CN117777131B - Synthesis method of paliperidone and key intermediate thereof - Google Patents
Synthesis method of paliperidone and key intermediate thereof Download PDFInfo
- Publication number
- CN117777131B CN117777131B CN202410211809.2A CN202410211809A CN117777131B CN 117777131 B CN117777131 B CN 117777131B CN 202410211809 A CN202410211809 A CN 202410211809A CN 117777131 B CN117777131 B CN 117777131B
- Authority
- CN
- China
- Prior art keywords
- paliperidone
- reaction
- benzyloxy
- methyl
- key intermediate
- 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
- PMXMIIMHBWHSKN-UHFFFAOYSA-N 3-{2-[4-(6-fluoro-1,2-benzoxazol-3-yl)piperidin-1-yl]ethyl}-9-hydroxy-2-methyl-6,7,8,9-tetrahydropyrido[1,2-a]pyrimidin-4-one Chemical compound FC1=CC=C2C(C3CCN(CC3)CCC=3C(=O)N4CCCC(O)C4=NC=3C)=NOC2=C1 PMXMIIMHBWHSKN-UHFFFAOYSA-N 0.000 title claims abstract description 47
- 229960001057 paliperidone Drugs 0.000 title claims abstract description 45
- 238000001308 synthesis method Methods 0.000 title claims abstract description 8
- 238000000034 method Methods 0.000 claims abstract description 38
- 238000007363 ring formation reaction Methods 0.000 claims abstract description 25
- 239000003054 catalyst Substances 0.000 claims abstract description 19
- 238000005658 halogenation reaction Methods 0.000 claims abstract description 15
- OMQHDIHZSDEIFH-UHFFFAOYSA-N 3-Acetyldihydro-2(3H)-furanone Chemical compound CC(=O)C1CCOC1=O OMQHDIHZSDEIFH-UHFFFAOYSA-N 0.000 claims abstract description 14
- 238000005984 hydrogenation reaction Methods 0.000 claims abstract description 14
- NMCBWICNRJLKKM-UHFFFAOYSA-N 3-(benzyloxy)pyridin-2-amine Chemical compound NC1=NC=CC=C1OCC1=CC=CC=C1 NMCBWICNRJLKKM-UHFFFAOYSA-N 0.000 claims abstract description 12
- 239000003153 chemical reaction reagent Substances 0.000 claims abstract description 12
- 125000000954 2-hydroxyethyl group Chemical group [H]C([*])([H])C([H])([H])O[H] 0.000 claims abstract description 9
- JLQMILPGYDOZDM-UHFFFAOYSA-N 6-fluoro-3-pyridin-4-yl-1,2-benzoxazole Chemical compound N=1OC2=CC(F)=CC=C2C=1C1=CC=NC=C1 JLQMILPGYDOZDM-UHFFFAOYSA-N 0.000 claims abstract description 9
- 238000006482 condensation reaction Methods 0.000 claims abstract description 8
- 230000026030 halogenation Effects 0.000 claims abstract description 6
- 125000000051 benzyloxy group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])O* 0.000 claims abstract description 5
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 23
- JIAARYAFYJHUJI-UHFFFAOYSA-L zinc dichloride Chemical compound [Cl-].[Cl-].[Zn+2] JIAARYAFYJHUJI-UHFFFAOYSA-L 0.000 claims description 22
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 21
- 238000006243 chemical reaction Methods 0.000 claims description 21
- VNDYJBBGRKZCSX-UHFFFAOYSA-L zinc bromide Chemical compound Br[Zn]Br VNDYJBBGRKZCSX-UHFFFAOYSA-L 0.000 claims description 16
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 claims description 15
- XTHFKEDIFFGKHM-UHFFFAOYSA-N Dimethoxyethane Chemical compound COCCOC XTHFKEDIFFGKHM-UHFFFAOYSA-N 0.000 claims description 14
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 12
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 12
- 239000011592 zinc chloride Substances 0.000 claims description 11
- 235000005074 zinc chloride Nutrition 0.000 claims description 11
- AYNDDJMEHBUOGI-UHFFFAOYSA-N 3-(2-hydroxyethyl)-2-methyl-9-phenylmethoxypyrido[1,2-a]pyrimidin-4-one Chemical compound C=1C=CN2C(=O)C(CCO)=C(C)N=C2C=1OCC1=CC=CC=C1 AYNDDJMEHBUOGI-UHFFFAOYSA-N 0.000 claims description 10
- 239000002904 solvent Substances 0.000 claims description 10
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 9
- 230000002194 synthesizing effect Effects 0.000 claims description 9
- 125000001340 2-chloroethyl group Chemical group [H]C([H])(Cl)C([H])([H])* 0.000 claims description 8
- 229940102001 zinc bromide Drugs 0.000 claims description 8
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 6
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 6
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 6
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 4
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 claims description 4
- 230000002140 halogenating effect Effects 0.000 claims description 4
- 239000008096 xylene Substances 0.000 claims description 4
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 claims description 2
- JTNCEQNHURODLX-UHFFFAOYSA-N 2-phenylethanimidamide Chemical compound NC(=N)CC1=CC=CC=C1 JTNCEQNHURODLX-UHFFFAOYSA-N 0.000 claims description 2
- 229910000343 potassium bisulfate Inorganic materials 0.000 claims description 2
- WBHQBSYUUJJSRZ-UHFFFAOYSA-M sodium bisulfate Chemical compound [Na+].OS([O-])(=O)=O WBHQBSYUUJJSRZ-UHFFFAOYSA-M 0.000 claims description 2
- 229910000342 sodium bisulfate Inorganic materials 0.000 claims description 2
- 239000000543 intermediate Substances 0.000 abstract description 28
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 abstract description 21
- 239000012535 impurity Substances 0.000 abstract description 18
- XHXFXVLFKHQFAL-UHFFFAOYSA-N phosphoryl trichloride Chemical compound ClP(Cl)(Cl)=O XHXFXVLFKHQFAL-UHFFFAOYSA-N 0.000 abstract description 17
- 238000003786 synthesis reaction Methods 0.000 abstract description 12
- 230000008569 process Effects 0.000 abstract description 8
- 238000005695 dehalogenation reaction Methods 0.000 abstract description 6
- 230000009467 reduction Effects 0.000 abstract description 6
- 239000002994 raw material Substances 0.000 abstract description 5
- -1 zinc halide Chemical class 0.000 abstract description 4
- 239000011701 zinc Substances 0.000 abstract description 3
- 229910052725 zinc Inorganic materials 0.000 abstract description 3
- 238000010189 synthetic method Methods 0.000 abstract description 2
- 239000000047 product Substances 0.000 description 19
- 238000005660 chlorination reaction Methods 0.000 description 11
- 230000015572 biosynthetic process Effects 0.000 description 10
- 238000005580 one pot reaction Methods 0.000 description 9
- JKVUGXRJSYRXFN-UHFFFAOYSA-N 3-(2-chloroethyl)-9-hydroxy-2-methyl-6,7,8,9-tetrahydropyrido[1,2-a]pyrimidin-4-one Chemical compound OC1CCCN2C(=O)C(CCCl)=C(C)N=C21 JKVUGXRJSYRXFN-UHFFFAOYSA-N 0.000 description 7
- JUJWROOIHBZHMG-UHFFFAOYSA-N pyridine Substances C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 7
- 238000003756 stirring Methods 0.000 description 7
- CRUISIDZTHMGJT-UHFFFAOYSA-L zinc;dichloride;hydrochloride Chemical compound Cl.[Cl-].[Cl-].[Zn+2] CRUISIDZTHMGJT-UHFFFAOYSA-L 0.000 description 7
- BMTSZVZQNMNPCT-UHFFFAOYSA-N 2-aminopyridin-3-ol Chemical compound NC1=NC=CC=C1O BMTSZVZQNMNPCT-UHFFFAOYSA-N 0.000 description 6
- 230000000052 comparative effect Effects 0.000 description 6
- 238000006722 reduction reaction Methods 0.000 description 6
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 5
- 238000001914 filtration Methods 0.000 description 5
- 231100000024 genotoxic Toxicity 0.000 description 5
- 230000001738 genotoxic effect Effects 0.000 description 5
- 239000007858 starting material Substances 0.000 description 5
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 5
- ICSNLGPSRYBMBD-UHFFFAOYSA-N 2-aminopyridine Chemical compound NC1=CC=CC=N1 ICSNLGPSRYBMBD-UHFFFAOYSA-N 0.000 description 4
- 239000007810 chemical reaction solvent Substances 0.000 description 4
- 230000007613 environmental effect Effects 0.000 description 4
- 229910052739 hydrogen Inorganic materials 0.000 description 4
- 239000001257 hydrogen Substances 0.000 description 4
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 4
- CTSLXHKWHWQRSH-UHFFFAOYSA-N oxalyl chloride Chemical compound ClC(=O)C(Cl)=O CTSLXHKWHWQRSH-UHFFFAOYSA-N 0.000 description 4
- 238000002360 preparation method Methods 0.000 description 4
- 238000001228 spectrum Methods 0.000 description 4
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 4
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 3
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- 238000006555 catalytic reaction Methods 0.000 description 3
- 238000001816 cooling Methods 0.000 description 3
- 230000007547 defect Effects 0.000 description 3
- 238000001035 drying Methods 0.000 description 3
- 239000000203 mixture Substances 0.000 description 3
- 230000035484 reaction time Effects 0.000 description 3
- 239000007787 solid Substances 0.000 description 3
- NHQDETIJWKXCTC-UHFFFAOYSA-N 3-chloroperbenzoic acid Chemical compound OOC(=O)C1=CC=CC(Cl)=C1 NHQDETIJWKXCTC-UHFFFAOYSA-N 0.000 description 2
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 2
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 2
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 2
- 238000005874 Vilsmeier-Haack formylation reaction Methods 0.000 description 2
- 229960000583 acetic acid Drugs 0.000 description 2
- 229910052799 carbon Inorganic materials 0.000 description 2
- 238000009903 catalytic hydrogenation reaction Methods 0.000 description 2
- 239000000460 chlorine Substances 0.000 description 2
- 229910052801 chlorine Inorganic materials 0.000 description 2
- 239000000706 filtrate Substances 0.000 description 2
- 238000010438 heat treatment Methods 0.000 description 2
- 238000004128 high performance liquid chromatography Methods 0.000 description 2
- 238000001819 mass spectrum Methods 0.000 description 2
- 238000000926 separation method Methods 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- JCLFDHCFFKIZDE-UHFFFAOYSA-N 3-(2-chloroethyl)-2-methyl-3,4-dihydropyridine Chemical compound ClCCC1C(=NC=CC1)C JCLFDHCFFKIZDE-UHFFFAOYSA-N 0.000 description 1
- BDAGIHXWWSANSR-UHFFFAOYSA-N Formic acid Chemical compound OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 239000003513 alkali Substances 0.000 description 1
- 239000003420 antiserotonin agent Substances 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 150000008316 benzisoxazoles Chemical class 0.000 description 1
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 1
- 239000006227 byproduct Substances 0.000 description 1
- 230000003197 catalytic effect Effects 0.000 description 1
- 230000008859 change Effects 0.000 description 1
- 239000012043 crude product Substances 0.000 description 1
- 238000003386 deoximation reaction Methods 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 238000004880 explosion Methods 0.000 description 1
- 239000012065 filter cake Substances 0.000 description 1
- WSFSSNUMVMOOMR-UHFFFAOYSA-N formaldehyde Substances O=C WSFSSNUMVMOOMR-UHFFFAOYSA-N 0.000 description 1
- 235000019253 formic acid Nutrition 0.000 description 1
- 238000009472 formulation Methods 0.000 description 1
- 239000007789 gas Substances 0.000 description 1
- 238000002290 gas chromatography-mass spectrometry Methods 0.000 description 1
- 239000012362 glacial acetic acid Substances 0.000 description 1
- 150000002431 hydrogen Chemical class 0.000 description 1
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 1
- 229910000041 hydrogen chloride Inorganic materials 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- 230000006872 improvement Effects 0.000 description 1
- 229940013946 invega Drugs 0.000 description 1
- OWFXIOWLTKNBAP-UHFFFAOYSA-N isoamyl nitrite Chemical compound CC(C)CCON=O OWFXIOWLTKNBAP-UHFFFAOYSA-N 0.000 description 1
- 238000002386 leaching Methods 0.000 description 1
- 238000013332 literature search Methods 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
- 229960001344 methylphenidate Drugs 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 238000003541 multi-stage reaction Methods 0.000 description 1
- 238000006386 neutralization reaction Methods 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 229910052763 palladium Inorganic materials 0.000 description 1
- 150000002978 peroxides Chemical class 0.000 description 1
- RLOWWWKZYUNIDI-UHFFFAOYSA-N phosphinic chloride Chemical compound ClP=O RLOWWWKZYUNIDI-UHFFFAOYSA-N 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 238000007670 refining Methods 0.000 description 1
- 229910052703 rhodium Inorganic materials 0.000 description 1
- 239000010948 rhodium Substances 0.000 description 1
- MHOVAHRLVXNVSD-UHFFFAOYSA-N rhodium atom Chemical compound [Rh] MHOVAHRLVXNVSD-UHFFFAOYSA-N 0.000 description 1
- RAPZEAPATHNIPO-UHFFFAOYSA-N risperidone Chemical class FC1=CC=C2C(C3CCN(CC3)CCC=3C(=O)N4CCCCC4=NC=3C)=NOC2=C1 RAPZEAPATHNIPO-UHFFFAOYSA-N 0.000 description 1
- 201000000980 schizophrenia Diseases 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-N sulfuric acid Substances OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 1
- 238000013268 sustained release Methods 0.000 description 1
- 239000012730 sustained-release form Substances 0.000 description 1
- 125000003944 tolyl group Chemical group 0.000 description 1
- 229910052723 transition metal Inorganic materials 0.000 description 1
- 150000003624 transition metals Chemical class 0.000 description 1
Landscapes
- Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
Abstract
The invention discloses a synthetic method of paliperidone and key intermediates thereof, which relates to the technical field of organic chemical synthesis, wherein 9- (benzyloxy) -3- (2-hydroxyethyl) -2-methyl-4H-pyrido [1,2-a ] pyrimidine-4-ketone is obtained by cyclization reaction of 2-amino-3-benzyloxy pyridine and alpha-acetyl-gamma-butyrolactone, the intermediates are obtained by halogenation and hydrogenation reaction, and finally the paliperidone is obtained by condensation reaction of the paliperidone and 6-fluoro-3- (4-pyridyl) -1, 2-benzisoxazole; the synthesis method provided by the invention has the advantages of easily available raw materials, simple and convenient operation, short process route, no p-toluenesulfonic acid as a catalyst in the cyclization reaction of the intermediate, no high-pollution reagent phosphorus oxychloride in the halogenation reaction, reduced dehalogenation impurity generation by using a zinc halide reagent in hydrogenation reduction, easy control of product quality and high yield.
Description
Technical Field
The invention relates to the technical field of organic chemical synthesis, in particular to a synthesis method of paliperidone and a key intermediate 3- (2-chloroethyl) -6,7,8, 9-tetrahydro-9-hydroxy-2-methyl-4H-pyrido [1,2-a ] pyrimidine-4-ketone thereof.
Background
Paliperidone, chemical name 3- [2- [4- (6-fluoro-1, 2-benzisoxazol-3-yl) -1-piperidinyl ] ethyl ] -6,7,8, 9-tetrahydro-9-hydroxy-2-methyl-4H-pyrido [1,2-a ] pyrimidin-4-one, having the structural formula:
Paliperidone, a 5-HT antagonist belonging to the class of benzisoxazole derivatives, is the major metabolite of risperidone, and its sustained release oral formulation is marketed under the trade name Invega in the United states for the treatment of schizophrenia.
There are many reports on the preparation method of Guan Pali-methylphenidate, and the method for industrial preparation mainly comprises the condensation reaction of 3- (2-chloroethyl) -6,7,8, 9-tetrahydro-9-hydroxy-2-methyl-4H-pyrido [1,2-a ] pyrimidin-4-one with 6-fluoro-3- (4-pyridyl) -1, 2-benzisoxazole to obtain paliperidone, wherein the reaction equation is as follows:
The 6-fluoro-3- (4-pyridyl) -1, 2-benzisoxazole has larger supply quantity and reasonable price on the market. 3- (2-chloroethyl) -6,7,8, 9-tetrahydro-9-hydroxy-2-methyl-4H-pyrido [1,2-a ] pyrimidin-4-one is less available on the market and is expensive. In order to solve the problem of the industrialization of paliperidone, the problem of the industrialized production of 3- (2-chloroethyl) -6,7,8, 9-tetrahydro-9-hydroxy-2-methyl-4H-pyrido [1,2-a ] pyrimidine-4-ketone needs to be solved. Through domestic and foreign literature search, the preparation method mainly adopts the following 6 preparation methods:
The patent CN101440093 takes 2-amino-3-hydroxypyridine and alpha-acetyl-gamma-butyrolactone as raw materials, and is cyclized under the catalysis of acid to obtain 3- (2-hydroxyethyl) -9-hydroxy-2-methyl-4H-pyrido [1,2-a ] pyrimidine-4-ketone, then the 3- (2-hydroxyethyl) -6,7,8, 9-tetrahydro-9-hydroxy-2-methyl-4H-pyrido [1,2-a ] pyrimidine-4-ketone is obtained through hydrogenation reduction under the catalysis of transition metal, and finally the target product is obtained through selective chlorination.
In the method, hydroxy on the 2-amino-3-hydroxypyridine ring may also participate in the reaction in the cyclization reaction, and impurities are introduced to reduce the yield; the final step of chlorination reaction has poor selectivity, the 9-hydroxyl group can be replaced by chlorine to form byproducts, the halogenation reaction yield is only 49%, and the total yield is about 37%, so that the application of the method is limited.
Patent WO2009074333 uses 2-amino-3-hydroxypyridine and alpha-acetyl-gamma-butyrolactone as raw materials, and performs cyclization and chlorination one-pot reaction to obtain 3- (2-hydroxyethyl) -2-methyl-9-benzyloxy-4H-pyridine [1,2-a ] pyrimidine-4-ketone, and then performs hydrogenation reduction to obtain a target product.
The method needs two steps of reactions, uses expensive rhodium metal, has a cyclization and chlorination one-pot reaction yield of 34-62%, and is found by repeated experiments: the reaction condition of one pot is complex, the impurity points are many, a large amount of black tarry substances can be generated by the neutralization of the post-treatment and alkali addition, the removal of the impurities needs column separation, and the yield of the separated intermediate is far lower than that of the intermediate obtained by cyclization and chlorination; and because the cyclization reaction produces water, a large amount of phosphorus oxychloride is often required to be added to complete the reaction, the cost is increased, and the reaction of the phosphorus oxychloride and the water produces a large amount of hydrogen chloride gas, which causes potential environmental hazard and limits the application of the method.
Patent WO2010003702 uses 2-aminopyridine as a starting material, performs cyclization and chlorination 'one-pot' reaction with alpha-acetyl-gamma-butyrolactone in the presence of phosphorus oxychloride to generate 3- (2-chloroethyl) -2-methyl-4H-pyridine [1,2-a ] pyrimidine-4-ketone, and then performs catalytic hydrogenation to obtain 3- (2-chloroethyl) -6,7,8, 9-tetrahydro-2-methyl-4H-pyridine [1,2-a ] pyrimidine-4-ketone, then performs a reaction with isopentyl nitrite to introduce 9-oxime, and finally performs deoximation and reduction reaction to obtain a target product.
The method needs 4 steps of reactions, has complex procedures, and still has the defects of cyclization and chlorination one-pot reaction.
Patent WO2009047499 uses 2-amino-3-hydroxypyridine as a starting material, cyclizes and chlorinates in the presence of phosphorus oxychloride to obtain 3- (2-chloroethyl) -2-methyl-9-hydroxy-4H-pyridine [1,2-a ] pyrimidine-4-ketone through one-pot reaction, then uses acetic anhydride and acetic acid as solvents to hydrogenate and reduce pyridine rings, and finally hydrolyzes under alkaline conditions to obtain a target product.
In the method, the hydroxyl on the 2-amino-3-hydroxypyridine ring can also participate in the reaction in the cyclization reaction, impurities are introduced, the yield is reduced, chlorine in the final hydrolysis reaction can be hydrolyzed into hydroxyl, in addition, the method still has the defects of the cyclization and chlorination one-pot reaction, the total yield of three steps is only 32%, and the application of the method is limited.
Patent WO2009074333 uses 2-aminopyridine and alpha-acetyl-gamma-butyrolactone as starting materials, and sequentially performs cyclization, chlorination and hydrogenation reduction to obtain 3- (2-chloroethyl) -6,7,8, 9-tetrahydro-2-methyl-4H-pyridine [1,2-a ] pyrimidine-4-ketone, then introduces 9-aldehyde group through Vilsmeier-Haack reaction (in the presence of DMF and POCl 3) to obtain 3- (2-chloroethyl) -2-methyl-4-oxo-4, 6,7, 8-tetrahydro-1H-pyridine [1,2-a ] pyrimidine-9-formaldehyde, and finally performs H 2O2/HCOOH or m-chloroperoxybenzoic acid (m-CPBA) treatment to obtain a target product.
The crude product of the 3- (2-chloroethyl) -2-methyl-4-oxo-4, 6,7, 8-tetrahydro-1H-pyridine [1,2-a ] pyrimidine-9-formaldehyde obtained in the Vilsmeier-Haack reaction needs column refining, and the yield of two steps after the reaction is only about 33%; and the last step, using peroxide, presents explosion hazards, limiting the industrial application of this route.
Patent US20080214809 uses 2-amino-3-hydroxypyridine as a starting material, and after the protection of hydroxyl by benzyl, the starting material is cyclized with alpha-acetyl-gamma-butyrolactone to obtain 3- (2-hydroxyethyl) -2-methyl-9-benzyloxy-4-pyridine [1,2-a ] pyrimidine-4-ketone, and then the target product is obtained through chlorination and catalytic hydrogenation.
The method requires four steps of reaction, has complex working procedures, also uses p-toluenesulfonic acid, and generates the risk of p-toluenesulfonate genotoxic impurities, so the route needs improvement.
In summary, the existing synthetic method of paliperidone key intermediate 3- (2-chloroethyl) -6,7,8, 9-tetrahydro-9-hydroxy-2-methyl-4H-pyrido [1,2-a ] pyrimidin-4-one mainly involves the following problems: the multi-step reaction is needed, the working procedure is complex, and the yield is low; or the defect of cyclization and chlorination one-pot reaction exists; or p-toluenesulfonic acid is used for catalysis, and the risk of p-toluenesulfonate genotoxic impurities exists; or require GC-MS analysis of the product, increasing costs; or using highly contaminated phosphorus oxychloride reagent; or Pd/C reduction may produce dechlorinated impurities.
Disclosure of Invention
The invention aims to provide a synthesis method of paliperidone and key intermediates thereof, which is characterized in that the key intermediates of paliperidone are obtained through three-step reaction, and then the intermediates are subjected to condensation reaction with 6-fluoro-3- (4-pyridyl) -1, 2-benzisoxazole to obtain paliperidone, so that the yield is improved, the process is simplified, and the environmental protection of the process is improved.
The technical problems to be solved by the invention are realized by adopting the following technical scheme:
The invention aims to provide a method for synthesizing a key intermediate of paliperidone, which comprises the steps of carrying out cyclization reaction on 2-amino-3-benzyloxy pyridine and alpha-acetyl-gamma-butyrolactone to obtain 9- (benzyloxy) -3- (2-hydroxyethyl) -2-methyl-4H-pyrido [1,2-a ] pyrimidine-4-ketone, and carrying out halogenation and hydrogenation reaction to obtain the key intermediate of paliperidone.
The synthetic route is as follows:
The second object of the present invention is to provide a synthesis method of paliperidone, which comprises the steps of performing cyclization reaction on 2-amino-3-benzyloxy pyridine and alpha-acetyl-gamma-butyrolactone to obtain 9- (benzyloxy) -3- (2-hydroxyethyl) -2-methyl-4H-pyrido [1,2-a ] pyrimidine-4-one, performing halogenation and hydrogenation reaction to obtain an intermediate, and performing condensation reaction on the intermediate and 6-fluoro-3- (4-pyridyl) -1, 2-benzisoxazole to obtain paliperidone.
The synthetic route is as follows:
in a further embodiment, the molar feed ratio of 2-amino-3-benzyloxypyridine to α -acetyl- γ -butyrolactone is 1 (1-3), preferably 1 (1.5-2).
In a further technical scheme, the catalyst for the cyclization reaction is selected from at least one of zinc chloride, zinc bromide, sodium bisulfate, potassium bisulfate, concentrated sulfuric acid and glacial acetic acid, preferably zinc chloride.
In a further embodiment, the catalyst for the cyclization reaction is used in an amount of 3-10%, preferably 5-10% by mass of 2-amino-3-benzyloxypyridine.
In a further embodiment, the solvent for the cyclization reaction is selected from at least one of toluene, xylene, dioxane, N-dimethylformamide, preferably toluene.
In the above synthetic route, dehalogenated impurities are easily generated in the process of synthesizing 3- (2-chloroethyl) -6,7,8, 9-tetrahydro-9-hydroxy-2-methyl-4H-pyrido [1,2-a ] pyrimidin-4-one from 9- (benzyloxy) -3- (2-hydroxyethyl) -2-methyl-4H-pyrido [1,2-a ] pyrimidin-4-one by a first halogenation and then hydrogenation one-pot methodThereby increasing the separation and purification costs and reducing the product yield. In order to solve the problem, the invention adopts the following technical scheme:
in a further embodiment, the halogenating reagent of the halogenation reaction is selected from at least one of thionyl chloride, oxalyl chloride, zinc chloride/hydrochloric acid, zinc bromide/hydrochloric acid, preferably zinc chloride/hydrochloric acid (Lucas reagent) and zinc bromide/hydrochloric acid.
In a further embodiment, the molar feed ratio of the halogenated reagent to 9- (benzyloxy) -3- (2-hydroxyethyl) -2-methyl-4H-pyrido [1,2-a ] pyrimidin-4-one is (1-2): 1.
In a further technical scheme, the solvent for the halogenation reaction is selected from at least one of toluene, xylene, ethylene glycol dimethyl ether, ethyl acetate and chloroform, and preferably ethylene glycol dimethyl ether.
In a further embodiment, the hydrogenation catalyst is Pd/C.
In the invention, p-toluenesulfonic acid is not used as a catalyst in the cyclization reaction of 2-amino-3-benzyloxy pyridine and alpha-acetyl-gamma-butyrolactone, so that the generation of p-toluenesulfonate genotoxic impurities is avoided; high-pollution phosphorus oxychloride is not used in the halogenation reaction process of 9- (benzyloxy) -3- (2-hydroxyethyl) -2-methyl-4H-pyrido [1,2-a ] pyrimidine-4-ketone and a halogenating reagent, so that the environmental protection of the process is improved; the excessive zinc halide in the hydrogenation reaction can prevent dehalogenation impurities from being generated, and greatly improves the yield and quality of key intermediates of paliperidone.
In a further technical scheme, the molar feed ratio of the 3- (2-chloroethyl) -6,7,8, 9-tetrahydro-9-hydroxy-2-methyl-4H-pyrido [1,2-a ] pyrimidin-4-one to the 6-fluoro-3- (4-pyridyl) -1, 2-benzisoxazole is 1 (0.95-1).
In a further technical scheme, the solvent of the condensation reaction is at least one selected from methanol, ethanol, isopropanol, dichloromethane and ethyl acetate.
The beneficial effects of the invention are as follows: the invention takes 2-amino-3-benzyloxy pyridine and alpha-acetyl-gamma-butyrolactone as initial raw materials, obtains paliperidone key intermediate through cyclization, halogenation and hydrogenation reaction, and obtains paliperidone through condensation reaction of the intermediate and 6-fluoro-3- (4-pyridyl) -1, 2-benzisoxazole; the synthesis method has the advantages of easily available raw materials, simple and convenient operation, short process route, no p-toluenesulfonic acid as a catalyst in the cyclization reaction of the intermediate, no high-pollution reagent phosphorus oxychloride in the halogenation reaction, capability of preventing dehalogenation impurities from being generated by zinc halide used in hydrogenation reduction, easy control of product quality and high yield.
Drawings
FIG. 1 is a hydrogen spectrum of a key intermediate of paliperidone synthesized in example 12 of the present invention;
FIG. 2 is a carbon spectrum of a key intermediate of paliperidone synthesized in example 12 of the present invention;
FIG. 3 is a mass spectrum of a key intermediate of paliperidone synthesized in example 12 of the present invention;
FIG. 4 is an HPLC plot of a key intermediate of paliperidone synthesized in example 12 of the present invention;
FIG. 5 is a hydrogen spectrum of paliperidone synthesized in example 22 of the present invention;
FIG. 6 is a carbon spectrum of paliperidone synthesized in example 22 of the present invention;
FIG. 7 is a mass spectrum of paliperidone synthesized in example 22 of the present invention;
FIG. 8 is an HPLC chart of paliperidone synthesized in example 22 of the present invention.
Detailed Description
The invention is further described below with reference to specific embodiments and illustrations in order to make the technical means, the creation features, the achievement of the purpose and the effect of the implementation of the invention easy to understand.
Example 1
Synthesis of 9- (benzyloxy) -3- (2-hydroxyethyl) -2-methyl-4H-pyrido [1,2-a ] pyrimidin-4-one:
2-amino-3-benzyloxypyridine (0.5 mol,100 g), alpha-acetyl-gamma-butyrolactone (1 mol,128 g), zinc chloride 5g and toluene 200 g were added into a reaction flask, heated and refluxed, added into a water separator, and stirred for reaction for 10 hours. Stopping the reaction, cooling to room temperature, adding methanol 200 mL, stirring and crystallizing 3 h, filtering and drying to obtain a light yellow solid.
Examples 2 to 8 and comparative example 1
Examples 2-8 and comparative example 1 the procedure for the synthesis of 9- (benzyloxy) -3- (2-hydroxyethyl) -2-methyl-4H-pyrido [1,2-a ] pyrimidin-4-one was the same as in example 1, except that the type or amount of catalyst was varied, as specified in Table 1.
TABLE 1
As can be seen from the data in table 1, when zinc chloride is used as a catalyst, the purity and yield of the obtained product are high; the catalyst dosage is 5-10%, and the product purity and yield have little change; however, since the amount of the catalyst is increased and the maximum amount of the single impurity becomes large, zinc chloride is preferable as the catalyst and the amount thereof is 5 to 10% by mass of 2-amino-3-benzyloxypyridine. In addition, compared with the method adopting the p-toluenesulfonic acid as the catalyst, the method can avoid the generation of p-toluenesulfonate genotoxic impurities and improve the purity and yield of the product.
Comparative example 2
Comparative example 2 the procedure for the synthesis of 9- (benzyloxy) -3- (2-hydroxyethyl) -2-methyl-4H-pyrido [1,2-a ] pyrimidin-4-one was followed as in example 1, except that the catalyst type and the reaction time were varied, as specified in Table 2.
TABLE 2
As can be seen from the data in table 2, when p-toluenesulfonic acid is used as a catalyst, it is necessary to lengthen the reaction time in order to achieve a catalytic effect equivalent to that of zinc chloride. That is, the use of p-toluenesulfonic acid as a catalyst not only produces p-toluenesulfonate genotoxic impurities but also increases the reaction time.
Examples 9 to 11
Examples 9-11 Synthesis of 9- (benzyloxy) -3- (2-hydroxyethyl) -2-methyl-4H-pyrido [1,2-a ] pyrimidin-4-one the procedure of example 1 was followed, except that the solvent type was varied as specified in Table 3.
TABLE 3 Table 3
As can be seen from the data in table 3, when the reaction solvent is toluene, the purity and yield of the obtained product are highest, and therefore toluene is preferable as the reaction solvent.
Synthesis of paliperidone key intermediate 3- (2-chloroethyl) -6,7,8, 9-tetrahydro-9-hydroxy-2-methyl-4H-pyrido [1,2-a ] pyrimidin-4-one:
Adding 31g of 9- (benzyloxy) -3- (2-hydroxyethyl) -2-methyl-4H-pyrido [1,2-a ] pyrimidine-4-ketone, 10mL of Lucas reagent (Guangdong Weng Jiang chemical reagent) and 100mL of ethylene glycol dimethyl ether into a reaction bottle, heating to 60 ℃ for stirring and reacting for 5H, filtering, leaching a filter cake with a small amount of ethylene glycol dimethyl ether, adding the filtrate into an autoclave, adding 10% Pd/C3 g, heating to 55 ℃ for stirring and reacting for 3H, introducing hydrogen, the hydrogen pressure is 0.2MPa, stopping the reaction, filtering, recovering the solvent from the filtrate under reduced pressure, adding 100mL of water into the residue for dissolving, adjusting the pH to 7-8 by using 20% sodium hydroxide, extracting the water layer by using 100mL of dichloromethane for 3 times, recovering the organic solvent under reduced pressure, adding 50mL of isopropanol into the residue, cooling to 0-5 ℃ for stirring for 1H, filtering, and drying to obtain an off-white solid.
Examples 13-15 the procedure for the synthesis of key intermediates for paliperidone was followed as in example 12, except that the molar feed ratio of 9- (benzyloxy) -3- (2-hydroxyethyl) -2-methyl-4H-pyrido [1,2-a ] pyrimidin-4-one to the Lucas reagent was varied as specified in Table 4.
TABLE 4 Table 4
As can be seen from the data in Table 4, the product purity and yield were highest when the molar feed ratio was 1:1.1; as the molar ratio increases, the product purity and yield decrease, so that the molar ratio of 9- (benzyloxy) -3- (2-hydroxyethyl) -2-methyl-4H-pyrido [1,2-a ] pyrimidin-4-one to the Lucas reagent is preferably 1:1.1.
Examples 16 to 19
Examples 16-19 key intermediates for the synthesis of paliperidone were prepared in the same manner as in example 12, except that the solvent type was changed as shown in Table 5.
TABLE 5
As can be seen from the data in Table 5, when the reaction solvent is ethylene glycol dimethyl ether, the product purity and yield are highest, and the dehalogenation impurity content is smallest, so that the reaction solvent is preferably ethylene glycol dimethyl ether.
Examples 20 to 21
Examples 20-21 the procedure for the synthesis of key intermediates for paliperidone was the same as in example 12, except that the Pd content of Pd/C was varied as shown in Table 6.
TABLE 6
As can be seen from the data in Table 6, the greater the Pd content in Pd/C, the greater will be the dehalogenation impurity content in the product; when 10% Pd/C is used, the product purity and yield are highest, so the catalyst is preferably 10% Pd/C.
Examples 22 to 24 and comparative example 1
Examples 22-24 and comparative example 1 the procedure for the synthesis of key intermediates for paliperidone was the same as in example 12, except that the type of halogenated reagent was varied, as specifically shown in Table 7.
TABLE 7
As can be seen from the data in Table 7, the use of Lucas reagent or zinc bromide/hydrochloric acid as the halogenating reagent, the product purity and yield were highest, and the dehalogenation impurity content was lowest; and compared with the common phosphorus oxychloride, oxalyl chloride and thionyl chloride, the use of the Lucas reagent can improve the environmental protection performance of the process. Wherein the zinc bromide and hydrochloric acid content in the zinc bromide/hydrochloric acid is identical to the zinc chloride and hydrochloric acid content in the Lucas reagent.
Example 25
Synthesis of paliperidone:
To the reaction flask was added 100.48g of 6-fluoro-3- (4-pyridyl) -1, 2-benzisoxazole hydrochloride, 1000mL of methanol, 133.25g of diisopropylethylamine, and the mixture was stirred for 45 minutes at 55℃and 100g of 3- (2-chloroethyl) -6,7,8, 9-tetrahydro-9-hydroxy-2-methyl-4H-pyrido [1,2-a ] pyrimidin-4-one was added, and the mixture was heated to 62℃and then refluxed with stirring for 24 hours. Stopping the reaction, stirring for 1h at room temperature, cooling to 0-10 ℃, stirring for 2h, filtering, and drying to obtain an off-white solid with the yield of 95.30% and the purity of 99.90%.
The foregoing has shown and described the basic principles and main features of the present invention and the advantages of the present invention. It will be understood by those skilled in the art that the present invention is not limited to the embodiments described above, and that the above embodiments and descriptions are merely illustrative of the principles of the present invention, and various changes and modifications may be made without departing from the spirit and scope of the invention, which is defined in the appended claims. The scope of the invention is defined by the appended claims and equivalents thereof.
Claims (7)
1. A method for synthesizing a key intermediate of paliperidone is characterized by comprising the following steps: firstly, carrying out cyclization reaction on 2-amino-3-benzyloxy pyridine and alpha-acetyl-gamma-butyrolactone to obtain 9- (benzyloxy) -3- (2-hydroxyethyl) -2-methyl-4H-pyrido [1,2-a ] pyrimidine-4-ketone, and then carrying out halogenation and hydrogenation reaction to obtain a key intermediate of paliperidone;
The synthetic route is as follows:
;
The catalyst of the cyclization reaction is at least one selected from zinc chloride, zinc bromide, sodium bisulfate and potassium bisulfate;
The halogenating reagent of the halogenation reaction is at least one selected from zinc chloride/hydrochloric acid and zinc bromide/hydrochloric acid;
The reaction temperature of the halogenation reaction is 60 ℃;
the molar feed ratio of the halogenated reagent to 9- (benzyloxy) -3- (2-hydroxyethyl) -2-methyl-4H-pyrido [1,2-a ] pyrimidine-4-one is (1.1-2): 1.
2. The method for synthesizing paliperidone key intermediate of claim 1, wherein: the molar feed ratio of the 2-amino-3-benzyloxy pyridine to the alpha-acetyl-gamma-butyrolactone is 1 (1-3).
3. The method for synthesizing paliperidone key intermediate of claim 1, wherein: the dosage of the catalyst for the cyclization reaction is 3-10% of the mass of the 2-amino-3-benzyloxy pyridine;
The solvent for the cyclization reaction is at least one selected from toluene, xylene, dioxane and N, N-dimethylformamide.
4. The method for synthesizing paliperidone key intermediate of claim 1, wherein: the solvent for halogenation reaction is at least one selected from toluene, xylene, ethylene glycol dimethyl ether, ethyl acetate and chloroform.
5. The method for synthesizing paliperidone key intermediate of claim 1, wherein: the catalyst for the hydrogenation reaction is Pd/C.
6. A method for synthesizing paliperidone, which is characterized in that: obtaining an intermediate by adopting the synthesis method of the paliperidone key intermediate as claimed in any one of claims 1-5, and performing condensation reaction on the intermediate and 6-fluoro-3- (4-pyridyl) -1, 2-benzisoxazole to obtain paliperidone;
The synthetic route is as follows:
。
7. The method of synthesizing paliperidone of claim 6, wherein: the molar feed ratio of the 3- (2-chloroethyl) -6,7,8, 9-tetrahydro-9-hydroxy-2-methyl-4H-pyrido [1,2-a ] pyrimidine-4-ketone to the 6-fluoro-3- (4-pyridyl) -1, 2-benzisoxazole is 1 (0.95-1);
the solvent for the condensation reaction is at least one selected from methanol, ethanol, isopropanol, dichloromethane and ethyl acetate.
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN202410211809.2A CN117777131B (en) | 2024-02-27 | 2024-02-27 | Synthesis method of paliperidone and key intermediate thereof |
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN202410211809.2A CN117777131B (en) | 2024-02-27 | 2024-02-27 | Synthesis method of paliperidone and key intermediate thereof |
Publications (2)
Publication Number | Publication Date |
---|---|
CN117777131A CN117777131A (en) | 2024-03-29 |
CN117777131B true CN117777131B (en) | 2024-06-11 |
Family
ID=90382063
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CN202410211809.2A Active CN117777131B (en) | 2024-02-27 | 2024-02-27 | Synthesis method of paliperidone and key intermediate thereof |
Country Status (1)
Country | Link |
---|---|
CN (1) | CN117777131B (en) |
Citations (8)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2008024415A2 (en) * | 2006-08-23 | 2008-02-28 | Teva Pharmaceutical Insustries Ltd. | Process for the synthesis of cmhtp and intermediates thereof |
WO2009047499A2 (en) * | 2007-10-09 | 2009-04-16 | Cipla Limited | Processes for the preparation of paliperidone and pharmaceutically acceptable salts thereof and intermediates for use in the processes |
CN101440093A (en) * | 2008-12-23 | 2009-05-27 | 上海立科药物化学有限公司 | Process for synthesizing paliperidone intermediate |
WO2009074333A1 (en) * | 2007-12-10 | 2009-06-18 | Synthon B.V. | Synthesis of paliperidone |
WO2009130710A2 (en) * | 2008-04-21 | 2009-10-29 | Glenmark Generics Limited | A process for the preparation of paliperidone intermediates |
CN101870695A (en) * | 2009-04-24 | 2010-10-27 | 上海同昌生物医药科技有限公司 | Preparation method of 3-(2-chloroethyl)-6, 7, 8, 9 - tetrahydro-9 - hydroxy - 2 - Methylenetetrahydrofolate - pyrido [1,2-alpha] pyrimidine -4 - ketone |
CN102126931A (en) * | 2010-12-30 | 2011-07-20 | 广东广益科技实业有限公司 | Preparation method of resveratrol |
CN106220622A (en) * | 2016-06-30 | 2016-12-14 | 广州仁恒医药科技有限公司 | A kind of preparation method of Palmic acid 9-hydroxy-risperidone |
-
2024
- 2024-02-27 CN CN202410211809.2A patent/CN117777131B/en active Active
Patent Citations (8)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2008024415A2 (en) * | 2006-08-23 | 2008-02-28 | Teva Pharmaceutical Insustries Ltd. | Process for the synthesis of cmhtp and intermediates thereof |
WO2009047499A2 (en) * | 2007-10-09 | 2009-04-16 | Cipla Limited | Processes for the preparation of paliperidone and pharmaceutically acceptable salts thereof and intermediates for use in the processes |
WO2009074333A1 (en) * | 2007-12-10 | 2009-06-18 | Synthon B.V. | Synthesis of paliperidone |
WO2009130710A2 (en) * | 2008-04-21 | 2009-10-29 | Glenmark Generics Limited | A process for the preparation of paliperidone intermediates |
CN101440093A (en) * | 2008-12-23 | 2009-05-27 | 上海立科药物化学有限公司 | Process for synthesizing paliperidone intermediate |
CN101870695A (en) * | 2009-04-24 | 2010-10-27 | 上海同昌生物医药科技有限公司 | Preparation method of 3-(2-chloroethyl)-6, 7, 8, 9 - tetrahydro-9 - hydroxy - 2 - Methylenetetrahydrofolate - pyrido [1,2-alpha] pyrimidine -4 - ketone |
CN102126931A (en) * | 2010-12-30 | 2011-07-20 | 广东广益科技实业有限公司 | Preparation method of resveratrol |
CN106220622A (en) * | 2016-06-30 | 2016-12-14 | 广州仁恒医药科技有限公司 | A kind of preparation method of Palmic acid 9-hydroxy-risperidone |
Non-Patent Citations (2)
Title |
---|
帕利哌酮有关物质的合成;汪武卫 等;《中国医药工业杂志》;20161231;第47卷(第3期);269-272、276 * |
帕潘立酮的合成;王超 等;《中国优秀硕士学位论文全文数据库 工程科技Ⅰ辑》;20110715;第B016-265卷(第07期);24、27-30、36-47 * |
Also Published As
Publication number | Publication date |
---|---|
CN117777131A (en) | 2024-03-29 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
Cheng et al. | [4+ 2+ 1] Domino cyclization in water for chemo-and regioselective synthesis of spiro-substituted benzo [b] furo [3, 4-e][1, 4] diazepine derivatives | |
CN109942576B (en) | Irbinitinib and preparation method of intermediate | |
CN108892669B (en) | Method for preparing 2-amino-6-chloropurine | |
AU2008309411B2 (en) | Processes for the preparation of paliperidone and pharmaceutically acceptable salts thereof and intermediates for use in the processes | |
CN111315742B (en) | Process for preparing aminopyrimidine derivatives | |
EP1038875A2 (en) | Imidazopyridine derivatives and process for making them | |
EP1280804B1 (en) | A process for the preparation of anti-psychotic 3- 2- 4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]ethyl]-6,7,8,9-tetrahydro-2-methyl-4h-pyrido 1,2,-a]pyrimidin-4-one | |
CN110183445B (en) | Synthetic method of moxifloxacin and derivatives thereof | |
CN117777131B (en) | Synthesis method of paliperidone and key intermediate thereof | |
JPH0477B2 (en) | ||
CN114685485B (en) | Synthesis method of pyridoimidazole thiopropionic acid anti-gout compound | |
CN113698317A (en) | Synthetic method of apatamide, intermediate and synthetic method thereof | |
CN115109056A (en) | Preparation method of paliperidone | |
NZ540504A (en) | 8-Substituted imidazopyridines for the treatment of gastrointestinal disorders | |
CN108623602A (en) | A method of prepare and purify and replaces Buddhist nun according to Shandong | |
CN107311998B (en) | A kind of preparation method of high-purity 9-hydroxy-risperidone intermediate | |
CN113620957B (en) | Preparation method of aminomethyl pyrazine compound | |
CN101353347B (en) | Preparation of risperidone | |
CN112794849B (en) | Synthetic method of 3- (2-chloroethyl) -2-methyl-4H-pyrido [1,2-a ] pyrimidine-4-ketone | |
EP1758900A1 (en) | Substituted tricyclic benzimidazoles | |
CN113045475A (en) | Preparation method of 5-bromo-7-methylindole | |
CN112979643B (en) | 3- (2-chloroethyl) -9-hydroxy-2-methyl-4H-pyrido [1,2-a ] pyrimidin-4-one | |
CN113929686A (en) | Preparation method of ibrutinib | |
CN111620889A (en) | Preparation method of levofloxacin intermediate | |
CN113264934B (en) | Method for synthesizing 6-alkoxymethyl-benzo [4,5] imidazo [1,2-c ] quinazoline by photocatalysis |
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 |