CH329208A - Process for the preparation of esters of (-) - 3-hydroxy-morphinans - Google Patents
Process for the preparation of esters of (-) - 3-hydroxy-morphinansInfo
- Publication number
- CH329208A CH329208A CH329208DA CH329208A CH 329208 A CH329208 A CH 329208A CH 329208D A CH329208D A CH 329208DA CH 329208 A CH329208 A CH 329208A
- Authority
- CH
- Switzerland
- Prior art keywords
- sep
- hydroxy
- esters
- morphinans
- morphinan
- Prior art date
Links
- 238000000034 method Methods 0.000 title claims description 7
- IYNWSQDZXMGGGI-NUEKZKHPSA-N 3-hydroxymorphinan Chemical class C1CCC[C@H]2[C@H]3CC4=CC=C(O)C=C4[C@]21CCN3 IYNWSQDZXMGGGI-NUEKZKHPSA-N 0.000 title description 4
- 150000002148 esters Chemical class 0.000 title description 3
- 238000002360 preparation method Methods 0.000 title description 2
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 claims description 6
- 229920006395 saturated elastomer Polymers 0.000 claims description 3
- 239000002253 acid Substances 0.000 claims description 2
- 150000008065 acid anhydrides Chemical class 0.000 claims description 2
- 125000004432 carbon atom Chemical group C* 0.000 claims description 2
- 150000004820 halides Chemical class 0.000 claims description 2
- 239000003795 chemical substances by application Substances 0.000 claims 2
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 6
- 150000001875 compounds Chemical class 0.000 description 6
- 238000002844 melting Methods 0.000 description 5
- 230000008018 melting Effects 0.000 description 5
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 3
- OZYUPQUCAUTOBP-QXAKKESOSA-N Levallorphan Chemical compound C([C@H]12)CCC[C@@]11CCN(CC=C)[C@@H]2CC2=CC=C(O)C=C21 OZYUPQUCAUTOBP-QXAKKESOSA-N 0.000 description 3
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 2
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 2
- 238000009835 boiling Methods 0.000 description 2
- 229940079593 drug Drugs 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 239000000446 fuel Substances 0.000 description 2
- 239000000155 melt Substances 0.000 description 2
- BQJCRHHNABKAKU-KBQPJGBKSA-N morphine Chemical compound O([C@H]1[C@H](C=C[C@H]23)O)C4=C5[C@@]12CCN(C)[C@@H]3CC5=CC=C4O BQJCRHHNABKAKU-KBQPJGBKSA-N 0.000 description 2
- 229960005181 morphine Drugs 0.000 description 2
- 229910052757 nitrogen Inorganic materials 0.000 description 2
- 239000011734 sodium Substances 0.000 description 2
- DKPFZGUDAPQIHT-UHFFFAOYSA-N Butyl acetate Natural products CCCCOC(C)=O DKPFZGUDAPQIHT-UHFFFAOYSA-N 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 1
- CPELXLSAUQHCOX-UHFFFAOYSA-N Hydrogen bromide Chemical compound Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 description 1
- 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 description 1
- 208000004880 Polyuria Diseases 0.000 description 1
- 125000004429 atom Chemical group 0.000 description 1
- PASDCCFISLVPSO-UHFFFAOYSA-N benzoyl chloride Chemical compound ClC(=O)C1=CC=CC=C1 PASDCCFISLVPSO-UHFFFAOYSA-N 0.000 description 1
- 125000003236 benzoyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C(*)=O 0.000 description 1
- 230000004071 biological effect Effects 0.000 description 1
- 238000009903 catalytic hydrogenation reaction Methods 0.000 description 1
- 238000006243 chemical reaction Methods 0.000 description 1
- 230000035619 diuresis Effects 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- FUZZWVXGSFPDMH-UHFFFAOYSA-N hexanoic acid Chemical compound CCCCCC(O)=O FUZZWVXGSFPDMH-UHFFFAOYSA-N 0.000 description 1
- 239000005457 ice water Substances 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 125000004433 nitrogen atom Chemical group N* 0.000 description 1
- WYVAMUWZEOHJOQ-UHFFFAOYSA-N propionic anhydride Chemical compound CCC(=O)OC(=O)CC WYVAMUWZEOHJOQ-UHFFFAOYSA-N 0.000 description 1
- 125000001501 propionyl group Chemical group O=C([*])C([H])([H])C([H])([H])[H] 0.000 description 1
- -1 propyl- Chemical group 0.000 description 1
- 230000000241 respiratory effect Effects 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 125000004417 unsaturated alkyl group Chemical group 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
Landscapes
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Description
Verfahren zur Herstellung von Estern von (-)-3-Hydroxy-morphinanen Die Erfindung betrifft. ein Verfahren zur lIer;stelhing von Estern des (-)-3-Hyclroxy- morphinans, welche am Stickstoff einen gesät tigten oder ungesättigten Alkyl-Substituenten von mindestens 3 Fohlenstoffatomen tragen. Diese Verbindungen besitzen wertvolle biolo gische Eigenschaften; sie vermögen in kleinen Dosen die uner ,ünschten Nebenwirkungen, z.
B. die atemlähmende und diuresehemmende Wirkung des Morphins und ähnlich wirkender Pharmaka rasch aufzuheben und sind daher als Arzneimittel von Interesse.
Nach dem erfindungsgemässen Verfahren erhält man. die neuen Verbindungen, indem man ein am qtiel-:stoffatoinidurch einen eesättig- ten oder ungesättigten, mindestens 3 Kohlen- stoffatome enthaltenden Alkvlrest substituier tes (-)-3-IIyclroxy-morphinan verestert. Das am Stickstoffatom substituierte (-)-3-Hydr- oxy-morpliinan, z.
B. (-)-3-II@#droxy-N-allyl-, -N-propargyl-, -N metlial.lyl-, -N-erotyl-, -N propyl-, oder .\-isohtttyl-morphinan kann mit. einem Säureanhydrid oder Säurehalogenid, wie z. B. Essigsäure-, Propionsäure-anhyd-rid oder Penzo:#1-ehlorid, behandelt werden.
Auf diese Weise erhält man die Aeetyl-, Propionyl- bzw. Benzoyl-Verbindungen der (-)-3-Hydr- oxv-N-allyl-, -propargv'l-, -metha:llyl-, -erotyl-, -propy l- bzw. -isobuty l-morphinane.
Die Ausgangsmaterialien sind teils bekannt. (für (-)-3-IIydros. -N-allyl-morphinan s. Hel v. 34, 2217 [1.951]) oder können in ana loger Weise wie die bekannte Verbindung aufs (-)-3-Hydroxy-morphinan durch Erwärmen mit dein entsprechenden gesättigten oder un gesättigten Alkyl-halogenid :dargestellt. wer den;
die N-Propyl- und N-Isobtityl-Verbin- dungen können auch .aus der N-Allyl- bzw. N- 3Tethally1-Verbindrzng durch katalytische Hy drierung gewonnen werden.
Beispiel <I>1</I> 30 g (-)-3-Hydroxy-N-allyl-morphinan werden mit 150 cm3 Essigsäure-anhydrid 4 Stunden auf 80 C erwärmt. Die Reaktions lösung wird im Vakuum eingedampft, der, Rückstand in Benzol gelöst und mit eiskalter n-Sodalösung und Eiswasser gewaschen.
Die mit. Natriumsulfat getrocknete Benzollösung wird im Vakuum eingedampft und das (-)- 3-Acetoxy-N-a.llyl-morphinan im Hochvakuum destilliert.. Siedepunkt bei 0,001 mm Hg156 C. Das Hydrobromid, aus Butwlaeetat kristalli siert, schmilzt bei 212-214 C und zeigt eine Drehung von [a]D = -41,4 (c = 3 in Fein sprit).
Beispiel <I>2</I> 50 g (-)-3-Hydroxy-N-allyl-morphinan werden in 500 cma Aceton suspendiert und unter Rühren bei 25-30 C mit. 30 cm3 Ben- zoylchl.orid versetzt. Das (-)-3-Hydroxy-N- allyl-morphinan geht rasch in Lösung und nach kurzer Zeit kristallisiert das (-)-3-Ben- zoyloxy-N-allyl-morphinän-hydrochlorid aus.
Nach Absaugen, Waschen mit Essigester und Umlösung aus Butylacetat schmilzt die Ver-
EMI0002.0001
bindung <SEP> bei <SEP> 1.49-15011 <SEP> C <SEP> und <SEP> zeit <SEP> eine <SEP> Dre hung <SEP> von <SEP> [a]D <SEP> = <SEP> -47,7 <SEP> (c <SEP> = <SEP> 3,0 <SEP> in <SEP> Fein sprit) <SEP> .
<tb>
<I>Beispiel <SEP> 3</I>
<tb> 30 <SEP> g <SEP> (-)-3-Hydro#-N-proparg@#1-morp@i nan <SEP> (Schmelzpunkt <SEP> 198-200 <SEP> C; <SEP> Schmelz punkt <SEP> des <SEP> Hy <SEP> drobromids <SEP> <B>160-1611)</B> <SEP> C) <SEP> wer den, <SEP> wie <SEP> in <SEP> Beisspiel <SEP> 1, <SEP> aeetyliert. <SEP> Das <SEP> (-)-3 -Acetoxy-N-pro@pa.rgyl-morphina.n <SEP> siedet <SEP> bei
<tb> l72 <SEP> C/0,002 <SEP> mm <SEP> Hg <SEP> und <SEP> zeigt <SEP> eine <SEP> Drehung
<tb> von <SEP> [a]D <SEP> =-84,3 <SEP> (c <SEP> = <SEP> 2,305 <SEP> in <SEP> Feinsprit.).
EMI0002.0002
<I>Beispiel <SEP> 4</I>
<tb> 30 <SEP> g <SEP> (-)-3-Hydi#o#-,y-N-propyl-inorphinan
<tb> (Schmelzpunkt <SEP> 165-167 <SEP> C; <SEP> Schmelzpunkt <SEP> des
<tb> Hydrobromids <SEP> 195-196 <SEP> C) <SEP> werden, <SEP> wie <SEP> in
<tb> Beispiel <SEP> 1, <SEP> acetyliert. <SEP> Siedepunkt <SEP> bei <SEP> 0,005 <SEP> mm
<tb> H- <SEP> 170 <SEP> C; <SEP> Schmelzpunkt <SEP> des <SEP> Hi-di-obroinicls
<tb> 265-267 <SEP> C, <SEP> [a] <SEP> 20 <SEP> = <SEP> -31,6% <SEP> (e <SEP> = <SEP> 2,23 <SEP> in
<tb> Feinsprit).
Process for the preparation of esters of (-) - 3-hydroxy-morphinans The invention relates to. a process for the production of esters of (-) - 3-Hyclroxy- morphinans, which carry a saturated or unsaturated alkyl substituent of at least 3 foal atoms on the nitrogen. These compounds have valuable biological properties; In small doses they can have undesirable side effects, e.g.
B. the respiratory paralyzing and diuresis-inhibiting effects of morphine and drugs with a similar effect quickly and are therefore of interest as drugs.
The process according to the invention gives. the new compounds by esterifying a (-) - 3-hydroxy-morphinan which is substituted on the qtiel-: stoffatoinid by an unsaturated or unsaturated alkyl radical containing at least 3 carbon atoms. The substituted on the nitrogen atom (-) - 3-Hydro- oxy-morpliinan, z.
B. (-) - 3-II @ # droxy-N-allyl-, -N-propargyl-, -N metlial.lyl-, -N-erotyl-, -N propyl-, or. \ - isohtttyl-morphinan can With. an acid anhydride or acid halide, such as. B. acetic acid, propionic acid anhydride or penzo: # 1-ehlorid treated.
In this way, the ethyl, propionyl and benzoyl compounds of (-) - 3-hydroxy-N-allyl-, -propargv'l-, -metha: llyl-, -erotyl-, -propy are obtained l- or -isobuty l-morphinane.
Some of the starting materials are known. (for (-) - 3-IIydros. -N-allyl-morphinan see Hel v. 34, 2217 [1.951]) or can be added to (-) - 3-hydroxy-morphinan in an analogous manner to the known compound by heating with the corresponding saturated or unsaturated alkyl halide: shown. will;
the N-propyl and N-isobtityl compounds can also be obtained from the N-allyl or N-3-tethally1 compound by catalytic hydrogenation.
Example <I> 1 </I> 30 g (-) - 3-hydroxy-N-allyl-morphinan are heated to 80 ° C. for 4 hours with 150 cm3 of acetic anhydride. The reaction solution is evaporated in vacuo, the residue is dissolved in benzene and washed with ice-cold sodium carbonate solution and ice water.
With. Sodium sulfate-dried benzene solution is evaporated in vacuo and the (-) - 3-acetoxy-Na.llyl-morphinan is distilled in a high vacuum. Boiling point at 0.001 mm Hg156 C. The hydrobromide, crystallized from Butwlaeetat, melts at 212-214 C and shows a rotation of [a] D = -41.4 (c = 3 in fine fuel).
Example <I> 2 </I> 50 g (-) - 3-hydroxy-N-allyl-morphinan are suspended in 500 cma acetone and mixed with stirring at 25-30 ° C. 30 cm3 of benzoyl chloride added. The (-) - 3-hydroxy-N-allyl-morphinan dissolves quickly and after a short time the (-) - 3-benzoyloxy-N-allyl-morphinan hydrochloride crystallizes out.
After suctioning off, washing with ethyl acetate and redissolving from butyl acetate, the compound melts
EMI0002.0001
binding <SEP> at <SEP> 1.49-15011 <SEP> C <SEP> and <SEP> time <SEP> a <SEP> rotation <SEP> of <SEP> [a] D <SEP> = <SEP> -47.7 <SEP> (c <SEP> = <SEP> 3.0 <SEP> in <SEP> fine fuel) <SEP>.
<tb>
<I> Example <SEP> 3 </I>
<tb> 30 <SEP> g <SEP> (-) - 3-Hydro # -N-proparg @ # 1-morp @ i nan <SEP> (melting point <SEP> 198-200 <SEP> C; <SEP> Melting point <SEP> of <SEP> Hy <SEP> drobromide <SEP> <B> 160-1611) </B> <SEP> C) <SEP>, <SEP> like <SEP> in <SEP> Example <SEP> 1, <SEP> aeetylated. <SEP> The <SEP> (-) - 3 -Acetoxy-N-pro@pa.rgyl-morphina.n <SEP> boils with <SEP>
<tb> l72 <SEP> C / 0.002 <SEP> mm <SEP> Hg <SEP> and <SEP> shows <SEP> a <SEP> rotation
<tb> from <SEP> [a] D <SEP> = -84.3 <SEP> (c <SEP> = <SEP> 2.305 <SEP> in <SEP> fine spirit).
EMI0002.0002
<I> Example <SEP> 4 </I>
<tb> 30 <SEP> g <SEP> (-) - 3-Hydi # o # -, y-N-propyl-inorphinane
<tb> (melting point <SEP> 165-167 <SEP> C; <SEP> melting point <SEP> des
<tb> Hydrobromids <SEP> 195-196 <SEP> C) <SEP> are, <SEP> like <SEP> in
<tb> Example <SEP> 1, <SEP> acetylated. <SEP> boiling point <SEP> at <SEP> 0.005 <SEP> mm
<tb> H- <SEP> 170 <SEP> C; <SEP> Melting point <SEP> of the <SEP> hi-di-obroinicl
<tb> 265-267 <SEP> C, <SEP> [a] <SEP> 20 <SEP> = <SEP> -31.6% <SEP> (e <SEP> = <SEP> 2.23 <SEP > in
<tb> fine spirit).
Claims (1)
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CH329208T | 1954-01-29 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CH329208A true CH329208A (en) | 1958-04-15 |
Family
ID=4501245
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CH329208D CH329208A (en) | 1954-01-29 | 1954-01-29 | Process for the preparation of esters of (-) - 3-hydroxy-morphinans |
Country Status (1)
| Country | Link |
|---|---|
| CH (1) | CH329208A (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| FR2129998A1 (en) * | 1971-03-25 | 1972-11-03 | Yamanouchi Pharma Co Ltd | Carbonyldioxy-morphinans |
-
1954
- 1954-01-29 CH CH329208D patent/CH329208A/en unknown
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| FR2129998A1 (en) * | 1971-03-25 | 1972-11-03 | Yamanouchi Pharma Co Ltd | Carbonyldioxy-morphinans |
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