Synthesis of small molecule agonists of neuroptrophins
A novel synthetic method for small molecule agonists of neurotrophins, bypassing solid supports, addresses inefficiencies in existing methods, enabling large-scale production with high purity.
Patent Information
- Application Number
- JP2025536772
- Authority / Receiving Office
- JP · JP
- Patent Type
- Applications
- Current Assignee / Owner
- Priority Date
- 2022-12-22
- Filing Date
- 2023-12-22
- Publication Date
- 2025-12-25
AI Technical Summary
Existing synthetic routes for small molecule agonists of neurotrophins, such as nerve growth factor (NGF) and brain-derived neurotrophic factor (BDNF), are not suitable for large-scale industrial production and often rely on solid supports, which are inefficient and costly.
A novel synthetic method for compounds of formula FI, involving a series of reactions in organic solvents without the use of solid supports, including steps with specific reactants and conditions to produce high-purity compounds.
The method enables the production of high-purity small molecule agonists of neurotrophins with reduced impurities, suitable for large-scale industrial synthesis.
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Figure 2025542370000001_ABST
Abstract
Description
Detailed Description of the Invention
[0001] [Technical Field] The present disclosure relates to the field of therapeutics for neurological disorders, psychiatric disorders, and aging. In particular, the present disclosure relates to a synthetic route to small molecule agonists of neurotrophins (nerve growth factor (NGF) or brain-derived neurotrophic factor (BDNF)), more specifically small molecules of formula FI: [ka] .
[0002] [Background technology] Synthetic routes to compounds of formula FI are known. For example, Masip et al. (Med. Chem. 13 (2005) 1929 (doi: / j.bmc.2005.01.024) disclose a solid-phase synthesis using a positional scanning format and a submonomer strategy. This synthetic route involves seven steps before a final cleavage step to recover the target molecule from the solid support (rink amide resin), as shown below: [ka] .
[0003] The first step in this synthetic pathway is the deprotection of the amine functional group on the solid support. The following six steps are a two-step sequence: acylation followed immediately by amination. Thus, this synthetic pathway allows for the sequential growth of molecules by using appropriate primary amines relative to the target molecule.
[0004] Although this synthesis process can be satisfactory under certain conditions, it would be beneficial to propose a synthetic route that does not use solid supports, particularly one that is more suitable for large-scale synthesis for industrial production.
[0005] 〔overview〕 1. A method for synthesizing a compound of formula FI, comprising: [ka] During the ceremony, R1 is phenyl substituted with halogen or trifluoromethyl, and optionally further substituted with one or two substituents selected from the group consisting of halogen, (C1-C6) alkyl, (C1-C6) alkoxy, and halo(C1-C6) alkyl; or R1 is pyrrolidin-1-yl; R2 is 2-oxo-pyrrolidin-1-ylmethyl or sulfamoylphenyl; and R3 is selected from propyl, 1-methylethyl, butyl, 2-methylpropyl, pentyl, 1-methylbutyl, 2-methylbutyl, hexyl, 4-methylpentyl, 3-methylpentyl, 2-methylpentyl, and 1-methylpentyl; A method is proposed, comprising the steps of: (S1) Providing a compound CS1 of formula FCS1: [ka] (S2) Providing a compound CS2 of formula FCS2: [ka] (S3) Providing a compound CS3 of formula FCS3: [ka] (S4) reacting CS1 with CS2 in an organic solvent to obtain a compound CS4 of formula FCS4: [ka] (S5) reacting CS3 with CS4 in an organic solvent to obtain a compound CS5 of formula FCS5: [ka] (S6) reacting CS5 with an acid in an alcohol solvent to obtain a compound CS6 of formula FCS6: [ka] (S7) A step of reacting CS6 with ammonia in an organic solvent.
[0006] BRIEF DESCRIPTION OF THE DRAWINGS Figure 1 FIG. 1 depicts a synthetic route to a compound of formula FI according to the present disclosure, where R1 is 2-fluorophenyl, R2 is methylpyrrolidin-2-one, and R3 is isobutyl.
[0007] Figure 2 Figure 2 shows the reaction of 2-{N-[2-(2-fluorophenyl)ethyl]formamido}acetic acid in CDCl3. 1 The H NMR spectrum is shown.
[0008] Figure 3 Figure 3 shows the reaction of 2-[(2-methylpropyl)amino]acetic acid hydrochloride in DMSO. 1 The H NMR spectrum is shown.
[0009] Figure 4 Figure 4 shows the reaction of 2-{[3-(2-oxopyrrolidin-1-yl)propyl]amino}acetic acid hydrochloride in DMSO. 1 The H NMR spectrum is shown.
[0010] Figure 5 Figure 5 shows the reaction of N-(carbamoylmethyl)-2-(2-{[2-(2-fluorophenyl)ethyl]amino}-N-(2-methylpropyl)acetamido)-N-[3-(2-oxopyrrolidin-1yl)propyl]acetamide in CD3OD. 1 The H NMR spectrum is shown.
[0011] Detailed Description of the Disclosure As noted above, the present disclosure provides a method for synthesizing a compound of formula FI: [ka] During the ceremony, R1 is phenyl substituted with halogen or trifluoromethyl, and optionally further substituted with one or two substituents selected from the group consisting of halogen, (C1-C6) alkyl, (C1-C6) alkoxy, and halo(C1-C6) alkyl; or R1 is pyrrolidin-1-yl; R2 is 2-oxo-pyrrolidin-1-ylmethyl or sulfamoylphenyl; and R3 is selected from propyl, 1-methylethyl, butyl, 2-methylpropyl, pentyl, 1-methylbutyl, 2-methylbutyl, hexyl, 4-methylpentyl, 3-methylpentyl, 2-methylpentyl, and 1-methylpentyl; The method comprises the steps of: (S1) Providing a compound CS1 of formula FCS1: [ka] (S2) Providing a compound CS2 of formula FCS2: [ka] (S3) Providing a compound CS3 of formula FCS3: [ka] (S4) reacting CS1 with CS2 in an organic solvent to obtain a compound CS4 of formula FCS4: [ka] (S5) reacting CS3 with CS4 in an organic solvent to obtain a compound CS5 of formula FCS5: [ka] (S6) reacting CS5 with an acid in an alcohol solvent to obtain a compound CS6 of formula FCS6: [ka] (S7) A step of reacting CS6 with ammonia in an organic solvent.
[0012] Process (S1) According to the present disclosure, step (S1) consists of providing a compound of formula FCS1. To the best of the applicant's knowledge, at the time of this disclosure, the compound of formula FCS1 is not commercially available.
[0013] CS1 can be obtained by reacting glyoxylic acid with an amine of formula NH2-CH2-CH2-R1. Thus, in one embodiment, step (S1) is carried out by reacting glyoxylic acid with an amine of formula NH2-CH2-CH2-R1 in water at a temperature of 65°C to 90°C, preferably 70°C to 85°C, and more preferably about 80°C.
[0014] In certain embodiments, step (S1) is carried out at a glyoxylic acid to amine ratio of about 2.05, such as 2.0 to 2.25.
[0015] According to the present disclosure, R1 is phenyl substituted with halogen or trifluoromethyl, and optionally further substituted with one or two substituents selected from the group consisting of halogen, (C1-C6) alkyl, (C1-C6) alkoxy, and halo(C1-C6) alkyl; or R1 is pyrrolidin-1-yl.
[0016] In a preferred embodiment, R1 is 2-fluorophenyl.
[0017] Process (S2) According to the present disclosure, step (S2) consists of providing a compound of formula FCS2, which, to the best of the applicant's knowledge, has already been disclosed at the time of this disclosure.
[0018] However, CS2 can be obtained by reacting glyoxylic acid with an amine of formula NH2-R3. Thus, in one embodiment, step (S2) is carried out by reacting glyoxylic acid with an amine of formula NH2-R3 in water at a temperature of 65°C to 90°C, preferably 70°C to 85°C, and more preferably about 80°C, followed by the addition of concentrated hydrochloric acid (HCl) at a temperature above 80°C, preferably above 90°C, and more preferably 100°C.
[0019] In one embodiment, the concentrated HCl is an aqueous solution of 35% HCl.
[0020] The ratio of HCl to the amine of formula NH2-R3 is comprised between 1.05 and 5, preferably between 1.5 and 4, more preferably between 2 and 3.
[0021] According to the present disclosure, R3 is selected from propyl, 1-methylethyl, butyl, 2-methylpropyl, pentyl, 1-methyl-butyl, 2-methylbutyl, hexyl, 4-methylpentyl, 3-methylpentyl, 2-methylpentyl, and 1-methylpentyl.
[0022] In a preferred embodiment, R3 is 2-methylpropyl.
[0023] Process (S3) According to the present disclosure, step (S3) consists of providing a compound of formula FCS3, which, to the applicant's knowledge, at the time of this disclosure, is not commercially available.
[0024] CS3 can be obtained by reacting glyoxylic acid with an amine of formula NH2-CH2-CH2-R2. Thus, in one embodiment, step (S3) is carried out by reacting glyoxylic acid with an amine of formula NH2-CH2-CH2-R2 in water at a temperature of 65°C to 90°C, preferably 70°C to 85°C, and more preferably about 80°C, followed by addition of concentrated HCl at a temperature of 80°C or higher, preferably 90°C or higher, and more preferably 100°C.
[0025] In one embodiment, the concentrated HCl is an aqueous solution of 35% HCl.
[0026] The ratio of HCl to the amine of formula NH2-R3 is comprised between 1.05 and 5, preferably between 1.5 and 4, and more preferably between 2 and 3.
[0027] According to the present disclosure, R2 is 2-oxo-pyrrolidin-1-ylmethyl or sulfamoylphenyl.
[0028] In a preferred embodiment, R2 is 2-oxo-pyrrolidin-1-ylmethyl.
[0029] Process (S4) According to the present disclosure, step (S4) consists of synthesizing a compound of formula FCS4, which, to the applicant's knowledge, at the time of this disclosure, is not commercially available.
[0030] CS4 can be obtained by reacting CS1 with CS2 in an organic solvent. Thus, in one embodiment, step (S4) is carried out by reacting CS1 with CS2 in the presence of 2,3,4,6,7,8,9,10-octahydropyrimido[1,2-a]azepine, also known as 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), and carbonyldiimidazole, from a starting temperature of 0° C. to room temperature of 20° C. to 25° C.
[0031] The organic solvent in step (S4) may be selected from the group consisting of dimethylformamide and acetonitrile.
[0032] Process (S5) According to the present disclosure, step (S5) consists of synthesizing a compound of formula FCS5, which, to the applicant's knowledge, at the time of this disclosure, is not commercially available.
[0033] CS5 can be obtained by reacting CS3 with CS4 in an organic solvent. Thus, in one embodiment, step (S5) is carried out in the presence of 2,3,4,6,7,8,9,10-octahydropyrimido[1,2-a]azepine, also known as 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), and carbonyldiimidazole at room temperature between 20° C. and 25° C.
[0034] The organic solvent in step (S4) may be selected from the group consisting of dimethylformamide, acetonitrile and dimethyl sulfoxide.
[0035] Process (S6) According to the present disclosure, step (S6) consists of synthesizing a compound of formula FCS6, which, to the applicant's knowledge, at the time of this disclosure, is not commercially available.
[0036] CS6 can be obtained by reacting CS5 with an acid in an alcoholic solvent, preferably H2SO4 in methanol.
[0037] In some embodiments, step (S6) is carried out at reflux.
[0038] Process (S7) Step (S7) is the final step in the synthesis of compounds of formula FI according to the present disclosure, in which CS6 reacts with ammonia.
[0039] In one embodiment, step (S7) is carried out at a temperature of -30°C to -50°C, preferably -35°C to -45°C, and more preferably -40°C.
[0040] In step (S7), the ammonia may be in liquid form, for example an aqueous or alcoholic, for example a methanol solution, or in gaseous form, with gaseous form being preferred.
[0041] In certain embodiments, the compound of formula FI is obtained at the end of step (S7) with less than 0.3% of each individual impurity.
[0042] Compound of Formula F-I According to the present disclosure, the compound of formula FI is: [ka] During the ceremony, R1 is phenyl substituted with halogen or trifluoromethyl, and optionally further substituted with one or two substituents selected from the group consisting of halogen, (C1-C6) alkyl, (C1-C6) alkoxy, and halo(C1-C6) alkyl; or R1 is pyrrolidin-1-yl; R2 is 2-oxo-pyrrolidin-1-ylmethyl or sulfamoylphenyl; and R3 is selected from propyl, 1-methylethyl, butyl, 2-methylpropyl, pentyl, 1-methylbutyl, 2-methylbutyl, hexyl, 4-methylpentyl, 3-methylpentyl, 2-methylpentyl, and 1-methylpentyl.
[0043] When R1 is (C1-C6) alkyl, R1 can be methyl, ethyl, propyl, butyl, 2-methylpropyl, pentyl, 2-methylbutyl, 2,2-dimethylpropyl, hexyl, 2-methylpentyl, 3-methylpentyl, 2,2-dimethylbutyl, 2,3-dimethylbutyl, and R1 is linked by any carbon.
[0044] When R1 is (C1-C6)alkoxy, R1 can be -O-R4, where R4 can be methyl, ethyl, propyl, butyl, 2-methylpropyl, pentyl, 2-methylbutyl, 2,2-dimethylpropyl, hexyl, 2-methylpentyl, 3-methylpentyl, 2,2-dimethylbutyl, 2,3-dimethylbutyl, and R4 is linked to the oxygen by any carbon and R1 is linked by the oxygen.
[0045] When R1 is halo(C1-C6)alkyl, R1 may be -X-R4, where X is a halogen atom, preferably selected from fluorine, chlorine and bromine, and where R4 may be methyl, ethyl, propyl, butyl, 2-methylpropyl, pentyl, 2-methylbutyl, 2,2-dimethylpropyl, hexyl, 2-methylpentyl, 3-methylpentyl, 2,2-dimethylbutyl, 2,3-dimethylbutyl, and R4 is linked to the halogen atom by any carbon and R1 is linked by an oxygen.
[0046] In a preferred embodiment, R1 is 2-fluorophenyl, R2 is 2-oxo-pyrrolidin-1-ylmethyl, and R3 is 2-methylpropyl. Thus, in a preferred embodiment, the compound of formula FI is: [ka] .
[0047] Compound CS1 Step (S1) of the method according to the present disclosure provides a compound of formula FCS1: [ka] .
[0048] In a preferred embodiment, R1 is 2-fluorophenyl. Thus, in a preferred embodiment, the compound of formula FCS1 is: [ka] .
[0049] Compound CS2 Step (S2) of the method according to the present disclosure provides a compound of formula FCS2: [ka] .
[0050] In a preferred embodiment, R3 is 2-methylpropyl. Thus, in a preferred embodiment, the compound of formula FCS2 is: [ka] .
[0051] Compound CS3 Step (S3) of the method according to the present disclosure provides a compound of formula FCS3: [ka] .
[0052] In a preferred embodiment, R2 is 2-oxo-pyrrolidin-1-ylmethyl. Thus, in a preferred embodiment, the compound of formula FCS3 is: [ka] .
[0053] Compound CS4 Step (S4) of the method according to the present disclosure provides a compound of formula FCS4: [ka] .
[0054] In a preferred embodiment, R1 is 2-fluorophenyl and R3 is 2-methylpropyl. Thus, in a preferred embodiment, the compound of formula FCS4 is: [ka] .
[0055] Compound CS5 Step (S5) of the method according to the present disclosure provides a compound of formula FCS5: [ka] .
[0056] In a preferred embodiment, R1 is 2-fluorophenyl, R2 is 2-oxo-pyrrolidin-1-ylmethyl, and R3 is 2-methylpropyl. Thus, in a preferred embodiment, the compound of formula FCS5 is: [ka] .
[0057] Compound CS6 Step (S6) of the method according to the present disclosure provides a compound of formula FCS6: [ka] .
[0058] In a preferred embodiment, R1 is 2-fluorophenyl, R2 is 2-oxo-pyrrolidin-1-ylmethyl, and R3 is 2-methylpropyl. Thus, in a preferred embodiment, the compound of formula FCS6 is: [ka] .
[0059] Pharmaceutical Composition The present disclosure also relates to pharmaceutical compositions comprising a compound of formula FI obtained by the above synthetic method, and optionally one or more pharmaceutically acceptable excipients.
[0060] In certain embodiments, the pharmaceutical composition contains less than 0.3% of each individual impurity. [Example] Synthesis of N-(carbamoylmethyl)-2-(2-{[2-(2-fluorophenyl)ethyl]amino}-N-(2-methylpropyl)acetamido)-N-[3-(2-oxopyrrolidin-1-yl)propyl]acetamide (Figure 1): [ka]
[0061] Process (S1) A solution of glyoxylic acid (50% by weight in water) (8939 ml, 81.02 mol) was added to a suspension of 2-fluorophenethylamine (5500 g, 39.52 mol) in water (27.5 L) and stirred at 80° C. (internal temperature). After addition of the amine, a creamy solid appeared.
[0062] The solid formed had a gummy consistency, after which the reaction was heated at 80° C. (internal temperature) for a further 3 hours.
[0063] Liquid chromatography-mass spectrometry (LC-MS) showed complete conversion to the desired product.
[0064] The reaction was cooled to 5°C (2 hours) and the solid that formed was filtered, washed with cold (5°C) water (5000 ml) and dried under vacuum at 50°C to constant weight.
[0065] The solid was triturated in 5000 ml of isopropanol (iPrOH) and filtered after 30 minutes. The solid was dried under vacuum at 50° C. to a constant weight.
[0066] Obtained 6410 g (72%) of 2-{N-[2-(2-fluorophenyl)ethyl]formamido}acetic acid as an off-white solid.
[0067] FIG. 2 shows the H NMR spectrum of 2-{N-[2-(2-fluorophenyl)ethyl]formamido}acetic acid in CDCl.
[0068] Process (S2) To a solution of isobutylamine (5400 ml, 54.34 mol) in water (16 L) was added glyoxylic acid (50% by weight in water) (12.3 L, 116.8 mol) (1 h 30 min) while keeping the internal temperature below 65° C. A lot of foaming occurred during the addition (CO2 evolution).
[0069] The solution was then stirred at 82-86°C (internal temperature) for 16 hours.
[0070] The solution turned into a dark brown liquid after 2 hours.
[0071] After 16 hours the reaction was cooled to 65°C and 12M HCl (4989 ml, 57.87 mol) was added in one portion and the solution heated at 82-86°C (internal temperature) for a further 24 hours.
[0072] After 24 hours, the water was removed and 5 L of acetonitrile was added to the residue, and the solvent was removed to remove traces of water.
[0073] The resulting crude product was dissolved in 25 L of acetonitrile and heated to 80° C. until complete solution was achieved. The solution was then cooled to 25° C. and seeded with the desired product (Lot BN01_FSC_075). After 16 hours, the solid was filtered.
[0074] The resulting solid was dried under vacuum at 70° C. to constant weight.
[0075] 5829 g (64%) of 2-[(2-methylpropyl)amino]acetic acid hydrochloride was obtained as white flakes.
[0076] Figure 3 shows the reaction of 2-[(2-methylpropyl)amino]acetic acid hydrochloride in DMSO. 1 The H NMR spectrum is shown.
[0077] Process (S3) A solution of 1-(3-aminopropyl)pyrrolidin-2-one (4000 g, 28.13 mol) and glyoxylic acid monohydrate (5821 g, 57.8 mol) in water (30 L) was heated at 85° C. for 12 hours. HCl (35%) (4 L, 33.9 mol) was then added and the reaction was heated at 90° C. for an additional 4 hours. The solvent was removed and 2000 ml of acetonitrile was added to remove traces of water. This operation was repeated two more times.
[0078] The resulting solid was recrystallized by heating with 12 L of iPrOH to 90° C., and then the suspension was cooled to 5° C. for 2 hours. The solid was filtered and washed with 3 L of iPrOH and 2 L of hexane. The solid was dried in an oven at 70° C. to constant weight to give 4479 g (67%) of 2-{[3-(2-oxopyrrolidin-1-yl)propyl]amino}acetic acid hydrochloride as a white solid.
[0079] Figure 4 shows the reaction of 2-{[3-(2-oxopyrrolidin-1yl)propyl]amino}acetic acid hydrochloride in DMSO. 1 The H NMR spectrum is shown.
[0080] Process (S4) To a solution of 2-{N-[2-(2-fluorophenyl)ethyl]formamido}acetic acid (1300 g, 5.77 mol) in DMF (6.5 L) was added CDI (1122 g, 6.92 mol). The resulting mixture was stirred for 1 h. Bubbling due to CO evolution was observed during the first 10 min.
[0081] After 15 minutes, the mixture was cooled to 5°C in a water / ice bath. 2-[(2-methylpropyl)amino]acetic acid hydrochloride (1936 g, 11.55 mol) and DBU (3450 ml, 23.08 mol) were then added sequentially. After the addition, the internal temperature reached 10°C. The mixture was stirred at 10°C for 15 minutes and then allowed to reach 25°C.
[0082] LC-MS control after 30 min showed complete conversion of starting material.
[0083] Afterwards, 10 L of water was added and the aqueous phase was washed twice with DCM (2 x 2000 ml). The pH of the aqueous phase was adjusted to 2 with HCl (35%) and extracted with ethyl acetate (3 x 2000 ml). The organics were collected, washed twice with brine, dried over MgSO4 and the solvent was evaporated to give 1560 g (80%) of the desired product as a brown oil. This crude product was used directly in the next step.
[0084] Process (S5) To a solution of 2-(2-{N-[2-(2-fluorophenyl)ethyl]formamido}-N-(2-methylpropyl)acetamido)acetic acid (1550 g, 4.58 mol) in acetonitrile (5600 ml) at 25° C. under a nitrogen atmosphere, carbonyldiimidazole (890 g, 5.49 mol) was added in one portion and stirred for 30 min at 25° C. A strong evolution of CO2 was observed.
[0085] After 30 minutes, the reactants were added to a solution of 2-{[3-(2-oxopyrrolidin-1-yl)propyl]amino}acetic acid hydrochloride (2164 g, 9.17 mol) and DBU (2735 ml, 18.32 mol) in acetonitrile (5600 ml) under a nitrogen atmosphere, keeping the internal temperature below 15° C. The reactants were then stirred at 25° C. for 1 hour.
[0086] At this time, LC-MS showed complete conversion to the desired product.
[0087] The solvent was removed, and water (10 L) was added to the residue and extracted twice with 2000 ml of dichloromethane (DCM). The aqueous phase was then acidified with HCl (35%) to pH = 2 and extracted with DCM (3 x 2000 ml). The organics were washed with brine, dried over magnesium sulfate, and evaporated to give 2032 g (85%) of 2-[2-(2-{N-[2-(2-fluorophenyl)ethyl]formamide}N-(2-methylpropyl)acetamido)-N-[3-(2-oxopyrrolidin-1-yl)propyl]acetamido]acetic acid as a colorless oil.
[0088] This sample is used in the next step without further purification.
[0089] Process (S6) To a solution of 2-[2-(2-{N-[2-(2-fluorophenyl)ethyl]formamido}-N-(2-methylpropyl)acetamido)-N-[3-(2-oxopyrrolidin-1-yl)propyl]acetamido]acetic acid (2032 g, 3.9 mol) in methanol (10 L) at 25° C. was added HSO 98% (311 ml, 5.85 mol). An exothermic transition was detected during the addition, the temperature rising to 53° C., and the reaction was then heated under reflux for 12 h.
[0090] After 12 h, LCMS showed complete conversion to the desired product.
[0091] The reaction was cooled to 25 °C and poured into a solution of 1040 g KHCO3 (10.4 mol) in 4 L water (pH buffered to 7.90-7.85). The product was then extracted with DCM (3 x 2000 ml). The organics were combined and washed with 4 L of K2CO3 (25% wt / wt in water) solution (pH buffered to 11.90-11.75).
[0092] The organics were washed with water (2x2000ml) and brine (1x2000ml), dried over magnesium sulfate and evaporated to give 1480g (75%) of methyl 2-[2-(2-{[2-(2-fluorophenyl)ethyl]amino}-N-(2-methylpropyl)acetamido)-N-[3-(2-oxopyrrolidin-1-yl)propyl]acetamido]acetate as a pale brown oil.
[0093] This material is used in the next step without further purification.
[0094] Process (S7) A solution of the methyl ester derivative (1480 g, 2.92 mol) in 7.4 L of methanol was bubbled with ammonia (gas) (695 g, 40.88 mol) at −35° C., allowing the internal temperature to rise to −3° C. during the addition of ammonia. The solution was allowed to reach 25° C. and stirred for 24 h.
[0095] After 24 hours, LCMS showed that the starting material was completely consumed, and the solvent was removed in vacuo.
[0096] The residue was heated under reflux in 5000 ml of ethyl acetate until complete solution was achieved, then 140 g of activated carbon (10% wt / wt limitant reagent) was added and the suspension was stirred under reflux of ethyl acetate for 1 hour.
[0097] The suspension was then filtered and washed with 2 L of ethyl acetate. The liquid was removed to a volume of 6 L (5 vol ethyl acetate + 1 Kg crude product).
[0098] A white precipitate formed. The solid was filtered, washed with 1000 ml of ethyl acetate and 1000 ml of MTBE, and dried under vacuum at 40° C. to constant weight (24 h).
[0099] 1010 g of N-(carbamoylmethyl)-2-(2-{[2-(2-fluorophenyl)ethyl]amino}-N-(2-methylpropyl)acetamido)-N-[3-(2-oxopyrrolidin-1-yl)propyl]acetamide was obtained as a white solid (71% yield).
[0100] FIG. 5 shows the reaction of N-(carbamoylmethyl)-2-(2-{[2-(2-fluorophenyl)ethyl]amino}-N-(2-methylpropyl)acetamido)-N-[3-(2-oxopyrrolidin-1yl)propyl]acetamide in CD3OD. 1 The H NMR spectrum is shown. [Brief explanation of the drawings]
[0101] [Figure 1] FIG. 1 depicts a synthetic route to a compound of formula FI according to the present disclosure, where R1 is 2-fluorophenyl, R2 is methylpyrrolidin-2-one, and R3 is isobutyl. [Figure 2] FIG. 2 shows the H NMR spectrum of 2-{N-[2-(2-fluorophenyl)ethyl]formamido}acetic acid in CDCl. [Figure 3] FIG. 3 shows the H NMR spectrum of 2-[(2-methylpropyl)amino]acetic acid hydrochloride in DMSO. [Figure 4] FIG. 4 shows the 1H NMR spectrum of 2-{[3-(2-oxopyrrolidin-1-yl)propyl]amino}acetic acid hydrochloride in DMSO. [Figure 5] FIG. 5 shows the H NMR spectrum of N-(carbamoylmethyl)-2-(2-{[2-(2-fluorophenyl)ethyl]amino}-N-(2-methylpropyl)acetamide)-N-[3-(2-oxopyrrolidin-1yl)propyl]acetamide in CD3OD.
Claims
1. 1. A method for synthesizing a compound of formula FI, comprising: 【Chemistry 1】 During the ceremony, R １ is substituted with halogen or trifluoromethyl, and is further optionally substituted with halogen, (C １ -C ６ ) alkyl, (C １ -C ６ ) alkoxy, and halo (C １ -C ６ phenyl substituted with one or two substituents selected from the group consisting of: alkyl; １ is pyrrolidin-1-yl; R ２ is 2-oxo-pyrrolidin-1-ylmethyl or sulfamoylphenyl; and R ３ is selected from propyl, 1-methylethyl, butyl, 2-methylpropyl, pentyl, 1-methyl-butyl, 2-methylbutyl, hexyl, 4-methylpentyl, 3-methylpentyl, 2-methylpentyl, and 1-methylpentyl; A method comprising the steps of: (S1) Providing a compound CS1 of formula FCS1: 【Chemistry 2】 (S2) Providing a compound CS2 of formula FCS2: 【Transformation 3】 (S3) Providing a compound CS3 of formula FCS3: 【Chemistry 4】 (S4) reacting CS1 with CS2 in an organic solvent to obtain a compound CS4 of formula FCS4: 【Transformation 5】 (S5) reacting CS3 with CS4 in an organic solvent to obtain a compound CS5 of formula FCS5: 【Transformation 6】 (S6) reacting CS5 with an acid in an alcohol solvent to obtain a compound CS6 of formula FCS6: 【Transformation 7】 (S7) A step of reacting CS6 with ammonia in an organic solvent.
2. 2. The method of claim 1, wherein step (S1) is carried out in water at a temperature of from 65°C to 90°C, preferably from 70°C to 85°C, and more preferably about 80°C.
3. 2. The method of claim 1, wherein step (S2) is carried out in water at a temperature of 65°C to 90°C, preferably 70°C to 85°C, and more preferably 80°C, and then in concentrated hydrochloric acid at a temperature of 80°C or higher, preferably 90°C or higher, and more preferably 100°C.
4. 2. The method of claim 1, wherein step (S3) is carried out in water at a temperature of 65°C to 90°C, preferably 70°C to 85°C, and more preferably 80°C, and then in concentrated hydrochloric acid at a temperature of 80°C or higher, preferably 90°C or higher, and more preferably 100°C.
5. 2. The process of claim 1, wherein step (S4) is carried out in the presence of 2,3,4,6,7,8,9,10-octahydropyrimido[1,2-a]azepine and carbonyldiimidazole from a starting temperature of 0°C to room temperature of 20°C to 25°C.
6. 2. The method of claim 1, wherein step (S5) is carried out in the presence of 2,3,4,6,7,8,9,10-octahydropyrimido[1,2-a]azepine and carbonyldiimidazole at room temperature of 20°C to 25°C.
7. 10. The method of claim 1, wherein step (S6) is carried out at reflux.
8. 2. The method of claim 1, wherein the compound obtained at the end of step (S7) contains the compound of formula FI and less than 0.3% of each individual impurity.
9. A compound of the formula: 【Transformation 8】 。
10. A compound of the formula: 【Chemistry 9】 , and its salts.
11. Compound of formula FCS4: 【Chemistry 10】 。
12. A compound of the formula: 【Chemistry 11】 。
13. A compound of the formula: 【Chemistry 12】 。
14. A pharmaceutical composition comprising a compound of formula FI obtained by the method of any one of claims 1 to 8, and optionally one or more pharmaceutically acceptable excipients, preferably containing less than 0.3% of each individual impurity.