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    • 专利摘要:
    METHOD FOR OBTAINING DERIVATIVES OF THE GENERAL I Formula HiXi X2% R: COOK Ktj-S-CH7-CH-CO - N hydrogen or lower alR where kil is lower alkyl or R, R and R. and R together form a polymethylene chain before the completion of the 5-or 6-membered ring, lower alkyl, haloR, and a lower alkyl. K. is hydrogen, a lower alkanoyl, or a group giving a bis -symmetric disulfide product of general formula II j-S-CHg-CH-CO-CL-COOR X and Xj are the same, oxygen or sulfur, which is replaced by a proline of general formula III RiXi XeRe - COOR UNSO where R, R, R, j, XT and Xg are indicated .. R. R. These values are reacted with an acid chloride of the general formula IV Ri, -S-CH2-Cli-COOH € D where RJ and R have the indicated values Od dd 00 followed by the separation of the target product or compound of the general formula (I), where R. is lower alkanoyl, is hydrolyzed and then oxidized with iodine to obtain Bis -symmetric disulfide product.
    公开号:SU1115668A3
    申请号:SU792860149
    申请日:1979-12-21
    公开日:1984-09-23
    发明作者:Кранчо Джон
    申请人:Е.Р.Сквибб Энд Санз,Инк (Фирма)；
    IPC主号:
    专利说明:

    The invention relates to the field of obtaining new derivative products that can be used in medicine. It is known 1a to react acylation of nitrogen-containing compounds of haloaiIRHApiyiarai acids C 13. The purpose of the invention {is to develop on the basis of the well-known method of the method of obtaining new compounds I have 15 valuable pharmacological properties. This goal is achieved by the method of obtaining the derivatives of the common formula KlXi X2R Ki} -S CH7 CH - CO-T4 lower alkyl of 5 kil; R and R ,, - lower alkyl or R. and RO together zx d t in polymethylene, R, is lower alkyl. Substituted lower alkyl; a noyl or group, o is decomposing with 5 and -c-.i-oi, metric disul1, the final product of the general formula -S-Clig-CH-CO-N-CODE X and X are the same, the oxygen is sulfur diminished proline of the general formula COOR X - are given where R, R ,,, R,.,. These values are subjected to the action with acid chloride of the acid of the general formula -CVij-CH 68 where RJ and R have the indicated values, followed by the isolation of the target product or compound of the general formula (I) JR, is lower alkanoyl, gi, is solubilized and then is oxidized with iodine to produce an L-symmetric d and with a straight-line strain. Compounds of the formula (t) suppress the straight-line powder. Hyotene nzina L to angiotensin is therefore useful for the treatment of hypertension associated with angiotensin. The action of the enzyme renin on angiotensinogenic pseudoglobulin in blood plasma leads to the formation of angiotexin 1, which is converted by the action of aiogotensin-converting enzyme (A.CE.) to angiotensin II, the latter being: an active vasculating agent that is considered to cause various forms of hypertonia, an active vascular agent which is considered as the causative agent of various forms of hypertonia, and if it is a common vascular disease agent, it is active in the angiotensin II. -Ix, for example in rats and dogs. The proposed compounds are mixed in a sequence. Conversion of angiotensinogen 5 (renic) angiotensin I - an angiotensin-converting enzyme (ACE) apiotensin 11 suppresses the angiotensin-transforming enzyme and reduces or eliminates the formation of a substance .; Increased blood pressure, angnotensin II. Thus, by introducing a composition containing one or a set of compounds of formula (I) ,. facilitate hypertension associated with angiotensinMg in a mammal; sufferers from it ... A single dose, preferably consisting of 2-4 individual daily dosages, prescribed on a basis of 0.1-100 mg / kg of dry weight per day (l-IS mg / kg hky) is suitable for reducing blood pressure. weight per day). The substance is administered orally, but parenteral routes of administration can be used (subcutaneous, intramuscular, intraperitoneal, or intraperitoneal). The table shows the proposed compounds, which are about 3-5 times more active than captopril 2 as determined by E-data, and also have a longer duration (the percentage of inhibition is determined 24 hours after the administration of the dosage of the compound to rats). The lower the concentration, the more active the compound, the higher the percentage of inhibition. After 24, the longer the duration of the compound.
    Compound
    ™,
    Cun
    HS-CH2-CH CO-N (captopril)
    eight
    SNS
    one
    COOH 0.0008
    CHo-CH-CO-N
    ABOUT
    SNS
    COOH 0.002
    Н§-СНо-СН-СО-1Т
    0. .0
    SNS
    COOH 0.002
    HS-CHg-CH-CO-N 3 is a con (mg / ml) test, with an angiotensin-converting image. Percentage of inhibition after 24 h in to after intravenous dosing Compound dosage 10 mg 7 kg equivalent of captopril. Example 1. 7 (3), 8SJ-7- (Acetylthio) -2-methyl-1-oxopropyl-1, 4-diox-7-azaspiro (4, 4) nonan-8-carboxylic acid. A. K-Carbobenzyloxy-4-hydroxy-L-proline. 26.5 g (0.20 mol) of 4-hydroxy-b-proline and 32.8 ml (0.23 mol) of benzyl chloroformate are reacted in 200 ml of water and 100 ml of acetone in the presence of 20 g (0.02 mol) of bicarbonate potassium and 69.2 g (0.50 mol) of potassium carbonate, and then treated with 90 ml of concentrated hydrochloric acid to obtain N-carbobenzyloxy-L-proline. This product
    Percent inhibition
    Cho
    0,005
    ten
    sixteen
    The 52% of the compound subjected to the waking 50% inhibition of the nzyme, isolated from the lungs, and the rest, is measured through the blood pressure of angiotensins I. React with cyclohexyl-MiHOM to obtain the cyclohexyl-amine salt in an amount of 69 g, m.p. 193-195 ° C. The salt (34 g) is neutralized with N-hydrochloric acid to obtain 27 g of the free acid as a colorless glass, i - 70 (s, 1% in chloroform). B. N-Carbobenzyloxy-4-keto-L-np oline. 21.5 g (0.81 mol). N-carbobenzyloxy-4-hydroxy-b-proline is oxidized, in 1.2 l of acetone with 83 ml of 8 N: phosphoric acid in sulfuric acid. To facilitate the subsequent filtration of chromium salts, 30 g are added to the acetone solution. celite (diatoic earth)
    prior to the introduction of the oxidant, using a razor-stirrer, React1; the omfl / tert ionic mixture and the acetone filtrate are concentrated to approximately 300 ml, after which it is diluted with 1 liter of chloroform. The solution is washed with 300, ml of saturated sodium chloride - (four times), dried (MgS04) 5 from the filter, and the solution is evaporated and the mixture is obtained, obtaining N-carbobenzyloxy 4 keto - b - prolip (2258 g), which can be removed from just. th ether (50 ml) -hexane (150 ml) to obtain 17.2 g (81%) of the product; T.n.iu 99101 ° C, o;: i (s, 1% in chloroform).
    B. K-Carbobenzyloxy 4 54 - ethylene 1 Ioxy-b - proline.
    riarpenfio re-mixable mixture of 12.8 g (0, OL9 mol) K-carbobenzyloxy-A-keto-L-proline, 53 ml (0.095) ethylene glycol n 0.35 g | 1-toluenesulphonic acid, HjO in 1j31 l of benzene, and the resulting solution with reflux. for 7 h (the water formed is collected in a Dean-Stark apparatus). After holding the night at room temperature, the nylse glycol layer is separated and the benzene solution is dispensed with 150 ml of 150 ml of nasicensus st. sodium, dried (MgSO4, j), and dissolve the dissolving solution to obtain 14.6 g of K-carbobenzyloxy 4,4-tylenediox 1-b-proline in the form of syrup braznogo residue. A polyurethane sand is packed in 60 MP of ethanol, the filter is treated with 5 g of cyclohexyl amine and diluted with ether. After that, the solution is seeded with crystals and friction drops the protective mixture of cyclohexylamine salt, after cooling. during the night 9 g so pl. 179 -180С (hardened, 173с). The material is recrystallized from a d o t o AI tr il a, t, pl. 182-18 4 C (hardened. 179 ° C) 21 (s, 1% in ethanol).
    The cyclohexylamine salt (8.4 g) is suspended in 40 ml of ethyl acetate, stirred, cooled and treated with 40 ml of 1N hydrochloric acid. The layers are separated, the aqueous phase is extracted by a digest of dopropyl-1 body by the amount of ethyl acetate, etat (3-40 ml), the mixed organic layers are dried (MgSO4) and the solvent is evaporated to the end, at 0.2 m and the syrup residue,
    which begins to crystallize is triturated under ether; ether is half a half - 1a 6.4 g (42%) of almost colorless M - carbobenzyloxy-4,4 ethylenedioxy-b-proline, t, mp, 101103-С (hardened. 98 ° C) , cll2 - 34 ° (s, 1% in SISEZ) G, 4 5 4-Ethylenedioxy 1 ..- proline, A solution of 3.2 g (0.124 mol) N-carbobenzyloxy-4, 4 ethylenedioxy-b- Prolipa in 100 ml The mixtures of the metapolour (2: 1) are treated with 1 g of a 5% ac-padi-carbon catalyst and on the Narr hydro-generator for 6 hours for three days. The catalyst is exhausted under nitrogen, washed with methanol and the mixed filtrates are added to the end and O L-0.2 mm. yielding 1.7 g (94%) of a colorless solid, 4,4-etr-1-dioxy-b-prolica; m.p. 245247-0 (decomposition,); 32 ° (s, 0.5 in 1: 1 MeON-HZO).
    D, 7 (3), H- (Acetylthio) -2-methyl-1-oxopropyl J-1, 4 Diox-7 azaspiro (4,4) nonan-8-carboxylic
    ACID
    A stirring solution of 3.2 g of 4 .4 - ethylenedioxy-L-proline (10.0185 mol) in 50 ml of water is cooled down and treated in portions of solid sodium carbonate to a pH of 8.5. Then, with continuous re-chilling and cooling, add portions of a solution of 3.7 g (0.020 mol) of D - 3-a n, etyl t, and about 2-methyl pr-opoyl chl o-1L of ether, with
    reed in
    This is kept up to pH 8, b with sodium carbonate solution (approximately 14 ml). After 1 1/4 h, the solution is treated with 50 t-w of ethyl acetate, stirred, cleaned, carefully acidified with hydrochloric acid (1: 1) to pH 2.0, mixed with sodium chloride and the layers separated. The aqueous phase is extracted with additional ethyl acetate (3-50 ml), the combined organic layers are dried (MgSO4, () and the solvent is evaporated to the end at 0.2 mm. The solid residue is triturated under ether and the mixture is repeated, 5.9 g (100% ) (7 (3), (acetylthio) 2-meTSA1-1-oxopropyl1, 4-dioxa-7-azaspiro (4,4) nonan-8-carboxylic
    .pl 108-111 sec.
    acids ,.
    The product is converted into the salt of dicyclohexylamine with 3.4 g di71
    iclohexylamine in 70 ml of ethnlaceta. After seeding the solution with crystals and rubbing, the crystalline salt is precipitated, it is recrystallized from 95 ml of acetonitrile, yield 6.7 g. 187-189 C (hardened), oL - 59 (s, 1% in ethane).
    The dicyclohexylamine salt is converted into the free acid, suspended in ethyl acetate and treated with 75 ml of 10% kai bisulfate, stirring until two layers are obtained. After separation, the aqueous phase is extracted with ethyl acetate (4 - 75 ml), the organic salts are mixed, dried (MgSO4) and the solvent is evaporated, yielding 4.1 g of colorless 7 (8), (acetylthio) -2-methyl-1-oxopropyl -1, 4-dioxa-7-azaspiro- (4,4) nonane-8-carboxylic acid, so pl. (solidified, 11–7 ° C), 15 J – 118 ° (s, 1% in ethanol).
    Example 2. 7 (S), (3-Mercapto-2-methyl-1-oxopropyl) -1, 4-dioxa-7-azaspiro- (4,4) nonan-8-carboxylic acid.
    Argon is passed through a cold solution of 8.5 ml of concentrated ammonium hydroxide in 20 ml of water. Then 4.0 g (0.013 mol) of 7 (5), (acetylthio) -2-methyl-1-oxopropyl -1, 4-dioxa-7-azaspiro (4,4) nonane-8-carboxylic acid from of Example 1D and the mixture is stirred in an ice bath for several minutes and then at room temperature under argon for 2 hours. The solution is treated with 30 ml of ethyl acetate, cooled, stirred and acidified with 16 ml of hydrochloric acid (1: 1) . The layers are separated and the aqueous phase is extracted with an additional portion of 30 ml of ethyl acetate (twice), the ethyl acetate extracts are mixed, dried (MgSO4) and the solvent is evaporated, yielding 7 (8), 83} -7- (3-mercapto-2-methyl-1- oxopropyl) -1,4-dioxa-7-azaspiro (4,4) nonane-8-carboxylic acid in the form of a solid residue. The product is triturated under ether and evaporation is repeated. The product is then triturated with 30 ml of hexane, cooled in TeieHHe for 1 hour, filtered under argon and dried under vacuum to give 2.7 g of a colorless solid, 7 (8), (3-mer 15668d
    Capto-2-methyl-1-oca opropyl) -1,4-dioxa-7-azaspiro- (4,4) -non-8-carboxylic acid, so pl. 1,31133 ° C (hardened. 125 ° C), d. - 66
    g (s, 1% in ethanol).
    Pr and 1 er 3. (S). (3-Acetylthio) -2-methyl-1-oxopropyl-A, 4-dimethox-L-proline.
    A. H-Carbobenzyloxy-4,4-dimethoc B-L-Proline, methyl ester.
    A stirred solution of 7.8 g (10.03 mol) of N-carbobenzyloxy-4-keto-L-proline from example 1 in 60 ml of methanol is treated with 96 ml
    5 of trimethyl orthoformate, then 0.6 ml of concentrated sulfuric acid and left to stand overnight at room temperature.
    The pale yellow solution is stirred, treated with 1.5 g of potassium carbonate, then 30 ml of water, and the bulk of the solvent is removed on a rotary evaporator to give a syrupy residue, which is shaken with 30 ml of water and 30 ml of chloroform. After separation of the layers, the aqueous phase is extracted with additional chloroform (3-30 ml) and the combined organic layers are washed with 45 ml
    2Q saturated solution of porous sodium and dried (Mg80c.). Evaporation of the solvent gives 8.4 g (88%) of H-carbobenzyloxy-4,4-dimethoxy-b-proline, methyl ester.
    B. H-Carbobenzyloxy-4,4-dimethoxy-b-proline.
    The ester (8.4 g, O, 026 mol) of part A is dissolved in 80 ml of methanol, treated dropwise with
    temperature from -1 to 4 С 18 ml
    (0.036 mol) 2N sodium hydroxide solution, held at 0 ° C for 1 hour and at room temperature overnight. After removing about half of the solvent on a rotary evaporator, the solution is diluted with 150 ml of water, washed with 100 ml of ether (washing washed), acidified with cooling 63 ml of 1: 1 hydrochloric acid to pH 2 and extracted with ethyl acetate (4 750 ml). The combined extracts were washed with 50 ml of a complete solution of sodium chloride solution, dried (MgSO4) and the solvent was evaporated, yielding 8.0 g of a pale yellow viscous oil. The oil is dissolved in 35 ml of ethanol, treated with 3.0 g of cyclohexylamine in 10 ml of ethanol and diluted to
    500 ml of ether. When seeding crpstal-jiaf ni and pacTiipani-nj, the PBX crystalchgestr introduced the M salt of carbobepsiloxy-4 (dt1methoxy -b - polycyclohexyl -) on after carrying ophalfy; Enis in 710, 7.0 g, 157–159C; 51O, ° C -34 ° (s, 1% in ethanol) This material is recrystallized from 100 ml of acetonitrile and creeping salt in the form of bes, i.e. j- about 3. mp 158-160 ° C (hardened, 154 ° C).
    H-Karbobezi.poxy-4., H-diimolyl-L-lrolicyclohexylamino salt is suspended in a DO ml of ethyl acetate, mixed and treated with 25 MTI IN of hydrochloric acid. After lol guvli of transparent layers of IDE pa, and i) a sneaky phase of extrapyio-dolol EMP: ethyl acetate (3 ml of ml), organic blended elephant was dried (KgSO ,;) and evaporated to a rat of 0.2 ml and 40 C /% 2 g (70% in 5 with saws about KS and 4,. 4-g ometoaci - 1, - prolkpa in the form of liquid yellow in s1; ovo 4,4-l), imethoxy - 1., Prolin, The solution of L-carbobenzshyuksI-:, - -dimethoxyl and L-prolia (72 g, 0.022 mol) in 210 ml of a mixture of metha; 1: 2 (1; 1) v K1batg pzayut 2, j g of 5% pure palladium carbon and tr 24 hours a day on a videogayizator Parra s telei1-e 6 l. Catalyst c) filtering out aiMocdxipe of nitrogen, pro1 - I; 1 — a me1-agolog- and smegtalny evaporate the filtrate,) I to ko} 1dlri (}., 2 cells to get 1 hp1; This residue is a solution of Kote in 200 ml of mtgiguil t; they are distilled. Pssle rub the solid substance under ether (repeat the words) and get 3.6 in (95%) almost two south 4, 4-dimethosn-b-Lrolil tltl ,, 192-194 ° C (decompose) fij 47 (C ;, I% in methanol).
    Sample5 was recrystallized from metalol-ether, colorless and silt-wits at 197-t98 ° C (decomposed), & - (s, 1% in metalol),
    G. (S) -1 (Methylthio) - 2-methyl-1 - oxioyiyl J-4,4- Dimethoxy-L-npoJU-ni.
    A stirred solution of 3.3 g (0.019 MOJib) 4,4-dimethoxy-b-Prol10
    The pH was adjusted to 8.5 by the addition of a 25% sodium carbonate solution (w / v). Then, when continuous mixing and cooling, jordi was added a 1M solution of HBT g (O ,, 021 mol) B-3-acetylthio 2 - methylpropanonechloride in 5 ml of ether, while pH of carbonate was added. When the pH value is stabilized at 852--8; .4 (approximately 15 and mixed and: continued cooling ;;: aioT for another 1h. Then the solution is washed with 50 m.) ;. ztytsetat; --- (flush the spine) 5 is poured into: over 50 yni ethyl;); etate S is cooled. Permmepp important. Carefully acidify 1: 1 with a solution of hydrochloric acid to a pH of 2.0, lamination with l-sodium, and separate the layers. The entire phase is extracted with a: ethylene glycol ethanol (mixed organic layers are dried with 1 M 80 r and the solvent is evaporated to a sorbent at 0.2 mm, half b, g of syrup-like prodlpsta. This syro
    6-1) g of the better salt (S) (, acetylthio) -2 -iverHj; - oxoprott (-gl -4 ,, 4 -di tetoks1-; -l-Lr olive, didiclohexilamia in the form of two lords (3 / and 3 „4 g) 5 T.nji. 158--160s (hardened„ 145 С) - 71 (s ,, 1% B eta1; ole)
    After the recrystallization of the 1 st step from 20 m of hot ztilaut7gta - 60 ml of hexa1- .V. loluchalot blind solid salt weighing 6.0 „tl. 158-166 С (hardened), М | - 69 ° (s, 1% in the thalol),
    The salt of didicloxylamine is converted and acidified by suslserizing 5.0 g of salt to 50 ml of acid, cooling and processing of 60 ml of 10% aqueous solution of potassium bisulfate, thus obtaining 2 irradiated layers. After separating the extragigrates, the aqueous phase is ethyladetate (3 50 MJ; :) j, the mixed organic layers are dried (MgS04) and the solvent is scorched to: o at 051-0.2 mm and 45 ° C, yielding 4.1 g (69%) (S) „1 (acetylthio) -2 - methyl-1-oxopropyl 1-4, 4-dimethoxy-b - prol: ln in the form of B5i3Koro almost glassy material, o-. - G 2 (s ,, 1% in ethanol).
    Gp and .m er 4. (5) 1- (3-Mercapto-2-methyl-1-oxoylpropyl) -4 54-dimetho-cn-L-npojn-iH.
    11 1
    Argon is passed through a cold solution of 8.5 ml of concentrated ammonium hydroxide in 20 ml of water for 0.25 hours. This solution is then added under cooling and under argon to 4.1 g (0.013 mol of (S) -1-3 - (acetylthio) -2-methyl-1 -oxypropyl A, 4-dimethoxy-b-proline, the mixture is stirred in an ice bath until 5 until a pale yellow solution is obtained (approximately 15 minutes). Stirring under argon is continued at room temperature for another 2 hours, then the solution is extracted with 30 ml of ethyl acetate (this and subsequent operations are carried out This is possible under argon atmosphere.) The aqueous layer is cooled, stirred, layered with 30 ml of ethyl acetate and acidified in portions about 16 ml of ethyl acetate and about 16 ml of 1: 1 hydrochloric acid; the layers are separated, the aqueous phase is extracted additional ethyl acetate (3 x 30 ml), mixed ethyl acetate layers were dried (MgSO4) and the solvent was evaporated, yielding 3.5 g (100%) of (S) -1 - (3-mercapto-2-methyl-1-oxopropyl) -4З4-dimethoxy-L-proline as a colorless viscous syrup, SI - 72 ° (s, 1% in ethanol).
    The latter (3.4 g) is dissolved with 20 ml of ethyl acetate, rubbed, diluted with 30 ml of hexane and cooled to give a colorless solid weighting 2.6 g, m.p. 108-110 ° С, 77 ° (s, 1% in ethanol).
    Example 5. (5) (acetyl thio) -2-methyl-1-oxopropyl 4,4-diethoxy-L proline.
    A. K-carbobenzyloxy 4,4-diethoxy-b-proline, ethyl ester.
    According to Example 3A, using triethyl orthoformate instead of trimethyl orthoformate, and ethanol instead of methanol, 10.8 g of N-carbobenzyloxy-4, 4-diethoxy-b-proline, ethyl ester is obtained as a yellow oil.
    B. N-Capabobenzyl-4,4-diethoxy-b-Proline.
    The crude ester from Part A (10.8 g, 0.13 mol) was scrubbed with 70. ml of III solution of sodium hydroxide solution according to Example 4B, 30 ml of ethanol was added in 10 ml portions to dissolve to give 10.5 g
    5668
    12
    yellow viscous oil. This oil is dissolved in 100 ml of ether and treated with and; iclohexylamine (3.0 g). When seeding with crystals and rubbing
    8.3 g of the crystalline salt of M-carbobenzyloxy-4,4-diethoxy-L proline, cyclohexylamine T. pl. 123 and ° C (sat-114 ° C), M.-12 (s, 1% in ethanol). This material
    recrystallized from 20 ml of acetonitrile to give 7.0 g of salt as a colorless solid, m.p. 125-128 ° С (hardened П5 ° С), 32 ° (с, - 1% в, ethanol).
    Salt N-carbobenzyloxy-4,4-diethoxy-L-proline, cyclohexylamine is suspended in 40 ml of ethyl acetate, stirred and treated with 20 ml of 1M hydrochloric acid solution. The layers are separated and the aqueous phase is extracted with additional ethyl acetate (ml), the organic salts are mixed, dried (MgSO4.) And the solvent is evaporated, yielding
    5.6 g (56%) of K-carbobenzyloxy-4,4 diethoxy-b-proline as a light yellow oil.
    B. 4,4-Diethoxy-b-Proline. A solution of H-carbobenzyloxy-4,4-diethoxy-L-proline (5.6 g, 0.017 mol) in 180 m of a 2: 1 ethanol-water mixture is treated with 2 g of a 5% palladium-carbon catalyst and shaken in an atmosphere in For 3 hours, the crude partially diluted substance is rubbed first under ethanol, then under ether at the corresponding evaporation, while 3 g (91%) of an almost colorless solid 4,4-diethoxy-b-proline, mp . 172174С (decomposed), before it gradually darkens and bakes from 1 ° - 40 (s, 1% in methanol).
    Elemental analysis.
    Found,%: C 52.22-, H 8.59 N 6.69. , 25 HjO
    Calculated,%: C 52.03; H 8.49; N 6.74.
    G. (S) (Acetylthio) -2-methyl 1-oxopropyl-4, 4-diethoxy-b-proline.
    4,4-Diethoxy-b-proline (2.9 g, 0.014 mol) from part B and 3 g
    (0.017 mol) B-3-acetylthio-2-methylpropionyl chloride, dissolved in 3.5 ml of ether, is reacted
    13
    in 35 ml of water in the presence of sodium carbonate according to Example 3 D, to obtain 5, g of a pale yellow viscous oil. This oily product is treated in 40 ml of ethyl acetate with 2.6 g of dicyclohexylamine and diluted with 60 ml of hexane, giving in two portions 4.9 g of (S) -1-G (3-acetylthio) -2-methyl 1-oxopropyl - 4, 4-diethoxy-L-prolindicyclohexylamine salt t.Sh1. 135-138 ° C (hardened. 132 ° C). After recrystallization from ml of hot ethyl acetate — 45 ml of hexane, a colorless solid salt weighing 4.2 g is obtained, mp. 138-1 40-С hardened 135 ° C), ci - 63 ° (s, 1% in etaJJ
    field).
    Elemental analysis.
    Found,%: C 61.48, H, N 5.25; S 5.91,
    - C H,
    Calculated,%: C, 61.33; H, 9.15;
    N 5.30; S 6.06.
    The dicyclohexeschmine salt is converted into free acid by suspending 4.2 g of this salt in 40 ml of ethyl acetate, cooling and processing .40 ml of 10% potassium bisulfate solution, two layers. After separation, the aqueous phase is extracted with ethyl acetate (3 g 50 ml), the displaced organic layers are dried (MgSO4) and the solvent is evaporated, yielding 3.0 g (61%) (3) (acetylthio) -2-methyl-1-oceanopropyl-4-4, 4-diethoxy-b-proline as a pale yellow viscous syrup.
    Example 6. (8) -4,4-Diethoxy-1- (3-mercapto-2-methyl-1-oxopropyl) -b-proline.
    Argon is passed through a cold solution of 5.5 ml of a concentrated solution of ammonium hydroxide in 13 ml of water for 0.25 hours. The latter is then added while cooling under argon to 3.0 g (0.0086 mol) (8) (acetylthio A) -2-methyl-1-oceanopropyl-4, 4-dieth-CH-L-proline and the mixture is treated as in example 4, yielding 2.4 g (92%) (3) -4,4-diethoxy-1- (3- mercapto-2-methyl-1-oxopropyl) -b-proline in the form of an almost colorless viscous syrup, 64 ° (s, 1% in ethanol
    Elemental analysis
    Found,%: C 50.68; H 7.96i N 4.78 S 10.07.
    C ,, HzjN05-0,25 HjO
    15668
    14
    Imported,%: C 50.38; H 7.64; N 4.52; S 10.35.
    Example 7. 2 (S), (Acetylthio) -2-methyl-1-oxopropyl J-6,10-diox-2-azaspiro- (4,5) decane-3-carboxylic acid.
    A. M-Carbobenzyloxy-4,4-trimethylenedioxy-L-strait.
    The interaction of 8.2 g (0-, 031 mol)
    Q N-carbobenzyl-4-keto-1-proline with 45 ml (0.62 mol) of 1,3-propanediol in 450 ml of benzene in the presence of 500 mg of para-toluenesulfonic acid get 12.3 crude viscous product
    5 ester. This product was scrubbed with 70 ml of a 1 N solution, sodium hydroxide, to obtain 10.6 g of crude M-carbobenzyloxy-4,4-trimethylenedioxy-b-proline as an yellow oil. The latter was dissolved in 40 ml of ethanol — 400 ml of ether and treated with 3.2 g of cyclohexylamine to obtain 10.1 g of the salt of N-carbobenzyloxy 4, 4-trimethylenedioxy-L-proline,
    5 cyclohexylamine, so pl. 163-165 ° C (hardened. 160 ° C) - 27 ° (s, 1% in ethiol); Crystallization of 9.8 g of salt in 300 ml of acetonitrile gives 9.5 g of a colorless solid cyclohexyl amine salt, m.p. 165-167 ° С (hardened. 162С) cij2j - 27 ° (с, 1% in ethanol).
    The cyclohexylamine salt (9.0 g) is suspended in 40 ml of ethyl acetate, stirred, cooled and treated with 45 ml of IN hydrochloric acid solution. The layers are separated and the aqueous phase is extracted with additional ethyl acetate (3 40 ml), the mixed organic salts are dried (N 50 504) and the solvent is evaporated, yielding 7.1 g (75%) of glass-like M-carbobenzyloxy 4,4-trimethylenedioxy-b - proline.
    B. 4, 4-T-methyl-Dioxy-L-pro-LIN.
    A solution of 7.1 g (0.022 mol) of N-carbobenzyloxy-4, 4-trimethylenoxy-L-proline in 200 ml of a mixture of 2: 1
     methanol-water is hydrogenated in the presence of 2 g of a 5% palladium carbon catalyst to obtain 3.8 g (93%) of an almost colorless 4,4-trimethylenedioxy-L-proline,
    5 m.p. 234-236С (decomposition), preceded by gradual darkening and sintering; dl - 36 ° (s, 0.5% in a 1: 1 mixture of methanol-water). 15 Elemental analysis; Found: C, 51.42; H, 7.11N. 7.40 Calculated,%: C, 51.33; H 7.00 N 7.48, B. 2 (5), (Acetylthio) -2-methyl-1-oxopropyl 3, 10-diox-2-azaspiro (4.5) decane-3-carboxylic acid. 4,4-Trimethylenedioxy-L-proline (3.7 g, 0.02 mol) is acylated with 4.0 g (0.022 mol) of B-3-acetylthio-2-methylpropionyl chloride in 50 ml of water in the presence of sodium carbonate in Example 1D, obtaining 7.3 g of glass-like crude product. The product is converted to its dicyclohexylamine salt with 3.6 dicyclohexylamine in 70 ml of ethyl acetate. A crystalline salt precipitated during seed and rubbing, yielding 7.5 g of salt, dicyclohexy-1 m on, so pl. 168-170 ° C (hardened. 166 ° C) - 59 ° (s, 1% in ethanol). Recrystallization from 30 ml of acetonitrile gives 6.5 g of a colorless solid salt, m.p. 169-1 71 ° С, o / j 63 ° (s, 1% in ethanol). In order to convert the dicyclohexamine salt to the free acidic 6.4g salt, it is suspended in 75 ml of ethyl acetate and treated with 75 ml of 10% potassium bisulfate and mixed until two layers are obtained. After separation, the aqueous phase is extracted with ethyl acetate (ml), the organic salts are mixed, dried (MgSO4) and the solvent is evaporated, yielding 4.3 g (67%) glass-like 2 (S), (acetylthio) -2-methyl-1-oxopropyl -6, 1O-dioxa-2-azaspiro- (4,5) decane-3-carboxylic acid. Example 8. 2 (8), 3SJ-2- (Z-Mercapto-2-methyl-1-oxopropyl) -6, 10-dioxa-2-azaspiro- (4,5) d can-3-carboxylic acid. 2 (8), (Acetylthio) -2methyl-1-oxopropyl-6, 10-dioxa-2-azaspiro (4,5) decane-3-carboxylic acid (4.3 g, 0.013 mol) is hydrolyzed to 8.5 ml of concentrated ammonia in 20 ml of water according to example 2 to obtain O, 9 g of a colorless solid product, otP - 64 (s, 0.5% in ethanol). An additional 0.8 g of 8 product is obtained by extraction of the aqueous phase with chloroform, o (7 66. Two portions are dissolved in chloroform, evaporated, rubbed under ether and evaporation repeated, 1.7 g (46%) 2 (8), ( 3-mercapto-2-methyl-1-oxopropyl) -6,10-diox-2-aaspiro- (4,5) decane-3-carboxylic acid, mp 169171 0 (hardened. 167 ° С), cij 71 (s, 1% in methanol). Elemental analysis Found,%: C 49.67; H 6.67, N 4.93, S 11.10. T, Calculated,%: C 49.81; H 6 , 62; N 4.84; 8 11.08. Example 9. 7 (8), (Acetylthio) -2-methyl-1-oxopropyl-7-aza-1, 4-dithiospiro (4,4) nonane 8-carboxylic acid. A. N-carboxybenzoyl-4,4-ethylenedithio-b-proline, me sludge ester. A stirred solution of 3.9 g (0.014 mol) of H-carbobenzyloxy-4-keTO-L-proline, methyl ester in 60 ml of methylene chloride is treated with 3 ml (0.036 mol) of ethanedithiol cooled to 8 ° C and in an argon atmosphere of 2 mp (0.024 mol) of ethereal boron trifluoride. After removing the cooling bath, the pale yellow solution is stirred for an additional hour and left to stand at room temperature. The solution is stirred, treated with several pieces of crushed ice, and then with 20 ml of water. After 30 minutes, the layers were separated and the aqueous phase (50 ml) was extracted with an additional portion of methylene chloride (3 x 30 ml). The combined organic layers were washed with 50 mp of saturated sodium chloride solution, dried (N§804) and the solvent was evaporated on a rotary evaporator, to give 6 g (100%) of a pale yellow oil, N-carbobenzyloxy-4,4-ethylenedithio-b-proline, methyl ester. B. M-Carbobenzyloxy-4,4-ethylenedithio-L-proline. Methyl complex, obtained as a product in part A (7.4 g, about 0.018 mol) is dissolved in 65 ml of methanol, treated dropwise at a temperature of from -1 to 4 With 14.5 ml (0.029 mol) of a 2N hydrate solution sodium oxide 5 v; keep at. 0 ° C for 1 h and at room temperature. By removing an example of a solvent solvent on a rotary evaporator, the solution is diluted with 125 ml of water, washed with ether (washing with viral from) 3 is acidified with water and 5 hours with 1 g of 1 solution of hydrochloric acid to RP 2 and extracted ethyl 1; etatom (4 x 50 ml), the mixed extracts are washed with 50 ml of saturated sodium hydrochloride solution, dried (iM.gSO) and the solvent is evaporated to give bg of a pale yellow, viscous oil. This oil is dissolved in 25 ml of ethanol, treated with 1.8 g of cyclohexylamine in 5 MJI of ethanol and diluted with 300 ml of Lry ether, seeded with crystals and rubbed on a precipitate ascristagic salt of cyclohexylamine 5 which gives after cooling off at night. five; 7 g with N carbobenzyloxn 4,4-etrhenditiO -1, -proline, cyclohexroxamine, t. square 205 2 О 7 ° С (zeta in Erd, 2 01 С), Refining of 50 ml of etaH07fa - 400 ml of ether gives 4 .; 9 g of a non-colored solid salt, mp 207-209C (hardened. 201C) Add (s, 1% in chloroform), Diclohexrglamine Sod (a.8 g) is suspended in 25 ml of ethyl acetate-t; 25 ml of IN solution of salt are mixed and treated; After the uony iemin of the two transparent layers, they are separated; mixed organic layers, dry out (MgSO4 and extract solution. lb5 to obtain 3.8 .g- (62%) of N-carbobenzyloxy - 4, 4-eti.1 chdnito of b-proline as a palette. ;; tonic viscous syrup, B. 4 5 4-Etilenditio b Proline hydrobromide. M Karbsbepsilokog-4, 4-etileneditio-1 ./-- proline (3.7 g, 0.11 mol) is treated with 20 ml of bromide zodoro- / yes in acetic acid (30-32%), tightly caulk and They mix up the material with a baler. Mixing is difficult due to the viscosity of the raw material, the latter is stirred as far as possible with a spatula. At the same time, a crystalline product starts to fall out, Ilocnen Toiifly portions of hydrogen bromide are added to acetic acid after 15 minutes 818 (10 ml) and after 25 1 hours (5 1 hl) and stirring, a total of 35 S-sh is continued. To complete the precipitation of the product, ether (250 Nm) is added and after cooling for 15 g-n-h, the cream color is washed off under nitrogen ether and vacuum dried floor ca 2.7 g of 4 ,, 4 ztilendi.tio-L-ppo .pina hydrobromide, m.p. 240242 0 (decomposition sintering and darkening at about 200 ° C5 (s, O, 5% in a mixture of 1 G |: shoroform - meth. H), d. 7 (5), 83 -7-GZ-CHAdetiltio) 2-methyl-1 - oxonrop-7-aza - 1 dCh-dithiospiro- (4 e4) nonan 8-carboxylic acid. A transfer solution of 2.6 g (O ,, 0091 mol) 4,; 4-eti. Penditio-L is proline, hydra bromide, and in 25 units of water is cooled to 5 ° C and adjusted to pH 8.2 by adding Sodium hydroxide solution (w / v). With continuous stirring and cooling - :; a solution of 1; 9 1 (O-01 mol) B-3-adatilthio-2 is added by portions; when: the pH is stabilized at 8,28,85 (after about 15 min); Continuing and cooling from 1 hour for 1 h - Then the solution is washed with 25 RS of ethyl acetate (npoHbHsKJi is extracted); exfoliate with 25 ml of ethyladetate. They are stirred, carefully poured in 1: 1 hydrochloric acid to a pH of 2j, o, decanted with sodium chloride and the layers are separated. The aqueous phase is extracted with an additional amount of ethyl. N, etat (3 25 ml), 5 mixed organic layers are dried (M.W.) and the solvent is evaporated to 0.2 ml condo, resulting in 2.6 g of the syrone-free product, which begins crystallize, the next is treated in 30 ml of ethyl acetate, 1.5 g of didiclohexylamine. to obtain 3.0 g of the colorless didiclohexyl salt: -1in, m.p. 176178 ° C (hardened. 1), L j - 55 ° (s, 1% in ethanol). This material is crushed in a mortar on an ad. 15 ml of acetonitrile, cooled for 1 h, filtered off, rinsing with 5 ml of cold acetonitrile and ether19
    rum and powder, yielding 2.9 g of dicyclohexylamine salt, m.p. 17179 ° С (hardened. 72 ° C}, d - 56 ° (s, 1% in ethanol).
    Elemental analysis.
    Found,%: C 56.21 H, 8.18; N 5.05-, S 18.00,
    C. -
    Calculated D: C 56.56; H 7.98; N 5.28-, S 18.12.
    To convert said dicyclichexylamine salt to free acid, 2.8 g of this salt is suspended in 30 ml of ethyl acetate, cooled and treated with EOT with 30 ml of 10% potassium bisulfate solution to form two clear layers. After separation, the aqueous phase is extracted with ethyl acetate (3. 30 ml), the combined organic salts are dried (MgSO4) and the solvent is evaporated until the end at 0.1-0.2 mm and 45c5 to obtain 2.0 g (63%) of a colorless solid, ( 5), 8S, -: 7-1 3- (acetylthio) -2-mets-1-oxo-propyl-7-aza-1-dithiospiro- (4,4) nonan-8-carboxylic acid, so pl. 125-126 ° С (hardened. 122 С) eilf - 101 ° (с, 1% in ethanol)
    Example 10. 7 (5), 8S-7- (3-Mercapto-2-methyl-1-oxopropyl) -7-aza-1, 4 dithiospiro- (4,4) nonane-8carboxylic acid.
    Argon is passed through a cold solution of 3.5 ml of concentrated ammonia in 8.5 ml of water for 15 minutes. The latter solution is then added while cooling and under argon atmospheres to 1.9 g (0.0054 mol) 7 (5), 3- (acetylthio) -2-methyl-1-oxopropyl-7-aza-1, 4-dithiospiro - (4.4nonane-8-carboxylic acid and the mixture is stirred in an ice bath until solution is obtained. Stirring under argon is continued at room temperature for another 2 h, then the solution is extracted with 15 ml of ethyl acetate under argon. The aqueous layer is cooled, stirred are layered with 15 ml of ethyl acetate and acidified in portions with about 6.5 MP of a 1: 1 solution of hydrochloric acid. The layers are separated and the aqueous ase extracted with additional ethyl acetate (3. 15 mL), mixed acetate
    the layers are dried (MgSO4) and the solvent is evaporated, obtaining a glass 15668
    20
    a similar residue, which closes when rubbed under ether. Evaporation is repeated and the colorless product is suspended in 30 ml of hexane, filtered and dried under vacuum to obtain 1.4 g (84%) 7 (S), 8S-7- (3-mercapto-2-methyl-1-o-scopropyl) - 7-aza-l, 4-dithiospiro- (4,4) nonan-8-carboxylic acid, so pl. 116-118 ° C (hardened. 105 ° C), o (2–44 ° (s, 1% in ethanol). Elemental analysis. Found,%: C 42.70; H 5.71; N 4.45; S 31.16, - SH 100% .CH
    Calculated,%: C, 42.97; H 5.57; N 4.56-, S 31.29; SH 100%.
    Example 11. (8S) -7- 3- (Acetylthio.) -2-trifluoromethyl-1-oxopropyl-1-1, 4-diox-7-azaspiro (4,4) nonan-8-carboxylic acid isomers A and B
    one
    L. B, L-3- (Acetylthio) -2-trifluoromethylpropionic acid.
    1-Trifluoromethylcarrylic acid (Yu g, 0.071 mol) is cooled in an ice-salt bath, stirred and treated in portions of 5.7 ml (0.075 mol) of 97% thiol acetic acid. After the addition, the yellow liquid was stirred in the cold for 1 hour, allowed to warm to room temperature and distilled to give 14 g (0.1%) of D 5 L-3- (acetylthio) -2 trifluoromethylpropionic acid as a light yellow oil, t kip. 149-153 ° C / 13 mm, the material hardens when carried out in the cold.
    B. D, L-3- (Acetylthio) -2-trifluoromethylpropionyl chloride.
    D, L-3 (Acetylthio) -2-trifluoromethylpropionic acid (7 g, O, 032 mol) is treated with 18 ml (0.25%) of double-distilled thionyl chloride and
    the mixture is heated under reflux for 3 hours. After removing excess thionyl chloride on a rotary evaporator, the residue is distilled, yielding 6.8 g B, L-3- (acetylthio) -2-trifluoromethylpropionyl chloride as a pale yellow oil, m. kip BO-82 ° C / 16 mm.
    B. (88) (Acetylthio) -2-trifluoromethyl 1-hydroxypropyl -1,4-diox-7-azaspiro (4,4) nonane-8-carboxylic acid (isomers A and B).
    4,4-Ethylenedioxy-L-proline (2.4 g, 0.014 mol) B, b-3- (acetylthio) -2th ester from example 3A, 2.4 g 0.032 mol) 1, 2-propanediol, Oh, h g. -unohydrate and -toluenesulfonic acid. The toluene is heated to reflux temperature (G10-112 ° C). The reflux rate is adjusted so that the solvent is slowly distilled off using an Lnn-Star tube in a graduated cylinder. After collecting 80 ml of the solvent, the same volume of the solvent is added to the reaction bottle through an additional crown. This removal and replacement procedure with 80 ml of solvent is repeated four times during the incomplete boiling time under reflux (1.25 hours).
    After standing overnight, the mixture is washed with water (2 100 ml), the mixed washes are extracted with 100 ml of toluene, the mixed organic layers are dried (1-1§304). And the solvent is triturated on a rotary evaporator until the end at 0.2 mm to obtain 8.2 g (99%) of N-carbobenzyloxy-4, 4- (1-methylenedioxy) -b-Prol-1N methyl ester as a yellow viscous oil,
    B. M-Karbobeg13-lokoi-4 ,, 4- (1-methylethylenedioxy) -l-proline.
    Crude methyl complex E1. 5 obtained from part A (8.2 g, 0.025 mol) is dissolved in 80 ml of metharol, treated dropwise at a temperature of from 1 to 4 ° C 18 ml (0.026 mol) of a 2 N solution of sodium hydroxide solution, held at 0 (in for 1 h and at room temperature overnight After removing about half of the solution on a rotary evaporator, the solution is diluted with 150 ml of water, washed with 100 ml of esyr (washing is poured), acidified while cooling with 6.3 ml of 1: 1 solution of hydrochloric acid acids to pH 2 and extracted with ethyl acetate (4-.75 ml). The combined extracts are washed with 50 ml of saturated sodium chloride , evaporate (MgSO4) and evaporate the solvent, giving 8 g of a red-orange; viscous oil. This oil is dissolved in 50 ml of acetonitrile, heated, firstly mixed and treated with 3.8 g of 1-adamantanamine. Solid salt is quickly After cooling to a temperature of 4 ° - the material is filtered, washed with cold acetonitrile and air and sucked out under vacuum, yielding 10.3 g of non-pure: salt: adamantane salt, t, mp 202-204 ° C (decomposition i d -13 ° (cj 1% in methanol). After dispensing with 50 ml of boiling acetome: tg: -:; l; l ohla; kdeni papa pale brown-brown solid salt weighing 9, g, m.p., 202-204 C (decomposed), ci -13 (from 5–1% in methanol).
    The said salt of adamactamine susne; 3-; pyioT in 40 ml of ethyl acetate, trans | -: iseshivat and treated with 1 N hydrochloric acid solution. When two transparent layers are formed, they are separated and the aqueous phase is extracted with additional material; .- quantity of ethyl acetate (g-sh) ,. the mixed organic layers are dried (MgSO4) and the solvent is scrambled to the end at 0.2 mm and 40 ° C, pol1, n: 1a 5.8 g (72%) K-carbobenzyloxy-4 54- (1-methylethylene1; O - : si-L-ijpo: iKHa in the form of yellowish, g, :: of viscous syrup.
    B. 4 S 4 - (1-Methylenedioxy) -L-proline.
    A solution of the indicated N-carbobenZI .TTOKS1G-4, 4 - (1-methylethylenecoxy) -l-prslin (5.6 g, 0.017 mol) in 150.t cbiecH 2: 1 methanol-water treatment-lt 1.6 G 5% - a palladium-carbon catalyst and a wind KIWPT IJ hydrogen atmosphere at a pressure of 3 atm for 5 h. The catalyst is filtered under nitrogen atmosphere, washed with methanol and mixed with hydrogen; 5 grades vrarivayut until the end of prtt C,; -0.2 m: - ,, Yochucha crystal-. cusk residue. The latter is suspended in 11,200 1 h of g-; etakol, and repeated with outglade. 3.0 g (94%) of bsg,;:: o-brown 4 54- (1-methyl ethanol, soxoxy-proline, mp 219 evil; -;:.), Before this post 12-
    It darkens and bakes, foi-1 1, -22 ° C (with 5 i% in a 1: 1 mixture of ethanol-water).
    G. 7 (S), 83 -7-Гз- (Acetylthio-2-lgeti, poxopr sawdust 1-1, 4-dioxa-7-az aspir o- (4, 4) ponan-2 - methyl-8 .-carboxylic acid.
    4 ,, 4- (1 -Methylethylevoxy) -b-proline (2.8 g, 0.015 mol) is subjected. reactions with 3.0 g (0.017 mol), 1 -3-acetyltno-2-methylpropionyl chloride in 40 ml of water according to Example 1D, half via 5.0 g of a viscous yellow product .. The latter is treated with 2.8 g of di-1Plclohexylamine in 45 mp of ethyl acetate, to obtain 4.2 g of the almost colorless dicyclohexylacium salt of 7 (S), 3- (acetylthio) -2-meth1-w-1 oxopropyl-, 1 .iox-U-azaspiro-CA,) got 2-methyl- 8-carboxylic acid, t lit. 170-1 72С (hardened, 168 ° С) 5 cill, 53 ° (с, 1% in ethanol), IlcicJie crystallization from 12 m :; Adetohacutril get colorless Tvirdu: 0 salt weighing 3, | 85 g (51%) 5 tons. square 1 7 О -1 7 2 с (3 а т п e rd. 6 В С)., (From 5 1% in ethanol).
    Found,%: C 60.93; P 8.72; N 5.43 S 6.35.
    C., H „, C.,
    Calculated,%: H 8 „65; Ы 5.465 S 6.26,
    Salt of dip.yclohexylamine is converted into the free acid, suslen 31-rub 3.8 g of salt in ethylamine and process it; A3 m, 10% aqueous solution of bisulphate Al1, stirring until then. until two layers are obtained, After the division of the Lh the aqueous phase is extracted with ethyl diadetate (ml), the organic layers are mixed with BaioT, evaporated (MgSO, a) to rasttorelt, evaporated to give 2, 5 g (51%) of a clear solid 7 (3). , 8S | -7- 2- (adylthio) 2 - methi1 - ;; - (4, 4) dopad -2 met1L-8-carbonone acid: s, t, sh1. 65--68 ° C (hardened, 48 ° C), -100 ° (s, 1% ethanol),
    D, 7 (S), 8S -7- (3-Mercapto-2 - methyl-1 -o ssoprod11L-1, 4 - other Ox 7- -asaspiro- (4.4) noir-2-methyl-8 - carbolic acid „
    The product from part G is hygienic end 1-; Tr1-ammonia ammonia as in example 2, yielding 2.05 g, 7 (8) 5 (3-mercapto 2 - methyl-1 -o; co-adag 1L) - 1 5 4-d iox a - 7-a c a c in-sp o - () nopai-2 - methyl-8-carbonic acid ACID in the form of a viscous colorless oil, d (s, 1% in ethanol).
    Example 15 (S., S, S5S) L-4HTno6v c (2-etil-1-oxo-3, 1-th (5 pandiyl-j 6-c-I 1 54 -diox-7- azaspiro (4, .4) noyan-8-carbolol sour-ia
    7 (S), 8S -7-- (W-mercapto-2-me-tyl-I oceanopropyl) -1 ,, 4 - diox-7-azasp 1- (h- „4):;: oian-8 - carboxylic acid (3.0 g; P, 1.ol-b) of
    The piimera 8 is dissolved in 80 i-iii voggas and adjusted to pH 6.5 with a fraction of a half; c 11 and 1, sodium oxide oxide. To this:; in the hierefieniaHHOMy solution is added over cappl in a pellet P ml 0.5 solution
    V; a iodine in 95% ethanol (s. 3 yr. Yo.)., A / 50 Mi jiacTBOva), with e: h; k. Under .ic pjiGfBaioT mean value of pH ,, ,, 5 seconds: 1:; o N riacTBOpa hydroxide ;; atri 1, Chepez 15 p.1y.ts: excess
    yo and yes ;; l: from yokoagyu rp zbav.nennogo thiosa sodium phosphate and the solution is concentrated to about 50 mn cooled and acidified 1: 1 rast; r0 -1 the ACID .. added from |
    .;.;. ory.; a: I.; ty (30; .. in) and a mixture of HacbiniaiOT 5 °; orsed sodium, labeled T and a R. section, layers, 1 just. Lazu is extracted with an additional amount of xjiopi-iCToro megilet-g. s
    (5 .-. 20;.;. :). Ci-e i; ir; Hoie organic p.1oi (MgSO ;;) and dissolving gel:. About 1 :; : watered to: co;: i.a ggoi O ,, 2 yn, the delicate residue was crushed under eL; and it was picked up and sorted; i.e., 2.8 g b.yumed-yellow solid residue in 50 j-ji of hloistoy etilzka, p) ohm: 1wow warrior (3, -hO mp), c; -isnja nnjie to one and 1: 1 G c.noi-f again
    20 ml of methylene chloride and .iicyiiHBa; i: T mixed layers (MgStX)) - B1; cropping and melting with ether gives 2.2 g (73%) of creamy amorphous T zerdo; About the substance (SjSjS.S) - /, 7-di hybio: - 2-meg1ig-1 - oxo -3. i propandiyl). -Ois 1, V-dioxa7-azasgium ro- (4, 4) li o na.n-8-carb o new acid, m.p. B-BZ S (. Expansion
    权利要求:
    Claims (1)
    [1]
    METHOD FOR PRODUCING PROLINE DERIVATIVES of the general formula I
    R is hydrogen or lower alkyl; · And - lower alkyl or R, and R 2 together enter the polymethylene chain until the completion of the 5- or 6-membered ring;
    Rj is lower alkyl; halogen is substituted lower alkyl;
    R + is hydrogen, lower alkanoyl or a group giving a bis-symmetric disulfide product of the general formula II * 2
    COOK.
    X 3 and X 2 are the same, oxygen or 'sulfur, characterized in that the substituted proline of general formula III
    Cd)
    I x ] <HN --- U- COOR where R, Rp R 2 , X 1 and X have the indicated meanings, are reacted with an acid chloride of the general formula IV tc-s - sn 2 -сн-соон where R 3 and R 4 have the indicated meanings, followed by isolation of the target product or compound of the general formula (I), where R ·. - lower alkanoyl, hydrolyzed and then oxidized with iodine to obtain a bis-symmetric disulfide product.
    8999111 - AS
    11 15668
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    同族专利:
    公开号 | 公开日
    NL7909246A|1980-06-24|
    CS215036B2|1982-06-25|
    ES488752A0|1981-02-16|
    AU533149B2|1983-11-03|
    JPS5594357A|1980-07-17|
    IT7951167D0|1979-12-21|
    IE792468L|1980-06-22|
    HU179644B|1982-11-29|
    IL58930D0|1980-03-31|
    FI70886B|1986-07-18|
    IE49321B1|1985-09-18|
    DK159115B|1990-09-03|
    ES8102094A1|1980-12-16|
    PH19213A|1986-02-04|
    BE880815A|1980-06-23|
    SE451839B|1987-11-02|
    NO794181L|1980-06-24|
    GB2039478B|1983-02-16|
    CH642065A5|1984-03-30|
    AU5371479A|1980-06-26|
    AT374174B|1984-03-26|
    NZ192449A|1984-05-31|
    SE7910550L|1980-06-23|
    GB2039478A|1980-08-13|
    NO153569B|1986-01-06|
    IT1126841B|1986-05-21|
    IL58930A|1983-07-31|
    FR2444669B1|1983-06-03|
    DK550079A|1980-06-23|
    FI70886C|1986-10-27|
    FR2444669A1|1980-07-18|
    FI794027A|1980-06-23|
    DE2951200A1|1980-07-10|
    PL133414B1|1985-05-31|
    CA1132985A|1982-10-05|
    ZA796720B|1980-11-26|
    ES8103039A1|1981-02-16|
    NO153569C|1986-05-21|
    HK15684A|1984-03-02|
    GR78384B|1984-09-26|
    ATA805479A|1983-08-15|
    LU82023A1|1980-04-23|
    YU314879A|1983-04-30|
    PT70620A|1980-01-01|
    DD148338A5|1981-05-20|
    PL220609A1|1980-12-01|
    DK159115C|1991-02-11|
    ES487180A0|1980-12-16|
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    法律状态:
    优先权:
    申请号 | 申请日 | 专利标题
    US97231478A| true| 1978-12-22|1978-12-22|
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