CN103396373A - Preparation method of deferasirox and intermediate compound of deferasirox - Google Patents
Preparation method of deferasirox and intermediate compound of deferasirox Download PDFInfo
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- CN103396373A CN103396373A CN201310308978XA CN201310308978A CN103396373A CN 103396373 A CN103396373 A CN 103396373A CN 201310308978X A CN201310308978X A CN 201310308978XA CN 201310308978 A CN201310308978 A CN 201310308978A CN 103396373 A CN103396373 A CN 103396373A
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- 229960001489 deferasirox Drugs 0.000 title claims abstract description 44
- 238000002360 preparation method Methods 0.000 title claims abstract description 27
- 150000001875 compounds Chemical class 0.000 title claims description 37
- FMSOAWSKCWYLBB-VBGLAJCLSA-N deferasirox Chemical compound C1=CC(C(=O)O)=CC=C1N(N\C(N\1)=C\2C(C=CC=C/2)=O)C/1=C\1C(=O)C=CC=C/1 FMSOAWSKCWYLBB-VBGLAJCLSA-N 0.000 title abstract 6
- -1 o-benzyloxy cyanophenyl Chemical group 0.000 claims abstract description 26
- 238000006243 chemical reaction Methods 0.000 claims description 48
- BOFQWVMAQOTZIW-UHFFFAOYSA-N deferasirox Chemical compound C1=CC(C(=O)O)=CC=C1N1C(C=2C(=CC=CC=2)O)=NC(C=2C(=CC=CC=2)O)=N1 BOFQWVMAQOTZIW-UHFFFAOYSA-N 0.000 claims description 39
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 27
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 24
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 24
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 24
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 23
- 239000002904 solvent Substances 0.000 claims description 15
- WTSAKMSVTHDBCS-UHFFFAOYSA-N benzoic acid;hydrazine Chemical compound [NH3+]N.[O-]C(=O)C1=CC=CC=C1 WTSAKMSVTHDBCS-UHFFFAOYSA-N 0.000 claims description 14
- 240000000203 Salix gracilistyla Species 0.000 claims description 13
- 150000001263 acyl chlorides Chemical class 0.000 claims description 12
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 12
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 10
- 239000003513 alkali Substances 0.000 claims description 10
- 230000000694 effects Effects 0.000 claims description 10
- 150000003839 salts Chemical class 0.000 claims description 10
- 238000005984 hydrogenation reaction Methods 0.000 claims description 9
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 claims description 8
- 239000003054 catalyst Substances 0.000 claims description 8
- 239000011541 reaction mixture Substances 0.000 claims description 8
- UKVIEHSSVKSQBA-UHFFFAOYSA-N methane;palladium Chemical group C.[Pd] UKVIEHSSVKSQBA-UHFFFAOYSA-N 0.000 claims description 7
- 239000007868 Raney catalyst Substances 0.000 claims description 6
- NPXOKRUENSOPAO-UHFFFAOYSA-N Raney nickel Chemical compound [Al].[Ni] NPXOKRUENSOPAO-UHFFFAOYSA-N 0.000 claims description 6
- 229910000564 Raney nickel Inorganic materials 0.000 claims description 6
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 5
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 5
- DKGAVHZHDRPRBM-UHFFFAOYSA-N Tert-Butanol Chemical compound CC(C)(C)O DKGAVHZHDRPRBM-UHFFFAOYSA-N 0.000 claims description 4
- 230000001476 alcoholic effect Effects 0.000 claims description 4
- 238000009903 catalytic hydrogenation reaction Methods 0.000 claims description 4
- 239000000203 mixture Substances 0.000 claims description 4
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 3
- 238000000746 purification Methods 0.000 claims description 3
- 238000000034 method Methods 0.000 abstract description 9
- 239000003814 drug Substances 0.000 abstract description 5
- 239000000126 substance Substances 0.000 abstract description 2
- DVIHKVWYFXLBEM-UHFFFAOYSA-N 2-hydroxybenzoyl chloride Chemical compound OC1=CC=CC=C1C(Cl)=O DVIHKVWYFXLBEM-UHFFFAOYSA-N 0.000 abstract 1
- PCNFLKVWBDNNOW-UHFFFAOYSA-N 4-hydrazinylbenzoic acid Chemical compound NNC1=CC=C(C(O)=O)C=C1 PCNFLKVWBDNNOW-UHFFFAOYSA-N 0.000 abstract 1
- 150000003840 hydrochlorides Chemical class 0.000 abstract 1
- XEEYBQQBJWHFJM-UHFFFAOYSA-N Iron Chemical compound [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 0.000 description 13
- 239000007787 solid Substances 0.000 description 12
- 238000010438 heat treatment Methods 0.000 description 11
- 239000002253 acid Substances 0.000 description 10
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 10
- 238000010992 reflux Methods 0.000 description 9
- QCQCHGYLTSGIGX-GHXANHINSA-N 4-[[(3ar,5ar,5br,7ar,9s,11ar,11br,13as)-5a,5b,8,8,11a-pentamethyl-3a-[(5-methylpyridine-3-carbonyl)amino]-2-oxo-1-propan-2-yl-4,5,6,7,7a,9,10,11,11b,12,13,13a-dodecahydro-3h-cyclopenta[a]chrysen-9-yl]oxy]-2,2-dimethyl-4-oxobutanoic acid Chemical compound N([C@@]12CC[C@@]3(C)[C@]4(C)CC[C@H]5C(C)(C)[C@@H](OC(=O)CC(C)(C)C(O)=O)CC[C@]5(C)[C@H]4CC[C@@H]3C1=C(C(C2)=O)C(C)C)C(=O)C1=CN=CC(C)=C1 QCQCHGYLTSGIGX-GHXANHINSA-N 0.000 description 8
- 206010065973 Iron Overload Diseases 0.000 description 8
- 238000005406 washing Methods 0.000 description 8
- 229960004756 ethanol Drugs 0.000 description 7
- 229910052742 iron Inorganic materials 0.000 description 7
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 6
- 238000001816 cooling Methods 0.000 description 6
- 239000000706 filtrate Substances 0.000 description 6
- 238000004128 high performance liquid chromatography Methods 0.000 description 6
- 150000004702 methyl esters Chemical class 0.000 description 6
- 230000009467 reduction Effects 0.000 description 6
- 230000004044 response Effects 0.000 description 6
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 6
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 5
- 239000012065 filter cake Substances 0.000 description 5
- 229910052739 hydrogen Inorganic materials 0.000 description 5
- 239000001257 hydrogen Substances 0.000 description 5
- 238000001291 vacuum drying Methods 0.000 description 5
- 0 *OC(c1ccccc1OCc1ccccc1)=N Chemical compound *OC(c1ccccc1OCc1ccccc1)=N 0.000 description 4
- ASSKVPFEZFQQNQ-UHFFFAOYSA-N 2-benzoxazolinone Chemical compound C1=CC=C2OC(O)=NC2=C1 ASSKVPFEZFQQNQ-UHFFFAOYSA-N 0.000 description 4
- SKZKKFZAGNVIMN-UHFFFAOYSA-N Salicilamide Chemical compound NC(=O)C1=CC=CC=C1O SKZKKFZAGNVIMN-UHFFFAOYSA-N 0.000 description 4
- 208000002903 Thalassemia Diseases 0.000 description 4
- 125000004494 ethyl ester group Chemical group 0.000 description 4
- 239000000047 product Substances 0.000 description 4
- HQQTZCPKNZVLFF-UHFFFAOYSA-N 4h-1,2-benzoxazin-3-one Chemical compound C1=CC=C2ONC(=O)CC2=C1 HQQTZCPKNZVLFF-UHFFFAOYSA-N 0.000 description 3
- 239000008280 blood Substances 0.000 description 3
- 210000004369 blood Anatomy 0.000 description 3
- 230000001419 dependent effect Effects 0.000 description 3
- 239000007789 gas Substances 0.000 description 3
- 238000009413 insulation Methods 0.000 description 3
- 238000004519 manufacturing process Methods 0.000 description 3
- YYROPELSRYBVMQ-UHFFFAOYSA-N 4-toluenesulfonyl chloride Chemical compound CC1=CC=C(S(Cl)(=O)=O)C=C1 YYROPELSRYBVMQ-UHFFFAOYSA-N 0.000 description 2
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 2
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 2
- 238000010521 absorption reaction Methods 0.000 description 2
- CUBCNYWQJHBXIY-UHFFFAOYSA-N benzoic acid;2-hydroxybenzoic acid Chemical compound OC(=O)C1=CC=CC=C1.OC(=O)C1=CC=CC=C1O CUBCNYWQJHBXIY-UHFFFAOYSA-N 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- 238000002655 chelation therapy Methods 0.000 description 2
- 229960000935 dehydrated alcohol Drugs 0.000 description 2
- 150000002148 esters Chemical class 0.000 description 2
- 230000007774 longterm Effects 0.000 description 2
- 210000000056 organ Anatomy 0.000 description 2
- 238000003786 synthesis reaction Methods 0.000 description 2
- 238000002560 therapeutic procedure Methods 0.000 description 2
- KCXVZYZYPLLWCC-UHFFFAOYSA-N EDTA Chemical compound OC(=O)CN(CC(O)=O)CCN(CC(O)=O)CC(O)=O KCXVZYZYPLLWCC-UHFFFAOYSA-N 0.000 description 1
- 201000003793 Myelodysplastic syndrome Diseases 0.000 description 1
- CHROPCMKBZZQJH-UHFFFAOYSA-N N#Cc1ccccc1OCc1ccccc1 Chemical compound N#Cc1ccccc1OCc1ccccc1 CHROPCMKBZZQJH-UHFFFAOYSA-N 0.000 description 1
- UBQYURCVBFRUQT-UHFFFAOYSA-N N-benzoyl-Ferrioxamine B Chemical compound CC(=O)N(O)CCCCCNC(=O)CCC(=O)N(O)CCCCCNC(=O)CCC(=O)N(O)CCCCCN UBQYURCVBFRUQT-UHFFFAOYSA-N 0.000 description 1
- IHBJTBBUEIIGJI-UHFFFAOYSA-N O=C1N=C(c(cccc2)c2OCc2ccccc2)Oc2c1cccc2 Chemical compound O=C1N=C(c(cccc2)c2OCc2ccccc2)Oc2c1cccc2 IHBJTBBUEIIGJI-UHFFFAOYSA-N 0.000 description 1
- YGSDEFSMJLZEOE-UHFFFAOYSA-N OC(c1ccccc1O)=O Chemical compound OC(c1ccccc1O)=O YGSDEFSMJLZEOE-UHFFFAOYSA-N 0.000 description 1
- NSWIROGSZPXREF-UHFFFAOYSA-N Oc1ccccc1C(Oc1c2cccc1)=NC2=O Chemical compound Oc1ccccc1C(Oc1c2cccc1)=NC2=O NSWIROGSZPXREF-UHFFFAOYSA-N 0.000 description 1
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 1
- 150000008065 acid anhydrides Chemical class 0.000 description 1
- UOBCZXSWQQWTGC-UHFFFAOYSA-N amino(phenyl)carbamic acid Chemical compound OC(=O)N(N)C1=CC=CC=C1 UOBCZXSWQQWTGC-UHFFFAOYSA-N 0.000 description 1
- 208000007502 anemia Diseases 0.000 description 1
- 238000009835 boiling Methods 0.000 description 1
- 239000000872 buffer Substances 0.000 description 1
- OEUUFNIKLCFNLN-LLVKDONJSA-N chembl432481 Chemical compound OC(=O)[C@@]1(C)CSC(C=2C(=CC(O)=CC=2)O)=N1 OEUUFNIKLCFNLN-LLVKDONJSA-N 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 230000001684 chronic effect Effects 0.000 description 1
- 230000006378 damage Effects 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 229960000958 deferoxamine Drugs 0.000 description 1
- 229960001425 deferoxamine mesylate Drugs 0.000 description 1
- 230000008021 deposition Effects 0.000 description 1
- IDDIJAWJANBQLJ-UHFFFAOYSA-N desferrioxamine B mesylate Chemical compound [H+].CS([O-])(=O)=O.CC(=O)N(O)CCCCCNC(=O)CCC(=O)N(O)CCCCCNC(=O)CCC(=O)N(O)CCCCCN IDDIJAWJANBQLJ-UHFFFAOYSA-N 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 230000010437 erythropoiesis Effects 0.000 description 1
- 230000029142 excretion Effects 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 239000012467 final product Substances 0.000 description 1
- 231100000025 genetic toxicology Toxicity 0.000 description 1
- 230000001738 genotoxic effect Effects 0.000 description 1
- 230000006589 gland dysfunction Effects 0.000 description 1
- 208000014951 hematologic disease Diseases 0.000 description 1
- 239000012535 impurity Substances 0.000 description 1
- 238000009776 industrial production Methods 0.000 description 1
- 229940075525 iron chelating agent Drugs 0.000 description 1
- 239000000797 iron chelating agent Substances 0.000 description 1
- 210000004185 liver Anatomy 0.000 description 1
- 230000004060 metabolic process Effects 0.000 description 1
- YTJSFYQNRXLOIC-UHFFFAOYSA-N octadecylsilane Chemical compound CCCCCCCCCCCCCCCCCC[SiH3] YTJSFYQNRXLOIC-UHFFFAOYSA-N 0.000 description 1
- 239000012044 organic layer Substances 0.000 description 1
- 230000007170 pathology Effects 0.000 description 1
- 230000008288 physiological mechanism Effects 0.000 description 1
- 238000007363 ring formation reaction Methods 0.000 description 1
- 230000035939 shock Effects 0.000 description 1
- 239000000377 silicon dioxide Substances 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 230000004083 survival effect Effects 0.000 description 1
- 208000011580 syndromic disease Diseases 0.000 description 1
- 239000011573 trace mineral Substances 0.000 description 1
- 235000013619 trace mineral Nutrition 0.000 description 1
Landscapes
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention belongs to the field of pharmaceutical chemicals, provides a preparation method of deferasirox which is an iron-overloaded medicament and particularly provides a method for preparing deferasirox mainly from salicyloyl chloride, o-benzyloxy cyanophenyl, p-hydrazinobenzoic acid (or hydrochlorides thereof) under mild conditions. The method for preparing the deferasirox is mild in condition and simple to operate; the deferasirox product is high in purity.
Description
Technical field
The invention belongs to field of medicine and chemical technology, more specifically relate to a kind of preparation method and relevant midbody compound of DEFERASIROX.
Background technology
DEFERASIROX, chemistry is by name: 4-[3,5-bis-(2-hydroxy phenyl)-1,2,4-triazol-1-yl] phenylformic acid (I), structure is shown below:
DEFERASIROX, by Novartis Co.,Ltd exploitation, unique oral iron chelator at present, obtained the FDA approval in November, 2005, for 2 years old and the above chronic iron overload patient who causes because of blood transfusion.In December, 2012, DEFERASIROX obtained EU Committee's approval, for because of deferoxamine mesylate therapy (deferoxamine therapy), avoiding or not enough 10 years old and the treatment of the chronic iron overload of above non-transfusion dependent thalassemia (non-transfusion-dependent thalassemia, NTDT) syndrome patient (chronic iron overload) that needs chelation therapy (chelation therapy).FDA approval on January 23rd, 2013 DEFERASIROX new indication, for 10 years old and above non-transfusion dependent thalassemia (NTDT) patient's chronic iron overload treatment.
Iron is a kind of trace element, and it is very important to the existence of oxyphorase.The normal people has adjusting and shock absorption to absorption and the metabolism of iron, iron in holder is an equilibrium state, but, some chronic hematologic disease such as thalassemia, reaping hook cell anemia, myelodysplastic syndrome need long-term, frequent blood transfusion, the increase that marrow " invalid erythropoiesis " and gi tract iron absorb often causes iron overload in body, and its sign may just can manifest after 10～20 blood transfusions.Because having physiological mechanism, human body can not remove unnecessary irony; long-term transfusion will cause the appearance of iron overload; if do not carry out suitable treatment, the iron overload will cause serious organ such as liver, heart and incretory gland dysfunction or death, finally cause death.Iron chelating agent is that treatment at present is due to the only active drug of transfusional iron overload, its iron ion in body is combined the excretion that can effectively improve iron, thereby the content of iron and in the pathology deposition of each organ in the reduction body, be used for preventing the end-organ damage and improve survival rate.
Existing DEFERASIROX synthesis technique, topmost route are to prepare the benzoxazolone intermediate, then with the carboxyl phenylhydrazine cyclization, obtain DEFERASIROX:
Present above-mentioned benzoxazolone intermediate is the most frequently used following method:
1) utilize Whitfield's ointment, salicylic amide, thionyl chloride 140-150 ℃ of reaction, preparation 2-(2-hydroxy phenyl)-4H-1,3-benzoxazine-4-ketone (benzoxazinone intermediate).But in the method, because the boiling point of thionyl chloride is low, high-temperature reaction process adds thionyl chloride, and thionyl chloride is difficult to cooling, reinforced being very restricted; In our research, find simultaneously, the speed that adds of thionyl chloride is directly connected to quality and the yield of intermediate, product, operates wayward.
2) W02012025935 proposes a new synthetic route, and Whitfield's ointment and tosic acid acyl chlorides form the mixture acid anhydrides, then with salicylic amide, in alcoholic solvent, react and obtain the benzoxazinone intermediate.And in this route, use Tosyl chloride and alcohol, and easily producing p-toluenesulfonic esters, p-toluenesulfonic esters belongs to genotoxicity impurity, in the preparation of medicine, should avoid as far as possible.
3) in WO2010023685, disclose a kind of method that is prepared the benzoxazinone intermediate by salicylic amide and bigcatkin willow acyl chloride reaction, but the method needs strict, loaded down with trivial details reaction process and temperature of reaction to control, and is unfavorable for suitability for industrialized production.
Therefore, provide a kind of preparation method of new, DEFERASIROX that technological operation is easy to control, for the suitability for industrialized production of DEFERASIROX medicine, have very important realistic meaning.
Summary of the invention
The invention provides the preparation method that a kind of DEFERASIROX is new, the method reaction conditions gentleness, easy to operate, avoided the defect that exists in the prior art, the product, the purity that make are high, are suitable for suitability for industrialized production.
For realizing goal of the invention, key intermediate compound and salt thereof that at first the present invention provides a class to prepare DEFERASIROX, structure is suc as formula shown in IV:
Wherein R is preferably methyl or ethyl; Salt is preferably hydrochloride.
Formula IV compound hydrochloride can be transformed and be obtained by adjacent benzyloxy cyanophenyl and HCl reaction:
Wherein R is described as defined above.
In the preferred implementation of a kind of preparation formula IV compound hydrochloride provided by the invention, adjacent benzyloxy cyanophenyl is reacted with HCl at low temperatures, transforms and obtains formula IV compound hydrochloride.
More preferably, comprise the steps: adjacent benzyloxy cyanophenyl is dissolved in to dehydrated alcohol, cool to 0 ℃, logical HCl gas, insulation reaction, concentrated, the solid that obtains adds the ether washing, obtains white solid, is formula IV compound hydrochloride.
Formula IV compound hydrochloride further gets final product to obtain formula IV compound through alkaline purification.
Formula IV compound or its salt can be used for further with the bigcatkin willow acyl chlorides, under the alkali effect, reacting and preparing formula V compound:
Wherein R is described as defined above, and described alkali is preferably triethylamine or N, the N'-diisopropyl ethyl amine.
Formula V compound can further with to hydrazine phenylformic acid or its hydrochloride react, and then through catalytic hydrogenation, obtains DEFERASIROX:
In a preferred embodiment, formula V compound prepare DEFERASIROX comprise the steps: formula V compound with to hydrazine phenylformic acid or its hydrochloride, take C1-4 alcohol as solvent, 50-80 ℃ of reaction; Hydrogenation under the post catalyst reaction effect, obtain DEFERASIROX.
Wherein said C1-4 alcoholic solvent is preferably methyl alcohol, ethanol, Virahol or the trimethyl carbinol; Described hydrogenation catalyst is preferably palladium carbon, Raney nickel.
The invention provides the preparation technology that a kind of one kettle way prepares DEFERASIROX: formula IV compound or its salt and bigcatkin willow acyl chlorides, under the alkali effect, obtain intermediate formula V compound 2-(2-benzyloxy phenyl)-4H-1,3-benzoxazine-4-ketone; Formula V compound and to the reaction of hydrazine phenylformic acid or its hydrochloride, then, through catalytic hydrogenation, obtain DEFERASIROX.Reaction equation is as follows:
Wherein R is described as defined above.
The invention provides the embodiment that a kind of preferred one kettle way prepares DEFERASIROX, comprise the steps:
(1) formula IV compound or its salt and bigcatkin willow acyl chlorides react under the alkali effect, and the reaction mixture that obtains is concentrated, obtains formula V compound;
(2) product of step (1) after concentrated with to hydrazine phenylformic acid or its hydrochloride, take C1-4 alcohol as solvent, 50-80 ℃ of reaction; Hydrogenation under the post catalyst reaction effect, obtain DEFERASIROX.
Wherein, in step (1), use solvent to be preferably tetrahydrofuran (THF) and/or methylene dichloride; Described alkali is preferably triethylamine or N, N '-diisopropyl ethyl amine; Temperature of reaction is 40-70 ℃.
Step (2) the C1-4 alcoholic solvent that uses is preferably methyl alcohol, ethanol, Virahol or the trimethyl carbinol; Described hydrogenation catalyst is preferably palladium carbon or Raney nickel.
The invention provides the new intermediate compound of DEFERASIROX and the syntheti c route of new DEFERASIROX, intermediate 2-(2-benzyloxy phenyl)-4H-1, preparation technology's reaction conditions gentleness of 3-benzoxazine-4-ketone (formula V compound), aftertreatment is simple, after reaction, take routine operation or concentrated or filtration, without additional purification.Further with to after the reaction of hydrazine phenylformic acid or its hydrochloride, directly normal pressure hydrogenation namely obtains the DEFERASIROX product, more than purity to 99.8%.With synthesis technique before, compare, the preparation technology of DEFERASIROX disclosed in this invention and intermediate thereof is simple without high temperature, aftertreatment, and intermediate preparation and lock out operation are simple, easily realize continuous industrial production.
Embodiment
Below with example, further illustrate the present invention, but it is pointed out that following examples to the present invention and do not constitute any limitation.
The HPLC chromatographic condition: octadecylsilane chemically bonded silica is weighting agent, and take edta buffer liquid-water-acetonitrile (10:45:45) as moving phase, the detection wavelength is 250nm, 30 ℃ of column temperatures.
Embodiment 1: adjacent benzyloxy phenylimino acid methyl ester hydrochloride salt preparation
Adjacent benzyloxy cyanophenyl (31.4g, 0.15mol) is dissolved in methyl alcohol (150mL), cools to 0 ℃, the logical about 2-3 hour of HCl gas, and insulation reaction is spent the night, and is concentrated, and the solid that obtains adds the ether washing, obtains white solid 39.4g, yield 90%.MS(ESI)m/z278.7(M+H)
+
1H?NMR(DMSO-d
6,500MHz)δ12.8（br，1H），12.2（br，1H），7.41-7.22（m,7H）,6.98-7.03(m,2H),5.11(s,2H),4.45(s,3H).
Embodiment 2: adjacent benzyloxy phenylimino acid ethyl ester hydrochloride salt preparation
Adjacent benzyloxy cyanophenyl (31.4g, 0.15mol) is dissolved in dehydrated alcohol (150mL), cools to 0 ℃, the logical about 3-4 hour of HCl gas, and insulation reaction is spent the night, and is concentrated, and the solid that obtains adds the ether washing, obtains white solid 41.3g, yield 94.7%.MS(ESI)m/z292.6(M+H)
+。
1H?NMR(DMSO-d
6,500MHz)δ12.8（br，1H），12.1（br，1H），7.38-7.18（m,7H）,6.97-7.02(m,2H),5.13(s,2H),4.40(q,J=7.0Hz,2H),1.27(t,J=7.0Hz,3H).
Embodiment 3: the preparation of formula IV compound
Adjacent benzyloxy phenylimino acid methyl ester hydrochloride salt (30g, 0.11mmol) add water (250mL), cool to 10-20 ℃, add solid sodium bicarbonate (11.0g, 0.13mmol) in batches, the mixture that obtains adds methylene dichloride (200mL * 3) extraction, the organic layer that merges, add anhydrous sodium sulfate drying, filters, concentrated adjacent benzyloxy phenylimino acid methyl esters 25g, the yield 96% of obtaining of filtrate.MS(ESI)m/z242.5(M+H)
+
1H?NMR(DMSO-d
6,500MHz)δ8.78（br，1H），7.36-7.20（m,7H）,6.95-7.00(m,2H),5.06(s,2H),4.41(s,3H).
Adjacent benzyloxy phenylimino acetoacetic ester can be made by similar approach, MS (ESI) m/z256.6 (M+H)
+.
Embodiment 4: the preparation of formula V compound
Bigcatkin willow acyl chlorides (15.7g, 0.1mol) add methylene dichloride (150mL), add adjacent benzyloxy phenylimino acid ethyl ester hydrochloride salt (29.1g, 0.1mol), drip triethylamine (35mL, 0.25mol), the reaction mixture heating reflux reaction that obtains (approximately 40 ℃ of temperature of reaction) approximately 12 hours, the concentration response system, obtain formula V compound.MS(ESI)m/z330.5(M+H)
+。
1H?NMR(DMSO-d
6,500MHz)δ12.94(s,1H),8.22-8.20(m,1H),8.08-8.07(m,1H),7.97-7.94(m,1H),7.81-7.79(m,1H),7.66-7.60(m,2H),7.39-7.20（m,5H），7.10-7.08(m,2H)。
Embodiment 5: the preparation of formula V compound
Bigcatkin willow acyl chlorides (15.7g, 0.1mol) add tetrahydrofuran (THF) (120mL), add adjacent benzyloxy phenylimino acid methyl ester hydrochloride salt (27.8g, 0.1mol), drip N, N '-diisopropyl ethyl amine (35mL, 0.25mol), the reaction mixture heating reflux reaction that obtains (approximately 65 ℃ of temperature of reaction) approximately 6 hours, the concentration response system, obtain formula V compound.
Embodiment 6: the DEFERASIROX preparation
Formula V compound (28.0g, 85mmol) adds methyl alcohol (120mL), adds to hydrazine phenylformic acid (13.7g, 90mmol) heating reflux reaction approximately 2 hours; Cool to 20-30 ℃, add palladium carbon (1.0g), hydrogen (0.15MPa) reduction, reaction 6-8 hour.Filter, filtrate is concentrated removes approximately half solvent, adds dilute hydrochloric acid (1N), adjusts pH to 2-3, and 20-30 ℃ is stirred 2-3 hour, filters.Filter cake adds cooling methanol/water (volume ratio 1:1) washing, and 50 ℃ of vacuum-dryings obtain DEFERASIROX white solid 22.8g, HPLC:99.83%, MS (ESI) m/z374.5 (M+H)
+.
1H?NMR(DMSO-d
6,500MHz)δ13.17(br,1H),10.8(s,1H),10.04(s,1H),8.07-8.05(m,1H),8.00(d,J=8.5Hz,2H),7.58-7.55(m,3H),7.42-7.37(m,2H),7.05-6.98(m,3H),6.88-6.86(m,1H)。
Embodiment 7: one kettle way prepares DEFERASIROX
Bigcatkin willow acyl chlorides (15.7g, 0.1mol) add methylene dichloride (150mL), add adjacent benzyloxy phenylimino acid ethyl ester hydrochloride salt (29.1g, 0.1mol), drip triethylamine (35mL, 0.25mol), the reaction mixture heating reflux reaction that obtains (approximately 40 ℃ of temperature of reaction) approximately 12 hours, concentration response system;
Mixture after aforementioned concentrating adds methyl alcohol (120mL), adds to hydrazine phenylformic acid (13.7g, 90mmol) heating reflux reaction approximately 2 hours.Cool to 20-30 ℃, add palladium carbon (1.0g), hydrogen (0.12MPa) reduction, reaction 6-8 hour.Filter, filtrate is concentrated removes approximately half solvent, adds dilute hydrochloric acid (1N), adjusts pH to 2-3, and 20-30 ℃ is stirred 2-3 hour, filters.Filter cake adds cooling methanol/water (volume ratio 1:1) washing.50 ℃ of vacuum-dryings obtain DEFERASIROX white solid 22.8g, HPLC:99.80%.
Embodiment 8: one kettle way prepares DEFERASIROX
Bigcatkin willow acyl chlorides (15.7g, 0.1mol add tetrahydrofuran (THF) (120mL), add adjacent benzyloxy phenylimino acid methyl ester hydrochloride salt (27.8g, 0.1mol), drip N, N '-diisopropyl ethyl amine (35mL, 0.25mol), the reaction mixture heating reflux reaction that obtains (approximately 65 ℃ of temperature of reaction) approximately 6 hours, the concentration response system; Add ethanol (150mL), add hydrazine benzoate hydrochlorate (17.0g, 90mmol), add triethylamine (25.0mL, 0.18mol) heating reflux reaction 1-2 hour.Cool to 20-30 ℃, add Raney nickel (about 1.0g), hydrogen (0.12MPa) reduction, reaction 6-8 hour.Filter, filtrate is concentrated removes approximately half solvent, adds dilute hydrochloric acid (1N), adjusts pH to 2-3, and 20-30 ℃ is stirred 2-3 hour, filters.Filter cake adds cooling ethanol/water (volume ratio 1:1) washing.50 ℃ of vacuum-dryings obtain DEFERASIROX white solid 21.6g, HPLC:99.90%.
Embodiment 9: one kettle way prepares DEFERASIROX
Bigcatkin willow acyl chlorides (15.7g, 0.1mol) add tetrahydrofuran (THF) (150mL), add adjacent benzyloxy phenylimino acid ethyl ester hydrochloride salt (29.1g, 0.1mol), drip N, N '-diisopropyl ethyl amine (43.5mL, 0.25mol), the reaction mixture 50-55 ℃ reacting by heating that obtains approximately 8 hours, the concentration response system; Add the trimethyl carbinol (150mL), add hydrazine benzoate hydrochlorate (17.0g, 90mmol), add 5-60 ℃ of reaction 2-3 hour of triethylamine (25.0mL, 0.18mol) heating.Cool to 20-30 ℃, add palladium carbon (1.0g), hydrogen (0.10MPa) reduction, reaction 6-8 hour.Filter, filtrate is concentrated removes approximately half solvent, adds dilute hydrochloric acid (1N), adjusts pH to 2-3, and 20-30 ℃ is stirred 2-3 hour, filters.Filter cake adds cooling ethanol/water (volume ratio 1:1) washing.50 ℃ of vacuum-dryings obtain DEFERASIROX white solid 20.0g, HPLC:99.87%.
Embodiment 10 one kettle ways prepare DEFERASIROX
Bigcatkin willow acyl chlorides (15.7g, 0.1mol add tetrahydrofuran (THF) (100mL), add adjacent benzyloxy phenylimino acid methyl esters (24.1g, 0.1mol), drip N, N '-diisopropyl ethyl amine (26mL, 0.15mol), the reaction mixture heating reflux reaction that obtains (approximately 65 ℃ of temperature of reaction) approximately 6 hours, the concentration response system; Add ethanol (150mL), add hydrazine benzoate hydrochlorate (17.0g, 90mmol), add triethylamine (25.0mL, 0.18mol) heating reflux reaction 1-2 hour.Cool to 20-30 ℃, add Raney nickel (about 1.0g), hydrogen (0.12MPa) reduction, reaction 6-8 hour.Filter, filtrate is concentrated removes approximately half solvent, adds dilute hydrochloric acid (1N), adjusts pH to 2-3, and 20-30 ℃ is stirred 2-3 hour, filters.Filter cake adds cooling ethanol/water (volume ratio 1:1) washing.50 ℃ of vacuum-dryings obtain DEFERASIROX white solid 21.8g, HPLC:99.92%.
Claims (10)
1. the preparation method of a DEFERASIROX, under the alkali effect, obtain intermediate formula V compound 2-(2-benzyloxy phenyl by formula IV compound or its salt and bigcatkin willow acyl chlorides)-4H-1,3-benzoxazine-4-ketone; Formula V compound and to the reaction of hydrazine phenylformic acid or its hydrochloride, then, through catalytic hydrogenation, obtain DEFERASIROX; Reaction equation is as follows:
Wherein R is methyl or ethyl.
2. preparation method as claimed in claim 1, is characterized in that, comprises the steps:
(1) formula IV compound and bigcatkin willow acyl chlorides react under the alkali effect, and the reaction mixture that obtains is concentrated, obtains formula V compound;
(2) mixture of step (1) after concentrated with to hydrazine phenylformic acid or its hydrochloride, take C1-4 alcohol as solvent, 50-80 ℃ of reaction; Hydrogenation under the post catalyst reaction effect, obtain DEFERASIROX.
3. preparation method as claimed in claim 2, is characterized in that, in step (1), uses solvent to be tetrahydrofuran (THF) or methylene dichloride; Described alkali is triethylamine or N, N '-diisopropyl ethyl amine; Temperature of reaction is 40-70 ℃; Step (2) the C1-4 alcoholic solvent that uses is methyl alcohol, ethanol, Virahol or the trimethyl carbinol; Described hydrogenation catalyst is palladium carbon or Raney nickel.
4. compound or its salt shown in formula IV,
Wherein R is methyl or ethyl.
5. compound or its salt as claimed in claim 4, is characterized in that, described salt is hydrochloride.
6. the preparation method of compound or its salt shown in a formula IV, transformed and obtained by adjacent benzyloxy cyanophenyl and HCl reaction,
Wherein R is methyl or ethyl.
7. preparation method as claimed in claim 4, is characterized in that, the adjacent benzyloxy cyanophenyl of formula III compound is reacted with HCl at low temperatures, transforms and obtains formula IV compound hydrochloride, and it further can obtain formula IV compound through alkaline purification.
8. the preparation method of a formula V compound, reacted and obtain under the alkali effect by formula IV compound or its hydrochloride and bigcatkin willow acyl chlorides
Wherein R is methyl or ethyl, and described alkali is triethylamine or N, the N'-diisopropyl ethyl amine.
9. preparation method as claimed in claim 8, is characterized in that, formula V compound can further with to hydrazine phenylformic acid or its hydrochloride react, and then through catalytic hydrogenation, obtains DEFERASIROX:
10. preparation method as claimed in claim 9, is characterized in that, comprise the steps: formula V compound with to hydrazine phenylformic acid or its hydrochloride, take C1-4 alcohol as solvent, 50-80 ℃ of reaction; Hydrogenation under the post catalyst reaction effect, obtain DEFERASIROX; Wherein said hydrogenation catalyst is palladium carbon or Raney nickel.
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| CN111978264A (en) * | 2020-09-01 | 2020-11-24 | 南京科默生物医药有限公司 | Industrial production method of deferasirox |
| CN114075146A (en) * | 2020-08-12 | 2022-02-22 | 江苏奥赛康药业有限公司 | Preparation method of deferasirox impurity |
| CN114994205A (en) * | 2022-05-30 | 2022-09-02 | 上海奥科达生物医药科技有限公司 | Method for detecting related impurities in deferasirox granules |
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| CN114994205A (en) * | 2022-05-30 | 2022-09-02 | 上海奥科达生物医药科技有限公司 | Method for detecting related impurities in deferasirox granules |
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