SI8512009A8 - Process for preparation of acylated cyclic diketonic compounds - Google Patents

Description

PROCEDURE FOR THE MANUFACTURE OF ACYLED DICETONE UNITS

The art of the invention belongs

The invention relates to the field of synthesis of aliphatic organic compounds 1 relates to the production of adlovanl dlketon compounds by the mixing of the corresponding enolesters.

Technical problem

Tlpovl compounds which will hereafter be called adloved dlketonsl compounds have the following formula:

in which the R group, as it is, is later defined here (1 mote mainly b1t1 aromatic 111 allphatic group). Compounds of this type have been described in a number of references to keo forlsl · for example, keo hemskl Intermediates 1/111 pesticides. The remainder of the molecule, which includes the dlketone group, has a predominantly dfcH structure. The most regrettable dlcatonic group includes a 6- 111 6-membered carbodlic ring. Adlanced dlketone compounds of this type Have a general structure «u

wherein R is as defined above and n is 2 111 3. The ring may b1t1 unsubstituted 111 substituted in one 111 v1ie position, for example, by alkyl, arll, alkylene. Etc., to groups.

The state of the art

Another procedure for the manufacture of adlovanl dlkatonsklh compounds is described in the European Patent Application. 90262 1 involves the reaction of a optionally substituted 1 '3-cyclohexandione with substituted benzol. However, such a procedure has some drawbacks. BenzolldJanldl are somewhat expensive reagents 1 dianodonyl is produced in this reaction in amounts of about one mole per mole of adduct ketone. Thus, it is desirable that the reactions be carried out by using a less expensive 1 elbow accessible type of adjuvant that does not produce such amounts of diatomaceous earth. For example, benzol chloride is a relatively inexpensive form of edible agent. However, benzochloridyls are stronger adjuvants than benzoyl cyanide 1 in the presence of well-rounded catalysts showing a tendency not to rotate the carbon atom between the two carbon groups, but to attack directly one of the carbobenzyl groups,

It is known from a number of references that advelic cyclic dlketone compounds can be produced by 1z of appropriate enolesters by tossing: ⁰

OCR

CH o

\ h-cr r

s

The references delimit several different tlp adlovanl dlketon compounds 1 various catallzatore 111 promoters for the loading of unolesters into aclated dlketones.

For example, Akhrem et al., Synthes1s, p. 925-927 (1978) process the production of a large number of adlovan dichlohexandlones by reaction

1,3-chlorohexandlone with adjuvant (especially with adhalogenide) in two phases. In the first phase, the adhhalogenld reacts with dchlohexandlono in the presence of pyridine so that it produces.

• nolestar, which then translates into adlovanl clklohtxandlon preaettanjea in the presence of a biaolar excess of alualnljua-hlorld. >

AcUing tools for the benefit of this 1ae1a are ^! the formula RCOC1 where R is a C 1 -C 1 alkyl (e.g. ethyl, ethyl, propyl), phenyl, substituted phenyl, benzyl 1 substituted benzyl group ·. i

Tanabe at al., Chem, lattars, p. 53 (1982) describe the work on the production of 3-ac11-4-h1drox1-2-pyrrone adduction of plrona aa adlhalogenylalkyl-111 a1ken11-t1pa 1 by converting the formed enolester using a catalytic amount of 4-diaet11aa1nop1r1d1na.

European Patent Application (Publication No.) 123001 describes that other aa1nop1r1dnsk1 derivatives are 1 1certain N-a1k111a1dazo1ak1 derivatives of a suitable boilerIsatorl for converting enolesters into adducted dichlohexandlones barking 5-carboxylic acid. i

USSR Patent 784,195 describes a re-reading of a single liter for production

European Patent Application, Publication No. 2-O11o11-c1k1ohexane-1,9-d1one in the presence of molten sodium ₍ acetate at 160-170 ° C).

80301 describes the conversion of 5- (pol1aet1lfen1l) -1,8- ί clklohexandlone enolesters to the corresponding aclated clklohexandlones in the presence of some Lew1s acid. The adjuvants used included the anhydrides and the adhalogenates of RCOC1 where R is alkyl, fluoroalkyl, alkenyl, alkynyl 111 phenyl.

Description of a solution to a technical problem with the Executors

The present invention relates to a process for the manufacture of an acHovel dllclonic compound of preaeltanje enolestra in which the conversion is carried out in the presence of a daytime Source.

The present invention relates to a process for the manufacture of an aclated dlketone compound by moving the enolester to a general reaction:

f

Ό • · oc 'CH

C 'O ^X CH-CR where the transfusions occur in the presence of a day source.

The determination of pramaltation is carried out in the presence of 111 (a) a catalytic amount of a daylong source and a non-alkaline, some unbranched base, on a prlner, a tertiary annal, an alkaline-natal carbonate 111 of an alkaline-natal phosphate; 111 (b) the atechlonetric quantities, relative to the enolester, of kalljumdjanld 111 llthium dianide, 1 of the catalytic lolllcl of the clerical ether crown 111 of its eelklll analogue.

/ - c o k *

J £ HCR "are to which R b1t1 different alkyl, alkenyl, aryl (e.g. phenyl 111 substituted phenyl), phenalkU (e.g. optionally substituted benzyl, phenethyl, etc.), 111 other substituents, to prlner, those sponsored by the above described »references.

The rest of the molecule includes a series of atoms that connect the carbon atoms of the two carbonyl groups such that diketone is a cyclic compound. Most preferably, diketone is a carbocyclic compound. Preferred forms of the diketone are cyclopantanedinyl-1-cyclohexandlonyl, which may be substituted at one 111 fork position on an alkyl ring, aryl 111 by another substituent group. Most preferred are 1,3-cyclohexandylone, optionally substituted with one 111 alkyl group.

A particularly preferred product class is one in which the diketone is clklohexandlon and the acylation group is a substituted benzoyl group. That is, R is a substituted phenyl. Basically, these compounds have the formula i

in which:

Rp R _2, R, R p R 1 R Independent hydrogen 111 Cj-Cg alkyl (preferably -C ₄ alkyl) 111

R _r R ₂ 111 Rg is R _and OC- flda is R _t CpC ₄ alkyl j phenyl, optionally substituted by from 2 to B methyl groups;

111 where R1 is 1Rg, 111Rg1Rp is taken together by Cg-Cg alkylene (such compounds have a structure);

R ₇ is halogen (chlorine, bronze, iodine 111 fluorine); cyano;

Cl-C ₄ alkyl; C 1 -C 8 haloalkyl (preferably trfluoronetyl); λ < ₍ Β (0) _η where R _{fc is} C 1 -C ₄ alkyl, and preferably B, 1 111 2;

_Cj-C4 alkoxy (preferably "etoksl) 111 nitro;

Rg »Rg 1 Rjq are independently hydrogen 111 substituents which include halogen; -C ₄ alkyl; C ~ C ₄ alkoxy, trifluoronetoksi; cyano; nitro; CpC ₄ haloalkyl; Cj-C ₄ alklltlo; phenoxyl; 111 substituent phenoxyl in which the substituent is halogen 111 halosetyl 111 both;

R _b S (0) _n where n is 0, 1 111 2; 1 R _fc is C 1 -C ₄ alkyl, CpC ₄ haloalkyl, phenyl 111 benzyl,

R _c CNH- where R ₍ CpC ₄ alkyl,

-NR ^ R _e where R ^ 1 R _{f are} independently hydrogen 111 CpC ₄ alkyl;

RfC (O), wherein Rf is hydrogen, -C ₄ alkyl, C ~ C ₄ haloalkll 111 C | -C ₄ alkoxy;

SO ^ NR ^ R ^ Where su R ^ 1 R & Independent hydrogen 111 -C ₄ alkyl;

111 Rg and Rg taken together form a ring structure with two adjacent carbon atoms of the phenyl ring to which they are attached.

(:

Compounds of this type having various substituents 111 on One, dichlohexene 111 1 on phenyl ring described au u t European Patent Application Publication No. 4 90262; next undecided U.S. patent application, all of U1111an J. M1chae1y et al., which belong to the present Dirt, 1 Have title 1 Have title: Certain 2- (2-substituent benzoyl) -1,3clcylohexandlonl: Serial No. No. 634,408, filed July 31, 1984; Serial No. 640,791, filed Aug. 17, 1984; Serial No. 752,702, filed July 8, 1985; 1 Serial No. 722,593, filed September 5, 1985; next U.S. patent applications pertaining to present-day Dirt, filed December 20, 1984: Str1Jsk1 683,900, entitled 'Certain 2- (2-ntrobenzoyl) -1,8-cyclohectandlone, by Charles 6. Carter *, Serial No, 683,899, entitled Certain 2- (2'-dianobenzo11) -1,3- c1klohexand1on1 by Charles G. Carter; Serial No. 683,898, under the heading Certain

2- (2 '- * upst1tuisen1 benzoyl) -1,3-c1k1ohexand1on1 * by Charles

6. Carter's at al. *, 1 Serial no. 683,884 under the heading Certain

2- (2'-Alkylbenzoyl) -1,3-cyclohexandylone1 by Charles 8. Carter (all of these patent applications relate to herbidding compounds) 1 Japanese Patent Applications (Publication Nos.) 51/13750 1 51/13755 from Nlppon Soda KK, which treat some compounds of this type as Intermediate Herbicides. The descriptions of these documents are incorporated herein by reference.

Some other compounds to which this process may be applied are described in undecided U.S. Pat. patent applications (usually indicated) No. 764,110, filed Aug. 26, 1985 by David L. Lee et al., Entitled Certain 2- (2-substituent phenylecetyl)

1,3-clklohexandlonl ·, 1 Serial no. 683,663, filed December 20, 1984, by David L. Lee et al., Under the title

2- (2'-Substituted benzoyl) -1,3-cyclohexandylone, 1 compounds described in literature 1 mentioned under the heading State of the Art.

The method of bridging 1z of the present invention is rotated in the presence of a cyanide Source. The term djanldnl Source refers to a substance 111 substances that, under bundling conditions, include 111 generltu c9janovodon1k 1/111 djanldnl anion. There are two primary realizations.

In one embodiment, the process is rotated in the presence of a catalytic

(. · 'The quantities of the anionic anion source 1/111 dianodon, together with the solar cell, in relation to enolettar, of some moderate bases.

Preferably cljanldnl Sources of alkali metal dianidl such as sodium potassium djan1d; c1janohldrlnl »etllalkllketone having 1-4 carbon atoms in alkyl groups, such as Ito tu c1Janoh1dr1n1 acetone 111 methylIsobutylketone clJanohldrlnl benzaldehylda 111 C * -Cg allfatlCnlh aldehylda aldehlda dldllda dldllda dld c1nk-c1Janld; tr1 (n121 alkyl) t1111c1jan1d1, especially tr1met11s1111dJanld; 1 there cljanovodonlk. Clajanovovodnlk considers you the most ingenious poito product! relatively quick reaction 1 cheap Is. He can use you! 111 in liquid 111 gaseous form; when you benefit! as gas can buy! from commercially available 111 ae generlle In dtu reaction of metallic cyanide with some acid. The preferred source of cyanide is among the djanldlm acetone djanohldrln.

In this embodiment, the cljanldnl Source is used in an amount up to about 50 mole percent based on the enolester. It can be used in as small an amount as Ito Je is about 1 mol% to provide an acceptable reaction rate at about 40 ° C in small scale. Vedic-scale reactions give reproductive results with a slightly v1I1m nlvolma of catalyst of about 2 mol%. It is generally preferable to have about 1-10 moles and a day source.

In this embodiment, the process is performed with a molar ratio relative to enoletar, some moderate bases. By the term moderate base is meant a substance that acts as bases and whose strength 111 activity as bases lies among those having such strong bases as Ito are hydroxides (which can call the enrollment of the enolester) those having such weak bases as Ito are bicarbonates (which will not work efficiently). Moderate bases suitable for use in this embodiment include 1 organic bases such as tertiary amines, 1 inorganic bases such as carbonates, 1 alkaline metal phosphates. Suitable tertiary amines include trialkylamine such as Ito is triethylamine, tralalkanolamines such as Ito trlethanolamine 1 pyridine. Suitable inorganic bases include potassium carbonate 1 trisodium phosphate.

The base is used in quantities! from about 1 to about 4 moles per mole of enolester,

- 8 preferably about 2 moles per mole.

When djanldnl is a source of djanld alkaline Metals, especially potassium-c1Janld, a phase transfer catalyst may be involved in the reaction. Particularly preferred catalysts for phase transfer are Crown Ethers.

In this process, eec1 number of different solvents may be used, depending on the nature of the chloride 111 chloride 111 of the finished product. A preferred solvent for this reaction is 1,2-dichloroethane. Other solvents that may be used, depending on the reactants 111 of the product, include toluene, acetonitrile, methylene chloride, ethyl acetate, dimethylformamide 1 methyl 11 isobutylketone (N1BK).

Generally, depending on the nature of the reactants 1 of the cellular source, the transfer can be carried out at temperatures up to about 8 D ° C. In some cases, for example, when a byproduct formation is a potential problem (for example, when using orthocyanobenzollhalogenld 1 alkali metal djanld 111 acetone djanohldrln as djanldnl Source) the temperature should be kept at a maximum of about 40 ° C.

In another embodiment of the present method, potassium 111 serves as a source, but is used in stoichiometric quantities relative to one liter without using a special base. C1jan1dn1 The source is used in conjunction with the catalyst catalyst for the phase transfer catalyst, which is Crown Ether 111 its acyclic analog.

Preferred djanldnl The source in this embodiment is ka11jum-djanld. A preferred Crown ether for this purpose is 18-Crown-6. Also suitable are other hexadentate compounds such as cyclohexoxyl-18-Crown-6, d1benzo-18-Crown-6 1 acyclic Compound pentaethylene glycol dlmetlleter.

For 11t1Jum-c1jan1d 1 & -Kruna-5 is suitable.

In this embodiment, a separate base is not required 1 is not used.

This embodiment is suitable for the production of compounds of the general type, but has been found to be particularly satisfactory for use when milder conditions are required 111 to suit the formation of the by-product, such as for the manufacture of benzoylated cyclohexanedione having an ortho-cyano substituent on the phenyl ring. This embodiment of the process can be carried out at room temperature. Similar solvents with the first realization may be used; preferably I acetone three 1.

The process according to r ', the realization of which can be performed using the enolester as a starting material, or by generating the enolester in its init, for example, by reaction of an acylating agent with dlketone. The term enolestar 'as used herein refers to a carboxylic acid one-ester.

When as a starting material! uses enolester in any embodiment of the process, it can be made from at least a number of known agents, including the alkylation of the diketone material with. for example, aci1halcgenide.

The production of acylated diketones according to the present invention, starting with acylated agents and diketones (for example, acyl halides and diketones such as cyclohexanedione) can be conveniently carried out with or by isolation of the intermediate enolester. When performed in two phases, acyl halide or other acylating agent and diketone are reacted in the presence of such a moderate base as triethylamine. The unilester can be isolated from the mixture of reaction products obtained by known techniques, for example, by washing the resulting solution with acid and base, and with saturated sodium chloride solution, and drying. Such a technique is advantageous when a different solvent is desired for the second phase - transferring the enolester to the acylated diketcn. The dried enolester can then be mixed with such a suitable solvent as acetonitrile or 1,2-dichloroethane, and contacted with a suitable solvent. the amounts of cyanide source and Hi with a moderate base or with Kruna ether, depending on the realization used, at the appropriate temperature, so that the final product is produced.

Alternatively, the unilester can be retained in the reaction product and • the second grade can be made (using the same solvent) addition, cyanide Source and supplementary base if necessary (in this embodiment) so that the acylated diketone is produced.

E;

In a second variant of the process, the adlovanl dlketon product of the skin is obtained in the J phase through the formation of In situ 1 enolester transfer reaction of another halogenation agent 111 in the presence of an appropriate amount of dianld Source 1 of an appropriate amount of some immersed ether base 111. depending on the step realization.

Comparison of 1v1 prlnosl can be obtained from 111 to 111 without isolation of onolesters.

The adlovanl dlketon product receives these 1z of this reaction in the form of its salt in the first embodied embodiment, the sorry acllovanl dlketon can be obtained by locking 1 extraction with a suitable ra solvent, if necessary. In some cases, the product should be contaminated with at 11m amounts of carboxylic acid corresponding to achalogen; such by-products of the leg are separated by contacting the swollen solution of the product with dilute aqueous sodium hydroxide 111 with another suitable base to form an acid salt. In another embodiment, the adlovanl dlketon knives are obtained per se.

The implementation of process 1z of the present invention is illustrated by the following examples.

EXAMPLE 1: Moving the onolester

A series of experiments were carried out to produce 2- (2 ^ 3 ^ 4 ¹ tr1h1orobenzoyl) -1,3-dichlohexandione by the premelting of its enoleater using various Dianlda 1 solvent sources. The general procedure is as follows: dissolve 3.0 grams (g) (0.0094 moles) of enolester (made by reacting "N, 3,4-trichlorobenzoyl chloride with 1,3-clechexandlone in the presence of triethylamine 1 Isolated) in 10 nHHtar (ml) of the indicated solvent 1 10 mole percent of the indicated catalyst is added 1 140 eole percent of triethylamine (both amounts relative to enoltstar). The bold is maintained at a cloudy temperature of 1 and the reaction is allowed to return for 4-18 hours. The reaction bold is diluted with water 1 the solvent is separated by distillation under reduced pressure. The resulting aqueous bold was acidified to pH about 1 light by addition of 6N hydrochloric acid, with milling. The solids obtained were collected by filtration 1 and concentrated to 75 ° C.

The crude yield of the crude ad-dcatonic product »not corroded by the total purity of the starting material is given below in Table 1.

TABLE 1 Catalyst Solvent Theoretical nose,% product purity,% KCN acetonitrile 91.3 62.8 KCN acetonitrile 91.0 81.9 KCN acetonitrile 95.3 84.6 KCN 1,2-dichloroethane 87.3 76.0 KCN 90Ϊ 1,2-d1h1oroethane / 10% dImet11formamide 66.0 75.7 NaCN 1,2-dichloroethane 78.7 80.3 acetone cyanochldrin acetonitrile 92.0 80.1 EXAMPLE 2 i Making adlovated dlketon without enolester Ifcolation

This Example Illustrates the Procedure aa Pole Thirst Than Adlhalogenld 1 of Some dlketone, in One Phase, Without Isolation of Intermediate Enolester. The procedure was as follows:

3.0 g (0.027 mol) of 1,3-dichlohexandlone, 15 ml of the indicated solvent 1 10 mole percent (relative to 1m enolester) of sodium cyanide are placed in the balloon. The reaction mixture is placed under a nitrogen layer 1 and maintained at a temperature around the atmosphere. It is then kept at room temperature after having previously added 300 mole percent of triethylamine (enolester based). 100 mole percent (relative to dione) of 2,3,4-trichlorobenzoyl chloride is then added to the mixture. The mixture is maintained at ordinary temperature 1 and the reaction is allowed to proceed for about 24 hours. The product was isolated as in Example 1, yielding 8.04 g of the crude product (93.2% of theory, unincorporated for purity of starting material).

EXAMPLES 3-6

A series of similar experiments were performed with those described in Example 2, but using different solvent catalyst 1. 1st1 reactants are used. All catallzatorl is used in an amount of 10 mol%, based on the Intermediate Enolester. Table 2 contains the results of these experiments, whereby the dirt is uncorrected for the purity of the starting material.

- 12 - C TABLE 2 Ex. No. Catalyst Solvent Theoretical yield, t purity of the product, X 3 KCN methylene chloride 81.1 80.5 4 KCN 1,2-d1 chloroethane 87.5 69.9 5 acetone cljanoMdrin 1,2-dichloroethane 90.7 82.6 6 acetone cljanoMdrin toluene 90.4 79.3

EXAMPLE 7: ₍ t

[·!

This example also involves performing the procedure without isolating the Intermediate Enolester. J

i.

15 grams (0.13 moles) of 1,3-clecheloxanedione, 75 ml of 1,8-dichloroethane 1 0.25 ml (2 mol% on one-liner balm) and acetone cyanochlorine were added to the balloon. Put the materials under a nitrogen cloth 1 balloon and put you on an ice bath.

54.36 ni (34.96 g, 0.39 moles) of triethylamine 1 were added to the balloon. 32.86 g (0.13 moles) of 2,3,4-trifluorobenzoylpyrrolidone dissolved in 125 ml of 1,2-dichloroethane. When the addition of the benzoyl chloride 1 'min 1 is complete, the temperature of the bold reactant is raised to 40 ° C 1 and the bold reacts for 2 hours. At the end of this period> crosslinking with liquid chromatography under flash pressure showed an area of 84.6 percent of the desired product, with the bulk of the remainder being unreacted dchlohexandlon.

The reaction bold was then cooled 1 diluted with 100 m! water. The pH, which was 9.8, was adjusted to 2.8 by the addition of 3 M tumor acid with an additional 100 ml of 1,2-dichloroethane added during this phase to re-dissolve the solids that began to precipitate. organic phases.

The aqueous layer (about 200 ml) 1 had a pH of 2.6.

The organic phase was washed with water 1 phases were separated again (water fax? Had pH 4). The organic phase is then washed with 2 batches of 2.5 N aqueous sodium hydroxide 1 phase again after each Renewal. The organic phase is again washed with 100 ml of water.

All the aqueous phases obtained from the 1z of the above separation phases were combined 1 acidified with 3 M sulfuric acid. pH decreased to 2.1. The coupled aqueous phases are kept at zero temperature in an ice bath. Deposited solids Collected by filtration from solution. The solids were dried to constant weight in vacuo · dry1c1. 39.19 grams of Desired Product is obtained »m.p. 150-15l ° C. The product structure was confirmed by high-pressure liquid chromatography annill 1 by comparison with a known sample. ;

j i

EXAMPLE 8: Production of 2-propanoyl-1,3-cyclohexandione

To a mixture of 3.0 g (0.027 mol) of 1,3-cyclohexandione 1 3.8 ml (0.027 | mol) of triethylamine in 15 ml of methylene chloride was added dropwise

2.3 ml (0.027 mol) of proplonllhlorld with stirring 1 cooling with a water bath at room temperature. After continued stirring at ambient temperature for about 4 hours, another 7.5 ml (0.054 mol) of triethylamine 1 was added 0.25 ml (10 mol% relative to one liter) of acetone danohydrile. The mixture was stirred at ordinary temperature overnight, then diluted with water 1 acidified with 6N hydrochloric acid. The phases are separated 1 aqueous phase is extracted with methylene chloride. The combined organic phases were dried over enhydrated sodium sulfate 1 and concentrated under reduced pressure to give 4.68 g of the crude product as a mixture of solid substance 1 of the liquid. The crude product was dissolved in methylene chloride and extracted with 2.5 M sodium hydroxide solution 1 then with water. The combined aqueous phases were acidified with 6 N hydrochloric acid 1 and extracted with methylene chloride. The organic extract was dried over anhydrous sodium sulfate 1 and concentrated under reduced pressure to give 3.83 g of an oily product (84% of theory). The structure of the product was confirmed by infrared spectroscopy using nuclear magnetic resonance imaging and mass spectroscopy.

EXAMPLES 9 1 10

These Examples illustrate the manufacture of the compounds described in U.S. Pat. Serial No. 683,900 by Charles G.

Carter, entitled Certain 2- (2-ntrobenzoyl-1,3-cyclohexandlonl ”, filed December 20, 1984.

ο

2-t1trobenzene1chloride (5.0 ¢, 0.027 moles) 1 c1k1ohexand1one (3.0 g, 0.027 moles) with a solution in methylenehlorld. Triethylamine (4.9 ml, 0.035 mol) was added dropwise and the resulting solution was stirred for one hour. The solution was washed with 2H hydrochloric acid (2N HCl), water, 52 potassium carbonate solution 1 with saturated sodium chloride solution, dried over anhydrous magnesium sulfate (MgSO ₄ ) 1, concentrated in vacuo. The residue was dissolved in 20 ml of acetonitrile. Triethylamine (1 equivalent) 1 cal 1µm-cyaneld (40 mol X) was added 1 solution was stirred for one hour at room temperature. After dilution with ether, the solution was washed with 2N HCl 1 and extracted with 5% potassium carbonate solution.

The aqueous extract was acidified with 1 ether. Filtration of the resulting mixture afforded 3.2 g of the desired compound (mp 132-135 ° C), which was identified by nuclear magnetic resonance imaging, Infrared 1 Meat Spectroscopy.

EXAMPLE 10: 2- (2 * -Hitrobenro11) -5,5-dyraet11-1,3-cyclohexandlon

CH

CH

Triethylamine (3.4 ml, 0.025 mol) was added dropwise to methylene chloride solution of 2-nitrobenzoyl chloride (3.5 g, 0.019 mol) 1

Of 5,5-d1methylcyclohexandlon (2.4 g, 0.019 mol). After stirring for one hour at room temperature, an additional 3 equivalents of triethylamine 1 0.4 ml of acetonocyanate are added. The solution was stirred for 2.5 hours, then washed with 2N HCl 1 extracted with 52 potassium carbonate solution. The base extracts were locked in with 2N HCl 1 and extracted with ether. The ether portion was washed with saturated sodium chloride solution, dried over anhydrous MgSO _{4 4 and} concentrated in vacuo. The residue was recrystallized from 1 g of ethyl acetate to give 2.0 g of the desired compound (mp 130-133 ° C) which 1dent 1 fluted as such by nuclear magnetic resonance. Infrared

- 15 .....- * // · <'·' K- · ν .:; * Λ · -. «_ Spectroscopy.

This example illustrates the production of a compound described in U.S. Pat. Serial No. 663,899, by Charles 6. Carter ». under the heading Certain 2- (2′-cyanobenzoll) -4,3-c1lohekssnd1on1 ·. filed December 20, 1964.

2-C1janobenzollhlorld (3.9 g, 0.024 mol) 1 4,4-dimethyl-l, 3clclohexanthione (3.3 g, 0.024 mol) was dissolved in 76-1 methylene chloride. Add the trlethylamine (5.0 «1, 0.036 salts) dropwise to a small solution 1 hour at room temperature. · The solution is washed with water, with ZN HCl, with 51 potassium carbonate solution (51 K ^ COj) 1 with saturated sodium chloride solution. of chloride (saline), tuf1 was concentrated in vacuo over anhydrous agneslium sulfate (MgSO4) 1. The residue was dissolved in 20 [mu] l of acetonitrile. Trlethylamine (4.4 »1, 0.032 mol) was added and acetone cyanohydrin (5 drops) 1 solution was stirred for two hours. After dilution with ether, the solution was washed with 2N HCl 1 and extracted with 51 K ₂ C0 ₃ . The aqueous extract was acidified with concentrated hydrochloric acid 1 and extracted with ether. The ether is washed with water and brine, suctioned over MgSO4 and concentrated in vacuo. The residue was purified by chromatography on silica gel to give 1.2 g of viscous oil, which is 1dent 1f1 as the desired compound by nuclear magnetic resonance imaging, infrared 1 mass spectroscopy.

EXAMPLE 12 and 2- (2'-Metnt1obenzoyl) -4,4,6-trimethyl-1,3-cyclohex * "

This example illustrates the production of Bedlnjtn that was paid for in the U.S. Serial No. 683,898 »by Charles 6.

Carter et al., Entitled Certain 2- (2'-substituted benzoyl) -1,3-cyclohexanedione1, which was competitively filed with this dirty.

2-Methyltlobenzolchloride (7.2 g, 0.039 mol) 1 4,4,6-trimethyldichlohexandlon (5.0 g, 0.039 mol) was dissolved in methylene chloride and triethylamine (7.0 ml) (0.050 mol) was added dropwise 1 obtained.

J solution was stirred one Cas at room temperature. The solution was washed with 2N HCl, with St K ^ CO ^ ¹ »* brine, dried over MgSO4 and concentrated in vacuo. The residue was dissolved in 20 ml of acetonitrile. Triethylamine (2.5 equivalents) 1 acetone cyanochloride (0.4 ml) 1 solution was added and the solution stirred for 45 minutes at room temperature. After dilution with ether, the solution was washed with 2N HCl 1 extracted with the ^aqueous solution acidified with hydrochloric acid 1 extracted with ether. The ether was washed with brine and concentrated under vacuum in MgSO * 1. The residue was purified by evaporation with ether to give 5.0 g of a fibrous oil which was 1dent 1fluxed as the desired compound by means of nuclear magnetic resonance imaging, infrared and mass spectroscopy (ms).

EXAMPLE 13; 2- (4'-Bromo-2'-trifluoromethylbenzo11) -4,4,6-triethylmethyl,3,3-cyclohexanedione

This example illustrates the production of a compound described in U.S. Pat. Serial No. 673,884, by Charles G. Carter, entitled Certain 2- (2-alk11benzo11) -4,3-cyclohexae palms, filed December 20, 1984.

4-Bromo-2-trifluoromethylbenzoyl chloride (4.3 g, 0.015 mol) 1 4,4,6-trifluoromethyl-1,3-cyclohexanedione (2.3 g, 0.015 mol) was dissolved in 100 ml of methylene chloride. The solution was cooled in an ice bath 1 was added dropwise with relethylamine (2.1 ml, 0.015 mol) in 10 ml of methylene chloride. The ice bath was then separated and the resulting solution was stirred for 30 minutes at room temperature. The solution was washed with 2Ν hydrochloric acid (2N HCl), with a 5Ϊ solution of cal 1ium carbonate (5% KgCOj) 1 with saturated sodium chloride solution (brine), and concentrated over anhydrous magnesium sulphate (MgSO 4) 1 in vacuo. The residue (5.1 g) was dissolved in 20 ml of acetonitrile. Add tr1et1lBm1n (3.5 ml, 0.025 mol)

0.4 ml of acetone cyanohydrate 1 solution was stirred for two hours at room temperature while being protected by a drying tube (calcium sulfate). After dilution with ether, the solution was washed with 2N HCl 1 extracted with 5% K ₂ CO _{3. The} aqueous solution was then acidified with concentrated hydrochloric acid 1 extracted with ether. The ether was washed with brine, dried (MgSO4) 1 and concentrated in vacuo. The resulting oil is purified on sIHkage! columns (80: 20: 1 hexane: et11 acetate: acetic xyellic eluent), so that

1.5 g of fibrous oil identified by nuclear magnetic resonance imaging, Infrared 1 mass spectroscopy.

EXAMPLE 14: 2- (4 ^< -Chlorobenzo11) -5,5-dichloroethyl-1,3-cyclohexandione

This example illustrates the implementation of a process using cyanogen (generated by the reaction of sodium sulphide with sulfuric acid) as a Cyanide Source.

5,5-Dimethylcyclohexane-1,3-dlon (7.01 g, 0.05 mol), acetonitrile (80 ml) 1 trimethylamine n (21 ml, 0.15 mol) were combined in a balloon 1 under a nitrogen atmosphere. A solution of 4-chlorobenzoylpyrrolidine (6.4 ml, 0.05 mol) in acetonitrile (20 ml) was added over 15 minutes with stirring 1 cooling with a water bath at ordinary temperature. In a special reacton balloon connected to the inlet tube which is Below the surface a solution of sulfuric acid (0.25 g, 0.0025 mol) in water (10 ml) is added over 10 minutes to a solution of sodium cyanide (0.25 g 0.005 mol) in water (30 ml) at 85 ° C with stirring 1 gently blowing nitrogen through secondary reactor 1 in the reactor. The primary reactor was then heated and stirred at 40 ° C for about 2 hours after which the reaction was complete.

The reaction mixture was diluted with 60 ml of water 1 slightly acidified with 40 ml of 6N HCl with product precipitation. After stirring for about £ minutes, the Solid product was collected by filtration, washed with water and dried to give 11.85 g (85.0% of theory) of a white solid. 134-134.5 ° C.

EXAMPLE 15: 2- (4 ¹ -Tylorobenzol) -5,5-d1-eth11-1 _t 3-cyclohexandlon

This example illustrates the implementation of the process by using trlnl elkylsilylcyanld as the Dianld Source,

5,5-Methylcyclohexyl-1,3-dlon (7.01 g, 0.05 mol), acetonitrile (80 ml), 1 triethylamine (21 ml, 0.15 mol) were combined in a balloon and placed under an esotope atmosphere. A solution of 4-chlorobenzolchloride (6.4 ml, 0.05 mol) in acetonitrile (20 ml) was added over 15 minutes with stirring 1 cooling with an aqueous bath at not ordinary temperature. Trilmethylldiamine (0.33 ml, 2.55 mmol) was added, 1 reaction was heated 1 stirred at 40 ° C for 3 hrs after which the reaction was complete.

The reaction mixture was diluted with 160 ml water and acidified with 40 ml 6N hydrochloric acid solution with product precipitation.

After stirring for about 10 minutes, the product was collected by filtration. 1 Washed with water 1 and dried to give 13.2 g (95% of theory) of the white solid: m.p.

135-134.5 ° C.

EXAMPLE 16; 2- (2 * -C 1 Cyanobenzoll) -1,3-c 1 chlohexandlon

This example illustrates the implementation of another embodiment of the process, using a stoichiometric amount of potassium dianld 1 Crown of ether.

Into the balloon are placed 1.2 g (0.C05 mol) of an enolester made by reaction of 1,3-cyclohexandione with 2-cyanobenzol chloride, potassium dianide (0.3 g, 0.05 mol), 18-Crown-6 (0.1 g, 0.0005 mol) and 10 ml of acetonyltril. The mixture was stirred at room temperature for 30 minutes, then poured into 300 ml of water. The pH was carefully adjusted to about 6 with concentrated hydrochloric acid; then the solution was extracted with 200 ml of ethyl acetate. It is then extracted with 300 ml of saturated aqueous sodium b1 carbonate solution. The bicarbonate extract was acidified (at pH about 3) with concentrated hydrochloric acid 1 extracted with 200 ml of ethyl acetate. The resulting solution was dried over sodium sulfate and separated to give 0.7 g (583 of theory) of the desired product as an orange-brown oil. The structure was confirmed by infrared, nuclear magnetic resonance 1 mass spectroscopy.

EXAMPLE 17: 2- (4 * -Chlorobenzoyl) -6,5-d <methyl-t, 3-cyclohectandone

This example illustrates the process of using metal carbonate as a base «

5,5-D1methyl 1-chloroxane-1,3-dione (S.SOg, 0.025 mol), potassium carbonate (10 g), cal 1-cyanalde (0.2 g) 1 dimethylformamide (40 ml) were combined in a balloon nitrogen. P-Chlorobenzoyl chloride (3.5 ml, 0.025 mol) was added dropwise. The mixture was stirred at 40 ° C for 3 hours 1 at 70 ° C for 2 hours.

The reaction mixture was diluted with methylene chloride 1 acidified with 3 N hydrochloric acid. The organic phase is washed with water 1 and extracted with 2.5 N sodium hydroxide solution.

Seak acid base extract with 3 N hydrochloric acid solution. The precipitated product was collected by filtration, washed with water 1 and dried to give 6.46 g (78.0% of theory) of the crude product. Product analysis using HPLC (high performance liquid chromatography) showed 63% of mixed 2- (4'-chlorobenzoll) -5,

1,3-dichlohexandlon. p-Chlorobenzoic acid was just the main impurity?

-2οExample 18: 2- (2-Chloro-4-methanesulfonylbenzoyl) -1,3cyclohexanedione

0.376 moles of 1,3-cyclohexanedione, 1,0 moles of trlethylammonium 0,026 moles of acetone cyanohydrin and 1.5 moles of toluene are added to the balloon. The temperature is maintained below 20 ° C. 0.3666 moles of 2-chloro-4-methanesulfonylbenzoyl chloride are then added through an addition funnel, which is then washed with toluene. The temperature is maintained at about 60 ° C. The reaction product is treated with water, neutralized with the base and the aqueous phase reacted with 20% by weight of hydrochloric acid. The product is separated, filtered and analyzed by means of infrared, nuclear magnetic resonance and mass spectroscopy to confirm the structure.

Example 19: 2- (2-Chloro-3-ethoxy-4-ethanesulfonylbenzoyl) 1,3-cyclohexanedione

355 g (3.07 mol) of 1,3-cyclohexanedione, 2.7 L, were placed in the reactor

1,2-dichloroethane and 1.29 L (9.21 moles) of triethylamine. The mixture was cooled to 3 ° C and then, over 76 minutes, 1003g (3.00 mol) of crude 2-chloro-4-ethanesulfonyl-3-ethoxybenzoyl chloride in 900ml of 1,2-dichloroethane was added while maintaining the temperature at 0 ° C. An aliquot analysis of the mixture using a gas chromatograph £ at the end of this period shows the formation of enol ester with residual hydrochloric acid as head impurity.

Then 25, Og (0.252 mol) trimethylsilyl cyanide was added at once, and allowed to rise in temperature. After five hours, analysis by gas> chromatography showed that there was no unreacted enol ester remaining. The mixture was allowed to stand overnight and treated with hydrochloric acid, water, sodium hydroxide and dichloromethane. 952g (78.3% of theoretical yield) of the desired product is obtained, the structure of which was confirmed by forward spectroscopic methods.

. -24- ·

The best way to use the invention in the economy that is known

Applicant

The invention can best be applied if the sv1 process parameters that are described in detail in Working Examples 1-17 of the application description are strictly followed.

Claims (13)

1. A process for the manufacture of acylamino cyclic and diketone compounds which. imal | n Where the structural formula is hydrogen or methyl, is hydrogen or methyl, vdoonik'ili methyl, and R zajedno su carbonyl is hydrogen or methyl, is hydrogen or methyl is halogen, cyano, C ₁ _ ₄ alkyl, C ₁ _ _(J haloalkyl, R ^ S FF) wherein R ^ is C, _ alkyl, n is 0,1 or 2, C ₁ _ alkoxy or nitro, g R is vdoonik, 3-C ^ _ ^ alkylthio, 3-halogen, C ₁ _ alkyl, nitro, cyano, C. .haloalkil or trifluoromfetoksi, and 9 R is hydrogen, 4-C ^ _ ^ alkoxy, 4-C ₁ _ ^ alkylthio, 4-C ₁ _ ^ alkylsulfonyl, 4-halogen, 4-C ^ alkyl, 4-nitro, 4-cyano, 4- € ₁ _ ₄ haloalkyl comprising the displacement of a suitable enol ester having the structural formula Where R - R are as defined above, in the presence of a cyanide source selected from a catalytic amount of cyanide source and molar excess with respect to the moderate base enol ester and stoichiometric amounts with respect to the enol ester. -Chalium cyanide or lithium cyanide and the catalytic amount of the cyclic Crown ether or its acyclic analogue. Process according to claim 1, characterized in that the transfer is carried out in the presence of a cyanide source which is an alkali metal cyanide, zinc cyanide, cyanohydrin methyl layered ion having 1-4 atoms in the alkyl group, benzaldehyde cyanohydrin, cyanohydrin ^C 2_5 ~ aliphatic aldehyde, three (lower alkyl) silyl cyanide or molar excess cyanide, relative to the enol ester, of moderate base. 3. The method of claim 2, wherein the cyanide source is cyanide. The process according to claim 2, wherein the cyanide source is sodium cyanide. The process of claim 2, wherein the cyanide source is potassium cyanide. 6. The process of claim 2 wherein the cyanide source is acetone cyanohydrin. 7. The process of claim 2, wherein the cyanide source is used in an amount of from about 1 to about 10 molar percent based on the enolester. The process according to claim 2, wherein the moderate base is tertiary amine, alkaline metal carbonate or alkaline metal phosphate. 9. The process of claims 2-8, wherein the moderate base is trilakyl amine. The process according to any of claims 2-9, wherein the moderate base is triethylamine. A process according to any one of claims 2-10, wherein the base is used in an amount of about 4 moles per mole of enolester. -TSV ' 12. The process of claim 1, wherein the transfer is carried out in the presence of a stoichiometric amount, in yield to the enol ester, potassium cyanide or lithium cyanide and the catalytic amount of cyclic Crown ether or its acyclic analog. The process of claim 1, wherein the acylated diketone compound is a cyclohexanedione derivative.