CN100482667C - Method for preparing 5-bromine-6-fluoro-8-methyl-1-ethyl-1,3,4,9- tetrahydropyrane[3,4-e] indole-1-ethyl acetate - Google Patents

Abstract

The present invention relates to a kind of 5-bromo-6-fluoro-8-methyl-1-ethyl-1,3,4,9-tetrahydropyrano[3,4-o]indole-1-acetic acid ethyl ester method of preparation. The intermediate product 4-(5- Bromo-4-fluoro-2-methylphenylhydrazono)-1-butanol and catalyst, solvent ethylene glycol under nitrogen atmosphere, carry out cyclization reaction, obtain intermediate 4-bromo-5-fluoro- 7-methyltryptol, then add the catalyst, add the condensing agent dropwise at 20-30°C under nitrogen atmosphere to react, and finally collect the target product from the reaction product. The purity of the target compound obtained by the preparation method of the invention reaches 99%, and the yield is greater than 80%. The method of the invention has the advantages of simple and convenient operation of the reaction process, short period, reduced product cost and stable quality, and is suitable for industrial production.

Description

5-bromo-6-fluoro-8-methyl isophthalic acid-ethyl-1,3,4, the preparation method of 9-tetrahydropyrans [3,4-is also] indoles-1-ethyl acetate

Technical field

The present invention relates to 5-bromo-6-fluoro-8-methyl isophthalic acid-ethyl-1,3,4, the preparation method of 9-tetrahydropyrans [3,4-also] indoles-1-ethyl acetate.

Background technology

R-ETODOLAC (Etodolac) is as a NSAID (non-steroidal anti-inflammatory drug), its easing pain and diminishing inflammation effect is better than or is similar to acetylsalicylic acid, optionally suppress the biosynthesizing of prostaglandin(PG) at inflammation part, the major cause that its side effect incidence is low is the not influence of generation to the prostaglandin(PG) of stomach and kidney.5-bromo-6-fluoro-8-methyl isophthalic acid-ethyl-1,3,4,9-tetrahydropyrans [3,4-is also] indoles-1-ethyl acetate is to a kind of by in the group conversion synthetic one class newtype drug of R-ETODOLAC (Etodolac) precursor structure, is applicable to rheumatoid arthritis, osteoarthritis, suppress slightly to moderate pain, as the medicine of R-ETODOLAC (Etodolac) similar structures, it also has anti-inflammatory and anticancer effect.

Its structural formula is as follows:

United States Patent (USP) U.S 4,585,877 reports, the synthetic general tryptophol with corresponding the position of substitution with compound of R-ETODOLAC (Etodolac) precursor structure is an intermediate, carries out condensation and obtains the purpose product.Because tryptophol just can obtain by silica gel column chromatography among this preparation method; The catalyzer boron trifluoride diethyl etherate that condensation reaction is adopted costs an arm and a leg, and the product preparation cycle is long, the cost height, and operation easier is big, has therefore limited the large-scale production of this class medicine.

Summary of the invention

The object of the present invention is to provide a kind of 5-bromo-6-fluoro-8-methyl isophthalic acid-ethyl-1,3,4,9-tetrahydropyrans [3,4-is also] preparation method of indoles-1-ethyl acetate, preparation tryptophol intermediate carries out chromatography with silicagel column, the expensive deficiency of condensation catalyst in the prior art to overcome.

Technical conceive of the present invention is such: with 5-bromo-4-fluoro-2-procarbazine hydrochloride is raw material, in reaction solvent with 2,3-dihydrofuran, sodium acetate, anhydrous react, intermediate product 4-(5-bromo-4-fluoro-2-aminomethyl phenyl hydrazono-)-1-butanols that obtains and catalyzer, solvent ethylene glycol are under the atmosphere of rare gas element, carry out ring-closure reaction, obtain intermediate 4-bromo-5-fluoro-7-methyl tryptophol; 4-bromo-5-fluoro-7-methyl tryptophol adds catalyzer, and under the atmosphere of rare gas element, 20-30 ℃ drips condensing agent and react, from reaction product, collect target product 5-bromo-6-fluoro-8-methyl isophthalic acid-ethyl-1,3 then, 4,9-tetrahydropyrans [3,4-also] indoles-1-ethyl acetate.

Reaction formula of the present invention is as follows:

Method of the present invention comprises the steps:

(1) 5-bromo-4-fluoro-2-procarbazine hydrochloride, 2,3-dihydrofuran, sodium acetate, anhydrous, be dissolved in the reaction solvent, under room temperature, anhydrous and oxygen-free condition, reacted 3～6 hours, concentration of reaction solution, intermediate product 4-(5-bromo-4-fluoro-2-aminomethyl phenyl hydrazono-)-1-butanols that separation obtains from organic phase and catalyzer, solvent ethylene glycol are under the atmosphere of nitrogen, and 150～170 ℃ were reacted 3～5 hours, collect from reaction product and obtain 4-bromo-5-fluoro-7-methyl tryptophol;

(2) in 4-bromo-5-fluoro-7-methyl tryptophol, add catalyzer, under the atmosphere of nitrogen, 20-30 ℃ drips Propionylacetic acid ethyl ester reaction 5～7 hours, target product 5-bromo-6-fluoro-8-methyl isophthalic acid-ethyl-1 was collected in 0-5 ℃ of reaction in 0～3 hour from reaction solution, 3,4,9-tetrahydropyrans [3,4-is also] indoles-1-ethyl acetate.

In the inventive method, the said reaction solvent of step (1) is a kind of in anhydrous methanol, dehydrated alcohol, anhydrous propyl alcohol, anhydrous isopropyl alcohol, the anhydrous tetrahydro furan.Wherein preferred anhydrous methanol; The consumption of reaction solvent is a 5-bromo-4-fluoro-2-procarbazine hydrochloride: reaction solvent=1.0: 10.0～15.0, weightmeasurement ratio; Said catalyzer is a kind of in Zinc Chloride Anhydrous, cuprous chloride, aluminum trichloride (anhydrous), the boron trifluoride, preferred Zinc Chloride Anhydrous; The mol ratio of 4-(5-bromo-4-fluoro-2-aminomethyl phenyl hydrazono-)-1-butanols and catalyzer is 1.0:2.0～3.0; 5-bromo-4-fluoro-2-procarbazine hydrochloride: 2,3 dihydro furan: the mol ratio of sodium acetate, anhydrous is 1.0:1～1.05:1～1.05;

The said catalyzer of step (2) is the methanol solution of hydrogenchloride, and its concentration is 5～10wt%; Ratio of components is a 4-bromo-5-fluoro-7-methyl tryptophol: the methanol solution=1.0:5.0 of catalyzer hydrogenchloride～10.0, weightmeasurement ratio; 4-bromo-5-fluoro-7-methyl tryptophol: Propionylacetic acid ethyl ester=1.0～1,2:1.0, mol ratio.

From reaction solution, collect target product 5-bromo-6-fluoro-8-methyl isophthalic acid-ethyl-1,3,4,9-tetrahydropyrans [3,4-also] indoles-1-ethyl acetate comprises the steps: the reaction solution petroleum ether extraction, concentrates, separate out solid with ethanol,, obtain target product with the mixed solvent recrystallization.According to the present invention, preferably the mixed solvent of sherwood oil and ethanol composition carries out recrystallization to target product, and the consumption of mixed solvent is a 4-bromo-5-fluoro-7-methyl tryptophol: mixed solvent=1.0: 2.0-5.0, weightmeasurement ratio; Mixed solvent is by sherwood oil: the volume ratio of ethanol=2: 1 is prepared.

Raw material 5-bromo-4-fluoro-2-procarbazine hydrochloride used in the present invention, obtain by general hydrazine class preparation method with 1-bromo-2-fluoro-4-methyl-5-nitro benzene, the preparation of 1-bromo-2-fluoro-4-methyl-5-nitro benzene can be referring to the method for document CA 130:P338112j report.

With 5-bromo-6-fluoro-8-methyl isophthalic acid-ethyl-1,3,4 that preparation method of the present invention obtains, 9-tetrahydropyrans [3,4-also] indoles-1-ethyl acetate purity reaches 99%, and productive rate is identified the structure of purpose product greater than 80% with nucleus magnetic resonance.

Beneficial effect

The present invention has that reaction process is easy and simple to handle, cycle weak point, product cost reduction, steady quality, is suitable for the advantage of suitability for industrialized production compared with prior art.

Specific implementation method

The invention will be further described below by embodiment, but embodiment does not limit protection scope of the present invention.

Embodiment 1

(1) preparation of 4-bromo-5-fluoro-7-methyl tryptophol:

In the reactor that has agitator, thermometer, add 5-bromo-4-fluoro-2-procarbazine hydrochloride 14.6g (57mmol), 2 respectively, 3-dihydrofuran 4.3ml (57mmol), sodium acetate, anhydrous 4.7g (57mmol) and anhydrous methanol 200ml, stirring reaction is 6 hours under the condition of room temperature, anhydrous and oxygen-free.Reaction solution steams and removes methyl alcohol, adds ethyl acetate 150ml and water 150ml, stirs, and tells organic phase after leaving standstill, and uses distilled water, saturated common salt water washing respectively, uses anhydrous sodium sulfate drying.Steaming desolventizes ethyl acetate, obtains yellow oily intermediate product 4-(5-bromo-4-fluoro-2-aminomethyl phenyl hydrazono-)-1-butanols 14.2g (49mmol);

In the reactor that has heating, agitator, reflux condensing tube, thermometer, add 4-(5-bromo-4-fluoro-2-aminomethyl phenyl hydrazono-)-1-butanols 14.2g (49mmol) respectively, Zinc Chloride Anhydrous 13.3g (98mmol) and ethylene glycol 75ml, under the nitrogen atmosphere, be heated to 160 ± 5 ℃ when stirring, insulation reaction 5 hours, be cooled to room temperature, add 5% dilute hydrochloric acid 50ml and ethyl acetate 100ml, stir 10min, tell organic phase after leaving standstill, with distilled water, saturated common salt water washing, anhydrous sodium sulfate drying.Steam and remove ethyl acetate, obtain the intermediate 4-bromo-5-fluoro-7-methyl tryptophol 13.0g (48mmol) of yellow oily.

(2) 5-bromo-6-fluoro-8-methyl isophthalic acid-ethyl-1,3,4, the preparation of 9-tetrahydropyrans [3,4-is also] indoles-1-ethyl acetate:

Methanol solution (weight/volume) 100ml that in the reactor that has agitator, thermometer, adds 5% hydrogenchloride, stir and add 4-bromo-5-fluoro-7-methyl tryptophol 13.0g (48mmol) down, under the nitrogen atmosphere, keep 20 ± 5 ℃, slowly splash into Propionylacetic acid ethyl ester 6.6g (46mmol) in 30 minutes, keep 25～30 ℃ of reactions 7 hours subsequently.Reaction solution adds sherwood oil (60～90 ℃) 100ml extraction.Extraction liquid is concentrated into 20ml, add ethanol 10ml, separate out solid, with sherwood oil/alcohol mixed solvent 30ml (volume ratio is 2:1) recrystallization, dry, obtain 5-bromo-6-fluoro-8-methyl isophthalic acid-ethyl-1,3,4,9-tetrahydropyrans [3,4-is also] indoles-1-ethyl acetate white crystal 14.7g, productive rate 80%, purity 99.1% (HPLC).

NMR[DMSO-d6，400MHz]δ?0.615(t，3H，CCH3)，1.05(t，3H，OCH2CH3)，1.95(q，2H，CCH2)，2.4(s，3H，CH3)，2.76(d，1H，CCH2CO)，2.96(m，2H，CCH2)，3.9(m，2H，CCH2O)，7.02(d，1H，ArH)，10.79(s，1H，NH)。

Embodiment 2

(1) preparation of 4-bromo-5-fluoro-7-methyl tryptophol:

In the reactor that has agitator, thermometer, add 5-bromo-4-fluoro-2-procarbazine hydrochloride 14.8g (58mmol), 2 respectively, 3-dihydrofuran 4.4ml (58mmol), sodium acetate, anhydrous 4.8g (58mmol) and anhydrous tetrahydro furan 200ml, stirring reaction is 3 hours under the condition of room temperature, anhydrous and oxygen-free.Reaction solution steams and removes tetrahydrofuran (THF), adds ethyl acetate 150ml and water 150ml, stirs, and tells organic phase after leaving standstill, and uses distilled water respectively, saturated common salt water washing, anhydrous sodium sulfate drying.Steaming desolventizes ethyl acetate, obtains intermediate product 4-(5-bromo-4-fluoro-2-aminomethyl phenyl the hydrazono-)-1-butanols 13.9g (48mmol) of yellow oily;

Intermediate product 4-(5-bromo-4-fluoro-2-aminomethyl phenyl hydrazono-)-1-butanols 13.9g (48mmol), the Zinc Chloride Anhydrous 13.3g that in the reactor that has heating, agitator, reflux condensing tube, thermometer, adds yellow oily respectively, (98mmol), ethylene glycol 75ml, under the nitrogen atmosphere, be heated to 160 ± 5 ℃ when stirring, after the insulation reaction 3 hours, be cooled to room temperature, add 5% dilute hydrochloric acid 50ml, ethyl acetate 100ml, stir 10mi, leave standstill, tell organic phase, use distilled water, saturated common salt water washing respectively, anhydrous sodium sulfate drying.Steam and remove ethyl acetate, obtain the intermediate 4-bromo-5-fluoro-7-methyl tryptophol 12.0g (44mmol) of yellow oily.

(2) 5-bromo-6-fluoro-8-methyl isophthalic acid-ethyl-1,3,4, the preparation of 9-tetrahydropyrans [3,4-is also] indoles-1-ethyl acetate:

Methanol solution (weight/volume) 100ml that in the reactor that has agitator, thermometer, adds 5% hydrogenchloride, stir and add 4-bromo-5-fluoro-7-methyl tryptophol 12.0g (44mmol) down, under the nitrogen atmosphere, keep 20 ± 5 ℃, slowly splash into Propionylacetic acid ethyl ester 6.1g (42mmol) in 30 minutes, keep 25～30 ℃ of reactions after 7 hours, be cooled to 0 ℃, keep 0～5 ℃ to continue reaction 3 hours.Reaction solution adds sherwood oil (60～90 ℃) 100ml extraction.Extraction liquid is concentrated into 20ml, add ethanol 10ml, separate out solid, with sherwood oil/alcohol mixed solvent 50ml (volume ratio is 2:1) recrystallization, dry, obtain 5-bromo-6-fluoro-8-methyl isophthalic acid-ethyl-1,3,4,9-tetrahydropyrans [3,4-is also] indoles-1-ethyl acetate white crystal 15.1g, productive rate 90%, purity 99.6% (HPLC).

Nucleus magnetic resonance identifies that its structure is identical with embodiment 1.

Claims (8)

1. A 5-bromo-6-fluoro-8-methyl-1-ethyl-1,3,4,9-tetrahydropyrano[3,4-o]indole-1-ethyl acetate The preparation method is characterized in that it comprises the following steps: (1) 5-bromo-4-fluoro-2-methylphenylhydrazine hydrochloride, 2,3-dihydrofuran, anhydrous sodium acetate, dissolved in the reaction solvent, react at room temperature, under anhydrous and oxygen-free conditions After 3 to 6 hours, the reaction solution was concentrated, and the intermediate product 4-(5-bromo-4-fluoro-2-methylphenylhydrazono)-1-butanol obtained from the organic phase was separated from the catalyst and the solvent ethylene glycol. The alcohol is reacted at 150-170°C for 3-5 hours under nitrogen atmosphere, and 4-bromo-5-fluoro-7-methyltryptol is collected from the reaction product; the catalyst is anhydrous zinc chloride, chlorine One of cuprous chloride, anhydrous aluminum trichloride and boron trifluoride; (2) Add catalyst to 4-bromo-5-fluoro-7-methyltryptol, under nitrogen atmosphere, add ethyl propionoacetate dropwise at 20-30°C for 5-7 hours, and react at 0-5°C After 0 to 3 hours, collect the target product 5-bromo-6-fluoro-8-methyl-1-ethyl-1,3,4,9-tetrahydropyrano[3,4-o]indene from the reaction liquid Indole-1-ethyl acetate; the catalyst is methanol solution of hydrogen chloride. 2. The method according to claim 1, characterized in that said reaction solvent is one of anhydrous methanol, absolute ethanol, absolute propanol, anhydrous isopropanol, anhydrous tetrahydrofuran. 3. The method according to claim 2, characterized in that the reaction solvent is anhydrous methanol. 4. The method according to claim 1, characterized in that the concentration of the methanol solution of hydrogen chloride in the step (2) is 5 to 10 wt%. 5. The method according to claim 1, characterized in that 5-bromo-4-fluoro-2-methylphenylhydrazine hydrochloride in step (1): 2,3-dihydrofuran: anhydrous sodium acetate The molar ratio is 1.0: 1～1.05: 1～1.05, the consumption of reaction solvent is 5-bromo-4-fluoro-2-methylphenylhydrazine hydrochloride: reaction solvent=1.0: 10.0～15.0, by weight volume ratio ; The mol ratio of 4-(5-bromo-4-fluoro-2-methylphenylhydrazono)-1-butanol and catalyst is 1.0: 2.0～3.0; The consumption of ethylene glycol solvent is 4-(5 -Bromo-4-fluoro-2-methylphenylhydrazono)-1-butanol: ethylene glycol solvent = 1.0: 5.0-8.0, by weight to volume ratio. 6. The method according to claim 1, characterized in that the proportioning ratio of step (2) is 4-bromo-5-fluoro-7-methyltryptol: methanol solution of catalyst hydrogen chloride=1.0: 5.0～10.0, by weight Volume ratio; 4-bromo-5-fluoro-7-methyltryptol:ethyl propionoacetate=1.0～1.2:1.0, molar ratio. 7. The method according to claim 1, characterized in that the target product 5-bromo-6-fluoro-8-methyl-1-ethyl-1,3,4,9-tetrahydropyridine is collected from the reaction solution The pyro[3,4-and]indole-1-acetic acid ethyl ester comprises the following steps: the reaction solution is extracted with petroleum ether, concentrated, the solid is precipitated with methanol or ethanol, and recrystallized with a mixed solvent to obtain the target product. 8. The method according to claim 7, characterized in that the mixed solvent used for recrystallization is composed of petroleum ether and ethanol with a volume ratio of 2:1, and its consumption is 4-bromo-5-fluoro-7-methyl color Alcohol: mixed solvent = 1.0: 2.0-5.0, weight to volume ratio.