DD250709A1 - PROCESS FOR THE SYNTHESIS OF NEW 2-HETEROCYCLO ALKYL AND SUBSTITUTED 2-AMINO-1,3,4-OXADIAZOLE - Google Patents

Abstract

In the invention, a synthesis process for 2-substituted 1,3,4-oxadiazoles is described. The invention should provide a rational, variable synthetic method for certain 2-substituted 1,3,4-oxadiazoles of interest in the pharmaceutical industry. From 4-1,3,4-oxadiazolin-2-ones is obtained with primary and secondary amines without the addition of solvents after 2-15 min. Reaction time 1-heterocycloalkyl or 1-subst. Amino-carbonyl-2-acylhydrazines of the general formula R1CNHNHCR2O, which are characterized by boiling in phosphoryl chloride to heterocycloalkyl- or 2-subst. For 1-3 hours. Amino-1,3,4-oxadiazoles of the general formula where R1 is an alkyl, aryl or heteroaryl group and R2 is a heterocycloalkyl or a substituted amino group. formula

Description

2 0

where R ^{1 is} an alkyl, aryl or heteroaryl group and H ^{2 is} a Heterocycloalkyi- or a substituted amino group.

Field of application of the invention

The compounds obtained by the indicated process are of interest as chemical intermediates

Characteristic of the known technical solutions

Substituted 2-amino substituted 1,3,4-oxadiazoles can be prepared by cyclization of the 4-substituted 1-amino thiazemicarbazides obtainable from carboxylic acid hydrazides and isothiocyanates (Marckwald, W.W., Bott, Ber., Dtsch., Ges., 29, 2914). 1896]) by H ₂ S cleavage (R. Stolle and K.Feh. -.Ibach, J. prakt. Chem. 122, 289 [1929]) synthesize. According to another method, the cyclization is also possible via the 4-substituted S-alkyl-isothiosemicarbazide by thermal Mercaptanabspalturig (E.Hoggarth, J. Chem Soc [London] 1949, 1918, 1950, 1579). These imaging methods require long reaction pathways, use toxic intermediates and run with moderate or poor overall yields. The recently described synthesis of 2-morpholino- and 2-dimethylamino-5-pyrid-2-yl-1,3,4-oxadiazole from N-trichloromethyl-morpholine and nicotinic acid hydrazide is also complicated and proceeds with only 37% yield. (SU-Pat. 770050 of 15.3.1985)

For 1-acylsemicarbazides and 1-acyl-4-phenyl (ethyl) semicarbazides (H.Gehlen and K.Möckel, Liebigs Ann. Chem. 6 (50,144 [1962]) and cyclic 1-acyl! Semicarbazides of the type 1- acylamino Ä ⁴ (H.Beyer A.Hetzheim u., Chem. Ber. 103, 272 [1970]) imidazoline-2-one is the cyclization in an acidic medium to the corresponding 1,3,4-oxadiazole derivatives known. There are however, no such cyclizations of 1 -heterocycloalkyl-carbonyl-2-acylhydrazines or other 1 -substhanolocarbonyl-2-acylhydrazines to 1,3,4-oxadiazoles are described.

Representatives of 1-Heterocycloalkyl- or 1-subst. Aminocarbonyl-2-acylhydrazines have hitherto been synthesized by ring-opening of * -1,3,4-oxadiazolin-2-ones with amines in various solvents, requiring a longer reaction time (A.Stempel, I.Zelauskasu.l.Aeschliman, J Org. Chemistry 20, 612 [1955]); W.R.Sherman u. A. von Esch, J. Org. Chemistry 27, 3472 [1962]; K. H. Pilgram, J. Heterocycl. Chem. 19, 823 [1982]).

Object of the invention

The invention provides an economical process for the synthesis of 2-heterocycloalkyl and substituted 2-amino-1,3,4-oxadiazoles to be developed with respect to the time required and the yields, which at the same time allows a wide range of variation of the substituents in the 2-amino group ,

Explanation of the essence of the invention

- The technical problem which is solved by the invention

The technical object of the invention is, starting from readily available basic chemicals, a process for the synthesis of new 2-subst. Amino-1,3,4-oxadiazoles to Entwickein, which allows, in contrast to previous methods, a wide range of variation of the substituents in the 2-amino group and requires less preparative effort.

Features of the invention

Synthesis according to the invention 2-heterocycloalkyl and substituted 2-amino-1,3,4-oxadiazoles of the general formula

where R ^{1 is} an alkyl, aryl or heteroaryl group and R ^{2 is} a heterocycloalkyl or a substituted amino group, by reacting accessible from carboxylic hydrazides and phosgene A ⁴ -1,3,4-oxadiazolin-2-ones with primary and secondary amines without solvent 2-15МІП. heated under reflux and the resulting 1-Hetorocycloalkyl- or 1-subst. Aminocarbonyl-2-acyl-hydrazines of the general formula

R ¹ ~ D-ira-im-o-ß ² , о о

where R ¹ and R ^{2 have} the same meaning as above, with phosphoryl chloride 1-3Sta. heated to boiling and this is removed in vacuo. The resulting reaction mixture is treated as indicated.

embodiments

Example 1 1-Pyrrolidino-carbonyl-2-benzoyl-hydra2in

1.0g (6.2mmol) of 2-phenyl-A ⁴ -1,3,4-oxadiazolin-2-one is added with 5mL of pyrrolidine 2Min. heated to reflux. After completion of the reaction, the reaction mixture solidifies. The substance obtained is recrystallized from H ₂ O / C ₂ HsOH.

Yield: 1.0g (70%) m.p .: 236-238 ⁰ C

¹ H-NMR / 1 /, (DMF-d,) δ = 1.85 (m, 4H, 2CH ₂ -pyrrolidine), 3.39 (m, 4H, CH ₂ - (NH) -CH ₂ -pyrrolidine) , 7.38-8.06 (m, 5H, C ₆ H ₅ ) 2-pyrrolidino-5-phenyl-1,3,4-oxadiazole

0.4 g (1.7 mmol) of 1-pyrrolidinoropropyl-2-benzoylhydrazine and 4 ml of phosphoryl chloride are heated for 1 h. under reflux. After removal of the phosphoryl chloride in vacuo, the residue is mixed with 4 ml H ₂ O and the solution is neutralized after cooling with 2 N NaOH. Recrystallization from H ₂ O gives a colorless substance.

Yield: 0.30 g (81%); M .: 93-95 ⁰ C

¹ H-NMR (CDCI ₃₎ δ = 2.03 (m, 4H, 2CH ₂ pyrrolidine), 3.60 (m, 4H, CH ₂ - (NH) -CH _{-pyrrolidin?),} 7,26- 8.00 (m, 5H, C ₆ H ₆ )

Example 2 i-Piperidino-carbonyl-2-benzoyl-hydrazine

1.0 g (6.2 mmol) of 5-phenyl-A ⁴ -1,3,4-oxadiazolin-2-one and 5 ml of piperidine are heated to boiling for 5 min. The substance thus obtained crystallizes from ethanol in colorless platelets.

Yield: 1.3 g (85%); M .: 212 ^C C

2-piperidino-5-phenyl-1,3,4-oxadiazole

1.0 g (4.04 mmol) of 1-piperidino-carbonyl-2-benzoyl-hydrazine and 10 ml of phosphoryl chloride are heated to boiling. After removal of the phosphorus chlorides in vacuo, the viscous residue is mixed with 10 ml H ₂ O. It is then neutralized with 2 N NaOH and recrystallized from H ₂ O / C ₂ H ₆ OH.

Y. : 0.7g (76%); M.p .: 108 ⁰ C

¹ H-NMR (CCI ₄ ), δ = 1.67 (s, 6H, 3CH ₂ -piperidine) 3.50 (s, 4H, CH ₂ - (NH) -CH ₂ -piperidine), 7.30-7 , 56 (m, 3H, aromat H at C-3, C-4, C-5), 7.82-8.04 (m, 2 H, aromat H at C-2, C-6).

Example 3 1-Piperidino-carbonyl-2-phenacetyl-hydrazine

1.0g (5.7mmol) of 5-benzyl-A ⁴ -1,3,4-oxadiazolin-2-one and 5 ml of piperidine become 8min. heated to reflux. The solution is taken up in a little H ₂ O and, after trituration, gives a colorless substance, which is recrystallized from H ₂ O.

Yield: 1.15 g (77%); M .: 150-151 ⁰ C

¹ H-NMR (CDCl ₃ ), δ = 1.52 (m, 6 H, 3CH ₂ -piperidine), 3.33 (m, 4 H, CH ₂ - (NH) -CH ₂ -piperidine !, 3, 55 (s, 2H, CH ₂ -C ₆ H ₅ ), 7.28 (s, 5H, C ₆ H ₅ ), 7.75 (d, 1H, NH-phenacetyl), 8.98 (d, 1H, NH-piperidinocarbonyl)

2-piperidino-5-benzyl-1,3,4-oxadiazof

0.70 g (2.7 mmol) of i-piperidino-carbonyl-2-phenacetyl-hydrazine are heated in 10 ml of 10M phosphoryl chloride. under reflux.

After blowing off the phosphoryl chloride, add 7 ml H ₂ O and neutralize with 2 N NaOH. The deposited oily liquid crystallizes after prolonged rubbing and cooling to 10 ⁰ C. It is recrystallized from H ₂ O.

Yield: 0.45 g (69%); M .: 68-70 ⁰ C

¹ H-NMR (CDCl ₃ ), δ = 1.62 (s, 6H, 3CH ₂ -piperidine), 3.39 (s, 4H, CH ₂ -NH-CH ₂ -piperidine), 4.03 (s, 2H, CH ₂ -C ₆ H ₅ ), 7.28 (s, 5H, C ₆ H ₅ )

Example 4 i-Morpholino-carbonyl-2-benzoyl-hydrazine

1.0 g (6.2 mmol) of 5-РпепуІ-Д ⁴ -1,3,4-oxadiazolin-2-one and 4 ml of morpholine is heated for 5 min. Under reflux. The viscous mass is mixed with wenicj H ₂ O. After trituration, a colorless substance is obtained which can be recrystallized from H ₂ O.

Yield: 1.15 g (75%); Mp .: 204-205 ° C

2-morpholino-5-phenyl-1,3,4-oxadiazole

1.0 g (4.01 mmol) of i-morpholino-carbonyl-benzoyl-hydrazine is refluxed in 10 ml of phosphoryl chloride for 1 h. The yellowish solution is added after blowing off the phosphoryl chloride under the hood with 10ml H ₂ O and then neutralized the resulting solution with 2 N NaOH. From little C ₂ H ₅ OH colorless Nadein crystallize.

Yield: 0.6g (64%); Schpip .: 109 ⁰ C

¹ H NMR (CDCl ₃ ), δ = 3.59 (m, 4H, CH ₂ - (N) -CH ₂ -MoIpholine), 3.80 (m, 4H, CHa-O-CHrMorpholine), 7.30 -7.60 (m, 3H, aromatic H at C-3, C-4, C-5). 7.78-7.98 (m, 2H, aromat H at C-2, C-6)

1 The ¹ H NMR spectra were recorded with the KRW-100R of the ZWG of the AdW Berlin (TMS. ", 6 in ppm)

Example 5 i-Morpholino-carbonyl-O-salicyloyl-hydrazine

0.50 g (2.8 mmol) of 5- (2-hydroxyphenyl) -A ⁴ -1,3,4-oxadiazolin-2-one and 1.6 ml of morpholine are heated to 15 ml. under reflux, the excess amine removed and added to the crystallized substance with H ₂ O. After filtering, washing with H ₂ O and Umkristalüsation from Berjzen to obtain a colorless substance.

AuGb .: 0.55g (74%); Mp .: 208 to 209.5 ⁰ C.

2-MorphQHno-5- (2-hydroxyphenyl) -1,3,4-oxadiazole

0.50 g (1.9 mmol) of i-morpholino-carbonyl-acyl-cyclohexane and 5 ml of phosphoryl chloride are refluxed for 90 min. After blowing off the phosphorus chloride, add 3 ml H ₂ O and neutralize with 2 N NaOH. The substance obtained is recrystallized from H ₂ O / C ₂ H ₅ OH.

Yield: 0.14 g (30%); Sclynp. 131-132 ° C

¹ H-NMR (CDCl ₃ ), δ = 3.62 (m, 4H, CH ₂ - (N) -CH ₂ -MorPhOIm), 3.84 (m, 4H, CH ₂ - (N) -CH ₂ - Morpholine), 6.97 (s, 1H, OH), 7.26 (m, 5H,

C ₆ H ₆ ) '

Example 6 i-Morpholino-carbonyl-2-methylbenzoyl-hydrazine

0.50 g (2.8 mmol) of 5-p-tolyl-A ⁴ -1,3,4-oxadiazolin-2-one and 1 ml of morpholine are heated under reflux for 10 min. After cooling, a colorless substance crystallizes out, which can be recrystallized from C ₂ H ₆ OH.

Yield: 0.50 (68%); M.p .: 182-183 ° C

2-morpholino-5-p-tolyl-1,3,4-oxadiazole

0.30 g (1.1 mmol) of 1-morpholino-carbonyl-p-methyl-benzene-hydrazine and 3 ml of phosphoryl chloride are heated to boiling for 1 h, the phosphoryl chloride is largely removed by blowing off or vacuum distillation, the residue is combined with 3 ml H ₂ O and neutralized with 2 N NaOH. After recrystallization from 50% ethanol, a colorless substance is obtained.

Yield: 0.17 g (60%); M .: 167-168 ⁰ C

Example 7 5- (2-Oxo-A ⁴ -1,3,4-oxadiazolin-5-yl) -A ⁴ -1,3,4-oxadiazolin-2-one

10.0 g (80 mmol) of oxalic acid dihydrazide is dissolved in 200 ml of H ₂ O / HCl and initiates phosgene. After cooling the solution to 0 ⁰ C precipitates a colorless substance, which can be recrystallized from DMF.

Yield: 9.3g (65%); M .: 280-283 ° C

2,2'-morpholino-carbonyl-ox & lsäuredihydrazid

0.7 g (4.1 mmol) of 5- (2-oxo-A ⁴ -1,3,4-oxadiazolin-5-yl) -A ⁴ -1,3,4-oxadiazoli ^r; ^ -on and 4ml morpholine are heated to 25min. under reflux. The crystallized on cooling compound is recrystallized from DMF.

Yield: 1.4g (quantitative); M.p .: 241-243 ° C

2-Morpholino-5- (2-morpholino-A ⁴ -1,3,4-oxadiazolin-5-yl) -1,3,4-oxadiazole

0.70 g (2.2 mmol) of 2,2'-morpholino-carbonyl-oxalsäuredihyarazid and 7 ml of phosphoryl chloride are heated for 3 h. under reflux.

After removal of the phosphoryl chloride is mixed with 7 ml of H ₂ O and neutralized with 2 N NaOH. After recrystallization from H ₂ O, a colorless powder is obtained.

Yield: 0.47 g (76%); M .: 271-274 ⁰ C

Example 8 i-Phenyla-getyl-4-cyclohexyl semicarbazide

1.00 g (5.7 mmol) of 5-benzyl-A ⁴ -1,3,4-oxadiazolin-2-one and 3 ml of cyclohexylamine are heated for about 1 min until solidification of the reaction mixture.

The recrystallization is carried out from ethanol.

Yield: 1.45 g (93%); M .: 206-207 ⁰ C

¹ H-NMR (DMF-d ₇ ), δ = 1.20-1.68 (m, 11 H, C ₆ H ₁ ,), 3.52 (s, 2H, CH ₂ - (C ₆ H ₅ ) ), 6.17 (d, 1H, NH- (C ₆ H ₁₁ )), 7.35 (d, 5H, C ₆ H ₅ ), 7.67 (s, 1H, 1NH), 9.03 (s, 1H, NH)

2-cyclohexylamino-5-benzyl-1,3,4oxadiazol

0.70 g (2.5 mmol) of i-phenylacetyl-4-cyclohexyl-semicarbazide are heated in 7 ml of phosphoryl chloride 75MІP. to boiling. Remove the phosphoryl chloride as indicated in the other examples, add H ₂ O, decant the liquid from the greasy substance, and rub again with H ₂ O several times to solidify. After recrystallization from 30% ethanol, colorless crystals are obtained.

Yield: 0.51 g (78%); M .: 147-148 ° C

¹ H-NMR (CDCl ₃ , δ = 1.29-2.01 (m, 11 H, C ₆ H ₁₁ ), 4.01 (s, 2H, CH ₂ - (C ₆ H ₆ )), 4, 67 (s, 1H, NH), 7.29 (s, 5H, C ₆ H ₆ )

Example 9

1-benzoyl-4-propyl semicarbazide

1 Og (6.2 mmol) of 5-РпепуІ-Д ⁴ -1,3,4-oxadiazolin-2-one is heated for 3 min in 1.6 ml of propylamine. To boiling. Towards the end of the reaction, the liquid solidifies. Colorless needles crystallize from H ₂ O.

 Yield: 0.9 g (66%); M.p .: 174-175 ° C

' ¹ H-NMR (C ₂ D ₅ OD), δ = 0.74-0.98 (t, 3H, CH ₃ ) 1.34-1.62 (q, 2H, CH ₂ (CH ₃ )), 3.00-3.20 (t, 2H, CH ₂ -NH), 7.32-8.04 (m, 5H, C ₆ H ₆ ) 2-propylamino-5-phenyl-1,3,4-oxadiazole

0.35 g (1.6 mmol) of 1-benzoyl-4-propyl semicarbazide are boiled in 3.5 ml of phosphoryl chloride for 1 h. After blowing off the phosphoryl chloride, the reaction mixture is mixed with 3.5 ml of H ₂ O and neutralized with 2 N NaOH. From H ₂ O / Ethano! is recrystallized

Yield: 0.23g (70%); M .: 104-105.5 ⁰ C

Claims (1)

Process for the synthesis of new 2-heterocycloalkyl and substituted 2-amino-1,3,4-oxadiazoles, characterized in that Δ ⁴ -1,3,4-oxadiazolin-2-ones with primary and secondary amines without solvent 2 ^ 15 minutes. heated to boiling and the resulting 1-heterocycloalkyl or, 1-subst. Amino-carbonyl-7-acylhydrazines of the general formula where R ^{1 is} alkyl, aryl or a heterocycle and R ^{2 is} a heterocycloalkyl radical or a primary or secondary amino group substituted by Alkyi, alkenyl, alkynyl, cycloalkyl, aralkyl and aryl, by 1-3h. Boiling in Phosphorylr.hlorid to Heterocycloalkyi- or 2-subst. Amino-1,3,4-oxadiazoles of the general formula