A synthetic method of SDNX-5613 and its intermediate compound

Abstract

The present invention discloses a synthesis method for the menin inhibitor SNDX-5613 (Revumenib) and an intermediate compound thereof. The synthesis method of the present invention has high yield, low cost, avoids the use of phosphorus oxychloride, and improves safety.

Description

Technical Field

[0001] The present invention belongs to the field of chemical synthesis, and in particular relates to a synthesis method of a menin inhibitor SNDX-5613 (Revumenib) and an intermediate compound thereof. Background Art

[0002] Mixed lineage leukemia (MLL) proteins are histone methyltransferases that are mutated in clinically and biologically distinct subtypes of acute leukemia. Spontaneous translocation of the MLL1 gene leads to the production of the MLL-r fusion protein, which interacts with the menin protein, leading to the abnormal activation of a series of gene clusters and the development of leukemia. Menin-MLL interaction inhibitors are epigenetic inhibitors that can block the interaction between menin and the MLL fusion protein (MLL-r) in leukemia cells. SNDX-5613, an inhibitor of the interaction between menin and MLL fusion protein developed by Syndax, entered Phase I / II clinical trials on August 22, 2019, and is the first Menin-MLL inhibitor to enter clinical trials.

[0003] The chemical name of SNDX-5613 is N-ethyl-2-((4-(7-(((1r,4r)-4-(ethylsulfonamido)cyclohexyl)methyl)-2,7-diazaspiro[3.5]nonan-2-yl)pyrimidin-5-yl)oxy)-5-fluoro-N-isopropylbenzamide, and its English name is N-ethyl-2-((4-(7-(((1r,4r)-4-(ethylsulfonamido)cyclohexyl)methyl)-2,7-diazaspiro[3.5]nonan-2-yl)pyrimidin-5-yl)oxy)-5-fluoro-N-isopropylbenzamide. Its drug name is Revumenib. Its chemical structure is as follows:

[0004]

[0005] Existing reports (such as WO2017214367A1 and CN109743875A) all use meta-chloroperbenzoic acid or urea peroxide to oxidize the pyrimidine ring, then chlorinate with phosphorus oxychloride, then use diazaspiro[3.5] ring nucleophilic substitution, and finally replace with the sulfonamide fragment (S1) to construct the corresponding structure. The first step requires the use of meta-chloroperbenzoic acid or urea peroxide. The use of meta-chloroperbenzoic acid will cause the acidity of the system to increase, resulting in diaryl ether bond scission, making the reaction yield of this step low and unstable. The acidic system also has high requirements for the reaction and processing equipment. In addition, the reaction will also produce a large amount of meta-chlorobenzoic acid byproduct. Urea peroxide is a controlled reagent and is currently difficult to obtain on the market. The second step requires the use of phosphorus oxychloride. Similarly, the acidity is too strong, which may cause diaryl ether bond scission, which has high requirements for the reaction equipment, and the post-processing is cumbersome and quite dangerous. The yield of the last step is too low, mainly because the diaryl ether fragment is easy to break under these conditions. In addition, the entire synthesis route is a linear synthesis, which has high time cost.

[0006] In order to overcome the shortcomings of the prior art, the present invention provides a method for synthesizing SNDX-5613 and its intermediate compounds with mild reaction conditions, simple operation and more reasonable route. Summary of the Invention

[0007] The present invention provides an intermediate compound for synthesizing the menin inhibitor SNDX-5613, which has the formula 2-2 and / or

[0008] The structure shown in formula 3-3:

[0009]

[0010] Preferably, the synthesis method of the intermediate compound 2-2 comprises step (3):

[0011] (3) Compound 1-1 is dissolved in a solvent, and an oxidant is added to oxidize the compound under the action of an acid. The reaction is carried out at 50-70°C for 16-24 hours to obtain the intermediate compound 2-2;

[0012] The reaction route is as follows:

[0013]

[0014] As a preference: the synthesis method of the intermediate compound 3-3 comprises steps (1) and (2):

[0015] (1) Dissolve compound S1 and the catalyst in a solvent, stir for 10-30 min, then add a base and compound 3-1. Heat to 70-80°C under nitrogen protection and react for 12-24 h to obtain intermediate 3-2.

[0016] (2) Dissolving the intermediate 3-2 in a solvent and adding an acid to remove the protecting group to obtain the intermediate compound 3-3;

[0017] The reaction route is as follows:

[0018]

[0019] Preferably, a method for synthesizing the menin inhibitor SNDX-5613 comprises the following steps:

[0020] (1) Dissolve compound S1 and the catalyst in a solvent, stir for 10-30 min, then add a base and compound 3-1. Heat to 70-80°C under nitrogen protection and react for 12-24 h to obtain intermediate 3-2.

[0021] (2) Dissolving the intermediate 3-2 in a solvent and adding an acid to remove the protecting group to obtain the intermediate compound 3-3;

[0022] (3) Compound 1-1 is dissolved in a solvent, and an oxidant is added to oxidize the compound under the action of an acid. The reaction is carried out at 50-70°C for 16-24 hours to obtain the intermediate compound 2-2;

[0023] (4) The intermediate compound 2-2 is dissolved in a solvent and reacted with the intermediate compound 3-3 at 0-30° C. for 12-24 h in the presence of a condensing agent and a base to obtain SNDX-5613.

[0024] The reaction route is as follows:

[0025]

[0026] Preferably, the molar ratio of compound S1 to the catalyst, compound 3-1, and base in step (1) is 1:(0.8-1):(0.5-1):(3-5), and the amount of solvent used is 4-15 mL of solvent per 1 g of compound S1.

[0027] Preferably, the catalyst in step (1) is any one or more of potassium iodide and sodium iodide.

[0028] Preferably, the base in step (1) is any one or more of potassium carbonate, sodium carbonate, sodium hydroxide, potassium hydroxide, and lithium hydroxide.

[0029] Preferably, the solvent in step (1) is any one or more of NMP (N-methylpyrrolidone), DMSO (dimethyl sulfoxide), DMF (N,N-dimethylformamide), and DMAC (N,N-dimethylacetamide).

[0030] Preferably, in step (2), the molar ratio of the intermediate 3-2 to the acid is 1:(3-15), and the amount of solvent used is 8-15 mL of solvent per 1 g of intermediate 3-2.

[0031] Preferably, the acid in step (2) is any one or more of hydrochloric acid and trifluoroacetic acid.

[0032] Preferably, the solvent in step (2) is any one or more of ethyl acetate, dichloromethane, and dioxane.

[0033] Preferably, in step (3), the molar ratio of compound 1-1 to the oxidant and the acid is 1:(2-6):1.05, and the mass ratio of compound 1-1 to the solvent is 1:4. In this step, if the amount of the oxidant is too low, the reaction period is long and the reaction is incomplete; if the amount of the oxidant is too high, the impurity content increases. If the amount of the acid is too low, the reaction is incomplete, and if the amount is too high, the by-product content increases.

[0034] Preferably, in step (3), the oxidant is hydrogen peroxide; the acid is one or more of sulfuric acid, hydrochloric acid, formic acid, and acetic acid. Further, the acid is sulfuric acid.

[0035] More preferably, the hydrogen peroxide is 30% by mass, as this concentration of hydrogen peroxide is readily available and safer to use.

[0036] More preferably, the sulfuric acid is concentrated sulfuric acid with a mass fraction greater than or equal to 70%. Concentrated sulfuric acid mainly plays the role of improving oxidation efficiency and promoting substrate dissolution.

[0037] Preferably, the solvent in step (3) is deionized water or tap water.

[0038] More preferably, the reaction temperature in step (3) is 50-70° C. When the reaction temperature is lower than 50° C., the reaction proceeds slowly; if the reaction temperature is higher than 70° C., impurities increase, resulting in a decrease in yield.

[0039] Preferably, in step (4), the molar ratio of the intermediate compound 2-2 to the intermediate compound 3-3, the condensing agent, and the base is 1:(1-1.5):(1-1.5):(3-6), and the amount of solvent used is 10-20 mL of solvent per 1 g of the intermediate compound 2-2.

[0040] Preferably, the condensing agent in step (4) is a phosphonium ion or a phosphate condensation reagent; the phosphonium ion or phosphate condensation reagent is selected from any one or more of BOP (benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate), PyBOP (1H-benzotriazol-1-yloxytripyrrolidino hexafluorophosphate), BOP-Cl (bis(2-oxo-3-oxazolidinyl)phosphinoyl chloride), FDP (sodium fructose-1,6-diphosphate), FDPP (pentafluorophenyl diphenyl phosphate), and DEPBT (3-(diethoxy-o-acyloxy)-1,2,3-benzotriazine-4-one).

[0041] Specifically, the condensing agent is benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate, namely Carter's condensing agent (BOP). If the amount of the condensing agent is too low, the reaction will not proceed completely; if the amount is too high, the condensing agent will be wasted.

[0042] Preferably, the base in step (4) is a commonly used organic base. Common organic bases include any one or more of triethylamine, diisopropylethylamine, diethylamine, and DBU (1,8-diazobisspiro[5.4.0]undec-7-ene). The excess organic base is used to neutralize the hydrochloride of the intermediate 3-3 and promote the condensation reaction. If the amount of organic base is too low, the reaction will be slow and incomplete.

[0043] Preferably, the solvent in step (4) is one or more polar aprotic solvents such as dichloromethane, dichloroethane or N,N-dimethylformamide; if the reaction solvent is dried dichloromethane, the reaction effect is better.

[0044] Preferably, the reaction in step (4) needs to be carried out under a nitrogen atmosphere.

[0045] Preferably, the reaction temperature in step (4) is room temperature, which refers to 20-30°C.

[0046] Further preferably, the condensation reaction in step (4) is carried out as follows: in an ice-water bath, the intermediate compound 2-2 is dissolved in a solvent, and after nitrogen protection, a condensing agent and a base are added in sequence, and the temperature is raised to room temperature (20-30°C) and the reaction is carried out for 1 hour; then the temperature is lowered to 0°C, the intermediate compound 3-3 is added, and the temperature is raised to room temperature and the reaction is carried out overnight.

[0047] The present invention determines that the structure of the oxidation product in a hydrogen peroxide system is the intermediate compound 2-2 through one-dimensional hydrogen spectrum.

[0048] Compared with the prior art, the present invention has the following positive effects:

[0049] 1. In step (3) of the present invention, a sulfuric acid / hydrogen peroxide system is used to replace m-chloroperbenzoic acid, thereby reducing reagent costs. At the same time, the formation of m-chlorobenzoic acid as a by-product is avoided, which not only greatly reduces the risk of environmental pollution but also reduces the cost of subsequent three waste treatment.

[0050] 2. The use of water as a solvent in step (3) of the present invention not only effectively reduces costs, but also avoids the use of an organic solvent, dichloromethane, effectively avoids environmental pollution, and reduces the cost of subsequent three waste treatment.

[0051] 3. The post-treatment in step (3) of the present invention only requires the addition of an organic solvent, extraction, and recrystallization to obtain the intermediate compound 2-2, avoiding column chromatography and saving a lot of time and cost.

[0052] 4. In step (4) of the present invention, intermediate compound 2-2 is directly condensed with intermediate compound 3-3 under condensation conditions to obtain the target product SNDX-5613 in one step. This reaction not only avoids the use of phosphorus oxychloride, effectively improving reaction safety, but also reduces the generation of waste gas and waste liquid, saves the cost of treating the three wastes, and avoids environmental pollution. Importantly, this reaction shortens the synthetic route, saving time and cost.

[0053] 5. The present invention advances the nucleophilic substitution reaction (reaction with fragment S1) in the last step of the existing technical route, thereby increasing the reaction yield of the carbon-nitrogen bond construction step from 36.8% to 92.6%.

[0054] 6. The present invention optimizes the five-step linear synthesis route of the existing technical route into a four-step convergent synthesis route, and optimizes the synthesis yield from 16.2% of the original route to 37.3%. DETAILED DESCRIPTION

[0055] The present invention is described in detail below by way of examples. It should be noted that the following examples are merely further explanations of the present invention and are not to be construed as limiting the scope of protection of the present invention. Non-essential adjustments and improvements made by those skilled in the art based on the above-mentioned invention still fall within the scope of protection of the present invention.

[0056] Example 1

[0057] Step (1) substitution reaction mainly consists of the following steps:

[0058] 1) Compound S1 (550 g, 1.46 mol) was dissolved in NMP (2.5 L), potassium iodide (159.3 g, 0.96 mol) was added, and the mixture was stirred at room temperature for 15 min after nitrogen displacement.

[0059] 2) Potassium carbonate (911.8 g, 6.60 mol) and compound 3-1 (264.3 g, 1.168 mol) were added to the reaction system in sequence, and the nitrogen atmosphere was replaced again, and the temperature was raised to 75°C and the reaction was allowed to proceed overnight;

[0060] 3) Monitoring the completion of the reaction using thin-layer chromatography or liquid chromatography-mass spectrometry;

[0061] 4) After the reaction mixture was cooled, it was filtered and the filter cake was washed three times with an appropriate amount of ethyl acetate. The filtrate was diluted with ethyl acetate (15 L), washed three times with water, and twice with saturated brine. The filtrate was dried over anhydrous sodium sulfate, and the organic phase was concentrated. The resulting crude product was dispersed and slurried in a mixture of petroleum ether and ethyl acetate = 5:1, and filtered to obtain the target product 3-2 (465 g, 1.08 mol). HPLC purity: 96%, mass spectrometry data: [M+H] + =430, yield: 92.6%.

[0062] Step (2) deprotection reaction mainly consists of the following steps:

[0063] 1) Intermediate 3-2 (465 g, 1.08 mol) was dissolved in ethyl acetate (1.1 L). 4 M hydrochloric acid in ethyl acetate (3.0 L, 12.0 mol) was added dropwise in an ice bath. The mixture was stirred at room temperature overnight.

[0064] 2) Monitoring the completion of the reaction using thin-layer chromatography or liquid chromatography-mass spectrometry;

[0065] 3) Filter, wash the filter cake three times with ethyl acetate, collect the filter cake and concentrate to obtain the target intermediate compound 3-3 (470 g). HPLC purity: 96%, mass spectrum data: [M+H] + =330, yield: 100%.

[0066] Step (3) oxidation reaction mainly consists of the following steps:

[0067] 1) Slowly add concentrated sulfuric acid (230 ml, 98%) to a reaction vessel containing solvent water (5.2 L) while cooling (<30°C) and stirring. At room temperature, add compound 1-1 (1.3 kg, 4.28 mol) and disperse it in the reaction system. Then, slowly add hydrogen peroxide (884 mL, 30%) dropwise. After completion of the addition, heat to 60°C and stir overnight.

[0068] 2) Monitoring the completion of the reaction using thin-layer chromatography or liquid chromatography-mass spectrometry;

[0069] 3) After the reaction is completed, a sodium sulfite aqueous solution is added dropwise to the reaction system while cooling to quench the excess hydrogen peroxide, and then dichloromethane is added to the reaction system for extraction three times. The organic phases are combined and concentrated to obtain a crude product;

[0070] 4) The crude product was recrystallized with an appropriate amount of ethyl acetate / petroleum ether and filtered to obtain the target intermediate compound 2-2 (723.6 g, 2.27 mol). HPLC purity: 95%, NMR data: 1 H NMR (400 MHz, DMSO-d6) δ 12.94 (s, 1H), 8.10 (d, J = 1.8 Hz, 1H), 7.77 (d, J = 3.0 Hz, 1H), 7.21–7.12 (m, 2H), 6.97–6.89 (m, 1H), 3.87 (p, J = 6.6 Hz, 1H), 3.37 (dt, J = 13.5, 6.7 Hz, 1H), 3.24 (dt, J = 13.6, 6.9 Hz, 1H), 1.18 (d, J = 7.1 Hz, 2H), 1.14–1.07 (m, 5H), 1.05 (d, J = 6.6 Hz, 2H). Mass spectral data: [M+H] + =320, yield: 53%.

[0071] The nuclear magnetic resonance data of intermediate 2-2 after heavy water exchange were measured: 1 H NMR (400MHz, DMSO-d6) δ8.05(d,J=1.8Hz,1H),7.71(d,J=3.0Hz,1H),7.18–7.09(m,2H),6.93–6.85(m,1H),3.82(p,J=6.6Hz,1 H),3.34(dt,J=13.5,6.7Hz,1H),3.19(dt,J=13.6,6.9Hz,1H),1.15(d,J=7.1Hz,2H),1.10–1.04(m,5H),1.01(d,J=6.6Hz,2H).

[0072] Step (4) condensation reaction mainly consists of the following steps:

[0073] 1) In an ice-water bath, intermediate compound 2-2 (220 g, 0.689 mol) was dissolved in dichloromethane (3.3 L). Under nitrogen protection, condensing agent BOP (336 g, 0.76 mol) and triethylamine (384 g, 3.79 mol) were added in sequence. The temperature was raised to room temperature (20-30°C) and the reaction was carried out for 1 h. The temperature was then lowered to 0°C, and intermediate compound 3-3 (272 g, 0.83 mol) was added. The temperature was returned to room temperature and the reaction was carried out overnight.

[0074] 2) Monitor the reaction completion using thin layer chromatography or liquid chromatography-mass spectrometry.

[0075] 3) After the reaction is completed, dichloromethane is added to dilute and quench. After extraction and separation, the organic phase is washed with water twice, washed with saturated ammonium chloride aqueous solution 6 times, washed with saturated brine 1-2 times, and the organic phase is concentrated to obtain a crude product.

[0076] 4) Disperse the crude product in an appropriate volume of ethyl acetate and heat until completely dissolved. Add petroleum ether dropwise at this temperature until the solution becomes turbid. Cool naturally and stir to precipitate a solid, which is filtered to obtain the target product SNDX-5613 (330 g, 0.523 mol). HPLC purity: 98.8% (HPLC determination). NMR data: 1 H NMR(600MHz,Chloroform-d)δ8.39–8.34(m,1H),7.76(d,J=1.7Hz,1H),7.01(qd,J=7.4,7.0,3.5Hz,2H),6.77(ddd,J=14.2,9. 5,4.1Hz,1H),4.62(p,J=6.9Hz,0.2H),4.02–3.77(m,5H),3.50(dd,J=13.7,7.0Hz,0.8H),3.31(dd,J=13.7,7.0Hz,1H),3.19(d d, J = 9.0, 5.6 Hz, 1H), 3.07–2.98 (m, 2H), 2.26 (s, 4H), 2.06 (dd, J = 11.8, 5.0 Hz, 4H), 1.78 (dd, J = 53.4, 9.5 Hz, 7H), 1.36 (ddd, J = 7.4, 5.8, 1.7 Hz, 3H), 1.27–1.19 (m, 5H), 1.14 (t, J = 6.6 Hz, 5H), 1.08 (dd, J = 7.9, 6.4 Hz, 1H), 0.94 (q, J = 12.9 Hz, 2H). Mass spectral data: [M+H] + =631, yield: 76%.

Claims

1. An intermediate compound for synthesizing the menin inhibitor SNDX-5613, having the structure shown in Formula 2-2 and / or Formula 3-3:

2. The method for synthesizing the intermediate compound 2-2 according to claim 1, comprising step (3): (3) Compound 1-1 is dissolved in a solvent, and an oxidant is added to oxidize the compound under the action of an acid. The reaction is carried out at 50-70°C for 16-24 hours to obtain the intermediate compound 2-2; The reaction route is as follows: The solvent in step (3) is water; the oxidant in step (3) is hydrogen peroxide; and the acid in step (3) is one or more of sulfuric acid, hydrochloric acid, formic acid, and acetic acid.

3. The method for synthesizing the intermediate compound 3-3 according to claim 1, comprising steps (1) and (2): (1) Dissolve compound S1 and the catalyst in a solvent, stir for 10-30 min, then add a base and compound 3-1. Heat to 70-80°C under nitrogen protection and react for 12-24 h to obtain intermediate 3-2. (2) Dissolving the intermediate 3-2 in a solvent and adding an acid to remove the protecting group to obtain the intermediate compound 3-3; The reaction route is as follows:

4. A method for synthesizing the menin inhibitor SNDX-5613, comprising the following steps: (1) Dissolve compound S1 and the catalyst in a solvent, stir for 10-30 min, then add a base and compound 3-1. Heat to 70-80°C under nitrogen protection and react for 12-24 h to obtain intermediate 3-2. (2) Dissolving the intermediate 3-2 in a solvent and adding an acid to remove the protecting group to obtain the intermediate compound 3-3; (3) Compound 1-1 is dissolved in a solvent, and an oxidant is added to oxidize the compound under the action of an acid. The reaction is carried out at 50-70°C for 16-24 hours to obtain the intermediate compound 2-2; (4) Dissolving the intermediate compound 2-2 in a solvent and reacting it with the intermediate compound 3-3 at 0-30° C. for 12-24 h in the presence of a condensing agent and a base to obtain SNDX-5613; The solvent in step (3) is water; the oxidant in step (3) is hydrogen peroxide; the acid in step (3) is one or more of sulfuric acid, hydrochloric acid, formic acid, and acetic acid; The above reaction scheme is as follows:

5. The method according to claim 3 or 4, characterized in that: The molar ratio of compound S1 to the catalyst, compound 3-1, and base in step (1) is 1:(0.8-1):(0.5-1):(3-5), and the amount of solvent used is 4-15 mL of solvent per 1 g of compound S1.

6. The method according to claim 5, characterized in that: The catalyst in step (1) is any one or more of potassium iodide and sodium iodide; the base in step (1) is any one or more of potassium carbonate, sodium carbonate, sodium hydroxide, potassium hydroxide, and lithium hydroxide; the solvent in step (1) is any one or more of N-methylpyrrolidone, dimethyl sulfoxide, N,N-dimethylformamide, and N,N-dimethylacetamide.

7. The method according to claim 3 or 4, characterized in that: The molar ratio of the intermediate 3-2 to the acid in step (2) is 1:(3-15), and the amount of solvent used is 8-15 mL of solvent per 1 g of intermediate 3-2.

8. The method according to claim 7, wherein: The acid in step (2) is any one or more of hydrochloric acid and trifluoroacetic acid; the solvent in step (2) is any one or more of ethyl acetate, dichloromethane and dioxane.

9. The method according to claim 2 or 4, characterized in that: The molar ratio of compound 1-1 to the oxidant and acid in step (3) is 1:(2-6): 1.05, and the mass ratio of compound 1-1 to solvent was 1:

4.

10. The method according to claim 4, characterized in that: In step (4), the molar ratio of the intermediate compound 2-2 to the intermediate compound 3-3, the condensing agent, and the base is 1:(1-1.5):(1-1.5):(3-6), and the amount of solvent used is 10-20 mL of solvent per 1 g of the intermediate compound 2-2.

11. The method according to claim 10, characterized in that: The solvent in step (4) is selected from any one or more of dichloromethane, dichloroethane or N,N-dimethylformamide; the condensing agent in step (4) is a phosphonium ion or a phosphate condensation reagent; the base in step (4) is selected from any one or more of triethylamine, diisopropylethylamine, diethylamine, and 1,8-diazobisspiro[5.4.0]undec-7-ene.

12. The method according to claim 11, wherein: The phosphonium ion or phosphate condensation reagent is selected from any one or more of benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate, 1H-benzotriazol-1-yloxytripyrrolidino hexafluorophosphate, bis(2-oxo-3-oxazolidinyl)phosphinoyl chloride, sodium fructose 1,6-diphosphate, pentafluorophenyl diphenyl phosphate, and 3-(diethoxy-o-acyloxy)-1,2,3-benzotriazine-4-one.

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