CN113637002B - Preparation method of Nilaparib - Google Patents
Preparation method of Nilaparib Download PDFInfo
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- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
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Abstract
The invention provides a preparation method of nilapanib, which comprises the following steps: compound 1
Description
Technical Field
The invention belongs to the technical field of biological medicines, and particularly relates to a preparation method of nilapanib.
Background
Nilaparib is a targeted drug for treating ovarian malignant tumor, is a poly adenosine diphosphate ribose polymerase inhibitor, is a third PARP inhibitor approved by FDA after Olaparib, and adds a new choice for treating ovarian cancer. The nilapanib has the function of repairing DNA double-strand damage and ensures that DNA damage in cells is repaired in time to avoid canceration. The patent literature in the prior art for synthesizing Nilaparib includes Discovery of 2- {4- [ (3S) -piperidine-3-yl]phenyl } -2H-indole-7-carboxamide (MK-4827) A Novel Oral Poly (ADP-rib) polymerase (PARP) Inhibitor efficiencies in BRCA-1and-2Mutant reactors, Development of a Fit-for-Purpose Large-Scale Synthesis of an Oral PARP Inhibitor and the like, disclosing synthetic routes to Nilaparib 1-2 。
The synthetic route takes 3-methyl-2-nitrobenzoic acid as a starting material, and obtains a target compound through 8 steps of reaction, wherein the reaction route is long, and hazardous reagents such as sodium azide and the like are used. The method has the disadvantages of great pollution to the environment, dangerous factors in the process and low yield.
The synthetic method of the second route comprises the steps of firstly obtaining (S) -3- (4-aminophenyl) piperidine through a chiral resolution mode, then condensing the obtained product with 3-formyl-2-nitrobenzoic acid methyl ester, and constructing a pyrazole ring under the action of sodium azide. The route uses dioxide in reduction of pyridine ring, the cost of platinum is high, and sodium azide dangerous reagent is also used, which is not beneficial to amplification.
Disclosure of Invention
In order to solve the problems, the invention provides a preparation method of nilapanib, which has the advantages of simple synthesis process route, high preparation efficiency, small damage to human bodies and environment and effective reduction of synthesis cost.
In order to achieve the purpose, the technical scheme of the invention is realized as follows:
a preparation method of Nilaparib comprises the following synthetic route:
wherein, the step a is as follows: the compound 1and bromobenzene are catalyzed by Pd catalyst to obtain a compound 2, and a key intermediate of nilapanib is obtained;
the step b and the step c are as follows: carrying out chiral resolution on the compound 2 to obtain a compound 4;
step d is: coupling the compound 4 and the compound 5 under the catalysis of copper bromide to obtain a compound 6, namely the protected nilapanib;
step e is as follows: removing the protective color of the compound 6 under the action of methanesulfonic acid, and pulping with tetrahydrofuran to obtain a compound 7, namely the target product nilapanib.
Further, the step a comprises: dissolving the compound 1and a Pd catalyst in bromobenzene; adding potassium formate, and uniformly mixing to obtain an orange turbid solution; irradiating the orange turbid solution, and stirring until HPLC shows that the compound 1 is completely reacted; after the reaction is finished, carrying out post-treatment to obtain a compound 2;
the compound 2 is 1- [3- (4-bromophenyl) piperidin-1-yl ] -2, 2-dimethylpropane-1-one, is NPv piperidine derivatives, and has a chemical formula:
further, the step b comprises: the compound 2 is deprotected under hydrochloric acid condition; chiral resolution is carried out by any one of D- (+) -dibenzoyl tartaric acid, D-tartaric acid or D-camphorsulfonic acid to obtain a compound 3.
Further, the step c comprises: protection of the secondary amine by PvCl in compound 3 affords compound 4.
Further, the step d includes: under the catalysis of copper bromide, 8-hydroxyquinoline is used as a ligand for the compound 4 and the compound 5, and the coupling is carried out at the temperature of 105-115 ℃ to obtain a compound 6; the compound 5 is NBoc-1H-indazole-7-carboxamide.
Further, the Pd catalyst is Pd (PPh) 3 ) 4 ，Pd(OAc) 2 ，Pd 2 (dba) 3 ，Pd(dppf)Cl 2 ，Pd(PPh 3 )2Cl 2 Or PdCl 2 Any one of them.
When the catalyst is illuminated, the radiated photons can excite the Pd catalyst to generate single electron transfer, so that alkyl free radicals are generated, free radical addition reaction is carried out on a substrate, and a key intermediate of the nilapanib is obtained through subsequent reaction.
Further, in the step a, the light source used for irradiation is visible light or light with the wavelength of 450nm-480nm or light with the wavelength of 500nm-560 nm.
Further, in the step a, the reaction temperature when the orange turbid solution is irradiated is 20 to 60 ℃.
Further, the post-treatment in the step a specifically includes: removing the solvent by adopting concentration treatment, and recrystallizing n-hexane and ethyl acetate to obtain a key intermediate of the nilapanib; or washing with saturated saline solution, extracting with ethyl acetate, mixing organic phases after extraction, drying and concentrating with anhydrous sodium sulfate, and performing silica gel column chromatography to obtain the key intermediate of Nilaparib.
Compared with the prior art, the preparation method of the nilapanib provided by the invention has the following advantages:
(1) the preparation method of the nilapanib provided by the invention has the advantages of simple and efficient synthesis process, low synthesis cost, no high-temperature and high-pressure reaction, wide applicable temperature range and simple and easily-obtained reaction conditions;
(2) the preparation method of the nilapanib adopts the Pd catalyst, utilizes clean light energy to generate free radical reaction, has good reaction activity and high selectivity, can replace the use of dangerous reagents, is environment-friendly, does not damage the health of human bodies, can efficiently realize the construction of target compounds, generates less waste, has high atom utilization rate, accords with the concept of green chemistry, can effectively reduce the synthesis cost of the nilapanib, and occupies the leading position of the technology in industrial production with more and more strict environmental protection requirements.
Detailed Description
Unless defined otherwise, technical terms used in the following examples have the same meanings as commonly understood by one of ordinary skill in the art to which the present invention belongs. The test reagents used in the following examples, unless otherwise specified, were all conventional biochemical reagents; the experimental methods are conventional methods unless otherwise specified.
The present invention will be described in detail with reference to examples.
A preparation method of Nilaparib comprises the following steps:
s1, dissolving the compound 1and a Pd catalyst (0.05eq) in bromobenzene, adding potassium formate (1.2eq), and mixing uniformly to obtain an orange turbid solution;
wherein compound 1 has the formula
The Pd catalyst is Pd (PPh) 3 ) 4 ，Pd(OAc) 2 ，Pd 2 (dba) 3 ，Pd(dppf)Cl 2 ，Pd(PPh 3 )2Cl 2 Or PdCl 2 Any one of the above;
s2, irradiating the orange turbid solution, and stirring the solution in a matching way until HPLC shows that the compound 1 is completely reacted;
wherein the light source used for irradiation is visible light or light with the wavelength of 450nm-480nm or light with the wavelength of 500nm-560 nm; the reaction temperature is 20-60 ℃;
s3, after the reaction is finished, carrying out post-treatment to obtain a compound 2, namely a key intermediate of nilapanib;
wherein the post-treatment specifically comprises the following steps: removing the solvent by adopting concentration treatment, and recrystallizing n-hexane and ethyl acetate to obtain a key intermediate of the nilapanib; or washing with saturated saline solution, extracting with ethyl acetate, mixing organic phases after extraction, drying and concentrating with anhydrous sodium sulfate, and performing silica gel column chromatography to obtain the key intermediate of Nilaparib.
The key intermediate of the nilapanib is 1- [3- (4-bromophenyl) piperidin-1-yl ] -2, 2-dimethylpropane-1-one, and the chemical formula of the key intermediate is as follows:
s4, deprotecting the compound 2 under hydrochloric acid condition; carrying out chiral resolution by any one of D- (+) -dibenzoyl tartaric acid, D-tartaric acid or D-camphorsulfonic acid to obtain a compound 3;
compound 3 has the formula:
s5, protecting secondary amine by the compound 3 through PvCl to obtain a compound 4;
compound 4 has the formula:
s6, and the compound 4 and the compound 5 are coupled at 105-115 ℃ by using 8-hydroxyquinoline as a ligand under the catalysis of copper bromide to obtain a compound 6;
the compound 5 is NBoc-1H-indazole-7-carboxamide, and has a chemical formula as follows:
the compound 6 is protected nilapanib having the formula:
s7, removing protective color of the compound 6 under the action of methanesulfonic acid, and pulping with tetrahydrofuran to obtain a compound 7, namely the target product nilapanib;
the chemical formula of the compound 7 is as follows:
the specific synthetic route is shown below (the catalyst is Pd (PPh) 3 ) 4 For example):
1. preparation of Compound 2, a key intermediate of Nilaparib, 1- [3- (4-bromophenyl) piperidin-1-yl ] -2, 2-dimethylpropan-1-one
Example 1
The compound 1(10.0g, 40.0mmol) was mixed with Pd (PPh) 3 ) 4 (0.94g, 0.80mmol) was dissolved in bromobenzene (300mL) and potassium formate (4.20g, 50.0mmol) was added to give an orange turbid solution; subsequently, under the irradiation of visible light, the mixture is heated to 50 ℃, stirred for 24 hours, and HPLC shows that the compound 1 is completely reacted; after the reaction was completed, it was washed with saturated sodium chloride (300mL), extracted with ethyl acetate (3 x 200mL), and the organic phases were combined, dried over anhydrous sodium sulfate, concentrated, and subjected to column chromatography on silica gel column (petroleum ether/ethyl acetate) to give the key intermediate of nilapanib as a white solid (6.97g, 54%) and melting point test 62.5 ℃ to 63.1 ℃.
Example 2
The compound 1(10.0g, 40.0mmol) was reacted with Pd (PPh) 3 )2Cl 2 (0.56g, 0.80mmol) was dissolved in bromobenzene (300mL) and potassium formate (4.20g, 50.0mmol) was added to give an orange turbid solution; subsequently, under the irradiation of visible light, the mixture is heated to 50 ℃ and stirred for 24h, and HPLC shows that the reaction of the first intermediate is complete; after completion of the reaction, the reaction mixture was washed with saturated sodium chloride (300mL), extracted with ethyl acetate (3 x 200mL), and the organic phases were combined, dried over anhydrous sodium sulfate, and concentratedThe nilapanib key intermediate was obtained as a white solid (5.67g, 44%) using silica gel column chromatography (petroleum ether/ethyl acetate) with melting point tests 62.5-63.1 ℃.
Example 3
Reaction of Compound 1(10.0g, 40.0mmol) with Pd (OAc) 2 (0.18g, 0.80mmol) was dissolved in bromobenzene (300mL) and potassium formate (4.20g, 50.0mmol) was added to give an orange turbid solution; subsequently, heating to 50 ℃ under the irradiation of visible light, stirring for 24h, and displaying complete reaction of the first intermediate by HPLC; after the reaction was completed, it was washed with saturated sodium chloride (300mL), extracted with ethyl acetate (3 x 200mL), the organic phases were combined, dried over anhydrous sodium sulfate, concentrated, and subjected to column chromatography on silica gel column (petroleum ether/ethyl acetate) to obtain a key intermediate for synthesis of nilapanib as a white solid (6.58g, 51%) with melting point test at 62.5 to 633.1 ℃.
The chemical formula of the nilapanib key intermediate obtained in the embodiment 1 to 3 is as follows:
the following data were obtained by detecting the key intermediate of nilapanib:
H NMR(400MHz,Chloroform-d)δ7.44–7.25(m,2H),7.03–6.95(m,2H),4.39–4.07(m,2H),2.89–2.68(m,3H),1.97(d,J＝9.1Hz,1H),1.74(d,J＝8.2Hz,1H),1.49(d,J＝10.5Hz,2H),1.20(s,9H)，
13 C NMR(100MHz,Chloroform-d)δ153.9,142.1,130.3,127.0,121.4,40.9，38.9,31.0,29.0,26.4。
2. preparation of Nilaparib
Example 4
Preparation of compound 3:
dissolving the key intermediate (10.0g,30.0mmol) of nilapanib prepared in example 1-3 in 120ml of dioxane hydrochloride solution 4N, and reacting for 1h at 30-40 ℃; then adding 300ml of saturated sodium bicarbonate solution into the reaction solution, extracting with 200ml of ethyl acetate, drying by anhydrous sodium sulfate, taking the filtrate, and spin-drying to obtain a white solid; dissolving the crude product in 150mL ethanol at room temperature, dissolving D- (+) -dibenzoyl tartaric acid (17.2g,48.0mmol) in 150mL ethanol, slowly dripping into the system, heating to 80 ℃, and refluxing for reaction for two hours; and then cooling to about 35-45 ℃, separating out solids, carrying out suction filtration while the solids are hot, washing a filter cake with a small amount of ethyl acetate, redissolving the filter cake, adjusting the pH value to be alkaline by using 2N NaOH, extracting and spin-drying to obtain a compound 3, namely a resolved S-shaped product 2.5g of a white solid, wherein the er is 96.3:3.7, and the yield is 25%.
Preparation of compound 4:
the resulting compound 3(2.5g,10.4mmol) was dissolved in 40mL of dichloromethane, and PvCl (1.4mL,11.4mol) was slowly added dropwise and reacted at room temperature for 1 h; after the reaction was completed, it was washed with saturated sodium chloride (50mL), extracted with ethyl acetate (3 x 50mL), and the organic phases were combined, dried over anhydrous sodium sulfate, concentrated, and subjected to column chromatography on silica gel column (petroleum ether/ethyl acetate) to give compound 4 as a colorless oil (3.2g, 96%);
nuclear magnetic detection of compound 4 gave the following data:
1 H NMR(400MHz,Chloroform-d)δ7.87(dd,2H),7.23(dd,2H),3.76(t,J＝8.8Hz,1H),3.31–3.24(m,3H),2.93(s,1H),1.94–1.55(m,4H),1.24(s,9H),
13 C NMR(100MHz,Chloroform-d)δ179.5,137.5,132.0,131.8,120.6,59.1,55.4,50.9,44.1,43.8,31.9,21.5。
preparation of compound 6:
the obtained compound 4(3.2g,10.00mmol) was dissolved in 40ml of DMA, and compound 5(2.3g,10.05mmol), cuprous bromide (72mg,0.5mmol), 8-hydroxyquinoline (145mg,1.0mmol), potassium carbonate (4.1g,30.0mmol,3.0eq), argon shield, reverse reaction at 105 ℃ to 115 ℃ for 48h were added in this order; washing with 40ml of water, EA extraction, and column chromatography (PE: EA ═ 8:1) gave compound 6 as a white solid (3.95g, 83% yield).
Nuclear magnetic detection of compound 6 gave the following data:
1 H NMR(400MHz,Methanol-d 4 )δ9.54(s,1H),8.06(dd,J＝7.1,1.0Hz,1H),7.95–7.89(m,3H),7.49–7.42(m,2H),7.20(dd,J＝8.4,7.0Hz,1H),4.18–4.05(m,2H),2.98–2.68(m,3H),2.01(dd,J＝11.1,3.7Hz,1H),1.81–1.69(m,2H),1.56(s,9H),1.47(s,9H). 13 C NMR(100MHz,Methanol-d 4 )δ166.3,156.5,147.7,145.4,139.7,130.5,129.6,126.3,125.1,123.7,123.1,123.1,121.6,81.1,79.5,52.5,43.5,32.7,29.3,28.7。
preparation of compound 7, the target product nilapanib:
dissolving the obtained compound 6(10.0g,22.0mmol) in 40ml o-xylene, slowly adding MSA (32ml,0.48mol) dropwise, and reacting at 40 ℃ for 3 h; adding water into the reaction solution, separating an organic phase, extracting the water phase with toluene, discarding, neutralizing the water phase with saturated sodium bicarbonate solution, extracting the water phase with dichloromethane solution, collecting the organic phase, concentrating, drying, dissolving the compound in 100ml of THF, adding p-toluenesulfonic acid monohydrate (4.00g,21mmol) with stirring, and reacting at 65 ℃ for 16 h; after filtration, a coffee-colored solid nilapanib (7.04g, 90% yield) was obtained;
the resulting nilapanib was subjected to nuclear magnetic detection to yield the following data:
1 H NMR(400MHz,Methanol-d 4 )δ8.97(s,1H),8.15(d,J＝7.0Hz,1H),8.01(t,J＝8.8Hz,3H),7.71(d,J＝7.8Hz,3H),7.49(d,J＝8.2Hz,2H),7.24(dd,J＝17.3,7.9Hz,4H),3.46(t,J＝8.8Hz,2H),3.18–3.04(m,3H),2.34(s,3H),2.07(d,J＝11.7Hz,2H),1.94–1.85(m,2H)，
13 C NMR(100MHz,Methanol-d 4 )δ169.5,147.9,142.9,141.8,140.3,131.6,129.9,129.6,127.2,127.0,125.3,124.1,123.1,122.2,121.8,50.0,45.0,40.9,30.7,23.8,21.3。
the above description is only for the purpose of illustrating the preferred embodiments of the present invention and is not to be construed as limiting the invention, and any modifications, equivalents, improvements and the like that fall within the spirit and principle of the present invention are intended to be included therein.
Claims (7)
1. A preparation method of Nilaparib is characterized by comprising the following steps: the method comprises the following synthetic routes:
wherein, the step a is as follows: adding potassium formate into the compound 1and bromobenzene under the photocatalysis of a Pd catalyst, uniformly mixing, and irradiating the solution to obtain a compound 2, namely a key intermediate of nilapanib;
the compound 2 is 1- [3- (4-bromophenyl) piperidin-1-yl ] -2, 2-dimethylpropane-1-one, and the chemical formula is as follows:
the step b is as follows: the compound 2 is deprotected under hydrochloric acid condition; carrying out chiral resolution by any one of D- (+) -dibenzoyl tartaric acid, D-tartaric acid or D-camphorsulfonic acid to obtain a compound 3;
the step c is as follows: protecting secondary amine by using PvCl for the compound 3 to obtain a compound 4;
step d is: coupling the compound 4 and the compound 5 under the catalysis of copper bromide to obtain a compound 6, namely the protected nilapanib;
step e is as follows: and (3) removing the protection of the compound 6 under the action of methanesulfonic acid, and pulping with tetrahydrofuran to obtain a compound 7, namely the target product nilapanib.
2. The method of claim 1, wherein the nilapanib is prepared by: the step a comprises the following steps: dissolving the compound 1and a Pd catalyst in bromobenzene; adding potassium formate, and uniformly mixing to obtain an orange turbid solution; irradiating the orange turbid solution, and stirring until HPLC shows that the compound 1 is completely reacted; after the reaction, the compound 2 is obtained by post-treatment.
3. A process for the preparation of nilapanib of claim 1 characterized in that: the step d comprises the following steps: under the catalysis of copper bromide, 8-hydroxyquinoline is used as a ligand for the compound 4 and the compound 5, and the coupling is carried out at the temperature of 105-115 ℃ to obtain a compound 6; the compound 5 is NBoc-1H-indazole-7-carboxamide.
4. The method of claim 1, wherein the nilapanib is prepared by: the Pd catalyst is Pd (PPh) 3 ) 4 ，Pd(OAc) 2 ，Pd 2 (dba) 3 ，Pd(dppf)Cl 2 ，Pd(PPh 3 )2Cl 2 Or PdCl 2 Any one of them.
5. The method of claim 2, wherein the nilapanib is prepared by: in the step a, the light source used for irradiation is visible light or light with the wavelength of 450nm-480nm or light with the wavelength of 500nm-560 nm.
6. The method of claim 2, wherein the nilapanib is prepared by: in the step a, the reaction temperature when the orange turbid solution is irradiated is 20-60 ℃.
7. The method of claim 2, wherein the nilapanib is prepared by: the post-treatment in the step a specifically comprises the following steps: removing the solvent by adopting concentration treatment, and recrystallizing n-hexane and ethyl acetate to obtain a key intermediate of the nilapanib; or washing with saturated saline solution, extracting with ethyl acetate, mixing organic phases after extraction, drying and concentrating with anhydrous sodium sulfate, and performing silica gel column chromatography to obtain the key intermediate of Nilaparib.
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