CH306511A - A process for preparing 1-methyl-3-piperidylmethyl 2-cyclopentyl-4-methylpentanoate. - Google Patents
A process for preparing 1-methyl-3-piperidylmethyl 2-cyclopentyl-4-methylpentanoate.Info
- Publication number
- CH306511A CH306511A CH306511DA CH306511A CH 306511 A CH306511 A CH 306511A CH 306511D A CH306511D A CH 306511DA CH 306511 A CH306511 A CH 306511A
- Authority
- CH
- Switzerland
- Prior art keywords
- methyl
- cyclopentyl
- sep
- methylpentanoate
- piperidylmethyl
- Prior art date
Links
- -1 1-methyl-3-piperidylmethyl 2-cyclopentyl-4-methylpentanoate Chemical compound 0.000 title claims description 9
- 238000004519 manufacturing process Methods 0.000 title claims description 3
- 239000002253 acid Substances 0.000 claims description 5
- 239000012458 free base Substances 0.000 claims description 5
- 239000002585 base Substances 0.000 claims description 3
- 150000004820 halides Chemical class 0.000 claims description 3
- 150000003839 salts Chemical class 0.000 claims description 3
- 238000000034 method Methods 0.000 claims description 2
- NGNBDVOYPDDBFK-UHFFFAOYSA-N 2-[2,4-di(pentan-2-yl)phenoxy]acetyl chloride Chemical compound CCCC(C)C1=CC=C(OCC(Cl)=O)C(C(C)CCC)=C1 NGNBDVOYPDDBFK-UHFFFAOYSA-N 0.000 claims 1
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 9
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 6
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 6
- UGXQXVDTGJCQHR-UHFFFAOYSA-N (1-methylpiperidin-3-yl)methanol Chemical compound CN1CCCC(CO)C1 UGXQXVDTGJCQHR-UHFFFAOYSA-N 0.000 description 3
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 3
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 3
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 3
- 239000000203 mixture Substances 0.000 description 3
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 2
- XBLVHTDFJBKJLG-UHFFFAOYSA-N Ethyl nicotinate Chemical compound CCOC(=O)C1=CC=CN=C1 XBLVHTDFJBKJLG-UHFFFAOYSA-N 0.000 description 2
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-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
- GZUXJHMPEANEGY-UHFFFAOYSA-N bromomethane Chemical compound BrC GZUXJHMPEANEGY-UHFFFAOYSA-N 0.000 description 2
- 150000001875 compounds Chemical class 0.000 description 2
- 150000002148 esters Chemical class 0.000 description 2
- 238000002844 melting Methods 0.000 description 2
- 230000008018 melting Effects 0.000 description 2
- 238000002360 preparation method Methods 0.000 description 2
- 150000003242 quaternary ammonium salts Chemical class 0.000 description 2
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 2
- ZGUFUYADDVHERQ-UHFFFAOYSA-N 2-cyclopentyl-4-methylpentanoic acid Chemical compound CC(C)CC(C(O)=O)C1CCCC1 ZGUFUYADDVHERQ-UHFFFAOYSA-N 0.000 description 1
- JRXTXRWPJBGFCP-UHFFFAOYSA-N 2-cyclopentyl-4-methylpentanoyl chloride Chemical compound C1(CCCC1)C(C(=O)Cl)CC(C)C JRXTXRWPJBGFCP-UHFFFAOYSA-N 0.000 description 1
- BMYNFMYTOJXKLE-UHFFFAOYSA-N 3-azaniumyl-2-hydroxypropanoate Chemical compound NCC(O)C(O)=O BMYNFMYTOJXKLE-UHFFFAOYSA-N 0.000 description 1
- 229930003347 Atropine Natural products 0.000 description 1
- LSNNMFCWUKXFEE-UHFFFAOYSA-M Bisulfite Chemical compound OS([O-])=O LSNNMFCWUKXFEE-UHFFFAOYSA-M 0.000 description 1
- RKUNBYITZUJHSG-UHFFFAOYSA-N Hyosciamin-hydrochlorid Natural products CN1C(C2)CCC1CC2OC(=O)C(CO)C1=CC=CC=C1 RKUNBYITZUJHSG-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
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 1
- 229940121948 Muscarinic receptor antagonist Drugs 0.000 description 1
- BQOWUDKEXDCGQS-UHFFFAOYSA-N [CH]1CCCC1 Chemical compound [CH]1CCCC1 BQOWUDKEXDCGQS-UHFFFAOYSA-N 0.000 description 1
- 229960000583 acetic acid Drugs 0.000 description 1
- 230000001476 alcoholic effect Effects 0.000 description 1
- 125000000217 alkyl group Chemical group 0.000 description 1
- 239000012736 aqueous medium Substances 0.000 description 1
- RKUNBYITZUJHSG-SPUOUPEWSA-N atropine Chemical compound O([C@H]1C[C@H]2CC[C@@H](C1)N2C)C(=O)C(CO)C1=CC=CC=C1 RKUNBYITZUJHSG-SPUOUPEWSA-N 0.000 description 1
- 229960000396 atropine Drugs 0.000 description 1
- 238000009835 boiling Methods 0.000 description 1
- 150000007942 carboxylates Chemical class 0.000 description 1
- 239000003054 catalyst Substances 0.000 description 1
- 239000000812 cholinergic antagonist Substances 0.000 description 1
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 1
- 238000004821 distillation Methods 0.000 description 1
- SRCZQMGIVIYBBJ-UHFFFAOYSA-N ethoxyethane;ethyl acetate Chemical compound CCOCC.CCOC(C)=O SRCZQMGIVIYBBJ-UHFFFAOYSA-N 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 229940064982 ethylnicotinate Drugs 0.000 description 1
- 239000012362 glacial acetic acid Substances 0.000 description 1
- WSFSSNUMVMOOMR-NJFSPNSNSA-N methanone Chemical compound O=[14CH2] WSFSSNUMVMOOMR-NJFSPNSNSA-N 0.000 description 1
- 229940102396 methyl bromide Drugs 0.000 description 1
- 150000007522 mineralic acids Chemical class 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- MUMZUERVLWJKNR-UHFFFAOYSA-N oxoplatinum Chemical compound [Pt]=O MUMZUERVLWJKNR-UHFFFAOYSA-N 0.000 description 1
- 229910052763 palladium Inorganic materials 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 229910003446 platinum oxide Inorganic materials 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 150000003254 radicals Chemical class 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 229920006395 saturated elastomer Polymers 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 239000010902 straw Substances 0.000 description 1
Landscapes
- Hydrogenated Pyridines (AREA)
Description
Procédé de préparation du 2-cyclopentyl-4-méthylpentanoate de 1-méthyl-3-pipéridylméthyle. La présente invention se rapporte à la pré paration de 2-cy cloa.lcoyle-4-méthy lpentanoates de 1-méthyl-3-pipéridylméthyle, ayant la for- niule.
EMI0001.0009
clans laquelle R est un radical cyclopentyle ou e yel ohexyle.
Ces nouveaux composés, de même que leurs sels d'acides et leurs sels d'ammonium quater naires, ont des propriétés pharmacologiques très utiles, et sont. particulièrement précieux comme agents anticholinergiqnes très efficaces. Par exemple, le composé dans lequel R est. un radical cyclopentyle a une efficacité presque double de celle de l'atropine.
Les esters à l'état de base libre peuvent être convertis en sels d'acides en faisant agir sur eux, de préférence dans un milieu non aqueux, un acide thérapeutiquement accepta ble, par exemple de l'acide chlorhydrique dans une solution éthérée ou alcoolique.
Les sels d'ammonium quaternaires sont préparés en mélangeant les esters à l'état de base libre avec un ester alcoylique inférieur ou aralcoyli- que d,'un acide inorganique fort, ou d'un acide organique sulfonique, de préférence dans un solvant organique inerte, tel que le benzène ou l'éther.
Le présent brevet a pour objet un procédé de préparation du 2-ëyclopentyl-4-méthylpen- tanoate de 1-méthyl-3-pipéridylméthyle, carac térisé en ce qu'on fait -réagir un halogénure de l'acide. 2-cyclopentyl-4-méthylpentanoique avec du 1-méthyl-3-pipéridylméthanol, et en ce qu'on fait réagir l'halogénhydrate résultant avec une base.
La base libre obtenue possède un indice de réfraction nD -1,4702.
<I>Exemple:</I> On chauffe au reflux une solution de 15,2 g (0,075 mole) de chlorure de 2-cyclo- pentyl-4-méthylpentanoyle préparé à partir d'acide 2-cyclopentyl-4-méthylpentanoïque et de chlorure de thionyle d'après Moffet et coll., J. Org. Chem. Vol. 15, 352 (1950) dans 50 cm3 de benzène et on y ajoute lentement une solution de 9,67 g (0,075 mole) de 1- méthyl-3-pipéridylméthanol (préparé comme décrit plus bas) dans 50 cms de benzène.
Le mélange est chauffé pendant un temps assez court, refroidi plus longtemps et ensuite éva poré jusqu'à ce qu'il soit sec. Le résidu est dissous d'ans de l'eau, la :solution est extraite avec de l'éther et. la couche aqueuse est rendue basique avec une solution à 101/a de carbo- nate de sodium. La base libre est. extraite avec de l'éther et la solution éthérée est. séchée avec du sulfate de magnésium anhydre.
Un petit échantillon de cette solution sé- ehée a été saturé avec de l'acide ehlorh;-dri- que gazeux. Le chlorhydrate de 2-cyeloperityl- 4-méthylpentanoate de 1-méthyl-3-pipéridyl- méthyle se sépare à l'état d'huile qui ne se solidifie pas. Un échantillon analogue, traité à l'acide bromhydrique, donne du bzomhydrate qui est aussi une huile. La plus grande partie de la solution éthérée a été traitée au bro mure de méthyle gazeux.
On obtient un préci pité semi-solide ayant un point, de fusion entre 90 et 150 C. Après plusieurs recristallisa- tions dans un mélange éther-acétate d'éthyle et finalement dans de l'acétate d'éthyle pur, on obtient 5,9 g de méthobromure clé 2-eyelo- pentyl-4-méthylpentanoate de 1- méthyl - 3 - pipéridylméthyle, fondant entre 1.59 6 et 162 6 C (eorr.).
Analyse:
EMI0002.0025
Calculé <SEP> pour <SEP> C19H3sBriVO.
<tb> C <SEP> : <SEP> 58,45; <SEP> H <SEP> : <SEP> 9,29; <SEP> Br: <SEP> 20,47.
<tb> Trouvé: <SEP> C: <SEP> 58,49; <SEP> H: <SEP> 9,08; <SEP> Br: <SEP> 20,55.
<tb> 58,43 <SEP> 9,07 La. base purifiée libre, le 2-cyclopentyl-4- méthylpenta.noate de 1- méthyl-3-pipéridyl- méthyle possède un indice de réfraction n D =l,4702.
Le 1-méthyl-3-pipéridylméthanol, employé comme l'un des produits de départ, est. pré paré à partir de nicotinate d'éthyle qu'on traite avec de l'acide acétique glacial, dilue et hydrogène d'abord en présence d'oxyde de platine d'Adams puis, après addition de formaldéhy de, en présence d'un catalyseur au palladium. Le produit. hydrogéné est traité avec de l'hydroxyde de potassium et fournit du 7-méthylpipéridine-3-earboxylate d'éthyle; point. d'ébullition: 98-99 5<B>C</B> sous<B>17-18</B> mni (76 I/o) ;<B>n25</B> = 1,4474.
Ce carboxylate est. traité à chaud avec du sodium métallique dans du toluène anhydre. Le mélange refroidi est lentement hydrolysé avec de l'eau, la couche aqueuse est. extraite avec du toluène et l'extrait. obtenu fournit, par distillation, du 1-niéthy l-3-pipér idyIlné- thanol sous forme d'huile (le couleur jaune paille, rtri = 1,4752 (82,8 0/0),
A process for preparing 1-methyl-3-piperidylmethyl 2-cyclopentyl-4-methylpentanoate. The present invention relates to the preparation of 1-methyl-3-piperidylmethyl 2-cy cloa.lcoyl-4-methylpentanoates, having the formula.
EMI0001.0009
where R is a cyclopentyl or e yel ohexyl radical.
These new compounds, as well as their acid salts and their quaternary ammonium salts, have very useful pharmacological properties, and are. particularly valuable as very effective anticholinergic agents. For example, the compound in which R is. a cyclopentyl radical is almost twice as effective as atropine.
Esters in the free base state can be converted to acid salts by causing them to act, preferably in a non-aqueous medium, with a therapeutically acceptable acid, for example hydrochloric acid in an ethereal or alcoholic solution. .
Quaternary ammonium salts are prepared by mixing the esters in the free base state with a lower alkyl or aralkyl ester of a strong inorganic acid, or of an organic sulfonic acid, preferably in an organic solvent. inert, such as benzene or ether.
The present patent relates to a process for the preparation of 1-methyl-3-piperidylmethyl 2-cyclopentyl-4-methyl pentanoate, characterized in that an acid halide is reacted. 2-Cyclopentyl-4-methylpentanoic with 1-methyl-3-piperidylmethanol, and in that the resulting hydrohalide is reacted with a base.
The free base obtained has a refractive index nD -1.4702.
<I> Example: </I> A solution of 15.2 g (0.075 mol) of 2-cyclopentyl-4-methylpentanoyl chloride prepared from 2-cyclopentyl-4-methylpentanoic acid is heated to reflux and thionyl chloride according to Moffet et al., J. Org. Chem. Flight. 15, 352 (1950) in 50 cm3 of benzene and a solution of 9.67 g (0.075 mol) of 1-methyl-3-piperidylmethanol (prepared as described below) in 50 cms of benzene is slowly added thereto.
The mixture is heated for a relatively short time, cooled longer and then evaporated until dry. The residue is dissolved in water, the solution is extracted with ether and. the aqueous layer is made basic with a 101 µl solution of sodium carbonate. The free base is. extracted with ether and the ethereal solution is. dried with anhydrous magnesium sulfate.
A small sample of this dried solution was saturated with hydrochloric acid gas. 1-Methyl-3-piperidyl-methyl 2-cyeloperityl-4-methylpentanoate hydrochloride separates as an oil which does not solidify. A similar sample, treated with hydrobromic acid, gives bzomhydrate which is also an oil. Most of the ethereal solution was treated with methyl bromide gas.
A semi-solid precipitate is obtained having a melting point between 90 and 150 C. After several recrystallizations in an ether-ethyl acetate mixture and finally in pure ethyl acetate, 5, 5. 9 g of 1-methyl-3-piperidylmethyl 2-eyelopentyl-4-methylpentanoate key methobromide, melting point between 1.59 6 and 162 6 C (eorr.).
Analysis:
EMI0002.0025
Calculated <SEP> for <SEP> C19H3sBriVO.
<tb> C <SEP>: <SEP> 58.45; <SEP> H <SEP>: <SEP> 9.29; <SEP> Br: <SEP> 20.47.
<tb> Found: <SEP> C: <SEP> 58.49; <SEP> H: <SEP> 9.08; <SEP> Br: <SEP> 20.55.
<tb> 58.43 <SEP> 9.07 The free purified base, 1-methyl-3-piperidyl-methyl 2-cyclopentyl-4-methylpenta.noate has a refractive index n D = 1.4702.
1-methyl-3-piperidylmethanol, used as one of the starting materials, est. prepared from ethyl nicotinate which is treated with glacial acetic acid, diluted and hydrogenated first in the presence of Adams platinum oxide then, after addition of formaldehyde, in the presence of a palladium catalyst. The product. hydrogenated is treated with potassium hydroxide to provide ethyl 7-methylpiperidine-3-earboxylate; point. boiling: 98-99 5 <B> C </B> under <B> 17-18 </B> mni (76 I / o); <B> n25 </B> = 1.4474.
This carboxylate is. heat treated with metallic sodium in anhydrous toluene. The cooled mixture is slowly hydrolyzed with water, the aqueous layer is. extracted with toluene and extract. obtained gives, by distillation, 1-niethy l-3-pipér idyIlnéthanol in the form of oil (the color straw yellow, rtri = 1.4752 (82.8 0/0),
Claims (1)
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US306511XA | 1951-07-20 | 1951-07-20 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CH306511A true CH306511A (en) | 1955-04-15 |
Family
ID=21855252
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CH306511D CH306511A (en) | 1951-07-20 | 1952-07-16 | A process for preparing 1-methyl-3-piperidylmethyl 2-cyclopentyl-4-methylpentanoate. |
Country Status (1)
| Country | Link |
|---|---|
| CH (1) | CH306511A (en) |
-
1952
- 1952-07-16 CH CH306511D patent/CH306511A/en unknown
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