Preparation method of givelastat intermediate

Abstract

The invention relates to the technical field of chemical intermediates, and particularly discloses a preparation method of a givelastat intermediate.According to the preparation method, an initiator compound 5 can be synthesized by adopting cheap 2-hydroxy-6-naphthoic acid (CAS: 16712-64-4, 141 yuan / kg), and the preparation method is different from a method in the prior art. A gemvelastat intermediate compound 4 is synthesized from a compound 5 through a three-step reaction, compared with the prior art, the yield is high, industrial amplification production is more facilitated, in the process of synthesizing a compound 6 from the compound 5, acetonitrile can be adopted as a cyanide source in a reaction system, activated hydroxyl is subjected to a coupling reaction, and the yield is high. In the process of synthesizing a compound 6 from a compound 7 instead of a traditional metal cyanide, or in the process of synthesizing a compound 6 from another compound 5, a cheap cuprous cyanide and cuprous iodide system is adopted for a coupling reaction, and in the process of synthesizing a compound 4 from a compound 7, an acetic acid and sodium triacetoxyborohydride reaction system is adopted, so that the compound 6 is synthesized. And the important intermediate of the givelastat can be obtained with high yield.

Description

Technical Field

[0001] The present invention relates to the technical field of chemical intermediates, and specifically discloses a preparation method of a givinostat intermediate. Background Art

[0002] Givinostat (trade name: Duvyzat) is a histone deacetylase (HDAC) inhibitor, mainly used for the treatment of Duchenne muscular dystrophy (DMD). Givinostat helps improve the symptoms of DMD patients by inhibiting the activity of HDAC, reducing inflammation and muscle loss. This drug was developed by the Italfarmaco pharmaceutical group and was approved by the US Food and Drug Administration (FDA) in March 2024 for the treatment of DMD patients aged 6 and above.

[0003] Among them, the key intermediate for the preparation of givinostat is compound 4, and the preparation methods in the literature and patents are as follows: This route uses 2,6-naphthalenedicarboxylic acid (compound 1. CAS: 1141-38-4) as the starting material, and undergoes a condensation reaction with diethylamine to synthesize 6-(diethylcarbamoyl)-2-naphthoic acid (compound 2. CAS: 199657-45-9). Compound 2 can be synthesized into (6-((diethylamino)methyl)naphthalen-2-yl)methanol (compound 4. CAS: 1429441-33-7) through two routes. The first is to directly reduce compound 2 with lithium aluminum hydride to obtain compound 4, and the reaction yield is 72.6% (WO_2013066835_A2). The second is to first esterify with thionyl chloride to obtain methyl 6-(diethylcarbamoyl)-2-naphthoate (compound 3. 1429441-32-6), and then reduce with borane to obtain compound 4. The two-step yield is 74.7%. The starting material compound 1 of this route has a relatively high market price (3267 yuan / kg), and the first-step condensation yield is relatively low, only 36.9%, which is not conducive to scale-up production. Therefore, developing a low-cost synthesis route has certain market prospects. Summary of the Invention

[0004] In view of the problems existing in the prior art, the first aspect of the present invention proposes a preparation method of a givinostat intermediate, including, Compound 7 which is mixed with acetaldehyde, acetic acid, and a first organic solvent, and sodium triacetoxyborohydride is added, and the temperature is controlled for reaction to obtain the givinostat intermediate compound 4. .

[0005] In some specific embodiments of the method for preparing Compound 4 according to the first aspect, the first organic solvent is selected from one or more of dichloroethane, chloroform, toluene, DMF, acetonitrile, and acetone.

[0006] In some specific embodiments of the method for preparing Compound 4 according to the first aspect, the molar amount of acetaldehyde charged per 1 L of the first organic solvent is 0.20 - 0.30 mol. In some embodiments of preparing Compound 4, the molar amount of acetaldehyde charged per 1 L of the first organic solvent is 0.25 mol.

[0007] In some specific embodiments of the method for preparing Compound 4 according to the first aspect, the molar amount of Compound 7 charged per 1 L of the first organic solvent is 0.04 - 0.06 mol. In some embodiments of preparing Compound 4, the molar amount of Compound 7 charged per 1 L of the first organic solvent is 0.05 mol.

[0008] In some specific embodiments of the method for preparing Compound 4 according to the first aspect, the molar ratio of acetic acid to Compound 7 is (0.15 - 0.30):1. In some embodiments of preparing Compound 4, the molar ratio of acetic acid to Compound 7 is 0.20:1. In some embodiments of preparing Compound 4, the molar ratio of acetic acid to Compound 7 is 0.25:1.

[0009] In some specific embodiments of the method for preparing Compound 4 according to the first aspect, the molar ratio of sodium triacetoxyborohydride charged per 1 L of the first organic solvent is 0.1 - 0.2 mol. In some embodiments of preparing Compound 4, the molar ratio of sodium triacetoxyborohydride charged per 1 L of the first organic solvent is 0.15 mol.

[0010] The second aspect of the present invention provides a method for preparing Compound 7. The synthesis method of Compound 7 includes Compound 6 , wherein Compound 6 is mixed with a second organic solvent and lithium aluminum hydride, and the temperature is controlled during the reaction to obtain Compound 7.

[0011] In some specific embodiments of the method for preparing Compound 7 according to the second aspect, the molar amount of Compound 6 charged per 1 L of the second organic solvent is 45 - 55 mmol. In some specific embodiments of the method for preparing Compound 7 according to the second aspect, the molar amount of Compound 6 charged per 1 L of the second organic solvent is 50 mmol.

[0012] In some specific embodiments of the method for preparing Compound 7 according to the second aspect, the molar amount of lithium aluminum hydride charged per 1 L of the second organic solvent is 0.1 - 0.2 mol.

[0013] In some specific embodiments of the method for preparing Compound 7 according to the second aspect, the temperature control is at 55 - 60 °C. In some specific embodiments of the method for preparing Compound 7 according to the second aspect, the temperature control is at 50 °C.

[0014] The third aspect of the present invention provides a method for preparing Compound 6, and the synthesis mode of Compound 6 includes Compound 5. , Compound 5, a cyano compound, a metal compound, and a third organic solvent are mixed, and the reaction is carried out under temperature control to obtain Compound 6. , R is selected from a hydroxyl protecting group.

[0015] In some specific embodiments of the method for preparing Compound 6 according to the third aspect, the hydroxyl protecting group is selected from any one of Ts, Tf, and Ms.

[0016] In some specific embodiments of the method for preparing Compound 6 according to the third aspect, one or more of elemental zinc, triphenylphosphine, and sodium carbonate are further added to the reaction system.

[0017] In some specific embodiments of the method for preparing Compound 6 according to the third aspect, the molar amount of elemental zinc added per 1 L of organic solvent is 500 - 700 mmol. In some specific embodiments of the method for preparing Compound 6 according to the third aspect, the molar amount of elemental zinc added per 1 L of organic solvent is 600 mmol.

[0018] In some specific embodiments of the method for preparing Compound 6 according to the third aspect, the metal compound is selected from any one of nickel chloride, nickel sulfate, and nickel nitrate. In some preferred embodiments of the method for preparing Compound 6 according to the third aspect, the molar amount of the metal compound added per 1 L of organic solvent is 10 - 20 mmol. In some further preferred embodiments of the method for preparing Compound 6 according to the third aspect, the third organic solvent is selected from acetonitrile.

[0019] In some specific embodiments of the method for preparing Compound 6 according to the third aspect, the cyano compound is selected from any one or a combination of zinc cyanide, potassium ferricyanide, cuprous cyanide, and acetonitrile.

[0020] In some specific embodiments of the method for preparing Compound 6 according to the third aspect, the metal compound is selected from any one or a combination of nickel chloride, tetrakis(triphenylphosphine)palladium, [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium, and cuprous iodide.

[0021] In some specific embodiments of the method for preparing Compound 6 according to the third aspect, the third organic solvent is selected from any one or more of acetonitrile, DMF, tetrahydrofuran, and toluene.

[0022] In some specific embodiments of the method for preparing Compound 6 of the third aspect, the molar amount of the cyano compound added to each 1 L of the third organic solvent is 10 to 100 mmol. In some specific embodiments of the method for preparing Compound 6 of the third aspect, the molar amount of the cyano compound added to each 1 L of the third organic solvent is 50 mmol.

[0023] In some specific embodiments of the method for preparing Compound 6 of the third aspect, the molar amount of the metal compound added to each 1 L of the third organic solvent is 10 to 20 mmol. In some specific embodiments of the method for preparing Compound 6 of the third aspect, the molar amount of the metal compound added to each 1 L of the third organic solvent is 15 mmol.

[0024] In the present invention, in some embodiments, the room temperature is 10 to 40 °C. In some embodiments, the room temperature is 15 to 35 °C. In some embodiments, the room temperature is 20 to 30 °C. In some embodiments, the room temperature is 25 °C.

[0025] The present invention Figure 2 In the present invention, the amino group and the hydroxyl group do not show peaks because they belong to active hydrogens. The present invention Figure 3 In the present invention, the hydroxyl group belongs to an active hydrogen and does not show a peak. As an optional way to further reduce costs, the starting material Compound 5 can be conveniently obtained from the relatively inexpensive 2-hydroxy-6-naphthoic acid (CAS: 16712-64-4, 141 yuan / kg) through two-step reactions.

[0026] 。

[0027] The medicaments used in the present invention are all purchased from publicly legal markets and have not been further purified.

[0028] Advantages of the present invention: The intermediate compound 4 of gevastatin is synthesized from the cheap compound 5 through three-step reactions by a method different from the prior art, with a high yield and being more conducive to industrial scale-up production compared to the prior art. As an optional way to further reduce costs, reference can be made to the prior art including but not limited to CN107108631B. Compound 5 is synthesized from the cheaper CAS: 16712-64-4 through CAS: 17295-11-3, and then by the method of the present invention, compound 5 is used as a substrate to synthesize compound 4 through one step or multiple steps. In the process of synthesizing compound 6 from compound 5, the reaction system of the present invention can use acetonitrile as a cyanide source to carry out a coupling reaction on the activated hydroxyl group, instead of using traditional metal cyanides. Or in some processes of synthesizing compound 6 from compound 5, the present invention uses a system of cheap cuprous cyanide and cuprous iodide for the coupling reaction, which is low in cost compared to precious metals. In the process of synthesizing compound 4 from compound 7, a common bulk chemical raw material acetic acid and sodium triacetoxyborohydride reaction system is used to obtain an important intermediate of gevastatin in a high yield. BRIEF DESCRIPTION OF THE DRAWINGS

[0029] Figure 1 Show the 1H NMR spectrum of compound 6; Figure 2 Show the 1H NMR spectrum of compound 7; Figure 3 Show the 1H NMR spectrum of compound 4. DETAILED DESCRIPTION OF THE EMBODIMENTS

[0030] In order to enable those skilled in the art to better understand the technical solutions of the present invention, some non-limiting embodiments are further disclosed below to further elaborate on the present invention.

[0031] Synthesis route of the intermediate of gevastatin

[0032] The present invention starts from compound 5, couples a cyano group in one step to obtain compound 6, then reduces it in one step to obtain compound 7, and then performs reductive amination in one step to obtain compound 4. The operation is simple, and the yield of each step is above 80%, which is easy to scale up the synthesis.

[0033] Example 1

[0034] Dissolve anhydrous nickel chloride (15 mmol) and triphenylphosphine (30 mmol) in 1000 mL of anhydrous acetonitrile. After evacuating and replacing with nitrogen three times, stir at room temperature for 30 minutes. Then add zinc powder (600 mmol, 2.0 eq.), and stir at room temperature for 10 minutes. Add methyl 6-(((trifluoromethyl)sulfonyl)oxy)-2-naphthoate (300 mmol) and acetic acid (150 mmol), and heat the reaction system to 70 - 80 °C and stir for 24 hours. After cooling, add 2500 mL of water to the reaction system, extract with ethyl acetate (500 mL) three times, combine the organic phases, wash with saturated brine (500 mL) three times, dry the organic phase with anhydrous sodium sulfate, filter by suction, and then concentrate to obtain a crude product as a pale yellow solid. The crude product is purified by column chromatography with PE / EA = 15:1 to obtain compound 6 (white solid, 80% yield).

[0035] Example 2

[0036] At room temperature, add compound 5 (1 mmol), zinc cyanide (2 mmol, 2.0 eq.), and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium (0.3 mmol) to a reaction flask. Then add 20 mL of anhydrous DMF and evacuate and replace with nitrogen three times. Heat the reaction system to 130 °C under nitrogen protection and stir for 8 hours. Monitor the reaction by TLC until the raw materials are completely converted. After cooling, add 50 mL of water to the reaction system, extract with ethyl acetate (50 mL) three times, combine the organic phases, wash with saturated brine (50 mL) three times, dry the organic phase with anhydrous sodium sulfate, filter by suction, and then concentrate to obtain a crude product as a pale yellow solid. The crude product is purified by column chromatography with PE / EA = 15:1 to obtain compound 6 (white solid, 90% yield).

[0037] Example 3

[0038] At room temperature, add compound 5 (1 mmol), zinc cyanide (2 mmol, 2.0 eq.), and tetrakis(triphenylphosphine)palladium (0.3 mmol) to a reaction flask. Add 20 mL of anhydrous DMF and evacuate and replace with nitrogen three times. Heat the reaction system to 130 °C under nitrogen protection and stir for 8 hours. Monitor the reaction by TLC until the raw materials are completely converted. After cooling, add 50 mL of water to the reaction system, extract with ethyl acetate (50 mL) three times, combine the organic phases, wash with saturated brine (50 mL) three times, dry the organic phase with anhydrous sodium sulfate, filter by suction, and then concentrate to obtain a crude product as a pale yellow solid. The crude product is purified by column chromatography with PE / EA = 15:1 to obtain compound 6 (white solid, 92% yield).

[0039] Example 4

[0040] At room temperature, compound 5 (1 mmol), potassium ferricyanide (2 mmol, 2.0 eq.), sodium carbonate (1 mmol), and tetrakis(triphenylphosphine)palladium (0.3 mmol) were added to a reaction flask. After adding 20 mL of anhydrous DMF, the mixture was evacuated and purged with nitrogen three times. The reaction system was heated to 130 °C under nitrogen protection and stirred for 8 hours. TLC analysis showed complete conversion of the starting materials. After cooling, 50 mL of water was added to the reaction system, and the mixture was extracted three times with ethyl acetate (50 mL). The organic phases were combined, washed three times with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain a crude product as a pale yellow solid. The crude product was purified by column chromatography on silica gel with PE / EA = 15:1 to give compound 6 (white solid, 86% yield).

[0041] Example 5

[0042] At room temperature, compound 5 (1 mmol), potassium ferricyanide (2 mmol, 2.0 eq.), sodium carbonate (1 mmol), and dichlorobis(diphenylphosphino)ferrocene palladium(II) (0.3 mmol) were added to a reaction flask. After adding 20 mL of anhydrous DMF, the mixture was evacuated and purged with nitrogen three times. The reaction system was heated to 130 °C under nitrogen protection and stirred for 8 hours. TLC analysis showed complete conversion of the starting materials. After cooling, 50 mL of water was added to the reaction system, and the mixture was extracted three times with ethyl acetate (50 mL). The organic phases were combined, washed three times with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain a crude product as a pale yellow solid. The crude product was purified by column chromatography on silica gel with PE / EA = 15:1 to give compound 6 (white solid, 82% yield).

[0043] Example 6

[0044] At room temperature, compound 5 (1 mmol), cuprous cyanide (2 mmol, 2.0 eq.), and cuprous iodide (0.3 mmol) were added to a reaction flask. After adding 20 mL of anhydrous DMF, the mixture was evacuated and purged with nitrogen three times. The reaction system was heated to 130 °C under nitrogen protection and stirred for 8 hours. TLC analysis showed complete conversion of the starting materials. After cooling, 50 mL of water was added to the reaction system, and the mixture was extracted three times with ethyl acetate (50 mL). The organic phases were combined, washed three times with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain a crude product as a pale yellow solid. The crude product was purified by column chromatography on silica gel with PE / EA = 15:1 to give compound 6 (white solid, 72% yield).

[0045] Example 7

[0046] At room temperature, compound 6 (1.0 mmol) was added to a reaction flask, 20 mL of anhydrous tetrahydrofuran was added, and lithium aluminum hydride (3.0 mmol) was added under an ice bath. Subsequently, the reaction solution was heated to 60 °C and stirred overnight. LCMS detected that the raw material was completely converted. The reaction was quenched by slowly dropping 15% aqueous sodium hydroxide solution under an ice bath. After filtration through diatomaceous earth, the mixture was extracted three times with ethyl acetate. The organic phases were combined, concentrated under reduced pressure to obtain the crude product of compound 7. The crude product was purified by column chromatography with DCM / CH3OH = 10:1 - 5:1 to obtain compound 7 (white solid, 90% yield).

[0047] Example 8

[0048] At room temperature, compound 6 (1.0 mmol) was added to a reaction flask, 20 mL of anhydrous tetrahydrofuran was added, and borane dimethyl sulfide solution (4.0 mmol) was added under an ice bath. Subsequently, the reaction solution was heated to 60 °C and stirred overnight. LCMS detected that the raw material was completely converted. The reaction was quenched by slowly dropping methanol solution under an ice bath. After concentration under reduced pressure, the crude product of compound 7 was obtained. The crude product was purified by column chromatography with DCM / CH3OH = 10:1 - 5:1 to obtain compound 7 (white solid, 92% yield). Example 9 Step 3: Synthesis of compound 4

[0049] At room temperature, compound 7 (2.0 mmol), acetaldehyde (10 mmol) and 1,2 - dichloroethane (40 mL) were added to a single - necked flask. Subsequently, a catalytic amount of acetic acid (0.2 eq.) was added, and then sodium triacetoxyborohydride (6.0 mmol) was added to the reaction solution. The reaction solution was continuously stirred at room temperature. After confirmation by LCMS that the raw materials had completely reacted, the reaction was quenched by adding saturated aqueous sodium carbonate solution. The mixture was extracted three times with dichloromethane (100 mL). The organic phases were combined, washed three times with saturated brine (200 mL), the organic phase was dried over anhydrous sodium sulfate, filtered, and then concentrated to obtain the crude product. The crude product was purified by column chromatography to obtain compound 4 (anhydrous oily liquid, yield 95%).

[0050] The above - mentioned are only the preferred embodiments of the present invention and are not intended to limit the present invention. Any modifications, equivalent replacements, improvements, etc. made within the spirit and principles of the present invention shall be included within the protection scope of the present invention.

Claims

1. A method for preparing the intermediate of gevestrant shown in Formula 4, characterized in that, including, Compound 7 is mixed with acetaldehyde, acetic acid, and a first organic solvent, and sodium triacetoxyborohydride is added. The reaction is carried out under temperature control to obtain the intermediate compound 4 of gevestrant. 。 2. The preparation method of the gevestrant intermediate according to claim 1, characterized in that, The first organic solvent is selected from one or more of dichloroethane, chloroform, toluene, DMF, acetonitrile, and acetone, and / or the molar amount of acetaldehyde fed per 1 L of the first organic solvent is 0.20 - 0.30 mol, and / or the molar amount of compound 7 fed per 1 L of the first organic solvent is 0.04 - 0.06 mol, and / or the molar ratio of acetic acid to compound 7 is (0.15 - 0.30):1, and / or the molar ratio of sodium triacetoxyborohydride fed per 1 L of the first organic solvent is 0.1 - 0.2 mol.

3. The preparation method of the gevestrant intermediate shown by formula 4 according to any one of claims 1 or 2, characterized in that The synthetic method of compound 7 includes mixing compound 6 with a second organic solvent and lithium aluminum hydride, and carrying out the reaction under temperature control to obtain compound 7. 。 4. The preparation method of the Givestat intermediate according to claim 3, characterized in that, The molar amount of compound 6 fed per 1 L of the second organic solvent is 45 - 55 mmol, and / or the molar amount of lithium aluminum hydride fed per 1 L of the second organic solvent is 0.1 - 0.2 mol, and / or the temperature for temperature control is 55 - 60 °C.

5. A method for preparing the Givinostat intermediate shown in Formula 6, characterized in that, The synthetic method of compound 6 includes mixing compound 5, a cyano compound, a metal compound, and a third organic solvent, and carrying out the reaction under temperature control to obtain compound 6. ， wherein R is selected from hydroxyl protecting groups.

6. The preparation method of the Givinostat intermediate according to claim 5, characterized in that, The hydroxyl protecting group is selected from any one of Ts, Tf, and Ms.

7. The preparation method of the Givestat intermediate according to any one of claims 5 or 6, characterized in that, One or more of elemental zinc, triphenylphosphine, and sodium carbonate are further added to the reaction system.

8. The preparation method of the Givinostat intermediate according to claim 7, wherein, The molar amount of elemental zinc fed per 1 L of the organic solvent is 500 - 700 mmol, and / or the metal compound is selected from any one of nickel chloride, nickel sulfate, and nickel nitrate. Preferably, the molar amount of the metal compound fed per 1 L of the organic solvent is 10 - 20 mmol. Further preferably, the third organic solvent is selected from acetonitrile.

9. The preparation method of the givinostat intermediate according to any one of claims 5 to 7, characterized in that, The cyano compound is selected from any one or combination of zinc cyanide, potassium ferricyanide, cuprous cyanide, and acetonitrile, and / or the metal compound is selected from any one or combination of nickel chloride, tetrakistriphenylphosphine palladium, [1,1'-bis(diphenylphosphino)ferrocene] dichloropalladium, and copper iodide, and / or the third organic solvent is selected from one or more of acetonitrile, DMF, tetrahydrofuran, and toluene, and / or the molar amount of the cyano compound fed per 1 L of the third organic solvent is 10 - 100 mmol, and / or the molar amount of the metal compound fed per 1 L of the third organic solvent is 10 - 20 mmol.

10. A preparation method of the Givinostat intermediate shown in Formula 4, characterized in that, as follows: 。

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