CN104628651B - Morpholine nitre azoles isomers and preparation method thereof - Google Patents

Morpholine nitre azoles isomers and preparation method thereof Download PDF

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Publication number
CN104628651B
CN104628651B CN201310546188.5A CN201310546188A CN104628651B CN 104628651 B CN104628651 B CN 104628651B CN 201310546188 A CN201310546188 A CN 201310546188A CN 104628651 B CN104628651 B CN 104628651B
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preparation
nitre azoles
isomers
reaction
morpholine nitre
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CN104628651A (en
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朱强
冯芮茂
余俊
杨宝海
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Jiangsu Hansoh Pharmaceutical Group Co Ltd
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Jiangsu Hansoh Pharmaceutical Group Co Ltd
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
    • C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
    • C07D233/66—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D233/91—Nitro radicals
    • C07D233/92—Nitro radicals attached in position 4 or 5
    • C07D233/95—Nitro radicals attached in position 4 or 5 with hydrocarbon radicals, substituted by nitrogen atoms, attached to other ring members

Abstract

The present invention relates to morpholine nitre azoles isomers and preparation method thereof.Specifically, the present invention relates to one kind such as formulas（I）Shown in antibacterials morpholine nitre azoles（1 [3 (4 morpholinyl) 2 hydroxypropyls] 2 methyl, 5 nitro 1H imidazoles）Isomer, entitled 3 (2 methyl, 5 nitro 1H imidazoles, 1 base) the 2 morpholinyl propyl alcohol of chemistry and its synthetic method, this method by the chlorination of morpholine nitre azoles, rearrangement, hydrolysis by obtaining target compound.

Description

Morpholine nitre azoles isomers and preparation method thereof
Technical field
The present invention relates to a kind of 3- (2- methyl-5-nitro -1H- imidazoles -1- bases) -2- morpholinyls propyl alcohol and its preparation sides Method, the compound are the isomers of morpholine nitre azoles.
Background technology
The nitro glyoxaline antibacterials sold on the market mainly have metronidazole, Ornidazole, secnidazole etc., especially For metronidazole as fungicide, anaerobe resistant spectrum is wide, highly sensitive to bacteroides fragilis, Eubacterium, C.perfringens, offsets Change coccus, peptostreptococcus, production melanocyte Prey viable bacteria medium sensitivity, it is poor to no gemma gram-positive bacillus sensibility.Morpholine Nitre azoles is the antibacterials of our company's independent research, and the imidazoles antibacterials in the cities morpholine Xiao Zuobi have better anti-anaerobism Bacterium, anti-trichomonal, anti-Amoeba characteristic, and be highly safe.
In the synthesis technology of morpholine nitre azoles, it is possible to create the isomer of morpholine nitre azoles, but due to reacting itself Limitation, morpholine nitre azoles isomers is difficult isolated.Morpholine nitre azoles isomers needs just obtain by special reaction, but It is the method for not yet finding that required isomers can be obtained efficient, high-qualityly at present.
Invention content
The purpose of the present invention is to provide one kind such as formulas（I）Shown in morpholine nitre azoles isomers.
Another object of the present invention is to provide one kind such as formula（I）Shown in morpholine nitre azoles isomers 3- (2- methyl- 5- nitro -1H- imidazoles -1- bases) -2- morpholinyl propyl alcohol preparation method, the preparation method is by formula（II）Morpholine nitre azoles warp Target product morpholine nitre azoles isomers is obtained after chlorination, rearrangement, hydrolysis.
Preferably, the preparation method specifically comprises the following steps：
1）Chlorination：Morpholine nitre azoles is dissolved in dichloromethane, triphenylphosphine is added, 20-35 DEG C of reaction of temperature control is added halogenated Reagent reacts 4h, and reaction is finished, is concentrated to dryness, and column chromatography purifying removes triphenylphosphine oxide and is concentrated to give after eluent To compound（III）；
2）It resets, hydrolysis：By formula（III）Compound be dissolved in organic solvent, be added alkali, tetrabutylammonium iodide, reflux Reaction, reaction finish, and filter, and filtrate is concentrated to dryness, and target product is obtained after preparing column purification.
Preferably, the step 1）In halogenating agent be selected from copper chloride, carbon tetrachloride, NCS, more preferable carbon tetrachloride.
Preferably, the step 1）Middle temperature control is 22-26 DEG C.
Preferably, the step 2）In hydrolysis halogeno-group alkali be selected from anhydrous sodium acetate, sodium tert-butoxide, potassium carbonate, more It is preferred that anhydrous sodium acetate.
Preferably, the step 2）In organic solvent be selected from methanol, ethyl alcohol, dichloromethane, more preferable ethyl alcohol.
Preferably, the step 1）In eluant, eluent be selected from CH2Cl2~CH3OH, more preferable 100:1 CH2Cl2-CH3OH ~CH3OH。
Particularly preferred reaction process is as follows：
Compound of formula I is a kind of isomers of morpholine nitre azoles, and at present without No. CAS, there has been no the prior arts to disclose newization Close object and preparation and the separation method of the compound.The present invention not only obtains the isomers first, and determining can be high Effect, high-quality production, the separating technology for obtaining required isomers, play an important role for pharmaceutical production from now on and quality control.
Description of the drawings
Fig. 1 is the chromatograms of 3- (2- methyl-5-nitro -1H- imidazoles -1- bases) -2- morpholinyl propyl alcohol；
Fig. 2 is the chromatograms of 3- (2- methyl-5-nitro -1H- imidazoles -1- bases) -2- morpholinyls propyl alcohol and morpholine nitre azoles Compare.
Specific implementation mode
Embodiment 1：
By morpholine nitre azoles（2.7g）It is dissolved in dichloromethane（50ml）In, triphenylphosphine is added（2.6g）, 25 DEG C or so of temperature control, NCS is added portionwise（1.3g）, 25 DEG C of reaction 4h.Reaction finishes, and is concentrated to dryness, flash column chromatography, eluant, eluent：CH2Cl2- CH3OH（100:1）~CH3OH collects qualified component, is concentrated to give compound III, 0.5g, yield 17.4%.
Through structural identification, products therefrom is same as Example 6.
Embodiment 2：
By morpholine nitre azoles（2.7g）It is dissolved in dichloromethane（50ml）In, triphenylphosphine is added（2.6g）, 25 DEG C or so of temperature control, Copper chloride is added portionwise（1.4g）, 25 DEG C of reaction 4h.Reaction finishes, and is concentrated to dryness, flash column chromatography, eluant, eluent: CH2Cl2-CH3OH（100:1）~CH3OH collects qualified component, is concentrated to give compound III, 0.8g, yield 27.4%.
Through structural identification, products therefrom is same as Example 6.
Embodiment 3：
By morpholine nitre azoles（2.7g）It is dissolved in dichloromethane（50ml）In, triphenylphosphine is added（2.6g）, 25 DEG C or so of temperature control, Carbon tetrachloride is added dropwise（1.5g）, it is added dropwise, 25 DEG C of reaction 4h.Reaction finishes, and is concentrated to dryness, column chromatography purifying, eluant, eluent: CH2Cl2-CH3OH（100:1）~CH3OH collects qualified component, is concentrated to give compound III, 1.8g, yield 62.5%.
Through structural identification, products therefrom is same as Example 6.
Embodiment 4：
By compound III（1.8g）It is dissolved in dichloromethane（20ml）, anhydrous sodium acetate is added（1g）, tetrabutylammonium iodide （0.1g）, back flow reaction is for 24 hours.Reaction finishes, and filtering, filtrate is concentrated to dryness, and prepares column purification and obtains morpholine nitre azoles isomers 0.4g, yield 23.7%.
Through structural identification, products therefrom is same as Example 6.
Embodiment 5：
By compound III（1.8g）It is dissolved in ethyl alcohol（20ml）, potassium carbonate is added（1g）, tetrabutylammonium iodide（0.1g）, return Stream reaction is for 24 hours.Reaction finishes, and filtering, filtrate is concentrated to dryness, and prepares column purification and obtains morpholine nitre azoles isomers 0.1g, yield 5.9%。
Through structural identification, products therefrom is same as Example 6.
Embodiment 6：
By compound III（1.8g）It is dissolved in ethyl alcohol（20ml）, anhydrous sodium acetate is added（1g）, tetrabutylammonium iodide （0.1g）, back flow reaction is for 24 hours.Reaction finishes, and filtering, filtrate is concentrated to dryness, and prepares column purification and obtains morpholine nitre azoles isomers 0.8g, yield 47.5%.
（a、ESI=271.10；b、1H-NMR（d6-DMSO）δ：2.312-2.362（2H, m）, 2.449（3H, s）, 2.574- 2.608（1H, m）, 2.710-2.761（2H, m）, 3.384-3.397（4H, m）, 3.509-3.550（1H, m）, 3.604-3.644 （1H, m）, 4.209-4.254（1H, m）, 4.406-4.466 (1H, m), 4.774-4.798（1H, t）, 7.971（1H, s）.）
Preparation condition：
Prepare column：Phenomenexe luna C1810μ100A250×250nm；
Mobile phase（Mp）:
A：0.01mol KH2PO4PH=7.0,
B：Acetonitrile；
λ=319nm；
Flow velocity:100ml/min；
Gradient：0′（10%）~20 '（31%）~21 '（70%）~25 '（70%）~26 '（10%）~30 '（10%）.

Claims (9)

  1. One kind 1. the morpholine nitre azoles isomers 3- as shown in formula (I) (2- methyl-5-nitro -1H- imidazoles -1- bases) -2- morpholinyls The preparation method of propyl alcohol, the preparation method are reset through chlorination by the morpholine nitre azoles of formula (II), obtain target product after hydrolysis Quinoline nitre azoles isomers,
  2. 2. preparation method according to claim 1, specifically comprises the following steps：
    1) chlorination, rearrangement：Morpholine nitre azoles is dissolved in dichloromethane, triphenylphosphine is added, halogen is added in 20-35 DEG C of reaction of temperature control For reagent, 4h is reacted, reaction is finished, is concentrated to dryness, and column chromatography purifying removes triphenylphosphine oxide, after eluent, concentration Obtain compound (III)；
    2) it hydrolyzes：The compound of formula (III) is dissolved in organic solvent, alkali, tetrabutylammonium iodide, back flow reaction, reaction is added It finishes, filters, filtrate is concentrated to dryness, and target product is obtained after preparing column purification.
  3. 3. preparation method according to claim 2, which is characterized in that the halogenating agent in the step 1) is selected from chlorination Copper, carbon tetrachloride or NCS.
  4. 4. preparation method according to claim 2, which is characterized in that the halogenating agent in the step 1) is selected from four chlorinations Carbon.
  5. 5. preparation method according to claim 2, which is characterized in that temperature control is 22-26 DEG C in the step 1).
  6. 6. preparation method according to claim 2, which is characterized in that alkali in the step 2) be selected from anhydrous sodium acetate, Sodium tert-butoxide or potassium carbonate.
  7. 7. preparation method according to claim 2, which is characterized in that the alkali in the step 2) is selected from anhydrous sodium acetate.
  8. 8. preparation method according to claim 2, which is characterized in that organic solvent in the step 2) be selected from methanol, Ethyl alcohol or dichloromethane.
  9. 9. preparation method according to claim 2, which is characterized in that the organic solvent in the step 2) is selected from ethyl alcohol.
CN201310546188.5A 2013-11-06 2013-11-06 Morpholine nitre azoles isomers and preparation method thereof Active CN104628651B (en)

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CN111973569A (en) * 2019-05-21 2020-11-24 江苏豪森药业集团有限公司 Pharmaceutical composition containing nitroimidazole derivatives and preparation method thereof

Citations (4)

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Publication number Priority date Publication date Assignee Title
WO2006058457A1 (en) * 2004-11-30 2006-06-08 Lianyungang Hengbang Pharmaceutical Co. Ltd. α-SUBSTITUTED 2-METHYL-5-NITROIMIDAZOL-1-ETHANOL DERIVATIVES
CN1810815A (en) * 2006-03-08 2006-08-02 西安新安医药科技有限公司 Nitroimidazole derivative for treatment
CN1981764A (en) * 2005-12-13 2007-06-20 江苏豪森药业股份有限公司 Usage of alpha-(Morpholin-1-base) methyl-2-methyl-5-azathio-1-alcohol in preparation of anti-trichomoniasis and anti-ameba medicines
CN104829541A (en) * 2015-05-05 2015-08-12 江苏豪森药业股份有限公司 High selectivity and high purity method for preparing morinidazole

Patent Citations (4)

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Publication number Priority date Publication date Assignee Title
WO2006058457A1 (en) * 2004-11-30 2006-06-08 Lianyungang Hengbang Pharmaceutical Co. Ltd. α-SUBSTITUTED 2-METHYL-5-NITROIMIDAZOL-1-ETHANOL DERIVATIVES
CN1981764A (en) * 2005-12-13 2007-06-20 江苏豪森药业股份有限公司 Usage of alpha-(Morpholin-1-base) methyl-2-methyl-5-azathio-1-alcohol in preparation of anti-trichomoniasis and anti-ameba medicines
CN1810815A (en) * 2006-03-08 2006-08-02 西安新安医药科技有限公司 Nitroimidazole derivative for treatment
CN104829541A (en) * 2015-05-05 2015-08-12 江苏豪森药业股份有限公司 High selectivity and high purity method for preparing morinidazole

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