CN103819454A - Preparation method of N-(2, 6-dioxo-3-piperidyl) phthalimide compound - Google Patents
Preparation method of N-(2, 6-dioxo-3-piperidyl) phthalimide compound Download PDFInfo
- Publication number
- CN103819454A CN103819454A CN201410091050.5A CN201410091050A CN103819454A CN 103819454 A CN103819454 A CN 103819454A CN 201410091050 A CN201410091050 A CN 201410091050A CN 103819454 A CN103819454 A CN 103819454A
- Authority
- CN
- China
- Prior art keywords
- formula
- compound
- hydrogen
- iii
- reaction
- 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
- -1 N-(2, 6-dioxo-3-piperidyl) phthalimide compound Chemical class 0.000 title claims description 17
- 238000002360 preparation method Methods 0.000 title description 16
- 238000000034 method Methods 0.000 claims abstract description 37
- 238000006243 chemical reaction Methods 0.000 claims abstract description 27
- 150000001875 compounds Chemical class 0.000 claims abstract description 21
- 229910052739 hydrogen Inorganic materials 0.000 claims abstract description 15
- 239000001257 hydrogen Substances 0.000 claims abstract description 15
- 150000003839 salts Chemical class 0.000 claims abstract description 14
- 229910052736 halogen Inorganic materials 0.000 claims abstract description 7
- 150000002367 halogens Chemical class 0.000 claims abstract description 7
- 125000004209 (C1-C8) alkyl group Chemical group 0.000 claims abstract description 5
- 125000004649 C2-C8 alkynyl group Chemical group 0.000 claims abstract description 5
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims abstract description 5
- 150000002431 hydrogen Chemical class 0.000 claims abstract description 5
- 239000012453 solvate Substances 0.000 claims abstract description 5
- 239000003795 chemical substances by application Substances 0.000 claims description 13
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 12
- VMHLLURERBWHNL-UHFFFAOYSA-M Sodium acetate Chemical compound [Na+].CC([O-])=O VMHLLURERBWHNL-UHFFFAOYSA-M 0.000 claims description 11
- 229940040526 anhydrous sodium acetate Drugs 0.000 claims description 11
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 10
- 239000002808 molecular sieve Substances 0.000 claims description 10
- URGAHOPLAPQHLN-UHFFFAOYSA-N sodium aluminosilicate Chemical compound [Na+].[Al+3].[O-][Si]([O-])=O.[O-][Si]([O-])=O URGAHOPLAPQHLN-UHFFFAOYSA-N 0.000 claims description 10
- KFIRODWJCYBBHY-UHFFFAOYSA-N 3-nitrophthalic acid Chemical compound OC(=O)C1=CC=CC([N+]([O-])=O)=C1C(O)=O KFIRODWJCYBBHY-UHFFFAOYSA-N 0.000 claims description 9
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 9
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 9
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 7
- 239000003960 organic solvent Substances 0.000 claims description 7
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 6
- 239000002904 solvent Substances 0.000 claims description 6
- PXHVJJICTQNCMI-UHFFFAOYSA-N Nickel Chemical compound [Ni] PXHVJJICTQNCMI-UHFFFAOYSA-N 0.000 claims description 4
- 229910000564 Raney nickel Inorganic materials 0.000 claims description 4
- UKVIEHSSVKSQBA-UHFFFAOYSA-N methane;palladium Chemical compound C.[Pd] UKVIEHSSVKSQBA-UHFFFAOYSA-N 0.000 claims description 4
- MUMZUERVLWJKNR-UHFFFAOYSA-N oxoplatinum Chemical compound [Pt]=O MUMZUERVLWJKNR-UHFFFAOYSA-N 0.000 claims description 4
- 229910003446 platinum oxide Inorganic materials 0.000 claims description 4
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 4
- 238000006722 reduction reaction Methods 0.000 claims description 4
- 230000002829 reductive effect Effects 0.000 claims description 4
- 125000002769 thiazolinyl group Chemical group 0.000 claims description 4
- 238000010531 catalytic reduction reaction Methods 0.000 claims description 3
- GSNUFIFRDBKVIE-UHFFFAOYSA-N DMF Natural products CC1=CC=C(C)O1 GSNUFIFRDBKVIE-UHFFFAOYSA-N 0.000 claims description 2
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 2
- 125000000218 acetic acid group Chemical group C(C)(=O)* 0.000 claims description 2
- 230000000694 effects Effects 0.000 claims description 2
- 239000002994 raw material Substances 0.000 abstract description 10
- 238000004519 manufacturing process Methods 0.000 abstract description 8
- 125000004648 C2-C8 alkenyl group Chemical group 0.000 abstract 1
- 238000009776 industrial production Methods 0.000 abstract 1
- 239000000126 substance Substances 0.000 abstract 1
- 238000009833 condensation Methods 0.000 description 11
- 230000005494 condensation Effects 0.000 description 11
- 150000002466 imines Chemical class 0.000 description 11
- 125000000217 alkyl group Chemical group 0.000 description 10
- 238000000967 suction filtration Methods 0.000 description 9
- 239000000706 filtrate Substances 0.000 description 6
- 239000007787 solid Substances 0.000 description 6
- 238000003756 stirring Methods 0.000 description 6
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 6
- 125000000304 alkynyl group Chemical group 0.000 description 5
- 150000001412 amines Chemical class 0.000 description 5
- 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 5
- 239000000047 product Substances 0.000 description 5
- 0 *C(CCC(N1)=O)(C1=O)N(C(c1cccc(N)c11)=O)C1=O Chemical compound *C(CCC(N1)=O)(C1=O)N(C(c1cccc(N)c11)=O)C1=O 0.000 description 4
- 238000005481 NMR spectroscopy Methods 0.000 description 4
- 229910052799 carbon Inorganic materials 0.000 description 4
- 150000001721 carbon Chemical group 0.000 description 4
- 125000003636 chemical group Chemical group 0.000 description 4
- 239000003814 drug Substances 0.000 description 4
- 230000035484 reaction time Effects 0.000 description 4
- XMVJITFPVVRMHC-UHFFFAOYSA-N roxarsone Chemical group OC1=CC=C([As](O)(O)=O)C=C1[N+]([O-])=O XMVJITFPVVRMHC-UHFFFAOYSA-N 0.000 description 4
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 3
- 229960000583 acetic acid Drugs 0.000 description 3
- 238000010009 beating Methods 0.000 description 3
- 239000012043 crude product Substances 0.000 description 3
- 238000001514 detection method Methods 0.000 description 3
- 230000008030 elimination Effects 0.000 description 3
- 238000003379 elimination reaction Methods 0.000 description 3
- 238000004845 hydriding Methods 0.000 description 3
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 3
- DCKVNWZUADLDEH-UHFFFAOYSA-N sec-butyl acetate Chemical compound CCC(C)OC(C)=O DCKVNWZUADLDEH-UHFFFAOYSA-N 0.000 description 3
- 238000005406 washing Methods 0.000 description 3
- 238000005160 1H NMR spectroscopy Methods 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
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 2
- 125000003342 alkenyl group Chemical group 0.000 description 2
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 2
- 239000002131 composite material Substances 0.000 description 2
- 229940125782 compound 2 Drugs 0.000 description 2
- 229940125898 compound 5 Drugs 0.000 description 2
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 2
- ZDXPYRJPNDTMRX-UHFFFAOYSA-N glutamine Natural products OC(=O)C(N)CCC(N)=O ZDXPYRJPNDTMRX-UHFFFAOYSA-N 0.000 description 2
- 230000007062 hydrolysis Effects 0.000 description 2
- 238000006460 hydrolysis reaction Methods 0.000 description 2
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 2
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 2
- UHOVQNZJYSORNB-UHFFFAOYSA-N monobenzene Natural products C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 2
- UVSMNLNDYGZFPF-UHFFFAOYSA-N pomalidomide Chemical compound O=C1C=2C(N)=CC=CC=2C(=O)N1C1CCC(=O)NC1=O UVSMNLNDYGZFPF-UHFFFAOYSA-N 0.000 description 2
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 2
- NPWMTBZSRRLQNJ-UHFFFAOYSA-N pyroglutamine Chemical compound NC1CCC(=O)NC1=O NPWMTBZSRRLQNJ-UHFFFAOYSA-N 0.000 description 2
- 238000007670 refining Methods 0.000 description 2
- 229940070710 valerate Drugs 0.000 description 2
- UEJJHQNACJXSKW-UHFFFAOYSA-N 2-(2,6-dioxopiperidin-3-yl)-1H-isoindole-1,3(2H)-dione Chemical class O=C1C2=CC=CC=C2C(=O)N1C1CCC(=O)NC1=O UEJJHQNACJXSKW-UHFFFAOYSA-N 0.000 description 1
- YCPULGHBTPQLRH-UHFFFAOYSA-N 3-aminopiperidine-2,6-dione;hydron;chloride Chemical compound Cl.NC1CCC(=O)NC1=O YCPULGHBTPQLRH-UHFFFAOYSA-N 0.000 description 1
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 description 1
- OKJADYKTJJGKDX-UHFFFAOYSA-N Butyl pentanoate Chemical compound CCCCOC(=O)CCCC OKJADYKTJJGKDX-UHFFFAOYSA-N 0.000 description 1
- SKMSVDDRWGVCMZ-UHFFFAOYSA-N CCC(I)[I](C(c1c2c(N)ccc1)=N)C2=[U] Chemical compound CCC(I)[I](C(c1c2c(N)ccc1)=N)C2=[U] SKMSVDDRWGVCMZ-UHFFFAOYSA-N 0.000 description 1
- 101150015280 Cel gene Proteins 0.000 description 1
- 208000034578 Multiple myelomas Diseases 0.000 description 1
- 206010035226 Plasma cell myeloma Diseases 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- HSFWRNGVRCDJHI-UHFFFAOYSA-N alpha-acetylene Natural products C#C HSFWRNGVRCDJHI-UHFFFAOYSA-N 0.000 description 1
- 125000003368 amide group Chemical group 0.000 description 1
- 125000004369 butenyl group Chemical group C(=CCC)* 0.000 description 1
- 125000000480 butynyl group Chemical group [*]C#CC([H])([H])C([H])([H])[H] 0.000 description 1
- 238000009903 catalytic hydrogenation reaction Methods 0.000 description 1
- 229940125904 compound 1 Drugs 0.000 description 1
- 229940126214 compound 3 Drugs 0.000 description 1
- 238000006482 condensation reaction Methods 0.000 description 1
- 230000003750 conditioning effect Effects 0.000 description 1
- 230000007812 deficiency Effects 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- PQLFROTZSIMBKR-UHFFFAOYSA-N ethenyl carbonochloridate Chemical compound ClC(=O)OC=C PQLFROTZSIMBKR-UHFFFAOYSA-N 0.000 description 1
- 125000002534 ethynyl group Chemical group [H]C#C* 0.000 description 1
- 239000012467 final product Substances 0.000 description 1
- 235000019253 formic acid Nutrition 0.000 description 1
- 239000012362 glacial acetic acid Substances 0.000 description 1
- 125000006038 hexenyl group Chemical group 0.000 description 1
- 230000003301 hydrolyzing effect Effects 0.000 description 1
- 230000036039 immunity Effects 0.000 description 1
- 239000013067 intermediate product Substances 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- 125000000740 n-pentyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000002255 pentenyl group Chemical group C(=CCCC)* 0.000 description 1
- 125000005981 pentynyl group Chemical group 0.000 description 1
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 1
- XKJCHHZQLQNZHY-UHFFFAOYSA-N phthalimide Chemical class C1=CC=C2C(=O)NC(=O)C2=C1 XKJCHHZQLQNZHY-UHFFFAOYSA-N 0.000 description 1
- 229960000688 pomalidomide Drugs 0.000 description 1
- 229940008606 pomalyst Drugs 0.000 description 1
- 125000004368 propenyl group Chemical group C(=CC)* 0.000 description 1
- 108090000623 proteins and genes Proteins 0.000 description 1
- 230000000306 recurrent effect Effects 0.000 description 1
- 238000011946 reduction process Methods 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 1
- 229920002554 vinyl polymer Polymers 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention relates to a method for preparing a compound represented as a formula (I) or pharmaceutically acceptable salt, solvate, polymorphic substance or stereoisomer, wherein the method has the advantages of short reaction period, simplicity in operation, low production cost, good product quality and suitability of industrial production, raw materials are easy to obtain, and an R group is hydrogen, halogen, benzyl, (C1-C8) alkyl, (C2-C8) alkenyl or (C2-C8) alkynyl.
Description
Technical field
The invention belongs to medical production technical field, be specifically related to the preparation method of N-(2, the 6-dioxo-3-piperidyl) phthalimide derivatives that does not replace and replace, the preparation method who especially moors horse degree amine.
Background technology
3-amino-N-(2,6-dioxo-3-piperidyl) O-phthalic imines, mooring horse degree amine (pomalidomide), is a kind of oral immunity conditioning agent of Sai Er gene drugmaker of the U.S. (Celgene Crop) exploitation, trade(brand)name Pomalyst.This medicine is ratified this medicine on February 8th, 2013 by FDA (Food and Drug Adminstration) (FDA) and is used for the treatment of recurrent and Refractory Multiple Myeloma, its racemic mixture of clinical use, and structural formula is shown below:
The preparation method of the relevant 3-amino-N-of bibliographical information (2,6-dioxo-3-piperidyl) O-phthalic group with imine moiety mainly contains following six kinds at present.
Method one: take 3-nitrophthalic acid as starting raw material, in acetic anhydride, dewater, obtain after 3-nitrophthalic acid acid anhydride and 3-amino-2, the condensation of 6-dioxopiperidine obtains 3-nitro-N-(2,6-dioxo-3-piperidyl)-phthalic imidine, obtain 3-amino-N-(2,6-dioxo-3-piperidyl) O-phthalic group with imine moiety finally by catalytic reduction.
Method two: 3-nitrophthalic acid acid anhydride reacts with glutamine to generate and reduces to obtain 5-amino-2-(3-aminophthalimide base)-5-oxopentanoic acid after 5-amino-2-(3-nitro phthalimide-based)-5-oxopentanoic acid, finally by intramolecular condensation Cheng Huan, obtain 3-amino-N-(2,6-dioxo-3-piperidyl) O-phthalic group with imine moiety.
Method three: 3-nitro phthalic imidine obtains 5-amino-2-(3-nitro phthalimide-based)-5-oxopentanoic acid butyl ester with the condensation of glutamine butyl ester react generation (3-nitro phthalic imidine)-ethyl formate with Vinyl chloroformate after, finally by hydrolysis, reduction and intramolecular condensation Cheng Huan, obtain 3-amino-N-(2,6-dioxo-3-piperidyl) O-phthalic group with imine moiety.
Method four: 3-aminophthalic acid and 3-amino-2,6-dioxopiperidine obtains 3-amino-N-(2,6-dioxo-3-piperidyl) O-phthalic group with imine moiety through single step reaction condensation.
Method five: (3-nitro phthalic imidine)-ethyl formate and the condensation of 5-formamyl-4-amino-butyl valerate obtain 3-amino-N-(2,6-dioxo-3-piperidyl) O-phthalic group with imine moiety through hydrolysis, reduction and intramolecular condensation after generating 4-(3-nitro phthalic imidine)-5-formamyl butyl valerate.
Method six: through reduction and intramolecular condensation, obtain 3-amino-N-(2,6-dioxo-3-piperidyl) O-phthalic group with imine moiety after 3-nitrophthalic acid acid anhydride and the condensation of 5-formamyl-4-amino-valeric acid.
In aforesaid method, method three reactions steps are longer, and in 5-amino-2-(3-nitro phthalimide-based)-5-oxopentanoic acid butyl ester hydrolytic process, the amide group in molecule also can be hydrolyzed, and has affected purity and the yield of product.Though method four reactions steps are short, in condensation reaction, can there is self condensation in raw material 3-aminophthalic acid, had a strong impact on the purity of product and final yield.In method five, in raw material 5-formamyl-4-amino-butyl valerate used and method six, raw material 5-formamyl-4-amino-valeric acid used does not all have market supply, purchasing of raw materials difficulty.Method one and method two raw materials market are in liberal supply, source and quality are secure, and syntheti c route is shorter, each step reaction is ripe chemical reaction, simple to operate, be easy to suitability for industrialized production, but research discovery, due to the impact of ortho position nitro, 3-nitrophthalic acid acid anhydride is very unstable, be easy to the moisture absorption, be hydrolyzed into the adjacent benzene of 3-nitro and formic acid.
Although these methods can be for the preparation of the N-(2 that does not replace and replace, 6-dioxo-3-piperidyl) O-phthalic imine compound, but still need to prepare substituting or improved method of this compound, especially for the method for commercial production scale.Therefore, find a kind of reaction time short, simple to operate, raw material is easy to get, production cost is low, the method of good product quality and applicable industrialized production is prepared N-(2,6-dioxo-3-piperidyl) O-phthalic imine compound and is especially moored horse degree amine and have very important significance at field of medicaments.
Summary of the invention
The object of the invention is for the deficiencies in the prior art, provide a kind of reaction time short, simple to operate, raw material is easy to get, production cost is low, the method preparation of good product quality and applicable industrialized production is suc as formula the method for compound shown in (I) or its pharmacy acceptable salt, solvate, many product type thing or steric isomer
Object of the present invention can reach by following measures:
A kind of preparation method of formula (I) compound, it comprises the steps:
A, amino the 3-of 3-nitrophthalic acid or its salt and formula (II) glutarimide compound or its salt is reacted in organic solvent to the step of the formula that obtains (TII),
B, the formula obtaining (III) compound is obtained to formula (I) compound wherein by reductive agent catalytic reduction; R in its Chinese style (I), formula (II) or formula (III) is hydrogen, halogen, benzyl, (C
1-C
8) alkyl, (C
2-C
8) thiazolinyl or (C
2-C
8) alkynyl.
Preferably, described R is H.
Described in steps A, in reaction process, add dewatering agent;
Described dewatering agent is the combination of molecular sieve, sodium acetate, anhydrous or molecular sieve and sodium acetate, anhydrous.
Described in steps A, solvent is selected from one or more in acetic acid, DMF, acetonitrile, ethanol, Virahol;
Preferably, described solvent is acetic acid.
Described in steps A, temperature of reaction is 60-120 ℃.
Described in steps A, the reaction times is 2-5h.
Reductive agent described in step B is selected from the one in hydrogen/palladium carbon, hydrogen/Raney's nickel, platinum oxide.
The solvent of the reaction described in step B is organic solvent, the one in particular methanol, DMF.
Described in step B, in reduction process, hydrogen pressure is 0.5-1.5MPa.
In the time that R is H, the invention provides 3-amino-N-(2,6-dioxo-3-piperidyl) O-phthalic imines, be the preparation method of Bo Madu amine, the method is with 3-nitrophthalic acid and 3-amino-2,6-dioxopiperidine or its salt are raw material, in acetum, obtain final product by adding thermal condensation, catalytic hydrogenation and refinement treatment.The building-up reactions formula of the method is as follows:
In the time that R is other groups, those skilled in the art can select suitable solvent and reaction times according to the solvability of different compounds and composite reactive on the basis of operational path provided by the invention.
Another object of the present invention is to provide one to prepare the method suc as formula compound shown in (III) or its pharmacy acceptable salt, solvate, polymorphic form or steric isomer, can realize by the following method: by amino the 3-of 3-nitrophthalic acid or its salt and formula (II) glutarimide compound or its salt in organic solvent, under the effect of dewatering agent, reaction obtains the step of formula (III)
Wherein, the R in formula (II) or formula (III) is hydrogen, halogen, benzyl, (C
1-C
8) alkyl, (C
2-C
8) thiazolinyl or (C
2-C
8) alkynyl; Described dewatering agent is the combination of molecular sieve, sodium acetate, anhydrous or molecular sieve and sodium acetate, anhydrous.
Unless stated otherwise, term used herein " halogen ", " halogen " etc. be-F ,-Cl ,-Br or-I, preferably-F or-C1.
Unless stated otherwise, the " (C in the present invention
1-C
8) alkyl ", the saturated aliphatic radical of 1-8 carbon atom of expression, comprises straight chain and branched group.Alkyl containing 1-4 carbon atom is called low alkyl group.In the time that low alkyl group does not have substituting group, be called unsubstituted low alkyl group.More preferably, alkyl is the medium sized alkyl that has 1-5 carbon atom, such as methyl, ethyl, propyl group, 2-propyl group, normal-butyl, isobutyl-, the tertiary butyl, amyl group etc.Preferably, alkyl is the low alkyl group that has 1-4 carbon atom, such as methyl, ethyl, propyl group, 2-propyl group, normal-butyl, isobutyl-or the tertiary butyl etc.Alkyl can be that replace or unsubstituted.
Unless stated otherwise, the " (C in the present invention
2-C
8) alkenyl group ", as vinyl, propenyl, butenyl, pentenyl, hexenyl, butadienyl, pentadienyl, hexadienyl, 2-ethyl hexyl thiazolinyl, 2-propyl group-crotyl, 4-(2-methyl-3-butenyl)-pentenyl.Alkenyl group can be unsubstituted, or is replaced by one or two suitable substituting group.
Unless stated otherwise, the " (C in the present invention
2-C
8) alkynyl " include but not limited to ethynyl, interior alkynyl, butynyl, pentynyl, alkynyl, methyl-prop alkynyl, 4-methyl isophthalic acid-butynyl, 4-propyl group-valerylene base and 4-butyl-2-hexin base.Alkynyl group can be unsubstituted, or is replaced by one or two suitable substituting group.
Unless stated otherwise, refer to that for describing the term " replacement " of compound or chemical group at least a portion of this compound or chemical group is substituted by another chemical group herein.This another chemical group can be any suitable synthetic invalid substituting group that can not cause the compounds of this invention or the intermediate product for the preparation of compound.Those skilled in the art easily selects suitable substituting group according to the stability of compound of the present invention and composite reactive.
Embodiment
With specific embodiment, content of the present invention is described in more detail below, but protection scope of the present invention is not limited to this.
The preparation of embodiment 1:3-nitro-N-(2,6-dioxo-3-piperidyl)-phthalic imidine
In the reaction flask of 2L, add successively 3-nitrophthalic acid (150g, 0.7mo1), 3-amino-2,6-dioxopiperidine hydrochloride (90g, 0.55mol), 100g molecular sieve and 1.6L Glacial acetic acid, after being heated to 105～115 ℃, add sodium acetate, anhydrous (50g, 0.37mol), keep reacting 3～4h at this temperature, after TLC detection reaction completes, stopped reaction.Suction filtration, fully dry pale solid (154g, 93%), mp282～283 ℃ of obtaining.
1H?NMR(DMSO-d
6)δ：11.19(s，1H，CONHCO)，8.32(d，1H，CHCNO
2)，8.24(d，1H，CHCCO)，8.10(d，1H，CHC
HCH)，5.14～5.21(m，1H，COC
HCH
aH
b)，2.81～2.86(m，1H，C
H aH
bCO)，2.55～2.60(m，1H，COCHC
H aH
b)，2.43～2.51(m，1H，CH
a H bCO)，2.02～2.06(m，1H，COCHCH
a H b)。
Embodiment 2: the preparation of Bo Madu amine
3-nitro-N-(2,6-dioxo-3-piperidyl)-phthalic imidine (80g, 0.26mol) is fully dissolved in to the N of 1.2L, in dinethylformamide, add 10g palladium carbon, proceed to hydriding reactor, hydrogen pressure 0.5-1.0MPa, reaction 12h.React and finish, elimination palladium carbon, adds 120g gac in filtrate, stirs 0.5h, and suction filtration, splashes into appropriate pure water in filtrate, stirs 1h, suction filtration, the rear crude product (68g, 95%) that is fully dried to obtain.Through hot water making beating washing, obtain yellow solid, mp>300 ℃.
1HNMR(DMSO-d
6)δ.1112(s，1H，CONHCO)，745(t，1H，CHC
HCH)，7.01(d，1H，CHCCO)，7.01(d，1H，C
HCNH
2)，6.54(s，2H，NH
2)，5.03～5.08(m，1H，COC
HCH
aH
b)，2.85～2.89(m，1H，C
H aH
bCO)，2.59～2.63(m，1H，COCHC
H aH
b)，2.51～2.54(m，IH，CH
aH
bCO)，1.99～2.03(m，1H，COCHCH
a H b)；
LC-MS(ESI)(m／z)∶296[M+Na]
+。
Embodiment 3: the preparation of compound 2
In the reaction flask of 2L, add successively 3-nitrophthalic acid, 0.55mol compound 1 and the 1.5L N of 0.8mol, dinethylformamide, adds 70g sodium acetate, anhydrous after being heated to 120 ℃, keeps reacting 5h at this temperature, after TLC detection reaction completes, stopped reaction.Suction filtration, the fully dry pale solid (yield 80%) that obtains.
1H?NMR(DMSO-d
6)δ：11.19(s，1H，CONHCO)，8.32(d，1H，CHCNO
2)，8.24(d，1H，CHCCO)，8.10(d，1H，CHC
HCH)，7.30～7.40(m，5H，
CHCHCHCHCH)，5.14～5.21(m，1H，COC
HCH
aH
b)，4.32(d，2H，CC
H 2C)，2.81～2.86(m，1H，C
H aH
bCO)，2.55～2.60(m，1H，COCHC
H aH
b)，2.43～2.51(m，1H，CH
a H bCO)，2.02～2.06(m，1H，COCHCH
a H b)。
LC-MS(ESI)(m／z)∶394[M+H]
+。
Embodiment 4: the preparation of compound 3
60g compound 2 is fully dissolved in the DMF of 1.2L, adds 6g platinum oxide, proceed to hydriding reactor, hydrogen pressure 1.0-1.5MPa, reaction 25h.React and finish, elimination platinum oxide, adds 120g gac in filtrate, stirs 0.6h, and suction filtration, splashes into appropriate pure water in filtrate, stirs 1h, suction filtration, the rear crude product (yield 85%) that is fully dried to obtain.Refining through hot water making beating washing, obtain yellow solid.
1H?NMR(DMSO-d
6)δ：I1.09(s，1H，CONHCO)，7.43(t，1H，CHC
HCH)，7.30～7.40(m，5H，
CHCHCHCHCH)，7.05(d，1H，CHCCO)，7.02(d，1H.C
HCNH
2)，6.56(s，2H，NH
2)，5.02～5.08(m.1H.COC
HCH
aH
b)，2.83～2.86(m.1H.C
H aH
bCO)，2.61～2.65(m，1H，COCHC
H aH
b)，2.50～2.55(m，1H，CH
aH
bCO)，1.97～2.02(m，1H，COCHCH
a H b)。
LC-MS(ESI)(m／z)∶364[M+H]
+。
Embodiment 5: the preparation of compound 5
In the reaction flask of 2L, add successively the 3-nitrophthalic acid (150g of 0.8mol, 0.7mol), 0.55mol compound 4 and 1.5L acetonitrile, 100g molecular sieve, after being heated to 60 ℃, add 70g sodium acetate, anhydrous, keep reacting 5h at this temperature, after TLC detection reaction completes, stopped reaction.Suction filtration, the fully dry pale solid (yield 81%) that obtains.
1H?NMR(DMSO-d
6)δ：11.32(s，1H，CONHCO)，8.38(d，1H，CHCNO
2)，8.20(d，1H，CHCCO)，8.16(d，1H，CHC
HCH)，2.83～2.85(m，1H，C
H aH
bCO)，2.52～2.59(m，1H，COCHC
H aH
b)，2.40～2.45(m，1H，CH
a H bCO)，2.00～2.03(m，1H，COCHCH
a H b)。
LC-MS(ESI)(m／z)∶338[M+H]
+。
Embodiment 6: the preparation of compound 6
Compound 70g compound 5 is fully dissolved in the methyl alcohol of 1.2L, adds 10g Raney's nickel, proceed to hydriding reactor, hydrogen pressure 0.8-1.3MPa, reaction 20h.React and finish, elimination Raney's nickel, adds 120g gac in filtrate, stirs 0.6h, and suction filtration, splashes into appropriate pure water in filtrate, stirs 1h, suction filtration, the rear crude product (yield 90%) that is fully dried to obtain.Refining through hot water making beating washing, obtain yellow solid and be compound 6.
1HNMR(DMSO-d6)δ：11.18(s，1H，CONHCO)，7.53(t，1H，CHC
HCH)，7.08(d，1H，CHCCO)，7.02(d，1H，C
HCNH
2)，6.55(s，2H，NH
2)，2.85～2.87(m，1H，C
H aH
bCO)，2.53～2.60(m，1H，COCHC
H aH
b)，2.49～2.52(m，1H，CH
aH
bCO)，2.00～2.05(m，1H，COCHCH
a H b)；
LC-MS(ESI)(m／Z)∶308[M+H]
+。
Claims (10)
1. prepare the method suc as formula compound shown in (I) or its pharmacy acceptable salt, solvate, polymorphic form or steric isomer,
It is characterized in that comprising the steps:
A, amino the 3-of 3-nitrophthalic acid or its salt and formula (II) glutarimide compound or its salt is reacted in organic solvent to the step of the formula that obtains (III);
B, the formula obtaining (III) compound is obtained to formula (I) compound by reductive agent catalytic reduction reaction; Wherein, the R in formula (I), formula (II) or formula (III) is hydrogen, halogen, benzyl, (C
1-C
8) alkyl, (C
2-C
8) thiazolinyl or (C
2-C
8) alkynyl.
2. method according to claim 1, is characterized in that: described R is H.
3. method according to claim 1, is characterized in that: in the reaction process of described steps A, add dewatering agent, described dewatering agent is the combination of molecular sieve, sodium acetate, anhydrous or molecular sieve and sodium acetate, anhydrous.
4. method according to claim 1, is characterized in that: the organic solvent of described steps A is selected from one or more in acetic acid, DMF, acetonitrile, ethanol, Virahol.
5. method according to claim 4, is characterized in that: described solvent is acetic acid.
6. according to method described in claim 2～5, it is characterized in that: described temperature of reaction is 60-120 ℃.
7. method according to claim 1, is characterized in that: the reductive agent described in step B is selected from the one in hydrogen/palladium carbon, hydrogen/Raney's nickel, hydrogen/platinum oxide.
8. method according to claim 1, is characterized in that: in reduction reaction process, hydrogen pressure is 0.5～1.5MPa.
9. method according to claim 7, is characterized in that: the solvent of the reaction described in step B is organic solvent, the one in particular methanol, DMF.
10. a method of preparing suc as formula compound shown in (III) or its pharmacy acceptable salt, solvate, polymorphic form or steric isomer, be characterised in that and comprise amino the 3-of 3-nitrophthalic acid or its salt and formula (II) glutarimide compound or its salt in organic solvent, under the effect of dewatering agent, reaction obtains the step of formula (III)
Wherein, the R in formula (II) or formula (III) is hydrogen, halogen, benzyl, (C
1-C
8) alkyl, (C
2-C
8) thiazolinyl or (C
2-C
8) alkynyl; Described dewatering agent is the combination of molecular sieve, sodium acetate, anhydrous or molecular sieve and sodium acetate, anhydrous.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201410091050.5A CN103819454A (en) | 2014-03-13 | 2014-03-13 | Preparation method of N-(2, 6-dioxo-3-piperidyl) phthalimide compound |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201410091050.5A CN103819454A (en) | 2014-03-13 | 2014-03-13 | Preparation method of N-(2, 6-dioxo-3-piperidyl) phthalimide compound |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN103819454A true CN103819454A (en) | 2014-05-28 |
Family
ID=50754786
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201410091050.5A Pending CN103819454A (en) | 2014-03-13 | 2014-03-13 | Preparation method of N-(2, 6-dioxo-3-piperidyl) phthalimide compound |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN103819454A (en) |
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104926786A (en) * | 2014-03-21 | 2015-09-23 | 合肥久诺医药科技有限公司 | Method for preparing 3-nitro-N-(2,6-dioxo-3-piperidinyl) phthalimide |
| CN109553603A (en) * | 2018-12-20 | 2019-04-02 | 河南师范大学 | A kind of preparation method of antineoplaston medicine pomalidomide |
| CN114605381A (en) * | 2020-12-03 | 2022-06-10 | 南京海辰药业股份有限公司 | Preparation method of pomalidomide |
| WO2024035626A1 (en) * | 2022-08-11 | 2024-02-15 | The United States Of America, As Represented By The Secretary, Department Of Health And Human Services | Halophthalimide compounds and methods of use against tbi, inflammatory disorder, autoimmune disorder, neurodegenerative disease or viral infection |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2014018866A1 (en) * | 2012-07-27 | 2014-01-30 | Celgene Corporation | Processes for preparing isoindoline-1,3-dione compounds |
-
2014
- 2014-03-13 CN CN201410091050.5A patent/CN103819454A/en active Pending
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2014018866A1 (en) * | 2012-07-27 | 2014-01-30 | Celgene Corporation | Processes for preparing isoindoline-1,3-dione compounds |
Non-Patent Citations (1)
| Title |
|---|
| 唐玫等: "抗肿瘤药Pomalidomide的合成", 《中国医药工业杂志》, vol. 40, no. 10, 31 December 2009 (2009-12-31), pages 721 - 723 * |
Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104926786A (en) * | 2014-03-21 | 2015-09-23 | 合肥久诺医药科技有限公司 | Method for preparing 3-nitro-N-(2,6-dioxo-3-piperidinyl) phthalimide |
| CN104926786B (en) * | 2014-03-21 | 2017-07-28 | 合肥久诺医药科技有限公司 | The preparation method of one kind 3 nitro N (piperidyl of 2,6 dioxo 3) phthalimide |
| CN109553603A (en) * | 2018-12-20 | 2019-04-02 | 河南师范大学 | A kind of preparation method of antineoplaston medicine pomalidomide |
| CN114605381A (en) * | 2020-12-03 | 2022-06-10 | 南京海辰药业股份有限公司 | Preparation method of pomalidomide |
| WO2024035626A1 (en) * | 2022-08-11 | 2024-02-15 | The United States Of America, As Represented By The Secretary, Department Of Health And Human Services | Halophthalimide compounds and methods of use against tbi, inflammatory disorder, autoimmune disorder, neurodegenerative disease or viral infection |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| FI106027B (en) | Process for Preparation of (S) (+) - 2-Ethoxy-4- [N- [1- (2-piperidinophenyl) -3-methyl-1-butyl] aminocarbonylmethyl] benzoic acid or its salt, and N-acetyl L-glutamine salts (s) (S) -1-2-piperidinophenyl) -3-methyl-1-butylamine and its preparation | |
| CN103819454A (en) | Preparation method of N-(2, 6-dioxo-3-piperidyl) phthalimide compound | |
| CN112062767B (en) | Preparation method and intermediate of rumepilone | |
| WO2016037514A1 (en) | Preparation method of nintedanib | |
| CN110452188A (en) | A kind of preparation method lying prostrate sulphur Xi Ting | |
| AU783786B2 (en) | 4-phenyl-1-piperazinyl, -piperidinyl and -tetrahydropyridyl derivatives | |
| JPH02215769A (en) | Nitrogen-containing cylic compound | |
| CN1437597A (en) | Substituted phenyl-Piperazine derivatives, their preparation and use | |
| Shirani et al. | Benzothiazolopyridine compounds: Facial synthesis, characterization, and molecular docking study on estrogen and progesterone receptors | |
| CN104844602B (en) | A kind of preparation method of Li Gelieting | |
| CN110105308A (en) | A kind of preparation method of vortioxetine | |
| CN101012147A (en) | Method of preparing R-(+)-3-chlorophenylpropanol | |
| CN114573569B (en) | Preparation method of isoquinoline compound | |
| JP4823063B2 (en) | HIV virus entry inhibitor | |
| CN102688234B (en) | Indolone derivatives is as the Synthesis and application of RSK2 inhibitor | |
| WO2016039393A1 (en) | Production method for amino acid derivative | |
| CN114230490A (en) | Preparation method of N-alkylated diamine | |
| CN108276380A (en) | A kind of synthetic method of pomalidomide | |
| CN110950770B (en) | Synthesis method of lacosamide | |
| CN106432195B (en) | Method for preparing (R) -2- (2-methylpyrrolidine-2-yl) -1H-benzimidazole-4-formamide | |
| CN109608434B (en) | Preparation method of lenalidomide | |
| CN103664911B (en) | The method for preparing vilazodone and its intermediate | |
| BR112018002881B1 (en) | Methods for producing praziquantel and its precursors | |
| CN103804350B (en) | A kind of preparation method of high purity pool horse degree amine | |
| CN105523939B (en) | A kind of preparation method of lenalidomide intermediate |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| C12 | Rejection of a patent application after its publication | ||
| RJ01 | Rejection of invention patent application after publication |
Application publication date: 20140528 |