CN111100128B - Synthetic method of Ribocini intermediate product and intermediate compound thereof - Google Patents
Synthetic method of Ribocini intermediate product and intermediate compound thereof Download PDFInfo
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- CN111100128B CN111100128B CN201811257137.XA CN201811257137A CN111100128B CN 111100128 B CN111100128 B CN 111100128B CN 201811257137 A CN201811257137 A CN 201811257137A CN 111100128 B CN111100128 B CN 111100128B
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Abstract
The invention discloses a synthetic method of a Riboxini intermediate product, which comprises the following steps: the compound 2 is prepared by taking barbituric acid as a starting material through chlorination and hydroformylation; then condensation, ring closing, dechlorination, elimination and the like are carried out to obtain the Ribociclib intermediate 2-chloro-7-cyclopentyl-N, N-dimethyl-7H-pyrrolo [2,3-d]Pyrimidine-6-carboxamides. In addition, intermediate compounds are also disclosed. The synthesis method avoids the use of noble metal catalysis, has simple process route, easily obtained raw materials, mild conditions and effectively reduced production cost, and is suitable for large-scale production.
Description
Technical Field
The invention belongs to the field of pharmaceutical chemicals, and particularly relates to a synthetic method of a Ribocini intermediate product and an intermediate compound thereof.
Background
Ribociclib is a novel highly potent oral anticancer drug developed by Nowa. As a highly specific cell cycle dependent kinase (CDK4/6 dual inhibitor), the drug can remarkably inhibit the growth of a plurality of neurocytoma. Clinical research results show that the medicine has obvious curative effect on the advanced treatment of the breast cancer, so that the medicine has wide market prospect.
The chemical name of Ribocini is: 7-cyclopentyl-N, N-dimethyl-2- [ [5- (1-piperazinyl) -2-pyridinyl ] amino ] -7H-pyrrolo [2,3-d ] pyrimidine-6-carboxamide, the structure of which is shown below.
Currently, the preparation of ribociclib is mainly performed by a key intermediate product, i.e., 2-chloro-7-cyclopentyl-N, N-dimethyl-7H-pyrrolo [2,3-d ] pyrimidine-6-carboxamide, and the preparation of the intermediate product is also widely reported.
PCT patent WO2010020675a1 discloses the synthesis of this key intermediate product, which is prepared as follows:
the route has the advantages of longer reaction steps, more complicated operation, low yield, and high process cost caused by using more noble metal catalysts.
The synthesis of this key intermediate product is also disclosed in US2012115878a1, which is an improvement over WO2010020675a1, and the preparation method is as follows:
compared with WO2010020675A1, the preparation method has a relatively short route and slightly improved coupling reaction yield, but uses highly toxic propargyl alcohol and still uses more noble metal catalysts; and finally, the oxidation and condensation reaction is completed in one step by adopting a one-pot method, although the reaction steps are shortened, a large amount of manganese dioxide is used, a large amount of solid waste is generated, and the operation risk is high due to the use of highly toxic sodium cyanide, so that the process amplification is not facilitated.
The Hangzhou KeChao Biotechnology Co., Ltd discloses a synthetic route of the key intermediate product in Chinese patent application CN 201610880076.7:
the route first prepares the propargylic acid derivative and then couples, thus shifting the most expensive one-step reaction to a relatively late position and increasing the yield. However, the following problems still exist with this route: the raw materials and reagents are expensive, the route is long, the catalyst still needs precious metal, and certain difficulty is brought to the amplification of the reaction. There is therefore still a need to find new synthesis methods which are simpler and more efficient.
Disclosure of Invention
The following is a summary of the subject matter described in detail herein. This summary is not intended to limit the scope of the claims.
The invention develops a preparation method of a ribociclib intermediate product, namely 2-chloro-7-cyclopentyl-N, N-dimethyl-7H-pyrrolo [2,3-d ] pyrimidine-6-formamide, and the method has the advantages of simple process route, easily obtained raw materials, lower cost and higher yield, and is suitable for industrial production.
The invention aims to provide a synthetic method of a Ribociclib intermediate product.
It is another object of the present invention to provide intermediate compounds useful in the preparation of the above mentioned rebuscini intermediate products.
Specifically, in an embodiment of the present application, the present invention provides a method for synthesizing a ribociclib intermediate, wherein the ribociclib intermediate is 2-chloro-7-cyclopentyl-N, N-dimethyl-7H-pyrrolo [2,3-d ] pyrimidine-6-carboxamide, and its chemical structure is shown as compound 9:
the method comprises the following steps:
1) in the presence of a Weilsmeier reagent and a chlorinated reagent, the barbituric acid, namely the compound 1, is subjected to hydroformylation and chlorination reaction to obtain a compound 2;
2) carrying out condensation reaction on the compound 2 and the compound 3 to obtain a compound 4;
3) carrying out a ring closing reaction on the compound 4 to obtain a compound 5;
4) in the presence of palladium-carbon and hydrogen, compound 5 is subjected to dechlorination reaction to generate compound 6;
5) the compound 6 undergoes elimination reaction to obtain a compound 7;
in the above synthesis methods, wherein the substituent R in compound 4, compound 5, compound 6 and compound 7 is unsubstituted C1-C4 alkyl, phenyl-substituted C1-C4 alkyl or alkyl-substituted phenyl-substituted C1-C4 alkyl, preferably, R is methyl, ethyl, tert-butyl or benzyl.
As an embodiment, the method for synthesizing the ribociclib intermediate product may further include: carrying out hydrolysis reaction on the compound 7 to obtain a compound 8;
then, reacting the compound 8 with dimethylamine to obtain the Ribociclib intermediate compound 9; or the compound 8 is subjected to acyl chlorination and then reacts with dimethylamine to obtain the Ribociclib intermediate compound 9;
as an embodiment, the above synthesis method may further include: and (3) directly reacting the compound 7 with dimethylamine to obtain the Ribociclib intermediate compound 9.
As an embodiment, the above synthesis method may further include: and (3) performing acyl chlorination on the compound 7 and then reacting with dimethylamine to obtain the Ribociclib intermediate compound 9.
Preferably, the weilsmeier reagent in step 1) is one or more selected from the group consisting of phosphorus oxychloride/N, N-dimethylformamide, oxalyl chloride/N, N-dimethylformamide, thionyl chloride/N, N-dimethylformamide, phosphorus oxychloride/N-methylformanilide.
Preferably, the chlorinating reagent in step 1) is selected from one or more of phosphorus oxychloride, oxalyl chloride and thionyl chloride.
Preferably, the reaction of step 1) is carried out in the presence of a solvent, or the reaction is carried out without a solvent (i.e., without additional solvent addition); here, the solvent of step 1) is selected from one or more of N, N-dimethylformamide, N-dimethylacetamide, and 1, 2-dichloroethane.
Preferably, the reaction temperature of the reaction in the step 1) is-10 ℃ to 150 ℃.
As an embodiment, the compound 3 in the step 2) may be prepared in the following manner: cyclopentanone and glycine ester (namely compound 10) are subjected to a reduction ammoniation reaction to obtain a compound 3;
here, the definition of the substituent R in the compound 10 is the same as that in the above-mentioned compound 3;
preferably, the reducing agent in the reductive amination reaction can be selected from one or more of sodium triacetoxyborohydride, sodium cyanoborohydride, sodium borohydride and potassium borohydride; the reductive amination reaction can be carried out in the presence of a solvent, and the solvent used in the reductive amination reaction is selected from one or more of methanol, ethanol, water and tetrahydrofuran; the molar ratio of the cyclopentanone, the compound of formula 10 and the reducing agent is 1 (1-2) to (0.75-2.5), preferably 1 (1-1.5) to (1-1.5).
Preferably, the condensation reaction in step 2) may be performed in the presence of a base and a solvent; wherein the base is selected from one or more of sodium carbonate, potassium carbonate, cesium carbonate, sodium tert-butoxide, potassium tert-butoxide, lithium hexamethyl-silamine, sodium hexamethyl-silamine, diisopropylethylamine, triethylamine, 1, 8-diazabicyclo [5.4.0] undec-7-ene (DBU), triethylenediamine; the solvent in the step 2) is one or more selected from dichloromethane, 1, 2-dichloroethane, tetrahydrofuran, methanol, ethanol, chloroform, acetone, 1, 4-dioxane, N-dimethylformamide and N, N-dimethylacetamide. In step 2), a compound of formula 2: a compound of formula 3: the molar ratio of the alkali is 1: (0.9-1.5): (1-2), preferably 1: (0.95-1.2): (1.1-1.5).
Preferably, the condensation reaction in step 2) is carried out at a reaction temperature of-80 ℃ to 80 ℃, more preferably 0 ℃ to 60 ℃.
Preferably, the ring-closure reaction in step 3) may be carried out in the presence of a base and a solvent; wherein the base is one or more selected from sodium methoxide, sodium ethoxide, sodium tert-butoxide, potassium tert-butoxide, sodium hydroxide, potassium hydroxide, diisopropylethylamine, triethylamine, 1, 8-diazabicyclo [5.4.0] undec-7-ene (DBU), triethylenediamine; the solvent in the step 3) is one or more selected from acetonitrile, toluene, dimethyl sulfoxide, tetrahydrofuran, 1, 4-dioxane, N-dimethylformamide and N, N-dimethylacetamide. In the step 3), the molar ratio of the compound of formula 4 to the base is 1 (1-3), preferably 1 (1.2-1.8).
Preferably, the reaction temperature of the cyclization reaction in the step 3) is-30 ℃ to 50 ℃, more preferably 0 ℃ to 30 ℃.
Preferably, the dechlorination reaction in the step 4) may be performed in the presence of a base and a solvent; here, the solvent of step 4) is selected from one or more of methanol, ethanol, ethyl acetate, methyl acetate and butyl acetate; the base is selected from one or more of sodium carbonate, potassium carbonate, cesium carbonate, sodium tert-butoxide, potassium tert-butoxide, lithium hexamethyl-silamine, sodium hexamethyl-silamine, diisopropylethylamine, triethylamine, 1, 8-diazabicyclo [5.4.0] undec-7-ene (DBU), and triethylene diamine. In the step 4), the molar ratio of the compound of formula 5 to the base is 1 (0.8-2), preferably 1 (1-1.5).
Preferably, the pressure of the hydrogen gas in the step 4) is 0.1 to 3Mpa, and more preferably 0.1 to 0.5 Mpa.
Preferably, the reaction temperature of the dechlorination reaction in the step 4) is 0 ℃ to 80 ℃, and is further preferably 10 ℃ to 30 ℃.
Preferably, the elimination reaction in step 5) is carried out in the presence of an elimination reagent and a solvent, wherein the elimination reagent is selected from thionyl chloride/pyridine, trifluoroacetic anhydride/diisopropylethylamine, methanesulfonyl chloride/potassium carbonate, p-toluenesulfonyl chloride/potassium carbonate, and one of concentrated hydrochloric acid, hydrobromic acid, hydroiodic acid and sulfuric acid; the solvent of the step 5) is one or more selected from toluene, dichloromethane, chloroform, tetrahydrofuran and 1, 4-dioxane.
Preferably, the reaction temperature in the elimination reaction in the step 5) is-10 ℃ to 100 ℃, and more preferably 0 ℃ to 50 ℃.
Preferably, the compound 7 is hydrolyzed in the presence of alkali and solvent, and then is acidified to obtain a compound 8; the alkali used in the hydrolysis reaction is selected from one or more of sodium hydroxide, potassium hydroxide and lithium hydroxide; the solvent used in the hydrolysis reaction is one or more selected from tetrahydrofuran, methanol, ethanol, isopropanol, acetone, 1, 4-dioxane, N-dimethylformamide, N-dimethylacetamide, acetonitrile and water; preferably, the reaction temperature of the hydrolysis reaction is 0 ℃ to 80 ℃; the acid used for acidification is selected from one or more of hydrochloric acid, sulfuric acid and acetic acid.
Preferably, the reaction of compound 8 with dimethylamine is carried out in the presence of a condensing agent, a base and a solvent, wherein the condensing agent is selected from the group consisting of N, N '-dicyclohexylcarbodiimide, N, N' -diisopropylcarbodiimide, 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride, 2- (7-azobenzotriazol) -N, N, N, N-tetramethylurea hexafluorophosphate, benzotriazol-N, N, N ', N' -tetramethylurea hexafluorophosphate, O- (6-chloro-1-benzotriazol-1-yl) -N, N, N ', N' -tetramethylurea hexafluorophosphate, (3H-1,2, 3-triazolo [4,5-b ] pyridin-3-yloxy) tris-1-pyrrolidinyl hexafluorophosphate One of a salt; the alkali is selected from one or more of sodium carbonate, potassium carbonate, cesium carbonate, diisopropylethylamine, triethylamine, 1, 8-diazabicyclo [5.4.0] undec-7-ene (DBU) and triethylene diamine; the solvent for the reaction is one or more selected from dichloromethane, toluene, dimethyl sulfoxide, tetrahydrofuran, acetone, 1, 4-dioxane, N-dimethylformamide and N, N-dimethylacetamide. The reaction temperature of the reaction is 0 ℃ to 80 ℃.
Preferably, compound 8 is subjected to an acyl chlorination reaction in the presence of an acylating agent, and then is subjected to a condensation reaction with dimethylamine in a base and a solvent to produce the compound of formula 9. Here, the acylating agent is selected from one or more of thionyl chloride, oxalyl chloride, phosphorus oxychloride; the base is one or more of diisopropylethylamine, triethylamine, 1, 8-diazabicyclo [5.4.0] undec-7-ene and triethylene diamine; the solvent is one or more selected from dichloromethane, 1, 2-dichloroethane, tetrahydrofuran, chloroform, acetone, 1, 4-dioxane, N-dimethylformamide and N, N-dimethylacetamide. The reaction temperature of the acyl chlorination reaction is-10 ℃ to 90 ℃, preferably 0 ℃ to 80 ℃, and the reaction temperature of the condensation reaction is-10 ℃ to 60 ℃, preferably 5 ℃ to 35 ℃.
Preferably, the compound 7 is directly ammonolyzed with dimethylamine in a base and a solvent to generate the compound of the formula 9, wherein the base is selected from one or more of sodium carbonate, potassium carbonate, cesium carbonate, diisopropylethylamine, triethylamine, 1, 8-diazabicyclo [5.4.0] undec-7-ene (DBU) and triethylene diamine, and the solvent is selected from one or more of dichloromethane, 1, 2-dichloroethane, tetrahydrofuran, chloroform, acetone, 1, 4-dioxane, N-dimethylformamide and N, N-dimethylacetamide. The reaction temperature is 0 ℃ to 80 ℃, preferably 30 ℃ to 60 ℃. The molar ratio of the compound 7 to dimethylamine is 1 (1-3), preferably 1 (1.1-1.5).
In another aspect, the present invention provides an intermediate compound for synthesizing the above mentioned intermediate product, compound 9, which is selected from one of the following compounds:
here, the substituents R in the compounds 4,5 and 6 are each independently unsubstituted C1-C4 alkyl, phenyl-substituted C1-C4 alkyl or alkyl-substituted phenyl-substituted C1-C4 alkyl, preferably R is methyl, ethyl, tert-butyl or benzyl.
The invention provides a synthetic method of a ribociclib intermediate product, which comprises the following steps: the compound 1 is prepared by taking barbituric acid as a starting material through chlorination and hydroformylation; then carrying out condensation, ring closing, dechlorination, elimination and other reactions to obtain the Ribociclib intermediate 2-chloro-7-cyclopentyl-N, N-dimethyl-7H-pyrrolo [2,3-d ] pyrimidine-6-formamide. Compared with the prior art, the synthesis method not only avoids the use of noble metal catalysts, but also has the advantages of simple process route, easily obtained raw materials, mild conditions, effectively reduced production cost and suitability for mass production.
Detailed Description
Hereinafter, embodiments of the present invention will be described in detail in order to make the objects, technical solutions and advantages of the present invention more apparent. It should be noted that the embodiments and features of the embodiments in the present application may be arbitrarily combined with each other without conflict.
The main raw materials, reagents and solvents used in the experiment are all chemical pure products or analytically pure products sold in the market, and are directly used without purification.
The main instruments and models used in this experimental example are: nuclear magnetic resonance apparatus: 600DD2 type, 600MHz, Agilent, USA; TMS is an internal standard; mass Spectrometry ESI-MS and HR-ESI-MS Finnigan LCQ Deca XP, electrospray ionization ion source.
Example 1
Adding phosphorus oxychloride (153.3g, 1000mmol) into a three-neck flask, stirring, cooling to-10-0 ℃ in an ice salt bath, slowly dropwise adding N, N-dimethylformamide (36.5g, 500mmol), controlling the temperature to be not higher than 5 ℃, stirring for 1 hour at a controlled temperature after dropwise adding is finished, adding barbituric acid 1(38.4g,300mmol), removing the ice salt bath, naturally returning to the room temperature, then, programming to 120 ℃, and stirring overnight. After TLC monitoring reaction is completed, slowly adding the reaction solution into ice water, separating out a large amount of solid, performing cold filtration, washing a filter cake until an effluent liquid is neutral to obtain a light yellow solid, and performing forced air drying at 50-60 ℃ to obtain a compound 2(58.3g, yield 92.5%). ESI M/z 211.01(M + 1).
Example 2
To a single-neck reaction flask were added methanol (200mL), cyclopentanone (16.8g,200mmol), glycine methyl ester (17.8g,200mmol), acetic acid (0.12g,2mmol) in that order. Stirring in an ice bath, adding sodium borohydride triacetate (63.6g,300mmol) in batches, heating to room temperature after the addition, stirring for 2 hours, monitoring the reaction completion by TLC, dropwise adding water (150g) to quench the reaction, concentrating under reduced pressure to remove methanol, adding 1mol/L hydrochloric acid (200mL), ethyl acetate (200mL), separating, detecting no product by an organic layer TLC, discarding, adjusting the pH of an aqueous phase to about 8 by adding solid sodium bicarbonate, extracting by ethyl acetate (200mL) for three times, combining organic phases, and concentrating under reduced pressure to dryness to obtain a brown oily substance, namely the compound 3-1(29.8g, yield 95.0%). ESI M/z 158.21(M + 1).
Example 3
Sequentially adding 2(31.6g,150mmol) and dichloromethane (300mL) into a three-neck flask, stirring in an ice bath, and cooling to 5-15 ℃; dropwise adding a dichloromethane (100mL) solution of a compound 3-1(25.9g,175mmol) and diisopropylethylamine (38g,200mmol), controlling the internal temperature to be 10-20 ℃, removing the ice bath after dropwise addition is finished, reacting at room temperature for 2-5 hours, after TLC monitoring reaction is completed, adding 150mL of water, separating, extracting a water phase with 100mL of dichloromethane, combining organic phases, washing with 200mL of saturated saline solution once, collecting the organic phases, concentrating to dryness to obtain brown semisolid, adding 50mL of ethyl acetate and 100mL of petroleum ether, heating to 50 ℃, stirring for 1 hour, cooling to 0-5 ℃, filtering, collecting filter cakes, and drying at 40-50 ℃ under reduced pressure to obtain a light yellow solid, namely the compound 4-1(44.3g, yield 89.2%). ESI M/z 332.12(M + 1). 1 H NMR(600MHz,CDCl 3 )δ10.44(s,1H),4.39(s,2H),4.26(s,3H),4.01–3.94(m,1H),2.17–2.06(m,2H),1.91–1.70(m,4H),1.65–1.49(m,2H)。
Example 4
Adding the compound 4-1(33.2g,100mmol) and acetonitrile (300mL) in a three-neck bottle in sequence, stirring in an ice bath, cooling to 0-10 ℃, and dropwise adding 1, 8-diazabicyclo [5.4.0]]Undec-7-ene (DBU) (18.2g,120mmol), controlling the internal temperature to be 5-20 ℃, removing the ice bath after finishing the dropwise addition, reacting for 0.5-2 hours at room temperature, monitoring the reaction process by TLC, concentrating under reduced pressure at 35-40 ℃ after the reaction is finished to obtain a brown solid, adding isopropanol (50g) and water (25g), stirring for 1 hour at normal temperature, filtering, leaching the filter cake with isopropanol (10mL) and water (5mL), and drying under reduced pressure at 40-50 ℃ to obtain a light yellow solid, namely the compound 5-1(29.6g, yield 89.2%). ESI M/z 332.06(M + 1). 1 H NMR(600MHz,CDCl 3 )δ5.44–5.38(m,1H),4.16(s,3H),3.83–3.77(m,1H),2.01–1.93(m,2H),1.83–1.66(m,4H),1.34–1.26(m,2H)。
Example 5
Adding the compound 5-1(26.6g,80mmol), ethyl acetate (200mL), 10% palladium carbon (2.66g) and potassium carbonate (13.6g,100mmol) into a single-mouth bottle, replacing with hydrogen, stirring at room temperature under hydrogen atmosphere, sampling every 0.5h to monitor the reaction process, after the reaction is completed, replacing hydrogen with nitrogen, filtering, rinsing filter cake ethyl acetate (20mL), collecting filtrate, and concentrating under reduced pressure to obtain an off-white solid, namely the compound 6-1(22.5g, yield 94.5%). ESI M/z 298.11(M + 1). 1 H NMR(600MHz,CDCl 3 )δ8.62(s,1H),5.28–5.19(m,1H),4.35(s,3H),3.66–3.59(m,1H),2.08–1.98(m,2H),1.95–1.77(m,4H),1.40–1.33(m,2H)。
Example 6
Sequentially adding a compound 6-1(20.8g,70mmol), dichloromethane (200mL), pyridine (11.1g,140mmol) into a three-neck flask, stirring in an ice salt bath, cooling to-5 ℃, slowly dropwise adding thionyl chloride (16.7g,140mmol), controlling the temperature to-5 ℃, stirring at room temperature for 2-4 hours after dropwise adding, monitoring the reaction by TLC, after the reaction is completed, slowly adding the reaction liquid into ice water (150g), separating, extracting once with aqueous phase dichloromethane (100mL), combining organic layers, concentrating until the mixture is dry to obtain a white-like solid, adding petroleum ether (100mL), pulping at room temperature for 1 hour, filtering, leaching once with the petroleum ether (20mL) of a filter cake, collecting the filter cake, and drying at 40-50 ℃ under reduced pressure to obtain a white solid compound 7-1(18.1g, wherein the yield is 92.7%). ESI M/z 280.10(M + 1).
Example 7
Adding the compound 7-1(16.7g,60mmol), methanol (50mL) and water (50mL) into a three-necked flask, uniformly stirring, adding a 10% sodium hydroxide solution (50g), and stirring at room temperature for 3-4 hours after the addition. After the reaction is finished, the methanol is removed through concentration under reduced pressure, dichloromethane (100mL) is added for back extraction once, the water phase is collected, the mixture is cooled to 5-20 ℃ through ice bath, 2.5mol/L hydrochloric acid (about 60mL) is added dropwise to adjust the pH value to 2-3, a large amount of white solid is separated out, the mixture is filtered, the filter cake is rinsed with water (100mL), the filter cake is collected, and air drying is carried out to obtain the white solid, namely the compound 8(14.9g, the yield is 93.5%). ESI M/z 266.15(M + 1).
Example 8
Adding the compound 8(13.2g and 50mmol) and N, N-dimethylformamide (65mL) into a three-necked bottle, uniformly stirring, carrying out ice bath, adding a mixture of 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (EDCI) (11.5g and 60mmol), controlling the temperature to be 0-10 ℃, dropwise adding triethylamine (12.1g and 120mmol) and a dimethylamine tetrahydrofuran solution (2.0M,37.5mL and 75mmol), reacting at room temperature for 6-10 hours after adding, adding water (200mL), ethyl acetate (200mL), separating, extracting with aqueous ethyl acetate (100mL) for 3 times, combining organic layers, washing with saturated saline (200mL) for 3 times, and concentrating the organic layer to be dry to obtain a light yellow solid. Adding methanol (20mL), heating, pulping, cooling, filtering, washing the filter cake with cold methanol (5mL), collecting the filter cake, and concentrating under reduced pressure at 45-55 ℃ to obtain off-white solid, namely the compound 9(13.3g, yield 91.4%). ESI M/z 293.17(M + 1).
Example 9
Compound 8(2.64g,10mmol), chloroform (30mL), and thionyl chloride (1.78g,15mmol) were added to the reaction flask in this order, heated to 50 ℃ and stirred to react, and after TLC monitoring complete conversion of compound 8, chloroform and unreacted thionyl chloride were removed by distillation under pressure to give a pale yellow acid chloride intermediate. The acid chloride intermediate was dissolved in chloroform (30mL), stirred in an ice bath, triethylamine (1.21g, 12mmol) was added dropwise, followed by dimethylamine tetrahydrofuran solution (2.0M,7.5mL,15 mmol). After the addition was completed, the ice bath was removed, the mixture was stirred at room temperature for 1 to 2 hours, and after completion of the reaction, water (20mL) was added, the mixture was separated, and the aqueous phase was extracted once with chloroform (20mL), and the organic layers were combined and washed once with water (30 mL). The organic phase was collected and concentrated to dryness to give a pale yellow solid, which was slurried with 5mL of methanol, filtered, and dried to give off-white solid, Compound 9(1.89g, yield 64.7%).
Example 10
Adding a compound 7-1(2.79g,10mmol), 1, 4-dioxane (10mL) and a dimethylamine tetrahydrofuran solution (2.0M,7.5mL and 15mmol) in sequence into a reaction bottle, adding a reflux device, heating the reaction solution to 45-50 ℃, reacting for 8-12 hours, monitoring the reaction process, and supplementing the dimethylamine tetrahydrofuran solution (2.0M,2mL and 4mmol) if the reaction is not finished until the reaction is complete. After completion of the reaction, the reaction solution was dropped into ice water (50g) to precipitate a solid, which was then filtered. To obtain a pale yellow solid, slurried with methanol (5mL), filtered, and dried to obtain an off-white solid, i.e., Compound 9(1.33g, yield 45.5%).
Although the embodiments disclosed in the present application are described above, the descriptions are only for the purpose of facilitating understanding of the present application, and are not intended to limit the present application. It will be understood by those skilled in the art that various changes in form and details may be made therein without departing from the spirit and scope of the disclosure as defined by the appended claims.
Claims (9)
1. A synthetic method of a ribociclib intermediate product is disclosed, wherein the ribociclib intermediate product is 2-chloro-7-cyclopentyl-N, N-dimethyl-7H-pyrrolo [2,3-d ] pyrimidine-6-formamide, and the chemical structure of the ribociclib intermediate product is shown as a compound 9:
the method comprises the following steps:
1) in the presence of a Weilsmeier reagent and a chlorinated reagent, the barbituric acid, namely the compound 1, is subjected to hydroformylation and chlorination reaction to obtain a compound 2;
2) carrying out condensation reaction on the compound 2 and the compound 3 to obtain a compound 4;
3) carrying out a ring closing reaction on the compound 4 to obtain a compound 5;
4) in the presence of palladium-carbon and hydrogen, compound 5 is subjected to dechlorination reaction to obtain compound 6;
5) the compound 6 undergoes elimination reaction to obtain a compound 7;
in the above synthesis method, the substituent R in compound 3, compound 4, compound 5, compound 6 and compound 7 is each independently an unsubstituted C1-C4 alkyl group, a phenyl-substituted C1-C4 alkyl group, or an alkyl-substituted phenyl-substituted C1-C4 alkyl group;
further comprising hydrolysis reaction of compound 7 to obtain compound 8;
then, reacting the compound 8 with dimethylamine to obtain the Ribociclib intermediate compound 9; or the compound 8 is subjected to acyl chlorination and then reacts with dimethylamine to obtain the Ribociclib intermediate compound 9;
further comprising: directly reacting the compound 7 with dimethylamine to obtain a Ribociclib intermediate, namely a compound 9;
further comprising: and (3) performing acyl chlorination on the compound 7 and then reacting with dimethylamine to obtain the Ribociclib intermediate compound 9.
2. The method of synthesis of claim 1, R is methyl, ethyl, tert-butyl, or benzyl.
3. The synthesis method according to any one of claims 1 to 2, wherein the willsmeier reagent in step 1) is selected from one or more of phosphorus oxychloride/N, N-dimethylformamide, oxalyl chloride/N, N-dimethylformamide, thionyl chloride/N, N-dimethylformamide, phosphorus oxychloride/N-methylformanilide; or
The chlorinating reagent in the step 1) is selected from one or more of phosphorus oxychloride, oxalyl chloride and thionyl chloride; or
The reaction in the step 1) is carried out in the presence of a solvent, wherein the solvent of the step 1) is one or more selected from N, N-dimethylformamide, N-dimethylacetamide and 1, 2-dichloroethane; alternatively, the reaction in step 1) is carried out in the absence of a solvent; or alternatively
The reaction temperature of the reaction in the step 1) is-10 ℃ to 150 ℃.
4. The synthesis method according to any one of claims 1 to 2, wherein the condensation reaction in step 2) is carried out in the presence of a base and a solvent; wherein the base is one or more selected from sodium carbonate, potassium carbonate, cesium carbonate, sodium tert-butoxide, potassium tert-butoxide, lithium hexamethyl-silamine, sodium hexamethyl-silamine, diisopropylethylamine, triethylamine, 1, 8-diazabicyclo [5.4.0] undec-7-ene, triethylenediamine; the solvent in the step 2) is one or more selected from dichloromethane, 1, 2-dichloroethane, tetrahydrofuran, methanol, ethanol, chloroform, acetone, 1, 4-dioxane, N-dimethylformamide and N, N-dimethylacetamide; or alternatively
The reaction temperature of the condensation reaction in the step 2) is-80 ℃ to 80 ℃.
5. The synthesis method according to any one of claims 1 to 2, wherein the ring closure reaction in step 3) is carried out in the presence of a base and a solvent; wherein the base is selected from one or more of sodium methoxide, sodium ethoxide, sodium tert-butoxide, potassium tert-butoxide, sodium hydroxide, potassium hydroxide, diisopropylethylamine, triethylamine, 1, 8-diazabicyclo [5.4.0] undec-7-ene, triethylenediamine; the solvent in the step 3) is one or more selected from acetonitrile, toluene, dimethyl sulfoxide, tetrahydrofuran, 1, 4-dioxane, N-dimethylformamide and N, N-dimethylacetamide; or
The reaction temperature of the ring closure reaction in the step 3) is-30 ℃ to 50 ℃.
6. The synthesis process according to any one of claims 1 to 2, wherein the dechlorination reaction in step 4) is carried out in the presence of a base and a solvent; here, the solvent of step 4) is selected from one or more of methanol, ethanol, ethyl acetate, methyl acetate and butyl acetate; the base is selected from one or more of sodium carbonate, potassium carbonate, cesium carbonate, sodium tert-butoxide, potassium tert-butoxide, lithium hexamethyl-silamine, sodium hexamethyl-silamine, diisopropylethylamine, triethylamine, 1, 8-diazabicyclo [5.4.0] undec-7-ene, triethylenediamine; or
The pressure of the hydrogen in the step 4) is 0.1 to 3 Mpa; or alternatively
The reaction temperature of the dechlorination reaction in the step 4) is 0-80 ℃.
7. The synthesis method according to any one of claims 1-2, wherein the elimination reaction in step 5) is carried out in the presence of an elimination reagent and a solvent, the elimination reagent being selected from thionyl chloride/pyridine, trifluoroacetic anhydride/diisopropylethylamine, methanesulfonyl chloride/potassium carbonate, p-toluenesulfonyl chloride/potassium carbonate, and one of concentrated hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid; the solvent in the step 5) is one or more selected from toluene, dichloromethane, chloroform, tetrahydrofuran and 1, 4-dioxane; or
The reaction temperature for the elimination reaction in the step 5) is-10 ℃ to 100 ℃.
8. An intermediate compound for the synthesis of compound 9, said intermediate compound being selected from one of the following compounds:
here, the substituents R in compound 4 and compound 5 are each independently unsubstituted C1-C4 alkyl, phenyl-substituted C1-C4 alkyl, or alkyl-substituted phenyl-substituted C1-C4 alkyl; the substituent R in compound 6 is unsubstituted C1-C4 alkyl, phenyl-substituted C1-C4 alkyl, or alkyl-substituted phenyl-substituted C1-C4 alkyl, and R is not ethyl.
9. The intermediate compound of claim 8, wherein the substituent R in compounds 4 and 5 is methyl, ethyl, t-butyl, or benzyl.
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