CN108727230B - Ibrutinib intermediate and preparation method thereof - Google Patents
Ibrutinib intermediate and preparation method thereof Download PDFInfo
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Abstract
The invention discloses an ibrutinib intermediate and a preparation method thereof. The structure of the ibrutinib intermediate is shown in a formula I, and the definition of R is shown in the specification and the claims. The ibrutinib intermediate can be used for preparing an ibrutinib key intermediate 3- (4-phenoxyphenyl) -1H-pyrazolo [3,4-d]A pyrimidin-4-amine comprising the steps of: preparing an active intermediate compound shown in formula II from the compound shown in formula I under the action of an active nucleophilic reagent; cyclizing the compound shown in the formula II to obtain a compound shown in the formula 4, namely 3-amino-5- (4-phenoxyphenyl) -4-cyano-1H-pyrazole; the compound of the formula 4 is subjected to ring closure to obtain an ibrutinib key intermediate. The method has the advantages of cheap and easily obtained raw materials, no need of hazardous reagents, mild reaction conditions, simple operation and suitability for industrial production.
Description
Technical Field
The invention relates to the field of pharmaceutical chemistry, in particular to an ibrutinib intermediate of a tyrosine kinase inhibitor and a preparation method thereof.
Background
The chemical name of Ibrutinib (Ibrutinib) is: 1- [ (3R) -3- [ 4-amino-3- (4-phenoxyphenyl) -1H-pyrazolo [3,4-d ] pyrimidin-1-yl ] -1-piperidinyl ] -2-propen-1-one of the formula:
ibrutinib is an original drug of an oral Bruton Tyrosine Kinase (BTK) inhibitor, and the drug inhibits BTK irreversibly by selectively and covalently bonding with a cysteine residue (Cys-481) of an active site of a target protein Btk, thereby effectively preventing tumor migration from B cells to lymphoid tissues adapted to a tumor growth environment. In 11 months 2013, the united states Food and Drug Administration (FDA) approved it for marketing for the treatment of a rare invasive leukemia, Mantle Cell Lymphoma (MCL), and in 7 months 2014, the FDA approved it for the treatment of Chronic Lymphocytic Leukemia (CLL).
3- (4-phenoxyphenyl) -1H-pyrazolo [3,4-d ] pyrimidin-4-amine (shown in a structure of a following formula 5, hereinafter referred to as a compound of the formula 5) is a key intermediate for synthesizing ibrutinib.
The method for synthesizing the compound of formula 5 reported in WO2008039218 is shown in scheme 1: 4-phenoxybenzoic acid is used as a raw material, and the compound shown in the formula 5 is obtained through acylation, condensation, methoxylation, pyrazole cyclization and pyrimidine cyclization. The method needs to use a dangerous reagent of trimethylsilyldiazomethane, and the reagent is not only difficult to obtain, but also easy to explode, dangerous to operate and not suitable for industrial production.
Route 1:
the method reported in CN103121999 (scheme 2) is: the compound shown in the formula 5 is obtained by Suzuki coupling reaction of 3-bromo-1H-pyrazolo [3,4-d ] -pyrimidine-4-amine. The process steps are reduced and the overall yield is improved relative to scheme 1. However, since the starting materials are not commercialized in a large scale, they are expensive, and the catalysts used in the preparation process, bis (triphenylphosphine) palladium chloride or bis (cyanophenyl) palladium chloride, are also very expensive, they are not suitable for industrial production.
Route 2:
therefore, the research and development of a synthetic method of ibrutinib, which has the advantages of easily available raw materials, simple operation and environmental friendliness, is needed in the field.
Disclosure of Invention
The invention aims to provide a synthetic method of ibrutinib and an ibrutinib intermediate, which have the advantages of easily obtained raw materials, simple operation and environmental friendliness.
In a first aspect of the present invention, an ibrutinib intermediate is provided, which has a structure shown in formula I:
wherein R is substituted or unsubstituted C1-C6Alkylsulfonyl or substituted or unsubstituted C6-C12Said substituent being selected from halogen or C1-C3Alkyl group of (1).
In another preferred embodiment, R is methylsulfonyl, trifluoromethanesulfonyl, phenylsulfonyl or p-toluenesulfonyl.
In a second aspect of the invention, there is provided a process for the preparation of a compound of formula I, comprising the steps of:
reacting 2- [ hydroxy (4-phenoxyphenyl) methylene ] malononitrile, a compound of formula 3, with a hydroxy activating reagent RX to obtain a compound of formula I,
wherein R is as defined above and X is halogen.
In another preferred embodiment, the hydroxyl activating reagent is p-toluenesulfonyl chloride, methanesulfonyl chloride, benzenesulfonyl chloride or trifluoromethanesulfonyl chloride.
In another preferred embodiment, the reaction is carried out in the presence of a base selected from one or a combination of triethylamine, diisopropylethylamine, 4-N, N-dimethylaminopyridine, pyridine, 2, 6-dimethylaminopyridine.
In another preferred embodiment, the compound 2- [ hydroxy (4-phenoxyphenyl) methylene ] malononitrile of formula 3 is prepared by the following steps:
a) acylating the 4-phenoxybenzoic acid of the compound of the formula 1 to obtain 4-phenoxybenzoyl chloride of a compound of a formula 2;
b) reacting the compound of formula 2 with malononitrile to obtain a compound of formula 3.
In another preferred embodiment, in the step a), the 4-phenoxybenzoic acid of the compound shown in the formula 1 is acylated by thionyl chloride to obtain the 4-phenoxybenzoyl chloride of the compound shown in the formula 2.
In another preferred embodiment, in the step b), the compound of formula 2 is reacted with malononitrile in the presence of a base selected from one or a combination of two or more of sodium bicarbonate, sodium carbonate, potassium bicarbonate, sodium hydroxide, potassium hydroxide, triethylamine, diisopropylethylamine, 4-N, N-dimethylaminopyridine, or pyridine.
In another preferred embodiment, in said step b), the compound of formula 2 is reacted with malononitrile in the presence of a base, wherein the base is preferably potassium carbonate, diisopropylethylamine or pyridine.
In a third aspect of the invention, there is provided the use of a compound of formula I for the preparation of a compound of formula 4, 3-amino-5- (4-phenoxyphenyl) -4-cyano-1H-pyrazole, comprising the steps of:
i') A compound of the formula I with an active nucleophilic activator NR1R2R3Reacting to obtain an active intermediate compound shown as a formula II;
II') subjecting the compound of formula II to cyclization reaction to obtain the compound of formula 4,
in each formula, R is as defined above;
R1is H or C1-C3Alkyl groups of (a);
R2is H or C1-C3Alkyl groups of (a);
R3selected from saturated or unsaturated heterocycles containing 5 to 8 atoms, or R2And R3Together form a saturated heterocyclic ring containing 5 to 8 atoms.
In another preferred embodiment, the saturated or unsaturated heterocyclic ring containing 5 to 8 atoms is selected from: furan ring, pyrrole ring, thiophene ring, pyridine ring, pyrimidine ring, pyran ring, tetrahydrofuran ring, tetrahydropyrrole ring, hexahydropyridine ring, 2, 3-dihydropyrrole ring, morpholine ring.
In another preferred embodiment, the saturated heterocyclic ring containing 5 to 8 atoms is selected from: tetrahydrofuran ring, tetrahydropyrrole ring, piperidine ring, morpholine ring.
In another preferred embodiment, the compound of formula I is reacted with an active nucleophilic activator in an organic solvent selected from one or a combination of tetrahydrofuran, 1,4 dioxane, 2-methyltetrahydrofuran, toluene, pyridine, or acetonitrile (preferably acetonitrile and pyridine).
In another preferred embodiment, the compound of formula I is reacted with an active nucleophilic activator in the presence of a base selected from one or a combination of triethylamine, diisopropylethylamine, 4-N, N-dimethylaminopyridine, pyridine, or 2, 6-lutidine.
In another preferred embodiment, the active nucleophilic activator is selected from the group consisting of N-methylmorpholine, 4-N, N-dimethylaminopyridine.
In another preferred embodiment, the cyclization reaction in step ii') employs a cyclization reagent, wherein the cyclization reagent is hydrazine hydrate or hydrazine hydrochloride or a combination thereof.
In a fourth aspect of the invention, there is provided the use of a compound of formula I for the preparation of a compound of formula 5, 3- (4-phenoxyphenyl) -1H-pyrazolo [3,4-d ] pyrimidin-4-amine, comprising the steps of:
i) a compound of formula I with an active nucleophilic activator NR1R2R3Reacting to obtain an active intermediate compound shown as a formula II;
II) carrying out cyclization reaction on the compound of the formula II to obtain a compound of a formula 4;
iii) carrying out a ring closing reaction on the compound of the formula 4 and formamide or formamidine acetate to obtain a compound of a formula 5,
in each formula, R is as defined above;
R1is H or C1-C3Alkyl groups of (a);
R2is H or C1-C3Alkyl groups of (a);
R3selected from saturated or unsaturated heterocycles containing 5 to 8 atoms, or R2And R3Together form a saturated heterocyclic ring containing 5 to 8 atoms.
In another preferred embodiment, the compound of formula I is reacted with an active nucleophilic activator in an organic solvent selected from one or a combination of tetrahydrofuran, 1,4 dioxane, 2-methyltetrahydrofuran, toluene, pyridine, or acetonitrile (preferably acetonitrile and pyridine).
In another preferred embodiment, the compound of formula I is reacted with an active nucleophilic activator in the presence of a base selected from one or a combination of triethylamine, diisopropylethylamine, 4-N, N-dimethylaminopyridine, pyridine, or 2, 6-lutidine.
In another preferred embodiment, the active nucleophilic activator is selected from the group consisting of N-methylmorpholine, 4-N, N-dimethylaminopyridine.
In another preferred embodiment, the cyclization reaction in step ii) employs a cyclization reagent, and the cyclization reagent is hydrazine hydrate or hydrazine hydrochloride or a combination thereof.
In another preferred embodiment, the ring closure reaction in step iii) is performed in an organic solvent, wherein the organic solvent is one or a combination of two or more of N-butanol, N-methylpyrrolidone and N, N-dimethylformamide.
In a fifth aspect of the present invention, there is provided a process for preparing a compound of formula 4, comprising the steps of:
a') reacting a compound 2- [ hydroxy (4-phenoxyphenyl) methylene ] malononitrile of formula 3 with a hydroxy activating reagent RX to obtain a compound of formula I;
b') A compound of the formula I with an active nucleophilic activator NR1R2R3Reacting to obtain an active intermediate compound shown as a formula II;
c') subjecting the compound of formula II to cyclization reaction to obtain a compound of formula 4,
wherein R is as defined above and X is halogen,
R1is H or C1-C3Alkyl groups of (a);
R2is H or C1-C3Alkyl groups of (a);
R3selected from saturated or unsaturated heterocycles containing 5 to 8 atoms, or R2And R3Together form a saturated heterocyclic ring containing 5 to 8 atoms.
In another preferred embodiment, the preparation method has one or more of the following characteristics:
1) the hydroxyl activating reagent is paratoluensulfonyl chloride, methylsulfonyl chloride, benzene sulfonyl chloride or trifluoromethanesulfonyl chloride;
2) the reaction of the step a') is carried out in the presence of a base, wherein the base is selected from one or a combination of triethylamine, diisopropylethylamine, 4-N, N-dimethylaminopyridine, pyridine and 2, 6-dimethylaminopyridine;
3) reacting the compound of the formula I with an active nucleophilic activating agent in an organic solvent, wherein the organic solvent is one or a combination of tetrahydrofuran, 1,4 dioxane, 2-methyltetrahydrofuran, toluene, pyridine and acetonitrile (preferably acetonitrile and pyridine);
4) reacting the compound shown in the formula I with an active nucleophilic activating agent in the presence of a base, wherein the base is selected from one or a combination of triethylamine, diisopropylethylamine, 4-N, N-dimethylaminopyridine, pyridine and 2, 6-dimethylpyridine;
5) the active nucleophilic activating agent is selected from N-methylmorpholine and 4-N, N-dimethylaminopyridine;
6) in the step c'), a cyclization reagent is adopted in the cyclization reaction, and the cyclization reagent is hydrazine hydrate or hydrazine hydrochloride or a combination thereof;
7) the three steps of the steps a '), b ') and c ') adopt a one-pot stir-frying mode.
The raw materials of the method are cheap and easy to obtain, and the method has no dangerous hypertoxic drugs which are conventional chemical reagents; the reaction condition is mild, deep cooling and high temperature are not needed; the process is simple to operate and is suitable for industrial mass production.
It is to be understood that within the scope of the present invention, the above-described features of the present invention and those specifically described below (e.g., in the examples) may be combined with each other to form new or preferred embodiments. Not to be reiterated herein, but to the extent of space.
Detailed Description
The inventor of the application researches extensively and deeply, and unexpectedly develops a new synthesis method of ibrutinib with easily obtained raw materials, simple operation and environmental friendliness for the first time. On the basis of this, the present invention has been completed.
Preparation method
In a preferred embodiment, the preparation method of the ibrutinib key intermediate compound 3- (4-phenoxyphenyl) -1H-pyrazolo [3,4-d ] pyrimidin-4-amine of formula 5 comprises the following steps:
a) reacting the compound shown in the formula I with an active nucleophilic activator N, N-dimethylaminopyridine in an organic solvent 1 in the presence of a base 2 to obtain an active intermediate compound shown in the formula IIa or reacting with an active nucleophilic activator N-methylmorpholine to obtain an active intermediate compound shown in the formula IIb;
b) reacting a compound of formula IIa or IIb with a cyclizing reagent to provide a compound of formula 4;
c) and (3) in an organic solvent 2, carrying out ring closure on the compound of the formula 4 and formamide or formamidine acetate to obtain the compound of the formula 5.
In step a), the organic solvent 1 is one or a combination of tetrahydrofuran, 1,4 dioxane, 2-methyltetrahydrofuran, toluene, pyridine or acetonitrile, preferably acetonitrile and pyridine; the base 2 is selected from one or the combination of triethylamine, diisopropylethylamine, 4-N, N-dimethylaminopyridine, pyridine and 2, 6-dimethylpyridine; the active nucleophilic agent is selected from N-methylmorpholine and 4-N, N-dimethylaminopyridine.
In step a), the reaction temperature is between 0 and 50 ℃ and preferably between 0 and 30 ℃.
The cyclization reagent in the step b) is selected from hydrazine hydrate or hydrazine hydrochloride.
In step b), the reaction temperature is from 0 to 50 ℃ and preferably from 0 to 30 ℃.
The organic solvent 2 in the step c) is one or a combination of N-butyl alcohol, N-methyl pyrrolidone or N, N-dimethylformamide.
In step c), the reaction temperature is 50 ℃ to 200 ℃, preferably 100 ℃ to 180 ℃.
In a preferred embodiment, the compound of formula I is prepared from 4-phenoxybenzoic acid, comprising the steps of:
1) in a toluene solvent, acylating 4-phenoxybenzoic acid of a compound of a formula 1 by thionyl chloride to obtain a compound of a formula 2;
2) reacting the compound of formula 2 with malononitrile in the presence of a base 1 to obtain a compound of formula 3;
3) reacting the compound of formula 3 with a hydroxyl activating reagent in the presence of a base 2 to obtain the compound of formula I.
The reaction temperature in step 1 is 20-110 deg.C, preferably 60-100 deg.C.
The base 1 in the step 2 is selected from inorganic bases such as sodium bicarbonate, sodium carbonate, potassium bicarbonate, sodium hydroxide or potassium hydroxide and the like, or one or a combination of organic bases such as triethylamine, diisopropylethylamine, 4-N, N-dimethylaminopyridine or pyridine and the like. Wherein the inorganic base is preferably potassium carbonate, and the organic base is preferably diisopropylethylamine or pyridine. The reaction temperature is 0-60 deg.C, preferably 0-30 deg.C.
The hydroxyl activating reagent in the step 3 is selected from tosyl chloride, methylsulfonyl chloride, benzene sulfonyl chloride or trifluoromethane sulfonyl chloride; the base 2 is selected from one or the combination of triethylamine, diisopropylethylamine, 4-N, N-dimethylaminopyridine, pyridine and 2, 6-dimethylpyridine.
In another preferred embodiment, the three steps of preparing the compound of formula I from the compound of formula 3, preparing the compound of formula II from the compound of formula I, and preparing the compound of formula 4 from the compound of formula II can be carried out in a one-pot stir-frying manner, i.e., the intermediate compound of formula I and the intermediate compound of formula II are not required to be separated and purified, and are directly used in the next step.
Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art. In addition, any methods and materials similar or equivalent to those described herein can be used in the methods of the present invention. The preferred embodiments and materials described herein are intended to be exemplary only.
The invention has the advantages that:
(1) the invention provides a novel ibrutinib intermediate.
(2) The invention provides a preparation method of novel ibrutinib.
(3) The method of the invention adopts cheap and easily available raw materials, does not need to use hazardous reagents, and is a conventional chemical reagent.
(4) The method has mild reaction conditions and simple process operation.
(5) The method is environment-friendly and suitable for industrial mass production.
The invention will be further illustrated with reference to the following specific examples. It should be understood that these examples are for illustrative purposes only and are not intended to limit the scope of the present invention. The experimental procedures for which specific conditions are not indicated in the following examples are generally carried out according to conventional conditions (e.g.as described in Sambrook et al, molecular cloning: A Laboratory Manual (New York: Cold Spring Harbor Laboratory Press, 1989)) or according to the conditions as recommended by the manufacturer. Unless otherwise indicated, percentages and parts are percentages and parts by weight.
Example 1
Preparation of 4-phenoxybenzoyl chloride, a compound of formula 2
250mL of toluene and 50.0g (0.23mol) of 4-phenoxybenzoic acid were added to the reaction flask, and the temperature was reduced to 5 ℃. Thionyl chloride 41.7g (0.35mol) was added and catalyzed by the addition of 2 drops of N, N-dimethylformamide. The reaction solution was heated to 80 ℃ and stirred to react for 3 hours. And (3) concentrating under reduced pressure, replacing the residual liquid with toluene twice, adding 200mL of toluene, stirring uniformly, and directly putting into the next reaction.
Example 2
Preparation of 2- [ hydroxy (4-phenoxyphenyl) methylene ] malononitrile, a compound of formula 3
150mL of toluene and 15.4g (0.23mol) of malononitrile were added to the reaction flask and the temperature was reduced to 5 ℃. A toluene solution of the product of example 1 was added. 60.3g (0.46mol) of N, N-diisopropylethylamine were added dropwise thereto, and the temperature was controlled at about 5 ℃. After the dropwise addition, the reaction mixture was heated to 20 ℃ to react for 16 hours. Concentrated under reduced pressure, the residual solvent was extracted with ethyl acetate, and the organic layer was washed with 1M hydrochloric acid and dried over sodium sulfate. Concentration under reduced pressure gave 58.1g of the compound of formula 3 in 95.1% yield.
1H-NMR:δ12.18,12.16(1H,-OH),7.85-7.83(2H,m,Ph-),7.43-7.39(2H,t,Ph-),7.18-7.16(2H,t,Ph-),7.08-7.06(1H,m,Ph-),6.52(2H,s,Ph-)。
Mass(+ESI):263.17[M+H]+。
Example 3
Preparation of 2, 2-dicyano-1- (4-phenoxyphenylalkenyl) -4-methylbenzenesulfonate, a compound of formula Ia
To a reaction flask were added 100mL of pyridine and 14.5g (76.1mmol) of p-toluenesulfonyl chloride, and the mixture was cooled to 10 ℃ to which was added 19.5g (74.4mmol) of the compound of formula 3. Stirring was continued for 1 hour to obtain a mixture containing the compound of formula Ia.
Purification can also be carried out: after concentration under reduced pressure, 60ml of ethyl acetate was added to dissolve the residue, which was washed with 1N hydrochloric acid and saturated brine, and dried over anhydrous sodium sulfate. Concentration under reduced pressure gave 30.6g of the compound of formula Ia in 98.8% yield.
1H-NMR:δ7.91-7.69(2H,m),7.76-7.73(2H,m),7.43-7.38(2H,m),7.35-7.31(2H,m),7.14-7.09(1H,m),7.02-6.99(2H,m),6.93-8.91(2H,m),2.47(3H,s)。
Mass(+ESI):439.17[M+Na]+。
Example 4
Preparation of 3-amino-5- (4-phenoxyphenyl) -4-cyano-1H-pyrazole, a compound of formula 4
To the mixture of the compound of formula Ia obtained in example 3 was added 9.3g (76.1mmol) of 4-N, N-dimethylaminopyridine and the temperature was reduced to 5 ℃. Stirring was continued for 2 hours until use. Taking a micro sample from the reaction mixed solution for mass spectrometry detection: mass (+ ESI):368.53[ M + H ] +
The reaction mixture was cooled to 0 ℃ and 5.3g (76.1mmol) of hydrazine hydrochloride was added and the reaction was allowed to proceed for 1 hour. After the reaction, filtering and concentrating under reduced pressure. 20ml of 50% ethanol is added into the residue, the pH value is adjusted to 2-3 by concentrated hydrochloric acid, and the mixture is stirred and crystallized to obtain 16.3g of light yellow solid with the yield of 80.0%.
1H-NMR:δ12.12-8.60(1H,s),δ7.82-7.80(2H,d,Ph-),7.48-7.39(2H,m,Ph-),7.21-7.17(2H,t,Ph-),7.11-7.07(2H,m,Ph-),6.48(2H,-NH2)。
Mass:(+ESI):277.61[M+H]+。
Example 5
Preparation of 3- (4-phenoxyphenyl) -1H-pyrazolo [3,4-d ] pyrimidin-4-amines as compounds of formula 5
5.0g (18.1mmol) of the compound of formula 4 and 20ml of methoxy ethylene glycol were added to a reaction flask, and the solid was dissolved by stirring. A solution of formamidine acetate (11.5 g, 11.0mmol) in toluene (20ml) was added, and the mixture was heated to reflux for 4 hours. After the reaction, the mixture is concentrated under reduced pressure, 20ml of water is added into the residue, the precipitate is crystallized, filtered, and pulped by water and 75% ethanol respectively. Drying gave 4.4g of the compound of formula 5 in 80.0% yield.
1H-NMR:δ13.86(1H,s,-NH-),8.25(1H,s,Ph-),7.70-7.68(2H,m,Ph-),7.45-7.41(2H,t,Ph-),7.18-7.12(5H,t,Ph-),6.94(2H,s,-NH2)。
Mass(+ESI):304.09。
Example 6
Preparation of 2, 2-dicyano-1- (4-phenoxyphenyl) -methanesulfonate as compound of formula Ib
100mL of pyridine and 9.8g (85.6mmol) of methanesulfonyl chloride were added to the reaction flask, and the reaction solution was cooled to 10 ℃ and 22.4g (85.6mmol) of the compound of formula 3 was added. Stirring was continued for 1 hour to obtain a mixture containing the compound of formula Ib.
Purification can also be carried out: after concentration under reduced pressure, 75ml of ethyl acetate was added to dissolve the residue, which was washed with 1N hydrochloric acid and saturated brine, and dried over anhydrous sodium sulfate. Concentration under reduced pressure gave 28.4g of the compound of formula Ia in 98.1% yield.
1H-NMR:δ7.70-7.68(2H,m),7.34-7.30(2H,m),7.13-7.09(2H,m),7.00-6.98(2H,m),6.91-6.88(1H,m),3.17(3H,s)。
Mass(+ESI):361.07[M+Na]+。
Example 7
Preparation of 3-amino-5- (4-phenoxyphenyl) -4-cyano-1H-pyrazole, a compound of formula 4
7.7g (76.2mmol) of N-methylmorpholine were added to the reaction solution of the compound of formula Ib obtained in example 6, the temperature was reduced to 10 ℃ and stirring was continued for 2 hours. Taking a micro sample from the reaction mixed solution for mass spectrometry detection: mass (+ ESI):347.16[ M + H ] +
9.0g (0.18mol) of hydrazine hydrate and 15mL of pyridine were added to the reaction flask and the temperature was reduced to 10 ℃. Dropwise adding the reaction mixed solution for standby in the previous step, and controlling the temperature to be 5-10 ℃. After dropping, the reaction was continued for 16 hours. And after the reaction is finished, adding the reaction mixed solution into water, adjusting the pH value to 6 by using concentrated hydrochloric acid, separating out solids, continuously stirring for 1 hour, performing suction filtration, and washing by using water to obtain a crude product. Drying under reduced pressure gave 16.1g of the compound of formula 4 in 76.5% yield.
1H-NMR:δ12.12-8.60(1H,s),δ7.82-7.80(2H,d,Ph-),7.48-7.39(2H,m,Ph-),7.21-7.17(2H,t,Ph-),7.11-7.07(2H,m,Ph-),6.48(2H,-NH2)。
Mass:(+ESI):277.61[M+H]+。
Example 8
Preparation of 3- (4-phenoxyphenyl) -1H-pyrazolo [3,4-d ] pyrimidin-4-amines as compounds of formula 5
5.0g (18.1mmol) of the compound of formula 4 and 50mL of formamide are added to a reaction flask, and the mixture is heated to 160 ℃ and 180 ℃ for reaction for 6 hours. After the reaction is finished, cooling to room temperature, and pouring into ice water. And (4) carrying out suction filtration, and washing a filter cake with water and methanol sequentially. Drying gave 2.8g of the compound of formula 5 in 51.0% yield.
1H-NMR:δ13.86(1H,s,-NH-),8.25(1H,s,Ph-),7.70-7.68(2H,m,Ph-),7.45-7.41(2H,t,Ph-),7.18-7.12(5H,t,Ph-),6.94(2H,s,-NH2)。
Mass(+ESI):304.09。
All documents referred to herein are incorporated by reference into this application as if each were individually incorporated by reference. Furthermore, it should be understood that various changes and modifications of the present invention can be made by those skilled in the art after reading the above teachings of the present invention, and these equivalents also fall within the scope of the present invention as defined by the appended claims.
Claims (16)
1. An ibrutinib intermediate has a structure shown in formula I:
wherein R is substituted or unsubstituted C1-C6Alkylsulfonyl or substituted or unsubstituted C6-C12Said substituent being selected from halogen or C1-C3Alkyl group of (1).
2. The ibrutinib intermediate of claim 1, wherein R is methanesulfonyl, trifluoromethanesulfonyl, benzenesulfonyl, p-toluenesulfonyl.
3. A process for the preparation of a compound of formula I, comprising the steps of:
reacting 2- [ hydroxy (4-phenoxyphenyl) methylene ] malononitrile, a compound of formula 3, with a hydroxy activating reagent RX to obtain a compound of formula I,
wherein R is as defined in claim 1 and X is halogen.
4. The method of claim 3, wherein the hydroxyl activating reagent is p-toluenesulfonyl chloride, methanesulfonyl chloride, benzenesulfonyl chloride, or trifluoromethanesulfonyl chloride.
5. The process of claim 3, wherein the reaction is carried out in the presence of a base selected from one or a combination of triethylamine, diisopropylethylamine, 4-N, N-dimethylaminopyridine, pyridine, 2, 6-dimethylaminopyridine.
6. The process of claim 3, wherein the compound of formula 3, 2- [ hydroxy (4-phenoxyphenyl) methylene ] malononitrile, is prepared by the following steps:
a) acylating the 4-phenoxybenzoic acid of the compound of the formula 1 to obtain 4-phenoxybenzoyl chloride of a compound of a formula 2;
b) reacting the compound of formula 2 with malononitrile to obtain a compound of formula 3.
7. The method of claim 6, wherein in step a), the compound of formula 1, 4-phenoxybenzoic acid, is acylated with thionyl chloride to provide the compound of formula 2, 4-phenoxybenzoyl chloride.
8. The method according to claim 6, wherein in the step b), the compound of formula 2 is reacted with malononitrile in the presence of a base selected from one or a combination of two or more of sodium bicarbonate, sodium carbonate, potassium bicarbonate, sodium hydroxide, potassium hydroxide, triethylamine, diisopropylethylamine, 4-N, N-dimethylaminopyridine and pyridine.
9. The process according to claim 6, wherein in step b) the compound of formula 2 is reacted with malononitrile in the presence of a base, preferably potassium carbonate, diisopropylethylamine or pyridine.
10. Use of a compound of formula I for the preparation of a compound of formula 4, 3-amino-5- (4-phenoxyphenyl) -4-cyano-1H-pyrazole, comprising the steps of:
i') A compound of the formula I with an active nucleophilic activator NR1R2R3Reacting to obtain an active intermediate compound shown as a formula II;
II') subjecting the compound of formula II to cyclization reaction to obtain the compound of formula 4,
wherein R is as defined in claim 1;
R1is H or C1-C3Alkyl groups of (a);
R2is H or C1-C3Alkyl groups of (a);
R3selected from saturated or unsaturated heterocycles containing 5 to 8 atoms, or R2And R3Together form a saturated heterocyclic ring containing 5 to 8 atoms.
11. Use according to claim 10, wherein the saturated or unsaturated heterocyclic ring containing 5 to 8 atoms is selected from: furan ring, pyrrole ring, thiophene ring, pyridine ring, pyrimidine ring, pyran ring, tetrahydrofuran ring, tetrahydropyrrole ring, hexahydropyridine ring, 2, 3-dihydropyrrole ring, morpholine ring.
12. The use according to claim 10, wherein the compound of formula I is reacted with the active nucleophilic activator in an organic solvent selected from one or a combination of tetrahydrofuran, 1,4 dioxane, 2-methyltetrahydrofuran, toluene, pyridine or acetonitrile; and/or
Reacting the compound shown in the formula I with an active nucleophilic activating agent in the presence of a base, wherein the base is selected from one or a combination of triethylamine, diisopropylethylamine, 4-N, N-dimethylaminopyridine, pyridine and 2, 6-dimethylpyridine; and/or
The active nucleophilic activating agent is selected from N-methylmorpholine and 4-N, N-dimethylaminopyridine; and/or
In the step ii'), a cyclization reagent is adopted for cyclization reaction, and the cyclization reagent is hydrazine hydrate or hydrazine hydrochloride or a combination thereof.
13. Use of a compound of formula I for the preparation of a compound of formula 5, 3- (4-phenoxyphenyl) -1H-pyrazolo [3,4-d ] pyrimidin-4-amine, comprising the steps of:
i) a compound of formula I with an active nucleophilic activator NR1R2R3Reacting to obtain an active intermediate compound shown as a formula II;
II) carrying out cyclization reaction on the compound of the formula II to obtain a compound of a formula 4;
iii) carrying out a ring closing reaction on the compound of the formula 4 and formamide or formamidine acetate to obtain a compound of a formula 5,
wherein R is as defined in claim 1;
R1is H or C1-C3Alkyl groups of (a);
R2is H or C1-C3Alkyl groups of (a);
R3selected from saturated or unsaturated heterocycles containing 5 to 8 atoms, or R2And R3Together forming a ring containing 5-8 atomsA saturated heterocyclic ring.
14. The use according to claim 13, wherein the compound of formula I is reacted with the active nucleophilic activator in an organic solvent selected from one or a combination of tetrahydrofuran, 1,4 dioxane, 2-methyltetrahydrofuran, toluene, pyridine or acetonitrile; and/or
Reacting the compound shown in the formula I with an active nucleophilic activating agent in the presence of a base, wherein the base is selected from one or a combination of triethylamine, diisopropylethylamine, 4-N, N-dimethylaminopyridine, pyridine and 2, 6-dimethylpyridine; and/or
The active nucleophilic activating agent is selected from N-methylmorpholine and 4-N, N-dimethylaminopyridine; and/or
In the step ii), a cyclization reagent is adopted in the cyclization reaction, and the cyclization reagent is hydrazine hydrate or hydrazine hydrochloride or a combination thereof; and/or
And in the step iii), the ring closure reaction is carried out in an organic solvent, wherein the organic solvent is one or a combination of more than two of N-butyl alcohol, N-methylpyrrolidone and N, N-dimethylformamide.
15. A process for the preparation of a compound of formula 4, said process comprising the steps of:
a') reacting a compound 2- [ hydroxy (4-phenoxyphenyl) methylene ] malononitrile of formula 3 with a hydroxy activating reagent RX to obtain a compound of formula I;
b') A compound of the formula I with an active nucleophilic activator NR1R2R3Reacting to obtain an active intermediate compound shown as a formula II;
c') subjecting the compound of formula II to cyclization reaction to obtain a compound of formula 4,
wherein R is as defined in claim 1, X is halogen,
R1is H or C1-C3Alkyl groups of (a);
R2is H or C1-C3Alkyl groups of (a);
R3selected from saturated or unsaturated heterocycles containing 5 to 8 atoms, or R2And R3Together form a saturated heterocyclic ring containing 5 to 8 atoms.
16. The method of claim 15, wherein the method has one or more of the following characteristics:
1) the hydroxyl activating reagent is paratoluensulfonyl chloride, methylsulfonyl chloride, benzene sulfonyl chloride or trifluoromethanesulfonyl chloride;
2) the reaction of the step a') is carried out in the presence of a base, wherein the base is selected from one or a combination of triethylamine, diisopropylethylamine, 4-N, N-dimethylaminopyridine, pyridine and 2, 6-dimethylaminopyridine;
3) reacting the compound shown in the formula I with an active nucleophilic activating agent in an organic solvent, wherein the organic solvent is one or the combination of tetrahydrofuran, 1,4 dioxane, 2-methyltetrahydrofuran, toluene, pyridine or acetonitrile;
4) reacting the compound shown in the formula I with an active nucleophilic activating agent in the presence of a base, wherein the base is selected from one or a combination of triethylamine, diisopropylethylamine, 4-N, N-dimethylaminopyridine, pyridine and 2, 6-dimethylpyridine;
5) the active nucleophilic activating agent is selected from N-methylmorpholine and 4-N, N-dimethylaminopyridine;
6) in the step c'), a cyclization reagent is adopted in the cyclization reaction, and the cyclization reagent is hydrazine hydrate or hydrazine hydrochloride or a combination thereof;
7) the three steps of the steps a '), b ') and c ') adopt a one-pot stir-frying mode.
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