WO2013117568A1 - Verfahren zur stereoselektiven synthese von 1,4-geschützten 9-hydroxy-5-oxo-1,4-diaza-spiro [5.5] undecane - Google Patents

Verfahren zur stereoselektiven synthese von 1,4-geschützten 9-hydroxy-5-oxo-1,4-diaza-spiro [5.5] undecane Download PDF

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Publication number
WO2013117568A1
WO2013117568A1 PCT/EP2013/052287 EP2013052287W WO2013117568A1 WO 2013117568 A1 WO2013117568 A1 WO 2013117568A1 EP 2013052287 W EP2013052287 W EP 2013052287W WO 2013117568 A1 WO2013117568 A1 WO 2013117568A1
Authority
WO
WIPO (PCT)
Prior art keywords
formula
compound
tautomers
optionally
salts
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/EP2013/052287
Other languages
German (de)
English (en)
French (fr)
Inventor
Juergen Schnaubelt
Wenjun Tang
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.)
Boehringer Ingelheim International GmbH
Original Assignee
Boehringer Ingelheim International GmbH
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
Priority to JP2014556029A priority Critical patent/JP6105631B2/ja
Priority to EA201400882A priority patent/EA201400882A1/ru
Priority to EP13703045.8A priority patent/EP2812317B1/de
Priority to BR112014019196A priority patent/BR112014019196A8/pt
Priority to KR1020147021922A priority patent/KR20140128318A/ko
Priority to CA2862520A priority patent/CA2862520A1/en
Priority to MX2014009033A priority patent/MX2014009033A/es
Priority to AU2013218119A priority patent/AU2013218119A1/en
Application filed by Boehringer Ingelheim International GmbH filed Critical Boehringer Ingelheim International GmbH
Priority to CN201380006918.0A priority patent/CN104080775A/zh
Publication of WO2013117568A1 publication Critical patent/WO2013117568A1/de
Priority to IL233370A priority patent/IL233370A/en
Priority to PH12014501760A priority patent/PH12014501760A1/en
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D241/00—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings
    • C07D241/36—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings condensed with carbocyclic rings or ring systems
    • C07D241/38—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings condensed with carbocyclic rings or ring systems with only hydrogen or carbon atoms directly attached to the ring nitrogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
    • C07D491/10—Spiro-condensed systems
    • C07D491/113—Spiro-condensed systems with two or more oxygen atoms as ring hetero atoms in the oxygen-containing ring

Definitions

  • the invention relates to a process for the stereoselective preparation
  • Quinazoline derivatives are known in the art as drugs, for example, for the treatment of tumors as well as diseases of the lung and the respiratory tract. Processes for the preparation of quinazoline derivatives are described in WO03082290 and WO07068552. WO2009098061 and WO201 1015526 disclose processes for the preparation of the compound (I).
  • the present invention solves the above object via the synthesis method described below.
  • the invention relates to a process for the stereoselective preparation of
  • SGi is a protecting group selected from the group consisting of
  • Trifluoroacetyl Trifluoroacetyl, acetyl, benzoyl and pivaloyl
  • SG 2 is a protective group selected from the group consisting of tertiary
  • reaction steps (C) and (D) are preceded by further reaction steps (A) and (B)
  • Another object of the invention is an intermediate of formula (2), optionally in the form of its tautomers or salts.
  • SGi is a protecting group selected from the group consisting of
  • Trifluoroacetyl Trifluoroacetyl, acetyl, benzoyl and pivaloyl
  • Another object of the invention is an intermediate of formula (4), optionally in the form of its tautomers or salts.
  • SGi is a protecting group selected from the group consisting of
  • Trifluoroacetyl Trifluoroacetyl, acetyl, benzoyl and pivaloyl
  • SG 2 is a protective group selected from the group consisting of tertiary
  • an intermediate of the formula (4A) Preference is given to an intermediate of the formula (4A), if appropriate in the form of its tautomers or salts.
  • the invention further relates to the use of the intermediates of the formula (2) or (4), preferably the intermediates (2A) or (4A), optionally in the form of their tautomers or salts, for the preparation of a compound of the formula (I), optionally in Form of their tautomers or salts.
  • intermediates (2) or (4) preferably intermediates (2A) or (4A), for the preparation of a compound of formula (I) can be described via the preparation of the compound of formula (5) and the following in WO2012104206 Synthesis steps (G) to (L) take place.
  • alternative reagents, catalysts and solvents can preferably be selected from the group consisting of the reagents, catalysts and solvents listed in Table 1.1 to I.4: Table 1.1 Alternative solvents
  • Scheme 1 illustrates the synthesis of the invention. All compounds are shown in the form of their bases. Scheme 1 Synthesis of compound (5)
  • process step (A) the starting material (1) is protected on the amine nitrogen with the aid of 2.0 to 3.0 molar equivalents of reagent in the presence of 2.2 to 3.2 molar equivalents of base.
  • Process step (B) describes the aqueous acidic deprotection of the ketal (2) to the corresponding ketone (3) with the aid of 2.0 to 4.0 molar equivalents of acid.
  • step (C) the still free amide nitrogen is protected with 1, 0 to 1, 5 molar equivalents of reagent in the presence of 2 to 10 mole percent of catalyst.
  • step (D) the catalytic stereoselective reduction of the keto group with hydrogen leads to the cis-configured alcohol (5).
  • process step (A) the starting material (1) is protected on the amine nitrogen with the aid of 2.2 molar equivalents of trifluoroacetic anhydride (TFAA) in the presence of 2.4 molar equivalents of N-methylmorpholine (NMM) trifluoroacetyl.
  • Process step (B) describes the aqueous acidic deprotection of the ketal (2) to the corresponding ketone (3) with the aid of 2.8 molar equivalents of acetic acid (HOAC).
  • step (C) the still free amide nitrogen is protected with 1.2 equivalents di-tert-butyl dicarbonate in the presence of 5 mol percent dimethylaminopyridine as carbamate.
  • step (D) the catalytic stereoselective reduction of the keto group with hydrogen to the c / s-configured alcohol (5).
  • Methylcyclohexane added. After 60 minutes, the suspension is cooled to 0 ° C. After 25 minutes, the precipitate is filtered off and washed with 100 ml of water and 100 ml Methylcyclohexane washed successively. After drying at 50 ° C. in vacuo, 137.9 g of product are obtained.

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Nitrogen Condensed Heterocyclic Rings (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Plural Heterocyclic Compounds (AREA)
  • Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
PCT/EP2013/052287 2012-02-09 2013-02-06 Verfahren zur stereoselektiven synthese von 1,4-geschützten 9-hydroxy-5-oxo-1,4-diaza-spiro [5.5] undecane Ceased WO2013117568A1 (de)

Priority Applications (11)

Application Number Priority Date Filing Date Title
MX2014009033A MX2014009033A (es) 2012-02-09 2013-02-06 Metodo para la sintesis estereoselectiva de 9-hidroxi-5-oxo-1,4-di aza-espiro[5,5]undecanos 1,4-protegidos.
EP13703045.8A EP2812317B1 (de) 2012-02-09 2013-02-06 Verfahren zur stereoselektiven synthese von 1,4-geschützten 9-hydroxy-5-oxo-1,4-diaza-spiro [5.5]undecane
BR112014019196A BR112014019196A8 (pt) 2012-02-09 2013-02-06 Método para síntese estereosseletiva de 9-hidróxi-5-oxo-1,4-diaza-espiro[5.5]undecanos 1,4-protegidos
KR1020147021922A KR20140128318A (ko) 2012-02-09 2013-02-06 1,4-보호된 9-하이드록시-5-옥소-1,4-디아자-스피로 [5.5] 운데칸의 입체선택적 합성 방법
CA2862520A CA2862520A1 (en) 2012-02-09 2013-02-06 Method for stereoselective synthesis of 1,4-protected 9-hydroxy-5-oxo-1,4-diaza-spiro[5.5]undecanes
JP2014556029A JP6105631B2 (ja) 2012-02-09 2013-02-06 １，４−保護９−ヒドロキシ−５−オキソ−１，４−ジアザ−スピロ［５．５］ウンデカンの立体選択的合成方法
EA201400882A EA201400882A1 (ru) 2012-02-09 2013-02-06 Способ стереоселективного синтеза 9-гидрокси-5-оксо-1,4-диазаспиро[5.5]ундеканов, содержащих защитные группы в 1,4-положениях
AU2013218119A AU2013218119A1 (en) 2012-02-09 2013-02-06 Method for stereoselective synthesis of 1,4-protected 9-hydroxy-5-oxo-1,4-diaza-spiro [5.5] undecanes
CN201380006918.0A CN104080775A (zh) 2012-02-09 2013-02-06 立体选择性合成1,4-保护的9-羟基-5-氧代-1,4-二氮杂-螺[5.5]十一烷的方法
IL233370A IL233370A (en) 2012-02-09 2014-06-25 Method for Stereoselective Synthesis of 9-Hydroxy-5-Oxo-4,1-Diaz-Spiro [5.5] Endanes Protected in Positions 1 and 4
PH12014501760A PH12014501760A1 (en) 2012-02-09 2014-08-05 Method for stereoselective synthesis of 1,4-protected 9-hydroxy-5-oxo-1,4-diaza-spiro[5.5]undecanes

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
EP12154688 2012-02-09
EP12154688.1 2012-02-09

Publications (1)

Publication Number Publication Date
WO2013117568A1 true WO2013117568A1 (de) 2013-08-15

Family

ID=47678813

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/EP2013/052287 Ceased WO2013117568A1 (de) 2012-02-09 2013-02-06 Verfahren zur stereoselektiven synthese von 1,4-geschützten 9-hydroxy-5-oxo-1,4-diaza-spiro [5.5] undecane

Country Status (14)

Country Link
US (1) US8629146B2 (https=)
EP (1) EP2812317B1 (https=)
JP (1) JP6105631B2 (https=)
KR (1) KR20140128318A (https=)
CN (1) CN104080775A (https=)
AU (1) AU2013218119A1 (https=)
BR (1) BR112014019196A8 (https=)
CA (1) CA2862520A1 (https=)
CL (1) CL2014001823A1 (https=)
EA (1) EA201400882A1 (https=)
IL (1) IL233370A (https=)
MX (1) MX2014009033A (https=)
PH (1) PH12014501760A1 (https=)
WO (1) WO2013117568A1 (https=)

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP2289881A1 (de) * 2009-08-06 2011-03-02 Boehringer Ingelheim International GmbH Verfahren zur stereoselektiven Synthese bicyclischer Heterocyclen

Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2003082290A1 (de) 2002-03-30 2003-10-09 Boehringer Ingelheim Pharma Gmbh & Co. Kg 4- ( n-phenylamino ) -chinazoline/chinoline als tyrosinkinaseinhibitoren
WO2007068552A1 (de) 2005-12-12 2007-06-21 Boehringer Ingelheim International Gmbh Bicyclische heterocyclen, diese verbindungen enthaltende arzneimittel, deren verwendung und verfahren zu ihrer herstellung
WO2009098061A1 (de) 2008-02-07 2009-08-13 Boehringer Ingelheim International Gmbh Spirocyclische heterocyclen, diese verbindungen enthaltende arzneimittel, deren verwendung und verfahren zu ihrer herstellung
WO2011015526A1 (de) 2009-08-06 2011-02-10 Boehringer Ingelheim International Gmbh Verfahren zur stereoselektiven synthese bicyclischer heterocyclen
WO2012104206A1 (de) 2011-02-01 2012-08-09 Boehringer Ingelheim International Gmbh 9-[4-(3-chlor-2-fluor-phenylamino)-7-methoxy-chinazolin-6- yloxy]-1,4-diaza-spiro[5.5]undecan-5-on dimaleat, dessen verwendung als arzneimittel und dessen herstellung

Family Cites Families (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4575507A (en) * 1985-05-29 1986-03-11 Pfizer Inc. Spiro-imidazolidines as aldose reductase inhibitors and their pharmaceutical use
US6924285B2 (en) 2002-03-30 2005-08-02 Boehringer Ingelheim Pharma Gmbh & Co. Bicyclic heterocyclic compounds, pharmaceutical compositions containing these compounds, their use and process for preparing them

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2003082290A1 (de) 2002-03-30 2003-10-09 Boehringer Ingelheim Pharma Gmbh & Co. Kg 4- ( n-phenylamino ) -chinazoline/chinoline als tyrosinkinaseinhibitoren
WO2007068552A1 (de) 2005-12-12 2007-06-21 Boehringer Ingelheim International Gmbh Bicyclische heterocyclen, diese verbindungen enthaltende arzneimittel, deren verwendung und verfahren zu ihrer herstellung
WO2009098061A1 (de) 2008-02-07 2009-08-13 Boehringer Ingelheim International Gmbh Spirocyclische heterocyclen, diese verbindungen enthaltende arzneimittel, deren verwendung und verfahren zu ihrer herstellung
WO2011015526A1 (de) 2009-08-06 2011-02-10 Boehringer Ingelheim International Gmbh Verfahren zur stereoselektiven synthese bicyclischer heterocyclen
WO2012104206A1 (de) 2011-02-01 2012-08-09 Boehringer Ingelheim International Gmbh 9-[4-(3-chlor-2-fluor-phenylamino)-7-methoxy-chinazolin-6- yloxy]-1,4-diaza-spiro[5.5]undecan-5-on dimaleat, dessen verwendung als arzneimittel und dessen herstellung

Also Published As

Publication number Publication date
CA2862520A1 (en) 2013-08-15
EP2812317B1 (de) 2016-02-03
JP2015506966A (ja) 2015-03-05
PH12014501760B1 (en) 2014-11-10
CL2014001823A1 (es) 2015-03-06
MX2014009033A (es) 2014-10-17
CN104080775A (zh) 2014-10-01
EA201400882A1 (ru) 2015-01-30
US8629146B2 (en) 2014-01-14
PH12014501760A1 (en) 2014-11-10
EP2812317A1 (de) 2014-12-17
IL233370A (en) 2015-04-30
KR20140128318A (ko) 2014-11-05
AU2013218119A1 (en) 2014-07-17
US20130211081A1 (en) 2013-08-15
BR112014019196A8 (pt) 2017-07-11
JP6105631B2 (ja) 2017-03-29
BR112014019196A2 (https=) 2017-06-20
IL233370A0 (en) 2014-08-31

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