Title of Invention

A PROCESS FOR THE PREPARATION OF 2-CHLORO-3(PHENYLMETHOXY) PROPIONIC ACID POTASSIUM SALT

Abstract

ABSTRAC T 3477/CHENP/2005 "A PROCESS FOR THE PREPARATION OF 2-CHLORO-3(PHENYLMETHOXY) PROPIONIC ACID POTASSIUM SALT" The present invention relates to a process for the preparation of 2-chloro-3(phenylmethoxy)propionic acid potassium salt (II) without isolating any intennediates, the process comprising the successive steps of: (a) chlorinating methyl acrylate in the presence of catalytic amounts of dimethylformamide to give 2.3,dichloropropionic methyl ester acid; (b) reacting 2,3-dichloropropionic methyl ester acid in an organic solvent with anhydrous sodium benzylate. and subsequently treating it with sodium hydroxide to give 2-chloro-3-(phenylmethoxy)proplonic acid sodium salt in an organic phase; (c) acidifying the organic phase from step (b) to give an aqueous solution of 2-chloro-3-(phenylmethoxy) propionic acid; and (d) neutralizing the acidic aqueous phase of step (C) with potassium hydroxide and recovering compound (II).

Full Text

It: is a object of the invention the preparation ct 2-chlDro-3~(phenylmethoxy)propionic acid potassium salt comprising the steps represented in the following Scheme 2, without isolating the intermediates: in which in step a') methyl acrylate is chlorinated in the presence of catalytic amounts of dimethylformamide to give 2,3-dichloropropionic acid methyl ester of formula (V); in st^ b') the solution from step a') is first added, without exceeding 10°C, to Che sodium benzylate anhydrous solution, prepared by reaction between benzyl alcohol and sodium hydroxide, subsequently dehydrated by azeotropical distillation, then treated with sodium hydroxide, to give an organic phase containing 2-chloro-3-(phenylmethoxy)propionic acid sodium salt of formula (VI); in step c'} the organic phase from step b') is acidified with hydrochloric acid to give an aqueous solution of 2-chloro-3- (phenylmethoxy)propionic acid of formula in which in step a') meChyl acrylace is chlorinated in the presence of catalytic amounts of dimethylformamide to give 2,3-dichloropropionic acid methyl ester of formula (V); in sc^ b') the solution from step a') is first added, without exceeding 10 «• C, to the sodium benzylate anhydrous solution, prepared by reaction between benzyl alcohol and sodium hydroxide, subsequently dehydrated by azeotropical distillation, then treated with sodium hydroxide, to give an organic phase containing 2-chloro-3-(phenylmethoxy)propionic acid sodium salt of formula (VI); in step c') the organic phase from step b') is acidified with hydrochloric acid to give an aqueous solution of 2-chloro-3-(phenylmethoxy)propionic acid of formula {VII); in step d') the acidic aqueous phase from step c') is neutralized with potassium hydroxide and the 2-chloro-(phenylmethoxy) propionic acid potassium salt of formula {II) is recovered by crystallization after addition of sec-butanol. In step a') methyl acrylate is reacted with the stoichiometric amount of chlorine in the presence of dimethylformamide as catalyst in an amount of about 3% in mols. Chlorine is bubbled through the reaction solution of methyl acrylate and DMF at room temperature: chlorine not immediately reacted saturates the reactor top thus promoting the reagents exchange. The internal pressure is kept to a maximum of 0.1 bar above the atmospheric pressure by dosing the chlorine flow. The reaction ia exothermic and the temperature is controlled at about 45°C by cooling with water. The reaction is considered completed when the stoichiometric amount of chlorine supplied has been absorbed. Lower temperatures have been found to slow down the chlorine adsorption, kinetics. The use of dimethylformamide as catalyst is mandatory: the tests carried out without catalyst have not been completed due to the exceedingly long times for chlorine adsorption. Sodium benzylate is prepared conventionally by reacting benzyl alcohol and 3 0% NaOH. The solution is dehydrated by distilling under vacuum the heterogeneous azeotrope water/benzyl alcohol and then humid benzyl alcohol to pressure lower than 20 mbars and at a temperature of llCC: (residual water content below 0.4% w/w by Karl Fischer). An amount of sodium benzylate solution equivalent to 120-140% on the snoichiometric to methyl acrylate is cooled to 5°C and then, without exceeding 10°C, the solution from step a') is dropped therein. At the end the mixture is stirred for 15-30 minutes at 5-10°C, then a 30% NaOH amount, ecjuivalent to 80-100% on the stoichiometric amount to methyl acrylate, is dropped therein without exceeding 15°C. Cooling is stopped and water is added. After stirring, the mixture is left to stand until complete, marked separation of the two phases. The mainly aqueous lower phase is discarded. The benzyl upper phase, containing 2-chloro-3-benzyloxypropionic acid sodium salt, is added with a sodium chloride solution. After the usual work up, the marked and completed separation of two phases is obtained, the lower acidic aqueous phase being discarded. In step C) the organic phase is acidified to pH 2.5 with 34% HCl w/w, stirring and at a temperature not above 20'C; stirring is interrupted and the mixture is left to stand until two phases separate markedly and completely. In step d' ) the organic phase containing 2-chloro-3-benzyloxy-propionic acid is adjusted to pH 7.2 by addition of 5 0% KOH. The formation of the potassium salt is exothermic and the temperature is conveniently kept below 35°C with circulating water. The solution containing compound (II) is partially dehydrated by distillation at a partial pressure of about 20 mbars and at a temperature not above 55°C. The water content should range from 4 to 10% w/w. Lower or higher values should be corrected by addition of water or continuing distillation. 2-Butanol is added at 50°c, slowly cooling to crystallize the desired product. The resulting humid product is dried at eo°c and under reduced pressure, preferably at 20 mbars. Yields starting from methyl acrylate are around 60-70%. The following examples illustrate the be§t experimental conditions to carry out the process of the invention. Experimental Section EXAMPLE 1 Isolation of 1- (aminoethyl) -2-oxo-3- [ (phenylmethoxy)methyl]-piperazine prepared according to the procedure deacribed in EP 230893 and Uggeri F., et al, Inorg. Chem., 1995, 34(3), 633-42. 42.9 g of 2-chloro-3-[(phenylmechoxy)methyl]propionic acid (0.2 mol) are reacted with 268.2 g of DETA (2.58 mol) at SQOC in 4QQ mL of water, and the solution is percolated on an Amberlite ^^' IRA 4 00 column (1880 mL) , then washed with water and the basic phase is collected. This basic phase contains the excess DETA and the desired product. The solution is neutralized with 37% HCl (465 mL) and evaporated to small volume, Chen acidified to pH 2 with 37% HCl (3 65 mL) . After concentration to about 800 g and standing overnight at room temperature, the solution is filtered, washed with absolute ethanol and dried to obtain DETA trihydrochloride (173.5 g, O.Sl mol). Mother liquors are concentrated to about 450 g, taJten up with the washing ethanol used above and 800 mL of absolute ethanol, then, after two hours at 0-5°C, filtered, washed with absolute ethanol and dried to obtain DETA trihydrochloride {313.4 g, 1.47 mol). Crystallization waters and washings are combined and evaporated to a residue, which is taken up with ethyl ether, triturated, filtered and dried, to obtain a mixture of DETA trihydrochloride and the desired product. The mixture is then dissolved in 8 0 mL of water and percolated on a XAD 2 700 mL column, washing with water. Fractions of about 70 mL are collected and subjected to TLC (Rf = 0.3B). The fractions containing the desired product are collected and evaporated to a residue, which is crystallized from absolute ethanol. The precipitate is filtered, washed with absolute ethanol and dried to obtain 7.1 g of the desired product {0,021 mol). Yield: 10.5% m.p.: 163=C HPLC assay: 95.8% [in area %) Elementary Analysis C H Cl N % calc.; 50.0 6.89 21.08 12.50 % found: 49.64 5.73 21.24 12.72 TLC: -Stationary phase: silica gel plate 60F 254 Merck Eluent: CHCI3/ACOH/H2O = 5/5/1 Detection: 1% KMnO^ in IN NaOH Rf = 0.38 ^H-NMR, ■'■^C-NMR, IR and MS spectra are consistent with the indicated structure. EXAMPLE 2 Preparation of compound (III) on an industrial scale according to the procedure described in the literature cited in Example 1 The reaction is carried out according to the conventional procedure, using 23.7 kg (110 mol) of 2-chloro-3 - (phenylmethoxy) propionic acid with 149 kg (1430 mol) of DETA in 250 L of water. After percolating the final solution on an Amberlice'^^ IRA 400 column {1000 L, OH"), and eluting the product with IN HCl, an aqueous solution made acidic by hydrochloric acid is evaporated to a concentration of about 1 mol/L, equivalent to 2200L. The solution is concentrated to small volume in about 15 hours at SO^C. The resulting residue is taken up into absolute ethanol. Upon cooling, a product precipitates which is filtered and washed with absolute ethanol. Crystallization from absolute ethanol and subsequent drying yield 24 kg of the desired product (71.5 mol). Yield: 65% The chemical-physical characteristics are in agreement with these cited in Example 1. EXAMPLE 3 2-Chloro-3- (phenylmethoxy)propionic acid (II) A) Preparation of 1,Z-dichloro-prDpionic acid methyl ester 3.23 kg of methyl acrylate and 0.096 kg of dimethylformamide are loaded in a reactor under vacuum. After completion of the operation, the reactor is isolated, kept under reduced pressure and connected with a chlorine cylinder equipped with a flow control valve. Chlorine is bubbled through the reaction solution at room temperature. The inner pressure is checked to a maximum of 0.1 bar above atmospheric pressure. The reaction is exothermic and temperature is kept at 4 5°C by cooling with water. The reaction is considered completed when 2.66 kg of chlorine have been supplied and absorbed. The operation takes place in about 2 hours and 30 minutes. The amount of chlorine supplied is controlled by weighing the cylinder. B) Preparation of sodium benzylate in solution of benzyl alcohol 34.5 kg of benzyl alcohol and 6.7 kg of 30% NaOH are loaded in a steel reactor equipped with stirrer and fitted for distillation under vacuum. The solution is dried, distilling under vacuum the heterogeneous water/benzyl alcohol azeotrope and then the humid benzyl alcohol at a pressure lower than 2 0 mbars and at 110°C. C) Preparation of 2-chloro-3-(phenylmethoxy) propionic acid potasBlum salt The sodium benzylate solution is placed in a stainless steel reactor equipped with stirrer and cooling jacket, cooled at 5°C, then, without exceeding lO^C, 1,2-dichloro-propionic acid methyl ester is dropped therein. The addition time depends on the ability of the plant to keep temperature within the predetermined limits; addition time should not exceed 4 hours, as in this case remarkable amounts of undesired side-products form. After corrpletion of the addition the mixture is stirred for 15-30 minutes at 5-10°C,- then 4.4 kg of 30% NaOH are added dropwise, without exceeding 15'C. Cooling is stopped and a suiltable amount of water is added. Stirring is continued for 30 minutes, then is stopped and the reaction mixture is left to stand until completion and marked separation of two phases. The mainly aqueous lower phase is discarded. The benzylic upper phase containing 2-chloro-3-benzyloxypropionic acid sodium salt is added with a NaCl water solution to promote the separation of the phases and the lower aqueous one is discarded. The organic phase is stirred below 20°C and adjusted to pH 2.5-3.0 with 34% HCl w/w. The phases are separated and the lower aqueous acidic phase is discarded, water is added and the phases are separated again, removing the upper aqueous phase. The organic phase containing 2-chloro-3-ben2yloxy-propionic acid is adjusted to pH 7.2 with 50% KOH, the reaction is exothermic and temperature is kept below 35°C with circulating water. The solution containing the desired compound is in part dried by distillation at partial pressure of about 20 mbars and at temperature not above 55°C. After that, water content is determined by Karl Fischer and adjusted to a value equivalent to 5%. The resulting solution is added with 54 kg of 2-butanol at 50*^0, and left to spontaneously cool under stirring. Once reached 40°C the solution is seeded: most product precipitates between 38 and 30°C. When temperature reaches 25°C, the solution is cooled to 15°C with circulating water, keeping this temperature for 1 hour, then is centrifuged and washed with 2'butanol to obtain the humid product, which is dried for 10 hours at eCC and at partial pressure of 20 mbars. 5.8 kg of dry product are obtained. Yield; e6% (on the starting methyl acrylate mols) K.F.: 3.0% (w/w) HPLC assay: 100.0% (ext. st. .) HPLC impurities: 0.15% (% area) Column LiChrospher 100 RP8 (5mm, 25 cm x 4 mm) Mobile phase A) Aqueous solution containing 1.2 mL/L of 85% H3PO4 (w/w) B) Acetonitrile Gradient linear t(min) %B(v/v) 0 40 15 60 25 60 26 40 36 40 Flow: 1 mL/min Temperature 30°C Detection UV, 215 nm The chemical-physical analytical characteristics are consistent with those indicated in the paper by Aime S., Inorg. Chem., 1992, 31, 1100. EXAMPLE 4 Preparation of 1,2-dichloro-propionic acid methyl ester without DMP 34.83 g of methyl acrylate are loaded in a reactor under vacuum, connected with a chlorine cylinder equipped with flow control valve. Chlorine is bubbled through the reaction solution at room temperature. Chlorine is absorbed very slowly. The mixture is heated to 40 °C. 2 hours later, 12.5 g of chlorine have been absorbed. After a further S hours, 6 g more have been absorbed. During 10 h at 40°C only 18.5 g of chlorine are absorbed equivalent to 64% on theoretical. EXAMPLE 5 Preparation of compound (I) A) Preparation of the aqueous solution of N-[2-[(2-aaninoethyl) amino] ethyl] -0- (phenylmethyl) serine sodium salt 265 kg of compound (II) (1.05 kmol) are reacted with 758 kg Of DETA (7.35 kmol) in the presence of 129 kg of water; temperature spontaneously raises to SO^C. When temperature exceeds 50°C, the reaction starts, and the temperature further raises due to the reaction exothermy and is kept at about 600-C by cooling with water. pH is kept at about 12 by addition of a 30% sodaum hydroxide solution (w/w) for about 10 hours, while keeping temperature at 600C. The solution is then cooled to 250C, diluted with water and percolated onto 120 0 L of a polystyrene-matrix strong anionic resin in OH" form. The product and the anionic impurities are adsorbed by the resin, whereas DETA, non-anionic impurities and cations (sodium, potassium) are eluted with water. Afterwards, the product is eluted with an aqueous solution containing sodium chloride and hydrochloric acid, the eluate is adjusted to pH 11.5 and fed to a column containing 210 L of macroporous polystyrene adsorbing resin, which removes the most lipophilic impurities of the product. The eluate from the adsorbing resin, containing compound (HI) together with sodium chloride, is concentrated and desalted by nanofiltration, afterwards it is adjusted to pH 12 to prevent lactamization and then thermally concentrated under reduced pressure. 650 kg of a 40% solution of the desired product (w/w) are obtained (0.67 kmol, yield from compound (II) 63%). The solution is then stored below 25'C, analyzed and used directly in the following step. B) Preparation of compound (I) 195.4 kg (0.20 kmol) of the solution of compound (III) sodium salt are heated to 55°C and reacted with 136.2 kg of an 80% bromoacetic acid aqueous solution, which are added slowly. pH is kept at 11.6 with a 30% (w/w) sodium hydroxide solution. The reaction is completed in about 55° C and at pH 11.2 in about 5 hours. The solution is then cooled to 25°C and pH is adjusted to about 5.5 with a 34% hydrochloric acid solution (w/w). The solution containing the crude compound (I) is percolated onto a chromatographic resin (XAD 1600, 150L) to remove the lipophilic impurities; the product is elated with water and the eluate is concentrated and partially desalted by nanofiltration. The retentate solution is warm concentrated under reduced pressure to obtain a crude solution having a compound (I) / water ratio of about 1/6. After that, pH is adjusted to 2.0 and temperature to 45'C; acetone and crystals of compound [I) are added at about 41°C. The crystallization mixture is kept under stirring at the same temperature for at least 18h; then it is slowly cooled to 25°C in about 5h and to 17°C for a further 24h. The solid is recovered by centrifugation and washed with an 10% acetone aqueous solution (w/w), then the crude is dissolved in deionized water at about 55°C. When the dissolution is completed, Che solution is cooled to about 47'C; and the previous procedure of seeding and subsequent crystallization is repeated. The obtained solid is then dissolved again in deionized water at about SS'C. When the dissolution is completed, the solution is filtered to remove the particles, and partially evaporated to remove any traces of volatile organic impurities contained in the acetone used In the two previous crystallizations. The solution is then cooled to 47°C and crystallized under the same conditions as defined above. 127 kg of humid crystalline product are recovered by centrifugation and dried at 35°C and 35 mbars, to yield 68 kg of the desired product (0.121 kmol). Yield; 50.5% from compound (II) K.F.: 8% (w/w) Titre : 100.1% (ext. standard .) HPLC impurities : 0.15% WE CLAIM: 1. A process for the preparation of 2-chloro-3(phenylmethoxy)propionic acid potassium salt (II) without isolating any intermediates, the process comprising the successive steps of: (a) chlorinating methyl acrylate in the presence of catalytic amounts of dimethylformamide to give 2,3,dichloropropionic methyl ester acid; (b) reacting 2,3-dichloropropionic methyl ester acid in an organic solvent with anhydrous sodium benzylate, and subsequently treating it with sodium hydroxide to give 2-chloro-3-{phenylmethoxy)proplonic acid sodium salt in an organic phase; (c) acidifying the organic phase from step (b) to give an aqueous solution of 2-chloro-3-(phenylmethoxy) propionic acid; and (d) neutralizing the acidic aqueous phase of step (c) with potassium hydroxide and recovering compound (Tf). 2. The process as claimed in claim 1, in which the amount dimethylformamide catalyst is of about 3 mo!%. 3. The process as claimed in claim 1, in which step a) is effected at a pressure up to a maximum of O.I bar above atmospheric pressure. 4. The process as claimed in claim 1, in which step a) is effected at a temperature of 5. The process as claimed in claim 1, in which step b) is effected at a temperature below lO0C. 6. The process as claimed in claim 1, in which the sodium benzylate of step b) is obtained by reaction between benzyl alcohol and sodium hydroxide and subsequent dehydration by azeotropical distillation. 7. The process as claimed in claim 1. in which the sodium benzylate used in step b) is in solution with a residual water content lower than 0.4% w/w. 8. The process as claimed in claim 1, in which in step b) the sodium bezylate solution is added in an amount equivalent to 120-140% of the stoichiometric amount to methyl acrylate. 9. The process as claimed in claim in 1. in which in step b) the amount of 30% by weight sodium hydroxide used is equivalent to 80-100% of the stoichiometric amount of the methyl acrytale, 10. The process as claimed in claim 1, in which the acidification of step c) is carried out with 34% w/w HCI to pH 2.5. 11. The process as claimed in claim 1. in which the neutralization of step d) is carried out by addition of 50% by weight KOH to pH 7.2. 12. The process as claimed in claim K in which the isolation of compound (II) of step d) is carried out by crystallization. 13. The process as claimed in claim 12, in which said isolation is carried out by partial dehydration of the solution containing compound (11) and subsequent addition of 2-butanol as a crystallization solvent, 14. The process as claimed in claim 13, in which the partial dehydration is carried out by distillation at a partial pressure of about 20 mbars and at a temperature below 55°C. 15. The process as claimed in claim 14, in which the distillation is carried out to a water content of from 4 to 10% w/w, 16. The process as claimed in claim 13, in which the addition of 2-butanol is carried out at a temperature of 50°C.

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