TW202342426A - N-[(6-bromopyridin-3-yl) methyl]-2-methoxyethan-1-amine salts and preparation thereof - Google Patents

Abstract

Disclosed herein are salts of N-[(6-bromopyridin-3-yl) methyl]-2-methoxyethan-1-amine, particularly semi-D- Tartrate of N-[(6-bromopyridin-3-yl) methyl]-2-methoxyethan-1-amine, and methods for preparing thereof.

Description

N-[(6-bromopyridin-3-yl)methyl]-2-methoxyethane-1-amine salt and preparation method thereof

Disclosed herein are salts of N-[(6-bromopyridin-3-yl)methyl]-2-methoxyethane-1-amine and methods for preparing the same.

International Publication Nos. WO2009/026717, WO2009/026720, WO2009/109035, WO2019/182274, WO2021/098769, and European Publication No. EP3819300 disclose inhibitory activities of multiple protein tyrosine kinases (such as VEGF receptor kinase and HGF receptor kinase inhibitory activity) compounds. In particular, the disclosed N-(3-fluoro-4-((2-(5-(((2-methoxyethyl)amino)methyl)pyridin-2-yl)thieno[3, 2-b]pyridin-7-yl)oxy)phenyl)-N-(4-fluorophenyl)cyclopropane-1,1-dimethylamide ( compound 1 ) is a closely related tyramine with the Multiple tyrosine kinase inhibitors that potently inhibit the acid kinase spectrum, including RET, CBL, CHR4q12, DDR, and Trk, which are key regulators of signaling pathways leading to cell growth, survival, and tumor progression: Compound 1

In WO2009/026717, WO2009/026720, WO2009/109035, WO2019/182274, WO2021/098769, and EP3819300, the intermediate N-[(6-bromopyridin-3-yl)methyl]-2-methoxyethane Alk-1-amines ( MGA3 ) are obtained by reductive amination between 6-bromopyridine-3-carbaldehyde and 2-methoxyethylamine in the presence of NaBH(OAc) ₃ . In addition, MGA3 is not obtained in the form of an ideal solid but in the form of an oil or liquid with lower chemical purity, which contains more than 8 impurities (impurities), and three of these impurities cannot migrate well. remove. Therefore, new methods for N-[(6-bromopyridin-3-yl)methyl]-2-methoxyethane-1-amine ( MGA3 ) are highly needed to provide MGA3 as a high quality intermediate, To satisfy compound 1 manufacture.

Six pharmaceutically acceptable acids, including D-(-)-tartaric acid, oxalic acid, p-toluenesulfonic acid, D-DTTA, citric acid, and malic acid, were used for N-[(6-bromopyridin-3-yl ) salt of methyl]-2-methoxyethane-1-amine ( MGA3 ) was formed, and six organic solvents, including 2-MeTHF, MTBE, IPAc, acetone, methanol, or acetonitrile, were used to prepare N- Reaction solvent for [(6-bromopyridin-3-yl)methyl]-2-methoxyethane-1-amine ( MGA3 ). However, it is only obtained when the acids are D-(-)-tartaric acid, p-toluenesulfonic acid, D-DTTA, and malic acid and the above reaction solvent is independently selected from 2-MeTHF, MTBE, IPAc, acetone, or methanol A limited number of solids in good physical form and of high purity.

Considering environmental friendliness and manufacturing cost, it is recommended to use D-(-)-tartaric acid for N-[(6-bromopyridin-3-yl)methyl]-2-methoxyethane-1-amine ( MGA3 ) salt is formed, and it is recommended to use 2-MeTHF as the reaction solvent for preparing MGA3 , which produces the D-tartrate salt of MGA3 . The D-tartrate salt of MGA3 is obtained as a fine solid, in which the molecular ratio of D-tartaric acid to MGA3 (free base) is from 0.5 to 1.2. However, MGA3 D-tartrate (1:1) did not show good enough physical form and contained more impurities when stirred. Finally, MGA3 hemi-D-tartrate is prepared in a white to off-white crystalline form, which provides chemical purity up to 99.9% (HPLC) and ideal yields greater than 80% of MGA3 , and MGA3 hemi-D-tartrate. The solid separates easily and shows minimal hygroscopicity and is stable. MGA3 hemi-D-tartrate showed good stability, including water content, when stored for up to 3 months at 20°C/60% RH and 40°C/75% RH. DVS data shows that MGA3 hemi-D-tartrate is minimally hygroscopic.

The inventors of the present invention discovered that all impurities in the salt solid obtained in the present invention arise from procedures similar to those in documents such as WO2009/026717, WO2009/026720, WO2009/109035, WO2019/182274, WO2021/098769, and EP3819300. Both are nicely removed. In addition, when the water content of MGA3 in an organic solvent (such as MGA3 2-MeTHF solution) is higher than 3.0% (wt%), N-[(6-bromopyridin-3-yl)methyl]-2- Significant loss of methoxyethane-1-amine hemi-D-tartrate ( MGA3 hemi-D-tartrate). In addition, when the added molecular ratio of D-tartrate to MGA3 in the water bath is about 1:1, N-[(6-bromopyridin-3-yl)methyl]-2-methoxy can be obtained in good physical form. Ethane-1-amine D-tartrate, MGA3 D-tartrate (1:1). In some batches, when approximately D-tartrate was added directly to the reaction (where the added molecular ratio of D-tartrate to MGA3 was approximately 0.8:1), MGA3 D-tartrate was obtained as an oil.

In a first aspect, provided herein are salts of N-[(6-bromopyridin-3-yl)methyl]-2-methoxyethane-1-amine having formula ( I ), (I) .

In a second aspect, provided herein are salts of N-[(6-bromopyridin-3-yl)methyl]-2-methoxyethane-1-amine having formula ( I ), (I) wherein the salt is tartrate, p-toluenesulfonate, DDTA salt, or malate.

In a third aspect, provided herein is a tartrate salt of N-[(6-bromopyridin-3-yl)methyl]-2-methoxyethane-1-amine having formula ( II ), (II) , where n is a number from 0.4 to 1.2.

The salts of the above first, second and third aspects can be in the form of fine solids to provide N-[(6-bromopyridin-3-yl)methyl]-2-methoxyethane-1 with high chemical purity. -Amine ( MGA3 ). Moreover, when the salt is a tartrate salt of MGA3 (especially a hemi-D-tartrate salt), the salt is in a good crystalline form with a chemical purity of up to 99.9% (HPLC) and an ideal yield of greater than 80%, and MGA3 is half -D-Tartrate solids can be easily separated and show little hygroscopicity and are stable.

In a fourth aspect, provided herein are methods for preparing salts of N-[(6-bromopyridin-3-yl)methyl]-2-methoxyethane-1-amine ( MGA3 ) according to The sequence includes the following steps, a) adding 2-methoxyethylamine to 6-bromopyridine-3-carbaldehyde in an organic solvent; b) adding sodium triacetyloxyborohydride to obtain N-[(6-bromo Pyridin-3-yl)methyl]-2-methoxyethane-1-amine; c) N-[(6-bromopyridin-3-yl)methyl]-2-methoxyethane- 1-amine is dissolved in an organic solvent; and d) acid is added to the mixture obtained in step c) to obtain the target salt,

In a fifth aspect, provided herein is a method for preparing a salt of N-[(6-bromopyridin-3-yl)methyl]-2-methoxyethane-1-amine ( MGA3 ) according to The sequence includes the following steps, a) adding 2-methoxyethylamine to 6-bromopyridine-3-carbaldehyde in an organic solvent; b) adding sodium triacetyloxyborohydride to obtain N-[(6-bromo Pyridin-3-yl)methyl]-2-methoxyethane-1-amine; c) N-[(6-bromopyridin-3-yl)methyl]-2-methoxyethane- The 1-amine is dissolved in the organic solvent; and d) the corresponding salt is added to the mixture obtained in step c) to obtain the product. The salt is tartrate, p-toluenesulfonate, DDTA salt, or malate.

In a sixth aspect, provided herein are methods for preparing N-[(6-bromopyridin-3-yl)methyl]-2-methoxyethane-1-amine D-tartrate, in the order Contains the following steps, a) Add 2-methoxyethylamine to 6-bromopyridine-3-carbaldehyde in an organic solvent (preferably 2-MeTHF); b) Add sodium triacetyloxyborohydride to obtain N-[(6-bromopyridin-3-yl)methyl]-2-methoxyethane-1-amine; c) Dissolve N-[(6-bromopyridin-3-yl)methyl]-2-methoxyethane-1-amine in an organic solvent; and d) Add D-tartaric acid to the mixture obtained in step c) to obtain the product.

In one embodiment, a molecular ratio of D-tartrate to MGA3 of about 1:1 is added batch by batch to obtain N-[(6-bromopyridin-3-yl)methyl]-2- in good physical form Methoxyethane-1-amine D-tartrate (1:1).

In a seventh aspect, provided herein is the preparation of N-[(6-bromopyridin-3-yl)methyl]-2-methoxyethane-1-amine semi-D-tartrate ( MGA3 semi -D - tartrate ) method, which includes the following steps in sequence, a) adding 2-methoxyethylamine to 6-bromopyridine-3-carbaldehyde in an organic solvent (preferably 2-MeTHF); b) adding Sodium triacetyloxyborohydride to obtain N-[(6-bromopyridin-3-yl)methyl]-2-methoxyethane-1-amine; c) N-[(6-bromopyridine -3-yl)methyl]-2-methoxyethane-1-amine is dissolved in the organic solvent; and d) D-tartaric acid is added to the mixture obtained in step c) to obtain the product.

The methods in the fourth, fifth, sixth and seventh aspects above can provide N-[(6-bromopyridin-3-yl)methyl]-2-methoxyethane-1- as a fine solid Amine ( MGA3 ) salts and provide MGA3 with high chemical purity.

In an eighth aspect, provided herein is the preparation of N-(3-fluoro-4-((2-(5-((2-methoxyethyl)amino)methyl)methyl)pyridin-2-yl )thieno[3,2-b]pyridin-7-yl)oxy)phenyl)-N-(4-fluorophenyl)cyclopropane-1,1-dimethylamide ( compound 1 ) or its medicine The method for preparing the above acceptable salts, which includes the preparation of N-[(6-bromopyridin-3-yl)methyl]-2-methoxyethane-1-amine hemi-D-tartrate ( MGA3 Semi -D- tartrate ) method, which includes the following steps in sequence, a) reacting 6-bromopyridine-3-carbaldehyde with 2-methoxyethylamine in an organic solvent (preferably 2-MeTHF); b) Add sodium triacetyloxyborohydride to obtain N-[(6-bromopyridin-3-yl)methyl]-2-methoxyethane-1-amine; c) Add N-[(6 -Bromopyridin-3-yl)methyl]-2-methoxyethane-1-amine is dissolved in the organic solvent; and d) D-tartaric acid is added to the mixture obtained in step c) to obtain the product.

In a first aspect, provided herein are salts of N-[(6-bromopyridin-3-yl)methyl]-2-methoxyethane-1-amine having formula ( I ), (I) .

In a second aspect, provided herein are salts of N-[(6-bromopyridin-3-yl)methyl]-2-methoxyethane-1-amine having formula ( I ), (I) wherein the salt is tartrate, p-toluenesulfonate, DDTA salt, or malate.

In one embodiment, the salt is in a solid state.

In one embodiment, the salt is a tartrate salt, or a DDTA salt (such as a D-DTTA salt), preferably a tartrate salt (such as a D-(-)-tartrate salt).

In a third aspect, provided herein is a tartrate salt of N-[(6-bromopyridin-3-yl)methyl]-2-methoxyethane-1-amine having formula ( II ), (II) , where n is a number from 0.4 to 1.2

In one embodiment, n ranges from 0.4 to 1.0. In a preferred embodiment, n is 0.5. In another preferred embodiment, n is 1.0.

In a fourth aspect, provided herein are methods for preparing salts of N-[(6-bromopyridin-3-yl)methyl]-2-methoxyethane-1-amine ( MGA3 ) according to The sequence includes the following steps, a) adding 2-methoxyethylamine to 6-bromopyridine-3-carbaldehyde in an organic solvent; b) adding sodium triacetyloxyborohydride to obtain N-[(6-bromo Pyridin-3-yl)methyl]-2-methoxyethane-1-amine; and c) adding the corresponding acid to the resulting mixture to obtain the target salt.

In a fifth aspect, provided herein is a method for preparing a salt of N-[(6-bromopyridin-3-yl)methyl]-2-methoxyethane-1-amine ( MGA3 ) according to The sequence includes the following steps, a) adding 2-methoxyethylamine to 6-bromopyridine-3-carbaldehyde in an organic solvent; b) adding sodium triacetyloxyborohydride to obtain N-[(6-bromo Pyridin-3-yl)methyl]-2-methoxyethane-1-amine; c) N-[(6-bromopyridin-3-yl)methyl]-2-methoxyethane- The 1-amine is dissolved in the organic solvent; and d) adding acid to the mixture obtained in step c) to obtain the target salt, wherein the salt is tartrate, p-toluenesulfonate, DDTA salt, or malate.

In a sixth aspect, provided herein are methods for preparing N-[(6-bromopyridin-3-yl)methyl]-2-methoxyethane-1-amine D-tartrate, in the order Contains the following steps, a) Add 2-methoxyethylamine to 6-bromopyridine-3-carbaldehyde in an organic solvent; b) Add sodium triacetyloxyborohydride to obtain N-[(6-bromopyridin-3-yl)methyl]-2-methoxyethane-1-amine; c) Dissolve N-[(6-bromopyridin-3-yl)methyl]-2-methoxyethane-1-amine in an organic solvent; and d) Add D-tartaric acid to the mixture obtained in step c) to obtain the product.

In one embodiment, D-tartaric acid is added batch by batch to obtain N-[(6-bromopyridin-3-yl)methyl]-2-methoxyethane-1-amine D- in good physical form Tartrate (1:1).

In a seventh aspect, provided herein is the preparation of N-[(6-bromopyridin-3-yl)methyl]-2-methoxyethane-1-amine semi-D-tartrate ( MGA3 semi -D - tartrate ) method, which includes the following steps in sequence, a) adding 2-methoxyethylamine to 6-bromopyridine-3-carbaldehyde in an organic solvent; b) adding sodium triacetyloxyborohydride To obtain N-[(6-bromopyridin-3-yl)methyl]-2-methoxyethane-1-amine; c) N-[(6-bromopyridin-3-yl)methyl] -2-Methoxyethane-1-amine is dissolved in the organic solvent; and d) D-tartaric acid is added to the mixture obtained in step c) to obtain the product.

In some embodiments, the organic solvent is selected from 2-MeTHF, MTBE, IPAc, acetone, or methanol, preferably 2-MeTHF, MTBE, or IPAc, and more preferably 2-MeTHF.

In one embodiment, the stoichiometric ratio of the D-tartrate added in step d) is 0.4 to 1.2, preferably 0.5, and it is with N-[(6-bromopyridin-3-yl)methyl]- 2-methoxyethane-1-amine for comparison.

In one embodiment, N-[(6-bromopyridin-3-yl)methyl]-2-methoxyethane-1-amine ( MGA3 ) in step c) is dissolved in an organic solvent such as 2- The water content in MeTHF solution) is controlled at 0~10%, preferably 0~5%, and preferably no more than 3.0% (wt%).

In one embodiment, the temperature for reacting 6-bromopyridine-3-carbaldehyde and 2-methoxyethylamine is 20°C ~ 30°C.

In one embodiment, seed crystals of MGA3 semi -D - tartaric acid salt are added before adding D-tartaric acid to the mixture obtained in step c) in step d).

In an eighth aspect, provided herein is the preparation of N-(3-fluoro-4-((2-(5-((2-methoxyethyl)amino)methyl)methyl)pyridin-2-yl )thieno[3,2-b]pyridin-7-yl)oxy)phenyl)-N-(4-fluorophenyl)cyclopropane-1,1-dimethylamide ( compound 1 ) or its medicine The method for preparing the above acceptable salts, which includes the preparation of N-[(6-bromopyridin-3-yl)methyl]-2-methoxyethane-1-amine hemi-D-tartrate ( MGA3 Semi -D- tartrate ) method, which includes the following steps in sequence, a) adding 2-methoxyethylamine to 6-bromopyridine-3-carbaldehyde in an organic solvent; b) adding triacetyloxy Sodium borohydride to obtain N-[(6-bromopyridin-3-yl)methyl]-2-methoxyethane-1-amine; c) N-[(6-bromopyridin-3-yl) Methyl]-2-methoxyethane-1-amine is dissolved in the organic solvent; and d) D-tartaric acid is added to the mixture obtained in step c) to obtain the product. Example

The present invention is further illustrated by the following examples that illustrate the invention, but are not limited to these examples. The following are examples for the preparation of N-[(6-bromopyridin-3-yl)methyl]-2-methoxyethane-1-amine and its salts. Analytical method:

NMR, water content testing, and HPLC can be performed by methods known to those of ordinary skill in the art to which the invention pertains. ¹ H NMR of MGA3 hemi- D- tartrate : ¹ H NMR (400 MHz, d-DMSO) 8.38 (d, J=2.3 Hz, 1H), 7.79 (dd, J=8.2, 2.5Hz, 1H), 7.63 (d, J=8.2 Hz, 1H), 6.39 (br s, 5 H), 4.04(s, 2 H), 3.88(s, 2 H), 3.47(t, J=5.5Hz, 2 H), 3.25 (s, 3 H), 2.80 (t, J=5.5Hz, 2 H).

HPLC is used to characterize the content of compounds during the process and to determine the molecular ratio of the salts formed in the present invention. In some embodiments, experimental error is known to one of ordinary skill in the art to which the invention pertains and is accepted by the pharmaceutical industry. Example 1 Research on reaction solvent

2-Methoxyethylamine (12.1 g, 161.4 mmol, 3.0 eq., MGA2 ) was added to 6-bromopyridine-3-carbaldehyde (10.0 g, 53.8 mmol, 1.0 eq., MGA1 ) in 2-methyltetrahydrofuran (100 mL, 2-MeTHF) or isopropyl acetate (IPAc) and stir the mixture at a temperature of 20 °C - 30 °C. After about 4 hours, sodium triacetyloxyborohydride (26.3 g, 124.1 mmol, 2.3 eq., NaBH(OAc) ₃ ) was added to the mixture and stirred for about 20 hours to obtain N-[(6- Bromopyridin -3- yl ) methyl ]-2- methoxyethane -1- amine ( MGA3 ) .

During the reaction, the test corresponds to IPC ( MGA1/MGA3 ) ( see Table 1 ). The results show that 1) 3.2% (HPLC area %) of MGA1 is left and potential transesterification may occur when the reaction solvent is IPAc, and 2) most of the MGA1 is converted to MGA3 when the reaction solvent is 2-MeTHF. Table 1 : reaction solvent IPC ( MGA1 /MGA3 , area % ) 2-MeTHF 0.8/97.3 IPAc 3.2/89.1 Example 2 Reaction temperature research step 1 : N-[(6- bromopyridin -3- yl ) methyl ]-2- methoxyethane -1- amine ( MGA3 )

The desired compound N-[(6-bromopyridin-3-yl)methyl]-2-methoxyethane-1-amine ( MGA3 ) was produced by a procedure similar to that disclosed in Example 1 , wherein The reaction temperature ranges from 10°C to 40°C, and the reaction solvent is 2-MeTHF.

The corresponding IPC ( MGA1/MGA3 ) was tested during the reaction ( see Table 2 ). The results showed: 1) When the reaction was carried out at 15°C for 20 hours, 5.0% (HPLC area %) of MGA1 was left, which was inconsistent with the IPC specification (not exceeding (NMT) 2.0%); 2) When the reaction temperature system At 18°C or higher, the starting material MGA1 was completely converted into MGA3 within 20 hours. However, when the reaction temperature increased to 40°C, the HPLC purity of MGA3 significantly decreased from 93.6% to 87.9%. Therefore, when the reaction temperature is within 20°C ~ 30°C (preferably 20°C) and the reaction time is about 20 hours, MGA3 with high purity and conversion rate is obtained. Table 2 : reaction temperature IPC at 20 h ( MGA1 /MGA3 ) 10℃ 49.9/45.9 15℃ 5.0/91.8 18℃ 1.2/94.0 20℃ 0.06/95.3 25℃ Not detected/93.6 40℃ Not detected/87.9 Example 3 Salt - Formation Solvent and Acid Research Step 1 : N-[(6- bromopyridin -3- yl ) methyl ]-2- methoxyethane -1- amine ( MGA3 )

2-Methoxyethylamine (21.8 g, 290.2 mmol, MGA2 ) was added to a solution of 6-bromopyridine-3-carbaldehyde (18.0 g, 96.8 mmol, MGA1 ) in dichloromethane (180 mL, DCM). And stir the mixture at a temperature of 20 °C - 30 °C. After approximately 4 hours, sodium triacetyloxyborohydride (47.3 g, 233.4 mmol, NaBH(OAc) ₃ ) was added to the mixture and stirred for approximately 20 hours. After the reaction was completed, water (60 mL) and 30% sodium hydroxide (67.0 g) were added to the reaction mixture in sequence. Wash the organic phase twice with 10% sodium sulfate solution (50.0 g * 2). The combined organic phases were concentrated to dryness. Divide the solution into thirty-six portions (each portion is equal to 0.5 g of reaction solution) and use them equally for the next step. Step 2 : N-[(6- bromopyridin -3- yl ) methyl ]-2- methoxyethane -1- amine salt ( MGA3 salt )

Six acids and six organic solvents were used for salt formation of MGA3 , see Table 3 .

In one example, N-[(6-bromopyridin-3-yl)methyl]-2-methoxyethane-1-amine ( MGA3 , 0.5 ) was cooled in a solution of 2-MeTHF (10 mL) g , 2.0 mmol ) and add D-tartaric acid (0.3 g, 2.0 mmol) in EtOH (2 mL) dropwise. The reaction mixture was stirred for about 6 hours and filtered to obtain N-[(6-bromopyridin-3-yl)methyl]-2-methoxyethane-1-amine hemi-D-tartrate ( MGA3 hemi -D -tartrate ) wet cake. The solid look is great.

The desired compound N-[(6- bromopyridin -3-yl)methyl]-2-methoxyethane-1-amine was produced by a procedure similar to that disclosed in the preparation of MGA3 hemi - D -tartrate. Salt ( MGA3 salt ). The following amounts of other acids were used: oxalic acid (0.18 g, 2.0 mmol), p-toluenesulfonic acid (0.38 g, 2.0 mmol), D-DTTA (0.77 g, 2.0 mmol), citric acid (0.38 g, 2.0 mmol), L -(-)-malic acid (0.27 g, 2.0 mmol); and other organic solvents were used in 10 mL volumes.

The corresponding physical forms of the desired compounds are recorded in Table 3 . The results show that when the acids D-(-)-tartaric acid, p-toluenesulfonic acid, D-DTTA, or malic acid are used in salt formation, the salts obtained are solids with good appearance in certain organic solvents. Considering the simplified procedure D-(-)-tartaric acid/2-MeTHF and D-DTTA/2-MeTHF are preferred as the salt-forming systems, compared to the use of D-(-)-tartaric acid (MW 150.09 g /mol) D-DTTA (MW 386.35 g/mol) may cause more waste to the reaction. table 3 : Solvent acid D-(-)- tartaric acid oxalic acid p-toluenesulfonic acid D-DTTA citric acid malic acid 2-MeTHF fine solid Not very thin Stick to the bottom fine solid Not very thin Stick to the bottom MTBE fine solid Clumping solid fine solid fine solid molten solid fine solid IPAc fine solid Clumping solid Clumping solid fine solid molten solid fine solid acetone fine solid Clumping solid clear solution Stick to the bottom clear solution clear solution Methanol clear solution Clumping solid clear solution fine solid clear solution clear solution Acetonitrile clear solution Clumping solid clear solution Stick to the bottom clear solution clear solution Example 4 Research Step 1 on the Effect of Water Content : N-[(6- bromopyridin -3- yl ) methyl ]-2- methoxyethane -1- amine ( MGA3 )

Add 2-methoxyethylamine (4.8 g, 64.4 mmol, MGA2 ) to 6-bromopyridine-3-carbaldehyde (4.0 g, 21.5 mmol, MGA1 ) in 2-methyltetrahydrofuran (40 mL, 2-MeTHF) solution in and stir the mixture at a temperature of 20 °C - 30 °C. After approximately 4 hours, sodium triacetyloxyborohydride (10.5 g, 49.6 mmol, NaBH(OAc) ₃ ) was added to the mixture and stirred for approximately 20 hours. After the reaction was completed, water (24 mL) and 30% sodium hydroxide (26.8 g) were added sequentially to the reaction mixture. Wash the organic phase twice with 10% sodium sulfate solution (20.0 g * 2). The combined organic phases were concentrated in vacuo and 2-MeTHF (24 mL) was added. The resulting solution was concentrated to dryness under vacuum to remove residual water, then 2-MeTHF (16 mL) was added to obtain a solution containing N-[(6-bromopyridin-3-yl)methyl]-2-methoxy Solution of ethane-1-amine ( MGA3 2-MeTHF solution). Divide the solution into four parts and add different amounts of water (0 g, 0.1 g, 0.3 g, and 0.48 g) to ensure that the water content of the corresponding solution is 0.1%, 1.0%, 3.0%, 5.0% (wt %). Step 2 : N-[(6- bromopyridin -3- yl ) methyl ]-2- methoxyethane -1- amine hemi -D- tartrate ( MGA3 D- tartrate)

Cool N-[(6-bromopyridin-3-yl)methyl]-2-methoxyethane-1-amine (1.0 g, 4.1 mmol) in 2-MeTHF ( MGA3 2-MeTHF solution, 10 mL) to the solution in and add D-tartaric acid (0.44 g, 2.9 mmol) in EtOH (3 mL) dropwise. The reaction mixture was stirred for about 6 hours and filtered to obtain N-[(6-bromopyridin-3-yl)methyl]-2-methoxyethane-1-amine hemi-D-tartrate ( MGA3 hemi -D -tartrate ) . After filtration, the loss of MGA3 semi -D- tartrate in the mother liquor was collected ( see Table 4 ). The results show that when the water content of the N-[(6-bromopyridin-3-yl)methyl]-2-methoxyethane-1-amine ( MGA3 ) solution obtained in step 1 is ≤ 3.0% (w %) When, the loss rate of MGA3 semi -D- tartrate in the mother liquor is ≤ 5%, which is acceptable. Table 4 : Water content of MGA3 2-MeTHF solution (step 1 ) Loss of MGA3 hemi-D- tartrate in the mother liquor (step 2 ) 0.1% 2.7% 1.0% 3.9% 3.0% 5% 5.0% 14.6% Example 5 Salt - formation and maturation temperature research step 1 : N-[(6- bromopyridin -3- yl ) methyl ]-2- methoxyethane -1- amine ( MGA3 )

Add 2-methoxyethylamine (12.1 g, 161.4 mmol, MGA2 ) to 6-bromopyridine-3-carbaldehyde (10.0 g, 53.8 mmol, MGA1 ) in 2-methyltetrahydrofuran (100 mL, 2-MeTHF) solution in and stir the mixture at a temperature of 20 °C - 30 °C. After approximately 4 hours, sodium triacetyloxyborohydride (26.3 g, 124.1 mmol, NaBH(OAc) ₃ ) was added to the mixture and stirred for approximately 20 hours. After the reaction was completed, water (60 mL) and 30% sodium hydroxide (67.0 g) were added to the reaction mixture in sequence. Wash the organic phase twice with 10% sodium sulfate solution (50.0 g * 2). The combined organic phases were concentrated in vacuo and 2-MeTHF (60 mL) was added. The obtained solution was concentrated under vacuum and the water content was controlled to ≤ 2.0% (wt), and then 2-MeTHF (45 mL) was added to obtain a solution containing N-[(6-bromopyridin-3-yl)methyl]-2- Solution of methoxyethane-1-amine. Step 2 : N-[(6- bromopyridin -3- yl ) methyl ]-2- methoxyethane -1- amine hemi -D- tartrate ( MGA3 hemi -D- tartrate)

Method A : Add D-tartaric acid (4.4 g, 29.3 mmol) in EtOH (30 mL) dropwise to the cooled solution obtained in step 1 at 10 °C. The reaction mixture was stirred for about 72 hours (a sample was taken when stirring for 6 hours) and filtered to obtain a wet cake. The wet cake obtained was dried under vacuum at 50°C for about 8 hours to obtain 13.7 g of MGA3 semi -D- tartrate as a white solid.

Method B : Add D-tartaric acid (4.4 g, 29.3 mmol) in EtOH (30 mL) dropwise to the cooled solution obtained in step 1 at 30 °C. The reaction mixture was stirred for about 6 hours and filtered to obtain a wet cake. The obtained wet cake was dried under vacuum at 50°C for about 8 hours to obtain 13.5 g of MGA3 semi -D- tartrate as a white solid, which could be used as a seed crystal.

The corresponding HPLC purity of MGA3 hemi -D- tartrate prepared in Methods A and B is shown in Table 5. table 5: Lath formation temperature MGA3 hemi -D- tartrate yield HPLC Purity of MGA3 Semi -D- Tartrate 10 °C for 6 hours ___ 99.93% 10 °C for 72 hours 13.7g 99.55% 30 °C for 6 hours 13.5 100.0% Example 6 Preparation of N-[(6- bromopyridin -3- yl ) methyl ]-2- methoxyethane -1- amine semi -D- tartrate ( MGA3 semi -D- tartrate) Step 1 : N-[(6- bromopyridin -3- yl ) methyl ]-2- methoxyethane -1- amine ( MGA3 )

Add 2-methoxyethylamine (1.63 kg, 21.70 mol, MGA2 ) to 6-bromopyridine-3-carbaldehyde (1.35 kg, 7.26 mol, MGA1 ) in 2-methyltetrahydrofuran (13.5 L, 2-MeTHF) solution in and stir the mixture at a temperature of 20 °C - 30 °C. After approximately 4 hours, sodium triacetyloxyborohydride (3.80 kg, 17.93 mol, NaBH(OAc) ₃ ) was added to the mixture and stirred for approximately 20 hours. After the reaction is completed ( IPC (MGA1/MGA3 , area %) = 0.02/95.5), water (8100 mL) and 30% sodium hydroxide (9.0 kg) are added sequentially at 10 °C -25 °C. reaction mixture. Wash the organic phase twice with 10% sodium sulfate solution (6.8 kg * 2). The combined organic phases were concentrated in vacuo and 2-MeTHF (8100 mL) was added. The obtained solution was concentrated under vacuum and the water content was controlled to ≤ 2.0%, and then 6100 ml of 2-MeTHF was added to obtain a solution containing N-[(6-bromopyridin-3-yl)methyl]-2-methoxy Solution of ethane-1-amine. Step 2 : N-[(6- bromopyridin -3- yl ) methyl ]-2- methoxyethane -1- amine hemi -D- tartrate ( MGA3 hemi -D- tartrate)

MGA3 hemi -D- tartrate seed crystals (10 g) were added to the cooled solution obtained in step 1 to obtain a suspension. After stirring for approximately 1 hour, D-tartaric acid (594 g, 3.96 mol) in EtOH (4050 mL) was added dropwise at 20°C. The reaction mixture was stirred for about 6 hours and filtered to obtain a wet cake. The wet cake obtained was dried under vacuum at 50 °C for about 8 hours to obtain 2.0 kg of MGA3 hemi -D- tartrate as a white solid (HPLC purity = 99.8%; yield = 87%). Example 7 : N-(3-fluoro-4-((2-(5-((2-methoxyethyl)amino)methyl)pyridin-2-yl)thieno[3,2- Preparation of b]pyridin-7-yl)oxy)phenyl)-N-(4-fluorophenyl)cyclopropane-1,1-dimethylamide ( compound 1 )

N-(3-fluoro-4-((2-(5-((2-methoxyethyl)amino)methyl)pyridin-2-yl)thieno[3,2-b]pyridine- 7-yl)oxy)phenyl)-N-(4-fluorophenyl)cyclopropane-1,1-dimethylamide ( compound 1 ) is the same as WO2009/026717, WO2009/026720, WO2009/109035, Prepared by methods similar to those disclosed in WO2019/182274, WO2021/098769, and EP3819300, wherein N-[(6-bromopyridin-3-yl)methyl]-2-methoxyethane- is prepared by one of the above procedures 1-Amine hemi-D-tartrate ( MGA3 hemi -D- tartrate ).

The above examples and description of certain implementations should be considered as illustrative and not limiting of the invention as defined by the claimed scope. As will be readily appreciated, numerous variations and combinations of the features described above may be utilized without departing from the invention as described in the claimed scope. All such variations are intended to be included within the scope of the invention. All cited documents are incorporated by reference in their entirety.

without

without

Claims (13)

A salt of N-[(6-bromopyridin-3-yl)methyl]-2-methoxyethane-1-amine having formula ( I ), (I) wherein the salt is tartrate, p-toluenesulfonate, DDTA salt, or malate. The salt of claim 1, wherein the salt is tartrate, or DDTA salt (such as D-DTTA salt). The salt of claim 1, wherein the salt is a tartrate (such as D-(-)-tartrate). A tartrate salt of N-[(6-bromopyridin-3-yl)methyl]-2-methoxyethane-1-amine having formula ( II ), (II) , wherein n is a number from 0.4 to 1.2, preferably n is 0.5. A method for preparing the salt of N-[(6-bromopyridin-3-yl)methyl]-2-methoxyethane-1-amine, which includes the following steps in sequence, a) Add 2-methoxyethylamine to 6-bromopyridine-3-carbaldehyde in an organic solvent; b) Add sodium triacetyloxyborohydride to obtain N-[(6-bromopyridin-3-yl)methyl]-2-methoxyethane-1-amine; c) Dissolve N-[(6-bromopyridin-3-yl)methyl]-2-methoxyethane-1-amine in an organic solvent; and d) Add acid to the mixture obtained in step c) to obtain the target salt, The salt is tartrate, p-toluenesulfonate, DDTA salt, or malate. A method for preparing N-[(6-bromopyridin-3-yl)methyl]-2-methoxyethane-1-amine D-tartrate, which includes the following steps in sequence, a) Add 2-methoxyethylamine to 6-bromopyridine-3-carbaldehyde in an organic solvent; b) Add sodium triacetyloxyborohydride to obtain N-[(6-bromopyridin-3-yl)methyl]-2-methoxyethane-1-amine; c) Dissolve N-[(6-bromopyridin-3-yl)methyl]-2-methoxyethane-1-amine in an organic solvent; and d) Add D-tartrate to the mixture obtained in step c) to obtain the product. A method for preparing N-[(6-bromopyridin-3-yl)methyl]-2-methoxyethane-1-amine semi-D-tartrate, which includes the following steps in sequence, a) Add 2-methoxyethylamine to 6-bromopyridine-3-carbaldehyde in an organic solvent; b) Add sodium triacetyloxyborohydride to obtain N-[(6-bromopyridin-3-yl)methyl]-2-methoxyethane-1-amine; c) Dissolve N-[(6-bromopyridin-3-yl)methyl]-2-methoxyethane-1-amine in an organic solvent; and d) Add D-tartaric acid to the mixture obtained in step c) to obtain the product. The method of any one of claims 5, 6, or 7, wherein the organic solvent in step a) or c) is selected from 2-MeTHF, MTBE, IPAc, acetone, or methanol, preferably 2-MeTHF, MTBE , or IPAc, preferably 2-MeTHF. The method of claim 5, 6, or 7, wherein the stoichiometric ratio of D-tartrate added in step d) is 0.4 to 1.2, preferably 0.5, which is with N-[(6- Bromopyridin-3-yl)methyl]-2-methoxyethane-1-amine for comparison. The method of claim 7, wherein in step c) N-[(6-bromopyridin-3-yl)methyl]-2-methoxyethane-1-amine is dissolved in an organic solvent (such as 2-MeTHF The water content of the solution) is controlled at 0~10%, preferably 0~5%, and preferably no more than 3.0% (w.t.%). Such as the method of claim 7, wherein the temperature for reacting 6-bromopyridine-3-carbaldehyde and 2-methoxyethylamine is between 20°C and 30°C. The method of claim 7, wherein crystals of N-[(6-bromopyridin-3-yl)methyl]-2-methoxyethane-1-amine semi-D-tartrate are added before step d) species. A method for preparing N-(3-fluoro-4-((2-(5-(((2-methoxyethyl)amino)methyl)pyridin-2-yl)thieno[3,2-b] A method for pyridin-7-yl)oxy)phenyl)-N-(4-fluorophenyl)cyclopropane-1,1-dimethylamide or a pharmaceutically acceptable salt thereof, comprising in order the following Method for preparing N-[(6-bromopyridin-3-yl)methyl]-2-methoxyethane-1-amine semi-D-tartrate, a) Add 2-methoxyethylamine to 6-bromopyridine-3-carbaldehyde in an organic solvent); b) Dissolve N-[(6-bromopyridin-3-yl)methyl]-2-methoxyethane-1-amine in an organic solvent; and c) Add D-tartaric acid to the mixture obtained in step c) to obtain the product.