CN109516998A - A kind of synthetic method of Ba Luoshawei intermediate - Google Patents
A kind of synthetic method of Ba Luoshawei intermediate Download PDFInfo
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- CN109516998A CN109516998A CN201811598135.7A CN201811598135A CN109516998A CN 109516998 A CN109516998 A CN 109516998A CN 201811598135 A CN201811598135 A CN 201811598135A CN 109516998 A CN109516998 A CN 109516998A
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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
- C07D498/12—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 three hetero rings
- C07D498/14—Ortho-condensed systems
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- C—CHEMISTRY; METALLURGY
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- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
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- C07B2200/07—Optical isomers
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- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
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- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
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Abstract
The invention discloses a kind of synthetic methods of Ba Luoshawei intermediate；Belong to organic chemical synthesis field.The method of the present invention is set out with pyridone, is deprotected, and condensation, chiral reduction obtains the key intermediate of Ba Luoshawei.Process route of the invention is brief, mild condition, and not needing progress chiral resolution can be obtained higher chiral purity, while being easy to industrialization, further decreases the production cost of Ba Luoshawei.
Description
Technical field
The invention belongs to organic chemical synthesis fields, and in particular to a kind of synthetic method of Ba Luoshawei intermediate.
Background technique
Ba Luoshawei is a kind of Cap dependent form endonuclease enzyme inhibitor developed by Shionogi, and few in the world
Number can inhibit the new drug of proliferation of influenza virus, and since it does not impact host cell, Small side effects are expected to replace department difficult to understand
His Wei Chengwei takes the lead in race the trump drug in influenza field.
Less to the synthetic method report of Bu Luoshawei at present, the synthesis of especially key intermediate only has Yuan Yan producer salt
Wild justice pharmacy is reported.
Route one is reported, is set out with phthalyl amido ethyl alcohol and substitution reaction occurs for bromoacetaldehyde dimethyl acetal, taken off
Level-one amine is obtained after protection, is carried out condensation reaction with boc-protected pyridinone compounds in acid condition, is obtained raceme,
Chemical resolution is further carried out by chiral furancarboxylic acid, obtains the intermediate of chiral purity.
Unstable, process repeatability under the route phthalimide-based ethyl alcohol alkaline condition that step uses in front
Difference；It is simultaneously raceme what is in the condensation process, obtained, needs further to split, the yield of loss nearly 60% could obtains
To the intermediate of chiral purity.The thus high production cost of the route, poor reproducibility are not suitable for industrialization.
Route two is reported, condensation strategy has been replaced, using morpholone as raw material, has been protected through amide groups, carbonyl reduction, methylated
Leaving group is constructed, then carries out condensation reaction with the pyridone after de- Boc protection, chemical resolution is finally carried out and obtains chiral purity
Intermediate.
The route is more easy on the strategy in condensation cyclization, but uses -78 DEG C in the building of morpholone segment
Cryogenic conditions, and n-BuLi the and DIBAL reagent sensitive to water and air is used, there is biggish security risk in amplification process；
In addition, condensation after obtain be still raceme, bypass chiral resolution the problem of, need to consume the material of more than half
Chiral purity intermediate is obtained, production cost is higher.So either still economically considering from safety, which is being produced
Industryization still allows of no optimist.
In conclusion the current technology of the intermediate of Ba Luoshawei still remains at high cost, safety and repeatability
The disadvantage of difference, is unfavorable for being mass produced, to restrict the industrialization of Ba Luoshawei and improve the production cost of bulk pharmaceutical chemicals, increases
The medication of patient is born.
Summary of the invention
To improve, Ba Luoshawei intermediate reaction condition is harsh, process safety is low, is difficult to produce amplification, high production cost
The disadvantages of, the present invention develops new process route.Specifically include following reaction step:
The compound that step 1. formula A is indicated in acid condition, removes Boc protecting group, the compound that production B is indicated；
The compound that the compound and formula C that step 2. formula B is indicated indicate carries out substitution reaction, then formula D table is obtained after being condensed
The compound shown；
Compound selective reduction under the action of chiral catalyst that step 3. formula D is indicated, obtains among Ba Luoshawei
Body；
Wherein, formula A
Formula B
Formula C
Formula D
R indicates alkyl in formula C.
Synthetic route of the invention are as follows:
Acid described in step 1 includes trifluoroacetic acid, methanesulfonic acid, trifluoromethanesulfonic acid, hydrogen chloride etc.；It is preferred that trifluoroacetic acid.
Further, R indicates methyl, ethyl, propyl etc. in formula C described in step 2；It is preferred that methyl.
The solvent that substitution reaction described in step 2 uses includes acetonitrile, N,N-dimethylformamide, dimethyl sulfoxide, N, N-
Dimethyl acetamide, tetrahydrofuran, toluene, dimethylbenzene etc., preferably acetonitrile.
The reaction temperature of substitution reaction described in step 2 is 30 DEG C -120 DEG C；It is preferred that 60 DEG C -100 DEG C；Optimal 80 DEG C -90 DEG C.
It is ruthenium catalyst that the chiral catalyst used is reacted described in step 3, is had the following structure:
Wherein, Ar1For aryl or alkyl substituting aromatic base, preferably p-methylphenyl；Ar2For phenyl ring or alkyl substituted benzene
Ring, preferably 1,3,5- trimethylbenzenes or p-Methylisopropylbenzene.
The reducing agent that Chemoselective reduction described in step 3 uses includes the salt of hydrogen, formic acid, formic acid and amine, preferably first
Triethylenetetraminehexaacetic acid amine salt.
Ba Luoshawei intermediate is produced using synthetic method of the invention, process route is brief, mild condition, do not need into
Row chiral resolution can be obtained higher chiral purity, while being easy to industrialization, further decrease the production of Ba Luoshawei
Cost.
Specific embodiment
Embodiment 1: the synthetic method of the present embodiment mini-bus Luo Shawei intermediate is completed by following reaction step:
The compound that step 1. formula A is indicated in acid condition, removes Boc protecting group, the compound that production B is indicated；
Compound 2.0g, trifluoroacetic acid 2.0g, methylene chloride 10mL that formula A is indicated are added in there-necked flask, is stirred under room temperature
3h is reacted, TLC detection consumption of raw materials is complete, and vacuum distillation removes solvent, and it is primary that toluene set steaming is added in residue.Residue methylene chloride
It is added in saturated sodium bicarbonate aqueous solution and stirs after dissolution, separate organic phase, (3x 50mL) is extracted with dichloromethane in water phase.
Merge organic phase, vacuum distillation removes solvent and obtains the compound 1.40g of formula B expression, yield 95%.
The compound that the compound and formula C that step 2. formula B is indicated indicate carries out substitution reaction, then formula D table is obtained after being condensed
The compound shown；
Compound 1.0g, 5- (first sulfydryl) -3,6- dihydro -2H-1,4- oxazines 0.53g that formula B is indicated are added in there-necked flask,
Acetonitrile 20ml, then back flow reaction 3h under nitrogen protection.TLC detects raw material end of reaction, is concentrated under reduced pressure into 5vol, cools to
Between 30-40 DEG C, 30ml water is added dropwise, is cooled to room temperature, filter, filter cake 10ml water washing, vacuum drying obtains 1.08g formula D
The compound of expression, yield 91%.
Compound selective reduction under the action of chiral catalyst that step 3. formula D is indicated, obtains among Ba Luoshawei
Body；
Compound 1.0g, methylene chloride 10ml that formula D is indicated are added in there-necked flask, 0 DEG C is cooled under nitrogen protection, is instilled
Then formic acid 0.43g is added dropwise triethylamine 0.93g, is eventually adding 0.05%eq (S, S)-N- (tolysulfonyl) -1,2- hexichol second
Alkane diamines (cumic aldehyde) ruthenic chloride is slowly raised to room temperature, reacts to the compound that TLC detection formula D is indicated and is exhausted.Instead
Liquid is answered to filter through a small amount of silica gel, filtrate water and saturated common salt water washing, anhydrous sodium sulfate is dry, crude product is obtained after concentration, slightly
Product crystallize to obtain 0.85g Ba Luoshawei intermediate, yield 84.5%, HPLC purity 99.2%, ee value through methyl tertiary butyl ether(MTBE)
98.7%.
Embodiment 2: the synthetic method of the present embodiment mini-bus Luo Shawei intermediate is completed by following reaction step:
The compound that step 1. formula A is indicated in acid condition, removes Boc protecting group, the compound that production B is indicated；
It is added the compound 2.0g that formula A is indicated in there-necked flask, 20% ethanol solution of hydrogen chloride 6ml is stirred to react under room temperature
1h, TLC detection consumption of raw materials are complete, and vacuum distillation removes solvent.Residue is added to saturated sodium bicarbonate after being dissolved with methylene chloride
It is stirred in aqueous solution, separates organic phase, (3x 50mL) is extracted with dichloromethane in water phase.Merge organic phase, vacuum distillation removes molten
Agent obtains the compound of 1.23g formula B expression, yield 84%.
The compound that the compound and formula C that step 2. formula B is indicated indicate carries out substitution reaction, then formula D table is obtained after being condensed
The compound shown；
Compound 1.0g, 5- (first sulfydryl) -3,6- dihydro -2H-1,4- oxazines 0.53g that formula B is indicated are added in there-necked flask,
Then toluene 20ml is heated to 100 DEG C of reaction 3h under nitrogen protection.TLC detect raw material end of reaction, cool to 0-10 DEG C it
Between, stirring and crystallizing 1h is filtered, and filter cake is washed with the toluene being pre-chilled on a small quantity, and vacuum drying obtains the compound of 0.97g formula D expression,
Yield 81.8%.
Compound selective reduction under the action of chiral catalyst that step 3. formula D is indicated, obtains among Ba Luoshawei
1 step 3 of embodiment is shown in body, concrete operations.
Finally, it should be noted that the above description is only a preferred embodiment of the present invention and oneself, be not intended to restrict the invention,
Although the present invention is described in detail referring to the foregoing embodiments, for those skilled in the art, still may be used
To modify the technical solutions described in the foregoing embodiments or equivalent replacement of some of the technical features.
All within the spirits and principles of the present invention, any modification, equivalent replacement, improvement and so on should be included in of the invention
Within protection scope.
Claims (10)
1. a kind of synthetic method of Ba Luoshawei intermediate, it is characterised in that this method includes following reaction step:
The compound that step 1. formula A is indicated in acid condition, removes Boc protecting group, the compound that production B is indicated；
The compound that the compound and formula C that step 2. formula B is indicated indicate carries out substitution reaction, then formula D expression is obtained after being condensed
Compound；
Compound selective reduction under the action of chiral catalyst that step 3. formula D is indicated, obtains Ba Luoshawei intermediate；
Wherein, formula A
Formula B
Formula C
Formula D
R indicates alkyl in formula C.
2. synthetic method according to claim 1, it is characterised in that acid described in step 1 is trifluoroacetic acid, methanesulfonic acid, three
One of fluorine methanesulfonic acid, hydrogen chloride.
3. synthetic method according to claim 1, it is characterised in that R indicates methyl, ethyl, propyl in formula C.
4. synthetic method according to claim 1, it is characterised in that the solvent that substitution reaction described in step 2 uses is second
One of nitrile, N,N-dimethylformamide, dimethyl sulfoxide, DMAC N,N' dimethyl acetamide, tetrahydrofuran, toluene, dimethylbenzene.
5. synthetic method according to claim 1, it is characterised in that the reaction temperature of substitution reaction described in step 2 is 30
℃-120℃。
6. synthetic method according to claim 1, it is characterised in that the reaction temperature of substitution reaction described in step 2 is 60
℃-100℃。
7. synthetic method according to claim 1, it is characterised in that the reaction temperature of substitution reaction described in step 2 is 80
℃-90℃。
8. synthetic method according to claim 1, it is characterised in that reacting the chiral catalyst used described in step 3 is ruthenium
Catalyst has the following structure:
Wherein, Ar1For aryl or alkyl substituting aromatic base, Ar2For phenyl ring or alkyl substituted benzene ring.
9. synthetic method according to claim 8, it is characterised in that Ar1For p-methylphenyl, Ar2For 1,3,5- trimethyl
Benzene or p-Methylisopropylbenzene.
10. synthetic method according to claim 1, it is characterised in that the reducing agent that selective reduction described in step 3 uses
For the salt of hydrogen, formic acid or formic acid and amine, the salt of formic acid and amine is triethylammonium formate.
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Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN110305091A (en) * | 2019-06-19 | 2019-10-08 | 江苏理工学院 | A kind of preparation method of Ba Luoshawei midbody compound |
| CN111018803A (en) * | 2019-11-25 | 2020-04-17 | 苏州楚凯药业有限公司 | Preparation method of Barosavir intermediate |
| CN112679522A (en) * | 2020-12-29 | 2021-04-20 | 南京友杰医药科技有限公司 | Preparation method of Barosavir intermediate |
| CN113960192A (en) * | 2021-10-08 | 2022-01-21 | 江苏正济药业股份有限公司 | Barosavir intermediate related substance and preparation method and application thereof |
| CN114014874A (en) * | 2021-12-20 | 2022-02-08 | 中国科学院上海药物研究所 | Preparation method of mabarosavir intermediate |
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| WO2017221869A1 (en) * | 2016-06-20 | 2017-12-28 | 塩野義製薬株式会社 | Method for producing substituted polycyclic pyridone derivative and crystal of same |
| CN107709321A (en) * | 2015-04-28 | 2018-02-16 | 盐野义制药株式会社 | The polycyclic Pyridione derivatives and its prodrug being substituted |
| CN108440564A (en) * | 2018-04-11 | 2018-08-24 | 朱孝云 | Substituted polycyclic carbamoylpyridone derivative and its prodrug |
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| CN107709321A (en) * | 2015-04-28 | 2018-02-16 | 盐野义制药株式会社 | The polycyclic Pyridione derivatives and its prodrug being substituted |
| WO2017221869A1 (en) * | 2016-06-20 | 2017-12-28 | 塩野義製薬株式会社 | Method for producing substituted polycyclic pyridone derivative and crystal of same |
| CN108440564A (en) * | 2018-04-11 | 2018-08-24 | 朱孝云 | Substituted polycyclic carbamoylpyridone derivative and its prodrug |
Cited By (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN110305091A (en) * | 2019-06-19 | 2019-10-08 | 江苏理工学院 | A kind of preparation method of Ba Luoshawei midbody compound |
| CN110305091B (en) * | 2019-06-19 | 2021-05-18 | 江苏理工学院 | Preparation method of Barosavir intermediate compound |
| CN111018803A (en) * | 2019-11-25 | 2020-04-17 | 苏州楚凯药业有限公司 | Preparation method of Barosavir intermediate |
| CN112679522A (en) * | 2020-12-29 | 2021-04-20 | 南京友杰医药科技有限公司 | Preparation method of Barosavir intermediate |
| CN112679522B (en) * | 2020-12-29 | 2023-02-14 | 南京正济医药研究有限公司 | Preparation method of balo Sha Wei intermediate |
| CN113960192A (en) * | 2021-10-08 | 2022-01-21 | 江苏正济药业股份有限公司 | Barosavir intermediate related substance and preparation method and application thereof |
| CN114014874A (en) * | 2021-12-20 | 2022-02-08 | 中国科学院上海药物研究所 | Preparation method of mabarosavir intermediate |
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