Title of Invention

PROCESS FOR THE PREPARATION OF ROCURONIUM BROMIDE AND INTERMEDIATES THEREOF

Abstract

A process for preparing a compound represented as compound-ll comprising, (i) acetylating compound - I using an acetylating agent in an organic solvent to obtain the compound -II, (ii) washing the compound obtained in step (i) with water to remove impurities (iii) evaporating the resulting compound obtained in step (ii) to dryness to obtain a crude product (iv) Crystallizing the crude product obtained in step (iii) using organic solvents or mixture thereof (v) recrystallizing the product using a mixture of organic solvents or mixture thereof to obtain highly pure compound - II.

Full Text

PROCESS FOR THE PREPARATION OF ROCURONIUM BROMIDE AND INTERMEDIATES THERE OF: FIELD OF INVENTION The Present invention relates to a novel regioselective process for preparing (2p, 3a, 5a, 16(3, 17P)-17 acetoxy-3-hydroxy-2-(4-morpholinyl)-16-(1-pyrrolidinyl) androstane and method for preparing rocuronium bromide thereof. BACKGROUND OF THE INVENTION Neuromuscular blocking agents are used as an adjunct to anesthesia. Neuromuscular blocking agents relax skeletal muscle tone by blocking transmission of key neurotransmitters through the neuron receptors at the neuromuscular junction (NMJ). They are divided into two major categories depending upon their action, namely, depolarizing and non-depolarizing neuromuscular blockers. Rocuronium is an aminosteroidal non-depolarizing neuromuscular blocker or muscle relaxant used in modern anaesthesia, to facilitate endotracheal intubation and to provide skeletal muscle relaxation during surgery or mechanical ventilation. Processes for preparing rocuronium bromide are described in US patents Nos. 4,894,369 and 5,817,803 and in Tuba, Z.et a!.(2002), "Synthesis and structure-activity relationships of neuromuscular blocking agents," Curr.Med.Chem, 9(16): 1507-36. which are all discussed herein. The process of US 4,894,369 employs acetyl chloride for acetylation of (2(3, 3a, 5a, 16(3, 17p)«2-(4-morpholinyl)-16-(1-pyrrolidinyl) androstan-3,17-diol (which is referred to herein throughout as compound-l) to yield (2(3, 3a, 5a, 16(3, 17(3)-17-acetoxy-3-hydroxy-2-(4-morpholinyl)-16-(1-pyrrolidinyl)androstane (which is referred to herein throughout as compound -II). Acetyl chloride is not a selective acetylating agent for this reaction and acetylation is done with 1.13 equivalents of acetyl chloride to give compound-ll. During the reaction, the desired compound-ll is obtained in low yield which may be due to formation of the undesired compound (20, 3a, 5a, 160, 17p) -2-(4-morpholinyl)-16-(1-pyrrolidinyl) androstan-3,17-diacetate (which is referred to herein throughout as compound- III) and significant quantity of compound -I may remain unchanged . Purification was done by column chromatography to give the desired compound-ll at a yield of 48%. This method reduces the overall efficiency of the process substantially and is further limited by the need to purify the product by column chromatography, which is inconvenient, time consuming and expensive on commercial scale. The process described in US 5,817,803, involves acetylation of (2p, 3a, 5a, 16(3, 17P)-2,3-epoxy-17-hydroxy-16-(1-pyrrolidinyl)androstane represented as compound A(scheme-I) to obtain compound B and treating compound B with morpholine to yield compound II which is a known intermediate in the synthesis of rocuronium bromide. This patent fails to provide any improved efficiency of the process in terms of yield and purity. Moreover the reaction of compound B with morpholine under the conditions described in the above patent may result in deacetylation by the reaction of morpholine with the acetoxy group at position 17 and therefore affecting the efficiency of the process. Another US patent application in 2005 by Eliezer Adar et al. describes a process where in reacting the compound-l with a molar excess of an acetylating agent, preferably acetyl chloride or acetic anhydride yields a reaction mixture containing mainly compound-Ill. Treating this reaction mixture with acid like aqueous hydrochloric acid selectively de acetylates the acetoxy group at position 3 to yield compound -II obtaining pure compound - by this process is tedious involving several purification steps, thereby resulting in low yields of compound-ll. Therefore, it is an object of the present invention to provide an improved regioselective process for the preparation of (2(3, 3a, 5a, 160, 170)-17-acetoxy-3-hydroxy-2-(4-morpholinyl)-16-(1-pyrrolidinyl)androstane (Compound- II) and, thus, rocuronium bromide. Another object of the present invention is to provide an industrially viable, easy, convenient, and inexpensive process for the preparation of very pure compound - II and thus very pure rocuronium bromide, in high yield. Summary of the invention First aspect of the present invention relates to process for the preparation of (2(3, 3a, 5a, 160, 17(3)-17-acetoxy-3-hydroxy-2-(4-morpholinyl)-16-(1-pyrrolidinyl) androstane (Compound - II). Another aspect of the present invention relates to process for the preparation of pure Compound - II in high yield. Yet another aspect of the present invention relates to process for the preparation of pure compound - II substantially free of impurities. Yet another aspect of the present invention relates to process for the preparation of pure compound - II where in column chromatography is dispensed with in the purification step. Still another aspect of the present invention relates to development of industrially viable, easy, convenient and inexpensive process for the manufacture of pure compound -II Yet another aspect of the present invention relates to process for the preparation of pure compound - II comprising: (i) regioselective acetylation of (2(3, 3a, 5a, 16(3, 17(3)-2-(4-morpholinyl)-16-(1 -pyrrolidinyl) androstan-3,17-diol (compound - I) using N-acetyl imidazole in the presence of a suitable solvent system to obtain compound-ll, (ii) crystallizing the crude product using a solvent or solvent mixture, preferably diethyl ether and petroleum ether (60-80°C) mixture to obtain pure compound-ll (iii) recrystallizing the product using a solvent or solvent mixture, preferably, dichloromethane and acetonitrile mixture, to obtain highly pure compound-ll in the range of 99.9% purity. Yet another aspect of the present invention relates to process for the preparation of rocuronium bromide. Further aspect of the present invention relates to process for the preparation of pure rocuronium bromide. Yet another aspect of the present invention relates to process for the preparation of very pure compound - II in high yield which facilitates the preparation of pure rocuronium bromide in high yield. Still another aspect of the present invention relates to industrially viable, easy, convenient and inexpensive process for the preparation of pure rocuronium bromide in high yield. Detailed Description The following detailed description sets forth numerous specific details to provide a thorough understanding of the invention. However, those skilled in the art will appreciate that the invention may be practiced without these specific details. Even so, this detailed description should not be construed to unduly limit the present invention as modifications and variations in the embodiments discussed herein which can be made by those of ordinary skill in the art without departing from the spirit or scope of the present invention. Accordingly the present invention, describes a novel, efficient and cost-effective process for the preparation of (2(3, 3a, 5a, 16(3, 17(3)-17-acetoxy-3-hydroxy-2-(4-morpholinyl)-16-1-pyrrolidinyl) androstane, a known intermediate in the synthesis of the neuromuscular blocking agent, rocuronium bromide and thus a novel process for the preparation of rocuronium bromide. One embodiment of the present invention is to provide process for the preparation of (2(3, 3a, 5a, 16(3, 17(3)-17-acetoxy-3-hydroxy-2-(4-morpholinyl)-16- (1-pyrrolidinyl) androstane (compound-ll) from 20, 3a, 5a, 160, 17(3)-2-(4-morpho!inyl)-16-(1-pyrrolidinyl) androstan-3,17-diol (compound-1). Another embodiment of the present invention is to provide process for the preparation of compound-ll comprising: (i) acetylating the compound - I using acetylating agent in an organic solvent to obtain the compound -II, (ii) washing the compound obtained in step (i) with water to remove the bye-products (iii) evaporating the resulting compound obtained in step (ii) to dryness to obtain a crude product (iv) crystallizing the crude product obtained in step (iii) using organic solvents or mixture thereof (v) recrystallizing the product using a mixture of organic solvents or mixture thereof to obtain highly pure compound of-II. Another embodiment of the present invention is to provide a process for the preparation of rocuronium bromide, (vi) by treating the compound-ll obtained by the above five steps with allylbromide in an organic solvent to obtain rocuronium bromide (vii) removing the volatiles present in the rocuronium bromide obtained in step (vi) by spray drying or freeze drying to obtain a product substantially free from residual solvents. In a preferred embodiment of the present invention, step (i) carried out in an organic solvent. The organic solvent used herein including halogenated hydrocarbons, acetonitrile, N,N-dimethylformamide, N,N-dimethy!acetamide, dimethylsulfoxide, and the like and mixture thereof, more preferably halogenated hydrocarbons, most preferably dichloromethane. In another embodiment of the present invention, step(i) is conducted at the temperature between 10° C and 55° C, more preferably between 15° C and 35° C, most preferably between 20° C and 30° C. In another embodiment of the present invention, step(i) acetylating agent used herein is selected from N-acetyl imidazole, N-acetyl saccharin and N-acetyl benzotriazole, preferably N-acetyl imidazole, more preferably N-acetyl imidazole in molar excess with respect to compound -1 It is found that using N-acetyl imidazole as a acetylating agent has provided high yield, more particularly in molar excess with respect to the compound -1 In a preferred embodiment of the present invention, the ratio of acetylating agent with respect to the compound -1 is between 1.1:1 and 2.5:1 moles. In another embodiment of the present invention, step (iv) organic solvent used is selected from diethyl ether, methyl tertiary butyl ether and petroleum ether (60-80°C), acetonitrile or mixture thereof. Yet another embodiment of the present invention, step (v) organic solvent used for crystallization to obtain highly pure compound is selected from dichloromethane, Acetonitrile, petroleum ether or mixture thereof. In another embodiment of the present invention, step (vi) organic solvent used for converting the compound Formula II is selected from halogenated hydrocarbons, acetonitrile, N,N-dimethylformamide, N,N-dimethylacetamide, dimethylsulfoxide, and the like and mixture thereof, more preferably halogenated hydrocarbon, most preferably dichloromethane. In another embodiment of the invention, N-acetyl imidazole is found to be an efficient acetylating agent under mild conditions employed in several acetylation reactions. It has preference to react at less hindered position due to its bulky nature which make it a suitable reagent for regioselective acetylation reactions. In another embodiment, several acetylation experiments with compound-l with several acetylating agents and different conditions was carried out and it was found that the hydroxy! group at 17-position can be preferably acetylated in preference to the hydroxy! group at 3-position under mild conditions and using minimum amount of acetylating agent. Based on the above findings we opted N-acetyl imidazole as an acetylating agent, which showed high selectively for hydroxyl group at 17-position compared td hydroxyl group at 3- position. Thus by reacting N-acetyl imidazole with compound-1 with a suitable solvent as reaction medium we achieved very high yield and with a purity in the range of 99.9 % . Thus, the present invention successfully addresses the short comings of the prior art by providing an improved process for preparing pure (2(3, 3a, 5a, 16(3, 17(3)-17-acetoxy-3-hydroxy-2-(4-morpholinyl)-16-(1 -pyrrolidinyl)androstane (compound- II) in high yield, which can be used in the preparation of rocuronium bromide. Although, the following examples illustrate the practice of the present invention in some of its embodiments, the examples should not be construed as limiting the scope of the invention. Other embodiments will be apparent to one skilled in the art from consideration of the specification and examples. It is intended that the specification, including the examples, is considered exemplary only, with the scope and spirit of the invention being indicated by the claims which follow. Example 1: (2(3, 3a, 5a, 16(3, 17p)-17-acetoxy-3-hydrbxy-2-(4-morpholinyl)-16-(1-pyrrolidinyl) androstane N-acetyl imidazole (32 g, 0.2909 mole) was treated with a solution of compound (2(3, 3a, 5a, 16(3, 17p)-2-(4-morpholinyl)-16-(1-pyrrolidinyl) androstan-3,17-diol (100g, 0.2242 mole) in 3.5 liters of dichloromethane at about 25°C for 48 hours. Then the said reaction mixture was washed with water several times to remove impurities and evaporated to dryness to yield a crude product. HPLC analysis of a reaction sample showed 92% of compound- II. Example-2: The crude product obtained in the Example - 1 was crystallized using a solvent mixture containing 4 L of Diethyl ether and 3.7 L of petroleum ether (60-80°C) to yield 93g compound - II which was 99% pure by HPLC. Example 3: The recrystallized compound 93 g obtained in Example - 2 was subjected to recrystallization using dichloromethane and acetonitrile solvent mixture to yield 90 g of compound - II, with a purity of about 99.9 % as determined by HPLC. Example 4: Allylbromide (135 mL) was added to a solution of compound - II (90 g), prepared according to the preceding examples, in 1.8 L of dichloromethane. The reaction was set aside at room temperature (about 25°C) for 24 hours. The reaction was worked up by removing the solvent under reduced pressure and adding the concentrated solution to diethyl ether to precipitate 90 grams of rocuronium bromide having a purity of 99 % as determined by HPLC. What is claimed is: 1. A process for preparing a compound represented as compound-ll comprising, (i) acetylating compound - I using an acetylating agent in an organic solvent to obtain the compound -II, (ii) washing the compound obtained in step (i) with water to remove impurities (iii) evaporating the resulting compound obtained in step (ii) to dryness to obtain a crude product (iv) Crystallizing the crude product obtained in step (iii) using organic solvents or mixture thereof (v) recrystallizing the product using a mixture of organic solvents or mixture thereof to obtain highly pure compound - II. 2. The process as claimed in claim 1, step (i) is carried out in an organic solvent such as halogenated hydrocarbons, acetonitrile, N,N-dimethylformamide, N,N-dimethylacetamide, dimethylsulfoxide, and the like and mixture thereof, more preferably halogenated hydrocarbon, most preferably dichloromethane. 3. The process as claimed in claim 1, wherein step(i) is conducted at the temperature between 10° C and 55° C, more preferably between 15° C and 35° C, most preferably between 20° C and 30° C. 4. The process as claimed in claim 1, step(i) acetylating agent used herein is selected from N-acetyl imidazole, N-acetyl saccharin and N-acetyl benzotriazole, preferably N-acetyl imidazole, more preferably N-acetyl imidazole in molar excess with respect to compound-1. 5. The process as claimed in claim 1, wherein the ratio of acetylating agent with respect to the compound -1 is between 1.1:1 and 2.5:1 moles. 6. The process as claimed in claim 1, wherein step (iv) organic solvent used is selected from diethyl ether, methyl tertiary butyl ether and petroleum ether (60-80°C), acetonitrile or mixture thereof, more preferably mixture of diethyl ether and petroleum ether (60-80°C). 7. The process as claimed in claim 1, wherein step (v) organic solvent used for crystallization to obtain highly pure compound is selected from dichloromethane, Acetonitrile, petroleum ether or mixture thereof, more particularly mixture of dichloromethane, Acetonitrile. 8. The process as claimed in claim 1, wherein the compound -II is obtained in a yield of over 90%, with purity more preferably over 98%, most preferably 99.9%. 9. Compound - II whenever prepared by the process claimed in claim 1 (i) acetylating the compound- I using acetylating agent in an organic solvent to obtain the compound - II, (ii) washing the compound obtained in step (i) with water to remove impurities (iii) evaporating the resulting compound obtained in step (ii) to dryness to obtain a crude product (iv) crystallizing the crude product obtained in step (iii) using organic solvents or mixture thereof (v) recrystallizing the product using a mixture of organic solvents or mixture thereof to obtain highly pure compound - II (vi) treating highly pure compound- II with allylbromide in an organic solvent to obtain rocuronium bromide (vii) removing the volatiles present in the rocuronium bromide obtained in step (vi) by spray drying or freeze drying to obtain a product substantially free from residual solvents. 11. The process as claimed in claim 10, step (i) is carried out in an organic solvent such as halogenated hydrocarbons, acetonitrile, N,N-dimethylformamide, N,N-dimethylacetamide, dimethylsulfoxide, and the like and mixture thereof, more preferably halogenated hydrocarbon, most preferably dichloromethane. 12.The process as claimed in claim 10, wherein step(i) is conducted at the temperature between 10° C and 55° C, more preferably between 15° C and 35° C, most preferably between 20° C and 30° C. 13. The process as claimed in claim 10, step(i) acetylating agent used herein is selected from N-acetyl imidazole, N-acetyl saccharin and N-acetyl benzotriazole, preferably N-acetyl imidazole, more preferably N-acetyl imidazole in molar excess with respect to compound-1. 14. The process as claimed in claim 10, wherein the ratio of acetylating agent with respect to the compound -1 is between 1.1:1 and 2.5:1 moles. 15. The process as claimed in claim 10, wherein step (iv) organic solvent used is selected from diethyl ether and petroleum ether (60-80°C), acetonitrile or mixture thereof, more preferably mixture of diethyl ether and petroleum ether (60-80°C). 16. The process as claimed in claim 10, wherein step (v) organic solvent used for crystallization to obtain highly pure compound is selected from dichloromethane, Acetonitrile, petroleum ether or mixture thereof, more particularly mixture of dichloromethane, Acetonitrile. 17.The process as claimed in claim 10, step (vi) organic solvent used for converting the compound - II is selected from halogenated hydrocarbons, acetonitrile, N,N-dimethylformamide, and the like and mixture thereof, more preferably halogenated hydrocarbon, most preferably dichloromethane. 18.The process as claimed in claim 10, wherein the rocuronium bromide obtained is in a yield of over 90%, with purity more than 98%, most precisely 99%.

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1657-che-2007-description(complete).pdf

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