RU2054416C1 - METHOD FOR PRODUCTION OF FLUOROALKYL-CONTAINING α,βAZIRIDINE KETONES - Google Patents

Abstract

FIELD: organic chemistry. SUBSTANCE: desired product has formula I where R^F-X(CF₂)_n, X represents H,F, n=1-8, R² represents H, CH₃, C₆H₁₃. Said product is prepared by treatment of α,β-unsaturated ketone having formula II by equimolar amount of bromine in organic solvent. The process takes place at 15-20 C and it is followed by treatment with ammonia or by primary amines in ethanol at 15-20 C. Said treatment is carried out in medium of pentane, hexane or heptane, molar ratio of reagents being 1:3. Compound I has structural formula

, compound II has structural formula R^F-CH=CH-C(O)-Ph-CH= C(O)-Ph. EFFECT: improves efficiency of method. 1 tbl

Description

CH_α-

-Ph (1) (I) где R^F X(CF₂)_n, X H, F, n 1-8, R² H, CH₃, н-C₆H₁₃, которые могут быть использованы в качестве полупродуктов органического синтеза, мономеров для полимеризации, а также как потенциальные противоопухолевые препараты [1]
Известен способ получения α, β -азиридинкетонов, содержащих трифторметильную группу, путем 1,3-диполярного присоединения N-метил-С-трифторметил нитрона к различным алкинам с последующей перегруппировкой образующихся 3-трифторметил-4-изоксазолинов [2] N-метил-С-трифторметилнитрон получают взаимодействием трифторацетальдегида с N-метилгидроксиламином. Суммарно процесс получения фторалкилсодержащих α, β -азиридинкетонов описывается схемой 1:
CF₃-C

CF₃-

-

H

C=

R¹ H, R Ph, n-CH₃Ph, н-C₆F₁₃, COOCH₃;
R Ph, R¹ CH₃; R CH₃, R₁ COOCH₃
R R¹ COOCH₃
Способу присущи существенные недостатки:
низкие суммарные выходы целевых продуктов (от 2,7 до 28,7%);
использование трифторацетальдегида, который является неудобным в обращении, так как легко полимеризуется, а при соприкосновении с влагой воздуха образует гидраты;
способ не позволяет получать азиридинкетоны, незамещенные в α -положении к карбонильной группе, а также N-незамещенные азиридинкетоны. Тип заместителя при азоте ограничивается метилом.The invention relates to the field of organic chemistry, and in particular to a method for producing fluoroalkyl-containing α, β, α-aziridine ketones of the general formula I
R ^F -C

CH _α -

-Ph (1) (I) where R ^F X (CF ₂ ) _n , XH, F, n 1-8, R ² H, CH ₃ , n-C ₆ H ₁₃ that can be used as intermediates in organic synthesis , monomers for polymerization, as well as potential antitumor drugs [1]
A known method for producing α, β -aziridinketones containing a trifluoromethyl group by 1,3-dipolar addition of N-methyl-C-trifluoromethyl nitron to various alkynes, followed by rearrangement of the resulting 3-trifluoromethyl-4-isoxazolines [2] N-methyl-C trifluoromethylnitron is prepared by reacting trifluoroacetaldehyde with N-methylhydroxylamine. In total, the process of obtaining fluoroalkyl-containing α, β -aziridine ketones is described by scheme 1:
CF ₃ -C

CF ₃ -

-

H

C =

R ¹ H, R Ph, n-CH ₃ Ph, n-C ₆ F ₁₃ , COOCH ₃ ;
R Ph, R ¹ CH ₃ ; R CH ₃ , R ₁ COOCH ₃
RR ¹ COOCH ₃
The method has significant disadvantages:
low total yields of target products (from 2.7 to 28.7%);
the use of trifluoroacetaldehyde, which is inconvenient to use, as it polymerizes easily and forms hydrates in contact with moisture in the air;
the method does not allow to obtain aziridine ketones unsubstituted in the α-position to the carbonyl group, as well as N-unsubstituted aziridine ketones. The type of substituent for nitrogen is limited to methyl.

R^F H(CF₂)_n, n 4,6
R¹ Ph, R² H, Ph
Недостатками способа-прототипа являются:
недостаточно высокий суммарный выход целевых продуктов (42-60%);
невозможность получения N-замещенных α, β -азиридинкетонов, так как N-фенилзамещенные β -аминокетоны в реакцию не вступают, а N-алкилзамещенные β -аминокетоны (III) (алкил=СН₃, С₂Н₅, С₃Н₇) получить не удалось: они не устойчивы и при попытке выделения разлагаются на исходные продукты;
необходимость выделения и очистки промежуточного соединения β-аминокетона (III).A known method of producing fluoroalkyl-substituted α, β-aziridine ketones by the interaction of β-amino ketones (III) with iodine in the presence of potassium carbonate. β-Aminoketones (III) are obtained by the interaction of α, β-unsaturated fluorine-containing ketones (II) with ammonia and amines [3]

R ^F H (CF ₂ ) _n , n 4,6
R ¹ Ph, R ² H, Ph
The disadvantages of the prototype method are:
insufficiently high total yield of target products (42-60%);
the impossibility of obtaining N-substituted α, β-aziridine ketones, since N-phenyl substituted β-amino ketones do not react, and N-alkyl substituted β-amino ketones (III) (alkyl = CH ₃ , C ₂ H ₅ , C ₃ H ₇ ) could not be obtained: they are not stable and decompose into initial products upon attempt to isolate;
the need for isolation and purification of the intermediate β-aminoketone (III).

 The objective of the invention is to obtain fluoroalkyl-containing α, β -aziridine ketones of the general formula I in high yield, expanding their assortment and simplifying the process.

Ph (I)
Предлагаемый способ осуществляют следующим образом: к раствору α, β -непредельного кетона II в углеводородном растворителе (пентане, гексане, гептане) при перемешивании прибавляют по каплям бром и перемешивают до обесцвечивания. Затем упаривают растворитель, остаток растворяют в 96%-ном этаноле и при перемешивании прибавляют аммиак или первичный амин (жидкие амины через капельную воронку, газообразные барботируют), выдерживают 2-3 ч, упаривают этанол, к остатку прибавляют эфир. Выпавший осадок гидробромида амина отфильтровывают, упаривают эфир, а остаток перекристаллизовывают из н-гексана либо хроматографируют на колонке с силикагелем. Строение полученных соединений подтверждают ИК- и ПМР-спектроскопией.The technical result of the high yield, the expansion range of α, β -aziridinketonov formula I and process simplification achieved by treatment with α, β -nepredelnogo ketone of general formula II with an equimolar amount of bromine in a hydrocarbon solvent at 15-20 ^{° C,} and then ammonia or primary amines in ethanol at 15-20 ^{° C,} with a molar ratio of α, β -nepredelny ketone amine ratio of 1: 3. when the molar ratio of α, β -nepredelny ketone amine of less than 1: 3, the product yield drops due to the presence in the reaction mixture free b hydrogen gas revealing the aziridine ring. With a molar ratio greater than 1: 3, the amine consumption increases unreasonably and product isolation is difficult

Ph (I)
The proposed method is carried out as follows: to a solution of α, β-unsaturated ketone II in a hydrocarbon solvent (pentane, hexane, heptane), bromine is added dropwise with stirring and the mixture is discolored. Then the solvent was evaporated, the residue was dissolved in 96% ethanol, and ammonia or a primary amine was added with stirring (liquid amines through a dropping funnel, gaseous sparges), incubated for 2-3 hours, ethanol was evaporated, ether was added to the residue. The precipitated amine hydrobromide precipitate was filtered off, the ether was evaporated, and the residue was recrystallized from n-hexane or chromatographed on a silica gel column. The structure of the obtained compounds is confirmed by IR and PMR spectroscopy.

PRI me R 1. To a solution of 29 g (0.145 mol) of 1-phenyl-4,4,4-trifluoro-2-buten-1-one in 30 ml of n-hexane was added with stirring 23.2 g (0.145 mol) of bromine. Stirred until discoloration. Then the solvent was evaporated, 30 ml of 96% ethanol was added to the residue, and ammonia was bubbled until the exothermic reaction ceased. Ethanol was evaporated, ether was added to the residue, and the precipitated ammonium hydrobromide precipitate was filtered off. The ether was evaporated, the residue was recrystallized from n-hexane. 25.9 g (83.2%) of 1-phenyl-4,4,4-trifluoro-2,3-aziridinbutan-1-one are obtained. Mp. 53.5-54 ^about C.

IR spectrum (ν, cm ^-1 ): 1660 (С = О), 3240 (N-Н).

= 8, J

2,5), 7,46-8,15 м (5Н, Ph).1 H-NMR spectrum (CDCl ₃ , δ, ppm J, Hz): 2.15-2.35 m. (1H, NH) disappears with the addition of CD ₃ SODE; 2.68 m (1H, H _β ), 3.74 dd. (1H, H _α ), J

= 8, J

2.5), 7.46-8.15 m (5H, Ph).

PRI me R 2. Analogously to example 1 of 4.5 g (12.8 mol) of 1-phenyl-4,4,5,5,6,6,7,7,7-nonafluorohept-2-en- 1-one, 2.45 g (12.8 mol) of bromine and ammonia gave 3.65 g (78.3%) of 1-phenyl-4,4,5,5,6,6,7,7,7- nonafluoro-2,3-aziridingheptan-1-one, mp. 71.5-72 ^about S.

IR spectrum (ν, cm ^-1 ): 1710 (С = О), 3280 (П-Н).

5,6, J

2,3), 7,46-8,10 м (5Н, Ph).The PMR spectrum of 2.45-2.62 m (1H, NH) disappears with the addition of CD ₃ SOD, 2.66-2.95 m (1H, H _β ), 3.79 dd (1H, H _α J

5,6, J

2.3), 7.46-8.10 m (5H, Ph).

 PRI me R 3. Analogously to example 1 of 10 g (0.018 mol) of 1-phenyl-4,4,5,5,6,6,7,7,8,8,9,9,10,10,11 , 11,11-hepta-fluorundecene-2-en-1-one, 2.9 g (0.018 mol) of bromine and 5.45 g (0.054 mol) of n-hexylamine received 8.9 g (76.5%) of 1- phenyl-4,4,5,5,6,6,7,7,8,8,9,9,10,10,11,11,11-hepta-decafluoro-2-3- (n-hexyl) - aziridinundecanone-1 as a thick oil.

IR spectrum: (ν cm ^-1 ): 1690 (C = O).

6 Гц), 1,10-1,61 м (8Н, С₄Н₈), 2,71 т (2Н, СН₂, J

5), 3,04-3,25 (1Н, H_β), 3,90 д (1Н, H_α J

2,3), 7,30-8,13 м (5Н, Ph).PMR spectrum: 0.82 t (3H, CH ₃ , J

6 Hz), 1.10-1.61 m (8Н, С ₄ Н ₈ ), 2.71 t (2Н, СН ₂ , J

5), 3.04-3.25 (1H, H _β ), 3.90 d (1H, H _α J

2.3), 7.30-8.13 m (5H, Ph).

 PRI me R 4. Analogously to example 1 of 8 g (0.0185 mol) of 1-phenyl-4,4,5,5,6,6,7,7,8,8,9,9-dodecafluoronon- 2-en-1-one, 2.96 g (0.0185 mol) of bromine and methylamine gave 6.2 g (73.0%) of 1-phenyl-4,4,5,5,6,6,7, 7,8,8,9,9-dodecafluoro-2,3- (methyl) -aziridinononanone-1 as a thick liquid.

IR spectrum (ν, cm ^-1 ): 1680 (C = O).

2,6), 6,08 т. т. (1Н, HCF₂CF₂, J_HCF2 52, J

= 5), 7,4-8,1 м (5Н, Ph).1 H-NMR spectrum: 2.25 s (3H, CH ₃ ), 2.95-3.25 m (1H, H _β ), 3.85 d (1H, H _α ), J

2.6), 6.08 _tt (1H, HCF ₂ CF ₂ , J _HCF2 52, J

= 5), 7.4-8.1 m (5H, Ph).

 A comparison of the methods for producing fluoroalkyl-containing α, β-aziridine ketones is given in the table.

Claims (1)

METHOD FOR PRODUCING fluoroalkyl-containing α, β - aziridine ketones of the general formula

where P ^F = X (CF ₂ ) _n ;
X is H, F;
n is 1-8;
R ₂ = H, CH ₃ , n - C ₆ H _{1 3} ,
from α, β - unsaturated ketones of the general formula

where R ^F has the indicated meanings,
with the addition of ammonia or a primary amine and an equimolar amount of halogen in an organic solvent, characterized in that first, α, β - unsaturated ketone is treated with bromine, and then ammonia or primary amine in a molar ratio of a, β - unsaturated ketone: ammonia or primary amine 1: 3, and the process is conducted in an environment of pentane, or hexane, or heptane.

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