Preparation Method and Use of a Ribociclib Intermediate

Abstract

The present invention relates to a preparation method and use of a ribociclib intermediate, specifically, the compound of formula A6 is prepared by a substitution reaction of the compound of formula A3 and the compound of formula B under the action of an acid-binding agent, selectively followed by a thiolation reaction, selectively followed by a condensation reaction, and then a ring-closing reaction. The compound of formula A6 of the present invention is prepared into ribociclib after an oxidation reaction, a substitution reaction, a deprotection reaction and a salt formation reaction, which is a process route with significant technical advantages, high reaction efficiency and industrial application prospects.

Description

Technical Field

[0001] The present invention belongs to the field of pharmaceutical chemistry, and relates to a preparation method and use of an intermediate for ribociclib. 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 the specific structural formula is as follows:

[0003] 。

[0004] There are currently two main methods reported in the prior art for synthesizing ribociclib.

[0005] Patent WO2012064805 reports that compound Al0 and cyclopentylamine A11 undergo an aromatic nucleophilic substitution reaction to obtain compound A20. Compound A20 undergoes a Sonogashira reaction to obtain compound A30. Subsequently, compound A30 is cyclized under the action of TBAF to obtain compound A40. Subsequently, compound A40 is obtained under the action of MnO2, NaCN, and dimethylamine hydrochloride to obtain compound A50. Compound A50 and the side chain compound A51 undergo a Buchwald-Hartwig amination reaction to obtain compound A60. Finally, the Boc protecting group is removed in the presence of HCl to obtain ribociclib. In this route, expensive metal Pd catalysts are used in two steps of the reaction, and the material cost is relatively high. In addition, a large amount of solid manganese dioxide is used as an oxidant in the process of oxidizing alcohol to prepare amide, which is inconvenient for process scale-up operation. Moreover, highly toxic sodium cyanide is used, which not only poses great danger to workers during operation, but also requires very high standards for reaction equipment, waste liquid and waste gas treatment, and is not conducive to industrial scale-up.

[0006] 。

[0007] Patent CN 106749259 B reports that using compound B10 as the raw material, compound B20 is obtained through an ester reduction to alcohol reaction. Compound B20 is oxidized from a hydroxyl group to an aldehyde group to obtain compound B30. Compound B30 undergoes an aromatic nucleophilic substitution reaction to generate compound B40. Compound B40 undergoes a nucleophilic addition and dehydration to form a pyrrole ring and then water is added. Through ester hydrolysis, compound B50 is obtained. In the presence of a condensing agent, compound B50 undergoes amide condensation to obtain compound B60. Compound B60 undergoes a thioether oxidation reaction to generate a sulfone compound B70. Compound B70 undergoes an aromatic nucleophilic substitution reaction to obtain compound B80. Finally, under acidic conditions, compound B80 removes Boc to generate ribociclib. In the process of preparing compound B50 in this synthetic route, flammable diisobutylaluminum hydride is used to reduce the ester group of B10 to a hydroxyl group, and the process operation risk is high. Then, manganese dioxide is used to reduce the hydroxyl group to an aldehyde group to obtain compound B30, and a large amount of solid waste is generated in this step of operation. Secondly, sodium hydride is used in the B50 step, and hydrogen is generated during production, posing a safety risk. Moreover, in the synthesis process of B50, the ester group of B10 is reduced to the corresponding alcohol, and this alcohol is oxidized to an aldehyde. This aldehyde then undergoes intramolecular cyclization to obtain B50. The entire process has poor atom economy, long reaction steps, and low synthesis efficiency. In the B60 step and the B70 step, ECDI, HOBT, and m-chloroperoxybenzoic acid are used respectively. These three reagents are expensive and not suitable for industrial production.

[0008] 。

[0009] Patent CN 108586356 B reports that using compounds B10 and B11 as raw materials, compound B20 is generated through an aromatic nucleophilic substitution reaction. Compound B20 undergoes an intramolecular substitution reaction in the presence of tert-butanol to generate compound B30. Compound B30 is reduced by sodium borohydride to obtain compound B40. After compound B40 forms a sulfonate ester with methanesulfonyl chloride, it undergoes elimination to form a pyrrole ring to obtain compound B50. First of all, the reaction raw material compound B10 in this route is expensive and not easily available. There is a selectivity problem in the two chlorine substitutions in B10 during the preparation of B20, which has a substantial impact on the purification and quality control of the product. Methanesulfonyl chloride is used in the preparation of B50 step. It is highly toxic and has a foul smell, and the reaction will generate genotoxic impurities, which is not conducive to quality control. An expensive metal Pd catalyst is used in the preparation of B60 step, and the cost is relatively high.

[0010] 。

[0011] Therefore, it is necessary to develop a simpler, more efficient, more environmentally friendly, highly economical synthetic route with significant advantages to prepare ribociclib. Summary of the Invention

[0012] Aiming at the deficiencies existing in the prior art, the purpose of the present invention is to provide an intermediate of ribociclib and a preparation method of ribociclib, which solves the problems in the prior art such as great operation danger, expensive reagent cost, affecting the yield, etc., and is not conducive to industrialized scale production.

[0013] The present invention firstly provides a compound of formula A, and the specific structural formula is:

[0014] ,

[0015] wherein, R1 is chlorine or C1-C12-alkylthio; R2 is hydrogen, formyl, , or ; R4 is C1-C6 alkyl; R3 is alkoxy or dimethylamino.

[0016] Furthermore, a compound of formula A5 is provided, and the structural formula is:

[0017] ,

[0018] wherein, R1 is C1-C12-alkylthio; R2 is formyl, , or ; R3 is alkoxy or dimethylamino; R4 is C1-C6 alkyl.

[0019] Furthermore, a compound of formula A4 and a compound of formula A8 are provided, and the structural formulas are:

[0020] , ,

[0021] wherein, R1 is C1-C12-alkylthio; R3 is alkoxy or dimethylamino;

[0022] wherein, when R1 is Cl, R2 is hydrogen; R3 is dimethylamino, it is a compound of formula A80, and the structural formula is:

[0023] ;

[0024] wherein, when R1 is methylthio, R2 is hydrogen; R3 is dimethylamino, it is a compound of formula A40, and the structural formula is:

[0025] ;

[0026] wherein, when R1 is methylthio, R2 is formyl or ; R3 is dimethylamino; it is a compound of formula A50-1 or A50-2, and the structural formula is:

[0027] 。

[0028] In a second aspect, the present invention provides a method for preparing a compound of formula A, which is an intermediate of ribociclib. Specifically, the compound of formula A is prepared by a substitution reaction of a compound of formula A3 and a compound of formula B under the action of an acid-binding agent:

[0029] ,

[0030] wherein, R1 is chlorine or C1-C12-alkylthio; R2 is hydrogen, formyl, , or ; R4 is C1-C6 alkyl; R3 is alkoxy or dimethylamino.

[0031] Further, a compound of formula A4 is prepared by a substitution reaction of a compound of formula A3 and a compound of formula B0 under the action of an acid-binding agent:

[0032] ,

[0033] wherein, R1 is C1-C12-alkylthio; R3 is alkoxy or dimethylamino.

[0034] Further, a compound of formula A5 is prepared by a substitution reaction of a compound of formula A3 and a compound of formula B under the action of an acid-binding agent:

[0035] ,

[0036] wherein, R1 is C1-C12-alkylthio; R2 is formyl, , or ; R4 is C1-C6 alkyl; R3 is alkoxy or dimethylamino.

[0037] Further, a compound of formula A8 is prepared by a substitution reaction of a compound of formula A31 and a compound of formula B0 under the action of an acid-binding agent:

[0038] ,

[0039] wherein, R1 is chlorine and R3 is alkoxy or dimethylamino.

[0040] Furthermore, a compound of formula A40 is prepared by a substitution reaction of a compound of formula A30 and a compound of formula B-1 under the action of an acid-binding agent:

[0041] ;

[0042] Furthermore, a compound of formula A80 is prepared by a substitution reaction of a compound of formula A31 and a compound of formula B-1 under the action of an acid-binding agent:

[0043] ;

[0044] Among them, the acid-binding agent is potassium carbonate (K2CO3), sodium carbonate, pyridine, diisopropylethylamine (DIPEA) or triethylamine; more preferably, the acid-binding agent is potassium carbonate.

[0045] The substitution reaction solvent can be common organic solvents such as acetonitrile and the like.

[0046] In the third aspect, the present invention provides another method for preparing a compound of formula A4, specifically, the compound of formula A4 is prepared by a thiolation reaction of a compound of formula A8 under the action of a thiolation reagent:

[0047] ,

[0048] Among them, R1 is C1-C12-alkylthio; R3 is an alkoxy group or a dimethylamino group.

[0049] More preferably, the compound of formula A40 is prepared by a thiolation reaction of a compound of formula A80 under the action of a thiolation reagent:

[0050] ,

[0051] Among them, the thiolation reagent is sodium alkyl mercaptide. More preferably, the thiolation reagent is sodium methyl mercaptide or sodium ethyl mercaptide; most preferably, the thiolation reagent is sodium methyl mercaptide.

[0052] The thiolation reaction solvent can be common organic solvents such as N-methylpyrrolidone and the like.

[0053] In the fourth aspect, the present invention provides a method for preparing a compound of formula A6, specifically, the compound of formula A6 is prepared by a condensation reaction and a ring-closing reaction of a compound of formula A4:

[0054] ,

[0055] Among them, R1 is C1-C12-alkylthio; R2 is formyl, , or ; R4 is C1-C6 alkyl; R3 is an alkoxy group or a dimethylamino group.

[0056] More preferably, the compound of formula A60 is prepared by a condensation reaction and a ring-closing reaction of a compound of formula A40:

[0057] .

[0058] Among them, the condensation reaction is carried out in the presence of a condensation reaction reagent, and the condensation reaction reagent is methyl formate, ethyl formate, propyl formate, tert-butyl formate, trimethyl orthoformate or triethyl orthoformate. More preferably, the condensation reaction reagent is methyl formate.

[0059] The condensation reaction is carried out in the presence of a base or an acid. More preferably, the base can be sodium bis(trimethylsilyl)amide (NaHMDS), lithium bis(trimethylsilyl)amide, potassium bis(trimethylsilyl)amide, lithium diisopropylamide or butyllithium; the acid is titanium tetrachloride (TiCl4), aluminum trichloride, iron trichloride, tin tetrachloride or boron trichloride. Most preferably, the base is sodium bis(trimethylsilyl)amide or the acid is titanium tetrachloride.

[0060] The solvent for the condensation reaction can be common organic solvents such as tetrahydrofuran (THF), etc.

[0061] The ring-closing reaction is carried out in the presence of an acid, and the acid is an organic acid or an inorganic acid. More preferably, the organic acid is acetic acid, trifluoroacetic acid or formic acid; the inorganic acid is hydrochloric acid, sulfuric acid or nitric acid, etc. Most preferably, the acid is acetic acid.

[0062] Furthermore, the preparation method of the compound of formula A6 provided by the present invention is to prepare the compound of formula A6 through a substitution reaction, optionally a thiolation reaction, optionally a condensation reaction, and then a ring-closing reaction from the compound of formula A3 and the compound of formula B under the action of an acid-binding agent. The reaction formula is:

[0063] ,

[0064] Among them, R1 is chlorine or C1-C12-alkylthio; R2 is hydrogen, formyl, , or ; R4 is C1-C6 alkyl; R3 is alkoxy or dimethylamino.

[0065] Among them, the optional thiolation reaction means that it can undergo a thiolation reaction or not; among them, the optional condensation reaction means that it can undergo a condensation reaction or not.

[0066] Finally, the present invention provides a preparation method of ribociclib, including the steps of: preparing ribociclib through a substitution reaction, optionally a thiolation reaction, then a condensation reaction, a ring-closing reaction, an oxidation reaction, a substitution reaction, a deprotection reaction and a salt formation reaction from the compound of formula A30 or the compound of formula A31 and the compound of formula B-1. The specific reaction formula is:

[0067] .

[0068] The present invention provides an intermediate of ribociclib, a preparation method thereof and uses thereof. This method is more convenient, simple, efficient and environmentally friendly in operation than the prior art, and also has an advantage in economic cost, which is conducive to industrial production. It also solves the technical problems existing in the prior art and has significant technical advantages. BRIEF DESCRIPTION OF THE DRAWINGS

[0069] Figure 1 The following shows the 1 1H-NMR spectrum of compound A80 prepared in Example 1.

[0070] Figure 2 The following shows the 1 1H-NMR spectrum of compound A40 prepared in Example 2.

[0071] Figure 3 The following shows the 1 1H-NMR spectrum of compound A60 prepared in Example 4.

[0072] Figure 4 The following shows the 1 1H-NMR spectrum of compound A41 prepared in Example 6. DETAILED DESCRIPTION OF THE EMBODIMENTS

[0073] To further understand the present invention, the following detailed description of the preparation method and uses of an intermediate of ribociclib provided by the present invention is given in conjunction with the embodiments. It should be understood that these descriptions of the embodiments are only for further detailed description of the features of the present invention, rather than a limitation on the scope of the present invention or the scope of the claims of the present invention.

[0074] Example 1:

[0075] ,

[0076] In a flask, compound B-1 (16.58 g, 1.0 eq), acetonitrile (165.8 mL, 10.0 V), compound A31 (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 h while maintaining the temperature. After the reaction was completed, the temperature was lowered to 15-25 °C, and the mixture was filtered to obtain a filtrate. The filtrate was concentrated under reduced pressure until no more liquid dropped to obtain a crude product of solid compound A80. The crude product was slurried with 5.0 V of ethyl acetate / n-heptane = 3 V / 7 V at 15-25 °C for 1.0 h. The mixture was filtered and dried to obtain 20.2 g of solid compound A80. The yield was 73%. MS(+ESI): 283.2 (100%, [M+H] + )

[0077] Example 2:

[0078] ,

[0079] Add compound A80 (20 g, 1.0 eq), N-methylpyrrolidone (80 mL, 4V), and 20% aqueous sodium methyl mercaptide solution (27.26 g, 1.1 eq) to the flask. Heat the mixture to 75 - 80 °C and stir for 5 h while maintaining the temperature. After the reaction is completed, cool the mixture to room temperature, add ethyl acetate (400 mL, 20V), and wash it four times with 15% aqueous sodium chloride solution (20V * 4). Concentrate the solution under reduced pressure and co-evaporate it once with tetrahydrofuran (5V) to obtain 19.7 g of the crude product. Purify the crude product by column chromatography to obtain 14.7 g of compound A40. Yield: 71%. MS(+ESI): 295.3 (100%, [M+H] + ).

[0080] Example 3:

[0081] ,

[0082] Add compound A30 (0.5 g, 1.0 eq), acetonitrile (5 mL, 10V), compound B-1 (0.53 g, 1.0 eq), and potassium carbonate (0.49 g, 1.5 eq) to the flask. Heat the mixture to 75 - 80 °C and stir for 48 h while maintaining the temperature. Sampling and LCMS detection of the reaction solution show that the purity of compound A40 is 74.0%.

[0083] Example 4:

[0084] ,

[0085] Under nitrogen protection, add compound A40 (0.5 g, 1.0 eq) and THF (2.5 mL, 5.0V) to flask A. Cool the mixture to -20 °C and slowly add 2.0 M NaHMDS (3.74 mL, 2.2 eq). After the addition is complete, maintain the temperature at -20 °C for 0.5 h to obtain a sodium salt solution of compound A40.

[0086] Under nitrogen protection, add THF (5 mL, 10.0V) and methyl formate (1.02 g, 10.0 eq) to flask B. Cool the mixture to -20 °C and slowly add the above sodium salt solution of compound A40 over about 10 min. After the addition is complete, heat the mixture to 0 °C and stir for 2.0 h. After the reaction is completed, add acetic acid (0.33 g, 3.2 eq). After the addition is complete, concentrate the solution under reduced pressure until no more liquid drips to obtain the crude product of compound A50. MS (+ESI): 323.2 (100%, [M+H]+).

[0087] Under nitrogen protection, in flask C, add 50 crude product of compound A and acetic acid (9 mL, 18.0 V). Heat to 100 °C and continue stirring for 19 h. After the reaction is completed, concentrate under reduced pressure until the liquid stops dripping to obtain 60 crude product of compound A. Purify by column chromatography to obtain 0.42 g of compound A60. The yield is 81%. MS(+ESI): 305.2 (100%, [M+H] + )。

[0088] Example 5:

[0089] ,

[0090] Under nitrogen protection, in flask A, add compound A40 (1.0 g, 1.0 eq), DCM (10 ml, 10 V), and ethyl formate (1.51 g, 6.0 eq). Replace the nitrogen three times, cool to 0 °C, and dropwise add TiCl4 (2.57 g, 4.0 eq) / DCM (1 ml, 1 V). After the addition is complete, dropwise add triethylamine (1.65 g, 4.8 eq) / DCM (1 ml, 1 V). After the addition is complete, stir at 0 °C for 1.0 h. After the reaction is completed, quench the reaction solution by dropping it into an aqueous sodium bicarbonate solution at 0 - 10 °C, and filter to obtain the filtrate. The filtrate is separated into an organic phase, dried over anhydrous sodium sulfate, and concentrated under reduced pressure until the liquid stops dripping to obtain 50 crude product of compound A. MS (+ESI): 323.2 (100%, [M+H]+).

[0091] Under nitrogen protection, in flask B, add 50 crude product of compound A and acetic acid (10 mL, 10 V). Heat to 100 °C and continue stirring for 19 h. After the reaction is completed, concentrate under reduced pressure until the liquid stops dripping to obtain 60 crude product of compound A. Purify by column chromatography to obtain 0.91 g of compound A60. The yield is 88%. MS(+ESI): 305.2 (100%, [M+H] + )。

[0092] Example 6:

[0093] ,

[0094] Use compound B-2 (0.53 g, 1.0 eq) to replace compound B-1, and carry out the reaction according to the same method as in Example 3 to obtain product A41. MS (+ESI): 296.2 (100%, [M+H]+).

[0095] Example 7:

[0096] ,

[0097] Use compound A41 (0.5 g, 1.0 eq) to replace compound A40, and carry out the reaction in the same manner as in Example 4. First, obtain the crude product of A51, and then continue the reaction. After post-treatment, the product A61 is obtained.

Claims

1. A ribociclib intermediate of formula A compound, characterized in that, The specific structure is as follows: Among them, R1 is chlorine or C1-C12-alkylthio; R2 is hydrogen, formyl or R3 is an alkoxy group or a dimethylamino group.

2. The compound according to claim 1, wherein The structural formula is: Among them, R1 is chlorine or C1-C12-alkylthio, and R3 is an alkoxy group or dimethylamino group.

3. The compound according to claim 1, characterized in that, The structural formula is:

4. A preparation method of a ribociclib intermediate of formula A compound, characterized in that, The compound of formula A is prepared by the substitution reaction of the compound of formula A3 and the compound of formula B under the action of an acid-binding agent: wherein, R1 is chlorine or C1-C12-alkylthio; R2 is hydrogen, formyl or R3 is an alkoxy group or dimethylamino group.

5. The preparation method according to claim 4, characterized in that, The compound of formula A8 is prepared by the substitution reaction of the compound of formula A3 and the compound of formula B0 under the action of an acid-binding agent: Among them, R1 is chlorine, and R3 is an alkoxy group or dimethylamino group.

6. A method for preparing a compound of formula A4, characterized in that, The compound of formula A4 is prepared by the thiolation reaction of the compound of formula A8 under the action of a thiolation reagent: Among them, R1 is C1-C12-alkylthio; R3 is an alkoxy group or dimethylamino group.

7. A method for preparing a compound of formula A6, characterized in that, The compound of formula A6 is prepared by the condensation reaction and ring-closing reaction of the compound of formula A4: Among them, R1 is C1-C12-alkylthio; R2 is formyl or R3 is an alkoxy group or a dimethylamino group.

8. A method for preparing a compound of formula A6, characterized in that, The compound of formula A6 is prepared by the substitution reaction of the compound of formula A3 and the compound of formula B under the action of an acid-binding agent, optionally by thiolation reaction, optionally by condensation reaction, and then by ring-closing reaction. The reaction formula is: wherein, R1 is chlorine or C1-C12-alkylthio; R2 is hydrogen, formyl or R3 is an alkoxy group or dimethylamino group.

9. The preparation method according to claim 4, 5 or 8, characterized in that, The acid-binding agent is potassium carbonate, pyridine, sodium carbonate, diisopropylethylamine or triethylamine.

10. The preparation method according to claim 6 or 8, characterized in that, The thiolation reagent is sodium alkyl mercaptide.

11. The preparation method according to claim 7 or 8, characterized in that, The condensation reaction is carried out in the presence of a condensation reaction reagent, and the condensation reaction reagent is methyl formate, ethyl formate, propyl formate, tert-butyl formate, trimethyl orthoformate or triethyl orthoformate.

12. The preparation method according to claim 7 or 8, characterized in that, The condensation reaction is carried out in the presence of a base or an acid.

13. The preparation method according to claim 7 or 8, characterized in that, The ring-closing reaction is carried out in the presence of an acid, and the acid is an organic acid or an inorganic acid.

14. A preparation method of ribociclib, characterized in that, It includes the steps of: preparing ribociclib by the substitution reaction of the compound of formula A30 or the compound of formula A31 and the compound of formula B-1, optionally by thiolation reaction, and then by condensation reaction, ring-closing reaction, oxidation reaction, substitution reaction, deprotection reaction and salt formation reaction. The specific reaction formula is:

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