CN107857761A - A kind of deuterated razaxaban and preparation method thereof - Google Patents
A kind of deuterated razaxaban and preparation method thereof Download PDFInfo
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- C07—ORGANIC CHEMISTRY
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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
- 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
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Abstract
The invention discloses a kind of deuterated razaxaban, has the structure as shown in formula (I)：Its preparation method, which is also disclosed, to be included：(1) the deuterated ketone of 4 p-aminophenyl morpholine 3 and (S) N glycidols phthalimide are washed filter cake after filtering, are dried under reduced pressure, obtain deuterated compound through condensation reaction；(2) by deuterated compound and N, N' carbonyl dimidazoles are concentrated under reduced pressure into dry through ring-closure reaction, are dried under reduced pressure filter cake after washing and filtering, obtain another deuterated compound；(3) ethanol solution of another deuterated compound and methylamine is used recrystallizing methanol, be dried under reduced pressure, obtain another deuterated compound through hydrolysis after being concentrated to dryness；(4) another deuterated compound and the acyl chlorides thiophene of 5 chlorine 2 are washed filter cake after filtering, filter cake is dried under reduced pressure, obtain deuterated razaxaban through condensation reaction.The advantage of the invention is that：Raw material is easy to get, easy to operate, high income, and the deuterium of initiation material retains to end-product.
Description
Technical field
The present invention relates to deuterated compound technical field, is more particularly to a kind of deuterated razaxaban and preparation method thereof.
Background technology
Razaxaban (Rivaroxaban), the entitled chloro- N- of 5- ({ (the 5S) -2- oxos -3- [4- (3- oxos -4- of chemistry
Quinoline base) phenyl] -1,3- oxazolidine -5- bases } methyl) -2- thenoyl amines, molecular formula C19H18ClN3O5S, molecular weight are
435.88 structure is shown below.
Razaxaban is the antithrombotic reagent having good prospects, and is the oral direct Xa factor inhibitor in first, the whole world, can
The Xa factor and prothrombin activity that high selectivity, Reverse transcriptase dissociate and combined, are extended with dose-dependent fashion and activated
Partial thromboplastin time plate (PT) and prothrombin time (aPTT), so as to extend the clotting time, reduce fibrin ferment and formed.Its
The features such as high with bioavilability, treatment spectrum of disease is wide, dose-effect relationship stabilization, convenient oral, and bleeding risk is low.
Deuterium is hydrogen isotope existing for nature, that is to say, that the deuterated isotopic body in common drug all containing trace.
Deuterium is nontoxic, "dead", is safe to human body, and C-D keys are more stable (6~9 times) than c h bond, in other words replace hydrogen
After deuterium, metabolism site may be closed, extend drug half-life, while do not influence pharmacological activity (H and D shape difference are small).
And deuterated razaxaban is the compound after razaxaban isotopic, there is isotope effect, therefore on deuterated chemical combination
The research of thing is very powerful and exceedingly arrogant, and the research on deuterated razaxaban is still few at present, and on the preparation side of deuterated razaxaban
Method is not reported.
The content of the invention
The technical problems to be solved by the invention be the provision of a kind of deuterated razaxaban that can be used as tracer and its
Preparation method.
The present invention is that solve above-mentioned technical problem by the following technical programs：
On the one hand, there is provided a kind of deuterated razaxaban, there is the structure as shown in formula (I)：
On the other hand, there is provided the preparation method of above-mentioned deuterated razaxaban, comprise the following steps：
(1) will be contracted such as the deuterated 4- p-aminophenyls morpholine -3- ketone shown in formula (VI) and (S)-N- as shown in formula (VII)
Water glyceryl phthalimide washs filter cake after filtering, filter cake is dried under reduced pressure, obtain as shown in formula (VIII) through condensation reaction
Deuterated compound；
(2) will be concentrated under reduced pressure into if the deuterated compound shown in formula (VIII) and N, N'- carbonyl dimidazoles are through ring-closure reaction
It is dry, filter cake is dried under reduced pressure after washing and filtering, obtains the deuterated compound as shown in formula (IX)；
(3) will be used after being concentrated to dryness if the deuterated compound shown in formula (IX) and the ethanol solution of methylamine are through hydrolysis
Recrystallizing methanol, it is dried under reduced pressure, obtains the deuterated compound shown in formula (X)；
(4) will be as anti-through being condensed with the chloro- 2- acyl chlorides thiophene of 5- as shown in formula (XI) such as the deuterated compound shown in formula (X)
Should, filter cake is washed after filtering, filter cake is dried under reduced pressure, obtains the deuterated razaxaban shown in formula (I)；
Preferably, the deuterated 4- p-aminophenyls morpholine -3- ketone as shown in formula (VI) is by by five deuterated bromobenzenes and ethanol
Amine is substituted, cyclization, nitrification, reduction be made.It is highly preferred that prepared by following process：
(a1) reaction will be substituted in the presence of cuprous iodide such as five deuterated bromobenzenes shown in formula (II) and monoethanolamine, extracted
Organic phase is concentrated after taking, then is purified through column chromatography, obtains the deuterated hydroxyethylaniline as shown in formula (III)；
(a2) will be as anti-through cyclization such as the deuterated hydroxyethylaniline shown in formula (III) and sodium hydrate aqueous solution and chloracetyl chloride
Should, filter cake is washed after filtering, filter cake is dried under reduced pressure, obtains the deuterated 4- phenylmorpholines -3- ketone as shown in formula (IV)；
(a3) will be if deuterated 4- phenylmorpholines -3- ketone, the concentrated sulfuric acid and the nitric acid shown in formula (IV) are through nitration reaction, regulation pH
To 7, filter cake is washed after filtering, filter cake is dried under reduced pressure, obtains the deuterated 4- p-nitrophenyls morpholine -3- ketone as shown in formula (V)；
(a4) the deuterated 4- p-nitrophenyls morpholine -3- ketone as shown in formula (V) and hydrogen in the presence of palladium carbon through reduction
Reaction, is filtered to remove palladium carbon, concentrates filtrate to dry, obtains the deuterated 4- p-aminophenyls morpholine -3- as shown in formula (VI)
Ketone.
Preferably, it is 5~25 with the volume ratio of ethanol and water in step (1):1 ethanol water is dissolved such as formula
(VI) the deuterated 4- p-aminophenyls morpholine -3- ketone shown in and (S)-N- glycidol phthalyls as shown in formula (VII)
Imines；And/or
Deuterated 4- p-aminophenyls morpholine -3- ketone as shown in formula (VI) shrinks sweet with (S)-N- as shown in formula (VII)
The mass ratio of oily phthalimide is 5:5~7；And/or
Then the process of the condensation reaction is cooled to 0 DEG C of 1~3h of stirring reaction to be warming up to 24~34h of back flow reaction；
And/or
The solvent of the washing is ethanol.
Preferably, in step (2),
Dissolved per deuterated compounds of the 1g as shown in formula (VIII) with 8~12mL dichloromethane, as shown in formula (VIII)
The mass ratio of deuterated compound and N, N'- carbonyl dimidazoles is 5:2~4；And/or
The process of the ring-closure reaction is 20~30 DEG C of 8~12h of reaction, and/or
The solvent of the washing is tetrahydrofuran.
Preferably, in step (3),
Dissolved per deuterated compounds of the 1g as shown in formula (IX) with 5~10mL ethanol, it is deuterated as shown in formula (IX) per 1g
The ethanol solution of 0.5~1.5mL methylamines is added in compound, the volume fraction of the ethanol solution of the methylamine is 30~40%；
And/or
The process of the hydrolysis reacts 4~8h to be warming up to 60~70 DEG C.
Preferably, in step (4),
The mass ratio of the deuterated compound as shown in formula (X) and the chloro- 2- acyl chlorides thiophene of 5- as shown in formula (XI) is
1:0.5~1；And/or
It by mass ratio is 1~2 that the process of the condensation reaction, which is,:1 deuterated compound and sodium carbonate as shown in formula (X)
It is dissolved in dichloromethane, the lower chloro- 2- acyl chlorides thiophene of 5- being added dropwise as shown in formula (XI) of 20~30 DEG C of stirrings, 20~30 DEG C of reactions
4~8h；And/or
Water is added into the reaction solution after condensation reaction, lower dropwise addition 2mol/L hydrochloric acid is stirred, then filters；And/or
The solvent of the washing is water.
Preferably, the temperature being dried under reduced pressure is 40~50 DEG C.
Another aspect, also provide the purposes that above-mentioned deuterated razaxaban is used as the tracer of research drug absorption.
The present invention has advantages below compared with prior art：Deuterated razaxaban is the change after razaxaban isotopic
Compound, on the premise of original pharmacological activity and selectivity is kept, drug half-life can be extended, reduce dosage, reduce medication time
Number, and because of the compound after isotopic, in addition to isotope effect, its chemical property does not change generally, may participate in
Similar chemical reaction；And deuterated razaxaban also is used as tracer to carry out analysis measure, drug absorption, distribution are studied
With the rule of metabolism；Preparation process raw material is easy to get, and synthesis step is easy to operate, and reaction overall yield is high, and initiation material is brought into
Deuterium retain to end-product.
Brief description of the drawings
Fig. 1 is the hydrogen nuclear magnetic resonance spectrogram of deuterated razaxaban；
Fig. 2 is the mass spectrogram of deuterated razaxaban；
Fig. 3 is the hydrogen nuclear magnetic resonance spectrogram of razaxaban.
Embodiment
Embodiments of the invention are elaborated below, the present embodiment is carried out lower premised on technical solution of the present invention
Implement, give detailed embodiment and specific operating process, but protection scope of the present invention is not limited to following implementation
Example.
All chemicals are commercial chemicals.
The preparation of deuterated 4- p-aminophenyl morpholine -3- ketone of the embodiment 1 as shown in formula (VI)
Synthesis flow is as follows：
Preparation process：Five deuterated bromobenzenes of the 40g as shown in formula (II), 47g monoethanolamines and 4.8g iodine are added into reaction bulb
Change cuprous, be warming up to 90~110 DEG C of reaction 8h, be cooled to 20~30 DEG C, add 100mL water and 80mL dichloromethane, stirring 10
Liquid separation after minute, concentration organic phase remove dichloromethane, and residual liquid column chromatography purifies to obtain 30.3g pale yellow oils, receives
Rate is 84%.The above-mentioned pale yellow oils of 100g, 100mL ethanol and 300mL water are added into reaction bulb, 40 are warming up under stirring
~50 DEG C, it is 10~13 to control reaction solution pH, while the sodium hydrate aqueous solutions of 580g 45% and 160mL chloracetyl chlorides is added dropwise, and is dripped
Being reacted 30 minutes at 40~50 DEG C after adding, separate out solid, be cooled to 0 DEG C of stirring 1h, filtering, filter cake is washed 2 times with cold water,
It is dried under reduced pressure at 50 DEG C, obtains white solid 92g, yield 72%.The above-mentioned white solids of 20g and 82g are added into reaction bulb
The concentrated sulfuric acid, stir 30 minutes at 20~30 DEG C, be cooled to -5~10 DEG C, the nitric acid of 11.5g 65% is added dropwise, -5 after being added dropwise
1h is stirred at~10 DEG C, 100mL water is slowly added dropwise, then pH to 7 is adjusted with concentrated ammonia liquor, separates out solid, filtering, filter cake is washed with water
Wash, 60 DEG C are dried under reduced pressure to obtain 20.5g light tan solids, yield 83%.The above-mentioned light browns of 22.6g are added into hydriding reactor to consolidate
Body, 250mL methanol, the palladium carbons of 2g 10% are added, be hydrogenated with to 4 atmospheric pressure, 40~50 DEG C of hydrogenation 6h, it is cooled to 20~
30 DEG C are filtered to remove palladium carbon, and filtrate decompression is concentrated to dryness, and obtain deuterated 4- p-aminophenyl of the faint yellow solid as shown in formula (VI)
Base morpholine -3- ketone 18.2g, yield 93%.It is as a result as follows with mass spectrum and the magnetic resonance detection faint yellow solid：1H NMR
(400MHz,CDCl3)δ4.32(s,2H),4.00(t,2H),3.72(bs,2H),3.69(t,2H)；MS(ESI):M/z=197
[M+H]+。
Embodiment 2
(1) preparation of the deuterated compound as shown in formula (VIII)
Synthesis flow is as follows：
Preparation process：Deuterated 4- p-aminophenyl morpholine -3- ketone of the 20g as shown in formula (VI), 24g are added into reaction bulb
(S)-N- glycidol phthalimides as shown in formula (VII), 250mL ethanol and 30mL water, are warming up to back flow reaction
30h, 0 DEG C of stirring 2h is cooled to, filtering, filter cake is washed with 50mL ethanol, is dried under reduced pressure to obtain white solid such as formula at 40 DEG C
(VIII) the deuterated compound 35.7g shown in, yield 88%.With mass spectrum and the magnetic resonance detection white solid, as a result such as
Under：1H NMR(DMSO-d6,400MHz):7.92-7.78(m,4H),5.65(t,1H),5.15(d,1H),4.13(s,2H),
4.08-3.87(m,3H),3.70-3.53(m,4H),3.26-2.92(m,2H)；MS(ESI):M/z=400 [M+H]+。
(2) preparation of the deuterated compound as shown in formula (IX)
Synthesis flow is as follows：
Preparation process：Deuterated compounds of the addition 20g as shown in formula (VIII) into reaction bulb, 200mL dichloromethane, then
12.3g N, N'- carbonyl dimidazoles are added, 20~30 DEG C of reaction 10h, are concentrated under reduced pressure into dry, gained solid addition 100mL tetrahydrochysenes
Furans, 20~30 DEG C of stirring 1h, filters, is dried under reduced pressure to obtain deuterated compound of the white solid as shown in formula (IX) at 40 DEG C
19.6g, yield 92%.It is as a result as follows with mass spectrum and the magnetic resonance detection white solid：1H NMR(DMSO-d6,
400MHz):7.98-7.82(m,4H),5.04-4.87(m,1H),4.23(t,1H),4.20(s,2H),4.05-3.84(m,
5H),3.72(dd,2H)；MS(ESI):M/z=426 [M+H]+。
(3) preparation of the deuterated compound as shown in formula (X)
Synthesis flow is as follows：
Preparation process：Deuterated compounds of the addition 17g as shown in formula (IX) into reaction bulb, 150mL ethanol, 20~30 DEG C
The lower ethanol solution for adding the methylamines of 20mL 35% of stirring, is warming up to 60~70 DEG C of reaction 6h, and reaction solution is concentrated to dryness, and gained is solid
Body recrystallizing methanol, it is dried under reduced pressure to obtain deuterated compound 10.6g of the white solid as shown in formula (X) at 40 DEG C, yield is
90%.It is as a result as follows with mass spectrum and the magnetic resonance detection white solid：1H NMR(DMSO-d6,400MHz):4.68-4.58
(m,1H),4.19(s,2H),4.09(t,1H),3.97(dd,2H),3.87(dd,1H),3.72(dd,2H),2.90-2.76(m,
2H),1.75-1.63(bs,2H)；MS(ESI):M/z=296 ([M+H]+)。
(4) preparation of the deuterated razaxaban as shown in formula (I)
Synthesis flow is as follows：
Preparation process：Deuterated compounds of the 10g as shown in formula (X), 10g sodium carbonate, dichloromethane are added into reaction bulb
50mL, the lower chloro- 2- acyl chlorides thiophene of 5- that 6.5g is added dropwise as shown in formula (XI) of 20~30 DEG C of stirrings, it is added dropwise latter 20~30 DEG C instead
6h is answered, adds 40mL water, lower 2mol/l (2N) hydrochloric acid that 15mL is added dropwise is stirred, filters, filter cake 50mL water washings, subtract at 45 DEG C
Pressure is dried to obtain deuterated razaxaban 12.7g of the white solid as shown in formula (I), yield 85%.With mass spectrum and nuclear magnetic resonance
The white solid is detected, it is as a result as follows：1H NMR(DMSO-d6,400MHz):8.97(t,1H),7.68(d,1H),7.19(d,
1H),4.84-4.83(m,1H),4.21-4.16(m,1H),4.19(s,2H),3.98-3.95(m,2H),3.84(dd,1H),
3.73-3.71(m,2H),3.62-3.59(m,2H)；MS(ESI):M/z=440 ([M+H]+).Its hydrogen nuclear magnetic resonance spectrogram is as schemed
Shown in 1, mass spectrogram is as shown in Figure 2.
It is as follows with nuclear magnetic resonance and Mass Spectrometer Method razaxaban, testing result in addition：1H NMR(DMSO-d6,400MHz):
9.10(t,1H),7.75(d,1H),7.56(d,2H),7.40(d,2H),7.19(d,1H),4.87-4.82(m,1H),4.21-
4.15(m,1H),4.19(s,2H),3.98-3.87(m,4H),3.72-3.69(m,2H),3.61-3.58(m,2H)；MS
(ESI):M/z=436 ([M+H]+).Its hydrogen nuclear magnetic resonance spectrogram is as shown in Figure 3.
Comparison diagram 1 and Fig. 3, two groups of totally four hydrogen on visible phenyl ring on razaxaban proton nmr spectra, and in deuterated profit
Cut down in husky class's nuclear magnetic spectrogram and do not occur at corresponding chemical displacement, illustrate the compound as shown in formula (I) and really cut down sand for deuterated profit
Class.
Embodiment 3
(1) preparation of the deuterated compound as shown in formula (VIII)
Preparation process：Deuterated 4- p-aminophenyl morpholine -3- ketone of the 20g as shown in formula (VI), 20g are added into reaction bulb
(S)-N- glycidol phthalimides as shown in formula (VII), 250mL ethanol and 50mL water, are warming up to back flow reaction
24h, 0 DEG C of stirring 3h is cooled to, filtering, filter cake is washed with 50mL ethanol, is dried under reduced pressure to obtain white solid such as formula at 40 DEG C
(VIII) the deuterated compound 30.5g shown in, yield 78%.With mass spectrum and the magnetic resonance detection white solid, as a result such as
Under：1H NMR(DMSO-d6,400MHz):7.92-7.78(m,4H),5.65(t,1H),5.15(d,1H),4.13(s,2H),
4.08-3.87(m,3H),3.70-3.53(m,4H),3.26-2.92(m,2H)；MS(ESI):M/z=400 [M+H]+。
(2) preparation of the deuterated compound as shown in formula (IX)
Preparation process：Deuterated compounds of the addition 20g as shown in formula (VIII) into reaction bulb, 160mL dichloromethane, then
10g N, N'- carbonyl dimidazoles are added, 20~30 DEG C of reaction 8h, are concentrated under reduced pressure into dry, gained solid addition 100mL tetrahydrochysene furans
Mutter, 20~30 DEG C of stirring 1h, filter, be dried under reduced pressure to obtain deuterated compound of the white solid as shown in formula (IX) at 40 DEG C
15.6g, yield 87%.It is as a result as follows with mass spectrum and the magnetic resonance detection white solid：1H NMR(DMSO-d6,
400MHz):7.98-7.82(m,4H),5.04-4.87(m,1H),4.23(t,1H),4.20(s,2H),4.05-3.84(m,
5H),3.72(dd,2H)；MS(ESI):M/z=426 [M+H]+。
(3) preparation of the deuterated compound as shown in formula (X)
Preparation process：Deuterated compounds of the addition 17g as shown in formula (IX) into reaction bulb, 85mL ethanol, 20~30 DEG C
The lower ethanol solution for adding the methylamines of 8.5mL 30% of stirring, is warming up to 60~70 DEG C of reaction 4h, and reaction solution is concentrated to dryness, and gained is solid
Body recrystallizing methanol, it is dried under reduced pressure to obtain deuterated compound 5.6g of the white solid as shown in formula (X) at 40 DEG C, yield is
70%.It is as a result as follows with mass spectrum and the magnetic resonance detection white solid：1H NMR(DMSO-d6,400MHz):4.68-4.58
(m,1H),4.19(s,2H),4.09(t,1H),3.97(dd,2H),3.87(dd,1H),3.72(dd,2H),2.90-2.76(m,
2H),1.75-1.63(bs,2H)；MS(ESI):M/z=296 ([M+H]+)。
(4) preparation of the deuterated razaxaban as shown in formula (I)
Preparation process：Deuterated compounds of the 10g as shown in formula (X), 10g sodium carbonate, dichloromethane are added into reaction bulb
50mL, 20~30 DEG C of stirrings are lower to be added dropwise 5- chloro- 2- acyl chlorides thiophene of the 5g as shown in formula (XI), 20~30 DEG C of reactions after being added dropwise
4h, 40mL water is added, stir lower 2mol/l (2N) hydrochloric acid that 15mL is added dropwise, filter, filter cake 50mL water washings, depressurized at 45 DEG C
It is dried to obtain deuterated razaxaban 12.7g of the white solid as shown in formula (I), yield 85%.Examined with mass spectrum and nuclear magnetic resonance
The white solid is surveyed, it is as a result as follows：1H NMR(DMSO-d6,400MHz):8.97(t,1H),7.68(d,1H),7.19(d,
1H),4.84-4.83(m,1H),4.21-4.16(m,1H),4.19(s,2H),3.98-3.95(m,2H),3.84(dd,1H),
3.73-3.71(m,2H),3.62-3.59(m,2H)；MS(ESI):M/z=440 ([M+H]+)。
Embodiment 4
(1) preparation of the deuterated compound as shown in formula (VIII)
Preparation process：Deuterated 4- p-aminophenyl morpholine -3- ketone of the 20g as shown in formula (VI), 28g are added into reaction bulb
(S)-N- glycidol phthalimides as shown in formula (VII), 250mL ethanol and 10mL water, are warming up to back flow reaction
34h, 0 DEG C of stirring 1h is cooled to, filtering, filter cake is washed with 50mL ethanol, is dried under reduced pressure to obtain white solid such as formula at 50 DEG C
(VIII) the deuterated compound 32.8g shown in, yield 80%.With mass spectrum and the magnetic resonance detection white solid, as a result such as
Under：1H NMR(DMSO-d6,400MHz):7.92-7.78(m,4H),5.65(t,1H),5.15(d,1H),4.13(s,2H),
4.08-3.87(m,3H),3.70-3.53(m,4H),3.26-2.92(m,2H)；MS(ESI):M/z=400 [M+H]+。
(2) preparation of the deuterated compound as shown in formula (IX)
Preparation process：Deuterated compounds of the addition 20g as shown in formula (VIII) into reaction bulb, 200mL dichloromethane, then
16g N, N'- carbonyl dimidazoles are added, 20~30 DEG C of reaction 12h, are concentrated under reduced pressure into dry, gained solid addition 100mL tetrahydrochysene furans
Mutter, 20~30 DEG C of stirring 1h, filter, be dried under reduced pressure to obtain deuterated compound of the white solid as shown in formula (IX) at 40 DEG C
17.2g, yield 85%.It is as a result as follows with mass spectrum and the magnetic resonance detection white solid：1H NMR(DMSO-d6,
400MHz):7.98-7.82(m,4H),5.04-4.87(m,1H),4.23(t,1H),4.20(s,2H),4.05-3.84(m,
5H),3.72(dd,2H)；MS(ESI):M/z=426 [M+H]+。
(3) preparation of the deuterated compound as shown in formula (X)
Preparation process：Deuterated compounds of the addition 17g as shown in formula (IX) into reaction bulb, 170mL ethanol, 20~30 DEG C
The lower ethanol solution for adding the methylamines of 25.5mL 40% of stirring, is warming up to 60~70 DEG C of reaction 8h, and reaction solution is concentrated to dryness, gained
Solid recrystallizing methanol, it is dried under reduced pressure to obtain deuterated compound 9.8g of the white solid as shown in formula (X) at 50 DEG C, yield is
82%.It is as a result as follows with mass spectrum and the magnetic resonance detection white solid：1H NMR(DMSO-d6,400MHz):4.68-4.58
(m,1H),4.19(s,2H),4.09(t,1H),3.97(dd,2H),3.87(dd,1H),3.72(dd,2H),2.90-2.76(m,
2H),1.75-1.63(bs,2H)；MS(ESI):M/z=296 ([M+H]+)。
(4) preparation of the deuterated razaxaban as shown in formula (I)
Preparation process：Deuterated compounds of the 20g as shown in formula (X), 10g sodium carbonate, dichloromethane are added into reaction bulb
50mL, the lower chloro- 2- acyl chlorides thiophene of 5- that 10g is added dropwise as shown in formula (XI) of 20~30 DEG C of stirrings, it is added dropwise latter 20~30 DEG C instead
8h is answered, adds 40mL water, lower 2mol/l (2N) hydrochloric acid that 15mL is added dropwise is stirred, filters, filter cake 50mL water washings, subtract at 50 DEG C
Pressure is dried to obtain deuterated razaxaban 10.7g of the white solid as shown in formula (I), yield 80%.With mass spectrum and nuclear magnetic resonance
The white solid is detected, it is as a result as follows：1H NMR(DMSO-d6,400MHz):8.97(t,1H),7.68(d,1H),7.19(d,
1H),4.84-4.83(m,1H),4.21-4.16(m,1H),4.19(s,2H),3.98-3.95(m,2H),3.84(dd,1H),
3.73-3.71(m,2H),3.62-3.59(m,2H)；MS(ESI):M/z=440 ([M+H]+)。
Above-mentioned deuterated razaxaban also is used as tracer to carry out analysis measure, studies drug absorption, distribution and metabolism
Rule.
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
All any modification, equivalent and improvement made within refreshing and principle etc., should be included in the scope of the protection.
Claims (9)
1. a kind of deuterated razaxaban, it is characterised in that there is the structure as shown in formula (I)：
2. the preparation method of deuterated razaxaban according to claim 1, it is characterised in that comprise the following steps：
(1) will be as sweet such as the deuterated 4- p-aminophenyls morpholine -3- ketone shown in formula (VI) and (S)-N- shrinks as shown in formula (VII)
Oily phthalimide washs filter cake after filtering, filter cake is dried under reduced pressure, obtain the deuterium as shown in formula (VIII) through condensation reaction
For compound；
(2) will if the deuterated compound shown in formula (VIII) and N, N'- carbonyl dimidazoles are through ring-closure reaction, be concentrated under reduced pressure into it is dry,
Filter cake is dried under reduced pressure after washing and filtering, obtains the deuterated compound as shown in formula (IX)；
(3) methanol will be used after being concentrated to dryness if the deuterated compound shown in formula (IX) and the ethanol solution of methylamine are through hydrolysis
Recrystallization, is dried under reduced pressure, obtains the deuterated compound shown in formula (X)；
(4) will as the deuterated compound shown in formula (X) with the chloro- 2- acyl chlorides thiophene of 5- as shown in formula (XI) through condensation reaction, mistake
Filter cake is washed after filter, filter cake is dried under reduced pressure, obtains the deuterated razaxaban shown in formula (I)；
3. the preparation method of deuterated razaxaban according to claim 2, it is characterised in that deuterated as shown in formula (VI)
4- p-aminophenyls morpholine -3- ketone is by the way that five deuterated bromobenzenes and monoethanolamine are substituted, cyclization, nitrification, reduction are made.
4. the preparation method of deuterated razaxaban according to claim 2, it is characterised in that in step (1), use ethanol
Volume ratio with water is 5~25:1 ethanol water dissolves the deuterated 4- p-aminophenyls morpholine -3- ketone as shown in formula (VI)
With (S)-N- glycidol phthalimides as shown in formula (VII)；And/or
Deuterated 4- p-aminophenyls morpholine -3- ketone as shown in formula (VI) and (the S)-N- glycidols as shown in formula (VII) are adjacent
The mass ratio of BIDA is 5:5~7；And/or
Then the process of the condensation reaction is cooled to 0 DEG C of 1~3h of stirring reaction to be warming up to 24~34h of back flow reaction；With/
Or
The solvent of the washing is ethanol.
5. the preparation method of deuterated razaxaban according to claim 2, it is characterised in that in step (2),
Dissolved per deuterated compounds of the 1g as shown in formula (VIII) with 8~12mL dichloromethane, it is deuterated as shown in formula (VIII)
The mass ratio of compound and N, N'- carbonyl dimidazoles is 5:2~4；And/or
The process of the ring-closure reaction is 20~30 DEG C of 8~12h of reaction, and/or
The solvent of the washing is tetrahydrofuran.
6. the preparation method of deuterated razaxaban according to claim 2, it is characterised in that in step (3),
Dissolved per deuterated compounds of the 1g as shown in formula (IX) with 5~10mL ethanol, per deuterated chemical combination of the 1g as shown in formula (IX)
The ethanol solution of 0.5~1.5mL methylamines is added in thing, the volume fraction of the ethanol solution of the methylamine is 30~40%；And/or
The process of the hydrolysis reacts 4~8h to be warming up to 60~70 DEG C.
7. the preparation method of deuterated razaxaban according to claim 2, it is characterised in that in step (4),
The mass ratio of the deuterated compound as shown in formula (X) and 5 as shown in formula (XI)~chloro- 2- acyl chlorides thiophene is 1:
0.5~1；And/or
It by mass ratio is 1~2 that the process of the condensation reaction, which is,:1 deuterated compound as shown in formula (X) dissolves with sodium carbonate
In dichloromethane, the lower chloro- 2- acyl chlorides thiophene of 5- being added dropwise as shown in formula (XI) of 20~30 DEG C of stirrings, 20~30 DEG C of reactions 4~
8h；And/or
Water is added into the reaction solution after condensation reaction, lower dropwise addition 2mol/L hydrochloric acid is stirred, then filters；And/or
The solvent of the washing is water.
8. the preparation method of deuterated razaxaban according to claim 2, it is characterised in that the temperature being dried under reduced pressure
For 40~50 DEG C.
9. the application of the deuterated razaxaban described in claim 1, it is characterised in that the deuterated razaxaban is used as research medicine
The tracer that thing absorbs.
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| CN115215854A (en) * | 2022-06-30 | 2022-10-21 | 湖南恒生制药股份有限公司 | Preparation process of efficient rivaroxaban bulk drug |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1434822A (en) * | 1999-12-24 | 2003-08-06 | 拜尔公司 | Substituted oxazolidinones and their use in the field of blood coagulation |
| CN101821260A (en) * | 2007-08-14 | 2010-09-01 | 康塞特医药品有限公司 | Substituted oxazolidinone derivatives |
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2017
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1434822A (en) * | 1999-12-24 | 2003-08-06 | 拜尔公司 | Substituted oxazolidinones and their use in the field of blood coagulation |
| CN101821260A (en) * | 2007-08-14 | 2010-09-01 | 康塞特医药品有限公司 | Substituted oxazolidinone derivatives |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN115215854A (en) * | 2022-06-30 | 2022-10-21 | 湖南恒生制药股份有限公司 | Preparation process of efficient rivaroxaban bulk drug |
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