CN102190650A - Method for preparing indoquinoline tartrate - Google Patents

Abstract

The invention relates to the field of drug synthesis. Be specifically related to the preparation method of the κ-opioid receptor agonist indene quinoline tartrate for analgesia, it is characterized in that: 1-(tetrahydropyrrole-1-methyl)-tetrahydroisoquinoline and 6-chloro -2,3-Dihydro-indene-3-one-1-carboxylic acid, prepared under the conditions of using thionyl chloride as the condensation agent, triethylamine as the acid-binding agent, and DMAP as the catalyst. The invention also discloses a preparation method of an intermediate used in the preparation of indenequinoline tartrate. The preparation method of the invention has easy-to-obtain raw materials, convenient post-treatment, high yield, avoids the use of highly toxic reagent potassium cyanide, and is more in line with the requirements of green chemistry.

Description

The preparation method of indenes quinolizidine morpholine tartrate

Technical field

The present invention relates to the synthetic field of medicine.Be specifically related to be used for the new preparation process of analgesic κ-opioid receptor agonist indenes quinolizidine morpholine tartrate.The used intermediates preparation of preparation indenes quinolizidine morpholine tartrate is also disclosed.

Background technology

The chemistry of indenes quinolizidine morpholine tartrate is called 1-(Pyrrolidine-1-methyl)-2-(6-chloro-2,3-dihydro-indenes-3-ketone-1-carbonyl)-1,2,3,4-tetrahydroisoquinoline tartrate is a kind of high reactivity of contriver's early-stage Study invention and the κ-opioid receptor agonist of highly selective.Show through radioligand-binding study, this compound has very high affinity and selectivity to κ-opiate receptor, in the mouse analgesic test, demonstrate stronger analgesic activities (CN1887872A and WO2008009215), more further investigate at present.The structural formula (I) of indenes quinolizidine morpholine tartrate is as follows:

The free alkali of the disclosed I of patent CN1887872A (the indenes quinolizidine morpholine, preparation method II) comprises:

Wherein DCC is a dicyclohexylcarbodiimide, and DMAP is the 4-Dimethylamino pyridine, and EDCI is 1-ethyl-3-(3-dimethylamino-propyl) carbodiimide hydrochloride, and HOBT is an I-hydroxybenzotriazole.

Wherein the preparation method of intermediate compound IV is as follows:

Patent CN1887872A is disclosed to exist following shortcoming by compound III and IV through the method for condensation prepared II, low as the condensation productive rate, the condensing agent costliness, and the by product of generation is difficult for removing, and increases post-processing difficulty.The synthetic route of key intermediate IV is long, and uses poisonous reagent potassium cyanide, and labour protection requires high, and is big to environmental hazard.Therefore, be necessary to seek the efficient height, toxicity is low, the synthetic method that environmental pollution is little.

Summary of the invention

The objective of the invention is to seek that a kind of reaction raw materials is easy to get, convenient post-treatment, yield are higher, constant product quality, eco-friendly indenes quinolizidine morpholine preparation method.

The preparation of target compound (I), the present invention adopts following method:

1-(Pyrrolidine-1-methyl)-tetrahydroisoquinoline (III) and 6-chloro-2,3-dihydro-indenes-3-ketone-1-carboxylic acid (IV) is that condensing agent, triethylamine are acid binding agent with the sulfur oxychloride, DMAP makes II under the catalyzer condition.Preferably under-15 ℃ to 45 ℃ temperature condition, reacted 45 minutes to 4 hours.Also preferably will react products obtained therefrom again through column chromatography purification.Reaction solvent is the mixed solvent of a kind of in toluene, methylene dichloride or acetonitrile or two kinds preferably.More preferably toluene.

The Compound I I that makes again with the tartrate salify, promptly get target compound indenes quinolizidine morpholine tartrate (I).This step reaction solvent is the mixed solvent of a kind of in acetone, isopropyl ether, glycol dimethyl ether, tetrahydrofuran (THF), ethyl acetate or methylene dichloride or two kinds preferably.More preferably acetone.

The reaction formula of above-mentioned preparation process is as follows:

When preparing II by compound III and IV, the molar ratio of III and IV and sulfur oxychloride preferred 1: 0.8～1.2: 1.1～2.5.Preferred 1: 1: 1.5.

When preparing II by compound III and IV, preferred-25 ℃～55 ℃ of temperature of reaction.More preferably-10 ℃～0 ℃.

When preparing II by compound III and IV, the investing method of IV adds in batches or is suspended in the solvent with solid and is added dropwise to.Preferably be suspended in the solvent and be added dropwise to.

When preparing with above-mentioned preparation method of the present invention, wherein the yield of intermediate II is than the yield high about 20% of patent WO2008009215A1 report.

The invention also discloses the preparation method of midbody compound IV, comprise that with 3-chloroaniline (VIII) be raw material, earlier through diazotization, again with the maleic anhydride condensation, promptly get 3-chlorobenzene Succinic Acid (VII), make acyl chlorides through sulfur oxychloride or phosphorus trichloride reaction, cyclization obtains intermediate (IV) under aluminum chloride catalysis again.

Reaction formula is as follows:

Wherein chlorizating agent is sulfur oxychloride or phosphorus trichloride; Solvent orange 2 A is methylene dichloride, chloroform or oil of mirbane.

When preparing IX by VIII, VIII: Sodium Nitrite: the molar ratio of fluoroboric acid preferred 1: 1～1.2: 1.1～2.5.More preferably preferred 1: 1: 2.

When preparing IX by compound VIII, preferred-25 ℃～25 ℃ of the temperature of dropping Sodium Nitrite.More preferably 0 ℃～5 ℃.

When preparing VII, preferably make catalyzer with titanous chloride or aluminum chloride by IX.

The preferred sulfur oxychloride of chlorizating agent wherein.Solvent orange 2 A is methylene dichloride more preferably.

When preparing IV by compound VI I, the mol ratio of VII and chlorizating agent, aluminum chloride preferred 1: 1.2～5: 1.2～3.More preferably 1: 3.5: 2.

The preparation method of above-mentioned intermediate compound IV compares with the method for WO2008009215A1, and this synthetic route has that reaction raw materials is easy to get, convenient post-treatment, yield be than advantages such as height, has avoided the use of poisonous reagent potassium cyanide simultaneously, more meets the requirement of Green Chemistry.

Embodiment

Embodiment 1

Synthesizing of 3-chlorine diazobenzene fluoroborate (IX)

With the 3-chloroaniline (63.8g, 0.5mol) and 41.2% fluoborate solution (220ml 1.0mol) mixes, stir also cryosel bath cooling down, (34.5g 0.5mol) is dissolved in the cold soln that 70ml water is made into to splash into Sodium Nitrite, dripped off 0～5 ℃ of controlled temperature in about 1 hour.0.5 after hour, filter, the solid diazonium salt is with 95% washing with alcohol twice, again with ether washing three times.Naturally dry, get product 3-chlorine diazobenzene fluoroborate 107g, yield 95%.m.p.142-143 ℃

Embodiment 2

Synthesizing of 3-chloro-phenyl-Succinic Acid (VII)

Adding 15% Titanium Trichloride Solution in the 1L three-necked bottle (350ml, 13mol), ice bath is cooled to 0 ℃, stir down, drip by maleic anhydride (19.6g, 0.2mol) and sodium hydroxide (16g, 0.4mol) be dissolved in the mixing solutions that 125ml water is made into, keep 0～5 ℃ of temperature, finished, and added acetone 500ml again in about 0.5 hour, stir down, add IX (45g 0.2mol), added in about 1 hour in batches.Rose to stirring at room 3 hours, and steamed and remove acetone, debris is put the refrigerator cold-storage crystallization, and filter next day, and frozen water is washed, and crude product water recrystallization gets product 3-chloro-phenyl-Succinic Acid 28.38g.Yield 62.2%.m.p.174-175℃.

Embodiment 3

6-chloro-2,3-dihydro-indenes-3-ketone-1-carboxylic acid (IV) synthetic

With VII (22.8g, 0.1mol) and sulfur oxychloride (25ml 0.35mol) mixes, and refluxes 2 hours, is cooled to room temperature, to wherein adding the 60ml anhydrous methylene chloride, must reaction solution A.

In addition with aluminum chloride (26.7g, 0.2mol) and anhydrous methylene chloride (100ml) mix, the ice bath cooling is also stirred down, drips above-mentioned reaction solution A, drips off in about 2 hours, is heated to backflow 3 hours.Reaction solution is poured in 10% hydrochloric acid (375ml), stirred after 0.5 hour suction filtration.The gained solid is with about 550ml acetic acid ethyl dissolution, and extract saturated sodium carbonate solution 100ml * 3, combining water layer, with ether 40ml washing, water layer is transferred pH=2 with hydrochloric acid, the solid filtering of generation is used the frozen water washed twice, dry product 13.38g, yield 63.58%.m.p.144～146℃.

Embodiment 4

1-(Pyrrolidine-1-methyl)-2-(6-chloro-2,3-dihydro-indenes-3-ketone-1-carbonyl)-1,2,3,4-tetrahydroisoquinoline (II) synthetic

In the 1L three-necked bottle; add III (10.8g; 50mmol), and triethylamine (11.8g, 150mmol); catalytic amount DMAP and dry toluene (200ml); under the nitrogen protection, be cooled to-10 ℃, drip IV (10.5g then with the cryosel bath; 50mmol) suspension made from dry toluene (100ml) dripped off in about 1 hour.Temperature control is below 0 ℃, and (8.9g 750mmol) and the solution that is made into of dry toluene (100ml), dripped dripping thionyl chloride in about 1 hour.Continue to stir 2 hours.Filter, the gained solid carries out column chromatography for separation (eluent: sherwood oil: ethyl acetate: triethylamine=4: 1: 0.1), get product 12.5g, yield 61.2%.m.p.120～122℃.

Embodiment 5

1-(Pyrrolidine-1-methyl)-2-(6-chloro-2,3-dihydro-indenes-3-ketone-1-carbonyl)-1,2,3,4-tetrahydroisoquinoline tartrate (I) synthetic

In the 500ml three-necked bottle, add II (5g, 12.3mmol) and acetone (100ml), after the stirring and dissolving, 0 ℃ of temperature control, drip tartrate (1.84g, 12.3mmol) and the solution of acetone (100ml) composition.Drip and finish, stir 0.5h, cooling crystallization.Filter, obtain white powdery crystallization 6g, yield 88.2%.m.p.167.7-169.6℃?MS(ESI(+)70V，m/z)：408.99([M+H] ⁺，base?peak).

¹H-NMR (500MHz, CD ₃OD+CF ₃COOD), δ (ppm): 7.93 (1H, d), 7.61～7.63 (1H, dd), 7.42～7.44 (1H, t), 7.18～7.26 (4H, m), 6.00～6.03 (1H, m), 4.90～4.93 (1H, m), 4.42 (2H, s), 3.87～4.29 (2H, m), 3.35～3.89 (2H, m), 3.40～3.61 (4H, m) and 2.51～3.11 (2H, m), 2.89～3.00 (2H, m), 2.06～2.10 (4H, m).

Claims (8)

1. a method for preparing indenequinoline tartrate (I), comprising the following preparation process:

2. the method for claim 1, when preparing II by III and IV, III: IV: the molar ratio of thionyl chloride is 1: 0.8～1.2: 1.1～2.5. 3. The method of claim 1, when preparing II by III and IV, the reaction solvent is selected from one or two mixed solvents in toluene, methylene dichloride or acetonitrile. 4. The method of claim 1, when preparing II from III and IV, the reaction temperature is -10°C to 0°C. 5. the method for claim 1, when preparing I by II and tartaric acid, reaction solvent is selected from one or both in acetone, isopropyl ether, ethylene glycol dimethyl ether, tetrahydrofuran (THF), ethyl acetate or methylene dichloride Mixed solvents. 6. The method for the compound (IV) of claim 1, comprising the following preparation process: Wherein the chlorinating agent is thionyl chloride or phosphorus trichloride; solvent A is dichloromethane, chloroform or nitrobenzene. 7. The method of claim 6, when preparing IX from VIII, VIII: sodium nitrite: the molar ratio of fluoboric acid is 1: 1～1.2: 1.1～2.5. 8. The method of claim 6, when preparing VII from IX, use titanium trichloride or aluminum trichloride as a catalyst.