Method of preparing hellebrigenic derivatives or their salts

专利摘要:

公开号:SU795487A3
申请号:SU782701599
申请日:1978-12-25
公开日:1981-01-07
发明作者:Изаац Отто；Поссельт Клаус；Утеманн Хорст；Тимер Клаус
申请人:Дегусса (Фирма)；
IPC主号:

专利说明:

The invention relates to a method for producing gellebrigenin derivatives of the general formula not described in the literature
where R 2 is alkyl with 1-4 carbon atoms ⁴ , unsubstituted or substituted with a methoxy group, alkenyl with 3-6 carbon atoms or an R ^ R ₂ N - group. a piperidine ring unsubstituted or substituted with a hydroxyl group, or a morpholine ring unsubstituted or substituted with one or two methyl groups; n = 1 or 2, or their salts with pharmacological activity.
A known method of producing esters. amino acids, namely, that the halogen-substituted carboxylic acid ester is reacted with an amine [1].
Using the well-known reaction ’allows you to get new pharmacologically active derivatives of gelle.brigenin of the formula их or their salts.
The purpose of the invention is the preparation of new pharmacologically active derivatives of gellebrigenin of formula 1 or their salts.
A method is proposed, which consists in the fact that the connection of the common formula
where η has the above meanings; 20 Hal is a halogen, is reacted with a compound of the general formula) in) r ₄ r ₂ nh, where and R2 have the above meanings, at 50-200 ° C followed by 25 isolation of the target product in free form or in the form of a salt.
The process is carried out in a solvent (acetone, aromatic hydrocarbon, alcohol or dimethylformamide) or without it, if necessary, use
795487 '’substances that bind acid, such as soda, potash, etc.
Example! .. Gellebrigenin-3 p chloroacetate.
g (0.048 mol) of gellebrigenin is boiled in 300 ml of methylene chloride and 20 ml of chloroacetyl chloride for 2 hours. The resulting reaction product (22 g) was recrystallized from 900 ml of methanol with the addition of activated carbon.
Yield 16 g; so pl. 197-198 ° C.
PRI me R 2. Gellebrigenin-3 β> (3-chloropropionate).
g (0.024 mol) of gellebrigenin is boiled in 190 mp of methylene chloride and 10 ml of P-chloropropionyl chloride for. 3 hours. The resulting reaction product (10 g) was recrystallized from 200 ml of methanol with the addition of activated carbon.
Yield 8 g; so pl. 168-169 ° C.
Example Z. Gellebrigenin-3 / ’” - diallylaminoacetate.
g (0.004 mol) of 3-chloroacetylglelebrigenin is boiled in 20 ml of acetone with 20 ml of diallylamine for 2 hours. After cooling, it is filtered off from diallylamine hydrochloride, the solvent is distilled off and the remaining reaction product is treated with 100 ml of water and recrystallized from isopropanol, mp. 189 ° C.
Getting hydrochloride.
2.4 g of the base are neutralized in ml of ethanol with hydrochloric acid, ether is added and left overnight. Precipitated 2.2 g of hydrochloride, which is recrystallized from ml of ethanol with the addition of 50 ml of ether. Yield 1.2 g; so pl. 23.0-231 ° C.
PRI me R 4. Gellebrigenin-3p> - [(i-methyl-2,2-dimethoxyethylamino) acetate].
4.5 g (0.009 mol) of 3-chloroacetylglelebrigenin is boiled in 70 ml of acetone with 1.3 mp (0.01 mol) of methylaminoacetaldehyde dimethyl acetal and 4.5 ml of triethylamine for 3 h. It is left overnight, filtered, the solvent is distilled off, the precipitate is treated with ether and then stirred with 150 ml of water for 1 hour. Obtain 2.5 g of a substance that crystallizes with 1 mole of water, and recrystallized twice from 40 ml of 50% methanol with the addition of activated carbon. Yield 1.2 g, ’mp. 174-17b ° C.
PRI me R 5. Gellebrigenin-3β> ~ - (2,6-dimethylmorpholinoacetate).
2.5 g '0.005 mol) of 3-chloroacetylgollebrygain is boiled in 25 ml of acetone and 5 ml of 2,6-dimethylmorpholine for 2 hours. The solvent is distilled off and the residue is stirred with 200 ml of water for 1 hour. 2 g of material are obtained, which after recrystallization from isopropanol melts at 196-198 ° C. Getting hydrochloride.
g of the base are dissolved in acetone, neutralized with hydrochloric acid, hydrochloride (2 g) is precipitated by adding 30 ml of ether and recrystallized from 30 ml of ethanol.
Yield 1 g; so pl. hydrochloride 178-180 ° C.
PRI me R 6. Gellebrigenin-3r> 44-hydroxypiperidinoacetate).
2.5 g (0.005 mol) of 3-chloroacetylglelebrigenin is boiled in 40 ml of acetone with 2 g of 4-hydroxypiperidine for 1 hour. After cooling, the mixture is filtered, the solvent is distilled off and the residue is stirred with 200 ml of water for 2 hours. To completely precipitate the base, the aqueous suspension is saturated with sodium chloride. 1.8 g of substance are obtained, which after recrystallization melts from isopropanol at 219-220 ° C.
The hydrochloride is obtained analogously to example 3.1.4 g of the hydrochloride are recrystallized from mi <1 and methanol ethanol (.2: 1) with the addition of 20 ml of ether. Yield 1 g; so pl. hydrochloride 126-127 ° C.
PRI me R 7. Gellebrigenin-3β ChZ-diethylaminopropionate).
g (0.0039 mol) of 3- (3-chloropropy “onyl) -gellebrigenin is boiled in 20 ml of acetone with 20 ml of diethylamine for 2 hours and treated, 'as in Example 3. The resulting reaction product (1.8 g) recrystallized from ethanol, so pl. base 192 ° C, mp hydrochloride 206 ° C.
The compounds of formula 1 have a positive inotropic effect, improving the contractility of the heart. They also cause brady cardia, while the heart rate decreases to 30%, which leads to normalization of the increased heart rate in case of heart failure.

权利要求:
Claims (1)
[1]
1. Vaygand-Hilgetag. Experimental methods in organic chemistry. M., Himi, 1968, p. 425.

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同族专利:

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DD133151A5|1978-12-13|

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PL203030A1|1979-03-26|

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DE2755122C2|1983-06-30|

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HU176767B|1981-05-28|

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IT1113251B|1986-01-20|

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CH639107A5|1983-10-31|

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FI58135B|1980-08-29|

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FR2374336A1|1978-07-13|

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ATA903877A|1983-02-15|

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SU751328A3|1980-07-23|

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PL110178B1|1980-07-31|

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AT372391B|1983-09-26|

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FI58135C|1980-12-10|

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JPS5395956A|1978-08-22|

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JPS591279B2|1984-01-11|

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BE861968A|1978-06-16|

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ES465136A1|1979-01-01|

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ZA777494B|1979-02-28|

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FI773814A|1978-06-18|

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FR2374336B1|1980-11-07|

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DE2755122A1|1978-06-22|

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GB1577633A|1980-10-29|

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ES465135A1|1978-10-01|

引用文献:

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WO2010102673A1|2009-03-13|2010-09-16|Unibioscreen S.A.|Hellebrin and hellebrigenin derivatives|

法律状态:

优先权:

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申请号 | 申请日 | 专利标题

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GB52759/76A|GB1577633A|1976-12-17|1976-12-17|Acyl derivatives of hellebrigenin|

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