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CN107118207B - Preparation method of CDK inhibitor - Google Patents

Preparation method of CDK inhibitor Download PDF

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CN107118207B
CN107118207B CN201710362092.1A CN201710362092A CN107118207B CN 107118207 B CN107118207 B CN 107118207B CN 201710362092 A CN201710362092 A CN 201710362092A CN 107118207 B CN107118207 B CN 107118207B
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amine
palladium
dimethylthiazole
aminosulfonyl
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CN107118207A (en
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吉民
胡海燕
李锐
张影
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Southeast Pharmaceuticals Co ltd
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
    • C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
    • C07D277/20—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D277/32—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D277/38—Nitrogen atoms
    • C07D277/42—Amino or imino radicals substituted by hydrocarbon or substituted hydrocarbon radicals
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    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
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Abstract

The invention discloses a preparation method of a CDK inhibitor, which comprises the steps of reacting monomethyl thiourea with 1-chloropropone to obtain N, 4-dimethylthiazole-2-amine, carrying out bromination reaction to obtain 5-bromo-N, 4-dimethylthiazole-2-amine, and then reacting with boric acid ester under the action of a catalyst to obtain an aromatic boric acid ester intermediate; carrying out suzuki coupling reaction on the aromatic borate intermediate and 2, 4-dichloro-5 fluorouracil under the catalysis of a palladium catalyst to obtain a coupling product, and then continuing carrying out Buchwald-Hartwig reaction on the coupling product and aromatic amine to finally obtain a target product.

Description

Preparation method of CDK inhibitor
Technical Field
The invention belongs to the field of pharmaceutical chemicals, and particularly relates to a CDK inhibitor and a preparation method thereof.
Background
Tumors are generally thought to be composed of a population of abnormally proliferating cells. It is essentially characterized by overactivation, sustained cell proliferation, and thus can effectively inhibit tumor growth by inducing cell cycle arrest. Cyclin Dependent Kinases (CDKs) belong to the serine/threonine protein kinase family and are key kinases involved in the regulation of the cell cycle. Currently, 20 different CDKs have been reported to bind to cyclins (cyclins) to form active heterodimers, which are involved in physiological processes such as transcription, metabolism, neural differentiation and development. In tumor cells, overexpression or overactivation of cyclins, inhibition of CDKI activity, sustained activation of upstream division signals, etc., all cause an altered CDK activity. The imbalance of CDK activity can directly or indirectly cause uncontrolled cell proliferation, unstable genome (DNA mutation increase, chromosome deletion and the like), unstable chromosome (chromosome number change) and the like, and participate in the occurrence and development of tumors. Because CDK activity is essential for cell division and CDK activity is often enhanced in tumor cells, CDK has long been considered as a better target for the development of anti-tumor and other proliferative disorders. Currently, 1 CDK inhibitor is in clinical use for anti-tumor therapy, and several tens of CDK inhibitors are currently under clinical or preclinical investigation. These CDK inhibitors differ in their mechanism of action and can be broadly classified into ATP competitive and non-competitive inhibitors. LS-007(CDKI-73, 17) is a CDK inhibitor newly developed in recent years and has the structure shown below:
Figure BDA0001300645820000011
the compound is CDK9 Inhibitor (IC) with the strongest activity in the current report50＝4nmol·L-1) One of them, its molecular level can also inhibit the activity of CDK1, CDK2, CDK7, IC50Are respectively 4, 3 and 91 nmol.L-1. Preliminary studies have shown that LS-007 is almost as good as healthy human T cells and B cellsHas no toxicity, but has good inhibition effect on CLL cells and good synergistic effect with fludarabine. In ovarian cancer, LS-007 exerts an anti-tumor effect by simultaneously targeting CDK9 and eIF 4E-related pathways. Other researches show that the compound also shows strong antitumor effect in lymphoma and other different types of leukemia. This compound is currently in the full preclinical phase of research.
Preparation of thiazole propyliminamides as inhibitors of Cyclic Dependent Kinases (CDKs) (WO2013156780) discloses a synthesis method of an LS-007 inhibitor, which comprises the steps of taking monomethyl thiourea 1 as a raw material, firstly reacting with 3-chloro-2, 4-pentanedione 2 to obtain a thiazole intermediate 3, then carrying out condensation reaction with N, N-dimethylformamide dimethyl acetal to obtain an intermediate 4, carrying out fluorination reaction by using a select fluorine reagent to obtain a fluorine-containing building block 5, and finally carrying out ring closing reaction with a compound 6 to obtain a target compound LS-007. The reaction equation is as follows:
Figure BDA0001300645820000021
the fluoro-reaction is carried out by adopting a select fluoro reagent, because the fluoro-reaction effect of the intermediate 4 and the select fluoro reagent is poor, the intermediate 5 accounts for 40 percent, the intermediate 4 accounts for 60 percent and the yield of the intermediate 5 is only about 30 percent after the reaction is finished, and during purification, because the adsorbability of the intermediate 4 and the intermediate 5 on silica gel is strong, the purification is difficult to carry out in a silica gel column chromatography mode; in addition, as the intermediate 5 and the intermediate 4 have extremely similar properties, the solubility of the two is very close, recrystallization purification is difficult, when purification is carried out in a recrystallization mode, when the purity of the intermediate 5 is more than 95%, the total yield is less than 5%, excessive waste liquid is generated, the environmental protection pressure is high, and thus industrial production is very difficult.
Disclosure of Invention
Aiming at the defects of the prior art, the invention provides a novel preparation method of a CDK inhibitor. The synthesis method is simple, mild in reaction conditions and suitable for industrial production.
The specific technical scheme of the invention is as follows:
a method for preparing a CDK inhibitor, the CDK inhibitor has a structure shown as the following formula,
Figure BDA0001300645820000022
the method comprises the following steps:
(a) reacting monomethyl thiourea with 1-chloropropone, adding pyridine or substituted pyridine, reacting to obtain N, 4-dimethylthiazole-2-amine,
Figure BDA0001300645820000023
the reaction uses alcohol solvent, preferably one or more of methanol, ethanol and isopropanol. The substituted pyridine is preferably 4-dimethylaminopyridine. The reaction temperature is preferably 10 to 50 ℃ and more preferably 20 to 40 ℃ and the reaction time is preferably 1 to 48 hours and more preferably 1 to 24 hours.
(b) Carrying out bromination reaction on the N, 4-dimethylthiazole-2-amine to obtain 5-bromine-N, 4-dimethylthiazole-2-amine,
Figure BDA0001300645820000031
the bromination reaction described above may select bromine and/or N-bromosuccinimide (NBS) as the bromine source. Preferably, NBS is selected as a bromine source, bromination reaction is carried out in a dichloromethane solution, the reaction temperature is preferably 0-25 ℃, and the reaction time is preferably 1-3 hours.
Bromine can also be selected as a bromine source, and bromination reaction is carried out in an acetic acid solution, preferably, the reaction temperature is 0-25 ℃, and the reaction time is 1-3 hours.
(c) Reacting 5-bromine-N, 4-dimethylthiazole-2-amine with pinacol boric acid ester in the presence of a palladium catalyst and alkali under the protection of inert gas to obtain an intermediate A,
Figure BDA0001300645820000032
the palladium catalyst is selected from Pd (dppf) Cl2([1,1' -bis (diphenylphosphino) bis)Cyclopentadienyl iron]Palladium dichloride), Pd (dppp) Cl2(1, 3-bis diphenylphosphinopropane Palladium chloride), Pd (OAc)2(Palladium acetate), Pd (PPh3)4One or more of (tetrakis (triphenylphosphine) palladium), tris (dibenzylideneacetone) dipalladium and palladium chloride, preferably Pd (dppf) Cl2. The alkali is organic alkali or inorganic alkali, and is selected from one or more of potassium acetate, sodium bicarbonate, potassium bicarbonate, sodium carbonate, potassium carbonate, cesium carbonate, sodium bis (trimethylsilyl) amide and tert-butoxide, preferably potassium acetate.
The reaction temperature is preferably 80-100 ℃, more preferably 80-85 ℃, and the reaction time is preferably 1-24 hours, more preferably 3-12 hours.
(d) Under the protection of inert gas, the intermediate A and 2, 4-dichloro-5 fluorouracil are subjected to Suzuki reaction to obtain an intermediate D,
Figure BDA0001300645820000033
the Suzuki reaction is carried out under the protection of nitrogen or argon, adding solvent, catalyst and alkali, and preferably using palladium catalyst selected from Pd (dppf) Cl and alkali2([1,1' -bis (diphenylphosphino) ferrocene)]Palladium dichloride), Pd (dppp) Cl2(1, 3-bis-diphenylphosphinopropane palladium chloride), Pd (OAc)2(Palladium acetate), Pd (PPh3)4One or more of (tetrakis (triphenylphosphine) palladium), tris (dibenzylideneacetone) dipalladium and palladium chloride, preferably Pd (PPh3)4. The alkali is organic alkali or inorganic alkali, and is selected from one or more of potassium acetate, sodium bicarbonate, potassium bicarbonate, sodium carbonate, potassium carbonate, cesium carbonate, sodium bis (trimethylsilyl) amide and tert-butoxide, preferably potassium carbonate. The reaction temperature is preferably 50 to 120 ℃ and more preferably 80 to 110 ℃ and the reaction time is preferably 5 to 48 hours and more preferably 12 to 24 hours.
(e) Dissolving the intermediate D and the substituted aromatic amine E in a solvent, carrying out Buchwald-Hartwig reaction to obtain a target product,
Figure BDA0001300645820000041
Buchwald-Hartwig reaction is carried out under the protection of nitrogen or argon and by using palladium catalyst selected from Pd (dppf) Cl and adding alkali and heating for reaction2([1,1' -bis (diphenylphosphino) ferrocene)]Palladium dichloride), Pd (dppp) Cl2(1, 3-bis-diphenylphosphinopropane palladium chloride), Pd (OAc)2(Palladium acetate), Pd (PPh3)4(tetrakis (triphenylphosphine) palladium), tris (dibenzylideneacetone) dipalladium, palladium chloride, preferably tris (dibenzylideneacetone) dipalladium. The alkali is organic alkali or inorganic alkali, and is selected from one or more of potassium acetate, sodium bicarbonate, potassium bicarbonate, sodium carbonate, potassium carbonate, cesium carbonate, sodium bis (trimethylsilyl) amide and tert-butoxide, preferably tert-butoxide. The reaction temperature is preferably 50 to 120 ℃ and more preferably 90 to 110 ℃ and the reaction time is preferably 1 to 24 hours and more preferably 5 to 12 hours.
In the above-mentioned chemical formula and reaction formula,
r1 is selected from the group consisting of hydrogen, sulfonamide, hydroxyl, cyano, halogen, substituted or unsubstituted: C1-C4 alkyl, C1-C4 alkoxy, C3-C6 cycloalkyl, C3-C6 cycloalkoxy, C1-C4 alkylamino, C1-C4 alkylcarbonylamino;
r2 is selected from the group consisting of hydrogen, sulfonamide, hydroxyl, cyano, halogen, substituted or unsubstituted: amino, C1-C4 alkyl, C1-C4 alkoxy, C3-C6 cycloalkyl, C3-C6 cycloalkoxy, C1-C4 alkylamino, C1-C4 alkylcarbonylamino, C1-C4 alkylsulfenylidene, C1-C4 alkylsulfonamide, C3-C6 cycloalkylsulfonamide, C1-C4 alkoxycarbonyloxy, C1-C4 alkylsulfonyloxy;
the substitution means that each of the above groups is independently substituted by a group selected from the group consisting of: sulfonamide, sulfenamide, hydroxyl, C1-C4 alkyl, C1-C4 alkoxy, C3-C7 cycloalkyl, C3-C7 cycloalkoxy, halogen, C1-C4 haloalkyl, cyano, nitro or amino;
preferably, the substitution position of R1 is the 4-position; the substitution position of R2 is the 3-position. R1 is selected from hydrogen, sulfonamide, or methyl; r2 is selected from hydrogen or a sulfonamide group.
More preferably, the R1 substitution position is the 4-position; the substitution position of R2 is 3, R1 is selected from hydrogen, R2 is selected from sulfonamide; alternatively, R1 is selected from methyl, R2 is selected from sulfonamido; alternatively, R1 is selected from sulfonamide and R2 is selected from hydrogen.
Preferably, the CDK inhibitor is structured as
Figure BDA0001300645820000051
One embodiment of the present invention is as follows:
(a) adding monomethyl thiourea and 1-chloropropanone into a reaction bottle, adding a proper amount of methanol, cooling to 0-30 ℃, slowly dropwise adding a methanol solution of pyridine, slowly heating to 20-40 ℃ after dropwise adding, and continuously stirring for 1-24 hours to obtain N, 4-dimethylthiazol-2-amine;
(b) dissolving N, 4-dimethylthiazole-2-amine in acetic acid, controlling the temperature to be 0-25 ℃, slowly dropwise adding a bromine acetic acid solution, keeping the temperature to be 0-25 ℃, and reacting to obtain 5-bromine-N, 4-dimethylthiazole-2-amine;
(c) dissolving 5-bromo-N, 4-dimethylthiazol-2-amine and pinacol borate in dimethyl sulfoxide, and adding Pd (dppf) Cl2Reacting a catalyst with alkali for 3-12 hours at 80-85 ℃ under the protection of nitrogen to obtain a key intermediate A;
(d) under the protection of normal-temperature inert gas, dissolving the key intermediate A and 2, 4-dichloro-5 fluorouracil in a solvent, adding palladium tetratriphenylphosphine chloride and alkali, heating to 80-110 ℃, and reacting for 12-24 hours under the inert gas to obtain a key intermediate D; (e) dissolving the key intermediate D and the substituted aromatic amine E in a solvent, adding a palladium catalyst and alkali, replacing gas in a reaction bottle with inert gas, heating to 90-110 ℃, and reacting for 5-12 hours to obtain a target product.
It is another object of the present invention to provide intermediates for the preparation of the compounds of the present invention, having the structure:
Figure BDA0001300645820000052
the method has the advantages that: the synthetic route of the invention avoids fluoro reaction, thereby avoiding the separation difficulty of the intermediate 4 and the intermediate 5, leading the post-treatment to be simple and feasible, greatly improving the yield compared with the original route, saving the production cost and being beneficial to the amplification production of the pharmaceutical industry.
Detailed Description
The following examples illustrate specific process steps of the present invention, but are not intended to limit the invention.
Terms used in the present invention generally have meanings commonly understood by those of ordinary skill in the art, unless otherwise specified.
The present invention is described in further detail below with reference to specific examples and with reference to the data. It will be understood that these examples are intended to illustrate the invention and are not intended to limit the scope of the invention in any way.
In the following examples, various procedures and methods not described in detail are conventional methods well known in the art.
EXAMPLE 1 preparation of N, 4-Dimethylthiazol-2-amine
Adding 9.01g (100.0mmol) of monomethylthiourea and 9.25g (100.0mmol) of 1-chloropropanone into a reaction bottle, adding a proper amount of methanol (100mL), cooling to 0-30 ℃, slowly dropwise adding 7.91g (100.0mmol) of pyridine methanol solution (20mL), after dropwise adding, slowly heating to 20-40 ℃, continuing stirring for 1-24 hours, cooling to-10-0 ℃, stirring for 1-2 hours at the temperature, filtering, washing the solid with cold ethanol, and drying under reduced pressure to obtain 10.3g of white solid with the yield of 80.5%.1H NMR(CDCl3-d3,400MHz)，4.6(br,1H)，5.7(s,1H)，2.6(s,3H)，2.1(s,3H)；MS(EI)m/e(M+)129.0.
EXAMPLE 25 preparation of bromo-N, 4-dimethylthiazol-2-amine
Dissolving 9.0g (70.0mmol) of N, 4-dimethylthiazole-2-amine in dichloromethane (150mL), controlling the temperature at-5 ℃, adding 12.5g (70.0mmol) of NBS1 in batches, keeping the temperature at-5 ℃, continuing to react for 0.5-2h at-5 ℃ after the addition is finished, drying the solvent by spinning under reduced pressure, adding ethanol (50mL), pulping for 1-2h at room temperature, filtering, and washing the solid with ethanol. Drying the solid under reduced pressure to obtain 5-bromine-N,4-dimethylthiazol-2-amine 10.7g (50.2mmol), yield 73.8%.1H NMR(CDCl3-d3,400MHz)，4.9(br,1H)，2.7(s,3H)，2.2(s,3H)；MS(EI)m/e(M+)207.0.
Example 3 preparation of key intermediate a
Under the protection of nitrogen, 2.07g (10.0mmol) of 5-bromo-N, 4-dimethylthiazol-2-amine is added into a reaction bottle, then DMSO (15mL), 2.94g (30.0mmol) of potassium acetate, 2.55g (10.1mmol) of bis (pinacolato) diboron and 0.22g (0.3mmol) of dppf palladium dichloride catalyst are sequentially added, then air in the bottle is replaced, the reaction is carried out for 3-12 hours at the temperature, after the reaction is finished, the temperature is reduced, water is added, ethyl acetate is used for extraction for three times, extraction solutions are combined, saturated saline solution is used for washing, anhydrous magnesium sulfate is used for drying, filtrate is dried in a reduced pressure condition, then ethanol is used for pulping and purification, filtration is carried out, solid is washed by cold ethanol, and the solid is dried in a reduced pressure condition, so that 1.89g of key intermediate A is obtained, and the yield is 70.5%.1HNMR(CDCl3-d3,400MHz)，3.2(s,6H)，2.3(s,3H)，1.3(s,12H)；MS(EI)m/e(M+)255.1
Example 4 preparation of key intermediate D
Under the protection of nitrogen/argon, key intermediates A0.54g (2.0mmol) and potassium carbonate 0.69g (5.0mmol), N, N-dimethylformamide (8mL), palladium tetratriphenylphosphine 12mg (0.01mmol) and 2, 4-dichloro-5 fluorouracil 0.334g (2.0mmol) are added, then 1mL of water is added, then the air in a bottle is replaced by nitrogen, the temperature is heated to 85-120 ℃, the reaction is carried out for 5-24 hours at the temperature, after the reaction is finished, the temperature is reduced, water is added, ethyl acetate is used for extraction for three times, the extract liquor is combined, the saturated saline solution is used for washing, anhydrous magnesium sulfate is used for drying, after the filtrate is dried under reduced pressure, ethanol is used for pulping and purification, the filtration is carried out, the solid is washed by cold ethanol, the solid is dried under reduced pressure, key intermediate D0.46 g is obtained, and the yield is 90%.1H NMR(CDCl3-d3,400MHz)，9.2(d,1H)，3.1(s,3H)，2.3(s,3H)；MS(EI)m/e(M+)259.0.
EXAMPLE 5 preparation of the Compound LS-007
Under the protection of nitrogen, 5-bromo-N, 4-dimethylthiazol-2-amine 0.26g (1.0mmol) was added to a reaction flask, followed by the sequential addition of THF (5mL), sodium tert-butoxide 0.29g (3.0mmol), tris (dibenzylideneacetone) dipalladium catalyst 0.11g (0.15mmol) and 3-aminobenzenesulfonamide 0.17g (1.0mmol), followed by displacement of the air in the flask, heating to 35-55 deg.C and reaction at this temperature for 1-12 hours, after completion of the reaction, cooling, addition of water, extraction three times with ethyl acetate, combining the extracts, washing with a saturated saline solution, followed by drying with anhydrous magnesium sulfate, spin-drying the filtrate under reduced pressure, followed by slurrying with ethanol, filtration, washing the solid with cold ethanol, and drying the solid under reduced pressure to give compound LS007, 0.31g, with a yield of 79.5%.1H NMR(CDCl3-d3,400MHz)，9.1(d,1H)，7.45-8.1(m,3H)，7.6(m,1H),3.1(s,3H),2.3(s,3H)；MS(ES+)m/e(M+)395.1.
The structural formula is as follows:
Figure BDA0001300645820000071
EXAMPLE 6 preparation of the Compound SEP-023
Under the protection of nitrogen, 0.26g (1.0mmol) of 5-bromo-N, 4-dimethylthiazol-2-amine is added into a reaction bottle, then THF (5mL), 0.29g (3.0mmol) of sodium tert-butoxide, 0.11g (0.15mmol) of tris (dibenzylideneacetone) dipalladium catalyst and 0.17g (1.0mmol) of 4-aminobenzenesulfonamide are sequentially added, then air in the bottle is replaced, the reaction is carried out for 1-12 hours at the temperature, after the reaction is finished, the temperature is reduced, water is added, ethyl acetate is used for extraction for three times, extract liquor is combined, saturated saline solution is used for washing, anhydrous magnesium sulfate is used for drying, filtrate is dried in a rotary manner under reduced pressure, then ethanol is used for pulping and purification, filtration is carried out, solid is washed by cold ethanol, and is dried under reduced pressure, the SEP-0230.29g of the compound is obtained, and the yield is 75.3%.1H NMR(CDCl3-d3,400MHz)，9.1(d,1H)，7.7(d,2H)，7.2(d,2H),3.0(s,3H),2.2(s,3H)；MS(ES+)m/e(M+)395.1.
The structural formula is as follows:
Figure BDA0001300645820000072
example preparation of SEP-027
Under the protection of nitrogen, 0.26g (1.0mmol) of 5-bromo-N, 4-dimethylthiazol-2-amine is added into a reaction bottle, then THF (5mL), sodium t-butoxide 0.29g (3.0mmol), tris (dibenzylideneacetone) dipalladium catalyst 0.11g (0.15mmol) and 4-methyl-3-aminobenzenesulfonamide 0.19g (1.0mmol) were added in this order, then replacing the air in the bottle, heating to 35-55 ℃, reacting for 1-12 hours at the temperature, after the reaction is finished, cooling, adding water, extracting for three times by using ethyl acetate, combining extract liquor, washing by using saturated saline solution, then drying with anhydrous magnesium sulfate, spin-drying the filtrate under reduced pressure, then pulping with ethanol for purification, filtering, washing the solid with cold ethanol, and drying the solid under reduced pressure to obtain SEP-0230.36g with the yield of 79%.1H NMR(CDCl3-d3,400MHz)，9.2(d,1H)，7.37-8.0(m,2H)，7.5(s,1H),2.9(s,3H),2.6(s,3H),2.1(s,3H)；MS(ES+)m/e(M+)409.1.
The structural formula is as follows:
Figure BDA0001300645820000081

Claims (7)

1. a method for preparing a CDK inhibitor, the CDK inhibitor has a structure shown as the following formula,
Figure FDA0002543123260000011
the method is characterized by comprising the following steps:
(a) reacting monomethyl thiourea with 1-chloropropanone, adding pyridine, reacting to obtain N, 4-dimethylthiazole-2-amine,
Figure FDA0002543123260000012
(b) carrying out bromination reaction on the N, 4-dimethylthiazole-2-amine to obtain 5-bromine-N, 4-dimethylthiazole-2-amine,
Figure FDA0002543123260000013
(c) carrying out boric acid esterification reaction on 5-bromine-N, 4-dimethylthiazole-2-amine and pinacol boric acid ester in the presence of a palladium catalyst and alkali under the protection of inert gas to obtain an intermediate A,
Figure FDA0002543123260000014
(d) under the protection of inert gas, the intermediate A and 2, 4-dichloro-5 fluorouracil are subjected to Suzuki reaction to obtain an intermediate D,
Figure FDA0002543123260000015
(e) dissolving the intermediate D and the substituted aromatic amine E in a solvent, carrying out Buchwald-Hartwig reaction to obtain a target product,
Figure FDA0002543123260000016
wherein R1 is selected from hydrogen, aminosulfonyl or methyl; r2 is selected from hydrogen or aminosulfonyl.
2. The method of claim 1, wherein the R1 substitution position is the 4 position; the substitution position of R2 is the 3-position.
3. The method of claim 1, wherein the R1 substitution position is the 4-position, and the R2 substitution position is the 3-position; r1 is selected from hydrogen, R2 is selected from aminosulfonyl; alternatively, R1 is selected from methyl, R2 is selected from aminosulfonyl; alternatively, R1 is selected from aminosulfonyl and R2 is selected from hydrogen.
4. The method according to claim 1, wherein the reaction system in the step (a) uses an alcohol solvent.
5. The method of claim 1, wherein the bromination in step (b) selects bromine and/or NBS as the bromine source.
6. The method of claim 1, wherein steps (c), (d), and (e) are catalyzed by a palladium-based catalyst and a base.
7. The method of claim 6, wherein the palladium-based catalyst is selected from the group consisting of Pd (dppf) Cl2、Pd(dppp)Cl2、Pd(PPh3)4One or more of tris (dibenzylideneacetone) dipalladium, palladium chloride and palladium acetate.
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CN108658966B (en) 2018-06-20 2020-03-20 常州千红生化制药股份有限公司 Tartrate salts of selective CDK9 inhibitors and crystalline forms thereof
CN114276341A (en) * 2021-07-05 2022-04-05 常州英诺升康生物医药科技有限公司 LS007 impurity compound A and preparation process and application thereof
CN114349747A (en) * 2021-07-05 2022-04-15 常州英诺升康生物医药科技有限公司 Preparation process of LS007 impurity compound A
CN115160307A (en) * 2022-08-02 2022-10-11 常州英诺升康生物医药科技有限公司 LS010 impurity compound B and preparation process and application thereof
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