DE1046059B - Process for the preparation of N-alkylalanine anilides useful as local anesthetic agents - Google Patents
Process for the preparation of N-alkylalanine anilides useful as local anesthetic agentsInfo
- Publication number
- DE1046059B DE1046059B DEA18202A DEA0018202A DE1046059B DE 1046059 B DE1046059 B DE 1046059B DE A18202 A DEA18202 A DE A18202A DE A0018202 A DEA0018202 A DE A0018202A DE 1046059 B DE1046059 B DE 1046059B
- Authority
- DE
- Germany
- Prior art keywords
- anilides
- preparation
- anesthetic agents
- useful
- alkylalanine
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
- 229940051881 anilide analgesics and antipyretics Drugs 0.000 title claims description 4
- 238000000034 method Methods 0.000 title claims description 4
- 238000002360 preparation method Methods 0.000 title claims description 4
- 150000003931 anilides Chemical class 0.000 title claims 2
- 239000003589 local anesthetic agent Substances 0.000 title description 2
- QUSNBJAOOMFDIB-UHFFFAOYSA-N Ethylamine Chemical compound CCN QUSNBJAOOMFDIB-UHFFFAOYSA-N 0.000 claims description 6
- 239000002253 acid Substances 0.000 claims description 3
- JJWLVOIRVHMVIS-UHFFFAOYSA-N isopropylamine Chemical compound CC(C)N JJWLVOIRVHMVIS-UHFFFAOYSA-N 0.000 claims description 3
- -1 n-propyl- Chemical group 0.000 claims description 3
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 2
- 239000003193 general anesthetic agent Substances 0.000 claims description 2
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 2
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 2
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims 1
- 150000001412 amines Chemical class 0.000 claims 1
- 229910052739 hydrogen Inorganic materials 0.000 claims 1
- 239000001257 hydrogen Substances 0.000 claims 1
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 claims 1
- 239000007858 starting material Substances 0.000 claims 1
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 9
- HIXDQWDOVZUNNA-UHFFFAOYSA-N 2-(3,4-dimethoxyphenyl)-5-hydroxy-7-methoxychromen-4-one Chemical compound C=1C(OC)=CC(O)=C(C(C=2)=O)C=1OC=2C1=CC=C(OC)C(OC)=C1 HIXDQWDOVZUNNA-UHFFFAOYSA-N 0.000 description 7
- RTZKZFJDLAIYFH-UHFFFAOYSA-N ether Substances CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 7
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 6
- 150000001875 compounds Chemical class 0.000 description 6
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 4
- 239000000243 solution Substances 0.000 description 3
- XEEYBQQBJWHFJM-UHFFFAOYSA-N Iron Chemical compound [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 0.000 description 2
- UCTWMZQNUQWSLP-UHFFFAOYSA-N adrenaline Chemical compound CNCC(O)C1=CC=C(O)C(O)=C1 UCTWMZQNUQWSLP-UHFFFAOYSA-N 0.000 description 2
- 229910021529 ammonia Inorganic materials 0.000 description 2
- 238000001816 cooling Methods 0.000 description 2
- 239000000284 extract Substances 0.000 description 2
- 230000002349 favourable effect Effects 0.000 description 2
- 231100000053 low toxicity Toxicity 0.000 description 2
- 238000002844 melting Methods 0.000 description 2
- 230000008018 melting Effects 0.000 description 2
- WGYKZJWCGVVSQN-UHFFFAOYSA-N propylamine Chemical compound CCCN WGYKZJWCGVVSQN-UHFFFAOYSA-N 0.000 description 2
- 239000005526 vasoconstrictor agent Substances 0.000 description 2
- DURPTKYDGMDSBL-UHFFFAOYSA-N 1-butoxybutane Chemical compound CCCCOCCCC DURPTKYDGMDSBL-UHFFFAOYSA-N 0.000 description 1
- 235000004279 alanine Nutrition 0.000 description 1
- 230000003444 anaesthetic effect Effects 0.000 description 1
- 229940035674 anesthetics Drugs 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 150000001555 benzenes Chemical class 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- XWBDWHCCBGMXKG-UHFFFAOYSA-N ethanamine;hydron;chloride Chemical compound Cl.CCN XWBDWHCCBGMXKG-UHFFFAOYSA-N 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 229910052742 iron Inorganic materials 0.000 description 1
- 238000002690 local anesthesia Methods 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- ISYORFGKSZLPNW-UHFFFAOYSA-N propan-2-ylazanium;chloride Chemical compound [Cl-].CC(C)[NH3+] ISYORFGKSZLPNW-UHFFFAOYSA-N 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C237/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Description
Die vorliegende Erfindung bezieht sich auf die Herstellung von N-Alkyl-alaninaniliden mit zwei oder drei Methylgruppen im Benzolkern, welche als Anästhetica brauchbar sind, insbesondere für die Lokalanästhesie. Verbindungen einer verwandten Gruppe sind im Patent 968 561 beschrieben. Es wurde bei letzteren festgestellt, daß sie sehr gute, in einigen Fällen außergewöhnlich günstige Eigenschaften für anästhetische Zwecke besitzen, z. B. eine verhältnismäßig niedrige Toxizität bzw. geringe Giftigkeit im Verhältnis zu ihrer Wirksamkeit, eine sehr rasche Wirkung, gute Verwendung ohne den Zusatz von Vasoconstriktoren bzw. gefäßverengernden Mitteln und die Bildung von Salzen, welche in wässerigen Lösungen und mit Adrenalin zusammen sehr stabil sind.The present invention relates to the preparation of N-alkyl-alanine anilides with two or three methyl groups in the benzene nucleus, which are useful as anesthetics, especially for the Local anesthesia. Related group compounds are described in the '968,561 patent. It was the latter found that they have very good, in some cases exceptionally favorable properties for have anesthetic purposes, e.g. B. a relatively low toxicity or low toxicity im Relative to its effectiveness, a very rapid effect, good use without the addition of Vasoconstrictors or vasoconstricting agents and the formation of salts, which in aqueous Solutions and together with adrenaline are very stable.
In der USA.-Patentschrift 2 441 498 ist eine dialkylierte Aminoverbindung der beschriebenen Art, das Diäthylamino-a-propionylxylidid-2,6 beschrieben. Untersuchungen ergaben aber, daß diese Verbindung bei Injektionen derart irritierend wirkt, daß sie für klinische Zwecke nicht in Frage kommt.In U.S. Patent 2,441,498 a dialkylated amino compound of the type described is the Diethylamino-a-propionylxylidide-2,6 described. Studies have shown, however, that this compound is so irritating when injected that it is used for clinical purposes are out of the question.
Es wurde nun festgestellt, daß Verbindungen der allgemeinen FormelIt has now been found that compounds of the general formula
CH3 CH3 CH 3 CH 3
R1— — NH- CO — CH- NH- R2 R 1 - - NH- CO - CH- NH- R 2
CH8 CH 8
in welcher Ri für H oder CH3 steht und R2 Äthyl, 11-Propyl oder Isopropyl bedeutet, sehr günstige Eigenschaften der eingangs erwähnten Art besitzen.in which Ri is H or CH 3 and R 2 is ethyl, 11-propyl or isopropyl, have very favorable properties of the type mentioned above.
Die Verbindungen nach vorliegender Erfindung werden hergestellt, indem man cc-Halogenpropionsäure-(2,6-dimethylanilid) oder α-Halogenpropionsäure-(2,4,6-trimethylanilid) mit Äthylamin, n-Propylamin oder Isopropylamin umsetzt. Die Herstellung wird durch die nachfolgende Beispiele erläutert.The compounds of the present invention are prepared by adding cc-halopropionic acid- (2,6-dimethylanilide) or α-halopropionic acid (2,4,6-trimethylanilide) with ethylamine, n-propylamine or isopropylamine. The production is illustrated by the following examples.
l.a-Isopropylamino-propionsäure-(2,6-dimethylanilid)l.a-Isopropylaminopropionic acid (2,6-dimethylanilide)
1 g-Mol a-Brompropionsäure-(2,6-dimethylanilid) wird mit 5 g-Mol Isopropylamin in 1000 cm3 trockenen Benzols in einem geschlossenen Gefäß 3 Stunden auf 70° C erhitzt. Nach dem Abkühlen wird das gebildete Isopropylaminhydrochlorid mit Äther ausgefällt. Die Ätherlösung wird mit wässeriger 2 n-Salzsäure geschüttelt. Aus den Salzsäureextrakten wird die Base mit Ammoniak frei gemacht und in Äther aufgenommen. Nach dem Trocknen wird der Äther abgetrieben, und man erhält einen festen Rückstand. Durch Umkristallisieren aus Dibutyläther erhält man Verfahren zur Herstellung von als1 g-mol of a-bromopropionic acid (2,6-dimethylanilide) is heated with 5 g-mol of isopropylamine in 1000 cm 3 of dry benzene in a closed vessel at 70 ° C. for 3 hours. After cooling, the isopropylamine hydrochloride formed is precipitated with ether. The ether solution is shaken with aqueous 2N hydrochloric acid. The base is freed from the hydrochloric acid extracts with ammonia and absorbed in ether. After drying, the ether is driven off and a solid residue is obtained. Recrystallization from dibutyl ether gives processes for the preparation of as
lokalanästhetische Mittel verwendbarenlocal anesthetic agents can be used
N-Alkyl-alaninanilidenN-alkyl alanine anilides
Anmelder:Applicant:
Aktiebolaget Astra, Apotekarnes Kemiska Fabriker, Södertälje (Schweden)Aktiebolaget Astra, Apotekarnes Kemiska Fabriker, Södertälje (Sweden)
Vertreter: Dr.-Ing. H. Ruschke, Berlin-Friedenau,Representative: Dr.-Ing. H. Ruschke, Berlin-Friedenau,
und Dipl.-Ing. K. Grentzenberg, München 27, Pienzenauerstr. 2, Patentanwälteand Dipl.-Ing. K. Grentzenberg, Munich 27, Pienzenauerstr. 2, patent attorneys
Beanspruchte Priorität: Schweden vom 12. Juni 1952Claimed priority: Sweden, June 12, 1952
Dr. phil. Nils Magnus Löfgren, Lidingö,Dr. phil. Nils Magnus Löfgren, Lidingö,
und Bengt Josef Lundqvist, Stockholm (Schweden), sind als Erfinder genannt wordenand Bengt Josef Lundqvist, Stockholm (Sweden), have been named as inventors
α - Isopropylamino - propionsäure- (2,6 - dimethylanilid) in Form weißer Nadeln mit einem Schmelzpunkt von 86 bis 87° C bei einer Ausbeute von etwa 87%.α - Isopropylamino - propionic acid (2,6 - dimethylanilide) in the form of white needles with a melting point of 86 to 87 ° C with a yield of about 87%.
2. c,-n-Propylamino-propionsäure-(2,6-dimethylanilid)2. c, -n-propylamino-propionic acid- (2,6-dimethylanilide)
Diese Verbindung wird analog der Isopropylverbindung hergestellt. Schmelzpunkt: 76 bis 77° C.This compound is produced analogously to the isopropyl compound. Melting point: 76 to 77 ° C.
3. a-Äthylamino-propionsäure-(2,4,6-trimethylanilid)3. a-ethylamino-propionic acid- (2,4,6-trimethylanilide)
1 g-Mol a-Brompropionsäure-(2,4,6-trimethylanilidj wird in 1200 cm3 trockenen Benzols suspendiert und die Suspension in einen eisernen, auf 0° C gekühlten Autoklav gegossen. Es werden 5 g-Mol Äthylamin hinzugesetzt, und nach dem Schließen wird der Autoklav 6 Stunden auf 80° C erhitzt und wiederholt geschüttelt. Nach dem Kühlen wird die Benzollösung mit einem gleichen Volumen Äther verdünnt, und der gebildete Niederschlag von Äthylaminhydrochlorid wird abfiltriert. Das Filtrat wird 5mal mit 2 n-Salzsäure extrahiert. Die Base wird dann durch Zusatz konzentrierten Ammoniaks aus den Extrakten frei gemacht und in Äther aufgenommen. Nach dem Trocknen der Ätherlösung wird das Lösungsmittel abgetrieben, und die gewünschte Verbindung kristallisiert in farblosen Nadeln aus. Schmelzpunkt 98 bis 100° C. Ausbeute: 89'%.1 g-mol of a-bromopropionic acid- (2,4,6-trimethylanilidj is suspended in 1200 cm 3 of dry benzene and the suspension is poured into an iron autoclave cooled to 0 ° C. 5 g-mol of ethylamine are added, and afterwards After closing, the autoclave is heated for 6 hours to 80 ° C. and shaken repeatedly. After cooling, the benzene solution is diluted with an equal volume of ether and the precipitate of ethylamine hydrochloride that has formed is filtered off. The filtrate is extracted 5 times with 2N hydrochloric acid Base is then freed from the extracts by adding concentrated ammonia and taken up in ether. After the ether solution has dried, the solvent is driven off and the desired compound crystallizes out in colorless needles. Melting point 98 to 100 ° C. Yield: 89%.
809 698/563809 698/563
Claims (1)
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| SE1046059X | 1952-06-12 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| DE1046059B true DE1046059B (en) | 1958-12-11 |
Family
ID=20419180
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| DEA18202A Pending DE1046059B (en) | 1952-06-12 | 1953-06-12 | Process for the preparation of N-alkylalanine anilides useful as local anesthetic agents |
Country Status (1)
| Country | Link |
|---|---|
| DE (1) | DE1046059B (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE2400540A1 (en) * | 1973-01-08 | 1974-08-15 | Astra Pharma Prod | PRIMAERAMINOACYLANILIDES, METHOD OF MANUFACTURING AND MEDICINAL PRODUCTS CONTAINING THEY |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US2441498A (en) * | 1943-07-15 | 1948-05-11 | Astra Apotekarnes Kem Fab | Alkyl glycinanilides |
-
1953
- 1953-06-12 DE DEA18202A patent/DE1046059B/en active Pending
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US2441498A (en) * | 1943-07-15 | 1948-05-11 | Astra Apotekarnes Kem Fab | Alkyl glycinanilides |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE2400540A1 (en) * | 1973-01-08 | 1974-08-15 | Astra Pharma Prod | PRIMAERAMINOACYLANILIDES, METHOD OF MANUFACTURING AND MEDICINAL PRODUCTS CONTAINING THEY |
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