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Method for the preparation of a 2,4,5-trisubstituted 1,2,4-triazolone

A compound, suitable technology, applied in the direction of organic chemical methods, pharmaceutical formulations, medical preparations containing active ingredients, etc., can solve problems such as low conversion rate, limited availability, large-scale composition problems, etc.

Pending Publication Date: 2021-01-15
BAYER AG +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0042] Compound (I) can be synthesized according to one of the above-mentioned routes, but all these synthetic routes have obvious disadvantages which pose problems especially on a larger scale:
[0054] Due to the relatively low electrophilicity of the amide, the conversion of the monosubstituted amide (XIX) to the desired product (I) was extremely low, and thus the availability of the synthetic route 3 was limited by industry, resulting in by-product formation and extensive purification efforts
This results in additional effort, costs and significantly lower yields - especially on an industrial scale

Method used

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  • Method for the preparation of a 2,4,5-trisubstituted 1,2,4-triazolone
  • Method for the preparation of a 2,4,5-trisubstituted 1,2,4-triazolone
  • Method for the preparation of a 2,4,5-trisubstituted 1,2,4-triazolone

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0591] 2-Tetrahydropyran-2-yloxyacetylhydrazide (A1)

[0592]

[0593] First, 450 g (3.40 mol) of butyl glycolate (xxx1) were added to 2250 ml of dichloromethane. 5.5 g (0.03 mol) of 4-toluenesulfonic acid monohydrate were added at 20°C. 3,4-Dihydro-2H-pyran (309 g, 3.68 mol) (xxx2) was added over 30 minutes at an internal temperature below 35°C. The mixture was then cooled to 22°C and stirred for a further 16 hours.

[0594] 1125 ml of saturated aqueous sodium bicarbonate solution were added, the organic phase was separated and first evaporated at 50°C bath temperature / 3 mbar reduced pressure, yielding 751 g of a dark orange oil. Further distillation to remove impurities (80°C bath temperature / 0.25 mbar) afforded 659 g of (A1 ) as a dark orange oily distillation residue, 89% yield.

[0595] This crude product was converted directly in the next stage.

[0596] 1 H NMR (400MHz, DMSO-d 6 )δppm 0.89 (t, J=7.40Hz, 3H) 1.33 (dq, J=14.93, 7.41Hz, 2H) 1.39-1.79 (m, 10H) 3.38...

Embodiment 2

[0599] 4-Ethyl-3-(tetrahydropyran-2-yloxymethyl)-1H-1,2,4-triazol-5-one (A4)

[0600]

[0601] Phase 1:

[0602]

[0603] At 20 °C, 375 g (1.734 mol) of intermediate (A1) were charged to the reactor, 104.2 g (2.081 mol) of hydrazine hydrate were added, and the mixture was heated to an internal temperature of 57 °C for 3 hours (slight reflux) . The mixture was then cooled to 22°C.

[0604] This crude intermediate (A2) was used directly in the next stage.

[0605] Intermediate (A2) was previously described in DE 2156472 (Ciba Geigy 1971).

[0606] Phase 2:

[0607]

[0608] Water (906ml) was added to intermediate (A2), and the mixture was cooled to 10°C. Ethyl isocyanate (172.6 g, 2.428 mol) was added over 50 minutes at an internal temperature of 10-15°C. The mixture was then warmed to 20°C over 30 minutes.

[0609] The crude reaction mixture of intermediate (A3) was used directly in the next stage.

[0610] Phase 3:

[0611]

[0612] 50% aqueous sodium hydr...

Embodiment 3

[0622] 4-[4-Ethyl-5-oxo-3-(tetrahydropyran-2-yloxymethyl)-1,2,4-triazol-1-yl]-2,5-difluoro -Benzonitrile (A5)

[0623]

[0624] Intermediate (A4) (250 g, 1.10 mol) and 2,4,5-trifluorobenzonitrile (xxx5) (190 g, 1.21 mol) were stirred in acetonitrile (2500 mL), and potassium phosphate (467 g, 2.20 mol) was added . The mixture was stirred at 70-73°C for 20 hours, then cooled to room temperature.

[0625] Water (1200 mL) was added, and the mixture was stirred for 15 minutes. The organic phase was separated, washed with 10% aqueous sodium chloride (1200 mL) and evaporated under reduced pressure at a bath temperature of 40°C to give 414 g of a brown viscous oil.

[0626] The residue was dissolved in absolute ethanol (915 mL) at 40°C, then cooled to 25°C to initiate crystallization. Water (1250 mL) was added and the suspension was stirred at 22°C.

[0627] After stirring for 16 hours, the solid was isolated, washed twice with ethanol / water (3:4v / v, 245mL), and dried under va...

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Abstract

The present invention provides methods for the preparation of Compound (I): Compound (I), the use of intermediates for the preparation of said compound and its crystalline form A.

Description

[0001] The present invention provides a method for preparing 2,4,5-trisubstituted 1,2,4-triazolone compounds, novel intermediate compounds and their preparation of the 2,4,5-trisubstituted 1,2, Use of a 4-triazolone compound in a method. Background technique [0002] Acute myeloid leukemia (AML) is the most common acute leukemia in humans, and its 5-year survival rate is only about 30%. The chemotherapy standard of care for AML has not changed significantly over the past few decades, and new therapies are urgently needed. About 10% of AML belong to the acute promyelocytic leukemia (APL) subtype, whose treatment with ATRA or arsenic trioxide led to a significant increase in patient survival, with an overall survival rate of more than 70%, but unfortunately, there is still a lack of targeting for the higher incidence Comparable Differentiation Therapies for Non-APL AML. Therefore, there is a high interest and medical need for new therapies. [0003] There are several preclini...

Claims

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Application Information

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IPC IPC(8): C07D405/12C07D249/12A61P35/00A61K31/4196
CPCC07D249/12C07D405/12A61P35/00A61K31/4196C07B2200/13
Inventor J.哈斯费尔德S.N.格拉迪尔P.鲁本鲍尔H.N.S.范德哈斯R.G.吉林
Owner BAYER AG
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