CN113214142B - Apixaban intermediate and preparation method thereof - Google Patents

Apixaban intermediate and preparation method thereof Download PDF

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CN113214142B
CN113214142B CN202010068239.8A CN202010068239A CN113214142B CN 113214142 B CN113214142 B CN 113214142B CN 202010068239 A CN202010068239 A CN 202010068239A CN 113214142 B CN113214142 B CN 113214142B
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CN113214142A (en
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刘阿情
郭必豹
高照波
梅杰
郑辉
何杨
于帅
刘声民
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Zhejiang Jiuzhou Pharmaceutical Co Ltd
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Zhejiang Jiuzhou Pharmaceutical Co Ltd
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    • C—CHEMISTRY; METALLURGY
    • 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
    • C07D211/80—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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems

Abstract

The present invention relates to a pharmaceutical composition useful as factor Xa inhibitorPharmaceutical intermediates, in particular to an intermediate of apixaban of formula (iv) and formula (v) and a preparation method thereof, and a method for synthesizing apixaban by using the intermediates. The reaction formula of the method is as follows:

Description

Apixaban intermediate and preparation method thereof
Technical Field
The invention relates to a drug intermediate which can be used as a factor Xa inhibitor, in particular to an intermediate of apixaban, a preparation method thereof and a method for synthesizing apixaban by using the intermediate.
Background
Apixaban (I) is a new generation of oral antithrombotic agents, among many inhibitors of coagulation factor Xa, which (I) exhibits high selectivity, good bioavailability and high therapeutic effect, and is mainly used for adult patients of hip or knee joint preferential replacement surgery, preventing Venous Thromboembolic Events (VTE). Apixaban was originally discovered by the beginner precious company in 2003 to develop the drug in 2007 together with the pyroxene, and sales increased year by year from 2011 to now on the market, with BMS & pyroxene aspects, ai Letuo (apixaban) having a total sales of 90.16 billions dollars in the first 3 quarters of 2019, which is a comparable 25% increase. Eliquis predicts sales of 120 billion dollars in 2025.
The first publication of US patent No. US2003181466A1 reports a synthetic route to apixaban: the compound (VII) is synthesized by 4-iodoaniline and 5-bromovaleryl chloride, the compound (VII) is chlorinated by phosphorus pentachloride and is treated by excessive morpholine to obtain the compound (VI), the compound (VI) is further reacted with the compound (V) to close the ring to obtain the derivative (IV) of 4, 5-dihydropyrazolo [3,4-c ] pyridine-2-ketone, then the compound (II) is synthesized by reacting with delta-valerolactam in a similar Ullmann condensation way, and the final ammonolysis of ethyl ester to obtain apixaban. The disadvantage of this route is that phosphorus pentachloride is used in the reaction process, a large amount of hydrochloric acid gas and phosphorus-containing byproducts are easily generated, and the environmental hazard is large.
In view of the drawbacks of the existing routes, there is a need to further develop an environmentally friendly route for apixaban suitable for commercial production.
Disclosure of Invention
The invention provides a novel intermediate for synthesizing apixaban and a preparation method thereof, and the method is simple and feasible, green and environment-friendly, reduces the cost and is convenient for industrial production.
In order to achieve the purpose of the invention, the invention provides the following technical scheme:
in a first aspect, an intermediate for the preparation of apixaban of formula (v) is of the formula:
wherein A is C 6-14 An aryl or a 5 to 14 membered heteroaryl group containing 1 to 4 heteroatoms selected from N, O or S, wherein when there are multiple heteroatoms, each heteroatom is the same or different; the aryl or heteroaryl group may be further substituted with 0 to 5R 2 A substitution, wherein when there are multiple substituents, each substituent is the same or different;
when B is absent, A is H, F, cl, br, I, hydroxy, -C (=O) OR 4 、C 1-4 Alkyl or C 1-4 The substituent of the alkoxycarbonyl group is substituted;
b is a 3-to 10-membered heterocyclic ring containing 1 to 4A heteroatom selected from N, O or S, and the heterocycle may be further substituted with 0 to 5 substituents selected from (=o), (=s) or R 4a ；
Represents the presence or absence of ring D;
when ring D is present, the two atoms to which ring E is attached are taken together to form a 5-to 6-membered ring, said 5-to 6-membered ring containing 0 to 2 heteroatoms selected from N, O or S, said 5-to 6-membered ring may be further substituted with 0 to 5R 4 Substitution; ring E is phenyl or a 5-to 6-membered heteroaryl group containing 1 to 3 heteroatoms selected from N, O or S, which phenyl or heteroaryl group may be further substituted with 0 to 3R 4 Substitution;
when ring D is absent, ring E is phenyl or a 5-to 6-membered heteroaryl group containing 1 to 3 heteroatoms selected from N, O or S, which phenyl or heteroaryl group may be further substituted with 0 to 5R 4 Substitution;
R 3 f, cl, br, I is selected from the group consisting of hydroxyl, mercapto, amino, nitro, cyano, trifluoromethyl, and C 1-4 Alkoxy, - (CR) 4 R 4a ) n NR 4 R 4a 、-(CR 4 R 4a ) n NR 4 R 4a 、-(CH 2 ) n C(＝NR 4b )NR 4 R 4a 、-(CR 4 R 4a ) n -C(＝O)NR 4 R 4a 、-(CR 4 R 4a ) n NR 4 C(＝O)R 4a 、-(CR 4 R 4a ) n OR 4 、-(CH 2 ) n C(＝O)R 4 Or- (CH) 2 ) n S(＝O) P R 4b ；
R 7 Is H, F, cl, br, I, cyano, trifluoromethyl, - (CR) 4 R 4a ) n OR、-(CR 4 R 4a ) n NR 4 R 4b 、-C(＝O)R 4 R 4a ) n 、-(CH 2 ) n S(＝O) n R 4 R 4a 、-C(R 4 R 4a )R；
R 9 H, F, cl, br, I is selected from the group consisting of hydroxyl, mercapto, amino, nitro, cyano, trifluoromethyl, and C 1-4 Alkoxy, - (CR) 4 R 4a ) n NR 4 R 4a 、-(CR 4 R 4a ) n NR 4 R 4a 、-(CH 2 ) n C(＝NR 4b )NR 4 R 4a 、-(CR 4 R 4a ) n -C(＝O)NR 4 R 4a 、-(CR 4 R 4a ) n NR 4 C(＝O)R 4a 、-(CR 4 R 4a ) n OR 4 、-(CH 2 ) n C(＝O)R 4 Or- (CH) 2 ) n S(＝O) P R 4b ；
R is H, -C (R) 4 R 4a )R 4b 、-(CR 4 R 4a ) n OR 4 、-(CR 4 R 4a ) n NR 4 R 4a 、-C(＝O)NR 4 R 4a 、-(CH 2 ) n S(＝O) P R 4b ；
R 2 Is H, - (CR) 4 R 4a ) n OR 4 、-(CR 4 R 4a ) n NR 4 R 4a 、-C(＝O)NR 4 R 4a 、-(CH 2 ) n S(＝O) P R 4b 、-C(R 4 R 4a )R 4b ；
R 4 、R 4a And R is 4b Is halogen, C 1-4 Alkyl, cyclopropyl, cyclopentyl, cyclohexyl, benzyl or phenyl and phenyl derivatives thereof; alternatively, NR 4 R 4a Is a 3-8 membered ring consisting of C, N, and 0-1O atoms;
n is 0, 1, 2,3 or 4;
p is 0, 1 or 2.
In a second aspect, the invention provides an intermediate for the preparation of apixaban of formula (iv), having the formula:
wherein A, B, ring D, ring E, R 3 And R is 7 Is as defined in claim 1;
R 4 h, OH, CN, NO of a shape of H, OH, CN, NO 2 Halogen, -S (=o) n R、-NR 1 R 2 、-C(＝O)OR、-C(＝O)NR 1 R 2 、-OR；
R 5 H, OH, CN, NO of a shape of H, OH, CN, NO 2 Halogen, -S (=o) n R、-NR 1 R 2 、-C(＝O)OR、-C(＝O)NR 1 R 2 、-OR；
R 1 Is H, - (CR) 4 R 4a ) n OR 4 、-(CR 4 R 4a ) n NR 4 R 4a 、-C(＝O)NR 4 R 4a 、-(CH 2 ) n S(＝O) P R 4b 、-C(R 4 R 4a )R 4b ；
R 2 Is H, - (CR) 4 R 4a ) n OR 4 、-(CR 4 R 4a ) n NR 4 R 4a 、-C(＝O)NR 4 R 4a 、-(CH 2 ) n S(＝O) P R 4b 、-C(R 4 R 4a )R 4b ；
R、R 4 、R 4a 、R 4b The definition of n and P is the same as above;
in a third aspect, the invention provides a method for preparing apixaban intermediate as formula (v), which is obtained by contacting lactam compound (iv) in the presence of alkali, and has the following reaction formula:
wherein A, B, ring D, ring E, R 3 、R 4 、R 5 、R 7 And R is 9 Is as defined above;
the base is selected from triethylamine, diisopropylethylamine, pyridine, piperidine and DBU;
in a fourth aspect, the present invention provides a process for preparing apixaban intermediate of formula (iv), which is obtained by contacting lactam compound of formula (ii) with compound of formula (iii) in the presence of a base and a catalyst, wherein the reaction formula is as follows:
wherein A, B, ring D, ring E, R 3 、R 4 、R 5 And R is 7 Is as defined above;
R 8 cl, br, cl, I, OSO of a shape of Cl, br, cl, I, OSO 2 Me、OSO 2 Ph and OSO 2 Ph-p-Me；
The base is selected from triethylamine, diisopropylethylamine, pyridine, piperidine and DBU;
the catalyst is selected from one or more of LiI, naI, KI, liBr, naBr, KBr, tetrabutylammonium bromide and tetrabutylammonium iodide;
in a fifth aspect, the present invention provides a process for the preparation of compound (ii), which is carried out by contacting a compound of formula (i) in the presence of a base, wherein the reaction is as follows:
therein A, B, R 3 、R 4 And R is 5 Is as defined above;
R 2 is cyano, - (CR) 4 R 4a ) n OR 4 、-(CR 4 R 4a ) n NR 4 R 4a 、-C(＝O)NR 4 R 4a 、
-(CH 2 ) n S(＝O) P R 4b 、-C(R 4 R 4a )R 4b ；
R 4 、R 4a 、R 4b Definition of n and PThe same as described above;
the alkali is selected from sodium methoxide, sodium ethoxide, sodium tert-butoxide and potassium tert-butoxide;
in a sixth aspect, the present invention provides a process for the preparation of apixaban-containing compound of formula (v), comprising the steps of: 1) Contacting a compound of formula (i) in the presence of a base to obtain a compound of formula (ii); 2) Contacting the lactam compound of formula (ii) with the compound of formula (iii) in the presence of a base and a catalyst to obtain a compound of formula (iv); 3) Contacting the lactam compound (iv) in the presence of a base to obtain a compound of formula (v), wherein the reaction formula is as follows:
wherein A, B, ring D, ring E, R 2 、R 3 、R 4 、R 5 、R 7 、R 8 And R is 9 The definition is the same as above;
the alkali in the step 1) is selected from sodium methoxide, sodium ethoxide, sodium tert-butoxide and potassium tert-butoxide;
steps 2) and 3) the base is selected from triethylamine, diisopropylethylamine, pyridine, piperidine, DBU;
step 2) the catalyst is selected from one or more of LiI, naI, KI, liBr, naBr, KBr, tetrabutylammonium bromide and tetrabutylammonium iodide;
the invention has the beneficial effects that: compared with the original process of apixaban, the synthesis process of the invention does not generate phosphorus-containing wastewater, and three wastes are easy to treat and less pollution is caused; the reaction process is simple and easy to implement, and expensive metal catalysts are not used. The synthesis scheme has higher yield in each step and controllable cost, and is suitable for large-scale industrial production.
Detailed Description
The invention is further defined in the following examples. It should be understood that these examples, while indicating preferred embodiments of the present invention, are given by way of illustration only and not limitation of the claims of the present invention.
Example 1
Preparation of ethyl 4- (aniline) butyrate
Ethyl 4-bromobutyrate (8.4 g,0.043 mol) was added to aniline (4.0 g,0.043 mol), triethylamine (5.2 g,0.052 mol) was added, stirred at 20-30℃for 15h-20h, when HPLC and TLC showed completion of the reaction, 50ml of water was added to adjust pH to 3-5, extracted with dichloromethane, and the layers separated, and the organic layer discarded; the aqueous layer was adjusted to pH 12-14, extracted with dichloromethane, separated, and the organic layer was dried over anhydrous sodium sulfate. Distillation under the reduced pressure gave the product (8.2 g, theoretical 8.9g, yield 92%). For 3, LCMS M/z 208 (M + +H,C 12 H 17 NO 2 )。
Example 2
Preparation of ethyl 4- ((4-nitrophenyl) amino) butyrate
To 4-nitroaniline (5.6 g,0.043 mol), ethyl 4-bromobutyrate (8.4 g,0.043 mol), triethylamine (5.2 g,0.052 mol) and stirring at 20-30℃for 15h-20h, when HPLC and TLC showed completion of the reaction, 50ml of water was added to adjust pH to 3-5, extracted with dichloromethane, and the layers separated, the organic layer was discarded; the aqueous layer was adjusted to pH 12-14, extracted with dichloromethane, separated, and the organic layer was dried over anhydrous sodium sulfate. Distillation under the reduced pressure gave the product (9.8 g, theoretical 10.9g, yield 90%). For 5, LCMS M/z253 (M + +H,C 12 H 16 N 2 O 4 )。
Example 3
Preparation of ethyl 4- ((4-bromophenyl) amino) butyrate
To 4-bromoaniline (7.4 g,0.043 mol) was added ethyl 4-bromobutyrate (8.4 g,0.043 mol), and triethylammonium bromide was addedAmine (5.2 g,0.052 mol), stirring at 20-30deg.C for 15-20 h, adding 50ml water to adjust pH to 3-5 when HPLC and TLC show that the reaction is complete, extracting with dichloromethane, separating, and discarding the organic layer; the aqueous layer was adjusted to pH 12-14, extracted with dichloromethane, separated, and the organic layer was dried over anhydrous sodium sulfate. Distillation under the reduced pressure gave the product (10.8 g, 12.3g, theory, yield 88%). For 7, LCMS M/z 286 (M + +H,C 12 H 16 BrNO 2 )。
Example 4
Preparation of ethyl 4- ((4-iodophenyl) amino) butyrate
To 4-iodoaniline (9.4 g,0.043 mol), ethyl 4-bromobutyrate (8.4 g,0.043 mol), triethylamine (5.2 g,0.052 mol) and stirring at 20-30℃for 15h-20h, when HPLC and TLC showed completion of the reaction, 50ml of water was added to adjust pH to 3-5, extraction with dichloromethane, separation, organic layer was discarded; the aqueous layer was adjusted to pH 12-14, extracted with dichloromethane, separated, and the organic layer was dried over anhydrous sodium sulfate. Distillation under the reduced pressure gave the product (13.0 g, theoretical 14.3g, yield 91%). For 9, LCMS M/z 334 (M + +H,C 12 H 16 INO 2 )。
Example 5
Preparation of ethyl 4- ((4- (2-oxopiperidin-1-yl) phenyl) amino) butyrate
4- (2-Oxopiperidin-1-yl) anilide (8.17 g,0.043 mol), ethyl 4-bromobutyrate (8.4 g,0.043 mol) and triethylamine (5.2 g,0.052 mol) were added to 50ml dichloromethane and stirred at 30-40℃for 15-20 h, when HPLC and TLC showed completion of the reaction, 30ml water was added, the pH was adjusted to 3-5, and the layers were extracted. Discarding the organic layer; the pH of the water layer is adjusted to 12-14, and dichloromethane is used for extraction and delamination. Adding magnesium sulfate pentahydrate into the organic layer, drying, and distilling under reduced pressure to obtain the final productThe product (11.64 g, 13.08g theory, 89% yield) was purified by LCMS M/z 305 (M+H for 11 + ，C 17 H 24 N 2 O 3 )
Example 6
Preparation of ethyl 4- (2-ethoxy-N- (4-nitrophenyl) -2-oxoacetamido) butyrate (i-1)
To a solution of ethyl 4- ((4-nitrophenyl) amino) butyrate (7.92 g,31.4 mmol) in methylene chloride (50 ml) at 0-20℃was added triethylamine (3.81 g,37.7 mmol), oxalyl chloride monoethyl ester (4.5 g,33.0 mmol) was added dropwise, and after the addition, the reaction was kept at 20-30℃for 2-4 hours, when HPLC and TLC showed completion, water was added, extraction was performed with methylene chloride, the organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give the product, (10.5 g, theoretical 11.06g, yield 95%). For i-1, LCMS M/z353 (M + +H,C 16 H 20 N 2 O 7 )。
Example 7
Preparation of ethyl 4- (2-ethoxy-N- (4-phenyl) -2-oxoacetamido) butyrate (i-2)
To a solution of ethyl 4- ((4-phenyl) amino) butyrate (6.51 g,31.4 mmol) in methylene chloride (50 ml) at 0-20℃was added triethylamine (3.81 g,37.7 mmol), oxalyl chloride monoethyl ester (4.5 g,33.0 mmol) was added dropwise, and after the dropwise addition, the reaction was kept at 20-30℃for 2-4h, when HPLC and TLC showed completion, water was added, extraction was performed with methylene chloride, the organic layer was washed with saturated brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure to give the product, (9.4 g, theoretical 9.6g, yield 98%). For i-2, LCMS M/z 308 (M + +H,C 16 H 21 NO 5 )。
Example 8
Preparation of ethyl 4- (2-ethoxy-N- (4-phenyl) -2-oxoacetamido) butyrate (i-3)
To a solution of ethyl 4- ((4-bromophenyl) amino) butyrate (8.98 g,31.4 mmol) in methylene chloride (50 ml) at 0-20℃was added triethylamine (3.81 g,37.7 mmol), oxalyl chloride monoethyl ester (4.5 g,33.0 mmol) was added dropwise, and after the addition, the reaction was kept at 20-30℃for 2-4 hours, when HPLC and TLC showed completion, water was added, extraction was performed with methylene chloride, the organic layer was washed with saturated brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure to give the product, (11.5 g, theoretical 12.1g, yield 95%). For i-3, LCMS M/z 386 (M + +H,C 16 H 20 BrNO 5 )。
Example 9
Preparation of ethyl 4- (2-ethoxy-N- (4-phenyl) -2-oxoacetamido) butyrate (i-4)
To a solution of ethyl 4- ((4-iodophenyl) amino) butyrate (10.46 g,31.4 mmol) in dichloromethane (50 ml) was added triethylamine (3.81 g,37.7 mmol), oxalyl chloride monoethyl ester (4.5 g,33.0 mmol) was added dropwise, and after the addition, the reaction was incubated at 20-30℃for 2-4h, when HPLC and TLC showed completion, water was added, extraction was performed with dichloromethane, the organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give the product, (13.1 g, theoretical 13.6g, yield 96%). For i-4, LCMS M/z434 (M + +H,C 16 H 20 INO 5 )。
Example 10
Preparation of 1- (4-nitrophenyl) piperidine-2, 3-dione-4-carboxylic acid ethyl ester (ii-1)
N 2 To a solution of ethyl 4- (2-ethoxy-N- (4-nitrophenyl) -2-oxoacetamido) butyrate (10.27 g,29.1 mmol) in t-butanol (200 ml) was added potassium t-butoxide (4.90 g,43.7 mmol) and incubated at 20-50℃for 2-5h, and when HPLC and TLC showed completion of the reaction, suction filtration was performed, and the filter cake was added to an aqueous hydrochloric acid solution, extracted with ethyl acetate, and the organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to give the product, (7.85 g, theoretical 8.92g, yield 88%). For ii-1, LCMS M/z 307 (M + +H,C 14 H 14 N 2 O 6 )。
Example 11
Preparation of 1- (4-phenyl) piperidine-2, 3-dione-4-carboxylic acid ethyl ester (ii-2)
N 2 To a solution of ethyl 4- (2-ethoxy-N- (4-phenyl) -2-oxoacetamido) butyrate (8.95 g,29.1 mmol) in t-butanol (180 ml) was added potassium t-butoxide (4.90 g,43.7 mmol) under protection, the mixture was incubated at 20-50℃for 2-5h, when HPLC and TLC showed completion of the reaction, suction filtration was performed, the filter cake was added to an aqueous hydrochloric acid solution, extraction was performed with ethyl acetate, and the organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to give the product, (6.93 g, theoretical 7.61g, yield 91%). For ii-2, LCMS M/z 262 (M + +H,C 14 H 15 NO 4 )。
Example 12
Preparation of 1- (4-bromophenyl) piperidine-2, 3-dione-4-carboxylic acid ethyl ester (ii-3)
N 2 To a solution of ethyl 4- (2-ethoxy-N- (4-bromophenyl) -2-oxoacetamido) butyrate (11.25 g,29.1 mmol) in t-butanol (230 ml) was added potassium t-butoxide (4.90 g,43.7 mmol) under protection, and the mixture was incubated at 20 to 50℃for 2 to 5 hours, and when HPLC and TLC showed the completion of the reaction, suction filtration was performed, and the filter cake was added to an aqueous hydrochloric acid solution, followed by extraction with ethyl acetateThe organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to give a product (9.41 g, theoretical 9.91g, yield 95%). For (ii-3), LCMS M/z 340 (M + +H,C 14 H 14 BrNO 4 )。
Example 13
Preparation of 1- (4-iodophenyl) piperidine-2, 3-dione-4-carboxylic acid ethyl ester (ii-4)
N 2 To a solution of ethyl 4- (2-ethoxy-N- (4-iodophenyl) -2-oxoacetamido) butyrate (11.25 g,29.1 mmol) in t-butanol (230 ml) was added sodium t-butoxide (4.20 g,43.7 mmol) and incubated at 20-50℃for 2-5h, and when HPLC and TLC showed completion of the reaction, suction filtration was performed, and the filter cake was added to an aqueous hydrochloric acid solution, extracted with ethyl acetate, and the organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to give the product, (11.74 g, 12.62g theory, yield 93%). For ii-4, LCMS M/z 388 (M + +H,C 14 H 14 INO 4 )。
Example 14
(E) Preparation of (iv-1) ethyl-4- (2-ethoxy-1- (2- (4-methoxyphenyl) hydrazino) 2-oxoethyl) -2, 3-dioxo-1- (4-nitrophenyl) piperidine-4 carboxylate
N 2 To a toluene solution (66 ml) of ethyl 1- (4-nitrophenyl) piperidine-2, 3-dione-4-carboxylate (6.56 g,21.43 mmol) was added triethylamine (3.25 g,32.14 mmol), KI (0.36 g,2.14 mmol) and chloro [ (4-methoxyphenyl) hydrazono under protection]Ethyl acetate (5.5 g,21.43 mmol), incubation at 20-50 ℃ for 8-15h, washing with 1% aqueous hydrochloric acid (20 ml) when HPLC and TLC showed completion of the reaction, separation, drying of the organic layer over anhydrous sodium sulfate, spin-drying purification directly by column chromatography (SiO 2 Gradient elution with 5-50% EtOAc/heptane) afforded the desired product (9.60 g, theory)11.28g, 85% yield). For iv-1, LCMS M/z 527 (M + +H,C 25 H 26 N 4 O 9 )。
Example 15
(E) Preparation of (iv-2) -ethyl-4- (2-ethoxy-1- (2- (4-methoxyphenyl) hydrazino) 2-oxoethyl) -2, 3-dioxo-1-phenylpiperidine-4-carboxylate
N 2 To a toluene solution (66 ml) of ethyl 1- (4-phenyl) piperidine-2, 3-dione-4-carboxylate (5.6 g,21.43 mmol) was added diisopropylethylamine (4.15 g,32.14 mmol), KI (0.36 g,2.14 mmol) and chloro [ (4-methoxyphenyl) hydrazono under protection]Ethyl acetate (5.5 g,21.43 mmol), incubation at 20-50 ℃ for 10-14h, washing with 1% aqueous hydrochloric acid (20 ml) when HPLC and TLC showed completion of the reaction, separation, drying of the organic layer over anhydrous sodium sulfate, spin-drying purification directly by column chromatography (SiO 2 5-50% EtOAc/heptane gradient elution) afforded the desired product (8.80 g, 10.32g theory, 85% yield). For iv-2, LCMS M/z 482 (M + +H,C 25 H 27 N 3 O 7 )。
Example 16
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(E) Preparation of (iv-3) ethyl-4- (2-ethoxy-1- (2- (4-methoxyphenyl) hydrazino) 2-oxoethyl) -2, 3-dioxo-1- (4-bromophenyl) piperidine-4 carboxylate
N 2 To a toluene solution (73 ml) of ethyl 1- (4-bromophenyl) piperidine-2, 3-dione-4-carboxylate (7.3 g,21.43 mmol) was added diisopropylethylamine (4.15 g,32.14 mmol), KI (0.36 g,2.14 mmol) and chloro [ (4-methoxyphenyl) hydrazono under protection]Ethyl acetate (5.5 g,21.43 mmol), incubation at 20-50 ℃ for 10-14h, washing with 1% aqueous hydrochloric acid (20 ml) when HPLC and TLC showed completion of the reaction, separating layers, organic layer with anhydrous sulfuric acidSodium was dried and spin dried directly by column chromatography (SiO 2 5-50% EtOAc/heptane gradient elution) afforded the desired product (8.80 g, 10.0g theory, 83% yield). For iv-3, LCMS M/z 560 (M + +H,C 25 H 26 BrN 3 O 7 )。
Example 17
(E) Preparation of (iv-4) ethyl-4- (2-ethoxy-1- (2- (4-methoxyphenyl) hydrazino) 2-oxoethyl) -2, 3-dioxo-1- (4-iodophenyl) piperidine-4 carboxylate
N 2 To a toluene solution (73 ml) of ethyl 1- (4-iodophenyl) piperidine-2, 3-dione-4-carboxylate (8.3 g,21.43 mmol) was added diisopropylethylamine (4.15 g,32.14 mmol), KI (0.36 g,2.14 mmol) and chloro [ (4-methoxyphenyl) hydrazono under protection]Ethyl acetate (5.5 g,21.43 mmol), incubation at 20-50 ℃ for 10-14h, washing with 1% aqueous hydrochloric acid (20 ml) when HPLC and TLC showed completion of the reaction, separation, drying of the organic layer over anhydrous sodium sulfate, spin-drying purification directly by column chromatography (SiO 2 5-50% EtOAc/heptane gradient elution) afforded the desired product (8.80 g, 10.0g theory, 83% yield). For iv-4, LCMS M/z 608 (M + +H,C 25 H 26 IN 3 O 7 )。
Example 18
(E) Preparation of-ethyl-4- (2-ethoxy-1- (2- (4-methoxyphenyl) hydrazino) 2-oxoethyl) -2, 3-dioxo-1- ((1-piperidine) -4-phenyl) piperidine-4-carboxylic acid ester (iv-5)
N 2 To a solution of 1- ((1-piperidine) -phenyl) piperidine-2, 3-dione-4-carboxylic acid ethyl ester (7.68 g,21.43 mmol) in toluene (77 ml) was added diisopropylethylamine (4.15 g,32.14 mmol), KI (0.36 g,2.14 mmol) and chloro [ (4-methoxyphenyl) hydrazono under protection]Ethyl acetate (5.5 g,21.43 mmol), incubation at 20-50 ℃ for 10-14h, washing with 1% aqueous hydrochloric acid (20 ml) when HPLC and TLC showed completion of the reaction, separation, drying of the organic layer over anhydrous sodium sulfate, spin-drying purification directly by column chromatography (SiO 2 5-50% EtOAc/heptane gradient elution) afforded the desired product (11.9 g, 12.4g theory, 96% yield). For iv-5, LCMS M/z 579 (M + +H,C 30 H 34 N 4 O 8 )。
Example 19
Preparation of diethyl 7 a-hydroxy-1- (4-methoxyphenyl) -7-oxo-6- (1-piperidinylphenyl) -3a,4,5,6,7 a-hexahydro-1H-pyrido [3,4-c ] pyridine-3, 3 a-dicarboxylic acid ester (v-5)
To a toluene solution (86 ml) of formula iv-5 (8.58 g,14.8 mmol), triethylamine (1.5 g,14.8 mmol) was added, and the mixture was incubated at 110℃for 1-4h, and when HPLC and TLC showed completion of the reaction, the solvent was dried by spin-drying, and the reaction mixture was purified directly by column chromatography (SiO 2 15-35% EtOAc/heptane gradient elution) afforded the desired product (8.2 g, 8.58g theory, 95% yield). For v-5, LCMS M/z 579 (M + +H,C 30 H 34 N 4 O 8 )。
Example 20
Preparation of diethyl 7 a-hydroxy-1- (4-methoxyphenyl) -7-oxo-6- (4-nitrophenyl) -3a,4,5,6,7 a-hexahydro-1H-pyrido [3,4-c ] pyridine-3, 3 a-dicarboxylic acid ester (v-1)
To a toluene solution (78 ml) of formula iv-1 (7.8 g,14.8 mmol), triethylamine (1.5 g,14.8 mmol) was added, and the mixture was incubated at 110℃for 1-4h, and when HPLC and TLC showed completion of the reaction, the solvent was dried by spin-drying, and the reaction mixture was purified directly by column chromatography (SiO 2 Gradient elution with 15-35% EtOAc/heptane) afforded the desired product (7.3 g, theory 7.8g, yield93%). For v-1, LCMS M/z 527 (M + +H,C 25 H 26 IN 4 O 9 )。
Example 21
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Preparation of diethyl 7 a-hydroxy-1- (4-methoxyphenyl) -7-oxo-6-phenyl-3 a,4,5,6,7 a-hexahydro-1H-pyrido [3,4-c ] pyridine-3, 3 a-dicarboxylic acid ester (v-2)
To a toluene solution (78 ml) of formula iv-2 (7.14 g,14.8 mmol) was added triethylamine (1.5 g,14.8 mmol), and the mixture was incubated at 110℃for 1-4h, and when HPLC and TLC showed completion of the reaction, the solvent was dried by spin-drying, and the reaction mixture was purified directly by column chromatography (SiO 2 15-35% EtOAc/heptane gradient elution) afforded the desired product (6.93 g, 7.14g theory, 97% yield). For v-2, LCMS M/z 482 (M + +H,C 25 H 27 N 3 O 7 )。
Example 22
Preparation of diethyl 7 a-hydroxy-1- (4-methoxyphenyl) -7-oxo-6- (4-bromophenyl) -3a,4,5,6,7 a-hexahydro-1H-pyrido [3,4-c ] pyridine-3, 3 a-dicarboxylic acid ester (v-3)
To a toluene solution (83 ml) of formula iv-3 (8.31 g,14.8 mmol), triethylamine (1.5 g,14.8 mmol) was added, and the mixture was incubated at 110℃for 1-4h, and when HPLC and TLC showed completion of the reaction, the solvent was dried by spin-drying, and the reaction mixture was purified directly by column chromatography (SiO 2 15-35% EtOAc/heptane gradient elution) afforded the desired product (7.12 g, 8.58g theory, 83% yield). For v-3, LCMS M/z 560 (M + +H,C 25 H 26 BrN 3 O 7 )。
Example 23
Diethyl 7 a-hydroxy-1- (4-methoxyphenyl) -7-oxo-6- (4-iodophenyl) -3a,4,5,6,7 a-hexahydro-1H-pyrido [3,4-c ]]Preparation of pyridine-3, 3 a-dicarboxylic acid ester (v-4) to a toluene solution (78 ml) of formula iv-4 (9.0 g,14.8 mmol), triethylamine (1.5 g,14.8 mmol) was added, and the reaction was incubated at 110℃for 1-4h, and when HPLC and TLC showed completion of the reaction, the solvent was dried by spin-drying, and the reaction mixture was purified directly by column chromatography (SiO 2 15-35% EtOAc/heptane gradient elution) afforded the desired product (7.12 g, 9.0g theory, 83% yield). For v-4, LCMS M/z 608 (M + +H,C 25 H 26 IN 3 O 7 )。
Example 24
Preparation of pyridine (vi-5) ethyl 1- (4-methoxyphenyl) -7-oxo-6- (4- (2-oxopiperidin-1-yl) phenyl) -4,5,6, 7-tetrahydro-1H-pyrazolo [3,4-c ] 3-carboxylate
Diethyl 7 a-hydroxy-1- (4-methoxyphenyl) -7-oxo-6- (4- (2-oxopiperidin-1-yl) phenyl) -1,4,5,6,7 a-hexahydro-3 aH-pyrazolo [3,4-c]Pyridine-3, 3 a-dicarboxylic acid ester (8.67 g,15 mmol) was dissolved in 50ml toluene, a solution of hydrogen bromide in acetic acid (33%) (1.33 g,5.5 mmol) was added, stirred at 40℃for 1-2 h, and when HPLC and TLC showed completion of the reaction, 20ml of saturated sodium bicarbonate solution was added, and the layers were extracted. The organic layer was dried over magnesium sulfate pentahydrate and distilled under reduced pressure to give the product (6.88 g, theory 7.32g, yield 94%) as vi-5, LCMS M/z 489 (M+H) + ，C 27 H 28 N 4 O 5 )。

Claims (5)

1. An intermediate for preparing apixaban with a formula (v) has a structural formula as follows:
the formula (v) is:
2. an intermediate for preparing apixaban with a formula (iv) has a structural formula as follows:
the formula (iv) is:
3. a preparation method of apixaban intermediate formula (v) is characterized in that triethylamine is added into toluene solution of lactam compound (iv), the temperature is kept at 110 ℃ for 1-4h, when HPLC and TLC show that the reaction is completed, solvent is dried by spin-drying, and the apixaban intermediate formula (v) is obtained by directly purifying by column chromatography, wherein the reaction formula is as follows:
formula (iv) is (iv) as defined in claim 2, and formula (v) is (v) as defined in claim 1.
4. A preparation method of apixaban intermediate formula (iv) is characterized by comprising the following steps of 2 Under the protection, diisopropylethylamine, KI and a compound formula (iii) are added into a toluene solution of a lactam compound formula (ii), the temperature is kept for 10-14h at 20-50 ℃, when HPLC and TLC show that the reaction is finished, 1% hydrochloric acid aqueous solution is added for washing, the layers are separated, an organic layer is dried by anhydrous sodium sulfate, and spin-drying is directly performed through column chromatography to obtain the compound with the following reaction formula:
the formula (ii) is:
the formula (iii) is:
formula (iv) is (iv) as claimed in claim 2.
5. The preparation method of the apixaban intermediate formula (v) is characterized by comprising the following steps: 1) N (N) 2 Under the protection, diisopropylethylamine, KI and a compound shown in a formula (ii) of a lactam compound are added into a toluene solution of the compound shown in the formula (ii), the temperature is kept for 10-14 hours at 20-50 ℃, when HPLC and TLC show that the reaction is finished, 1% hydrochloric acid aqueous solution is added for washing, the layers are separated, an organic layer is dried by anhydrous sodium sulfate, and the compound shown in the formula (iv) is directly obtained through column chromatography purification by spin drying; 2) Adding triethylamine into toluene solution of lactam compound (iv), preserving at 110 ℃ for 1-4 hours, and when HPLC and TLC show that the reaction is finished, spin-drying the solvent, and directly purifying by column chromatography to obtain a compound of formula (v), wherein the reaction formula is as follows:
formula (ii) is (ii) as claimed in claim 4; formula (iii) is (iii) as defined in claim 4; formula (iv) is (iv) as claimed in claim 2; formula (v) is (v) according to claim 1.
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Citations (3)

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CN1639147A (en) * 2001-12-10 2005-07-13 布里斯托尔-迈尔斯斯奎布公司 Synthesis of 4,5-dihydro-pyrazolo [3,4-c] pyrid-2-ones
CN104039788A (en) * 2012-09-18 2014-09-10 上海恒瑞医药有限公司 Pyrazol[3,4-c] pyridine derivative, preparation method and use in medicine thereof
CN107690426A (en) * 2015-05-29 2018-02-13 杜邦公司 Substituted cyclic amides as herbicide

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US9227972B2 (en) * 2012-05-09 2016-01-05 Merck Sharp & Dohme Corp. Aliphatic spirolactam CGRP receptor antagonists

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Publication number Priority date Publication date Assignee Title
CN1639147A (en) * 2001-12-10 2005-07-13 布里斯托尔-迈尔斯斯奎布公司 Synthesis of 4,5-dihydro-pyrazolo [3,4-c] pyrid-2-ones
CN104039788A (en) * 2012-09-18 2014-09-10 上海恒瑞医药有限公司 Pyrazol[3,4-c] pyridine derivative, preparation method and use in medicine thereof
CN107690426A (en) * 2015-05-29 2018-02-13 杜邦公司 Substituted cyclic amides as herbicide

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