US5118853A Expired / Lapsed US ⏱️ 0.0 years remaining

Processes for the synthesis of 3-disubstituted aminoacroleins

Assignee: Novartis AG

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Filing: 1991-02-26

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Granted: 1992-06-02

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Expires: 2011-02-26

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Abstract

Abstract Process for the synthesis of compounds of the formula ##STR1## comprising the steps of (i) reacting a compound of the formula ##STR2## with oxalyl chloride or oxalyl bromide to form the corresponding compound of the formula ##STR3## (ii) reacting said compound of the formula ##STR4## with a compound of the formula ##STR5## to form the corresponding compound of the formula ##STR6## (iii) hydrolyzing said compound of the formula ##STR7## to obtain the corresponding compound of the formula ##STR8## the use of the compounds of the formula ##STR9## for the synthesis of the compounds of the formula ##STR10## and the use of the intermediates of Formula VII for the direct synthesis of the compounds of Formula II, wherein R 1 is C 1-3 alkyl, phenyl or phenyl substituted by 1 to 3 substituents each of which is independently C 1-3 alkyl, C 1-3 alkoxy, fluoro, chloro, bromo or nitro (maximum of two nitro groups), R 1b is phenyl or phenyl substituted by 1 to 3 substituents each of which is independently C 1-3 alkyl, C 1-3 alkoxy, fluoro, chloro, bromo or nitro (maximum of two nitro groups), R 2 is C 1-3 alkyl, one of R 3 and R 4 is ##STR11## and the other is primary or secondary C 1-6 alkyl not containing an asymmetric carbon atom, C 3-6 cycloalkyl or phenyl-(CH 2 ) m -, wherein R 7 is hydrogen, C 1-3 alkyl, n-butyl, i-butyl, t-butyl, C 1-3 alkoxy, n-butoxy, i-butoxy, trifluoromethyl, fluoro, chloro, phenoxy or benzyloxy, R 8 is hydrogen, C 1-3 alkyl, C 1-3 alkoxy, trifluoromethyl, fluoro, chloro, phenoxy or benzyloxy, R 9 is hydrogen, C 1-2 alkyl, C 1-2 alkoxy, fluoro or chloro, and m is 1, 2 or 3, with the provisos that not more than one of R 7 and R 8 is trifluoromethyl, not more than one of R 7 and R 8 is phenoxy, and not more than one of R 7 and R 8 is benzyloxy, R 5 is hydrogen, C 1-3 alkyl, n-butyl, i-butyl, t-butyl, C 3-6 cycloalkyl, C 1-3 alkoxy, n-butoxy, i-butoxy, trifluoromethyl, fluoro, chloro, phenoxy or benzyloxy, and R 6 is hydrogen, C 1-3 alkyl, C 1-3 alkoxy, trifluoromethyl, fluoro, chloro, phenoxy, or benzyloxy, with the provisos that not more than one of R 5 and R 6 is trifluoromethyl, not more than one of R 5 and R 6 is phenoxy, and not more than one of R 5 and R 6 is benzyloxy, R 10 is C 1-6 alkyl, each X is chloro or bromo, and each X.sup.⊖ is chloride or bromide.

Inventors

👤 George T. Lee
👤 Oljan Repic

Bibliographic Details

Application Number —

Jurisdiction US

Data Source google_patents

Last Synchronized 2026-10-25 04:06

CPC Classifications

C; C07; C07D; C07D233/00; C07D233/54; C07D233/64; C07C; C07C51/00; C07C51/347; C07C51/367; C07D209/00; C07D209/02; C07D209/04; C07D209/10; C07D209/12; C07D209/18; C07D209/24

Claims Analysis

Total Claims: 24

Claim 1

Independent Claim 141 words

A process for synthesizing a comopund of the formula ##STR74## comprising the steps of (i) reacting a compound of the formula ##STR75## with a compound of the formula X--CO--CO--X to form the corresponding compound of the formula ##STR76## (ii) reacting said compound of the formula ##STR77## with a compound of the formula ##STR78## to form the corresponding compound of the formula ##STR79## (iii) hydrolyzing said compound of the formula ##STR80## to obtain the corresponding compound of the formula ##STR81## wherein R 1 is C 1-3 alkyl, phenyl or phenyl substituted by 1 to 3 substituents each of which is independently C 1-3 alkyl, C 1-3 alkoxy, fluoro, chloro, bromo or nitro (maximum of two nitro groups), R 2 is C 1-3 alkyl, R 10 is C 1-6 alkyl, each X is chloro or bromo, and each X.sup.⊖ is chloride or bromide.

Claim 2

Dependent Claim 141 words

Claim 3

Dependent Claim 27 words

A process according to claim 1 wherein Steps (i) and (ii) are carried out in inert anhydrous organic media, and Step (iii) is carried out with base.

Claim 4

Dependent Claim 13 words

A process according to claim 2 wherein R 1 is C 1-3 alkyl.

Claim 5

Dependent Claim 52 words

A process according to claim 3 comprising the further step of (iv) treating the crude compound of the formula ##STR82## with the corresponding compound of the formula ##STR83## to convert any compound of the formula ##STR84## present therein into additional compound of the formula ##STR85## wherein R 1a is C 1-3 alkyl.

Claim 6

Dependent Claim 37 words

A process according to claim 4 wherein R 1a is C 1-2 alkyl, R 2 is C 1-2 alkyl, R 10 is primary or secondary C 2-4 alkyl, each X is chloro, and each X.sup.⊖ is chloride.

Claim 7

Dependent Claim 13 words

A process according to claim 5 wherein R 10 is n-C 2-4 alkyl.

Claim 8

Dependent Claim 40 words

A process according to claim 6 wherein Steps (i) and (ii) are carried out in a liquid halogenated lower alkane, Step (iii) is carried out in an aqueous medium, and Step (iv) is carried out in a C 1-4 alkanol.

Claim 9

Dependent Claim 61 words

A process according to claim 7 wherein Step (i) is carried out in methylene chloride at a temperature of 0°-20° C., Step (ii) is carried out in methylene chloride at a temperature of 25°-40° C., Step (iii) is carried out in water at a temperature of 20°-65C., and Step (iv) is carried out in methanol at a temperature of 10°-20° C.

Claim 10

Dependent Claim 138 words

A process according to claim 8 comprising the steps of (i) reacting N,N-dimethylformamide with oxalyl chloride in methylene chloride at a temperature of 0°-15° C. to form the compound of the formula ##STR86## (ii) reacting said compound of the formula ##STR87## with ethyl vinyl ether in methylene chloride at a temperature of 25°-40° C. to form the compound of the formula ##STR88## (iii) hydrolyzing said compound of the formula ##STR89## with water at 20°-60° C. and subsequently treating with potassium carbonate in an aqueous medium at a temperature of 20°-30° C. to form a mixture of the compounds of the formulae ##STR90## (iv) treating the mixture of the compounds of the formulae ##STR91## with dimethylamine in methanol at a temperature of 10°-20° C. to convert the compound of the formula ##STR92## into additional compound of the formula ##STR93##

Claim 11

Dependent Claim 327 words

A process according to claim 9 wherein (1) the molar ratio of oxalyl chloride to N,N-dimethylformamide in Step (i) is 1-1.2:1, and Step (i) is carried out by adding oxalyl chloride to a solution of N,N-dimethylformamide in methylene chloride over a period of 1.5-4 hours at a rate such that the temperature is maintained at 5°-15° C., (2) in Step (ii) the molar ratio of ethyl vinyl ether to the N,N-dimethylformamide utilized in Step (i) is 1-1.2:1, and Step (ii) is carried out by adding ethyl vinyl ether to the reaction mixture over a period of 0.4-1.5 hours at a rate such that the temperature does not exceed 30° C. and, upon completion of the addition, refluxing the reaction mixture at 35°-40° C. for 0.3-1 hour and recovering as much methylene chloride as possible at a temperature not in excess of 45° C., (3) in Step (iii) the molar ratio of potassium carbonate to the oxalyl chloride utilized in Step (i) is 1-2:1, and Step (iii) is carried out by adding water to the product of Step (ii) stirred at 20°-30° C., allowing the temperature to rise to 45°-60° C., maintaining this temperature during the balance of the addition of the water and for an additional 0.3-1 hour, cooling the reaction mixture to 15°-25° C., adding an aqueous solution of potassium carbonate over a period of 0.3-1.25 hours at this temperature, extracting the mixture with methylene chloride and distilling as much methylene chloride as possible at a temperature not in excess of 45° C., and (4) in Step (iv) the molar ratio of dimethylamine to the N,N-dimethylformamide utilized in Step (i) is 0.15-0.4:1, and Step (iv) is carried out by adding anhydrous dimethylamine to a solution of the product of Step (iii) in methanol stirred at 10°-20° C. at a rate such that the temperature does not exceed 20° C. and distilling the solvent and any excess dimethylamine at a temperature not in excess of 120° C.

Claim 12

Dependent Claim 40 words

A process according to claim 2 wherein R 1 is phenyl or phenyl substituted by 1 to 3 substituents each of which is independently C 1-3 alkyl, C 1-3 alkoxy, fluoro, chloro, bromo or nitro (maximum of two nitro groups).

Claim 13

Dependent Claim 56 words

A process according to claim 11 wherein R 1 is phenyl or phenyl substituted by 1 or 2 substituents each of which is independently C 1-3 alkyl, C 1-2 alkoxy or chloro, R 2 is C 1-2 alkyl, R 10 is primary or secondary C 2-4 alkyl, each X is chloro, and each X.sup.⊖ is chloride.

Claim 14

Dependent Claim 27 words

A process according to claim 12 wherein R 1 is phenyl or phenyl substituted by 1 or 2 methyl groups, and R 10 is n-C 2-4 alkyl.

Claim 15

Dependent Claim 22 words

A process according to claim 13 wherein R 1 is phenyl, R 2 is methyl, and R 10 is ethyl or n-butyl.

Claim 16

Dependent Claim 41 words

A process according to claim 13 wherein Steps (i) and (ii) are carried out in a liquid halogenated lower alkane or acetonitrile, and Step (iii) is carried out in a mixture of water and a liquid halogenated lower alkane or acetonitrile.

Claim 17

Dependent Claim 71 words

A process according to claim 15 wherein Step (i) is carried out prior to Step (ii), Step (i) is carried out in methylene chloride or acetonitrile at a temperature of -20°-45° C., Step (ii) is carried out in methylene chloride or acetonitrile at a temperature of 10°-40° C., and Step (iii) is carried out in a mixture of water and either methylene chloride or acetonitrile at a temperature of 0°-35° C.

Claim 18

Dependent Claim 95 words

A process according to claim 16 comprising the steps of (i) reacting N-methylformanilide with oxalyl chloride in methylene chloride at a temperature of 15°-45° C. to form the compound of the formula ##STR94## (ii) reacting said compound of the formula ##STR95## with ethyl vinyl ether in methylene chloride at a temperature of 15°-40° C. to form the compound of the formula ##STR96## (iii) hydrolyzing said compound of the formula ##STR97## with sodium carbonate in a mixture of methylene chloride and water at a temperature of 20°-30° C. to obtain the compound of the formula ##STR98##

Claim 19

Dependent Claim 248 words

A process according to claim 17 wherein (1) the molar ratio of oxalyl chloride to N-methylformanilide in Step (i) is 1-1.2:1, and Step (i) is carried out by adding oxalyl chloride to a solution of N-methylformanilide in methylene chloride at 15°-20° C. over a period of 1-2 hours and, upon completion of the addition, gradually raising the temperature of the reaction mixture to 40°-45° C. over a period of 0.75-1.25 hours and then refluxing it for 0.75-1.25 hours, (2) in Step (ii) the molar ratio of ethyl vinyl ether to the N-methylformanilide utilized in Step (i) is 1-1.3:1, and Step (ii) is carried out by cooling the product of Step (i) to 15°-20° C., adding ethyl vinyl ether over a period of 0.5-1.5 hours at a rate such that the temperature does not exceed 30° C., and, upon completion of the addition, refluxing the reaction mixture for 0.3-0.7 hour, and (3) in Step (iii) the molar ratio of sodium carbonate to the oxalyl chloride utilized in Step (i) is 1-1.2:1, and Step (iii) is carried out by cooling the product of Step (ii) to 15°-20° C., adding, over a period of 0.5-1 hour, an aqueous solution of sodium carbonate at a rate such that the temperature of the reaction mixture is 20°-30° C. and, upon completion of the addition, stirring the mixture at 20°-30° C. for 0.2-0.5 hour, allowing the mixture to separate into two phases, separating the two phases and recovering the product from the organic phase.

Claim 20

Dependent Claim 90 words

A process according to claim 16 comprising the (i) reacting N-methylformanilide with oxalyl chloride in acetonitrile at a temperature of -20°-20° C. to form the compound of the formula ##STR99## (ii) reacting said compound of the formula ##STR100## with n-butyl vinyl ether in acetonitrile at a temperature of 10°-40° C. to form the compound of the formula ##STR101## (iii) hydrolyzing said compound of the formula ##STR102## with sodium carbonate in a mixture of acetonitrile and water at a temperature of 0°-25° C. to obtain the compound of the formula ##STR103##

Claim 21

Dependent Claim 255 words

A process according to claim 19 wherein (1) the molar ratio of oxalyl chloride to N-methylformanilide in Step (i) is 1-1.2:1, and Step (i) is carried out by adding oxalyl chloride to a solution of N-methylformanilide in acetonitrile at -18°-8° C. over a period of 1-2 hours and, upon completion of the addition, gradually raising the temperature of the reaction mixture to 12°-20° C. over a period of 0.4-0.75 hour and then stirring it for 0.2-0.4 hour at this temperature, (2) in Step (ii) the molar ratio of n-butyl vinyl ether to the N-methylformanilide utilized in Step (i) is 1-1.2:1, and Step (ii) is carried out by adding n-butyl vinyl ether to the product of Step (i) stirred at 12°-20° C. over a period of 0.5-1.5 hours at a rate such that the temperature does not exceed 30° C., and, upon completion of the addition, stirring the reaction mixture for 0.3-0.7 hour at 25°-35° C., and (3) in Step (iii) the molar ratio of sodium carbonate to the oxalyl chloride utilized in Step (i) is 1-1.3:1, and Step (iii) is carried out by cooling the product of Step (ii) to 0°-5° C. adding, over a period of 0.5-1.2 hours, an aqueous solution of sodium carbonate at a rate such that the temperature of the reaction mixture is 5°-12° C. and, upon completion of the addition, adding toluene, stirring the mixture at 15°-25° C. for 0.2-0.5 hour, allowing the mixture to separate into two phases, separating the two phases and recovering the product from the organic

Claim 22

Dependent Claim 49 words

A process according to claim 15 wherein Steps (i) and (ii) are carried out simultaneously in methylene chloride or acetonitrile at a temperature of -15°-35° C., and Step (iii) is carried out in a mixture of water and either methylene chloride or acetonitrile at a temperature of 0°-35° C.

Claim 23

Dependent Claim 89 words

A process according to claim 21 comprising the (i) and (ii) reacting N-methylformanilide with oxalyl chloride in acetonitrile at -10°--30° C. in the presence of n-butyl vinyl ether to form the compound of the formula ##STR104## which compound then reacts with the n-butyl vinyl ether in the reaction mixture to form the compound of the formula ##STR105## (iii) hydrolyzing said compound of the formula ##STR106## with sodium carbonate in a mixture of acetonitrile and water at a temperature of 0°-25° C. to obtain the compound of the formula ##STR107##

Claim 24

Dependent Claim 201 words

A process according to claim 22 wherein (1) in Steps (i) and (ii), the molar ratio of oxalyl chloride and n-butyl vinyl ether to N-methylformanilide is 1-1.2:1-1.2:1, and Steps (i) and (ii) are carried out by adding a solution of N-methylformanilide and n-butyl vinyl ether in acetonitrile to a solution of oxalyl chloride in acetonitrile stirred at -10°-10° C. over a period of 2-3 hours and, upon completion of the addition, gradually raising the temperature of the reaction mixture to 20°-30° C. over a period of 0.4-1.5 hours and then stirring the reaction mixture at this temperature for 0.5-1.5 hours, and (2) in Step (iii) the molar ratio of sodium carbonate to the oxalyl chloride utilized in Step (i) is 1-1.3:1, and Step (iii) is carried out by cooling the product of Step (ii) to 0°-5° C., adding, over a period of 0.5-1.2 hours, an aqueous solution of sodium carbonate at a rate such that the temperature of the reaction mixture is 0°-12° C. and, upon completion of the addition, adding toluene, stirring the mixture at 15°-25° C. for 0.2-0.5 hour, allowing the mixture to separate into two phases, separating the two phases and recovering the product from the organic phase.

References Cited (Backward Citations)

GB945536A Cited

US4739073A Cited

EP0363934A1 Cited

USPTO Annuity & Maintenance Windows

Annuity Stage	Window Opens	Payment Deadline	Surcharge Period Until	Estimated Fee	Status
3.5 Years (Year 4)	1995-06-02	1995-12-02	1996-06-02	$2000.00	Window Closed / Lapsed
7.5 Years (Year 8)	1999-06-02	1999-12-02	2000-06-02	$3760.00	Window Closed / Lapsed
11.5 Years (Year 12)	2003-06-02	2003-12-02	2004-06-02	$7700.00	Window Closed / Lapsed

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