A PROCESS FOR THE PREPARATION OF 1,5-DIPROTECTED-1,5,10-TRIAZADECANE, INTERMEDIATES THEREOF AND THEIR PREPARATION

Abstract: The present invention relates to a process for the prepara­ tion of 1,5-diprotected-1,5,10-triazadecane, to intermediates thereof and their preparation. The 1,5-diprotected-1,5,10-tria­ zadecanes are very useful intermediates for synthesizing N³-­ substituted spermidines.

Description: The present invention relates to processes for preparing 1,5-diprotected-1,5,l0-triazadecanes, to intermediates thereof and theIr preparation. More specifically, the invention relates to a process for preparing 1,5-diprotected-1,5,iO-triazadecanes of the general formula EMI1.1 wherein R1 and R2 are identical or different and represent an amino-protecting group other than a phthalyl group, which comprises reacting 10-phthalyl-1,5-diprotected- 1,5,10-triazadecanes of the general formula II EMI1.2 wherein R1 and R2 are as defined above with hydrazine or a hydrazine derivative to eliminate the phthalyl group. The present invention relates furthermore to 10-phthalyl 1,5-diprotected-1,5,10-triazadecanes of the general formula II and to a process for preparing the same, which comprises reacting a compound of the formula III EMI1.3 either with a protective group introducing agent to form a compound of the formula II EMI2.1 wherein R1 and R2 are identical, or first with a R2-introducing agent in the presence of a Crown ether to form a compound of the formula IV EMI2.2 and, after removing the Crown ether, reacting the compound obtained with an R1-introducing agent to form a compound of the formula II wherein R1 and R2 are different. 1,5-diprotected-1,5,I0-triazadecanes of the general formula (I) are very useful compounds for synthesizing 10subtituted 1,5,10-triazadecanes (N3-substituted spermidines). Spergualin, for example, is an antitumor substance isolated from culture broth of a microorganism (T. Takeuchi et al., J. Antibiotics, 345 1619)). This substance, having the following structural formula (H. Umezawa et al., J. Antibiotics, 34, 1622 (1981)), EMI2.3 was synthesized from 1,5-di-tert-butoxycarbonyl-1,5,10- triazadecane (S. Kondo et al., J. Antibiotics, 34, 1625 (1981)). The hitherto known compound of the general formula (I) has been 1,5-di-tert-butoxycarbonyl-1,5,10- triazadecane disclosed in the above reference. This compound was synthesized by a 6-step method in accordance with the following reaction scheme: EMI3.1 In detail, 3-aminopropanol (A) is tert-butoxycarbonyl (Boc)ated with tert-butyl-4 ,6dimethylpyrimidin-2-yl- thiolcarbonate to form the compound (B). p-Toluenesulfonyl (Tos) chloride is caused to act on (B) to form (C). (C) is reacted with benzyloxycarbonyl(Z) aminobutylamine to form (E). (E) is tert-butoxycarbonyl(Boc)ated with tert-butyl-4,6-dimethylpyrimidine-2-ylthiolcarbonate to form (F). (F) is s catalytically reduced with 5 % palladium-barium carbonate to form 1,5-di-tert-butoxycarbonyl-1,5,10-triazadecane (G). Now, it has been found that the compounds of the formula I can be synthesized easily from triazadecane (spermidine) and that this synthesis needs less steps than the known process. The present invention will be described in more detail below. In compound of the general formula (II-), the starting materials of this invention, R1 and R2 are each an amino-protecting group other than a phthalyl group and may be the same or different. Their examples include an aryl-C1-C3-alkoxycarbonyl group and an Cl-C6-alkoxy- carbonyl group. The phenyl group or alkyl group in these groups may have a substituent. Examples of the substituents for the phenyl group are halogen atoms, the nitro group, methyl or methoxy. Examples of the substituent for the Cl-C6-alkoxy group are halogen atoms. Preferred examples of the above-mentioned protective group are a benzyloxycarbonyl group or a benzyloxycarbonyl group having a substituent, such as a C1-C3 alkoxy group, a halogen atom or a nitro group, on the phenyl group (e.g. a p-methoxybenzyloxycarbonyl group, a p-chlorobenzyloxycarbonyl group, a p-bromobenzyloxycarbonyl group, or a p-nitrobenzyloxycarbonyl group); and a tert-alkoxycarbonyl group, such as a tert-butoxycarbonyl group or a tert-pentoxyearbonyl group. Typical examples of the compounds expressed by the general formula (I) are listed below. 10-Phthalyl-1,5-dibenzyloxyearbonyl-1,5,10-triazadecane 10-Phthalyl-1 ,5-di-p-methoxybenzyloxycarbonyl-1 ,5,l0- triazadecane 10-Phthalyl-1,5-di-p-chlorobenzyloxyearbonyl-1,5,10-- triazadecane 10-Phthalyl-1 , 5-di-p-bromobenzyloxycarbonyl-1 ,5,10- triazadecane 10-Phthalyl-1,5-di-p-n,trobenzyloxyearbonyl-1,5,10- triazadecane 10-Phthalyl-l,5-di-tert-butoxyearbonyl-1,5,10-triaza- decane 10-Phthalyl-1,5-di-tert-pentoxyearbonyi-1,5,10-triaza- decane 10-Phthalyl-1-tert-butoxyearbonyl-8-benzyloxyearbonyl- 1,5,10-triazadecane 10-Phthalyl-1-benzyloxycarbonyl-5-tert-butoxycarbonyl- 1,5,10-triazadecane Elimination of the phthalyl group from these compounds may be carried out by any of known methods such as disclosed in the following references: Shiroh Akabori, Takeo Kaneko and Kohzoh Narita: Tanpakushitsu Kagaku (Protein Chemistry) 1, Amino acids Peptides, Kyohritsu Shuppan, 1969; Nobuo Izumiya, Tetsuo Katoh, Motoyoshi Ohno and Akihiko Aoyagi: Peptide Gosei (Peptides Synthesis), Maruzen, 1975; E. Schrbder and K. Luke: The Peptides, Academic Press, New York, 1965; E. Wüsch: Methoden der Organischen Chemie (Houben-Weyl), Synthese von Peptiden, Georg Thieme Verlag Stuttgart, 1974; and M. Bodanszky and M.A. Ondetti: Peptide Synthesis, Interecience Publisheres, New York, 1976. Specifically, the phthalyl group can be eliminated by reacting compounds of the general formula (II) with hydrazines or their derivatives in ordinary organic solvents or hydrous organic solvents. The organic solvents or hydrous organic solvents used for the above purpose are not restricted to specific types. Their examples include lower alcohols with 1 to 4 carbon atoms, such as methanol, ethanol, propanol, isopropanol and n-butanol; ethers such as tetrahydrofuran and dioxane; and mixtures of water and aromatic organic solvents such as benzene, toluene and xylene. Examples of the hydrazines are hydrazlne, hydrazine hydrate, organic acid salts or inorganic acid salts of hydrazine, lower alkyl hydrazines such as methylhydrazine, and phenylhydrazine. A preferred method of eliminating the phthalyl group is to subject compounds of the general formula (II) to the action of hydrazines, such as hydrazine, hydrazine hydrate or hydrazine acetate, in lower alcohols such as methanol or ethanol. The amount of the hydrazine used is l equivalent or more per equivalent of the phthalyl compound, but preferably, it should be about 1 to 5 equivalents. The reaction temperature is usually above room temperature, preferably, from 500C to the boiling point of the solvent. The isolation of the 1,5-diprotected-1,5,10triazadecane of the general formula (I) from the reaction mixture can be performed in a known manner. In case the phthalyl group has been eliminated using hydrazine in ethanol, for example, the isolation can be effected as follows: The reaction mixture is concentrated to dryness under reduced pressure. Water is added to the residue, and the mixture is adjusted to a pH of 2 or 3 by addition of hydrochloric acid. The insolubles are removed by filtration, and the filtrate is adjusted to a pH of 10 by addition of an aqueous solution of sodium hydroxide. This liquid extracted with ethyl acetate, and the ethyl acetate layer is washed with water. The wshed layer is dried over anhydrous sodium sulfate, and the desiccant is removed by filtration. The filtrate is concentrated under reduced pressure to obtain the compound of the general formula (I). If the reaction mixture does not adversely affect a next reaction, it can be used as such in the next reaction. Typical examples of 1,5-diprotected-1,5,l0-triazadecanes so obtained are given below, 1,5-Dibenzyloxyearbonyl-1,5,10-triazadecane 1,5-Di-p-methoxybenzyloxyearbonyl-1,5,10-triazadecane 1,5-Di-p-chlorobenzyloxyearbonyl-1,5,10-triazadecane 1,5-Di-p-bromobenzyloxyearbonyl-1,5,10-triazadecane 1,5-Di-p-nitrobenzyloxycarbonyl-1,5,10-triazadecane 1,5-Di-tert-butoxyearbonyl-1,5,10-triazadecane 1,5-Di-tert-pentoxyearbonyl-1,5,10-triazadecane 1-Tert-butoxyearbonyl-5-benzyloxyearbonyl-1,5,10-triaza- decane 1-Benzyloxycarbonyl-5-tert-butoxycarbonyl-1 '5 , 10-triaza- decane 10-Phthalyl-1,5-diprotected-1 ,5-10-triazadecanes of the general formula (II), the starting compounds of this invention, are novel compounds that have not been disclosed in the literature. The compound of the general formula (II), in which the substituents R1 and R2 are the same, can be synthesized from known 1-(4-aminobutyl) hexahydropyrimidine (1) - obtained by reactig formalin with spermidine - by three steps in accordnce with the following reaction scheme: Phthalyl-introduci.rsg agent EMI7.1 EMI7.2 EMI7.3 Hydrolysis using acid Protection o amino groups EMI7.4 EMI7.5 EMI7.6 EMI7.7 Rl: Defined earlier in the specification R1 and R2 Defined earlier in the specification. In detail, N-ethoxycarbonylphthalide, for example, is used to introduce a phthalyl group into (I), thereby forming 1(4-phthaliminobutyl)hexahydropyrimidine (2). (2) is hydrolyzed in the presence of hydrochloric acid to form 10-phthalyl-1,5,10-triazadecane (3). Then, a protective agent for the amino groups is caused to act on (3), to form the compound (4) expressed by the formula (II) in which R1 and R2 are the same. Compounds of the general formula (II) in which the substituents R1 and R2 are different can be synthesized from 10-phthalyl-1,5,10-triazadecane (3) by 2 steps in accordance with the following reaction scheme: EMI8.1 R1 and R2: Defined earlier in the specification. Detailedly speaking, Crown ether (e.g. 18-Crown-6) is added to 10-Phthalyl-1,5,10-triazadecane for the reversible protection of the primary amino group, and an agent for introducing R2 is reacted with the secondary amino group to form 1,5-diprotected-triazadecane (5). Then, the Crown ether is removed, followed by reacting an R1-introducing agent with the deprotected amino group to form the compound (6) of the general formula (II) in which R1 and R2 are different. The present invention will be described in more detail with reference to working examples. In these examples, Rf values on thin-layer chromatography (TLC) were obtained by spotting a sample solution on a plate of silica gel (Silical Gel 60 F254, plate thickness: 0.25 mm, a product of Merck) or a plate of alumina (Aluminium oxide 60 F254 plate thickness: 0.25 mm, a product of Merck), developing the plate for a distance of about 8 cm with the developer described in the example, and dividing the distance from the origin of the spotting to the center of the resulting spot of the desired substance by; the distance from the origin of the spotting to the front end of the developer region on the plate. The spot of the desired substance was detected using ninhydrin and W absorption spectrum (2537 A). Example 1 (a) 27.9 grams (80.0 mmols) of 10-phthalyl-1,5,10-triaza decane dihydrochloride was suspended In 300 ml of chloroform. 43.9 g (160 mmols) of benzyl S-4,6-di- methylpyrimidine-2-ylthiocarbonate and 17.8 g (176 mmols) of triethylamine were added to the suspension. The mixture was reacted at room temperature for 6 hours with stirring. The reaction mixture was washed sequentially with 1N hydrochloric acid and an aqueous solution of sodium chloride. The washed liquid was dried over anhydrous magnesium sulfate. The residue was concentrated under reduced pressure to obtain 43.1 g (yield: quantitative) of I0-phthalyl-1,5-di benzyloxycarbonyl-1,5-10-triazadecane as a pale yellow oil. NMR (CDC13) 6= 1.3-2.1 (b,6H), 1.9-3.9 (b,8H), 5.1 (b,2H), 5.1 (S.4H), 7.30, 73.33 (S,S1OH), (7.73 (m,4H) IR (Neat) v(cm-l) 3350, 2950, 1770, 1720, 1525, 1395, 1245, 1150, 1040, 715, 690 TLC (n-propanol:water: 29 % ammonium hydroxide= 10:1:0.15 v/v) Rf= 0.4 (silica gel plate) b) 31.3 g (57.6 mmols) of 10-phthalyl-1,5-dibenzyloxy- carbonyl-1,5,10-triazadecane was dissolved in 600 ml of ethanol. 18.2 g (291 mmols) of 80 % hydrazine hydrate was added to the solution. The mixture was heated overnigth under reflux. Crystals that formed as precipitates were removed by filtration. The filtrate was concentrated under reduced pressure. The residue was dissolved in 300 ml of ehtyl acetate. The solution was extracted with dilute hydrochloric acid in an attempt to obtain the desired product. The aqueous layer was washed with ethyl acetate. Then, sodium carbonate was added to adjust the liquid to a pH of 10. The oil that resulted was extracted with 500 ml of ethyl acetate. The extract was washed with a saturated aqueous solution of sodium chloride. The washed liquid was concentrated under reduced pressure to give 20.1 g (yield: 84.8 %) of 1,5-dibenzyloxy carbonyl-1,5,10-triazadecane as a pale yellow oil. NMR (CDC13) 6= 1.0-2.3 (b,8H), 2.3-2.9 (b,8H), 2.9-3.5 (b,6H), 5.05 (S.2H) 5.07 (S,S2H), 5.1-6.1 7.30 (S,1OH) IR (Neat) v(cm1)= 3340, 3335, 2940, 1695, 1530, 1475, 1450, 1420, 1245 TLC (n-propanol:water: 29 % ammonium hydroxide= 10:1:0.15 v/v Rf= 0.1 (silica gel plate), 0.4 (alumina-plate) Example 2 (a) 2.85 g (8.18 mmols) of 10-phthalyl-1,5,10-triaza decane dihydrochloride was suspended in 40 ml of chloroform. 5.48 g (18.0 mmols) of p-methoxybenzyl s-4,6-dimethylpyrimidin-2-yl-thiocarbonate and 1.82 g (18.0 mmols) of triethylamin were added to the sus pension. The mixture was reacted for 6 hours at room temperature with stirring. The reaction mixture was washed sequentially with 0.5N hydrochloric acid and an aqueous solution of sodium chloride. The washed liquid was dried over anhydrous sodium sulfate. The residue was concen trated under reduced pressure to give 4.70 g (yield: 95.1 %) of 10-phthalyl-1,5-di-p-methoxybenzyloxy carbonyl-1,5,10-triazadecane as a pale yellow oil. NMR (CDCl3) 6= 1.3-2.0 (b,6H), 2.8-3.5 (b,6H), 3.5-3.9 (b,2H), 3.78 (S.6H), 5.00 (S, 4H), 5.0-6.0 (b,lH), 6.6-7.0 (m,4H), 7.1-7.5 (m,4H), 7.5-8.0 (m,4H) IR (Neat) v(cm1)= 3370, 2945, 1770, 1615, 1590, 1515, 1400, 1250, 1035, 825, 755, 725 TLC (n-propanol:water: 29 % ammonium hydroxide= 10:1:0.15 v/v) Rf= 0.8 (silica gel plate) (b) 1.00 g (1.66 mmols) of 10-phthalyl-1,5-di-p-methoxy benzyloxyearbonyl-1,5,10-triazedecane was dissolved in 30 ml of ehtanol. 0.530 g (8.47 mmols) of 80 % hydrazine hydrate was added to the solution. The mixture was heated overnigthunder reflux. Crystals that formed as precipitates were removed by filtrat ion. The filtrate was concentrated under reduced pressure. The residue was dissolved in 50 ml of ehtyl acetate. The insoluble were removed by filtration. 50 ml of distilled water was added to the filtrate. With the mixture being stirred, phosphoric acid was added to adjust the pH to 5. The aqueous layer was separated, followed by adding to it sodium carbonate to adjust the pK to 10. The mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with distilled water. The washed liquid wad dried over an- hydrous sodium sulfate. The residue was concentrated under reduced pressure to give 0.55G g (yield: 72.4 %) of 1,5-di-p-methoxybenzyloxyearbonyl-1,5,10-triaza- decane as a pale yellow oil. NMR (CDCl3) 6= 1.0-2.1 (m,8H), 2.4-2.8 (5,2H,J=6Hz), 2.9-3.6 (m.6H), 3.8 (s,6H), 5.03 (s,4H), 5.2-5.8 (b,lH), 6.6-7.0 (m,4M), 7.1-7.5 (m,4H) IR (Neat) v(cm¯1)= 3350, 2940, 1690, 1615, 1590, 1515, 1305, 1245, 1175, 1030, 825 TLC (n-propanol:water: 29 % ammonium hydroxide= 10:1:0.15 v/v) Rf= 0.7 (alumina plate) Example 3 (a) 502 mg (1.44 mmols) of 10-phthalyl-1,5,10-triazadecane dihydrochloride was dissolved in 15 ml of chloroform. 762 ing (3.15 mmols) of tert-butyl S-4,6-dimethyl- pyrimidine-2-ylthiocarbonate and 321 mg (3.17 mmols) of triethylamin were added to the solution. The mixture was reacted overnight at room temperature with stirring. The reaction mixture was washed sequentially with 5 % phosphoric acid and an aqueous solution of sodium chloride. The washed liquid was dried over anhydrous sodium sulfate. The residue was concentrated under reduced pressure to obtain 602 mg (yield: 88.0%) of 10-phthalyl-1,5-di-tert-butyloxyearbonyl-1,5,10-tri- azadecane which was dissolved in 30ml of ethanol. 0.45g triazadecane which was dissolved in 30 ml of ethanol. 0.45 g (7.19 mmols) of 80 % hydrazine hydrate was added to the solution. The mixture was heated overnight under reflux. Crystals that formed as precipitates were removed by filtration. The filtrate was concentrated under reduced pressure. 30 ml of ethyl acetate and 30 ml of distilled water were added to the residue. Phosphoric acid was added to the mixture to adjust it to a pH of 5. The aqueous layer was separated and washed with ethyl acetate. Sodium bicarbonate was added to the washed liquid to adjust it to a pH of 10. The mixture was extracted with 100 ml of ethyl acetate. The ethyl acetate layer was washed with a saturated aqueous solution of sodium chloride. The washed liquid was dried over anhydrous sodium sulfate. The residue ws concentrated under reduced pressure to obtain 0.25 g (yield: 62.6 %) of 1,5-di tert-butoxycarbonyl-1,5,10-triazadecane as a pale yellow oil. NMR (CDC13) 6= 1.0-2.0 (b,8K), 1.48 (s,18H), 2.3-2.9 (b,2H), 2.9-3.5 (m,6H), 4.7-5.6 (b,lH) IR (KBr) v(cm-l)= 3355, 2975, 2925, 2865, 1690, 1415, 1360, 1245, 1160 TLC (n-propanol: water: 29% ammonium hydroxide= 10:1:0.15 v/v) Rf= 0.5 (alumina plate) Example 4 (a) 0.350 g (1.0 mmols) of 10-phthalyl-1,5,10-triazadecane dihydrochloride was suspended in 2ml of chloroform. 0.530 g (2.0 mmols) of 18-Crown-6 was added to the suspension. With the mixture being cooled with ice water, 0.171 g (1 mmol) of benzyloxycarbonyl chloride and 0t303 g (3 mmols) of triethylamine were added. The reaction system ws returned to room temperature, and reacted for 3 hours with stirring. The reaction mixture was diluted with 35 ml of chloroform. The dilution was washed sequentially with water and a saturated aqueous solution of sodium bicarbonate, water, iN hydrochloric acid and water. The chloroform layer was dried over anhydrous sodium sulfate. The residue was concentrated under reduced pressure to give 0.730 g of a transparent oil. 0.700 g of the resulting oil was dissolved in 7.0 ml of chloroform. 0.745 g (10 mmols) of potassium chloride was added to the solution. With the mixture being cooled with ice water, 0.240 g (1 mmol) of tert butyl-S-4 ,6-dimethylpyrimidin-2-yI-thiocarbonate and 0.101 mg (1 mmol) of triethylamine were added. The reaction systems was brought back to room temperature, and reacted overnight at this temperature with.stirr- ing. The reaction mixture was diluted with 30 ml of chloro form. The dilution was washed sequentially with water, a 10 % aqueous solution of phosphoric acid, a saturat ed aqueous solution of sodium bicarbonate, and water. The washed liquid was dried over anhydrous magnesium sulfate. The residue was concentrated under reduced pressure to yield 0.560 g of a yellow oil. The re sulting oil was chromatographed on a 4O g column of silica gel (Wako Gel C-200). The column ws developed with benzene-ethyl acetate (5:1 v/v). 0.210 g of 1 tert-butoxycarbonyi-5-benzyloxyearbonyl-10-phthalyl- triazadecane was obtained as an oil in a yield of 43.0 %. NMR (CDC13) 6= 1.47 (s,9H), 1.1-2.0 (m,6H), 2.9-3.5 (m,6H), 3.67 (b,2H), 4.4-5.5 (b,lH), 5.12(s,2H), 7.32 (s,5H), 7.75 (m,4H) IR (Neat) v(cm1)= 3370, 2940, 1770, 1715, 1550, 1475, 1420, 1390, 1365, 1250, 1165, 1035, 720, 680 TLC (benzene:ethyl acetate = 5:1 v/v) Rf= 0.2 (silica gel plate) (b) 0.080 g (0.15 mmols) of 10-phthalyl 1-tert-butoxy- carbonyl-5-benzyloxyearbonyl-1,5,10-triazadecane was dissolved in 2 ml of ethanol. 0.063 (1.00 mmols) of 80 % hydrazine hydrate was added to the solution. The mixture was heated overnight under reflux. Crystals that formed as precipitates were removed by filtration. The filtrate was concentrated under reduced pressure. The residue was dissolved in 30 ml of ethyl acetate. The solution was extracted with 30 ml of a 5 % aqueous solution of phosphoric acid. The aqueous layer was washed with ethyl acetate. The washed liquid was adjusted to a pH of more than 10 by addition of sodium carbonate. The mixture was extracted with 50 ml of ethyl acetate. The ethyl acetate layer was washed with a saturated aqueous solution of sodium chloride, and dried over anhydrous sodium sulfate. The residue was concentrated under reduced pressure to obtain 0.030 g of 1-tert-butoxyearbonyl-5-benzyl- oxycarbonyl-1,5,10-triazadecane as an oil. Yield: 54.9 %. NMR (CDC13) 6= 0.8-2.4 (b,8H), 1.43 (s,9H), 2.4-2.9 (b,2H) 2.9-3.5 (m,6H), 4.5-5.6 (b,lH), 5.10 (s,2H), 7.33 (s.5H) IR (Neat) v(cm-1)= 3350, 2930, 1700, 1520, 1475, 1420, 1360, 1250, 1165 TLC (n-propanol:water: 29 % ammoniumhydroxide= 10:1:0.15 v/v RF= 0.6 (alumina plate) Referential Example Synthesis of 10-phthalyl-1 '5, 10-triazadecane dihydrochloride (a) 290 g (2.00 mole) of spermidine was dissolved in 500 ml of water. With the solution being cooled with ice water, 162 g (2.00 mols) of 37 % formalin was added. The reaction system was reacted overnight at room temperature with stirring. The reaction mixture was concentrated under reduced pressure. The residue was distilled in vacuous The dlstillates at boIling points of 90 - 920C/2 mm Hg were collected. 63 g of 1-(4 aminobutyl)hexahydropyrimidine was obtained as trans lucent needles. Yield: 83.8 % Mp: 39 - 420C NMR (CDC13) 6= 1.1-1.9 (m,9H), 2.0-2.4 (m,2H), 2.4-3.0 (m,6Hl, 3.34 (s,2H) IR (KBr) #(cm-1)= 3315, 3265, 3215, 2940, 1620, 1465, 1375, 1300, 1235, 1205, 1155, 1100, 1000 (b) 55.0 g (350 mmols) of 1-(4-aminobutyl)hexahydro pyrimidine was dissolved in 580 ml of dimethyl sulf- oxide. With the solution being cooled, 42.0 g (700 mmols) of glacial acetic acid was added. Then, 92.0 g (420 mmols) of N-ethoxycarbonylphtha'imide was added to the mixture. The reaction system was reacted over night at room temperature with stirring. The reaction mixture was concentrated under reduced pressure by means of a vacuum pump. The residue was dissolved in 200 ml of distilled water. The solution was adjusted to a pH of 1.0 by addition of concentrated hydrochloric acid. Then, the solution was concentrated under reduced presure. The residue was recrystallized from ethanol. 46.9 g of 10-phthalyl-1,5,10-triazadecane dihydrochloride was obtained as pale yellow crystals. Yield: 38.5 % Mp: 244 - 2460C NMR (D20) 6= 1.5-2.0 (b,4H), 2.0-2.5 (m,H), 2.9-3.5 (b,6H), 3.5-3.9 (b,2H), 7.77 (s,4H) IR (KBr) v(cm-l)= 3430, 2930, 1775, 1710, 1465, 1435, 1400, 1380, 1050

Claims: CLAIMS: l. A process for preparing a 1,5-diprotected-1,5-triaza decane of the general formula I H2N-(CH2)4-N-(CH2)3-NH-RI I R2 wherein R1 and R2 are identical or different and each represent an amino-protecting group other than a phthalyl group, which comprises reacting 10-phthalyl 1,5-diprotected-I,5,10-triazadecane of the general formula II EMI18.1 wherein R1 and R2 are as defined above with hydrazine or a hydrazine derivative to eliminate the phthalyl group. 2. A process for preparing a 1,5-diprotected-1,5-triaza decane of the general formula I as defined in claim I which comprises reacting a compound of the formula III EMI18.2 either with a protective group introducing agent to form a compound of the formula II EMI19.1 wherein R1 and R2 are identical, or first with a R2-introducing agent in the presence of a Crown-ether to form a compound of the formula IV EMI19.2 and, after removing the Crown ether, reacting the compound obtained with an R1-introducing agent tq form a compound of the formula II wherein R1 and R2 are different, and reacting the compound obtained with hydrazine or a hydrazine derivative to eliminate the phthalyl group. 3. A process as claimed in claims 1 and 2 wherein R1 and R2 represent aryl-C1-C3-alkoxycarbonyl where the phenyl group is unsubstituted or substituted with halogen, nitro, C1-C3-alkyl or -alkoxy or R1 and R2 represent C1-C6-alkoxyearbonyl. 4. A process as claimed in claims 1 or 2 wherein the phthalyl group is eliminated from a compound of the formula II with hydrazine, hydrazin hydrate, an organic or inorganic salt of hydrazine, a loweralkyl hydrazine or phenylhydrazine. 5. A compound of the general formula II EMI20.1 wherein R1 and R2 are identical or different and re present each an amino-protecting group other than the phthalyl group. 6. The compound as claimed in claim 5 wherein R1 and R2 represent aryl-C1-C3-alkoxycarbonyl where the phenyl is unsubstituted or substituted with halogen, nitro, Cl-C3-alkyl or -alkoxy, or R1 and R2 represent Cl-C6- alkoxy carbonyl. 7. A process for preparing a compound of the formula II as claimed in claim 5 which comprises reacting a com pound of the formula III EMI20.2 either with a protective group introducing agent to form a compound of the formula II EMI20.3 wherein R1 and R2 are identical, or first with a R2-introducing agent in the presence of a Crown ether to form a compound of the formula IV EMI21.1 and, after removing the Crown ether, reacting the compound obtained with an R1 introducing agent to form a compound of the formula II wherein R1 and R2 are different.

Inventors: NAKAMURA, TERUYA, NISHIZAWA, RINZO, SUZUKI, MASAO, TAKEI, YUKIO, TOMIYOSHI, TSUGIO, UMEZAWA, HAMAO, PROF., YOSHIDA, MASAO
Applicants: MICROBIAL CHEMISTRY RESEARCH FOUNDATION
Application year: 1984
Main classification: C07C125
IPC codes: C07D209, C07C67, C07C239, C07C269