CN103304538B - Method for synthesizing dextromefloquine - Google Patents

Method for synthesizing dextromefloquine Download PDF

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CN103304538B
CN103304538B CN201310246354.XA CN201310246354A CN103304538B CN 103304538 B CN103304538 B CN 103304538B CN 201310246354 A CN201310246354 A CN 201310246354A CN 103304538 B CN103304538 B CN 103304538B
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mefloquine hydrochloride
mefloquine
dextrorotation
protected
erythro
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CN103304538A (en
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陈卫平
周钢
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Fourth Military Medical University FMMU
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Fourth Military Medical University FMMU
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    • 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

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Abstract

The invention discloses dextromefloquine shown in a structural formula (I) in the specification. The absolute configuration of the dextromefloquine is (11S,12R)-(+)-erythro mefloquine hydrochloride. A synthesis method comprises the steps of using organic lithium agents to carry out lithiation on 4-bromo-2,8-2-trifluoromethylquinoline 2 to obtain an intermediate 3, then subjecting the intermediate 3 to react with N- protected (R)-2-piperidinecarboxaldehyde(R)-4 to obtain N- protected (11S,12R)-mefloquine (11S,12R)-5, and carrying out further deprotection to convert N- protected (11S,12R)-mefloquine(11S,12R)-5 to hydrochloride, thus obtaining dextromefloquine, wherein P is an N- protecting group. The absolute configuration of dextro erythro mefloquine hydrochloride is determined to be (11S,12R) by the chemical synthesis method beyond all doubt, thereby laying a solid foundation for developing dextro erythro mefloquine hydrochloride single enantiomer drugs.

Description

The synthesis of dextrorotation Mefloquine hydrochloride
Technical field
The present invention relates to a kind of new synthetic method of dextrorotation Mefloquine hydrochloride, belong to technical field of organic synthesis.
Background technology
Malaria is serious communicable disease, and the death caused by it exceedes other parasitosis any, and wherein the malaria harm that causes of plasmodium falciparum is maximum, estimates the malaria that the whole world has 150 ~ 2,700,000 people to die from plasmodium falciparum to cause.Mefloquine hydrochloride (Mefloquine hydrochloride, trade(brand)name: Lariam) (Fig. 1) is that the blood with high activity kills to grow and splits body medicine, can kill the plasmodium falciparum of multidrug resistance.Containing two chiral carbon atoms in mefloquine molecule, it is a chiral drug.At present, the erythro mefloquine hydrochloride of clinical application is raceme mixture, the long half time of erythro mefloquine hydrochloride, only need be administered once weekly, easy to use.But racemize erythro Mefloquine hydrochloride can produce serious central nervous system side effect, comprise impact sleep, increase anxiety, panic attack, depression and psychiatric disorder etc.Research shows, anti-plasmodium falciparum activity 1.69 times (Karle, the J. M.s stronger than left-handed Mefloquine hydrochloride of dextrorotation Mefloquine hydrochloride; Olmeda, R.; Gerena, L.; Milhous, W. K. exp. Pharmacol. 1993, 76,345), transformation period shorter (Dow, the G. S. of left-handed erythro Mefloquine hydrochloride; Koenig, M. L.; Wolf, L.; Gerena, L.; Lopez-Sanchez, M.; Hudson, T. H.; Bhattacharjee, A.K. antimicrob. Agents Chemother. 2004, 48, 2624 – 2632.), the adenosine receptor of left-handed Mefloquine hydrochloride central nervous system capable of blocking, thus the various side effects producing neuropsychiatric, dextrorotation erythro Mefloquine hydrochloride then can not produce these side effects (Dow, G. S.; Koenig, M. L.; Wolf, L.; Gerena, L.; Lopez-Sanchez, M.; Hudson, T. H.; Bhattacharjee, A.K. antimicrob. Agents Chemother. 2004, 48, 2624 – 2632.).Therefore, develop dextrorotation erythro mefloquine hydrochloride to be extremely important.
Because erythro mefloquine hydrochloride two enantiomorphs have different pharmacological actions and toxic side effect, over nearly 40 years, the absolute configuration determining dextrorotation erythro mefloquine hydrochloride is attempted by many research groups, but the absolute configuration of the dextrorotation erythro mefloquine hydrochloride that several group is fixed is uncertain, and conflicting, there are six groups the absolute configuration of dextrorotation erythro mefloquine hydrochloride to be decided to be (11R, 12S), and have three groups the absolute configuration of dextrorotation erythro mefloquine hydrochloride to be decided to be (11S, 12R).
Summary of the invention
The object of the invention is to provide the synthetic method of the dextrorotation erythro mefloquine hydrochloride that a kind of synthetic route is short, stereoselectivity is high.
Implementation procedure of the present invention is as follows:
Dextrorotation Mefloquine hydrochloride shown in structural formula (I), its absolute configuration is (11S, 12R)-(+)-erythro mefloquine hydrochloride,
。
The synthetic method of above-mentioned dextrorotation Mefloquine hydrochloride, comprises the following steps:
(1) with organolithium reagent by bromo-for 4-2,8-bis-Trifluoromethylquinocarboxylics 2lithiumation becomes intermediate 3, then with N-protected ( r)-2-piperidinealdehyde ( r)- 4react N-protected ( 11S, 12R)-Mefloquine hydrochloride ( 11S, 12R)- 5, wherein P is N-protected base;
(2) N-protected ( 11S, 12R)-Mefloquine hydrochloride ( 11S, 12R)- 5deprotection, is transformed into hydrochloride and namely obtains dextrorotation Mefloquine hydrochloride.
Described organolithium reagent is MeLi, n-BuLi, s-BuLi, t-BuLi, HexLi; N-protected base is Boc, Cbz, Fmoc, trityl, benzyl or to methoxybenzyl; Reaction solvent is selected from ether, tetrahydrofuran (THF), methyl tertiary butyl ether, diisopropyl ether, dioxane, methyltetrahydrofuran; Temperature of reaction is-100 ° of C to 50 ° of C.
The absolute configuration that the present invention's chemical synthesis process unambiguously determines dextrorotation erythro mefloquine hydrochloride is (11S, 12R), this work is that the exploitation of dextrorotation erythro mefloquine hydrochloride single enantiomer medicine lays a solid foundation.
figure of description
Fig. 1 is the structure of mefloquine hydrochloride (Lariam).
Embodiment
1, ( r)-(+)-1-Boc-2-piperidine methyl formate [( r)-(+)-6] synthesis
( r)-(+)-1-Boc-2-piperidine carboxylic acid (5.0 g, 22 mmol) adds Cs in the solution of DMF (100 mL) 2cO 3(3.5 g, 10.9 mmol) and MeI (1.5 mL, 24 mmol), stirring at room temperature 4 h, add methyl tertiary butyl ether (250 mL), wash with water (2 × 100 mL), saturated aqueous common salt (100 mL) is washed, anhydrous sodium sulfate drying, concentrating under reduced pressure, residue column chromatography purification, obtains product (5.1 g, 96%); [α] d 20=+55.6 (c=0.7, CHCl 3). 1h NMR (CDCl 3, 400 MHz): δ 4.73-4.90 (m, 1H); 3.92-4.01 (m, 1H), 2.87-2.98 (m; 1H), 2.18-2.22 (m, 1H); 1.65-1.71 (m; 3H), 1.47 (m, 10H); 1.25-1.29 (m, 1H); 13c NMR (CDCl 3, 100 MHz): δ 172.5,155.9,80.0,54.9,53.7,52.0,42.1,41.1,28.3,26.8,24.7,20.8.
2, ( r)-(+)-1-Boc-2-piperidinealdehyde [( r)-(+)-4] synthesis
At-78 ° of C, ( r)-(+)-1-Boc-2-piperidine methyl formate (2.7 g, 11.1 mmol) in the solution of toluene (25 mL), slowly drip 1.5M DIBAL in solution (17 mL of toluene, 25.4 mmol), then methyl alcohol (60 mL) is added, reaction mixture is cooled with an ice bath, add 10% wt aqueous citric acid solution (250 mL), stir 1 h, extract by ethyl acetate, extracting solution water (2 × 100 mL) is washed, saturated aqueous common salt (100 mL) is washed, anhydrous sodium sulfate drying, concentrating under reduced pressure, residue column chromatography purification (SiO 2, EtOAc:PE=1:6), obtain product (2 g, 76%), [α] d 20=+77.6 (c=1.5, CHCl 3). 1h NMR (CDCl 3, 400 MHz): δ 9.59 (s, 1H), 4.51-4.61 (m, 1H), 3.90-4.01 (m, 1H), 2.93 (m, 1H), 2.15-2.18 (m, 1H), 1.65-1.67 (m, 3H), 1.46 (m, 10H), 1.20-1.27 (m, 1H), 13c NMR (CDCl 3, 100 MHz): δ 201.3,80.4,77.2,61.5,60.7,43.1,41.9,28.2,24.7,23.6,20.9.
3, Boc-protection ( 11S, 12R)-(+)- erythro-Mefloquine hydrochloride [( 11S, 12R)-(+)-5] synthesis
At-78 ° of C, add in the solution of ether (20 mL) at 4-bromo-2,8-bis-(trifluoromethyl) quinoline (1 g, 2.9 mmol) n-BuLi (2 mL of 1.6M, 3.2 mmol), after stirring 1 h, add ( r)-(+)-1-Boc-2-piperidinealdehyde (0.62 g, 2.9 mmol) in the solution of ether (5 mL), 20 min are stirred at-78 ° of C, then remove cooling bath, continue stirring 2 h, extract with ether (3 × 20 mL), united extraction liquid, with anhydrous sodium sulfate drying, concentrating under reduced pressure, residue column chromatography purification (SiO 2, EtOAc:PE=1:6), obtain product (805 mg, 58%) as a colorless crystals. [α] d 20=+21.7 (c=0.23, CHCl 3), 1h NMR (CDCl 3, 400 MHz): δ 8.63 (d, 1 H, J=8.4 Hz), 8.17 (d, 1 H, J=7.2 Hz), 8.05 (s, 1 H), 7.75 (t, 1 H, J=8.0 Hz), 5.82 (s, 1 H), 4.30 (d, 1 H, J=5.2 Hz), 3.83 (d, 1 H, J=12.8 Hz), 3.33 (br s, 1 H), 3.24 (ddd, 1 H, J=13.6, 10.8, 4.0), 1.90 (m, 1H), 1.79 (m, 1 H), 1.52 (m, 2 H), 1.35 (m, 2 H), 1.32 (s, 9 H), 13c NMR (CDCl 3, 100 MHz): δ 155.5,151.0,148.0 (q, J=44.8 Hz), 143.8,129.5,129.2,128.8 (q, J=5.5 Hz), 127.1,127.0,123.6 (q, J=272 Hz), 121.3 (q, J=274 Hz), 115.6,80.3,71.5,57.1,42.2,28.2,24.2,22.8,19.9.
4, ( 11S, 12R)-(+)- erythro-mefloquine hydrochloride [( 11S, 12R)-(+)-1] synthesis
Boc-is protected ( 11S, 12R)-(+)- erythro-Mefloquine hydrochloride (100 mg, 0.2 mmol) is dissolved in CH 2cl 2(10 mL), adds trifluoroacetic acid (1.2 mL), after stirring at room temperature 1 h, adds saturated NaHCO 3solution (10 mL), separates organic layer, water layer CH 2cl 2(4 × 5 mL) extracts. and united extraction liquid, with anhydrous sodium sulfate drying, concentrating under reduced pressure, obtains free alkali, is white solid.
Free alkali is dissolved in EtOH (5 mL), add concentrated hydrochloric acid (50 μ L), concentrating under reduced pressure, adds Et 2o leaches white solid, dry, ( 11S, 12R)-(+)- erythro-mefloquine hydrochloride (76 mg, 88%). [α] d 20=+33.7 (c=0.5, MeOH); 1h NMR (DMSO-d 6, 400 MHz): δ 10.48 (br s, 1 H), 9.04 (d; 1 H, J=8.4 Hz), 8.50 (br s; 1 H), 8.39 (d, 1 H; J=7.2 Hz), 8.10 (s, 1 H); 7.97 (t, 1 H, J=8.0 Hz); 6.85 (d, 1 H, J=4.4 Hz); 6.15 (s, 1 H), 3.30 (m; 1 H), 3.25 (m, 1H); 2.91 (m, 1 H), 1.66 (m; 4 H), 1.33 (m, 2 H); 13c NMR (DMSO-d 6, 100 MHz): δ 151.8,147.1 (q, J=34.3 Hz), 143.2,130.4 (q, J=5.4 Hz), 129.8,128.8,127.6 (q, J=29.4 Hz), 126.9,124.1 (q, J=272 Hz), 121.7 (q, J=280 Hz), 115.8,67.1,59.2,44.6,22.0,21.6,21.3.

Claims (5)

1. a synthetic method for dextrorotation Mefloquine hydrochloride salt, is characterized in that comprising the following steps:
(1) with organolithium reagent by bromo-for 4-2,8-bis-Trifluoromethylquinocarboxylics 2lithiumation becomes intermediate 3, then with N-protected ( r)-2-piperidinealdehyde ( r)- 4react N-protected ( 11S, 12R)-Mefloquine hydrochloride ( 11S, 12R)- 5, wherein P is N-protected base;
(2) N-protected ( 11S, 12R)-Mefloquine hydrochloride ( 11S, 12R)- 5deprotection, is transformed into hydrochloride and namely obtains dextrorotation Mefloquine hydrochloride.
2. the synthetic method of dextrorotation Mefloquine hydrochloride salt according to claim 1, is characterized in that: described organolithium reagent is MeLi, n-BuLi, s-BuLi, t-BuLi, HexLi.
3. the synthetic method of dextrorotation Mefloquine hydrochloride salt according to claim 1, is characterized in that: N-protected base is Boc, Cbz, Fmoc, trityl, benzyl or to methoxybenzyl.
4. the synthetic method of dextrorotation Mefloquine hydrochloride salt according to claim 1, is characterized in that: reaction solvent is selected from ether, tetrahydrofuran (THF), methyl tertiary butyl ether, diisopropyl ether, dioxane, methyltetrahydrofuran.
5. the synthetic method of dextrorotation Mefloquine hydrochloride salt according to claim 1, is characterized in that: temperature of reaction is-100 ° of C to 50 ° of C.
CN201310246354.XA 2013-06-21 2013-06-21 Method for synthesizing dextromefloquine Expired - Fee Related CN103304538B (en)

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Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US1594282A (en) * 1923-11-24 1926-07-27 Fort Pitt Bedding Co Cushion seat and the like

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* Cited by examiner, † Cited by third party
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AU730818B2 (en) * 1997-03-07 2001-03-15 Vernalis Research Limited Use of (+)mefloquine for the treatment of malaria
US6500955B1 (en) * 2001-02-02 2002-12-31 National Institute Of Pharmaceutical Education And Research One pot synthesis of [2,8-Bis (trifluoromethyl)-4-quinolinyl]-2-pyridinylmethanone, a mefloquine intermediate

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US1594282A (en) * 1923-11-24 1926-07-27 Fort Pitt Bedding Co Cushion seat and the like

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
Sarva Jayaprakash, et al..Design, Synthesis, and SAR Studies of Mefloquine-Based Ligands as Potential Antituberculosis Agents.《ChemMedChem》.2006,第1卷第593-597页. *
The Absolute Configuration of (+)- and (-)-erythro-Mefloquine;Michael Muller, et al.;《angewandte chemie international edtion》;20130424;第52卷;第6047-6049页 *

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