CN104592048A - Method for preparing tertiary leucine methyl ester hydrochloride - Google Patents
Method for preparing tertiary leucine methyl ester hydrochloride Download PDFInfo
- Publication number
- CN104592048A CN104592048A CN201410849180.0A CN201410849180A CN104592048A CN 104592048 A CN104592048 A CN 104592048A CN 201410849180 A CN201410849180 A CN 201410849180A CN 104592048 A CN104592048 A CN 104592048A
- Authority
- CN
- China
- Prior art keywords
- compound
- preparation
- temperature
- vitriol oil
- methylcarbonate
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
- KWWFNGCKGYUCLC-RXMQYKEDSA-N CC(C)(C)[C@@H](C(O)=O)NC Chemical compound CC(C)(C)[C@@H](C(O)=O)NC KWWFNGCKGYUCLC-RXMQYKEDSA-N 0.000 description 1
Landscapes
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention discloses a method for preparing tertiary leucine methyl ester hydrochloride. The method is characterized by comprising the following steps: preparing a compound 2 under the action of dimethyl carbonate and concentrated sulfuric acid, thereby obtaining a compound 1. The method is simple in process, high in yield, low in production cost and suitable for large-scale production. The structural formulae are as shown in the specification.
Description
Technical field:
The present invention relates to a kind of preparation method of Terleu methyl ester hydrochloride, belong to organic synthesis field.
Background technology:
Terleu methyl ester hydrochloride has a wide range of applications in pharmaceutical chemistry and organic synthesis field, is conventional nutrition-fortifying agent, animal feeding additive, and is the important intermediate of multi-medicament.Such as it can as a kind of important intermediate of VX-960 (Telaprevir).VX-960, on May 23rd, 2011, is used for the treatment of Adult chronic's hepatitis C by U.S. FDA approval.Can be used for not accepting interferons pharmacological agent or the patient invalid to pharmacological agent before.The molecular structure of Terleu methyl esters is as shown in the formula 1a:
For Terleu methyl esters synthesis, the method reported at present has following several:
Patent WO2012040242 discloses the synthetic method of tertiary fourth leucine methyl ester hydrochloride, and the method utilizes raw material to be obtained by reacting product in the methanol solution of hydrochloric acid, but the shortcoming of this method is raw material can not be converted into product completely, low conversion rate, and purity is low; Hydrochloric acid waste gas is unfriendly to environment, has corrodibility to equipment, corresponding off gas treatment and the technical requirements of production unit high.
Patent WO2013190509, Enzyme an Microbial Tecrobial Technology, 21 (4), 252-257; 1997 bibliographical informations such as the grade synthetic method of another tertiary fourth leucine methyl ester, the method take thionyl chloride as reagent, preparing product under methanol solvate, equally, the method Raw can not be converted into product completely, low conversion rate, purity is low, generates hydrochloric acid waste gas, unfriendly to environment, have corrosion to equipment, the amplification being not suitable for carrying out industry is produced.
The shortcoming that above-mentioned route exists: low conversion rate, yield is low, and aftertreatment bothers, environmental pollution and have corrodibility to equipment, is unfavorable for suitability for industrialized production.
Therefore, we need to develop new easy, and environmental friendliness, yield is high, the synthetic method that production cost is low, is beneficial to suitability for industrialized production.
Summary of the invention:
The technical problem to be solved in the present invention is to provide a kind of synthetic method of Terleu methyl esters of green high-efficient.Methylcarbonate (dimethyl carbonate, DMC), a kind of nontoxic, environmental-protecting performance is excellent, broad-spectrum industrial chemicals, (chemical intermediate is used as methylating reagent under weakly alkaline of being everlasting catalytic condition, 2008, the first phase, 20-23), we are when attempting with methylcarbonate methylated compounds 2, pleasantly surprised discovery, under vitriol oil effect, compound 2 can to methylate obtained Terleu methyl esters through methylcarbonate, the method is green, easy, efficiently, productive rate reaches more than 90%, compared with prior art, the method not only operation is simpler, and cost is low, be conducive to suitability for industrialized production.
Below in conjunction with specific embodiment, set forth the present invention further.Should be understood that these embodiments are only not used in for illustration of the present invention to limit the scope of the invention.The experimental technique of unreceipted actual conditions in the following example, conveniently condition is carried out usually.
Raw material used in embodiment or reagent except special instruction, all commercially.
Room temperature described in embodiment all refers to 20 ~ 35 DEG C.Unless otherwise indicated, the not purified direct use of described reagent.The equal available from commercial supplier of all solvents, such as aldrich (Aldrich), and not treatedly just can to use.Reaction is analyzed by TLC and/or is analyzed by LC-MS, is judged the termination of reacting by the consumption of parent material.The thin-layer chromatography (TLC) analyzed carries out on the sheet glass (EMD chemical company (EMD Chemicals)) of pre-coated silica gel 60F2540.25 millimeter plate, with the iodine developing on UV light (254nm) and/or silica gel, and/or heat together with alcohol phospho-molybdic acid, ninidrine solution, potassium permanganate solution or ceric sulfate solution with TLC product dyed thereby.
1H-NMR spectrum is on ten thousand Ruian-Mo Qiuli-VX400 (Varian Mercury-VX400) instrument, records under 400MHz operation.
The abbreviation used in the present invention has this area conventional sense, as: DCM represents methylene dichloride, and HMDS represents hmds.
Preparation method of the present invention can represent by following flow process:
R1, R2 can distinguish or be simultaneously alkyl, the alkoxyl group of C1 ~ C4, the haloalkyl of C1 ~ C4, the alkyl amide of C1 ~ C4 of H, C1 ~ C4.Described halogen such as F, Cl, Br or I.
Compound 2, under the effect of methylcarbonate and the vitriol oil, prepares compound 1.
Compound 2 is 1 ~ 20 with the molar feed ratio of methylcarbonate, is preferably 1 ~ 4.
Compound 2 is 1 ~ 20 with the molar feed ratio of the vitriol oil, is preferably 1 ~ 1.5.
Temperature of reaction be room temperature to solvent reflux temperature, be preferably reflux temperature.
The compound of the structural formula that the important intermediate of a kind of VX-960 (Telaprevir) described in the present invention is espespecially following:
The advantage of the inventive method is mainly:
1) acid waste gas is not had to discharge, environmentally friendly.
2) simple to operate, aftertreatment is simple, and transformation efficiency is high, and yield is high, and purity is high.
3) production cost is low, can suitability for industrialized production, has larger implementary value and economic results in society.
Present method is a brand-new synthetic route capable of being industrialized.Meanwhile, this route has good methodology meaning to the new Adult chronic's hepatitis C medicine of exploitation.
Embodiment
Below in conjunction with specific embodiment, set forth the present invention further.Should be understood that these embodiments are only not used in for illustration of the present invention to limit the scope of the invention.The experimental technique of unreceipted actual conditions in the following example, conveniently condition is carried out usually.
Embodiment 1: the preparation of compound 1a
The tertiary fourth leucine (950g, 7.24mol, 1.0eq) of L-is added in the reaction flask of 10L, methylcarbonate (2600g, 28.89mol, 4.0eq), the vitriol oil (1080g, 95% concentration, 10.84mol, 1.5eq), after mixture stirring and dissolving, after temperature rising reflux 12h, TLC detection reaction is complete, and reaction system is cooled to room temperature.Add DCM (4500ml), reaction system is cooled to 0-5 DEG C.At the temperature of 0-5 DEG C, slowly drip the mixture of strong aqua (1500g) and water (1500ml), until system pH=10, stratification after mixture stirring 30min.Aqueous phase DCM (4500ml*2) extraction, merge organic phase, saturated sodium-chloride (3000ml*2) washs, anhydrous sodium sulfate drying.Filter, concentrate to obtain yellow oily liquid 1 (1070g, productive rate 94%, purity 95%).
1H NMR(300MHz,DMSO-d6):δ8.57(brs,2H),3.74(s,3H),3.74-3.68(m,1H),1.00(s,9H).ESI/MS:m/z=146(M+H)+.
Embodiment 2: the preparation of compound 1b
Compound 2b (1042g, 7.24mol, 1.0eq) is added in the reaction flask of 10L, methylcarbonate (2600g, 28.89mol, 4.0eq), the vitriol oil (1080g, 95% concentration, 10.84mol, 1.5eq), after mixture stirring and dissolving, after temperature rising reflux 12h, TLC detection reaction is complete, and reaction system is cooled to room temperature.Add DCM (4500ml), reaction system is cooled to 0-5 DEG C.At the temperature of 0-5 DEG C, slowly drip the mixture of strong aqua (1500g) and water (1500ml), until system pH=10, stratification after mixture stirring 30min.Aqueous phase DCM (4500ml*2) extraction, merge organic phase, saturated sodium-chloride (3000ml*2) washs, anhydrous sodium sulfate drying.Filter, concentrate to obtain yellow oily liquid 2a (1093g, productive rate 95%, purity 95%).
1H NMR(300MHz,DMSO-d6):δ8.55(brs,1H),3.68(s,3H),3.41-3.44(m,1H),3.26(s,3H),0.94(s,9H).ESI/MS:m/z=160(M+H)+.
Embodiment 3: the preparation of compound 1b
Compound 2b (1042g, 7.24mol, 1.0eq) is added in the reaction flask of 10L, methylcarbonate (2600g, 28.89mol, 4.0eq), the vitriol oil (1080g, 80% concentration, 10.84mol, 1.5eq), after mixture stirring and dissolving, after temperature rising reflux 24h, TLC detection reaction is complete, and reaction system is cooled to room temperature.Add DCM (4500ml), reaction system is cooled to 0-5 DEG C.At the temperature of 0-5 DEG C, slowly drip the mixture of strong aqua (1500g) and water (1500ml), until system pH=10, stratification after mixture stirring 30min.Aqueous phase DCM (4500ml*2) extraction, merge organic phase, saturated sodium-chloride (3000ml*2) washs, anhydrous sodium sulfate drying.Filter, concentrate to obtain yellow oily liquid 2a (1035g, productive rate 90%, purity 95%).
1H NMR(300MHz,DMSO-d6):δ8.55(brs,1H),3.68(s,3H),3.41-3.44(m,1H),3.26(s,3H),0.94(s,9H).ESI/MS:m/z=160(M+H)+.
Embodiment 4: the preparation of compound 1b
Compound 2b (1042g, 7.24mol, 1.0eq) is added in the reaction flask of 10L, methylcarbonate (2600g, 28.89mol, 4.0eq), the vitriol oil (1080g, 67% concentration, 10.84mol, 1.5eq), after mixture stirring and dissolving, after temperature rising reflux 48h, TLC detection reaction is complete, and reaction system is cooled to room temperature.Add DCM (4500ml), reaction system is cooled to 0-5 DEG C.At the temperature of 0-5 DEG C, slowly drip the mixture of strong aqua (1500g) and water (1500ml), until system pH=10, stratification after mixture stirring 30min.Aqueous phase DCM (4500ml*2) extraction, merge organic phase, saturated sodium-chloride (3000ml*2) washs, anhydrous sodium sulfate drying.Filter, concentrate to obtain yellow oily liquid 2a (575.2g, productive rate 50%, purity 95%).
1H NMR(300MHz,DMSO-d6):δ8.55(brs,1H),3.68(s,3H),3.41-3.44(m,1H),3.26(s,3H),0.94(s,9H).ESI/MS:m/z=160(M+H)+.
Embodiment 5: the preparation of compound 1c
Compound 2c (1817g, 7.24mol, 1.0eq) is added in the reaction flask of 10L, methylcarbonate (2600g, 28.89mol, 4.0eq), the vitriol oil (1080g, 10.84mol, 98% concentration, 1.5eq), after mixture stirring and dissolving, after temperature rising reflux 12h, TLC detection reaction is complete, and reaction system is cooled to room temperature.Add DCM (4500ml), reaction system is cooled to 0-5 DEG C.At the temperature of 0-5 DEG C, slowly drip the mixture of strong aqua (1500g) and water (1500ml), until system pH=10, stratification after mixture stirring 30min.Aqueous phase DCM (4500ml*2) extraction, merge organic phase, saturated sodium-chloride (3000ml*2) washs, anhydrous sodium sulfate drying.Filter, concentrate to obtain yellow oily liquid 1c (1841g, productive rate 95%, purity 95%).
1H NMR(300MHz,DMSO-d6):δ8.05(brs,1H),7.29(m,2H),7.42(m,2H),7.26(m,1H),4.40(s,1H),3.68(s,3H),0.93(s,9H).ESI/MS:m/z=266(M+H)+.
Embodiment 6: the preparation of compound 1c
Compound 2c (1817g, 7.24mol, 1.0eq) is added in the reaction flask of 10L, methylcarbonate (2600g, 28.89mol, 4.0eq), the vitriol oil (1080g, 10.84mol, 80% concentration, 1.5eq), after mixture stirring and dissolving, after temperature rising reflux 12h, TLC detection reaction is complete, and reaction system is cooled to room temperature.Add DCM (4500ml), reaction system is cooled to 0-5 DEG C.At the temperature of 0-5 DEG C, slowly drip the mixture of strong aqua (1500g) and water (1500ml), until system pH=10, stratification after mixture stirring 30min.Aqueous phase DCM (4500ml*2) extraction, merge organic phase, saturated sodium-chloride (3000ml*2) washs, anhydrous sodium sulfate drying.Filter, concentrate to obtain yellow oily liquid 1c (1647g, productive rate 85%, purity 95%).
1H NMR(300MHz,DMSO-d6):δ8.05(brs,1H),7.29(m,2H),7.42(m,2H),7.26(m,1H),4.40(s,1H),3.68(s,3H),0.93(s,9H).ESI/MS:m/z=266(M+H)+.
Embodiment 7: the preparation of compound 1c
Compound 2c (1817g, 7.24mol, 1.0eq) is added in the reaction flask of 10L, methylcarbonate (2600g, 28.89mol, 4.0eq), the vitriol oil (1080g, 10.84mol, 67% concentration, 1.5eq), after mixture stirring and dissolving, after temperature rising reflux 12h, TLC detection reaction is complete, and reaction system is cooled to room temperature.Add DCM (4500ml), reaction system is cooled to 0-5 DEG C.At the temperature of 0-5 DEG C, slowly drip the mixture of strong aqua (1500g) and water (1500ml), until system pH=10, stratification after mixture stirring 30min.Aqueous phase DCM (4500ml*2) extraction, merge organic phase, saturated sodium-chloride (3000ml*2) washs, anhydrous sodium sulfate drying.Filter, concentrate to obtain yellow oily liquid 1c (678g, productive rate 35%, purity 95%).
1H NMR(300MHz,DMSO-d6):δ8.05(brs,1H),7.29(m,2H),7.42(m,2H),7.26(m,1H),4.40(s,1H),3.68(s,3H),0.93(s,9H).ESI/MS:m/z=266(M+H)+.
Embodiment 8: the preparation of compound 1d
Compound 2d (1498g, 7.24mol, 1.0eq) is added in the reaction flask of 10L, methylcarbonate (2600g, 28.89mol, 4.0eq), the vitriol oil (1080g, 98% concentration, 10.84mol, 1.5eq), after mixture stirring and dissolving, after temperature rising reflux 12h, TLC detection reaction is complete, and reaction system is cooled to room temperature.Add DCM (4500ml), reaction system is cooled to 0-5 DEG C.At the temperature of 0-5 DEG C, slowly drip the mixture of strong aqua (1500g) and water (1500ml), until system pH=10, stratification after mixture stirring 30min.Aqueous phase DCM (4500ml*2) extraction, merge organic phase, saturated sodium-chloride (3000ml*2) washs, anhydrous sodium sulfate drying.Filter, concentrate to obtain yellow oily liquid 1d (1488g, productive rate 93%, purity 95%).
1H NMR(300MHz,DMSO-d6):δ8.03(brs,1H),4.38(s,1H),3.66(s,3H),0.95(s,9H).ESI/MS:m/z=222(M+H)+.
Embodiment 9: the preparation of compound 1d
Compound 2d (1498g, 7.24mol, 1.0eq) is added in the reaction flask of 10L, methylcarbonate (2600g, 28.89mol, 4.0eq), the vitriol oil (1080g, 80% concentration, 10.84mol, 1.5eq), after mixture stirring and dissolving, after temperature rising reflux 12h, TLC detection reaction is complete, and reaction system is cooled to room temperature.Add DCM (4500ml), reaction system is cooled to 0-5 DEG C.At the temperature of 0-5 DEG C, slowly drip the mixture of strong aqua (1500g) and water (1500ml), until system pH=10, stratification after mixture stirring 30min.Aqueous phase DCM (4500ml*2) extraction, merge organic phase, saturated sodium-chloride (3000ml*2) washs, anhydrous sodium sulfate drying.Filter, concentrate to obtain yellow oily liquid 1d (1200g, productive rate 75%, purity 95%).
1H NMR(300MHz,DMSO-d6):δ8.03(brs,1H),4.38(s,1H),3.66(s,3H),0.95(s,9H).ESI/MS:m/z=222(M+H)+.
Embodiment 10: the preparation of compound 1d
Compound 2d (1498g, 7.24mol, 1.0eq) is added in the reaction flask of 10L, methylcarbonate (2600g, 28.89mol, 4.0eq), the vitriol oil (1080g, 67% concentration, 10.84mol, 1.5eq), after mixture stirring and dissolving, after temperature rising reflux 12h, TLC detection reaction is complete, and reaction system is cooled to room temperature.Add DCM (4500ml), reaction system is cooled to 0-5 DEG C.At the temperature of 0-5 DEG C, slowly drip the mixture of strong aqua (1500g) and water (1500ml), until system pH=10, stratification after mixture stirring 30min.Aqueous phase DCM (4500ml*2) extraction, merge organic phase, saturated sodium-chloride (3000ml*2) washs, anhydrous sodium sulfate drying.Filter, concentrate to obtain yellow oily liquid 1d (480g, productive rate 30%, purity 95%).
1H NMR(300MHz,DMSO-d6):δ8.03(brs,1H),4.38(s,1H),3.66(s,3H),0.95(s,9H).ESI/MS:m/z=222(M+H)+.
The invention provides a kind of synthetic method of Terleu methyl esters, technique is simple, and yield is high, and production cost is low, is applicable to scale production.
The all documents mentioned in the present invention are quoted as a reference all in this application, are just quoted separately as a reference as each section of document.In addition should be understood that those skilled in the art can make various changes or modifications the present invention after having read above-mentioned teachings of the present invention, these equivalent form of values fall within the application's appended claims limited range equally.
Claims (10)
1. such as formula a preparation method for the Telaprevir intermediate compound shown in 1, it is characterized in that comprising the following step: by compound 2 under the effect of methylcarbonate and the vitriol oil, prepare compound 1;
R1, R2 are selected from alkyl, the alkoxyl group of C1 ~ C4, the haloalkyl of C1 ~ C4, the alkyl amide of C1 ~ C4 of H, C1 ~ C4, and R1, R2 can be identical or different.
2. the preparation method as described in claim 1, is characterized in that: described vitriol oil concentration is 67%-98%.
3. the preparation method as described in claim 2, is characterized in that: described vitriol oil concentration is 95%-98%.
4. the preparation method as described in claim 1, is characterized in that: compound 2 is 1 ~ 20:1 with the molar feed ratio of methylcarbonate.
5. preparation method as claimed in claim 1, is characterized in that: compound 2 is 1 ~ 4:1 with the molar feed ratio of methylcarbonate.
6. the preparation method as described in claim 1, is characterized in that: compound 2 is 1 ~ 20:1 with the molar feed ratio of the vitriol oil.
7. the preparation method as described in claim 1, is characterized in that: compound 2 is 1 ~ 1.5:1 with the molar feed ratio of the vitriol oil.
8. the preparation method as described in claim 1, is characterized in that: temperature of reaction is that room temperature is to solvent reflux temperature.
9. the preparation method as described in claim 8, is characterized in that: temperature of reaction is solvent reflux temperature.
10. the preparation method as described in claim 1-9, is characterized in that: R1, R2 are H.
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN201410849180.0A CN104592048A (en) | 2014-12-31 | 2014-12-31 | Method for preparing tertiary leucine methyl ester hydrochloride |
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN201410849180.0A CN104592048A (en) | 2014-12-31 | 2014-12-31 | Method for preparing tertiary leucine methyl ester hydrochloride |
Publications (1)
Publication Number | Publication Date |
---|---|
CN104592048A true CN104592048A (en) | 2015-05-06 |
Family
ID=53118155
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CN201410849180.0A Pending CN104592048A (en) | 2014-12-31 | 2014-12-31 | Method for preparing tertiary leucine methyl ester hydrochloride |
Country Status (1)
Country | Link |
---|---|
CN (1) | CN104592048A (en) |
Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN108689891A (en) * | 2018-06-29 | 2018-10-23 | 广州市润研基因科技有限公司 | A kind of synthetic method of quaternary ammonium salt |
Citations (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
DE4311424A1 (en) * | 1993-04-07 | 1994-10-13 | Bayer Ag | Process for the O-alkylation of carboxylic acids |
CN101277927A (en) * | 2005-09-29 | 2008-10-01 | 帝斯曼知识产权资产管理有限公司 | Process for esterification of an organic acid |
WO2012040242A1 (en) * | 2010-09-22 | 2012-03-29 | Intermune, Inc. | Substituted proline inhibitors of hepatitis c virus replication |
WO2014083582A2 (en) * | 2012-11-29 | 2014-06-05 | Msn Laboratories Limited | Novel process for the preparation of (1s,3ar,6as)-2-[(2s)-2-({(2s)-2-cyclohexyl-2-[(pyrazin-2-ylcarbonyl)amino]acetyl}amino)-3,3-dimethylbutanoyl]-n-[(3s)-1-(cyclopropylamino)-1,2-dioxohexan-3-yl]-3,3a,4,5,6,6a-hexahydro-1h-cyclopenta[c] pyrrole-1-carboxamide and its intermediates |
-
2014
- 2014-12-31 CN CN201410849180.0A patent/CN104592048A/en active Pending
Patent Citations (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
DE4311424A1 (en) * | 1993-04-07 | 1994-10-13 | Bayer Ag | Process for the O-alkylation of carboxylic acids |
CN101277927A (en) * | 2005-09-29 | 2008-10-01 | 帝斯曼知识产权资产管理有限公司 | Process for esterification of an organic acid |
WO2012040242A1 (en) * | 2010-09-22 | 2012-03-29 | Intermune, Inc. | Substituted proline inhibitors of hepatitis c virus replication |
WO2014083582A2 (en) * | 2012-11-29 | 2014-06-05 | Msn Laboratories Limited | Novel process for the preparation of (1s,3ar,6as)-2-[(2s)-2-({(2s)-2-cyclohexyl-2-[(pyrazin-2-ylcarbonyl)amino]acetyl}amino)-3,3-dimethylbutanoyl]-n-[(3s)-1-(cyclopropylamino)-1,2-dioxohexan-3-yl]-3,3a,4,5,6,6a-hexahydro-1h-cyclopenta[c] pyrrole-1-carboxamide and its intermediates |
Non-Patent Citations (1)
Title |
---|
VAMSI V. REKHA等: "A Simple, Efficient, Green, Cost Effective and Chemoselective Process for the Esterification of Carboxylic Acids", 《ORGANIC PROCESS RESEARCH & DEVELOPMENT》 * |
Cited By (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN108689891A (en) * | 2018-06-29 | 2018-10-23 | 广州市润研基因科技有限公司 | A kind of synthetic method of quaternary ammonium salt |
CN108689891B (en) * | 2018-06-29 | 2021-07-30 | 广州市润研基因科技有限公司 | Synthesis method of quaternary ammonium salt |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
CN103992225A (en) | Salicylaldehyde derivatives and preparation method thereof | |
CN107586285B (en) | Preparation method of 2, 3-dihydrobenzopyran-4-one derivative | |
CN104803897A (en) | Synthetic process of Apremilast intermediate | |
CN104592048A (en) | Method for preparing tertiary leucine methyl ester hydrochloride | |
CN107903209B (en) | Synthetic method of 2-amino-5-fluoropyridine-3-methyl formate | |
CN103694182B (en) | A kind of preparation method of quinoxaline compound | |
CN102516133A (en) | Preparation method of methanesulfonic acid derivative | |
CN103275034B (en) | Preparation method of micromolecule cathepsin D inhibitor | |
CN101585783B (en) | Preparing method of ortho-nitrobenzonitrile series compound | |
CN104447391A (en) | Methylenebisamide derivative and preparation method thereof | |
CN104311469B (en) | A kind of synthetic method of substituted indole-3-acetic acid | |
CN104030941B (en) | A kind of 3-(4-hydroxy phenyl) synthetic method of propionic acid amide | |
CN101774995B (en) | Method for preparing flavanone compound | |
CN111518148A (en) | Synthetic method of gastrodin intermediate | |
CN103804447B (en) | Aza guanosine and synthetic method thereof and the purposes in DNA sequencing | |
Jin et al. | A contribution to the study of the modified Marschalk reaction: Hydroxymethylation of 6, 8-O-dimethyl emodin | |
CN112724089B (en) | Synthesis process of 2-amino-3-bromo-6-chloropyrazine | |
CN110343047B (en) | Preparation method of aminopyrene compound | |
CN110437112B (en) | Preparation method of formamidosulfuron or derivative intermediate thereof | |
CN103910615A (en) | Method for synthesizing curcumin | |
CN103864715B (en) | A kind of method catalyzing and synthesizing 2-acyl group benzothiazole or derivatives thereof | |
CN108822060B (en) | 3-aryl substituted oxetane and preparation method thereof | |
CN108191903B (en) | Method for synthesizing coronadimide and derivative thereof based on perylene diimide | |
CN108484495B (en) | Synthetic method of 3-bromo-7-hydroxyquinoline | |
CN104311415A (en) | Method for etherification of carboxyl acid and dimethyl malonate |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
C06 | Publication | ||
PB01 | Publication | ||
C10 | Entry into substantive examination | ||
SE01 | Entry into force of request for substantive examination | ||
C02 | Deemed withdrawal of patent application after publication (patent law 2001) | ||
WD01 | Invention patent application deemed withdrawn after publication |
Application publication date: 20150506 |