WO2023155777A1 - N- [ (6-bromopyridin-3-yl) methyl] -2-methoxyethan-1-amine salts and preparation thereof - Google Patents

N- [ (6-bromopyridin-3-yl) methyl] -2-methoxyethan-1-amine salts and preparation thereof Download PDF

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WO2023155777A1
WO2023155777A1 PCT/CN2023/075938 CN2023075938W WO2023155777A1 WO 2023155777 A1 WO2023155777 A1 WO 2023155777A1 CN 2023075938 W CN2023075938 W CN 2023075938W WO 2023155777 A1 WO2023155777 A1 WO 2023155777A1
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methyl
methoxyethan
bromopyridin
amine
tartrate
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PCT/CN2023/075938
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French (fr)
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Zhengfeng LI
Qun JIANG
Weiqiang Hu
Juntao Liu
Zhengming Du
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Beigene (Suzhou) Co., Ltd.
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/61—Halogen atoms or nitro radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C309/00—Sulfonic acids; Halides, esters, or anhydrides thereof
    • C07C309/01—Sulfonic acids
    • C07C309/28—Sulfonic acids having sulfo groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton
    • C07C309/29—Sulfonic acids having sulfo groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton of non-condensed six-membered aromatic rings
    • C07C309/30—Sulfonic acids having sulfo groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton of non-condensed six-membered aromatic rings of six-membered aromatic rings substituted by alkyl groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C59/00—Compounds having carboxyl groups bound to acyclic carbon atoms and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups
    • C07C59/235—Saturated compounds containing more than one carboxyl group
    • C07C59/245—Saturated compounds containing more than one carboxyl group containing hydroxy or O-metal groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C59/00—Compounds having carboxyl groups bound to acyclic carbon atoms and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups
    • C07C59/235—Saturated compounds containing more than one carboxyl group
    • C07C59/245—Saturated compounds containing more than one carboxyl group containing hydroxy or O-metal groups
    • C07C59/255—Tartaric acid
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D495/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
    • C07D495/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D495/04—Ortho-condensed systems

Definitions

  • 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-dicarboxamide (Compound 1) is a multi-tyrosine kinase inhibitor with demonstrated potent inhibition of a closely related spectrum of tyrosine kinases, including RET, CBL, CHR4q12, DDR and Trk, which are key regulators of signaling pathways that lead to cell growth, survival and tumor progression:
  • MGA3 N- [ (6-bromopyridin-3-yl) methyl] -2-methoxyethan-1-amine
  • D- (-) -tartaric acid was recommended to the salt formation of N- [ (6-bromopyridin-3-yl) methyl] -2-methoxyethan-1-amine (MGA3)
  • 2-MeTHF was recommended to be the reaction solvent of preparing MGA3, which produced D-Tartrate of MGA3.
  • the D-Tartrates of MGA3 were obtained as a fine solid, wherein the mole ratio of D-tartaric acid to MGA3 (free base) is from 0.5 to 1.2.
  • the MGA3 D-Tartrate (1: 1) did not show good enough physical form, and more impurities were involved when stirring.
  • MGA3 semi-D-Tartrate as a white to off-white crystalline form was prepared, which could provide MGA3 with a chemical purity up to 99.9% (HPLC) and ideal yield above 80%, and the solid of MGA3 semi-D-Tartrate could be easy isolation and showed slightly hygroscopicity and stable. Under 20°C/60%RH and 40°C/75%RH, MGA3 semi-D-Tartrate showed good stability, including water content, when being stored for 3 months. The DVS data shows that MGA3 semi-D-Tartrate is very slight hygroscopic.
  • MGA3 D-Tartrate (1: 1) when adding mole ratio of D-Tartrate to MGA3 about 1: 1 in bathes, D-Tartrates of N- [ (6-bromopyridin-3-yl) methyl] -2-methoxyethan-1-amine, MGA3 D-Tartrate (1: 1) with good physical form could be obtained.
  • MGA3 D-Tartrate was obtained as an oil when adding about D-Tartrate into the reaction directly, wherein the adding mole ratio of D-Tartrate to MGA3 is about 0.8 : 1.
  • the salt is a tartrate, a p-toluenesulfonate, a DDTA salt, or a malate.
  • n is a number from 0.4 to 1.2.
  • the salt of the first, second and third aspects above could be a fine solid, to provide N- [ (6-bromopyridin-3-yl) methyl] -2-methoxyethan-1-amine (MGA3) with high chemical purity.
  • MGA3 (6-bromopyridin-3-yl) methyl] -2-methoxyethan-1-amine
  • the salt is a tartrate of MGA3, practically semi-D- Tartrate, the salt is a good crystalline form with a chemical purity up to 99.9% (HPLC) and ideal yield above 80%, and the solid of MGA3 semi-D-Tartrate could be easy isolation and showed slightly hygroscopicity and stable.
  • a method of preparing a salt of N- [ (6-bromopyridin-3-yl) methyl] -2-methoxyethan-1-amine (MGA3) comprising the following steps in the consist of,
  • step d) adding an acid into the resulting mixture in step c) to obtain the target salt.
  • a method of preparing a salt of N- [ (6-bromopyridin-3-yl) methyl] -2-methoxyethan-1-amine (MGA3) comprising the following steps in the consist of,
  • step c) adding the corresponding salt into the resulting mixture in step c) to obtain the product
  • the salt is a tartrate, a p-toluenesulfonate, a DDTA salt, or a malate.
  • a method of preparing N- [ (6-bromopyridin-3-yl) methyl] -2-methoxyethan-1-amine D-Tartrate comprising the following steps in the consist of,
  • step c) adding D-tartaric acid into the resulting mixture in step c) to obtain the product.
  • the mole ratio of D-Tartrate to MGA3 about 1: 1 is added in batches to obtain N- [ (6-bromopyridin-3-yl) methyl] -2-methoxyethan-1-amine D-Tartrate (1: 1) with good physical form.
  • a seventh aspect provided herein is a method of preparing N- [ (6-bromopyridin-3-yl) methyl] -2-methoxyethan-1-amine semi D-Tartrate (MGA3 semi-D-Tartrate) , comprising the following steps in the consist of,
  • step c) adding D-tartaric acid into the resulting mixture in step c) to obtain the product.
  • the method in the fourth, fifth, sixth and seventh aspects above could provide a salt of N- [ (6-bromopyridin-3-yl) methyl] -2-methoxyethan-1-amine (MGA3) as a fine solid, as well as provide MGA3 with high chemical purity.
  • step c) adding D-tartaric acid into the resulting mixture in step c) to obtain the product.
  • the salt is a tartrate, a p-toluenesulfonate, a DDTA salt, or a malate.
  • the salt is in solid-state.
  • the salt is a tartrate, or a DDTA salt (such as a D-DTTA salt) , preferably, a tartrate (such as a D- (-) -tartrate) .
  • n is a number from 0.4 to 1.
  • n is from 0.4 to 1.0. In one preferred embodiment, n is 0.5. In another preferred embodiment, n is 1.0.
  • a method of preparing a salt of N- [ (6-bromopyridin-3-yl) methyl] -2-methoxyethan-1-amine (MGA3) comprising the following steps in the consist of,
  • a method of preparing a salt of N- [ (6-bromopyridin-3-yl) methyl] -2-methoxyethan-1-amine (MGA3) comprising the following steps in the consist of,
  • step c) adding an acid into the resulting mixture in step c) to obtain the target salt, wherein the salt is a tartrate, a p-toluenesulfonate, a DDTA salt, or a malate.
  • a method of preparing N- [ (6-bromopyridin-3-yl) methyl] -2-methoxyethan-1-amine D-Tartrate comprising the following steps in the consist of,
  • step c) adding D-tartaric acid into the resulting mixture in step c) to obtain the product.
  • the D-tartaric acid is added in batches to obtain N- [ (6-bromopyridin-3-yl) methyl] -2-methoxyethan-1-amine D-Tartrate (1: 1) with good physical form.
  • a seventh aspect provided herein is a method of preparing N- [ (6-bromopyridin-3-yl) methyl] -2-methoxyethan-1-amine semi D-Tartrate (MGA3 semi-D-Tartrate) , comprising the following steps in the consist of,
  • step c) adding D-tartaric acid into the resulting mixture in step c) to obtain the product.
  • the organic solvent is selected from 2-MeTHF, MTBE, IPAc, acetone, or methanol, preferably, 2-MeTHF, MTBE or IPAc, more preferably, 2-MeTHF.
  • the stoichiometric ratio of added D-Tartrate in step d) is from 0.4 to 1.2, preferably 0.5, comparing to N- [ (6-bromopyridin-3-yl) methyl] -2-methoxyethan-1-amine.
  • the water content of N- [ (6-bromopyridin-3-yl) methyl] -2-methoxyethan-1-amine (MGA3) in organic solvent (such as 2-MeTHF solution) in step c) is controlled to 0 ⁇ 10%, preferably 0 ⁇ 5%, more preferably no more than 3.0%(w.t. %) .
  • the temperature of reacting 6-bromopyridine-3-carboxaldehyde with 2-methoxyethylamine is at 20 °C ⁇ 30 °C.
  • the crystal seed of MGA3 semi-D-Tartrate is added before step d) adding D-tartaric acid into the resulting mixture in step c) .
  • step c) adding D-tartaric acid into the resulting mixture in step c) to obtain the product.
  • the present invention is further exemplified, but not limited to, by the following examples that illustrate the invention.
  • HPLC HPLC was used to characterize the compound content in the progress, as well as determine the mole ratio of the formed salt in the present disclosure.
  • the experiment error is known by a skilled person in the art and accepted by pharmaceutical industry.
  • Step 1 N- [ (6-bromopyridin-3-yl) methyl] -2-methoxyethan-1-amine (MGA3)
  • the desired compound N- [ (6-bromopyridin-3-yl) methyl] -2-methoxyethan-1-amine (MGA3) was produced by the similar procedure as that disclosed in Example 1, wherein the reaction temperature was from 10 °C to 40 °C, and the reaction solvent was 2-MeTHF.
  • Step 1 N- [ (6-bromopyridin-3-yl) methyl] -2-methoxyethan-1-amine (MGA3)
  • the organic phase was washed twice with 10%sodium sulfate solution (50.0 g *2) .
  • the combined organic phase was concentrated to dryness.
  • the solution was divided into thirty-six sections (each section equal to 0.5 g reaction solution) , which were used in the next step.
  • Step 2 N- [ (6-bromopyridin-3-yl) methyl] -2-methoxyethan-1-amine salt (MGA3 Salt)
  • N- [ (6-bromopyridin-3-yl) methyl] -2-methoxyethan-1-amine (MGA3, 0.5 g, 2.0 mmol) in 2-MeTHF (10 mL) solution was cooled and D-tartaric acid (0.3 g, 2.0 mmol) in EtOH (2 mL) was added dropwise.
  • the reaction mixture was stirred for about 6 hours and filtered to obtain a wet cake of N- [ (6-bromopyridin-3-yl) methyl] -2-methoxyethan-1-amine semi-D-Tartrate (MGA3 semi-D-Tartrate) .
  • the solid appearance was well.
  • a desired compound N- [ (6-bromopyridin-3-yl) methyl] -2-methoxyethan-1-amine salt was produced by the similar procedure as that disclosed in preparing MGA3 semi-D-Tartrate.
  • the other acids were used as followed amount, Oxalic acid (0.18 g, 2.0 mmol) , p-toluene sulfonic acid (0.38 g, 2.0 mmol) , D-DTTA (0.77 g, 2.0 mmol) , critic acid (0.38 g, 2.0 mmol) , L- (-) -malic acid (0.27 g, 2.0 mmol) ; and the other organic solvents were used with 10mL volume.
  • Step 1 N- [ (6-bromopyridin-3-yl) methyl] -2-methoxyethan-1-amine (MGA3)
  • the organic phase was washed twice with 10%sodium sulfate solution (20.0 g *2) .
  • the combined organic phase was concentrated by under vacuum and charged with 2-MeTHF (24 mL) .
  • the obtained solution was concentrated under vacuum to dry to swap out the residue water, and then 2-MeTHF (16 mL) was added to obtain a solution containing N- [ (6-bromopyridin-3-yl) methyl] -2-methoxyethan-1-amine (MGA3 2-MeTHF solution) .
  • the solution was divided into four sections, which were added different amount of water (0 g, 0.1 g, 0.3 g, and 0.48 g) to ensure the water content of the corresponding solutions were 0.1%, 1.0%, 3.0 %, 5.0 % (w. t. %) .
  • Step 2 N- [ (6-bromopyridin-3-yl) methyl] -2-methoxyethan-1-amine semi-D- Tartrate (MGA3 D-Tartrate)
  • N- [ (6-bromopyridin-3-yl) methyl] -2-methoxyethan-1-amine (1.0 g, 4.1 mmol) in 2-MeTHF (MGA3 2-MeTHF solution, 10 mL) solution was cooled and D-tartaric acid (0.44 g, 2.9 mmol) in EtOH (3 mL) was added dropwise. The reaction mixture was stirred for about 6 hours and filtered to obtain N- [ (6-bromopyridin-3-yl) methyl] -2-methoxyethan-1-amine semi-D-Tartrate (MGA3 semi-D-Tartrate) .
  • Step 1 N- [ (6-bromopyridin-3-yl) methyl] -2-methoxyethan-1-amine (MGA3)
  • the organic phase was washed twice with 10%sodium sulfate solution (50.0 g *2) .
  • the combined organic phase was concentrated by under vacuum and charged with 2-MeTHF (60 ml) .
  • the obtained solution was concentrated under vacuum with controlling the water content ⁇ 2.0% (w.t. ) , and then 2-MeTHF (45 mL) was added to obtain a solution containing N- [ (6-bromopyridin-3-yl) methyl] -2-methoxyethan-1-amine.
  • Step 2 N- [ (6-bromopyridin-3-yl) methyl] -2-methoxyethan-1-amine semi-D- Tartrate (MGA3 semi-D-Tartrate)
  • Step 1 To the cooled solution obtained in Step 1, D-tartaric acid (4.4 g, 29.3 mmol) in EtOH (30 mL) was added dropwise at 10 °C. The reaction mixture was stirred for about 72 hours (Take sample when stir at 6 hours) and filtered to obtain a wet cake. The obtained wet cake was dried at 50 °C under vacuum for about 8 hours, to give 13.7 g white solid of MGA3 semi-D-Tartrate.
  • Step 2 To the cooled solution obtained in Step 1, D-tartaric acid (4.4 g, 29.3 mmol) in EtOH (30 mL) was added dropwise 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 at 50 °C under vacuum for about 8 hours, to give 13.5 g white solid of MGA3 semi-D-Tartrate, which could be used as crystal seed.
  • the reaction mixture was charged with water (8100 mL) and 30%sodium hydroxide (9.0 kg) of successively within 10 °C -25 °C.
  • the organic phase was washed twice with 10%sodium sulfate solution (6.8 kg *2) .
  • the combined organic phase was concentrated by under vacuum and charged with 2-MeTHF (8100 ml) .
  • the obtained solution was concentrated under vacuum with controlling the water content ⁇ 2.0%, and then 6100 ml 2-MeTHF was added to obtain a solution containing N- [ (6-bromopyridin-3-yl) methyl] -2-methoxyethan-1-amine.
  • Step 2 N- [ (6-bromopyridin-3-yl) methyl] -2-methoxyethan-1-amine semi-D- Tartrate (MGA3 Semi-D-Tartrate)
  • 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-dicarboxamide (Compound 1) was prepared by the similar method disclosed in WO2009/026717, WO2009/026720, WO2009/109035, WO2019/182274, WO2021/098769, and EP3819300, wherein N- [ (6-bromopyridin-3-yl) methyl] -2-methoxyethan-1-amine semi-D-Tartrate (MGA3 semi-D-Tartrate) was prepared by one of procedures above.

Abstract

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 are provided.

Description

N- [ (6-BROMOPYRIDIN-3-YL) METHYL] -2-METHOXYETHAN-1-AMINE SALTS AND PREPARATION THEREOF FIELD
Disclosed herein are salts of N- [ (6-bromopyridin-3-yl) methyl] -2-methoxyethan-1-amine, and methods for preparing thereof.
BACKGROUND
International publication Nos. WO2009/026717, WO2009/026720, WO2009/109035, WO2019/182274 , WO2021/098769, and European publication No. EP3819300 disclosed compounds with the inhibition activities of multiple protein tyrosine kinases, for example, the inhibition activities of VEGF receptor kinase and HGF receptor kinase. In particular, 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-dicarboxamide (Compound 1) is a multi-tyrosine kinase inhibitor with demonstrated potent inhibition of a closely related spectrum of tyrosine kinases, including RET, CBL, CHR4q12, DDR and Trk, which are key regulators of signaling pathways that lead to cell growth, survival and tumor progression:
In WO2009/026717, WO2009/026720, WO2009/109035, WO2019/182274, WO2021/098769, and EP3819300, intermediate N- [ (6-bromopyridin-3-yl) methyl] -2-methoxyethan-1-amine (MGA3) was obtained by the reductive amination between 6-bromopyridine-3-carboxaldehyde and 2-methoxyethylamine under the existing of NaBH (OAc) 3. In addition, the MGA3 was not obtained as an ideal solid but an oil or liquid with lower chemical purities, which contained more than 8 impurities, and three  of the impurities could not be removed well. Thus, a new process for N- [ (6-bromopyridin-3-yl) methyl] -2-methoxyethan-1-amine (MGA3) is highly desirable to provide MGA3 as an intermate with high quality, to meet the Compound 1 manufacture.
SUMMARY
Six pharmaceutical accepted acids, including D- (-) -tartaric acid, oxalic acid, p-toluenesulfonic acid, D-DTTA, citric acid and malate acid, were used to the salt formation of N- [ (6-bromopyridin-3-yl) methyl] -2-methoxyethan-1-amine (MGA3) , and six organic solvents including 2-MeTHF, MTBE, IPAc, acetone, methanol or acetonitrile, were used as reaction solvent of preparing N- [ (6-bromopyridin-3-yl) methyl] -2-methoxyethan-1-amine (MGA3) . However, limited solids with good physical form and high purity were obtained, only when the acid was D- (-) -tartaric acid, p-toluenesulfonic acid, D-DTTA, and malate acid, combined with the reaction solvent above was independently selected from 2-MeTHF, MTBE, IPAc, acetone, or methanol.
Considering to the environment friendly and manufacture cost, D- (-) -tartaric acid was recommended to the salt formation of N- [ (6-bromopyridin-3-yl) methyl] -2-methoxyethan-1-amine (MGA3) , and 2-MeTHF was recommended to be the reaction solvent of preparing MGA3, which produced D-Tartrate of MGA3. The D-Tartrates of MGA3 were obtained as a fine solid, wherein the mole ratio of D-tartaric acid to MGA3 (free base) is from 0.5 to 1.2. However, the MGA3 D-Tartrate (1: 1) did not show good enough physical form, and more impurities were involved when stirring. Finally, MGA3 semi-D-Tartrate as a white to off-white crystalline form was prepared, which could provide MGA3 with a chemical purity up to 99.9% (HPLC) and ideal yield above 80%, and the solid of MGA3 semi-D-Tartrate could be easy isolation and showed slightly hygroscopicity and stable. Under 20℃/60%RH and 40℃/75%RH, MGA3 semi-D-Tartrate showed good stability, including water content, when being stored for 3 months. The DVS data shows that MGA3 semi-D-Tartrate is very slight hygroscopic.
The inventor of the present disclosure discovered that, all the impurities generated from the similar processes in the publications such as WO2009/026717, WO2009/026720, WO2009/109035, WO2019/182274, WO2021/098769, and EP3819300 were well removed, in the salt solid obtained in the present disclosure.  Furtherly, when the water content of MGA3 in organic solvent (such as MGA3 2-MeTHF solution) was above 3.0% (w. t. %) ., the N- [ (6-bromopyridin-3-yl) methyl] -2-methoxyethan-1-amine semi-D-Tartrate (MGA3 semi-D-Tartrate) were lost significantly. In addition, when adding mole ratio of D-Tartrate to MGA3 about 1: 1 in bathes, D-Tartrates of N- [ (6-bromopyridin-3-yl) methyl] -2-methoxyethan-1-amine, MGA3 D-Tartrate (1: 1) with good physical form could be obtained. In some batches, the MGA3 D-Tartrate was obtained as an oil when adding about D-Tartrate into the reaction directly, wherein the adding mole ratio of D-Tartrate to MGA3 is about 0.8 : 1.
In a first aspect, provided herein is a salt of N- [ (6-bromopyridin-3-yl) methyl] -2-methoxyethan-1-amine having formula (I) ,
In a second aspect, provided herein is a salt of N- [ (6-bromopyridin-3-yl) methyl] -2-methoxyethan-1-amine having formula (I) ,
wherein the salt is a tartrate, a p-toluenesulfonate, a DDTA salt, or a malate.
In a third aspect, provided herein is a tartrate of N- [ (6-bromopyridin-3-yl) methyl] -2-methoxyethan-1-amine having formula (II) ,
wherein n is a number from 0.4 to 1.2.
The salt of the first, second and third aspects above could be a fine solid, to provide N- [ (6-bromopyridin-3-yl) methyl] -2-methoxyethan-1-amine (MGA3) with high chemical purity. And, when the salt is a tartrate of MGA3, practically semi-D- Tartrate, the salt is a good crystalline form with a chemical purity up to 99.9% (HPLC) and ideal yield above 80%, and the solid of MGA3 semi-D-Tartrate could be easy isolation and showed slightly hygroscopicity and stable.
In a fourth aspect, provided herein is a method of preparing a salt of N- [ (6-bromopyridin-3-yl) methyl] -2-methoxyethan-1-amine (MGA3) , comprising the following steps in the consist of,
a) charging 6-bromopyridine-3-carboxaldehyde with 2-methoxyethylamine in an organic solvent;
b) adding sodium triacetoxyborohydride to obtain N- [ (6-bromopyridin-3-yl) methyl] -2-methoxyethan-1-amine;
c) dissolving N- [ (6-bromopyridin-3-yl) methyl] -2-methoxyethan-1-amine in an organic solvent; and,
d) adding an acid into the resulting mixture in step c) to obtain the target salt.
In a fifth aspect, provided herein is a method of preparing a salt of N- [ (6-bromopyridin-3-yl) methyl] -2-methoxyethan-1-amine (MGA3) , comprising the following steps in the consist of,
a) charging 6-bromopyridine-3-carboxaldehyde with 2-methoxyethylamine in an organic solvent;
b) adding sodium triacetoxyborohydride to obtain N- [ (6-bromopyridin-3-yl) methyl] -2-methoxyethan-1-amine;
c) dissolving N- [ (6-bromopyridin-3-yl) methyl] -2-methoxyethan-1-amine in an organic solvent; and,
d) adding the corresponding salt into the resulting mixture in step c) to obtain the product,
wherein the salt is a tartrate, a p-toluenesulfonate, a DDTA salt, or a malate.
In a sixth aspect, provided herein is a method of preparing N- [ (6-bromopyridin-3-yl) methyl] -2-methoxyethan-1-amine D-Tartrate, comprising the following steps in the consist of,
a) charging 6-bromopyridine-3-carboxaldehyde with 2-methoxyethylamine in an organic solvent (preferably 2-MeTHF) ;
b) adding sodium triacetoxyborohydride to obtain N- [ (6-bromopyridin-3-yl) methyl] -2-methoxyethan-1-amine;
c) dissolving N- [ (6-bromopyridin-3-yl) methyl] -2-methoxyethan-1-amine in an organic solvent; and,
d) adding D-tartaric acid into the resulting mixture in step c) to obtain the product.
In one embodiment, the mole ratio of D-Tartrate to MGA3 about 1: 1 is added in batches to obtain N- [ (6-bromopyridin-3-yl) methyl] -2-methoxyethan-1-amine D-Tartrate (1: 1) with good physical form.
In a seventh aspect, provided herein is a method of preparing N- [ (6-bromopyridin-3-yl) methyl] -2-methoxyethan-1-amine semi D-Tartrate (MGA3 semi-D-Tartrate) , comprising the following steps in the consist of,
a) charging 6-bromopyridine-3-carboxaldehyde with 2-methoxyethylamine in an organic solvent (preferably 2-MeTHF) ;
b) adding sodium triacetoxyborohydride to obtain N- [ (6-bromopyridin-3-yl) methyl] -2-methoxyethan-1-amine;
c) dissolving N- [ (6-bromopyridin-3-yl) methyl] -2-methoxyethan-1-amine in an organic solvent; and,
d) adding D-tartaric acid into the resulting mixture in step c) to obtain the product.
The method in the fourth, fifth, sixth and seventh aspects above could provide a salt of N- [ (6-bromopyridin-3-yl) methyl] -2-methoxyethan-1-amine (MGA3) as a fine solid, as well as provide MGA3 with high chemical purity.
In an eighth aspect, provided herein is a method of preparing 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-dicarboxamide (Compound 1) , or a pharmaceutically acceptable salt thereof, comprising the method of preparing N- [ (6-bromopyridin-3-yl) methyl] -2-methoxyethan-1-amine semi-D-Tartrate (MGA3 semi-D-Tartrate) , comprising the following steps in the consist of,
a) reacting 6-bromopyridine-3-carboxaldehyde with 2-methoxyethylamine in an organic solvent (preferably 2-MeTHF) ;
b) adding sodium triacetoxyborohydride to obtain N- [ (6-bromopyridin-3-yl) methyl] -2-methoxyethan-1-amine;
c) dissolving N- [ (6-bromopyridin-3-yl) methyl] -2-methoxyethan-1-amine in an organic solvent; and,
d) adding D-tartaric acid into the resulting mixture in step c) to obtain the product.
DETAILED DESCRIPTION
In a first aspect, provided herein is a salt of N- [ (6-bromopyridin-3-yl) methyl] -2-methoxyethan-1-amine having formula (I) ,
In a second aspect, provided herein is a salt of N- [ (6-bromopyridin-3-yl) methyl] -2-methoxyethan-1-amine having formula (I) ,
wherein the salt is a tartrate, a p-toluenesulfonate, a DDTA salt, or a malate.
.
In one embodiment, the salt is in solid-state.
In one embodiment, the salt is a tartrate, or a DDTA salt (such as a D-DTTA salt) , preferably, a tartrate (such as a D- (-) -tartrate) .
In a third aspect, provided herein is a tartrate of N- [ (6-bromopyridin-3-yl) methyl] -2-methoxyethan-1-amine having formula (II) ,
wherein n is a number from 0.4 to 1.
In one embodiment, n is from 0.4 to 1.0. In one preferred embodiment, n is 0.5. In another preferred embodiment, n is 1.0.
In a fourth aspect, provided herein is a method of preparing a salt of N- [ (6-bromopyridin-3-yl) methyl] -2-methoxyethan-1-amine (MGA3) , comprising the following steps in the consist of,
a) charging 6-bromopyridine-3-carboxaldehyde with 2-methoxyethylamine in an organic solvent;
b) adding sodium triacetoxyborohydride to obtain N- [ (6-bromopyridin-3-yl) methyl] -2-methoxyethan-1-amine; and,
c) adding the corresponding acid into the resulting mixture to obtain the target salt.
In a fifth aspect, provided herein is a method of preparing a salt of N- [ (6-bromopyridin-3-yl) methyl] -2-methoxyethan-1-amine (MGA3) , comprising the following steps in the consist of,
a) charging 6-bromopyridine-3-carboxaldehyde with 2-methoxyethylamine in an organic solvent;
b) adding sodium triacetoxyborohydride to obtain N- [ (6-bromopyridin-3-yl) methyl] -2-methoxyethan-1-amine;
c) dissolving N- [ (6-bromopyridin-3-yl) methyl] -2-methoxyethan-1-amine in an organic solvent; and,
d) adding an acid into the resulting mixture in step c) to obtain the target salt, wherein the salt is a tartrate, a p-toluenesulfonate, a DDTA salt, or a malate.
In a sixth aspect, provided herein is a method of preparing N- [ (6-bromopyridin-3-yl) methyl] -2-methoxyethan-1-amine D-Tartrate, comprising the following steps in the consist of,
a) charging 6-bromopyridine-3-carboxaldehyde with 2-methoxyethylamine in an organic solvent;
b) adding sodium triacetoxyborohydride to obtain N- [ (6-bromopyridin-3-yl) methyl] -2-methoxyethan-1-amine;
c) dissolving N- [ (6-bromopyridin-3-yl) methyl] -2-methoxyethan-1-amine in an organic solvent; and,
d) adding D-tartaric acid into the resulting mixture in step c) to obtain the product.
In one embodiment, the D-tartaric acid is added in batches to obtain N- [ (6-bromopyridin-3-yl) methyl] -2-methoxyethan-1-amine D-Tartrate (1: 1) with good physical form.
In a seventh aspect, provided herein is a method of preparing N- [ (6-bromopyridin-3-yl) methyl] -2-methoxyethan-1-amine semi D-Tartrate (MGA3 semi-D-Tartrate) , comprising the following steps in the consist of,
a) charging 6-bromopyridine-3-carboxaldehyde with 2-methoxyethylamine in an organic solvent ;
b) adding sodium triacetoxyborohydride to obtain N- [ (6-bromopyridin-3-yl) methyl] -2-methoxyethan-1-amine;
c) dissolving N- [ (6-bromopyridin-3-yl) methyl] -2-methoxyethan-1-amine in an organic solvent; and,
d) adding D-tartaric acid into the resulting mixture in step c) to obtain the product.
In some embodiment, the organic solvent is selected from 2-MeTHF, MTBE, IPAc, acetone, or methanol, preferably, 2-MeTHF, MTBE or IPAc, more preferably, 2-MeTHF.
In one embodiment, the stoichiometric ratio of added D-Tartrate in step d) is from 0.4 to 1.2, preferably 0.5, comparing to N- [ (6-bromopyridin-3-yl) methyl] -2-methoxyethan-1-amine.
In one embodiment, the water content of N- [ (6-bromopyridin-3-yl) methyl] -2-methoxyethan-1-amine (MGA3) in organic solvent (such as 2-MeTHF solution) in step c) is controlled to 0～10%, preferably 0～5%, more preferably no more than 3.0%(w.t. %) .
In one embodiment, the temperature of reacting 6-bromopyridine-3-carboxaldehyde with 2-methoxyethylamine is at 20 ℃ ～ 30 ℃.
In one embodiment, the crystal seed of MGA3 semi-D-Tartrate is added before step d) adding D-tartaric acid into the resulting mixture in step c) .
In an eighth aspect, provided herein is a method of preparing 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-dicarboxamide (Compound 1) , or a pharmaceutically acceptable salt thereof, comprising the method of preparing N-  [ (6-bromopyridin-3-yl) methyl] -2-methoxyethan-1-amine semi-D-Tartrate (MGA3 semi-D-Tartrate) , comprising the following steps in the consist of,
a) charging 6-bromopyridine-3-carboxaldehyde with 2-methoxyethylamine in an organic solvent;
b) adding sodium triacetoxyborohydride to obtain N- [ (6-bromopyridin-3-yl) methyl] -2-methoxyethan-1-amine;
c) dissolving N- [ (6-bromopyridin-3-yl) methyl] -2-methoxyethan-1-amine in an organic solvent; and,
d) adding D-tartaric acid into the resulting mixture in step c) to obtain the product.
EXAMPLES
The present invention is further exemplified, but not limited to, by the following examples that illustrate the invention. The following examples for preparing N- [ (6-bromopyridin-3-yl) methyl] -2-methoxyethan-1-amine and its salt.
Analytical Method:
The NMR, water content testing and HPLC can be conducted by the method known by a person skilled in the art. 1H NMR of MGA3 semi-D-Tartrate: 1H 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 was used to characterize the compound content in the progress, as well as determine the mole ratio of the formed salt in the present disclosure. In some embodiments, the experiment error is known by a skilled person in the art and accepted by pharmaceutical industry.
Example 1 Study of reaction solvent
To a solution of 6-bromopyridine-3-carboxaldehyde (10.0 g, 53.8 mmol, 1.0 eq., MGA1) in 2-methyltetrahydrofuran (100 mL, 2-MeTHF) or isopropyl acetate (IPAc) was added 2-methoxyethylamine (12.1 g, 161.4 mmol, 3.0 eq., MGA2) , and the mixture was stirred at a temperature of 20 ℃ -30 ℃. After about 4 hours, sodium triacetoxyborohydride (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-methoxyethan-1-amine (MGA3) .
The corresponding IPC (MGA1/MGA3) were tested in the reaction progress (see Table 1) . The result showed that 1) 3.2% (HPLC area%) of MGA1 was left and potential transesterification could occur when the reaction solvent was IPAc, 2) most of MGA1 was converted into MGA3 and when the reaction solvent was 2-MeTHF.
Table 1:
Example 2 Study of reaction temperature
Step 1: N- [ (6-bromopyridin-3-yl) methyl] -2-methoxyethan-1-amine (MGA3)
The desired compound N- [ (6-bromopyridin-3-yl) methyl] -2-methoxyethan-1-amine (MGA3) was produced by the similar procedure as that disclosed in Example 1, wherein the reaction temperature was from 10 ℃ to 40 ℃, and the reaction solvent was 2-MeTHF.
The corresponding IPC (MGA1/MGA3) were tested in the reaction progress (see Table 2) . The result showed that: 1) 5.0% (HPLC area%) of MGA1 was left when the reaction were conducted at 15 ℃ for 20 hours, which did not meet the IPC specification (no more than (NMT) 2.0%) ; 2) the staring material MGA1 converted into MGA3 completely within 20 hours when the reaction temperature was at or above 18 ℃, but the HPLC purity of MGA3 was decreased significantly from 93.6%to 87.9%when the reaction temperature was raised to 40 ℃. Hence, MGA3 with high purity and conversion rate was obtained when the reaction temperature was within 20 ℃ ～ 30 ℃ (preferably 20 ℃) , and the reaction time was about 20 hours.
Table 2:

Example 3 Study of solvent and acid of salt-formation
Step 1: N- [ (6-bromopyridin-3-yl) methyl] -2-methoxyethan-1-amine (MGA3)
To a solution of 6-bromopyridine-3-carboxaldehyde (18.0 g, 96.8 mmol, MGA1) in Dichloromethane (180 mL, DCM) was added 2-methoxyethylamine (21.8 g, 290.2 mmol, MGA2) , and the mixture was stirred at a temperature of 20 ℃ -30 ℃. After about 4 hours, sodium triacetoxyborohydride (47.3 g, 233.4 mmol, NaBH (OAc) 3) was added to the mixture and stirred for about 20 hours. Upon the reaction completion, the reaction mixture was charged with water (60 mL) and 30%sodium hydroxide (67.0 g) of successively. The organic phase was washed twice with 10%sodium sulfate solution (50.0 g *2) . The combined organic phase was concentrated to dryness. The solution was divided into thirty-six sections (each section equal to 0.5 g reaction solution) , which were used in the next step.
Step 2: N- [ (6-bromopyridin-3-yl) methyl] -2-methoxyethan-1-amine salt (MGA3  Salt)
Six acids and six organic solvents were used for the salt formation of MGA3, see Table 3.
In one example, N- [ (6-bromopyridin-3-yl) methyl] -2-methoxyethan-1-amine (MGA3, 0.5 g, 2.0 mmol) in 2-MeTHF (10 mL) solution was cooled and D-tartaric acid (0.3 g, 2.0 mmol) in EtOH (2 mL) was added dropwise. The reaction mixture was stirred for about 6 hours and filtered to obtain a wet cake of N- [ (6-bromopyridin-3-yl) methyl] -2-methoxyethan-1-amine semi-D-Tartrate (MGA3 semi-D-Tartrate) . The solid appearance was well.
A desired compound N- [ (6-bromopyridin-3-yl) methyl] -2-methoxyethan-1-amine salt (MGA3 salt) was produced by the similar procedure as that disclosed in preparing MGA3 semi-D-Tartrate. The other acids were used as followed amount, Oxalic acid (0.18 g, 2.0 mmol) , p-toluene sulfonic acid (0.38 g, 2.0 mmol) , D-DTTA (0.77 g, 2.0 mmol) , critic acid (0.38 g, 2.0 mmol) , L- (-) -malic acid (0.27 g, 2.0 mmol) ; and the other organic solvents were used with 10mL volume.
The corresponding physical form of the desired compound were recorded in Table 3. The result showed that, when the acid used in salt formation was D- (-) - tartaric acid, p-toluenesulfonic acid, D-DTTA or Malate acid, the obtained salt was a well appearance solid in certain organic solvents. Considering simplify the process D- (-) -tartaric acid /2-MeTHF and D-DTTA /2-MeTHF were preferred as the salt-formation systems, while D-DTTA (M. W. 386.35 g /mol) may cause more waste to the reaction comparing with D- (-) -tartaric acid (M.W. 150.09 g /mol) .
Table 3:
Example 4 Study of water content impact
Step 1: N- [ (6-bromopyridin-3-yl) methyl] -2-methoxyethan-1-amine (MGA3)
To a solution of 6-bromopyridine-3-carboxaldehyde (4.0 g, 21.5 mmol, MGA1) in 2-methyltetrahydrofuran (40 mL, 2-MeTHF) was added 2-methoxyethylamine (4.8 g, 64.4 mmol, MGA2) , and the mixture was stirred at a temperature of 20 ℃ -30 ℃. After about 4 hours, sodium triacetoxyborohydride (10.5 g, 49.6 mmol, NaBH (OAc) 3) was added to the mixture and stirred for about 20 hours. Upon the reaction completion, the reaction mixture was charged with water  (24 mL) and 30%sodium hydroxide (26.8 g) of successively. The organic phase was washed twice with 10%sodium sulfate solution (20.0 g *2) . The combined organic phase was concentrated by under vacuum and charged with 2-MeTHF (24 mL) . The obtained solution was concentrated under vacuum to dry to swap out the residue water, and then 2-MeTHF (16 mL) was added to obtain a solution containing N- [ (6-bromopyridin-3-yl) methyl] -2-methoxyethan-1-amine (MGA3 2-MeTHF solution) . The solution was divided into four sections, which were added different amount of water (0 g, 0.1 g, 0.3 g, and 0.48 g) to ensure the water content of the corresponding solutions were 0.1%, 1.0%, 3.0 %, 5.0 % (w. t. %) .
Step 2: N- [ (6-bromopyridin-3-yl) methyl] -2-methoxyethan-1-amine semi-D- Tartrate (MGA3 D-Tartrate)
N- [ (6-bromopyridin-3-yl) methyl] -2-methoxyethan-1-amine (1.0 g, 4.1 mmol) in 2-MeTHF (MGA3 2-MeTHF solution, 10 mL) solution was cooled and D-tartaric acid (0.44 g, 2.9 mmol) in EtOH (3 mL) was added dropwise. The reaction mixture was stirred for about 6 hours and filtered to obtain N- [ (6-bromopyridin-3-yl) methyl] -2-methoxyethan-1-amine semi-D-Tartrate (MGA3 semi-D-Tartrate) . After filter, the loss of MGA3 semi-D-Tartrate in mother liquid were collected (see Table 4) . The result shows that when the water content of the obtained N- [ (6-bromopyridin-3-yl) methyl] -2-methoxyethan-1-amine (MGA3) solution in Step 1 was ≤ 3.0% (w %) , the lost yield of MGA3 semi-D-Tartrate in the mother liquid was ≤ 5%, which was acceptable.
Table 4:
Example 5 Study of salt-formation aging temperature
Step 1: N- [ (6-bromopyridin-3-yl) methyl] -2-methoxyethan-1-amine (MGA3)
To a solution of 6-bromopyridine-3-carboxaldehyde (10.0 g, 53.8 mmol, MGA1) in 2-methyltetrahydrofuran (100 mL, 2-MeTHF) was added 2- methoxyethylamine (12.1 g, 161.4 mmol, MGA2) , and the mixture was stirred at a temperature of 20 ℃ -30 ℃. After about 4 hours, sodium triacetoxyborohydride (26.3 g, 124.1 mmol, NaBH (OAc) 3) was added to the mixture and stirred for about 20 hours. Upon the reaction completion, the reaction mixture was charged with water (60 mL) and 30%sodium hydroxide (67.0 g) of successively. The organic phase was washed twice with 10%sodium sulfate solution (50.0 g *2) . The combined organic phase was concentrated by under vacuum and charged with 2-MeTHF (60 ml) . The obtained solution was concentrated under vacuum with controlling the water content ≤ 2.0% (w.t. ) , and then 2-MeTHF (45 mL) was added to obtain a solution containing N- [ (6-bromopyridin-3-yl) methyl] -2-methoxyethan-1-amine.
Step 2: N- [ (6-bromopyridin-3-yl) methyl] -2-methoxyethan-1-amine semi-D- Tartrate (MGA3 semi-D-Tartrate)
Method A: To the cooled solution obtained in Step 1, D-tartaric acid (4.4 g, 29.3 mmol) in EtOH (30 mL) was added dropwise at 10 ℃. The reaction mixture was stirred for about 72 hours (Take sample when stir at 6 hours) and filtered to obtain a wet cake. The obtained wet cake was dried at 50 ℃ under vacuum for about 8 hours, to give 13.7 g white solid of MGA3 semi-D-Tartrate.
Method B: To the cooled solution obtained in Step 1, D-tartaric acid (4.4 g, 29.3 mmol) in EtOH (30 mL) was added dropwise at 30 ℃. The reaction mixture was stirred for about 6 hours and filtered to obtain a wet cake. The obtained wet cake was dried at 50 ℃ under vacuum for about 8 hours, to give 13.5 g white solid of MGA3 semi-D-Tartrate, which could be used as crystal seed.
The corresponding HPLC purity of MGA3 semi-D-Tartrate prepared in Methods A and B were showed in Table 5.
Table 5:
Example 6 Preparation of N- [ (6-bromopyridin-3-yl) methyl] -2-methoxyethan-1-amine semi-D-Tartrate (MGA3 Semi-D-Tartrate)
Ste1: N- [ (6-bromopyridin-3-yl) methyl] -2-methoxyethan-1-amine (MGA3)
To a solution of 6-bromopyridine-3-carboxaldehyde (1.35 kg, 7.26 mol, MGA1) in 2-methyltetrahydrofuran (13.5 L, 2-MeTHF) was added 2-methoxyethylamine (1.63 kg, 21.70 mol, MGA2) , and the mixture was stirred at a temperature of 20 ℃ -30 ℃. After about 4 hours, sodium triacetoxyborohydride (3.80 kg, 17.93 mol, NaBH (OAc) 3) was added to the mixture and stirred for about 20 hours. Upon the reaction completion (IPC (MGA1/MGA3, Area%) =0.02/95.5) , the reaction mixture was charged with water (8100 mL) and 30%sodium hydroxide (9.0 kg) of successively within 10 ℃ -25 ℃. The organic phase was washed twice with 10%sodium sulfate solution (6.8 kg *2) . The combined organic phase was concentrated by under vacuum and charged with 2-MeTHF (8100 ml) . The obtained solution was concentrated under vacuum with controlling the water content ≤ 2.0%, and then 6100 ml 2-MeTHF was added to obtain a solution containing N- [ (6-bromopyridin-3-yl) methyl] -2-methoxyethan-1-amine.
Step 2: N- [ (6-bromopyridin-3-yl) methyl] -2-methoxyethan-1-amine semi-D- Tartrate (MGA3 Semi-D-Tartrate)
To the cooled solution obtained in Step 1, MGA3 semi-D-Tartrate crystal seed (10 g) was added to obtain a suspension. After stirred for about 1 hours, D-tartaric acid (594 g, 3.96 mol) in EtOH (4050 mL) was added dropwise at 20℃. The reaction mixture was stirred for about 6 hours and filtered to obtain a wet cake. The obtained wet cake was dried at 50 ℃ under vacuum for about 8 hours, to give 2.0 kg white solid of MGA3 semi-D-Tartrate (HPLC purity = 99.8%; yield = 87%) .
Example 7: Preparation of 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-dicarboxamide (Compound 1)
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-dicarboxamide (Compound 1) was prepared by the similar method disclosed in  WO2009/026717, WO2009/026720, WO2009/109035, WO2019/182274, WO2021/098769, and EP3819300, wherein N- [ (6-bromopyridin-3-yl) methyl] -2-methoxyethan-1-amine semi-D-Tartrate (MGA3 semi-D-Tartrate) was prepared by one of procedures above.
The foregoing examples and description of certain embodiments should be taken as illustrating, rather than as limiting the present invention as defined by the claims. As will be readily appreciated, numerous variations and combinations of the features set forth above can be utilized without departing from the present invention as set forth in the claims. All such variations are intended to be included within the scope of the present invention. All references cited are incorporated herein by reference in their entireties.

Claims (13)

  1. A salt of N- [ (6-bromopyridin-3-yl) methyl] -2-methoxyethan-1-amine having formula (I) ,
    wherein the salt is a tartrate, a p-toluenesulfonate, a DDTA salt, or a malate.
  2. The salt of claim 1, wherein the salt is a tartrate, or a DDTA salt (such as a D-DTTA salt) .
  3. The salt of claim 1, wherein the salt is a tartrate (such as a D- (-) -tartrate) .
  4. A tartrate of N- [ (6-bromopyridin-3-yl) methyl] -2-methoxyethan-1-amine having formula (II) ,
    wherein n is a number from 0.4 to 1.2, preferably n is 0.5.
  5. A method of preparing a salt of N- [ (6-bromopyridin-3-yl) methyl] -2-methoxyethan-1-amine, comprising the following steps in the consist of,
    a) charging 6-bromopyridine-3-carboxaldehyde with 2-methoxyethylamine in an organic solvent;
    b) adding sodium triacetoxyborohydride to obtain N- [ (6-bromopyridin-3-yl) methyl] -2-methoxyethan-1-amine;
    c) dissolving N- [ (6-bromopyridin-3-yl) methyl] -2-methoxyethan-1-amine in an organic solvent; and,
    d) adding an acid into the resulting mixture in step c) to obtain the target salt, wherein the salt is a tartrate, a p-toluenesulfonate, a DDTA salt, or a malate.
  6. A method of preparing N- [ (6-bromopyridin-3-yl) methyl] -2-methoxyethan-1-amine D-Tartrate, comprising the following steps in the consist of,
    a) charging 6-bromopyridine-3-carboxaldehyde with 2-methoxyethylamine in an organic solvent;
    b) adding sodium triacetoxyborohydride to obtain N- [ (6-bromopyridin-3-yl) methyl] -2-methoxyethan-1-amine;
    c) dissolving N- [ (6-bromopyridin-3-yl) methyl] -2-methoxyethan-1-amine in an organic solvent; and,
    d) adding the D-Tartrate into the resulting mixture in step c) to obtain the product.
  7. A method of preparing N- [ (6-bromopyridin-3-yl) methyl] -2-methoxyethan-1-amine semi D-Tartrate, comprising the following steps in the consist of,
    a) charging 6-bromopyridine-3-carboxaldehyde with 2-methoxyethylamine in an organic solvent;
    b) adding sodium triacetoxyborohydride to obtain N- [ (6-bromopyridin-3-yl) methyl] -2-methoxyethan-1-amine;
    c) dissolving N- [ (6-bromopyridin-3-yl) methyl] -2-methoxyethan-1-amine in an organic solvent; and,
    d) adding D-tartaric acid into the resulting mixture in step c) to obtain the product.
  8. The method of any 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, more preferably, 2-MeTHF.
  9. The method of any of claims 5, 6 or 7, wherein the stoichiometric ratio of added D-Tartrate in step d) is from 0.4 to 1.2, preferably 0.5, comparing to N- [ (6-bromopyridin-3-yl) methyl] -2-methoxyethan-1-amine.
  10. The method of claim 7, wherein the water content of N- [ (6-bromopyridin-3-yl) methyl] -2-methoxyethan-1-amine in organic solvent (such as 2-MeTHF solution) in  step c) is controlled to 0～10%, preferably 0～5%, more preferably no more than 3.0% (w.t. %) .
  11. The method of claim 7, wherein the temperature of reacting 6-bromopyridine-3-carboxaldehyde with 2-methoxyethylamine is at 20 ℃ ～ 30 ℃.
  12. The method of claim 7, wherein a crystal seed of N- [ (6-bromopyridin-3-yl) methyl] -2-methoxyethan-1-amine semi-D-Tartrate is added before step d) .
  13. A method of preparing 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-dicarboxamide, or a pharmaceutically acceptable salt thereof, comprising the method of preparing N- [ (6-bromopyridin-3-yl) methyl] -2-methoxyethan-1-amine semi-D-Tartrate, comprising the following steps in the consist of,
    a) charging 6-bromopyridine-3-carboxaldehyde with 2-methoxyethylamine in an organic solvent) ;
    b) dissolving N- [ (6-bromopyridin-3-yl) methyl] -2-methoxyethan-1-amine in an organic solvent; and,
    c) adding D-tartaric acid into the resulting mixture in step c) to obtain the product.
PCT/CN2023/075938 2022-02-15 2023-02-14 N- [ (6-bromopyridin-3-yl) methyl] -2-methoxyethan-1-amine salts and preparation thereof WO2023155777A1 (en)

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Citations (5)

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WO2009026720A1 (en) * 2007-08-29 2009-03-05 Methylgene Inc. Processes and intermediates for preparing fused heterocyclic kinase inhibitors
CN101932586A (en) * 2007-08-29 2010-12-29 梅赛尔基因股份有限公司 The inhibition of protein tyrosine kinase activity
CN102015723A (en) * 2008-03-05 2011-04-13 梅特希尔基因公司 Inhibitors of protein tyrosine kinase activity
EP3819300A1 (en) * 2019-09-06 2021-05-12 Wellmarker Bio Co., Ltd. Biomarker-based therapeutic composition
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