FR2569194A1 - PROCESS FOR THE PREPARATION OF AMINOLACTONE - Google Patents

Abstract

PROCESS FOR PREPARING AN AMINOLACTONE OF FORMULA I: (CF DRAWING IN BOPI) IN WHICH: A1. A COMPOUND OF GENERAL FORMULA III IS REDUCED: (CF DRAWING IN BOPI) OR R REPRESENTS AN ALCOHOL GROUP IN CAC, TO GIVE A COMPOUND OF FORMULA GENERALII: (CF DRAWING IN BOPI) OR RA THE SAME MEANING AS ABOVE, THIS LATEST COMPOUND IS TREATED IN THE PRESENCE OF AN ALKANECARBOXYLIC ACID HAVING A LOWER ALCOHYL CHAIN IN THE ALCOHYL FRACTION, WITH A COMPLEX HYDRIDE THEN WITH ACID CONCENTRATED AQUEOUS HYDROCHLORIC AND AMINOLACTONE COLLECTED; OR A2.ON TREAT A COMPOUND OF GENERAL FORMULA II, OR RA THE SAME MEANING AS ABOVE, IN THE PRESENCE OF AN ALKANECARBOXYLIC ACID HAVING A LOWER ALCOHYL CHAIN IN THE ALKANE FRACTION, WITH A COMPLEX HYDRIDE THEN WITH AQUEOUS CHLORYDRIC ACID CONCENTRATE, AND COLLECT THE AMINOLACTONE.

Description

2569194.

  The present invention relates to a new preparation process

an aminolactone of formula (I).

H k /

HO 0C "" "

HOOC \\ X

H

NH2 HC

  The compound of formula (I) is an intermediate in the synthesis

  total of the known antibiotic thienamycin and related compounds.

  Said total synthesis as well as the process for the preparation of the amino-lactone are described in the European patent published under N 32400. This process starts from diethyl- (E) -2-acetyl-3-benzylamino-2pentenedioate, which

  first treated with cyanoborohydride and then with chlorinated

  concentrated aqueous hydrate, and after a reductive debenzylation step, the aminolactone is obtained in the form of an oil with a total yield of

20-25%.

  The aim of the applicants is to find a better synthetic route for the preparation of aminolactone. It has been found that via the reducing cleavage of an isoxazole derivative of the general formula (III)

ROOC-H2C COOR

(-III)

NO.CH

0 C H3

2 2569194

  R represents a C1-C6 alkyl group, a compound of general formula (11) is obtained, COOR

ROOC-H2C CH3

  It has the same meaning as given above, which is treated with a complex hydride and then with concentrated aqueous hydrochloric acid to give the crystalline aminolactone with a total yield of 40%. This synthetic route eliminates the introduction and removal of the benzyl group

  protector, or otherwise, two essential steps of the prior process.

  The starting materials of general formula (III) as well as the processes for their preparation have been described in the earlier Hungarian patent applications of applicants N 661/83 (= 8E 899007) and 939/84; however, their method of preparation is also given in the present application to

title of precision.

  Thus, the invention relates to a process for preparing an amino

  lactone of formula (I), oa 1), a compound of general formula (III), where R represents a C1-C6 alkyl group, is subjected to a reduction to give a compound of general formula (II), where R a same meaning as above, and the compound thus obtained is treated in the presence of an alkanecarboxylic acid having a lower alkyl chain in the alkane moiety, with a complex hydride and then with concentrated aqueous hydrochloric acid to give the compound of formula (1), or 2) a compound of the general formula (II), wherein R has the same meaning as above, in the presence of an alkanecarboxylic acid having a lower alkyl chain in the alkane moiety, with a complex hydride and then with concentrated hydrochloric acid to give the compound of formula

(I).

  According to variant 1 of the process, the synthesis starts from an isocyanate derivative

  xazole of general formula (III), wherein R represents a C1-C6 alkyl group, more particularly an ethyl or n-butyl group. To transform

  the compound of general formula (III) in the respective compound of general formula

  (II), the starting material is subjected to reduction, preferably to catalytic hydrogenation. The hydrogenation is carried out in the presence of a platinum metal catalyst, preferably in the presence of palladium on charcoal in a suitable organic solvent, that is to say in

  a lower alkanol or an alkane-carboxylic acid at atmospheric pressure.

America.

  The compound of general formula (II) is then reacted with a complex hydride, more particularly with sodium borohydride.

  or sodium cyanoborohydride in the presence of a lower alkane acid

  carboxylic acid, examples of which are glacial acetic acid or propionic acid, and then treated in the same medium with concentrated aqueous hydrochloric acid. The treatment with the said acid takes place at a temperature

  high, preferably at the boiling point of the reaction mixture.

  According to a particularly preferred embodiment of the invention,

  the three reaction stages are conducted without collecting any of the intermediate

  diaries, thus p. ex. in glacial acetic acid in a one-step synthesis the target compound is obtained directly, which can be collected after

evaporation and crystallization.

  The invention is specified in detail with the aid of the nonlimiting examples below.

Example 1

  Dibutyl (E) -2-acetyl-3-amino-2-pentenedioate

  20 g (0.067 mol) of n-butyl-5-methyl-4-n-butoxycarbonyl are dissolved

  isoxazol-3-yl-acetate in 130 ml of methanol and is hydrogenated in the presence of 2 g of palladium on charcoal at atmospheric pressure and at room temperature (TAY) When the hydrogenation is complete, the reaction mixture is separated. by filtration, and the filtrate is evaporated.

  the residue with pentane to give 17.8 g (88%) of the title compound

Tallin. Mp 45-46 ° C (pentane).

  1H-NMR (CDCl3):? X93 (3H); 0.95 t (3H); 1.15-1.9 m (8H); 2.29 s (3H); 3.6 s (2H); 4.15 t (2H);

4X18 t (2H).

  Two methods of preparing the product of

  starting point, process A and process 8.

PROCESS A

  A 1) To a solution of 229 9 (10 mMoles) of ethyl trans-5-methyl-4-methoxy-

  carbonyl-4,5-dihydroisoxazol-3-yl-acetate in 7.5 ml of tetrahydrofuran (THF) is added a solution of 5.68 g (34 mmol) of potassium iodide and 2.68 g (10.5 g). mMoles) of iodine in 25 ml of water and the reaction mixture is refluxed for 6 h while stirring. The excess iodine is decomposed with sodium hydrogen sulphite and then the reaction mixture is extracted 5 times with 10 ml portions of dichloromethane. The organic layers are combined, washed twice with 10 ml portions of saturated aqueous sodium chloride solution and finally the organic layer is dried over magnesium sulfate, filtered and the filtrate is concentrated. Triturate the residue with

  ether to give 1.56 g (79%) of 5-methyl-4-methoxycarbonylisoxyacetic acid.

  zole-3-yl-crystalline acetic acid. Pf 135 C.

  IR (IKBr): 3500-2400, 1730 (sh), 1710, 1600 cm -1 ¹H NMR (CDCl13): ₂ 2.63 s (31H); 3.76 s t 3H); 3.88 s (2H);

, 10 s (1H).

256e194

  A 2) To 1.99 g (10 mMoles) of 5-methyl-4-methoxycarbonylisoxazole-3- acid

  In accordance with step A 1, 10 ml of water and 10 ml of concentrated aqueous hydrochloric acid are added, and the emulsion thus obtained is refluxed for 2 hours. The resulting solution is clarified in the hot state, filtered and the filtrate is concentrated to half its volume. When it cools, the residue crystallizes. The crystalline residue is filtered off and

  to give 1.78 g (96%) of 4-carboxy-5-methylisoxazol-3-yl

acetic. Pf 230 (water).

  -J. IR (IKBr): 3600-2400, 1720, 1690, 1610 cm 1

  1 H-NMR (D 2 O): c 2.55 (3H); 3 s (s (2H).

  1H-NMR (DMSSO.-d6): J 2.4 s (3H); 3.55 s (2H).

  3) 13 g (70.2 mMoles) of 4-carboxy-5-methylisoxazole acid are refluxed.

  3-β-acetic acid prepared according to step A 2) in a mixture of 60 ml of

  butanol, 150 ml of benzene and 15 ml of concentrated sulfuric acid

  16 h using a reflux condenser equipped with a water separator.

  The reaction mixture is then poured into ice. The phases are separated.

  The aqueous layer is extracted twice with 75 ml portions of benzene.

  The organic phases are combined, washed twice with 1 ml water, then twice with 5% aqueous sodium hydrogen carbonate and then twice with 1 ml water. The organic layer is dried over calcium chloride and then the solvent is distilled off in vacuo to give 23 g of product in the form of an oil, directly applicable without further purification. If desired, it can be purified by vacuum distillation (Peb: 130131 ° C / 0.01 mm Hg) to give pure n-butyl-5-methyl-4-n-butoxycarbonylisoxazol-3-yl-acetate.

PROCESS B

  B 1) 350 g (1.88 moles) of α-ethoxymethylene acetoacetate are dissolved in 400 ml of ethanol. To this solution was added 154.9 (2.2 moles) of hydroxylamine hydrochloride in 500 ml of water and 180 g (2.2 moles) of sodium acetate, and the resulting solution was refluxed for 30 minutes. The reaction mixture is poured into 2 liters of water and the phases are separated. The aqueous layer is extracted 3 times with 250 ml portions of dichloromethane, the extracts are combined with the organic layer and washed twice with

  fractions of 300 ml of water. The phases are separated and removed by distillation.

  dichloromethane from the organic layer in vacuo to give 281 g (96%) of ethyl-5-methyl-4-isoxazolecarboxylate; Peb 58-60.C (0.3 mm Hg),

  that can be used in subsequent reaction steps without purification.

  fication. 1 H-NMR (CDCl 3): 1.4 t (-II) 2.7 s (31), 4.25 g (2H),

8.5 s (1H).

  B 2) 2.81 g (1.81 mol) of the product obtained in stage B 1) are refluxed into a mixture of 200 ml of glacial acetic acid, 200 ml of water and 200 ml of hydrochloric acid. concentrated water for 8 h. The reaction mixture is then evaporated to dryness. To the residue is added 400 ml of acetone and is separated by distillation. The residue is dried to give 201 g (87%)

  5-methyl-4-isoxazolecarboxylic acid; Mp 146-147 ° C (toluene).

  B 3) To 201 g (1.58 mol) of the product obtained in step B 2) is added -

  350 ml of thionyl chloride while stirring for 10 minutes, and then the reaction mixture is refluxed on an oil bath at a temperature of 120 C for 1 h. The excess thionyl chloride is distilled off and the residue is purified by vacuum distillation to give 191 g (83%).

  5-methyl-4-isoxazolecarboxylic acid chloride; Peb 100-102 C / 18 mm Hg.

  Analysis: Calculated for C 5 H 14 ClO 2 O (145.55): C 41.25; H, 2.77; N, 9.68; Cl 24, 36%; found: C 41.19; H, 2.92; N, 9.57; Cl 24.22% B 4) 66.5 g (2.73 atoms) of magnesium turnings are refluxed into a mixture of 20 ml of ethanol and 1 ml of carbon tetrachloride. To this boiling mixture was added 436 ml (2.73 moles) of diethyl malonate in a mixture of 600 ml of benzene and 140 ml of ethanol for 1 hour and then

  refluxed the reaction mixture for a further 3 hours. Remove by distillation

  a fraction of about 500 ml of the solvent and the residue is first added 400 ml of dioxane, then in 200 ml of benzene is added 191 g

  of the product obtained in step B 3) while stirring vigorously at 35.degree.

   C. The reaction mixture is stirred for a further 10 minutes, then cooled and poured into a mixture of 400 ml of acid. concentrated aqueous hydrochloric acid, 600 g of ice and 1 liter of water. The phases are separated,

  the aqueous layer is extracted twice with 300 ml portions of benzene.

  The organic layers are combined and washed first with a mixture of 80 ml of concentrated aqueous hydrochloric acid and 400 ml of water and then twice with 400 ml portions of water. The organic layer is filtered, and its benzene content is distilled off. To the residue we add first

  1 liter of dichloromethane and distilled, then remove the excess of diethyl

  malonate on an oil bath with a temperature of 135-140 ° C. (7080 ° C. Cb / 0.4 mm Hg, about 230 ml). After cooling from the residue, the crystalline ethyl 1-ethoxycarbonyl-2-hydroxy-2- (5-methyl-4-isoxazolyl) acrylate is obtained in a yield of 330 g (94%), 140-144 ° C. Peb. , 4 mm Hg;

Mp 56 ° C (ether-hexane, 1: 1).

  1H NMR (CDCl3:? 1.3 t (3H); 2.7 s (31I); 4.25 g (2I);

4.9 s (1H); 8.5 s (11). -

  B 5) Reflux 292 g (1.08 mol) of the product obtained in step B 4)

  in 1 liter of ethanol with 100 g (1.45 mol) of hydroxylamine hydrochloride.

  The reaction mixture is then concentrated, the hot residue is dissolved in 1.2 liters of dichloromethane and filtered. The residue is washed twice with 200 ml portions of dichloromethane. The washings are combined with the filtrate, washed twice with 300 ml portions of water. The organic layer is concentrated in vacuo. To the residue is added 750 ml of dichloromethane and then distilled, the residue triturated with 120 ml of ethyl acetate and left to stand at a temperature of 0 C. The crystals are filtered, washed twice with fractions of 25 ml. ml of cold ethyl acetate, then 2 times with 200 ml portions of n-hexane and dried to give 154 g (62%)

  ethyl 3- (5-methyl-4-isoxazolyl) -5-hydroxy-4-isoxazolecarboxylate; Pf 153-

154 C (ethyl acetate).

  1-NMR (DMSO-d6): 1.1 t (3H); 2.4 sec (3H); 4.0q (2H);

8, 6 s (1H); l1d 0 s (1H).

  B 6) 154 g (0.646 mol) of the product obtained in step B 5) are refluxed into 650 ml of acetic acid in the presence of 14 ml of concentrated sulfuric acid for 15 minutes. When the evolution of carbon dioxide is complete, 40 g of sodium acetate is added to the solution which is then concentrated in vacuo. To the residue is added 300 ml of water and extracted twice with 500 ml portions of dichloromethane. We combine the organic layers, - we wash

  Twice with 250 ml portions of water and concentrate the organic layer.

  500 ml of dichloromethane and 300 ml of n-heptane are first removed by distillation from the residue and finally recrystallized from 130 ml of 2-propanol. The crystals are filtered, washed twice with 1 ml fractions of ice-cold 2-propanol and then 2 times with 75 ml portions of n-hexane.

  and air dried to give 93.4 g (87%) of 3- (5-methyl-4-isoxazolyl) -

  4,5-dihydro-5-isoxazolone; Pf 94-95 C.

  11H-NMR (CDCl 3): Co 2.7 s (3H); 3.8 s (2H); 8.4 s (1H).

  B 7) To a solution of 57 g (1.42 mol) of sodium hydroxide in 350 ml of water, 93.4 g (0.563 mol) of the compound obtained in step B 6) are added in a portion. while stirring at 25 ° C. Stirring is continued for about 2 minutes while the temperature rises to about 70 ° C. The reaction mixture is cooled on an ice-water bath and then 150 ml of aqueous HCl are added. concentrated in the mixture, which is then cooled repeatedly. The reaction mixture is first extracted with 300 ml and then twice with 150 ml portions of dichloromethane. The phases are separated, the organic layer is washed twice with 80 ml portions of saturated aqueous sodium chloride solution and then concentrated in vacuo. 250 ml of dichloromethane and then ml of n-hexane are distilled off from the residue. From the residue, crystalline 4-cyano-5-methyl-3-isoxazoleacetic acid is left standing with a yield of

  91.5 g (98%); Mp 90-910C (benzene).

  1H-NMR (CDCl3): C 2, -6 s (3H); 4.0 s (2H).

  B 8) In a mixture of 100 ml of water and 100 ml of concentrated aqueous HCl, 91.5 g (0.55 mol) of the compound obtained in step B 7) are refluxed for 3 hours. The reaction mixture is cooled, the precipitated product is washed twice with ice water and air dried to give 95.7 g (92%) of 4-carboxy-5-methyl-3-isoxazole acetic acid. , product with characteristics

  identical to those of the product given in step A 2).

Example 2

  (2RS, 3RS, 4SR) -4-Amino-2-methyl-6-oxo-tetrahydro-hydrochloride

pyran-3-carboxylic acid

  10 g (0.0334 moles of dibutyl (E) -2-acetyl-3-amino-2-pentene-

  dioate prepared according to Example 1 in 60 ml of glacial acetic acid. To this solution is added 3.8 g (100 mMoles) of sodium borohydride while stirring and with external cooling for about 2 hours. Let's rest

  the reaction mixture at RT overnight, then concentrated in vacuo.

  The residue is partitioned between 100 ml of 10% aqueous sodium carbonate solution and 100 ml of ethyl acetate and then solid sodium carbonate is added until bubbling ceases. We separate the phases, we rediscover

  2 times the aqueous layer with 20 ml portions of ethyl acetate.

  The organic layers are combined, dried over magnesium sulfate, filtered and the filtrate is concentrated. To the residue is added 40 ml of aqueous 20% hydrochloric acid solution, the mixture is refluxed for 5 h. then concentrate. The residue is dissolved in 10 ml of concentrated aqueous HCl at -50 ° C. and then cooled to -10 ° C. to give 3 g (43%) of the title compound.

  in the form of a crystalline solid; Mp 150-155 ° C (dec).

  1H-NMR (CD30D):? 1.36d (3H, J = 6.5Hz); 2.82 t (1H, J = 3.5 Hz); 2.85 d (2H, J = 6.5 Hz); 3.9 98 dt (1H, J = 6.5 and 3.5 Hz); 4, 30 dq

(J = 6.5 and 3.5 Hz).

Example 3

  (2RS, 3RS, 4SR) -4-Amino-2-methyl-6-oxo-tetrahydro-hydrochloride

pyran-3-carboxylic acid

  70 g (0.235 moles) of n-butyl (5-methyl-4-n-butylcarbonyl)

  isoxazol-3-yl) -acetate in 350 ml of glacial acetic acid, and is hydrogenated in the presence of 14 g of palladium-on-charcoal catalyst at atmospheric pressure. The temperature of the reaction mixture rises to about 40 ° C. When the reaction is complete, the catalyst is filtered off, and to the filtrate is added 26.8 g (0.705 mol) of sodium borohydride while cooling on the outside with ice in about 2 hours. The reaction mixture is stirred at RT for 3 h. allowed to stand overnight and then concentrated in vacuo. The residue is partitioned between 300 ml of ethyl acetate and 300 ml of saturated aqueous sodium bicarbonate solution, and with vigorous stirring, sodium hydrogen carbonate is added until bubbling ceases. The phases are separated, the aqueous layer is extracted twice with 50 ml portions of ethyl acetate. The organic layers are combined, dried over magnesium sulfate, filtered and filtered.

the filtrate is concentrated.

  The residue is taken up with 200 ml of 20% aqueous HCl solution, refluxed for 5 h and then concentrated. The residue is dissolved in 1 ml concentrated aqueous iCl with gentle heating and then crystallized in a freezer to give 19.8 g (40%) of the title compound. The constants

  are identical to those given in the previous example.

Claims (4)

  1. Process for preparing an aminolactone of formula (I), H HO OC ô H NH.2- HCI   wherein 1) a compound of the general formula ROOC cH2 is reduced. Wherein R represents a C1-C6 alkyl group, to give a compound of general formula (II), COOR; ROOC- H2C CH3   Here (II) H o R has the same meaning as above, the latter compound is treated in the presence of an alkanecarboxylic acid having a lower alkyl chain in the alkyl moiety, with a complex hydride and then with hydrochloric acid. aqueous concentrated and aminolactone is collected; or 2) treating a compound of general formula (II), wherein R has the same meaning as above, in the presence of an alkanecarboxylic acid having a lower alkyl chain in the alkane moiety, with a complex hydride then   with concentrated aqueous hydrochloric acid, and the aminolactone is collected.   2. The process of claim 1, wherein the reduction is a hydro- catalytic genesis.   3. The process of claim 1, process 1 or 2, wherein the complex hydride   is sodium borohydride or sodium cyanoborohydride.   The method of claim 1, substantially as described above with reference to examples.