CN115215835B - Preparation method of 2- (2, 6-dioxopiperidin-3-yl) -1-oxyisoindoline-4-yl) acetic acid - Google Patents
Preparation method of 2- (2, 6-dioxopiperidin-3-yl) -1-oxyisoindoline-4-yl) acetic acid Download PDFInfo
- Publication number
- CN115215835B CN115215835B CN202210990711.2A CN202210990711A CN115215835B CN 115215835 B CN115215835 B CN 115215835B CN 202210990711 A CN202210990711 A CN 202210990711A CN 115215835 B CN115215835 B CN 115215835B
- Authority
- CN
- China
- Prior art keywords
- compound
- acetic acid
- reaction
- dioxopiperidin
- oxyisoindoline
- 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.)
- Active
Links
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 title claims abstract description 108
- -1 2, 6-dioxopiperidin-3-yl Chemical group 0.000 title claims abstract description 41
- 238000002360 preparation method Methods 0.000 title claims abstract description 6
- 238000006243 chemical reaction Methods 0.000 claims abstract description 30
- 230000002194 synthesizing effect Effects 0.000 claims abstract description 6
- 150000001875 compounds Chemical class 0.000 claims description 34
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 22
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 19
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 claims description 17
- 239000003153 chemical reaction reagent Substances 0.000 claims description 13
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 claims description 12
- 238000000034 method Methods 0.000 claims description 12
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 claims description 8
- VNDYJBBGRKZCSX-UHFFFAOYSA-L zinc bromide Chemical compound Br[Zn]Br VNDYJBBGRKZCSX-UHFFFAOYSA-L 0.000 claims description 8
- 239000003960 organic solvent Substances 0.000 claims description 7
- 239000000243 solution Substances 0.000 claims description 7
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 6
- 239000003054 catalyst Substances 0.000 claims description 6
- 239000003446 ligand Substances 0.000 claims description 6
- 229910052763 palladium Inorganic materials 0.000 claims description 6
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 6
- HCHKCACWOHOZIP-UHFFFAOYSA-N Zinc Chemical compound [Zn] HCHKCACWOHOZIP-UHFFFAOYSA-N 0.000 claims description 5
- 239000011701 zinc Substances 0.000 claims description 5
- 229910052725 zinc Inorganic materials 0.000 claims description 5
- 229910052786 argon Inorganic materials 0.000 claims description 4
- 125000004213 tert-butoxy group Chemical group [H]C([H])([H])C(O*)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 4
- CXNIUSPIQKWYAI-UHFFFAOYSA-N xantphos Chemical compound C=12OC3=C(P(C=4C=CC=CC=4)C=4C=CC=CC=4)C=CC=C3C(C)(C)C2=CC=CC=1P(C=1C=CC=CC=1)C1=CC=CC=C1 CXNIUSPIQKWYAI-UHFFFAOYSA-N 0.000 claims description 4
- 229940102001 zinc bromide Drugs 0.000 claims description 4
- CYPYTURSJDMMMP-WVCUSYJESA-N (1e,4e)-1,5-diphenylpenta-1,4-dien-3-one;palladium Chemical compound [Pd].[Pd].C=1C=CC=CC=1\C=C\C(=O)\C=C\C1=CC=CC=C1.C=1C=CC=CC=1\C=C\C(=O)\C=C\C1=CC=CC=C1.C=1C=CC=CC=1\C=C\C(=O)\C=C\C1=CC=CC=C1 CYPYTURSJDMMMP-WVCUSYJESA-N 0.000 claims description 2
- KZPYGQFFRCFCPP-UHFFFAOYSA-N 1,1'-bis(diphenylphosphino)ferrocene Chemical compound [Fe+2].C1=CC=C[C-]1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=C[C-]1P(C=1C=CC=CC=1)C1=CC=CC=C1 KZPYGQFFRCFCPP-UHFFFAOYSA-N 0.000 claims description 2
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 claims description 2
- NFHFRUOZVGFOOS-UHFFFAOYSA-N Pd(PPh3)4 Substances [Pd].C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 NFHFRUOZVGFOOS-UHFFFAOYSA-N 0.000 claims description 2
- 229910002666 PdCl2 Inorganic materials 0.000 claims description 2
- YNHIGQDRGKUECZ-UHFFFAOYSA-L PdCl2(PPh3)2 Substances [Cl-].[Cl-].[Pd+2].C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 YNHIGQDRGKUECZ-UHFFFAOYSA-L 0.000 claims description 2
- KTWOOEGAPBSYNW-UHFFFAOYSA-N ferrocene Chemical compound [Fe+2].C=1C=C[CH-]C=1.C=1C=C[CH-]C=1 KTWOOEGAPBSYNW-UHFFFAOYSA-N 0.000 claims description 2
- 238000010438 heat treatment Methods 0.000 claims description 2
- PIBWKRNGBLPSSY-UHFFFAOYSA-L palladium(II) chloride Chemical compound Cl[Pd]Cl PIBWKRNGBLPSSY-UHFFFAOYSA-L 0.000 claims description 2
- YJVFFLUZDVXJQI-UHFFFAOYSA-L palladium(ii) acetate Chemical compound [Pd+2].CC([O-])=O.CC([O-])=O YJVFFLUZDVXJQI-UHFFFAOYSA-L 0.000 claims description 2
- UGOMMVLRQDMAQQ-UHFFFAOYSA-N xphos Chemical group CC(C)C1=CC(C(C)C)=CC(C(C)C)=C1C1=CC=CC=C1P(C1CCCCC1)C1CCCCC1 UGOMMVLRQDMAQQ-UHFFFAOYSA-N 0.000 claims description 2
- 239000000463 material Substances 0.000 claims 1
- 230000035484 reaction time Effects 0.000 claims 1
- 238000001308 synthesis method Methods 0.000 abstract description 22
- 238000005859 coupling reaction Methods 0.000 abstract description 5
- 230000015572 biosynthetic process Effects 0.000 abstract description 3
- 230000003197 catalytic effect Effects 0.000 abstract description 3
- 230000007062 hydrolysis Effects 0.000 abstract description 3
- 238000006460 hydrolysis reaction Methods 0.000 abstract description 3
- 238000003786 synthesis reaction Methods 0.000 abstract description 3
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 abstract description 3
- 239000002994 raw material Substances 0.000 abstract description 2
- 238000007039 two-step reaction Methods 0.000 abstract description 2
- 230000002349 favourable effect Effects 0.000 abstract 1
- 238000011031 large-scale manufacturing process Methods 0.000 abstract 1
- 238000007086 side reaction Methods 0.000 abstract 1
- 239000002904 solvent Substances 0.000 description 10
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 9
- 238000010791 quenching Methods 0.000 description 7
- 238000003756 stirring Methods 0.000 description 7
- 238000005406 washing Methods 0.000 description 7
- 238000001035 drying Methods 0.000 description 6
- 238000000605 extraction Methods 0.000 description 6
- 230000000171 quenching effect Effects 0.000 description 6
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical class [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 4
- GWVMLCQWXVFZCN-UHFFFAOYSA-N isoindoline Chemical class C1=CC=C2CNCC2=C1 GWVMLCQWXVFZCN-UHFFFAOYSA-N 0.000 description 4
- 239000000047 product Substances 0.000 description 4
- 238000000746 purification Methods 0.000 description 4
- 239000007787 solid Substances 0.000 description 4
- 238000000108 ultra-filtration Methods 0.000 description 4
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 4
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 3
- 239000000706 filtrate Substances 0.000 description 3
- 238000001914 filtration Methods 0.000 description 3
- 239000007788 liquid Substances 0.000 description 3
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 2
- 239000002253 acid Substances 0.000 description 2
- 239000012445 acidic reagent Substances 0.000 description 2
- 239000003795 chemical substances by application Substances 0.000 description 2
- 238000004440 column chromatography Methods 0.000 description 2
- 239000012141 concentrate Substances 0.000 description 2
- 125000004122 cyclic group Chemical group 0.000 description 2
- 230000007547 defect Effects 0.000 description 2
- 238000001514 detection method Methods 0.000 description 2
- 238000010790 dilution Methods 0.000 description 2
- 239000012895 dilution Substances 0.000 description 2
- 229940079593 drug Drugs 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- 238000002474 experimental method Methods 0.000 description 2
- 238000004108 freeze drying Methods 0.000 description 2
- 230000003301 hydrolyzing effect Effects 0.000 description 2
- 238000004519 manufacturing process Methods 0.000 description 2
- 239000012074 organic phase Substances 0.000 description 2
- 239000000376 reactant Substances 0.000 description 2
- 238000013341 scale-up Methods 0.000 description 2
- 238000000926 separation method Methods 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- 231100000331 toxic Toxicity 0.000 description 2
- 230000002588 toxic effect Effects 0.000 description 2
- 238000012546 transfer Methods 0.000 description 2
- 238000005160 1H NMR spectroscopy Methods 0.000 description 1
- SCZFMUWTABGOGF-UHFFFAOYSA-N BrC1=C2CN(C(C2=CC=C1)=O)C1C(NC(CC1)=O)=O Chemical compound BrC1=C2CN(C(C2=CC=C1)=O)C1C(NC(CC1)=O)=O SCZFMUWTABGOGF-UHFFFAOYSA-N 0.000 description 1
- 229940126062 Compound A Drugs 0.000 description 1
- NLDMNSXOCDLTTB-UHFFFAOYSA-N Heterophylliin A Natural products O1C2COC(=O)C3=CC(O)=C(O)C(O)=C3C3=C(O)C(O)=C(O)C=C3C(=O)OC2C(OC(=O)C=2C=C(O)C(O)=C(O)C=2)C(O)C1OC(=O)C1=CC(O)=C(O)C(O)=C1 NLDMNSXOCDLTTB-UHFFFAOYSA-N 0.000 description 1
- 238000005481 NMR spectroscopy Methods 0.000 description 1
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 1
- BZKJTJDQFHKZLD-UHFFFAOYSA-M [Br-].C(C)(C)(C)OC(CC[Zn+])=O Chemical compound [Br-].C(C)(C)(C)OC(CC[Zn+])=O BZKJTJDQFHKZLD-UHFFFAOYSA-M 0.000 description 1
- 235000019270 ammonium chloride Nutrition 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 230000004071 biological effect Effects 0.000 description 1
- 239000006227 byproduct Substances 0.000 description 1
- 230000008878 coupling Effects 0.000 description 1
- 238000010168 coupling process Methods 0.000 description 1
- 230000007613 environmental effect Effects 0.000 description 1
- 239000002360 explosive Substances 0.000 description 1
- 239000005457 ice water Substances 0.000 description 1
- GOTYRUGSSMKFNF-UHFFFAOYSA-N lenalidomide Chemical compound C1C=2C(N)=CC=CC=2C(=O)N1C1CCC(=O)NC1=O GOTYRUGSSMKFNF-UHFFFAOYSA-N 0.000 description 1
- 229960004942 lenalidomide Drugs 0.000 description 1
- 125000000325 methylidene group Chemical group [H]C([H])=* 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- 229930014626 natural product Natural products 0.000 description 1
- 150000002894 organic compounds Chemical class 0.000 description 1
- 150000002978 peroxides Chemical class 0.000 description 1
- KNCYXPMJDCCGSJ-UHFFFAOYSA-N piperidine-2,6-dione Chemical compound O=C1CCCC(=O)N1 KNCYXPMJDCCGSJ-UHFFFAOYSA-N 0.000 description 1
- 102000004169 proteins and genes Human genes 0.000 description 1
- 108090000623 proteins and genes Proteins 0.000 description 1
- 239000011541 reaction mixture Substances 0.000 description 1
- 229920006395 saturated elastomer Polymers 0.000 description 1
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 238000010189 synthetic method Methods 0.000 description 1
- NJYVNVLRCTWJKS-UHFFFAOYSA-N tert-butyl 2-bromoacetate;zinc Chemical compound [Zn].CC(C)(C)OC(=O)CBr NJYVNVLRCTWJKS-UHFFFAOYSA-N 0.000 description 1
- 238000001291 vacuum drying Methods 0.000 description 1
- 239000002699 waste material Substances 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
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
- Plural Heterocyclic Compounds (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention provides a new preparation method for synthesizing 2- (2, 6-dioxopiperidine-3-yl) -1-oxyisoindoline-4-yl) acetic acid, which is synthesized into 2- (2, 6-dioxopiperidine-3-yl) -1-oxyisoindoline-4-yl) acetic acid through a catalytic coupling reaction and a hydrolysis and tert-butyl removal two-step reaction; the synthesis method has the advantages of short steps of the whole synthesis route, less side reaction, high conversion rate and yield, cheap and easily obtained raw materials, mild operation conditions and high safety, and is favorable for large-scale production and industrialized popularization and application.
Description
Technical Field
The invention relates to the technical field of organic compound synthesis, in particular to a synthesis method of 2- (2, 6-dioxopiperidine-3-yl) -1-oxyisoindoline-4-yl) acetic acid.
Background
The isoindoline derivative is an important nitrogenous compound, exists in various medicines and natural products, and can be matched with different biological protein macromolecular space structures in organisms due to the structural characteristics of the isoindoline derivative, so that the isoindoline derivative shows wide biological activity. 2- (2, 6-dioxopiperidin-3-yl) -1-oxyisoindolin-4-yl) acetic acid is an important intermediate compound for synthesizing various isoindolin medical novel drug compounds because of its active structure and a freely rotatable methylene structure.
The method for synthesizing 2- (2, 6-dioxopiperidin-3-yl) -1-oxyisoindolin-4-yl) acetic acid is characterized by comprising the following steps of starting lenalidomide, diazotizing, hydrolyzing, coupling and hydrolyzing, wherein the method has the defects of longer integral reaction route, peroxide and highly toxic reagents are needed for reaction, a large amount of three wastes are generated in the reaction process, the third step of coupling reaction has low yield and by-products which are difficult to separate and purify, the total yield is low, and the method is not suitable for industrial scale-up production and industrial application.
Accordingly, those skilled in the art have focused on developing a novel method for synthesizing 2- (2, 6-dioxopiperidin-3-yl) -1-oxoisoindolin-4-yl) acetic acid, aiming at solving the drawbacks of the above-mentioned synthetic methods of such compounds in the prior art.
Disclosure of Invention
The invention aims to solve the technical problems that in the prior art, the synthesis method of 2- (2, 6-dioxopiperidine-3-yl) -1-oxyisoindoline-4-yl) acetic acid has the defects of poor reaction selectivity, low yield, difficulty in separation and purification, poor safety, difficulty in obtaining starting materials, poor universality and environment friendliness, and is not suitable for industrial scale-up production and industrial practical application.
In order to achieve the aim, the invention provides a synthesis method of 2- (2, 6-dioxopiperidin-3-yl) -1-oxyisoindolin-4-yl) acetic acid, wherein the structure of the 2- (2, 6-dioxopiperidin-3-yl) -1-oxyisoindolin-4-yl) acetic acid is shown as follows,
The novel synthesis method of the 2- (2, 6-dioxopiperidin-3-yl) -1-oxyisoindolin-4-yl) acetic acid is shown in the following route I:
Route I:
the specific operation steps are as follows:
Step 1, dissolving a compound A-1 in tetrahydrofuran, sequentially adding tris (dibenzylideneacetone) dipalladium, 1,2,3,4, 5-pentylphenyl-1' - (di-tert-butylphosphino) ferrocene and 2- (tert-butoxycarbonyl) ethylzinc bromide under the protection of argon, heating to 70 ℃ for reaction, and performing post-treatment to obtain a compound A-2;
And 2, dissolving the compound A-2 in dichloromethane, adding trifluoroacetic acid for room temperature reaction, and performing post-treatment to obtain the target compound 2- (2, 6-dioxopiperidin-3-yl) -1-oxyisoindoline-4-yl) acetic acid (formula A).
According to the novel method for synthesizing 2- (2, 6-dioxopiperidin-3-yl) -1-oxoisoindolin-4-yl) acetic acid, in step 1, the palladium catalyst is Pd2(dba)3、Pd(OAc)2、Pd(PPh3)4、PdCl2(PPh3)2、PdCl2(dppf);, preferably Pd 2(dba)3;
According to the synthesis method of the 2- (2, 6-dioxopiperidin-3-yl) -1-oxyisoindolin-4-yl) acetic acid, in the step 1, the ligand reagent is X-Phos, Q-Phos, xant-Phos; preferably Q-Phos;
according to the synthesis method of the 2- (2, 6-dioxopiperidin-3-yl) -1-oxyisoindolin-4-yl) acetic acid, in the step 1, the organic solvent is Et 2 O, TBME, toluene, THF; preferably THF;
According to the synthesis method of the 2- (2, 6-dioxopiperidin-3-yl) -1-oxyisoindolin-4-yl) acetic acid, in the step 1, the molar ratio of the compound A-1 to the palladium catalyst is 1:0.03-1:0.15; preferably 1:0.06;
According to the synthesis method of the 2- (2, 6-dioxopiperidin-3-yl) -1-oxyisoindolin-4-yl) acetic acid, in the step 1, the molar ratio of the compound A-1 to the ligand reagent is 1:0.03-1:0.15; preferably 1:0.07;
according to the synthesis method of the 2- (2, 6-dioxopiperidin-3-yl) -1-oxyisoindolin-4-yl) acetic acid, in the step 1, the molar ratio of the compound A-1 to the zinc reagent is 1:1-1:3; preferably 1:2;
According to the synthesis method of the 2- (2, 6-dioxopiperidin-3-yl) -1-oxyisoindolin-4-yl) acetic acid, in the step 1, the weight-volume ratio (g/ml) of the compound A-1 to the organic solvent is 1:15-1:25; preferably 1:20;
According to the synthesis method of 2- (2, 6-dioxopiperidin-3-yl) -1-oxyisoindoline-4-yl) acetic acid, in the step 1, the temperature in the reaction process is controlled to be room temperature, and after the reactants are added dropwise, the temperature is slowly raised to 70 ℃ and stirred for 1-2 hours;
According to the synthesis method of the 2- (2, 6-dioxopiperidin-3-yl) -1-oxyisoindolin-4-yl) acetic acid, in the step 2, the acid reagent is trifluoroacetic acid;
According to the synthesis method of the 2- (2, 6-dioxopiperidin-3-yl) -1-oxyisoindolin-4-yl) acetic acid, in the step 2, the organic solvent is Et 2 O, DCM, THF; preferably DCM;
According to the synthesis method of the 2- (2, 6-dioxopiperidin-3-yl) -1-oxyisoindolin-4-yl) acetic acid, in the step 2, the weight-volume ratio (g/ml) of the compound A-1 to the solvent is 1:15-1:25; preferably 1:20;
according to the synthesis method of the 2- (2, 6-dioxopiperidin-3-yl) -1-oxyisoindolin-4-yl) acetic acid, in the step 2, the molar ratio of the compound A-1 to the acid reagent trifluoroacetic acid is 1:8-1:15; preferably 1:10;
According to the synthesis method of 2- (2, 6-dioxopiperidin-3-yl) -1-oxyisoindolin-4-yl) acetic acid, in the step 2, the temperature of the reaction process is controlled to be room temperature, and the reaction is continuously stirred at room temperature until the reaction of A-1 is complete after the dropwise addition of reactants;
according to the synthesis method of the 2- (2, 6-dioxopiperidin-3-yl) -1-oxyisoindolin-4-yl) acetic acid, the specific operation of the step 1 is as follows:
Dissolving A-1 in tetrahydrofuran solution, adding Pd 2(dba)3 and Q-Phos, (2- (tert-butoxy) -2-oxyethyl) zinc bromide under the protection of argon, slowly raising the temperature to 70 ℃ and stirring for reaction for 2 hours; after the reaction is finished, adding saturated ammonium chloride solution into the reaction solution for quenching, extracting by ethyl acetate, collecting an organic phase, washing by saturated saline solution, drying by anhydrous sodium sulfate, filtering, concentrating the filtrate to remove the solvent, and separating and purifying the concentrate by column chromatography to obtain a target product compound A-2;
according to the synthesis method of the 2- (2, 6-dioxopiperidin-3-yl) -1-oxyisoindolin-4-yl) acetic acid, the specific operation of the step 2 is as follows:
dissolving the compound A-2 in a dichloromethane solvent, adding trifluoroacetic acid under stirring at room temperature, continuing stirring at room temperature for reaction for 2 hours until the reaction is finished, and concentrating to remove the solvent to obtain the target product compound.
The technical parameter characteristics in the preparation method of the invention can be combined arbitrarily.
In the above description, the post-treatment includes, but is not limited to, quenching with a quencher, stirring, extraction, transfer of liquid or solid, washing with water, alkaline washing, acid washing, filtration, ultrafiltration, cyclic ultrafiltration, dilution, concentration, drying, purification, lyophilization, etc., or one or a combination of several of quenching with water, stirring, extraction, transfer of liquid or solid, washing with water, alkaline washing, acid washing, filtration, ultrafiltration, cyclic ultrafiltration, dilution, concentration, drying, purification, lyophilization, etc.
In a preferred embodiment of the present invention, the quenching means a process of adding a quenching agent to the reaction solution to stop the reaction from proceeding to the right;
The quenching agent is saturated aqueous solution of water, ice water and ammonium chloride;
in a preferred embodiment of the present invention, the extraction solvent used in the extraction is ethyl acetate or dichloromethane;
in a preferred embodiment of the present invention, the drying includes anhydrous sodium sulfate drying of the filtrate, vacuum drying;
In a preferred embodiment of the present invention, the concentration refers to a process of removing the liquid solvent, including vacuum concentration, normal pressure concentration, low Wen Xuangan, etc.;
The steps, solvents, reagents, drying, concentration, extraction, separation and the like in the synthesis method of the 2- (2, 6-dioxopiperidin-3-yl) -1-oxoisoindoline-4-yl) acetic acid can be combined/split arbitrarily, and the purpose of the invention can be achieved.
The room temperature of the application is 15-30 ℃.
The synthesis method of 2- (2, 6-dioxopiperidine-3-yl) -1-oxyisoindoline-4-yl) acetic acid takes 3- (4-bromo-1-oxyisoindoline-2-yl) piperidine-2, 6-dione as a raw material, and adopts a two-step reaction route method of catalytic coupling reaction and hydrolysis tert-butyl removal to synthesize the target product compound 2- (2, 6-dioxopiperidine-3-yl) -1-oxyisoindoline-4-yl) acetic acid (formula A), the catalytic coupling reaction and the hydrolysis tert-butyl removal product are single, the conversion rate is high, the purification is easy, and the yield of the whole synthesis route is improved; the whole synthesis method does not use extremely toxic and explosive chemical dangerous substances, has mild reaction conditions and high operation safety; the method has the advantages of good route step repeatability, high conversion rate and yield, suitability for amplifying workshop operation and wide application prospect.
Detailed Description
The following describes embodiments of the present invention to make the technical contents thereof more clear and easy to understand. The invention may be embodied by embodiments.
If there are experimental methods for which specific conditions are not specified, the experimental methods are usually carried out according to conventional conditions, such as the related instructions or manuals.
Examples
Step 1, 3- (4-bromo-1-oxoisoindolin-2-yl) piperidine-2, 6-dione (1 g,3.1 mmol) (compound A-1) was dissolved in tetrahydrofuran (20 mL), pd 2(dba)3 (0.17 g,0.19 mmol), Q-Phos (0.15 g,0.22 mmol) and zinc (2- (tert-butoxy) -2-oxoethyl) bromide (12.4 mL,6.2 mmol) were added under argon and the mixture was stirred and reacted for 2 hours at 70℃slowly; after the reaction was completed, a saturated ammonium chloride solution was added to the reaction mixture to quench it, extraction was performed with ethyl acetate, the organic phase was collected and washed with saturated brine, dried over anhydrous sodium sulfate, filtered, the solvent was removed by concentration of the filtrate, and the concentrate was isolated and purified by column chromatography to give the desired compound a-2 (0.8 g, yield 72%) as an off-white solid.
Step 2, compound A-2 (0.8 g,2.2 mmol) was dissolved in dichloromethane (16 mL) solvent, trifluoroacetic acid (2.5 g,22 mmol) was added with stirring at room temperature, and the reaction was continued with stirring at room temperature for 2 hours; after the reaction was completed, the solvent was removed by concentration to give the objective compound a (0.67 g, yield 99%) as a pale yellow solid;
The structure of the compound a obtained above was detected by NMR, and the detection results were as follows:
1H NMR(400MHz,DMSO-d6)δ12.05(s,1H),10.96(s,1H),7.60(d,J＝7.1Hz,1H),7.46(d,J＝7.0Hz,2H),5.16-5.08(m,1H),4.45(d,J＝17.2Hz,1H),4.33(d,J＝17.1Hz,1H),3.60(s,2H),2.97-2.85(m,1H),2.63-2.58(m,1H),2.42-2.38(m,1H),2.05-1.94(m,1H);
The detection result shows that the synthesized compound A has correct structure.
The novel method for preparing 2- (2, 6-dioxopiperidine-3-yl) -1-oxyisoindoline-4-yl) acetic acid has the advantages of high yield, mild reaction conditions, high operation safety, environmental friendliness, further reduced cost, suitability for amplifying workshop operation and wide application prospect.
Claims (3)
1. A preparation method for synthesizing 2- (2, 6-dioxopiperidin-3-yl) -1-oxyisoindoline-4-yl) acetic acid is characterized in that the structure of the 2- (2, 6-dioxopiperidin-3-yl) -1-oxyisoindoline-4-yl) acetic acid is shown in the following formula A,
The preparation method of the 2- (2, 6-dioxopiperidin-3-yl) -1-oxyisoindolin-4-yl) acetic acid is shown in the following route I:
Route I:
Characterized in that in the step 1,
The palladium catalyst is Pd2(dba)3、Pd(OAc)2、Pd(PPh3)4、PdCl2(PPh3)2、PdCl2(dppf);
The ligand reagent is X-Phos, Q-Phos and Xant-Phos;
The zinc reagent (2- (tert-butoxy) -2-oxyethyl) zinc bromide is 0.5mol/L tetrahydrofuran solution;
the organic solvent is Et 2 O, TBME, toluene, THF;
The temperature of the reaction process is controlled to be room temperature, and the reaction materials are stirred and reacted for about 2 hours at 70 ℃ after being added;
the molar ratio of the compound A-1 to the palladium catalyst is 1:0.03-1:0.15;
The molar ratio of the compound A-1 to the ligand reagent is 1:0.03-1:0.15;
the molar ratio of the compound A-1 to the zinc reagent is 1:1-1:3;
The weight-volume ratio of the compound A-1 to the organic solvent is 1:15-1:25 g/ml;
2. The method according to claim 1, wherein in step 1,
The selected palladium catalyst is Pd 2(dba)3;
the ligand reagent selected is Q-Phos;
the selected zinc reagent is a tetrahydrofuran solution of 0.5mol/L of (2- (tert-butoxy) -2-oxyethyl) zinc bromide;
the organic solvent is THF;
The reaction temperature and the reaction time are selected to be kept at 70 ℃ and stirred for 2 hours;
the molar ratio of the selected compound A-1 to the palladium catalyst is 1:0.06;
The molar ratio of the selected compound A-1 to the ligand reagent was 1:0.07;
the molar ratio of the selected compound A-1 to the zinc reagent is 1:2;
the weight volume ratio of the selected compound A-1 to the organic solvent is 1:20 g/ml;
3. the method according to any one of claims 1 and 2, characterized in that the specific operating steps are:
Step 1, dissolving a compound A-1 in tetrahydrofuran, sequentially adding tris (dibenzylideneacetone) dipalladium, 1,2,3,4, 5-pentylphenyl-1 , - (di-tert-butylphosphino) ferrocene and (2- (tert-butoxy) -2-oxyethyl) zinc bromide under the protection of argon, and then heating to 70 ℃ for reaction, and carrying out aftertreatment to obtain a compound A-2;
And 2, dissolving the compound A-2 in dichloromethane, adding trifluoroacetic acid for room temperature reaction, and performing post-treatment to obtain the target compound 2- (2, 6-dioxopiperidin-3-yl) -1-oxyisoindoline-4-yl) acetic acid (formula A).
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202210990711.2A CN115215835B (en) | 2022-08-18 | 2022-08-18 | Preparation method of 2- (2, 6-dioxopiperidin-3-yl) -1-oxyisoindoline-4-yl) acetic acid |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202210990711.2A CN115215835B (en) | 2022-08-18 | 2022-08-18 | Preparation method of 2- (2, 6-dioxopiperidin-3-yl) -1-oxyisoindoline-4-yl) acetic acid |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN115215835A CN115215835A (en) | 2022-10-21 |
| CN115215835B true CN115215835B (en) | 2024-09-17 |
Family
ID=83615260
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN202210990711.2A Active CN115215835B (en) | 2022-08-18 | 2022-08-18 | Preparation method of 2- (2, 6-dioxopiperidin-3-yl) -1-oxyisoindoline-4-yl) acetic acid |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN115215835B (en) |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2020047208A1 (en) * | 2018-08-29 | 2020-03-05 | Morphic Therapeutic, Inc. | Inhibitors of (alpha-v)(beta-6) integrin |
Family Cites Families (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN107739389B (en) * | 2017-11-03 | 2020-03-31 | 华东师范大学 | 3-substituted (1-oxoisoindoline-2-yl) piperidine-2, 6-diketone compound and synthetic method thereof |
| WO2020047207A1 (en) * | 2018-08-29 | 2020-03-05 | Morphic Therapeutics, Inc. | Inhibitors of (alpha-v)(beta-6) integrin |
-
2022
- 2022-08-18 CN CN202210990711.2A patent/CN115215835B/en active Active
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2020047208A1 (en) * | 2018-08-29 | 2020-03-05 | Morphic Therapeutic, Inc. | Inhibitors of (alpha-v)(beta-6) integrin |
Non-Patent Citations (3)
| Title |
|---|
| Design and synthesis of new lenalidomide analogs via Suzuki cross-coupling reaction;Xiao, Donghuai et al.;Archiv der Pharmazie;第353卷(第7期);e1900376 * |
| Palladium-Catalyzed α-Arylation of Esters with Chloroarenes;Hama, Takuo et al.;Organic Letters;第10卷(第8期);1549-1552 * |
| Xiao, Donghuai et al..Design and synthesis of new lenalidomide analogs via Suzuki cross-coupling reaction.Archiv der Pharmazie.2020,第353卷(第7期),e1900376. * |
Also Published As
| Publication number | Publication date |
|---|---|
| CN115215835A (en) | 2022-10-21 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN108129288B (en) | Synthesis method of trans-3-hydroxycyclobutylformic acid | |
| CN103204801A (en) | Synthesis method for N-Boc-3-piperidone | |
| CN115215835B (en) | Preparation method of 2- (2, 6-dioxopiperidin-3-yl) -1-oxyisoindoline-4-yl) acetic acid | |
| CN112479993A (en) | Synthetic method applied to KRAS inhibitor drug heterocyclic intermediate | |
| CN115197153B (en) | Preparation method of 1, 4-diazacycloalkane compound | |
| CN111116587A (en) | Preparation method of avibactam intermediate compound | |
| CN112142713A (en) | Synthesis method of imazethapyr | |
| CN113501771A (en) | Preparation method of N- (2-aminoethyl) glycine derivative | |
| CN112062705A (en) | Synthesis method of 7-methyltryptophan | |
| CN109134351B (en) | Synthesis method of S-3- (4-aminophenyl) piperidine | |
| CN109096105B (en) | Reduction method of alkenyl active methylene compound and reduction product | |
| CN101654426B (en) | Method for preparing ilomastat | |
| CN114890942B (en) | 3-Bromo-6-chloropyridine-2-carboxylic acid and preparation method thereof | |
| CN111138355A (en) | Preparation method of formaldehyde-substituted aza-condensed ring compound | |
| CN106748725B (en) | preparation method of 4-chloro-2-fluoro-phenylpropionic acid | |
| JP3088561B2 (en) | Method for producing 2,3-diaminopyridines | |
| CN113416188B (en) | Synthetic method of [1,2,4] triazolo [1,5-A ] pyridine compound | |
| CN114349690B (en) | Synthesis method of doravirine intermediate | |
| CN113582920B (en) | Synthetic method of 4- (4-pyridyl) morpholine | |
| CN112624966B (en) | Synthetic method of 2-aminomethyl-4-methyl-5-pyridine carboxylic acid | |
| CN115181031B (en) | Preparation method of 2-amino-5-chlorobenzoic acid derivative | |
| CN109776415B (en) | Preparation method of Roxadustat intermediate | |
| CN101412678A (en) | Method for synthesizing memantine hydrochloride | |
| CN111747874B (en) | Ericoxib intermediate and preparation method and application thereof | |
| CN108299236B (en) | Synthetic method of alpha-cyanoacrylate compound |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| GR01 | Patent grant | ||
| GR01 | Patent grant |