CN109134428A - A kind of preparation method of Ba Luoshawei intermediate - Google Patents
A kind of preparation method of Ba Luoshawei intermediate Download PDFInfo
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- CN109134428A CN109134428A CN201811247366.3A CN201811247366A CN109134428A CN 109134428 A CN109134428 A CN 109134428A CN 201811247366 A CN201811247366 A CN 201811247366A CN 109134428 A CN109134428 A CN 109134428A
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- ring
- thia
- acetonitrile
- fluoro
- difluorodiphenyl
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D337/00—Heterocyclic compounds containing rings of more than six members having one sulfur atom as the only ring hetero atom
- C07D337/02—Seven-membered rings
- C07D337/06—Seven-membered rings condensed with carbocyclic rings or ring systems
- C07D337/10—Seven-membered rings condensed with carbocyclic rings or ring systems condensed with two six-membered rings
- C07D337/12—[b,e]-condensed
Abstract
The invention discloses a kind of preparation methods of Ba Luoshawei intermediate, characterized by the following steps: (1) in solvent A by 2- bromomethyl -3,4- difluorophenyl acetonitrile replaces to obtain the fluoro- 2- of 3,4- bis- [(thiophenyl) methyl] benzene acetonitrile through benzenethiol sodium；(2) reacted in solvent B by resulting 3, the 4- bis- of step (1) fluoro- 2- [(thiophenyl) methyl] benzene acetonitrile with cyclizing agent, cyclization obtains 7,8- difluorodiphenyl simultaneously seven ring -11(6H of [b, e] thia) -one；(3) restore resulting 7, the 8- difluorodiphenyl of step (2) simultaneously seven ring -11(6H of [b, e] thia) -one to obtain 7,8- difluorodiphenyl simultaneously seven ring -11(6H of [b, e] thia) -ol.Reaction step in the present invention, which is reduced by 5 step in the prior art reaction to 3 steps, reacts, and reduces the generation of side reaction, improves reaction yield.With benzenethiol sodium instead of stench and the benzenethiol of severe toxicity, reduce the harm in production to experimenter.
Description
Technical field
The present invention relates to field of medicine production, and in particular to a kind of preparation method of Ba Luoshawei intermediate.
Background technique
Ba Luoshawei (Baloxavir marboxil, S-033188, RG-6152, Zofluza, Xofluza®,
Baloxavir it is) a kind of novel hat shape dependence endonuclease enzyme inhibitor, is developed to treatment A type or B-mode stream
Sense.Different from the infection neuraminidase inhibitor of host cell releasing virus is inhibited, Ba Luoshawei is by inhibiting mRNA synthesis
Starting block proliferation of influenza virus.On 2 23rd, 2018, Ba Luoshawei got the Green Light in Japan, for treat paediatrics and
The A type or influenza B virus of adult patient infect.The U.S., European Union and other countries are carrying out the A type or B-mode of III phase
Influenza infection treatment.In Japan, Ba Luoshawei is also at the preclinical study stage of influenza A virus H5N1 hypotype.
At present about the few of the synthetic method report of Ba Luoshawei, it is synthesis Ba Luo that patent JP6212678, which discloses segment A,
One of crucial building block of two of Sha Wei, the synthetic route of segment A is as follows: 3,4- difluoro-benzoic acids (A5) and N, N- dimethyl formyl
Amine cyclization generates fluoro- 3- hydroxyl isobenzofuran -1 (3H) -one (A4) of 4,5- bis-, and A4 replaces generation 4,5- bis- fluoro- through benzenethiol
3- thiophenyl isobenzofuran -1 (3H) -one (A3), A3 open loop obtain the fluoro- 2- Ophenylthiomethyl benzoic acid (A2) of 3,4- bis-, A2
In the presence of polyphosphoric acids, heating cyclization generates fluoro- 6,11- dihydro-dibenzo [b, the e] thiotropilium -11- ketone of 7,8- bis-
(A1), A1 obtains object: 7,8- bis- fluoro- 6,11- dihydro-dibenzo [b, e] thiotropilium -11- alcohol (segment A) through reduction.With
Upper route is tediously long, and uses the benzenethiol of stench and severe toxicity in second step, which is obviously not suitable for commercially producing segment
A。
In conclusion being badly in need of developing a kind of new synthesis Ba Luoshawei key intermediate: 8- difluorodiphenyl simultaneously [b, e] thia
Seven ring -11(6H) -ol (segment A) method.
Summary of the invention
In order to solve the above problem, the present invention provides a kind of preparation methods of Ba Luoshawei intermediate.
A kind of preparation method of Ba Luoshawei intermediate, it is characterised in that the following steps are included:
(1) 2- bromomethyl -3,4- difluorophenyl acetonitrile is replaced in solvent A to obtain 3,4-, bis- fluoro- 2- [(benzene sulphur through benzenethiol sodium
Base) methyl] benzene acetonitrile；
(2) it is reacted in solvent B by resulting 3, the 4- bis- of step (1) fluoro- 2- [(thiophenyl) methyl] benzene acetonitrile with cyclizing agent, ring
Conjunction obtains 7,8- difluorodiphenyl simultaneously seven ring -11(6H of [b, e] thia) -one；
(3) it restores resulting 7, the 8- difluorodiphenyl of step (2) simultaneously seven ring -11(6H of [b, e] thia) -one to obtain 7,8- difluoro two
Seven ring -11(6H of benzo [b, e] thia) -ol.
Further, the molar ratio of benzenethiol sodium and 2- bromomethyl -3,4- difluorophenyl acetonitrile is 1.5 ~ 3.0 in step (1):
1。
Further, solvent A used in step (1) be acetone, acetonitrile, Isosorbide-5-Nitrae-dioxane, n,N-Dimethylformamide,
N,N-dimethylacetamide, tetrahydrofuran, ethyl alcohol, any one in methanol.
Further, the reaction temperature in step (1) is 10 DEG C ~ 50 DEG C.
Further, the cyclizing agent that cyclization is used in step (2) is phosphorus pentoxide, any one in polyphosphoric acids
?.
Further, the cyclizing agent and 3 that cyclization is used in step (2), the fluoro- 2- of 4- bis- [(thiophenyl) methyl] benzene second
The molar ratio of nitrile is 1.0 ~ 10.0:1.
Further, solvent B used in step (2) is dimethylbenzene, any one in diphenyl ether.
The utility model has the advantages that
1, reaction step is reduced to 3 steps by 5 step in the prior art reaction and is reacted, and reduces the generation of side reaction, is improved anti-
Answer yield.2, reduce the harm in production to experimenter instead of stench and the benzenethiol of severe toxicity with benzenethiol sodium.
Detailed description of the invention
Fig. 1 is preparation method schematic diagram of the invention
Fig. 2 is the schematic diagram for synthesizing Ba Luoshawei
Fig. 3 is the preparation method schematic diagram for producing Ba Luoshawei intermediate in the prior art.
Specific embodiment
The present invention is specifically described below by embodiment, it is necessary to it is again noted that following embodiment is only used
In invention is further explained, it should not be understood as limiting the scope of the invention.
Embodiment 1:
In 3L three neck round bottom flask, it is charged with 2- bromomethyl -3,4- difluorophenyl acetonitrile (100.00g, 430.99mmol), third
Ketone (800ml) is charged with water (900ml) solution of benzenethiol sodium (113.92g, 861.98mmol) after stirring clarification,
Triethylamine (91.58g, 905.08mmol).System mixed at room temperature stirs 5 hours, after removing acetone under reduced pressure, is extracted with dichloromethane
(1L × 2) merge methylene chloride phase, and washing, after salt washing, anhydrous sodium sulfate is dry, and vacuum rotary steam obtains residue
110.00g, yield 97.7% are direct plungeed into without further purification for the next step.
In 5L there-necked flask, it is charged with the fluoro- 2- of 3,4- bis- [(thiophenyl) methyl] benzene acetonitrile that step reaction generates
(100.00g, 382.72mmol) and phosphorus pentoxide (271.62g, 1.91mol), dimethylbenzene (2.5L), diatomite
(270.00g) after system is stirred at reflux 5 hours, is down to room temperature, and filtering, filtrate water (800ml) is washed, 10% sodium carbonate
The washing of (800ml) solution, organic phase vacuum rotary steam remove solvent, obtain yellowish-brown residue, normal heptane is added into residue
(500ml), heating stirring flow back 1 hour, after be down to room temperature, filter, obtain khaki solid powder 89.25g, yield
88.9%。
The nuclear magnetic resonance spectroscopy of khaki solid powder is1H NMR (500 MHz,CDCl3) δ: 4.16 (2H),
7.10 ~ 7.19 (1H), 7.26 ~ 7.33(1H), 7.33 ~ 7.45(3H), 8.19(1H)；I.e. khaki solid powder mainly at
It is divided into 7,8- difluorodiphenyl simultaneously seven ring -11(6 of [b, e] thiaH)-ketone.
In 2L three-necked flask, it is charged with 7,8- difluorodiphenyl simultaneously seven ring -11(6 of [b, e] thiaH)-ketone
(80.00g, 305.02mmol), anhydrous methanol (800ml) mixing are cooled to -10 DEG C.A small amount of repeatedly total addition thereto
Reaction flask is moved to after adding and is stirred at room temperature 4 hours by sodium borohydride (27.70g, 732.06mmol).It is careful thereto again to be added dropwise
Water (50ml), after being sufficiently stirred, removes methanol under reduced pressure, and methylene chloride (800ml) is added into residue, washing (400ml ×
2), anhydrous sodium sulfate dries, filters, and is spin-dried for obtaining yellowish-brown residue, and toluene (500ml) is added into residue and is heated to reflux
Stir to clarify, after be down to 5 ~ 10 DEG C, filtering is dried to obtain Light brown solid powder 75.16g, yield 93.2%.
The nuclear magnetic resonance spectroscopy of Light brown solid powder is1H NMR (500 MHz,CDCl3) δ: 2.68 (1H), 4.20
(2H), 4.70(2H), 7.04(1H), 7.14 ~ 7.24(4H) and, 7.43 ~ 7.51(1H)；That is the main component of Light brown solid powder
Among 7,8- difluorodiphenyl simultaneously seven ring -11(6H of [b, e] thia)-alcohol (1) target product Ba Luoshawei namely of the present invention
Body.
Embodiment 2:
In 3L three neck round bottom flask, it is charged with 2- bromomethyl -3,4- difluorophenyl acetonitrile (120.00g, 517.20mmol), second
Alcohol (900ml) is charged with water (900ml) solution of benzenethiol sodium (132.56g, 1.003mol) after stirring clarification, and three
Ethamine (103.57g, 1.024mol).System mixed at room temperature stirs 5 hours, and after removing ethyl alcohol under reduced pressure, (1L is extracted with dichloromethane
× 2), merge methylene chloride phase, washing, after salt washing, anhydrous sodium sulfate is dry, and vacuum rotary steam obtains residue 124.3g, receives
Rate 96.9% is direct plungeed into without further purification for the next step.
In 250ml there-necked flask, be charged with the fluoro- 2- of 3,4- bis- [(thiophenyl) methyl] benzene acetonitrile (3.00g,
11.47mmol), phosphorus pentoxide (8.12g), dimethylbenzene (80ml), diatomite (8.00g), after system is stirred at reflux 4 hours,
It is down to room temperature, is filtered, filtrate water (30ml) is washed, and the washing of 10% sodium carbonate (50ml) solution, organic phase vacuum rotary steam removes molten
Agent obtains yellowish-brown residue, and normal heptane (20ml) is added into residue, and heating stirring flows back 1 hour, rear near room temperature,
Filtering, obtains khaki solid powder 2.17g, yield 82.3%.
The nuclear magnetic resonance spectroscopy of khaki solid powder is1H NMR (500 MHz,CDCl3) δ: 4.16 (2H),
7.10 ~ 7.19 (1H), 7.26 ~ 7.33(1H), 7.33 ~ 7.45(3H), 8.19(1H)；I.e. khaki solid powder mainly at
It is divided into 7,8- difluorodiphenyl simultaneously seven ring -11(6 of [b, e] thiaH)-ketone.
In 2L three-necked flask, it is charged with 7,8- difluorodiphenyl simultaneously seven ring -11(6 of [b, e] thiaH)-ketone
(90.00g, 343.14mmol), anhydrous methanol (900ml) mixing are cooled to -10 DEG C.A small amount of repeatedly total addition thereto
Reaction flask is moved to after adding and is stirred at room temperature 4 hours by sodium borohydride (28.40g, 750.72mmol).It is careful thereto again to be added dropwise
Water (50ml), after being sufficiently stirred, removes methanol under reduced pressure, and methylene chloride (800ml) is added into residue, washing (400ml ×
2), anhydrous sodium sulfate dries, filters, and is spin-dried for obtaining yellowish-brown residue, and toluene (500ml) is added into residue and is heated to reflux
Stir to clarify, after be down to 5 ~ 10 DEG C, filtering is dried to obtain Light brown solid powder 79.6g, yield 92.7%.
The nuclear magnetic resonance spectroscopy of Light brown solid powder is1H NMR (500 MHz, CDCl3) δ: 2.68 (1H), 4.20
(2H), 4.70(2H), 7.04(1H), 7.14 ~ 7.24(4H) and, 7.43 ~ 7.51(1H)；That is the main component of Light brown solid powder
Among 7,8- difluorodiphenyl simultaneously seven ring -11(6H of [b, e] thia)-alcohol (1) target product Ba Luoshawei namely of the present invention
Body.
Claims (7)
1. a kind of preparation method of Ba Luoshawei intermediate, it is characterised in that the following steps are included:
(1) 2- bromomethyl -3,4- difluorophenyl acetonitrile is replaced in solvent A to obtain 3,4-, bis- fluoro- 2- [(benzene sulphur through benzenethiol sodium
Base) methyl] benzene acetonitrile；
(2) it is reacted in solvent B by resulting 3, the 4- bis- of step (1) fluoro- 2- [(thiophenyl) methyl] benzene acetonitrile with cyclizing agent, ring
Conjunction obtains 7,8- difluorodiphenyl simultaneously seven ring -11(6H of [b, e] thia) -one；
(3) it restores resulting 7, the 8- difluorodiphenyl of step (2) simultaneously seven ring -11(6H of [b, e] thia) -one to obtain 7,8- difluoro two
Seven ring -11(6H of benzo [b, e] thia) -ol.
2. according to the method described in claim 1, it is characterized by: benzenethiol sodium and 2- bromomethyl -3,4- in the step (1)
The molar ratio of difluorophenyl acetonitrile is 1.5 ~ 3.0:1.
3. according to the method described in claim 1, it is characterized by: solvent A used in the step (1) be acetone, acetonitrile, 1,
4- dioxane, n,N-Dimethylformamide, n,N-dimethylacetamide, tetrahydrofuran, ethyl alcohol, any one in methanol.
4. according to the method described in claim 1, it is characterized by: the reaction temperature in the step (1) is 10 DEG C ~ 50 DEG C.
5. according to the method described in claim 1, it is characterized by: the cyclizing agent that cyclization is used in the step (2) is
Phosphorus pentoxide, any one in polyphosphoric acids.
6. according to the method described in claim 1, it is characterized by: the cyclizing agent that cyclization is used in the step (2) with
The molar ratio of 3,4- bis- fluoro- 2- [(thiophenyl) methyl] benzene acetonitriles is 1.0 ~ 10.0:1.
7. according to the method described in claim 1, it is characterized by: solvent B used in the step (2) be dimethylbenzene, two
Any one in phenylate.
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Cited By (7)
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| CN110105327A (en) * | 2019-06-05 | 2019-08-09 | 南京焕然生物科技有限公司 | A kind of preparation method of the fluoro- 6,11- dihydro-dibenzothiophenes of 7,8- bis- simultaneously -11- alcohol |
| CN111018803A (en) * | 2019-11-25 | 2020-04-17 | 苏州楚凯药业有限公司 | Preparation method of Barosavir intermediate |
| CN111808069A (en) * | 2020-07-21 | 2020-10-23 | 中国药科大学 | Preparation method of baroxavir key intermediate and intermediate thereof |
| CN112300120A (en) * | 2019-07-31 | 2021-02-02 | 北京四环制药有限公司 | Compound for preparing balsalavir or derivatives thereof, preparation method and application thereof |
| CN112409379A (en) * | 2020-09-28 | 2021-02-26 | 长沙晶易医药科技有限公司 | Deuterated dihydrodibenzothiazepine compounds and pharmaceutical compositions containing the same |
| CN112812095A (en) * | 2021-01-29 | 2021-05-18 | 成都安满生物医药科技有限公司 | Synthesis method of baroxavir pivoxil intermediate |
| CN113354519A (en) * | 2020-03-07 | 2021-09-07 | 广东东阳光药业有限公司 | Synthetic method of heterocyclic compound |
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Cited By (11)
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| CN110105327A (en) * | 2019-06-05 | 2019-08-09 | 南京焕然生物科技有限公司 | A kind of preparation method of the fluoro- 6,11- dihydro-dibenzothiophenes of 7,8- bis- simultaneously -11- alcohol |
| CN112300120A (en) * | 2019-07-31 | 2021-02-02 | 北京四环制药有限公司 | Compound for preparing balsalavir or derivatives thereof, preparation method and application thereof |
| CN112300120B (en) * | 2019-07-31 | 2023-04-14 | 北京四环制药有限公司 | Compound for preparing balsalavir or derivatives thereof, preparation method and application thereof |
| CN111018803A (en) * | 2019-11-25 | 2020-04-17 | 苏州楚凯药业有限公司 | Preparation method of Barosavir intermediate |
| CN113354519A (en) * | 2020-03-07 | 2021-09-07 | 广东东阳光药业有限公司 | Synthetic method of heterocyclic compound |
| CN111808069A (en) * | 2020-07-21 | 2020-10-23 | 中国药科大学 | Preparation method of baroxavir key intermediate and intermediate thereof |
| CN111808069B (en) * | 2020-07-21 | 2022-05-17 | 中国药科大学 | Preparation method of baroxavir key intermediate and intermediate thereof |
| CN112409379A (en) * | 2020-09-28 | 2021-02-26 | 长沙晶易医药科技有限公司 | Deuterated dihydrodibenzothiazepine compounds and pharmaceutical compositions containing the same |
| WO2022063016A1 (en) * | 2020-09-28 | 2022-03-31 | 长沙晶易医药科技有限公司 | Deuterated dihydrodibenzothiepine compound, and pharmaceutical composition containing same |
| CN112409379B (en) * | 2020-09-28 | 2023-07-28 | 长沙晶易医药科技股份有限公司 | Deuterated dihydrodibenzothiazepine compound and pharmaceutical composition containing same |
| CN112812095A (en) * | 2021-01-29 | 2021-05-18 | 成都安满生物医药科技有限公司 | Synthesis method of baroxavir pivoxil intermediate |
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Application publication date: 20190104 |