CN104177372A - Synthetic method of anti-tuberculosis candidate drug PA-824 - Google Patents

Synthetic method of anti-tuberculosis candidate drug PA-824 Download PDF

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Publication number
CN104177372A
CN104177372A CN201410372448.6A CN201410372448A CN104177372A CN 104177372 A CN104177372 A CN 104177372A CN 201410372448 A CN201410372448 A CN 201410372448A CN 104177372 A CN104177372 A CN 104177372A
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compound
reaction
synthetic method
temperature
mol ratio
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刘雪英
王力彬
弥乐
陈卫平
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Fourth Military Medical University FMMU
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Fourth Military Medical University FMMU
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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
    • C07D498/04—Ortho-condensed systems

Abstract

The invention relates to a synthetic method of an anti-tuberculosis candidate drug PA-824. The method involves an eight-step reaction and comprises the following steps: firstly obtaining a key intermediate compound 8 and then reacting with 4-trifluoromethoxy benzyl bromide to obtain the final product PA-824. The entire reaction has the advantages of easily available raw materials, simplicity in operation, convenience in purification and easiness in scale production. The compound 8 is as shown in the specification.

Description

The synthetic method of tuberculosis drug candidate PA-824
Technical field
The present invention relates to the synthetic method of tuberculosis drug candidate PA-824, belong to pharmaceutical chemistry field.
Background technology
PA-824 is a kind of nitroimidazopyran compounds, to responsive and resistance tubercule bacillus is effective, can kill and be in preclinical tubercule bacillus, and with the antitubercular agent of a line without crossing drug resistant phenomenon.2002, whole world tuberculosis alliance (TB alliance) and the state-run allergy of the U.S. and transmissible disease institute reach an agreement, PA-824 is studied as Newer Antibuberculotics, now entered the II phase clinical, it forms new compound preparation-PaMZ as active ingredient and Moxifloxacin, pyrazinoic acid amide simultaneously, also clinical in the II phase at present.
PA-824, light yellow crystalline powder, molecular formula is: C 13h 12n 3o 5f 3, molecular weight is: 359.PA-824 is synthesized by Pathogenesis company, has adopted silicon protecting group and a large amount of reagent such as tetrabutyl ammonium fluoride in its synthetic route, and price is high.
Summary of the invention
The object of the invention is the synthetic method of existing PA-824 to improve, and avoids low-temp reaction, develop one simple, simple to operate, be easy to novel method prepared by mass-producing.
Implementation procedure of the present invention is as follows:
The synthetic method of nitroimidazopyran class tuberculosis drug candidate PA-824, comprises the steps:
(1) compound 1 nitration obtains compound 2;
(2) compound 2 again nitration obtain compound 3;
(3), in chlorobenzene, compound 3 carries out thermal rearrangement and obtains compound 4;
(4) compound 4 and ( s)-(+)-Glycidyl Butyrate carries out nucleophilic ring opening reaction and obtains compound 5;
(5) at CH 2cl 2in, compound 5 and 3,4-dihydropyrane are protected hydroxyl under catalyst P PTS effect, obtain compound 6;
(6) compound 6 carries out nucleophilic ring closure reaction in ester hydrolysis and molecule, obtains compound 7;
(7) compound 7 deprotections obtain compound 8;
(8) compound 8 reacts with equimolar amount 4-trifluoromethoxy bromobenzyl, obtains final product PA-824.
In above-mentioned steps (1), at dense H 2sO 4in, compound 1 and dense HNO 3carry out nitration and obtain compound 2, temperature of reaction is 100 ~ 125 ℃, and the reaction times is 6 ~ 8h, compound 1, dense H 2sO 4with dense HNO 3the mol ratio of consumption is 1:2:4.
In above-mentioned steps (2), in acetic acid and diacetyl oxide, compound 2 reacts with nitrosonitric acid and carries out nitration again and obtain compound 3, and temperature of reaction is 20 ~ 50 ℃, and the reaction times is 2 ~ 6h, compound 2, acetic acid, acetic anhydride, nitrosonitric acid consumption mol ratio be 1:3:4:2.
In above-mentioned steps (3), temperature of reaction is 100-120 ℃, and the reaction times is 10 ~ 12h.
In above-mentioned steps (4), described reaction is solvent-free, and temperature of reaction is 30 ~ 60 ℃, and the reaction times is 2 ~ 3d, compound 4, ( s)-(+) mol ratio of-Glycidyl Butyrate consumption is 1:1.1 ~ 1.5.
In above-mentioned steps (5), temperature of reaction is 10 ~ 40 ℃, and the reaction times is 15 ~ 20h, compound 5with the mol ratio of DHP, PPTS consumption be 3:6 ~ 9:1.
In above-mentioned steps (6), at CH 3in OH, compound 6 is at the K of equimolar amount 2cO 3under effect, carry out nucleophilic ring closure reaction in ester hydrolysis and molecule and obtain compound 7, reaction solvent is CH 3oH, temperature of reaction is 0 ~ 20 ℃, the reaction times is 2 ~ 5h, described compound 6 and K 2cO 3mol ratio be 1:1 ~ 2.
In above-mentioned steps (7), at CH 3in OH, compound 7 deprotection under dense HCl effect obtains compound 8, and reaction solvent is CH 3oH, temperature of reaction is 20 ~ 40 ℃, and the reaction times is 2 ~ 5h, and compound 7 is 1:1 ~ 2 with the mol ratio of dense HCl consumption.
In above-mentioned steps (8), in DMF, compound 8 reacts under NaH effect with equimolar amount 4-trifluoromethoxy bromobenzyl, obtain final product PA-824, temperature of reaction is-10 ~ 0 ℃, and the reaction times is 10 ~ 14h, compound 8 with to the mol ratio of trimethylammonium bromobenzyl, NaH consumption, be 1:1:1 ~ 2.
The present invention be take imidazoles and is prepared nitroimidazopyran class tuberculosis drug candidate PA-824 as raw material, and raw material is easy to get, and has avoided low-temp reaction, and operational path is simple to operate, be easy to mass-producing preparation.
Embodiment
Below embodiments of the invention are elaborated: the present embodiment is implemented take technical solution of the present invention under prerequisite, provided at length embodiment and process, but protection scope of the present invention is not limited to following embodiment.
The synthetic method of nitroimidazopyran class tuberculosis drug candidate PA-824, draw together following steps:
(1) at dense H 2sO 4in, the dense HNO of compound 1 and 4 times 3nitration is carried out in reaction, obtains compound 2;
(2) in acetic acid and diacetyl oxide, compound 2 reacts and carries out nitration again with nitrosonitric acid, obtains compound 3;
(3), in chlorobenzene, compound 3 carries out thermal rearrangement, obtains compound 4;
(4) compound 4 and ( s)-(+)-Glycidyl Butyrate carries out nucleophilic ring opening reaction and obtains compound 5;
(5) at CH 2cl 2in, compound 5 and 3,4-dihydropyrane are protected hydroxyl under catalyst P PTS effect, obtain compound 6;
(6) at CH 3in OH, compound 6 is at the K of equimolar amount 2cO 3under effect, carry out nucleophilic ring closure reaction in ester hydrolysis and molecule, obtain compound 7;
(7) at CH 3in OH, compound 7 is deprotection under dense HCl effect, obtains compound 8;
(8), in DMF, compound 8 reacts under NaH effect with equimolar amount 4-trifluoromethoxy bromobenzyl, obtains final product PA-824.
In above-mentioned steps (1), temperature of reaction is 100 ~ 125 ℃, and the reaction times is 6 ~ 8h, compound 1, dense H 2sO 4with dense HNO 3the mol ratio of consumption is 1:2:4, and last handling process comprises extraction, washing, dry and removal of solvent under reduced pressure, obtains compound 2.
In above-mentioned steps (2), temperature of reaction is 20 ~ 50 ℃, and the reaction times is 2 ~ 6h, compound 2with the mol ratio of acetic acid, acetic anhydride, nitrosonitric acid consumption be 1:3:4:2, last handling process comprises extraction, washing, dry and removal of solvent under reduced pressure, obtains compound 3.
In above-mentioned steps (3), reaction solvent is chlorobenzene, and temperature of reaction is 100-120 ℃, and the reaction times is 10 ~ 12h, and last handling process comprises that filtering and washing is dry, obtains compound 4.
In above-mentioned steps (4), react solvent-free, temperature of reaction is 30 ~ 60 ℃, and the reaction times is 2 ~ 3d, compound 4with ( s)-(+) mol ratio of-Glycidyl Butyrate consumption is 1:1.1 ~ 1.5, last handling process comprises extraction, filtering insolubles, saturated NaHCO 3washing, dry and removal of solvent under reduced pressure, column chromatography, obtains compound 5.
In above-mentioned steps (5), reaction solvent is CH 2cl 2, temperature of reaction is 10 ~ 40 ℃, the reaction times is 15 ~ 20h, compound 5with the mol ratio of DHP, PPTS consumption be 3:6 ~ 9:1, last handling process comprises that extraction, washing, dry and removal of solvent under reduced pressure obtain compound 6.
In above-mentioned steps (6), reaction solvent is CH 3oH, temperature of reaction is 0 ~ 20 ℃, the reaction times is 2 ~ 5h, compound 6 and mineral alkali (K 2cO 3) mol ratio of consumption is 1:1 ~ 2, last handling process comprises that being poured into water solid separates out, suction filtration, washing, dry, obtain compound 7.
In above-mentioned steps (7), described reaction solvent is CH 3oH, described temperature of reaction is 20 ~ 40 ℃, and the described reaction times is 2 ~ 5h, and compound 7 is 1:1 ~ 2 with the mol ratio of mineral acid (dense HCl) consumption, and last handling process comprises suction filtration, washing, dry, obtains compound 8.
In above-mentioned steps (8), described reaction solvent is DMF, and described temperature of reaction is-10 ~ 0 ℃, the described reaction times is 10 ~ 14h, compound 8 with to the mol ratio of trimethylammonium bromobenzyl, NaH consumption, be 1:1:1 ~ 2, last handling process comprises extraction, washing, is dried, and obtains final product PA-824.
Embodiment 1
Compound 2preparation
In the three-necked bottle of 2000 ml, add the dense H of 320 ml 2sO 4, under stirring under ice bath, slowly add 100 g imidazoles, add rear continuation and stir, solution becomes after clarification, slowly drips the dense HNO of 240 ml 3.After dripping off, be warming up to after 125 ℃ of back flow reaction 10 h, stopped reaction, is cooled to room temperature, pour in the trash ice of approximately 10 times, a large amount of white solids are separated out, suction filtration, with cold water washing, filter cake obtains product 4-nitroimidazole 155g after drying, and filtrate regulates pH to 3-4 with strong aqua, separate out solid, suction filtration, with cold water washing, filter cake obtains product 4-nitroimidazole 13 g after drying, be total to obtain product 178 g, productive rate 85.04%. 1H-NMR (400M, d6- DMSO): δ 7.85 (s, 1H), 8.32 (s, 1H)。
Compound 3preparation
By acetic acid (175 ml, 3.06 mol) and diacetyl oxide (350 ml, 3.70 mol) join in the there-necked flask of 1000 ml, cooling bath slowly adds 4-nitroimidazole (100 g under stirring, 884.4 mmol), after adding, stir 30 min, then at 30 ℃ with interior slow dropping nitrosonitric acid (98%, 75 ml), 30 min drip off, in dropping process, can see reaction solution flavescence gradually, drip off rear 30 ℃ of isothermal reaction 5h, TLC(sherwood oil: ethyl acetate=2:1) detect raw material point and disappear.By in the trash ice of approximately 10 times of reaction solution impourings, stirring is cooled to room temperature, suction filtration, and filter cake obtains product 1 after drying, 4-Nitroimidazole 83 g, dichloromethane extraction twice for filtrate collection, saturated sodium bicarbonate is washed till pH and is neutral, and washing is once, saturated common salt washing once, collect oil reservoir and be spin-dried for to obtain product 32 g, so be total to obtain product 115 g, productive rate 82.26%. 1H NMR (400 MHz, CDCl 3)： δ 8.39(s，1H), 8.53(s, 1H)。
Compound 4preparation
Take Isosorbide-5-Nitrae-Nitroimidazole (26.05 g, 167.60 mmol) and be placed in 250 ml round-bottomed flasks, add the chlorobenzene of 120 ml, after stirring and dissolving, be warming up to 115 ℃ of post-heating, 12 h that reflux, have a large amount of faint yellow solids to separate out.Suction filtration, sherwood oil is washed, and filter cake obtains 21.88 g pale yellow powders, productive rate 83% after drying. 1H-NMR (400M, d6- DMSO): δ 8.46(s, 1H)。
Compound 5preparation
Will ( s)-(+)-Glycidyl Butyrate (25.90 g, 163.92 mmol) joins in 250 ml three-necked bottles, under stirring, slowly adds pressed powder 2,4-Nitroimidazole (21.60 g, 136.60 mmol).Be warming up to 50 ℃, react 72 h under nitrogen protection, reaction solution is emulsion state, TLC(sherwood oil: ethyl acetate=2:1) detect raw material point and disappear.100 ml methylene dichloride and 100 ml water are joined in reaction flask and stirred, and mixed solution is transferred to separatory in separating funnel, and dichloromethane extraction twice for water layer merges organic phase, with a small amount of distillation washing twice, then uses saturated NaCl solution washing once, anhydrous Mg 2sO 4dry.Pressure reducing and steaming solvent, adds 2eq silica gel powder (200-300 order) to mix sample in residue, column chromatography (sherwood oil: ethyl acetate=8: 1), obtain 25.65 g light yellow oil, productive rate 62%. 1H NMR (400 MHz，CDCl 3): δ 0.96 (t, J = 7.5, 3H), 1.63-1.70 (m, 2H), 2.34-2.37 (t, J = 7.2, 2H), 4.23-4.24 (m, 2H), 4.32-4.33 (m, 1H), 4.43-4.49 (m, 1H), 4.88-4.91 (m, 1H), 8.11 (s, 1H)。
Compound 6preparation
Take compound 5(25.50 g, 84.25 mmol) be placed in 250 ml round-bottomed flasks, after adding 200 ml anhydrous methylene chlorides to dissolve, add successively 3,4-dihydropyrane (14.20 g, 168.50 mmol) and PPTS(7.50 g, 25.30 mmol), 16 h that react under room temperature, TLC(sherwood oil: ethyl acetate=1:1) detect raw material point disappearance, the saturated NaHCO of reaction solution 3solution washing twice, then with 200 ml distilled water and 200 ml saturated nacl aqueous solutions, respectively wash once successively anhydrous MgSO 4dry, decompression is striven for obtaining 30.05 g crude products after solvent, without purifying, can be directly used in the next step.
The preparation of compound 7
Compound 6 crude products (30.05 g, 53.90 mmol) are dissolved in methyl alcohol, are cooled to 0 ℃, add salt of wormwood, stir 1h, TLC(sherwood oil at 0 ℃: ethyl acetate=1:2) detect raw material point disappearance.Remove by filter salt of wormwood, normal hexane rinses, suction filtration, and filter cake obtains 11.25 g crude products after drying, and without purifying, can be directly used in the next step, productive rate 78 %.
The preparation of compound 8
By compound 7 crude products (11.20 g, 42.02 mmol) be dissolved in 100 ml anhydrous methanols, be cooled to 0 ℃, slowly drip concentrated hydrochloric acid 11.2 ml, dropwise recession deicing and bathe, be warming up to voluntarily room temperature, continue reaction 2 h, have a large amount of white solids to separate out, suction filtration, after filtration cakes torrefaction, obtain 6.75 g products, productive rate 87%. 1H-NMR (400M, d6- DMSO)： δ 3.96 (d, J = 12.8Hz, 1H), 4.16-4.20 (m, 1H), 4.27-4.34 (m, 2H), 4.39 (d, J = 11.1 Hz, 1H), 8.08 (s, 1H)。
The preparation of PA-824
Under nitrogen protection; by compound 8(6.70 g; 36.20 mmol) be dissolved in 80 ml dry DMF; add trifluoromethoxy bromobenzyl (11.07 g, 43.44 mmol), add NaH after being cooled to 0 ℃; at 0 ℃, stir 30 min; be warming up to voluntarily room temperature, continue reaction 4 h, TLC(sherwood oil: ethyl acetate=1:2) detect raw material point and disappear.With frozen water cancellation reaction, add dichloromethane extraction, the anhydrous MgSO of organic phase 4after dry, remove solvent under reduced pressure, column chromatography (sherwood oil: obtain 13.33 g light yellow solids ethyl acetate=1:1), productive rate is 80 %.HPLC measures purity and is greater than 99 %, and chromatographic condition is---chromatographic column: Inertsil oDS3 C 18column(150 mm * 4.6 mm, 5 μ m); Detect wavelength: 321 nm; Moving phase: acetonitrile: water=35: 65; Flow velocity: 0.5 mL/min. m.p.:149-150 ℃; 1h NMR (400 MHz, CDCl 3): δ4.15-4.23 (m, 3H), 4.38 (d, j=11.2 Hz, 1H), 4.61-4.64 (m, 2H), 4.73 (d, j=8.0 Hz, 1H), 7.22 (d, j=7.6 Hz, 2 H), 7.36 (d, j=8.4 Hz, 2H), 7.43 (s, 1H). 13c NMR (100 MHz, CDCl 3) δ149.12,147.05,143.63,135.17,129.15,121.67,119.12,115.22,70.20,67.20,65.53,47.56. HRMS Calcd for C 15h 14f 3n 2o 5([M+H] +): 359.0855, Found:360.3247.

Claims (9)

1. the synthetic method of nitroimidazopyran class tuberculosis drug candidate PA-824, is characterized in that, comprises the steps:
(1) compound 1 nitration obtains compound 2;
(2) compound 2 again nitration obtain compound 3;
(3), in chlorobenzene, compound 3 carries out thermal rearrangement and obtains compound 4;
(4) compound 4 and ( s)-(+)-Glycidyl Butyrate carries out nucleophilic ring opening reaction and obtains compound 5;
(5) compound 5 and 3,4-dihydropyrane are protected hydroxyl under catalyst P PTS effect, obtain compound 6;
(6) compound 6 carries out nucleophilic ring closure reaction in ester hydrolysis and molecule, obtains compound 7;
(7) compound 7 deprotections obtain compound 8;
(8) compound 8 reacts with equimolar amount 4-trifluoromethoxy bromobenzyl, obtains PA-824.
2. synthetic method according to claim 1, is characterized in that: in step (1), at dense H 2sO 4in, compound 1 and dense HNO 3carry out nitration and obtain compound 2, temperature of reaction is 100 ~ 125 ℃, and the reaction times is 6 ~ 8h, compound 1, dense H 2sO 4with dense HNO 3the mol ratio of consumption is 1:2:4.
3. synthetic method according to claim 1, it is characterized in that: in step (2), in acetic acid and diacetyl oxide, compound 2 reacts with nitrosonitric acid and carries out nitration again and obtain compound 3, temperature of reaction is 20 ~ 50 ℃, reaction times is 2 ~ 6h, and the mol ratio of compound 2, acetic acid, acetic anhydride, nitrosonitric acid consumption is 1:3:4:2.
4. synthetic method according to claim 1, is characterized in that: in step (3), temperature of reaction is 100-120 ℃, and the reaction times is 10 ~ 12h.
5. synthetic method according to claim 1, is characterized in that: in step (4), described reaction is solvent-free, and temperature of reaction is 30 ~ 60 ℃, and the reaction times is 2 ~ 3d, compound 4, ( s)-(+) mol ratio of-Glycidyl Butyrate consumption is 1:1.1 ~ 1.5.
6. synthetic method according to claim 1, is characterized in that: in step (5), at CH 2cl 2in, temperature of reaction is 10 ~ 40 ℃, and the reaction times is 15 ~ 20h, and compound 5 is 3:6 ~ 9:1 with the mol ratio of DHP, PPTS consumption.
7. synthetic method according to claim 1, is characterized in that: in step (6), at CH 3in OH, compound 6 is at the K of equimolar amount 2cO 3under effect, carry out nucleophilic ring closure reaction in ester hydrolysis and molecule and obtain compound 7, reaction solvent is CH 3oH, temperature of reaction is 0 ~ 20 ℃, the reaction times is 2 ~ 5h, compound 6 and K 2cO 3mol ratio be 1:1 ~ 2.
8. synthetic method according to claim 1, is characterized in that: in step (7), at CH 3in OH, compound 7 deprotection under dense HCl effect obtains compound 8, and temperature of reaction is 20 ~ 40 ℃, and the reaction times is 2 ~ 5h, and compound 7 is 1:1 ~ 2 with the mol ratio of dense HCl.
9. synthetic method according to claim 1, it is characterized in that: in step (8), in DMF, compound 8 reacts and obtains final product PA-824 with equimolar amount 4-trifluoromethoxy bromobenzyl under NaH effect, temperature of reaction is-10 ~ 0 ℃, reaction times is 10 ~ 14h, compound 8 with to the mol ratio of trimethylammonium bromobenzyl, NaH consumption, be 1:1:1 ~ 2.
CN201410372448.6A 2014-07-31 2014-07-31 Synthetic method of anti-tuberculosis candidate drug PA-824 Pending CN104177372A (en)

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Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN106380451A (en) * 2016-08-25 2017-02-08 西安天生物技术股份有限公司 Synthesis and purification method of 2, 4-dinitroimidazole
CN106565744A (en) * 2016-10-31 2017-04-19 瑞阳制药有限公司 Crystal form of PA-824 compound and preparation method of crystal form
CN106632393A (en) * 2016-12-28 2017-05-10 荆楚理工学院 Preparation method for antituberculous candidate drug namely PA-824
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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Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN106380451A (en) * 2016-08-25 2017-02-08 西安天生物技术股份有限公司 Synthesis and purification method of 2, 4-dinitroimidazole
CN106565744A (en) * 2016-10-31 2017-04-19 瑞阳制药有限公司 Crystal form of PA-824 compound and preparation method of crystal form
CN106565744B (en) * 2016-10-31 2019-04-12 瑞阳制药有限公司 The crystal form and preparation method thereof of PA-824 compound
CN106632393A (en) * 2016-12-28 2017-05-10 荆楚理工学院 Preparation method for antituberculous candidate drug namely PA-824
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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Application publication date: 20141203