KR101236669B1 - 알킬-치환된 2-데옥시-2-플루오로-ｄ-리보퓨라노실피리미딘 및 퓨린 및 그 유도체의 제조 - Google Patents

알킬-치환된 2-데옥시-2-플루오로-ｄ-리보퓨라노실피리미딘 및 퓨린 및 그 유도체의 제조 Download PDF

Info

Publication number
KR101236669B1
KR101236669B1 KR1020077003980A KR20077003980A KR101236669B1 KR 101236669 B1 KR101236669 B1 KR 101236669B1 KR 1020077003980 A KR1020077003980 A KR 1020077003980A KR 20077003980 A KR20077003980 A KR 20077003980A KR 101236669 B1 KR101236669 B1 KR 101236669B1
Authority
KR
South Korea
Prior art keywords
alkyl
formula
trityl
independently
benzyl
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.)
Expired - Lifetime
Application number
KR1020077003980A
Other languages
English (en)
Korean (ko)
Other versions
KR20070114344A (ko
Inventor
페이유안 왕
우즈시에취 스텍
천병권
중싱 쉬
진파 두
Original Assignee
길리어드 파마셋 엘엘씨
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 길리어드 파마셋 엘엘씨 filed Critical 길리어드 파마셋 엘엘씨
Publication of KR20070114344A publication Critical patent/KR20070114344A/ko
Application granted granted Critical
Publication of KR101236669B1 publication Critical patent/KR101236669B1/ko
Anticipated expiration legal-status Critical
Expired - Lifetime legal-status Critical Current

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H19/00—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H19/00—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof
    • C07H19/02—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof sharing nitrogen
    • C07H19/04—Heterocyclic radicals containing only nitrogen atoms as ring hetero atom
    • C07H19/16—Purine radicals
    • C07H19/173—Purine radicals with 2-deoxyribosyl as the saccharide radical
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A61P31/14—Antivirals for RNA viruses
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H19/00—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof
    • C07H19/02—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof sharing nitrogen
    • C07H19/04—Heterocyclic radicals containing only nitrogen atoms as ring hetero atom
    • C07H19/06—Pyrimidine radicals
    • C07H19/073—Pyrimidine radicals with 2-deoxyribosyl as the saccharide radical
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H21/00—Compounds containing two or more mononucleotide units having separate phosphate or polyphosphate groups linked by saccharide radicals of nucleoside groups, e.g. nucleic acids
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H5/00—Compounds containing saccharide radicals in which the hetero bonds to oxygen have been replaced by the same number of hetero bonds to halogen, nitrogen, sulfur, selenium, or tellurium
    • C07H5/04—Compounds containing saccharide radicals in which the hetero bonds to oxygen have been replaced by the same number of hetero bonds to halogen, nitrogen, sulfur, selenium, or tellurium to nitrogen
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H5/00—Compounds containing saccharide radicals in which the hetero bonds to oxygen have been replaced by the same number of hetero bonds to halogen, nitrogen, sulfur, selenium, or tellurium
    • C07H5/04—Compounds containing saccharide radicals in which the hetero bonds to oxygen have been replaced by the same number of hetero bonds to halogen, nitrogen, sulfur, selenium, or tellurium to nitrogen
    • C07H5/06—Aminosugars
    • 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

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Molecular Biology (AREA)
  • Biochemistry (AREA)
  • General Health & Medical Sciences (AREA)
  • Genetics & Genomics (AREA)
  • Biotechnology (AREA)
  • Engineering & Computer Science (AREA)
  • Virology (AREA)
  • Medicinal Chemistry (AREA)
  • Communicable Diseases (AREA)
  • Animal Behavior & Ethology (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • General Chemical & Material Sciences (AREA)
  • Oncology (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Saccharide Compounds (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
KR1020077003980A 2004-07-21 2005-07-21 알킬-치환된 2-데옥시-2-플루오로-ｄ-리보퓨라노실피리미딘 및 퓨린 및 그 유도체의 제조 Expired - Lifetime KR101236669B1 (ko)

Applications Claiming Priority (5)

Application Number Priority Date Filing Date Title
US58986604P 2004-07-21 2004-07-21
US60/589,866 2004-07-21
US60823004P 2004-09-09 2004-09-09
US60/608,320 2004-09-09
PCT/US2005/025916 WO2006012440A2 (en) 2004-07-21 2005-07-21 Preparation of alkyl-substituted 2-deoxy-2-fluoro-d-ribofuranosyl pyrimidines and purines and their derivatives

Related Child Applications (1)

Application Number Title Priority Date Filing Date
KR1020117006244A Division KR101235548B1 (ko) 2004-07-21 2005-07-21 2'-데옥시-2'-플루오로-2'-Ｃ-메틸-β-Ｄ-리보퓨라노실 뉴클레오사이드의 제조 방법

Publications (2)

Publication Number Publication Date
KR20070114344A KR20070114344A (ko) 2007-12-03
KR101236669B1 true KR101236669B1 (ko) 2013-02-22

Family

ID=35786706

Family Applications (2)

Application Number Title Priority Date Filing Date
KR1020117006244A Expired - Lifetime KR101235548B1 (ko) 2004-07-21 2005-07-21 2'-데옥시-2'-플루오로-2'-Ｃ-메틸-β-Ｄ-리보퓨라노실 뉴클레오사이드의 제조 방법
KR1020077003980A Expired - Lifetime KR101236669B1 (ko) 2004-07-21 2005-07-21 알킬-치환된 2-데옥시-2-플루오로-ｄ-리보퓨라노실피리미딘 및 퓨린 및 그 유도체의 제조

Family Applications Before (1)

Application Number Title Priority Date Filing Date
KR1020117006244A Expired - Lifetime KR101235548B1 (ko) 2004-07-21 2005-07-21 2'-데옥시-2'-플루오로-2'-Ｃ-메틸-β-Ｄ-리보퓨라노실 뉴클레오사이드의 제조 방법

Country Status (16)

Country Link
EP (2) EP2348029A1 (enExample)
JP (2) JP5078612B2 (enExample)
KR (2) KR101235548B1 (enExample)
CN (1) CN102199181B (enExample)
AT (1) ATE543789T1 (enExample)
AU (2) AU2005267051B2 (enExample)
CA (2) CA2574651C (enExample)
DK (1) DK1773856T3 (enExample)
ES (1) ES2386005T3 (enExample)
IL (2) IL180832A (enExample)
MX (1) MX2007000803A (enExample)
NZ (1) NZ552927A (enExample)
PL (1) PL1773856T3 (enExample)
PT (1) PT1773856E (enExample)
RU (1) RU2407747C2 (enExample)
WO (1) WO2006012440A2 (enExample)

Families Citing this family (41)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
MY164523A (en) 2000-05-23 2017-12-29 Univ Degli Studi Cagliari Methods and compositions for treating hepatitis c virus
YU92202A (sh) 2000-05-26 2006-01-16 Idenix (Cayman) Limited Metode i smeše za lečenje flavi virusa i pesti virusa
AU2003248748A1 (en) 2002-06-28 2004-01-19 Idenix (Cayman) Limited 2'-c-methyl-3'-o-l-valine ester ribofuranosyl cytidine for treatment of flaviviridae infections
US7608600B2 (en) 2002-06-28 2009-10-27 Idenix Pharmaceuticals, Inc. Modified 2′ and 3′-nucleoside prodrugs for treating Flaviviridae infections
NZ537662A (en) 2002-06-28 2007-10-26 Idenix Cayman Ltd 2'-C-methyl-3'-O-L-valine ester ribofuranosyl cytidine for treatment of flaviviridae infections
PT1576138T (pt) 2002-11-15 2017-05-03 Idenix Pharmaceuticals Llc 2'-metil-nucleósidos em combinação com interferão e mutação de flaviviridae
RU2005121904A (ru) 2002-12-12 2006-01-20 Айденикс (Кайман) Лимитед (Ky) Способ получения 2`-разветвленных нуклеозидов
SI2604620T2 (sl) 2003-05-30 2024-10-30 Gilead Pharmasset Llc Modificirani fluorirani nukleozidni analogi
CN101023094B (zh) 2004-07-21 2011-05-18 法莫赛特股份有限公司 烷基取代的2-脱氧-2-氟代-d-呋喃核糖基嘧啶和嘌呤及其衍生物的制备
US8492539B2 (en) 2004-09-14 2013-07-23 Gilead Pharmasset Llc Preparation of 2′-fluoro-2′-alkyl-substituted or other optionally substituted ribofuranosyl pyrimidines and purines and their derivatives
WO2008045419A1 (en) * 2006-10-10 2008-04-17 Pharmasset, Inc. Preparation of nucleosides ribofuranosyl pyrimidines
EP2094679B1 (en) * 2006-12-18 2012-01-25 F. Hoffmann-La Roche AG Process for preparing 3,5-di-omicron-acyl-2-fluoro-2-c-methyl-d-ribono-gamma-lactone
US20080261913A1 (en) 2006-12-28 2008-10-23 Idenix Pharmaceuticals, Inc. Compounds and pharmaceutical compositions for the treatment of liver disorders
WO2008090046A1 (en) * 2007-01-23 2008-07-31 F. Hoffmann-La Roche Ag Alternate process for preparing 3,5-di-omicron-acyl-2-fluoro-2-c-methyl-d-ribono-gamma-lactone
US7964580B2 (en) 2007-03-30 2011-06-21 Pharmasset, Inc. Nucleoside phosphoramidate prodrugs
US8551973B2 (en) 2008-12-23 2013-10-08 Gilead Pharmasset Llc Nucleoside analogs
US8716263B2 (en) * 2008-12-23 2014-05-06 Gilead Pharmasset Llc Synthesis of purine nucleosides
PA8855601A1 (es) 2008-12-23 2010-07-27 Forformidatos de nucleósidos
TWI598358B (zh) 2009-05-20 2017-09-11 基利法瑪席特有限責任公司 核苷磷醯胺
US8618076B2 (en) 2009-05-20 2013-12-31 Gilead Pharmasset Llc Nucleoside phosphoramidates
WO2011123668A2 (en) 2010-03-31 2011-10-06 Pharmasset, Inc. Stereoselective synthesis of phosphorus containing actives
JP5716500B2 (ja) 2010-06-03 2015-05-13 セントラル硝子株式会社 （２Ｒ）−２−フルオロ−２−Ｃ−メチル−Ｄ−リボノ−γ−ラクトン類前駆体の製造方法
EP2646453A1 (en) 2010-11-30 2013-10-09 Gilead Pharmasset LLC Compounds
EP2691409B1 (en) 2011-03-31 2018-02-21 Idenix Pharmaceuticals LLC. Compounds and pharmaceutical compositions for the treatment of viral infections
AU2012242517B2 (en) 2011-04-13 2016-12-15 Gilead Sciences, Inc. 1'-substituted pyrimidine N-nucleoside analogs for antiviral treatment
SMT201800087T1 (it) 2011-09-16 2018-03-08 Gilead Pharmasset Llc Metodi per trattare hcv
US8889159B2 (en) 2011-11-29 2014-11-18 Gilead Pharmasset Llc Compositions and methods for treating hepatitis C virus
EA029081B9 (ru) 2013-01-31 2018-09-28 Джилид Фармассет Ллс Комбинированный состав двух противовирусных соединений
WO2014132975A1 (ja) * 2013-02-28 2014-09-04 セントラル硝子株式会社 （２Ｒ）－２－フルオロ－２－Ｃ－メチル－Ｄ－リボノ－γ－ラクトンの製造方法
JP6476591B2 (ja) * 2013-06-05 2019-03-06 セントラル硝子株式会社 （２Ｒ）−２−フルオロ−２−Ｃ−メチル−Ｄ−リボノ−γ−ラクトン類の製造方法
PL3038601T3 (pl) 2013-08-27 2020-08-24 Gilead Pharmasset Llc Formulacja złożona dwóch związków przeciwwirusowych
US10100075B2 (en) * 2013-12-23 2018-10-16 Mylan Laboratories Limited Process for the preparation of sofosbuvir
WO2016035006A1 (en) * 2014-09-01 2016-03-10 Dr. Reddy’S Laboratories Limited Novel nucleotide analogs, process for the preparation of sofosbuvir and its analogs, novel forms of sofosbuvir and solid dispersion of sofosbuvir
WO2016042576A1 (en) 2014-09-16 2016-03-24 Cadila Healthcare Limited Co-crystal of sofosbuvir and amino acid and process for preparation thereof
CN104327138B (zh) * 2014-10-21 2017-05-10 齐鲁制药有限公司 Psi‑7977中间体化合物的制备方法
USD791845S1 (en) 2015-09-22 2017-07-11 Samsung Electronics Co., Ltd. Door guard for refrigerator
USD791200S1 (en) 2015-09-24 2017-07-04 Samsung Electronics Co., Ltd. Door guard for refrigerator
US10239910B2 (en) 2016-07-20 2019-03-26 Optimus Drugs (P) Limited Process for the preparation of sofosbuvir
CN109422710B (zh) * 2017-08-28 2022-06-21 常州制药厂有限公司 一种索非布韦氟内酯中间体的制备方法
CN111362989B (zh) * 2020-03-19 2022-03-08 江苏工程职业技术学院 一种索非布韦关键中间体的制备方法
WO2021202669A2 (en) 2020-04-01 2021-10-07 Reyoung Corporation Nucleoside and nucleotide conjugate compounds and uses thereof

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5118820A (en) * 1983-03-10 1992-06-02 Eli Lilly And Company Difluro antivirals and intermediate therefor

Family Cites Families (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5A (en) * 1836-08-10 Thomas Blanchard Machine for mortising solid wooden shells of ships' tackle-blocks
YU25500A (sh) * 1999-05-11 2003-08-29 Pfizer Products Inc. Postupak za sintezu analoga nukleozida
US6462191B1 (en) * 2000-07-13 2002-10-08 Air Products And Chemicals, Inc. Synthesis of 2-deoxy-2-fluoro-arabinose derivatives
CN1267446C (zh) * 2001-01-22 2006-08-02 默克公司 作为依赖于rna的rna病毒聚合酶的抑制剂的核苷衍生物
WO2004007512A2 (en) * 2002-07-16 2004-01-22 Merck & Co., Inc. Nucleoside derivatives as inhibitors of rna-dependent rna viral polymerase
SI2604620T2 (sl) * 2003-05-30 2024-10-30 Gilead Pharmasset Llc Modificirani fluorirani nukleozidni analogi

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5118820A (en) * 1983-03-10 1992-06-02 Eli Lilly And Company Difluro antivirals and intermediate therefor

Also Published As

Publication number Publication date
CN102199181A (zh) 2011-09-28
PL1773856T3 (pl) 2013-01-31
WO2006012440A3 (en) 2006-07-27
EP1773856B1 (en) 2012-02-01
CN102199181B (zh) 2014-09-17
CA2735079C (en) 2013-11-05
RU2407747C2 (ru) 2010-12-27
EP1773856A4 (en) 2010-10-13
PT1773856E (pt) 2012-05-14
IL180832A0 (en) 2007-06-03
WO2006012440A8 (en) 2011-06-16
EP1773856A2 (en) 2007-04-18
WO2006012440A2 (en) 2006-02-02
CA2574651C (en) 2013-05-21
AU2005267051B2 (en) 2011-07-14
ES2386005T3 (es) 2012-08-07
IL211606A0 (en) 2011-05-31
JP2008507547A (ja) 2008-03-13
JP5078612B2 (ja) 2012-11-21
ATE543789T1 (de) 2012-02-15
MX2007000803A (es) 2007-04-02
HK1106249A1 (en) 2008-03-07
CA2574651A1 (en) 2006-02-02
IL180832A (en) 2011-07-31
KR101235548B1 (ko) 2013-02-21
EP2348029A1 (en) 2011-07-27
KR20070114344A (ko) 2007-12-03
NZ552927A (en) 2010-05-28
AU2011200941A1 (en) 2011-03-24
KR20110034699A (ko) 2011-04-05
AU2011200941B2 (en) 2011-11-24
AU2011200941C1 (en) 2012-05-10
AU2005267051A1 (en) 2006-02-02
JP2011148817A (ja) 2011-08-04
DK1773856T3 (da) 2012-05-21
JP5351919B2 (ja) 2013-11-27
CA2735079A1 (en) 2006-02-02
RU2007106574A (ru) 2008-08-27

Similar Documents

Publication Publication Date Title
KR101236669B1 (ko) 알킬-치환된 2-데옥시-2-플루오로-ｄ-리보퓨라노실피리미딘 및 퓨린 및 그 유도체의 제조
US7601820B2 (en) Preparation of alkyl-substituted 2-deoxy-2-fluoro-D-ribofuranosyl pyrimidines and purines and their derivatives
US10577359B2 (en) Preparation of 2′-fluoro-2′-alkyl-substituted or other optionally substituted ribofuranosyl pyrimidines and purines and their derivatives
JP2008507547A6 (ja) アルキル置換された２−デオキシ−２−フルオロ−ｄ−リボフラノシルピリミジン類及びプリン類及びそれらの誘導体の調製
HK1106249B (en) Preparation of alkyl-substituted 2-deoxy-2-fluoro-d-ribofuranosyl pyrimidines and purines and their derivatives
HK1160141A (en) Preparation of alkyl-substituted 2-deoxy-2-fluoro-d-ribofuranosyl pyrimidines and purines and their derivatives
NZ584752A (en) Preparation of alkyl-substituted 2-deoxy-2-fluoro-D-ribofuranosyl pyrimidines and purines and their derivatives

Legal Events

Date Code Title Description
PA0105 International application

Patent event date: 20070220

Patent event code: PA01051R01D

Comment text: International Patent Application

PG1501 Laying open of application
A201 Request for examination
PA0201 Request for examination

Patent event code: PA02012R01D

Patent event date: 20100610

Comment text: Request for Examination of Application

A107 Divisional application of patent
PA0104 Divisional application for international application

Comment text: Divisional Application for International Patent

Patent event code: PA01041R01D

Patent event date: 20110317

PE0902 Notice of grounds for rejection

Comment text: Notification of reason for refusal

Patent event date: 20120425

Patent event code: PE09021S01D

E701 Decision to grant or registration of patent right
PE0701 Decision of registration

Patent event code: PE07011S01D

Comment text: Decision to Grant Registration

Patent event date: 20121126

GRNT Written decision to grant
PR0701 Registration of establishment

Comment text: Registration of Establishment

Patent event date: 20130218

Patent event code: PR07011E01D

PR1002 Payment of registration fee

Payment date: 20130218

End annual number: 3

Start annual number: 1

PG1601 Publication of registration
FPAY Annual fee payment

Payment date: 20160204

Year of fee payment: 4

PR1001 Payment of annual fee

Payment date: 20160204

Start annual number: 4

End annual number: 4

FPAY Annual fee payment

Payment date: 20170215

Year of fee payment: 5

PR1001 Payment of annual fee

Payment date: 20170215

Start annual number: 5

End annual number: 5

FPAY Annual fee payment

Payment date: 20180206

Year of fee payment: 6

PR1001 Payment of annual fee

Payment date: 20180206

Start annual number: 6

End annual number: 6

FPAY Annual fee payment

Payment date: 20190208

Year of fee payment: 7

PR1001 Payment of annual fee

Payment date: 20190208

Start annual number: 7

End annual number: 7

FPAY Annual fee payment

Payment date: 20200212

Year of fee payment: 8

PR1001 Payment of annual fee

Payment date: 20200212

Start annual number: 8

End annual number: 8

PR1001 Payment of annual fee

Payment date: 20210115

Start annual number: 9

End annual number: 9

PR1001 Payment of annual fee

Payment date: 20220118

Start annual number: 10

End annual number: 10

PR1001 Payment of annual fee

Payment date: 20230117

Start annual number: 11

End annual number: 11

PR1001 Payment of annual fee

Payment date: 20240109

Start annual number: 12

End annual number: 12

PR1001 Payment of annual fee

Payment date: 20250106

Start annual number: 13

End annual number: 13