GB1594282A - Process for the manufacture of mefloquine - Google Patents
Process for the manufacture of mefloquine Download PDFInfo
- Publication number
- GB1594282A GB1594282A GB6207/78A GB620778A GB1594282A GB 1594282 A GB1594282 A GB 1594282A GB 6207/78 A GB6207/78 A GB 6207/78A GB 620778 A GB620778 A GB 620778A GB 1594282 A GB1594282 A GB 1594282A
- Authority
- GB
- United Kingdom
- Prior art keywords
- bis
- trifluoromethyl
- quinolinemethanol
- piperidyl
- erythro
- 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
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- 238000004519 manufacturing process Methods 0.000 title claims abstract description 7
- 238000000034 method Methods 0.000 title claims description 16
- XEEQGYMUWCZPDN-DOMZBBRYSA-N (-)-(11S,2'R)-erythro-mefloquine Chemical compound C([C@@H]1[C@@H](O)C=2C3=CC=CC(=C3N=C(C=2)C(F)(F)F)C(F)(F)F)CCCN1 XEEQGYMUWCZPDN-DOMZBBRYSA-N 0.000 title description 5
- 229960001962 mefloquine Drugs 0.000 title description 4
- MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 claims abstract description 14
- DXALAFAFIXJDOS-UHFFFAOYSA-N 4-bromo-2,8-bis(trifluoromethyl)quinoline Chemical compound C1=CC=C(C(F)(F)F)C2=NC(C(F)(F)F)=CC(Br)=C21 DXALAFAFIXJDOS-UHFFFAOYSA-N 0.000 claims abstract description 13
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims abstract description 9
- 239000001257 hydrogen Substances 0.000 claims abstract description 9
- 229910052739 hydrogen Inorganic materials 0.000 claims abstract description 9
- CSDSSGBPEUDDEE-UHFFFAOYSA-N 2-formylpyridine Chemical compound O=CC1=CC=CC=N1 CSDSSGBPEUDDEE-UHFFFAOYSA-N 0.000 claims abstract description 7
- ULGZDMOVFRHVEP-RWJQBGPGSA-N Erythromycin Chemical compound O([C@@H]1[C@@H](C)C(=O)O[C@@H]([C@@]([C@H](O)[C@@H](C)C(=O)[C@H](C)C[C@@](C)(O)[C@H](O[C@H]2[C@@H]([C@H](C[C@@H](C)O2)N(C)C)O)[C@H]1C)(C)O)CC)[C@H]1C[C@@](C)(OC)[C@@H](O)[C@H](C)O1 ULGZDMOVFRHVEP-RWJQBGPGSA-N 0.000 claims description 14
- 238000005984 hydrogenation reaction Methods 0.000 claims description 11
- 239000003054 catalyst Substances 0.000 claims description 6
- BASFCYQUMIYNBI-UHFFFAOYSA-N platinum Chemical compound [Pt] BASFCYQUMIYNBI-UHFFFAOYSA-N 0.000 claims description 4
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 4
- ZDHFMOCJUGEJGW-UHFFFAOYSA-N [3-piperidin-1-yl-2,8-bis(trifluoromethyl)quinolin-4-yl]methanol Chemical compound OCc1c(N2CCCCC2)c(nc2c(cccc12)C(F)(F)F)C(F)(F)F ZDHFMOCJUGEJGW-UHFFFAOYSA-N 0.000 claims description 2
- 238000011065 in-situ storage Methods 0.000 claims description 2
- 229910052697 platinum Inorganic materials 0.000 claims description 2
- 239000010970 precious metal Substances 0.000 claims description 2
- 239000000126 substance Substances 0.000 claims 1
- LUDFDSXDVJABBT-UHFFFAOYSA-N [2,8-bis(trifluoromethyl)quinolin-4-yl]-pyridin-2-ylmethanol Chemical compound C=1C(C(F)(F)F)=NC2=C(C(F)(F)F)C=CC=C2C=1C(O)C1=CC=CC=N1 LUDFDSXDVJABBT-UHFFFAOYSA-N 0.000 abstract 1
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 29
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 12
- 238000002844 melting Methods 0.000 description 10
- 230000008018 melting Effects 0.000 description 10
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 8
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 7
- 238000003756 stirring Methods 0.000 description 7
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 7
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 6
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 6
- 239000000203 mixture Substances 0.000 description 6
- 150000001875 compounds Chemical class 0.000 description 5
- 238000002425 crystallisation Methods 0.000 description 5
- 238000001914 filtration Methods 0.000 description 5
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 4
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 4
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 description 4
- 238000006243 chemical reaction Methods 0.000 description 4
- 239000007787 solid Substances 0.000 description 4
- VBLXCTYLWZJBKA-UHFFFAOYSA-N 2-(trifluoromethyl)aniline Chemical compound NC1=CC=CC=C1C(F)(F)F VBLXCTYLWZJBKA-UHFFFAOYSA-N 0.000 description 3
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- 239000012044 organic layer Substances 0.000 description 3
- 238000001953 recrystallisation Methods 0.000 description 3
- 150000003839 salts Chemical class 0.000 description 3
- 229910052938 sodium sulfate Inorganic materials 0.000 description 3
- 235000011152 sodium sulphate Nutrition 0.000 description 3
- 238000011282 treatment Methods 0.000 description 3
- JIWHKBAFGFPZKM-UHFFFAOYSA-N 2,8-bis(trifluoromethyl)-1h-quinolin-4-one Chemical compound C1=CC=C2C(O)=CC(C(F)(F)F)=NC2=C1C(F)(F)F JIWHKBAFGFPZKM-UHFFFAOYSA-N 0.000 description 2
- 241000223960 Plasmodium falciparum Species 0.000 description 2
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 2
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 2
- VCWREBFAYARZEI-UHFFFAOYSA-N [3-piperidin-2-yl-2,8-bis(trifluoromethyl)quinolin-4-yl]methanol Chemical compound FC(F)(F)C1=NC2=C(C(F)(F)F)C=CC=C2C(CO)=C1C1CCCCN1 VCWREBFAYARZEI-UHFFFAOYSA-N 0.000 description 2
- 239000002253 acid Substances 0.000 description 2
- 239000000538 analytical sample Substances 0.000 description 2
- 229910052786 argon Inorganic materials 0.000 description 2
- 238000007796 conventional method Methods 0.000 description 2
- 238000001816 cooling Methods 0.000 description 2
- 239000002178 crystalline material Substances 0.000 description 2
- 238000001035 drying Methods 0.000 description 2
- 239000000706 filtrate Substances 0.000 description 2
- 239000002244 precipitate Substances 0.000 description 2
- 239000002904 solvent Substances 0.000 description 2
- 239000007858 starting material Substances 0.000 description 2
- 239000012258 stirred mixture Substances 0.000 description 2
- 238000000859 sublimation Methods 0.000 description 2
- 230000008022 sublimation Effects 0.000 description 2
- 239000000725 suspension Substances 0.000 description 2
- WHTVZRBIWZFKQO-AWEZNQCLSA-N (S)-chloroquine Chemical compound ClC1=CC=C2C(N[C@@H](C)CCCN(CC)CC)=CC=NC2=C1 WHTVZRBIWZFKQO-AWEZNQCLSA-N 0.000 description 1
- QKJAZPHKNWSXDF-UHFFFAOYSA-N 2-bromoquinoline Chemical compound C1=CC=CC2=NC(Br)=CC=C21 QKJAZPHKNWSXDF-UHFFFAOYSA-N 0.000 description 1
- 241000282708 Aotus <primate> Species 0.000 description 1
- CTUYBUXNBUTGOW-UHFFFAOYSA-N C1=CC=C2C([Li])=CC(C(F)(F)F)=NC2=C1C(F)(F)F Chemical compound C1=CC=C2C([Li])=CC(C(F)(F)F)=NC2=C1C(F)(F)F CTUYBUXNBUTGOW-UHFFFAOYSA-N 0.000 description 1
- 241000282693 Cercopithecidae Species 0.000 description 1
- 241000699670 Mus sp. Species 0.000 description 1
- PHSPJQZRQAJPPF-UHFFFAOYSA-N N-alpha-Methylhistamine Chemical compound CNCCC1=CN=CN1 PHSPJQZRQAJPPF-UHFFFAOYSA-N 0.000 description 1
- 241000224017 Plasmodium berghei Species 0.000 description 1
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 1
- 239000008346 aqueous phase Substances 0.000 description 1
- 239000002585 base Substances 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 229960003677 chloroquine Drugs 0.000 description 1
- WHTVZRBIWZFKQO-UHFFFAOYSA-N chloroquine Natural products ClC1=CC=C2C(NC(C)CCCN(CC)CC)=CC=NC2=C1 WHTVZRBIWZFKQO-UHFFFAOYSA-N 0.000 description 1
- 238000004587 chromatography analysis Methods 0.000 description 1
- 239000012043 crude product Substances 0.000 description 1
- 125000004177 diethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 150000002170 ethers Chemical class 0.000 description 1
- OCJKUQIPRNZDTK-UHFFFAOYSA-N ethyl 4,4,4-trifluoro-3-oxobutanoate Chemical compound CCOC(=O)CC(=O)C(F)(F)F OCJKUQIPRNZDTK-UHFFFAOYSA-N 0.000 description 1
- 239000012458 free base Substances 0.000 description 1
- 229930195733 hydrocarbon Natural products 0.000 description 1
- 150000002430 hydrocarbons Chemical class 0.000 description 1
- 150000003840 hydrochlorides Chemical class 0.000 description 1
- 239000002198 insoluble material Substances 0.000 description 1
- 238000002955 isolation Methods 0.000 description 1
- 201000004792 malaria Diseases 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 230000007935 neutral effect Effects 0.000 description 1
- MUMZUERVLWJKNR-UHFFFAOYSA-N oxoplatinum Chemical compound [Pt]=O MUMZUERVLWJKNR-UHFFFAOYSA-N 0.000 description 1
- 239000003208 petroleum Substances 0.000 description 1
- 239000012071 phase Substances 0.000 description 1
- UXCDUFKZSUBXGM-UHFFFAOYSA-N phosphoric tribromide Chemical compound BrP(Br)(Br)=O UXCDUFKZSUBXGM-UHFFFAOYSA-N 0.000 description 1
- 229910003446 platinum oxide Inorganic materials 0.000 description 1
- 229920000137 polyphosphoric acid Polymers 0.000 description 1
- 238000002360 preparation method Methods 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- LISFMEBWQUVKPJ-UHFFFAOYSA-N quinolin-2-ol Chemical compound C1=CC=C2NC(=O)C=CC2=C1 LISFMEBWQUVKPJ-UHFFFAOYSA-N 0.000 description 1
- HREHOXSRYOZKNT-UHFFFAOYSA-N quinolin-2-ylmethanol Chemical compound C1=CC=CC2=NC(CO)=CC=C21 HREHOXSRYOZKNT-UHFFFAOYSA-N 0.000 description 1
- 125000002943 quinolinyl group Chemical group N1=C(C=CC2=CC=CC=C12)* 0.000 description 1
- 239000011541 reaction mixture Substances 0.000 description 1
- 239000001117 sulphuric acid Substances 0.000 description 1
- 235000011149 sulphuric acid Nutrition 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- LMBFAGIMSUYTBN-MPZNNTNKSA-N teixobactin Chemical compound C([C@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H](CCC(N)=O)C(=O)N[C@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H]1C(N[C@@H](C)C(=O)N[C@@H](C[C@@H]2NC(=N)NC2)C(=O)N[C@H](C(=O)O[C@H]1C)[C@@H](C)CC)=O)NC)C1=CC=CC=C1 LMBFAGIMSUYTBN-MPZNNTNKSA-N 0.000 description 1
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-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
- C07D215/20—Oxygen atoms
- C07D215/22—Oxygen atoms attached in position 2 or 4
- C07D215/233—Oxygen atoms attached in position 2 or 4 only one oxygen atom which is attached in position 4
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P33/00—Antiparasitic agents
- A61P33/02—Antiprotozoals, e.g. for leishmaniasis, trichomoniasis, toxoplasmosis
-
- 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
- C07D215/18—Halogen atoms or nitro radicals
Landscapes
- Organic Chemistry (AREA)
- Chemical & Material Sciences (AREA)
- Health & Medical Sciences (AREA)
- Veterinary Medicine (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Tropical Medicine & Parasitology (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Plural Heterocyclic Compounds (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Pyridine Compounds (AREA)
Abstract
Process for preparing erythro- alpha -2-piperidyl-2,8-bis-(trifluoromethyl)-4-quinolinemethanol, characterised in that 2,8-bis-(trifluoromethyl)-4-bromoquinoline is reacted with n-butyllithium, the resulting 2,8-bis-(trifluoromethyl)-4-quinolyllithium is reacted with pyridine-2-aldehyde, and the resulting alpha -2-pyridyl-2,8-bis-(trifluoromethyl)-4-quinolinemethanol is hydrogenated with 3 molar equivalents of hydrogen.
Description
(54) A PROCESS FOR THE MANUFACTURE OF
MEFLOQUINE
(71) We, F. HOFFMANN-LA ROCHE & CO., AKTIENGESLLCHAFT, a
Swiss Company of 124-184 Grenzacherstrasse, Basle, Switzerland, do hereby declare the invention, for which we pray that a patent may be granted to us, and the method by which it is to be performed, to be particularly described in and by the following statement:- The present invention is concerned with a process for the manufacture of mefloquine.
Mefloquine, which is erythro a - 2 - piperidyl - 2,8 - bis(tri - fluoromethyl) 4 - quinolinemethanol (I) and a known compound, useful in the treatment of malaria, has been previously prepared in a six-step synthesis from 2trifluoromethylaniline via 2,8 - bis(trifluoromethyl) - 4 - bromoquinoline as described by C. J. Ohnmacht et al., J. Med. Chem., 14, 926 (1971).
The present invention is concerned with a process for the manufacture of erythro a - 2 - piperidyl - 2,8 - bis(trifluoromethyl) - 4 - quinolinemethanol, which process comprises reacting 2,8 - bis(trifluoromethyl) - 4 - bromoquinoline (IV) with n - butyllithium, treating the resulting 2,8 - bis(trifluoromethyl) - 4 quinolylithium (III) with 2-pyridinecarboxaldehyde and hydrogenating the resulting a - 2 - pyridyl - 2,8 - bis(trifluoromethyl) - 4 - quinoline - methanol (11) to give the desired erythro a - 2 - piperidyl - 2,8 - bis(trifluoromethyl) - 4 quinolinemethanol.
The present invention is also concerned with a - 2- pyridyl - 2,8 bis(trifluoromethyl) - 4 - quinolinemethanol of formula
which is useful as an intermediate in the process of the present invention.
The process provided by the present invention as well as the preparation of the starting material (IV) from 2- trifluoro-methylaniline in accordance with
Ohnmacht et al. (supra) is illustrated in the following Formula Scheme:
Formula Scheme
While in the process according to Ohnmacht et al., 2,8 - bis(trifluoromethyl) 4 - bromoquinoline (IV) is treated with n-butyllithium and the 4-lithio derivative obtained is carboxylated to yield the 4-carboxy derivative which, prior to hydrogenation, is reacted with 2-lithiumpyridyl, in accordance with the present invention 2,8 - bis(trifluoromethyl) - 4 - bromo quinoline (IV) is treated with n - butyllithium to yield 2,8 - bis(trifluoromethyl) 4 - lithioquinoline which is then reacted in situ with 2-pyridinecarboxaldehyde.
This reaction is preferably carried out at a low temperature in the range of from -30" to -700C, most preferably at -700C or below, depending upon the solvent used. Solvents which may be used are ethers such as tetrahydrofuran or diethyl ether or hydrocarbons such as hexane and mixtures thereof. In a preferred embodiment, the reaction may be carried out in diethyl etherln-hexane(l:l, v/v). The a - 2 - pyridyl - 2,8 - bis(trifluoromethyl) 4 - quinolinemethanol (II) can be recovered from the reaction mixture according to conventional methods; for example, by crystallisation. a - 2 - Pyridyl - 2,8 - bis(trifluoromethyl) - 4 - quinolinemethanol (II) is
hydrogenated with 3 mole equivalents of hydrogen to yield erythro a - 2 piperidyl - 2,8 - bis(trifluoromethyl) - 4 - quinolinemethanol (I). The hydrogenation can be carried out in an alkanol such as ethanol containing 1% of a concentrated strong acid such as hydrochloric acid, sulphuric acid, trifluoroacetic acid over a catalyst commonly used in such hydrogenations, for example precious metal catalysts such as a platinum catalyst, preferably at room temperature. The pressure at which the hydrogenation is carried out is not critical, although atmospheric pressure is preferred.
It should be noted that the hydrogenation does not stop at the compound I and that continuation of the hydrogenation with excess hydrogen will lead to derivatives of the compound I with the quinoline ring being partially or totally reduced.
Therefore, the uptake of hydrogen during the hydrogenation should be closely monitored and the hydrogenation should be stopped to obtain compound I after the theoretical amount of hydrogen has been absorbed; that is to say, when three moles of hydrogen per mole of compound of formula II have been absorbed.
Depending upon the nature of the acid used in the hydrogenation, compound I is recovered in the form of a salt (e.g. in the form of a hydrochloride). Isolation of the salt, conversion of the salt into the free base and purification can be carried out according to conventional methods such as crystallisation, chromatography and treatment with a base (e.g. with sodium methoxide in methanolic solution).
The erythro a - 2 - piperidyl - 2,8 - bis(trifluoromethyl) - 4 quinolinemethanol has been shown to be highly active against Plasmodium berghei in mice and Plasmodium falciparum in Aotus monkeys. In man, erythro a - 2 - piperidyl - 2,8, - bis(trifluoromethyl) - 4 - quinolinemethanol was highly effective against chloroquine-sensitive strains of Plasmodium falciparum [Tremholme et al.,
Science 190, 792 (1975)].
The following Examples illustrate the present invention:
Example I
To 400 ml of anhydrous diethyl ether were added 23.5 ml of a 2.04-M solution of n-butyllithium in hexane. To the resulting stirred solution was added at -700C under argon a solution of 16.5 g of 2,8 - bis(trifluoromethyl) - 4 - bromoquinoline dissolved in 200 ml of anhydrous diethyl ether at such a rate as to maintain a temperature of -70"C. After completion of the addition, the stirring was continued for 1 hour at the same temperature and then 5.35 g of freshly distilled 2pyridinecarboxaldehyde dissolved in 100 ml of anhydrous diethyl ether were added slowly. The mixture was stirred at -700C for an additional hour, hydrolysed with 20 ml of water and allowed to warm to room temperature. The organic layer was separated, washed with two 100 ml portions of water, dried over sodium sulphate and evaporated to dryness under reduced pressure. Crystallisation of the residue from ether/hexane gave 11.1 g (620) of a - 2 - pyridyl - 2,8 - bis(trifluoromethyl) - 4 - quinolinemethanol of melting point 1350-1390C.
Sublimation of part of the crystalline material at 1350--1400C/0.1 mm gave analytically pure a - 2 - pyridyl - 2,8 - bis(trifluoromethyl) - 4 quinolinemethanol of melting point 1390-1410C.
A mixture of 1000 ml of ethanol and 10 ml of concentrated hydrochloric acid
containing 1 g of platinum oxide was presaturated with hydrogen at room temperature and atmospheric pressure. A solution of 12.5 g of a - 2 - pyridyl 2,8 - bis(trifluoromethyl) - 4 - quinolinemethanol dissolved in 100 ml of ethanol was injected into the flask through a septum. The stirred mixture was hydrogenated under slight positive pressure at room temperature until 2340 ml of hydrogen had been consumed. The catalyst was removed by filtration through "Celite" (Trade
Mark) and the filtrate was evaporated to dryness to give 13.2 g of a light yellow solid. Recrystallisation of this solid from acetonitrile gave, in two crops, a total of 10.1 g (72.5%) of erythro a - 2 - piperidyl - 2,8 - bis(trifluoromethyl) - 4 quinoline - methanol hydrochloride of melting point 2590-2610C. An analytical sample of the hydrochloride was obtained by recrystallisation from acetonitrile and drying for 20 hours at 1000C/0.l mm; melting point 2590-2610C.
A solution of 0.224 g of erythro a - 2 - piperidyl - 2,8 - bis(trifluoromethyl) 4 - quinolinemethanol hydrochloride in 5 ml of methanol was combined with 2 ml of a 2.7-N methanolic solution of sodium methoxide. The solution was evaporated to dryness under reduced pressure and the residue was taken up in 10 ml of anhydrous diethyl ether. Insoluble material was removed by filtration and the filtrate was evaporated to dryness under reduced pressure. Slow crystallisation of the white solid residue from 1.5 ml of benzene gave 140 mg (68.5%) of erythro a 2 - piperidyl - 2,8 - bis(trifluoromethyl) - 4 - quinolinemethanol of melting point 174"--1760C.
The starting material was prepared as follows:
To a stirred mixture of 73.6 g of ethyl 4,4,4-trifluoroacetoacetate in 400 ml of polyphosphoric acid were added slowly at 100"C 64.4 g of 2-trifluoromethylaniline.
After completion of the addition, the mixture was heated at 1400--15i)OC with continued stirring for 1.5 hours, kept at room temperature overnight and then poured on to 1200 g of crushed ice with vigorous stirring. Stirring was continued until the ice had melted. The crystalline precipitate was collected by filtration and dissolved in 2 litres of chloroform. The organic layer was washed with 1 litre of water, dried over anhydrous sodium sulphate, filtered and concentrated under reduced pressure until crystallisation was observed. The crystalline material was collected by filtration to yield 67.14 g (60%) of 2,8-bis(trifluoromethyl) - 4 quinolinol of melting point 1290-1310C. An analytical sample of the quinolinol was obtained by recrystallisation from chloroform; melting point l300-l3l0C (white needles).
A suspension of 25.5 g of 2,8 - bis(trifluoromethyl) - 4 - quinolinol in 50 ml of phosphorus tribromide was heated to 70"C. 70 g (25 ml) of phosphorus oxybromide were added in one portion. The temperature was raised to 1400C and the mixture was maintained at this temperature of 4 hours. The mixture was cooled to room temperature and added carefully to 1 litre of crushed ice with vigorous stirring.
Additional ice was added, as necessary, until the exothermic reaction ceased. The solution was made alkaline with 12-N sodium hydroxide while again adding ice for cooling. The yellow solid precipitate was collected by filtration and air-dried overnight. Sublimation at 500C/0.2 mm yielded 28.6 g (92%) of 2,8 bis(trifluoromethyl) - 4 - bromoquinoline of melting point 570-580C. 1 g of the sublimed material was recrystallised from 95% ethanol to yield 0.7 g of the desired bromoquinoline of melting point 59"--60"C.
Example 2
A solution of 6 litres of n-butyllithium in 30 litres of dry n-hexane was placed in a 60 litre vessel, cooled to -700C under argon with efficient stirring and then treated dropwise with a pre-cooled solution of 1800 g of 2,8 - bis(trifluoromethyl) 4 - bromoquinoline in 4 litres of dry diethyl ether. After stirring for 1 hour with constant cooling, a solution of 1170 g of 2 - pyridine - carboxaldehyde was added over a period of 45 minutes. After an additional hour, 25 litres of ether and 1 litre of water were added portionwise to the suspension formed. The solution thus obtained was extracted with 10 litres of water, the aqueous phase was rinsed with 10 litres of diethyl ether and the entire ether phase was washed until neutral with two 10 litre portions of water, 10 litres of 0.5-N hydrochloric acid and twice with 10 litres of water each time. The organic layer was dried over anhydrous sodium sulphate and evaporated to dryness under reduced pressure. The crude product obtained (19996 g) was purified by treatment with 5 litres of petroleum ether and drying. There were thus obtained 1709 g (87.5%) of pure a - 2 - pyridyl - 2,8 bis(trifluoromethyl) - 4 - quinolinemethanol of melting point 1400--142"C.
The foregoing quinolinemethanol was then hydrogenated to yield erythro a 2 - piperidyl - 2,8 - bis(trifluoromethyl) - 4 - quinoline - methanol in a manner analogous to that described in Example 1.
Claims (6)
1) A process for the manufacture of erythro a - 2 piperidyl - 2,8 bis(trifluoromethyl) - 4 - quinolinemethanol, which process comprises reacting 2,8 - bis(trifluoromethyl) - 4 - bromoquinoline with n - butyllithium, treating the resulting 2,8 - bis(trifluoromethyl) - 4 - quinolyllithium with 2pyridinecarboxaldehyde and hydrogenating the resulting a - 2 - pyridyl - 2,8 bis(trifluoromethyl) - 4 - quinolinemethanol with three moles of hydrogen per mole to give the desired erythro a - 2 - piperidyl - 2,8 - bis(trifluoromethyl) - 4 quinolinemethanol.
2) A process according to claim 1, wherein 2,8 - bis(trifluoromethyl) - 4 quinolyllithium is reacted in situ with 2-pyridinecarboxaldehyde.
3) A process according to claim 1 or claim 2, wherein the hydrogenation is carried out in the presence of a precious metal catalyst.
4) A process according to any one of claims 1 to 3 inclusive, wherein the hydrogenation is carried out in the presence of a platinum catalyst.
5) A process for the manufacture of erythro α - 2 - piperidyl - 2,8 - bis(trifluoromethyl) - 4 - quinolinemethanol, substantially as hereinbefore described with reference to the foregoing Examples.
6) Erythro a - 2 - piperidyl - 2,8 - bis(trifluoromethyl) - 4 - quinolinemethanol, when manufactured by the process claimed in any one of claims 1 to 5 inclusive or by an obvious chemical equivalent thereof.
7) a - 2 - Pyridyl - 2,8 - bis(trifluoromethyl) - 4 @ quinolinemethanol.
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US76981677A | 1977-02-17 | 1977-02-17 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| GB1594282A true GB1594282A (en) | 1981-07-30 |
Family
ID=25086585
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| GB6207/78A Expired GB1594282A (en) | 1977-02-17 | 1978-02-16 | Process for the manufacture of mefloquine |
Country Status (9)
| Country | Link |
|---|---|
| JP (1) | JPS53103478A (en) |
| AT (1) | AT358044B (en) |
| BE (1) | BE864002A (en) |
| CH (2) | CH640530A5 (en) |
| DE (1) | DE2806909A1 (en) |
| FR (1) | FR2381044A1 (en) |
| GB (1) | GB1594282A (en) |
| IT (1) | IT1158450B (en) |
| NL (1) | NL7801787A (en) |
Families Citing this family (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE2940443A1 (en) * | 1979-10-05 | 1981-04-16 | Basf Ag, 6700 Ludwigshafen | METHOD FOR PRODUCING ERYTHRO- (ALPHA) -2-PIPERIDYL-2,8-BIS- (TRIFLUORMETHYL) -4-QUINOLINE-METHANOL |
| FR2485014A1 (en) * | 1980-06-20 | 1981-12-24 | Pharmindustrie | NOVEL DERIVATIVES OF (QUINOLYL-2, -3 OR -4) -1 (PIPERIDYL OR PYRROLIDINYL-2 OR -3) -2 OR -3 ETHANONE OR PROPANONE, PROCESSES FOR THEIR PREPARATION, AND THEIR USE AS MEDICAMENTS |
| US4507482A (en) * | 1982-04-14 | 1985-03-26 | Hoffmann-La Roche Inc. | Purification of mefloquin hydrochloride |
| DK160499C (en) * | 1982-09-10 | 1991-08-26 | Hoffmann La Roche | PROCEDURE FOR MANUFACTURING MEFLOQUIN AND INTERMEDIATE FOR USE THEREOF |
| JPH0234129U (en) * | 1989-05-25 | 1990-03-05 | ||
| HUT54363A (en) * | 1989-07-25 | 1991-02-28 | Alkaloida Vegyeszeti Gyar | Process for producing pyridyl-methyl-quinolin derivatives |
| GB9819382D0 (en) * | 1998-09-04 | 1998-10-28 | Cerebrus Ltd | Chemical compounds I |
Family Cites Families (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CH590274A5 (en) * | 1970-03-16 | 1977-07-29 | Hoffmann La Roche | |
| CH605916A5 (en) * | 1973-12-07 | 1978-10-13 | Hoffmann La Roche |
-
1978
- 1978-02-15 FR FR7804271A patent/FR2381044A1/en active Granted
- 1978-02-16 AT AT113378A patent/AT358044B/en not_active IP Right Cessation
- 1978-02-16 CH CH169578A patent/CH640530A5/en not_active IP Right Cessation
- 1978-02-16 IT IT20331/78A patent/IT1158450B/en active
- 1978-02-16 BE BE185206A patent/BE864002A/en not_active IP Right Cessation
- 1978-02-16 NL NL7801787A patent/NL7801787A/en not_active Application Discontinuation
- 1978-02-16 JP JP1601378A patent/JPS53103478A/en active Granted
- 1978-02-16 GB GB6207/78A patent/GB1594282A/en not_active Expired
- 1978-02-17 DE DE19782806909 patent/DE2806909A1/en active Granted
-
1982
- 1982-05-14 CH CH301282A patent/CH640531A5/en not_active IP Right Cessation
Also Published As
| Publication number | Publication date |
|---|---|
| CH640530A5 (en) | 1984-01-13 |
| CH640531A5 (en) | 1984-01-13 |
| ATA113378A (en) | 1980-01-15 |
| JPS6257631B2 (en) | 1987-12-02 |
| FR2381044A1 (en) | 1978-09-15 |
| JPS53103478A (en) | 1978-09-08 |
| DE2806909C2 (en) | 1988-04-07 |
| AT358044B (en) | 1980-08-11 |
| IT7820331A0 (en) | 1978-02-16 |
| DE2806909A1 (en) | 1978-08-24 |
| BE864002A (en) | 1978-08-16 |
| IT1158450B (en) | 1987-02-18 |
| FR2381044B1 (en) | 1983-06-10 |
| NL7801787A (en) | 1978-08-21 |
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Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PS | Patent sealed [section 19, patents act 1949] | ||
| 704A | Declaration that licence is not available as of right for an excepted use (par. 4a/1977) | ||
| 732 | Registration of transactions, instruments or events in the register (sect. 32/1977) | ||
| PCNP | Patent ceased through non-payment of renewal fee |
Effective date: 19930216 |