Rosemeltirome intermediate, synthetic method thereof and synthetic method of rosemeltirome

Abstract

The invention relates to the technical field of medicine synthesis, in particular to a rosmeltirol intermediate, a synthesis method thereof and a synthesis method of rosmeltirol. According to the present invention, the rosmeltirol intermediate II is selected from the compounds represented by the following structural formula: # imgabs0, the new intermediate can be adopted to synthesize the rosmeltirol by using the new synthesis path, and the steps of amino protection and deprotection are avoided during the synthesis process, such that the synthesis path is effectively shortened, and the synthesis steps are simplified. Meanwhile, the final product is prevented from forming a DMAc solvate, the solvent is prevented from being removed through multiple times of refining, and the yield of the final product can be increased.

Description

Technical Field

[0001] The present invention relates to the technical field of drug synthesis, and in particular to a resmetirol intermediate, a synthesis method thereof and a synthesis method of resmetirol. Background Art

[0002] The Chinese name of Resmetiro is 2-(3,5-dichloro-4-((5-isopropyl-6-oxo-1,6-dihydropyridazin-3-yl)oxy)phenyl)-3,5-dioxy-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbonitrile; 2-[3,5-dichloro-4-[(5-isopropyl-6-oxo-1,6-dihydropyridazin-3-yl)oxy]phenyl]-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbonitrile, CAS No. 920509-32-6, which is used to treat non-cirrhotic non-alcoholic steatohepatitis (NASH) with advanced liver fibrosis in adults, with the structural formula:

[0003] In the prior art, resimetirol is generally obtained by chemical synthesis, for example, the synthesis route disclosed in CN200680026731:

[0004] The specific process is to condense 4-isopropyl-3,6-dichloropyridazine with 4-amino-2,6-dichlorophenol, convert chloropyridazine into pyridazinone, react with cyanoacetylcarbamate, and finally cyclize to obtain the product. However, the synthesis process requires amino protection and deprotection operations, resulting in a too long synthesis path, and the final product is a DMAc solvate. Therefore, in order to obtain pure resmetiro, the solvate needs to be refined multiple times to remove the solvent. Excessive refining times leads to a significant reduction in yield.

[0005] In view of this, the present invention is proposed. Summary of the invention

[0006] The object of the present invention is to provide a resmetiro intermediate, a synthesis method thereof and a synthesis method of resmetiro. The present invention provides a new resmetiro intermediate, and the new intermediate can be used to synthesize resmetiro using a new synthesis path, avoiding amino protection and deprotection steps during the synthesis process, effectively shortening the synthesis path and simplifying the synthesis steps. At the same time, the final product avoids the formation of DMAc solvate, avoids removing the solvent by multiple refining, and can improve the yield of the final product.

[0007] The present invention is achieved in that:

[0008] In a first aspect, the present invention provides a resmetirol intermediate II, which is selected from the compounds represented by the following structural formula:

[0009]

[0010] In a second aspect, the present invention provides a method for synthesizing the resmetirome intermediate II described in the aforementioned embodiment, comprising: synthesizing according to the following synthesis route:

[0011]

[0012] In an optional embodiment, the method comprises: mixing the intermediate I with ethyl N-cyanoacetylcarbamate, an organic acid-aqueous solution, a nitrite and an inorganic acid to react.

[0013] In an optional embodiment, the molar ratio of the intermediate I to the N-cyanoacetyl ethyl carbamate is 1:(1.1-1.3);

[0014] The volume ratio of organic acid to water in the organic acid-water solution is (1-10):1;

[0015] The molar ratio of the intermediate I to the inorganic acid is 1:(3-4);

[0016] The molar ratio of the intermediate I to the nitrite is 1:(1.0-1.2);

[0017] Preferably, the organic acid is selected from any one of formic acid, acetic acid and propionic acid;

[0018] The inorganic acid is selected from hydrochloric acid or sulfuric acid;

[0019] The nitrite is selected from potassium nitrite or sodium nitrite.

[0020] In a third aspect, the present invention provides a resmetirol intermediate III, which is selected from the compounds represented by the following structural formula:

[0021]

[0022] In a fourth aspect, the present invention provides a method for synthesizing the resmetirome intermediate III described in the aforementioned embodiment, and the synthesis is performed according to the following synthesis route:

[0023]

[0024] In an optional embodiment, the method comprises: mixing resmetirole intermediate II, a basic substance and a solvent to react under an inert gas atmosphere.

[0025] In an optional embodiment, the reaction temperature is 100-120°C;

[0026] Preferably, the alkaline substance includes any one of potassium acetate, sodium acetate, potassium formate, sodium formate and potassium propionate;

[0027] Preferably, the molar ratio of the resmetirole intermediate II to the alkaline substance is 1:(1-1.1).

[0028] In a fifth aspect, the present invention provides a method for synthesizing resmetirol, which is synthesized by referring to the following synthetic route:

[0029]

[0030] In an optional embodiment, the method comprises: mixing resmetirole intermediate III, an organic acid and an alkaline substance and reacting them at 90-110° C.;

[0031] Preferably, the molar ratio of the resmetirome intermediate III to the alkaline substance is 1:(2-5).

[0032] The present invention has the following beneficial effects: the embodiment of the present invention provides a new intermediate for synthesizing resmetiro, and the new intermediate can be used to synthesize resmetiro using a new synthesis route, and the synthesis route avoids the operation of amino protection-deprotection, thereby simplifying the synthesis operation of resmetiro. At the same time, the final product avoids the formation of DMAc solvate, avoids the removal of solvent through multiple refining, reduces the loss of the final product due to multiple refining, and improves the yield of the final product. BRIEF DESCRIPTION OF THE DRAWINGS

[0033] In order to more clearly illustrate the technical solutions of the embodiments of the present invention, the drawings required for use in the embodiments are briefly introduced below. It should be understood that the following drawings only show certain embodiments of the present invention and therefore should not be regarded as limiting the scope. For ordinary technicians in this field, other related drawings can be obtained based on these drawings without creative work.

[0034] Figure 1 The mass spectrum of Resmetirol intermediate II provided in Example 1 of the present invention;

[0035] Figure 2 The HPLC spectrum of Resmetirol intermediate II provided in Example 1 of the present invention;

[0036] Figure 3 The mass spectrum of the resmetirol intermediate III provided in Example 1 of the present invention;

[0037] Figure 4 The HPLC spectrum of the resmetirol intermediate III provided in Example 1 of the present invention;

[0038] Figure 5The HPLC spectrum of the resmetirol intermediate provided in Example 1 of the present invention;

[0039] Figure 6 The HPLC spectrum of resmetirole intermediate III provided in Example 2 of the present invention. DETAILED DESCRIPTION

[0040] In order to make the purpose, technical scheme and advantages of the embodiments of the present invention clearer, the technical scheme in the embodiments of the present invention will be described clearly and completely below. If the specific conditions are not specified in the embodiments, they are carried out according to conventional conditions or conditions recommended by the manufacturer. If the manufacturer of the reagents or instruments used is not specified, they are all conventional products that can be purchased commercially.

[0041] In a first aspect, the present invention provides a resmetirol intermediate II, which is selected from the compounds represented by the following structural formula:

[0042]

[0043] In a second aspect, the present invention provides a method for synthesizing the resmetirome intermediate II described in the aforementioned embodiment, comprising: synthesizing according to the following synthesis route:

[0044]

[0045] Wherein, the synthesis of intermediate I is as follows:

[0046] Specifically, 4-isopropyl-3,6-dichloropyridazine and 4-amino-2,6-dichlorophenol are mixed with a solvent (such as an amide solvent such as DMAC) and a catalyst (such as cesium carbonate) at a molar ratio of 1:1.1-1.3 and reacted at 60-80°C.

[0047] Then, the intermediate I, N-cyanoacetyl ethyl carbamate, organic acid-water solution, nitrite and inorganic acid are mixed for reaction. Specifically, the intermediate I, N-cyanoacetyl ethyl carbamate and organic acid-water solution are mixed under an inert gas atmosphere, cooled to 0-10° C., and then inorganic acid is added, and then the temperature is controlled at 5-10° C. and the aqueous solution of nitrite is added dropwise for reaction.

[0048] Wherein, the molar ratio of the intermediate I to the N-cyanoacetyl ethyl carbamate is 1:(1.1-1.3); the volume ratio of the organic acid to water in the organic acid-water solution is (1-10):1; the molar ratio of the intermediate I to the inorganic acid is 1:(3-4); the molar ratio of the intermediate I to the nitrite is 1:(1.0-1.2). The organic acid is selected from any one of formic acid, acetic acid and propionic acid; the inorganic acid is selected from hydrochloric acid or sulfuric acid; the nitrite is selected from potassium nitrite or sodium nitrite. The use of the above ratios and substances can be conducive to the reaction.

[0049] In a third aspect, the present invention provides a resmetirol intermediate III, which is selected from the compounds represented by the following structural formula:

[0050]

[0051] The synthesis method of the resmetirol intermediate III is synthesized by referring to the following synthesis route:

[0052]

[0053] Specifically, resmetiro intermediate II, alkaline substance and solvent are mixed and reacted at 100-120° C. under an inert gas atmosphere. The alkaline substance includes any one of potassium acetate, sodium acetate, potassium formate, sodium formate and potassium propionate; the solvent includes but is not limited to amide solvents (such as DMAc). The molar ratio of resmetiro intermediate II and the alkaline substance is 1: (1-1.1).

[0054] The synthesis method of resmetirol is synthesized by referring to the following synthesis route: The specific operation is as follows: Resmetiro intermediate III, an organic acid (such as glacial acetic acid) and an alkaline substance (such as sodium acetate) are mixed and reacted at 90-110° C.; wherein the molar ratio of the Resmetiro intermediate III to the alkaline substance is 1:(2-5).

[0055] In each step of the reaction of the present invention, TLC was used to monitor whether the reaction was complete, and therefore, the reaction time was not provided.

[0056] After each step of the reaction in the embodiment of the present invention is completed, post-processing will be performed, and the post-processing includes but is not limited to filtering, eluting, drying and refining.

[0057] The purity of the above substances was tested by HPLC, and the specific HPLC conditions were as follows:

[0058] Chromatographic column: Waters Symmetry C18 4.6×150mm, 3.5μm; Mobile phase A: 0.1% phosphoric acid aqueous solution; Mobile phase B: acetonitrile; Detection wavelength: 210nm; Flow rate: 1.0ml / min; Column temperature: 25℃; Injection volume: 5μl; Gradient elution according to the following table:

[0059] Time (min) Mobile phase A (%) Mobile phase B (%) 0 90 10 5 90 10 50 30 70 60 30 70 61 90 10 70 90 10

[0060] Test sample solution: Take about 10 mg of the test sample, weigh it accurately, put it in a 20 ml volumetric flask, add an appropriate amount of acetonitrile or a few drops of DMAC and sonicate to dissolve it, dilute it to the scale with acetonitrile, shake well, and you have it.

[0061] The features and performance of the present invention are further described in detail below in conjunction with the embodiments.

[0062] Example 1

[0063] The embodiment of the present invention provides a method for synthesizing resmetirol, comprising: synthesizing according to the following synthesis path:

[0064]

[0065] The specific operations are as follows:

[0066] S1, synthetic intermediate I;

[0067] Add 4-isopropyl-3,6-dichloropyridazine (95.5g, 0.5mol), 4-amino-2,6-dichlorophenol (97.9g, 0.55mol) and DMAC (500mL of N,N-dimethylacetamide) to the reaction bottle and stir. Add cesium carbonate (212g, 0.65mol) to the resulting solution, react at 70°C for 24h, and TLC detects the completion of the reaction. The reaction solution is cooled to room temperature, 200ml of ethyl acetate is added, filtered to remove salt, the filter cake is rinsed with 2*250ml EA, washed with 2*500ml brine, and ethyl acetate solution is obtained, which is concentrated to dryness under reduced pressure, 130ml EA is added to the residue, stirred, 650ml of n-heptane is added, stirred and crystallized, filtered, and dried at 60°C for 8h to obtain 96g of solid, with a yield of 57.8% (based on the raw material 4-isopropyl-3,6-dichloropyridazine).

[0068] S2, synthesis of resmetirol intermediate II;

[0069] Add intermediate Ⅰ (166g, 0.5mol), N-cyanoacetyl ethyl carbamate (86g, 0.55mol) and 900ml glacial acetic acid / 200ml water into the reaction flask, start stirring, cool to 0-10℃ under nitrogen atmosphere, add concentrated hydrochloric acid (150ml, 1.8mol) dropwise to the reaction flask, and then control the temperature to 5℃ and add NaNO2 aqueous solution (34.5g / 80ml water). After 1h of plate reaction, control the temperature to 5℃ and add sodium acetate aqueous solution (115g / 500ml water). Stir and react at 25℃ for 13h, filter, and rinse with 300ml water to obtain 230g of solid, with a yield of 92.3% (based on intermediate Ⅰ) and a purity of 96%.

[0070] The characterization spectra of the obtained compounds can be found in Figure 1 and Figure 2 ,in Figure 1 is the mass spectrum, Figure 2 The HPLC spectrum is shown in Figure 2. The hydrogen spectrum data of the obtained compound are as follows: 1 H-NMR (400MHz, DMSO-d6) δ: 1.24~1.27(m,3H), 1.29~1.31(m,6H), 3.16~3.19(s, 1H), 4.15~4.20(m,2H),7.78(s,1H),7.85(s,2H),10.33(br,1H),11.95(br,1H).

[0071] S3, synthesis of resmetirol intermediate III;

[0072] Resmetiro intermediate II (250 g, 0.5 mol), potassium acetate (54 g, 0.55 mol), N, N-dimethylacetamide (DMAc 1.3 L) were added to the reaction bottle, stirred, and heated to 115 ° C under nitrogen atmosphere. After 2 h of TLC spot reaction, the temperature was lowered to 25 ° C, acetic acid (62 ml, 1.08 mol) was added, stirred for 2 h, and then filtered. The filter cake was rinsed with 50 ml of DMAc, and the filtrate was transferred to the reaction bottle. 2.1 L of water was slowly added under stirring at 10 ° C. Solid precipitated and 206 g was obtained by filtration. The yield was 91% (based on intermediate II) and the purity was 98%.

[0073] The characterization spectra of the obtained compounds can be found in Figure 3 and Figure 4 ,in Figure 3 is the mass spectrum, Figure 4 The HPLC spectrum is shown in Figure 2. The hydrogen spectrum data of the obtained compound are as follows: 1 H-NMR (400MHz, DMSO-d6) δ: 1.30~1.32(d,6H), 3.16~3.23(m,1H), 7.83(s,2H), 7.88(s,1H), 13.27(br,1H).

[0074] S4, synthetic resmetirol;

[0075] Add resmetiro intermediate III (227g, 0.5mol), 900ml glacial acetic acid, sodium acetate (143g, 1.7mol) to the reaction bottle, react at 100°C for 24h, and the reaction is complete by TLC detection. The reaction solution is cooled to room temperature, 1.2L EA and 1L water are added, a large amount of solid is precipitated, filtered, and dried to obtain a crude product, which is refined once with ethanol to obtain 128g, a yield of 58.8% (based on intermediate III), and a purity of 100%.

[0076] The characterization spectra of the obtained compounds can be found in Figure 5 ,in Figure 5 The HPLC spectrum is shown in Figure 2. The hydrogen spectrum data of the obtained compound are as follows: 1 H-NMR (400MHz, DMSO-d6) δ: 1.19~1.21(d,6H), 3.03~3.09(m,1H), 7.79(s,1H), 7.44(s,2H), 12.25(s,1H), 13.29(br,1H).

[0077] Example 2

[0078] This example adopts the method of reference example 1 for synthesis, the only difference is that the solvent used in S3 to synthesize the intermediate III of resmetiro is different, and the solvent used in example 2 is acetonitrile, and the other conditions and steps are the same as those in example 1. The intermediate III of resmetiro obtained in this example is 205g, the yield is 90.3%, and the purity is 97%. Its HPLC spectrum is shown in Figure 6 .

[0079] Embodiment 3-8

[0080] This example adopts the method of Example 1 for synthesis, the only difference is that the conditions for synthesizing resmetirol in S4 are different, see Table 1 for details, and the other conditions and steps are the same as those in Example 1.

[0081] Example glacial acetic acid Sodium acetate Reaction temperature ℃ / reaction time (h) Yield % purity 3 900 143 90 / 30h 125g / 57.5 100％ 4 900 143 110 / 23h 126g / 57.9 100％ 5 900 210 100 / 24h 128g / 58.8 100％ 6 900 100 100 / 24h 126g / 57.9 100％ 7 400 143 100 / 24h 124g / 57.0 100％ 8 1800 143 100 / 24h 127g / 58.4 100％

[0082] Research Example 1——Synthesis of Resmetirol Intermediate II

[0083] The steps and conditions for synthesizing Resmetiro Intermediate II in this optimization example are basically the same as the steps and conditions for synthesizing Resmetiro Intermediate II in Example 1, with only some conditions being different, as shown in Table 2 for details.

[0084] Table 2 Synthesis of resmetiro intermediate II in different solvents

[0085] Acid / dosage (ml) Water (ml) Acid / water (v / v) Yield (Intermediate II) Purity Acetic acid / 1000 100 10:1 228g / 91.2％ 96％ Acetic acid / 550 550 1:1 226g / 90.4％ 96％ Acetic acid / 0 1100 _ 215g / 86.3％ 90％ Formic acid / 900 200 4.5:1 228g / 91.2％ 95％

[0086] It can be seen that the purity and yield of intermediate II are low when pure water is used as the reaction solvent. When organic acid and water are used as mixed solvent, the purity and yield of intermediate II are improved with the increase of acid dosage.

[0087] Study 2

[0088] The steps and conditions for synthesizing Resmetiro Intermediate II in this optimization example are basically the same as those in Example 1, except that 900 ml of glacial acetic acid is replaced by 450 ml of glacial acetic acid and 450 ml of DMAC. As a result, 216 g of Intermediate II is obtained with a purity of 92% and a yield of 86.7%.

[0089] Study 3

[0090] The steps and conditions for synthesizing resmetiro intermediate II in this optimization example are basically the same as those in Example 1, except that 900 ml of glacial acetic acid is replaced by 900 ml of DMAC. As a result, 194 g of intermediate II is obtained with a purity of 90% and a yield of 77.9%.

[0091] Study 4

[0092] The steps and conditions for synthesizing Resmetiro Intermediate II in this optimization example are basically the same as the steps and conditions for synthesizing Resmetiro Intermediate II in Example 1, with the only difference being the different feed ratios of Intermediate I and N-cyanoacetyl ethyl carbamate, as shown in the following table.

[0093]

[0094] Study 5

[0095] The steps and conditions for synthesizing Resmetiro Intermediate II in this optimization example are basically the same as the steps and conditions for synthesizing Resmetiro Intermediate II in Example 1, with the only difference being the amount of concentrated hydrochloric acid used, as shown in the following table.

[0096] Serial number Concentrated hydrochloric acid Yield (Intermediate II) Purity 1 120ml / 1.44mol 228g / 91.2％ 96％ 2 180ml / 2.16mol 230g / 92.3％ 94％

[0097] Study 6

[0098] The steps and conditions for synthesizing Resmetiro Intermediate II in this optimization example are basically the same as the steps and conditions for synthesizing Resmetiro Intermediate II in Example 1, with the only difference being the amount of sodium nitrite used, as shown in the following table.

[0099] Serial number Sodium Nitrite Yield (Intermediate II) Purity 1 38g / 0.55mol 230g / 92.3％ 96％ 2 41g / 0.6mol 229g / 92.0％ 96％

[0100] The above description is only a preferred embodiment of the present invention and is not intended to limit the present invention. For those skilled in the art, the present invention may have various modifications and variations. Any modification, equivalent replacement, improvement, etc. made within the spirit and principle of the present invention shall be included in the protection scope of the present invention.

Claims

1. A resmetirome intermediate II, characterized in that: It is selected from the compounds represented by the following structural formula:

2. A method for synthesizing the resmetirole intermediate II according to claim 1, characterized in that: include: The synthesis was carried out according to the following synthesis route:

3. The synthesis method according to claim 2, characterized in that The method comprises: mixing an intermediate I with N-cyanoacetyl ethyl carbamate, an organic acid-water solution, a nitrite and an inorganic acid to react.

4. The synthesis method according to claim 3, characterized in that The molar ratio of the intermediate I to the N-cyanoacetyl ethyl carbamate is 1:(1.1-1.3); The volume ratio of organic acid to water in the organic acid-water solution is (1-10):1; The molar ratio of the intermediate I to the inorganic acid is 1:(3-4); The molar ratio of the intermediate I to the nitrite is 1:(1.0-1.2); Preferably, the organic acid is selected from any one of formic acid, acetic acid and propionic acid; The inorganic acid is selected from hydrochloric acid or sulfuric acid; The nitrite is selected from potassium nitrite or sodium nitrite.

5. A resmetirome intermediate III, characterized in that: It is selected from the compounds represented by the following structural formula:

6. A method for synthesizing the resmetirome intermediate III according to claim 5, characterized in that: The synthesis was carried out according to the following synthesis route:

7. The synthesis method according to claim 6, characterized in that include: The resmetirole intermediate II, the alkaline substance and the solvent are mixed and reacted under an inert gas atmosphere.

8. The synthesis method according to claim 7, characterized in that The reaction temperature is 100-120°C; Preferably, the alkaline substance includes any one of potassium acetate, sodium acetate, potassium formate, sodium formate and potassium propionate; Preferably, the molar ratio of the resmetirole intermediate II to the alkaline substance is 1:(1-1.1).

9. A method for synthesizing resmetirol, characterized in that: The synthesis was carried out according to the following synthesis route:

10. The synthesis method according to claim 9, characterized in that include: The resmetirol intermediate III, the organic acid and the alkaline substance are mixed and reacted at 90-110° C.; Preferably, the molar ratio of the resmetirome intermediate III to the alkaline substance is 1:(2-5).

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