[go: up one dir, main page]

WO2018003867A1 - Procédé de production de n- (3, 5-dichloropyrid-4-yl)-n-méthyle-3-cyclopropylméthoxy-4-difluorométhoxybenzamide - Google Patents

Procédé de production de n- (3, 5-dichloropyrid-4-yl)-n-méthyle-3-cyclopropylméthoxy-4-difluorométhoxybenzamide Download PDF

Info

Publication number
WO2018003867A1
WO2018003867A1 PCT/JP2017/023772 JP2017023772W WO2018003867A1 WO 2018003867 A1 WO2018003867 A1 WO 2018003867A1 JP 2017023772 W JP2017023772 W JP 2017023772W WO 2018003867 A1 WO2018003867 A1 WO 2018003867A1
Authority
WO
WIPO (PCT)
Prior art keywords
alkali metal
compound
cyclopropylmethoxy
formula
added
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.)
Ceased
Application number
PCT/JP2017/023772
Other languages
English (en)
Japanese (ja)
Inventor
高田　恭憲
智史 天野
健治 新
崇 安河内
睦 園部
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Hisamitsu Pharmaceutical Co Inc
Original Assignee
Hisamitsu Pharmaceutical Co Inc
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 Hisamitsu Pharmaceutical Co Inc filed Critical Hisamitsu Pharmaceutical Co Inc
Priority to JP2018525221A priority Critical patent/JP6727302B2/ja
Publication of WO2018003867A1 publication Critical patent/WO2018003867A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/72—Nitrogen atoms
    • C07D213/75—Amino or imino radicals, acylated by carboxylic or carbonic acids, or by sulfur or nitrogen analogues thereof, e.g. carbamates
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A61P11/02—Nasal agents, e.g. decongestants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/02—Ophthalmic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/08—Antiallergic agents

Definitions

  • the present invention relates to a process for producing N- (3,5-dichloropyrid-4-yl) -N-methyl-3-cyclopropylmethoxy-4-difluoromethoxybenzamide.
  • Phosphodiesterase (PDE) inhibitors are known to be effective for treating inflammatory diseases.
  • PDE4 inhibitors include N- (3,5-dichloropyrid-4-yl) -3-cyclopropylmethoxy-4-difluoromethoxybenzamide (also called roflumilast).
  • Patent Documents 1 to 3 are known as methods for producing roflumilast.
  • Non-Patent Document 1 discloses that N- (3,5-dichloropyrid-4-yl) -N-methyl-3-cyclopropylmethoxy-4-difluoromethoxybenzamide was produced, but Roflumilast Only Patent Document 3 and Non-Patent Document 2 that disclose the production method are cited, and specific methods, yields, and the like are not described (see Patent Document 3, Non-Patent Documents 1 and 2).
  • an object of the present invention is to provide a compound represented by formula (I) (N- (3,5-dichloropyrid-4-yl) -N-methyl-3-cyclopropylmethoxy-4-difluoromethoxybenzamide, “compound (I) is also provided in a high yield and high purity.
  • the present inventors have found a method for producing compound (I), which includes a step of obtaining compound (I) by reacting compound (II) with alkali metal salt (III).
  • X represents a halogen atom or a C 1-4 alkylcarbonyloxy group
  • M represents an alkali metal ion.
  • the method preferably includes reacting compound (IV) with an alkali metal hydride or alkali metal alkoxide to obtain an alkali metal salt (III).
  • a preferred alkali metal is sodium.
  • a new method for producing compound (I) can be provided. Moreover, according to the method of the present invention, compound (I) can be obtained in high yield and high purity.
  • One embodiment of the present invention is a method for producing compound (I), comprising the step of obtaining compound (I) by reacting compound (II) with alkali metal salt (III).
  • X represents a halogen atom or a C 1-4 alkylcarbonyloxy group
  • M represents an alkali metal ion.
  • This embodiment includes a step (step A) of reacting compound (II) with alkali metal salt (III) to obtain compound (I).
  • step A represents a halogen atom or a C 1-4 alkylcarbonyloxy group
  • M represents an alkali metal ion.
  • Compound (II) is a compound in which the carboxyl group of 3-cyclopropylmethoxy-4-difluoromethoxybenzoic acid is more activated, and X in formula (II) represents a halogen atom or a C 1-6 alkylcarbonyloxy group. Show.
  • halogen atom examples include a fluorine atom, a chlorine atom and a bromine atom, and a preferred halogen atom is a chlorine atom.
  • the C 1-6 alkylcarbonyloxy group is a group in which a carbonyloxy group is bonded to an alkyl group having 1 to 6 carbon atoms.
  • Examples of the C 1-6 alkylcarbonyloxy group include acetyl group, propionyl group, butyryl group, 2-methylpropionyl group, pentanoyl group, 2-methylbutyryl group, 3-methylbutyryl group, pivaloyl group, hexanoyl group, 2-methyl Examples include a pentanoyl group, a 3-methylpentanoyl group, and a 4-methylpentanoyl group.
  • the alkali metal salt (III) is a salt composed of an anion obtained by deprotonation of the amine nitrogen of the compound (IV) and an alkali metal ion.
  • alkali metal examples include lithium, sodium and potassium.
  • the preferred alkali metal is sodium.
  • the number of moles of the alkali metal salt (III) used is preferably 1 to 10 times, and more preferably 1 to 3 times, based on the number of moles of the compound (II).
  • Process A is usually performed in a solvent.
  • the solvent should just be what does not inhibit reaction of the process A.
  • Examples of the solvent include dichloromethane, toluene, xylene, tetrahydrofuran, dimethylformamide, and N-methylpyrrolidone.
  • a preferred solvent is toluene or tetrahydrofuran.
  • alkali metal salt (III) or a solution thereof may be added to compound (II) or a solution thereof, and compound (II) or a solution thereof is added to alkali metal salt (III) or a solution thereof. May be.
  • Compound (II) or a solution thereof is preferably added to alkali metal salt (III) or a solution thereof.
  • the reaction temperature in step A is usually between 0 ° C. and the boiling point of the solvent used.
  • a preferable reaction temperature is 0 to 100 ° C., and a more preferable reaction temperature is 5 to 35 ° C.
  • the obtained compound (I) can be purified by a method that can be used by those skilled in the art in the field of organic chemistry.
  • This embodiment may further comprise preparing compound (II) from 3-cyclopropylmethoxy-4-difluoromethoxybenzoic acid (step B).
  • X represents a halogen atom or a C 1-4 alkylcarbonyloxy group.
  • Step B is a step for preparing compound (II) by adding an activator to a solution containing, for example, 3-cyclopropylmethoxy-4-difluoromethoxybenzoic acid and an organic solvent.
  • the activator is a reagent that activates the carboxyl group of 3-cyclopropylmethoxy-4-difluoromethoxybenzoic acid.
  • Examples of the activator include thionyl chloride, oxalyl chloride, and pivaloyl chloride.
  • X in formula (II) is a chlorine atom
  • X in formula (II) is a pivaloyloxy group.
  • the amount of the activator is preferably 1 to 10 times, and more preferably 1 to 3 times, based on the number of moles of 3-cyclopropylmethoxy-4-difluoromethoxybenzoic acid.
  • N, N-dimethylformamide is used to promote the reaction between 3-cyclopropylmethoxy-4-difluoromethoxybenzoic acid and the activator. It may be added.
  • the amount of DMF used may be 1 to 5% by weight or 1 to 3% by weight based on the weight of thionyl chloride.
  • the organic solvent may be any one that does not inhibit the reaction in the step B.
  • examples of the organic solvent include tetrahydrofuran, toluene, and xylene.
  • a preferred organic solvent is toluene.
  • the reaction temperature in Step B is usually 0 to 100 ° C., preferably 30 to 60 ° C.
  • the following method is used.
  • a catalytic amount of DMF is added, heated to 40-50 ° C., and then thionyl chloride is slowly added.
  • the resulting reaction mixture was stirred at 40-50 ° C., and after a specified time, the reaction mixture was concentrated under reduced pressure to give 3-cyclopropylmethoxy-4-difluoromethoxybenzoyl. Get the chloride.
  • the resulting 3-cyclopropylmethoxy-4-difluoromethoxybenzoyl chloride can be subjected to the next reaction without further purification.
  • the present embodiment may further include a step (step C) of preparing the alkali metal salt (III) by reacting the compound (IV) with an alkali metal hydride or an alkali metal alkoxide.
  • step C of preparing the alkali metal salt (III) by reacting the compound (IV) with an alkali metal hydride or an alkali metal alkoxide.
  • M represents an alkali metal ion.
  • alkali metal hydride examples include sodium hydride and potassium hydride.
  • the number of moles of alkali metal hydride is preferably 1 to 10 times greater, more preferably 1 to 3 times greater, based on the number of moles of compound (IV).
  • alkali metal alkoxide examples include sodium methoxide, sodium ethoxide, sodium propoxide, sodium n-butoxide, sodium t-butoxide, potassium methoxide, potassium ethoxide, potassium propoxide, potassium n-butoxide and potassium t- Butoxide is mentioned.
  • a preferred alkali metal alkoxide is sodium t-butoxide.
  • the number of moles of alkali metal alkoxide is preferably 1 to 10 times greater, more preferably 1 to 3 times greater, based on the number of moles of compound (IV).
  • Step C is preferably performed in a solvent.
  • Any solvent may be used as long as it does not inhibit the reaction in Step C, and examples thereof include tetrahydrofuran.
  • the reaction temperature in step C is preferably 0 to 45 ° C.
  • Step C for example, sodium hydride is added little by little at a temperature of 10 to 25 ° C. with stirring to a tetrahydrofuran solution of Compound (IV).
  • deprotonation of compound (IV) can proceed under mild conditions, and a salt of compound (IV) and sodium ion can be prepared.
  • Compound (IV) can be prepared from 4-cyano-3,5-dichloropyridine by the method described in Non-Patent Document 3, for example.
  • This embodiment may further comprise preparing compound (IV) by reacting readily available 4-amino-3,5-dichloropyridine with a methylating agent in the presence of a base (step D). Good.
  • Examples of the base include alkali metal hydrides and alkali metal alkoxides. Specific examples of the base include sodium hydride, potassium hydride, sodium methoxide, sodium ethoxide, sodium propoxide, sodium n-butoxide, sodium t-butoxide, potassium methoxide, potassium ethoxide, potassium propoxide, potassium n-butoxide, potassium t-butoxide and the like.
  • a preferred base is sodium hydride or potassium t-butoxide.
  • the number of moles of the base is preferably 1 to 10 times greater, more preferably 1 to 3 times greater, based on the number of moles of 4-amino-3,5-dichloropyridine.
  • methylating agent examples include halogenated methane such as iodomethane and bromomethane, and dimethyl sulfate. Preferred methylating agents are iodomethane or dimethyl sulfate.
  • the number of moles of the methylating agent is preferably 1 to 10 times, and more preferably 1 to 3 times, based on the number of moles of 4-amino-3,5-dichloropyridine.
  • Step D is preferably performed in an organic solvent.
  • the organic solvent should just be what does not inhibit a monomethylation reaction.
  • examples of the organic solvent include tetrahydrofuran, dimethylformamide, dimethyl sulfoxide, and N-methylpyrrolidone.
  • a preferred organic solvent is tetrahydrofuran.
  • step D is, for example, the following methods. 4-Amino-3,5-dichloropyridine is dissolved in tetrahydrofuran, potassium t-butoxide is slowly added with stirring, further iodomethane is added, and the resulting reaction mixture is stirred at 5-15 ° C. for 2 hours. Water and isopropyl acetate are added to the reaction mixture and stirred, and then the organic layer is separated. The organic layer is washed successively with water and saturated brine, and the organic layer is concentrated.
  • Compound (I) is excellent in water solubility and transdermal absorbability, and is rapidly converted into roflumilast in vivo.
  • Compound (I) can exert effects that can be expected by administration of roflumilast. That is, by administering the compound or a pharmaceutical composition containing the compound, acute and chronic (especially performance and allergen-induced) airway diseases (eg, bronchitis, allergic bronchitis, bronchial asthma, Emphysema, chronic obstructive pulmonary disease (COPD), proliferative, inflammatory or allergic skin diseases (eg psoriasis (eg psoriasis vulgaris), toxic and allergic contact dermatitis, atopic dermatitis, Seborrheic dermatitis, lichen planus, sunburn, pruritus in the genital area, alopecia, hypertrophic scar, discoid lupus erythematosus, follicular and pervasive pyoderma, intrinsic and extrinsic acne, Tadpole So and other proliferative, inflammatory and allergic skin diseases), diseases based on excessive release of TNF
  • the obtained solid was suspended in 22.4 g of an aqueous sodium hydroxide solution having a pH of 10 and stirred for 30 minutes.
  • the obtained solid was collected by filtration, washed with water, and dried under reduced pressure to give 3.54 g (yield 62%, purity 99.4%) of crude crystals of the title compound.
  • the obtained crude crystals (3.00 g) were recrystallized from hydrous isopropyl alcohol to obtain 2.14 g (recovery: 71%, purity: 99.8%) of the title compound.

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pyridine Compounds (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

La présente invention concerne un procédé de production d'un composé représenté par la formule (I), qui comprend une étape d'obtention d'un composé représenté par la formule (I) par la réaction d'un composé représenté par la formule (II) et un sel de métal alcalin représenté par la formule (III) l'un avec l'autre. (Dans les formules, X représente un atome d'halogène ou un groupe alkyle carbonyloxy C 1-4 ; et M représente un ion de métal alcalin.)
PCT/JP2017/023772 2016-07-01 2017-06-28 Procédé de production de n- (3, 5-dichloropyrid-4-yl)-n-méthyle-3-cyclopropylméthoxy-4-difluorométhoxybenzamide Ceased WO2018003867A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
JP2018525221A JP6727302B2 (ja) 2016-07-01 2017-06-28 Ｎ−（３，５−ジクロロピリド−４−イル）−ｎ−メチル−３−シクロプロピルメトキシ−４−ジフルオロメトキシベンズアミドの製造方法

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
JP2016131650 2016-07-01
JP2016-131650 2016-07-01

Publications (1)

Publication Number Publication Date
WO2018003867A1 true WO2018003867A1 (fr) 2018-01-04

Family

ID=60786396

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/JP2017/023772 Ceased WO2018003867A1 (fr) 2016-07-01 2017-06-28 Procédé de production de n- (3, 5-dichloropyrid-4-yl)-n-méthyle-3-cyclopropylméthoxy-4-difluorométhoxybenzamide

Country Status (3)

Country Link
JP (1) JP6727302B2 (fr)
TW (1) TW201803852A (fr)
WO (1) WO2018003867A1 (fr)

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2006519818A (ja) * 2003-03-10 2006-08-31 アルタナ　ファルマ　アクチエンゲゼルシャフト ロフルミラストの新規の製造方法
CN103497150A (zh) * 2013-10-12 2014-01-08 国药集团致君（苏州）制药有限公司 一种高纯度罗氟司特的精制方法
WO2016063906A1 (fr) * 2014-10-24 2016-04-28 久光製薬株式会社 Promédicament

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2006519818A (ja) * 2003-03-10 2006-08-31 アルタナ　ファルマ　アクチエンゲゼルシャフト ロフルミラストの新規の製造方法
CN103497150A (zh) * 2013-10-12 2014-01-08 国药集团致君（苏州）制药有限公司 一种高纯度罗氟司特的精制方法
WO2016063906A1 (fr) * 2014-10-24 2016-04-28 久光製薬株式会社 Promédicament

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
XIANG, Z-J. ET AL.: "Synthesis and polymorphic study of roflumilast N-oxide", JOURNAL OF CHINA PHARMACEUTICAL UNIVERSITY, vol. 43, no. 6, 2012, pages 492 - 496 *

Also Published As

Publication number Publication date
JP6727302B2 (ja) 2020-07-22
JPWO2018003867A1 (ja) 2019-01-17
TW201803852A (zh) 2018-02-01

Similar Documents

Publication Publication Date Title
CN102276538B (zh) 嘧菌酯及其关键中间体的制备方法
WO2012147098A2 (fr) Nouveau procédé de préparation de 3-(cyclopropylméthoxy)-n-(3,5-dichloropyridin-4-yl)-4-(difluorométhoxy) benzamide
CN103044263A (zh) 一种治疗囊性纤维化药物的中间体的制备方法
US9688657B2 (en) Synthesis of dabigatran
CA2886973C (fr) Procedes de synthese de 2-amino-4,6-dimethoxybenzamide et d'autres composes de benzamide
JP6727302B2 (ja) Ｎ−（３，５−ジクロロピリド−４−イル）−ｎ−メチル−３−シクロプロピルメトキシ−４−ジフルオロメトキシベンズアミドの製造方法
CN103508965B (zh) 一种二苯西平类衍生物的合成方法
US9745264B2 (en) Method for preparing silodosin and intermediate thereof
JP7453365B2 (ja) 高純度のｎ－（５－メトキシ―２－フェノキシフェニル）メタンスルホンアミド及びその製造方法
JPWO2009028608A1 (ja) オルト位がヨウ素置換されたフェノール誘導体の製造方法
JP2009035513A (ja) ４−ｎ−（メチルベンゾイル）アミノ−２−メチル安息香酸の製法
EP2562151A1 (fr) Procédés de préparation dýagomélatine et ses intermédiaires
JP5478508B2 (ja) ｔｒａｎｓ−｛４−［（アルキルアミノ）メチル］シクロヘキシル｝酢酸エステルの製造方法
CN107698501A (zh) 5,6‑二甲基‑2‑羟基烟酸的制备工艺
JP4356111B2 (ja) Ｎ−（２−アミノ−１，２−ジシアノビニル）ホルムアミジンの製造方法
JP2013221025A (ja) ビフェニルアセトアミド誘導体の製造方法及びその中間体
JP4675234B2 (ja) 光学活性なキノロンカルボン酸誘導体の製造中間体およびその製造法
CA2930089C (fr) Procede de preparation du chlorhydrate de fingolimod
WO2015012271A1 (fr) Procédé de production d'un composé hétérocyclique
WO2018028665A1 (fr) Procédé de préparation d'un intermédiaire d'un composé de 6-arylaminopyridonecarboxamide en tant qu'inhibiteur de mek
CN103415514B (zh) 用于生产苯氧基吡啶衍生物的方法
JPS62187467A (ja) ４−アセチルイソキノリノン化合物の新規製造法
CN110105354A (zh) 一种制备丁苯那嗪的方法
CN108368050A (zh) 制备巴豆酰基氨基吡啶的改进方法
JP2007230906A (ja) Ｎ，ｎ−ジメチルカルバモイルメチル４‐ヒドロキシフェニルアセテートの製造法

Legal Events

Date Code Title Description
WWE Wipo information: entry into national phase

Ref document number: 2018525221

Country of ref document: JP

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

Ref document number: 17820221

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 17820221

Country of ref document: EP

Kind code of ref document: A1