RU2395488C1 - Method of producing pharmaceutically acceptable dec-glaucine salts - Google Patents
Method of producing pharmaceutically acceptable dec-glaucine salts Download PDFInfo
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- RU2395488C1 RU2395488C1 RU2008149899/04A RU2008149899A RU2395488C1 RU 2395488 C1 RU2395488 C1 RU 2395488C1 RU 2008149899/04 A RU2008149899/04 A RU 2008149899/04A RU 2008149899 A RU2008149899 A RU 2008149899A RU 2395488 C1 RU2395488 C1 RU 2395488C1
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- Prior art keywords
- glaucine
- pharmaceutically acceptable
- water
- dec
- salts
- Prior art date
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- 238000000034 method Methods 0.000 title claims abstract description 13
- 229940113086 glaucine Drugs 0.000 claims abstract description 11
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 11
- RUZIUYOSRDWYQF-HNNXBMFYSA-N (S)-glaucine Chemical class CN1CCC2=CC(OC)=C(OC)C3=C2[C@@H]1CC1=C3C=C(OC)C(OC)=C1 RUZIUYOSRDWYQF-HNNXBMFYSA-N 0.000 claims abstract description 8
- 150000003839 salts Chemical class 0.000 claims abstract description 5
- DABPOQZSGVNAAS-UHFFFAOYSA-N Glaucocalactone Natural products O=CC12C3C(C4)OC(=O)C2C(C)(C)CCC1OC(=O)C13CC4C(=C)C1OC(=O)C DABPOQZSGVNAAS-UHFFFAOYSA-N 0.000 claims description 4
- 229930004041 glaucine Natural products 0.000 claims description 4
- 230000003993 interaction Effects 0.000 claims 3
- 238000006243 chemical reaction Methods 0.000 abstract description 2
- 239000000126 substance Substances 0.000 abstract 1
- LZJRNLRASBVRRX-ZDUSSCGKSA-N Boldine Chemical compound CN1CCC2=CC(O)=C(OC)C3=C2[C@@H]1CC1=C3C=C(OC)C(O)=C1 LZJRNLRASBVRRX-ZDUSSCGKSA-N 0.000 description 2
- 239000012298 atmosphere Substances 0.000 description 2
- 239000003153 chemical reaction reagent Substances 0.000 description 2
- 231100000331 toxic Toxicity 0.000 description 2
- 230000002588 toxic effect Effects 0.000 description 2
- QAEDZJGFFMLHHQ-UHFFFAOYSA-N trifluoroacetic anhydride Chemical compound FC(F)(F)C(=O)OC(=O)C(F)(F)F QAEDZJGFFMLHHQ-UHFFFAOYSA-N 0.000 description 2
- KYVJVURXKAZJRK-UHFFFAOYSA-N (+)-laurolitsine Natural products N1CCC2=CC(O)=C(OC)C3=C2C1CC1=C3C=C(OC)C(O)=C1 KYVJVURXKAZJRK-UHFFFAOYSA-N 0.000 description 1
- KRMYOICRUJJKEZ-RSAXXLAASA-N (6as)-1,2,9,10-tetramethoxy-6-methyl-5,6,6a,7-tetrahydro-4h-dibenzo[de,g]quinoline;hydrochloride Chemical compound [Cl-].C[NH+]1CCC2=CC(OC)=C(OC)C3=C2[C@@H]1CC1=C3C=C(OC)C(OC)=C1 KRMYOICRUJJKEZ-RSAXXLAASA-N 0.000 description 1
- XVMSFILGAMDHEY-UHFFFAOYSA-N 6-(4-aminophenyl)sulfonylpyridin-3-amine Chemical compound C1=CC(N)=CC=C1S(=O)(=O)C1=CC=C(N)C=N1 XVMSFILGAMDHEY-UHFFFAOYSA-N 0.000 description 1
- 229910019142 PO4 Inorganic materials 0.000 description 1
- 230000000954 anitussive effect Effects 0.000 description 1
- 239000012300 argon atmosphere Substances 0.000 description 1
- KCXMKQUNVWSEMD-UHFFFAOYSA-N benzyl chloride Chemical compound ClCC1=CC=CC=C1 KCXMKQUNVWSEMD-UHFFFAOYSA-N 0.000 description 1
- 229940073608 benzyl chloride Drugs 0.000 description 1
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 1
- MHVCSDLBQKSFQV-HNNXBMFYSA-N boldine Natural products COc1cc2c(C[C@@H]3N(C)CCc4cc(C)c(OC)c2c34)cc1O MHVCSDLBQKSFQV-HNNXBMFYSA-N 0.000 description 1
- LZJRNLRASBVRRX-UHFFFAOYSA-N boldine trifluoroacetic acid salt Natural products CN1CCC2=CC(O)=C(OC)C3=C2C1CC1=C3C=C(OC)C(O)=C1 LZJRNLRASBVRRX-UHFFFAOYSA-N 0.000 description 1
- 150000003842 bromide salts Chemical class 0.000 description 1
- 239000003054 catalyst Substances 0.000 description 1
- 150000001805 chlorine compounds Chemical class 0.000 description 1
- 150000001860 citric acid derivatives Chemical class 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 239000013078 crystal Substances 0.000 description 1
- 230000001747 exhibiting effect Effects 0.000 description 1
- 230000007062 hydrolysis Effects 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- 239000012535 impurity Substances 0.000 description 1
- 238000002329 infrared spectrum Methods 0.000 description 1
- 238000006317 isomerization reaction Methods 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 229930015710 phenanthrene alkaloid Natural products 0.000 description 1
- 125000001792 phenanthrenyl group Chemical class C1(=CC=CC=2C3=CC=CC=C3C=CC12)* 0.000 description 1
- 235000021317 phosphate Nutrition 0.000 description 1
- 150000003013 phosphoric acid derivatives Chemical class 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- 238000002360 preparation method Methods 0.000 description 1
- 238000000425 proton nuclear magnetic resonance spectrum Methods 0.000 description 1
- 125000004044 trifluoroacetyl group Chemical group FC(C(=O)*)(F)F 0.000 description 1
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- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
Description
Изобретение относится к способам получения фенантреновых алкалоидов, а именно, к получению фармацевтически приемлемых солей (хлоридов, бромидов, фосфатов, цитратов и др.) 1-[2-(N-метиламиноэтил)]-3,4,6,7-тетраметоксифенантрена, то есть солей дес-глауцина (secoglaucine), формулы IThe invention relates to methods for producing phenanthrene alkaloids, namely to the preparation of pharmaceutically acceptable salts (chlorides, bromides, phosphates, citrates, etc.) of 1- [2- (N-methylaminoethyl)] - 3,4,6,7-tetramethoxyphenanthrene, that is, salts of des-glaucine (secoglaucine), formula I
проявляющего противокашлевую активность.exhibiting antitussive activity.
Известен способ получения бензил дес-глауцина, из болдина, действием на него хлористым бензилом в среде ДМФА (патент США №5594033, С07С 213/02, 1997 г.).A known method of producing benzyl des-glaucine, from boldine, by acting on it with benzyl chloride in DMF medium (US patent No. 5594033, С07С 213/02, 1997).
Недостатком способа является длительность процесса и необходимость использования органического растворителя и катализатора.The disadvantage of this method is the length of the process and the need to use an organic solvent and catalyst.
Наиболее близким по выполнению является способ получения трифторацетильного производного дес-глауцина (I) 1-[2-(N-метил-N-трифторацетиламиноэтил)]-3,4,6,7-тетраметоксифенантрена, (J.L.Castro et al., J.Org.Chem., 1987, 52, 3579-3584), действием на глауцин ангидрида трифторуксусной кислоты в пиридине в атмосфере аргона. Последующим гидролизом может быть получен дес-глауцин.The closest to the implementation is a method of producing a trifluoroacetyl derivative of des-glaucine (I) 1- [2- (N-methyl-N-trifluoroacetylaminoethyl)] - 3,4,6,7-tetramethoxyphenanthrene, (JLCastro et al., J. Org.Chem., 1987, 52, 3579-3584), the action of glaucin with trifluoroacetic anhydride in pyridine in an argon atmosphere. Subsequent hydrolysis can be obtained des-glaucine.
Недостатком способа является необходимость использования высокотоксичных реагентов, инертной атмосферы и сложного оборудования.The disadvantage of this method is the need to use highly toxic reagents, inert atmosphere and sophisticated equipment.
Техническим результатом является упрощение процесса за счет отсутствия необходимости использования токсичных органических реагентов, инертной атмосферы и сложного оборудования.The technical result is to simplify the process due to the absence of the need to use toxic organic reagents, inert atmosphere and sophisticated equipment.
Технический результат достигается тем, что глауцин изомеризуют водой в герметических условиях при температуре 200-300°С, то есть в субкритической воде (при температуре выше 100°С). Компоненты могут быть взяты в соотношении соответственно 1:1-1000 частей, предпочтительно 1:10-150 частейThe technical result is achieved by the fact that glaucine isomerized with water under sealed conditions at a temperature of 200-300 ° C, that is, in subcritical water (at a temperature above 100 ° C). The components can be taken in a ratio of 1: 1-1000 parts, preferably 1: 10-150 parts, respectively
Изобретение обладает изобретательским уровнем, так как не известно проведение изомеризации, в том числе превращение глауцина в дес-глауцин (изомерную форму), в среде субкритической воды.The invention has an inventive step, since it is not known to carry out isomerization, including the conversion of glaucine to des-glaucine (isomeric form), in subcritical water.
Ниже приведен пример получения гидрохлорида дес-глауцина (secoglaucine).The following is an example of producing des-glaucine hydrochloride (secoglaucine).
Пример.Example.
Раствор 0,3 г (0,001 моля) гидрохлорида глауцина в 6 мл (0,33 моля) воды нагревают в реакторе объемом 10 см3 в течение 2 часов при температуре 250°С. Теплый раствор отфильтровывают от механических примесей. Образовавшийся после охлаждения кристаллический осадок отфильтровывают и промывают. Выход зеленых кристаллов составляет 53% (0,16 г). Т.пл. 136-137°С.A solution of 0.3 g (0.001 mol) of glaucine hydrochloride in 6 ml (0.33 mol) of water is heated in a 10 cm 3 reactor for 2 hours at a temperature of 250 ° C. The warm solution is filtered off from mechanical impurities. The crystalline precipitate formed after cooling is filtered off and washed. The yield of green crystals is 53% (0.16 g). Mp 136-137 ° C.
Спектр ЯМР 1Н (CDCl3, δ, м.д.): 3,53 (м., 4Н, 2СН2), 3,82 (с, 12Н, 6OСН3), 4,80 (д, 3Н, 3СН2), 6,80-7,30 (6Н, аром). 9,53 (кв., 2Н, NH2) 1 H NMR spectrum (CDCl 3 , δ, ppm): 3.53 (m, 4H, 2CH 2 ), 3.82 (s, 12H, 6CH 3 ), 4.80 (d, 3H, 3CH 2 ), 6.80-7.30 (6H, arom). 9.53 (q, 2H, NH 2 )
ИК-спектр, см-1: 1150, 1590, 1600.IR spectrum, cm -1 : 1150, 1590, 1600.
Найдено, %: С 77,10, Н 5,79. Брутто-формула C21H26O4N. Вычислено, %: С 76,98, H 6,1Found,%: C 77.10, H 5.79. Gross formula C 21 H 26 O 4 N. Calculated,%: C 76.98, H 6.1
Аналогичные результаты получают при использовании соотношений глауцин:вода 1:1, 1:10, 1:150, 1:1000 частей и температуре 200°С и 300°С.Similar results are obtained using the ratios of glaucine: water 1: 1, 1:10, 1: 150, 1: 1000 parts and a temperature of 200 ° C and 300 ° C.
Claims (3)
заключающийся в том, что фармацевтически приемлемую соль глауцина вводят во взаимодействие с водой при температуре 200-300°С в герметических условиях.1. The method of obtaining pharmaceutically acceptable salts of 1- [2- (N-methylaminoethyl)] - 3,4,6,7-tetramethoxyphenanthrene (des-glaucine) of the formula I
consisting in the fact that a pharmaceutically acceptable salt of glaucine is introduced into interaction with water at a temperature of 200-300 ° C in sealed conditions.
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| RU2008149899/04A RU2395488C1 (en) | 2008-12-18 | 2008-12-18 | Method of producing pharmaceutically acceptable dec-glaucine salts |
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| RU2008149899/04A RU2395488C1 (en) | 2008-12-18 | 2008-12-18 | Method of producing pharmaceutically acceptable dec-glaucine salts |
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| Publication Number | Publication Date |
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| RU2395488C1 true RU2395488C1 (en) | 2010-07-27 |
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| Application Number | Title | Priority Date | Filing Date |
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| RU2008149899/04A RU2395488C1 (en) | 2008-12-18 | 2008-12-18 | Method of producing pharmaceutically acceptable dec-glaucine salts |
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Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5594033A (en) * | 1993-08-13 | 1997-01-14 | National Science Council | Secoaporphine compound on arrhythmia |
-
2008
- 2008-12-18 RU RU2008149899/04A patent/RU2395488C1/en not_active IP Right Cessation
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5594033A (en) * | 1993-08-13 | 1997-01-14 | National Science Council | Secoaporphine compound on arrhythmia |
Non-Patent Citations (1)
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Effective date: 20161219 |