CN105085508B - A kind of method for synthesizing razaxaban key intermediate - Google Patents
A kind of method for synthesizing razaxaban key intermediate Download PDFInfo
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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
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
- C07D209/44—Iso-indoles; Hydrogenated iso-indoles
- C07D209/48—Iso-indoles; Hydrogenated iso-indoles with oxygen atoms in positions 1 and 3, e.g. phthalimide
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D265/00—Heterocyclic compounds containing six-membered rings having one nitrogen atom and one oxygen atom as the only ring hetero atoms
- 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
Abstract
The invention discloses one kind to synthesize razaxaban key intermediate (S) 2 { [base of 2 oxygen 3 (4 (3 oxygen morpholine) phenyl) oxazolidine 5] methyl } iso-indoles 1, the method of 3 diketone, 4 (4 first ammonia alkenyl phenyl) 3 morpholones and (S) { 1 (chloro-carbonic acid ester group) 2 [2 (1,3 dioxy iso-indoles) base] ethyl } halide salt are carried out into ring closure reaction to produce.This method is easy to operate, raw material is easy to get, yield may be up to 90% or so, obtained (S) 2 { [base of 2 oxygen 3 (4 (3 oxygen morpholine) phenyl) oxazolidine 5] methyl } iso-indoles 1,3 diketone purity are good, purity may be up to more than 98%, be suitably applied industrialized production.
Description
Technical field
The invention belongs to chemosynthesis technical field, in particular to one kind synthesis razaxaban key intermediate (S)-
The method of 2- { [2- oxygen -3- (4- (3- oxygen morpholine) phenyl) oxazolidine -5- bases] methyl } iso-indoles -1,3- diketone.
Background technology
DVT, i.e. local blood grumeleuse are formed.Wherein arterial thrombus can cause such as miocardial infarction, apoplexy, acute coronary
Artery syndrome and peripheral arterial disease etc..Arteriovenous thrombus is the first cause of the morbidity and the death that trigger angiocardiopathy,
It is also one of first cause of cancer death simultaneously.Traditional anticoagulant heparin and warfarin are to treat and prevent to move
The conventional method of arteries and veins, phlebothrombosis, clinical trial and clinical practice establish the status of its traditional anticoagulant.But liver
Element is parenteral, and patient dependence is poor, is not suitable for long-term use.
Razaxaban（Rivaroxaban）Chemistry is entitled：The chloro- N- of 5- ({ (5S) -2- oxos -3- [4- (3- oxos -4-
Quinoline base) phenyl] -1,3- oxazolidine -5- bases }-methyl) -2- thenoyl amines, its chemical structural formula is as follows：
(S) -2- { [2- oxygen -3- (4- (3- oxygen morpholine) phenyl) oxazolidine -5- bases] methyl } iso-indoles -1,3- diketone is system
The key intermediate of standby razaxaban, its structural formula are as follows：
Razaxaban（Rivaroxaban）It is a kind of efficient FXa suppressions researched and developed jointly by Beyer Co., Ltd and Johson ＆ Johnson
Preparation, listed first in Canada within 2008, be global first FXa factor inhibitors that can be directly oral, for preventing and treating
Thrombus.
(S) -2- { [2- oxygen -3- (4- (3- oxygen morpholine) phenyl) oxazolidine -5- bases] methyl } iso-indoles -1,3- two at this stage
The synthetic route of ketone and razaxaban mainly has following several：
First, patent WO2001047919 is disclosed using 4- (4- aminophenyls) -3- morpholones as raw material, through open loop, cyclization,
Obtain razaxaban key intermediate 4- { 4- [(5S) -5- (amino methyl) -2- oxos -1,3-oxazoles alkane -3- bases] phenyl }
Quinoline -3- ketone, is further prepared into razaxaban again, and reaction scheme is as follows：
The reagents such as poisonous DMAP have been used in the program, and have needed column chromatography to be separated, yield is low.
2nd, patent WO2005068456 is disclosed using 4- (4- aminophenyls) -3- morpholones as raw material, through open loop, cyclization,
Obtain razaxaban key intermediate 4- { 4- [(5S) -5- (amino methyl) -2- oxos -1,3-oxazoles alkane -3- bases] phenyl }
Quinoline -3- keto hydrochlorides, then further the method for razaxaban processed, its anti-route are as follows：
The route is avoided using toxic reagents such as DMAP, and without with chromatogram post separation, but yield is still very low, only
65.9%。
3rd, WO2009023233 is disclosed using morpholine with being initiation material to fluorine nitro, through being condensed to yield 4- morpholine nitre
Base benzene, then 4- morpholine ketone group nitrobenzene is made with potassium permanganate oxidation, then through the steps such as catalytic hydrogenation finally with the chloro- thiophene of 2--
Razaxaban is made under pyridine catalysis in 5- formyl chlorides, and its reaction scheme is as follows：
Above method synthetic route is longer, and total recovery is relatively low to cause cost height.
4th, US2007157456 and WO2006055951 is reported using ethyl chloroacetate and ethylaminoethanol as raw material, is passed through
Following route synthesizes razaxaban：
The above method needs to carry out chiral separation, and cost is high, and yield is low, is not suitable for large-scale production.
5th, CN1852902A is reported using aniline as raw material, and 2- phenylaminos are made in back flow reaction in aqueous with chlorethanol
Base ethanol, obtained 4- phenyl -3- morpholones are reacted in the basic conditions with chloracetyl chloride, through nitrification, catalytic hydrogenation and epoxidation
Razaxaban raceme is made in the steps such as thing open loop, then chiral post splits to obtain razaxaban, and reaction scheme is as follows：
Above-mentioned route, which equally exists, needs chromatographic column to carry out the problem of chiral separation causes cost to raise.
The content of the invention
To solve various problems present in above-mentioned prior art, a kind of synthesis razaxaban of offer of the invention is crucial middle
The method of body (S) -2- { [2- oxygen -3- (4- (3- oxygen morpholine) phenyl) oxazolidine -5- bases] methyl } iso-indoles -1,3- diketone.
Specifically, synthesis (S) -2- { [2- oxygen -3- (4- (3- oxygen morpholine) phenyl) oxazolidine -5- provided by the invention
Base] methyl } iso-indoles -1,3- diketone（Formula VII）Method be：Make 4- (4- first ammonia alkenyls phenyl) -3- morpholones（Formula III）With
(S)-{ 1- (chloro-carbonic acid ester group) -2- [2- (1,3- dioxies iso-indoles) base] ethyl } halide salt（Formula IV）Prepared by ring closure reaction
Formula VII compound.Its reaction equation is as follows：
Wherein, X is halogen, preferably chlorine or bromine, more preferably chlorine；M is magnesium or zinc, preferably magnesium.
Preferably, the ring closure reaction temperature of above-mentioned formula III compound and Formula IV compound is -25 DEG C to 25 DEG C；More preferably
For -10 DEG C to 5 DEG C.Cyclization temperature is too low to cause reaction speed slack-off, and the reaction time extends；Cyclization temperature is too high to increase pair
Reaction.
Preferably, the ring closure reaction time of above-mentioned formula III compound and Formula IV compound is 1~10 hour；More preferably 3
~8 hours.Cyclization overlong time can increase product impurity；Time is too short to cause reaction incomplete.
Preferably, the solvent of above-mentioned formula III compound and Formula IV compound ring closure reaction is tetrahydrofuran, dichloromethane
And/or toluene；More preferably tetrahydrofuran.
Preferably, the mol ratio of above-mentioned formula III compound and Formula IV compound is (0.9~1.1): 1, more preferably 1: 1.
Mol ratio it is too low or it is too high can all cause cost of material to increase, while can also give that follow-up to remove impurity band difficult.
Above-mentioned formula III compound 4- (4- first ammonia alkenyls phenyl) -3- morpholones are by 4- (4- aminophenyls) -3- morpholones
（Formula II compound）It is made with formaldehyde reaction：
Preferably, in the reaction of above-mentioned formula III compounds, the mol ratio of Formula II compound and formaldehyde is 1:(1~
5), more preferably 1: (1.5~2.5).Mol ratio is too high to cause reaction incomplete；Mol ratio is too low to increase cost of material.
Preferably, the reaction temperature of above-mentioned formula III compounds is 10 DEG C to 40 DEG C, more preferably 20 DEG C to 30 DEG C.
Temperature is too high to cause impurity to increase；Temperature is too low to cause reaction incomplete.
Preferably, the reaction time of above-mentioned formula III compounds is 1~8 hour, more preferably 2~5 hours.Reaction
Overlong time can cause impurity to increase；Time is too short to cause reaction incomplete.
Preferably, the reaction dissolvent of above-mentioned formula III compounds is dichloromethane, chloroform and/or ethanol, is more preferably
Dichloromethane.
It is prepared by the method that above-mentioned Formula II compound may be referred to disclosed in European patent EP 1479675A1.
Above-mentioned Formula IV compound can be prepared as follows：By (S) -1- halos -2- [2- (1,3- dioxies iso-indoles)
Base] ethyl chloroformate（Formula V）Trigger through initiator, in non-protonic solvent, radical reaction occurs with metal M and is made
(S)-{ 1- (chloro-carbonic acid ester group) -2- [2- (1,3- dioxies iso-indoles) base] ethyl } halide salt（Formula IV）：
Wherein, X represents halogen, preferably chlorine or bromine；M is magnesium or zinc, preferably magnesium.
Preferably, the reaction dissolvent of above-mentioned formula VI compounds is ether, methyl tertiary butyl ether(MTBE) and/or tetrahydrofuran；
More preferably tetrahydrofuran.
Preferably, the initiator used in the reaction of above-mentioned formula VI compounds is iodine, iodomethane and/or 1,2- dibromo second
Alkane；More preferably iodine.
Preferably, in the reaction of above-mentioned formula VI compounds, (S) -1- halos -2- [2- (1,3- dioxy iso-indoles) base]
The mol ratio of ethyl chloroformate and initiator is (40~80):1, more preferably (50~60):1.Mol ratio is too high to be caused
Trigger incomplete；Mol ratio is too low to make initiator excessive, add cost of material.
Preferably, the reaction time of above-mentioned formula VI compounds is 2~8 hours；More preferably 3~6 hours.During reaction
Between it is long increase product decompose possibility；Time is too short to cause reaction incomplete.
Preferably, the reaction temperature of above-mentioned formula VI compounds is 0 DEG C to 50 DEG C；More preferably 10 DEG C to 40 DEG C.Instead
Answer temperature is too high impurity can be caused to increase；Temperature is too low to cause reaction incomplete.
Preferably, in the reaction of above-mentioned formula VI compounds, (S) -1- halos -2- [2- (1,3- dioxy iso-indoles) base]
Ethyl chloroformate and active metal M mol ratio are 1:(1.0~2.0), more preferably 1:(1.0~1.5).Mol ratio is too low
Cost of material can be increased；It is too high that reaction can be made incomplete.
Above-mentioned Formula V compound (S) -1- halos -2- [2- (1,3- dioxies iso-indoles) base] ethyl chloroformate can pass through
Initiation material (S) -2- (2- halo -2- hydroxyethyls) iso-indoles -1,3- diketone（Formula IV）Acylation reaction system is carried out with triphosgene
：
Wherein, X is halogen, preferably chlorine or bromine, more preferably chlorine.
Preferably, the reaction time of the acylation reaction of above-mentioned formula V compounds is 1~12 hour；More preferably 2~7
Hour.Reaction time is long to cause impurity to increase；Time is too short to cause reaction incomplete.
Preferably, the reaction temperature of the acylation reaction of above-mentioned formula V compounds is -10 DEG C to 50 DEG C；More preferably 0 DEG C
To 30 DEG C.Reaction temperature is too high to cause impurity to increase, and there is a possibility that part racemization；Temperature is too low, can cause to react
Time lengthening.
Preferably, the acylation reaction of above-mentioned formula V compounds is carried out under organic base catalytic, and organic base used can
To be pyridine, triethylamine or DMA, more preferably pyridine.Wherein, formula IV compound and the mol ratio of organic base
For 1:(1.0~6.0), more preferably 1:(1.5~2.5).Mol ratio is too high to cause reaction incomplete；It is too low to increase raw material
Cost.
Preferably, in the acylation reaction of above-mentioned formula V compounds, the mol ratio of formula IV compound and triphosgene is 1:
(0.5~3.0), more preferably 1:(1.0~1.2).Mol ratio is too high to cause reaction incomplete；It is too low to increase cost of material.
Preferably, the reaction dissolvent of the acylation reaction of above-mentioned formula V compounds be tetrahydrofuran, Isosorbide-5-Nitrae-dioxane,
Toluene and/or ethyl acetate, more preferably tetrahydrofuran.
Above-claimed cpd IV may be referred to document Yu, Jianping;Zhang,Changfu;Synthetic
It is prepared by the method in Communications, 2008, vol.38, #12P.1875-1887.
Further, deprotection reaction is carried out to Formula VII compound, 4- { 4- [(5S) -5- (amino methyl) -2- oxygen is made
Generation -1,3-oxazoles alkane -3- bases] phenyl } morpholine -3- keto hydrochlorides（Formula VIII）；Formula VIII is anti-with 2- chloroformyl -5- chlorothiophenes again
Razaxaban should be obtained（Formulas I）.
The present invention has the advantage that compared with prior art and good effect：
1. present invention firstly provides a kind of new Rivaroxaban intermediate 4- (4- first ammonia alkenyls phenyl) -3- morpholones
（Formula III）And preparation method thereof.
Intermediate 4- (4- first ammonia alkenyls phenyl) -3- morpholones（Formula III）Obtained first for the present invention, its preparation method is
It is raw material under the conditions of appropriate experimental to refer to using 4- (4- aminophenyls) -3- morpholones, through reacting to obtain shown in formula III with formaldehyde
Compound.Above-mentioned preparation method is easy to operate, and gained intermediate III purity is good, and high income is up to 90% or so.
2. secondly the present invention provides another new Rivaroxaban intermediate (S) -1- halos -2-, [(1,3- dioxies are different by 2-
Indoles) base] ethyl chloroformate（Formula V）And preparation method thereof.
Intermediate (S) -1- halos -2- [2- (1,3- dioxies iso-indoles) base] ethyl chloroformate（Formula V）For head of the invention
Secondary to obtain, its preparation method refers to (S) -2- (2- halo -2- hydroxyethyls) iso-indoles -1,3- diketone（Formula IV）It is former for starting
Material carries out acylation reaction under organic base catalytic with triphosgene, and the compound shown in Formula V is made.Above-mentioned preparation method safety letter
Just, gained intermediate V purity is high, and this step reaction yield can be up to 85% or so, particularly the preferred technical solution of the present invention
Purity may be up to more than 97%.
3. the present invention still further provides a kind of new intermediate (S)-{ 1- (chloro-carbonic acid ester group) -2- [2- (1,3- dioxies
Iso-indoles) base] ethyl } halide salt（Formula IV）And preparation method thereof.
The intermediate (S)-{ 1- (chloro-carbonic acid ester group) -2- [2- (1,3- dioxies iso-indoles) base] ethyl } halide salt（Formula IV）
Obtained first for the present invention, its preparation method is (S) -1- halos -2- [2- (1,3- dioxy iso-indoles) base] ethyl chloroformate
（Formula V）Trigger through initiator, radical reaction, which occurs, with metal in non-protonic solvent is made (S)-{ 1- (chloro-formates
Base) -2- [2- (1,3- dioxies iso-indoles) base] ethyl } halide salt（Formula IV）.Above-mentioned preparation method mature and reliable, industry can be realized
Change big production.
4. present invention also offers one kind synthesis (S) -2- { [2- oxygen -3- (4- (3- oxygen morpholine) phenyl) oxazolidine -5- bases]
Methyl } iso-indoles -1,3- diketone new method.
This method is by intermediate 4- (4- first ammonia alkenyls phenyl) -3- morpholones（Formula III）With intermediate (S)-{ 1- (chloromethanes
Perester radical) -2- [2- (1,3- dioxies iso-indoles) base] ethyl } halide salt（Formula IV）Carry out ring-closure reaction and prepare (S) -2- { [2-
Oxygen -3- (4- (3- oxygen morpholine) phenyl) oxazolidine -5- bases] methyl } iso-indoles -1,3- diketone（Formula VII）.Described method is made
(S) -2- { [2- oxygen -3- (4- (3- oxygen morpholine) phenyl) oxazolidine -5- bases] methyl } iso-indoles -1,3- diketone（Formula VII）'s
Purity is good, high income, and optimal technical scheme yield particularly of the present invention may be up to 90% or so, and purity may be up to more than 98%.And
And the method for the present invention is easy to operate, raw material is easy to get, and is suitably applied industrialized production.
5. the present invention finally provides a kind of new method for synthesizing razaxaban
Based on the inventive method, final obtained razaxaban purity is good, up to more than 99.0%, the particularly present invention
Preferable technical scheme, its chemical purity and optical purity are all more than 99.5%；It is former and the method for the present invention is easy to operate
Material is easy to get, and is suitably applied industrialized production.
6. the preparation technology of the present invention carries out a step ring closure reaction using new intermediate III and VI and prepares razaxaban pass
Key intermediate (S) -2- { [2- oxygen -3- (4- (3- oxygen morpholine) phenyl) oxazolidine -5- bases] methyl } iso-indoles -1,3- diketone（Formula
VII）, then through being deprotected, acylated obtained razaxaban, technical process avoids using with serious pollution DMAP, effectively reduces
Effluent pressure.In addition, products obtained therefrom of the present invention carries out chiral separation without using chromatographic column, yield is improved, reduces production
Cost.
7. prepared by the present invention, razaxaban mild condition, technique are simple, cost is low, high income, suitable for industrialized production.
Embodiment
Below by way of the description of embodiment, the invention will be further described, but this is not the limit to the present invention
System, those skilled in the art according to the present invention basic thought, various modifications may be made or improve, but without departing from this
The basic thought of invention, within the scope of the present invention.
In the examples below, HPLC, which detects instrument, to be（Such as）The Shimadzu of Japanese Shimadzu Corporation's production
LC-20A.The computational methods of chemical purity and optical purity are using area normalization method；The calculation formula of molar yield is：
（Product molar number/main material molal quantity) × 100%.Mass Spectrometer Method instrument can be the API5500 of American AB SCIES companies
Type liquid chromatography mass combined instrument.NMR detections instrument can be the AM400MHZ type NMRs of BRUKER companies.
Agents useful for same of the present invention is commercially available.
In one embodiment of the invention, first by (S) -2- (2- halo -2- hydroxyethyls) iso-indoles -
1,3- diketone（Formula IV）(S) -1- halos -2- [2- (1,3- dioxies iso-indoles) base] ethyl chloroformate is made（Formula V）, Ran Houjing
Initiator triggers, and in non-protonic solvent, radical reaction occurs with metal (S)-{ 1- (chloro-carbonic acid ester group) -2- [2- are made
(1,3- dioxies iso-indoles) base] ethyl } halide salt（Formula IV）.In addition, by raw material 4- (4- aminophenyls) -3- morpholones（Formula II）System
Into 4- (4- first ammonia alkenyls phenyl) -3- morpholones（Formula III）.With intermediate VI ring closure reaction occurs for intermediate III, and obtained profit is cut down
Husky class's key intermediate (S) -2- { [2- oxygen -3- (4- (3- oxygen morpholine) phenyl) oxazolidine -5- bases] methyl } iso-indoles -1,3- two
Ketone（Formula VII）.Last intermediate VII is through being deprotected, acylated obtained razaxaban.Its course of reaction is as follows：
Embodiment 1：4- (4- first ammonia alkenyls phenyl) -3- morpholones（Formula III）Preparation：
192.2g (1.0mol) 4- (4- aminophenyls) -3- morpholones (Formula II) are added in reaction bulb, with 700ml dichloros
Methane stirring and dissolving, 25 DEG C are cooled to, 45.0g is added dropwise（1.5mol）Formaldehyde, process temperature control is added dropwise at 20 DEG C to 30 DEG C, drop
Add complete, stirring reaction 5 hours, controlled in TLC（Dichloromethane:Methanol:Triethylamine=20:1:0.5, volume ratio）, reaction is complete,
Stop stirring, decompression（- 0.1MPa~-0.09MPa）Dichloromethane is evaporated off, 600ml ethyl acetate temperature rising reflux is added, under stirring
Temperature fall, is down to 10 DEG C to 15 DEG C crystallizations 8 hours, filtering, decompression drying, obtains off-white color intermediate III product 185.4g, rubs
That yield 90.8%, HPLC purity 98.8%.
The detection data of the title product obtained by nuclear magnetic resonance and mass spectral analysis are as follows：1H NMR (400MHz,
CDCl3)：δ=50.56 (s, 2H), 7.65 (d, 2H), 6.59（D, 2H）, 4.30 (s, 2H), 3.51 (q, 4H)；13C NMR
(75MHz, CDCl3)：δ=164.5,162.7,143.6,136.3,131.0,131.0,122.5,122.4,73.0,65.9,
54.8ppm；HR-MS(ESI)：C11H12N2O2Molecular weight：204.2, [M+H]+Measured value：205.6.
Embodiment 2：4- (4- first ammonia alkenyls phenyl) -3- morpholones（Formula III）Preparation：
192.2g is added in reaction bulb（1.0mol）4- (4- aminophenyls) -3- morpholones, stirred with 700ml dichloromethane
Dissolving is mixed, is cooled to 25 DEG C, 75.0g is added dropwise（2.5mol）Formaldehyde, process temperature control is added dropwise at 20 DEG C to 30 DEG C, drips
Finish, stirring reaction 2 hours, controlled in TLC（Dichloromethane:Methanol:Triethylamine=20:1:0.5, volume ratio）, reaction is complete, stops
Stirring, decompression（- 0.1MPa~-0.09MPa）Dichloromethane is evaporated off, adds 600ml ethyl acetate temperature rising reflux, stirs lower nature
Cooling, is down to 10 DEG C to 15 DEG C crystallizations 8 hours, filtering, decompression drying,
Obtain off-white color intermediate III product 188.1g, molar yield 92.1%, HPLC purity 98.3%.
The detection data of the title product obtained by nuclear magnetic resonance and mass spectral analysis are as follows：1H NMR (400MHz,
CDCl3)：δ=50.56 (s, 2H), 7.65 (d, 2H), 6.59（D, 2H）, 4.30 (s, 2H), 3.51 (q, 4H)；13C NMR
(75MHz, CDCl3)：δ=164.5,162.7,143.6,136.3,131.0,131.0,122.5,122.4,73.0,65.9,
54.8ppm；HR-MS(ESI)：C11H12N2O2Molecular weight：204.2, [M+H]+Measured value：205.1.
Embodiment 3：(S) -1- chloros -2- [2- (1,3- dioxies iso-indoles) base] ethyl chloroformate（Formula V）Preparation：
In the present embodiment, it is above-mentioned in X be Cl.
270.7g is added in reaction bulb（1.2mol）(S) -2- (2- chloro -2- hydroxyethyls) iso-indoles -1,3- diketone
（Formula IV）、158.2g（2.0mol）Pyridine and 1000ml tetrahydrofurans, stir, and are cooled to 10 DEG C to 20 DEG C, add
267.1g（0.9mol）Triphosgene, insulated and stirred add 89.0g again after reacting 2 hours（0.3mol）Triphosgene, it is anti-to continue stirring
Answer 3 hours, controlled in HPLC, raw material disappears substantially, stops reaction, decompression（- 0.1MPa~-0.09MPa）Tetrahydrofuran is evaporated off, it is residual
In remaining grease add 800ml dichloromethane stirring and dissolvings, with 0 DEG C to 5 DEG C of 1% glacial acetic acid and purified water wash successively to
Aqueous pH values are about 6 or so, and the organic layer that liquid separation is obtained depressurizes（- 0.1MPa~-0.09MPa）Dichloromethane is evaporated off, obtains class
Yellow oil intermediate V294.6g, molar yield 85.2%, HPLC purity 97.8%.
The detection data of the title product obtained by nuclear magnetic resonance and mass spectral analysis are as follows：1H NMR (400MHz,
CDCl3)：δ=7.89 (q, 2H), 7.83（Q, 2H）, 6.55 (t, 1H), 4.15 (q, 2H)；13C NMR (75MHz, CDCl3)：δ=
168.2,168.2,150.5,132.3,132.3,131.8,131.8,123.5,123.5,89.7,50.1ppm；HR-MS
(ESI)：C11H7Cl2NO4Molecular weight：288.1, [M+H]+Measured value：289.0.
Embodiment 4：(S) -1- chloros -2- [2- (1,3- dioxies iso-indoles) base] ethyl chloroformate（Formula V）Preparation：
270.7g is added in reaction bulb（1.2mol）(S) -2- (2- halo -2- hydroxyethyls) iso-indoles -1,3- diketone,
197.8g（2.5mol）Pyridine and 1000ml tetrahydrofurans, stir, and are cooled to 10 DEG C to 20 DEG C, add 267.1g
（0.9mol）Triphosgene, insulated and stirred add 89.0g again after reacting 2 hours（0.3mol）Triphosgene, it is small to continue stirring reaction 3
When, control in HPLC, raw material disappears substantially, stops reaction, decompression（- 0.1MPa~-0.09MPa）Tetrahydrofuran, residual oil is evaporated off
800ml dichloromethane stirring and dissolvings are added in shape thing, are washed successively to aqueous phase with 0 DEG C to 5 DEG C of 1% glacial acetic acid and purified water
PH value is about 6 or so, and the organic layer that liquid separation is obtained depressurizes（- 0.1MPa~-0.09MPa）Dichloromethane is evaporated off, obtains class yellow
Grease intermediate V298.4g, molar yield 86.3%, HPLC purity 97.2%.
The detection data of the title product obtained by nuclear magnetic resonance and mass spectral analysis are as follows：1H NMR (400MHz,
CDCl3)：δ=7.89 (q, 2H), 7.83（Q, 2H）, 6.55 (t, 1H), 4.15 (q, 2H)；13C NMR (75MHz, CDCl3)：δ=
168.2,168.2,150.5,132.3,132.3,131.8,131.8,123.5,123.5,89.7,50.1ppm；HR-MS
(ESI)：C11H7Cl2NO4Molecular weight：288.1, [M+H]+Measured value：289.3.
Embodiment 5：(S)-{ 1- (chloro-carbonic acid ester group) -2- [2- (1,3- dioxies iso-indoles) base] ethyl } magnesium chloride（Formula IV）
Preparation：
X in the present embodiment, above formula is Cl, M Mg.
300ml THF, magnesium chips 23.1g after pretreatment are added in reaction bulb（0.95mol）, iodine 3.55g
（0.014mol）, stirred under nitrogen atmosphere is uniform, and the reality for being dissolved in 400ml THF is slowly added dropwise at 10 DEG C to 20 DEG C in temperature control
Apply 224.7g (0.78mol) (S) -1- halos -2- made from example 3 [2- (1,3- dioxies iso-indoles) base] ethyl chloroformate（Formula
V）, drop is complete, insulation reaction 5 hours, and (S)-{ 1- (chloro-carbonic acid ester group) -2- [2- (1,3- dioxy iso-indoles) base] ethyl } chlorine is made
Change magnesium（Formula IV）, it is stand-by.
Magnesium chips preprocess method：With 10% salt acid elution 30 minutes, rapid filtration under suction, eluted, be dried in vacuo, directly with acetone
Connect in input reaction and use.
Embodiment 6：(S)-{ 1- (chloro-carbonic acid ester group) -2- [2- (1,3- dioxies iso-indoles) base] ethyl } magnesium chloride（Formula IV）
Preparation：
300ml THF, magnesium chips 23.1g after pretreatment are added in reaction bulb（0.95mol）, iodine 3.55g
（0.014mol）, stirred under nitrogen atmosphere is uniform, and the reality for being dissolved in 400ml THF is slowly added dropwise at 30 DEG C to 40 DEG C in temperature control
Apply 224.7g (0.78mol) (S) -1- halos -2- made from example 4 [2- (1,3- dioxies iso-indoles) base] ethyl chloroformate（Formula
V）, drop is complete, insulation reaction 5 hours, and (S)-{ 1- (chloro-carbonic acid ester group) -2- [2- (1,3- dioxy iso-indoles) base] ethyl } chlorine is made
Change magnesium（Formula IV）, it is stand-by.
Magnesium chips preprocess method：With 10% salt acid elution 30 minutes, rapid filtration under suction, eluted, be dried in vacuo, directly with acetone
Connect in input reaction and use.
Embodiment 7：(S) -2- { [2- oxygen -3- (4- (3- oxygen morpholine) phenyl) oxazolidine -5- bases] methyl } iso-indoles -1,3-
Diketone（Formula VII）Preparation：
X in the present embodiment, above formula is Cl, M Mg.
159.3g prepared by embodiment 1 is added in reaction bulb（0.78mol）4- (4- first ammonia alkenyls phenyl) -3- morpholones
(formula III), 300ml tetrahydrofurans, stir, the intermediate VI that temperature control is added dropwise embodiment 5 and prepared at 0 DEG C to 5 DEG C, drop
Insulation reaction 7 hours after adding, the clear liquid in extracting reaction solution, which is cooked in HPLC, to be controlled, and intermediate III reaction is complete, filtering, filter cake
Washed successively with 200ml tetrahydrofurans and 200ml 95% ethanol, decompression drying, obtain off-white powder（Formula VII compound）
300.4g, molar yield 91.4%, HPLC purity 98.9%.
The detection data for the title product that mass spectral analysis obtains are as follows：HR-MS(ESI)：C22H19N3O6Molecular weight：421.4
[M+H]+Measured value：422.5.
Embodiment 8：(S) -2- { [2- oxygen -3- (4- (3- oxygen morpholine) phenyl) oxazolidine -5- bases] methyl } iso-indoles -1,3-
Diketone（Formula VII）Preparation：
159.3g prepared by embodiment 2 is added in reaction bulb（0.78mol）4- (4- first ammonia alkenyls phenyl) -3- morpholones
(formula III), 300ml tetrahydrofurans, stir, the intermediate VI that temperature control is added dropwise embodiment 6 and prepared at -10 DEG C to 0 DEG C,
Rear insulation reaction is added dropwise 4 hours, the clear liquid in extracting reaction solution, which is cooked in HPLC, to be controlled, and intermediate III reaction is complete, filters, filter
Cake is washed successively with 200ml tetrahydrofurans and 200ml 95% ethanol, decompression drying, obtains off-white powder（Formula VII compound）
293.5g, molar yield 89.3%, HPLC purity 98.4%.
The detection data for the title product that mass spectral analysis obtains are as follows：HR-MS(ESI)：C22H19N3O6Molecular weight：421.4
[M+H]+measured value：422.1.
Embodiment 9：4- { 4- [(5S) -5- (amino methyl) -2- oxos -1,3-oxazoles alkane -3- bases] phenyl } morpholine -3- ketone
Hydrochloride（Formula VIII）Preparation：
210.7g prepared by embodiment 7 is added in reaction bulb（0.5mol）(S) -2- { [2- oxygen -3- (4- (3- oxygen morpholine) benzene
Base) oxazolidine -5- bases] methyl } iso-indoles -1,3- diketone（Formula VII）, 1500ml absolute ethyl alcohols, 500ml 30% methylamine it is water-soluble
Liquid, stir, be warming up to 40 DEG C to 60 DEG C and react 8 hours, controlled in TLC（Dichloromethane:Methanol=20:1, volume ratio）Reaction
Completely, with 10% salt acid for adjusting pH value to a large amount of white solids between 1-2, are separated out, 15 DEG C or so are cooled to, is stirred 2 hours, mistake
Filter, filter cake are washed with 300ml absolute ethyl alcohols, decompression drying, obtain off-white powder（Formula VIII compound）147.0g, molar yield
89.7%, HPLC purity 98.7%.
The detection data for the title product that mass spectral analysis obtains are as follows：HR-MS(ESI)：C14H18ClN3O4Molecular weight：
327.8, [M+H]+Measured value：328.3.
Embodiment 10：4- { 4- [(5S) -5- (amino methyl) -2- oxos -1,3-oxazoles alkane -3- bases] phenyl } morpholine -3-
Keto hydrochloride（Formula VIII）Preparation：
210.7g prepared by embodiment 8 is added in reaction bulb（0.5mol）(S) -2- { [2- oxygen -3- (4- (3- oxygen morpholine) benzene
Base) oxazolidine -5- bases] methyl } iso-indoles -1,3- diketone（Formula VII）, 1500ml absolute ethyl alcohols, 500ml 30% methylamine it is water-soluble
Liquid, stir, be warming up to 40 DEG C to 60 DEG C and react 3 hours, controlled in TLC（Dichloromethane:Methanol=20:1, volume ratio）Reaction
Completely, with 10% salt acid for adjusting pH value to a large amount of white solids between 1-2, are separated out, 15 DEG C or so are cooled to, is stirred 2 hours, mistake
Filter, filter cake are washed with 300ml absolute ethyl alcohols, decompression drying, obtain off-white powder（Formula VIII compound）144.4g, molar yield
88.1%, HPLC purity 98.6%.
The detection data for the title product that mass spectral analysis obtains are as follows：HR-MS(ESI)：C14H18ClN3O4Molecular weight：
327.8, [M+H]+Measured value：328.8.
Embodiment 11：Li Daishaban preparation：
4- { 4- [(5S) -5- (amino methyl) -2- oxygen prepared by 131.19 (0.4mol) embodiments 9 is added in reaction bulb
Generation -1,3-oxazoles alkane -3- bases] phenyl } morpholine -3- keto hydrochlorides（Formula VIII）, 500ml N,N-dimethylformamide, 50.6g
（0.5mol）Triethylamine, 86.9g（0.48mol）2- chloroformyl -5- chlorothiophenes, are stirred, and it is small that 5 are reacted at 30 DEG C to 40 DEG C
When, control in TLC（Dichloromethane:Methanol=20:1, volume ratio）Reaction is complete, adds 500ml purified waters, has a large amount of solids to separate out,
Stirring 2 hours, filtering, filter cake 200ml purify water washing, decompression drying, obtain razaxaban product 149.1g, molar yield
85.5%, HPLC chemical purity 99.7%, optical purity 100.0%.
The detection data for the title product that mass spectral analysis obtains are as follows：HR-MS(ESI)：C19H18ClN3O5S molecular weight：
435.9, [M+H]+Measured value：436.6.
Embodiment 12：Li Daishaban preparation：
131.1g is added in reaction bulb（0.4mol）4- { 4- [(5S) -5- (amino methyl) -2- oxygen prepared by embodiment 10
Generation -1,3-oxazoles alkane -3- bases] phenyl } morpholine -3- keto hydrochlorides（Formula VIII）, 500ml N,N-dimethylformamide, 50.6g
（0.5mol）Triethylamine, 101.4g（0.56mol）2- chloroformyl -5- chlorothiophenes, are stirred, and it is small that 5 are reacted at 30 DEG C to 40 DEG C
When, control in TLC（Dichloromethane:Methanol=20:1, volume ratio）Reaction is complete, adds 500ml purified waters, has a large amount of solids to separate out,
Stirring 2 hours, filtering, filter cake 200ml purify water washing, decompression drying, obtain razaxaban product 150.1g, molar yield
86.1%, HPLC chemical purity 99.8%, optical purity 100.0%.
The detection data for the title product that mass spectral analysis obtains are as follows：HR-MS(ESI)：C19H18ClN3O5S molecular weight：
435.9, [M+H]+Measured value：436.5.
Claims (38)
- Formula VII compound 1. (S) -2- { [2- oxygen -3- (4- (3- oxygen morpholine) phenyl) oxazolidine -5- bases] methyl } iso-indoles -1, The preparation method of 3- diketone, make formula III compound 4- (4- first ammonia alkenyls phenyl) -3- morpholones and Formula IV compound (S)-{ 1- (chloro-carbonic acid ester group) -2- [2- (1,3- dioxies iso-indoles) base] ethyl } Formula VII compound is made by ring closure reaction in halide salt：Wherein, X is halogen；M is magnesium or zinc.
- 2. preparation method according to claim 1, it is characterised in that X is chlorine or bromine.
- 3. preparation method according to claim 1, it is characterised in that ring closure reaction temperature is -25 DEG C to 25 DEG C.
- 4. preparation method according to claim 3, it is characterised in that ring closure reaction temperature is -10 DEG C to 5 DEG C.
- 5. preparation method according to claim 1, it is characterised in that the ring closure reaction time is 1~10 hour.
- 6. preparation method according to claim 5, it is characterised in that the ring closure reaction time is 3~8 hours.
- 7. preparation method according to claim 1, it is characterised in that the solvent of ring closure reaction is tetrahydrofuran, dichloromethane Alkane and/or toluene.
- 8. preparation method according to claim 1, it is characterised in that the ring closure reaction compound of formula III and Formula IV The mol ratio of compound is (0.9~1.1): 1.
- 9. according to any described preparation method of claim 1~8, it is characterised in that formula III compound 4- (the 4- first ammonia Alkenyl phenyl) -3- morpholones be by Formula II compound 4- (4- aminophenyls) -3- morpholones and formaldehyde reaction be made：
- 10. preparation method according to claim 9, it is characterised in that Formula II chemical combination in the reaction of formula III compounds The mol ratio of thing 4- (4- aminophenyls) -3- morpholones and formaldehyde is 1: (1~5).
- 11. preparation method according to claim 10, it is characterised in that Formula II in the reaction of formula III compounds The mol ratio of compound 4- (4- aminophenyls) -3- morpholones and formaldehyde is 1: (1.5~2.5).
- 12. preparation method according to claim 9, it is characterised in that the reaction temperature of formula III compounds is 10 DEG C To 40 DEG C.
- 13. preparation method according to claim 12, it is characterised in that the reaction temperature of formula III compounds is 20 DEG C to 30 DEG C.
- 14. preparation method according to claim 9, it is characterised in that the reaction time of formula III compounds is 1~8 Hour.
- 15. preparation method according to claim 14, it is characterised in that the reaction time of formula III compounds be 2~ 5 hours.
- 16. preparation method according to claim 9, it is characterised in that the reaction dissolvent of formula III compounds is dichloro Methane, chloroform and/or ethanol.
- 17. according to any described preparation method of claim 1~8, it is characterised in that Formula IV compound (S)-{ 1- (chlorine Formic acid ester group) -2- [2- (1,3- dioxies iso-indoles) base] ethyl halide salt be by Formula V compound (S) -1- halos -2- [2- (1, 3- dioxies iso-indoles) base] ethyl chloroformate triggers through initiator, in non-protonic solvent, it is anti-that free radical occurs with metal M Should be obtained：Wherein, X represents halogen；M is magnesium or zinc.
- 18. preparation method according to claim 17, it is characterised in that described in the reaction of formula VI compounds Non-protonic solvent is ether, methyl tertiary butyl ether(MTBE) and/or tetrahydrofuran.
- 19. preparation method according to claim 17, it is characterised in that described in the reaction of formula VI compounds Initiator is iodine, iodomethane and/or glycol dibromide.
- 20. preparation method according to claim 17, it is characterised in that in the reaction of formula VI compounds, (S)- The mol ratio of 1- halos -2- [2- (1,3- dioxies iso-indoles) base] ethyl chloroformates and initiator is (40~80):1.
- 21. preparation method according to claim 20, it is characterised in that in the reaction of formula VI compounds, (S)- The mol ratio of 1- halos -2- [2- (1,3- dioxies iso-indoles) base] ethyl chloroformates and initiator is (50~60):1.
- 22. preparation method according to claim 17, it is characterised in that the reaction time of formula VI compounds is 2~8 Hour.
- 23. preparation method according to claim 22, it is characterised in that the reaction time of formula VI compounds is 3~6 Hour.
- 24. preparation method according to claim 17, it is characterised in that the reaction temperature of formula VI compounds is 0 DEG C To 50 DEG C.
- 25. preparation method according to claim 24, it is characterised in that the reaction temperature of formula VI compounds is 10 DEG C To 40 DEG C.
- 26. preparation method according to claim 17, it is characterised in that in the reaction of formula VI compounds, (S)- 1- halos -2- [2- (1,3- dioxies iso-indoles) base] ethyl chloroformates and metal M mol ratio are 1:(1.0~2.0).
- 27. preparation method according to claim 26, it is characterised in that in the reaction of formula VI compounds, (S)- 1- halos -2- [2- (1,3- dioxies iso-indoles) base] ethyl chloroformates and metal M mol ratio are 1:(1.0~1.5).
- 28. preparation method according to claim 17, it is characterised in that Formula V compound be by formula IV compound (S)- 2- (2- halo -2- hydroxyethyls) iso-indoles -1,3- diketone carries out acylation reaction with triphosgene and is made：Wherein, X is halogen.
- 29. preparation method according to claim 28, it is characterised in that the acylation reaction of formula V compounds Reaction time is 1~12 hour.
- 30. preparation method according to claim 29, it is characterised in that the acylation reaction of formula V compounds Reaction time is 2~7 hours.
- 31. preparation method according to claim 28, it is characterised in that the acylation reaction of formula V compounds Reaction temperature is -10 DEG C~50 DEG C.
- 32. preparation method according to claim 31, it is characterised in that the acylation reaction of formula V compounds Reaction temperature is 0 DEG C~30 DEG C.
- 33. preparation method according to claim 28, it is characterised in that the acylation reaction of formula V compounds is Carried out under organic base catalytic, organic base used is pyridine, triethylamine or DMA.
- 34. preparation method according to claim 33, it is characterised in that in the acylation reaction of formula V compounds, The formula IV compound and the mol ratio of organic base are 1:(1.0~6.0).
- 35. preparation method according to claim 34, it is characterised in that in the acylation reaction of formula V compounds, The formula IV compound and the mol ratio of organic base are 1:(1.5~2.5).
- 36. preparation method according to claim 28, it is characterised in that in the acylation reaction of formula V compounds, The mol ratio of the formula IV compound and triphosgene is 1:(0.5~3.0).
- 37. preparation method according to claim 36, it is characterised in that in the acylation reaction of formula V compounds, The mol ratio of the formula IV compound and triphosgene is 1:(1.0~1.2).
- 38. preparation method according to claim 28, it is characterised in that the acylation reaction of formula V compounds Reaction dissolvent is tetrahydrofuran, 1,4- dioxane, toluene and/or ethyl acetate.
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