Ribociclib intermediate and preparation method thereof

Abstract

The ribociclib intermediate compound and the preparation method thereof have the advantages that raw materials and auxiliary materials are cheap, atom economy is high, the ribociclib intermediate compound is green and safe, substrate universality is high, technological operation is simple, the ribociclib intermediate compound is suitable for industrial production, and the ribociclib intermediate compound has great potential in the field.

Description

Technical Field

[0001] The present invention belongs to the field of pharmaceutical chemistry, and particularly relates to a ribociclib intermediate and a preparation method thereof. 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] Current reports in the prior art show that there are mainly two methods for synthesizing ribociclib. In Patent WO2012064805, compound Al0 and cyclopentylamine A11 undergo an aromatic nucleophilic substitution reaction to obtain compound A20. Compound A20 is converted to compound A30 through a Sonogashira reaction. Subsequently, compound A30 is cyclized under the action of TBAF to obtain compound A40. Then, compound A40 is reacted 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, resulting in a relatively high material cost. 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, posing a great risk to workers during operation. Also, the reaction equipment, waste liquid, and waste gas treatment need to meet very high standards, which is not conducive to process scale-up.

[0004] 。

[0005] Patent CN 106749259 B uses compound B10 as a raw material, reduces the ester group of B10 to an alcohol group through ester reduction to obtain compound B20, oxidizes the hydroxyl group of compound B20 to an aldehyde group to obtain compound B30, generates compound B40 through aromatic nucleophilic substitution reaction, undergoes nucleophilic addition and dehydration to form a pyrrole ring and then adds water to compound B40, and obtains compound B50 through ester hydrolysis. Compound B50 undergoes amide condensation in the presence of a condensing agent to obtain compound B60. Compound B60 undergoes a sulfide oxidation reaction to generate a sulfone compound B70. Compound B70 undergoes an aromatic nucleophilic substitution reaction to obtain compound B80. Finally, compound B80 removes Boc under acidic conditions to produce 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; manganese dioxide is also 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; sodium hydride is used in the B50 step, and hydrogen is generated during production, posing a safety risk; in the synthesis process of B50, the ester group of B10 is reduced to the corresponding alcohol, and this alcohol is then 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 efficiency. The ECDI, HOBT, and m-chloroperoxybenzoic acid reagents used in the B60 step and the B70 step are expensive and not suitable for industrial production.

[0006] 。

[0007] Patent CN108586356 B uses compounds B10 and B11 as raw materials, generates compound B20 through aromatic nucleophilic substitution, generates compound B30 through intramolecular substitution of compound B20 in the presence of tert-butanol, and then obtains compound B40 through reduction with sodium borohydride. After compound B40 forms a sulfonate ester with methanesulfonyl chloride, it undergoes elimination to form a pyrrole ring to obtain compound B50. The raw material compound B10 in this route is expensive. 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, which is highly toxic and has a foul odor, 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 the B60 step, resulting in a high cost.

[0008] 。

[0009] Therefore, it is necessary to develop a more simple, efficient, environmentally friendly, highly economical synthetic route with significant advantages for the preparation of ribociclib. Summary of the Invention

[0010] In order to overcome the above-mentioned disadvantages of the prior art, the present invention provides a method for preparing an intermediate compound of ribociclib:

[0011] The present invention provides a ribociclib intermediate of formula A compound on the one hand, and the specific structure is: ,

[0012] wherein, R1 is hydrogen, formyl, , , ; R2 is hydrogen, an amino protecting group; R3 is an alkoxy group, dimethylamino; R4 is a C1-C6 alkyl group. The amino protecting group is tert-butoxycarbonyl, benzyloxycarbonyl, benzyl, acetyl, formyl, benzoyl, methoxycarbonyl, ethoxycarbonyl, trifluoroacetyl, methanesulfonyl or p-toluenesulfonyl.

[0013] The ribociclib intermediate of formula A compound provided by the present invention has the structures of the following formula A1 compound and formula A3 compound: ,

[0014] wherein, in the formula A1 compound, R2 is an amino protecting group, R3 is an alkoxy group, dimethylamino; in the formula A3 compound, R1 is formyl, , , , R2 is an amino protecting group, R4 is a C1-C6 alkyl group.

[0015] Preferably, the ribociclib intermediate of formula A compound provided by the present invention has the following structure: , , , .

[0016] On the other hand, the present invention provides a preparation method of a ribociclib intermediate of formula A compound, which is prepared from a compound of formula A30 through a substitution reaction under alkaline conditions and selectively through a condensation reaction to obtain a compound of formula A, and the reaction equation is as follows: .

[0017] wherein, R1 is hydrogen, formyl, , , ; R2 is hydrogen, an amino protecting group; R3 is an alkoxy group, dimethylamino; R4 is a C1-C6 alkyl group.

[0018] The preparation method of a ribociclib intermediate of formula A compound provided by the present invention includes preparing a compound of formula A from a compound of formula A40 through a condensation reaction under alkaline conditions, and the reaction equation is as follows: .

[0019] Among them, R1 is a formyl group, , , ; R2 is an amino protecting group; R3 is an alkoxy group, dimethylamino group; R4 is a C1-C6 alkyl group.

[0020] The condensation reaction is carried out in the presence of a base, and the base is preferably lithium diisopropylamide (LDA), lithium bis(trimethylsilyl)amide (Li-HMDS), sodium bis(trimethylsilyl)amide (Na-HMDS), potassium bis(trimethylsilyl)amide (K-HMDS), lithium methoxide, sodium methoxide, sodium ethoxide, lithium tert-butoxide, sodium tert-butoxide, potassium tert-butoxide.

[0021] 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; preferably methyl formate, ethyl formate, propyl formate, tert-butyl formate.

[0022] The organic solvent can be toluene, methyl tert-butyl ether, tetrahydrofuran, 2-methyltetrahydrofuran, dichloromethane, chloroform, carbon tetrachloride, n-hexane, n-heptane; preferably can be tetrahydrofuran, dichloromethane, 2-methyltetrahydrofuran, chloroform.

[0023] Secondly, the present invention also provides a preparation method of an intermediate formula A40 compound, which is obtained by a substitution reaction of a formula 30 compound and a formula B8 compound under alkaline conditions:

[0024] Among them, R2 is an amino protecting group; R3 is an alkoxy group, dimethylamino group.

[0025] The reaction is carried out in the presence of a strong base, and the base is lithium diisopropylamide (LDA), lithium bis(trimethylsilyl)amide (Li-HMDS), sodium bis(trimethylsilyl)amide (Na-HMDS), potassium bis(trimethylsilyl)amide (K-HMDS), lithium methoxide, sodium methoxide, sodium ethoxide, lithium tert-butoxide, sodium tert-butoxide, potassium tert-butoxide; preferably sodium bis(trimethylsilyl)amide.

[0026] In some specific embodiments, the intermediate formula A30 compound can be obtained by a substitution reaction of a formula 20 compound and a formula 21 compound under alkaline conditions: ,

[0027] 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.

[0028] The organic solvent may be toluene, xylene, tetrahydrofuran, 2-methyltetrahydrofuran, dioxane, methanol, ethanol, propanol, isopropanol, n-butanol, tert-butanol, tert-pentanol, acetonitrile, chloroform, carbon tetrachloride; preferably acetonitrile.

[0029] In some specific embodiments, the intermediate compound of formula A3-1 can be cyclized to obtain the compound of formula A60:

[0030] Wherein, R2 is an amino protecting group.

[0031] The reaction is carried out in an acidic environment, and the acid may be formic acid, acetic acid, trifluoroacetic acid, benzoic acid, p-nitrobenzoic acid, p-toluenesulfonic acid, methanesulfonic acid, aluminum trichloride, titanium tetrachloride, boron trifluoride diethyl ether, boron trifluoride, tetrahydrofuran, boron tribromide. Preferably acetic acid, trifluoroacetic acid, benzoic acid. Most preferably acetic acid.

[0032] The reaction temperature is preferably 80-110 °C, and the reaction time is 15-18 h.

[0033] In some specific embodiments, ribociclib can be obtained through condensation reaction, cyclization reaction, deprotection reaction, and salt formation reaction to obtain the compound ribociclib, and the reaction equation is: .

[0034] The ribociclib intermediate and synthesis method provided by the present invention have the advantages of cheap raw materials and auxiliary materials, high atom economy, green safety, high substrate generality, simple process operation, and are suitable for industrial production, and have great potential in this field. Description of the Drawings

[0035] Figure 1 Shown is the 1 1H-NMR spectrum of the compound V prepared in Example 3.

[0036] Figure 2 Shown is the 1 1H-NMR spectrum of the compound VII prepared in Example 4.

[0037] Figure 3 Shown is the 1 1H-NMR spectrum of the compound IX prepared in Example 5.

[0038] Figure 4 Shown is the 1 1H-NMR spectrum of the compound V-1 prepared in Example 6.

[0039] Figure 5Shown is the 1 H-NMR spectrum of compound VII-1 prepared in Example 7. Detailed implementation mode

[0040] To further understand the present invention, the preparation method of a ribociclib intermediate compound provided by the present invention will be described in detail below in conjunction with examples. It should be understood that these example descriptions 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.

[0041] Example 1:

[0042] In a flask, add compound II (168.12 g, 4.eeq), tetrahydrofuran (360 mL, 6V), and cool to 0 °C. Dropwise add a solution of compound I (60.0 g, 1.0eq) / THF (240 mL, 4V), and the dropping time is 1.0 h. After the addition is complete, warm up to 30 °C and stir at 30 °C for 16 h. After the reaction is completed, filter to obtain a filtrate, concentrate the filtrate under reduced pressure until no more liquid drips, add DCM (5.0V), and stir to dissolve clearly. Wash three times with water (3.0V * 3). Dry the organic phase with sodium sulfate, and concentrate under reduced pressure until no more liquid drips to obtain 72.81 g of oily compound III, which can be directly used for the next step. The yield is 87%.

[0043] Example 2:

[0044] In a flask, add compound II (5.60 g, 4.0eq), toluene (12 mL, 6V), potassium carbonate (3.41 g, 1.5eq), and dropwise add compound I (2.0 g, 1.0eq) / toluene (8 mL, 4V), and the dropping time is 0.5 h. After the addition is complete, stir at 30 °C for 16 h. After the reaction is completed, filter to obtain a filtrate, concentrate the filtrate under reduced pressure until no more liquid drips to obtain 2.66 g of oily compound III, which can be directly used for the next step. The yield is 95%.

[0045] Example 3:

[0046] In a flask, add 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), and stir. Heat the mixture to 40 °C and stir for 16 h while maintaining the temperature. After the reaction is completed, cool the mixture to 15 - 25 °C, filter to obtain a filtrate. Concentrate the filtrate under reduced pressure until no more liquid drips to obtain a crude solid of compound V. The crude product is slurried with 5.0 V of ethyl acetate / n - heptane = 3 V / 7 V at 15 - 25 °C for 1.0 h. Filter and dry to obtain 20.2 g of solid compound V with a yield of 73.34%. MS(+ESI): 283.2 (100%, [M+H] + )。

[0047] Example 4:

[0048] Under nitrogen protection, add compound V (1.0 g, 1.0 eq), tetrahydrofuran (15 ml, 15 V), and compound VI (1.01 g, 1.03 eq) to a flask. Heat the mixture to 35 °C and stir until clear. After it becomes clear, add 1.85 M NaHMDS (3.6 ml, 1.9 eq) dropwise over 2.0 h. After the addition is complete, add an additional 1.85 M NaHMDS (0.1 eq) and stir for 18 h while maintaining the temperature. After the reaction is completed, add acetic acid (3.8 eq) / tetrahydrofuran (1 V) dropwise and stir. Add water (10 V) and stir. Concentrate the tetrahydrofuran to dryness under reduced pressure at 45 °C. After concentration, extract twice with ethyl acetate (10 V * 2). Combine the organic phases, dry over anhydrous sodium sulfate, and concentrate the organic phase under reduced pressure to obtain a crude product of compound VII. The crude product is 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] + )。

[0049] Example 5:

[0050] Under nitrogen protection, in flask A, add compound VII (2.0 g, 1.0 eq), tetrahydrofuran (14 mL, 7.0 V), cool down to -20 °C, and dropwise add 1.0 M LiHMDS (12.2 mL, 3.2 eq). After dropping, keep the temperature at -20 °C for 0.5 h to obtain a lithium salt solution of compound VII. Under nitrogen protection, in flask B, add tetrahydrofuran (6 mL, 3.0 V) and methyl formate (2.29 g, 10.0 eq). Cool down to -20 °C, and dropwise add the above-mentioned lithium salt solution of compound VII, which takes about 10 min. After dropping, warm up to 0 °C and keep stirring for 2.0 h. After the reaction is completed, dropwise add acetic acid (0.96 g, 4.2 eq) / tetrahydrofuran (2 mL, 1 V). After dropping, stir and concentrate under reduced pressure until the liquid no longer drips to obtain 3.32 g of crude compound VIII. Under nitrogen protection, in flask C, add the crude compound VIII (1.0 g, 1.0 eq) and acetic acid 10 ml (10.0 V), warm up to 90 °C and keep stirring for 16 h. After the reaction is completed, concentrate under reduced pressure until the liquid no longer drips to obtain a crude product, which is purified by column chromatography to obtain 0.33 g of compound IX, and the two-step yield is 54%. MS(+ESI): 535.5(100%, [M+H] + )。

[0051] Example 6:

[0052] Use compound III-1 (1.0 g, 1.0 eq) to replace compound III, and carry out the reaction according to the process of Example 3 to obtain the target product V-1. MS(+ESI): 284.2 (100%, [M+H] + )。

[0053] Example 7:

[0054] Use compound V-1 (0.5 g, 1.0 eq) to replace compound V, and carry out the reaction according to the process of Example 4 to obtain the target product VII-1.

Claims

1. A ribociclib intermediate of formula A compound, characterized in that, The structural formula is: ， Among them, R1 is hydrogen, formyl group, , or ; R2 is hydrogen, amino protecting group; R3 is alkoxy group, dimethylamino group; R4 is C1-C6 alkyl group.

2. The compound of formula A according to claim 1, characterized in that, The compound of formula A has the structure of the following compound of formula A1 or compound of formula A3: ， ， Among them, R1 is a formyl group, , or ; R2 is an amino protecting group; R3 is an alkoxy group, dimethylamino group; R4 is a C1-C6 alkyl group.

3. The compound of formula A according to claim 1, characterized in that, The structural formula is: ， ， ， 。 4. A method for preparing a ribociclib intermediate of formula A compound, characterized in that, The compound of formula A is prepared from the compound of formula A30 through a substitution reaction under alkaline conditions and optionally through a condensation reaction. The reaction equation is as follows: ， Among them, R1 is hydrogen, formyl, , or ; R2 is hydrogen, an amino protecting group; R3 is an alkoxy group, dimethylamino; R4 is a C1-C6 alkyl group.

5. A method for preparing a ribociclib intermediate of formula A compound, characterized in that, The compound of formula A is prepared from the compound of formula A40 through a condensation reaction under alkaline conditions. The reaction equation is as follows: ， Among them, R1 is a formyl group, , or ; R2 is an amino protecting group; R3 is an alkoxy group, dimethylamino group; R4 is a C1-C6 alkyl group.

6. The preparation method according to claim 4 or 5, characterized in that, The said condensation reaction is carried out in the presence of a base.

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

8. A method for preparing a compound of formula A40, characterized in that, The compound of formula A40 is prepared from the compound of formula A30 and the compound of formula B8 through a substitution reaction under alkaline conditions. The reaction equation is as follows: ， Wherein, R2 is an amino protecting group; R3 is an alkoxy group or dimethylamino group.

9. The preparation method according to claim 4 or 8, characterized in that, The said substitution reaction is carried out under strong alkaline conditions.

10. A method for preparing a compound of formula A60, characterized in that, The compound of formula A60 is obtained from the compound of formula A3-1 through a ring-closing reaction under acidic conditions. The reaction equation is as follows: ， Wherein, R2 is an amino protecting group.

11. The preparation method according to claim 10, characterized in that, The said acid is formic acid, acetic acid, trifluoroacetic acid, benzoic acid, p-nitrobenzoic acid, p-toluenesulfonic acid or methanesulfonic acid.

12. A preparation method of ribociclib, characterized in that, It includes a condensation reaction, a ring-closing reaction, a deprotection reaction and a salt-forming reaction to obtain the compound ribociclib. The reaction equation is: 。

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