FORM 2
THE PATENT ACT, 1970
(39 OF 1970)
AND
The Patents Rules, 2003
COMPLETE SPECIFICATION
(See section 10 and rule 13)
1. TITLE OF THE INVENTION:
NOVEL METHOD FOR SYNTHESIS OF INTERMEDIATES OF NEUROMUSCULAR BLOCKING AGENTS
2. APPLICANT:
a. NAME: SURAJLOK CHEMICALS PRIVATE LIMITED
b. NATIONALITY: INDIAN
c. ADDRESS: 128 CD, Charkop Cooperative Industrial Estate Ltd,
Near Hindustan Naka, Charkop, Kandivali (West), Mumbai - 400067 Maharashtra, India.
3. PREAMBLE TO THE DESCRIPTION:
The following specification particularly describes the invention and the manner in
which it is to be performed.

NOVEL METHOD FOR SYNTHESIS OF INTERMEDIATES OF NEUROMUSCULAR BLOCKING AGENTS
FIELD OF THE INVENTION
The present invention describes a novel process for acetylation of androstanediols resulting in di-acetylated intermediates of neuromuscular blocking agents, that are substantially free of mono- acetylated impurities. Further, the present invention restricts the formation of precursors of the pharmacopoieal impurities in neuromuscular blocking agents.
BACKGROUND OF THE INVENTION
Neuromuscular-blocking agents block neuromuscular transmission at the neuromuscular junction, causing paralysis of the affected skeletal muscles. This is accomplished either by acting presynaptically via the inhibition of acetylcholine (ACh) synthesis or release, or by acting postsynaptically at the acetylcholine receptors of the motor nerve end-plate.
In clinical use, neuromuscular block is used adjunctively to anesthesia to produce paralysis, firstly to paralyse the vocal cords, and permit intubation of the trachea, and secondly to optimise the surgical field by inhibiting spontaneous ventilation and causing relaxation of skeletal muscles. Because the appropriate dose of neuromuscular-blocking drug may paralyze muscles required for breathing (i.e. the diaphragm), mechanical ventilation should be available to maintain adequate respiration.
Neuromuscular-blocking drugs are classified into two groups viz. non-depolarizing blocking agents and depolarizing blocking agents.
Depolarizing blocking agents:
A depolarizing neuromuscular blocking agent is a form of neuromuscular blocker that depolarizes the motor end plate. An example is succinylcholine. Depolarizing blocking agents work by depolarizing the plasma membrane of the muscle fiber, similar to acetylcholine. However, these agents are more resistant to degradation by acetylcholinesterase, the enzyme responsible for degrading acetylcholine, and can thus more persistently depolarize the muscle fibers. This differs from acetylcholine, which is rapidly degraded and only transiently depolarizes the muscle.

Non-depolarizing blocking agents:
A neuromuscular non-depolarizing agent is a form of neuromuscular blocker that does not depolarize the motor end plate. These agents constitute the majority of the clinically relevant neuromuscular blockers. They act by competitively blocking the binding of ACh to its receptors, and in some cases, they also directly block the ionotropic activity of the ACh receptors. Quaternary ammonium muscle relaxants belong to the class of non-depolarizing blocking agents.
Quaternary ammonium muscle relaxants are quaternary ammonium salts used as drugs for muscle relaxation, most commonly in anesthesia. It is necessary to prevent spontaneous movement of muscle during surgical operations. Muscle relaxants inhibit neuron transmission to muscle by blocking the nicotinic acetylcholine receptor. What they have in common, and is necessary for their effect, is the structural presence of quaternary ammonium groups.
Following are examples some quaternary ammonium muscle relaxants:
2. Vecuronium Bromide - chemically identified as l-[(2P,3a,5a, 16(3,17P)-3,17-bis(acety!oxy)-2-(piperidin-1 -yl)androstan-16-yl]-1 -methylpiperidinium bromide
1. Pancuronium Bromide - chemically identified as l,l'-((2β,3β,5a,16β,17β)-3,17-bis(acetyloxy)androstate-2,16-diyl)bis(l-methylpiperidinium) dibromide.


3. Pipecuronium Bromide - chemically identified as (2β,3α,5a,16β,17β)-3,17-bis(acetyloxy)-2,16-bis(4,4-dimethylpiperazin-4-ium-1 -yl)androstane dibromide


It is clear from the aforementioned structures that di-acetylation of androstane-3,17-diols is one of the steps in synthesis of these neuromuscular-blocking drugs.
Acetylation refers to a process of introducing an acetyl group into a compound, to be specific, the substitution of an acetyl group for an active hydrogen atom. A reaction involving the replacement of the hydrogen atom of a hydroxyl group with an acetyl group (CH3CO) yields a specific ester, the acetate.
Acetic anhydride is a commonly used reagent for acetylation of hydroxyl groups, including di-acetylation of androstane-3,17-diols.
However, acetic anhydride is an irritant and flammable. Vapors of acetic anhydride are harmful. Moreover, use of acetic anhydride is restricted in India and many other countries.
Following are the drawbacks of Acetylation with acetic anhydride:
1. Conversion of androstanediol is not optimum.
2. Huge volume of acetic anhydride (which is a controlled substance) is required for acetylation.

3. Conversion of androstanediols requires high temperature and results in coloured acetylated derivatives which are decolourised using alumina resulting in decrease in the product yield
The present invention is a process for di-acetylation of androstanediols resulting in highly pure androstanediols-di-acetates substantially free of mono acetate impurities. It is well known that conventional processes fail to control the formation of the below mentioned pharmacopoeial impurities in subsequent stages of synthesis of neuromuscular blocking agents.

Vecuronium bromide - Impurity C Vecuronium bromide - Impurity E
(European Pharmacopoiea) (European Pharmacopoiea)

Pancuronium bromide - Impurity A Pancuronium bromide - Impurity B
(European Pharmacopoiea) (European Pharmacopoiea)
It is clear from the structures of these impurities that the precursors of these impurities i.e. compound of formula (la) and (lb) are formed during acetylation stage and converted into the pharmacopoeial impurities in the subsequent quaternization stage.


It is observed from the reaction mechanism that during diacetylation of a diol the formation of mono-acetylated impurities is inevitable and hence cannot be reduced to zero. Therefore, these impurities need be reduced to the lowest possible levels.
It is known that for synthesis of neuromuscular blocking agents, quaternization is either final stage of the synthesis or optionally followed by purification of the resulting product. During the quaternization reaction possibility of formation of mono-acetylated pharmacopoeial impurities is reduced if the precursors of these impurities are well controlled in the acetylation stage.
Therefore, it is advantageous to control the formation of precursors of these impurities during acetylation stage of the synthesis of neuromuscular blocking agents so that formation of the pharmacopoeial impurities will be further minimised in the later stages of the synthesis.
Therefore, there is a need in the prior art to develop a process for acetylation of androstanediols resulting in di-acetylated product which is substantially free of mono-acetylated impurities.
US7579461 discloses processes for the preparation of Rocuronium bromide where androstane-3,17-diol compound is di-acetylated using molar excess of acetyl chloride. Reaction monitoring by HPLC after 24 hours indicated that the reaction mixture contained mono-acetate compound (35.5%), di-acetate compound (55.5%) and unreacted androstane-3,17-diol (0.3%). This indicates that even though acetylation is carried out for 24 hours; the process fails to provide di-acetylated compound of high yield and purity.
The patent numbers US5591735, CN109160934 and the article reported in European Journal of Medicinal Chemistry (2012), 56, 332-347 disclose di-acetylation of androstanediol using acetyl chloride.

However, the major drawback of the prior art processes is the time required for di-acetylation is 12 to 48 hours and hence not feasible on commercial scale. Moreover, these prior art references are silent about purity of the di-acetylated products and do not detail the identity and quantity of mono-acetylated impurities.
Prior art processes fail to disclose acetylation of androstanediols using easily available acetylation agent resulting in di-acetylated products in high yield and purity; thereby controlling formation of mono-acetylated impurities.
The present invention is a solution to the aforementioned problems & provides an industrially viable process for di-acetylation of androstanediols wherein the said process controls formation of mono-acetylated impurities well within the pharmacopoieal limits.
OBJECT OF THE INVENTION:
An object of the invention is to provide a novel method for synthesis of neuromuscular blocking agents; said method avoiding the use of acetic anhydride which is a controlled substance; for acetylation of androstanediols.
Another object of the invention is to provide a novel method for di-acetylation of androstanediols controlling formation of mono-acetylated impurities well within the pharmacopoeial limits.
Yet another object of the invention is to control formation of mono-acetylated impurities in initial stages of the process so that the pure intermediates further improve quality of the final API.
Yet another object of the invention is quaternization of the resulting di-acetates thus providing a short, easy, convenient, inexpensive and industrially viable method for synthesis of pharmacopoeial grade neuromuscular blocking agents.
An object of the invention is to provide a process requiring reduced time for di-acetylation.
Another object of the invention is to provide a process providing di-acetylated compound in high yield and purity.

A further object of the invention is to provide a process that maximises the conversion of androstanediol.
Yet another object of the invention is to avoid the formation of coloured acetylated derivatives that require decolourization resulting in decrease in the product yield.
Another object of the invention is to avoid high reaction temperatures that minimize the decomposition of products and impurity formation.
SUMMARY OF THE INVENTION:
In accordance with the above objectives, the present invention discloses a novel method for di-acetylation of androstan-3,17-diols using an acetylating agent in the presence of an alkali salt of carboxylic acid to provide androstan-3,17-diols-diacetates in high yield and purity thereby controlling formation of mono-acetylated impurities well within the pharmacopoeial limits. Further quaternisation of the resulting androstane-3,17-diacetates provide pharmacopoeial grade neuromuscular blocking agents.
DETAILED DESCRIPTION OF THE INVENTION:
In describing the embodiments of the invention, specific terminology is used for the
sake of clarity. However, it is not intended that the invention be limited to the specific
terms so selected and it is to be understood that each specific term includes all
technical equivalents that operate in a similar manner to accomplish a similar
purpose.
As used herein, the singular forms "a," "an" and "the" include plural referents unless
the content clearly dictates otherwise.
As used herein, the terms "comprising" "including" "having" "containing",
"involving" and the like are understood to mean including but not limited to.
The terms "preferred" and "preferably" refer to embodiments of the invention that
may afford certain benefits, under certain circumstances
As used herein, the term "about" shall be interpreted to mean "approximately" or
"reasonably close to" and any statistically insignificant variations therefrom.
As used herein, the term "at least" indicates that a number or amount is the smallest
or the minimum that is possible and that a greater number or amount is possible.
The recitation of ranges of values herein is merely intended to serve as a shorthand
method of referring individually to each separate value falling within the range.

Unless otherwise indicated herein, each individual value is incorporated into the specification as if it were individually recited herein.
All processes described herein can be performed in suitable order unless otherwise indicated herein or otherwise clearly contradicted by context. The use of any and all examples, or exemplary language (for example "such as") provided with respect to certain embodiments herein is intended merely to better illuminate the invention and does not pose a limitation on the scope of the invention otherwise claimed.
The present invention provides a process for preparing compounds of formula (I)

comprising reacting a compound of (II) with an acetylation agent in presence of an alkali salt of carboxylic acid and organic solvent.

Where R1 and R2 are independently O, (CH2)n or NCH3, n is 0 or 1. Preferably R1 and R2 are (CH2)n and n is 1.
The alkali salt of carboxylic acid comprises alkali salt of acetic acid or formic acid; preferably sodium formate, potassium formate, sodium acetate or potassium acetate. The most preferred alkali salt of carboxylic acid is sodium acetate.
The acetylation agent includes acetyl chloride and acetyl bromide.

Acetyl chloride used in the synthesis is 2 to 10 equivalents per one mol of the androstan-3,17-diols of formula (II). The preferred quantity of the acetyl chloride is 6 to 7 equivalents per one mol of the androstan-3,17-diols of formula (II). Sodium acetate used in the synthesis is 5 to 15 equivalents per one mol of the androstan-3,17-diols of formula (II). The preferred quantity of the sodium acetate is 8 to 10 equivalents per one mol of the androstan-3,17-diols of formula (II).
The organic solvent used in the synthesis comprises ketone, ether, hydrocarbon or halogenated alkane. The preferred solvents used in the synthesis are acetone, methyl isobutyl ketone, diethyl ether, tetrahydrofuram, chloroform, dichloromethane, toluene or xylene. The most preferred solvent used in the synthesis is dichloromethane.
To minimize the decomposition of products and impurity formation the reaction is carried out at 10°C to reflux temperature. Preferably the process is carried out at ambient temperature.
The reaction normally completes in 6 to 24 hours, preferably in 6 to 8 hours and provides pure androstane-3,17-diol-acetates of formula (I) in 80 - 90% yield. Purity of the resulting di-acetates is upto 99.95% (by HPLC) with content of 17(3-mono-acetoxy impurity 0.01% to 0.05% and undetectable 3α-mono-acetoxy impurity.
The pure androstane-3,17-diol-acetates of formula (I) obtained by the process of the present invention can be quatemized with alkyl bromide (e.g. methyl bromide) or allyl bromide to afford pharmacopoeial grade neuromuscular blocking agents.
Advantageously, the process provides 2β,16β-Bis(piperidin-l-yl)-5α-androstane-3α,17β-diyl diacetate of formula (Id) having purity greater than 99.9% by HPLC wherein the impurities content of compounds of formula (la) and (lb) is less than 0.1%w/w each.


Quaterinization of androstane-3,17-diol-acetate of formula (Id) using Methyl bromide provides Vecuronium bromide with more than 99.90% HPLC purity having content of impurity C only 0.03 - 0.07% (pharmacopoieal limit - 0.15%) and impurity E undetectable (pharmacopoieal limit - 0.10%). Also, the precursors of these pharmaceutical impurities are undetected.
Therefore, the compound of formula (Id) is further quaternized using Methyl bromide to form Vecuronium bromide of formula (Ic) having content of impurities of formula (la) and (lb) less than 0.1%w/w each,

Also the compound of formula (Id) is further di-quaternized using Methyl bromide to form Pancuronium bromde bromide of formula (Ie) having content of impurities of formula (la) and (lb) less than 0.1%w/w each.

Thus, the present invention enables to control the formation of precursors (compounds of formula (la) and (lb)) of the pharmacopoieal impurities in Vecuronium bromide below 0.1% each.
Further degradation of Vecuronium bromide to form the impurities 'C and 'E' as well as precursors thereof can be prevented using stringent packing conditions (i.e. dark bags and moisture absorbent silica).

The neuromuscular blocking agents obtained show desirable pharmacological activity, broad safety margins without toxicity or unfavourable side effects, and may be formulated into a dosage form by combining with one or more pharmaceutically acceptable excipients using known techniques.
Further details of the process of the present invention will be apparent from the examples presented below. Examples presented are purely illustrative and should not be construed as limiting the scope of the invention in any manner.
EXAMPLE 1 - Preparation of 2p,16β-Bis(piperidin-l-yl)-5α-androstane-3α,17β-diyl diacetate
A clean and dry four neck round bottom flask was charged with dichloromethane (150 ml) and sodium acetate (48.28 g, 0.58 mole) at 25 to 30°C. 2β,16β-Bis-piperidino-5α-androstane-3α,17β-diol (30.0 g, 0.065 mole) was added to this solution. The resulting reaction mass was stirred 10 to 15 minutes at 25 to 30°C. The reaction mass was cooled to 0 to 10°C. Acetyl chloride (30.80 g, 0.39 mole) was added dropwise to this cold reaction mass, the reaction mass was stirred 10 to 15 minutes at 0 to 10°C and maintained at 25 to 30°C for 6 to 7 hours. The reaction progress was monitored by HPLC. After completion of the reaction, unreacted sodium acetate was filtered off and 2β,16β-bis(piperidin-l-yl)-5α-androstane-3α,17β-diyl diacetate was isolated using conventional work-up.
Yield: 29 g, 81.69%
HPLC Purity: 99.92 %
17p-acetoxy-3-OH compound (precursor of impurity of C of Vecuronium bromide):
0.01%
3a-acetoxy-17P-OH compound (precursor of impurity of E of vecuronium bromide):
Not detected
OBSERVATION: It is observed that the present novel and inventive process for di-acetylation of androstanediols in the presence of an alkali salt of carboxylic acid (sodium acetate) results in increased yield of highly pure androstanediols-di-acetates (purity greater than 99.9%) with substantially reduced mono acetate impurities.
EXAMPLE 2 - Preparation of 2β,16p-Bis(piperidin-l-yI)-5αandrostane-3α,17β-diyl diacetate

A clean and dry four neck round bottom flask was charged with dichloromethane (750 ml) and sodium acetate (214.5 g, 2.61 moles) at 25 to 30°C. 2p,16β-Bis-piperidino-5a-androstane-3a,17(3-diol (150.0 g, 0.34 mole) was added to this solution. The resulting reaction mass was stirred 10 to 15 minutes at 25 to 30°C. The reaction mass was cooled to 0 to 10°C. Acetyl chloride (128.32 g, 1.63 moles) was added dropwise to this cold reaction mass, the reaction mass was stirred 10 to 15 minutes at 0 to 10°C and maintained at 25 to 30°C for 6 to 7 hours. The reaction progress was monitored by HPLC. After completion of reaction, sodium acetate was filtered off and 20,160-bis(piperidin-l-yl)-5a-androstane-3α,17(3-diyl diacetate was isolated using conventional work-up.
Yield: 157.5 g, 88.37%
HPLC Purity: 99.95%
17β~acetoxy-3-OH compound (precursor of impurity of C of Vecuronium bromide):
0.05%
3a-acetoxy-17β-OH compound (precursor of impurity of E of vecuronium bromide):
Not detected
OBSERVATION: It is observed that the present novel and inventive process provides high yield of di-acetylated intermediates of neuromuscular blocking agents, that are substantially free of mono- acetylated impurities and have purity greater than 99.9%.
EXAMPLE 3 - Preparation of 2β,16β-Bis(piperidin-l-yl)-5α-androstane-3α,17β-diyl diacetate (No sodium acetate in used)
A clean and dry four neck round bottom flask was charged with dichloromethane (10.0 ml) and 2p,16p-Bis-piperidino-5a-androstane-3a,17β-diol (2.0 g 0.0043 mole) at 25 to 30°C. The reaction mass was stirred for 10 to 15 minutes at 25 to 30°C and cooled to 0 to 10°C. To this cool reaction mass Acetyl chloride (2.05 g 0.0261 mole) was added dropwise. The reaction mass was stirred 10 to 15 minutes at 0 to 10°C and maintained at 25 to 30°C for 20 hours. Reaction progress was monitored by HPLC (Product formation 94.22%), unreacted starting material - 0.12%, 17p-mono-acetoxy impurity - 0.38%) and 3α -mono-acetoxy impurity - 5.28%). After completion of the reaction, the product was isolated using conventional work-up.
Weight of the wet solid: 1.8 g
17β-acetoxy-3-OH compound (precursor of impurity of C of Vecuronium bromide):
11.2%
3α -acetoxy-17p-OH compound (precursor of impurity of E of vecuronium bromide):
0.13%

OBSERVATION: It is observed that when the di-acetylation of androstanediols was carried out without using an alkali salt of carboxylic acid, the process did not yield product of high yield or purity. The impurities measured were substantially higher as compared to when sodium acetate is used, for example, 11.2% as compared to 0.01% in Example 1 and 0.05% in Example 2. Therefore, the comparative efficacy of the present process (Example 1 & 2) is effectively demonstrated.
EXAMPLE 4 - Preparation of Vecuronium bromide
A clean and dry four neck round bottom flask was charged with 2p,16P-Bis(piperidin-l-yl)-5a-androstane-3α,17P-diyl diacetate (10.0 g 0.018 mole) prepared in the Example - 1 and acetone (60.0 ml) at 25 to 30°C and the reaction mass was stirred 10 to 15 minutes. The reaction mass was cooled to 0 to 5°C followed by addition of methyl bromide (35.01 g, 0.37 mole). The reaction mass was maintained at 0 to 5°C for 25 to 30 minutes. The reaction mixture then stirred at 25 to 30°C for 24 to 28 hours. The reaction progress was monitored by HPLC. After completion of the reaction, the reaction mixture was cooled to 0 to 5°C and maintained for 1.0 hour at 0 to 5°C. The solid was filtered off and worked-up to obtain Vecuronium bromide.
Yield: 7.3 g, 62.13%
HPLC Purity: 99.93%
Impurity C: 0.07% (pharmacopoieal limit - 0.15%)
Impurity E: Not detected (pharmacopoieal limit - 0.10%)
Precursor of impurity of C: Not detected
Precursor of impurity of E: Not detected
OBSERVATION: Example 4 demonstrates that when the di-acetylated compound yielded by the present process (Example 1) is used in the synthesis of neuromuscular blocking agent Vecuronium bromide, the formation of mono-acetylated pharmacopoeial impurities (impurity C & E) is reduced in the quaternization stage (i.e. these impurities are controlled in the acetylation step below the detection level). Therefore, the efficacy of the process of Example 1 is established.
EXAMPLE 5 - Preparation of Vecuronium bromide
A clean and dry four neck round bottom flask was charged with 2p,16β-Bis(piperidin-l-yl)-5a-androstane-3α,17β-diyl diacetate (50.0 g, 0.09 mole) prepared in the Example - 2 and acetone (300.0 ml) at 25 to 30°C and the reaction mass was stirred 10 to 15 minutes. The reaction mass was cooled to 0 to 5°C followed by addition of methyl

bromide (175.0 g, 1.84 mole). The reaction mass was maintained at 0 to 5°C for 25 to 30 minutes. The reaction mixture then stirred at 25 to 30°C for 24 to 28 hours. The reaction progress was monitored by HPLC. After completion of the reaction, the reaction mixture was cooled to 0 to 5°C and maintained for 1.0 hour at 0 to 5°C. The solid was filtered off and worked-up to obtain Vecuronium bromide.
Yield: 32.0 g, 53.26%
HPLC Purity: 99.97%
Impurity C: 0.03% (pharmacopoieal limit-0.15%)
Impurity E: Not detected (pharmacopoieal limit - 0.10%)
Precursor of impurity of C: Not detected
Precursor of impurity of E: Not detected
OBSERVATION: Example 5 demonstrates that when the di-acetylated intermediates yielded by the present process (Example 2) are used in the synthesis of quaternary ammonium muscle relaxants, the formation of mono-acetylated impurities is well within pharmacopoieal limits (i.e. these impurities are controlled in the acetylation step below the detection level). Therefore, the efficacy of the process of Example 2 is established.

We claim,
1. A process for preparing compounds of Formula (I) having purity greater than 99.9%

comprising reacting a compound of Formula (II) with an acetylation agent in the presence of an alkali salt of carboxylic acid.

wherein R1 and R2 comprise O, (CH2)n or NCH3; n is 0 or 1.
2. The process as claimed in claim 1, wherein R1 and R2 are (CH2)n; n is 1.
3. The process as claimed in claim 1, wherein said acetylation agent comprises acetyl chloride or acetyl bromide.
4. The process as claimed in claim 1, wherein the alkali salt of carboxylic acid comprises alkali salt of acetic acid or alkali salt of formic acid.

5. The process as claimed in claims 1 and 4, wherein the alkali salt of carboxylic acid comprises sodium formate, potassium formate, sodium acetate or potassium acetate.
6. The process as claimed in claim 1, wherein the reaction is carried out in an organic solvent.
7. The process as claimed in claim 6, wherein the organic solvent comprises ketone, ether, hydrocarbon or halogenated alkane.
8. The process as claimed in claim 7, wherein the organic solvent comprises acetone, methyl isobutyl ketone, diethyl ether, tetrahydrofuram, chloroform, dichloromethane, toluene or xylene.
9. The process as claimed in claim 8, wherein the organic solvent is dichloromethane.
10. A 2β,16β-Bis(piperidin-l-yl)-5α-androstane-3a,17β-diyl diacetate of formula (Id)
prepared by the process of claims 1-9, said diacetate having purity greater than 99.9%
by HPLC wherein the content of impurities of compounds of formula (la) and (lb)
each is less than 0.1%w/w.



11. A process for preparing Vecuronium bromide of formula (Ic) having less than 0.1%w/w content of impurities of formula (la) and (lb) each,

the process comprising,
reacting a compound of Formula (II) with an acetylation agent in the presence of an
alkali salt of carboxylic acid to provide a compound of formula (I).


wherein R1 and R2 are (CH2)n,n is 1; and
reacting the resulting compound of formula (I) with methyl bromide.
12. The process as claimed in claim 11, wherein said acetylation agent comprises acetyl chloride or acetyl bromide.
13. The process as claimed in claim 11, wherein the alkali salt of carboxylic acid comprises alkali salt of acetic acid or alkali salt of formic acid.
14. The process as claimed in claim 13, wherein the alkali salt of carboxylic acid comprises sodium formate, potassium formate, sodium acetate or potassium acetate.
15. A Vecuronium bromide compound of formula (Ic) prepared by the process of claims 11-14, said compound having less than 0.1%w/w content of impurities of formula (Ia) and (Ib) each.



16. A Pancuronium bromide compound of formula (Ie) prepared by the process of claims 11-14, said compound having less than 0.1%w/w content of impurities of formula (la) and (lb) each.