阅读说明：本技术 吗啉基喹唑啉化合物的制备方法及其中间体 (Morpholinyl quinazoline compounds, processes for their preparation and intermediates therefor ) 是由 许祖盛 李纪志 吴剑峰 楼杨通 于 2019-12-24 设计创作，主要内容包括：本发明公开了一种吗啉基喹唑啉化合物的制备方法及其中间体。本发明提供的吗啉基喹唑啉化合物的制备方法,其包括以下步骤：步骤S1：将化合物S和化合物IV,进行如下式的Suzuki反应,得到化合物V；步骤S2：将甲基磺酰氯和所述化合物V在有机溶剂中进行如下式反应,得到化合物VI；步骤S3：将化合物VII和所述化合物VI在溶剂中,进行如下式的偶联反应,得到化合物YY-20394。本发明的制备方法收率较高,选择性较好,且操作简便,反应条件温和,适合工业化生产。<Image he="491" wi="700" file="DDA0002332704800000011.GIF" imgContent="drawing" imgFormat="GIF" orientation="portrait" inline="no"></Image>(The invention discloses a preparation method and an intermediate of a morpholinyl quinazoline compound. The preparation method of the morpholinyl quinazoline compound provided by the invention comprises the following steps: step S1: carrying out the Suzuki reaction of the compound S and the compound IV as shown in the following formula to obtain a compound V; step S2: carrying out the following reaction on methylsulfonyl chloride and the compound V in an organic solvent to obtain a compound VI; step S3: and (3) carrying out coupling reaction on the compound VII and the compound VI in a solvent to obtain a compound YY-20394. The preparation method has the advantages of high yield, good selectivity, simple operation and mild reaction conditions, and is suitable for industrial production.)

1. A preparation method of a compound shown as a formula V is characterized by comprising the following steps:

under the action of a palladium catalyst and an alkaline reagent, carrying out the Suzuki reaction of the following formula on a compound S and a compound IV in a solvent to obtain a compound V;

wherein R is¹And R²Independently is H orM isor-BF₃K；X¹Is Cl or Br; x²Is halogen,

R³Is C_1-4An alkyl group; r^4a、R^4b、R^4c、R^4dAnd R^4eIndependently H, C_1-6Alkyl, nitro or halogen.

2. The method of claim 1, wherein X is²Wherein said halogen is Cl, Br and I, preferably Cl;

and/or, R³In (A), the C_1-4The alkyl is methyl, ethyl, n-propyl, isopropyl, n-butyl,Or tert-butyl, preferably methyl;

and/or, R^4a、R^4b、R^4c、R^4dAnd R^4eWherein said halogen is independently Cl, Br or I;

and/or, R^4a、R^4b、R^4c、R^4dAnd R^4eIn (A), the C_1-6Alkyl is independently C_1-3The alkyl group is more preferably a methyl group, an ethyl group, an n-propyl group or an isopropyl group, and still more preferably a methyl group.

3. The method of claim 1, wherein M isPreference is given to

And/or, X¹Is chlorine;

and/or, X²Is halogen,Preference is given toFurther preferred is

And/or, R^4a、R^4b、R^4dAnd R^4eIndependently is H.

4. The method according to claim 1, wherein the palladium catalyst in the Suzuki reaction is tetrakis (triphenylphosphine) palladium, palladium acetate, bis (triphenylphosphine) palladium dichloride, bis (tris-o-methylphenylphosphine) palladium (II) dichloride, tris (dibenzylideneacetone) dipalladium, bis (tri-t-butylphosphine) palladium (Pd [ P (t-Bu)₃]₂) [1,1' -bis (diphenylphosphino) ferrocene]Palladium dichloride and [1,1' -bis (diphenylphosphino) ferrocene]One or more of a palladium dichloride dichloromethane complex, preferably tetrakis (triphenylphosphine) palladium;

and/or, in the Suzuki reaction, when the palladium catalyst is reacted in the presence of a ligand; the ligand is one or more of triphenylphosphine, tri-o-phenylphosphine, tri-tert-butylphosphine tetrafluoroborate, 2-dicyclohexylphosphine-2 ',4',6 '-triisopropylbiphenyl, 2-dicyclohexylphosphine-2', 6 '-dimethoxy-biphenyl and 2-dicyclohexylphosphine-2', 6 '-diisopropoxy-1, 1' -biphenyl;

and/or in the Suzuki reaction, the molar ratio of the palladium catalyst to the compound IV is 0.01-0.5, preferably 0.02-0.2;

and/or in the Suzuki reaction, the solvent is a mixed solvent of an organic solvent and water; the organic solvent is one or more of aromatic hydrocarbon solvent, alcohol solvent, chlorohydrocarbon solvent and ether solvent, and preferably a mixed solvent of aromatic hydrocarbon solvent and alcohol solvent; the volume ratio of the organic solvent to the water is 1: 1-10: 1, preferably 5: 1-10: 1;

and/or, in the Suzuki reaction, the alkaline reagent is one or more of alkali metal carbonate, alkali metal fluoride salt, alkali metal phosphate, alkali metal tert-butoxide and alkali metal hydroxide;

and/or in the Suzuki reaction, the molar ratio of the alkaline reagent to the compound IV is 1-10, preferably 2-10;

and/or in the Suzuki reaction, the molar ratio of the compound S to the compound IV is 0.9-3, preferably 0.9-1.5;

and/or in the Suzuki reaction, the temperature of the Suzuki reaction is 0-130 ℃, and preferably 20-70 ℃;

and/or the Suzuki reaction is carried out under protective gas;

and/or in the Suzuki reaction, the compound S is

And/or in the Suzuki reaction, the compound IV is

5. The process according to any one of claims 1 to 4, which further comprises a process for producing the compound IV, which is process 1 or process 2:

the method comprises the following steps: which comprises the following steps: carrying out halogenation reaction on the compound III and the phosphorus trihalide and/or the phosphorus halide to obtain a compound IV;

the method 2 comprises the following steps: which comprises the following steps: carrying out nucleophilic substitution reaction of the compound III and a sulfonylation reagent in an organic solvent under the action of an alkaline reagent to obtain a compound IV;

the sulfonylation reagent is

When X is present²When halogen is contained, the preparation method of the compound IV is the method 1;

when X is present²Is composed ofThe preparation method of the compound IV is the method 2.

6. The process according to claim 5, wherein in Process 1, the halogenation is carried out in the absence of a solvent;

and/or, the halogen in the "phosphorus trihalide oxide and/or phosphorus halide" is halogen, and the halogen is Cl, Br or I, preferably Cl;

and/or, in the method 1, the molar ratio of the phosphorus trihalide and/or the phosphorus halide to the compound III is more than or equal to 1, preferably 1 to 30;

and/or in the method 1, the temperature of the halogenation reaction is 20-130 ℃, preferably 60-110 ℃;

and/or, in the method 2, the alkaline reagent is an organic weak base and/or an inorganic weak base salt, and the organic weak base is preferably a tertiary amine organic weak base and/or a pyridine organic weak base; the inorganic weak base salt is preferably an alkali metal carbonate;

and/or, in method 2, when the sulfonylating agent isWhen is in use, theIs composed of

And/or, in method 2, when the sulfonylating agent isWhen is in use, theIs composed of

And/or, in the method 2, the molar ratio of the sulfonylation reagent to the compound III is 1-1.5;

and/or, in the method 2, the organic solvent is one or more of a nitrile solvent, a chlorinated hydrocarbon solvent and an ether solvent;

and/or in the method 2, the volume-to-mass ratio of the organic solvent to the compound III is 5-15 m L/g.

7. The method of claim 5 or 6, further comprising the steps of: in an organic solvent, carrying out nucleophilic substitution reaction of a compound II and a compound A as shown in the following formula to obtain a compound III;

8. the method of claim 7, further comprising the steps of: under the action of an alkaline reagent, carrying out the following reaction of a compound I in a solvent to obtain a compound II;

9. a preparation method of a compound shown as a formula YY-20394 is characterized by comprising the following steps:

step S1: under the action of a palladium catalyst and an alkaline reagent, carrying out a Suzuki reaction of the following formula on a compound S and a compound IV in a solvent to obtain a compound V;

step S2: under the action of an alkaline reagent, carrying out the following reaction on methylsulfonyl chloride and the compound V in an organic solvent to obtain a compound VI;

step S3: under the conditions of a palladium catalyst and a ligand and under the action of an alkaline reagent, carrying out coupling reaction of a compound VII and the compound VI in a solvent as shown in the following formula to obtain a compound YY-20394;

wherein, when R in the compound V¹And R²At the same time areThe compound V is directly subjected to the coupling reaction of step S3 without step S2;

in step S1, the conditions and operation of the process for producing Compound V are as defined in any one of claims 1 to 8.

10. The process of claim 9, wherein in the process for the preparation of the compound of formula YY-20394, when R is present in compound V¹And R²Is not H or at the same timeThe compound V is directly subjected to the coupling reaction of step S3 without step S2;

and/or, in step S2, the alkaline reagent is organic weak base; the organic weak base is preferably pyridine organic weak base and/or tertiary amine organic weak base, more preferably pyridine organic weak base, and even more preferably pyridine;

and/or in step S2, the molar ratio of the methylsulfonyl chloride to the compound V is 1-5;

and/or in step S2, the molar ratio of the alkaline reagent to the compound V is 3-25;

and/or, in step S2, the organic solvent is a chlorinated hydrocarbon solvent, more preferably dichloromethane;

and/or in the step S2, the reaction temperature is 10-50 ℃;

and/or, in step S2, the compound V is

And/or, in step S3, the palladium catalyst is tetrakis (triphenylphosphine) palladium, palladium acetate, bis (triphenylphosphine) palladium dichloride, bis (tri-o-tolylphosphine) palladium (II) dichloride, tris (dibenzylideneacetone) dipalladium, bis (tri-tert-butylphosphine) palladium (Pd [ P (t-Bu)₃]₂) [1,1' -bis (diphenylphosphino) ferrocene]Palladium dichloride and [1,1' -bis (diphenylphosphino) ferrocene]One or more of a palladium dichloride dichloromethane complex, preferably palladium acetate;

and/or in step S3, the molar ratio of the palladium catalyst to the compound VI is 0.01-0.2;

and/or, in step S3, the ligand is one or more of triphenylphosphine, tri-o-methylphenyl phosphorus, tri-tert-butylphosphine tetrafluoroborate, 2-dicyclohexylphosphine-2 ',4',6' -triisopropylbiphenyl, 2-dicyclohexylphosphine-2 ',6' -dimethoxy-biphenyl and 2-dicyclohexylphosphine-2 ',6' -diisopropoxy-1, 1' -biphenyl, preferably 2-dicyclohexylphosphine-2 ',4',6' -triisopropylbiphenyl;

and/or in step S3, the molar ratio of the ligand to the compound VI is 0.02-0.4;

and/or, in step S3, the alkaline reagent is one or more of alkali metal carbonate, alkali metal fluoride, alkali metal phosphate, alkali metal tert-butoxide and alkali metal hydroxide;

and/or in step S3, the molar ratio of the alkaline reagent to the compound VI is 1-20;

and/or in step S3, the molar ratio of the compound VII to the compound VI is 0.8-6, preferably 1-3;

and/or, in step S3, the solvent is a mixed solvent of a water-soluble organic solvent and water; the organic solvent is a water-soluble organic solvent; the water-soluble organic solvent is preferably an ether solvent and/or an alcohol solvent, more preferably an ether solvent, even more preferably one or more of tetrahydrofuran, 1, 4-dioxane and ethylene glycol dimethyl ether, and even more preferably tetrahydrofuran; the volume ratio of the water-soluble organic solvent to water is 1: 1-15: 1, preferably 3: 1-15: 1;

and/or, in step S3, the compound VI is

And/or in step S3, the coupling reaction is carried out under a protective gas, and the protective gas is nitrogen or argon.

11. A compound of formula IV:

wherein, X¹And X²Are as defined in claims 1 to 5Any of the above;

or, a compound of formula III:

wherein, X¹Is Cl or Br;

or, a compound of formula II:

or, a compound of formula V-2:

wherein R is¹And R²Independently is H or

12. The compound IV of claim 11, wherein the compound IV is

Or, the compound of formula V-2 according to claim 11, wherein the compound of formula V-2 is

Technical Field

The invention relates to a preparation method and an intermediate of a morpholinyl quinazoline compound.

Background

The morpholinyl quinazoline compound YY-20394 has a chemical structure ofHas effect in inhibiting phosphatidylinositol 3-kinase (PI 3K).

PI3K is an intracellular phosphoinositide kinase that catalyzes the phosphorylation of the hydroxyl group at position 3 of phosphatidylinositol PI3K can be divided into class I, class II and class III kinases, while the most widely studied class I PI3k mammalian cells, which are activated by cell surface receptors, are divided into class Ia and class Ib according to structure and receptor, which transmit signals from tyrosine kinase-coupled receptors and G protein-coupled receptors, class Ia PI3K includes PI3K α, PI3K β, PI3K subtypes, class Ib PI3K includes PI3K γ subtype (trends. biochem. sci.,1997,22, 267-pro 272), class Ia PI3K is a dimeric protein composed of catalytic subunit p110 and regulatory subunit p 4, with dual activity of kinases and protein kinases (nat. rev. cecr 2002,2, 9-pro) and inflammatory diseases related to cell proliferation and immune-associated diseases.

Patent WO2015055071A1 discloses a compound YY-20394 and a preparation method thereof. In the patent, 2-amino-5-fluorobenzoic acid is used as a raw material, a trichloro intermediate I-11 is synthesized through a 3-step reaction, and then a product YY-20394 is obtained through a four-step reaction conversion. The route is mainly suitable for the modification of a pharmaceutical chemical structure, but the reaction step of the compound I-11 to the compound I-11-a has poor selectivity and more generated impurities, and the yield of the compound I11-a is only 28 percent, so that the method is not beneficial to industrial production.

In view of this, it is urgently needed to develop a preparation method of the compound YY-20394, which has the advantages of high yield, good selectivity, capability of avoiding the generation of a byproduct at the 2-position on a quinazoline ring, simple operation, mild reaction conditions and suitability for industrial production.

Disclosure of Invention

The invention provides a preparation method and an intermediate of a morpholinyl quinazoline compound different from the prior art. The preparation method has the advantages of high yield, good selectivity, avoidance of generation of a byproduct at the 2-position of a quinazoline ring, improvement of the selectivity of a Suzuki reaction at the 4-position of the quinazoline ring, simple and convenient operation, mild reaction conditions and suitability for industrial production.

The invention is realized by the following technical scheme.

The invention provides a preparation method of a compound shown as a formula V, which comprises the following steps:

under the action of a palladium catalyst and an alkaline reagent, carrying out the Suzuki reaction of the following formula on a compound S and a compound IV in a solvent to obtain a compound V;

wherein R is¹And R²Independently is H or(-Ms); m isor-BF₃K；

X¹Is Cl or Br;

X²is halogen,(-OTf) or

R³Is C_1-4An alkyl group;

R^4a、R^4b、R^4c、R^4dand R^4eIndependently H, C_1-6Alkyl, nitro or halogen.

R³In (A), the C_1-4The alkyl group is preferably a methyl group, an ethyl group, an n-propyl group, an isopropyl group, an n-butyl group, a n-butyl group,Or a tert-butyl group, more preferably a methyl group.

X²Among them, the halogen is preferably Cl, Br and I, and more preferably Cl.

R^4a、R^4b、R^4c、R^4dAnd R^4eWherein said halogen is independently preferably Cl, Br or I.

R^4a、R^4b、R^4c、R^4dAnd R^4eIn (A), the C_1-6Alkyl is independently preferably C_1-3The alkyl group is more preferably a methyl group, an ethyl group, an n-propyl group or an isopropyl group, and still more preferably a methyl group.

In one embodiment, M isPreference is given to

In a certain embodiment, X is¹Is chlorine.

In a certain embodiment, X is²Is halogen,Preference is given to

In a certain embodiment, R^4a、R^4b、R^4dAnd R^4eIndependently is H.

In a certain embodiment, R^4cPreferably nitro or C_1-6Alkyl, more preferably C_1-6An alkyl group.

In a certain embodiment, when X is²Is composed ofWhen is in use, theIs composed of(-OTs)。

The Suzuki reaction may be a reaction conventional in the art for such reactions.

In the Suzuki reaction, the palladium catalyst may be a palladium catalyst conventional in the art for such reactions, preferably tetrakis (triphenylphosphine) palladium (Pd (PPh)₃)₄) Palladium acetate Pd (OAc)₂Bis (triphenylphosphine) palladium dichloride (PdCl)₂(PPh₃)₂) Bis (tri-o-phenylphosphino) palladium (II) dichloride (PdCl)₂[P(o-tol)₃]₂) Tris (dibenzylideneacetone) dipalladium (Pd)₂(dba)₃) Bis (tri-tert-butylphosphine) palladium (Pd [ P (t-Bu) ]₃]₂) [1,1' -bis (diphenylphosphino) ferrocene]Palladium dichloride (PdCl)₂(dppf)) and [1,1' -bis (diphenylphosphino) ferrocene]Palladium dichloride dichloromethane complex (PdCl)₂(dppf) DCM), more preferably tetrakis (triphenylphosphine) palladium.

In the Suzuki reaction, the palladium catalyst can also be reacted in the presence of a ligand. The ligand may be one conventional in the art for such reactions, preferably triphenylphosphine (PPh)₃) Tri-o-methylphenyl phosphorus (P (o-tol)₃) One or more of tri-tert-butylphosphine tetrafluoroborate, 2-dicyclohexylphosphine-2 ',4',6 '-triisopropylbiphenyl (x-Phos), 2-dicyclohexylphosphine-2', 6 '-dimethoxy-biphenyl (s-Phos) and 2-dicyclohexylphosphine-2', 6 '-diisopropoxy-1, 1' -biphenyl (Ru-Phos)And (4) a plurality of.

In the Suzuki reaction, the molar ratio of the palladium catalyst to the compound IV can be 0.01 to 0.5, preferably 0.02 to 0.2, for example 0.06.

In the Suzuki reaction, the solvent may be a solvent conventional in such reactions in the art, and is preferably a mixed solvent of an organic solvent and water. The organic solvent may be an organic solvent conventional in such reactions in the art, preferably one or more of aromatic hydrocarbon solvents, alcohol solvents, chlorinated hydrocarbon solvents and ether solvents, more preferably a mixed solvent of aromatic hydrocarbon solvents and alcohol solvents. The aromatic hydrocarbon solvent and the alcohol solvent are preferably toluene and isopropanol. The volume ratio of the aromatic hydrocarbon solvent to the alcohol solvent is preferably 1:1 to 5:1, more preferably 3:1 to 5:1, for example, 4: 1. The volume ratio of the organic solvent to the water may be a volume ratio conventional for such reactions in the art, preferably 1:1 to 10:1, more preferably 5:1 to 10: 1.

In the Suzuki reaction, the amount of the mixed solvent may not be specifically limited as long as the reaction is not affected.

In the Suzuki reaction, the basic agent may be one conventional in the art for such reactions, preferably one or more of alkali metal carbonates, alkali metal fluorides, alkali metal phosphates, alkali metal tert-butoxide, and alkali metal hydroxides. The alkali metal carbonate can be one or more of sodium carbonate, potassium carbonate and cesium carbonate, and potassium carbonate is preferred. The alkali metal fluoride salt may be potassium fluoride. The alkali metal phosphate may be potassium phosphate. The alkali metal tert-butoxide may be sodium tert-butoxide and/or potassium tert-butoxide. The alkali metal hydroxide may be one or more of sodium hydroxide, potassium hydroxide and lithium hydroxide.

In the Suzuki reaction, the molar ratio of the basic agent to the compound IV can be 1 to 10, such as 1.2, further such as 1.7, preferably 2 to 10, such as 9.

In the Suzuki reaction, the molar ratio of the compound S to the compound IV may be 0.9 to 3, preferably 0.9 to 1.5, such as 1.0, and also such as 1.2.

In the Suzuki reaction, the temperature of the Suzuki reaction may be a temperature that is conventional for such reactions in the art, preferably 0 to 130 ℃, more preferably 20 to 70 ℃, such as 45 ℃, and further such as 70 ℃.

The Suzuki reaction can be carried out under protective gas. The shielding gas may be a shielding gas conventional in the art for such reactions, such as nitrogen, and further such as argon.

The progress of the Suzuki reaction can be monitored by methods of monitoring such conventional in the art (e.g., T L C, again, e.g., L C-MS), typically with complete disappearance or no further reaction of the compound IV as the end point of the reaction, preferably for a period of 1 to 18 hours, e.g., 12 hours, again, e.g., 7 hours, again, e.g., 1 hour.

In the Suzuki reaction, the compound S is preferably

In the Suzuki reaction, the compound IV is preferably

After the Suzuki reaction is finished, the method also comprises the following post-treatment steps: cooling the reaction liquid after the reaction to room temperature, extracting, concentrating and carrying out column chromatography.

The preparation method of the compound shown in the formula V can also comprise a preparation method of the compound IV, which is a method 1 or a method 2:

the method comprises the following steps: which comprises the following steps: carrying out halogenation reaction on the compound III and the phosphorus trihalide and/or the phosphorus halide to obtain a compound IV;

the method 2 comprises the following steps: which comprises the following steps: carrying out nucleophilic substitution reaction of the compound III and a sulfonylation reagent in an organic solvent under the action of an alkaline reagent to obtain a compound IV;

the sulfonylation reagent is

Wherein R is³、R^4a、R^4b、R^4c、R^4d、R^4e、X¹And X²The definitions of (A) and (B) are the same as described above;

when X is present²When halogen is contained, the preparation method of the compound IV is the method 1;

when X is present²Is composed ofThe preparation method of the compound IV is the method 2.

In method 1, the halogenation reaction may be a halogenation reaction conventional in the art for such a reaction.

In the method 1, the halogenation reaction is preferably carried out in the absence of a solvent (neat reaction).

In the method 1, the halogen in the "phosphorus trihalide and/or phosphorus halide" is a halogen, and the halogen is preferably Cl, Br or I, and more preferably Cl.

In the method 1, the molar ratio of the "phosphorus trihalide and/or phosphorus halide" to the compound III may be 1 or more, preferably 1 to 30, for example 20, and further for example 10.

In the method 1, the temperature of the halogenation reaction can be a temperature conventional in such reactions in the art, preferably 20 to 130 ℃, preferably 60 to 110 ℃, for example 105 ℃.

In method 1, the progress of the halogenation reaction can be monitored by such conventional monitoring methods in the art (e.g., T L C, e.g., L C-MS), and the end point of the reaction is generally defined as the complete disappearance of the compound III. the time of the halogenation reaction is preferably 2 to 24 hours, e.g., 3 hours.

In the method 1, after the halogenation reaction is finished, the following post-treatment steps can be further included: and quenching, extracting, washing and concentrating the reaction liquid after the halogenation reaction is finished.

In the method 1, in the post-treatment step, the reaction solution may be concentrated before the quenching.

In method 1, the said post-treatment step, the said quenching may be carried out in a manner conventional in the art for such reactions, preferably by adding water, more preferably by adding ice-water.

In method 1, the operation and conditions of the extraction in the post-treatment step may be those conventional in the art for such reactions. The extracted organic solvent may be a chlorinated hydrocarbon solvent, preferably dichloromethane.

In the method 1, in the post-treatment step, the water washing may be a conventional water washing in this type of reaction in the art, and preferably a water washing with saturated sodium chloride is used.

In the method 1, the operation and conditions of the concentration in the post-treatment step may be those conventional in the art for such reactions, such as concentration under reduced pressure.

In method 2, the alkaline agent may be an alkaline agent conventional in such reactions in the art, preferably an organic weak base and/or an inorganic weak base salt, more preferably an organic weak base. The organic weak base can be tertiary amine organic weak base and/or pyridine organic weak base. The tertiary amine organic weak base is preferably Triethylamine (TEA) and/or N, N-Diisopropylethylamine (DIPEA). The inorganic weak base salt may be an alkali metal carbonate, and potassium carbonate is further preferred.

In the process 2, when the sulfonylating agent isWhen is in use, thePreference is given to

In the process 2, when the sulfonylating agent isWhen is in use, thePreference is given to

In method 2, the molar ratio of the sulfonylating agent to the compound III may be a molar ratio customary in such reactions in the art, preferably 1 to 1.5, for example 1.

In method 2, the organic solvent may be an organic solvent conventional in such reactions in the art, preferably one or more of nitrile solvents, chlorinated hydrocarbon solvents and ether solvents. The nitrile solvent is preferably acetonitrile. The chlorinated hydrocarbon solvent is preferably dichloromethane and/or chloroform. The ether solvent is preferably one or more of tetrahydrofuran, 1, 4-dioxane and ethylene glycol dimethyl ether.

In the method 2, the amount of the organic solvent is not particularly limited as long as the reaction is not affected, and for example, the volume-to-mass ratio of the organic solvent to the compound III may be 5 to 15m L/g, for example, 10m L/g.

In method 2, the progress of the reaction can be monitored by methods conventional in the art for monitoring such reactions (e.g., T L C, also e.g., L C-MS), generally with complete disappearance of the compound III as the end point of the reaction, preferably for a period of 0.5 to 5 hours, e.g., 2 hours.

In the method 2, the temperature of the nucleophilic substitution reaction may be a conventional temperature for such a reaction in the art, and may be 0 to 130 ℃, or 50 to 100 ℃, for example, 70 ℃, or 80 ℃.

In the method 2, after the nucleophilic substitution reaction is finished, the following post-treatment steps can be further included: and cooling the reaction solution after the reaction to room temperature, adding water until solid is separated out, filtering and drying.

The compound III is preferably

The preparation method of the compound shown in the formula V can further comprise the following steps: in an organic solvent, carrying out nucleophilic substitution reaction of a compound II and a compound A as shown in the following formula to obtain a compound III;

the conditions for the nucleophilic substitution reaction may be those conventional in the art for such reactions.

In the nucleophilic substitution reaction, the organic solvent may be an organic solvent conventional in such reactions in the art, preferably a polar aprotic solvent. The polar aprotic solvent may be an amide-based solvent. The amide solvent may be N, N-Dimethylformamide (DMF) and/or N, N-Dimethylacetamide (DMAC), preferably N, N-dimethylacetamide.

In the nucleophilic substitution reaction, the amount of the organic solvent used is not particularly limited as long as the reaction is not affected, for example, the volume-to-mass ratio of the organic solvent to the compound II is 5 to 15m L/g, for example, 10m L/g.

In the nucleophilic substitution reaction, the molar ratio of the compound a to the compound II may be a conventional molar ratio in such reactions in the art, and may be 1 to 10, and may also be 1 to 3, for example, 2.4.

Wherein the temperature of the nucleophilic substitution reaction may be a temperature conventional in such reactions in the art, preferably 20 to 100 ℃, for example 85 ℃.

The progress of the nucleophilic substitution reaction can be monitored by methods conventionally used in the art (e.g., T L C, e.g., L C-MS), and the complete disappearance of the compound II is generally used as the end point of the reaction, and the time for the nucleophilic substitution reaction is preferably 1 to 24 hours, more preferably 1 to 5 hours, e.g., 2 hours.

Among them, the compound II is preferably

After the nucleophilic substitution reaction is finished, the following post-treatment steps can be further included: and (3) cooling the reaction liquid after the nucleophilic substitution reaction to room temperature, adding water until solid is separated out, filtering and drying.

The preparation method of the compound shown in the formula V can further comprise the following steps: under the action of an alkaline reagent, carrying out the following reaction of a compound I in a solvent to obtain a compound II,

the reaction conditions may be those conventional in such reactions in the art.

Among them, the solvent may be a solvent conventional in such reactions in the art, and a mixed solvent of an organic solvent and water is preferred. The organic solvent may be an organic solvent conventionally used in such reactions in the art, preferably one or more of a nitrile solvent, a ketone solvent, an ether solvent and an amide solvent, preferably a nitrile solvent. The nitrile solvent is preferably acetonitrile.

The amount of the solvent used is not particularly limited, as long as the reaction is not affected.

Wherein, the alkaline reagent can be the alkaline reagent conventional in the reaction in the field, and inorganic strong base is preferred. The inorganic strong base may be one or more of sodium hydroxide, potassium hydroxide, lithium hydroxide and calcium hydroxide, preferably sodium hydroxide.

Wherein, the molar ratio of the alkaline reagent to the compound I can be the conventional molar ratio in the reaction in the field, and is preferably 1-20, such as 4.

Wherein the temperature of the reaction may be a temperature conventional in the art for such reactions, preferably 0 to 80 ℃, e.g. 45 ℃.

Wherein the progress of the substitution reaction can be monitored by methods conventional in the art (e.g. T L C, e.g. L C-MS), and the end point of the reaction is generally the complete disappearance of the compound I. the reaction time is preferably 8 to 18 hours, e.g. 12 hours.

After the reaction is finished, the method also comprises the following post-treatment steps: and cooling the reaction liquid after the reaction to room temperature, adjusting the pH value of the reaction liquid to 5-6, filtering and drying.

The invention also provides a preparation method of the compound shown as the formula YY-20394, which comprises the following steps:

step S1: under the action of a palladium catalyst and an alkaline reagent, carrying out a Suzuki reaction of the following formula on a compound S and a compound IV in a solvent to obtain a compound V;

step S2: under the action of an alkaline reagent, carrying out the following reaction on methylsulfonyl chloride and the compound V in an organic solvent to obtain a compound VI;

step S3: under the conditions of a palladium catalyst and a ligand and under the action of an alkaline reagent, carrying out a coupling reaction of a compound VII and a compound VI in a solvent as shown in the following formula to obtain a compound YY-20394;

wherein, X¹、X²、R¹And R²The definitions of (A) and (B) are the same as described above; when R in said compound V¹And R²At the same time areThe compound V is directly subjected to the coupling reaction of step S3 without step S2; the conditions and operation of the process for the preparation of the compound V are as described above.

In the preparation method of the compound shown as the formula YY-20394, when R in the compound V is¹And R²Is not H or at the same timeThe compound V can be directly subjected to the coupling reaction of the step S3 without the step S2。

In step S2, the reaction conditions may be those conventional in such reactions in the art, and the following conditions are preferred in the present invention:

in step S2, the alkali agent is preferably a weak organic base. The weak organic base may be a weak organic base conventional in such reactions in the art. The organic weak base can be pyridine organic weak base and/or tertiary amine organic weak base, and pyridine organic weak base is preferred. The pyridine organic weak base can be pyridine.

In step S2, the molar ratio of the methanesulfonyl chloride to the compound V may be 1 to 5, for example, 2.

In step S2, the molar ratio of the alkaline reagent to the compound V may be 3 to 25, for example 23.

In step S2, the organic solvent is preferably a chlorinated hydrocarbon solvent. The halogenated hydrocarbon solvent is preferably dichloromethane.

In step S2, the reaction temperature may be 10-50 ℃.

In step S2, the progress of the reaction can be monitored by a monitoring method (such as T L C, e.g., L C-MS) which is conventional in the art, and the end point of the reaction is generally the complete disappearance of the compound V.

In step S2, the compound V is preferably

In step S2, after the reaction is completed, the method may further include the following post-treatment steps: quenching, filtering and pulping the reaction solution after the reaction is finished.

In step S3, the coupling reaction may be a coupling reaction conventional in the art.

In step S3, the palladium catalyst may be a palladium catalyst conventional in the art for such reactions, preferably tetrakis (triphenylphosphine) palladium (Pd (PPh)₃)₄) Palladium acetate Pd (OAc)₂Bis (triphenylphosphine) palladium dichloride (PdCl)₂(PPh₃)₂) Bis (tri-o-phenylphosphino) palladium (II) dichloride (PdCl)₂[P(o-tol)₃]₂) Tris (dibenzylideneacetone) dipalladium (Pd)₂(dba)₃) Bis (tri-tert-butylphosphine) palladium (Pd [ P (t-Bu) ]₃]₂) [1,1' -bis (diphenylphosphino) ferrocene]Palladium dichloride (PdCl)₂(dppf)) and [1,1' -bis (diphenylphosphino) ferrocene]Palladium dichloride dichloromethane complex (PdCl)₂(dppf) DCM), more preferably palladium acetate.

In step S3, the molar ratio of the palladium catalyst to the compound VI may be 0.01 to 0.2, for example, 0.1.

In step S3, the ligand may be a ligand conventional in the art for such reactions, preferably triphenylphosphine (PPh)₃) Tri-o-methylphenyl phosphorus (P (o-tol)₃) One or more of tri-tert-butylphosphine tetrafluoroborate, 2-dicyclohexylphosphine-2 ',4',6' -triisopropylbiphenyl (x-Phos), 2-dicyclohexylphosphine-2 ',6' -dimethoxy-biphenyl (s-Phos) and 2-dicyclohexylphosphine-2 ',6' -diisopropoxy-1, 1' -biphenyl (Ru-Phos), preferably 2-dicyclohexylphosphine-2 ',4',6' -triisopropylbiphenyl.

In step S3, the molar ratio of the ligand to the compound VI may be 0.02-0.4, such as 0.2.

In step S3, the alkaline agent may be an alkaline agent conventional in such reactions in the art, preferably one or more of alkali metal carbonates, alkali metal fluorides, alkali metal phosphates, alkali metal tert-butoxide, and alkali metal hydroxides. The alkali metal carbonate can be one or more of sodium carbonate, potassium carbonate and cesium carbonate, preferably cesium carbonate (Cs)₂CO₃). The alkali metal fluoride salt may be potassium fluoride. The alkali metal phosphate may be potassium phosphate. The alkali metal salt of t-butanol may be sodium t-butoxide and/or potassium t-butoxide. The alkali metal hydroxide may be one or more of sodium hydroxide, potassium hydroxide and lithium hydroxide.

In step S3, the molar ratio of the basic agent to the compound VI may be 1 to 20, such as 3, such as 6, such as 10, such as 15, such as 20.

In step S3, the molar ratio of the compound VII to the compound VI may be 0.8 to 6, preferably 1 to 3, such as 5, and further such as 1.5.

In step S3, the solvent may be a solvent conventional in such reactions in the art, and is preferably a mixed solvent of a water-soluble organic solvent and water. The water-soluble organic solvent may be a water-soluble organic solvent which is conventional in such reactions in the art. The water-soluble organic solvent is preferably an ether solvent and/or an alcohol solvent, and more preferably an ether solvent. The ethereal solvent is preferably one or more of Tetrahydrofuran (THF), 1, 4-dioxane and ethylene glycol dimethyl ether, and more preferably tetrahydrofuran. The volume ratio of the organic solvent to water may be as conventional in the art, preferably 1:1 to 15:1, more preferably 3:1 to 15:1, such as 10:1, for example 4: 1.

In step S3, the coupling reaction may be performed in a manner conventional in the art, and may be performed in a conventional heating manner, or in a microwave condition.

When the coupling reaction is a conventional heating method, the temperature of the coupling reaction may be 30 to 130 ℃, preferably 80 to 120 ℃. The time of the coupling reaction can be 2-16 h, such as 12 h.

When the coupling reaction is a microwave reaction, the temperature of the coupling reaction can be 50-120 ℃. The time of the coupling reaction can be 5-16 h, such as 8h, and further such as 12 h.

In step S3, the compound VI is preferably

In step S3, the coupling reaction may also be carried out under a protective gas. The shielding gas may be a shielding gas conventional in the art, such as nitrogen, and further such as argon.

In step S3, after the coupling reaction is completed, the following post-treatment steps may be further included: and (3) extracting, washing, concentrating and carrying out chromatographic separation on the reaction solution after the reaction is finished.

The invention also provides a compound shown as the formula IV:

wherein, X¹And X²All as described above.

The compound IV is preferably More preferably

The invention also provides a preparation method of the compound shown in the formula IV, which comprises the following steps of 1 or 2:

the method comprises the following steps: which comprises the following steps: carrying out halogenation reaction on the compound III and the phosphorus trihalide and/or the phosphorus halide to obtain a compound IV;

the method 2 comprises the following steps: which comprises the following steps: carrying out nucleophilic substitution reaction of the compound III and a sulfonylation reagent in an organic solvent under the action of an alkaline reagent to obtain a compound IV; the sulfonylation reagent is

Wherein R is³、R^4a、R^4b、R^4c、R^4d、R^4e、X¹And X²The definitions of (A) and (B) are the same as described above;

when X is present²When halogen is contained, the preparation method of the compound IV is the method 1;

when X is present²Is composed ofThe preparation method of the compound IV is the method 2.

In the above reaction, the conditions of method 1 and method 2 are the same as those described above.

The invention also provides a compound III:

wherein, X¹Is Cl or Br.

The compound III is preferably

The invention also provides a preparation method of the compound III, which comprises the following steps: in an organic solvent, carrying out nucleophilic substitution reaction of a compound II and a compound A as shown in the following formula to obtain a compound III;

wherein, X¹Is Cl or Br.

Wherein, the conditions of the nucleophilic substitution reaction are the same as those described above.

The invention also provides a compound shown as the formula II:

the invention also provides a compound shown as the formula V-2:

wherein R is¹And R²Independently is H or

The compound V-2 is preferably

The above-mentioned preparation methods of the compounds may be combined as desired to obtain a synthetic route of the compound represented by the formula III, IV, V or YY-20394 (e.g., I → II → III → IV → V → VI → YY-20394, II → III → IV → V → VI → YY-20394, I → II → III → IV → V, I → II → III → IV, II → III → IV, I → II → III, etc.).

In the present invention, the following abbreviations are used:

tetrahydrofuran, t-Bu-t-butyl, DCM, dichloromethane, NCS, N-chlorosuccinimide, Ts, p-toluenesulfonyl, Ns, p-nitrotoluenesulfonyl, Ms, Tf, trifluoromethanesulfonyl, Ac, acetyl, DIPEA, diisopropylethylamine, DMF, N-dimethylformamide, DMAC, N-dimethylacetamide, DMSO, dimethyl sulfoxide, dba, dibenzylideneacetone, dppf, 1' -bis (diphenylphosphino) ferrocene, x-Phos 2-dicyclohexylphosphine-2 ',4',6' -triisopropylbiphenyl, s-Phos 2-dicyclohexylphosphine-2 ',6' -dimethoxy-biphenyl, Ru-Phos mass spectrometry 2-dicyclohexylphosphine-2 ',6' -diisopropoxyl-1, 1' -biphenyl, mg, 21mg, 85mg, electrospray, CMS, mass spectrometry, electrospray ionization, mass spectrometry, CMS, and electrospray ionization, mass spectrometry, or electrospray;¹h NMR ═ nuclear magnetic resonance; MHz-MHz; brs ═ broad singlet; d is doublet; t is a triplet; q is quartet; m is multiplet; dd ═ doublet; j is a coupling constant; n is moles per liter.

In the invention, the room temperature refers to the ambient temperature and is 10-35 ℃.

In the present invention, "overnight" means 8 to 16 hours.

In the present invention, "water-soluble organic solvent" means a solvent generally having a polar group in the molecule, for example, such as-OH, -SO₃H、-NH₂、-NHR、-COOH、-CN、-CO-、-CONH₂-a group and a carbon chain of 8 carbons or less. Acetone, acetonitrile and N, N-dimethylformamide are all common "water-soluble organic solvents".

The above preferred conditions can be arbitrarily combined to obtain preferred embodiments of the present invention without departing from the common general knowledge in the art.

The reagents and starting materials used in the present invention are commercially available.

The positive progress effects of the invention are as follows: the preparation method of the morpholinyl quinazoline compound improves the selectivity of the Suzuki reaction on the 4-position of the quinazoline ring, solves the problem of more byproducts in the reaction, has high yield, is simple and convenient to operate, has mild reaction conditions, and is suitable for industrial production.

Detailed Description

The invention is further illustrated by the following examples, which are not intended to limit the scope of the invention. The experimental methods without specifying specific conditions in the following examples were selected according to the conventional methods and conditions, or according to the commercial instructions.