CN112961152B - Synthesis method of palbociclib impurity - Google Patents
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Abstract
The invention discloses a synthesis method of palbociclib impurities, which can effectively avoid the defects of harsh reaction conditions, unstable intermediates and the like in the prior art, has the advantages of readily available raw materials, mild reaction conditions, simple operation, no flammable and explosive toxic materials, easy purification of the intermediates and products, high yield and the like, and provides a basis for the research on palbociclib related substances.
Description
Technical Field
The invention belongs to the technical field of organic chemical synthesis, and particularly relates to a synthesis method of a palbociclib impurity.
Background
Palbociclib (Palbociclib) is a cell cycle dependent kinase (CDK4/6) inhibitor developed by Pfizer, inc, entitled "breakthrough therapy" by the FDA in us in 2013 for 4 months. Because of its clinically good performance in phase III, the pfeiy company filed a marketing application to the us FDA in 2014 8 and received prior qualification for first-line treatment of estrogen receptor positive (ER +) and human epidermal growth factor receptor 2 negative (HER2-) advanced breast cancer. The research of the medicine is successful, and a new choice is provided for patients with metastatic breast cancer. The synthesis processes of the pabulicin, which are reported in the prior art, are WO2003062236, WO201003997, WO2012068381 and WO2014128588, and relate to the following synthesis processes:
the synthetic route of the palbociclib impurity 24(PBB051-24) designed according to the synthetic process of palbociclib is as follows:
this route has the following problems during synthesis: the synthesis of PBB051-24-03 requires high-temperature melting reaction, and the yield is not high; the PBB051-24-04 is easy to be cut off under the condition of solvent alcohol after being synthesized, and the invention provides the method for preparing the impurity PBB051-24, which has the advantages of easy acquisition of raw materials and mild reaction conditions.
Since the pharmaceutical impurities are very important in the aspects of pharmaceutical process research, optimization and quality control, the research on the impurities of the palbociclib is also very necessary.
Disclosure of Invention
In order to improve the problem, the invention provides a method for synthesizing a compound shown as a formula (I) (namely the palbociclib impurity 24), which comprises the following steps:
1) carrying out reduction reaction on the compound D to obtain a compound E;
2) carrying out hydrolysis reaction on the compound E to obtain a compound shown in a formula (I);
wherein R is C1-12Alkyl is, for example, methyl, ethyl, propyl, isopropyl, n-butyl, tert-butyl, pentyl, hexyl.
According to an embodiment of the present invention, the reduction reaction in step 1) preferably takes place in the presence of hydrogen, which may be at a pressure of 0.5 to 3atm, preferably 1.2 atm;
according to an embodiment of the invention, step 1) may be carried out under catalytic conditions, which may be palladium on carbon or palladium hydroxide on carbon, e.g. 10% palladium on carbon; the mass ratio of compound D to catalyst may be from 1:0.05 to 1:0.5, for example 1: 0.2;
according to an embodiment of the invention, the reaction temperature in step 1) is 10 to 35 ℃, e.g. 25 ℃, and the reaction time is 6 to 25 hours, e.g. 10 to 16 hours; the reaction solvent is at least one of tetrahydrofuran, dichloromethane and methanol; preferably a mixed solution of dichloromethane and methanol; preferably, the volume ratio of dichloromethane to methanol is from 1:1 to 1:5, such as from 1:2 to 1: 3;
according to an embodiment of the present invention, in step 1), the mass to volume ratio (g: mL) of compound D to the total amount of reaction solvent may independently be from 1:40 to 1:60, for example from 1:45 to 1: 50.
According to an embodiment of the present invention, step 2) is reacted in the presence of an acid, which may be methanesulfonic acid, hydrochloric acid, acetic acid, trifluoroacetic acid, preferably methanesulfonic acid; the molar ratio of compound E to the acid may be: 1:1 to 1:10, for example 1: 6;
according to an embodiment of the invention, the reaction temperature in step 2) is between 30 and 70 ℃, for example 50 ℃; the reaction time is 1-6h, for example 3 h; the reaction solvent is at least one of acetone, methanol, dichloromethane and water, such as a mixed solvent of acetone and water; preferably, the volume ratio of acetone to water may be from 1:1 to 1:5, such as from 1:2 to 1: 3;
according to an embodiment of the present invention, in step 2), the mass-to-volume ratio (g: mL) of compound E to the total amount of reaction solvent may independently be 1:20 to 1:40, for example 1: 30.
The invention also provides a synthesis method of the compound D, which comprises the following steps:
A1) carrying out substitution reaction on the compound A to obtain a compound B;
A2) carrying out coupling reaction on the compound B and a compound B1 to obtain a compound C;
the compound b1 may be tributyl (1-ethoxyethylene) tin or trimethyl (1-ethoxyethylene) tin, exemplified by tributyl (1-ethoxyethylene) tin;
A3) carrying out coupling reaction on the compound C and a compound C1 to obtain a compound D;
the compound c1 may be a 5-nitropyridine substituted in the 2-position with a leaving group, such as 2-fluoro-5-nitropyridine, 2-chloro-5-nitropyridine, 2-bromo-5-nitropyridine or 2-iodo-5-nitropyridine, exemplified by 2-bromo-5-nitropyridine;
wherein R is1Is C1-12Alkyl, such as methyl, ethyl, propyl, isopropyl, n-butyl, tert-butyl, pentyl, hexyl, preferably butyl;
r has the definition described above;
X1and X2Identical or different, independently of one another, from fluorine, chlorine, bromine or iodine; for example, X1Preferably bromine, X2Chlorine is preferred.
According to an embodiment of the invention, step a1) is reacted in the presence of an ammonia solution, which is an aqueous solution of ammonia (ammonia water), a methanolic solution of ammonia or an ethanolic solution of ammonia, for example ammonia water; the mass to volume ratio (g: mL) of compound A to ammonia solution may be from 1:5 to 5:1, for example 5: 2; the concentration of the ammonia solution may be 25%;
according to an embodiment of the invention, the reaction temperature of the reaction in step a1) is 50-100 ℃, e.g. 70 ℃; the reaction time may be 6-18h, for example 12 h; the reaction solvent may be at least one of N, N-dimethylformamide, N-dimethylacetamide, tetrahydrofuran, dioxane, such as N, N-dimethylacetamide;
according to an embodiment of the present invention, the mass to volume ratio (g: mL) of compound a to the reaction solvent in step a1) may independently be 1:2 to 1:6, for example 1: 4.
According to an embodiment of the invention, the reaction of step a2) is carried out in the presence of a catalyst, which may be Pd (PPh)3)4、Pd2(dba)3、Pd(dppf)Cl2At least one of; preferably Pd (PPh)3)4(ii) a The molar ratio of compound B to catalyst may be from 1:0.02 to 1:0.3, for example 1: 0.1;
according to an embodiment of the present invention, the molar ratio of compound B to compound B1 in step a2) may be 1:0.8 to 1:5, e.g. 1: 3.5;
according to an embodiment of the invention, the reaction temperature of the reaction in step a2) is 80-130 ℃, e.g. 110 ℃; the reaction time may be 6-18h, for example 12 h; the reaction solvent may be at least one of toluene and dioxane, such as toluene;
according to an embodiment of the present invention, the mass to volume ratio (g: mL) of compound B to the reaction solvent in step a2) may independently be from 1:5 to 1:10, for example 1: 7.7.
According to an embodiment of the invention, the molar ratio of compound C to compound C1 in step a3) is 1:0.5 to 1:2, e.g. 1: 1;
according to an embodiment of the invention, the reaction in step a3) is carried out in the presence of a catalyst, which may be Pd (PPh)3)4、Pd2(dba)3、Pd(dppf)Cl2At least one of; preferably Pd2(dba)3(ii) a The molar ratio of compound C to catalyst is from 1:0.02 to 1:0.3, for example 1: 0.05;
according to an embodiment of the present invention, the reaction in step a3) is carried out in the presence of an inorganic base selected from at least one of sodium carbonate, potassium carbonate, cesium carbonate, preferably cesium carbonate; the molar ratio of compound C to base may be from 1:0.8 to 1:3, for example 1: 2;
according to an embodiment of the invention, the reaction temperature in step a3) is 80 to 130 ℃, e.g. 95 to 100 ℃; the reaction time may be 6-15h, for example 10 h; the reaction solvent can be at least one of acetonitrile, dioxane and toluene, such as dioxane;
according to an embodiment of the present invention, the mass to volume ratio (g: mL) of compound C to the reaction solvent in step a3) may independently be 1:4 to 1:8, for example 1: 6.
According to an embodiment of the present invention, the steps a1) to A3) may be reacted under a gas inert to the reaction, such as at least one of nitrogen and argon.
As an example, a compound of formula (I) is prepared by a process comprising:
B1) carrying out substitution reaction on the compound a and ammonia water to prepare a compound b;
B2) carrying out Stille coupling reaction on the compound b and tributyl (1-ethoxyethylene) tin under the catalysis of palladium tetratriphenylphosphine to obtain a compound c;
B3) compound c with 2-bromo-5-nitropyridine in the presence of cesium carbonate and Pd2(dba)3Carrying out Buchwald-Hartwig coupling reaction under catalysis to obtain a compound d;
B4) the compound d and hydrogen are subjected to reduction reaction under the catalysis of palladium-carbon, and the nitro is reduced to obtain a compound e;
B5) and (3) carrying out hydrolysis reaction on the compound e in the presence of methanesulfonic acid to obtain the compound shown in the formula (I).
The invention also provides intermediate compounds represented by formula D and formula E:
wherein R is as defined above;
according to an embodiment of the invention, the intermediate compound is:
the invention also provides application of the synthesis method in pharmaceutical process research, and the synthesis method can be used for impurity research of the palbociclib.
The invention also provides application of the intermediate compound in the research of the palbociclib impurity.
Advantageous effects
The invention provides a synthesis method of palbociclib impurities, which has the advantages of easily available raw materials, mild reaction conditions, simple operation, no flammable and explosive toxic materials, easy purification of intermediates and products, high yield, effective avoidance of the defects of harsh reaction conditions, unstable intermediates and the like in the prior art, and provides a basis for the research of palbociclib related substances.
Drawings
FIG. 1 is a photograph of Compound (I) prepared in example 51H NMR chart, solvent is deuterated chloroform.
FIG. 2 is a MS picture of Compound (I) prepared in example 5.
FIG. 3 is a liquid chromatography (HPLC) chart of Compound (I) prepared in example 5.
Fig. 4 is a liquid chromatogram of compound d prepared in example 3.
FIG. 5 is a MS plot of Compound d prepared in example 3.
Terms and definitions
The term "C1-12Alkyl "is understood to mean straight-chain and branched alkyl groups having 1,2, 3, 4,5, 6, 7, 8, 9, 10, 11 or 12 carbon atoms. The alkyl group is, for example, a methyl group, an ethyl group, a propyl group, a butyl group, a pentyl group, a hexyl group, a heptyl group, an octyl group, a nonyl group, a decyl group, an undecyl group, a dodecyl group, an isobutyl group, a sec-butyl group, a tert-butyl group, an isopentyl group, a 2-methylbutyl group, a 1-ethylpropyl group, a1, 2-dimethylpropyl group, a neopentyl group, a1, 1-dimethylpropyl group, a 4-methylpentyl group, a 3-methylpentyl group, a 2-methylpentyl group, a 1-methylpentyl group, a 2-ethylbutyl group, a 1-ethylbutyl group, a3, 3-dimethylbutyl group, a2, 2-dimethylbutyl group, a1, 1-dimethylbutyl group, a2, 3-dimethylbutyl group, a1, 2-dimethylbutyl group, or the like or isomers thereof.
Detailed Description
The technical solution of the present invention will be further described in detail with reference to specific embodiments. It is to be understood that the following examples are only illustrative and explanatory of the present invention and should not be construed as limiting the scope of the present invention. All the technologies realized based on the above-mentioned contents of the present invention are covered in the protection scope of the present invention.
Unless otherwise indicated, the raw materials and reagents used in the following examples are all commercially available products or can be prepared by known methods.
EXAMPLE 1 Synthesis of Compound b
6-bromo-2-chloro-8-cyclopentyl-5-methyl-pyrido [2,3-D ] pyrimidin-7 (8H) -one (20g), 80mL of N, N-dimethylacetamide, and 8mL of aqueous ammonia (25% concentration) were added to a 150mL sealed jar, and the mixture was heated to 70 ℃ for 12 hours. TLC monitoring reaction: developing agent: petroleum ether: ethyl acetate (V/V) ═ 2:1, after the reaction of the raw materials is finished, adding 200mL of water into the reaction solution, separating out solids, magnetically stirring for 20min, carrying out reduced pressure filtration, pulping a filter cake by using n-hexane, filtering, and drying to obtain: 18.5g of a pale yellow solid, yield: 98%, purity: 99 percent.
EXAMPLE 2 Synthesis of Compound c
A250 mL three-necked flask was charged with compound b (7.8g, 0.02mol), tributyl (1-ethoxyethylene) tin (26g, 0.07mol), 60mL toluene, and palladium tetratriphenylphosphine (2.78g, 0.1eq), under nitrogen, and heated to 110 deg.C for 12h under reflux. TLC plates were as follows: developing agent: petroleum ether: ethyl acetate (V/V) ═ 2:1, the starting material and the product are basically not separated, the LCMS confirms that the starting material reaction is finished, the heating is closed, the temperature is reduced to room temperature, 50mL of water is added into the reaction liquid, ethyl acetate (50mL × 3) is used for extraction, the ethyl acetate phases are combined, saturated salt water is used for washing, drying and concentrating to obtain a crude product, the crude product is subjected to column chromatography, and the eluent: petroleum ether: ethyl acetate (V/V) ═ 2:1, concentrating the eluent under reduced pressure to obtain: and (3) pulping the crude product by using ethyl acetate, filtering and drying to obtain: 6.2g of a pale yellow solid, yield: 82%, purity: 97 percent.
EXAMPLE 3 Synthesis of Compound d
Into a 250mL three-necked flask, compound c (6.6g, 0.02mol), 2-bromo-5-nitropyridine (4.3g, 0.02mol), tris (dibenzylideneacetone) dipalladium (1.5g, 0.001mol), 4, 5-bis-diphenylphosphino-9, 9-dimethylxanthene (Phos, CAS:161265-03-8, 1.8g, 0.003mol), cesium carbonate (13.7g, 0.04mol), 40mL dioxane, and argon shield were added, and the temperature was raised to 95 ℃ for reaction for 10 hours.
TLC plates were as follows: petroleum ether: ethyl acetate (V/V) ═ 2:1, closing heating, cooling to room temperature, adding 30mL of water into reaction liquid, extracting with dichloromethane (50mL of water is multiplied by 3), combining dichloromethane phases, washing with saturated saline, drying with anhydrous sodium sulfate, filtering, concentrating under reduced pressure to obtain a crude product, pulping the crude product with ethyl acetate, filtering, and drying to obtain: 5g of pale yellow solid, yield: 55%, purity: 95 percent. The liquid chromatogram of compound d is shown in FIG. 4, and the MS profile is shown in FIG. 5.
EXAMPLE 4 Synthesis of Compound e
To a 500mL single-neck flask, compound d (6.6g), 200mL of methanol, 100mL of dichloromethane, and a clear solution were added, and 1.4g of 10% Pd/C and hydrogen (pressure 1.2atm) were added and the mixture was replaced three times, followed by reaction at room temperature for 16 hours. TLC plates were as follows: petroleum ether: ethyl acetate (V/V) ═ 2:1, after the raw materials react, filtering the reaction solution under reduced pressure, concentrating the filtrate under reduced pressure, and drying to obtain: 5g yellow solid, yield: 81%, purity: 95 percent.
EXAMPLE 5 Synthesis of Compound (I)
Compound e (5g, 0.01mol), 50mL acetone, 100mL water, methanesulfonic acid (6g, 0.06mol) were added to a 500mL three-necked flask, and the reaction system was dissolved and reacted at 50 ℃ for 3 h. TLC plates were as follows: dichloromethane: methanol 10: 1, TLC detection, no separation of the raw material and the product point, and LCMS detection of the completion of the raw material reaction. Concentrating the reaction solution under reduced pressure to remove acetone, adding 50mL of water into the residue, adjusting pH to 8-9 with sodium bicarbonate solution, separating out solid, filtering under reduced pressure, pulping the filter cake twice with acetone, filtering,drying to obtain: 4.3g dark yellow solid, yield: 95%, purity: 95.6 percent.1The H NMR is shown in FIG. 1, the MS spectrum is shown in FIG. 2, and the HPLC spectrum is shown in FIG. 3.
The embodiments of the present invention have been described above. However, the present invention is not limited to the above embodiment. Any modification, equivalent replacement, or improvement made within the spirit and principle of the present invention should be included in the protection scope of the present invention.
Claims (23)
1. A method for synthesizing a compound shown as a formula (I) comprises the following steps:
1) carrying out reduction reaction on the compound D to obtain a compound E;
2) carrying out hydrolysis reaction on the compound E to obtain a compound shown in a formula (I);
wherein R is C1-12An alkyl group.
2. The method of claim 1, wherein R is selected from the group consisting of methyl, ethyl, propyl, isopropyl, n-butyl, t-butyl, pentyl, and hexyl.
3. The synthesis method according to claim 1 or 2, wherein the step 1) is a reduction reaction in the presence of hydrogen, the pressure of the hydrogen is 0.5-3 atm;
step 1) is carried out under the condition of a catalyst, wherein the catalyst is palladium carbon or palladium hydroxide carbon; the mass ratio of the compound D to the catalyst is 1:0.05-1: 0.5.
4. The synthesis method according to claim 1 or 2, wherein the reaction temperature in the step 1) is 10-35 ℃;
the reaction time in the step 1) is 6-25 h;
the reaction solvent in the step 1) is at least one of tetrahydrofuran, dichloromethane and methanol.
5. The synthesis method according to claim 1 or 2, wherein the reaction solvent in step 1) is a mixed solution of dichloromethane and methanol;
the volume ratio of the dichloromethane to the methanol is 1:1-1: 5.
6. The synthesis method according to claim 1 or 2, wherein in step 1), the mass-to-volume ratio of the compound D to the total amount of the reaction solvent is 1:40 to 1:60 g: mL.
7. The synthesis method according to claim 1, wherein the step 2) is carried out in the presence of acid, wherein the acid is methanesulfonic acid, hydrochloric acid, acetic acid, trifluoroacetic acid; the molar ratio of compound E to the acid is: 1:1-1:10.
8. The synthesis method according to claim 1, wherein the reaction temperature in the step 2) is 30-70 ℃;
the reaction time in the step 2) is 1-6 h;
in the step 2), the reaction solvent is at least one of acetone, methanol, dichloromethane and water.
9. The synthesis method according to claim 1, wherein the reaction solvent in step 2) is a mixed solvent of acetone and water;
the volume ratio of the acetone to the water is 1:1-1: 5;
the mass-to-volume ratio of the compound E to the total amount of the reaction solvent in the step 2) is 1:20-1:40 g: mL.
10. A method of synthesizing compound D as claimed in claim 1 comprising the steps of:
A1) carrying out substitution reaction on the compound A to obtain a compound B;
A2) carrying out coupling reaction on the compound B and a compound B1 to obtain a compound C;
A3) carrying out coupling reaction on the compound C and a compound C1 to obtain a compound D;
the compound c1 is 5-nitropyridine substituted in the 2-position with a leaving group;
wherein R is1Is C1-12An alkyl group; x1And X2Identical or different, independently of one another, from fluorine, chlorine, bromine or iodine; r has the meaning indicated in claim 1.
11. The synthesis method according to claim 10, wherein the compound b1 in step a2) is tributyl (1-ethoxyethylene) tin or trimethyl (1-ethoxyethylene) tin;
in step a3), the compound c1 is 2-fluoro-5-nitropyridine, 2-chloro-5-nitropyridine, 2-bromo-5-nitropyridine or 2-iodo-5-nitropyridine;
R1is methyl, ethyl, propyl, isopropyl, n-butyl, tert-butyl, pentyl or hexyl; x1Is bromine, X2Is chlorine.
12. The synthesis method according to claim 10, wherein the step a1) is carried out in the presence of ammonia solution, wherein the ammonia solution is ammonia water solution, ammonia methanol solution or ammonia ethanol solution; the mass-volume ratio of the compound A to the ammonia solution is 1:5-5:1 g/mL.
13. The synthesis method according to claim 10, wherein the reaction temperature in step a1) is 50-100 ℃, and the reaction time is 6-18 h;
in the step A1), the reaction solvent is at least one of N, N-dimethylformamide, N-dimethylacetamide, tetrahydrofuran and dioxane;
the mass-to-volume ratio of the compound A to the reaction solvent in the step A1) is 1:2-1:6 g: mL.
14. The synthesis process according to claim 10, characterized in that the reaction of step a2) is carried out in the presence of a catalyst, said catalyst being Pd (PPh)3)4、Pd2(dba)3、Pd(dppf)Cl2At least one of;
the molar ratio of the compound B to the catalyst in the step A2) is 1:0.02-1: 0.3.
15. The synthesis method according to claim 10, wherein the molar ratio of compound B to compound B1 in step a2) is 1:0.8-1: 5;
the reaction temperature in the step A2) is 80-130 ℃;
the reaction time in the step A2) is 6-18 h;
in the step A2), the reaction solvent is at least one of toluene and dioxane;
the mass-to-volume ratio of the compound B to the reaction solvent in the step A2) is 1:5-1:10 g: mL.
16. The synthesis method according to claim 10, wherein the molar ratio of compound C in step a3) to compound C1 is 1:0.5-1: 2;
the reaction in step A3) is carried out in the presence of a catalyst, the catalyst being Pd (PPh)3)4、Pd2(dba)3、Pd(dppf)Cl2At least one of;
the molar ratio of compound C to catalyst in step A3) is 1:0.02-1: 0.3.
17. The synthesis method according to claim 10, wherein the reaction in step a3) is carried out in the presence of an inorganic base selected from at least one of sodium carbonate, potassium carbonate, cesium carbonate;
the molar ratio of the compound C to the inorganic base in the step A3) is 1:0.8-1: 3.
18. The synthesis method according to claim 10, wherein the reaction temperature in the step A3) is 80-130 ℃;
the reaction time in the step A3) is 6-18 h;
in the step A3), the reaction solvent is at least one of acetonitrile, dioxane and toluene;
the mass-to-volume ratio of the compound C to the reaction solvent in the step A3) is 1:4-1:8 g: mL.
19. A method for synthesizing a compound represented by formula (I), wherein the method comprises the following steps:
B1) carrying out substitution reaction on the compound a and ammonia water to synthesize a compound b;
B2) carrying out Stille coupling reaction on the compound b and tributyl (1-ethoxyethylene) tin under the catalysis of palladium tetratriphenylphosphine to obtain a compound c;
B3) compound c with 2-bromo-5-nitropyridine in the presence of cesium carbonate and Pd2(dba)3Carrying out Buchwald-Hartwig coupling reaction under catalysis to obtain a compound d;
B4) the compound d and hydrogen are subjected to reduction reaction under the catalysis of palladium-carbon, and the nitro is reduced to obtain a compound e;
B5) and (3) carrying out hydrolysis reaction on the compound e in the presence of methanesulfonic acid to obtain the compound shown in the formula (I).
20. An intermediate compound of formula D and formula E in claim 1:
wherein R is as defined in claim 1.
21. The intermediate compound of claim 20, having the structure:
22. use of the synthesis method according to any one of claims 1 to 9 in pharmaceutical technology research, for the study of impurities in palbociclib.
23. Use of an intermediate compound as claimed in claim 20 or claim 21 in the study of pabulib impurities.
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