CN104478790A - Preparation method of S-type apremilast - Google Patents
Preparation method of S-type apremilast Download PDFInfo
- Publication number
- CN104478790A CN104478790A CN201410782052.9A CN201410782052A CN104478790A CN 104478790 A CN104478790 A CN 104478790A CN 201410782052 A CN201410782052 A CN 201410782052A CN 104478790 A CN104478790 A CN 104478790A
- Authority
- CN
- China
- Prior art keywords
- reaction
- type
- apremilast
- preparation
- formula
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
Classifications
-
- 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
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Indole Compounds (AREA)
Abstract
The invention discloses a preparation method of apremilast (+)-2-[1-(3-ethoxy-4-methoxyphenyl)-2-mesylethyl]-4-acetamidoisoindolinyl-1,3-dione. The method comprises the following steps: (1) converting a compound 1-(3-ethoxy-4-methoxyphenyl)-2-(methanesulfonyl)ethylamine racemate disclosed as Formula (II) into a salification substance disclosed as Formula (III) by using a resolving agent; and (2) connecting the compound disclosed as Formula (III) with 3-acetamidophthalic anhydride to obtain the compound disclosed as Formula (I). The method can be utilized to obtain the stable apremilast acceptable finished product, has the advantages of mild technological conditions, simple after-treatment, high purity and low reaction cost, and can easily implement industrial production.
Description
Technical field
The invention belongs to chemicals synthesis technical field, relate to the preparation method of S type Apremilast (+)-2-[1-(3-oxyethyl group-4-methoxyphenyl)-2-methylsulfonylethyl]-4-acetamido isoindoline-1,3-diketone.
Background technology
Apremilast (apremilast), chemistry (+)-2-[1-(3-oxyethyl group-4-methoxyphenyl)-2-methylsulfonylethyl]-4-acetamido isoindoline-1,3-dione compounds by name, structural formula is as follows:
Apremilast (apremilast, trade(brand)name Otezla), by the independent development of new base medicine, is a kind of oral small molecules phosphodiesterase 4 (PDE4) inhibitor, is used for the treatment of psoriatic arthritis, psoriasis in plaques.Apremilast optionally suppresses PDE4, stops similar rheumatism synovial cell's secreting tumor necrosis factor α (TNF-α) and produce anti-inflammatory activity, can alleviate arthroncus and improve the physiological function of joint part.
The synthetic method of S type Apremilast is a lot, and the method summary of related documents report is as follows:
(1) method preparing Apremilast is disclosed in patent WO 2012083153 as follows:
With (s)-4-amino-2-, (1-(3-oxyethyl group-4-methoxyphenyl)-2-(methylsulfonylethyl) isoindoline-1,3-diketone, for starting raw material, carries out condensation reaction and obtains Apremilast the method.The shortcoming of the method is expensive raw material price.
(2) a kind of method preparing Apremilast is disclosed in United States Patent (USP) us20140081032 as follows:
The metal catalyst two (1 that the method is used in preparation process, 5-cyclooctadiene)-trifluoromethanesulfonic acid rhodium (I) and (R)-(-)-1-[(S)-2-diphenylphosphine ferrocene ethyl di-t-butyl phosphorus, environmental pollution is comparatively large, and production cost is high.
Summary of the invention
In view of the deficiencies in the prior art; it is shorter that technical problem to be solved by this invention is to provide a kind of synthesis step; be easy to purifying; simple to operate; the preparation method of (+)-2-[1-(3-oxyethyl group-4-methoxyphenyl)-2-methylsulfonylethyl]-4-acetamido isoindoline-1, the 3-diketone that yield is higher.
In order to realize object of the present invention, the present inventor is studied by lot of experiments, finally obtains following technical scheme:
A preparation method for S type Apremilast, comprises the following steps:
(1) formula II compound 1-(3-ethoxy-4-methoxyphenyl)-2-(methyl sulphonyl) ethamine raceme resolving agent is converted into the S type salify thing of formula III:
(2) formula III compound docks with 3-acetamido Tetra hydro Phthalic anhydride and obtains formula I oily compound:
(3) the refining of formula I oily compound to obtain solid formula I
Be S type Apremilast after gained formula I compound crystallization.
Preferably, the preparation method of above-mentioned S type Apremilast, wherein the temperature of reaction of step (1) is 70-80 DEG C, and the reaction times is 1-2 hour, reaction solvent be selected from ethanol, methyl alcohol and Virahol one or more; Described resolution reagent be selected from ALANINE, L-arginine, L-Aspartic acid, L-Leu one or more.
Further preferably, the preparation method of above-mentioned S type Apremilast, is characterized in that: the temperature of reaction in step (1) is 72 DEG C, and the described reaction times is 1.5 hours.
Preferably, the preparation method of above-mentioned S type Apremilast, is characterized in that: the temperature of reaction of step (2) is 118-125 DEG C, and the reaction times is 7-9 hour, reaction solvent be selected from formic acid, acetic acid and tetrahydrofuran (THF) one or more; 3-acetamido Tetra hydro Phthalic anhydride consumption is 1.0-1.05 times (M/M) of formula III; The times amount of reaction solvent is 3-6 times of reactant.
Further preferably, the preparation method of above-mentioned S type Apremilast, it is characterized in that: the temperature of reaction in step (2) is 125 DEG C, described solvent is formic acid, the consumption of described 3-acetamido Tetra hydro Phthalic anhydride is 1.03 times of formula III, and the times amount of described reaction solvent is 4 times of formula III and 3-acetamido Tetra hydro Phthalic anhydride consumption.
Preferably, the preparation method of above-mentioned S type Apremilast, the purification reaction temperature of step (3) is 80-90 DEG C, and the reaction times is 0.5-3 hour, and reaction solvent is selected from one or more of methyl alcohol, ethanol, n-propyl alcohol, Virahol and amylalcohol; Recrystallization temperature is 20-30 DEG C, and the crystallization time is 0.5-1 hour.
Further preferably, the preparation method of above-mentioned S type Apremilast, the reaction solvent wherein in step (3) is ethanol.
The present inventor, in research process, has found that one prepares S type Apremilast method.Compared with the conventional method comparatively, it is shorter that the method has synthesis step, simple to operate, is easy to purifying, and yield is high, the advantage that finished product is stable.In addition, present invention effectively prevents and use inflammable, deadly poisonous compound, simultaneously greatly reduce reactions steps, thus reduce reaction difficulty, and then simplify aftertreatment, improve yield and considerably reduce reaction cost, be beneficial to industrialized production.
Embodiment
Form is described in further detail foregoing of the present invention again by the following examples, but this should be interpreted as that the scope of the above-mentioned theme of the present invention is only limitted to following embodiment, all technology realized based on foregoing of the present invention all belong to scope of the present invention.
The preparation of embodiment S type Apremilast
(1) synthesis of compound 1-(3-ethoxy-4-methoxyphenyl)-2-(methyl sulphonyl) ethamine L-Leu salt (formula III)
In four mouthfuls of round-bottomed flasks of 1000mL; mechanical stirring is installed; reflux condensing tube; thermometer; 500ml methyl alcohol is added in round-bottomed flask; open and stir; add 64g1-(3-ethoxy-4-methoxyphenyl)-2-(methyl sulphonyl) ethamine, be warming up to 70 ~ 80 DEG C, reflux is dissolved completely to 1-(3-ethoxy-4-methoxyphenyl)-2-(methyl sulphonyl) ethamine; add 22gN-ethanoyl-L-Leu; insulation reaction 1h, close heating nature and be down to room temperature, suction filtration obtains solid; yield: 40%, ee value: 98.84%.
(2) synthesis of (+)-2-[1-(3-oxyethyl group-4-methoxyphenyl)-2-methylsulfonylethyl]-4-acetamido isoindoline-1,3-diketone (formula I)
In 500mL there-necked flask, 40g formula III, 20g3-acetamido Tetra hydro Phthalic anhydride and 300ml acetic acid add wherein, are heated to 115 ~ 125 DEG C, back flow reaction 8h, Liquid Detection formula III reacts completely, stopped reaction, is spin-dried for solvent, adds 80ml ethyl acetate and water, layering retains organic phase, aqueous phase ethyl acetate is washed, and merges organic phase, adds saturated NaHCO
3in and acetic acid, regulate pH value, organic phase anhydrous Na
2sO
4drying, adds 3g decolorizing with activated carbon, suction filtration, is spin-dried for organic phase and steams bottle constant weight to revolving, obtain oil product, be directly used in next step.
(3) S type Apremilast finished product is refining
Above-mentioned formula I oily matter, adds 150ml ethanol, reflux 0.5h, cooling crystallization, obtains off-white color solid.Yield: 90%
Relevant physico-chemical property, the spectroscopy data of compound (formula I) are as follows:
Fusing point: 142-145 DEG C;
1h NMR (300MHz, CDCl
3) δ (ppm): 9.5 (s, 1H), 8.7 (d, 1H), 6.8-7.7 (m, 5H), 5.9 (t, 1H), 4.5 (t, 1H), 4.1 (q, 2H), 3.8 (s, 3H), 3.6 (d, 1H), 3.6 (s, 2H), 2.9 (s, 3H), 2.3 (s, 3H), 1.5 (t, 3H); MS (ES) m/z461.1 ([M+H]
+).
The instrument adopted in the various embodiments described above and reagent as follows:
X-4 type micro-meldometer; Varian Mercury plus-500MHz type nuclear magnetic resonance analyser, AGILENTLC-MSD-Trap-SL mass spectrograph.
Other reagent used is commercially available analytical pure or chemical pure, not purified before using.
Claims (7)
1. a preparation method for S type Apremilast, is characterized in that comprising the following steps:
(1) formula II compound 1-(3-ethoxy-4-methoxyphenyl)-2-(methyl sulphonyl) ethamine raceme resolving agent is converted into the S type salify thing of formula III:
(2) formula III compound docks the formula of obtaining I oily compound with 3-acetamido Tetra hydro Phthalic anhydride:
(3) the refining of formula I oily compound to obtain solid type I, is S type Apremilast after gained formula I compound crystallization.
2. the preparation method of S type Apremilast according to claim 1, is characterized in that: the temperature of reaction of step (1) is 70-80 DEG C, and the reaction times is 1-2 hour, reaction solvent be selected from ethanol, methyl alcohol and Virahol one or more; Described resolution reagent be selected from ALANINE, L-arginine, L-Aspartic acid, L-Leu one or more.
3. the preparation method of S type Apremilast according to claim 2, it is characterized in that: the temperature of reaction in step (1) is 72 DEG C, the described reaction times is 1.5 hours.
4. the preparation method of S type Apremilast according to claim 1, is characterized in that: the temperature of reaction of step (2) is 118-125 DEG C, and the reaction times is 7-9 hour, reaction solvent be selected from formic acid, acetic acid and tetrahydrofuran (THF) one or more; 3-acetamido Tetra hydro Phthalic anhydride consumption is 1.0-1.05 times of formula III; The times amount of reaction solvent is 3-6 times of reactant, and consumption is with M/M molar ratio computing.
5. the preparation method of S type Apremilast according to claim 4, it is characterized in that: the temperature of reaction in step (2) is 125 DEG C, described solvent is formic acid, the consumption of described 3-acetamido Tetra hydro Phthalic anhydride is 1.03 times of formula III, the times amount of described reaction solvent is 4 times of formula III and 3-acetamido Tetra hydro Phthalic anhydride consumption, and consumption is with M/M molar ratio computing.
6. the preparation method of S type Apremilast according to claim 1, it is characterized in that: the purification reaction temperature of step (3) is 80-90 DEG C, reaction times is 0.5-3 hour, and reaction solvent is selected from one or more of methyl alcohol, ethanol, n-propyl alcohol, Virahol and amylalcohol; Recrystallization temperature is 20-30 DEG C, and the crystallization time is 0.5-1 hour.
7. the preparation method of S type Apremilast according to claim 6, is characterized in that: the reaction solvent in step (3) is ethanol.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201410782052.9A CN104478790A (en) | 2014-12-16 | 2014-12-16 | Preparation method of S-type apremilast |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201410782052.9A CN104478790A (en) | 2014-12-16 | 2014-12-16 | Preparation method of S-type apremilast |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN104478790A true CN104478790A (en) | 2015-04-01 |
Family
ID=52753425
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201410782052.9A Pending CN104478790A (en) | 2014-12-16 | 2014-12-16 | Preparation method of S-type apremilast |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN104478790A (en) |
Cited By (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104892486A (en) * | 2015-06-25 | 2015-09-09 | 济南纽华医药科技有限公司 | Novel Apremilast crystal form and preparation method thereof |
| CN104910062A (en) * | 2015-05-16 | 2015-09-16 | 南京海纳医药科技有限公司 | Apremilast refining method |
| CN104945306A (en) * | 2015-05-25 | 2015-09-30 | 山东铭康医药技术有限公司 | Method for preparing optically pure apremilast |
| CN105111127A (en) * | 2015-08-20 | 2015-12-02 | 济南纽华医药科技有限公司 | Apremilast amorphous form and preparation method therefor |
| 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 |
| CN106187857A (en) * | 2016-06-30 | 2016-12-07 | 浙江华海药业股份有限公司 | A kind of method preparing Apremilast |
| WO2017033116A1 (en) | 2015-08-26 | 2017-03-02 | Glenmark Pharmaceuticals Limited | Process for preparation of apremilast |
-
2014
- 2014-12-16 CN CN201410782052.9A patent/CN104478790A/en active Pending
Non-Patent Citations (1)
| Title |
|---|
| HON-WAH MAN 等: ""Discovery of (S)-N-{2-[1-(3-Ethoxy-4-methoxyphenyl)-2-methanesulfonylethyl]-1,3-dioxo-2,3-dihydro-1H- isoindol-4-yl}acetamide (Apremilast), a Potent and Orally Active Phosphodiesterase 4 and Tumor Necrosis Factor-α Inhibitor"", 《J. MED. CHEM.》 * |
Cited By (13)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104910062A (en) * | 2015-05-16 | 2015-09-16 | 南京海纳医药科技有限公司 | Apremilast refining method |
| CN104945306A (en) * | 2015-05-25 | 2015-09-30 | 山东铭康医药技术有限公司 | Method for preparing optically pure apremilast |
| CN104945306B (en) * | 2015-05-25 | 2017-07-21 | 山东铭康医药技术有限公司 | The method for preparing optical voidness Apremilast |
| WO2016206534A1 (en) * | 2015-06-25 | 2016-12-29 | 济南纽华医药科技有限公司 | New crystal form of apremilast and preparation method therefor |
| CN104892486A (en) * | 2015-06-25 | 2015-09-09 | 济南纽华医药科技有限公司 | Novel Apremilast crystal form and preparation method thereof |
| CN105111127A (en) * | 2015-08-20 | 2015-12-02 | 济南纽华医药科技有限公司 | Apremilast amorphous form and preparation method therefor |
| WO2017033116A1 (en) | 2015-08-26 | 2017-03-02 | Glenmark Pharmaceuticals Limited | Process for preparation of apremilast |
| EP3341359A4 (en) * | 2015-08-26 | 2019-04-24 | Glenmark Pharmaceuticals Limited | Process for preparation of apremilast |
| EP3341359B1 (en) | 2015-08-26 | 2022-03-23 | Glenmark Life Sciences 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 |
| CN106187857A (en) * | 2016-06-30 | 2016-12-07 | 浙江华海药业股份有限公司 | A kind of method preparing Apremilast |
| WO2018001353A1 (en) * | 2016-06-30 | 2018-01-04 | 浙江华海药业股份有限公司 | Method for preparing apremilast |
| US10781173B2 (en) | 2016-06-30 | 2020-09-22 | Zhejiang Huahai Pharmaceutical Co., Ltd | Method for preparing apremilast |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN104478790A (en) | Preparation method of S-type apremilast | |
| CN101891649B (en) | Novel 3-cyano methyl benzoate preparing method | |
| CN109232178B (en) | Novel method for preparing high-purity hydroxytyrosol | |
| CN103664677A (en) | Asymmetric synthesis method of (R,R)-formoterol tartrate | |
| CN115233243A (en) | Preparation method of 2,4, 5-trisubstituted oxazole derivative under electrocatalysis | |
| CN110330440A (en) | A kind of technique that 5-ALA is prepared with 5- chloromethyl furfural | |
| CN113181850A (en) | Microchannel preparation method of indole compound | |
| CN102942560A (en) | Preparation method of 3-(2-methylindolyl-3-)pyrryl-2,5-dione | |
| CN103435477B (en) | A kind of method of synthesizing paraethoxybenxoic acid | |
| CN103396338B (en) | Method for synthesizing nitrile from aldoxime under catalyzing of selenium-containing catalyst | |
| CN116283707A (en) | Synthesis method of indole compound promoted by visible light | |
| CN106892807B (en) | A kind of preparation method of the isophorone using organic imidazoles system quaternary ammonium strong base catalyst | |
| CN101704788B (en) | Improved preparation process of 2-Butyl-1,3-diazapira[4,4]nonane-1-en-4-one | |
| CN104130146A (en) | Preparation method of (4S)-3, 6, 9-triaza-3, 6, 9-tri(carboxymethyl)-4-(4-ethoxy benzyl)undecanedioic acid | |
| SHALLU et al. | First total synthesis of a guanidine alkaloid Nitensidine D using immobilized ionic liquid, microwaves and formamidinesulfinic acid | |
| CN106478422A (en) | A kind of preparation method of paranitrophenylacetic acid | |
| CN106883192A (en) | The synthetic method of the benzoic acid derivative of nitrogenous class heterocyclic antineoplastic pharmaceutical actives oxazolyl modification | |
| CN100554252C (en) | A kind of preparation method of Sumatriptan Succinate | |
| CN103804373A (en) | Synthesis process of azasetron hydrochloride | |
| CN109879775A (en) | A kind of environment-friendly preparation method of 5-ALA hydrochloride intermediate | |
| CN107501136B (en) | A method of it prepares together with diaryl methylamines | |
| CN101723879B (en) | Method for synthesizing (R)-3-ethyl piperidine hydrochloride | |
| CN104211652A (en) | Method for preparing plerixafor | |
| CN112876383B (en) | Preparation method of 4H-pyran compound | |
| CN114105796B (en) | Synthesis method of stable isotope deuterium labeled isoleucine |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| WD01 | Invention patent application deemed withdrawn after publication | ||
| WD01 | Invention patent application deemed withdrawn after publication |
Application publication date: 20150401 |