WO2015003670A1 - A new process for the preparation of elvitegravir - Google Patents
A new process for the preparation of elvitegravir Download PDFInfo
- Publication number
- WO2015003670A1 WO2015003670A1 PCT/CZ2014/000076 CZ2014000076W WO2015003670A1 WO 2015003670 A1 WO2015003670 A1 WO 2015003670A1 CZ 2014000076 W CZ2014000076 W CZ 2014000076W WO 2015003670 A1 WO2015003670 A1 WO 2015003670A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- formula
- elvitegravir
- reaction
- converted
- production
- Prior art date
Links
- 0 CC(C)[C@@](COC1OCCCC1)N(C=C(C(O)=O)C(C1=CC2(C)CC(C=CC)=C(*(Cl)=C)F)=O)C1=CC2F Chemical compound CC(C)[C@@](COC1OCCCC1)N(C=C(C(O)=O)C(C1=CC2(C)CC(C=CC)=C(*(Cl)=C)F)=O)C1=CC2F 0.000 description 2
- YAFWVDSOUGAFCM-YDYLCMSLSA-N CC(C)[C@@H](CO)N(C(C)(C1)C2C(C)C(Br)=C1OC)C=C(C(O)=O)C2=O Chemical compound CC(C)[C@@H](CO)N(C(C)(C1)C2C(C)C(Br)=C1OC)C=C(C(O)=O)C2=O YAFWVDSOUGAFCM-YDYLCMSLSA-N 0.000 description 1
- TXVCFUAPUFPKKR-LJQANCHMSA-N CC(C)[C@@H](CO)N(C=C1C(O)=O)c2cc(OC)c(Cc(cccc3N)c3F)cc2C1=O Chemical compound CC(C)[C@@H](CO)N(C=C1C(O)=O)c2cc(OC)c(Cc(cccc3N)c3F)cc2C1=O TXVCFUAPUFPKKR-LJQANCHMSA-N 0.000 description 1
- XWJKGGXWGHAIJZ-SCFJQAPRSA-N CC/C=C\C=C(/C)\Cl Chemical compound CC/C=C\C=C(/C)\Cl XWJKGGXWGHAIJZ-SCFJQAPRSA-N 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
- C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
- C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms 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
- C07D215/48—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
- C07D215/54—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen attached in position 3
- C07D215/56—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen attached in position 3 with oxygen atoms in position 4
-
- 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 invention relates to an improved process for the production of elvitegravir
- the carbonate reacts, in the presence of an organopalladium catalyst, with 3-chloro-2- fluorobenzyl zinc bromide (11) (prepared from 3-chloro-2-fluorobenzyl bromide (10) in the conditions of Negishi coupling) producing the protected benzyl quinolone derivative 12a.
- 3-chloro-2- fluorobenzyl zinc bromide (11) prepared from 3-chloro-2-fluorobenzyl bromide (10) in the conditions of Negishi coupling
- This is, in the next step, subjected to alkaline deprotection to the intermediate 13, which is, in the final step, subjected to reaction with sodium methoxide providing the end product elvitegravir (Scheme 1).
- Patent application WO 2011/004389 of Matrix Laboratories describes a synthetic procedure analogous to the method of the basic patent, using protection of the hydroxyl with the tetrahydropyranyl group (Scheme 3).
- the hydroxyl group of the enamine 22 is, in the next step, protected by a reaction with tert-butyldimethylsilyl chloride and the resulting 23 is subsequently cycled to the protected quinolone derivative 24.
- both hydrolysis of the ethyl ester and removal of the protecting TBDMS group are performed (Scheme 4).
- This invention provides an improved process for the production of elvitegravir of formula I,
- a suitable catalyst e.g. a palladium catalyst.
- the purity of the intermediate Ila according to HPLC generally exceeds 99%.
- the general protecting group PG may be, e.g., the trimethylsilyl group or other protecting groups suitable for protection of an oxygen atom, e.g., di-t-butyldimethylsilyl, benzyl, tetrahydropyranyl, tetrahydrofuranyl, others being mentioned, e.g,. in Protective Groups in Organic Synthesis, Third Edition. Theodora W. Greene, Peter G.M. Wuts, John Wiley, 1999. The compounds V and VII conveniently need not be isolated.
- elvitegravir is obtained by easy removal of the protecting groups - the protecting group on the carbonyl function is removed with water, alcohol; the protecting group on the hydroxyl is removed by reaction with a diluted aqueous acid or water at an elevated temperature. Alternatively, the deprotection can be carried out at the room temperature.
- PdCl 2 (PPh 3 ) 2 39 mg was added as a catalyst and 10 ml of a solution of 3-chloro-2- fluorobenzyl zinc bromide in tetrahydrofuran (0.5 M) was added at 60°C during 1 h; the mixture was further heated up at 60°C for 1.5 h.
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Oxygen Or Sulfur (AREA)
Priority Applications (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
HU1600128A HUP1600128A2 (en) | 2013-07-11 | 2014-07-03 | A new process for the preparation of elvitegravir |
CN201480038026.3A CN105377818B (zh) | 2013-07-11 | 2014-07-03 | 用于制备埃替拉韦的新方法 |
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CZ2013-544A CZ307255B6 (cs) | 2013-07-11 | 2013-07-11 | Nový způsob přípravy elvitegraviru |
CZPV2013-544 | 2013-07-11 |
Publications (1)
Publication Number | Publication Date |
---|---|
WO2015003670A1 true WO2015003670A1 (en) | 2015-01-15 |
Family
ID=51229772
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/CZ2014/000076 WO2015003670A1 (en) | 2013-07-11 | 2014-07-03 | A new process for the preparation of elvitegravir |
Country Status (4)
Country | Link |
---|---|
CN (1) | CN105377818B (cs) |
CZ (1) | CZ307255B6 (cs) |
HU (1) | HUP1600128A2 (cs) |
WO (1) | WO2015003670A1 (cs) |
Families Citing this family (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN105315203A (zh) * | 2014-06-06 | 2016-02-10 | 上海迪赛诺化学制药有限公司 | 一种v型埃替拉韦晶体及其制备方法 |
Citations (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2004046115A1 (ja) | 2002-11-20 | 2004-06-03 | Japan Tobacco Inc. | 4−オキソキノリン化合物及びそのhivインテグラーゼ阻害剤としての利用 |
WO2005113509A1 (en) * | 2004-05-20 | 2005-12-01 | Japan Tobacco Inc. | Novel 4-oxoquinoline compound and use thereof as hiv integrase inhibitor |
US20090318702A1 (en) * | 2006-03-06 | 2009-12-24 | Koji Matsuda | Process for production of 4-oxoquinoline compound |
US7825252B2 (en) | 2006-09-12 | 2010-11-02 | Gilead Sciences, Inc. | Process and intermediates for preparing integrase inhibitors |
WO2011004389A2 (en) | 2009-06-18 | 2011-01-13 | Matrix Laboratories Ltd | An improved process for the preparation of elvitegravir |
Family Cites Families (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CZ304983B6 (cs) * | 2012-10-12 | 2015-03-11 | Zentiva, K.S. | Způsob výroby a nové intermediáty syntézy elvitegraviru |
CZ304984B6 (cs) * | 2012-10-12 | 2015-03-11 | Zentiva, K.S. | Zlepšený způsob výroby a nové intermediáty syntézy elvitegraviru |
-
2013
- 2013-07-11 CZ CZ2013-544A patent/CZ307255B6/cs not_active IP Right Cessation
-
2014
- 2014-07-03 CN CN201480038026.3A patent/CN105377818B/zh not_active Expired - Fee Related
- 2014-07-03 HU HU1600128A patent/HUP1600128A2/hu unknown
- 2014-07-03 WO PCT/CZ2014/000076 patent/WO2015003670A1/en active Application Filing
Patent Citations (7)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2004046115A1 (ja) | 2002-11-20 | 2004-06-03 | Japan Tobacco Inc. | 4−オキソキノリン化合物及びそのhivインテグラーゼ阻害剤としての利用 |
EP1564210A1 (en) | 2002-11-20 | 2005-08-17 | Japan Tobacco Inc. | 4-oxoquinoline compounds and utilization thereof as hiv integrase inhibitors |
US7176220B2 (en) | 2002-11-20 | 2007-02-13 | Japan Tobacco Inc. | 4-oxoquinoline compound and use thereof as pharmaceutical agent |
WO2005113509A1 (en) * | 2004-05-20 | 2005-12-01 | Japan Tobacco Inc. | Novel 4-oxoquinoline compound and use thereof as hiv integrase inhibitor |
US20090318702A1 (en) * | 2006-03-06 | 2009-12-24 | Koji Matsuda | Process for production of 4-oxoquinoline compound |
US7825252B2 (en) | 2006-09-12 | 2010-11-02 | Gilead Sciences, Inc. | Process and intermediates for preparing integrase inhibitors |
WO2011004389A2 (en) | 2009-06-18 | 2011-01-13 | Matrix Laboratories Ltd | An improved process for the preparation of elvitegravir |
Non-Patent Citations (1)
Title |
---|
THEODORA W. GREENE; PETER G.M WUTS: "Protective Groups in Organic Synthesis", 1999, JOHN WILEY |
Also Published As
Publication number | Publication date |
---|---|
CN105377818A (zh) | 2016-03-02 |
CZ307255B6 (cs) | 2018-05-02 |
CZ2013544A3 (cs) | 2015-01-21 |
CN105377818B (zh) | 2018-03-30 |
HUP1600128A2 (en) | 2016-07-28 |
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