CN107459532A - A kind of new Anti-cancer medicament intermediate - Google Patents

A kind of new Anti-cancer medicament intermediate Download PDF

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CN107459532A
CN107459532A CN201710327505.2A CN201710327505A CN107459532A CN 107459532 A CN107459532 A CN 107459532A CN 201710327505 A CN201710327505 A CN 201710327505A CN 107459532 A CN107459532 A CN 107459532A
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CN107459532B (en
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刘登贵
杨坤于
周伟
陈浩
曾庆东
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Chongqing Kaibo Chemi Biological Pharmaceutical Co Ltd
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
    • C07F9/02—Phosphorus compounds
    • C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
    • C07F9/6536—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having nitrogen and sulfur atoms with or without oxygen atoms, as the only ring hetero atoms
    • C07F9/6539—Five-membered rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
    • C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
    • C07D277/20—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D277/32—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D277/56—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen

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  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Biochemistry (AREA)
  • General Health & Medical Sciences (AREA)
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  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

The invention discloses a kind of new Anti-cancer medicament intermediate, compound of formula III（IIIa or IIIb）, using 2 acetyl 4 formic acid esters thiazolium compounds as raw material, it is made by halogenating reaction, then with the reaction such as triphenylphosphine, Trimethyl phosphite, triethyl phosphite.Further can by formula III compound be used for prepare Anti-cancer medicament intermediate, such as and isobutylaldehyde, by Wittig reaction or Wittig Horner react, obtain compound of formula I.Whole technique is new technology, can not only reduce the prices of raw materials, and reaction condition is also gentle, and the caused three wastes are few, easy industrial applications.

Description

A kind of new Anti-cancer medicament intermediate
Technical field
The invention belongs to field of medicine and chemical technology, is specifically related to a kind of cancer therapy drug Tubulysins new intermediates and preparation side Method.
Background technology
Tubulysins is a kind of medicine for having important curative effect to prostate cancer, most earlier than 2000 by Hofle etc. from viscous Extracted in bacterium, but its crystal structure was just determined until 2004.Tubulysins is family's compound （Table 1.1）, contain a series of Tubulysins A-Z members.
The Tubulysins of table 1.1 family member's table（Tubulysins A-Z）
Because cytotoxin very high Tubulysins causes extensive concern, find that there is very high suppressing cell reproduction to live for it later Property, can be with the tumour cell of selective depression quick copy, Tubulysins anti-cell mitosis mechanism and colchicin （colchicine）, vinblastine etc. is similar, has individual binding site all on 'beta '-tubulin, with reference to the tubulin two of medicine Aggressiveness is assembled into microtubule ends, can prevent other tubulins continue assembling so as to prevent the poly- of micro-pipe and, so as to break indirectly The formation of spindle in bad mitosis.
Tubulysins, especially active anticancer extremely strong Tubulysin D excite the research interest of scientific circles quickly, The increasing toxic side effect and drug resistance clinically shown with vincaleukoblastinum, vinblastine and taxol, Tubulysins will promise to be the nova molecule for clinically substituting above-mentioned anticarcinogen.Because with other anti-mitosis medicines Compare, Tubulysins have other medicines molecule can not and the advantages of.
（1）Tubulysins high activity：It is more excellent that although Tubulysins anticancer mechanism is similar to vincaleukoblastinum one kind Cancer therapy drug.But activity that taxol, vincaleukoblastinum with current clinical practice etc. compare its protrusion becomes and received much concern Focus.Calculated according to the IC50 for external a variety of cancer cells, Tubulysins is higher by vincaleukoblastinum（Such as Vinblastine） More than 100 times of tumor-suppression activity.Especially family member Tubulysin D can be resisted effectively in mankind's KB-V head ＆ neck cancer cells The expression of multidrug resistance P- glycoprotein, its IC50 only have 0.31nM.Tubulysin D IC50 is about the thing 00- of taxol 5000 times, for more than 10 times of epothilone B（Table 1.2）, and can effectively suppress have the drug resistant cancer cells such as taxol Growth, Tubulysins water solubility is higher than taxol and Epothilones in addition.Therefore, Tubulysins turn into after taxol and Another study hotspot after Epothilones, there are substantial amounts of Tubulysins medicines to carry out clinical research at present.
The taxol of table 1.2, vincaleukoblastinum, Epothilones, Tubulysin D, dorastine 10 are to the cell toxicant of mdr cell Property（IC50ng/ml）
A rat cancer cells, b human marrow leukaemias, c human uterus' cancer cells, d multidrug resistance KB clone cells
（2）Suppress tumor angiogenesis：Research shows Tubulysins while also there is the new life for suppressing blood vessel will block The energy supply of growth of cancer cells, to accelerate the apoptosis of tumour cell.
（3）Anti- multidrug resistance：Although structure is much like, the mechanism of action is also all and micro-pipe egg vincaleukoblastinum one kind compound The position combined in vain is different, although all being combined with beta tubulin, their binding site is non-competing.To current Untill, the position of Tubulysins and tubulin binding is unclear, and Epothilones and taxol are although and Tubulysins Proliferative cell mitosis is equally resistant to, but their the specific mechanism of action is opposite with Tubulysins, that is, is promoted micro- The polymerization of tubulin.Ironically, the microtubule depolymerization as caused by Tubulysins is that Epothilones and taxol can not press down System, and can effectively suppress the growth for having the drug resistant cancer cells such as taxol, so Tubulysins gets a good chance of into For the drug candidate of cancer therapy drug moderate resistance multidrug resistance in future.
Tubulysins is a kind of native compound, so effective method how is developed, its is artificial synthesized out As important, current existing synthetic method has：
Synthetic route in the patent that 1.2002 years Hofle are delivered
The article that 2.Peter Wipf deliver in Org.Lett.
Friestad etc. has reported the synthesis in route 1, and it synthesizes oneself that Tuv and Tup committed step is the regulations of Mn2 (CO) 10 Reacted by base, the stereoselectivity for generating compound 10 with 14 is very good（dr>98:2）, but Tuv synthesis is not yet completed, Mn2 (CO) 10 prices are somewhat expensive and last chiral control reagent may go to pot under the conditions of TFAA, and gross production rate also needs into one Step improves.
As for Wipf route, its Tuv, Tup synthesis has 10 steps or so, the reaction yields of several steps more than 60% nor Very well, Tup synthesis 3:1 selectivity is bad.
The article that 3.2006 years Domling deliver in Angew.Chem.Int.Ed.
Domling employs " one pot " method very ingenious, three steps of compound 22,23 and 24 one is condensed into chemical combination Thing 25, its unfortunate yield 40% and selectivity 3:1 is all very low.As for its two Tup synthetic route, also do not asked selectively The result obtained in topic, selectivity are all 4:1.
The article that 4.2006 years Ellman deliver in J.Am.Chem.Soc.
In the synthetic route of Ellman reports, employ of a sort chipal compounds butylsulfinyl chloride and tried for chiral control Agent, obtain 2 chipal compounds 34 and 38.The route of synthesis Tup fragments is simplified very much, plus 32 preparation, is also only had altogether Three-step reaction.But expensive chiral auxiliary is destroyed in deprotection reaction；Crucial radical reaction（34 conjunction Into）80:15:3:2 non-corresponding isomers are not selectively fine, are incited somebody to action with the program of 4 diastereoisomers of silica gel post separation A large amount of synthesis are made to become extremely difficult.As for Tuv fragments, with 8 steps reaction synthesis 39（Wherein 37 synthesize 4 steps）Scheme do not have There is stereoselectivity also good（dr=92:8）, but expensive chiral auxiliary will also become no optically active sulfinic acid, And 2 diastereoisomers that compound 38 is separated with silicagel column are restricted in production.
The article that 5.2007 years Peter Wipf deliver in Org.Lett.
As for Wipf this second article, synthetic route is similar with 2004, simply in structure Tuv key reaction In used asymmetric reduction reaction, but 1:2 selectivity is very poor, and route is up to 14 steps.And Tup synthesis is not when there be Change, the problem of again without poor selectivity is avoided.
The article that 6.2009 years Srivari Channdrasekhar are delivered on J.Org.Chem
Srivari Chandrasekar route either Tuv17 is walked, or the nearly 10 step reaction schemes of Tup are all too cumbersome, though It is not very low so often to walk yield, but each fragment is up to more than ten steps, is not good route for fully synthetic.
The article that 7.2009 years Osamu Tamura deliver in Tetrahedron. Lett.
The chiral sugar of selection one and chiral camphorsulfonic acid try for Stereo control when Osamu Tamurawg synthesize Tuv fragments Agent, employ 1, a 3 dipolar additions reaction, but 4:1 selectivity is not fine, and the route of 11 steps is also oversize.
It is all very long that the current synthetic routes of Tubulysins are can be seen that from above Tubulysins synthetic method, are received Rate is not also high, and the synthesis technique for how shortening Tubulysins or its key intermediate is just particularly important.
For Tubulysins involved in the present invention ketenes intermediate 2- (4- methyl -2- alkene) pentanone base -4- formic acid Ester thiazole, the Louis acid catalysis such as conventional TiCl4 at present, either with modes of base catalysis such as sodium alkoxide, KOH or with sour or alkali It is catalyzed beta-hydroxy ketone compound, ketenes intermediate 2- (4- methyl -2- alkene) pentanone base -4- formic acid esters is prepared through dehydration again Thiazole.Preparation method such as following formula：
But because two kinds of raw material activity are more compared with high, reaction site and required reaction temperature low (- 78oC, control anhydrous and oxygen-free behaviour Make), the accessory substances such as self-condensation are easily produced, reaction is unmanageable, all difficult by changing the modes such as charging sequence, material proportion To suppress side reaction, post processing is difficult to separate target product.
The content of the invention
In order to overcome existing difficulty, the invention discloses the new intermediate general formula III of new Tubulysins a kind of, so Compound III further synthesizes the synthetic method of ketenes intermediate 2- (4- methyl -2- alkene) pentanone base -4- formic acid esters thiazoles afterwards. The new method, technique is shorter, and yield is higher.
First, using formula RM as raw material, by halogenating reaction, formula II compounds,
Wherein, R is C1-C6 alkyl, and X is halogen atom.Halogenating agent needed for reaction is NBS, Br2、Br2One kind in/HBr It is or several.Test of many times proves, uses Br2/ HBr mix reagent, effect are more preferable.Reaction solvent for use is glacial acetic acid, ethanol, Chloroform equal solvent.For temperature in the range of 20-80 DEG C, it is 45-55 DEG C that experiment, which preferably goes out the preferable temperature range of effect,.
Then, Formula II compound and triphenylphosphine reaction, prepare general formula III a compounds,
Or Formula II compound and phosphite ester, such as Trimethyl phosphite, triethyl phosphite react, and obtain general formula III b Compound,
Wherein, R is C1-C6 alkyl, and R and R1 are respectively C1-C6 alkyl, be can be the same or different.It is molten used in reaction Agent is toluene, ethanol, chloroform, isopropyl ether, DMF equal solvents.For temperature in the range of 60-100 DEG C, it is preferable that experiment preferably goes out effect Temperature range is 45-55 DEG C.
Compound of formula III, very important effect is played to the beneficial effect of the route, especially for following structure When：
Finally, formula III compound is reacted with isobutylaldehyde by Wittig or Wittig-Horner reacts, and can enter one Step prepares compound of formula I,
Wherein, R is C1-C6 alkyl.Reaction solvent for use is chloroform, ethanol, isopropyl ether.Temperature is at 30-100 DEG C needed for reaction In the range of, it is 60-70 DEG C that experiment, which preferably goes out the preferable temperature range of effect,.
Specific embodiment：
Embodiment 1
Compound II synthesis
1.1 take 500ml three-necked flask, add 100ml glacial acetic acid, then add 2- acetyl group -4- Ethyl formate thiazoles 19.9g（0.1mol）, add 16.0g bromines（0.1mol）, the hydrogen bromide solutions of 20ml 30%, stir dissolved clarification.It is to slowly warm up to 45 ~ 55 DEG C, and stirring reaction 5h, middle control check that reaction finishes substantially.Stop reaction, system be added in 1L water, stir 1h, Filter, filter cake is washed with water 3 times, dries, obtains Formula II compound（R=Et）, it is gray solid 26.2g, purity 98%.
1.2 according to 1.1 method, take 500ml three-necked flask, add 100ml glacial acetic acid, then add 2- second Acyl group -4- propyl formate thiazoles 21.3g（0.1mol）, add 16.0g bromines（0.1mol）, the hydrogen bromide solutions of 20ml 30%, Stir dissolved clarification.45 ~ 55 DEG C are to slowly warm up to, and stirring reaction 5h, middle control check that reaction finishes substantially.Stop reaction, by system It is added in 1L water, stirs 1h, filter, filter cake is washed with water 3 times, dries, obtains Formula II compound（R=Pr）, it is gray solid 24.3g, purity 95%.
1.3 according to 1.1 method, take 500ml three-necked flask, add 100ml ethanol, then add 2- second Acyl group -4- Ethyl formate thiazoles 19.9g（0.1mol）, add 16.0g bromines（0.1mol）, stir dissolved clarification.It is to slowly warm up to 45 ~ 55 DEG C, and stirring reaction 5h, middle control checks that reactant residue is more, continues reaction 1 hour, checks reactant residue still It is more.Stop reaction, system is added in 1L water, stir 1h, filter, filter cake is washed with water 3 times, dries, obtains Formula II Compound（R=Et）, it is gray solid 19.8g, purity 85%.
1.4 according to 1.1 method, take 500ml three-necked flask, add 100ml glacial acetic acid, then add 2- second Acyl group -4- methyl formate thiazoles 18.5g（0.1mol）, add 16.0g bromines（0.1mol）, the hydrogen bromide solutions of 20ml 30%, Stir dissolved clarification.45 ~ 55 DEG C are to slowly warm up to, and stirring reaction 5h, middle control check that reaction finishes substantially.Stop reaction, by system It is added in 1L water, stirs 1h, filter, filter cake is washed with water 3 times, dries, obtains Formula II compound（R=Me）, it is gray solid 23.1g, purity 96%.
1.5 according to 1.1 method, take 500ml three-necked flask, add 100ml chloroforms, then add 2- acetyl Base -4- Ethyl formate thiazoles 19.9g（0.1mol）, add the BPO of catalytic amount（Dibenzoyl peroxide）, control temperature 45 ~ 55 DEG C, NBS 35.6g are added portionwise（0.2mol）, finish insulation reaction 2h.System is added in 500ml water, liquid separation, extracted Take, wash, dry precipitation, obtain Formula II compound（R=Et）, it is gray solid 23.9g, purity 97%.
Embodiment 2
Compound III synthesis
2.1 take 500ml three-necked flask, add 100ml toluene, then add compound II（R=Et）22.2g （0.08mol）, 21.0g is added while stirring（0.08mol）Triphenyl phosphorus, 80 ~ 85 DEG C are warming up to, insulation reaction 8h.Then cross Filter, filter cake washs with 50ml toluene, dry 40.6g.
Gained solid is added in 350ml water, stirred, it is 8 ~ 9 stirring 30 minutes to adjust pH with 1N sodium hydroxide solutions, is taken out Filter.Filter cake is washed with water to neutrality.Dry IIIa（R=Et）Compound 32.8g, purity 98.9%.
2.2 according to 2.1 method, take 500ml three-necked flask, add 150ml isopropyl ethers, then add chemical combination Thing II（R=Et）30.5g（0.11mol）, 28.8g is added while stirring（0.11mol）Triphenyl phosphorus, 80 ~ 85 DEG C are warming up to, protected Temperature reaction 12h.Then filter, filter cake is washed with 50ml isopropyl ethers, dry 55.5g.
Gained solid is added in 350ml water, stirred, it is 8 ~ 9 stirring 30 minutes to adjust pH with 1N sodium hydroxide solutions, is taken out Filter.Filter cake is washed with water to neutrality.It is dry must be dry IIIa（R=Et）Compound 44.3g, purity 98%.
2.3 according to 2.1 method, take 500ml three-necked flask, add 100ml toluene, then add compound II（R=Et）22.2g（0.08mol）, 9.9g is added while stirring（0.08mol）Trimethyl phosphite, 80 ~ 85 DEG C are warming up to, protected Temperature reaction 8h.Then filter, filter cake is washed with 50ml toluene, dry 24.6g.
Gained solid is added in 350ml water, stirred, it is 8 ~ 9 stirring 30 minutes to adjust pH with 1N sodium hydroxide solutions, is taken out Filter.Filter cake is washed with water to neutrality.Dry IIIb（R1=Me, R=Et）Compound 17.1g, purity 86%.
2.4 according to 2.1 method, take 500ml three-necked flask, add 100ml toluene, then add compound II （R=Et）22.2g（0.08mol）, 13.3g is added while stirring（0.08mol）Triethyl phosphite, 80 ~ 85 DEG C are warming up to, protected Temperature reaction 8h.Then filter, filter cake is washed with 50ml toluene, dry 28.0g.
Gained solid is added in 350ml water, stirred, it is 8 ~ 9 stirring 30 minutes to adjust pH with 1N sodium hydroxide solutions, is taken out Filter.Filter cake is washed with water to neutrality.Dry IIIb（R1=Et, R=Et）Compound 19.1g, purity 90%.
Embodiment 3
Compound I synthesis
3.1 take 500ml three-necked flask, add 25ml chloroforms, then add compound IIIa（R=Et）4.6 g （0.01nol）, stirring and dissolving, add 3.9g isobutylaldehydes, 60 ~ 70 DEG C of reaction 45h of stirring heating.After depressurizing precipitation, with positive heptan Alkane is refining to obtain 2.4g white solids, purity 99%.
3.2 according to 3.1 method, take 500ml three-necked flask, add 25ml chloroforms, then add compound IIIb（R1=Me, R=Et）3.1g（0.01nol）, stirring and dissolving, add 3.9g isobutylaldehydes, 60 ~ 70 DEG C of reactions of stirring heating 45h, after depressurizing precipitation, 1.9g white solids, purity 90% are refining to obtain with normal heptane.
3.3 according to 3.1 method, take 500ml three-necked flask, add 25ml chloroforms, then add compound IIIb（R1=Et, R=Et）3.4g（0.01nol）, stirring and dissolving, add 3.9g isobutylaldehydes, 60 ~ 70 DEG C of reactions of stirring heating 45h, after depressurizing precipitation, 2.0g white solids, purity 91% are refining to obtain with normal heptane.
Finally illustrate, the above embodiments are merely illustrative of the technical solutions of the present invention and it is unrestricted, although with reference to compared with The present invention is described in detail good embodiment, it will be understood by those within the art that, can be to the skill of the present invention Art scheme is modified or equivalent substitution, and without departing from the objective and scope of technical solution of the present invention, it all should cover at this Among the right of invention.

Claims (13)

1. a kind of compound of formula III, structure as shown in IIIa or IIIb,
Wherein, R and R1 is respectively C1-C6 alkyl, be can be the same or different.
2. the formula III compound of claim 1, itself specifically,
。
3. a kind of preparation method of claim 1 formula of III compounds, it is characterised in that by Formula II compound and triphenylphosphine Reaction, is prepared IIIa compounds, or be prepared by Formula II compound and Trimethyl phosphite or triethyl phosphite IIIb compounds,
Wherein, R is C1-C6 alkyl, and X is halogen atom.
4. according to the method described in claim 3, formula III compounds, reaction dissolvent is toluene, ethanol, chloroform, isopropyl Ether, DMF.
5. according to the method described in claim 3, formula III compounds, temperature needed for reaction is 70-90 DEG C.
6. according to the method described in claim 3, a kind of preparation method of formula III compound, in addition to Formula II compound Prepare, be raw material by RM (2- acetyl group -4- formic acid esters thiazole), by halogenating reaction, be prepared,
Wherein, R is C1-C6 alkyl.
7. according to the method described in claim 6, in the preparation of Formula II compound, halogenating agent NBS, Br2、Br2In/HBr One or more.
8. according to the method described in claim 7, halogenating agent is preferably Br2/ HBr mix reagent.
9. according to the method described in claim 6, in the preparation of Formula II compound, solvent for use is glacial acetic acid, ethanol, chlorine It is imitative.
10. according to the method described in claim 6, in the preparation of Formula II compound, temperature needed for reaction is preferably 45-55 ℃。
11. a kind of preparation method of compound of formula I, usage right requires 1 formula of III compounds and isobutyl aldehyde reaction,
Wherein, R is C1-C6 alkyl.
12. according to the method described in claim 11, compound of formula I is prepared, reaction dissolvent is chloroform, ethanol, isopropyl ether, chlorine It is imitative.
13. according to the method described in claim 11, compound of formula I is prepared, temperature needed for reaction is 60-70 DEG C.
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Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE10008089A1 (en) * 2000-02-22 2001-10-31 Biotechnolog Forschung Gmbh Production of tubulysin compounds comprises multi-stage process including condensation of N-methylpipecolinoyl-isoleucine with substituted thiazole-4-carboxylic acid derivative
WO2008138561A1 (en) * 2007-05-10 2008-11-20 R & D Biopharmaceuticals Gmbh Tubulysine derivatives
US20110200581A1 (en) * 2009-07-22 2011-08-18 KEMOTECH S.r.I Pharmaceutical compositions

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE10008089A1 (en) * 2000-02-22 2001-10-31 Biotechnolog Forschung Gmbh Production of tubulysin compounds comprises multi-stage process including condensation of N-methylpipecolinoyl-isoleucine with substituted thiazole-4-carboxylic acid derivative
WO2008138561A1 (en) * 2007-05-10 2008-11-20 R & D Biopharmaceuticals Gmbh Tubulysine derivatives
US20110200581A1 (en) * 2009-07-22 2011-08-18 KEMOTECH S.r.I Pharmaceutical compositions

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
DONDONI, ALESSANDRO ET AL.: "Installation of the Pyruvate Unit in Glycidic Aldehydes via a Wittig Olefination-Michael Addition Sequence Utilizing a Thiazole-Armed Carbonyl Ylide. A New Stereoselective Route to 3-Deoxy-2-Ulosonic Acids and the Total Synthesis of DAH, KDN, and 4-epi", 《 JOURNAL OF THE AMERICAN CHEMICAL SOCIETY》 *

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