CN104650057B - A method of preparing razaxaban - Google Patents
A method of preparing razaxaban Download PDFInfo
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- CN104650057B CN104650057B CN201310592103.7A CN201310592103A CN104650057B CN 104650057 B CN104650057 B CN 104650057B CN 201310592103 A CN201310592103 A CN 201310592103A CN 104650057 B CN104650057 B CN 104650057B
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- C—CHEMISTRY; METALLURGY
- 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
- C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
Abstract
The present invention relates to a kind of methods for preparing razaxaban, including by the 4- of Formula II 4- [(5S) -5-(amino methyl) -2- oxo -1, 3- oxazolidine -3- base] phenyl } morpholine -3- ketone or its salt, it is being selected from 2, 4, 6- tri- chloro- 1, 3, 5- triazine (TCT), 4, 6, dimethoxy -2- chloro- 1, 3, 5- triazine, 2- methoxyl group -4, 6- bis- chloro- 1, 3, 5- triazine, 4, 6,-two Bian oxygroup -2- chloro- 1, 3, 5- triazine and 4, 6,-two phenoxy group -2- chloro- 1, 3, in the presence of the condensing agent of 5- triazine, it reacts and is made with the chloro- thiophene -2-carboxylic acid of the 5- of formula III in the system containing organic base.This method is easy to operate practical, inexpensive, in high yield and environmental protection, raw material are easy to get, post-processs simple, yield and purity is greatly improved, suitable large-scale industrial production.
Description
Technical field
The invention belongs to field of medicinal chemistry, and in particular to a method of prepare razaxaban.
Background technique
Deep vein thrombosis (DVT) is commonly formed in pelvis or deep veins of lower limb, and usual symptom is unobvious, but thrombus division stream
Pulmonary embolisms can be caused by entering lung, serious to can lead to death.DVT is common in surgical operation, long-term inpatients patient and long-distance trip
Passerby.Razaxaban (formula I) is by first, the whole world direct inhibitor of Xa of Bayer and Johson & Johnson's joint development, it can be quick
Reverse transcriptase Xa, inhibition thrombosis reach anticoagulation.In October, 2008 is first in Canada and European Union
City, U.S. FDA in 2009 agree to its clinical data significance, and the second half year in the same year is visitd auspicious appropriate in Discussion on Chinese Listed with trade name.Benefit
It is high to cut down husky class's oral administration biaavailability, liver and kidney tolerance are good.Existing clinic is mainly used for treating acute deep venous thrombosis
(DVT), prevent postoperative acute deep venous thrombosis.
Patent WO0147919 makes public for the first time the chemical structure and preparation method of razaxaban, and synthetic route is as follows:
4- in this method { 4- [(5S) -5-(amino methyl) -2- oxo -1,3- oxazolidine -3- base] phenyl } morpholine -3- ketone
(II) and chloro- thiophene -2- formyl chloride (IV) reaction in pyridine of 5- prepares razaxaban (I).Pyridine is more toxic, as molten
Agent is highly detrimental to industrialized production.In addition, this method products obtained therefrom demand pole chromatographic purifying, it is clear that be also not suitable for commercial scale
Metaplasia produces.
Patent WO2005068456 also discloses a kind of method for preparing razaxaban, first by 4- { 4- [(5S) -5-(amino
Methyl) -2- oxo -1,3-oxazoles alkane -3- base] phenyl } morpholine -3- ketone (II) is prepared into hydrochloride (Ⅸ), then by hydrochloride
(Ⅸ) it is reacted in acetone and water equal solvent with the chloro- thiophene -2- formyl chloride (IV) of 5-, does acid binding agent with inorganic bases such as sodium carbonate,
This method optimizes industrial process conditions, reduces costs, but the route has continued to use the chloro- thiophene -2- formyl chloride of 5-, due to
Formula IV needs are prepared in situ by the chloro- thiophene -2- formic acid (III) of 5- and thionyl chloride, and the damage to equipment is larger, therefore, the road
Line exists obvious insufficient.
Patent CN102746288, patent WO2012035057, patent WO2013053739 and WO2013098833 also divide
It is other to 4- { 4- [(5S) -5-(amino methyl) -2- oxo -1,3- oxazolidine -3- base] phenyl } morpholine -3- ketone (II) at salt
Form and acid binding agent are optimized, but the constraint without being detached from the chloro- thiophene -2- formyl chloride (IV) of 5-.
Patent WO2013118130 disclose by 4- 4- [(5S) -5-(amino methyl) -2- oxo -1,3- oxazolidine -3-
Base] phenyl } morpholine -3- ketone (II) and the chloro- thiophene -2- formic acid (III) of 5-, in boric acid and/or substitution or unsubstituted phenyl
It is prepared under boric acid catalysis razaxaban (I), this method has abandoned the preparation of the acyl chlorides of formula IV, but boric acid and replaces or do not take
The phenylboric acid price in generation is higher, and the reaction time is too long, and yield is not high, without cost advantage.
。
Summary of the invention
The object of the present invention is to provide a kind of methods for preparing razaxaban, and this method overcomes of the existing technology
Problem such as avoids the problems such as being prepared in situ of the acyl chlorides of toxic solvent pyridine and formula IV, method of the invention reality easy to operate
With, low cost, in high yield and environmental protection, raw material be easy to get, post-process simply, yield and purity be greatly improved, be suitble to extensive work
Industry metaplasia produces.
To achieve the purpose of the present invention, the scheme of being implemented as follows is provided.
In one embodiment, a kind of method preparing razaxaban (I) of the invention, including by 4- { 4- [(5S) -5-
(amino methyl) -2- oxo -1,3-oxazoles alkane -3- base] phenyl } morpholine -3- ketone or its salt (Formula II compound), 2,4 are being selected from,
The chloro- 1,3,5- triazine (TCT) of 6- tri-, 4,6, the chloro- 1,3,5- triazine (CDMT) of-dimethoxy -2-, 2- methoxyl group -4,6- two are chloro-
1,3,5- triazine, 4,6, the chloro- 1,3,5- triazine of-two Bian oxygroup -2- and 4,6, the condensation of the chloro- 1,3,5- triazine of-two phenoxy group -2-
In the presence of agent, reacts and is made with the chloro- thiophene -2-carboxylic acid of the 5- of formula III in the system containing organic base, reaction equation is as follows:
In the above-described embodiment, method of the invention, and the 4- { 4- [(5S) -5-(amino methyl) -2- oxo -1,3-
Oxazolidine -3- base] phenyl } salt of morpholine -3- ketone includes inorganic acid salt or acylate, wherein and the inorganic acid salt includes
Hydrochloride, sulfate, sulphite, phosphate, phosphite or nitrate, preferably hydrochloride；The acylate includes first
Hydrochlorate, acetate, propionate, trifluoroacetate, mesylate, benzene sulfonate, tosilate, mandelate, oxalates,
Maleate, succinate, fumarate, malate, citrate, tartrate, lactate, benzoate, naphthalene diacid
Salt or succinate, preferably formates.
In the above-described embodiment, method of the invention, the organic base include triethylamine, diethylamine, diisopropyl second
Amine, N-methylmorpholine, N-methylcyclohexylamine or N, N- dimethyl aminopyridine, preferably N-methylmorpholine (NMM) or triethylamine.
In the above-described embodiment, method of the invention, still further comprises reaction dissolvent, and the reaction dissolvent includes two
First sulfoxide, N,N-dimethylformamide, methylene chloride, chloroform, tetrahydrofuran, dioxane, acetonitrile, propionitrile, ethyl acetate, vinegar
Isopropyl propionate, n-butyl acetate or their mixing, preferably n,N-Dimethylformamide, methylene chloride or their mixture.
In the above-described embodiment, method of the invention, the condensing agent be 2,4,6- tri- chloro-1,3,5-triazines (TCT),
Bis- chloro-1,3,5-triazines of 4,6,-dimethoxy -2- chloro-1,3,5-triazines (CDMT) or 2- methoxyl group -4,6-, more preferably 2,
4,6- tri- chloro-1,3,5-triazines (TCT) or 4,6,-dimethoxy -2- chloro-1,3,5-triazines.
In the embodiment above, the molar ratio of condensing agent and Formula II compound is at least 1.01:1, organic base and Formula II
The molar ratio for closing object is at least 1.01:1.
In one embodiment, a kind of method preparing razaxaban of the invention, comprising:
By 4- { 4- [(5S) -5-(amino methyl) -2- oxo -1,3- oxazolidine -3- base] phenyl } morpholine -3- ketone (II)
Or its salt is reacted with the chloro- thiophene -2-carboxylic acid of 5- (III) in reaction dissolvent and is obtained in the presence of condensing agent and organic base,
In, the condensing agent is 2,4,6- tri- chloro-1,3,5-triazines (TCT), 4,6,-dimethoxy -2- chloro-1,3,5-triazines (CDMT)
Or the chloro- 1,3,5- triazine of 2- methoxyl group -4,6- two.Reaction equation is as follows:
。
In above-mentioned specific embodiment, method of the invention, wherein 4,6,-dimethoxy -2- chloro-1,3,5-triazines
(CDMT) it is one of the derivative of 2,4,6- tri- chloro-1,3,5-triazines (TCT), both prepares the common coupling of one kind of peptide bond
Agent can be bought by commercial sources.
In above-mentioned specific embodiment, method of the invention, the 4- { 4- [(5S) -5-(amino methyl) -2- oxo -
1,3-oxazoles alkane -3- base] phenyl } salt of morpholine -3- ketone includes inorganic acid salt or acylate, wherein the inorganic acid salt
Including hydrochloride, sulfate, sulphite, phosphate, phosphite or nitrate etc., preferably hydrochloride, the acylate
Including formates, acetate, propionate, trifluoroacetate, mesylate, benzene sulfonate, tosilate, mandelate,
Oxalates, maleate, succinate, fumarate, malate, citrate, tartrate, lactate, benzoate,
Naphthalene diacid salt or succinate etc., preferably formates.
In above-mentioned specific embodiment, method of the invention, the organic base includes triethylamine, diethylamine, diisopropyl
Base ethamine, N-methylmorpholine, N-methylcyclohexylamine or N, N- dimethyl aminopyridine, preferably N-methylmorpholine (NMM), triethylamine
Or their mixture.
In above-mentioned specific embodiment, method of the invention, the solvent includes dimethyl sulfoxide, N, N- dimethyl formyl
Amine, methylene chloride, chloroform, tetrahydrofuran, dioxane, acetonitrile, propionitrile, ethyl acetate, isopropyl acetate, n-butyl acetate or
Their mixture of person, preferably n,N-Dimethylformamide, methylene chloride or their mixture.
In above-mentioned specific embodiment, the molar ratio of condensing agent and Formula II compound is at least 1.01:1, organic base and formula
The molar ratio of II compound is at least 1.01:1.
In a preferred embodiment, a kind of method preparing razaxaban of the invention, comprising:
By 4- { 4- [(5S) -5-(amino methyl) -2- oxo -1,3- oxazolidine -3- base] phenyl } morpholine -3- ketone (II)
Or its hydrochloride or formates, in the presence of condensing agent and organic base N-methylmorpholine (NMM) or triethylamine, in reaction dissolvent
N,N-Dimethylformamide, methylene chloride or its in the mixed solvent are reacted with the chloro- thiophene -2-carboxylic acid of 5- (III) and are obtained, wherein institute
State condensing agent be 2,4,6- tri- chloro-1,3,5-triazines (TCT) or 4,6,-dimethoxy -2- chloro-1,3,5-triazines (CDMT).
For the method provided by the invention for preparing razaxaban using cheap TCT and CDMT as condensing agent, reaction yield is high,
The problem of purity is high, also there is no racemizations, post-processing is simple, reduces costs, and is suitble to large-scale industrial production.
Specific embodiment
Following embodiment is not limited the scope of the invention for furtheing elucidate and understanding the present invention with this.
Embodiment 1
Take 1L three-necked bottle, by the chloro- thiophene -2-carboxylic acid of 26.0g 5-, 50.0g 4- 4- [(5S) -5-(amino methyl) -2-
Oxo -1,3- oxazolidine -3- base] phenyl } morpholine -3- keto hydrochloride and 33.0gCDMT be suspended in 450mL N, N- dimethyl methyl
In amide, the lower mixed solution that 40.0g NMM and 50.0mL n,N-Dimethylformamide composition is added dropwise of ice-water bath stirring, 20 points
Continue stirring 1 hour after being added dropwise in clock, is then warming up to and is stirred at room temperature 1.5 hours or so.Stop stirring, by reaction solution plus
It being beaten, ice bath crystallization, filters into water, decompression drying obtains white solid 63.25g, yield 95.2%, HPLC 99.82%, ee >
99.9%。
Embodiment 2
Take 500mL three-necked bottle, by 5.2g 5- chlor-2-thiophenecar-boxylic acid, 10.0g4- 4- [(5S) -5-(amino methyl) -2-
Oxo -1,3- oxazolidine -3- base] phenyl } morpholine -3- ketone formates and 33.0gCDMT be suspended in 120mL N, N- dimethyl methyl
In amide, the lower mixed solution that 6.8g NMM and 30.0mL n,N-Dimethylformamide composition is added dropwise of ice-water bath stirring, 20 minutes
Continue stirring 1 hour after being inside added dropwise, is then warming up to and the stirring of stopping in 2 hours or so is stirred at room temperature, reaction solution is added to water
Middle mashing, ice bath crystallization, filtering, decompression drying obtain white solid 12.3g, yield 94.8%, HPLC 99.72%, ee > 99.9%.
Embodiment 3
5L three-necked bottle is taken, by the chloro- thiophene -2-carboxylic acid of 104g 5-, 108gCDMT, 178.0g 4- { 4- [(5S) -5-(amino
Methyl) -2- oxo -1,3-oxazoles alkane -3- base] phenyl } morpholine -3- ketone is suspended in 1.5L n,N-Dimethylformamide, ice water
62.4gNMM and 280mL n,N-Dimethylformamide mixed liquor is added dropwise in 1 hour, 20 minutes in bath stirring, then maintains ice-water bath
Then stirring 1 hour is stirred at room temperature the stirring of stopping in 1 hour or so, reaction solution is added in water and is beaten, ice bath crystallization, filtering subtracts
Pressure dries to obtain white solid 252g, yield 94.7%, HPLC 99.70%, ee > 99.9%.
Embodiment 4
Take 1L three-necked bottle, by the chloro- thiophene -2-carboxylic acid of 26.0g 5-, 50.0g4- 4- [(5S) -5-(amino methyl) -2- oxygen
Generation -1,3- oxazolidine -3- base] phenyl } morpholine -3- keto hydrochloride and 10.3gTCT be suspended in 450mL N,N-dimethylformamide
In, the lower mixed solution that 40.0g NMM and 50.0mL n,N-Dimethylformamide composition is added dropwise of ice-water bath stirring, in 20 minutes
Continue stirring 1 hour after being added dropwise, is then warming up to and is stirred at room temperature 1 hour or so.Stop stirring, reaction solution is added in water
Mashing, ice bath crystallization, filtering, decompression drying obtain white solid 62.01g, yield 93.2%, HPLC 99.43%, ee > 99.9%.
Embodiment 5
2L three-necked bottle is taken, the chloro- thiophene -2-carboxylic acid of 54g 5-, 53.3gCDMT, 80.0gNMM are suspended in 500.0mL dichloro
Methane and 100.0mL n,N-Dimethylformamide in the mixed solvent, ice-water bath stirs to be added several times in 1 hour, 20 minutes
100.0g 4- { 4- [(5S) -5-(amino methyl) -2- oxo -1,3- oxazolidine -3- base] phenyl } morpholine -3- keto hydrochloride powder
End, ice-water bath stirs 40 minutes after charging, is warming up to and is stirred at room temperature 1.5 hours or so, by reaction solution and 2L methylene chloride,
3L water is sufficiently mixed, and separates organic phase, and water phase is extracted twice with 1L methylene chloride, merges organic phase, then with 3L unsaturated carbonate hydrogen
Sodium water solution washs 2 times, and 5L is washed 1 time, and organic phase is 2 hours dry with anhydrous sodium sulfate, then filters, is evaporated to obtain crude product
122.3g, yield 92.2%, HPLC 97.2%, ee > 99.9%.
Embodiment 6
Take 500mL three-necked bottle, by the chloro- thiophene -2-carboxylic acid of 5.2g 55-, 10.0g4- 4- [(5S) -5-(amino methyl) -
2- oxo -1,3- oxazolidine -3- base] phenyl } morpholine -3- keto hydrochloride and 33.0gCDMT be suspended in 120mL N, N- dimethyl
In formamide, the lower mixed solution that 6.8g triethylamine and 30.0mL n,N-Dimethylformamide composition is added dropwise of ice-water bath stirring,
Continue stirring 1 hour after being added dropwise in 20 minutes, is then warming up to and is stirred at room temperature.HPLC monitors 10.0g4- { 4- [(5S) -5-
(amino methyl) -2- oxo -1,3-oxazoles alkane -3- base] phenyl } the stopping stirring of morpholine -3- keto hydrochloride end of reaction, it will react
Liquid is added in water and is beaten, ice bath crystallization, and filtering, decompression drying obtains white solid 11.5g, yield 86.5%, HPLC 99.65%, ee
>99.9%。
Claims (10)
1. a kind of method of the razaxaban of preparation formula I, including by the 4- of Formula II 4- [(5S) -5-(amino methyl) -2- oxo -
1,3-oxazoles alkane -3- base] phenyl } morpholine -3- ketone (II) or its salt, it is being selected from 2,4,6- tri- chloro-1,3,5-triazines, 4,6,-two
Methoxyl group -2- chloro-1,3,5-triazines, bis- chloro-1,3,5-triazines of 2- methoxyl group -4,6- condensing agent in the presence of, having
It reacts and is made with the chloro- thiophene -2-carboxylic acid of the 5- of formula III in the system of machine alkali,
。
2. according to the method described in claim 1, the salt is inorganic acid salt or acylate.
3. according to the method described in claim 2, the inorganic acid salt is hydrochloride, sulfate, sulphite, phosphate, Asia
Phosphate or nitrate.
4. according to the method described in claim 2, the acylate be formates, acetate, propionate, trifluoroacetate,
Mesylate, benzene sulfonate, tosilate, mandelate, oxalates, maleate, succinate, fumarate, apple
Tartaric acid salt, citrate, tartrate, lactate, benzoate, naphthalene diacid salt or succinate.
5. according to the method described in claim 1, the salt is hydrochloride or formates.
6. according to the method described in claim 1, the organic base is triethylamine, diethylamine, diisopropylethylamine, N- methyl
Quinoline, N-methylcyclohexylamine, N, N- dimethyl aminopyridine or pyridine.
7. according to the method described in claim 6, the organic base is N-methylmorpholine or triethylamine.
8. the reaction dissolvent is dimethyl sulfoxide, N, N- diformazan according to the method described in claim 1, further including reaction dissolvent
Base formamide, methylene chloride, chloroform, tetrahydrofuran, dioxane, acetonitrile, propionitrile, ethyl acetate, isopropyl acetate, acetic acid are just
Butyl ester or their mixture.
9. according to the method described in claim 8, reaction dissolvent is n,N-Dimethylformamide, methylene chloride or theirs is mixed
Close object.
10. according to the method described in claim 1, the molar ratio of condensing agent and Formula II compound is at least 1.01:1, organic base
It is at least 1.01:1 with the molar ratio of Formula II compound.
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| CN108250193B (en) * | 2018-01-09 | 2021-05-28 | 江苏中邦制药有限公司 | Method for preparing rivaroxaban by one-pot method |
| CN110172060A (en) * | 2018-12-27 | 2019-08-27 | 苏州二叶制药有限公司 | Razaxaban, synthesis and refining methd |
| CN114989159A (en) * | 2022-07-11 | 2022-09-02 | 天津力生制药股份有限公司 | Synthetic method of rivaroxaban |
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