CN110041160A - Iodo- 4- benzyloxy-3- methyl-1-ene compound of (3R)-2- and its preparation method and application - Google Patents
Iodo- 4- benzyloxy-3- methyl-1-ene compound of (3R)-2- and its preparation method and application Download PDFInfo
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- CN110041160A CN110041160A CN201810039069.3A CN201810039069A CN110041160A CN 110041160 A CN110041160 A CN 110041160A CN 201810039069 A CN201810039069 A CN 201810039069A CN 110041160 A CN110041160 A CN 110041160A
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- 238000002360 preparation method Methods 0.000 title claims abstract description 36
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- 238000000034 method Methods 0.000 claims abstract description 32
- -1 bis- iodo -3- methyl but-1-ene Chemical compound 0.000 claims abstract description 14
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 15
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- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 claims description 14
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- 125000001424 substituent group Chemical group 0.000 claims description 12
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- 125000001584 benzyloxycarbonyl group Chemical group C(=O)(OCC1=CC=CC=C1)* 0.000 claims description 11
- IKDUDTNKRLTJSI-UHFFFAOYSA-N hydrazine monohydrate Substances O.NN IKDUDTNKRLTJSI-UHFFFAOYSA-N 0.000 claims description 11
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- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 6
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 6
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Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C17/00—Preparation of halogenated hydrocarbons
- C07C17/093—Preparation of halogenated hydrocarbons by replacement by halogens
- C07C17/16—Preparation of halogenated hydrocarbons by replacement by halogens of hydroxyl groups
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C259/00—Compounds containing carboxyl groups, an oxygen atom of a carboxyl group being replaced by a nitrogen atom, this nitrogen atom being further bound to an oxygen atom and not being part of nitro or nitroso groups
- C07C259/04—Compounds containing carboxyl groups, an oxygen atom of a carboxyl group being replaced by a nitrogen atom, this nitrogen atom being further bound to an oxygen atom and not being part of nitro or nitroso groups without replacement of the other oxygen atom of the carboxyl group, e.g. hydroxamic acids
- C07C259/06—Compounds containing carboxyl groups, an oxygen atom of a carboxyl group being replaced by a nitrogen atom, this nitrogen atom being further bound to an oxygen atom and not being part of nitro or nitroso groups without replacement of the other oxygen atom of the carboxyl group, e.g. hydroxamic acids having carbon atoms of hydroxamic groups bound to hydrogen atoms or to acyclic carbon atoms
-
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Abstract
The present invention provides iodo- 4- benzyloxy-3- methyl-1-ene compounds of a kind of medicine intermediate (3R)-2- and its preparation method and application, more particularly relate to noval chemical compound ERP-2 and its preparation method and application, the present invention also provides a kind of new preparations (3R) -2, the preparation method of bis- iodo -3- methyl but-1-ene (ERP) of 4-, and it is related to using new compound ERP-2, the method significantly improves the yield and quality of ERP-1 and ERP when preparing ERP-1 and ERP by compound ERP-2 compared with the prior art, without using the dangerous material such as zinc methide or dimethyl aluminium in reaction process, and it does not need to use expensive Hoveyda-Grubbs catalyst, field lipase PS-8000 etc., reaction Post-processing is simple, not only greatlys save production cost, but also improve the safety of production, is more suitable for industrialized production.
Description
Technical field
The present invention relates to medicinal chemistry arts, and in particular to a kind of iodo- 4- benzyloxy -3- first of medicine intermediate (3R) -2-
Base -1- ene compound and its preparation method and application.
Background technique
Halichondrin B (Halichondrin B) is to separate from sponge Halichondria okadai for 1986
The natural products with anticancer activity, as a kind of effective anticancer agent be it is known (participate in US6214865,
WO2005118565A1, WO2009124237A1 etc.).Harvard University Y Kishi research group to Halichondrin B
Fully synthetic research in, it was found that it is simpler than Halichondrin B structure, the better eribulin of drug effect (Eribulin,
CAS:253128-41-5).Eribulin is developed by Eisai company, ratifies to list by FDA November 15 in 2010, trade name
Halaven, for treating the metastatic breast cancer for once receiving the treatment of at least two chemical drugs.On January 28th, 2016, FDA ratify first
A kind of (can not cut off) or advanced stage (metastatic) embryonal-cell lipoma (specific shape of the sulfonic acid eribulin for that cannot be removed by operation
The soft tissue sarcoma of formula) treatment.
Two iodo -3- methyl but-1-ene (ERP) of (3R) -2,4- can be used as halichondrins natural products and derivative such as
Important intermediate in eribulin synthesis, referring to document Katrina (Katrina), L. et al., Angewandte Chemie
(" applied chemistry "), international version, volume 2009,48, the 13rd phase, 2346-2350；Kim (gold), D-S. et al., Journal of
The American Chemical Society (" American Chemical Society "), volume 2009,131, the 43rd phase, 15636-
15641；Guo (Guo), H. et al., " American Chemical Society ", volume 2009,131, the 42nd phase, 15387-15393；Choi (Cui),
H-w. et al., Organic Letters (" organic flash report "), volume 2002,4, the 25th phase, 4435-4438 etc., these documents are logical
Reference is crossed to be integrated in the present invention.Wherein, Kim (gold), D-S. et al., Journal of the American Chemical
Society (" American Chemical Society "), volume 2009,131, the 43rd phase, 15636-15641, which is disclosed, passes through two kinds of synthetic method systems
Standby bis- iodo -3- methyl but-1-ene (ERP) of (3R) -2,4-, as follows:
The first approach is related to the asymmetric SN2 ' reaction of cuprate, and needs to use Hoveyda-Grubbs catalysis
Agent, catalyst higher cost, and need to use hazardous chemical zinc methide, zinc methide low boiling point, inflammable, valence in reaction
Lattice are expensive, are not easy to industrialized production, and isolated product ERP yield 96%, 98% enantiomter is excessive (e.e.), wherein
Its enantiomer just exists to be higher than 0.10%, this is just above when its finished product drug registration quality standard controls to list
Miscellaneous overall upper limit requirement.
Second method needs to use field lipase PS-800, and the stereoselectivity catalysis of enzyme has unicity, enzyme
Screening is also equally to use hazardous chemical trimethyl during an extremely complex job, yield 46%, and synthesis S7 react
Aluminium, trimethyl aluminium is height combustible material, expensive, is not easy to industrialized production, and production cost is very high.
When using ERP as the intermediate of industrialized production ecteinascidin B or its analog such as eribulin, both the above method
Be not suitable for large-scale production ERP.
Vemula Praveen Kumar et al., Org.Lett.2017,19,2766-2769 disclose by compound S5 system
The reaction of standby compound ERP, yield 86%.But inventor is repeated several times according to method disclosed in document, and yield is not achieved
86%, highest only reaches 67%.
WO2013078559 specification embodiment is disclosed using methylene chloride as solvent, compound ERP-1 and triphenyl phosphorus
Prepare compound ERP is reacted with N- N-iodosuccinimide, post-processing uses silica gel column purification, and hexamethylene elution, yield is only up to
To 56%.Or it is dissolved in compound ERP-1 and triphenyl phosphorus in toluene, acetonitrile solution and solid the Iod R preparation of imidazoles
Compound ERP, post-processing use silica gel column separating purification, yield 69.8%.These methods require during purifying products
Silica gel column chromatography is used, consumption of organic solvent is big, and the solid waste of generation is non-recyclable and reusable, it causes serious pollution to the environment, and
And high production cost, cumbersome, the production cycle is long.In addition, product yield is lower, lead to high production cost.
Eribulin is drug most complicated with the structure of the development of pure chemistry synthetic method and production so far, is contained in molecule
There are 19 chiral carbons, is synthesized by the simple raw material of industry through the reaction of 62 steps.Initial synthetic route can only synthesize the sample of Gamma Magnitude
Product, research institute, Eisei company YU etc. optimize synthetic method, and important intermediate and simplified object are prepared with g grades of amounts, but
Due to the unique antitumor mechanism of methanesulfonic acid eribulin, significant antitumous effect, the huge market demand, it is still desirable to open
The process for sending out new meets market needs, reduces production cost, benefits more patients.
Wherein ERP is as an intermediate in eribulin synthetic method, the reduction of production cost and mentioning for quality
Height will also directly affect the production cost and quality of finished product eribulin.
It is reported at present about the preparation process of compound ERP fewer, it is still desirable to develop more preferably produced compounds ERP
Method, to improve the yield and purity of compound ERP, and reduce its production cost, so indirectly reduce downstream product Chinese mugwort
The production cost of Bu Lin.
Summary of the invention
In order to achieve the above objectives, the present invention provides the intermediates and preparation method of a kind of new prepare compound ERP.
Further, the present invention provides a kind of compound ERP-2 having the following structure:
Wherein Ar is benzyl, Cbz (benzyloxycarbonyl group), or benzyl or Cbz containing one or more substituent groups, the substituent group
Selected from methyl, ethyl, propyl, isopropyl, cyclopropyl, methoxyl group, ethyoxyl and isopropoxy.It is preferred that the Ar is benzyl.
On the other hand, the present invention also provides the preparation method of the compound ERP-2, include the following steps, by chemical combination
Object ERP-3 is converted to compound ERP-2:
Wherein, Ar is benzyl, Cbz, or benzyl or Cbz containing one or more substituent groups, the substituent group be selected from methyl,
Ethyl, propyl, isopropyl, cyclopropyl, methoxyl group, ethyoxyl and isopropoxy.It is preferred that Ar is benzyl.
Further preferably compound ERP-3 is first reacted with hydrazine hydrate (more preferable 80% hydrazine hydrate), reaction terminates
Afterwards, it is extracted with suitable organic solvent (such as THF, acetonitrile, Isosorbide-5-Nitrae-dioxane or toluene), merges organic phase, dry or concentration
After processing, then with iodine reagent (preferably I2) reaction in suitable solvent (such as THF, acetonitrile, Isosorbide-5-Nitrae-dioxane or toluene),
Further, preferably be added in iodine reagent reaction process suitable catalyst (such as organic alkali catalyst, it is more preferably described to urge
Agent is tetramethylguanidine), and reaction temperature is controlled at -10 DEG C~10 DEG C；After reaction, it is purified using suitable method
Product, it is preferable that after reaction using aqueous solution of sodium bisulfite quenching reaction is added, separate organic phase, with ammonium chloride and/or
Brine It is dried to obtain compound ERP-2, for the compound ERP-2 for reaching higher purity, can also further select to adopt
Gained ERP-2 is refined with liquid phase preparation or silicagel column, when refining for example, by using silicagel column, petroleum ether/second can be used
Acetoacetic ester=50/1 is eluted.Further, in the method, the molar ratio 1:1 of preferred compound ERP-3 and iodine reagent~
3, preferably 1:1.5~1:2；Wherein preferred 1:2~10 of the molar ratio of compound ERP-3 and hydrazine hydrate, more preferable 1:5；Compound
Preferred 1:2~10 of molar ratio of ERP-3 and organic alkali such as tetramethylguanidine, more preferable 1:5.
In the above method, wherein compound ERP-3 is converted by compound ERP-4:
It is preferred that including but is not limited to methyl-magnesium-chloride (MeMgCl), methyl bromide by compound ERP-4 and Grignard Reagent
Magnesium, the reaction in suitable solvent (such as THF, acetonitrile, Isosorbide-5-Nitrae-dioxane, toluene, preferably THF), prepare compound ERP-4,
After reaction, it includes but is not limited to after reaction, saturation chlorination to be added into reaction mixture that suitable method, which can be used,
Ammonium, stratification, aqueous layer with ethyl acetate extraction, organic phase saturated common salt water washing is dry, obtains crude product, as needed
It can also further include that purification is further purified to gained crude product using efficient liquid phase preparation method or silica column purification method,
When for example, by using silica gel column purification, it can be eluted using petrol ether/ethyl acetate 10/1.Wherein, preferred compound ERP-4
With Grignard Reagent be molar feed ratio be 1:1~3, preferably 1:1.25.
In the above method, wherein compound ERP-4 is converted by compound ERP-5:
By compound ERP-5 and N, O- dimethyl hydroxylamine hydrochloride is in suitable molten (such as methylene chloride) and suitable condensation
Reaction in agent (such as CDI), preferable reaction temperature are 0 DEG C~10 DEG C, and further preferably, reaction is carried out under alkali existence condition,
The alkali is preferably triethylamine, morpholine, N-Methyl pyrrolidone, DIPEA or imidazoles, is purified product after reaction, can be with
Further reaction solution is extracted, silica gel column purification (such as selecting PE/EA=10/1 as eluent) or high performance liquid chromatography preparation, with
Obtain the compound ERP-4 for meeting purity requirement.Wherein, preferably ERP-5 and N, O- dimethyl hydroxylamine hydrochloride mole feed intake
Than for 1:1~1:2, more preferable 1:1.1；Further, it is preferable that the molar feed ratio of ERP-5 and condensing agent such as CDI be 1:1~
2, more preferable 1:1.2~1.5.
Compound ERP-5 can be bought by market and be obtained in the above method, or be obtained using methods known in the art
Obtain such as Tetrahedron Letters (2002), 43 (52), 9691-9693, Chemistry-An Asian Journal
(2011), 6 (7), 1791-1799, Journal of Organic Chemistry (2007), 72 (7), 2558-2563,
Synlett (1996), (12), method disclosed in the documents such as 1176-1178.
Third aspect present invention additionally provides the preparation method of compound ERP a kind of, comprising the following steps:
(1) compound ERP-2 is converted to compound ERP-1:
(2) compound ERP-1 is converted to compound ERP:
Wherein, Ar is benzyl, Cbz, or benzyl or Cbz containing one or more substituent groups, the substituent group be selected from methyl,
Ethyl, propyl, isopropyl, cyclopropyl, methoxyl group, ethyoxyl and isopropoxy.
In the above method, preferably Ar is benzyl.Wherein, compound ERP-2 is sloughed into Ar, such as by ERP-2 and tri-chlorination
Boron or Iodotrimethylsilane, preferentially and boron chloride in suitable solvent includes but is not limited to methylene chloride, THF, isopropanol, second
It is reacted in nitrile, toluene or Isosorbide-5-Nitrae-dioxane, sloughs Ar, after reaction, extracted by organic solvent such as DCM or ethyl acetate
It takes, obtains crude product, crude product is further passed through to silicagel column (such as PE/EA=5/1) purifying as needed, or pass through efficient liquid phase system
Standby column purification, obtains ERP-1 fine work.It is preferred that the molar ratio of ERP-2 and boron chloride be 1:0.8~1:10, more preferably 1:
1.18。
Then by ERP-1 and iodine reagent (such as carbon tetraiodide, iodine etc.) reaction preparation ERP, preferably by ERP-1 and triphenyl phosphorus
Be added in organic solvent such as DCM or THF (preferably THF), then add imidazoles under the conditions of suitable temperature with Iod R,
Water quenching reaction is added after completion of the reaction, separates organic phase, aqueous solution of sodium bisulfite is added, separates organic phase, washs, does
It is dry, polishing purification is carried out using silicagel column or distillation under pressure.
Wherein the method for compound ERP-1 prepare compound ERP can also be with bibliography Vemula Praveen Kumar
Et al., Org.Lett.2017, method disclosed in 19,2766-2769 method or WO2013078559 specification embodiment 13.
In another preferred embodiment of the present invention, such as, but not limited to, there is structure ERP-1, ERP-2, ERP-
The enantiomeric purity of any of the compound of 3, ERP-4, ERP-5 is about 99.0%, 99.1%, 99.2%, 99.3%
99.4%, 99.5%, 99.6%, 99.7%, 99.8%, 99.9%e.e. or between any value.
Another aspect of the present invention additionally provides a kind of method for preparing halichondrin B or derivatives thereof, including aforementioned offer
Compound ERP-2's and/or compound ERP's preparation method.Further, it is preferable that the halichondrin B derivative is Chinese mugwort
Bu Lin.
Abbreviation: DABCO refers to:；CDI refers to；DCM refers to methylene chloride；THF refers to tetrahydrofuran；PE refers to petroleum ether；
EA refers to ethyl acetate；
Compound ERP-2 structure novel provided by the invention is used as and prepares halichondrin B derivative especially Ai Bu
When woods intermediate, with having significant advantage, eribulin important intermediate ERP- is on the one hand prepared by compound ERP-2
The yield and quality of ERP-1 and ERP are significantly improved when 1 and ERP compared with the prior art, is not necessarily to use dimethyl in reaction process
The dangerous material such as zinc or dimethyl aluminium, and do not need to use expensive Hoveyda-Grubbs catalyst, field lipase PS-
8000 etc., post-reaction treatment is simple, not only greatlys save production cost, but also improves the safety of production, is more suitable for industry
Metaplasia produces；On the other hand, the preparation method of compound ERP-2 provided by the invention is simple, and yield and purity is high are conducive to downstream
The control of the quality of product E RP and eribulin；And these two aspects plays significantly on reducing eribulin production of raw medicine cost
Effect, ERP-2 provided by the invention and preparation method thereof and its preparing the application in ERP, be able to achieve hundred feather weight
Large-scale production, this also promotes eribulin large-scale production indirectly.
Specific embodiment
Further explaination is done to the contents of the present invention below in conjunction with specific embodiment, it should be understood that these embodiments not with
Any form limitation present invention.
Embodiment 1: the preparation method of compound ERP-4A:
7Kg compound ERP-5A is added in 70L dichloromethane solution, after stirring and dissolving, reaction kettle is cooled to 10
DEG C when, be added portionwise 7Kg CDI solid, keep reaction kettle heat preservation at 10-15 DEG C, be stirred to react about 1h.Then 0 DEG C is cooled to, f
The N of 3.58Kg is added portionwise, O- dimethyl hydroxylamine hydrochloride is then slowly added into 7.3kg triethylamine, is raised to room after being added dropwise
20 DEG C of reactions of temperature, after TCL detects raw material fully reacting, 30L water is added into system, stirs, layering, organic layer saturated common salt
Water washing, anhydrous sodium sulfate is dry, then uses silica gel column purification, and eluent (PE/EA=10/1) obtains ERP-4A, yield
89%, HPLC:98%.LCMS；MW=237.30.
Embodiment 2: the preparation method of compound ERP-3A:
In the reaction kettle of 100L, the dry THF solution of 7.3Kg compound ERP-3A and 50L, stirring is added in nitrogen protection
After dissolution, reaction kettle is cooled down, when interior temperature drop is to -5 DEG C, the concentration that 13L is slowly added dropwise is the methyl-magnesium-chloride of 3mol/L, is kept
Temperature is at 0 DEG C hereinafter, then insulated and stirred is reacted.TLC detects raw material fully reacting, and 30L saturated ammonium chloride is added, and stirring is quiet
Layering is set, water layer is extracted with the EA of 600ml*2, and combined organic phase saturated common salt water washing, anhydrous sodium sulfate is dry, then
With silica gel column purification, eluent (PE/EA=10/1) obtains compound ERP-3A, yield 95%, HPLC:98%.LCMS；MW=
192.26。
Embodiment 3: the preparation of compound ERP-2A:
(1) in the reaction kettle of 50L, under nitrogen protection, the 80% of 5.5Kg compound ERP-3A and 15L is added portionwise
Then hydrazine hydrate is warming up to 80 DEG C of reflux 2h, TLC and detects raw material fully reacting；Reaction kettle is cooled down and is layered, water phase is anti-with THF
Extraction is primary, and combined organic phase saturated common salt water washing, anhydrous sodium sulfate dries, filters for use；
(2) in 100L reaction kettle, with nitrogen protection, the THF solvent of 20L is added and is stirred, nitrogen displacement, then
13.6Kg iodine is added portionwise, reaction kettle is cooled to -5 DEG C, 15kg tetramethylguanidine is slowly added dropwise, and stir 30min, then slowly
Reaction kettle, is raised to after dripping and 2h is stirred at room temperature by the THF mixed solution of a dropping step (1), after reaction, it is full that 30L is added
The aqueous solution of sodium bisulfite of sum, stirring, stratification, organic phase saturated ammonium chloride and saturated salt solution respectively washed once,
Anhydrous sodium sulfate is dried to obtain crude product, crude product silica gel column purification, and eluent (PE/EA=50/1) obtains compound
ERP-2A, yield 93%, HPLC:96%.LCMS；MW=302.16.
Embodiment 4: the preparation of compound ERP-1:
In the reaction kettle of 100L, under nitrogen protection, the DCM solvent of 4.83Kg compound ERP-2A and 30L is added portionwise, into
Row stirring, cools to -5 DEG C for reaction kettle, and the boron chloride tetrahydrofuran solution of the 1mol/L of 15L is then slowly added dropwise to system
In, insulated and stirred 1h is reacted, then reaction kettle, which is raised to, is stirred at room temperature to fully reacting, 20L saturated sodium bicarbonate aqueous solution is added,
Stir stratification after 10min, water layer is extracted twice with DCM, combined organic phase with brine It twice, anhydrous sodium sulfate
It is dry, obtain crude product.Crude product silica gel column purification, eluent (PE/EA=5/1) obtain product E RP-1, yield 94%,
HPLC:95%.LCMS；MW=212.03.
Embodiment 5: the preparation of compound ERP:
Into the reaction kettle of 100L, nitrogen protection, be added portionwise 2.35Kg compound ERP-1,3.525Kg triphenyl phosphorus and
The THF solvent of 25L is simultaneously stirred, and the THF solution of 1.81Kg imidazoles is then slowly added dropwise, and reaction kettle is cooled to 0 DEG C, in batches
The iodine of 3.38Kg is added, adds rear reaction kettle and is raised to 55 DEG C of stirring 2h and reaction kettle is cooled to 10 DEG C, then after reaction
Be added 10L water quenching reaction, separation it is organic be added to 10L saturation aqueous solution of sodium bisulfite stirring 10min, stratification,
Then organic phase washed once with saturated salt solution, and anhydrous sodium sulfate is dry, and precipitation obtains crude product.Crude product vacuum distillation,
The fraction that 65-70 DEG C is collected under 4mmHg column pressure obtains compound ERP, yield 95%, purity 98.5%, enantiomeric purity
99% or more.LCMS；MW=321.93.
Embodiment 6: the preparation of compound ERP-1:
The similar approach that wherein compound ERP-3B can refer to previous embodiment 1~2 is prepared.
The preparation of compound ERP-2B:
(1) in the reaction kettle of 50L, under nitrogen protection, the 80% of 5.9Kg compound ERP-3B and 15L is added portionwise
Then hydrazine hydrate is warming up to 80 DEG C of reflux 2h, TLC and detects raw material fully reacting；Reaction kettle is cooled down and is layered, water phase is anti-with THF
Extraction is primary, and combined organic phase saturated common salt water washing, anhydrous sodium sulfate dries, filters for use；
(2) in 100L reaction kettle, with nitrogen protection, the THF solvent of 20L is added and is stirred, nitrogen displacement, then
13.6Kg iodine is added portionwise, reaction kettle is cooled to -5 DEG C, 15kg tetramethylguanidine is slowly added dropwise, and stir 30min, then slowly
Reaction kettle, is raised to after dripping and 2h is stirred at room temperature by the THF mixed solution of a dropping step (1), after reaction, it is full that 30L is added
The aqueous solution of sodium bisulfite of sum, stirring, stratification, organic phase saturated ammonium chloride and saturated salt solution respectively washed once,
Anhydrous sodium sulfate is dried to obtain crude product, crude product silica gel column purification, and eluent (PE/EA=50/1) obtains compound
ERP-2B, yield 82%, HPLC:91%.LCMS；MW=316.03.
The preparation of compound ERP-1:
In the reaction kettle of 100L, under nitrogen protection, the DCM solvent of 4.9Kg compound ERP-2B and 30L is added portionwise, into
Row stirring, cools to -5 DEG C for reaction kettle, and the boron chloride tetrahydrofuran solution of the 1mol/L of 15L is then slowly added dropwise to system
In, insulated and stirred 1h is reacted, then reaction kettle, which is raised to, is stirred at room temperature to fully reacting, 20L saturated sodium bicarbonate aqueous solution is added,
Stir stratification after 10min, water layer is extracted twice with DCM, combined organic phase with brine It twice, anhydrous sodium sulfate
It is dry, obtain crude product.Crude product silica gel column purification, eluent (PE/EA=5/1) obtain product E RP-1, yield 86%,
HPLC:93%.LCMS；MW=212.03.
Embodiment 7: the preparation of compound ERP-1:
The similar approach that wherein compound ERP-3C can refer to previous embodiment 1~2 is prepared.
The preparation of compound ERP-2C:
(1) in the reaction kettle of 50L, under nitrogen protection, the 80% of 6.3Kg compound ERP-3C and 15L is added portionwise
Then hydrazine hydrate is warming up to 80 DEG C of reflux 2h, TLC and detects raw material fully reacting；Reaction kettle is cooled down and is layered, water phase is anti-with THF
Extraction is primary, and combined organic phase saturated common salt water washing, anhydrous sodium sulfate dries, filters for use；
(2) in 100L reaction kettle, with nitrogen protection, the THF solvent of 20L is added and is stirred, nitrogen displacement, then
13.6Kg iodine is added portionwise, reaction kettle is cooled to -5 DEG C, 15kg tetramethylguanidine is slowly added dropwise, and stir 30min, then slowly
Reaction kettle, is raised to after dripping and 2h is stirred at room temperature by the THF mixed solution of a dropping step (1), after reaction, it is full that 30L is added
The aqueous solution of sodium bisulfite of sum, stirring, stratification, organic phase saturated ammonium chloride and saturated salt solution respectively washed once,
Anhydrous sodium sulfate is dried to obtain crude product, crude product silica gel column purification, and eluent (PE/EA=50/1) obtains compound
ERP-2C, yield 80%, HPLC:90%.LCMS；MW=316.03.
The preparation of compound ERP-1:
In the reaction kettle of 100L, under nitrogen protection, the DCM solvent of 4.97Kg compound ERP-2C and 30L is added portionwise, into
Row stirring, cools to -5 DEG C for reaction kettle, and the boron chloride tetrahydrofuran solution of the 1mol/L of 15L is then slowly added dropwise to system
In, insulated and stirred 1h is reacted, then reaction kettle, which is raised to, is stirred at room temperature to fully reacting, 20L saturated sodium bicarbonate aqueous solution is added,
Stir stratification after 10min, water layer is extracted twice with DCM, combined organic phase with brine It twice, anhydrous sodium sulfate
It is dry, obtain crude product.Crude product silica gel column purification, eluent (PE/EA=5/1) obtain product E RP-1, yield 83%,
HPLC:92%.LCMS；MW=212.03.
Embodiment 8: the preparation of compound ERP-2A:
3 similar approach of reference implementation example carries out the reaction that feeds intake according to following material ratio, and obtained yield difference is as follows,
| Name of material | Molecular weight | Molar equivalent (eq.) | Molar equivalent (eq.) | Molar equivalent (eq.) |
| ERP-3A | 192.25 | 1.0 | 1.0 | 1.0 |
| Hydrazine hydrate | 50.06 | 3.0 | 8.1 | 5.0 |
| DABCO | 112.17 | 3.0 | 10 | 5.0 |
| Iodine | 253.81 | 3.0 | 3 | 2.0 |
| Yield | 78% | 77% | 92% |
As can be seen from the table, the molar ratio 1:2 of compound ERP-3 and iodine reagent；Mole of compound ERP-3 and hydrazine hydrate
Compare 1:5；When the compound ERP-3 and molar ratio 1:5 of organic alkali such as tetramethylguanidine (DABCO), other feed ratios, reaction are compared
Yield is best.
Comparative example 1: by following formula: compound 1b prepare compound 2b
The preparation of compound 2b:
In the reaction flask of 250mL, under nitrogen protection, the THF solvent of 3.52g compound 1b and 20mL is added portionwise, carries out
Stirring, cools to 0 DEG C for reaction, 10% sodium hydrate aqueous solution of 10mL is then added into system, then reaction is raised to
2h is stirred at room temperature to fully reacting, reaction is extracted twice with EA, combined organic phase with brine It twice, anhydrous sodium sulfate
It is dry, obtain crude product.Crude product silica gel column purification, eluent (PE/EA=5/1) obtain product 2c, yield 72%, HPLC:
92%.LCMS；MW=212.03.
Comparative example 2: by following formula: compound 1c prepare compound 2c
The preparation of compound 2c:
In the reaction flask of 500mL, under nitrogen protection, the DCM solvent of 10g compound 1c and 50L is added portionwise, is stirred
It mixes, reaction is cooled to 0 DEG C, the solution of hydrogen fluoride pyridine complex compound of the 70% of 6mL is then slowly added dropwise into system, then
Reaction, which is raised to, is stirred at room temperature 18h to fully reacting, 100mL saturated sodium bicarbonate aqueous solution quenching reaction is added, after stirring 10min
Stratification, water layer are extracted twice with DCM, combined organic phase brine It, and anhydrous sodium sulfate is dry, are slightly produced
Product.Crude product silica gel column purification, eluent (PE/EA=5/1) obtain product E RP-1, yield 75%, HPLC:90%.LCMS；
MW=212.03.
Comparative example 3: by following formula: compound 1c prepare compound 2c
The preparation of compound 2c:
In the reaction flask of 500mL, under nitrogen protection, the THF solvent of 18.5g compound 1c and 100mL is added portionwise, carries out
Stirring, cools to 0-5 DEG C for reaction, the tetrabutyl ammonium fluoride solution of the 1M of 45.2mL is then slowly added dropwise into system, is added dropwise
Reaction temperature is no more than 10 DEG C, and then reaction, which is raised to, is stirred at room temperature 4h to fully reacting, and 20mL saturated aqueous ammonium chloride is added
Quenching reaction, water layer are extracted twice with DCM, and twice with brine It, anhydrous sodium sulfate is dry for combined organic phase, are obtained thick
Product.Crude product silica gel column purification, eluent (PE/EA=5/1) obtain product 2c, yield 73%, HPLC:91%.LCMS；
MW=212.03.
Claims (12)
1. the compound having the following structure
Wherein Ar is benzyl, Cbz, or benzyl or Cbz containing one or more substituent groups, the substituent group be selected from methyl, ethyl,
Propyl, isopropyl, cyclopropyl, methoxyl group, ethyoxyl and isopropoxy.
2. a kind of preparation method of compound described in claim 1, includes the following steps,
Compound ERP-3 is converted to compound ERP-2:
Wherein, Ar is benzyl, Cbz or benzyl or Cbz containing one or more substituent groups, the substituent group be selected from methyl, ethyl,
Propyl, isopropyl, cyclopropyl, methoxyl group, ethyoxyl and isopropoxy.
3. method according to claim 2, wherein compound ERP-3 is converted by compound ERP-4:
4. method according to claim 3, wherein compound ERP-4 is converted by compound ERP-5:
5. according to any one of claim 2~4 the method, which is characterized in that first by compound ERP-3 and hydration hydrazine reaction,
The product that will be obtained after reaction, then reacted with iodine reagent.
6. method according to claim 5, which is characterized in that the hydrazine hydrate is the hydrazine hydrate of 80% (w/w)；With iodine reagent
Catalyst is added in reaction process, the catalyst is organic alkali, and the preferably described catalyst is tetramethylguanidine.
7. according to any one of claim 5~6 the method, which is characterized in that the molar ratio 1 of compound ERP-3 and iodine reagent:
1~3, preferably 1:1.5~1:2；The molar ratio of compound ERP-3 and hydrazine hydrate is 1:2~10, preferably 1:5；Compound ERP-3
Molar ratio with organic alkali is 1:2~10, preferably 1:5.
8. a kind of preparation method of compound ERP, comprising the following steps:
(1) compound ERP-2 is converted to compound ERP-1:
(2) compound ERP-1 is converted to compound ERP:
Wherein, Ar is benzyl Cbz, or benzyl or Cbz containing one or more substituent groups, the substituent group be selected from methyl, ethyl,
Propyl, isopropyl, cyclopropyl, methoxyl group, ethyoxyl and isopropoxy.
9. according to claim 2~4, any one of 6~7 the methods, it is characterised in that Ar is benzyl.
10. a kind of method for preparing halichondrin B or derivatives thereof, including claim 2~4, defined in 6~7 any one
Method.
11. a kind of method for preparing halichondrin B or derivatives thereof, including make as defined in any one of claim 1~2
Compound reaction.
12. according to the described in any item methods of claim 9~10, wherein the halichondrin B derivative is eribulin.
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN111875470A (en) * | 2020-08-17 | 2020-11-03 | 苏州正济药业有限公司 | Preparation method of intermediate (R) -2-methyl-1-bromo-3-iodo-3-butene for preparing eribulin |
| CN112441998A (en) * | 2019-08-27 | 2021-03-05 | 南通诺泰生物医药技术有限公司 | Preparation method of eribulin intermediate |
| WO2024021261A1 (en) * | 2022-07-29 | 2024-02-01 | 上海皓元医药股份有限公司 | Method for preparing eribulin intermediate |
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| WO2004009574A1 (en) * | 2002-07-22 | 2004-01-29 | Novartis Ag | Synthesis of discodermolide |
| WO2013078559A1 (en) * | 2011-11-30 | 2013-06-06 | Alphora Research Inc. | Process for preparation of (3r)-2,4-di-leaving group-3-methylbut-1-ene |
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| WO2004009574A1 (en) * | 2002-07-22 | 2004-01-29 | Novartis Ag | Synthesis of discodermolide |
| WO2013078559A1 (en) * | 2011-11-30 | 2013-06-06 | Alphora Research Inc. | Process for preparation of (3r)-2,4-di-leaving group-3-methylbut-1-ene |
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Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN112441998A (en) * | 2019-08-27 | 2021-03-05 | 南通诺泰生物医药技术有限公司 | Preparation method of eribulin intermediate |
| CN112441998B (en) * | 2019-08-27 | 2024-05-03 | 南通诺泰生物医药技术有限公司 | Preparation method of eribulin intermediate |
| CN111875470A (en) * | 2020-08-17 | 2020-11-03 | 苏州正济药业有限公司 | Preparation method of intermediate (R) -2-methyl-1-bromo-3-iodo-3-butene for preparing eribulin |
| CN111875470B (en) * | 2020-08-17 | 2023-02-03 | 苏州正济药业有限公司 | Preparation method of intermediate (R) -2-methyl-1-bromo-3-iodo-3-butene for preparing eribulin |
| WO2024021261A1 (en) * | 2022-07-29 | 2024-02-01 | 上海皓元医药股份有限公司 | Method for preparing eribulin intermediate |
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