Novel methods for the production of MDM2-p53 antagonists

Abstract

The present invention relates to a novel method for the synthesis of substituted anilines of formula (1) or salts thereof via hydroxyindolinones of formula (13). The method of the present invention is palladium-free and uses oxygen as an environmentally friendly and safe oxidant for the copper-promoted ring-opening reaction of the hydroxyindolinone bicycle to tetrasubstituted anilines. JPEG2025540433000021.jpg2698

Description

[Technical Field]

[0001] The present invention relates to an efficient, sustainable method for preparing compounds useful as intermediates in the synthesis of MDM2-p53 antagonists. [Background technology]

[0002] The aniline of formula (1) is a sequentially tetrasubstituted aromatic compound [ka] and are used as building blocks for more complex chemical structures, such as the structurally complex MDM2-p53 antagonists described in WO 2017 / 060431. MDM2-p53 antagonists offer an important approach to cancer therapy, either as single agents or in combination with a wide variety of antitumor therapies, and therefore an efficient and sustainable supply of these compounds is needed.

[0003] Previous synthesis (R * = methyl, see WO2017 / 060431, utilizes three steps that rely on homogeneous palladium catalysis. The reaction sequence begins with ortho-selective bromination, as described in Angew. Chem. Int. Ed. 2011, 50, 5524-5527, using up to 5 mol% Pd(OAc) to produce a phenyl bromide of formula (3). This is followed by a Sonogashira coupling, as described in Chem. Rev. 2007, 107, 874, between the phenyl bromide of formula (3) and a terminal alkyne of formula (4), to produce a compound of formula (5). The Sonogashira coupling utilizes a palladium catalyst and a copper cocatalyst to form a carbon-carbon bond, but the other reaction conditions are relatively mild. In the third palladium-catalyzed step, the alkyne is hydrated with the aid of the oxygen of the adjacent amide group to give a compound of formula (6), J. Org. Chem., 2015, 80, 7594.

[0004] Scheme 1 [ka] This not only poses economic and ecological problems, but also the challenge of reducing the heavy metal palladium in products to low residual levels that meet the stringent limits required for pharmaceutical products administered to humans. Therefore, there is a need to develop palladium-free methods for intermediates such as the highly substituted anilines of compounds of formula (1) for the synthesis of MDM2-p53 antagonists. Summary of the Invention

[0005] The present invention relates to a novel method for the synthesis of substituted anilines of formula (1) via isatin-derived compounds of formula (13). In particular, the sequential tetrasubstitution of aromatic rings present in compounds of formula (14) and (1) presents a synthetic challenge. The method of the present invention is palladium-free and uses oxygen as an environmentally friendly and safe oxidant for the copper-promoted ring-opening reaction of hydroxyindolinones of formula (13). DETAILED DESCRIPTION OF THE INVENTION

[0006] The present invention relates to a process for the preparation of anilines of formula (1), wherein the substitution pattern of the anilines of formula (1) is derived from isatins of formula (9).

[0007] Scheme 2 [ka]

[0008] In a first aspect, the present invention relates to a method for preparing a compound of formula (14) or (1), comprising the oxidative ring-opening of a hydroxyindolinone of formula (13). PG represents a protecting group. Possible amino protecting groups are known to those skilled in the art. Any amino protecting group described in TW Greene & PGM Wuts, "Protective Groups in Organic Synthesis," 4th Edition, John Wiley & Sons, Inc. (2007) can also be used. Preferably, the protecting group is selected from the group comprising the electron-withdrawing group -C(=O)-R, where R is R' or -O-R', and R' represents a linear, branched, or cyclic aliphatic or aromatic group or a combination thereof, which may be substituted. Preferably, the PG used is Ac or Boc. R * represents a cleavable carboxyl protecting group. * is preferably optionally substituted C 1-6 The most preferred R is an alkyl or optionally substituted benzyl group. * is methyl, ethyl, isopropyl or benzyl. In the literature, K3[Fe(CN)6] was reported as an oxidizing agent in CN102675125 and t-BuOOH (3.0 equiv.) in the presence of KOH to form the aniline product in Org. Lett. 2017, 19, 5, 988.

[0009] Thus, in one aspect of the present invention, the oxidative ring-opening of a compound of formula (13) involves the use of an Fe oxidant. In one embodiment, the Fe oxidant used in the oxidative ring-opening is K3[Fe(CN)6], preferably used with KOH as a base. It has been found that when K3[Fe(CN)6] is used as the oxidant, it is preferred that at least one equivalent of KOH be used for the ring-opening. Furthermore, it has been found that a preferred solvent system is a mixture of MeCN / HO. Conversion of compounds of formula (13) to products of formula (14) described above with an Fe oxidant gives moderate to good yields, thus providing a cost-effective alternative to tetrasubstituted anilines. [ka] In an alternative approach, it has surprisingly been found that the use of a Cu catalyst for the oxidative ring-opening of the compound of formula (13) provides the most promising results. The Cu catalyst can be selected from a non-exhaustive list of CuI, CuBr, CuCl, CuO, CuCN, CuF, CuNO, CuO, CuCl, CuSO, Cu(NO), Cu(OAc), and Cu(acac), with CuCl being preferably used.

[0010] The amount of CuCl used for ring opening can be between 0.2 and 1.0 equivalents, preferably between 0.4 and 0.8 equivalents, and most preferably around 0.6 equivalents. The ligand may be selected from a non-exhaustive list of 8-hydroxyquinoline, 1,10-phenanthroline, dibenzoylmethane, DMEDA, TMEDA, bipyridine, diaminocyclohexane and related diamine or pincer ligands, preferably DMEDA is used. The amount of DMEDA used is preferably between 2 and 10 equivalents, more preferably between 3 and 6 equivalents, most preferably around 5 equivalents.

[0011] The molar ratio of Cu:DMEDA can be between 1:2 and 1:5, most preferably 3:10. The oxidizing agent can be selected from a non-exhaustive list of air, O2, O2 mixed with an inert gas such as CO2, argon, or N2, H2O2, tBuOOH, and NaIO4. Preferably, the oxidative ring-opening uses oxygen as the stoichiometric oxidizing agent, where the oxygen is obtained from air or a mixture of O2 in N2. The concentration of O2 in N2 used is preferably between 8 and 21% v / v. To safely handle oxygen and organic vapors, a concentration of 8 to 10% v / v is most preferred. Lower concentrations of oxygen result in slower reaction rates. In a further aspect of the present invention, the compound of formula (13) used for the oxidative ring-opening described herein is synthesized by a method comprising catalytic hydrogenation of the nitrile of formula (11). Such catalytic hydrogenation leads to the amine of formula (12), which then, after introduction of the protecting group PG, leads to the compound of formula (13). Catalytic hydrogenation can be performed using Pd / C, Pd / Al2O3, PtO 2、 This can be achieved using a variety of heterogeneous heavy metal catalysts, such as Ru / C, Rh / C, or sponge nickel. Preferably, sponge nickel is used due to its stability and high catalytic activity at room temperature. Typically, the catalyst can be recycled and reused for subsequent batches. Furthermore, residues in the product are very low due to the heterogeneous nature of the nickel catalyst.

[0012] Surprisingly, it has been found that the hydrogenation of the nitrile of formula (11) and the protection of the amine of formula (12) can be achieved in a one-pot reaction when the protecting group PG is a Boc protecting group. One-pot reactions have the advantage that multiple transformations can be accomplished in a single reaction vessel without isolation or purification, and the reduction in the required time, reagents, and solvents can impact the economics and ecology of the process. In the present invention, hydrogenation over sponge nickel is carried out in the presence of a protecting reagent, which can be directly converted to the Boc carbamate of formula (13).

[0013] In a further aspect of the present invention, the compound of formula (11) used for the catalytic hydrogenation described herein is synthesized by a method involving the decarboxylative addition of cyanoacetic acid to an isatin of formula (9). Here, the base and solvent were optimized for large-scale production. DMF and THF were utilized as organic solvents, but a mixture of DMF / THF (1V / 3V) was found to reduce the amount of unwanted by-products. The yield can be improved by increasing the amount of TEA from 0.2 to 1.0 equivalents. In a further aspect of the present invention, isatins of formula (9) used in the decarboxylative addition described herein are synthesized by a process involving isatin ring formation of the oxime of formula (8). Preferably, the ring formation is carried out in high yield using concentrated H2SO4, preferably in the temperature range of 90-100°C. Temperature control is critical, as decomposition of the compound of formula (9) has been observed starting at 120°C.

[0014] Finally, in a further embodiment of the present invention, oximes of formula (8) were synthesized by a process comprising reacting anilines of formula (7) with chloral hydrate in the presence of hydroxylamine hydrochloride. The well-known Sandmeyer method was applied for isatin formation, but the reaction conditions had to be intensively investigated depending on the substitution pattern of the starting aniline. It was also found that one advantage of using an acid-substituted aniline of formula (7) (e.g., instead of the corresponding ester) as the starting material is that the product of formula (8) is a solid, which can be used without further purification. In another alternative embodiment of the present invention, isatin formation and decarboxylative addition can also be carried out using, for example, the methyl ester analogs of each of formulae (7')-(11') instead of the free acids according to Scheme 3.

[0015] Scheme 3 [ka] However, this requires column chromatography to purify the oxime of formula (8') for isatin ring closure. Furthermore, milder conditions for isatin ring formation are required; otherwise, unwanted by-products are formed in up to 70% yield. This can be achieved by utilizing MsOH at lower temperatures.

[0016] Another aspect of the present invention is the use of the methods described herein for producing intermediates and starting materials for MDM2-p53 antagonists. Another aspect is the use of the methods described herein for the synthesis of MDM2-p53 antagonists.

[0017] Terms and definitions used [Table 1] JPEG2025540433000008.jpg130132 [Example]

[0018] general Unless otherwise stated, all reactions are carried out with commercially available equipment using methods commonly used in chemical laboratories. Air- and / or moisture-sensitive starting materials are stored under protective gas, and the corresponding reactions and manipulations with these materials are carried out under protective gas (nitrogen or argon). When a compound is represented by both a structural formula and its nomenclature, in the event of a conflict, the structural formula shall prevail.

[0019] Chromatography Analytical HPLC (reaction control) of intermediates and final compounds is performed using a Waters column (designation: XBridge™ CSH Phenyl Hexyl, 3.5 μm, 3×100 mm, 3.5 μm) and an Agilent column (designation: Eclipse XDB-C8, 5 μm, 4.6×150 mm).

[0020] HPCL Method A: HPLC gradient HPLC device (Agilent 1260 series system) Detection signal 250 nm (bandwidth 4 nm, reference off) Column: Xselect CSH Phenyl Hexyl, 3 x 100 mm, 3.5 μm, Part Number: 186005372 Column temperature: 35°C Solvent A: 100% buffer solution B: 100% acetonitrile (HPLC grade) Buffer: Dissolve 770.8 mg of NH4OAc (HPLC grade) in 1.0 L of HPLC water and adjust the pH to 3.8 with acetic acid (AR grade). Flow rate 1.2mL / min Gradient 0min 5%B 15min 95%B

[0021] HPCL method B: HPLC gradient HPLC device (Agilent 1260 series system) Detection signal: 225 nm (bandwidth 4 nm, reference off) Column: Xselect CSH Phenyl Hexyl, 3 x 100 mm, 3.5 μm, Part Number: 186005372 Column temperature: 35°C Solvent A: 100% buffer solution B: 100% acetonitrile (HPLC grade) Buffer: Dissolve 770.8 mg of NH4OAc (HPLC grade) in 1.0 L of HPLC water and adjust the pH to 3.8 with acetic acid (AR grade). Flow rate 1.2mL / min Gradient 0min 5%B 15min 95%B

[0022] HPCL method C: HPLC gradient HPLC device (Agilent 1260 series system) Detection signal: 225 nm (bandwidth 4 nm, reference off) Column: Eclipse XDB-C8, 4.6 x 150 mm, 5 μm, Agilent; part number 993967-906 Column temperature: 40°C Solvent A: Buffer solution / acetonitrile = 9 / 1 (V / V) B: Buffer solution / acetonitrile = 2 / 8 (V / V) Buffer: Dissolve 1.0 g of KH2PO4 (AR grade) in 1.0 L of water and adjust the pH to 1.7 with HClO4 (AR grade). Flow rate 1.0mL / min Gradient 0min 0%B 2min 10%B 7min 60%B 10min 100%B 12min 100%B

[0023] Example 1 3-(2-(hydroxyimino)acetamido)-2-methylbenzoic acid (8) [ka] 1973 g (7.0 equivalents) of Na2SO4 was stirred in 3900 g of water at 40-50°C for 1 hour. Then, 120 g of HCl was added. conc。 and 300 g (1.0 equiv.) of compound 7 are added, and the temperature is raised to approximately 55 °C. Then, 483 g (3.5 equiv.) of NHOH·HCl and 492 g (1.5 equiv.) of chloral hydrate in 1200 g of water are added, and the mixture is stirred at 55 °C for 5 h. Then, the temperature is lowered to 40 °C and filtered. The filter cake is washed with 2400 g of water and dried under reduced pressure for 72 h to give 380 g of compound 8 (yield 86.2%, 94.8 A%). 1 H NMR (400 MHz, DMSO-d6) δ 2.35 (s, 3H), 7.29 (dd, J = 7.8 Hz, 1H), 7.55 (d, J = 7.8 Hz, 1H), 7.62 (dd, J = 7.7, 1.3 Hz, 1H), 7.68 (s, 1H), 9.73 (s, 1H), 12.22 (s, 1H), 12.98 (s, 1H).13 C NMR (100 MHz, DMSO-d6) δ 14.99, 125.57, 127.21, 129.08, 132.65, 133.30, 136.49, 143.67, 160.68, 169.03. 3-(2-(hydroxyimino)acetamido)-2-methylbenzoic acid (8) was analyzed by HPLC method A. Ret :2.05min.

[0024] Example 2 7-Methyl-2,3-dioxoindoline-6-carboxylic acid (9) [ka] 2000g HSO 4conc. The mixture is heated to 85-90°C and 370 g of compound 8 (1.0 equiv.) is added. The reaction is stirred at approximately 90°C for 30 min, then cooled to 15-25°C. 3100 g of water and 440 g of acetone are combined in a second vessel and cooled to 0-10°C. The reaction mixture is transferred to a second reaction vessel, maintaining the temperature below 20°C. After complete addition, the reaction mixture is stirred between 10-20°C for 1 h. The reaction is filtered, the filter cake is washed with 1500 g of water, and dried under reduced pressure for 72 h to give 224 g of compound 9 (65.6% yield, 83.5% A). 1 H NMR (400 MHz, DMSO-d6) δ 2.31 (s, 3H), 7.34 - 7.43 (m, 2H), 11.22 (s, 1H), 13.34 (s, 1H). 13 C NMR (100 MHz, DMSO-d) δ 13.36, 119.12, 121.28, 121.53, 123.55, 139.95, 149.97, 159.85, 168.14, 184.65. 7-Methyl-2,3-dioxoindoline-6-carboxylic acid (9) was analyzed by HPLC method A. Ret :1.42min.

[0025] Example 3 Sodium 3-(cyanomethyl)-3-hydroxy-7-methyl-2-oxoindoline-6-carboxylate (11) [ka] 220 g of compound 9 (1.0 equiv.) was added to a mixture of 314 g of DMF, 370 g of THF, and 110 g of TEA (1.0 equiv.) at a rate that maintained the temperature between 15 and 35 °C. The reaction mixture was then warmed to 60 °C, and 99 g (1.1 equiv.) of cyanoacetic acid (10) in 98 g of THF was added and stirred for 2 h. The mixture was then cooled to 25 to 35 °C, and 440 g of 10% aqueous NaOH was added at a rate that maintained the temperature below 35 °C, and stirred for 30 min. The mixture was then cooled to 10 to 20 °C and filtered. The filter cake was washed with 390 g of THF and dried under reduced pressure to give 202 g of compound 11 (70.2% yield and 98.9% yield). 1 H NMR (400 MHz, DMSO-d6) δ 2.30 (s, 3H), 2.91 (d, J = 16.6 Hz, 1H), 3.04 (d, J = 16.6 Hz, 1H), 6.74 (s, 1H), 7.16 (m, 2H), 10.49 (s, 1H). 13 C NMR (100 MHz, DMSO-d6) δ 14.37, 26.15, 72.33, 117.19, 120.14, 120.14, 121.76, 127.78, 140.11, 144.74, 172.59, 177.42. Sodium 3-(cyanomethyl)-3-hydroxy-7-methyl-2-oxoindoline-6-carboxylate (11) was analyzed by HPLC method B. Ret :1.75min.

[0026] Example 4 3-(2-((tert-butoxycarbonyl)amino)ethyl)-3-hydroxy-7-methyl-2-oxoindoline-6-carboxylic acid (13a) [ka] 70 g (1.0 equiv.) of compound 11 and 28 g (1.0 equiv.) of Na2CO3 are dissolved in 490 g of water. 14 g of Ni catalyst in 140 g of water is added, followed by the addition of a solution of 114 g (2.0 equiv.) of Boc2O in 187 g of THF. The mixture is purged with N2 three times and pressurized with 12-14 bar of H2. After stirring for 12 h at ambient temperature, the H2 pressure is released, purged with N2 three times, and filtered. The filter cake is washed with 140 g of water, and the filtrate is transferred to a second reactor, to which 183 g of IPAc is added. The mixture is stirred for 20 min at ambient temperature, and the aqueous layer is collected. 57 g of HCl is added. conc The pH of the aqueous layer is adjusted to pH 4.9-5.2 by adding HCl, then 0.15 g of seed crystals are added and stirring is continued for 1.5 h. conc. The pH is adjusted to pH 3.0-4.0 by the addition of HCl, the temperature is cooled to 10-20°C, and stirring is continued for 2 h. If the pH remains below 4.0, the crystalline product can be collected; otherwise, the pH is adjusted to 4.0 and an additional amount of HCl is added. conc The filter cake is washed with 140 g of water and dried under reduced pressure at approximately 70° C. for at least 16 h to give 77 g of 13a (yields 80.2% and 95.8% A). 1 H NMR (400 MHz, DMSO-d6) δ 1.33 (s, 9H), 1.81 - 1.96 (m, 2H), 2.37 (s, 3H), 2.85 (tdd, J = 15.3, 10.0, 5.5 Hz, 2H), 6.04 (s, 1H), 6.69 (t, J = 5.5 Hz, 1H), 7.18 (d, J = 7.7 Hz, 1H), 7.47 (d, J = 7.7 Hz, 1H), 10.47 (s, 1H), 12.86 (s, 1H). 13C NMR (100 MHz, DMSO-d6) δ 14.35, 28.15, 34.81, 37.36, 74.58, 77.46, 119.73, 120.92, 123.91, 131.70, 134.93, 141.16, 155.29, 168.66, 179.24. 3-(2-((tert-butoxycarbonyl)amino)ethyl)-3-hydroxy-7-methyl-2-oxoindoline-6-carboxylic acid (13a) was analyzed by HPLC method C. Ret :5.78min.

[0027] Example 5 3-Amino-4-(3-((tert-butoxycarbonyl)amino)propanoyl)-2-methylbenzoic acid (14a) [ka] Add 24 g (0.6 equiv.) of CuCl and 70 g (2.0 equiv.) of DMEDA to a solution of 316 g of MeCN and 100 g of water and stir at ambient temperature for 30 min. Add 140 g (1.0 equiv.) of compound 13a and 67 g (3.0 equiv.) of KOH in 300 g of water. A gas mixture of 10% O2 in N2 was passed through the solution at a rate of 50 mL / min at 60-70 °C for 18 h. The mixture was cooled to 0-10 °C, and 470 g of 6 N HCl was added to adjust the pH to 2.0-2.5. Stirring was continued at 0-15 °C for 2 h. The mixture was filtered and the filter cake was washed with 280 g of water. The cake was transferred to a separate reaction vessel and dissolved in 400 g of MeCN. A solution of 43 g of KOH in 500 g of water is added and stirred at ambient temperature for 2 h. The mixture is filtered over Celite and the filter cake is washed with 280 g of water. The filtrate is cooled to 0-10 °C, and 135 g of 6 N HCl is added to adjust the pH to 3.0-4.0. Stirring is continued at 0-15 °C for 2 h. The mixture is filtered, the filter cake is washed with 280 g of water, and dried under reduced pressure at approximately 50-60 °C for at least 16 h to give 77 g of 14a (yields 91.8% and 98.0% A). 1H NMR (400 MHz, DMSO-d6) δ 1.37 (s, 9H), 2.21 (s, 3H), 3.09 (s, 1H), 3.12 (s, 1H), 3.26 (td, J = 6.5 Hz, 2H), 6.75 - 6.85 (m, 2H), 7.30 (s, 2H), 7.71 (d, J = 8.4 Hz, 1H), 13.13 (s, 1H). 13 C NMR (100 MHz, DMSO-d6) δ 13.84, 28.18, 36.17, 36.17, 77.55, 113.94, 116.88, 122.52, 128.72, 128.72, 149.81, 155.48, 169.83, 201.04. 3-Amino-4-(3-((tert-butoxycarbonyl)amino)propanoyl)-2-methylbenzoic acid (14a) was analyzed by HPLC method C. Ret :8.40min.

[0028] Example 6 Methyl 3-amino-4-(3-aminopropanoyl)-2-methylbenzoate dihydrochloride (1a) [ka] Stir 100 g (1.0 equiv.) of 14a in 950 g of MeOH and heat to 50–60 °C. Then, add SOCl2 (266 g, 6.0 equiv.) at a rate that maintains the temperature between 50–60 °C. After the addition is complete, stir the reaction at 55–65 °C for 1 h. Remove the solvent under reduced pressure to obtain 500–600 mL of distillate. The residue is azeotropically distilled with THF at 55–65 °C in three portions: 350 g, 700 g, and 700 g. Cool the reaction to 10–20 °C and filter. Wash the filter cake with THF and dry under reduced pressure to obtain 98 g of 1 (85.6% yield, 98.47 w / w%). 1H NMR (400 MHz, DMSO-d6) δ 2.22 (s, 2H), 3.08-3.14 (m, 2H), 3.44 (t, J = 8.0 Hz, 2H), 3.85 (s, 3H), 6.85 (d, J = 8.5 Hz, 1H), 7.71 (d, J = 8.5 Hz, 1H), 8.29 (d, J = 6.3 Hz, 3H), 9.25 (s, 3H). 13 C NMR (101 MHz, DMSO-d6) δ 13.98, 34.25, 36.38, 52.26, 114.35, 116.92, 123.46, 128.46, 136.01, 149.39, 168.27, 199.25. Methyl 3-amino-4-(3-aminopropanoyl)-2-methylbenzoate dihydrochloride (1a) was analyzed by HPLC method C. Ret :5.91min.

Claims

1. Compound of formula (1) 【Chemistry 1】 or a salt thereof, comprising: Compound of formula (13) 【Chemistry 2】 [In the formula, R * is a cleavable carboxyl protecting group, preferably an optionally substituted C 1~6 an alkyl or optionally substituted benzyl group, most preferably selected from the group consisting of methyl, ethyl, isopropyl and benzyl; PG is a suitable amino protecting group, preferably a -C(=O)-R group, wherein R is R' or -O-R', and R' is an optionally substituted linear, branched or cyclic aliphatic or aromatic group, or a combination thereof, most preferably a protecting group selected from the group consisting of acetyl (Ac) and tert-butyloxycarbonyl (Boc).

2. 10. The method of claim 1, wherein the oxidative ring-opening uses an Fe oxidizing agent.

3. The oxidizing agent is K 3 [Fe(CN) 6 3. The method of claim 2, wherein

4. 4. The method of claim 3, wherein KOH is used as the base.

5. 10. The method of claim 1, wherein the oxidative ring-opening uses a Cu catalyst.

6. 6. The method of claim 5, wherein the oxidative ring-opening uses oxygen as the stoichiometric oxidant.

7. The oxygen used is between 8 and 21% v / v, preferably between 8 and 10% v / v N 2 Middle O 2 The method of claim 6, wherein the concentration is

8. The compound of formula (13) is a compound of formula (11) 【Transformation 3】 The method according to any one of claims 1 to 7, wherein the compound is synthesized by a process comprising catalytic hydrogenation of

9. 9. The process of claim 8, wherein the catalytic hydrogenation of the compound of formula (11) is catalyzed by sponge nickel.

10. The compound of formula (11) is a compound of formula (9) of cyanoacetic acid. 【Chemistry 4】 The method according to claims 8 and 9, wherein the compound is synthesized by a method comprising decarboxylation of the compound to

11. The compound of formula (9) is a compound of formula (8) 【Transformation 5】 The method according to claim 10, wherein the compound is synthesized by a method comprising the isatin ring formation of

12. Isatin ring formation is achieved by the enrichment of H 2 SO 4 The method of claim 11 , wherein the method is carried out using

13. The compound of formula (8) is reacted with the compound of formula (7) in the presence of hydroxylamine hydrochloride. 【Transformation 6】 13. The method of claims 11 and 12, wherein the compound is synthesized by a process comprising reacting

14. Use of the method according to any one of claims 1 to 13 for the synthesis of an MDM2-p53 antagonist.

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