Preparation method of lalotinib intermediate

Abstract

The invention relates to a preparation method of a lalotinib intermediate, and provides a novel synthesis method of (R)-5-(2-(2, 5-difluorophenyl) pyrrolidine-1-yl) pyrazolo [1, 5-A] pyrimidine-3-amine through an iodination reaction and an amination reaction in sequence, and the method comprises the following steps: taking (R)-5-[2-(2, 5-difluorophenyl) pyrrolidine-1-yl] pyrazolo [1, 5-A] pyrimidine as a starting raw material, and carrying out a reaction at the temperature of 60-80 DEG C to obtain the lalotinib intermediate. The method comprises the following steps of: synthesizing (R)-5-(2-(2, 5-difluorophenyl) pyrrolidine-1-yl)-3-iodo-pyrazolo [1, 5-A] pyrimidine by using elemental iodine or recovered elemental iodine as an iodine source and hydrogen peroxide as an oxidant under the combined action, and performing copper catalytic amination reaction on (R)-5-(2-(2, 5-difluorophenyl) pyrrolidine-1-yl)-3-iodo-pyrazolo [1, 5-A] pyrimidine to obtain (R)-5-(2-(2, 5-difluorophenyl) pyrrolidine-1-yl)-3-iodo-pyrazolo [1, 5-A] pyrimidine. According to the present invention, the 2-(2, 5-difluorophenyl) pyrrolidine-1-yl) pyrazolo [1, 5-A] pyrimidine-3-amine is used as the raw material, the whole reaction step has characteristics of high regioselectivity, simple post-treatment and convenient operation, the yield and the purity of the obtained product are high, the HPLC purity can achieve more than 98.5%, and the large-scale production can be easily achieved.

Description

Technical Field

[0001] The present invention relates to the technical field of the synthesis of arylamine compounds, and particularly to a preparation method of a larotrectinib intermediate. Background Art

[0002] The neurotrophic tyrosine kinase receptors TRKA, TRKB, and TRKC of the TRK family are encoded by the NTRK1, NTRK2, and NTRK3 genes respectively, and are involved in the growth, differentiation, and survival of neurons. Gene fusions (TRK fusions) involving NTRK1, NTRK2, and NTRK3 have been widely found in pediatric and adult malignancies.

[0003] TRK fusions rarely occur in many common adult malignancies and childhood cancers. On the contrary, in certain rare pediatric tumors, including infantile fibrosarcoma, cellular congenital mesoblastic nephroma, and papillary thyroid carcinoma, the frequency of TRK fusions is higher, and thus may represent clinically targetable driver alterations in these tumor types. Infantile fibrosarcoma is particularly notable because these tumors are usually locally advanced and invasive, requiring chemotherapy or potentially mutilating surgery, or both, to achieve a cure.

[0004] Larotrectinib (Formula (4) below) is an oral ATP-competitive inhibitor of TRKA, TRKB, and TRKC, developed by Loxo Oncology in cooperation with Bayer AG for the treatment of adult and pediatric cancer patients with specific genetic biomarkers (i.e., NTRK gene fusions). The in vitro 50% inhibitory concentration (IC50) is 5 - 11 nM, and the selectivity for TRK is more than 100 times that of other kinases. In tumor cell lines containing TRK fusions, the cells are sensitive to larotrectinib, and the IC50 values are in the low nanomolar range.

[0005]

[0006] It is known from the patents publicly disclosed by the original research company (WO2010048314, WO2016077841, WO2016077841) that (R)-5-(2-(2,5-difluorophenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidin-3-amine is a key intermediate for the synthesis of larotrectinib. The mainstream methods for synthesizing (R)-5-(2-(2,5-difluorophenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidin-3-amine are all nitro reduction methods, and the nitro compound of Formula (5) is synthesized into the compound of Formula (1) under different reduction conditions.

[0007]

[0008] WO2010048314, WO2016077841, and WO2016077841 disclose a method for synthesizing the compound of formula (1) by reducing the nitro group of the nitro compound of formula (5) in a methanol / dichloromethane solution using zinc powder / ammonium chloride as a reducing agent. CN111362946 discloses a method for catalytic hydrogenation reduction of nitro group to synthesize formula (1) using Pd / C. CN110804059 discloses a method for synthesizing formula (1) using Zn / HCl as a reducing agent in tetrahydrofuran. CN116003469 discloses a method for reducing the nitro group in methanol using Fe / NH4Cl as a reducing agent to synthesize formula (1).

[0009] Although the methods disclosed above can all achieve industrial production, the use of nitro compounds cannot be avoided. The production process of nitro compounds is one of the eighteen hazardous chemical processes, which has high requirements for safety, environmental protection, and production equipment, and there are few sites that can achieve production capacity. Based on the importance of (R)-5-(2-(2,5-difluorophenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidin-3-amine in the synthesis process of larotrectinib, it is particularly necessary to develop a new method for synthesizing this intermediate. Summary of the Invention

[0010] The technical problem to be solved by the present invention is to provide a preparation method of a larotrectinib intermediate that can reduce the danger of the process, improve the selectivity and the yield of the product, simplify the operation, and shorten the reaction time, in view of the current situation of the prior art.

[0011] The technical solution adopted by the present invention to solve the above technical problems is as follows:

[0012] A preparation method of a larotrectinib intermediate, comprising the following steps:

[0013] (1) Iodination reaction

[0014] In an alcohol solution, in the presence of an iodine source and an oxidizing agent, using (R)-5-[2-(2,5-difluorophenyl)pyrrolidin-1-yl]pyrazolo[1,5-a]pyrimidine as a starting material, the (R)-5-[2-(2,5-difluorophenyl)pyrrolidin-1-yl]pyrazolo[1,5-a]pyrimidine undergoes iodination reaction at the C-3 position to synthesize the following compound of formula (3);

[0015]

[0016] After the reaction is completed, the temperature is lowered, the reaction is quenched, acid is added to form a salt, crystallization is carried out under heat preservation, filtration, washing, and drying to obtain the salt of (R)-5-(2-(2,5-difluorophenyl)pyrrolidin-1-yl)-3-iodopyrazolo[1,5-a]pyrimidine; the salt of (R)-5-(2-(2,5-difluorophenyl)pyrrolidin-1-yl)-3-iodopyrazolo[1,5-a]pyrimidine is neutralized with a base in an aqueous solution to free it, crystallization is carried out under heat preservation, filtration, washing, drying, and vacuum drying to obtain the pure product of the compound of formula (3);

[0017] (2) Amination reaction

[0018] The compound of formula (3) is dissolved in an alcohol solution and undergoes a substitution reaction with an ammonia source under the action of a copper catalyst to obtain the compound of formula (1);

[0019]

[0020] After the reaction is completed, the temperature is lowered, filtration is carried out, and the filtrate is concentrated to dryness under reduced pressure; extraction is carried out with dichloromethane and saturated brine, and the dichloromethane layer is washed with purified water again; the organic phase is concentrated to half of its volume under reduced pressure, the temperature is lowered, a weakly polar organic solvent is added for crystallization, filtration, washing, drying, and vacuum drying to obtain the pure product of the compound of formula (1).

[0021] In the present invention, the reaction temperature of the iodination reaction in step (1) is 45-50 °C. After the iodination reaction is completed, the temperature is first lowered to 20-30 °C, and then a quenching agent is added to carry out the quenching reaction; crystallization is carried out with stirring under heat preservation at 20-30 °C. The reaction temperature of the amination reaction in step (2) is 60-100 °C. After the amination reaction is completed, the temperature is first lowered to 20-30 °C, and then filtration and concentration are carried out; crystallization is carried out with stirring under heat preservation at 10-15 °C.

[0022] Preferably, the alcohol solution in the iodination reaction is one or more of methanol, ethanol, 95% ethanol, n-propanol, isopropanol, n-butanol, and 2-butanol, and further preferably ethanol, with a dosage of 3-10W of the mass of (R)-5-[2-(2,5-difluorophenyl)pyrrolidin-1-yl]pyrazolo[1,5-a]pyrimidine; the iodine source in the iodination reaction is one or two of elemental iodine and recycled elemental iodine, and further preferably elemental iodine, with a dosage of 0.5-1.1 eq of the molar amount of (R)-5-[2-(2,5-difluorophenyl)pyrrolidin-1-yl]pyrazolo[1,5-a]pyrimidine.

[0023] Preferably, the oxidant in the iodination reaction is one of hydrogen peroxide, tert-butyl hydroperoxide, urea peroxide, potassium hydrogen persulfate, sodium hypochlorite, sodium iodate, potassium iodate, and sodium periodate, and further preferably hydrogen peroxide, with a dosage of 0.5-3.0 eq of the molar amount of (R)-5-[2-(2,5-difluorophenyl)pyrrolidin-1-yl]pyrazolo[1,5-a]pyrimidine.

[0024] Preferably, the quenching agent after the iodination reaction is one of hydrazine hydrate, sodium sulfite, sodium bisulfite, and sodium thiosulfate, and more preferably hydrazine hydrate; the acid is one of hydrochloric acid, hydrobromic acid, and sulfuric acid, and more preferably hydrochloric acid, and the dosage is 1.0 - 5.0 eq in terms of the molar amount of (R)-5-[2-(2,5-difluorophenyl)pyrrolidin-1-yl]pyrazolo[1,5-a]pyrimidine; the base is one of sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, and sodium bicarbonate, and more preferably sodium hydroxide, which is used to adjust the pH to 8 - 10.

[0025] Preferably, the alcohol solution in the amination reaction is one or more of methanol, ethanol, 95% ethanol, n-propanol, isopropanol, n-butanol, and 2-butanol, and more preferably methanol, and the dosage is 3 - 10W of the mass of (R)-5-(2-(2,5-difluorophenyl)pyrrolidin-1-yl)-3-iodopyrazolo[1,5-a]pyrimidine.

[0026] Preferably, the copper catalyst in the amination reaction is one of copper powder, nano-copper powder, cuprous oxide, cuprous iodide, cuprous bromide, cuprous chloride, copper oxide, nano-copper oxide, copper chloride, copper bromide, and copper acetate, and more preferably copper powder, and the dosage is 0.1 - 1.1 eq in terms of the molar amount of (R)-5-(2-(2,5-difluorophenyl)pyrrolidin-1-yl)-3-iodopyrazolo[1,5-a]pyrimidine.

[0027] Preferably, the ammonia source in the amination reaction is one of ammonia water, ammonium chloride, and ammonium acetate, and more preferably ammonia water, and the dosage is 1.0 - 10.0 eq in terms of the molar amount of (R)-5-(2-(2,5-difluorophenyl)pyrrolidin-1-yl)-3-iodopyrazolo[1,5-a]pyrimidine.

[0028] Preferably, the weakly polar organic solvent is one or more of n-hexane, cyclohexane, n-heptane, petroleum ether, and toluene, and more preferably n-hexane, and the dosage is 1 - 10W of the mass of (R)-5-(2-(2,5-difluorophenyl)pyrrolidin-1-yl)-3-iodopyrazolo[1,5-a]pyrimidine.

[0029] Compared with the prior art, the advantages of the present invention are as follows: The present invention provides a new method for synthesizing (R)-5-(2-(2,5-difluorophenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidin-3-amine through an iodination reaction and an amination reaction in sequence. This method uses (R)-5-[2-(2,5-difluorophenyl)pyrrolidin-1-yl]pyrazolo[1,5-a]pyrimidine as the starting material, uses elemental iodine or recycled elemental iodine as the iodine source, and hydrogen peroxide as the oxidant. They act together to synthesize (R)-5-(2-(2,5-difluorophenyl)pyrrolidin-1-yl)-3-iodopyrazolo[1,5-a]pyrimidine. (R)-5-(2-(2,5-difluorophenyl)pyrrolidin-1-yl)-3-iodopyrazolo[1,5-a]pyrimidine is then subjected to a copper-catalyzed amination reaction to obtain (R)-5-(2-(2,5-difluorophenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidin-3-amine. The entire reaction step has high regioselectivity, simple post-treatment, convenient operation, and the obtained product has high yield and purity. The HPLC purity can reach more than 98.5%, and it is easy to achieve scalable production, providing theoretical and technical guidance for the synthesis and production of (R)-5-(2-(2,5-difluorophenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidin-3-amine. Detailed implementation mode

[0030] The present invention will be further described in detail below in conjunction with examples.

[0031] Example 1:

[0032] The preparation method of the larotrectinib intermediate in this example includes the following steps:

[0033] (1) After purging with nitrogen, (R)-5-[2-(2,5-difluorophenyl)pyrrolidin-1-yl]pyrazolo[1,5-a]pyrimidine (100.00 g, 332.99 mmol) and absolute ethanol (750 mL) were successively added to a clean reaction flask. Stirring was started, and after stirring evenly, it was heated to 45-50 °C, and elemental iodine (42.26 g, 166.49 mmol) was added; the temperature of the reaction solution was controlled at 45-50 °C, and hydrogen peroxide (113.26 g, 998.96 mmol) was slowly added dropwise over 2.5-3.0 h. After the addition was completed, the reaction was kept at 45-50 °C for 24 h; the reaction solution was sampled for detection. When the raw materials in the reaction solution detected by HPLC were ≤1%, the reaction ended. Otherwise, the reaction was continued to be kept warm, and detection was carried out every 1 h until it was qualified;

[0034] The temperature was lowered to 20-30°C, and hydrazine hydrate was added to quench the excess hydrogen peroxide. The quenching was complete when the peroxide test paper was used; the temperature of the reaction solution was controlled at 20-30°C, and concentrated hydrochloric acid (85 mL) was added dropwise. After the addition was complete, the solution was stirred at 20-30°C to form salt crystals for 5 hours; after the crystallization was completed, the solution was filtered, and the filter cake was rinsed with an appropriate amount of anhydrous ethanol and filtered to dryness; the (R)-5-(2-(2,5-difluorophenyl)pyrrolidin-1-yl)-3-iodopyrazolo[1,5-A]pyrimidine hydrochloride wet material was transferred to another clean reaction bottle, 500 mL of purified water was added, stirring was started, the temperature of the reaction solution was controlled at 20-30°C, 20% NaOH solution was added dropwise, the pH was adjusted to 8-10, and the reaction was kept at 20-30°C for 1 hour, and the pH was retested. 8-10, otherwise repeat the pH adjustment step; after heat preservation, filter, rinse the filter cake with an appropriate amount of purified water, filter until dry, and vacuum dry at 50-55°C to obtain (R)-5-(2-(2,5-difluorophenyl)pyrrolidin-1-yl)-3-iodopyrazolo[1,5-A]pyrimidine (light yellow solid, 123.78 g, 87%, HPLC purity>98.5%). HRMS-ESI (m / z): C16H14F2IN4, calcd: [M+H]+427.0226; found 427.0236.

[0035] (2) After nitrogen replacement, add (R)-5-(2-(2,5-difluorophenyl)pyrrolidin-1-yl)-3-iodopyrazolo[1,5-A]pyrimidine (120.00 g, 281.55 mmol), methanol (500 mL), copper powder (8.95 g, 140.78 mmol) and ammonia water (435 mL) to the clean pressure reactor in sequence, close the lid of the reactor, start stirring, and react at 90-100°C for 24 h; after cooling and releasing the pressure, take samples for testing. If the raw material content in the reaction liquid is ≤1% by HPLC, the reaction is over. Otherwise, continue to keep the temperature for reaction and test every 4 h until it is qualified;

[0036] After the reaction was completed, the temperature was lowered and the pressure was released. The insoluble substances were removed by filtration, and the filtrate was concentrated under reduced pressure to dryness. 300 mL of dichloromethane was added to dissolve it, and then 200 mL of saturated brine was added. Extraction was carried out, and after standing, layering occurred. The aqueous layer was discarded, and the dichloromethane layer was washed again with 200 mL of purified water. The organic phase was concentrated under reduced pressure to half of its original volume, cooled to 20 - 30 °C, and n-hexane (600 mL) was added dropwise for crystallization. The dropping time was 4 - 5 h. After the dropping was completed, the temperature was lowered to 10 - 15 °C, and crystallization was carried out while maintaining the temperature for 5 h. After crystallization was completed, filtration was carried out, and it was washed with an appropriate amount of n-hexane and suction-filtered to dryness. It was dried under vacuum at 35 - 45 °C to obtain (R)-5-(2-(2,5-difluorophenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidin-3-amine (light brown solid, 78.31 g, 88%, HPLC purity > 98.5%). HRMS-ESI (m / z): C16H16F2N5, calcd: [M + H]+ 316.1368; found 316.1371.

[0037] Examples 2 - 7 were carried out in the same manner as in Example 1, except that the solvents for the iodination reaction were replaced with the following solvents respectively. The solvents used and the yields and purities of the corresponding products are shown in the following table.

[0038]

[0039] Example 8:

[0040] The preparation method of the larotrectinib intermediate in this example includes the following steps:

[0041] (1) After purging with nitrogen, (R)-5-[2-(2,5-difluorophenyl)pyrrolidin-1-yl]pyrazolo[1,5-a]pyrimidine (100.00 g, 332.99 mmol) and absolute ethanol (750 mL) were successively added to a clean reaction flask. Stirring was started, and after stirring evenly, it was heated to 45 - 50 °C, and recycled elemental iodine (content 85%, 49.71 g, 166.49 mmol) was added. The temperature of the reaction solution was controlled at 45 - 50 °C, and hydrogen peroxide (113.26 g, 998.96 mmol) was slowly added dropwise. The dropping time was 2.5 - 3.0 h. After the dropping was completed, the reaction was carried out while maintaining the temperature at 45 - 50 °C for 24 h. Sampling and testing were carried out. When the raw materials in the reaction solution detected by HPLC were ≤ 1%, the reaction was completed; otherwise, the reaction was continued while maintaining the temperature, and it was detected every 1 h until it was qualified.

[0042] The temperature was lowered to 20-30°C, and hydrazine hydrate was added to quench the excess hydrogen peroxide. The quenching was complete when the peroxide test paper was used; the temperature of the reaction liquid was controlled at 20-30°C, and concentrated hydrochloric acid (85 mL) was added dropwise. After the addition was completed, the mixture was stirred at 20-30°C to form salt crystals for 5 hours; after the crystallization was completed, the mixture was filtered, and the filter cake was rinsed with an appropriate amount of anhydrous ethanol and filtered to dryness; the (R)-5-(2-(2,5-difluorophenyl)pyrrolidin-1-yl)-3-iodopyrazolo[1,5-A]pyrimidine hydrochloride wet material was transferred to another clean reaction bottle, 500 mL of purified water was added, stirring was started, the temperature of the reaction liquid was controlled at 20-30°C, 20% NaOH solution was added dropwise, the pH was adjusted to 8-10, and the mixture was kept at 20-30°C for 1 hour, and the pH was measured again. 8-10, otherwise repeat the pH adjustment step; after the heat preservation is completed, filter, rinse the filter cake with an appropriate amount of purified water, filter until dry, and dry in vacuo at 50-55°C to obtain (R)-5-(2-(2,5-difluorophenyl)pyrrolidin-1-yl)-3-iodopyrazolo[1,5-A]pyrimidine (light yellow solid, 121.57 g, 86%, HPLC purity>98.5%).

[0043] (2) After nitrogen replacement, add (R)-5-(2-(2,5-difluorophenyl)pyrrolidin-1-yl)-3-iodopyrazolo[1,5-A]pyrimidine (120.00 g, 281.55 mmol), methanol (500 mL), copper powder (8.95 g, 140.78 mmol) and ammonia water (435 mL) to the clean pressure reactor in sequence, close the lid of the reactor, start stirring, and react at 90-100°C for 24 h; after cooling and releasing the pressure, take samples for testing. If the raw material content in the reaction liquid is ≤1% by HPLC, the reaction is over. Otherwise, continue to keep the temperature for reaction and test every 4 h until it is qualified;

[0044] After the reaction was completed, the temperature was lowered and the pressure was released. The insoluble matter was removed by filtration, and the filtrate was concentrated to dryness under reduced pressure. 300 mL of dichloromethane was added to dissolve, and then 200 mL of saturated brine was added. The mixture was extracted, allowed to stand, and separated into layers. The aqueous layer was discarded, and the dichloromethane layer was washed with 200 mL of purified water. The organic phase was concentrated under reduced pressure to half of the volume, cooled to 20-30° C., and n-hexane (600 mL) was added dropwise for crystallization for 4-5 h. After the addition was completed, the temperature was lowered to 10-15° C., and the temperature was kept for crystallization for 5 h. After the crystallization was completed, the mixture was filtered, washed with an appropriate amount of n-hexane, filtered to dryness, and dried in vacuo at 35-45° C. to obtain (R)-5-(2-(2,5-difluorophenyl)pyrrolidin-1-yl)pyrazolo[1,5-A]pyrimidin-3-amine (light brown solid, 78.41 g, 88%, HPLC purity>98.5%).

[0045] Examples 9-15 were carried out in the same manner as Example 1, except that the oxidizing agents in the iodination reaction were replaced by the following reagents. The oxidizing agents used and the yields and purities of the corresponding products are shown in the following table.

[0046]

[0047] Examples 16 - 25 were carried out in the same manner as Example 1, except that the copper catalysts for the amination reactions were replaced with the following reagents respectively. The yields and purities of the copper catalysts used and the corresponding products are shown in the following table.

[0048]

Claims

1. A preparation method of a larotrectinib intermediate, characterized in that It includes the following steps: (1) Iodination reaction In an alcohol solution, in the presence of an iodine source and an oxidant, using (R)-5-[2-(2,5-difluorophenyl)pyrrolidin-1-yl]pyrazolo[1,5-a]pyrimidine as the starting material, the (R)-5-[2-(2,5-difluorophenyl)pyrrolidin-1-yl]pyrazolo[1,5-a]pyrimidine undergoes iodination reaction at the C-3 position to synthesize the compound of formula (3) below; After the reaction is completed, the temperature is lowered, the reaction is quenched, then acid is added to form a salt, crystallization is carried out under heat preservation, filtration, washing, and drying are carried out to obtain the salt of (R)-5-(2-(2,5-difluorophenyl)pyrrolidin-1-yl)-3-iodopyrazolo[1,5-a]pyrimidine; the salt of (R)-5-(2-(2,5-difluorophenyl)pyrrolidin-1-yl)-3-iodopyrazolo[1,5-a]pyrimidine is neutralized with a base in an aqueous solution to free it, crystallization is carried out under heat preservation, filtration, washing, drying are carried out, and vacuum drying is carried out to obtain the pure product of the compound of formula (3); (2) Amination reaction The compound of formula (3) is dissolved in an alcohol solution, and a substitution reaction is carried out with an ammonia source under the action of a copper catalyst to obtain the compound of formula (1); After the reaction is completed, the temperature is lowered, filtration is carried out, and the filtrate is concentrated to dryness under reduced pressure; extraction is carried out with dichloromethane and saturated brine, and the dichloromethane layer is washed with purified water again; the organic phase is concentrated to half of its volume under reduced pressure, the temperature is lowered, a weakly polar organic solvent is added for crystallization, filtration, washing, drying are carried out, and vacuum drying is carried out to obtain the pure product of the compound of formula (1).

2. The preparation method of the larotrectinib intermediate according to claim 1, wherein: The reaction temperature of the iodination reaction in step (1) is 45-50 °C. After the iodination reaction is completed, the temperature is first lowered to 20-30 °C, and then a quenching agent is added to quench the reaction; crystallization is carried out with stirring under heat preservation at 20-30 °C.

3. The preparation method of the larotrectinib intermediate according to claim 1, characterized in that: The reaction temperature of the amination reaction in step (2) is 60-100 °C. After the amination reaction is completed, the temperature is first lowered to 20-30 °C, and then filtration and concentration are carried out; crystallization is carried out with stirring under heat preservation at 10-15 °C.

4. The preparation method of the larotrectinib intermediate according to claim 1 or 2 or 3, characterized in that: The alcohol solution in the iodination reaction is one or more of methanol, ethanol, 95% ethanol, n-propanol, isopropanol, n-butanol, 2-butanol, and the dosage is 3-10W of the mass of (R)-5-[2-(2,5-difluorophenyl)pyrrolidin-1-yl]pyrazolo[1,5-a]pyrimidine; the iodine source in the iodination reaction is one or two of elemental iodine and recycled elemental iodine, and the dosage is 0.5-1.1eq of the molar amount of (R)-5-[2-(2,5-difluorophenyl)pyrrolidin-1-yl]pyrazolo[1,5-a]pyrimidine.

5. The preparation method of the larotrectinib intermediate according to claim 1 or 2 or 3, characterized in that: The oxidant in the iodination reaction is one of hydrogen peroxide, tert-butyl hydroperoxide, urea peroxide, potassium peroxymonosulfate, sodium hypochlorite, sodium iodate, potassium iodate, and sodium periodate, and the dosage is 0.5-3.0eq of the molar amount of (R)-5-[2-(2,5-difluorophenyl)pyrrolidin-1-yl]pyrazolo[1,5-a]pyrimidine.

6. The preparation method of the larotrectinib intermediate according to claim 1 or 2 or 3, characterized in that: The quenching agent after the iodination reaction is one of hydrazine hydrate, sodium sulfite, sodium bisulfite, and sodium thiosulfate; the acid is one of hydrochloric acid, hydrobromic acid, and sulfuric acid, and the dosage is 1.0 - 5.0 eq in terms of the molar amount of (R)-5-[2-(2,5-difluorophenyl)pyrrolidin-1-yl]pyrazolo[1,5-a]pyrimidine; the base is one of sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, and sodium bicarbonate, which is used to adjust the pH to 8 - 10.

7. The preparation method of the larotrectinib intermediate according to claim 1 or 2 or 3, characterized in that: The alcohol solution in the amination reaction is one or more of methanol, ethanol, 95% ethanol, n-propanol, isopropanol, n-butanol, and 2-butanol, and the dosage is 3 - 10 W based on the mass of (R)-5-(2-(2,5-difluorophenyl)pyrrolidin-1-yl)-3-iodopyrazolo[1,5-a]pyrimidine.

8. The preparation method of the larotrectinib intermediate according to claim 1 or 2 or 3, characterized in that: The copper catalyst in the amination reaction is one of copper powder, nano-copper powder, cuprous oxide, cuprous iodide, cuprous bromide, cuprous chloride, copper oxide, nano-copper oxide, copper chloride, copper bromide, and copper acetate, and the dosage is 0.1 - 1.1 eq in terms of the molar amount of (R)-5-(2-(2,5-difluorophenyl)pyrrolidin-1-yl)-3-iodopyrazolo[1,5-a]pyrimidine.

9. The preparation method of the larotrectinib intermediate according to claim 1 or 2 or 3, characterized in that: The ammonia source in the amination reaction is one of ammonia water, ammonium chloride, and ammonium acetate, and the dosage is 1.0 - 10.0 eq in terms of the molar amount of (R)-5-(2-(2,5-difluorophenyl)pyrrolidin-1-yl)-3-iodopyrazolo[1,5-a]pyrimidine.

10. The preparation method of the larotrectinib intermediate according to claim 1 or 2 or 3, characterized in that: The weakly polar organic solvent is one or more of n-hexane, cyclohexane, n-heptane, petroleum ether, and toluene, and the dosage is 1 - 10 W based on the mass of (R)-5-(2-(2,5-difluorophenyl)pyrrolidin-1-yl)-3-iodopyrazolo[1,5-a]pyrimidine.

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