FI69832C - FREQUENCY REARING FOR C1-4 ALKYLANILINFOERENINGAR - Google Patents

Description

RSSF®1 ΓΒ1 ANNOUNCEMENT

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Patent 'e 1 at 20.5.30 (51) Kv.lk.4 / lnt.CI.' ° 0 / ° ^ 7/10, 101/52 »121 // 8> 'C 07 D 317/66, 319 / 18, C 07 C 85/08 FINLAND (21) Patent application - PatentansSkning 770182 (22) Application date - Ansökningsdag 20.01 .77

IFH

'' (23) Start date - Giltighetsdag 20.01.7 7 (41) Has become public - Blivit offentlig ^ q 07.77

National Board of Patents and Registration Date of publication and publication. _, 1 \ o * 0c

Patent and registration authorities '' Ansökan utlagd och utl.skriften publicerad -5 3 (32) (33) (31) Claim claimed privilege — Begärd priority 29.01.76 29.01.76, 26.11.76 USA (US) 653362, 653361, 7 * »5284 (71) Sandoz AG, Basel, Switzerland-Switzerland (CH) (72) Paul Gerard Mattner, Staten Island, New York,

Joseph Antonio Smith, Fanwood, New Jersey,

William Joseph Houlihan, Mountain Lakes, New Jersey, USA (US) (7 * 0 Oy Kolster Ab (5 * i) Method C ._ ^ - starting with 1 Ian i 1 i in i compounds i -Förfarande för framstäl lning av C ^ - alkylani 1 införeningar

The present invention relates to a process for the preparation of C 1-4 alkylaniline compounds of formula I

R1. R 2 fH (I) TY "wherein R 1 and which may be the same or different, each represent alkyl having 1 to 3 carbon atoms, provided that the total number of carbon atoms of R 1 and R 2 does not exceed A , R 1 and R 2 are the same or different and each represents hydrogen, fluorine, chlorine, straight-chain alkyl or alkoxy having 1 to 4 carbon atoms, or trifluoromethyl, provided that R 1 is in position 2 69832 5 or 6, and that at most one of R 2 and R 4 is trifluoromethyl, or R 8 and R 2 together represent alkylenedioxy having 1 or 2 carbon atoms, and X is -CM, -COOR wherein R is hydrogen or alkyl of 1 to 5 carbon atoms, or --C 1 - "· t

Y

wherein Y and Y 1, which may be the same or different, represent straight-chain alkyl or alkoxy or trifluoromethyl containing hydrogen, fluorine, chlorine, a 1-M carbon atom, provided that at most one of the substituents Y and Y 2 is trifluoromethyl. This method is characterized in that the compound of formula II

. NH „Γ dl) h x

wherein, R 1 and X are as defined above, are reacted in a liquid medium at a temperature in the range of -40 to + 10 ° C with a compound of formula III

R1 -.

"; c = o (m)

V

wherein R 1 and are as defined above in the presence of boron tetrahydride and a dibasic organic carboxylic and / or sulfonic acid having the same acid groups attached to the rigid carbon backbone, or a reaction product of boron tetrahydride and said acid in an molar ratio of acid / borohydride : 1 to 10: 1, and said acid being: tl 3 69832 1) an acyclic unsaturated dibasic acid having a carbon-carbon double bond having a carboxylic or sulfonic acid group on each carbon atom, the compound being in the cis-isomeric form; 2) a cyclic unsaturated dibasic acid having an unsaturated carbon-carbon bond in the ring and having, at two ring carbon atoms having an unsaturated carbon-carbon bond, each having a carboxylic or sulfonic acid group and are either a) adjacent to each other, or b) each is adjacent to the condensed carbon atoms of the two condensed rings; or 3) a cyclic dibasic acid in which each of the two saturated ring carbon atoms has a carboxylic or sulfonic acid group, which acid groups are rigidly attached to each other at either the endo- or exo-position due to the molecular structure.

The compounds of the formula I and their preparation by alkylation are known from DE-A-1 805 501. The advantage of the process according to the present invention is that it achieves a much shorter reaction time than before.

This is clear when comparing the reaction times with each other. For example, according to the first part of Example 3 of DE-A-1 805 501, the reaction time is 5 days, while the reaction time required according to the present invention according to Example 1 is 165 minutes. In addition, the reagents used in this invention, acetone and borohydride are much cheaper than those used in this invention. isopropyl halides used in a known method.

Suitable borohydrides for use in the process of the invention are conventional reducing borohydrides, in particular alkali metal borohydrides in which the alkali metal is the only metal present, more particularly alkali metal borohydrides such as lithium borohydride, potassium borohydride or preferably sodium borohydride. Other useful reducing alkali metal borohydrides are sodium cyanoborohydride.

Borohydride is preferably used in finely divided form. Preferably, its particles are sized to pass through Tyler's Standard Sieve No. 20, more preferably screen no. 60.

69832

Most preferably, the borohydride is in powder form.

A wide variety of acids can be used in the process of the invention and the preferred reaction conditions will, of course, depend, at least to some extent, on the acid used as well as on other factors such as the starting materials and borohydride used.

Suitable acids for use in the process of the invention are dibasic organic acids in which the acidic groups are carboxyl (-CQOH) and / or sulfone (SO 2 H) acid groups and which are geometrically attached to one another, i.e. they are in the same geometric plane. Such acids can be divided into three main groups, which are: 1) acyclic, unsaturated dibasic acids having a carbon-carbon double bond having a carboxylic or sulfonic acid group on each carbon atom, the compounds being in a cis-isomeric moiety, e.g. maleic acid; 2) cyclic unsaturated dibasic acids having an unsaturated carbon-carbon bond in the ring and having a carboxylic or sulfonic acid group on each ring carbon atom between which there is an unsaturated carbon-carbon bond and are either a) side by side, e.g. o-phthalic acid , 2-benzenedisulfonic acid, 2-carboxybenzenesulfonic acid, o-dicarboxynaphthalenes, e.g. 2,3-dicarboxynaphthalene, or o-disulfonaphthalenes, e.g.

2,3-disulfonaphthalene, or b) adjacent to a fused carbon atom of two fused rings, e.g. naphthalic acid; and 3) cyclic dibasic acids having a carboxylic or sulfonic acid group on each saturated ring carbon atom, which acid groups are rigidly attached to each other at either the endo or exo position due to the structure of the molecule. e.g. bicyclo [2.2.1] hta-2-ene-2,3-dicarboxylic acid.

Preferred such acids are the acids of classes 1 and 2a), in particular the acids of formula IV tl 69832

Ζχ AC1H

n (IV) c / \

Z2 'AC2H

wherein AC 1 and AC 2 are each -C00- or -SO 2 - and are in positions corresponding to each other in the cis configuration, and Z 1 and Z 2 are each an organic hydrocarbon group and Z 1 and Z 2 are optionally linked to each other.

Preferably the acid groups of the dibasic acids used are the same and even more preferably both acid groups are -COOH groups.

It is preferred that the process be carried out by reacting the compounds of formulas II and III in a liquid medium, in particular in solution, with a reaction product of a dibasic organic acid containing carboxylic and / or sulfonic acid groups and boron tetrahydride, in particular alkali metal borohydride.

Such a reaction product is a boron-containing salt which is believed, at least mainly, to be of the formula 'λ ^ φ X 0 M- (V) wherein X is an anion of a dibasic organic carboxylic and / or sulfonic acid having acid groups attached to the rigid carbon backbone and M is a metal cation obtained from boron tetrahydride used.

Thus, e.g. when using acids of formula IV, the reaction product is believed to have, at least mainly, the structure Va

ΖΊ AC, H

lv S 1 y XB '© M® <Va> c / \ / \ / \ Z2 AC2 h 6 69832 where Z ^,, AC ^, AC ^ and M are as defined above.

In the case of o-phthalic acid, the reaction product is believed to have essentially the structure Va,

2/0 H

r ^ Yc \ / 1 I * B 0 (Vaa)

Ö ^ 0 H

where M is as defined above.

In the case of naphthalic acid, the reaction product is believed to have essentially the structure Vb 0 /: λ "

<'- —C · -0. B

f- (Vab) // \\ _ c_o ^ ~

\ _ / - -H

where M is as defined above.

As will be apparent, M is preferably an alkali metal cation, especially a lithium, potassium or preferably sodium cation.

The reaction products of dibasic acids, the acid groups of which are bonded to the rigid carbon backbone and the tetraborohydrides, are themselves reducing agents and also form part of this invention.

They can generally be prepared by reacting an acid with tetraborohydride in a liquid medium at a temperature in the range of -40 to + 85 ° C, with a molar ratio of acid to tetraborohydride of 0.7: 1 to 5: 1.

Preferred methods for preparing these reaction products are described below with reference to their use in the process of this invention.

In this embodiment, the process is carried out at a temperature of 0 to 100 ° C, preferably 20 to 85 ° C, most preferably 30 to 65 ° C. As indicated above, the reaction is carried out in a liquid medium, mainly in solution. The reaction medium is preferably designed to use, at least in part 7 69832, an excess of a compound of formula III.

The reaction mixture may additionally contain other inert organic solvents. The reaction mixture may also contain small amounts of water due to its presence in the technical starting materials. However, the amount of water should not exceed 8% by weight of the total amount of solvent present (the term "solvent" does not include the proportion of a compound of formula III reacting with a compound of formula II) and preferably should not exceed 2%, most preferably 0 .5% by weight of the amount of solvent. A suitable amount of water is 0.05 to 0.4% by weight of the total amount of solvent.

The reaction product of a dibasic organic carboxylic and / or sulfonic acid having the same acid groups attached to the rigid carbon backbone and a tetraborohydride (i.e., a boron-containing salt) can be conveniently prepared in situ, i. in the presence of at least one other reactant, or ex situ. The molar ratio of borohydride or boron-containing salt (expressed as borohydride in the in situ reaction and boron-containing salt in ex situ reactions) to the compound of formula II is 0.7: 1 to 10: 1.

The boron-containing salt is preferably prepared in situ or ex situ, preferably it is prepared in situ. For in situ preparation, the reaction is most conveniently carried out in the presence of a compound of formula III which acts as a reaction medium, with the other components of the reaction mixture containing a compound of formula II. Thus, it is convenient to add borohydride to the mixture of other reagents, the desired temperature being lower than the actual reaction temperature, for example 0-30 ° C, preferably 10-25 ° C. Once the initial reaction between the borohydride and the acid has taken place, it is convenient to raise the temperature, e.g. to between 30-85 ° C, preferably 40-65 ° C, to complete any unfinished salt formation reaction and to create conditions conducive to final substitution.

In the in situ preparation of a boron-containing salt, a suitable molar ratio of acid to borohydride is between 0.7: 1 and 10: 1, preferably 1: 1 to 2: 1, preferably 1.1: 1 to 1.8: 1, especially 1, 1: 1 to 1: 6.1. Thus, in order to stabilize the boron-containing salt, it is desirable that free acid be present in the reaction mixture. The free acid is obtained from 8 69832 mixtures of excess dibasic acid.

The boron-containing salt can also be prepared by the ex-situ method. In this case, the reaction is most conveniently carried out in an inert solvent such as tetrahydrofuran. The reaction temperature is -40 to + 85 ° C, preferably 0 to 35 ° C, most preferably 10 to 30 ° C. A suitable molar ratio of dibasic acid to borohydride may be somewhat lower than in in situ preparation, and may be, for example, between 0.7: 1 and 5: 1, preferably 1: 1 to 2: 1, preferably 1, 1: 1 to 1.8: 1, especially 1.1: 1 to 1.5: 1, even more particularly 1.1: 1 to 1.3: 1. The reaction is conveniently carried out by adding boron hydride gradually to the dibasic acid solution, the rate of addition being controlled so as to maintain the desired reaction temperature. The resulting boron-containing salt can be stored in the solution in which it is formed, and such a solution is used directly in the next step. Alternatively, the salt can be isolated and purified by conventional techniques.

As mentioned above, the preparation of the boron-containing salt is preferably carried out in solution. It should be noted, however, that the amount and quality of the various reagents may be such that the reaction system as a whole forms a mixture or a multiphase system comprising, for example, a suspension or slurry of one or more ingredients.

The obtained compounds of formula I can be isolated and purified in a conventional manner. If necessary, the compounds in the form of the free base can be converted into acid addition salts in the customary manner and vice versa.

The compounds of the formula I are known intermediates in the preparation of cyclically active compounds, in particular the known anti-inflammatory compounds of the formula VII

II

9 69832

CH

I 2

R3v "v'V

γ || > o (VII) «: Λ

Y --4-. I

Y1 wherein R, R2, Rg, R1, Y and are as defined above.

The cyclization can be carried out in a known manner, and suitable reagents containing a / NCCO.7 bond are well known. Examples of these are urea and alkyl carbamates. The possible conversion of compounds of the formula I in which X is CN or C00H into other compounds of the formula I is carried out in a manner known per se, e.g. compounds to react with a suitable aryl-Grignard reagent or aryllithium compound and then hydrolyzing the reaction product. Compounds in which X is -COO-alkyl can be converted, e.g., by hydrolysis to compounds in which X is -C00H.

Preferred compounds of formula I (and formula VII) are those wherein R 1 and R 2 both represent methyl; either R 1 is hydrogen and R 2 is methyl or R 1 and R 2 together form a group -O-CH 2 -O-; Y is hydrogen; and Y 1 is hydrogen or fluorine.

More preferred compounds have substituents corresponding to the above-mentioned primary meanings in combinations.

The following examples illustrate the invention.

Example 1: 2- (N-Isopropylamino) -4-methylbenzophenone 422.6 g (2 moles) of 2-amino-4-methylbenzophenone are dissolved in 2.34 liters (40.29 moles) of acetone, and 10,698,3240,540 g ( 3.25 moles) of o-phthalic acid. To the resulting suspension is added portionwise 80 g (2.14 moles) of sodium borohydride over 45 minutes so as to maintain the temperature of the reaction mixture at 20-25 ° C. At the end of the addition, the cooling is changed so that the temperature can rise to 30-35 ° C, and this temperature is maintained for 30 minutes. The condenser is removed and the temperature is carefully allowed to rise to 50 ° C and adjusted to 50-55 ° C for 90 minutes. The mixture is then cooled to 15 [deg.] C., 808 g of 8% aqueous NaOH solution (1.625 mol) are added, the phases are separated and the acetone phase (upper layer) is collected and concentrated. The aqueous layer is extracted with one liter of heptane, and the concentrated acetone phase is added to the heptane extract. The heptane solution is washed with 250 ml of H 2 O 3, then concentrated by distillation to give 496 g of 2- (N-isopropylamino) -4-methylbenzophenone, b.p. 180-185 ° C / 5 mmHg (yield 99%).

Example 2:

In the same manner as in Example 1, but using approximately equivalent amounts of the appropriate starting materials, the following compounds are prepared: a) 2- (N-isopropylamino) -5-chlorobenzophenone, IR spectrum (in CH 2 Cl 2): -NH stretch at 3300 cm -1 and C = O-stretch at 1640 1 * t cm, b) 2- (N-isopropylamino) -4,5-methylenedioxy-benzophenone, m.p. 77-78 ° C and c) 2- (N-isopropylamino) -4 * -fluorobenzophenone, b.p. 184-187 ° C / 2.5 mmHg.

Example 3: Sodium dihydro (phthalate) borate (1-) / Boron salt / 0 ° '\ e I M. B- VN *, \ N. ^ o il 11 69832

To a stirred solution of 10.8 g of phthalic acid in 100 ml of tetrahydrofuran is added portionwise 1.6 g of powdered sodium borohydride over 5 minutes at 25-30 ° C under ice-cooling. The resulting mixture was stirred at 25 ° C for 16 h, filtered and the filtrate concentrated to a solid weighing 15.2 g which was triturated with chloroform, filtered and dried in vacuo at 60 ° C under a stream of nitrogen to give crude sodium dihydro (phthalate) borate. (1-) as a white solid, melting at 60 ° C and decomposing to a white foam at 150 ° C.

Example 4: Sodium dihydro (phthalate) borate (1-) ZiToor salt7

By repeating the procedure of Example 3, but using 1.15 g of phthalic acid instead of 10.8 g, the same product is obtained in the form of a white solid, m.p. > 320 ° C, with a very slight golden brown color appearing at 180 ° C.

Example 5: 2- (N-Isopropylamino) -4-methylbenzophenone

The products of Examples 3 and 4 give the title compound when reacted at 30-35 ° C with a suitable mixture of 2-aminobenzophenone and acetone.

Example 6: 2-Isopropylamino-4-methylbenzonitrile

To a mixture of 264 g of 2-amino-4-methylbenzonitrile, 504 g of phthalic acid and 2.32 l of acetone (reagent grade) is added 80 g of sodium borohydride portionwise with stirring over 40 minutes at 18-30 ° C. The resulting solution is stirred for 30 minutes, during which time the temperature rises from 29-30 ° C to 35 ° C and then drops to 34 ° C. The solution is then heated for 30 minutes from 34 ° C to 53 ° C and then kept at 55 ° C for one hour. The mixture is cooled to 37 ° C, 500 ml of water are added and then 417 g of 50% aqueous sodium hydroxide solution are added, after which the temperature is allowed to rise to 56 ° C to prevent precipitation. An additional 92 mL of water is added and the acetone and water-salt layer is separated at 45-50 ° C. The acetone layer is evaporated in vacuo to give a brown oil and brine which is diluted with 800 ml of heptane, after which the aqueous and heptane layers are separated. The heptane layer is dried, filtered and cooled to 10 ° C to give most of the desired 2-isopropylamino-4-methylbenzonitrile, m.p. 55-57 ° C.

i2 69832

Additional product is obtained from the mother liquor, and phthalic acid is recovered from the aqueous-salt layer by diluting with a total of 1.5 liters of water, filtering, acidifying with sulfuric acid (the other alkaline aqueous solutions obtained in the process are combined with the aqueous-hydrochloric acid layer).

Example 7: N-isopropylanthranilic acid

To a mixture of 2.7 g of anthranilic acid and 5.1 g of phthalic acid in 23 ml of acetone is added 0.7 g of powdered sodium borohydride over 30 minutes at 20-30 ° C with stirring. The resulting slurry is then stirred at 35-40 ° C for 1 hour, diluted with 2 to 5 mL of chloroform and filtered. The filtrate is evaporated in vacuo, the residue is dissolved in 20 ml of chloroform and the solution is treated with 30 ml of hexane, filtered and the filtrate is evaporated in vacuo to give a crude solid which is crystallized 5 times from cyclohexane to give (second batch of crystalline) mp. 109 to 109.5 ° C.

Example 8:

In analogy to Example 7, but using an equivalent molar amount of anthranilic acid ethyl ester instead of anthranilic acid, N-isopropylanthranilic acid ethyl ester is obtained.

Il

Claims (6)

1. A process for the preparation of C ^^ - alkyl alkylaniline compounds of formula I, R R2 R2, R I )H (I) R \ \ Ar-NH \ 6 and R ^, which may be the same or different, however, the total number of carbon atoms in R 2 and R 2 does not exceed 4, R 2 and R that R 2 is in position 5 or 6 and that at most one of the substituents R 2 and R 2 is trifluoromethyl, or R 2 and R 2 together denote an alkylenedioxy of 1 or 2 carbon atoms, and X is -CN, -COOR R is hydrogen or an alkyl of 1-5 carbon atoms, or * -Q - '* Y is Y and Y 2, which may be the same or different, and denotes hydrogen, fluorine, chlorine, a straight-chain 1-4 carbon atoms containing alkyl or alkoxy or trifluoromethyl, provided that at most one of the substituents Y and Y Y is trifluoromethyl, characterized in that a compound of formula II, R3 (II) where Rg, and X denotes the same as above, are reacted, in a liquid medium at a temperature in the range of -40 ... + 100 ° C, to react with a compound of formula III, V ^, C = O (III) where R 2 and R 2 denote the same as above, in the presence of boron tetrahydride and a dibasic organic carboxylic and / or sulfonic acid, whose acid groups are bonded in the same plane to a rigid carbon backbone, or a reaction product of boron tetrahydride and said acid, wherein the acid / boron tetrahydride molar ratio is 0.7: 1-10: 1, wherein said acid is: 1. an acyclic unsaturated dibasic acid having a carbon-carbon double bond, both carbon atoms having a carboxylic or a sulfonic acid residue, the compound being in cis -isomeriform; 2. a cyclic unsaturated dibasic acid having an unsaturated carbon-carbon bond in the ring structure and having two ring carbon atoms, the carbon-carbon bond being unsaturated, each having a carboxylic or a sulfonic acid residue and being either a) adjacent to each other, or b) each being adjacent two condensed carbon atoms condensed; or 3. a cyclic dibasic acid in which both of the two saturated ring carbon atoms have a carboxylic or a sulfonic acid group, which acid groups are rigidly bound relative to each other, depending on the molecular structure in either endo or exo position. 2. A process according to claim 1, characterized in that an acid of formula IV, Z1 + AC1H CM (IV) C Z2 "" - -ac2h II is AC9 and AC2 are each - C00 eller or -SO₂ - and relative to each other are in a position corresponding to the cis configuration, and Z₂ and Z₂ are each an organic hydrocarbon residue and Z₂ and Z₂ are optionally bonded to each other. 3. A process according to claim 1, characterized in that a reaction product of 7 is tetrahydride and acid, which has the formula V, wherein M is a dibasic organic carboxylic acid, is used. and / or sulfonic acid anion, whose acid groups are bound in the same plane to a rigid carbon backbone and M is a metal cation obtained from the boron tetrahydride used. H. Process according to Claim 3, characterized in that a reaction product of boron tetrahydride and acid is used, the product having the formula Va, Z 2, Z 2, AC 2, AC 2 and M denote the same as above. 5. A process according to claim 4, characterized in that a reaction product of boron tetrahydride and acid is used, the product having the formula Vaa, O (Ca M indicates the same as above.