CS216574B1 - Method of making the amids of the 18-methylenaspidospermidine - Google Patents
Method of making the amids of the 18-methylenaspidospermidine Download PDFInfo
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- CS216574B1 CS216574B1 CS12681A CS12681A CS216574B1 CS 216574 B1 CS216574 B1 CS 216574B1 CS 12681 A CS12681 A CS 12681A CS 12681 A CS12681 A CS 12681A CS 216574 B1 CS216574 B1 CS 216574B1
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- Czechoslovakia
- Prior art keywords
- methylenaspidospermidine
- mmol
- iii
- formula
- amids
- Prior art date
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- 238000004519 manufacturing process Methods 0.000 title description 3
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 15
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 claims description 12
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 9
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 8
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 6
- 238000000034 method Methods 0.000 claims description 6
- 150000004945 aromatic hydrocarbons Chemical class 0.000 claims description 4
- 150000008280 chlorinated hydrocarbons Chemical class 0.000 claims description 4
- 150000001805 chlorine compounds Chemical class 0.000 claims description 4
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 4
- 235000011181 potassium carbonates Nutrition 0.000 claims description 4
- BVKZGUZCCUSVTD-UHFFFAOYSA-M Bicarbonate Chemical compound OC([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-M 0.000 claims description 3
- 239000002253 acid Substances 0.000 claims description 3
- 239000007864 aqueous solution Substances 0.000 claims description 3
- 125000001995 cyclobutyl group Chemical group [H]C1([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 claims description 3
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 claims description 3
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 3
- 235000015497 potassium bicarbonate Nutrition 0.000 claims description 3
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 claims description 2
- 150000001408 amides Chemical class 0.000 claims description 2
- 238000002360 preparation method Methods 0.000 claims description 2
- 235000015424 sodium Nutrition 0.000 claims description 2
- CDBYLPFSWZWCQE-UHFFFAOYSA-L sodium carbonate Substances [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 2
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 6
- 239000000203 mixture Substances 0.000 description 4
- 239000000243 solution Substances 0.000 description 4
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- 238000003756 stirring Methods 0.000 description 3
- 125000000217 alkyl group Chemical group 0.000 description 2
- 239000012455 biphasic mixture Substances 0.000 description 2
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- 238000001035 drying Methods 0.000 description 2
- 238000001704 evaporation Methods 0.000 description 2
- 230000008020 evaporation Effects 0.000 description 2
- 239000000543 intermediate Substances 0.000 description 2
- 239000012074 organic phase Substances 0.000 description 2
- 239000012071 phase Substances 0.000 description 2
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 1
- UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical compound [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 description 1
- XYQRXRFVKUPBQN-UHFFFAOYSA-L Sodium carbonate decahydrate Chemical compound O.O.O.O.O.O.O.O.O.O.[Na+].[Na+].[O-]C([O-])=O XYQRXRFVKUPBQN-UHFFFAOYSA-L 0.000 description 1
- WETWJCDKMRHUPV-UHFFFAOYSA-N acetyl chloride Chemical compound CC(Cl)=O WETWJCDKMRHUPV-UHFFFAOYSA-N 0.000 description 1
- 239000012346 acetyl chloride Substances 0.000 description 1
- 230000010933 acylation Effects 0.000 description 1
- 238000005917 acylation reaction Methods 0.000 description 1
- 229910000288 alkali metal carbonate Inorganic materials 0.000 description 1
- 150000008041 alkali metal carbonates Chemical class 0.000 description 1
- PASDCCFISLVPSO-UHFFFAOYSA-N benzoyl chloride Chemical compound ClC(=O)C1=CC=CC=C1 PASDCCFISLVPSO-UHFFFAOYSA-N 0.000 description 1
- 239000012267 brine Substances 0.000 description 1
- 229910052799 carbon Inorganic materials 0.000 description 1
- 125000004432 carbon atom Chemical group C* 0.000 description 1
- -1 carbon ethers Chemical class 0.000 description 1
- 150000001875 compounds Chemical class 0.000 description 1
- JFWMYCVMQSLLOO-UHFFFAOYSA-N cyclobutanecarbonyl chloride Chemical compound ClC(=O)C1CCC1 JFWMYCVMQSLLOO-UHFFFAOYSA-N 0.000 description 1
- 150000007530 organic bases Chemical class 0.000 description 1
- 229910000028 potassium bicarbonate Inorganic materials 0.000 description 1
- 239000011736 potassium bicarbonate Substances 0.000 description 1
- TYJJADVDDVDEDZ-UHFFFAOYSA-M potassium hydrogencarbonate Chemical compound [K+].OC([O-])=O TYJJADVDDVDEDZ-UHFFFAOYSA-M 0.000 description 1
- 229940018038 sodium carbonate decahydrate Drugs 0.000 description 1
- 229910052938 sodium sulfate Inorganic materials 0.000 description 1
- 235000011152 sodium sulphate Nutrition 0.000 description 1
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 1
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- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Saccharide Compounds (AREA)
Description
Amidy 18-methj vzorce I,18-Methylamides of formula I,
ve kterém R značí spidospermidinu obecného (I) alkyl s 1 až 3 atomy uhlíku, nebo skupinu cyklopropylovou, cyklobutylovou, cyklopentylovou nebo fenylovou, jsou meziprodukty výroby léčiv. Vyrábějí se acylacíwherein R is spidospermidine of general (I) alkyl having 1 to 3 carbon atoms, or a cyclopropyl, cyclobutyl, cyclopentyl or phenyl group, are intermediates in the manufacture of medicaments. They are made by acylation
chloridy kyselin obecného vzorce III, ve kterém R má shora uvedený význam, ve dvoufázovém systému chlorovaného nebo aromatického uhlovodíku a vodného roztoku uhličitanu nebo hydrogenuhličitanu alkalického kovu.acid chlorides of the formula III, in which R is as defined above, in a two-phase system of a chlorinated or aromatic hydrocarbon and an aqueous solution of an alkali metal carbonate or bicarbonate.
(51) Int Cl.’(51) Int Cl. '
C 07 D 209/56, // C 07 D 227/04 způsobu výroby amidů 18-methylenaapidospermidinu obecného vzorce I,C 07 D 209/56, // C 07 D 227/04 for a process for the preparation of 18-methylenaapidospermidine amides of the general formula I,
Vynýlez se týk rInvention related to r
(I) ve kterém R značí alkylovou skupinu a 1 až 3 etomy uhlíku, nebo skupinu cyklopropylovou, cyklo butylovou, cyklopentylovou nebo fenylovou.(I) wherein R represents an alkyl group and 1 to 3 carbon ethers, or a cyclopropyl, cyclobutyl, cyclopentyl or phenyl group.
Sloučeniny vzorce I jsou vesměs známy a jsou meziprodukty výroby léčiv.The compounds of formula I are generally known and are intermediates in the manufacture of medicaments.
Podle známého způsobu (Hájíček J., Trojánek J.: Cel. autorské osvědčení č. 214 361) se vyrábí tak, že se 18-methylenaspidosperimidin acyluje aoylchloridy v bezvodých podmínkách v přítomnosti terč. organické base. Cílem vynálezu je vypracování postupu, který při dosahování srovnatelných výtěžků dovoluje technologicky mnohem schůdnější práci ve vodném prostředí.According to a known method (Hajicek J., Trojanek J .: Cel. Autor certificate No. 214 361) it is produced by acylating 18-methylenaspidosperimidine with aoyl chlorides under anhydrous conditions in the presence of targets. organic base. It is an object of the present invention to provide a process which, in achieving comparable yields, allows a more technologically feasible work in an aqueous environment.
Podstata vynélezu spočívá v tom, že se 18-methylenaspidospermidin vzorce II (Čel. autorské osvědčení č. 214 361) ; e acyluje chloridy kyselin obecného vzorce UlilThe essence of the invention is that 18-methylenaspidospermidine of formula II (Art. No. 214 361); e) acylates the acid chlorides of the general formula (Ulil)
R - CO - Cl (II) (III) ve kterém R má shora uvedený význam,ve dvoufázovém systému chlorovaného nebo aromatického uhlovodíku a vodného roztoku uhličitanu nebo hydrogenuhličitanu sodného nebo draselného při teplotě 0 °C až 25 °C.R-CO-Cl (II) (III) wherein R is as defined above, in a two-phase system of a chlorinated or aromatic hydrocarbon and an aqueous solution of sodium or potassium carbonate or bicarbonate at a temperature of 0 ° C to 25 ° C.
Jako chlorovaného uhlovodíku se použije výhodně methylenchloridu nebo chloroformu, jak aromatického uhlovodíku např. benzenu nebo toluenu.The chlorinated hydrocarbon used is preferably methylene chloride or chloroform, such as an aromatic hydrocarbon such as benzene or toluene.
Následující pžíklsdy ilustrují, avšak nikterak neomezují obecnost způsobu podle vynálezu. Příklady provedení Příklad 1The following examples illustrate but do not limit the generality of the process of the invention. EXAMPLES Example 1
K roztoku 1,51 g (5,13 mmol) 18-methylenaspidospermidinu (II) v 50 ml methylenchloridu se přidá 40 ml vody θ 3,11 g (22,5 mmol) uhličitanu draselného. Dvoufázová směs se ochladí na 6 °C a za míchání se během 10 minut přikape roztok 0,89 ml (12,5 mmol) acetylchloridu (III:To a solution of 1.51 g (5.13 mmol) of 18-methylenaspidospermidine (II) in 50 ml of methylene chloride is added 40 ml of water θ 3.11 g (22.5 mmol) of potassium carbonate. The biphasic mixture is cooled to 6 ° C and a solution of 0.89 ml (12.5 mmol) of acetyl chloride (III) is added dropwise with stirring over 10 minutes:
R = CH^) v 5 ml methylenchloridu. Směs se míchá při 20 °C 1 h a organická fáze se oddělí, promyje 20 ml vody, 20 ml solanky a po vysušení síranem sodným se odpaří ve vakuu vodní vývěvy. Dokonalým odpařením ve vakuu olejové vývěvy se získá 1,72 g (99,8 %) sklovitého l-scetyl-18-methylenaspidospermidinu (IíR^H^).R = CH3) in 5 ml of methylene chloride. The mixture was stirred at 20 ° C for 1 h and the organic phase was separated, washed with 20 ml of water, 20 ml of brine and, after drying over sodium sulfate, evaporated in a water pump vacuum. Complete evaporation in an oil pump vacuum gave 1.72 g (99.8%) of glassy 1-scethyl-18-methylenaspidospermidine (1R, 4H).
Příklad 2Example 2
Ke dvoufázové směsi 2,94 g (10 mmol) 18-methylenaspidospermidinu (ΙΓ), 3,36 g (40 mmol) hydrogenuhličitanu sodného, 120 ml toluenu a 60 ml vody se přikape 1,54 g (13 mmol) cyklobutankarbonylchloridu (III:R = ^Hg-CCHgjg -GR·) za míchání během 15 minut při teplotě 10 °C.To a biphasic mixture of 2.94 g (10 mmol) of 18-methylenaspidospermidine (ΙΓ), 3.36 g (40 mmol) of sodium bicarbonate, 120 ml of toluene and 60 ml of water was added dropwise 1.54 g (13 mmol) of cyclobutanecarbonyl chloride (III: With stirring for 15 minutes at 10 ° C.
Směs se míchá ještě 2 h při teplotě místnosti s zpracuje postupem dle příkladu 1. Získá seThe mixture was stirred for another 2 h at room temperature and worked up as in Example 1. It was obtained
3,70 g sklovitého l-cyklobutankerbonyl-ie-methylenaspidoapermidinu (I:R = CHo-(CHo).s-CH-), což3.70 g of L-glassy cyklobutankerbonyl-IE-methylenaspidoapermidinu (I: R = CH a - (CH o) s-CH) which
I 2 2 2 I odpovídá 98,3 % teorie.I 2 2 2 I corresponds to 98.3% of theory.
Příklad 3Example 3
Postupem podle příkladu 1 a tím, že místo karbonátu draselného a methylenchloridu se použije hydrogenuhllčitanu draselného a chloroformu, se získá 99,1 % l-butanoyl-18-methylenaspidospermidinu (I: R - CHg-CHgCÍPj).Following the procedure of Example 1, and using potassium bicarbonate and chloroform instead of potassium carbonate and methylene chloride, 99.1% of 1-butanoyl-18-methylenaspidospermidine (I: R-CH2-CH2Cl3) was obtained.
Příklad 4Example 4
Ke směsi 2,35 g (8 mmol) 18-methylenaspidospermidinu (II), 7,15 g (25 mmol) dekahydrátu uhličitanu sodného, 100 ml benzenu a 7U ml vody se přikape během 10 minut za míchání 1,69 g (12 mmol) benzoylchloridu (III: R = CgH^) P^i teplotě 25 °C. Směs se dále míchá při této teplotě lha organická fáze se oddělí. Benzenový roztok ae promyje 20 ml 1% roztoku hydroxidu sodného, 20 ml vody a po vysušení se odpaří na rotační vakuové odparce. Dokonalým odpařením ve vakuu olejové vývěvy se získá (98,8 %) 3,15 g sklovitého l-benzoyl-18-methylenaspidospermidinu (I: R = CgHj).To a mixture of 2.35 g (8 mmol) of 18-methylenaspidospermidinu (II), 7.15 g (25 mmol) of sodium carbonate decahydrate, 100 ml of benzene and 7 U mL water was added dropwise over 10 minutes with stirring 1.69 g (12 mmol) of benzoyl chloride (III: R = C 8 H 4) at 25 ° C. The mixture is further stirred at this temperature and the organic phase is separated. The benzene solution is washed with 20 ml of 1% sodium hydroxide solution, 20 ml of water and, after drying, evaporated on a rotary evaporator. Perfect evaporation in an oil pump vacuum gave (98.8%) 3.15 g of glassy 1-benzoyl-18-methylenaspidospermidine (I: R = C 8 H 3).
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Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CS12681A CS216574B1 (en) | 1981-01-07 | 1981-01-07 | Method of making the amids of the 18-methylenaspidospermidine |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CS12681A CS216574B1 (en) | 1981-01-07 | 1981-01-07 | Method of making the amids of the 18-methylenaspidospermidine |
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| Publication Number | Publication Date |
|---|---|
| CS216574B1 true CS216574B1 (en) | 1982-11-26 |
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| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CS12681A CS216574B1 (en) | 1981-01-07 | 1981-01-07 | Method of making the amids of the 18-methylenaspidospermidine |
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| CS (1) | CS216574B1 (en) |
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1981
- 1981-01-07 CS CS12681A patent/CS216574B1/en unknown
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