CN115785103A

CN115785103A - Synthetic method of medicine fubatinib for treating bile duct cancer

Info

Publication number: CN115785103A
Application number: CN202211700124.1A
Authority: CN
Inventors: 程刚
Original assignee: Beijing Kang Lisheng Pharmaceutical Technology Development Co ltd
Current assignee: Beijing Kang Lisheng Pharmaceutical Technology Development Co ltd
Priority date: 2022-12-28
Filing date: 2022-12-28
Publication date: 2023-03-14

Abstract

The invention discloses a synthetic method of fubatinib, which adopts single-configuration (S) -3- (4-amino-3-iodo-1H-pyrazolo [3,4-d ] pyrimidin-1-yl) tetrahydropyrrole as a starting material, performs acryloyl group butt joint firstly, performs coupling reaction with the starting material 1-ethynyl-3, 5-dimethoxybenzene, and obtains high-purity fubatinib through 2 steps of reaction.

Description

Synthetic method of medicine fubatinib for treating bile duct cancer

Technical Field

The invention belongs to the field of chemical medicines, and particularly relates to a synthetic method of a bile duct cancer treatment medicine fubatinib.

Background

Bile duct cancer is also called 'small cancer king', and the malignancy degree is comparable to the accepted 'cancer king' pancreatic cancer. Bile duct cancer is generally insensitive to both radiotherapy and chemotherapy, with a median overall survival of only about 1 year for advanced first-line chemotherapy (gemcitabine + cisplatin) and only 6.2 months for second-line chemotherapy (FOLFOX).

Treatment of cholangiocarcinoma is extremely surgery dependent, and most patients undergo a tentative surgical procedure unless there is clear evidence that the patient cannot survive the procedure. Bile duct cancer has a 3-year recurrence rate as high as 85% after surgery, and a 5-year survival rate of only about 5%; patients who cannot be surgically resected are more difficult in circumstances, and the 5-year survival rate is once as low as 0. The emergence of accurate cancer treatment schemes brings hope of breaking predicaments for bile duct cancer patients.

Futibinib (Futibatinib) is a kinase inhibitor useful in the treatment of previously treated unresectable, locally advanced or metastatic adult patients with intrahepatic bile duct cancer carrying fibroblast growth factor receptor 2 (FGFR 2) gene fusions or other rearrangements that constitute FGFR signaling to support the proliferation and survival of malignant cells.

Forbatib reduces cell viability of cancer cell lines with FGFR alterations by inhibiting FGFR phosphorylation and downstream signaling, including FGFR fusion/rearrangement, amplification, and mutation, through covalent binding to FGFR. Fubatinib showed antitumor activity in mouse and rat xenograft models with human tumors that activated FGFR gene alterations.

The fubatinib is a high-selectivity irreversible FGFR inhibitor, can be orally taken, has a good inhibition effect on small molecule kinases of FGFR 1, 2, 3 and 4, and the IC of the fubatinib ₅₀ Values were less than 4nM.

The Chinese cultural name of fubatinib: 1- [ (3S) -3- { 4-amino-3- [ (3, 5-dimethoxyphenyl) ethynyl group]-1H-pyrazolo [3,4-d]Pyrimidin-1-yl } pyrrolidin-1-yl]-2-propen-1-one of formula: c ₂₂ H ₂₂ N ₆ O ₃ Molecular weight: 418.45, CAS registry number 1448169-71-8, having the following chemical structure:

the prior art document CN201380003870 reports the synthetic route of forbatinib as follows:

the route takes 4-chloro-3-iodo-1H-pyrazolo [3,4-d ] pyrimidine, 1-ethynyl-3, 5-dimethoxybenzene, (R) -N-Boc-3-benzpyrolol and acryloyl chloride as raw materials to obtain the fubatinib through 4 steps of reaction, and the main steps are as follows:

step 1: 3-iodo-1H-pyrazolo [3,4-d]Pyrimidin-4-amine and 1-ethynyl-3, 5-dimethoxybenzene in PdCl ₂ (dppf)CH ₂ Cl ₂ Performing Sonogashira coupling reaction under the catalysis of cuprous iodide to obtain an intermediate 1- ((3, 5-dimethoxyphenyl) ethynyl) -1H-pyrazolo [3,4-d]Pyrimidin-4-amine;

and 2, step: reacting (R) -N-Boc-3-pyrrolidinol with methanesulfonyl chloride to obtain an intermediate, i.e., tert-butyl 2 (R) -3- (methylsulfonyloxy) pyrrolidine-1-carboxylate;

and step 3: carrying out butt-joint reaction on the intermediate 1 obtained in the step 1 and the intermediate 2 obtained in the step 2 to obtain an intermediate 3 (S) -3- (4-amino-3- ((3, 5-dimethoxyphenyl) ethynyl) -1H-pyrazolo [3,4-d ] pyrimidin-1-yl) pyrrolidine-1-carboxylic acid tert-butyl ester;

and 4, step 4: removing the Boc protecting group of the intermediate 3 obtained in the step 3, and reacting with acryloyl chloride to obtain fubatinib;

the route is long, the yield is low, and the specific route is as follows:

the final reaction in the route is optimized by a master academic thesis of Hunan university, namely the synthetic research of a kinase fluorescent probe based on an FGFR inhibitor FIIN-2 and a pan FGFR inhibitor futibatinib, and by replacing acryloyl chloride with acrylic anhydride and carrying out the reaction at low temperature, the generation of byproducts of fubatinib can be effectively reduced. The specific synthetic route is as follows:

in addition, the document provides a synthetic route of the starting materials of 4-chloro-3-iodo-1H-pyrazolo [3,4-d ] pyrimidine and 1-ethynyl-3, 5-dimethoxybenzene in the above route, and the improvement has a certain effect on reducing the cost of synthesizing the fubatinib, but also leads to a longer synthetic route, and the specific synthetic route is as follows:

the invention aims to provide a new synthetic route of fubatinib, which is different from the synthetic route in the prior art, has the advantages of cheap and easily-purchased raw materials, short route, high yield, low cost and more environmental friendliness, and is beneficial to relieving the drug accessibility of fubatinib which is a bile duct cancer treatment drug.

Disclosure of Invention

The synthetic process route of the fubatinib is as follows:

the invention provides a synthetic method of fubatinib, wherein in step 1, (S) -3- (4-amino-3-iodo-1H-pyrazolo [3,4-d ] pyrimidin-1-yl) tetrahydropyrrole and acylate are used as starting materials, organic base is used as an acid-binding agent, and an intermediate (S) -1- (3- (4-amino-3-iodo-1H-pyrazolo [3,4-d ] pyrimidin-1-yl) pyrrolidin-1-yl) -2-propen-1-one is obtained through amidation reaction.

The invention provides a synthetic method of fuberinib, wherein in step 2, an intermediate (S) -1- (3- (4-amino-3-iodo-1H-pyrazolo [3,4-d ] pyrimidin-1-yl) pyrrolidin-1-yl) -2-propen-1-one and a starting material 1-ethynyl-3, 5-dimethoxybenzene are subjected to Sonogashira coupling reaction under the catalysis of an inorganic iodide and a palladium catalyst and by taking an organic base as an acid-binding agent to obtain the fuberinib.

Compared with the prior art, the method mainly adopts the scheme that Sonogashira coupling reaction is firstly carried out, and finally acrylamide reaction is carried out to obtain fubatinib, and a high-purity product can be obtained only through column chromatography.

The invention puts the Sonogashira coupling reaction at the last step (step 2) of the synthesis of forbatib, and does not generate a large amount of side products due to the premature introduction of acryloyl groups through strict reaction condition control.

The invention has the advantages of shorter steps and lower cost, greatly improves the synthesis efficiency, and can directly recrystallize to obtain high-purity fubatinib without column chromatography. The invention is more environment-friendly due to shorter route, and reduces the damage to the health of production operators.

The steps of the above-mentioned forbatinib synthesis method will be further described below in conjunction with the above-mentioned forbatinib synthesis process route, and the beneficial effects of the novel forbatinib synthesis method of the present invention will be further elucidated.

In the step 1 of the synthetic method, single-configuration (S) -3- (4-amino-3-iodo-1H-pyrazolo [3,4-d ] pyrimidin-1-yl) tetrahydropyrrole and acylate are used as starting materials, organic base is used as an acid-binding agent, and in the process of obtaining the intermediate (S) -1- (3- (4-amino-3-iodo-1H-pyrazolo [3,4-d ] pyrimidin-1-yl) pyrrolidin-1-yl) -2-propen-1-one through amidation reaction, the type, the charge ratio, the reaction catalyst and other reaction conditions of the acylate have great influence on the chemical purity of the intermediate 1.

In step 1 of the synthesis method of the present invention, the acylate in the amidation reaction is selected from acryloyl chloride or acrylic anhydride; acryloyl chloride is preferred as the acylate because it has a strong activity, a slightly high reaction yield, and a low price.

In step 1 of the synthesis method of the invention, the acid-binding agent organic base in the amidation reaction is selected from triethylamine, pyridine, N-diisopropylethylamine, N-diethylethylamine and the like, wherein triethylamine is the most commonly used organic base, is low in price and moderate in alkalinity, and is used as a preferred acid-binding agent.

In step 1 of the synthesis method of the present invention, the molar charge ratio of (S) -3- (4-amino-3-iodo-1H-pyrazolo [3,4-d ] pyrimidin-1-yl) tetrahydropyrrole to acylate in the amidation reaction needs to be strictly controlled, because excessive charge of acylate will cause the primary amine group in the structure of the intermediate 1 to continue to react with acylate to generate impurities; and too little acylate feeding can cause incomplete reaction of the starting materials, and also can cause excessive impurities in the intermediate 1, thereby increasing the purification difficulty. Therefore, the molar feed ratio of (S) -3- (4-amino-3-iodo-1H-pyrazolo [3,4-d ] pyrimidin-1-yl) pyrrolidine to acylate is strictly controlled to be 1.9 to 1.1, preferably 1.

In step 1 of the synthesis method of the present invention, the molar charge ratio of (S) -3- (4-amino-3-iodo-1H-pyrazolo [3,4-d ] pyrimidin-1-yl) pyrrolidine to acid-binding agent organic base in the amidation reaction also needs to be controlled, the reaction process is affected with a small amount of the compound, the compound is used in an excessive amount, which not only wastes materials and increases environmental protection pressure, but also increases the generation of byproducts, and the molar charge ratio needs to be controlled to be 1.2-1, preferably 1.5-1, 2.5, and particularly preferably 1.

In step 1 of the synthesis method, in the amidation reaction, because the stability of the acryloyl structure in the structure of the intermediate 1 is slightly poor, the reaction temperature and the reaction time are strictly controlled, which is beneficial to reducing the generation of byproducts; if the reaction temperature of the dropwise addition of the acylate is-20-10 ℃, preferably-10-0 ℃, the temperature is continuously controlled to react for 0.5-1 h after the dropwise addition. The intermediate (S) -1- (3- (4-amino-3-iodo-1H-pyrazolo [3,4-d ] pyrimidin-1-yl) pyrrolidin-1-yl) -2-propen-1-one is obtained in high purity by the operation of recrystallization from absolute ethanol.

In step 2 of the synthesis method of the present invention, in the Sonogashira coupling reaction, the inorganic iodide is copper iodide, which is a classical application in the Sonogashira coupling reaction.

In step 2 of the synthesis method of the invention, in the Sonogashira coupling reaction, the palladium catalyst is selected from bis (triphenylphosphine) palladium dichloride, tetrakis (triphenylphosphine) palladium, 1-bis (diphenylphosphino) ferrocene palladium dichloride dichloromethane complex, preferably bis (triphenylphosphine) palladium dichloride, which is a classical application in Sonogashira coupling reaction, and bis (triphenylphosphine) palladium dichloride is used as the catalyst, so that fewer byproducts are produced, and the reaction yield is higher.

In step 2 of the synthetic method, in the Sonogashira coupling reaction, the organic base is selected from triethylamine, pyridine, N-diisopropylethylamine and N, N-diethylethylamine, wherein triethylamine is the most common organic base, is low in price and moderate in alkalinity, and is used as a preferred acid-binding agent.

In step 2 of the synthesis method of the present invention, in order to ensure the completion of the reaction of intermediate 1, the generation of by-products is reduced, and the material 1-ethynyl-3, 5-dimethoxybenzene is fed in an excessive amount considering that it is easier to remove, but too much excess increases the material cost. Through research and exploration, when the molar charge ratio of the intermediate (S) -1- (3- (4-amino-3-iodo-1H-pyrazolo [3,4-d ] pyrimidin-1-yl) pyrrolidin-1-yl) -2-propen-1-one to the starting material 1-ethynyl-3, 5-dimethoxybenzene is controlled to be 1.

In step 2 of the synthesis method of the invention, the palladium catalyst is a precious heavy metal reagent, and the dosage of the palladium catalyst does not only increase the cost, but also increases the residue of element impurities in the finished product; but insufficient amounts resulted in incomplete reactions. Through research and exploration, the molar feeding ratio of the intermediate (S) -1- (3- (4-amino-3-iodo-1H-pyrazolo [3,4-d ] pyrimidin-1-yl) pyrrolidin-1-yl) -2-propen-1-one to the palladium catalyst is controlled to be 1.

In step 2 of the synthesis method of the present invention, the molar amount of copper iodide is generally the same as the amount of palladium catalyst, so as to achieve the best reaction effect. The molar feed ratio of (S) -1- (3- (4-amino-3-iodo-1H-pyrazolo [3,4-d ] pyrimidin-1-yl) pyrrolidin-1-yl) -2-propen-1-one to copper iodide is thus controlled to be 1.

In step 2 of the synthesis method of the present invention, in the Sonogashira coupling reaction, the molar charge ratio of (S) -1- (3- (4-amino-3-iodo-1H-pyrazolo [3,4-d ] pyrimidin-1-yl) pyrrolidin-1-yl) -2-propen-1-one to the acid-binding agent organic base needs to be strictly controlled, the reaction process is affected with a small amount, and the use of too much amount not only wastes materials and increases the environmental protection pressure, but also increases the production of byproducts, and the molar ratio needs to be strictly controlled to be 1.

In the step 2 of the synthesis method, the acryloyl structure in fuberidazura has slightly poor stability in the Sonogashira coupling reaction, so that strict oxygen control is realized, and the reaction temperature and the reaction time are controlled, which are both beneficial to reducing the generation of byproducts; under the controlled nitrogen atmosphere, DMF is taken as a solvent, and the reaction is carried out for 3 to 4 hours at the temperature of between 10 and 30 ℃, preferably between 15 and 25 ℃, so that the reaction is complete and byproducts are less.

In step 2 of the synthetic process of the present invention, the final stage of the cyclization is amidation cyclization. The stage conditions include: heating and reacting in solvent dioxane at 90-120 deg.C, preferably 100-115 deg.C for 1-2h. The reaction conditions not only can ensure complete cyclization reaction, but also can avoid generating more byproducts by long-time high-temperature reaction.

In the step 2 of the synthetic method, salifying extraction impurities, salt-dissolving extraction products and recrystallization of the concentrate with ethanol-water are adopted to obtain the high-purity fubatinib. Compared with the method for purifying by adopting column chromatography in the prior art, the method adopts a recrystallization method, has low requirement on equipment and is easier to realize.

According to the invention, through the design of a new synthetic route of fubatinib and the optimization of the synthetic method, the synthetic method of fubatinib, which is shorter in route, lower in cost and more industrial potential, is found and can benefit from the synthetic method.

The new synthetic method of forbatinib and the advantages of forbatinib synthesized by the method will be further described below with reference to examples 1-2 and comparative example 1, wherein the synthetic route of forbatinib is as follows:

drawings

FIG. 1: the invention relates to a synthetic process route of fubatinib

The specific implementation method comprises the following steps:

the technical solutions in the embodiments of the present invention will be described in detail below with reference to the embodiments of the present invention, but the following embodiments are only for understanding the present invention and do not limit the present invention, and the present invention can be implemented in various ways as defined and covered by the claims.

The novel synthetic process for forbatinib and the advantages resulting from this process will be further illustrated below with reference to examples 1 and 2 and comparative examples.

Example 1:

the synthesis method of fubatinib comprises the following steps:

step 1: synthesis of intermediate (S) -1- (3- (4-amino-3-iodo-1H-pyrazolo [3,4-d ] pyrimidin-1-yl) pyrrolidin-1-yl) -2-propen-1-one

Reacting (S) -3- (4-amino-3-iodo-1H-pyrazolo [3, 4-d)]Pyrimidin-1-yl) tetrahydropyrrole (33.0 g,0.1mol) and triethylamine (20.2 g,0.2 mol) are added into 220ml of dichloromethane, cooled to-10 ℃ to 0 ℃, 110ml of dichloromethane solution of acryloyl chloride (9.0 g,0.1 mol) is slowly dripped at controlled temperature, after dripping is finished, the temperature is continuously controlled for reaction for 0.5 h to 1h, and the temperature is returned to room temperature; washing the reaction solution with water (300 ml. Times.3), adding 15g anhydrous sodium sulfate into dichloromethane phase, drying for 2H, filtering, evaporating the filtrate under reduced pressure, adding 250ml anhydrous ethanol into the residue, heating to reflux for dissolution, cooling and crystallizing to obtain the title compound, intermediate (S) -1- (3- (4-amino-3-iodo-1H-pyrazolo [3, 4-d)]Pyrimidin-1-yl) pyrrolidin-1-yl) -2-propen-1-one (28.9 g, 75% yield, 98.5% purity), ms M/z 385.0 (M + 1). ¹ H NMR(300MHz d ₆ -DMSO)：δ2.12,2.37(m,2H)，3.41,3.51(m,2H),3.78,4.00(t,2H),4.03,(m,1H),5.59,6.05(d,2H),6.63(d,1H),8.29(s,1H)。

Step 2: fubatinib synthesis

Under the nitrogen atmosphere, the intermediate (S) -1- (3- (4-amino-3-iodine-1H-pyrazolo [3, 4-d)]Pyrimidin-1-yl) pyrrolidin-1-yl) -2-propen-1-one (19.2 g, 0.05mol), 1-ethynyl-3, 5-dimethoxybenzene (12.2 g,0.075 mol), bis-triphenylphosphine palladium dichloride (7.0g, 0.01mol), cuI (1.9g, 0.01mol) and triethylamine (10.1g, 0.10mol) were added to 150ml of DMF, reacted at 15 to 25 ℃ for 3 to 4 hours, filtered, added with 300ml of dichloromethane and 200ml of water, stirred and separated, washed with 150ml of an organic phase saturated sodium chloride solution, added with 300ml of a 0.2mol/L dilute hydrochloric acid solution and stirred and separated, added with 200ml of dichloromethane in an aqueous phase, added with a saturated sodium bicarbonate solution to adjust ph to 7 to 8, separated, washed with water (200 ml. Times.2), dried over anhydrous sodium sulfate (15 g) for 2 hours, filtered, the filtrate was evaporated to dryness under reduced pressure, and the residue was recrystallized using ethanol-water to obtain the title compound (12.61,419 mol%, optical purity, 1.419%, purity (M + 1% M), ¹ H NMR(300MHz,d ₆ -DMSO):δ8.36(s,1H),6.75(t,2H),6.55(d,1H),5.52(m,1H),3.94(m,3H),3.83(s,6H),3.68(m,1H),2.47(m,5H),1.18(q,3H)。

example 2:

the synthesis method of fubatinib comprises the following steps:

Adding (S) -3- (4-amino-3-iodo-1H-pyrazolo [3,4-d ] pyrimidin-1-yl) tetrahydropyrrole (33.0 g,0.10 mmol) and triethylamine (20.2 g,0.2 mmol) into 220ml of dichloromethane, cooling to-10-0 ℃, slowly dripping 110ml of dichloromethane solution of acrylic anhydride (12.6 g,0.1 mmol) at controlled temperature, continuing to react at controlled temperature for 30min after dripping is finished, and returning the temperature to room temperature; the reaction mixture was washed with water (300 ml. Times.3), the dichloromethane phase was dried over 15g anhydrous sodium sulfate for 2H, filtered, the filtrate was evaporated to dryness under reduced pressure, 250ml anhydrous ethanol was added to the residue, and the mixture was heated to reflux and dissolved, and cooled to crystallize to obtain the title compound, intermediate (S) -1- (3- (4-amino-3-iodo-1H-pyrazolo [3,4-d ] pyrimidin-1-yl) pyrrolidin-1-yl) -2-propen-1-one (26.3 g, yield 68.5%, purity 97.6%)

And 2, step: fubatinib synthesis

The intermediate (S) -1- (3- (4-amino-3-iodo-1H-pyrazolo [3,4-d ] pyrimidin-1-yl) pyrrolidin-1-yl) -2-propen-1-one (19.2 g, 0.05mol), 1-ethynyl-3, 5-dimethoxybenzene (12.2 g,0.075 mol), tetrakis (triphenylphosphine) palladium (11.6 g, 0.01mol), cuI (1.9g, 0.01mol) and triethylamine (10.11g, 0.10mol) were added to 150ml of DMF under a nitrogen atmosphere, reacted at room temperature for 3-4H, filtered, 300ml of dichloromethane and 200ml of water were added, the separated by stirring, 150ml of saturated sodium chloride solution of the organic phase was washed, the organic phase was added to 300ml of dilute hydrochloric acid solution, separated by stirring, 200ml of dichloromethane was added to the aqueous phase, saturated sodium bicarbonate solution was added to 7-8, separated, the organic phase was washed with water again (200 ml), the filtrate was dried without water (15 ml), the residue was dried under reduced pressure, and the title compound was obtained by evaporation to dryness (2.11%) to obtain a crystal having a purity of 100% purity.

Comparative example 1:

the synthetic process of fubatinib related in the Chinese patent CN201380003870 comprises the following steps:

chinese patent CN201380003870 example 1:

(step 1) Synthesis of 3- ((3, 5-Dimethoxyphenyl) ethynyl) -1H-pyrazolo [3,4-d ] pyrimidin-4-amine (intermediate 1)

To 3-iodo-1H-pyrazolo [3,4-d synthesized by the method disclosed in WO2007/126841]PdCl was added to a mixture of pyrimidin-4-amine (520 mg), 1-ethynyl-3, 5-dimethoxybenzene (504 mg), copper (I) iodide (57.3 mg) and triethylamine (0.56 ml) in DMF (10 ml) ₂ (dppf)CH ₂ Cl ₂ (163 mg). After nitrogen purge, the resulting mixture was stirred at 90 ℃ for 6 hours. Chloroform and water were added to the reaction mixture to separate an organic layer. After washing with a saturated sodium chloride solution, the organic layer was dried over anhydrous sodium sulfate, and then the solvent was distilled off under reduced pressure. The resulting residue was purified by basic silica gel column chromatography (developer: chloroform/methanol) to obtain the title compound (120 mg) as a dark brown solid.

(step 4) Synthesis of Compound of example 1 (Fubatinib in Mixed configuration)

Tert-butyl 3- (4-amino-3- ((3, 5-dimethoxyphenyl) ethynyl) -1H-pyrazolo [3,4-d ] pyrimidin-1-yl) pyrrolidine-1-carboxylate (32 mg) 4N-hydrochloric acid/1, 4-dioxane (4 ml) was added, and the mixture was stirred at room temperature for 1.5 hours. After the solvent of the resultant reaction mixture was distilled off under reduced pressure, toluene azeotropic distillation was subsequently conducted to obtain a crude product of 3- ((3, 5-dimethoxyphenyl) ethynyl) -1- (pyrrolidin-3-yl) -1H-pyrazolo [3,4-d ] pyrimidin-4-amine (32 mg). To a portion of the resulting crude product (12 mg) were added chloroform (2.0 ml) and triethylamine (20. Mu.l). After cooling to 0 ℃, acryloyl chloride (2.3 μ l) dissolved in chloroform (100 μ l) was added thereto, and the mixture was stirred at room temperature for 10 minutes. After the reaction was terminated with a saturated aqueous sodium hydrogencarbonate solution, the resulting product was extracted with ethyl acetate. After drying the resultant over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure. The resulting residue was purified by column chromatography on silica gel (developer: ethyl acetate/methanol) to obtain the title compound (6.5 mg) as a white solid.

Chinese patent CN201380003870 example 2:

synthesis of (S) -1- (3- (4-amino-3- ((3, 5-dimethoxyphenyl) ethynyl) -1H-pyrazolo [3,4-d ] pyrimidin-1-yl) pyrrolidin-1-yl) prop-2-en-1-one (the compound fobatinib of example 2)

(step 1) Synthesis of tert-butyl (R) -3- (methylsulfonyloxy) pyrrolidine-1-carboxylate (intermediate 2)

(R) -N-Boc-3-pyrrolidinol (935 mg) was dissolved in chloroform (15 ml), and triethylamine (1.04 ml) and methanesulfonyl chloride (467. Mu.l) were added thereto at 0 ℃. After stirring at room temperature for 1.5 hours, ethyl acetate and water were added thereto to separate an organic layer. After washing with saturated aqueous sodium hydrogencarbonate, saturated aqueous ammonium chloride and water, the organic layer was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure to obtain the title compound (1.1 g) as a colorless oily compound.

(step 2) Synthesis of tert-butyl (S) -3- (4-amino-3- ((3, 5-dimethoxyphenyl) ethynyl) -1H-pyrazolo [3,4-d ] pyrimidin-1-yl) pyrrolidine-1-carboxylate (intermediate 3)

A suspension of 3- ((3, 5-dimethoxyphenyl) ethynyl) -1H-pyrazolo [3,4-d ] pyrimidin-4-amine (334 mg) obtained in example 1 (step 1), tert-butyl (R) -3- (methylsulfonyloxy) pyrrolidine-1-carboxylate (379 mg) obtained above (step 1), and potassium carbonate (391 mg) in DMF (4.0 ml) was stirred at 70 ℃ for 3 hours. Ethyl acetate and water were added thereto to separate an organic layer. The organic layer was dried over anhydrous sodium sulfate, and then the solvent was distilled off under reduced pressure. The resulting residue was purified by basic silica gel column chromatography (developer: hexane/ethyl acetate) to obtain the title compound (149 mg) as a pale yellow amorphous substance.

(step 3) Synthesis of Compound (fubatinib) of example 2

A crude product of (S) -3- ((3, 5-dimethoxyphenyl) ethynyl) -1- (pyrrolidin-3-yl) -1H-pyrazolo [3,4-d ] pyrimidin-1-yl) pyrimidin-4-amine was obtained by removing the Boc group under acidic conditions according to example 1 (step 4) but using tert-butyl (S) -3- (4-amino-3- ((3, 5-dimethoxyphenyl) ethynyl) -1H-pyrazolo [3,4-d ] pyrimidin-1-yl) pyrrolidine-1-carboxylate obtained in the above (step 2) instead of tert-butyl 3- (4-amino-3- ((3, 5-dimethoxyphenyl) ethynyl) -1H-pyrazolo [3,4-d ] pyrimidin-1-yl) pyrrolidine-1-carboxylate. Thereafter, amidation was performed to obtain the title compound as a white solid.

The invention provides a new synthetic method of fubatinib, fubatinib synthesized by the method and a fubatinib synthetic intermediate, which are completely different from the scheme for synthesizing fubatinib in the prior art.

The invention adopts low-cost single-configuration (S) -3- (4-amino-3-iodine-1H-pyrazolo [3,4-d ] pyrimidine-1-yl) tetrahydropyrrole as a starting material, performs acryloyl group butt joint, performs Sonogashira coupling reaction with the starting material 1-ethynyl-3, 5-dimethoxybenzene, and obtains high-purity fubatinib through 2 steps of reaction. Wherein (S) -3- (4-amino-3-iodo-1H-pyrazolo [3,4-d ] pyrimidin-1-yl) tetrahydropyrrole with high optical purity is adopted as a starting material, so that the high-optical-purity forbatinib is ensured to be obtained; the method has the advantages of shorter steps and lower cost, and greatly improves the synthesis efficiency. Meanwhile, the method provided by the invention is short in steps, environment-friendly and more friendly to the health of operators.

The above is only a preferred embodiment of the present invention, and is not intended to limit the present invention, and various modifications and changes will occur to those skilled in the art. Any modification, equivalent replacement, or improvement made within the spirit and principle of the present invention should be included in the protection scope of the present invention.

Claims

1. A synthetic method of a medicine fubatinib for treating cholangiocarcinoma is characterized in that:

step 1, (S) -3- (4-amino-3-iodo-1H-pyrazolo [3,4-d ] pyrimidin-1-yl) tetrahydropyrrole and acylate undergo amidation reaction to obtain an intermediate (S) -1- (3- (4-amino-3-iodo-1H-pyrazolo [3,4-d ] pyrimidin-1-yl) pyrrolidin-1-yl) -2-propen-1-one

Step 2, coupling reaction is carried out on the intermediate (S) -1- (3- (4-amino-3-iodo-1H-pyrazolo [3,4-d ] pyrimidine-1-yl) pyrrolidine-1-yl) -2-propylene-1-ketone and the starting material 1-ethynyl-3, 5-dimethoxybenzene to obtain fubatinib

2. The synthesis process according to claim 1, wherein the acylates in the amidation reaction in step 1 are selected from acryloyl chloride, acrylic anhydride, preferably acryloyl chloride.

3. The synthesis process according to claim 1, wherein the catalyst for amidation reaction in step 1 is an organic base selected from triethylamine, pyridine, N-diisopropylethylamine, N-diethylethylamine, preferably triethylamine.

4. The synthesis process according to claim 1, wherein the molar feed ratio of (S) -3- (4-amino-3-iodo-1H-pyrazolo [3,4-d ] pyrimidin-1-yl) tetrahydropyrrole to acylate in the amidation reaction of step 1 is 1.

5. The synthesis process according to claims 1 and 3, characterized in that the molar ratio of (S) -3- (4-amino-3-iodo-1H-pyrazolo [3,4-d ] pyrimidin-1-yl) tetrahydropyrrole to organic base catalyst in the amidation reaction of step 1 is 1.2-1, preferably 1.5-1, particularly preferably 1.

6. The synthesis process according to claim 1, characterized in that the conditions of the amidation reaction of step 1 comprise: the reaction temperature of the dropwise added acylate is-20 to 10 ℃, preferably-10 to 0 ℃, and the temperature is continuously controlled to react for 0.5 to 1 hour after the dropwise addition is finished.

7. The method of synthesis according to claim 1, wherein step 1 further comprises: recrystallizing by absolute ethyl alcohol to obtain the high-purity intermediate (S) -1- (3- (4-amino-3-iodine-1H-pyrazolo [3,4-d ] pyrimidine-1-yl) pyrrolidine-1-yl) -2-propylene-1-ketone.

8. The method of claim 1, wherein step 2 is catalyzed by copper iodide.

9. The synthesis method according to claim 1, wherein the step 2 coupling reaction is catalyzed by a palladium catalyst, and the palladium catalyst is selected from bis (triphenylphosphine) palladium dichloride, tetrakis (triphenylphosphine) palladium, 1-bis (diphenylphosphino) ferrocene palladium dichloride dichloromethane complex, and preferably bis (triphenylphosphine) palladium dichloride.

10. The synthesis method according to the claim 1, 8 and 9, characterized in that the step 2 coupling reaction needs to add organic base as acid-binding agent, the organic base is selected from triethylamine, pyridine, N-diisopropylethylamine, N-diethylethylamine, preferably triethylamine; and/or;

the molar charge ratio of (S) -1- (3- (4-amino-3-iodo-1H-pyrazolo [3,4-d ] pyrimidin-1-yl) pyrrolidin-1-yl) -2-propen-1-one to the starting material 1-ethynyl-3, 5-dimethoxybenzene in the step 2 coupling reaction is 1; and/or;

the molar charge ratio of (S) -1- (3- (4-amino-3-iodo-1H-pyrazolo [3,4-d ] pyrimidin-1-yl) pyrrolidin-1-yl) -2-propen-1-one to the palladium catalyst in the step 2 coupling reaction is 1; and/or;

the molar charge ratio of (S) -1- (3- (4-amino-3-iodo-1H-pyrazolo [3,4-d ] pyrimidin-1-yl) pyrrolidin-1-yl) -2-propen-1-one to inorganic iodide in the step 2 coupling reaction is 1; and/or;

the molar charge ratio of (S) -1- (3- (4-amino-3-iodo-1H-pyrazolo [3,4-d ] pyrimidin-1-yl) pyrrolidin-1-yl) -2-propen-1-one to acid-binding agent organic base in the step 2 coupling reaction is 1-1; and/or;

the conditions of the step 2 coupling reaction comprise: reacting for 3-4h at 10-30 ℃ and preferably 15-25 ℃ under nitrogen atmosphere; and/or;

the solvent of the coupling reaction in the step 2 is dimethylformamide.