CN104892593B - Relevant material F, G of razaxaban a kind of synthetic method - Google Patents
Relevant material F, G of razaxaban a kind of synthetic method Download PDFInfo
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- 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
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Abstract
The present invention proposes relevant material F, G of a kind of razaxaban synthetic method.Relevant material F, G of a kind of razaxaban provided by the invention synthetic method high income, it is easy to accomplish industrialized production and technology conversion.
Description
Technical field
The invention belongs to chemosynthesis technical field, is related to razaxaban about a kind of new synthetic method of material F, G.
Background technology
Thrombotic diseases are a kind of diseases for seriously endangering human health, can involve the multiple organs of whole body and system, and it is sent out
Sick rate, disability rate and the death rate are all very high.Anticoagulant therapy is always the core of thrombotic diseases rescue and prevention.Xa is a kind of
Serine protease, positioned at the intersection of intrinsic coagulation pathway and exogenous cruor pathway, the lifting in coagulation cascade reaction
Act on, it finally adjusts the generation of fibrin ferment by cracking factor, therefore suppression Xa can produce efficient anticoagulation
Effect.
Razaxaban (rivaroxaban, 1, formula 1), the entitled chloro- N- of 5- [[(5S) -2- oxos -3- [4- (the 3- oxygen of chemistry
Generation -4- morpholinyls)-phenyl] -1,3- oxazolidine -5- bases] methyl] -2- thenoyl amines are by Bayer and Johson ＆ Johnson's joint
The direct inhibitor of first oral Xa factor of exploitation, clinic are mainly used in preventing hip joint or the vein of knee replacements patient
Thrombus, listed in Canada and European Union within 2008,2009 in Discussion on Chinese Listed.
Patent US7351823, report that its synthesis route is as follows, be original with 4- (4- aminophenyls) -3- morpholones (2)
Material, flow back, obtain in ethanol water in the mixed solvent with (S) -2- (2- oxiranylmethyl radicals) -1H- iso-indoles -1,3- diketone (3)
(R) -2- (2- hydroxyls -3- { [4- (3- oxo -4- morpholinyls) phenyl] amino } propyl group) -1H- iso-indoles -1,3- diketone (4)；Change
Compound (4) is condensed to yield (S) -2- ({ 2- oxos -3- [4- (3- oxo -4- morpholines under the DMAP effects of catalytic amount with CDI
Base) phenyl] -1,3- oxazolidine -5- bases } methyl) -1H- iso-indoles -1,3- diketone (5)；Compound (5) is under methylamine water solution
Phthalyl is sloughed, obtains the chloro- N- of (S) -5- ({ 2- oxos -3- [4- (3- oxo -4- morpholinyls) phenyl] -1,3- oxazoles
Alkane -5- bases } methyl) -2- formamides (6)；Compound (6) is reacted with 5- chlorothiophene -2- formyl chlorides, is obtained with triethylamine as acid binding agent
To razaxaban (rivaroxaban).
2014, Cai Zhengyan [1] etc., it was recently reported that 8 impurity that may be present of razaxaban, and progress is synthesized to it
Research.Patent WO2012035057 also elaborates 2 impurity synthetic methods that may be present of razaxaban.But patent of the present invention
On the basis of experimental study is carried out to patent process route, with reference to the quality standard of razaxaban, Cai Zhengyan and patent are found
WO2012035057 lacks known existing partial impurities in reporting, and impurity synthetic method is cumbersome.Then the present invention is special
Profit passes through the means such as impurity enriched, destructive test, column chromatography, HPLC and structural identification, it is determined that 5 that may be present relevant
Material (table 1, code and structure of the razaxaban about material).
Table 1, code and structure of the razaxaban about material
Bibliography：
[1] Cai is just gorgeous, and synthesis and structural identification [J] Chinese Medicine industry of the Wen Yingling razaxabans about material are miscellaneous
Will, 2014,45 (4), 303-308.
The content of the invention
The present invention proposes a kind of relevant material synthetic method of razaxaban, to entering about substance A, B, E synthetic method
Optimization is gone, on the basis of having screened a plurality of route about material F and the synthetic method about material G, it is determined that this patent
The synthetic route being related to optimizes to preparation method.
In order to realize above-mentioned technical proposal, the present invention provides a kind of method of the relevant material F synthesis of razaxaban, material
F synthetic line is as follows：
.Wherein, the synthesis step about material F is as follows：
Step 1, it is the tert-butyl group -4- amino anilines formic acid esters 6-12 parts and (S) -2- (2- oxiranylmethyl radicals) -1H- is different
Indoles -1,3- diketone 8-17 parts are dissolved in 150-230 part isopropanols；Slow temperature rising reflux reaction 4-9 hours, and pass through TLC
After monitoring reaction completely, room temperature is down to；The solid of precipitation is filtered, is dried to obtain compound 3；
Step 2, successively by 8-12 parts compound 3, DMF35-50 parts, dicarbapentaborane imidazoles (CDI) 7-9 parts, catalytic amount
DMAP is added in reaction bulb；It is warming up to 80-110 DEG C of stirring reaction, TLC monitoring reaction process, after reaction completely, to reactant
Water 100-120 parts, agitation and filtration, dry compound 4 are added in system；
Step 3,10-14 parts compound 4 is dissolved in 50-70 part absolute ethyl alcohols, stirs lower addition 2.9-3.2 parts hydration
Hydrazine, temperature rising reflux reaction 2-3 hours, after TLC monitoring reaction process reactions completely, it is filtered to remove solid, alcohol layer concentration, through silicon
Plastic column chromatography separates to obtain compound 5；
Step 4,7-8 parts compound 5 is dissolved in 60-90 part dichloromethane, adds dry triethylamine 3-4 parts and stir
Mix, argon gas protection drops to 0-2 DEG C, and the chloro- 2 acyl chlorides thiophene of 3-3.5 parts 5- is slowly added dropwise；Drip off after 0 DEG C of stirring reaction 10-12
Hour, TLC monitoring reaction process, reaction completely after, 30~50 parts of washing reaction liquids of 2N hydrochloric acid twice, organic layer anhydrous sodium sulfate
Dry, evaporated under reduced pressure, by column chromatography, obtain compound 6；
Step 5,7-10 parts compound 6 is dissolved in 100-120 part dichloromethane；10-13 part hydrogen chloride is added at room temperature
Ethanol solution, stirring reaction 3-6 hours；After reaction completely, evaporated under reduced pressure solvent, residue adds 100-120 part acetic acid second
Ester dissolves, and saturated sodium bicarbonate solution washs 2 times, each 40-50 parts, organic layer anhydrous sodium sulfate drying, evaporated under reduced pressure solvent,
By column chromatography, compound 7 is obtained；
Step 6,5-6 parts compound 7,20-30 part triethylamines, chloroethoxy ethyl acetate 25-30 parts are sealed in tube sealing
In；110-115 DEG C is warming up to, stirring reaction 22-24 hours；After reaction completely, 300-400 part elutriations are slowly dropped under stirring and are gone out
Solid, agitation and filtration；Filter cake crosses post purifying, obtains compound 8；
Step 7,5-7 parts compound 8 is dissolved in the dichloromethane of 60-80 parts drying, adds triethylamine 15-18 parts,
Argon gas protection stirring, it is cooled to 0 DEG C；The chloro- 2 acyl chlorides thiophene 2.5-3.5 parts of 5- are slowly added dropwise, drip off after 0 DEG C of stirring reaction 10-
12 hours, TLC monitoring reaction process, after reaction completely, twice, saturation NaCl solution washed two to 2N watery hydrochloric acid washing reaction liquid
It is secondary, anhydrous sodium sulfate drying, evaporated under reduced pressure solvent, pass through post, and obtain compound 9；
Step 8, compound 9 is sealed in the methanol solution tube sealing of 90-120 part methylamines, reaction 24 hours is stirred at room temperature,
After reaction completely, solvent is spin-dried for, crosses post purifying；Obtain relevant material F.
It is a kind of that the method about material G is synthesized about material F based on razaxaban, chemical combination is first prepared into using the above method
Thing 9, then using following synthetic line synthetic G synthetic line：
Wherein, the synthesis step about material G is as follows：
Step 1, the synthesis of compound 10,3-4 parts compound 9 is dissolved in 45-55 parts tetrahydrofuran/methanol=2/1
In dry mixed solvent；Lithium hydroxide 0.2-0.3 parts, stirring reaction 5-6 hours are added at room temperature；After reaction completely, decompression rotation
Dry solvent；Residue adds 15-16 parts water to dissolve, and 2N watery hydrochloric acid regulation PH is 1.7-2.2；Solid is with dichloromethane 50-55 parts
After dissolving, layering, water layer is discarded, organic phase is spin-dried for, and by column chromatography, obtains compound 10；
Step 2, the synthesis about material G, by compound obtained by previous step, (S) -4- (4- (5- (amino methyl) -2- oxygen
Generation -1,3- oxazolidine -3- bases) phenyl) morpholine -3- keto hydrochloride 1.5-1.7 parts, the DMAP of catalytic amount is dissolved in 30-32 parts and does
In dry DCM；Under nitrogen protection, under conditions of 0-2 DEG C, HOBT1-3 parts are sequentially added, EDCI1.5-2.2 parts, and in the temperature
The lower stirring reaction of degree 10 hours；After TLC detection reactions completely, gone out reaction with 10-11 part water quenchings, organic layer saturation NaCl solution
20-30 parts wash twice, and evaporated under reduced pressure solvent, are crossed post separation, obtain relevant material G.
A kind of synthetic line of the relevant substance A of razaxaban is as follows：
Synthesis step about substance A is as follows：
At room temperature, Anhydrous potassium carbonate 6.5-7.0 parts are added to the chloro- N- of (S) -5- ({ 2- oxos -3- [4- (3- oxos -4-
Morpholinyl) phenyl] -1,3- oxazolidine -5- bases methyl) -2- formamide hydrochloride 16-18 parts 100-130 part aqueous solution in,
React at room temperature 2-2.5 hours；Concentration removes reaction solution reclaimed water, then is washed, filtered with 30-50 part methanol, and filtrate is concentrated, and does
It is dry obtain the chloro- N- of (S) -5- ({ 2- oxos -3- [4- (3- oxo -4- morpholinyls) phenyl] -1,3- oxazolidine -5- bases } methyl) -
2- formamides；Under the protection of room temperature argon gas, 4.5-5 part anhydrous triethylamines are added into the chloro- N- of (S) -5- ({ 2- oxos -3- [4- (3-
Oxo -4- morpholinyls) phenyl] -1,3- oxazolidine -5- bases methyl) -2- formamides 600-800 part anhydrous tetrahydro furans it is outstanding
In supernatant liquid, then 5-7 part chloroacetic chlorides are added dropwise, reacted at room temperature 2 hours；Add successively again anhydrous 2.2-2.5 parts triethylamine and
2.2-2.5 part chloroacetic chlorides continue to react 2-3 hours, and TCL (EA/MeOH=10/1) monitorings, raw material point disappears substantially；Use 20-
22 parts of water quenching reactions；Concentration carries out silica gel column chromatography (EA/MeOH=10:1) relevant substance A is obtained.
A kind of synthetic line of the relevant substance B of razaxaban is as follows：
The step of relevant substance B synthesis, is as follows：
Weigh the chloro- N- of (S) -5- ({ 2- oxos -3- [4- (3- oxo -4- morpholinyls) phenyl] -1,3- oxazolidine -5- bases }
Methyl) -2- formamide hydrochloride 32-33 parts in 250-300 part anhydrous tetrahydro furans, are added dropwise to the second of 15-17 parts three under stirring
Amine；Finish, ice-water bath is cooled to 0-5 DEG C, obtains white suspension；Insulation, it is disposable to add triphosgene 15-22 parts, stir about 2-3
Hour, 10-12 part triethylamines are added, and go to and be stirred overnight at room temperature；TLC (DCM/MeOH=10/1) monitoring raw materials have reacted
Entirely, reaction is stopped；Filtering, filtrate are washed with 1000-1200 part saturated sodium carbonates；Saturation NaCl solution 600- is added in organic layer
800 parts, 2-4 hours are stirred at room temperature, there is white solid precipitation；Filtering, filter cake washing, vacuum drying, obtains relevant substance B.
A kind of relevant material E synthetic lines of razaxaban are as follows：
The step of relevant material E synthesis, is as follows：
Step 1, the formic acid 10-12 parts of 4,5- dichloro-thiophenes -2 are weighed to be dissolved in 100-130 part toluene, instill 0.3-0.5 parts
DMF；Under stirring, thionyl chloride 7-9 parts are added dropwise；It is added dropwise, goes in oil bath and be heated to flowing back, 118-121 DEG C of oil bath temperature,
Reaction solution is gradually clarified, and is reacted 2 hours；Stop heating, be cooled to room temperature, be concentrated under reduced pressure to obtain grease；By residue 50-60
Part toluene dissolving, that is, it is prepared into the toluene solution of 4,5- dichloro-thiophene -2- formyl chlorides；
Step 2, (S) -4- (4- (5- (amino methyl) -2- oxo -1,3- oxazolidine -3- bases) phenyl) morpholine -3- ketone is taken
14 parts of hydrochloride is dissolved in the solution of 150-200 parts water/acetone=2/1, and 11 parts of sodium carbonate of lower addition are stirred at room temperature, must clarify
Bright solution；The toluene solution of above-mentioned 4, the 5- dichloro-thiophene -2- formyl chlorides prepared, TLC detections (PE/ are added dropwise into reaction bulb
EA=2/3) reaction finishes, about 2-3 hours；50-55 part acetone, filtering, filter cake water 45-60 successively are added into reaction system
Part, the washing of acetone 50-55 parts；Pale solid is obtained, vacuum drying, obtains relevant material E.
Compared with prior art, technical scheme provided by the invention, it is to provide a kind of having for razaxaban
Close substance A, B, E, F, G preparation method.Particularly cut down relevant material F, G of husky class a kind of new preparation method.Profit cuts down sand
The relevant material F of class novel preparation method, includes step：1) tert-butyl group -4- amino anilines formic acid esters and (S) -2- (2- epoxy second
Alkyl methyl) condensation of -1H- iso-indoles -1,3- diketone；2) with the cyclization of imidazoles；3) phthalyl protection is sloughed；And 5- 4)
Chloro- 2 acyl chlorides thiophene is reacted into acid amides；5) Boc blocking groups are sloughed；6) with chloroethoxy acetic acid ethyl reaction, one on amino
Ethoxy ethyl acetate；7) 2 acyl chlorides thiophene chloro- with 5- is reacted into acid amides again；8) with the methanol solution ester exchange of methylamine.Profit is cut down
The relevant material G of husky class novel preparation method, includes step：1) on the basis of relevant material F is prepared, second ester hydrolysis；2)
With the chloro- N- of (S) -5- ({ 2- oxos -3- [4- (3- oxo -4- morpholinyls) phenyl] -1,3- oxazolidine -5- bases } methyl) -2- first
Amide condensed reaction.
Embodiment
Technical scheme is clearly and completely described below in conjunction with embodiment, it is clear that described reality
It is only part of the embodiment of the present invention to apply example, rather than whole embodiments.It is general based on the embodiment in the present invention, this area
The every other embodiment that logical technical staff is obtained under the premise of creative work is not made, belong to what the present invention protected
Scope.
In following embodiments, nuclear magnetic resonance is by Bruker AMX-400 type nmr determinations, and TMS is internal standard, chemistry
Displacement unit is ppm；Efficient liquid phase (HPLC) is detected by Agilent 1100；TLC silica gel plates GF254 is Haiyang Chemical Plant, Qingdao
Production, is developed the color using uviol lamp；If unspecified operating method in embodiment, the finger Rotary Evaporators that are concentrated under reduced pressure will
Solvent in prepare compound solution steams；Described drying refers to refers to use with anhydrous sodium sulfate or magnesium sulfate, the vacuum drying
Prepare compound is dried in vacuo in vacuum drying chamber.
The english abbreviation being related in text
MeOH=methanol
TLC=tlc analysis
EA=ethyl acetate
DCM=dichloromethane
DMF=N, dinethylformamide
PE=petroleum ethers
DMAP=4- dimethyl aminopyridines
EDCI=1- ethyls-(3- dimethylaminopropyls) phosphinylidyne diimmonium salt hydrochlorate
HOBt=1- hydroxybenzotriazoles
Synthesis about substance A
Synthetic route
Embodiment 1
At room temperature, Anhydrous potassium carbonate 6.7g adds the chloro- N- of (S) -5- ({ 2- oxos -3- [4- (3- oxo -4- morpholinyls)
Phenyl] -1,3- oxazolidine -5- bases methyl) -2- formamide hydrochlorides 16g the 100mL aqueous solution in, react at room temperature 2 hours.
Concentration removes reaction solution reclaimed water, then is washed with 30mL methanol, filters, and filtrate is concentrated, and is dried to obtain chloro- the N- ({ 2- of (S) -5-
Oxo -3- [4- (3- oxo -4- morpholinyls) phenyl] -1,3- oxazolidine -5- bases } methyl) -2- formamides, protected in room temperature argon gas
Under shield, by 4.5mL anhydrous triethylamines add to the chloro- N- of (S) -5- (2- oxos -3- [4- (3- oxo -4- morpholinyls) phenyl] -1,
3- oxazolidine -5- bases } methyl) -2- formamides 600mL anhydrous tetrahydro furans suspension in, then 5mL chloroacetic chlorides are added dropwise
Enter, react at room temperature 2 hours.TCL (EA/MeOH=10:1) tracking display, still with the presence of part material.Add successively again anhydrous
2.2mL triethylamines and 2.2mL chloroacetic chlorides continue reaction 2 hours, TCL (EA/MeOH=10/1) monitorings, and raw material point disappears substantially
Lose.It is quenched and is reacted with 20mL water.Concentration carries out silica gel column chromatography (EA/MeOH=10:1) relevant substance A is obtained, is white powder
13.2g, yield 80.7%.
ES-MS(m/z):356[M+Na]+；
1H-NMR(DMSO-d6,400MHz)δ：8.25 (t, J=3.6Hz, 1H)；7.56 (d, J=6Hz, 2H)；7.40(d,J
=6Hz, 2H)；4.70-4.74 (m, 1H)；4.19 (s, 2H)；4.12 (t, J=6Hz, 1H)；3.96 (t, J=3.6Hz, 2H)；
3.75 (d, J=4.4Hz, 1H)；3.71 (d, J=3.2Hz, 2H)；3.42 (t, J=3.6Hz, 2H)；1.84 (s, 3H).
Embodiment 2
At room temperature, Anhydrous potassium carbonate 70g adds the chloro- N- of (S) -5- ({ 2- oxos -3- [4- (3- oxo -4- morpholinyls)
Phenyl] -1,3- oxazolidine -5- bases methyl) -2- formamide hydrochlorides 180g the 1.3mL aqueous solution in, room temperature reaction is 2.5 small
When.Concentration removes reaction solution reclaimed water, then is washed with 500mL methanol, filters, and filtrate is concentrated, and is dried to obtain the chloro- N- of (S) -5-
({ 2- oxos -3- [4- (3- oxo -4- morpholinyls) phenyl] -1,3- oxazolidine -5- bases } methyl) -2- formamides, in room temperature argon
Under gas shielded, 500mL anhydrous triethylamines are added into the chloro- N- of (S) -5- ({ 2- oxos -3- [4- (3- oxo -4- morpholinyls) benzene
Base] -1,3- oxazolidine -5- bases methyl) -2- formamides 8.0L anhydrous tetrahydro furans suspension in, then by 70mL chloroacetic chlorides
It is added dropwise, reacts at room temperature 2 hours.TCL (EA/MeOH=10:1) tracking display, still with the presence of part material.Add successively again
Anhydrous 25mL triethylamines and 25mL chloroacetic chlorides continue reaction 2 hours, TCL (EA/MeOH=10/1) monitorings, and raw material point disappears substantially
Lose.It is quenched and is reacted with 220mL water.Concentration carries out silica gel column chromatography (EA/MeOH=10:1) relevant substance A is obtained, is white powder
112g, yield 61.2%.
Embodiment 3
At room temperature, Anhydrous potassium carbonate 65g adds the chloro- N- of (S) -5- ({ 2- oxos -3- [4- (3- oxo -4- morpholinyls)
Phenyl] -1,3- oxazolidine -5- bases methyl) -2- formamide hydrochlorides 160g the 1.2mL aqueous solution in, react at room temperature 2 hours.
Concentration removes reaction solution reclaimed water, then is washed with 400mL methanol, filters, and filtrate is concentrated, and is dried to obtain the chloro- N- of (S) -5-
({ 2- oxos -3- [4- (3- oxo -4- morpholinyls) phenyl] -1,3- oxazolidine -5- bases } methyl) -2- formamides, in room temperature argon
Under gas shielded, by 46mL anhydrous triethylamines add to the chloro- N- of (S) -5- (2- oxos -3- [4- (3- oxo -4- morpholinyls) phenyl] -
1,3- oxazolidine -5- bases } methyl) -2- formamides 7L anhydrous tetrahydro furans suspension in, then 6mL chloroacetic chlorides are added dropwise
Enter, react at room temperature 2 hours.TCL (EA/MeOH=10:1) tracking display, still with the presence of part material.Add successively again anhydrous
25mL triethylamines and 25mL chloroacetic chlorides continue reaction 2 hours, TCL (EA/MeOH=10/1) monitorings, and raw material point disappears substantially.
It is quenched and is reacted with 210mL water.Concentration carries out silica gel column chromatography (EA/MeOH=10:1) relevant substance A is obtained, is white powder
126g, yield 77.4%.
Synthesis about substance B
Synthetic route
Embodiment 1
Weigh the chloro- N- of (S) -5- ({ 2- oxos -3- [4- (3- oxo -4- morpholinyls) phenyl] -1,3- oxazolidine -5- bases }
Methyl) -2- formamides hydrochlorides 32.7g is added dropwise to 15.2g triethylamines under 2.5L anhydrous tetrahydro furans, stirring.Finish, ice
Water-bath cooling obtains white suspension to 0-5 DEG C.Insulation, it is disposable to add triphosgene 15g, stir about 2 hours, add the second of 10g tri-
Amine, and go to and be stirred overnight at room temperature.TLC (DCM/MeOH=10/1) monitoring raw material reactions are complete, stop reaction.Filtering, filtrate
Washed with 1L saturated sodium carbonates；Saturation NaCl solution 600mL is added in organic layer, stirs 2 hours at room temperature, there is white solid analysis
Go out.Filtering, filter cake washing, vacuum drying.Relevant substance B, be white solid powder 6.4g, yield 10.5%.
Mp:224-226℃；
ES-MS(m/z):631[M+Na]+；
1H-NMR(DMSO-d6,400MHz)δ：7.55 (d, J=9.2Hz, 4H)；7.39 (d, J=9.2Hz, 4H)；6.43
(t, J=6.0Hz, 2H)；4.60-4.67 (m, 2H)；4.17 (s, 4H)；4.08 (t, J=9.0Hz, 2H)；3.95 (t, J=
5.0Hz, 4H)；3.75-3.79 (m, 2H)；3.69 (t, J=5.0Hz, 4H)；3.38 (t, J=5.2Hz, 4H).
Embodiment 2
Weigh the chloro- N- of (S) -5- ({ 2- oxos -3- [4- (3- oxo -4- morpholinyls) phenyl] -1,3- oxazolidine -5- bases }
Methyl) -2- formamides hydrochlorides 16g is added dropwise to 7.5g triethylamines under 1.35L anhydrous tetrahydro furans, stirring.Finish, frozen water
Bath is cooled to 0-5 DEG C, obtains white suspension.Insulation, it is disposable to add triphosgene 8g, stir about 2 hours, add the second of 5.5g tri-
Amine, and go to and be stirred overnight at room temperature.TLC (DCM/MeOH=10/1) monitoring raw material reactions are complete, stop reaction.Filtering, filtrate
Washed with 450mL saturated sodium carbonates；Saturation NaCl solution 300mL is added in organic layer, is stirred 2 hours at room temperature, has white solid
Body separates out.Filtering, filter cake washing, vacuum drying.Relevant substance B, be white solid powder 3.5g, yield 11.8%.
Embodiment 3
Weigh the chloro- N- of (S) -5- ({ 2- oxos -3- [4- (3- oxo -4- morpholinyls) phenyl] -1,3- oxazolidine -5- bases }
Methyl) -2- formamides hydrochlorides 33g is added dropwise to 17g triethylamines under 3L anhydrous tetrahydro furans, stirring.Finish, ice-water bath is cold
But to 0-5 DEG C, white suspension is obtained.Insulation, it is disposable to add triphosgene 22g, stir about 2 hours, 12g triethylamines are added, and
Go to and be stirred overnight at room temperature.TLC (DCM/MeOH=10/1) monitoring raw material reactions are complete, stop reaction.Filtering, filtrate are satisfied with 1L
Washed with sodium carbonate；Saturation NaCl solution 800mL is added in organic layer, stirs 2 hours at room temperature, there is white solid precipitation.Cross
Filter, filter cake washing, vacuum drying.Relevant substance B, be white solid powder 8g, yield 13.1%.
Synthesis about material E
Synthetic route
Embodiment 1
The formic acid 10g of 4,5- dichloro-thiophenes -2 is weighed in 100mL toluene, instills 10 drop DMF.Under stirring, protochloride is added dropwise
Sulfone 7.2g.It is added dropwise, goes in oil bath and be heated to flowing back (120 DEG C of oil bath temperature), reaction solution is gradually clarified, and reaction two is small
When.Stop heating, be cooled to room temperature, be concentrated under reduced pressure to obtain grease.Residue 50mL toluene is dissolved, that is, is prepared into 4,5- bis-
The toluene solution of chlorothiophene -2- formyl chlorides, it is stand-by.
Take (S) -4- (4- (5- (amino methyl) -2- oxo -1,3- oxazolidine -3- bases) phenyl) morpholine -3- keto hydrochlorides
14g is dissolved in the solution of 150mL (water/acetone=2/1), and lower addition 11g sodium carbonate is stirred at room temperature, obtains clear transparent solutions.To
The toluene solution of above-mentioned 4, the 5- dichloro-thiophene -2- formyl chlorides prepared is added dropwise in reaction bulb, there is pale solid precipitation.TLC
Detection (PE/EA=2/3) reaction finishes, about 2-3 hours.50mL acetone, filtering, filter cake water successively are added into reaction system
50mL, acetone 50mL are washed.Pale solid is obtained, vacuum drying, obtains relevant material E 13.7g, yield 49.1%.
Mp：208-210 DEG C,
ES-MS(m/z):469[M-H]-；
1H-NMR(DMSO-d6,400MHz)δ:9.01 (t, J=5.8Hz, 1H)；7.85 (s, 1H), 7.54-7.57 (m,
2H)；7.38-7.42 (m, 2H)；4.81-4.87 (m, 1H)；4.19 (s, 2H)；4.17-4.21 (m, 1H)；3.97 (t, J=
5.0Hz, 2H)；3.83-3.87(m,1H)；3.71 (t, J=5.2Hz, 2H)；3.63 (t, J=5.2Hz, 2H).
13C-HMRR(DMSO-d6,400MHz)δ:165.96；159.95；154.06；137.07；136.67；136.47；
128.55；127.77；125.94；123.30；118.33；71.26；67.73；63.47；49.01；47.40；42.27.
Embodiment 2
The formic acid 110g of 4,5- dichloro-thiophenes -2 is weighed in 1.2L toluene, instills 10 drop DMF.Under stirring, protochloride is added dropwise
Sulfone 80g.It is added dropwise, goes in oil bath and be heated to flowing back, reaction solution is gradually clarified, and is reacted two hours.Stop heating, be cooled to
Room temperature, be concentrated under reduced pressure to obtain grease.Residue 550mL toluene is dissolved, that is, is prepared into 4,5- dichloro-thiophene -2- formyl chlorides
Toluene solution, it is stand-by.
Take (S) -4- (4- (5- (amino methyl) -2- oxo -1,3- oxazolidine -3- bases) phenyl) morpholine -3- keto hydrochlorides
140g is dissolved in the solution of 1.8L (water/acetone=2/1), and lower addition 110g sodium carbonate is stirred at room temperature, obtains clear transparent solutions.To
The toluene solution of above-mentioned 4, the 5- dichloro-thiophene -2- formyl chlorides prepared is added dropwise in reaction bulb, there is pale solid precipitation.TLC
Detection (PE/EA=2/3) reaction finishes, about 2-3 hours.520mL acetone, filtering, filter cake water successively are added into reaction system
500mL, acetone 520mL are washed.Pale solid is obtained, vacuum drying, obtains relevant material E 165g, yield 82.1%.
Embodiment 3
The formic acid 120g of 4,5- dichloro-thiophenes -2 is weighed in 1.3L toluene, instills 50 drop DMF.Under stirring, protochloride is added dropwise
Sulfone 90g.It is added dropwise, goes in oil bath and be heated to flowing back (120 DEG C of oil bath temperature), reaction solution is gradually clarified, and is reacted two hours.
Stop heating, be cooled to room temperature, be concentrated under reduced pressure to obtain grease.Residue 600mL toluene is dissolved, that is, is prepared into 4,5- dichloros
The toluene solution of thiophene -2- formyl chlorides, it is stand-by.
Take (S) -4- (4- (5- (amino methyl) -2- oxo -1,3- oxazolidine -3- bases) phenyl) morpholine -3- keto hydrochlorides
140g is dissolved in the solution of 150mL (water/acetone=2/1), and lower addition 110g sodium carbonate is stirred at room temperature, obtains clear transparent solutions.
The toluene solution of above-mentioned 4, the 5- dichloro-thiophene -2- formyl chlorides prepared is added dropwise into reaction bulb, there is pale solid precipitation.
TLC detections (PE/EA=2/3) reaction finishes, about 3 hours.550mL acetone, filtering, filter cake water successively are added into reaction system
600mL, acetone 550mL are washed.Pale solid is obtained, vacuum drying, obtains relevant material E 114g, yield 56.75%.
Synthesis about material F
Synthetic route
Embodiment 1
1.1st, the synthesis of compound 3：
By the tert-butyl group -4- amino anilines formic acid esters 1 (10g, 48mmol) and (S) -2- (2- oxiranylmethyl radicals) -1H-
Iso-indoles -1,3- diketone 2 (15g, 72mmol) is dissolved in 200mL isopropanols；Slow temperature rising reflux reaction, TLC monitoring reactions.
After reaction completely in about 5 hours, room temperature is down to；The solid of precipitation is filtered, is dried to obtain 20g compounds 3, yield 99%.
ES-MS(m/z):412[M+H]+。
1.2nd, the synthesis of compound 4：
Successively by compound 3 (10.46g, 25.4mmol), DMF 40mL, dicarbapentaborane imidazoles (CDI) obtained by previous step
(8.6g, 50.8mmol), catalytic amount DMAP are added in reaction bulb；Be warming up to 100 DEG C of stirring reactions, TLC monitorings react into
Journey.After reaction completely, water 100ml is added into reaction system, agitation and filtration, dry compound 4, is white solid
10.08g yield 90%.
ES-MS(m/z):438[M+H]+。
1.3rd, the synthesis of compound 5：
Compound 4 (12g, 27.6mmol) is dissolved in 60mL absolute ethyl alcohols, stirs lower addition (3.09g, 46mmol)
Hydrazine hydrate.Temperature rising reflux reacts 2 hours, TLC monitoring reaction process.After reaction completely, solid is filtered to remove, alcohol layer concentrates,
Compound 5 is separated to obtain through silica gel column chromatography (MeOH/DCM=15/1,0.5% ammoniacal liquor), is white solid 7.6g, yield
89.5%.
ES-MS(m/z):308[M+H]+。
1.4th, the synthesis of compound 6：
Compound 5 (7.6g, 24.7mmol) is dissolved in 80mL dichloromethane, add dry triethylamine (3.25g,
32.11mmol) stir, argon gas protection drops to 0 DEG C, and the chloro- 2 acyl chlorides thiophene of (3.2g, 32.11mmol) 5- is slowly added dropwise；Drip off
After 0 DEG C of stirring reaction 10 hours, TLC monitoring reaction process.After reaction completely, 2N hydrochloric acid 30mL washing reaction liquids twice, have
Machine layer anhydrous sodium sulfate drying, evaporated under reduced pressure, by column chromatography, compound 7 is obtained, be white solid 8.1g, yield 72.5%.
ES-MS(m/z):453[M+H]+。
1.5th, the synthesis of compound 7：
Compound 6 (8.1g, 17.9mmol) is dissolved in 100mL dichloromethane；The second of 10mL hydrogen chloride is added at room temperature
Alcoholic solution, stirring reaction 5 hours；After reaction completely, evaporated under reduced pressure solvent.Residue adds the dissolving of 100mL ethyl acetate, saturation
Sodium bicarbonate solution washs 2 times, each 40mL, organic layer anhydrous sodium sulfate drying.Evaporated under reduced pressure solvent, by column chromatography, obtain
It is off-white powder 5.6g to compound 6, yield 89%.
ES-MS(m/z):375[M+Na]+。
1.6th, the synthesis of compound 8：
By compound G (5.6g, 15.9mmol), 50mlDMF, 20ml triethylamines, chloroethoxy ethyl acetate (27g,
159mmol) it is sealed in tube sealing；110 DEG C are warming up to, stirring reaction 24 hours；After reaction completely, it is slowly dropped under stirring
300ml elutriations go out solid, agitation and filtration；Filter cake crosses post purifying, obtains compound 8, is light yellow solid 6.4g, yield
83.3%.
ES-MS(m/z):483[M+H]+。
1.7th, the synthesis of compound 9
Compound 8 (6.4g, 13.2mmol) is dissolved in the dichloromethane of 70ml dryings, addition triethylamine (17.36g,
17.16mmol), argon gas protection stirs, is cooled to 0 DEG C；The chloro- 2 acyl chlorides thiophene (3.0g, 17.16mmol) of 5- are slowly added dropwise, drip off
After 0 DEG C of stirring reaction 10 hours, TLC monitoring reaction process.After reaction completely, 2N watery hydrochloric acid washs 50ml reaction solutions twice,
Saturation NaCl solution 50 is washed 2 times, anhydrous sodium sulfate drying.Evaporated under reduced pressure solvent, passed through post, obtained compound 9, was pale yellow
Color solid 7.0g, yield 84.6%.
ES-MS(m/z):627[M+H]+。
1.8th, the synthesis about material F：
The methanol solution of compound 9 (3.0g, 4.78mmol) 20ml methylamines is sealed in 100mL tube sealings, is stirred at room temperature
Reaction 24 hours, TLC monitoring reaction ends.After reaction completely, solvent is spin-dried for, crosses post purifying；Relevant material F is obtained, for white
Solid 1.1g, yield 37.6%.
ES-MS(m/z):611[M+H]+；
1H-NMR(CDCl3,400MHz)δ:7.61 (d, J=8.8Hz, 2H)；7.36 (d, J=4.0Hz, 1H), 7.28 (s,
2H)；6.91 (d, J=4Hz, 1H)；6.71-6.74 (m, 1H)；6.63-6.67 (m, 3H)；4.87-4.93 (m, 1H)；4.15 (d,
J=9.2Hz, 2H)；4.03 (t, J=7.2Hz, 2H)；3.94 (s, 4H)；3.89-3.92 (m, 1H)；3.69-3.21 (m, 2H)；
2.80 (d, J=4.8Hz, 3H).
Embodiment 2
2.1st, the synthesis of compound 3：
By the tert-butyl group -4- amino anilines formic acid esters 1 (6g, 28.8mmol) and (S) -2- (2- oxiranylmethyl radicals) -1H-
Iso-indoles -1,3- diketone 2 (8g, 38.4mmol) is dissolved in 150mL isopropanols；Slow temperature rising reflux reaction, TLC monitorings are anti-
Should.After reaction completely in about 5 hours, room temperature is down to；The solid of precipitation is filtered, is dried to obtain 11.4g compounds 3, yield 90%.
ES-MS(m/z):412[M+H]+。
2.2nd, the synthesis of compound 4：
Successively by compound 3 (8g, 19.4mmol), DMF 35mL, dicarbapentaborane imidazoles (CDI) 7g, catalysis obtained by previous step
Dosage DMAP is added in reaction bulb；It is warming up to 100 DEG C of stirring reactions, TLC monitoring reaction process.After reaction completely, to reaction
Add water 110mL in system, agitation and filtration, dry compound 4 is white solid 7.8g, yield 92%.
ES-MS(m/z):438[M+H]+。
2.3rd, the synthesis of compound 5：
Compound 4 (14g, 32.0mmol) is dissolved in 70mL absolute ethyl alcohols, stirs lower addition (3.2g, 64.0mmol)
Hydrazine hydrate.Temperature rising reflux reacts 3 hours, TLC monitoring reaction process.After reaction completely, solid is filtered to remove, alcohol layer concentrates,
Compound 5 is separated to obtain through silica gel column chromatography (MeOH/DCM=15/1,0.5% ammoniacal liquor), is white solid 8.36g, yield
85.0%.
ES-MS(m/z):308[M+H]+。
2.4th, the synthesis of compound 6：
Compound 5 (16.0g, 52.0mmol) is dissolved in 160mL dichloromethane, add dry triethylamine (8.0g,
79.mmol) stir, argon gas protection drops to 0 DEG C, and the chloro- 2 acyl chlorides thiophene of (14.3g, 79.0mmol) 5- is slowly added dropwise；After dripping off
In 0 DEG C of stirring reaction 12 hours, TLC monitoring reaction process.After reaction completely, 2N hydrochloric acid 60mL washing reaction liquids are twice, organic
Layer anhydrous sodium sulfate drying, evaporated under reduced pressure, by column chromatography, obtains compound 6, is white solid 15g, yield 63.8%.
ES-MS(m/z):453[M+H]+。
2.5th, the synthesis of compound 7：
Compound 6 (32g, 70.8mmol) is dissolved in 350mL dichloromethane；The second of 110mL hydrogen chloride is added at room temperature
Alcoholic solution, stirring reaction 5 hours；After reaction completely, evaporated under reduced pressure solvent.Residue adds the dissolving of 450mL ethyl acetate, saturation
Sodium bicarbonate solution washs 2 times, each 150mL, organic layer anhydrous sodium sulfate drying.Evaporated under reduced pressure solvent, by column chromatography, obtain
It is off-white powder 20.6g to compound 7, yield 82.7%.
ES-MS(m/z):375[M+Na]+。
2.6th, the synthesis of compound 8：
By compound 7 (20.0g, 56.84mmol), DMF 250ml, triethylamine 220ml, chloroethoxy ethyl acetate
(100g, 150mmol) is sealed in tube sealing；110 DEG C are warming up to, stirring reaction 24 hours；After reaction completely, lower slowly drop is stirred
Enter 1.5l elutriations and go out solid, agitation and filtration；Filter cake crosses post purifying, obtains compound 8, is light yellow solid 14.5g, yield
52.9%.
ES-MS(m/z):483[M+H]+。
2.7th, the synthesis of compound 9
Compound 8 (12g, 24.9mmol) is dissolved in the dichloromethane of 120ml dryings, addition triethylamine (3.6g,
35.6mmol), argon gas protection stirs, is cooled to 0 DEG C；The chloro- 2 acyl chlorides thiophene (6.4g, 35.6mmol) of 5- are slowly added dropwise, after dripping off
In 0 DEG C of stirring reaction 10 hours, TLC monitoring reaction process.After reaction completely, 2N watery hydrochloric acid washing 120ml reaction solutions 2 times, satisfy
Washed 2 times with NaCl solution 120ml, anhydrous sodium sulfate drying.Evaporated under reduced pressure solvent, by column chromatography for separation, obtain compound
9, it is light yellow solid 13.8g, yield 88.46%.
ES-MS(m/z):627[M+H]+。
2.8th, the synthesis about material F：
The methanol solution that compound 9 (13.0g, 20.75mmol) is added to 145ml methylamines is sealed in 1.0L tube sealings,
Reaction 24 hours, TLC monitoring reaction ends is stirred at room temperature.After reaction completely, solvent is spin-dried for, crosses post purifying；Obtain relevant material
F, is white solid 6.1g, yield 48.0%.
Embodiment 3
3.1st, the synthesis of compound 3：
By the tert-butyl group -4- amino anilines formic acid esters 1 (12g, 57.62mmol) and (S) -2- (2- oxiranylmethyl radicals) -
1H- iso-indoles -1,3- diketone 2 (17g, 83.66mmol) is dissolved in 230mL isopropanols；Slow temperature rising reflux reaction, TLC prisons
Survey reaction.After reaction completely in about 5 hours, room temperature is down to；The solid of precipitation is filtered, is dried to obtain 21g compounds 3, yield
88.58%.ES-MS(m/z):412[M+H]+。
3.2nd, the synthesis of compound 4：
Successively by compound 3 (14g, 34mmol) obtained by previous step, DMF 50mL, dicarbapentaborane imidazoles (CDI) (9g,
50.8mmol), catalytic amount DMAP is added in reaction bulb；It is warming up to 100 DEG C of stirring reactions, TLC monitoring reaction process.Reaction
After completely, water 150ml is added into reaction system, agitation and filtration, dry compound 4 is white solid 12.94g, yield
87%.
ES-MS(m/z):438[M+H]+。
3.3rd, the synthesis of compound 5：
Compound 4 (20g, 45.7mmol) is dissolved in 100mL absolute ethyl alcohols, stirs lower addition (7g, 138mmol) water
Close hydrazine.Temperature rising reflux reacts 2 hours, TLC monitoring reaction process.After reaction completely, solid, alcohol layer concentration, warp are filtered to remove
Silica gel column chromatography (MeOH/DCM=15/1,0.5% ammoniacal liquor) separates to obtain compound 5, is white solid 16.5g, yield 85%.
ES-MS(m/z):308[M+H]+。
3.4th, the synthesis of compound 6：
Compound 5 (16g, 52mmol) is dissolved in 180mL dichloromethane, add dry triethylamine (8g,
79mmol) stir, argon gas protection drops to 0 DEG C, and the chloro- 2 acyl chlorides thiophene of (14.3g, 79mmol) 5- is slowly added dropwise；Drip off after 0
DEG C stirring reaction 10 hours, TLC monitoring reaction process.Reaction completely after, 2N hydrochloric acid 80mL washing reaction liquids twice, organic layer without
Aqueous sodium persulfate is dried, and evaporated under reduced pressure, by column chromatography, obtains compound 6, is white solid 16.2g, yield 69%.ES-MS
(m/z):453[M+H]+。
3.5th, the synthesis of compound 7：
Compound 6 (10g, 22.1mmol) is dissolved in 120mL dichloromethane；The ethanol of 13mL hydrogen chloride is added at room temperature
Solution, stirring reaction 5 hours；After reaction completely, evaporated under reduced pressure solvent.Residue adds the dissolving of 100mL ethyl acetate, saturated carbon
Sour hydrogen sodium solution washs 2 times, each 50mL, organic layer anhydrous sodium sulfate drying.Evaporated under reduced pressure solvent, by column chromatography, obtain
Compound 7, is off-white powder 6.37g, yield 82%.
ES-MS(m/z):375[M+Na]+。
3.6th, the synthesis of compound 8：
By compound 7 (14g, 15.9mmol), 50mlDMF, 20ml triethylamines, chloroethoxy ethyl acetate (27g,
159mmol) it is sealed in tube sealing；110 DEG C are warming up to, stirring reaction 24 hours；After reaction completely, it is slowly dropped under stirring
300ml elutriations go out solid, agitation and filtration；Filter cake crosses post purifying, obtains compound 8, is light yellow solid 6.4g, yield
83.3%.
ES-MS(m/z):483[M+H]+。
3.7th, the synthesis of compound 9
Compound 8 (7g, 14.5mmol) is dissolved in the dichloromethane of 80ml dryings, addition triethylamine (18g,
17.78mmol), argon gas protection stirs, is cooled to 0 DEG C；The chloro- 2 acyl chlorides thiophene (3.2g, 17.78mmol) of 5- are slowly added dropwise, drip off
After 0 DEG C of stirring reaction 11 hours, TLC monitoring reaction process.After reaction completely, 2N watery hydrochloric acid washs 50ml reaction solutions twice,
Saturation NaCl solution 50 is washed 2 times, anhydrous sodium sulfate drying.Evaporated under reduced pressure solvent, passed through post, obtained compound 9, was pale yellow
Color solid 6.8g, yield 74.8%.
ES-MS(m/z):627[M+H]+。
3.8th, the synthesis about material F：
The methanol solution of compound 9 (10.0g, 16mmol) 100ml methylamines is sealed in 1L tube sealings, reaction is stirred at room temperature
24 hours, TLC monitoring reaction ends.After reaction completely, solvent is spin-dried for, crosses post purifying；Relevant material F is obtained, is white solid
4.1g, yield 41.9%.
Synthesis about material G
Synthetic route
Embodiment 1
1.1st, the synthesis of compound 10
Compound 9 (3.5g, 5.58mmol) is dissolved in the dry mixed solvent of 50mL (tetrahydrofuran/methanol=2/1)
In；Lithium hydroxide (267mg, 12.6mmol), stirring reaction 5 hours are added at room temperature；After reaction completely, decompression is spin-dried for solvent；
Residue adds 15mL water to dissolve, and 2N watery hydrochloric acid regulation PH is 2, and a large amount of solids separate out.After solid is dissolved with dichloromethane 50mL,
Layering, discards water layer, and organic phase is spin-dried for, and by column chromatography, obtains compound 10, is white solid 3.0g, yield 89.8%.
ES-MS(m/z):599[M+H]+。
1.2nd, the synthesis about material G：
By compound 10 (3.0g, 5mmol), (S) -4- (4- (5- (amino methyl) -2- oxos -1,3- Evil obtained by previous step
Oxazolidine -3- bases) phenyl) morpholine -3- keto hydrochlorides (1.5g, 7.5mmol), the DMAP of catalytic amount is dissolved in the DCM of 30mL dryings
In.Under nitrogen protection, HOBT (1.35g, 10mmol), EDCI (1.97g, 10mmol) are sequentially added in 0 DEG C, and at this temperature
Stirring reaction 10 hours.After TLC detection reactions completely, gone out reaction with 10mL water quenchings, organic layer is washed with saturation NaCl solution 20mL
Wash twice, evaporated under reduced pressure solvent, crossed post separation, obtain relevant material G, be white solid 1.7g, yield 39%.
ES-MS(m/z):872[M+H]+；
1H-NMR(d6-DMSO,400MHz)δ:8.98 (t, 2H)；8.04 (t, 1H)；7.68 (t, 1H)；7.65 (m, 2H)；
7.54 (d, J=8.8Hz, 2H)；7.43 (d, J=8.8Hz, 2H)；7.39 (d, J=8.8Hz, 2H)；7.19 (d, J=4.0Hz,
1H)；6.94 (d, J=4.4Hz, 1H)；4.83-4.88 (m, 1H)；4.72-4.78 (m, 1H)；4.23 (t, 3H)；4.24 (s,
1H)；4.11-4.13 (m, 4H)；4.03 (t, J=7.2Hz, 2H)；3.90-3.95 (m, 5H)；3.78-3.82 (m, 1H)；3.72
(d, J=5.2Hz, 2H)；3.63-3.69 (m, 4H)；3.62 (d, J=4.8Hz, 2H).
Embodiment 2
2.1st, the synthesis of compound 10
Compound 9 (12g, 27.8mmol) is dissolved in the dry mixed solvent of 160mL (tetrahydrofuran/methanol=2/1)
In；Lithium hydroxide (900mg, 37.6mmol), stirring reaction 5 hours are added at room temperature；After reaction completely, decompression is spin-dried for solvent；
Residue adds 50mL water to dissolve, and 2N watery hydrochloric acid regulation PH is 2, and a large amount of solids separate out.Solid dichloromethane 150mL dissolves
Afterwards, it is layered, discards water layer, organic phase is spin-dried for, and by column chromatography, obtains compound 10, is white solid 14.2g, yield
85.2%.
ES-MS(m/z):599[M+H]+。
2.2nd, the synthesis about material G：
By compound 10 (14g, 23.4mmol), (S) -4- (4- (5- (amino methyl) -2- oxos -1,3- obtained by previous step
Oxazolidine -3- bases) phenyl) morpholine -3- keto hydrochlorides (15g, 51mmol), the DMAP of catalytic amount is dissolved in the DCM of 30mL dryings
In.Under nitrogen protection, HOBT (4g, 35mmol), EDCI (8g, 39mmol) are sequentially added in 0 DEG C, and it is anti-in stirring at this temperature
Answer 10 hours.After TLC detection reactions completely, being gone out reaction with 50mL water quenchings, organic layer is washed twice with saturation NaCl solution 90mL,
Evaporated under reduced pressure solvent, is crossed post separation, obtains relevant material G, is white solid 8.75g, yield 42.6%.
Embodiment 3
3.1st, the synthesis of compound 10
Compound 9 (9g, 14.36mmol) is dissolved in the dry mixed solvent of 150mL (tetrahydrofuran/methanol=2/1)
In；Lithium hydroxide (900mg, 37.6mmol), stirring reaction 5 hours are added at room temperature；After reaction completely, decompression is spin-dried for solvent；
Residue adds 45mL water to dissolve, and 2N watery hydrochloric acid regulation PH is 2, and a large amount of solids separate out.Solid dichloromethane 200mL dissolves
Afterwards, it is layered, discards water layer, organic phase is spin-dried for, and by column chromatography, obtains compound 10, is white solid 6.5g, yield
75.6%.
ES-MS(m/z):599[M+H]+。
3.2nd, the synthesis about material G：
By compound 10 (6.5g, 10.85mmol) obtained by previous step, (S) -4- (4- (5- (amino methyl) -2- oxo -1,
3- oxazolidine -3- bases) phenyl) morpholine -3- keto hydrochlorides (3.82g, 13mmol), the DMAP of catalytic amount is dissolved in 30mL dryings
In DCM.Under nitrogen protection, HOBT (2.7g, 20mmol), EDCI (3.9g, 20mmol) are sequentially added in 0 DEG C, and in the temperature
Lower stirring reaction 10 hours.After TLC detection reactions completely, gone out reaction with 35mL water quenchings, organic layer saturation NaCl solution 60mL
Wash twice, evaporated under reduced pressure solvent, crossed post separation, obtain relevant material G, be white solid 3.7g, yield 39%.
The foregoing is merely illustrative of the preferred embodiments of the present invention, is not intended to limit the invention, all essences in the present invention
God any modification, equivalent substitution and improvements made etc., should be included in the scope of the protection with principle.
Claims (3)
1. the method for the relevant material F synthesis of a kind of razaxaban, it is characterised in that material F synthetic line is as follows：
2. the synthetic method according to claim 1 about material F, Unit Weight part, it is characterised in that including following step
Suddenly：
Step 1, by the tert-butyl group -4- amino anilines formic acid esters 6-12 parts and the different Yin of (S) -2- (2- oxiranylmethyl radicals) -1H-
Diindyl -1,3- diketone 8-17 parts are dissolved in 150-230 part isopropanols；Slow temperature rising reflux reaction 4-9 hours, and supervised by TLC
After surveying reaction completely, room temperature is down to；The solid of precipitation is filtered, is dried to obtain compound 3；
Step 2,8-12 parts compound 3, DMF35-50 parts, dicarbapentaborane imidazoles (CDI) 7-9 parts, catalytic amount DMAP are added successively
Enter into reaction bulb；80-110 DEG C of stirring reaction is warming up to, TLC monitoring reaction process, after reaction completely, is added into reaction system
Enter water 100-120 parts, agitation and filtration, dry compound 4；
Step 3,10-14 parts compound 4 is dissolved in 50-70 part absolute ethyl alcohols, stirs lower addition 2.9-3.2 part hydrazine hydrates,
Temperature rising reflux reacts 2-3 hours, after TLC monitoring reaction process reactions completely, is filtered to remove solid, alcohol layer concentration, through silica gel
Column chromatography for separation obtains compound 5；
Step 4,7-8 parts compound 5 is dissolved in 60-90 part dichloromethane, adds dry triethylamine 3-4 parts stirring, argon
Gas shielded drops to 0-2 DEG C, and the chloro- 2 acyl chlorides thiophene of 3-3.5 parts 5- is slowly added dropwise；Drip off after 0 DEG C of stirring reaction 10-12 hour,
TLC monitor reaction process, reaction completely after, 2N hydrochloric acid 30-50 parts washing reaction liquid twice, organic layer anhydrous sodium sulfate drying,
Evaporated under reduced pressure, by column chromatography, obtain compound 6；
Step 5,7-10 parts compound 6 is dissolved in 100-120 part dichloromethane；The second of 10-13 part hydrogen chloride is added at room temperature
Alcoholic solution, stirring reaction 3-6 hours；After reaction completely, evaporated under reduced pressure solvent, it is molten that residue adds 100-120 part ethyl acetate
Solution, saturated sodium bicarbonate solution wash 2 times, each 40-50 parts, organic layer anhydrous sodium sulfate drying, evaporated under reduced pressure solvent, pass through
Column chromatography, obtain compound 7；
Step 6,5-6 parts compound 7,20-30 part triethylamines, chloroethoxy ethyl acetate 25-30 parts are sealed in tube sealing；Rise
Warm to 110-115 DEG C, stirring reaction 22-24 hours；After reactions completely, 300-400 part elutriations are slowly dropped under stirring and go out solid,
Agitation and filtration；Filter cake crosses post purifying, obtains compound 8；
Step 7,5-7 parts compound 8 is dissolved in the dichloromethane of 60-80 parts drying, adds triethylamine 15-18 parts, argon gas
Protection stirring, it is cooled to 0 DEG C；The chloro- 2 acyl chlorides thiophene 2.5-3.5 parts of 5- are slowly added dropwise, drip off small after 0 DEG C of stirring reaction 10-12
When, TLC monitoring reaction process, after reaction completely, twice, saturation NaCl solution washes twice 2N watery hydrochloric acid washing reaction liquid, nothing
Aqueous sodium persulfate is dried, and evaporated under reduced pressure solvent, was passed through post, and was obtained compound 9；
Step 8, compound 9 is sealed in the methanol solution tube sealing of 90-120 part methylamines, reaction 24 hours, reaction is stirred at room temperature
After completely, solvent is spin-dried for, crosses post purifying；Obtain relevant material F.
3. the relevant material G of a kind of razaxaban method, it is characterised in that using being prepared into of method in claim 2
Compound 9, then according to following synthetic line synthetic G：
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| CN105651871A (en) * | 2015-12-18 | 2016-06-08 | 重庆植恩药业有限公司 | Determination method of rivaroxaban and related substances |
| CN107941936B (en) * | 2017-11-17 | 2020-06-16 | 重庆华邦制药有限公司 | Method for separating and determining rivaroxaban and impurities thereof and application |
| CN110118836B (en) * | 2019-05-29 | 2021-10-29 | 北京悦康科创医药科技股份有限公司 | Method for determining genotoxic impurities in rivaroxaban by high performance liquid chromatography |
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| CN104098558A (en) * | 2014-07-22 | 2014-10-15 | 常州市第四制药厂有限公司 | Amide compound and preparation method thereof |
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