Synthesis of small molecule agonists of neurotrophic factors
Through the new synthesis route, solid support is avoided, and a series of organic reaction steps are used to synthesize compounds of formula FI, which solves the problem that cannot be applied to large-scale industrial manufacturing in the prior art, and achieves efficient and low-impact compound production.
Patent Information
- Application Number
- CN202380087288.8
- Authority / Receiving Office
- CN · China
- Patent Type
- Applications(China)
- Current Assignee / Owner
- Priority Date
- 2022-12-22
- Filing Date
- 2023-12-22
- Publication Date
- 2025-07-25
AI Technical Summary
The prior art When synthesizing neurotrophic factor small molecule compounds, especially compounds of formula FI, there is a problem that they cannot be applied to large-scale industrial manufacturing, especially due to the limitations of relying on solid support synthesis routes.
A new synthesis route is adopted, through a series of organic reaction steps, including providing compounds CS1, CS2, CS3, CS4, CS5 and CS6, and reacting in an organic solvent, ultimately reacting with ammonia to form a compound of formula FI, avoiding the use of solid support.
The efficient synthesis of the compounds of formula FI is achieved, with an impurity content of less than 0.3%, which is suitable for industrial-scale production, improving production efficiency and product purity.
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Figure CN120379966A_ABST
Abstract
Description
Technical Field
[0001] The present disclosure relates to the field of the treatment of neurological disorders, mental disorders and aging. Specifically, the present disclosure relates to small molecule agonists of neurotrophic factors (nerve growth factor (NGF) or brain-derived neurotrophic factor (BDNF)), and more specifically to a synthetic route of small molecules of formula FI:
[0002] Background Art
[0003] The synthetic route of the compound of formula FI is known. For example, Masip et al. (Med. Chem. 13 (2005) 1929 (doi: / j.bmc.2005.01.024)) disclosed solid-phase synthesis using a position-scanning format and a submonomer strategy. This synthetic route includes 7 steps before the final cleavage step of recovering the target molecule from the solid support (Rink amide resin), as follows:
[0004]
[0005] The first step of this synthetic route is the deprotection of the amine functional group of the solid support. The subsequent six steps are the sequential repetition of two steps, namely acylation followed immediately by amination. Thus, in this synthetic route, the molecule is generated sequentially by using a suitable primary amine related to the target molecule.
[0006] Although this synthetic step can be satisfactory under certain conditions, it would be beneficial to propose a synthetic route that does not use a solid support, especially that it would be more suitable for large-scale synthesis for industrial manufacturing. Summary of the Invention
[0008] A method for synthesizing the compound of formula FI is proposed:
[0009]
[0010] Wherein:
[0011] R1 is phenyl substituted by halogen or trifluoromethyl and further optionally substituted by one or two substituents selected from halogen, (C1-C6) alkyl, (C1-C6) alkoxy and halo (C1-C6) alkyl; or R1 is pyrrolidin-1-yl;
[0012] R2 is 2-oxo-pyrrolidin-1-ylmethyl or sulfamoylphenyl; and
[0013] 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;
[0014] The method comprises the following steps:
[0015] (S1) Provide a compound CS1 of formula FCS1:
[0016]
[0017] (S2) Provide a compound CS2 of formula FCS2:
[0018]
[0019] (S3) Provide a compound CS3 of formula FCS3:
[0020]
[0021] (S4) React CS1 with CS2 in an organic solvent to obtain a compound CS4 of formula FCS4:
[0022]
[0023] (S5) React CS3 with CS4 in an organic solvent to obtain a compound CS5 of formula FCS5:
[0024]
[0025] (S6) React CS5 with an acid in an alcohol solvent to obtain a compound CS6 of formula FCS6:
[0026]
[0027] (S7) React CS6 with ammonia in an organic solvent. Description of the Drawings
[0028] Figure 1
[0029] Figure 1 Represents the synthetic route of the compound of formula FI according to the present disclosure, wherein R1 is 2-fluorophenyl, R2 is methylpyrrolidin-2-one and R3 is isobutyl.
[0030] Figure 2
[0031] Figure 2 Represents 2-{N-[2-(2-fluorophenyl)ethyl]carbamoyl}acetic acid in 1 1H NMR spectrum in CDCl3.
[0032] Figure 3
[0033] Figure 3Representing the 1H NMR spectrum of 2-[(2-methylpropyl)amino]acetic acid hydrochloride in DMSO 1 1H NMR spectrum.
[0034] Figure 4
[0035] Figure 4 Representing the 1H NMR spectrum of 2-{[3-(2-oxopyrrolidin-1-yl)propyl]amino}acetic acid hydrochloride in DMSO 1 1H NMR spectrum.
[0036] Figure 5
[0037] Figure 5 Representing the 1H NMR spectrum of N-(carbamoylmethyl)-2-(2-{[2-(2-fluorophenyl)ethyl]amino}-N-(2-methylpropyl)acetamido)-N-[3-(2-oxopyrrolidin-1-yl)propyl]acetamide in CD3OD 1 1H NMR spectrum. Detailed Description of the Invention
[0039] As described above, the present disclosure relates to a method for synthesizing a compound of formula FI:
[0040]
[0041] Wherein:
[0042] R1 is a phenyl group substituted by a halogen or trifluoromethyl, and further optionally substituted by one or two substituents selected from halogen, (C1-C6)alkyl, (C1-C6)alkoxy, and halo(C1-C6)alkyl; or R1 is pyrrolidin-1-yl;
[0043] R2 is 2-oxopyrrolidin-1-ylmethyl or sulfamoylphenyl; and
[0044] 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;
[0045] The method comprises the following steps:
[0046] (S1) Providing a compound CS1 of formula FCS1:
[0047]
[0048] (S2) Providing a compound CS2 of formula FCS2:
[0049]
[0050]
[0051] (S3) Provide compound CS3 of formula FCS3:
[0052]
[0053] (S4) React CS1 with CS2 in an organic solvent to obtain compound CS4 of formula FCS4:
[0054]
[0055] (S5) React CS3 with CS4 in an organic solvent to obtain compound CS5 of formula FCS5:
[0056]
[0057] (S6) React CS5 with an acid in an alcohol solvent to obtain compound CS6 of formula FCS6:
[0058]
[0059] (S7) React CS6 with ammonia in an organic solvent.
[0060] Step (S1)
[0061] According to the present disclosure, step (S1) consists of providing a compound of formula FCS1. To the applicant's knowledge, at the time of the present disclosure, the compound of formula FCS1 is not commercially available.
[0062] 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.
[0063] In a specific embodiment, step (S1) is carried out at a ratio of glyoxylic acid to amine of about 2.05, such as 2.0 to 2.25.
[0064] According to the present disclosure, R1 is a phenyl group substituted by halogen or trifluoromethyl and further optionally substituted by one or two substituents selected from halogen, (C1-C6) alkyl, (C1-C6) alkoxy and halo(C1-C6) alkyl; or R1 is pyrrolidin-1-yl.
[0065] In a preferred embodiment, R1 is 2-fluorophenyl.
[0066] Step (S2)
[0067] According to the present disclosure, step (S2) consists of providing a compound of formula FCS2. To the applicant's knowledge, at the time of the present disclosure, compounds of formula FCS2 have been disclosed.
[0068] 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, and then adding concentrated hydrochloric acid (HCl) at a temperature of 80 °C or above, preferably 90 °C or above and more preferably 100 °C.
[0069] In one embodiment, the concentrated HCl is an aqueous solution of 35% HCl.
[0070] The ratio of HCl to the amine of formula NH2-R3 is 1.05 to 5, preferably 1.5 to 4, more preferably 2 to 3.
[0071] 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.
[0072] In a preferred embodiment, R3 is 2-methylpropyl.
[0073] Step (S3)
[0074] According to the present disclosure, step (S3) consists of providing a compound of formula FCS3. To the applicant's knowledge, at the time of the present disclosure, compounds of formula FCS3 are not commercially available.
[0075] 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, and then adding concentrated hydrochloric acid (HCl) at a temperature of 80 °C or above, preferably 90 °C or above and more preferably 100 °C.
[0076] In one embodiment, the concentrated HCl is an aqueous solution of 35% HCl.
[0077] The ratio of HCl to the amine of formula NH2-R3 is 1.05 to 5, preferably 1.5 to 4, more preferably 2 to 3.
[0078] According to the present disclosure, R2 is 2-oxo-pyrrolidin-1-ylmethyl or sulfamoylphenyl.
[0079] In a preferred embodiment, R2 is 2-oxo-pyrrolidin-1-ylmethyl.
[0080] Step (S4)
[0081] According to the present disclosure, step (S4) consists of synthesizing a compound of formula FCS4. As far as the applicant is aware, at the time of the present disclosure, the compound of formula FCS4 is not commercially available.
[0082] 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 at a temperature starting from 0 °C to room temperature of 20 °C to 25 °C.
[0083] The organic solvent in step (S4) can be selected from dimethylformamide and acetonitrile.
[0084] Step (S5)
[0085] According to the present disclosure, step (S5) consists of synthesizing a compound of formula FCS5. As far as the applicant is aware, at the time of the present disclosure, the compound of formula FCS5 is not commercially available.
[0086] CS5 can be obtained by reacting CS3 with CS4 in an organic solvent. Thus, in one embodiment, step (S5) is carried out at room temperature of 20 °C to 25 °C 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.
[0087] The organic solvent in step (S4) can be selected from dimethylformamide, acetonitrile and dimethyl sulfoxide.
[0088] Step (S6)
[0089] According to the present disclosure, step (S6) consists of synthesizing a compound of formula FCS6. As far as the applicant is aware, at the time of the present disclosure, the compound of formula FCS6 is not commercially available.
[0090] CS6 can be obtained by reacting CS5 with an acid in an alcohol solvent, preferably with H2SO4 in methanol.
[0091] In one embodiment, step (S6) is carried out under reflux.
[0092] Step (S7)
[0093] Step (S7) is the final step in the synthesis of the FI compound according to the present disclosure. In this final step, CS6 reacts with ammonia.
[0094] In one embodiment, step (S7) is carried out at a temperature of -30 °C to -50 °C, preferably -35 °C to -45 °C, more preferably -40 °C.
[0095] In step (S7), ammonia can be in liquid form, such as in the form of an aqueous solution or an alcohol (e.g., a methanol solution), or in gaseous form, preferably in gaseous form.
[0096] In one embodiment, the FI compound obtained at the end of step (S7) has less than 0.3% of each individual impurity.
[0097] Compound of formula FI
[0098] According to the present disclosure, the FI compound is as follows:
[0099]
[0100] wherein:
[0101] R1 is phenyl substituted by halogen or trifluoromethyl and further optionally substituted by one or two substituents selected from halogen, (C1-C6)alkyl, (C1-C6)alkoxy, and halo(C1-C6)alkyl; or R1 is pyrrolidin-1-yl;
[0102] R2 is 2-oxopyrrolidin-1-ylmethyl or sulfamoylphenyl; and
[0103] 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.
[0104] When R1 is (C1-C6)alkyl, it 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 attached through any carbon.
[0105] When R1 is a (C1-C6) alkoxy group, it 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, R4 is connected to oxygen through any carbon, and R1 is connected through oxygen.
[0106] When R1 is a halo(C1-C6)alkyl group, it can be -X-R4, where X is a halogen atom, preferably selected from fluorine, chlorine, and bromine, 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, R4 is connected to the halogen atom through any carbon, and R1 is connected through oxygen.
[0107] 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 as follows:
[0108]
[0109] Compound CS1
[0110] Step (S1) of the method according to the present disclosure provides a compound of formula FCS1:
[0111]
[0112] In a preferred embodiment, R1 is 2-fluorophenyl. Thus, in a preferred embodiment, the compound of formula FCS1 is as follows:
[0113]
[0114] Compound CS2
[0115] Step (S2) of the method according to the present disclosure provides a compound of formula FCS2:
[0116]
[0117]
[0118] In a preferred embodiment, R3 is 2-methylpropyl. Thus, in a preferred embodiment, the compound of formula FCS2 is as follows:
[0119]
[0120] Compound CS3
[0121] Step (S3) of the method according to the present disclosure provides a compound of formula FCS3:
[0122]
[0123] In a preferred embodiment, R2 is 2-oxo-pyrrolidin-1-ylmethyl. Thus, in a preferred embodiment, the compound of formula FCS3 is as follows:
[0124]
[0125] Compound CS4
[0126] Step (S4) of the method according to the present disclosure provides a compound of formula FCS4:
[0127]
[0128] In a preferred embodiment, R1 is 2-fluorophenyl and R3 is 2-methylpropyl. Thus, in a preferred embodiment, the compound of formula FCS4 is as follows:
[0129]
[0130] Compound CS5
[0131] Step (S5) of the method according to the present disclosure provides a compound of formula FCS5:
[0132]
[0133]
[0134] 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 as follows:
[0135]
[0136] Compound CS6
[0137] Step (S6) of the method according to the present disclosure provides a compound of formula FCS6:
[0138]
[0139] In a preferred embodiment, R1 is 2-fluorophenyl, R2 is 2-oxopyrrolidin-1-ylmethyl and R3 is 2-methylpropyl. Thus, in a preferred embodiment, the compound of formula FCS6 is as follows:
[0140]
[0141] Pharmaceutical Composition
[0142] The present disclosure also relates to a pharmaceutical composition comprising a compound of formula FI obtained by the above synthesis method, and optionally one or more pharmaceutically acceptable excipients.
[0143] In one embodiment, the pharmaceutical composition comprises less than 0.3% of each individual impurity. Examples
[0144] N-(carbamoylmethyl)-2-(2-{[2-(2-fluorophenyl)ethyl]amino}-N-(2-methylpropyl)acetamide Synthesis of (base)-N-[3-(2-oxopyrrolidin-1-yl)propyl]acetamide( Figure 1 ):
[0145]
[0146] Step (S1)
[0147] A solution of glyoxylic acid (50% wt 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). A creamy solid appeared after the addition of the amine.
[0148] The previously formed solid became of viscous consistency. The reaction was then reheated at 80 °C (internal temperature) for 3 hours.
[0149] Liquid chromatography - mass spectrometry (LC - MS) indicated complete conversion to the desired product.
[0150] The reaction was cooled to 5 °C (2 hours) and the solid formed was filtered and washed with cold water (5 °C) (5000 ml) and dried under vacuum at 50 °C until constant weight.
[0151] The solid was triturated in 5000 ml of isopropanol (iPrOH) and filtered after 30 min. The solid was dried under vacuum at 50 °C until constant weight.
[0152] 6410 g (72%) of 2-{N-[2-(2-fluorophenyl)ethyl]carbamoyl}acetic acid as an off - white solid was obtained.
[0153] Figure 2 Representing 2-{N-[2-(2-fluorophenyl)ethyl]carbamoyl}acetic acid in CDCl31 HNMR spectrum.
[0154] Step (S2)
[0155] Glyoxylic acid (50% wt in water) (12.3 L, 116.8 mol) was added to an aqueous (16 L) solution of isobutylamine (5400 ml, 54.34 mol), maintaining the internal temperature below 65 °C (1 h 30 min). A large amount of bubbles (CO2 evolution) appeared during the addition.
[0156] The solution was then stirred at 82 °C to 86 °C (internal temperature) for 16 h.
[0157] The solution became a dark brown liquid after 2 h.
[0158] After 16 h, the reaction was cooled to 65 °C and 12 M HCl (4989 ml, 57.87 mol) was added in one portion. The solution was reheated at 82 to 86 °C (internal temperature) for 24 h.
[0159] After 24 h, water was removed and 5 L of acetonitrile was added to the residue. The solvent was removed to remove traces of water.
[0160] The crude product obtained was dissolved in 25 L of acetonitrile and heated at 80 °C until completely dissolved. The solution was then cooled to 25 °C and inoculated with the desired product (lot BN01_FSC_075). After 16 h, the solid was filtered.
[0161] The solid obtained was dried in vacuo at 70 °C until a constant weight was achieved.
[0162] 5829 g (64%) of 2-[(2-methylpropyl)amino]acetic acid hydrochloride as white flakes was obtained.
[0163] Figure 3 Representing the 1 HNMR spectrum of 2-[(2-methylpropyl)amino]acetic acid hydrochloride in DMSO.
[0164] Step (S3)
[0165] 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 h. Then HCl (35%) (4 L, 33.9 mol) was added and the reaction was reheated at 90 °C for 4 h. The solvent was removed and 2000 ml of acetonitrile was added to remove traces of water. This operation was carried out 2 more times.
[0166] The obtained solid was recrystallized by heating with 12 LiPrOH at 90 °C, and then the suspension was cooled to 5 °C for 2 hours. The solid was filtered and washed with 3 LiPrOH and 2 L of hexane. The solid was dried in an oven at 70 °C until constant weight to obtain 4479 g (67%) of 2-{[3-(2-oxopyrrolidin-1-yl)propyl]amino}acetic acid hydrochloride as a white solid.
[0167] Figure 4 Represents the 1H NMR spectrum of 2-{[3-(2-oxopyrrolidin-1-yl)propyl]amino}acetic acid hydrochloride in DMSO. 1 1H NMR spectrum.
[0168] Step (S4)
[0169] Carbonyl diimidazole (1122 g, 6.92 mol) was added to a solution of 2-{N-[2-(2-fluorophenyl)ethyl]carbamoyl}acetic acid (1300 g, 5.77 mol) in DMF (6.5 L). The resulting mixture was stirred for 1 hour. Bubbles due to the evolution of CO2 were observed within the first 10 minutes.
[0170] After 15 minutes, the mixture was cooled in a water / ice bath at 5 °C. Then 2-[(2-methylpropyl)amino]acetic acid hydrochloride (1936 g, 11.55 mol) and DBU (3450 ml, 23.08 mol) were added successively. 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.
[0171] LC-MS control after 30 minutes indicated complete conversion of the starting material.
[0172] Then 10 L of water was added, and the aqueous phase was washed twice with DCM (2 × 2000 ml). The pH of the aqueous phase was adjusted to 2 with HCl (35%) and extracted with ethyl acetate (3 × 2000 ml). The organic matter was collected, washed twice with brine, dried over MgSO4 and the solvent was evaporated to obtain 1560 g (80%) of the desired product as a brown oil. The crude product was used as such for the next step.
[0173] Step (S5)
[0174] Carbonyl diimidazole (890 g, 5.49 mol) was added in one portion to a solution of 2-(2-{N-[2-(2-fluorophenyl)ethyl]carbamoyl}-N-(2-methylpropyl)acetamido)acetic acid (1550 g, 4.58 mol) in acetonitrile (5600 ml) under a nitrogen atmosphere at 25 °C, and stirred at 25 °C for 30 minutes. A strong evolution of CO2 was observed.
[0175] After 30 minutes, the reactant was 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 while maintaining the internal temperature below 15 °C. The reactant was then stirred at 25 °C for 1 hour.
[0176] At this point, LC-MS indicated complete conversion to the desired product.
[0177] The solvent was removed, and water (10 L) was added to the residue, which was extracted twice with 2000 ml of dichloromethane (DCM). The aqueous phase was then acidified with HCl (35%) until pH = 2 and extracted with DCM (3 × 2000 ml). The organic matter was washed with brine, dried over magnesium sulfate and evaporated to obtain 2032 g (85%) of 2-[2-(2-{N-[2-(2-fluorophenyl)ethyl]formamido}-N-(2-methylpropyl)acetamido)-N-[3-(2-oxopyrrolidin-1-yl)propyl]acetamido]acetic acid as a colorless oil.
[0178] This sample was used in the next step without further purification.
[0179] Step (S6)
[0180] At 25 °C, 98% H2SO4 (311 ml, 5.85 mol) was added 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). An exothermic transition was detected during the addition, and the temperature rose to 53 °C and then the reaction was heated under reflux for 12 hours.
[0181] After 12 hours, LCMS indicated complete conversion to the desired product.
[0182] The reaction was cooled to 25 °C and poured into a solution of 1040 g of KHCO3 (10.4 mol) in 4 L of water (pH buffered between 7.90 and 7.85). The product was then extracted with DCM (3 × 2000 ml). The organic matter was combined and washed with 4 L of K2CO3 solution (25% wt / wt in water) (pH buffered between 11.90 and 11.75).
[0183] The organic matter was washed with water (2 × 2000 ml) and brine (1 × 2000 ml), dried over magnesium sulfate and evaporated to obtain 1480 g (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 light brown oil.
[0184] This material was used in the next step without further purification.
[0185] Step (S7)
[0186] 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, and the internal temperature rose to -3 °C during the addition of ammonia. The solution was brought to 25 °C and stirred for 24 hours.
[0187] After 24 hours, LCMS indicated complete consumption of the starting material. The solvent was removed under vacuum.
[0188] The residue was heated to reflux in 5000 ml of ethyl acetate until completely dissolved. Then 140 g (10% wt / wt limiting reagent) of activated carbon was added and the suspension was stirred for 1 hour under reflux in ethyl acetate.
[0189] The suspension was then filtered and washed with 2 L of ethyl acetate. The liquid was removed until the volume was 6 L (5 vol ethyl acetate + 1 Kg of crude product).
[0190] A white precipitate appeared. The solid was filtered, washed with 1000 ml of ethyl acetate and 1000 ml of MTBE, and dried in vacuo at 40 °C until constant weight (24 hours).
[0191] 1010 g (71% yield) 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.
[0192] Figure 5 The HNMR spectrum of N-(carbamoylmethyl)-2-(2-{[2-(2-fluorophenyl)ethyl]amino}-N-(2-methylpropyl)acetamido)-N-[3-(2-oxopyrrolidin-1-yl)propyl]acetamide in CD3OD 1 HNMR spectrum.
Claims
1. A method for synthesizing a FI compound: Wherein: R1 is a phenyl group substituted by halogen or trifluoromethyl and further optionally substituted by one or two substituents selected from 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-methyl-butyl, 2-methylbutyl, hexyl, 4-methylpentyl, 3-methylpentyl, 2-methylpentyl, and 1-methylpentyl; The method comprises the following steps: (S1) Providing a compound CS1 of formula FCS1: (S2) Providing a compound CS2 of formula FCS2: (S3) Providing a compound CS3 of formula FCS3: (S4) Reacting CS1 with CS2 in an organic solvent to obtain a compound CS4 of formula FCS4: (S5) Reacting CS3 with CS4 in an organic solvent to obtain a compound CS5 of formula FCS5: (S6) Reacting CS5 with an acid in an alcohol solvent to obtain a compound CS6 of formula FCS6: (S7) Reacting CS6 with ammonia in an organic solvent.
2. The method according to claim 1, wherein step (S1) is carried out in water at a temperature of 65°C to 90°C, preferably 70°C to 85°C, and more preferably about 80°C.
3. The method according to 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, more preferably 80°C, and then in concentrated HCl at a temperature of 80°C or above, preferably 90°C or above, more preferably 100°C.
4. The method according to 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, more preferably 80°C, and then in concentrated HCl at a temperature of 80°C or above, preferably 90°C or above, more preferably 100°C.
5. The method according to 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 at a temperature starting from 0°C to room temperature of 20°C to 25°C.
6. The method according to 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. The method according to claim 1, wherein step (S6) is carried out under reflux.
8. The method according to claim 1, wherein the compound obtained at the end of step (S7) contains the FI compound and less than 0.3% of each individual impurity.
9. A compound of the following formula:
10. A compound of the following formula and its salts:
11. A compound of formula FCS4:
12. A compound of the following formula:
13. A compound of the following formula:
14. A pharmaceutical composition comprising a compound of formula FI obtained by the method according to any one of claims 1 to 8, and optionally one or more pharmaceutically acceptable excipients, wherein the pharmaceutical composition comprises preferably less than 0.3% of each individual impurity.