SU491233A3 - The method of obtaining spirobenzocyclan acetic acid - Google Patents

Description

where Ra iiY-as indicated above, the acid chain is lengthened;

where Ra, Y and p are as defined above, the reaction of the Lgherodta-Kindler is reacted with sulfur and sec: ammonia of the general formula

TO

/

HN:

R.

where RS n KB is lower alkyl or Rr, and RsBwec those with a nitrogen atom form a heterocyclic radical, in a w1O1-free OH environment, the resulting thiocarboxylic derivative of the general formula

Ч1-1

where is ra. Rr. Re. The type is as above, subjected to alkaline hydrolysis, an acetic acid derivative of the general formula

BUT „S-NOC f

where R2, Y and p - kgchk y-gazano above, schzlizuyut in the presence of an acid agent, a compound of general formula

but.

where R2, Y and ha are as defined above, they are reduced and the resulting T1 is cnwpobenzocyclic 11ucc; the uonic acid, in which Ri is hydrogen, is separated "whether translated into ether or salt, lh if necessary, a-alkylated with an alkylating agent containing the radical RI , after preliminary etherification: Acid groats and acidic ether, if necessary, are converted to acid 1 and free acid. Separated in B1 racemate or optically aKTHiBHoro isomer

or re: water or ether or salt by conventional methods.

Diethylene ketal is preferably used as the catalyst, loluche; No. from 2 - (“- R2n-bromo, nile) -2-methyl-1,3-dioxolane and magnesium in tetrahydrofuran medium,

For an alkaline hydrol: isotrite group, sodium hydroxide or potassium hydroxide is usually used: and the process is carried out in an aqueous medium, preferably in the presence of diethylene glycol, at a temperature sufficiently high to decompose the resulting ammonium salt by hydrolyzing the nitrile to the corresponding acid and a, mmoniac.

An example of an acidic agent is strong acids, such as hydrochloric, sulfuric, and chlorine.

To extend the chain of acetic acid, the Aridt-Eistert method is applied, including the treatment of the acetic acid derivative with thioNyl chloride, "the interaction of the resulting chlorine anhydride with diazomethane and the decomposition of diazoketone with silver oxide.

The secondary used in the Wilgerodt-Kindler reaction is, for example, dimethylammonium; n, diethylamin or morpholine. When morpholine is used, the process is carried out at atmospheric pressure in the presence of an acid (Catalyst, for example, p-toluenesulfonic acid.

The alkaline hydrolysis of the product of Acid Acid, Sulfur and Secondary Amine is carried out in the presence of alkali, for example caustic soda, 1OR potassium hydroxide, in an organic solvent, for example, methanol or ethanol. The resulting acetic acid salt derivative is converted to an acid by the action of a strong acid.

As a cyclization agent, poly® phospho is taken; pirous silt: and sulfuric acid.

The reduction of the keto acid is preferably carried out according to the Wolf-Kizhner method or zinc in hydrochloric acid.

When Y is methylene or oxygen, the reduction can be carried out with hydrogen in the presence of a catalyst, for example palladium on carbon. In this case, the process is carried out in the presence of chloric acid.

a-Altsylation of the obtained acid, where RI is Hydrogen, is carried out as indicated above.

When a-alkylating a named acid after pre-esterification, it is acted upon with an alkaline agent, for example, a hydride, amide or dialkylamido m alkali metal, and then an alkylation agent of the general formula RX, RSOsR, ArSOsR or S02 {OR) 2, where X is chlorine , bromine IL | and iodine; R is linear or branched Ci-C4-alkyl; Ag - Arl.

The lower alkyl esters of 4-tetrahydrothiranylphenylsidanic acetic acid can be obtained by the method, and the analogous ones known to be used for the preparation of ethyl -1-tetrah1 D; rothypyr1 ordientiacetic acid.

The lower alkyl esters of 4-tetrahydrolyl-phenyl-diphenyl acetic acid can be obtained in the same way as the ethyl ester of 4-tetrahydr Ilpyl, or ethyl acetate (1) of acetic acid (see examples).

In all examples, the NMR spectrum is taken up in chloroform.

Example 1. 2,3,5,6-Tetrahydrospiro- (thia1pyran-4, G - "" dan) -15-ousic acid.

In 25 ml of tetrahydrofur a and 0.5 ml of dibromethane are injected under an iert atmosphere 4.86 g of magnesium, maintaining the temperature at 35 ° C, a solution of 48.4 g of 2-p-bromophenyl-2- is added at 135 ° C for 135 minutes methyl-1,3-dioxolane in 485 ml of anhydrous tetragvdrofuran, stirred for 1.5 hours at 37 ° C /

At another temperature of up to 28 ° C, a solution of 29.54 g of ethyl 3F, 4-tetrahydrodipyra (H) or cyanthian acetic acid solution in 80 ° C is introduced over 3 minutes. Keeping the temperature at 38 ° C, the mixture is stirred for 16 hours At room temperature, the mixture is concentrated to dryness with iB vacuum, a mixture of ice and dilute hydrochloric acid is added to the residue, stirred, the organic layer is separated by decantation, the aqueous layer is extracted with ether, and the ether layers are washed successively with 2 l. hydrochloric acid, water, aqueous sodium bicarbonate solution and water are treated with animal charcoal, the solvent is removed by distillation in vacuo and 62.1 g of 4- (p-acetylphenyl) 2, 3,5,6-tetrahydro1 shapyran-4-acetic are obtained acids. In an inert atmosphere, 62.1 g of the product obtained are dissolved in 150 liters of ethylene glycol, a solution of 60 g of caustic potassium in 60 ml of ether and 210 ml of ethylene glycol are added. The mixture is stirred for 24 hours in a bath (140 ° C), catching ammonia 2 n. water, cooled, poured onto a mixture of ice and water, the aqueous layer was extracted with ether, the extracts were washed with water, the combined washings and the aqueous layer were acidified to pH 1 with dilute hydrochloric acid, extracted with methylene chloride, the extracts were washed with water, extracted with aqueous sodium bicarbonate solution, the extracts are washed with methylene chloride, the acid is precipitated with dilute hydrochloric acid, the precipitate is separated by filtration under vacuum, washed with water, dried, and 28.84 g of crude 4- (haacetylphenyl) -2,3,6,6 - is obtained tetrapi draw and Atgiriyev; n-4uksusnoy acid, mp.. 167 ° C (benzene). Calculated,%: C 64.72; H 6.52; S 11.62.

CisHigOsS (mol. Weight 278.35).

Found,%: C 65.0; H 6.6; S 11.8.

In an inert atmosphere, stir and give 33.95 g of crude 4- (α-acetyl phen yl) -2.3, b, 6-tetrag11 Drotiapyran-4-acetic acid, 0.6 & p-toluene sulfate acid, 143 g anhydrous morpholia and 7.85 g precipitated sulfur, stirred for 16 hours in a bath (140 ° C), cooled, poured on ice, acidified to pH 1 with hydrochloric acid, filtered

Acid 3 vacuum, rinse it with water, add methanol to it, heat it with a condenser backward, cool to 5 ° C, incubate for one hour at this temperature, filter under vacuum, wash the precipitate with water and obtain 25.9 g of crude 4 - (p-morpholinothiocarbonylmethylphenyl) - 2,3,5,6 - tetrahydro-thiopyran-4-acetic acid, t.- pl. 160 ° C; m.p. 178 ° C (methanol).

Calculated,%: C 60.13; H 6.64; N 3.69; O 12.65; S 16.89.

Ci9H, 5NOsS2 (mol. Weight. 379.53). Found,%: C 59.5; H 6.8; N 4.2; O 13.1; S 16.3.

In an inert atmosphere, 25.9 g of the obtained product and 25.9 g of potassium hydroxide are introduced into 500 ml of ethanol, heated under reflux for 15 hours with stirring, cooled, the solvent is removed in a vacuum, water is added to the residue, filtered, and acidified the filtrate is adjusted to pH 1 with dilute hydrochloric acid, the aqueous layer is extracted with methylene chloride, the extracts are washed with water, dried, animal charcoal is added, stirred, filtered, concentrated to dryness in vacuo, the residue is crystallized from benzene, treated with animal charcoal and 13 are obtained 06 g 4- (L-carb oK10metilfeiil) -2,3,5,6-tetrahydropyr. anan-4-y Xuonic acid, so pl. 146 ° C. Calculated,%: C 61.2; H 6.16; S 10.89. CisHisO + S (mol. Weight 294.35). Naidio,%: C 61.1; H 6D S 10.7. 9.41 g of 4- (p- (carboxymethylphenyl) -2,3,5,6-tetrahydrothiachiran-4-y "hydrochloric acid and 188 g of polyphosphoric acid containing 83% of phosphoric anhydride are mixed with stirring, heated to 115 ° C, incubated for 1.5 hours at 115 ° C, cooled, poured on ice, stirred, e-xirapirut with ethyl acetate, the combined extracts washed with water, dried, mixed with animal charcoal, filtered, concentrated to dryness in vacuum, crystallized from toluene and get 5.82 g of 3-oxo-2,3,5,6-tetrahydrospiro- (tiapran-4, G-I1Ndan) -5-acetic acid, mp 160 ° C.

Calculated,%: C 65.19; H 5.84; S 11.60. CigHieOaS (mol. Weight. 276.34). Found,%: C 65.1; H 5.8; S 11.5. In an inert atmosphere, 4.81 g of synthesized 1-acid, 6 ml of hydrazine hydrate, 3.4 ml of water, 3.4 g of potassium hydroxide and 70 ml of ethyl GL1COAL are mixed for 35 MU, I is heated to 197 ° C, distilled off with 25 ml of liquid, 4 hours under reflux, cooled, ice-water is added, and water is extracted with ethyl acetate, the extracts are washed with water, the combined washings and the aqueous layer are acidified to pH 1, diluted with hydrochloric acid, stirred, and the precipitate is filtered off under vacuum washed it, dried "get 4,265 g of 2,3,5,6-tetrahydrospiro- (t apirai-4,1-in en) -5-acetic acid, m. pl. 132 ° C (cyclohexane). Calculated,%: C 68.67; H 6.91; S 12.22.

C 5Hi8O2S (MOL. Weight. 262.35).

Found,%: C 68.7: H 7.0; S 11.9.

NMR spectrum, Hz: 105-109-117-127 (CH2 hydrogens in the p-position and from sulfur to the atoll of Sulfur and to phenyl); .142-156-159,5-164

(in SNG c); 427

(aromatic arches); 647 (carbon hydrogen sludge).

PRI and 1I e p 2. L-a-Methyl-2,3,5.6-tetrappdrospiro (tiapran-4, G-i11 dan) -5-} 1 acetic acid.

To a solution of 4.33 g of 2,3,5,6-tetrag Drostro (t1 iapyran-4, G - indous) - 5 - acetic acid in 50 ml of methylene chloride Priba | Ply 70 ml of chlorine methylene solution containing 1 : 1 g / l of diazomethane, stirred for 30 minutes, concentrated in vacuo to vacuum, and 4.7 g of taken acid methyl ester were obtained.

In the atmosphere of the inerta, a mixture of 1.22 g of diethylamine, 25 ml of GexametlIlphosphate triamide 25m. (In tetrahydrofuran is cooled to -40 ° C, 20.1 ml of a 0.83n solution of butyl lithium in hexane are added at one time to get lithium diethylamide, which is stirred with 5 liter of "n, at -40 ° C, immediately synthesized methyl ester is added, dissolved in a mixture of 8 ml of methylphosphate and imide and 8 ml of teprahydrofuran, mixed with 5 l {in, at -40 ° Afterwards, g {once introduced, 6.99 g of methyl iodide, stirred for 30 minutes at -35 ° C, removed the o.cooled: and stirred for 25 minutes, poured onto a mixture of ice and water, They build a water layer with ether, rinse the extracts with water, dry, add milk, coal, stir, filter and concentrate in vacuo to dryness.

A mixture of 5 ml of water, 5 ml of caustic mistra (40 ° Böhme) and 50 ml of methanol is added to the product obtained under an atmosphere of an inert atmosphere, heated for 30 minutes under reflux, water is added, methanol is removed in a vacuum. Water is extracted, the aqueous layer is extracted with ether, the extracts are washed with water, the combined wash waters are acidified to pH 1, diluted with 1-hydrochloric acid, cooled, the precipitate is separated by filtration into Ea, heated, washed with water, dried, crystallized from methanol, treated JiBOTiHbi .M carbon m and get 3,44 target product, so pl. 134 ° C

Another 0.28 g of the substance is evaporated from the methanol uterine solutions, mp 134 ° C.

Calculated,%: C 69.53; H 7.29; S 11.60.

CinHsoOzS (mol. Weight 276.38).

Found,%: C 69.2; H 7.3; S 11.5.

NMR spectrum, Hz: 85-92 (hydrogens CH); 105-24 (CH2 hydrogens in the p-position and with respect to the sulfur atom and phenyl); 152-179 (Eodorol SNG in the a-position on the basis to the sulfur atom and phenyl); 211-218-225- 232.5 (asaorods in a-possessed to carboxyl); 428.5 (aromatic hydrogens); 640 (carboxyl hydrogen).

For example 3. 2,3,5,6-Tetrapidrospiro- (| PIran-4, G-.indan) -5-yk, Suona acid. Analogously to example I, 4-acetylphenylmapipium bromide and 4-acetylphenylmapnium bromide and 4-(p-acet-lphenyl) -2,3,5,6-tetrahydrot1-1-4-acetic acid are obtained from ethyl 4-tetrapidropyran-1IL | m.p. 134 ° C

For the synthesis of the starting 4-tetragl / idropyran orideNcyane acetic acid ethyl ester a mixture of 85 ml of ethyl cyanoacetate, 7.5 g of ammonium acetate, 22 ml

y, caustic acid and 250 ml of benzene are heated under reflux and a Dean-Stark nozzle for 3 hours and receive 83.5 g of the target ester, t.kip. 108-110 ° C / 0.6 mm. Calculated,%: C, 61.52; H 6.71; S 7.18.

Found,%: C 61.4; H 6.5; S 7.5.

In an inert atmosphere, 2.68 g of 4- {pa. Acet1Ilfe1Nyl) -2,3,5,6-tetrahydropyran.n-4-acetic acid, 0.64 g of precipitated sulfur, 12 ml of anhydrous morpholine and 0.050 g p-toluenesulfonic acid, heated for 18 hours under reflux, cooled, poured into a mixture of water and ice, the precipitate was separated, the filtrate was acidified to pH 3 with diluted hydrochloric acid, stirred, separated by filtration

under vacuum, the precipitate is washed with water, methanol, and dried to obtain 2.65 g of crude 4- (pm6 -fol1NOT11Ocarbon; ylmetilfe 111l) -2,3,5,6-tetrahydrs p, iran-4-acetic acid, so pl. 190 ° C. After recrystallization of metatula

m.p. 191 ° C.

Calculated,%; C, 62.78; H 6.93; N 3.84; S 8.62.

CigHzsNO S (mol. Weight 363.46). Found,%; C, 62.7; H 6.8; K 4,0; S 8.7.

2.4 g of potassium hydroxide and 2.4 g of crude 4- (and-1 morphol1 (.nothio1carboxy.methylphenyl) -2,3,5,6 - tetragropy1: wound-4-t of hydrochloric acid is dissolved in 48 A l. , heated for 16 hours under reflux, cooled, evaporated to dryness 3 under vacuum, water was added to the residue, filtered, acidified to pH 3 with dilute hydrochloric acid, extracted with this {lasetato.m, dried extract , animal charcoal is added to it, mixed, filtered, cannulated to dryness in vacuo, and 1.8 g of crude 4- (p-1 carboxymethylphenyl) 2, 3,5,6-tetrahydropyran-4-1-acetic acid are obtained.

In an inert atmosphere, 20 g of a polyphosphoric c-acid containing 84% of phosphoric anhydride is heated to 115 ° C, 2 g of crude 4- (l-carboxymethylphenium) -2,3,3,5,6-tetra-rapOrO (Piran-4 -acetic acid, stirred for 1.5 hours at 115 ° C, cooled, added with a mixture of ice-water, extracted with ethyl acetate, washed with water, dried, concentrated to dryness in vacuo, methylene chloride added to the residue, treated with animal carbon, concentrated to dryness in vacuum and get 1.47 g of crude 3-oxo-2,3,5,6 tetrahydrosp Iro- (liran-4, G-indan) - 5 - acetic acid.

In a hydrogenator, 2.05 g of 3-oxo-2, 3,5,6-tetrahydro-pyro- (p1Irap-4, G-indai) b-acetic acid is dissolved in 40 HAL acetic acid, 2 g of carbon containing 10% palladium is added, and 0.4 ml of a 67% aqueous acid solution, rinsed and stirred for an hour in an atmosphere of hydrogen (400 ml of hydrogen instead of 355 ml according to theory) were taken, the catalyst was separated, the filtrate was concentrated to dryness, in vacuo, ethyl ether was added to the residue and the water is stirred, the ether layer is separated by decantation, washed with water and then aq. M with bicarbonate solution, acidified to. H 3 with dilute hydrochloric; hydrochloric acid, filtered in vacuo ,. wash the precipitate with water, dry, and obtain 1.9 g of 2.3.5.6-tetrahydrospiro- (pyran-4, G-I1Ndan) -5uxonic acid, m.p. 110 ° C

(After recrystallization (From Cshslohexa-a. Pl. 112 ° C.

Calculated,%: C 73.84; H 7.37.

CisHisOs (mol. Weight 246.29).

Found,%: C 72.8; 7.5.

NMR spectrometer, Hz: 78-132 (different protons); 167-174-181 (hydrogens of CH 3 a-position to fei1il); (hydrogen CH2 in a-position to the oxygen atom); 216.5 (voorodorod SNZ in a-positivity to phenyl and COOH); 628 (carboxyl hydrogen).

Example 4. L-a-Methyl-2,3.5,6-tetragkdrospiro- (p1Iran-4, G-and: ndan) -5-yK1acetic acid.

A solution of 2.84 g of 2,3,5,6-tetrapidrospiro (pyran-4. G-Indane) -5-uksuoic acid in 25 ml of methylene chloride is added dropwise with a chloromethylene solution of diao-methane until a steady yellow color is obtained, mixed for 10 minutes, a few drops are added acetic acid to decolorization and concentrated to dryness in vacuo and dissolve the methyl ester in a mixture of 2.5 ml of tetrapidrofurans and 2.5 ml of hexa-methyl phosphate triamide.

In an inert atmosphere, 26 ml of tetrahydrofuran are mixed. 26 ml of hexamethylphosphate triamide and 1.11 ml of diethylamine are cooled down to -40 ° C, 13.2 ml (0.33 mole) of a solution of butyl lithium in hexane are quickly added and the solution of the methyl ester is added,

To the resulting reaction mixture at -35 ° C, add 2 ml of methyl iodide, bring the temperature to 20 ° C, stir for 30 minutes at 20 ° C, and pour into the zod. extract the aqueous layer with efnrom, wash the extract with water, dry and concentrate to dryness in a zakuma.

50 ml of methanol, 15 ml of water and 10 ml of 2 N were added to the residue. caustic soda, heated to 80 ° C, kept for 30 minutes at this temperature), methanol is distilled off in a slight vacuum, water, animal charcoal is added, filtered, the filtrate is acidified to pH 3 with dilute salt mistrel, cooled to 5 ° C are recovered by filtration in vacuo cheioc-i; . washed it with water tt get 2.12 g of the target product. m. 16GS (shzhlogeks. L).

Calculated. %: C, 73.82; H 7.74. CbNgoOz (mol. Weight 260.32).

Found,%: C 73.7; H 8.0.

NMR spectrum, Hz: B & -93 (hydrogens CH,; -

--СН); 100-132 (SNg hydrogens in the p-position

research on oxygen to oxygen); 118.5-125.5-132.5 l 167-174-181 (hydrogens of СНг pentagonal cycle); 204-250 (hydrogens CH2 in a-position with respect to oxygen. And proton a-carbonyl); 430 (aromatic hydrogens); 630 (hydrogen carbocyl .a).

Example 4: 4- (ha-Carboxymethylphenyl) 2, 3,5,6-tetrapidropyran-4-acetic acid. B, a solution of 19.5 g of ethyl 4-tetrahydropl-alumina acetic acid in 100 liters: l of ether in an inert atmosphere, for 45 minutes, 120 ml (0.88 mol) of solution / g-tolylmagnyl bromide in ether l are maintained for 2 hours at Lagrevanli with reverse holodedel-peak. After hydrolysis, 25 g of ethyl eff. Ira of α-cyano-4- (l-methylfsnyl) 2, 3,5,6-tetrahydropyral-4-acetic acid, t. 100 ° C

After recrystallization from ethanol, m. Pl. 102 ° C

Calculated. %: C 71.05; H 7.37; N 4.8.

Found,%; C, 71.1; H 7.4; N 5.1.

A mixture of 25 g of potassium hydroxide, 25 ml of water and 150 ml of glycol is introduced into 25.4 g of a-cia HO-4- (l-methylphenyl) -2,3,5.6-tetrahydrapyl iran-4-acetic acid ethyl ester, 24 hour under reflux, 83/85 theoretical amount of ammonia is collected, poured onto a mixture of ice-water, filtered, the filtrate is acidified with dilute hydrochloric acid, the precipitate is filtered off under vacuum, washed with c) sat 16.5 g - (rt-methylphenll) - 2,3,5,6-tetrahydropyran-4 acetic acid, so pl. 130 ° C (lzopropyl ether).

Calculated. %: C, 71.77; H 7.74.

Found %; C, 71.8; H 7.7.

In the atmosphere of the inert, 9.5 g of (4-pmethylphenyl) -tetrapidroplra; n-acetic acid, 95 ML of carbon tetrachloride, 8.3 g of imide N-bromine of succinic acid and 0.250 g of 2,2-azobiC - (( 2-methylpropnonitrile). Heat slowly and after the start of the reaction (exothermic) is heated for 45 minutes under reflux, cooled, filtered, the filtrate is concentrated to dryness in vacuo, ether is added, the precipitate is filtered off under vacuum and washed. 10.65 g of 4- (l-brammethylphenyl) -2.3,5.6-tetrahndropioa are obtained, and {- 4-y of hydrochloric acid, t. pl. 127 ° C

Calculated. %; C 53.69; H 5.47; Br 25.52.

Found,%; C 53.2; H 5.3; Br 26.9.

In the atmosphere and mouth at 100 ° C, a mixture of 4.5 g of cyanide is heated. 7 ml of water and

25 ml dississane, rastrator 9.5 g of 4- (l-bromomethylphenyl) -2,3,5,6 tetrahydropyran-4-1-acetic acid is added over 30 minutes, heated for 30 minutes with a reflux cooler, cooled, water is added, and the aqueous layer of chlorine / methylene chloride, washed, dried, concentrated to dryness in vacuo, and 7.45 g of 4- (p-tiamomet, ylphenyl) -2,3,5,6 tetragi Dropyran-4-acetic acid are obtained.

6 g of the crude nitrile obtained are injected in an inert atmosphere into a mixture of 60 ml of this glycol, 3 ml of water and 12 g of potassium hydroxide, kept for 1 hour in a bath (250 ° C) and 5.4 g of crude target acid is obtained, which is identical to the product obtained in example 3.

The subject of the invention

1. A method for preparing opiobenzocyclan acetic acids of the general formula

TO,

HOjC-CH-f i - | CH2) „

Rj

where RI is hydrogen, linear or branched C -C-alkyl; Ra is hydrogen or chlorine. C-C4-alko "forces

or trifluoromethyl; Y is methylene, oxygen or sulfur; -2.3 or 4;

as well as "x esters of Il1I salts, characterized in that the lower alkyl ester of cyanoacetic acid of the general formula.

3 g

ABOUT

where ns is alkyl; Y has the above-mentioned values, is reacted with Ketal 2-aa1M € 4g of 4-acet1Slphenylmagnesium bromide of the general formula

f-o-r

Vg

vG

where R2, Rs, R4 and Y have the abovementioned values, undergo alkaline hydrolysis triluльную gruypa, hyd1M) lysate the ketal grupp to carboxyl, decarboxylate it in the presence of an acidic agent and

SLEEP

CH, -G

where R2 and Y are the above values, extend the acid chain, a substance of the general formula

 about

CH, S-, COjH,

(..

25 where Ra, Y and tg-ka) K is indicated above, is reacted with sulfur and secondary amine of the general formula

Re

/

H

R

where RS and Re are lower alkyl or Rs and fte together with the nitrogen atom form a heterocyclic radical, in an anhydrous medium, a compound of the general formula

where Ra, Rs, Re, Y and n are as defined above, are subjected to alkaline hydrolysis, an acetic acid derivative of the general formula

BUT, С – Н, Г

2) P-1

R

where R2 is as above; R4 is a ketal residue in the resulting compound of the general formula.

where R2, Y and p are as defined above, cyclized in the presence of an acidic agent, a substance of the general formula

COrRj CH-CN

НОГС-Н 13 where R2, Y, and p are, as indicated above, the cost of production and the resulting opio-iso-cytochloxyxyl 1KIslota, where Ri is hydrogen, is isolated or translated into ester or salt and, if necessary, cc-alkylated is alkylating they are agen-5, containing the radical Rt, where Ri is as indicated above, after preloading ester14 acidic acid group, received a second alkyl ester in the case of: (necessary; 1 riep; BOT to the inlet and free oxygen transfer, 1 selected in the rat racemate NLK of the optically active isomer, or translated into the ether or salt using common methods,