CN115215749A - Apixaban intermediate and preparation method thereof - Google Patents

Apixaban intermediate and preparation method thereof Download PDF

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Publication number
CN115215749A
CN115215749A CN202110425516.0A CN202110425516A CN115215749A CN 115215749 A CN115215749 A CN 115215749A CN 202110425516 A CN202110425516 A CN 202110425516A CN 115215749 A CN115215749 A CN 115215749A
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formula
compound
reaction
apixaban
subjected
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郭雷雷
于帅
郭必豹
阮振宇
王一能
何杨
梅义将
胡剀
李永刚
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Zhejiang Jiuzhou Pharmaceutical Co Ltd
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Zhejiang Jiuzhou Pharmaceutical Co Ltd
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Priority to PCT/CN2021/133634 priority patent/WO2022222473A1/en
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    • C07C69/00—Esters of carboxylic acids; Esters of carbonic or haloformic acids
    • C07C69/34—Esters of acyclic saturated polycarboxylic acids having an esterified carboxyl group bound to an acyclic carbon atom
    • C07C69/36—Oxalic acid esters
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    • C07—ORGANIC CHEMISTRY
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    • C07C15/00—Cyclic hydrocarbons containing only six-membered aromatic rings as cyclic parts
    • C07C15/02—Monocyclic hydrocarbons
    • C07C15/107—Monocyclic hydrocarbons having saturated side-chain containing at least six carbon atoms, e.g. detergent alkylates
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    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C231/00—Preparation of carboxylic acid amides
    • C07C231/02—Preparation of carboxylic acid amides from carboxylic acids or from esters, anhydrides, or halides thereof by reaction with ammonia or amines
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C233/00—Carboxylic acid amides
    • C07C233/01—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms
    • C07C233/56—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having carbon atoms of carboxamide groups bound to carbon atoms of carboxyl groups, e.g. oxamides
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    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C67/00—Preparation of carboxylic acid esters
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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/68—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member
    • C07D211/72—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, directly attached to ring carbon atoms
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    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/80—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members
    • C07D211/84—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two 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 directly attached to ring carbon atoms
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    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/80—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members
    • C07D211/84—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two 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 directly attached to ring carbon atoms
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    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
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    • C07D211/80—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members
    • C07D211/84—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two 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 directly attached to ring carbon atoms
    • C07D211/90—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen

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Abstract

The invention relates to a novel intermediate for synthesizing apixaban and a preparation method thereof. The method specifically comprises the following steps: 1) Carrying out aminolysis reaction on p-phenylenediamine and a compound of formula (1-a) to obtain a compound of formula (2), and carrying out substitution reaction on the compound of formula (2) to obtain a compound of formula(3) The compound, 3) the compound of formula (3) is subjected to substitution reaction to prepare a compound of formula (4 i), and then the compound is subjected to cyclization reaction to obtain a compound of formula (4), or the compound of formula (3) is directly subjected to reaction to prepare a compound of formula (4), 4) the compound of formula (4) is subjected to cyclization reaction to prepare a compound of formula (5), 5) the compound of formula (5) is subjected to hydrolysis reaction to prepare a compound of formula (6), 6) the compound of formula (6) is subjected to reaction to prepare a compound of formula (7), or the compound of formula (6) is subjected to decarboxylation reaction to obtain a compound of formula (6 i), and then the compound of formula (7) is subjected to condensation reaction, wherein the reaction formula is as follows:

Description

Apixaban intermediate and preparation method thereof
Technical Field
The invention relates to the field of pharmaceutical chemicals, and particularly relates to a novel intermediate for synthesizing apixaban and a preparation method thereof.
Background
Apixaban is a new generation of oral antithrombotic agents showing high selectivity, good bioavailability and highly effective therapeutic effect among numerous coagulation factor Xa inhibitors, and is mainly used for adult patients in hip or knee joint phase-selective replacement for the prevention of Venous Thromboembolic Events (VTE). The apixaban was originally discovered by bexaban corporation, bexaban, in 2003, and the drug was developed in 2007 together with the pfeiri, and from the time of marketing in 2011 to the present, the sales increased year by year, in terms of BMS & pfeiri, ai Letuo (Eliquis) (apixaban) for a total sales of 90.16 hundred million dollars 3 quarters before 2019, and the increase was 25% on a par. Eliquis projected a sale of $ 120 billion in 2025.
Figure BDA0003029387930000011
In the current market, a few processes for synthesizing apixaban are available, but most of the process routes are synthesized through a key intermediate 5,6-dihydro-3- (4-morpholinyl) -1- [4- (2-oxo-1-piperidinyl) phenyl ] -2 (1H) -pyridone, so that the synthesis process is crucial to synthesis of the apixaban intermediate make internal disorder or usurp, and the key intermediate has the following structural formula:
Figure BDA0003029387930000021
the following prior art reports methods for preparing this intermediate:
one route proposed by Bristol-Myers Squibb, inc. in the 2003 world patent W02003049681: p-iodoaniline is used as a raw material, amidation-cyclization, dichlorination and morpholine substitution are carried out to obtain a compound, and the compound is reacted with 2-piperidone in a Cu (PPh) catalyst 3 ) 3 Br and cesium carbonate are subjected to a coupling reaction in the presence of a catalyst to obtain a compound I. The route uses p-nitroiodobenzene 1 as a starting material, so that piperidone groups are introduced, the p-nitroiodobenzene is expensive, and the auxiliary reagent, namely the cuprous triphenyl phosphorobromide, is large in dosage and expensive, so that the application of the route is limited.
Figure BDA0003029387930000022
2. Another process route is provided in chinese patent CN101967145 published in 2011 by the university of eastern science and technology: taking p-nitroaniline and 5-chlorovaleryl chloride as raw materials, carrying out amidation-cyclization, dichlorination, elimination and condensation reaction to obtain a compound 2, reducing the compound 2 into a corresponding amino compound 4 by sodium sulfide, and carrying out amidation-cyclization on the compound 4 and the 5-chlorovaleryl chloride to obtain a compound I. In the route, p-nitroaniline is introduced to cyclize to form a piperidone group, the cost of p-nitroaniline raw materials is low, but the p-nitroaniline can influence the smooth proceeding of acylation reaction due to the strong electron withdrawing action of the nitro group, and meanwhile, alkaline sulfide is adopted to cause incomplete reduction of the nitro group and has a destructive effect on an amido bond, so that more byproducts are generated, thereby limiting the practical application of the route.
Figure BDA0003029387930000031
3. The Shanghai pharmaceutical industry institute improves the two preparation methods, and applies for Chinese patent CN103626689A in 2012, and provides the following process route: aniline is used as a starting material, and amidation-cyclization, nitration, dichlorization and morpholine substitution reactions are carried out to obtain a compound 4, the compound 4 is reduced by sodium sulfide to obtain a corresponding amino compound 3, and the compound 3 and 5-chloropentanoyl chloride are subjected to amidation-cyclization to obtain a compound. The starting materials in the route are low in price, but the nitration reaction in the route is rapid in heat release, the reaction process is dangerous, more impurities can be introduced, the post-treatment is difficult, and the method is not suitable for industrialization.
Figure BDA0003029387930000032
4. Patent document CN101967145 discloses a method, which uses p-nitroaniline as a starting material, and after amidation cyclization, phosphorus pentachloride is eliminated, sodium sulfide is reduced and then acylated and cyclized again, and finally 5,6-dihydro-3- (4-morpholinyl) -1- [4- (2-oxo-1-piperidinyl) phenyl ] -2 (1H) -pyridinone is obtained.
5. Patent CN110143914 uses p-chloroaniline as a starting material, and after acylation cyclization and chlorination, p-chloroaniline reacts with morpholine to eliminate hydrogen chloride, and then 5,6-dihydro-3- (4-morpholinyl) -1- [4- (2-oxo-1-piperidyl) phenyl ] -2 (1H) -pyridone is obtained through 2-piperidone coupling.
6. In patent CN104030972, p-diphenylamine is used as a raw material, after bilateral acylation cyclization, phosphorus pentachloride is subjected to unilateral chlorination, and then the phosphorus pentachloride is reacted with morpholine to eliminate the reaction to obtain 5,6-dihydro-3- (4-morpholinyl) -1- [4- (2-oxo-1-piperidyl) phenyl ] -2 (1H) -pyridone, and the selectivity of chlorination in the method is a key problem, so that the yield is unstable.
In conclusion, the synthesis methods for preparing the apixaban intermediate 5,6-dihydro-3- (4-morpholinyl) -1- [4- (2-oxo-1-piperidyl) phenyl ] -2 (1H) -pyridone at the present stage are approximately the same, and the similar processes have the same problems and defects of poor reaction repeatability; the post-treatment process is relatively complicated; the process has high requirements on equipment; expensive starting materials, high cost and the like.
In view of some of the drawbacks of the existing routes, there is a need to further develop an apixaban key intermediate route that is environmentally friendly and suitable for commercial production.
Disclosure of Invention
The invention provides a novel intermediate for synthesizing apixaban and a preparation method thereof, the method has the advantages of simplicity and easiness in operation, the yield of each step of reaction is higher, the synthesis route is green and environment-friendly, meanwhile, the cost is reduced, and the industrial production is convenient to implement.
In order to realize the purpose of the invention, the invention provides the following technical scheme:
in a first aspect, the present invention provides an intermediate for the preparation of apixaban of formula (1-a), the structural formula is as follows:
Figure BDA0003029387930000041
in a second aspect, the invention provides a preparation method for preparing an apixaban intermediate with the formula (1-a): in an organic solvent, under the catalysis of organic base, tert-butyl alcohol and oxalyl chloride are subjected to acylation reaction and then are subjected to acylation reaction with phenol to obtain the product;
(1-a) the selectivity of ammonolysis reaction is high during the synthesis of (2);
the preparation method for preparing the apixaban intermediate with the formula (1-a) is preferably as follows: the organic base is triethylamine, and the triethylamine and the tertiary butanol are mixed and dripped into the organic solvent of oxalyl chloride according to the molar ratio of 1:1; triethylamine and tertiary butanol are controlled to be added in dropwise in the same equivalent, so that the stability of oxalyl chloride is ensured, and the generation of disubstituted products by reaction is further reduced.
In a third aspect, an intermediate for the preparation of apixaban of formula (2) having the formula:
Figure BDA0003029387930000051
in a fourth aspect, the invention provides a preparation method of an apixaban intermediate formula (2), which is characterized in that p-phenylenediamine and a compound of formula (1-a) are subjected to ammonolysis reaction to prepare a compound of formula (2), wherein the reaction formula is as follows:
Figure BDA0003029387930000052
in a fifth aspect, the present invention provides an intermediate for the preparation of apixaban of formula (3-1), having the following structural formula:
Figure BDA0003029387930000053
in a sixth aspect, the present invention provides an intermediate for the preparation of apixaban of formula (4), the structural formula is as follows:
Figure BDA0003029387930000061
wherein R is 1 、R 2 Each independently is a C1-C6 aliphatic hydrocarbon, phenyl or substituted phenyl;
wherein "substituted phenyl" in the present invention includes benzyl, benzene, halogenobenzene, nitrobenzene, alkoxybenzene and benzyloxybenzene.
In a seventh aspect, the present invention provides an intermediate for the preparation of apixaban of formula (4 i), the structural formula is as follows:
Figure BDA0003029387930000062
wherein R is 1 、R 2 Each independently is a C1-C6 aliphatic hydrocarbon, phenyl or substituted phenyl; x is halogen, OSO 2 Ph-p-Me、OSO 2 Me or OSO 2 Ph。
Wherein "substituted phenyl" in the present invention includes benzyl, benzene, halogenobenzene, nitrobenzene, alkoxybenzene and benzyloxybenzene.
In an eighth aspect, the invention provides a preparation method of an apixaban intermediate formula (4), which is characterized in that a compound of a formula (3) is subjected to substitution reaction to prepare a compound of a formula (4 i), and then subjected to cyclization reaction to obtain the compound of the formula (4) or directly subjected to cyclization reaction to obtain the compound of the formula (4),
the reaction formula is as follows:
Figure BDA0003029387930000071
wherein R is 1 、R 2 Each independently is a C1-C6 aliphatic hydrocarbon, phenyl or substituted phenyl; x is halogen, OSO 2 Ph-p-Me、OSO 2 Me or OSO 2 Ph。
Wherein "substituted phenyl" in the present invention includes benzyl, benzene, halogenobenzene, nitrobenzene, alkoxybenzene and benzyloxybenzene.
Wherein the compound of formula (4 i) may or may not be isolated.
In a ninth aspect, the present invention provides an intermediate for the preparation of apixaban of formula (4 i-1), the structural formula is as follows:
Figure BDA0003029387930000072
in a tenth aspect, the present invention provides an intermediate for the preparation of apixaban of formula (4-1), having the following structural formula:
Figure BDA0003029387930000081
in an eleventh aspect, the invention provides a preparation method of an apixaban intermediate formula (4-1), which is characterized in that tert-butyl 4-bromobutyrate and a compound of formula (3) are subjected to substitution reaction to prepare a compound of formula (4 i-1), and then subjected to cyclization reaction to obtain a compound of formula (4-1) or directly prepared from the compound of formula (4 i-1) to obtain the compound of formula (4-1), wherein the reaction formula is as follows:
Figure BDA0003029387930000082
wherein the compound of formula (4 i-1) may or may not be isolated.
Preferably, the synthesis step of (4-1) is that 3 and 4-bromobutyric acid tert-butyl ester are subjected to substitution reaction at the temperature of 50-70 ℃ in an organic solvent under the catalysis of an inorganic base to prepare a compound shown as a formula (4 i-1), and then the temperature is raised to 70-80 ℃ to carry out cyclization reaction to generate the compound shown as the formula (4-1);
the inorganic base is one or more of potassium carbonate, cesium carbonate, sodium carbonate, lithium carbonate, magnesium carbonate and calcium carbonate.
The optimal selection method comprises two reactions but can be completed in one step, thereby greatly simplifying the reaction time and the cost, ensuring the yield and facilitating the mass production.
Further, the inorganic base is preferably potassium carbonate or cesium carbonate. The reaction catalyzed by the two inorganic bases can lead the reaction to proceed toward the target direction, and the reaction selectivity is high.
4-1 introduces 4-bromobutyric acid tert-butyl ester, so that a tert-butyl ester group is added after 5 ring closure, and the tert-butyl ester group can ensure that the yield of decarboxylated 6 is high.
In a twelfth aspect, the invention provides a preparation method of the Apixaban intermediate formula (4-1), which is characterized in that the compound of the formula (3) is reacted to obtain the compound of the formula (4-1), wherein the reaction formula is as follows:
Figure BDA0003029387930000091
in a thirteenth aspect, the present invention provides an intermediate for the preparation of apixaban of formula (5-1), having the following structural formula:
Figure BDA0003029387930000092
in a fourteenth aspect, the invention provides a preparation method of an apixaban intermediate formula (5), which is characterized in that a compound of formula (4) is subjected to cyclization reaction to prepare a compound of formula (5), wherein the reaction formula is as follows:
Figure BDA0003029387930000101
wherein R is 1 、R 2 Each independently is a C1-C6 aliphatic hydrocarbon, phenyl or substituted phenyl.
In a fifteenth aspect, the invention provides a preparation method of an apixaban intermediate formula (5-1), which is characterized in that a compound of a formula (4-1) is subjected to cyclization reaction to prepare a compound of a formula (5-1), wherein the reaction formula is as follows:
Figure BDA0003029387930000102
in a sixteenth aspect, the present invention provides an intermediate for the preparation of apixaban of formula (6), having the formula:
Figure BDA0003029387930000111
in a seventeenth aspect, the invention provides a preparation method of an apixaban intermediate formula (6), which is characterized in that the compound of the formula (5-1) is subjected to cyclization reaction to prepare the compound of the formula (6), wherein the reaction formula is as follows:
Figure BDA0003029387930000112
in an eighteenth aspect, the present invention provides an intermediate for the preparation of apixaban of formula (6 i), the structural formula is as follows:
Figure BDA0003029387930000113
in a nineteenth aspect, the invention provides a preparation method of the apixaban intermediate formula (7), which is characterized in that the compound of the formula (6) is subjected to condensation reaction to prepare the compound of the formula (7) or the compound of the formula (6) is subjected to decarboxylation reaction to obtain the compound of the formula (6 i) and then subjected to condensation reaction to obtain the compound of the formula (70),
the reaction formula is as follows:
Figure BDA0003029387930000121
in a twentieth aspect, the invention provides a preparation method of apixaban intermediate formula 7, which is characterized by comprising the following steps:
1) Carrying out aminolysis reaction on p-phenylenediamine and a compound shown in a formula (1-a) to prepare a compound shown in a formula (2),
2) Carrying out substitution reaction on the compound of the formula (2) to prepare a compound of a formula (3),
3) Carrying out substitution reaction on the 4-bromobutyric acid tert-butyl ester and a compound of a formula (3-1) to prepare a compound of a formula (4 i-1), carrying out cyclization reaction to obtain the compound of the formula (4-1) or directly carrying out reaction on the compound of the formula (3-1) to prepare the compound of the formula (4-1),
4) The compound of the formula (4-1) is subjected to cyclization reaction to prepare a compound of a formula (5-1),
5) The compound of the formula (5-1) is hydrolyzed to obtain the compound of the formula (6),
6) The compound of the formula (6) is subjected to condensation reaction to prepare a compound of a formula (7) or the compound of the formula (6) is subjected to decarboxylation reaction to obtain a compound of a formula (6 i) and then subjected to condensation reaction to obtain a compound of a formula (70),
the reaction formula is as follows
Figure BDA0003029387930000131
In a twenty-first aspect, the invention provides a preparation method of apixaban intermediate formula 7, which is characterized by comprising the following steps:
1) Carrying out aminolysis reaction on p-phenylenediamine and a compound shown in a formula (1-a) to prepare a compound shown in a formula (2),
2) Carrying out substitution reaction on the compound of the formula (2) to prepare a compound of a formula (3),
3) Carrying out substitution reaction on the compound of the formula (3) to obtain a compound of a formula (4 i), carrying out cyclization reaction to obtain a compound of a formula (4) or directly carrying out reaction on the compound of the formula (3) to obtain the compound of the formula (4),
4) The compound of the formula (4) is subjected to cyclization reaction to prepare a compound of a formula (5),
5) The compound of the formula (5) is hydrolyzed to obtain a compound of a formula (6),
6) The compound of formula (6) is reacted to obtain the compound of formula (7) or the compound of formula (6) is decarboxylated to obtain the compound of formula (6 i) and then condensed to obtain the compound of formula (7), wherein the reaction formula is as follows:
Figure BDA0003029387930000141
compared with the prior art, the new intermediate for synthesizing apixaban and the preparation method thereof have the following remarkable progress:
(1) The method is simple and easy to implement: the initial raw materials with tert-butyl ester in the raw materials of the synthetic route adopted by the invention have the advantage of easy preparation, the stability of the products in each step is greatly increased, and the transportation stability, the storage stability and the use stability during factory production are greatly increased, so that the quality control of each intermediate in the reaction is more convenient, the requirements on equipment are reduced, and no complex reaction exists in the synthetic route, so that the whole synthetic route has the advantages of simplicity and easy operation;
(2) The cost is low: the synthesis route of the invention does not use expensive catalysts or auxiliary reagents in all raw materials and reactions, also avoids using expensive iodine-containing compounds, ensures that the three wastes generated by each step of process are less polluted and easy to treat, and can greatly reduce the cost while ensuring that the reaction is green and environment-friendly;
(3) The yield is high: by adopting the novel intermediate of apixaban and the preparation method thereof, the yield of each step of reaction can be more than 85%, and the post-treatment is simple and convenient, thereby being more beneficial to regulation and control during mass production.
Detailed Description
The invention is further defined in the following examples. It should be understood that these examples, while indicating the preferred embodiment of the invention, are given by way of illustration only, and are not limiting upon the claims of the invention.
Example 1: the preparation method of the apixaban precursor compound adopts the following specific process steps.
(1) Synthesis of Compound 1-a:
Figure BDA0003029387930000151
dichloromethane (70 ml) was added to the reaction flask, oxalyl chloride (10.0 g, 0.079mol) was added, stirring at-10 ℃ for 0.5h, tert-butanol (5.85g, 0.079mol) was added dropwise: dichloromethane (10 ml): triethylamine (7.97g, 0.079mol) mixed solution, after the dropwise addition, stirring at-10 ℃ for 0.5h while keeping the temperature, and then dropwise adding phenol (7.43g, 0.079mol): dichloromethane (10 ml): triethylamine (7.97g, 0.079mol) mixed solution, after the dropwise addition, stirring at-10 ℃ for 0.5h under the condition of keeping the temperature, when HPLC and TLC show that the reaction is finished; filtration and concentration of the filtrate under reduced pressure gave the product (11.6 g, 12.9g theory, yield 90.2%), LCMS M/z 223 (M) + +H,C 12 H 14 O 4 )。
(2) Synthesis of Compound 2:
Figure BDA0003029387930000152
adding ethyl acetate (100 ml) into a reaction bottle, adding p-phenylenediamine (10.0g, 0.093mol) and tert-butyl phenolate (21.1g, 0.095 mol), stirring at 18 ℃ for 3.5 hours, adding 50g of water and concentrated hydrochloric acid (6.94ml, 0.083mol) to extract a layering layer when HPLC and TLC show that the reaction is finished, and adding 100g of water and concentrated hydrochloric acid (0.77ml, 0.009mol) to extract the layering layer in an ethyl acetate layer; mixing water layers, adding sodium carbonate into the water layer to adjust PH to 7, suction filtration, washing and drying of a filter cake with water to obtain a product (19.7 g, a theoretical value of 21.8g and a yield of 90.3 percent), LCMS M/z 236 (M) + +H,C 12 H 16 N 2 O 3 )。
(3) Synthesis of Compound 3:
Figure BDA0003029387930000161
adding dichloromethane (100 ml) into a reaction bottle, adding compound 2 (10.0g, 0.042 mol), adding triethylamine (4.5g, 0.044 mol), cooling to 15 ℃, keeping the temperature and stirring, dropwise adding 5-chloropentanoyl chloride (6.9g, 0.044 mol) while stirring, keeping the temperature at 15 ℃ for 0.5h after completing dropwise adding, when HPLC and TLC show that the reaction is finished, adding 40g of water, stirring, filtering, adding 40g of water into a filter cake, stirring, filtering again, washing and drying the filter cake with water to obtain a product, mixing filtrate obtained in two times, demixing a dichloromethane layer, recrystallizing the dichloromethane layer, drying to obtain the product, mixing product obtained in two times (14.3 g, theoretical value 15.0g, yield 95.3%), and LCMS M/z 355 (M/S/z) (M) + +H,C 17 H 23 ClN 2 O 4 )。
(4) Synthesis of Compound 4-1:
Figure BDA0003029387930000162
compound 3 (10.0 g, 0.028mol) was charged to a reaction flask, potassium carbonate (38.8 g, 0.282mol) was added, DMF (100 ml) was added, tert-butyl 4-bromobutyrate (7.55g, 0.034mol) was added, the mixture was stirred at 55 ℃ for 12 hours, the mixture was warmed to 80 ℃ for 3 hours, and when HPLC and TLC showed completion of the reaction, suction filtration and concentration under reduced pressure were carried out, the concentrate was separated by extraction with dichloromethane and water, the organic layer was dried over anhydrous sodium sulfate, and concentration under reduced pressure was carried out to obtain the product (11.6 g, theoretical 12.9g, yield 89.9%), LCMS M/z 461 (M.6 g, M.S M/z 461) + +H,C 25 H 36 N 2 O 6 )。
(5) Synthesis of Compound 5:
Figure BDA0003029387930000163
adding sodium tert-butoxide (2.71g, 0.028mol) into a reaction bottle, adding tetrahydrofuran (90 ml), stirring while keeping the temperature at 65 ℃, adding a tetrahydrofuran (30 ml) solution of compound 4-1 (10.0 g, 0.022mol) and keeping the temperature for reaction for 1h, concentrating under reduced pressure when HPLC and TLC show that the reaction is complete, adding water (100 ml) and ethyl acetate (100 ml) at 5 ℃, adding hydrochloric acid to adjust the pH to 2, carrying out phase separation, drying the ethyl acetate layer with anhydrous sodium sulfate, and concentrating under reduced pressure to obtain a product (6.9 g, 7.9g of theory, 87.3 percent of yield), LCMS M/z 387 (M) + +H,C 21 H 26 N 2 O 5 )。
(6) Synthesis of Compound 6:
Figure BDA0003029387930000171
adding dichloromethane (70 ml) into a reaction flask, adding tetrahydrofuran (30 ml), adding compound 5 (10.0 g, 0.026mol), stirring at 20 deg.C under constant temperature, introducing hydrogen chloride gas, reacting for 2.5h under constant temperature, concentrating under reduced pressure when HPLC and TLC show that the reaction is completed, adding heptane (50 ml) at 20 deg.C under constant temperature, stirring for 0.5h, filtering, washing the filter cake with heptane, and oven drying to obtain product (7.7 g, theoretical value of 8.5g, yield of 90.5%), LCMS M/z331 (M/M) + +H,C 17 H 18 N 2 O 5 )。
(7) Synthesis of compound 7:
Figure BDA0003029387930000172
the reaction flask was charged with Compound 6 (10.0 g, 0.033mol), acetonitrile (100 ml), morpholine (4.5 g, 0.052mol), acetic acid (3.1g, 0.052mol), stirred at 80 ℃ for 4h, and when HPLC and TLC showed completion of the reaction, recrystallized to give the product (9.7 g, theoretical 10.7g, yield 90.7%), LCMS M/z 356 (M M.M.M./z.)% + +H,C 20 H 25 N 3 O 3 )。
Example 2: in contrast to example 1, the process for the preparation of apixaban precursor compounds in this example employs the following specific process steps.
(1) Synthesis of Compound 1-a:
dichloromethane (80 ml) was added to the reaction flask, oxalyl chloride (10.0 g, 0.079mol) was added, the mixture was stirred at-5 ℃ for 0.5h, tert-butanol (5.85g, 0.079mol) was added dropwise: dichloromethane (10 ml): a mixed solution of triethylamine (8.10g, 0.080mol) was stirred at-10 ℃ for 0.5h after the completion of the addition, and phenol (7.43g, 0.079mol): dichloromethane (10 ml): triethylamine (8.10g, 0.080mol) mixed solution, after the dropwise addition, stirring at the temperature of minus 5 ℃ for 0.5h, when HPLC and TLC show that the reaction is finished; filtration and concentration of the filtrate under reduced pressure gave the product (11.5 g, 12.9g theory, yield 90.2%), LCMS M/z 223 (M) + +H,C 12 H 14 O 4 )。
(2) Synthesis of Compound 2:
adding ethyl acetate (100 ml), adding p-phenylenediamine (10.0g, 0.093mol), adding tert-butyl phenolate (20.6 g, 0.093mol), stirring at 15 ℃ for 4h, adding 40g of water and concentrated hydrochloric acid (6.94ml, 0.083mol) to extract a layering layer when HPLC and TLC show that the reaction is finished, and adding 90g of water and concentrated hydrochloric acid (0.77ml, 0.009mol) to extract a layering layer in an ethyl acetate layer; combining the aqueous layers, adding NA into the aqueous layer 2 CO 3 The pH was adjusted to 8, filtration was carried out, and the filter cake was dried after washing with water to give the product (19.3 g, theoretical value 21.8g, yield 88.5%).
(3) Synthesis of Compound 3:
adding dichloromethane (100 ml) into a reaction bottle, adding compound 2 (10.0g, 0.042mol), adding triethylamine (4.4g, 0.043mol), cooling to 20 ℃, keeping the temperature and stirring, dropwise adding 5-chloropentanoyl chloride (6.69g, 0.043mol) while stirring, keeping the temperature at 20 ℃ for 0.5h after the dropwise adding is finished, when HPLC and TLC show that the reaction is finished, adding 40g of water, stirring, performing suction filtration, adding 40g of water into a filter cake, stirring, performing suction filtration again, washing a filter cake with water, drying to obtain a product, mixing filtrate obtained in two times, demixing, recrystallizing a dichloromethane layer, and drying to obtain a product, mixing products obtained in two times, (14.2 g, 15.0g of theoretical value, and obtaining the yield of 94.6%).
(4) Synthesis of Compound 4-1:
compound 3 (10.0g, 0.028mol) was charged into a reaction flask, potassium carbonate (38.8g, 0.282mol) was added, DMF (90 ml) was added, tert-butyl 4-bromobutyrate (7.3g, 0.033mol) was added, the mixture was stirred at 50 ℃ for 11 hours, the mixture was warmed to 80 ℃ for 3 hours, and when HPLC and TLC showed completion of the reaction, suction filtration was conducted, concentration was conducted under reduced pressure, the concentrate was extracted with dichloromethane and water, and the organic layer was dried over anhydrous sodium sulfate, and concentration was conducted under reduced pressure to obtain the product (11.3 g, theoretical 12.9g, yield 87.5%).
(5) Synthesis of Compound 5:
sodium tert-butoxide (2.71g, 0.028mol) was added to a reaction flask, tetrahydrofuran (80 ml) was added, stirring with stirring at 60 ℃ was maintained, a solution of compound 4-1 (10.0 g, 0.022mol) in tetrahydrofuran (20 ml) was added and the reaction was maintained for 0.5h, and when HPLC and TLC showed completion of the reaction, concentration was carried out under reduced pressure, water (100 ml) and ethyl acetate (100 ml) were added at 0 ℃, hydrochloric acid was added to adjust the pH to 3, the phases were separated, the ethyl acetate layer was dried over anhydrous sodium sulfate, and concentration under reduced pressure gave the product (6.8 g, 7.9g theoretical, 86.1% yield).
(6) Synthesis of Compound 6:
adding dichloromethane (80 ml) into a reaction bottle, adding tetrahydrofuran (20 ml), adding compound 5 (10.0 g, 0.026mol), keeping the temperature and stirring at 15 ℃, introducing hydrogen chloride gas for keeping the temperature and reacting for 2h, when HPLC and TLC show that the reaction is finished, concentrating under reduced pressure, adding heptane (45 ml) at 15 ℃, keeping the temperature and stirring for 0.5h, filtering, leaching a filter cake with heptane and drying to obtain a product (7.5 g, the theoretical value is 8.5g, and the yield is 88.2%).
(7) Synthesis of compound 7:
compound 6 (10.0g, 0.033mol) was added to a reaction flask, acetonitrile (90 ml) was added, morpholine (4.4g, 0.050mol) was added, acetic acid (3.0g, 0.050mol) was added, the reaction was stirred at 60 ℃ for 3 hours, and when HPLC and TLC showed completion of the reaction, the product was recrystallized (9.3 g, theoretical 10.7g, yield 86.9%).
Example 3: in contrast to example 1, the process for the preparation of apixaban precursor compounds in this example employs the following specific process steps.
(1) Synthesis of Compound 1-a:
dichloromethane (70 ml) was added to the reaction flask, oxalyl chloride (10.0 g, 0.079mol) was added, stirring at 0 ℃ for 0.5h, tert-butanol (5.92g, 0.08mol): dichloromethane (10 ml): triethylamine (7.97g, 0.079mol) mixed solution was stirred at-10 ℃ for 0.5h after the addition was completed, and phenol (7.53g, 0.08mol): dichloromethane (10 ml): triethylamine (7.97g, 0.079mol) mixed solution, after the dropwise addition, stirring at 0 ℃ for 0.5h under the condition of heat preservation, when HPLC and TLC show that the reaction is finished; filtration and concentration of the filtrate under reduced pressure gave the product (11.3 g, 12.9g theory, 87.5% yield), LCMS M/z 223 (M) + +H,C 12 H 14 O 4 )。
(2) Synthesis of Compound 2:
adding ethyl acetate (110 ml) into a reaction bottle, adding p-phenylenediamine (10.0g, 0.093mol) and tert-butyl oxalate phenolic ester (21.6 g, 0.097mol), stirring at 20 ℃ for 4 hours, adding 45g of water and concentrated hydrochloric acid (7.5ml, 0.097mol) to extract a layering layer when HPLC and TLC show that the reaction is finished, and adding 95g of water and concentrated hydrochloric acid (0.83ml, 0.01mol) to extract the layering layer in an ethyl acetate layer; mixing the water layers, adding NA into the water layer 2 CO 3 The pH was adjusted to 7, filtration was carried out, and the filter cake was dried after washing with water to give the product (19.5 g, theoretical value 21.8g, yield 89.4%).
(3) Synthesis of Compound 3:
adding dichloromethane (100 ml), adding compound 2 (10.0g, 0.042 mol), adding triethylamine (4.6 g, 0.045mol), cooling to 15 ℃, keeping the temperature and stirring, dropwise adding 5-chloropentanoyl chloride (6.98g, 0.045mol) while stirring, keeping the temperature at 15 ℃ for 0.5h after dropwise adding, when HPLC and TLC show that the reaction is finished, adding 50g of water and stirring, carrying out suction filtration, adding 50g of water and stirring to a filter cake, carrying out suction filtration again, carrying out washing and drying on the filter cake with water to obtain a product, mixing filtrate obtained in two times, recrystallizing a dichloromethane layer, and drying to obtain the product, mixing the product obtained in two times (14.3 g, 15.0g of theoretical value, and 95.3% of yield).
(4) Synthesis of Compound 4:
compound 3 (10.0g, 0.028mol) was charged into a reaction flask, potassium carbonate (42.8g, 0.310mol) was added, DMF (110 ml) was added, tert-butyl 4-bromobutyrate (7.7g, 0.035 mol) was added, the mixture was stirred at 70 ℃ for 11 hours, the mixture was warmed to 70 ℃ for 4 hours, and when HPLC and TLC showed completion of the reaction, suction filtration and concentration under reduced pressure were carried out, the concentrated solution was separated by extraction with dichloromethane and water, the organic layer was dried over anhydrous sodium sulfate, and the product was obtained by concentration under reduced pressure, (11.3 g, theoretical 12.9g, yield 87.5%).
(5) Synthesis of Compound 5:
sodium tert-butoxide (2.71g, 0.031mol) was added to a reaction flask, tetrahydrofuran (100 ml) was added, stirring with stirring at 75 ℃ was maintained, a solution of compound 4-1 (10.0 g, 0.022mol) in tetrahydrofuran (20 ml) was added and the reaction was allowed to proceed for 1 hour, and when HPLC and TLC showed completion of the reaction, concentration was carried out under reduced pressure, water (100 ml) and ethyl acetate (100 ml) were added at 0 ℃, hydrochloric acid was added to adjust pH to 2, phase separation was carried out, the ethyl acetate layer was dried over anhydrous sodium sulfate, and concentration under reduced pressure gave the product (6.8 g, 7.9g theoretical, 86.1% yield).
(6) Synthesis of Compound 6:
adding dichloromethane (60 ml), adding tetrahydrofuran (40 ml), adding compound 5 (10.0g, 0.026mol), stirring at 15 ℃ for heat preservation, introducing hydrogen chloride gas for heat preservation reaction for 3h, concentrating under reduced pressure when HPLC and TLC show that the reaction is finished, adding heptane (55 ml) at 18 ℃ for heat preservation stirring for 0.5h, filtering, washing a filter cake with heptane, and drying to obtain a product (7.8 g, the theoretical value is 8.5g, and the yield is 91.7%).
(7) Synthesis of compound 7:
compound 6 (10.0g, 0.033mol) was added to a reaction flask, acetonitrile (90 ml) was added, morpholine (4.6g, 0.054mol) was added, acetic acid (3.2g, 0.054mol) was added, the reaction was stirred at 80 ℃ for 3h, and when HPLC and TLC showed completion of the reaction, the product was recrystallized (9.4 g, theoretical 10.7g, yield 87.9%).
Example 4: in contrast to example 1, the process for the preparation of apixaban precursor compounds in this example employs the following specific process steps.
(1) Synthesis of Compound 1-a, example 1 was repeated except that: the organic solvent is acetonitrile, the temperature is kept at-8 ℃ to obtain the product (11.4 g, the theoretical value is 12.9g, the yield is 88.3 percent), LCMS M/z 223 (M) + +H,C 12 H 14 O 4 )。
(2) Synthesis of Compound 2, the same as in example 1, except for the following differences: acetonitrile, tert-butyl oxalate phenolic ester (20.8g, 0.094mol) and concentrated hydrochloric acid (7.16ml, 0.086 mol) were used as organic solvents to obtain a product (19.1 g, theoretical 21.8g, yield 87.6%).
(3) Synthesis of Compound 3, the same as in example 1, except for the following differences: the organic solvent was acetonitrile, compound 2:5-chloropentanoyl chloride triethylamine =1.0:1.1 (mol) to give the product (14.0 g, theoretical 15.0g, yield 93.3%).
(4) Synthesis of Compound 4 i-1:
Figure BDA0003029387930000211
compound 3 (10.0 g, 0.028mol) was charged into a reaction flask, potassium carbonate (38.8g, 0.282mol) was added, DMF (100 ml) was added, t-butyl 4-bromobutyrate (7.55g, 0.034 mol) was added, stirring was carried out at 50 ℃ for 12 hours, suction filtration was carried out when the reaction was completed as shown by HPLC and TLC, concentration under reduced pressure was carried out, the concentrate was extracted with dichloromethane and water for liquid separation, the organic layer was dried over anhydrous sodium sulfate, and concentration under reduced pressure was carried out to give a product (12.6 g, theoretical 14.0g, yield 90.0%) LCMS M/z 497 (M S M/z 497 (M) + +H,C 25 H 37 ClN 2 O 6 )。
(5) Synthesis of Compound 5:
Figure BDA0003029387930000212
sodium tert-butoxide (4.42g, 0.046 mol) was added to the reaction flask, tetrahydrofuran (90 ml) was added, stirring with incubation at 65 ℃ was added, a solution of compound 4i-1 (10.0 g, 0.020mol) in tetrahydrofuran (30 ml) was added and the reaction was incubated for 1h, and when HPLC and TLC showed completion, concentration was carried out under reduced pressure, water (100 ml) and ethyl acetate (100 ml) were added at 5 ℃, hydrochloric acid was added to adjust pH to 2, phase separation was carried out, the ethyl acetate layer was dried over anhydrous sodium sulfate, and concentration under reduced pressure gave product (6.7 g, 7.8g theoretical, yield 85.8%), LCMS M/z 387 (M M.S/z 387) + +H,C 21 H 26 N 2 O 5 )。
(6) Synthesis of Compound 6: tetrahydrofuran (100 ml) was added to a reaction flask, compound 5 (10.0 g, 0.026mol) was added, the mixture was stirred at 20 ℃ with heat preservation, hydrogen chloride gas was introduced and the reaction was stirred at 20 ℃ with heat preservation for 2.5 hours, when HPLC and TLC showed completion of the reaction, concentration was performed under reduced pressure, ethyl acetate (50 ml) was added, filtration was performed, heptane (50 ml) was added at 20 ℃ with heat preservation and stirring for 0.5 hour, suction filtration was performed, the filter cake was washed with heptane and dried to obtain a product (7.4 g, theoretical 8.5g, yield 87.1%).
(7) Synthesis of compound 6 i:
Figure BDA0003029387930000221
acetonitrile (100 ml) was added to a reaction flask, compound 6 (10.0 g, 0.026mol) was added, the reaction was stirred at 80 ℃ for 5h, and when HPLC and TLC showed completion of the reaction, concentration under reduced pressure gave the product (8.4 g, theoretical 8.6g, yield 97.7%), LCMS M/z 287 (M/z 287) + +H,C 16 H 18 N 2 O 3 )。
(8) Synthesis of compound 7:
Figure BDA0003029387930000222
morpholine (4.5 g, 0.052mol) was added to a reaction flask, acetic acid (3.1g, 0.052mol) was added and stirred for 0.5h, acetonitrile (100 ml) was added, compound 6i (10.0 g,0.035 mol) was added, the reaction was stirred at 80 ℃ for 4h, and when HPLC and TLC showed completion of the reaction, recrystallization gave the product (10.7 g, theoretical 12.4g, yield 86.3%).
The route to preparation 6 of the present invention can also be prepared from the following examples.
Example 5: the preparation method of preparation 6 of the present invention employs the following specific process steps.
(1) Synthesis of the compound ethyl 4- (2-ethoxy-2-oxo-N- (4- (2-oxopiperidin-1-yl) -phenyl) acetamide) butyrate:
Figure BDA0003029387930000231
adding 2- ((4- (5-chloropentanamide) phenyl) amino) -2-oxoacetamido ethyl ester (10.0g, 0.031mol) into a reaction bottle, adding potassium carbonate (42.2g, 0.306mol), adding DMF (100 ml), adding 4-bromobutyric acid ethyl ester (6.52g, 0.034 mol), keeping the temperature and stirring for 12h at 50 ℃, heating to 80 ℃ and keeping the temperature for 3h, when HPLC and TLC show that the reaction is finished, performing suction filtration and concentration under reduced pressure, extracting the concentrated solution by using dichloromethane and water for liquid separation, drying an organic layer by using anhydrous sodium sulfate, reducing the pressure and concentrating to obtain a product (11.1 g, the theoretical value is 12.4g, and the yield is 89.5 percent), and LCMS M/z 405 (M/Z405 (M) + +H,C 21 H 28 N 2 O 6 )。
(2) Synthesis of the compound ethyl 4- (2-ethoxy-2-oxo-N- (4- (2-oxopiperidin-1-yl) -phenyl) acetamide) butyrate:
Figure BDA0003029387930000232
2- ((4- (5-Bromopentanamide) phenyl) amino) -2-oxoacetamido ethyl ester (10.0 g, 0.027mol) was charged in a reaction flask, potassium carbonate (37.3g, 0.270mol) was added, DMF (100 ml) was added, ethyl 4-bromobutyrate (6.52g, 0.034 mol) was added, stirring was maintained at 50 ℃ for 12h, the temperature was raised to 80 ℃ for 3h, when HPLC and TLC showed that the reaction was complete, suction filtration and concentration under reduced pressure were performed, the concentrate was separated by extraction with dichloromethane and water, the organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to give the product (11.2 g, theoretical 12.4g, yield 90.3%), LCMS M/z 405 (M S M/z 405) (M.3 g, yield 90.3%) and + +H,C 21 H 28 N 2 O 6 )。
(3) Synthesis of the compound ethyl 1- (4- (2-oxopiperidin-1-yl) -phenyl) piperidine-2,3-dione-4-carboxylate:
Figure BDA0003029387930000241
sodium tert-butoxide (3.17g, 0.033mol) was added to a reaction flask, tetrahydrofuran (90 ml) was added thereto, and the mixture was stirred at 65 ℃ and addedThe reaction was carried out with incubation of a solution of the compound ethyl 4- (2-ethoxy-2-oxo-N- (4- (2-oxopiperidin-1-yl) -phenyl) acetamide butyrate (10.0g, 0.025 mol) in tetrahydrofuran (30 ml) for 1h, and when HPLC and TLC showed completion of the reaction, concentration was carried out under reduced pressure, water (100 ml) and ethyl acetate (100 ml) were added at 5 ℃ to adjust pH to 2 by addition of hydrochloric acid, phase separation was carried out, the ethyl acetate layer was dried over anhydrous sodium sulfate, and concentration was carried out under reduced pressure to give a product (7.8 g, theoretical 8.9g, yield 87.6%), LCMS M/z 359 (M) + +H,C 19 H 22 N 2 O 5 )。
(4) Synthesis of Compound 6:
Figure BDA0003029387930000242
adding dichloromethane (70 ml) into a reaction bottle, adding tetrahydrofuran (30 ml), adding compound 1- (4- (2-oxo-piperidine-1-yl) phenyl) piperidine-2,3-diketone-4-carboxylic acid ethyl ester (10.0g, 0.028mol), stirring at 20 ℃, keeping warm by introducing hydrogen chloride gas, keeping warm for reaction for 2.5 hours, concentrating under reduced pressure when HPLC and TLC show that the reaction is finished, adding heptane (50 ml) at 20 ℃, keeping warm and stirring for 0.5 hours, filtering, washing a filter cake with heptane, drying to obtain a product (0.7 g, 9.21g of theoretical value, 7.6 percent of yield), LCMS M/z331 (M/z 331) (M is + +H,C 17 H 18 N 2 O 5 )。
Example 6: the preparation method of preparation 6 of the present invention employs the following specific process steps.
(1) Synthesis of the compound methyl 4- (2-methoxy-2-oxo-N- (4- (2-oxopiperidin-1-yl) -phenyl) acetamide) butyrate:
Figure BDA0003029387930000243
2- ((4- (5-Chloropentanylamide) phenyl) amino) -2-oxoacetamidomethyl ester (10.0 g, 0.032mol) was charged into a reaction flask, potassium carbonate (44.2g, 0.320mol) was added, DMF (100 ml) was added, methyl 4-bromobutyrate (6.84g, 0.038mol) was added, stirring was maintained at 50 ℃ for 12 hours, the temperature was raised to 80 ℃ for 3 hours, and when the reaction was completed as shown by HPLC and TLC, suction filtration was carried out,concentrating under reduced pressure, extracting the concentrated solution with dichloromethane and water, separating, drying the organic layer with anhydrous sodium sulfate, and concentrating under reduced pressure to obtain product (9.8 g, theory 11.3g, yield 86.7%), LCMS M/z 377 (M) + +H,C 19 H 24 N 2 O 6 )。OSO 2 Ph
(2) Synthesis of the compound methyl 4- (2-methoxy-2-oxo-N- (4- (2-oxopiperidin-1-yl) -phenyl) acetamide) butyrate:
Figure BDA0003029387930000251
a reaction flask was charged with 2- ((4- (5-sulfophenyl valeramide) phenyl) amino) -2-oxoacetamido methyl ester (10.0g, 0.023mol), potassium carbonate (31.7g, 0.230mol), DMF (100 ml), methyl 4-bromobutyrate (6.84g, 0.038mol), stirred at 50 ℃ for 12h, warmed to 80 ℃ for 3h, suction filtered when HPLC and TLC showed completion of the reaction, concentrated under reduced pressure, the concentrate was extracted with dichloromethane and water for liquid separation, the organic layer was dried over anhydrous sodium sulfate, concentrated under reduced pressure to give the product (7.6 g, theoretical 8.7g, yield 87.3%), LCMS M/z 377 (M.M.S.M.M.P./m. + +H,C 19 H 24 N 2 O 6 )。
(3) Synthesis of the compound 1- (4- (2-oxopiperidin-1-yl) -phenyl) piperidine-2,3-dione-4-carboxylic acid methyl ester:
Figure BDA0003029387930000252
sodium tert-butoxide (3.11g, 0.032mol) was added to the reaction flask, tetrahydrofuran (90 ml) was added, stirring at 65 ℃ with stirring, a solution of the compound 4- (2-methoxy-2-oxo-N- (4- (2-oxopiperidin-1-yl) -phenyl) acetamide) methyl butyrate (10.0 g, 0.027mol) in tetrahydrofuran (30 ml) was added and the reaction was allowed to proceed for 1h, when HPLC and TLC showed completion of the reaction, concentration was performed under reduced pressure, water (100 ml) and ethyl acetate (100 ml) were added at 5 ℃, hydrochloric acid was added to adjust the pH to 2, the phases were separated, the ethyl acetate layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to give the product (8.2 g, 9.2g theoretical, 89.1% yield), LCMS m/z 345(M + +H,C 19 H 22 N 2 O 5 )。
(4) Synthesis of Compound 6:
Figure BDA0003029387930000261
adding dichloromethane (70 ml) into a reaction bottle, adding tetrahydrofuran (30 ml), adding a compound of methyl 1- (4- (2-oxopiperidin-1-yl) phenyl) piperidine-2,3-dione-4-carboxylate (10.0g, 0.029mol), stirring at 20 ℃, introducing hydrogen chloride gas, stirring at 20 ℃, carrying out an incubation reaction for 2.5 hours, concentrating under reduced pressure when HPLC and TLC show that the reaction is finished, adding heptane (50 ml) at 20 ℃, stirring at 20 ℃ for 0.5 hours, carrying out suction filtration, washing a filter cake with heptane, drying to obtain a product (0.9 g, 9.6g of theoretical value, 9.3 percent of yield), LCMS M/z331 (M2/z, M2-L, M3 percent of yield and the like) + +H,C 17 H 18 N 2 O 5 )。
Example 7: the preparation method of preparation 6 of the present invention employs the following specific process steps.
(1) Synthesis of the Compound Ethyl 4- (2-tert-butoxy-2-oxo-N- (4- (2-oxopiperidin-1-yl) -phenyl) acetamide) butyrate:
Figure BDA0003029387930000262
compound 3 (10.0 g, 0.028mol) was charged to a reaction flask, potassium carbonate (38.8g, 0.282mol) was added, DMF (100 ml) was added, ethyl 4-bromobutyrate (6.56g, 0.034 mol) was added, stirring was carried out at 50 ℃ for 12 hours, the temperature was raised to 80 ℃ for 3 hours, suction filtration was carried out when HPLC and TLC showed completion of the reaction, concentration was carried out under reduced pressure, the concentrate was extracted with dichloromethane and water for liquid separation, the organic layer was dried over anhydrous sodium sulfate, and concentration was carried out under reduced pressure for 4 hours to give a product (10.8 g, theoretical 12.2g, yield 88.5%), LCMS M/z 433 (LCMM M LCMS M) + +H,C 21 H 28 N 2 O 6 )。
(2) Synthesis of the Compound 1- (4- (2-oxopiperidin-1-yl) -phenyl) piperidine-2,3-dione-4-carboxylic acid methyl ester:
Figure BDA0003029387930000271
sodium tert-butoxide (2.88g, 0.030mol) was added to the reaction flask, tetrahydrofuran (90 ml) was added, stirring at 65 ℃ and incubation was continued for 1h, a solution of the compound methyl 4- (2-tert-butoxy-2-oxo-N- (4- (2-oxopiperidin-1-yl) -phenyl) acetamide butyrate (10.0 g, 0.023mol) in tetrahydrofuran (30 ml) was added and the reaction was allowed to proceed for 1h, concentrated under reduced pressure when HPLC and TLC showed completion of the reaction, water (100 ml) and ethyl acetate (100 ml) were added at 5 ℃ and hydrochloric acid was added to adjust the pH to 2, the phases were separated, the ethyl acetate layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to give the product (7.0 g, 8.0g theoretical, 87.5% yield), LCMS M/z 345 (M) + +H,C 19 H 22 N 2 O 5 )。
(3) Synthesis of Compound 6, same as in example 5.
The above general description of the invention and the description of the specific embodiments thereof referred to in this application should not be construed as limiting the technical solutions of the invention. Those skilled in the art can add, reduce or combine the technical features disclosed in the general description and/or the embodiments to form other technical solutions within the protection scope of the present application without departing from the present disclosure.

Claims (23)

1. An intermediate for preparing apixaban having formula (1-a), the structural formula is as follows:
Figure FDA0003029387920000011
2. the preparation method of the Apixaban intermediate (1-a) is characterized in that the synthesis step of the (1-a) comprises the step of carrying out acylation reaction on tert-butyl alcohol and oxalyl chloride in an organic solvent under the catalysis of an organic base, and then carrying out acylation reaction on the tert-butyl alcohol and phenol to obtain the Apixaban intermediate.
3. The method according to claim 2, wherein the organic base is triethylamine, and the triethylamine and tert-butanol are mixed at a molar ratio of 1:1 and added dropwise to an organic solvent of oxalyl chloride.
4. An intermediate for preparing apixaban of formula (2), the structural formula is as follows:
Figure FDA0003029387920000012
5. the preparation method of the Apixaban intermediate formula (2) is characterized in that p-phenylenediamine and the compound of the formula (1-a) are subjected to ammonolysis reaction to prepare the compound of the formula (2), wherein the reaction formula is as follows:
Figure FDA0003029387920000013
6. an intermediate for preparing apixaban of formula (3-1), the structural formula is as follows:
Figure FDA0003029387920000021
7. an intermediate for preparing apixaban of formula (4), the structural formula is as follows:
Figure FDA0003029387920000022
wherein R is 1 、R 2 Each independently is a C1-C6 aliphatic hydrocarbon, phenyl or substituted phenyl.
8. An intermediate for the preparation of apixaban of formula (4 i) having the formula:
Figure FDA0003029387920000023
wherein R is 1 、R 2 Each independently is a C1-C6 aliphatic hydrocarbon, phenyl or substituted phenyl; x is halogen, OSO 2 Ph-p-Me、OSO 2 Me or OSO 2 Ph。
9. The preparation method of the apixaban intermediate formula (4) is characterized in that a compound of the formula (3) is subjected to substitution reaction to prepare a compound of the formula (4 i), and then subjected to cyclization reaction to obtain the compound of the formula (4) or directly subjected to cyclization reaction to obtain the compound of the formula (4), wherein the reaction formula is as follows:
Figure FDA0003029387920000031
wherein R is 1 、R 2 Each independently is a C1-C6 aliphatic hydrocarbon, phenyl or substituted phenyl; x is halogen, OSO 2 Ph-p-Me、OSO 2 Me or OSO 2 Ph。
10. An intermediate for preparing apixaban having the formula (4 i-1), the structural formula is as follows:
Figure FDA0003029387920000032
11. an intermediate for preparing apixaban of formula (4-1), the structural formula is as follows:
Figure FDA0003029387920000041
12. a preparation method of Apixaban intermediate formula (4-1) is characterized in that tert-butyl 4-bromobutyrate and a compound of formula (3-1) are subjected to substitution reaction to obtain a compound of formula (4 i-1), and then subjected to cyclization reaction to obtain a compound of formula (4-1) or directly prepared from the compound of formula (4 i-1) to obtain the compound of formula (4-1), wherein the reaction formula is as follows:
Figure FDA0003029387920000042
13. the preparation method of apixaban intermediate formula (4-1) according to claim 12, characterized in that: the synthesis step (4) comprises the steps of carrying out substitution reaction on the formula (3-1) and tert-butyl 4-bromobutyrate at the temperature of 50-70 ℃ in an organic solvent under the catalysis of an inorganic base, and then heating to 70-80 ℃ for carrying out cyclization reaction to generate the formula (4-1).
14. The preparation method of apixaban intermediate formula (4-1) according to claim 13, characterized in that: the inorganic base is one or more of potassium carbonate, cesium carbonate, sodium carbonate, lithium carbonate, magnesium carbonate and calcium carbonate.
15. The preparation method of the Apixaban intermediate formula (4-1) is characterized in that the compound of the formula (3-1) is subjected to cyclization reaction to obtain the compound of the formula (4-1), wherein the reaction formula is as follows:
Figure FDA0003029387920000051
16. an intermediate for preparing apixaban having formula (5-1), the structural formula is as follows:
Figure FDA0003029387920000052
17. the preparation method of the apixaban intermediate formula (5) is characterized in that the compound of the formula (4) is subjected to cyclization reaction to prepare the compound of the formula (5), wherein the reaction formula is as follows:
Figure FDA0003029387920000053
wherein R is 1 、R 2 Each independently is a C1-C6 aliphatic hydrocarbon, phenyl or substituted phenyl.
18. The preparation method of the Apixaban intermediate formula (5-1) is characterized in that the compound of the formula (4-1) is subjected to cyclization reaction to obtain the compound of the formula (5-1), wherein the reaction formula is as follows:
Figure FDA0003029387920000061
19. an intermediate for preparing apixaban having formula (6), the structural formula is as follows:
Figure FDA0003029387920000062
20. the preparation method of the apixaban intermediate formula (6) is characterized in that the compound of the formula (5-1) is subjected to cyclization reaction to obtain the compound of the formula (6), wherein the reaction formula is as follows:
Figure FDA0003029387920000063
21. an intermediate for the preparation of apixaban of formula (6 i) having the formula:
Figure FDA0003029387920000071
22. the preparation method of the apixaban intermediate formula (7) is characterized in that the compound of the formula (6) is reacted to obtain the compound of the formula (7) or the compound of the formula (6) is firstly subjected to decarboxylation reaction to obtain the compound of the formula (6 i), and then subjected to condensation reaction to obtain the compound of the formula (7), wherein the reaction formula is as follows:
Figure FDA0003029387920000072
23. the preparation method of the Apixaban intermediate compound 7 is characterized by comprising the following steps:
1) Carrying out aminolysis reaction on p-phenylenediamine and a compound shown in a formula (1-a) to prepare a compound shown in a formula (2),
2) Carrying out substitution reaction on the compound of the formula (2) to prepare a compound of a formula (3),
3) Carrying out substitution reaction on the 4-tert-butyl bromobutyrate and a compound of a formula (3-1) to prepare a compound of a formula (4 i-1), carrying out cyclization reaction to obtain the compound of the formula (4-1) or directly carrying out reaction on the compound of the formula (3-1) to prepare the compound of the formula (4-1),
4) The compound of the formula (4-1) is subjected to cyclization reaction to prepare a compound of a formula (5-1),
5) The compound of the formula (5-1) is hydrolyzed to obtain the compound of the formula (6),
6) The compound of the formula (6) is reacted to prepare the compound of the formula (7) or the compound of the formula (6) is firstly decarboxylated to obtain the compound of the formula (6 i) which is then condensed to obtain the compound of the formula (7),
the reaction formula is as follows
Figure FDA0003029387920000081
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