FI94626C - Processes for the preparation of aryl pyrroles and intermediates - Google Patents

Description

! - 94626

Methods for the preparation of arylpyrroles and intermediates

This invention relates to processes for the preparation of arylpyrrole compounds as described in claim 1. These compounds are useful in the preparation of highly effective insecticides, acaricides and nematicides useful for controlling insect, mite and nematode pests and for protecting crops on crops, both growing and harvested, from damage caused by said pests. The invention also relates to intermediates useful in the process according to claim 4 and to their preparation as described in claim 6.

The invention relates to a process for the preparation of a novel arylpyrrole compound having the structural formula:

U

B

25 /

R

wherein W is CN or NO 2; L is H, F, Cl or Br; and M and R are each independently H, C 1-3 alkyl, C 1-3 alkoxy, C 1-4 alkylsulfonyl, cyano, F, Cl, Br, nitro, CF 3, OFF 3 or R 2 CO, and when M and R are adjacent at the positions, they:: together with the carbon atoms to which they are attached may form a ring in which MR represents the structure: and R 2 is C 1-6 alkyl or C 1-4 alkoxy.

35 2 94626

The compounds of the invention are useful in the preparation of novel arylpyrrole compounds (I), T N N / n wherein X is F, Cl, Br, I or CF 3; Y is F, Cl, Br, I, CF 3 10 or CN; W is CN or NO 2 or A is H; C 1 -C 4 alkyl / optionally substituted with one to three halogen atoms, one hydroxy, one C 1 -C 4 alkoxy or one C 1-4 alkylthio, one phenyl optionally substituted with C 1-4 alkyl or C 1-3 alkyl -alkoxy or one to three ha-15 halogen atoms, one phenoxy optionally substituted with one to three halogen atoms or one benzyloxy optionally substituted with one halogen substituent; C ^ -karbalkoksimetyyli; C3-4 alkenyl optionally substituted with one to three to 20 mee halogen atoms; cyano; C3-4 alkynyl optionally substituted with one halogen atom; di-C 1-4 alkyl) aminocarbonyl; or C 4-6 cycloalkylaminocarbonyl; L is H, F, Cl or Br; and M and R are each independently H, C 1-4 alkyl, C 1-4 alkoxy, C 1-4 alkylsulfone. 25 yl, cyan. F, Cl, Br, I, nitro, CF 3, OCF 3 or R 2 CO, and when M and R are in adjacent positions, together with the carbon atoms to which they are attached, may form a ring in which MR represents the structural formula:: “O '• · and R 2 is C 1-6 alkyl or C 1-4 alkoxy.

The term C 4-6 cycloalkylaminocarbonyl denotes a C 4-6 cycloalkylamino group which is directly attached to the carbonyl group via a nitrogen atom.

3 - 94626

The process according to the invention is characterized in that benzoylacetonitrile or α-nitroacetophenone having the structural formula: wherein L, M, R and H are as described above, is reacted with 2,2-di (C 1-4 alkoxy) ethylamine at elevated temperature, to give α- [2,2-di (C 1-4 alkoxy) ethylamino] -β-cyanystyrene or α- [2,2-di (C 1-4 alkoxy) ethylamino] -β-nitrostyrene of structural formula on: 15

X is N-CH 2 CH (C 1 -C 4 H

Wherein L, M, R and N are as described above, and the α- [2,2-di (C 1-4 alkoxy) ethylamino] -β-cyano styrene or α- [2,2-di (C 1-4 alkoxy) thus obtained amino] -β-nitrostyrene is treated with an inorganic or organic acid.

The present invention also relates to a compound having the structural formula:

L

X is f-R 1 -N-CH 2 CH (C 1 -C 4 alkoxy) 2 • n wherein W is CN or NO 2; L is H, F, Cl or Br; M and R are each independently H, C 1-4 alkyl, C 1-3 alkoxy, C 1-3 alkylsulfonyl, cyano, F, Cl, Br, nitro, CF 3, CF 3 4-94626 or R 2 CO, and when M and R are at adjacent positions, they may together with the carbon atoms to which they are attached form a ring in which MR represents the structure: O and R 2 is C 1-3 alkyl or C 1-3 alkoxy.

The primary group of β- (substituted) styrene compounds of this invention has the above structural formula wherein W is CN; L is H, Cl or Br; M is H, F, Cl,

Br is OCH 3; R is H, F, Cl, Br, CF 3, NO 2, OFF 3 or OCH 3; or when in adjacent positions M and R may, together with the carbon atoms to which they are attached, form a ring in which MR represents the structure:

Another preferred group of β- (βυO 3 ΐ-supported) styrene compounds of the present invention has the above structural formula wherein W is NO 2; L is H, Cl or Br, M is H, F, Cl, Br or OCH 3; R is H, F, Cl, Br, CF 3, NO 2, OFF 3 or. 25CH3; or when in adjacent positions M and R may, together with the carbon atoms to which they are attached, form a ring in which MR represents the structure:.

Although the compounds of this invention are referred to above as β-cyanostyrenes and β-nitrostyrenes, they may also be referred to as dialkyl acetals.

li s - 94626

Some preferred dialkyl acetal compounds of this invention are (E) and (Z) (I) p-chloro-β - [(formylmethyl) amino] cinnamonitrile diethyl acetal; 5 (2) β - [(formylmethyl) amino] -3,4-dimethoxycinnamonitrile-diethyl acetal; (3) (Z) -methyl p- {2-cyano-1 - [(formylmethyl) amino] vinyl] benzoate-diethyl acetal; (4) (Z) -β - [(formylmethyl) amino] -1-naphthaleneacrylonitrile-diethyl acetal; (5) (Z) -β - [(formylmethyl) amino] -p-methylcinnamonitrile dimethyl acetal; (6) N- (formylmethyl) -p-methyl-α- (nitromethylene) -benzylamine-diethylacetal; (7) N- (formylmethyl) -3,4-dimethoxy-α- (nitromethylene) benzylamine diethyl acetal; (8) N- (formylmethyl) -α- (nitromethylene) -2-naphthalenemethylamine diethyl acetal; (9) methyl N- [α - [(formylmethyl) amino] -β-nitrovinyl} benzoate - (diethyl acetal); (10) N-formylmethyl) -3,4-dimethoxy-α- (nitromethylene) -benzylamine-dimethylacetal; (II) (E) - and Z) -E-chloro-p - [(formylmethyl) amino] Kinnamitrile dimethyl acetal; . (12) β - [(formylmethyl) amino] -3,4-dimethoxycinnamonitrile dimethyl acetal; (13) 3,4-dichloro-p - [(formylmethyl) amino] cinnamonitrile-diethyl acetal ;. and (14) ε-trifluoromethyl-β - [(formylmethyl) amino] cinnamonitrile diethyl acetal.

β-Cyano styrenes, also called Kinna monitrile dialkyl acetals, can be prepared by reacting a substituted or unsubstituted benzoylacetonitrile with 2,2-di (C 1-4 alkoxy) ethylamine 35 in the presence of an aromatic solvent to give a 6 to 94626 aromatic solvent. in the presence of a solvent to form α- (2,2-di (C 1-4 alkoxy) ethylamino) -N-cyano- (substituted) styrene, which can then be converted to 2- (substituted-phenyl) -pyrrole-3-carbonitrile anta-5 miles react with said β-3-cyano-substituted) styrene compound with trifluoroacetic acid. Chlorination of the cyanophenylpyrrole thus prepared with sodium hypochlorite or sulfuryl chloride in an inert solvent gives 4,5-dichloro-2- (substituted-phenyl) pyrrole-3-carbonitrile from the insecticide, acaricide, and nematicide. Conversion to the pyrrole intermediate can also be performed using concentrated HCl at a temperature between about 20-40 ° C. The reactions can be represented graphically as follows: f «» 7 94626

Reaction Scheme 5 VKv // 0 (C C 4 · H.NCH 2 CH <OC? H «)?

\ -CN

/ ^ / / aromatic solvent 10 CN o-R6

Sc-1 / \ JL ά 3a e R s ° -r * 15 CF3CO2h or HCl

_ / CN X_ CN

20 NaOCl n \ —Xv or * H \ // ^ R SO2C12 \ -> x

or Br2 R

koc <ch3) 3 bi • 25 x β - 94626 wherein A is hydrogen, C 1-4 alkyl optionally substituted with one C 1-4 alkoxy group, one C 1-4 alkylthio group, one to three halogen groups, or phenyl, optionally substituted with one or two C 1-5 alkyl, C 1-4 alkoxy, or halogen groups; C3-4 alkenyl optionally substituted with three halogen groups; or C3-4 alkynyl; X is Cl or Br; R 6 is C 1-6 alkyl and L, R and M are as described above.

Arylpyrrole compounds of formula I wherein 10 A is hydrogen; W is CN and X, Y, L, M and R are as described above, can be prepared by administering N-formyl-DL-phenyl-glycine or substituted N-formylphenylglycine represented by Structural Formula VIII:

15 L _ CO2H

XV. df (viii) NHCH = 0

R

Wherein L is H, F, Cl or Br; R and M are each independently H, C 1-6 alkyl, C 1-3 alkoxy, C 1-6 alkylsulfonyl, cyano. F, Cl, Br, nitro, CF 3, OFF 3 or R 2 CO, and when in adjacent positions M and R can together with the 25 carbon atoms to which they are attached form a ring in which MR represents the structure: O and R 2 is C 1-3 alkyl or C 1-3 alkoxy, react with at least an equivalent amount of 2-chloroacrylonitrile and two to three equivalents of acetic anhydride.

9,94626

The reaction is carried out at an elevated temperature, preferably about 70-100 ° C.

The reaction can be represented as follows:

5 L

n I co2h ci / V1 flc2o CH + CH2 = C + CN - ^ NsNHCH = 0

CN

10 r (A / (VIII) n \ // '

R

Conversion of 2-phenylpyrrole-3-carbonitrile or 2- (substituted phenyl) pyrrole-3-carbonitrile thus prepared to 4-halogen, 5-halogen or 4,5-dihalo-2- (substituted phenyl) of formula 11 ) pyrrole-3-carbonitrile is readily accomplished by reacting the aforementioned 2-phenylpyrrole-3-carbonitrile or 2- (substituted phenyl) pyrrole-3-carbonitrile with at least about 1 or 2 equivalents of sulfuryl halide, bromine, or chlorine in the presence of a solvent such as dioxane, THF, acetic acid or a chlorinated hydrocarbon solvent. To prepare monohalopyrrole-3-carbonitrile, it is necessary to use about 1 equivalent of halogenating agent; while the preparation of di-halopyrrole-3-carbonitrile requires 2-3 equivalents of said halogenating agent.

When sulfuryl chloride or sulfuryl bromide is used, the reaction is generally carried out at a temperature below about -94626 10 40 ° C and preferably at about 0-30 ° C, but when the bromine element is used, the reaction is usually carried out at about 30-40 ° C. . Other effective halogenating agents that can be used in these reactions include sodium hypochlorite, t-butyl hypochlorite, N-bromosuccinimide, N-iodosuccinimide, and the like. The reaction can be described as follows: 10 / CN * c »1 ^ Bre, Clg, SO0 <x? Z ^ \ f- \

H HORc * H \ y / 'aC

15 <”>

The carbonitrile compounds of formula 11 can also be prepared by reacting a substituted or unsubstituted benzoylacetonitrile with 2,2-di (C 1-4 alkoxy-20) ethylamine in the presence of an aromatic solvent to form α- (2,2-di (C 1-4). 4-alkoxy) ethylamino) -4-cyano- (substituted) styrene, which is then converted to 2- (substituted-phenyl) -pyrrole-3-carbonitrile of formula II by giving said β-3-cyano-25 (substituted) -styrene to react with trifluoroacetic acid or concentrated HCl at a temperature between about 20-40 ° C. The reaction can be described graphically as follows: «i • i li 11 - 94626

reaction scheme

L

5 + H2NCH2CH <0C2H5> 2

/ ^ = - Γ \ —CN

R \ / \ / aromatic Y solvent

10 I

) ΖκΧ.

15 CF3CO2H or

Ihci

CN

Ov Jk. "

20 H

R

Wherein R 9 is C 1-4 alkyl and L, R and M are as described above. Likewise, in accordance with the present invention, the 3-nitro-2-phenylpyrrole and 3-nitro-2- (substituted) phenylpyrrole compounds of formula II can be prepared by reacting o <, - nitroacetophenone or substituted o6-nitro-30 acetophenone with 2.2 -di (C 1-4 alkoxy) with ethylamine. The reaction is usually carried out in the presence of an inert organic solvent, preferably an aromatic solvent, at elevated temperature to give O 6 - (2,2-di (C 1-4 alkoxy) ethylamino) -β-nitrostyrene 35 or substituted οί, - (2.2 -di (C 1-4 alkoxy) ethylamino) -β-12-94626 nitrostyrene which is converted to 3-nitro-2-phenylpyrrole of formula II or 3-nitro-2- (substituted) -phenylpyrrole by treatment with an inorganic acid such as hydrochloric acid or hydrobromic acid.

Reaction of the nitrophenylpyrrole thus prepared with sodium hydrochloride in the presence of an inert organic solvent at reduced temperature gives 2,3-dichloro-4-nitro-5-phenyl or 5- (substituted) -phenylpyrrole of formula II.

10 The above reactions can be described graphically as follows: vk s' V-C-CHgNOg + H2NCH2CH (OC2H5) 2 _ is y <= zj

R

L

x = / N — CH 2 CH (OCl 2 H 5) p

.n R H

20

| CFCl 3 CF 3 CO 2 H

no2 25 H \ _X Cl NO2 I NaOCl 1 [n 1-1ci 30

R

M

<11> 13 - 94626

In addition to several methods described in the literature for the preparation of substituted and unsubstituted benzoylacetonitriles, it has surprisingly been found that these compounds can also be prepared by reacting an appropriately substituted benzoyl halide with an alkali metal hydride and an alkylated butylate These reactions can be described graphically as follows:

LO n V

C-Cl ♦ N «H ♦. (ΗΓ ^ 3’3 C0-C-C0-0C <CH3> 3

R CH

The cyanoacetate ester thus formed can then be converted to substituted or unsubstituted benzoylacetonitrile by heating the compound in toluene with p-toluenesulfonic acid. The reaction can be described graphically as follows: C0-C-C0-0C (CH3> 3 i

.. 25> <= y {„3 toluene ^ μM

Examples of t-butyl (benzyl and substituted benzoyl) acetonitriles used in the above reactions are shown in the tables below.

4 I

• 4 1 · 14,94626 t-butyl (benzyl and substituted benzyl) cyanoacetates 5

L

ΙΊ 10 r) \\ - C0-C-C0-0C (CH3) 3

R '^ -' CN

15 LM R SP ° C

H 3 -Cl 4 -Cl 91-94 HH 4-OCF3 81-84 HH 4-Br 113-115 HH 4-CF3 146-147 20 HH 4-F 98-100 HH 4-CN 127-128 HH 4-CF3CH2O 136-139 HH 4-CH 3 SO 2 127-129 H 3-F 4-F 91-94 25 HH 4-CH 3 S 117-119.5 HH 4-CHF 2 CF 2 92-94 3-Cl 5 -Cl 4-CH 3 O-15 - 94626

Benzoyl acetonitriles 5 L 0 n

^ T ^ C CHjCN

R

15 L M R SP ° C

HH 4 -Cl 128.5-129.5 H 3 -Cl 4 -Cl 105-107 HH 2 -C 153-55 HH 4- ° CF3 79-81 20 HH 4-CF3 44-45 H 2-Cl 4- Cl 66-67 HH 3-Cl 80-83 HH 4-CN 126-128 HH 4-F 78-80 25 HH 4-SO 2 CH 3 129-132 H 3 — F 4-F 74-75 HH 3-CF 3 58-60 HH 4_CH3 103.5-106 HH 4 -NO2 119-124 30 3-Cl 5 -Cl 4-OCH- ---

• J

1, 94626

The arylpyrroles of formula (I) are effective in controlling insects, mites and nematodes. These compounds are also effective in protecting growing or harvested cereals from attack by the aforementioned pests.

The following examples are provided for the purpose of illustrating this invention.

The examples marked with an asterisk (*) illustrate the preparation of the final products of formula (I).

Example 1 (not the method of claim 1) 2-phenylpyrrole-3-carbonitrile

CN

C02H Cl / = \ / I 0c20 15 \\ /) CH + CHg = C-CN = —► V \ '-' \ hCH = 0 [j \

The following method is similar to that described in 20 JOC, 43, 4273-6 (1978). The magnetically stirred mixture of 30.00 g of N-formyl-phenylglycine is heated at 90 ° C for 1 1/2 hours. The bright yellow reaction solution is evaporated to dryness in vacuo to give 42.5 g of an oily brown-orange solid. The material, which has been partially purified by chromatography on silica gel, is shown by a proton NMR spectrum to be a mixture of 73% 2-phenylpyrrole-3-carbonitrile and 27% 2-phenyl-3-cyano-5-methylpyrrole. Recrystallization once from chloroform and twice from 1,2-dichloroethane gives 1.69 g of an off-white solid which is shown by proton NMR to be 96% 2-phenylpyrrole-3-carbonitrile, mp 148-152 ° C. .

17 94626

Microanalysis (mp 168.19):

Calculated: C 78.55, H 4.79, N 16.66%

Found: C 78.52, H 4.73, N 16.54%

Example 2 * 5 4,5-Dichloro-2-phenylpyrrole-3-carbonitrile and 5-chloro-2-phenylpyrrole-3-carbonitrile

CN

I Cl CN

10 / T ~ \ 2eq S02C12 ΙΓ ~ 1 + ____ \, _,

h \ Q> 2 2 C1 H \ / ^ \ H \ J

To a magnetically stirred ice-cooled solution of 2.00 g (11.9 mmol) of 2-phenyl-3-cyanopyrrole in 80 mL of methylene chloride is added dropwise via syringe over 5 minutes 1-90 mL (3.19 g, 23.6 mmol) sulfuryl chloride. During the addition, the heat-20 state is maintained between 5-10 ° C. Stirring is continued at 5-10 ° C for 90 minutes. The reaction mixture is filtered under vacuum to remove the precipitated solid (1.28 g) which is identified as 5-chloro-2-phenylpyrrole-3-carbonitrile, mp 192.5-105 ° C. The filtrate is diluted with 400 ml of ethyl acetate, washed twice with 200 ml of water, dried (sodium sulfate), treated with charcoal, filtered, and then evaporated to dryness in vacuo to give (after slurrying the residue with hexane) 0, 60 g (yield 21.3%) of nei-30 dirty-purple solid. This solid was recrystallized from 5 mL of hot acetone to give 0.32 g (9% yield) of 4,5-dichloro-2-phenyl-pyrrole-3-carbonitrile as an orange-brown solid, mp 254-255 °. C.

is 94626

Majj (Mull, Nujoi): 3165 (brs), 3120 (s), 2245 (s), 1570 (m), 1513 (m), 1440 (s), 1252 (m), 1069 (m), 996 (m ), 920 (m), 768 (s), 698 (s), 665 (s) cm-1.

1 H-NMR (DMSO): 57.73 (d, J = 6.6Hz, 1f97H, two phen-prot. At 5 C-2.6), 57.52 (t, J = 7f3Hz, 2.04H , 2 phenyl-proton at C-3.5), 57.44 (t, J = 7.3Hz, 1.02H, 2 phon-protons at C-4).

C-NMR (DMSO): £ 137.51 (C-2 pyrrole carbon), & 129.25 (C-4 phenyl carbon), £ 129.04 (C-3.5 phenyl carbons), £ 10 128.37 (C1-phenyl carbon), £ 125.88 (C-2.6 phenyl carbons), h 114.32 (either C-5 pyrrole or nitrile carbon), £ 114.14 (either C- 5 pyrrole or nitrile carbon), £ 110.72 (C-4 pyrrole carbon), S 89.78 (C-3 pyrrole carbon).

Microanalysis (mp 237.09): Calculated: C, 55.72%; H, 2.55%; N, 11.82%; Cl, 29.91%

Found: C, 55.78%; H, 2.59%; N, 11.12%; Cl, 29.74%

Example 3 p-Chloro (5-formylmethyl) amino] cinnamonitrile, diethyl acetal 20 toluene o- ^ 25 Magnetically stirred solution of 250.00 g (1-39 moles) of ε-chlorobenzoylacetonitrile, 203 ml (185.95 g, 1.39 moles) of 2,2-diethoxyethylamine and 1300 ml of dried toluene, heated at reflux for 20 hours. Water is collected in a Dean-Stark trap (23.8 ml, 95.2% of theory). A hot cloudy dark brown solution with a large amount of insoluble solids is filtered through a diatomaceous earth filter. After diluting with 200 ml of ethyl acetate, the solution is filtered through a 7 cm x 13.5 cm silica gel column. The filtrate is concentrated in vacuo to give 354.38 g (yield 19-94626 86.4% crude product) of a clear dark oil which slowly converts to a solid. This solid is recrystallized from hot cyclohexane to give 324.26 g (79.1% yield) of a waxy orange solid. NMR of this product shows a mixture of ε-chloro-S - [(formylmethyl) amino] cinnamitrile, diethyl acetal (Z) -isomer 78% and (E) -isomer 23%, mp 60-72 ° C. The following analytical values are the values of another sample 10 prepared in the same manner.

Max (mull.Nuioi): 3325 (s), 3065 (m), 2197 (s), 1600 (s), 1530 (s), 1314 (m), 1265 (m), 1173 (m), 1154 (m ), 1128 (s), 1100 (s), 1060 (s), 1022 (s), 939 (m), 895 (m), 844 (s), 768 (m), 730 (m) cm-1.

1 H-NMR (chloroform): $ 7.47 (d, J = 8.6Hz, 2.12H, two aromatic protons), $ 7.37 (d, J = 8.6Hz, 2.12H, two aromatic protons) , £ 5.10 (E) & 4.86 (Z) / br t, 1.25, one NH proton, <$ 4.69 (Z) & 4.60 (E) (t, J = 5.1 Hz, 1.05H, one methine proton on acetal carbon7, 4.07 (E) & S 20 4.05 (Z), / s, 0.83H, enamine / 3-protonx7, £> 3.71 (E) & S

3.68 (Z), / q, J = 7.1 Hz, 2.22H, two methylene protons from the other two ethoxy groups £ 7, δ 3.56 (Z) & <^ 3.53 (E) / q, J = 7.1 Hz, 2.22H, two methylene protons from the other two ethoxy groups / ', <$ 3.18 (t, J = 5.1 Hz, 1.77H, two methylene protons from the ethylene acetal group), & 20 (t, J = 7.1 Hz, 4.90H, six methyl protons from two ethoxy groups).

C-NMR (chloroform): δ 161.21 (α, β-enamine carbon), S36.29 (Z) & 134.60 (E) ε in either the Cl or C-4 phenyl ring7, 134.148 (Z ) & £ 132.30 (E) / 30 ^ 0 in Cl or C-4 phenyl ring / ring7, <$ 129.34 (Z) & <$ 129.89 (E) / either C-2.6 or C- In the 3,5-phenyl ring7, ^ 128.94 (Z) & ^ 128.63 (E) ^ in either the C-2.6 or C-3.5 phenyl ringJ7, £ 21.19 (Z) 119.50 ( E) (nitrile carbon),? 99.43 (Z) & <£ 100.63 (E) 35 £ / <? - enamine-carbon7, £ 61.88 (Z) & δ · 63.25 (E) / methine in carbon acetate ?, δ 62.64 (Z) & 63.03 (E) / methylene carbons of ethoxy groups /, £ 46.32 (Z) & ^ 47.33 (E) / ethylamine group methylene carbon /, £ 15.26 (methyl carbons of ethoxy groups).

Microanalysis (mp 294.78): δ Calculated: C / 61.11%; H, 6.50%; N, 9.51% Cl, 12.03%.

Found: c, 61.25%; H, 6.25%; N, 9.34%; Cl, 12.35%.

Example 4 2- (p-Chlorophenyl) pyrrole-3-carbonitrile

10 / CN CN 10 c I

ci — A + cf3c ° 2h - * Cx / = \ w H \ ^ - C 'mp 294.78 mp 114.02 mp 202.64 To 108 ml of trifluoroacetic acid stirred at 23 ° C is added 54.00 g (0.183 moles) of solid. E-chloro-η 5 - [(formylmethyl) amino] cinnamonitrile, diethyl acetal over 45 minutes. This addition caused an exothermic reaction up to 38 ° C and 32 minutes after the addition a solid began to precipitate. After stirring for 30 minutes at room temperature, the reaction mixture is filtered under vacuum and the collected solid is washed first with trifluoroacetic acid, secondly with ethyl acetate-hexane and finally with hexane. Yield 16.83 g (45.4%) of an off-white solid, mp 165-166 ° C. The following analytical values are those given for a sample prepared in the same way.

Maxfmull. Nujol): 3275 (br s), 2225 (s), 1502 (s), 30 1410 (m), 1275 (m), 1200 (m), 1108 (s), 1023 (m), 999 (m), ;; 908 (m), 843 (s), 752 (s), 722 (s), 695 (s), 620 (s) cm-1.

1 H-NMR (acetone): δ 11.22 (v br s, 0.99H, one pyrrole NH proton), δ 7.82 (d, J = 8.9Hz, 2.46H, two aromatic phenyl protons), £ 7.51 (d, J = 8.9Hz, 2.46Hz, two to 35 aromatic phenyl protons), S 7.02 (t, J = 2.6Hz, 1.01H, one pyrrole proton C- 5), £ 6.58 (t, J = 2.6 Hz, 0.77H, one pyrrole proton in C-4).

21-94626 C-NMR (acetone): δ 137.73 (pyrrole C-2), 134.42 (E-chlorophenyl in C-4), E 129.93 (methine carbons in the C-ring of the phenyl ring); 3.5), g 129.93 (methine carbons in phenyl ring C-3.5), $ 128.07 (methine carbons in phenyl ring C-2.6), fc- 121.21 (pyrrole in C-5), b 117.93 (nitrile carbon), h 113.78 (pyrrole carbon in C-4),% 90.86 (pyrrole carbon in C-3) ).

Microanalysis (mp-202.64):

Calculated: C, 65.19%; H, 3.48%; N, 13.83%; Cl, 17.50% Found: C, 64.18%; H, 3.52%; N, 13.63%; Cl, 17.74% Using the above procedure or substituting concentrated hydrochloric acid for trifluoroacetic acid, the following compounds are obtained:

CN

r ("

/ - v R

OF

20 M ia / or R so ° C spent acid

4-Cl 165-166 conc. HCl, CF 3 COOH

3.4- di-Cl 216-221 CF3COOH

2- Cl 156-157 CF3COOH

4-OCF3 143-145 CF3COOH

25 4 — CF3 179-180 CF3COOH

2.4- di-Cl 197-199 CF3COOH

3- Cl 150-156 CF 3 COOH

4- CN 210-212 CF3COOH

4 — F 167-170 cone. HCl

30 4-SO 2 CH 3 221-221.5 CF 3 COOH

: 3,4-di-F 173-175.5 CF 3 COOH

3- CF3 166-168 CF3COOH

4- COOCH3 155.5-158 CF3COOH

4-CH3 117-137 CF3COOH

35 4-NO 2 174-177 CF 3 COOH

22 94626

Example 5 * 4,5-Dichloro-2- (p-chlorophenyl) pyrrole-3-carbonitrile

5 J "Cl CN

jj ^ 2.2 eq. S02C12 jj ^ HOfic * / γ \ H C1 01 H \ j) - {: l 10

To a mechanically stirred solution of 16.83 g (83.1 imol) of 2- (E-chlorophenyl) pyrrole-3-carbonitrile in 450 ml of glacial acetic acid at 36 ° C is added dropwise over 18 minutes 14.7 ml (24 , 70 g, 183.0 mmol) of sulfuryl chloride. The addition causes the temperature to rise exothermically to 39 ° C and after a further 16 minutes, the reaction mixture is filtered under vacuum. The collected solids are washed first with acetic acid and then with water. After recrystallization from hot ethyl acetate, this solid melts at 259-261 ° C. Other samples of this product were prepared by similar methods and the analytical values of one such product are shown below.

Max (Mull, Nujol): 3170 (br s), 3100 (m), 2225 (s), 25 1508. (m), 1097 (m), 825 (s), 717 (m), 660 (m) cm -1.

1 H-NMR (DMSO): δ, 12 (d, J = 8.6Hz, 2.0OH, two aromatic protons), δ 7.56 (d, J = 8.6Hz, 2.0OH, two aromatic protons) .

C-NMR (DMSO): δ 136.01 (pyrrole C-2 carbon), δ 133.92 δ (E-chlorophenyl C-4 carbon),% 129.09 (E-chlorophenyl C-3.5 carbons), S 127.41 (E-chlorophenyl C-4 carbon), 127.11 (E-chlorophenyl Cl-carbon), 114.49 (nitrile carbon), S 114.10 (pyrrole C-5 carbon), £ 110.92 ( pyrrole C-4 carbon), S 90.09 (pyrrole C-3 carbon).

35 Microanalysis (mp 271.64): 23,94626

Calculated: C, 48.65%, H, 1.86%; N, 10.32%; Cl, 39, 17%

Found: C, 49.22%; H, 2.12%; N, 9.85%; Cl, 39.03%

Example 6 * 4,5-Dibromo-2- (alpha, N, C-trifluoro-p-tolyl) -5-pyrrole-3-carbonitrile

Γ Br CN

+ Br2 -► / = \ 10 H X> -3 BP ”CFa

To a stirred mixture of 0.8 g of 2- (N, N, N, N-trifluoro-E-tolyl) -pyrrole-3-carbonitrile in 70 ml of chloroform is added 2 ml of bromine. Upon stirring overnight, a white solid precipitates which is collected by filtration. Thin chromatography (1: 1 ethyl acetate-hexane) shows a single component; mp> 230 ° C.

Analysis for C ^ 2H5Br2 ^ 3 ^ 2:

Calculated: C 35.55, H 1.27, N 7.11, Br 40.61%

Found: C 36.40, H 1.08, N 6.99, Br 40.55%

Following the procedures of Examples 5 and 6, but substituting the appropriately substituted phenylpyrrole-3-carbonitrile for 2- (c, N, N-trifluoro-p-tolyl) -25 pyrrole-3-carbonitrile, the following compounds are obtained.

- * · • · 24 94626

X CN

= jT \ v ^ \ / \ / - V fl: XX,

10 L M R X Y s p ° C

HH 4 -NO2 Br Br 274-277 HH 4-F Cl Cl> 220 HH 4-F Br Br> 220 HH 4-SO2CH3 Cl Cl> 230 15 H 3-F 4-F Cl Cl> 230 H 3-F 4 -F Br Br> 220 2-Cl 3-Cl 4-Cl Cl Cl 2-Br 3-Br 4-Br Br Br HH 4-OCF3 Cl Cl 222-225 20 HH 4-OCF3 Br Br 231-232

H H 4-OCF3 Cl H

HH 4-CN Br Br> 230 HH 4-CN Cl Cl> 240 HH 4-SO2 CH3 Br Br> 230 25 HH 4-NO2 Cl Cl 246-2'49 H 3-Cl 4-Cl Br Br> 260 HH 3- CF 3 Cl Cl> 230 HH 4-COCH 3 Cl Cl 251-254 H 2,3-CH = CH- Cl Cl 244-247 30 HH 4-CH. Cl Cl 215-217: 3 H 2 -Cl 4-Cl Br Br> 230 25 94626

Jj M R X Y S.P ° C

H H 3-Cl Cl Cl> 230 H 2 “Cl 4-Cl Cl Cl> 230 5 H H 4 — Cl Br Br 273-274 H H 2-Cl Br Br> 230 H H 4_CF3 C1 C1> 23 ° H H. 4-Br Cl Cl> 235 HH 2 — Cl Cl Cl> 230 10 H 3-Cl 4-Cl Cl Cl> 235 HHH Cl Cl 254-255 HH 4-Cl Cl Cl 255-257 HH 4 “CF3 Br Br> 230 HH 4-Cl Cl Br 262-263 (dec.) 15 HH 4-Cl Br Cl 250-258 (dec.) H 3-Cl 5 — Cl Cl Cl> 230 H 3-Cl 4-Cl Cl Br> 230 2 -C1 4 -Cl 5 -F Cl Cl 207-210 20 Example 7 3-nitro-2-phenylpyrrole NOg / \ —CCH-NO, ♦ HgNCHgCH <OEl), C = CH-NOg * \ / r = \ ot- Nitroacetophenone (5.7 g, 0.0345 mol) is dissolved in 100 ml of toluene and 4.6 g (0.0345 mol) of aminoacetaldehyde diethyl acetal are added. The reagents are placed in a 250 ml RB flask fitted with a Dean-Stark trap. The trap is filled with a 4A molecular sieve and the mixture is heated at reflux for 18 hours. The toluene is removed in vacuo to give 8.36 g of ci - (2,2-diethoxyethyl-35-amino) -γ * 5-nitrostyrene as a brown oil. To this oil is added 26 ml of concentrated HCl. When the bottle is swirled, the oil forms a yellow suspension. After 10 minutes, the solid is filtered off to give 2.48 g of a yellow solid. Recrystallization from ether / ethyl acetate / hexane gives the product in two fractions, 2.08 g, mp 190-192 ° C; (31%).

Max 1485 cm-1 (NO 2), 1 H-NMR (CDCl 3 / DMSO) δ 6.73 (m, 2H), 7.46 (m, 5H).

Example 8 * 10 2,3-Dichloro-4-nitro-5-phenylpyrrole no2 Cl no2

/ Γ \ + NaOCl - »jfX

A mixture of 3-nitro-2-phenylpyrrole (1.56 g, 0.0083 mol) in 60 ml of dioxane is cooled in an ice bath by the dropwise addition of 25.9 g (0.0182 mol) of technical grade sodium hypochlorite. After stirring for 45 minutes, the mixture is acidified with concentrated HCl. Add water and Et 2 O. The layers are separated and; The organic layer was washed with Et 2 O, dried over anhydrous MgSO 4 and evaporated to dryness in vacuo to give 2.21 g of a yellow solid. Purification by chromatography on silica gel, eluting with increasing proportions of ethyl acetate / hexane, gives, after evaporation to dryness, 0.77 g of a yellow solid (36%), m.p. 190-190.5 ° C.

Analysis for c 10 H 6 N 2 O 2 Cl 2:

Calculated: C 46.72, H 2.35, N 10.90% 35 Found: C 46.96, H 2.86, N 10.02% 27,94626

Following the procedures of Examples 7 and 8, but using an appropriately substituted o-nitroacetophenone and 2,2-di (C 1-4 alkoxy) ethylamine, substituted O (7 (2,2-di (C 1-4 alkoxy)) ethylamino is obtained. ) - β-nitrostyrene, which is then converted to 3-nitro-2- (substituted) phenylpyrrole by treatment with NCl, HBr or CF 3 CO 2 H. Reaction of the substituted phenylpyrrole thus formed with sodium hypochlorite in dioxane gives chloro analogues; while the reaction of substituted phenyl-10 pyrrole with bromine in chloroform gives bromine analogs.

x no2 15 Y \ m / --- * \ ^ 3 ~ n

R

L M R X Y sb ° C

20 HHH Cl Cl 190-190f5 H 4-Cl H Cl Cl 214-215 H 4-Cl H Br Br 203-204 (dec.) HHH Br Br 148.5-149 3-Cl 4-Cl C Cl Cl 219- 220 (dec.) 25 H 4-Br H Cl Cl 222-223 (dec.) HH 4-CF3 Cl Cl 166-168

Example 9 * 3q 4,5-Dichloro-2- (3,4-dichlorophenyl) -1-methylpyrrole-3-carbonitrile, CN Cl cn h / ci y ^ i ci

Cl J yluci + »eI + koc <ch3) 3 - * Cl 35 \ = / ne \ _ / ~ C1 28 94626 in a 100 ml flask of 2 g of 4,5-dichloro-2- (3,4-dichlorophenyl ) -pyrrole-3-carbonitrile forms a clear brown solution in 60 ml of dry THF. 1 equivalent of KOtBu is added with stirring to give a clear solution after a few minutes. Using a syringe, add 1 equivalent of methyl iodide and heat the solution to boiling for 4 hours. It is then stirred at room temperature overnight. The next day, 50 mL of IVO is added and the mixture is extracted with 4 x 50 mL of 10 CHCl 3. The organic phases are combined, dried over MgSO 4 and evaporated to dryness. The white solid formed is purified by flash chromatography on silica gel using a 50/50 mixture of ethyl acetate / hexane as eluent. This gives 1.80 g of a white solid.

Yield = 86%

Mp = 154-156 ° C.

Following the above procedure but substituting the appropriately substituted phenylpyrrole-3-carbonitrile or 3-nitro-2- (3,4-dichlorophenyl) -pyrro-20β-3-carbonitrile for 3-nitro-2- (substituted) - phenylpyrrole, the compounds shown below are obtained.

«29 94626

X CN

5 J / \

Y / - \ M

10 N- A L M R X Y s P ° c CH3 H H 4 -Cl Cl Cl 152-153 C_HcOCH, H 3-Cl 4-Cl Cl Cl 128-130

Z D Z

C, Hc H 3 — Cl 4-Cl Cl Cl 137-138 1 c 2 5 15 CH3 H 3-Cl 4-Cl Cl Cl 154-156 CH3 H H 4-CF3 Br Br 145-146

CcHc-CH, H H 4-CF, Br Br 145-147

o d z J

C £ Hc-CH, H 3 -Cl 4 -Cl Cl Cl 95-96

. O D 'Z

CH = CH-CH H 3 -Cl 4 -Cl Cl Cl 69-70 20 Z ^ CH2 = C-CH2 H3-Cl 4-Cl Cl Cl

Cl CH = C-CH2 H 3 — Cl 4-Cl Cl Cl 147-148 CH3SCH2 H 3-Cl 4-Cl Cl Cl: ·. c (ch3) 3 HH 4-cf3 Cl Cl 25 CH3 HH 4-CF3 Cl Cl 99-100 CH3SC2H5 H 3-Cl 4-Cl Cl Cl 74-75 0 C_Hc-0C-CH_ H 3-Cl 4-Cl Cl Cl 118-120

2 D Z

C_H_-OCH_ H H 4-CF, Cl Cl 99-100

J

CH3 h H 4-OCH3 Br Br 112-115 CH3 HH 4-Cl Br Br 197-201 C, HcOCH, HH 4-OCF Cl Cl 46-47 CH3 HH 4-OCF3 Cl Cl 72-73 CH - CH- HH 4-0CF_ Cl Cl oil 35652 3 c2h5och2 HH 4-Cl Cl Cl 30 94626

Ä LM R X Y S-R ^ C

HOCH2CH2 H 3-Cl 4-Cl Cl Cl 143-145 NC H 3-Cl 4-Cl Cl Cl 251-252 5 C_HcCH_OCH_ H 3-Cl 4-Cl Cl Cl 88-89

Cl 0-CH 2 h 3 -Cl 4 -Cl Cl Cl 118-120 IC = C-CH2 H 3 -Cl 4-Cl Cl Cl 115-116 CH3 HH 4-Cl Br CF3 126-129 C2H5OCH2 HH 4-Cl Br CF3 91-92 10 C-Hc-OCH_ H 3 -Cl 4 -Cl Cl Cl 118-120 2D 2 C2H5-OCH2 HH 4-Cl Br Br 104-105 C-.Hj.-CH_HH 4-Cl Br Br- 82 CH3 HH 4-Cl Br Br 197-201 CN HH 4-CF3 Cl Cl 138-139 15 C2H5-OCH2 HH 4 "CF3 Br CF 3 104-105 C2H5-OCH2 HH 4-CF3 H CF3 76-77 C2H5OCH2 H 3 -Cl 4 -Cl Br CF 3 80-81 Example 10 * 1-Benzyl-4,5-dibromo-2- (oC, οό, <5E-trifluoro-p-tolyl) pyrrole-3-carbonitrile

Br cn 25 * K0C (CH3’3 ♦ <^ - CH2Br - * Br ^

Br iTV ^ -cr,? Ha ό 30 In a 100 ml flask, 1.5 g of 4,5-dibromo-2- (o, O- * trifluoro-ε-tolyl) pyrrole-3-carbonitrile are mixed with 50 ml dry in THF to give a clear dark solution. Add with stirring 1 eq. K0tBu added. After a few minutes, the solution clears. Add 35 benzyl bromide (0.65 g) via syringe. The mixture is heated to reflux overnight. The next day, TLC (ethyl acetate / hexane 50/50) shows the presence of both starting material and product. The reaction mixture is further treated as follows; 50 ml of water are added and the mixture is extracted with 4 x 50 ml of CHCl 3. The organic phases are combined and washed with 4 x 50 ml of 10% aqueous NaOH solution. The organic phase is dried over MgSO 4 and evaporated to dryness.

This gives a brown solid which is crystallized from ethyl acetate / hexane.

Yield = 0.75 g = 40.7%

Mp = 145-147 ° C with decomposition.

Example 11 * 4,5-Dichloro-2- (3,4-dichlorophenyl) -1- (ethoxymethyl) pyrrole-3-carbonitrile 15 ci. cm

Cl CN \ - / \ / THF \ XA + * 0C <CH *> * + cich2oc2h5 Cl 1AyTVc!

Cl I X = f 1 / CH 2 Cl 2 H 5 Cl 2 A sample of 4,5-dichloro-2- (3,4-dichlorophenyl) pyrrole-3-carbonitrile (1.0 g, 0.003 mol) is dissolved in 10 ml of dry tetrahydrofuran. To this solution is added potassium t-butylate (0.37 g, 0.0033 mol) * 'followed by chloromethyl ethyl ether (0.312 g, 0.0033 mol). The mixture is stirred for about an hour at room temperature and then poured into a large volume of water which precipitates the product. The white solid is collected and dried to give * · 1.0 g (91%) of product, mp 128-130 ° C.

Example 12 * 4-Chloro-3-cyano-2- (p-chlorophenyl) pyrrole ci cn ci cn ci · '"·" - · ci' Yy - ^ _ C1 h N / '' \ _ci dioxane \ = / \ = s 32 94626

To a magnetically stirred solution of 17.87 g (88.2 mmol, 1.00 equivalents) of 2- (E-chlorophenyl) -3-cyanopyrrole in 800 ml of dioxane at 20 ° C is added dropwise over 30 minutes. 5,250.15 g (13.13 g of solid, 176.4 mmol, 2.00 equivalents) of 5.25% by weight of bleach.

After stirring for a further 30 minutes at room temperature, the reaction solution is poured into 2200 ml of water. The resulting mixture is filtered under vacuum to remove a small amount of black solid. The filtrate is acidified to pH 2 with concentrated HCl to give a brown solid. This solid is filtered off in vacuo and the collected solids are washed with water to give 22.41 g of a brown solid. This solid is treated with 100 mL of 5% aqueous sodium hydroxide to dissolve the bulk of the material, leaving a small amount of insoluble black solid. This black solid, dissolved in 100 ml of ethyl acetate,; Wash with 75 mL portions of 5% aqueous NaOH, water, and saturated aqueous NaCl. The ethyl acetate layer is dried (MgSO 4), treated with charcoal, filtered, and then evaporated to dryness on a rotary evaporator in vacuo to give 1.10 g (yield; 5.3 to 5.3%) of an orange-brown solid. This solid was recrystallized from ethyl acetate-chloroform to give 0.51 g (2.4% yield) of an off-white solid, 4-chloro-3-cyano-2- (p-chlorophenyl) pyrrole, mp 251- 253.5 ° C.

Example 13 * 5-Bromo-2- (3,4-dichlorophenyl) pyrrole-3-carboxylate

manufacture of nitrile CN CN

n-Λ dioxane n— \ 3v + Brz - * χ χ 35 Br \ 1 \ 1 33 94626 A sample of 2- (3,4-dichlorophenyl) pyrrole-3-carbonitrile (2.0 g, 0.008 mol) is dissolved in 100 ml to dioxane by heating at 4-50 ° C. The solution is then cooled to 30 ° C and bromine (1.3 g, 0.008 mol) is added. After stirring for 1 hour at room temperature, the solution is poured into water and the gray solid (2.2 g, 88%) is collected. Mp 233-236 ° C, dec.

In a similar manner, 5-bromo-2- (3,4-dichloro) -3-nitropyrrole can be prepared starting from 2- (3,4-dichlorophenyl) -3-nitropyrrole.

Example 14 * Preparation of 5-bromo-4-chloro-2- (3,4-dichlorophenyl) -pyrrole-3-carbonitrile

Cl CN

15 CN v / + CCH3> 3C0C1 - * j!

A sample of 5-bromo-2- (3,4-dichlorophenyl) pyrrole-3-carbonitrile (0.158 g, 0.005 mol) is dissolved in tetrahydrofuran (5 ml). An equivalent amount of t-butyl hypochlorite is added and the solution is stirred overnight. The solution is poured into water and the precipitate (0.052 g, 30%) is collected. Sp is> 275 C.

In a similar manner, 2-bromo-3-chloro-5- (3,4-dichlorophenyl) -4-nitropyrrole can be prepared starting from 2-bromo-5- (3,4-dichlorophenyl) -4-nitropyrrole.

30 Example 15 * *. 5-bromo-4-chloro-2- (p-chlorophenyl) pyrrole-3

carbonitrile production Cl CN Cl CN

ri ♦ CHC1 »] T \ 35, —v CHC i 3, —v H \ A ^ _C1 Br H y — Cl 34 94626

To a magnetically stirred solution at 22 ° C of 0.17 g (0.67 mmol, 1.00 equivalents) of 4-chloro-2- (E-chlorophenyl) pyrrole-3-carbonitrile in 100 mL of chloroform is added dropwise over 30 minutes a solution of 0.20 mL (0.62 g, 3.88 mmol, 5.79 equivalents) of bromine in 5 mL of chloroform. The addition does not cause exotherm. After stirring for 1 1/4 hours at room temperature, the clear red reaction solution is evaporated to dryness in vacuo to give 0.28 g of an off-white solid. This solid is slurried with hexane-methylene chloride to give 0.23 g of an off-white fluffy solid in vacuo; mp 262-263 ° C; with decomposition.

Example 16 * Preparation of 5-chloro-4-bromo-2- (p-chlorophenyl) pyrrole-3-carbonitrile

CN Br \ CN

20 χΐ * 0Γί "“ “Γ * Χχ ^ 25 To a magnetically stirred solution at 45 ° C of 1.00 g (4.22 mmol, 1.00 equivalents) of 5-chloro-2- (E-chlorophenyl) pyrrole-3-carbonitrile in 300 ml of chloroform, a solution of 0.40 ml (1.24 g, 7.76 mmol, 1.84 equivalents) of bromine in 25 ml of chloroform is added dropwise over 30 minutes. does not cause exotherm and at the end of the addition a small amount of solid begins to precipitate After stirring for 19 1/2 hours at room temperature, the reaction mixture is evaporated to dryness in vacuo to give 1.49 g of an orange-white solid.

3594626 This solid is slurried with hexane-methylene chloride to give 1.33 g (100% yield) of a fluffy white solid by vacuum filtration; mp 250-258 ° C, dec.

Example 17 * Preparation of 5-chloro-2- (p-chlorophenyl) pyrrole-3-carbonitrile

CN CN

1 n __ / HOflc __ / 1 ° ♦ SO 2 Cl 2 - * —Cl Cl 1 -Cl 15 to a magnetically stirred solution at 35 ° C of 2.40 g (11.8 mmol, 1.00 equivalents) of 2- (p-chlorophenyl) pyrrole-3-carbonitrile and 65 mL of glacial acetic acid are added dropwise via syringe to 0.75 mL (1.26 g, 9.34 mmol, 0.79 equivalents) of sulfuryl chloride over 5 minutes. Approximately 5 minutes after the end of the addition, a solid precipitated from the reaction solution. After stirring for 45 minutes at room temperature, the reaction mixture is filtered and the collected solid is washed with very cold vinegar. With an acid to give 2.08 g (74% of crude product Santo) of an off-white solid. This solid is recrystallized from 75 ml of hot acetic acid to give 1.63 g (58% yield) of 97% by weight pure product; mp 258.5-261 ° C.

Example 18 * *: Preparation of 2- (3,4-dichlorophenyl) -1-methylpyrrole-3-carbonitrile

CN

CN _ / [j- / Cl + K0C <CH3> 3 + CH3I - »► / C1 35 ^ r \ rL iNfVc! H CH3 \ = / 36 94626 In a 100 ml flask, 2.0 g of 2- (3,4-dichlorophenyl) pyrrole-3-carbonitrile are dissolved in 50 ml of dry THF and 1 equivalent of potassium t-butylate is added.

This forms a slightly turbid solution. One equivalent of methyl iodide is then pipetted into the mixture li-5.

This causes a slight lightening of the color. A drying tube is connected to the flask and stirred at ambient temperature overnight.

The next morning, the bottle contains a faint pale-10 colored precipitate. 50 ml of water are then added and the solution clarifies before a solid precipitates out of solution. This solid is filtered off from solution and compared to the starting material by TLC (25% ethyl acetate in hexane). This shows a new single spot 15 which moves faster than the starting material. It is dried in a vacuum oven at 50 ° C overnight. 1.31 g of product are obtained or the yield is 62% and its melting point is 140-142 ° C.

Example 19 * Preparation of 4,5-dichloro-2- (3,4-dichlorophenyl) -1-methyl-pyrrole-3-carbonitrile

v CN Cl CN

fj ~ {Cl + SO2C12 - * JT \ / C1 25 f \ K_ci C1 I VVci CH3 \ - / CH3 \ m / 50 ml round bottom flask 0.5 g of 2- (3,4-dichlorophenyl) -1-methylpyrrole -3-Carbonitrile is mixed with 35 ml of glacial acetic acid. The mixture is slightly heated in a heater to dissolve all the pyrrole.

To this clear solution is added by pipette 2 eq. sulfuryl chloride. The solution is stirred at room temperature for 12 hours. After 12 hours, the solution is poured into 50 ml of water, resulting in the formation of a white precipitate. This is filtered off and dried in a vacuum oven at 50 ° C for 3 hours.

The solid obtained is identical to the product of Example 9 by TLC (25% ethyl acetate in hexane) and infrared analysis. The product yield is 0.36 (56%).

Example 20 * Preparation of 4,5-dichloro-2- (3,4-dichlorophenyl) -1- (2-hydroxyethyl) pyrrole-2-carbonitrile 10

Cl CN

JC + BrCICHOH + K * C ^ -1-Bu-►

15 H

Cl CN

I '^ X ^ ci 20 k

OH

To a stirred mixture of 2.0 g (6.5 mmol) *. 4,5-dichloro-2- (3,4-dichlorophenyl) -pyrrole-3-carbonitrile and 0.88 g (7.8 mmol) of potassium tert-butylate, which is heated to boiling in 50 ml of dioxane, 0.98 g (7.8 mmol) of bromoethanol are added. The mixture is stirred at reflux for 12 hours, cooled, diluted with 50 ml of water and extracted several times with chloroform.

The combined chloroform extracts are dried over magnesium sulphate and evaporated to dryness in vacuo to leave a solid which, on heating and dissolving in ethyl acetate, precipitates on cooling most of the starting pyrrole. Evaporation of the mother liquor to dryness and recrystallization of the residual solid from 20% ethyl acetate in hexane gave 0.31 g of a white solid, mp 143-145 ° C; IR 5077A.

Analysis for c 16 H 23 NO 4: δ Calculated: C 44.57, H 2.29, N 8.00, Cl 40, 57%

Found: (Agm 33139): C 44.77, H 2.29, N 8.09, Cl 40.14% Example 21 * 4,5-Dichloro-2- (3,4-dichlorophenyl) pyrrole-1.3 Preparation of -dicarbonitrile 10

Cl CN

w

Cl ^ \ / CNBr + K + t-BuO ”-

K

15

Cl CN

\ _ /

Cl • i 20 1

CN

Potassium t-butylate (617 mg, 55 mmol) is added portionwise to a solution of 3-cyano-4,5-dichloro-2- (3,4-dichlorophenyl) pyrrole (1.52 g, 5 mmol). · 25 lia) in dry THF (20 ml). After 30 minutes, a solution of cyanogen bromide (583 mg, 5.5 mmol) in THF (1 mL) is added. The reaction mixture is kept at room temperature overnight. The solvent is removed on a rotary evaporator. The residue is treated with water and extracted with ethyl acetate. The organic layer is washed with water. and saturated sodium chloride solution and dried (MgSO 4). Evaporation to dryness and crystallization of the residue from ethyl acetate gave white crystals (1.07 g); m.p.

250.5 to 252.0 ° C? IR (nujol) 2255, 2245 cm-1 (CN); 13C NMR

35 (DMSO-d 6) 102.7 (N-CN), 113.7 (3-CN); mass spectrum 331.9 (M + 1).

39 9 4 6 2 6

Analysis for ci2H3CP4N3 (330.99):

Calculated: C 43.54, H 0.91, N 12.70, Cl 42.85%

Found: C 43.62, H 0.93, N 12.63, Cl 41.95%

Example 22 * 4,5-Dichloro-2- (3,4-dichlorophenyl) -1- (3-iodo-2-

propynyl) -pyrrole-3-carbonitrile Cl 2 CN

10 * NaOH -1

• c \ c \ / CN

^ CHI

To a stirred mixture of 1.91 g (5.5 mmol / 20 l) of 4,5-dichloro-2- (3,4-dichlorophenyl) -1- (2-propynyl) pyrrole-3-carbonitrile 500 in methanol, 69 ml of 10% aqueous sodium hydroxide solution and then 0.70 g (2.7 mmol) of iodine are added. The mixture is stirred for 12 hours and then acidified and diluted with 200 ml of water. The precipitated solids are collected and recrystallized from methanol to give 0.51 g of crystals, mp 115-116 ° C.

This reaction is also applicable to the conversion of any of the substituted N-alkynylarylpyrroles of formulas III, IV, V, VI or VII of this invention to the N-substituted 3-iodo-2-propynylarylpyrroles of said invention.

Example 23 * Preparation of 2, (3,4-dichlorophenyl) -4,5-diiodopyrrole-3-carbon-35 nitrile 40-94626 r CN CN! N-iodosuccinimide (5.7 g, 0.0254 mol) is slowly added to a solution of 2- (3,4-dichloro-10-phenyl) -pyrrole-3-carbonitrile (3.0 g, 0.0127 mol) in 100 ml of THF The reaction mixture is stirred for several hours at 25 [deg.] C. until thin-layer chromatographic analysis (silica gel; ether / petroleum ether: acetic acid = 100: 100: 1) shows that the reaction is complete. The mixture is evaporated in vacuo to give a residue containing pyrrole and succinimide The crude solid is dissolved in 500 ml of ether and shaken with 5 x 400 ml of water to remove succinimide.

The ether is dried over Na 2 SO 4 and evaporated to dryness in vacuo to leave 2.0 g (32.3%) of a gray-brown solid, m.p. 230 ° C (purple vapor).

Example 24 p-Chloro-β - [(formylmethyl) amino] cinnamonitrile-25, diethyl acetal

Cl- ^ 11 ^ CN * H2NCH2CH <0Et> 2 30 _ / toluene / -v °: -

H UA

A magnetically stirred solution of 35,250.0 g (1.39 moles) of p-chlorobenzoylacetonitrile, <94626 203 ml (185.9 g, 1.39 moles) of 2,2-diethoxyethylamine, and 1300 ml of dry toluene is heated to reflux. 20 hours. Water is collected in a Dean-Stark trap (23.8 ml, 95.2% of theory). A hot cloudy, dark brown solution with a large amount of insoluble solids is filtered through a diatomaceous earth filter device. After dilution with 200 ml of ethyl acetate, the solution is filtered through a column of silica gel, measuring 7 cm x 13.5 cm. The filtrate is evaporated to dryness in vacuo to give 10,354.3 g (crude product yield 86.4%) of a clear dark oil which slowly becomes a solid. This solid is recrystallized from hot cyclohexane to give 324.2 g (79.1% yield) of a waxy orange solid. NMR of this product shows that it is 15? -Chloro-β- (formylmethyl) amino] cinnamonitrile, a mixture of diethyl acetal (JS) isomer (78%) and (E) isomer (23%), mp 60-72 ° C. The following analytical values are those of another similarly prepared sample.

·. Msa (»ull, Nujol): 3325 (s), 3065 (111), 2197 (s), 1600 (s), 20 1530 (s), 1314 (m), 1265 (m), 1173 (m), 1154 (m), 1128 (s), 1100 (s), 1060 (S), 1022 (s), 939 (m), 895 (m), 844 (s), 768 (m), 730 (m) Cm ” 1.

1 H-NMR (chloroform): δ 7.47 (d, J = 8.6Hz, 2.12H, two aromatic protons), δ 7.37 (d, J = 8.6Hz, 2.12H, two • 25 aromatic proton), £ 5.10 (E) & 4.86 (j5) £ br t, 1.25H, one NH proton, £ 4.69 (Z) & $ 4.60 (E) £ t, J = 5, 1Hz, 1.05H, one methine proton on acetal carbon7, S 4.07 (E) & S 4.05 (Z) / s, 0.83H, enamine proton ?, ^ 3.71 (E) & <$ 3.68 (ZJ / g, J = 7.1 Hz, 2.22H, two methylene protons 30 in one of the two ethoxy groups7, £ 3.56 (Z) & S 3.53 (E) / jq, J = 7, 1Hz, 2.22H, two methylene protons in one of the two ethoxy groups7, $ $ 3.18 (t, J = 5.1 Hz, 1.77H, two methylene protons in the ethylene acetal group), $ 1.20 (t, J = 7 , 1 Hz, 4.90H, six methyl-35 protons of two ethoxy groups).

42 94626 C-NMR (chloroform): ε161.21 (-enamine-carbon), 136.29 (Z) λ> 134.60 (E) ε-phenyl ring for either Cl or C-47, 134134.08 (Z) & S 132.30 (E) / phenyl ring either Cl or C-47, <£ 129.34 (Zj & b 129.89 (E) / phenyl ring 5 either C-2.6 or C -3.57, S 128.94 (Z) & 8 128.63 (E) For either the C-2.6 or C-3.57 phenyl ring, £ 121.19 (Z_) & $ 119.50 (E ) / nitrile carbon7, £ 99.43 (Z), & £ 100.63 (E) 77/3-enamine carbon, £ 6188 (Zj & £ 63.25 (E) / acetal methine carbon7, b 62 , 64 (Z) 63.03 (E) / methylene carbons of ethoxy groups ?, 10 £ 46.32 (Zj & £ 41.33 (E) / methylene carbon of ethylamine group ?, b 15.26 (methyl carbons of ethoxy groups ).

Microanalysis (mp 294.78):

Calculated: C 61.11, H 6.50, N 9.51, Cl 12.03%

Found: C 61.25, H 6.25, N 9.34, Cl 12.35% Following the above procedure but substituting the appropriate benzoylacetylacetonitrile for E-chlorobenzoylacetonitrile and / or 2,2-diethoxyethylamine with the appropriate 2.2- di (C 1 -C 4 alkoxy) ethylamine, the following compounds are obtained: * · - ♦ 43 - 94626 / Λ V> -CO-CH 2 CN + H 2 NCH 2 CH (C 1 -C 4 alkoxy) 2-A_ = 1 / toluene n

5 P

K -HjO

N-CH 2 CH (C 1 -C 4 alkoxy) 2 R H

10

J H H -8111 ° 118 ^ 2 Mp C

H H E-CH 3 OCO (OC 2 H 5) 2 68-73 15 H E-CH 3 H (OC 2 H 5) 2 5.9-69 H m-OCH. e-OCH- (OC-H,) _ red-orange semi- 3 3 ^ ^ solid H _ _ (° c2h5) 2 62-70 20 E “C1 HH (° ch3) 2 --- HE“ CH3 H ( OCH3) 2 --- H m -Cl E “C1 (OC2H5) 2 --- HH E-OCF3 (OC2H5) 2 HH E-CF (OCJHc) 2 25 44 94626

Example 25

2- (p-chlorophenyl) pyrrole-3-carbonitrile .CN

c o I

To 108 ml of trifluoroacetic acid stirred at 23 ° C are added 54.00 g (0.183 moles) of solid ε-chloro-r / 6- [E (formylmethyl) amino] cinnamonitrile, diethyl acetal over 45 minutes. This addition exothermically raises the temperature to 38 ° C and 32 minutes after the addition, a solid began to precipitate. After stirring for 30 minutes at room temperature, the reaction mixture is filtered under vacuum and the collected solid is washed first with trifluoroacetic acid, secondly with ethyl acetate-hexane, and finally with hexane. Yield 16.83 g (45.4%) of an off-white solid, mp 165-166 ° C. The following analytical values are obtained from a similarly prepared sample.

M * (Mull, Nujol): 3275 (brs), 2225 (s), 1502 (s), 1410 (m), 1275 (B), 1200 (m), 1108 (s), 1023 (m), 999 ( m), 908 (m), 25,843 (S), 752 (s), 722 (s), 695 (s), 620 (s) Cm ”1.

1 H-NMR (acetone): δ 11.22 (v br s, 0.99H, one pyrrole NH proton), δ 7.82 (d, J = 8.9Hz, 2.46H, two aromatic phenyl protons), S 7.51 (d, J = 8.9Hz, 2.46Hz, two aromatic phenyl protons), $ 7.02 (t, J = 2.6Hz, 1.01J, one pyrrole proton at C-5 ), S 6.58 (t, ·; J = 2.6Hz, 0.77H, one pyrrole proton at C-4).

C-NMR (acetone): δ 137.73 (pyrrole C-2), ε 134.42 (ε-chlorophenyl for C-4),, 129.93 (methine carbons for the phenyl ring C-3.5), £ 128.07 (methine carbons at 35 phenyl ring C-2.6), S 121.21 (pyrrole at C-5), & 117.93 (nitrile carbon), £ 113.78 (pyrrole I: 45 94626 carbon at C-4), 90.86 (pyrrole carbon at C-3).

Microanalysis (mp 202.64):

Calculated: C, 65.19%; H, 3.48%; N, 13.83%; Cl, 17.50% Found: C, 64.18%; H, 3.52%; N, 13.63%; Cl, 17.74% Using the above procedure or replacing trifluoroacetic acid with concentrated hydrochloric acid, the following compounds are obtained:

CN

10 _ / 15 M and / or R gpoc Acid used

4-C1 165-166 cone. HCl, CF 3 COOH

3.4- di-Cl 216-221 CF3COOH

2- Cl 156-157 CF3COOH

20 4-OCF3 143-145 CF3COOH

4-CF3 179-180 CF3C00H

2.4- di-Cl 197-199 CF3COOH

3- Cl 150-156 CF 2 COOH

4- CN 210-212 CF3COOH

25 4 — F 167-170 cone. HC1

4-SO 2 CH 3 221-221.5 CF 3 COOH

3.4- di-F 173-175.5 CF 3 COOH

3- CF3 166-168 CF3COOH

4- COOCH3 155.5-158 CF3COOH

30 4-CH3 117-137 CF3C00H

4-NO2 174-177 CF3COOH

«·« 46 94626

Example 26 * 4,5-Dichloro-2- (p-chlorophenyl) pyrrole-3-carbonitrile

CN C1 CN

n ^ 2.26 ^ .503013 β ^ HORc \ r 1 H ^ A-Cl C1 H // 10

To a mechanically stirred solution of 16.83 g (83.1 mmol) of 2- (E-chlorophenyl) pyrrole-3-carbonitrile in 450 ml of glacial acetic acid at 36 ° C is added dropwise over 18 minutes 14.7 ml (24 , 70g, 183.0 mmol) sulfuryl chloride. The addition causes a slight exotherm to 39 ° C and after a further 16 minutes the reaction mixture is filtered under vacuum. The collected solids are washed first with acetic acid and then with water. This solid melts after recrystallization from hot ethyl acetate at 259-261 ° C. Other samples of this product were prepared by similar methods and the analytical values for one such product are shown below.

Haamun, Nujol) s 3170 (brs), 3100 (m), 2225 (s), 1508 (m), 25 1097 (m), 825 (s), 717 (m), 660 (m) cm -1.

1 H-NMR (DMSO): δ 7.72 (d, J = 8.8Hz, 2.0OH, two aromatic protons), δ 7.56 (d, J = 8.6Hz, 2.0OH, two aromatic protons) ).

C-NMR (DMSO): 5136.01 (pyrrole-C-2-carbon), δ 133.92 (ε-chlorophenyl-C-4 carbon), 5129.09 (p-chlorophenyl, 03.5 carbons), S 127.41 (ε-chlorophenyl 04 carbon), δ 127.11 (p-chlorophenyl O1 carbon), £ 114.49 (nitrile-1-carbon), S 114.10 (pyrrole 05 carbon), £ 110.92 (pyrrole-C-4 carbon), δ 90.09 (pyrrole-03 carbon).

35 Microanalysis (mp 271.54):

Calculated: Cf 48.65%, H, 1.86%; N, 10.32%; Cl, 39.17%

Found: C, 49.22%; H, 2.12%; N, 9r85%; Cl, 39.03% 47 9 4 6 2 6

Example 271 4,5-Dibromo-2- (pC, α, α, trifluoro-p-tolyl) -pyrrole-3-tolyl) -pyrrole-3-carbonitrile

5 CN Br CN

+ Br2 -—1 i \ QhcF3 Br h CFa 10

To a stirred mixture of 0.8 g of 2- (N, O, 6'-trifluoro-p-tolyl) -pyrrole-3-carbonitrile in 70 ml of chloroform is added 2 ml of bromine. Upon stirring overnight, a white solid precipitates which is collected by filtration. The thin layer chromatography plate (ethyl acetate-hexane 1: 1) shows a single component; mp> 230 ° C.

Analysis for ci2H5Br2F3N2:

Calculated: C 36.55, H 1.27, N 7.11, Br 40.61% Found: C 36.40, H 1.08, N 6.99, Br 40.55%

Following the procedure described above, but substituting appropriately substituted phenylpropyl-3-carbonitrile for 2- (oC, α, α, trifluoro-p-tolyl) pyrrole-3-carbonitrile, the following compounds are obtained.

25 • o

X CN

· «48 9 4 6 2 6 LHEXX Sp ° c HH 4 -NO2 Br Br 274-277 HH 4-F Cl Cl> 220 5 HH 4-F Br Br> 220 HH 4-SO2CH3 Cl Cl> 230 H 3-F 4-F Cl Cl> 230 H 3-F 4-F Br Br> 220 2 — Cl 3-Cl 4-Cl Cl Cl 10 2-Br 3-Br 4-Br Br Br HH 4-OCF3 Cl Cl 222-225 HH 4-OCF3 Br Br

H H 4-OCF3 Cl H

HH 4-CN Br Br> 230 15 HH 4-CN Cl Cl> 240 HH 4-SO2 CH3 Br Br> 230 HH 4-NO2 Cl Cl 246-249 H 3-Cl 4-Cl Br Br> 260 HH 3-CF- j Cl Cl> 230 20 HH 4-COCH3 Clx Cl 251-254 H 2,3-CH = CH- Cl Cl 244-247 HH 4-CH3 Cl Cl 215-217 H 2-Cl 4-Cl Br Br> 230 HH 3-Cl Cl Cl> 230, · 25 H 2 -Cl 4-C1 C1 Cl> 23 ° HH 4-C1 Br Br 273-274 HH 2-C1 Br Br> 230 HH 4-CF3 Cl Cl> 230 HH 4- Br Cl Cl> 235 30 HH 2-Cl Cl Cl> 230, H 3 — Cl 4-Cl Cl Cl> 235 HHH Cl Cl 254-255 49 9 4 6 2 6

Example 28 oL- (2,2-Diethoxyethylamino) -β-nitrostyrene and 3-nitro-2-phenylpyrrole-N, N-C-CH-O, N-C-CH-O HH-CH 2 CH 2 OEDj Ϊ Xx // ού-nitroacetophenone (5.7 g, 0.0345 mol) is dissolved in 100 ml of antholuene and 4.6 g (0.0345 mol) of aminoacetaldehyde diethyl acetal are added. The reagents are placed in a 250 ml round-bottomed flask fitted with a Dean-Stark trap. The trap is filled with a 4A molecular sieve and the mixture is heated at reflux for 18 hours. The toluene is removed in vacuo to give 8.36 g of oC- (2,2-diethoxyethylamino) -p-nitrostyrene as a brown oil.

To this oil is added 50 mL of concentrated HCl. As the bottle is swirled, the oil turns into a yellow suspension. After 10 minutes, the solid is filtered off to give 2.48 g of a yellow solid. Recrystallization from ether / ethyl acetate / hexane gives the product in two fractions, 2.08 g, mp 190-192 ° C, (31%).

Max 1485 cm-1 (NO 2), 1 H-NMR (CDCl 3) DMSO) δ 6.73 (m, 2H), δ; Δ 7.46 (m, 5 H).

According to the above reaction, other β-nitrosyrene compounds can be prepared by replacing o-nitroacetophenone with an appropriately substituted o-i-nitroacetone and / or aminoacetaldehyde diethyl acetal with suitable 2,2-di (C 1-4 alkoxy). ) with ethylamine to give the following compounds: i.e. 94626 CCH 9 NO 8 + H 9 NCH 9 CH 2 CO 2 -C 1-4 alkoxy) g toluene

5 R

L> ry <^ ”· —I

N-CH 2 CH (C 1 -C 4 alkoxy) 2 R H

10

Il H g (C 1-4 alkoxy) 2 HH E-CH 3 OCO (OC 2 H 5) 2 15 H E-CH 3 H (° C 2 H 5> 2 H m -OCH 3 e -OCH 3 (OC 2 H 5) 2 H - - <° C 2 H 5> 2 20 E- Cl HH (OCH3) 2 H E_CH3 H iOCH3) 2 HH E-CF3 <0C2H5) 2

Example 29 ^ 2,3-Dichloro-4-nitro-5-phenylpyrrole NO 2 Cl no 2 30 ^ + NaOCl

A mixture of 3-nitro-2-phenylpyrrole (1.56 g, 0.0083 mol) in 60 ml of dioxane is cooled to 25.9 g (0.0182 mol) of technical grade sodium hypochlorite by adding dropwise to ice bath 94626. After stirring for 45 minutes, the mixture is acidified with concentrated Helium. Add water and ethyl ether. The layers are separated and the supernatant is washed with IVO, dried over anhydrous MgSO 4 and evaporated to dryness in vacuo to give 2.21 g of a yellow solid. Purification by chromatography, using silica gel and eluting in increasing proportions with 10 ml of ethyl acetate / hexane gives, after evaporation to dryness, 0.77 g of a yellow solid (36%), m.p. 190-190.5 ° C;

Analysis for C10HgN2O2Cl2:

Calculated: C 46.72, H 2.35, N 10.90% Found: C 46.96, H 2.86, N 10.02%.

# · • · ·

Claims (8)

A process for preparing a new aryl pyrrole compound of structural formula 5 U 10 wherein W is CN or NO 2; L is H, F, Cl or Br; and M and R are each independently H, C ^-alkyl, C ^-alkoxy, C ^-alkylsulfonyl, cyano, F, Cl, Br, nitro, CF3, OCF3 or R2CO, and where M and R are in adjacent positions, they may be associated with the carbon atoms to which they are attached may form a ring where M 1 represents a structure: O · 1 where R 2 is C 1-3 alkyl or C 1-3 alkoxy, characterized in that, a benzoylacetonitrile or an α-nitroacetophenone having the structural formula: X = / V in which L, M, R and W are as defined above are reacted with 2,2-di (C 1-4 alkoxy) ethylamine, at an elevated temperature, whereby F k 57 - 94626 an α- [ 2,2-di (C1-4-alkoxy) ethylamino] -B-cyanostyrene or an α- [2,2-di (C1-4-alkoxy) ethylamino] -B-nitrostyrene having the structural formula: L 5 Π N -CH 2 CH (C 1 -C 4 - okalkoxy) 2 H 10 where L, M, R and W are as defined above, and the so-called α- [2,2-di (C 1-4 alkoxy) ethylamino] -B -cyanstyrene or α- [2,2-di (C1-4 alkoxy) amino] -B-nitrostyrene is treated with an inorganic or organic acid. 2. A process according to claim 1, characterized in that the reaction of the 2,2-di (C 1-4 alkoxy) ethylamine with the benzoylacetonitrile or the solvent. 3. A process according to claim 1, characterized in that α-t2,2-di (C1-4-alkoxy) ethylamino] -B-cyano-tyrene or a- [2,2-di (C1) 4-Alkoxy) ethylamino] -B-nitrostyrene is treated with hydrochloric, hydrobromic or trifluoroacetic acid. A compound having the structural formula: - 'N-CH 2 CH 2 Cl 2 -C 6 alkoxy where W is CN or NO 2, L is H, F, Cl or Br; M and R are independently H, C 1-4 alkyl, C 1-4 alkoxy, C 1-6 alkylsulfonyl, cyano, F, Br, nitro, CF 3, OCF 3 or R2 CO, and dd M and R are in adjacent positions, they may together with the 58,94626 carbon atoms to which they are attached form a ring where M 1 represents a structure: O and R 2 are C 1-4 alkyl or C 1-4 alkoxy. . 5. A compound according to claim 4, characterized in that it is (E) -p-chloro-B - [(formylmethyl) amino] cinnamonitrile diethyl acetal; (Z) p-chloro-B - [(formylmethyl) amino] cinnamonitrile-dietylace-speech; B- [(formylmethyl) amino] -3,4-dimethoxycinnamonitrile diethylacetal; or (Z) -β- [(formylmethyl) amino] -p-methylcinnamonitrile diethyl acetal. A process for preparing a compound having the structural formula: r L 'N-CH 2 CH 2 Cl 2 C-C 1-4 alkoxy where W is CN or NO 2; L is H, F, Cl or Br; and M and R are each independently H, C 1-4 alkyl, C 1-3 alkoxy, C 1-4 alkylsulfonyl, cyano, F, Cl, Br, nitro, CF 3, OCF 3 or R 2 CO, and where M and R are in adjacent positions, they, together with the carbon atoms to which they are attached, can form a ·· ring, where MRI represents a structure: where R 2 is C 1-4 alkyl or C 1-6 alkoxy; characterized in that a benzoylacetonitrile or an a-nitroacetophenone having the structural formula: (p, y - c - ch 2 R 10 where L, M, R and W are as defined above) is reacted with a 2, 2-di (C 1-4 alkoxy) ethylamine at an elevated temperature