FI87354B - Process for the preparation of 2-amino-4-(isoxazolyl)- thiazole derivatives - Google Patents

Abstract

The invention relates to a process for the preparation of 2-amino-4-(isoxazolyl)-thiazole derivatives of the formula <IMAGE> wherein R and R1 are independently hydrogen, chloro, bromo, hydroxy, methyl, methoxy, ethoxy, benzyloxy, phenyl, phenyl substituted with halogen, hydroxymethyl, methoxymethyl, ethoxymethyl or carbetoxy and R7 is hydrogen or C 1-3 alkyl. According to the process, a compound of the formula <IMAGE> wherein R, R1 and R7 are as defined above, is reacted with thiourea. Compounds having the structural formula III are useful intermediates in the preparation of therapeutically active compounds.

Description

1 87ο 5 -3

Process for the preparation of 2-amino-4- (isoxazolyl) thiazole derivatives

Divided out of application 86 1329 5

The invention relates to a process for the preparation of 2-amino-4- (isoxazolyl) thiazole derivatives of the formula 10 r7 - s R - r -, 1 · J nh2 (III)

»| OF

N JLRx 15 s0 wherein R and R3 independently of one another are hydrogen, chlorine, bromine, hydroxy, methyl, methoxy, phenyl, 2-chloro-6-fluorophenyl, hydroxymethyl or methoxymethyl and R7 is hydrogen or ethyl.

These compounds are useful as intermediates in the preparation of the therapeutically active compounds of formula 25 described in FI patent application 86 1329.

- S

R 1 J_NHCOOCR, (I) 30 Hi N J | _Rl ·. : NO 35 wherein R, R 1 and R 7 are as defined above and R 2 is hydroxy, OR 3 or NR 4 R b, wherein R 3 is a C 1-4 alkyl group optionally substituted by 1-3 groups which may be hydroxyl, alkoxyl, amino. , a carboxyl and alkoxycarbonyl group; A C 5-6 cycloalkyl group optionally substituted with 1-3 alkyl groups; A C7-9 phenylalkyl group optionally containing 1 to 3 substituents on the phenyl ring, which may be halogen and methyl and methoxyl groups; or a group of the formula (CH_-CH_O) -R, wherein n 5 is an integer from 2 to 4 and R 8 is a hydrogen atom or an alkyl group: and each of the groups R 4 and R 8, which may be the same or different, is a hydrogen atom, an alkyl, A C8-8 cycloalkyl, C7-8 phenylalkyl or phenyl group; or R 1 and R 8 together with the nitrogen atom to which they are attached form a 1-piperidyl, 1-piperazinyl, 4-methyl-1-piperazinyl, pyrazolyl, thiazolyl or imidazolyl group; or either or Rg is a hydrogen atom and the other is a group of the formula, V ί · il_ή-.

N V

wherein R and have the meanings given above. The compounds of formula (I) are valuable immunosuppressive, mammalian immune responses in mammals.

The process according to the invention is characterized in that the compound of formula

COCHBrR

* i f "".! ", where R, R 1 and R 7 have the same meaning as above, is reacted with thiourea.

.20 The preparation of compounds of formula I from the compounds of formula III can be described by the following reaction equations: 3 87554

Scheme 1 R ~ r - »COCHBrR7” J! Lr * v-cs- ™ -, un 5

R τι -JTL

"Dll) J— RN 2 X (T 1 io 2):; i + u-co-co-y (u = r3o) -> i (R2 = OR3) 3) 1 (R_ = GR_) OH" 1 (R_ = 0H) 2 3 - * 2 4) 1 (R = 0R,) + HNR .R. _7 1 (R. = NR R) 2 3 4 5 7 2 4 5 (Rr R- | »1 * 2 'R3' r4 · R5 3a r7 have the same meaning as above, Y is chlorine or bromine, W is chlorine, bromine or a group R (O).

The bromoacetyl isoxazole derivative (Formula II) is condensed (Reaction 1, Scheme 1) with thiourea,? 0 to give 2-amino-4-ixoxazolylthiazole] compound (formula III).

The condensation is carried out by heating a mixture of reactants in a protic or aprotic polar solvent, preferably at a temperature of 50-100 ° C.

The compound of formula (III) is then reacted (reaction 2) with a halide of an oxalic acid monoester to give compounds of formula (I) having an OR 2 group.

Reaction 2 is preferably carried out in pyridine or a 1 ° inert solvent in the presence of an acid acceptor.

From the compounds of formula (I) in which R 2 = OR 2, free acids (I, R 2 = OH) are prepared by reaction with an aqueous solution of an inorganic base (reaction 3) and by reaction with an organic compound of formula HNR, R 2.

T C

with its base (reaction 4) compounds of formula (I) wherein R 2 = NR 2 R 2.

<87b! 'I Λ

For example, esters of formula (I) (R = OR 3) may also be prepared by transesterification to other esters of formula (I) or by reacting an acyl halide of formula (I) (R 2 = OH) or an acid with a suitable alcohol of formula R 1 -OH , with.

In a similar manner, compounds of formula (I-A), 10 R7V ~ s S- / 7 J1 are prepared

S li | \ l j— NHCOCONH-Q-Fl · R

^> »1 N VN

(1 -A) 15 normally by the reactions of Scheme 1, but when the two pairs formed by the substituents R 1 and R 2 are identical, they can also be prepared by condensing 2 moles of a suitable compound of formula (III) oxalyl dihalide (W-CO-CO-Y; W = Y = halide) 20.

Salts may likewise be prepared by reacting a compound of formula (I) wherein R 2 contains a basic functional group (for example R 2 = 4-methyl-1-piperidinyl group) with a pharmaceutically acceptable organic or inorganic acid.

The compounds of formula (II) are known in part as such or at the precursor level.

In any case, they are prepared using known procedures.

One example of the synthesis is shown in Scheme 2.

8 7 35 4

Scheme 2 R — Il-Π1 1 R —Π- "" T -COCH2R7 5 V ~ R1 "^ 0 ^ (IV) (V) R — ri-n — COCHBrR-, o (11)

Reaction 1 of Scheme 2 is performed by reacting the acyl chloride (IV) with diethyl malonate or diethyl alkyl malonate and carbon tetrachloride in the presence of magnesium following known procedures.

Reaction 2 of Scheme 2 is performed by bromination of intermediate (V) with pyridine perbromide hydrobromide or other brominating agents in a solvent such as carbon tetrachloride, chloroform, methylene chloride, and the like.

The compounds of formula (III) are new.

The following examples illustrate the invention.

Example A

1- [3- (2-chloro-6-fluorophenyl) -5-isoxazolyl] ethanol 27.60 g (273 mmol) of triethylamine were added dropwise to a solution of 28.4 g (136.5 mmol) of alpha, 2-dichloro -6-fluorobenzaldoxime and 19.14 g (273 mmol) of 3-butyn-2-ol in 250 ml of benzene and kept at 8-10 ° C with stirring.

30 0

At the end of the addition, the mixture was heated to 60 ° C, and after 1 hour, the mixture was cooled and extracted with 10% hydrochloric acid and then with water.

6 8 74

Evaporation of the organic phase gave 31.1 g of an oil which was purified by distillation and the fraction boiling at 140-150 ° C (0.3 mmHg) was collected.

1 H-NMR (CDCl 3) δ 7.6-7 (m, 3H); 6.4 (s, 1 H); r 5.1 (q, 1H); 1.6 (t. 3H)

Example B

1) 3- (2-chloro-6-fluorophenyl) -5-acetylisoxazole

To a solution of 30 g (124 mmol) of 1- [3- (2-chloro-6-fluorophenyl) -5-isoxazolyl] ethanol in 187 ml of acetic acid, kept at 5 ° C with stirring, was added dropwise 9.07 g (90.7 mmol) of CrO 2 in 9.34 ml of water and 132 ml of acetic acid.

The mixture was kept overnight at room temperature with stirring, then the solvent was removed by evaporation, and the residue was stirred in water, neutralized with sodium hydrogencarbonate and extracted with ethyl ether.

The ether extracts were combined, washed with water, dried and evaporated to dryness; 27.8 g of an orange oily product were obtained. The oil was distilled under reduced pressure, and the fraction boiling at 120-122 ° C (0.4 mmHg) was collected; yield 23.7 g.

The oil was allowed to crystallize on standing and then recrystallized from isopropyl ether; mp. 46-47 ° C.

1 H-NMR (DMSO): δ 7.9 - 7.3 (m, 4H); 2.8 (s. 3H)

In a similar manner there was obtained: 3-carbethoxy-5-acetylisoxazole

Yield 82%; mp. 67-68 ° C (isopropyl ether) 1 H-NMR (CDCl 3): delta 7.3 (s, 1H); 4.5 (q. 2H); 2.7 (s. 3H); 1.5 (t, 3H) The starting material, m.p. 1- (3-carbethoxy-5-isoxazolyl) ethanol, prepared according to EP 28 355.

7,87554 3-Methoxymethyl-5-acetyl-isoxazole

Yield 58.5%; colorless oil, kp. 72-74 ° C (0.4 mmHg) 1 H-NMR (CDCl 3): δ 7.0 (s, 1H); 4.6 (s. 2H); 3.4 (s. 3H); 2.6 (s, 3H) The starting material, m.p. 1- (3-methoxymethyl-5-isoxazolyl) ethanol, prepared according to DE patent 2,754,832.

2) 3-Benzyloxy-5-acetylisoxazole 2.2 g (90.5 mmol) of magnesium turnings were added to a solution of 14 g (87 mmol) of diethyl malonate in 78 ml of ethyl ether, 63 g of anhydrous ethyl alcohol and 0.90 ml of carbon tetrachloride. , stirring at the same time.

The mixture was refluxed for 2 hours, and then a solution of 18.8 g (79 mmol) of 3-benzyloxy-5-isoxazolylcarbonyl chloride (BE Patent 665,249) in 65 ml of ethyl ether was added dropwise.

The mixture was refluxed for 2 hours, cooled to room temperature, and 159 ml of 2M sulfuric acid was added.

.. After vigorous stirring, the organic ker-; The ros was separated, washed with water and evaporated to dryness.

The oily residue thus obtained (29.9 g) was added to a solution of 4.8 g of concentrated sulfuric acid in 36.3 ml of acetic acid and 25 ml of water, and the mixture was refluxed for 8 hours.

The mixture was cooled to 20 ° C and neutralized (pH 6.5) with 10 M potassium hydroxide at constant temperature.

-; The mixture was extracted with chloroform, and the combined organic extracts were evaporated to give an oily residue which was stirred in 150 ml of hexane. The crystalline precipitate was collected by filtration (6.7 g, yield 39%) and recrystallized from 3R> diisopropyl ether; mp. 77-78 ° C.

Δ 87554 1 H-NMR (CDCl 3) δ 7.5 (m, 5H); 7.2 (s. 1H); 5.4 (s. 2H); 2,5 (s, 3H) 3) 3- (2-chloro-6-fluorophenyl) -5-methyl-4-acetylisoxazole 5 To a solution of 2.3 g (100 mol) of sodium in 220 ml of anhydrous ethanol, 10 g (100 mmol) of acetylacetone were added.

The reaction mixture was cooled to 0 ° C, and 17 g (81.6 mmol) of alpha, 2-dichloro-6-1q fluorobenzaloxime (DE-A-2 323 809) was added dropwise while stirring vigorously and maintaining the temperature at about 5 ° C: as.

The mixture was stirred at room temperature overnight and then neutralized with 10% hydrochloric acid. The mixture was evaporated to dryness and the residue was taken up in 100 ml of water and 150 ml of ethyl ether.

The organic layer was separated and washed with dilute sodium hydroxide and then with water until neutral.

20 The solvent was evaporated off, and the oily ice was distilled off under reduced pressure; tr. 129-131 (0.5 mmHg); yield 14.5 g (70 L) of a clear colorless oil.

1 H-NMR (CDCl 3): δ 7.9 - 7.3 (m, 3H); 2.8 (s. 3H); 2.3 (s. 3H)

Example C

· * 1) 3-Chloro-5-bromoacetyl-isoxazole

To a solution of 25 g (172 mmol) of 3-chloro-· * ·. 5-Acetylisoxazole 4.9 ml of glacial acetic acid was added. a solution of 28.65 g (179 mmol) of bromine in 20 ml of chloroform was added dropwise over 10 minutes while maintaining the reaction mixture at 48-50 ° C and stirring.

After 5 minutes, the mixture was poured into 330 g of water and crushed ice.

9,875.4.4

The organic layer was separated, washed with water, dried and evaporated to a residue.

Yield 37 g (96%) of an oily compound which can be purified by distillation; tr. 97-99 ° C (2 mmHg).

1 H-NMR (CDCl 3): δ 7.00 (s, 1H); 4.37 (s. 2H)

In a similar manner the following compounds were prepared: from 3-methoxy-5-bromoacetylisoxazole / 3-methoxy-5-acetylisoxazole, Acta Chem. Scand.

28 B (1 947) 639.7, yield 91%; hydrogenated crystalline compound 10 1 H-NMR (CDCl 3): delta 6.63 (s, 1H); 4.33 (s. 2H); 4.00 (s, 3H) 3-Benzyloxy-5-bromoacetyl-isoxazole

Yield 83%; white crystalline compound, m.p. 80-81 ° C

(Ether); 1 H-NMR (DMSO-d 6): δ 7.37 (s, 5H); 7.29 (s, 1 H); 5.28 (s. 2H); 4.71 (s. 2H)

From 3-phenyl-5-methyl-4-bromoacetylisoxazole / 3-phenyl-5-methyl-4-acetylisoxazole, Gazz. Chim. It. 76 (1946) 200.7? Yield 87%; white ki-20 second compound, m.p. 46-48 ° C

1 H-NMR (CDCl 3): δ 7.57 (m, 5H); 3.22 (s. 2H); 2.71 (s, 3H) 5-hydroxymethyl-3-bromoacetylisoxazole: from 5-hydroxyethyl-3-acetylisoxazole, Il Farmaco, "25 £ d. Sei., 39 (1,984) 4877; Yield 94% oily compound, bp 160 ° C / 0.3 mmHg 1 H-NMR (CDCl 3): delta 6.72 (s, 1H), 4.85 (s, 2H), 4.60 (s, 2H ) · (·: 3-methyl-5-bromoacetylisoxazole) from O 2 -methyl-5-acetylisoxazole, Gazz, Chim.

Ital. 72 (1942) 242]; Yield 87%; white crystalline compound, m.p. 44-46 ° C (isopropyl ether) 1 H-NMR (CDCl 3): delta 7.00 (s, 1H); 4.42 (s. 2H); 2.43 (s, 3H) 10 87354 3- (2-Chloro-6-fluorophenyl) -5-bromoacetylisoxazole

Yield 85%; oily compound, b.p. 145-150 ° C / 0.3 imHg 1 H-NMR (CDCl 3): δ 7.8-7 (m, 4H); 4.60 (s, 2H) 3-Carbethoxy-5-bromoacetyl-isoxazole

Yield 83%; white crystalline compound, m.p. 74-75 ° C

(isopropyl ether) 1 H-NMR (CDCl 3): delta 7.5 (s, 1H); 4.52 (q, 2 H); 4.50 (s. 2H); 1,5 (t, 3H) 3-methoxymethyl-5-bromoacetylisoxazole from N-3-methoxy-5-acetylisoxazole, Acta Chem. Scand.

28 B (1947) 6397; Yield 91%, oily compound 1 H-NMR (CDCl 3): delta 7.1 (s, 1H); 4.4 (s. 2H); 3,4 (s, 3H) 1- (3-bromo-5-isoxazolyl) -2-bromo-1-butanone

Yield 98%; white crystalline substance, m.p. 53-54 ° C 15 (hexane) 1 H-NMR (CDCl 3): delta 7.2 (s, 1H); 5.0 (t, 1 H); 2.2 (m. 4H); 1.1 (t. 3H); 3- (2-Chloro-6-fluorophenyl) -5-methyl-4-bromoacetylisoxazole 20

Yield 86%; white crystalline compound, m.p. 74-75 ° C δ (isopropyl ether) 1 H-NMR (CDCl 3): δ 7.88 - 7.10 (m, 3H); 3.80 (s. 2H); 2.84 (s. 3H).

..... 25 Example D

* ·: 1) 2-Amino-4- (3-bromo-5-isoxazolyl) thiazole

A mixture of 32.4 g (120.4 mmol) of 5-bromoacetyl-3-bromoisoxazole and 18.4 g (240 mmol) of thiourea in 400 ml of anhydrous ethanol was refluxed for 30 minutes.

The solvent was removed by distillation, and the residue was mixed with 750 ml of ethyl ether and 160 ml of 10% aqueous potassium hydroxide solution. The ether extraction solution was separated and washed with 50 ml of ethyl ether.

n 875S4

The extraction solutions and ether washings were combined, washed with water until neutral, dried over sodium sulfate and then evaporated to dryness.

The crystalline residue (28.7 g, 97%) was purified by recrystallization from methanol; mp. 160-162 ° C.

1 H-NMR (DMSO-d 6): δ 7.47 (s, 1H); 6.97 (s, 1 H)

In a similar manner the following compounds were prepared: 2-amino-4-Z3- (2-chloro-6-fluorophenyl) -5-methyl-4-isoxazolyl] thiazole 1 q Yield 81.5%; crystalline compound, m.p. 48 DEG-149 DEG C. (isopropyl alcohol) 1 H-NMR (DMSO-d6): delta 7.9-7.4 (m, 3H); 6.0 (s, 1H); 2.8 (s, 3H) 2-Amino-4- (3-phenyl-5-methyl-4-isoxazolyl) thiat-15 sol

Yield 69.5%; crystalline compound, m.p. 223-224 ° C (methyl alcohol) 1 H-NMR (DMSO-d 6): delta 7.62 (s, 1H); 6.43 (s, 1 H); 2.58 (s, 3H) 2 O) 2-Amino-4- (3-methoxy-5-isoxazolyl) thiazole

A mixture of 9.2 g (41.8 mmol) of 3-methoxy-5-bromoacetylisoxazole and 6.36 g (83.6 mmol) of thiourea in 140 ml of methyl alcohol was refluxed for 90 minutes and cooled. after 1 hour in an ice bath.

The precipitate was collected by filtration and added to 120 ml of 1% sodium hydroxide solution with vigorous stirring.

; The solution was allowed to stand for 30 minutes at room temperature, and the precipitate was collected by filtration and washed with water until neutral.

Yield 6.9 g (83.7%); after recrystallization from methyl alcohol, the compound melts at 215-217 ° C. 1 H-NMR (DMSO-d 6): δ 7.37 (s, 1H); 6.43 (s, 1H); 4.03 (s, 3 H) 12 8 7554

In a similar manner there were prepared: 2-amino-4- (5-hydroxymethyl-3-isoxazolyl) -thiazole

Yield 62.5%; mp. 185-187 ° C (methyl alcohol) δ 1 H-NMR (DMSO-d 6): delta 7.3 (s, 1H); 6.7 (s, 1 H); 5.7 (t, 1H); 4,6 (d, 2H) 3) 2-Amino-4- (3-chloro-5-isoxazolyl) thiazole

A mixture of 11.2 g (50 mmol of 3-chloro-10 5-bromoacetylisoxazole and 7.6 g (100 mol) of thiourea in 164 ml of ethyl alcohol was refluxed for 90 minutes and then cooled for 1 hour. j ice bath.

The precipitate was collected by filtration and added to a mixture of 25 ml of 10% aqueous sodium hydroxide solution and 100 ml of ethyl acetate while stirring vigorously.

The organic layer was separated, washed, dried and evaporated to dryness. Yield 7.7 g (77%); After recrystallization from 20 acetonitriles, the compound melts at 169-170 ° C.

In a similar manner the following compounds were prepared: 2-amino-4- (3-benzyloxy-5-isoxazolyl) thiazole ____ 25 Yield 76.5%; mp. 129-131 ° C (acetonitrile) 1 H-NMR (CDCl 3): delta 7.3 (s, 1H); 6.5 (s, 1H); 5.4 (s, 2H) 2-amino-4- (5-phenyl-3-isoxazolyl) thiazole / 5-phenyl-3-bromoacetylisoxazole, J. Med.

30 Chem. 10 (1967) 4117; Yield 74.5%; mp. 215-216 ° C

(Methyl alcohol)

Analysis: S = 12.98 L (calculated 13.18%) of 2-amino-4- (3-phenyl-5-isoxazolyl) thiazole / 1-phenyl-5-bromoacetylisoxazole, J. Med.

35 Chem. 10 (1967) 4117; Yield 65.5%; mp. 192-193 ° C

(acetonitrile) 13 87554

Analysis: S = 13.39% (calculated 13.18%) 2-Amino-4- [3- (2-chloro-6-fluorophenyl) -5-isoxazolyl] thiazole

Yield 56.6%; mp. 168-169 ° C (acetonitrile) δ Analysis: S = 11.03% (calculated 10.84%) 2-amino-4- (3-methyl-5-isoxazolyl) thiazole Yield 57%; mp. 208-210 ° C (acetonitrile) 1 H-NMR (DMSO-d 6): δ 7.03 (s, 1H); 6.5 (s. 1H); 2.3 (s. 3H); 2-Amino-4- (3-methoxymethyl-5-isoxazolyl) thiazole '

Yield 49%; mp. 137-138 ° C (acetonitrile) 1 H-NMR (DMSO-d 6): delta 7.3 (s, 1H); 6.6 (s, 1H)? 4.5 (s. 2H); 3,4 (s, 3H) 2-amino-4- (3-bromo-5-isoxazolyl) -5-ethylthiazole Yield 70%; mp. 151-152 ° C (acetonitrile) 1 H-NMR (DMSO-d 6): delta 6.8 (s, 1H); 3.0 (q. 2H); 1,2 (t, 3H) 4) 2-Amino-4- (3-hydroxymethyl-5-isoxazolyl) thiazole To a solution of 13.9 g (58.1 mmol) of 2-amino-4- ( 3-Carbethoxy-5-isoxazolyl) thiazole: In 40 ml of dimethylformamide and 80 ml of methyl alcohol, 4.4 g (116.2 mmol) of sodium borohydride were gradually added with stirring at about 35 ° C.

At the end of the addition, the reaction mixture was stirred at room temperature for 90 minutes and then acidified by the careful addition of 60 ml of 10% hydrochloric acid.

. . The reaction mixture was evaporated under reduced pressure; The residue was taken up in water and basified with potassium carbonate.

The precipitate was collected by filtration and washed with water. Yield 11.1 g (97%); mp. 184-185 ° C (acetonitrile): 35 1 H-NMR (DMSO-d 6): δ 7.4 (s, 1H); 6.6 (s, 1H); : · · ·; 4.6 (d, 2H) 14 87 35-1 5) 2-Amino-4- (3-carbethoxy-5-isoxazolyl) -thiazole

A solution of 54.8 g (209 mmol) of 3-carbethoxy-5-bromoacetylisoxazole and 31.8 g of β (418 mmol) of thiourea in 685 ml of ethanol was refluxed for 90 minutes and then cooled for 1 hour. in an ice bath.

The precipitate was collected by filtration and added to aqueous potassium hydrogen carbonate with vigorous stirring.

The reaction mixture was shaken with ethyl acetate. The combined organic extracts were washed with water, dried and evaporated. Yield 43.4 g (86.7%); mp. 156-157 ° C (acetonitrile) 1 H-NMR (DMSO-d 6): delta 7.4 (s, 1H); 7.0 (s, 1 H); 4.4 (d. 2H); 1,4 (t, 3H) 6) 2-Amino-4- (3-hydroxy-5-isoxazolyl) -thiazole hydrobromide

A mixture of 13.5 g (68.5 mmol) of 2-amino-20-no-4- (3-methoxy-5-isoxazolyl) -2-thiazole and 135 ml of 48% hydrobromic acid was heated externally. la in a bath at 100 ° C for 1 hour with stirring.

After cooling in an ice-water bath, the precipitate 25 was collected by filtration under reduced pressure and dried.

13.3 g (73.6%) of a white crystalline compound were obtained, which was purified by crystallization from 1% hydrobromic acid.

1 H-NMR (DMSO-d 6): δ 7.5 (s, 1H); 6.6 (s. 1H)

Example E

1) Ethyl 4- (3-bromo-5-isoxazolyl) thiazole-2-oxamate

To a mixture of 7.38 g (30 mmol) of 4- (3-35 bromo-5-isoxazolyl) -2-thiazolamine and 3.50 g of δ 7 o54 (34.6 mmol) of triethylamine in 60 ml of pyridine and stirred at a temperature of up to 10 ° C, 4.71 g (34.5 mmol) of ethoxalyl chloride was added dropwise.

At the end of the addition, the solution was stirred overnight and then diluted with 120 ml of water.

The precipitate was collected by filtration and washed on the filter with copious amounts of water.

After drying under reduced pressure at 50 ° C, the compound was crystallized twice from acetonitrile (one batch of 110 ml and the other 130 ml) to give 6.90 g of a crystalline compound which was analytically pure; mp. 196.5 - 197 ° C.

1 H-NMR (DMSO-d 6): δ 8.20 (s, 1H); 7.20 (s, 1 H); 4.42 (q, 2 H); 1.40 (t, 3 H)

In a similar manner the following compound was prepared: Ethyl 4- (3-phenyl-5-methyl-4-isoxazolyl) thiazole-2-oxamate

Yield 78%; mp. 157-159 ° C (acetonitrile) 1 H-NMR (DMSO-d 6): delta 7.6 (m, 5H); 7.3 (s. 1H); 3.2 (q. 2H); 2.6 (s. 3H); 1,3 (s, 3H) 2) Ethyl 4- (3-methoxy-5-isoxazolyl) thiazole-2-oxamate ·. To a mixture of 6.60 g (33.5 mmol) of 2-amino-4- (3-methoxy-5-isoxazolyl) thiazole in 67 ml of pyridine was added dropwise 5.25 g (38 , 5 mmol) · *; · Ethoxalyl chloride at the same temperature of 5-10 ° C.

The reaction mixture was stirred overnight and then poured onto 120 g of crushed ice and acidified with concentrated hydrochloric acid.

The mixture was extracted with 750 ml of 1,2-dichloroethane, and the organic layer was separated and washed with water.

The organic extraction solutions were evaporated; yield 35.40 g (94.5%); mp. 204-205 ° C.

16 8 7 o b 4 1 H-NMR (DMSO-d 6): δ 8.10 (s, 1H); 6.6 (s. 1H); 4.4 (q, 2 H); 4.0 (s. 3H); 1.4 (t. 3H)

In a similar manner the following compounds were prepared: Ethyl 4- (5-phenyl-3-isoxazolyl) thiazole-2-oxamate

Yield 47%; mp. 169-170 ° C (ethyl alcohol) 1 H-NMR (DMSO-d 6): delta 8.2-7.4 (m, 5H); 8.1 (s. 1H); 7.5 (s. 1H); 4.4 (q. 2H); 1,4 (t, 3H) 10 Ethyl 4- (3-ethoxalyloxymethyl-5-isoxazolyl) thiazole-2-oxamate

Yield 68%; mp. 150-151 ° C (ethyl alcohol) 1 H-NMR (DMSO-d 6): delta 8.1 (s, 1H); 7.0 (s, 1 H); 5.5 (s. 2H); 4.4 (q, 4 H); 1,4 (t, 6H) Benzyl 4- [3- (2-chloro-6-fluorophenyl) -5-isoxazolyl] thiazole-2-oxamate Yield 67%; mp. 199-200 ° C (acetonitrile) 1 H-NMR (DMSO-d 6): delta 8.3 (s, 1H); 7.5 (m. 8H); 7.2 (s. 1H); 5.5 (s, 2H) 20 Cyclohexyl 4- [3- (2-chloro-6-fluorophenyl) -5-isoxazolyl] thiazole-2-oxamate

Yield 74%; mp. 77-78 ° C (ethyl alcohol). 1 H-NMR (DMSO-d 6): delta 8.2 (s, 1H); 7.6 (m. 3H); 7.1 (s. 1H); 4.9 (m, 1 H); 2.2 - 1.1 (m, 10H): -: 2i 3) 2-Ethoxyethyl [* 4- (3-benzyloxy-5-isoxat- [2 · solyl] thiazole-2-oxamate)

To a mixture of 5.6 g (20.5 mmol) of 2-amino-4- (3-benzyloxy-5-isoxazolyl) thiazole in 37.4 ml of pyridine and kept at 5 ° C with stirring was added 4.25 g (23.6 mmol) of 2-ethoxyethyloxalyl chloride drop by drop.

The reaction mixture was stirred overnight, then poured into 100 g of crushed ice, acidified with concentrated hydrochloric acid and extracted with chloroform. 35 with.

17 87354

The chloroform extraction solutions were washed with water, dried and evaporated to dryness. The residue (8.30 g) was recrystallized from 65 ml of acetonitrile; mp. 142-144 ° C.

1 H-NMR (DMSO-d 6): δ 8.2 (s, 1H); 7.6 (m. 5H); 6.7 (s, 1 H); 4.5 (in, 2 H); 3.8 (m. 2H); 3.6 (q. 2H); 1.2 (t, 3 H)

In a similar manner the following compounds were obtained: 2-ethoxyethyl [4- (5-phenyl-3-isoxazolyl) thiazole] 2-oxamate

Yield 82%; mp. 146-147 ° C (acetonitrile) 1 H-NMR (DMSO-d 6): delta 8.1 (s, 1H); 8.1 - 7.5 (m. 5H); 7.5 (s, 1H); 4.5 (m. 2H); 3 (m, 2 H); 3.6 (q. 2H); 1.2 (t, 3H) 15 2-ethoxyethyl / 4- (3-phenyl-5-isoxazolyl) thiazole-2-oxamate7

Yield 84%; mp. 146-147 ° C (acetonitrile) 1 H-NMR (DMSO-d 6): delta 8.2 (s, 1H); 8.2 - 7.4 (m. 5H); 7.4 (s, 1H); 4.5 (m. 2H); 3.8 (m. 2H)? 3.6 (q. 2H); 1,2 (t, 3H) 2-ethoxyethyl [4 -? - (2-chloro-6-fluorophenyl) -5-isoxat-; solyyli7tiatsoli-2-oksamaatti7

Yield 87%; mp. 140-141 ° C (acetonitrile) • 1 H-NMR (DMSO-dc): delta 8.2 (s, 1H); 7.7 (m. 3H); 7.2 (s, 1H); 4.5 (m. 2H); 3.8 (m. 2H); 3.6 (q. 2H); 1.2 (t, 3 H)

2-Ethoxyethanol Z3-Z3- (2-chloro-6-fluorophenyl) -5-methyl-4-isoxazolyl] thiazole-2-oxinate 7 Yield 85%; mp. 47-58 ° C

1 H-NMR (DMSO-d 6): δ δ - 7.3 (m, 3H); 6.7 (s, 1H); 4.4 (m. 2H); 3.7 (m. 2H); 3.5 (q, 2 H); 2.8 (s. 3H); 1,1 (t, 3H) 2-ethoxyethyl E 4- (3-methyl-5-isoxazolyl) thiazole-2-oxamate [7:35 Yield 91%; mp. 155-156 ° C (acetonitrile) δ 7,554 18 1 H-NMR (DMSO-d 6): delta 8.0 (s, 1H); 6.7 (s, 1 H); 4.5 (m. 2H); 3.8 (m. 2H); 3.6 (q. 2H); 2.3 (s. 3H); 1.1 (t, 3H) 2-Ethoxyethyl / 4- (3-carbethoxy-5-isoxazolyl) thiat-5-sol-2-oxamate7

Yield 75%; mp. 145-146 ° C (acetonitrile) 1 H-NMR (CDCl 3): delta 7.7 (s, 1H); 7.0 (s, 1 H); 4.5 (q. 2H); 4.5 (m. 2H); 3.8 (m. 2H); 3.6 (q. 2H); 1.4 (t, 3 H); 1,2 (t, 3H) 1 g of 2-ethoxyethyl / 4- {3-methoxymethyl-5-isoxazolyl Inthiazole-2-oxamate

Yield 86%; mp. 136-137 ° C (ethyl alcohol) 1 H-NMR (DMSO-d 6): delta 8.1 (s, 1H); 6.8 (s, 1 H); 4.6 (s. 2H); 4.4 (m. 2H); 3.7 (m. 2H); 3.6 (q. 2H); 3.4 (s, 3 H); 1,2 (t, 3H) 2-Ethoxyethyl / 4- (5-hydroxymethyl-3-isoxazolyl) -thiazole-2-oxamate_7

Yield 58%; mp. 159-161 ° C (acetonitrile) 1 H-NMR (DMSO-d 6): delta 8.0 (s, 1H); 6.9 (s, 1 H); Δ 4.7 (s, 2 H); 4.5 (m. 2H); 3.8 (m. 2H); 3.6 (q, 2 H)? 1.2 (t, 3H) 2-Ethoxyethyl / 4- (3-hydroxy-5-isooxazolyl) thiazole-2-oxamate7

Sp. 217-219 ° C (acetonitrile) 1 H-NMR (DMSO-d 6): delta 8.00 (s, 1H); 6.37 (s, 1 H); ·· ·: 4.43 (m, 2 H); 3.73 (m. 2H); 3.53 (q, 2 H); 1.13 (t, 3H) 2-ethoxyethyl 4- [3-bromo-5-isoxazolyl) thiazole-2-oxamate] - Yield 92%; mp. 128-129 ° C (acetonitrile): δ 30 H-NMR (DMSO-d 6): delta 7.0 (s, 1H); 4.4 (m. 2H)? 3.7 (m. 2H); 3.5 (q, 2 H); 3.1 (q. 2H); 1.3 (t. 3H); : 1,1 (t, 3H) 2-Ethoxyethyl [1- (3-bromo-5-isoxazolyl) thiazole-2-oxamate] Yield 70%; mp. 162-164 ° C (acetonitrile) 19 87554 1 H-NMR (DMSO-d 6): delta 8.2 (s, 1H); 7.1 (s. 1H); 4.5 (m. 2H); 3.8 (m. 2H); 3.6 (q. 2H); 1.18 (t, 3H) 2-ethoxyethyl 4- (3-chloro-5-isoxazolyl) thiozole-2-oxamate Yield 81%; mp. 154-156 ° C (acetonitrile) 1 H-NMR (DMSO-d 6): delta 8.2 (s, 1H); 7.1 (s. 1H); 4.5 (m. 2H); 3.8 (m. 2H); 3.6 (q. 2H); 1,2 (t, 3H) 2-ethoxyethyl 4- (3-methoxy-5-isoxazolyl) thiazole-2-oxamate / 10 Yield 78%; mp. 142-143 ° C (acetonitrile) 1 H-NMR (DMSO-d 6): delta 8.10 (s, 1H); 6.58 (s, 1 H); 4.5 (m. 2H); 4.02 (s. 3H); 3.8 (m. 2H); 3.60 (q, 2 H); 1.18 (t, 3H)

2-Ethoxyethyl 4- (3-phenyl-5-methyl-4-isoxazolyl) thiazole-2-oxamate

Yield 80%; mp 113-115 ° C (ethyl alcohol) 1 H-NMR (DMSO-d 6): delta 7.50 (m, 5H); 7.20 (s, 1 H); 4.4 (m. 2H); 3.7 (m. 2H); 3.5 (q, 2 H); 2.57 (s. 3H); 1.13 (t, 3H) 2 O 4) 2-Methoxyethyl Z4- (3-bromo-5-isoxazolyl) thiazole-2-oxamate_7

To a mixture of 2.50 g (10 mmol) of 2-amino-4- (3-bromo-5-isoxazolyl) -2-thiazole and 1.16 g (11.5 mmol) of triethylamine in 20 ml of pyridine and 25 stirred continuously at 5 ° C, 1.91 g (11.5 mmol) of 2-methoxyethyl was added dropwise. oxalyl chloride (prepared by adding 2-methoxyethanol to excess oxalyl chloride and recovering by distillation a fraction having a b.p. of 124-308 ° C / 90 mmHg). At the end of the addition, the solution was stirred overnight and then diluted with 50 ml of water.

The precipitate was collected by filtration under reduced pressure, washed on the filter with copious amounts of water and dried under reduced pressure at 50 ° C. 87.10 g of crude product were obtained, which was recrystallized twice from acetonitrile to give 2.30 g (61%) of analytically pure crystalline compound, m.p. 175.5-177 ° C.

1 H-NMR (DMSO-d 6): δ 8.17 (s, 1H); 7.13 (s, 1H); 4.50 (m. 2H); 3.50 (m. 2H); 3.35 (s. 3H)

Example F

1) 4- (3-bromo-5-isoxazolyl) thiazole-2-oxamic acid A suspension containing 12.60 g (36.4 mmol) of ethyl 4- (3-bromo-5-isoxazolyl) thiazole-2- oxamate in 500 mL of 0.1 N sodium hydroxide, stirred at ✓ 40 ° C for 45 minutes.

The reaction mixture was cooled to room temperature, extracted twice with 150 ml of ethyl ether, treated with activated carbon and filtered.

The filtrate was acidified with 60 ml of 1 N hydrochloric acid, and the precipitate was collected by filtration and washed on the filter with copious amounts of water.

9.80 g (84%); mp. 217-218.5 ° C (decomposes).

1 H-NMR (DMSO-d 6): δ 8.13 (s, 1H); 7.16 (s, 1H) '2) 2-Aminoethanol / 4- (3-bromo-5-isoxazolyl) -thiazole-2-oxamate_7: A suspension containing 2.85 g (8.95 mmol) of' 4- (3-Bromo-5-isoxazolyl) -thiazole-2-oxamic acid: in 25 ml of ethanol, heated on a steam bath with stirring. To this mixture was added 0.59 g (9.66 mmol) of ethanolamine in 10 ml of ethyl alcohol and 20 ml of water.

... 30 The solution was cooled to room temperature and then allowed to stand at 4 ° C overnight.

The precipitate was collected by filtration, dried:; and recrystallized from 65 ml of ethyl alcohol-water (2: 1).

Yield 2 g (59%); mp. 190-193 ° C (dec.) 21 87354 1 H-NMR (DMSO-d 6): delta 8.0 (s, 1H); 7 (s, 1 H); 3.7 (m. 2H); 3.0 (m, 2H) 3) Tromethamine 4- (3-bromo-5-isoxazolyl) -thiazole-2-oxamate To a solution of 3.20 g (26.4 mmol) of tromethamine in 75 mL: in methanol and stirred gently at reflux, 8.4 g (26.3 mmol) of 4- (3-bromo-5-isoxazolyl) -2-thiazolyloxamic acid were added in one portion. The reaction mixture was cooled to room temperature, and after about 15 minutes, the precipitate was collected by filtration, washed on the filter with cold methanol and dried.

The crude product (7.10 g, 61.5%) was recrystallized from methanol; mp. 183 ° C (decomposes).

15 H-NMR (DMSO-d 6 + D 2 O): delta 8.07 (s, 1H); 7.17 (s, 1H); 3.65 (s, 6H) 4) L-Lysine 4- (3-bromo-5-isoxazolyl) thiazole-2-oxamate

To a solution of 1.25 g (8.6 mmol) of L-ly-20in in 140 mL of 75% aqueous ethanol was added 2.6 g (8.2 mmol) of 4- (3-bromo-5 -isoxazolyl) thiazole-2-oxamic acid while refluxing and stirring.

. After cooling to 0 ° C, the mixture was stirred for 3 hours. The precipitate was collected by filtration; yield 2.7 g (71%); mp. 196-197 ° C (decomposes).

1 H-NMR (D 2 O): delta 7.5 (s, VH); 6.5 (s. 1H); 3.9 (t. 3H); 3.1 (m. 2H); 2.2 - 1.3 (m, 6 H)

In a similar manner the following compounds were prepared: 4- (3-methoxy-5-isoxazolyl) thiazole-2-oxamic acid

Yield 82%; mp. 224-225 ° C (dec.) 1 H-NMR (DMSO-d 6): delta 8.0 (s, 1H); 6.5 (s. 1H); 4.0 (s, 3H) 2-Aminoethanol / 4- (3-methoxy-5-isoxazolyl) thiazole-35 2-oxamate 22 227554

Yield 83.7%; mp. 214-215 ° C (75% ethyl alcohol) 1 H-NMR (DMSO-d 6): delta 7.1 (s, 1H); 6.5 (s. 1H); 4.0 (s, 3H); 3.7 (m. 2H); 3.0 (m, 2H) 2-Aminoethanol 4- (3-chloro-5-isoxazolyl) thiazole-5-oxarate17

Yield 71%; mp. 211 ° C (70% ethyl alcohol; decomposes) 1 H-NMR (TFAA): delta 8.1 (s, 1H); 7.1 (s. 1H); 3.7 (m. 2H); 3.0 (m, 2H) 2-Aminoethanol / 4- (5-phenyl-3-isoxazolyl) thiazole 2-oxamate

Yield 68.5%; mp. 210-211 ° C (75% methyl alcohol; dec.) 1 H-NMR (DMSO-d 6): delta 8.2-7.1 (m, 5H); 8.2 (s, 1H); 7.4 (S, 1H); 3.8 (m. 2H); 3.0 (m, 2H) 2-Aminoethanol / 4- (3-phenyl-5-isoxazolyl) thiazole-2-oxamate_7

Yield 73%; mp. 207-208 ° C (85% ethyl alcohol; dec.) 1 H-NMR (DMSO-d 6): delta 9-7.3 (m, 6H); 7.4 (s. 1H); Δ 3.8 (m, 2 H); 3.1 (m, 2H) L-Lysine-4- (5-phenyl-3-isoxazolyl) thiazole-2- oxamate · "; Yield 64.5%; m.p. 240-241 ° C (20% methylalcohol; decomposition) 25 H-NMR (TFAA): delta 8.1-7.3 (m, 5H); 8.0 (s. 1H); 7.3 (s, 1H); 4.0 (t, 1 H); 2.9 (m. 2H); 2.2-1.3: (m, 6H) 2-Aminoethanol [4-Z3- (2-chloro-6-fluorophenyl) -5-: isoxazolyl] thiazole-2-oxamate]: Yield 56%; m.p. 230-231 ° C (70% ethyl alcohol; decomposes) 1 H-NMR (DMSO-d 6): delta 8.2-7.0 (m, 3H), 8.1 (s, 1H); , 1 (s, 1H), 3.7 (m, 2H), 3.0 (m, 2H) -: 4- (3-phenyl-5-methyl-4-isoxazolyl) thiazole-2-35 oxamic acid 23 8 7 554

Yield 62%; mp. 187-188 ° C (isopropyl alcohol; decomp.) 1 H-NMR (DMSO-d 6): delta 7.6 (m, 5H); 7.2 (s. 1H); 2,6 (s, 3H) 2-Aminoethanol [4- [3- (2-chloro-6-fluorophenyl) -5-methyl-5'-4-isoxazolyl] thiazole-2-oxamate]

Yield 60%? mp. 164-166 ° C (isopropyl alcohol; decomposes) 1 H-NMR (DMSO-dc): delta δ-7.3 (m, 3H); 6.6 (s. 1H); O '3.7 (m. 2H); 2.9 (m. 2H); 2.8 (s, 3H) 2-Aminoethanol 2- (5-hydroxymethyl-3-isoxazolyl) -1H-thiazole-2-oxamate

Yield 61%; mp. 185-187 ° C (methyl alcohol; dec.) 1 H-NMR (DMSO-d 6): delta 7.9 (s, 1H); 6.8 (s, 1 H); 4.6 (s. 2H); 3.7 (m. 2H); 3.0 (m, 2H) 2-Aminoethanol / 4- (3-hydroxymethyl-5-isoxazolyl) -thiazole-2-oxamate_7

Yield 69%; mp. 196-197 ° C (75% methyl alcohol; dec.) 1 H-NMR (DMSO-d 6): delta 7.9 (s, 1H); 6.8 (s, 1 H); 4.6 (s. 2H); 3.7 (m. 2H); 3.0 (m, 2H) 2 O) Sodium 4- (3-methoxy-5-isoxazolyl) thiazole-2-oxamate

A suspension of 11.9 g (35 mmol) of ethoxy-ethyl 4- (3-methoxy-5-isoxazolyl) thiazole-2-oxamate in 500 ml of 0.1 N sodium hydroxide was stirred. 25 at 40 ° C for 30 minutes.

After cooling to 0 ° C, the precipitate was collected by filtration and dried.

Yield 2.4 g (23.5%); mp. 320 ° C (decomposes) 1 H-NMR (TFAA): delta 8.1 (s, 1H); 6.8 (s, 1H); 4.2 '(s. 3H).

’· Example G

1) N- [4- (3-Bromo-5-isoxazolyl) -2-thiazolyl] oxamide

A mixture of 3.50 g (10 mmol) of ethyl 4-: 35 (3-bromo-5-isoxazolyl) thiazole-2-oxamate and 24 8 7 5 b 4 25 ml of 10% ammonia methyl alcohol solution was stirred at room temperature. at 24 hours.

The precipitate was collected by filtration, dried under reduced pressure at 50 ° C (2.70 g) and crystallized from 55 ml of glacial acetic acid to give 2.20 g (69%) of analytically pure crystalline product which decomposes without melting 255 ° C.

1 H-NMR (DMSO-d 6): δ 8.20 (s, 1H); 7.20 (s, 1H) 2) N- [4- (3-methoxy-5-isoxazolyl) -2-thiazolyl] oxamide

A mixture of 8.6 g (28.9 mmol) of ethyl 4- (3-methoxy-5-isoxazolyl) thiazole-2-oxamate in 143 ml of a 16% solution of sodium hydroxide in methyl alcohol was stirred at room temperature overnight. .

The solvent was evaporated and the residue (7.5 g) was recrystallized from 220 ral of glacial acetic acid. Yield 6.2 g (80%); a crystalline compound which decomposes without melting at 250 ° C.

1 H-NMR (DMSO-d 6): δ 8.0 (s, 1H); 6.5 (s, 1H); Δ 4.0 (s, 3 H)

In a similar manner the following compounds were prepared: N- [4- (3-phenyl-5-methyl-4-isoxazolyl) -2-thiazolyl] -1-oxamide

Yield 73%; mp. 204-205 ° C (acetonitrile) .25 1 H-NMR (DMSO-d 6): δ 7.6 (m, 5H); 7.2 (s. 1H); 2,6 (s, 3H) -N- [4- (5-phenyl-3-isoxazolyl) -2-thiazolyl] oxamide

Yield 74%; mp. 246-247 ° C (glacial acetic acid) 30 H-NMR (DMSO-d 6): delta 8.2-7.4 (m, 5H); 8.1 (s, H); : V; 7'5 (s, 1H). N - [/ [4- (2-chloro-6-phenyl) -5-isoxazolyl] -2-thiazolyl] oxamide ··: Yield 77%; mp 235-237 ° C (glacial acetic acid) ... 35 1 H -NMR (DMSO-d 6): delta 8.2 (s, 1H); 7.6 (m, 3H); 25 87554 7.2 (s, 1H) -N- [4- (3-methyl-5-isoxazolyl) - 2-tiatsolyyliJroksa-midi

Yield 90%; mp. 245-246 ° C (glacial acetic acid) δ 1 H-NMR (DMSO-d 6): delta 8.0 (s, 1H); 6.7 (s, 1H); 3.3 (s, 3H) N- [4- (3-bromo-5-isoxazolyl) -5-ethyl-2-thiazolyl] oxamide

Yield 85%; mp. 219-221 ° C (glacial acetic acid, decomp.) 1 H-NMR (DMSO-d 6): delta 7.0 (s, 1H); 3.1 (q. 2H); 1.3 (t, 3H) N- [4- (3-hydroxymethyl-5-isoxazolyl) -2-thiazolyl] oxamide

Yield 45%; mp. 250-255 ° C (glacial acetic acid; decomp.) 1 H-NMR (DMSO-d 6): delta 8.0 (s, 1H); 6.8 (s, 1 H); 4,6 (s, 2H) 3) 1- [1- (3-Bromo-5-isoxazolyl) -thiazole-2-oxamoyl] -4-methylpiperazine

A mixture of 7.3 g (21.1 mmol) of ethyl 2- [4- (3-bromo-5-isoxazolyl) thiazole-2-oxamate and. 36.5 ml of N-methylpiperazine, was stirred at room temperature overnight.

. ··. The solution was then poured into 350 ml of isopropyl ether with stirring, and the precipitate was collected by filtration and stirred with hot methyl alcohol.

The suspension was refluxed and stirred for 30 minutes, then cooled to 0 ° C and filtered.

The filter residue was dissolved at 80 ° C in 80 ml of dimethylformamide. The solution was cooled to 0 ° C and the precipitate was collected by filtration and dried. Yield 3.5 g (41.5%) of a crystalline compound which melts slowly at 200 ° C.

1 H-NMR (TFAA): δ 8.1 (s, 1H); 7.2 (s. 1H); 4.2-35 3.2 (m. 8H); 3.2 (s, 3H) 26 8 7 554 4) Ν, Ν'-bis Z4- (3-bromo-5-isoxazolyl) -2-thiazolyl ioxamide

To a solution of 10.1 g (41 mmol) of 2-amino-4- (3-bromo-5-isoxazolyl) -thiazole in 160 mL of N-dichloroethane was added 4.13 g (41 mmol) of triethyl amine in 15 ml of 1,2-dichloroethane.

o

The mixture was heated to 60 ° C and stirred; a solution of 2.60 g (20.5 mmol) of oxalyl chloride in 15 ml of 1 Ω dichloroethane was slowly added dropwise.

The mixture thus obtained was stirred at room temperature overnight. The precipitate was collected by filtration and washed with methyl alcohol.

The crude product (5.8 g) was recrystallized from 195195 ml of tetrahydrofuran.

Yield 4.5 g (40%) of a crystalline compound which decomposes slowly at 280 ° C.

1 H-NMR (DMSO-d 6): δ 8.1 (s, 1H); 7.1 (s, 1H) 5) N- [1- (3-bromo-5-isoxazolyl) -2-thiazolyl] -N'-isopropyloxamide::: A solution containing 7.1 g (20.5 mmol) of ethyl 4- (3-bromo-5-isoxazolyl) -thiazole-2-oxamate in 30 ml of isopropylamine, was stirred at room temperature overnight.

_____: The solvent was removed by evaporation, and the residue was crystallized from 300 ml of methyl alcohol.

Yield 3.2 g (43.5%); mp. 194-195 ° C. . 1 H-NMR (DMSO-d 6): δ 8.1 (s, 1H); 7.1 (s. 1H); .5 4.1 (m, 1H); 1.2 (d. 6H).

Claims (3)

27 87 354 A process for the preparation of 2-amino-4- (isoxazolyl) thiazole derivatives of the formula 5 R7 - S R -. J_nh2 (m) li | ^ Ny 10. R 1 wherein R 1 and R 2 independently of one another are hydrogen, chlorine, bromine, hydroxy, methyl, methoxy, phenyl, 2-chloro-6-fluorophenyl, hydroxymethyl or methoxymethyl and R 7 is hydrogen or ethyl, characterized in that that compound of formula 20 R7 - S R -, -J-NHCOCOR2 (I) I 'Il N N jJ_R1; 25 v: wherein R, Rj and R7 have the same meaning as above, are reacted with thiourea, Process according to Claim 1, characterized in that the reaction is carried out in a protic. . or aprotic polar solvent at a temperature of 50 to 100 ° C. 28 8 7 354