Title of Invention	PROCESS FOR MANUFACTURE OF HIGH PURITY D-(-)-N,N-DIETHYL-2-(α-NAPHTHOXY)PROPIONAMIDE
Abstract	According to one aspect of the present invention there is provided a substantially high purity D-(-)-N,N-diethyl-2-(α-naphthoxy)propionamide and a process for the manufacture of substantially higher purity D-(-)-N,N-diethyl-2-(α-naphthoxy) propionamide having chemical purity near about or above 95%, and chiral purity near about or more than 97%. According to another aspect pf the invention is to provide an agrochemical compositions containing highly pure optically active D-(-)-N,N-diethyl-2-(α-naphthoxy)propionamide.

Title of Invention

PROCESS FOR MANUFACTURE OF HIGH PURITY D-(-)-N,N-DIETHYL-2-(α-NAPHTHOXY)PROPIONAMIDE

Abstract

According to one aspect of the present invention there is provided a substantially high purity D-(-)-N,N-diethyl-2-(α-naphthoxy)propionamide and a process for the manufacture of substantially higher purity D-(-)-N,N-diethyl-2-(α-naphthoxy) propionamide having chemical purity near about or above 95%, and chiral purity near about or more than 97%. According to another aspect pf the invention is to provide an agrochemical compositions containing highly pure optically active D-(-)-N,N-diethyl-2-(α-naphthoxy)propionamide.

Full Text	FORM 2 THE PATENTS ACT, 1970 (39 of 1970) PROVISIONAL SPECIFICATION (See Section 10) "PROCESS FOR MANUFACTURE OF HIGH PURITY D-(-)-N, W-DIETHYL-2- (A-NAPHTHOXY) PROPIONAMIDE" We , UNITED PHOSPHORUS LIMITED, a company incorporated under the Companies Act, 1956 and having its registered office at 3-11, GIDC, Vapi - 396 195, State of Gujarat, India and having its office at Uniphos House, 11th Road. C.D.Marg, Khar (West), Mumbai - 400 052, State Of Maharashtra, India, INDIAN. The following specification describes the invention: -1- TECHNICAL FIELD This invention relates to a process for manufacture of high purity D-{-)-N,N-diethyl-2-(α-naphthoxy)propionamide (Herbicide), particularly from L-2-Chloro propionic Acid or (s)-(-)-2-Chloropropionic Acid. BACKGROUND AND PRIOR ART A/,A/-diethyl-2-(a-naphthoxy)propionamide is known as napropamide, and its racemic mixture is generally marketed under trade name as "Devrinol". It is used for pre-emergence control of annual grasses and broad-leaved weeds in many crops and plantations. The second carbon atom at the propionamide group in napropamide has a hydrogen atom, a methyl group, a naphthoxy moiety and a carboxamide group thereby forming a chiral center. Hence the molecule [Fig I] can exist in two chiral stereoisomers: D or (R) and L or (S)-isomers. Various processes reported in the literature for the synthesis of this compound generally results in producing different mixture of these isomers, usually racemic mixtures and they are difficult to separate. Fig 1 Both D and L isomers and/ or their racemic mixtures of the compound N,N-diethyl-2-(a-naphthoxy)propionamide have herbicidal activity. However, Chan et a/., J. Agric. Food Chem., 23(5), 1008-1010, (1975), reported that the (D)-isomer of napropamide shows 8 times more activity than the (L)-isomer and 1.7-2 times more than it's racemic mixture, for certain weeds. Hence, effective herbicidal compositions can be made using about half the quantity of the current racemic napropamide. This has directed the attention of researchers to devise methods to synthesize D-(-) isomer. Various synthetic strategies have been reported for the preparation of optically active 2-arylpropionamide and their different homologues as for e.g., (a) optically active base for resolving recemates. (b) a resolution of diasteromeric derivatives as salts of esters, anhydrides (c) biochemical methods ( asymmetric hydrolysis of esters or oxidation of aromatic hydrocarbons ( T. Sugai and K. Mori, Agric. Bio. Chem., 48,2501 (1984)) or (d) stereo-specific reactions where starting material is having chiral center. Various processes have been reported for the preparation of D-(-)- A/,A/-diethyl-2-(a-naphthoxy)propionamide. Published literatures relevant to this subject are given below, in chronological order. However, the exact chemical as well as chiral purity of the D-(-) product obtained by some of these processes has not been reported. US Patent No 3480671 (1969) (Tilles et al), describes the preparation of racemic A/,A/-diethyl-2-(a-naphthoxy)propionamide from a-naphthol and A/,A/—diethyl-bromo propionamide in methanol as solvent and by using sodium methoxide. US Patent 3718455 (1973) (Baker et at) disclosed the process for the preparation of the D-isomer of the napropamide. According to this process, the resolution of dl-2-(a-naphthoxy) propionic acid resulted in d-acid of 90 % by weight purity and -3- l-acid of 85 % by weight purity. The process further disclosed the conversion of the d-acid into acid chloride in DMF by using phosgene. The acid chloride is then converted into D- isomer of A/,A/-diethyl-2-(α-naphthoxy)propionamide through the amidation by using diethyl amine and triethyl amine as acid acceptor. The molar yield of D- isomer of A/,A/-diethyl-2-(α-naphthoxy)propionamide as disclosed in the patent is 61 % by wt. Preparation by this process produced product in overall low yield. The chemical or optical purity of the product was not addressed by this process. Further, this process involves resolution technique, which is highly expensive and time consuming. Hence, this process is not suitable for commercial manufacture of D-isomer of A/,A/-diethyl-2-( α-naphthoxy) propionamide. James H. H Chan era/, J. Agric. Food Chem., 23(5), 1008-1010, (1975), reported the procedure for the D-isomer of the napropamide. The process involves the use of L (+) form of lactic acid as starting material and then conversion into ester and after subsequent reactions into D-isomer of napropamide. This process involves multi steps and overall yield is low. The process is also dependant on the availability of L (+) form of Lactic acid, which is not easily available. Therefore, this process is not suitable for large-scale preparation. US 3998880 (1976) (Simone et al) described the following process of preparing racemic N,N - diethyl-2-(α-naphthoxy) propionamide The process comprises reacting 2-chloropropionic acid with diethyl amine in the presence of phosphoryl chloride giving an intermediate 2-chloropropionyl diethyl amide, which is then reacted with a -naphthol and sodium hydroxide to give A/,A/-diethyl-2-(α- naphthoxy) propionamide. However, this process teaches the preparation of racemic A/,/V-diethyl-2-(α-naphthoxy) propionamide. US Patent 4,548,641(1985) (Walker et al) described the two methods for the preparation of optically active isomer of A/,A/-dialkyl-2-(4-substituted- a - -4- naphthoxy)propionamide. According to the first method, optically active lower alkyl ester of 2-halopropionic acid is reacted with 4-substituted α -naphthol, to produce optically active 4-substituted- α -naphthoxy propionic acid. This acid is then converted into acid chloride by using_phosgene and subsequently reacted with dialkyl amine to obtain the desired optically active isomer. This method involving conversion of lower alkyl ester of 2-halopropionic acid to the optically active 4-substituted-a-naphthoxy propionic acid gives low yield and may give some by-product (e.g., furan type ring condensed with a naphthalene ring) which was very difficult to be separated from the desired product. According to the second method, optically active amide is prepared by reacting an ester with an amine in the presence of a promoter which is halide of a group MIA metal having molecular weight of 26 or greater, or of a group IVB metal. This dialkylated amide is treated with substituted naphthol to produce a product with desired isomer. The products obtained by this method are not sufficiently rich in chiral and / or optical rotation. Lin Jin etal, Pesticides, 39, 18-20, (2000) reported different resolution process of the preparation of the optically active isomer. These resolution techniques involved very complex, tedious procedures and expensive resolving agents. The resolution techniques also required a large amount of solvent leading to the high cost. The commercially available Devrinol is as per US 3480671 (1969) and is described as (RS) N,N-diethyl-2-(1-naphthyloxy)-propionamide. There is therefore a need to make commercially available a highly pure optically active D-(-)-/N,N-diethyl-2-( α -naphthoxy)propionamide for better herbicidal activity and a process suitable for making a commercially feasible high purity D-isomer of Devrinol. -5- DESCRIPTION OF INVENTION The main object of the present invention is to provide substantially high purity D-(-)-N,N-diethyl-2-(α-naphthoxy)propionamide and a process for the manufacture of substantially high purity D-(-)-N,N-diethyl-2-(α -naphthoxy) propionamide. Another object of the present invention is to provide the process for the manufacture of D-(-)-N,N-diethyl-2-( α -naphthoxy)propionamide to give a product with high chiral purity and acceptable high yield for the large scale manufacture with commercial feasibility. Yet another object of this invention is to provide a process for manufacture of D-(-)-N,N-diethyl-2-( α -naphthoxy)propionamide of further substantially higher, chemical, chiral and optical purity, from the substantially high purity D-Devrinol. Accordingly the present invention provides a process for the manufacture of high purity D-(-)-N,N-diethyl-2-(α-naphthoxy) propionamide including: (i) reacting L-2-(-) chloropropionic acid with a chlorinating agent, preferably thionyl chloride and dimethylformamide in an organic solvent to form L-2(+)-chloropropionyl chloride and recovering the product by fractional distillation of the mass after completion of the reaction; (ii) reacting the L-2-(+) - chloropropionyl chloride obtained at the end of step-(i), with aqueous solution of diethyl amine in presence of excess of an aqueous solution of alkali metal hydroxide in an organic solvent to form L(+)-2-chloro-A/,A/-diethyl propionamide and distilling out part of the solvent after completion of the reaction; and using the remaining reaction mass in situ for next step; -6- (iii) reacting in situ, the mass containing L-(+)-2-halo N,N-diethyl propionamide, formed in step (ii) with a-naphthol in the presence of aqueous alkali in an organic solvent to form D-(-)-N,N-diethyl-2-"(naphthoxy)propionamide; and separating the organic phase from the aqueous phase after completion of the reaction, followed by recovering the high purity product rich in chemical and chiral purity, from the organic phase, by washing said organic phase with water and removing the solvent under vacuum. This high purity product having chemical purity above about 90 % by wt and chiral purity above about 80 % by wt may be further upgraded to higher purity product. A process for upgrading high purity D-(-)-N,N-diethyl-2-(α-naphthoxy)propionamide to higher purity D-(-)-N,N-diethyl-2-(α-naphthoxy)propionamide includes dissolving and crystallizing the high purity product, D-(-)N,N-diethyl-2-(α-naphthoxy)propionamide obtained at the end of step (iii) in the manufacture of high purity product, in a solvent, filtrating and washing the crystals with chilled hexane and removing the solvent from the crystals to obtain the crystalline higher purity D-(-)N,N-diethyl-2-(α-naphthoxy)propionamide having chemical and chiral purity near about or above 95 % by wt. The process of the present invention thus provides products having high purity D-(-)-N,N-diethyl-2-(α -naphthoxy)propionamide. The process of present invention can be used to get any desired purity product but as a desirable level of purity following guidelines are useful. (a) HIGH PURITY PRODUCT having chemical purity near about or above 90 % by wt, chiral purity near about or more than 80 % by wt and optical purity near about or more than 64 % by wt.; and / or -7- (b) HIGHER PURITY PRODUCT having chemical purity near about or above 95 % by wt, chiral purity near about or more than 97 %by wt and optical purity near about or more than 94 % by wt.. A process for upgrading high purity D-(-)-N,N-diethyl-2-α-naphthoxy) propionamide obtained at the end of step 3 to the higher purity product having higher chemical, chiral and optical purity. High Purity Product Step I: Conversion of (L)-(-)-2-chloropropionic acid to (L)- (+)-2-chloropropionyl chloride In this reaction, (L)-(-)-2-Chloropropionic acid (L-CPA) having [a]D26: -16.2° (neat, 1=10 cm) is reacted with excess of thionyl chloride in the presence of small amounts of dimethyl formamide to obtained a (L)-(+)-2-chloropropionyl chloride. The thionyl chloride is added at 50°C to 60°C, preferably at 50 to 55°C. The reaction is carried out either with the inert organic solvents like toluene, hexane etc. or without the solvents. Preferably, reaction carried out without the solvents. The mole ratio of the reactants - (L)-(-)-2-chloropropionic acid to thionyl chloride is 1: 1 to 1.5 moles, but the preferable ratio is 1:1.3-1.5 moles. The temperature of the reaction mixture is in the range of 65 to 75 °C. The reaction is monitored by GC using DB-5 capillary column and goes to completion when the L- CPA content is £ 1 % by area in about 5-8 hrs. After completion of the reaction, the HCI and S02 gases in the scrubber cease to evolve. The (L)-(+)-2-chloropropionyl chloride is distillated from the crude mass. The liquid is distilled under atmospheric pressure using fractionating column. The chemical purity of the distilled (L)-(+)-2-chloropropionyl chloride is determined by gas chromatography and confirmed with comparison the retention time (RT) with standard sample of 2-chloropropionyl chloride. Step II: Conversion of (L)- (+)-2-chloropropionyl chloride to (!_)-(+)- N,N diethyl- 2- chloropropionamide. The second step of the present invention is reaction of optically active (L)-2-chloro propionyl chloride with the slight excess of diethyl amine. This reaction is carried out in by addition of (L)-(+)-2-Chloropropionyl chloride into diethyl amine solution in water and an aqueous solution of an alkali metal hydroxide, preferably sodium hydroxide. -9- Preferably, the diethyl amine is employed 1.01 -2 moles, but preferably 1.01 -1.5 moles based on the one mole of (L)-(+)-2-Chloropropionyl chloride. The alkali metal hydroxide is utilized in an aqueous solution of 25-50 % by wt, and is present 1 - 3 moles per mole of (L)-(+)-2-chloropropionyl chloride. The organic solvent used for the reaction in the second step is preferably selected from inert or aromatic hydrocarbons like benzene, toluene, xylene or mixtures thereof; more preferably the organic solvent selected is toluene. The addition of the acid chloride in to the aqueous solution of amine is done at 20 to 30°C, preferably at 25 to 27°C. The reaction mixture is generally maintained at 20 to 30°C, preferably at 25 to 27°C. The reaction is monitored by Capillary GC (DB-5) column and continued till (L)-(+)-(2)-chloropropionyl chloride content is £ 0.1 % by area. The reaction is generally completed within 4 to 7 hrs preferably within 4 to 5 hrs. After completion of the reaction, the organic and aqueous layers are separated and one third to one half of the organic layer is distilled out under reduced pressure. The remaining undistilled mass containing 42 to 48 % (by w/w) concentration of optically active (L)- (+)-N,N-diethyl-2-chloropropionamide is used as such for the next step. The chemical purity of the amide is determined using standard sample of amide and matching with retention time in gas chromatography. Step III : Conversion of (L)-(+)- N,N diethyl-2-chloro propionamide to (D)-(-)-N,N diethyl-2-(α-naphthoxy)propionamide In this step, a-naphthol is reacted with an excess of optically active (L)- (+)-N,N diethyl-2-chloropropionamide obtained at the end of step II in the presence of alkali. It is observed that the reaction of a-naphthol with (L)-(+)-N,N diethyl-2-chloro propionamide is the bimolecular nucleophilic substitution (SN2) type -10- reaction accompanied by exclusive inversion of configuration. Thus, this produces A/,A/-diethyl-2-(a-naphthoxy) propionamide with D-configuration. In the SN2 type reaction, solvents play very vital role for preventing racemization. As reaction solvents, solvent used is selected from various aliphatic or aromatic hydrocarbons like toluene, cyclohexane, and xylene or mixtures thereof. Toluene is preferred solvent. In the preferred embodiment, the reaction of sodium salt of a-naphthol with an excess of the amide obtained at the end of step II, is carried out by addition of an aqueous solution of sodium hydroxide (25 - 50 % by wt) into the reaction mixture. The alkali hydroxide is present in excess. It is 1-5 moles and preferably in 2 - 5 moles with respect to the mole of α-naphthol The amide is 1-1.5 moles per mole of α-naphthol. The addition of the sodium hydroxide solution into the a-naphthol and the amide solution in toluene is carried out at 50°C to 60°C, preferably at 55°C to 57°C The temperatures of the reaction mixture are also very important factor for preventing the racemization. A temperature range from about 60°C to 100°C is appropriate, but considering the reaction time and other convenience, reaction mixture is generally maintained from about 90°C to below 100°C and preferably 95°C to 98°C. The reaction is monitored by gas chromatography using DB-5 capillary column. Generally the reaction is complete when the a-naphthol content is 1% (by GC area) which happens in 5 to 8 hrs, but mostly in 6 to 7 hrs. The reaction mass is then washed with water and extracted with sodium hydroxide solution and water to eliminate unreacted a-naphthol. In order to obtain desired product in good yield and purity, the reaction between a-naphthol and amide must be carried out to completion and the excess of -11- amide, solvents and other low boiling impurities are removed by distillation under reduced pressure. After complete recovery of solvent, high purity D-Devrinol- is obtained as light brown solid in 84-85 % yield (on mole basis of L-CPC) and has melting point of 75°C -79°C. The chemical purity of the product is determined by gas chromatography on Packed column (10 %by wt. OV-7) by using internal standard method and against pure reference standard of (D)-(-)-N,N-Diethyl-2-(α-naphthoxy)propionamide. The chiral purity is determined by normal phase HPLC using Hexane: ethanol (99:1 v/v) mobile phase and OD-H chiral column at 230 nm in UV detector. The chemical purity of the high purity D-Devrinol solid product obtainable by this preferred embodiment of the process may be as high as of the order of 93-94 % by wt. The chiral purity as high as 81 - 83 % by wt. of D-isomer. The Specific optical rotation (SOR) (of 1 %by wt. solution in ethanol, 1=10cm) is around [a]D20 -86° Therefore, the calculated optical purity may be as high as 62- 67 %by wt. The product obtained at the end of step III, is high in chemical purity and rich in chiral purity and hence can be used as napropamide concentrate in herbicidal compositions. In order to obtain higher purity product higher in optical purity, chiral purity and chemical purity further upgradation of the product may be carried out as described. The upgradation of the high purity material (solid, light brown color) can be carried out with various organic solvents, generally polar and different mix solvent systems having polar and /non-polar solvents. Preferably, Isopropyl alcohol (IPA): water with varying ratios like 5:5(v/v) and 7:3 (v/v) is suitable for upgradation, but other solvents can also be used. -12- Higher Purity Product Upgradation of high purity D-(-)-N,N-diethyl-2-(α-naphthoxy) propionamide obtained at the end of step 3 to the higher purity product having higher chemical, chiral and optical purity. A process for upgrading high purity D-(-)-N,N-diethyl-2-(α-naphthoxy)propionamide to higher purity D-(-)-N,N-diethyl-2-(α-naphthoxy)propionamide includes dissolving and crystallizing the high purity product, D-(-) N,N -diethyl-2α- naphthoxy)propionamide obtained at the end of step (iii) in the manufacture of high purity product, in a solvent, filtrating and washing the crystals with chilled hexane and removing the solvent from the crystals to obtain the crystalline higher purity D-(-)N,N-diethyl-2-(α-naphthoxy)propionamide having chemical and chiral purity near about or above 95 % by wt. In this process, solvent may be selected from polar organic solvents or from polar aqueous organic solvents. The solvent is preferably isopropanol and water mixed in the ratio of (65 - 75) to (25 - 35) % by volume. And more preferably, in the ratio of (70- 30) % by volume. In this process the high purity D - Devrinol is dissolved in the solvent at not above about 70°C The high purity product, obtained is dissolved and maintained in isopropyl alcohol: water in the vol. ratio of (65-75: 35 -25) preferably in the ratio of (70:30 v/v) at 60 to 650C with stirring for about 45 minutes. The mass is first cooled to room temperature and then to 10 to 12°C and maintained at that temperature for 3 to 5 hrs for crystallization. The crystals are collected by filtration and the solid crystals are washed with chilled hexane and kept under vacuum for about 3 to 5 hrs to remove last traces of solvent moisture and the volatile impurities if any to get off-white crystalline solid with 65-66 % by weight yield based on 100 %by wt. of starting material L-CPC]. The melting point of the technical grade off-white -13- solid is in the range around 94-96°C. The chemical purity of the product is determined by gas chromatography on packed column (10 % OV-7) by using internal standard method and against reference standard of (D)-(-)- N,N -Diethyl-2-(α-naphthoxy)propionamide and it shows the purity to be around 96 % (w/w). The chiral purity is determined by normal phase HPLC using Hexane: ethanol (99:1 v/v) mobile phase and OD-H chiral column at 230 nm in UV detector and the isomer content in the solid raises to near about 98 %by wt. of R-isomer and near about 2 %by wt. of S-isomer. In addition to that its specific optical rotation [a] D20 is 126° (1 % by wt. solution in ethanol, l=10cm) and optical purity of the material raises to near about 95 %by wt. The products obtainable at the end of this step are higher Purity D-(-)-N,N-diethyl-2-(α-naphthoxy) propionamide having chemical purity above 95 % by weight, chiral purity more than 97% by wt. and Optical purity more than 94 % by wt. The product obtained at the end of upgrading process, is higher in chemical, chiral and optical purity and hence can be used as napropamide concentrate of higher strength, in herbicidal compositions. EXAMPLES The present invention will now be described with the help of following examples. Examples are for the purpose of illustration only and in no way restrict the scope of the invention. EXAMPLE 1 The process of the present invention will now be illustrated in this example step by step. -14- STEP I: Preparation of (L)-(+)-2-Chloropropionyl chloride from L (-) 2-Chloropropionic Acid. In a three-necked round bottomed kettle, (L)-(-)-2-Chloropropionic acid (108. 5 g, 98% chiral purity, 1.0 mole) was taken and dimethylformamide (5 ml) was added to it under continuous stirring. The temperature of the reaction mass was raised to 55°C and thionyl chloride (178.5 g, 98%by wt. purity, 1.5 moles) was added slowly. During the addition, temperature of the reaction mass was maintained at 55-57°C. After the addition was over the temperature of the reaction mass was increased up to 68-70°C and maintained at this temperature till completion of the reaction ( The reaction was monitored by GC using DB-5 column. The reaction gets completed in 7 hrs. During the process, HCI and SO2 gases evolved were absorbed in the scrubber containing dilute sodium hydroxide solution. After completion of the reaction, the evolution of the HCI and SO2 gases in the scrubber had ceased. The (L)-(+)-2-chloro-propionyl chloride liquid was distilled under atmospheric pressure by using a 30-cm fractionating column. The material distills at 105-109°C giving 113.0 g pure material (90 % by weight yield based on 100 %by wt. L-(-) -2-Chloropropionic acid. The chemical purity of the compound was 96 %by wt. calculated by GC area and having optical rotation: [a]o26: + 3.5° (neat, 1=10cm.) The chemical purity of the distilled (L)-(+)-2-chloropropionyl chloride is confirmed with standard sample of 2-chloropropionyl chloride in gas chromatography. STEP II: Preparation of (L)-(+)- N,N-diethyl-2-chloropropionamide from (L)-(+)-2-Chloropropionyl chloride -15- A mixture of Diethyl amine (81 g, 1.1 mole, 99 % by wt. purity), 48 % aqueous sodium hydroxide (100 g, 1.20 mole), water (120 ml) and toluene (250 gm) were charged in to a reaction kettle. The reaction mixture was cooled up to 20 to 22°C temp and L (+)- 2-chloropropionyl chloride (127 g, 1 mole) was added drop wise under continuous stirring. During the addition, temperature was not allowed to exceed beyond 30°C. After addition was completed, cooling was stopped and mixture was allowed to come to 30°C and maintained until the (L)-(+)-(2)-chloropropionyl chloride was £ 0.1 % by GC area. The reaction was monitored by Capillary GC (DB-5) column and completed in within 5 hrs. After completion of reaction the aqueous phase was separated and organic phase containing product in toluene was washed with water till pH of washing was neutral from the washed organic phase, the 1/3 of toluene was distilled out of the total mass. The residual organic mass was 255 g. This was found to contain 48 % by weight of the (L)-(+)- 2-Chloro N, N—diethyl chloropropionamide in toluene. This corresponds to 93-94 % yield of amide based on L (+)- 2-Chloropropionyl chloride. The organic mass was carried out for the next step (in situ). The chemical purity of the amide and reaction monitoring is confirmed with standard sample of (L)-(+)-N,,/V—diethyl chloropropionamide. STEP III: Preparation of D-(-)- N,N -Diethyl-2-(α-naphthoxy)propionamide Into a 3-litre round bottom kettle were placed a-Naphthol (517 g, 3.59 mole, 99 %by wt. purity) and 647 g (3.95 mole) of amide obtained in step II (based on 48 % purity assay w/w analysis) solution in toluene (total wt: 1345 g). The mixture was stirred and aqueous sodium hydroxide solution (642 g, 7.7mole, 48 %by wt.) was added drop wise to the reaction mass at 55-57°C temperature. After completion of addition, reaction mass was heated to reflux at about 95°C. When reflux began, sodium chloride began to separate out. Refluxing was continued for 6 to 7 hours till completion of the reaction -16- The reaction mixture was cooled to 50°C and 500 ml water and 500 ml Toluene at this temperature was added. The reaction mass stirred for 45 min. at this temperature and aqueous phase, which was lighter in color than the organic phase was separated. The organic phase including the inter-phase (emulsion) was reheated to 50°C. A solution of 250 ml sodium hydroxide (10 % by wt) and 250 ml of hot water were added and the phases were separated again. The organic phase again extracted with 250 ml water and the phases separated. The organic layer was collected and evaporated at 80°C under reduced pressure and then further for three hrs under high vacuum for complete removal of toluene. After complete removal of solvent, the 850 g of high purity product obtained which is light brown solid with 83 % by wt. yield based on starting material as L-CPC and had melting point of 75°C - 79 °C. The chemical purity of the high purity product was found to be 94% by wt. by gas chromatography on Packed column (10 % by wt. OV-7) by using internal standard method and against reference standard of (D)-(-)- N,N-diethyl-2-(α-naphthoxy)propionamide When examined by normal phase HPLC using Hexane: ethanol (99:1 v/v) mobile phase and OD-H chiral column at 230 nm in UV detector, the high purity product showed 82- % of D- isomer and 16 % of L-isomer. The Specific optical rotation (SOR) (of 1 %by wt. solution in ethanol, 1=10cm) is [a]D20 -86°. Therefore, the calculated optical purity may be as high as 64 %by wt. EXAMPLE II Upgradation of high purity D-(-)- N,N-diethyl-2-(α-naphthoxy) propionamide obtained at the end of step III to the higher purity product having higher chemical, chiral and optical purity This example describes upgradation of high purity product obtained in the Example I. -17- To the brown colour solid material obtained at the end of step III, in Example I was added 600.0 gm of isopropyl alcohol: water (70:30 v/v) mixture and it was heated at 60°C -64°C with constant stirring. Heating and stirring was continued till the high purity product was completely dissolved. Stirring was further continued for 45 minutes at this temperature. The mass was brought first to room temperature and then cooled to and maintained at 10°C -12°C for 3-4 hrs. The solid crystals were filtered and washed with chilled hexane and the solid crystals were kept under vacuum for 3 hrs. The higher purity product (690 g) was obtained at the end of step IV, as off-white crystalline solid with overall yield 66 % by wt. based on starting material L-Chloropropionic acid. The melting point of the higher purity product was found to be 94.4-96.1°C. The higher purity product was examined for purity by the same methods used for examining the crude product. The chemical purity of the upgraded product was found to be 96 % by wt. The isomer ratio of the upgraded product was found to be 98 % of (D-isomer) and 1.8 % of (L-isomer). The Specific Optical Rotation: [α]o20 was found to be -126° (1 % by wt. solution in ethanol, 1=10cm) and the optical purity of the purified product was 95 % by weight. The purity and the structure of the high purity products are further confirmed as D-isomer of napropamide by DSC analysis and GCMS as well as other spectral studies Dated o4/o5/2007 -18-

Full Text

FORM 2
THE PATENTS ACT, 1970
(39 of 1970)
PROVISIONAL SPECIFICATION
(See Section 10)
"PROCESS FOR MANUFACTURE OF HIGH PURITY D-(-)-N, W-DIETHYL-2-
(A-NAPHTHOXY) PROPIONAMIDE"
We , UNITED PHOSPHORUS LIMITED, a company incorporated under the Companies Act, 1956 and having its registered office at 3-11, GIDC, Vapi - 396 195, State of Gujarat, India and having its office at Uniphos House, 11th Road. C.D.Marg, Khar (West), Mumbai - 400 052, State Of Maharashtra, India, INDIAN.
The following specification describes the invention:
-1-

TECHNICAL FIELD
This invention relates to a process for manufacture of high purity D-{-)-N,N-diethyl-2-(α-naphthoxy)propionamide (Herbicide), particularly from L-2-Chloro propionic Acid or (s)-(-)-2-Chloropropionic Acid.
BACKGROUND AND PRIOR ART
A/,A/-diethyl-2-(a-naphthoxy)propionamide is known as napropamide, and its racemic mixture is generally marketed under trade name as "Devrinol". It is used for pre-emergence control of annual grasses and broad-leaved weeds in many crops and plantations.
The second carbon atom at the propionamide group in napropamide has a hydrogen atom, a methyl group, a naphthoxy moiety and a carboxamide group thereby forming a chiral center. Hence the molecule [Fig I] can exist in two chiral stereoisomers: D or (R) and L or (S)-isomers.
Various processes reported in the literature for the synthesis of this compound generally results in producing different mixture of these isomers, usually racemic mixtures and they are difficult to separate.

Fig 1
Both D and L isomers and/ or their racemic mixtures of the compound N,N-diethyl-2-(a-naphthoxy)propionamide have herbicidal activity. However, Chan et a/., J. Agric. Food Chem., 23(5), 1008-1010, (1975), reported that the (D)-isomer of napropamide shows 8 times more activity than the (L)-isomer and 1.7-2 times more than it's racemic mixture, for certain weeds. Hence, effective herbicidal compositions can be made using about half the quantity of the current racemic napropamide. This has directed the attention of researchers to devise methods to synthesize D-(-) isomer.
Various synthetic strategies have been reported for the preparation of optically active 2-arylpropionamide and their different homologues as for e.g., (a) optically active base for resolving recemates. (b) a resolution of diasteromeric derivatives as salts of esters, anhydrides (c) biochemical methods ( asymmetric hydrolysis of esters or oxidation of aromatic hydrocarbons ( T. Sugai and K. Mori, Agric. Bio. Chem., 48,2501 (1984)) or (d) stereo-specific reactions where starting material is having chiral center.
Various processes have been reported for the preparation of D-(-)- A/,A/-diethyl-2-(a-naphthoxy)propionamide. Published literatures relevant to this subject are given below, in chronological order. However, the exact chemical as well as chiral purity of the D-(-) product obtained by some of these processes has not been reported.
US Patent No 3480671 (1969) (Tilles et al), describes the preparation of racemic A/,A/-diethyl-2-(a-naphthoxy)propionamide from a-naphthol and A/,A/—diethyl-bromo propionamide in methanol as solvent and by using sodium methoxide.
US Patent 3718455 (1973) (Baker et at) disclosed the process for the preparation of the D-isomer of the napropamide. According to this process, the resolution of dl-2-(a-naphthoxy) propionic acid resulted in d-acid of 90 % by weight purity and
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l-acid of 85 % by weight purity. The process further disclosed the conversion of the d-acid into acid chloride in DMF by using phosgene. The acid chloride is then converted into D- isomer of A/,A/-diethyl-2-(α-naphthoxy)propionamide through the amidation by using diethyl amine and triethyl amine as acid acceptor. The molar yield of D- isomer of A/,A/-diethyl-2-(α-naphthoxy)propionamide as disclosed in the patent is 61 % by wt.
Preparation by this process produced product in overall low yield. The chemical or optical purity of the product was not addressed by this process. Further, this process involves resolution technique, which is highly expensive and time consuming. Hence, this process is not suitable for commercial manufacture of D-isomer of A/,A/-diethyl-2-( α-naphthoxy) propionamide.
James H. H Chan era/, J. Agric. Food Chem., 23(5), 1008-1010, (1975), reported the procedure for the D-isomer of the napropamide. The process involves the use of L (+) form of lactic acid as starting material and then conversion into ester and after subsequent reactions into D-isomer of napropamide. This process involves multi steps and overall yield is low. The process is also dependant on the availability of L (+) form of Lactic acid, which is not easily available. Therefore, this process is not suitable for large-scale preparation.
US 3998880 (1976) (Simone et al) described the following process of preparing racemic N,N - diethyl-2-(α-naphthoxy) propionamide The process comprises reacting 2-chloropropionic acid with diethyl amine in the presence of phosphoryl chloride giving an intermediate 2-chloropropionyl diethyl amide, which is then reacted with a -naphthol and sodium hydroxide to give A/,A/-diethyl-2-(α- naphthoxy) propionamide. However, this process teaches the preparation of racemic A/,/V-diethyl-2-(α-naphthoxy) propionamide.
US Patent 4,548,641(1985) (Walker et al) described the two methods for the preparation of optically active isomer of A/,A/-dialkyl-2-(4-substituted- a -
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naphthoxy)propionamide. According to the first method, optically active lower alkyl ester of 2-halopropionic acid is reacted with 4-substituted α -naphthol, to produce optically active 4-substituted- α -naphthoxy propionic acid. This acid is then converted into acid chloride by using_phosgene and subsequently reacted with dialkyl amine to obtain the desired optically active isomer. This method involving conversion of lower alkyl ester of 2-halopropionic acid to the optically active 4-substituted-a-naphthoxy propionic acid gives low yield and may give some by-product (e.g., furan type ring condensed with a naphthalene ring) which was very difficult to be separated from the desired product.
According to the second method, optically active amide is prepared by reacting an ester with an amine in the presence of a promoter which is halide of a group MIA metal having molecular weight of 26 or greater, or of a group IVB metal. This dialkylated amide is treated with substituted naphthol to produce a product with desired isomer. The products obtained by this method are not sufficiently rich in chiral and / or optical rotation.
Lin Jin etal, Pesticides, 39, 18-20, (2000) reported different resolution process of the preparation of the optically active isomer. These resolution techniques involved very complex, tedious procedures and expensive resolving agents. The resolution techniques also required a large amount of solvent leading to the high cost.
The commercially available Devrinol is as per US 3480671 (1969) and is described as (RS) N,N-diethyl-2-(1-naphthyloxy)-propionamide.
There is therefore a need to make commercially available a highly pure optically active D-(-)-/N,N-diethyl-2-( α -naphthoxy)propionamide for better herbicidal activity and a process suitable for making a commercially feasible high purity D-isomer of Devrinol.
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DESCRIPTION OF INVENTION
The main object of the present invention is to provide substantially high purity D-(-)-N,N-diethyl-2-(α-naphthoxy)propionamide and a process for the manufacture of substantially high purity D-(-)-N,N-diethyl-2-(α -naphthoxy) propionamide.
Another object of the present invention is to provide the process for the manufacture of D-(-)-N,N-diethyl-2-( α -naphthoxy)propionamide to give a product with high chiral purity and acceptable high yield for the large scale manufacture with commercial feasibility.
Yet another object of this invention is to provide a process for manufacture of D-(-)-N,N-diethyl-2-( α -naphthoxy)propionamide of further substantially higher, chemical, chiral and optical purity, from the substantially high purity D-Devrinol.
Accordingly the present invention provides a process for the manufacture of high purity D-(-)-N,N-diethyl-2-(α-naphthoxy) propionamide including:
(i) reacting L-2-(-) chloropropionic acid with a chlorinating agent, preferably thionyl chloride and dimethylformamide in an organic solvent to form L-2(+)-chloropropionyl chloride and recovering the product by fractional distillation of the mass after completion of the reaction;
(ii) reacting the L-2-(+) - chloropropionyl chloride obtained at the end of step-(i), with aqueous solution of diethyl amine in presence of excess of an aqueous solution of alkali metal hydroxide in an organic solvent to form L(+)-2-chloro-A/,A/-diethyl propionamide and distilling out part of the solvent after completion of the reaction; and using the remaining reaction mass in situ for next step;
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(iii) reacting in situ, the mass containing L-(+)-2-halo N,N-diethyl propionamide, formed in step (ii) with a-naphthol in the presence of aqueous alkali in an organic solvent to form D-(-)-N,N-diethyl-2-"(naphthoxy)propionamide; and separating the organic phase from the aqueous phase after completion of the reaction, followed by recovering the high purity product rich in chemical and chiral purity, from the organic phase, by washing said organic phase with water and removing the solvent under vacuum.
This high purity product having chemical purity above about 90 % by wt and chiral purity above about 80 % by wt may be further upgraded to higher purity product.
A process for upgrading high purity D-(-)-N,N-diethyl-2-(α-naphthoxy)propionamide to higher purity D-(-)-N,N-diethyl-2-(α-naphthoxy)propionamide includes dissolving and crystallizing the high purity product, D-(-)N,N-diethyl-2-(α-naphthoxy)propionamide obtained at the end of step (iii) in the manufacture of high purity product, in a solvent, filtrating and washing the crystals with chilled hexane and removing the solvent from the crystals to obtain the crystalline higher purity D-(-)N,N-diethyl-2-(α-naphthoxy)propionamide having chemical and chiral purity near about or above 95 % by wt.
The process of the present invention thus provides products having high purity D-(-)-N,N-diethyl-2-(α -naphthoxy)propionamide. The process of present invention can be used to get any desired purity product but as a desirable level of purity following guidelines are useful.
(a) HIGH PURITY PRODUCT having chemical purity near about or above 90 % by wt, chiral purity near about or more than 80 % by wt and optical purity near about or more than 64 % by wt.; and / or
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(b) HIGHER PURITY PRODUCT having chemical purity near about or above 95 % by wt, chiral purity near about or more than 97 %by wt and optical purity near about or more than 94 % by wt..
A process for upgrading high purity D-(-)-N,N-diethyl-2-α-naphthoxy) propionamide obtained at the end of step 3 to the higher purity product having higher chemical, chiral and optical purity.

High Purity Product
Step I: Conversion of (L)-(-)-2-chloropropionic acid to (L)- (+)-2-chloropropionyl
chloride In this reaction, (L)-(-)-2-Chloropropionic acid (L-CPA) having [a]D26: -16.2° (neat, 1=10 cm) is reacted with excess of thionyl chloride in the presence of small amounts of dimethyl formamide to obtained a (L)-(+)-2-chloropropionyl chloride.
The thionyl chloride is added at 50°C to 60°C, preferably at 50 to 55°C. The reaction is carried out either with the inert organic solvents like toluene, hexane etc. or without the solvents. Preferably, reaction carried out without the solvents. The mole ratio of the reactants - (L)-(-)-2-chloropropionic acid to thionyl chloride is 1: 1 to 1.5 moles, but the preferable ratio is 1:1.3-1.5 moles. The temperature of the reaction mixture is in the range of 65 to 75 °C. The reaction is monitored by GC using DB-5 capillary column and goes to completion when the L- CPA content is £ 1 % by area in about 5-8 hrs. After completion of the reaction, the HCI and S02 gases in the scrubber cease to evolve. The (L)-(+)-2-chloropropionyl chloride is distillated from the crude mass. The liquid is distilled under atmospheric pressure using fractionating column. The chemical purity of the distilled (L)-(+)-2-chloropropionyl chloride is determined by gas chromatography and confirmed with comparison the retention time (RT) with standard sample of 2-chloropropionyl chloride.
Step II: Conversion of (L)- (+)-2-chloropropionyl chloride to (!_)-(+)- N,N diethyl- 2-
chloropropionamide.
The second step of the present invention is reaction of optically active (L)-2-chloro propionyl chloride with the slight excess of diethyl amine. This reaction is carried out in by addition of (L)-(+)-2-Chloropropionyl chloride into diethyl amine solution in water and an aqueous solution of an alkali metal hydroxide, preferably sodium hydroxide.
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Preferably, the diethyl amine is employed 1.01 -2 moles, but preferably 1.01 -1.5 moles based on the one mole of (L)-(+)-2-Chloropropionyl chloride. The alkali metal hydroxide is utilized in an aqueous solution of 25-50 % by wt, and is present 1 - 3 moles per mole of (L)-(+)-2-chloropropionyl chloride.
The organic solvent used for the reaction in the second step is preferably selected from inert or aromatic hydrocarbons like benzene, toluene, xylene or mixtures thereof; more preferably the organic solvent selected is toluene.
The addition of the acid chloride in to the aqueous solution of amine is done at 20 to 30°C, preferably at 25 to 27°C. The reaction mixture is generally maintained at 20 to 30°C, preferably at 25 to 27°C. The reaction is monitored by Capillary GC (DB-5) column and continued till (L)-(+)-(2)-chloropropionyl chloride content is £ 0.1 % by area. The reaction is generally completed within 4 to 7 hrs preferably within 4 to 5 hrs.
After completion of the reaction, the organic and aqueous layers are separated and one third to one half of the organic layer is distilled out under reduced pressure. The remaining undistilled mass containing 42 to 48 % (by w/w) concentration of optically active (L)- (+)-N,N-diethyl-2-chloropropionamide is used as such for the next step. The chemical purity of the amide is determined using standard sample of amide and matching with retention time in gas chromatography.
Step III : Conversion of (L)-(+)- N,N diethyl-2-chloro propionamide to (D)-(-)-N,N diethyl-2-(α-naphthoxy)propionamide
In this step, a-naphthol is reacted with an excess of optically active (L)- (+)-N,N diethyl-2-chloropropionamide obtained at the end of step II in the presence of alkali. It is observed that the reaction of a-naphthol with (L)-(+)-N,N diethyl-2-chloro propionamide is the bimolecular nucleophilic substitution (SN2) type
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reaction accompanied by exclusive inversion of configuration. Thus, this produces A/,A/-diethyl-2-(a-naphthoxy) propionamide with D-configuration.
In the SN2 type reaction, solvents play very vital role for preventing racemization. As reaction solvents, solvent used is selected from various aliphatic or aromatic hydrocarbons like toluene, cyclohexane, and xylene or mixtures thereof. Toluene is preferred solvent.
In the preferred embodiment, the reaction of sodium salt of a-naphthol with an excess of the amide obtained at the end of step II, is carried out by addition of an aqueous solution of sodium hydroxide (25 - 50 % by wt) into the reaction mixture.
The alkali hydroxide is present in excess. It is 1-5 moles and preferably in 2 - 5 moles with respect to the mole of α-naphthol The amide is 1-1.5 moles per mole of α-naphthol.
The addition of the sodium hydroxide solution into the a-naphthol and the amide solution in toluene is carried out at 50°C to 60°C, preferably at 55°C to 57°C The temperatures of the reaction mixture are also very important factor for preventing the racemization. A temperature range from about 60°C to 100°C is appropriate, but considering the reaction time and other convenience, reaction mixture is generally maintained from about 90°C to below 100°C and preferably 95°C to 98°C.
The reaction is monitored by gas chromatography using DB-5 capillary column. Generally the reaction is complete when the a-naphthol content is 1% (by GC area) which happens in 5 to 8 hrs, but mostly in 6 to 7 hrs. The reaction mass is then washed with water and extracted with sodium hydroxide solution and water to eliminate unreacted a-naphthol.
In order to obtain desired product in good yield and purity, the reaction between a-naphthol and amide must be carried out to completion and the excess of
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amide, solvents and other low boiling impurities are removed by distillation under reduced pressure.
After complete recovery of solvent, high purity D-Devrinol- is obtained as light brown solid in 84-85 % yield (on mole basis of L-CPC) and has melting point of 75°C -79°C. The chemical purity of the product is determined by gas chromatography on Packed column (10 %by wt. OV-7) by using internal standard method and against pure reference standard of (D)-(-)-N,N-Diethyl-2-(α-naphthoxy)propionamide. The chiral purity is determined by normal phase HPLC using Hexane: ethanol (99:1 v/v) mobile phase and OD-H chiral column at 230 nm in UV detector.
The chemical purity of the high purity D-Devrinol solid product obtainable by this preferred embodiment of the process may be as high as of the order of 93-94 % by wt. The chiral purity as high as 81 - 83 % by wt. of D-isomer. The Specific optical rotation (SOR) (of 1 %by wt. solution in ethanol, 1=10cm) is around [a]D20 -86° Therefore, the calculated optical purity may be as high as 62- 67 %by wt.
The product obtained at the end of step III, is high in chemical purity and rich in chiral purity and hence can be used as napropamide concentrate in herbicidal compositions.
In order to obtain higher purity product higher in optical purity, chiral purity and chemical purity further upgradation of the product may be carried out as described. The upgradation of the high purity material (solid, light brown color) can be carried out with various organic solvents, generally polar and different mix solvent systems having polar and /non-polar solvents. Preferably, Isopropyl alcohol (IPA): water with varying ratios like 5:5(v/v) and 7:3 (v/v) is suitable for upgradation, but other solvents can also be used.
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Higher Purity Product
Upgradation of high purity D-(-)-N,N-diethyl-2-(α-naphthoxy) propionamide obtained at the end of step 3 to the higher purity product having higher chemical, chiral and optical purity.
A process for upgrading high purity D-(-)-N,N-diethyl-2-(α-naphthoxy)propionamide to higher purity D-(-)-N,N-diethyl-2-(α-naphthoxy)propionamide includes dissolving and crystallizing the high purity product, D-(-) N,N -diethyl-2α- naphthoxy)propionamide obtained at the end of step (iii) in the manufacture of high purity product, in a solvent, filtrating and washing the crystals with chilled hexane and removing the solvent from the crystals to obtain the crystalline higher purity D-(-)N,N-diethyl-2-(α-naphthoxy)propionamide having chemical and chiral purity near about or above 95 % by wt. In this process, solvent may be selected from polar organic solvents or from polar aqueous organic solvents. The solvent is preferably isopropanol and water mixed in the ratio of (65 - 75) to (25 - 35) % by volume. And more preferably, in the ratio of (70- 30) % by volume.
In this process the high purity D - Devrinol is dissolved in the solvent at not above about 70°C
The high purity product, obtained is dissolved and maintained in isopropyl alcohol: water in the vol. ratio of (65-75: 35 -25) preferably in the ratio of (70:30 v/v) at 60 to 650C with stirring for about 45 minutes. The mass is first cooled to room temperature and then to 10 to 12°C and maintained at that temperature for 3 to 5 hrs for crystallization. The crystals are collected by filtration and the solid crystals are washed with chilled hexane and kept under vacuum for about 3 to 5 hrs to remove last traces of solvent moisture and the volatile impurities if any to get off-white crystalline solid with 65-66 % by weight yield based on 100 %by wt. of starting material L-CPC]. The melting point of the technical grade off-white
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solid is in the range around 94-96°C. The chemical purity of the product is determined by gas chromatography on packed column (10 % OV-7) by using internal standard method and against reference standard of (D)-(-)- N,N -Diethyl-2-(α-naphthoxy)propionamide and it shows the purity to be around 96 % (w/w). The chiral purity is determined by normal phase HPLC using Hexane: ethanol (99:1 v/v) mobile phase and OD-H chiral column at 230 nm in UV detector and the isomer content in the solid raises to near about 98 %by wt. of R-isomer and near about 2 %by wt. of S-isomer. In addition to that its specific optical rotation [a] D20 is 126° (1 % by wt. solution in ethanol, l=10cm) and optical purity of the material raises to near about 95 %by wt.
The products obtainable at the end of this step are higher Purity D-(-)-N,N-diethyl-2-(α-naphthoxy) propionamide having chemical purity above 95 % by weight, chiral purity more than 97% by wt. and Optical purity more than 94 % by wt.
The product obtained at the end of upgrading process, is higher in chemical, chiral and optical purity and hence can be used as napropamide concentrate of higher strength, in herbicidal compositions.
EXAMPLES
The present invention will now be described with the help of following examples. Examples are for the purpose of illustration only and in no way restrict the scope of the invention.
EXAMPLE 1
The process of the present invention will now be illustrated in this example step by step.
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STEP I: Preparation of (L)-(+)-2-Chloropropionyl chloride from L (-) 2-Chloropropionic Acid.
In a three-necked round bottomed kettle, (L)-(-)-2-Chloropropionic acid (108. 5 g,
98% chiral purity, 1.0 mole) was taken and dimethylformamide (5 ml) was added
to it under continuous stirring. The temperature of the reaction mass was raised
to 55°C and thionyl chloride (178.5 g, 98%by wt.
purity, 1.5 moles) was added slowly. During the addition, temperature of the reaction mass was maintained at 55-57°C. After the addition was over the temperature of the reaction mass was increased up to 68-70°C and maintained at this temperature till completion of the reaction ( The reaction was monitored by GC using DB-5 column. The reaction gets completed in 7 hrs. During the process, HCI and SO2 gases evolved were absorbed in the scrubber containing dilute sodium hydroxide solution. After completion of the reaction, the evolution of the HCI and SO2 gases in the scrubber had ceased. The (L)-(+)-2-chloro-propionyl chloride liquid was distilled under atmospheric pressure by using a 30-cm fractionating column. The material distills at 105-109°C giving 113.0 g pure material (90 % by weight yield based on 100 %by wt. L-(-) -2-Chloropropionic acid.
The chemical purity of the compound was 96 %by wt. calculated by GC area and having optical rotation: [a]o26: + 3.5° (neat, 1=10cm.) The chemical purity of the distilled (L)-(+)-2-chloropropionyl chloride is confirmed with standard sample of 2-chloropropionyl chloride in gas chromatography.
STEP II: Preparation of (L)-(+)- N,N-diethyl-2-chloropropionamide from (L)-(+)-2-Chloropropionyl chloride
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A mixture of Diethyl amine (81 g, 1.1 mole, 99 % by wt. purity), 48 % aqueous sodium hydroxide (100 g, 1.20 mole), water (120 ml) and toluene (250 gm) were charged in to a reaction kettle. The reaction mixture was cooled up to 20 to 22°C temp and L (+)- 2-chloropropionyl chloride (127 g, 1 mole) was added drop wise under continuous stirring. During the addition, temperature was not allowed to exceed beyond 30°C. After addition was completed, cooling was stopped and mixture was allowed to come to 30°C and maintained until the (L)-(+)-(2)-chloropropionyl chloride was £ 0.1 % by GC area. The reaction was monitored by Capillary GC (DB-5) column and completed in within 5 hrs.
After completion of reaction the aqueous phase was separated and organic phase containing product in toluene was washed with water till pH of washing was neutral from the washed organic phase, the 1/3 of toluene was distilled out of the total mass. The residual organic mass was 255 g. This was found to contain 48 % by weight of the (L)-(+)- 2-Chloro N, N—diethyl chloropropionamide in toluene. This corresponds to 93-94 % yield of amide based on L (+)- 2-Chloropropionyl chloride. The organic mass was carried out for the next step (in situ). The chemical purity of the amide and reaction monitoring is confirmed with standard sample of (L)-(+)-N,,/V—diethyl chloropropionamide.
STEP III: Preparation of D-(-)- N,N -Diethyl-2-(α-naphthoxy)propionamide Into a 3-litre round bottom kettle were placed a-Naphthol (517 g, 3.59 mole, 99 %by wt. purity) and 647 g (3.95 mole) of amide obtained in step II (based on 48 % purity assay w/w analysis) solution in toluene (total wt: 1345 g). The mixture was stirred and aqueous sodium hydroxide solution (642 g, 7.7mole, 48 %by wt.) was added drop wise to the reaction mass at 55-57°C temperature.
After completion of addition, reaction mass was heated to reflux at about 95°C. When reflux began, sodium chloride began to separate out. Refluxing was continued for 6 to 7 hours till completion of the reaction -16-

The reaction mixture was cooled to 50°C and 500 ml water and 500 ml Toluene at this temperature was added. The reaction mass stirred for 45 min. at this temperature and aqueous phase, which was lighter in color than the organic phase was separated. The organic phase including the inter-phase (emulsion) was reheated to 50°C. A solution of 250 ml sodium hydroxide (10 % by wt) and 250 ml of hot water were added and the phases were separated again. The organic phase again extracted with 250 ml water and the phases separated. The organic layer was collected and evaporated at 80°C under reduced pressure and then further for three hrs under high vacuum for complete removal of toluene. After complete removal of solvent, the 850 g of high purity product obtained which is light brown solid with 83 % by wt. yield based on starting material as L-CPC and had melting point of 75°C - 79 °C.
The chemical purity of the high purity product was found to be 94% by wt. by gas chromatography on Packed column (10 % by wt. OV-7) by using internal standard method and against reference standard of (D)-(-)- N,N-diethyl-2-(α-naphthoxy)propionamide
When examined by normal phase HPLC using Hexane: ethanol (99:1 v/v)
mobile phase and OD-H chiral column at 230 nm in UV detector, the high purity
product showed 82- % of D- isomer and 16 % of L-isomer.
The Specific optical rotation (SOR) (of 1 %by wt. solution in ethanol, 1=10cm) is
[a]D20 -86°. Therefore, the calculated optical purity may be as high as 64 %by
wt.
EXAMPLE II
Upgradation of high purity D-(-)- N,N-diethyl-2-(α-naphthoxy) propionamide obtained at the end of step III to the higher purity product having higher chemical, chiral and optical purity
This example describes upgradation of high purity product obtained in the Example I.
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To the brown colour solid material obtained at the end of step III, in Example I was added 600.0 gm of isopropyl alcohol: water (70:30 v/v) mixture and it was heated at 60°C -64°C with constant stirring. Heating and stirring was continued till the high purity product was completely dissolved. Stirring was further continued for 45 minutes at this temperature. The mass was brought first to room temperature and then cooled to and maintained at 10°C -12°C for 3-4 hrs. The solid crystals were filtered and washed with chilled hexane and the solid crystals were kept under vacuum for 3 hrs. The higher purity product (690 g) was obtained at the end of step IV, as off-white crystalline solid with overall yield 66 % by wt. based on starting material L-Chloropropionic acid. The melting point of the higher purity product was found to be 94.4-96.1°C. The higher purity product was examined for purity by the same methods used for examining the crude product.
The chemical purity of the upgraded product was found to be 96 % by wt. The
isomer ratio of the upgraded product was found to be 98 % of (D-isomer) and 1.8
% of (L-isomer).
The Specific Optical Rotation: [α]o20 was found to be -126° (1 % by wt. solution in
ethanol, 1=10cm) and the optical purity of the purified product was 95 % by
weight.
The purity and the structure of the high purity products are further confirmed as
D-isomer of napropamide by DSC analysis and GCMS as well as other spectral
studies
Dated o4/o5/2007

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PROCESS FOR MANUFACTURE OF HIGH PURITY D-(-)-N,N-DIETHYL-2-(α-NAPHTHOXY)PROPIONAMIDE

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