinyl)-16-(1-pyrrolidinyl)-androstane-3,17-diol + 2α,3α-epoxy-16α-(pyrrolidin-1-yl)-17β-hydroxy-5α-androstan (930092-98-1) + C27H46N2O2 (144209-33-6)

Conditions	Yield
zinc diacetate In water at 20 - 110℃; for 40h; Product distribution / selectivity; Heating / reflux;

morpholine (110-91-8) + (2α,3α,5α,16β,17β)-2,3-epoxy-16-(1-pyrrolidinyl)-androstan-17-ol (119302-19-1) → (2β,3α,5α,16β,17β)-2-(4-morpholinyl)-16-(1-pyrrolidinyl)androstane-3,17-diol (119302-20-4) + 2α,3α-epoxy-16α-(pyrrolidin-1-yl)-17β-hydroxy-5α-androstan (930092-98-1) + C23H39NO3 + C27H46N2O2 (144209-33-6)

Conditions	Yield
In water at 20 - 110℃; for 40h; Product distribution / selectivity; Heating / reflux;

morpholine (110-91-8) + (2α,3α,5α,16β,17β)-2,3-epoxy-16-(1-pyrrolidinyl)-androstan-17-ol (119302-19-1) → (2β,3α,5α,16β,17β)-2-(4-morpholinyl)-16-(1-pyrrolidinyl)androstane-3,17-diol (119302-20-4) + 2α,3α-epoxy-16α-(pyrrolidin-1-yl)-17β-hydroxy-5α-androstan (930092-98-1) + C23H39NO3

Conditions	Yield
hydrogenchloride In water at 20 - 110℃; for 40h; Product distribution / selectivity; Heating / reflux;
toluene-4-sulfonic acid In water at 20 - 110℃; for 40h; Product distribution / selectivity; Heating / reflux;

morpholine (110-91-8) + (2α,3α,5α,16β,17β)-2,3-epoxy-16-(1-pyrrolidinyl)-androstan-17-ol (119302-19-1) → (2β,3α,5α,16β,17β)-2-(4-morpholinyl)-16-(1-pyrrolidinyl)androstane-3,17-diol (119302-20-4) + C27H46N2O2 (144209-33-6)

Conditions	Yield
sulfuric acid In water at 20 - 110℃; for 40h; Product distribution / selectivity; Heating / reflux;

morpholine (110-91-8) + (2α,3α,5α,16β,17β)-2,3-epoxy-16-(1-pyrrolidinyl)-androstan-17-ol (119302-19-1) → (2β,3α,5α,16β,17β)-2-(4-morpholinyl)-16-(1-pyrrolidinyl)androstane-3,17-diol (119302-20-4) + C23H39NO3 + C27H46N2O2 (144209-33-6)

Conditions	Yield
iron(III) chloride In water at 20 - 110℃; for 40h; Product distribution / selectivity; Heating / reflux;

5α-androst-2-en-17-one (14639-79-3, 24174-20-7, 82467-84-3, 963-75-7) → (2β,3α,5α,16β,17β)-2-(4-morpholinyl)-16-(1-pyrrolidinyl)androstane-3,17-diol (119302-20-4)

Conditions	Yield
Multi-step reaction with 5 steps 1.1: dihydrogen peroxide; formic acid / dichloromethane / 5 h / 20 °C 2.1: iron(III) chloride / water / 0.5 h / 20 °C 2.2: 24 h / 130 °C 3.1: copper(ll) bromide / methanol / 30 h / 70 °C / Inert atmosphere 4.1: acetonitrile / 8 h / Inert atmosphere; Reflux 5.1: sodium tetrahydroborate / methanol / 2 h / -3 °C View Scheme
Multi-step reaction with 4 steps 1: 3-chloro-benzenecarboperoxoic acid / chloroform / 0 - 5 °C 2: iron(III) chloride / water / Reflux 3: copper(ll) bromide / methanol / Reflux 4: acetonitrile / Reflux View Scheme

2α,3α-epoxy-5α-androstan-17-one (965-67-3, 7676-05-3, 13094-19-4) → (2β,3α,5α,16β,17β)-2-(4-morpholinyl)-16-(1-pyrrolidinyl)androstane-3,17-diol (119302-20-4)

Conditions	Yield
Multi-step reaction with 4 steps 1.1: iron(III) chloride / water / 0.5 h / 20 °C 1.2: 24 h / 130 °C 2.1: copper(ll) bromide / methanol / 30 h / 70 °C / Inert atmosphere 3.1: acetonitrile / 8 h / Inert atmosphere; Reflux 4.1: sodium tetrahydroborate / methanol / 2 h / -3 °C View Scheme
Multi-step reaction with 3 steps 1: iron(III) chloride / water / Reflux 2: copper(ll) bromide / methanol / Reflux 3: acetonitrile / Reflux View Scheme

3α-hydroxy-2β-(4-morpholinyl)-5α(H)-androstan-17-one (52-72-2) → (2β,3α,5α,16β,17β)-2-(4-morpholinyl)-16-(1-pyrrolidinyl)androstane-3,17-diol (119302-20-4)

Conditions	Yield
Multi-step reaction with 3 steps 1: copper(ll) bromide / methanol / 30 h / 70 °C / Inert atmosphere 2: acetonitrile / 8 h / Inert atmosphere; Reflux 3: sodium tetrahydroborate / methanol / 2 h / -3 °C View Scheme
Multi-step reaction with 2 steps 1: copper(ll) bromide / methanol / Reflux 2: acetonitrile / Reflux View Scheme

3α-hydroxy-2β-(4-morpholinyl)-16α-bromo-5α-androstan-17-one → (2β,3α,5α,16β,17β)-2-(4-morpholinyl)-16-(1-pyrrolidinyl)androstane-3,17-diol (119302-20-4)

Conditions	Yield
Multi-step reaction with 2 steps 1: acetonitrile / 8 h / Inert atmosphere; Reflux 2: sodium tetrahydroborate / methanol / 2 h / -3 °C View Scheme

(2β,3α,5α,16β,17β)-2-(4-morpholinyl)-16-(1-pyrrolidinyl)androstane-3,17-diol (119302-20-4) + 4-nitrophenol acetate (830-03-5) → (2β,3α,5α,16β,17β)-17-acetoxy-3-hydroxy-2-(4-morpholinyl)-16-(1-pyrrolidinyl)androstane (119302-24-8)

Conditions	Yield
With triethylamine In 1,2-dichloro-ethane at 80 - 85℃; regioselective reaction;	94.1%

N-Acetylimidazole (2466-76-4) + (2β,3α,5α,16β,17β)-2-(4-morpholinyl)-16-(1-pyrrolidinyl)androstane-3,17-diol (119302-20-4) → (2β,3α,5α,16β,17β)-17-acetoxy-3-hydroxy-2-(4-morpholinyl)-16-(1-pyrrolidinyl)androstane (119302-24-8)

Conditions	Yield
In dichloromethane at 25℃; for 48h; Product distribution / selectivity;	92%

(2β,3α,5α,16β,17β)-2-(4-morpholinyl)-16-(1-pyrrolidinyl)androstane-3,17-diol (119302-20-4) + acetic acid (64-19-7) → (2β,3α,5α,16β,17β)-17-acetoxy-3-hydroxy-2-(4-morpholinyl)-16-(1-pyrrolidinyl)androstane (119302-24-8)

Conditions	Yield
With N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline In acetonitrile for 4.5h; Solvent; Reagent/catalyst; Reflux;	91.4%

(2β,3α,5α,16β,17β)-2-(4-morpholinyl)-16-(1-pyrrolidinyl)androstane-3,17-diol (119302-20-4) + acetyl chloride (75-36-5) → (2β,3α,5α,16β,17β)-17-acetoxy-3-hydroxy-2-(4-morpholinyl)-16-(1-pyrrolidinyl)androstane (119302-24-8)

Conditions	Yield
In dichloromethane at 20 - 25℃;	89.7%
In dichloromethane at 35℃; for 4h;
Stage #1: (2β,3α,5α,16β,17β)-2-(4-morpholinyl)-16-(1-pyrrolidinyl)androstane-3,17-diol; acetyl chloride In dichloromethane at 20℃; for 18h; Stage #2: With sodium carbonate In dichloromethane; water Product distribution / selectivity;

(2β,3α,5α,16β,17β)-2-(4-morpholinyl)-16-(1-pyrrolidinyl)androstane-3,17-diol (119302-20-4) + acetic anhydride (108-24-7) → (2β,3α,5α,16β,17β)-17-acetoxy-3-hydroxy-2-(4-morpholinyl)-16-(1-pyrrolidinyl)androstane (119302-24-8) + (2β,3α,5α,16β,17β)-2-(4-morpholinyl)-16-(1-pyrrolidinyl)-3,17-bis(acetyloxyoxy)androstane (119302-22-6)

Conditions	Yield
With triethylamine In dichloromethane at 20 - 22℃; for 22h; Product distribution / selectivity;	A 68.8% B n/a
In acetonitrile for 1h; Product distribution / selectivity; Heating / reflux;	A 53.4 - 96.1 %Chromat. B 0.2 - 39.5 %Chromat.
With pyridine In dichloromethane at 20 - 22℃; for 22h; Product distribution / selectivity;

(2β,3α,5α,16β,17β)-2-(4-morpholinyl)-16-(1-pyrrolidinyl)androstane-3,17-diol (119302-20-4) + acetyl chloride (75-36-5) → (2β,3α,5α,16β,17β)-17-acetoxy-3-hydroxy-2-(4-morpholinyl)-16-(1-pyrrolidinyl)androstane (119302-24-8) + (2β,3α,5α,16β,17β)-2-(4-morpholinyl)-16-(1-pyrrolidinyl)-3,17-bis(acetyloxyoxy)androstane (119302-22-6)

Conditions	Yield
In dichloromethane at 0 - 40℃; for 18h; Product distribution / selectivity;	A 56.7 - 67.2 %Chromat. B 6.2 - 21.7 %Chromat.
In dichloromethane at 23℃; for 24h; Product distribution / selectivity;	A 94.1 %Chromat. B 2.1 %Chromat.
With triethylamine In dichloromethane at 20 - 22℃; for 22h; Product distribution / selectivity;
Stage #1: (2β,3α,5α,16β,17β)-2-(4-morpholinyl)-16-(1-pyrrolidinyl)androstane-3,17-diol; acetyl chloride In dichloromethane at 20℃; for 29h; Stage #2: With sodium carbonate In dichloromethane; water Product distribution / selectivity;

diethyl ether-n-hexane + (2β,3α,5α,16β,17β)-2-(4-morpholinyl)-16-(1-pyrrolidinyl)androstane-3,17-diol (119302-20-4) + acetyl chloride (75-36-5) → (2β,3α,5α,16β,17β)-17-acetoxy-3-hydroxy-2-(4-morpholinyl)-16-(1-pyrrolidinyl)androstane (119302-24-8)

Conditions	Yield
In dichloromethane

(2β,3α,5α,16β,17β)-2-(4-morpholinyl)-16-(1-pyrrolidinyl)androstane-3,17-diol (119302-20-4) + acetyl chloride (75-36-5) → (2β,3α,5α,16β,17β)-2-(4-morpholinyl)-16-(1-pyrrolidinyl)-3,17-bis(acetyloxyoxy)androstane (119302-22-6)

Conditions	Yield
In dichloromethane

(2β,3α,5α,16β,17β)-2-(4-morpholinyl)-16-(1-pyrrolidinyl)androstane-3,17-diol (119302-20-4) + acetic anhydride (108-24-7) → (2β,3α,5α,16β,17β)-17-acetoxy-3-hydroxy-2-(4-morpholinyl)-16-(1-pyrrolidinyl)androstane (119302-24-8) + (2β,3α,5α,16β,17β)-2-(4-morpholinyl)-16-(1-pyrrolidinyl)-3,17-bis(acetyloxyoxy)androstane (119302-22-6) + 2α,3α-epoxy-16β-(1-pyrrolidinyl)-5α-androstane-17-one (159325-45-8)

Conditions	Yield
In dichloromethane; water at 20 - 22℃; for 22h; Product distribution / selectivity;

(2β,3α,5α,16β,17β)-2-(4-morpholinyl)-16-(1-pyrrolidinyl)androstane-3,17-diol (119302-20-4) → (2β,3α,5α,16β,17β)-17-acetoxy-3-hydroxy-2-(4-morpholinyl)-16-(1-pyrrolidinyl)androstane (119302-24-8)

Conditions	Yield
Multi-step reaction with 2 steps 1: dichloromethane / 0 - 5 °C / Large scale 2: hydrogenchloride / dichloromethane / 20 - 25 °C / Large scale View Scheme

(2β,3α,5α,16β,17β)-2-(4-morpholinyl)-16-(1-pyrrolidinyl)androstane-3,17-diol (119302-20-4) → rocuronium bromide

Conditions	Yield
Multi-step reaction with 3 steps 1: dichloromethane / 0 - 5 °C / Large scale 2: hydrogenchloride / dichloromethane / 20 - 25 °C / Large scale 3: dichloromethane / 10 °C / Inert atmosphere; Large scale View Scheme

(2β,3α,5α,16β,17β)-2-(4-morpholinyl)-16-(1-pyrrolidinyl)androstane-3,17-diol (119302-20-4) + acetic anhydride (108-24-7) → (2β,3α,5α,16β,17β)-2-(4-morpholinyl)-16-(1-pyrrolidinyl)-3,17-bis(acetyloxyoxy)androstane (119302-22-6)

Conditions	Yield
In dichloromethane at 0 - 5℃; Large scale;	3.4 kg

(2β,3α,5α,16β,17β)-2-(4-morpholinyl)-16-(1-pyrrolidinyl)androstane-3,17-diol (119302-20-4) + acetic anhydride (108-24-7) → (2β,3α,5α,16β,17β)-17-acetoxy-3-hydroxy-2-(4-morpholinyl)-16-(1-pyrrolidinyl)androstane (119302-24-8)

Conditions	Yield
With triethylamine In dichloromethane at 25℃; for 22h;

(2β,3α,5α,16β,17β)-2-(4-morpholinyl)-16-(1-pyrrolidinyl)androstane-3,17-diol (119302-20-4) → 1-[(2β,3α,5α,16β,17β)-17-acetyloxy-3-hydroxy-2-(4-morpholinyl)-androstan-16-yl]-1-methylpyrrolidinium bromide

Conditions	Yield
Multi-step reaction with 2 steps 1: dichloromethane View Scheme

(2β,3α,5α,16β,17β)-2-(4-morpholinyl)-16-(1-pyrrolidinyl)androstane-3,17-diol (119302-20-4) → 1-[(2β,3α,5α,16β,17β)-3,17-bis(acetyloxy)-2-(4-morpholinyl)-androstan-16-yl]-1-(2-propenyl)pyrrolidinium bromide

Conditions	Yield
Multi-step reaction with 2 steps 1: dichloromethane View Scheme

Upstream product

• 14639-79-3 5α-androst-2-en-17-one 
• 965-67-3 2α,3α-epoxy-5α-androstan-17-one 
• 52-72-2 3α-hydroxy-2β-(4-morpholinyl)-5α(H)-androstan-17-one 
• 123-75-1 pyrrolidine 
• 110-91-8 morpholine 
• 119302-19-1 (2α,3α,5α,16β,17β)-2,3-epoxy-16-(1-pyrrolidinyl)-androstan-17-ol 

Downstream Products

• 119302-24-8 (2β,3α,5α,16β,17β)-2-(4-morpholinyl)-16-(1-pyrrolidinyl)-3-hydroxy-17-acetoxyandrostane 
• 119302-22-6 (2β,3α,5α,16β,17β)-2-(4-morpholinyl)-16-(1-pyrrolidinyl)-3,17-bis(acetyloxyoxy)androstane 
• 159325-45-8 2α,3α-epoxy-16β-(1-pyrrolidinyl)-5α-androstane-17-one 
• 122483-73-2 1-[(2β,3α,5α,16β,17β)-3,17-bis(acetyloxy)-2-(4-morpholinyl)-androstan-16-yl]-1-(2-propenyl)pyrrolidinium bromide 

Relevant articles and documents

A new and efficient method for the synthesis of rocuronium bromide

Rocuronium bromide has been used as an aminosteroid non-depolarizing neuromuscular blocker and muscle relaxant. In this work, a new and efficient route for preparing a key intermediate 2β-(4-morpholinyl)-16β-(1-pyrrolidinyl)-5α-androstan-3α,17β-diol (6) was developed through a ring-opening of epoxide followed by introducing and pyrrolidine. Compound 6 can easily provide rocuronium bromide and the overall yield of compound 6 in 5 steps increased to 57.8%, which was higher than currently reported methods. Extraordinarily, this method would avoid the generation of disubstituted impurities E and F which are difficult to remove.

Processes for the synthesis of rocuronium bromide

The invention encompasses processes for synthesizing 1-[17β-acetyloxy-3α-hydroxy-2β-(4-morpholinyl)-5α-androstan-16β-yl]-1-(2-propenyl)pyrrolidinium bromide (rocuronium bromide) and intermediates thereof.

Novel 2β-morpholino-androstane derivatives

Compounds having the formula: STR1 wherein R 1 is H or an optionally substituted acyl group having 1-12 carbon atoms,R 2 is H or an acyl group having 1-12 carbon atoms andR 3 is C, N--CH 3 or a direct bond;and mono- or bisquaternary ammonium compounds thereof and acid addition salts of the non- or mono-quaternary ammonium compounds. Process for the preparation of these compounds. Compositions comprising at least one of the above compounds as the active ingredient. The compounds are favorable neuromuscular blocking agents.