Method of producing optically active trans-1-n-propyl-6-oxo-hydroquinolines

专利摘要:
4aR,8aR-1-n-Propyl-6-oxodecahydroquinoline is prepared from the corresponding racemate using optically active ditoluoyltartrate acid.
公开号:SU1282815A3
申请号:SU833622809
申请日:1983-07-27
公开日:1987-01-07
发明作者:Мехнерт Шаус Джон；Нолан Бухер Ричард
申请人:Эли Лилли Энд Компани (Фирма)；
IPC主号:

专利说明:


s
1i2
The invention relates to methods for the production of optically active trans 1-n-propi-p-6 oxohydroquinolines, but compounds that can be used in the synthesis of octahydropyrasol-3,4-g-quinolins used in medicine.
The purpose of the invention is to obtain new optically active trans-l-n-prop-6-oxyhydroxylinolines, the use of which allows to increase the yield and simplify the process of obtaining optically active derivatives.
Selection of separation agent.
As potential separating agents, a number of optically active acids are tested: (+) - tartaric, (-) - dibenzoyl tartaric, (+) - camphoric, (+) - 10-camphorsulfonic acid, (-) - almond, (-) - block, N-acetyl-1-glutamic acid and t-butyloxycarbonyl-b-phenylglycine. These acids are either incapable of forming a crystalline salt with dl-TpaHc-1-propyl-b-oxodecahydroquinoline, or, in those cases when a crystalline salt is formed, recrystallization does not give an effective optical purification. Thus, (-) - di-para-toluoyl tartaric acid and (+) - di-para-toluic acid are unique, readily available, effective separating agents for gRance-dl-1-n-propyl-6-o-skdedek-
hydr o quinoline a
The solvent system is a fish from those that give crystalline salt with high optical purity and high yield,
the table shows the solvent systems used, the yields of the salt (-) - di-para-toluoyl tartaric acid, based on the starting trans-dl-ketone, melting points, сА-1 and tcf-l (both with c 1, CHjOH).
Although all the solvents listed in the table are suitable, plus the methanol from Example 1, the preferred straight chain C-C.-Alcae
NOLS, such as methanol, ethanol
and n-propanol, either individually or in combination with methylisobutyl ketone or acetonitrile. It is preferable to use a mixture of methanol and acetonitrile in a ratio of (1: 4) - (1:10) as a solvent for separating (-) - di-11lro-toluoyl tartaric acid, although
ABOUT
five
five
0
40

SP
Stencils are not (;. creegy -1 h: r; they, as long as there is sufficient penetration of methanol. In addition, better separation is achieved at a salt concentration of 0.15-0.16 mol / l, although concentrations are quite acceptable this range.
Example I. South of (-) - di-para-toluoyl tartaric acid is dissolved in 75 MJI warm methanol. The solution is added to a solution of 5.05 gtrans-dl-l-h-propyl-6-oxo dehydroquinoline in 15 ml of methanol. The reaction mixture is brought to a boil, and then allowed to cool to room temperature. After overnight, at room temperature, crystallization is stimulated by the addition of previously obtained seed crystals. The crystalline tartaric acid salt is filtered off and the filter residue is washed with methanol. Yield 2.813 g (18.7%) of a white crystalline solid containing (-) - dinar -toluoyl tartrate 4aR, 8aR-1-H-prop-6-oxo decahydroquinoline; Co "- -107.49 (СН, ОН,). Recrystallization of the salt from methanol gives 1, 943 g of optically pure salt, LcLl -108.29 ° (CHjOH,). The (-) - di-nafe-Toluoyl-tartaric acid salt thus obtained is treated with a dilute aqueous solution of sodium hydroxide, and the resulting alkaline solution is extracted with methylene chloride. The methylene chloride extract is dried, concentrated, and the solvent is removed from it under vacuum. The residue obtained is distilled to give a colorless oil containing purified 4aR, 8aR-1-H-nap-pil-6-oxodecahydroquinoline, t, kip. 82-86 with at 0.13 Torr, output 40-60% Cot. -88.51 (CH, OH,).
Other salts are obtained by dissolving the free base in ether, passing HCl gas through the solution, or adding an ethereal acid solution, followed by isolation by filtration of the salt insoluble in ether. Alternatively, a solution of the free base in a lower alkanol can be mixed with an acid solution in the same solvent, and soluble salt can be separated by evaporation of the solvent.
31
EXAMPLE 2 Following the procedure of Example 1, 48.8 g of tronc-dl-1-h-propyl-b-oxodecahydroquinol in 200 ml of acetonitrile are added to a warm solution of 101 g of (-) - di-porp -toluoyl tartaric acid in 1 liter of acetonitrile and 300 ml of methanol. The mixture is heated to reflux and then left to stand at ambient temperature overnight. Crystals fall out. The first harvest is 32 g (22% yield) of 4aR, 8aK-1-n-prop-6-OXODECAHYDROCHINOLINE (-) - DI naptictoluoyl tartaric acid, having
m.p. 158-9H; Co.r.p - -107.5 (s,
SNZON); Со6} -515,5 (,)
This separation is also carried out using 41.4 g of TPQHC -dl-1-n-propyl-6-oxodecahehydroquinoline and 80.8 g of monohydrate, and (-) - di-pschtra-luoyl tartaric acid in 500 ml of anhydrous methanol. Yield 34.5 g (28%),
W1 -107, -512.E-. (both with s), CH OH); optical purity i 97%.
PRI me R 3. Preparation of 4aR, 8aK-1-n-propyl-6-oxodecahydroquinoline and its (-) - di-para-toluoyltartrate.
A solution of 10 g (1 SQ.) Of (-) - di-para-toluoyl tartaric acid in 75 MP of thermal methanol is introduced into a solution of 5.05 g of trans- (t) -l-n-propyl-6-oxo-dehydroquinoline 15 ml of methanol. The reaction mixture is brought to a boil and then cooled to room temperature. The solution is incubated for 12 hours at room temperature and induces crystallization by adding previously obtained seed crystals. The crystalline tartrate is filtered, and the filter cake is washed with methanol. 2.813 g (18.7%) of a white crystalline solid is obtained, which is (-) - di-g Arv-toluyl tartrate 4aR, 8aR- -4-npomm-6- oxodecahydroquinoline. d 7 jj -107.49 ° (methanol, с l, 0); Cdf -512.89 (methanol, с 1.0).
The resulting (-) - tartrate (2.77 g) is dissolved in 60 ml of hot methanol, filtered and concentrated to 30 ml. Crystallization is initiated by the addition of seed crystals. After cessation of cristaapization, the crystals are filtered. Receive (-) - di-p -toluoyl tartrate 4aR, 8aR-l-H
j Oh
 five
20
EL
35 0

0
154
propyl-6-oxodecahydroquinoline as a white solid with so pl. 165.5-166.5 C (decomp.). Yield 1.943 g (70%). (D; / -108.29 ° (methanol, 1.0); (J) -516.48 ° (methanol, c 1.0).
The resulting (-) - tartrate (1.903 g) is recrystallized from 50 MP of methanol while the flask is shaken to initiate crystallization. Fine white needles are obtained, which are collected by filtration with a yield of 863 mg (45%) of (-) - 4aR, 8aR-l-n-propyl-6-octo-Pyproquinoline di-pro-toluoyl tartrate; m.p. 169.5 - 172 ° (decomp.) Optical purity. -107.89 ° (methanol, s 1.0); d7-516.48 ° (methanol, s).
22 g of (-) - 4aR, 8aR-l-n-propyl-6-oxodecahydroquinoline di-pro-toluoyl tartrate is suspended in 600 MP of water. The solution is alkalinized by the addition of an aqueous solution of sodium hydroxide. The resulting turbid solution is extracted with dichloromethane. The extract is dried over sodium sulfate and concentrated to form 4aR, 8aR-l-H-propyl-6-oxodecahydroquinoline as a brownish oil, mp. 84 - 87 ° C (0.25 Torr). Yield 17.52 g (93%). (D) p -87.9 ° (methanol, c 1.0); (dlj -380.2 ° (methanol, 1.0). The optical purity is 99%.
PRI me R 4. Preparation of 4aS, 8aS-1-H-propyl-6-oxodecahydroquinoline and its () -di-plrsx-toluoyltartrate.
To a solution of 192.0 g (0.95 eq.) Of the monohydrate of (:) - di-p-toluoyltartaric acid in 1 l of methanol was added 97.5 g of (1) -1-n-propyl-6-oxo-decahydroquinoline in 200 ml of methanol (1-and-propyl-6-oxodecahehydroquinoline is enriched with respect to the 4aS, 8a5 isomer). The solution is stirred, shaken to initiate crystallization, allowed to stand for two days, then filtered to obtain a white crystalline (±) -di-di-po-ra-toluo-4raS, 8aS-1-and-propyl-6-oxodecahydroquinoline; Mj + 106.0 ° (methanol, s 1.0); (d) 507.0 (methanol, c 1.0). Optical purity is 90% (admixture is an excess of enantiomorphic isomers).
The resulting salt is recrystallized from methanol to form, in the form of a white solid, 126.6 g of () di-parcene-toluoyl tartrate 4aS, 8aS-1-f -propyl-b-oxodecahydroquinoline. T.SH1. 166.5-167.0 ° C (Disag.); (D). + 107.0 ° (methanol, with l, 0); (d) n-512.0 ° (methanol, with 1.0). Optical purity.
The resulting salt (81.3 g) is introduced into a dilute sodium hydroxide solution, extracted with dichloromethane, and dried over sodium sulfate to form 29.7 g of light pink oil. The oil is distilled to give 26.1 g of a colorless oily product boiling at 79-97 ° and 0.2 torr pressure, which is 4aS, 8a5-1-n-propyl-6-oxo-dehydroquinoline; JЗ J,, 9 (methanol, с 1, 0); tdl-25. 370.5 ° (methanol, with 1, 0). Optical ска ska 96% purity.
PRI me R 5. Preparation of (-) - 4aR di-para-toluoyl tartrate, propyl-6-oxodecahydroquinoline.
To a solution of 82.6 g (0.92 eq.) Of (-) DI-parSHT-LUOLEVlIC ACID in 400 M
43.5 g of trans (1) -1-n-propyl-6-oxodecahydroquinoline in 100 MP methanol was added to methanol. The solution is stirred, then seeded and allowed to stand overnight. The solution is shaken several times a day over the next five days. The resulting solid was collected by filtration, giving 38.8 g (30%) of a white solid, representing (-) - di para-toluoyl tartrate 4aR, 8aK-1- -propyl-6-oxodecahydroquinoline; (d) -106.6 ° (methanol, c l, 0); Cd) g -507.8 (methanol, c 1.0). The optical purity is 92%.
The salt obtained is combined with other fractions (114.5 g) and recrystallized from 100 ml of methanol. Filtration of the resulting white solid yields 82.3 g (72%) of (-) - 4aR di-para-toluoyl tartrate, 8aH-1-n-propyl-6-oxodecahydroquinoline, m.p. 174-.176 ° С (decomp.); (d) -108.10 ° (methanol,, 0); (d) -516.3 ° (methanol,, 0). Optical purity “100%.
Example 6. Obtaining 4aR hydrochloride, 8aR-5-n-propyl-4,4a, 5,6,
828156
7.8, 8a, 9-octahydro-1I (m 211) -pirzolo (3,4-g) quinoline.
A solution of 52 g of optically pure 4aR, 8aR-l-H-propyl-6-oxodecahydro5 quinoline and 79 g of ethyl formate in 250 ml of tetrahydrofuran is introduced into a solution of 59.8 g of potassium tert-butylate in 600 ml of tetrahydrofuran, previously cooled to about.
to gas during addition. The reaction mixture is stirred at
temperature
for half an hour, and then at ambient temperature for another hour. 25.6 g of hydrazine is added to this mixture, and the pH of the solution is adjusted to 9 with 10% aqueous hydrochloric acid (approximately 500 ml). The reaction mixture was stirred vigorously for 2 hours at ambient temperature, after which it was poured into water. The aqueous mixture is made alkaline (pH 13) by the addition of a distributed aqueous solution of sodium hydroxide. The alkaline mixture is extracted with dichloromethane, the dichloromethane extract is separated and dried. The solvent is evaporated, a yellow foam is obtained in the residue, which, as indicated by thin layer chromatography, contains the necessary pyrazoloquinoline and a small amount of contaminant. The residue is dissolved. in 1 liter of hot methanol, to which 5- was added 250 ml of 1N. an aqueous solution of hydrochloric acid. The solution is concentrated, 65.4 g of 4aR, 8aR-5-H-propyl-4, 4a hydrochloride are obtained, 5,6,7,8,8a, 9-octahydro-1H (and 2H) - nHpa3ono 3; 4-g quinoline as a light yellow solid. Recrystallization from a mixture of methanol and ethyl acetate yields 51.7 g (76%) of a slightly yellow granulated solid; td.T at -121.0 ° (H, 0, s 1); Idl i -377.40 ° (HjjO, c 1).
 Calculated,%: C 61.04; H 8.67; N 16.43; C1 13.86. 50 Found,%: C, 61.32; H 8.53; N 16.22; C1 14.08.
Example 7. Preparation of 4aS hydrochloride, 8a8-5th propyl-4,4a, 5,6,7,
55
8, 8a, 9-octahydra) -1H (and 2H) -pyrazolo S 3,4-g quinoline.
7.7 g of potassium t-butylate are dissolved in 85 ml of tetrahydrofuran. The resulting solution is cooled to about
7
to 0 ° C. To this solution is added a mixture of 6.7 g of 4a, 8a-1-n-prop-b-oxo-decahydroquinoline and 10.2 g of ethyl formate in 40 ml of tetrahydrofuran. Gas added during addition. The reaction mixture is then allowed to warm to room temperature. Thin layer chromatography showed no starting material. Six ml of hydrazine hydrate was then added to the mixture, followed by the addition of a sufficient amount of 10% aqueous hydrochloric acid solution to bring the pH to about 9. This mixture was vigorously stirred at ambient temperature until completely absent. thin layer chromatography of intermediate formylketone. Re
 5 o
2828158
Radiate the latter with a simpler scheme and with a higher yield due to the absence of the need for separation into the antipodes of the final product.

权利要求:
Claims (4)
[1]
1. A method for producing optically active t (L "1-n-propyl-6-oxohydroquinolines of formula 1
0
xp
N-SzNt
characterized in that the racemic TpckHc-n-propyl-6-c
The mixture mixture is then drunk at times-20. Sodecahydroquinoline is introduced into the mutually added aqueous solution of sodium hydroxide, and the alkaline mixture is extracted with dichloromethane. The dichloromethane extract is dried, the solvent is removed in vacuo to form 9 g of a colorless foam. The resulting foam is dissolved in 100 MP of methanol, an equivalent amount of 1 M aqueous hydrochloric acid solution is added to the solution.
The resulting solution is concentrated to a white solid, which is recrystallized from a solvent mixture of methanol and ethyl acetate. The white solid is filtered off to give 5.68 g (65%) of chlorine 1drate 4aS, 8a5-5th propyl-4,4a, 5,6,7,8,8a, 9-octahydro-III (and 2H pyrazole- 3.4-g quinoline; (d) -j ± 120.6 (, c 1.0); (± 375.6 (, c 1.0). Optical purity.
Calculated,%: C 61.04; H 8.67; N 16.43; C1 13.86.
Found,%: C 61.10; H 8.45; N 16.60; C1 13.83.
The implementation of the proposed method allows to obtain optically active trlns -1-n-propyl-6-oxohydroquinolines, which are then used in the synthesis of optically active derivatives of pyrazoloquinolines, which allows 5
0
action with di-p-toluoyl tartaric acid at a molar ratio of initial reagents (1-0.9): 1 in a polar organic solvent at the boiling point of the reaction mass, after cooling the reaction mass and crystallizing the salt, the latter is filtered and the resulting tartrate is treated with sodium hydroxide solution with the subsequent selection of the target product in free form.
[2]
2. Method POP.1, characterized in that as a polar organic solvent
5, methanol, a mixture of methanol and acetonitrile in a volume ratio from 1: 4 to 1:10, a mixture of methanol and methyl isobutyl ketone in a volume ratio of 1:15 are used.
[3]
 3, the method according to claim 1, or 2, in which the preparation of the salt 4aR, 8aC-1-and-propyl-6-oxodec-hydrochipoline by reacting (-) - di-paro-toluoyl tartonyl acid with
 trshns (±) -1-and-propyl-6-oxodecahydroquinol-; n.
[4]
4. The method according to claim I-3, about tl and - that the preparation of 4aS, 8a81-n-propyl-6-oxohydroquinoline is obtained by reacting (- | -) - di-paro-toluoyl tartaric acid with trans (±) -1-I-propyl-6-oxodecahydroquinoline.
0
146-9 O 10 152-4 3 20
-105.39 -503.39

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引用文献:

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公开号 | 申请日 | 公开日 | 申请人 | 专利标题

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US4230861A|1979-01-22|1980-10-28|Eli Lilly And Company|1-And/or 7-substituted-6-hydroxy -3-decahydroquinoline carboxylic acids|

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US4198415A|1979-01-22|1980-04-15|Eli Lilly And Company|Prolactin inhibiting octahydro pyrazolo[3,4-g]quinolines|IL73001D0|1983-09-26|1984-12-31|Lilly Co Eli|Improvements in and relating to 6-oxodecahydroquinolines|

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US4778894A|1983-09-26|1988-10-18|Eli Lilly And Company|6 oxo-decahydroquinolines|

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US4764609A|1986-03-31|1988-08-16|Eli Lilly And Company|Synthesis of 2-aminopyrimido[4,5-g]quinolines|

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US4826986A|1986-06-16|1989-05-02|Eli Lilly And Company|6-Oxo-trans-octa- and decahydroquinolines|

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US4977160A|1986-06-16|1990-12-11|Eli Lilly And Company|BCD tricyclic ergoline part-structure analogues|

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US5134143A|1986-06-16|1992-07-28|Eli Lilly And Company|BCD tricyclic ergoline part-structure analogues|

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FR2600649B1|1986-06-26|1989-02-24|Rhone Poulenc Sante|PROCESS FOR THE PREPARATION OF LEVOMEPROMAZINE ACID MALEATE|

法律状态:

优先权:

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申请号 | 申请日 | 专利标题

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US06/439,107|US4471121A|1982-11-03|1982-11-03|Method of resolving trans-d alpha-1-n-propyl-6-oxodecahydroquinoline and di-p-toluoyltartaric acid salts thereof|

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