CN104045646A - Synthetic method of harringtonine intermediate with D-ring - Google Patents
Synthetic method of harringtonine intermediate with D-ring Download PDFInfo
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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
Technical field
The present invention relates to a kind of synthetic method of pharmaceutical intermediate, be specially the synthetic method of harringtonine intermediate.
Background technology
Harringtonine is a kind of alkaloid extracting from cephalotaxus plant, there is good antitumour activity, be mainly used in clinically treating the diseases such as acute myeloblastic leukemia, acute monokaryon type chronic myeloid leukemia, promyelocytic leukemia, chronic myelocytic leukemia and true polycyth(a)emia, lymphoma is also had to certain result for the treatment of that has.
At present, the kind of harringtonine as medicinal materials medicine using clinically all extracts from plant, because Cephalotaxus fortunei plant resources is limited, growth cycle is long, and the aconitines content of antitumour activity extremely low (in every 100g Cephalotaxus fortunei branches and leaves, total alkaloid content only has 0.39%) in plant, if will drop in a large number for making cancer therapy drug, relies on the method for extracting from plant, obviously be unable to supply, its price can be quite expensive.In addition, a large amount of felling of plant cause seeds endangered, the havoc eubiosis.Therefore, develop new medicine source very meaningful, synthetic harringtonine is exactly an important channel.
The synthetic method of the harringtonine of bibliographical information has more than ten bars, but these routes or route are oversize, or raw material is too expensive, or too low consumption is high causes serious environmental pollution because of yield, far apart with practical application.The problem that synthetic method based on current report exists, the present invention's expectation provides a kind of new synthetic route.
As above shown in structural formula, be the basic structure of harringtonine, comprise A, B, C, D, five rings of E, the present invention relates generally to the synthetic method of the harringtonine intermediate that contains A, B, C, D ring.
Summary of the invention
The invention provides the intermediate that the synthetic harringtonine of a kind of simple synthetic method efficiently contains D ring.Present method is simple to operate, and each walks reaction product all can carry out effective separation, purifying by recrystallization, and total recovery is up to 81%, for later suitability for industrialized production provides a practical route.
Synthetic method primary process of the present invention is with N-acyl group-3, and the sub-methoxyl group benzo-3-N-of 4-heterocycle heptanone is raw material, and in sloughing acyl group protecting group, N-propionyl, molecule, carbonyl alpha-position is alkylated into ring, builds harringtonine D ring.
The present invention specifically can comprise three steps:
(1) step: slough acyl group protecting group: make N-acyl group-3; the sub-methoxyl group benzo-3-N-heterocycle heptanone of 4-(chemical compounds I) removes the acyl group protecting group on N and changes into 3; the ketone salt (compound ii) of the sub-methoxyl group benzo-3-N-of 4-heterocycle heptanone, reaction process is expressed as follows:
Wherein, when R=acyl group, alkylsulfonyl, A is the acid group of organic acid or mineral acid.
Preferably, A=F
-, Cl
-, Br
-, I
-, CF
3cO
2 -, BF
4 -or HCOO
-.
In said process, the upper acyl group of N removes condition because of the difference difference of acyl group, and range of reaction temperature is about between 0～60 ℃, specifically:
Removing of tertiary fourth oxygen formyl radical; with the dichloromethane solution of trifluoroacetic acid, 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, fluoborate aqueous solution; better for 0～30 ℃ of reaction 20min～3h; in order to remove the acyl group on N, form corresponding ketone salt.
Removing of carbobenzoxy, in methylene dichloride, realizes by the method for Pd/C catalysis normal pressure hydrogenolysis, after removing carbobenzoxy, can pass into haloid acid and form corresponding salt.
Alkylsulfonyl; comprise p-nitrophenyl alkylsulfonyl, ortho-nitrophenyl alkylsulfonyl, methyl sulphonyl, removing Methyl benzenesulfonyl base, trifluoromethyl sulfonyl; be adopt thiophenol sodium, to methoxybenzenethiol, thiophenol, Thiovanic acid, 1; the mixture of a kind of or any two kinds in 2-bis-mercaptan is for removing agent; under alkaline condition, in aprotic polar solvent, implement.After removing alkylsulfonyl, can pass into haloid acid and form corresponding salt.
Preferably, alkali used can be salt of wormwood, sodium ethylate or lithium hydroxide.
Preferably, aprotic polar solvent used can be a kind of or aforementioned every any mixture in methylene dichloride, dimethyl sulfoxide (DMSO), dimethyl formamide, N,N-DIMETHYLACETAMIDE, acetonitrile, acetone.
After the first step reaction, slough acyl group protecting group, the yield of product II can reach 76～98%.
(2) step: aminopropan acylations: compound ii reacts and obtains N-3-replacement propionyl-3 with 3-replacement propanoic derivatives under alkaline condition, the sub-methoxyl group benzo-3-N-heterocycle heptanone (compound III) of 4-, 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;
Preferably, to replace propanoic derivatives be a kind of in a kind of or 3-sulfonyloxy propionyl chloride 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 bromide to 3-; Halogen is a kind of of chlorine and bromine; Methyl benzenesulfonyl oxygen base is preferably Methyl benzenesulfonyl oxygen.
Preferably, described alkali, is chosen as a kind of or aforementioned every arbitrary combination in pyridine, triethylamine, Dimethylamino pyridine, diisopropylethylamine, salt of wormwood, sodium carbonate.Mol ratio 1:2～12 of propionyl agent and alkali, desirable mol ratio is 1:3～6.
Preferably, described solvent, is chosen as methylene dichloride, chloroform, tetrahydrofuran (THF), methyl tertiary butyl ether, glycol dimethyl ether, 1, a kind of and several mixture in 2-ethylene dichloride.
Preferably, in described reaction, the mol ratio that compound ii and 3-replace propanoic derivatives is 1:1～4, and preferably mol ratio is 1:1～1.5, and the yield of product III reaches 63～93%.
(3) step: become ring step: compound III is the alkylation of carbonyl alpha-position in strong alkaline condition issues son estranged; be the carbon atom and the formation of the carbonyl alpha-carbon on C ring connecting key that 3-that the N of compound III connects replaces No. 3 positions of propionyl; 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:
Preferably, the alkali using in reaction is chosen as 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 arbitrary combination in 4-lutidine and 2,6-lutidine.Wherein the mol ratio of compound III and alkali is 1:1～5, and desirable mol ratio is 1:1～4.
Preferably, the solvent using is chosen as methylene dichloride, chloroform, tetrahydrofuran (THF), methyl tertiary butyl ether, glycol dimethyl ether, 1, a kind of or arbitrary combination in 2-ethylene dichloride, acetonitrile, dimethyl formamide, N-Methyl pyrrolidone, methyl-sulphoxide.
Preferably, suitable temperature is implemented in reaction, and-45～78 ℃, the temperature of optimization is 0～48 ℃.The suitable reaction times is 3～15h, and the desirable reaction times is 4～9h.
Three steps of the present invention are that the first step makes N-acyl group-3 successively, the sub-methoxyl group benzo-3-N-heterocycle heptanone of 4-(chemical compounds I) removes under environment at specific acyl group, remove the upper acyl group protecting group that connects of N, make Compound I change into corresponding ketone salt, and activate N-H key, for the N acylations of second step provides favourable condition; Second step replaces propanoic derivatives acylations through 3-, and for example 3-halopropanoic acid, 3-halo propionyl halogen or 3 halopropanoic acid esters etc., make N by acylations, and connect a 3-, replaces propionyl, for the 3rd step becomes ring, provides condition; The 3rd step is carbonyl alpha-position alkylated reaction in strong alkaline condition issues son estranged, and No. 3 carbon atoms and the carbonyl alpha-position carbon bond of the upper connection of N propionyl are formed ring.Because the H on upper No. three carbon of propionyl that connect of N is by replacements such as halogens, and the H of carbonyl alpha-position is active maximum, is easily substituted, therefore make the one-tenth ring process of the 3rd step have selectivity and the specificity of height, makes the overall yield of product IV can reach 81%.
The present invention also provides a kind of raw materials used N-of previous reaction acyl group-3 of preparing, the method for the sub-methoxyl group benzo-3-N-heterocycle heptanone of 4-(chemical compounds I), its be with 3,4-methylene-dioxy phenylethylamine I for raw material, this preparation method comprises the steps:
Step (1-1): amido protecting and N-H bond activation step: with 3; 4-methylene-dioxy phenylethylamine (compound I) is raw material; under alkaline condition, generate intermediate N acyl group-3 of nitrogen end protection with acylation reaction; 4-methylene-dioxy phenylethylamine (compound II), its general formula is expressed as:
Described acylating agent is one of them of carboxylic acid halides, sulfonic acid halide, acid anhydrides and sulphonic acid anhydride;
R
1for alkyl, alkoxyl group, phenmethyl, or the phenmethyl being replaced by alkyl, nitro or halogen on phenyl ring; R
2for alkyl, the alkyl, the phenyl that replace through halogen, or the phenyl being replaced by alkyl, nitro or halogen on phenyl ring.
Alkaline condition described in above-mentioned reaction, can be by triethylamine, pyridine, diisopropylethylamine, DBU or N, and N-dimethylethanolamine is realized; Acylating agent is acetic anhydride, vinegar acyl chlorides, two tertiary fourth oxygen carbonic anhydrides, trifluoromethyl sulfonic acid anhydride, methylsulphonic acid acid anhydride, Benzoyl chloride, ortho-nitrophenyl formyl chloride, Tosyl chloride, 4-Nitrobenzenesulfonyl chloride, ortho-nitrophenyl SULPHURYL CHLORIDE, 2,4-difluoro chloride and 2,4,6-trifluoro-benzene SULPHURYL CHLORIDE a kind of; Temperature of reaction, conventionally at-10～84 ℃, favourable temperature is chosen in 0-62 ℃, and preferred temperature is at 5～52 ℃.After reaction finishes, the mixed solvent recrystallization that the purifying of compound i is main body with sherwood oil or hexane, its productive rate almost reaches 100%.
Step (1-2): aminoalkyl group step: under alkaline condition; alkylated reaction on compound II and halogenated acetic acids or halogenated acetic acids derivative generation nitrogen; obtain intermediate N acidylate-3,4-methylenedioxybenzenes ethylamino acetic acid (compound III), its general formula is expressed as:
Wherein: X is F, Cl or Br; R ' is H, Na, K or alkyl;
Alkali described in above-mentioned reaction can be any one of Anhydrous potassium carbonate, waterless nano salt of wormwood, anhydrous sodium carbonate, waterless nano sodium carbonate, sodium hydroxide, potassium hydroxide, sodium tert-butoxide, potassium tert.-butoxide, sodium ethylate, potassium ethylate, sodium methylate, potassium methylate, sodium hydride and LDA; The halogenated acetic acids using is Mono Chloro Acetic Acid or bromoacetic acid, the derivative of described halogenated acetic acids refers to chloracetate or salt, or be bromacetate or salt, specifically can be any one of 2-methyl chloroacetate, 2-ethyl chloroacetate, 2-propyl chloroacetate, 2-isopropyl chloracetate, 2-chloroacetic acid tert-butyl ester, sodium chloroacetate, 2-methyl bromoacetate, 2-ethyl bromoacetate, 2-acid propyl bromide, 2-isopropyl acetate bromide, 2-bromo-acetic acid tert-butyl and bromoacetic acid sodium; The mol ratio of compound II and halogenated acetic acids or halogenated acetic acids derivative is 1:1～7, and preferably mol ratio is 1:1.5～3; And halogenated acetic acids (or halogenated acetic acids ester or salt) is 1:1～8 with the mol ratio of alkali, preferably mol ratio is 1:1.5～6; The organic solvent using is non-polar solvent, aprotic polar solvent and protic polar solvent.Wherein: non-polar solvent comprises tetrahydrofuran (THF) (THF), ether, isopropyl ether, methyl tertiary butyl ether, glycol dimethyl ether and ethylene glycol diethyl ether; Aprotic polar solvent comprises dimethyl formamide (DMF), N,N-DIMETHYLACETAMIDE (DMA), dimethyl sulfoxide (DMSO) (DMSO); Protic polar solvent comprises ethanol, methyl alcohol, Virahol, the trimethyl carbinol, ethylene glycol monomethyl ether.After reaction finishes, intermediate product C yield reaches more than 95%.
Step (1-3): become ring step: compound III friedel-crafts acylation reaction in Louis acid catalysis issues son estranged obtains N-acyl group-3, the sub-methoxyl group benzo-3-N-of 4-heterocycle heptanone, form harringtonine C ring intermediate, so that the raw material I of synthetic D ring intermediate to be provided; The general formula of its reaction is expressed as:
The Lewis acid that above-mentioned reaction is used, can be any one of aluminum trichloride (anhydrous), FERRIC CHLORIDE ANHYDROUS, Zinc Chloride Anhydrous, anhydrous stannic chloride, boron trifluoride, boron trifluoride ether solution, hydrofluoric acid, polyphosphoric acid, trifluoro-acetic anhydride and acetic anhydride; Temperature of reaction is-8～18 ℃, and preferably temperature is-5～10 ℃; The solvent that uses is non-protonic solvent, is specially any one of methylene dichloride, trichloromethane, ethylene dichloride, glycol dimethyl ether and tetrahydrofuran (THF); Compound III and lewis acidic mol ratio 1:2～8, preferably mol ratio is 1:2～5.After reaction finishes, product I can obtain sterling with the mixed solvent recrystallization that sherwood oil or hexane are main body, is N-acyl group-3, and the sub-methoxyl group benzo-3-N-heterocycle heptanone (chemical compounds I) of 4-, to provide the raw material of synthetic harringtonine D ring intermediate.
Embodiment
In order to further illustrate synthetic method of the present invention, below lift specific embodiment and describe, refer to below:
Embodiment 1
Be below 3,4-methylene-dioxy phenylethylamine to 3, the synthetic route of the sub-methoxyl group benzo-3-N-of 4-heterocycle heptanone pyrrolizine ketone, can be divided into two processes substantially:
First by 3,4-methylene-dioxy phenylethylamine, synthesize N-p-nitrophenyl sulphonyl-3, the sub-methoxyl group benzo-3-N-of 4-heterocycle heptanone; And then by N-p-nitrophenyl sulphonyl-3, the sub-methoxyl group benzo-3-N-of synthetic 3, the 4-of the sub-methoxyl group benzo-3-N-of 4-heterocycle heptanone heterocycle heptanone pyrrolizine ketone.
First introduce with the synthetic N-p-nitrophenyl of 3,4-methylene-dioxy phenylethylamine sulphonyl-3 process of the sub-methoxyl group benzo-3-N-of 4-heterocycle heptanone:
Step 1: amido protecting and N-H bond activation: will fill 1.652g (10mmol) 3, the flask of the 80mL dichloromethane solution of 4-methylene-dioxy phenylethylamine is placed in ice bath, then adds triethylamine 12mmol, so that alkaline environment to be provided.When stirring, slowly drip 4-Nitrobenzenesulfonyl chloride 20mmol.0.5h recession deicing is bathed, and continues reaction 4h, stopped reaction under room temperature condition.Reaction solution is washed through twice washing and a saturated sodium-chloride, then uses anhydrous sodium sulfate drying.Filter, revolve to steam and reclaim solvent, remain in red oily liquids and add sherwood oil, to be crystallized completely after, recrystallization obtains faint yellow solid product N-p-nitrophenyl sulphonyl-3,4-methylene-dioxy phenylethylamine 3.501g, yield 100%.
Step 2: aminoalkyl group: will fill N-p-nitrophenyl sulfonylation-3; the flask that 4-methylene-dioxy phenylethylamine II 3.501g (10mmol) is dissolved in the solution of the absolute anhydrous tetrahydro furan formation of 90mL is placed in ice bath; under nitrogen environment, add 20mmol potassium tert.-butoxide, so that alkaline environment to be provided.Subsequently the chloroacetic 10mL tetrahydrofuran solution of 1.418g is slowly added drop-wise in above-mentioned reactor, drips off rear continuation and stir 30min, then reflux 6h.Reacting liquid temperature is down to room temperature, adds a small amount of frozen water and 50mL methylene dichloride, and extraction is removed a small amount of impurity, retains water.Water is adjusted pH to 1 with 6N hydrochloric acid, then uses dichloromethane extraction three times, merges organic phase.Organic phase washing 1 time, saturated sodium-chloride is washed 1 time, then uses anhydrous sodium sulfate drying, concentrates to obtain yellow solid.With ethyl acetate-sherwood oil recrystallization, obtain N-p-nitrophenyl sulfonylation-3,4-methylenedioxybenzenes ethylamino acetic acid 3.757g, yield 95%.
Step 3: in molecule, Fu-Ke acyl group changes into ring step: filling 4.084g (10mmol) N-p-nitrophenyl sulphonyl-3; in the reactor of the 150mL dichloromethane solution of 4-methylenedioxybenzenes ethylamino acetic acid; in nitrogen, under room temperature condition, slowly drip 43ml (30mmol) trifluoroacetic anhydride.After stirring reaction 1h, reactor is placed in to ice bath, slowly drips the complexing of 43.8mL (35mmol) Eorontrifluoride etherate and make catalyzer, drip off under rear continuation condition of ice bath and react 4h.With 1N sodium carbonate solution, regulate pH to 8, separate organic phase, water 30mL dichloromethane extraction 3 times.Merge organic phase, water, saturated sodium-chloride are respectively washed 1 time respectively, anhydrous sodium sulfate drying.Filter, be concentrated into 45mL, add sherwood oil recrystallization, obtain faint yellow solid N-p-nitrophenyl sulphonyl-3, the sub-methoxyl group benzo-3-N-of 4-heterocycle heptanone 3.427g, yield 92%.The 3rd step product nucleus magnetic resonance:
1h NMR (500MHz CDCl
3) δ 7.87 (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;
13c NMR (125MHz CDCl
3) δ 200.25,151.08,146.90,146.59,134.41,134.35,132.40131.23,130.38,129.82,124.04,109.69,107.32,101.97,54.26,46.57,30.98ppm; HRMS (ESI) m/z[M+H]
+found for391.0582, calc for C
17h
15n
2o
7s391.0594.
Above reaction process is expressed as follows:
Be below N-p-nitrophenyl sulphonyl-3, the detailed process of the sub-methoxyl group benzo-3-N-of synthetic 3, the 4-of the sub-methoxyl group benzo-3-N-of 4-heterocycle heptanone heterocycle heptanone pyrrolizine ketone, is divided into again three steps.
The first step: slough acyl group protecting group: to N-p-nitrophenyl sulphonyl-3, the sub-methoxyl group benzo-3-N-of 4-heterocycle heptanone removes " p-nitrophenyl alkylsulfonyl "
Filling 3.904g (10mmol) N-p-nitrophenyl sulphonyl-3, in the reactor of the 150mL dichloromethane solution of 4-methylene-dioxy benzo-3-N-heterocycle heptanone, under 40 ℃ of conditions, add 1.322g (25mmol) thiophenol sodium, after stirring reaction 1h, concentration and recovery methylene dichloride.In resistates, add 150mL ethyl acetate, remove by filter insolubles.In filtrate, pass into hydrogenchloride to saturated, after solid is separated out completely, filter to obtain yellow solid 3, the sub-methoxyl group benzo-3-N-of 4-heterocycle heptanone hydrochloride, 2.37g, yield 98%.The nucleus magnetic resonance of product:
1h NMR (500MHz D
2o) 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);
13c NMR (125MHz D
2o) δ 196.72,152.78,147.39,133.79,128.92,109.77,107.87,102.23,1.30,43.16,27.49ppm; HRMS (ESI) m/z[M-Cl]
-found for206.0808, calc for C
11h
12nO
3206.0812.Reaction process is expressed as follows:
Second step: the sub-methoxyl group benzo-3-N-of aminopropan acylations: 3,4-heterocycle heptanone hydrochloride reacts with the different propylene of 3-chloropropionic acid and obtains N-3-(chloro propionyl)-3 under alkaline condition, the sub-methoxyl group benzo-3-N-of 4-heterocycle heptanone:
The sub-methoxyl group benzo-3-N-heterocycle heptanone hydrochloride 2.417g of 3,4-(10mmol) is joined to two-mouth bottle, then add 180mL methylene dichloride (solvent).Under 0～-5 ℃, nitrogen atmosphere condition, add 0.885mL pyridine, after stirring reaction 35min, then add 15mmol triethylamine, so that alkaline environment to be provided.Continue to stir after 10min, slowly add the 20mL dichloromethane solution of the different propylene of 2.23g (15mmol) 3-chloropropionic acid.Control 30～35 ℃, continue reaction 3h.Reaction solution is respectively with 2% dilute hydrochloric acid, respectively wash once with saturated sodium bicarbonate aqueous solution, water, saturated sodium-chloride, anhydrous sodium sulfate drying, concentrated, obtain white solid product N-(3-chloro propionyl)-3, the sub-methoxyl group benzo-3-N-of 4-heterocycle heptanone 2.75g, 93%; Product nucleus magnetic resonance:
1h NMR (500MHz CDCl
3) δ 7.27 (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;
13cNMR (125MHz CDCl
3) δ 200.30,198.18,170.66,170.25,152.48,151.77,147.59,135.74,133.48,130.92,129.88,110.17,109.46,109.05,108.76,102.18,102.07,55.44,53.14,46.10,43.35,39.48,36.55,36.49,32.98,32.77ppm; MS (ESI) m/z[M+H]
+found for296.0, calcd for C
14h
15clNO
4296.07.Reaction process is expressed as follows:
The 3rd step: become ring step: N-(3-chloro propionyl)-3, the carbonyl alpha-position alkylation in strong alkaline condition issues son estranged of the sub-methoxyl group benzo-3-N-heterocycle heptanone of 4-, generates the sub-methoxyl group benzo-3-N-of 3,4-heterocycle heptanone pyrrolizine ketone:
Filling 2.957g (10mmol) N-(3-chloro propionyl)-3; in the reactor of the 300mL anhydrous tetrahydrofuran solution of the sub-methoxyl group benzo-3-N-of 4-heterocycle heptanone; under-5 ℃, nitrogen protection; when stirring, add 1.68g (15mmol) potassium tert.-butoxide, strong basicity environment is provided.Continue, after reaction 2h, slowly to drip a small amount of water with the excessive potassium tert.-butoxide of cancellation.Separate water, organic phase concentration and recovery tetrahydrofuran (THF).In residuum, add methylene dichloride, organic phase washes with water 3 times, and saturated sodium-chloride is washed 2 times.Be dried, filter, concentrate, through the separated white solid 3 that obtains of quick silica gel column chromatography, the sub-methoxyl group benzo-3-N-of 4-heterocycle heptanone pyrrolizine ketone 2.13g, yield 82%, the nucleus magnetic resonance of product:
1h NMR (500MHz CDCl
3) δ 7.213 (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;
13c NMR (125MHz CDCl
3) δ 202.27,175.24,152.04,147.54,135.23,131.15,109.70,108.88,102.09,64.74,41.43,32.76,30.02,23.75ppm; MS (ESI) m/z[M+H]
+found for260.2, calcd for C
14h
14nO
4260.09.Reaction process is expressed as follows:
Embodiment 2
About raw material " N-sulfonyloxy methyl-3, the sub-methoxyl group benzo-3-N-of 4-heterocycle heptanone " acquisition, can be with reference to the process of embodiment 1, just 3, 4-methylene-dioxy phenylethylamine synthesizes " N-p-nitrophenyl sulphonyl-3, the process of the sub-methoxyl group benzo-3-N-of 4-heterocycle heptanone " in, acylating agent " 4-Nitrobenzenesulfonyl chloride " is replaced to " toluene sulfonyl chloride ", other processes are similar to Example 1, or as required to alkaline condition or slightly inching of solvent, can prepare N-sulfonyloxy methyl-3, the sub-methoxyl group benzo-3-N-of 4-heterocycle heptanone, for forming the harringtonine D ring intermediate source of supplying raw materials.
With N-sulfonyloxy methyl-3, the operating process of the synthetic harringtonine D ring of the sub-methoxyl group benzo-3-N-of 4-heterocycle heptanone intermediate is as follows:
The first step: remove amino protecting group: filling 10mmol N-sulfonyloxy methyl-3; in the reactor of the 150mL acetonitrile solution of 4-methylene-dioxy benzo-3-N-heterocycle heptanone; under 55 ℃ of agitation conditions; add respectively 35mmol to methoxybenzenethiol and 35mmol lithium hydroxide; after stirring reaction 1.5h, concentration and recovery acetonitrile.In resistates, add 150mL ethyl acetate, remove by filter insolubles.Under condition of ice bath, in filtrate, add ethyl acetate solution to the solid of hydrogen bromide to separate out completely, filter to obtain yellow solid 3, the sub-methoxyl group benzo-3-N-of 4-heterocycle heptanone Hydrogen bromide, yield 87%.
Second step: aminopropan acylations: 3 of acquisition; after the sub-methoxyl group benzo-3-N-of 4-heterocycle heptanone Hydrogen bromide; by 10mmol3; the sub-methoxyl group benzo-3-N-of 4-heterocycle heptanone hydrobromate joins two-mouth bottle; add the anhydrous chloroform of 180mL, under 0～-5 ℃, nitrogen atmosphere condition, add 13mmol triethylamine; after stirring reaction 20min, then add 35mmol salt of wormwood.Continue to stir after 20min, slowly add the 20mL chloroformic solution of 15mmol3-bromo propionyl chloro, room temperature reaction 2.5h.Reacting liquid filtering, removes solid inorganic salt.Filtrate is respectively with 2% dilute hydrochloric acid, respectively wash once with saturated sodium bicarbonate aqueous solution, water, saturated sodium-chloride, anhydrous sodium sulfate drying, concentrated, obtain white solid product N-(3-bromo propionyl)-3, the sub-methoxyl group benzo-3-N-of 4-heterocycle heptanone 2.96g, yield 87%.
The 3rd step: in molecule, carbonyl alpha-position is alkylated into ring: filling 10mmol N-(3-bromo propionyl)-3; in the reactor of the 300mL dichloromethane solution of the sub-methoxyl group benzo-3-N-of 4-heterocycle heptanone; under room temperature, nitrogen protection, when stirring, add 40mmol to receive a micron salt of wormwood.Room temperature continues after reaction 0.5h, heating reflux reaction 6h.Filtered and recycled inorganic salt, filtrate water is washed 3 times, and saturated sodium-chloride is washed 2 times.Dry, filtration, concentrated, obtain white solid 3, the sub-methoxyl group benzo-3-N-of 4-heterocycle heptanone pyrrolizine ketone 2.36g, yield 91%.
Reaction process is expressed as follows:
Embodiment 3
Be below 3,4-methylene-dioxy phenylethylamine to 3, the synthetic route of the sub-methoxyl group benzo-3-N-of 4-heterocycle heptanone pyrrolizine ketone, can be divided into two processes substantially:
First by 3,4-methylene-dioxy phenylethylamine, synthesize the tertiary fourth oxygen of N-formyl-3, the sub-methoxyl group benzo-3-N-of 4-heterocycle heptanone; And then by the tertiary fourth oxygen of N-formyl-3, the sub-methoxyl group benzo-3-N-of synthetic 3, the 4-of the sub-methoxyl group benzo-3-N-of 4-heterocycle heptanone heterocycle heptanone pyrrolizine ketone.
Following brief description 3, the synthetic tertiary fourth oxygen of N-of 4-methylene-dioxy phenylethylamine formyl-3, the process of the sub-methoxyl group benzo-3-N-of 4-heterocycle heptanone:
Step 1: amido protecting and N-H bond activation: will fill 1.652g (10mmol) 3; the flask of the 15mL ethanolic soln of 4-methylene-dioxy phenylethylamine (ethanol is solvent) is placed in ice bath; add 10mmol triethylamine and 3mmol DBU (1; 8-diazacyclo [5; 4; 0] hendecene-7), so that alkaline environment to be provided.When stirring, slowly in system, drip di tert butyl carbonate carbonic anhydride 20mmol, dropwise 0.5h recession deicing and bathe, under room temperature condition, continue reaction 5h.Concentrated after completion of the reaction, in residuum, add again 150mL ethyl acetate, wash respectively 1 time, saturated sodium-chloride with water and wash 1 time, use anhydrous sodium sulfate drying.Suction filtration, filtrate is concentrated, then obtains the tertiary fourth oxygen of white solid N-formyl-3,4-methylene-dioxy phenylethylamine, yield 94% with ethyl acetate-sherwood oil recrystallization.
Step 2: aminoalkyl group: will fill the tertiary fourth oxygen of N-formyl-3, the flask that 4-methylene-dioxy phenylethylamine 10mmol is dissolved in the solution of 90mL glycol dimethyl ether (as solvent) formation is placed in ice bath, under enclosing environment, nitrogen adds 20mmol sodium hydride, so that alkaline environment to be provided.Subsequently the 10mL ethylene glycol dimethyl ether solution of 12mmol bromoacetic acid is slowly added drop-wise in reactor, drips off rear continuation and stir 30min, then reflux 8h.Reacting liquid temperature is down to room temperature, adds a small amount of frozen water and 50mL methylene dichloride, and extraction is removed a small amount of impurity, retains water.Water is adjusted pH to 1 with 6N hydrochloric acid, then uses dichloromethane extraction three times, merges organic phase.Organic phase washing 1 time, saturated sodium-chloride is washed 1 time, and anhydrous sodium sulfate drying concentrates to obtain yellow solid, uses sherwood oil recrystallization, yield 81%, product is the tertiary fourth oxygen of N-formyl-3,4-methylenedioxybenzenes ethylamino acetic acid.
Step 3: become the ring tertiary fourth oxygen of step: N-formyl-3; 4-methylenedioxybenzenes ethylamino acetic acid friedel-crafts acylation reaction in Louis acid catalysis effect issues son estranged; generate the tertiary fourth oxygen of N-formyl-3; 4-methylene-dioxy benzo-3-N-heterocycle heptanone; the Lewis acid of selecting can use aluminum trichloride (anhydrous), FERRIC CHLORIDE ANHYDROUS, Zinc Chloride Anhydrous, anhydrous stannic chloride, polyphosphoric acid, trifluoro-acetic anhydride and acetic anhydride wherein any, the primary process of reaction is as follows:
Be below the tertiary fourth oxygen of N-formyl-3, the detailed process of the sub-methoxyl group benzo-3-N-of synthetic 3, the 4-of 4-methylene-dioxy benzo-3-N-heterocycle heptanone heterocycle heptanone pyrrolizine ketone, is divided into again three steps.
The first step: remove amino protecting group: filling the tertiary fourth oxygen of 10mmol N-formyl-3, in the reactor of the 150mL dichloromethane solution of 4-methylene-dioxy benzo-3-N-heterocycle heptanone, adding the dichloromethane solution of 30% (v/v) trifluoroacetic acid.After stirring reaction 3h, concentration and recovery methylene dichloride, obtains sticky solid 3 at ambient temperature, the sub-methoxyl group benzo-3-N-of 4-heterocycle heptanone trifluoroacetate, yield 93%.
Second step: aminopropan acylations: by 10mmol3, the sub-methoxyl group benzo-3-N-of 4-heterocycle heptanone trifluoroacetate joins two-mouth bottle, adds 130mL glycol dimethyl ether; under 0～-5 ℃, nitrogen atmosphere condition; add 15mmol salt of wormwood, after stirring reaction 20min, then add 15mmol pyridine.Continue to stir after 20min, slowly add the 20mL ethylene glycol dimethyl ether solution of 15mmol3-tolysulfonyl oxygen base propionyl bromide, room temperature reaction 3h.Reacting liquid filtering, removes solid inorganic salt.Filtrate decompression concentration and recovery glycol dimethyl ether.In residuum, add chloroform 50mL, solution is respectively with 2% dilute hydrochloric acid, respectively wash once with saturated sodium bicarbonate aqueous solution, water, saturated sodium-chloride, anhydrous sodium sulfate drying, concentrated, obtain white solid product N-(3-tolysulfonyl oxygen base propionyl)-3, the sub-methoxyl group benzo-3-N-of 4-heterocycle heptanone, yield 92%.
The 3rd step: in molecule, carbonyl alpha-position is alkylated into ring: filling 10mmol N-(3-tolysulfonyl oxygen base propionyl)-3; in the reactor of the 300mL acetonitrile solution of the sub-methoxyl group benzo-3-N-of 4-heterocycle heptanone; under room temperature, nitrogen protection, when stirring, add 15mmol DBU.Room temperature continues after reaction 0.5h, heating reflux reaction 4h.Remove by filter tosilate, filtrate water is washed 3 times, and saturated sodium-chloride is washed 2 times.Dry, filtration, concentrated, obtain white solid 3, the sub-methoxyl group benzo-3-N-of 4-heterocycle heptanone pyrrolizine ketone 2.41g, yield 93%.
Embodiment 4
With N-carbobenzoxy-3; the sub-methoxyl group benzo-3-N-of 4-heterocycle heptanone prepares 3; the implementation process of the sub-methoxyl group benzo-3-N-of 4-heterocycle heptanone pyrrolizine ketone; its raw material N-carbobenzoxy-3; the sub-methoxyl group benzo-3-N-of 4-heterocycle heptanone equally can 3; 4-methylene-dioxy phenylethylamine is raw material, usings " benzyloxy formyl halide or benzyloxy formic acid anhydrides " as acylating agent, through " in amido protecting and N-H bond activation, aminoalkyl group, molecule, Fu-Ke acyl group changes into ring step ", prepares.
N-carbobenzoxy-3; " de-carbobenzoxy " step of the sub-methoxyl group benzo-3-N-of 4-heterocycle heptanone: filling 10mmol N-benzyloxy formyl-3; in the reactor of the 150mL dichloromethane solution of 4-methylene-dioxy benzo-3-N-heterocycle heptanone, add 5%Pd/C5g.Under oxygen-free environment, room temperature condition, along with stirring passes into hydrogen, after reaction 3h, filtering recovering catalyst, filtrate concentration and recovery methylene dichloride.In resistates, add 150mL ethyl acetate, under condition of ice bath, pass into hydrogen chloride gas to saturated, after solid is separated out completely, filter to obtain yellow solid 3, the sub-methoxyl group benzo-3-N-of 4-heterocycle heptanone hydrochloride, yield 92%.
Obtain 3; the sub-methoxyl group benzo-3-N-of 4-heterocycle heptanone hydrochloride carries out " aminopropan acylations ", " in molecule, carbonyl alpha-position is alkylated into ring " again to synthesize white solid 3; the sub-methoxyl group benzo-3-N-of 4-heterocycle heptanone pyrrolizine ketone is identical with three-step reaction process with the second step of embodiment 1.
Embodiment 5
With embodiment 1, obtain 3, the sub-methoxyl group benzo-3-N-of 4-heterocycle heptanone hydrochloride reacts with 3-trimethyl fluoride sulfonyl oxygen base propionyl halogen and obtains N-3-(3-trimethyl fluoride sulfonyl oxygen base propionyl)-3 under alkaline condition, the sub-methoxyl group benzo-3-N-of 4-heterocycle heptanone.
Then filling 10mmol N-(3-trimethyl fluoride sulfonyl oxygen base propionyl)-3; the 150mL1 of the sub-methoxyl group benzo-3-N-of 4-heterocycle heptanone; in the reactor of 2-dichloroethane solution, under room temperature, nitrogen protection, when stirring, add 20mmol4-Dimethylamino pyridine.After stirring at room 15min, in 50 ℃ of reaction 4h.Remove by filter trifluoromethyl sulfonic acid, filtrate water is washed 3 times, and saturated sodium-chloride is washed 2 times.Dry, filtration, concentrated, obtain white solid 3, the sub-methoxyl group benzo-3-N-of 4-heterocycle heptanone pyrrolizine ketone 2.38g, yield 92%.
1H?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；
13C?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
14H
14NO
4260.09。
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.
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