Synthetic method of nitrogen-containing heterocyclic compound and intermediate thereof

A synthetic method and compound technology, applied in organic chemistry, bulk chemical production, etc., can solve the problems of lengthy synthetic method routes, unfavorable industrial scale-up production, high cost of raw materials and equipment, etc.

Pending Publication Date: 2022-05-31
上海陶术生物科技有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0006] The synthesis method has a lengthy route, and uses a nationally regulated highly toxic drug (methyl chloroformate). At the same time, reactions with potential safety hazards such as catalytic hydrogenation are required. The cost of raw materials and equipment is high, which is not conducive to industrial scale-up production.

Method used

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  • Synthetic method of nitrogen-containing heterocyclic compound and intermediate thereof
  • Synthetic method of nitrogen-containing heterocyclic compound and intermediate thereof
  • Synthetic method of nitrogen-containing heterocyclic compound and intermediate thereof

Examples

Experimental program
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Effect test

preparation example Construction

[0060] The present invention provides a method for synthesizing intermediates of nitrogen-containing heterocyclic compounds, comprising the steps of:

[0061] carrying out photochemical reaction of compound 1 and compound 2 to prepare the intermediate;

[0062] The structure of the compound 1 is as follows:

[0063]

[0064] The structure of the compound 2 is as follows:

[0065]

[0066] The structure of the intermediate is shown below:

[0067]

[0068] Among them, Y 1 , Y 2 , Y 3 , Y 4 , Y 5 Each independently is CH 2 or NR, and at least one is NR; R represents a protecting group;

[0069] x 1 、X 2 each independently is a halogen;

[0070] Ar is C6~C10 aryl or C5~C10 heteroaryl;

[0071] R 1 , R 2 each independently hydrogen, halogen, cyano, hydroxyl, C1-C6 alkoxy or -S(O) 2 R 3 , R 3 It is a C1-C6 alkyl group.

[0072] In one specific example, the light source used for the photochemical reaction is an 8W-12W blue light. Specifically, the power o...

Embodiment 1

[0120] The synthesis of embodiment one compound 3A

[0121]

[0122]Under nitrogen protection, 3-bromopiperidine-1-carboxylic acid tert-butyl ester (compound 1A) (896mg, 3.40mmol, 1.3eq), 4-bromochlorobenzene (compound 2A) (500mg, 2.61mmol, 1.00eq), [4,4′-bis(1,1-dimethylethyl)-2,2′-bipyridineN1,N1]bis[3,5-difluoro-2-[5-(trifluoromethyl) -2-pyridyl N]phenyl-C]iridium(III) hexafluorophosphate (29.3mg, 0.01eq), [4,4′-bis(1,1-dimethylethyl)-2,2′ - bipyridine N1, N1] nickel(II) chloride (15.6mg, 0.015eq), tris(trimethylsilyl) silane (650mg, 1.00eq), sodium carbonate (554mg, 2.00eq) and 26ml of Ethylene glycol dimethyl ether was added into a 40 ml reaction bottle, irradiated with a 10W blue LED light at a distance of 3 cm from the reaction bottle, and the mixture was stirred and reacted at 25° C. for 14 hours. After the reaction was monitored by LCMS, the mixture was filtered, and the filtrate was concentrated to obtain a crude product. The crude product was separated by prep...

Embodiment 2

[0126] The synthesis of embodiment two compound A1

[0127]

[0128] A mixture of compound 3A (20.0mg, 67.6μmol, 1.00eq) and hydrochloric acid / ethyl acetate (4M, 1mL) was stirred at 15°C for 2 hours. After the reaction was monitored by LCMS, the reaction solution was concentrated to obtain Compound A1 (15 mg, 64.3 μmol, 99.5% purity, 95.1% yield) as a white solid.

[0129] 1 H NMR: (400MHz, DMSO-d 6 )δ9.08(br s,1H),7.41(d,J=8.4Hz,2H),7.32(d,J=8.4Hz,2H),,3.30-3.25(m,3H),3.03-2.98(m ,2H), 2.89-2.83(m,1H),1.88-1.65(m,4H).

[0130] LC-MS: (M+H) + :196.2.

[0131] HPLC: 99.5% purity (220nm, Rt=2.306min).

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Abstract

The invention relates to a nitrogen-containing heterocyclic ring compound and an intermediate synthesis method thereof. The synthesis method of the intermediate comprises the following step: carrying out photochemical reaction on a compound 1 and a compound 2 to prepare the intermediate. The synthesis method is short in route, safe to operate, low in cost and convenient for industrial large-scale production.

Description

technical field [0001] The invention relates to the technical field of organic synthesis, in particular to a synthesis method of nitrogen-containing heterocyclic compounds and intermediates thereof. Background technique [0002] Nitrogen-containing heterocyclic compounds have a very important research status in the field of medicinal chemistry technology. On the one hand, nitrogen-containing heterocyclic compounds are easy to undergo structural modification and facilitate the introduction of various functional groups, so nitrogen-containing heterocyclic compounds have played an important role in drug design in the past few decades. On the other hand, many drug lead molecules contain nitrogen-containing heterocyclic compound structures, and some nitrogen-containing heterocyclic compounds have been found to have certain biological activities, such as anticancer, antioxidation, antibacterial, antiviral, antifungal, Anti-inflammatory, etc., can be used as an important synthetic...

Claims

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Application Information

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IPC IPC(8): C07D211/18C07D211/22C07D211/24
CPCC07D211/18C07D211/22C07D211/24Y02P20/55
Inventor 段震王艾唐小伍杨小平
Owner 上海陶术生物科技有限公司
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