119302-20-4

Usage

Uses

Used in Pharmaceutical Industry:
(2b,3a,5a,16b,17b)-2-(4-Morpholinyl)-16-(1-pyrrolidinyl)androstane-3,17-diol is used as an intermediate in the synthesis of neuromuscular blocking agents, specifically for the production of rocuronium bromide. (2b,3a,5a,16b,17b)-2-(4-Morpholinyl)-16-(1-pyrrolidinyl)androstane-3,17-diol plays a crucial role in the development of medications that are essential for surgical procedures, as they help to facilitate muscle relaxation and ensure patient safety during operations.
Chemical Properties:
(2b,3a,5a,16b,17b)-2-(4-Morpholinyl)-16-(1-pyrrolidinyl)androstane-3,17-diol is a white solid, which indicates its stable and solid-state nature. Its chemical properties contribute to its utility in the pharmaceutical industry, particularly in the synthesis of neuromuscular blocking agents.

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

• 110-91-8 morpholine 
• 119302-19-1 (2α,3α,5α,16β,17β)-2,3-epoxy-16-(1-pyrrolidinyl)-androstan-17-ol 
• 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 

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 academic research and scientific papers

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.

Novel method for preparing rocuronium bromide

The invention relates to a novel method for preparing rocuronium bromide 1-[17beta-acetoxyl-3alpha-hydroxyl-2beta-(4-morpholinyl)-androstane-16beta-yl]-1-(2-propenyl) pyrrole bromide, the problem of chemoselectivity of pyrrolidine open epoxy in an original line is solved, generation of byproducts is avoided, reaction yield is greatly improved, the production cost is reduced, column chromatography separation is avoided, and aftertreatment purification is implemented easily.

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.

Method of reprocessing quaternary ammonium-containing neuromuscular blocking agents

Provided is a method for reprocessing neuromuscular blocking agents containing a quaternary ammonium salt, e.g., Rocuronium bromide, using a novel dealkylation method. The process is effective in obtaining a highly pure product from a contaminated starting material by heating, optionally in the presence of an organic solvent, to produce a dealkyated product. The dealkylated product is purified, e.g., by crystallization, and converted by any known method to a stable, highly-pure neuromuscular blocking agent.

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.