Description:FIELD OF INVENTION
[0001] The present invention relates to method for synthesis of glycopyrronium compounds. More particularly, the present invention relates to a method for synthesizing glycopyrronium base through a mixed anhydride intermediate by a one pot reaction and preparation of glycopyrronium bromide therefrom.

BACKGROUND OF THE INVENTION
[0002] Background description includes information that may be useful in understanding the present invention. It is not an admission that any of the information provided herein is prior art or relevant to the presently claimed invention, or that any publication specifically or implicitly referenced is prior art.
[0003] Glycopyrronium bromide chemically known as 3-[(cyclopentyl-hydroxyphenylacetyl)oxy]-1,1-dimethyl-pyrrolidinium bromide and commonly referred as glycopyrrolate is an antimuscarinic agent. It is used to reduce secretions during anaesthesia by administration through injection and to treat gastric ulcers by oral administration.
[0004] Glycopyrronium Bromide (Glycopyrronium Bromide) is a quaternary ammonium salt having two chiral carbon atoms, i.e. the 3-and 2 ' –carbon and two pairs of enantiomers (R, R), (S, S) and (S, R), (R, S). The desired drug is the racemic mixture of the S,R and R,S pair of enantiomers. Glycopyrronium bromide is prepared by various chemical routes.
[0005] One of the approaches involves preparing 1-methyl-3-pyrrolidyl alpha-cyclopentyl mandelate by transesterifying methyl glycolate with an amino alcohol under the influence of metallic sodium to give a glycolate intermediate. However, in such process, metallic sodium is highly reactive, which poses health and safety risks that make its use undesirable on an industrial scale for commercial manufacture.
[0006] Another approach involves preparing a mixture of diastereoisomers. However, the relative proportions of the diastereoisomers can vary widely between batches. Such variation can give rise to unexpected differences while preparing dry powder formulations from glycopyrronium bromide, which can cause problems when formulating such dry powders for pharmaceutical use.
[0007] One more approach as disclosed in United States patent application US 2007/0123557 involves preparation of 1-(alkoxycarbonylmethyl)-1-methylpyrrolidyl anticholinergic esters through coupling (R)-cyclopentylmandelic acid with (R,S)-1-methyl-pyrrolidin-3-ol under Mitsunobu conditions to give pure (R)-stereoisomeric compounds, which are reacted with a bromoacetate to give the desired esters. However, chemicals used in Mitsunobu reactions, specifically dialkyl azodicarboxylates and triphenylphosphine, pose health, safety and ecological risks that make their use undesirable on an industrial scale for commercial manufacture. They are also generally too expensive to source and too laborious to use in commercial manufacture.
[0008] Most process of synthesis of glycopyrronium bromide involve reactions that require, highly reactive sodium metal, very large quantity of alcohol, involving very lengthy steps, form impurities lowering yield and purity.
[0009] Thus, there remains an unmet need in the art to provide a method for synthesis of glycopyrronium bromide that can address one or more of aforementioned shortcomings, especially the process that is rapid and provide product with high purity and yield.

OBJECTS OF THE INVENTION
[00010] An object of the present invention is to provide a method for synthesizing glycopyrronium base through a mixed anhydride intermediate.
[00011] Another object of the present invention is to provide one pot synthesis of glycopyrronium base.
[00012] Another object of the present invention is to provide a method for synthesizing glycopyrronium bromide through a mixed anhydride intermediate.

SUMMARY
[00013] In general aspects the present invention provides a method for synthesis of glycopyrronium compound.
[00014] In another aspect the present invention provides one pot synthesis of glycopyrronium base through a mixed anhydride intermediate.
[00015] In an aspect the present invention provides a method for synthesis of glycopyrronium base through a mixed anhydride intermediate.
[00016] In an aspect, the present disclosure invention a method for synthesis of glycopyrronium base of formula (Ia) through a mixed anhydride intermediate of formula (IV), the process comprising: reacting alpha-cyclopentylmandelic acid (CPMA) of formula (II) with a compound of formula (III) to provide a mixed anhydride of formula (IV), and in situ reacting the mixed anhydride of formula (IV) with N-methyl-3-pyrrolidinol (NMP) of formula (V) to form glycopyrronium base of formula (Ia)

(II) (III) (IV) (V)

(Ia)
wherein R is C1-C10 branched or straight chain alkyl, phenyl, or alkyl aryl.
[00017] In an aspect the present invention provides a method for synthesis of glycopyrronium bromide of formula (I) though a mixed anhydride intermediate of formula (IV), the process comprising: reacting alpha cyclopentylmandelic acid (CPMA) of formula (II) with a compound of formula (III) to provide a mixed anhydride of formula (IV), in situ reacting the mixed anhydride of formula (IV) with N-methyl-3-pyrrolidinol (NMP) of formula (V) to form glycopyrronium base of formula (Ia), and reacting glycopyrronium base of formula (Ia) with methylbromide to form glycopyrronium bromide of formula (I):

wherein R is C1-C10 branched or straight chain alkyl, phenyl, or alkyl aryl.
[00018] These and other features, aspects, and advantages of the present subject matter will be better understood with reference to the following description and appended claims. This summary is provided to introduce a selection of concepts in a simplified form. This summary is not intended to identify key features or essential features of the claimed subject matter, nor is it intended to be used to limit the scope of the claimed subject matter.

DETAILED DESCRIPTION OF THE INVENTION
[00019] Those skilled in the art will be aware that the present disclosure is subject to variations and modifications other than those specifically described. It is to be understood that the present disclosure includes all such variations and modifications. The disclosure also includes all such steps, features, compositions and compounds referred to or indicated in this specification, individually or collectively, and any and all combinations of any or more of such steps or features.
[00020] Unless the context requires otherwise, throughout the specification which follow, the word “comprise” and variations thereof, such as, “comprises” and “comprising” are to be construed in an open, inclusive sense that is as “including, but not limited to.”
[00021] Reference throughout this specification to “one embodiment” or “an embodiment” means that a particular feature, structure or characteristic described in connection with the embodiment is included in at least one embodiment. Thus, the appearances of the phrases “in one embodiment” or “in an embodiment” in various places throughout this specification are not necessarily all referring to the same embodiment. Furthermore, the particular features, structures, or characteristics may be combined in any suitable manner in one or more embodiments.
[00022] As used in the description herein and throughout the claims that follow, the meaning of “a,” “an,” and “the” includes plural reference unless the context clearly dictates otherwise. Also, as used in the description herein, the meaning of “in” includes “in” and “on” unless the context clearly dictates otherwise.
[00023] In some embodiments, the numbers expressing quantities of ingredients, properties such as concentration, and so forth, used to describe and claim certain embodiments of the invention are to be understood as being modified in some instances by the term “about.” The term “about” may refer to + 5 of the specific figure preceding the term “about”. Accordingly, in some embodiments, the numerical parameters set forth in the written description are approximations that can vary depending upon the desired properties sought to be obtained by a particular embodiment. In some embodiments, the numerical parameters should be construed in light of the number of reported significant digits and by applying ordinary rounding techniques. Notwithstanding that the numerical ranges and parameters setting forth the broad scope of some embodiments of the invention are approximations, the numerical values set forth in the specific examples are reported as precisely as practicable.
[00024] 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.
[00025] Groupings of alternative elements or embodiments of the invention disclosed herein are not to be construed as limitations. Each group member can be referred to and claimed individually or in any combination with other members of the group or other elements found herein. One or more members of a group can be included in, or deleted from, a group for reasons of convenience and/or patentability.
[00026] All methods 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 (e.g. “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. No language in the specification should be construed as indicating any non-claimed element essential to the practice of the invention.
[00027] All publications herein are incorporated by reference to the same extent as if each individual publication or patent application were specifically and individually indicated to be incorporated by reference. Where a definition or use of a term in an incorporated reference is inconsistent or contrary to the definition of that term provided herein, the definition of that term provided herein applies and the definition of that term in the reference does not apply.
[00028] The headings and abstract of the invention provided herein are for convenience only and do not interpret the scope or meaning of the embodiments.
[00029] Various terms are used herein. To the extent a term used in a claim is not defined below, it should be given the broadest definition persons in the pertinent art have given that term as reflected in printed publications and issued patents at the time of filing.
[00030] The present invention relates to a method for synthesis of glycopyrronium compound and intermediates thereof.
[00031] In an embodiment, the present disclosure provides a method for synthesis of glycopyrronium base through a mixed anhydride intermediate.
[00032] In one embodiment, the present disclosure provides a method for synthesis of glycopyrronium base of formula (Ia) through a mixed anhydride intermediate of formula (IV), the process comprising: reacting alpha cyclopentylmandelic acid (CPMA) of formula (II) with a compound of formula (III) to provide a mixed anhydride of formula (IV), and in situ reacting the mixed anhydride of formula (IV) with h N-methyl-3-pyrrolidinol (NMP) of formula (V) to form glycopyrronium base of formula (Ia):

wherein R is C1-C10 branched or straight chain alkyl, phenyl or alkyl aryl.
[00033] In one embodiment the present disclosure provides a method for synthesis of glycopyrronium bromide of formula (I) though a mixed anhydride intermediate of formula (IV), the process comprising: reacting alpha cyclopentylmandelic acid (CPMA) of formula (II) with a compound of formula (III) to provide a mixed anhydride of formula (IV), in situ reacting the mixed anhydride of formula (IV) with N-methyl-3-pyrrolidinol (NMP) of formula (V) to form glycopyrronium base of formula (Ia), and reacting glycopyrronium base of formula (Ia) with methylbromide to form glycopyrronium bromide of formula (I).

wherein R is C1-C10 branched or straight chain alkyl, phenyl or alkyl aryl.
[00034] The reaction of alpha cyclopentylmandelic acid (CPMA) of formula (II) with a compound of formula (III) in accordance with the present disclosure is carried out in the presence of a base and a solvent.
[00035] In one embodiment, the base can be selected from but not limiting to triethylamine, Di-isopropyl amine, ethyldiisopropylamine.
[00036] In one embodiment, the solvent can be selected from but not limiting to dimethylformamide (DMF), dimethyl sulfoxide (DMSO), n-methyl-2-pyrrolidone, sulfolane, dimethyl propyleneurea (DMPU), dimethyl imidazolidone.
[00037] In one embodiment, the CPMA of formula (II) with solvent and base is mixed in one lot at 20-30°C and reacted with the compound of formula (III) to provide a mixed anhydride of formula (IV).
[00038] In one embodiment, the compound of formula (III) is added to the CPMA of formula (II) dissolved in the solvent and base over a period of about 10 mins to about 30 mins.
[00039] In one embodiment, the reaction of CPMA of formula (II) dissolved in the solvent and base with the compound of formula (III) is carried out for a period of about 0.5 h to 3 h to provide a mixed anhydride of formula (IV).
[00040] In one embodiment, the mixed anhydride of formula (IV) is reacted with N-methyl-3-pyrrolidinol (NMP) at a temperature in the range of about 40°C to about 75°C to form glycopyrronium base of formula (III).
[00041] The present invention provides a method of synthesis of glycopyrronium bromide, avoids use of highly reactive sodium metal, does not require separation of intermediate and is a one pot reaction method.
[00042] The present invention provides glycopyrronium bromide with much high purity of over 99%, preferably over 99.5%, more preferably over 99.7%.
[00043] The present disclosure satisfies the existing needs, as well as others, and generally overcomes the deficiencies found in the existing art.

EXAMPLES
[00044] The disclosure will now be illustrated with working examples, which is intended to illustrate the working of disclosure and not intended to take restrictively to imply any limitations on the scope of the present disclosure. Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood to one of ordinary skill in the art to which this disclosure belongs. Although methods and materials similar or equivalent to those described herein can be used in the practice of the disclosed methods and compositions, the exemplary methods, devices and materials are described herein. It is to be understood that this disclosure is not limited to particular methods, and experimental conditions described, as such methods and conditions may vary.

Example 1
Synthesis of glycopyrronium base with ethyl chloroformate
[00045] Alpha-Cyclopentylmandelic acid (CPMA) (10 g) was dissolved in DMSO (5 Vol), to it was added triethyl amine (2.4 mol eq.) in one lot at 20-30°C, ethyl chloroformate (1.2 mol eq.) was added to the same over 30 min and stirred for about 1 hr at 20-30°C. The reaction was monitored on TLC to obtain mixed anhydride complex. 1-methyl-3-pyrrolidinol (1.2 mol eq.) was added in the mixed anhydride complex and heated up to 60-65°C; the progress of the reaction was monitored on TLC. The reaction mass was quenched with water after completion of the reaction and the product was extracted using toluene to obtain base after toluene distillation. The base was further treated with acid-base treatment (using 10% HCl and aqueous ammonia) to obtain glycopyrronium base (8g) of HPLC purity: 98.90%.

Example 2
Synthesis of glycopyrronium base with phenyl chloroformate
[00046] Alpha-Cyclopentylmandelic acid (CPMA) (10 g) was dissolved in DMF (5.0 Vol), to it was added triethyl amine (2.4 mol eq.) in one lot at 15-20°C, phenyl chloroformate (1.2 mol eq.) was added over 15 min and stirred for 3 hrs at 20-25°C to obtain mixed anhydride complex. 1-methyl-3-pyrrolidinol (1.2 mol eq.) was added in the mixed anhydride complex and heated up to 55-60°C; the progress of the reaction was monitored on TLC. The reaction mass was quenched with water after completion of the reaction and the product was extracted using toluene to obtain the Glycopyrronium base after toluene distillation of HPLC purity: 62.91%.

Example 3
Synthesis of glycopyrronium base with n-pentyl chloroformate
[00047] Alpha-Cyclopentylmandelic acid CPMA (10 g) was dissolved in DMF (5.0 Vol), to it was added triethyl amine (2.4 mol eq.) in one lot at 20-25°C, n-pentyl chloroformate (1.2 mol eq.) was added over 15 min and stirred for about 2 hrs at 20-25°C. 1-methyl-3-pyrrolidinol (1.2 mol eq.) was added in the mixed anhydride complex and heated up to 60-65°C; the progress of the reaction was monitored on TLC. The reaction mass was quenched with water after completion of the reaction and the product was extracted using toluene to obtain the Glycopyrronium base after toluene distillation of HPLC purity: 68.25%.

Example 4
Glycopyrronium base prepared using methyl chloroformate
[00048] Alpha-Cyclopentylmandelic acid (CPMA) (10g) was dissolved in DMSO (3.0 Vol), to it was added triethyl amine (2.4 mol eq.) in one lot at 20-25°C, methyl chloroformate (1.2 mol eq.) in 15min and stirred for 2hrs at 20-25°C. 1-methyl-3-pyrrolidinol (1.0 mol eq.) was added in the mixed anhydride complex and heated up to 45-50°C; the progress of the reaction was monitored on TLC. The reaction mass was quenched with water after completion of the reaction and the product was extracted using toluene to obtain glycopyrronium base after toluene distillation of HPLC purity: 72.9 %.

Example 5
Synthesis of Glycopyrronium bromide
[00049] Glycopyrronium base (2.0g) was dissolved in isopropyl alcohol (IPA) (4.0 Vol), to which was added 3.2 ml methyl bromide solution in Acetonitrile (25% in Acetonitrile) and reacted at 25-30oC, the progress of the reaction was monitored on TLC, followed by distillation with IPA after completion of the reaction and isolation of glycopyrronium bromide product in methyl ethyl ketone (6.0 Vol), to obtain 0.7 g product after drying. HPLC purity: 99.80% .

ADVANTAGES OF THE PRESENT INVENTION
[00050] The method of the present invention is a one pot reaction for synthesizing glycopyrronium base from alpha-cyclopentylmandelic acid (CPMA) without isolating ester of CPMA.
[00051] The method of the present invention for synthesis of glycopyrronium bromide or glycopyrronium base for trans esterification does not require highly reactive sodium metal, hence is safe.
[00052] The present invention provides glycopyrronium bromide with much high purity of over 99%.
[00053] Overall, the present invention provides a novel and inventive method which is superior to methods known in the art, and overcomes product limitation in terms of purity.
[00054] From the foregoing, it will be appreciated that, although specific embodiments of the invention have been described herein merely for purposes of illustration, various modifications may be made without deviating from the spirit and scope of the invention and should not be construed so as to limit the scope of the invention or the appended claims in any way.
, Claims:1. A method for synthesis of glycopyrronium base of formula (Ia) through a mixed anhydride intermediate of formula (IV), the process comprising: reacting alpha cyclopentylmandelic acid (CPMA) of formula (II) with a compound of formula (III) to provide a mixed anhydride of formula (IV), and in situ reacting the mixed anhydride of formula (IV) with h N-methyl-3-pyrrolidinol (NMP) of formula (V) to form glycopyrronium base of formula (Ia):

wherein R is C1-C10 branched or straight chain alkyl, phenyl or alkyl aryl.

2. A method for synthesis of glycopyrronium bromide of formula (I) though a mixed anhydride intermediate of formula (IV), the process comprising: reacting alpha cyclopentylmandelic acid (CPMA) of formula (II) with a compound of formula (III) to provide a mixed anhydride of formula (IV), in situ reacting the mixed anhydride of formula (IV) with N-methyl-3-pyrrolidinol (NMP) of formula (V) to form glycopyrronium base of formula (Ia), and reacting glycopyrronium base of formula (Ia) with methylbromide to form glycopyrronium bromide of formula (I):

wherein R is C1-C10 branched or straight chain alkyl, phenyl or alkyl aryl.

3. The method as claimed in claim 1 or 2, wherein the reaction of alpha cyclopentylmandelic acid (CPMA) of formula (II) with a compound of formula (III) is carried out in the presence of a base and a solvent.

4. The method as claimed in claim 1 or 2, wherein the base is selected from but not triethylamine, di-isopropyl amine, ethyldiisopropylamine, N-methyl-2-pyrrolidone, sulfolane, dimethyl propyleneurea (DMPU), dimethyl imidazolidone

5. The method as claimed in claim 1 or 2, wherein the solvent is selected from dimethylformamide (DMF), dimethyl sulfoxide (DMSO), N-methyl-2-pyrrolidone N-methyl-2-pyrrolidone, sulfolane, dimethyl propyleneurea (DMPU), dimethyl imidazolidone. The method as claimed in claim 1, wherein the CPMA of formula (II) with solvent and base is mixed in one lot at 20-30°C.

6. The method as claimed in claim 1 or 2, wherein the mixed anhydride of formula (IV) is reacted with N-methyl-3-pyrrolidinol (NMP) of formula (V) at a temperature in the range of about 40°C to about 75°C to form glycopyrronium base of formula (III).