A ribociclib intermediate and its preparation method

Abstract

The present invention relates to a ribociclib intermediate compound and a preparation method thereof, which has the advantages of cheap raw and auxiliary materials, high atom economy, green and safe, high substrate universality, simple process operation, and suitability for industrial production, and has great potential in this field.

Description

Technical Field

[0001] The present invention belongs to the field of pharmaceutical chemicals, and specifically relates to a ribociclib intermediate and a preparation method. Background Art

[0002] The chemical name of Ribociclib is succinic acid-7-cyclopentyl-N,N-dimethyl-2-{[5-(piperazin-1-yl)-piperidin-2-yl]amino}-7H-pyrrolo[2,3-d]pyrimidine-6-carboxamide, and its specific structural formula is as follows:

[0003] .

[0004] Prior art reports indicate that there are currently two main methods for synthesizing ribociclib. Patent WO2012064805 utilizes compound A10 and cyclopentylamine A11 for aromatic nucleophilic substitution to yield compound A20. Compound A20 undergoes a Sonogashira reaction to yield compound A30. Compound A30 is then cyclized in the presence of TBAF to yield compound A40. Compound A40 is then treated with MnO2, NaCN, and dimethylamine hydrochloride to yield compound A50. Compound A50 and side chain compound A51 undergo a Buchwald-Hartwig amination reaction to yield compound A60. Finally, the Boc protecting group is removed in the presence of HCl to yield ribociclib. Two steps in this route utilize expensive metal Pd catalysts, resulting in high material costs. Furthermore, the oxidation of alcohols to amides utilizes a large amount of solid manganese dioxide as an oxidant, making process scale-up inconvenient. Furthermore, the use of highly toxic sodium cyanide creates significant operator risks. Furthermore, the reaction equipment and waste gas treatment must meet very high standards, hindering scale-up.

[0005] .

[0006] Patent CN 106749259 B uses compound B10 as a raw material, and obtains compound B20 through ester reduction of alcohol. Compound B20 is oxidized to an aldehyde group through a hydroxyl group to obtain compound B30. Compound B30 undergoes an aromatic nucleophilic substitution reaction to produce compound B40. Compound B40 undergoes nucleophilic addition dehydration to a pyrrole ring and then adds water, and is hydrolyzed to produce compound B50. Compound B50 undergoes amide condensation in the presence of a condensing agent to obtain compound B60. Compound B60 undergoes a thioether oxidation reaction to produce a sulfone compound B70. Compound B70 undergoes an aromatic nucleophilic substitution reaction to obtain compound B80. Finally, compound B80 is de-Bocated under acidic conditions to produce ribociclib. In the preparation of compound B50, this synthetic route uses flammable diisobutylaluminum hydride to reduce the ester group of B10 to a hydroxyl group, posing a high operational risk. Manganese dioxide is then used to reduce the hydroxyl group to an aldehyde group, yielding compound B30, generating significant solid waste. Step B50 utilizes sodium hydride, generating hydrogen gas during production, posing a safety risk. During the synthesis of B50, the ester group of B10 is reduced to the corresponding alcohol, which is then oxidized to an aldehyde. This aldehyde then undergoes intramolecular cyclization to yield B50. This entire process suffers from poor atom economy, lengthy reaction steps, and low efficiency. The expensive reagents used in steps B60 and B70, ECDI, HOBT, and m-chloroperbenzoic acid, respectively, make them unsuitable for industrial production.

[0007] .

[0008] Patent CN108586356 B uses compounds B10 and B11 as raw materials, undergoing aromatic nucleophilic substitution to produce compound B20. Compound B20 undergoes intramolecular substitution in the presence of tert-butyl alcohol to produce compound B30, which is then reduced with sodium borohydride to produce compound B40. Compound B40 reacts with methanesulfonyl chloride to form a sulfonate, which is then eliminated to form a pyrrole ring to produce compound B50. This route uses compound B10 as the raw material, which is expensive. The two chlorine substitutions in B10 during the preparation of B20 present selectivity issues, significantly impacting product purification and quality control. The use of methanesulfonyl chloride in the preparation of B50 is highly toxic and has a foul odor, and the reaction produces genotoxic impurities, hindering quality control. The expensive metal Pd catalyst used in the preparation of B60 is also costly.

[0009] .

[0010] Therefore, it is necessary to develop a simpler, more efficient, more environmentally friendly, more economical and more advantageous synthetic route to prepare Ribociclib. Summary of the Invention

[0011] In order to overcome the above-mentioned shortcomings of the prior art, the present invention provides a method for preparing a ribociclib intermediate compound:

[0012] On the one hand, the present invention provides a ribociclib intermediate compound of formula A, the specific structure of which is:

[0013] ,

[0014] Wherein, R1 is hydrogen, formyl, , , R2 is hydrogen, an amino protecting group; R3 is an alkoxy group, a dimethylamino group; and R4 is a C1-C6 alkyl group. The amino protecting group is tert-butyloxycarbonyl, benzyloxycarbonyl, benzyl, acetyl, formyl, benzoyl, methoxycarbonyl, ethoxycarbonyl, trifluoroacetyl, methanesulfonyl, or p-toluenesulfonyl.

[0015] The present invention provides a ribociclib intermediate compound of formula A having the structures of the following compounds of formula A1 and formula A3:

[0016] ,

[0017] Wherein, in the compound of formula A1, R2 is an amino protecting group, R3 is an alkoxy group, a dimethylamino group; in the compound of formula A3, R1 is a formyl group, , , , R2 is an amino protecting group, and R4 is a C1~C6 alkyl group.

[0018] Preferably, the ribociclib intermediate compound of formula A provided by the present invention has the following structure:

[0019] , , , .

[0020] Another aspect of the present invention provides a method for preparing a compound of formula A, an intermediate of ribociclib, wherein the compound of formula A30 is prepared by a substitution reaction and a selective condensation reaction under alkaline conditions to obtain the compound of formula A. The reaction equation is as follows:

[0021] .

[0022] Wherein, R1 is hydrogen, formyl, , , ; R2 is hydrogen, an amino protecting group; R3 is an alkoxy group, a dimethylamino group; R4 is a C1~C6 alkyl group.

[0023] The present invention provides a method for preparing a ribociclib intermediate compound of formula A, comprising preparing a compound of formula A by condensation reaction of a compound of formula A40 under alkaline conditions, and the reaction equation is as follows:

[0024] .

[0025] Wherein, R1 is formyl, , , ; R2 is an amino protecting group; R3 is an alkoxy group, a dimethylamino group; R4 is a C1~C6 alkyl group.

[0026] The condensation reaction is carried out in the presence of a base, and the base is preferably lithium diisopropylamide (LDA), lithium bistrimethylsilylamide (Li-HMDS), sodium bistrimethylsilylamide (Na-HMDS), potassium bistrimethylsilylamide (K-HMDS), lithium methoxide, sodium methoxide, sodium ethoxide, lithium tert-butoxide, sodium tert-butoxide, potassium tert-butoxide.

[0027] The condensation reaction is carried out in the presence of a condensation reaction reagent, which is methyl formate, ethyl formate, propyl formate, tert-butyl formate, trimethyl orthoformate or triethyl orthoformate; preferably methyl formate, ethyl formate, propyl formate, or tert-butyl formate.

[0028] The organic solvent can be toluene, methyl tert-butyl ether, tetrahydrofuran, 2-methyltetrahydrofuran, dichloromethane, chloroform, carbon tetrachloride, n-hexane, n-heptane; preferably, it can be tetrahydrofuran, dichloromethane, 2-methyltetrahydrofuran, chloroform.

[0029] Secondly, the present invention also provides a method for preparing an intermediate compound of formula A40, which is obtained by a substitution reaction of a compound of formula 30 and a compound of formula B8 under alkaline conditions:

[0030]

[0031] Among them, R2 is an amino protecting group; R3 is an alkoxy group, a dimethylamino group.

[0032] The reaction is carried out in the presence of a strong base, wherein the base is lithium diisopropylamide (LDA), lithium bistrimethylsilylamide (Li-HMDS), sodium bistrimethylsilylamide (Na-HMDS), potassium bistrimethylsilylamide (K-HMDS), lithium methoxide, sodium methoxide, sodium ethoxide, lithium tert-butoxide, sodium tert-butoxide, potassium tert-butoxide; preferably sodium bistrimethylsilylamide.

[0033] In some specific embodiments, the intermediate compound of formula A30 can be obtained by a substitution reaction of a compound of formula 20 and a compound of formula 21 under alkaline conditions:

[0034] ,

[0035] The base can be cesium carbonate, potassium carbonate, sodium carbonate, lithium carbonate, potassium bicarbonate, sodium bicarbonate, potassium acetate, sodium acetate, sodium cyanate, potassium cyanate, potassium phosphate, disodium hydrogen phosphate, preferably potassium carbonate, sodium carbonate, sodium bicarbonate, potassium acetate.

[0036] The organic solvent can be toluene, xylene, tetrahydrofuran, 2-methyltetrahydrofuran, dioxane, methanol, ethanol, propanol, isopropanol, n-butanol, tert-butanol, tert-amyl alcohol, acetonitrile, chloroform, carbon tetrachloride; preferably acetonitrile.

[0037] In some embodiments, the intermediate compound of formula A3-1 can be subjected to a ring-closure reaction to obtain a compound of formula A60:

[0038]

[0039] Wherein, R2 is an amino protecting group.

[0040] The reaction is carried out in an acidic environment. The acid can be formic acid, acetic acid, trifluoroacetic acid, benzoic acid, p-nitrobenzoic acid, p-toluenesulfonic acid, methanesulfonic acid, aluminum trichloride, titanium tetrachloride, boron trifluoride etherate, boron trifluoride, tetrahydrofuran, or boron tribromide. Preferably, the acid is acetic acid, trifluoroacetic acid, or benzoic acid. Most preferably, the acid is acetic acid.

[0041] The reaction temperature is preferably 80-110° C., and the reaction time is 15-18 h.

[0042] In some specific embodiments, ribociclib can be subjected to condensation reaction, ring closure reaction, deprotection reaction, and salt formation reaction to obtain the compound ribociclib. The reaction equation is:

[0043] .

[0044] The present invention provides a ribociclib intermediate and a synthesis method, which have the advantages of cheap raw materials, high atom economy, green safety, high substrate universality, simple process operation, and suitability for industrial production, and has great potential in this field. BRIEF DESCRIPTION OF THE DRAWINGS

[0045] Figure 1 Shown is the compound V prepared in Example 3 1 H-NMR spectrum.

[0046] Figure 2 Shown is the compound VII prepared in Example 4 1 H-NMR spectrum.

[0047] Figure 3 Shown is the compound IX prepared in Example 5 1 H-NMR spectrum.

[0048] Figure 4 Shown is the compound V-1 obtained in Example 6 1 H-NMR spectrum.

[0049] Figure 5 Shown is the compound VII-1 prepared in Example 7 1 H-NMR spectrum. DETAILED DESCRIPTION

[0050] In order to further understand the present invention, the preparation method of a ribociclib intermediate compound provided by the present invention is described in detail below with reference to the examples. It should be understood that these examples are only for further illustrating the features of the present invention in detail, and are not intended to limit the scope of the present invention or the scope of the claims of the present invention.

[0051] Example 1:

[0052]

[0053] To a flask, add Compound II (168.12 g, 4.0 eq) and tetrahydrofuran (360 mL, 6 V) and cool to 0°C. Add a solution of Compound I (60.0 g, 1.0 eq) in THF (240 mL, 4 V) dropwise over 1.0 h. After addition, raise the temperature to 30°C and stir at 30°C for 16 h. After the reaction, filter the filtrate, concentrate under reduced pressure until the liquid stops dripping, add DCM (5.0 V), and stir to dissolve. Wash three times with water (3.0 V x 3). Dry the organic phase over sodium sulfate and concentrate under reduced pressure until the liquid stops dripping, yielding 72.81 g of Compound III as an oil, which can be used directly in the next step. The yield is 87%.

[0054] Example 2:

[0055]

[0056] To a flask, compound II (5.60 g, 4.0 eq), toluene (12 mL, 6 V), and potassium carbonate (3.41 g, 1.5 eq) were added dropwise over 0.5 h. The mixture was stirred at 30°C for 16 h. After the reaction, the filtrate was filtered and concentrated under reduced pressure until no liquid remained, yielding 2.66 g of compound III as an oil, which was used directly in the next step. The yield was 95%.

[0057] Example 3:

[0058]

[0059] In a flask, compound III (16.58 g, 1.0 eq), acetonitrile (165.8 mL, 10.0 V), compound IV (14.51 g, 1.0 eq), and K2CO3 (20.19 g, 1.5 eq) were added and stirred. The temperature was raised to 40°C and stirred for 16 hours. After the reaction, the temperature was lowered to 15-25°C and the filtrate was filtered. The filtrate was concentrated under reduced pressure until no liquid was dripped, yielding a crude solid compound V. The crude product was slurried with 5.0 V ethyl acetate / n-heptane (3 V / 7 V) at 15-25°C for 1.0 hour. Filtered and dried to yield 20.2 g of solid compound V, a yield of 73.34%. MS (+ESI): 283.2 (100%, [M+H] + ).

[0060] Example 4:

[0061]

[0062] Under nitrogen, compound V (1.0 g, 1.0 eq), tetrahydrofuran (15 ml, 15 V), and compound VI (1.01 g, 1.03 eq) were added to a flask. The temperature was raised to 35°C and stirred to dissolve. Once dissolved, 1.85 M NaHMDS (3.6 ml, 1.9 eq) was added dropwise over 2.0 h. After the addition, an additional 1.85 M NaHMDS (0.1 eq) was added, and the mixture was stirred at this temperature for 18 h. After the reaction, acetic acid (3.8 eq) in tetrahydrofuran (1 V) was added dropwise with stirring. Water (10 V) was added and stirred. The tetrahydrofuran was concentrated under reduced pressure at 45°C to dryness. After concentration, the mixture was extracted twice with ethyl acetate (10 V x 2). The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to yield crude compound VII. The crude product was slurried with methanol (4 V) for 17 h. Filter and dry to obtain 1.4 g of solid compound VII with a yield of 75.5%. MS (+ESI): 525.5 (100%, [M+H] + ).

[0063] Example 5:

[0064]

[0065] Under nitrogen, add compound VII (2.0 g, 1.0 eq) and tetrahydrofuran (14 mL, 7.0 V) to flask A. Cool the mixture to -20°C, and then add 1.0 M LiHMDS (12.2 mL, 3.2 eq) dropwise. After the addition is complete, incubate at -20°C for 0.5 h to obtain a lithium salt solution of compound VII. Under nitrogen, add tetrahydrofuran (6 mL, 3.0 V) and methyl formate (2.29 g, 10.0 eq) to flask B. Cool the mixture to -20°C, and then add the lithium salt solution of compound VII dropwise over approximately 10 min. After the addition is complete, warm the mixture to 0°C and stir for 2.0 h. After the reaction is complete, add acetic acid (0.96 g, 4.2 eq) in tetrahydrofuran (2 mL, 1 V) dropwise. After the addition is complete, stir, and concentrate under reduced pressure until no more liquid remains, yielding 3.32 g of crude compound VIII. Under nitrogen, crude compound VIII (1.0 g, 1.0 eq) and 10 ml of acetic acid (10.0 V) were added to flask C. The temperature was raised to 90°C and stirred for 16 hours. After the reaction, the mixture was concentrated under reduced pressure until the liquid stopped dripping, yielding the crude product. Column chromatography purification afforded 0.33 g of compound IX, a two-step yield of 54%. MS (+ESI): 535.5 (100%, [M+H] + ).

[0066] Example 6:

[0067]

[0068] Compound III-1 (1.0 g, 1.0 eq) was used to replace compound III, and the reaction was carried out according to the process of Example 3 to obtain the target product V-1. MS (+ESI): 284.2 (100%, [M+H] + ).

[0069] Example 7:

[0070]

[0071] Compound V-1 (0.5 g, 1.0 eq) was used to replace compound V, and the reaction was carried out according to the process of Example 4 to obtain the target product VII-1.

Claims

1. A compound of formula A, an intermediate of Ribociclib, characterized in that: The structural formula is: Wherein, R1 is hydrogen, formyl or R2 is hydrogen, tert-butyloxycarbonyl, benzyloxycarbonyl, benzyl, acetyl, formyl, benzoyl, methoxycarbonyl, ethoxycarbonyl, trifluoroacetyl, methanesulfonyl or p-toluenesulfonyl; R3 is dimethylamino.

2. The ribociclib intermediate compound of formula A according to claim 1, characterized in that The Ribociclib intermediate compound of formula A has the structure of the following compound of formula A1 or formula A3: Wherein, R1 is formyl or R2 is tert-butyloxycarbonyl, benzyloxycarbonyl, benzyl, acetyl, formyl, benzoyl, methoxycarbonyl, ethoxycarbonyl, trifluoroacetyl, methanesulfonyl or p-toluenesulfonyl; R3 is dimethylamino.

3. The compound of formula A, an intermediate of Riboxil according to claim 1, is characterized in that: The structural formula is:

4. A method for preparing a compound of formula A, an intermediate of Ribociclib, characterized in that: The compound of formula A40 is prepared by condensation reaction under alkaline conditions to obtain the compound of formula A. The reaction equation is as follows: Wherein, R1 is formyl or R2 is tert-butyloxycarbonyl, benzyloxycarbonyl, benzyl, acetyl, formyl, benzoyl, methoxycarbonyl, ethoxycarbonyl, trifluoroacetyl, methanesulfonyl or p-toluenesulfonyl; R3 is dimethylamino.

5. The preparation method according to claim 4, characterized in that The condensation reaction is carried out in the presence of a condensation reaction reagent, which is methyl formate, ethyl formate, propyl formate, tert-butyl formate, trimethyl orthoformate or triethyl orthoformate.

6. A method for preparing a compound of formula A40, characterized in that: The compound of formula A40 is prepared by a substitution reaction between the compound of formula A30 and the compound of formula B8 under alkaline conditions. The reaction equation is as follows: Wherein, R2 is tert-butyloxycarbonyl, benzyloxycarbonyl, benzyl, acetyl, formyl, benzoyl, methoxycarbonyl, ethoxycarbonyl, trifluoroacetyl, methanesulfonyl or p-toluenesulfonyl; and R3 is dimethylamino.

7. A method for preparing a compound of formula A60, characterized in that: The compound of formula A3-1 is subjected to a ring-closure reaction under acidic conditions to obtain the compound of formula A60. The reaction equation is as follows: Wherein, R2 is tert-butyloxycarbonyl, benzyloxycarbonyl, benzyl, acetyl, formyl, benzoyl, methoxycarbonyl, ethoxycarbonyl, trifluoroacetyl, methylsulfonyl or p-toluenesulfonyl.

8. The preparation method according to claim 7, characterized in that The acid is formic acid, acetic acid, trifluoroacetic acid, benzoic acid, p-nitrobenzoic acid, p-toluenesulfonic acid or methanesulfonic acid.

9. A method for preparing Ribociclib, characterized in that: The compound Ribociclib is obtained through condensation reaction, ring closure reaction, deprotection reaction, and salt formation reaction. The reaction equation is:

10. A compound of formula VII-1, characterized in that The structural formula is:

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