CN110790747A - Vatalanib succinate intermediate, and synthesis method and application thereof - Google Patents
Vatalanib succinate intermediate, and synthesis method and application thereof Download PDFInfo
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- 238000001308 synthesis method Methods 0.000 title abstract description 11
- YCOYDOIWSSHVCK-UHFFFAOYSA-N vatalanib Chemical compound C1=CC(Cl)=CC=C1NC(C1=CC=CC=C11)=NN=C1CC1=CC=NC=C1 YCOYDOIWSSHVCK-UHFFFAOYSA-N 0.000 title description 3
- 238000006243 chemical reaction Methods 0.000 claims abstract description 42
- -1 1-chloro-4- (4-picolyl) naphthyridine Chemical compound 0.000 claims abstract description 36
- 238000000034 method Methods 0.000 claims abstract description 26
- LGMNBLFPWQROHD-UHFFFAOYSA-N 2-(1-aminoethyl)benzonitrile Chemical compound CC(N)C1=CC=CC=C1C#N LGMNBLFPWQROHD-UHFFFAOYSA-N 0.000 claims abstract description 22
- KDYFGRWQOYBRFD-UHFFFAOYSA-L succinate(2-) Chemical compound [O-]C(=O)CCC([O-])=O KDYFGRWQOYBRFD-UHFFFAOYSA-L 0.000 claims abstract description 13
- 239000007858 starting material Substances 0.000 claims abstract description 4
- 238000001704 evaporation Methods 0.000 claims abstract 2
- 238000001914 filtration Methods 0.000 claims abstract 2
- 239000000376 reactant Substances 0.000 claims description 41
- 238000003756 stirring Methods 0.000 claims description 21
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 18
- CPELXLSAUQHCOX-UHFFFAOYSA-N Hydrogen bromide Chemical compound Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 claims description 18
- 230000015572 biosynthetic process Effects 0.000 claims description 18
- 238000003786 synthesis reaction Methods 0.000 claims description 18
- 238000010438 heat treatment Methods 0.000 claims description 11
- 238000001816 cooling Methods 0.000 claims description 10
- BGUWFUQJCDRPTL-UHFFFAOYSA-N pyridine-4-carbaldehyde Chemical compound O=CC1=CC=NC=C1 BGUWFUQJCDRPTL-UHFFFAOYSA-N 0.000 claims description 10
- HCHKCACWOHOZIP-UHFFFAOYSA-N Zinc Chemical compound [Zn] HCHKCACWOHOZIP-UHFFFAOYSA-N 0.000 claims description 9
- BZRRQSJJPUGBAA-UHFFFAOYSA-L cobalt(ii) bromide Chemical compound Br[Co]Br BZRRQSJJPUGBAA-UHFFFAOYSA-L 0.000 claims description 9
- 229910000042 hydrogen bromide Inorganic materials 0.000 claims description 9
- WBQTXTBONIWRGK-UHFFFAOYSA-N sodium;propan-2-olate Chemical compound [Na+].CC(C)[O-] WBQTXTBONIWRGK-UHFFFAOYSA-N 0.000 claims description 9
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 8
- 239000000203 mixture Substances 0.000 claims description 7
- 230000002194 synthesizing effect Effects 0.000 claims description 7
- 239000002994 raw material Substances 0.000 abstract description 10
- 239000000126 substance Substances 0.000 abstract description 6
- 230000035484 reaction time Effects 0.000 abstract description 5
- 238000003763 carbonization Methods 0.000 abstract description 4
- 238000009776 industrial production Methods 0.000 abstract description 4
- 229910003002 lithium salt Inorganic materials 0.000 abstract description 4
- 159000000002 lithium salts Chemical class 0.000 abstract description 4
- 239000003814 drug Substances 0.000 abstract description 2
- 229940079593 drug Drugs 0.000 abstract description 2
- 239000000047 product Substances 0.000 description 14
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 12
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 description 4
- 239000012065 filter cake Substances 0.000 description 4
- 239000000706 filtrate Substances 0.000 description 4
- 108091008605 VEGF receptors Proteins 0.000 description 3
- 102000009484 Vascular Endothelial Growth Factor Receptors Human genes 0.000 description 3
- 230000009286 beneficial effect Effects 0.000 description 3
- 238000002390 rotary evaporation Methods 0.000 description 3
- LLDWLPRYLVPDTG-UHFFFAOYSA-N vatalanib succinate Chemical compound OC(=O)CCC(O)=O.C1=CC(Cl)=CC=C1NC(C1=CC=CC=C11)=NN=C1CC1=CC=NC=C1 LLDWLPRYLVPDTG-UHFFFAOYSA-N 0.000 description 3
- QSNSCYSYFYORTR-UHFFFAOYSA-N 4-chloroaniline Chemical compound NC1=CC=C(Cl)C=C1 QSNSCYSYFYORTR-UHFFFAOYSA-N 0.000 description 2
- QUSNBJAOOMFDIB-UHFFFAOYSA-N Ethylamine Chemical compound CCN QUSNBJAOOMFDIB-UHFFFAOYSA-N 0.000 description 2
- 238000002474 experimental method Methods 0.000 description 2
- XHXFXVLFKHQFAL-UHFFFAOYSA-N phosphoryl trichloride Chemical compound ClP(Cl)(Cl)=O XHXFXVLFKHQFAL-UHFFFAOYSA-N 0.000 description 2
- 238000005086 pumping Methods 0.000 description 2
- 229940124617 receptor tyrosine kinase inhibitor Drugs 0.000 description 2
- 238000003746 solid phase reaction Methods 0.000 description 2
- 229950000578 vatalanib Drugs 0.000 description 2
- NWZSZGALRFJKBT-KNIFDHDWSA-N (2s)-2,6-diaminohexanoic acid;(2s)-2-hydroxybutanedioic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O.NCCCC[C@H](N)C(O)=O NWZSZGALRFJKBT-KNIFDHDWSA-N 0.000 description 1
- AVORXWIYCOTNFE-UHFFFAOYSA-N 1-azabicyclo[1.1.0]butane Chemical compound C1N2CC21 AVORXWIYCOTNFE-UHFFFAOYSA-N 0.000 description 1
- ACZGCWSMSTYWDQ-UHFFFAOYSA-N 3h-1-benzofuran-2-one Chemical compound C1=CC=C2OC(=O)CC2=C1 ACZGCWSMSTYWDQ-UHFFFAOYSA-N 0.000 description 1
- 206010067484 Adverse reaction Diseases 0.000 description 1
- 206010059866 Drug resistance Diseases 0.000 description 1
- 206010028980 Neoplasm Diseases 0.000 description 1
- 108091008606 PDGF receptors Proteins 0.000 description 1
- LGRFSURHDFAFJT-UHFFFAOYSA-N Phthalic anhydride Natural products C1=CC=C2C(=O)OC(=O)C2=C1 LGRFSURHDFAFJT-UHFFFAOYSA-N 0.000 description 1
- 102000011653 Platelet-Derived Growth Factor Receptors Human genes 0.000 description 1
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 1
- KDYFGRWQOYBRFD-UHFFFAOYSA-N Succinic acid Natural products OC(=O)CCC(O)=O KDYFGRWQOYBRFD-UHFFFAOYSA-N 0.000 description 1
- 238000007259 addition reaction Methods 0.000 description 1
- 230000006838 adverse reaction Effects 0.000 description 1
- 238000007098 aminolysis reaction Methods 0.000 description 1
- 239000002246 antineoplastic agent Substances 0.000 description 1
- 210000000481 breast Anatomy 0.000 description 1
- KDYFGRWQOYBRFD-NUQCWPJISA-N butanedioic acid Chemical compound O[14C](=O)CC[14C](O)=O KDYFGRWQOYBRFD-NUQCWPJISA-N 0.000 description 1
- JHIWVOJDXOSYLW-UHFFFAOYSA-N butyl 2,2-difluorocyclopropane-1-carboxylate Chemical compound CCCCOC(=O)C1CC1(F)F JHIWVOJDXOSYLW-UHFFFAOYSA-N 0.000 description 1
- 239000006227 byproduct Substances 0.000 description 1
- 238000006555 catalytic reaction Methods 0.000 description 1
- 210000004027 cell Anatomy 0.000 description 1
- 239000012295 chemical reaction liquid Substances 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 229940044683 chemotherapy drug Drugs 0.000 description 1
- VXIVSQZSERGHQP-UHFFFAOYSA-N chloroacetamide Chemical compound NC(=O)CCl VXIVSQZSERGHQP-UHFFFAOYSA-N 0.000 description 1
- 210000001072 colon Anatomy 0.000 description 1
- 229940125904 compound 1 Drugs 0.000 description 1
- 238000010586 diagram Methods 0.000 description 1
- YWEUIGNSBFLMFL-UHFFFAOYSA-N diphosphonate Chemical compound O=P(=O)OP(=O)=O YWEUIGNSBFLMFL-UHFFFAOYSA-N 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- IKDUDTNKRLTJSI-UHFFFAOYSA-N hydrazine monohydrate Substances O.NN IKDUDTNKRLTJSI-UHFFFAOYSA-N 0.000 description 1
- 229910052744 lithium Inorganic materials 0.000 description 1
- 238000002844 melting Methods 0.000 description 1
- 230000008018 melting Effects 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 238000010534 nucleophilic substitution reaction Methods 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- DLYUQMMRRRQYAE-UHFFFAOYSA-N phosphorus pentoxide Inorganic materials O1P(O2)(=O)OP3(=O)OP1(=O)OP2(=O)O3 DLYUQMMRRRQYAE-UHFFFAOYSA-N 0.000 description 1
- 230000026731 phosphorylation Effects 0.000 description 1
- 238000006366 phosphorylation reaction Methods 0.000 description 1
- IJAPPYDYQCXOEF-UHFFFAOYSA-N phthalazin-1(2H)-one Chemical group C1=CC=C2C(=O)NN=CC2=C1 IJAPPYDYQCXOEF-UHFFFAOYSA-N 0.000 description 1
- 210000002307 prostate Anatomy 0.000 description 1
- 238000006462 rearrangement reaction Methods 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- 230000019491 signal transduction Effects 0.000 description 1
- 150000003384 small molecules Chemical class 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 238000010189 synthetic method Methods 0.000 description 1
- 210000001519 tissue Anatomy 0.000 description 1
- ILWRPSCZWQJDMK-UHFFFAOYSA-N triethylazanium;chloride Chemical compound Cl.CCN(CC)CC ILWRPSCZWQJDMK-UHFFFAOYSA-N 0.000 description 1
- 230000005747 tumor angiogenesis Effects 0.000 description 1
- 210000003556 vascular endothelial cell Anatomy 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
Images
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C55/00—Saturated compounds having more than one carboxyl group bound to acyclic carbon atoms
- C07C55/02—Dicarboxylic acids
- C07C55/10—Succinic acid
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D237/00—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings
- C07D237/26—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings condensed with carbocyclic rings or ring systems
- C07D237/30—Phthalazines
- C07D237/32—Phthalazines with oxygen atoms directly attached to carbon atoms of the nitrogen-containing ring
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F3/00—Compounds containing elements of Groups 2 or 12 of the Periodic Table
- C07F3/06—Zinc compounds
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pyridine Compounds (AREA)
Abstract
The invention belongs to the technical field of medicines, and particularly relates to a vartanib succinate intermediate, a synthesis method and application thereof, wherein the synthesis method comprises the following steps: 2- (1-aminoethyl) benzonitrile as an initial starting material; and filtering, rotary evaporating and vacuumizing to obtain the 1-chloro-4- (4-picolyl) naphthyridine; the synthesis method of the invention selects 2- (1-aminoethyl) benzonitrile as the initial raw material, the raw material is cheap and easy to obtain, the use of lithium salt is avoided, the carbonization phenomenon is avoided, the reaction steps are few, the reaction time is short, and the industrial production is facilitated. The chemical purity of the product can reach more than 90.582 percent, the yield can reach more than 79.25 percent, and the method has better industrial prospect.
Description
Technical Field
The invention relates to the technical field of medicines, and particularly relates to a vartanib succinate intermediate, and a synthesis method and application thereof.
Background
Vartanib succinate with the chemical name of PTK787, ZK222584, CGP79787D and the like and N- (4-chlorophenyl) -4- (4-picolyl) phthalazin-1-amine succinate is a selective VEGF receptor tyrosine kinase inhibitor cooperatively developed by Novartis and Schering AG company, and can block the phosphorylation process in the VEGF and PDGF receptor signal transduction processes. Pharmacological test results prove that vartanib succinate is a small-molecule VEGF receptor tyrosine kinase inhibitor with strong effect, safety, good tolerance and excellent pharmacokinetic property, and can be orally taken for a long time. Vartanib succinate is currently in the clinical stage T and is used in the treatment of prostate, colon and rectal, renal cell, breast, and the like. Compared with the traditional chemotherapeutic drugs, PTK787 mainly has the following advantages of 1) high oral bioavailability and good tolerance; 2) directly acts on tumor vascular endothelial cells to inhibit tumor angiogenesis; 3) drug resistance is not easy to generate; 4) has slight influence on normal tissues and small adverse reaction. The 1-chloro-4- (4-picolyl) naphthyridine is a key intermediate for synthesizing vartanib succinate, and has wide market prospect.
At present, the synthesis process of vartanib succinate reported at home and abroad mainly comprises two methods:
one method is that phthalic anhydride is used as raw material, and is rearranged after reacting with 4 pyridine methyl lithium to generate an intermediate; the 1 st route uses expensive reagent lithium salt, so the method is not suitable for popularization;
and the other is that the benzofuranone is taken as a starting material, the intermediate 3 is generated after the addition and rearrangement reaction with 4 pyridine formaldehyde, the intermediate 3 is reacted with hydrazine hydrate to generate a phthalazinone ring intermediate 4, the intermediate is sequentially subjected to substitution reaction with phosphorus oxychloride, aminolysis reaction with 4 chloroaniline and salt forming reaction with succinic acid, and the target compound 1 can be prepared. And (3) dehydrating the intermediate 3 under the catalysis of triethylamine hydrochloride and phosphorus pentoxide, carrying out solid-phase reaction by melting at 200 ℃, and carrying out nucleophilic substitution reaction with parachloroaniline to directly obtain an intermediate 5. The high-temperature solid-phase reaction condition is not easy to control, the reactants are too viscous after being melted to be beneficial to stirring, and the carbonization phenomenon often occurs.
Disclosure of Invention
The invention aims to provide a vartanib succinate intermediate, and a synthesis method and application thereof.
In order to solve the technical problem, the invention provides a method for synthesizing 1-chloro-4- (4-picolyl) naphthyridine, which comprises the following steps: 2- (1-aminoethyl) benzonitrile as an initial starting material; and rotary evaporation and vacuum pumping are carried out to obtain the 1-chloro-4- (4-picolyl) naphthyridine.
Further, the reaction formula of the first reaction is as follows:
further, the first reaction comprises: dropwise adding hydrogen bromide into absolute ethyl alcohol, and stirring; adding 2- (1-aminoethyl) benzonitrile, heating, adding sodium isopropoxide, and continuing stirring; and cooling and standing to obtain a first reactant.
Further, the mole ratio of the 2- (1-aminoethyl) benzonitrile, sodium isopropoxide and hydrogen bromide is 1: 2-2.5: 3-5.
Further, the reaction formula of the second reaction is:
further, the second reaction comprises: heating and stirring a mixture of zinc powder and anhydrous acetonitrile, and cooling; and adding the first reactant and cobalt bromide and continuously stirring to obtain a second reactant.
Furthermore, the molar ratio of the 2- (1-aminoethyl) benzonitrile, the zinc powder and the cobalt bromide is 1:0.2-0.4: 0.1-0.2.
Further, the reaction formula of the third reaction is:
further, the third reaction comprises: adding 4-pyridylaldehyde into the second reactant, and heating and stirring; and cooling to room temperature.
Further, the molar ratio of the 2- (1-aminoethyl) benzonitrile to the 4-pyridinecarboxaldehyde is 1: 1-1.2.
In yet another aspect, the present invention provides a 1-chloro-4- (4-picolyl) naphthyridine, wherein the structural formula of the 1-chloro-4- (4-picolyl) naphthyridine is:
in a third aspect, the present invention also provides a first reactant for the synthesis of 1-chloro-4- (4-picolyl) naphthyridine, the first reactant having the formula:
in a fourth aspect, the present invention also provides a second reactant for the synthesis of 1-chloro-4- (4-picolyl) naphthyridine, the second reactant having the formula:
in a fifth aspect, the invention also provides application of the 1-chloro-4- (4-picolyl) naphthyridine as an intermediate for synthesizing vartanib succinate.
The synthesis method has the beneficial effects that ethylamine and chloroacetamide are used as initial raw materials, the raw materials are cheap and easy to obtain, the synthesis of an intermediate 1-azabicyclo [1.1.0] butane is avoided, the reaction steps are few, the reaction time is short, and the industrial production is facilitated. The chemical purity of the product can reach more than 90.44 percent, the yield can reach more than 79.13 percent, and the method has better industrial prospect.
Drawings
The invention is further illustrated with reference to the following figures and examples.
FIG. 1 is a process flow diagram of the synthetic method of the present invention.
Detailed Description
To make the objects, technical solutions and advantages of the embodiments of the present invention clearer, the technical solutions of the present invention will be clearly and completely described below with reference to the accompanying drawings, and it is apparent that the described embodiments are some, but not all embodiments of the present invention. All other embodiments, which can be derived by a person skilled in the art from the embodiments given herein without making any creative effort, shall fall within the protection scope of the present invention.
Example 1
As shown in fig. 1, this example 1 provides a method for synthesizing 1-chloro-4- (4-picolyl) naphthyridine, which includes the following steps: step S1, carrying out multiple reactions in sequence by taking 2- (1-aminoethyl) benzonitrile as an initial raw material; and step S2, performing rotary evaporation and vacuumizing to obtain the 1-chloro-4- (4-picolyl) naphthyridine.
Specifically, in the synthesis method of embodiment 1, 2- (1-aminoethyl) benzonitrile is used as an initial raw material, which is cheap and easy to obtain, so that the use of lithium salt is avoided, the carbonization phenomenon is avoided, the reaction steps are few, the reaction time is short, and the method is beneficial to industrial production. The chemical purity of the product can reach more than 90.582 percent, the yield can reach more than 79.25 percent, and the method has better industrial prospect.
Further, the reaction formula of the first reaction is as follows:
as an alternative to the first reaction.
The first reaction comprises the following steps: adding hydrogen bromide into absolute ethyl alcohol dropwise, keeping the temperature at 30-40 ℃, adding 2- (1-aminoethyl) benzonitrile into the absolute ethyl alcohol under the condition of a stirring speed of 2000 r/min, heating to 60-70 ℃, adding sodium isopropoxide, increasing the speed to 5000-.
Further, the mole ratio of the 2- (1-aminoethyl) benzonitrile, sodium isopropoxide and hydrogen bromide is 1: 2-2.5: 3-5.
Further, the reaction formula of the second reaction is:
as an alternative embodiment of the second reaction.
The second reaction comprises the following steps: adding zinc powder and anhydrous acetonitrile into a flask, heating to 50-55 ℃, stirring for 0.5 hour, cooling by using a water bath with the temperature of 20 ℃ for 25-30 ℃, keeping the water bath cool, sequentially adding a first reactant and cobalt bromide, and continuously stirring the obtained mixture for 0.5 hour to obtain a second reactant.
Furthermore, the molar ratio of the 2- (1-aminoethyl) benzonitrile, the zinc powder and the cobalt bromide is 1:0.2-0.4: 0.1-0.2.
Further, the reaction formula of the third reaction is:
as an alternative embodiment of the third reaction.
The third reaction comprises: keeping the water bath cool, adding 4-pyridylaldehyde into the second reactant, heating to 75-80 ℃, stirring for 3 hours, and cooling to room temperature.
Specifically, the reaction liquid after the third reaction is filtered, tert-butyl methyl ether is used for washing a filter cake, filtrate is subjected to rotary evaporation, and vacuum pumping is performed at the temperature of 60 ℃ for 24 hours to obtain the required product 1-chloro-4- (4-picolyl) naphthyridine.
Further, the molar ratio of the 2- (1-aminoethyl) benzonitrile to the 4-pyridinecarboxaldehyde is 1: 1-1.2.
Further, the third reactant was rotary evaporated and then vacuumed at 60 ℃ for 24 hours to obtain 1-chloro-4- (4-picolyl) naphthyridine.
Example 2
Based on example 1, this example 2 provides 1-chloro-4- (4-picolyl) naphthyridine, wherein the structural formula of the 1-chloro-4- (4-picolyl) naphthyridine is:
for the content and specific implementation of 1-chloro-4- (4-picolyl) naphthyridine, reference is made to the discussion of example 1, which is not repeated here.
Example 3
Based on example 1, this example 3 provides a first reactant for the synthesis of 1-chloro-4- (4-picolyl) naphthyridine, the first reactant having the formula:
for the contents of the components of the first reactant and the specific implementation process, refer to the related discussion of example 1, and are not repeated here.
Example 4
Based on example 1, this example 4 provides a second reactant for the synthesis of 1-chloro-4- (4-picolyl) naphthyridine, the second reactant having the formula:
for the contents of the components of the second reactant and the specific implementation process, refer to the related discussion of example 1, and are not repeated here.
Example 5
Based on example 1, this example 5 provides the use of 1-chloro-4- (4-picolyl) naphthyridine as an intermediate for the synthesis of vartanib succinate.
For the content and specific implementation of 1-chloro-4- (4-picolyl) naphthyridine, reference is made to the discussion of example 1, which is not repeated here.
Example 6
Example 6 illustrates three experiments in which the influence of purity and yield of 1-chloro-4- (4-picolyl) naphthyridine, the product of the three experiments, was investigated, as shown in table 1.
TABLE 1 component content and product yield
Group 1
(1) 242.7g of hydrogen bromide is added into 500ml of absolute ethyl alcohol drop by drop, the temperature is kept at 30 ℃, 148g of 2- (1-aminoethyl) benzonitrile is added under the condition of stirring speed of 2000 r/min, the temperature is increased to 60 ℃, 164g of sodium isopropoxide is added, the speed is increased to 5000 r/min, stirring is continued for 2 hours, the temperature is cooled to 20 ℃, and the mixture is kept stand for 2 hours, so that a first reactant is obtained;
(2) 13g of zinc powder and 300ml of anhydrous acetonitrile were charged into a flask, heated to 50 ℃ and stirred for 0.5 hour, then cooled to 25 ℃ using a 20 ℃ water bath, and the water bath was kept cooled, and the first reactant and 23.68g of cobalt bromide were added in this order. The resulting mixture was stirred for an additional 0.5 hours to obtain a second reactant.
(3) The water bath was kept cool and 107g of 4-pyridinecarboxaldehyde was added to the second reactant, which was heated to 75 ℃ and stirred for 3 hours, cooled to room temperature, filtered, the filter cake was rinsed with tert-butyl methyl ether, the filtrate was rotary evaporated, and a vacuum was applied at 60 ℃ for 24 hours to give the desired product, 1-chloro-4- (4-picolyl) naphthyridine. (the obtained product, 1-chloro-4- (4-picolyl) naphthyridine, has the mass of 223.7g, the purity of 90.582% and the yield of 79.25%).
Group 2
(1) Adding 323.6g of hydrogen bromide into 500ml of absolute ethyl alcohol dropwise, keeping the temperature at 35 ℃, adding 148g of 2- (1-aminoethyl) benzonitrile into the solution under the condition of a stirring speed of 2000 revolutions per minute, heating to 65 ℃, adding 180.4g of sodium isopropoxide, increasing the speed to 5000 revolutions per minute, continuing stirring for 2 hours, cooling to 25 ℃, and standing for 2 hours to obtain a first reactant;
(2) 19.5g of zinc powder and 300ml of anhydrous acetonitrile were charged into a flask, heated to 52 ℃ and stirred for 0.5 hour, then cooled to 28 ℃ using a 20 ℃ water bath, and the water bath was kept cooled, and the first reactant and 35.51g of cobalt bromide were added in this order. The resulting mixture was stirred for an additional 0.5 hours to obtain a second reactant.
(3) The water bath was kept cool and 117.7g of 4-pyridinecarboxaldehyde were added to the second reactant, heated to 78 ℃ and stirred for 3 hours, cooled to room temperature, filtered, the filter cake was rinsed with tert-butyl methyl ether, the filtrate was rotary evaporated and evacuated at 60 ℃ for 24 hours to give the desired product 1-chloro-4- (4-picolyl) naphthyridine. (the obtained product, 1-chloro-4- (4-picolyl) naphthyridine, has the mass of 225.71g, the purity of 90.859 percent and the yield of 79.95 percent).
Group 3
(1) Adding 404.5g of hydrogen bromide into 500ml of absolute ethyl alcohol dropwise, keeping the temperature at 40 ℃, adding 148g of 2- (1-aminoethyl) benzonitrile into the absolute ethyl alcohol under the condition of a stirring speed of 2000 r/min, heating to 70 ℃, adding 205g of sodium isopropoxide, increasing the speed to 6000 r/min, continuing stirring for 2 hours, cooling to 30 ℃, and standing for 2 hours to obtain a first reactant;
(2) 26g of zinc powder and 300ml of anhydrous acetonitrile were charged into a flask, heated to 55 ℃ and stirred for 0.5 hour, then cooled to 30 ℃ using a 20 ℃ water bath, and the water bath was kept cooled, and the first reactant and 47.35g of cobalt bromide were added in this order. The resulting mixture was stirred for an additional 0.5 hours to obtain a second reactant.
(3) The water bath was kept cool, 128.4g of 4-pyridinecarboxaldehyde was added to the second reactant, heated to 80 ℃ and stirred for 3 hours, cooled to room temperature, filtered, the filter cake was rinsed with tert-butyl methyl ether, the filtrate was rotary evaporated, and a vacuum was applied at 60 ℃ for 24 hours to give the desired product, 1-chloro-4- (4-picolyl) naphthyridine. (the obtained product, 1-chloro-4- (4-picolyl) naphthyridine, has a mass of 225g, a purity of 92.330% and a yield of 81.25%).
In conclusion, the vartanib succinate intermediate and the synthesis method and application thereof select 2- (1-aminoethyl) benzonitrile as an initial raw material, sequentially carry out multiple reactions in combination with subsequently added reactants, and finally synthesize the 1-chloro-4- (4-picolyl) naphthyridine, wherein the reaction rate can be effectively improved and the reaction time can be shortened by controlling the reaction conditions (such as reaction conditions, reactant adding time, reaction temperature and the like) of each reaction; by reasonably setting the component content proportion of each raw material, the purity and yield of the product can be effectively improved. Therefore, the synthesis method has the advantages of cheap and easily-obtained raw materials, easy treatment of byproducts, short reaction time, high chemical purity of the product, high yield and the like, particularly the chemical purity of the product can reach more than 90.582%, and the yield can reach more than 79.25%, so that the method is very suitable for large-scale industrial production and has better industrial prospect. In addition, the high-purity 1-chloro-4- (4-picolyl) naphthyridine is more suitable to be used as an important intermediate for synthesizing vartanib succinate, so that the use of lithium salt is avoided, and the carbonization phenomenon is avoided.
In light of the foregoing description of the preferred embodiment of the present invention, many modifications and variations will be apparent to those skilled in the art without departing from the spirit and scope of the invention. The technical scope of the present invention is not limited to the content of the specification, and must be determined according to the scope of the claims.
Claims (14)
1. A method for synthesizing 1-chloro-4- (4-picolyl) naphthyridine, which is characterized by comprising the following steps:
2- (1-aminoethyl) benzonitrile as an initial starting material; and
filtering, rotary evaporating and vacuumizing to obtain the 1-chloro-4- (4-picolyl) naphthyridine.
2. The method of synthesis according to claim 1,
the reaction formula of the first reaction is as follows:
3. the method of synthesis according to claim 1,
the first reaction comprises the following steps:
dropwise adding hydrogen bromide into absolute ethyl alcohol, and stirring;
adding 2- (1-aminoethyl) benzonitrile, heating, adding sodium isopropoxide, and continuing stirring; and
and cooling and standing to obtain a first reactant.
4. The method of synthesis according to claim 3,
the mole ratio of the 2- (1-aminoethyl) benzonitrile, sodium isopropoxide and hydrogen bromide is 1: 2-2.5: 3-5.
5. The method of synthesis according to claim 1,
the reaction formula of the second reaction is as follows:
6. the method of synthesis according to claim 3,
the second reaction comprises the following steps:
heating and stirring a mixture of zinc powder and anhydrous acetonitrile, and cooling; and
adding the first reactant and cobalt bromide, and continuously stirring to obtain a second reactant.
7. The method of synthesis according to claim 6,
the molar ratio of the 2- (1-aminoethyl) benzonitrile, the zinc powder and the cobalt bromide is 1:0.2-0.4: 0.1-0.2.
8. The method of synthesis according to claim 1,
the reaction formula of the third reaction is as follows:
9. the method of synthesis according to claim 6,
the third reaction comprises:
adding 4-pyridylaldehyde into the second reactant, and heating and stirring;
and cooling to room temperature.
10. The method of synthesis according to claim 9,
the molar ratio of the 2- (1-aminoethyl) benzonitrile to the 4-pyridinecarboxaldehyde is 1: 1-1.2.
11. 1-chloro-4- (4-picolyl) naphthyridine characterized in that,
the structural formula of the 1-chloro-4- (4-picolyl) naphthyridine is as follows:
12. a first reactant for the synthesis of 1-chloro-4- (4-picolyl) naphthyridine,
the structural formula of the first reactant is:
13. a second reactant for the synthesis of 1-chloro-4- (4-picolyl) naphthyridine,
the structural formula of the second reactant is:
14. an application of 1-chloro-4- (4-picolyl) naphthyridine as an intermediate for synthesizing vartanib succinate.
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