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Novel intermediate of Iclaprim as well as preparation method and application thereof

A reactive and unsaturated technology, applied in organic chemistry, bulk chemical production, etc., can solve the problems of no cyclization of dehydroxylated protected substances, difficult control of dehydroxylated protection of palladium complexes, and impossibility of purification, so as to achieve easy control, Production cost reduction, cheap effect

Pending Publication Date: 2019-12-24
SHANGHAI DUDE MEDICAL SCI & TECH CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

And the final dehydroxylation protection and / or acid-catalyzed cyclization of the palladium complex is also difficult to control. There are a large number of dehydroxylation protections that do not undergo cyclization, and cannot be purified and entered into the next step.

Method used

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  • Novel intermediate of Iclaprim as well as preparation method and application thereof
  • Novel intermediate of Iclaprim as well as preparation method and application thereof
  • Novel intermediate of Iclaprim as well as preparation method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0042] Compound of formula III (R'=CH(CH 3 ) 2 , R=allyl) synthesis:

[0043] 3.5g formula II (R' = CH (CH 3 ) 2 , R=allyl) was suspended in 70ml of isopropanol, replaced with nitrogen, cooled to 0°C, and 2.38g of cerium chloride heptahydrate was added. 2.17g of sodium borohydride was dissolved in 14ml of N,N-dimethylformamide, and slowly added dropwise to the reaction solution. Keep stirring for 1 hour. After completion of the reaction, add 70ml of water and stir at room temperature for 0.5 hours, then extract with 70ml of ethyl acetate, wash the organic phase with 70ml of saturated brine, dry and filter over anhydrous magnesium sulfate, concentrate to obtain formula III (R'=CH(CH 3 ) 2 , R=allyl) compound, the crude raw material was directly used in the next reaction without purification.

[0044] [M+H] + =553, and the impurity that the double bond of α, β-unsaturated ketone was reduced was not detected by HPLC.

Embodiment 2

[0046] Compound of formula III (R'=CH(CH 3 ) 2 , R=allyl) synthesis:

[0047] 7g formula II (R' = CH (CH 3 ) 2 , R=allyl) was suspended in 140ml of ethanol, replaced with nitrogen, cooled to 0°C, and 4.76g of cerium chloride heptahydrate was added. 4.34 g of sodium borohydride was added to the reaction solution in batches. Keep stirring for 1 hour. After completion of the reaction, add 140ml of water and stir at room temperature for 0.5 hours, then extract with 140ml of ethyl acetate, wash the organic phase with 140ml of saturated brine, dry and filter over anhydrous magnesium sulfate, concentrate to obtain the formula III (R'=CH(CH 3 ) 2 , R=allyl) compound, the crude raw material was directly used in the next reaction without purification.

[0048] [M+H] + =553, and the impurity that the double bond of α, β-unsaturated ketone was reduced was not detected by HPLC.

Embodiment 3

[0050]Compound of formula III (R'=C(CH 3 ) 3 , R=allyl) synthesis:

[0051] 3.5g formula II (R' = C (CH 3 ) 3 , R=allyl) was suspended in 70ml of isopropanol, replaced with nitrogen, cooled to -5°C, and 2.26g of cerium chloride heptahydrate was added. 2.95g of potassium borohydride was dissolved in 12ml of N,N-dimethylformamide, and slowly added dropwise to the reaction solution. Keep stirring for 1 hour. After completion of the reaction, add 70ml of water and stir at room temperature for 0.5 hours, then extract with 70ml of ethyl acetate, wash the organic phase with 70ml of saturated brine, dry and filter over anhydrous magnesium sulfate, concentrate to obtain the formula III (R'=C(CH 3 ) 3 , R=allyl) compound, the crude raw material was directly used in the next reaction without purification.

[0052] [M+H] + =553, and the impurity that the double bond of α, β-unsaturated ketone was reduced was not detected by HPLC.

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Abstract

The invention provides a new intermediate compound (formula I) of a dihydrofolate reductase inhibitor Iclaprim. According to the method and the intermediate compound shown as the formula I, the initial raw materials are easy to obtain and low in price, each step of reaction in the whole reaction step route is easy to control, the generation of impurities can be reduced, the obtained intermediate is solid and does not need to be purified, the total yield is high, and the production cost is greatly reduced.

Description

technical field [0001] The present invention relates to the technical field of preparation method of dihydrofolate reductase inhibitor, ie compound Iclaprim of formula IV. Background technique [0002] Compounds of formula IV below have important antibacterial properties and are useful in the control or prevention of infectious diseases in mammals (human and non-human). In particular, it shows remarkable antibacterial activity even against multi-antibiotic Gram-positive strains and methicillin-resistant Staphylococcus aureus (MRSA). Typical combinations are, for example, sulfonamides or other enzyme inhibitors involved in folic acid biosynthesis, such as pteridine derivatives. The compound can also be co-administered with known antibacterial active substances, and exhibits synergistic effects on some of them. [0003] [0004] Patent US5773446A describes the synthesis of the intermediate compound II of the following formula with expensive starting materials, and the fin...

Claims

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Application Information

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IPC IPC(8): C07D239/49C07D405/06
CPCC07D239/49C07D405/06Y02P20/55
Inventor 崔伟袁哲东魏艳
Owner SHANGHAI DUDE MEDICAL SCI & TECH CO LTD
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