CN1562974A - Method for synthesizing 1,2,3,4 ramification of tetrahydro-isoquinoline - Google Patents

Abstract

This invention relates prepn. of 1,2,3,4-terahydroiso-quinoline derivatives by using phenylalnine acid esters as raw material, using benzyl for protecting amino, and using di(methoxy) methyl ether in ring-forming reaction. In this invention process, chloroformate is not used, so eliminating prodn. of alpha-haloether a kind of carcinogenic substance, due to no used of formaldehyde and concentrated hydrochloric acid, with advantages of: available raw material, commercialization prodn.

Description

A method for synthesizing 1,2,3,4-tetrahydroisoquinoline derivatives

technical field

The invention relates to a method for synthesizing 1,2,3,4-tetrahydroisoquinoline derivatives, especially a method for synthesizing 1,2,3,4-tetrahydroisoquinoline derivatives using phenylalanine ester as raw material The method of morphine derivatives.

Background technique

1,2,3,4-Tetrahydroisoquinoline derivatives are synthetic intermediates of biologically active molecules. The structural formula of this type of compound is as follows, where R can be hydroxyl, alkoxy, primary amino, secondary amino , The benzene ring may contain substituents such as hydrocarbyl or hydrocarbyloxy.

1,2,3,4-tetrahydroisoquinoline derivatives 1

1,2,3,4-Tetrahydroisoquinoline derivatives are an important class of intermediates, in which (S)-tetrahydroisoquinoline-3-formyl tert-butylamine 4 (R=NHBu') undergoes catalytic hydrogenation The obtained decahydroisoquinoline-3-formyl tert-butylamine is a key synthetic intermediate of the anti-AIDS drugs saquinavir and nelfinavir. There are mainly two methods for the synthesis of 1,2,3,4-tetrahydroisoquinoline derivatives reported with industrial application value:

(1) (L)-Phenylalanine 2 undergoes Pictet-Spengler cyclization under formaldehyde and concentrated hydrochloric acid to generate (S)-tetrahydroisoquinoline-3-carboxylic acid 3, which reacts with phosgene or triphosgene to generate N- After the carboxylic anhydride, react with tert-butylamine to obtain (S)-tetrahydroisoquinoline-3-formyl tert-butylamine 4 (see US 6433177; 6340760; No. 5587481 patent), the synthetic route is as follows:

(2) (L)-Phenylalanine 2 was protected by benzyl chloroformate to obtain N-benzyloxyacylphenylalanine 5, and then reacted with tert-butyl chloroformate to form an activated ester, which reacted with tert-butylamine to form amide 6 . Amide 6 is cyclized in di(methoxy)methane under the action of mixed acid (concentrated sulfuric acid and concentrated acetic acid) to generate N-benzyloxyformyl tetrahydroisoquinoline-3-formyl tert-butylamine 7, under palladium-carbon catalysis Hydrogenolysis deprotection obtains (S)-tetrahydroisoquinoline-3-formyl tert-butylamine 4 (see patent No. US 5256783), and the synthetic route is as follows:

Although the synthetic route of method 1 is convenient, the main limitation is the formaldehyde and concentrated hydrochloric acid used in the Pictet-Spengler ring closure reaction in the synthetic route, and the by-product α-halogenated ether (mainly chlorine Methyl ether and bischloromethyl ether) have serious carcinogenic effects. Therefore, the use of formaldehyde and concentrated hydrochloric acid systems in industrial production is usually limited (ArchEnviron Health, 1975, 30: 61-72). At the same time, due to the severe reaction conditions of the Pictet-Spengler cyclization reaction, partial racemization will occur, usually with a racemization rate of about 32%, which is necessary for the synthesis of optically pure 1,2,3,4-tetrahydroisoquinone Phenyl derivatives are unfavorable. The advantages of method 2 mainly lie in the mild cyclization reaction conditions, avoiding the racemization phenomenon in the cyclization reaction, and using dimethoxymethane/mixed acid instead of formaldehyde/hydrochloric acid system to avoid the formation of carcinogenic α-halogenated ethers . But the main limitation of this reaction scheme is the need to use chloroformate twice. Chloroformic ester compounds have problems such as corrosion to reaction equipment, environmental pollution and safety no matter in production or in use.

Contents of the invention

The object of the present invention is to provide a kind of with phenylalanine ester as raw material, adopt benzyl to protect amino method, bis(methoxy) methyl ether ring closure condition synthesizes 1,2,3,4-tetrahydroisoquinoline derivative way of things.

The synthetic route of the present invention is as follows:

Concrete reaction process is as follows:

1) Phenylalanine 8 and benzaldehyde are condensed under the catalysis of acid to generate N-benzylidene phenylalanine, and then undergo catalytic hydrogenation to obtain N-benzyl phenylalanine 9. The condensation reaction solvent can be halogenated hydrocarbon, such as: dichloromethane, trichloromethane or 1,2-dichloroethane and the like. The reaction temperature is 30-55°C. Acid catalysts include inorganic acids or organic acids, such as hydrochloric acid, sulfuric acid, acetic acid or propionic acid and the like. The solvent for the hydrogenation reduction reaction generally adopts lower alcohol or a mixed solvent of lower alcohol and ether. The lower alcohol refers to methanol, ethanol, propanol or isopropanol, etc., and the ether is mainly diethyl ether or isopropyl ether. The catalytic hydrogenation catalyst is Raney-Ni, the reaction temperature of the catalytic hydrogenation is 10-50° C., and the hydrogen pressure is 5-20 bar.

2) Base-catalyzed hydrolysis of N-benzylphenylalanine ester affords N-benzylphenylalanine 10. The hydrolysis catalyst adopts inorganic base, such as sodium hydroxide, potassium hydroxide or lithium hydroxide etc. The reaction solvent is lower alcohol or a mixed solvent of lower alcohol and water. Lower alcohol refers to methanol, ethanol, propanol or isopropanol, etc., and the reaction temperature is generally 50-100°C.

3) N-benzylphenylalanine 10 reacts with triphosgene under anaerobic and anhydrous conditions to produce N-carboxylic anhydride, and then slowly adds the solution of N-carboxylic anhydride to tert-butylamine at low temperature for acylation The reaction produces N-benzylphenylalanyl tert-butylamine 11. The N-carboxylic acid anhydride reaction is carried out in an ether solvent, such as dioxane. The reaction temperature is between 60°C and 120°C. The acylation reaction solvent is a halogenated hydrocarbon, such as dichloromethane, trichloromethane, 1,2-dichloroethane, etc., and the reaction temperature is -75-0°C.

4) N-benzylphenylalanyl tert-butylamine 11 was cyclized with dimethoxymethane under acid catalysis to generate N-benzyltetrahydroisoquinoline-3-formyl tert-butylamine 12. The catalyst can be an inorganic acid, or a mixed acid of an inorganic acid and an organic acid, or boron trifluoride ether. The reaction solvent is a halogenated hydrocarbon, such as dichloromethane, chloroform, 1,2-dichloroethane and the like. The reaction temperature is 30-60°C.

5) N-benzyltetrahydroisoquinoline-3-formyl tert-butylamine 12 is catalyzed by hydrogenolysis and debenzylation to obtain tetrahydroisoquinoline-3-formyl tert-butylamine 4. The hydrogenolysis reaction catalyst is palladium-carbon, and hydrogen/palladium-carbon or ammonium formate/palladium-carbon hydrogenation system can be used. The reaction solvent is a lower alcohol, such as methanol, ethanol or propanol. The reaction temperature is 50-100°C.

The synthetic route of the present invention is characterized in that a novel synthetic method is used to prepare 1,2,3,4-tetrahydroisoquinoline derivatives. Using phenylalanine ester as raw material, the method of protecting amino group with benzyl group avoids the use of chloroformate. The cyclization reaction adopts bis(methoxy)methyl ether cyclization conditions to avoid the hidden danger of using formaldehyde/concentrated hydrochloric acid to generate carcinogenic α-halogenated ethers. The raw materials used are easy to obtain and low in price, and are suitable for industrial production.

Detailed ways

Below by embodiment the present invention will be further described.

Example 1:

Step 1. (L)-N-benzylidene phenylalanine methyl ester (L)-phenylalanine methyl ester (1.526g, 8.52mmol) was added dichloromethane 15ml, anhydrous magnesium sulfate 0.88g and 4 Drop concentrated sulfuric acid. 0.58 ml of benzaldehyde was added dropwise with stirring at room temperature. Heated to reflux at 50°C for 24h, filtered, and concentrated under reduced pressure to obtain a pale yellow oil. Add 20ml of anhydrous diethyl ether. Wash with saturated sodium chloride solution (10ml×2) and water (10ml×2) successively. Dry over anhydrous magnesium sulfate, filter, and concentrate under reduced pressure to obtain 1.797 g of a light yellow liquid. Yield 79%.

¹ H-NMR (CDCl ₃ , 500MHz) δ: 8.11(s, 1H, N=CH), 7.50～7.10(m, 10H, 2×Ph-H), 4.35(m, 1H, BnCH), 3.70(m , 3H, OCH ₃ ), 3.40 (m, 1H, PhCH ₂ ), 3.20 (m, 1H, PhCH ₂ ).

Step 2. (L)-N-benzylphenylalanine methyl ester Add (L)-N-benzylidene phenylalanine methyl ester (3.204g, 12.0mmol) and 25ml of absolute ethanol to the autoclave reactor and Raney-Ni 0.35g. Pass hydrogen at 25°C, keep the hydrogen pressure at 7bar, stir the reaction for 7h, filter, and concentrate under reduced pressure to obtain 3.227g of yellow liquid. Yield 100%.

¹ H-NMR (CDCl ₃ , 500MHz) δ: 7.25～7.15 (m, 10H, 2×Ph-H), 3.80 (d, 2H, CH ₂ N), 3.74 (s, 1H, CHN), 3.64 (s , 3H, OCH ₃ ), 2.95 (dd, J=1.53×4.91 Hz, 2H, CCH ₂ ), 1.85 (s, 1H, NHBn).

Step 3. Add 25ml methanol to (L)-N-benzylphenylalanine (L)-N-benzylphenylalanine methyl ester (10.95g, 40.71mmol), and add 3mol/L hydrogen dropwise under stirring Sodium 27ml. Heated to reflux at 68°C for 9h. Concentrate under reduced pressure. 30 ml of water was added, followed by extraction with 15 ml of ethyl acetate. The pH of the aqueous layer was adjusted to 5-6 with 10% hydrochloric acid, and a large amount of white solid appeared, which was filtered. The white solid was washed with a small amount of water and anhydrous methanol. Vacuum drying at 40°C for 5 hours gave 9.19 g of a white solid. Yield 88.5%. m.p.185.5～186.5℃.

MS (ESI): 256 (MH ⁺ , 100).

Step 4. Add 20ml of anhydrous dioxane to (L)-N-benzylphenylalanyl tert-butylamine (L)-N-benzylphenylalanine (1.76g, 6.90mmol), and add Sanko dropwise under stirring Gas dioxane solution (triphosgene: 1.6g, 5.4mmol+dioxane: 6ml), the addition was completed in about 10 minutes. Heat to reflux at 110°C for 1 hour, and pass nitrogen once every 15 minutes. Concentrate under reduced pressure at 75°C. Toluene (13ml×2) was added, stirred for 5min and then concentrated under reduced pressure at 55°C. 17 ml of dichloromethane was added. The obtained N-carboxylic acid anhydride solution was added dropwise to 1.64ml of tert-butylamine cooled to -75°C, stirred for 2.5h, and then slowly raised to room temperature. Concentrate under reduced pressure, and add 25 ml of dichloromethane. Insoluble materials were removed by filtration. 20ml of water was added, and 10% hydrochloric acid was added dropwise to adjust the pH to about 5. Separate the organic layer. The pH of the aqueous layer was adjusted to about 10 with 3mol/L sodium hydroxide solution, and 20ml of ethyl acetate was added for extraction. The aqueous layer was extracted with ethyl acetate (10ml×2), and the organic phases were combined. The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain 1.579 g of a yellow liquid. Yield 73.8%.

¹ H-NMR (CDCl ₃ , 500MHz) δ: 7.4～7.15 (m, 10H, 2×Ph-H), 4.13 (m, 1H, CHN), 3.60 (s, 2H, CH ₂ N), 3.20 (m , 1H, CH ₂ C), 2.75 (m, 1H, CH ₂ C), 2.00 (s, 1H, NHBn), 1.33-1.25 (m, 9H, 3×CH ₃ ).

Step 5. Add 40ml of dichloromethane to (S)-N-benzyltetrahydroisoquinoline-3-formyl tert-butylamine (L)-N-benzylphenylalanyl tert-butylamine (1.181g, 3.81mmol) and stir 3.9 ml of a diethyl ether solution (40%) of boron trifluoride was added dropwise. Dimethoxymethane (0.7ml, 7.92mmol) was added dropwise with stirring. Heat to reflux at 40-45°C for 48h. Add water 9ml. Add 3.0 ml of ammonia water (27%) dropwise to adjust the pH to about 8. Separate the organic layer. The aqueous layer was extracted with dichloromethane (15ml×2), and the organic layers were combined. Wash with saturated sodium chloride solution until neutral. Dry over anhydrous sodium sulfate, filter, and concentrate under reduced pressure. Recrystallized with 5 ml of n-hexane to obtain 0.756 g of white flaky crystals. Yield 61.6%.

mp107.5～108℃. [α] ₅₈₉ ²⁰ = -6.919° (c = 1.03, MeOH).

MS (ESI): 323 (MH ⁺ , 100).

¹ H-NMR (CDCl ₃ , 500MHz) δ: 7.35～7.25 (m, 9H, 2×Ph-H), 4.10 (d, J=5.22Hz, 1H, CHC=O), 3.78 (m, 1H, CH _2N ), 3.74(m, 1H, _CH2N ), 3.40(m, 1H, _CH2N ), 3.36(m, 1H, CH2N), 3.12(m, _1H , _CH2CC =O), 2.95 (m, 1H, _CH2CC =O), 2.00 (s, 1H, NHBn), 1.30 (s, 9H, 3 x _CH3 ).

Step 6. (S)-Tetrahydroisoquinoline-3-formyl tert-butylamine in methanol solution of (S)-N-benzyltetrahydroisoquinoline-3-formyl tert-butylamine [(S)-N-benzyl Tetrahydroisoquinoline-3-formyl tert-butylamine: 1.66g, 5.15mmol+methanol: 25ml] was added methanol solution of ammonium formate (ammonium formate: 0.98g, 15.5mmol+methanol: 10ml) and palladium carbon 0.4g. Heated to reflux at 75°C for 7h, filtered and concentrated under reduced pressure. 20 ml of ethyl acetate and 5 ml of water were successively added. Separate the organic layer. Concentrate under reduced pressure. 8 ml of n-hexane was added for recrystallization to obtain 0.991 g of a white solid. Yield 83.0%.

mp94.5～95℃. [α] ₅₈₉ ²⁰ = -104.3° (c = 1.03, MeOH).

MS (ESI): 233 (MH ⁺ , 100).

¹ H-NMR (CDCl ₃ , 500MHz) δ: 7.20～7.00 (m, 4H, Ph-H), 4.0 (m, 2H, CH ₂ N), 3.45 (m, 1H, CHC=O), 3.20 (m , 1H, PhCH ₂ C), 2.80 (m, 1H, PhCH ₂ C), 1.65 (s, 1H, NHC), 1.40 (s, 9H, 3×CH ₃ ).

Example 2:

Step 1. (L)-N-benzylidene phenylalanine methyl ester (L)-phenylalanine methyl ester (1.513g, 8.44mmol) was added dichloromethane 15ml, anhydrous magnesium sulfate 0.88g and 10 Drops of acetic acid. 0.58 ml of benzaldehyde was added dropwise with stirring at room temperature. Heated to reflux at 50°C for 24h. filter. Concentration under reduced pressure gave a pale yellow oil. Add 20ml of anhydrous diethyl ether. Wash with saturated sodium chloride solution (10ml×2) and water (10ml×2) successively. Dry over anhydrous magnesium sulfate, filter, and concentrate under reduced pressure to obtain 1.683 g of a light yellow liquid. Yield 75%.

Step 2. (L)-N-benzylphenylalanine methyl ester Add (L)-N-benzylidene phenylalanine methyl ester (1.600g, 6.0mmol) and 12ml of absolute ethanol to the autoclave reactor Isopropyl ether 6ml and Raney-Ni 0.35g. Pass hydrogen at 25°C, keep the hydrogen pressure at 7bar, stir the reaction for 7h, filter, and concentrate under reduced pressure to obtain 1.613g of yellow liquid. Yield 100%.

Step 3.(L)-N-benzylphenylalanine Same as Example 1.

Step 4.(L)-N-benzylphenylalanyl tert-butylamine Same as Example 1.

Step 5. Add 40ml of dichloromethane to (S)-N-benzyltetrahydroisoquinoline-3-formyl tert-butylamine (L)-N-benzylphenylalanyl tert-butylamine (1.178g, 3.80mmol) and stir 1.2 ml of sulfuric acid/acetic acid (1/2 volume ratio) was added dropwise. Dimethoxymethane (0.7ml, 7.92mmol) was added dropwise with stirring. Heat to reflux at 40-45°C for 48h. Add water 9ml. Add 5.0 ml of ammonia water (27%) dropwise to adjust the pH to about 8. Separate the organic layer. The aqueous layer was extracted with dichloromethane (15ml×2), and the organic layers were combined. Wash with saturated sodium chloride solution until neutral. Dry over anhydrous sodium sulfate, filter, and concentrate under reduced pressure. Recrystallized with 5 ml of n-hexane to obtain 0.653 g of white flaky crystals. Yield 53.3%.

Step 6. (S)-Tetrahydroisoquinoline-3-formyl tert-butylamine in methanol solution of (S)-N-benzyltetrahydroisoquinoline-3-formyl tert-butylamine [(S)-N-benzyl Tetrahydroisoquinoline-3-formyl tert-butylamine: 1.68g, 5.22mmol+methanol: 25ml] was added 0.4g of palladium carbon. Pass through hydrogen, stir the reaction at 50°C and 10bar hydrogen pressure for 7h, filter and concentrate under reduced pressure. 20 ml of ethyl acetate and 5 ml of water were successively added. Separate the organic layer. Concentrate under reduced pressure. 8 ml of n-hexane was added for recrystallization to obtain 0.989 g of a white solid. Yield 81.7%.

Claims (8)

1. a method for synthesizing 1,2,3,4-tetrahydroisoquinoline derivatives, 1,2,3, the structural formula of 4-tetrahydroisoquinoline derivatives is:

                                                                                                                                                                                                                                        1, 2, 3, 4-Tetrahydroisoquinoline Derivatives 1 Wherein R can be a hydroxyl group, an alkoxy group, a primary amino group, a secondary amino group, and the benzene ring can contain substituents such as a hydrocarbon group or an alkoxy group, and it is characterized in that said synthetic route is:

Its reaction steps are as follows: 1) Phenylalanine ester 8 and benzaldehyde are condensed under the catalysis of acid to generate N-benzylidene phenylalanine ester, and then N-benzyl phenylalanine ester 9 is obtained through catalytic hydrogenation, and the condensation reaction solvent adopts halogen Substituted hydrocarbons, the reaction temperature is 30-55°C; acid catalysts include inorganic acids or organic acids, the solvent for the hydrogenation reduction reaction is a lower alcohol or a mixed solvent of a lower alcohol and ether, and the catalytic hydrogenation catalyst is Raney nickel, which catalyzes the hydrogenation reaction The temperature is 10-50°C, and the hydrogen pressure is 5-20bar; 2) The base-catalyzed hydrolysis of N-benzylphenylalanine ester to obtain N-benzylphenylalanine 10, the hydrolysis catalyst adopts inorganic base, the reaction solvent is a lower alcohol or a mixed solvent of lower alcohol and water, and the reaction temperature is 50 ~ 100°C; 3) N-benzylphenylalanine 10 reacts with triphosgene under anaerobic and anhydrous conditions to produce N-carboxylic anhydride, and then slowly adds the solution of N-carboxylic anhydride to tert-butylamine at low temperature for acyl Acylation reaction to generate N-benzylphenylalanyl tert-butylamine 11, N-carboxylic acid anhydride reaction is carried out in ether solvent, the reaction temperature is 60 ~ 120 ° C; the acylation reaction solvent is halogenated hydrocarbon, the reaction temperature is -75 ~ 0 ℃; 4) N-benzylphenylalanyl tert-butylamine 11 and dimethoxymethane are cyclized under acid catalysis to generate N-benzyltetrahydroisoquinoline-3-formyl tert-butylamine 12. The catalyst can be inorganic acid or inorganic acid Mixed acid with organic acid or boron trifluoride diethyl ether, the reaction solvent is halogenated hydrocarbon, and the reaction temperature is 30-60°C; 5) N-benzyltetrahydroisoquinoline-3-formyl tert-butylamine 12 is catalyzed by hydrogenolysis and debenzyl to obtain tetrahydroisoquinoline-3-formyl tert-butylamine 4. The hydrogenolysis reaction catalyst is palladium-carbon, and hydrogen/ Palladium-carbon or ammonium formate/palladium-carbon hydrogenation system, the reaction solvent is lower alcohol, and the reaction temperature is 50-100°C. 2. a kind of method for synthesizing 1,2,3,4-tetrahydroisoquinoline derivatives as claimed in claim 1, is characterized in that said halogenated hydrocarbon in step 1,3,4 is dichloromethane , chloroform or 1,2-dichloroethane. 3. a kind of method for synthesizing 1,2,3,4-tetrahydroisoquinoline derivatives as claimed in claim 1, is characterized in that said inorganic acid in step 1,4 is hydrochloric acid or sulfuric acid; Organic acid For acetic acid or propionic acid. 4. a kind of method for synthesizing 1,2,3,4-tetrahydroisoquinoline derivatives as claimed in claim 1, is characterized in that said lower alcohol in step 1,2,5 refers to methyl alcohol, ethanol, propanol or isopropanol. 5. A method for synthesizing 1,2,3,4-tetrahydroisoquinoline derivatives as claimed in claim 1, characterized in that said ether in step 1 is diethyl ether or isopropyl ether. 6. a kind of method for synthesizing 1,2,3,4-tetrahydroisoquinoline derivatives as claimed in claim 1, is characterized in that said inorganic base in step 2 is sodium hydroxide, potassium hydroxide or lithium hydroxide. 7. A method for synthesizing 1,2,3,4-tetrahydroisoquinoline derivatives as claimed in claim 1, characterized in that the N-carboxylic anhydride reaction in step 3 is carried out in a dioxane solvent. 8. A method for synthesizing 1,2,3,4-tetrahydroisoquinoline derivatives as claimed in claim 1, characterized in that the catalyst for the ring-closure reaction in step 4 is boron trifluoride ether.