CN104045645B - The synthetic method of harringtonine C ring intermediates - Google Patents
The synthetic method of harringtonine C ring intermediates Download PDFInfo
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- CN104045645B CN104045645B CN201410225442.6A CN201410225442A CN104045645B CN 104045645 B CN104045645 B CN 104045645B CN 201410225442 A CN201410225442 A CN 201410225442A CN 104045645 B CN104045645 B CN 104045645B
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- 0 C/C(/C/C=C(\CC*C(*)=O)/C/*=C1)=C1\NCC* Chemical compound C/C(/C/C=C(\CC*C(*)=O)/C/*=C1)=C1\NCC* 0.000 description 3
- SZMOQZSEGILIKE-UHFFFAOYSA-N C[O]1c(ccc(CCN)c2)c2OC1 Chemical compound C[O]1c(ccc(CCN)c2)c2OC1 SZMOQZSEGILIKE-UHFFFAOYSA-N 0.000 description 1
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
- C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
- C07D491/04—Ortho-condensed systems
- C07D491/056—Ortho-condensed systems with two or more oxygen atoms as ring hetero atoms in the oxygen-containing ring
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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
Technical field
The present invention relates to a kind of synthetic method of pharmaceutical intermediate, especially harringtonines to contain the intermediate of C rings
Synthetic method.
Background technology
Harringtonine is a kind of alkaloid extracted from cephalotaxus plant, has preferable active anticancer, is facing
It is mainly used for treating acute myeloblastic leukemia, acute monokaryon type chronic myeloid leukemia, progranulocyte leukemia, chronic grain on bed
The diseases such as chronic myeloid leukemia and true polycythemia, also having to lymthoma certain has therapeutic effect.
Currently, the harringtonine as medicinal materials drug clinically used is all extracted from plant, since cepehalotaxus fortunei plant provides
Source is limited, and growth cycle is long, and the active aconitines content of anticancer is extremely low in plant (is always given birth in per 100g cepehalotaxus fortunei branches and leaves
0.39%) alkaloids content only has, to largely put into for making anticancer drug, by the method extracted from plant, it is clear that
It is unable to supply, price can be fairly expensive.In addition, a large amount of felling of plant cause seeds endangered, serious ecology of destroying is put down
Weighing apparatus.Therefore, it is very significant to develop new medicine source, artificial synthesized harringtonine is exactly an important channel.
The synthetic method of the harringtonine of document report has more than ten items, but these routes either route it is too long or
Raw material is prohibitively expensive, or leads to serious environmental pollution because yield too low consumption is high, far apart with practical application.Based on mesh
The synthetic method of preceding report there are the problem of, present invention contemplates that providing a kind of new synthetic route.
It is main for the basic structure of harringtonine, including five rings of A, B, C, D, E, the present invention shown in structural formula as above
It is related to the synthetic method of the harringtonine intermediate containing A, B, C ring.
Invention content
The present invention provides a kind of intermediate that the synthetic method synthesis harringtonine being simple and efficient contains C rings.This method
Easy to operate, each reaction product that walks can be all effectively separated by recrystallization, be purified, and total recovery is up to 87.4%, after being
Industrialized production provide a practical route.
The synthetic method of the present invention includes three steps altogether：
(1) step：Amido protecting and N-H bond activation steps：With 3,4- methylene-dioxies phenyl ethylamine I for raw material, in alkalinity
Under the conditions of with acylation reaction generate nitrogen end protection intermediate N acyl group -3,4- methylene-dioxy phenyl ethylamine II, general formula table
It is shown as：
Or it is
The acylating agent is one of carboxylic acid halides, sulfonic acid halide, acid anhydrides and sulphonic acid anhydride；
R1For the benzyl replaced by alkyl, nitro or halogen on alkyl, alkoxy, benzyloxy or phenyl ring；R2For alkane
The phenyl replaced by alkyl, nitro or halogen on base, the alkyl through halogen substitution, phenyl or phenyl ring.
Preferably, (1) step reaction alkaline condition, can by triethylamine, pyridine, diisopropylethylamine, DBU or N,
N- dimethylethanolamines are realized.
Preferably, the acylating agent used in the reaction of (1) step is acetic anhydride, vinegar acyl chlorides, two tertiary fourth oxygen carbonic anhydrides, fluoroform
Base sulphonic acid anhydride, pyrovinic acid acid anhydride, chlorobenzoyl chloride, ortho-nitrophenyl formyl chloride, paratoluensulfonyl chloride, 4-Nitrobenzenesulfonyl chloride, adjacent nitre
Base benzene sulfonyl chloride, 2,4 difluorobenzene sulfonic acid chloride and 2,4,6- trifluoro benzene sulfonyl chlorides any one or it is every arbitrary group aforementioned
It closes.
Preferably, (1) step reaction reaction temperature, usually at -10~84 DEG C, advantageous temperature selection is in 0-62
DEG C, preferred temperature is at 5~52 DEG C.(1) step is after reaction, mixed based on the purifying petroleum ether or hexane of product I
Bonding solvent recrystallizes, and yield nearly reaches 100%.
After the reaction of the amino group of (1) step, the acylating agent can not only provide acyl function, make amino
It is acylated, and while protecting amino, the ability with activating terephthalamide amine N-H keys, is that the alkylation of next step amino is anti-
Advantage should be provided.
(2) step：Aminoalkylated step：Under alkaline condition, compound ii derives with halogenated acetic acids or halogenated acetic acids
Alkylated reaction on nitrogen occurs for object, obtains intermediate N and is acylated -3,4- methylenedioxybenzenes ethylaminos acetic acid III, general formula table
It is shown as：
Or it is
Wherein：X is F, Cl or Br；R ' is H, Na, K or alkyl；
Preferably, the alkali described in the reaction of (2) step can be Anhydrous potassium carbonate, waterless nano potassium carbonate, Carbon Dioxide
Sodium, waterless nano sodium carbonate, sodium hydroxide, potassium hydroxide, sodium tert-butoxide, potassium tert-butoxide, sodium ethoxide, potassium ethoxide, sodium methoxide, first
The arbitrary combination of any one or aforementioned items of potassium alcoholate, sodium hydride and LDA.
Preferably, the halogenated acetic acids used in (2) step is monoxone or bromoacetic acid, the derivative of the halogenated acetic acids
Object refers to chloracetate or salt, or is bromacetate or salt, concretely 2- methyl chloroacetates, 2- ethyl chloroacetates, 2- monoxones
Propyl ester, 2- isopropyl chloracetates, 2- chloroacetic acid tert-butyl esters, sodium chloroacetate, 2- methyl bromoacetates, 2- bromoacetates, 2- bromine second
The arbitrary combination of any one or aforementioned items of propyl propionate, 2- isopropyl acetate bromides, 2- bromo-acetic acid tert-butyls and bromoacetic acid sodium.
Preferably, compound ii and the molar ratio of halogenated acetic acids or halogenated acetic acid derivative are 1:1~7, preferable mole
Than being 1:1.5~3；And the molar ratio of halogenated acetic acids (or halogenated acetic acids ester or salt) and alkali is 1:1~8, preferable molar ratio is
1:1.5~6
Preferably, the organic solvent used in (2) step is nonpolar solvent, aprotic polar solvent and proton
Property polar solvent.Wherein：Nonpolar solvent can be tetrahydrofuran (THF), ether, isopropyl ether, methyl tertiary butyl ether(MTBE), ethylene glycol
Dimethyl ether or ethylene glycol diethyl ether；Aprotic polar solvent can be dimethylformamide (DMF), dimethylacetylamide (DMA)
Or dimethyl sulfoxide (DMSO) (DMSO)；Protic polar solvent can be ethyl alcohol, methanol, isopropanol, the tert-butyl alcohol or glycol monoethyl ether.
After reaction, III yield of intermediate product reaches 95% or more to (2) step.
After the aminoalkylated reaction of (2) step, particularly using halogenated acetic acids or halogenated acetic acids ester or salt as alkane
Base agent, connects CH on N2- COOH can provide condition for the friedel-crafts acylation reaction of next step, to ensure in next step
The specificity of intramolecular friedel-craft reaction, improves the yield of N- acyl group -3,4- methylene oxygroup benzo -3-N- heterocycle heptanone.
(3) step：Ring-forming sequence：Compound III issues raw intramolecular friedel-crafts acylation reaction in Louis acid catalysis and obtains
To N- acyl group -3,4- methylene oxygroup benzo -3-N- heterocycle heptanone, i.e. harringtonine C rings intermediate；Its general formula is expressed as：
Or it is
Preferred (3) step reaction lewis acid used can be aluminum trichloride (anhydrous), anhydrous ferric trichloride, anhydrous chlorine
Change zinc, anhydrous stannic chloride, boron trifluoride, boron trifluoride ether solution, hydrofluoric acid, polyphosphoric acids, trifluoro-acetic anhydride and acetic anhydride
Any one or aforementioned items arbitrary combination.
Preferably, (3) step reaction temperature is -8~18 DEG C, and preferable temperature is -5~10 DEG C.
Preferably, it is non-protonic solvent, specially dichloromethane, chloroform, two that (3) step, which reacts used solvent,
The arbitrary combination of any one or aforementioned items of chloroethanes, glycol dimethyl ether and tetrahydrofuran.
Preferably, compound III and lewis acidic molar ratio 1:2~8, preferable molar ratio is 1:2~5.
After reaction, product IV need to use the mixed solvent recrystallization based on petroleum ether or hexane to (3) step
Sterling is obtained, the yield of (3) step reaction reaches 92%.The total recovery of the final product IV of three steps is up to 87.4%.
After the reaction of (3) step, under lewis acidic catalytic action molecule occurs for the connected CH2-COOH of N of amino
The H of No. 6 position of interior friedel-crafts acylation reaction, i.e. phenyl ring is replaced by acyl group, forms a seven membered heterocyclic containing N to get to point
China fir ester alkali C ring intermediates.
Since the reaction condition of friedel-crafts acylation reaction mitigates, product purity is high；And the pair of Friedel-Crafts alkylation is anti-
Ying Duo, purification difficult, low yield, therefore present invention selection introduces acetoxy group rather than second in the alkylated reaction of (2) on N
Alkyl, can effectively improve the yield that (3) step of the invention generates the seven membered heterocyclic containing N has to ensure the high-purity of product IV
Conducive to follow-up further purification.
Specific implementation mode
In order to enable the present invention synthetic method further understood, enumerate several specific embodiments below,
It please refers to hereafter：
Embodiment 1：
N- p-nitrophenyls sulphonyl -3,4- methylene oxygroup benzo -3-N- heterocycle heptan is prepared with 3,4- methylene-dioxy phenyl ethylamines
Ketone
The first step：Amido protecting and N-H bond activations：1.652g (10mmol) 3,4- methylene-dioxy phenyl ethylamines will be filled
The flask of 80mL dichloromethane solutions is placed in ice bath, triethylamine 12mmol is then added, to provide alkaline environment.In stirring
Meanwhile 4-Nitrobenzenesulfonyl chloride 20mmol is slowly added dropwise.Ice bath is removed in 0.5h recession, in the reaction was continued under room temperature 4h, stops
Reaction.Reaction solution is washed through washing twice with a saturated sodium-chloride, then is dried with anhydrous sodium sulfate.Filtering, revolving recycling design,
Be added petroleum ether in remaining red oil, it is to be crystallized completely after, recrystallize to obtain faint yellow solid product N- p-nitrophenyl sulphurs
Acyl -3,4- methylene-dioxy phenyl ethylamine 3.501g, yield 100%.First step product nuclear magnetic resonance：1H NMR(500MHz
DMSO) δ 8.11 (t, J=5.25,1H) 7.93 (m, 2H) 7.81 (m, 2H) 6.79 (d, J=8,1H) 6.75 (d, J=1.5,1H)
6.67 (t, J=1.5,1H) 3.70 (d, J=3.5,6H) 3.15 (q, J=6.75,2H) 2.66 (t, J=7.25,2H) ppm；13C
NMR(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.Reaction process indicates as follows：
Second step：It is aminoalkylated：N- p-nitrophenyl sulfonylation -3,4- methylene-dioxies phenyl ethylamine II will be filled
The flask that 3.501g (10mmol) is dissolved in the solution of 90mL absolute tetrahydrofurans formation is placed in ice bath, in a nitrogen environment
20mmol potassium tert-butoxides are added, to provide alkaline environment.Then the chloroacetic 10mL tetrahydrofuran solutions of 1.418g are slowly dripped
It is added in above-mentioned reactor, continues to stir 30min after dripping off, be then heated to reflux 6h.Reacting liquid temperature is down to room temperature, is added few
Ice water and 50mL dichloromethane are measured, extraction removes a small amount of impurity, retains water phase.Water phase is extracted with 6N hydrochloric acid tune pH to 1, then with dichloromethane
It takes three times, merges organic phase.Organic phase is washed 1 time, and saturated sodium-chloride is washed 1 time, then is dried with anhydrous sodium sulfate, and yellow is concentrated to give
Solid.N- p-nitrophenyl sulfonylation -3,4- methylenedioxybenzenes ethylamino acetic acid is recrystallized to obtain with ethyl acetate-light petrol
3.757g yield 95%.Second step product nuclear magnetic resonance：1H NMR(500MHz CDCl3)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；13C NMR(125MHzCDCl3)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,calc for C15H15N2O6S351.0645.Reaction process indicates as follows：
Third walks：Ring-forming sequence：Filling 4.084g (10mmol) N- p-nitrophenyl sulphonyl -3,4- methylenedioxybenzenes second
In the reactor of the 150mL dichloromethane solutions of aminoacetic acid, in nitrogen, 43ml (30mmol) three is slowly added dropwise under room temperature
Fluoroacetic acid acid anhydride.It is stirred to react after 1h and reactor is placed in ice bath, the complexing of 43.8mL (35mmol) Eorontrifluoride etherate is slowly added dropwise
Catalyst is made, continues to react 4h under condition of ice bath after dripping off.PH to 8 is adjusted with 1N sodium carbonate liquors, separates organic phase, water phase is used
30mL dichloromethane extracts 3 times.Merge organic phase, is respectively washed 1 time with water, saturated sodium-chloride respectively, anhydrous sodium sulfate drying.It crosses
It filters, be concentrated into 45mL, petroleum ether recrystallization is added, obtains faint yellow solid N- p-nitrophenyl sulphonyl -3,4- methylene oxygroup benzos -3-
N- heterocycle heptanone 3.427g, yield 92%.Third walks product nuclear magnetic resonance：1H NMR(500MHz CDCl3) δ 7.87 (d, J=
3.85 (t, J=6.75,2H) 2.99 of 1.5,2H) 7.61 (d, J=1.5,2H), 6.97 (s, 1H) 6.65 (s, 1H) 4.23 (s, 1H)
(t, J=6.75,2H) ppm；13C NMR(125MHz CDCl3)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 C17H15N2O7S391.0594.Reaction
Procedural representation is as follows：
Embodiment 2：
N- trimethyl fluoride sulfonyls -3,4- methylene oxygroup benzo -3-N- heterocycle heptan is prepared with 3,4- methylene-dioxy phenyl ethylamines
Ketone
The first step：Amido protecting and N-H bond activations：1.652g (10mmol) 3,4- methylene-dioxy phenyl ethylamines will be filled
The flask of 80mL chloroformic solutions is placed in ice bath, diisopropylethylamine 11mmol is then added, to provide alkaline environment.It is stirring
While, three fluorosulfonic anhydride 18mmol are slowly added dropwise.Ice bath is removed in 1h recession, in the reaction was continued under room temperature 3h, stops reaction.
Reaction solution is washed through 3 times, after 1 time saturated sodium-chloride is washed, is dried with anhydrous sodium sulfate.Filtering, revolving recycling design, remaining oily
Hexane is added in liquid makes crystallization, it is to be crystallized completely after, recrystallize that obtain faint yellow solid product N- trimethyl fluoride sulfonyls -3,4- sub-
Methylenedioxy group phenyl ethylamine, yield 98%.
Reaction process indicates as follows：
Second step：It is aminoalkylated：N- trimethyl fluoride sulfonyl -3,4- methylene-dioxy phenyl ethylamines 10mmol will be filled to be dissolved in
The flask for the solution that 100mL absolute ethyl alcohol is formed is placed in ice bath, 30mmol sodium ethoxides is added in a nitrogen environment, to carry
For alkaline environment.Then 2.33g sodium chloroacetates are slowly added in above-mentioned reactor, continue to stir 30min after dripping off, then
It is heated to reflux 6h.Reacting liquid temperature is down to room temperature, and a small amount of ice water and 50mL dichloromethane is added, and extraction removes a small amount of impurity, retains water
Phase.Water phase is extracted three times with 6N hydrochloric acid tune pH to 1, then with dichloromethane, merges organic phase.Organic phase is washed 1 time, and chlorination is saturated
Sodium is washed 1 time, then is dried with anhydrous sodium sulfate, and yellow solid is concentrated to give.N- trifluoromethyls are recrystallized to obtain with ethyl acetate-light petrol
Sulfonylation -3,4- methylenedioxybenzenes ethylamino acetic acid 2.652g, yield 88%.
Reaction process indicates as follows：
Third walks：Ring-forming sequence：Filling 10mmolN- trimethyl fluoride sulfonyl -3,4- methylenedioxybenzenes ethylamino acetic acid
120mL anhydrous chloroform solution reactor in, in nitrogen, 50mmol acetic anhydrides are slowly added dropwise under room temperature.It is stirred to react
Reactor is placed in ice bath after 1h, 50mmol Eorontrifluoride etherate solution is slowly added dropwise, continues to react under condition of ice bath after dripping off
4h.PH to 8 is adjusted with 1N sodium carbonate liquors, separates organic phase, water phase is extracted 3 times with 30mL chloroforms.Merge organic phase, uses respectively
Water, saturated sodium-chloride are respectively washed 1 time, anhydrous sodium sulfate drying.It filters, be concentrated into 45mL, petroleum ether recrystallization is added, obtains faint yellow
Solid N- trimethyl fluoride sulfonyl -3,4- methylene oxygroup benzo -3-N- heterocycle heptanone, yield 90%.1H NMR(500MHz CDCl3)
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 for337.0240,calc for
C12H10F3NO5337.0232。
Reaction process indicates as follows：
Embodiment 3
The tertiary fourth oxygen formyl -3,4- methylenes oxygroup benzo -3-N- heterocycle heptanone of N- is prepared with 3,4- methylene-dioxy phenyl ethylamines
The first step：Amido protecting and N-H bond activations：1.652g (10mmol) 3,4- methylene-dioxy phenyl ethylamines will be filled
The flask of 15mL ethanol solutions (ethyl alcohol is solvent) is placed in ice bath, and 10mmol triethylamines and 3mmol DBU (1,8- phenodiazines is added
Heterocycle [5,4,0] hendecene -7), to provide alkaline environment.While agitating, di tert butyl carbonate carbonic acid is slowly added dropwise into system
Acid anhydride 20mmol is added dropwise 0.5h recession and removes ice bath, in the reaction was continued under room temperature 5h.It concentrates after completion of the reaction, residue
In add 150mL ethyl acetate, be washed with water respectively 1 time, saturated sodium-chloride wash 1 time, dried with anhydrous sodium sulfate.It filters,
Filtrate concentrates, then recrystallizes to obtain tertiary fourth oxygen formyl -3, the 4- methylenedioxybenzenes second of white solid N- with ethyl acetate-light petrol
Amine, yield 94%.First reaction product nuclear magnetic resonance：1H NMR (500MHz, DMSO) δ 6.83 (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；13C 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。
Reaction process indicates as follows：
Second step：It is aminoalkylated：The tertiary fourth oxygen formyl -3,4- methylene-dioxies phenyl ethylamine 10mmol of N- will be filled to be dissolved in
The flask for the solution that 90mL glycol dimethyl ethers (as solvent) are formed is placed in ice bath, and 20mmol is added under nitrogen collarette border
Sodium hydride, to provide alkaline environment.The 10mL ethylene glycol dimethyl ether solutions of 12mmol bromoacetic acids are then slowly dropped to reaction
In device, continues to stir 30min after dripping off, be then heated to reflux 8h.Reacting liquid temperature is down to room temperature, and a small amount of ice water and 50mL is added
Dichloromethane, extraction remove a small amount of impurity, retain water phase.Water phase is extracted three times with 6N hydrochloric acid tune pH to 1, then with dichloromethane, is merged
Organic phase.Organic phase is washed 1 time, and saturated sodium-chloride is washed 1 time, and anhydrous sodium sulfate drying is concentrated to give yellow solid, with petroleum ether weight
Crystallization, yield 81%, product are tertiary fourth oxygen formyl -3, the 4- methylenedioxybenzenes ethylamino acetic acid of N-.
Reaction process indicates as follows：
Third walks：Ring-forming sequence：In the tertiary fourth oxygen formyl -3,4- methylenedioxybenzenes ethylamino acetic acid of N- for filling 10mmol
120mL dry ethylene glycol dimethyl ether solution reactor in, in nitrogen, 40mmol trifluoroacetic acids are slowly added dropwise under room temperature
Acid anhydride.It is stirred to react after 1h and reactor is placed in ice bath, 45mmol anhydrous ferric trichlorides are slowly added dropwise, continue condition of ice bath after dripping off
Lower reaction 4h.PH to 8 is adjusted with 1N sodium carbonate liquors, separates organic phase, water phase is extracted 3 times with 30mL dichloromethane.It is associated with
Machine phase is respectively washed 1 time with water, saturated sodium-chloride respectively, anhydrous sodium sulfate drying.It filters, be concentrated into 45mL, petroleum ether is added and ties again
Crystalline substance obtains faint yellow solid N- trimethyl fluoride sulfonyl -3,4- methylene oxygroup benzo -3-N- heterocycle heptanone, yield 86%.1H NMR
(500MHzCDCl3) δ 6.87 (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]+found
for305.1257,calc for C16H19NO5305.1263。
Reaction process is as follows：
Embodiment 4
N- (2,4 difluorobenzene sulphonyl) -3,4- methylene-dioxy benzos -3-N- is prepared by 3,4- methylene-dioxy phenyl ethylamines
Heterocycle heptanone
The first step：Amido protecting and N-H bond activations：The 80mL dichloros of 10mmol3,4- methylene-dioxy phenyl ethylamines will be filled
The flask of dichloromethane is placed in ice bath, pyridine 13mmol is then added, to provide alkaline environment.While agitating, slowly
2,4 difluorobenzene sulfonic acid chloride 18mmol is added dropwise.Ice bath is removed in 1h recession, in the reaction was continued under room temperature 3h, stops reaction.Reaction
Liquid is washed through 3 times, after 1 time saturated sodium-chloride is washed, is dried with anhydrous sodium sulfate.Filtering, revolving recycling design, remaining oily liquids
Middle addition hexane makes crystallization, it is to be crystallized completely after, recrystallize that obtain faint yellow solid product N- (2,4- difluoro benzene sulfonyl) -3,4- sub-
Methylenedioxy group phenyl ethylamine, yield 99%.Reaction process indicates as follows：
Second step：It is aminoalkylated：N- (2,4 difluorobenzene sulphonyl) -3,4- methylene-dioxy phenyl ethylamines 10mmol will be filled
The flask for being dissolved in the solution of the DMF formation of 90mL is placed in ice bath, 40mmol Anhydrous potassium carbonates is added in a nitrogen environment, to carry
For alkaline environment.Then while agitating by the 10mL DMF solutions of 35mmol ethyl chloroacetates (derivative of halogenated acetic acids)
It is slowly dropped in reactor, continues to stir 30min after dripping off, then react 6h at 65 DEG C.Reacting liquid temperature is down to room temperature,
It is filtered to remove inorganic salts, filtrate decompression revolving recycling DMF.25mL8M sodium hydroxide ethanol waters, room are added in residue
Temperature stirring 2h.50mL dichloromethane is added, with 6N hydrochloric acid tune pH to 1.Sub-argument goes out organic phase, and water phase extracts 3 with dichloromethane
It is secondary, merge organic phase, mutually wash 1 time, saturated sodium-chloride is washed 1 time, and anhydrous sodium sulfate drying is concentrated to give solid.With ethyl acetate-
Petroleum ether recrystallizes, and obtains N- (2,4- difluoro benzene sulfonyl) -3,4- methylenedioxybenzenes ethylamino acetic acid, yield 92%.It reacted
Journey indicates as follows：
Third walks：Ring-forming sequence：Filling 10mmolN- (2,4 difluorobenzene sulphonyl) -3,4- methylenedioxybenzenes ethylaminos
In the reactor of the 120mL anhydrous chloroform solution of acetic acid, in nitrogen, 30mmol trifluoroacetic anhydride is slowly added dropwise under room temperature.
It is stirred to react after 1h and reactor is placed in ice bath, 35mmol aluminum trichloride (anhydrous)s are slowly added dropwise, continue under condition of ice bath after dripping off
React 4h.PH to 8 is adjusted with 1N sodium carbonate liquors, separates organic phase, water phase is extracted 3 times with 30mL chloroforms.Merge organic phase, point
It is not washed respectively 1 time with water, saturated sodium-chloride, anhydrous sodium sulfate drying.It filters, be concentrated into 45mL, petroleum ether recrystallization is added, obtains light
Yellow solid N- (2,4- difluoro benzene sulfonyl) -3,4- methylene-dioxy benzo -3-N- heterocycle heptanone, yield 84%.1H NMR
(500MHz CDCl3)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]+found
for381.0471,calc for C17H13F2NO5S381.0482。
Reaction process is as follows：
Embodiment 5
N- ortho-nitrophenyls sulphonyl -3,4- methylene oxygroup benzo -3-N- heterocycle heptan is prepared by 3,4- methylene-dioxy phenyl ethylamines
Ketone
The first step：Amido protecting and N-H bond activations：The 80mL dichloros of 10mmol3,4- methylene-dioxy phenyl ethylamines will be filled
The flask of dichloromethane is placed in ice bath, triethylamine 12mmol is then added, to provide alkaline environment.While agitating, delay
It is slow that ortho-nitrophenyl sulfonic acid chloride 15mmol is added dropwise.Ice bath is removed in 1h recession, in the reaction was continued under room temperature 3h, stops reaction.Reaction
Liquid is washed through 3 times, after 1 time saturated sodium-chloride is washed, is dried with anhydrous sodium sulfate.Filtering, revolving recycling design, remaining oily liquids
Middle addition hexane makes crystallization, it is to be crystallized completely after, recrystallize to obtain faint yellow solid product N- ortho-nitrophenyl sulphonyl -3,4- methylene two
Oxygroup phenyl ethylamine, yield 97%.Reaction process indicates as follows：
Second step：It is aminoalkylated：N- ortho-nitrophenyl sulphonyl -3,4- methylene-dioxy phenyl ethylamines 10mmol will be filled to be dissolved in
The flask for the solution that the absolute DMA of 90mL is formed is placed in ice bath, and 40mmolLDA is added in a nitrogen environment, to provide
Alkaline environment.It is then while agitating that the 10mL DMA solution of 40mmol bromoacetates (derivative of halogenated acetic acids) is slow
Slowly it is added drop-wise in reactor, continues to stir 30min after dripping off, then react 6h at 100 DEG C.Reacting liquid temperature is down to room temperature,
It is filtered to remove inorganic salts, filtrate decompression revolving recycling DMA.30mL8M sodium hydroxide ethanol waters, room are added in residue
Temperature stirring 2h.50mL dichloromethane is added, with 6N hydrochloric acid tune pH to 1.Sub-argument goes out organic phase, and water phase is extracted 3 times with dichloromethane,
Merge organic phase, mutually wash 1 time, saturated sodium-chloride is washed 1 time, and anhydrous sodium sulfate drying is concentrated to give solid.With ethyl acetate-stone
Oily ether recrystallization, obtains N- ortho-nitrophenyl sulphonyl -3,4- Asia methoxybenzene ethylamino acetic acid, reaction process is as follows：
Third walks：Ring-forming sequence：In the N- ortho-nitrophenyl sulphonyl -3,4- methylenedioxybenzenes ethylamino vinegar for filling 10mmol
In the reactor of the 150mL tetrahydrofuran solutions of acid, in nitrogen, 20mmol acetic anhydrides are slowly added dropwise under room temperature.Stirring is anti-
It answers and reactor is placed in ice bath after 0.5h, 40mmol anhydrous zinc chlorides (lewis acidic one kind) are added, react under room temperature
5h.Filtering, filtrate adjust pH to 8 with 1N sodium carbonate liquors, separate organic phase, and water phase is extracted 3 times with 30mL tetrahydrofurans.Merge
Organic phase is respectively washed 1 time with water, saturated sodium-chloride respectively, anhydrous sodium sulfate drying.It filters, be concentrated into 45mL, petroleum ether weight is added
Crystallization, obtains faint yellow solid N- p-nitrophenyl sulphonyl -3,4- methylene oxygroup benzo -3-N- heterocycle heptanone 3.427g, yield 82%
。1H NMR(500MHz CDCl3) 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 CDCl3)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 for391.0586,calc for C17H15N2O7S391.0594。
Reaction process indicates as follows：
Claims (4)
1. one kind is with 3,4- methylene-dioxy phenyl ethylamines for raw material, the method for synthesizing harringtonine C ring intermediates was reacted
Journey includes following three steps：
Step (1)：Amido protecting and N-H bond activation steps：With 3,4- methylene-dioxies phenyl ethylamine I for raw material, in alkaline condition
Lower and acylation reaction generates intermediate N acyl group -3,4- methylene-dioxy phenyl ethylamine II of nitrogen end protection, and general formula is expressed as：
Or it is
The acylating agent be two tertiary fourth oxygen carbonic anhydrides, ortho-nitrophenyl formyl chloride, trifluoromethyl sulfonic acid anhydride, pyrovinic acid acid anhydride, to nitre
One kind or preceding paragraph in base benzene sulfonyl chloride, ortho-nitrophenyl sulfonic acid chloride, 2,4 difluorobenzene sulfonic acid chloride and 2,4,6- trifluoro benzene sulfonyl chlorides
Arbitrary combination；
Step (2)：Aminoalkylated step：Under alkaline condition, compound ii occurs with halogenated acetic acids or halogenated acetic acid derivative
Alkylated reaction on nitrogen obtains intermediate N and is acylated -3,4- methylenedioxybenzenes ethylaminos acetic acid III, and general formula is expressed as：
Or it is
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-forming sequence：Compound III issues raw intramolecular friedel-crafts acylation in Louis acid catalysis and obtains acyl group -3 N-,
4- methylene oxygroup benzo -3-N- heterocycle heptanone, i.e. harringtonine C rings intermediate；Its general formula is expressed as：
Or it is
The reaction temperature of step (1) is between 5-52 degrees Celsius；Reaction dissolvent is dichloromethane, chloroform or ethyl alcohol；
The alkali that step (2) uses is one kind in Anhydrous potassium carbonate, potassium tert-butoxide, sodium ethoxide, sodium hydride and LDA；
The solvent that step (2) uses is nonpolar solvent, aprotic polar solvent or protic polar solvent；It is wherein nonpolar molten
Agent is tetrahydrofuran (THF) or glycol dimethyl ether；Aprotic polar solvent is glycol dimethyl ether, dimethylformamide
(DMF) or dimethylacetylamide (DMA)；Protic polar solvent is ethyl alcohol；
Lewis acid used in step (3) be aluminum trichloride (anhydrous), anhydrous zinc chloride, boron trifluoride, boron trifluoride ether solution,
The arbitrary combination of any one or aforementioned items in hydrofluoric acid, polyphosphoric acids, trifluoro-acetic anhydride and acetic anhydride.
2. synthetic method according to claim 1, it is characterised in that：The alkaline environment of step (1) reaction is by triethylamine, pyrrole
Pyridine, diisopropylethylamine, 11 carbon -7- alkene of 1,8- diazabicyclos [5.4.0] or N, N- dimethylethanolamine provide.
3. synthetic method according to claim 1, it is characterised in that：The halogenated acetic acids that step (2) uses refers to monoxone
Or bromoacetic acid, halogenated acetic acid derivative refer to chloracetate or salt, or are bromacetate or salt.
4. synthetic method according to claim 3, it is characterised in that：The halogenated acetic acid derivative used in step (2) is
Refer to 2- methyl chloroacetates, 2- ethyl chloroacetates, 2- propyl chloroacetates, 2- isopropyl chloracetates, 2- chloroacetic acid tert-butyl esters, monoxone
Sodium, 2- bromoacetic acids potassium or bromoacetic acid sodium.
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