CN104478820A - Preparation method of rivaroxabanintermediate - Google Patents
Preparation method of rivaroxabanintermediate Download PDFInfo
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- CN104478820A CN104478820A CN201410805459.9A CN201410805459A CN104478820A CN 104478820 A CN104478820 A CN 104478820A CN 201410805459 A CN201410805459 A CN 201410805459A CN 104478820 A CN104478820 A CN 104478820A
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- C07D265/28—1,4-Oxazines; Hydrogenated 1,4-oxazines
- C07D265/30—1,4-Oxazines; Hydrogenated 1,4-oxazines not condensed with other rings
- C07D265/32—1,4-Oxazines; Hydrogenated 1,4-oxazines not condensed with other rings with oxygen atoms directly attached to ring carbon atoms
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Abstract
The invention discloses a synthetic method of rivaroxabanintermediate4-(4-nitrosobenzene)-3-morpholine. The method comprises steps as follows: (1), halogenated benzene (I) and ethanolamine react under the condition of a catalyst and alkali to generate N-ethoxylaniline (II), N-ethoxylaniline (II) and nitrous acid or nitrite react to generate 4-nitroso-N-ethoxylaniline (III), and 4-nitroso-N-ethoxylaniline (III) and chloroacetyl chloride react to generate 4-(4-nitrosobenzene)-3-morpholine (IV). According to the synthetic method of 4-(4-nitrosobenzene)-3-morpholine, required raw materials and reagents are cheap and are easy to obtain, the yield is high, and the cost is low; the reaction condition is mild; fewer three wastes are produced; and the product quality is reliable and stable, and the whole process is very suitable for industrial production.
Description
Technical field
The invention belongs to chemical pharmacy field, be specifically related to a kind of anticoagulant Rivaroxaban intermediate and preparation technology thereof.
Background technology
The razaxaban chemistry chloro-N-of 5-(((5S)-2-oxo-3-(4-(3-oxomorpholin-4-base) phenyl)-1 by name, 3-oxazoline-5-base) methyl) thiophene-2-carboxamide derivatives (VI), the oral pharmaceutical of a kind of highly selective, direct supressor Xa.Endogenous and the extrinsic pathway of blood coagulation waterfall can be interrupted, the generation of Trombin inhibiting and thrombosis by supressor Xa.
According to the report of Wu Xiang paper in 2013, compound (VI) is Material synthesis by 4-(4-aminophenyl)-3-morpholone mai (V), the chloro-N-of 5-(2-oxiranylmethyl radical)-2-thenoyl amine (VII) etc.
WO-A 01/47919 describes the preparation method of 4-(4-aminophenyl)-3-morpholone mai (V), first morpholine-3-ketone deprotonation under basic conditions, then react with p-fluoronitrobenzene and generate 4-(4-nitro amino phenyl)-3-morpholone mai, obtain 4-(4-aminophenyl)-3-morpholone mai (V) with Pd/C shortening:
The method yield is lower, and the first step yield is 17.6%, and second step yield is 37.6%, is obviously not suitable for large-scale production.
Document " Chlorothio-phenecarboxamides as P1 surrogates of inhibitors of blood coagulation factor Xa " (Bioorg.Med.Chem.Lett, 2004,14 (23): 5817 – 5822) in describe following 4-(4-aminophenyl)-3-morpholone mai (V) preparation method:
Three-step reaction total recovery 69%, but starting raw material 2-(2-chloroethoxy) Acetyl Chloride 98Min. is not easy to obtain and expensive, limits suitability for industrialized production.
Patent US, 20060160821 to describe by paraiodoaniline be the method that starting raw material prepares 4-(4-aminophenyl)-3-morpholone mai (V):
The method only needs a step substitution reaction can obtain compound (V), but paraiodoaniline price is more expensive, and reaction needed is carried out under the high temperature conditions, is not suitable for quantizing to produce.
Patent US, 7598378 describe the method being carried out digesting and preparing after hydrogenation 4-(4-aminophenyl)-3-morpholone mai (V) by 4-phenyl-3-morpholone mai (III):
The nitration reaction yield that the method relates to is medium, although raw material is easy to get, has used a large amount of concentrated nitric acid and the vitriol oil in denitrification step, dangerous high, comparatively strong to equipment corrosion, and creates a large amount of waste water and waste gas, is not suitable for suitability for industrialized production.
Summary of the invention
Instant invention overcomes the deficiencies in the prior art, solving aforesaid method by new technique can not completely for the problem of industrialization.
One object of the present invention there are provided a kind of Rivaroxaban intermediate 4-(4-nitroso-group phenyl)-3-morpholone mai (IV), and it has following structure:
Another object of the present invention is to provide above-mentioned Rivaroxaban intermediate 4-(4-nitroso-group phenyl)-3-morpholone mai (IV) synthesis technique, take halogeno-benzene as raw material, through ammonification, Guan Huan, nitrosification, reduction synthesis Rivaroxaban intermediate 4-(4-nitroso-group phenyl)-3-morpholone mai.Above-mentioned technique comprises the steps:
(1) under the condition of catalyzer, alkali, halogeno-benzene (I) and ethylol amine reaction generate N-β-anilino-ethanol (II);
(2) N-β-anilino-ethanol (II) reacts with nitrous acid or nitrite and generates 4-nitroso-group-N-β-anilino-ethanol (III);
(3) 4-nitroso-group-N-β-anilino-ethanol (III) and chloroacetyl chloride react and generate 4-(4-nitroso-group phenyl)-3-morpholone mai (IV);
In described method steps (1), the catalyzer related to is independently selected from one or more in potassiumiodide, sodium iodide, cuprous iodide, cuprous bromide, cuprous chloride, and preferred catalyzer is potassiumiodide; The relevant amounts of catalyzer is the 2%-100% of compound (I) quality, is preferably 5%-20%.
In step (1), alkali, independently selected from one or more in sodium hydroxide, potassium hydroxide, sodium carbonate, salt of wormwood, diethylamine, triethylamine, pyridine, N-picoline etc., is preferably salt of wormwood; The consumption of alkali is the 100%-500% of compound (I) amount of substance, is preferably 200-300%.
In step (1), halogeno-benzene (I) is selected from fluorobenzene, chlorinated benzene, bromobenzene or phenyl-iodide, is preferably bromobenzene.
In step (1), temperature of reaction independently selected from being 0-100 DEG C, preferably from 60-80 DEG C.
In step (1), add an ethylol amine, temperature reaction 1-20 hour, be preferably 15 hours.Reaction terminates rear dissolving, washing, dry, decolouring, and concentrated, rectifying obtains compound (II).
In step (2), described nitrite can be selected from Sodium Nitrite, potassium nitrite, zinc nitrite or ammonium nitrite.
In step (2), compound (II) is mixed with dilute acid soln, adds nitrite, reaction 1-20 hour, preferred 2-5 hour; Described dilute acid soln is the organic acid such as the mineral acids such as hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid or formic acid, acetic acid, propionic acid, trifluoroacetic acid, and concentration is 1-50% (m/V), is preferably 5-20% (m/V).
In step (2), temperature of reaction independently selected from-30 DEG C-60 DEG C, preferably from-5 DEG C-10 DEG C; Reaction terminates rear washing, and drying obtains compound (III).
In step (3), compound (III) is dissolved in organic solvent, adds alkali, drip chloroacetyl chloride, insulation reaction 1-20 hour, preferably from 2-5 hour; Described organic solvent independently selected from one or more in methyl alcohol, ethanol, Virahol, ethylene glycol, ethyl acetate, butylacetate, tetrahydrofuran (THF), methyltetrahydrofuran, methylene dichloride, trichloromethane, preferred tetrahydrofuran (THF); Alkali independently selected from one or more in sodium hydroxide, potassium hydroxide, sodium carbonate, salt of wormwood, diethylamine, triethylamine, pyridine, N-picoline etc., preferred triethylamine; The relevant amounts of alkali independently selected from compound (III) amount of substance 1-5 doubly, preferred 1.5-2 is doubly; Temperature of reaction independently selected from 0-100 DEG C, preferably from 20-50 DEG C; Filter after completion of the reaction, drip alkali lye, insulation reaction, layering, extraction, concentrated, recrystallization, drying obtains compound (IV); Recrystallization solvent independently selected from one or more in ethyl acetate, butylacetate, methylene dichloride, trichloromethane, toluene, dimethylbenzene, sherwood oil, normal hexane, normal heptane, preferred normal hexane.
Another object of the present invention is to a kind of method providing synthesis Rivaroxaban intermediate 4-(4-aminophenyl)-3-morpholone mai (V), described method comprises the steps:
4-(4-nitroso-group phenyl)-3-morpholone mai (IV) is generated 4-(4-aminophenyl)-3-morpholone mai (V) by catalytic hydrogenating reduction.
In described method, catalyzer independently selected from the simple substance of palladium, nickel, platinum or complex compound, oxide compound, muriatic one, preferred palladium; Catalyzer relevant amounts independently selected from the 1%-100% of compound (IV) quality, preferably from 5%-20%; Temperature of reaction independently selected from 10-100 DEG C, preferably from 30-50 DEG C.Also nitroso reduction can be carried out with the material such as iron powder, hydrazine hydrate.
Another object of the present invention is to the synthetic method providing a kind of razaxaban, described method comprises the steps:
(1) 4-(4-nitroso-group phenyl)-3-morpholone mai (IV) is generated 4-(4-aminophenyl)-3-morpholone mai (V) by catalytic hydrogenating reduction
(2) by 4-(4-aminophenyl)-3-morpholone mai (V) and the chloro-N-of 5-(2-oxiranylmethyl radical)-2-thenoyl amine (VII) reaction generate 5-chlorothiophene-2-{ (R)-2-hydroxyl-3-[4-(3-oxomorpholin-4-base) phenyl amino-propyl group } acid amides (VIII);
(3) by 5-chlorothiophene-2-{ (R)-2-hydroxyl-3-[4-(3-oxomorpholin-4-base) phenyl amino-propyl group } acid amides (VIII) and carbonyl dimidazoles (CDI) etc. be obtained by reacting razaxaban (VI).
The synthetic method of Rivaroxaban intermediate 4-provided by the invention (4-nitroso-group phenyl)-3-morpholone mai, desired raw material and reagent cheap and easy to get, cost is low; Reaction conditions is gentle; The three wastes are relatively less; Reliable product quality is stablized.
Compared with prior art, the invention has the advantages that and replace nitrated with nitrosification, solid sodium nitrite can be used under diluted acid condition, to complete reaction for nitrosation agent, easy and simple to handle, yield is high, intermediate 4-(4-aminophenyl)-3-morpholone mai total recovery reaches 63-68%, far above the synthesis yield of this intermediate that WO 01/47919 reports; And reaction conditions is gentle, environmentally friendly, cost is low, is obviously superior to other synthetic technology routes of prior art report.Utilize the constant product quality that the inventive method obtains, be very applicable to razaxaban suitability for industrialized production.
Accompanying drawing explanation
Fig. 1 is the hydrogen nuclear magnetic resonance spectrogram of intermediate 4-nitroso-group-N-β-anilino-ethanol (III) of the present invention.
Fig. 2 is the mass spectrum of intermediate 4-nitroso-group-N-β-anilino-ethanol (III) of the present invention.
Fig. 3 is the hydrogen nuclear magnetic resonance spectrogram of intermediate 4-of the present invention (4-nitroso-group phenyl)-3-morpholone mai (IV).
Fig. 4 is the mass spectrum of intermediate 4-of the present invention (4-nitroso-group phenyl)-3-morpholone mai (IV).
Embodiment
Below in conjunction with embodiment, the present invention is described in further detail.For a person skilled in the art, the amendment carried out based on the present invention or delete still belongs within protection scope of the present invention.
Embodiment 1:
The preparation of N-β-anilino-ethanol (II)
Bromobenzene 21.2mL (0.20mol) is added successively in the 250mL four-hole bottle that mechanical stirring, prolong, thermometer are housed, thanomin 18.5mL (0.30mol), cuprous iodide 4.0g (0.02mol), salt of wormwood 55.2g (0.4mol), water 100mL, temperature control 80 DEG C stirs 15h.Suction filtration, filtrate rectifying can obtain colourless liquid 25.2g (under 10mmHg boiling point 165 DEG C), is target compound N-β-anilino-ethanol (II), productive rate: 91.1%.
Embodiment 2:
The preparation of 4-nitroso-group-N-β-anilino-ethanol (III)
87.6g 10% hydrochloric acid is added in the 500mL four-hole bottle that mechanical stirring, thermometer are housed, be cooled to 5 DEG C, add 29g (0.21mol) N-β-anilino-ethanol (II), be incubated 0 ~ 5 DEG C and drip 58g 30% sodium nitrite in aqueous solution (0.25mol), time for adding is about 3h, drip and finish, insulation reaction 2h, filters, filter cake appropriate washing 2 times, 60 DEG C of hot-air seasonings obtain yellow solid 31.7g, yield 90.2%.
III:
1H NMR(300MHz,DMSO-d
6):δ7.92(s,1H),6.67-6.74(br,3H),4.89(t,1H,J＝4.2Hz),3.58(m,2H),3.30(m,2H)；ESI-MS m/z＝165(M-1)，201(M+Cl
-)。
Embodiment 3:
The preparation of 4-nitroso-group-N-β-anilino-ethanol (III)
87.6g 10% hydrochloric acid is added in the 500mL four-hole bottle that mechanical stirring, thermometer are housed, be cooled to 5 DEG C, add 29g (0.21mol) N-β-anilino-ethanol (II), temperature control≤-10 DEG C drip 58g 30% sodium nitrite in aqueous solution (0.25mol), and time for adding is about 2.5h, drip and finish, insulation reaction 6h, filters, filter cake appropriate washing 2 times, 60 DEG C of hot-air seasonings obtain yellow solid 30.2g, yield 86.0%.
III:
1H NMR(300MHz,DMSO-d
6):δ7.92(s,1H),6.67-6.74(br,3H),4.89(t,1H,J＝4.2Hz),3.58(m,2H),3.30(m,2H)；ESI-MS m/z＝165(M-1)，201(M
+Cl
-)。
Embodiment 4:
The preparation of 4-nitroso-group-N-β-anilino-ethanol (III)
87.6g 10% hydrochloric acid is added in the 500mL four-hole bottle that mechanical stirring, thermometer are housed, be cooled to 5 DEG C, add 29g (0.21mol) N-β-anilino-ethanol (II), temperature control≤-5 DEG C drip 49g 30% sodium nitrite in aqueous solution (0.21mol), and time for adding is about 1.5h, drip and finish, insulation reaction 8h, filters, filter cake appropriate washing 2 times, 60 DEG C of hot-air seasonings obtain yellow solid 28.8g, yield 82.0%.
III:
1H NMR(300MHz,DMSO-d
6):δ7.92(s,1H),6.67-6.74(br,3H),4.89(t,1H,J＝4.2Hz),3.58(m,2H),3.30(m,2H)；ESI-MS m/z＝165(M-1)，201(M
+Cl
-)。
Embodiment 5:
The preparation of 4-(4-nitroso-group phenyl)-3-morpholone mai (IV)
22g (0.13moL) 4-nitroso-group-N-β-anilino-ethanol (III) is added in the 500mL four-hole bottle that mechanical stirring, thermometer are housed, tetrahydrofuran (THF) 300mL, triethylamine 25mL (0.16moL), ice bath cools, open mechanical stirring, temperature of reaction drops to 0 DEG C.Getting 22g (0.2moL) chloroacetyl chloride is dissolved in 70mL tetrahydrofuran (THF), is chilled to 0 DEG C in advance, is slowly added drop-wise in above-mentioned reaction system in 40min.Drip and finish, 0 DEG C of reaction 4h.Reaction is finished, and filters, and it is for subsequent use that tetrahydrofuran (THF) washing leaching cake merges organic phase three times afterwards.
Mechanical stirring is being housed, the sodium hydroxide solution 200mL of 40% is added in the 1000mL there-necked flask of thermometer and vacuum distillation apparatus, start mechanical stirring, be warming up to 35 DEG C, and open underpressure distillation, the slowly above-mentioned tetrahydrofuran solution of instillation, drips Bi Jixu and stirs 20min, close vacuum distillation apparatus, continue reaction 1h.React complete, with dichloromethane extraction, combined dichloromethane organic phase, concentrating under reduced pressure removing methylene dichloride obtains needle-like crystal, and normal hexane recrystallization obtains white needle-like crystals 21.9g, fusing point 111-112 DEG C, yield 80.2%.
IV:
1H NMR(300MHz,CDCl3):δ8.38(d,1H,J＝9.3Hz),8.26(d,1H,J＝9.0Hz),7.52(m,2H),4.38(d,1H,J＝2.7Hz),4.08(m,2H),3.85(m,2H)；EI-MS m/z＝206(M)。
Embodiment 6:
The preparation of 4-(4-nitroso-group phenyl)-3-morpholone mai (IV)
22g (0.13moL) 4-nitroso-group-N-β-anilino-ethanol (III) is added in the 500mL four-hole bottle that mechanical stirring, thermometer are housed, methylene dichloride 300mL, triethylamine 25mL (0.16moL), ice bath cools, open mechanical stirring, temperature of reaction drops to 0 DEG C.Getting 22g (0.2moL) chloroacetyl chloride is dissolved in 70mL methylene dichloride, is chilled to 0 DEG C in advance, is slowly added drop-wise in above-mentioned reaction system in 40min.Drip and finish, 0 DEG C of reaction 4.5h.Reaction is finished, and filters, and it is for subsequent use that washed with dichloromethane filter cake merges organic phase three times afterwards.
Mechanical stirring is being housed, the sodium hydroxide solution 200mL of 40% is added in the 1000mL there-necked flask of thermometer and vacuum distillation apparatus, start mechanical stirring, be warming up to 35 DEG C, and open underpressure distillation, the slowly above-mentioned tetrahydrofuran solution of instillation, drips Bi Jixu and stirs 60min, close vacuum distillation apparatus, continue reaction 4h.React complete, with dichloromethane extraction, combined dichloromethane organic phase, concentrating under reduced pressure removing methylene dichloride obtains needle-like crystal, and normal hexane recrystallization obtains white needle-like crystals 20.6g, fusing point 110-112 DEG C, yield 75.5%.
IV:
1H NMR(300MHz,CDCl3):δ8.38(d,1H,J＝9.3Hz),8.26(d, 1H,J＝9.0Hz),7.52(m,2H),4.38(d,1H,J＝2.7Hz),4.08(m,2H),3.85(m,2H)；EI-MS m/z＝206(M)。
Embodiment 7:
The preparation of 4-(4-nitroso-group phenyl)-3-morpholone mai (IV)
22g (0.13moL) 4-nitroso-group-N-β-anilino-ethanol (III) is added in the 500mL four-hole bottle that mechanical stirring, thermometer are housed, tetrahydrofuran (THF) 300mL, sodium hydroxide 6.4g (0.16moL), ice bath cools, open mechanical stirring, temperature of reaction drops to 0 DEG C.Getting 22g (0.2moL) chloroacetyl chloride is dissolved in 70mL tetrahydrofuran (THF), is chilled to 0 DEG C in advance, is slowly added drop-wise in above-mentioned reaction system in 40min.Drip and finish, 0 DEG C of reaction 3h.Reaction is finished, and filters, and it is for subsequent use that tetrahydrofuran (THF) washing leaching cake merges organic phase three times afterwards.
Mechanical stirring is being housed, the sodium hydroxide solution 200mL of 40% is added in the 1000mL there-necked flask of thermometer and vacuum distillation apparatus, start mechanical stirring, be warming up to 35 DEG C, and open underpressure distillation, the slowly above-mentioned tetrahydrofuran solution of instillation, drips Bi Jixu and stirs 20min, close vacuum distillation apparatus, continue reaction 3h.React complete, with dichloromethane extraction, combined dichloromethane organic phase, concentrating under reduced pressure removing methylene dichloride obtains needle-like crystal, and normal heptane recrystallization obtains white needle-like crystals 18.5g, fusing point 110-111 DEG C, yield 67.8%.
IV:
1H NMR(300MHz,CDCl3):δ8.38(d,1H,J＝9.3Hz),8.26(d,1H,J＝9.0Hz),7.52(m,2H),4.38(d,1H,J＝2.7Hz),4.08(m,2H),3.85(m,2H)；EI-MS m/z＝206(M)。
Embodiment 8:
The preparation of 4-(4-aminophenyl)-3-morpholone mai (V)
30g (0.15mol) 4-(4-nitroso-group phenyl)-3-morpholone mai (IV) and 200g ethanol is added in 500ml hydriding reactor, add 5%Pd/C 1.5g after nitrogen replacement air, open stirring, be warming up to 40 DEG C, pass into 40psi hydrogen, stir 2h.After reaction terminates, reaction solution is added 40g ethanol and 150g water, be warming up to 40 DEG C, filter, filtrate reduced in volume, to dry, add 100ml methyl alcohol reflux, stirs clearly molten, 1h is stirred after being cooled to 10 DEG C, filter, at filter cake 50 DEG C, decompression drying obtains off-white color to light red solid 25.0g, yield 89.5%, fusing point 169-170 DEG C, nucleus magnetic resonance is consistent with bibliographical information with data such as mass spectrums.
Embodiment 9:
The preparation of 4-(4-aminophenyl)-3-morpholone mai (V)
30g (0.15mol) 4-(4-nitroso-group phenyl)-3-morpholone mai (IV) and 200g ethanol is added in 500ml hydriding reactor, add Raney's nickel 6g after nitrogen replacement air, open stirring, be warming up to 60 DEG C, pass into 40psi hydrogen, stir 5h.After reaction terminates, reaction solution is added 40g ethanol and 150g water, be warming up to 60 DEG C, filter, filtrate reduced in volume, to dry, add 100ml methyl alcohol reflux, stirs clearly molten, 1h is stirred after being cooled to 10 DEG C, filter, at filter cake 50 DEG C, decompression drying obtains off-white color to light red solid 24.8g, yield 88.7%, fusing point 168-169 DEG C, nucleus magnetic resonance is consistent with bibliographical information with data such as mass spectrums.
Embodiment 10:
The preparation of 4-(4-aminophenyl)-3-morpholone mai (V)
30g (0.15mol) 4-(4-nitroso-group phenyl)-3-morpholone mai (IV) and 200g ethanol is added in 500ml hydriding reactor, add 3%Pt/C after nitrogen replacement air, open stirring, be warming up to 80 DEG C, pass into 40psi hydrogen, stir 4h.After reaction terminates, reaction solution is added 40g ethanol and 150g water, be warming up to 80 DEG C, filter, filtrate reduced in volume, to dry, add 100ml methyl alcohol reflux, stirs clearly molten, 1h is stirred after being cooled to 10 DEG C, filter, at filter cake 50 DEG C, decompression drying obtains off-white color to light red solid 20.5g, yield 73.3%, fusing point 168-169 DEG C, nucleus magnetic resonance is consistent with bibliographical information with data such as mass spectrums.
Embodiment 11:
5-chlorothiophene-2-{ (R)-2-hydroxyl-3-[4-(3-oxomorpholin-4-base) phenyl amino-propyl group } preparation of acid amides (VIII)
Taking 29g magnesium perchlorate adds in dry reaction flask; then 10g intermediate 4-(4-aminophenyl)-3-morpholone mai (V) and the chloro-N-of 13.6g5-(2-oxiranylmethyl radical)-2-thenoyl amine (VII) is added; add 250ml anhydrous tetrahydro furan again; nitrogen protection, stirs 24h at 40 DEG C.Reaction is finished, and adds 250ml water and 500ml ethyl acetate, separate ethyl acetate layer after stirring in reaction flask, and dry concentrating obtains faint yellow solid 15.6g, fusing point 121-123 DEG C, yield 73.3%.
Ⅷ:
1HNMR(400MHz,CDCl3)：δ3.71(t,2H,J＝5.4Hz),3.81(t,3H,J＝5.4Hz),3.85(m,1H),3.90(t,2H,J＝4.5Hz),4.15(t,3H,J＝7.5Hz),4.84(m,1H,)7.17(d,1H,J＝4.2Hz),7.40(d,3H, J＝9.0Hz),7.55(t,2H,J＝9.0Hz),7.69(d,1H,J＝4.2Hz),8.90(t,1H,J＝5.7Hz)。
Embodiment 12:
The preparation of razaxaban (VI)
Take 8.7g5-chlorothiophene-2-{ (R)-2-hydroxyl-3-[4-(3-oxomorpholin-4-base) phenyl amino-propyl group } acid amides (VIII) puts into reaction flask, then add 7g carbonyl dimidazoles (CDI) and 1g DMAP (DMAP) and 100ml dry DMF, open and stir.Reflux 6h at 100 DEG C.Reaction is finished, and adds 100ml water, be extracted with ethyl acetate in reaction flask, and dry concentrated ethyl acetate layer, obtains yellow solid razaxaban 9.3g, fusing point 227-229 DEG C, yield 93.1%.
Ⅵ:
1HNMR(DMSO-d6)：δ3.61(t，J＝5.4Hz,2H)，3.71(t，J＝5.4Hz，3H)，3.85(m，1H)，3.97(t，J＝4.5Hz,2H)，4.19(t，J＝7.5Hz,3H)，4.84(m，lH)，7.19(d，J＝4.2Hz，1H)，7.40(d，J＝9.0Hz，3H)，7.58(t，J＝9.0Hz，2H)，7.69(d，J＝4.2Hz，1H)，8.96(t，j＝5.7Hz，1H).
13CNMR(101MHz，DMSO)：δ168.55(C＝O)，166.28(C＝O)，147.94(Ar-C)，134.71(Ar-C)，132.27(Ar-C)，130.88(Ar-C)，126.91(Ar-C)，123.37(Ar-C)，1 12.53(Ar-C)，68.24(CH：)，66.87(CH：)，64.06(CH：)，50.09(CH：)，47.97(CH：)，42.87(CH
2) 。
Claims (10)
1. a Rivaroxaban intermediate, its structural formula is as follows:
2. prepare a production method for Rivaroxaban intermediate according to claim 1, comprise the steps:
(1) under the condition of catalyzer, alkali, halogeno-benzene (I) and ethylol amine reaction generate N-β-anilino-ethanol (II);
(2) N-β-anilino-ethanol (II) reacts with nitrous acid or nitrite and generates 4-nitroso-group-N-β-anilino-ethanol (III);
(3) 4-nitroso-group-N-β-anilino-ethanol (III) and chloroacetyl chloride react and generate 4-(4-nitroso-group phenyl)-3-morpholone mai (IV).
3. production method according to claim 2, is characterized in that, in described method steps (1), the catalyzer related to is independently selected from one or more in potassiumiodide, sodium iodide, cuprous iodide, cuprous bromide, cuprous chloride.
4. production method according to claim 2, it is characterized in that, in described method steps (1), alkali is independently selected from one or more in sodium hydroxide, potassium hydroxide, sodium carbonate, salt of wormwood, diethylamine, triethylamine, pyridine, N-picoline etc.
5. production method according to claim 2, is characterized in that, in described method steps (1), halogeno-benzene (I) is selected from fluorobenzene, chlorinated benzene, bromobenzene or phenyl-iodide.
6. production method according to claim 2, is characterized in that, in described method steps (2), described nitrite is selected from Sodium Nitrite, potassium nitrite, zinc nitrite or ammonium nitrite.
7. production method according to claim 2, is characterized in that, in described method steps (3), compound (III) is dissolved in organic solvent, adds alkali, drips chloroacetyl chloride, insulation reaction 1-20 hour.
8. utilize a production method for intermediate synthesis Rivaroxaban intermediate 4-(4-aminophenyl)-3-morpholone mai (V) described in claim 1, described method comprises the steps:
4-(4-nitroso-group phenyl)-3-morpholone mai (IV) is generated 4-(4-aminophenyl)-3-morpholone mai (V) by catalytic hydrogenating reduction.
9. production method according to claim 35, is characterized in that, in described method, catalyzer is independently selected from the simple substance of palladium, nickel, platinum or complex compound, oxide compound, muriatic one.
10. a synthetic method for razaxaban, described method comprises the steps:
(1) 4-(4-nitroso-group phenyl)-3-morpholone mai (IV) is generated 4-(4-aminophenyl)-3-morpholone mai (V) by catalytic hydrogenating reduction
(2) by 4-(4-aminophenyl)-3-morpholone mai (V) and the chloro-N-of 5-(2-oxiranylmethyl radical)-2-thenoyl amine (VII) reaction generate 5-chlorothiophene-2-{ (R)-2-hydroxyl-3-[4-(3-oxomorpholin-4-base) phenyl amino-propyl group } acid amides (VIII);
(3) by 5-chlorothiophene-2-{ (R)-2-hydroxyl-3-[4-(3-oxomorpholin-4-base) phenyl amino-propyl group } acid amides (VIII) and carbonyl dimidazoles (CDI) etc. be obtained by reacting razaxaban (VI).
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| CN104788444A (en) * | 2015-05-12 | 2015-07-22 | 浙江天顺生物科技有限公司 | Preparation method of rivaroxaban |
| CN104788444B (en) * | 2015-05-12 | 2018-11-06 | 浙江天顺生物科技有限公司 | The preparation method of razaxaban |
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| CN112110910A (en) * | 2019-06-19 | 2020-12-22 | 上海特化医药科技有限公司 | Method for preparing rivaroxaban intermediate and method for preparing rivaroxaban by using same |
| CN112110910B (en) * | 2019-06-19 | 2024-03-19 | 上海特化医药科技有限公司 | Method for preparing rivaroxaban intermediate and method for preparing rivaroxaban from rivaroxaban intermediate |
| CN110407841A (en) * | 2019-08-20 | 2019-11-05 | 东华大学 | A kind of synthetic method of anti-tumor drug Rui Boxini |
| CN114014820A (en) * | 2021-12-18 | 2022-02-08 | 南京焕然生物科技有限公司 | Preparation method of 4- (4-aminophenyl) -3-morpholinone |
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