CN106458919A - Intermediate preparation method - Google Patents
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- CN106458919A CN106458919A CN201580024420.6A CN201580024420A CN106458919A CN 106458919 A CN106458919 A CN 106458919A CN 201580024420 A CN201580024420 A CN 201580024420A CN 106458919 A CN106458919 A CN 106458919A
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- 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
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- 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
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- 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
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- 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
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- 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
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- 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
Abstract
The present invention relates to the field of pharmaceutical technology. Disclosed is an intermediate preparation method. The intermediate is used to prepare Ibrutinib. The preparation method comprises enabling a halogenated compound to react with hydrazine under a definite condition to obtain a target intermediate compound. The halogenated compound can be prepared via the reaction of a hydroxyl compound and a halogenating reagent. The preparation method is easy to operate, reduces cost, and facilitates industrial production.
Description
The present invention relates to for preparing according to Shandong for intermediate of Buddhist nun and preparation method thereof, belong to pharmaceutical technology field.
Bruton's tyrosine kinase (BTK) is the important medium of at least three kinds crucial B cell survival mechanisms, and B cell malignant tumour can be made to enter lymphoid tissue, tumour cell is contacted necessary microenvironment and existence.Optionally suppress bruton's tyrosine kinase (BTK), the propagation of tumour can be suppressed, so as to reach the effect for the treatment of tumour.
Buddhist nun (English name Ibrutinib) is replaced according to Shandong, it is a kind of bruton's tyrosine kinase (BTK) selective depressant, available for diseases such as treatment relapsed or stubborn lymphoma mantle cells (MCL), commercially with breakthrough status.According to Shandong for shown in Buddhist nun's structure such as formula (1):
Patent application WO2008039218, WO2013101136, WO2013003629, WO2001019829 etc. are disclosed to be prepared according to Shandong for Buddhist nun or the method for other compounds acted on pharmacological activity with compound shown in formula (04) by series of steps.During preparation replaces Buddhist nun according to Shandong, compound shown in formula (04) is important intermediate, and shown in its structure such as formula (04), compound shown in formula (04) has dynamic isomer, is shown below:
The dynamic isomer of compound shown in formula (04).
In method disclosed in these documents, it is necessary to low using the reagent or yield of the high poison high risk such as dimethyl suflfate or azido compound during compound shown in formula (04), it is unsuitable for industrialized production.The method for finding compound shown in a kind of more excellent formula (04) suitable for industrialized production is necessary.
The content of the invention
Summary of the invention
It is used to prepare the preparation method according to Shandong for compound shown in the intermediate formula (04) of Buddhist nun the invention provides a kind of.
The invention provides for noval chemical compound of compound and preparation method thereof shown in formula (04).
Term is defined
Buddhist nun (English name Ibrutinib) is replaced according to Shandong, refer to the compound of chemical entitled 1- [(3R) -3- [4- amino -3- (4- Phenoxyphenyls) -1H- pyrazolos [3,4-D] pyrimidine -1- bases] -1- piperidyls] -2- propylene -1- ketone.
Separation finger during the multistep reaction of target product is prepared, is not separated the intermediate to the product of middle reactions steps, without concentrating or crystallizing to obtain the process of concentrate or solid product.
In the description of the invention, it is to be understood that term similar terms such as " first ", " second " are only used for describing purpose, and it is not intended that indicating or implying relative importance or the implicit quantity for indicating indicated technical characteristic.Thus, " first " is defined, at least one this feature can be expressed or be implicitly included to the feature of " second ".
In the description of the invention, " multiple ", " a variety of " are meant that at least two, such as two, three etc., unless otherwise specifically defined.
Detailed description of the invention
Inventor is by research, the method for developing compound shown in a kind of new formula (04).This preparation method is simple to operate, and cost is low, is conducive to industrialized production, so as to be conducive to preparation of industrialization to replace Buddhist nun according to Shandong.
Therefore, in a first aspect, the invention provides the method for compound shown in a kind of formula (04), it includes:Compound shown in formula (03) carries out ring-closure reaction with hydrazine, prepares compound shown in formula (04),
Wherein, R3For leaving group, chlorine, bromine, or iodine may be selected from.In some embodiments, the R3For chlorine.In some embodiments, the R3For bromine.
According to the present invention, in the ring-closure reaction, compound shown in the formula (03) in the 4th organic solvent, is carried out with hydrazine in the 4th thermotonus,
Prepare compound (04).
According to the present invention, the hydrazine can be other solvent things of the aqueous solution of hydrazine, the salt of hydrazine, or hydrazine.In one embodiment, the hydrazine is the hydrazine aqueous solution that concentration is 40%-80%.When adding hydrazine, the temperature of reaction solution is controlled at -10 DEG C -100 DEG C.After hydrazine is added, control the temperature of reaction solution at -10 DEG C -100 DEG C, react -2 hours 0.1 hour;Then by separation, it can obtain compound (04).
According to the present invention, compound shown in formula (03) and the mol ratio of hydrazine can be 1:1-1:2.In some embodiments, compound (03) and the mol ratio of hydrazine are 1:1-1:1.5.
According to the present invention, the 4th organic solvent is selected from the one or more in dichloromethane, toluene, dimethylbenzene, acetonitrile, 2- methyltetrahydrofurans, ethyl acetate, isopropyl acetate.In one embodiment, the 4th organic solvent is toluene.In one embodiment, the 4th organic solvent is acetonitrile.
According to the present invention, the 4th reaction temperature is -10 DEG C -100 DEG C.In some embodiments, the 4th reaction temperature is 0 DEG C -30 DEG C.In some embodiments, the 4th reaction temperature is 30 DEG C -80 DEG C.
In some embodiments, R3For chlorine, compound shown in formula (03) extremely reacts complete in toluene with hydrazine in 20 DEG C of -40 DEG C of reactions, prepares compound shown in formula (04).
Compound shown in above-mentioned use formula (03) passes through the method that ring-closure reaction obtains compound shown in formula (04), is conducive to operation and cost control, suitable for industrialized production.
According to the present invention, compound can be prepared by compound (02) shown in above-mentioned formula (03).The method of prepare compound (03) includes:Under halide reagent effect halogenation occurs for compound shown in formula (02), and compound (03) is made,
Wherein, R3For leaving group, chlorine, bromine, iodine may be selected from.
According to the present invention, in the halogenation, in the 3rd organic solvent, at a temperature of the 3rd, compound shown in formula (03) is made with halide reagent in compound shown in formula (02).
According to the present invention, the halide reagent is thionyl chloride, POCl3, phosphorus pentachloride, brominated halide reagent such as N- bromo-succinimides etc., or halide reagent containing iodine etc..In one embodiment, the halide reagent is POCl3.In one embodiment, the halide reagent is thionyl chloride.
According to the present invention, compound shown in formula (02) and the mol ratio of halide reagent are 1:1-1:3.In some embodiments, chemical combination shown in formula (02)
The mol ratio of thing and halide reagent is 1:1.2-1:3.In some embodiments, compound shown in formula (02) and halide reagent and mol ratio be 1:2.4-1:3.
According to the present invention, the 3rd organic solvent is selected from the one or more in toluene, dimethylbenzene, acetonitrile, 2- methyltetrahydrofurans, ethyl acetate, isopropyl acetate.In one embodiment, the 3rd organic solvent is toluene.In one embodiment, the organic solvent S3 is ethyl acetate.
According to the present invention, the 3rd temperature is 15 DEG C -100 DEG C.In some embodiments, the 3rd temperature is 50 DEG C -80 DEG C.
In one embodiment, compound shown in formula (02) is reacted -4 hours 2 hours with POCl3 in toluene at 60 DEG C -80 DEG C, and compound shown in formula (03) is made.
The method of compound shown in above-mentioned formula (03), it is to avoid using high risk, high toxicity reagents such as nitrine class or dimethyl suflfates, is conducive to operation and producers' health, environment-friendly, cost can also be reduced, suitable for industrialized production.
According to the present invention, compound shown in the formula (02) can be prepared with compound shown in formula (01) or prepared by method of the other known method as disclosed in patent application WO2008039218.The present invention also provides a kind of method for the prepare compound (02) for being different from prior art, and it includes:Compound shown in formula (01) is reacted with malononitrile, and compound shown in formula (02) is made,
Wherein, R1For methoxyl group, ethyoxyl, propoxyl group, or benzyloxy.
According to the present invention, compound shown in formula (01) is reacted with malononitrile, and compound shown in formula (02) is made.
According to the present invention, compound shown in the formula (01) is in the presence of the second alkali, in a second organic solvent, to be carried out in second temperature with malononitrile reaction.
According to the present invention, second alkali is selected from the one or more in triethylamine, N, N- diisopropyl ethyl amines, DMA, N-methylmorpholine.In one embodiment, second alkali is triethylamine.In one embodiment, second alkali is N, N- diisopropyl ethyl amines.
According to the present invention, second organic solvent is selected from the one or more in dichloromethane, toluene, dimethylbenzene, acetonitrile, 2- methyltetrahydrofurans, ethyl acetate, isopropyl acetate.In one embodiment, second organic solvent is dichloromethane.In one embodiment, second organic solvent is toluene.In one embodiment, second organic solvent is ethyl acetate.
According to the present invention, the second temperature is -20 DEG C -30 DEG C.In some embodiments, the second temperature is -15 DEG C -30 DEG C.In some embodiments, second reaction temperature is -10 DEG C -30 DEG C.In some embodiments, second reaction temperature is 15 DEG C -30 DEG C.
In some embodiments, the second temperature is -5 DEG C -10 DEG C.In some embodiments, the second temperature is -5 DEG C -5 DEG C.
According to the present invention, compound shown in formula (01) and the mol ratio of malononitrile are 1:1-1:2.In some embodiments, compound shown in formula (01) and the mol ratio of malononitrile are 1:1-1:1.2.
According to the present invention, the mol ratio of compound shown in formula (01) and the second alkali can be 1:1-1:3.5.In one embodiment, compound shown in formula (01) and the mol ratio of second alkali are 1:1.2-1:3.In one embodiment, formula institute (01) shows that the mol ratio of compound and second alkali is 1:1.2-1:2.6.
In one embodiment, compound shown in formula (01) in the presence of triethylamine, is reacted -3 hours 2 hours at -5 DEG C -5 DEG C with malononitrile in toluene, compound shown in formula (02) is made.
The method of compound shown in preparation of compounds of formula (02) shown in above-mentioned use formula (01), without reacting for a long time overnight, technique is easy, and simple operation is conducive to cost control, suitable for industrialized production.
Above-claimed cpd (01) can be prepared by compound 4- phenoxy benzoic acids by acylation.A kind of method of prepare compound (01) includes:4- phenoxy benzoic acids carry out acylation reaction with compound shown in formula (01-1), and compound shown in formula (01) is made,
Wherein, R1For methoxyl group, ethyoxyl, propoxyl group, or benzyloxy;X is fluorine, chlorine, bromine, or iodine.
According to the present invention, in above-mentioned acylation reaction, 4- phenoxy benzoic acids with compound is in the first organic solvent shown in formula (01-1), in the presence of the first alkali, acylation reaction is carried out at the first temperature, be made formula (01) shown in compound.
According to the present invention, first alkali is selected from one or more in triethylamine, N, N- diisopropyl ethyl amines, DMA, N-methylmorpholine.In one embodiment, first alkali is triethylamine.In one embodiment, first alkali is N, N- diisopropyl ethyl amines.
According to the present invention, first organic solvent is selected from one or more in dichloromethane, toluene, dimethylbenzene, acetonitrile, 2- methyltetrahydrofurans, ethyl acetate, isopropyl acetate, dimethylformamide (DMF).In one embodiment, first organic solvent is dichloromethane.In one embodiment, first organic solvent is toluene.In one embodiment, first organic solvent is ethyl acetate.
According to the present invention, first temperature is -20 DEG C -20 DEG C.In some embodiments, first temperature is -15 DEG C -20 DEG C.In some embodiments, first temperature is -10 DEG C -20 DEG C.In some embodiments, first temperature is -10 DEG C -10 DEG C.In some embodiments, first temperature is -5 DEG C -5 DEG C.
According to the present invention, the mol ratio of the 4- phenoxy benzoic acids and compound shown in formula (01-1) can be 1:1-1:1.5.In some embodiments,
The mol ratio of 4- phenoxy benzoic acids and compound shown in formula (01-1) is 1:1.05-1:1.2.
According to the present invention, the mol ratio of the 4- phenoxy benzoic acids and the first alkali can be 1:1-1:3.5.In some embodiments, the mol ratio of 4- phenoxy benzoic acids and first alkali is 1:1.3-1:3.In some embodiments, the mol ratio of 4- phenoxy benzoic acids and first alkali is 1:2.5-1:3.
In one embodiment, 4- phenoxy benzoic acids in toluene, react -3 hours 2 hours at -10 DEG C -10 DEG C with ethyl chloroformate in the presence of triethylamine, prepare compound shown in formula (01).
According to the present invention, compound shown in formula (01) can be isolated, next step reaction is then carried out in compound shown in formula (01-1) and 4- phenoxy benzoic acids after completion of the reaction;It can not also separate, directly carry out next step reaction.
The method that above-mentioned 4- phenoxy benzoic acids carry out acylation reaction prepare compound (01) with compound (01-1), it is not necessary to which vacuum distillation removes strong acid reaction reagent, is conducive to operation, is conducive to controlling cost, suitable for industrialized production.
In some embodiments, 4- phenoxy benzoic acids react with compound shown in formula (01-1), and compound shown in formula (01) is made;Compound shown in formula (01) is reacted with malononitrile, and compound shown in formula (02) is made;Compound shown in formula (02) is reacted with halide reagent, and compound shown in formula (03) is made;Compound and hydrazine reaction shown in formula (03), prepare compound shown in formula (04);It is shown below, wherein, R1, R3, X is as defined above:
According to the present invention, each step in above-mentioned preparation method is reacted, and can be used identical reaction dissolvent, can also be used different reaction dissolvents;Identical alkali can be used, different alkali can also be used.
According to the present invention, during compound shown in the formula for preparing (04), compound shown in compound shown in compound shown in intermediate formula (01) and/or formula (02) and/or formula (03) can be isolated, can not also compound shown in compound shown in compound shown in separation of intermediates formula (01) and/or formula (02) and/or formula (03).
In some embodiments, R1For ethyoxyl.
In some embodiments, R3For chlorine.
In some embodiments, X is chlorine.In some embodiments, X is bromine.
In some embodiments, compound shown in formula (01-1) and 4- phenoxy benzoic acids, in the presence of the first alkali, in the first organic solvent, react at the first temperature, and compound shown in formula (01) is made;Then compound and malononitrile shown in formula (01), in a second organic solvent, in the presence of the second alkali, react at the second temperature, and compound shown in formula (02) is made;During this two-step reaction, the first alkali and the second alkali can be
Identical alkali, the first organic solvent and the second organic solvent can be identical organic solvents;The identical alkali is selected from the one or more in triethylamine, N, N- diisopropyl ethyl amines, DMA, N-methylmorpholine;The identical organic solvent is selected from the one or more in dichloromethane, toluene, dimethylbenzene, acetonitrile, 2- methyltetrahydrofurans, ethyl acetate, isopropyl acetate.The alkali or organic solvent can be added disposably in reactor, can also be added portionwise;Compound shown in intermediate formula (01) can be isolated, can not also compound shown in separation of intermediates formula (01).
In some embodiments, 4- phenoxy benzoic acids react with compound (01-1), and compound (01) is made;Compound (01) is reacted with malononitrile, and compound (02) is made;Compound (02) is reacted with halide reagent, and compound (03) is made;In the process, midbody compound (01) and/or compound (02) can be isolated;Midbody compound (01) and/or compound (02) can not also be separated.
In some embodiments, reacted using 4- phenoxy benzoic acids and compound shown in formula (01-1), compound shown in production (01);Then reacted with malononitrile, compound shown in production (02);Again with phosphorus oxychloride reaction, compound shown in production (03);Then acted on by hydrazine, obtain compound shown in formula (04);In the process, compound shown in intermediate formula (01), and/or compound shown in formula (02), and/or compound shown in formula (03) are isolated.
In some embodiments, reacted using 4- phenoxy benzoic acids and compound shown in formula (01-1), compound shown in production (01);Then malononitrile, compound shown in production (02) are added;Pass through POCl3 chlorination, compound shown in production (03) again;Then acted on by hydrazine, obtain compound shown in formula (04);In the process, compound shown in intermediate formula (02) is isolated, other intermediates are not separated.
In some embodiments, reacted using 4- phenoxy benzoic acids and compound shown in formula (01-1), compound shown in production (01);Then malononitrile, compound shown in production (02) are added;Pass through POCl3 chlorination, compound shown in production (03) again;Then acted on by hydrazine, obtain compound shown in formula (04);In the process, compound shown in intermediate formula (03) is isolated, other intermediates are not separated.
In some embodiments, reacted using 4- phenoxy benzoic acids and compound shown in formula (01-1), compound shown in production (01);Then malononitrile, compound shown in production (02) are added;Pass through POCl3 chlorination, compound shown in production (03) again;Then acted on by hydrazine, obtain compound shown in formula (04);In the process, each intermediate is not separated.
The method of the present invention for preparing compound shown in intermediate formula (04), by using compound shown in noval chemical compound shown in formula (03) and/or formula (01), it can avoid using high risk, high toxicity reagent or solvents such as nitrine class or dimethyl suflfates, and it is easy to operate, environment-friendly, be conducive to production control and producers' health, cost can be reduced, suitable for industrialized production.
Second aspect, the invention provides a kind of compound, shown in its structure such as formula (03):
Wherein, R3For chlorine, bromine or iodine.
The third aspect, the invention provides the method for compound shown in a kind of formula (03), including:Under halide reagent effect halogenation occurs for compound shown in formula (02), and compound (03) is made,
Wherein, R3For leaving group, chlorine, bromine, iodine may be selected from.
According to the present invention, in the halogenation, in the 5th organic solvent, in the 5th thermotonus, compound shown in formula (03) is made with halide reagent in compound shown in formula (02).
According to the present invention, the halide reagent is thionyl chloride, POCl3, phosphorus pentachloride, brominated halide reagent such as N- bromo-succinimides etc., or halide reagent containing iodine etc..In one embodiment, the halide reagent is POCl3.In one embodiment, the halide reagent is thionyl chloride.
According to the present invention, compound shown in formula (02) and the mol ratio of halide reagent are 1:1-1:3.In some embodiments, compound shown in formula (02) and the mol ratio of halide reagent are 1:1.2-1:3.In some embodiments, compound shown in formula (02) and halide reagent and mol ratio be 1:2.4-1:3.
According to the present invention, the 5th organic solvent is selected from the one or more in toluene, dimethylbenzene, acetonitrile, 2- methyltetrahydrofurans, ethyl acetate, isopropyl acetate.In one embodiment, the 5th organic solvent is toluene.In one embodiment, the 5th organic solvent is ethyl acetate.
According to the present invention, the 5th temperature is 15 DEG C -100 DEG C.In one embodiment, the 5th temperature is 50 DEG C -80 DEG C.
In one embodiment, compound shown in formula (02) is reacted -4 hours 2 hours with POCl3 in toluene at 60 DEG C -80 DEG C, and compound shown in formula (03) is made.
The method of compound shown in above-mentioned formula (03), it is to avoid using high risk, high toxicity reagents such as nitrine class or dimethyl suflfates, favorably
It is environment-friendly in operation and producers' health, cost can also be reduced, suitable for industrialized production.
In the present invention, compound shown in the formula (02) can be prepared with compound shown in formula (01) or prepared by method of the other known method as disclosed in patent application WO2008039218.The present invention also provides a kind of method for the prepare compound (02) for being different from prior art, and it includes:Compound shown in formula (01) is reacted with malononitrile, and compound shown in formula (02) is made,
Wherein, R1For methoxyl group, ethyoxyl, propoxyl group, or benzyloxy.
According to the present invention, compound shown in formula (01) is reacted with malononitrile, and compound shown in formula (02) is made.
According to the present invention, compound shown in the formula (01) is reacted in the presence of the 3rd alkali with malononitrile, in the 6th organic solvent, is carried out in the 6th temperature.
According to the present invention, the 3rd alkali is selected from one or more in triethylamine, N, N- diisopropyl ethyl amines, DMA, N-methylmorpholine.In one embodiment, the 3rd alkali is triethylamine.In one embodiment, the 3rd alkali is N, N- diisopropyl ethyl amines.
According to the present invention, the 6th organic solvent is selected from one or more in dichloromethane, toluene, dimethylbenzene, acetonitrile, 2- methyltetrahydrofurans, ethyl acetate, isopropyl acetate.In one embodiment, the 6th organic solvent is dichloromethane.In one embodiment, the 6th organic solvent is toluene.In one embodiment, the 6th organic solvent is ethyl acetate.
According to the present invention, the 6th temperature is -20 DEG C -30 DEG C.In one embodiment, the 6th temperature is -15 DEG C -30 DEG C.In one embodiment, the 6th reaction temperature is -10 DEG C -30 DEG C.In one embodiment, the 6th reaction temperature is 15 DEG C -30 DEG C.In one embodiment, the 6th temperature is -5 DEG C -10 DEG C.In one embodiment, the 6th temperature is -5 DEG C -5 DEG C.
According to the present invention, compound shown in formula (01) and the mol ratio of malononitrile are 1:1-1:2.In some embodiments, compound shown in formula (01) and the mol ratio of malononitrile are 1:1-1:1.2.
According to the present invention, the mol ratio of compound shown in formula (01) and the second alkali can be 1:1-1:3.5.In some embodiments, compound shown in formula (01) and the mol ratio of the 3rd alkali are 1:1.2-1:3.In one embodiment, formula institute (01) shows that the mol ratio of compound and the 3rd alkali is 1:1.2-1:2.6.
In one embodiment, compound shown in formula (01) in the presence of triethylamine, is reacted -3 hours 2 hours at -5 DEG C -5 DEG C with malononitrile in toluene, compound shown in formula (02) is made.
The method of compound shown in preparation of compounds of formula (02) shown in above-mentioned use formula (01), without reacting for a long time overnight, technique is easy, and operation is just
Victory, is conducive to cost control, suitable for industrialized production.
Above-claimed cpd (01) can be prepared by compound 4- phenoxy benzoic acids by acylation.The method of compound includes shown in a kind of formula (01):4- phenoxy benzoic acids carry out acylation reaction with compound shown in formula (01-1), and compound shown in formula (01) is made,
Wherein, R1For methoxyl group, ethyoxyl, propoxyl group, or benzyloxy;X is fluorine, chlorine, bromine, or iodine.
According to the present invention, in above-mentioned acylation reaction, 4- phenoxy benzoic acids with compound is in the 7th organic solvent shown in formula (01-1), in the presence of the 4th alkali, the 7th temperature carry out acylation reaction, be made formula (01) shown in compound.
According to the present invention, the 4th alkali is selected from one kind or many in triethylamine, N, N- diisopropyl ethyl amines, DMA, N-methylmorpholine.In one embodiment, the 4th alkali is triethylamine.In one embodiment, the 4th alkali is N, N- diisopropyl ethyl amines.
According to the present invention, the 7th organic solvent is selected from the one or more in dichloromethane, toluene, dimethylbenzene, acetonitrile, 2- methyltetrahydrofurans, ethyl acetate, isopropyl acetate, dimethylformamide (DMF).In one embodiment, the 7th organic solvent is dichloromethane.In one embodiment, the 7th organic solvent is toluene.In one embodiment, the 7th organic solvent is ethyl acetate.
According to the present invention, the 7th temperature is -20 DEG C -20 DEG C.In some embodiments, the 7th temperature is -15 DEG C -20 DEG C.In some embodiments, the 7th temperature is -10 DEG C -20 DEG C.In some embodiments, the 7th temperature is -10 DEG C -10 DEG C.In one embodiment, the 7th temperature is -5 DEG C -5 DEG C.
According to the present invention, the mol ratio of the 4- phenoxy benzoic acids and compound shown in formula (01-1) can be 1:1-1:1.5.In some embodiments, the mol ratio of 4- phenoxy benzoic acids and compound shown in formula (01-1) is 1:1.05-1:1.2.
According to the present invention, the mol ratio of the 4- phenoxy benzoic acids and the first alkali can be 1:1-1:3.5.In some embodiments, the mol ratio of 4- phenoxy benzoic acids and the 4th alkali is 1:1.3-1:3.In one embodiment, the mol ratio of 4- phenoxy benzoic acids and the 4th alkali is 1:2.5-1:3.
In one embodiment, 4- phenoxy benzoic acids in toluene, react -3 hours 2 hours at -10 DEG C -10 DEG C with ethyl chloroformate in the presence of triethylamine, prepare compound shown in formula (01).
According to the present invention, compound shown in formula (01) can be isolated, next step reaction is then carried out in compound shown in formula (01-1) and 4- phenoxy benzoic acids after completion of the reaction;It can not also separate, directly carry out next step reaction.
The method that above-mentioned 4- phenoxy benzoic acids carry out acylation reaction prepare compound (01) with compound (01-1), it is not necessary to which vacuum distillation removes highly acid
Reaction reagent, is conducive to operation, is conducive to controlling cost, suitable for industrialized production.
In some embodiments, 4- phenoxy benzoic acids react with compound shown in formula (01-1), and compound shown in formula (01) is made;Compound shown in formula (01) is reacted with malononitrile, and compound shown in formula (02) is made;Compound shown in formula (02) is reacted with halide reagent, and compound shown in formula (03) is made;It is shown below, wherein, R1, R3, X is as defined above:
According to the present invention, each step in above-mentioned preparation method is reacted, and can be used identical reaction dissolvent, can also be used different reaction dissolvents;Identical alkali can be used, different alkali can also be used.
According to the present invention, during compound shown in the formula for preparing (04), compound shown in compound shown in compound shown in intermediate formula (01) and/or formula (02) and/or formula (03) can be isolated, can not also compound shown in compound shown in compound shown in separation of intermediates formula (01) and/or formula (02) and/or formula (03).
In one embodiment, R1For ethyoxyl.
In one embodiment, R3For chlorine.
In one embodiment, X is chlorine.In one embodiment, X is bromine.
In one embodiment, compound shown in formula (01-1) and 4- phenoxy benzoic acids, in the presence of the 4th alkali, in the 7th organic solvent, in the 7th thermotonus, are made compound shown in formula (01);Then compound and malononitrile shown in formula (01), in the 6th organic solvent, in the presence of the 3rd alkali, in the 6th thermotonus, are made compound shown in formula (02);During this two-step reaction, the 3rd alkali and the 4th alkali can use identical alkali, and the 6th organic solvent and the 7th organic solvent can use identical organic solvent;The identical alkali is selected from the one or more in triethylamine, N, N- diisopropyl ethyl amines, DMA, N-methylmorpholine;The identical organic solvent is selected from the one or more in dichloromethane, toluene, dimethylbenzene, acetonitrile, 2- methyltetrahydrofurans, ethyl acetate, isopropyl acetate.The alkali or organic solvent can be added disposably in reactor, can also be added portionwise;Compound shown in intermediate formula (01) can be isolated, can not also compound shown in separation of intermediates formula (01).
In one embodiment, 4- phenoxy benzoic acids react with compound (01-1), and compound (01) is made;Compound (01) is reacted with malononitrile, and compound (02) is made;Compound (02) is reacted with halide reagent, and compound (03) is made;In the process, midbody compound (01) and/or compound (02) can be isolated;Midbody compound (01) and/or compound (02) can not also be separated.
In one embodiment, reacted using 4- phenoxy benzoic acids and compound shown in formula (01-1), compound shown in production (01);Then with third
Dintrile reacts, compound shown in production (02);Again with phosphorus oxychloride reaction, compound shown in production (03);In the process, compound shown in intermediate formula (01), and/or compound shown in formula (02), and/or compound shown in formula (03) are isolated.
In one embodiment, reacted using 4- phenoxy benzoic acids and compound shown in formula (01-1), compound shown in production (01);Then malononitrile, compound shown in production (02) are added;Pass through POCl3 chlorination, compound shown in production (03) again;In the process, compound shown in intermediate formula (02) is isolated, other intermediates are not separated.
In one embodiment, reacted using 4- phenoxy benzoic acids and compound shown in formula (01-1), compound shown in production (01);Then malononitrile, compound shown in production (02) are added;Pass through POCl3 chlorination, compound shown in production (03) again;In the process, compound shown in intermediate formula (03) is isolated, other intermediates are not separated.
In one embodiment, reacted using 4- phenoxy benzoic acids and compound shown in formula (01-1), compound shown in production (01);Then malononitrile, compound shown in production (02) are added;Pass through POCl3 chlorination, compound shown in production (03) again;In the process, each intermediate is not separated.
The method of the present invention for preparing compound shown in intermediate formula (03), by using compound shown in formula (01), it can avoid using high risk, high toxicity reagent or solvents such as nitrine class or dimethyl suflfates, and it is easy to operate, environment-friendly, be conducive to production control and producers' health, cost can be reduced, suitable for industrialized production.
In order that those skilled in the art more fully understands technical scheme, some non-limiting embodiments are disclosed further below, and the present invention is described in further detail.
Reagent used in the present invention can from the market be bought or can be prepared by method described in the invention.
1H H NMR spectroscopies are recorded using Bruker 400MHz or 600MHz nuclear magnetic resonance spectrometer.1H H NMR spectroscopies are with CDCl3、DMSO-d6、CD3OD or acetone-d6For solvent (in units of ppm), reference standard is used as with TMS (0ppm) or chloroform (7.26ppm).When there is multiplet, following abbreviation will be used:S (singlet, it is unimodal), d (doublet, it is bimodal), t (triplet, triplet), m (multiplet, multiplet), br (broadened, broad peak), dd (doublet of doublets, double doublet), dt (doublet of triplets, double triplets).Coupling constant, is represented with hertz (Hz).
The condition determination of Algorithm (MS) data is:Level Four bar HPLC-M (the pillar models of Agilent 6120:Zorbax SB-C18,2.1x 30mm, 3.5 microns, 6min, flow velocity is 0.6mL/min.Mobile phase:5%-95% (contains the CH of 0.1% formic acid3CN) (H of 0.1% formic acid is being contained2O the ratio in)), using electron spray ionisation (ESI), under 210nm/254nm, detected with UV.
Use Agilent 1260pre-HPLC or Calesep pump 250pre-HPLC (the pillar models of pure compound:NOVASEP50/80mm DAC), detected in 210nm/254nm with UV.
In the present invention, g represents gram that mL represents milliliter.
In following examples, R1For ethyoxyl, R3For chlorine;Work as R1And R3During for other groups, following examples execution refer to.
Embodiment 1:Prepare compound (01)
In reactor, 2.00g 4- phenoxy benzoic acids are added, 10mL toluene after mixing, adds 1.11g ethyl chloroformates, stirring is cooled to 0 DEG C;Triethylamine 1.42g is dissolved in 10mL toluene, is slowly added dropwise into previous solu, 0 DEG C of temperature control is stirred 2 hours;Then reaction solution is washed with water 3 times, each 10mL, toluene layer vacuum distillation obtains yellow oil 2.60g to dry, and compound (01) is confirmed as in mass spectrum and nucleus magnetic hydrogen spectrum detection;
Mass spectrum MS:[M+Na]+:309.10,
Nucleus magnetic hydrogen spectrum1H 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).
Embodiment 2:Prepare compound (02)
In reactor, 1.00g compounds (01) are added, 10mL toluene is added, 0.53g triethylamine is added, stirring is cooled to 0 DEG C;Malononitrile 0.25g, stirring reaction 2 hours are slowly added into reaction solution;After completion of the reaction, reaction solution vacuum distillation is to doing, and residue 15mL ethyl acetate dissolves;Then add saturated sodium bicarbonate solution to wash 3 times, each 10mL;Saturated common salt water washing is used again 3 times, each 10mL;Gained ethyl acetate layer is evaporated, and obtains faint yellow solid 0.91g;Compound (02) is confirmed as in mass spectrum and nucleus magnetic hydrogen spectrum detection;
Mass spectrum MS:262.20,261.15;
Nucleus magnetic hydrogen spectrum1H 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).
Embodiment 3:Prepare compound (02)
In reactor, 2.00g 4- phenoxy benzoic acids are added, 15mL toluene after mixing, adds 1.11g ethyl chloroformates, stirring is cooled to 0 DEG C;N, N- diisopropyl ethyl amines 3.14g are dissolved in 10mL toluene, be slowly added dropwise into previous solu, 0 DEG C of temperature control is stirred 2 hours.Then at 0 DEG C, 0.67g malononitrile is added into above-mentioned reaction solution;0 DEG C of temperature control is stirred 2 hours.After completion of the reaction, by reaction solution vacuum distillation to dry, residue 15mL ethyl acetate dissolves, and adds saturated sodium bicarbonate solution and washs 3 times, each 10mL, then with saturated common salt water washing 3 times, each 10mL;Gained ethyl acetate layer is evaporated, and obtains faint yellow solid 2.56g, is compound (02).
Embodiment 4:Prepare compound (03)
2.00g compounds (02) are added in reactor, toluene 10mL stirs dissolved clarification;POCl3 2.92g is added thereto, 75 DEG C are warming up to, stirs 2 hours, reaction solution is then down to room temperature, saturated sodium bicarbonate solution is added and washs 3 times, and then each 10mL uses saturated common salt water washing 3 times again, each 10mL;Gained toluene layer is evaporated, brownish red grease 1.85g is obtained;Compound (03) is confirmed as in mass spectrum and nucleus magnetic hydrogen spectrum detection;
Mass spectrum MS:280.0;
Nucleus magnetic hydrogen spectrum1H 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).
Embodiment 5:Prepare compound (03)
In reactor, 1.00g compounds (01) are added, 10mL toluene is added, stirring adds 0.68g N, and N- diisopropyl ethyl amines are cooled to 0 DEG C, malononitrile 0.25g, stirring reaction 2 hours are slowly added into reaction solution;Then POCl3 1.34g is added into reaction solution, reaction solution is heated to 75 DEG C, is stirred 2 hours.Then reaction solution is down to room temperature, adds saturated sodium bicarbonate solution and wash 3 times, then each 10mL uses saturated common salt water washing 3 times again, and gained toluene layer is evaporated by each 10mL, obtains brownish red grease 0.79g, is compound (03).
Embodiment 6:Prepare compound (03)
In reactor, 2.00g 4- phenoxy benzoic acids are added, 10mL toluene, stirring adds 1.11g ethyl chloroformates, is cooled to 0 DEG C;N, N- diisopropyl ethyl amines 3.14g are dissolved in 10mL toluene, be slowly added dropwise into previous solu, 0 DEG C of temperature control is stirred 2 hours.Then at 0 DEG C, 0.67g malononitrile is added into above-mentioned reaction solution, 0 DEG C of temperature control is stirred 2 hours.Then POCl3 3.58g is added into reactor, reaction solution is heated to 75 DEG C, is stirred 2 hours;After completion of the reaction, reaction solution is down to room temperature, adds saturated sodium bicarbonate solution and wash 3 times, then each 10mL uses saturated common salt water washing 3 times again, and gained toluene layer is evaporated by each 10mL, obtains brownish red grease 2.08g, is compound (03).
Embodiment 7:Prepare compound (04)
1.00g compounds (03) are added in reactor, toluene 10mL stirs dissolved clarification, hydrazine hydrate 0.34g (concentration is then slowly added dropwise thereto:80%), there are a large amount of yellow solids to separate out, finish, stir 1 hour;Filtering, filter cake is dried after mashing 1 hour, filtering, filter cake water wash to neutrality are carried out with saturated sodium bicarbonate solution 5mL and ethanol 5mL mixed solution, obtains light yellow solid 0.84g;Compound (04) is confirmed as in mass spectrum and nucleus magnetic hydrogen spectrum detection;
Mass spectrum MS:278.10,277.10;
Nucleus magnetic hydrogen spectrum1H 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).
Embodiment 8:Prepare compound (04)
1.42g compounds (02) are added in reactor, toluene 10mL stirs dissolved clarification;POCl3 0.58g is added thereto, 75 DEG C are warming up to, and is stirred 2 hours;Cooling, reaction solution is cooled to after 20 DEG C, and hydrazine hydrate 0.72g (concentration is slowly added dropwise thereto:80%), there are a large amount of yellow solids to separate out, finish, stir 1 hour;Filtering, filter cake is beaten with saturated sodium bicarbonate solution 5mL and ethanol 5mL mixed solution, is filtered after 1 hour, filter cake water wash to neutrality, obtains faint yellow solid 1.15g after drying, compound (04) is confirmed as after testing.
Embodiment 9:Prepare compound (04)
In reactor, 1.00g compounds (01) are added, 10mL toluene is added, stirring adds N, N- diisopropyl ethyl amine 0.68g, is cooled to 0 DEG C, malononitrile 0.25g, stirring reaction 2 hours are slowly added into reaction solution.Then POCl3 1.34g is added into reaction solution, reaction solution is heated to 75 DEG C, is stirred 2 hours.Reaction solution is down to room temperature, saturated sodium bicarbonate solution is added and washs 3 times, each 10mL,
Then saturated common salt water washing is used again 3 times, each 10mL;The stirring of gained organic phase is cooled to 10 DEG C, 80% hydrazine hydrate 0.33g is slowly added dropwise thereto, there are a large amount of yellow solids to separate out, stirring is filtered after 1 hour, filter cake carries out mashing 1 hour, filtering, filter cake water wash to neutrality with saturated sodium bicarbonate solution 5mL and ethanol 5mL mixed solution, light yellow solid 0.71g is obtained after drying, compound (04) is confirmed as after testing.
Embodiment 10:Prepare compound (04)
In reactor, 2.00g 4- phenoxy benzoic acids are added, 10mL toluene, stirring adds 1.11g ethyl chloroformates, is cooled to 0 DEG C;Triethylamine 2.46g is dissolved in 10mL toluene, is slowly added dropwise into previous solu, 0 DEG C of temperature control is stirred 2 hours.Then at 0 DEG C, 0.67g malononitrile is added into above-mentioned reaction solution, 0 DEG C of temperature control is stirred 2 hours.Then POCl3 3.58g is added into reaction solution, reaction solution is heated to 75 DEG C, is stirred 2 hours;After completion of the reaction, reaction solution is down to room temperature, adds saturated sodium bicarbonate solution and wash 3 times, then each 10mL uses saturated common salt water washing 3 times again, each 10mL;10 DEG C of stirring organic phases of temperature control, 80% hydrazine hydrate 0.87g is slowly added dropwise thereto, there are a large amount of yellow solids to separate out, stirring is filtered after 1 hour, filter cake is filtered after carrying out mashing 1 hour with saturated sodium bicarbonate solution 5mL and ethanol 5mL mixed solution, filter cake water wash to neutrality;Light yellow solid 1.84g is obtained after drying, compound (04) is confirmed as after testing.
The method of the present invention is described by preferred embodiment, and related personnel method described herein and application can be substantially modified in present invention, spirit and scope or suitably change is with combining, to realize and apply the technology of the present invention.Those skilled in the art can use for reference present disclosure, be suitably modified technological parameter realization.In particular, all similar replacements and change are apparent to those skilled in the art, and they are considered as being included in the present invention.
Claims (13)
- A kind of method of compound shown in formula (04), including:Compound and hydrazine reaction shown in formula (03), are made compound shown in formula (04):Wherein, R3For chlorine, bromine, or iodine.
- Method described in claim 1, further comprises:Compound shown in formula (02) is reacted with halide reagent, and compound shown in the formula (03) is made:
- Method described in claim 2, further comprises:Compound shown in formula (01) is reacted with malononitrile, and compound shown in the formula (02) is made:Wherein, R1For methoxyl group, ethyoxyl, propoxyl group, or benzyloxy.
- Method described in claim 3, further comprises:Compound shown in formula (01-1) is reacted with 4- phenoxy benzoic acids, and compound shown in the formula (01) is made:Wherein, X is fluorine, chlorine, bromine or iodine;R1For methoxyl group, ethyoxyl, propoxyl group or benzyloxy.
- According to any described methods of claim 2-4, not compound shown in separation of intermediates formula (01), and/or compound shown in formula (02), and/or compound shown in formula (03).
- According to any described methods of claim 1-3, compound shown in the formula (03) in the 4th organic solvent, is carried out with hydrazine reaction in the 4th temperature;Wherein, the 4th organic solvent is selected from the one or more in dichloromethane, toluene, dimethylbenzene, acetonitrile, 2- methyltetrahydrofurans, ethyl acetate, isopropyl acetate, dimethylformamide;4th temperature is -10 DEG C -100 DEG C.
- Method according to claim 2, compound shown in the formula (02) is reacted in the 3rd organic solvent with halide reagent, is carried out in the 3rd temperature;Wherein, the 3rd organic solvent is selected from the one or more in dichloromethane, toluene, dimethylbenzene, acetonitrile, 2- methyltetrahydrofurans, ethyl acetate, isopropyl acetate, dimethylformamide;3rd temperature is 15 DEG C -100 DEG C.
- Method according to claim 3, compound shown in the formula (01) is reacted in the presence of the second alkali with malononitrile, in a second organic solvent, is carried out in second temperature;Wherein, second organic solvent is selected from the one or more in dichloromethane, toluene, dimethylbenzene, acetonitrile, 2- methyltetrahydrofurans, ethyl acetate, isopropyl acetate, dimethylformamide;Second alkali is selected from the one or more in triethylamine, N, N- diisopropyl ethyl amines, DMA, N-methylmorpholine;The second temperature is -20 DEG C -30 DEG C.
- Method according to claim 4, compound shown in the formula (01-1) is reacted in the presence of the first alkali with 4- phenoxy benzoic acids, in the first organic solvent, is carried out in the first temperature;Wherein, first organic solvent is selected from the one or more in dichloromethane, toluene, dimethylbenzene, acetonitrile, 2- methyltetrahydrofurans, ethyl acetate, isopropyl acetate, dimethylformamide;First alkali is selected from the one or more in triethylamine, N, N- diisopropyl ethyl amines, DMA, N-methylmorpholine;First temperature is -20 DEG C -20 DEG C.
- The mol ratio of method according to claim 8, compound shown in the formula (01) and second alkali is 1:1.2-1:3.
- The mol ratio of method according to claim 9, the 4- phenoxy benzoic acids and first alkali is 1:1-1:3.5.
- Method according to claim 2, the halide reagent is thionyl chloride, POCl3, or phosphorus pentachloride.
- A kind of compound, shown in its structure such as formula (03):Wherein, R3For chlorine, bromine or iodine.
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Non-Patent Citations (1)
Title |
---|
TETSUO TAKAYAMA ET AL.: "Ring-fused pyrazole derivatives as potent inhibitors of lymphocyte-specific kinase (Lck): Structure, synthesis, and SAR", 《BIOORGANIC & MEDICINAL CHEMISTRY LETTERS》 * |
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