CN105348144B - A kind of synthetic method of the vinylcyclopropanecaracidlic acidlic ethyl ester of (1R, 2S) 1 amino 2 - Google Patents
A kind of synthetic method of the vinylcyclopropanecaracidlic acidlic ethyl ester of (1R, 2S) 1 amino 2 Download PDFInfo
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- C07C227/14—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton from compounds containing already amino and carboxyl groups or derivatives thereof
- C07C227/18—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton from compounds containing already amino and carboxyl groups or derivatives thereof by reactions involving amino or carboxyl groups, e.g. hydrolysis of esters or amides, by formation of halides, salts or esters
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Abstract
The invention belongs to medicament intermediates capable of resisting hepatitis C virus preparing technical field, and in particular to a kind of synthetic method of the vinylcyclopropanecaracidlic acidlic ethyl ester of (1R, 2S) 1 amino 2, concretely comprise the following steps：Step 1: using benzaldehyde, glycine ethyl ester hydrochloride, toluene, triethylamine as raw material, compound 4 is synthesized；Step 2: prepare compound 3 is reacted in toluene, caustic alcohol by compound 4 and anti-1,4 dibromo butene；Step 3: by the He of compound 3（2S）‑2‑[（3,5 dichloro-benzoyls）Epoxide] propionic acid adds isopropanol after being reacted in toluene and hexane obtains compound 2；Step 4: compound 2 reacts to obtain the vinylcyclopropanecaracidlic acidlic ethyl ester of (1R, 2S) 1 amino 2 in toluene and sodium hydroxide.The present invention is simple to operate, and raw material is cheap and easy to get, is adapted to industrialized production；Obtained object purity and chiral purity is high.
Description
Technical field
The present invention relates to the synthetic method of (1R, 2S) -1- amino -2- vinylcyclopropanecaracidlic acidlic ethyl esters, belong in medicine
Mesosome preparing technical field.
Background technology
Western miaow Wei（Simeprevir）It is NS3/4A protease inhibitors of new generation, is oral drugs, it is public by Medivir
Department and Yang Sen（Janssen）Develop jointly, for treating the compensatory hepatopathy of chronic hepatitis C adult patients.Western miaow Wei
（Simeprevir）Structural formula it is as follows：
。
Compound 1（Chinese name：(1R, 2S) -1- amino -2- vinylcyclopropanecaracidlic acidlic ethyl esters）As Simeprevir medicines
The key intermediate of thing, the chiral purity of compound 1 directly affect the effect of Simeprevir medicines.The existing conjunction of compound 1
Low into method yield, the chiral purity of One-step crystallization there was only 86%ee, it is necessary to which carrying out the recrystallization of 1 ~ 2 time can be only achieved 95%,
The reaction of two steps is using than relatively hazardous activating reagent tert-butyl lithium or butyl lithium.
The content of the invention
It is an object of the invention to provide the synthesis side of one kind (1R, 2S) -1- amino -2- vinylcyclopropanecaracidlic acidlic ethyl esters
Method, this method is simple to operate, and raw material is cheap and easy to get, and is adapted to industrialized production, and product chiral purity is high.
The present invention is realized by following technical proposals.(1R, 2S) -1- amino -2- vinylcyclopropanecaracidlic acidlic ethyl esters
Synthetic method, its synthetic route are as follows：
Concretely comprise the following steps：
Step 1: using benzaldehyde, glycine ethyl ester hydrochloride, toluene, triethylamine as raw material, compound 4 is synthesized；
Step 2: by compound 4Prepare compound 3；
Step 3: by compound 3With（2S）-2-[（4- chlorobenzoyls）Epoxide] propionic acid prepares chemical combination
Thing 2；
Step 4: compound 2With toluene chemical combination is obtained in 0-10 DEG C of reaction
Thing 1, it is (1R, 2S) -1- amino -2- vinylcyclopropanecaracidlic acidlic ethyl esters.
In the step 1, by benzaldehyde, glycine ethyl ester hydrochloride（Glycine ethyl ester hydrochloride is that benzaldehyde mole is thrown
The 1.0 ~ 1.3 of doses, optimal is 1.1）, after toluene stirs, then triethylamine is added dropwise, insulation reaction 2 hours（Reaction time model
Enclose for 1 ~ 10 hour, optimal 2 ~ 5 hours）；Water is put into, stratification removes water layer after stirring, and be concentrated under reduced pressure to obtain compound 4.First
Benzene can be replaced as solvent with benzene, dimethylbenzene, ethyl acetate, dichloromethane, chloroform.Triethylamine can use three fourths as acid binding agent
The organic amines such as amine, pyridine replace.
In the step 2, toluene, caustic alcohol are put into reaction bulb（Its mole of inventory is trans- 1,4- dibromo butenes
1.5 ~ 2.5, optimal value 2）, feed intake end, be cooled to Wen Du≤0 DEG C；Control is counter to answer liquid temperature Du≤0 DEG C（Optimal Temperature is -15
~-10℃）, trans- Isosorbide-5-Nitrae-dibromo butene is put into successively（Its mole of inventory is the 0.7 ~ 1.0 of benzaldehyde）, compound 4, feed intake knot
Beam, insulation reaction 2 hours（Reaction time range is 1 ~ 10 hour, optimal 2 ~ 5 hours）；Nei Wen≤30 DEG C are controlled, are initially added into
Water, then control interior 0 ~ 30 DEG C of addition hydrochloric acid of temperature；Completion of dropwise addition, insulated and stirred；Stratification separates water layer；First is put into water layer
Benzene, stir lower dropwise addition liquid caustic soda；Completion of dropwise addition, stratification separates organic layer after insulated and stirred；Organic layer is the first of compound 3/
Benzole soln.Toluene can be replaced as solvent with benzene, dimethylbenzene, ethyl acetate, dichloromethane, chloroform.
In the step 3, put into reaction bulb the toluene solution of previous step compound 3/,（2S）-2-[（3,5- dichloro-benzenes
Formyl）Epoxide] propionic acid（Its mole of inventory is the 0.8 ~ 1.0 of trans- Isosorbide-5-Nitrae-dibromo butene, optimal value 0.9）, feed intake end,
Insulation reaction 5 hours（Reaction time range is 3 ~ 10 hours, 5 ~ 6 hours peak optimization reaction time）；Insulation terminates, and puts into isopropyl
Alcohol, then control interior 20 ~ 40 DEG C of dropwise addition hexanes of temperature（The rate of charge of isopropanol and hexane is 0.5 ~ 1:1, optimal rate of charge is 0.6:
1）, completion of dropwise addition, insulated and stirred 1 hour（Time range 1 ~ 5 hour）；Temperature of charge is reduced to 10 ~ 15 DEG C, cooling terminates, and protects
Temperature stirring 1 hour（Time range 1 ~ 5 hour）；Filtering, and using hexane washing filter cake, obtain compound 2.
In the step 4, a collection of compound 2, toluene, water are put into reaction bulb, 0 ~ 10 DEG C of control material temperature, is added
Enter sodium hydroxide, insulated and stirred, stratification obtains organic layer；Add water into organic layer, branch vibration layer after insulated and stirred, must have
Machine layer, organic layer is concentrated under reduced pressure into dry, obtains compound 1.Wherein sodium hydroxide can use potassium hydroxide, carbon as alkaline reagent
Sour potassium, sodium carbonate replace.
The present invention is simple to operate, and raw material is cheap and easy to get, is adapted to industrialized production；Obtained object purity and chiral purity
It is high；Using composite solvent system, the chiral purity of object is greatly improved in the reaction, and chiral purity is promoted to by a step
95%, butyl lithium or tert-butyl lithium are instead of with safer caustic alcohol in process of production, easily operated, total recovery reaches
28.3%；3rd, product purity reaches 99.5%.
Embodiment
Step 1, by benzaldehyde, glycine ethyl ester hydrochloride（It is the 1.0 ~ 1.3 of benzaldehyde mole inventory, it is optimal to be
1.1）, after toluene stirs, then triethylamine is added dropwise, insulation reaction 2 hours（Reaction time range be 1 ~ 10 hour, optimal 2 ~ 5
Hour）；Water is put into, stratification removes water layer after stirring, and be concentrated under reduced pressure to obtain compound 4.Toluene can use benzene, two as solvent
Toluene, ethyl acetate, dichloromethane, chloroform replace.Triethylamine can be replaced as acid binding agent with organic amines such as tri-n-butylamine, pyridines.
Step 2, toluene, caustic alcohol are put into reaction bulb（Its mole of inventory be trans- 1,4- dibromo butenes 1.5 ~
2.5, optimal value 2）, feed intake end, be cooled to Wen Du≤0 DEG C；Control is counter to answer liquid temperature Du≤0 DEG C（Optimal Temperature is -15 ~ -10
℃）, trans- Isosorbide-5-Nitrae-dibromo butene is put into successively（Its mole of inventory is the 0.7 ~ 1.0 of benzaldehyde）, compound 4, feed intake end,
Insulation reaction 2 hours（Reaction time range is 1 ~ 10 hour, optimal 2 ~ 5 hours）；Nei Wen≤30 DEG C are controlled, are initially added into water,
Interior 0 ~ 30 DEG C of addition hydrochloric acid of temperature is controlled again；Completion of dropwise addition, insulated and stirred；Stratification separates water layer；Toluene is put into water layer,
Stirring is lower to be added dropwise liquid caustic soda；Completion of dropwise addition, stratification separates organic layer after insulated and stirred；Organic layer is that the toluene of compound 3/ is molten
Liquid.Toluene can be replaced as solvent with benzene, dimethylbenzene, ethyl acetate, dichloromethane, chloroform.
Step 3, put into reaction bulb the toluene solution of previous step compound 3/,（2S）-2-[（3,5- dichloro-benzoyls）
Epoxide] propionic acid（Its mole of inventory is the 0.8 ~ 1.0 of trans- Isosorbide-5-Nitrae-dibromo butene, optimal value 0.9）, feed intake end, insulation
Reaction 5 hours（Reaction time range is 3 ~ 10 hours, 5 ~ 6 hours peak optimization reaction time）；Insulation terminates, and puts into isopropanol, then
20 ~ 40 DEG C of dropwise addition hexanes of temperature in control（The rate of charge of isopropanol and hexane is 0.5 ~ 1:1, optimal rate of charge is 0.6:1）, it is added dropwise
Terminate, insulated and stirred 1 hour（Time range 1 ~ 5 hour）；Temperature of charge is reduced to 10 ~ 15 DEG C, cooling terminates, insulated and stirred 1
Hour（Time range 1 ~ 5 hour）；Filtering, and using hexane washing filter cake, obtain compound 2.
Step 4, a collection of compound 2, toluene, water are put into reaction bulb, 0 ~ 10 DEG C of control material temperature, adds hydrogen-oxygen
Change sodium, insulated and stirred, stratification obtains organic layer；Add water into organic layer, branch vibration layer after insulated and stirred, obtain organic layer,
Organic layer is concentrated under reduced pressure into dry, obtains compound 1.Wherein Sodium Hydroxide Alkaline reagent, potassium hydroxide, potassium carbonate, carbonic acid can be used
Sodium replaces.
Embodiment 1
Step 1: compound 4Synthesis：
1. put into 66g in 1000ml reaction bulbs（0.62mol）Benzaldehyde, 95.2g（0.68mol）Glycine ethyl ester hydrochloric acid
Salt, 200ml toluene, after stirring, 68.8g triethylamines are added dropwise.Completion of dropwise addition, insulation reaction 2 hours.
2. put into 200ml water, stratification branch vibration layer after stirring.
3. be concentrated under reduced pressure to obtain compound 4,.
Step 2: compound 3（Its structural formula is as follows）Synthesis：
1. 400ml toluene, 72g are put into 1000ml reaction bulbs（1.06mol）Caustic alcohol, feed intake end, is cooled to temperature
Du≤0 DEG C.
2. control is counter to answer liquid temperature Du≤0 DEG C, 112.7g is put into successively（0.53mol）Trans- Isosorbide-5-Nitrae-dibromo butene, compound 4,
Feed intake end, insulation reaction 2 hours.
3. controlling Nei Wen≤30 DEG C, start that 200ml water is added dropwise, then control interior 0 ~ 30 DEG C of dropwise addition 57g hydrochloric acid of temperature.Knot is added dropwise
Beam, insulated and stirred.Stratification separates water layer.
4. putting into 300ml toluene into water layer, lower dropwise addition 70g liquid caustic soda is stirred.Completion of dropwise addition, stratification after insulated and stirred
Separate organic layer.Organic layer is the toluene solution of compound 3/, yield 85%.
Step 3: compound 2（Its structural formula is as follows）Synthesis：
1. in 500ml reaction bulbs, batch toluene solution of compound 3/, 126.3g in input（0.48mol）（2S）-2-[（3,
5- dichloro-benzoyls）Epoxide] propionic acid, feed intake end, insulation reaction 5 hours.
2. insulation terminates, 131g isopropanols are put into, then control interior 20 ~ 40 DEG C of dropwise addition 174g n-hexanes of temperature, completion of dropwise addition, are protected
Temperature stirring 1 hour.
3. reducing temperature of charge to 10 ~ 15 DEG C, cooling terminates, insulated and stirred 1 hour.Filtering, and use 200ml n-hexanes
Filter cake is washed, obtains 77.1g（0.18mol）Compound 2, yield 35%.
Step 4: compound 1（That is (1R, 2S) -1- amino -2- vinylcyclopropanecaracidlic acidlic ethyl esters）Synthesis
1. a collection of compound 2,200ml toluene, 100ml water are put into 500ml reaction bulbs.
2. 0 ~ 10 DEG C of control material temperature, adds 8g sodium hydroxides, insulated and stirred, stratification obtains organic layer.
3. adding 100ml water into organic layer, branch vibration layer after insulated and stirred, organic layer is obtained.
4. organic layer is concentrated under reduced pressure into dry.Obtain compound 1.Yield 95%, total recovery 28.3%.Detection gained (1R, 2S)-
The chiral purity 95.5% of 1- amino -2- vinylcyclopropanecaracidlic acidlic ethyl esters, purity 99.5%.
Embodiment 2
Step 1: compound 4Synthesis：
1. put into 53.1g in 1000ml reaction bulbs（0.5mol）Benzaldehyde, 76.8g（0.55mol）Glycine ethyl ester salt
Hydrochlorate, 160ml ethyl acetate, after stirring, 55.2g is added dropwise（0.55mol）Triethylamine.Completion of dropwise addition, insulation reaction 2 are small
When.
2. putting into 160ml water, stratification removes water layer after stirring.
3. be concentrated under reduced pressure to obtain compound 4,.
Step 2: compound 3（Its structural formula is as follows）Synthesis：
1. 330ml ethyl acetate, 47.6g are put into 1000ml reaction bulbs（0.7mol）Caustic alcohol, feed intake end, cooling
To Wen Du≤0 DEG C.
2. control is counter to answer liquid temperature Du≤0 DEG C, 74.9g is put into successively（0.35mol）Trans- Isosorbide-5-Nitrae-dibromo butene, compound 4,
Feed intake end, insulation reaction 2 hours.
3. controlling Nei Wen≤30 DEG C, start that 160ml water is added dropwise, then control interior 0 ~ 30 DEG C of dropwise addition 46g hydrochloric acid of temperature.Knot is added dropwise
Beam, insulated and stirred.Stratification separates water layer.
4. putting into 240ml toluene into water layer, lower addition 56.5g liquid caustic soda is stirred.Completion of dropwise addition, stands after insulated and stirred point
Layer separates organic layer.Organic layer is the ethyl acetate solution of compound 3/, yield 82%.
Step 3: compound 2（Its structural formula is as follows）Synthesis：
1. in 500ml reaction bulbs, a collection of ethyl acetate solution of compound 3/, 82.9g are put into（0.315mol）（2S）-2-
[（3,5- dichloro-benzoyls）Epoxide] propionic acid, feed intake end, insulation reaction 5 hours.
2. insulation terminates, 140g isopropanols are put into, then control interior 20 ~ 40 DEG C of dropwise addition 140g n-hexanes of temperature, completion of dropwise addition, are protected
Temperature stirring 1 hour.
3. reducing temperature of charge to 10 ~ 15 DEG C, cooling terminates, insulated and stirred 1 hour.Filtering, and use 160ml n-hexanes
Filter cake is washed, obtains compound 2, yield 30%.
Step 4: compound 1（That is (1R, 2S) -1- amino -2- vinylcyclopropanecaracidlic acidlic ethyl esters）Synthesis
1. a collection of compound 2,160ml toluene, 80ml water are put into 500ml reaction bulbs.
2. 0 ~ 10 DEG C of control material temperature, adds 6.4g sodium hydroxides, insulated and stirred, stratification obtains organic layer.
3. adding 80ml water into organic layer, branch vibration layer after insulated and stirred, organic layer is obtained.
4. organic layer is concentrated under reduced pressure into dry.Obtain compound 1.Yield 95%, total recovery 23.4%.Detection gained (1R, 2S)-
The chiral purity 95.9% of 1- amino -2- vinylcyclopropanecaracidlic acidlic ethyl esters, purity 99.8%.
Embodiment 3
Step 1: compound 4Synthesis：
1. put into 53.1g in 1000ml reaction bulbs（0.5mol）Benzaldehyde, 90.7g（0.65mol）Glycine ethyl ester salt
Hydrochlorate, 160ml toluene, after stirring, 65.8g is added dropwise（0.65mol）Triethylamine.Completion of dropwise addition, insulation reaction 2 hours.
2. putting into 160ml water, stratification removes water layer after stirring.
3. be concentrated under reduced pressure to obtain compound 4,.
Step 2: compound 3（Its structural formula is as follows）Synthesis：
1. 330ml toluene, 52.4g are put into 1000ml reaction bulbs（0.77mol）Caustic alcohol, feed intake end, is cooled to
Wen Du≤0 DEG C.
2. control is counter to answer liquid temperature Du≤0 DEG C, 74.9g is put into successively（0.35mol）Trans- Isosorbide-5-Nitrae-dibromo butene, compound 4,
Feed intake end, insulation reaction 2 hours.
3. controlling Nei Wen≤30 DEG C, start that 160ml water is added dropwise, then control interior 0 ~ 30 DEG C of dropwise addition 53g hydrochloric acid of temperature.Knot is added dropwise
Beam, insulated and stirred.Stratification separates water layer.
4. putting into 240ml toluene into water layer, lower addition 64g liquid caustic soda is stirred.Completion of dropwise addition, stratification after insulated and stirred
Separate organic layer.Organic layer is the toluene solution of compound 3/, yield 84%.
Step 3: compound 2（Its structural formula is as follows）Synthesis：
1. in 500ml reaction bulbs, a collection of toluene solution of compound 3/, 92.1g are put into（0.35mol）（2S）-2-[（3,
5- dichloro-benzoyls）Epoxide] propionic acid, feed intake end, insulation reaction 5 hours.
2. insulation terminates, 70g isopropanols are put into, then control interior 20 ~ 40 DEG C of dropwise addition 140g n-hexanes of temperature, completion of dropwise addition, are protected
Temperature stirring 1 hour.
3. reducing temperature of charge to 10 ~ 15 DEG C, cooling terminates, insulated and stirred 1 hour.Filtering, and use 160ml n-hexanes
Filter cake is washed, obtains compound 2, yield 35%.
Step 4: compound 1（That is (1R, 2S) -1- amino -2- vinylcyclopropanecaracidlic acidlic ethyl esters）Synthesis
1. a collection of compound 2,160ml toluene, 80ml water are put into 500ml reaction bulbs.
2. 0 ~ 10 DEG C of control material temperature, adds 6.5g sodium hydroxides, insulated and stirred, stratification obtains organic layer.
3. adding 80ml water into organic layer, branch vibration layer after insulated and stirred, organic layer is obtained.
4. organic layer is concentrated under reduced pressure into dry.Obtain compound 1.Yield 95%, total recovery 27.9%.Detection gained (1R, 2S)-
The chiral purity 94.5% of 1- amino -2- vinylcyclopropanecaracidlic acidlic ethyl esters, purity 99.1%.
Claims (6)
1. the synthetic method of one kind (1R, 2S) -1- amino -2- vinylcyclopropanecaracidlic acidlic ethyl esters, it is characterised in that synthetic route
It is as follows：
Concretely comprise the following steps：
Step 1: after benzaldehyde, glycine ethyl ester hydrochloride, toluene are stirred, triethylamine, insulation reaction are added；Throw
Enter water, stratification removes water layer after stirring, and be concentrated under reduced pressure to obtain compound 4：
Step 2: in reaction bulb put into toluene, caustic alcohol, feed intake end, be cooled to Wen Du≤0 DEG C；Control is counter to answer liquid temperature Du≤0
DEG C, trans- Isosorbide-5-Nitrae-dibromo butene, compound 4 are put into successively, and feed intake end, insulation reaction；Nei Wen≤30 DEG C are controlled, add water, then
0~30 DEG C of dropwise addition hydrochloric acid of temperature in control；Completion of dropwise addition, insulated and stirred；Stratification separates water layer；Toluene is put into water layer,
Stirring is lower to be added dropwise liquid caustic soda；Completion of dropwise addition, stratification separates organic layer after insulated and stirred；Organic layer is that the toluene of compound 3/ is molten
Liquid；
Step 3: a collection of toluene solution of compound 3/, (2S) -2- [(3,5- dichloro-benzoyls) epoxide] third are put into reaction bulb
Acid, feed intake end, insulation reaction；Insulation terminates, and puts into isopropanol, then controls interior 20~40 DEG C of dropwise addition hexanes of temperature, completion of dropwise addition,
Insulated and stirred；Temperature of charge Zhi≤15 DEG C are reduced, cooling terminates, insulated and stirred；Filtering, and using hexane washing filter cake, must change
Compound 2：
Step 4: putting into a collection of compound 2, toluene, water into reaction bulb, 0~10 DEG C of control material temperature, hydroxide is added
Sodium, insulated and stirred, stratification obtain organic layer；Add water into organic layer, branch vibration layer after insulated and stirred, obtain organic layer, will
Organic layer is concentrated under reduced pressure into dry, obtains compound 1：
As (1R, 2S) -1- amino -2- vinylcyclopropanecaracidlic acidlic ethyl esters.
2. the synthetic method of (1R, 2S) -1- amino -2- vinylcyclopropanecaracidlic acidlic ethyl esters according to claim 1, its feature
It is, the solvent is any one in toluene, benzene, dimethylbenzene, ethyl acetate, dichloromethane, chloroform.
3. the synthetic method of (1R, 2S) -1- amino -2- vinylcyclopropanecaracidlic acidlic ethyl esters according to claim 1, its feature
It is, the acid binding agent is triethylamine, tri-n-butylamine or pyridine.
4. the synthetic method of (1R, 2S) -1- amino -2- vinylcyclopropanecaracidlic acidlic ethyl esters according to claim 1, its feature
It is, in the step 1, glycine ethyl ester hydrochloride is the 1.0~1.3 of benzaldehyde mole inventory.
5. the synthetic method of (1R, 2S) -1- amino -2- vinylcyclopropanecaracidlic acidlic ethyl esters according to claim 1, its feature
It is, in step 2, mole inventory of caustic alcohol is the 1.5~2.5 of trans- Isosorbide-5-Nitrae-dibromo butene；Trans- 1,4- dibromo butenes
Mole inventory is the 0.7~1.0 of benzaldehyde.
6. the synthetic method of (1R, 2S) -1- amino -2- vinylcyclopropanecaracidlic acidlic ethyl esters according to claim 1, its feature
It is, in step 3, mole inventory of (2S) -2- [(3,5- dichloro-benzoyl) epoxide] propionic acid is trans- Isosorbide-5-Nitrae-dibromo butene
0.8~1.0, optimal value 0.9), the rate of charge of isopropanol and hexane is 0.5~1:1.
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101228180A (en) * | 2005-05-10 | 2008-07-23 | 布里斯托尔-迈尔斯斯奎布公司 | Tripeptides as hepatitis C virus inhibitors |
| CN102470158A (en) * | 2009-08-27 | 2012-05-23 | 默沙东公司 | Processes for preparing protease inhibitors of hepatitis c virus |
| CN102906064A (en) * | 2010-06-15 | 2013-01-30 | 株式会社钟化 | Method for producing (1r, 2s)-1-amino-2-vinyl cyclopropane carboxylic acid ester that has improved optical purity |
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| WO2008095058A1 (en) * | 2007-02-01 | 2008-08-07 | Taigen Biotechnology Co. Ltd. | Hcv protease inhibitors |
| EP2448912A4 (en) * | 2009-07-02 | 2014-05-28 | Reddys Lab Ltd Dr | Enzymes and methods for resolving amino vinyl cyclopropane carboxylic acid derivatives |
| JPWO2015146881A1 (en) * | 2014-03-28 | 2017-04-13 | 株式会社カネカ | Method for producing 1-arylimino-2-vinylcyclopropanecarboxylic acid derivative |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101228180A (en) * | 2005-05-10 | 2008-07-23 | 布里斯托尔-迈尔斯斯奎布公司 | Tripeptides as hepatitis C virus inhibitors |
| CN102470158A (en) * | 2009-08-27 | 2012-05-23 | 默沙东公司 | Processes for preparing protease inhibitors of hepatitis c virus |
| CN102906064A (en) * | 2010-06-15 | 2013-01-30 | 株式会社钟化 | Method for producing (1r, 2s)-1-amino-2-vinyl cyclopropane carboxylic acid ester that has improved optical purity |
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