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Umifoxolaner, ML 878
CAS 2021230-37-3
| Molecular Weight | 643.86 |
|---|---|
| Formula | C26H16ClF10N3O3 |
- 4-[(5S)-5-[3-Chloro-4-fluoro-5-(trifluoromethyl)phenyl]-4,5-dihydro-5-(trifluoromethyl)-3-isoxazolyl]-N-[2-oxo-2-[(2,2,2-trifluoroethyl)amino]ethyl]-1-naphthalenecarboxamide (ACI)
- 4-{(5S)-5-[3-chloro-4-fluoro-5-(trifluoromethyl)phenyl]-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl}-N-{2-oxo-2-[(2,2,2-trifluoroethyl)amino]ethyl}naphthalene-1-carboxamide
- ML 878
- 4-[(5S)-5-[3-chloro-4-fluoro-5-(trifluoromethyl)phenyl]-5-(trifluoromethyl)-4H-1,2-oxazol-3-yl]-N-[2-oxo-2-(2,2,2-trifluoroethylamino)ethyl]naphthalene-1-carboxamide
- WHO 11642
umifoxolaner (ML-878) is a γ-aminobutyric acid (GABA) regulated chloride channels antagonist. Umifoxolaner is an anti-parasitic agent
Animals such as mammals and birds are often susceptible to parasite infestations/infections. These parasites may be ectoparasites, such as insects, and endoparasites such as filariae and other worms. Domesticated animals, such as cats and dogs, are often infested with one or more of the following ectoparasites:
– fleas (e.g. Ctenocephalides spp., such as Ctenocephalides felis and the like);
– ticks (e.g. Rhipicephalus spp., Ixodes spp., Dermacentor spp., Amblyomma spp., and the like);
– mites (e.g. Demodex spp., Sarcoptes spp., Otodectes spp., and the like);
– lice (e.g. Trichodectes spp., Cheyletiella spp., Linognathus spp. and the like);
– mosquitoes (Aedes spp., Culex spp., Anopheles spp. and the like); and
– flies (Haematobia spp., Musca spp., Stomoxys spp., Dermatobia spp., Cochliomyia spp. and the like).
Fleas are a particular problem because not only do they adversely affect the health of the animal or human, but they also cause a great deal of psychological stress. Moreover, fleas are also vectors of pathogenic agents in animals and humans, such as dog tapeworm {Dipylidium caninum).
Similarly, ticks are also harmful to the physical and psychological health of the animal or human. However, the most serious problem associated with ticks is that they are the vector of pathogenic agents in both humans and animals. Major diseases which are caused by ticks include borreliosis (Lyme disease caused by Borrelia burgdorferi), babesiosis (or piroplasmosis caused by Babesia spp.) and rickettsioses (also known as Rocky Mountain spotted fever). Ticks also release toxins which cause inflammation or paralysis in the host. Occasionally, these toxins are fatal to the host.
Likewise, farm animals are also susceptible to parasite infestations. For example, cattle are affected by a large number of parasites. A parasite which is very prevalent among farm animals is the tick genus Rhipicephalus {Boophilus), especially those of the species microplus (cattle tick), decolor atus and annulatus. Ticks, such as Rhipicephalus {Boophilus) microplus, are particularly difficult to control because they live in the pasture where farm animals graze.
Animals and humans also suffer from endoparasitic infections including, for example, helminthiasis which is most frequently caused by a group of parasitic worms categorized as cestodes (tapeworm), nematodes (roundworm) and trematodes (flatworm or flukes). These parasites adversely affect the nutrition of the animal and cause severe economic losses in pigs, sheep, horses, and cattle as well as affecting domestic animals and poultry. Other parasites which occur in the gastrointestinal tract of animals and humans include Ancylostoma, Necator, Ascaris, Strongyloides, Trichinella, Capillaria, Toxocara, Toxascaris, Trichuris, Enterobius and parasites which are found in the blood or other tissues and organs such as filarial worms and the extra intestinal stages of Strongyloides, Toxocara and Trichinella.
SCHEME
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Patents
WO2017176948
https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2017176948&_cid=P12-M8S60W-88110-1
Cinchonanium, 9-hydroxy-6′-methoxy-1-[[3,4,5-tris(phenylmethoxy)phenyl]methyl]-, chloride (1:1), (8α,9R)- 2138407-51-7, HYDROXYL AMINE, NAOH, MDC , WATER]
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Example 5: Synthesis of (R)-IA-3 using chiral phase transfer catalyst (IIIb-13-1)
Step 1 : Synthesis of intermediate 4-2.
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1) The substituted iodobenzene starting material (SM) (200.0 g, 1.0 eq.) and THF (400 ml, 10 volumes) were placed into a 1 L reactor and the mixture was cooled to -10 to -5° C.
2) /‘-PrMgCl (340 ml, 1.1 eq.) added dropwise over 1.5 hours at -10 to -5°C to the mixture. 3) After the addition was complete, the mixture was stirred for 1 h at -10 to -5°C.
4) TLC analysis showed the complete consumption of SM (quenching sample with 1 M HCl).
5) CF3COOMe (94.7 g, 1.2 eq.) was added over an hour at -10~-5°C to the reaction mixture.
6) The mixture was stirred for another 12 hours -10~-5°C.
7) TLC analysis showed the almost complete consumption of intermediate 4-1 (quench with 1M HCl).
8) 1 M HCl 1000 ml was added dropwise to the reaction mixture slowly at 0~5°C over 2 hours.
9) The reaction mixture was extracted with hexane twice (1000 ml, 500 ml).
10) Add ^-toluenesulfonic acid 1.0 g to the organic layer and then the mixture was refluxed for 30 min.
11) The resulting mixture was then concentrated under vacuum at 20~25°C to remove the hexane.
12) Sodium bicarbonate (NaHC03, 300mg) was added and the mixture distilled in vacuum to afford compound 4-2 at 80~82°C, as a red liquid (85.0 grams, purity was 92.5% by HPLC, and the yield was 47.0%).
Step 2: Preparation of the compound of Formula (IIA-3):
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4-1 IIA-3
1) Compound 4-2 (70.0 g, 1.0 eq.) and acetonitrile (ACN, 350ml, 5 volumes) were placed into a 1 L reactor. The solid was dissolved completely.
2) Compound 4-1 (70.2 g, 1.2 eq.) was then added to the mixture, and the mixture was heated to 90-95° C.
3) The ACN/water azeotrope was removed by distillation (b.p. 79°C).
4) K2C03 (2.0 g, 0.1 eq.) was then added to the mixture.
5) Distillation was continued to remove ACN/water at 90~95°C for about 6 hours.
6) After this time, about 28% Compound 4-2 remained by HPLC.
7) The mixture was cooled to 15~20°C over 1.5 hours and solid precipitated.
8) Water (50 ml) was added and then the mixture was cooled further to 0° C over 40 min.
9) The mixture was then held at 0° C for 40 minutes.
10) The mixture was filtered and the cake was washed with 100 ml of cold ACN/water (ACN/water, 25:6v/v) to yield 75.0 g of a yellow solid after drying (purity: 95.1%, yield: 50.0%).
Step 3 : Preparation of (R)-IA-3 using chiral phase transfer catalyst IIIb-13-1
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1) The Compound of Formula IIA-3 (40.0 g, 1.0 eq.) and DCM (1.2 L, 30 volumes) were placed into a 2 L reactor; the solid was dissolved completely.
2) The mixture was cooled to 0° C and some starting material precipitated out.
3) The catalyst of formula IIIb-13-1 (1.47g, 3% mol) was added to the mixture and the mixture was cooled to -10° C.
4) Hydroxylamine (21. Og, 5.0 eq., 50% in water) was added to a solution of NaOH (15.3 g, 6.0 eq., in 5 volumes of water) in another reactor and stirred for 30 minutes.
5) The hydroxylamine/NaOH solution was then added dropwise to the 2 L reactor over about 4 hours.
6) The resulting reaction mixture was stirred for 16 h at -10°C.
7) In-process samples were taken and analyzed by HPLC until the content of starting material was < 1.0%.
8) When the reaction was complete, the mixture was warmed to 10°C and 200 ml of water was added. The mixture was stirred for 10 minutes.
9) After mixing, the mixture was allowed to stand to separate the aqueous and organic layers and the organic layer was collected.
10) The organic layer was washed with 200 ml of 5% KH2PO4.
11) The two layers were allowed to separate and organic layer was collected.
12) The organic layer was then washed with 200 ml brine, the two layers allowed to separate and the organic layer was again collected.
13) The resulting organic layer was concentrated under vacuum at 25-30°C to about 2 volumes.
14) Toluene (400 ml, 10 volumes) was charged to the vessel and concentration under vacuum was continued at 40~45°C to about 3 volumes. The solvent exchange was repeated twice more using the same procedure.
15) When the solvent exchange was complete, the solution was heated to 55-60°C.
16) The mixture was then cooled to 40° C over 1.5 hours and stirred at 40°C for 3 hours.
17) The mixture was then cooled to 25°C over 2 hours and stirred at 25°C for 3hours.
18) The mixture was finally cooled to 5-10°C over 1 hour and stirred at 8° C for 12 hours.
19) After this time, the mixture was filtered and the filter cake was washed with cold toluene (80 ml, 2 volumes).
20) The product was dried under vacuum at 70~75°C for 12h to yield a white solid (22.0 g, chiral purity: 98.0% by area using the chiral HPLC method described in Example 3, chemical purity: 97.1% by area (HPLC), yield: 48.8%). The 1H MR and LCMS spectra are consistent with the structure of the product.
Example 6: Preparation of (S)-IA-3 using chiral phase transfer catalyst IIIa-13-1
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) The compound of Formula IIA-3 (11.6 g, 1.0 eq.) and DCM 360 ml, 30 volumes) were placed into a 1 L reactor; the solid was dissolved completely.
) The mixture was cooled to 0°C and some starting material was precipitated out.
) The catalyst (0.43 g, 3% mol) was added to the resulting mixture, and the mixture was cooled to -10° C.
) Hydroxylamine (6.1 g, 5.0 eq., 50% in water) was added to a solution of NaOH (4.4 g, 6.0 eq., in 5 volumes of water) in another reactor, and the mixture was stirred for 30 minutes.
) The hydroxylamine and NaOH solution was added dropwise to the 1 L reactor over about 2 hours, after which the mixture was stirred for 16 h at -10° C.
) Samples were taken and analyzed by HPLC to monitor the extent of reaction until the content of starting material was < 1.0%.
) When the reaction was complete, the mixture was warmed to 10°C and 50 ml of water was added. The mixture was stirred for 10 minutes.
) The mixture was allowed to settle to separate the aqueous and organic layers and the organic layer was collected.
) The organic layer was washed with 50 ml of 5% KH2PO4.
0) The mixture was allowed to separate and the organic layer was collected.
1) The organic layer was washed with 50 ml brine and the organic layer was again collected. 2) The organic layer was concentrated under vacuum at 25-30°C to about 2 volumes.
3) Toluene (230 ml, 10 volumes) was charged and concentration under vacuum was continued at 40~45°C to about 3 volumes. The solvent exchange was repeated twice more using the same procedure.
14) After the solvent exchange was complete, the solution was heated to 55-60°C.
15) The mixture was then cooled to 40° C over 1.5 hours and stirred at 40° C for 3 hours.
16) The mixture was cooled to 25° C over 2 hours and stirred at 25° C for 3 hours.
17) Finally, the mixture was cooled to 5-10° C over 1 hour and stirred at 8° C for 12 hours, after which the mixture was filtered.
18) The filter cake was washed with cold toluene (25 ml, 2 volumes).
19) The product was dried under vacuum at 85~90°C for 24h, resulting in the product as a white solid (6.8 g, chiral purity: 98.7% by area using the chiral FTPLC method described in Example 3, chemical purity: 99.3% by area (FTPLC), yield: 52.1%).
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SEE ALSO US20170239218
//////////Umifoxolaner, ML 878, ML878, CS072E2C38, ML-878, WHO 11642