CN109400612A - A kind of preparation method of Rui Boxini and products thereof and purposes - Google Patents
A kind of preparation method of Rui Boxini and products thereof and purposes Download PDFInfo
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- CN109400612A CN109400612A CN201811579797.XA CN201811579797A CN109400612A CN 109400612 A CN109400612 A CN 109400612A CN 201811579797 A CN201811579797 A CN 201811579797A CN 109400612 A CN109400612 A CN 109400612A
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- preparation
- rui boxini
- cyclopenta
- piperazine
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- 238000002360 preparation method Methods 0.000 title abstract description 22
- 239000002585 base Substances 0.000 abstract description 34
- ROSDSFDQCJNGOL-UHFFFAOYSA-N Dimethylamine Chemical compound CNC ROSDSFDQCJNGOL-UHFFFAOYSA-N 0.000 abstract description 26
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 abstract description 25
- CWXPZXBSDSIRCS-UHFFFAOYSA-N tert-butyl piperazine-1-carboxylate Chemical compound CC(C)(C)OC(=O)N1CCNCC1 CWXPZXBSDSIRCS-UHFFFAOYSA-N 0.000 abstract description 18
- 238000001914 filtration Methods 0.000 abstract description 17
- 150000003927 aminopyridines Chemical class 0.000 abstract description 13
- 239000007787 solid Substances 0.000 abstract description 10
- 238000006243 chemical reaction Methods 0.000 abstract description 8
- 239000007788 liquid Substances 0.000 abstract description 8
- 239000003960 organic solvent Substances 0.000 abstract description 8
- 238000000926 separation method Methods 0.000 abstract description 8
- CZPWVGJYEJSRLH-UHFFFAOYSA-N Pyrimidine Chemical compound C1=CN=CN=C1 CZPWVGJYEJSRLH-UHFFFAOYSA-N 0.000 abstract description 7
- 239000000706 filtrate Substances 0.000 abstract description 7
- 239000003054 catalyst Substances 0.000 abstract description 6
- ICSNLGPSRYBMBD-UHFFFAOYSA-N 2-aminopyridine Chemical compound NC1=CC=CC=N1 ICSNLGPSRYBMBD-UHFFFAOYSA-N 0.000 abstract description 5
- 239000003463 adsorbent Substances 0.000 abstract description 5
- YJVFFLUZDVXJQI-UHFFFAOYSA-L palladium(ii) acetate Chemical compound [Pd+2].CC([O-])=O.CC([O-])=O YJVFFLUZDVXJQI-UHFFFAOYSA-L 0.000 abstract description 5
- HKSQZEGSMBFHGC-UHFFFAOYSA-N pyrimidine-4-carboxamide Chemical compound NC(=O)C1=CC=NC=N1 HKSQZEGSMBFHGC-UHFFFAOYSA-N 0.000 abstract description 5
- 239000002253 acid Substances 0.000 abstract description 4
- MUALRAIOVNYAIW-UHFFFAOYSA-N binap Chemical compound C1=CC=CC=C1P(C=1C(=C2C=CC=CC2=CC=1)C=1C2=CC=CC=C2C=CC=1P(C=1C=CC=CC=1)C=1C=CC=CC=1)C1=CC=CC=C1 MUALRAIOVNYAIW-UHFFFAOYSA-N 0.000 abstract description 4
- FJDQFPXHSGXQBY-UHFFFAOYSA-L caesium carbonate Chemical compound [Cs+].[Cs+].[O-]C([O-])=O FJDQFPXHSGXQBY-UHFFFAOYSA-L 0.000 abstract description 4
- 229910000024 caesium carbonate Inorganic materials 0.000 abstract description 4
- 239000003513 alkali Substances 0.000 abstract description 3
- -1 filtering is added Substances 0.000 abstract description 3
- RUPAXCPQAAOIPB-UHFFFAOYSA-N tert-butyl formate Chemical compound CC(C)(C)OC=O RUPAXCPQAAOIPB-UHFFFAOYSA-N 0.000 abstract description 3
- NTIZESTWPVYFNL-UHFFFAOYSA-N Methyl isobutyl ketone Chemical compound CC(C)CC(C)=O NTIZESTWPVYFNL-UHFFFAOYSA-N 0.000 abstract description 2
- UIHCLUNTQKBZGK-UHFFFAOYSA-N Methyl isobutyl ketone Natural products CCC(C)C(C)=O UIHCLUNTQKBZGK-UHFFFAOYSA-N 0.000 abstract description 2
- 239000002250 absorbent Substances 0.000 abstract description 2
- 230000002745 absorbent Effects 0.000 abstract description 2
- 230000001681 protective effect Effects 0.000 abstract description 2
- 239000002994 raw material Substances 0.000 abstract description 2
- 239000002904 solvent Substances 0.000 abstract description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 29
- 238000003756 stirring Methods 0.000 description 19
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 14
- 239000010410 layer Substances 0.000 description 13
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 12
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 10
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 9
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 9
- 238000004440 column chromatography Methods 0.000 description 9
- 239000000741 silica gel Substances 0.000 description 8
- 229910002027 silica gel Inorganic materials 0.000 description 8
- KDYFGRWQOYBRFD-UHFFFAOYSA-N succinic acid Chemical compound OC(=O)CCC(O)=O KDYFGRWQOYBRFD-UHFFFAOYSA-N 0.000 description 8
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 7
- 229910052799 carbon Inorganic materials 0.000 description 7
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 6
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 6
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 6
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 6
- 239000012065 filter cake Substances 0.000 description 6
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 6
- 238000001179 sorption measurement Methods 0.000 description 6
- 206010013786 Dry skin Diseases 0.000 description 5
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 5
- 238000004061 bleaching Methods 0.000 description 5
- 238000002425 crystallisation Methods 0.000 description 5
- 230000008025 crystallization Effects 0.000 description 5
- 238000001035 drying Methods 0.000 description 5
- 239000000047 product Substances 0.000 description 5
- 238000010992 reflux Methods 0.000 description 5
- 238000010792 warming Methods 0.000 description 5
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 4
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 4
- JUJWROOIHBZHMG-UHFFFAOYSA-N pyridine Substances C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 4
- 239000000243 solution Substances 0.000 description 4
- 239000001384 succinic acid Substances 0.000 description 4
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 3
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 3
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 3
- 239000012535 impurity Substances 0.000 description 3
- 238000002156 mixing Methods 0.000 description 3
- 229910052757 nitrogen Inorganic materials 0.000 description 3
- BCXCYTDCJBHFEP-UHFFFAOYSA-N C(=O)N.C(=O)N.N1=CN=CC=C1C(=O)O Chemical compound C(=O)N.C(=O)N.N1=CN=CC=C1C(=O)O BCXCYTDCJBHFEP-UHFFFAOYSA-N 0.000 description 2
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 2
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 2
- LXNAVEXFUKBNMK-UHFFFAOYSA-N acetic acid;palladium Chemical compound [Pd].CC(O)=O.CC(O)=O LXNAVEXFUKBNMK-UHFFFAOYSA-N 0.000 description 2
- 150000001875 compounds Chemical class 0.000 description 2
- GLUUGHFHXGJENI-UHFFFAOYSA-N diethylenediamine Natural products C1CNCCN1 GLUUGHFHXGJENI-UHFFFAOYSA-N 0.000 description 2
- 238000010438 heat treatment Methods 0.000 description 2
- 238000004128 high performance liquid chromatography Methods 0.000 description 2
- 239000003446 ligand Substances 0.000 description 2
- 238000010606 normalization Methods 0.000 description 2
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 2
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 2
- 235000017557 sodium bicarbonate Nutrition 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- 238000010189 synthetic method Methods 0.000 description 2
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 2
- KAESVJOAVNADME-UHFFFAOYSA-N 1H-pyrrole Natural products C=1C=CNC=1 KAESVJOAVNADME-UHFFFAOYSA-N 0.000 description 1
- RHXHGRAEPCAFML-UHFFFAOYSA-N 7-cyclopentyl-n,n-dimethyl-2-[(5-piperazin-1-ylpyridin-2-yl)amino]pyrrolo[2,3-d]pyrimidine-6-carboxamide Chemical compound N1=C2N(C3CCCC3)C(C(=O)N(C)C)=CC2=CN=C1NC(N=C1)=CC=C1N1CCNCC1 RHXHGRAEPCAFML-UHFFFAOYSA-N 0.000 description 1
- 206010006187 Breast cancer Diseases 0.000 description 1
- 208000026310 Breast neoplasm Diseases 0.000 description 1
- 101000715943 Caenorhabditis elegans Cyclin-dependent kinase 4 homolog Proteins 0.000 description 1
- 206010011224 Cough Diseases 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- 125000002252 acyl group Chemical group 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 229910052792 caesium Inorganic materials 0.000 description 1
- TVFDJXOCXUVLDH-UHFFFAOYSA-N caesium atom Chemical compound [Cs] TVFDJXOCXUVLDH-UHFFFAOYSA-N 0.000 description 1
- BVKZGUZCCUSVTD-UHFFFAOYSA-N carbonic acid Chemical compound OC(O)=O BVKZGUZCCUSVTD-UHFFFAOYSA-N 0.000 description 1
- 238000006555 catalytic reaction Methods 0.000 description 1
- 210000004027 cell Anatomy 0.000 description 1
- 230000004663 cell proliferation Effects 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 230000007812 deficiency Effects 0.000 description 1
- 238000006073 displacement reaction Methods 0.000 description 1
- 238000011143 downstream manufacturing Methods 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 238000010828 elution Methods 0.000 description 1
- 235000019441 ethanol Nutrition 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 239000000499 gel Substances 0.000 description 1
- 238000009776 industrial production Methods 0.000 description 1
- JMMWKPVZQRWMSS-UHFFFAOYSA-N isopropanol acetate Natural products CC(C)OC(C)=O JMMWKPVZQRWMSS-UHFFFAOYSA-N 0.000 description 1
- 229940011051 isopropyl acetate Drugs 0.000 description 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- GWYFCOCPABKNJV-UHFFFAOYSA-N isovaleric acid Chemical compound CC(C)CC(O)=O GWYFCOCPABKNJV-UHFFFAOYSA-N 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 229910052751 metal Inorganic materials 0.000 description 1
- 239000002184 metal Substances 0.000 description 1
- 238000000034 method Methods 0.000 description 1
- 239000012046 mixed solvent Substances 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- 239000012044 organic layer Substances 0.000 description 1
- 229910052763 palladium Inorganic materials 0.000 description 1
- GGHDAUPFEBTORZ-UHFFFAOYSA-N propane-1,1-diamine Chemical compound CCC(N)N GGHDAUPFEBTORZ-UHFFFAOYSA-N 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- 239000002516 radical scavenger Substances 0.000 description 1
- 238000012827 research and development Methods 0.000 description 1
- 229950003687 ribociclib Drugs 0.000 description 1
- 239000000377 silicon dioxide Substances 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 210000004881 tumor cell Anatomy 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
- C07D487/04—Ortho-condensed systems
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Plural Heterocyclic Compounds (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
Abstract
A kind of preparation method of Rui Boxini; it has follow steps; 1) with 4- (6- aminopyridine -3- base) piperazine -1- carboxylic acid tert-butyl ester and the chloro- 4- cyclopenta-N of 2-; N- dimethyl -7H- pyrroles [2; 3-d] and pyrimidine -6- formamide be raw material; under protective atmosphere; using palladium acetate/BINAP as catalyst; cesium carbonate is acid absorbent; using 4-methyl-2 pentanone as solvent; reaction obtains 4- (6- (7- cyclopenta -6- (dimethyl amine formoxyl) -7H- pyrrolo- [2,3-d] pyrimidine -2-base) aminopyridine -3- base) piperazine -1- carboxylic acid tert-butyl ester)；2) 4- (6- (7- cyclopenta -6- (dimethyl amine the formoxyl) -7H- pyrrolo- [2 obtained step 1); 3-d] pyrimidine -2-base) aminopyridine -3- base) piperazine -1- carboxylic acid tert-butyl ester) it is dissolved in organic solvent; drop acid removing t-butyl formate at room temperature; liquid separation; water-miscible organic solvent is added in water layer; solid is precipitated, Rui Boxini hydrochlorate is obtained by filtration；3) Rui Boxini hydrochlorate is dissolved in water, and adsorbent, filtering is added, and filtrate adds alkali to obtain Rui Boxini.
Description
Technical field
The present invention relates to pharmaceutical field, in particular to a kind of preparation method of Rui Boxini and products thereof and purposes.
Background technique
Rui Boxini is that one kind of Novartis Co., Ltd, Switzerland research and development is novel, has selective depression CDK4/6, restores cell
Period control, blocks tumor cell proliferation, to reach the drug for the treatment of breast cancer.Obtain U.S. FDA approval in March, 2017
Listing, trade name Kisqali, chemical name are 7- cyclopenta -2- (5- piperazine -1- base-pyridine -2- base amino) -7H- pyrrole
Cough up simultaneously [2,3-d] pyrimidine -6- carboxylic acid diformamide.7- cyclopenta -2- (5- piperazine -1- base-pyridine -2- base amino) -7H- pyrroles
And the chemical structural formula of [2,3-d] pyrimidine -6- carboxylic acid diformamide is shown below:
Patent of invention WO2010020675 discloses the synthetic method of the compound, shown in the following route of reaction process:
Expensive metal scavenger (the Si-Thiol functionalized silica of Reusability in the route
Gel), complicated for operation, industrial production cost is high.
Patent of invention CN201510800951 discloses the synthetic method of the compound, shown in the following route of reaction process:
It is higher to prepare difficulty by SM2 in the route, and reacting is that ultralow temperature reacts, and the preparation of intermediate A 1 needs column chromatography pure
Change, isolate and purify difficulty, industrialization difficulty is big.
Therefore, the Rui Boxini of how at low cost, simple controllable synthesis high-purity, is that those skilled in the art urgently solve
Certainly the problem of.
Summary of the invention
In view of the deficiencies of the prior art, it is an object of the present invention to provide the preparation method of Rui Boxini a kind of, this preparation
Method is at low cost, reaction condition is mild, easy to operate controllable, is suitable for heavy industrialization application.Obtained Rui Boxini is received
Rate, purity is high meet enterprise's production requirement.
The technical scheme is that a kind of preparation method of Rui Boxini, has follow steps,
1) with 4- (6- aminopyridine -3- base) piperazine -1- carboxylic acid tert-butyl ester (formula 1) and chloro- 4- cyclopenta-N, the N- diformazan of 2-
Simultaneously pyrimidine -6- formamide (formula 2) is raw material to base -7H- pyrroles [2,3-d], is catalysis with palladium acetate/BINAP under protective atmosphere
Agent, cesium carbonate are acid absorbent, and using 4-methyl-2 pentanone as solvent, reaction obtains 4- (6- (7- cyclopenta -6- (dimethyl amine first
Acyl group) -7H- pyrrolo- [2,3-d] pyrimidine -2-base) aminopyridine -3- base) piperazine -1- carboxylic acid tert-butyl ester) (formula 3)；
2) ((7- cyclopenta -6- (dimethyl amine formoxyl) -7H- pyrrolo- [2,3-d] is phonetic by 6- by the 4- obtained step 1)
Pyridine -2- base) aminopyridine -3- base) piperazine -1- carboxylic acid tert-butyl ester) (formula 3) be dissolved in organic solvent, hydrochloric acid removing is dripped at room temperature
Water-miscible organic solvent is added in water layer for t-butyl formate, liquid separation, and solid is precipitated, Rui Boxini hydrochlorate is obtained by filtration；
3) Rui Boxini hydrochlorate is dissolved in water, and adsorbent, filtering is added, and filtrate adds alkali to obtain Rui Boxini (formula 4).
Above-mentioned preparation method reaction equation is as follows:
Step 1) 4- (6- aminopyridine -3- base) piperazine -1- carboxylic acid tert-butyl ester, chloro- 4- cyclopenta-N, the N- dimethyl-of 2-
7H- pyrroles [2,3-d] and pyrimidine -6- formamide, palladium acetate, BINAP, cesium carbonate molar ratio be 1:1.02~1.2:0.02~
0.05:0.03~0.06:1.2~1.5, it is preferred that 4- (6- aminopyridine -3- base) piperazine -1- carboxylic acid tert-butyl ester, the chloro- 4- of 2-
Cyclopenta-N, N- dimethyl -7H- pyrroles [2,3-d] and pyrimidine -6- formamide, palladium acetate, the molar ratio 1 of BINAP, cesium carbonate:
1.1:0.02:0.03:1.4.
Organic solvent described in step 2) is toluene, methylene chloride, ethyl acetate, isopropyl acetate, n-hexane, normal heptane
Any one or more of mixing, it is preferred that be n-hexane.
Water-miscible organic solvent described in step 2) is tetrahydrofuran, isopropanol, methanol, ethyl alcohol, acetonitrile, appointing in acetone
One or more mixing, it is preferred that be acetone.
Water-miscible organic solvent is added in step 2) water layer, is cooled to 0-10 DEG C, solid is precipitated.
Adsorbent described in step 3) is active carbon and/or column chromatography silica gel.
The column chromatography silica gel specification is 60-400 mesh, it is preferred that is 200-300 mesh.
Alkali described in step 3) be triethylamine, sodium hydroxide, sodium carbonate, in any in sodium bicarbonate or several mixing,
It preferably, is sodium bicarbonate.
The present invention also provides the Rui Boxini being prepared using any of the above-described preparation method.
The present invention also provides the purposes that the Bo Ruixini being prepared is used to prepare succinic acid Rui Boxini.
It has the advantages that by adopting the above technical scheme
1, the present invention utilizes 4- (6- (7- cyclopenta -6- (dimethyl amine formoxyl) -7H- pyrrolo- [2,3-d] pyrimidine -2-
Base) aminopyridine -3- base) piperazine -1- carboxylic acid tert-butyl ester) it is dissolved in organic solvent, t-butyl formate is removed through drop hydrochloric acid, through dividing
Liquid, obtained Rui Boxini hydrochlorate are dissolved in water layer, and remaining catalyst is dissolved in organic layer, are realized to title intermediate, miscellaneous
The initial gross separation of matter reacts mild, easy to operate controllable, downstream process is facilitated to handle.
2, after the Rui Boxini hydrochlorate that the present invention obtains is dissolved in water, target product intermediate is dissolved in water, remaining
Impurity catalyst acetic acid palladium and ligand are not soluble in water, and after being adsorbed by adsorbent, removing largely remains in Rui Boxini hydrochlorate
In catalyst further filter off remaining catalyst using filter, can effectively ensure that the purity of Rui Boxini hydrochlorate, it is this
Purification process is convenient and simple for operation, the Rui Boxini hydrochlorate very high purity isolated and purified, the adsorbent used be active carbon and/
Or column chromatography silica gel, cost is relatively low for absorption, high to impurity catalyst acetic acid palladium and ligand adsorption efficiency, is very suitable to extensive work
Industry application.
It is further described combined with specific embodiments below.
Specific embodiment
Condition, experimental method of the embodiment of the present invention etc. are in addition to what is specifically mentioned below the general of this field
All over knowledge and common knowledge or operating condition recommended by the manufacturer.
One 4- of embodiment (6- (7- cyclopenta -6- (dimethyl amine formoxyl) -7H- pyrrolo- [2,3-d] pyrimidine -2-base)
Aminopyridine -3- base) piperazine -1- carboxylic acid tert-butyl ester) (formula 3) preparation, reaction equation is as follows:
In 2L four round flask, chloro- 4- cyclopenta-N, the N- dimethyl -7H- pyrroles [2,3-d] of 100g2- is added simultaneously
Pyrimidine -6- formamide (formula 2), 104.6g4- (6- aminopyridine -3- base) piperazine -1- carboxylic acid tert-butyl ester (formula 1), 155.8g carbonic acid
800g4- methyl -2 pentanone, 1.534g palladium acetate, 6.38gBINAP is added after nitrogen displacement three times in caesium.After charging,
Under nitrogen protection environment, 90~100 DEG C are warming up to, is reacted 3 hours.It is cooled to 65 DEG C, is added 800g water, 270g normal heptane,
10ml propane diamine is down to room temperature, and filtering, filter cake is washed once with 500g bubble, with 160g4- methyl -2 pentanone/270g normal heptane
Mixed solvent elution is primary, 60 DEG C of dry 4- (6- (7- cyclopenta -6- (dimethyl amine formoxyl) -7H- pyrrolo-es [2,3-d]
Pyrimidine -2-base) aminopyridine -3- base) piperazine -1- carboxylic acid tert-butyl ester) (formula 3) 168g.Yield 92.2% measures (face through HPLC
Product normalization method), obtained 4- (6- (7- cyclopenta -6- (dimethyl amine formoxyl) -7H- pyrrolo- [2,3-d] pyrimidine -2-base)
Aminopyridine -3- base) piperazine -1- carboxylic acid tert-butyl ester) purity be 98.8%.
The preparation of two Rui Boxini hydrochloride of embodiment
20g4- (6- (7- cyclopenta -6- (dimethyl amine formoxyl) -7H- pyrrolo- [2,3-d] is added in 1L four-hole bottle
Pyrimidine -2-base) aminopyridine -3- base) piperazine -1- carboxylic acid tert-butyl ester) (formula 3), 100g n-hexane, stirring and dissolving drips at room temperature
Add 100g3mol/L hydrochloric acid, react 1 hour, liquid separation, 200g acetone is added into water layer for layer of fetching water.It is warming up to reflux, is then dropped
Temperature stirs 3 hours, filtering obtains Rui Boxini hydrochloride to 10 DEG C of following crystallization.
The preparation of three Rui Boxini of embodiment (formula 4)
Rui Boxini hydrochloride is dissolved in 200g water, 1g active carbon, the mesh column chromatography silica gel of 0.5g100~200 is added, stirs
Adsorption bleaching is mixed, is filtered, saturated sodium bicarbonate aqueous solution is added into filtrate and adjusts pH to 9~10, solid is precipitated, is cooled to 10
DEG C stirring.Filtering, 60 DEG C of dryings of filter cake, get Rui Boxini (formula 4) 14g, yield 85.0%.
The preparation of example IV Rui Boxini hydrochloride
20g4- (6- (7- cyclopenta -6- (dimethyl amine formoxyl) -7H- pyrrolo- [2,3-d] is added in 1L four-hole bottle
Pyrimidine -2-base) aminopyridine -3- base) piperazine -1- carboxylic acid tert-butyl ester) (formula 3), and 100g methylene chloride, stirring and dissolving, at room temperature
50g6mol/L hydrochloric acid is added dropwise, reacts 1 hour, liquid separation, 200g tetrahydrofuran is added into water layer for layer of fetching water.Reflux is warming up to,
Then 10 DEG C of following crystallization are cooled to, are stirred 3 hours, filtering obtains Rui Boxini hydrochloride.
The preparation of five Rui Boxini of embodiment (formula 4)
Rui Boxini hydrochloride is dissolved in 200g water, 1g active carbon, the mesh column chromatography silica gel of 0.5g200~300 is added, stirs
Adsorption bleaching is mixed, is filtered, 10% sodium hydroxide solution is added into filtrate and adjusts pH to 9~10, solid is precipitated, is cooled to 10 DEG C
Stirring.Filtering, 60 DEG C of dryings of filter cake, get Rui Boxini (formula 4) 10g, yield 60.1%.
The preparation of six Rui Boxini hydrochloride of embodiment
20g4- (6- (7- cyclopenta -6- (dimethyl amine formoxyl) -7H- pyrrolo- [2,3-d] is added in 1L four-hole bottle
Pyrimidine -2-base) aminopyridine -3- base) piperazine -1- carboxylic acid tert-butyl ester) (formula 3), 100g toluene, stirring and dissolving is added dropwise at room temperature
25g12mol/L hydrochloric acid reacts 1 hour, liquid separation, and 200g acetonitrile is added into water layer for layer of fetching water.It is warming up to reflux, is then cooled down
It to 10 DEG C of following crystallization, stirs 3 hours, filtering obtains Rui Boxini hydrochloride.
The preparation of seven Rui Boxini of embodiment (formula 4)
Rui Boxini hydrochloride is dissolved in 200g water, 1g active carbon, the mesh column chromatography silica gel of 0.5g100~200 is added, stirs
Adsorption bleaching is mixed, is filtered, 10% sodium hydroxide solution is added into filtrate and adjusts pH to 9~10, solid is precipitated, is cooled to 10 DEG C
Stirring.Filtering, 60 DEG C of dryings of filter cake, get Rui Boxini (formula 4) 8g, yield 48.5%.
The preparation of eight Rui Boxini hydrochloride of embodiment
20g4- (6- (7- cyclopenta -6- (dimethyl amine formoxyl) -7H- pyrrolo- [2,3-d] is added in 1L four-hole bottle
Pyrimidine -2-base) aminopyridine -3- base) piperazine -1- carboxylic acid tert-butyl ester) (formula 3), and 100g ethyl acetate, stirring and dissolving, at room temperature
50g6mol/L hydrochloric acid is added dropwise, reacts 1 hour, liquid separation, 200g isopropanol is added into water layer for layer of fetching water.It is warming up to reflux, so
After be cooled to 10 DEG C of following crystallization, stir 3 hours, filtering obtains Rui Boxini hydrochloride.
The preparation of nine Rui Boxini of embodiment (formula 4)
Rui Boxini hydrochloride is dissolved in 200g water, 1g active carbon, the mesh column chromatography silica gel of 0.5g60~80, stirring is added
10% sodium hydroxide solution is added into filtrate and adjusts pH to 9~10, solid is precipitated, is cooled to 10 DEG C and stirs for adsorption bleaching, filtering
It mixes.Filtering, 60 DEG C of dryings of filter cake, get Rui Boxini (formula 4) 13.6g, yield 82.4%.
The preparation of ten Rui Boxini hydrochloride of embodiment
40g4- (6- (7- cyclopenta -6- (dimethyl amine formoxyl) -7H- pyrrolo- [2,3-d] is added in 1L four-hole bottle
Pyrimidine -2-base) aminopyridine -3- base) piperazine -1- carboxylic acid tert-butyl ester) (formula 3), and 100g methylene chloride, stirring and dissolving, at room temperature
50g6mol/L hydrochloric acid is added dropwise, reacts 1 hour, liquid separation, 100g isopropanol, 100g methanol are added into water layer for layer of fetching water.Heating
To reflux, 10 DEG C of following crystallization are then cooled to, are stirred 3 hours, filtering obtains Rui Boxini hydrochloride.
The preparation of 11 Rui Boxini of embodiment (formula 4)
Rui Boxini hydrochloride is dissolved in 200g water, 1g active carbon, the mesh column chromatography silica gel of 0.5g200~300 is added, stirs
Adsorption bleaching is mixed, is filtered, saturated sodium carbonate solution is added into filtrate and adjusts pH to 9~10, solid is precipitated, is cooled to 10 DEG C and stirs
It mixes.Filtering, 60 DEG C of dryings of filter cake, get Rui Boxini (formula 4) 25g, yield 75.8%.
The preparation of ten disuccinic acid Rui Boxini (formula 5) of embodiment, reaction equation are as follows:
100g Rui Boxini (formula 4) is added in 2L there-necked flask, 1200g isopropanol is heated to 85 DEG C, while by 28.53g
Succinic acid is added in 240g isopropanol, is dissolved by heating.Then succinic acid/isopropyl alcohol mixture is added dropwise into 2L there-necked flask,
It is added dropwise, a large amount of solids is precipitated, insulated and stirred 30min is naturally cooling to room temperature, stirs 2~3 hours, filtering, and solid is with less
Cold isopropanol washing is measured, 60 DEG C are dried under reduced pressure 24 hours.Obtain succinic acid Rui Boxini (formula 5) dry product 120g, yield 95.0%, warp
It is 99.91% that HPLC, which measures (area normalization method) purity, and largest single impurity 0.06%, palladium remains 0.2ppm.
Claims (10)
1. a kind of preparation method of Rui Boxini, which is characterized in that it has follow steps,
1) with 4- (6- aminopyridine -3- base) piperazine -1- carboxylic acid tert-butyl ester and chloro- 4- cyclopenta-N, the N- dimethyl -7H- pyrrole of 2-
Coughing up [2,3-d] and pyrimidine -6- formamide is raw material, and under protective atmosphere, using palladium acetate/BINAP as catalyst, cesium carbonate is to inhale
Sour agent, using 4-methyl-2 pentanone as solvent, reaction obtains 4- (6- (7- cyclopenta -6- (dimethyl amine formoxyl) -7H- pyrroles
And [2,3-d] pyrimidine -2-base) aminopyridine -3- base) piperazine -1- carboxylic acid tert-butyl ester)；
2) 4- (6- (7- cyclopenta -6- (dimethyl amine formoxyl) -7H- pyrrolo- [2,3-d] pyrimidine -2- obtained step 1)
Base) aminopyridine -3- base) piperazine -1- carboxylic acid tert-butyl ester) it is dissolved in organic solvent, hydrochloric acid is dripped at room temperature removes t-butyl formate,
Water-miscible organic solvent is added in water layer for liquid separation, and solid is precipitated, Rui Boxini hydrochloride is obtained by filtration；
3) Rui Boxini hydrochloride is dissolved in water, and adsorbent, filtering is added, and filtrate adds alkali to obtain Rui Boxini.
2. preparation method according to claim 1, which is characterized in that step 1) 4- (6- aminopyridine -3- base) piperazine -1-
Chloro- 4- cyclopenta-N, the N- dimethyl -7H- pyrroles [2,3-d] of carboxylic acid tert-butyl ester, 2- and pyrimidine -6- formamide, palladium acetate,
BINAP, cesium carbonate molar ratio be 1:1.02~1.2:0.02~0.05:0.03~0.06:1.2~1.5, it is preferred that 4- (6-
Aminopyridine -3- base) piperazine -1- carboxylic acid tert-butyl ester, chloro- 4- cyclopenta-N, the N- dimethyl -7H- pyrroles [2,3-d] of 2- and phonetic
Pyridine -6- formamide, palladium acetate, BINAP, cesium carbonate molar ratio 1:1.1:0.02:0.03:1.4.
3. preparation method according to claim 1, which is characterized in that organic solvent described in step 2) is toluene, dichloro
Any one or more of methane, ethyl acetate, isopropyl acetate, n-hexane, normal heptane mixing, it is preferred that be n-hexane.
4. preparation method according to claim 1, which is characterized in that water-miscible organic solvent described in step 2) is tetrahydro
Any one or more of furans, isopropanol, methanol, ethyl alcohol, acetonitrile, acetone mixing, it is preferred that be acetone.
5. preparation method according to claim 1, which is characterized in that water-miscible organic solvent is added in step 2) water layer,
It is cooled to 0-10 DEG C, solid is precipitated.
6. preparation method according to claim 1, which is characterized in that adsorbent described in step 3) be active carbon and/or
Column chromatography silica gel.
7. preparation method according to claim 6, which is characterized in that the column chromatography silica gel specification is 60~400 mesh, excellent
Choosing, be 200~300 mesh.
8. preparation method according to claim 1, which is characterized in that alkali described in step 3) be triethylamine, sodium hydroxide,
In any in sodium carbonate, sodium bicarbonate or several mixing, it is preferred that be sodium bicarbonate.
9. the Rui Boxini being prepared using any preparation method of claim 1-8.
10. being used to prepare the purposes of succinic acid Rui Boxini using Bo Ruixini described in claim 9.
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