CN107628983A - The Apremilast of high chiral purity - Google Patents
The Apremilast of high chiral purity Download PDFInfo
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- CN107628983A CN107628983A CN201710356919.8A CN201710356919A CN107628983A CN 107628983 A CN107628983 A CN 107628983A CN 201710356919 A CN201710356919 A CN 201710356919A CN 107628983 A CN107628983 A CN 107628983A
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Abstract
The invention discloses a kind of Apremilast of high chiral purity.It is prepared by the key intermediate of low chiral purity.Specifically; ee values are recrystallized for the 65% 89% mesyl ethamine N acetyl group L leucine salt of Apremilast key intermediate 1 (methoxyphenyl of 3 ethyoxyl 4) 2 with water; obtain the intermediate purification product that ee values are more than 99.9%; further reaction can obtain the Apremilast that ee values are more than 99.9% to the intermediate purification product, so as to ensure pharmaceutical preparation safely, effectively.The present invention is simple to operate, environment-friendly, suitable for industrialized production.
Description
Technical field
The present invention relates to pharmaceutical synthesis field, more particularly, to the process for purification and system of Apremilast key intermediate
The high chiral purity Apremilast obtained.
Background technology
Apremilast (Apremilast), it is the first PDE4 inhibitor of Celgene companies of U.S. research and development, obtains within 2014
U.S. FDA is ratified, for treating psoriatic arthritis and psoriasis in plaques.Entitled (S) -2- [1- (the 3- second of Apremilast chemistry
Epoxide -4- methoxyphenyls) -2- methylsulfonylethyls] -4- acetylaminoisoindoline -1,3- diketone, structural formula is：
Report that the drug effect of S type isomers is R type isomers according to document (J.Med.Chem.2009,52,1522-1524.)
More than 5 times, so the chiral purity of S type Apremilasts is higher, the drug effect and quality of Apremilast medicine are better.
At present, Apremilast and its intermediate have a variety of preparation methods, and a kind of common method is：
A1 is split as into A2, A2 and A3 by chiral reagent N- acetyl group-L-Leu to react to obtain Apremilast.Due to
Preliminary obtained intermediate A 2 contains a certain amount of isomers, and the reaction that A2 synthesizes Apremilast with A3 shows in the absence of racemization
As so obtained Apremilast chiral purity is not high, containing the enantiomter being difficult to by recrystallizing removing.And intermediate
A2 diastereoisomer is relatively easy to purification and removed, so, by refining intermediate A 2, you can obtain the A Pu of high chiral purity
Si Te.It is presently disclosed by refined intermediate A 2 so as to which the method for obtaining high chiral purity Apremilast has：
CN100427085 ((+) -2- [1- (3- ethoxy-4-methoxyphenyls) -2- methylsulfonylethyls] -4- acetyl ammonia
The pharmaceutical applications of base isoindoline -1,3- diketone) in disclose the preparation method of Apremilast, A1 and the bright ammonia of N- acetyl group-L-
After acid reaction generation A2 crude products, crude product is heated to reflux being beaten with methanol, obtains the highly finished product of ee values 98.4%；By highly finished product system
The Apremilast obtained recrystallizes through ethanol water, finally gives the product that ee values are 98%.
CN105218428 (a kind of preparation method of the Apremilast of high chiral purity), which discloses, adds A2 crude products with methanol
Heat backflow mashing is refined, and highly finished product and A3 add the method that Apremilast is made as catalyst for acetic acid in toluene solution.Most
Obtained Apremilast chiral purity reaches as high as 99.8% afterwards.
CN104529869 (one kind (S) -2- [1- (3- ethoxy-4-methoxyphenyls) -2- methylsulfonylethyls] -4- second
The preparation method of acyl amino isoindoline -1,3- diketone isomers) disclose A2 crude products is water-soluble in methanol aqueous solution, ethanol
It is heated to reflux being beaten in the aqueous solutions of organic solvent such as liquid, aqueous acetone solution or acetonitrile solution, obtains chiral purity more than 99%
Intermediate A 2, wherein, especially 50% methanol aqueous solution best using methanol aqueous solution reaction effect, be by ee values
89.4% crude product, the A2 that ee values are 99.9% can be refining to obtain, so as to which the Apremilast that ee values are 99.9% further be made,
For the crude product that ee values are 85.8%-88.5%, highly finished product ee values after purification are less than 99.9%, further obtained A Pusi
Special ee values are less than 99.9%.
In addition, WO2016161996 (A method of chiral resolution of the key
intermediate of the synthesis of apremilast and its use for the preparation
Of pure apremilast) A1 and chiral tartaric acid derivative (3) reaction generated into chiral salt intermediate (S) -4a, preferably
(S)-4aa.When entering water-filling recrystallization from (the S) -4aa crude products of ee values more than 92%, ee values can be obtained and be more than 99%
(S) -4aa highly finished product, it finally can obtain the Apremilast that ee values are more than 99%.High chiral purity intermediate is obtained in the patent
Purification process is applied to the crude product of chiral purity high (ee values are more than 92%).And it is less than 92% crude product for refined preceding ee values,
Recrystallization effect does not disclose.
To sum up, it is still necessary to new purifying process is developed to refine the crude product of intermediate A 2, especially for relatively low thick of ee values
Product it is refined, so that the Apremilast that ee values reach 99.9% is made, make it to meet simultaneously that medicine produces and industrialized production
It is required that.
The content of the invention
It is an object of the invention to provide a kind of Apremilast key intermediate 1- (3- ethyoxyl -4- methoxybenzenes
Base) purification process of -2- mesyls-second amine-n-acetyl group-L-Leu salt and obtained high chiral pure by it
The Apremilast of degree.This method in neat solvent by recrystallizing key intermediate 1- (3- ethoxy-4-methoxyphenyls) -2-
Mesyl-second amine-n-acetyl group-L-Leu salt, further reaction is available for the high chiral purity intermediate after recrystallization
The Apremilast of high chiral purity.The purpose of the present invention can be achieved through the following technical solutions：
The invention provides a kind of method of purifying formula (I) compound, wherein, the ee values of formula (I) crude compound are
65%-89%,
It is characterized in that：Formula (I) crude compound is recrystallized in pure water.
In a preferred embodiment, described re-crystallization step is：By formula (I) chemical combination that ee values are 65%-89%
Thing crude product is soluble in water, and solid is warming up under stirring and is all dissolved, and cool crystallization, filters, and dries.
In a preferred embodiment, ee values are that the weight ratio of 65%-89% formulas (I) crude compound and water is 1:
18-1:30, preferably 1:20-1:25.
In a preferred embodiment, the temperature that solid all dissolves is warming up under the stirring described in re-crystallization step is
90-100 DEG C, preferably 95-100 DEG C.
In a preferred embodiment, the recrystallization temperature described in re-crystallization step is 0-30 DEG C, preferably 0-10 DEG C, more excellent
Select 0-5 DEG C.
In a preferred embodiment, the crystallization time described in re-crystallization step is 0.5-5 hours.
Present invention also offers a kind of method for preparing high chiral purity Apremilast, it is characterised in that using following step
Suddenly：
A. formula (I) compound that ee values are 65%-89% is recrystallized to give formula (II) of the ee values more than 99.9% with water
Compound highly finished product；
B. formula (I) compound highly finished product and 3-acetamidophthalic anhydride reaction generation ee values be more than 99.9% Ah
Pu Site；
Process for refining disclosed by the invention is directed to the relatively low Apremilast intermediate of ee values, and WO2016161996 institutes are public
The method opened, there is good refining effect for the Apremilast intermediate of high ee values, but be not suitable for the centre of low ee values
Body refines.
The present invention does the key intermediate of solvent recrystallization Apremilast using water, greatly reduces organic in whole technique
The use of solvent, safety and environmental protection, cost is low, is extremely suitable for industrial production.
The present invention is simple to operate, significantly reduces Apremilast isomer impurities content, finally gives ee values and be more than
99.9% Apremilast, so as to ensure final pharmaceutical preparation safely, effectively, meet the requirement of medicine production.
Brief description of the drawings
Fig. 1 is the HPLC chromatogram of crude product used in embodiment 1, and ee values are 67.27%；
Fig. 2 is the HPLC chromatogram of crude product used in embodiment 2, and ee values are 77.71%；
Fig. 3 is the HPLC chromatogram of crude product used in embodiment 3, and ee values are 82.96%；
Fig. 4 is the HPLC chromatogram of crude product used in embodiment 4 to embodiment 8, and ee values are 88.36%；
Fig. 5 is the HPLC chromatogram of the product of the embodiment of the present invention 1, and ee values are 99.93%；
Fig. 6 is the HPLC chromatogram of the gained Apremilast of the embodiment of the present invention 9, and ee values are 99.95%.
Embodiment
Content for a better understanding of the present invention, technical scheme is done into one with reference to specific embodiment
The explanation of step, but specific embodiment is not meant to there are any restrictions to the present invention.
With reference to patent CN104529869, obtained crude product ee values scope is 65%- for the preparation of formula (I) crude compound
89%；
Embodiment 1
(S) -1- (3- ethoxy-4-methoxyphenyls) -2- mesyls-second amine-n-acetyl group-L- is added in reaction bulb
Leucine salt crude product (10g, ee value：67.27%) water (200mL), is added, temperature is risen to 95 DEG C under stirring, solid is all molten
Solution, room temperature is naturally cooling to, and is kept for 1 hour, filtering, filter cake is washed with water.By filter cake dry (S) -1- (3- ethyoxyls -
4- methoxyphenyls) -2- mesyls-second amine-n-acetyl group-L-Leu salt refining product (6.15g, are contained based on S type isomers
The yield of amount：73.6%, ee value：99.93%), HPLC chromatogram is as shown in Figure 5.
Embodiment 2
(S) -1- (3- ethoxy-4-methoxyphenyls) -2- mesyls-second amine-n-acetyl group-L- is added in reaction bulb
Leucine salt crude product (10g, ee value：77.71%) water (200mL), is added, temperature is risen to 95 DEG C under stirring, solid is all molten
Solution, 10 DEG C are naturally cooling to, and are kept for 1 hour, filtering, filter cake is washed with water.By filter cake dry (S) -1- (3- ethyoxyls -
4- methoxyphenyls) -2- mesyls-second amine-n-acetyl group-L-Leu salt refining product (6.62g, are contained based on S type isomers
The yield of amount：75.6%, ee value：99.92%), HPLC chromatogram is similar to Fig. 5.
Embodiment 3
(S) -1- (3- ethoxy-4-methoxyphenyls) -2- mesyls-second amine-n-acetyl group-L- is added in reaction bulb
Leucine salt crude product (10g, ee value：82.96%) water (200mL), is added, temperature is risen to 95 DEG C under stirring, solid is all molten
Solution, 10 DEG C are naturally cooling to, and are kept for 1.5 hours, filtering, filter cake is washed with water.Filter cake is dried into (S) -1- (3- ethoxies
Base -4- methoxyphenyls) -2- mesyls-second amine-n-acetyl group-L-Leu salt refining product (7.15g, based on S type isomeries
The yield of body content：78.2%, ee value：99.94%), HPLC chromatogram is similar to Fig. 5.
Embodiment 4
(S) -1- (3- ethoxy-4-methoxyphenyls) -2- mesyls-second amine-n-acetyl group-L- is added in reaction bulb
Leucine salt crude product (10g, ee value：88.36%) water (180mL), is added, backflow is warming up under stirring, dissolved clarification, is naturally cooling to
5 DEG C, maintain the temperature 1 hour, filter, filter cake water wash, filter cake is dried into (S) -1- (3- ethyoxyl -4- methoxybenzenes
Base) -2- mesyls-second amine-n-acetyl group-L-Leu salt refining product (7.60g, yield based on S type content of isomer：
80.7%, ee value：99.96%), HPLC chromatogram is similar to Fig. 5.
Embodiment 5
(S) -1- (3- ethoxy-4-methoxyphenyls) -2- mesyls-second amine-n-acetyl group-L- is added in reaction bulb
Leucine salt crude product (10g, ee value：88.36%) water (200mL), is added, temperature is risen to 90 DEG C under stirring, dissolved clarification, dropped naturally
Temperature maintains the temperature 1 hour to 5 DEG C, filters, filter cake water wash, filter cake is dried into (S) -1- (3- ethyoxyl -4- methoxies
Base phenyl) -2- mesyls-second amine-n-acetyl group-L-Leu salt refining product (7.74g, receipts based on S type content of isomer
Rate：82.2%, ee value：99.95%), HPLC chromatogram is similar to Fig. 5.
Embodiment 6
(S) -1- (3- ethoxy-4-methoxyphenyls) -2- mesyls-second amine-n-acetyl is added in 30L reactors
Base-L-Leu salt crude product (1kg, ee value：88.36%) water (20L), is added, backflow is warming up under stirring, solid is all molten
Solution, is naturally cooling to 0 DEG C, maintains the temperature 3 hours, filters, filter cake water wash, filter cake is dried into (S) -1- (3- ethoxies
Base -4- methoxyphenyls) and -2- mesyls-second amine-n-acetyl group-L-Leu salt refining product (0.786kg, it is different based on S types
The yield of structure body content：83.5%, ee value：99.95%), HPLC chromatogram is similar to Fig. 5.
Embodiment 7
(S) -1- (3- ethoxy-4-methoxyphenyls) -2- mesyls-second amine-n-acetyl group-L- is added in reaction bulb
Leucine salt crude product (10g, ee value：88.36%) water (250mL), is added, temperature is risen to 90 DEG C under stirring, dissolved clarification, dropped naturally
Temperature is kept for 3 hours to 0 DEG C, and filtering, filter cake is washed with water, and filter cake is dried into (S) -1- (3- ethyoxyl -4- methoxybenzenes
Base) -2- mesyls-second amine-n-acetyl group-L-Leu salt refining product (7.52g, yield based on S type content of isomer：
79.8%, ee value：99.93%), HPLC chromatogram is similar to Fig. 5.
Embodiment 8
(S) -1- (3- ethoxy-4-methoxyphenyls) -2- mesyls-second amine-n-acetyl group-L- is added in reaction bulb
Leucine salt crude product (10g, ee value：88.36%) water (300mL), is added, temperature is risen to 90 DEG C under stirring, dissolved clarification, dropped naturally
Temperature is kept for 5 hours to 0 DEG C, and filtering, filter cake is washed with water, and filter cake is dried into (S) -1- (3- ethyoxyl -4- methoxybenzenes
Base) -2- mesyls-second amine-n-acetyl group-L-Leu salt refining product (7.36g, yield based on S type content of isomer：
78.1%, ee value：99.94%), HPLC chromatogram is similar to Fig. 5.
Embodiment 9
(S) -1- (3- ethoxy-4-methoxyphenyls) -2- mesyls-second amine-n-acetyl group-L- is added in reaction bulb
Leucine salt refining product (1.0kg, ee value：99.95%), 3-acetamidophthalic anhydride (0.47kg) and glacial acetic acid
(10L), system are warming up to backflow, stir 5 hours, are concentrated under reduced pressure after naturally cooling to room temperature, into residue plus water (5L) and
Dichloromethane (5L), liquid separation is stood, organic phase washed with water (5L), saturated sodium bicarbonate solution (5L x 2) and water (5L) are washed
Wash, anhydrous sodium sulfate drying, filter, filtrate decompression is concentrated, and acetone (3L) is added in residue, is heated dissolved clarification, is added anhydrous
Ethanol (6L), room temperature is naturally cooled to, stirred 10 hours, filtered, drying, obtain Apremilast (0.81kg, yield：78.6%, ee
Value：99.95%), HPLC chromatogram is as shown in Figure 6.
Embodiment 10
As described in patent document WO2016161996 specifications, crude product (S) -4aa crude products are prepared, measuring its ee value is
88.0%.Enter water-filling weight crystalline substance by WO2016161996 embodiments 8, (S) -4aa highly finished product are made, measure its ee value as 98.8%.
Claims (7)
1. a kind of method of purifying formula (I) compound, wherein, the ee values of formula (I) crude compound are 65%-89%,
It is characterized in that：Formula (I) crude compound is recrystallized in pure water.
2. the method for purifying formula (I) compound according to claim 1, it is characterised in that：The re-crystallization step is：Will
Ee values are that 65%-89% formula (I) crude compound is soluble in water, and solid is warming up under stirring and is all dissolved, and cool crystallization, mistake
Filter, dry.
3. the method for purifying formula (I) compound according to claim 1 or 2, it is characterised in that：Ee values are 65%-89%
Formula (I) crude compound and water weigh-volume ratio be 1:18-30.
4. the method for purifying formula (I) compound according to claim 2, it is characterised in that：It is warming up under the stirring solid
The temperature that body all dissolves is 90-100 DEG C.
5. the method for purifying formula (I) compound according to claim 2, it is characterised in that：The temperature of the Crystallization Process
For 0-30 DEG C.
6. the method for purifying formula (I) compound according to claim 2, it is characterised in that：The time of the Crystallization Process
For 0.5-5 hours.
A kind of 7. method for preparing high chiral purity Apremilast, it is characterised in that using following steps：
A. formula (I) compound that ee values are 65%-89% is recrystallized to give formula (I) compound of ee values more than 99.9% with water
Highly finished product；
B. formula (I) compound highly finished product are more than 99.9% A Pusi with 3-acetamidophthalic anhydride reaction generation ee values
It is special；
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Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104529869A (en) * | 2014-12-19 | 2015-04-22 | 苏州亚宝药物研发有限公司 | Preparation method of (S)-2-[1-(3-ethoxy-4-methoxyphenyl)-2-methylsulfonyl ethyl]-4-acetyl amino isoindoline-1, 3-diketone isomer |
| CN105218428A (en) * | 2015-10-20 | 2016-01-06 | 南京美嘉宁逸医药研究开发有限公司 | A kind of preparation method of Apremilast of high chiral purity |
| CN105348172A (en) * | 2015-12-04 | 2016-02-24 | 新发药业有限公司 | Preparation of (S)-1-(4-methoxy-3-ethoxy)phenyl-2-methylsulfonyl ethylamine and preparation method of apremilast |
| WO2016161996A1 (en) * | 2015-04-09 | 2016-10-13 | Zentiva, K.S. | A method of chiral resolution of the key intermediate of the synthesis of apremilast and its use for the preparation of pure apremilast |
| WO2017033116A1 (en) * | 2015-08-26 | 2017-03-02 | Glenmark Pharmaceuticals Limited | Process for preparation of apremilast |
-
2017
- 2017-05-19 CN CN201710356919.8A patent/CN107628983B/en active Active
Patent Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104529869A (en) * | 2014-12-19 | 2015-04-22 | 苏州亚宝药物研发有限公司 | Preparation method of (S)-2-[1-(3-ethoxy-4-methoxyphenyl)-2-methylsulfonyl ethyl]-4-acetyl amino isoindoline-1, 3-diketone isomer |
| WO2016161996A1 (en) * | 2015-04-09 | 2016-10-13 | Zentiva, K.S. | A method of chiral resolution of the key intermediate of the synthesis of apremilast and its use for the preparation of pure apremilast |
| WO2017033116A1 (en) * | 2015-08-26 | 2017-03-02 | Glenmark Pharmaceuticals Limited | Process for preparation of apremilast |
| CN105218428A (en) * | 2015-10-20 | 2016-01-06 | 南京美嘉宁逸医药研究开发有限公司 | A kind of preparation method of Apremilast of high chiral purity |
| CN105348172A (en) * | 2015-12-04 | 2016-02-24 | 新发药业有限公司 | Preparation of (S)-1-(4-methoxy-3-ethoxy)phenyl-2-methylsulfonyl ethylamine and preparation method of apremilast |
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