Preparation method of intermediates for tyrosine kinase inhibitors

Abstract

This invention discloses a method for preparing an intermediate of a tyrosine kinase inhibitor. The method involves mixing a compound of formula (I) or an acid addition salt of formula (I), a solvent, and a base, followed by the addition of a compound of formula (II), heating the reaction, and then post-processing to obtain the intermediate of the tyrosine kinase inhibitor of formula (III). The base is selected from cesium fluoride or potassium tert-butoxide. This method significantly improves the yield of the intermediate, achieving high raw material conversion efficiency and a product yield exceeding 60%, while maintaining a purity of over 70%, thus effectively reducing the subsequent preparation cost of the tyrosine kinase inhibitor.

Description

TECHNICAL FIELD

[0001] The present application relates to the technical field of organic synthesis, and more particularly to a preparation method of an intermediate of a tyrosine kinase inhibitor. BACKGROUND

[0002] Tyrosine kinase inhibitors are a class of compounds capable of inhibiting the activity of tyrosine kinase. Tyrosine kinase inhibitors can act as competitive inhibitors of adenosine triphosphate (ATP) and tyrosine kinase, or as tyrosine analogs to block the activity of tyrosine kinase, inhibit cell proliferation, and accelerate cell apoptosis. Tyrosine kinase inhibitors have the advantages of high selectivity and few side effects.

[0003] Tyrosine kinase inhibitors have become a hot field of research on anti-tumor drugs in the world. International research institutions and pharmaceutical groups attach great importance to the research and development of drugs targeting tyrosine kinase, including the development of small molecule tyrosine kinase inhibitors, specific monoclonal antibodies of tyrosine kinase, and antisense oligonucleotides. Currently, the marketed tyrosine kinase inhibitors include Gefitinib, Erlotinib, Lapatinib, etc. However, due to the low effective response rate of these marketed drugs, the easy occurrence of drug resistance, and some toxic side effects, there is an urgent need to develop other anti-tumor drugs with excellent anti-tumor effects, the ability to overcome drug resistance, and good tolerance.

[0004] Patent CN201410175636.X discloses a class of aminoquinazoline tyrosine kinase inhibitors with Pan-HER irreversible inhibition. These compounds have excellent anti-tumor effects, reduce the occurrence of drug resistance, and have good tolerance. In the patent, the synthesis process of the intermediate of the aminoquinazoline tyrosine kinase inhibitor: (4aR, 7aS)-6-(2,2-diethoxyethyl)hexahydro-5H-[1,4]dioxino[2,3-c]pyrrole is disclosed in Example 9, Step 2. (4aR, 7aS)-hexahydro-2H-[1,4]dioxino[2,3-c]pyrrole, 2-bromo-1,1-diethoxyethane, and diisopropylethylamine are dissolved in DMF, heated to 80°C, and reacted for 8.0 h to obtain the intermediate of the aminoquinazoline tyrosine kinase inhibitor: (4aR, 7aS)-6-(2,2-diethoxyethyl)hexahydro-5H-[1,4]dioxino[2,3-c]pyrrole (compound of formula III).

[0005]

[0006] However, the yield of the intermediate compound obtained by this synthesis process is low, only 37.1%. How to improve the yield and purity of the intermediate of aminoquinazoline tyrosine kinase inhibitor has become an urgent technical problem to be solved. Summary of the Invention

[0007] To address the aforementioned problems in the prior art, the primary objective of this invention is to provide a method for preparing intermediates of tyrosine kinase inhibitors. This method significantly improves the yield of intermediates of tyrosine kinase inhibitors, has high raw material conversion efficiency, and effectively reduces the subsequent preparation cost of tyrosine kinase inhibitors.

[0008] The above-mentioned objective of the present invention is achieved by the following solution:

[0009] This invention provides a method for preparing an intermediate for a tyrosine kinase inhibitor, the intermediate being named (4aR,7aS)-6-(2,2-diethoxyethyl)hexahydro-5H-[1,4]dioxanolo[2,3-c]pyrrole. This intermediate can be used to synthesize (E)-N-(4-((3-chloro-4-fluorophenyl)amino)-7-(methoxy-d3)quinazolin-6-yl)-4-((4aR,7aS)-hexahydro-6H-[1,4]dioxanolo[2,3-c]pyrrole-6-yl)but-2-enamide, which is a known tyrosine kinase inhibitor compound.

[0010] The present invention provides a method for preparing an intermediate of a tyrosine kinase inhibitor, comprising mixing a compound of formula (I) or an acid addition salt of compound (I), a solvent and a base, followed by the addition of a compound of formula (II), heating reaction, and post-treatment to obtain an intermediate of a tyrosine kinase inhibitor of compound (III); wherein the base is selected from cesium fluoride or potassium tert-butoxide; the structures of the compounds of formula (I), formula (II) and formula (III) are shown below:

[0011]

[0012] This invention optimized and screened the above-mentioned reactions, finding that using organic bases in the reaction system led to excessively long reaction times and a large amount of residual raw materials in the product; while using inorganic bases such as K2CO3, KHCO3, and Na2CO3 resulted in complex reactions and low yields. Furthermore, the inventors discovered through screening that, in a reaction system using cesium fluoride or potassium tert-butoxide, combined with a specific reaction solvent, the product yield obtained was ≥48%, with a purity ≥60%, and high raw material conversion efficiency. The preparation method significantly improved the yield and purity of (4aR,7aS)-6-(2,2-diethoxyethyl)hexahydro-5H-[1,4]dioxane[2,3-c]pyrrole. In addition, the high raw material conversion efficiency significantly reduced the cost of subsequent tyrosine kinase inhibitor preparation.

[0013] Preferably, the acid addition salt of the compound of formula (I) is the hydrochloride salt of the compound of formula (I), or the hydrobromide salt of the compound of formula (I), or the phosphate salt of the compound of formula (I), or the acetate salt of the compound of formula (I). More preferably, the acid addition salt of the compound of formula (I) is the hydrochloride salt of the compound of formula (I). The acid addition salt of the compound of formula (I) is more conducive to preservation than the compound of formula (I).

[0014] Preferably, the solvent is selected from one or more of dimethyl sulfoxide, 1,2-ethylene glycol or tert-butanol.

[0015] Preferably, the base is selected from potassium tert-butoxide.

[0016] More preferably, the solvent is selected from 1,2-ethylene glycol or tert-butanol. To further improve the yield of the intermediate, the base is potassium tert-butoxide, and the solvent is selected from one or both of 1,2-ethylene glycol and tert-butanol. With this selection, the product yield is ≥60%, and the purity is ≥70%.

[0017] Most preferably, the base is potassium tert-butoxide and the solvent is tert-butanol.

[0018] Preferably, the equivalence ratio of the compound of formula (I) or the acid addition salt of the compound of formula (I) to the compound of formula (II) is 1.0:(0.9-1.5); preferably, the equivalence ratio of the compound of formula (I) or the acid addition salt of the compound of formula (I) to the compound of formula (II) is 1.0:(1.2-1.5); more preferably, the equivalence ratio of the compound of formula (I) or the acid addition salt of the compound of formula (I) to the compound of formula (II) is 1.0:1.2.

[0019] Preferably, the equivalent ratio of the compound of formula (I) or the acid addition salt of the compound of formula (I) to the base is 1.0:(1.8-2.5); preferably, the equivalent ratio of the compound of formula (I) or the acid addition salt of the compound of formula (I) to the base is 1.0:(2.0-2.5); more preferably, the equivalent ratio of the compound of formula (I) or the acid addition salt of the compound of formula (I) to the base is 1.0:2.0.

[0020] Preferably, the ratio of the compound of formula (I) or its acid addition salt to the solvent is 1 g : (4-8) mL. More preferably, the ratio of the compound of formula (I) or its acid addition salt to the solvent is 1 g : (4-5) mL.

[0021] Preferably, the heating temperature is 80–100°C. More preferably, the heating temperature is 90°C.

[0022] Preferably, the post-treatment involves adding water to the reaction solution, followed by extraction with an organic solvent, washing, drying, and concentration to obtain the compound of formula (III). More specifically, the organic solvent extraction is performed twice: first, extraction with n-hexane, discarding the n-hexane layer, and then extraction of the aqueous layer with dichloromethane.

[0023] Compared with the prior art, the present invention has the following beneficial effects:

[0024] This invention provides a method for preparing an intermediate for tyrosine kinase inhibitors. The intermediate is (4aR,7aS)-6-(2,2-diethoxyethyl)hexahydro-5H-[1,4]dioxane[2,3-c]pyrrole. The method significantly improves the yield of the intermediate, has high raw material conversion efficiency, and effectively reduces the cost of subsequent tyrosine kinase inhibitor preparation. The method features a simple reaction process and convenient post-reaction processing, making it suitable as an intermediate for preparing antitumor drug tyrosine kinase inhibitors, and thus possessing very broad application prospects. Detailed Implementation

[0025] The present invention will be further described in detail below with reference to specific embodiments. These embodiments are only used to explain the present invention and are not intended to limit the scope of the present invention. Unless otherwise specified, the experimental methods used in the following embodiments are conventional methods; the materials and reagents used are commercially available unless otherwise specified.

[0026] In this invention, the equivalence ratio is a molar equivalence ratio, and the unit of equivalence is eq. For example, the equivalence ratio of compound (I) or its acid addition salt to compound (II) is 1.0:(0.9 to 1.5), which means that when the amount of compound (I) or its acid addition salt is 1.0 mol, the amount of compound (II) is 0.9 to 1.5 mol. That is, when the relative amounts of the two are expressed in equivalence, the amount of compound (I) or its acid addition salt is 1.0 eq, and the amount of the base is 0.9 to 1.5 eq.

[0027] In this invention, DMSO represents dimethyl sulfoxide, DME represents dimethyl ether, MeCN represents acetonitrile, NMP represents N-methylpyrrolidone, EtOH represents ethanol, THF represents tetrahydrofuran, DMF represents N,N-dimethylformamide, t-BuOH represents tert-butanol, t-BuOK represents potassium tert-butoxide, CsF represents cesium fluoride, DIPEA represents N,N-diisopropylethylamine, Cs2CO3 represents cesium carbonate, 1,4-Dioxane represents 1,4-dioxane, 1,2-ethanediol represents 1,2-ethylene glycol, and Acetone represents acetone.

[0028] Low-resolution mass spectrometry (MS) data were determined using an Agilent 6320 series LC-MS spectrometer equipped with a G1312A binary pump and a G1316A TCC (column temperature maintained at 30°C). A G1329A autosampler and a G1315B DAD detector were used for analysis, and an ESI source was used in the LC-MS spectrometer.

[0029] Low-resolution mass spectrometry (MS) data were determined using an Agilent 6120 series LC-MS spectrometer equipped with a G1311A quaternary pump and a G1316ATCC (column temperature maintained at 30°C). A G1329A autosampler and a G1315D DAD detector were used for analysis, and an ESI source was used in the LC-MS spectrometer.

[0030] Both spectrometers were equipped with an Agilent Zorbax SB-C18 column, measuring 2.1 × 30 mm and 5 μm. The injection volume was determined by the sample concentration; the flow rate was 0.6 mL / min; HPLC peak values ​​were recorded and read using UV-Vis wavelengths at 210 nm and 254 nm. The mobile phase consisted of a 0.1% formic acid-acetonitrile solution (phase A) and a 0.1% formic acid ultrapure aqueous solution (phase B).

[0031] Nuclear magnetic resonance (NMR) spectral data were determined using a Bruker Avance 400 NMR spectrometer or a Bruker Avance III HD600 NMR spectrometer, with CDCl3, DMSO-d6, CD3OD, or Acetone-d6 as solvents (reported in ppm), and TMS (0 ppm) or chloroform (7.25 ppm) as reference standards. When multiple peaks occur, the following abbreviations are used: s (single), d (doublet), t (triplet), m (multiplet), q (quartet), br (broadened), dd (doublet of doublets), dt (doublet of triplets), dq (doublet of quartets), ddd (doublet of doublets), ddt (doublet of doublets), dddd (doublet of doublets). The coupling constant is represented by Hertz (Hz).

[0032] Compound purity was evaluated by Agilent 1100 series high performance liquid chromatography (HPLC), with UV detection at 210 nm and 254 nm, Zorbax SB-C18 column, specifications 2.1 × 30 mm, 4 μm, 10 min, flow rate 0.6 mL / min, 5-95% (0.1% formic acid acetonitrile solution) (0.1% formic acid aqueous solution), column temperature maintained at 40 °C.

[0033] Example 1: Preparation of intermediates for tyrosine kinase inhibitors

[0034] At 25 °C, compound (I) (chemical name: (4aR,7aS)-hexahydro-2H-[1,4]dioxane[2,3-c]pyrrole hydrochloride, 10.35 g, 62.49 mmol) was dissolved in t-BuOH (50 mL), followed by the addition of t-BuOK (17.7 g, 156.2 mmol, 99% purity), and the reaction was heated to 90 °C. Then, compound (II) bromoacetaldehyde diethanol condensate (equivalent ratio of compound (I) hydrochloride to compound (II) was 1:1.2) was slowly added dropwise, and the reaction was continued after the addition was complete. TLC was used for monitoring, and GC (gas chromatography) was used for monitoring until compound (I) ≤ 1.0%. The mixture was cooled to room temperature, and the reaction solution was poured into water (80 mL). Then, n-hexane (80 mL × 2) was added for extraction twice. The n-hexane layer was discarded, and the aqueous layer was further extracted with dichloromethane (80 mL). The organic phase was washed with saturated brine (80 mL × 3), dried over anhydrous sodium sulfate, and concentrated to obtain compound (III) (an intermediate for a tyrosine kinase inhibitor), specifically named (4aR,7aS)-6-(2,2-diethoxyethyl)hexahydro-5H-[1,4]dioxane[2,3-c]pyrrole, 9.5 g (yield: 62%, HPLC: 69.43%). The chromatographic data are shown below: MS (ESI, pos.ion) m / z: 246.2 [M+1] + ; 1 ¹H NMR (400MHz, CDCl₃): δ 4.54 (t, 1H), 4.05 (s, 2H), 3.75 (m, 2H), 3.68 (m, 2H), 3.54 (m, 4H), 2.88 (m, 2H), 2.80 (m, 2H), 2.65 (d, 2H), 1.21 (t, 6H). The specific reaction formula is as follows:

[0035]

[0036] Process optimization of intermediates for tyrosine kinase inhibitors (Examples 2-19)

[0037] Examples 2-19 follow the preparation process of Example 1, with the differences shown in Table 1 below. The specific reaction results are also shown in Table 1. The alkaline auxiliaries used include CsF, DIPEA, Cs₂CO₃, and t-BuOK. The solvents used include DMSO, NMP, THF, DMF, MeCN, 1,4-Dioxane, 1,2-ethanediol, EtOH, DME, t-BuOH, and Acetone.

[0038] Table 1

[0039]

[0040] Note: In the table, "N / A" indicates that the yield was not calculated further because the HPLC purity of compound (III) in the reaction solution after the reaction was too low or the HPLC of the reaction solution showed a lot of impurities (HPLC purity was much lower than 40%); "produced a lot of impurities" means that the HPLC purity was much lower than 40%.

[0041] As shown in Table 1 above, when CsF is used as an alkaline additive in processes 2-7, the yields of the products in processes 2 and 3 are 50% and 48% respectively, and the purities are 70% and 67% respectively, when DMSO is used as the solvent. However, when other solvents are selected, the purity of the products is too low.

[0042] Processes 8 and 9-13 use DIPEA and Cs₂CO₃ as alkaline additives, respectively. Data shows that when DIPEA is used as the alkaline additive, the product yield and purity are too low. When Cs₂CO₃ is used as the alkaline additive, the product purity is 50%, 40%, and 60% respectively when the solvents are THF, DMF, and NMP, which are also too low.

[0043] Processes 14-19 are examples using 0.1g of compound (I) hydrochloride and t-BuOH as an alkaline auxiliary agent. As shown in the table, the product purity is too low when the solvent is THF, MeCN, or DMF. When DMSO, 1,2-ethylene glycol, or t-BuOH are used as solvents, the product yield is between 50% and 62% and the purity is between 40% and 80% at 80°C.

[0044] Finally, it should be noted that the above embodiments are only used to illustrate the technical solutions of the present invention and are not intended to limit the scope of protection of the present invention. For those skilled in the art, other variations or modifications can be made based on the above description and ideas, and it is neither necessary nor possible to exhaustively describe all implementation methods here. Any modifications, equivalent substitutions, and improvements made within the spirit and principles of the present invention should be included within the scope of protection of the claims of the present invention.

Claims

1. A process for the preparation of an intermediate of a tyrosine kinase inhibitor, characterized in that, The compound of formula (I) or the acid addition salt of the compound of formula (I) is mixed with a base selected from cesium fluoride or potassium tert-butoxide, heated, and the compound of formula (II) is added to react, and after treatment, an intermediate of the tyrosine kinase inhibitor of formula (III) is obtained; when the base is cesium fluoride, the solvent is selected from dimethyl sulfoxide; when the base is potassium tert-butoxide, the solvent is selected from one or more of dimethyl sulfoxide, 1,2-ethanediol or tert-butanol; the structures of the compound of formula (I), the compound of formula (II) and the compound of formula (III) are as follows: ， ， 。 2. The production method according to claim 1, characterized by, The acid addition salt of the compound of formula (I) is a hydrochloride salt of the compound of formula (I), or a hydrobromide salt of the compound of formula (I), or a phosphate salt of the compound of formula (I), or an acetate salt of the compound of formula (I).

3. The preparation method according to claim 1, characterized in that, The base is selected from potassium tert-butoxide.

4. The production method according to claim 1, characterized by, The equivalent ratio of the compound of formula (I) or the acid addition salt of the compound of formula (I) to the compound of formula (II) is 1.0:(0.9-1.5).

5. The preparation method according to claim 4, characterized in that, The equivalent ratio of the compound of formula (I) or the acid addition salt of the compound of formula (I) to the compound of formula (II) is 1.0:(1.2-1.5).

6. The production method according to claim 5, wherein The equivalent ratio of the compound of formula (I) or the acid addition salt of the compound of formula (I) to the compound of formula (II) is 1.0:1.

2.

7. The preparation method according to claim 1, characterized in that, The equivalent ratio of the compound of formula (I) or the acid addition salt of the compound of formula (I) to the base is 1.0:(1.8-2.5).

8. The production method according to claim 7, characterized by, The equivalent ratio of the compound of formula (I) or the acid addition salt of the compound of formula (I) to the base is 1.0:(2.0-2.5).

9. The production method according to claim 8, characterized by, The equivalent ratio of the compound of formula (I) or the acid addition salt of the compound of formula (I) to the base is 1.0:2.

0.

10. The method of claim 1, wherein, The amount ratio of the compound of formula (I) or the acid addition salt of the compound of formula (I) to the solvent is 1g:(4-8)mL.

11. The method of claim 1, wherein, The heating temperature is 80-100°C.

12. The method of claim 1, wherein, The after-treatment is: water is added to the reaction solution, followed by extraction with an organic solvent, washing, drying, and concentration to obtain the compound of formula (III).

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