CN104045646A - Synthetic method of harringtonine intermediate with D-ring - Google Patents

Abstract

The invention relates to an efficient synthetic method of a natural product harringtonine intermediate with D-ring. A raw material of N-acyl-3,4-methoxy methylene benzo-3-N-heterocyclic heptanone is subjected to three steps including deacylation, N-C acylation and carbonyl alpha-site alkylation to complete construction of the D-ring of harringtonine, namely 3,4-methoxy methylene benzo-3-N-heterocyclic heptanone and ketopyrrolidine. Products from each step can be purified by a recrystallization method, and the method has simple operation, total yield reaching 81% and good industrial prospect.

Description

Synthetic method of harringtonine D ring intermediate

technical field

The invention relates to a method for synthesizing a drug intermediate, in particular to a method for synthesizing a harringtonine intermediate. the

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. the

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. the

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. the

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 harringtonine intermediates containing rings A, B, C, and D synthetic method. the

Contents of the invention

The invention provides a simple and efficient synthetic method for synthesizing the intermediate of harringtonine containing D ring. The method is simple to operate, and the reaction products of each step can be effectively separated and purified through recrystallization, and the total yield is as high as 81%, which provides a practical route for future industrial production. the

The basic process of the synthesis method of the present invention is to use N-acyl-3,4-methyleneoxybenzo-3-N-heptanone as raw material, remove the acyl protecting group, N-propionylation, intramolecular The α-position of the carbonyl is alkylated into a ring to construct the harringtonine D ring. the

The present invention specifically can comprise three steps:

Step (1): Remove the acyl protecting group: make N-acyl-3,4-methyleneoxybenzo-3-N-heptanone (compound Ⅰ) remove the acyl protecting group on N and transform Become the keto salt (compound Ⅱ) of 3,4-methyleneoxybenzo-3-N-heptanone, and the reaction process is as follows:

Wherein, when R=acyl group, sulfonyl group, A is the acid group of organic acid or inorganic acid. the

Preferably, A=F ^— , Cl ^— , Br ^— , I ^— , CF ₃ CO ₂ ^— , BF ₄ ^— or HCOO ^— .

In the above process, the conditions for removing the acyl group on the N vary depending on the acyl group, and the reaction temperature ranges from about 0 to 60°C. Specifically:

For the removal of tert-butoxyformyl, use dichloromethane solution of trifluoroacetic acid, ethyl acetate solution of hydrogen chloride, ether solution of hydrogen chloride, tetrahydrofuran solution of hydrogen chloride, hydrochloric acid aqueous solution, fluoroboric acid ethyl ether solution, fluoroboric acid aqueous solution, preferably React at 0-30°C for 20min-3h to remove the acyl group on N to form the corresponding ketone salt. the

The removal of the benzyloxyformyl group is realized by Pd/C catalyzed atmospheric pressure hydrogenolysis in dichloromethane. After the benzyloxyformyl group is removed, hydrohalic acid can be introduced to form the corresponding salt. the

Sulfonyl, including p-nitrobenzenesulfonyl, o-nitrobenzenesulfonyl, methylsulfonyl, p-toluenesulfonyl, and trifluoromethylsulfonyl, is removed by sodium thiophenate, p-methoxy One of thiophenol, thiophenol, thioglycolic acid, and 1,2-dithiol or a mixture of any two is used as a removal agent, and it is implemented in an aprotic polar solvent under alkaline conditions. After removal of the sulfonyl group, hydrohalic acid can be introduced to form the corresponding salt. the

Preferably, the base used can be potassium carbonate, sodium ethoxide or lithium hydroxide. the

Preferably, the aprotic polar solvent used may be one of dichloromethane, dimethylsulfoxide, dimethylformamide, dimethylacetamide, acetonitrile, acetone or any mixture of the foregoing items. the

After the first step of reaction, the acyl protecting group is removed, and the yield of product II can reach 76-98%. the

Step (2): Aminopropionylation: Compound II reacts with 3-substituted propionic acid derivatives under basic conditions to obtain N-3-substituted propionyl-3,4-methyleneoxybenzo-3-N -Heteroheptanone (compound Ⅲ), the reaction process is as follows:

Wherein Y=Cl, Br, OMe, OEt, OCH=CH ₂ or OC(CH ₃ )=CH ₂ ;

X=Cl, Br, I, methylsulfonyloxy, methylbenzenesulfonyloxy or trifluoromethylsulfonyloxy;

Preferably, the 3-substituted propionic acid derivatives are 3-halogenated propionyl chloride, 3-halogenated propionyl bromide, 3-halogenated propionic acid methyl ester, 3-halogenated propionic acid ethyl ester, 3-halogenated propionic acid Vinyl ester, one of isopropenyl 3-halopropionate or one of 3-sulfonyloxypropionyl chloride, 3-sulfonyloxypropionyl bromide; halogen is one of chlorine and bromine; The phenylsulfonyloxy group is preferably p-toluenesulfonyloxy. the

Preferably, the base is selected as one of pyridine, triethylamine, dimethylaminopyridine, diisopropylethylamine, potassium carbonate, sodium carbonate or any combination of the foregoing. The molar ratio of propionylating agent to base is 1:2-12, and the ideal molar ratio is 1:3-6. the

Preferably, the solvent is selected from one or a mixture of dichloromethane, chloroform, tetrahydrofuran, methyl tert-butyl ether, ethylene glycol dimethyl ether, and 1,2-dichloroethane. the

Preferably, in the reaction, the molar ratio of the compound II to the 3-substituted propionic acid derivative is 1:1-4, the preferred molar ratio is 1:1-1.5, and the yield of the product III is 63-93%. . the

Step (3): Ring formation step: Compound III undergoes intramolecular carbonyl α-position alkylation under strong basic conditions, that is, the carbon atom at the 3rd position of the N-linked 3-substituted propionyl group of compound III is combined with C The carbonyl α-carbon on the ring forms a linkage to generate 3,4-methyleneoxybenzo-3-N-heptanopyrrolidone, the harringtonine D ring intermediate, and the reaction process is shown as follows:

Preferably, the base used in the reaction is selected from lithium diisopropylamide, sodium hydride, sodium ethylate, potassium tert-butoxide, sodium tert-butoxide, nanometer potassium carbonate, anhydrous potassium carbonate, DBU, 4-dimethylamino One or any combination of pyridine, 2,4,6-collidine, 2,4-lutidine and 2,6-lutidine. The molar ratio of compound III to base is 1:1-5, and the ideal molar ratio is 1:1-4. the

Preferably, the solvent used is selected from dichloromethane, chloroform, tetrahydrofuran, methyl tert-butyl ether, ethylene glycol dimethyl ether, 1,2-dichloroethane, acetonitrile, dimethylformamide, N- One or any combination of methylpyrrolidone and dimethyl sulfoxide. the

Preferably, the suitable temperature for carrying out the reaction is -45-78°C, and the optimum temperature is 0-48°C. The suitable reaction time is 3-15 hours, and the ideal reaction time is 4-9 hours. the

The three steps of the present invention are the first step in order to remove N-acyl-3,4-methyleneoxybenzo-3-N-heptanone (compound I) under a specific acyl removal environment. N is connected with an acyl protecting group to convert compound I into the corresponding ketone salt, and activate the N-H bond to provide favorable conditions for the N acylation of the second step; the second step is acylated by a 3-substituted propionic acid derivative, such as 3 -Halogenated propionic acid, 3-halogenated propionyl halide or 3-halogenated propionate, etc., N is acylated, and a 3-substituted propionyl is connected to provide conditions for the third step to form a ring; the third step It is an intramolecular carbonyl α-position alkylation reaction under strong alkaline conditions, and the No. 3 carbon atom connected to the propionyl group on the N is bonded with the carbonyl α-position carbon to form a ring. Since the H on the third carbon of the propionyl group connected to the N has been replaced by a halogen, etc., and the H at the α-position of the carbonyl is the most active and easy to be substituted, so the third step of the ring-forming process is highly selective and specific properties, the highest total yield of product IV can reach 81%. the

The present invention also provides a method for preparing the raw material N-acyl-3,4-methyleneoxybenzo-3-N-heptanone (compound I) used in the aforementioned reaction, which is based on 3,4-methylene Dioxyphenylethylamine i is a raw material, and the preparation method may further comprise the steps:

Step (1-1): Amino protection and N-H bond activation Step: Using 3,4-methylenedioxyphenethylamine (compound i) as raw material, reacting with an acylating agent under alkaline conditions to generate nitrogen-terminal protected Intermediate N-acyl-3,4-methylenedioxyphenethylamine (compound ii), its general formula is expressed as:

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

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

The alkaline conditions described in the above reaction can be realized by triethylamine, pyridine, diisopropylethylamine, DBU or N,N-dimethylethanolamine; the acylating agent is acetic anhydride, acetyl chloride, di-tert-butoxy Carbonic anhydride, trifluoromethanesulfonic anhydride, methanesulfonic anhydride, benzoyl chloride, o-nitrobenzoyl chloride, p-toluenesulfonyl chloride, p-nitrobenzenesulfonyl chloride, o-nitrobenzenesulfonyl chloride, 2,4-di One of fluorobenzenesulfonyl chloride and 2,4,6-trifluorobenzenesulfonyl chloride; the reaction temperature is usually -10-84°C, the favorable temperature is 0-62°C, and the preferred temperature is 5-52°C. After the reaction, the compound i was purified by recrystallization with petroleum ether or hexane as the main mixed solvent, and the yield almost reached 100%. the

Step (1-2): Amino alkylation step: Under basic conditions, compound ii undergoes an alkylation reaction on nitrogen with haloacetic acid or haloacetic acid derivatives to obtain the intermediate N-acylate-3, 4-methylenedioxyphenethylamino acetic acid (compound Ⅲ), its general formula is expressed as:

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

The base described in the above 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, ethanol Any one of sodium, potassium ethylate, sodium methylate, potassium methylate, sodium hydride and LDA; the haloacetic acid used is chloroacetic acid or bromoacetic acid, and the derivative of said haloacetic acid refers to chloroacetic ester or salt, Or bromoacetate or salt, specifically methyl 2-chloroacetate, ethyl 2-chloroacetate, propyl 2-chloroacetate, isopropyl 2-chloroacetate, tert-butyl 2-chloroacetate, chlorine Any one of sodium acetate, methyl 2-bromoacetate, ethyl 2-bromoacetate, propyl 2-bromoacetate, isopropyl 2-bromoacetate, tert-butyl 2-bromoacetate and sodium bromoacetate; Compound Ⅱ The molar ratio to haloacetic acid or haloacetic acid derivatives is 1:1~7, and the preferred molar ratio is 1:1.5~3; and the molar ratio of haloacetic acid (or haloacetic acid ester or salt) to alkali The ratio is 1:1-8, and the preferred molar ratio is 1:1.5-6; the organic solvents used are non-polar solvents, aprotic polar solvents and protic polar solvents. Wherein: non-polar solvents include tetrahydrofuran (THF), diethyl ether, isopropyl ether, methyl tert-butyl ether, ethylene glycol dimethyl ether and ethylene glycol diethyl ether; aprotic polar solvents include dimethylformamide ( DMF), dimethylacetamide (DMA), dimethyl sulfoxide (DMSO); protic polar solvents include ethanol, methanol, isopropanol, tert-butanol, and ethylene glycol monomethyl ether. After the reaction, the yield of the intermediate product C reaches more than 95%. the

Step (1-3): Cycling step: Intramolecular Friedel-Crafts acylation reaction of compound Ⅲ under Lewis acid catalysis to obtain N-acyl-3,4-methyleneoxybenzo-3-N-heptane Ketone, forming harringtonine C ring intermediate, to provide the raw material I for the synthesis of D ring intermediate; the general formula of its reaction is expressed as:

The Lewis acid used in the above reaction can be anhydrous aluminum trichloride, anhydrous ferric chloride, anhydrous zinc chloride, anhydrous tin chloride, boron trifluoride, boron trifluoride ether solution, hydrofluoric acid , polyphosphoric acid, trifluoroacetic anhydride, and acetic anhydride; the reaction temperature is -8 to 18°C, preferably -5 to 10°C; the solvent used is an aprotic solvent, specifically dichloro Any one of methane, chloroform, dichloroethane, ethylene glycol dimethyl ether and tetrahydrofuran; the molar ratio of compound Ⅲ to Lewis acid is 1:2-8, and the preferred molar ratio is 1:2-5. After the reaction, the product I can be recrystallized from a mixed solvent based on petroleum ether or hexane to obtain a pure product, which is N-acyl-3,4-methyleneoxybenzo-3-N-heptanone ( Compound I) to provide raw materials for the synthesis of harringtonine D ring intermediates. the

Detailed ways

In order to further illustrate the synthetic method of the present invention, the following specific examples are given for illustration, please refer to the following:

Example 1

The following is the synthetic route of 3,4-methylenedioxyphenethylamine to 3,4-methyleneoxybenzo-3-N-heteroheptanopyrrolidone, which can be basically divided into two processes: 

First synthesize N-p-nitrobenzenesulfonyl-3,4-methyleneoxybenzo-3-N-heptanone from 3,4-methylenedioxyphenethylamine; Synthesis of 3,4-methyleneoxybenzo-3-N-heteroheptanopyrrolidone from nitrobenzenesulfonyl-3,4-methyleneoxybenzo-3-N-heptanone. the

First introduce the process of synthesizing N-p-nitrobenzenesulfonyl-3,4-methyleneoxybenzo-3-N-heteroheptanone with 3,4-methylenedioxyphenethylamine: 

Step 1: Amino group protection and N-H bond activation: Place a flask containing 1.652g (10mmol) of 3,4-methylenedioxyphenethylamine in 80mL of dichloromethane solution in an ice bath, then add 12mmol of triethylamine , 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%. the

Step 2: Amino alkylation: Dissolve 3.501 g (10 mmol) of N-p-nitrobenzenesulfonyl-3,4-methylenedioxyphenethylamine II in 90 mL of absolute anhydrous tetrahydrofuran The flask was placed in an ice bath, and 20 mmol of potassium tert-butoxide was added under nitrogen to provide an alkaline environment. The 10mL tetrahydrofuran solution of 1.418g chloroacetic acid was slowly added dropwise in the above-mentioned reactor subsequently, 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 3.757 g of N-p-nitrobenzenesulfonylated-3,4-methylenedioxyphenethylaminoacetic acid, with a yield of 95%. the

Step 3: Intramolecular Friedel-Crafts acylation to form a ring Step: in 150mL dichloromethane solution filled with 4.084g (10mmol) N-p-nitrobenzenesulfonyl-3,4-methylenedioxyphenethylaminoacetic acid In the reactor, 43ml (30mmol) 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 43.8 mL (35 mmol) of boron trifluoride-ether complex was slowly added dropwise as a catalyst, 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. 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(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, 132.40 131.23, 130.38, 129.82, 124.04, 109.69, 107.32, 101.97, 54.26, 46.57, 30.98ppm; calc for C ₁₇ H ₁₅ N ₂ O ₇ S391.0594.

The above reaction process is expressed as follows:

The following is the synthesis of 3,4-methyleneoxybenzo-3-N-heptanone from N-p-nitrobenzenesulfonyl-3,4-methyleneoxybenzo-3-N-heptanone The specific process of pyrrolidone is divided into three steps. the

The first step: remove the acyl protecting group: p-Nitrobenzenesulfonyl-3,4-methyleneoxybenzo-3-N-heptanone removes "p-nitrobenzenesulfonyl"

40 Under the condition of ℃, 1.322g (25mmol) sodium thiophenate was added, and after stirring for 1 hour, dichloromethane was recovered by concentration. 150 mL of ethyl acetate was added to the residue, and the insoluble matter was removed by filtration. Hydrogen chloride was passed through the filtrate to saturation, and after the solid was completely precipitated, the yellow solid 3,4-methyleneoxybenzo-3-N-hepanone hydrochloride was obtained by filtration, 2.37 g, with a yield of 98%. NMR of the product: ¹ H NMR (500MHz D ₂ O) δ (ppm) 7.25 (s, 1H) 6.80 (s, 1H) 6.05 (s, 1H) 4.45 (s, 2H) 3.78 (t, J = 6.5, 2H) 3.28 (t, J=6.5, 2H); ¹³ C NMR (125MHz D ₂ O) δ 196.72, 152.78, 147.39, 133.79, 128.92, 109.77, 107.87, 102.23, 1.30, 43.16, 27.49 ppm; HRMS (ESI) m /z[M-Cl] ^- found for 206.0808, calc for C ₁₁ H ₁₂ NO ₃ 206.0812. The reaction process is expressed as follows:

The second step: aminopropionylation: 3,4-methyleneoxybenzo-3-N-hepanone hydrochloride reacts with isopropenyl 3-chloropropionate under alkaline conditions to obtain N-3 -(Chloropropionyl)-3,4-methyleneoxybenzo-3-N-heptanone:

2.417 g (10 mmol) of 3,4-methyleneoxybenzo-3-N-hepanone hydrochloride was added to the two-necked flask, and 180 mL of dichloromethane (solvent) was added. Add 0.885mL of pyridine at 0～-5°C under a nitrogen atmosphere, stir for 35min, and then add 15mmol of triethylamine to provide an alkaline environment. After continuing stirring for 10 min, a solution of 2.23 g (15 mmol) of isopropenyl 3-chloropropionate in 20 mL of dichloromethane was slowly added. Control 30 ~ 35 ℃, continue to react for 3h. The reaction solution was washed with 2% dilute hydrochloric acid, saturated aqueous sodium bicarbonate solution, water, and saturated sodium chloride, dried over anhydrous sodium sulfate, and concentrated to obtain the white solid product N-(3-chloropropionyl)-3 , 4-methyleneoxybenzo-3-N-heteroheptanone 2.75g, 93%; product nuclear magnetic resonance: ¹ H NMR (500MHz CDCl ₃ ) δ7.27 (d, J=45.5, 1H) 6.68 ( d,J=14.5,1H)6.02(d,J=5.5,2H)4.33(d,J=31.5,2H)3.839(t,J=6.25,1H)3.73(m,2H)3.66(t,J= 7.5,1H)3.07(d,J=4.5,2H)2.68(s,J=6.5,2H)ppm; ¹³ CNMR(125MHz CDCl ₃ )δ200.30,198.18,170.66,170.25,152.48,151.77,147.59,135.74,133.48 ,130.92,129.88,110.17,109.46,109.05,108.76,102.18,102.07,55.44,53.14,46.10,43.35,39.48,36.55,36.49,32.98,32.77ppm; MS(ESI)m ^/ z+f[M+H] for 296.0, calcd for C ₁₄ H ₁₅ ClNO ₄ 296.07. The reaction process is expressed as follows:

The third step: ring formation step: N-(3-chloropropionyl)-3,4-methyleneoxybenzo-3-N-heptanone generates intramolecular carbonyl α- Alkylation to generate 3,4-methyleneoxybenzo-3-N-heptanopyrrolidone: 

In a reactor containing 2.957g (10mmol) N-(3-chloropropionyl)-3,4-methyleneoxybenzo-3-N-heteroheptanone in 300mL of anhydrous tetrahydrofuran solution, in 1.68 g (15 mmol) of potassium tert-butoxide was added while stirring at -5°C under nitrogen protection to provide a strong alkaline environment. After continuing the reaction for 2 h, a small amount of water was slowly added dropwise to quench excess potassium tert-butoxide. The aqueous phase was separated, and the organic phase was concentrated to recover tetrahydrofuran. Dichloromethane was added to the residue, and the organic phase was washed 3 times with water and 2 times with saturated sodium chloride. Dry, filter, concentrate, and separate by flash silica gel column chromatography to obtain 2.13 g of white solid 3,4-methyleneoxybenzo-3-N-heptanopyrrolidone with a yield of 82%. The nuclear magnetic resonance of the product: ¹ H NMR (500MHz CDCl ₃ ) δ7.213(s,1H)5.99(s,2H)4.32(d,J=8.5)3.89(ddd,J=4.17,J=14,1H)3.37(dd,J= 3.75, J = 12.5, 1H) 3.12 (ddd, J = 5, J = 14.5, 1H) 2.89 (m, 1H) 2.65 (m, 1H) 2.33 (m, 3H) ppm; ¹³ C NMR (125MHz CDCl ₃ ) δ202.27,175.24,152.04,147.54,135.23,131.15,109.70,108.88,102.09,64.74,41.43,32.76,30.02,23.75ppm; MS(ESI)m/z[M+H] ⁺ found for260.2,calcd for C _{14H14NO4 260.09 .} The reaction process is expressed as follows:

Example 2

Regarding the acquisition of the raw material "N-methylsulfonyl-3,4-methyleneoxybenzo-3-N-heptanone", refer to the process of Example 1, except that the 3,4-methylene di In the synthesis of oxyphenethylamine "N-p-nitrobenzenesulfonyl-3,4-methyleneoxybenzo-3-N-hepanone", the acylating agent "p-nitrobenzenesulfonyl Acyl chloride" is replaced by "methylbenzenesulfonyl chloride", other processes are similar to Example 1, or slightly adjusted to alkaline conditions or solvents as required, N-methylsulfonyl-3,4-methyleneoxybenzene can be prepared And-3-N-heteroheptanone provides a source of raw materials for the formation of harringtonine D ring intermediates. the

The operation process of synthesizing the D ring intermediate of harringtonine with N-methylsulfonyl-3,4-methyleneoxybenzo-3-N-heptanone is as follows:

The first step: remove the amino protecting group: in a reactor filled with 10mmol N-methylsulfonyl-3,4-methylenedioxybenzo-3-N-heteroheptanone in 150mL of acetonitrile solution, Under the condition of stirring at 55°C, 35mmol p-methoxythiophenol and 35mmol lithium hydroxide were added respectively, and after stirring for 1.5h, acetonitrile was recovered by concentration. 150 mL of ethyl acetate was added to the residue, and the insoluble matter was removed by filtration. Under ice bath conditions, hydrogen bromide in ethyl acetate solution was added to the filtrate until the solid was completely precipitated, and a yellow solid 3,4-methyleneoxybenzo-3-N-hepanone hydrobromide was obtained by filtration. Yield 87%. the

The second step: aminopropionylation: after the obtained 3,4-methyleneoxybenzo-3-N-hepanone hydrobromide, 10mmol3,4-methyleneoxybenzo-3-N -Heteroheptanone hydrobromide was added to a two-necked flask, 180mL of anhydrous chloroform was added, and 13mmol of triethylamine was added at 0～-5°C under a nitrogen atmosphere. After stirring for 20min, 35mmol of potassium carbonate was added. After continuing to stir for 20 min, a solution of 15 mmol 3-bromopropionyl chloride in 20 mL of chloroform was slowly added and reacted at room temperature for 2.5 h. The reaction solution was filtered to remove solid inorganic salts. The filtrate was washed with 2% dilute hydrochloric acid, saturated aqueous sodium bicarbonate solution, water, and saturated sodium chloride respectively, dried over anhydrous sodium sulfate, and concentrated to obtain the white solid product N-(3-bromopropionyl)-3, 2.96 g of 4-methyleneoxybenzo-3-N-hepanone, yield 87%. the

The third step: alkylation of the carbonyl α-position in the molecule to form a ring: in a container containing 10 mmol N-(3-bromopropionyl)-3,4-methyleneoxybenzo-3-N-heptanone In a reactor containing 300 mL of dichloromethane solution, at room temperature under nitrogen protection, 40 mmol of nanometer potassium carbonate was added while stirring. After continuing the reaction at room temperature for 0.5h, the reaction was heated to reflux for 6h. Inorganic salts were recovered by filtration, and the filtrate was washed 3 times with water and 2 times with saturated sodium chloride. After drying, filtering and concentrating, 2.36 g of white solid 3,4-methyleneoxybenzo-3-N-heptanopyrrolidone was obtained, with a yield of 91%. the

The reaction process is expressed as follows:

Example 3

The following is the synthetic route of 3,4-methylenedioxyphenethylamine to 3,4-methyleneoxybenzo-3-N-heteroheptanopyrrolidone, which can be basically divided into two processes: 

First, N-tert-butoxyformyl-3,4-methyleneoxybenzo-3-N-heptanone is synthesized from 3,4-methylenedioxyphenethylamine; then N-tert-butyl Synthesis of 3,4-methyleneoxybenzo-3-N-heptanopyrrolidone from oxyformyl-3,4-methyleneoxybenzo-3-N-heptanone. the

The following briefly describes the process of synthesizing N-tert-butoxyformyl-3,4-methyleneoxybenzo-3-N-heteroheptanone 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 15mL ethanol solution (ethanol as the solvent) in an ice bath, add 10mmol tris Ethylamine 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

Step 2: aminoalkylation: a flask filled with a solution formed by dissolving 10 mmol of N-tert-butoxyformyl-3,4-methylenedioxyphenethylamine in 90 mL of ethylene glycol dimethyl ether (as a solvent) Place in an ice bath, and add 20 mmol of sodium hydride 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

Step 3: Ring formation step: N-tert-butoxyformyl-3,4-methylenedioxyphenethylaminoacetic acid undergoes intramolecular Friedel-Crafts acylation reaction under the catalysis of Lewis acid to generate N-tert-butoxy Formyl-3,4-methylenedioxybenzo-3-N-heptanone, the selected Lewis acid can be anhydrous aluminum trichloride, anhydrous ferric chloride, anhydrous zinc chloride, anhydrous Any one of tin chloride hydrate, polyphosphoric acid, trifluoroacetic anhydride and acetic anhydride, the basic process of the reaction is as follows:

The following is the synthesis of 3,4-methyleneoxybenzo-3-N-heptanone from N-tert-butoxyformyl-3,4-methylenedioxybenzo-3-N-heptanone The specific process of pyrrolidone is divided into three steps. the

The first step: removal of amino protecting group: reaction in 150mL dichloromethane solution containing 10mmol N-tert-butoxyformyl-3,4-methylenedioxybenzo-3-N-heteroheptanone A 30% (v/v) solution of trifluoroacetic acid in dichloromethane was added to the vessel. After stirring and reacting at room temperature for 3 h, the dichloromethane was recovered by concentration to obtain viscous solid 3,4-methyleneoxybenzo-3-N-hepanone trifluoroacetate with a yield of 93%. the

The second step: aminopropionylation: 10mmol3,4-methyleneoxybenzo-3-N-hepanone trifluoroacetate was added to the two-necked flask, 130mL ethylene glycol dimethyl ether was added, and the At ~-5°C and nitrogen atmosphere, 15 mmol of potassium carbonate was added, and after stirring for 20 minutes, 15 mmol of pyridine was added. After continuing to stir for 20 min, slowly add 15 mmol of 3-p-toluenesulfonyloxypropionyl bromide in 20 mL of ethylene glycol dimethyl ether solution, and react at room temperature for 3 h. The reaction solution was filtered to remove solid inorganic salts. The filtrate was concentrated under reduced pressure to recover ethylene glycol dimethyl ether. Add 50 mL of chloroform to the residue, wash the solution with 2% dilute hydrochloric acid, saturated aqueous sodium bicarbonate solution, water, and saturated sodium chloride, dry over anhydrous sodium sulfate, and concentrate to obtain the white solid product N-(3-para Tosyloxypropionyl)-3,4-methyleneoxybenzo-3-N-heptanone, yield 92%. the

The third step: alkylation of the carbonyl α-position in the molecule to form a ring: in a 10 mmol N-(3-p-toluenesulfonyloxypropionyl)-3,4-methyleneoxybenzo-3-N-hetero In the reactor of the 300mL acetonitrile solution of cycloheptanone, at room temperature, under nitrogen protection, add 15mmol DBU while stirring. After continuing to react at room temperature for 0.5h, the reaction was heated to reflux for 4h. The p-toluenesulfonate was removed by filtration, and the filtrate was washed 3 times with water and 2 times with saturated sodium chloride. After drying, filtering and concentrating, 2.41 g of white solid 3,4-methyleneoxybenzo-3-N-heptanopyrrolidone was obtained, with a yield of 93%. the

Example 4

Preparation of 3,4-methyleneoxybenzo-3-N-heptanopyrrolidone from N-benzyloxyformyl-3,4-methyleneoxybenzo-3-N-heptanone In the implementation process, the raw material N-benzyloxyformyl-3,4-methyleneoxybenzo-3-N-heptanone can also be 3,4-methylenedioxyphenethylamine as raw material, with " Benzyloxyformyl halide or benzyloxyformic acid anhydride" is used as an acylating agent, and it is prepared through "protection of amino group and activation of N-H bond, alkylation of amino group, intramolecular Friedel-Crafts acylation to form a ring". the

"Debenzyloxyformyl" step of N-benzyloxyformyl-3,4-methyleneoxybenzo-3-N-heptanone: - 5% Pd/C 5g was added to the reactor of 150mL dichloromethane solution of methylenedioxybenzo-3-N-hepanone. Under the condition of anaerobic environment and room temperature, hydrogen was introduced with stirring, and after reacting for 3 hours, the catalyst was recovered by filtration, and the filtrate was concentrated to recover dichloromethane. Add 150mL of ethyl acetate to the residue, and in an ice bath, pass hydrogen chloride gas to saturation. After the solid is completely precipitated, filter to obtain a yellow solid 3,4-methyleneoxybenzo-3-N-heterocycle Heptanone hydrochloride, yield 92%. the

The obtained 3,4-methyleneoxybenzo-3-N-heptanone hydrochloride is then subjected to "aminopropionylation" and "alkylation of the carbonyl α-position in the molecule to form a ring" to synthesize a white solid 3 , 4-methyleneoxybenzo-3-N-heptanopyrrolidone, the same as the second step and third step reaction process of Example 1. the

Example 5

The 3,4-methyleneoxybenzo-3-N-heptanone hydrochloride obtained in Example 1 reacts with 3-trifluoromethylsulfonyloxypropionyl halide under alkaline conditions to obtain N -3-(3-Trifluoromethylsulfonyloxypropionyl)-3,4-methyleneoxybenzo-3-N-hepanone. the

Then in 150mL 1,2-dichloroethane containing 10mmol N-(3-trifluoromethylsulfonyloxypropionyl)-3,4-methyleneoxybenzo-3-N-hepanone In the reactor of the solution, at room temperature under the protection of nitrogen, 20 mmol of 4-dimethylaminopyridine was added while stirring. After stirring at room temperature for 15 min, the reaction was carried out at 50° C. for 4 h. The triflate was removed by filtration, and the filtrate was washed three times with water and twice with saturated sodium chloride. After drying, filtering and concentrating, 2.38 g of white solid 3,4-methyleneoxybenzo-3-N-heptanopyrrolidone was obtained, with a yield of 92%. ¹ H NMR (500MHz CDCl ₃ ) δ7.213(s,1H)5.99(s,2H)4.32(d,J=8.5)3.89(ddd,J=4.17,J=14,1H)3.37(dd,J= 3.75, J = 12.5, 1H) 3.12 (ddd, J = 5, J = 14.5, 1H) 2.89 (m, 1H) 2.65 (m, 1H) 2.33 (m, 3H) ppm; ¹³ C NMR (125MHz CDCl ₃ ) δ202.27,175.24,152.04,147.54,135.23,131.15,109.70,108.88,102.09,64.74,41.43,32.76,30.02,23.75ppm; MS(ESI)m/z[M+H] ⁺ found for260.2, calcd for C _{14H14NO4 260.09 .}

Claims (10)

1. one kind with N-acyl group-3, and the sub-methoxyl group benzo-3-N-of 4-heterocycle heptanone is raw material, the method for the sub-methoxyl group benzo-3-N-of synthetic 3,4-heterocycle heptanone pyrrolizine ketone, and its synthesis path comprises three steps:

(1), slough acyl group protecting group: make N-acyl group-3, the sub-methoxyl group benzo-3-N-of 4-heterocycle heptanone I removes the acyl group protecting group on N and changes into 3, the ketone salt II of the sub-methoxyl group benzo-3-N-of 4-heterocycle heptanone, reaction process is expressed as follows:

Wherein R is acyl group or alkylsulfonyl, and A is the acid group of organic acid or mineral acid;

(2), N-replaces propionyl: compound ii replaces propanoic derivatives with 3-and react and obtain N-3-and replace propionyl-3 under alkaline condition, 4-Asia methoxyl group benzo-3-N-heterocycle heptanone (compound III), reaction process is expressed as follows:

Wherein Y=Cl, Br, OMe, OEt, OCH=CH ₂or OC (CH ₃)=CH ₂,

X=Cl, Br, I, sulfonyloxy methyl oxygen base, Methyl benzenesulfonyl oxygen or trimethyl fluoride sulfonyl oxygen base;

(3), become ring step: compound III is the alkylation of carbonyl alpha-position in strong alkaline condition issues son estranged; carbon atom and the carbonyl alpha-carbon on C ring that the 3-that the N of compound III connects replaces No. 3 positions of propionyl form connecting key; generate 3; the sub-methoxyl group benzo-3-N-of 4-heterocycle heptanone pyrrolizine ketone; be harringtonine D ring intermediate, reaction process is expressed as follows:

2. synthetic method according to claim 1, is characterized in that: in step (1), A is F ^-, Cl ^-, Br ^-, CF ₃cO ₂ ^-, BF ₄ ^-or HCOO ^-.

3. synthetic method according to claim 1, it is characterized in that: in step (1), if the acyl group of the upper connection of N is tertiary fourth oxygen formyl radical, by add the dichloromethane solution of trifluoroacetic acid to substrate, the diethyl ether solution of the ethyl acetate solution of hydrogenchloride, hydrogenchloride, the tetrahydrofuran solution of hydrogenchloride, aqueous hydrochloric acid, fluoroboric acid diethyl ether solution or fluoborate aqueous solution remove;

If the acyl group of the upper connection of N is carbobenzoxy, by add Pd/C catalyzer to substrate, and pass into H under oxygen free condition ₂remove;

If the acyl group of the upper connection of N is alkylsulfonyl; by adding thiophenol sodium to substrate, to methoxybenzenethiol, thiophenol, Thiovanic acid and 1; the mixture of a kind of or any two kinds in 2-bis-mercaptan, under alkaline condition, removes in aprotic polar solvent.

4. synthetic method according to claim 3, is characterized in that: in step (1), described aprotic polar solvent is chosen as dimethyl formamide, N,N-DIMETHYLACETAMIDE, acetonitrile or acetone.

5. synthetic method according to claim 1, it is characterized in that: in step (2), 3-that propionyl is used replaces propanoic derivatives and is chosen as a kind of in 3-halo propionyl chloride, 3-halo propionyl bromide, 3-halopropanoic acid methyl esters, 3-halopropanoic acid ethyl ester, 3-halopropanoic acid vinyl acetate, the different propylene of 3-halopropanoic acid, 3-sulfonyloxy propionyl chloride, 3-sulfonyloxy propionyl bromide; Sulfonyloxy is a kind of in Methyl benzenesulfonyl oxygen base, sulfonyloxy methyl oxygen base and trimethyl fluoride sulfonyl oxygen base.

6. synthetic method according to claim 1, is characterized in that: the alkali in step (2) is chosen as one or more the combination in pyridine, triethylamine, Dimethylamino pyridine, diisopropylethylamine, salt of wormwood and sodium carbonate.

7. synthetic method according to claim 1, it is characterized in that: the solvent in step (2) is chosen as methylene dichloride, chloroform, tetrahydrofuran (THF), methyl tertiary butyl ether, glycol dimethyl ether, 1 a kind of the or aforementioned every any mixing in 2-ethylene dichloride.

8. synthetic method according to claim 1, it is characterized in that: the alkali using in step (3) for di-isopropyl ammonia lithium, sodium hydride, sodium ethylate, potassium tert.-butoxide, sodium tert-butoxide, receive a micron salt of wormwood, Anhydrous potassium carbonate, DBU, DMAP, 2,4,6-trimethylpyridine, 2, a kind of or aforementioned every mixing arbitrarily in 4-lutidine and 2,6-lutidine.

9. synthetic method according to claim 1, it is characterized in that: the solvent in step (3) is methylene dichloride, chloroform, tetrahydrofuran (THF), methyl tertiary butyl ether, glycol dimethyl ether, 1 a kind of the or aforementioned every mixing arbitrarily in 2-ethylene dichloride, acetonitrile, dimethyl formamide, N-Methyl pyrrolidone and methyl-sulphoxide.

10. synthetic method according to claim 1, is characterized in that: raw material N-acyl group-3 of using in step (1), and the sub-methoxyl group benzo-3-N-of 4-heterocycle heptanone I is synthetic by the following method:

(1-1): with 3,4-methylene-dioxy phenylethylamine, for raw material, react intermediate N acyl group-3 that generate the protection of nitrogen end under alkaline condition with acylating agent under the temperature condition of-10-84 ℃, 4-methylene-dioxy phenylethylamine, to protect amino and activation N-H key;

(1-2): under alkaline condition, in organic solvent, intermediate N acyl group-3, the alkylated reaction on 4-methylene-dioxy phenylethylamine and 2-halogenated acetic acids, 2-halogenated acetic acids ester or 2-halogenated acetic acids salt generation nitrogen, obtain intermediate N acidylate-3,4-methylenedioxybenzenes ethylamino acetic acid;

(1-3): under Louis acid catalysis, intermediate N acidylate-3, friedel-crafts acylation reaction in 4-methylenedioxybenzenes ethylamino acetic acid generation molecule, obtains N-acyl group-3, the sub-methoxyl group benzo-3-N-of 4-heterocycle heptanone.