CN108069941A - A kind of method for preparing his Wei of Dacca - Google Patents
A kind of method for preparing his Wei of Dacca Download PDFInfo
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- CN108069941A CN108069941A CN201611003703.5A CN201611003703A CN108069941A CN 108069941 A CN108069941 A CN 108069941A CN 201611003703 A CN201611003703 A CN 201611003703A CN 108069941 A CN108069941 A CN 108069941A
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- Prior art keywords
- formula
- compound shown
- dacca
- wei
- mixture
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- 0 CC(*)[C@](C(N(CCC1)[C@]1C(NC(c1ccc(C(CC#CC)C=C)cc1)=CN)=C)=O)NC(C)=O Chemical compound CC(*)[C@](C(N(CCC1)[C@]1C(NC(c1ccc(C(CC#CC)C=C)cc1)=CN)=C)=O)NC(C)=O 0.000 description 2
Classifications
-
- C—CHEMISTRY; METALLURGY
- 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
Abstract
The present invention provides a kind of methods for preparing his Wei of Dacca, belong to field of medicine and chemical technology；The method of the invention is by will be after compound carries out condensation reaction shown in compound shown in Formula II and formula III, obtain mixture A, then alkali is added in, it stirs at a certain temperature, the mixture A is made to react, after completion of the reaction, add in organic solvent extracted, liquid separation, his Wei of Dacca is obtained after organic phase concentration is dry；The characteristics of product purity that this method produces is high, and high income is at low cost, easy to operate, process stabilizing.
Description
Technical field
The present invention relates to field of medicine and chemical technology, and in particular, to a kind of method for preparing his Wei of Dacca.
Background technology
His Wei of Dacca, entitled ((1S) -1- (((2S) -2- (5- (4 '-(2- ((2S) -1- ((2S) -2- ((the methoxy carbonyls of chemistry
Base) amino) -3- methylbutyryls) -2- pyrrolidinyls) -1H- imidazoles -5- bases) -4- xenyls) -1H- imidazoles -2- bases) -1- pyrroles
Cough up alkyl) carbonyl) -2- methyl-propyls) methyl carbamate, structural formula is as follows：
His Wei of Dacca belongs to a kind of NS5A inhibitor, and merging available for treatment chronic hepatitis C includes 1 type of genotype, and 2
The compensatory hepatopathy of type, 3 types and 4 types.The prior art shows that his Wei yield of Dacca is not high, therefore the preparation process of his Wei of Dacca is also
It is further improved.
The content of the invention
It is contemplated that it solves at least some of the technical problems in related technologies.For this purpose, the present invention
One purpose is to propose a kind of method for preparing his Wei of Dacca, and this method has product purity high, and high income is at low cost,
It is easy to operate, the characteristics of process stabilizing, it is suitble to the industrialized production of his Wei of Dacca.
According to an aspect of the present invention, the present invention proposes a kind of method for preparing his Wei of Dacca, comprises the following steps：
(1) compound shown in Formula II is contacted with compound shown in formula III, after being reacted, obtains mixture A；
(2) step (1) the mixture A stirs under alkali effect, obtains mixture B at a certain temperature；
(3) organic solvent and water will be added in step (2) the mixture B, extracts liquid separation, obtained after organic phase concentration is dry
His Wei of Dacca shown in Formulas I.
The present invention prepares compound shown in the method using Formula II of his Wei of Dacca, compound shown in formula III as initial action
His Wei of Dacca is prepared through one kettle way in material.This method have efficiently, economy, that reaction time is short, product purity is high etc. is excellent
Point.
According to some embodiments of the present invention, step (1) is carried out according to the following steps：
Compound shown in Formula II is contacted mixing with compound shown in formula III by (1-1), and generation includes his Wei, 1 institute of formula of Dacca
Show the mixture A of compound shown in compound and/or formula 2,
According to some embodiments of the present invention, step (2) is carried out according to the following steps：
Mixture A obtained by step (1-1) under the action of alkali, is heated to 20 degrees Celsius -40 degrees Celsius and controlled by (2-1)
When temperature reaction 1 is small -10 it is small when, generate mixture B.
According to some embodiments of the present invention, step (3) further comprises：
Organic solvent and water are added in (3-1) mixture B obtained to step (2-1), extracts liquid separation, organic phase concentration
The finished product of his Wei of Dacca is obtained after dry.
According to some embodiments of the present invention, the organic solvent be dichloromethane, toluene, ethyl acetate, acetic acid it is different
Propyl ester, isobutyl acetate, etc..
According to some embodiments of the present invention, preferred organic solvent for dichloromethane, ethyl acetate, isopropyl acetate or
Isobutyl acetate.
According to some embodiments of the present invention, compared with compound shown in 1 mole of Formula II, the dosage of the alkali is 1-10
Mole.
According to some embodiments of the present invention, the alkali for ammonium hydroxide, diisopropylethylamine, triethylamine, N-methylmorpholine, 1,
11 carbon -7- alkene of 8- diazabicylos, sodium hydroxide, potassium hydroxide, potassium phosphate, sodium carbonate, sodium acid carbonate, sodium phosphate, phosphoric acid
At least one of disodium hydrogen.
According to some embodiments of the present invention, preferred alkali is ammonium hydroxide, sodium hydroxide, potassium hydroxide, diisopropylethylamine
Or potassium phosphate.
According to some embodiments of the present invention, the reaction temperature is at 20 DEG C~40 DEG C.
According to some embodiments of the present invention, the dosage of the organic solvent is compound shown in 5mL-10mL/g Formula II.
According to some embodiments of the present invention, the dosage of the water is compound shown in 3mL-6mL/g Formula II.
Description of the drawings
Fig. 1 is the HPLC figures in the reaction process of the embodiment of the present invention 1.
Fig. 2 is the HPLC figures of the product of the embodiment of the present invention 1.
Fig. 3 be the embodiment of the present invention 2 reaction process in HPLC scheme.
Fig. 4 is the HPLC figures of the product of the embodiment of the present invention 2.
Fig. 5 be the embodiment of the present invention 3 reaction process in HPLC scheme.
Fig. 6 is the HPLC figures of the product of the embodiment of the present invention 3.
Fig. 7 be the embodiment of the present invention 4 reaction process in HPLC scheme.
Fig. 8 is the HPLC figures of the product of the embodiment of the present invention 4.
Fig. 9 is the LC-MS figures of the compounds of this invention formula 1.
Figure 10 is the LC-MS figures of the compounds of this invention formula 2.
Specific embodiment
The embodiment of the present invention is described below in detail.The embodiments described below is exemplary, and is only used for explaining this hair
It is bright, and be not considered as limiting the invention.Particular technique or condition are not specified in embodiment, according to text in the art
It offers described technology or condition or is carried out according to product description.Reagents or instruments used without specified manufacturer,
For can be with conventional products that are commercially available.
For the description present invention, embodiment is listed below.But it is to be understood that the present invention is not limited to these Examples, simply
The method that the practice present invention is provided.
The embodiments described below, unless other aspects show that all temperature are set to degree Celsius.Reagent is bought in business
Product supplier such as Aldrich Chemical Company, Arco Chemical Company and Alfa Chemical
Company, all without by not being further purified during use, unless other aspects show.General reagent is from the western Gansu Province chemical industry in Shantou
Factory, Guangdong brilliance chemical reagent factory, Guangzhou Chemical Reagent Factory, Tianjin Hao Yuyu Chemical Companies, Tianjin good fortune morning chemistry
Chemical reagent work, Wuhan Xin Huayuan developments in science and technology Co., Ltd, Qingdao Teng Long chemical reagent Co., Ltd and Haiyang Chemical Plant, Qingdao's purchase
It can buy.
Column chromatography is to use silicagel column.Silica gel (300-400 mesh) is purchased from Haiyang Chemical Plant, Qingdao.
The determination condition of Algorithm (MS) data is：6120 level Four bar HPLC-M (pillar models of Agilent：
Zorbax SB-C18,2.1x 30mm, 3.5 microns, 6min, flow velocity 0.6mL/min.Mobile phase：5%-95% (contains 0.1%
The CH of formic acid3CN) (H of 0.1% formic acid is being contained2O the ratio in)), using electron spray ionisation (ESI), under 210nm/254nm,
It is detected with UV.
Compound purity is measured using high performance liquid chromatography (HPLC), uses Agilent 1260HPLC (pillar models：
Agilent zorbax Eclipse Plus C18), and detected with DAD detectors, finally calculated using area normalization method
To compound purity.
According to an embodiment of the invention, the typical synthesis step of his Wei (compound shown in Formulas I) of Dacca is prepared as following
Shown in synthetic schemes.
Embodiment 1
Feed intake compound shown in 5g Formula II, compound shown in 3.5g formula IIIs, and add in compound shown in Formula II 2.5 times rub
1- ethyls-(3- dimethylaminopropyls) phosphinylidyne diimmonium salt hydrochlorate of your amount and dichloromethane 20ml, HPLC detection reaction.Instead
After answering (compound≤0.5% shown in Formula II), ammonium hydroxide 10ml is added in, reacts 1h, thin-layer chromatography (solvent two at 30 DEG C
Chloromethanes:Methanol=8:1) detection reaction, treats that compound shown in compound shown in formula 1 and formula 2 converts (chemical combination shown in formula 1 completely
Compound shown in object and formula 2 is ≤0.5%) into after his Wei of Dacca, dichloromethane 30ml and water 25ml is added in, extracts liquid separation, point
From organic phase is obtained, the finished product of his Wei of Dacca is obtained after organic layer concentration is dry：6.38g, yield 98.5%, HPLC purity
97.36%.
Embodiment 2
Feed intake compound shown in 5g Formula II, compound I shown in 3.5g Formula II, and add in compound shown in Formula II 2.5 times rub
1- ethyls-(3- dimethylaminopropyls) phosphinylidyne diimmonium salt hydrochlorate of your amount and methanol 20ml, HPLC detection reaction.Reaction knot
After beam (compound≤0.5% shown in Formula II), diisopropylethylamine 10ml is added in, reacts 3h, thin-layer chromatography (solvent at 30 DEG C
For dichloromethane:Methanol=8:1) detection reaction, treat the conversion completely of Formula 1 and Formula 2 (compound shown in formula 1 and
Compound shown in formula 2 is ≤0.5%) into after his Wei of Dacca, ethyl acetate 30mL and water 20mL is added in, liquid separation is extracted, separates
To organic phase, the finished product of his Wei of Dacca is obtained after organic layer concentration is dry:6.32g, yield 97.5%, HPLC purity 99.47%.
Embodiment 3
Feed intake compound shown in 5g Formula II, compound I shown in g Formula II, adds in 2.5 moles of compound shown in Formula II
1- ethyls-(3- dimethylaminopropyls) phosphinylidyne diimmonium salt hydrochlorate and acetone 20ml, HPLC detection reaction.After reaction
(compound≤0.5% shown in Formula II) adds in sodium hydroxide (2.1g, 6eq), reacts 1.5h, thin-layer chromatography (solvent at 20 DEG C
For dichloromethane:Methanol=8:1) detection reaction, treat the conversion completely of Formula 1 and Formula 2 (compound shown in formula 1 and
Compound shown in formula 2 is ≤0.5%) into after his Wei of Dacca, isopropyl acetate 30mL and water 25mL is added in, extracts liquid separation, separation
Organic phase is obtained, the finished product of his Wei of Dacca is obtained after organic layer concentration is dry:6.41g, yield 99.0%, HPLC purity
99.48%.
Embodiment 4
Feed intake compound shown in 5g Formula II, compound I shown in g Formula II, adds in 2.5 moles of compound shown in Formula II
1- ethyls-(3- dimethylaminopropyls) phosphinylidyne diimmonium salt hydrochlorate and ethyl alcohol 20ml, HPLC detection reaction.After reaction
(compound≤0.5% shown in Formula II) adds in K3PO4.7H2O (12.68g, 6eq) reacts 6h, thin-layer chromatography at 40 DEG C
(solvent is dichloromethane:Methanol=8:1) Formula 1 and Formula 2 conversion (1 shownization of formula completely are treated in detection reaction
Close compound shown in object and formula 2≤0.5%) into after his Wei of Dacca, add in isobutyl acetate 45mL and water 20mL, extraction point
Liquid, isolated organic phase obtain the finished product of his Wei of Dacca after organic layer concentration is dry:6.48g, yield 98.5%, HPLC is pure
Degree 98.71%.
In the description of this specification, reference term " one embodiment ", " one embodiment ", " example ", " specifically show
The description of example " or " some examples " etc. means specific features, structure, material or the spy for combining the embodiment or example description
Point is contained at least one embodiment of the present invention or example.In the present specification, schematic expression of the above terms is not
It must be directed to identical embodiment or example.Moreover, particular features, structures, materials, or characteristics described can be in office
It is combined in an appropriate manner in one or more embodiments or example.In addition, without conflicting with each other, the skill of this field
Art personnel can tie the different embodiments described in this specification or example and different embodiments or exemplary feature
It closes and combines.
Although the embodiment of the present invention has been shown and described above, it is to be understood that above-described embodiment is example
Property, it is impossible to limitation of the present invention is interpreted as, those of ordinary skill in the art within the scope of the invention can be to above-mentioned
Embodiment is changed, changes, replacing and modification.
Claims (8)
- A kind of 1. method for preparing his Wei of Dacca, which is characterized in that including：(1) compound shown in compound shown in Formula II and formula III is contacted, mixture A is obtained by the reaction；(2) by mixture A under the action of alkali, under certain temperature, mixture B is stirred to get；(3) organic solvent and water are added in mixture B, extracts liquid separation, his Wei Chengpin of Dacca is obtained after organic phase concentration is dry；Structural formula of compound shown in compound and formula III is as follows wherein shown in Formula II：
- 2. the method as described in claim 1, it is characterised in that the mixture A described in step (1) includes compound shown in formula 1 And/or compound shown in formula 2,
- 3. the method as described in claim 1, it is characterised in that the alkali described in step (2) is ammonium hydroxide, diisopropylethylamine, three Ethamine, N-methylmorpholine, 11 carbon -7- alkene of 1,8- diazabicylos, sodium hydroxide, potassium hydroxide, potassium phosphate, sodium carbonate, carbon At least one of sour hydrogen sodium, sodium phosphate or disodium hydrogen phosphate.
- 4. the method as described in claim 1, it is characterised in that compared with compound shown in 1 mole of Formula II, institute in step (2) The dosage for stating alkali is 1-10 moles.
- 5. the method as described in claim 1, it is characterised in that the reaction temperature described in step (2) is 20 DEG C~40 DEG C.
- 6. the method as described in claim 1, it is characterised in that the dosage of the organic solvent described in step (3) is 5mL-10mL/g Compound shown in Formula II.
- 7. the method as described in claim 1, it is characterised in that the organic solvent described in step (3) is dichloromethane, acetic acid second Ester, isopropyl acetate or isobutyl acetate or its combination.
- 8. the method as described in claim 1, it is characterised in that the dosage of the water described in step (3) is 3mL-6mL/g Formula II institute Show compound.
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| Application Number | Priority Date | Filing Date | Title |
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| CN201611003703.5A CN108069941A (en) | 2016-11-15 | 2016-11-15 | A kind of method for preparing his Wei of Dacca |
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| CN201611003703.5A CN108069941A (en) | 2016-11-15 | 2016-11-15 | A kind of method for preparing his Wei of Dacca |
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| Publication Number | Publication Date |
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Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101778841A (en) * | 2007-08-08 | 2010-07-14 | 百时美施贵宝公司 | Be used for the synthetic method that is used for the treatment of the compound of hepatitis C |
| CN104447707A (en) * | 2006-08-11 | 2015-03-25 | 百时美施贵宝公司 | Hepatitis c virus inhibitors |
| CN106496199A (en) * | 2016-10-19 | 2017-03-15 | 上海博志研新药物技术有限公司 | His Wei of Dacca and its preparation method of intermediate |
-
2016
- 2016-11-15 CN CN201611003703.5A patent/CN108069941A/en active Pending
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104447707A (en) * | 2006-08-11 | 2015-03-25 | 百时美施贵宝公司 | Hepatitis c virus inhibitors |
| CN101778841A (en) * | 2007-08-08 | 2010-07-14 | 百时美施贵宝公司 | Be used for the synthetic method that is used for the treatment of the compound of hepatitis C |
| CN106496199A (en) * | 2016-10-19 | 2017-03-15 | 上海博志研新药物技术有限公司 | His Wei of Dacca and its preparation method of intermediate |
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Application publication date: 20180525 |