WO2015172713A1 - 一种中间体的制备方法 - Google Patents

一种中间体的制备方法 Download PDF

Info

Publication number
WO2015172713A1
WO2015172713A1 PCT/CN2015/078800 CN2015078800W WO2015172713A1 WO 2015172713 A1 WO2015172713 A1 WO 2015172713A1 CN 2015078800 W CN2015078800 W CN 2015078800W WO 2015172713 A1 WO2015172713 A1 WO 2015172713A1
Authority
WO
WIPO (PCT)
Prior art keywords
compound
formula
temperature
organic solvent
base
Prior art date
Application number
PCT/CN2015/078800
Other languages
English (en)
French (fr)
Inventor
姚博
杨凤智
肖毅
李华
Original Assignee
广东东阳光药业有限公司
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by 广东东阳光药业有限公司 filed Critical 广东东阳光药业有限公司
Priority to CN201580024420.6A priority Critical patent/CN106458919B/zh
Publication of WO2015172713A1 publication Critical patent/WO2015172713A1/zh

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C15/00—Cyclic hydrocarbons containing only six-membered aromatic rings as cyclic parts
    • C07C15/40—Cyclic hydrocarbons containing only six-membered aromatic rings as cyclic parts substituted by unsaturated carbon radicals
    • C07C15/42—Cyclic hydrocarbons containing only six-membered aromatic rings as cyclic parts substituted by unsaturated carbon radicals monocyclic
    • C07C15/44—Cyclic hydrocarbons containing only six-membered aromatic rings as cyclic parts substituted by unsaturated carbon radicals monocyclic the hydrocarbon substituent containing a carbon-to-carbon double bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C253/00—Preparation of carboxylic acid nitriles
    • C07C253/30—Preparation of carboxylic acid nitriles by reactions not involving the formation of cyano groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C255/00—Carboxylic acid nitriles
    • C07C255/01—Carboxylic acid nitriles having cyano groups bound to acyclic carbon atoms
    • C07C255/32—Carboxylic acid nitriles having cyano groups bound to acyclic carbon atoms having cyano groups bound to acyclic carbon atoms of a carbon skeleton containing at least one six-membered aromatic ring
    • C07C255/37—Carboxylic acid nitriles having cyano groups bound to acyclic carbon atoms having cyano groups bound to acyclic carbon atoms of a carbon skeleton containing at least one six-membered aromatic ring the carbon skeleton being further substituted by etherified hydroxy groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C68/00—Preparation of esters of carbonic or haloformic acids
    • C07C68/02—Preparation of esters of carbonic or haloformic acids from phosgene or haloformates
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C69/00—Esters of carboxylic acids; Esters of carbonic or haloformic acids
    • C07C69/96—Esters of carbonic or haloformic acids
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
    • C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
    • C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D231/14—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D231/38—Nitrogen atoms

Definitions

  • the invention relates to an intermediate for preparing ibrutinib and a preparation method thereof, and belongs to the technical field of pharmacy.
  • Bruton's tyrosine kinase is an important mediator of at least three key B cell survival mechanisms, allowing B-cell malignancies to enter lymphoid tissues, allowing tumor cells to survive the necessary microenvironment. Selective inhibition of Bruton's tyrosine kinase (BTK) can inhibit tumor proliferation and thus achieve tumor treatment.
  • Ibrutinib the English name Ibrutinib, is a selective inhibitor of Bruton's tyrosine kinase (BTK), which can be used to treat diseases such as relapsed or refractory mantle cell lymphoma (MCL) on the market.
  • BTK Bruton's tyrosine kinase
  • MCL mantle cell lymphoma
  • Patent applications WO2008039218, WO2013101136, WO2013003629, WO2001019829 and the like disclose a process for obtaining ibrutinib or other pharmacologically active compound by a series of steps using a compound of the formula (04).
  • the compound represented by the formula (04) is an important intermediate, and its structure is represented by the formula (04), and the compound represented by the formula (04) exists as a tautomer, and the following formula Show:
  • the present invention provides a process for the preparation of a compound of the formula (04) for the preparation of ibrutinib.
  • the present invention provides novel compounds for the preparation of compounds of formula (04) and processes for their preparation.
  • Ibrutinib (English name Ibrutinib) refers to the chemical name 1-[(3R)-3-[4-amino-3-(4-phenoxyphenyl)-1H-pyrazole[3,4 a compound of -D]pyrimidin-1-yl]-1-piperidinyl]-2-propen-1-one.
  • the separation of the intermediate means that the product of the intermediate reaction step is not separated during the multi-step reaction for preparing the target product, and is not subjected to concentration or crystallization to obtain a concentrate or a solid product.
  • the inventors have developed a new method for preparing a compound of the formula (04) by research.
  • the preparation method is simple in operation, low in cost, and is favorable for industrial production, thereby facilitating industrial preparation of ibrutinib.
  • the present invention provides a process for the preparation of a compound of the formula (04), which comprises: a compound of the formula (03) is subjected to a cyclization reaction with hydrazine to prepare a compound of the formula (04).
  • R 3 is a leaving group and may be selected from chlorine, bromine, or iodine. In some embodiments, the R 3 is chlorine. In some embodiments, the R 3 is bromine.
  • the hydrazine may be an aqueous solution of hydrazine, a salt of hydrazine, or other solvent of hydrazine.
  • the hydrazine is an aqueous solution of hydrazine having a concentration of from 40% to 80%.
  • the temperature of the reaction liquid is controlled to be -10 ° C to 100 ° C.
  • the temperature of the reaction liquid is controlled at -10 ° C to 100 ° C for 0.1 to 2 hours; and then, the compound (04) is obtained by separation.
  • the molar ratio of the compound of the formula (03) to hydrazine may be from 1:1 to 1:2. In some embodiments, the molar ratio of compound (03) to hydrazine is from 1:1 to 1:1.5.
  • the fourth organic solvent is selected from one or more of the group consisting of dichloromethane, toluene, xylene, acetonitrile, 2-methyltetrahydrofuran, ethyl acetate and isopropyl acetate.
  • the fourth organic solvent is toluene.
  • the fourth organic solvent is acetonitrile.
  • the fourth reaction temperature is from -10 °C to 100 °C. In some embodiments, the fourth reaction temperature is between 0 ° C and 30 ° C. In some embodiments, the fourth reaction temperature is from 30 °C to 80 °C.
  • R 3 is chloro, and the compound of formula (03) is reacted with hydrazine in toluene at 20 ° C to 40 ° C until the reaction is complete to prepare a compound of formula (04).
  • the above-mentioned method of obtaining a compound represented by the formula (04) by a cyclization reaction using a compound represented by the formula (03) is advantageous for reaction operation and cost control, and is suitable for industrial production.
  • the compound of the above formula (03) can be produced from the compound (02).
  • the method for preparing the compound (03) comprises: halogenating a compound represented by the formula (02) by a halogenating agent to obtain a compound (03).
  • R 3 is a leaving group and may be selected from the group consisting of chlorine, bromine and iodine.
  • a compound of the formula (03) is obtained by reacting a compound of the formula (02) with a halogenating agent in a third organic solvent at a third temperature.
  • the halogenating agent is dichlorosulfoxide, phosphorus oxychloride, phosphorus pentachloride, a bromine-containing halogenating agent such as N-bromosuccinimide or the like, or an iodine-containing halogenating agent or the like.
  • the halogenating agent is phosphorus oxychloride.
  • the halogenating reagent is thionyl sulfoxide.
  • the molar ratio of the compound of the formula (02) to the halogenating agent is from 1:1 to 1:3.
  • the combination of formula (02) The molar ratio of the substance to the halogenating agent was 1:1.0-1:3.
  • the molar ratio of the compound of formula (02) to the halogenating agent is from 1:2.4 to 1:3.
  • the third organic solvent is selected from one or more of toluene, xylene, acetonitrile, 2-methyltetrahydrofuran, ethyl acetate and isopropyl acetate.
  • the third organic solvent is toluene.
  • the organic solvent S3 is ethyl acetate.
  • the third temperature is from 15 °C to 100 °C. In some embodiments, the third temperature is from 50 °C to 80 °C.
  • the compound of the formula (02) is reacted with phosphorus oxychloride in toluene at 60 ° C to 80 ° C for 2 hours to 4 hours to obtain a compound of the formula (03).
  • the above method for preparing the compound represented by the formula (03) avoids the use of high-risk, highly toxic reagents such as azide or dimethyl sulfate, is beneficial to the health of the operation and production personnel, is environmentally friendly, and can also reduce the cost, and is suitable for Industrial production.
  • the compound of the formula (02) can be produced by a compound of the formula (01) or by another known method as disclosed in the patent application WO2008039218.
  • the present invention also provides a method for preparing the compound (02) which is different from the prior art, which comprises reacting a compound of the formula (01) with malononitrile to obtain a compound of the formula (02).
  • R 1 is methoxy, ethoxy, propoxy or benzyloxy.
  • a compound of the formula (01) is reacted with malononitrile to obtain a compound of the formula (02).
  • the reaction of the compound of the formula (01) with malononitrile is carried out in the presence of a second base in a second organic solvent at a second temperature.
  • the second base is selected from one or more of triethylamine, N,N-diisopropylethylamine, N,N-dimethylaniline, N-methylmorpholine. In one embodiment, the second base is triethylamine. In one embodiment, the second base is N,N-diisopropylethylamine.
  • the second organic solvent is selected from one or more of the group consisting of dichloromethane, toluene, xylene, acetonitrile, 2-methyltetrahydrofuran, ethyl acetate and isopropyl acetate.
  • the second organic solvent is dichloromethane.
  • the second organic solvent is toluene.
  • the second organic solvent is ethyl acetate.
  • the second temperature is between -20 ° C and 30 ° C. In some embodiments, the second temperature is between -15 ° C and 30 ° C. In some embodiments, the second reaction temperature is from -10 °C to 30 °C. In some embodiments, the second reaction temperature is from 15 ° C to 30 ° C. In some embodiments, the second temperature is between -5 ° C and 10 ° C. In some embodiments, the second temperature is between -5 °C and 5 °C.
  • the molar ratio of the compound of the formula (01) to malononitrile is from 1:1 to 1:2. In some embodiments, the molar ratio of the compound of formula (01) to malononitrile is from 1:1 to 1:1.2.
  • the molar ratio of the compound of the formula (01) to the second base may be from 1:1 to 1:3.5. In one embodiment, the molar ratio of the compound of formula (01) to the second base is 1:1.2-1:3. In one embodiment, the molar ratio of the compound of formula (01) to the second base is 1:1.2-1:2.6.
  • the compound of the formula (01) is reacted with malononitrile in toluene in the presence of triethylamine at -5 ° C to 5 ° C for 2 hours to 3 hours to obtain the formula (02).
  • the above method for preparing the compound of the formula (02) using the compound represented by the formula (01) does not require an overnight reaction for a long time, has a simple process, is easy to operate, is advantageous for cost control, and is suitable for industrial production.
  • the above compound (01) can be obtained by subjecting the compound 4-phenoxybenzoic acid to acylation.
  • a method for preparing the compound (01) comprises: acylation of 4-phenoxybenzoic acid with a compound of the formula (01-1) to obtain a compound of the formula (01),
  • R 1 is methoxy, ethoxy, propoxy or benzyloxy; and X is fluorine, chlorine, bromine or iodine.
  • the first base is selected from one or more of triethylamine, N,N-diisopropylethylamine, N,N-dimethylaniline and N-methylmorpholine.
  • the first base is triethylamine.
  • the first base is N,N-diisopropylethylamine.
  • the first organic solvent is selected from the group consisting of dichloromethane, toluene, xylene, acetonitrile, 2-methyltetrahydrofuran, ethyl acetate, isopropyl acetate, dimethylformamide (DMF) or A variety.
  • the first organic solvent is dichloromethane.
  • the first organic solvent is toluene.
  • the first organic solvent is ethyl acetate.
  • the first temperature is between -20 ° C and 20 ° C. In some embodiments, the first temperature is between -15 °C and 20 °C. In some embodiments, the first temperature is between -10 °C and 20 °C. In some embodiments, the first temperature is between -10 °C and 10 °C. In some embodiments, the first temperature is between -5 °C and 5 °C.
  • the molar ratio of the 4-phenoxybenzoic acid to the compound represented by the formula (01-1) may be from 1:1 to 1:1.5. In some embodiments, The molar ratio of 4-phenoxybenzoic acid to the compound of the formula (01-1) is 1:1.05-1:1.2.
  • the molar ratio of the 4-phenoxybenzoic acid to the first base may be from 1:1 to 1:3.5. In some embodiments, the molar ratio of 4-phenoxybenzoic acid to the first base is 1:1:1 to 1:3. In some embodiments, the molar ratio of 4-phenoxybenzoic acid to the first base is from 1:2.5 to 1:3.
  • 4-phenoxybenzoic acid and ethyl chloroformate are reacted in the presence of triethylamine in toluene at -10 ° C to 10 ° C for 2 hours to 3 hours to prepare a formula (01). Show compound.
  • the compound of the formula (01) can be isolated and then subjected to the next reaction; or it can be directly carried out without isolation.
  • the next step is to react.
  • the method for preparing the compound (01) by the acylation reaction of the above 4-phenoxybenzoic acid with the compound (01-1) does not require vacuum distillation to remove the strong acidic reagent, which is advantageous for operation, is advantageous for controlling cost, and is suitable for industrialization. produce.
  • 4-phenoxybenzoic acid is reacted with a compound of formula (01-1) to produce a compound of formula (01); a compound of formula (01) is reacted with malononitrile to produce a compound of the formula (02); a compound of the formula (02) is reacted with a halogenating reagent to obtain a compound of the formula (03); a compound of the formula (03) is reacted with hydrazine to prepare a compound of the formula (04).
  • R 1 , R 3 , X are as defined above:
  • the same reaction solvent or different reaction solvents may be used for the respective steps in the above production method; the same base may be used, or a different base may be used.
  • the compound represented by the formula (01) and/or the compound of the formula (02) and/or the compound of the formula (03) can be isolated.
  • the compound represented by the formula (01) and/or the compound of the formula (02) and/or the compound of the formula (03) may not be isolated.
  • R 1 is ethoxy
  • R 3 is chloro
  • X is chlorine. In some embodiments, X is bromine.
  • the compound of formula (01-1) is reacted with 4-phenoxybenzoic acid in the presence of a first base in a first organic solvent at a first temperature to produce formula (01). a compound of the formula (02); and then a compound of the formula (01) is reacted with malononitrile in a second organic solvent in the presence of a second base at a second temperature to obtain a compound of the formula (02);
  • the first base and the second base may be The same base, the first organic solvent and the second organic solvent may be the same organic solvent; the same base is selected from the group consisting of triethylamine, N,N-diisopropylethylamine, N,N-dimethyl One or more of aniline, N-methylmorpholine; the same organic solvent is selected from the group consisting of dichloromethane, toluene, xylene, acetonitrile, 2-methyltetrahydrofuran, ethyl acetate,
  • 4-phenoxybenzoic acid is reacted with compound (01-1) to produce compound (01); compound (01) is reacted with malononitrile to produce compound (02); compound (02)
  • the compound (03) is obtained by reacting with a halogenating reagent; in the process, the intermediate compound (01) and/or the compound (02) may be isolated; or the intermediate compound (01) and/or the compound (02) may not be isolated. ).
  • 4-phenoxybenzoic acid is reacted with a compound of formula (01-1) to form a compound of formula (01); and then reacted with malononitrile to form a compound of formula (02) And reacting with phosphorus oxychloride to form a compound of the formula (03); and then subjected to hydrazine to obtain a compound of the formula (04); in the process, the compound of the formula (01) is isolated, and / Or a compound represented by the formula (02), and/or a compound represented by the formula (03).
  • 4-phenoxybenzoic acid is reacted with a compound of formula (01-1) to form a compound of formula (01); then malononitrile is added to form a compound of formula (02); After chlorination with phosphorus oxychloride, a compound of the formula (03) is formed; then, by hydrazine, a compound of the formula (04) is obtained; in the process, the compound of the formula (02) is isolated, and the other intermediate The body does not separate.
  • 4-phenoxybenzoic acid is reacted with a compound of formula (01-1) to form a compound of formula (01); then malononitrile is added to form a compound of formula (02); After chlorination with phosphorus oxychloride, a compound of the formula (03) is formed; then, by hydrazine, a compound of the formula (04) is obtained; in the process, the compound of the formula (03) is isolated, and the other intermediate The body does not separate.
  • 4-phenoxybenzoic acid is reacted with a compound of formula (01-1) to form a compound of formula (01); then malononitrile is added to form a compound of formula (02); Further, chlorination with phosphorus oxychloride produces a compound of the formula (03); and then, by hydrazine, a compound of the formula (04) is obtained; in the process, the respective intermediates are not isolated.
  • the method for preparing the intermediate compound of the formula (04) according to the present invention can avoid the use of azide or dimethyl sulfate by using the novel compound represented by the formula (03) and/or the compound represented by the formula (01).
  • Hazardous, highly toxic reagents or solvents, and easy to operate, environmentally friendly, good for production control and production personnel health, can reduce costs, suitable for industrial production.
  • the present invention provides a compound having the structure shown in formula (03):
  • R 3 is chlorine, bromine or iodine.
  • the present invention provides a process for preparing a compound of the formula (03), which comprises: a compound represented by the formula (02) is subjected to a halogenation reaction under the action of a halogenating agent to obtain a compound (03).
  • R 3 is a leaving group and may be selected from the group consisting of chlorine, bromine and iodine.
  • the compound of the formula (02) is reacted with a halogenating agent in a fifth organic solvent at a fifth temperature to obtain a compound of the formula (03).
  • the halogenating agent is dichlorosulfoxide, phosphorus oxychloride, phosphorus pentachloride, a bromine-containing halogenating agent such as N-bromosuccinimide or the like, or an iodine-containing halogenating agent or the like.
  • the halogenating agent is phosphorus oxychloride.
  • the halogenating reagent is thionyl sulfoxide.
  • the molar ratio of the compound of the formula (02) to the halogenating agent is from 1:1 to 1:3. In some embodiments, the molar ratio of the compound of formula (02) to the halogenating agent is 1:1.2-1:3. In some embodiments, the molar ratio of the compound of formula (02) to the halogenating agent is from 1:2.4 to 1:3.
  • the fifth organic solvent is selected from one or more of toluene, xylene, acetonitrile, 2-methyltetrahydrofuran, ethyl acetate and isopropyl acetate.
  • the fifth organic solvent is toluene.
  • the fifth organic solvent is ethyl acetate.
  • the fifth temperature is from 15 °C to 100 °C. In one embodiment, the fifth temperature is from 50 °C to 80 °C.
  • the compound of the formula (02) is reacted with phosphorus oxychloride in toluene at 60 ° C to 80 ° C for 2 hours to 4 hours to obtain a compound of the formula (03).
  • the above method for preparing the compound represented by the formula (03) avoids the use of high-risk, highly toxic reagents such as azide or dimethyl sulfate, which is advantageous. It is economical and environmentally friendly for operators and production personnel, and it can also reduce costs and is suitable for industrial production.
  • the compound of the formula (02) can be produced by a compound of the formula (01) or by another known method as disclosed in the patent application WO2008039218.
  • the present invention also provides a method for preparing the compound (02) which is different from the prior art, which comprises reacting a compound of the formula (01) with malononitrile to obtain a compound of the formula (02).
  • R 1 is methoxy, ethoxy, propoxy or benzyloxy.
  • a compound of the formula (01) is reacted with malononitrile to obtain a compound of the formula (02).
  • the compound of the formula (01) is reacted with malononitrile in the presence of a third base in a sixth organic solvent at a sixth temperature.
  • the third base is selected from one or more of triethylamine, N,N-diisopropylethylamine, N,N-dimethylaniline and N-methylmorpholine. In one embodiment, the third base is triethylamine. In one embodiment, the third base is N,N-diisopropylethylamine.
  • the sixth organic solvent is selected from one or more of the group consisting of dichloromethane, toluene, xylene, acetonitrile, 2-methyltetrahydrofuran, ethyl acetate and isopropyl acetate.
  • the sixth organic solvent is dichloromethane.
  • the sixth organic solvent is toluene.
  • the sixth organic solvent is ethyl acetate.
  • the sixth temperature is -20 ° C to 30 ° C. In one embodiment, the sixth temperature is between -15 ° C and 30 ° C. In one embodiment, the sixth reaction temperature is from -10 °C to 30 °C. In one embodiment, the sixth reaction temperature is from 15 ° C to 30 ° C. In one embodiment, the sixth temperature is between -5 °C and 10 °C. In one embodiment, the sixth temperature is between -5 °C and 5 °C.
  • the molar ratio of the compound of the formula (01) to malononitrile is from 1:1 to 1:2. In some embodiments, the molar ratio of the compound of formula (01) to malononitrile is from 1:1 to 1:1.2.
  • the molar ratio of the compound of the formula (01) to the second base may be from 1:1 to 1:3.5. In some embodiments, the molar ratio of the compound of formula (01) to the third base is 1:1.2-1:3. In one embodiment, the molar ratio of the compound of formula (01) to the third base is from 1:1.2 to 1:2.6.
  • the compound of the formula (01) is reacted with malononitrile in toluene in the presence of triethylamine at -5 ° C to 5 ° C for 2 hours to 3 hours to obtain the formula (02).
  • the above method for preparing the compound of the formula (02) using the compound represented by the formula (01) does not require an overnight reaction for a long period of time, and the process is simple and convenient. It is good for cost control and suitable for industrial production.
  • the above compound (01) can be obtained by subjecting the compound 4-phenoxybenzoic acid to acylation.
  • a method for preparing a compound of the formula (01) comprises: acylation of 4-phenoxybenzoic acid with a compound of the formula (01-1) to obtain a compound of the formula (01),
  • R 1 is methoxy, ethoxy, propoxy or benzyloxy; and X is fluorine, chlorine, bromine or iodine.
  • the fourth base is selected from one or more of triethylamine, N,N-diisopropylethylamine, N,N-dimethylaniline, N-methylmorpholine. In one embodiment, the fourth base is triethylamine. In one embodiment, the fourth base is N,N-diisopropylethylamine.
  • the seventh organic solvent is selected from the group consisting of dichloromethane, toluene, xylene, acetonitrile, 2-methyltetrahydrofuran, ethyl acetate, isopropyl acetate, and dimethylformamide (DMF). Or a variety.
  • the seventh organic solvent is dichloromethane.
  • the seventh organic solvent is toluene.
  • the seventh organic solvent is ethyl acetate.
  • the seventh temperature is between -20 ° C and 20 ° C. In some embodiments, the seventh temperature is between -15 °C and 20 °C. In some embodiments, the seventh temperature is between -10 °C and 20 °C. In some embodiments, the seventh temperature is between -10 °C and 10 °C. In one embodiment, the seventh temperature is between -5 °C and 5 °C.
  • the molar ratio of the 4-phenoxybenzoic acid to the compound represented by the formula (01-1) may be from 1:1 to 1:1.5. In some embodiments, the molar ratio of 4-phenoxybenzoic acid to the compound of formula (01-1) is from 1:1.05 to 1:1.2.
  • the molar ratio of the 4-phenoxybenzoic acid to the first base may be from 1:1 to 1:3.5. In some embodiments, the molar ratio of 4-phenoxybenzoic acid to the fourth base is 1:1.3 to 1:3. In one embodiment, the molar ratio of 4-phenoxybenzoic acid to the fourth base is from 1:2.5 to 1:3.
  • 4-phenoxybenzoic acid and ethyl chloroformate are reacted in the presence of triethylamine in toluene at -10 ° C to 10 ° C for 2 hours to 3 hours to prepare the formula (01). Show compound.
  • the compound of the formula (01) can be isolated and then subjected to the next reaction; or it can be directly carried out without isolation.
  • the next step is to react.
  • the method for preparing the compound (01) by subjecting the above 4-phenoxybenzoic acid to the acylation reaction of the compound (01-1), does not require vacuum distillation to remove the strong acidity
  • the reaction reagent is advantageous for operation, is advantageous for controlling cost, and is suitable for industrial production.
  • 4-phenoxybenzoic acid is reacted with a compound of formula (01-1) to produce a compound of formula (01); a compound of formula (01) is reacted with malononitrile to produce A compound of the formula (02); a compound of the formula (02) is reacted with a halogenating reagent to obtain a compound of the formula (03); wherein R 1 , R 3 , X are as defined above:
  • the same reaction solvent or different reaction solvents may be used for the respective steps in the above production method; the same base may be used, or a different base may be used.
  • the compound represented by the formula (01) and/or the compound of the formula (02) and/or the compound of the formula (03) can be isolated.
  • the compound represented by the formula (01) and/or the compound of the formula (02) and/or the compound of the formula (03) may not be isolated.
  • R 1 is ethoxy
  • R 3 is chloro
  • X is chlorine. In one embodiment, X is bromine.
  • the compound of formula (01-1) is reacted with 4-phenoxybenzoic acid in the presence of a fourth base in a seventh organic solvent at a seventh temperature to produce formula (01).
  • a compound of the formula (01) which is then reacted with malononitrile in a sixth organic solvent in the presence of a third base at a sixth temperature to produce a compound of the formula (02);
  • the third base and the fourth base may use the same base
  • the sixth organic solvent and the seventh organic solvent may use the same organic solvent;
  • the same base is selected from triethylamine, N, N-di One or more of isopropylethylamine, N,N-dimethylaniline, N-methylmorpholine;
  • the same organic solvent is selected from the group consisting of dichloromethane, toluene, xylene, acetonitrile, 2 One or more of methyltetrahydrofuran, ethyl acetate, and isopropyl acetate.
  • 4-phenoxybenzoic acid is reacted with compound (01-1) to produce compound (01); compound (01) is reacted with malononitrile to produce compound (02); compound (02)
  • the compound (03) is obtained by reacting with a halogenating reagent; in the process, the intermediate compound (01) and/or the compound (02) may be isolated; or the intermediate compound (01) and/or the compound (02) may not be isolated. ).
  • 4-phenoxybenzoic acid is reacted with a compound of formula (01-1) to form a compound of formula (01);
  • the dinitrile is reacted to form a compound of the formula (02); and then reacted with phosphorus oxychloride to form a compound of the formula (03); in the process, the compound of the formula (01) is isolated, and/or a compound represented by (02), and/or a compound represented by the formula (03).
  • 4-phenoxybenzoic acid is reacted with a compound of formula (01-1) to form a compound of formula (01); then malononitrile is added to form a compound of formula (02); After chlorination with phosphorus oxychloride, a compound of the formula (03) is formed; in the process, the compound of the formula (02) is isolated, and the other intermediates are not isolated.
  • 4-phenoxybenzoic acid is reacted with a compound of formula (01-1) to form a compound of formula (01); then malononitrile is added to form a compound of formula (02); After chlorination with phosphorus oxychloride, a compound of the formula (03) is produced; in the process, the compound of the formula (03) is isolated, and the other intermediates are not isolated.
  • 4-phenoxybenzoic acid is reacted with a compound of formula (01-1) to form a compound of formula (01); then malononitrile is added to form a compound of formula (02); The mixture is further chlorinated with phosphorus oxychloride to form a compound of the formula (03); in the process, the respective intermediates are not isolated.
  • the method for preparing the intermediate compound of the formula (03) according to the present invention can avoid the use of a highly dangerous, highly toxic reagent or solvent such as azide or dimethyl sulfate by using the compound represented by the formula (01). Simple and environmentally friendly, it is conducive to the health of production control and production personnel, can reduce costs, and is suitable for industrial production.
  • reagents used in the present invention are all commercially available or can be prepared by the methods described herein.
  • MS mass spectrometry
  • Pure compounds were detected by UV using an Agilent 1260 pre-HPLC or Calesep pump 250 pre-HPLC (column model: NOVASEP 50/80 mm DAC) at 210 nm / 254 nm.
  • g represents gram and mL represents milliliter.
  • R 1 is an ethoxy group and R 3 is chlorine; when R 1 and R 3 are other groups, the following examples are carried out.
  • reaction liquid was cooled to room temperature, and washed with a saturated sodium hydrogencarbonate solution for 3 times, 10 mL each time, and then washed with saturated brine for 3 times, 10 mL each time, and the obtained toluene layer was evaporated to dryness to give a brown-yellow oil of 0.79 g. , is the compound (03).

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

本发明涉及一种中间体的制备方法，属于制药技术领域。所述中间体可用于制备依鲁替尼，所述制备方法包括将一种卤代化合物与肼在一定条件下反应，得到目标中间体化合物。所述卤代化合物可通过羟基化合物与卤化试剂反应而制得。所述制备方法操作简便，可以降低成本，有利于工业化生产。

Description

一种中间体的制备方法 技术领域
本发明涉及用于制备依鲁替尼的中间体及其制备方法，属于制药技术领域。
背景技术
布鲁顿酪氨酸激酶(BTK)是至少三种关键B细胞生存机制的重要介质，可以使B细胞恶性肿瘤进入淋巴组织，使肿瘤细胞能够接触必要的微环境而得以生存。选择性地抑制布鲁顿酪氨酸激酶(BTK)，可以抑制肿瘤的增殖，从而达到治疗肿瘤的作用。
依鲁替尼(英文名Ibrutinib)，是一种布鲁顿酪氨酸激酶(BTK)的选择性抑制剂，可用于治疗复发或难治性套细胞淋巴瘤(MCL)等疾病，在市场上具有突破性地位。依鲁替尼结构如式(1)所示：
Figure PCTCN2015078800-appb-000001
专利申请WO2008039218、WO2013101136、WO2013003629、WO2001019829等公开了用式(04)所示化合物经过一系列步骤制备得到依鲁替尼或其它具有药理活性作用的化合物的方法。在制备依鲁替尼的过程中，式(04)所示化合物是重要的中间体，其结构如式(04)所示，式(04)所示化合物存在互变异构体，如下式所示：
Figure PCTCN2015078800-appb-000002
式(04)所示化合物的互变异构体。
这些文献公开的方法中，在制备式(04)所示化合物过程中，需要使用硫酸二甲酯或叠氮化合物等高毒高危险性的试剂或者收率低，不适于工业化生产。寻找一种更优的适于工业化生产的制备式(04)所示化合物的方法是有必要的。
发明内容
发明概述
本发明提供了一种用于制备依鲁替尼的中间体式(04)所示化合物的制备方法。
本发明提供了用于制备式(04)所示化合物的新化合物及其制备方法。
术语定义
依鲁替尼(英文名Ibrutinib)，是指化学名为1-[(3R)-3-[4-氨基-3-(4-苯氧基苯基)-1H-吡唑并[3,4-D]嘧啶-1-基]-1-哌啶基]-2-丙烯-1-酮的化合物。
所述中间体不分离指在制备目标产物的多步反应过程中，对中间的反应步骤的产物不予以分离，不进行浓缩或结晶以获得浓缩液或者固体产物的过程。
在本发明的描述中，需要理解的是，术语例如“第一”、“第二”等类似术语仅用于描述目的，而不能理解为指示或暗示相对重要性或者隐含指明所指示的技术特征的数量。由此，限定有“第一”、“第二”的特征可以明示或者隐含地包括至少一个该特征。
在本发明的描述中，“多个”、“多种”的含义是至少两个，例如两个，三个等，除非另有明确具体的限定。
发明详述
发明人通过研究，开发了一种新的制备式(04)所示化合物的方法。这种制备方法操作简单，成本低，有利于工业化生产，从而有利于工业化制备依鲁替尼。
因此，第一方面，本发明提供了一种制备式(04)所示化合物的方法，其包括：式(03)所示化合物与肼进行环合反应，制备得到式(04)所示化合物，
Figure PCTCN2015078800-appb-000003
其中，R3为离去基团，可选自氯，溴，或碘。在一些实施方式中，所述R3为氯。在一些实施方式中，所述R3为溴。
根据本发明，所述环合反应中，所述式(03)所示化合物与肼在第四有机溶剂中，在第四温度反应进行， 制备得到化合物(04)。
根据本发明，所述肼可为肼的水溶液，肼的盐，或肼的其它溶剂物。在一实施方式中，所述肼是浓度为40％-80％的肼水溶液。加入肼时，控制反应液的温度在-10℃-100℃。在加入肼后，控制反应液的温度在-10℃-100℃，反应0.1小时-2小时；然后经过分离，可得到化合物(04)。
根据本发明，式(03)所示化合物与肼的摩尔比可为1:1-1:2。在一些实施方式中，化合物(03)与肼的摩尔比为1:1-1:1.5。
根据本发明，所述第四有机溶剂选自二氯甲烷，甲苯，二甲苯，乙腈，2-甲基四氢呋喃，乙酸乙酯，乙酸异丙酯中的一种或多种。在一实施方式中，所述第四有机溶剂为甲苯。在一实施方式中，所述第四有机溶剂为乙腈。
根据本发明，所述第四反应温度为-10℃-100℃。在一些实施方式中，所述第四反应温度为0℃-30℃。在一些实施方式中，所述第四反应温度为30℃-80℃。
在一些实施方式中，R3为氯，式(03)所示化合物与肼在甲苯中在20℃-40℃反应至反应完全，制备得到式(04)所示化合物。
上述使用式(03)所示化合物经过环合反应得到式(04)所示化合物的方法，有利于反应操作和成本控制，适于工业化生产。
根据本发明，上述式(03)所示化合物可由化合物(02)制备得到。制备化合物(03)的方法包括：式(02)所示化合物在卤化试剂作用下发生卤化反应，制得化合物(03)，
Figure PCTCN2015078800-appb-000004
其中，R3为离去基团，可选自氯，溴，碘。
根据本发明，所述卤化反应中，式(02)所示化合物与卤化试剂在第三有机溶剂中，在第三温度下，制得式(03)所示化合物。
根据本发明，所述卤化试剂为二氯亚砜，三氯氧磷，五氯化磷，含溴卤化试剂如N-溴代丁二酰亚胺等，或含碘卤化试剂等。在一实施方式中，所述卤化试剂为三氯氧磷。在一实施方式中，所述卤化试剂为二氯亚砜。
根据本发明，式(02)所示化合物与卤化试剂的摩尔比为1:1-1:3。在一些实施方式中，式(02)所示化合 物与卤化试剂的摩尔比为1:1.2-1:3。在一些实施方式中，式(02)所示化合物与卤化试剂与的摩尔比为1:2.4-1:3。
根据本发明，所述第三有机溶剂选自甲苯，二甲苯，乙腈，2-甲基四氢呋喃，乙酸乙酯，乙酸异丙酯中的一种或多种。在一实施方式中，所述第三有机溶剂为甲苯。在一实施方式中，所述有机溶剂S3为乙酸乙酯。
根据本发明，所述第三温度为15℃-100℃。在一些实施方式中，所述第三温度为50℃-80℃。
在一实施方式中，式(02)所示化合物与三氯氧磷在甲苯中，在60℃-80℃反应2小时-4小时，制得式(03)所示化合物。
上述制备式(03)所示化合物的方法，避免了使用叠氮类或硫酸二甲酯等高危险性、高毒性试剂，有利于操作和生产人员健康，环境友好，还可以降低成本，适于工业化生产。
根据本发明，所述式(02)所示化合物可用式(01)所示化合物制备得到或者其它已知的方法如专利申请WO2008039218中公开的方法制备。本发明还提供一种有别于现有技术的制备化合物(02)的方法，其包括：式(01)所示化合物与丙二腈反应，制得式(02)所示化合物，
Figure PCTCN2015078800-appb-000005
其中，R1为甲氧基，乙氧基，丙氧基，或苄氧基。
根据本发明，式(01)所示化合物与丙二腈反应，制得式(02)所示化合物。
根据本发明，所述式(01)所示化合物与丙二腈反应是在第二碱存在下，在第二有机溶剂中，在第二温度进行的。
根据本发明，所述第二碱选自三乙胺，N,N-二异丙基乙基胺，N,N-二甲基苯胺，N-甲基吗啉中的一种或多种。在一实施方式中，所述第二碱为三乙胺。在一实施方式中，所述第二碱为N,N-二异丙基乙基胺。
根据本发明，所述第二有机溶剂选自二氯甲烷，甲苯，二甲苯，乙腈，2-甲基四氢呋喃，乙酸乙酯，乙酸异丙酯中的一种或多种。在一实施方式中，所述第二有机溶剂为二氯甲烷。在一实施方式中，所述第二有机溶剂为甲苯。在一实施方式中，所述第二有机溶剂为乙酸乙酯。
根据本发明，所述第二温度为-20℃-30℃。在一些实施方式中，所述第二温度为-15℃-30℃。在一些实施方式中，所述第二反应温度为-10℃-30℃。在一些实施方式中，所述第二反应温度为15℃-30℃。在 一些实施方式中，所述第二温度为-5℃-10℃。在一些实施方式中，所述第二温度为-5℃-5℃。
根据本发明，式(01)所示化合物与丙二腈的摩尔比为1:1-1:2。在一些实施方式中，式(01)所示化合物与丙二腈的摩尔比为1:1-1:1.2。
根据本发明，式(01)所示化合物与第二碱的摩尔比可为1:1-1:3.5。在一实施方式中，式(01)所示化合物与所述第二碱的摩尔比为1:1.2-1:3。在一实施方式中，式所(01)示化合物与所述第二碱的摩尔比为1:1.2-1:2.6。
在一实施方式中，式(01)所示化合物与丙二腈在甲苯中，在三乙胺存在下，在-5℃-5℃反应2小时-3小时，制得式(02)所示化合物。
上述使用式(01)所示化合物制备式(02)所示化合物的方法，无需过夜长时间反应，工艺简便，操作便捷，有利于成本控制，适于工业化生产。
上述化合物(01)可由化合物4-苯氧基苯甲酸经过酰化制备得到。一种制备化合物(01)的方法包括：4-苯氧基苯甲酸与式(01-1)所示化合物进行酰化反应，制得式(01)所示化合物，
Figure PCTCN2015078800-appb-000006
其中，R1为甲氧基，乙氧基，丙氧基，或苄氧基；X为氟，氯，溴，或碘。
根据本发明，上述酰化反应中，4-苯氧基苯甲酸与式(01-1)所示化合物在第一有机溶剂中，在第一碱存在下，在第一温度下进行酰化反应，制得式(01)所示化合物。
根据本发明，所述第一碱选自三乙胺，N,N-二异丙基乙基胺，N,N-二甲基苯胺，N-甲基吗啉中一种或多种。在一实施方式中，所述第一碱为三乙胺。在一实施方式中，所述第一碱为N,N-二异丙基乙基胺。
根据本发明，所述第一有机溶剂选自二氯甲烷，甲苯，二甲苯，乙腈，2-甲基四氢呋喃，乙酸乙酯，乙酸异丙酯，二甲基甲酰胺(DMF)中一种或多种。在一实施方式中，所述第一有机溶剂为二氯甲烷。在一实施方式中，所述第一有机溶剂为甲苯。在一实施方式中，所述第一有机溶剂为乙酸乙酯。
根据本发明，所述第一温度为-20℃-20℃。在一些实施方式中，所述第一温度为-15℃-20℃。在一些实施方式中，所述第一温度为-10℃-20℃。在一些实施方式中，所述第一温度为-10℃-10℃。在一些实施方式中，所述第一温度为-5℃-5℃。
根据本发明，所述4-苯氧基苯甲酸与式(01-1)所示化合物的摩尔比可为1:1-1:1.5。在一些实施方式中， 4-苯氧基苯甲酸与式(01-1)所示化合物的摩尔比为1:1.05-1:1.2。
根据本发明，所述4-苯氧基苯甲酸与第一碱的摩尔比可为1:1-1:3.5。在一些实施方式中，4-苯氧基苯甲酸与所述第一碱的摩尔比为1:1.3-1:3。在一些实施方式中，4-苯氧基苯甲酸与所述第一碱的摩尔比为1:2.5-1:3。
在一实施方式中，4-苯氧基苯甲酸与氯甲酸乙酯在三乙胺存在下，在甲苯中，在-10℃-10℃反应2小时-3小时，制备得到式(01)所示化合物。
根据本发明，在式(01-1)所示化合物与4-苯氧基苯甲酸反应完毕后，可以分离出式(01)所示化合物，然后进行下一步反应；也可以不分离，直接进行下一步反应。
上述4-苯氧基苯甲酸与化合物(01-1)进行酰化反应制备化合物(01)的方法，不需要减压蒸馏除去强酸性反应试剂，有利于操作，有利于控制成本，适于工业化生产。
在一些实施方式中，4-苯氧基苯甲酸与式(01-1)所示化合物反应，制得式(01)所示化合物；式(01)所示化合物与丙二腈反应，制得式(02)所示化合物；式(02)所示化合物与卤化试剂反应，制得式(03)所示化合物；式(03)所示化合物与肼反应，制备得到式(04)所示化合物；如下式所示，其中，R1，R3，X如前述所定义：
Figure PCTCN2015078800-appb-000007
根据本发明，上述制备方法中的各步反应，可以使用相同的反应溶剂，也可以使用不同的反应溶剂；可以使用相同的碱，也可以使用不同的碱。
根据本发明，在制备得到式(04)所示化合物的过程中，可以分离出中间体式(01)所示化合物和/或式(02)所示化合物和/或式(03)所示化合物，也可以不分离中间体式(01)所示化合物和/或式(02)所示化合物和/或式(03)所示化合物。
在一些实施方式中，R1为乙氧基。
在一些实施方式中，R3为氯。
在一些实施方式中，X为氯。在一些实施方式中，X为溴。
在一些实施方式中，式(01-1)所示化合物与4-苯氧基苯甲酸，在第一碱存在下，在第一有机溶剂中，在第一温度下反应，制得式(01)所示化合物；然后式(01)所示化合物与丙二腈，在第二有机溶剂中，在第二碱存在下，在第二温度下反应，制得式(02)所示化合物；在此两步反应过程中，第一碱和第二碱可以是 相同的碱，第一有机溶剂和第二有机溶剂可以是相同的有机溶剂；所述相同的碱选自三乙胺，N,N-二异丙基乙基胺，N,N-二甲基苯胺，N-甲基吗啉中的一种或多种；所述相同的有机溶剂选自二氯甲烷，甲苯，二甲苯，乙腈，2-甲基四氢呋喃，乙酸乙酯，乙酸异丙酯中的一种或多种。所述碱或有机溶剂可以一次性加入反应器中，也可以分批加入；可以分离出中间体式(01)所示化合物，也可以不分离中间体式(01)所示化合物。
在一些实施方式中，4-苯氧基苯甲酸与化合物(01-1)反应，制得化合物(01)；化合物(01)与丙二腈反应，制得化合物(02)；化合物(02)与卤化试剂反应，制得化合物(03)；在此过程中，可以分离出中间体化合物(01)和/或化合物(02)；也可以不分离中间体化合物(01)和/或化合物(02)。
在一些实施方式中，使用4-苯氧基苯甲酸与式(01-1)所示化合物反应，生成式(01)所示化合物；然后与丙二腈反应，生成式(02)所示化合物；再与三氯氧磷反应，生成式(03)所示化合物；然后经过肼作用，得到式(04)所示化合物；在此过程中，分离出中间体式(01)所示化合物，和/或式(02)所示化合物，和/或式(03)所示化合物。
在一些实施方式中，使用4-苯氧基苯甲酸与式(01-1)所示化合物反应，生成式(01)所示化合物；然后加入丙二腈，生成式(02)所示化合物；再经过三氯氧磷氯化，生成式(03)所示化合物；然后经过肼作用，得到式(04)所示化合物；在此过程中，分离出中间体式(02)所示化合物，其它中间体不分离。
在一些实施方式中，使用4-苯氧基苯甲酸与式(01-1)所示化合物反应，生成式(01)所示化合物；然后加入丙二腈，生成式(02)所示化合物；再经过三氯氧磷氯化，生成式(03)所示化合物；然后经过肼作用，得到式(04)所示化合物；在此过程中，分离出中间体式(03)所示化合物，其它中间体不分离。
在一些实施方式中，使用4-苯氧基苯甲酸与式(01-1)所示化合物反应，生成式(01)所示化合物；然后加入丙二腈，生成式(02)所示化合物；再经过三氯氧磷氯化，生成式(03)所示化合物；然后经过肼作用，得到式(04)所示化合物；在此过程中，不分离各中间体。
本发明所述制备中间体式(04)所示化合物的方法，通过使用式(03)所示新化合物和/或式(01)所示化合物，可以避免使用叠氮类或硫酸二甲酯等高危险性、高毒性试剂或溶剂，并且操作简便、环境友好，有利于生产控制和生产人员健康，可以降低成本，适于工业化生产。
第二方面，本发明提供了一种化合物，其结构如式(03)所示：
Figure PCTCN2015078800-appb-000008
其中，R3为氯，溴或碘。
第三方面，本发明提供了一种制备式(03)所示化合物的方法，包括：式(02)所示化合物在卤化试剂作用下发生卤化反应，制得化合物(03)，
Figure PCTCN2015078800-appb-000009
其中，R3为离去基团，可选自氯，溴，碘。
根据本发明，所述卤化反应中，式(02)所示化合物与卤化试剂在第五有机溶剂中，在第五温度反应，制得式(03)所示化合物。
根据本发明，所述卤化试剂为二氯亚砜，三氯氧磷，五氯化磷，含溴卤化试剂如N-溴代丁二酰亚胺等，或含碘卤化试剂等。在一实施方案中，所述卤化试剂为三氯氧磷。在一实施方案中，所述卤化试剂为二氯亚砜。
根据本发明，式(02)所示化合物与卤化试剂的摩尔比为1:1-1:3。在一些实施方案中，式(02)所示化合物与卤化试剂的摩尔比为1:1.2-1:3。在一些实施方案中，式(02)所示化合物与卤化试剂与的摩尔比为1:2.4-1:3。
根据本发明，所述第五有机溶剂选自甲苯，二甲苯，乙腈，2-甲基四氢呋喃，乙酸乙酯，乙酸异丙酯中的一种或多种。在一实施方案中，所述第五有机溶剂为甲苯。在一实施方案中，所述第五有机溶剂为乙酸乙酯。
根据本发明，所述第五温度为15℃-100℃。在一实施方案中，所述第五温度为50℃-80℃。
在一实施方案中，式(02)所示化合物与三氯氧磷在甲苯中，在60℃-80℃反应2小时-4小时，制得式(03)所示化合物。
上述制备式(03)所示化合物的方法，避免了使用叠氮类或硫酸二甲酯等高危险性、高毒性试剂，有利 于操作和生产人员健康，环境友好，还可以降低成本，适于工业化生产。
本发明中，所述式(02)所示化合物可用式(01)所示化合物制备得到或者其它已知的方法如专利申请WO2008039218中公开的方法制备。本发明还提供一种有别于现有技术的制备化合物(02)的方法，其包括：式(01)所示化合物与丙二腈反应，制得式(02)所示化合物，
Figure PCTCN2015078800-appb-000010
其中，R1为甲氧基，乙氧基，丙氧基，或苄氧基。
根据本发明，式(01)所示化合物与丙二腈反应，制得式(02)所示化合物。
根据本发明，所述式(01)所示化合物与丙二腈反应在第三碱存在下，在第六有机溶剂中，在第六温度进行。
根据本发明，所述第三碱选自三乙胺，N,N-二异丙基乙基胺，N,N-二甲基苯胺，N-甲基吗啉中一种或多种。在一实施方案中，所述第三碱为三乙胺。在一实施方案中，所述第三碱为N,N-二异丙基乙基胺。
根据本发明，所述第六有机溶剂选自二氯甲烷，甲苯，二甲苯，乙腈，2-甲基四氢呋喃，乙酸乙酯，乙酸异丙酯中一种或多种。在一实施方案中，所述第六有机溶剂为二氯甲烷。在一实施方案中，所述第六有机溶剂为甲苯。在一实施方案中，所述第六有机溶剂为乙酸乙酯。
根据本发明，所述第六温度为-20℃-30℃。在一实施方案中，所述第六温度为-15℃-30℃。在一实施方案中，所述第六反应温度为-10℃-30℃。在一实施方案中，所述第六反应温度为15℃-30℃。在一实施方案中，所述第六温度为-5℃-10℃。在一实施方案中，所述第六温度为-5℃-5℃。
根据本发明，式(01)所示化合物与丙二腈的摩尔比为1:1-1:2。在一些实施方案中，式(01)所示化合物与丙二腈的摩尔比为1:1-1:1.2。
根据本发明，式(01)所示化合物与第二碱的摩尔比可为1:1-1:3.5。在一些实施方案中，式(01)所示化合物与所述第三碱的摩尔比为1:1.2-1:3。在一实施方案中，式所(01)示化合物与所述第三碱的摩尔比为1:1.2-1:2.6。
在一实施方案中，式(01)所示化合物与丙二腈在甲苯中，在三乙胺存在下，在-5℃-5℃反应2小时-3小时，制得式(02)所示化合物。
上述使用式(01)所示化合物制备式(02)所示化合物的方法，无需过夜长时间反应，工艺简便，操作便 捷，有利于成本控制，适于工业化生产。
上述化合物(01)可由化合物4-苯氧基苯甲酸经过酰化制备得到。一种制备式(01)所示化合物的方法包括：4-苯氧基苯甲酸与式(01-1)所示化合物进行酰化反应，制得式(01)所示化合物，
Figure PCTCN2015078800-appb-000011
其中，R1为甲氧基，乙氧基，丙氧基，或苄氧基；X为氟，氯，溴，或碘。
根据本发明，上述酰化反应中，4-苯氧基苯甲酸与式(01-1)所示化合物在第七有机溶剂中，在第四碱存在下，在第七温度进行酰化反应，制得式(01)所示化合物。
根据本发明，所述第四碱选自三乙胺，N,N-二异丙基乙基胺，N,N-二甲基苯胺，N-甲基吗啉中的一种或多。在一实施方案中，所述第四碱为三乙胺。在一实施方案中，所述第四碱为N,N-二异丙基乙基胺。
根据本发明，所述第七有机溶剂选自二氯甲烷，甲苯，二甲苯，乙腈，2-甲基四氢呋喃，乙酸乙酯，乙酸异丙酯，二甲基甲酰胺(DMF)中的一种或多种。在一实施方案中，所述第七有机溶剂为二氯甲烷。在一实施方案中，所述第七有机溶剂为甲苯。在一实施方案中，所述第七有机溶剂为乙酸乙酯。
根据本发明，所述第七温度为-20℃-20℃。在一些实施方案中，所述第七温度为-15℃-20℃。在一些实施方案中，所述第七温度为-10℃-20℃。在一些实施方案中，所述第七温度为-10℃-10℃。在一实施方案中，所述第七温度为-5℃-5℃。
根据本发明，所述4-苯氧基苯甲酸与式(01-1)所示化合物的摩尔比可为1:1-1:1.5。在一些实施方案中，4-苯氧基苯甲酸与式(01-1)所示化合物的摩尔比为1:1.05-1:1.2。
根据本发明，所述4-苯氧基苯甲酸与第一碱的摩尔比可为1:1-1:3.5。在一些实施方案中，4-苯氧基苯甲酸与所述第四碱的摩尔比为1:1.3-1:3。在一实施方案中，4-苯氧基苯甲酸与所述第四碱的摩尔比为1:2.5-1:3。
在一实施方案中，4-苯氧基苯甲酸与氯甲酸乙酯在三乙胺存在下，在甲苯中，在-10℃-10℃反应2小时-3小时，制备得到式(01)所示化合物。
根据本发明，在式(01-1)所示化合物与4-苯氧基苯甲酸反应完毕后，可以分离出式(01)所示化合物，然后进行下一步反应；也可以不分离，直接进行下一步反应。
上述4-苯氧基苯甲酸与化合物(01-1)进行酰化反应制备化合物(01)的方法，不需要减压蒸馏除去强酸性 反应试剂，有利于操作，有利于控制成本，适于工业化生产。
在一些实施方案中，4-苯氧基苯甲酸与式(01-1)所示化合物反应，制得式(01)所示化合物；式(01)所示化合物与丙二腈反应，制得式(02)所示化合物；式(02)所示化合物与卤化试剂反应，制得式(03)所示化合物；如下式所示，其中，R1，R3，X如前述所定义：
Figure PCTCN2015078800-appb-000012
根据本发明，上述制备方法中的各步反应，可以使用相同的反应溶剂，也可以使用不同的反应溶剂；可以使用相同的碱，也可以使用不同的碱。
根据本发明，在制备得到式(04)所示化合物的过程中，可以分离出中间体式(01)所示化合物和/或式(02)所示化合物和/或式(03)所示化合物，也可以不分离中间体式(01)所示化合物和/或式(02)所示化合物和/或式(03)所示化合物。
在一实施方案中，R1为乙氧基。
在一实施方案中，R3为氯。
在一实施方案中，X为氯。在一实施方案中，X为溴。
在一实施方案中，式(01-1)所示化合物与4-苯氧基苯甲酸，在第四碱存在下，在第七有机溶剂中，在第七温度反应，制得式(01)所示化合物；然后式(01)所示化合物与丙二腈，在第六有机溶剂中，在第三碱存在下，在第六温度反应，制得式(02)所示化合物；在此两步反应过程中，第三碱和第四碱可以使用相同的碱，第六有机溶剂和第七有机溶剂可以使用相同的有机溶剂；所述相同的碱选自三乙胺，N,N-二异丙基乙基胺，N,N-二甲基苯胺，N-甲基吗啉中的一种或多种；所述相同的有机溶剂选自二氯甲烷，甲苯，二甲苯，乙腈，2-甲基四氢呋喃，乙酸乙酯，乙酸异丙酯中的一种或多种。所述碱或有机溶剂可以一次性加入反应器中，也可以分批加入；可以分离出中间体式(01)所示化合物，也可以不分离中间体式(01)所示化合物。
在一实施方案中，4-苯氧基苯甲酸与化合物(01-1)反应，制得化合物(01)；化合物(01)与丙二腈反应，制得化合物(02)；化合物(02)与卤化试剂反应，制得化合物(03)；在此过程中，可以分离出中间体化合物(01)和/或化合物(02)；也可以不分离中间体化合物(01)和/或化合物(02)。
在一实施方案中，使用4-苯氧基苯甲酸与式(01-1)所示化合物反应，生成式(01)所示化合物；然后与丙 二腈反应，生成式(02)所示化合物；再与三氯氧磷反应，生成式(03)所示化合物；在此过程中，分离出中间体式(01)所示化合物，和/或式(02)所示化合物，和/或式(03)所示化合物。
在一实施方案中，使用4-苯氧基苯甲酸与式(01-1)所示化合物反应，生成式(01)所示化合物；然后加入丙二腈，生成式(02)所示化合物；再经过三氯氧磷氯化，生成式(03)所示化合物；在此过程中，分离出中间体式(02)所示化合物，其它中间体不分离。
在一实施方案中，使用4-苯氧基苯甲酸与式(01-1)所示化合物反应，生成式(01)所示化合物；然后加入丙二腈，生成式(02)所示化合物；再经过三氯氧磷氯化，生成式(03)所示化合物；在此过程中，分离出中间体式(03)所示化合物，其它中间体不分离。
在一实施方案中，使用4-苯氧基苯甲酸与式(01-1)所示化合物反应，生成式(01)所示化合物；然后加入丙二腈，生成式(02)所示化合物；再经过三氯氧磷氯化，生成式(03)所示化合物；在此过程中，不分离各中间体。
本发明所述制备中间体式(03)所示化合物的方法，通过使用式(01)所示化合物，可以避免使用叠氮类或硫酸二甲酯等高危险性、高毒性试剂或溶剂，并且操作简便、环境友好，有利于生产控制和生产人员健康，可以降低成本，适于工业化生产。
具体实施方式
为了使本领域的技术人员更好地理解本发明的技术方案，下面进一步披露一些非限制实施例对本发明作进一步的详细说明。
本发明所使用的试剂均可以从市场上购得或者可以通过本发明所描述的方法制备而得。
1H NMR谱使用Bruker 400MHz或600MHz核磁共振谱仪记录。1H NMR谱以CDCl3、DMSO-d6、CD3OD或丙酮-d6为溶剂(以ppm为单位)，用TMS(0ppm)或氯仿(7.26ppm)作为参照标准。当出现多重峰的时候，将使用下面的缩写：s(singlet，单峰)、d(doublet，双峰)、t(triplet，三重峰)、m(multiplet，多重峰)、br(broadened，宽峰)、dd(doublet of doublets，双二重峰)、dt(doublet of triplets，双三重峰)。偶合常数，用赫兹(Hz)表示。
低分辨率质谱(MS)数据的测定条件是：Agilent 6120四级杆HPLC-M(柱子型号：Zorbax SB-C18,2.1x 30mm,3.5微米,6min,流速为0.6mL/min。流动相：5％-95％(含0.1％甲酸的CH3CN)在(含0.1％甲酸的H2O)中的比例)，采用电喷雾电离(ESI)，在210nm/254nm下，用UV检测。
纯的化合物的使用Agilent 1260pre-HPLC或Calesep pump 250pre-HPLC(柱子型号：NOVASEP50/80mm DAC)，在210nm/254nm用UV检测。
本发明中，g表示克，mL表示毫升。
以下实施例中，R1为乙氧基，R3为氯；当R1和R3为其它基团时，请参照以下实施例施行。
实施例1：制备化合物(01)
反应器中，加入2.00g的4-苯氧基苯甲酸，10mL甲苯，混合后，加入1.11g氯甲酸乙酯，搅拌，降温至0℃；将三乙胺1.42g溶于10mL甲苯，缓慢滴加至前述溶液中，控温0℃搅拌2小时；然后将反应液用水洗涤3次，每次10mL，甲苯层减压蒸馏至干，得到黄色油状物2.60g，质谱和核磁氢谱检测确认为化合物(01)；
质谱MS：[M+Na]+：309.10，
核磁氢谱1H NMR(600MHz,DMSO-d6)δ(ppm):8.04(d,J＝8.9Hz,2H),7.50(dd,J＝8.5,7.5Hz,2H),7.30(s,1H),7.19(dd,J＝8.6,1.0Hz,2H),7.10(d,J＝8.9Hz,2H),4.36(q,J＝7.1Hz,2H),1.32(t,J＝7.1Hz,3H)。
实施例2：制备化合物(02)
反应器中，加入1.00g化合物(01)，加入10mL甲苯，加入0.53g的三乙胺，搅拌，降温至0℃；向反应液中缓慢加入丙二腈0.25g，搅拌反应2小时；反应完毕后，反应液减压蒸馏至干，残余物用15mL乙酸乙酯溶解；然后加入饱和碳酸氢钠溶液洗涤3次，每次10mL；再用饱和食盐水洗涤3次，每次10mL；所得乙酸乙酯层蒸干，得到淡黄色固体0.91g；质谱和核磁氢谱检测确认为化合物(02)；
质谱MS：262.20，261.15；
核磁氢谱1H NMR(600MHz,DMSO-d6)δ(ppm):8.17(s,1H),7.65-7.60(m,2H),7.42(dd,J＝8.5,7.5Hz,2H),7.19(t,J＝7.4Hz,1H),7.07(dd,J＝8.6,1.0Hz,2H),6.97-6.91(m,2H)。
实施例3：制备化合物(02)
反应器中，加入2.00g的4-苯氧基苯甲酸，15mL甲苯，混合后，加入1.11g氯甲酸乙酯，搅拌，降温至0℃；将N,N-二异丙基乙基胺3.14g溶于10mL甲苯，缓慢滴加至前述溶液中，控温0℃搅拌2小时。然后在0℃下，向上述反应液中加入0.67g丙二腈；控温0℃搅拌2小时。反应完毕后，将反应液减压蒸馏至干，残余物用15mL乙酸乙酯溶解，加入饱和碳酸氢钠溶液洗涤3次，每次10mL，再用饱和食盐水洗涤3次，每次10mL；所得乙酸乙酯层蒸干，得到淡黄色固体2.56g，为化合物(02)。
实施例4：制备化合物(03)
反应器中加入2.00g化合物(02)，甲苯10mL，搅拌溶清；向其中加入三氯氧磷2.92g，升温至75℃，搅拌2小时，然后将反应液降至室温，加入饱和碳酸氢钠溶液洗涤3次，每次10mL，然后再用饱和食盐水洗涤3次，每次10mL；将所得甲苯层蒸干，得到棕红色油状物1.85g；质谱和核磁氢谱检测确认为化合物(03)；
质谱MS：280.0；
核磁氢谱1H NMR(600MHz,DMSO-d6)δ(ppm):7.66(d,J＝8.7Hz,2H),7.44(t,J＝7.9Hz,2H),7.21(t, J＝7.4Hz,1H),7.09(d,J＝7.9Hz,2H),7.00(d,J＝8.7Hz,2H)。
实施例5：制备化合物(03)
反应器中，加入1.00g化合物(01)，加入10mL甲苯，搅拌，加入0.68g的N,N-二异丙基乙基胺，降温至0℃，向反应液中缓慢加入丙二腈0.25g，搅拌反应2小时；然后向反应液中加入三氯氧磷1.34g，将反应液加热至75℃，搅拌2小时。然后将反应液降至室温，加入饱和碳酸氢钠溶液洗涤3次，每次10mL，然后再用饱和食盐水洗涤3次，每次10mL，将所得甲苯层蒸干，得到棕红色油状物0.79g，为化合物(03)。
实施例6：制备化合物(03)
反应器中，加入2.00g的4-苯氧基苯甲酸，10mL甲苯，搅拌，加入1.11g氯甲酸乙酯，降温至0℃；将N,N-二异丙基乙基胺3.14g溶于10mL甲苯，缓慢滴加至前述溶液中，控温0℃搅拌2小时。然后在0℃下，向上述反应液中加入0.67g丙二腈，控温0℃搅拌2小时。然后向反应器中加入三氯氧磷3.58g，将反应液加热至75℃，搅拌2小时；反应完毕后，将反应液降至室温，加入饱和碳酸氢钠溶液洗涤3次，每次10mL，然后再用饱和食盐水洗涤3次，每次10mL，将所得甲苯层蒸干，得到棕红色油状物2.08g，为化合物(03)。
实施例7：制备化合物(04)
反应器中加入1.00g化合物(03)，甲苯10mL，搅拌溶清，然后向其中缓慢滴加水合肼0.34g(浓度：80％)，有大量黄色固体析出，加毕，搅拌1小时；过滤，滤饼用饱和碳酸氢钠溶液5mL和乙醇5mL的混合溶液进行打浆1小时，过滤，滤饼用水淋洗至中性后干燥，得浅黄色固体0.84g；质谱和核磁氢谱检测确认为化合物(04)；
质谱MS：278.10，277.10；
核磁氢谱1H NMR(400MHz,DMSO-d6)δ(ppm):12.11(s,1H),7.80(d,J＝8.7Hz,2H),7.48-7.34(m,2H),7.17(t,J＝7.4Hz,1H),7.08(t,J＝7.9Hz,4H),6.44(s,2H)。
实施例8：制备化合物(04)
反应器中加入1.42g化合物(02)，甲苯10mL，搅拌溶清；向其中加入三氯氧磷0.58g，升温至75℃，搅拌2小时；降温，反应液降温至20℃后，向其中缓慢滴加水合肼0.72g(浓度：80％)，有大量黄色固体析出，加毕，搅拌1小时；过滤，滤饼用饱和碳酸氢钠溶液5mL和乙醇5mL的混合溶液进行打浆，1小时后过滤，滤饼用水淋洗至中性，干燥后得淡黄色固体1.15g，经检测确认为化合物(04)。
实施例9：制备化合物(04)
反应器中，加入1.00g化合物(01)，加入10mL甲苯，搅拌，加入N,N-二异丙基乙基胺0.68g，降温至0℃，向反应液中缓慢加入丙二腈0.25g，搅拌反应2小时。然后向反应液中加入三氯氧磷1.34g，将反应液加热至75℃，搅拌2小时。将反应液降至室温，加入饱和碳酸氢钠溶液洗涤3次，每次10mL， 然后再用饱和食盐水洗涤3次，每次10mL；所得有机相搅拌降温至10℃，向其中缓慢滴加80％的水合肼0.33g，有大量黄色固体析出，搅拌1小时后过滤，滤饼用饱和碳酸氢钠溶液5mL和乙醇5mL的混合溶液进行打浆1小时，过滤，滤饼用水淋洗至中性，干燥后得浅黄色固体0.71g，经检测确认为化合物(04)。
实施例10：制备化合物(04)
反应器中，加入2.00g的4-苯氧基苯甲酸，10mL甲苯，搅拌，加入1.11g氯甲酸乙酯，降温至0℃；将三乙胺2.46g溶于10mL甲苯，缓慢滴加至前述溶液中，控温0℃搅拌2小时。然后在0℃下，向上述反应液中加入0.67g丙二腈，控温0℃搅拌2小时。然后向反应液中加入三氯氧磷3.58g，将反应液加热至75℃，搅拌2小时；反应完毕后，将反应液降至室温，加入饱和碳酸氢钠溶液洗涤3次，每次10mL，然后再用饱和食盐水洗涤3次，每次10mL；控温10℃搅拌有机相，向其中缓慢滴加80％的水合肼0.87g，有大量黄色固体析出，搅拌1小时后过滤，滤饼用饱和碳酸氢钠溶液5mL和乙醇5mL的混合溶液进行打浆1小时后过滤，滤饼用水淋洗至中性；干燥后得浅黄色固体1.84g，经检测确认为化合物(04)。
本发明的方法已经通过较佳实施例进行了描述，相关人员明显能在本发明内容、精神和范围内对本文所述的方法和应用进行改动或适当变更与组合，来实现和应用本发明技术。本领域技术人员可以借鉴本文内容，适当改进工艺参数实现。特别需要指出的是，所有类似的替换和改动对本领域技术人员来说是显而易见的，它们都被视为包括在本发明内。

Claims (13)

  1. 一种制备式(04)所示化合物的方法，包括：式(03)所示化合物与肼反应，制得式(04)所示化合物：
    Figure PCTCN2015078800-appb-100001
    其中，R3为氯，溴，或碘。
  2. 权利要求1所述的方法，进一步包括：式(02)所示化合物与卤化试剂反应，制得所述式(03)所示化合物：
    Figure PCTCN2015078800-appb-100002
  3. 权利要求2所述的方法，进一步包括：式(01)所示化合物与丙二腈反应，制得所述式(02)所示化合物：
    Figure PCTCN2015078800-appb-100003
    其中，R1为甲氧基，乙氧基，丙氧基，或苄氧基。
  4. 权利要求3所述的方法，进一步包括：式(01-1)所示化合物与4-苯氧基苯甲酸反应，制得所述式(01)所示化合物：
    Figure PCTCN2015078800-appb-100004
    其中，X为氟，氯，溴或碘；R1为甲氧基，乙氧基，丙氧基或苄氧基。
  5. 根据权利要求2-4任一所述的方法，不分离中间体式(01)所示化合物，和/或式(02)所示化合物，和/或式(03)所示化合物。
  6. 根据权利要求1-3任一所述的方法，所述式(03)所示化合物与肼反应在第四有机溶剂中，在第四温度进行；其中，所述第四有机溶剂选自二氯甲烷，甲苯，二甲苯，乙腈，2-甲基四氢呋喃，乙酸乙酯，乙酸异丙酯，二甲基甲酰胺的中的一种或多种；所述第四温度为-10℃-100℃。
  7. 根据权利要求2所述的方法，所述式(02)所示化合物与卤化试剂反应在第三有机溶剂中，在第三温度进行；其中，所述第三有机溶剂选自二氯甲烷，甲苯，二甲苯，乙腈，2-甲基四氢呋喃，乙酸乙酯，乙酸异丙酯，二甲基甲酰胺的中的一种或多种；所述第三温度为15℃-100℃。
  8. 根据权利要求3所述的方法，所述式(01)所示化合物与丙二腈反应在第二碱存在下，在第二有机溶剂中，在第二温度进行；其中，所述第二有机溶剂选自二氯甲烷，甲苯，二甲苯，乙腈，2-甲基四氢呋喃，乙酸乙酯，乙酸异丙酯，二甲基甲酰胺的中的一种或多种；所述第二碱选自三乙胺，N,N-二异丙基乙基胺，N,N-二甲基苯胺，N-甲基吗啉中的一种或多种；所述第二温度为-20℃-30℃。
  9. 根据权利要求4所述的方法，所述式(01-1)所示化合物与4-苯氧基苯甲酸反应在第一碱存在下，在第一有机溶剂中，在第一温度进行；其中，所述第一有机溶剂选自二氯甲烷，甲苯，二甲苯，乙腈，2-甲基四氢呋喃，乙酸乙酯，乙酸异丙酯，二甲基甲酰胺的中的一种或多种；所述第一碱选自三乙胺，N,N-二异丙基乙基胺，N,N-二甲基苯胺，N-甲基吗啉的中的一种或多种；所述第一温度为-20℃-20℃。
  10. 根据权利要求8所述的方法，所述式(01)所示化合物与所述第二碱的摩尔比为1:1.2-1:3。
  11. 根据权利要求9所述的方法，所述4-苯氧基苯甲酸与所述第一碱的摩尔比为1:1-1:3.5。
  12. 根据权利要求2所述的方法，所述卤化试剂为二氯亚砜，三氯氧磷，或五氯化磷。
  13. 一种化合物，其结构如式(03)所示：
    Figure PCTCN2015078800-appb-100005
    其中，R3为氯，溴或碘。
PCT/CN2015/078800 2014-05-13 2015-05-12 一种中间体的制备方法 WO2015172713A1 (zh)

Priority Applications (1)

Application Number Priority Date Filing Date Title
CN201580024420.6A CN106458919B (zh) 2014-05-13 2015-05-12 一种中间体的制备方法

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
CN201410201170.6 2014-05-13
CN201410201170 2014-05-13

Publications (1)

Publication Number Publication Date
WO2015172713A1 true WO2015172713A1 (zh) 2015-11-19

Family

ID=54479335

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/CN2015/078800 WO2015172713A1 (zh) 2014-05-13 2015-05-12 一种中间体的制备方法

Country Status (2)

Country Link
CN (1) CN106458919B (zh)
WO (1) WO2015172713A1 (zh)

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN101674834A (zh) * 2007-03-28 2010-03-17 环状药物公司 布鲁顿氏酪氨酸激酶(Bruton’s tyrosine kinase)抑制剂
CN102656173A (zh) * 2009-10-12 2012-09-05 药品循环公司 布鲁顿酪氨酸激酶抑制剂

Family Cites Families (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP2019101A1 (en) * 2007-07-26 2009-01-28 GPC Biotech AG Pyrazol[3,4-d]pyrimidin-4-one useful as Kinase Inhibitor

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN101674834A (zh) * 2007-03-28 2010-03-17 环状药物公司 布鲁顿氏酪氨酸激酶(Bruton’s tyrosine kinase)抑制剂
CN102656173A (zh) * 2009-10-12 2012-09-05 药品循环公司 布鲁顿酪氨酸激酶抑制剂

Also Published As

Publication number Publication date
CN106458919A (zh) 2017-02-22
CN106458919B (zh) 2019-03-15

Similar Documents

Publication Publication Date Title
Sridhar et al. Synthesis of quinoline acetohydrazide-hydrazone derivatives evaluated as DNA gyrase inhibitors and potent antimicrobial agents
CA2659564C (en) Phenyl-pyrazole derivatives as non-steroidal glucocoricoid receptor ligands
ES2533873T3 (es) Derivados de 6-(pirrolopiridinil)-pirimidin-2-il-amina y su utilización para el tratamiento del cáncer y del SIDA
EA038226B1 (ru) Синтез ингибитора mcl-1
WO2005095419A1 (ja) チアゾロピリミジン誘導体
US9603846B2 (en) Process for the preparation of apixaban
WO2015007249A1 (zh) N-烷基色胺酮衍生物及其制备方法和应用
WO2016110224A1 (zh) 玻玛西尼的制备方法
WO2019141131A1 (zh) 溴结构域抑制剂化合物及其用途
CN106674136B (zh) 嘧啶类抗肿瘤化合物及其制备方法
Guo et al. An I 2-mediated cascade reaction of 2′-bromoacetophenones with benzohydrazides/benzamides leading to quinazolino [3, 2-b] cinnoline or tryptanthrin derivatives
CA2994036A1 (en) Novel fused pyrimidinone and triazinone derivatives, their process of preparation and their therapeutic uses as antifungal and/or antiparasitic agents
CA3048602A1 (en) Antitumor agent and bromodomain inhibitor
Ravichandiran et al. Synthesis, molecular docking and antibacterial evaluation of 2-(4-(4-aminophenylsulfonyl) phenylamino)-3-(thiophen-2-ylthio) naphthalene-1, 4-dione derivatives
Yan et al. Structural modifications of CH (OH)-DAPYs as new HIV-1 non-nucleoside reverse transcriptase inhibitors
Lin et al. An efficient and convenient synthesis of heterocycle-fused indazoles via the N–N bond forming reaction of nitroarenes induced by low-valent titanium reagent
US8258168B2 (en) 2H or 3H-benzo[E]indazol-1-YL carbamate derivatives, the preparation and therapeutic use thereof
WO2015172713A1 (zh) 一种中间体的制备方法
CN114276330B (zh) 一种哌啶酮系化合物及其制备方法和应用
CN106588909B (zh) 一种喹啉类衍生物的制备及其在抗炎中的应用
WO2023077678A1 (zh) 靶向srsf6蛋白的小分子化合物及其制备方法和用途
JP5530939B2 (ja) Ｈｄａｃ阻害剤としてのスルホニルピロールの新規製造法
WO2016110237A1 (zh) α-咔啉类化合物，其制备方法以及用途
WO2017049983A1 (zh) 库潘尼西的制备方法
JPH039915B2 (zh)

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 15792369

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 15792369

Country of ref document: EP

Kind code of ref document: A1