JPS59222477A - Trans-dl-1-alkyl-6-alkoxyoctahydroquinoline - Google Patents

Abstract

(57) [Summary] This bulletin contains application data before electronic filing, so abstract data is not recorded.

Description

DETAILED DESCRIPTION OF THE INVENTION US Patent U9. ytys discloses a series of octahydropyrazolo[3,+-g]quinolines that are useful as prolactin inhibitors and in the treatment of Parkinson's disease. The compounds disclosed therein are said to have dopamine agonist (dopaminergic) activity. One drug that shows high activity is n- on the quinoline nitrogen.
It has a propyl group.

An important intermediate in the production of these octahydropyrazolo[3, hiro-g]quinolines is trans-di-”/-alkyl-ot-oxodecahydroquinoline, one of its stereoisomers (11taα, taβ compound) is disclosed in U.S. Pat. No. 4+!,/9 in column j of No.

The same intermediates are related compounds described in U.S. Pat.

Deoctahydro-2H-pyrrolo[4'l-g] is used in the production of coquinolines. Octahydro-2H-pioo[3,4g]quinolines C, F.

Regarding activity, octahydro-/H (and 2H)
-Pirazoro [! [Hiro-g] Similar to quinolines.

Trans-dl-/- disclosed in the above two patents
The synthesis method of alkyl-6-oxodecahydroquinoline is as follows:
Although feasible, it requires five steps from commercially available starting materials. Furthermore, the yield is not as high as desired for a commercial process.

The present invention relates to an improved process for the preparation of trans-dJ-/-alkyl-ot-oxodecahydroquinolines, which is easier to carry out and provides higher yields than previously known processes.

The present invention provides trans-dJ −/-alki Jl/ −1
This invention relates to an important new intermediate for producing -oxodecahydroquinolines, namely trans-octahydroquinoline represented by formula (1).

Insect [in the formula, R and R) independently C7-C, ? Represents alkyl. C1 of the transformer expressed by the expression ■? j mixture is represented by the following formula.

[In the formula, R and R) have the same meanings as above. The octahydroquinoline compound of the above formula (2) has the formula (1) [wherein R and R have the same meanings as above, and the nine-dotted line indicates the presence of a double bond/even. Hexavitroquinoline represented by Formula 1 MBH.

Alternatively, MCNBH is produced by reacting with a reducing agent represented by M (representing an alkali metal) in a non-reactive solvent.

Examples of alkali metals in reducing agents are sodium,
Potassium or lithium are preferred, but sodium is preferred. The preferred reducing agent is:

Sodium borohydride or sodium cyanoborohydride. An important property of a reducing agent is its stereoselective reducing ability. Mutually inert solvents used are, for example, tetrahydrofuran, dioxane, dimethoxyethane, diglyme.

C, -C, alkanol (especially methanol or ethanol). The preferred temperature is room temperature, i.e. about 20
-25'C. If necessary, a small amount of mineral acid (e.g. HC71 or H,2So4t) or c, -cj
An alkanoic acid (preferably glacial acetic acid) may be present.

The isomer mixture of the compound represented by formula (2) consists of the following primary compounds.

■aIvbIvC [In the formula, R and Ri have the same meanings as above. ] In the above formula, R and bow are C7-C5 alekyl.

For example, methyl, ethyl or n-propyl.

The total synthetic route starting from a known compound and passing through nine intermediates of the present invention to a drug-active compound is shown in a flowchart. In the formula, R and R each independently represent c, -cJF, X represents halogen or pseudohalogen, 9M represents an alkali metal, and R1 represents aryl.

(The following is a blank space.) According to flowchart A, Otsu-afrekoxyquinoline (e.g. Otsu-methoxyquinoline, available for purchase) is mixed with an alkyl or allyl halide or Pseudohalides (preferably alkyl iodites).

Quaternize with RI). Here “Shuudohalide”
The term refers to groups that act chemically similar to halogens, such as mesyloxy and tosyloxy. This quaternization reaction is conveniently carried out at the boiling point of the solvent used. Quaternary salts (IF) are crystalline substances. In the second step of this synthetic route, the salt described above is hydrogenated under pressure in the presence of a noble metal catalyst 1, such as platinum (which serves as an oxidation tip), palladium, rhodium, etc. This hydrogenation.

Preferably, it is carried out in an acidic medium 9, for example glacial acetic acid, with heating (i.e. at θ-/θθ°C). Both low-pressure and high-pressure conditions are possible; 3. for low-pressure hydrogenation; ,! ;-'A, can be operated under various pressures from 2 kqi♂ to 703 kQ/σ2 for high pressure hydrogenation. For example, 0 mol of ① is reduced in glacial acetic acid using platinum oxide as a catalyst with yo3tcg/cJ, /-alkyl-6
- It takes about 70 hours to obtain medoxytetrahydroquinoline by converting it to the hydroiodide salt (■a).

The free base (III) is prepared by treating an aqueous solution of the above salt with a base and extracting the base-insoluble tetrahydroquinoline with a water-immiscible solvent.

In the second reduction step, the above-mentioned tetrahydroquinoline was dissolved in liquid ammonia using an alkali metal.

For example, sodium or lithium. Reduce under the Birch reducing conditions used. Quinoline is added to an alkali metal solution in liquid ammonia, usually as a solution in tetrahydrofuran. After stirring the reduced mixture at the temperature of liquid ammonia for a suitable time, absolute ethanol is added until the blue color disappears. Leave the reaction solution at room temperature to evaporate the ammonia. The remaining tetrahydrofuran solution is a hexahydrofuran of formula (i) [i.e., lV&. (/-alkyl-ot-alkoxy-/: 2.3, beg'l-aS,
j-hexahydroquinoline, IVb(/-alkyl-
Otsu-Alkoxy-/2 3, % HiroaR. j-hexahydroquinoline) and ■C(two-alkyl-et-alkoxy-1) 2.3.

Contains a mixture of (Hum♂-hexahydrofuran)].

The mixture of hexahydroquinoline isomers is then prepared with the formula MB
It is stereoselectively reduced using a reducing agent represented by H, or MCNBHJ (M is an alkali metal), such as sodium borohydride or sodium cyanoborohydride. For this reaction, tetrahydrofuran or c,-
cJylukanol is used as a solvent. Also, small amounts of mineral acids (e.g. HCI).

H. 2So□) or C,-C-yoalkanoic acid (e.g.
Glacial acetic acid) may be added, with glacial acetic acid being preferred. This reduction is carried out at room temperature.

The product of this reduction is the racemate of formula (i.e., Va
(/-alkyl-3<t, 4as, J:fas-octahydroquinoline) and VIA(,/-alkyl-QaR, aR-octahydroquinoline)]. When this racemate is treated with water-soluble, preferably hydrochloric acid, a racemic mixture of trans-dJ-/-alkyl-6-oxidecahydroquinoline (I) is obtained. Formula I
Reaction of the d-oxo compound with dimethylformamide dimethyl acetal yields trans-di-/-alkyl-dimethylaminomethylene decahydroquinoline (■). The intermediate of formula (1) is further subjected to one of the following two reactions. Namely.

When reacted with glycine potassium salt and then with acetic anhydride, trans-dl-,2-acetyl-! -alkyl-hydro-, 2H-pyrrolo[3,! -g]quinoline (V[
) is obtained. When this compound of formula (1) is then subjected to basic hydrolysis, trans-di-! ;-Alkyl'l,
4ta l diot, Zpeza a + 9-octahydropyrrolo・
[3hiro-g]quinoline ((2) is obtained. On the other hand, the formula ■
When reacting the compound with hydrazine, US patent t6i
trans-dJ-, which is described in 'yyais issue.
5--alkyl-lAgua,orotsu,ZbefFL. 9-octahydro-/H (or 2H)-pyrazolo [3.
A tautomeric mixture of g = g coquinoline (]Xa, Kb) is obtained.

The method for producing the above compound will be explained below using examples.

Production of starting materials.

Reference Example / Production of /-n-propyl-O-methoxyquinolinium iodide O-Methoxyquinoline θθg was mixed with 2.3 l of acetonitrile containing n-propyl iodite and rstttty.
The solution was heated at reflux in a nitrogen stream for about 1/2 hour. Cool the reaction mixture.

The solvent was distilled off under reduced pressure. The residue was dissolved in acetone and ether was added until precipitation started. Crystals were formed by scraping the vessel wall. The crystalline n-propyl-methoxyquinolinium iodide thus produced was analyzed. Amount gained! ;l/-7,21,"P///-173°C
0Rr (g:/, chloroform:methanol)=o
Jf. Further, the target substance of /3 and 2f was obtained from the furnace liquid.

NMR was compatible with the structure above.

Reference Example Co/-n-propyl-6-medoxy/, 2.3. !
-Tetrahydroquinoline in Reference Example/By hydrogenating /-n-propyl-6-medoxyquinolinium iodide obtained in /-n-propyl-B-
Methoxy 12.3.4t-tetrahydroquinoline was obtained. A typical operation was as follows. Quaternary salt 74
Dissolve 3g in glacial acetic acid/9/7#Il and add 20f of platinum oxide.
added. Hydrogenation is approximately /θθ°C1703kg/c
I went with w'. After about 70 hours, the theoretical amount of hydrogen had been absorbed. The hydrogenation mixture was filtered to remove the catalyst, r=#L
The solvent was distilled off under reduced pressure. The residue was dissolved in water, and a saturated aqueous solution of sodium hydrogen carbonate was added to this aqueous solution to make it basic.

Extracted with ether. /-n-propyl-6-medoxy 123. produced in the above reaction. 'A- Wash the ether extract containing tetrahydroquinoline with water.

Dry. The ether was distilled off under reduced pressure to obtain +/''-propyl-methoxy<2s, ta-tetrahydroquinoline 929.
It is also possible to carry out the process at a low pressure of about 1 A22 kq/cytr'. Furthermore, instead of platinum oxide.

Equivalent or better results can also be obtained using palladium/carbon or rhodium/alumina.

Allyl halides, such as allyl bromide, can also be used to quaternize O-methoxyquinoline. When the resulting N-allyl-6-medoxyquinolinium bromide is hydrogenated with a noble metal catalyst such as platinum oxide, the final product is the same /-n-propyl-methoxy- as described above with λ,3gatetrahydro. Get quinoline.

Reference Example 3 /-n-propyl-6-medoxy t23-hexahydroquinoline+/n-propyl-6-medoxy 42. J, 4% gaR, j-hexahydroquinoline and/-n-propyl-6-methoxy 123, II,
Preparation of %aS,,j;-hexahydroquinoline Ammonia 31 was dried over metallic sodium for about 7 hours. 0) ml of the thus dried ammonia ♂ was introduced by distillation into a three-necked flask equipped with a gas inlet tube, a condenser with a drying tube, and a dropping funnel. Stir the ammonia with a magnetic stirrer.

/-n-propyl-6-medoxy i obtained in Reference Example 2,
23. It-tetrahydroquinoline≠θf was dissolved in THF (dry, distilled method) 2θθml and added. Metallic lithium/θf was cut into pieces of approximately /i size and added all at once to the liquid ammonia tetrahydroquinoline-THF solution. The reaction mixture was stirred for about 20 minutes and about 0 tsl of absolute ethanol was added dropwise over 75 minutes. The mixture was stirred overnight in a stream of nitrogen without external cooling, during which time the ammonia was evaporated. θOygl of water was added, and the mixture was extracted three times with 2θθml of dichloromethane. b The chloromethane layers were combined, washed with saturated aqueous sodium chloride, dried and the solvent was evaporated under reduced pressure. The thus obtained /-n-propyl-6-medoxy has 23. 'A2-hexahydroquinoline, /-n-propyl-6-medoxy 2.
3. II,! aR,! ;-hexahydroquinoline and/-n-propyl-6-methyl-12゜ulA%a
S, a mixture of terhexahydroquinolines.

Pressure θθ3 Torr, Temperature range Zatt-/, :zooC
distilled in. Yield, 32.6y (Za0j section).

Manufacture of target substance.

Example/trans-dl-/-n-propyl-6-medoxy 1.2. ．． 3.1A11. Preparation of a, j 4 Ja -octahydroquinoline A solution was prepared by dissolving 1 Attty of sodium cyanoborohydride in 2!0 ynl of THF by dry distillation.

/-n-propyl-O-methoxy-/ obtained in Reference Example 3
2.3. 'A muza-hexahydroquinoline,/-n-propyl-6-medoxy 42.3. %'AaR, mixture of 3-hexahydroquinoline and /-n-propyl-Otsuichi methoxy 12.31%≠aS-hexahydroquinoline/-'1. ff was dissolved in THF/θθml, and then 17 tgl of glacial acetic acid was added. The reaction mixture was stirred at room temperature for approximately 7.25 hours, at which point 17 mL of glacial acetic acid
1 was added. Stirring was continued for an additional 30 minutes and the entire reaction mixture was pressurized into 3θ0 tttl of water. The entire aqueous mixture was extracted three times with 2θθtttl portions of dichloromethane. Combine the organic layers and wash 7 times with 1 equal volume of water.

It was then dried. The solvent was removed under reduced pressure and a yellow viscous oily residue was distilled off. Thus obtained trans-di-/
-n-propyl-methoxy-23゜1A4La
, a-octahydroquinoline has a pressure θ/3-
Distilled at 0.20 Torr, temperature 7θ-/g 0°C. yield, 10 IC yield).

Example λ trans-dJ −/-n-propyl-methoxyt2,3+a, 4. Production of yza-octahydroquinoline/-n-propyl-6-medoxy/: 2J, % g-
Hexahydroquinoline, /-n-propyl-methoxy-42,3k1ilaR,j-hexahydroquinoline and /-n-propyl-6-medoxy with λ, 3.
mixture of j-hexahydroquinolines/θ
A solution of g dissolved in ethanol/Hiro θtttl.

Sodium cyanoborohydride2. / 9f and HC
12 ml of trans-rll-/-n-propyl-methoxy-l having the same boiling point range as Example/2. A-octahydroquinoline was obtained (yield 9jl).

Example 3 Trans-dj! -/-n-propyl-6-medoxy 12.3. 'l,'lJh,3,1. Production of IFL-octahydroquinoline/-n-propyl-O-methoxy-/: 2.3. '
A-hexahydroquinoline, /-n-propyl-O-methoxy-12,3,'A,'I-aFL, 5-hexahydroquinoline and /-n-propyl-6-medoxy 12.3. 2.3 ml of glacial acetic acid was added at once to a solution of a mixture of hexahydroquinolines/θg dissolved in 110 g of ethanol. An ethanol solution of sodium borohydride 132f was added dropwise to the above mixture. The reaction mixture was cooled and heated in a nitrogen stream to approx.
Stir for an hour. Following the procedure of Example 1, the product trans-d71-/-n-propyl-methoxy-42
, 3, 1A Hiroa, 4.5: , ra-octahydroquinoline was isolated and identified as the product of Example 1 (yield: 2).

Example Hirotrans-di-/-n-propyl-ot-methoxy-/
: 2.3.41. Preparation of QB, j4J&-octahydroquinoline The procedure of Example 3 was carried out using isopropanol pufferfish θtxl in place of ethanol to produce the same trans-dJ-/-n-propyl- as the product of Example/. 6-Medoxy 12.3. A-octahydroquinoline was obtained (yield: 2).

Example! trans-dl-/-n-propyl-ot-methoxy-1
Preparation of 2,3,lAga + Mpeza a-octahydroquinoline The procedure of Example 3 was repeated using methanol/'A□tl instead of ethanol to produce the same trans-di-/ -n-propyl-ot-methoxy-z,l
, Kuga, J4ffa-octahydroquinoline was obtained (
Yield: 92).

Example O trans-dJ-/-n-provir-6-methoxy 1
2,33. 'Aa, 3,1. Preparation of IFh-octahydroquinoline Ethanol 11 is used to dissolve sodium borohydride.
The same procedure as in Example 3 was carried out using 0πl and methanol/θθml instead of ethanol/llθtnl to obtain the same trans-dl−/− as the product of Example/.
n-Propyl-O-methoxy-12゜3, 41. ga
, MuJJa-octahydroquinoline was obtained (yield 9g
%).

Example 7 Trans-d7B-/-1-propyl-MeVxy-
Preparation of 12,3,% 4ta, Mu5Ja-octahydroquinoline The procedure of Example A was carried out by omitting the use of glacial acetic acid.

Trans-dil-/-n identical to the product of Example/
-Propyl-methoxy-12,3,'A, Mpezaa-octahydroquinoline was obtained (yield: 9).

Examples and trans-d7-/-n-propyl-ethoxy-/, 2,3. lAga, J:♂a Me octahydroquinoline production/-n-propyl-methoxy-hexahydroquinoline mixture/θg, sodium borohydride dissolved in ethanol≠θ3/θ7f, methanol 10θπt and glacial acetic acid 2 The same trans-di-/-n-propyl-methoxy-/2J,lAga,J assay a-
Octahydroquinoline was obtained (yield: 99 pieces).

Reference example for the production of active substances Hirotrans-di-/-n-propyl-O-oxo-
/ 2.3.1 AIILALUM B, Z PEZA - Preparation of a-decahydroquinoline THF Example 23/ Trans-di-/
-n-propyl-O-methoxy-/: 2.3. 'A
Hiroa, Mu JJ & - Octahydroquinoline 3. If was dissolved and /theta sulfuric acid 'Ayttl was added, the biphasic mixture was heated to reflux temperature for about 77 hours and then pressed into a replenishing aqueous sodium hydroxide solution. This alkaline aqueous solution was extracted with dichloromethane, the extract was dried, and the solvent was distilled off under reduced pressure. Residual oily substance2. If is trans-di-/-
Contains n-propyl-O-oxodecahydroquinoline,
It was distilled at a temperature range of 3 to 7 °C at Q/Torr. TLC showed that this distillation fraction contained over 90 molecules of trans-dJ-/-n-propyl-O-oxodecahydroquinoline.

Alternatively, trans-di-/-n-propyl-
6-Medoxy 12.3. lAAc15pezatohexahydroquinoline 0g in THF! ; Dissolved in Oml. /N hydrochloric acid 2! Add i'ml of the mixture and stir for 0 hours in a nitrogen stream. The reaction mixture was then made basic with a /HiroN aqueous sodium hydroxide solution, and the alkaline aqueous solution was extracted three times with dichloromethane. Combine the organic extracts.

After drying, the solvent was distilled off under reduced pressure to obtain a transparent orange oil 1Aiy as a residue. TLC showed a single spot with small amounts of leading and trailing impurities. This is distilled to obtain a boiling point of 77-7°C10θ2jTorr, (y
)') Lance-di-/-n-propyl-ot-oxodecahydroquinoline was obtained. Yield, 'A39f (94</
Section).

As mentioned above, when trans-dF/-alkyl-6-oxodecahydroquinoline is reacted with dimethylformamide dimethyl attar, trans-dJ-/-alkyl-methylamino methylenedecahydroquinoline (■) is obtained. It will be done. This intermediate is reacted with glycine potassium salt,
Treatment with acetic anhydride produces trans-di-2-acetyl-
5-alkyl-? -Octahydro2H-pyrrolo[3, hiro-g]quinoline (■) is given. When this acetyl compound is subjected to alkaline hydrolysis, trans-di-j-alkyl-[3,'l-g]quinoline (■) is obtained. The crystal is no(-
It is a dopamine agonist useful in treating Kinson's symptoms or hyperprolactin secretion (US patent %23-09). Moreover, when 7-dimethyJ rare methylene compound (■) is reacted with hydrazine.

Tran X -di-! ;-alkyl lA*a, 4
Otsu, 7J7J'a.

? A tautomeric mixture consisting of -octahydro/H-pyrazolo[3g-g]quinoline and the corresponding 2H compounds (■a and ■b) is obtained. Quartz crystals are also useful as dopamine agonists (U.S. Pat.
j).

Claims (1)

[Claims] l Formula V [wherein R and R2 independently represent c/'J alkyl. ] Trans-octahydroquinoline represented by. 2, trans-dl/-'n-propyl-methoxy/, 2% ga, 45 ya-octahydroquinoline. 3 Formula ■ [In the formula, R and - independently represent C7-CJ alkyl, and the dotted line indicates the presence of 7 double bonds. ] in a non-reactive solvent. Formula MCN
BH, t? :-HaMBH, [wherein M represents a potash metal. ] by reacting with a reducing agent represented by the formula (1) Blue [where R and bow have the same meanings as above. ] A manufacturing method characterized by obtaining trans-octahydroquinoline represented by: Hiroshi The method according to claim 3, wherein the reducing agent is sodium cyanoborohydride. The method according to the claims, wherein the non-reactive solvent is tetrahydrofuran. B. Claim 3, described method 7, in which the reducing agent is sodium borohydride. Claim 3, described method 7, in which the non-reactive solvent is methanol or ethanol. and the method described in Claim 3, H or O, in which the reaction is carried out in the presence of a mineral acid. ? Claims FIJJ in which the reaction is carried out in the presence of glacial acetic acid
3. 'A method is described in B. /θ/-n-propyl-methoxyt, 2 g. lA4.5'-hexahydroquinoline, /-n-propyl-methoxy-ni, 3. 4taR, j-hexahydroquinoline and/-n-propyl-ethoxy-12,3,1A11. FLS, j-hexahyl'
A mixture of
-n-propyl-O-methoxy-/: 2,3.1Al
4. A process as claimed/described for obtaining It&, 4, gza-octahydroquinoline. /i/-n-propyl-6-medoxy X2. In this case, -hexahydroquinoline, /-n-propyl-methoxy-2,3. %1laR,J-monohexahydroquinoline and/-n~propyl-6-medoxy/:
2.3. Beg4La8. j;-A mixture of hexahydroquinolines was reacted with sodium perate hydride and glacial acetic acid to form trans-di-/-n-, propyl-6-medoxy 12,3. '1,4ta,9. Claims/Description of the process for obtaining za-octahydroquinoline.