CN105153128A - Novel method for synthesizing daclatasvir intermediate - Google Patents

Novel method for synthesizing daclatasvir intermediate Download PDF

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CN105153128A
CN105153128A CN201510672012.3A CN201510672012A CN105153128A CN 105153128 A CN105153128 A CN 105153128A CN 201510672012 A CN201510672012 A CN 201510672012A CN 105153128 A CN105153128 A CN 105153128A
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formula
compound
compound shown
ammonium
group
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黄成军
任毅
王琼
李巍
朱燕燕
傅绍军
魏哲文
富刚
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SHANGHAI FOREFRONT PHARMA
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    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C45/00—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds
    • C07C45/45—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by condensation
    • C07C45/46—Friedel-Crafts reactions

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  • Chemical Kinetics & Catalysis (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)

Abstract

The invention provides a novel method for synthesizing a daclatasvir intermediate, particularly a preparation method of a compound disclosed as Formula 1. The method uses biphenyl and halogen acyl bromide as initial raw materials, and avoids using high-cost reaction raw materials. Thus, the preparation method is simple and safe, and is suitable for industrial production.

Description

Novel method for synthesizing daclatasvir intermediate
Technical Field
The invention relates to the field of preparation of pharmaceutical intermediates, and particularly provides a preparation method of a daclatasvir intermediate.
Background
Daclatasvir (Daclatasvir) is a hepatitis C treatment drug developed by BMSquibb company, is marketed in the United states, Europe and Japan respectively, the clinical hepatitis C cure rate of the Daclatasvir and Sofosbuvir (Sofosbuvir) orally combined can be more than 90%, the Daclatasvir and Sofosbuvir are listed in the most important list of essential basic treatment drugs by WHO, and the Daclatasvir has good treatment effect and market prospect.
Among the methods for preparing Daclatasvir (Daclatasvir) known in the art, the compound of formula I is the most important and economical intermediate, and thus there is a need in the art for a method capable of synthesizing the compound of formula I with high efficiency for the industrial production of Daclatasvir.
US20100158862a1 reports the following preparation method:
the method has more synthesis steps, and uses expensive Pd catalyst for 2 times, so that the cost of raw materials is high; and the finished product has the possibility of heavy metal pollution, and the preparation of qualified API needs a fussy Pd removing step.
US8629171B2 reports the following processes:
compared with the prior method, the method has great progress, but the compound 10 in the method still needs to be prepared independently, and the steps are more, so that the cost of raw materials is increased; meanwhile, expensive liquid bromine with poor safety is used, labor protection needs to be well done, and meanwhile safety protection equipment is installed and a safety plan is made.
In view of the foregoing, there is still no method in the art for preparing daclatasvir with low cost, high efficiency and environmental friendliness.
Disclosure of Invention
The invention aims to provide a method for preparing daclatasvir with low cost, high efficiency and environmental friendliness.
In a first aspect of the invention, there is provided a process for the preparation of a compound of formula 1,
the method comprises the following steps:
i) reacting a compound shown in a formula II with a compound shown in a formula III under the action of a catalyst to obtain a compound shown in a formula IV;
ii) reacting the compound of formula IV with the compound of formula V to obtain a compound of formula VI;
iii) carrying out cyclization reaction on the compound shown in the formula VI and ammonium salt to obtain a compound shown in the formula I;
wherein:
X1、X2each independently selected from the group consisting of: cl, Br, I;
X3selected from the group consisting of: H. NH (NH)4Alkali metal, alkaline earth metal, preferably H, NH4And an alkali metal;
R1selected from the group consisting of: r2OCO-, Cbz-, Bn-and R3CO-, wherein R2Is C1-C4 alkyl, R3Is H or C1-C4 alkyl; preferably R2OCO-。
In another preferred embodiment, in step i), the catalyst is selected from the group consisting of: AlZ3、BZ3Or its reaction with Et2O complex, FeZ3、ZnZ2、TiZ4、H2SO4HF, polyphosphoric acid, sulfonic acid type ion exchange resins, orWherein R is3Is H or C1-C4 alkyl; or any combination of the above catalysts; wherein Z is F, Cl, Br, I.
In another preferred embodiment, in the step i), the catalyst is AlZ3(ii) a Wherein Z is F, Cl, Br, I.
In another preferred embodiment, R is2OCO-is Boc-.
In another preferred embodiment, the cyclizing reagent is an ammonium salt, and the ammonium salt is selected from the group consisting of: ammonium formate, ammonium acetate, ammonium chloride, ammonium sulfate, ammonium bisulfate, ammonium nitrate, ammonium carbonate, ammonium bicarbonate, urea, or a combination thereof; ammonium formate, ammonium acetate, or ammonium bicarbonate is preferred.
In a second aspect of the present invention, there is provided a process for the preparation of a compound of formula IV, said process comprising the steps of:
i) reacting a compound shown in a formula II with a compound shown in a formula III under the action of a catalyst to obtain a compound shown in a formula IV;
wherein,
X1、X2each independently selected from the group consisting of: cl, Br and I.
In another preferred embodiment, in step i), the catalyst is selected from the group consisting of: AlZ3、BZ3Or its reaction with Et2O complex, FeZ3、ZnZ2、TiZ4、H2SO4HF, polyphosphoric acid, sulfonic acid type ion exchange resins, orWherein R is3Is H, or C1-C4 alkyl; or any combination of the above catalysts; wherein Z is F, Cl, Br, I.
In another preferred embodiment, in the step i), the catalyst is AlZ3(ii) a Wherein Z is F, Cl, Br, I.
In a third aspect of the invention, a preparation method of the compound shown in the formula I is provided,
the method comprises the following steps:
i) reacting a compound shown in a formula II with a compound shown in a formula III under the action of a catalyst to obtain a compound shown in a formula IV;
and
preparing a compound of formula I from said compound of formula IV;
X1、X2each independently selected from the group consisting of: cl, Br and I.
In a fourth aspect of the present invention, there is provided a preparation method of daclatasvir, comprising the steps of:
i) reacting a compound shown in a formula II with a compound shown in a formula III under the action of a catalyst to obtain a compound shown in a formula IV;
and
preparing daclatasvir from said compound of formula IV;
wherein, X1、X2Each independently selected from the group consisting of: cl, Br and I.
In another preferred embodiment, the method further comprises the steps of:
ii) reacting the compound of formula IV with the compound of formula V to obtain a compound of formula VI;
iii) carrying out cyclization reaction on the compound shown in the formula VI and ammonium salt to obtain a compound shown in the formula I;
and
preparing daclatasvir from said compound of formula I;
wherein:
X1、X2each independently selected from the group consisting of: cl, Br, I;
X3selected from the group consisting of: H. NH (NH)4Alkali metal, alkaline earth metal, preferably H, NH4And an alkali metal;
R1comprises the following steps: r2OCO-, Cbz-, Bn and R3CO-, wherein R2Is C1-C4 alkyl, R3Is H or C1-C4 alkyl; preferably R2OCO-。
It is to be understood that within the scope of the present invention, the above-described features of the present invention and those specifically described below (e.g., in the examples) may be combined with each other to form new or preferred embodiments. Not to be reiterated herein, but to the extent of space.
Detailed Description
The inventor of the invention obtains a method for preparing the daclatasvir intermediate compound shown as the formula I through long-term and intensive research, and compared with the prior art, the method avoids the use of expensive raw materials, is simple to operate, has good safety and has good industrial application value. Based on the above findings, the inventors have completed the present invention.
Preparation of daclatasvir intermediate
The invention provides a preparation method of a daclatasvir intermediate, namely a compound shown in a formula 1,
the method comprises the following steps:
i) reacting a compound shown in a formula II with a compound shown in a formula III under the action of a catalyst to obtain a compound shown in a formula IV;
and
preparing a compound of formula I from said compound of formula IV; wherein, the preparation can be prepared by referring to the existing method in the field or designed by the person skilled in the art according to the common general knowledge in the field.
X1、X2Each independently selected from the group consisting of: cl, Br and I.
More preferably, the method comprises the steps of:
i) reacting a compound shown in a formula II with a compound shown in a formula III under the action of a catalyst to obtain a compound shown in a formula IV;
ii) reacting the compound of formula IV with the compound of formula V to obtain a compound of formula VI;
iii) carrying out cyclization reaction on the compound shown in the formula VI and ammonium salt to obtain a compound shown in the formula I;
wherein:
X1、X2each independently selected from the group consisting of: cl, Br, I;
X3selected from the group consisting of: H. NH (NH)4Alkali metal, alkaline earth metal, preferably H, NH4And an alkali metal;
R1comprises the following steps: r2OCO-, Cbz-, Bn and R3CO-, wherein R2Is C1-C4 alkyl, R3Is H or C1-C4 alkyl; preferably R2OCO-。
In another preferred embodiment, in step i), the catalyst is selected from the group consisting of: AlZ3、BZ3Or its reaction with Et2O complex, FeZ3、ZnZ2、TiZ4、H2SO4HF, polyphosphoric acid, sulfonic acid type ion exchange resins, orWherein R is3Is H or C1-C4 alkyl; or any combination of the above catalysts; z is Cl, Br or I.
In another preferred embodiment, in the step i), the catalyst is AlZ3(ii) a Wherein Z is Cl, Br or I.
In another preferred embodiment, in said step i), the molar ratio of said catalyst to the compound of formula II is from 2.0:1.0 to 15.0: 1.0.
In another preferred embodiment, in said step i), said reaction is carried out in a solvent selected from the group consisting of: dichloromethane, chloroform, 1, 2-dichloroethane, chlorobenzene, dichlorobenzene, trifluoromethylbenzene, freon, heptane, diethyl ether, methyl tert-butyl ether, DMF, DMA, DMSO, DMI, methylpyrrolidone, formamide, carbon disulfide, ethylene glycol dimethyl ether, nitrobenzene, or combinations thereof.
In another preferred embodiment, in step i), the molar ratio of the compound of formula II to the compound of formula III is 1:1.0-20 (preferably 1: 1.0-5.0).
In another preferred embodiment, in the step i), the reaction temperature is-40 ℃ to 140 ℃.
In another preferred embodiment, in the step i), the reaction time is 0.5 to 72 hours.
In another preferred embodiment, said R2OCO-is Boc-.
In another preferred embodiment, in said step ii), said compound of formula IV and said compound of formula V are present in a molar ratio of 1.0:1.0 to 20 (preferably 1:1.0 to 5.0).
In another preferred embodiment, in the step ii), the reaction temperature is-20 ℃ to 140 ℃.
In another preferred embodiment, in the step ii), the reaction time is 10min to 10 hours.
In another preferred embodiment, in said step ii), said reaction is carried out in a solvent selected from the group consisting of: tetrahydrofuran, dioxane, 2-methyltetrahydrofuran, methylcyclopentyl ether, toluene, xylene, acetone, methyl ethyl ketone, methyl isobutyl ketone, ethyl acetate, isopropyl acetate, butyl acetate, ethylene glycol dimethyl ether, ethylene glycol methyl ether, acetonitrile, propionitrile benzonitrile, DMF, N-dimethylacetamide, DMSO, DMI, methylpyrrolidone, formamide, or a combination thereof.
In another preferred embodiment, in step iii), said ammonium salt is selected from the group consisting of: ammonium formate, ammonium acetate, ammonium chloride, ammonium sulfate, ammonium bisulfate, ammonium nitrate, ammonium carbonate, ammonium bicarbonate, urea, or a combination thereof; ammonium formate, ammonium acetate, or ammonium bicarbonate is preferred.
In another preferred embodiment, in the step iii), the reaction is performed in a solvent selected from the group consisting of: dioxane, tetrahydrofuran, 2-methyltetrahydrofuran, methylcyclopentyl ether, anisole, phenetole, toluene, xylene, chlorobenzene, dichlorobenzene, trifluoromethylbenzene, heptane, ethylene glycol dimethyl ether, ethylene glycol methyl ether, acetonitrile, propionitrile, benzonitrile, DMF, N-dimethylacetamide, DMSO, DMI, methylpyrrolidone, formamide, or a combination thereof.
In another preferred embodiment, in said step iii), said compound of formula V and said cyclizing reagent (ammonium salt) are present in a molar ratio of 1.0:1.0 to 1: 50.
In another preferred embodiment, in the step iii), the reaction temperature is 20 ℃ to 180 ℃.
In another preferred embodiment, in the step iii), the reaction time is 30min to 72 hours.
Preparation of intermediates of formula IV
The invention also provides a preparation method of the compound shown in the formula IV, which is characterized by comprising the following steps:
i) reacting a compound shown in a formula II with a compound shown in a formula III under the action of a catalyst to obtain a compound shown in a formula IV;
wherein,
X1、X2each independently selected from the group consisting of: cl, Br and I.
In step i), the catalyst is selected from the group consisting of: AlZ3、BZ3Or its reaction with Et2O complex, FeZ3、ZnZ2、TiZ4、H2SO4HF, polyphosphoric acid, sulfonic acid type ion exchange resins, orWherein R is3Is H, or C1-C4 alkyl; or any combination of the above catalysts; wherein Z is Cl, Br or I. More preferably, in the step i), the catalyst is AlZ3(ii) a Wherein Z is Cl, Br or I.
In the invention, the compound of the formula III is directly reacted with biphenyl to prepare the compound of the formula IV, and liquid bromine is not needed in the reaction process, so that the reaction efficiency and the safety are improved.
Preparation of daclatasvir
The intermediate of formula IV or the intermediate of formula I prepared by the invention can also be used as an intermediate in the preparation of daclatasvir, so that the daclatasvir can be efficiently, simply and conveniently prepared.
The invention also provides a preparation method of the daclatasvir, which is characterized by comprising the following steps:
i) reacting a compound shown in a formula II with a compound shown in a formula III under the action of a catalyst to obtain a compound shown in a formula IV;
and
preparing daclatasvir from said compound of formula IV;
wherein, X1、X2Each independently selected from the group consisting of: cl, Br and I.
The preparation may be carried out by methods known in the art, for example, as reported in the literature.
In another preferred embodiment, the method further comprises the steps of:
ii) reacting the compound of formula IV with the compound of formula V to obtain a compound of formula VI;
iii) carrying out cyclization reaction on the compound shown in the formula VI and ammonium salt to obtain a compound shown in the formula I;
and
preparing daclatasvir from said compound of formula VI;
wherein:
X1、X2each independently selected from the group consisting of: cl, Br, I;
X3selected from the group consisting of: H. NH (NH)4Alkali metal, alkaline earth metal, preferably H, NH4And an alkali metal;
R1comprises the following steps: r2OCO-, Cbz-, Bn and R3CO-, wherein R2Is C1-C4 alkyl, R3Is H or C1-C4 alkyl; preferably R2OCO-。
Compared with the prior art, the invention has the following advantages:
1) the invention takes biphenyl as raw material, and one-step direct introduction of alpha-halogenated acetyl is carried out through Friedel-crafts reaction, so that the bromination step is reduced, the use of expensive liquid bromine is eliminated, and the raw material cost is greatly reduced;
2) because the use of liquid bromine is eliminated, the potential safety hazard is eliminated, and the method has better safety, simple operation, easy realization of reaction, easy amplification and better industrial application value;
3) the method obviously reduces the discharge of three wastes due to the improvement of the yield and the elimination of the use of liquid bromine.
The invention will be further illustrated with reference to the following specific examples. It should be understood that these examples are for illustrative purposes only and are not intended to limit the scope of the present invention. The experimental procedures, in which specific conditions are not noted in the following examples, are generally carried out under conventional conditions or conditions recommended by the manufacturers. Unless otherwise indicated, percentages and parts are by weight.
Example 1
21.7g (163.0mmol, 2.5eq) of aluminum trichloride and 80ml of dichloromethane were charged into a 250ml four-necked flask, stirred, and a mixed solution of 10.0g of biphenyl (65.0mmol, 1.0eq) and 20ml of dichloromethane was slowly added dropwise at 20 to 25 ℃ with stirring, and stirred for 30 minutes until most of the aluminum trichloride was dissolved.
The reaction mixture was cooled to 0 deg.C and 22.0g (194.8mmol, 3.0eq) chloroacetyl chloride was slowly added dropwise, after the addition was complete, it was held at 0 deg.C for 1 hour, then allowed to warm to room temperature naturally, stirring was continued for 2 hours, and TLC traces showed the disappearance of the starting material.
The reaction mixture was poured into 100ml of an 10% ice water-hydrochloric acid mixture, and stirred for 30 minutes to separate an organic layer. The organic phase was washed with water, 10% sodium hydrogencarbonate solution, saturated brine, dried over anhydrous sodium sulfate and concentrated to give 18.6g of the compound IV-Cl, Cl (yield: 93.5%).
1HNMR(DMSO)：7.7-8.2(m,8H)；5.2(s,4H)。
Example 2
30.0g (97.7mmol,1.0eq) of IV-Cl, Cl and 62.2g (107.5mmol,2.2eq) of compound 11 were placed in 500ml of acetone, stirring was turned on, heating was carried out to 50-55 ℃ for 2h reaction, TLC showed disappearance of the starting material, concentration was carried out to dryness, 300ml of water was added, extraction was carried out 3 times with 200ml of X3 toluene, toluene layers were combined, 300ml of water was washed, dried over anhydrous sodium sulfate, filtered, and the obtained toluene solution was used directly in the next reaction.
Example 3
135g of ammonium acetate was added to the toluene solution of example 2, the reaction was stirred under reflux overnight, and TLC showed disappearance of the starting material. Cooling to 78-80 deg.C, adding 300ml water, stirring at 78-80 deg.C for 15min, and removing water layer; the aqueous layer was extracted once with 300ml of toluene at 78-80 ℃ and the organic layers were combined; the organic layer was washed with 300ml of water at 78-80 ℃ and the aqueous layer was separated. The toluene layer was concentrated to about 350ml, 110ml of methanol was added, cooled to room temperature, stirred for 3 hours, and a solid was gradually precipitated, filtered, washed, and dried to obtain 36.0g of I-Boc, Boc (yield: 59.0% in terms of compounds IV-Cl, Cl).
1HNMR(DMSO)：13.00-11.00(m,2H),7.90-7.75(m,4H),7.75-7.60(m,4H),7.60-7.30(S,2H),4.92-4.72(m,2H),3.65-3.49(m,2H),3.49-3.28(m,2H),2.39-2.10(m,2H),2.10-1.87(m,6H),1.60-1.33(s,8H),1.33-1.07(s,10H).
MS(M++1,ESI+)：625.3
Example 4
25.0g (40.0mmol, 1eq) of I-Boc, Boc, 250ml of methanol were placed in a 500ml four-necked flask, stirred and added dropwise with 32.85ml (400.1mmol, 10eq) of 6M aqueous hydrochloric acid. Heated to 50 ℃ and reacted for 5 h. Cooling to room temperature and reacting for 18 h. And (5) filtering. The filter cake was washed with 90ml methanol: the column was washed once with 10ml of water and once with 100ml of methanol.
After baking at 50 ℃ for 18 hours, 18.1g of Compound I-HCl was obtained (yield: 79.4%).
Example 5
100ml acetonitrile, 13.69g (89.4mmol, 2.5eq) HOBT,15.07g (86mmol,2.4eq) moc-L-valine, 16.46g (85.9mmol,2.4eq) EDCI, 100ml acetonitrile are added into a 1000ml four-neck flask, stirring is started, the reaction is carried out at 20-25 ℃ for 1h, 20.4g (35.8mmol,1eq) I-HCl is added, the temperature is reduced to 0 ℃, 10.0g (142.9mmol, 4.0eq) DIPEA is slowly added dropwise, and the dropping is completed in half an hour. The temperature is increased to 15 ℃ and the mixture is stirred for 16 h.
To the reaction mixture was added 13% aqueous sodium chloride solution (120ml), and the mixture was heated to 50 ℃ and stirred for 1 hour. Cooling to 20 deg.C, adding 100ml isopropyl acetate, stirring for 30min, and standing for liquid separation. The organic phase is washed twice with 240ml of 0.5M aqueous NaOH solution (containing 13% NaCl) and once with 120ml of 13% aqueous NaCl solution. And (5) drying by distillation. 140ml of absolute ethanol were added, and after heating to 50 ℃ 66.4ml (82.3mmol,2.3eq) of a 1.24M HCl solution in ethanol were slowly added dropwise. The mixture was kept at 50 ℃ for 3 hours, then cooled to room temperature naturally, and stirred for another 22 hours. Filtration, rinsing with 100ml (acetone: ethanol 2:1), and vacuum drying at 70 ℃ give 22.15g of compound I-moc-valine-HCl (yield: 76.3%).
1HNMR(DMSO-d6,80℃)：8.02(d,J＝8.34Hz,4H),7.97(s,2H),7.86(d,J＝8.34Hz,4H),6.75(s,2H),5.27(t,J＝6.44Hz,2H),4.17(t,J＝6.95Hz,2H),3.97-4.11(m,2H),3.74-3.90(m,2H),3.57(s,6H),2.32-2.46(m,2H),2.09-2.31(m,6H),1.91-2.07(m,2H),0.88(d,J＝6.57Hz,6H),0.79(d,J＝6.32Hz,6H)。
All documents referred to herein are incorporated by reference into this application as if each were individually incorporated by reference. Furthermore, it should be understood that various changes and modifications of the present invention can be made by those skilled in the art after reading the above teachings of the present invention, and these equivalents also fall within the scope of the present invention as defined by the appended claims.

Claims (10)

1. A process for the preparation of a compound of formula 1,
the method is characterized by comprising the following steps:
i) reacting a compound shown in a formula II with a compound shown in a formula III under the action of a catalyst to obtain a compound shown in a formula IV;
ii) reacting the compound of formula IV with the compound of formula V to obtain a compound of formula VI;
iii) carrying out cyclization reaction on the compound shown in the formula VI and a cyclization reagent to obtain a compound shown in the formula I;
wherein:
X1、X2each independently selected from the group consisting of: cl, Br, I;
X3selected from the group consisting of: h+、NH4 +Alkali metal, alkaline earth metal, preferably H+、NH4 +And an alkali metal;
R1selected from the group consisting of: r2OCO-, Cbz-, Bn-and R3CO-, wherein R2Is C1-C4 alkyl, R3Is H or C1-C4 alkyl; preferably R2OCO-。
2. The process of claim 1 wherein in step i), the catalyst is selected from the group consisting of: AlZ3、BZ3Or its reaction with Et2O complex, FeZ3、ZnZ2、TiZ4、H2SO4HF, polyphosphoric acid, sulfonic acid type ion exchange resins, orWherein R is3Is H or C1-C4 alkyl; or any combination of the above catalysts; wherein Z is F, Cl, Br, I.
3. The method of claim 2, wherein said step of determining is performed in a batch processIn step i), the catalyst is AlZ3(ii) a Wherein Z is F-、Cl-、Br-、I-。
4. The method of claim 1, wherein R is2OCO-is Boc-.
5. The method of claim 1, wherein the cyclizing reagent is an ammonium salt and the ammonium salt is selected from the group consisting of: ammonium formate, ammonium acetate, ammonium chloride, ammonium sulfate, ammonium bisulfate, ammonium nitrate, ammonium carbonate, ammonium bicarbonate, urea, or a combination thereof; ammonium formate, ammonium acetate, or ammonium bicarbonate is preferred.
6. A process for preparing a compound of formula IV, comprising the steps of:
i) reacting a compound shown in a formula II with a compound shown in a formula III under the action of a catalyst to obtain a compound shown in a formula IV;
wherein,
X1、X2each independently selected from the group consisting of: cl, Br and I.
7. The process of claim 6 wherein in step i), the catalyst is selected from the group consisting of: AlZ3、BZ3Or its reaction with Et2O complex, FeZ3、ZnZ2、TiZ4、H2SO4HF, polyphosphoric acid, sulfonic acid type ion exchange resins, orWherein R is3Is H, or C1-C4 alkyl; or any combination of the above catalysts; wherein Z is F, Cl, Br, I.
8. The method of claim 7, wherein in step i), the catalyst is AlZ3(ii) a Wherein Z is F, Cl, Br, I.
9. A method for preparing a compound shown as a formula I,
the method is characterized by comprising the following steps:
i) reacting a compound shown in a formula II with a compound shown in a formula III under the action of a catalyst to obtain a compound shown in a formula IV;
and
preparing a compound of formula I from said compound of formula IV;
X1、X2each independently selected from the group consisting of: cl, Br and I.
10. A preparation method of daclatasvir, which is characterized by comprising the following steps:
i) reacting a compound shown in a formula II with a compound shown in a formula III under the action of a catalyst to obtain a compound shown in a formula IV;
and
preparing daclatasvir from said compound of formula IV;
wherein, X1、X2Each independently selected from the group consisting of: cl, Br and I.
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CN106432204A (en) * 2016-09-12 2017-02-22 上海步越化工科技有限公司 Anti-hepatitis C Daclatasvir synthesis method
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
WO2018007984A1 (en) * 2016-07-08 2018-01-11 Lupin Limited Crystalline forms of daclatasvir dihydrochloride
CN108727171A (en) * 2017-04-21 2018-11-02 上海迪赛诺化学制药有限公司 4,4 '-two（2- acetyl bromides）The preparation method of biphenyl
CN109503557A (en) * 2018-12-29 2019-03-22 常州吉恩药业有限公司 A kind of industrialized preparing process of his Wei key intermediate of Dacca
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