WO2002059103A1 - Synthesis of beta-lapachone and its intermediates - Google Patents
Synthesis of beta-lapachone and its intermediates Download PDFInfo
- Publication number
- WO2002059103A1 WO2002059103A1 PCT/US2002/002359 US0202359W WO02059103A1 WO 2002059103 A1 WO2002059103 A1 WO 2002059103A1 US 0202359 W US0202359 W US 0202359W WO 02059103 A1 WO02059103 A1 WO 02059103A1
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- WO
- WIPO (PCT)
- Prior art keywords
- lapachone
- lapachol
- synthesis
- triethylamine
- weak base
- Prior art date
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- QZPQTZZNNJUOLS-UHFFFAOYSA-N CC(C)(CC1)OC(c(cccc2)c2C2=O)=C1C2=O Chemical compound CC(C)(CC1)OC(c(cccc2)c2C2=O)=C1C2=O QZPQTZZNNJUOLS-UHFFFAOYSA-N 0.000 description 1
- CIEYTVIYYGTCCI-UHFFFAOYSA-N CC(C)=CCC(C(c(cccc1)c1C1=O)=O)=C1O Chemical compound CC(C)=CCC(C(c(cccc1)c1C1=O)=O)=C1O CIEYTVIYYGTCCI-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D311/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings
- C07D311/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings ortho- or peri-condensed with carbocyclic rings or ring systems
- C07D311/78—Ring systems having three or more relevant rings
Definitions
- the present invention is directed to a process for the synthesis of ⁇ -lapachone (Beta- lapachone) and lapachol, the ⁇ -lapachone (Beta-lapachone) intermediate, which are important agents in cancer chemotherapy.
- ⁇ -lapachone has demonstrated significant antineoplastic activity against human cancer cell lines at concentrations typically in the range of 1-10 ⁇ M (IC 5 o). Cytotoxicity has been demonstrated in transformed cell lines derived from patients with promyelocytic leukemia (Planchon et al., Cancer Res., 55 (1996) 3706), prostate ( Li, C.J., et al., Cancer Res., 55 (1995) 3712), malignant glioma (Weller, M. et al., Int. J.
- Topoisomerase I is an enzyme that unwinds the DNA that makes up the chromosomes.
- the chromosomes must be unwound in order for the cell to use the genetic information to synthesize proteins; ⁇ -lapachone keeps the chromosomes wound tight, so that the cell cannot make proteins. As a result, the cell stops growing. Because cancer cells are constantly replicating and circumvent many mechanisms that restrict replication in normal cells, they are more vulnerable to topoisomerase inhibition than are normal cells.
- ⁇ -lapachone (3,4-dihydro-2,2-dimethyl-2H-naphtho[l,2-b]pyran-5,6-dione), a quinone, is derived from lapachol (a naphthoquinone) which can be isolated from the lapacho tree (Tabebuia avellanedae), a member of the catalpa family (Bignoniaceae).
- Lapachol and ⁇ -lapachone have the following chemical structures:
- Method (1) is described in Schaffner-Sabba, K., et al., ⁇ -Lapachone: Synthesis of Derivatives and Activities in Tumor Models, J. Med. Chem., 27, (1984) 990-994, and is known as the potassium salt method.
- Method (2) is described in Sun, J.S. et al., A Preparative Synthesis of Lapachol and Related Naphthoquinones, Tetrahedron Letters, 39 (1998) 8221-8224), and is know as the lithium salt method. Both of these methods require the formation of a metal salt.
- Amaral, A., et al. in The Total Synthesis of ⁇ -lapachone, J.
- the present invention is directed generally to a process for the synthesis of ⁇ - lapachone and its intermediate, lapachol. More specifically, the invention is directed to process for synthesizing ⁇ -lapachone and its intermediates, derivatives and analogs, by a safe and simple process and which produces ⁇ -lapachone in high yield and high quality.
- the process of the present invention teaches a novel method for the synthesis of the ⁇ -lapachone intermediate, lapachol.
- Lapachol is then quantitatively converted to ⁇ -lapachone and purified.
- a metal (lithium or potassium) salt of 2- hydroxy-l,4-naphtoquinone was prepared in situ by addition of lithium hydride or separately by addition of potassium hydroxide to the quinone solution as the first step and then reacting the metal salt with bromide compound to form lapachol
- the process of the present invention eliminates this first step and commences directly with 2-hydroxy-l,4-naphthoquinone to react with l-bromo-3-methyl-2-butene in the presence of sodium iodide and a weak base such as triethylamine, pyridine, trimethylamine, N,N-diisopropylethylamine, 2,6-lutidine, preferably triethylamine or pyridine, most preferably triethy
- FIG. 1 is a schematic diagram that generally depicts the synthetic process of the present invention for the production of lapachol
- FIG. 2 is schematic diagram that generally depicts the synthetic process of the present invention for the production of ⁇ -lapachone;
- FIG. 3 A is an HPLC chromatogram of 2-hydroxy-l,4-naphthoquinone (96.56%) at 252 nm;
- FIG. 3B is an HPLC chromatogram of lapachol (100%) at 252 nm prepared in accordance with the synthesis of the present invention.
- FIG. 3C is an HPLC chromatogram of lapachol sample with 1% of 2-hydroxy-l,4- naphthoquinone (starting material, 0.96%; second impurity peak , 0.55%; lapachol peak, 98.49%);
- FIG. 3D is an HPLC chromatogram at 258 nm of ⁇ -lapachone (99.36% ⁇ -lapachone , 0.17% unknown peak, 0.47% lapachol);
- FIG. 3E is an HPLC chromatogram at 258 nm of ⁇ -lapachone sample with 1% lapachol (98.70% ⁇ -lapachone , 0.37% unknown material, 0.93% lapachol)
- TLC thin layer chromatography
- NMR nuclear magnetic resonance spectroscopy
- HPLC high pressure liquid chromatography
- the synthetic process for preparing the ⁇ -lapachone intermediate, lapachol commences with the preparation of a reaction mixture comprised of 2-hydroxyl-l,4- napthoquinone, l-bromo-3-methyl-2-butene, triethylamine (TEA) and dimethylsulfoxide (DMSO).
- This reaction mixture is first stirred at room temperature under a noble gas atmosphere for about one hour.
- the reaction mixture is then heated and subsequently cooled to stop the reaction
- the mixture is then extracted three times with CH 2 C1 2 (e.g., 500 ml, 300 ml, 200 ml) and the organic phases pooled and successively washed with water, followed by two washings with 5% sodium bicarbonate (NaHC0 3 ) and one washing with 1% sodium chloride (NaCl).
- the organic phase is then dried with sodium sulfate (Na 2 S0 ) and the filtrate, after filtration, is evaporated by Rotovap.
- the residue is then dissolved in toluene heated in a water bath at 50 °C and any existing insoluble material is filtered off.
- the resulting toluene solution is then extracted three times with 2 N NaOH (e.g., 800 ml, 300 ml, 200 ml).
- the resulting combined aqueous phase is then neutralized with 220 ml concentrated hydrochloric acid (HCl) and the mixture is extracted three times with toluene (e.g., 500 ml, 300 ml, 300 ml).
- the organic phases are then pooled and any (black) solids existing in the organic phase is removed by filtration.
- the combined organic phase is then washed successively with 1% NaCl, 5% aqueous sodium bicarbonate and 1% aqueous sodium chloride, the resulting organic phase is then dried with sodium sulfate and the resulting filtrate is evaporated by Rotovap to dryness, followed by the addition of isopropanol for co-evaporation to completely remove residual toluene. The residue is then dissolved in isopropanol, heated and then cooled. Pure lapachol is obtained after filtering washing with cold isopropanol and drying under vacuum. With reference to FIG.
- the synthesis of ⁇ -lapachone from lapachol commences with preparation of a reaction mixture comprised of the pure lapachol (30 g) in 300 ml of sulfuric acid.
- the reaction mixture is stirred at room temperature for 30 minutes and poured into ice water with manual stirring.
- the mixture is then extracted twice with toluene (e.g., 600 ml and 400 ml) to provide a combined organic phase, which is then washed successively with 800 ml of 1% NaCl, 400 ml of 1% NaHC0 3 and 800 ml of 1% NaCl.
- the resulting organic phase is then dried with 50 g Na 2 SO 4 and the solid is filtered off.
- the residue was dissolved in toluene (1,000 ml) with heating in a 50 °C water bath, and any insoluble material existing was filtered off.
- the warm toluene solution was extracted three times with freshly prepared, warm 2N sodium hydroxide (800 ml, 300 ml and 200 ml).
- the aqueous phases were pooled and neutralized by addition of hydrochloric acid (220 ml) with vigorous manual stirring, then extracted three times with toluene (500 ml, 300 ml and 300 ml).
- the organic phase were pooled and any black solid existing in the organic phases was removed by filtration.
- the combined organic phase was washed successively with 1% aqueous sodium chloride (800 ml), 5% aqueous sodium bicarbonate (500 ml) and 1% aqueous sodium chloride (800 ml), and then dried with sodium sulfate (50 g). After filtration, the filtrate was evaporated to dryness by Rotovap, then isopropanol (300 ml) was added for co-evaporation to completely remove residual toluene. The residue was dissolved in isopropanol (300 ml) with heating in an 80 °C water bath and then was cooled to 4 °C slowly.
- lapachol (30 g, 0.124 mol) was added in portions slowly over 5 minutes at room temperature while stirring vigorously. After addition, the dark mixture was stirred for an additional 30 min and then poured into ice water (800 g) with manual stirring in a 2,000 ml beaker. The mixture was transferred into a 2,000 ml separatory funnel and extracted twice with toluene (600 ml and 400 ml).
- the toluene phases were pooled and washed successively with 1% aqueous sodium chloride (800 ml), 1% aqueous sodium bicarbonate (400 ml) and 1% aqueous sodium chloride (800 ml), and then dried with sodium sulfate (50 g). After filtration, the filtrate was evaporated to dryness by Rotovap and then ethanol (300 ml) was added for co-evaporation to completely remove residual toluene. The residue was dissolved in 75% ethanol or absolute ethanol, preferably absolute ethanol (ethanol/water, 3:1, 300 ml) with heating in an 80 °C water bath, then was filtered and cooled to 4 °C slowly.
- TAA triethylamine
- pyridine may also be used
- strong inorganic bases such as potassium hydroxide or lithium hydroxide as used in prior art lapachol syntheses to trap the acid generated from the reaction between the quinone and bromide compound
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Pyrane Compounds (AREA)
- Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
- Catalysts (AREA)
- Steroid Compounds (AREA)
Abstract
Description
Claims
Priority Applications (7)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
DK02707586T DK1363896T3 (en) | 2002-01-23 | 2002-01-23 | Synthesis of beta-lapachol and intermediates therefore |
AT02707586T ATE282033T1 (en) | 2001-01-25 | 2002-01-23 | SYNTHESIS OF BETA-LAPACHONE AND CORRESPONDING INTERMEDIATE PRODUCTS |
DE60201890T DE60201890T2 (en) | 2001-01-25 | 2002-01-23 | SYNTHESIS OF BETA-LAPACHONE AND CORRESPONDING PRODUCTS |
EP02707586A EP1363896B1 (en) | 2001-01-25 | 2002-01-23 | Synthesis of beta-lapachone and its intermediates |
CA002436125A CA2436125C (en) | 2001-01-25 | 2002-01-23 | Synthesis of beta-lapachone and its intermediates |
AU2002241985A AU2002241985B2 (en) | 2001-01-25 | 2002-01-23 | Synthesis of beta-lapachone and its intermediates |
JP2002559405A JP4434585B2 (en) | 2001-01-25 | 2002-01-23 | Synthesis of β-lapachone and its intermediates |
Applications Claiming Priority (4)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US26411601P | 2001-01-25 | 2001-01-25 | |
US60/264,116 | 2001-01-25 | ||
US09/957,260 | 2001-09-19 | ||
US09/957,260 US6458974B1 (en) | 2001-01-25 | 2001-09-19 | Synthesis of β-lapachone and its intermediates |
Publications (2)
Publication Number | Publication Date |
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WO2002059103A1 true WO2002059103A1 (en) | 2002-08-01 |
WO2002059103A9 WO2002059103A9 (en) | 2003-01-03 |
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Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
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PCT/US2002/002359 WO2002059103A1 (en) | 2001-01-25 | 2002-01-23 | Synthesis of beta-lapachone and its intermediates |
Country Status (9)
Country | Link |
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US (1) | US6458974B1 (en) |
EP (1) | EP1363896B1 (en) |
JP (1) | JP4434585B2 (en) |
AT (1) | ATE282033T1 (en) |
AU (1) | AU2002241985B2 (en) |
CA (1) | CA2436125C (en) |
DE (1) | DE60201890T2 (en) |
ES (1) | ES2230471T3 (en) |
WO (1) | WO2002059103A1 (en) |
Cited By (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN103239430A (en) * | 2013-05-08 | 2013-08-14 | 首都医科大学 | Application of lapachol in preparation of product for preventing and/or treating spongioblastoma |
CN113372298A (en) * | 2021-05-21 | 2021-09-10 | 温州医科大学 | Preparation method of 2-iodine-3-amino naphthoquinone compound |
Families Citing this family (19)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US20050222246A1 (en) * | 1999-04-14 | 2005-10-06 | Li Chiang J | Beta-lapachone is a broad spectrum anti-cancer agent |
US20050192360A1 (en) * | 1999-04-14 | 2005-09-01 | Li Chiang J. | Method of treatment of pancreatic cancer |
US20040209942A1 (en) * | 2002-07-17 | 2004-10-21 | Li Chiang J. | Activated checkpoint therapy and methods of use thereof |
US20050197405A1 (en) * | 2000-11-07 | 2005-09-08 | Li Chiang J. | Treatment of hematologic tumors and cancers with beta-lapachone, a broad spectrum anti-cancer agent |
US6816571B2 (en) * | 2002-02-06 | 2004-11-09 | L-3 Communications Security And Detection Systems Corporation Delaware | Method and apparatus for transmitting information about a target object between a prescanner and a CT scanner |
AU2003293333A1 (en) | 2002-12-02 | 2004-06-23 | Arqule, Inc. | Method of treating cancers |
US20050187288A1 (en) * | 2004-02-20 | 2005-08-25 | Chiang Li | Beta-lapachone and methods of treating cancer |
WO2005082356A2 (en) | 2004-02-20 | 2005-09-09 | Arqule, Inc. | Use of beta-lapachone for the treatment of lung cancer |
EP1732539A2 (en) | 2004-02-20 | 2006-12-20 | Arqule, Inc. | Use of beta-lapachone for the treatment of colon cancer |
JP2007523193A (en) | 2004-02-20 | 2007-08-16 | アークル・インコーポレーテツド | Use of β-lapachone for the treatment of pancreatic cancer |
US20050192247A1 (en) * | 2004-02-23 | 2005-09-01 | Li Chiang J. | Method of treating cancers |
EP1877097B1 (en) * | 2004-08-11 | 2012-06-20 | Arqule, Inc. | Aminoacid conjugates of beta-lapachone for tumor targeting |
US8614228B2 (en) * | 2004-08-11 | 2013-12-24 | Arqule, Inc. | Quinone prodrug compositions and methods of use |
US20060204981A1 (en) | 2005-01-07 | 2006-09-14 | Chiang Li | Compositions for modulation of PARP and methods for screening for same |
ES2532656T3 (en) * | 2007-04-30 | 2015-03-30 | Arqule, Inc. | Quinone hydroxy sulfonate compounds and their uses |
CN105294638A (en) * | 2015-10-30 | 2016-02-03 | 成都科创佳思科技有限公司 | Catalyzed synthesis method of dehydrogenated alpha-lapachol |
BR112019009089A2 (en) | 2016-11-03 | 2019-07-16 | Univ Cornell | cosmetic composition, method for treating sunburn, signs of aging or a combination thereof in mammals and method for enhancing DNA repair |
US11013673B2 (en) | 2016-11-03 | 2021-05-25 | Repairogen Corp. | Cosmetic compositions containing quinones and their topical use on skin and hair |
WO2019213494A1 (en) | 2018-05-03 | 2019-11-07 | Repairogen Corp | Cosmetic compositions containing quinones and their topical use on skin and hair |
Family Cites Families (1)
Publication number | Priority date | Publication date | Assignee | Title |
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US5824700A (en) * | 1996-02-20 | 1998-10-20 | Wisconsin Alumni Research Foundation | Ortho-quinone derivatives novel synthesis therefor and their use in the inhibition of neoplastic cell growth |
-
2001
- 2001-09-19 US US09/957,260 patent/US6458974B1/en not_active Expired - Lifetime
-
2002
- 2002-01-23 JP JP2002559405A patent/JP4434585B2/en not_active Expired - Fee Related
- 2002-01-23 ES ES02707586T patent/ES2230471T3/en not_active Expired - Lifetime
- 2002-01-23 EP EP02707586A patent/EP1363896B1/en not_active Expired - Lifetime
- 2002-01-23 AU AU2002241985A patent/AU2002241985B2/en not_active Ceased
- 2002-01-23 AT AT02707586T patent/ATE282033T1/en active
- 2002-01-23 WO PCT/US2002/002359 patent/WO2002059103A1/en active IP Right Grant
- 2002-01-23 CA CA002436125A patent/CA2436125C/en not_active Expired - Fee Related
- 2002-01-23 DE DE60201890T patent/DE60201890T2/en not_active Expired - Lifetime
Non-Patent Citations (2)
Title |
---|
SCHAFFNER-SABBA K ET AL: "BETA-LAPACHONE: SYNTHESIS OF DERIVATIVES AND ACTIVITIES IN TUMOR MODELS", JOURNAL OF MEDICINAL CHEMISTRY, AMERICAN CHEMICAL SOCIETY. WASHINGTON, US, vol. 27, no. 8, 1 August 1984 (1984-08-01), pages 990 - 994, XP000651650, ISSN: 0022-2623 * |
SUN J S ET AL: "A Preparative Synthesis of Lapachol and Related Naphthoquinones", TETRAHEDRON LETTERS, ELSEVIER SCIENCE PUBLISHERS, AMSTERDAM, NL, vol. 39, no. 45, 5 November 1998 (1998-11-05), pages 8221 - 8224, XP004139378, ISSN: 0040-4039 * |
Cited By (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN103239430A (en) * | 2013-05-08 | 2013-08-14 | 首都医科大学 | Application of lapachol in preparation of product for preventing and/or treating spongioblastoma |
CN103239430B (en) * | 2013-05-08 | 2015-01-07 | 首都医科大学 | Application of lapachol in preparation of product for preventing and/or treating spongioblastoma |
CN113372298A (en) * | 2021-05-21 | 2021-09-10 | 温州医科大学 | Preparation method of 2-iodine-3-amino naphthoquinone compound |
CN113372298B (en) * | 2021-05-21 | 2022-04-19 | 温州医科大学 | Preparation method of 2-iodine-3-amino naphthoquinone compound |
Also Published As
Publication number | Publication date |
---|---|
ATE282033T1 (en) | 2004-11-15 |
DE60201890T2 (en) | 2005-12-08 |
DE60201890D1 (en) | 2004-12-16 |
JP2004520378A (en) | 2004-07-08 |
AU2002241985B2 (en) | 2006-01-19 |
ES2230471T3 (en) | 2005-05-01 |
WO2002059103A9 (en) | 2003-01-03 |
US20020137952A1 (en) | 2002-09-26 |
US6458974B1 (en) | 2002-10-01 |
CA2436125C (en) | 2009-03-31 |
EP1363896A1 (en) | 2003-11-26 |
JP4434585B2 (en) | 2010-03-17 |
CA2436125A1 (en) | 2002-08-01 |
EP1363896B1 (en) | 2004-11-10 |
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