CN107868039A - A kind of shellfish Qu Shaban intermediate Ns（5- chloro-2-pyridyls）- 2-（4- cyanobenzoyls）Amino ］ -5- methoxy benzamides preparation method - Google Patents
A kind of shellfish Qu Shaban intermediate Ns（5- chloro-2-pyridyls）- 2-（4- cyanobenzoyls）Amino ］ -5- methoxy benzamides preparation method Download PDFInfo
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- CN107868039A CN107868039A CN201711254533.2A CN201711254533A CN107868039A CN 107868039 A CN107868039 A CN 107868039A CN 201711254533 A CN201711254533 A CN 201711254533A CN 107868039 A CN107868039 A CN 107868039A
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D213/72—Nitrogen atoms
- C07D213/75—Amino or imino radicals, acylated by carboxylic or carbonic acids, or by sulfur or nitrogen analogues thereof, e.g. carbamates
Abstract
The invention discloses the preparation method of shellfish Qu Shaban intermediates N (pyridine radicals of 5 chlorine 2) 2 [(4 cyanobenzoyl) amino] 5 methoxy benzamides.The present invention adopts the following technical scheme that, comprises the following steps：1. the nitrobenzoic acid of 5 methoxyl group 2 (1) and POCl3 chloro, then obtain compound 2 through amidatioon with 2 aminopyridines；2. compound 2 obtains compound 3 through catalytic hydrogenation；3. compound 3 is with being condensed to yield compound 4 to cyano-benzoyl chloride；4. compound 4 obtains compound 5, total recovery 57.2% through chloro, its major advantage be material be easy to get, be easy to operate, cost it is relatively low, and reduce the generation of accessory substance, be advantageous to industrialized production.
Description
Technical field
The present invention relates to a kind of shellfish Qu Shaban intermediate Ns (5- chloro-2-pyridyls) -2- [(4- cyanobenzoyls) ammonia
Base] -5- methoxy benzamides preparation method.
Background technology
Shellfish Qu Shaban (Betrixaban), chemical name：N- (5- chloro-2-pyridyls) -2- [[4- [(dimethylamino) imino groups
Methyl] benzoyl] amino] -5- methoxy benzamides (6) are that a kind of Xa factor developed by Bo Tuola drugmakers is high
Selective depressant.Shellfish Qu Shaban is pressed down conversion of the factor to fibrin ferment by being combined with Xa factor avtive spot
System, and hinder fibrin and formed, so as to effectively suppress the formation of thrombus.The medicine is in Nikkei FDA approvals June 23 in 2017
Listing, trade name Bevyxxa, for preventing the VTE and pulmonary embolism of acute onset but non-row patient with operation.
N- (5- chloro-2-pyridyls) -2- [(4- cyanobenzoyls) amino] -5- methoxy benzamides are that synthesis shellfish is bent
The important intermediate of husky class, patent document CN1391555A, WO0164643A2, WO2007056517A2,
WO2008057972A1、US2010197929A1、CN101595092B、CN102762538A、CN104693114A、
CN105732490A successively discloses shellfish Qu Shaban preparation method.
WO0164643A2 is reported using 5- methoxyl group -2- nitrobenzoic acids as initiation material, in the presence of POCl3,
Reacted with 2- amino -5- chloropyridines, nitro is reduced to amino, gained by pressure hydration under the platinum carbon effect poisoned through sulphur afterwards
Amino-compound obtains N- (5- chloro-2-pyridyls) -2- [(4- cyanobenzoyls) ammonia with being condensed to cyano-benzoyl chloride
Base] -5- methoxy benzamides (5).Expensive vulcanization platinum carbon is used in this method, causes production cost to increase, and
5 chlorine are easily caused on pyridine ring by hydrogenolysis, cause impurity to increase.
Wherein WO2008057972A1 reports similar synthetic route, and difference is the patent utilization stannous chloride pair
Nitro is reduced, but the impurity that the restoring method is formed during the course of the reaction is more, is unfavorable for the separation of product, therefore unfavorable
In industrialized production.CN104693114A reports to be reduced using iron powder-acetate system to nitro, but course of reaction need to add
Enter a large amount of acetic acid, and iron powder is also significantly excessive, so as to cause a large amount of spent acid and iron cement, causes the three wastes to increase.
CN105732490A report using 5- methoxyl groups isatoic anhydride as raw material, in the presence of potassium tert-butoxide with 2- amino-
5- chloropyridines react, then with reacting cyano-benzoyl chloride to obtain N- (5- chloro-2-pyridyls) -2- [(4- Cyanophenacyls
Base) amino] -5- methoxy benzamides (5).The route is although short, but initiation material 5- methoxyl group isatoic anhydrides be not easy to obtain and
Expensive, there is free amino in the intermediate formed in technique, easily continue to react with raw material 5- methoxyl group isatoic anhydrides,
Form impurity.
CN106518758 is reported using 5- methoxyl group -2- aminobenzoic acids as initiation material, and it is anti-that esterification occurs with benzylalcohol
Should, then with reacting cyano-benzoyl chloride, take off benzyl by hydrogenolysis and obtain free carboxyl, it is finally anti-with 2- amino -5- chloropyridines
N- (5- chloro-2-pyridyls) -2- [(4- cyanobenzoyls) amino] -5- methoxy benzamides (5) should be formed.The route walks
It is rapid cumbersome, and hydrogenolysis goes cyano group during benzyl to be easily reduced, and makes impurity increase in course of reaction, so as to be unfavorable for point of compound 5
From purifying.
The content of the invention
The problem of existing for existing route, the invention provides one kind to synthesize shellfish Qu Shaban intermediate N (the chloro- 2- pyrroles of 5-
Piperidinyl) -2- [(4- cyanobenzoyls) amino] -5- methoxy benzamides (5) new method, its route is as follows：
With 5- methoxyl group -2- nitrobenzoic acids (1) for initiation material, passed through through POCl3 chloro, then with PA
Amidatioon obtains compound 2, and compound 2 obtains compound 3 through catalytic hydrogenation, and compound 3 to cyano-benzoyl chloride with being condensed
To compound 4, compound 4 obtains compound 5 through chloro.
Step 1：Compound 1 and POCl3 chloro, then obtain compound 2 through amidatioon with PA.
Step 2：Compound 2 obtains compound 3 through palladium carbon catalytic hydrogenation.
Step 3：Compound 3 with being condensed to yield compound 4 to cyano-benzoyl chloride in the basic conditions.
Step 4：Compound 4 obtains compound 5 through NCS chloros.
As the preferred scheme of above-mentioned technical proposal, in step 1, the building-up process of compound 2 is as follows：Compound 1 is taken to add
Enter into acetonitrile, POCl3 be added dropwise, PA and pyridine are added after reacting completely, suitable quantity of water is added dropwise after reacting completely,
Filtering, filter cake are washed till neutrality, are dried under reduced pressure to obtain compound 2.
It is further preferred that the mol ratio of described compound 1, PA, pyridine, POCl3 is 1: 1: (3~
5): (1~2), wherein pyridine are acid binding agent；Described solvent is selected from tetrahydrofuran, acetonitrile, benzene, toluene, dichloromethane, acetic acid
One or more combination in ethyl ester, DMF, preferred solvent of the present invention are acetonitrile, compound 1 and acetonitrile
Mass volume ratio is 1: (10~15)；Acylating reagent is selected from POCl3, phosphorus trichloride, phosphorus pentachloride, thionyl chloride, tribromo oxygen
Phosphorus, phosphorus tribromide, phosphorus pentabromide, preferred reagent of the present invention are POCl3.
As the preferred scheme of above-mentioned technical proposal, in step 2, the building-up process of compound 3 is as follows：Take compound 2,
Palladium carbon is added in methanol, normal pressure hydrogenation, is filtered after reacting completely, is concentrated under reduced pressure to give compound 3.
It is further preferred that the mass ratio of the compound 2, palladium carbon is (15~20): 1.
As the preferred scheme of above-mentioned technical proposal, in step 3, the building-up process of compound 4 is as follows：Take compound 3,
Pyridine is added in dichloromethane, and the solution that 4- cyano-benzoyl chlorides are made into dichloromethane is slowly added dropwise, after reaction completely, washes
Liquid separation is washed, anhydrous sodium sulfate drying, is concentrated under reduced pressure, obtains compound 4.
It is further preferred that the solvent is selected from water, tetrahydrofuran, dioxane, acetonitrile, toluene, dimethylbenzene, benzene, two
Chloromethanes, chloroform, carbon tetrachloride, ethyl acetate, butyl acetate, isopropyl acetate, DMF, N, N- diethyl
One or more combination in acetamide, triethylamine, pyridine, diethylisopropylamide, acetone, butanone, the preferred dichloromethane of the present invention
Alkane is solvent.
It is further preferred that alkali used includes sodium methoxide, caustic alcohol, sodium isopropylate, potassium tert-butoxide, sodium tert-butoxide, tertiary fourth
Magnesium alkoxide, Sodamide, sodium hydride, calcium hydride, ammoniacal liquor, triethylamine, pyridine, DMAP, diethylisopropylamide, DBU, benzene
Amine, DMA, methylphenylamine, potassium carbonate, sodium carbonate, cesium carbonate, sodium acid carbonate, saleratus, sodium hydroxide,
Potassium hydroxide, calcium hydroxide, the present invention are preferably pyridine.
It is further preferred that compound 3 and the mol ratio to cyano-benzoyl chloride are 1: (1~2)；Reaction temperature is -10
DEG C~40 DEG C, the present invention is preferably 20 DEG C~30 DEG C.
As the preferred scheme of above-mentioned technical proposal, in step 4, the building-up process of compound 5 is as follows：By compound 4,
Chlorinating agent, initiator are added in DMF, heating response, after reaction completely, add dichloromethane, water,
Liquid separation is washed, anhydrous sodium sulfate drying, filtering, filtrate decompression concentration, is recrystallized, obtained with tetrahydrofuran-ethyl alcohol mixed solvent
Compound 5.
It is further preferred that the solvent is DMF, DMA, N, N- diethyl first
Acid amides, N, N- diethyl acetamides, dichloromethane, chloroform, carbon tetrachloride, benzene, toluene, pentamethylene, pentane, hexamethylene
One or more combination in alkane, n-hexane, cycloheptane, normal heptane, tetrahydrofuran, dioxane, acetonitrile, water, the present invention are excellent
It is solvent to select DMF, and the mass volume ratio of compound 4 and DMF is 1: (5~10).
It is further preferred that the chlorinating agent be selected from N-chlorosuccinimide, N- chloros saccharin,
Chloro- 5, the 5- DMHs of N- chloros phthalimide, 1,3- bis-, the chloro- 5- methyl -5- ethylhydantoins of 1,3- bis-, chlorine, the present invention
It is preferred that chlorinating agent is N-chlorosuccinimide, and compound 4 and the mol ratio of N-chlorosuccinimide are 1: (1.0~
2.0)。
It is further preferred that the initiator is benzoyl peroxide, TBHP, peroxide cyclohexanone, azo two
One or more combination in isobutyronitrile, ABVN, the present invention preferably benzoyl peroxide, and compound 4 and peroxide
The mol ratio of benzoyl is 1: (0.05~0.1).
It is further preferred that the reaction temperature is 0 DEG C~100 DEG C, preferably 70 DEG C~80 DEG C of the present invention.
It is further preferred that the reaction time is 2h~8h, the present invention is preferably 3h.
It is further preferred that the recrystallization solvent be selected from tetrahydrofuran, dioxane, ethyl acetate, methanol, ethanol,
One or more combination in normal propyl alcohol, isopropanol, n-butanol, dichloromethane, n-hexane, hexamethylene, preferred solvent of the present invention
For tetrahydrofuran and alcohol mixed solvent.
Compared with prior art, the present invention is to shellfish Qu Shaban intermediate Ns (5- chloro-2-pyridyls) -2- [(4- cyano group benzene first
Acyl group) amino] improvement of -5- methoxy benzamides overcomes many deficiencies, total recovery 57.2%, and its major advantage is thing
Material is easy to get, is easy to operate, cost is relatively low, and reduces the generation of accessory substance, is advantageous to industrialized production.
Embodiment
Following Examples further illustrate the present invention, but the present invention is not intended to be limited thereto.
Embodiment：
The preparation of the compound 2 of embodiment 1
Compound 1 (20g, 102mmol) is taken to be added in 150ml acetonitriles, room temperature dropwise addition POCl3 (23g,
300mmol), finish, PA (9.5g, 101mmol) and pyridine (23.7g, 300mmol), room are added after reacting completely
Temperature continues to react 4h.150ml water is slowly added dropwise, filters, filter cake is washed with water to neutrality, and 50 DEG C are dried under reduced pressure to obtain 24.6g compounds
2, yield 98.04%.
The preparation of the compound 3 of embodiment 2
Compound 2 (16g, 59mmol), 10% palladium carbon (1g) is taken to be added in 300ml methanol, normal pressure hydrogenation, room temperature reaction
6h, filtering, yellowish green solution decompression is concentrated, obtains 13.6g compounds 3, yield 94.82%.1H NMR (500MHz, DMSO-d6)δ
10.55 (s, 1H), 8.46-8.32 (m, 1H), 8.13 (d, J=8.4Hz, 1H), 7.84 (m, J=8.3,7.8,1.9Hz, 1H),
7.33 (d .J=2.9Hz, 1H), 7.23-7.07 (m, 1H), 6.93 (dd, J=8.9,2.9Hz, 1H), 6.78 (d, J=
8.9Hz, 1H), 6.00 (s, 2H), 3.77 (s, 3H)
The preparation of the compound 4 of embodiment 3
Compound 3 (10g, 41mmol), pyridine 5ml is taken to be added in 100ml dichloromethane, room temperature is slowly added dropwise by 4- cyanogen
The solution that base chlorobenzoyl chloride (8.16g, 49mmol) is prepared with dichloromethane 10ml, is finished, and room temperature continues to react 3h, uses respectively
80ml water, 80ml saturated sodium bicarbonates, 80ml water washings, liquid separation, anhydrous sodium sulfate drying, filtrate decompression concentration, obtain 12.3gization
Compound 4, yield 80.62%.1H NMR (500MHz, DMSO-d6) δ 11.14 (s, 1H), 10.91 (s, 1H), 8.50-8.35 (m,
1H), 8.18-7.96 (m, 6H), 7.96-7.76 (m, 1H), 7.49 (d, J=2.9Hz, 1H), 7.21 (m, J=7.5,4.2Hz,
2H), 3.90 (s, 3H)
The preparation of the compound 5 of embodiment 4
Compound 4 (10g, 27mmol), NCS (3.6g, 27mmol), benzoyl peroxide (0.5g, 2.1mmol) is taken to be added to
In DMF (80ml), reaction solution is warming up to 70 DEG C~80 DEG C and reacts 3h, is cooled to room temperature, to reaction solution plus
Enter dichloromethane (100ml) and respectively with 150ml saturated sodium bicarbonates, 150ml water washings, liquid separation, anhydrous sodium sulfate drying, filter
Liquid is concentrated under reduced pressure, and gained residue is recrystallized with 70ml tetrahydrofuran-ethyl alcohols mixed solvent, obtains 8.39g compounds 5, yield
76.38%.MS(ESI)m/z：[M+Na]+429.11H NMR (500MHz, DMSO-d6) δ 11.10 (s, 1H), 11.03 (s,
1H), 8.47 (s, 1H), 8.15 (d, J=9.0Hz, 1H), 8.05 (q, J=8.2Hz, 4H), 8.00-7.93 (m, 2H), 7.44
(d, J=2.9Hz, 1H), 7.20 (dd, J=8.9,2.8Hz, 1H), 3.88 (s, 3H)
Claims (10)
1. one kind prepares shellfish Qu Shaban intermediate Ns (5- chloro-2-pyridyls) -2- [(4- cyanobenzoyls) amino] -5- methoxies
The method of yl-benzamide, it comprises the following steps：
(1) under alkali effect, 5- methoxyl group -2- amino-N- (pyridine -2- bases) benzamides (3) to cyano-benzoyl chloride with contracting
Conjunction obtains 2- [(4- cyanobenzoyls) amino] -5- methoxyl groups-N- (pyridine -2- bases) benzamide (4)；
(2) 2- [(4- cyanobenzoyls) amino] -5- methoxyl groups-N- (pyridine -2- bases) benzamide (4) obtains shellfish through chloro
Qu Shaban intermediate Ns (5- chloro-2-pyridyls) -2- [(4- cyanobenzoyls) amino] -5- methoxy benzamides (5).
2. method as claimed in claim 1, it is characterised in that：The preparation of the compound 4, solvent for use be water, tetrahydrofuran,
Dioxane, acetonitrile, toluene, dimethylbenzene, benzene, dichloromethane, chloroform, carbon tetrachloride, ethyl acetate, butyl acetate, acetic acid are different
Propyl ester, DMF, N, in N- diethyl acetamides, triethylamine, pyridine, diethylisopropylamide, acetone, butanone
One or more combination, the present invention are preferably dichloromethane.
3. method as claimed in claim 1, it is characterised in that：The preparation of the compound 4, alkali used include sodium methoxide, ethanol
Sodium, sodium isopropylate, potassium tert-butoxide, sodium tert-butoxide, tert-butyl alcohol magnesium, Sodamide, sodium hydride, calcium hydride, ammoniacal liquor, triethylamine, pyridine,
DMAP, diethylisopropylamide, DBU, aniline, DMA, methylphenylamine, potassium carbonate, sodium carbonate,
Cesium carbonate, sodium acid carbonate, saleratus, sodium hydroxide, potassium hydroxide, calcium hydroxide, the present invention are preferably pyridine.
4. method as claimed in claim 1, it is characterised in that：The preparation of the compound 4, compound 3 and to Cyanophenacyl
The mol ratio of chlorine is 1: (1~2)；Reaction temperature is -10 DEG C~40 DEG C, and the present invention is preferably 20 DEG C~30 DEG C.
5. method as claimed in claim 1, it is characterised in that：The preparation of the compound 5, chlorinating agent used in chlorination are
Chloro- 5, the 5- dimethyl sea of N-chlorosuccinimide, N- chloros saccharin, N- chloros phthalimide, 1,3- bis-
Cause, the chloro- 5- methyl -5- ethylhydantoins of 1,3- bis-, chlorine, the present invention preferably N-chlorosuccinimide, and compound 4 and N-
The mol ratio of chlorosuccinimide is 1: (1.0~2.0).
6. method as claimed in claim 1, it is characterised in that：The preparation of the compound 5, initiator used are peroxide benzene first
One or more combination in acyl, TBHP, peroxide cyclohexanone, azodiisobutyronitrile, ABVN, this hair
Bright is preferably benzoyl peroxide, and compound 4 and the mol ratio of benzoyl peroxide are 1: (0.05~0.1).
7. method as claimed in claim 1, it is characterised in that：The preparation of the compound 5, solvent for use N, N- dimethyl methyl
Acid amides, DMA, N, N- diethylformamides, N, N- diethyl acetamides, dichloromethane, chloroform, four
Chlorination carbon, benzene, toluene, pentamethylene, pentane, hexamethylene, n-hexane, cycloheptane, normal heptane, tetrahydrofuran, dioxane, second
One or more combination in nitrile, water, the present invention preferably DMF, and compound 4 and N, N- dimethyl methyl
The mass volume ratio of acid amides is 1: (5~10).
8. method as claimed in claim 1, it is characterised in that：The preparation of the compound 5, reaction temperature are 0 DEG C~100 DEG C,
The present invention is preferably 70 DEG C~80 DEG C.
9. method as claimed in claim 1, it is characterised in that：The preparation of the compound 5, reaction time are 2h~8h, this hair
Bright is preferably 3h.
10. method as claimed in claim 1, it is characterised in that：The preparation of the compound 5, recrystallization solvent are selected from tetrahydrochysene furan
Mutter, in dioxane, ethyl acetate, methanol, ethanol, normal propyl alcohol, isopropanol, n-butanol, dichloromethane, n-hexane, hexamethylene
One or more combination, preferred solvent of the present invention is tetrahydrofuran and alcohol mixed solvent.
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| CN201711254533.2A CN107868039A (en) | 2017-11-27 | 2017-11-27 | A kind of shellfish Qu Shaban intermediate Ns（5- chloro-2-pyridyls）- 2-（4- cyanobenzoyls）Amino ］ -5- methoxy benzamides preparation method |
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| CN201711254533.2A CN107868039A (en) | 2017-11-27 | 2017-11-27 | A kind of shellfish Qu Shaban intermediate Ns（5- chloro-2-pyridyls）- 2-（4- cyanobenzoyls）Amino ］ -5- methoxy benzamides preparation method |
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Cited By (2)
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| CN109180573A (en) * | 2018-09-17 | 2019-01-11 | 珠海润都制药股份有限公司 | A kind of preparation method of betrixaban intermediate |
| CN115057854A (en) * | 2022-04-19 | 2022-09-16 | 河北常山生化药业股份有限公司 | Preparation method of Alvatripopa maleate intermediate |
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN109180573A (en) * | 2018-09-17 | 2019-01-11 | 珠海润都制药股份有限公司 | A kind of preparation method of betrixaban intermediate |
| CN115057854A (en) * | 2022-04-19 | 2022-09-16 | 河北常山生化药业股份有限公司 | Preparation method of Alvatripopa maleate intermediate |
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