CN106866493A - A kind of preparation method of Apremilast - Google Patents
A kind of preparation method of Apremilast Download PDFInfo
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- CN106866493A CN106866493A CN201510919937.3A CN201510919937A CN106866493A CN 106866493 A CN106866493 A CN 106866493A CN 201510919937 A CN201510919937 A CN 201510919937A CN 106866493 A CN106866493 A CN 106866493A
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- China
- Prior art keywords
- ammonia
- methoxyphenyls
- apremilast
- ethoxy
- reaction
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- 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 35
- 229960001164 apremilast Drugs 0.000 title claims abstract description 33
- 238000002360 preparation method Methods 0.000 title claims abstract description 23
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 claims abstract description 46
- 238000006243 chemical reaction Methods 0.000 claims abstract description 34
- 229910021529 ammonia Inorganic materials 0.000 claims abstract description 23
- 238000000034 method Methods 0.000 claims abstract description 21
- -1 methyl sulphonyl Chemical group 0.000 claims abstract description 11
- 125000006216 methylsulfinyl group Chemical group [H]C([H])([H])S(*)=O 0.000 claims abstract description 9
- PAUAJOABXCGLCN-UHFFFAOYSA-N n-(1,3-dioxo-2-benzofuran-4-yl)acetamide Chemical compound CC(=O)NC1=CC=CC2=C1C(=O)OC2=O PAUAJOABXCGLCN-UHFFFAOYSA-N 0.000 claims abstract description 6
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 14
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 12
- 239000000243 solution Substances 0.000 claims description 11
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 8
- WHXSMMKQMYFTQS-UHFFFAOYSA-N Lithium Chemical compound [Li] WHXSMMKQMYFTQS-UHFFFAOYSA-N 0.000 claims description 7
- 229910052744 lithium Inorganic materials 0.000 claims description 7
- 239000003054 catalyst Substances 0.000 claims description 6
- 239000002994 raw material Substances 0.000 claims description 6
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical class [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 5
- 238000007254 oxidation reaction Methods 0.000 claims description 5
- 230000001590 oxidative effect Effects 0.000 claims description 5
- 239000007800 oxidant agent Substances 0.000 claims description 4
- 239000007864 aqueous solution Substances 0.000 claims description 3
- 230000003647 oxidation Effects 0.000 claims description 3
- 230000035484 reaction time Effects 0.000 claims description 3
- 229920006395 saturated elastomer Polymers 0.000 claims description 3
- JYLNVJYYQQXNEK-UHFFFAOYSA-N 3-amino-2-(4-chlorophenyl)-1-propanesulfonic acid Chemical compound OS(=O)(=O)CC(CN)C1=CC=C(Cl)C=C1 JYLNVJYYQQXNEK-UHFFFAOYSA-N 0.000 claims description 2
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical class [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 2
- JFDZBHWFFUWGJE-UHFFFAOYSA-N benzonitrile Chemical compound N#CC1=CC=CC=C1 JFDZBHWFFUWGJE-UHFFFAOYSA-N 0.000 claims 3
- OQVYMXCRDHDTTH-UHFFFAOYSA-N 4-(diethoxyphosphorylmethyl)-2-[4-(diethoxyphosphorylmethyl)pyridin-2-yl]pyridine Chemical compound CCOP(=O)(OCC)CC1=CC=NC(C=2N=CC=C(CP(=O)(OCC)OCC)C=2)=C1 OQVYMXCRDHDTTH-UHFFFAOYSA-N 0.000 claims 1
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical class [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 claims 1
- 150000002576 ketones Chemical class 0.000 claims 1
- TYJJADVDDVDEDZ-UHFFFAOYSA-M potassium hydrogencarbonate Chemical class [K+].OC([O-])=O TYJJADVDDVDEDZ-UHFFFAOYSA-M 0.000 claims 1
- 230000006698 induction Effects 0.000 abstract description 2
- 238000004519 manufacturing process Methods 0.000 abstract description 2
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 12
- 238000003756 stirring Methods 0.000 description 12
- 239000012286 potassium permanganate Substances 0.000 description 8
- 238000005406 washing Methods 0.000 description 7
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 6
- 238000004128 high performance liquid chromatography Methods 0.000 description 6
- 125000000217 alkyl group Chemical group 0.000 description 5
- FKLJPTJMIBLJAV-UHFFFAOYSA-N Compound IV Chemical compound O1N=C(C)C=C1CCCCCCCOC1=CC=C(C=2OCCN=2)C=C1 FKLJPTJMIBLJAV-UHFFFAOYSA-N 0.000 description 4
- 201000001263 Psoriatic Arthritis Diseases 0.000 description 4
- 208000036824 Psoriatic arthropathy Diseases 0.000 description 4
- GCTFWCDSFPMHHS-UHFFFAOYSA-M Tributyltin chloride Chemical compound CCCC[Sn](Cl)(CCCC)CCCC GCTFWCDSFPMHHS-UHFFFAOYSA-M 0.000 description 4
- 239000002585 base Substances 0.000 description 4
- 239000012065 filter cake Substances 0.000 description 4
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 4
- 238000001556 precipitation Methods 0.000 description 4
- 150000003839 salts Chemical class 0.000 description 4
- 239000007787 solid Substances 0.000 description 4
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 4
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 3
- 230000015572 biosynthetic process Effects 0.000 description 3
- 239000000047 product Substances 0.000 description 3
- 238000003786 synthesis reaction Methods 0.000 description 3
- ZWEHNKRNPOVVGH-UHFFFAOYSA-N 2-Butanone Chemical compound CCC(C)=O ZWEHNKRNPOVVGH-UHFFFAOYSA-N 0.000 description 2
- 0 CC([*+]c(cccc1C([O+]2)=O)c1*2=O)=* Chemical compound CC([*+]c(cccc1C([O+]2)=O)c1*2=O)=* 0.000 description 2
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 2
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical class [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 2
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 2
- 235000011054 acetic acid Nutrition 0.000 description 2
- 125000000218 acetic acid group Chemical class C(C)(=O)* 0.000 description 2
- 125000003118 aryl group Chemical group 0.000 description 2
- 150000001875 compounds Chemical class 0.000 description 2
- 239000012141 concentrate Substances 0.000 description 2
- 201000010099 disease Diseases 0.000 description 2
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- 238000001035 drying Methods 0.000 description 2
- 235000019441 ethanol Nutrition 0.000 description 2
- NLFBCYMMUAKCPC-KQQUZDAGSA-N ethyl (e)-3-[3-amino-2-cyano-1-[(e)-3-ethoxy-3-oxoprop-1-enyl]sulfanyl-3-oxoprop-1-enyl]sulfanylprop-2-enoate Chemical compound CCOC(=O)\C=C\SC(=C(C#N)C(N)=O)S\C=C\C(=O)OCC NLFBCYMMUAKCPC-KQQUZDAGSA-N 0.000 description 2
- 125000005909 ethyl alcohol group Chemical group 0.000 description 2
- 239000000706 filtrate Substances 0.000 description 2
- 238000001914 filtration Methods 0.000 description 2
- 235000019341 magnesium sulphate Nutrition 0.000 description 2
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 2
- 239000012046 mixed solvent Substances 0.000 description 2
- 239000000843 powder Substances 0.000 description 2
- 239000008213 purified water Substances 0.000 description 2
- 239000002893 slag Substances 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- 238000000967 suction filtration Methods 0.000 description 2
- 125000000475 sulfinyl group Chemical group [*:2]S([*:1])=O 0.000 description 2
- 239000003643 water by type Substances 0.000 description 2
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 1
- 101150015280 Cel gene Proteins 0.000 description 1
- 206010009900 Colitis ulcerative Diseases 0.000 description 1
- 208000011231 Crohn disease Diseases 0.000 description 1
- 206010018364 Glomerulonephritis Diseases 0.000 description 1
- 206010018691 Granuloma Diseases 0.000 description 1
- SIKJAQJRHWYJAI-UHFFFAOYSA-N Indole Chemical compound C1=CC=C2NC=CC2=C1 SIKJAQJRHWYJAI-UHFFFAOYSA-N 0.000 description 1
- 206010061218 Inflammation Diseases 0.000 description 1
- 229940123932 Phosphodiesterase 4 inhibitor Drugs 0.000 description 1
- 229910021627 Tin(IV) chloride Inorganic materials 0.000 description 1
- 201000006704 Ulcerative Colitis Diseases 0.000 description 1
- 230000001154 acute effect Effects 0.000 description 1
- 150000001335 aliphatic alkanes Chemical class 0.000 description 1
- 239000003513 alkali Substances 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 230000001684 chronic effect Effects 0.000 description 1
- 125000000753 cycloalkyl group Chemical group 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- VGGRCVDNFAQIKO-UHFFFAOYSA-N formic anhydride Chemical compound O=COC=O VGGRCVDNFAQIKO-UHFFFAOYSA-N 0.000 description 1
- 238000005194 fractionation Methods 0.000 description 1
- 230000007233 immunological mechanism Effects 0.000 description 1
- 230000004054 inflammatory process Effects 0.000 description 1
- 238000009413 insulation Methods 0.000 description 1
- DLEDOFVPSDKWEF-UHFFFAOYSA-N lithium butane Chemical compound [Li+].CCC[CH2-] DLEDOFVPSDKWEF-UHFFFAOYSA-N 0.000 description 1
- 125000004170 methylsulfonyl group Chemical group [H]C([H])([H])S(*)(=O)=O 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 210000000056 organ Anatomy 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 230000008506 pathogenesis Effects 0.000 description 1
- 239000002587 phosphodiesterase IV inhibitor Substances 0.000 description 1
- 239000000376 reactant Substances 0.000 description 1
- 238000012827 research and development Methods 0.000 description 1
- 201000000306 sarcoidosis Diseases 0.000 description 1
- 150000003457 sulfones Chemical class 0.000 description 1
- 238000010189 synthetic method Methods 0.000 description 1
- 238000012360 testing method Methods 0.000 description 1
- 239000012974 tin catalyst Substances 0.000 description 1
- HPGGPRDJHPYFRM-UHFFFAOYSA-J tin(iv) chloride Chemical compound Cl[Sn](Cl)(Cl)Cl HPGGPRDJHPYFRM-UHFFFAOYSA-J 0.000 description 1
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
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C315/00—Preparation of sulfones; Preparation of sulfoxides
- C07C315/02—Preparation of sulfones; Preparation of sulfoxides by formation of sulfone or sulfoxide groups by oxidation of sulfides, or by formation of sulfone groups by oxidation of sulfoxides
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention discloses a kind of preparation method of Apremilast; (1S) -1- (3- ethoxy-4-methoxyphenyls) -2- (methyl sulphonyl) second ammonia is obtained using the oxidized reaction of intermediate (1S) -1- (3- ethoxy-4-methoxyphenyls) -2- (methylsulfinyl) second ammonia, then Apremilast is prepared with 3-acetamidophthalic anhydride reaction.By way of chiral induction, utilization space steric hindrance introduces chiral centre to the method when intermediate (1S) -1- (3- ethoxy-4-methoxyphenyls) -2- (methylsulfinyl) second ammonia is prepared.The step of being split using N- acetyl group-L-Leu is avoided compared to prior art, synthetic route is simplified, high income, low cost is adapted to industrialized production.
Description
Technical field
The invention belongs to technical field of medicine synthesis, and in particular to a kind of preparation method of Apremilast.
Background technology
Apremilast (apremilast) is the PDE4 inhibitor of Celgene research and development, and clinical practice is closed in rheumatoid
Multiple indications such as section inflammation, psoriatic arthritis, Crohn diseases, ulcerative colitis.Sarcoidosis be a kind of cause of disease not
Bright disease, is characterized in there is granuloma in one or more organs, it may be possible to which acute is also likely to be chronic.
Great mass of data shows that immunologic mechanism is critically important in the pathogenesis of disease, clinical tests prove that Apremilast is being controlled
There is preferable security and validity when treating activities of adults psoriatic arthritis (PsA), be approved as controlling by FDA
Treat the medicine of PsA.Evaluate Pharma predict that Apremilast sales volume in 2018 will be more than 1,200,000,000 dollars.
Apremilast chemical structural formula is as shown in following formula I：
Its chemical name is that (S) -2- [1- (3- ethoxy-4-methoxyphenyls) -2- methylsulfonylethyls] -4- acetylaminos are different
Indoline -1,3- diketone.
Disclosed Apremilast synthetic method is as follows in the prior art：
Apremilast synthesis road used by United States Patent (USP) US20100324108A1 and Chinese patent CN102781443A
Line is as follows：
The method is needed using N- acetyl group-L-Leu to racemic intermediate 1- (3- ethoxy-4-methoxyphenyls) -2- (methyl
Sulfonyl) second ammonia carries out into salt fractionation, and technical process yield is low, relatively costly.
The content of the invention
To solve above-mentioned problems of the prior art, the present invention provides a kind of preparation method of Apremilast.
Technical scheme is as follows：
A kind of preparation method of Apremilast, comprises the following steps：
1) intermediate shown in formula IV (1S) -1- (3- ethoxy-4-methoxyphenyls) -2- (methylsulfinyl) second ammonia is oxidized anti-
Compound shown in Formula V (1S) -1- (3- ethoxy-4-methoxyphenyls) -2- (methyl sulphonyl) second ammonia should be obtained：
2) (1S) -1- (3- ethoxy-4-methoxyphenyls) -2- (methyl sulphonyl) second ammonia (Formula V) and 3- acetylaminos neighbour's benzene two
Formic acid anhydride reactant prepares Apremilast (Formulas I)：
In the preparation method of above-mentioned Apremilast, step 1) used by oxidant be preferably potassium permanganate, sodium permanganate；
More preferably potassium permanganate.
In the preparation method of above-mentioned Apremilast, step 1) oxidizing reaction temperature be -10 DEG C to 40 DEG C；Preferably 0 DEG C
To 30 DEG C.
In the preparation method of above-mentioned Apremilast, step 1) used by reaction dissolvent be preferably acetone, butanone；More preferably
It is acetone.
In the preparation method of above-mentioned Apremilast, step 1) oxidation time be 1~5 hour；Preferably 1.5~3
Hour.
In the preparation method of above-mentioned Apremilast, step 1) used by oxidant be with the mol ratio of intermediate compound IV
0.8~2.0: 1；Preferably 1.0~1.5: 1.
In the preparation method of above-mentioned Apremilast, step 2) reaction time is 3~12 hours；Preferably 6~8 hours.
In the preparation method of above-mentioned Apremilast, step 2) (1S) -1- (3- ethoxy-4-methoxyphenyls) -2- (sulfonyloxy methyls
Base) mol ratio of second ammonia (Formula V) and 3-acetamidophthalic anhydride is 1: 1.0~1.5；Preferably 1: 1.1~1.3.
In the preparation method of above-mentioned Apremilast, step 2) product is carried out with alkalescence saturated aqueous solution after the completion of reaction
Washing, then crystallizes to obtain Apremilast.The alkaline saturated aqueous solution can be saturated sodium carbonate, saturated potassium carbonate,
Saturated sodium bicarbonate, saturated potassium hydrogen carbonate；Preferably saturated sodium carbonate.
In the preparation method of above-mentioned Apremilast, intermediate compound IV can be prepared by the following method：It is sub- with diformazan
Sulfone (Formula II) and 3- ethyoxyl -4- methoxy benzonitriles (formula III) are raw material, in the presence of lithium alkylide, using having
Machine tin catalyst forms coordinate bond in building-up process with Lewis alkali raw material, so as to reach spatiall induction, chiral synthesis
Purpose, be obtained (1S) -1- (3- ethoxy-4-methoxyphenyls) -2- (methylsulfinyl) second ammonia (formula IV).It is shown below：
Wherein, organotin catalysts used are preferably R3SnCl, R represent alkyl or aryl, the preferably alkane of C1~C12
The straight or branched alkyl of base or aryl, more preferably C1~C6.The organotin catalysts such as tributyltin chloride,
Tripropyl stannic chloride, more preferably tributyltin chloride.
The lithium alkylide is expressed as R'Li, and wherein R' represents straight or branched alkyl, cycloalkyl, preferably C1~C12
Straight or branched alkyl, the more preferably straight or branched alkyl of C1~C6.The lithium alkylide is most preferably normal-butyl
Lithium.
In the method for above-mentioned formula IV compounds, reaction dissolvent is non-proton organic solvent, such as tetrahydrofuran,
Dioxane；Preferably tetrahydrofuran.Reaction temperature is -10 DEG C to 60 DEG C；Preferably 0 DEG C to 20 DEG C.
The method concrete operations of above-mentioned formula IV compounds are：Dimethyl sulfoxide and lithium alkylide are individually first reacted into a period of time,
It is subsequently adding 3- ethyoxyl -4- methoxy benzonitriles (formula III) and organotin catalysts continues to react, obtains the A Pu
This special intermediate.Wherein, reaction temperature is most preferably 0~5 DEG C when dimethyl sulfoxide individually reacts with lithium alkylide, adds 3-
15~20 DEG C are warmed up to naturally after ethyoxyl -4- methoxy benzonitriles (formula III) and organotin catalysts to be reacted.
Dimethyl sulfoxide is preferably 0.5-3 hours, more preferably 1-1.5 hours with the independent reaction time of lithium alkylide.Add 3-
After ethyoxyl -4- methoxy benzonitriles (formula III) and organotin catalysts reaction a period of time (usual 1~3 hour),
Add water continuation insulation reaction 8-16 hours (preferably 10-12 hours).
The present invention has the advantage that compared with prior art：
1. the present invention provides a kind of method that utilization intermediate compound IV prepares Apremilast.
2. the present invention realizes the preparation of Apremilast by steps such as oxidations with compound IV as raw material.With existing skill
Art is compared, and the present invention improves process overall yields not into salt splitting step, reduces cost.
3. it is more satisfactory that what the present invention was provided prepare Apremilast method yield, raw materials used to be common agents, is adapted to work
The big production of industryization.
Specific embodiment
The invention will be further described by the following examples, but this is not limitation of the present invention, those skilled in the art
Basic thought of the invention, various modifications may be made or improves, but without departing from basic thought of the invention,
Within the scope of the present invention.
Embodiment 1：The preparation of (1S) -1- (3- ethoxy-4-methoxyphenyls) -2- (methylsulfinyl) second ammonia (formula IV)
400mL tetrahydrofurans and 62.5g (0.8mol) dimethyl sulfoxide are added in reaction bulb, 0 DEG C is cooled under stirring
To 5 DEG C, 1.6M n-BuLis normal hexane solution 500mL (0.8mol) for adding temperature to be similarly 0 DEG C to 5 DEG C is stirred
Reaction 1.5 hours is mixed, 179.0g (0.55mol) tributyltin chloride being placed in 450mL tetrahydrofurans is added
With 88.6g (0.5mol) 3- ethyoxyl -4- methoxy benzonitriles (formula III), stir 0.5 hour, warm naturally to 15 DEG C
Reacted 2 hours to 20 DEG C, add 1000mL purified waters, continued to be incubated and reacted 12 hours at 15 DEG C to 20 DEG C.Stop
Only react, by the solid filtering of gained in reaction solution, successively with purified water, normal hexane, each 100mL of tetrahydrofuran
Washing filter cake.Through dry off-white powder 109.6g, molar yield 85.2% is calculated by compound III, HPLC is pure
It is 98.1%, ee values 97.3% to spend.
Embodiment 2：The preparation of (1S) -1- (3- ethoxy-4-methoxyphenyls) -2- (methylsulfinyl) second ammonia (formula IV)
400mL tetrahydrofurans and 62.5g (0.8mol) dimethyl sulfoxide are added in reaction bulb, 0 DEG C is cooled under stirring
To 5 DEG C, 1.6M n-BuLis normal hexane solution 500mL (0.8mol) for adding temperature to be similarly 0 DEG C to 5 DEG C is stirred
Reaction 1.5 hours is mixed, 179.0g (0.55mol) tributyltin chloride being placed in 450mL tetrahydrofurans is added
With 88.6g (0.5mol) 3- ethyoxyl -4- methoxy benzonitriles (formula III), stir 0.5 hour, warm naturally to 15 DEG C
Reacted 2 hours to 20 DEG C, add 1000mL purified waters, continued to be incubated and reacted 10 hours at 15 DEG C to 20 DEG C.Stop
Only react, by the solid filtering of gained in reaction solution, successively with purified water, normal hexane, each 100mL of tetrahydrofuran
Washing filter cake.Through dry off-white powder 107.9g, molar yield 83.9% is calculated by compound III, HPLC is pure
It is 97.9%, ee values 97.1% to spend.
Embodiment 3：The preparation of (1S) -1- (3- ethoxy-4-methoxyphenyls) -2- (methyl sulphonyl) second ammonia (Formula V)
600mL acetone, 77.2g (0.3mol) (1S) -1- (3- ethoxy-4-methoxyphenyls) -2- (methyl are added in reaction bulb
Sulfinyl) second ammonia (formula IV) stirring and dissolving, it is cooled to 10 DEG C to 20 DEG C；50g anhydrous magnesium sulfates are added, stirring is equal
Potassium permanganate is added (to be added in reaction bulb 47.4g (0.3mol) potassium permanganate in three times, per minor tick after even
0.5 hour).Last time potassium permanganate is reacted 0.5 hour after adding, and stops reaction, and reaction solution is filtered through diatomite,
Remove the solid slag in reaction solution.Concentrate the filtrate to do, it is 97.1% to obtain pale yellow oil 72.3g, HPLC purity,
Ee values 97.7%.
Embodiment 4：The preparation of (1S) -1- (3- ethoxy-4-methoxyphenyls) -2- (methyl sulphonyl) second ammonia (Formula V)
600mL acetone, 77.2g (0.3mol) (1S) -1- (3- ethoxy-4-methoxyphenyls) -2- (methyl are added in reaction bulb
Sulfinyl) second ammonia (formula IV) stirring and dissolving, it is cooled to 10 DEG C to 20 DEG C；50g anhydrous magnesium sulfates are added, stirring is equal
Potassium permanganate is added (to be added in reaction bulb 71.1g (0.45mol) potassium permanganate in three times, per minor tick after even
0.5 hour).Last time potassium permanganate is reacted 0.5 hour after adding, and stops reaction, and reaction solution is filtered through diatomite,
Remove the solid slag in reaction solution.Concentrate the filtrate to do, it is 96.8% to obtain pale yellow oil 73.6g, HPLC purity,
Ee values 98.1%.
Embodiment 5：The preparation of Apremilast (Formulas I)：
350mL glacial acetic acids, 60.1g (0.22mol) (1S) -1- (3- ethyoxyl -4- methoxybenzenes are added in reaction bulb
Base) -2- (methyl sulphonyl) second ammonia (Formula V), 51.3g (0.25mol) 3-acetamidophthalic anhydride, stirring is equal
Even, back flow reaction 6 hours stops reaction, and residue 400mL ethyl acetate dissolves after precipitation, uses unsaturated carbonate
Sodium water solution washs (300mL × 2 time), then with salt water washing (150mL × 1 time).Again 400mL is added after precipitation
The mixed solvent stirring and crystallizing of absolute ethyl alcohol and 150mL acetone 5 hours, suction filtration, filter cake 100mL absolute ethyl alcohols
Washing, obtains 81.3g products, molar yield 80.2% after drying, HPLC purity is 98.1%, ee values 98.2%.
Mass spectrometric data is as follows：C22H24N2O7S, molecular weight：460.5, [M+H]+Measured value：461.3.
Embodiment 6：The preparation of Apremilast (Formulas I)：
350mL glacial acetic acids, 60.1g (0.22mol) (1S) -1- (3- ethyoxyl -4- methoxybenzenes are added in reaction bulb
Base) -2- (methyl sulphonyl) second ammonia (Formula V), 57.4g (0.28mol) 3-acetamidophthalic anhydride, stirring is equal
Even, back flow reaction 6 hours stops reaction, and residue 400ml ethyl acetate dissolves after precipitation, uses unsaturated carbonate
Sodium water solution washs (300mL × 2 time), then with salt water washing (150mL × 1 time).Again 400mL is added after precipitation
The mixed solvent stirring and crystallizing of absolute ethyl alcohol and 150mL acetone 5 hours, suction filtration, filter cake 100mL absolute ethyl alcohols
Washing, obtains 82.6g products, molar yield 81.5% after drying, HPLC purity is 98.3%, ee values 97.9%.
Mass spectrometric data is as follows：C22H24N2O7S, molecular weight：460.5, [M+H]+Measured value：461.5.
Claims (10)
1. a kind of preparation method of Apremilast, comprises the following steps：
1) intermediate shown in formula IV (1S) -1- (3- ethoxy-4-methoxyphenyls) -2- (methylsulfinyl) second ammonia is oxidized anti-
Compound shown in Formula V (1S) -1- (3- ethoxy-4-methoxyphenyls) -2- (methyl sulphonyl) second ammonia should be obtained：
2) (1S) -1- (3- ethoxy-4-methoxyphenyls) -2- (methyl sulphonyl) second ammonia reacts with 3-acetamidophthalic anhydride
Apremilast is obtained：
2. method according to claim 1, it is characterised in that step 1) oxidant used by oxidation reaction is height
Potassium manganate or sodium permanganate.
3. method according to claim 1, it is characterised in that step 1) temperature of oxidation reaction is -10 DEG C
To 40 DEG C；Preferably 0 DEG C to 30 DEG C.
4. method according to claim 1, it is characterised in that step 1) used by reaction dissolvent be acetone or fourth
Ketone.
5. method according to claim 1, it is characterised in that step 1) oxidation time is 1-5 hours；
Preferably 1.5-3 hours.
6. method according to claim 1, it is characterised in that step 1) used by oxidant with shown in formula IV
The mol ratio of intermediate is 0.8~2.0: 1；Preferably 1.0~1.5: 1.
7. method according to claim 1, it is characterised in that step 2) reaction time is 3~12 hours；
Preferably 6~8 hours.
8. method according to claim 1, it is characterised in that in step 2) in, (1S) -1- (3- ethyoxyls -4-
Methoxyphenyl) mol ratio of -2- (methyl sulphonyl) second ammonia and 3-acetamidophthalic anhydride is 1: 1.0~1.5；It is preferred that
It is 1: 1.1~1.3.
9. method according to claim 1, it is characterised in that step 2) after the completion of reaction with alkaline saturation water
Solution is washed to product, then crystallizes to obtain Apremilast；Wherein, the alkaline saturated aqueous solution is unsaturated carbonate
Sodium, saturated potassium carbonate, saturated sodium bicarbonate or saturated potassium hydrogen carbonate.
10. method according to claim 1, it is characterised in that intermediate shown in formula IV (1S) -1- (3- ethyoxyls
- 4- methoxyphenyls) -2- (methylsulfinyl) second ammonia is prepared by the following method：With dimethyl sulfoxide and 3- ethyoxyl -4- methoxies
Base benzonitrile is raw material, in the presence of lithium alkylide, using organotin catalysts R3SnCl in building-up process with raw material
Coordinate bond is formed, (1S) -1- (3- ethoxy-4-methoxyphenyls) -2- (methylsulfinyl) second ammonia is obtained, be shown below：
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|---|---|---|---|---|
| US20140081032A1 (en) * | 2012-09-14 | 2014-03-20 | Celgene Corporation | Processes for the preparation of isoindole compounds and isotopologues thereof |
| CN103864670A (en) * | 2014-03-17 | 2014-06-18 | 苏州明锐医药科技有限公司 | Preparation method of Apremilast |
| CN104447443A (en) * | 2014-12-05 | 2015-03-25 | 新发药业有限公司 | Preparation method for apremilast and intermediate of apremilast |
| WO2015181249A1 (en) * | 2014-05-28 | 2015-12-03 | Lek Pharmaceuticals D.D. | PROCESSES FOR THE PREPARATION OF β-AMINOSULFONE COMPOUNDS |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20140081032A1 (en) * | 2012-09-14 | 2014-03-20 | Celgene Corporation | Processes for the preparation of isoindole compounds and isotopologues thereof |
| CN103864670A (en) * | 2014-03-17 | 2014-06-18 | 苏州明锐医药科技有限公司 | Preparation method of Apremilast |
| WO2015181249A1 (en) * | 2014-05-28 | 2015-12-03 | Lek Pharmaceuticals D.D. | PROCESSES FOR THE PREPARATION OF β-AMINOSULFONE COMPOUNDS |
| CN104447443A (en) * | 2014-12-05 | 2015-03-25 | 新发药业有限公司 | Preparation method for apremilast and intermediate of apremilast |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN112694426A (en) * | 2020-12-29 | 2021-04-23 | 山东铂源药业有限公司 | Synthetic method of apremilast intermediate |
| CN112694426B (en) * | 2020-12-29 | 2022-11-04 | 山东铂源药业股份有限公司 | Synthetic method of apremilast intermediate |
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