CN107686439A - A kind of preparation method of the key intermediate of ALK inhibitor - Google Patents
A kind of preparation method of the key intermediate of ALK inhibitor Download PDFInfo
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- CN107686439A CN107686439A CN201710807341.3A CN201710807341A CN107686439A CN 107686439 A CN107686439 A CN 107686439A CN 201710807341 A CN201710807341 A CN 201710807341A CN 107686439 A CN107686439 A CN 107686439A
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C29/00—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom not belonging to a six-membered aromatic ring
- C07C29/74—Separation; Purification; Use of additives, e.g. for stabilisation
- C07C29/88—Separation; Purification; Use of additives, e.g. for stabilisation by treatment giving rise to a chemical modification of at least one compound
- C07C29/92—Separation; Purification; Use of additives, e.g. for stabilisation by treatment giving rise to a chemical modification of at least one compound by a consecutive conversion and reconstruction
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B57/00—Separation of optically-active compounds
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C29/00—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom not belonging to a six-membered aromatic ring
- C07C29/132—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom not belonging to a six-membered aromatic ring by reduction of an oxygen containing functional group
- C07C29/136—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom not belonging to a six-membered aromatic ring by reduction of an oxygen containing functional group of >C=O containing groups, e.g. —COOH
- C07C29/143—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom not belonging to a six-membered aromatic ring by reduction of an oxygen containing functional group of >C=O containing groups, e.g. —COOH of ketones
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/07—Optical isomers
Abstract
The invention discloses a kind of preparation method of the key intermediate of ALK inhibitor, comprise the following steps：1) fluoro acetophenone of 2,5 dichloro 3 is added in ethanol, adds sodium borohydride and carry out carbonyl reduction reaction, generate enantiomer alcohol；2) esterification and then by enantiomer alcohol and phthalic anhydride is carried out, generates derivative；3) derivative is subjected to salt-forming reaction with R Chiral Amines and S Chiral Amines respectively, is isolated to the chiral compound salt of R and the compound salt of S chiralitys；4) R chiral alcohols and S chiral alcohols and then by the chiral compound salt of chiral R compound salt and S are obtained through hydrolysis respectively.The advantage of the invention is that：The chiral alcohol after derivative is separated using chiral ammonia, efficiency high, two kinds of chiral alcohols can be reclaimed, and reagent used at the same time also can be reclaimed smoothly, economical and efficient, and cost is cheap；The key intermediate of two kinds of bulk drugs is efficiently and economically synthesized, method is simple, can amplify production.
Description
Technical field
The present invention relates to field of medicine preparing technology, is more particularly to a kind of preparation of the key intermediate of ALK inhibitor
Method.
Background technology
Anaplastic lymphoma kinase (anaplasticlymphoma kinase, ALK) inhibitor have gram azoles for Buddhist nun and
Ensartinib etc..
Gram azoles for Buddhist nun (Crizotinib) be the suppression Met/ALK/ROS developed by Pfizer ATP it is emulative more
Target point protein kinase inhibitor.Confirm gram azoles for Buddhist nun to people in the tumor patient of ALK, ROS and MET abnormal kinase respectively
Body has notable clinical efficacy, ratifies to list in FDA at present.Gram azoles is as follows for the structural formula of Buddhist nun：
Ensartinib is also a kind of effective ALK inhibitor, for treating non-small cell lung cancer, there is extraordinary treatment
Effect, wide market.Ensartinib structural formula is as follows：
It is following identical by caning be found that they have to Bick azoles for the structural formula of two medicines of Buddhist nun and Ensartinib
Structure：
In terms of gram azoles is for the synthesis of Buddhist nun, route more common at present is as follows：
Wherein, the synthetic method of intermediate 6 is as follows：
Wherein, using the method for pork liver hydrolase, specific method is as follows for the synthesis of chiral alcohol 3 (i.e. compound I)：
In Ensartinib (code name X396 or X376) synthetic route, use with gram azoles for the similar chirality of Buddhist nun
Alcohol A5 (i.e. compound II), the synthetic route part of the medicine is including as follows：
By above synthetic route can be seen that compound I and compound II respectively as synthesis gram azoles for Buddhist nun and
Ensartinib key intermediate is indispensable in gram azoles is for Buddhist nun and Ensartinib preparation, is developed a kind of economical
Efficient method production compound I and II are necessary.Derivative is after prior art production key intermediate I and II use reduction
Ester, then the ester of selective hydrolysis particular chiral is removed by pork liver enzyme, so as to reach the purpose of separation, this method is cumbersome, simultaneously
Specific biology enzyme is not easy to obtain, and conventional method is difficult to control to its quality, and use cost is higher.
The content of the invention
The technical problems to be solved by the invention, which are the provision of a kind of economical and efficient and can produce a synthesis gram azoles simultaneously, to be replaced
The preparation method of the key intermediate of the ALK inhibitor of Buddhist nun and Ensartinib key intermediate.
The present invention is that solve above-mentioned technical problem by the following technical programs：
A kind of preparation method of the key intermediate of ALK inhibitor shown in formula (I) and formula (II), methods described include with
Lower step：
1) the chloro- 3- fluoro acetophenones of 2,5- bis- shown in formula (III) are added in ethanol, adds sodium borohydride and carry out carbonyl
Reduction reaction, generate the enantiomer alcohol shown in formula (IV)；
2) esterification and then by the phthalic anhydride shown in the enantiomer alcohol shown in formula (IV) and formula (V) is carried out, it is raw
Into the derivative shown in formula (VI)；
3) derivative shown in formula (VI) is subjected to salt-forming reaction with R Chiral Amines and S Chiral Amines respectively, obtained respectively through separating
The compound salt chiral to the S shown in chiral the R shown in formula (VII) compound salt and formula (VIII)；
4) and then by compound the salinity chiral S shown in chiral the R shown in formula (VII) compound salt and formula (VIII)
The R chiral alcohols shown in formula (I) and the S chiral alcohols shown in formula (II) are not obtained through hydrolysis；
Preferably, in the step 1), the chloro- 3- fluoro acetophenones of 2,5- bis- shown in formula (III) are added in ethanol,
Sodium borohydride is slowly added at a temperature of 20 DEG C in batches, 20~40 DEG C of 2~4h of reaction of keeping temperature, question response is complete, and temperature is dropped
To 10 DEG C；Then 4N aqueous hydrochloric acid solutions are slowly added dropwise to highly acid, ethanol are spin-dried for, through extracting, washing, dry, production
(IV) the enantiomer alcohol shown in.
Preferably, the mass ratio of the chloro- 3- fluoro acetophenones of 2,5- bis- and sodium borohydride shown in formula (III) is 10:1~2, second
The volume ratio of alcohol and 4N aqueous hydrochloric acid solutions is 1~2:1, often added in the chloro- 3- fluoro acetophenones of 2,5- bis- shown in 1g formulas (III)
3.75mL ethanol.
Preferably, the solvent of the extraction is that volume ratio is 2:3 water and ethyl acetate, the solvent of the washing is saturation
Saline solution.
Preferably, in the step 2), the enantiomer alcohol shown in formula (IV) is added in dichloromethane, then added
Phthalic anhydride shown in formula (V), stir and be warming up to 40 DEG C of 3~4h of reaction, question response is complete, is concentrated and dried, obtains formula
(VI) derivative shown in.
Preferably, the mass ratio of the enantiomer alcohol shown in formula (IV) and the phthalic anhydride shown in formula (V) is 5:3~5,
10mL dichloromethane is added in enantiomer alcohol shown in per 1g formulas (IV).
Preferably, in the step 3), the derivative shown in formula (VI) is added in ethanol, stirs and is warming up to backflow
Derivative solution is dissolved to obtain, R- phenyl ethylamines and S- phenyl ethylamines, slow cooling to 0~10 are separately added into the derivative solution
DEG C solid is separated out, filtered after stirring 1~2h, respectively obtain the chiral compound salt of R shown in formula (VII) and filtrate A and formula
(VIII) the compound salt and liquor B of the S chiralitys shown in.
It is highly preferred that S- phenyl ethylamines are added into filtrate A, and after stirring and being warming up to more than 60 DEG C dissolvings, slow cooling analysis
Crystalline substance, after 0~10 DEG C of 4~5h of stirring and crystallizing, filter, obtain the compound salt of the S chiralitys shown in formula (VIII).Shown in formula (VI)
Derivative is mixture, and after adding the chiral compound salt of R- phenyl ethylamines generation R thereto, unreacted composition may be used also in filtrate
The chiral compound salt of generation S is reacted with S- phenyl ethylamines, can so improve organic efficiency.
Preferably, the enantiomer alcohol shown in formula (IV) and the mass ratio of R Chiral Amines or S Chiral Amines are 5:1~3.
Preferably, in the step 4), by the S shown in chiral the R shown in formula (VII) compound salt and formula (VIII)
Chiral compound salt is separately added into the sodium hydroxide solution that concentration is 2M, and stirring is hydrolyzed, after the completion of question response, regulation
PH to less than 3, layering is extracted with ethyl acetate, a small amount of petroleum ether is added after organic phase is concentrated and separates out solid, is distinguished after suction filtration
Obtain the R chiral alcohols shown in formula (I) and the S chiral alcohols shown in formula (II).
The present invention has advantages below compared with prior art：The present invention uses a kind of pure chemistry method, uses chiral ammonia pair
Chiral alcohol after derivative is separated, efficiency high, and two kinds of chiral alcohols can be reclaimed, and reagent used at the same time also can be reclaimed smoothly,
Economical and efficient, cost are cheap；The key intermediate of two kinds of bulk drugs of synthesis of high-efficiency and economic, method is simple, can amplify production.
Embodiment
Embodiments of the invention are elaborated below, the present embodiment is carried out lower premised on technical solution of the present invention
Implement, give detailed embodiment and specific operating process, but protection scope of the present invention is not limited to following implementation
Example.
Embodiment 1：The key intermediate of ALK inhibitor shown in preparation formula (I) and formula (II), reaction equation are as follows：
Step is as follows：
1) the enantiomer alcohol shown in reduction reaction generation formula (IV)：
The chloro- 3- fluoro acetophenones of 2,5- bis- shown in 8000g formulas (III) are added in 30L ethanol, at a temperature of 20 DEG C in batches
888g sodium borohydrides are slowly added to, 20~40 DEG C of 2~4h of reaction of keeping temperature, reaction process are monitored with TLC, question response is complete,
Stop reaction, cool the temperature to 10 DEG C；Then 20L 4N aqueous hydrochloric acid solutions are slowly added dropwise, heat release is deflated acutely, there are a large amount of whites
Solid generates, and is added dropwise to highly acid, the ethanol in reaction solution is spin-dried for, and adds 10L water and 15L ethyl acetate to extract, saturated common salt
Washing once, is dried, and generates the enantiomer alcohol shown in formula (IV).
2) derivative shown in esterification generation formula (VI)：
Take the enantiomer alcohol shown in 100g formulas (IV) to be added in 1L dichloromethane, then add the neighbour shown in 80g formulas (V)
Phthalate anhydride, stir and be warming up to 40 DEG C of 3~4h of reaction, question response is complete, and reaction solution is concentrated and dried, and obtains formula (VI) institute
The derivative shown, the derivative shown in formula (VI) are mixture.
3) chemical combination chiral S shown in compound salt chiral R shown in salt-forming reaction generation formula (VII) and formula (VIII)
Thing salt；
Derivative shown in above-mentioned formula (VI) is added in 500mL ethanol, stirs and is warming up to backflow and dissolve to obtain derivative
Solution, 40g R- phenyl ethylamines are added into the derivative solution, and slow cooling stirs mistake after 1~2h to 0~10 DEG C of precipitation solid
Filter, obtain the compound salt and filtrate A of the R chiralitys shown in formula (VII).
Derivative shown in above-mentioned formula (VI) is added in 500mL ethanol, stirs and is warming up to backflow and dissolve to obtain derivative
Solution, 40g S- phenyl ethylamines are added into the derivative solution, and slow cooling stirs mistake after 1~2h to 0~10 DEG C of precipitation solid
Filter, obtain the compound salt and liquor B of the S chiralitys shown in formula (VIII).
Due in filtrate A in addition to the composition reacted with R- phenyl ethylamines, in addition to can with S- phenyl ethylamines react into
Point, therefore 40g S- phenyl ethylamines are added in the filtrate A to after being reacted with R- phenyl ethylamines, stir and be warming up to more than 60 DEG C and dissolve
Afterwards, slow cooling crystallization, after 0~10 DEG C of 4~5h of stirring and crystallizing, filter, obtain the compound of the S chiralitys shown in formula (VIII)
Salt, it can so improve the rate of producing effects of the chiral compound salt of S.
4) hydrolysis obtains the R chiral alcohols shown in formula (I) and the S chiral alcohols shown in formula (II)：
The chiral compound salt of R shown in above-mentioned formula (VII) is added in the sodium hydroxide solution that 500mL concentration is 2M,
Stirring is hydrolyzed, TLC monitoring reaction process, after the completion of question response, salt acid for adjusting pH is added into reaction solution to less than 3, is used
500mL ethyl acetate is extracted, and is layered after stirring, and organic phase point concentrated to (aqueous phase can be by reclaiming benzene second after alkali tune
Amine), a small amount of petroleum ether is added in the grease obtained after organic phase is concentrated and separates out solid, after suction filtration R hands shown in formula (I)
Property alcohol, after testing, chiral purity be more than 99%.
The chiral compound salt of S shown in above-mentioned formula (VIII) is added in the sodium hydroxide solution that 500mL concentration is 2M,
Stirring is hydrolyzed, TLC monitoring reaction process, after the completion of question response, salt acid for adjusting pH is added into reaction solution to less than 3, is used
500mL ethyl acetate is extracted, and is layered after stirring, and organic phase point concentrated to (aqueous phase can be by reclaiming benzene second after alkali tune
Amine), a small amount of petroleum ether is added in the grease obtained after organic phase is concentrated and separates out solid, after suction filtration S shown in formula (II)
Chiral alcohol, after testing, chiral purity are more than 99%.
The chiral alcohol after derivative is separated using R chiralitys ammonia and S chiralitys ammonia respectively, separative efficiency is high, two kinds of chiralitys
Alcohol can be recovered, and reagent such as phenyl ethylamine used at the same time also can be by smoothly reclaiming after alkali tune, economical and efficient, and cost is low
It is honest and clean, and can simultaneously synthesizing two kinds of ALK inhibitor key intermediate, i.e., gram azoles for Buddhist nun obtain key intermediate I and
Ensartinib key intermediate II, this method is simple, can amplify production.
The foregoing is merely illustrative of the preferred embodiments of the present invention, is not intended to limit the invention, all essences in the present invention
All any modification, equivalent and improvement made within refreshing and principle etc., should be included in the scope of the protection.
Claims (10)
1. the preparation method of the key intermediate of the ALK inhibitor shown in a kind of formula (I) and formula (II), it is characterised in that described
Method comprises the following steps：
1) the chloro- 3- fluoro acetophenones of 2,5- bis- shown in formula (III) are added in ethanol, adds sodium borohydride and carry out carbonyl reduction
Reaction, generate the enantiomer alcohol shown in formula (IV)；
2) esterification, production and then by the phthalic anhydride shown in the enantiomer alcohol shown in formula (IV) and formula (V) are carried out
(VI) derivative shown in；
3) derivative shown in formula (VI) is subjected to salt-forming reaction with R Chiral Amines and S Chiral Amines respectively, through respectively obtaining formula
(VII) the compound salt of the S chiralitys shown in the compound salt and formula (VIII) of the R chiralitys shown in；
4) and then by the chiral compound salt of the S shown in chiral the R shown in formula (VII) compound salt and formula (VIII) pass through respectively
Hydrolysis obtains the R chiral alcohols shown in formula (I) and the S chiral alcohols shown in formula (II)；
2. the preparation method of the key intermediate of the ALK inhibitor shown in formula (I) according to claim 1 and formula (II),
Characterized in that, in the step 1), the chloro- 3- fluoro acetophenones of 2,5- bis- shown in formula (III) are added in ethanol, at 20 DEG C
At a temperature of be slowly added to sodium borohydride in batches, 20~40 DEG C of 2~4h of reaction of keeping temperature, question response is complete, cools the temperature to 10
℃；Then 4N aqueous hydrochloric acid solutions are slowly added dropwise to highly acid, ethanol is spin-dried for, through extracting, washing, dry, generates formula (IV) institute
The enantiomer alcohol shown.
3. the preparation method of the key intermediate of the ALK inhibitor shown in formula (I) according to claim 2 and formula (II),
Characterized in that, the mass ratio of the chloro- 3- fluoro acetophenones of 2,5- bis- and sodium borohydride shown in formula (III) is 10:1~2, ethanol with
The volume ratio of 4N aqueous hydrochloric acid solutions is 1~2:1, often add 3.75mL in the chloro- 3- fluoro acetophenones of 2,5- bis- shown in 1g formulas (III)
Ethanol.
4. the preparation method of the key intermediate of the ALK inhibitor shown in formula (I) according to claim 2 and formula (II),
Characterized in that, it is 2 that the solvent of the extraction, which is volume ratio,:3 water and ethyl acetate, the solvent of the washing is saturated common salt
Water.
5. the preparation method of the key intermediate of the ALK inhibitor shown in formula (I) according to claim 1 and formula (II),
Characterized in that, in the step 2), the enantiomer alcohol shown in formula (IV) is added in dichloromethane, then adds formula
(V) phthalic anhydride shown in, stir and be warming up to 40 DEG C of 3~4h of reaction, question response is complete, is concentrated and dried, obtains formula
(VI) derivative shown in.
6. the preparation method of the key intermediate of the ALK inhibitor shown in formula (I) according to claim 5 and formula (II),
Characterized in that, the mass ratio of the enantiomer alcohol shown in formula (IV) and the phthalic anhydride shown in formula (V) is 5:3~5, per 1g
10mL dichloromethane is added in enantiomer alcohol shown in formula (IV).
7. the preparation method of the key intermediate of the ALK inhibitor shown in formula (I) according to claim 1 and formula (II),
Characterized in that, in the step 3), the derivative shown in formula (VI) is added in ethanol, stirs and is warming up to backflow dissolving
Derivative solution is obtained, R- phenyl ethylamines and S- phenyl ethylamines, slow cooling to 0~10 DEG C of analysis are separately added into the derivative solution
Go out solid, filtered after stirring 1~2h, respectively obtain the compound salt and filtrate A and formula (VIII) of the R chiralitys shown in formula (VII)
Compound salt chiral shown S and liquor B.
8. the preparation method of the key intermediate of the ALK inhibitor shown in formula (I) according to claim 7 and formula (II),
Characterized in that, S- phenyl ethylamines are added into filtrate A, and after stirring and being warming up to more than 60 DEG C dissolvings, slow cooling crystallization, 0
After~10 DEG C of 4~5h of stirring and crystallizing, filter, obtain the compound salt of the S chiralitys shown in formula (VIII).
9. the preparation method of the key intermediate of the ALK inhibitor shown in formula (I) according to claim 1 and formula (II),
Characterized in that, the enantiomer alcohol and the mass ratio of R Chiral Amines or S Chiral Amines shown in formula (IV) are 5:1~3.
10. the preparation method of the key intermediate of the ALK inhibitor shown in formula (I) according to claim 1 and formula (II),
Characterized in that, in the step 4), the S shown in chiral the R shown in formula (VII) compound salt and formula (VIII) is chiral
Compound salt be separately added into concentration be 2M sodium hydroxide solution in, stirring is hydrolyzed, after the completion of question response, regulation pH to
Less than 3, layering is extracted with ethyl acetate, a small amount of petroleum ether is added after organic phase is concentrated and separates out solid, formula is obtained respectively after suction filtration
(I) the S chiral alcohols shown in R chiral alcohols and formula (II) shown in.
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN114315494A (en) * | 2021-12-29 | 2022-04-12 | 苏州楚凯药业有限公司 | Preparation method of (S) -2-methylazetidine hydrochloride |
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| CN1153161A (en) * | 1995-08-26 | 1997-07-02 | 日本农药株式会社 | Production of optically active 2-halo-1-(substituted phenyl) ethanol and substituted styrene oxide |
| CN104058935A (en) * | 2014-06-19 | 2014-09-24 | 浙江中欣化工股份有限公司 | Preparation method of (S)-1-(2,6-dichloro-3-fluorophenyl) ethanol |
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN114315494A (en) * | 2021-12-29 | 2022-04-12 | 苏州楚凯药业有限公司 | Preparation method of (S) -2-methylazetidine hydrochloride |
| CN114315494B (en) * | 2021-12-29 | 2023-09-22 | 苏州楚凯药业有限公司 | Preparation method of (S) -2-methylazetidine hydrochloride |
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