CN104045645B - The synthetic method of harringtonine C ring intermediates - Google Patents

Abstract

The present invention relates to a kind of methods of artificial synthesized harringtonine C ring intermediates; this method is with 3; 4 methylene-dioxy phenyl ethylamines (chemical compounds I) are raw material; it is acylated under alkaline condition; it obtains N and is acylated 3; 4 methylene-dioxy phenyl ethylamines (compound ii) then generate N with the derivatives reaction of halogenated acetic acids or halogenated acetic acids and are acylated 3,4 methylenedioxybenzenes ethylaminoacetic acids (compound III).Compound (III) issues raw intramolecular friedel-crafts acylation in lewis acidic catalysis and obtains 3,4 methylene oxygroup benzo of N acyl groups, 3 N heterocycle heptanone, i.e. the C rings of harringtonine.Each step product in preparation process is purified by the method washed and recrystallized, easy to operate, and total recovery has preferable industrial prospect up to 87.4%.

Description

The synthetic method of harringtonine C ring intermediate

technical field

The invention relates to a method for synthesizing a drug intermediate, in particular to a method for synthesizing an intermediate containing a C ring of harringtonine.

Background technique

Horringtonine is a kind of alkaloid extracted from the plant of the genus Spicera, which has good anticancer activity and is mainly used clinically for the treatment of acute myeloid leukemia, acute monocytic leukemia, promyelocytic leukemia, and promyelocytic leukemia. Cell leukemia, chronic myelogenous leukemia and polycythemia vera and other diseases, also have a certain therapeutic effect on lymphoma.

At present, the harringtonine drugs used clinically are all extracted from plants, because the harringtonine plant resources are limited, the growth cycle is long, and the content of ester alkaloids with anticancer activity in plants is extremely low (per 100g The total alkaloid content in the cloverleaf branches and leaves is only 0.39%). If a large amount of it is used to make anticancer drugs, it is obviously impossible to supply it by extracting it from plants, and its price will be quite expensive. In addition, a large number of felling of plants has led to the endangerment of tree species, seriously disrupting the ecological balance. Therefore, it is very meaningful to develop new drug sources, and the artificial synthesis of harringtonine is an important way.

There are more than ten synthetic methods of harringtonine reported in the literature, but these routes are either too long, or the raw materials are too expensive, or cause serious environmental pollution due to the low yield and high consumption, which are far from practical application. . Based on the problems existing in the currently reported synthetic methods, the present invention expects to provide a new synthetic route.

As shown in the above structural formula, it is the basic structure of harringtonine, including five rings A, B, C, D, and E. The present invention mainly relates to the synthesis of harringtonine intermediates containing rings A, B, and C method.

Contents of the invention

The invention provides a simple and efficient synthetic method for synthesizing the intermediate of harringtonine containing C ring. The method is simple to operate, and the reaction products of each step can be effectively separated and purified by recrystallization, and the total yield is as high as 87.4%, which provides a practical route for future industrial production.

Synthetic method of the present invention comprises three steps altogether:

Step (1): Amino protection and N-H bond activation Step: 3,4-methylenedioxyphenethylamine Ⅰ is used as raw material to react with an acylating agent under alkaline conditions to generate a nitrogen-terminal protected intermediate N- Acyl-3,4-methylenedioxyphenethylamine II, its general formula is expressed as:

or for

The acylating agent is one of acid halide, sulfonyl halide, acid anhydride and sulfonic anhydride;

R ₁ is alkyl, alkoxy, benzyloxy, or benzyl substituted by alkyl, nitro or halogen on the benzene ring; R ₂ is alkyl, alkyl substituted by halogen, phenyl, or Phenyl substituted by alkyl, nitro or halogen on the benzene ring.

Preferably, the basic conditions described in the reaction in step (1) can be realized by triethylamine, pyridine, diisopropylethylamine, DBU or N,N-dimethylethanolamine.

Preferably, the acylating agent used in the (1) step reaction is acetic anhydride, acetyl chloride, di-tert-butoxycarbonic anhydride, trifluoromethanesulfonic anhydride, methanesulfonic anhydride, benzoyl chloride, ortho-nitrobenzoic acid Acyl chloride, p-toluenesulfonyl chloride, p-nitrobenzenesulfonyl chloride, o-nitrobenzenesulfonyl chloride, 2,4-difluorobenzenesulfonyl chloride and 2,4,6-trifluorobenzenesulfonyl chloride or any of the above any combination of .

Preferably, the reaction temperature in the step (1) is usually -10-84°C, preferably 0-62°C, preferably 5-52°C. After the reaction in step (1), the purification of the product I is recrystallized with petroleum ether or hexane as the main mixed solvent, and the yield almost reaches 100%.

After the amino acylation reaction in step (1), the acylating agent can not only provide an acyl functional group to acylate the amino group, but also has the ability to activate the amide N-H bond while protecting the amino group, which is the next step for the amino group The alkylation reaction provides favorable conditions.

Step (2): Amino alkylation step: under basic conditions, compound II reacts with haloacetic acid or haloacetic acid derivatives on nitrogen to obtain intermediate N-acylated-3,4 -Methylenedioxyphenethylaminoacetic acid III, its general formula is expressed as:

or for

Wherein: X is F, Cl or Br; R' is H, Na, K or alkyl;

Preferably, the base described in the (2) step reaction can be anhydrous potassium carbonate, anhydrous nano potassium carbonate, anhydrous sodium carbonate, anhydrous nano sodium carbonate, sodium hydroxide, potassium hydroxide, sodium tert-butoxide , Potassium tert-butoxide, sodium ethoxide, potassium ethoxide, sodium methoxide, potassium methoxide, sodium hydride and LDA or any combination of the foregoing.

Preferably, the haloacetic acid used in step (2) is chloroacetic acid or bromoacetic acid, and the derivative of said haloacetic acid refers to chloroacetic acid ester or salt, or bromoacetic acid ester or salt, specifically can be Methyl 2-chloroacetate, ethyl 2-chloroacetate, propyl 2-chloroacetate, isopropyl 2-chloroacetate, tert-butyl 2-chloroacetate, sodium chloroacetate, methyl 2-bromoacetate, 2 -Any one of ethyl bromoacetate, 2-propyl bromoacetate, isopropyl 2-bromoacetate, tert-butyl 2-bromoacetate and sodium bromoacetate or any combination of the foregoing.

Preferably, the molar ratio of compound II to haloacetic acid or haloacetic acid derivatives is 1:1-7, and the preferred molar ratio is 1:1.5-3; and haloacetic acid (or haloacetic acid ester or salt ) to the base in a molar ratio of 1:1 to 8, preferably 1:1.5 to 6

Preferably, the organic solvent used in step (2) is a non-polar solvent, an aprotic polar solvent and a protic polar solvent. Wherein: the non-polar solvent can be tetrahydrofuran (THF), ether, isopropyl ether, methyl tert-butyl ether, ethylene glycol dimethyl ether or ethylene glycol diethyl ether; the aprotic polar solvent can be dimethyl formaldehyde Amide (DMF), dimethylacetamide (DMA) or dimethyl sulfoxide (DMSO); the protic polar solvent can be ethanol, methanol, isopropanol, tert-butanol or ethylene glycol monomethyl ether.

After the reaction in step (2) is finished, the yield of the intermediate product III reaches above 95%.

After the amino alkylation reaction in step (2), specifically use haloacetic acid or haloacetate or salt as an alkylating agent, and connect CH ₂ —COOH on N, which can be used in the next step. - Gram acylation reaction provides conditions to ensure the specificity of the next step intramolecular Friedel-Crafts reaction and improve the yield of N-acyl-3,4-methyleneoxybenzo-3-N-heteroheptanone .

Step (3): ring formation step: compound III undergoes intramolecular Friedel-Crafts acylation reaction under the catalysis of Lewis acid to obtain N-acyl-3,4-methyleneoxybenzo-3-N-hepanone , that is, the C ring intermediate of harringtonine; its general formula is expressed as:

or for

The Lewis acid used in the preferred (3) step reaction can be anhydrous aluminum trichloride, anhydrous iron trichloride, anhydrous zinc chloride, anhydrous tin chloride, boron trifluoride, boron trifluoride Any one of ether solution, hydrofluoric acid, polyphosphoric acid, trifluoroacetic anhydride and acetic anhydride or any combination of the foregoing.

Preferably, the reaction temperature in step (3) is -8 to 18°C, preferably -5 to 10°C.

Preferably, the solvent used in the step (3) reaction is an aprotic solvent, specifically any one of methylene chloride, chloroform, ethylene dichloride, ethylene glycol dimethyl ether and tetrahydrofuran or any of the aforementioned items random combination.

Preferably, the molar ratio of compound III to Lewis acid is 1:2-8, preferably 1:2-5.

After the reaction in step (3), the pure product can be obtained only by recrystallization of the product IV in a mixed solvent with petroleum ether or hexane as the main body, and the yield of the reaction in step (3) reaches 92%. The total yield of the final product IV in the three steps is as high as 87.4%.

After the reaction in step (3), the CH2-COOH connected to the N of the amino group undergoes intramolecular Friedel-Crafts acylation reaction under the catalysis of Lewis acid, that is, the H at the 6th position of the benzene ring is replaced by an acyl group to form a A seven-membered heterocyclic ring containing N can be obtained as an intermediate of the C ring of pilotaxine.

Because the reaction condition of Friedel-Crafts acylation reaction is gentle, the product purity is high; And the side reaction of Friedel-Crafts alkylation reaction is many, and purification is difficult, and productive rate is low, so the present invention selects the alkylation reaction of (2) Among them, introducing an acetate group instead of an ethyl group on the N can effectively improve the yield of the N-containing seven-membered heterocycle generated in step (3) of the present invention, thereby ensuring the high purity of the product IV, which is beneficial to subsequent further purification.

Detailed ways

In order to make the synthetic method of the present invention be further understood, enumerate several specific embodiments below, please refer to the following:

Example 1:

Preparation of N-p-nitrobenzenesulfonyl-3,4-methyleneoxybenzo-3-N-heteroheptanone from 3,4-methylenedioxyphenethylamine

The first step: Amino protection and NH bond activation: put the flask containing 1.652g (10mmol) 3,4-methylenedioxyphenethylamine in 80mL dichloromethane solution in an ice bath, and then add triethylamine 12mmol to provide an alkaline environment. While stirring, 20 mmol of p-nitrobenzenesulfonyl chloride was slowly added dropwise. After 0.5 h, the ice bath was removed, and the reaction was continued for 4 h at room temperature, and the reaction was stopped. The reaction solution was washed twice with water and once with saturated sodium chloride, and then dried over anhydrous sodium sulfate. Filtration, rotary evaporation to recover the solvent, add petroleum ether to the remaining red oily liquid, after the crystallization is complete, recrystallize to obtain a light yellow solid product N-p-nitrobenzenesulfonyl-3,4-methylenedioxyphenethylamine 3.501 g, yield 100%. NMR of the first step product: ¹ H NMR (500MHzDMSO) δ8.11(t, J=5.25,1H)7.93(m,2H)7.81(m,2H)6.79(d,J=8,1H)6.75(d ¹³ CNMR (125MHz DMSO) δ148.53, 147.61, 147.33, 133.85, 132.82, 132.53, 130.79, 129.41, 124.25, 120.58, 112.52, 111.78, 55.45, 55.32, 44.40, 34.91ppm. The reaction process is expressed as follows:

The second step: Aminoalkylation: Dissolve 3.501g (10mmol) of N-p-nitrobenzenesulfonylated-3,4-methylenedioxyphenethylamine II in 90mL absolute anhydrous tetrahydrofuran to form a solution The flask was placed in an ice bath, and 20 mmol potassium tert-butoxide was added under a nitrogen atmosphere to provide an alkaline environment. Subsequently, 1.418g of chloroacetic acid in 10mL of tetrahydrofuran solution was slowly added dropwise into the above-mentioned reactor, and continued to stir for 30min after the dropwise completion, and then heated to reflux for 6h. The temperature of the reaction solution was lowered to room temperature, a small amount of ice water and 50 mL of dichloromethane were added to extract a small amount of impurities, and the aqueous phase was retained. The aqueous phase was adjusted to pH 1 with 6N hydrochloric acid, extracted three times with dichloromethane, and the organic phases were combined. The organic phase was washed once with water and once with saturated sodium chloride, dried over anhydrous sodium sulfate, and concentrated to obtain a yellow solid. Recrystallized from ethyl acetate-petroleum ether to obtain 3.757 g of N-p-nitrobenzenesulfonylated-3,4-methylenedioxyphenethylaminoacetic acid, with a yield of 95%. The second step product NMR: ¹ H NMR (500MHz CDCl ₃ ) δ8.08(m,1H)7.84(m,1H)7.72(m,2H)6.66(d,J=8.5,1H)6.53(dd,J = 2.5, J = 4, 2H) 5.91 (s, 2H) 5.31 (m, 1H) 3.35 (q, J = 6.5, 2H) 2.75 (t, J = 7, 2H) ppm; ¹³ C NMR (125MHzCDCl ₃ ) δ147.95,146.57,133.95,133.55,132.93,131.17,131.00,125.51,121.87,108.98,108.56,101.08,45.33,35.75ppm; HRMS(ESI)m/z[M+H] ⁺ found for351.0638, ₁₅ H ₁₅ N ₂ O ₆ S351.0645. The reaction process is expressed as follows:

The third step: ring-forming step: in a reactor containing 4.084g (10mmol) of N-p-nitrobenzenesulfonyl-3,4-methylenedioxyphenethylaminoacetic acid in 150mL of dichloromethane solution, Under nitrogen gas, 43ml (30mmol) trifluoroacetic anhydride was slowly added dropwise at room temperature. After stirring and reacting for 1 h, the reactor was placed in an ice bath, and 43.8 mL (35 mmol) of boron trifluoride-ether complex was slowly added dropwise as a catalyst. The pH was adjusted to 8 with 1N sodium carbonate solution, the organic phase was separated, and the aqueous phase was extracted 3 times with 30 mL of dichloromethane. The organic phases were combined, washed once with water and saturated sodium chloride, and dried over anhydrous sodium sulfate. Filtration, concentration to 45mL, recrystallization by adding petroleum ether, to obtain 3.427g of light yellow solid N-p-nitrobenzenesulfonyl-3,4-methyleneoxybenzo-3-N-heteroheptanone, yield 92 %. The product of the third step NMR: ¹ H NMR (500MHz CDCl ₃ ) δ7.87(d, J=1.5,2H)7.61(d, J=1.5,2H),6.97(s,1H)6.65(s,1H) 4.23(s,1H)3.85(t,J=6.75,2H)2.99(t,J=6.75,2H)ppm; ¹³ C NMR(125MHz CDCl ₃ )δ200.25,151.08,146.90,146.59,134.41,134.35,132.40131. 23,130.38,129.82,124.04,109.69,107.32,101.97,54.26,46.57,30.98ppm; HRMS(ESI)m/z[M+H] ⁺ found for391.0582, calc for C ₁₇ H ₁₅ N ₂ O ₇ S391.0594 . The reaction process is expressed as follows:

Example 2:

Preparation of N-trifluoromethylsulfonyl-3,4-methyleneoxybenzo-3-N-hepanone from 3,4-methylenedioxyphenethylamine

Step 1: Amino protection and N-H bond activation: Place a flask containing 1.652g (10mmol) of 3,4-methylenedioxyphenethylamine in 80mL of chloroform solution in an ice bath, then add diisopropylethylamine Amine 11mmol to provide an alkaline environment. While stirring, 18 mmol of trifluorosulfonic anhydride was slowly added dropwise. After 1 h, the ice bath was removed, and the reaction was continued for 3 h at room temperature, and the reaction was stopped. The reaction solution was washed with water three times and saturated sodium chloride once, and dried over anhydrous sodium sulfate. Filtration, rotary evaporation to recover the solvent, adding hexane to the remaining oily liquid to crystallize, after the crystallization is complete, recrystallize to obtain the light yellow solid product N-trifluoromethylsulfonyl-3,4-methylenedioxyphenethylamine , yield 98%.

The reaction process is expressed as follows:

The second step: aminoalkylation: put the flask containing the solution of 10mmol of N-trifluoromethylsulfonyl-3,4-methylenedioxyphenethylamine dissolved in 100mL of absolute absolute ethanol in an ice bath 30 mmol sodium ethoxide was added under nitrogen atmosphere to provide an alkaline environment. Then 2.33g of sodium chloroacetate was slowly added in the above-mentioned reactor, continued to stir for 30min after dripping, then heated to reflux for 6h. The temperature of the reaction solution was lowered to room temperature, a small amount of ice water and 50 mL of dichloromethane were added to extract a small amount of impurities, and the aqueous phase was retained. The aqueous phase was adjusted to pH 1 with 6N hydrochloric acid, extracted three times with dichloromethane, and the organic phases were combined. The organic phase was washed once with water and once with saturated sodium chloride, dried over anhydrous sodium sulfate, and concentrated to obtain a yellow solid. Recrystallized from ethyl acetate-petroleum ether to obtain 2.652 g of N-trifluoromethylsulfonyl-3,4-methylenedioxyphenethylaminoacetic acid with a yield of 88%.

The reaction process is expressed as follows:

The third step: ring formation step: in a reactor containing 10mmol N-trifluoromethylsulfonyl-3,4-methylenedioxyphenethylaminoacetic acid in 120mL of anhydrous chloroform solution, under nitrogen, room temperature Slowly add 50mmol of acetic anhydride dropwise. After stirring and reacting for 1 h, the reactor was placed in an ice bath, and 50 mmol of boron trifluoride-ether solution was slowly added dropwise, and the reaction was continued for 4 h under ice bath conditions after the drop was completed. The pH was adjusted to 8 with 1N sodium carbonate solution, the organic phase was separated, and the aqueous phase was extracted three times with 30 mL of chloroform. The organic phases were combined, washed once with water and saturated sodium chloride, and dried over anhydrous sodium sulfate. After filtering and concentrating to 45 mL, petroleum ether was added for recrystallization to obtain N-trifluoromethylsulfonyl-3,4-methyleneoxybenzo-3-N-heteroheptanone as a pale yellow solid with a yield of 90%. ¹ H NMR (500MHz CDCl ₃ )δ: 6.87(s,1H),6.75(s,1H),6.68(dd,J=1.5,J=8,1H),4.51(s,1H),3.98(t, J = 6.75, 2H), 3.12 (t, J = 6.75, 2H); HRMS (ESI) m/z [M+H] ⁺ found for 337.0240, calc for C ₁₂ H ₁₀ F ₃ NO ₅ 337.0232.

The reaction process is expressed as follows:

Example 3

Preparation of N-tert-butoxycarbonyl-3,4-methyleneoxybenzo-3-N-heptanone from 3,4-methylenedioxyphenethylamine

The first step: amino group protection and NH bond activation: put the flask containing 1.652g (10mmol) 3,4-methylenedioxyphenethylamine in 15mL ethanol solution (ethanol as solvent) in an ice bath, add 10mmol Triethylamine and 3 mmol DBU (1,8-diazacyclo[5,4,0]undecene-7) to provide a basic environment. While stirring, 20 mmol of di-tert-butyl carbonate anhydride was slowly added dropwise to the system, and the ice bath was removed 0.5 h after the dropwise addition, and the reaction was continued for 5 h at room temperature. After the reaction was completed, it was concentrated, and 150 mL of ethyl acetate was added to the residue, washed once with water and once with saturated sodium chloride, and dried over anhydrous sodium sulfate. Filtrate with suction, concentrate the filtrate, and recrystallize from ethyl acetate-petroleum ether to obtain N-tert-butoxyformyl-3,4-methylenedioxyphenethylamine as a white solid with a yield of 94%. The first reaction product NMR: ¹ H NMR (500MHz, DMSO) δ6.83 (m, 1H), 6.77 (d, J = 1.5, 1H), 6.68 (dd, J = 1.5, J = 8, 1H), 3.72(d, J=14.5, 6H), 3.11(m, 2H), 2.61(t, J=7.5, 2H), 1.37(s, 9H) ppm; ¹³ C NMR(125MHz, DMSO) δ155.50, 148.61, 147.19 , 131.89, 120.41, 112.49, 111.92, 77.42, 55.51, 55.32, 41.66, 35.04, 28.24ppm.

The reaction process is expressed as follows:

The second step: aminoalkylation: Dissolve 10mmol of N-tert-butoxyformyl-3,4-methylenedioxyphenethylamine in 90mL of ethylene glycol dimethyl ether (as a solvent) to form a solution The flask was placed in an ice bath, and 20 mmol of sodium hydride was added under a nitrogen atmosphere to provide an alkaline environment. Subsequently, 10 mL of 10 mL of ethylene glycol dimethyl ether solution of 12 mmol of bromoacetic acid was slowly added dropwise into the reactor. After the drop was completed, stirring was continued for 30 min, and then heated to reflux for 8 h. The temperature of the reaction solution was lowered to room temperature, a small amount of ice water and 50 mL of dichloromethane were added to extract a small amount of impurities, and the aqueous phase was retained. The aqueous phase was adjusted to pH 1 with 6N hydrochloric acid, extracted three times with dichloromethane, and the organic phases were combined. The organic phase was washed once with water, once with saturated sodium chloride, dried over anhydrous sodium sulfate, and concentrated to obtain a yellow solid, which was recrystallized from petroleum ether with a yield of 81%. The product was N-tert-butoxyformyl-3,4- Methylenedioxyphenethylaminoacetic acid.

The reaction process is expressed as follows:

The third step: the ring-forming step: in a reactor containing 120 mL of anhydrous ethylene glycol dimethyl ether solution of 10 mmol of N-tert-butoxyformyl-3,4-methylenedioxyphenethylamino acetic acid, 40 mmol trifluoroacetic anhydride was slowly added dropwise under nitrogen gas at room temperature. After stirring and reacting for 1 h, the reactor was placed in an ice bath, and 45 mmol of anhydrous ferric chloride was slowly added dropwise, and the reaction was continued for 4 h under ice bath conditions after the dropping was completed. The pH was adjusted to 8 with 1N sodium carbonate solution, the organic phase was separated, and the aqueous phase was extracted 3 times with 30 mL of dichloromethane. The organic phases were combined, washed once with water and saturated sodium chloride, and dried over anhydrous sodium sulfate. After filtration and concentration to 45 mL, petroleum ether was added for recrystallization to obtain N-trifluoromethylsulfonyl-3,4-methyleneoxybenzo-3-N-heteroheptanone as a light yellow solid with a yield of 86%. ¹ H NMR (500MHzCDCl ₃ )δ6.87(s,1H),6.75(s,1H),6.68(dd,J=1.5,J=8,1H),4.23(s,1H),3.85(t,J =6.75,2H),2.99(t,J=6.75,2H),1.37(s,9H)ppm; HRMS(ESI)m/z[M+H] ⁺ foundfor305.1257,calc for C ₁₆ H ₁₉ NO ₅ 305.1263.

The reaction process is as follows:

Example 4

Preparation of N-(2,4-difluorobenzenesulfonyl)-3,4-methylenedioxybenzo-3-N-hepanone from 3,4-methylenedioxyphenethylamine

The first step: amino protection and N-H bond activation: put the flask containing 10mmol of 3,4-methylenedioxyphenethylamine in 80mL of dichloromethane solution in an ice bath, and then add 13mmol of pyridine to provide an alkaline environment . While stirring, 18 mmol of 2,4-difluorobenzenesulfonyl chloride was slowly added dropwise. After 1 h, the ice bath was removed, and the reaction was continued for 3 h at room temperature, and the reaction was stopped. The reaction solution was washed with water three times and saturated sodium chloride once, and dried over anhydrous sodium sulfate. Filter and rotary evaporate to recover the solvent, add hexane to the remaining oily liquid to crystallize, after the crystallization is complete, recrystallize to obtain the light yellow solid product N-(2,4-difluorobenzenesulfonyl)-3,4-methylenedi Oxyphenethylamine, yield 99%. The reaction process is expressed as follows:

The second step: amino alkylation: put the flask containing 10mmol of N-(2,4-difluorobenzenesulfonyl)-3,4-methylenedioxyphenethylamine dissolved in 90mL of DMF to form In an ice bath, 40 mmol of anhydrous potassium carbonate was added under nitrogen atmosphere to provide an alkaline environment. Then, 35 mmol of ethyl chloroacetate (a derivative of haloacetic acid) in 10 mL of DMF was slowly dropped into the reactor while stirring. After the drop was completed, the stirring was continued for 30 min, and then reacted at 65° C. for 6 h. The temperature of the reaction solution was lowered to room temperature, the inorganic salt was removed by filtration, and the filtrate was rotary evaporated under reduced pressure to recover DMF. Add 25 mL of 8M sodium hydroxide ethanol aqueous solution to the residue, and stir at room temperature for 2 h. Add 50 mL of dichloromethane, and adjust the pH to 1 with 6N hydrochloric acid. The organic phase was separated, the aqueous phase was extracted three times with dichloromethane, the combined organic phases were washed once with water and once with saturated sodium chloride, dried over anhydrous sodium sulfate, and concentrated to obtain a solid. Recrystallize from ethyl acetate-petroleum ether to obtain N-(2,4-difluorobenzenesulfonyl)-3,4-methylenedioxyphenethylaminoacetic acid with a yield of 92%. The reaction process is expressed as follows:

The third step: ring-forming step: in a reactor containing 120 mL of anhydrous chloroform solution of 10 mmol N-(2,4-difluorobenzenesulfonyl)-3,4-methylenedioxyphenethylamino acetic acid, 30 mmol trifluoroacetic anhydride was slowly added dropwise under nitrogen gas at room temperature. After stirring and reacting for 1 h, the reactor was placed in an ice bath, and 35 mmol of anhydrous aluminum trichloride was slowly added dropwise, and the reaction was continued under ice bath conditions for 4 h after the dripping was completed. The pH was adjusted to 8 with 1N sodium carbonate solution, the organic phase was separated, and the aqueous phase was extracted three times with 30 mL of chloroform. The organic phases were combined, washed once with water and saturated sodium chloride, and dried over anhydrous sodium sulfate. Filtrate, concentrate to 45mL, add petroleum ether for recrystallization, and obtain light yellow solid N-(2,4-difluorobenzenesulfonyl)-3,4-methylenedioxybenzo-3-N-hepanone , yield 84%. ¹ H NMR (500MHz CDCl ₃ )δ7.82(m,1H),7.28(m,1H),7.02(m,1H),6.97(s,1H),6.65(s,1H),4.23(s,1H ), 3.85(t, J=6.75,2H), 2.99(t, J=6.75,2H) ppm; HRMS(ESI) m/z[M+H] ⁺ foundfor381.0471, calc for C ₁₇ H ₁₃ F ₂ NO ₅ S381.0482.

The reaction process is as follows:

Example 5

Preparation of N-o-nitrobenzenesulfonyl-3,4-methyleneoxybenzo-3-N-hepanone from 3,4-methylenedioxyphenethylamine

The first step: amino protection and N-H bond activation: put the flask containing 10mmol of 3,4-methylenedioxyphenethylamine in 80mL of dichloromethane solution in an ice bath, and then add 12mmol of triethylamine to provide a base sexual environment. While stirring, 15 mmol of o-nitrobenzenesulfonyl chloride was slowly added dropwise. After 1 h, the ice bath was removed, and the reaction was continued for 3 h at room temperature, and the reaction was stopped. The reaction solution was washed with water three times and saturated sodium chloride once, and dried over anhydrous sodium sulfate. Filter and rotary evaporate to recover the solvent, add hexane to the remaining oily liquid to crystallize, after the crystallization is complete, recrystallize to obtain the light yellow solid product N-o-nitrobenzenesulfonyl-3,4-methylenedioxyphenethylamine , yield 97%. The reaction process is expressed as follows:

The second step: aminoalkylation: put the flask containing 10mmol of N-o-nitrobenzenesulfonyl-3,4-methylenedioxyphenethylamine dissolved in 90mL of absolute anhydrous DMA to form a solution on ice In the bath, 40 mmol LDA was added under nitrogen atmosphere to provide an alkaline environment. Then, 40 mmol of ethyl bromoacetate (a derivative of haloacetic acid) in 10 mL of DMA was slowly dropped into the reactor while stirring. After the drop was completed, stirring was continued for 30 min, and then reacted at 100° C. for 6 h. The temperature of the reaction solution was lowered to room temperature, the inorganic salt was removed by filtration, and the filtrate was rotary evaporated under reduced pressure to recover DMA. Add 30 mL of 8M sodium hydroxide ethanol aqueous solution to the residue, and stir at room temperature for 2 h. Add 50 mL of dichloromethane, and adjust the pH to 1 with 6N hydrochloric acid. The organic phase was separated, the aqueous phase was extracted three times with dichloromethane, the combined organic phases were washed once with water and once with saturated sodium chloride, dried over anhydrous sodium sulfate, and concentrated to obtain a solid. Recrystallize with ethyl acetate-petroleum ether to obtain N-o-nitrobenzenesulfonyl-3,4-methyleneoxyphenethylaminoacetic acid. The reaction process is as follows:

The third step: the ring-forming step: in a reactor containing 10 mmol of N-nitrobenzenesulfonyl-3,4-methylenedioxyphenethylaminoacetic acid in 150 mL of tetrahydrofuran solution, under nitrogen, room temperature 20mmol of acetic anhydride was slowly added dropwise. After stirring and reacting for 0.5 h, the reactor was placed in an ice bath, 40 mmol of anhydrous zinc chloride (a kind of Lewis acid) was added, and the reaction was carried out at room temperature for 5 h. Filter, adjust the pH of the filtrate to 8 with 1N sodium carbonate solution, separate the organic phase, and extract the aqueous phase with 30 mL tetrahydrofuran three times. The organic phases were combined, washed once with water and saturated sodium chloride, and dried over anhydrous sodium sulfate. Filtration, concentration to 45mL, adding petroleum ether for recrystallization, yielded 3.427g of light yellow solid N-p-nitrobenzenesulfonyl-3,4-methyleneoxybenzo-3-N-heteroheptanone, yield 82 %. ¹ H NMR (500MHz CDCl ₃ )δ7.87(dd, J=1.5, J=7.5,1H)7.61(m,2H)7.52(dd,J=1.5, J=7.5,1H)6.97(s,1H) 6.65(s,1H)4.23(s,1H)3.85(t,J=6.75,2H)2.99(t,J=6.75,2H)ppm; ¹³ C NMR(125MHz CDCl ₃ )δ200.25,151.08,146.90,146.59, ^{134.41,134.35,132.40131.23,130.38,129.82,124.04,109.69,107.32,101.97,54.26,46.57,30.98ppm} _{; _ 2} O ₇ S391.0594.

The reaction process is expressed as follows:

Claims (4)

1. a kind of with 3,4-methylenedioxyphenethylamine as raw material, the method of synthetic harringtonine C ring intermediate, its reaction process comprises following three steps: Step (1): Amino group protection and N-H bond activation Step: Use 3,4-methylenedioxyphenethylamine Ⅰ as raw material, react with an acylating agent under alkaline conditions to form an intermediate N-acyl group protected at the nitrogen end -3,4-methylenedioxyphenethylamine II, its general formula is expressed as: or for The acylating agent is di-tert-butoxycarbonic anhydride, o-nitrobenzoyl chloride, trifluoromethanesulfonic anhydride, methanesulfonic anhydride, p-nitrobenzenesulfonyl chloride, o-nitrobenzenesulfonyl chloride, 2,4- One of difluorobenzenesulfonyl chloride and 2,4,6-trifluorobenzenesulfonyl chloride or any combination of the preceding items; Step (2): Amino alkylation step: under basic conditions, compound II reacts with haloacetic acid or haloacetic acid derivatives on the nitrogen to obtain the intermediate N-acylated-3,4- Methylenedioxyphenethylaminoacetic acid III, its general formula is expressed as: or for Wherein: X is I, Cl or Br; R' is H, Na, K or alkyl; when X is Br, R' is H, Na, K; (3) Ring formation step: compound III undergoes intramolecular Friedel-Crafts acylation reaction under the catalysis of Lewis acid to obtain N-acyl-3,4-methyleneoxybenzo-3-N-heteroheptanone, namely tricuspid Pinetaxel C ring intermediate; its general formula is expressed as: or for The reaction temperature of step (1) is between 5-52 degrees centigrade; The reaction solvent is methylene chloride, chloroform or ethanol; The alkali that step (2) uses is the one in anhydrous potassium carbonate, potassium tert-butoxide, sodium ethylate, sodium hydride and LDA; The solvent used in step (2) is a non-polar solvent, an aprotic polar solvent or a protic polar solvent; wherein the non-polar solvent is tetrahydrofuran (THF) or ethylene glycol dimethyl ether; the aprotic polar solvent is ethyl Glycol dimethyl ether, dimethylformamide (DMF) or dimethylacetamide (DMA); the protic polar solvent is ethanol; Lewis acid used in step (3) is anhydrous aluminum trichloride, anhydrous zinc chloride, boron trifluoride, boron trifluoride ether solution, hydrofluoric acid, polyphosphoric acid, trifluoroacetic anhydride and acetic anhydride any one or any combination of the foregoing. 2. synthetic method according to claim 1, is characterized in that: the alkaline environment of step (1) reaction is made of triethylamine, pyridine, diisopropylethylamine, 1,8-diazabicyclo [5.4. 0] Undec-7-ene or N,N-dimethylethanolamine provided. 3. The synthetic method according to claim 1, characterized in that: the haloacetic acid used in step (2) refers to chloroacetic acid or bromoacetic acid, and the derivative of haloacetic acid refers to chloroacetic ester or salt, or is bromine Acetate or salt. 4. synthetic method according to claim 3, it is characterized in that: the haloacetic acid derivative used in the step (2) refers to 2-methyl chloroacetate, 2-ethyl chloroacetate, propyl 2-chloroacetate , isopropyl 2-chloroacetate, tert-butyl 2-chloroacetate, sodium chloroacetate, potassium 2-bromoacetate or sodium bromoacetate.