CN105777719A - Synthesis method of Daclatasvir - Google Patents
Synthesis method of Daclatasvir Download PDFInfo
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- CN105777719A CN105777719A CN201610191144.9A CN201610191144A CN105777719A CN 105777719 A CN105777719 A CN 105777719A CN 201610191144 A CN201610191144 A CN 201610191144A CN 105777719 A CN105777719 A CN 105777719A
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- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
- C07D403/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing three or more hetero rings
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Abstract
The invention relates to a synthesis method of Daclatasvir. The method comprises the following steps: step 1, performing a bromination reaction on 4.4-diacetyl biphenyl which serves as a raw material so as to obtain an intermediate 1; step 2, performing a substitution reaction on the intermediate 1 so as to obtain an intermediate 2; step 3, performing a cyclization reaction on the intermediate 2 so as to finally obtain the Daclatasvir. Compared with reported synthesis routes, a synthesis route of the method has the following advantages that the route is short, and the yield is high; general means such as suction filtration, extraction and concentration are adopted for aftertreatment, and aftertreatment is simple and convenient; severe-pollution and high-toxicity reagents such as bromine are avoided, and a process of repeatedly using an acetic acid washing reaction system is avoided.
Description
Technical field
The present invention relates to the synthetic method of a kind of hepatitis C virus NS5A inhibitor, be specifically related to his Wei of a kind of Dacca
The synthetic method of (Daclatasvir dihydrocholide).
Background technology
Hepatitis C virus (HCV) is the main cause causing chronic hepatic diseases, there is no vaccine prevention HCV at present
Infect.The existing standard of HCV infection nursing for treating scheme relates to individually or interferon-' alpha ' is used in combination with virazole, and this is controlled
Treating relatively complicated, and have weak or other serious adverse reactions of cause, many patient for treatment can not sustained response.Dacca
His Wei (Daclatasvir dihydrocholide) as a kind of high selectivity hepatitis C virus NS5A inhibitor, be have straight
Connect the small-molecule drug of antivirus action, be also that the first NS5A clinical for hepatitis C replicates complex inhibitor.
Reported that relatively more schemes were Shawn K.Pack (US7728027B2, publication date 2010 06 month in recent years
01 day) et al. with 4.4-diacetyl biphenyl as raw material, through bromination reaction obtain intermediate 1, neutralize reaction obtain centre
Body 2, cyclization intermediate 3, acid deprotection obtains intermediate 4, condensation reaction obtains target product.This route is in system
Need to use the bromine that toxicity is big during standby intermediate 1, prepare the post processing needs of intermediate 3 repeatedly, substantial amounts of glacial acetic acid
Washing, post processing are difficult to operation, prepare intermediate 4 needs and use the ethanol-hydrogen chloride of danger, and condensation reaction is used in a large number
The condensing agent such as HOBT/EDCI/DCC, cause post processing to be difficult to obtain qualified product, and condensing agent can cause portion
Dividing the generation of diastereomer, total recovery is 24.4%, and its synthetic route is as follows:
Song Baohui et al. (" synthesis of anti-hepatitis C new drug Daclatasvir dihydrocholide ", " Chinese Journal of New Drugs ",
2013,22 (22): 2679-2683) with biphenyl as raw material, obtain intermediate 1 through Friedel-Crafts reaction, neutralize during reaction obtains
Mesosome 2, cyclization obtain intermediate 3, acid deprotection obtains intermediate 4 and condensation reaction obtains target product.This
Route can produce large amount of sewage when preparing intermediate 1, when preparing intermediate 3 needs repeatedly, substantial amounts of glacial acetic acid washing,
Post processing is difficult to operation, prepares intermediate 4 needs and uses the ethanol-hydrogen chloride of danger, and condensation reaction is used substantial amounts of
The condensing agents such as HOBT/EDCI/DCC, cause post processing to obtain and take qualified product, and condensing agent can cause part
The generation of diastereomer, total recovery is 23.9%, and its synthetic route is as follows:
Synthetic schemes (WO2011068941A2, publication date on 06 09th, 2011) is that first to synthesize this right earlier
Claim the half of structure, then use the method for coupling to be recombinated by structure fragment, thus obtain target product；But therefore route exists
When preparing intermediate 3 and intermediate 4, the coupling reagent of costliness used by needs and route is longer, be difficult to industrialized production and meet with
Eliminating, its synthetic route is as follows:
Therefore, the synthetic method of his Wei of Dacca is existed and further improves and optimize demand, this just the present invention be able to
The power completed and starting point place.
Summary of the invention
For the above-mentioned technical problem overcoming prior art to exist, the present inventor after having carried out substantial amounts of further investigation,
Provide the synthetic method of his Wei of a kind of new Dacca, have that raw material is cheap and easy to get, route is short, yield is high, reaction easily behaviour
Make, environmental pollution is little, the advantage of applicable industrialized production.
The present invention is achieved through the following technical solutions, the synthetic method of his Wei of a kind of Dacca, comprises the following steps:
Step one, obtains intermediate 1 for raw material through bromo-reaction with 4.4-diacetyl biphenyl；
Step 2, described intermediate 1 is substituted reaction and prepares intermediate 2；
Step 3, described intermediate 2 finally prepares his Wei of Dacca through cyclization；
As the preferred version of technique scheme, in step one, the building-up process of intermediate 1 is as follows: take 4.4-diethyl
Acyl group biphenyl and DIPEA are dissolved in dichloromethane, and the dichloromethane solution of 0 DEG C of dropping TMSOTf and NBS is carried out
Reaction, is poured into water whole reaction system after reaction completely, layering, and anhydrous sodium sulfate is dried, sucking filtration, concentrates and removes
Dichloromethane obtains intermediate 1.It is further preferred that described 4.4-diacetyl biphenyl, DIPEA, TMSOTf and NBS
Mol ratio be 1:(2.2～2.5): (2.1～2.4): (2.1～2.4).
As the preferred version of technique scheme, in step 2, the building-up process of intermediate 2 is as follows: take described centre
Described in body 1 and reaction equation, L-PROLINE derivant is dissolved in acetonitrile, is slowly increased to room temperature anti-after 20 DEG C of dropping triethylamines
Should, reaction is washed with saturated aqueous common salt after terminating, and organic layer obtains solid after concentrating, and to obtain final product.It is further preferred that institute
State intermediate 1, L-PROLINE derivant, the mol ratio of triethylamine are 1:(2.2～2.5): (2.5～3.0).
As the preferred version of technique scheme, in step 3, his building-up process of Wei of Dacca is as follows: take described centre
Body 2 and ammonium acetate are dissolved in toluene, and system is warming up to 90 DEG C of reactions, and reaction is cooled to room temperature, to reactant liquor after terminating
Middle addition water, is layered after stirring 30min, and organic layer uses water, saturated aqueous common salt washing, sucking filtration, dry, concentration successively,
Be subsequently adding ethanol solution hydrochloride, stirring, after through sucking filtration, dry after obtain his Wei of Dacca.It is further preferred that institute
The mol ratio stating intermediate 2 and ammonium acetate is 1:(10～20).
Compared with prior art, beneficial effects of the present invention is as follows:
(1) present invention obtains intermediate 1 for raw material through bromo-reaction with 4.4-diacetyl biphenyl, substitution reaction prepares intermediate
2, cyclization finally prepares his Wei of Dacca, and total recovery reaches 61.8%, is significantly larger than and has reported total recovery；
(2) raw material (4.4-diacetyl biphenyl and L-PROLINE derivant) of synthetic route of the present invention is cheap and easily-available；
(3) synthetic route of the present invention is compared with the synthetic route reported, reaction easily operation, post processing is easy, locates afterwards
Reason operation is all sucking filtration, extracts and the conventional means such as concentration；
(4) present invention synthesis is compared with the synthetic route reported, pollutes little, it is to avoid the pollutions such as use bromine are big, malicious
The reagent that property is big, it also avoid the process of Reusability acetic acid washing reaction system；
(5) synthetic route of the present invention is because simplifying operating process, decreasing pollution, is suitable for industrial mass production.
Therefore, the synthesis technique of the present invention have that raw material is cheap and easy to get, route is short, yield is high, easy operation, environmental pollution
Advantage little, that be suitable for industrialization large-scale production.
Detailed description of the invention
Below in conjunction with specific embodiment, the present invention is described in detail.Following example will assist in those skilled in the art
Member is further appreciated by the present invention, but limits the present invention the most in any form.It should be pointed out that, the common skill to this area
For art personnel, without departing from the inventive concept of the premise, it is also possible to make some deformation and improvement.These broadly fall into
Protection scope of the present invention.
The reaction equation of embodiment 1-3 is as follows:
Embodiment 1
The present embodiment relates to the synthetic method of his Wei of a kind of Dacca, comprises the steps of:
Step one, the synthesis of intermediate 1
Take 4.4-diacetyl biphenyl (40g, 0.17mol) and DIPEA (53g, 0.41mol) and be dissolved in 1000mL
In dichloromethane, 0 DEG C of dropping TMSOTf (0.37mol), drip and finish stirring 15 minutes, dropping NBS (0.39mol)
Dichloromethane (200mL) solution, drip and finish 0 DEG C of stirring reaction 2h, completely, system is poured in 500mL water in reaction,
Layering, anhydrous sodium sulfate are dried, sucking filtration, concentration removing dichloromethane, obtain intermediate 1 crude product, and toluene crystallization obtains 61
G solid, yield 91%；
MP:224-226 DEG C,1H NMR(400MHz,CDCl3):δ(ppm):7.96-7.84(m,4H),7.61-7.52(m,4H),
4.26 (s, 4H), HRMS (ESI): m/z [M+H]-394.93。
Step 2, the synthesis of intermediate 2
Take intermediate 1 (40g, 0.101mol) and L-PROLINE derivant (60g, 0.222mol) is dissolved in 400mL
In acetonitrile, being slowly increased to room temperature reaction 4h after 20 DEG C of droppings triethylamine (0.278mol), reaction is complete, with 13%
Saturated aqueous common salt washs, and dense the doing of organic layer directly carries out next step without purification；
Step 3, the synthesis of his Wei of Dacca
Take above-mentioned intermediate 2 and ammonium acetate (80g, the mol ratio of intermediate 2 and ammonium acetate is 1:10) is dissolved in 400mL
In toluene, system is warming up to 90 DEG C, stirring reaction 12h, after reaction terminates, is cooled to room temperature, adds 200mL in system
With 400mL water, stirring 30min, layering, organic layer washes with water successively, saturated common salt is washed, anhydrous sodium sulfate is dried,
Dense dry addition 200mL ethanol, stirring is lower adds the 30mL ethanol solution containing 0.3mol hydrochloric acid, stirs 2h, sucking filtration, filter
Cake washing with acetone is dried and is obtained 70g off-white color solid crude product, and methanol/acetone is recrystallized to give 56g white solid powder,
Two step total recoverys of step 2 and step 3 are 68%.
MP:266-268 DEG C,1H NMR(400MHz,d6-DMSO):δ(ppm):12.03(s,2H),7.76(d,4H),7.62
(d,4H),7.45(s,2H),7.29(s,2H),5.03(t,2H),4.02(t,2H),3.76(m,4H),3.42(s,6H),2.10(m,2H),1.99
(m, 2H), 1.93 (m, 4H), 0.84-0.89 (d, 12H), HRMS (ESI): m/z [M+2Cl]-738.24。
Embodiment 2
The present embodiment relates to the synthetic method of his Wei of a kind of Dacca, comprises the steps of:
Step one, the synthesis of intermediate 1
Take 4.4-diacetyl biphenyl (40g, 0.17mol) and DIPEA (49g, 0.38mol) and be dissolved in 1000mL
In dichloromethane, 0 DEG C of dropping TMSOTf (0.39mol), drip and finish stirring 15 minutes, dropping NBS (73g, 0.41mol)
Dichloromethane (200mL) solution, drip and finish 0 DEG C of stirring reaction 2h, completely, system is poured in 500mL water in reaction,
Layering, anhydrous sodium sulfate are dried, sucking filtration, concentration removing dichloromethane, obtain intermediate 1 crude product, and toluene crystallization obtains 62
G solid, yield 92%；
MP:224.5-226.5 DEG C,1H NMR(400MHz,CDCl3):δ(ppm):7.95-7.84(m,4H),7.62-7.52(m,
4H), 4.27 (s, 4H), HRMS (ESI): m/z [M+H]-394.94。
Step 2, the synthesis of intermediate 2
Take intermediate 1 (40g, 0.101mol) and L-PROLINE derivant (60g, 0.252mol) is dissolved in 400mL
In acetonitrile, being slowly increased to room temperature reaction 4h after 20 DEG C of droppings triethylamine (25.5g, 0.302mol), reaction completely, is used
The saturated aqueous common salt washing of 13%, dense the doing of organic layer directly carries out next step without purification；
Step 3, the synthesis of his Wei of Dacca
Take above-mentioned intermediate 2 and ammonium acetate (160g, the mol ratio of intermediate 2 and ammonium acetate is 1:20) is dissolved in 400mL
In toluene, system is warming up to 80 DEG C, stirring reaction 15h, after reaction terminates, is cooled to room temperature, adds 200mL in system
With 400mL water, stirring 30min, layering, organic layer washes with water successively, saturated common salt is washed, anhydrous sodium sulfate is dried,
Dense dry addition 200mL ethanol, stirring is lower adds the 30mL ethanol solution containing 0.3mol hydrochloric acid, stirs 2h, sucking filtration, filter
Cake washing with acetone obtains 74g crude white solid, and methanol/acetone is recrystallized to give 59g white solid powder, step 2
It is 71% with two step total recoverys of step 3.
MP:266-268.5 DEG C,1H NMR(400MHz,d6-DMSO):δ(ppm):12.02(s,2H),7.75(d,4H),7.62
(d,4H),7.45(s,2H),7.28(s,2H),5.03(t,2H),4.03(t,2H),3.76(m,4H),3.41(s,6H),2.10(m,2H),1.98
(m, 2H), 1.92 (m, 4H), 0.85-0.89 (d, 12H), HRMS (ESI): m/z [M+2Cl]-738.25。
Embodiment 3
The present embodiment relates to the synthetic method of his Wei of a kind of Dacca, comprises the steps of:
Step one, the synthesis of intermediate 1
Take 4.4-diacetyl biphenyl (40g, 0.17mol) and DIPEA (0.39mol) and be dissolved in 1000mL dichloro
In methane, 0 DEG C of dropping TMSOTf (91g, 0.41mol), drip and finish stirring 15 minutes, dropping NBS (66g, 0.37
Mol) dichloromethane (200mL) solution, drips and finishes 0 DEG C of stirring reaction 2h, and completely, system pours 500mL in reaction
In water, layering, anhydrous sodium sulfate are dried, sucking filtration, concentration removing dichloromethane, obtain intermediate 1 crude product, toluene crystallization
Obtain 62g solid, yield 92%；
MP:225-226 DEG C,1H NMR(400MHz,CDCl3):δ(ppm):7.96-7.85(m,4H),7.60-7.52(m,4H),
4.27 (s, 4H), HRMS (ESI): m/z [M+H]-394.93。
Step 2, the synthesis of intermediate 2
Take intermediate 1 (40g, 0.101mol) and L-PROLINE derivant (60g, 0.237mol) is dissolved in 400mL
In acetonitrile, being slowly increased to room temperature reaction 4h after 20 DEG C of droppings triethylamine (26g, 0.252mol), reaction completely, is used
The saturated aqueous common salt washing of 13%, dense the doing of organic layer directly carries out next step without purification；
Step 3, the synthesis of his Wei of Dacca
Take above-mentioned intermediate 2 and ammonium acetate (120g, the mol ratio of intermediate 2 and ammonium acetate is 1:15) is dissolved in 400mL
In toluene, system is warming up to 90 DEG C, stirring reaction 12h, after reaction terminates, is cooled to room temperature, adds 200mL in system
With 400mL water, stirring 30min, layering, organic layer washes with water successively, saturated common salt is washed, anhydrous sodium sulfate is dried,
Dense dry addition 200mL ethanol, stirring is lower adds the 30mL ethanol solution containing 0.3mol hydrochloric acid, stirs 2h, sucking filtration, filter
Cake washing with acetone is dried and is obtained 72g off-white color solid crude product, and methanol/acetone is recrystallized to give 57g white solid powder,
Two step total recoverys of step 2 and step 3 are 69%.
MP:266.5-268 DEG C,1H NMR(400MHz,d6-DMSO):δ(ppm):12.04(s,2H),7.76(d,4H),7.61
(d,4H),7.45(s,2H),7.28(s,2H),5.03(t,2H),4.02(t,2H),3.76(m,4H),3.41(s,6H),2.11(m,2H),1.99
(m, 2H), 1.94 (m, 4H), 0.84-0.88 (d, 12H), HRMS (ESI): m/z [M+2Cl]-738.23。
The ultimate principle of the present invention and principal character and advantages of the present invention have more than been shown and described.The technology people of the industry
Member, it should be appreciated that the present invention is not restricted to the described embodiments, simply illustrating this described in above-described embodiment and description
The principle of invention, without departing from the spirit and scope of the present invention, the present invention also has various changes and modifications, this
A little changes and improvements both fall within scope of the claimed invention.Claimed scope is by appended claim
Book and equivalent thereof define.
Claims (7)
1. the synthetic method of his Wei of Dacca, it is characterised in that comprise the following steps:
Step one, obtains intermediate 1 for raw material through bromo-reaction with 4.4-diacetyl biphenyl；
Step 2, described intermediate 1 is substituted reaction and prepares intermediate 2；
Step 3, described intermediate 2 finally prepares his Wei of Dacca through cyclization；
The synthetic method of his Wei of a kind of Dacca the most as claimed in claim 1, it is characterised in that in step one, intermediate 1
Building-up process as follows: take 4.4-diacetyl biphenyl and DIPEA be dissolved in dichloromethane, 0 DEG C dropping TMSOTf and
The dichloromethane solution of NBS reacts, and whole reaction system is poured into water after reaction completely, layering, anhydrous slufuric acid
Sodium is dried, sucking filtration, concentrates removing dichloromethane and obtains intermediate 1.
The synthetic method of his Wei of a kind of Dacca the most as claimed in claim 2, it is characterised in that described 4.4-diacetyl
Biphenyl, the mol ratio of DIPEA, TMSOTf and NBS are 1:(2.2～2.5): (2.1～2.4): (2.1～2.4).
The synthetic method of his Wei of a kind of Dacca the most as claimed in claim 1, it is characterised in that in step 2, intermediate
The building-up process of 2 is as follows: takes L-PROLINE derivant described in described intermediate 1 and reaction equation and is dissolved in acetonitrile, 20 DEG C
Being slowly increased to room temperature reaction after dropping triethylamine, reaction is washed with saturated aqueous common salt after terminating, and organic layer is consolidated after concentrating
Body, to obtain final product.
The synthetic method of his Wei of a kind of Dacca the most as claimed in claim 4, it is characterised in that described intermediate 1, L-
Proline derivative, the mol ratio of triethylamine are 1:(2.2～2.5): (2.5～3.0).
The synthetic method of his Wei of a kind of Dacca the most as claimed in claim 1, it is characterised in that in step 3, Dacca he
The building-up process of Wei is as follows: take described intermediate 2 and ammonium acetate is dissolved in toluene, and system is warming up to 90 DEG C of reactions, instead
Should be cooled to room temperature after terminating, add water, be layered after stirring 30min in reactant liquor, organic layer is successively with water, saturated
Brine It, sucking filtration, be dried, concentrate, be subsequently adding ethanol solution hydrochloride, stirring, after through sucking filtration, dry after
Obtain his Wei of Dacca.
The synthetic method of his Wei of a kind of Dacca the most as claimed in claim 6, it is characterised in that described intermediate 2 and acetic acid
The mol ratio of ammonium is 1:(10～20).
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| CN201610191144.9A CN105777719A (en) | 2016-03-29 | 2016-03-29 | Synthesis method of Daclatasvir |
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| CN201610191144.9A CN105777719A (en) | 2016-03-29 | 2016-03-29 | Synthesis method of Daclatasvir |
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2017076358A1 (en) * | 2015-11-06 | 2017-05-11 | 苏州晶云药物科技有限公司 | New crystal form of imidazolyl biphenyl compound salt and preparation method thereof |
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| WO2017076358A1 (en) * | 2015-11-06 | 2017-05-11 | 苏州晶云药物科技有限公司 | New crystal form of imidazolyl biphenyl compound salt and preparation method thereof |
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Application publication date: 20160720 |