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1, 3, 4-oxadiazole-2-cyclobutyl compound and preparation method thereof

A compound and heterocyclic group technology, applied in the field of medicinal chemistry, can solve the problems of immunogenic drug administration route restrictions and other problems

Active Publication Date: 2020-05-05
NANJING SANHOME PHARMACEUTICAL CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0003] At present, anti-PD-1 / PD-L1 antibody therapy has been shown to have an advantageous effect in clinical practice, but biomacromolecules also have some disadvantages, such as immunogenicity and limitations of administration routes

Method used

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  • 1, 3, 4-oxadiazole-2-cyclobutyl compound and preparation method thereof
  • 1, 3, 4-oxadiazole-2-cyclobutyl compound and preparation method thereof
  • 1, 3, 4-oxadiazole-2-cyclobutyl compound and preparation method thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0084] Example 1: ((1r,3S)-3-(cyanomethyl)-1-(5-((4S,5R)-5-methyl-2-oxooxazolidinone-4-yl)- 1,3,4-oxadiazol-2-yl)cyclobutyl) tert-butyl cyanoformate

[0085]

[0086] Step 1: Preparation of (4S,5R)-5-methyl-2-oxooxazolidinone-4-carboxylic acid

[0087]

[0088] To the sodium hydroxide (1mol / L, 450mL) solution of L-threonine (15.0g, 125.92mmol), slowly drop three (trichloromethyl) carbonate (37.4g, 125.92mmol) of 1,4- Dioxane (300 mL) solution was stirred at room temperature for 6 hours after dropping, concentrated to dryness under reduced pressure, added hot acetonitrile (450 mL) and stirred, filtered, and the filtrate was concentrated to dryness to obtain the title compound (18.1 g, yield 99.0%). m / z calcd for C 5 h 7 NO 4 [M+H] + 146.0, found 146.1.

[0089] Step 2: Preparation of benzyl 2-((4S,5R)-5-methyl-2-oxooxazolidinone-4-carbonyl)hydrazine-1-carboxylate

[0090]

[0091] Under nitrogen protection, at -10°C, drop successively into a solution of (4S,5R)-...

Embodiment 2

[0116] Example 2: 2-((1S,3r)-3-amino-3-(5-((4S,5R)-5-methyl-2-oxooxazolidinone-4-yl)-1, 3,4-Oxadiazol-2-yl)cyclobutyl)acetonitrile trifluoroacetate

[0117]

[0118] Under nitrogen protection, to ((1r,3S)-3-(cyanomethyl)-1-(5-((4S,5R)-5-methyl-2-oxooxazolidinone-4-yl) -1,3,4-oxadiazol-2-yl)cyclobutyl) tert-butyl cyanoformate (1.5g, 3.97mmol) in dichloromethane (15mL) solution was added dropwise trifluoroacetic acid (4.5g, 39.70 mmol), stirred at room temperature for 2 h after dropping, and monitored the end point of the reaction by TLC. Concentrate to dryness under reduced pressure, and the resulting residue is purified by column chromatography to obtain the title compound (1.2 g, 77.3%). 1 HNMR (D 2 O,400MH Z )δ5.02~5.07(m,2H), 3.03~3.13(m,1H), 2.76~2.77(d,J=4Hz, 2H), 2.59~2.67(m,4H), 1.59~1.61(d,J =8Hz,3H); m / z calcd for C 12 h 15 N 5 o 3 [M+H] + 278.12, found 278.2.

Embodiment 3

[0119] Example 3: 2-((1S,3r)-3-amino-3-(5-((4S,5R)-5-methyl-2-oxooxazolidinone-4-yl)-1, 3,4-oxadiazol-2-yl)cyclobutyl)acetonitrile

[0120]

[0121] The preparation method was similar to that of Example 2, except that the amount of trifluoroacetic acid was reduced to obtain the title compound.

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Abstract

The invention belongs to the field of medical chemistry, and relates to a 1, 3, 4-oxadiazole-2-cyclobutyl structure and a preparation method thereof, in particular to a compound shown as a formula I or stereoisomers, salts, solvates and crystals thereof, a preparation method of the compound and application of the compound serving as an intermediate in preparation of drugs for treating cancers or infectious diseases. The compound provided by the invention has the advantages of high yield, purity and optical purity in preparation of drugs for treating cancers or infectious diseases, mild reaction conditions, easiness in purification, stable process and easiness in operation, and can meet industrial-scale production and application.

Description

technical field [0001] The invention belongs to the field of medicinal chemistry, and specifically relates to a compound having a 1,3,4-oxadiazole-2-cyclobutyl structure or an isomer, salt, solvate, crystal, and a preparation method of the compound and its use as an intermediate in the preparation of medicines for treating cancer or infectious diseases. Background technique [0002] Programmed Cell Death-1 (PD-1) and its ligand PD-L1 (B7·H1) belong to the CD28 / B7 superfamily. PD-1 is mainly expressed on the membrane surface of T cells, B cells, and natural killer cells (Natual Killer Cells, NK cells), and PD-L1 is mainly expressed on mature CD4 T cells, CD8 T cells, B cells, monocytes, and dendrites. Dendritic cells (Dendritic Cells, DCs), macrophages and other hematopoietic cells and some non-hematopoietic cells, such as endothelial cells, islet cells, mast cells and other membrane surfaces. Among them, PD-L1 is highly expressed in a variety of tumors, such as lung cancer...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D271/10C07D413/04A61P35/00A61P31/00
CPCC07D271/10C07D413/04A61P35/00A61P31/00C07B2200/07Y02P20/55
Inventor 赵立文张瑾陈程李阳王成
Owner NANJING SANHOME PHARMACEUTICAL CO LTD
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