CN106632393A - Preparation method for antituberculous candidate drug namely PA-824 - Google Patents
Preparation method for antituberculous candidate drug namely PA-824 Download PDFInfo
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D498/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
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Abstract
The invention relates to a synthetic method for an antituberculous candidate drug namely PA-824. The method realizes synthesis of the PA-824 through four steps of reactions which comprise a nucleophilic ring-opening reaction, an o-alkylation reaction, an ester deprotection reaction and a transition metal catalyzed carbon-hydrogen bond activated alkoxylation reaction. The preparation method provided by the invention has the advantages of cheap and easily available raw materials needed in the whole preparation process, avoids using an explosive raw material namely 2,4-dinitroimidazole, has simple and easily controllable operation, is convenient to purify, and facilitates to large-scale production.
Description
Technical field
The invention belongs to medicinal chemistry art, and in particular to a kind of synthesis of nitroimidazopyran class compound PA-824,
The compound is treating tuberculosis drug candidate.
Background technology
PA-824 is a kind of nitroimidazopyran class compound, effective to sensitive and resistance tubercle bacillus, can be killed
In preclinical tubercle bacillus, and with the antituberculotic of a line without crossing drug resistant phenomenon.2002, global treating tuberculosis connection
Alliance (TB alliances) and US National allergy and Infectious Disease Research Institute reach an agreement, and grind PA-824 as Newer Antibuberculotics
Study carefully, completed II phase clinic (result is not yet announced) at present, while new as active component and MOXIFLOXACIN, pyrazinamide composition
Compound preparation-PaMZ, be also at for II phase at present clinical.
PA-824, light yellow crystalline powder, molecular formula is：C13H12N3O5F3, molecular weight is：359.26.1997,
First synthetic route of PA-824 has been invented by Pathogenesis companies, and synthetic line employs silicon protection group and substantial amounts of
The reagents such as tetrabutyl ammonium fluoride, price is high.2007, first step reaction of the Orita seminar to first route changed
Enter, from solvent-free reaction, yield is significantly improved, but the use of silicon protection group causes synthesis relatively costly and deprotection base cyclization
Reaction is relatively difficult.Palmer seminar in 2009 reports a more synthetic line of accessory substance, using few.2010
Five step synthetic routes of the Sorensen seminar with the chloro- 4- nitroimidazoles of 2- as raw material, the overall yield of route is not high.2010
Upper Haiyang sail company reports the synthetic thread with 2,4- Nitroimidazoles (compound need to pass through 3 steps and react preparation) as raw material
Road, and 2014 patent " synthetic method for the treatment of tuberculosis drug candidate PA-824 " (application number 201410372448.6) it is disclosed
Synthetic method, although the yield of synthetic route is significantly improved, but remain a need for use explosive raw material 2,4- Nitroimidazoles,
It is unfavorable for large-scale production.
The content of the invention
It is an object of the invention to provide a kind of synthetic method of nitroimidazopyran class treating tuberculosis drug candidate PA-824,
The synthetic method of existing PA-824 is improved, it is to avoid using explosive raw material 2,4- Nitroimidazoles, develop one
Simple, simple to operate, reactions steps are few, be easy to the new method of prepare with scale, realize PA-824's by four-step reaction
Synthesis.
The present invention's realizes that process is as follows：
A kind of synthetic method of nitroimidazopyran class treating tuberculosis drug candidate PA-824, comprises the steps：
(1) 4- nitroimidazoles carry out nucleophilic ring opening reaction and obtain compound 1 with (S)-(+)-Glycidyl Butyrate；
(2) compound 1 reacts with 4- trifluoromethoxies bromobenzyl, obtains compound 2；
(3) compound 2 takes off ester protection group and obtains compound 3；
(4) compound 3 carries out the reaction of intramolecular carbon-hydrogen bond activation alkoxide under the catalysis of transition metal, obtains PA-
824。
In above-mentioned steps (1), under nitrogen protection, in DMF (DMF), 4- nitroimidazoles and (S)-
(+)-Glycidyl Butyrate carries out nucleophilic ring opening reaction and obtains compound 1, and reaction temperature is 60～80 DEG C, and the reaction time is 48
～96h, 4- nitroimidazole is 1 with the mol ratio of (S)-(+)-Glycidyl Butyrate consumption: (1～2).
In above-mentioned steps (2), under nitrogen protection, compound 1 and 4- trifluoros are added in DMF (DMF)
Methoxyl group bromobenzyl, then adds sodium hydride NaH under the conditions of -10～0 DEG C, and 20～25 DEG C are warming up to after adding, and reaction 3h is obtained
Compound 2, compound 1 is 1 with the mol ratio of 4- trifluoromethoxy bromobenzyls, NaH consumptions: (1～2): 1.
In above-mentioned steps (3), compound 2 carries out ester hydrolysis reaction in the presence of potassium carbonate and obtains compound 3, reacts molten
Agent is methyl alcohol, and reaction temperature is 20～25 DEG C, and the reaction time is 2h, and compound 2 is 1 with the mol ratio of potassium carbonate: (2～4).
In above-mentioned steps (4), in toluene, compound 3 is in the presence of CuCl catalysis and di-t-butyl peroxide oxidation
Reaction obtains final product PA-824, and reaction temperature is 80～100 DEG C, and the reaction time is 8～12h, compound 3 and peroxidating two
The tert-butyl group, the mol ratio of CuCl consumptions are 1: (2～4): (0.05～0.5).
Advantages of the present invention：Imidazoles pyran treating tuberculosis drug candidate PA-824 is prepared by raw material of 4- nitroimidazoles, it is former
Material is easy to get, it is to avoid using explosive raw material, and process route easy to control, purifying simple to operate facilitates, is easy to prepare with scale.
Specific embodiment
Embodiments of the invention are elaborated below：The present embodiment is carried out under premised on technical solution of the present invention
Implement, give embodiment in detail and process, but protection scope of the present invention is not limited to following embodiments.
Embodiment 1：
A kind of synthetic method of nitroimidazopyran class treating tuberculosis drug candidate PA-824, its step is as follows：
(1) in DMF, mol ratio is that 1: 1.2 4- nitroimidazoles and (S)-(+)-Glycidyl Butyrate carry out nucleophilic
Ring-opening reaction obtains compound 1：
Under nitrogen protection, by 76.5g (0.531mol) (S)-(+)-Glycidyl Butyrate and 400mL N, N- dimethyl
Formamide (DMF) is added in 1000mL three-necked bottles, adds 50.0g (0.442mol) pressed powder 4- nitroimidazoles, and mixing is equal
70 DEG C of reaction 72h are warming up to after even, TLC detection raw material points disappear, reactant liquor is poured in 20 DEG C of water of 400mL, and water layer is used
600mL ethyl acetate is extracted three times, merges organic phase, be washed once with saturated nacl aqueous solution, and anhydrous magnesium sulfate is dried, mistake
Filter, removal of solvent under reduced pressure obtains 88.7g with silica gel (200-300 mesh) column chromatography (ethyl acetate: petroleum ether=1: 1, volume ratio)
Pale yellowish oil compound 1, yield 78%.
(2) in DMF, compound 1 reacts with 4- trifluoromethoxies bromobenzyl under NaH effects, and mol ratio is 1: 1.2：1,
Obtain compound 2：
Under nitrogen protection, compound 1 (88.7g, 0.345mol) is dissolved in into 760mL DMFs (DMF)
In, 105.6g (0.414mol) 4- trifluoro-methoxyl bromobenzenes are added, 13.8g (0.345mol) hydrogen is dividedly in some parts after being cooled to 0 DEG C
Change sodium, 25 DEG C of reaction 3h are warming up to after adding, TLC detection raw material points disappear.Gone out reaction with 20 DEG C of water quenchings of 800mL, water layer is used
800mL ethyl acetate is extracted twice, and merges organic phase, washed once with saturated nacl aqueous solution, and anhydrous magnesium sulfate is dried, mistake
Filter, removal of solvent under reduced pressure is obtained with silica gel (200-300 mesh) column chromatography (ethyl acetate: petroleum ether=2: 3, volume ratio)
122.0g compounds 2, yield 82%.
(3) in CH3In OH, compound 2 K2CO3Ester hydrolysis reaction is carried out under effect, mol ratio is 1: 3, obtains chemical combination
Thing 3：
Compound 2 (122.0g, 0.283mol) is dissolved in 620mL methyl alcohol, 117.3g (0.848mol) potassium carbonate is added,
2h is reacted at 25 DEG C, TLC detection raw material points disappear.Filter, 80mL ethyl acetate rinse cake layers, filtrate decompression is obtained after removing
The crude product 92.0g of compound 3, without the need for purifying, directly carries out next step reaction.
(4) in toluene, mol ratio is that in the presence of 0.5: 3 CuCl and di-t-butyl peroxide, compound 3 occurs to divide
C-H bond alkoxide reaction in sub obtains final product PA-824：
Under room temperature, compound 3 (92.0g, 0.256mol), 12.6g (0.127mol) stannous chloride are added in reaction bulb
With 2100mL DMFs (DMF), addition 111.7g (0.768mol) peroxidating two in reaction system under stirring
The tert-butyl group (DBTP), reaction system is heated to 80 DEG C of confined reaction 12h.TLC detections show that raw material reaction is complete.Use 2000mL
20 DEG C of water quenchings are gone out reaction, and water layer is extracted three times with 900mL ethyl acetate, merge organic phase, and with saturated nacl aqueous solution one is washed
It is secondary, anhydrous magnesium sulfate be dried, filter, removal of solvent under reduced pressure, with silica gel (200-300 mesh) column chromatography (ethyl acetate: petroleum ether=
1: 1, volume ratio) obtain 75.9g light yellow solids, yield 83%.HPLC determines purity and is more than 99%, and chromatographic condition is --- color
Spectrum post：Diamonsil 5μm C18(2),250×4.6mm；Detection wavelength：321nm；Mobile phase：Acetonitrile:Water=30:70；Stream
Speed：1.0mL/min.m.p.:149～150 DEG C；1H NMR(400MHz,CDCl3):δ 4.13-4.26 (m, 3H), 4.37 (d, J=
11.2Hz, 1H), 4.60-4.67 (m, 2H), 4.73 (d, J=8.0Hz, 1H), 7.21 (d, J=7.6Hz, 2H), 7.38 (d, J=
8.4Hz,2H),7.43(s,1H)；13CNMR(100MHz,CDCl3):δ47.58,65.50,67.19,70.21,115.23,
119.10,121.60,129.12,135.19,143.63,147.08,149.13.HRMS(ESI)Calcd.for
C15H14F3N2O5(M++H):359.0855,Found:359.0893.
Embodiment 2
A kind of synthetic method of nitroimidazopyran class treating tuberculosis drug candidate PA-824, its step is as follows：
(1) in DMF, mol ratio is that 1: 1 4- nitroimidazoles and (S)-(+)-Glycidyl Butyrate carry out nucleophilic and open
Ring reaction obtains compound 1：
Under nitrogen protection, by 63.7g (0.442mol) (S)-(+)-Glycidyl Butyrate and 400mL N, N- dimethyl
Formamide (DMF) is added in 1000mL three-necked bottles, adds 50.0g (0.442mol) pressed powder 4- nitroimidazoles, and mixing is equal
80 DEG C of reaction 48h are warming up to after even, TLC detection raw material points disappear, reactant liquor is poured in 20 DEG C of water of 400mL, and water layer is used
600mL ethyl acetate is extracted three times, merges organic phase, be washed once with saturated nacl aqueous solution, and anhydrous magnesium sulfate is dried, mistake
Filter, removal of solvent under reduced pressure obtains 79.6g with silica gel (200-300 mesh) column chromatography (ethyl acetate: petroleum ether=1: 1, volume ratio)
Pale yellowish oil compound 1, yield 70%.
(2) in DMF, compound 1 reacts with 4- trifluoromethoxies bromobenzyl under NaH effects, and mol ratio is 1: 1.0: 1,
Obtain compound 2：
Under nitrogen protection, compound 1 (79.6g, 0.309mol) is dissolved in into 680mL DMFs (DMF)
In, 78.8g (0.309mol) 4- trifluoro-methoxyl bromobenzenes are added, 12.4g (0.309mol) hydrogenations are dividedly in some parts after being cooled to 0 DEG C
Sodium, is warming up to 20 DEG C of reaction 3h after adding, TLC detection raw material points disappear.Gone out reaction with 20 DEG C of water quenchings of 700mL, water layer is used
700mL ethyl acetate is extracted twice, and merges organic phase, washed once with saturated nacl aqueous solution, and anhydrous magnesium sulfate is dried, mistake
Filter, removal of solvent under reduced pressure is obtained with silica gel (200-300 mesh) column chromatography (ethyl acetate: petroleum ether=2: 3, volume ratio)
103.9g compounds 2, yield 78%.
(3) in CH3In OH, compound 2 is in K2CO3Ester hydrolysis reaction is carried out under effect, mol ratio is 1: 2, obtains compound
3：
Compound 2 (103.9g, 0.241mol) is dissolved in 520mL methyl alcohol, 66.6g (0.482mol) potassium carbonate is added,
22 DEG C of reaction 2h, TLC detection raw material point disappears.Filter, 80mL ethyl acetate rinse cake layers, filtrate decompression is changed after removing
The crude product 78.3g of compound 3, without the need for purifying, directly carries out next step reaction.
(4) in toluene, mol ratio is that in the presence of 0.1: 2 CuCl and di-t-butyl peroxide, compound 3 occurs to divide
C-H bond alkoxide reaction in sub obtains final product PA-824：
Under room temperature, compound 3 (78.3g, 0.217mol), 2.1g (0.0217mol) stannous chloride are added in reaction bulb
With 1700mL DMFs (DMF), addition 63.4g (0.433mol) peroxidating two in reaction system under stirring
The tert-butyl group (DBTP), reaction system is heated to 90 DEG C of confined reaction 10h.TLC detections show that raw material reaction is complete.Use 1500mL
20 DEG C of water quenchings are gone out reaction, and water layer is extracted three times with 800mL ethyl acetate, merge organic phase, and with saturated nacl aqueous solution one is washed
It is secondary, anhydrous magnesium sulfate be dried, filter, removal of solvent under reduced pressure, with silica gel (200-300 mesh) column chromatography (ethyl acetate: petroleum ether=
1: 1, volume ratio) obtain 61.5g light yellow solids, yield 79%.HPLC determines purity and is more than 99%, and chromatographic condition is --- color
Spectrum post：Diamonsil 5μm C18(2),250×4.6mm；Detection wavelength：321nm；Mobile phase：Acetonitrile:Water=30:70；Stream
Speed：1.0mL/min.m.p.:149～150 DEG C.
Embodiment 3
A kind of synthetic method of nitroimidazopyran class treating tuberculosis drug candidate PA-824, its step is as follows：
(1) in DMF, mol ratio is that 1: 2 4- nitroimidazoles and (S)-(+)-Glycidyl Butyrate carry out nucleophilic and open
Ring reaction obtains compound 1：
Under nitrogen protection, by 127.4g (0.884mol) (S)-(+)-Glycidyl Butyrate and 400mL N, N- dimethyl
Formamide (DMF) is added in 1000mL three-necked bottles, adds 50.0g (0.442mol) pressed powder 4- nitroimidazoles, and mixing is equal
60 DEG C of reaction 96h are warming up to after even, TLC detection raw material points disappear, reactant liquor is poured in 20 DEG C of water of 400mL, and water layer is used
600mL ethyl acetate is extracted three times, merges organic phase, be washed once with saturated nacl aqueous solution, and anhydrous magnesium sulfate is dried, mistake
Filter, removal of solvent under reduced pressure obtains 92.1g with silica gel (200-300 mesh) column chromatography (ethyl acetate: petroleum ether=1: 1, volume ratio)
Pale yellowish oil compound 1, yield 81%.
(2) in DMF, compound 1 reacts with 4- trifluoromethoxies bromobenzyl under NaH effects, and mol ratio is 1: 2.0: 1,
Obtain compound 2：
Under nitrogen protection, compound 1 (92.1g, 0.358mol) is dissolved in into 960mL DMFs (DMF)
In, 182.6g (0.716mol) 4- trifluoro-methoxyl bromobenzenes are added, 14.3g (0.358mol) is dividedly in some parts after being cooled to -10 DEG C
Sodium hydride, is warming up to 25 DEG C of reaction 3h after adding, TLC detection raw material points disappear.Gone out reaction with 20 DEG C of water quenchings of 900mL, water layer
It is extracted twice with 900mL ethyl acetate, merges organic phase, be washed once with saturated nacl aqueous solution, anhydrous magnesium sulfate is dried, mistake
Filter, removal of solvent under reduced pressure is obtained with silica gel (200-300 mesh) column chromatography (ethyl acetate: petroleum ether=2: 3, volume ratio)
129.7g compounds 2, yield 84%.
(3) in CH3In OH, compound 2 is in K2CO3Ester hydrolysis reaction is carried out under effect, mol ratio is 1: 4, obtains compound
3：
Compound 2 (129.7g, 0.300mol) is dissolved in 620mL methyl alcohol, 166.2g (1.20mol) potassium carbonate is added,
20 DEG C of reaction 2h, TLC detection raw material point disappears.Filter, 80mL ethyl acetate rinse cake layers, filtrate decompression is changed after removing
The crude product 95.3g of compound 3, without the need for purifying, directly carries out next step reaction.
(4) in toluene, mol ratio is that in the presence of 0.05: 4 CuCl and di-t-butyl peroxide, compound 3 occurs
The reaction of intramolecular C-H bond alkoxide obtains final product PA-824：
Under room temperature, compound 3 (95.3g, 0.264mol), 1.31g (0.0132mol) stannous chloride are added in reaction bulb
With 2100mL DMFs (DMF), addition 154.4g (1.056mol) peroxidating two in reaction system under stirring
The tert-butyl group (DBTP), reaction system is heated to 100 DEG C of confined reaction 8h.TLC detections show that raw material reaction is complete.Use 2000mL
20 DEG C of water quenchings are gone out reaction, and water layer is extracted three times with 900mL ethyl acetate, merge organic phase, and with saturated nacl aqueous solution one is washed
It is secondary, anhydrous magnesium sulfate be dried, filter, removal of solvent under reduced pressure, with silica gel (200-300 mesh) column chromatography (ethyl acetate: petroleum ether=
1: 1, volume ratio) obtain 75.8g light yellow solids, yield 80%.HPLC determines purity and is more than 99%, and chromatographic condition is --- color
Spectrum post：Diamonsil 5μm C18(2),250×4.6mm；Detection wavelength：321nm；Mobile phase：Acetonitrile:Water=30:70；Stream
Speed：1.0mL/min.m.p.:149～150 DEG C.
Claims (5)
1. a kind of synthetic method of nitroimidazopyran class treating tuberculosis drug candidate PA-824, it is characterised in that including following step
Suddenly：
(1) 4- nitroimidazoles carry out necleophilic reaction with (S)-(+)-Glycidyl Butyrate, obtain compound 1；
(2) compound 1 reacts with 4- trifluoromethoxies bromobenzyl, obtains compound 2；
(3) compound 2 takes off ester protection group and obtains compound 3；
(4) compound 3 carries out the reaction of intramolecular carbon-hydrogen bond activation alkoxide under the catalysis of transition metal, obtains PA-824.
2. the synthetic method of nitroimidazopyran class treating tuberculosis drug candidate PA-824 according to claim 1, its feature
It is：In step (1), under nitrogen protection, add 4- nitroimidazoles and (S)-(+)-shrink sweet in DMF
Oily butyrate carries out necleophilic reaction and obtains compound 1, and reaction temperature is 60～80 DEG C, and the reaction time is 48～96h, 4- nitro miaows
Azoles is 1 with the mol ratio of (S)-(+)-Glycidyl Butyrate consumption: (1～2).
3. the synthetic method of nitroimidazopyran class treating tuberculosis drug candidate PA-824 according to claim 1, its feature
It is：In step (2), under nitrogen protection, compound 1 and 4- trifluoromethoxy bromobenzyls are added in DMF,
Then sodium hydride is added under the conditions of -10～0 DEG C, 20～25 DEG C is warming up to after adding, reaction 3h obtains compound 2, compound 1
It is 1 with the mol ratio of 4- trifluoromethoxy bromobenzyls, NaH consumptions: (1～2): 1.
4. the synthetic method of nitroimidazopyran class treating tuberculosis drug candidate PA-824 according to claim 1, its feature
It is：In step (3), compound 2 carries out ester hydrolysis reaction in the presence of potassium carbonate and obtains compound 3, and reaction dissolvent is first
Alcohol, reaction temperature is 20～25 DEG C, and the reaction time is 2h, and compound 2 is 1 with the mol ratio of potassium carbonate: (2～4).
5. the synthetic method of nitroimidazopyran class treating tuberculosis drug candidate PA-824 according to claim 1, its feature
It is：In step (4), in toluene, compound 3 reacts in the presence of CuCl catalysis and di-t-butyl peroxide oxidation and obtains
Final product PA-824, reaction temperature is 80～100 DEG C, and the reaction time is 8～12h, compound 3 and di-t-butyl peroxide,
The mol ratio of CuCl consumptions is 1: (2～4): (0.05～0.5).
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN113717197A (en) * | 2021-10-13 | 2021-11-30 | 沈阳红旗制药有限公司 | Preparation method and application of antituberculosis drug Pretomanid |
| CN115385930A (en) * | 2022-08-19 | 2022-11-25 | 药璞(上海)医药科技有限公司 | Preparation method of Primanib |
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| CN104177372A (en) * | 2014-07-31 | 2014-12-03 | 中国人民解放军第四军医大学 | Synthetic method of anti-tuberculosis candidate drug PA-824 |
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Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN113717197A (en) * | 2021-10-13 | 2021-11-30 | 沈阳红旗制药有限公司 | Preparation method and application of antituberculosis drug Pretomanid |
| CN113717197B (en) * | 2021-10-13 | 2023-09-12 | 沈阳红旗制药有限公司 | Preparation method and application of antituberculosis drug Pretomoid |
| CN115385930A (en) * | 2022-08-19 | 2022-11-25 | 药璞(上海)医药科技有限公司 | Preparation method of Primanib |
| CN115385930B (en) * | 2022-08-19 | 2024-04-05 | 药璞(上海)医药科技有限公司 | Preparation method of primani |
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