US20040214989A1 - Compatible-multiphase organic solvent system - Google Patents

Compatible-multiphase organic solvent system Download PDF

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US20040214989A1
US20040214989A1 US10/486,383 US48638304A US2004214989A1 US 20040214989 A1 US20040214989 A1 US 20040214989A1 US 48638304 A US48638304 A US 48638304A US 2004214989 A1 US2004214989 A1 US 2004214989A1
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group
solvent
carbon number
mixed
solvent system
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Kazuhiro Chiba
Yusuke Kono
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Japan Science and Technology Agency
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Japan Science and Technology Agency
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Priority claimed from JP2001254109A external-priority patent/JP3538672B2/ja
Priority claimed from JP2001385493A external-priority patent/JP4283469B2/ja
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Assigned to JAPAN SCIENCE AND TECHNOLOGY AGENCY reassignment JAPAN SCIENCE AND TECHNOLOGY AGENCY ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: CHIBA, KAZUHIRO, KONO, YUSUKE
Publication of US20040214989A1 publication Critical patent/US20040214989A1/en
Priority to US11/556,492 priority Critical patent/US8344103B2/en
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C69/00—Esters of carboxylic acids; Esters of carbonic or haloformic acids
    • C07C69/74—Esters of carboxylic acids having an esterified carboxyl group bound to a carbon atom of a ring other than a six-membered aromatic ring
    • C07C69/757—Esters of carboxylic acids having an esterified carboxyl group bound to a carbon atom of a ring other than a six-membered aromatic ring having any of the groups OH, O—metal, —CHO, keto, ether, acyloxy, groups, groups, or in the acid moiety
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B61/00—Other general methods
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C43/00—Ethers; Compounds having groups, groups or groups
    • C07C43/02—Ethers
    • C07C43/20—Ethers having an ether-oxygen atom bound to a carbon atom of a six-membered aromatic ring
    • C07C43/23—Ethers having an ether-oxygen atom bound to a carbon atom of a six-membered aromatic ring containing hydroxy or O-metal groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2602/00—Systems containing two condensed rings
    • C07C2602/02—Systems containing two condensed rings the rings having only two atoms in common
    • C07C2602/14—All rings being cycloaliphatic
    • C07C2602/26—All rings being cycloaliphatic the ring system containing ten carbon atoms
    • C07C2602/28—Hydrogenated naphthalenes

Definitions

  • the present invention basically relates to a solvent system characterising that the controlling of the reaction is easy and the recovery of the reaction product is easy, further relates to a method for preparation of chemical compound utilizing said reaction solvent system.
  • the present invention is the solvent system comprising two or more single organic solvents or two or more mixed organic solvents
  • this solvent system is characterized as follows. That is, said solvent system can change the state reversibly by changing temperature condition from one state which is the homogeneously compatibilized mixed solvent system in which two or more single organic solvents or two or more mixed organic solvents constituting the solvent system are homogeneously compatibilized and mixed to another one state which is the separated solvent system in which the solvent system is separated into two or more phases consisting mainly of the two or more single organic solvents or mixed organic solvents constituting the solvent system, and can dissolve the chemical component which is soluble in only one single organic solvent or mixed organic solvent homogeneously.
  • the present invention is a method for preparation of compound which makes easy the controlling of reaction and the separation and the recovery of the product comprising, progressing the compound reaction in the homogeneously compatibilized mixed solvent system in which two or more single organic solvents or mixed organic solvents constituting the solvent system are homogeneously compatibilized, then stopping substantially said reaction by separating it into two or more phases consisting mainly of the two or more single organic solvents or mixed organic solvents, recovering the generated product in one phase composing single organic solvents or mixed organic solvents as the main component or recovering as the deposit.
  • the present invention relates to the solvent system which can easily change the state reversibly from the state of the homogeneously compatibilized mixed solvent system dissolving the electrolyte to the state of separated solvent which makes possible to separate the electrolyte by dissolving the electrolyte in one separated phase consisting mainly of the two or more single organic solvents or mixed organic solvents, the reactive solvent system and the method for preparation of compound utilizing said reactive solvent system, still further the present invention relates to the method for synthesis of polymer compound such as peptide making possible to utilize above mentioned reactive solvent system, by finding out a compound residue having the function to dissolve the compound having a bonding part of amino acid unit from which the formation of peptide in conventional solid-phase peptide synthesis is initiated, a function to load peptide chain extended by bonding the amino acid units in order and a bonding part of amino acid unit before the starting of synthesis of the peptide and the compound to which synthesizing peptide
  • each components consisting of the solvent are compatible by heating.
  • the usable solvent is limited to the low polar solvent which has relatively high affinity with fluorinated solvent of low polar.
  • this method has problems, that is, expensive fluorinated solvent is necessary, the substance to be dissolved is necessary to be fluorinated because it is dissolved in fluorinated solvent, and in the case of reaction dissolving an organic or an inorganic salt, there is a difficulty to handle a polor substance such as biomolecule, because high permittivity solvent does not have this characteristic.
  • the method 3 can be said as the reaction system which combines high permittivity or high polar solvent with low permittivity or low polar solvent. Although these solvents forms two-phases structure according to the difference of the physical property, the solvent which forms reversibly homogeneous compatible mixed solvent by simplified change of outer condition is not obtained yet. Further, the reaction is limited at the interface of separated two layers, and the reactivity can not be said to be high.
  • the subject of this invention is to construct the reaction system which solve the problem of controlling the reaction and the problem of separation and refining of the reacted product.
  • the inventors of the present invention have found that the specific non polar organic solvent and polar organic solvent have different solubility to the chemical component and can transfer reversibly and easily to two solvent states, that is, the homogeneous compatibilized mixed solvent state and the separated solvent state in which the phase is separated by only changing the temperature condition, further, can separate single or plural low molecule solute components whose physical properties are different spatially and almost completely, still further, the substantial reaction condition is only satisfied in homogeneous compatibilized mixed solvent state, thus dissolved above mentioned problems.
  • non polar organic solvent and polar organic solvent are respectively single organic solvent composed of one organic solvent or mixed organic solvent which mixes two or more solvents belonging to each organic solvent by adequate mixing ratio.
  • the polar solvent which dissolves ordinary electrolyte does not form the homogeneous compatibilized mixed solvent state with non polar organic solvent by simple condition, and especially it is difficult to make it reversible.
  • one solvent can dissolve electrolyte, and the homogeneous compatibilized mixed solvent state dissolving electrolyte—the separable state by dissolving electrolyte only in single organic solvent mainly composed of one organic solvent which is phase separated or mixed organic solvent can be accomplished reversibly only by controlling the temperature.
  • this solvent system is extremely useful for the designing and construction of various reaction system in the future, because ionic substance is frequently used in the reaction system and the separation of ionic substance after reaction is difficult. Further, this solvent system can construct the functional system which control not only reaction process but also refining process, compativility—phase separation, for example, the system which flows an electric current at the critical temperature, and is hopeful as the new functional material.
  • the inventors of the present invention are aimed to use said solvent system practically and have synthesized the compound which is utilized so as the practical use of the solvent system to be possible, for example, have designed the compound having a bonding part of amino acid unit from which the formation of peptide in the method for peptide synthesis is initiated with a residue which make the utilization of the solvent system possible such as the compound represented by following general formula A, and have constructed the reaction system utilizing the solvent system positively.
  • L 1 is hydroxyl group which bonds with amino acid, a single bond which bonds with thiol group, amino group or carbonyl group, an atomic group which bonds with said hydroxyl group, thiol group, amino group or carbonyl group or an atomic group which forms fused aromatic ring of two rings bonding with dotted line, wherein the dotted line is an atomic group which forms said fused aromatic ring by bonding with H or L 1 ,
  • X is O, S, ester group, sulfide group or imino group
  • R is hydro carbon group of carbon number 10 or more which can contain O, S or N having a possibility to improve the solubility to cycloalkane solvents as a bonding atom
  • n is a integer from 1 to 5, further in the case when said hydro carbon group of carbon number 10 or more is to improve the solubility to cycloalkane solvents, R possesses a side chain with functional group which bonds with the amino group and/or substituent.
  • This peptide synthesis reactions can be applied to the synthesis of oligomers or polymers such as protein, DNA, RNA or polysaccharides.
  • the 1 st one of the present invention is a solvent system comprising, two or more single organic solvent or mixed organic solvent, and said solvent system can change the state reversibly by changing temperature condition from one state which is a homogeneously compatibilized mixed solvent system in which two or more single organic solvents or mixed organic solvents constituting the solvent system are homogeneously compatibilized and mixed to another one state which is a separated solvent system in which the solvent system is separated into two or more phases consisting mainly of the two or more single organic solvents or mixed organic solvents constituting the solvent system, and can dissolve the chemical component which is soluble in only one single organic solvent or mixed organic solvent homogeneously.
  • the 1 st on of the present invention is the solvent system of A, wherein the chemical component takes part in the reaction, and a phase whose main component is at least one organic solvent or organic solvents constructing the solvent system dissolves at least one component of the chemical components which take part in the reaction, and in the state of separated solvent does not satisfy the condition which progress the substantial chemical reaction, and only in the state of homogeneous compatibilized mixed solvent system satisfies the condition which progress the substantial chemical reaction.
  • the 1 st on of the present invention is the solvent system of A or B, wherein one single organic solvent or mixed organic solvent is composed of cycloalkanes and another single organic solvent or mixed organic solvent is composed of at least one selected group consisting of nitroalkane, nitrile, alcohol, halogenated alkyl, amide and sulfoxide.
  • the 1 st on of the present invention is the solvent system of C, wherein carbon number of alkyl group of nitro alkane is 1, 2 or 3, carbon number of alkyl group of nitrile is 1, 2 or 3, amide is N-dialkyl or N-monoalkyl amide, the total carbon number of alkyl group and formyl group or acyl group is 6 or less, carbon number of alcohol is 8 or less, carbon number of alkyl group of sulfoxide is 1, 2 or 3 and carbon number of alkyl group of halogenated alkyl is 6 or less.
  • the 2 nd one of the present invention is the method for preparation of the compound comprising, using the solvent system of two or more single organic solvent or mixed organic solvent, and said solvent system can change the state reversibly by changing temperature condition from one state which is a homogeneously compatibilized mixed solvent system in which two or more single organic solvents or mixed organic solvents constituting the solvent system are homogeneously compatibilized and mixed to another one state which is a separated solvent system in which the solvent system is separated into two or more phases consisting mainly of the two or more single organic solvents or mixed organic solvents constituting the solvent system, and can dissolve the chemical component which is soluble in only one single organic solvent or mixed organic solvent homogeneously, using a chemical component which takes part in the reaction as chemical component, after said chemical component is added, the reaction is progressed under the temperature condition realizing the state of homogeneous compatibilized mixed solvent system which satisfy the condition of chemical reaction, then the condition is changed to the temperature by which two or more single organic solvent or mixed organic solvent is separated into two or more phases
  • the 2 nd one of the present invention is the method for preparation of the compound of E, wherein one single organic solvent or mixed organic solvent is composed of cycloalkanes and another single organic solvent or mixed organic solvent is composed of at least one selected group consisting of nitroalkane, nitrile, alcohol, halogenated alkyl, amide and sulfoxide.
  • the 2 nd one of the present invention is the method for preparation of the compound of F, wherein carbon number of alkyl group of nitro alkane is 1, 2 or 3, carbon number of alkyl group of nitrile is 1, 2 or 3, amide is N-dialkyl or N-monoalkyl amide, the total carbon number of alkyl group and formyl group or acyl group is 6 or less, carbon number of alcohol is 8 or less, carbon number of alkyl group of sulfoxide is 1, 2 or 3 and carbon number of alkyl group of halogenated alkyl is 6 or less.
  • the 3 rd one of the present invention is the method for preparation of the compound of E, F and G, wherein electrolyte is used as the chemical component which takes part in the reaction, and the reaction is progressed by electrolysis.
  • the 4 th one of the present invention is the method for preparation of the compound of above mentioned items, wherein the reaction is progressed by irradiating the light of ultra violet-visible light.
  • the 5 th one of the present invention is the method for preparation of peptide utilising the solvent system of A and specifically mentioned as folloow. That is, the 5 th one of the present invention is the method for preparation of peptide by liquid phase synthesis comprising,
  • the 5 th one of the present invention is the method for preparation of peptide by liquid phase synthesis of J, wherein the organic solvent composing one solvent or mixed solvent is composed by cycloalkane compounds, and organic solvent composing another solvent or mixed solvent B to be combined with the organic solvent composing said solvent or mixed solvent A is at least one selected from the group consisting of nitroalkane, nitrile, alcohol, halogenated alkyl, amide and sulfoxide.
  • the 5 th one of the present invention is the method for preparation of peptide by liquid phase synthesis of J, wherein carbon number of alkyl group of nitro alkane is 1, 2 or 3, carbon number of alkyl group of nitrile is 1, 2 or 3, amide is N-dialkyl or N-monoalkyl amide, the total carbon number of alkyl group and formyl group or acyl group is 6 or less, carbon number of alcohol is 8 or less, carbon number of alkyl group of sulfoxide is 1, 2 or 3 and carbon number of alkyl group of halogenated alkyl is 6 or less.
  • the 5 th one of the present invention is the method for preparation of peptide by liquid phase synthesis of J, K and L, wherein the carrier which forms the peptide starting compound is the residue from aromatic hydrocarbon ring represented by general formula A or fundamental skeletal compound having 10 or more carbons having a functional group which can bond with amino acid with cycloalkanephilic solvent part.
  • the 5 th one of the present invention is the method for preparation of peptide by liquid phase synthesis of M, wherein the compound represented by general formula A is the compound selected from the group of represented by general formulae B.
  • R 5 is hydroxyl group, thiol group, amino group or carbonyl group which bonds with amino acid.
  • FIG. 1 shows the state of solvent A′ in which starting material is dissolved and solvent A′′ in which catalyst and reaction additive agents are dissolved are respectively separated to single organic solvent or mixed organic solvent.
  • B illustrates the process B which progresses the reaction by adjusting the temperature condition to the state of homogeneous compatibilized mixed solvent system.
  • C illustrates the separated solvent system which is separated reversibly to each solvent phase whose main component are solvents composing the solvent system, for example, separated to the solution phase C′ which dissolves the product and the solution phase C′′ in which the catalyst and the reaction additive agent are dissolved.
  • FIG. 1 illustrates the method to separate the product and to recycle the catalyst and the reaction additive agent according to the theory of the solvent system of the present invention.
  • FIG. 2 shows the correlation between mixing ratio, temperature and state change of compatibility of cyclohexane CH: homogeneous compatibilized mixed solvent system of nitroalkane nitromethane NM, nitroethane NE solvent system—separated solvent system.
  • FIG. 3 shows the temperature characteristic of state change of cyclohexane-dimethyl formamide(DMF)-dimethylacetoamide(DMA) mixed solvent system to homogeneous compatibilized mixed solvent system.
  • FIG. 4 shows the correlation between mixing ratio, temperature and change of homogeneous compatibilized mixed solvent system—separated solvent system of cyclohexane CH-acetonitrile AN-propionitrile PN mixed solvent system.
  • FIG. 5 shows the measuring results of state change of homogeneous compatibilized mixed solvent system—separated solvent system and selective oxidation reaction using solvent system containing electrolyte and oxidisable organic compound measured by following method. That is, a glassy carbon electrode (working electrode), a platinum cathode and silver-silver chloride electrode are inserted and cycled from ⁇ 0.2 to 2.0 volt and potential is changed by 100 mv/second, and corresponding electric current is measured.
  • a is the case when homogeneous compatibilized mixed solvent system is formed by heating to 55° C.
  • b is the case of nitroalkane phase of 20° C.
  • c is the case of cycloalkane phase of 20° C.
  • the solvent system of the present invention is composed of two or more kind of single organic solvent or mixed organic solvent which can reversibly form the state of homogeneous compatibilized mixed solvent system and the state of separated solvent system which is separated to plural phases by small temperature change.
  • One single organic solvent or mixed organic solvent is basically a low polar solvent, and as the compounds which compose said solvent, alkane, cycloalkane, alkene, alkyne or aromatic compound, desirably cycloalkane compound, more desirably cyclohexane can be mentioned. From the fact that the transformation of chair conformation-boat conformation isomer of cyclohexane can be carried out by comparative mild condition in connection with other solvent, it can be guessed that the solvent system of the present invention is realised. By this guessed characteristic, in said two phases solvent system, it is possible to consider to form the state that the majority part of solutes are distributed almost completely to either one phase.
  • cyclohexane since the melting point of cyclohexane is 6.5° C. and is relatively high, cyclohexane has a merit which can separate the reactive product by solidification. Therefore, from this view point, cyclohexane can be said as a desirable solvent.
  • the solute having high polar which dissolves selectively the compound for example, inorganic salts, organic salts, inorganic base, inorganic acid, organic base, organic acid, Lewis acid, Lewis base, amphoteric ion substance, ionic photo sensitizer (methylene blue), supporting electrolyte, organic metal compound, polar organic molecule such as alcohol, phenol, aromatic compound, carboxylic acid, amine, aldehyde, ketone, ether, amide, nitro compound, halogenide, thiol, sulfone, sulfoxide, isonitrile, acid anhydride or esters, water, polar polymer, amino acid, peptide, protein and derivatives thereof, nucleic acid and derivatives thereof, saccaride and derivatives thereof, lipid and derivatives thereof can be mentioned.
  • the solvent system is necessary to be used in various reactions, the solvent system is necessary to dissolve solute, catalyst, carrier and additives to be used in the reaction in the state of homogeneous compatibilized mixed solvent system, and is necessarily selected from this view point.
  • the product when cyclohexane is used as the solvent to dissolve the product, following advantage can be mentioned. That is, the product can be separated as solid by cooling the solution to 0° C., and the product which is separated as the solid is heated to vaporize and remove the coexisting cyclohexane, thus the product can be refined easily.
  • amino acid used in the method for preparation of peptide by liquid phase synthesis protective amino acid used in the conventional method for preparation of solid phase peptide, for example, Fmoc (9-fluorenylmethoxycarbonyl)-amino acid, Boc (t-butoxycarbonyl) amino acid or Cbz (bezyloxycarbonyl)-amino acid can be used.
  • the mixtures of mixing ratio of nitromethane:nitroethane is from 10:0 to 3:7 were separated to 2 phases (upper layer whose main component is cyclohexane and lower layer whose main component is nitroalkane) at 10° C.
  • the solvents of nitromethane:nitroethane ratio is from 2:8 to 0:10 became homogeneous solvent at the temperature of 10° C. and separated to two phases by cooling down. And by heating these solvents became homogeneous compatibilized mixed solvent again, that is, regarding these solvents the state change phenomenon of homogeneous compatibilized mixed solvent system—separated solvent system could be repeated reversibly.
  • Example 1 When cyclohexane:nitroalkane (nitroalkane is nitromethane or nitroethane or mixture thereof) ratio in Example 1 was changed, the temperature which shows the state change of homogeneous compatibilized mixed solvent system—separated solvent system was changed. As shown in FIG.
  • the mixtures of mixing ratio of MeCN/EtCN is 2:8 or more were separated to 2 phases (upper layer whose main component is cyclohexane and lower layer whose main component is nitrile organic solvent) at 10° C. (separated solvent system).
  • these solvents became complete homogeneous compatibilized mixed solvents by elevating the temperature over than the temperature shown in the graph.
  • These homogeneous compatibilized mixed solvent systems could maintain the state of homogeneous solution without performing physical operation such as stirring from outside, as long as keeping the temperature higher than the homogenized temperature.
  • this mixed solution became homogeneous compatibilized mixed solvent by heating to 45° C., and also methylene blue was dissolved into homogeneous compatibilized mixed solvent. Further, when this solution was cooled down to 25° C., the solution separated to two phases (separated solvent system) immediately and more than 99.9% of methylene blue was dissolved in the lower layer (nitroalkane layer).
  • methylene blue could be refined by changing the ratio of cyclohexane and nitroalkane voluntarily and repeat the state change of homogeneous compatibilized mixed solvent system—separated solvent system and in separated solvent system methylene blue could be refined in nitroalkane phase.
  • a glassy carbon electrode working electrode
  • a platinum cathode and silver-silver chloride electrode are inserted and cycled from ⁇ 0.2 to 2.0 volt (cyclic voltanometory) and potential is changed by 100 mv/second, and corresponding electric current is measured. Since the solvent system was in the state of separated solvent state at this temperature, consequently the oxidation of hexadecanethiol did not occurred, and the remarkable peak showing the oxidation of thiol group was not observed.
  • lithium perchloride acceleration of carbon-sulfur cleavage reaction along with the photo electron transportation of a sulfur atom progressed by light irradiation to methylene blue and acceleration of inner molecular ring forming reaction
  • 2.3 mg of methylene blue were added and dissolved completely.
  • Lithium perchloride and methylene blue were completely dissolved in the lower layer (nitroalkane layer).
  • argon gas flow halogen lamp visible ray lamp, wave length from 400 nm to 700 nm
  • electrolysis substrate oxidizable substance, in the case of electrolysis oxidation
  • electrolysis substrate and supporting salt are added into single compatibilized solution and carry out the electrode reaction and after reaction, the product obtained by chemical transformation from the electrolysis substrate and the supporting salt must be separated.
  • Examples 5, 6, 7 and 8 by using the solvent system which can perform the state change of two states reversibly, that is, the homogeneous compatibilized mixed solvent system and the separated solvent system, by changing the temperature, the chemical reaction (photo chemical reaction, electrolysis reaction) is carried out in the state of homogeneous compatibilized mixed solvent system and in the state of separated solvent system, the separation of 2 or more components (for example, product and electrolyte) can be realized.
  • the chemical reaction photo chemical reaction, electrolysis reaction
  • soluble carrier SC (3,4,5-trioctadecyloxyphenyl)methane-1-ol, which is R is C 18 H 37 —, X is 0, n is 3, Q is CH 2 and R 2 is OH in general formulae B was used.
  • Process (2) 57 mg of Fmoc-Gly, 55 mg of HOBt and 25 mg of diisopropylcarbodiimide (DIPCD) were dissolved in 2 mL of DMF and stirred for 150 minutes at the room temperature. This solution was used as the activated Fmoc-Gly-OH/DMF solution. That is, after 2 mL of this solution was colled down to 5, 2 mL of SC -Val-NH 2 /cyclohexane obtained in Process (1) was added. The temperature of the reaction solution was elevated from 5° C. to 50° C. by 1 hour and maintain at 50° C. for 30 minutes.
  • DIPCD diisopropylcarbodiimide
  • the state change of the homogeneous compatibilized mixed solvent system and the separated solvent system can easily control by changing temperature, and by the controlling of the state change, the excellent effect that can perform the treating system or reacting system handling the chemical substances in which the controlling of reaction and the separation refining of the product can be easily realised is provided. Further, since by the state change of the homogeneous compatibilized mixed solvent system and the separated solvent system the electric characteristics can be controlled, it is possible to design the functional system utilizing these characteristics, and the excellent effect to expect to perform a novel technique is provided.

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  • Chemical & Material Sciences (AREA)
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JP2001-254109 2001-08-24
JP2001254109A JP3538672B2 (ja) 2001-08-24 2001-08-24 相溶性−多相有機溶媒システム
JP2001-385493 2001-12-19
JP2001385493A JP4283469B2 (ja) 2001-12-19 2001-12-19 相溶性−多相有機溶媒システムによりアミノ酸を逐次的に付加する液相ペプチド合成法
PCT/JP2002/008501 WO2003018188A1 (fr) 2001-08-24 2002-08-23 Systeme de solvant multiphase compatible

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US20100184952A1 (en) * 2007-07-25 2010-07-22 Ajinomoto Co., Inc Method for selective removal of dibenzofulvene derivative
US8546534B2 (en) 2010-08-30 2013-10-01 Ajinomoto Co., Inc. Branched chain-containing aromatic compound
US9353147B2 (en) 2011-05-31 2016-05-31 Ajinomoto Co., Inc. Method for producing peptide
US11098078B2 (en) 2015-03-04 2021-08-24 Jitsubo Co., Ltd. Peptide synthesis method
US11420997B2 (en) 2018-04-13 2022-08-23 Jitsubo Co., Ltd. Peptide synthesis method
US11827660B2 (en) 2019-02-01 2023-11-28 Sederma Synthesis strategy for gap protecting group

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US20060104869A1 (en) * 2002-08-29 2006-05-18 Tokyo University Of Agriculture And Technology Tlo Co., Ltd. Apparatus for carrying out chemical process using set of solvents undergoing reversible change between mutual dissolution and separation depending on temperature
US20070039881A1 (en) * 2003-05-01 2007-02-22 Kazuhiro Chiba Method and apparatus for solution/separation at predetermined temperature with solvent set undergoing temperature-dependent reversible change between solution phase and separation phase
AU2006293180A1 (en) * 2005-09-20 2007-03-29 Jitsubo Co., Ltd. Carrier for separation, method for separation of compound, and method for synthesis of peptide using the carrier
CN101405240B (zh) 2006-03-24 2012-07-25 日商·Jitsubo株式会社 有机合成用试剂、以及使用该试剂的有机合成反应方法
JP7163916B2 (ja) * 2017-07-05 2022-11-01 日産化学株式会社 ベンジル化合物
CN110317130B (zh) * 2018-03-29 2021-12-21 深圳翰宇药业股份有限公司 化合物及其制备方法和应用

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US8546534B2 (en) 2010-08-30 2013-10-01 Ajinomoto Co., Inc. Branched chain-containing aromatic compound
US9499579B2 (en) 2010-08-30 2016-11-22 Ajinomoto Co., Inc. Branched chain-containing aromatic compound
US10711033B2 (en) 2010-08-30 2020-07-14 Ajinomoto Co., Inc. Branched chain-containing aromatic compound
US9353147B2 (en) 2011-05-31 2016-05-31 Ajinomoto Co., Inc. Method for producing peptide
US11098078B2 (en) 2015-03-04 2021-08-24 Jitsubo Co., Ltd. Peptide synthesis method
US11420997B2 (en) 2018-04-13 2022-08-23 Jitsubo Co., Ltd. Peptide synthesis method
US11827660B2 (en) 2019-02-01 2023-11-28 Sederma Synthesis strategy for gap protecting group

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EP1426101A4 (fr) 2006-11-15
DE60238846D1 (de) 2011-02-17
CN1289182C (zh) 2006-12-13
EP1426101A1 (fr) 2004-06-09
WO2003018188A1 (fr) 2003-03-06
US20070066799A1 (en) 2007-03-22
EP1426101B1 (fr) 2011-01-05
US8344103B2 (en) 2013-01-01

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