CN110818583A - Preparation and refining method of apremilast key intermediate - Google Patents
Preparation and refining method of apremilast key intermediate Download PDFInfo
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- CN110818583A CN110818583A CN201810913325.7A CN201810913325A CN110818583A CN 110818583 A CN110818583 A CN 110818583A CN 201810913325 A CN201810913325 A CN 201810913325A CN 110818583 A CN110818583 A CN 110818583A
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- 238000002360 preparation method Methods 0.000 title claims abstract description 15
- 238000000034 method Methods 0.000 title claims abstract description 14
- IMOZEMNVLZVGJZ-QGZVFWFLSA-N apremilast Chemical compound C1=C(OC)C(OCC)=CC([C@@H](CS(C)(=O)=O)N2C(C3=C(NC(C)=O)C=CC=C3C2=O)=O)=C1 IMOZEMNVLZVGJZ-QGZVFWFLSA-N 0.000 title claims abstract description 11
- 229960001164 apremilast Drugs 0.000 title claims abstract description 10
- 238000007670 refining Methods 0.000 title claims abstract description 10
- 150000001875 compounds Chemical class 0.000 claims description 29
- 238000006243 chemical reaction Methods 0.000 claims description 23
- 238000003756 stirring Methods 0.000 claims description 23
- 238000001914 filtration Methods 0.000 claims description 22
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 21
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 15
- 239000000047 product Substances 0.000 claims description 15
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 claims description 12
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 11
- 239000002904 solvent Substances 0.000 claims description 11
- 238000001035 drying Methods 0.000 claims description 9
- 238000004537 pulping Methods 0.000 claims description 9
- 239000007810 chemical reaction solvent Substances 0.000 claims description 8
- 239000012065 filter cake Substances 0.000 claims description 8
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 claims description 8
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical group CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 7
- VZTDIZULWFCMLS-UHFFFAOYSA-N ammonium formate Chemical compound [NH4+].[O-]C=O VZTDIZULWFCMLS-UHFFFAOYSA-N 0.000 claims description 7
- 239000000706 filtrate Substances 0.000 claims description 7
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 7
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 6
- 238000010438 heat treatment Methods 0.000 claims description 6
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 claims description 5
- 238000004519 manufacturing process Methods 0.000 claims description 5
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 claims description 4
- 239000003054 catalyst Substances 0.000 claims description 4
- 239000012043 crude product Substances 0.000 claims description 4
- 235000019253 formic acid Nutrition 0.000 claims description 4
- 239000000852 hydrogen donor Substances 0.000 claims description 4
- 125000003158 alcohol group Chemical group 0.000 claims description 3
- 238000001816 cooling Methods 0.000 claims description 3
- 238000002425 crystallisation Methods 0.000 claims description 2
- 230000008025 crystallization Effects 0.000 claims description 2
- 229910052763 palladium Inorganic materials 0.000 claims description 2
- 230000001502 supplementing effect Effects 0.000 claims description 2
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims 2
- 239000002002 slurry Substances 0.000 claims 1
- WGLQHUKCXBXUDV-UHFFFAOYSA-L 3-aminophthalate Chemical compound NC1=CC=CC(C([O-])=O)=C1C([O-])=O WGLQHUKCXBXUDV-UHFFFAOYSA-L 0.000 abstract description 5
- 238000011031 large-scale manufacturing process Methods 0.000 abstract description 3
- -1 apremilast intermediate compound Chemical class 0.000 description 7
- 235000019441 ethanol Nutrition 0.000 description 5
- UKVIEHSSVKSQBA-UHFFFAOYSA-N methane;palladium Chemical compound C.[Pd] UKVIEHSSVKSQBA-UHFFFAOYSA-N 0.000 description 5
- ZBZAVEORKXFUQB-UHFFFAOYSA-N 3-aminophthalic acid;hydron;chloride Chemical compound Cl.NC1=CC=CC(C(O)=O)=C1C(O)=O ZBZAVEORKXFUQB-UHFFFAOYSA-N 0.000 description 4
- 238000005984 hydrogenation reaction Methods 0.000 description 4
- 239000012071 phase Substances 0.000 description 4
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 3
- 201000004681 Psoriasis Diseases 0.000 description 3
- 239000007791 liquid phase Substances 0.000 description 3
- 238000001228 spectrum Methods 0.000 description 3
- MSYGAHOHLUJIKV-UHFFFAOYSA-N 3,5-dimethyl-1-(3-nitrophenyl)-1h-pyrazole-4-carboxylic acid ethyl ester Chemical compound CC1=C(C(=O)OCC)C(C)=NN1C1=CC=CC([N+]([O-])=O)=C1 MSYGAHOHLUJIKV-UHFFFAOYSA-N 0.000 description 2
- WGLQHUKCXBXUDV-UHFFFAOYSA-N 3-aminophthalic acid Chemical compound NC1=CC=CC(C(O)=O)=C1C(O)=O WGLQHUKCXBXUDV-UHFFFAOYSA-N 0.000 description 2
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 2
- 201000001263 Psoriatic Arthritis Diseases 0.000 description 2
- 208000036824 Psoriatic arthropathy Diseases 0.000 description 2
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 2
- 102000011017 Type 4 Cyclic Nucleotide Phosphodiesterases Human genes 0.000 description 2
- 108010037584 Type 4 Cyclic Nucleotide Phosphodiesterases Proteins 0.000 description 2
- 238000001514 detection method Methods 0.000 description 2
- 229910052739 hydrogen Inorganic materials 0.000 description 2
- 239000001257 hydrogen Substances 0.000 description 2
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 description 2
- RWSOTUBLDIXVET-UHFFFAOYSA-N Dihydrogen sulfide Chemical compound S RWSOTUBLDIXVET-UHFFFAOYSA-N 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 239000008186 active pharmaceutical agent Substances 0.000 description 1
- 206010003246 arthritis Diseases 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 229910052799 carbon Inorganic materials 0.000 description 1
- 230000003197 catalytic effect Effects 0.000 description 1
- 238000009903 catalytic hydrogenation reaction Methods 0.000 description 1
- 238000010828 elution Methods 0.000 description 1
- 239000000945 filler Substances 0.000 description 1
- 239000007789 gas Substances 0.000 description 1
- 229910000037 hydrogen sulfide Inorganic materials 0.000 description 1
- 239000003112 inhibitor Substances 0.000 description 1
- 229910017053 inorganic salt Inorganic materials 0.000 description 1
- YTJSFYQNRXLOIC-UHFFFAOYSA-N octadecylsilane Chemical compound CCCCCCCCCCCCCCCCCC[SiH3] YTJSFYQNRXLOIC-UHFFFAOYSA-N 0.000 description 1
- 229940126701 oral medication Drugs 0.000 description 1
- 229940011530 otezla Drugs 0.000 description 1
- NXJCBFBQEVOTOW-UHFFFAOYSA-L palladium(2+);dihydroxide Chemical compound O[Pd]O NXJCBFBQEVOTOW-UHFFFAOYSA-L 0.000 description 1
- 239000008213 purified water Substances 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- 238000013341 scale-up Methods 0.000 description 1
- 239000000377 silicon dioxide Substances 0.000 description 1
- 229910052979 sodium sulfide Inorganic materials 0.000 description 1
- GRVFOGOEDUUMBP-UHFFFAOYSA-N sodium sulfide (anhydrous) Chemical compound [Na+].[Na+].[S-2] GRVFOGOEDUUMBP-UHFFFAOYSA-N 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C227/00—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton
- C07C227/04—Formation of amino groups in compounds containing carboxyl groups
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C227/00—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton
- C07C227/38—Separation; Purification; Stabilisation; Use of additives
- C07C227/40—Separation; Purification
- C07C227/42—Crystallisation
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Crystallography & Structural Chemistry (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention provides a preparation and refining method of an apremilast key intermediate 3-aminophthalate, which is safe, efficient, economic and suitable for large-scale production.
Description
Technical Field
The invention belongs to the field of pharmaceutical chemistry, and particularly relates to a preparation and refining method of an apremilast intermediate compound, namely 3-aminophthalic acid hydrochloride shown in a formula (II).
Background
Apremilast (Apremilast) is a phosphodiesterase-4 (PDE-4) inhibitor useful in the treatment of active psoriatic arthritis in adults. Apremilast was first developed by cytogene corporation under the trade name OTEZLA®(ii) a In 2008, the prevalence rate of psoriasis in 6 provinces and cities in China is 0.47%, 624 ten thousand patients are calculated to exist in China, about 5-7% of patients with psoriasis are suffering from arthritis, the prevalence rate of the psoriatic arthritis in China is about 1.23 per thousand, and no less than 100 thousand patients in China are calculated. Apremilast was the first oral drug approved for the treatment of psoriasis for 20 years. The sale amount reaches 4.72 billion dollars in 2015, and the sale amount is estimated to exceed 20 billion dollars in 2019; the original patent US9642836B2 discloses the preparation method and the key intermediateThe compound formula (II) is prepared by catalytic hydrogenation reduction of the compound formula (I), and the reaction requires hydrogen pressurization and comprises the following steps:
the method takes 3-nitro-collarbenzenedicarboxylic acid as a starting material, and prepares the 3-aminophthalic acid by reducing nitro through palladium-carbon catalytic pressure hydrogenation, hydrogenation equipment such as a high-pressure hydrogenation reaction kettle is required for the reaction, the reaction is used as an API intermediate for production, the production is limited by equipment, and potential safety hazards exist in the pressure hydrogenation reaction;
the document Chemische Berichte (vol.34; (1901); p.3744) reports a process for reducing nitro groups using sodium sulfide, the route being as follows:
the method has slow reaction, incomplete reaction along with batch increase, generates a large amount of odorous hydrogen sulfide gas, the reaction solvent is usually water or alcohol, the free state or hydrochloride form water-soluble alcohol solubility of the target product is good, salt is difficult to remove through post-treatment, and the target product with high content is difficult to obtain
The above-mentioned documents report that the preparation methods of the compound of formula (II) 3-aminophthalic acid all have a number of disadvantages, which are disadvantageous for scale-up production.
Disclosure of Invention
The purpose of the invention is as follows: provides a safe, efficient and economic preparation and refining method of an apremilast key intermediate 3-aminophthalic acid hydrochloride compound shown as a formula (II) and is suitable for large-scale production.
In order to achieve the purpose, the invention adopts the following technical scheme:
a preparation and refining method of an apremilast key intermediate 3-aminophthalic acid hydrochloride compound shown as a formula (II) comprises the following steps:
the synthetic route is as follows:
the preparation and refining steps are as follows:
(1) adding a compound shown as a formula (I) into a reaction bottle, adding a solvent, a hydrogen donor and a catalyst, and heating and stirring for reaction;
(2) when the reaction solvent is alcohol, after the reaction is completed, adding hydrochloric acid to adjust the pH to a proper pH, supplementing alcohol, stirring and filtering, collecting the filtrate, concentrating under reduced pressure to dryness, adding a proper solvent, stirring and pulping, filtering, and drying under reduced pressure to obtain a target product compound formula (II); when the reaction solvent is water, filtering after complete reaction, adding hydrochloric acid to adjust to proper PH, cooling for crystallization, filtering, collecting filter cakes, adding proper solvent, stirring for pulping, filtering, and drying under reduced pressure to obtain a target product compound formula (II);
in the present invention, the solvent in step (1) is preferably one selected from water, methanol and ethanol;
in the preferred mode of the invention, the hydrogen donor in step (1) can be one or two of ammonium formate and formic acid;
as preferred for the present invention, the catalyst of step (1) may be Pd/C, Pd (OH)2One of (1);
as preferred in the present invention, the slurrying solvent in step (2) may be selected from acetone, methyl tert-butyl ether, dichloromethane, etc.;
compared with the prior art, the invention adopting the technical scheme has the following beneficial effects:
the compound formula (II) is prepared by using palladium hydroxide carbon and an ammonium formate system, the reaction is safe, environment-friendly, fast and clean, the product purity is high, and the compound formula (II) almost contains no inorganic salt, and is suitable for large-scale production.
Drawings
FIG. 1 is a liquid phase spectrum of 3-aminophthalic acid hydrochloride of the compound of example 1 of formula (II);
FIG. 2 is a liquid phase spectrum of 3-aminophthalic acid hydrochloride of the compound of example 4 of formula (II);
FIG. 3 is a hydrogen spectrum of 3-aminophthalic acid hydrochloride of the compound of example 1 of formula (II);
Detailed Description
The following examples of the present invention are illustrative, and are not to be construed as limiting the invention:
example 1 preparation of the compound 3-aminophthalic acid hydrochloride of formula (II): respectively adding 1kg of a compound shown as a formula (I), 5kg of absolute ethyl alcohol, 100g of palladium carbon hydroxide and 1.2kg of ammonium formate into a 30L reaction kettle, starting stirring, heating to 78-80 ℃, carrying out reflux reaction for about 1 hour to completely react, adding concentrated hydrochloric acid, adjusting the pH to be below 1, additionally adding 5kg of absolute ethyl alcohol, stirring for 1 hour, filtering, concentrating the filtrate at 40-45 ℃ under reduced pressure to obtain a crude product, then adding 5kg of methyl tert-butyl ether, stirring and pulping for 1 hour, filtering, collecting a filter cake, and drying in vacuum at 30 ℃ to obtain 852.0g of a white-like target product, namely a compound shown as a formula (II), 3-aminophthalate, with the yield of 82.9% and the purity: 98.35% (figures 1 and 3)
Example 2 preparation of the compound 3-aminophthalic acid hydrochloride of formula (II): respectively adding 1kg of compound formula (I), 5kg of anhydrous methanol, 100g of palladium carbon hydroxide and 1.0kg of ammonium formate into a 30L reaction kettle, starting stirring, heating to about 65 ℃, stirring for about 1 hour for complete reaction, adding concentrated hydrochloric acid, adjusting the pH to be below 1, adding 3kg of anhydrous methanol, stirring for 1 hour, filtering, concentrating the filtrate at 40-45 ℃ under reduced pressure to obtain a crude product, adding 5kg of methyl tert-butyl ether, stirring and pulping for 1 hour, filtering, collecting a filter cake, and drying in vacuum at 30 ℃ to obtain 931.0g of a white-like target product compound formula (II), namely 3-aminophthalate, with the yield of 90.6%.
Example 3 preparation of the compound 3-aminophthalic acid hydrochloride of formula (II): respectively adding 200g of a compound shown as a formula (I), 500g of anhydrous methanol, 20g of palladium carbon hydroxide, 130g of ammonium formate and 180g of formic acid into a 5L reaction kettle, starting stirring, heating to about 65 ℃, stirring for about 1 hour for complete reaction, filtering, adding concentrated hydrochloric acid into filtrate, adjusting the pH to be below 1, stirring for 1 hour, filtering, concentrating the filtrate at 40-45 ℃ under reduced pressure to obtain a crude product, adding 600g of acetone, stirring and pulping for 1 hour, filtering, collecting a filter cake, and drying in vacuum at 30 ℃ to obtain 123.6g of a white-like target product, namely a compound shown as a formula (II), namely 3-aminophthalate, with the yield of 60.1%.
Example 4 preparation of the compound 3-aminophthalic acid hydrochloride of formula (II): respectively adding 1kg of a compound shown as a formula (I), 2kg of purified water, 100g of palladium carbon hydroxide and 1.0kg of ammonium formate into a 30L reaction kettle, starting stirring, heating to about 40 ℃, stirring for about 1 hour to react completely, filtering, adding concentrated hydrochloric acid into filtrate, adjusting the pH to be below 1, stirring and cooling to 0-10 ℃, crystallizing, filtering, adding 5kg of methyl tert-butyl ether into filter cake, stirring and pulping for 1 hour, filtering, collecting filter cake, and drying in vacuum at 30 ℃ to obtain 722.9g of a white-like target product compound shown as a formula (II), namely 3-aminophthalate, with the yield of 70.1 percent and the purity: 99.28% (fig. 2).
The liquid phase detection conditions were as follows:
octadecylsilane chemically bonded silica is used as a filling agent; taking 0.1% formic acid as a mobile phase A and acetonitrile as a mobile phase B, and carrying out linear gradient elution according to the following table; the detection wavelength is 230 nm; the column temperature was 35 ℃.
| Time (minutes) | Mobile phase A (%) | Mobile phase B (%) |
| 0 | 95 | 5 |
| 25 | 30 | 70 |
| 35 | 30 | 70 |
| 36 | 95 | 5 |
| 45 | 95 | 5 |
Claims (7)
1. A preparation and refining method of an apremilast key intermediate compound shown as a formula (II) comprises the following synthetic route:
1) adding a compound shown as a formula (I) into a reaction bottle, adding a solvent, a hydrogen donor and a catalyst, and heating and stirring for reaction;
2) when the reaction solvent is alcohol, after the reaction is completed, adding hydrochloric acid to adjust the pH to a proper pH, supplementing alcohol, stirring and filtering, collecting the filtrate, concentrating under reduced pressure to dryness, adding a proper solvent, stirring and pulping, filtering, and drying under reduced pressure to obtain a target product compound formula (II);
3) when the reaction solvent is water, filtering after complete reaction, adding hydrochloric acid to adjust to proper PH, cooling for crystallization, filtering, collecting filter cakes, adding proper solvent, stirring for pulping, filtering, and drying under reduced pressure to obtain the target product compound formula (II).
2. The process for preparing the compound of formula (ii) according to claim 1, wherein the reaction solvent is selected from the group consisting of water, methanol and ethanol.
3. The process for preparing the compound of formula (ii) according to claim 1, wherein the hydrogen donor is selected from one or both of ammonium formate and formic acid.
4. A process for the preparation of the compound of formula (II) according to claim 1, wherein the catalyst is selected from the group consisting of Pd/C, Pd (OH)2One kind of (1).
5. The method for refining the compound of formula (II) as claimed in claim 1, wherein the reaction solvent is alcohol, after the reaction is completed, concentrated hydrochloric acid is added to adjust to a suitable pH value for filtration, the filter cake is collected and concentrated to obtain a crude product, and then a suitable solvent is added for pulping, filtration and drying to obtain a finished product.
6. The method for refining the compound of formula (II) according to claim 1, wherein the reaction solvent is water, the reaction is completed, then the product is filtered, concentrated hydrochloric acid is added to adjust the pH to a proper value, the temperature is reduced to crystallize, and then a proper solvent is added to pulp, filter and dry the product, thus obtaining the finished product.
7. A process for purifying the compound of formula (II) according to claim 1, wherein the suitable solvent for the post-treatment of the slurry is acetone, acetonitrile, isopropanol, methyl tert-butyl ether, preferably methyl tert-butyl ether.
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| Application Number | Priority Date | Filing Date | Title |
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| CN201810913325.7A CN110818583A (en) | 2018-08-13 | 2018-08-13 | Preparation and refining method of apremilast key intermediate |
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Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20150258063A1 (en) * | 2011-01-14 | 2015-09-17 | Celgene Corporation | Isotopologues of isoindole derivatives |
| CN105294534A (en) * | 2014-07-15 | 2016-02-03 | 上海优拓医药科技有限公司 | Industrial method for preparing apremilast and intermediate thereof |
| WO2017033116A1 (en) * | 2015-08-26 | 2017-03-02 | Glenmark Pharmaceuticals Limited | Process for preparation of apremilast |
-
2018
- 2018-08-13 CN CN201810913325.7A patent/CN110818583A/en active Pending
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20150258063A1 (en) * | 2011-01-14 | 2015-09-17 | Celgene Corporation | Isotopologues of isoindole derivatives |
| CN105294534A (en) * | 2014-07-15 | 2016-02-03 | 上海优拓医药科技有限公司 | Industrial method for preparing apremilast and intermediate thereof |
| WO2017033116A1 (en) * | 2015-08-26 | 2017-03-02 | Glenmark Pharmaceuticals Limited | Process for preparation of apremilast |
Non-Patent Citations (1)
| Title |
|---|
| BACHIR LATLI等: "Potent and selective inhibitors of 11β‐hydroxysteroid dehydrogenase type 1 labeled with carbon‐13 and carbon‐14", 《J LABEL COMPD RADIOPHARM.》 * |
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