Process for preparation of fluoropyrimidine ester derivatives

Abstract

The present disclosure relates to processes for preparing fluoropyrimidine ester derivatives. Specifically, the invention provides 2-(cyclopropyldifluoromethyl)-4-phenoxy pyrimidine-5-formate, the method comprises the step of oxidizing a compound shown in a formula A in the presence of an oxidizing agent to form a compound shown in a formula B. The process is mild in condition, low in cost, high in process yield and suitable for industrial production. # imgabs0 #

Description

Technical Field

[0001] The present invention belongs to the field of medicine and relates to a method for preparing fluoropyrimidine ester derivatives. Background Art

[0002] ECQ helicases are DNA-dependent ATPases that unwind DNA from 3' to 5'. RECQ helicases include BLM, Werner (WRN), and RECQL4, which, when their expression is altered or lost, lead to overlapping human syndromes. Additionally, multiple research groups have independently identified WRN as a potential synthetic lethal target in cancers expressing high levels of microsatellite instability (MSI-H cancers).

[0003] WO2024010782 discloses a class of WRN helicase inhibitors, such as (S,E)-N-(1-cyclopropyl-3-(methylsulfonyl)allyl)-2-(cyclopropyldifluoromethyl)-4-phenoxypyrimidine-5-carboxamide,

[0004] At the same time, WO2024010782 discloses that 2-(cyclopropyldifluoromethyl)-4-phenoxypyrimidine-5-carboxylate is a key intermediate for synthesizing compound AA.

[0005] The corresponding preparation process adopts a photocatalytic reaction step, an oxidation step and a fluorination step to obtain the target product. The synthesis route is generally as follows (see pages 202-203 of the specification). However, the photocatalytic reaction efficiency is low and the cost is high, which leads to a low overall process yield and is difficult to be suitable for industrial production.

[0006] Summary of the invention

[0007] The present invention provides a method for preparing a compound represented by formula C or a salt thereof

[0008] The method comprises the steps of subjecting the compound represented by formula A to oxidation reaction in the presence of an oxidant to form a compound represented by formula B,

[0009] Where R 1 Selected from C 1-6 Alkyl, C 3-8 Cycloalkyl or C 6-10 Aryl, the C 1-6 Alkyl, C 3-8 Cycloalkyl or C 6-10 The aryl group is optionally substituted with one or more selected from halogen, hydroxy, cyano, nitro, amino, C 1-6 Alkyl or C 1-6 Alkoxy substituted;

[0010] R 2 Selected from C 1-6 Alkyl, C 3-8 Cycloalkyl or C 6-10 Aryl, the C 1-6 Alkyl, C 3-8 Cycloalkyl or C 6-10 The aryl group is optionally substituted with one or more selected from halogen, hydroxy, cyano, nitro, amino, C 1-6 Alkyl or C 1-6 Alkoxy substituted;

[0011] R 3 Selected from C 1-6 Alkyl, C 3-8 Cycloalkyl, the C 1-6 Alkyl or C 3-8 The cycloalkyl group is optionally substituted with one or more radicals selected from halogen, hydroxy, cyano, nitro, amino, C 1-6 Alkyl or C 1-6 Alkoxy substituted.

[0012] In some embodiments, the compound represented by formula A is oxidized in the presence of selenium dioxide to form the compound represented by formula B.

[0013] In some embodiments, the molar ratio of the compound represented by Formula A to selenium dioxide is 1:1.5 to 1:3, including but not limited to 1:1.5, 1:1.6, 1:1.7, 1:1.8, 1:1.9, 1:2, 1:2.1, 1:2.2, 1:2.3, 1:2.4, 1:2.5, 1:2.6, 1:2.7, 1:2.8, 1:2.9, 1:3 or any value between two numbers.

[0014] In some embodiments, the solvent used in the oxidation reaction is selected from dioxane.

[0015] In some embodiments, the oxidation reaction temperature is 60-90°C, including but not limited to 60°C, 65°C, 70°C, 75°C, 80°C, 85°C, 90°C or any value between two numbers.

[0016] In another aspect, the method for preparing the compound of formula C or a salt thereof further comprises the step of reacting the compound of formula B with a fluorination agent to form the compound of formula C,

[0017] Where R 1 , R 2 , R 3 As defined above.

[0018] In some embodiments, the fluorination agent is selected from diethylaminosulfur trifluoride (DAST).

[0019] In some embodiments, R 1 Selected from C 3-8 Cycloalkyl (e.g., cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl), the C 3-8 The cycloalkyl group is optionally substituted with one or more radicals selected from halogen, hydroxy, cyano, nitro, amino, C 1-6 Alkyl or C 1-6 Alkoxy substituted.

[0020] In some embodiments, R 1 Selected from cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.

[0021] In some embodiments, R 1 Selected from C 6-10 Aryl (e.g. phenyl), the C 6-10 The aryl group is optionally substituted with one or more selected from halogen, hydroxy, cyano, nitro, amino, C 1-6 Alkyl or C 1-6 Alkoxy substituted.

[0022] In some embodiments, R 1 Selected from phenyl.

[0023] In some embodiments, R 2 Selected from C 3-8 Cycloalkyl (e.g., cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl), the C 3-8 The cycloalkyl group is optionally substituted with one or more radicals selected from halogen, hydroxy, cyano, nitro, amino, C 1-6 Alkyl or C 1-6 Alkoxy substituted.

[0024] In some embodiments, R 2 Selected from cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.

[0025] In some embodiments, R 2 Selected from C 6-10 Aryl (e.g. phenyl), the C 6-10 The aryl group is optionally substituted with one or more selected from halogen, hydroxy, cyano, nitro, amino, C 1-6 Alkyl or C 1-6 Alkoxy substituted.

[0026] In some embodiments, R 2 Selected from phenyl.

[0027] In some embodiments, R3 Selected from C 1-6 Alkyl (eg, methyl, ethyl or propyl), the C 1-6 The alkyl group is optionally substituted with one or more radicals selected from halogen, hydroxy, cyano, nitro, amino, C 1-6 Alkyl or C 1-6 Alkoxy substituted.

[0028] In some embodiments, R 1 is selected from cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl; R 2 Selected from phenyl; R 3 Selected from C 1-6 Alkyl (eg, methyl, ethyl or propyl).

[0029] In some embodiments, the compound represented by formula C is The method for preparing compound 1C comprises the steps of subjecting compound 1A to an oxidation reaction in the presence of an oxidant to form compound 1B,

[0030]

[0031] In some embodiments, the method for preparing compound 1C further comprises the step of reacting compound 1B with DAST to form compound 1C.

[0032]

[0033] Furthermore, the method for preparing compound 1C further comprises the steps of reacting compound a-1 with compound a-2 in the presence of a base (1) to form compound a-3, reacting compound a-3 in the presence of phosphorus oxychloride or thionyl chloride to form compound a-4, and reacting with phenol to form compound 1A, wherein the base (1) is selected from sodium ethoxide, potassium tert-butoxide or sodium tert-butoxide,

[0034]

[0035] In some embodiments, compound a-4 reacts with phenol in the presence of a base (2) to form compound 1A, wherein the base (2) is selected from potassium carbonate or sodium carbonate. For specific reaction procedures, see WO2024010782, and the relevant contents are introduced herein for illustration.

[0036] The present disclosure also provides the use of the aforementioned method for preparing the compound represented by formula C or a salt thereof in preparing a WRN helicase inhibitor, wherein the WRN helicase inhibitor is:

[0037]

[0038] The present disclosure provides a method for preparing Compound AA or a pharmaceutically acceptable salt thereof, the method comprising the steps of the aforementioned method for preparing Compound 1A or a salt thereof.

[0039] In some embodiments, the method for preparing Compound AA or a pharmaceutically acceptable salt thereof further comprises the step of converting Compound 1C to Compound AA.

[0040] In some embodiments, the method comprises the step of reacting compound 1C with compound D to form compound AA,

[0041]

[0042] In some embodiments, the method comprises the step of reacting compound 1C-1 with compound D to form compound AA,

[0043]

[0044] For specific reaction conditions and operations, please refer to WO2024010782, and the relevant contents are introduced herein for illustration.

[0045] On the other hand, the preparation method disclosed in the present invention further comprises one or more steps of filtration, concentration, purification by column chromatography and drying.

[0046] The term "converted" in the present disclosure does not specifically mean that the conversion reaction between two substrates is a single step, but may be a single step or multi-step reaction between two substrates. If the intermediate contains a protecting group, the intermediate is subjected to a step of removing the protecting agent, and then reacts with the corresponding substrate to obtain the corresponding target product.

[0047] "Alkyl" refers to a saturated aliphatic hydrocarbon group, including straight and branched groups of 1 to 6 carbon atoms. Non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl and various branched isomers thereof. Alkyl can be substituted or unsubstituted, and when substituted, the substituent can be substituted at any available point of attachment, preferably one or more of the following groups, including but not limited to halogen, hydroxyl, cyano or amino.

[0048] "Cycloalkyl" refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent, the cycloalkyl ring containing 3 to 8 carbon atoms, such as 4 carbons or 5 carbons. Non-limiting examples of monocyclic cycloalkyls include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, etc.; polycyclic cycloalkyls include cycloalkyls of spirocyclic, fused and bridged rings. Cycloalkyls may be substituted or unsubstituted. When substituted, the substituent is preferably one or more of the following groups, including but not limited to halogen, hydroxyl, cyano or amino.

[0049] The term "aryl" or "aromatic ring" refers to a 6- to 10-membered all-carbon monocyclic or fused polycyclic (ie, rings which share adjacent pairs of carbon atoms) group having a conjugated pi-electron system, such as phenyl and naphthyl.

[0050] Aryl groups may be substituted or unsubstituted, and when substituted, the substituents are preferably one or more of the following groups including but not limited to halogen, hydroxy, cyano or amino.

[0051] The term "amino" refers to -N(R a )2, where R c are each independently selected from hydrogen, C 1-6 Alkyl, C 3-6 Cycloalkyl or 3 to 6 membered heterocycloalkyl, the alkyl, cycloalkyl or heterocycloalkyl being optionally substituted with one or more selected from halogen, hydroxy, cyano, nitro, C 1-6 Alkyl or C 1-6 In some embodiments, "amino" can be an unsubstituted amino group (ie, -NH2) or a substituted amino group (-N(R a )2,R a not all hydrogen).

[0052] The term "hydroxy" refers to an -OH group.

[0053] The term "halogen" refers to fluorine, chlorine, bromine or iodine.

[0054] The term "cyano" refers to -CN.

[0055] The term "nitro" refers to -NO2.

[0056] "Substituted" means that one or more hydrogen atoms, preferably up to 5, more preferably 1 to 3 hydrogen atoms in the group are replaced independently of each other by a corresponding number of substituents. It goes without saying that the substituents are only in their possible chemical positions, and the skilled person can determine (by experiment or theory) possible or impossible substitutions without undue effort.

[0057] The numerical values ​​in this disclosure are instrumental measurements, which have a certain degree of error. Generally speaking, plus or minus 10% is within the reasonable error range. Of course, the context in which the numerical value is used needs to be considered. For example, the particle size of the active ingredient, the numerical value is the error change after measurement does not exceed plus or minus 10%, which can be plus or minus 9%, plus or minus 8%, plus or minus 7%, plus or minus 6%, plus or minus 5%, plus or minus 4%, plus or minus 3%, plus or minus 2% or plus or minus 1%, preferably plus or minus 5%.

[0058] The pharmaceutically acceptable salt of the compound in the present disclosure can be selected from an inorganic pharmaceutically acceptable salt or an organic pharmaceutically acceptable salt, such as hydrochloride. In some embodiments, the pharmaceutically acceptable salt of Compound D is selected from Compound D hydrochloride.

[0059] The salt of the compound in the present disclosure can be selected from inorganic salts or organic salts, including "acid" addition salts and "base" addition salts. For example, salts formed by acid-base reaction with a basic group (amino group), the acid includes organic acid or inorganic acid.

[0060] In the chemical structures of the compounds disclosed herein, the bond Indicates that the configuration is not specified, that is, if there are chiral isomers in the chemical structure, the bond Can be or or include both and Two configurations. DETAILED DESCRIPTION

[0061] The present disclosure is further described below with reference to embodiments, but these embodiments are not intended to limit the scope of the present disclosure.

[0062] The experimental methods in the examples of this disclosure that do not specify specific conditions are usually carried out under conventional conditions or under conditions recommended by raw material or product manufacturers. Reagents that do not specify specific sources are conventional reagents purchased from the market.

[0063] The structures of the compounds were determined by nuclear magnetic resonance (NMR) and / or mass spectrometry (MS). NMR shifts (δ) are given in units of 10-6 (ppm).

[0064] NMR measurements were performed using a Bruker AVANCE-400 nuclear magnetic spectrometer, and the measurement solvent was deuterated chloroform (CDCl3).

[0065] MS was determined using a Waters Micromass Quattro micro API triple quadrupole mass spectrometer in positive / negative ion mode with a mass scan range of 120-1300.

[0066] HPLC column: YMC-Pack ODS-A (3μm, 4.6mmx 150mm)

[0067] The thin layer chromatography silica gel plate used was Yantai Huanghai HSGF254 silica gel plate. The specification of silica gel plate used in thin layer chromatography (TLC) was 0.2mm±0.03mm, and the specification of thin layer chromatography separation and purification product was 0.4mm-0.5mm.

[0068] Example 1

[0069]

[0070] Step 1

[0071] Compound 1 (5 g, 61.6405 mmol) was dissolved in EtOH (50 mL), cooled to 0°C, ethanolic hydrochloride (30 mL) was added, stirred at room temperature for 12 hours, concentrated to dryness under reduced pressure at 40°C, added with 7 M ammonia methanol solution (50 mL), stirred at room temperature for 6 hours, and concentrated to dryness under reduced pressure at 40°C to obtain 7 g (100%) of a crude product.

[0072] Step 2

[0073] Compound 2 (14 g, 104.01 mmol) was dissolved in ethanol (200 mL), sodium ethoxide (14.16 g, 208.01 mmol) was added at 0°, and finally diethyl ethoxymethylenemalonate (22.49 g, 104.01 mmol) was added and stirred at room temperature for 2 h. The reaction was completed after LCMS monitoring. Water was added to dissolve, and the pH was adjusted to 6 with a saturated solution of citric acid. Dichloromethane was added to extract 3 times, washed with a saturated solution of sodium chloride, dried over anhydrous sodium sulfate, and concentrated under reduced pressure at 40°C to obtain 16.5 g of a crude product (yield 71%).

[0074] Step 3:

[0075] Compound 3 (16 g, 71.99 mmol) was added to POCl3 (70 mL), heated to 80°C with stirring for 6 h, and the reaction was completed by LCMS (a small amount of the reaction solution was taken and methanol was added for quenching). The reaction was concentrated under reduced pressure at 40°C to obtain 16.5 g of crude product (yield 100%).

[0076] Step 4:

[0077] Compound 4 (12 g, 49.86 mmol) was dissolved in acetonitrile (120 mL), and phenol (5.63 g, 59.83 mmol) and potassium carbonate (68.80 g, 498.58 mmol) were added at room temperature. The mixture was stirred and heated to 80° for 5 h. The reaction was complete under LCMS monitoring. Silica gel was added to the reaction solution, and the mixture was directly concentrated under reduced pressure. Column chromatography (EA:PE=0-20%) was performed to purify the mixture to obtain 11 g of an off-white solid (yield 74%).

[0078] Step 5:

[0079] Compound 5 (1 g, 3.35 mmol) was dissolved in dioxane (50 mL), and selenium dioxide (0.7 g, 6.7 mmol) was added at room temperature. The mixture was stirred and heated to 80° for 6 h. The raw material disappeared after monitoring by LCMS. Silica gel was added to the reaction solution, and the mixture was directly concentrated under reduced pressure. Column chromatography (EA:PE = 0-20%) was performed to purify the mixture to obtain 0.6 g of an off-white solid (yield 60%).

[0080] MS m / z(ESI):313.1[M+1]

[0081] 1H NMR (400MHz, CDCl3): δ9.19 (s, 1H), 7.34-7.40 (m, 2H), 7.14-7.23 (m, 3H), 4.41 (q, J = 7.2 Hz, 2H), 2.80-2.87 (m, 1H), 1.37 (t, J = 7.2Hz, 3H), 1.13-1.18 (m, 2H), 0.76-0.82 (m, 2H).

[0082] Step 6:

[0083] Compound 6 (1.3 g, 4.1624 mmol) was dissolved in DAST (15 mL) and stirred at room temperature for 48 h. The reaction was completed under LCMS monitoring. The reaction solution was quenched in aqueous sodium bicarbonate solution, extracted with ethyl acetate, and separated to obtain an organic phase. Silica gel was added to the organic phase and the sample was spin-dried and purified by column chromatography (EA:PE=0-10%) to obtain 1.15 g (yield 80%).

[0084] Step 7:

[0085] Compound 7 (550 mg, 1.6451 mmol) was dissolved in THF (6 mL) and LiOH (118.1954 mg, 4.9354 mmol) H2O (3 mL) was added. The mixture was stirred at room temperature for 2 h. The reaction was completed after monitoring by LCMS. 1M HCL aqueous solution was added to adjust the pH to 6. Ethyl acetate was added to extract the organic layer, which was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure at 40°C to obtain 470 mg (yield 93%).

[0086] Step 8:

[0087] The raw material (S, E)-1-cyclopropyl-3-(methylsulfonyl)prop-2-en-1-amine (324.8940 mg, 1.5346 mmol) and compound 8 (470 mg, 1.5346 mmol) were dissolved in DMF (7 mL), and DIEA (991.6991 mg, 7.6731 mmol) and HATU (875.2642 mg, 2.3019 mmol) were added at room temperature. After the addition was completed, the mixture was stirred at room temperature for 2 h. The reaction of the raw material was completed under LCMS monitoring. Water and ethyl acetate were added to the reaction solution, and the organic layer was obtained by separation and extraction. Silica gel was added to the organic layer, and the mixture was concentrated and mixed at 40°C. The mixture was purified by silica gel column chromatography (EA:PE=0-50%) to obtain a yellow solid slurry to obtain 460 mg (yield 65%).

[0088] Example 2

[0089]

[0090] step:

[0091] Compound 5 (100 mg, 3.35 mmol) was dissolved in 1,2-dichloroethane (5 mL), and manganese dioxide (0.87 g, 10 mmol) was added, stirred, heated to 70°, and reacted for 12 h. LCMS monitored the generation of a very small amount of raw materials. The reaction solution was directly concentrated under reduced pressure and liquid phase preparation was performed to obtain 5 mg of an off-white solid (yield 5%).

[0092] Example 3

[0093]

[0094] step:

[0095] Compound 5 (100 mg, 3.35 mmol) was dissolved in water (2 mL) and acetonitrile (2 mL), and tert-butyl hydroperoxide aqueous solution (70%) (1.3 g, 10 mmol) was added at room temperature. The mixture was stirred and heated to 50° for 12 h. A small amount of raw materials was generated under LCMS monitoring. Silica gel was added to the reaction solution, and it was directly concentrated under reduced pressure. Column chromatography (EA:PE=0-20%) was performed to purify the mixture to obtain 21 mg of an off-white solid (yield 20%).

Claims

1. A method for preparing a compound represented by formula C or a salt thereof, The method comprises the steps of subjecting the compound represented by formula A to an oxidation reaction in the presence of an oxidant to form a compound represented by formula B, wherein the oxidant is preferably selenium dioxide. Where R 1 Selected from C 1-6 Alkyl, C 3-8 Cycloalkyl or C 6-10 Aryl, the C 1-6 Alkyl, C 3-8 Cycloalkyl or C 6-10 The aryl group is optionally substituted with one or more selected from halogen, hydroxy, cyano, nitro, amino, C 1-6 Alkyl or C 1-6 Alkoxy substituted; R 2 Selected from C 1-6 Alkyl, C 3-8 Cycloalkyl or C 6-10 Aryl, the C 1-6 Alkyl, C 3-8 Cycloalkyl or C 6-10 The aryl group is optionally substituted with one or more selected from halogen, hydroxy, cyano, nitro, amino, C 1-6 Alkyl or C 1-6 Alkoxy substituted; R 3 Selected from C 1-6 Alkyl, C 3-8 Cycloalkyl, the C 1-6 Alkyl or C 3-8 The cycloalkyl group is optionally substituted with one or more radicals selected from halogen, hydroxy, cyano, nitro, amino, C 1-6 Alkyl or C 1-6 Alkoxy substituted.

2. The method according to claim 1, wherein the solvent used in the oxidation reaction is selected from dioxane.

3. The method according to claim 1 or 2, wherein the oxidation reaction temperature is 60 to 90°C.

4. The method according to any one of claims 1 to 3, wherein the method further comprises the step of reacting the compound represented by formula B with a fluorinating agent to form a compound represented by formula C, wherein the fluorinating agent is preferably diethylaminosulfur trifluoride, Where R 1 , R 2 , R 3 As defined in claim 1.

5. The method according to claim 1, wherein the compound shown in formula C is The method for preparing compound 1C comprises the steps of subjecting compound 1A to an oxidation reaction in the presence of an oxidant to form compound 1B, 6. The method according to claim 5, further comprising the step of reacting compound 1B with DAST to form compound 1C 7. The method according to claim 5 or 6, further comprising the steps of reacting compound a-1 with compound a-2 in the presence of a base (1) to form compound a-3, reacting compound a-3 in the presence of phosphorus oxychloride or thionyl chloride to form compound a-4, and reacting with phenol to form compound 1A, wherein the base (1) is preferably sodium ethoxide, potassium tert-butoxide or sodium tert-butoxide, 8. Use of the method for preparing a compound represented by formula C or a salt thereof according to any one of claims 1 to 4 in preparing a WRN helicase inhibitor, wherein the WRN helicase inhibitor is preferably:

9. A method for preparing compound AA or a pharmaceutically acceptable salt thereof, the method comprising the steps of the method according to claim 5 or 6 10. The method according to claim 7, further comprising the step of converting compound 1C into compound AA, preferably comprising the step of reacting compound 1C with compound D to form compound AA,

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