CN113651765A - Synthesis of afurana - Google Patents
Synthesis of afurana Download PDFInfo
- Publication number
- CN113651765A CN113651765A CN202110964614.1A CN202110964614A CN113651765A CN 113651765 A CN113651765 A CN 113651765A CN 202110964614 A CN202110964614 A CN 202110964614A CN 113651765 A CN113651765 A CN 113651765A
- Authority
- CN
- China
- Prior art keywords
- trifluoromethyl
- chloro
- phenyl
- naphthacenitrile
- solvent
- 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.)
- Pending
Links
- 238000003786 synthesis reaction Methods 0.000 title abstract description 6
- 230000015572 biosynthetic process Effects 0.000 title abstract description 5
- -1 3-chloro-5- (trifluoromethyl) phenyl Chemical group 0.000 claims abstract description 32
- 238000000034 method Methods 0.000 claims abstract description 17
- WTDHULULXKLSOZ-UHFFFAOYSA-N Hydroxylamine hydrochloride Chemical compound Cl.ON WTDHULULXKLSOZ-UHFFFAOYSA-N 0.000 claims abstract description 16
- 238000002360 preparation method Methods 0.000 claims abstract description 14
- ACUOJJBRHCFOKT-UHFFFAOYSA-N 2-amino-n-(2,2,2-trifluoroethyl)acetamide Chemical compound NCC(=O)NCC(F)(F)F ACUOJJBRHCFOKT-UHFFFAOYSA-N 0.000 claims abstract description 7
- 230000009471 action Effects 0.000 claims abstract description 7
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 24
- 239000002904 solvent Substances 0.000 claims description 22
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 18
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 18
- 238000006243 chemical reaction Methods 0.000 claims description 18
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 claims description 12
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 claims description 8
- JWUJQDFVADABEY-UHFFFAOYSA-N 2-methyltetrahydrofuran Chemical compound CC1CCCO1 JWUJQDFVADABEY-UHFFFAOYSA-N 0.000 claims description 8
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 claims description 8
- 239000003153 chemical reaction reagent Substances 0.000 claims description 8
- 239000008096 xylene Substances 0.000 claims description 8
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 claims description 7
- 229960000549 4-dimethylaminophenol Drugs 0.000 claims description 6
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 6
- SJRJJKPEHAURKC-UHFFFAOYSA-N N-Methylmorpholine Chemical compound CN1CCOCC1 SJRJJKPEHAURKC-UHFFFAOYSA-N 0.000 claims description 6
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 6
- 239000012046 mixed solvent Substances 0.000 claims description 5
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 5
- GQHTUMJGOHRCHB-UHFFFAOYSA-N 2,3,4,6,7,8,9,10-octahydropyrimido[1,2-a]azepine Chemical compound C1CCCCN2CCCN=C21 GQHTUMJGOHRCHB-UHFFFAOYSA-N 0.000 claims description 4
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 claims description 4
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 4
- 230000008569 process Effects 0.000 claims description 4
- 239000003513 alkali Substances 0.000 claims description 3
- 239000002585 base Substances 0.000 claims description 3
- 229910006124 SOCl2 Inorganic materials 0.000 claims description 2
- 230000003197 catalytic effect Effects 0.000 claims description 2
- 239000012973 diazabicyclooctane Substances 0.000 claims description 2
- AUHZEENZYGFFBQ-UHFFFAOYSA-N mesitylene Substances CC1=CC(C)=CC(C)=C1 AUHZEENZYGFFBQ-UHFFFAOYSA-N 0.000 claims description 2
- 125000001827 mesitylenyl group Chemical group [H]C1=C(C(*)=C(C([H])=C1C([H])([H])[H])C([H])([H])[H])C([H])([H])[H] 0.000 claims description 2
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 2
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Substances ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 claims description 2
- IMNIMPAHZVJRPE-UHFFFAOYSA-N triethylenediamine Chemical compound C1CN2CCN1CC2 IMNIMPAHZVJRPE-UHFFFAOYSA-N 0.000 claims description 2
- 239000000203 mixture Substances 0.000 claims 3
- 238000006482 condensation reaction Methods 0.000 abstract description 6
- 125000002560 nitrile group Chemical group 0.000 abstract description 3
- 239000007858 starting material Substances 0.000 abstract description 2
- 230000002194 synthesizing effect Effects 0.000 abstract 1
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 15
- 239000012074 organic phase Substances 0.000 description 9
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 8
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 6
- 241000282472 Canis lupus familiaris Species 0.000 description 6
- 239000003814 drug Substances 0.000 description 6
- 239000000047 product Substances 0.000 description 6
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 5
- 239000007787 solid Substances 0.000 description 5
- 239000000706 filtrate Substances 0.000 description 4
- BTCSSZJGUNDROE-UHFFFAOYSA-N gamma-aminobutyric acid Chemical compound NCCCC(O)=O BTCSSZJGUNDROE-UHFFFAOYSA-N 0.000 description 4
- 238000003756 stirring Methods 0.000 description 4
- WEQPBCSPRXFQQS-UHFFFAOYSA-N 4,5-dihydro-1,2-oxazole Chemical compound C1CC=NO1 WEQPBCSPRXFQQS-UHFFFAOYSA-N 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- 239000003054 catalyst Substances 0.000 description 3
- 238000001816 cooling Methods 0.000 description 3
- 229940079593 drug Drugs 0.000 description 3
- 238000001035 drying Methods 0.000 description 3
- 239000003446 ligand Substances 0.000 description 3
- 229910052757 nitrogen Inorganic materials 0.000 description 3
- LYGJENNIWJXYER-UHFFFAOYSA-N nitromethane Chemical compound C[N+]([O-])=O LYGJENNIWJXYER-UHFFFAOYSA-N 0.000 description 3
- 244000045947 parasite Species 0.000 description 3
- OGNSCSPNOLGXSM-UHFFFAOYSA-N (+/-)-DABA Natural products NCCC(N)C(O)=O OGNSCSPNOLGXSM-UHFFFAOYSA-N 0.000 description 2
- HPBFCKYJZVYHRS-UHFFFAOYSA-N 4-(hydroxyiminomethyl)naphthalene-1-carboxylic acid Chemical compound C1=CC=C2C(C=NO)=CC=C(C(O)=O)C2=C1 HPBFCKYJZVYHRS-UHFFFAOYSA-N 0.000 description 2
- YNFPTDDRPNHRHQ-UHFFFAOYSA-N 4-acetyl-n-[2-oxo-2-(2,2,2-trifluoroethylamino)ethyl]naphthalene-1-carboxamide Chemical compound C1=CC=C2C(C(=O)C)=CC=C(C(=O)NCC(=O)NCC(F)(F)F)C2=C1 YNFPTDDRPNHRHQ-UHFFFAOYSA-N 0.000 description 2
- 241000238876 Acari Species 0.000 description 2
- 241000238631 Hexapoda Species 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- 241000002163 Mesapamea fractilinea Species 0.000 description 2
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 2
- 125000003368 amide group Chemical group 0.000 description 2
- 210000000941 bile Anatomy 0.000 description 2
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 2
- 239000007910 chewable tablet Substances 0.000 description 2
- 229940068682 chewable tablet Drugs 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 125000004185 ester group Chemical group 0.000 description 2
- 239000012065 filter cake Substances 0.000 description 2
- 238000001914 filtration Methods 0.000 description 2
- 229960003692 gamma aminobutyric acid Drugs 0.000 description 2
- 238000001727 in vivo Methods 0.000 description 2
- 208000015181 infectious disease Diseases 0.000 description 2
- 239000012528 membrane Substances 0.000 description 2
- 210000002569 neuron Anatomy 0.000 description 2
- 230000007935 neutral effect Effects 0.000 description 2
- 229910052763 palladium Inorganic materials 0.000 description 2
- 238000000746 purification Methods 0.000 description 2
- 238000006798 ring closing metathesis reaction Methods 0.000 description 2
- 238000007086 side reaction Methods 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- JXPDQVDWOLFMMB-UHFFFAOYSA-N 1-chloro-3-(trifluoromethyl)-5-(3,3,3-trifluoroprop-1-en-2-yl)benzene Chemical compound FC(F)(F)C(=C)C1=CC(Cl)=CC(C(F)(F)F)=C1 JXPDQVDWOLFMMB-UHFFFAOYSA-N 0.000 description 1
- OXDDDHGGRFRLEE-UHFFFAOYSA-N 4-[5-[3-chloro-5-(trifluoromethyl)phenyl]-5-(trifluoromethyl)-4h-1,2-oxazol-3-yl]-n-[2-oxo-2-(2,2,2-trifluoroethylamino)ethyl]naphthalene-1-carboxamide Chemical compound C12=CC=CC=C2C(C(=O)NCC(=O)NCC(F)(F)F)=CC=C1C(C1)=NOC1(C(F)(F)F)C1=CC(Cl)=CC(C(F)(F)F)=C1 OXDDDHGGRFRLEE-UHFFFAOYSA-N 0.000 description 1
- ZNBNBTIDJSKEAM-UHFFFAOYSA-N 4-[7-hydroxy-2-[5-[5-[6-hydroxy-6-(hydroxymethyl)-3,5-dimethyloxan-2-yl]-3-methyloxolan-2-yl]-5-methyloxolan-2-yl]-2,8-dimethyl-1,10-dioxaspiro[4.5]decan-9-yl]-2-methyl-3-propanoyloxypentanoic acid Chemical compound C1C(O)C(C)C(C(C)C(OC(=O)CC)C(C)C(O)=O)OC11OC(C)(C2OC(C)(CC2)C2C(CC(O2)C2C(CC(C)C(O)(CO)O2)C)C)CC1 ZNBNBTIDJSKEAM-UHFFFAOYSA-N 0.000 description 1
- DOCFRBZXXQJPBD-UHFFFAOYSA-N 4-acetylnaphthalene-1-carboxylic acid Chemical compound C1=CC=C2C(C(=O)C)=CC=C(C(O)=O)C2=C1 DOCFRBZXXQJPBD-UHFFFAOYSA-N 0.000 description 1
- 241001465677 Ancylostomatoidea Species 0.000 description 1
- GYNZKWNKHZGXQN-PXNMLYILSA-N CC(C=C(C=C1)C(/C=C(\C(F)(F)F)/C2=CC(Cl)=CC(Cl)=C2)=O)=C1C#N Chemical compound CC(C=C(C=C1)C(/C=C(\C(F)(F)F)/C2=CC(Cl)=CC(Cl)=C2)=O)=C1C#N GYNZKWNKHZGXQN-PXNMLYILSA-N 0.000 description 1
- 241000282465 Canis Species 0.000 description 1
- 108091006146 Channels Proteins 0.000 description 1
- 108010062745 Chloride Channels Proteins 0.000 description 1
- 102000011045 Chloride Channels Human genes 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 1
- 102100034983 E3 ubiquitin-protein ligase ZNRF4 Human genes 0.000 description 1
- 101000802410 Homo sapiens E3 ubiquitin-protein ligase ZNRF4 Proteins 0.000 description 1
- 238000006736 Huisgen cycloaddition reaction Methods 0.000 description 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 1
- 241001465754 Metazoa Species 0.000 description 1
- 150000001204 N-oxides Chemical class 0.000 description 1
- 241000244206 Nematoda Species 0.000 description 1
- 208000000291 Nematode infections Diseases 0.000 description 1
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 1
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 1
- 230000000895 acaricidal effect Effects 0.000 description 1
- 239000000642 acaricide Substances 0.000 description 1
- 238000007605 air drying Methods 0.000 description 1
- 230000000507 anthelmentic effect Effects 0.000 description 1
- 239000008346 aqueous phase Substances 0.000 description 1
- 230000005540 biological transmission Effects 0.000 description 1
- 150000004768 bromobenzenes Chemical class 0.000 description 1
- ARPUHYJMCVWYCZ-UHFFFAOYSA-N ciprofloxacin hydrochloride hydrate Chemical compound O.Cl.C12=CC(N3CCNCC3)=C(F)C=C2C(=O)C(C(=O)O)=CN1C1CC1 ARPUHYJMCVWYCZ-UHFFFAOYSA-N 0.000 description 1
- 238000005859 coupling reaction Methods 0.000 description 1
- 238000006352 cycloaddition reaction Methods 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 244000078703 ectoparasite Species 0.000 description 1
- 239000002360 explosive Substances 0.000 description 1
- 239000007789 gas Substances 0.000 description 1
- 230000002496 gastric effect Effects 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 239000001257 hydrogen Substances 0.000 description 1
- 229910052739 hydrogen Inorganic materials 0.000 description 1
- 229910000378 hydroxylammonium sulfate Inorganic materials 0.000 description 1
- 230000006872 improvement Effects 0.000 description 1
- 239000012535 impurity Substances 0.000 description 1
- 238000009776 industrial production Methods 0.000 description 1
- 239000002917 insecticide Substances 0.000 description 1
- 150000002576 ketones Chemical class 0.000 description 1
- 210000003734 kidney Anatomy 0.000 description 1
- 238000011031 large-scale manufacturing process Methods 0.000 description 1
- 238000002386 leaching Methods 0.000 description 1
- 210000004185 liver Anatomy 0.000 description 1
- 229910052751 metal Inorganic materials 0.000 description 1
- 239000002184 metal Substances 0.000 description 1
- CKVMAPHTVCTEMM-ALPQRHTBSA-N milbemycin oxime Chemical compound O1[C@H](C)[C@@H](C)CC[C@@]11O[C@H](C\C=C(C)\C[C@@H](C)\C=C\C=C/2[C@]3([C@H](C(=O)O4)C=C(C)C(=N/O)/[C@H]3OC\2)O)C[C@H]4C1.C1C[C@H](C)[C@@H](CC)O[C@@]21O[C@H](C\C=C(C)\C[C@@H](C)\C=C\C=C/1[C@]3([C@H](C(=O)O4)C=C(C)C(=N/O)/[C@H]3OC\1)O)C[C@H]4C2 CKVMAPHTVCTEMM-ALPQRHTBSA-N 0.000 description 1
- 229940099245 milbemycin oxime Drugs 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 239000002858 neurotransmitter agent Substances 0.000 description 1
- 229940058878 nexgard Drugs 0.000 description 1
- 239000012071 phase Substances 0.000 description 1
- 230000036470 plasma concentration Effects 0.000 description 1
- 230000001242 postsynaptic effect Effects 0.000 description 1
- 239000002243 precursor Substances 0.000 description 1
- 238000004321 preservation Methods 0.000 description 1
- 230000003518 presynaptic effect Effects 0.000 description 1
- 108090000623 proteins and genes Proteins 0.000 description 1
- 102000004169 proteins and genes Human genes 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 230000009467 reduction Effects 0.000 description 1
- 239000000741 silica gel Substances 0.000 description 1
- 229910002027 silica gel Inorganic materials 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 210000002784 stomach Anatomy 0.000 description 1
- 230000001839 systemic circulation Effects 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D261/00—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings
- C07D261/02—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings not condensed with other rings
- C07D261/04—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C253/00—Preparation of carboxylic acid nitriles
- C07C253/30—Preparation of carboxylic acid nitriles by reactions not involving the formation of cyano groups
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Nitrogen And Oxygen As The Only Ring Hetero Atoms (AREA)
Abstract
The invention relates to the synthesis of afuravir, in particular to a method for synthesizing afuravir by using 1- (3-chloro-5- (trifluoromethyl) phenyl) -2,2, 2-trifluoroethyl-1-ketone and 4-acetyl-1-naphthanil as starting materials and directly connecting a nitrile group of an intermediate in the last step with Zn (OTf)2The preparation of the alfilamide is realized by the condensation reaction of the alfilamide and 2-amino-N- (2,2, 2-trifluoroethyl) acetamide under the action of hydroxylamine hydrochloride.
Description
Technical Field
The invention belongs to the field of chemical synthesis, and particularly relates to a novel preparation method of alfilana.
Background
Aforana (English name: Afxolaner) is one of the members of the isoxazoline family, and the drug is used as an isoxazoline insecticide and acaricide, and can block the transmission of chloride ions from a presynaptic membrane to a postsynaptic membrane by acting on a ligand-gated chloride ion channel, particularly a channel gated by a neurotransmitter gamma-aminobutyric acid (GABA), so that the activity of insect neurons is increased and the insect neurons are excited and die excessively. The medicine is approved by the American FDA and jointly acts with the milbemycin oxime, and can conveniently meet the requirement of a pet owner of 'internal and external compatibility' as the first oral in-vivo and external parasite expelling product for dogs, and 6 major in-vivo and external common parasites such as heartworms, roundworms, hookworms, whipworms, fleas, ticks and the like can be expelled and prevented by dogs only taking the medicine once per month. The department of agriculture in China approved the imported drug, namely the afulloxime chewable tablet, in 2018 to be used for treating flea and tick infections of dogs and simultaneously preventing heartworm infections of dogs and/or treating gastrointestinal nematode infections. In addition, the afuram can also be independently prepared into a medicament (Nixin, NexGard, afuram chewable tablet), and is the first oral anthelmintic for dogs which can kill two parasites, namely ticks and fleas in China.
Further studies have found that alfilamide, as a palatable beef-flavored product, can be administered to animals on an empty stomach or with food. After oral administration, the canine is rapidly absorbed into the systemic circulation. Aframa has high protein binding (> 99%) and the unbound fraction is moderately distributed in the tissue. Free alfacarina is excreted via bile, metabolized alfacarina is metabolized via liver, and subsequently cleared via bile and kidney, and the drug is slowly cleared from the body. This slow clearance allows alfilana to have a longer half-life in dogs and retain activity against ectoparasites. In the oral bioavailability study, alfopram is rapidly absorbed (Tmax 2-4 hours), the maximum plasma concentration (Cmax) is 1,655 ± 332ng/ml, showing a bioavailability of 73.9% and a terminal plasma half-life of 15 days.
Aforana is more complex in structural formula and has the chemical name of 4- [5- [ 3-chloro-5- (trifluoromethyl) phenyl ] -4, 5-dihydro-5- (trifluoromethyl) -3-isoxazolyl ] -N- [ 2-oxo-2- [ (2,2, 2-trifluoroethyl) amino ] ethyl ] -1-naphthamide, and has the following chemical structural formula:
the synthesis of afuravir has been reported in some patent documents. The synthetic route of patent WO2009126668 starts from the condensation reaction of 4-acetyl-1-naphthoic acid and 2-amino-N- (2,2, 2-trifluoroethyl) acetamide to prepare 4-acetyl-N- (2-oxo-2- ((2,2, 2-trifluoroethyl) amino) ethyl) -1-naphthamide; then 4-acetyl-N- (2-oxo-2- ((2,2, 2-trifluoroethyl) amino) ethyl) -1-naphthamide and 1- (3-chloro-5- (trifluoromethyl) phenyl) -2,2, 2-trifluoroethyl-1-ketone are subjected to condensation reaction under the action of alkali to prepare (Z) -4- (3- (3-chloro-5- (trifluoromethyl) phenyl) -4,4, 4-trifluorobutyl-2-enoyl) -N- (2-oxo-2- ((2,2, 2-trifluoroethyl) amino) ethyl) -1-naphthamide; finally, the (Z) -4- (3- (3-chloro-5- (trifluoromethyl) phenyl) -4,4, 4-trifluoro butyl-2-alkenoyl) -N- (2-oxo-2- ((2,2, 2-trifluoroethyl) amino) ethyl) -1-naphthamide reacts with hydroxylamine sulfate to prepare the alfilamide. The relevant synthetic route is as follows:
chinese patent CN101765592 reported another synthetic route to afuravir. The synthetic route involves the reaction of an ester compound and hydroxylamine hydrochloride to prepare 4- ((hydroxyimino) methyl) -1-naphthoate; then 4- ((hydroxyimino) methyl) -1-naphthoate is reacted with NCS and alkali to produce an intermediate N-oxide, which is further subjected to 1, 3-dipolar cycloaddition reaction with 1-chloro-3- (trifluoromethyl) -5- (3,3, 3-trifluoroprop-1-en-2-yl) benzene to prepare 4- (5- (3-chloro-5- (trifluoromethyl) phenyl) -5- (trifluoromethyl) -4, 5-dihydroisoxazolyl-3-yl) -1-naphthoate; finally, the condensation reaction of 4- (5- (3-chloro-5- (trifluoromethyl) phenyl) -5- (trifluoromethyl) -4, 5-dihydroisoxazolyl-3-yl) -1-naphthoate with 2-amino-N- (2,2, 2-trifluoroethyl) acetamide realizes the preparation of afuramide. Patent CN109879826 also adopts a similar synthetic route, except that the order of addition of the raw materials is changed. The related synthetic route of patent CN101765592 is as follows:
patent CN112457267 reports another synthetic route for the preparation of alfilamide, the key of which is the dipolar cycloaddition reaction of nitromethane intermediate and 1-chloro-3- (trifluoromethyl) -5- (3,3, 3-trifluoroprop-1-en-2-yl) benzene compound. The starting material nitromethane compound is prepared by bromobenzene derivatives and nitromethane through coupling reaction under the action of palladium catalyst and ligand. Although the synthetic route is short, the following defects exist in the route: relates to the use of industrially explosive nitromethane as a reaction reagent; involving the use of relatively expensive metallic palladium catalysts and ligands; the yield of each step is low. The relevant synthetic route is as follows:
in combination with the existing preparation method of afurana, we find that the reported methods all involve the step of preparing 4, 5-dihydroisoxazole intermediate by ring closure, and the existing ring closure precursor contains a plurality of active groups, such as ester group, amido group, carboxyl group and the like, and some synthetic routes involve the use of reaction reagents which are easy to explode industrially and the use of expensive metal palladium catalysts and ligands, and the active groups are very easy to participate in the reaction, thereby causing impurities in the whole synthetic process and bringing bottlenecks to subsequent product purification and industrial production. Therefore, the development of a new preparation method of the alfilana is very important for the industrialization of the alfilana, the reduction of the industrialization cost and the improvement of the market competitiveness of the product.
Disclosure of Invention
The invention aims to provide a method for preparing alfilana.
Research shows that 1- (3-chloro-5- (trifluoromethyl) phenyl) -2,2, 2-trifluoroethyl-1-ketone and 4-acetyl-1-naphthacenitrile can realize the preparation of 4- (3- (3-chloro-5- (trifluoromethyl) phenyl) -4,4, 4-trifluoro-3-hydroxybutyryl) -1-naphthacenitrile under the action of a solvent and a base; 4- (3- (3-chloro-5- (trifluoromethyl) phenyl) -4,4, 4-trifluoro-3-hydroxybutyryl) -1-naphthacenitrile further under the action of a solvent and a dehydrating reagent to obtain an alpha, beta-unsaturated ketone compound- - - (Z) -4- (3- (3-chloro-5- (trifluoromethyl) phenyl) -4,4, 4-trifluorobut-2-enonyl) -1-naphthacenitrile; (Z) -4- (3- (3-chloro-5- (trifluoromethyl) phenyl) -4,4, 4-trifluorobut-2-enoyl) -1-naphthacenitrile with hydroxylamine hydrochloride to obtain 4- (5- (3-chloro-5- (trifluoromethyl) phenyl) -5- (trifluoromethyl) -4, 5-dihydroisoxazol-3-yl) -1-naphthacenitrile; finally, 4- (5- (3-chloro-5- (trifluoromethyl) phenyl) -5- (trifluoromethyl) -4, 5-dihydroisoxazol-3-yl) -1-naphthacenitrile and 2-amino-N- (2,2, 2-trifluoroethyl) acetamide are subjected to condensation reaction to prepare the alfilamide. The method has less side reaction in the reaction process because the nitrile group does not contain active hydrogen and is a relatively inert group compared with ester group, amido group and carboxyl group. The relevant reaction scheme is as follows:
the solvent used in step 1 includes toluene, xylene, mesitylene, acetonitrile, 1, 4-dioxane, THF, 2-MeTHF and a mixed solvent of any combination of these solvents.
The base used in step 1 comprises DABCO, triethylamine, DIPEA, DBU, DMAP, N-methylmorpholine and pyridine.
The solvent used in step 2 includes acetonitrile, toluene, xylene, THF, 2-MeTHF, 1, 4-dioxane and a mixed solvent of any combination of these solvents.
The reagent used in step 2 comprises Ac2O、SOCl2And a catalytic amount of DMAP.
The solvent used in step 3 includes THF, 2-MeTHF, 1, 4-dioxane, acetonitrile and a mixed solvent of any combination of these solvents.
The reagent used in the step 4 is Zn (OTf)2Hydroxylamine hydrochloride.
The solvent used in step 4 comprises DMSO, 1, 4-dioxane and H2O, xylene, THF, 2-MeTHF, and a mixed solvent of any combination of these solvents.
According to the method for preparing the alfilamide, the relatively inert nitrile group and the 2-amino-N- (2,2, 2-trifluoroethyl) acetamide are subjected to condensation reaction to realize the preparation of the alfilamide, so that the side reaction in the whole synthesis process is less, and the method is suitable for industrial large-scale production.
Detailed Description
The following exemplary embodiments are provided to illustrate the present invention, and simple replacement and modification of the present invention by those skilled in the art are within the technical scheme of the present invention.
EXAMPLE one preparation of 4- (3- (3-chloro-5- (trifluoromethyl) phenyl) -4,4, 4-trifluoro-3-hydroxybutyryl) -1-naphthacenitrile
Under the protection of nitrogen, 4-acetyl-1-naphthalene is added into a four-mouth bottle in sequenceCarbonitrile (65g,333.0mmol), 1- (3-chloro-5- (trifluoromethyl) phenyl) -2,2, 2-trifluoroethyl-1-one (110.5g,399.6mmol), DMAP (66.6g,545.1mmol) and xylene (450 mL). After the addition, the system is stirred at room temperature until the system is clear. Then, the reaction system is slowly heated to 110 ℃ for reaction until the TLC tracking reaction is completed until the 4-acetyl-1-naphthanitrile is basically reacted completely. Naturally cooling the system to 25-30 ℃, and then stirring for 2.5 hours under heat preservation; system addition of H2O (450mL), adjusting the pH value of the system to be neutral by using 2M hydrochloric acid, separating an organic phase, and extracting an aqueous phase by using toluene (300mL) once; combining organic phases, drying the organic phases by anhydrous sodium sulfate, filtering the organic phases, concentrating the filtrate under high vacuum and reduced pressure until the filtrate is dry, and adding toluene (300 mL); heating the system to be clear, then further slowly cooling the system to-5 ℃, and keeping the temperature and stirring overnight; the filtrate was filtered, and the filter cake was washed with toluene (55mL) cooled in advance to give a solid, which was dried by air blow at 40 ℃ to constant weight to give 4- (3- (3-chloro-5- (trifluoromethyl) phenyl) -4,4, 4-trifluoro-3-hydroxybutyryl) -1-naphthacenitrile (off-white solid, 128.2g, 81.6%).
EXAMPLE two preparation of (Z) -4- (3- (3-chloro-5- (trifluoromethyl) phenyl) -4,4, 4-trifluorobut-2-enoyl) -1-naphthacenitrile
4- (3- (3-chloro-5- (trifluoromethyl) phenyl) -4,4, 4-trifluoro-3-hydroxybutyryl) -1-naphthacenitrile (85.0g,180.2mmol), DMAP (1.8g,14.7mmol), acetic anhydride (28.8g,282.1mmol) and toluene (250mL) were added sequentially in a three-necked flask under nitrogen. After the addition, the system was stirred at room temperature for 15 minutes, and then the system was slowly heated to 80 ℃ to react for 6.5 hours. The temperature of the system is reduced to about 50 ℃, and the water solution of dilute sodium bicarbonate (with gas released) is slowly added to adjust the pH value to be neutral while maintaining the temperature. Then the system is layered at 50 ℃, an organic phase is collected, the temperature of the organic phase is reduced to room temperature, silica gel Pad is used for passing, the obtained organic phase is subjected to high vacuum and reduced pressure to remove the solvent to obtain (Z) -4- (3- (3-chloro-5- (trifluoromethyl) phenyl) -4,4, 4-trifluoro-but-2-enoyl) -1-naphthanitrile (79.2g), and the product is directly used for the next reaction without further purification.
EXAMPLE three preparation of 4- (5- (3-chloro-5- (trifluoromethyl) phenyl) -5- (trifluoromethyl) -4, 5-dihydroisoxazol-3-yl) -1-naphthanenitrile
Under the protection of nitrogen, sodium hydroxide (20.0g,500mmol) and H are added into a reaction bottle in sequence2O (250mL), hydroxylamine hydrochloride (34.8g,500.8mmol) and THF (180mL), and after the addition, the system is stirred for 20 minutes, and the system is cooled to 5 ℃; then, a solution of (Z) -4- (3- (3, 5-dichlorophenyl) -4,4, 4-trifluorobut-2-enoyl) -2-methyl-benzonitrile (79.2g, product of example two) in THF (250mL) was added dropwise to the reaction system, and after the dropwise addition was completed, the system was slowly warmed to room temperature and stirred for 6 hours. Then removing the solvent in the system under high vacuum and reduced pressure, adding ethyl acetate (500mL) and water (500mL) into the residue, fully stirring, standing for layering, extracting water phase ethyl acetate for 1 time (200mL), combining organic phases, removing the solvent by organic phase under reduced pressure, adding ethyl acetate (300mL) into the residue, slowly dropwise adding n-heptane (600mL) after the system is heated and dissolved, slowly and naturally cooling the system to 0 ℃ after dropwise adding, stirring and crystallizing for 2 hours at 0 ℃, filtering by using a Buchner funnel, leaching the filter cake by using the n-heptane (80mL) cooled in advance, drying and drying the obtained solid for 8.0 hours in a forced air drying oven at 50 ℃ to obtain 4- (5- (3-chloro-5- (trifluoromethyl) phenyl) -5- (trifluoromethyl) -4, 5-dihydro isoxazol-3-yl) -1-naphthanenitrile (light yellow solid, 65.5g, 77.5% (combined yield in two steps)).
EXAMPLE IV preparation of Aforana
Hydroxylamine hydrochloride (525mg,7.56mmol), Zn (OTf) were added in this order to a pressure-resistant reaction flask2(2.73g,7.51mmol), 4- (5- (3-chloro-5- (trifluoromethyl) phenyl) -5- (trifluoromethyl) -4, 5-dihydroisoxazol-3-yl) -1-naphthacenitrile (35.0g,74.66mmol), 2-amino-N- (2,2, 2-trifluoroethyl) acetamide (14.1g,90.32mmol), H2O (2.5g) and xylene (60mL), and the reaction system was sealed and heated to about 110 ℃ for 8 hours. The system is naturally cooled, the solvent is removed under high vacuum, the residue is dissolved by adding ethyl acetate (300mL), the solution is filtered, and the solvent is removed from the filtrate under reduced pressure. The residue was recrystallized from ethyl acetate/heptane (75mL/225mL) to yield Aforamide (pale yellow)Solid, 38.04g, 81.4%).
Claims (8)
1. A process for the preparation of alfilana. In particular to a method for preparing 4- (3- (3-chloro-5- (trifluoromethyl) phenyl) -4,4, 4-trifluoro-3-hydroxybutyryl) -1-naphthacenitrile by 1- (3-chloro-5- (trifluoromethyl) phenyl) -2,2, 2-trifluoroethyl-1-ketone and 4-acetyl-1-naphthacenitrile under the action of a solvent and alkali; 4- (3- (3-chloro-5- (trifluoromethyl) phenyl) -4,4, 4-trifluoro-3-hydroxybutyryl) -1-naphthacenitrile is further prepared under the action of a solvent and a dehydrating reagent to obtain (Z) -4- (3- (3-chloro-5- (trifluoromethyl) phenyl) -4,4, 4-trifluorobut-2-enonyl) -1-naphthacenitrile; preparation of (Z) -4- (3- (3-chloro-5- (trifluoromethyl) phenyl) -4,4, 4-trifluorobut-2-enoyl) -1-naphthacenitrile by reaction with hydroxylamine hydrochloride to give 4- (5- (3-chloro-5- (trifluoromethyl) phenyl) -5- (trifluoromethyl) -4, 5-dihydroisoxazol-3-yl) -1-naphthacenitrile; the afuramide is prepared by the reaction of 4- (5- (3-chloro-5- (trifluoromethyl) phenyl) -5- (trifluoromethyl) -4, 5-dihydroisoxazol-3-yl) -1-naphthacenitrile and 2-amino-N- (2,2, 2-trifluoroethyl) acetamide. The reaction formula is as follows:
2. the method of claim 1, wherein the solvent used in step 1 comprises toluene, xylene, mesitylene, acetonitrile, 1, 4-dioxane, THF, 2-MeTHF, or a mixture thereof.
3. The process of claim 1, wherein the base used in step 1 comprises DABCO, triethylamine, DIPEA, DBU, DMAP, N-methylmorpholine, pyridine.
4. The method of claim 1, wherein the solvent used in step 2 comprises acetonitrile, toluene, xylene, THF, 2-MeTHF, 1, 4-dioxane, or a mixture thereof.
5. As claimed inThe method of claim 1, wherein the reagent used in step 2 comprises Ac2O、SOCl2And a catalytic amount of DMAP.
6. The method of claim 1, wherein the solvent used in step 3 comprises THF, 2-MeTHF, 1, 4-dioxane, acetonitrile, or a mixture thereof.
7. The method of claim 1, wherein the reagent used in step 4 is Zn (OTf)2Hydroxylamine hydrochloride.
8. The method of claim 1, wherein the solvent used in step 4 comprises DMSO, 1, 4-dioxane, H2O, xylene, THF, 2-MeTHF, and a mixed solvent of any combination of these solvents.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202110964614.1A CN113651765A (en) | 2021-08-20 | 2021-08-20 | Synthesis of afurana |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202110964614.1A CN113651765A (en) | 2021-08-20 | 2021-08-20 | Synthesis of afurana |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN113651765A true CN113651765A (en) | 2021-11-16 |
Family
ID=78492514
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN202110964614.1A Pending CN113651765A (en) | 2021-08-20 | 2021-08-20 | Synthesis of afurana |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN113651765A (en) |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101990530A (en) * | 2008-04-09 | 2011-03-23 | 杜邦公司 | Method for preparing 3-trifluoromethyl chalcones |
| CN111194316A (en) * | 2017-08-14 | 2020-05-22 | 勃林格殷格翰动物保健美国公司 | Pesticidal and parasiticidal pyrazole-isoxazoline compounds |
| CN112955426A (en) * | 2018-10-29 | 2021-06-11 | 巴斯夫欧洲公司 | Process for preparing optically enriched aldol compounds |
-
2021
- 2021-08-20 CN CN202110964614.1A patent/CN113651765A/en active Pending
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101990530A (en) * | 2008-04-09 | 2011-03-23 | 杜邦公司 | Method for preparing 3-trifluoromethyl chalcones |
| CN111194316A (en) * | 2017-08-14 | 2020-05-22 | 勃林格殷格翰动物保健美国公司 | Pesticidal and parasiticidal pyrazole-isoxazoline compounds |
| CN112955426A (en) * | 2018-10-29 | 2021-06-11 | 巴斯夫欧洲公司 | Process for preparing optically enriched aldol compounds |
Non-Patent Citations (3)
| Title |
|---|
| MAXIM FRIZLER ET.AL.: "Structural Optimization of Azadipeptide Nitriles Strongly Increases Association Rates and Allows the Development of Selective Cathepsin Inhibitors", J. MED. CHEM., vol. 54, pages 396 * |
| 吴梦雅等: "新型异噁唑啉类药物合成研究进展", 中国兽药杂志, vol. 54, no. 11, pages 72 - 78 * |
| 马忠华等: "三氟甲基磺酸锌催化选择性合成2-苄基-4-氯苯酚", 应用化学, vol. 27, no. 3, pages 304 - 307 * |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| ES2208265T3 (en) | TELMISARTAN POLYMORPHES, PROCEDURE FOR PREPARATION AND USE FOR THE PREPARATION OF A MEDICINAL PRODUCT. | |
| CN113512007A (en) | Synthesis of flurarana | |
| CN103965273B (en) | A kind of macrolides compound | |
| BR112018014534B1 (en) | METHOD AND INTERMEDIATE FOR THE PREPARATION OF TULATHROMYCIN | |
| KR101330063B1 (en) | The five crystal forms of the nicousamide, the preparation methods, the pharmaceutical compositions and the uses thereof | |
| CN115286544A (en) | Florfenicol derivative, preparation method and application thereof in resisting bacterial infection | |
| CN113121383A (en) | Related substances of Aforana and frailana synthesized building blocks and synthesis method thereof | |
| CN113651765A (en) | Synthesis of afurana | |
| CN112500306A (en) | Synthesis method of aspirin-lysine | |
| JP2005053916A (en) | Method for purifying moxidectin through crystallization | |
| CN111559985A (en) | Oxazolone compound with bactericidal effect and preparation method thereof | |
| TW202348229A (en) | Preparation method of pyridine nitrogen oxide compound | |
| CN112724098A (en) | Preparation method of nifuratel related substance C | |
| CN111362873B (en) | Synthetic method of gatifloxacin metabolite | |
| CN102086212B (en) | Antifungal agents of 2,3,4,5-tetrahydro-4H-benzo[b]thiopyrano[4,3,c]pyrazole-2-formamide derivatives | |
| JP2010529076A (en) | Macrocycles and uses thereof | |
| CN111233871B (en) | Preparation method of temozolomide | |
| CN103113408A (en) | Novel method for preparing fosfomycin phenylethylamine | |
| CN112724095A (en) | Crystal form of fluranide sodium and preparation method thereof | |
| CN111333512A (en) | Preparation of Aforana key intermediate 4-acetyl-1-naphthoate | |
| CN115504971B (en) | Synthetic method of loratadine | |
| CN118047728B (en) | Preparation method of fluororalrana | |
| CN112745273A (en) | Preparation method of nifuratel related substance C hydrochloride | |
| CN100390144C (en) | Process for preparing 1-methyl-5-p-toluoylpyrroel-2-acetamidoacetic acid guaiacyl ester | |
| CN103570639A (en) | Synthetic method of linezolid |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| WD01 | Invention patent application deemed withdrawn after publication |
Application publication date: 20211116 |
|
| WD01 | Invention patent application deemed withdrawn after publication |