CN103965184A - Synthesis method for rivaroxaban intermediate - Google Patents

Synthesis method for rivaroxaban intermediate Download PDF

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CN103965184A
CN103965184A CN201410157927.6A CN201410157927A CN103965184A CN 103965184 A CN103965184 A CN 103965184A CN 201410157927 A CN201410157927 A CN 201410157927A CN 103965184 A CN103965184 A CN 103965184A
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张席妮
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Fang Nan Bio Tech Ltd Shanghai
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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/10—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing aromatic rings
    • C—CHEMISTRY; METALLURGY
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    • C07F9/02—Phosphorus compounds
    • C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
    • C07F9/6558—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing at least two different or differently substituted hetero rings neither condensed among themselves nor condensed with a common carbocyclic ring or ring system
    • C07F9/65583—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing at least two different or differently substituted hetero rings neither condensed among themselves nor condensed with a common carbocyclic ring or ring system each of the hetero rings containing nitrogen as ring hetero atom
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    • Y02P20/00—Technologies relating to chemical industry
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    • Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

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Abstract

The invention discloses a synthesis method for a rivaroxaban intermediate. The method comprises the following steps: converting a hydroxide radical of a compound V into a high-activity leaving group so as to generate a compound IV; enabling a nucleophilic reagent W1(NH)W2 to form nitrogen anions under existence of alkali, and enabling the nitrogen anions to react with the compound IV so as to obtain a compound III; enabling the compound III to be subjected to a protecting group removing reaction to obtain a rivaroxaban intermediate compound II, namely 4-(4-((5S)-5-(aminomethyl)-2-oxo-1,3-oxazolidine-3-radical) phenyl) morpholine-3-ketone or salt thereof. The new method provided by the invention is mild in reaction conditions, simple to operate, convenient in purification, low in production cost, environment-friendly and suitable for industrial production.

Description

A kind of synthetic method of razaxaban intermediate
Technical field
The present invention relates to the synthetic method of anticoagulation medicine razaxaban intermediate, relate to particularly the synthetic method of razaxaban intermediate 4-(4-((5S)-5-(amino methyl)-2-oxo-1,3-oxazolidine-3-yl) phenyl) morpholine-3-ketone and salt thereof.
Background technology
Razaxaban (Rivaroxaban), chemical name is the chloro-N-of 5-(((5S)-2-oxo-3-(4-(3-oxo-4-morpholinyl) phenyl)-1,3-oxazolidine-5-yl) methyl-2-thenoyl amine, its structure as shown in the formula (I):
Razaxaban (Rivaroxaban) is the anticoagulation medicine of researched and developed by Bayer A.G a kind of novel, highly selective, and English name is , and obtain EU Committee's license listing in September, 2008.Razaxaban contestable suppresses Xa factor and the prothrombin activity of free and combination, extend prothrombin time (PT) and activated partial thromboplastin time (APTT) in dosage dependence mode, for preventing the formation of hip joint and knee prosthesis postoperative patient person deep venous thrombosis (DVT) and pulmonary infarction (PE).
Along with the clinical application of razaxaban, will increase gradually the demand of razaxaban.
European patent WO2005068456 discloses the method for synthetic Rivaroxaban a kind of.
European patent WO0147919 and WO2005068456 disclose the aminophenyl with compound 4-(4-)-morpholine-3-ketone and 2-((2S)-2-Oxyranyle-methyl)-1-H-isoindole-1,3 (2H)-diketone are the method that starting raw material is prepared Rivaroxaban, and reactions steps is as follows:
The subject matter of the method is: the chiral centre in razaxaban molecular structure is by 2-((2S)-2-Oxyranyle-methyl)-1-H-isoindole-1,3 (2H)-diketone are introduced, and this intermediate prepares with (S)-2-chloro propylene oxide and phthalic imidine industrial.As everyone knows, (S)-2-chloro propylene oxide is highly toxic product, and industrial use is subject to a lot of restrictions.On Ling Wai ， oxazolidone ring, nitrogen-atoms is protected by phthalic imidine, need further slough protecting group with aqueous methylamine solution, and aqueous methylamine solution should not use on a large scale because of its toxicity and the character such as explosive.
For finding safer synthetic route, avoid using the toxic reagents such as chloro propylene oxide, methylamine in recent years, many variation routes are reported in succession.
Patent WO2011080341 discloses a 4-(4-aminophenyl taking carbobenzoxy-(Cbz) protection)-morpholine-3-ketone is the route of starting raw material:
Chiral centre in this Lu Xian oxazole ring is introduced by (R)-Glycidyl butyrate, avoids using poisonous chloro propylene oxide.But this route uses TERTIARY BUTYL AMINE as nitrogenous source, generate intermediate 4-(4-((5S)-5-(tertiary fourth amino methyl)-2-oxo-1,3-oxazolidine-3-yl) phenyl) after morpholine-3-ketone again with the condensation of 5-chlorothiophene carboxylic acid chloride, the yield of condensation reaction and purity are not high, finally also need under strong acidic condition, remove the tertiary butyl and obtain razaxaban.Therefore the step of whole piece route is more, and cost is also higher, is not suitable for suitability for industrialized production.
Patent WO2013098833 also discloses one taking 4-(4-aminophenyl)-morpholine-3-ketone is the route of starting raw material:
Although this route also utilizes the chiral centre in (R)-Glycidyl butyrate Yin Ru oxazole ring, avoid using poisonous chloro propylene oxide, but simultaneously again using phthalic imidine as nitrogenous source, still can bring because using methylamine safety problem.
Patent WO2013105110 also discloses one taking 4-(4-aminophenyl)-morpholine-3-ketone is the route of starting raw material:
This route provides 3 kinds of nitrogenous sources, is respectively azido-, dibenzylamine and ammoniacal liquor.Ammoniacal liquor is nucleophilic reagent the most, although cheap and easy to get, reaction is difficult to control, and tends to generate the by products such as secondary amine, tertiary amine and quaternary ammonium salt, and reaction yield is not high.Metal azide is as nucleophilic reagent, and yield and the purity of reaction are higher, and shortcoming is that metal azide itself is hazardous agents, has very large potential safety hazard, and next step can use palladium charcoal that price is higher as catalyzer, and cost is higher.Use dibenzylamine as nucleophilic reagent, can produce equally the by products such as quaternary ammonium salt, reaction yield is not high, and next step can use palladium charcoal as catalyzer, and cost is higher.
Therefore, find the synthesis technique of safer, effective and cheap razaxaban, reduce the price of bulk drug, will produce larger pushing effect to the promotion and application of razaxaban.
Summary of the invention
The object of this invention is to provide a kind of synthetic razaxaban intermediate 4-(4-((5S)-5-(amino methyl)-2-oxo-1,3-oxazolidine-3-yl) phenyl } method of morpholine-3-ketone and salt thereof, reaction conditions gentleness, simple to operate, be convenient to purifying, low production cost, environmentally friendly and applicable suitability for industrialized production.
For achieving the above object, technical scheme of the present invention is:
A synthetic method for razaxaban intermediate II, the steps include:
A) hydroxyl of compound V is changed into highly active leavings group, generate compound IV;
B) nucleophilic reagent W 1(NH) W 2under the effect of alkali, form nitrogen anion, then react and obtain compound III with compound IV;
C) compound III obtains Compound I I by deprotection radical reaction, i.e. 4-(4-((5S)-5-(amino methyl)-2-oxo-1,3-oxazolidine-3-yl) phenyl) morpholine-3-ketone or its salt;
Its reaction formula is as follows:
Further, in described method, the leavings group L of step a) compound IV is halogen or sulphonate-OSO 2r, wherein halogen is selected from chlorine, bromine or iodine, and R is selected from C 1-C 6alkyl, replacement or unsubstituted aromatic base.
Again further, the nucleophilic reagent W of step b) in described method 1(NH) W 2w 1and W 2be respectively the one being selected from carbonic acyl radical, carbalkoxy, trialkyl silyl or dialkoxy phosphoryl, W 1and W 2can be identical, also can be different.
Preferably, the nucleophilic reagent W of step b) in described method 1(NH) W 2for hexamethyldisilazane, succimide, N-formyl radical methane amide, two (tertbutyloxycarbonyl) amine, N-tertbutyloxycarbonyl oxalic acid acid amides ethyl ester, N-(tert.-butoxy carbonyl acyl) phosphorus propylhomoserin diethyl ester or O, the trimethyl silicon based acid amides of O-diethyl phosphoric acid-N-.
Further, in described method, step c) can be selected comparatively gentle method according to different groups, the nucleophilic reagent W in step b) when deprotection base 1(NH) W 2for being selected from hexamethyldisilazane, N-formyl radical methane amide, succimide, two (tertbutyloxycarbonyl) amine, N-tertbutyloxycarbonyl oxalic acid acid amides ethyl ester, N-(tert.-butoxy carbonyl acyl) phosphorus propylhomoserin diethyl ester or O, when the trimethyl silicon based acid amides of O-diethyl phosphoric acid-N-, protecting group can remove in protonic acid, and corresponding protonic acid is selected from hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid, methylsulphonic acid, tosic acid, Phenylsulfonic acid or trifluoroacetic acid; Succimide also can remove under basic solution condition, and corresponding alkali comprises that alkali metal hydroxide is as sodium hydroxide or potassium hydroxide.
Preferably, in described method, the alkali of step b) is selected from alkali-metal carbonate, metal hydroxides, metal hydride, metal alkoxide or metal aikylide.
Further, described alkali-metal carbonate is preferably sodium carbonate, salt of wormwood or cesium carbonate, metal hydroxides is preferably potassium hydroxide or sodium hydroxide, metal hydride is preferably sodium hydride or potassium hydride KH, metal alkoxide is preferably sodium methylate, sodium ethylate, potassium tert.-butoxide or trimethyl carbinol lithium, and metal aikylide is preferably n-Butyl Lithium, lithium methide or phenyl lithium.
The present invention also provides a kind of compound as shown in formula III:
W 1and W 2be respectively and be selected from carbonic acyl radical, carbalkoxy, trialkyl silyl or dialkoxy phosphoryl, W 1and W 2identical or different, but W 1(NH) W 2it is not phthalic imidine.
Further, the W of the compound shown in formula III 1(NH) W 2for being selected from hexamethyldisilazane, succimide, N-formyl radical methane amide, two (tertbutyloxycarbonyl) amine, N-tertbutyloxycarbonyl oxalic acid acid amides ethyl ester, N-(tert.-butoxy carbonyl acyl) phosphorus propylhomoserin diethyl ester or O, the one in the trimethyl silicon based acid amides of O-diethyl phosphoric acid-N-.
Synthetic razaxaban midbody compound II provided by the invention, it is 4-(4-((5S)-5-(amino methyl)-2-oxo-1, 3-oxazolidine-3-yl) phenyl) novel method of morpholine-3-ketone, in reaction process, avoid using the chloro propylene oxide of hypertoxicity, the reaction substrates such as the noble metal catalyst palladium carbon of explosive triazo-compound and costliness, post-reaction treatment process also avoids using methylamine etc. easily to bring the chemical of safety issue, synthesising method reacting condition gentleness of the present invention, simple to operate, be convenient to purifying, low production cost, environmentally friendly and applicable suitability for industrialized production.
Embodiment
In order further to understand the present invention, below in conjunction with embodiment, the preferred embodiment of the invention is described, but should be appreciated that these are described is for further illustrating the features and advantages of the present invention, instead of limiting to the claimed invention.
Embodiment 1
1. compound IV a(L=OSO 2me) preparation, reaction formula is as follows:
Compound V is by 4-(4-aminophenyl)-morpholine-3-ketone makes, and its preparation method is identical with the disclosed method of WO2013105110.
At 0 DEG C, to compound V(4-(4-((5R)-5-(hydroxymethyl)-2-oxo-1,3-oxazolidine-3-yl) phenyl) morpholine-3-ketone) (0.47g, in anhydrous methylene chloride (30mL) solution 1.6mmol), drip triethylamine (0.67mL), and add subsequently Methanesulfonyl chloride (0.16mL), mixture was stirring at room temperature 4 hours, solution is water, saturated common salt water washing respectively, organic layer is through anhydrous sodium sulfate drying, and vacuum-concentrcted obtains compound IV a(0.5g).Product need not purifying, is directly used in next step reaction.
2. compound III a(W 1(NH) W 2for two (tertbutyloxycarbonyl) amine) preparation, reaction formula is as follows:
By two (tertbutyloxycarbonyl) amine (0.33g, 1.5mmol), the compound IV a(4-(4-(R of the 1st step gained)-5-(mesyloxy methyl)-2-Yang Dai oxazolidine-3-yl) phenyl) morpholine-3-ketone) (0.38g, 1.0mmol) and cesium carbonate (0.49g, 1.5mmol) add in 10mLDMSO, this mixing solutions is heated to 80oC, stirring reaction 4 hours, to be cooled to room temperature, add 50mL water, extracted with diethyl ether (50mL × 3), merge organic phase, anhydrous sodium sulfate drying, vacuum concentration, crude product obtains white solid IIIa(0.36g through column chromatography (100% ethyl acetate), two step yields 73%). 1HNMR（600MHz，CDCl 3）δ7.58(d,J=9.0Hz,2H),7.35(d,J=8.4Hz,2H),4.86-4.90(m,1H),4.35(s,2H),4.04-4.10(m,4H),3.88-3.91(m,1H),3.81-3.83(m,1H),3.75(t,J=4.8Hz,2H),1.52(s,18H); 13CNMR（150MHz，CDCl 3）δ166.8,154.2,152.5,137.1,136.9,126.2,118.9,83.4,71.0,68.6,64.1,49.7,48.4,48.0,28.0;LC-MS(ESI)m/z492[M+1]。
3. the preparation of Compound I I, reaction formula is as follows:
The compound III a(0.123g that the 2nd step is obtained, 0.25mmol) be dissolved in methylene dichloride (5.0mL), add wherein trifluoroacetic acid (0.5mL), this mixture stirring at room temperature 2 hours, after vacuum concentration, add wherein methylene dichloride (5.0mL), again concentrated, repeat after this operation 3 times, add methylene dichloride (20mL), in this solution, add 10% sodium hydroxide solution (10mL) neutralization, separatory, methylene dichloride for water (10 × 3mL) extraction, merge organic phase, after anhydrous sodium sulfate drying, after vacuum concentration is dry, obtain product compound II(0.071g, yield 97%. 1HNMR（600MHz，CDCl 3）δ7.60(d,J=9.0Hz,2H),7.34(d,J=8.4Hz,2H),4.66-4.70(m,1H),4.34(s,2H),4.03-4.07(m,4H),3.86-3.88(m,1H),3.81-3.83(m,1H),3.75-3.76(m,2H),3.10-3.13(m,1H),2.96-3.00(m,1H),1.40(brs,2H); 13C（150MHz，CDCl 3）NMRδ166.8,154.7,137.0,136.9,126.2,118.9,73.9,68.6,64.1,49.7,47.6,44.9;LC-MS(ESI)m/z292[M+1]。
Embodiment 2
1. compound IV b(L=I) preparation, reaction formula is as follows:
The preparation method of Compound I va is with embodiment 1 the 1st step, by oily matter compound IV a(0.5g) be dissolved in acetone (5mL), then add sodium iodide (0.28g, 1.76mmol), reflux 4 hours.Reaction mixture is concentrated into dry, add again methyl tertiary butyl ether (10mL), organic layer is used respectively saturated sodium thiosulfate solution (10mL) and saturated common salt water washing (10mL), and by dried over sodium sulfate, filtering and concentrating obtains light yellow solid IVb(0.59g, yield 92%), LC-MS (ESI) m/z403[M+1].Crude product is not purified, can be directly used in next step.
2. Compound I I and compound III b(W 1(NH) W 2for N-formyl radical methane amide) preparation, reaction formula is as follows:
N-formyl radical methane amide sodium is according to document Synthesis, prepared by the method in 1990,122-124.
By the compound IV b(2.0g, the 5.0mmol that are prepared by embodiment 2 the 1st step) be dissolved in tetrahydrofuran (THF) (40mL), add N-formyl radical methane amide sodium (0.7g, 7.5mmol), reflux 3 hours.Get 2mL reaction solution, the hydrochloric acid with 1N after water cancellation regulates pH=7, is extracted with ethyl acetate, is dried and concentrate, and after purifying, obtains a small amount of solid chemical compound IIIb for Structural Identification with rapid column chromatography, 1hNMR(600MHz, CDCl 3) δ 9.20 (s, 2H), 7.58 (d, J=9.0Hz; 2H), 7.35 (d, J=8.4Hz, 2H); 4.86-4.90 (m, 1H), 4.35 (s, 2H); 4.04-4.10 (m, 4H), 3.88-3.90 (m; 1H), 3.82-3.84 (m, 1H); (3.75 t, J=4.8Hz, 2H); LC-MS (ESI) m/z438[M+1].
Above-mentioned residue reaction mixture is chilled to room temperature, adds concentrated hydrochloric acid (20mL) cancellation reaction, and vacuum concentration removes tetrahydrofuran (THF), resistates adds ethanol (40mL) crystallization, and obtaining white solid is the hydrochloride (1.56g, yield 84%) of Compound I I.
Embodiment 3
Compound III c(W 1(NH) W 2for N-tertbutyloxycarbonyl oxalic acid acid amides ethyl ester) and the preparation of Compound I I, reaction formula is as follows:
N-tertbutyloxycarbonyl oxalic acid acid amides ethyl ester is according to document The Journal of Organic Chemistry, prepared by the method in 2000,5469-5475.
By the compound IV b(L=I being prepared by embodiment 2 the 1st step) (2.0g, 5.0mmol) be dissolved in tetrahydrofuran (THF) (40mL), add N-tertbutyloxycarbonyl oxalic acid acid amides ethyl ester (1.6g, 7.4mmol) and sodium methylate (0.43g, 7.9mmol), reflux 3 hours.Get 2mL reaction solution, the hydrochloric acid with 1N after water cancellation regulates pH=7, is extracted with ethyl acetate, is dried and concentrate, and after purifying, obtains a small amount of solid chemical compound IIIc for Structural Identification with rapid column chromatography, 1hNMR(600MHz, CDCl 3) δ 7.58 (d, J=9.0Hz, 2H), 7.35 (d, J=8.4Hz; 2H), 4.86-4.90 (m, 1H), 4.35 (s, 2H); 4.24 (t, J=8.4Hz, 2H), 4.04-4.10 (m, 4H); 3.86-3.88 (m, 1H), 3.78-3.80 (m, 1H); 3.74 (t, J=4.8Hz, 2H), 1.49 (s; 9H), 1.29 (t, J=8.4Hz, 3H); LC-MS (ESI) m/z476[M+1].
Above-mentioned residue reaction mixture is chilled to room temperature, adds concentrated hydrochloric acid (20mL) cancellation reaction, and vacuum concentration removes tetrahydrofuran (THF), resistates adds ethanol (40mL) crystallization, and obtaining white solid is the hydrochloride (1.2g, yield 73%) of Compound I I.
Embodiment 4
Compound III d(W 1(NH) W 2for N-(tert.-butoxy carbonyl acyl) phosphorus propylhomoserin diethyl ester) and the preparation of Compound I I
N-(tert.-butoxy carbonyl acyl) phosphorus propylhomoserin diethyl ester is according to document Synthesis, prepared by the method in 1982,922-924.
At 0 DEG C, to compound V(4-(4-((5R)-5-(hydroxymethyl)-2-oxo-1,3-oxazolidine-3-yl) phenyl) morpholine-3-ketone) (4.7g, in anhydrous methylene chloride (30mL) solution 1.6mmol), drip triethylamine (6.7mL), and add subsequently Methanesulfonyl chloride (1.6mL), mixture was stirring at room temperature 4 hours, solution is water, saturated common salt water washing respectively, and organic layer is through anhydrous sodium sulfate drying, and vacuum-concentrcted obtains product IV a(5.0g).By N,N-dimethylacetamide (50mL) dilution for IVa of above-mentioned oily matter, add N-(tert.-butoxy carbonyl acyl) phosphorus propylhomoserin diethyl ester (6.1g, 24mmol) and sodium hydride (0.58g, 24mmol), stirring at room temperature 3 hours.Get 2mL reaction solution, after water cancellation, be extracted with ethyl acetate, be dried and concentrate, after purifying with rapid column chromatography, obtain a small amount of solid chemical compound IIId for Structural Identification, 1hNMR(600MHz, CDCl 3) δ 7.58 (d, J=9.0Hz, 2H), 7.35 (d, J=8.4Hz; 2H), 4.86-4.90 (m, 1H), 4.42 (t, J=8.4Hz; 4H), 4.35 (s, 2H), 4.04-4.10 (m, 4H); 3.88-3.90 (m, 1H), 3.83-3.85 (m, 1H); 3.79 (t, J=4.8Hz, 2H), 1.52 (s; 9H), 1.28 (t, J=8.4Hz, 6H); LC-MS (ESI) m/z528[M+1].
To slowly dripping water (100mL) cancellation reaction in above-mentioned residue reaction mixture, and with 5% salt acid for adjusting pH be 5～6, have Precipitation, filter, and water and methanol wash filter cake, be dried and obtain Compound I I(3.9g, yield 80%).
Embodiment 5
Compound III e(W 1(NH) W 2for O, the trimethyl silicon based acid amides of O-diethyl phosphoric acid-N-) and the preparation of Compound I I, reaction formula is as follows:
O, the trimethyl silicon based acid amides of O-diethyl phosphoric acid-N-is according to document Synthesis, and prepared by the method for 1982,920-922 kind.
At 0 DEG C, to compound V(4-(4-((5R)-5-(hydroxymethyl)-2-oxo-1,3-oxazolidine-3-yl) phenyl) morpholine-3-ketone) (4.7g, in anhydrous methylene chloride (30mL) 16mmol), drip triethylamine (6.7mL), and add subsequently Methanesulfonyl chloride (1.6mL), mixture was stirring at room temperature 4 hours, solution is water, saturated common salt water washing respectively, and organic layer is through anhydrous sodium sulfate drying, and vacuum-concentrcted obtains product compound IV a(5.0g).By tetrahydrofuran (THF) (50mL) dilution for a of above-mentioned oily matter compound IV, add O, the trimethyl silicon based acid amides of O-diethyl phosphoric acid-N-(5.4g, 24mmol) and sodium hydride (0.58g, 24mmol), reflux 3 hours.Get 3mL reaction solution, after water cancellation, be extracted with ethyl acetate, be dried and concentrate, after purifying with rapid column chromatography, obtain a small amount of solid chemical compound IIIe for Structural Identification, 1hNMR(600MHz, CDCl 3) δ 7.58 (d, J=9.0Hz, 2H), 7.35 (d, J=8.4Hz; 2H), 4.86-4.90 (m, 1H), 4.35 (s, 2H); 4.23 (t, J=8.4Hz, 4H), 4.04-4.10 (m, 4H); 3.88-3.90 (m, 1H), 3.81-3.83 (m, 1H); 3.75 (t, J=4.8Hz, 2H), 1.29 (t; J=8.4Hz, 6H), 0.08 (s, 9H); LC-MS (ESI) m/z500[M+1].
To slowly dripping water (100mL) cancellation reaction in above-mentioned residue reaction mixture, and with 5% salt acid for adjusting pH be 5～6, have Precipitation, filter, and water and methanol wash filter cake, be dried and obtain Compound I I(3.3g, yield 71%).
Finally should be noted that, above embodiment is only unrestricted in order to technical scheme of the present invention to be described, although the present invention is had been described in detail with reference to preferred embodiment, those of ordinary skill in the art is to be understood that, can modify or be equal to replacement the technical scheme of invention, and not departing from the spirit and scope of technical solution of the present invention, it all should be encompassed in claim scope of the present invention.

Claims (10)

1. a synthetic method for razaxaban intermediate II, its step is as follows:
A) hydroxyl of compound V is changed into highly active leavings group, generate compound IV;
B) nucleophilic reagent W 1(NH) W 2existence at alkali forms nitrogen anion, then reacts and obtain compound III with compound IV;
C) compound III obtains Compound I I by deprotection radical reaction, i.e. 4-(4-((5S)-5-(amino methyl)-2-oxo-1,3-oxazolidine-3-yl) phenyl) morpholine-3-ketone or its salt;
Its reaction formula is as follows:
2. method according to claim 1, is characterized in that, in step a), the leavings group L of compound IV is halogen or sulphonate-OSO 2r, wherein halogen is selected from chlorine, bromine or iodine, and R is selected from C 1-C 6alkyl, replacement or unsubstituted aromatic base.
3. method according to claim 1, is characterized in that, the W in step b) 1and W 2be respectively the one being selected from carbonic acyl radical, carbalkoxy, trialkyl silyl or dialkoxy phosphoryl, W 1and W 2identical or different.
4. method according to claim 1, is characterized in that, the nucleophilic reagent W in step b) 1(NH) W 2for being selected from hexamethyldisilazane, succimide, N-formyl radical methane amide, two (tertbutyloxycarbonyl) amine, N-tertbutyloxycarbonyl oxalic acid acid amides ethyl ester, N-(tert.-butoxy carbonyl acyl) phosphorus propylhomoserin diethyl ester or O, the one in the trimethyl silicon based acid amides of O-diethyl phosphoric acid-N-.
5. method according to claim 4; it is characterized in that; step c) compound III deprotection radical reaction removes with protonic acid, and wherein protonic acid is the one being selected from hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid, methylsulphonic acid, tosic acid, Phenylsulfonic acid or gifblaar poison.
6. method according to claim 4, is characterized in that, nucleophilic reagent W in step b) 1(NH) W 2during for succimide, step c) compound III deprotection radical reaction is carried out under basic solution condition, and alkali is wherein alkali metal hydroxide sodium hydroxide or potassium hydroxide.
7. method according to claim 1, is characterized in that, the alkali in step b) is the one being selected from alkali-metal carbonate, metal hydroxides, metal hydride, metal alkoxide, metal aikylide.
8. method according to claim 7, it is characterized in that, described alkali-metal carbonate is sodium carbonate, salt of wormwood or cesium carbonate, metal hydroxides is potassium hydroxide or sodium hydroxide, metal hydride is sodium hydride or potassium hydride KH, metal alkoxide is sodium methylate, sodium ethylate, potassium tert.-butoxide or trimethyl carbinol lithium, and metal aikylide is n-Butyl Lithium, lithium methide or phenyl lithium.
9. the compound as shown in formula III:
W 1and W 2be respectively and be selected from carbonic acyl radical, carbalkoxy, trialkyl silyl or dialkoxy phosphoryl,
W 1and W 2identical or different, but W 1(NH) W 2it is not phthalic imidine.
10. compound according to claim 9, is characterized in that, described W 1(NH) W 2for being selected from hexamethyldisilazane, succimide, N-formyl radical methane amide, two (tertbutyloxycarbonyl) amine, N-tertbutyloxycarbonyl oxalic acid acid amides ethyl ester, N-(tert.-butoxy carbonyl acyl) phosphorus propylhomoserin diethyl ester or O, the one in the trimethyl silicon based acid amides of O-diethyl phosphoric acid-N-.
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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN105566310A (en) * 2014-10-15 2016-05-11 常州诺贝朗生物医药科技有限公司 Rivaroxaban intermediate preparation method
CN105777734A (en) * 2014-12-22 2016-07-20 常州方楠医药技术有限公司 Synthetic method of rivaroxaban intermediate

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2013098833A2 (en) * 2011-09-08 2013-07-04 Cadila Healthcare Limited Processes and intermediates for preparing rivaroxaban
CN103360380A (en) * 2013-03-13 2013-10-23 浙江天宇药业股份有限公司 Synthesis method of rivaroxaban, and rivaroxaban intermediate and preparation thereof
CN103524447A (en) * 2013-10-24 2014-01-22 山东铂源药业有限公司 Method for synthesizing rivaroxaban intermediate 4-(4-aminophenyl)-3-molindone

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2013098833A2 (en) * 2011-09-08 2013-07-04 Cadila Healthcare Limited Processes and intermediates for preparing rivaroxaban
CN103360380A (en) * 2013-03-13 2013-10-23 浙江天宇药业股份有限公司 Synthesis method of rivaroxaban, and rivaroxaban intermediate and preparation thereof
CN103524447A (en) * 2013-10-24 2014-01-22 山东铂源药业有限公司 Method for synthesizing rivaroxaban intermediate 4-(4-aminophenyl)-3-molindone

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
高娜娜，等: "利伐沙班衍生物的合成及Ⅹa因子抑制活性", 《中国药科大学学报》 *

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN105566310A (en) * 2014-10-15 2016-05-11 常州诺贝朗生物医药科技有限公司 Rivaroxaban intermediate preparation method
CN105777734A (en) * 2014-12-22 2016-07-20 常州方楠医药技术有限公司 Synthetic method of rivaroxaban intermediate

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