FI66839C - PROCEDURE FOR THERAPEUTIC ADMINISTRATION OF THERAPEUTIC ANALYTICAL PRODUCTS AVOID 1-ISOPROPYLAMINO-3-PHENOXY-2-PROPANOLER SAMT MELLA NPODUKT - Google Patents
PROCEDURE FOR THERAPEUTIC ADMINISTRATION OF THERAPEUTIC ANALYTICAL PRODUCTS AVOID 1-ISOPROPYLAMINO-3-PHENOXY-2-PROPANOLER SAMT MELLA NPODUKT Download PDFInfo
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- FI66839C FI66839C FI824411A FI824411A FI66839C FI 66839 C FI66839 C FI 66839C FI 824411 A FI824411 A FI 824411A FI 824411 A FI824411 A FI 824411A FI 66839 C FI66839 C FI 66839C
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- Finland
- Prior art keywords
- therapeutic
- isopropylamino
- phenoxy
- procedure
- propanoler
- Prior art date
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- 238000000034 method Methods 0.000 title claims description 12
- 230000001225 therapeutic effect Effects 0.000 title 2
- 101100148710 Clarkia breweri SAMT gene Proteins 0.000 title 1
- 238000002360 preparation method Methods 0.000 claims description 11
- 150000001875 compounds Chemical class 0.000 claims description 9
- DLFVBJFMPXGRIB-UHFFFAOYSA-N Acetamide Chemical compound CC(N)=O DLFVBJFMPXGRIB-UHFFFAOYSA-N 0.000 claims description 4
- 125000004200 2-methoxyethyl group Chemical group [H]C([H])([H])OC([H])([H])C([H])([H])* 0.000 claims description 3
- ONXLHKFGTDDVLQ-UHFFFAOYSA-N 1-phenoxy-3-(propan-2-ylamino)propan-2-ol Chemical compound CC(C)NCC(O)COC1=CC=CC=C1 ONXLHKFGTDDVLQ-UHFFFAOYSA-N 0.000 claims description 2
- 125000000218 acetic acid group Chemical group C(C)(=O)* 0.000 claims description 2
- 239000003054 catalyst Substances 0.000 claims description 2
- GVNVAWHJIKLAGL-UHFFFAOYSA-N 2-(cyclohexen-1-yl)cyclohexan-1-one Chemical compound O=C1CCCCC1C1=CCCCC1 GVNVAWHJIKLAGL-UHFFFAOYSA-N 0.000 claims 1
- 101150065749 Churc1 gene Proteins 0.000 claims 1
- 102100038239 Protein Churchill Human genes 0.000 claims 1
- 241001122767 Theaceae Species 0.000 claims 1
- 239000000047 product Substances 0.000 description 14
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 7
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 6
- 239000002904 solvent Substances 0.000 description 5
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 4
- -1 benzhydryl group Chemical group 0.000 description 4
- KFZMGEQAYNKOFK-UHFFFAOYSA-N 2-propanol Substances CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 3
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 description 3
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 2
- WCUXLLCKKVVCTQ-UHFFFAOYSA-M Potassium chloride Chemical compound [Cl-].[K+] WCUXLLCKKVVCTQ-UHFFFAOYSA-M 0.000 description 2
- 239000012043 crude product Substances 0.000 description 2
- 239000000706 filtrate Substances 0.000 description 2
- 239000001257 hydrogen Substances 0.000 description 2
- 229910052739 hydrogen Inorganic materials 0.000 description 2
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 2
- 239000000203 mixture Substances 0.000 description 2
- 125000001424 substituent group Chemical group 0.000 description 2
- METKIMKYRPQLGS-GFCCVEGCSA-N (R)-atenolol Chemical compound CC(C)NC[C@@H](O)COC1=CC=C(CC(N)=O)C=C1 METKIMKYRPQLGS-GFCCVEGCSA-N 0.000 description 1
- FAYGEALAEQKPDI-UHFFFAOYSA-N 4-(2-methoxyethyl)phenol Chemical compound COCCC1=CC=C(O)C=C1 FAYGEALAEQKPDI-UHFFFAOYSA-N 0.000 description 1
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 description 1
- CPELXLSAUQHCOX-UHFFFAOYSA-M Bromide Chemical compound [Br-] CPELXLSAUQHCOX-UHFFFAOYSA-M 0.000 description 1
- AMWBCNZNJZIZFF-UHFFFAOYSA-N CC(C)N(CC(COC1=CC=C(C=C1)CC(=O)N)O)C(C2CC=CC=C2)C3=CC=CC=C3 Chemical compound CC(C)N(CC(COC1=CC=C(C=C1)CC(=O)N)O)C(C2CC=CC=C2)C3=CC=CC=C3 AMWBCNZNJZIZFF-UHFFFAOYSA-N 0.000 description 1
- BNARQWKNQHAJCW-UHFFFAOYSA-N CC(C)N(CC(COC1=CC=C(C=C1)CCOC)O)C(C2=CC=CC=C2)C3=CC=CC=C3 Chemical compound CC(C)N(CC(COC1=CC=C(C=C1)CCOC)O)C(C2=CC=CC=C2)C3=CC=CC=C3 BNARQWKNQHAJCW-UHFFFAOYSA-N 0.000 description 1
- DRSHXJFUUPIBHX-UHFFFAOYSA-N COc1ccc(cc1)N1N=CC2C=NC(Nc3cc(OC)c(OC)c(OCCCN4CCN(C)CC4)c3)=NC12 Chemical compound COc1ccc(cc1)N1N=CC2C=NC(Nc3cc(OC)c(OC)c(OCCCN4CCN(C)CC4)c3)=NC12 DRSHXJFUUPIBHX-UHFFFAOYSA-N 0.000 description 1
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 1
- ZDVDCDLBOLSVGM-UHFFFAOYSA-N [chloro(phenyl)methyl]benzene Chemical compound C=1C=CC=CC=1C(Cl)C1=CC=CC=C1 ZDVDCDLBOLSVGM-UHFFFAOYSA-N 0.000 description 1
- 229960002122 acebutolol Drugs 0.000 description 1
- GOEMGAFJFRBGGG-UHFFFAOYSA-N acebutolol Chemical compound CCCC(=O)NC1=CC=C(OCC(O)CNC(C)C)C(C(C)=O)=C1 GOEMGAFJFRBGGG-UHFFFAOYSA-N 0.000 description 1
- 125000003368 amide group Chemical group 0.000 description 1
- 150000001412 amines Chemical class 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 125000003118 aryl group Chemical group 0.000 description 1
- METKIMKYRPQLGS-UHFFFAOYSA-N atenolol Chemical compound CC(C)NCC(O)COC1=CC=C(CC(N)=O)C=C1 METKIMKYRPQLGS-UHFFFAOYSA-N 0.000 description 1
- 229960002274 atenolol Drugs 0.000 description 1
- 239000002876 beta blocker Substances 0.000 description 1
- 229940097320 beta blocking agent Drugs 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 229910052799 carbon Inorganic materials 0.000 description 1
- 238000009903 catalytic hydrogenation reaction Methods 0.000 description 1
- 239000003610 charcoal Substances 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 238000003776 cleavage reaction Methods 0.000 description 1
- 238000000354 decomposition reaction Methods 0.000 description 1
- QILSFLSDHQAZET-UHFFFAOYSA-N diphenylmethanol Chemical compound C=1C=CC=CC=1C(O)C1=CC=CC=C1 QILSFLSDHQAZET-UHFFFAOYSA-N 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 235000019253 formic acid Nutrition 0.000 description 1
- 125000004435 hydrogen atom Chemical group [H]* 0.000 description 1
- 238000002955 isolation Methods 0.000 description 1
- WSMBTEDNTPDCJM-UHFFFAOYSA-N n-benzhydryl-n-(oxiran-2-ylmethyl)propan-2-amine Chemical compound C=1C=CC=CC=1C(C=1C=CC=CC=1)N(C(C)C)CC1CO1 WSMBTEDNTPDCJM-UHFFFAOYSA-N 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N phenol group Chemical group C1(=CC=CC=C1)O ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 description 1
- 125000000951 phenoxy group Chemical group [H]C1=C([H])C([H])=C(O*)C([H])=C1[H] 0.000 description 1
- 239000001103 potassium chloride Substances 0.000 description 1
- 235000011164 potassium chloride Nutrition 0.000 description 1
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 1
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 239000011541 reaction mixture Substances 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 230000007017 scission Effects 0.000 description 1
- 239000000243 solution Substances 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D303/00—Compounds containing three-membered rings having one oxygen atom as the only ring hetero atom
- C07D303/02—Compounds containing oxirane rings
- C07D303/36—Compounds containing oxirane rings with hydrocarbon radicals, substituted by nitrogen atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C217/00—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton
- C07C217/02—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton
- C07C217/04—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated
- C07C217/28—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated having one amino group and at least two singly-bound oxygen atoms, with at least one being part of an etherified hydroxy group, bound to the carbon skeleton, e.g. ethers of polyhydroxy amines
- C07C217/30—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated having one amino group and at least two singly-bound oxygen atoms, with at least one being part of an etherified hydroxy group, bound to the carbon skeleton, e.g. ethers of polyhydroxy amines having the oxygen atom of at least one of the etherified hydroxy groups further bound to a carbon atom of a six-membered aromatic ring
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Description
1 668391 66839
Menetelmä terapeuttisesti käyttökelpoisten 1-isopropyyli-amino-3-fenoksi-2-propanolijohdannaist8n valmistamiseksi ja siinä käytettävä välituote j Tämä keksintö koskee menetelmää terapeuttisesti käyttökelpoisten 1-isopropyyliamino-3-fenoksi-2-p rop ano 1 i johdannaisten valmistamiseksi. Yhdisteillä on kaava 1J /=^1 R2"^\ //-°CH2!j:HC;H2NHCH[CH3J2 1This invention relates to a process for the preparation of therapeutically useful 1-isopropylamino-3-phenoxy-2-propanol derivatives. The compounds have the formula 1J / = ^ 1 R2 "^ \ // - ° CH2!
V---/ 0HV --- / 0H
jossa on vety tai asetyyli ja on asetamidi, butyryyli-15 amido tai 2 - metoksietyy1i .wherein there is hydrogen or acetyl and is acetamide, butyryl-15 amido or 2-methoxyethyl.
Keksintö koskee myös uutta yhdistettä 3-(l\|-is opropyy li-Ν-ο e n tshy dry y 1 i ami no ) - 1, 2 - epoks i p ropaani a käytettäväksi välituotteena keksinnÖnmukaisessa menetelmässä. Välituotteen 20 kaava on IIThe invention also relates to a novel compound 3- (1R-isopropyl-β-ο e n tshy dry y 1 i amino) -1,2-epoxy propane a for use as an intermediate in the process according to the invention. The formula of intermediate 20 is II
CH(CH3)2 CH. -OH- CHo-illj /7=r\ W 2 Ν;ηΥΚΛ\ ii oCH (CH3) 2 CH. -OH- CHo-illj / 7 = r \ W 2 Ν; ηΥΚΛ \ ii o
Kaavan I mukaisia yhdisteitä käytetään lääketieteessä ns. β-salpaajina. Aikaisempia valmistustapoja on kuvattu 30 lukuisissa julkaisuissa, joista mainittakoon patenttijulkaisut GB- 1 247 284, GB- 1 285 038 ja SE- 354 85 1 .The compounds of the formula I are used in medicine in the so-called β-blockers. Previous methods of preparation have been described in numerous publications, including GB-1 247 284, GB-1 285 038 and SE-354 85 1.
Haluttaessa valmistaa useampia samaan vai kutusryhmää n kuuluvia yhdisteitä on tunnettujen menetelmien mukaan 35 jouduttu aina valmistamaan lähtöaine, jossa yhdisteen aromaattinen osa on valmiina ja tähän osaan on liitetty __ - I.If it is desired to prepare several compounds belonging to the same active group n, it is always necessary, according to known methods, to prepare a starting material in which the aromatic part of the compound is ready and __-I is attached to this part.
66839 sopivia substi tue ntteja tai olemassaolevia substituentteja on sopivasti modifioitu.66839 suitable substituents or existing substituents have been suitably modified.
Nyt on keksitty yllättäen, että menetelmä voidaan suorittaa 5 myös siten, että kaikille halutuille yhdisteille valmistetaan yhteinen välituote, johon sitten liitetään synteesin kallein raaka-aine, fenolikomponentti.It has now surprisingly been found that the process can also be carried out by preparing a common intermediate for all the desired compounds, to which the phenolic component, the most expensive raw material for the synthesis, is then added.
Keksinnön mukaan saatetaan välituote, jonka kaava on 1JAccording to the invention, an intermediate of formula 1J is obtained
CH(CH3]2 ChU-CH-CH-,-Ν^ ΛΖΓχCH (CH3] 2 ChU-CH-CH -, - Ν ^ ΛΖΓχ
2 XCH-/fy\ II2 XCH- / fy \ II
6°6 °
reagoimaan yhoisteen IIIto respond to Coalition III
/=<Rl '' J R \ /·/' " 111/ = <Rl '' J R \ / · / '"111
\anssa ja muodostuneesta tuotteesta IV\ anssa and the resulting product IV
2:j ,_^R1 CH(CH3)2 R9~(\ /)-öch7chl:h -NCj /7=r\ V v ^ch—(f y\ iv o"2: j, _ ^ R1 CH (CH3) 2 R9 ~ (\ /) - öch7chl: h -NCj / 7 = r \ V v ^ ch— (f y \ iv o "
olJOLJ
poistetaan bentshydryyli ryhmä tavanomaisin keinoin· ja merkitsevät kaavoissa samaa kuin edellä.remove the benzhydryl group by conventional means · and denote in the formulas the same as above.
3i. Uentshydryyli ry h mä n poistaminen suoritetaan keksinnön mukaisesti varsin lievissä olosuhteissa, käyttämällä esimerkiksi muurahaishappoa tai etikkahappoa lohkaisu- 66839 aineina. Katalyyttinen hydraus on eräs vaihtoehto bentshyd-ryyli ryhmän poistamiseksi. Muodostuva bentshydroli voidaan helposti ottaa talteen prosessista ja muuttaa sen jälkeen takaisin bentshydryy1ikloridiksi tai -bromidiksi, sekä 5 käyttää uudelleen.3i. The removal of the uenzhydryl group according to the invention is carried out under rather mild conditions, for example using formic acid or acetic acid as cleavage agents. Catalytic hydrogenation is one option for removing the benzhydryl group. The benzhydrol formed can be easily recovered from the process and then converted back to benzhydryl chloride or bromide, and reused.
Keksinnön mukainen menetelmä on myös taloudellisesti hyvä ja teollisesti käyttökelpoinen, sillä menetelmän saanto on h y vä .The process according to the invention is also economically good and industrially applicable, since the yield of the process is good.
1010
Seuraavat esimerkit kuvaavat tarkemmin sekä välituotteen että lopputuotteiden valmistustaThe following examples illustrate in more detail the preparation of both the intermediate and the final products
Esimerkki 1 1 5 Vä1ituotteena käytettävän 3-(N-isopropyy1i-N~bentshydryy1i ami no)- 1,2-epoksipropaani n vaImis tami ne n a) 1-kloori-3-(N-isopropyyli-IM-bentshydryyliamino)-2-. 20 propano1i 500 g:aa [6,4 moolia) 1 - kloori-2,3-epoksinropaania ja 225 g:aa [1 mooli) is opropyy1ibe ntshydryyli amiinia kuumennettiin 20 tuntia 120°C:ssa palautuksella. Ylimääräinen 25 1-kloori-2,3-epoksipropaani poistettiin alennetussa pai- neessa, jolloin saatiin 31B g In. 100 %) haluttua tuotetta viskoosina öljynä; Kp. 150°C/0,2 mm (hajoaa osittain).Example 1 Preparation of 3- (N-isopropyl-N-benzhydrylamino) -1,2-epoxypropane as an intermediate a) 1-Chloro-3- (N-isopropyl-1-benzhydrylamino) -2-. Propanol 500 g [6.4 moles] of 1-chloro-2,3-epoxynropane and 225 g of [1 mole] of isopropylhydryl amine were heated at 120 ° C under reflux for 20 hours. Excess 25-1-chloro-2,3-epoxypropane was removed under reduced pressure to give 31B g of In. 100%) of the desired product as a viscous oil; Kp. 150 ° C / 0.2 mm (partial decomposition).
b) 3-(lNl-Isopropyyli-N-bentshydryyliamino)-1,2-epoksipropaani 30 318 g:aa (1 mooli) kohdassa a) saatua raakatuotetta sekä 112 g:aa (1 mooli) kaliumtert.butoksidi a kuumennettiin 1000 ml:ssa DMA:ta 5 tuntia 70°C:ssa. Ka 1iumk1oridi suodatettiin pois ja suodoksesta haihdutettiin liuottimet alenne-35 tussa paineessa, jolloin saatiin 280 g (n. 100 % ) haluttua tuotetta viskoosina öljynä; Kp. 128°C/0,15 mm.b) 3- (1N-Isopropyl-N-benzhydrylamino) -1,2-epoxypropane 31 318 g (1 mol) of the crude product obtained in a) and 112 g (1 mol) of potassium tert-butoxide were heated to 1000 ml: DMA for 5 hours at 70 ° C. The potassium chloride was filtered off and the solvents were evaporated from the filtrate under reduced pressure to give 280 g (ca. 100%) of the desired product as a viscous oil; Kp. 128 ° C / 0.15 mm.
_ - τ:- 4 66839 E s i me rk k i 2 aJ 1-(IM-Isopropyyli-N-bentshydryyliamino)-3-(2-asetyyli- 4-butyryyliamidofenoksi)-2-propanolin valmis tami nen 5 28,1 g:aa (0,1 moolia) esimerkin 1 kohdassa b) saatua raaka-tuotetta ja 22,1 g:aa (0,1 moolia) 2-asetyyli-4-butyryyli -amidofenolia sekä 0,3 g:aa kaliumtert.butoksidia 17 ml:ssa OMAtta kuumennettiin 20 tuntia 130°C:ssa typpivirrassa.Preparation of 1- (1-isopropyl-N-benzhydrylamino) -3- (2-acetyl-4-butyrylamidophenoxy) -2-propanol 5 28.1 g: aa (0.1 mol) of the crude product obtained in Example 1 (b) and 22.1 g (0.1 mol) of 2-acetyl-4-butyrylamidophenol and 0.3 g of potassium tert-butoxide in 17 ml OMA was heated for 20 hours at 130 ° C under a stream of nitrogen.
13 Reaktioseos liuotettiin· 250 ml:aan tolueenia ja pestiin laimealla NaOH-liuokse1la sekä vedellä. Liuotin poistettiin alennetussa paineessa, jolloin saatiin 48,0 g (96 %) haluttua tuotetta; (Tuote voidaan kiteyttää eetteristä) sp. 1 15 - 117°C .13 The reaction mixture was dissolved in 250 ml of toluene and washed with dilute NaOH solution and water. The solvent was removed under reduced pressure to give 48.0 g (96%) of the desired product; (The product can be crystallized from ether) m.p. 1 15-117 ° C.
15 b) 1-Isopropyy1iamino-3-(2-asetyyli -4-butyryy1iamidofe~ noksi)-2-propanoli n (asebutolo1i) valmistaminen 25.0 g:aa (0,05 moolia) kohdassa a) saatua tuotetta sekä 20 1 g 10 % oalladium-hiilikatalyyttiä 100 ml:ssa metanolia hydrattiin normaalipaineessa ja -lämpötilassa vetyilma-kehässä 2-3 tuntia. Seos suodatettiin ja liuotin poistettiin alennetussa paineessa. Jäännös liuotettiin 1N kloorivety-happoon ja uutettiin metyleenikloridi 1la. Vesikerros käsi-75 teltiin aktiivihiilellä, suodatettiin ja suodos tehtiin emäksiseksi IMaOH-li uoksel la, jolloin tuote kiteytyi; saanto 16.0 g (95 %), sp. 119 -122°C.15 b) Preparation of 1-Isopropylamino-3- (2-acetyl-4-butyrylamidophenoxy) -2-propanol (acebutolol) 25.0 g (0.05 mol) of the product obtained in a) and 20 l of 10% oalladium carbon catalyst in 100 ml of methanol was hydrogenated at normal pressure and temperature under a hydrogen atmosphere for 2-3 hours. The mixture was filtered and the solvent was removed under reduced pressure. The residue was dissolved in 1N hydrochloric acid and extracted with methylene chloride. The aqueous layer was hand-activated with charcoal, filtered and the filtrate basified with IMaOH to crystallize the product; yield 16.0 g (95%), m.p. 119-122 ° C.
Esimerkki 3 30 a) 1-(N-isopropyyli-N-bentshydryyliamino)~3-(4-(2-metoksi-etyyli)fenoksi)-2-propanolin valmistaminen 28.1 g:aa (0,1 moolia) tuotetta, joka oli saatu esimerkin 1 35 kohdassa b), ja 15,2 g:aa (0,1 moolia) 4-(2-metoksietyyli)- fenolia sekä 0,3 g:aa kaliumtert.butoksidia 20 ml:ssa DMA:ta 5 kuumennettiin 20 tuntia 130°C:ssa. Eristys suoritettiin kutun esimerkin 2 välituotteelle, jolloin saatiin 42,0 g [97 %) haluttua tuotetta viskoosina öljynä.Example 3 a) Preparation of 1- (N-isopropyl-N-benzhydrylamino) -3- (4- (2-methoxyethyl) phenoxy) -2-propanol 28.1 g (0.1 mol) of product which was obtained in Example 1, item 35 b), and 15.2 g (0.1 mol) of 4- (2-methoxyethyl) phenol and 0.3 g of potassium tert-butoxide in 20 ml of DMA 5 were heated at 20 ° C. hours at 130 ° C. Isolation was performed on the intermediate of Example 2 to give 42.0 g [97%] of the desired product as a viscous oil.
66839 5 b] 1-isopropyyliamino-3-[4-[2-metoksietyyli)fenoksi)-2-propanolin (metopro1bli) valmistaminen66839 5 b] Preparation of 1-isopropylamino-3- [4- [2-methoxyethyl) phenoxy) -2-propanol (methopropyl)
Bentsnydryyliryhmä poistettiin, kuten tehtiin esimerkin 2 kohdassab). Seos suodatettiin ja liuotin poistettiin alen-10 netussa paineessa. Jäännös liuotettiin 1N kloorivetyhappoon ja uutetti i n metyleeniklori di 11a di fenyy limetaani n poistamiseksi. Vesiliuos tehtiin emäksiseksi ja tuote uutettiin tolueenilla. Liuotin poistettiin alennetussa paineessa, jolloin saatiin haluttua tuotetta; sp. n. 46°C, saanto 95 %. 15The benznydryyl group was removed as in Example 2 (bab). The mixture was filtered and the solvent was removed under reduced pressure. The residue was dissolved in 1N hydrochloric acid and extracted with methylene chloride di 11a to remove phenylmethane. The aqueous solution was basified and the product was extracted with toluene. The solvent was removed under reduced pressure to give the desired product; mp. about 46 ° C, yield 95%. 15
Esimerkki 4 a] 1-(N-isopropyyli-l\|-bentshydryyliamino)-3- ( 4-karbamoyy lime tyylifenoksi)-2-propanolin valmistaminen 20Example 4 a] Preparation of 1- (N-isopropyl-1H-benzhydrylamino) -3- (4-carbamoylmethylphenoxy) -2-propanol
Meneteltiin kuten esimerkin 2 kohdassa a) käyttäen 28,1 g:aa yhdistettä II ja 15,1 g:aa 4-karbamoyy1 imetyyli feno li a, jolloin saatiin 42,3 g (98 %) haluttua tuotetta visKoosina öljynä.The procedure was as in Example 2 (a) using 28.1 g of compound II and 15.1 g of 4-carbamoylmethylphenyl to give 42.3 g (98%) of the desired product as a viscous oil.
25 b] 1-isopropyyliamino-3-(4-karbamoyylimetyylifenoksi)-2-propanolin (atenololiJ valmistaminen25 b] Preparation of 1-isopropylamino-3- (4-carbamoylmethylphenoxy) -2-propanol (atenolol)
Meneteltiin kuten esimerkin 2 kohdassa b), jolloin saatiin 30 haluttua tuotetta; saanto 94 %, sp. 146-6°C.The procedure was as in Example 2 (b) to give the desired product; yield 94%, m.p. 146-6 ° C.
Claims (2)
Priority Applications (6)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| FI824411A FI66839C (en) | 1982-12-22 | 1982-12-22 | PROCEDURE FOR THERAPEUTIC ADMINISTRATION OF THERAPEUTIC ANALYTICAL PRODUCTS AVOID 1-ISOPROPYLAMINO-3-PHENOXY-2-PROPANOLER SAMT MELLA NPODUKT |
| DK586083A DK586083A (en) | 1982-12-22 | 1983-12-20 | PROCEDURE FOR PREPARING 1-ISOPROPYLAMINO-3-ARYLOXY-2-PROPANOLS AND INTERMEDIATE FOR USE BY THE PROCEDURE |
| SU833703901A SU1321371A3 (en) | 1982-12-22 | 1983-12-21 | Method of producing 1-isopropylamino-3-phenoxy-2-propanol |
| NL8304392A NL8304392A (en) | 1982-12-22 | 1983-12-21 | 1-Isopropyl-amino-3-aryloxy-2-propanol(s) prodn. - for use as beta-blockers, by reacting 3-(N-isopropyl-N-benzhydrylamino)-1,2-epoxy-propane with phenolic cpd. |
| DD83258478A DD212957A5 (en) | 1982-12-22 | 1983-12-22 | PROCESS FOR THE PREPARATION OF 1-ISOPROPYLAMINO-3-ARYLOXY-2-PROPANOLS AND MEANS FOR THEIR PREPARATION |
| SE8307129A SE8307129L (en) | 1982-12-22 | 1983-12-22 | PREPARATION OF 1-ISOPROPYLAMINO-3-ARYLOXY-2-PROPANOLS |
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| FI824411 | 1982-12-22 | ||
| FI824411A FI66839C (en) | 1982-12-22 | 1982-12-22 | PROCEDURE FOR THERAPEUTIC ADMINISTRATION OF THERAPEUTIC ANALYTICAL PRODUCTS AVOID 1-ISOPROPYLAMINO-3-PHENOXY-2-PROPANOLER SAMT MELLA NPODUKT |
Publications (4)
| Publication Number | Publication Date |
|---|---|
| FI824411A0 FI824411A0 (en) | 1982-12-22 |
| FI824411L FI824411L (en) | 1984-06-23 |
| FI66839B FI66839B (en) | 1984-08-31 |
| FI66839C true FI66839C (en) | 1984-12-10 |
Family
ID=8516499
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| FI824411A FI66839C (en) | 1982-12-22 | 1982-12-22 | PROCEDURE FOR THERAPEUTIC ADMINISTRATION OF THERAPEUTIC ANALYTICAL PRODUCTS AVOID 1-ISOPROPYLAMINO-3-PHENOXY-2-PROPANOLER SAMT MELLA NPODUKT |
Country Status (6)
| Country | Link |
|---|---|
| DD (1) | DD212957A5 (en) |
| DK (1) | DK586083A (en) |
| FI (1) | FI66839C (en) |
| NL (1) | NL8304392A (en) |
| SE (1) | SE8307129L (en) |
| SU (1) | SU1321371A3 (en) |
-
1982
- 1982-12-22 FI FI824411A patent/FI66839C/en not_active IP Right Cessation
-
1983
- 1983-12-20 DK DK586083A patent/DK586083A/en not_active Application Discontinuation
- 1983-12-21 NL NL8304392A patent/NL8304392A/en not_active Application Discontinuation
- 1983-12-21 SU SU833703901A patent/SU1321371A3/en active
- 1983-12-22 SE SE8307129A patent/SE8307129L/en not_active Application Discontinuation
- 1983-12-22 DD DD83258478A patent/DD212957A5/en unknown
Also Published As
| Publication number | Publication date |
|---|---|
| SE8307129L (en) | 1984-06-23 |
| DK586083A (en) | 1984-06-23 |
| SU1321371A3 (en) | 1987-06-30 |
| FI824411A0 (en) | 1982-12-22 |
| SE8307129D0 (en) | 1983-12-22 |
| FI66839B (en) | 1984-08-31 |
| DD212957A5 (en) | 1984-08-29 |
| FI824411L (en) | 1984-06-23 |
| DK586083D0 (en) | 1983-12-20 |
| NL8304392A (en) | 1984-07-16 |
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Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| MM | Patent lapsed |
Owner name: ORION-YHTYMAE OY |