CN107188842A - A kind of method for preparing high-purity Apremilast - Google Patents
A kind of method for preparing high-purity Apremilast Download PDFInfo
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- CN107188842A CN107188842A CN201710238205.7A CN201710238205A CN107188842A CN 107188842 A CN107188842 A CN 107188842A CN 201710238205 A CN201710238205 A CN 201710238205A CN 107188842 A CN107188842 A CN 107188842A
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- apremilast
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
- C07D209/44—Iso-indoles; Hydrogenated iso-indoles
- C07D209/48—Iso-indoles; Hydrogenated iso-indoles with oxygen atoms in positions 1 and 3, e.g. phthalimide
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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
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Abstract
The title of the present invention is " a kind of method for preparing high-purity Apremilast ", is related to field of pharmaceutical chemistry technology, and in particular to the preparation method of high-purity Apremilast.Formula (I) Apremilast is prepared the invention provides one kind：(S) preparation method of the high-purity of the diketone of 2 [1 (methoxyphenyl of 3 ethyoxyl 4) 2 methylsulfonylethyls] 4 acetylaminoisoindoline 1,3：Chiral Amine：(S) 1 (methoxyphenyl of 3 ethyoxyl 4) 2 (mesyl) ethamine and acid anhydrides：3 acetylamino phthalic anhydrides are in acetic acid solvent, alkali metal acetate is catalyst, reaction generation is such as formula (I) Apremilast, after being refined again through acetone ethanol mixed solvent crystallization, purity is obtained up to 99.9%, it is single it is miscellaneous be not more than 0.05% high-purity finished product, reaction yield is up to more than 90%.Technological reaction mild condition, production cost are low, suitable industrialized production, there is good economic benefits.
Description
Technical field
The present invention relates to field of pharmaceutical chemistry technology, and in particular to the preparation method of high-purity Apremilast.
Background technology
Apremilast (Apremilast), entitled (S) -2- [1- (3- the ethoxy-4-methoxyphenyls) -2- first sulphurs of chemistry
Methylaminosulfonylethyl] -4- acetylaminoisoindoline -1,3- diketone, molecular formula is C22H24N207S, and molecular weight is 460.50, chemistry
Structural formula is as follows：
Apremilast is a kind of selective small molecule phosphodiesterase 4 (PDE4) inhibitor, biological (Celgene) by new base
Company is developed, trade name Otezla, and U.S. FDA approval is obtained on March 21st, 2014 as the mouth for the treatment of psoriatic arthritis
Take medicine thing listing, the granted new idicatio of in September, 2014, in treatment to severe plaque psoriasis patient.
Apremilast is that the first of FDA approvals is also that only one is used for the PDE4 inhibitor that psoriasis in plaques is treated,
Compared with current clinical conventional anti-TNF monoclonal antibodies, with brand-new mechanism of action.Psoriasis in plaques is that immune response is lost
The scorching disease of chronic skin caused by control, global sufferer number is more than 1.25 hundred million.Clinical test shows that Apremilast is heavy in can reducing
Spend the erythema of psoriasis in plaques sufferer, thicken and furfur.After being treated 16 weeks with Apremilast, by static doctor's total evaluation
(sPGA) scoring is weighed, and shows clinical improvementses, including tenderness, arthroncus and body function.Evaluate Pharma are predicted
The annual sales amount of Apremilast 2018 is 12.19 hundred million dollars.
Apremilast is used as a kind of oral small molecule phosphodiesterase (PDE4) inhibitor, the suppression of energy selectivity
PDE4, can specific effect in CAMP (cAMP).PDE4 suppresses to cause intracellular cAMP levels to increase, and thus prevents class
The inflammatory cytokines such as rheumatism synovial cell's secreting tumor necrosis factor α (TNF-α) lower inflammatory reaction.Except granted psoriasis
Outside arthritis and severe plaque psoriasis indication, Apremilast also includes Behcet's syndrome in the indication ground simultaneously
(II phases), ankylosing spondylitis (III phases), rheumatoid arthritis (II phases) and atopic dermatitis (II phases).Therefore A Pusi
The special scope in treatment of inflammatory diseases field is expected to further expansion.
The preparation method of Apremilast intermediate is a lot, primarily to obtaining (S) -1- (3- ethyoxyls -4- of chiral purity
Methoxyphenyl) -2- mesyl ethamine.But most critical one-step synthesis document report is seldom, last synthetic method (including original
Grind patent CN1652772) often it is aggregated into shown in following reaction equation：
Original grinds patent CN1652772 reports by the N- acetyl group-L-Leu salt and acid anhydrides of Chiral Amine using acetic acid as solvent,
Reaction backflow (117 DEG C of acetic acid boiling point) is stayed overnight.But the reaction can generate acetyl impurity, influence production under the conditions of high-temperature acidic
Thing purity.
Patent CN105218428 reports reaction condition and makees solvent for toluene, and acetic acid is catalyst, more than 110 degrees Celsius
Back flow reaction.The condition is not avoided that high temperature not only, also uses two class solvent toluenes, adds the wind of product residue solvent
Danger.
Patent CN105085373 is reported using acid anhydrides and Chiral Amine as raw material, and acetic acid is solvent, and back flow reaction treats chirality
Amine adds aceticanhydride after disappearing continues to react, and acetyl impurity is removed to reduce.The reaction condition is not avoided that pyroreaction, Er Qieyong yet
To control class chemicals aceticanhydride (easily system poison), increase production difficulty and cost.
Patent CN106187857 is reported using acid anhydrides and Chiral Amine as raw material, in non-protonic solvent, add tertiary amine or
Sodium alkoxide or alkali metal hydride, are reacted at a temperature of 40~90 DEG C, it is to avoid acetyl impurity is removed in high temperature generation when long.But the reaction
Sodium alkoxide that condition is used, alkali metal hydride belong to highly basic, easily put hydrogen, are applied in production than relatively hazardous.
The content of the invention
The present invention seeks to there is provided a kind of new preparation process of Apremilast, this method reaction in view of the shortcomings of the prior art
Mild condition, yield are up to more than 90%, purity up to 99.9%, and production technology is more suitable for industrialization.
In order to reach as above purpose, the invention provides following technical scheme：
A kind of preparation method of Apremilast as shown in pre-structure formula (I), includes following process：
Chiral amine salt and acid anhydrides are fed intake, reaction condition is that acetic acid is solvent, and alkali metal acetate is catalyst, plus
Under heat condition, a few hours are reacted, occur acylated ring-closure reaction generation product Apremilast as shown in formula (I)：
Here, described acid anhydrides is 3-acetamidophthalic anhydride；The chiral amine salt is (S) -1- (3- ethoxies
Base -4- methoxyphenyls) -2- mesyl ethamine N- acetyl group-L-Leu salt.
Wherein, alkali metal acetate is selected from lithium acetate, potassium acetate and sodium acetate or its combination, preferably sodium acetate；
Wherein, it is 0.5~1.5, preferably 0.8~1.2 that alkali metal acetate, which feeds intake for the relatively chiral amine salt of equivalent,；
Wherein, chiral amine salt is generally 1g with quality of acetic acid volume ratio: (5~15) ml, preferably 1g: (8~12) ml；
Wherein, the mass ratio of chiral amine salt and acid anhydrides is generally 1: (0.46~0.68), preferably 1: (0.46~0.50)
Wherein, reaction temperature control is in 50~120 DEG C of progress, preferably in 70~100 DEG C of scopes；
Wherein, reaction time general control was at 2~8 hours, and further preferably control was at 4~6 hours.
Wherein, reaction obtain Apremilast crude product need to be by being refining to obtain high-purity Apremilast finished product, specific method is
With acetone and alcohol mixed solvent crystallization twice.
Wherein, in the process for purification, the w/v of Apremilast crude product and mixed solvent is：1g: (6~12)
Ml, preferably 1g: (8~10) ml；
Wherein, in the process for purification, the mixed solvent, the volume ratio of acetone and ethanol is 1: 1~5, further excellent
Choosing, the volume ratio of acetone and ethanol is 1: 2.5~3.5 when crystallizing for the first time, the volume ratio of acetone and ethanol when crystallizing for the second time
For 1: 1.3~1.5；
Wherein, in the process for purification, whipping temp during crystallization is 30~40 DEG C, preferably 32~38 DEG C.
The reaction provided according to the present invention and polishing purification method, grind patented method with original and are compared, can make reaction temperature
90 DEG C or so are dropped to from more than 110 DEG C, the reaction time shortens nearly 10 hours, while improving reaction yield nearly 20%, simultaneously
It can effectively make the single impurity of Apremilast relatively low to less than 0.05%, Apremilast purity is up to 99.9%.A Pu of the present invention
This special Preparation Method has that reaction condition is gentle, reaction yield is high, the low advantage of production cost, is suitable for Apremilast industry
Metaplasia is produced.
Brief description of the drawings
Fig. 1 is the high-efficient liquid phase chromatogram of the product of embodiment 1；
Fig. 2 is the high-efficient liquid phase chromatogram of comparative example product；
Fig. 3 is the hydrogen nuclear magnetic resonance spectrogram of the product of embodiment 1；
Fig. 4 is the carbon-13 nmr spectra figure of the product of embodiment 1；
Fig. 5 is the mass spectrogram of the product of embodiment 1；
Fig. 6 is the infrared spectrogram of the product of embodiment 1
Embodiment
Below to being illustrated by particular specific embodiment to embodiments of the present invention, embodiment is not constituted to this hair
Bright limitation.
Embodiment one：
By (S) -1- (3- ethoxy-4-methoxyphenyls) -2- mesyl ethamine N- acetyl group-L-Leu salt
(4.46g, 10mmol) and 3-acetamidophthalic anhydride (2.15g, 10.5mmol) add tri- mouthfuls of reaction flasks of 100ml
In, 45ml glacial acetic acid is added, sodium acetate (0.82g, 10mmol) is added.80 DEG C are heated with stirring to, is reacted 5 hours.TLC is monitored
Reaction is finished, and be concentrated under reduced pressure removing glacial acetic acid, and 50ml ethyl acetate is added in residue, with water, saturated sodium bicarbonate solution, is satisfied
With each 20ml of saline solution washings, organic phase anhydrous sodium sulfate drying, filtering and concentrating.Absolute ethyl alcohol is added in concentrated residues thing
30ml, acetone 10ml mixed solvents, backflow are stirred 1 hour.Be down to room temperature, stirring and crystallizing 5 hours, filtering be dried under reduced pressure Ah
This general extraordinarily thick product 4.4g.Crude product is put into reaction bulb, absolute ethyl alcohol 25ml, acetone 9ml mixed solvents is added, flow back dissolved clarification,
Stirring 1 hour, is down to room temperature, stirring and crystallizing 5 hours.Solid is collected by filtration, is dried under reduced pressure and obtains the white solid powder of 4.2g classes.Receive
Rate 91.3%, HPLC purity 99.9%, wherein going acetyl impurity to be 0.03%.
Embodiment two：
By (S) -1- (3- ethoxy-4-methoxyphenyls) -2- mesyl ethamine N- acetyl group-L-Leu salt
(4.46g, 10mmol) and 3-acetamidophthalic anhydride (2.15g, 10.5mmol) add tri- mouthfuls of reaction flasks of 100ml
In, 45ml glacial acetic acid is added, potassium acetate (0.98g, 10mmol) is added.80 DEG C are heated with stirring to, is reacted 5 hours.TLC is monitored
Reaction is finished, and be concentrated under reduced pressure removing glacial acetic acid, and 50ml ethyl acetate is added in residue, with water, saturated sodium bicarbonate solution, is satisfied
With each 20ml of saline solution washings, organic phase anhydrous sodium sulfate drying, filtering and concentrating.Absolute ethyl alcohol is added in concentrated residues thing
30ml, acetone 10ml mixed solvents, backflow are stirred 1 hour.Be down to room temperature, stirring and crystallizing 5 hours, filtering be dried under reduced pressure Ah
This general extraordinarily thick product 4.35g.Crude product is put into reaction bulb, absolute ethyl alcohol 25ml, acetone 9ml mixed solvents is added, flow back dissolved clarification,
Stirring 1 hour, is down to room temperature, stirring and crystallizing 5 hours.Solid is collected by filtration, is dried under reduced pressure and obtains the white solid powder of 4.14g classes.
Yield 90.1%, HPLC purity 99.9%, wherein going acetyl impurity to be 0.03%.
Embodiment three：
By (S) -1- (3- ethoxy-4-methoxyphenyls) -2- mesyl ethamine N- acetyl group-L-Leu salt
(4.46g, 10mmol) and 3-acetamidophthalic anhydride (2.15g, 10.5mmol) add tri- mouthfuls of reaction flasks of 100ml
In, 45ml glacial acetic acid is added, lithium acetate (0.66g, 10mmol) is added.80 DEG C are heated with stirring to, is reacted 5 hours.TLC is monitored
Reaction is finished, and be concentrated under reduced pressure removing glacial acetic acid, and 50ml ethyl acetate is added in residue, with water, saturated sodium bicarbonate solution, is satisfied
With each 20ml of saline solution washings, organic phase anhydrous sodium sulfate drying, filtering and concentrating.Absolute ethyl alcohol is added in concentrated residues thing
30ml, acetone 10ml mixed solvents, backflow are stirred 1 hour.Be down to room temperature, stirring and crystallizing 5 hours, filtering be dried under reduced pressure Ah
This general extraordinarily thick product 4.33g.Crude product is put into reaction bulb, absolute ethyl alcohol 25ml, acetone 9ml mixed solvents is added, flow back dissolved clarification,
Stirring 1 hour, is down to room temperature, stirring and crystallizing 5 hours.Solid is collected by filtration, is dried under reduced pressure and obtains the white solid powder of 4.08g classes.
Yield 88.7%, HPLC purity 89.9%, wherein going acetyl impurity to be 0.04%.
Comparative example：
According to the former preparation method for grinding compound A in 5.2 embodiments 2 in patent CN1652772：Feed intake (S) -1- (3- second
Epoxide -4- methoxyphenyls) -2- mesyl ethamine N- acetyl group-L-Leu salt 5g, 3-acetamidophthalic anhydride
2.42g, adds 50ml glacial acetic acid, and reactant mixture is heated to 115 DEG C, reacts 18 hours, then cooling vacuum concentration, by remnants
Thing is dissolved in 50ml ethyl acetate, is washed with water, saturated sodium bicarbonate solution, each 50ml of saturated aqueous common salt, and anhydrous sodium sulfate is done
It is dry.It is concentrated in vacuo, residue is crystallized with 30ml ethanol and 15ml acetone mixed solvents, is filtered and is washed solid with ethanol, is depressurized
Dry to constant weight, obtain 3.97g white solid powder Apremilasts.Yield 77%, HPLC purity 99.7%, wherein removing acetyl
Impurity is 0.13%.
The foregoing is only a preferred embodiment of the present invention, but protection scope of the present invention not limited to this, it is any
Those skilled in the art are familiar with the technical scope of present disclosure, technique according to the invention scheme and its inventive concept
It is subject to equivalent substitution or change, is regarded as falling into the scope of the present invention.
Claims (11)
1. a kind of preparation method of Apremilast as shown in formula (I)：Acetic acid is as reaction dissolvent, and chiral amine salt is with acid anhydrides in alkali
Metal acetate obtains high-purity A Pu under catalyst heating condition, to obtain formula (I) compound Apremilast after refined
This special finished product.
2. preparation method according to claim 1, it is characterised in that：Alkali metal acetate be selected from lithium acetate, potassium acetate and
Sodium acetate or its combination, preferably sodium acetate.
3. preparation method according to claims 1 to 2, it is characterised in that：The alkali metal acetate equivalent that feeds intake is relatively chiral
It is 0.5~1.5, preferably 0.8~1.2 for amine salt.
4. preparation method according to claims 1 to 3, it is characterised in that：Chiral amine salt and quality of acetic acid volume ratio are general
For 1g: (5~15) ml, preferably 1g: (8~12) ml.
5. preparation method according to claim 1, it is characterised in that：The mass ratio of chiral amine salt and acid anhydrides is generally 1:
(0.46~0.68), preferably 1: (0.46~0.50).
6. preparation method according to claims 1 to 5, it is characterised in that：Reaction temperature control is carried out at 50~120 DEG C,
It is preferred that in 70~100 DEG C of scopes.
7. preparation method according to claims 1 to 6, it is characterised in that：Reaction time general control entered at 2~8 hours
One step is preferably controlled in 4~6 hours.
8. process for purification according to claim 1, it is characterised in that：With acetone and alcohol mixed solvent crystallization twice.
9. the process for purification according to claim 1,8, it is characterised in that：The weighing body of Apremilast crude product and mixed solvent
Accumulating ratio is：1g: (6~12) ml, preferably 1g: (8~10) ml.
10. the process for purification according to claim 1,8,9, it is characterised in that：The body of the mixed solvent, acetone and ethanol
Product ratio is 1: 1~5, further preferably, and the volume ratio of acetone and ethanol is 1: 2.5~3.5 when crystallizing for the first time, is crystallized for the second time
When acetone and ethanol volume ratio be 1: 1.3~1.5.
11. the process for purification according to claim 1,8,9,10, it is characterised in that：Whipping temp during crystallization is 30~40
DEG C, preferably 32~38 DEG C.
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN107698485A (en) * | 2017-11-23 | 2018-02-16 | 中山奕安泰医药科技有限公司 | A kind of refined preparation technology of high-purity Apremilast |
| WO2019073431A1 (en) * | 2017-10-12 | 2019-04-18 | Piramal Enterprises Limited | An improved process for the preparation of apremilast and its intermediate |
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| CN105085373A (en) * | 2015-09-01 | 2015-11-25 | 苏州大学 | Purification method of apremilast product |
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2019073431A1 (en) * | 2017-10-12 | 2019-04-18 | Piramal Enterprises Limited | An improved process for the preparation of apremilast and its intermediate |
| CN107698485A (en) * | 2017-11-23 | 2018-02-16 | 中山奕安泰医药科技有限公司 | A kind of refined preparation technology of high-purity Apremilast |
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