Process for production of glycopyrronium tosylate

Abstract

Provided herein are methods for the production of glycopyrronium tosylate and glycopyrronium tosylate compositions. Also provided herein are compositions useful in the production of glycopyrronium tosylate. Additionally provided herein are glycopyrronium tosylate compositions. Glycopyrronium tosylate is useful for the treatment of, among other conditions, hyperhidrosis.

Claims

1. A glycopyrrolate base composition comprising threo-glycopyrrolate base and erythro-glycopyrrolate base, wherein the threo-glycopyrrolate base is at least 95% of the total glycopyrrolate base content of the composition and the erythro-glycopyrrolate base is less than 5% of the total glycopyrrolate base content of the composition.

2. The glycopyrrolate base composition of claim 1, wherein the threo-glycopyrrolate base is at least 96% of the total glycopyrrolate base content of the composition and the erythro-glycopyrrolate base is less than 4% of the total glycopyrrolate base content of the composition.

3. The glycopyrrolate base composition of claim 1, wherein the threo-glycopyrrolate base is at least 97% of the total glycopyrrolate base content of the composition and the erythro-glycopyrrolate base is less than 3% of the total glycopyrrolate base content of the composition.

4. A glycopyrrolate base composition comprising threo-glycopyrrolate base and erythro-glycopyrrolate base, wherein the composition is produced by: (i) contacting cyclopentylmandelic acid with 1-methylpyrrolidin-3-ol to form glycopyrrolate base: ##STR00031## (ii) contacting the glycopyrrolate base with 5-nitroisophthalic acid to form glycopyrrolate base, 5-nitroisophthalate salt: ##STR00032## and (iii) contacting the glycopyrrolate base, 5-nitroisophthalate salt with an inorganic base to form glycopyrrolate base: ##STR00033## (iv) purifying the glycopyrrolate base obtained in step (iii) by contacting it with an organic solvent to obtain a purified glycopyrrolate base; wherein the organic solvent is a water-immiscible organic solvent.

5. A method of producing a glycopyrrolate tosylate composition comprising threo-glycopyrronium tosylate and erythro-glycopyrronium tosylate, wherein: the threo-glycopyrronium tosylate is at least 95% of the total glycopyrrolate tosylate content of the composition; the erythro-glycopyrronium tosylate is less than 5% of the total glycopyrrolate base content of the composition; and the composition is produced by glycopyrronium base: contacting the glycopyrronium base composition of claim 1 with methyl tosylate to produce glycopyrronium tosylate: ##STR00034##

6. The method of claim 5, wherein the threo-glycopyrronium tosylate is at least 96% of the total glycopyrronium tosylate content of the composition and the erythro-glycopyrronium tosylate is less than 4% of the total glycopyrronium tosylate content of the composition.

7. The method of claim 5, wherein the threo-glycopyrronium tosylate is at least 97% of the total glycopyrronium tosylate content of the composition and the erythro-glycopyrronium tosylate is less than 3% of the total glycopyrronium tosylate content of the composition.

8. The method of claim 5, wherein the threo-glycopyrronium tosylate is at least 99% of the total glycopyrronium tosylate content of the composition and the erythro-glycopyrronium tosylate is less than 1% of the total glycopyrronium tosylate content of the composition.

9. The method of claim 5, wherein the threo-glycopyrronium tosylate is at least 99.5% of the total glycopyrronium tosylate content of the composition and the erythro-glycopyrronium tosylate is less than 0.5% of the total glycopyrronium tosylate content of the composition.

10. The method of claim 5, wherein the threo-glycopyrronium tosylate is at least 99.6% of the total glycopyrronium tosylate content of the composition and the erythro-glycopyrronium tosylate is less than 0.4% of the total glycopyrronium tosylate content of the composition.

11. The composition of claim 4, wherein the organic solvent is selected from a group consisting of: benzene, n-butanol, carbon tetrachloride, chloroform, cyclohexane, ethylene chloride, heptane, hexane, pentane, toluene, trichloroethylene, and xylene.

12. The composition of claim 11, wherein the organic solvent is toluene.

Description

EXAMPLES

(1) As used herein, the symbols and conventions used in these processes, schemes and examples, regardless of whether a particular abbreviation is specifically defined, are consistent with those used in the contemporary scientific literature, for example, the Journal of the American Chemical Society or the Journal of Biological Chemistry. Specifically, but without limitation, the following abbreviations may be used in the examples and throughout the specification: g (grams); mg (milligrams); mL (milliliters); μL (microliters); mM (millimolar); μM (micromolar); Hz (Hertz); MHz (megahertz); mmol (millimoles); hr or hrs (hours); min (minutes); MS (mass spectrometry); ESI (electrospray ionization); TLC (thin layer chromatography); HPLC (high pressure liquid chromatography); THF (tetrahydrofuran); CDCl.sub.3 (deuterated chloroform); AcOH (acetic acid); DCM (dichloromethane); DMSO (dimethylsulfoxide); DMSO-d.sub.6 (deuterated dimethylsulfoxide); EtOAc (ethyl acetate); MeOH (methanol); and BOC (t-butyloxycarbonyl).

(2) For all of the following examples, standard work-up and purification methods known to those skilled in the art can be utilized. Unless otherwise indicated, all temperatures are expressed in ° C. (degrees Celsius). All reactions are conducted at room temperature unless otherwise noted. Synthetic methodologies illustrated herein are intended to exemplify the applicable chemistry through the use of specific examples and are not indicative of the scope of the disclosure.

Example 1

Preparation of Glycopyrronium Tosylate Using Methyl Tosylate as Methylation Agent

Step 1: Preparation of Glycopyrrolate Base (Mixture of Erythro/Threo Base)

(3) ##STR00026##

(4) Cyclopentylmandelic acid is activated by reaction under heating with 1,1-carbonyldiimidazole in toluene. N-methyl-3-pyridinol is added and stirred for at least five hours. After in-process testing to confirm completion of reaction, the mixture is cooled, washed with water, and the toluene solution concentrated to a mixture containing between 20-40% toluene and less than 4% residual cyclopentyl mandelic acid. This mixture is used directly in the next step.

Step 2: Preparation of Glycopyrrolate Base Threo Pair as 5-Nitroisophthalate Salt

(5) ##STR00027##

(6) This step effectively resolves the mixture of threo and erythro diastereomers of the free base intermediate to provide the threo pair at greater than 96%. The process relies on the significantly different solubilities of the 5-nitroisophthalate salts of the threo and erythro diastereomers of glycopyrrolate free base.

(7) 5-Nitroisophthalic acid (1 eq.) was dissolved in methanol (20 vol) at room temperature with moderate agitation. The glycopyrrolate base (1 eq.) obtained in Step 1 was then added. After crystallization was initiated, the mixture was stirred for an additional 4 hours at room temperature. The solids were then recovered in a filtration centrifuge and washed with methanol.

(8) The crude product was then suspended in approximately 6 volumes of methanol. The suspension was stirred at approximately 65° C. for one hour, then cooled to 20° C. and stirred for an additional 4 hours. The product was again recovered in a filtration centrifuge, washed with methanol, spun dry at 1290 RPM for 15 minutes, and then discharged as wet glycopyrrolate 5-nitroisophthalate. The product was tested for identification, loss on drying, and melting point. The ratio of threo:erythro diastereomeric pairs was typically 96:4.

Step 3: Preparation of Threo-Glycopyrrolate Base

(9) ##STR00028##

(10) The threo-glycopyrrolate base was obtained by treatment of the wet 5-nitroisophthalate salt obtained in Step 2 with aqueous sodium hydroxide and toluene. A biphasic mixture was obtained in which the disodium salt of 5-nitroisophthalic acid resided in the aqueous layer and the threo-glycopyrrolate base was contained in the toluene layer.

(11) The wet 5-nitroisophthalate salt of threo-glycopyrrolate base was dissolved in approximately 8 volumes of purified water at room temperature. Toluene (approximately 3 volumes) was added. With agitation, a slight excess of 30% aqueous sodium hydroxide was added and the mixture stirred for 15 minutes. A sample of the biphasic mixture was then taken and the pH of the aqueous layer verified to be in the range 11.5 to 12.5. In some instances, the pH was adjusted by addition of additional aqueous sodium hydroxide. The lower aqueous layer was removed by decanting and the upper toluene layer washed three times with purified water. The toluene was then removed by distillation under reduced pressure to yield the free base as an oil which was used directly in the next step.

Step 4: Preparation of Crude Glycopyrronium Tosylate

(12) ##STR00029##

(13) The threo-glycopyrrolate base obtained in the previous step was dissolved in four volumes of acetone and treated with 1.1 eq. of methyl-p-toluenesulfonate. The mixture was stirred for a minimum of three hours at room temperature, typically for about 12 hours at room temperature. Completion of the reaction was monitored by TLC until the remaining free base was not more than about 2%. The crude glycopyrronium tosylate was recovered using a filtration centrifuge and washed twice with a minimum of acetone. The wet cake obtained was dried under vacuum at 50° C. until the loss on drying was not more than 2.0%.

Step 5: Purification and Isolation of Threo-Glycopyrronium Tosylate

(14) ##STR00030##

(15) The purpose of the following purification steps was to reduce the content of the erythro isomer to the release limit of not more than 0.4%.

(16) In the first purification step, the dried crude glycopyrronium tosylate was triturated in three volumes of purified water for five hours. The product was recovered using a filtration centrifuge and washed with 1 volume of cold (<10° C.) purified water. The wet cake was then dissolved in four volumes of purified water at 60° C. with agitation. The solution obtained was cooled to 35° C. and held until crystallization began (typically about 1 hour). The mixture was then cooled to 20° C. and agitated for a further 5 hours. The product was then recovered using a filtration centrifuge and washed with 1 volume of cold (<10° C.) purified water. Finally, the product was recrystallized a second time in a similar fashion from 3 volumes of purified water with polish filtration of the 60° C. solution prior to cooling.

(17) At each step of the purification process, the wet cake was sampled and analyzed for loss on drying and erythro isomer content. The erythro isomer limit of 0.4% was typically met after the second crystallization, however additional recrystallization steps were performed as required until the erythro isomer limit was met. The product was tray dried at not more than 40° C. without vacuum for a minimum of 8 hours until the water content met the release criteria of 2.5%-4.0%.

(18) Elemental analysis: C, 61.59%; H, 7.27%; N, 2.80%; S, 6.31%. The molecular formula of glycopyrronium tosylate monohydrate is C.sub.26H.sub.37NO.sub.7S, which corresponds to: C, 61.51%; H, 7.35%; N, 2.76%; and S, 6.32%.

(19) .sup.1H NMR (DMSO-d.sub.6): δ=1.15 (m, 1H), 1.20 (m, 1H), 1.40 (m, 1H), 1.50 (m, 2H), 1.60 (m, 3H), 2.05 (m, 1H), 2.30 (s, 3H), 2.65 (m, 1H), 2.90 (m, 1H), 3.05 (s, 3H), 3.15 (s, 3H), 3.50 (m, 1H), 3.60 (d, 1H), 3.70 (m, 1H), 3.80 (dd, 1H), 5.37 (m, 1H), 5.82 (s, 1H), 7.10 (d, 2H), 7.27 (t, 1H), 7.35 (7.47 (d, 2H), 7.59 (d, 2H).

(20) ESI-MS(+): m/z 318 (glycopyrronium); ESI-MS(−): m/z 171 (tosylate).

(21) IR (ATR): 681-907 cm−1 (C-H arom.); 1012, 1036 cm.sup.−1 (C—N, C—O, C═S str); 1195 cm.sup.−1 (C—O ester str); 1320, 1361, 1445 cm.sup.—1 (S═O); 1734 cm.sup.−1 (C═O ester); 2868-3033 cm.sup.−1 (C—H aliph); 3419, 3569 cm.sup.−1 (O—H str).

Impurity Profile

(22) The measured impurities were consistent with those of the United States Pharmacopeia monograph of Glycopyrrolate, the bromide salt. They are: Impurity A (5-nitroisophthalic acid), believed to be from the chiral resolution of the glycopyrrolate base intermediate; Impurity B (glycopyrrolate base intermediate); and Impurity C (cyclopentylmandelic acid) which is used in the first step of the synthesis, and is also believed to be the primary degradation product. No other impurities were observed in the batches or forced degradation studies. All batches have contained very low levels of total impurities and easily met the limit of 0.15%.

(23) An additional potential impurity is methyl tosylate used in the quaternization step. Methyl tosylate is believed to be unstable in aqueous medium and effectively cleared by the final crystallization steps. Methyl tosylate levels are consistently not detected, at a limit of detection of 2.25 ppm.

(24) All publications, patents, and patent applications cited in this specification are herein incorporated by reference as if each individual publication, patent, or patent application were specifically and individually indicated to be incorporated by reference. While the claimed subject matter has been described in terms of various embodiments, the skilled artisan will appreciate that various modifications, substitutions, omissions, and changes may be made without departing from the spirit thereof. Accordingly, it is intended that the scope of the claimed subject matter is limited solely by the scope of the following claims, including equivalents thereof.