MXPA99009046A - Process for preparing o-(3-amino-2-hydroxy-propyl)-hydroxymic acid halides - Google Patents

Abstract

The present invention relates to a novel process for preparing O-(3-amino-2-hydroxy-propyl)-hydroxymic acid halides of formula (I) by reacting a carboxamide oxime of formula (II) wherein R1 is as specified above with reactive 3-amino-2-hydroxy-propane derivative, diazotizing the O-substituted carboxamide oxime thus obtained with sodium nitrite in the presence of hydrogen halide, decomposing the diazonium salt and if desired, separating the optically active enantiomers and/or reacting the resulting base with an organic or mineral acid, wherein the carboxamide oxime of formula (II) is reacted with a 3-hydroxy azetidinium salt of formula (III) wherein R2 and R3 are as defined above and Y- is a salt forming anion, in a lower alcoholic, preferably ethanolic medium optionally containing water and made alkaline with an alkali hydroxide, and before diazotizing the O-substituted carboxamide oxime intermediate obtained, the reaction mixture is neutralised and the organic solvent is removed. The process according to the invention provides the compounds of formula (I) with a higher yield compared to the prior art processes.

Description

PROCESS FOR PREPARING HALOGENURS OF ACID 0-Í3-AMINO-2-HIDROXI-PROPlL) -HlDROXiMICO TECHNICAL FIELD The present invention relates to a novel process for preparing halides of 0- (3-amino-2-hydroxy-propyl) -hydroxymic acid of the formula (I) wherein: R 1 is phenyl, pyridyl or thienyl or substituted phenyl, where one or more substituents can be halogen and / or haloalkyl and / or nitro, X is halogen, R2 and R3 are independently of each other straight or branched chain lower alkyl or R2 and R3 together with the nitrogen which are connected thereto form a saturated 5- to 7-membered heterocyclic group, which may contain heterogeneous atoms additional and can be replaced.

The invention also relates to a process for preparing the acid addition salts and optically active forms of the above compounds.

BACKGROUND OF THE INVENTION The halides of 0- (3-amino-2-hydroxy-propyl) -hydroxyme acid of the general formula (I) are well known as active substances in the treatment of pathological changes in the vascular system in relation to diabetes mellitus, especially with diabetic angiopathies. These compounds are particularly described in, for example, WO-A-90/04584. The 0- (3-amino-2-hydroxy-propyl) -hydroxyme acid halides of the general formula (I) can be prepared in many different forms, some of which are also described in WO-A-90/04584 . Although the synthetic routes known to be manufactured are suitable for the preparation of the compounds of the formula (I), they are not sufficient for the preparation of said compounds on an industrial scale. Their disadvantage is that they need reagents that are difficult to handle or prepare or understand unfavorable reactions with unsatisfactory yields due to the possibility of lateral reactions. The urgent need for compounds of the formula (I) requires a novel process, which is safe, has a satisfactory production and can be carried out under industrial conditions.

DESCRIPTION OF THE INVENTION The present invention has for its object to provide a process for preparing halides of 0- (3-amino-2-hydroxy-propyl) -hydroxy acid on an industrial scale. The present invention provides an industrially applicable process for preparing the compounds of the formula (I) i) reacting an amidoxime compound of the formula (II) with a 3-hydroxy-acetidinium salt of the formula (III), wherein: R2 and R3 have the meaning described above, and Y- is a forming anion of salt, in a basic-alcoholic medium, ii) neutralizing the mixture and removing the organic solvent, ii) reacting the residue with sodium nitrite in an aqueous medium in the presence of hydrochloric acid, iv) decomposing the diazonium salt thus obtained , and v) isolating the crude product of formula (1) from the mixture. Reactions of amidoxime compounds of formula II and suitably substituted 3-amino-2-hydroxypropane derivatives (usually 1-halo or 1,2-epoxy derivatives) are described in Great Britain Patent No. 1,582,029. However, the 3-hydroxy acetydinium salts of the formula (III) are more suitable reactants than the 1 -halo derivatives or 1, 2-epoxy used in the known reactions. Primarily, the compounds of the formula (I II) are solid materials which can be easily prepared, isolated and stored unlike the reagents formerly used, which are difficult to isolate and handle and are generally liquid materials. The use of these was made known from WO-A-90/081 31, but in the process described there neither these nor the other two reactants are directly reacted with the compounds of the formula (II), but with a complex of amidoxime prepared therefrom with alkaline hydroxide or alkali alcoholate or dimethylformamide or 1,3-dimethyl-2-imidazolidinone in a medium containing dimethyl formamide. In this way, O-substituted amidoxime derivatives were isolated which, however, appear only as non-isolated intermediates in the reaction sequence according to the present invention. Based on the observations, efforts were made to eliminate the technologically difficult complex by forming from the process and to avoid the use of dimethyl formamide as a solvent. Dimethyl formamide is dangerous to health because it causes cancer, it is also difficult to regenerate and purify and extremely difficult to be free of water. This is especially important since the impurity of dimethyl formamide should be minimized as presented in WO-A-90/08131. In addition, it is preferred that the solvent contains only a very small amount of water, practically less than 1% to achieve an appropriate performance. An additional disadvantage of using dimethyl formamide is that it decomposes when exposed to light and contaminated by toxic compounds developed. It has been found that the reaction can be carried out safely and easily by reacting the compounds of formulas (II) and (III) directly in a basic alcoholic medium, which can also contain water. With respect to the production of the synthesis, it is very difficult that the O-substituted carboxamide oxime intermediate is not isolated from the reaction mixture, but directly reacts more after neutralizing the mixture of removing the organic solvent. It has also been found that the side products formed during the steps presented can all be removed through a single step of suitable isolation and, thus, the synthesis is appropriate for the manufacture of the product in the desired purity. Based on these observations, the invention provides a process for preparing compounds of the formula (I), wherein: R 1 is phenyl, pyridyl or thienyl, or substituted phenyl, wherein one or more substituents can be halogen and / or haloalkyl and or nitro, X is halogen, R 2 and R 3 are independently of each other straight or branched chain lower alkyl, or R 2 and R 3 together with the nitrogen connected thereto form a saturated 5- to 7-membered heterocyclic group, which can containing an additional heterogeneous atom and can be substituted, and the acid addition salts and optically active forms thereof by reacting a carboxamide oxime of the formula (II), wherein the meaning of R1 is as specified above with a Reactive 3-amino-2-hydroxy-propane derivative, diazotizing the resulting O-substituted carboxamide oxime with sodium nitrite in the presence of halogenated salt, decomposing the diazonium salt, isolating the obtained product and, if desired, separating the optically active enantiomers and / or reacting the resulting base with an organic or mineral acid; which comprises reacting the carboxamide oxime of the formula (II) with a 3-hydroxy acetidinium salt of the formula (III), wherein R2 and R3 have the meaning presented above, and, Y "is an anion forming salt in an alcoholic medium of 1 to 4 carbon atoms, preferably ethanolic, which is made alkaline with an alkaline hydroxide, the medium optionally containing water while the reaction mixture is neutralized and the organic solvent is removed from it before diazotizing the O-substituted carboxamide oxime intermediate resulting.

BEST MODE FOR CARRYING OUT THE INVENTION A preferred mode for carrying out the process according to the invention is as follows: The carboxamide oxime of the formula (II) and the 3-hydroxy acetidinium salt of the formula (III) are reacted at a stoichiometric ratio, however , it may be advantageous to apply the compound of the formula (III) in a slight excess. The reaction can be carried out with any order of addition of the reactants, preferably the compound of the formula (II) is added to the basic-alcohol solution of the compound of the formula (III). As a softener, an alkanol of 1 to 4 carbon atoms, preferably ethanol, is preferably used, and the reaction is preferably carried out with heating, most preferably at the boiling point of the solvent. After completion of the reaction, the mixture is cooled and neutralized with a mineral oil, preferably hydrochloric acid, and the alcohol is conveniently distilled at lower pressure. After removing the solvent, the reaction mixture is diluted with water, the concentrated hydrochloric acid necessary for diazotization is added, cooled to the diazotization temperature and diazotized through the addition of sodium nitrite under cooling at a temperature from 0 to + 5 ° C. The diazonium salt is decomposed in situ to the corresponding hydroperoyl halide derivative. To isolate the crude product, the reaction mixture is made alkaline with an inorganic alkaline compound, extracted with an organic solvent not miscible with water, preferably ethyl acetate, the extract is dried and concentrated, or an addition salt is formed directly of acid from the product by adding a suitable acid to the mixture and separating the acid addition salt through filtration. The crude product can be purified by recrystallization or by any other means known in the art. Using the above process, an appropriately pure product can be prepared with an economically satisfactory yield. The advantage of the present invention lies in the fact that it is possible to produce 0- (3-amino-2-hydroxy-propyl) -hydroxime acid halides through a safe and simple method also under industrial conditions. The invention is further illustrated in the following examples: EXAMPLE 1 (Z) -2-N-R 2 -hydroxy-3- (1-piperidinip-3-pyridinecarboximidoyl chloride) butenedioate 50.4 kg of 2-hydroxy-4-azoniaspiro- [3,5] -nonano chloride were dissolved in 28 liters of water with stirring. To the solution, 11.4 kg of sodium hydroxide was added and the resulting milk-type mixture was stirred for an additional hour. While stirring, 420 liters of ethanol and 35 kg of 3-pyridinecarboxamide oxime were added thereto and the mixture was heated under reflux for 1-5 hours followed by cooling of the reaction mixture. 270-290 liters of alcohol were distilled and 110 liters of deionized water and 45.5 liters of concentrated hydrochloric acid were added followed by the distillation of the remaining ethanol. To the oily residue, 160 liters of concentrated hydrochloric acid were added under cooling, so that the temperature remained below 30 ° C. The solution was then cooled to 0 ° C and for diazotization, a mixture of 17.7 kg of sodium nitrite and 60 liters of deionized water was added under continuous stirring and cooling, while maintaining the temperature of the reaction mixture between 0 and + 5 ° C. After the addition, the mixture was stirred for a further 1 hour at this temperature and for the decomposition of the excess nitrite, 1.5 kg of urea was added. After the total decomposition of the nitrite (approximately 1.5 hours), 350 liters of ethyl acetate were added to the reaction mixture followed by alkalization through the addition of 150-200 liters of concentrated sodium hydroxide under stirring and intense cooling. The layers were separated, the organic phase was washed with 2 x 70 liters of water and dried over 15 kg of anhydrous Na 2 SO 4. The drying agent leaked, washed with 20 liters of ethyl acetate, the organic layers were combined and the amount of the N- [2-hydroxy-3- (piperidin-1-yl) -propoxy-3-piperidine-carboxyl chloride base Midoyl was determined. Maleic acid was added in a calculated amount (21-22 kg) and the mixture was stirred for 4 hours. The product was separated in a centrifuge, washed with 30 liters of acetone and the resulting crude product was dissolved in 70 liters of hot acetone and recrystallized. The product was separated in a centrifuge and washed with 30 liters of acetone. After recrystallization, 50-55 kg of N- [2-hydroxy-3- (1-piperidinyl) -propoxy] -3-pyridinecarboximidoyl chloride (Z) -2-butenedioate were obtained (1: 1) like pink-beige crystals. (p.p. 123-124 ° C, acetone, yield: 53%).

LB_ (v, KBr / cm-1): 3350, 2941, 1580, 1480, 1350, 1022, 982, 867, 702. 1 H-NMR (250 MHz, DMSO-d 6, ref .: DMSO-d 6 = 2, 5.d (ppm): 9.00 (1H, s), 8.74 (1H, d), 8.18 (1H, d), 7.56 ( 1H, dd), 6.03 (2H, s), 5.85-6.00 (1H, s / br), 4.21-4.37 (3H.m), 3.2-3.33 (2H, m), 2.49-2.55 (4H, m ); 1.54-1.77 (6H, m). 13C-NMR (63 MHz, solvent: DMSO-d6; ref DMSO-d6 = 39.3.5 (ppm): 167.0 (COOH); 151.4, 127.9, 134.3, 123.5, 147.2 (pyridine 2-3-4-5-6) ); 135.4 (CH = CH); 134.9 (C / C1 / = NO); 77.2 (NOCH2); 63.5 (CHOH, 58.3 (NCH2); 52.9, 22.1, 21.2 (piperidine).

In accordance with Example 1, the following compounds were prepared: EXAMPLE 2 N-R 2 -hydroxy-3- (1-piperidinyl) -propoxy-1-benzimidoyl chloride hydrochloride (mp: 140-144 ° C, isopropanol, yield: 66%) LR (KBr): 3234, 2951, 1504, 1448, 1389, 1289, 1119, 1059, 972, 768, 690.

EXAMPLE 3 (Z) -2-Butenedioate of Nf 2-hydroxy-3-ri - (4-methyl) -piperazinop-propoxy) -3-pyridinecarboxydomdoyl chloride (1: 2) ) (mp: 174-175 ° C, ethanol, yield: 48%) IR. (KBr): 3207, 1693, 1578, 1456, 1358, 1304, 1020, 974, 864, 702.

EXAMPLE 4 N-R 2 -hydroxy-3- (dimethylamino) -propoxp-3-pyridinecarboximidoyl chloride hydrochloride (mp: 118-119 ° C, acetone, yield: 67%) J_R (KBr): 3425, 3289, 2951, 2667. 1818, 1443, 1337, 1238, 1178, 1115, 1078, 1049, 997, 910, 804, 781, 696, 683 ctrT1.

EXAMPLE 5 (Z) -2-Butenedioate of N-r2-hydroxy-3- (4-morpholinyl) -propoxyl-3-pyridinecarboximidoyl chloride (mp: 137-138 ° C, isopropanol, yield: 52%) JR . (KBr): 3310, 1580, 1483, 1464, 1443, 1354, 1072, 1024, 982.

EXAMPLE 6 N-R 2 -hydroxy-3- (1-piperidinium-propoxyl-2-thiophenecarboxamidoyl chloride (mp: 115-123C0, isopropanol-hexane, yield: 38%) 1 H-NMR (250 MHz, DMSO -d6; ref .: DMSO-d6 = 2.5d (ppm); 10.2 (1H, s / br); 7.81, 7.63, 7.20 (1H, 1H, 1H, d, d, dd); 5.98 (1H, s / b), 4.42 (1H, s / b), 4.35 (2H, d), 3.60-2.90 (6H, m), 1.95-1.60 (4H, m), 1.45-1.20 (2H, m). NMR (63 MHz, DMSO-d6; ref .: DMSO-d6 = 39.3d (ppm): 133.8 [C (CI) = N]; 132.1, 130.3, 130.1, 127.6 (thiophene 3-2-5-4); 76.8 (NOCH2); 63.2 (CHOH); 58.5 (CH2N); 53.3, 51.8 (piperidine 2 x NCH2) 22.0, 21.9, 21.0 (piperidine 3 x CH2).

EXAMPLE 7 N-R 2 -hydroxy-3- (1-piperidinium-propoxy-2-trifluoromethyl benzimidoyl chloride hydrochloride (mp: 119-123 ° C, ethyl acetate, yield: 30%) JR. (KBr ): 3366, 2937, 2854, 2737, 2673, 2538, 1616, 1570, 1439, 1404, 1337, 1290, 1236, 1199, 1165, 1129, 1101, 1074, 1030, 984, 972, 933, 901, 829, 804, 788, 717, 699, 685, 646 c? Tf1.

EXAMPLE 8 N-r 2 -hydroxy-3- (1-piperidinium-propoxyl-2'-nitrobenzimidoyl chloride hydrochloride (mp 159-162 ° C, isopropanol, yield: 43%) IR (KBr): 3298, 2983, 2932, 2746, 1593, 1574, 1535, 1445, 1391, 1354, 1317, 1288, 1242, 1198, 1117, 1092, 1069, 1020, 968, 947, 914, 852, 793, 756, 708, 577 cm "1.

EXAMPLE 9 (Z) -2- (+) N-R 2 -hydroxy-3- (1-piperidin-1-yl) -propoxyl-3-pyridinecarboximidoyl chloride (1: 1) butenedioate 2-Hydroxy-4-azoniaspiro [3.5] nonane and 3-pyridinecarboxamide chloride were reacted according to Example 1 by following the reaction steps to separate the N- [2-hydroxy-3- (1- piperidin-1-yl) -propoxy] -3-pyridinecarboximidoyl with ethyl acetate. 15 g (50 mmoles) of N- [2-hydroxy-3- (1-piperidin-1-fl) -propoxy] -3-pyridinecarboximidoyl chloride in ethyl acetate was added dropwise to a mixed anhydride. prepared from 13.52 g (50 mmoles) of N- (t-butoxycarbonyl) -L-phenylalanine and 5.0 ml of ethyl chloroformate in dichloromethane through a per se method and the mixture was stirred for one hour at room temperature. To isolate the ester thus obtained, the solution was extracted with 2 x 200 ml of a solution of aqueous acetic acid (10%) and 1 x 200 ml of water, the organic layer was dried over anhydrous Na 2 SO 4 and concentrated. The oily residue was dissolved in 140 ml of acetone, 3.0 g of maleic acid was added to the solution. In this manner, 5.2 g (7.8 mmol, 16%) of the (Z) -2-butenedioate salt of (-) N- [2- (N'-BOC- / L / -phenylalanyloxy) chloride were obtained. 3- (1-piperidinyl) -propoxy] -3-pyridinecarboximidoyl (1: 1) (mp: 146.5-148 ° C). 5.2 g of the salt prepared above were boiled in methanol for 1 hour. The solution was distilled to dryness and the residue was crystallized from 50 ml of ethyl acetate giving 3.18 g (98% >;) of the (+) N- [2-hydroxy-3- (1-piperidin-1-yl) -propoxy] -3-pyridine-carboxy-imidoyl chloride (Z) -2-butenedioate salt (1: 1) ), (mp: 136-137 ° C). The IR and the NMR spectrum of the compound corresponded to those of the racemic compound. According to chiral displacement spectroscopy the compound was a homogeneous enantiomer. The (-) isomer can be prepared in an analogous manner, but using N- (t-butoxycarbonyl) - / D / -phenylalanine as a reagent. The method according to the invention was compared with the method described in the prior art mentioned previously. 3-pyridinecarboxamide oxime was reacted with 3-piperidino-2-hydroxy-1-chloropropane prepared according to the method described in Great Britain Patent No. 1,582,029 in an absolute alcoholic medium. After the reaction was finished, the solution was made alkaline, the product was extracted with benzene and from the base, dihydrochloride was formed with gaseous hydrochloric acid. The 0- (3-piperidino-2-hydroxy-1-propyl) -3-pyridine-carboxamide oxime thus obtained was diazotized according to the method described in Hungarian Patent No. 207,988, the diazonium salt decomposed and the resulting product was reacted with maleic acid to give the product according to Example 1. The final yield of the process based on the starting product was 38%, while the same in Example 1 was 53 %, which rose up to 60% during commercial production. It can be established that the process according to the invention provides the compounds of the formula (1) with a higher yield compared to the processes of the prior art. An additional advantage of the process according to the invention is the possibility of avoiding the solvent. To prepare 1 kg of the product according to the process described in the present invention, only 17 kg of solvent was necessary, while the same according to the processes known in the past represented 40 kg. An additional advantage of the process according to the invention on an industrial scale is that the technology time necessary for the preparation of the compounds of the formula (I) is shorter. To produce a batch of the product related to a reactor volume of 3 m 3 according to the invention, 4 consecutive displacements were needed while the processes of the prior art required 8 displacements. In summary, the process according to the present invention provides a method for preparing the OH- (3-amino-2-hydroxy-propyl) -hydroxy acid halides with a higher yield and with substantially reduced technological costs than the processes previously known.

Claims (2)

1. - A process for preparing O- (3-amino-2-hydroxy-propyl) -hydroxymic acid halides of the formula (I), wherein: R1 is phenyl, pyridyl or thienyl, or substituted phenyl, wherein one or more substituents can be halogen and / or haloalkyl and / or nitro, X is halogen, R2 and R3 are independently of each other straight or branched chain lower alkyl, or R2 and R3 together with the nitrogen connected thereto form a saturated heterocyclic group from 5 to 7 members, which may contain an additional heterogeneous atom and may be substituted, and the acid addition salts and optically active forms thereof by reacting a carboxamide oxime of the formula (II), wherein the meaning of R1 is as specified above with a reactive 3-amino-2-hydroxy-propane derivative, diazotizing the O-substituted carboxamide oxime thus obtained with sodium nitrite in the presence of sodium halide, decomposing the diazonium sai, and if I wish a, separating the optically active enantiomers and / or reacting the resulting base with an organic or mineral acid; where the carboxamide oxime of the formula (II) is reacted with a 3-hydroxy acetidinium salt of the formula (III), wherein R2 and R3 are as defined above, and, Y is a salt-forming anion, in an alcoholic medium of 1 to 4 carbon atoms, optionally containing water and which is made alkaline with an alkali metal hydroxide, and before diazotizing the obtained O-substituted carboxamide oxime intermediate, the reaction mixture is neutralized and the organic solvent is removed.

2. The process according to claim 1, characterized in that ethanol is used as the alcohol of 1 to 4 carbon atoms. SUMMARY The present invention relates to a novel process for preparing halides of 0- (3-amino-2-hydroxy-propyl) -hydroxymic acid of the formula (I), by reacting a carboxamide oxime of the formula (II), where R1 is as specified above with a reactive 3-amino-2-hydroxypropane derivative, diazotizing the O-substituted carboxamide oxime thus obtained with sodium nitrite in the presence of hydrogen halide, decomposing the diazonium salt and if desired , separating the optically active enantiomers and / or reacting the resulting base with an organic or mineral acid, wherein the carboxamide oxime of the formula (II) is reacted with a 3-hydroxy acetidinium salt of the formula (III) , wherein R2 and R3 are as defined above and, Y "is a salt forming anion, in a lower alcoholic medium, preferably ethanolic, optionally containing water and which is made alkaline with an alkali metal hydroxide, and before diazotizing the obtained O-substituted carboxamide oxime intermediate, the reaction mixture is neutralized and the organic solvent is removed. The process according to the present invention provides the compounds of the formula (I) with a higher yield compared to the processes of the prior art. 1/1 X R '^ R2 N-O-CH2-CH-CH2-N; (I) R3 OH NH, R'-C N-OH (II) R2 HO- K Y (III) R3