Title of Invention	"AN IMPROVED PROCESS FOR TEH PREPARATION OF REMIFENTANIL AND ITS ANALOGUES"
Abstract	The present invention provides an improved process for the preparation compound having the formula methyl 1-benzyl 4-(phenylpropionylamino)piperidine-4-carboxylate (II), which can be used for the synthesis of remifentanil and its analogues. This invention results in an efficient process for the preparation of remifentanil and its analogues with less number of steps, reduced reaction time and more economical than the known processes and does not require harsh chemicals in any of the steps of the process, forming very small amount of decomposition products which decreases the effluent load of the process utilizing low energy and can be used for industrial scale preparations of remifentanil and its analogues.

Title of Invention

"AN IMPROVED PROCESS FOR TEH PREPARATION OF REMIFENTANIL AND ITS ANALOGUES"

Abstract

The present invention provides an improved process for the preparation compound having the formula methyl 1-benzyl 4-(phenylpropionylamino)piperidine-4-carboxylate (II), which can be used for the synthesis of remifentanil and its analogues. This invention results in an efficient process for the preparation of remifentanil and its analogues with less number of steps, reduced reaction time and more economical than the known processes and does not require harsh chemicals in any of the steps of the process, forming very small amount of decomposition products which decreases the effluent load of the process utilizing low energy and can be used for industrial scale preparations of remifentanil and its analogues.

Full Text	HELD OF INVENTION: The present invention comprises an improved process for the preparation of Remifentanil and its analogues of formula (I). Particularly, the present invention provides the preparation of a key intermediate compound of formula n, which is used for the synthesis of remifentanil and its analogues. The process of present invention is an efficient process for the preparation of remifentanil and its analogues with less number of process steps, reduced reaction time and more economical than the known processes. (Formula Removed) wherein, Ri =Me, Et and R=CH2CH2COO(CH2)aCH3; CH2CH2COOC6H5 wherein n=0-5 BACKGROUND OF THE INVENTION: Remifentanil is a potent ultra short-acting synthetic opioid analgesic drug. It is given to patients during surgery to relieve pain as an adjunct to an anesthetic, Indicated to provide analgesia and sedation in mechanically ventilated Intensive care unit (ICU) patients. Its unique properties, e.g. organ independent metabolism, lack of accumulation, rapid offset of action, set it apart from other opioid agents. It is structurally unique as it has an ester linkage that renders it susceptible to hydrolysis by nonspecific plasma and tissue esterases to inactive metabolites and is readily excreted by the body. This pathway of metabolism is responsible for its uniquely evanescent effect. Thus, the side effects for which opioids are much maligned, are extremely transient when remifentanil is used. Thus remifentanil (I) is found to have special attention and is distinguished from other 4-anilidopiperidines analgesics by its rapid onset and very short duration of action [Ref: Battershill et al, Remifentanil: A review of its Analgesic and Sedative Use in the Intensive Care Unit, Drugs, 2006, 66(3), 365; Shmuel et al., Remifentanil: A Novel Systemic Analgesic for Labor Pain, Anesth. Analg., 2005,100, p 233]. Remifentanil has certain remarkable pharmacokinetic features [Ref: Egan, T.D. Et al., The pharmacokinetics of the new short acting opioid remifentanil in healthy adult male volunteers, Anesthesiology, 1993, 79, p. 881] such as an extraordinary clearance of nearly 3 liters/minute, very short half-life of 3-10 minutes, exceptionally short time to peak effect of about 1.6 minutes. Clinically, these properties translate in to prompt achievement of steady state concentration in the plasma and its effect site leading to rapid onset of effect and less accumulation than other opioids irrespective of the duration of the infusion. It also implies predictable termination of effects, hence allowing precise titration of its dose and action. The pharmacokinetics are unchanged in renal or hepatic failure. In addition, esterase metabolism appears to be very well preserved system with little variability between individuals, which contribute further to the predictability of drug effect and enhance its safety profile. The utility of remifentanil stems from rapidity of onset of its effect, ability to titrate its desired effect and to maintain a sufficient plasma opioid concentration to suppress the stress response and finally rapidity of recovery from its effects. It has proven to be of immense value in anesthetic practice. It is because of these features, remifentanil has been called a "designer drug" and rightly so, since it allows the user to practically "dial" its effect making it truly the opioid for the 21st century [Sreevestava et al., Medical Journal Armed Forces India, 2004, 60(2), p.177]. In spite of the importance of this compound, only few reported methods are available for synthesis of remifentanil. (i) Cheng, B., Process for . synthesizing remifentanil, Patent Application No. WO2007/061555; (ii) J. Cervello Pages and M. Canto Vallverdu, Process for preparing Remifentanil, intermediates thereof, use of said intermediates and processs for their preparation, Patent Application No. WO2007/144391. (iii) Feldman et al, A novel route to the 4-Anilido-4-(methoxycarbonyl) piperidine class of analgesics, J Org Chem, 1990, 55, p 4207. (iv) Kiricojevic et al, An optimized synthesis of a key pharmaceutical intermediate methyl-4-[(l-oxopropyl) phenylamino]piperidine-4-carboxylate, J Serb Chem Soc, 2002,67(12), 793. All these methods are cumbersome and require multiple reaction steps ultimately resulting in the decreased product yield and increased process cost and thereby making the process less economical. The various drawbacks of the processes known in the art are described below. The process for synthesizing remifentanil, by Cheng, B. vide patent application no. WO2007/061555 involves five steps starting from 4-piperidonehydrochloride. The process involved the following steps: Step 1: (formula Removed) The first step of the process involved the reaction of piperidone hydrochloride (1) with methyl acrylate in organic solvent in presence of a base to give alkylated piperidine (2). Step 2: (Formula Removed) The alkylated piperidone (2), obtained in step 1, is reacted with alkali cyanide like potassium cyanide, sodium cyanide and ammonium cyanide, preferably potassium cyanide and aniline to give anilino nitrile (3). Step 3 & 4: (formula Removed) The anilino nitrile (3), obtained in step 2, is hydrolyzed in the presence of an acid to give the corresponding amide (4), which is further reacted in situ with methanol to give the anilino ester (5). Step 5: (Formula Removed) The anilino ester (5), obtained in step 4, is further reacted with propionyl chloride to give Remifentanil (I). The various disadvantages in the above method are: (i) The starting compound 4-piperidone is unstable in the free base form. Hence, its salt form, i.e. 4-piperidone hydrochloride (1) is used as the starting material and the reaction is carried out by in-situ neutralization of the salt with a base. 4-piperidone undergoes polymerization in its free form during the reaction which leads to loss of starting material. (ii) The conversion of (1) to (2) takes long time i.e. 24 hrs to couple of days. (iii) During step 3, conversion of anilino nitrile (3) to the ester (5) is carried out by acid and methanol. Under these conditions, it is reported that instead of getting the desired ester, reverse reaction, known as Retro-Strecker reaction i.e., conversion to the starting piperidone (2) predominates. It leads to the formation of mixture of products. This point is reported in Feldman et al, A novel route to the 4-anilido-4-(methoxycarbonyl)piperidine class of analgesics, J Org Chem, 1990, 55, page 4207, paragraph 2. (Formula Removed) Thus the over all yield of the product decreases drastically due to this reverse reaction, (iv) In step 3 and 4, isolation of product (5) from the reaction mixture becomes difficult. The disadvantage (iii) of the above said method was overcome in the method disclosed by J. Cervello Pages in the patent application no. WO2007/144391. This method involves the following reactions: (Formula Removed) In this method, the acylation of the anilino nitrile (3) was carried out first with acyl chloride to get anilido nitrile (6) which was then treated with an alcohol and acid to give the corresponding ester (remifentanil in case the alcohol is methanol). The second step of the above reaction involves the conversion of nitrile to the ester and the trans-esterification reaction by the replacement of R3 group of 6 with R2 in I. This reaction sequence, opposite to that of Chang's method, removed the possibility of the Retero-Strecker type reaction because the anilino group is not free. However, this method still suffers from following disadvantages: i. The method suffers from the disadvantage that it involves the use of a strong acid like hydrocloric acid, hydrobromic acid, methanesulphonic acid or sulphonic acid and an alcohol preferably the acid is hydrochloric acid and alcohol is methanol, for the conversion of nitrile group to the ester group. This reagent is, however, unstable and has to be prepared freshly just prior to its use. Moreover, the strength of the alcoholic HC1 has to be estimated by titration every time before its use in the reaction. ii. Use of strong acids lead to formation of unwanted side products. This follows that separation of the compound I from these side products is required to proceed for next step. iii. Another disadvantage of this method is that it is not applicable for the preparation of remifentanil analogues in which R3 is different from R^. iv. Another disadvantage of this method is that the method is applicable to prepare limited remifentanil analogues only in which the nature of the substiruents attached to the piperidine ring is CH2CH2COOR group where R is C1-C4 alkyl group. Another method for the synthesis of remifentanil is reported by Feldman et al in their research paper entitled "A novel route to the 4-anilido-4-(methoxycarbonyl)piperidine class of analgesics" in J. Org Chem, 1990,55, p 4207. This method involves the preparation of intermediate (12) from commercially available N-benzyl-4-piperidone (7) which can be converted in to remifentanil and its analogs. (Formula Removed) This intermediate (12) can be converted in to remifentanil and its analogs. The various drawbacks in this process are : (i) Even though the conversion reaction of (8) to (9) occurs to give almost quantitative yield of (9), further acid hydrolysis of this to obtain (10) leads to by-products (7) and (8). i.e. the starting materials are obtained to about 40%. This clearly indicates the problem of separation of the product (10) to carry forward the further steps. (ii) Because of the above reversible reactions, the overall yield of the process is low. (iii) Conversion of the hydrantoin (10) to sodium salt (11) requires heating of (10) in a sealed vessel in 8 N sodium hydroxide at 225°C. Thus a harsh reaction condition such as sealed reaction vessel, high temperature are required to carry out this step. (iv) Conversion of the sodium carboxylate salt (11) to (12) is also not simple. The general acid catalyzed esterification of (11) with methanol is reported to be sluggish and difficult. This conversion could be achieved by methyl iodide in dimethylformamide as solvent and the yield in this step is 55-60% only. (v) Thus this process involves various above drawbacks indicating clearly that it is not suitable for up scaling. (vi) This process is not cost effective also even at laboratory scale. One of the method reported by Kiricojevic et al entitled "An optimized synthesis of a key pharmaceutical intermediate methyl 4-[(l-oxopropyl) phenyl amino] piperidine-4-carboxylate" J. Serb. Chem. Soc, 2002, 67 (12), p 793 requires seven steps for the synthesis of remifentanil from the commercially available starting material. Basically, it described the preparation of methyl 4-[(l-oxopropyl)phenyl amino]piperidine-4-carboxylate (13) which is a key intermediate for the synthesis of remifentanil and other related compounds and can be considered as a common precursor. The reported process involved following steps starting from l-benzyl-4-piperidone (7): Step 1: (Formula Removed) The first step of the process involved the Strecker type reaction of l-benzyl-4-piperidone (7) with aniline and potassium cyanide in dicholoromethane in presence of acetic acid to give anilino nitrile (8) with 85% yield. Step 2(Formula Removed) The anilino nitrile (8), obtained in step 1, is hydrolyzed with concentrated sulfuric acid at room temperature for 24 hours to give aniline amide (13) in 83% yield. (Formula Removed) Step 3: The anilinoamide (13), obtained in step 2, is reacted with KOH in 1, 2-propylene glycol with catalytic amount of 18-crown-6 at 200°C for 12 hours to yield the anilino carboxylic acid (14).(Formula Removed)Step 4:The anilino carboxylic acid (14), obtained in step 3, is heated with excess thionyl chloride in chlorobenzene with catalytic amount of DMF at 120°C for 3-4 hours to give the corresponding acid chloride which is further reacted in situ with excess methanol at room temperature to give anilino ester (12) (40% yield over two steps).Step 5: (Formula Removed) The aniline ester (12), obtained from step 4, on subsequent reaction with propionyl chloride in boiling dichloromethane in presence of triethylamine gave anilido ester (15) in 60 % yield. Step 6: (Formula Removed) Methyl 4-[(l-oxopropyl)phenyl amino] piperidine 4-carboxylate (15a) is obtained in 90% yield by the debenzylation of anilido ester (15), obtained from step 5, with hydrogen in presence of 10% palladium charcoal catalyst. Step 7: Remifentanil (I) can be synthesized from methyl 4-[(l-oxopropyl)phenyl amino] piperidine 4- carboxylate (15a) obtained in step 6, by reacting it with alkyl acrylate. The various drawbacks in the above method are: (i) It gives low over all yield of the product and takes longer reaction time. (ii) It requires harsh reaction conditions such as high temperature as in step 3. (iii) It uses moisture sensitive chemical like thionyl chloride which requires special attention and extra precautions. (iv) A large number decomposition products are formed which require special chromatographic techniques for the purification of the product for its use in subsequent step. (v) The purification of the products requires a large amount of organic solvent which makes the process less eco-friendly. Thus, there arise a need to develop a better process for the preparation of remifentanil and their analogues which can overcome the drawbacks of the process known in the art and develop a simple, cost effective, time-saving and energy saving process for the preparation of remifentanil and its analogs. OBJECTIVE OF THE PRESENT INVENTION: An aspect of the present invention is to provide a process for the preparation of remifentanil wherein intermediate compound (II) in which the reversible reaction i.e. Retro-Strecker reaction is not possible, thus the formation of side products is eliminated.. (Formula Removed) Another aspect of the present invention is to provide a process for the preparation of remifentanil, in particular, intermediate (II) required for the preparation of remifentanil and its analogues. Still another aspect of the present invention is to provide a process for the preparation of intermediate (II) in which simple reaction conditions are employed with out any harsh chemicals in any of the steps of the process which makes the process for the preparation of remifentanil and its analogs to a better method. Yet another aspect of the present invention is to provide a process for the preparation of intermediate (II) in which very small amount of decomposition products are formed which will decrease the effluent load of the process. Still yet another aspect of the present invention is to provide a process for the preparation of intermediate (II) in which the purification of the product does not require any special chromatographic technique. Another aspect of the present invention is to provide a process for the preparation of intermediate (II) which utilizes low energy and is cost effective. Yet another aspect of the present invention is to provide a process for the preparation of intermediate (II) which can be used for industrial scale preparations of remifentanil and its analogues. SUMMARY OF THE INVENTION: (Formula Removed) The present invention provides a process for the synthesis of remifentanil and its analogues. The present invention proposes an improved process for the synthesis of methyl or ethyl 1-benzyl 4-(phenylpropionylamino)piperidine-4-carboxylate (II) which is the intermediate in the synthesis of remifentanil and its various analogues. The synthetic process involves l-benzyl-4-(phenylamino) piperidine-4-carbonitrile (8) as the starting material which has been prepared from commercially available l-benzyl-4-piperidone (7) by the procedure as described in the known art. The important aspects of the present invention are: (a) Design and development of a process for the preparation of remifentanil or its analogs in which the Retro-Stecker reaction is not possible; (b) Design and development of a simple, cost effective, time-saving and energy saving process to obtain important intermediate (II) required for the preparation of remifentanil and its analogs. The improved process involves reacting (8) with propionyl chloride in organic solvent like toluene, dichloromethane, dichloroethane to give l-benzyl-4-(phenylpropionylamino) piperidine-4-carbonitrile (17), treating (17) with chlorotrialkylsilane and an alcohol in absence of organic solvent to give the desired intermediate ethyl or methyl 1-benzyl 4-(phenylpropionylamino)piperidine-4-carboxylate (II), which is then debenzylated with hydrogen in presence of palladium-charcoal catalyst by a known procedure, as described in the known art, to give the desired intermediate ethyl or methyl 4-(phenylpropionylamino)piperidine-4-carboxylate (16) and finally compound (16) is stirred with a suitable acrylate with isopropanol and conc. HC1, and cooling to obtain remifentanil analogues. STATEMENT OF THE INVENTION: Accordingly, the present invention provides a process preparation of remifentanil and its analogues having the formula: (Formula Removed) Formula (I) wherein, Ri is selected from the group consisting of methyl or ethyl group and R=CH2CH2COO(CH2)nCH3; CH2CH2COOC6H5 wherein n=0-5; wherein the process comprising the steps of: a) reacting compound (8) having the formula: (Formula Removed) with acid chloride in an organic solvent to form compound (17) having the formula: (Formula Removed) 17 b) reacting the compound (17) obtained in step (a) with chlorotrialkylsilane and an alcohol under nitrogen atmosphere to obtain compound (II) having the formula: (Formula Removed) wherein R1=Methyl group or Ethyl group; c) reacting the compound obtained in step (b) with hydrogen in presence of palladium-charcoal catalyst to form compound (16) having the formula: Wherein R Methyl or ethyl group; d) reacting the compound (16) obtained in step (c) with acrylates selected from CH2CHCOO(CH2)nCH3 and CH2CHCOOC6H5 ,wherein n= 0 to 5 to obtain compound of formula (I). (Formula Removed) DETAILED DESCRIPTION OF THE INVENTION: The present invention comprises an improved process for the preparation of compound II used for preparation of remifentanil and its analogues (I) (Formula Removed) wherein, R1 =Me, Et and R=CH2CH2COO(CH2)nCH3; CH2CH2COOC6H5 wherein n=0-5 Said process comprising the steps of: 1. Reacting l-benzyl-4-(phenylamino)piperidine-4-carbonitrile (8) with propionyl chloride in organic solvent like toluene, dichloromethane and dichloroethane to give 1-benzyl-4-(phenylpropionyl amino)piperidine-4-carbonitrile (17) in 80-85 % yield. 2. In the second step, l-Benzyl-4- (phenylpropionyl amino)piperidine-4-carbonitrile (17) obtained in first step, is treated with chlorotrialkyl silane and an alcohol like methanol or ethanol in absence of any other organic solvent in nitrogen atmosphere to give methyl or ethyl 1-benzyl 4-(phenylpropionylamino)piperidine-4-carboxylate (II) respectively in 70-75 % yield. The intermediate (It), thus can be converted into remifentanil and its various analogues using the method reported by Kiricojevic et al in J serb Chem Soc, 2002,67(12), p793. The chlorotrialkyl silane used in the process of preparation of compound II is represented by the following formula: (Formula Removed) wherein n = 0 to 3. The process of the present invention for the synthesis of compound (II) comprises of the following steps: Step 1: Preparation of l-benzvl-4-(phenvlamino)piperidine-4-carbonitrile (8) from l-benzvl-4-piperidone (7) This step is carried out as per procedure reported in the prior art viz V.D. Kiricojevic, M.D. Ivanovic, I.V. Micovic, J.B.Djordjevic, G.M. Roglic and L.J. Dosen-Micovic, J.Serb. Chem. Soc., 2002, 67(12), 739-802. (Formula Removed) To a solution of 2-5 % by weight, preferably 3-4 % by weight of l-benzyl-4-piperidone in organic solvents like 30-80 % by weight of dichloromethane, chloroform, preferably 50-60 % by weight of dichloromethane, 4-10 % by weight, preferably 6-8 % by weight of aniline and 2.5-7 % by weight, preferably 4-5.5 % by weight of potassium cyanide, are added and the resulting mixture is cooled to 0-5° C in an ice bath for 5-20 min, preferably 10 min. To this stirred solution, 2-50 % by weight of acetic acid, preferably, 30-40 % by weight, are added drop-wise and after the addition is complete, the reaction mixture is heated to 30-50 ° C, preferably 35-40° C, in an oil bath. After completion of the reaction, reaction mixture is cooled to room temperature and then neutralized by adding 25% sodium hydroxide solution (5-15 % by weight, preferably 7-10% by weight). From the resulting biphasic solution, the organic phase is separated and the aqueous phase is extracted with 15-25 % by weight of organic solvents like dichloromethane, chloroform and ether, preferably 8-12 % by weight dichloromethane. The combined organic phases are dried over anhydrous sodium sulphate and the solvent is evaporated under vacuum to get the crude compound. It is further purified by recrystallization with petroleum ether to give l-benzyl-4-phenylaminopiperidine-4-carbonitrile (8) as colorless compound (80-85% yield). Step 2: Preparation of l-benzvl-4-phenvlpropionvl amino)pjperidine-4-carbonitrile (17) from 1-benzvl-4-(phenvlamino) piperidine-4-carbonitrile (8): (Formula Removed) To the stirred solution of 10-30 % by weight, preferably 15-20 % by weight of l-benzyl-4-(phenylamino) piperidine-4-carbonitrile (8) in 40-80 % by weight of organic solvents like toulene, dichloromethane and chloroform, preferably 50-60 % by weight of dichloromethane, 10-30 % by weight, preferably 15-20 % by weight, were added. The reaction mixture is refluxed for 2-10 hours, preferably 3-5 hours, followed by gradual addition of 4-10 % by weight, preferably 6-8 % by weight of triethylamine. After the reaction is complete, the reaction mixture is cooled and poured into 40-80 % by weight, preferably 50-60 % by weight of 25% potassium carbonate solution to form layers. The layers are separated and the aqueous layer is extracted with the 20-40 % by weight organic solvent like toluene, dichlomethane and dichloroethane, preferably 25-30 % by weight dichlorometahne. The combined organic layers are mixed, dried over sodium sulphate and concentrated under vacuum to give the crude l-benzyl-4-(phenylpropionyl amino)piperidine-4-carbonitrile (17) as oil (80-85% yield). Step 3: Preparation of ethyl or methyl 1-benzyl 4-(phenvlpropionvlamino)piperidine-4-carboxylate (II) from 1-benzvl 4-(phenylpropionylamino)piperidine-4-carbonitrile (17) (Formula Removed) In a three neck round bottom flask, 30-80 % by weight, 40 - 60 % by weight of dry methanol or ethanol, 20-50 % by weight, preferably 30-35 % by weight of trialkylsilyl chloride, and 10-40 % by weight, preferably 20-25 % by weight of l-benzyl-4-(phenylpropionyl amino)piperidine 4-carbonitrile (17), were mixed under nitrogen atmosphere and stirred at 40-60° C, preferably at 45-50° C for 2-10 hours, preferably for 4-5 hours. After cooling to room temperature, 300-500 % by weight, preferably 400-450 % by weight of water, 20-50 % by weight, preferably 30-35 % by weight of sodium carbonate, and 300-500 % by weight, preferably 400-450 % by weight of dichloromethane, are added to the reaction mixture. The resulting mixture is then extracted with 20-40 % by weight, preferably 25 - 30 % by weight of organic solvent like dichloromethane, chloroform, diethyl ether, preferably dichloromethane. The organic extract is dried over anhydrous sodium sulphate and the solvent is evaporated under vacuum to obtain ethyl or methyl 1-benzyl 4-(phenylpropionylamino)piperidine-4-carboxylate (II) as oil (70-75% yield). Step 4: Preparation of ethyl or methyl 4-(phenvlpropionvlamino)peridine-4-carboxvlate (16) from ethyl or methyl 1-benzyl 4-(phenvlpropionylamino)piperidine-4-carboxvlate (ID: This step is also carried out as per procedure reported in the prior art, viz V.D. Kiricojevic, M.D. Ivanovic, I.V. Micovic, J.B. Djordjevic, G.M. Roglic and L.J. Dosen Micovic, J.Serb. Chem Soc., 2002, 67 (12), 739-802. (Formula Removed) A solution of 5-15 % by weight, preferably 8-10% by weight of methyl or ethyl l-benzyl-4-(phenylpropionylamino)piperidine-4-carboxylate (II) obtained in step 3, in 60-90 % by weight, preferably 70-80 % by weight of acetic acid and water (4:6) and 8-20 % by weight, preferably 10-12 % by weight of concentrated hydrochloric acid, is added to it. The resulting mixture is hydrogenated in Parr apparatus in the presence of 0.50-2.00 % by weight, preferably 0.70-1.00 % by weight of 10% palladium-charcoal catalyst. After competition of the reaction, the reaction mixture is poured in to cold water and neutralized with 30 -50 % by weight, preferably 40-45 % by weight of 20% sodium hydroxide solution. The resulting solution is then extracted with organic solvents like chloroform, diethyl ether, dichloromethane, ethyl acetate, preferably dichloromethane, the organic phase dried over sodium sulphate and concentrated under reduced pressure to give compound 16 as colourless solid (90-95% yield). Step 5: Preparation of Remifentanil and its analogues (I) from compound 16: A mixture of 60-90 % by weight, preferably 70-75 % by weight of compound 16, obtained in step 4 and 15-25 % by weight, preferably 20-22 % by weight of an acrylate selected from CH2CHCOO(CH2)nCH3 and CHoCHCOOC6H5 (wherein n= 0 to 5) are stirred for 2-6 hours, preferably 3-5 hours. To the reaction mixture, 60-90 % by weight of isopropanol, preferably 70- 75 % by weight and 15-25 % by weight, preferably 20-22 % by weight of concentrated hydrochloric acid are added and after shaking, kept in refrigerator for 12 hrs. The solid is separated by filtration and dried under vacuum to give hydrochloride salt of compound I (85-90% yield). The substituent R of compound I corresponds to the acrylate used in the process. For the synthesis of remifentanil the acrylate used is methyl acrylate and Rl is methyl. (Table Removed) The following examples are given by way of illustration and therefore should not be construed to limit the scope of the present invention. EXAMPLE 1: To a solution of 8.92gm of l-benzyl-4-piperidone in 100 ml dichloromethane, 18.24 ml aniline and 13.00 g potassium cyanide are added and resulting is cooled in an ice bath. To this stirred solution, 90 ml of acetic acid is added drop-wise and after complete addition, the reaction mixture is heated to 40 ° C in an oil bath for 24 hrs. The reaction mixture is then cooled to room temperature and neutralized by adding 25% sodium hydroxide solution to it. From the resulting biphasic solution, the organic phase is separated and the aqueous phase is extracted with dichloromethane. The combined organic phases are dried over sodium sulphate and concentrated under vacuum to get the crude compound. It is further purified by recrystallization with petroleum ether to give l-benzyl-4-(phenylamino)piperidine-4-carbonitrile (8) as colorless compound; yield 11.75g (86%). To the stirred solution of 10.87g of l-benzyl-4-(phenylarmno)piperidine-4-carbonitrile (8) in 100 ml of chloroform, 9.75 ml of propionly chloride is added. The reaction mixture is refluxed for three hours, followed by the gradual addition of 5.25 ml of triethylamine. After the reaction is complete, the reaction mixture is cooled and poured in to 25% potassium carbonate solution(100 ml). The layers are separated and the aquous layer is extracted with dichloromethane. The combined organic layers are mixed, dried over sodium sulphate and concentrated under vacuum to give the crude 1-benzyl 4-(phenylpropionylamino)piperidine-4-carbonitrile (17) as oil; yield 10.27 g (80%). In a three neck round bottom flask, 100 ml of dry methanol, 6.00 ml of trimethylsilyl chloride and 7.50 g of 1-benzyl 4-(phenylpropionylamino)piperidine-4-carbonitrile (17) obtained from above step, are mixed under nitrogen atmosphere and stirred at 50 ° C for three hours. After cooling to room temperature, water (20 ml), 7.50 g sodium carbonate and dichlomethane (50 ml) are added to the reaction mixture. The resulting mixture is then extracted with dichloromethane. The organic extract is dried over anhydrous sodium sulphate and concentrated under vacuum to give methyl 1-benzyl 4-(phenylpropionylamino)piperidine-4-carboxylate (II) as a oil; yields 6.15 gm (73%). A solution of 5.39 g methyl 1-benzyl 4-(phenylpropionylamino)piperidine-4-carboxylate (II), obtained from above steps, in 50ml of acetic acid and water (6:4 ratio) mixture is prepared and hydrogenated in Parr apparatus in the presence of 0.32g of 10% palladium charcoal catalyst. After competition of the reaction, the reaction mixture is poured in to cold water and neutralized with 20% sodium hydroxide solution. The resulting solution is then extracted with organic solvents like chloroform, diethyl ether, dichloromethane, ethyl acetate preferably dichloromethane, the organic phase dried over anhydrous sodium sulphate and concentrated under reduced pressure to give methyl 4-[(l-anhydrous sodium sulphate and concentrated under reduced pressure to give methyl 4-(phenylpropionylamino)piperidine-4-carboxylate (16) as the colorless solid; yield 3.65 g (90%). A mixture of 2.90 g of methyl 4-(phenylpropionylamino)piperidine-4-carboxylate (16) and 0.89 mL of methyl acrylate is stirred for two hours. After competition of recation, 10 ml of isopropanol and 1 ml concentrated hydrochloric acid are added sequentially to the reaction mixture. The resulting solution is kept in refrigator over night and the solid thus preciopated by filteration and dried under vacuum to give hydrochloride salt of Remifentanil. The salt is dissolved in water and reacted with 20% sodium hydroxide solution followed by extraction with dichloromethane. The organic phase is dried over anhydrous sodium sulphate and concentrated under vacuum to give remifentanil (I) as oil; yield 3.19g (85%). EXAMPLE 2: To a solution of 18.90 gm of l-benzyl-4-piperidone in 200 ml dichlorometahne, 36.48 ml aniline and 26.00 g potassium cyanide are added and resulting is cooled in an ice bath. To this stirred solution, 180 ml of acetic acid is added drop-wise and after complete addition, the reaction mixture is heated to 40 c C in an oil bath for 24 hrs. The reaction mixture is then cooled to room temperature and neutralized by adding 25% sodium hydroxide solution to it. From the resulting biphasic solution, the organic phase is separated and the aqueous phase is extracted with dichloromethane. The combined organic phases are dried over sodium sulphate and concentrated under vacuum to get the crude compound. It is further purified by recrystallization with petroleum ether to give l-benzyl-4-(phenylamino)piperidine-4-carbonitrile (8) as colorless compound; yield 23.50g (80%). To the stirred solution of 21.74g of l-benzyl-4-(phenylamino)piperidine-4-carbonitrile (8) in 200 ml of chloroform, 19.50 ml of propionyl chloride is added. The reaction mixture is refluxed for four hours, followed by the gradual addition of 10.50 ml of triethylamine. After the reaction is complete, the reaction mixture is cooled and poured in to 25% extracted with dichloromethane. The combined organic layers are mixed, dried over sodium sulphate and concentrated under vacuum to give the crude 1-benzyl 4-(phenylpropionylamino)piperidine-4-carbonitrile (17) as oil; yield 19.91 g (82%). In a three neck round bottom flask, 200 ml of dry methanol, 12.00 ml of trimethylsilyl chloride and 15.00 g ofl-benzyl 4-(phenylpropionylamino)piperidine-4-carbonitrile (17) are mixed under nitrogen atmosphere and stirred at 50 ° C for three hours. After cooling to room temperature, water (40 ml), 15.0 g sodium carbonate and dichlomethane (75 ml) are added to the reaction mixture. The resulting mixture is then extracted with dichloromethane. The organic extract is dried over anhydrous sodium sulphate and concentrated under vacuum to give ethyl l-benzyl-4-[(1-oxopropyl) phenylamino] piperidine-4-carboxylate (II) as a oil; yield 11.40 gm (75%). A solution of 10.78 g ethyl l-benzyl-4-[(l-oxopropyl) phenylamino] piperidine-4-carboxylate (II), obtained from above steps, in 75ml of acetic acid and water (6:4 ratio) mixture is prepared and hydrogenated in Parr apparatus in the presence of l.OOg of 10% palladium charcoal catalyst. After competition of the reaction, the reaction mixture is poured in to cold water and neutralized with 20% sodium hydroxide solution. The resulting solution is then extracted with organic solvents like chloroform, diethyl ether, dichloromethane, ethyl acetate preferably dichloromethane, the organic phase dried over anhydrous sodium sulphate and concentrated under reduced pressure to give ethyl 4-(phenylpropionylamino)piperidine-4-carboxylate (16) as the colorless solid; yield 7.32 g (89%). A mixture of 5.80 g of ethyl 1-benzyl 4-(phenylpropionylamino)piperidine-4-carboxylate (II) and 1.78 mL of methyl acrylate is stirred for two hours. After competition of reaction, 25 mL of isopropanol and 3 ml concentrated hydrochloric acid are added sequentially to the reaction mixture. The resulting solution is kept in refrigerator over night and the solid thus precipitated is separated by filtration and dried under vacuum to give hydrochloride salt of Remifentanil. The salt is dissolved in water and reacted with 20% sodium hydroxide solution followed by extraction with dichloromethane. The organic phase is dried over anhydrous sodium sulphate and concentrated under vacuum to give remifentanil analog as oil; yield 6.54 g (87%). ADVANTAGES: One of the main advantage of the present invention is to design and develop a simple, cost effective, time-saving and energy saving process for the preparation of compound (II) used for the preparation of remifentanil and its analogs. Another advantage of the present invention is to provide an improved process for the preparation of compound (II) which can give remifentanil and its analogs in better yield in comparison to the reported methods which does not require harsh chemicals in any of the steps of the process and forming very small amount of decomposition products which decreases the effluent load of the process and utilizes low energy and is cost effective which can be used for industrial scale preparations of remifentanil and its analogues. WE CLAIM: 1. An improved process for the preparation of remifentanil and its analogues having the formula: (Formula Removed) R Formula (I) wherein, R1 is selected from the group consisting of methyl or ethyl group and R=CH2CH2COO(CH2)nCH3; CH2CH2COOC6H5 wherein n=0-5; wherein the process comprising the steps of: a) reacting compound (8) having the formula: (Formula Removed) 8 with acid chloride in an organic solvent to form compound (17) having the formula: (Formula Removed) b) reacting the compound (17) obtained in step (a) with chlorotrialkylsilane and an alcohol under nitrogen atmosphere to obtain compound (II) having the formula : (Formula Removed) wherein R1=Methyl group or Ethyl group; c) reacting the compound obtained in step (b) with hydrogen in presence of palladium-charcoal catalyst to form compound (16) having the formula: (Formula Removed) Wherein R1=Methyl or ethyl group; d) reacting the compound (16) obtained in step (c) with acrylates selected from CH2CHCOO(CH2)nCH3 and CH2CHCOOC6H5,wherein n= 0 to 5 to obtain compound of formula (I). 2. The process as claimed in claim 1(a), wherein the organic solvent is selected from the group consisting of toluene, dichloromethane and dichloroethane, preferably dichloromethane. 3. The process as claimed in claim 1(a), wherein the amount of organic solvent ranges from 40 to 80 % by weight, preferably in the range of 50 to 60 % by weight. 4. The process as claimed in claim 1(a), wherein the acid chloride is propionyl chloride. 5. The process as claimed in claim 1, wherein the alcohol used is selected from the group consisting of methyl alcohol and ethyl alcohol. 6. The process as claimed in claim 1(b), wherein the chlorotrialkylsilane is having the structure: (Formula Removed) wherein, n ranges from 0 to 3. 7. The process as claimed in claim 1(b), wherein the amount of chlorotrialkylsilane ranges from 20-50 % by weight, preferably 30-35 % by weight. 8. The process as claimed in claim 1, wherein the yield of rcmifentanil and its analogue ranges from 30 to 46.3%. 9. The process as claimed in claim 1, wherein remifentanil and its analogues are used as an analgesic or anesthetic agent. 10. A process for the preparation of remifentanil and its analogues substantially as herein described in the specification with reference to the foregoing examples.

Full Text

HELD OF INVENTION:
The present invention comprises an improved process for the preparation of Remifentanil and its analogues of formula (I). Particularly, the present invention provides the preparation of a key intermediate compound of formula n, which is used for the synthesis of remifentanil and its analogues. The process of present invention is an efficient process for the preparation of remifentanil and its analogues with less number of process steps, reduced reaction time and more economical than the known processes.
(Formula Removed)
wherein, Ri =Me, Et and R=CH2CH2COO(CH2)aCH3; CH2CH2COOC6H5 wherein n=0-5
BACKGROUND OF THE INVENTION:
Remifentanil is a potent ultra short-acting synthetic opioid analgesic drug. It is given to patients during surgery to relieve pain as an adjunct to an anesthetic, Indicated to provide analgesia and sedation in mechanically ventilated Intensive care unit (ICU) patients. Its unique properties, e.g. organ independent metabolism, lack of accumulation, rapid offset of action, set it apart from other opioid agents. It is structurally unique as it has an ester linkage that renders it susceptible to hydrolysis by nonspecific plasma and tissue esterases to inactive metabolites and is readily excreted by the body. This pathway of metabolism is responsible for its uniquely evanescent effect. Thus, the side effects for which opioids are much maligned, are extremely transient when remifentanil is used. Thus remifentanil (I) is found to have special attention and is distinguished from other 4-anilidopiperidines analgesics by its rapid onset and very short duration of action [Ref: Battershill et al, Remifentanil: A review of its Analgesic and Sedative Use in the Intensive
Care Unit, Drugs, 2006, 66(3), 365; Shmuel et al., Remifentanil: A Novel Systemic Analgesic
for Labor Pain, Anesth. Analg., 2005,100, p 233].
Remifentanil has certain remarkable pharmacokinetic features [Ref: Egan, T.D. Et al., The
pharmacokinetics of the new short acting opioid remifentanil in healthy adult male volunteers,
Anesthesiology, 1993, 79, p. 881] such as an extraordinary clearance of nearly 3 liters/minute,
very short half-life of 3-10 minutes, exceptionally short time to peak effect of about 1.6 minutes.
Clinically, these properties translate in to prompt achievement of steady state concentration in
the plasma and its effect site leading to rapid onset of effect and less accumulation than other
opioids irrespective of the duration of the infusion. It also implies predictable termination of
effects, hence allowing precise titration of its dose and action. The pharmacokinetics are
unchanged in renal or hepatic failure. In addition, esterase metabolism appears to be very well
preserved system with little variability between individuals, which contribute further to the
predictability of drug effect and enhance its safety profile.
The utility of remifentanil stems from rapidity of onset of its effect, ability to titrate its desired
effect and to maintain a sufficient plasma opioid concentration to suppress the stress response
and finally rapidity of recovery from its effects. It has proven to be of immense value in
anesthetic practice. It is because of these features, remifentanil has been called a "designer
drug" and rightly so, since it allows the user to practically "dial" its effect making it truly the
opioid for the 21st century [Sreevestava et al., Medical Journal Armed Forces India, 2004, 60(2),
p.177].
In spite of the importance of this compound, only few reported methods are available for
synthesis of remifentanil.
(i) Cheng, B., Process for . synthesizing remifentanil, Patent Application No.
WO2007/061555;
(ii) J. Cervello Pages and M. Canto Vallverdu, Process for preparing Remifentanil,
intermediates thereof, use of said intermediates and processs for their preparation, Patent
Application No. WO2007/144391.
(iii) Feldman et al, A novel route to the 4-Anilido-4-(methoxycarbonyl) piperidine class of
analgesics, J Org Chem, 1990, 55, p 4207.
(iv) Kiricojevic et al, An optimized synthesis of a key pharmaceutical intermediate methyl-4-[(l-oxopropyl) phenylamino]piperidine-4-carboxylate, J Serb Chem Soc, 2002,67(12), 793. All these methods are cumbersome and require multiple reaction steps ultimately resulting in the decreased product yield and increased process cost and thereby making the process less economical. The various drawbacks of the processes known in the art are described below.
The process for synthesizing remifentanil, by Cheng, B. vide patent application no. WO2007/061555 involves five steps starting from 4-piperidonehydrochloride. The process involved the following steps: Step 1:
(formula Removed)
The first step of the process involved the reaction of piperidone hydrochloride (1) with methyl acrylate in organic solvent in presence of a base to give alkylated piperidine (2). Step 2:
(Formula Removed)
The alkylated piperidone (2), obtained in step 1, is reacted with alkali cyanide like potassium cyanide, sodium cyanide and ammonium cyanide, preferably potassium cyanide and aniline to give anilino nitrile (3).
Step 3 & 4:
(formula Removed)
The anilino nitrile (3), obtained in step 2, is hydrolyzed in the presence of an acid to give the corresponding amide (4), which is further reacted in situ with methanol to give the anilino ester (5). Step 5:
(Formula Removed)
The anilino ester (5), obtained in step 4, is further reacted with propionyl chloride to give
Remifentanil (I).
The various disadvantages in the above method are:
(i) The starting compound 4-piperidone is unstable in the free base form. Hence, its salt
form, i.e. 4-piperidone hydrochloride (1) is used as the starting material and the reaction is
carried out by in-situ neutralization of the salt with a base. 4-piperidone undergoes
polymerization in its free form during the reaction which leads to loss of starting material.
(ii) The conversion of (1) to (2) takes long time i.e. 24 hrs to couple of days.
(iii) During step 3, conversion of anilino nitrile (3) to the ester (5) is carried out by acid and
methanol. Under these conditions, it is reported that instead of getting the desired ester, reverse
reaction, known as Retro-Strecker reaction i.e., conversion to the starting piperidone (2)
predominates. It leads to the formation of mixture of products. This point is reported in
Feldman et al, A novel route to the 4-anilido-4-(methoxycarbonyl)piperidine class of analgesics, J Org Chem, 1990, 55, page 4207, paragraph 2.
(Formula Removed)
Thus the over all yield of the product decreases drastically due to this reverse reaction, (iv) In step 3 and 4, isolation of product (5) from the reaction mixture becomes difficult.
The disadvantage (iii) of the above said method was overcome in the method disclosed by J. Cervello Pages in the patent application no. WO2007/144391. This method involves the following reactions:
(Formula Removed)
In this method, the acylation of the anilino nitrile (3) was carried out first with acyl chloride to get anilido nitrile (6) which was then treated with an alcohol and acid to give the corresponding ester (remifentanil in case the alcohol is methanol). The second step of the above reaction involves the conversion of nitrile to the ester and the trans-esterification reaction by the replacement of R3 group of 6 with R2 in I. This reaction sequence, opposite to that of Chang's method, removed the possibility of the Retero-Strecker type reaction because the anilino group
is not free. However, this method still suffers from following disadvantages:
i. The method suffers from the disadvantage that it involves the use of a strong acid like hydrocloric acid, hydrobromic acid, methanesulphonic acid or sulphonic acid and an alcohol preferably the acid is hydrochloric acid and alcohol is methanol, for the conversion of nitrile group to the ester group. This reagent is, however, unstable and has to be prepared freshly just prior to its use. Moreover, the strength of the alcoholic HC1 has to be estimated by titration every time before its use in the reaction.
ii. Use of strong acids lead to formation of unwanted side products. This follows that separation of the compound I from these side products is required to proceed for next step.
iii. Another disadvantage of this method is that it is not applicable for the preparation of remifentanil analogues in which R3 is different from R^.
iv. Another disadvantage of this method is that the method is applicable to prepare limited remifentanil analogues only in which the nature of the substiruents attached to the piperidine ring is CH2CH2COOR group where R is C1-C4 alkyl group.
Another method for the synthesis of remifentanil is reported by Feldman et al in their research paper entitled "A novel route to the 4-anilido-4-(methoxycarbonyl)piperidine class of analgesics" in J. Org Chem, 1990,55, p 4207.
This method involves the preparation of intermediate (12) from commercially available N-benzyl-4-piperidone (7) which can be converted in to remifentanil and its analogs.
(Formula Removed)
This intermediate (12) can be converted in to remifentanil and its analogs.
The various drawbacks in this process are :
(i) Even though the conversion reaction of (8) to (9) occurs to give almost quantitative
yield of (9), further acid hydrolysis of this to obtain (10) leads to by-products (7) and (8). i.e. the
starting materials are obtained to about 40%. This clearly indicates the problem of separation of
the product (10) to carry forward the further steps.
(ii) Because of the above reversible reactions, the overall yield of the process is low.
(iii) Conversion of the hydrantoin (10) to sodium salt (11) requires heating of (10) in a sealed
vessel in 8 N sodium hydroxide at 225°C. Thus a harsh reaction condition such as sealed
reaction vessel, high temperature are required to carry out this step.
(iv) Conversion of the sodium carboxylate salt (11) to (12) is also not simple. The general
acid catalyzed esterification of (11) with methanol is reported to be sluggish and difficult. This
conversion could be achieved by methyl iodide in dimethylformamide as solvent and the yield in
this step is 55-60% only.
(v) Thus this process involves various above drawbacks indicating clearly that it is not
suitable for up scaling.
(vi) This process is not cost effective also even at laboratory scale.
One of the method reported by Kiricojevic et al entitled "An optimized synthesis of a key pharmaceutical intermediate methyl 4-[(l-oxopropyl) phenyl amino] piperidine-4-carboxylate" J. Serb. Chem. Soc, 2002, 67 (12), p 793 requires seven steps for the synthesis of remifentanil from the commercially available starting material. Basically, it described the preparation of methyl 4-[(l-oxopropyl)phenyl amino]piperidine-4-carboxylate (13) which is a key intermediate for the synthesis of remifentanil and other related compounds and can be considered as a common precursor. The reported process involved following steps starting from l-benzyl-4-piperidone (7):
Step 1:
(Formula Removed)
The first step of the process involved the Strecker type reaction of l-benzyl-4-piperidone (7) with aniline and potassium cyanide in dicholoromethane in presence of acetic acid to give anilino nitrile (8) with 85% yield.
Step 2(Formula Removed)

The anilino nitrile (8), obtained in step 1, is hydrolyzed with concentrated sulfuric acid at room temperature for 24 hours to give aniline amide (13) in 83% yield. (Formula Removed) Step 3:
The anilinoamide (13), obtained in step 2, is reacted with KOH in 1, 2-propylene glycol with catalytic amount of 18-crown-6 at 200°C for 12 hours to yield the anilino carboxylic acid (14).(Formula Removed)Step 4:The anilino carboxylic acid (14), obtained in step 3, is heated with excess thionyl chloride in chlorobenzene with catalytic amount of DMF at 120°C for 3-4 hours to give the corresponding acid chloride which is further reacted in situ with excess methanol at room temperature to give anilino ester (12) (40% yield over two steps).Step 5: (Formula Removed)
The aniline ester (12), obtained from step 4, on subsequent reaction with propionyl chloride in boiling dichloromethane in presence of triethylamine gave anilido ester (15) in 60 % yield. Step 6:
(Formula Removed)
Methyl 4-[(l-oxopropyl)phenyl amino] piperidine 4-carboxylate (15a) is obtained in 90% yield by the debenzylation of anilido ester (15), obtained from step 5, with hydrogen in presence of 10% palladium charcoal catalyst.
Step 7:
Remifentanil (I) can be synthesized from methyl 4-[(l-oxopropyl)phenyl amino] piperidine 4-
carboxylate (15a) obtained in step 6, by reacting it with alkyl acrylate.
The various drawbacks in the above method are:
(i) It gives low over all yield of the product and takes longer reaction time.
(ii) It requires harsh reaction conditions such as high temperature as in step 3.
(iii) It uses moisture sensitive chemical like thionyl chloride which requires special attention
and extra precautions.
(iv) A large number decomposition products are formed which require special
chromatographic techniques for the purification of the product for its use in subsequent step.
(v) The purification of the products requires a large amount of organic solvent which makes
the process less eco-friendly.
Thus, there arise a need to develop a better process for the preparation of remifentanil and their analogues which can overcome the drawbacks of the process known in the art and develop a simple, cost effective, time-saving and energy saving process for the preparation of remifentanil and its analogs.
OBJECTIVE OF THE PRESENT INVENTION:
An aspect of the present invention is to provide a process for the preparation of remifentanil wherein intermediate compound (II) in which the reversible reaction i.e. Retro-Strecker reaction is not possible, thus the formation of side products is eliminated.. (Formula Removed)
Another aspect of the present invention is to provide a process for the preparation of
remifentanil, in particular, intermediate (II) required for the preparation of remifentanil and its
analogues.
Still another aspect of the present invention is to provide a process for the preparation of
intermediate (II) in which simple reaction conditions are employed with out any harsh chemicals
in any of the steps of the process which makes the process for the preparation of remifentanil
and its analogs to a better method.
Yet another aspect of the present invention is to provide a process for the preparation of
intermediate (II) in which very small amount of decomposition products are formed which will
decrease the effluent load of the process.
Still yet another aspect of the present invention is to provide a process for the preparation of
intermediate (II) in which the purification of the product does not require any special
chromatographic technique.
Another aspect of the present invention is to provide a process for the preparation of
intermediate (II) which utilizes low energy and is cost effective.
Yet another aspect of the present invention is to provide a process for the preparation of
intermediate (II) which can be used for industrial scale preparations of remifentanil and its
analogues.
SUMMARY OF THE INVENTION:
(Formula Removed)
The present invention provides a process for the synthesis of remifentanil and its analogues. The present invention proposes an improved process for the synthesis of methyl or ethyl 1-benzyl 4-(phenylpropionylamino)piperidine-4-carboxylate (II) which is the intermediate in the synthesis of remifentanil and its various analogues. The synthetic process involves l-benzyl-4-(phenylamino) piperidine-4-carbonitrile (8) as the starting material which has been prepared from commercially available l-benzyl-4-piperidone (7) by the procedure as described in the known art. The important aspects of the present invention are:
(a) Design and development of a process for the preparation of remifentanil or its analogs in which the Retro-Stecker reaction is not possible;
(b) Design and development of a simple, cost effective, time-saving and energy saving process to obtain important intermediate (II) required for the preparation of remifentanil and its analogs.
The improved process involves reacting (8) with propionyl chloride in organic solvent like toluene, dichloromethane, dichloroethane to give l-benzyl-4-(phenylpropionylamino) piperidine-4-carbonitrile (17), treating (17) with chlorotrialkylsilane and an alcohol in absence of organic solvent to give the desired intermediate ethyl or methyl 1-benzyl 4-(phenylpropionylamino)piperidine-4-carboxylate (II), which is then debenzylated with hydrogen in presence of palladium-charcoal catalyst by a known procedure, as described in the known art,
to give the desired intermediate ethyl or methyl 4-(phenylpropionylamino)piperidine-4-carboxylate (16) and finally compound (16) is stirred with a suitable acrylate with isopropanol and conc. HC1, and cooling to obtain remifentanil analogues.
STATEMENT OF THE INVENTION:
Accordingly, the present invention provides a process preparation of remifentanil and its analogues having the formula:
(Formula Removed)
Formula (I) wherein, Ri is selected from the group consisting of methyl or ethyl group and R=CH2CH2COO(CH2)nCH3; CH2CH2COOC6H5 wherein n=0-5; wherein the process comprising the steps of: a) reacting compound (8) having the formula: (Formula Removed)

with acid chloride in an organic solvent to form compound (17) having the formula:
(Formula Removed)
17 b) reacting the compound (17) obtained in step (a) with chlorotrialkylsilane and an alcohol under nitrogen atmosphere to obtain compound (II) having the formula:
(Formula Removed)
wherein R1=Methyl group or Ethyl group;
c) reacting the compound obtained in step (b) with hydrogen in presence of palladium-charcoal catalyst to form compound (16) having the formula:
Wherein R Methyl or ethyl group;
d) reacting the compound (16) obtained in step (c) with acrylates selected from CH2CHCOO(CH2)nCH3 and CH2CHCOOC6H5 ,wherein n= 0 to 5 to obtain compound of formula (I).
(Formula Removed)

DETAILED DESCRIPTION OF THE INVENTION:
The present invention comprises an improved process for the preparation of compound II used for preparation of remifentanil and its analogues (I)
(Formula Removed)
wherein, R1 =Me, Et and R=CH2CH2COO(CH2)nCH3; CH2CH2COOC6H5 wherein n=0-5 Said process comprising the steps of:
1. Reacting l-benzyl-4-(phenylamino)piperidine-4-carbonitrile (8) with propionyl chloride in organic solvent like toluene, dichloromethane and dichloroethane to give 1-benzyl-4-(phenylpropionyl amino)piperidine-4-carbonitrile (17) in 80-85 % yield.
2. In the second step, l-Benzyl-4- (phenylpropionyl amino)piperidine-4-carbonitrile (17) obtained in first step, is treated with chlorotrialkyl silane and an alcohol like methanol or ethanol in absence of any other organic solvent in nitrogen atmosphere to give methyl or ethyl 1-benzyl 4-(phenylpropionylamino)piperidine-4-carboxylate (II) respectively in 70-75 % yield.
The intermediate (It), thus can be converted into remifentanil and its various analogues using the method reported by Kiricojevic et al in J serb Chem Soc, 2002,67(12), p793. The chlorotrialkyl silane used in the process of preparation of compound II is represented by the following formula:
(Formula Removed)
wherein n = 0 to 3. The process of the present invention for the synthesis of compound (II) comprises of the
following steps:
Step 1: Preparation of l-benzvl-4-(phenvlamino)piperidine-4-carbonitrile (8) from l-benzvl-4-piperidone (7)
This step is carried out as per procedure reported in the prior art viz V.D. Kiricojevic, M.D. Ivanovic, I.V. Micovic, J.B.Djordjevic, G.M. Roglic and L.J. Dosen-Micovic, J.Serb. Chem. Soc., 2002, 67(12), 739-802.
(Formula Removed)
To a solution of 2-5 % by weight, preferably 3-4 % by weight of l-benzyl-4-piperidone in organic solvents like 30-80 % by weight of dichloromethane, chloroform, preferably 50-60 % by weight of dichloromethane, 4-10 % by weight, preferably 6-8 % by weight of aniline and 2.5-7 % by weight, preferably 4-5.5 % by weight of potassium cyanide, are added and the resulting mixture is cooled to 0-5° C in an ice bath for 5-20 min, preferably 10 min. To this stirred solution, 2-50 % by weight of acetic acid, preferably, 30-40 % by weight, are added drop-wise
and after the addition is complete, the reaction mixture is heated to 30-50 ° C, preferably 35-40° C, in an oil bath. After completion of the reaction, reaction mixture is cooled to room temperature and then neutralized by adding 25% sodium hydroxide solution (5-15 % by weight, preferably 7-10% by weight). From the resulting biphasic solution, the organic phase is separated and the aqueous phase is extracted with 15-25 % by weight of organic solvents like dichloromethane, chloroform and ether, preferably 8-12 % by weight dichloromethane. The combined organic phases are dried over anhydrous sodium sulphate and the solvent is evaporated under vacuum to get the crude compound. It is further purified by recrystallization with petroleum ether to give l-benzyl-4-phenylaminopiperidine-4-carbonitrile (8) as colorless compound (80-85% yield).
Step 2: Preparation of l-benzvl-4-phenvlpropionvl amino)pjperidine-4-carbonitrile (17) from 1-benzvl-4-(phenvlamino) piperidine-4-carbonitrile (8): (Formula Removed)
To the stirred solution of 10-30 % by weight, preferably 15-20 % by weight of l-benzyl-4-(phenylamino) piperidine-4-carbonitrile (8) in 40-80 % by weight of organic solvents like toulene, dichloromethane and chloroform, preferably 50-60 % by weight of dichloromethane, 10-30 % by weight, preferably 15-20 % by weight, were added. The reaction mixture is refluxed for 2-10 hours, preferably 3-5 hours, followed by gradual addition of 4-10 % by weight, preferably 6-8 % by weight of triethylamine. After the reaction is complete, the reaction mixture is cooled and poured into 40-80 % by weight, preferably 50-60 % by weight of 25% potassium
carbonate solution to form layers. The layers are separated and the aqueous layer is extracted with the 20-40 % by weight organic solvent like toluene, dichlomethane and dichloroethane, preferably 25-30 % by weight dichlorometahne. The combined organic layers are mixed, dried over sodium sulphate and concentrated under vacuum to give the crude l-benzyl-4-(phenylpropionyl amino)piperidine-4-carbonitrile (17) as oil (80-85% yield).
Step 3: Preparation of ethyl or methyl 1-benzyl 4-(phenvlpropionvlamino)piperidine-4-carboxylate (II) from 1-benzvl 4-(phenylpropionylamino)piperidine-4-carbonitrile (17)

(Formula Removed)
In a three neck round bottom flask, 30-80 % by weight, 40 - 60 % by weight of dry methanol or ethanol, 20-50 % by weight, preferably 30-35 % by weight of trialkylsilyl chloride, and 10-40 % by weight, preferably 20-25 % by weight of l-benzyl-4-(phenylpropionyl amino)piperidine 4-carbonitrile (17), were mixed under nitrogen atmosphere and stirred at 40-60° C, preferably at 45-50° C for 2-10 hours, preferably for 4-5 hours. After cooling to room temperature, 300-500 % by weight, preferably 400-450 % by weight of water, 20-50 % by weight, preferably 30-35 % by weight of sodium carbonate, and 300-500 % by weight, preferably 400-450 % by weight of dichloromethane, are added to the reaction mixture. The resulting mixture is then extracted with 20-40 % by weight, preferably 25 - 30 % by weight of organic solvent like dichloromethane, chloroform, diethyl ether, preferably dichloromethane. The organic extract is dried over anhydrous sodium sulphate and the solvent is evaporated under vacuum to obtain ethyl or methyl 1-benzyl 4-(phenylpropionylamino)piperidine-4-carboxylate (II) as oil (70-75% yield).
Step 4: Preparation of ethyl or methyl 4-(phenvlpropionvlamino)peridine-4-carboxvlate (16)
from ethyl or methyl 1-benzyl 4-(phenvlpropionylamino)piperidine-4-carboxvlate (ID: This step is also carried out as per procedure reported in the prior art, viz V.D. Kiricojevic, M.D. Ivanovic, I.V. Micovic, J.B. Djordjevic, G.M. Roglic and L.J. Dosen Micovic, J.Serb. Chem Soc., 2002, 67 (12), 739-802.
(Formula Removed)
A solution of 5-15 % by weight, preferably 8-10% by weight of methyl or ethyl l-benzyl-4-(phenylpropionylamino)piperidine-4-carboxylate (II) obtained in step 3, in 60-90 % by weight, preferably 70-80 % by weight of acetic acid and water (4:6) and 8-20 % by weight, preferably 10-12 % by weight of concentrated hydrochloric acid, is added to it. The resulting mixture is hydrogenated in Parr apparatus in the presence of 0.50-2.00 % by weight, preferably 0.70-1.00 % by weight of 10% palladium-charcoal catalyst. After competition of the reaction, the reaction mixture is poured in to cold water and neutralized with 30 -50 % by weight, preferably 40-45 % by weight of 20% sodium hydroxide solution. The resulting solution is then extracted with organic solvents like chloroform, diethyl ether, dichloromethane, ethyl acetate, preferably dichloromethane, the organic phase dried over sodium sulphate and concentrated under reduced pressure to give compound 16 as colourless solid (90-95% yield).
Step 5: Preparation of Remifentanil and its analogues (I) from compound 16: A mixture of 60-90 % by weight, preferably 70-75 % by weight of compound 16, obtained in step 4 and 15-25 % by weight, preferably 20-22 % by weight of an acrylate selected from CH2CHCOO(CH2)nCH3 and CHoCHCOOC6H5 (wherein n= 0 to 5) are stirred for 2-6 hours, preferably 3-5 hours. To the reaction mixture, 60-90 % by weight of isopropanol, preferably 70-
75 % by weight and 15-25 % by weight, preferably 20-22 % by weight of concentrated hydrochloric acid are added and after shaking, kept in refrigerator for 12 hrs. The solid is separated by filtration and dried under vacuum to give hydrochloride salt of compound I (85-90% yield). The substituent R of compound I corresponds to the acrylate used in the process. For the synthesis of remifentanil the acrylate used is methyl acrylate and Rl is methyl.

(Table Removed)
The following examples are given by way of illustration and therefore should not be construed to limit the scope of the present invention.
EXAMPLE 1:
To a solution of 8.92gm of l-benzyl-4-piperidone in 100 ml dichloromethane, 18.24 ml aniline and 13.00 g potassium cyanide are added and resulting is cooled in an ice bath. To this stirred solution, 90 ml of acetic acid is added drop-wise and after complete addition, the reaction mixture is heated to 40 ° C in an oil bath for 24 hrs. The reaction mixture is then cooled to room temperature and neutralized by adding 25% sodium hydroxide solution to it. From the resulting biphasic solution, the organic phase is separated and the aqueous phase is extracted with dichloromethane. The combined organic phases are dried over sodium sulphate and concentrated under vacuum to get the crude compound. It is further purified by recrystallization
with petroleum ether to give l-benzyl-4-(phenylamino)piperidine-4-carbonitrile (8) as colorless compound; yield 11.75g (86%).
To the stirred solution of 10.87g of l-benzyl-4-(phenylarmno)piperidine-4-carbonitrile (8) in 100 ml of chloroform, 9.75 ml of propionly chloride is added. The reaction mixture is refluxed for three hours, followed by the gradual addition of 5.25 ml of triethylamine. After the reaction is complete, the reaction mixture is cooled and poured in to 25% potassium carbonate solution(100 ml). The layers are separated and the aquous layer is extracted with dichloromethane. The combined organic layers are mixed, dried over sodium sulphate and concentrated under vacuum to give the crude 1-benzyl 4-(phenylpropionylamino)piperidine-4-carbonitrile (17) as oil; yield 10.27 g (80%).
In a three neck round bottom flask, 100 ml of dry methanol, 6.00 ml of trimethylsilyl chloride and 7.50 g of 1-benzyl 4-(phenylpropionylamino)piperidine-4-carbonitrile (17) obtained from above step, are mixed under nitrogen atmosphere and stirred at 50 ° C for three hours. After cooling to room temperature, water (20 ml), 7.50 g sodium carbonate and dichlomethane (50 ml) are added to the reaction mixture. The resulting mixture is then extracted with dichloromethane. The organic extract is dried over anhydrous sodium sulphate and concentrated under vacuum to give methyl 1-benzyl 4-(phenylpropionylamino)piperidine-4-carboxylate (II) as a oil; yields 6.15 gm (73%).
A solution of 5.39 g methyl 1-benzyl 4-(phenylpropionylamino)piperidine-4-carboxylate (II), obtained from above steps, in 50ml of acetic acid and water (6:4 ratio) mixture is prepared and hydrogenated in Parr apparatus in the presence of 0.32g of 10% palladium charcoal catalyst. After competition of the reaction, the reaction mixture is poured in to cold water and neutralized with 20% sodium hydroxide solution. The resulting solution is then extracted with organic solvents like chloroform, diethyl ether, dichloromethane, ethyl acetate preferably dichloromethane, the organic phase dried over anhydrous sodium sulphate and concentrated under reduced pressure to give methyl 4-[(l-anhydrous sodium sulphate and concentrated under reduced pressure to give methyl 4-(phenylpropionylamino)piperidine-4-carboxylate (16) as the colorless solid; yield 3.65 g (90%).
A mixture of 2.90 g of methyl 4-(phenylpropionylamino)piperidine-4-carboxylate (16) and 0.89 mL of methyl acrylate is stirred for two hours. After competition of recation, 10 ml of isopropanol and 1 ml concentrated hydrochloric acid are added sequentially to the reaction mixture. The resulting solution is kept in refrigator over night and the solid thus preciopated by filteration and dried under vacuum to give hydrochloride salt of Remifentanil. The salt is dissolved in water and reacted with 20% sodium hydroxide solution followed by extraction with dichloromethane. The organic phase is dried over anhydrous sodium sulphate and concentrated under vacuum to give remifentanil (I) as oil; yield 3.19g (85%).
EXAMPLE 2:
To a solution of 18.90 gm of l-benzyl-4-piperidone in 200 ml dichlorometahne, 36.48 ml aniline and 26.00 g potassium cyanide are added and resulting is cooled in an ice bath. To this stirred solution, 180 ml of acetic acid is added drop-wise and after complete addition, the reaction mixture is heated to 40 c C in an oil bath for 24 hrs. The reaction mixture is then cooled to room temperature and neutralized by adding 25% sodium hydroxide solution to it. From the resulting biphasic solution, the organic phase is separated and the aqueous phase is extracted with dichloromethane. The combined organic phases are dried over sodium sulphate and concentrated under vacuum to get the crude compound. It is further purified by recrystallization with petroleum ether to give l-benzyl-4-(phenylamino)piperidine-4-carbonitrile (8) as colorless compound; yield 23.50g (80%).
To the stirred solution of 21.74g of l-benzyl-4-(phenylamino)piperidine-4-carbonitrile (8) in 200 ml of chloroform, 19.50 ml of propionyl chloride is added. The reaction mixture is refluxed for four hours, followed by the gradual addition of 10.50 ml of triethylamine. After the reaction is complete, the reaction mixture is cooled and poured in to 25% extracted with dichloromethane. The combined organic layers are mixed, dried over sodium sulphate and concentrated under vacuum to give the crude 1-benzyl 4-(phenylpropionylamino)piperidine-4-carbonitrile (17) as oil; yield 19.91 g (82%). In a three neck round bottom flask, 200 ml of dry methanol, 12.00 ml of trimethylsilyl chloride
and 15.00 g ofl-benzyl 4-(phenylpropionylamino)piperidine-4-carbonitrile (17) are mixed under nitrogen atmosphere and stirred at 50 ° C for three hours. After cooling to room temperature, water (40 ml), 15.0 g sodium carbonate and dichlomethane (75 ml) are added to the reaction mixture. The resulting mixture is then extracted with dichloromethane. The organic extract is dried over anhydrous sodium sulphate and concentrated under vacuum to give ethyl l-benzyl-4-[(1-oxopropyl) phenylamino] piperidine-4-carboxylate (II) as a oil; yield 11.40 gm (75%). A solution of 10.78 g ethyl l-benzyl-4-[(l-oxopropyl) phenylamino] piperidine-4-carboxylate (II), obtained from above steps, in 75ml of acetic acid and water (6:4 ratio) mixture is prepared and hydrogenated in Parr apparatus in the presence of l.OOg of 10% palladium charcoal catalyst. After competition of the reaction, the reaction mixture is poured in to cold water and neutralized with 20% sodium hydroxide solution. The resulting solution is then extracted with organic solvents like chloroform, diethyl ether, dichloromethane, ethyl acetate preferably dichloromethane, the organic phase dried over anhydrous sodium sulphate and concentrated under reduced pressure to give ethyl 4-(phenylpropionylamino)piperidine-4-carboxylate (16) as the colorless solid; yield 7.32 g (89%).
A mixture of 5.80 g of ethyl 1-benzyl 4-(phenylpropionylamino)piperidine-4-carboxylate (II) and 1.78 mL of methyl acrylate is stirred for two hours. After competition of reaction, 25 mL of isopropanol and 3 ml concentrated hydrochloric acid are added sequentially to the reaction mixture. The resulting solution is kept in refrigerator over night and the solid thus precipitated is separated by filtration and dried under vacuum to give hydrochloride salt of Remifentanil. The salt is dissolved in water and reacted with 20% sodium hydroxide solution followed by extraction with dichloromethane. The organic phase is dried over anhydrous sodium sulphate and concentrated under vacuum to give remifentanil analog as oil; yield 6.54 g (87%).
ADVANTAGES:
One of the main advantage of the present invention is to design and develop a simple, cost effective, time-saving and energy saving process for the preparation of compound (II) used for the preparation of remifentanil and its analogs. Another advantage of the present invention is
to provide an improved process for the preparation of compound (II) which can give remifentanil and its analogs in better yield in comparison to the reported methods which does not require harsh chemicals in any of the steps of the process and forming very small amount of decomposition products which decreases the effluent load of the process and utilizes low energy and is cost effective which can be used for industrial scale preparations of remifentanil and its analogues.

WE CLAIM:
1. An improved process for the preparation of remifentanil and its analogues having the formula:
(Formula Removed)
R Formula (I) wherein, R1 is selected from the group consisting of methyl or ethyl group and R=CH2CH2COO(CH2)nCH3; CH2CH2COOC6H5 wherein n=0-5; wherein the process comprising the steps of: a) reacting compound (8) having the formula:
(Formula Removed)
8 with acid chloride in an organic solvent to form compound (17) having the formula:
(Formula Removed)
b) reacting the compound (17) obtained in step (a) with chlorotrialkylsilane and an alcohol
under nitrogen atmosphere to obtain compound (II) having the formula :
(Formula Removed)

wherein R1=Methyl group or Ethyl group;
c) reacting the compound obtained in step (b) with hydrogen in presence of palladium-charcoal catalyst to form compound (16) having the formula:
(Formula Removed)
Wherein R1=Methyl or ethyl group;
d) reacting the compound (16) obtained in step (c) with acrylates selected from CH2CHCOO(CH2)nCH3 and CH2CHCOOC6H5,wherein n= 0 to 5 to obtain compound of formula (I).
2. The process as claimed in claim 1(a), wherein the organic solvent is selected from the group consisting of toluene, dichloromethane and dichloroethane, preferably dichloromethane.
3. The process as claimed in claim 1(a), wherein the amount of organic solvent ranges from 40 to 80 % by weight, preferably in the range of 50 to 60 % by weight.
4. The process as claimed in claim 1(a), wherein the acid chloride is propionyl chloride.
5. The process as claimed in claim 1, wherein the alcohol used is selected from the group consisting of methyl alcohol and ethyl alcohol.
6. The process as claimed in claim 1(b), wherein the chlorotrialkylsilane is having the structure: (Formula Removed)
wherein, n ranges from 0 to 3.
7. The process as claimed in claim 1(b), wherein the amount of chlorotrialkylsilane ranges from 20-50 % by weight, preferably 30-35 % by weight.
8. The process as claimed in claim 1, wherein the yield of rcmifentanil and its analogue ranges from 30 to 46.3%.
9. The process as claimed in claim 1, wherein remifentanil and its analogues are used as an analgesic or anesthetic agent.
10. A process for the preparation of remifentanil and its analogues substantially as herein described in the specification with reference to the foregoing examples.

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Patent Number

269981

Indian Patent Application Number

756/DEL/2010

PG Journal Number

48/2015

Publication Date

27-Nov-2015

Grant Date

23-Nov-2015

Date of Filing

31-Mar-2010

Name of Patentee

DIRECTOR GENERAL, DEFENCE RESEARCH & DEVELOPMENT ORGANISATION

Applicant Address

DRDO, MINISTRY OF DEFENCE, ROOM NO. 348, B-WING, DRDO BHAVAN, RAJAJI MARG, NEW DELHI-110011 (INDIA);

Inventors:

#	Inventor's Name	Inventor's Address
1	GUPTA, PRADEEP KUMAR	DEFENCE R&D ESTABLISHMENT, JHANSI ROAD, GWALIOR-474 002 (INDIA);
2	GANESAN, KUMARAN	DEFENCE R&D ESTABLISHMENT, JHANSI ROAD, GWALIOR-474 002 (INDIA);
3	VIJAYARAGHAVAN, RAJAGOPALAN	DEFENCE R&D ESTABLISHMENT, JHANSI ROAD, GWALIOR-474 002 (INDIA);

PCT International Classification Number

A61K31/192;

PCT International Application Number

N/A

PCT International Filing date

PCT Conventions:

#	PCT Application Number	Date of Convention	Priority Country
1			NA