CN109705117A - Tricyclic compounds, preparation method and the usage - Google Patents
Tricyclic compounds, preparation method and the usage Download PDFInfo
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Abstract
The invention belongs to medicinal chemistry arts, N- (2- ((2- (dimethylamino) ethyl) (methyl) amino) -4- methoxyl group -5- ((4- (6 is used for more particularly to tricyclic compounds, preparation method and its as control comparisons product, 7,8,9- tetrahydropyridine simultaneously [1,2-a] indoles -10- base) pyrimidine -2-base) amino) phenyl) related impurities are qualitative in allyl amide methane sulfonates bulk pharmaceutical chemicals quality research and/or the purposes of quantitative analysis.
Description
Technical field
The invention belongs to medicinal chemistry arts, and in particular to tricyclic compounds, preparation method and its as reference pair
N- (2- ((2- (dimethylamino) ethyl) (methyl) amino) -4- methoxyl group -5- ((4- (6,7,8,9- tetrahydro pyrrole is used for according to product
Pyridine simultaneously [1,2-a] indoles -10- base) pyrimidine -2-base) amino) phenyl) in allyl amide methane sulfonates bulk pharmaceutical chemicals quality research
Related impurities are qualitative and/or the purposes of quantitative analysis.
Background technique
EGF-R ELISA (EGFR) is the transmembrane protein tyrosine kinase members of erbB receptor family.ErbB receptor
Homologous dimerization and/or heterodimeric lead to the phosphorylation of key tyrosine residue in Intracellular domain, stimulation participate in cell Proliferation and
Many Cellular Signaling Transduction Mediated accesses of existence.The imbalance of erbB family signal transduction promotes proliferation, intrusion, transfer, blood vessel raw
It survives at tumour cell, and has been described in many cancers, such as lung cancer, head-neck carcinoma and breast cancer etc..Small point
Sub- EGFR tyrosine kinase inhibitor and ATP competitive binding inhibit EGFR from process phosphoric acid to EGFR intracellular region phosphorylation site
And downstream signaling pathway is blocked, to achieve the purpose that inhibit tumour cell.
Gefitinib, Tarceva are the reversible micromolecular inhibitors of the first generation of EGFR, are mainly used for treating non-small cell
Lung cancer.But clinical research shows that many patients just generate anti-medicine to these EGFR micromolecular inhibitors quickly (12-14 months)
Property.Research shows that residue T790M mutation of guarding the gate is EGFR gene 20 exon, one catastrophe point, it is the master for causing drug resistance to generate
Want one of mechanism.Second generation irreversible inhibitor, as Afatinib have to the EGFR that L858R and T790M are mutated it is very strong
Inhibiting effect has significant curative effect to the patient that Gefitinib or Tarceva have developed drug resistance.However second generation EGFR
Mutant inhibitor similarly has very strong inhibiting effect to Wild type EGFR, so as to cause most of in treatment clinical course
Patient generates toxic side effect, for example fash, diarrhea.
Therefore third generation EGFR inhibitor should be kept to EGFR firstL858RActivated mutant body, Exon19 lack activated mutant
Body and T790M resistant mutants have stronger inhibiting effect, while should overcome the toxic side effect of second generation inhibitor, that is, reduce
To the inhibiting effect of Wild type EGFR.Compound AZD9291 (also known as N- (the 2- of Astrazeneca AB (AstraZeneca) research and development
{ 2- dimethylaminoethyl-methylamino } -4- methoxyl group -5- { [4- (1- methyl indol -3- base) pyrimidine -2-base] amino } phenyl)
Propyl- 2- acrylamide) it is a kind of oral, irreversible EGFR inhibitor, which is mutated positive non-small cell to EGFR-T790M
Patients with lung cancer has preferable therapeutic effect.But its metabolin AZ5104 also has very strong inhibiting effect to Wild type EGFR.
Therefore, the new E GFR inhibitor that exploitation has more preferable drug effect is still needed to.The inventors of the present invention discovered through researches that the compound of formula A is
A kind of irreversible new E GFR kinase inhibitor.
The chemical name of formula A compound is N- (2- ((2- (dimethylamino) ethyl) (methyl) amino) -4- methoxyl group -
5- ((4- (6,7,8,9- tetrahydropyridine simultaneously [1,2-a] indoles -10- base) pyrimidine -2-base) amino) phenyl) allyl amide.In vitro
Kinase activity detects discoverable type A compound to mutant egf R kinases, such as EGFRL858R/T790MKinases is lived with good inhibition
Property, IC50Value is less than 1nM, small on the influence of Wild type EGFR kinases, has preferable selectivity.In vitro cell experiment the result shows that
The compound of formula A is preferable to the inhibiting effect of double-mutant cell, and small to the inhibition of EGFR wild-type cell, and selectivity is good.
Further study show that formula A compound methane sulfonates good water solubility, bioavilability are high, this will be helped the present inventor
In raising clinical efficacy and reduction adverse reaction etc..
It is well known that, for safety factor requirement, internal and international management organization is to bulk pharmaceutical chemicals for human administration
(API) it is not confirmed in or the limit of the uncertain impurity of toxicity provides very low, usually less than 0.1% (weight).It needs heavy to these
It wants impurity to be furtherd investigate, meets medicinal standard to ensure to be prepared, can be used in preparation safely and effectively pharmaceutical preparation
Bulk pharmaceutical chemicals.Impurity in bulk pharmaceutical chemicals may be the degradation due to itself and generate, it is also possible to derive from preparation method, example
Such as, chemical derivative, synthesising by-product and degradation including the impurity for including in unreacted starting material, starting material
Product etc..By understanding the chemical structure and route of synthesis of impurity, and the ginseng by identifying impurity content in influence final product
Number, can greatly enhance the control to related impurities.
N- (2- ((2- (dimethylamino) ethyl) (methyl) amino) -4- methoxyl group -5- ((4- (6,7,8,9- tetrahydro pyrrole
Pyridine simultaneously [1,2-a] indoles -10- base) pyrimidine -2-base) amino) phenyl) allyl amide methane sulfonates may wrap as bulk pharmaceutical chemicals
Impurity containing a variety of sources brings hidden danger to its druggability, safety and validity.Therefore, its by-product or impurity are studied
Property carries out detection control to these by-products or impurity and is of great significance.
Summary of the invention
The first purpose of the invention is to provide formula B, formula C, formula D, formula E, formula F, formula G, formula H or Formulas I compounds represented
Or its hydrate, solvate or crystallization:
Preferably, formula B, formula C, formula D, formula E, formula F, formula G, formula H, compound of formula I or its hydrate, solvent of preparation are separated
Object or crystallization are closed respectively comprising the formula A compound (judging according to HPLC, area normalization method) less than 1%, or separates preparation
Formula B, formula C, formula D, formula E, formula F, formula G, formula H, compound of formula I or its hydrate, solvate or the purity of crystallization are at least
85% (being judged according to HPLC, area normalization method).In some embodiments, formula B, formula C, formula D, the formula E, formula of preparation are separated
F, formula G, formula H, compound of formula I or its hydrate, solvate or the purity of crystallization are at least 90% and (are judged according to HPLC, face
Product normalization method).In other embodiments, formula B, formula C, formula D, formula E, formula F, formula G, formula H, the Formulas I chemical combination of preparation are separated
The purity of object or its hydrate, solvate or crystallization is at least 95% (judging according to HPLC, area normalization method).Another
In a little embodiments, formula B, formula C, formula D, formula E, formula F, formula G, formula H, compound of formula I or its hydrate of preparation are separated, solvent closes
Object or the purity of crystallization are at least 98% (judging according to HPLC, area normalization method).In other embodiments, separation system
Standby formula B, formula C, formula D, formula E, formula F, formula G, formula H, compound of formula I or its hydrate, solvate or the purity of crystallization are at least
For 99% (being judged according to HPLC, area normalization method).
A second object of the present invention is to provide formula B, formula C, formula D, formula E, formula F, formula G, formula H and compound of formula I or its water
Close object, solvate or the preparation method of crystallization:
The preparation method of the formula B compound or its hydrate, solvate or crystallization includes depositing in alkaline reagent
Under, make N1(2- (dimethylamino) ethyl) -5- methoxyl group-N1Methyl-N4((6,7,8,9- tetrahydropyridine is simultaneously [1,2-a] by 4-
Indoles -10- base) pyrimidine -2-base) benzene -1,2,4- triamine and acryloyl chloride the step of reacting.In some specific embodiments
In, wherein the preferred inorganic base of alkaline reagent or organic base, the inorganic base or organic base are selected from sodium carbonate, bicarbonate
One or more of sodium, potassium carbonate, triethylamine, n,N-diisopropylethylamine, further preferably n,N-diisopropylethylamine.
In some specific embodiments, the present invention provides formula B compound or its hydrate, solvate or crystallization
Preparation method, wherein reaction dissolvent is n,N-dimethylacetamide.
The preparation method of the formula C compound or its hydrate, solvate or crystallization includes the following steps:
1) compound of formula C-1 is reacted with methylamine, and the compound of formula C-2 is made；
2) compound of formula C-2 reacts the compound that formula C-3 is made with amino protecting agent, wherein R1For amino protecting group；
3) compound of formula C-4 is made through reduction reaction for the nitro on the compound of formula C-3；
4) compound of formula C-4 reacts the compound that formula C-5 is made with acryloyl halide；
5) compound of formula C-5 is through removing the compound of amino protecting group production C.
Wherein, the amino protecting agent is the reagent for introducing amino protecting group, and the amino protecting group is such as
Trimethyl silicon substrate, trimethyl silicane base oxethyl, benzyloxycarbonyl group, tertbutyloxycarbonyl, 2- xenyl -2- propylene carbonyl oxygen, tablet held before the breast by officials methoxy carbonyl
Base, formoxyl, trifluoroacetyl group, trityl, benzyl etc., preferably tertbutyloxycarbonyl；The reduction reaction can be also
It is carried out in substance system such as hydrogen-palladium/carbon, iron powder/ammonium chloride；The acryloyl halide is propylene acyl fluorides, acryloyl chloride, acryloyl
Bromine, propylene acyl iodides, preferably acryloyl chloride and propylene acylbromide.
The preparation method of the formula D compound or its hydrate, solvate or crystallization includes the following steps:
1) compound of formula C-1 reacts the compound that formula D-2 is made with the compound of formula D-1, wherein R1For amido protecting
Base has definition described above；
2) compound of formula D-3 is made through reduction reaction for the nitro on the compound of formula D-2；
3) compound of formula D-3 reacts the compound that formula D-5 is made with the compound of formula D-4, wherein X1、X2It is respectively independent
Ground is selected from fluorine, chlorine, bromine and iodine；
4) then formula D-5 compound reacts production D compound through removing amino protecting group with trifluoroacetic acid.
The preparation method of the formula E compound or its hydrate, solvate or crystallization includes making N- (2- ((2- (two
Methylamino) ethyl) (methyl) amino) -4- methoxyl group -5- ((4- (6,7,8,9- tetrahydropyridine simultaneously [1,2-a] indoles -10-
Base) pyrimidine -2-base) amino) phenyl) allyl amide the step of carrying out oxidation reaction, wherein the oxidation reaction passes through addition
Oxidising agent occurs, it is preferable that the oxidising agent includes but is not limited to hydrogen peroxide and metachloroperbenzoic acid, preferably
30% hydrogen peroxide.
The compound of the formula F or the preparation method of its hydrate, solvate or crystallization include making N1(2- (diformazan
Amino) ethyl) -5- methoxyl group-N1Methyl-N4(4- (6,7,8,9- tetrahydropyridine simultaneously [1,2-a] indoles -10- base) pyrimidine -2-
Base) benzene -1,2,4- triamine the step of being reacted with 3- chlorpromazine chloride.
The compound of the formula G or the preparation method of its hydrate, solvate or crystallization include the following steps:
1) compound of formula G-1 reacts the compound that formula G-3 is made with the compound of formula G-2；
2) compound of formula G-3 reacts the compound that formula G-5 is made with the compound of formula G-4；
3) compound of formula G-5 reacts the compound that formula G-7 is made with the compound of formula G-6；
4) compound of formula G-8 is made through reduction reaction for the compound of formula G-7；
5) compound of formula G-8 reacts the compound that formula G is made with the compound of formula G-9, wherein X3、X4Each independently
Selected from fluorine, chlorine, bromine and iodine.
In some preferred embodiments, the compound of formula G-1 and the compound of formula G-2 in glycol dimethyl ether,
React the compound of obtained formula G-3 under the catalysis of anhydrous aluminum chloride；The compound of the compound of formula G-3 and formula G-4 are secondary
In butanol, under the catalysis of one water object of p-methyl benzenesulfonic acid, the compound for the obtained formula G-5 that reacts；The compound and formula of formula G-5
The compound of G-6 is in n,N-dimethylacetamide, and under the action of n,N-diisopropylethylamine, react obtained formula G-7
Compound；The compound of G-8 reacts in n,N-dimethylacetamide with the compound of formula G-9, then in the work of triethylamine
It is generated with lower removing hydrogen chloride and reacts the compound that formula G is made.
The compound of the formula H or the preparation method of its hydrate, solvate or crystallization include: in alkaline reagent
Under, make N1(2- (dimethylamino) ethyl) -5- methoxyl group-N1Methyl-N4(4- (6,7,8,9- tetrahydropyridine simultaneously [1,2-a] Yin
Diindyl -10- base) pyrimidine -2-base) benzene -1,2,4- triamine and the step of acetic anhydride.In some specific embodiments,
Described in the preferred inorganic base of alkaline reagent or organic base, the inorganic base or organic base are selected from sodium carbonate, sodium bicarbonate, carbon
One or more of sour potassium, triethylamine, n,N-diisopropylethylamine, further preferably triethylamine.
The preparation method of the compound of the Formulas I or its hydrate, solvate or crystallization includes the following steps:
1) compound of formula G-1 reacts the compound that Formulas I -1 is made with the compound of formula G-2；
2) compound of Formulas I -1 reacts the compound that Formulas I -2 is made with the compound of formula G-4；
3) compound of Formulas I -2 reacts the compound that Formulas I -3 is made with the compound of formula G-6；
4) compound of Formulas I -4 is made through reduction reaction for the compound of Formulas I -3；
5) compound of Formulas I -4 reacts in n,N-dimethylacetamide with 3- chlorpromazine chloride, then in the work of triethylamine
With lower removing hydrogen chloride, the reaction mother liquor is taken, using preparation chromatography, isolates and purifies the compound of obtained Formulas I.
In some preferred embodiments, catalysis of the compound of the compound of formula G-1 and formula G-2 in anhydrous aluminum chloride
Under, it in glycol dimethyl ether, reacts, the compound of Formulas I -1 is made；The compound of Formulas I -1 and the compound of formula G-4 exist
It under the catalysis of one water object of p-methyl benzenesulfonic acid, in sec-butyl alcohol, reacts, the compound of Formulas I -2 is made；The compound of Formulas I -2
Compound with formula G-6 is under the action of n,N-diisopropylethylamine, in n,N-dimethylacetamide, reacts, and is made
The compound of Formulas I -3；The chemical combination of Formulas I -4 is made through reduction reaction under the action of iron powder and ammonium chloride for the compound of Formulas I -3
Object；The compound of Formulas I -4 reacts in n,N-dimethylacetamide with 3- chlorpromazine chloride, then removes under the action of triethylamine
Hydrogen chloride takes the reaction mother liquor, using preparation chromatography, isolates and purifies the compound of obtained Formulas I.
Third object of the present invention is to provide be used as by-product in a kind of positioning, quantitative A compound methane sulfonates
Formula B, formula C, formula D, formula E, formula F, formula G, formula H and Formulas I compound HPLC method.When formula A compound methane sulfonates are made
When for production of raw medicine, may exist in product a certain amount of as the formula B of by-product, formula C, formula D, formula E, formula F, formula G, formula
H and compound of formula I.For the requirement for meeting drug, need to detect and control the formula B as impurity, formula C, formula D, formula E, formula F, formula
G, the content of formula H and compound of formula I.Therefore, formula B, formula C, formula D, formula E, formula F, formula G, formula H and compound of formula I can be used as ginseng
It can be used for formula applied to the ownership and positioning of related impurities in HPLC method analysis mode A compound methane sulfonates than reference substance
Quantitative point in A compound methane sulfonates as the formula B of by-product, formula C, formula D, formula E, formula F, formula G, formula H and compound of formula I
Analysis and for formula A compound methane sulfonates quality analysis.It is of the invention it is described using formula B, formula C, formula D, formula E, formula F,
The HPLC method of formula G, formula H and compound of formula I analysis mode A compound methane sulfonates the following steps are included:
1) the respectively positioning containing formula B, formula C, formula D, formula E, formula F, formula G, formula H, Formulas I, formula A compound methane sulfonates is prepared
Solution；
2) prepare containing formula B, formula C, formula D, formula E, formula F, formula G, formula H, Formulas I and formula A compound methane sulfonates system
Applicability solution；With
3) pass through high-efficient liquid phase color using system suitability solution made from step 1) positioning solution obtained and step 2)
Spectrometry separate type B, formula C, formula D, formula E, formula F, formula G, formula H, Formulas I and formula A compound methane sulfonates, and determine formula B, formula C, formula
D, position and the content of formula E, formula F, formula G, formula H, Formulas I and formula A compound methane sulfonates.
It is according to the present invention to utilize formula B, formula C, formula D, formula E, formula F, formula G, formula H, formula in some specific embodiments
The HPLC method of I and formula A compound methane sulfonates, wherein the preparation method packet of the system suitability solution of step 2)
It includes:
I) accurately weighed formula B, formula C, formula D, formula E, formula F, formula G, formula H and compound of formula I, are dissolved with alcohols solvent respectively,
Obtain eight parts of solution；With
II) accurately weighed formula A compound methane sulfonates, are dissolved with alcohols solvent, add step I) made from eight parts
Solution is diluted with alcohols solvent again later, obtains system suitability solution,
Wherein the alcohols solvent is preferably methanol, ethyl alcohol, propyl alcohol or isopropanol, more preferably methanol.
Herein, formula B, formula C, formula D, formula E, formula F, formula G, formula H, Formulas I and formula A compound methane sulfonates further include institute
State hydrate, solvate, crystallization or the pharmaceutically acceptable salt of compound.
Detailed description of the invention
Fig. 1 is the HPLC of formula A compound methane sulfonates and impurity formula C, formula D, formula E, formula G, formula H compound mixing sample introduction
Map, wherein 12.467min is formula A compound methane sulfonates, and 8.286min is impurity formula C compound, and 7.754min is miscellaneous
Matter formula D compound, 4.898min are impurity formula E compound, and 12.009min is impurity formula G compound, and 10.029min is impurity
Formula H compound, 13.106min are impurity F compound.
Specific embodiment
The present invention is further elaborated below with reference to embodiment, but the present invention is not limited to these Examples.Below
Material used in embodiment is commercially available unless otherwise specified.
Embodiment 1N- (2- ((2- (dimethylamino) ethyl) (methyl) amino) -4- methoxyl group -5- ((4- (6,7,8,9-
Tetrahydropyridine simultaneously [1,2-a] indoles -10- base) pyrimidine -2-base) amino) phenyl) allyl amide methane sulfonates preparation
The synthesis of step 1:10- (2- chlorine pyrimidine-4-yl) -6,7,8,9- tetrahydropyridine simultaneously [1,2-a] indoles
In the vertical jacketed glass kettle of 100L, it is added glycol dimethyl ether (39.15kg) and 2,4- dichloro pyrimidine
Solidliquid mixture is cooled to 10 DEG C hereinafter, being added portionwise anhydrous aluminum chloride (3.855kg) by (3.915kg), and speed is added in control
Degree, temperature are not higher than 30 DEG C.Addition finishes, 25 ± 5 DEG C stir 30 minutes, be then added 6,7,8,9- tetrahydropyridines simultaneously [1,
2-a] indoles (4.500kg), heating reacts 3 hours at 60 ± 5 DEG C, and HPLC is monitored to 6,7,8,9- tetrahydropyridines simultaneously [1,2-
A] indoles content be no more than 1.0%, determine fully reacting.By reaction solution be cooled to 25 DEG C hereinafter, be added purified water (90.0kg),
Filter cake is added in acetonitrile (17.8kg) for stirring, filtering, is beaten, and filtering is dried to obtain yellow powdery solid, altogether
6.652kg yield 89.2%.
Step 2:N- (the fluoro- 2- methoxyl group -5- nitrobenzophenone of 4-) -4- (6,7,8,9- tetrahydropyridine simultaneously [1,2-a] indoles -
10- yl) pyrimidine -2- amine synthesis
Sec-butyl alcohol (80.82kg), 10- (2- chlorine pyrimidine-4-yl) -6,7,8,9- four are added in 500L glassed steel reaction vessels
The pyridinium hydroxide simultaneously fluoro- 2- methoxyl group -5- nitroaniline (4.363kg) of [1,2-a] indoles (6.652kg), 4-, one water of p-methyl benzenesulfonic acid
Object (4.816kg), obtains solidliquid mixture, and reaction solution is warming up to reflux, and solid gradually dissolves, and as reaction carries out, there is Huang
Color solid is precipitated, and after reflux 7.5 hours, HPLC is monitored to fully reacting.Stop heating, by reaction solution be cooled to 15 DEG C hereinafter,
Acetonitrile (31.5kg) is added in filter cake in solid centrifugal filtration by stirring 1 hour, is beaten 1.5 hours at 25 ± 5 DEG C, centrifugation,
Dry title compound, total 9.548kg, yield 94.0%.
Step 3:N1(2- dimethyl aminoethyl) -5- methoxyl group-N1Methyl -2- nitro-N4(4- (6,7,8,9- tetra-
Pyridinium hydroxide simultaneously [1,2-a] indoles -10- base) pyrimidine -2-base) phenyl -1,4- diamines synthesis
DMAC N,N' dimethyl acetamide (44.7kg), N- (the fluoro- 2- methoxy of 4- are added in the vertical jacketed glass kettle of 100L
Base -5- nitrobenzophenone) -4- (6,7,8,9- tetrahydropyridine simultaneously [1,2-a] indoles -10- base) pyrimidine -2- amine (9.548kg), N, N,
N '-trimethyl ethylenediamine (3.380kg) and n,N-diisopropylethylamine (4.841kg), under nitrogen protection, reaction mixture is 85
± 5 DEG C are reacted 2 hours, and HPLC is monitored to fully reacting.By reaction solution be cooled to 70 DEG C hereinafter, be added purified water (95.5kg),
Filtering, is dried to obtain title compound, total 8.206kg, yield 72.2%.
Step 4:N1(2- (dimethylamino) ethyl) -5- methoxyl group-N1Methyl-N4((6,7,8,9- tetrahydropyridine is simultaneously by 4-
[1,2-a] indoles -10- base) pyrimidine -2-base) benzene -1,2,4- triamine synthesis
Dehydrated alcohol (32.39kg), purified water (14.32kg), N are added in the vertical jacket reactor of 100L1(2- bis-
Methylaminoethyl) -5- methoxyl group-N1Methyl -2- nitro-N4(4- (6,7,8,9- tetrahydropyridine simultaneously [1,2-a] indoles -10-
Base) pyrimidine -2-base) phenyl-Isosorbide-5-Nitrae-diamines (4.103kg), reduced iron powder (2.224kg) and ammonium chloride (2.129kg), react mixed
After closing object reflux 1.5 hours, HPLC is monitored to fully reacting.Reaction solution is cooled to 50 DEG C hereinafter, using diatomite drainage, is incited somebody to action
Solid filters out, and filtrate is concentrated, and tetrahydrofuran (3.45kg) and purified water (34.71kg) are added into residue, is beaten, filtering,
It is dried to obtain title compound 3.244kg, yield 84.0%.
Step 5:N- (2- ((2- (dimethylamino) ethyl) (methyl) amino) -4- methoxyl group -5- ((4- (6,7,8,9-
Tetrahydropyridine simultaneously [1,2-a] indoles -10- base) pyrimidine -2-base) amino) phenyl) allyl amide synthesis
N,N-dimethylacetamide (48.6kg) is added in the vertical jacketed glass kettle of 100L, is warming up to 40 DEG C, it will
N1(2- (dimethylamino) ethyl) -5- methoxyl group-N1Methyl-N4(4- (6,7,8,9- tetrahydropyridine simultaneously [1,2-a] indoles-
10- yl) pyrimidine -2-base) benzene -1,2,4- triamine (6.487kg) be added, then start be added dropwise 3- chlorpromazine chloride (1.777kg), control
Rate of addition processed is not higher than 60 DEG C, is added dropwise, and opens cooling, and after 40 ± 5 DEG C are stirred 1 hour, sampling HPLC is monitored to anti-
It should be complete.Purified water (0.253kg) is added, is stirred 30 minutes.
Reaction solution is heated, under conditions of 80 ± 5 DEG C, triethylamine (13.52kg) is added, is warming up to 95 ± 5 DEG C, instead
After answering 2 hours, HPLC is detected to fully reacting.Cooling is added methanol (83.0kg), and then cool down crystallization, filtering, so dry that mark
Inscribe compound 4.953kg, yield 68.6%.
Step 6:N- (2- ((2- (dimethylamino) ethyl) (methyl) amino) -4- methoxyl group -5- ((4- (6,7,8,9-
Tetrahydropyridine simultaneously [1,2-a] indoles -10- base) pyrimidine -2-base) amino) phenyl) allyl amide methane sulfonates preparation
N- made from title step 5 (2- ((2- (dimethylamino) ethyl) (methyl) amino) -4- methoxyl group -5- ((4- (6,
7,8,9- tetrahydropyridines simultaneously [1,2-a] indoles -10- base) pyrimidine -2-base) amino) phenyl) allyl amide (148.5mg,
0.28mmol) be dissolved in the acetone of 1.49mL 95%, solid dissolved clarification at 55 DEG C, with 1mL acetone dilution methanesulfonic acid (29.11mg,
0.30mmol), the acetone soln of methanesulfonic acid is added in the acetone soln of above compound (I) at 55 DEG C, is filtered after reacting 2h,
Acetone washing, vacuum drying obtains methane sulfonates 155mg at room temperature.1H NMR(500MHz,DMSO-d6):δ9.56(s,1H,
Disappear after heavy water exchange), 9.20 (s, 1H disappear after heavy water exchange), 8.50 (s, 1H), 8.36 (d, 1H), 8.09 (d, 1H),
7.91 (s, 1H disappear after heavy water exchange), 7.43 (d, 1H), 7.16 (t, 1H), 7.12 (t, 1H), 7.05 (d, 1H), 6.97 (s,
1H,),6.63(dd,1H,),6.29(dd,1H),5.78(d,1H),4.11(t,2H),3.90(s,3H),3.33-3.31(m,
2H),3.26-3.21(m,4H),2.81(s,6H),2.62(s,3H),2.45(s,3H),2.03-2.02(m,2H),1.84-
1.83(m,2H)。ESI-Ms m/z:540.2[M-CH3SO3H+H]+。
Embodiment 2N- (5- acrylamido -4- ((2- (dimethylamino) ethyl) methyl) amino) -2- methoxybenzene
Base)-N- (4- (6,7,8,9- tetrahydropyridine simultaneously [1,2-a] indoles -10- base) pyrimidine -2-base) allyl amide
N is added in 250mL there-necked flask1(2- (dimethylamino) ethyl) -5- methoxyl group-N1Methyl-N4-(4-(6,7,
8,9- tetrahydropyridines simultaneously [1,2-a] indoles -10- base) pyrimidine -2-base) benzene -1,2,4- triamine (1.60g, 3.3mmol, 1.0eq),
DMAC N,N' dimethyl acetamide (16mL), acryloyl chloride (0.90g, 9.9mmol, 3.0eq), N, N- diisopropylethylamine (2.13g,
16.5mmol, 5.0eq), reaction 1.5 hours is stirred at room temperature in mixture.50mL methanol is added into reaction mixture, is precipitated solid
Body, filtering, vacuum drying obtain title compound, total 0.60g, yield 30.0%.1HNMR(300MHz,DMSO-d6)δ10.03
(s, 1H), 8.59 (d, J=5.5Hz, 1H), 8.19 (s, 1H), 7.91 (d, J=8.0Hz, 1H), 7.45-7.42 (m, 2H),
7.17 (d, J=7.0Hz, 1H), 7.09-7.06 (m, 2H), 6.77 (dd, J1=17.0Hz, J2=10.3Hz, 1H), 6.42 (dd,
J1=17.0Hz, J2=10.0Hz, 1H), 6.29 (d, J=16.0Hz, 1H), 6.20 (d, J=16.5Hz, 1H), 5.75-5.73
(m, 2H), 4.09 (t, J=5.5Hz, 2H), 3.71 (s, 3H), 3.01-2.99 (m, 2H), 2.93-2.92 (m, 2H), 2.79 (s,
3H), 2.43 (t, J=5.5Hz, 2H), 2.24 (s, 6H), 2.00-1.98 (m, 2H), 1.80 (m, 2H) .ESI-Ms m/z:
594.3[M+H]+。
Embodiment 3N- (4- methoxyl group -2- (methylamino) -5- ((4- (6,7,8,9- tetrahydropyridine simultaneously [1,2-a] indoles -
10- yl) pyrimidine -2-base) amino) phenyl) allyl amide
Step 1:2- methoxyl group-N4Methyl-5-nitro-N1(4- (6,7,8,9- tetrahydropyridine simultaneously [1,2-a] indoles -10-
Base) pyrimidine -2-base) phenyl -1,4- diamines preparation
By N- (the fluoro- 2- methoxyl group -5- nitrobenzophenone of 4-) -4- (6,7,8,9- tetrahydropyridine simultaneously [1,2-a] indoles -10-
Base) pyrimidine -2- amine (6.00g, 13.8mmol, 1.0eq), methylamine tetrahydrofuran solution (50mL, 100mmol, 7.2eq) and N, N-
Dimethyl acetamide (60mL) is added in reaction flask, stirs lower room temperature reaction overnight.Next day post-processes to obtain 5.50g title compound
Object.
((4- (6,7,8,9- tetrahydropyridine simultaneously [1,2-a] indoles -10- base) is phonetic by step 2:(5- methoxyl group -2- nitro -4-
Pyridine -2- base) amino) phenyl) and (methyl) t-butyl carbamate preparation
Take 2- methoxyl group-N made from step 14Methyl-5-nitro-N1((6,7,8,9- tetrahydropyridine is simultaneously [1,2-a] by 4-
Indoles -10- base) pyrimidine -2-base) phenyl -1,4- diamines (2.00g, 4.5mmol, 1.0eq), Boc acid anhydrides (2.95g,
13.5mmol, 3.0eq), N, N- diisopropylethylamine (1.45g, 11.3mmol, 2.5eq) and 1,4- dioxane (50mL) plus
Enter into reaction flask, mixture reacts 5 hours at 100 DEG C.It is cooled to room temperature, post-processes to obtain 2.65g solid.
((4- (6,7,8,9- tetrahydropyridine simultaneously [1,2-a] indoles -10- base) is phonetic by step 3:(5- methoxyl group -2- amino -4-
Pyridine -2- base) amino) phenyl) and (methyl) t-butyl carbamate preparation
By (5- methoxyl group -2- nitro -4- ((4- (6,7,8,9- tetrahydropyridine simultaneously [1,2-a] indoles-made from step 2
10- yl) pyrimidine -2-base) amino) phenyl) (methyl) t-butyl carbamate (2.30g, 4.2mmol), palladium carbon (0.23g), first
50mL three-necked flask is added in alcohol (5mL) and methylene chloride (5mL), and normal pressure hydrogenation 46 hours, palladium carbon is filtered out at room temperature, filtrate warp
Post-processing obtains title compound as brown oil 2.30g.
Step 4:(5- methoxyl group -2- acrylamido -4- ((4- (6,7,8,9- tetrahydropyridine simultaneously [1,2-a] indoles -10-
Base) pyrimidine -2-base) amino) phenyl) (methyl) t-butyl carbamate preparation
By (5- methoxyl group -2- amino -4- ((4- (6,7,8,9- tetrahydropyridine simultaneously [1,2-a] indoles-made from step 3
10- yl) pyrimidine -2-base) amino) phenyl) (methyl) t-butyl carbamate (2.30g, 3.6mmol, 1.0eq), N, N- bis- is different
Propylethylamine (0.68g, 5.4mmol, 1.5eq) is added in 25mL three-necked flask, by acryloyl chloride (0.32g, 3.6mmol,
It 1.0eq) is dissolved in methylene chloride (5mL), is added drop-wise in the cooling above-mentioned reaction mixture of ice-water bath, is added dropwise, in ice
Continue stirring 2 hours in water-bath, it is post-treated to obtain 2.80g solid.
Step 5:N- (4- methoxyl group -2- (methylamino) -5- ((4- (6,7,8,9- tetrahydropyridine simultaneously [1,2-a] indoles -
10- yl) pyrimidine -2-base) amino) phenyl) allyl amide preparation
By ((((6,7,8,9- tetrahydropyridine is simultaneously [1,2-a] by 4- by 5- methoxyl group -2- acrylamido -4- made from step 4
Indoles -10- base) pyrimidine -2-base) amino) phenyl) (methyl) t-butyl carbamate (2.80g), trifluoroacetic acid (20mL) and two
Chloromethanes (60mL) is added in 250mL three-necked flask, is stirred 0.5 hour under ice cooling, 4, post-treated to purify to obtain title
The total 0.50g of compound.1H NMR(300MHz,DMSO-d6) δ 9.30 (s, 1H), 8.27 (d, J=5.5Hz, 1H), 8.07 (d, J=
8.0Hz, 1H), 7.80 (s, 1H), 7.71 (s, 1H), 7.41 (d, J=8.0Hz, 1H), 7.16-7.09 (m, 2H), 6.94 (d, J
=5.5Hz, 1H), 6.45 (dd, J1=17.0Hz, J2=10.5Hz, 1H), 6.34 (s, 1H), 6.19 (dd, J1=17.0Hz, J2
=2.0Hz, 1H), 5.68 (dd, J1=10.0Hz, J2=2.0Hz, 1H), 4.89 (s, 1H), 4.09 (t, J=6.0Hz, 2H),
3.84 (s, 3H), 3.18 (t, J=6.0Hz, 2H), 2.79 (s, 3H), 2.02-1.99 (m, 2H), 1.83-1.81 (m, 2H)
.ESI-Ms m/z:469.2[M+H]+.
((((6,7,8,9- tetrahydropyridine is simultaneously by 4- by 4- methoxyl group -2- (methyl (Methyaminomethyl) amino) -5- by embodiment 4N-
[1,2-a] indoles -10- base) pyrimidine -2-base) amino)) allyl amide trifluoroacetate salt
Step 1:(((5- methoxyl group -2- nitro -4- ((4- (6,7,8,9- tetrahydropyridine simultaneously [1,2-a] indoles -10- base)
Pyrimidine -2-base) amino) phenyl) (methyl) amino) methyl) and (methyl) t-butyl carbamate preparation
By N- (the fluoro- 2- methoxyl group -5- nitrobenzophenone of 4-) -4- (6,7,8,9- tetrahydropyridine simultaneously [1,2-a] indoles -10-
Base) pyrimidine -2- amine (7.20g, 16.6mmol, 1.0eq), boc-protected dimethyl-ethylenediamine (4.69g, 24.9mmol,
1.5eq), n,N-diisopropylethylamine (3.65g, 28.2mmol, 1.7eq) and n,N-dimethylacetamide (35mL), are warming up to
It 95 DEG C, reacts 3 hours.Post-process to obtain Red oil title compound.
((((6,7,8,9- tetrahydropyridine is simultaneously by 4- by 4- methoxyl group -2- (methyl (Methyaminomethyl) amino) -5- by step 2:N-
[1,2-a] indoles -10- base) pyrimidine -2-base) amino)) preparation of allyl amide trifluoroacetate salt
Preparation method with 3 step 3-5 of embodiment preparation method, unlike by raw material (5- methoxyl group -2- nitro -4-
((4- (6,7,8,9- tetrahydropyridine simultaneously [1,2-a] indoles -10- base) pyrimidine -2-base) amino) phenyl) (methyl) carbamic acid uncle
Butyl ester replaces with (((5- methoxyl group -2- nitro -4- ((4- (6,7,8,9- tetrahydropyridine simultaneously [1,2-a] indoles -10- base) pyrimidine -
2- yl) amino) phenyl) (methyl) amino) methyl) (methyl) t-butyl carbamate, title compound is made, purity is
96.23%.1H NMR(300MHz,DMSO-d6)δ9.39(s,1H),9.33(s,1H),8.72(s,1H),8.71(s,1H),
8.37 (s, 1H), 8.29 (d, J=6.5Hz, 1H), 8.09 (d, J=7.5Hz, 1H), 7.48 (d, J=8.0Hz, 1H), 7.23-
7.19(m,2H),7.15(dd,J1=7.5Hz, J2=7.0HZ, 1H), 7.02 (s, 1H), 6.69 (dd, J1=17.0Hz, J2=
10.5Hz,1H),6.25(dd,J1=17.0Hz, J2=2.0Hz, 1H), 5.75 (dd, J1=10.5Hz, J2=1.0Hz, 1H),
4.13 (t, J=6.0Hz, 2H), 3.84 (s, 3H), 3.28 (t, J=6.0Hz, 2H), 3.20 (t, J=6.0Hz, 2H), 3.15
(t, J=5.5Hz, 2H), 2.63 (s, 6H), 2.03-2.01 (m, 2H), 1.84-1.82 (m, 2H) .ESI-Ms m/z:526.3
[M-CF3COOH+H]+.
5 2- of embodiment ((2- allyl amide groups -5- methoxyl group -4- ((4- (6,7,8,9- tetrahydropyridine simultaneously [1,2-a] Yin
Diindyl -10- base) pyrimidine -2-base) amino) phenyl) (methyl) amino)-N, N- dimethyl ethane -1- amino-oxide
By N- (2- ((2- (dimethylamino) ethyl) (methyl) amino) -4- methoxyl group -5- ((4- (6,7,8,9- tetrahydro
Pyrido [1,2-a] indoles -10- base) pyrimidine -2-base) amino) phenyl) allyl amide (3.00g) and 30% hydrogen peroxide be added to
100mL three-necked flask is stirred at room temperature 1.5 hours, post-treated, obtain title compound, total 0.58g after purification, and purity is
98.37%.1H NMR(300MHz,DMSO-d6) δ 11.93 (s, 1H), 8.67 (s, 1H), 8.32 (d, J=5.0Hz, 1H), 8.07
(d, J=7.5Hz, 1H), 7.89 (s, 1H), 7.41 (d, J=7.5Hz, 1H), 7.16-7.10 (m, 2H), 7.06 (m, 1H),
7.01 (d, J=5.5Hz, 1H), 6.93 (s, 1H), 6.12 (dd, J1=18.0Hz, J2=2.0Hz, 1H), 5.58 (dd, J1=
11.3Hz,J2=1.5Hz, 1H), 4.09 (t, J=6.0Hz, 2H), 3.83 (s, 3H), 3.44-3.43 (m, 2H), 3.27-3.24
(m, 8H), 3.20 (t, J=6.0Hz, 2H), 2.71 (s, 3H), 2.00 (m, 2H), 1.82-1.81 (m, 2H) .ESI-Ms m/z:
556.2[M+H]+.
The chloro- N- of 6 3- of embodiment (2- ((2- dimethylaminoethyl) (methyl) amino) -4- methoxyl group -5- ((4- (6,7,8,
9- tetrahydropyridine simultaneously [1,2-a] indoles -10- base) pyrimidine -2-base) amino) phenyl) propionamide
By N1(2- (dimethylamino) ethyl) -5- methoxyl group-N1Methyl-N4(4- (and 6,7,8,9- tetrahydropyridine simultaneously [1,
2-a] indoles -10- base) pyrimidine -2-base) benzene -1,2,4- triamine (0.70g, 1.44mmol, 1.0eq), DMAC N,N' dimethyl acetamide
(7mL) and 3- chlorpromazine chloride (0.18g, 1.44mmol.1.0eq) are added in 50mL three-necked flask, are reacted at room temperature 1.5 hours.
The solid of precipitation is filtered out, the total 0.30g of title compound, purity 95.16% are dried in vacuo to obtain.1H NMR(300MHz,
DMSO-d6) δ 10.90 (s, 1H), 9.96 (s, 1H), 8.26 (d, J=6.0Hz, 1H), 8.14-8.11 (m, 2H), 7.49 (d, J
=7.5Hz, 1H), 7.25-7.20 (m, 3H), 6.99 (s, 1H), 4.12 (t, J=5.5Hz, 2H), 3.87-3.83 (m, 5H),
3.39-3.35(m,4H),3.15-3.13(m,4H),2.75(s,3H),2.74(s,3H),2.68(s,3H),2.00(m,2H),
1.83(m,2H).ESI-Ms m/z:576.3[M+H]+.
Embodiment 7N- (2- ((2- dimethylaminoethyl) (methyl) amino) -4- methoxyl group -5- ((2- (6,7,8,9- tetrahydro
Pyrido [1,2-a] indoles -10- base) pyrimidine-4-yl) amino) phenyl) allyl amide
The synthesis of step 1:10- (4- chlorine pyrimidine -2-base) -6,7,8,9- tetrahydropyridine simultaneously [1,2-a] indoles
By 2,4- dichloro pyrimidine (43.52g, 292mmol, 1.0eq), alchlor (42.82g, 321mmol, 1.1eq),
Glycol dimethyl ether (500mL) is added in 2L there-necked flask, at 35 DEG C hereinafter, stirring 0.5 hour.6,7,8,9- tetrahydropyridine is added
And [1,2-a] indoles (50.00g, 292mmol, 1.0eq), reaction mixture is warming up to 60 DEG C and is stirred 3 hours.It then will be anti-
It answers liquid to be slowly added into 1000mL water, controls accelerating velocity, make temperature that must not cross 35 DEG C, the solid that solid is precipitated is filtered out,
The total 1.0g of title compound is purified to obtain using silica gel column chromatography.
Step 2:N- (2- ((2- dimethylaminoethyl) (methyl) amino) -4- methoxyl group -5- ((2- (6,7,8,9- tetrahydro
Pyrido [1,2-a] indoles -10- base) pyrimidine-4-yl) amino) phenyl) allyl amide preparation
The preparation method of the preparation method is the same as that of Example 1 step 2-5, unlike by raw material 10- (2- chlorine pyrimidine-4-yl)-
Simultaneously [1,2-a] indoles is substituted for 10- (4- chlorine pyrimidine -2-base) -6,7,8,9- four obtained in step 1 to 6,7,8,9- tetrahydropyridine
Title compound, purity 75.59% is made in pyridinium hydroxide simultaneously [1,2-a] indoles.1H NMR(300MHz,DMSO-d6)δ10.06
(s, 1H), 8.58 (s, 1H), 8.51 (s, 1H), 8.41 (d, J=8.0Hz, 1H), 8.27 (d, J=5.5Hz, 1H), 7.34 (d, J
=8.0Hz, 1H), 7.10 (t, J=7.5Hz, 1H), 7.04 (t, J=7.5Hz, 1H), 7.00 (s, 1H), 6.54-6.48 (m,
2H), 6.21 (d, J=17.0Hz, 1H), 5.75 (d, J=11.0Hz, 1H), 4.04 (t, J=6.0Hz, 2H), 3.81 (s, 3H),
3.27 (t, J=6.0Hz, 2H), 3.00 (t, 2H), 2.69 (s, 3H), 2.54 (s, 2H), 2.32 (s, 6H), 1.96-1.95 (m,
2H),1.76-1.75(m,2H).ESI-Ms m/z:540.3[M+H]+.
Embodiment 8N- (2- ((2- dimethylaminoethyl) (methyl) amino) -4- methoxyl group -5- ((4- (6,7,8,9- tetrahydro
Pyrido [1,2-a] indoles -10- base) pyrimidine -2-base) amino) phenyl) acetamide
By N1(2- (dimethylamino) ethyl) -5- methoxyl group-N1Methyl-N4(4- (and 6,7,8,9- tetrahydropyridine simultaneously [1,
2-a] indoles -10- base) pyrimidine -2-base) benzene -1,2,4- triamine (2.00g, 4.12mmol, 1.0eq), acetic anhydride (0.50g,
4.94mmol, 1.2eq), triethylamine (0.83g, 8.24mmol, 2.0eq) and methylene chloride 20mL be added in 100mL there-necked flask,
25 DEG C of temperature control, stir about 2.0h.Stop reaction, it is post-treated to obtain 1.80g brown solid.Take 1.50g solid that 15mL bis- is added
Chloromethanes dissolution, is added with stirring 30mL heptane, 0 DEG C of crystallization 1h, filters to obtain off-white color filter cake, dry 0.95g solid, yield
63.3%, purity 99.00%.1H NMR(300MHz,DMSO-d6) δ 9.92 (s, 1H), 8.61 (s, 1H), 8.32 (d, J=
5.0Hz, 1H), 8.08 (d, J=7.5Hz, 1H), 7.97 (s, 1H), 7.42 (d, J=7.0Hz, 1H), 7.16 (dd, J1=J2=
7.5Hz,1H),7.11(dd,J1=J2=7.5Hz, 1H), 7.00 (d, J=5.0Hz, 1H), 6.97 (s, 1H), 4.10 (s, 2H),
3.80(s,3H),3.19(s,2H),2.86(s,2H),2.70(s,3H),2.30(s,2H),2.22(s,6H),2.01(s,5H),
1.82(s,2H).ESI-Ms m/z:528.3[M+H]+.
Embodiment 9N- (2- ((2- dimethyl aminoethyl) (methyl) amino) -4- methoxyl group -5- ((4- (6,7,8,9- tetra-
Pyridinium hydroxide simultaneously [1,2-a] indoles -10- base) pyrimidine -2-base) amino) phenyl)-N- (3- ((2- ((2- dimethylaminoethyl) (first
Base) amino) -4- methoxyl group -5- ((4- (6,7,8,9- tetrahydropyridine simultaneously [1,2-a] indoles -10- base) pyrimidine -2-base) amino)
Phenyl) amino) -3- oxopropyl) allyl amide
The reaction mother liquor of 1 step 5 of Example isolates and purifies to obtain title compound 0.45g, purity using preparation chromatography
87.88%,1HNMR(300MHz,DMSO-d6)δ10.02(bs,1H),9.26(bs,1H),8.42(s,1H),8.31-8.28(m,
2H), 8.08-8.07 (m, 2H), 7.94 (s, 1H), 7.71 (d, J=8.0Hz, 1H), 7.46 (d, J=8.0Hz, 1H), 7.29-
7.25 (m, 1H), 7.22 (t, J=7.5Hz, 1H), 7.14-7.10 (m, 2H), 7.06-7.03 (t, J=7.5Hz, 2H), 6.98-
6.97 (d, J=5.5Hz, 1H), 6.94 (s, 2H), 6.80-6.75 (m, 1H), 6.25 (dd, J1=17Hz, J2=1.5Hz, 1H),
5.77 (d, J=11.5Hz, 1H), 4.60 (s, 2H), 4.06 (t, J=6.0Hz, 2H), 3.96 (s, 2H), 3.86 (s, 3H),
3.74 (s, 3H), 3.35-3.20 (m, 10H), 3.16-3.14 (t, J=6.0Hz, 2H), 2.90 (s, 2H), 2.83-2.82 (m,
12H),2.72(s,3H),2.61(s,3H),1.98-1.97(m,2H),1.94-1.93(m,2H),1.80(m,2H),1.65(m,
2H).ESI-Ms m/z:1079.6[M+H]+.
Experimental example 1: formula C, formula D, formula E, formula F, formula G, formula H compound positioning analysis
The preparation of mixed solution: precision weighs impurity formula C, formula D, formula E, formula F, formula G, formula H compound and formula A compound first
Alkyl sulfonate reference substance is appropriate, is dissolved with methanol, is configured to every 1mL containing 500 μ g formula A compound methane sulfonates, contains each impurity 1
The solution of μ g.By mixed solution, sample introduction is analyzed, and the chromatographic column used is Agilent Eclipse Plus C18 column (4.6*
150mm, 5 μm), mobile phase is water phase: the potassium dihydrogen phosphate (potassium hydroxide tune pH to 7.5) of 10mmol/L, organic phase: second
Nitrile, flow velocity 1.0ml/min；Column temperature is 40 DEG C, and gradient shortens time such as the following table 1:
Table 1
| Time (min) | Water phase (%) | Organic phase (%) |
| 0 | 60 | 40 |
| 15 | 15 | 85 |
| 15.1 | 60 | 40 |
| 25 | 60 | 40 |
Position and content are determined at 260nm wavelength using UV detector.
Experimental result shows that 12.467min is formula A compound methane sulfonates in Fig. 1, and 8.286min is impurity formula C
Compound, 7.754min are impurity formula D compound, and 4.898min is impurity formula E compound, and 12.009min is impurity formula G chemical combination
Object, 10.029min are impurity formula H compound, and 13.106min is impurity F compound, are specifically shown in Fig. 1.
Although being described in detail above to the present invention, however it is understood by skilled practitioners that without departing from this hair
The present invention can be carry out various modifications and be changed under the premise of bright spirit and scope.Interest field of the invention is not limited to
Detailed description made by above, and claims should be belonged to.
Claims (11)
1. following formula B, formula C, formula D, formula E, formula F, formula G, formula H or Formulas I compound represented or its hydrate, solvate or knot
It is brilliant:
2. formula B according to claim 1, formula C, formula D, formula E, formula F, formula G, formula H or Formulas I compound represented or its hydration
Object, solvate or crystallization, wherein formula B, formula C, formula D, formula E, formula F, formula G, formula H and Formulas I compound represented or its hydrate,
Solvate or the purity of crystallization are at least 85%.
3. following formula B compound represented or its hydrate, solvate or the method for crystallization are prepared,
The method includes making N in the presence of alkaline reagent1(2- ((dimethylamino) ethyl) -5- methoxyl group-N1Methyl-
N4(4- (6,7,8,9- tetrahydropyridine simultaneously [1,2-a] indoles -10- base) pyrimidine -2-base) benzene -1,2,4- triamine and acryloyl chloride
The step of reaction.
4. following formula C compound represented or its hydrate, solvate or the method for crystallization are prepared,
The described method includes:
The compound of formula C-1 is reacted with methylamine, and the compound of formula C-2 is made；
The compound of formula C-2 reacts the compound that formula C-3 is made with amino protecting agent, wherein R1For amino protecting group；
The compound of formula C-4 is made through reduction reaction for nitro on the compound of formula C-3；
The compound of formula C-4 reacts the compound that formula C-5 is made with acryloyl halide；With
The compound of formula C-5 through remove amino protecting group production C compound the step of.
5. following formula D compound represented or its hydrate, solvate or the method for crystallization are prepared,
The described method includes:
The compound of formula C-1 reacts the compound that formula D-2 is made with the compound of formula D-1, wherein R1For amino protecting group；
The compound of formula D-3 is made through reduction reaction for nitro on the compound of formula D-2；
The compound of formula D-3 reacts the compound that formula D-5 is made with the compound of formula D-4, wherein X1、X2It selects each independently
From fluorine, chlorine, bromine and iodine；With
The step of compound of formula D-5 is through removing amino protecting group, the compound of production D then being reacted with trifluoroacetic acid.
6. following formula E compound represented or its hydrate, solvate or the method for crystallization are prepared,
The method includes make N- (2- ((2- (dimethylamino) ethyl) (methyl) amino) -4- methoxyl group -5- ((4- (6,7,
8,9- tetrahydropyridine simultaneously [1,2-a] indoles -10- base) pyrimidine -2-base) amino) phenyl) allyl amide carries out the step of oxidation reaction
Suddenly, wherein the oxidation reaction is by being added oxidising agent, it is preferable that the oxidising agent selected from hydrogen peroxide and
Chloroperoxybenzoic acid, more preferably 30% hydrogen peroxide.
7. following formula F compound represented or its hydrate, solvate or the method for crystallization are prepared,
Including making N1(2- (dimethylamino) ethyl) -5- methoxyl group-N1Methyl-N4(4- (and 6,7,8,9- tetrahydropyridine simultaneously [1,
2-a] indoles -10- base) pyrimidine -2-base) benzene -1,2,4- triamine the step of being reacted with 3- chlorpromazine chloride.
8. following formula G compound represented or its hydrate, solvate or the method for crystallization are prepared,
The described method includes:
The compound of formula G-1 reacts the compound that formula G-3 is made with the compound of formula G-2；
The compound of formula G-3 reacts the compound that formula G-5 is made with the compound of formula G-4；
The compound of formula G-5 reacts the compound that formula G-7 is made with the compound of formula G-6；
The compound of formula G-8 is made through reduction reaction for the compound of formula G-7；With
The compound of formula G-8 reacts the step of compound that formula G is made with the compound of formula G-9, wherein X3、X4It is respectively independent
Ground is selected from fluorine, chlorine, bromine and iodine.
9. following formula H compound represented or its hydrate, solvate or the method for crystallization are prepared,
The method includes making N under alkaline reagent1(2- (dimethylamino) ethyl) -5- methoxyl group-N1Methyl-N4-(4-
(6,7,8,9- tetrahydropyridine simultaneously [1,2-a] indoles -10- base) pyrimidine -2-base) benzene -1,2,4- triamine and acetic anhydride step
Suddenly.
10. following formula I compound represented or its hydrate, solvate or the method for crystallization are prepared,
The described method includes:
The compound of formula G-1 reacts the compound that Formulas I -1 is made with the compound of formula G-2；
The compound of formula I-1 reacts the compound that Formulas I -2 is made with the compound of formula G-4；
The compound of formula I-2 reacts the compound that Formulas I -3 is made with the compound of formula G-6；
The compound of Formulas I -4 is made through reduction reaction for the compound of formula I-3；With
The compound of formula I-4 reacts in n,N-dimethylacetamide with 3- chlorpromazine chloride, then under the action of triethylamine
Hydrogen chloride is removed, the reaction mother liquor is taken, uses the step of preparing chromatography, isolating and purifying the compound of obtained Formulas I.
11. formula B according to claim 1, formula C, formula D, formula E, formula F, formula G, formula H or Formulas I compound represented or its hydrate,
The purposes of solvate or crystallization as control comparisons product.
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