+

WO2018159628A1 - Acylborane de type acide aminé et procédé pour sa production - Google Patents

Acylborane de type acide aminé et procédé pour sa production Download PDF

Info

Publication number
WO2018159628A1
WO2018159628A1 PCT/JP2018/007313 JP2018007313W WO2018159628A1 WO 2018159628 A1 WO2018159628 A1 WO 2018159628A1 JP 2018007313 W JP2018007313 W JP 2018007313W WO 2018159628 A1 WO2018159628 A1 WO 2018159628A1
Authority
WO
WIPO (PCT)
Prior art keywords
group
hydrogen atom
compound
alkyl group
acylborane
Prior art date
Application number
PCT/JP2018/007313
Other languages
English (en)
Japanese (ja)
Inventor
伊藤　肇
純平 田口
俊希 池田
Original Assignee
国立大学法人北海道大学
Priority date (The priority date 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 date listed.)
Filing date
Publication date
Application filed by 国立大学法人北海道大学 filed Critical 国立大学法人北海道大学
Priority to JP2019503031A priority Critical patent/JP7244921B2/ja
Publication of WO2018159628A1 publication Critical patent/WO2018159628A1/fr

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F5/00—Compounds containing elements of Groups 3 or 13 of the Periodic Table
    • C07F5/02—Boron compounds
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
    • Y02P20/00—Technologies relating to chemical industry
    • Y02P20/50—Improvements relating to the production of bulk chemicals
    • Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

Definitions

  • the present invention relates to an amino acid acylborane and a method for producing the same.
  • a peptide is a molecule having a structure in which a plurality of amino acids are connected, and is known to exhibit a very important role in the living body as an enzyme, a neurotransmitter, a hormone and the like.
  • peptides have attracted attention as pharmaceuticals, and the development of methods for synthesizing peptides is extremely important.
  • a biochemical method and an organic chemical method are known.
  • the organic chemistry method especially the method called chemical ligation, has advantages in that it can freely synthesize peptides of the desired amino acid sequence and can easily introduce non-natural amino acid residues, and various methods have been proposed.
  • KAT potassium acyltrifluoroborate
  • MIDA N-methyliminodiacetic acid
  • Non-Patent Documents 4 to 6 methods described in Non-Patent Documents 4 to 6 are known.
  • a desired hemiaminal ether is boronated, followed by treatment with n-butyllithium and KHF 2 to obtain the desired acylborane.
  • the target acylborane is obtained by allowing n-butyllithium to act on a substrate derived from an aryl halide and thioformamide.
  • Non-Patent Document 6 After conversion of ⁇ -borylcarboxylic acid to thiooxamate ester and then MIDA ⁇ -hydroxyboronate, acyl borane is finally obtained by using Dess-Martin oxidation.
  • Non-Patent Documents 4 and 5 have a problem that the functional group tolerance of the reaction is low because an organic lithium reagent is used.
  • the method of Non-Patent Document 6 requires a multi-step reaction, and there is a problem that the synthesis is very time-consuming.
  • amino acid acyl borane acyl boranes having a structure corresponding to amino acids, that is, acyl boranes in which an amino group is bonded to the ⁇ carbon of a carbonyl group
  • amino acid acyl borane it is also preferable to use the amino acid type acylborane.
  • an object of the present invention is to provide an amino acid acylborane that can be synthesized by a method that is relatively simple and has high functional group tolerance, and a method for producing the same.
  • the present invention provides an acylborane represented by the following general formula (1).
  • R 1 and R 2 each independently represent a hydrogen atom, a protecting group, a peptide residue, an alkyl group, an aryl group, an alkoxy group or an acyloxy group, and R 3 has a hydrogen atom or a substituent.
  • R 4 represents a —B (MIDA) group, a —BF 3 K group or a —B (OR A ) (OR B ) group
  • R a and R B each independently represent a hydrogen atom or an alkyl group
  • R a and R B are the two oxygen atoms and the two oxygen atoms bonded thereto, together with the boron atom bonded ring May be formed
  • R 1 and R 3 may form a ring together with the nitrogen atom and the carbon atom to which each is bonded.
  • the acyl borane of the present invention is an amino acid type acyl borane in which an amino group is bonded to the ⁇ carbon of the carbonyl group, and is expected to be applied to peptide ligation.
  • the acylborane of the present invention can be synthesized relatively easily by the production method of the present invention shown below.
  • the present invention also provides a method for producing an acylborane including a step of obtaining an acylborane represented by the following general formula (1 ′) by ozonolysis of vinylborane represented by the following general formula (2).
  • R 1 and R 2 each independently represent a hydrogen atom, a protecting group, a peptide residue, an alkyl group, an aryl group, an alkoxy group or an acyloxy group
  • R 3 has a hydrogen atom or a substituent.
  • R 5 and R 6 each independently represent a hydrogen atom, an alkyl group, an aryl group, a silyl group, or an acyl group.
  • R 1 , R 2 and R 3 have the same meaning as in formula (2).
  • an amino acid acylborane applicable to peptide ligation can be produced relatively easily.
  • ozonolysis has higher functional group tolerance as compared with conventional acylborane production methods, and the production method of the present invention can be applied to a wider range of compounds.
  • the present invention further provides an acylborane production method including a step of obtaining an acylborane represented by the following general formula (1 ′′) by oxidizing ⁇ -hydroxytrifluoroborate represented by the following general formula (3).
  • R 1 and R 2 each independently represent a hydrogen atom, a protecting group, a peptide residue, an alkyl group, an aryl group, an alkoxy group or an acyloxy group, and R 3 has a hydrogen atom or a substituent. An alkyl group which may be substituted or an aryl group which may have a substituent is shown.
  • R 1 , R 2 and R 3 have the same meaning as in formula (3). ]
  • an amino acid acylborane that can be synthesized by a method that is relatively simple and has high functional group tolerance, and a method for producing the same.
  • protecting group for R 1 and R 2
  • those conventionally known as protecting groups for amino groups can be appropriately used.
  • amino groups described in Protective Groups in Organic Synthesis, published by John Wiley and Sons can be used.
  • Protecting groups can be used. Specific examples thereof include acetyl group (Ac group), trifluoroacetyl group, pivaloyl group, tert-butoxycarbonyl group (Boc group), 2,2,2-trichloroethoxycarbonyl group, benzyloxycarbonyl group (Cbz group).
  • the “peptide residue” in R 1 and R 2 has no OH group in the terminal carboxyl group of the peptide molecule, and the carbon atom of the carbonyl group in the carboxyl group is directly bonded to the nitrogen atom in the general formula (1) What you did.
  • the other group is usually a hydrogen atom.
  • the peptide residues in R 1 and R 2 may be those in which some or all of the nitrogen atoms are protected.
  • the “alkyl group” in R 1 and R 2 may be linear, branched or cyclic, and the number of carbon atoms is not particularly limited.
  • an alkyl group having 1 to 6 carbon atoms is preferable. Specific examples thereof include a methyl group, an ethyl group, a propyl group, a butyl group, a pentyl group, a hexyl group, a cyclopentyl group, and a cyclohexyl group.
  • Examples of the “aryl group” in R 1 and R 2 include a phenyl group and a naphthyl group.
  • alkoxy group examples include a group in which the above alkyl group is bonded to an oxygen atom. Specific examples thereof include methoxy group, ethoxy group, propoxy group, butyloxy group, pentyloxy group, hexyloxy group, and cyclohexyloxy group.
  • acyloxy group examples include an acetoxy group, a pivaloyloxy group, and a diethylcarbamoyloxy group.
  • Examples of the “alkyl group” of the “alkyl group optionally having substituent (s)” for R 3 include the same “alkyl group” for R 1 and R 2 .
  • the “substituent” is not particularly limited, but is preferably a guanidino group, a carbamoyl group, a thiol group, a carboxy group, a heteroaryl group, an aryl group, a hydroxy group or a hydroxyaryl group from the viewpoint of being the same as the amino acid constituting the protein .
  • Examples of the ring formed by combining R 1 and R 3 together with the nitrogen atom and carbon atom to which each is bonded include a pyrrolidine ring.
  • the —B (MIDA) group in R 4 is a group represented by the following formula (A), but the coordination from the nitrogen atom to the boron atom is omitted as shown in the following formula (A ′). There is also a case.
  • Ashiruboran represented by the general formula (1) but when R 3 is a group other than a hydrogen atom Asymmetric centers exist, the Ashiruboran can be racemic be optically active substance Good.
  • the said acyl borane to peptide ligation etc. it is preferable that it is an optically active substance like a natural amino acid.
  • the optically active substance can be obtained by using an optically active substance as a raw material or optically resolving a racemate.
  • Examples of the “alkyl group” and “aryl group” in R 5 and R 6 include the same as the “alkyl group” and “aryl group” in R 1 and R 2 .
  • the “silyl group” in R 5 and R 6 may be any of a trialkylsilyl group, a dialkylarylsilyl group, an alkyldiarylsilyl group, or a triarylsilyl group. Specific examples thereof include a trimethylsilyl group, a methyldiphenylsilyl group, a dimethylphenylsilyl group, and a triphenylsilyl group.
  • Examples of the “acyl group” in R 5 and R 6 include an acetyl group, a pivaloyl group, a benzoyl group (Bz group), and a cyclohexanecarbonyl group.
  • the acylborane production method in the first embodiment of the present invention is obtained by ozonolysis of the vinylborane represented by the general formula (2) to produce the acylborane (MIDA) represented by the general formula (1 ′).
  • MIDA acylborane
  • Acyl borane The acylborane represented by the general formula (1 ′) is included in the acylborane represented by the general formula (1).
  • the method for producing an acylborane in the present embodiment is represented by the general formula (1 ′).
  • the acyl borane to be converted may be converted by a conventionally known method.
  • the acylborane represented by the general formula (1 ′) has, for example, a bulky alkyl group in addition to the glycine-type amino acid derivative (compound 4) and the alanine-type amino acid derivative (compound 9) synthesized in the examples.
  • Examples include amino acid derivatives, amino acid derivatives having basic functional groups, amino acid derivatives having acidic functional groups, amino acid derivatives having hydroxy groups, amino acid derivatives having amide groups, and the like.
  • amino acid derivatives having a bulky alkyl group examples include amino acid derivatives such as leucine type, isoleucine type, valine type, phenylalanine type, and proline type shown in the following compound group (I). These amino acid derivatives can be synthesized in the same manner as the amino acid derivatives of glycine type and alanine type.
  • the raw material vinylboron compound (compound 1 or compound 7 in the examples) can be synthesized, for example, by a boronation reaction described in J. Am. Chem. Soc. 2011, 133, 7859. When the yield in the reaction is low, the reaction temperature is raised to 0 ° C. or room temperature.
  • amino acid derivative having a basic functional group examples include amino acid derivatives having an amino group such as lysine type, tryptophan type, and histidine type shown in the following compound group (II).
  • the amino acid derivatives having these amino groups are glycine-type by using a tert-butoxycarbonyl (Boc) group, a benzyloxycarbonyl (Cbz) group, an allyloxycarbonyl group (Alloc) group or the like as a protective group for the amino group, It can be synthesized by the same synthesis method as an alanine type amino acid derivative.
  • the Boc, Cbz, and Alloc groups are general protecting groups widely used in solid phase synthesis of peptides.
  • the Boc group is treated with acid (TFA), and the Cbz group uses hydrogen gas and Pd / C.
  • Each of the Alloc groups can be deprotected by treatment with hydrogenation and treatment with Pd (PPh 3 ) 4 .
  • amino acid derivative having an acidic functional group examples include amino acid derivatives having a carboxy group such as an aspartic acid type and a glutamic acid type shown in the following compound group (III).
  • carboxy group-containing amino acid derivatives can be synthesized by the same synthesis method as glycine-type and alanine-type amino acid derivatives by using t-butyl, benzyl, and allyl groups as carboxy-protecting groups.
  • t-Butyl group, benzyl group and allyl group are general protecting groups widely used in solid phase synthesis of peptides.T-butyl group is treated with acid (TFA), benzyl group is hydrogen gas and Pd.
  • Each of the allyl groups can be deprotected by treatment with hydrogenation using / C and treatment with Pd (PPh 3 ) 4 .
  • t-Butyl group and trityl group are general protecting groups widely used in solid phase synthesis of peptides and can be deprotected by treatment with acid (TFA).
  • amino acid derivatives having an amide group examples include amino acid derivatives such as asparagine type and glutamine type shown by the following compound group (V). These amino acid derivatives can be synthesized by the same synthesis method as glycine-type and alanine-type amino acid derivatives by using a trityl group as a protecting group for the nitrogen atom of the amide structure.
  • the trityl group is a general protecting group widely used in peptide solid-phase synthesis, and can be deprotected by treatment with acid (TFA).
  • the acylborane represented by the general formula (1 ′) can be converted into another acylborane by a conventionally known method. For example, as shown in Example, by the action of KHF 2, it can be converted to KAT. Further, acylborane in which R 4 is —B (OH) 2 can be obtained by allowing trimethylsilyl chloride to act on the obtained KAT. Further, acylborane in which R 4 is —B (OR A ) (OR B ) can be obtained by allowing trimethylsilyl chloride and the corresponding alcohol to act on the obtained KAT.
  • R 1 , R 2 and R 3 can also be converted by a conventionally known method.
  • a vinylborane R 1 and R 2 is a hydrogen atom as a starting material, conventionally known after the reaction It is also possible to introduce a peptide chain by this method.
  • ozonolysis can be performed by a conventionally known method, for example, it can be performed by the following method.
  • ozone gas O 3 gas
  • acetone, methanol, ethyl acetate or the like as a solvent
  • O 3 gas ozone gas
  • the reaction mixture by excess free ozone becomes blue, after confirming that the reaction was complete, bubbling oxygen gas (O 2 gas), followed by reduction with a reducing agent such as dimethyl sulfide, obtained Ashiruboran purposes It is done.
  • Ozonolysis does not use strong acids or strong bases, and therefore has relatively high functional group tolerance.
  • the present inventors examined ozonolysis for various vinylboranes, and vinylborane is a protecting group other than MIDA, for example, -BF 3 K group, pinacol ester group (B (pin) group), diaminonaphthalene group (B ( With respect to vinylborane protected with dan) group), only a complex mixture was given, and the desired acylborane could not be obtained.
  • the acylborane production method according to the second embodiment of the present invention is represented by the following general formula (1 ′′) by oxidizing ⁇ -hydroxytrifluoroborate represented by the general formula (3) as described above.
  • the acyl borane represented by the general formula (1 ′′) is included in the acyl borane represented by the general formula (1), and the method for producing the acyl borane of the present embodiment is described below.
  • the acylborane represented by the general formula (1 ′′) may be converted by a conventionally known method.
  • the ⁇ -hydroxytrifluoroborate represented by the general formula (3) is synthesized in Synthesis Example 7. In the same manner as above, the corresponding aldehyde can be synthesized by hydroboration.
  • the oxidation of ⁇ -hydroxytrifluoroborate represented by the general formula (3) can be carried out by a conventionally known method.
  • Albright Goldman oxidation, swarnic acid oxidation, Parrick-Dering oxidation, Moffatt oxidation, TEMPO Oxidized soot (including those using AZADO and nor-AZADO), Ray Griffith oxidation, etc. can be applied.
  • reaction product was extracted with NH 4 Cl aqueous solution and ethyl acetate, and the obtained organic solvent was washed with brine and dried over MgSO 4 .
  • the organic solvent was filtered and concentrated under reduced pressure, and then Compound 13 was isolated by silica gel column chromatography.
  • reaction product was extracted with NH 4 Cl aqueous solution and ethyl acetate, and the obtained organic solvent was washed with brine and dried over MgSO 4 .
  • the organic solvent was filtered and concentrated under reduced pressure, and then Compound 16 was isolated by silica gel column chromatography.
  • the reaction solution was cooled to 0 ° C., and benzyl (2-oxoethyl) carbamate (the above compound 21 described in Tetrahedron Lett. 1984, 25, 5303.) (386.1 mg, 2.0 mmol) and MeOH (162 ⁇ L, 4.0 mmol) were sequentially added. The mixture was warmed to room temperature and stirred for 4 hours. The reaction solution was cooled again to 0 ° C., MeOH (3.0 mL) and KHF 2 aqueous solution (2.5 M, 3.5 mL) were added, and the mixture was stirred for 1 hour.

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)

Abstract

L'invention concerne un acylborane représenté par la formule générale (1) et un procédé de production de l'acylborane. (Dans la formule, chacun parmi R1 et R2 représente, indépendamment, un atome d'hydrogène, un groupe de protection, un résidu de peptide, un groupe alkyle, un groupe aryle, un groupe alcoxy ou un groupe acyloxy ; R3 représente un atome d'hydrogène, un groupe alkyle éventuellement substitué ou un groupe aryle éventuellement substitué ; et R4 représente un groupe -B(MIDA), un groupe -BF3K ou un groupe -B(ORA)(ORB) (dans lesquels chacun parmi RA et RB représente, indépendamment, un atome d'hydrogène ou similaire). A cet égard, toutefois, R1 et R3 peuvent se combiner l'un avec l'autre et former un cycle conjointement avec un atome d'azote et un atome de carbone auxquels R1 et R3 sont respectivement liés).
PCT/JP2018/007313 2017-02-28 2018-02-27 Acylborane de type acide aminé et procédé pour sa production WO2018159628A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
JP2019503031A JP7244921B2 (ja) 2017-02-28 2018-02-27 アミノ酸型アシルボランおよびその製造方法

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
JP2017-037087 2017-02-28
JP2017037087 2017-02-28

Publications (1)

Publication Number Publication Date
WO2018159628A1 true WO2018159628A1 (fr) 2018-09-07

Family

ID=63370930

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/JP2018/007313 WO2018159628A1 (fr) 2017-02-28 2018-02-27 Acylborane de type acide aminé et procédé pour sa production

Country Status (2)

Country Link
JP (1) JP7244921B2 (fr)
WO (1) WO2018159628A1 (fr)

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2003033506A1 (fr) * 2001-10-12 2003-04-24 Kyorin Pharmaceutical Co., Ltd. Derive d'acide d'aminoborane et medicament inhibiteur de proteasomes le contenant

Family Cites Families (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN103387601B (zh) * 2012-05-11 2017-01-11 南开大学 抗登革热病毒(denv)杂环肽类化合物及其制备方法和用途
CN103421083A (zh) * 2012-05-16 2013-12-04 南开大学 具有1,2,3-三氮唑结构的抗登革热病毒杂环肽类化合物及其制备方法和用途

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2003033506A1 (fr) * 2001-10-12 2003-04-24 Kyorin Pharmaceutical Co., Ltd. Derive d'acide d'aminoborane et medicament inhibiteur de proteasomes le contenant

Non-Patent Citations (4)

* Cited by examiner, † Cited by third party
Title
MAZUNIN, DMITRY ET AL.: "Potassium Acyltrifluoroborate (KAT) Ligations are Orthogonal to Thiol-Michael and SPAAC Reactions: Covalent Dual Immobilization of Proteins onto Synthetic PEG Hydrogels", HELVETICA CHIMICA ACTA, vol. 100, no. 2, 16 December 2016 (2016-12-16), pages 1 - 10, XP055543171, Retrieved from the Internet <URL:https://doi.org/10.1002/hlca.201600311> *
MURAR, CLAUDIA E. ET AL.: "KAHA Ligations That Form Aspartyl Aldehyde Residues as Synthetic Handles for Protein Modification and Purification", J. AM. CHEM. SOC., vol. 136, no. 52, 31 December 2014 (2014-12-31), pages 18140 - 18148, XP055543138, Retrieved from the Internet <URL:DOI:10.1021/ja511231f> *
TAGUCHI, JUMPEI. ET AL.: "Synthesis of Acylborons by Ozonolysis of Alkenylboronates: Preparation of an Enantioenriched Amino Acid Acylboronate", ANGEWANDTE CHEMIE, vol. 56, no. 44, 14 September 2017 (2017-09-14), pages 13847 - 13851, XP055543181, Retrieved from the Internet <URL:https://doi.org/10.1002/anie.201707933> *
TSENG, CLAIRE C. ET AL.: "Characterization of the Surfactin Synthetase C-Terminal Thioesterase Domain as a Cyclic Depsipeptide Synthase", BIOCHEMISTRY, vol. 41, no. 45, 12 November 2002 (2002-11-12), pages 13350 - 13359, XP002304806 *

Also Published As

Publication number Publication date
JP7244921B2 (ja) 2023-03-23
JPWO2018159628A1 (ja) 2019-12-26

Similar Documents

Publication Publication Date Title
RU2637924C2 (ru) Способы синтеза аматоксинового структурного блока и аматоксинов
CN102498124B (zh) 环状氨基酸分子及其制备方法
CN1073946A (zh) 制备脯氨酸硼酸酯的方法
Hanessian et al. Novel access to (3 R)-and (3 S)-3-hydroxy-L-aspartic acids,(4 S)-4-hydroxy-L-glutamic acid, and related amino acids
EP4538279A2 (fr) Agent de réaction pour des réactions amide et procédé de production de composé amide l&#39;utilisant
CN110799193B (zh) 铜和镍催化的脱羧硼化反应
JP2023052381A (ja) 液相ペプチド合成のための方法およびその保護戦略
WO2016047794A1 (fr) Procédé pour produire un peptide hydrophobe
JP4117009B2 (ja) ムギネ酸類の効率的製造方法
Zarezin et al. Diazocarbonyl derivatives of amino acids: unique chiral building blocks for the synthesis of biologically active compounds
WO2018159628A1 (fr) Acylborane de type acide aminé et procédé pour sa production
CN114080395A (zh) α-鹅膏蕈碱及其衍生物的合成方法
Chiarello et al. Routes to the Tripeptide Unit of Geodiamoude-A
CN112585116A (zh) (2s，3r，4r)-4，5-二羟基异亮氨酸及衍生物的合成
JPH04502908A (ja) アミノ酸のトリアルキルシリルエステルおよびペプチド合成におけるその使用
An et al. Solution-phase-peptide synthesis without purification of column chromatography and recrystallization by protecting amino acid esters with phosphinyl chloride
US20240368217A1 (en) Peptide compound production method and amidation agent
US20090163696A1 (en) Method for preparing lysobactin derivatives
CN107365352A (zh) 一种新型含9‑腺嘌呤丙氨酸的三肽化合物及其制备方法和应用
Reginato et al. A stereoselective approach to the synthesis of γ-silylated amino acids
CN1113067C (zh) 新活性肽及其制备
EP3792250A1 (fr) Synthèse d&#39;alpha-amanitine et de ses dérivés
Olma et al. An efficient synthesis of optically active 3-amino-3-alkyl-2-oxetanones
CN101445550B (zh) 焦谷酰胺基小肽的合成方法
CN113166057A (zh) (s)-6-羟基色氨酸及其衍生物的合成

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 18761672

Country of ref document: EP

Kind code of ref document: A1

ENP Entry into the national phase

Ref document number: 2019503031

Country of ref document: JP

Kind code of ref document: A

NENP Non-entry into the national phase

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 18761672

Country of ref document: EP

Kind code of ref document: A1

点击 这是indexloc提供的php浏览器服务，不要输入任何密码和下载