CN101230040A - Process for preparing 17-allyl amino geldanamycin (17-AAG) and other ansamycins - Google Patents
Process for preparing 17-allyl amino geldanamycin (17-AAG) and other ansamycins Download PDFInfo
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Abstract
Efficient chemical processes for preparing high yields, purities, and different polymorphic forms of 17-allyl amino geldanamycin (17-AAG) and other ansamycins are described and claimed.
Description
The application is that the name of submitting on September 18th, 2002 is called dividing an application of " method that is used to prepare 17-allyl amino geldanamycin mycin (17-AAG) and other ansamycins " No. 02818718.0 application for a patent for invention.
Related application
The U.S. Provisional Application the 60/331st that the application requires Zhang etc. to submit to September 21 calendar year 2001, the U.S. Provisional Application the 60/326th that submit to September 24 calendar year 2001 such as No. 893 and Zhang, No. 639 right of priority, the title of these two pieces of applications is " method that is used to prepare 17-allyl amino geldanamycin mycin (17-AAG) and other ansamycins ", and it full content that comprises all figures and chart is hereby expressly incorporated by reference.
Technical field
The present invention relates to chemical preparation process is applied to the preparation of ansamycins compound, this compound is as microbiotic and very useful aspect treatment such as the various proliferative disease such as cancer.
Background technology
Comprise that those are for the helpful information of understanding meeting of the present invention in below describing.This is not that approval is a prior art or relevant with the present invention of applying in this any information that provides, and perhaps the public publication clear and definite or hint of its institute's reference is a prior art.
17-allyl amino-geldanamycin (17-AAG) is the synthetic analogues of geldanamycin (GDM).These two kinds of molecules all belong to sensu lato antibiotic molecule, are called ansamycins (ansamycins).As the GDM that at first separates from microorganism streptomyces hygroscopicus element (Streptomyceshygroscopicus), being confirmed as at first is some kinase whose effective inhibitor, showed afterwards that they played a part to promote the kinases degraded, specially with target directing " molecular chaperoning (molecular chaperones) ", for example, heat shock protein 90s (HSP90s).Afterwards, various other ansamycinss also demonstrated activity more or less, and wherein 17-AAG is hopeful most, the concentrated clinical study of just implementing by national cancer association (NCI) at present with it as research object.Referring to Federal Register, 66 (129); 35443-35444; Erlichman et al.Proc.AACR (2001), 42, abstract 4474.
HSP90s is ubiquitous chaperonins matter, and it relates to folding, activate and combination of relative broad range internal protein, and it also comprises key protein matter such as relating to signal transduction, cell cycle control and transcriptional regulatory.Personnel report according to the study, HSP90 chaperonins matter is relevant with important signal-proteins, and such as steroid hormone receptor and protein kinase, (Buchner J.1999 to comprise Raf-1, EGFR, v-Src family kinases, Cdk4 and ErbB-2, TIBS, 24:136-141; Stepanova, L.et al.1996, Genes Dev.10:1491-502; Dai, K.et al.19 96, J.Biol.Chem.271:22030-4).Research further shows some associating chaperonins, for example, Hsp70, p60/Hop/Stil, Hip, Bag1, HSP40/Hdj2/Hsj1, immunophilins, p23 and p50 can help the performance of HSP90 function (referring to Caplan, A.1999, Trends in Cell Biol.9:262-68).
It is believed that the ansamycins microbiotic, for example, Antibiotic TAN 420F (HA), geldanamycin (GM) and 17-AAG can by with the terminal bag of the N-of HSP90 combine closely produce anticancer effect (Stebbins, C.et al.1997, Cell, 89:239-250).This bag (pocket capsule) is by being preserved to heavens, and and the ATP combining site of dna gyrase between more weak homology (Stebbins, C.et al.supra are arranged; Grenert, J.P.et al.1997, J.Biol.Chem.272:23843-50).In addition, had the result to show that ATP and ADP all combine with this bag with more weak avidity, the two all has weak atpase activity (Proromou, C.et al.1997, Cell, 90:65-75 simultaneously; Panaretou, B.et al.1998, EMBO are J.17:4829-36).Studies show that in vitro and in vivo because the terminal bag of N-is occupied by ansamycins and other HSP90 inhibitor, therefore changed the function of HSP90 and suppressed Protein Folding.Show simultaneously that under high density ansamycins and other HSP90 inhibitor can stop (Scheibel, T.H.et al.1999, the Proc.Natl.Acad.Sci.USA 96:1297-302 of combining of protein substrate and HSP90; Schulte, T.W.etal.1995, J.Biol.Chem.270:24585-8; Whitesell, L.et al.1994, Proc.Natl.Acad.Sci.USA 91:8324-8328).Shown also simultaneously that ansamycins can suppress to accompany release (Schneider, C.L.et al.1996, Proc.Natl.Acad.Sci.USA, the 93:14536-41 of the ATP dependence material in the related protein substrate; Sepp-Lorenzino, et al.1995, J.Biol.Chem.270:16580-16587).Which kind of situation no matter, substrate is all existed in the proteolytic enzyme a kind of generally independently process degraded (Schneider, C.L.supra; Sepp-Lorenzino, L.et al.1995, J.Biol.Chem.270:16580-16587; Whitesell, L.et al.1994, Proc.Natl.Acad.Sci.USA, 91:8324-8328).
The unstable of this substrate usually occurs in the analogues such as knurl and non-transitional cell, it is simultaneously verified that it is effective especially to following material, it is the subgroup (subset) of Signal Regulation thing, for example, Raf (Schulte, T.W.et al.1997, Biochem.Biophys.Res.Commun.239:655-9; Schulte, T.W.et al.1995, J.Biol.Chem.270:24585-8), karyon steroid receptors (nuclear steroid receptors) (Segnitz, B. and U.Gehring.1997, J.Biol.Chem.272:18694-18701; Smith, D.F.et al.1995, Mol.Cell.Biol.15:6804-12), v-src (Whitesell, L.etal.1994, Proc.Natl.Acad.Sci.USA 91:8324-8328) and some transmembrane Tyrosylprotein kinase (Sepp-Lorenzino, L.et al.1995, J.Biol.Chem.270:16580-16587), EGF acceptor (EGFR) and Her2/Neu (Hartmann, F.et al.1997, Int.J.Cancer 70:221-9 for example; Miller, P.et al.1994, CancerRes.54:2724-2730; Mimnaugh, E.G.et al.1996, J.Biol.Chem.271:22796-801; Schnur, R.et al.1995, J.Med.Chem.38:3806-3812), CDK4 and mutant p53.Erlichman et al.Proc.AACR(2001)，42，abstract4474。These are proteinic induces the ansamycins loss to cause some to regulate path to suffer selective destruction, and cause at the particular stage of cell cycle and stagnate growth (Muise-Heimericks, R.C.et al.1998, J.Biol.Chem.273:29864-72), and apoptosis and/or cause being treated the differentiation (Vasilevskaya of cell, A, et al.1999, Cancer Res.59:3935-40).
Therefore, the ansamycins utmost point is hopeful to be used for the treatment of and/or prevents polytype cancer and proliferative disorders.But, the whole bag of tricks of present known preparation ansamycins shows following one or more problems, promptly low yield, low-purity, unstable, the environmental toxicity relevant with the use of halogenation organic solvent and extra attendant expense are as time, spending, waste treatment with take the patient's of this medicine health risk etc.Comprise the United States Patent (USP) the 4th that transfers Kaken Chemical Co.Ltd.Sasaki etc. in the example of currently known methods, 261, No. 989, this patent is reported the synthetic of various ansamycins derivatives, comprising using various organic solvents and single abstraction technique synthesize 17-AAG, also comprise the United States Patent (USP) the 5th, 932 that transfers Pfizer Inc.Schnur etc. in the while example, No. 566 and PCT/IB94/00160 (WO95/01342) have similar methods to describe in this patent.
The objective of the invention is to improve the one or more defectives that exist in the prior art, for example, improve following one or more problem, promptly, low yield, low-purity, unstable, the environmental toxicity relevant with the use of halogenation organic solvent and extra attendant expense are as time, spending, waste treatment and health risk etc.
Summary of the invention
Creativeness of the present invention is embodied in the following aspects.At first, the invention is characterized in by making of volatility aprotic solvent and volatility protonic solvent and be used for effectively preparing the chemical process of ansamycins.The same with other preparation method, this method is for by 4 of benzoquinones geldanamycin (GDM) preparation such as 17-AAG or it, and benzoquinones geldanamycin derivants such as 5-dihydro analogue are useful.In the latter's a embodiment, 4,5-dihydro geldanamycin or geldanamycin (or have other benzoquinones geldanamycin of reactive moieties, as having methoxyl group on the benzoquinones) generate a kind of crude product with nucleophile material chemical combination in volatility aprotic solvent (such as the component of from Table II, selecting), this product of evaporation concentration, and in the product that generates, add the volatility protonic solvent, the purpose that adds solvent be used for washing or make the ansamycins product under suitable condition from the solution crystallization or be precipitated out.Which kind of situation no matter, can by adopt such as filter, methods such as centrifugal, decantation and/or evaporation remove this solvent of two types easily.According to the difference of specific embodiment, its advantage includes but not limited to purify the raising of minimizing, yield and/or purity of inspection and the use that can accept reagent clinically.
Below be an example reaction equation in the embodiment of the invention:
R wherein
1And R
2Perhaps be hydrogen, in the case, the key between C4 and the C5 is singly-bound, perhaps R
1And R
2All do not exist, in the case, the key between C4 and the C5 is two keys.Dotted line between C4 and the C5 represents that two kinds may all exist.Nu-H is a nucleophile, between the reaction period with the R on the position of substitution 17
3The O group.Preferred R
3Be 1-4 carbon atom, preferred methoxyl group.Be reflected in the volatility aprotic solvent and carry out, solvent is chosen from following solvents, and promptly THF, ether, MTBE, THP, diox, ethyl sec-butyl ether, methyl butyl ether, ethyl acetate or methyl acetate finally generate a kind of commutable crude product.The non-halogenated solvent of preferred employing.In some embodiments, nucleophile adds at leisure to be intended in the substituted benzoquinones geldanamycin derivant, thereby generates singly to be substituted by main product.For the monitoring of this step, also can be by using such as TLC, HPLC isochromatic spectrum technology, or known other step in the prior art, for example, methods such as spectrophotometry, NMR are measured the performance level of reaction.This technology also can be used in the following technology subsequent step.In a preferred embodiment, make reaction continue to carry out till thoroughly finishing, thereby make whole benzoquinones ansamycins reactants be changed into corresponding derivative fully.
Below be about in the volatility aprotic solvent preparation thick substitution product description, product after evaporation concentration, in such as volatility protonic solvents such as Virahol, ethanol and/or water slurry (slurried) or the dissolving.Term " slurry " is meant solid suspension in liquid as mentioned herein, and wherein solid such as ansamycins are insoluble slightly.In the case, " washing " may come into force, and be especially more like this when impurity solubleness is bigger than solid solubility.Following examples 1 have certain illustrative.Alternative washing or the step relevant with washing are crystallisation steps, as the enforcement among the following embodiment 2.
Each volatility aprotic solvent and protonic solvent can by adopt evaporation or evaporation with centrifugal, heat and/or vacuumize method such as combine and remove easily.As what these those skilled in the art knew from experience, as long as pressure reduces (gas clean-up) and just can adopt lower temperature.Can heat individually in some embodiments or drying under normal room temperature.Also can adopt the one or many filtration step, thereby use volatility protonic solvent washing and filtering material to reduce the content of impurity easily.
In some embodiments, used nucleophile is selected from the group of being made up of amine, thio-alcohol, thiolate, thioether, alcohols and alkoxide, each formation, have or can after modification, have one or more functional groups, functional group is added extra chemical ingredients subsequently, and for example the benzoquinones ansamycins of Sheng Chenging is restricted to another kind of structure.In some preferred embodiment, nucleophile has the primary amine or the secondary amine of following structure:
R wherein
4And R
5Represent hydrogen, (C independently
1-C
12) alkyl the or by (C of optional replacements such as allyl group, propargyl, hydroxyl, amino, sulfydryl, carboxylate salt or halogenation functional group
1-C
12) alkyl.Generally speaking, operable amine is too numerous to mention, wherein also comprises the listed amine of Table I in No. the 4th, 261,989, the United States Patent (USP) of Sasaki.It will be appreciated that simultaneously, can also add other functional group such as alkene.For example, in some embodiments, preparation 17-AAG or 4, the employed nucleophile of 5-dihydro analogue is an allyl amine.Operable other useful nucleophile includes but not limited to describe in detail those nucleophiles that part occurs.
Among some embodiment, stop or reduce the photochemical degradation of product and/or reactant by use the method that weakens illumination in one or more steps of method, this is useful.Even in the end the time, final product is left in the fast light container, thereby keep or help the stability and the storage life of product.
An aspect of preceding method of the present invention it is characterized in that described embodiment can be combined to be applied, and these embodiment is consistent with each other.From the wider aspect of processing method, the invention is characterized in the method for concentrated and/or purification ansamycins.This method is utilized the volatility aprotic solvent, and preferred non-halogenated solvent then evaporates, washs or crystallization with the volatility protonic solvent that uses among following embodiment 1 and the embodiment 2 as solvent.Another aspect of the present invention is characterized in that product can be made by this method, and every kind of product can be prepared according to aforesaid arbitrary embodiment.
On the other hand, the invention is characterized in the method for preparing 17-AAG, comprising: the 17-AAG that is dissolved in the protonic solvent solution provided, crystallization 17-AAG from described protonic solvent solution, described protonic solvent solution is not moisture substantially, and removes this protonic solvent solution.That term " preparation " is meant is concentrated, purify or existing 17-AAG polymorphic form is changed into the 17-AAG of another kind of form.When " comprising " followed by the transition speech behind this term, it is meant the subsequent step that also comprises other, as is dissolved in the solution, generates a kind of prescription or the like.Term " removes " and not necessarily just means thoroughly and remove, but preferably removes substantially, thereby makes after this step is finished, be retained based on the product of solid 17-AAG, and the solvent of remaining minute quantity only.In one embodiment, this protonic solvent is a Virahol, removes the 17-AAG after Virahol and the crystallization, and its fusing point is about 146 ℃ to 153 ℃, perhaps is about 155 ℃ or be lower than 155 ℃.The aspect of being correlated with but being not quite similar makes that the fusing point of formed polymorphic form 17-AAG is higher, and preferred fusing point is in about scope more than 200 ℃ or 200 ℃.In some preferred embodiment, fusing point is about 206-212 ℃, and the acquisition of this fusing point can be realized that as ethanol, wherein protonic solvent solution possibility is moisture may be not moisture yet by crystallization in protonic solvent solution.The application personnel have observed the moisture final melting temperature that can improve the 17-AAG polymorphic form that is generated usually in the solvent.By the also requirement of compound that preceding method makes, finally can sneak into also and can not sneak into other one or more reagent.Alternatively, said composition is left in the fast light container to stop, to reduce or to suppress the generation of degraded.Can expect that other lipophilic compound can the same polymorphic form that produces different melting points.The feature of these polymorphic forms maybe might produce and be characterised in that it has different effectiveness, and for example, the fusing point of the compound that forms is low more, easy more dissolving and preparation, and the fusing point of the compound that forms is high more, and then stability can be lasting more.
On the other hand, the invention is characterized in the first polymorphic form ansamycins is changed into the second polymorphic form ansamycins that wherein being included in is enough to generate under the condition of the second polymorphic form ansamycins, and the first polymorphic form ansamycins is dissolved in the protonic solvent solution.The material of high-melting-point type can be converted to the material of low melting point type, and vice versa.Preferably, ansamycins is 17-AAG, but can expect that this technology can produce the effectiveness the same with other lipophilic compound, this point from embodiment 1 to 5 as can be seen.Relevant this potential embodiment on the one hand can obtain with reference to the feature of aforementioned related embodiment.
Different according to accurate content and specific embodiment, implement the present invention and can bring following one or more advantage, be the minimizing of high yield, high purity, stability, minimizing to environment and patient's toxicity and extra attendant expense, as the time, pay wages, be easy to configuration, refuse is deposited and processing etc.Other advantage, embodiment content and embodiment can be apparent from following data, detailed description and claim.
Description of drawings
Fig. 1 is the HPLC color atlas (Current Chromatogram (s)) of the 17-allyl amino geldanamycin mycin that makes, wherein use Zorbax 300 SB-C8 (250cm * 4.6mm, 5 μ) chromatographic column, moving phase: acetonitrile (0.05%TFA): water (0.05%TFA); 30: 70; Flow velocity: detecting at the 254nm place is 1mL/min (ml/min); The retention time at peak value place is 16.49 minutes.
Fig. 2 is
1H NMR (400MHz, CDCl
3) spectrogram.Chemical shift and diversity are consistent with the generation of required product.
Embodiment
The present invention relates to be used to prepare ansamycins, as the benzoquinones ansamycins, and derivative, as 4 of 17-AAG and it, the improving one's methods of 5-dihydro analogue.This method can also be avoided preparing relevant time consumption that causes and expensive work such as inspection processing with extraction and chromatographic separation when obtaining better purity and yield.
In some aspects with embodiment in, used technology comprises: under reactant and product can both the dissolved conditions, nucleophile was attacked one or more volatility aprotic solvent, for example, ether or acetate, preferred non-halide.Then, with the product evaporation concentration that generates, add the volatility protonic solvent in enriched product, as volatile alcohol and/or water, wherein the volatility protonic solvent plays cleaning function or takes on (again) crystalline medium.The carrying out that filter, centrifugal, decantation and/or evaporation all helps each step.The product that generates can be used as the effectiveness relevant with ansamycins directly or indirectly, for example as microbiotic or carcinostatic agent.With regard to indirect utility, product also is useful, for example as ansamycins derivative synthetic intermediate, as giving Schnur etc. and transferring the United States Patent (USP) the 5th of Pfizer Inc, disclosed in 932, No. 566 and the PCT/IB94/00160 (WO95/01342).
Before the present invention, DMF, DMSO, CH
2Cl
2, and CHCl
3All be to prepare ansamycins and finish substitution reaction and the alternative medium of nucleophilic addition.The application need of such reagent and method relates to bothersome inspection (work-ups) work of treatment and repeatedly washing and EtOAc extraction.In the epoch of current climate controlled, especially do not encourage to use chlorated solvent.Chlorated solvent is harmful to environment, and the existence of its residuals constitutes potential to HUMAN HEALTH and threatens.In addition, the applicant has been found that this kind solvent can impel product degradation, thereby injures degree of purity of production and yield.Method of the present invention is more direct, and the product of generation has higher yield and purity usually, and the while has also been avoided or farthest reduced consequent environment and health problem, therefore can be advantageously applied to suitability for industrialized production.
The term that uses in the claim " alternatively " is meant and can carries out the step behind this term and then but might not implement.
Term " removes " and " concentrating " not necessarily means 100% ground except that desolvating, and can allow removing or concentrating of less per-cent.
Term " non-halogenated " is meant and do not contain one or more halogen atoms, for example F, Cl, Br and I.Have certain illustrative halogenated solvent and comprise CHCl
3(chloroform).
" washing " expression protonic solvent insoluble slightly ansamycins under the condition that is adopted.Washing may comprise the generation of mixed solution, and, in any case, to removing impurity certain effect is arranged.
" volatility aprotic solvent " is meant the solvent of boiling point between about 35 ℃ to 102 ℃.Shown in the preferred following Table III of aprotic solvent.Aprotic solvent is considered to " non-structured ", that is to say, under pure liquid state, lacks the hydrogen bond network of extension.But, some aprotic solvent have the ability dissolving and stable compound, or dissolve and self make it protonated, for example, alcohol or water itself.Water and THF are miscible.Generally speaking, the self-decomposition of aprotic solvent shortage becomes the ionic ability under conventional environment.
" volatility protonic solvent " comprises Virahol, ethanol, water and their mixture thereof.Water is traditional protonic solvent.Liquid phase water is characterised in that it has the hydrogen bond network of extension.In liquid phase, each is water molecules and adjacent 4 hydrogen bonds of water molecules formation independently.The hydrogen bond network of destroying this extension need provide lot of energy, and the cost of this energy is reflected in low-molecular weight compound to be had on the high relatively boiling point (100 ℃).Alcohols, especially low-molecular-weight alcohols (alcohol that is less than 12 carbon atoms) demonstrates and characteristic like the water.A hydrogen bond network is set up under liquid state.But, by the hydrogen bond network that alkanol molecule is set up, its hydrogen bond number and water different: only produce 3 hydrogen bonds between the alcoholic solvent molecule, and 4 such keys are arranged between the liquid water molecules usually.This just makes to have bigger " looseness " between the alcoholic solvent molecule, means that it has lower boiling point and condensing temperature with respect to glassware for drinking water.One of physical properties of water/alcohol mixture is to form azeotropic mixture.Alcohol is added to the water causes the reduction of water boiling point.The ethanol that following table has been illustrated Xiang Shuizhong adding 10% will generate the solvent of a kind of volatility greater than water itself.
Table I
| Wt% ethanol | Zero pour (℃) | Boiling point (℃) |
| 0 10 20 40 50 60 70 80 90 92.4 95.57 100 | 0 -4.5 -10.7 -27.0 -37.0 45.0 53.0 64.5 -109 -123 -119.3 -114.5 | 100 91.45 87.15 83.1 81.90 81.0 80.20 79.35 78.5 78.24 78.15 78.3 |
Table I further shows the mixture of being formed based on ethanol, and 95% ethanol and 5% water seethe with excitement under the temperature identical with straight alcohol according to appointment.Therefore based on this reason, in fact can not obtain straight alcohol by the distillation of water/alcohol mixture, this is the known fact in distillation technique field.Another characteristics of protonic solvent are that to a certain degree self-ionization can take place for they.For example, be dissociated into the ion of oppositely charged according to following equation water:
2H
2OH
3O
++
-OH
The dissociation degree of pure water own is very little, but can record, and this is a well known fact, i.e. pure water [H under 25 ℃
3O
+]=10
-7(or pH value is 7).
" non-oxygenated environment " be not meant can not or reality oxidation does not take place, just the simple explanation possibility that this thing happens reduces.The application that such example includes but not limited to reduce illumination and/or reduces gaseous oxygen.If air or oxygen is replaced by nitrogen and/or argon gas, then belong to latter event.
Ansamycins and benzoquinones ansamycins
Term " ansamycins " is well-known in the literature, and it has the structure of broad classification, it is characterized in that it is made of the cycloaliphatic ring of different lengths, the composition of bridging aromatic ring structure opposite end and their reduction equivalent thereof.Be included in the subclass-benzoquinones ansamycins that also have it of this width variety within not.Having illustrative kind comprises:
Geldanamycin (GM) 17-amino geldanamycin mycin (17-AG) 17-allyl amino geldanamycin mycin (17-AAG)
" benzoquinones ansamycins " has the benzoquinones composition as used herein, also comprises known benzoquinones ansamycins in this technical field simultaneously.It has the feature of nucleophilic addition(Adn) in some aspects, and preferably, the benzoquinones of molecule partly comprises an alkoxyl group, preferred methoxyl group, and simultaneously preferably, 17 position can be replaced by nucleophile.The result of reaction forms " benzoquinones ansamycins derivative ".According to the present invention, ansamycins and benzoquinones ansamycins can synthesize and make, and also can be spontaneous or the two bonded product, i.e. " semi-synthetic ".They also can be monomer or dimer.The illustrated examples of relevant dimer ansamycins include but not limited on April 7th, 2000 submit to and the international application patent PCT US00/09512 (WO 00/61578) of the Rosen that announces on October 19th, 2000 etc. in the dimer ansamycins mentioned.Other useful exemplary benzoquinones ansamycins and preparation method thereof includes but not limited to United States Patent (USP) the 3rd, 595 in the inventive method, No. 955 (having described the preparation of geldanamycin), the 4th, 261, No. 989, the 5th, 387, No. 584 and the 5th, 932, the content described in 566.Geldanamycin also can be in commercial acquisition, for example, can be from CN Biosciences, the Merck KGaA branch office of a tame German Darmstadt, general headquarters are located at San Diego, CA, USA (No. the 345805th, cat.) and obtain.About purifying 4 from streptomyces hygroscopicus substratum (ATCC 55256) mesophytization, the content of 5-dihydro geldanamycin and hydroquinone derivatives thereof, in transferring the patent that Pfizer Inc., international application be numbered PCT/US92/10189, have disclosed, this patent came forth as WO 93/14215 on July 22nd, 1993, and with classify as the inventor such as Cullen; Another is by adopting geldanamycin shortening preparation 4, and the synthetic method of 5-dihydro geldanamycin is also known by the people.Referring to Progress in the Chemistry of Organic Natural Products, Chemistry ofthe Ansamycin Antibiotics, 33 1976, p.278.
Nucleophile
There is the nucleophile of many types all to can be used for inventive method described herein at present.Preferably, the group that their optional free thio-alcohols, thiolate, thioether, alcohols and alkoxide are formed, has or has one or more functional groups at its each formation after modification, and functional group adds extra chemical ingredients, for example antibody subsequently.In some preferred embodiment, nucleophile is primary amine or the secondary amine with following structure:
R wherein
4And R
5Represent hydrogen, (C independently
1-C
12) alkyl the or by (C of optional replacements such as allyl group, propargyl, hydroxyl, amino, sulfydryl, carboxylate salt or halogenation functional group
1-C
12) alkyl.Generally speaking, operable amine is too numerous to mention, wherein also comprises the listed amine of Table I in No. the 4th, 261,989, the United States Patent (USP) that gives Sasaki.It will be appreciated that simultaneously, also can add other functional group such as alkene.For example, in some embodiments, preparation 17-AAG or 4, the employed nucleophile of 5-dihydro analogue is an allylamine.Allylamine and other nucleophile described herein all are commercially available, as obtaining from Sigma-Aldrich.Following table has been enumerated some preferred nucleophiles, and these nucleophiles can be used in different embodiments of the invention.
Table II
The volatility aprotic solvent
Table III has been listed the example to the useful volatility aprotic solvent of various embodiments of the invention.
Table III
More than tabulation just schematically, it will be recognized by those skilled in the art that other existing volatility aprotic solvent also can use.Because it is ether and acetate are polarity, non-proton medium, therefore particularly useful; The various organic compound of their solubilized have the character of water and hydrocarbon concurrently, have alkyl " part " simultaneously and have the Sauerstoffatom of lone electron pair.
Reaction vessel
Being suitable for reaction vessel of the present invention is the commercial glass reaction bottle that obtains, is equipped with the mat glass joint.When using such container, use magnetic force splash bar usually by teflon (teflon tetrafluoroethylene) or the coating of other inert material, for example, coating PTFE or other inertia coating.When the industry amplification was synthetic, many metal reaction containers sealed, and therefore itself is just fast light.Also can adopt mechanical stirring, wherein stir shaft and/or splash bar are inserted in the reaction vessel.In order to get rid of illumination, use simple dark room light to get final product.Alternatively, reaction flask and the reactive moieties with photochromics can be wrapped up with aluminium foil, perhaps adopt fast light container bottling of another kind well known in the prior art or packing.
Need can carry out in flask at the bottom of the garden of many bottlenecks the reaction that adding speed is controlled, flask is furnished with adding funnel (addition funnel).The simple funnel that adds is similar to separatory funnel, and outlet has the standard cone Y joint of protrusion, can realize that liquid reactants or solution are dropwise added, and wherein stopcock is used to control rate of addition.The stopcock that is used to add funnel is the teflon stopcock preferably, like this, just can avoid the use of stopcock lubricating grease, in order to avoid it immerses in organic solvent needed product is polluted.
Many small-sized reactions adopt syringes to add liquid, do convenient and easyly like this, and it is precisely controlled that it can make time per unit add the amount of reactant.But the well-known another kind of method that adds liquid reactants is to use syringe pump in the document.Can certainly use governor impeller and miscellaneous equipment.
Reaction monitoring
Term in the claim " use chromatographic technique monitoring " is meant and is used for determining whether existing what of needed product and/or amount, perhaps, whether do not have what of reactant or unwanted product and/or amount.Method well known in the prior art has multiple, below wherein several discussion the just only.
TLC
Tlc (TLC) is a kind of of adsorption chromatography, and the thin layer sorbent material that wherein is loaded on the plane serves as stationary phase.The most frequently used sorbent material of TLC is silica gel and aluminum oxide.Diatomite and Mierocrystalline cellulose are least commonly used.Make capillary motion by solvent along the sorbent material thin layer and realize TLC stratographic wash-out or expansion (development).
The selection of TLC elutriant is depended on and is remained the avidity of analysis of compounds in sorbent material type and the sorbent material.TLC is for monitoring reaction process, detection reaction intermediate, analysis crude product or unknown mixture, thereby all many-sides such as the number of definite component and check purification efficiency are very useful.For colourless organic compound, can manifest compound on the sorbent material by many technology well known in the prior art.Yet the color of starting raw material and product is respectively macroscopic yellow and purple among the present invention.
HPLC
In high pressure liquid chromatography (HPLC), liquid phase relies on pressure bursts by stationary phase, thereby has improved the flow of elutriant by the sorbent material chromatographic column.Can use modernized industrial instrument detecting solvent mixture and solvent gradient.Usually adopt the variable wavelength Ultraviolet Detector that starting raw material and product are carried out optimum detection, and pass through the suitable calibration of signal, use commercially available software and detect the raw material consumption quantitatively.
Solvent removal
Product in order needing to obtain from reaction mixture, extraction liquid, chromatographic component or (again) crystalline mother liquor usually is necessary concentrated solution or removes solvent up hill and dale.This process can be finished by simple distillation or fractionation under normal pressure or the decompression.Sometimes, adopt air distillation to remove most solvent, the residue a small amount of solvent under reduced pressure removes.In any case but, must need consider the stability and the volatility of product, that is to say to must be noted that and avoid decomposing because of the overheated product that causes.
Remove and the lyophylization of solvent can adopt present commercially available rotary evaporation equipment to realize.Other adoptable simple device is known to those skilled in the art.The method that removes solvent under higher vacuum, lesser temps also is well known to those skilled in the art.
Filter
Filtering is exactly the use of passing through the porous blocking layer, as strainer, insoluble solid is separated from liquid; Solid is retained on the strainer liquid by strainer.Rely on gravity (gravity filtration) and/or use suction (suction strainer) to make liquid be passed through strainer.Filtration step is used for settled solution and/or collects solid.The most frequently used strainer is filter paper and sintered frit in the organic chemistry, and the two can both obtain from commercially available various sources, and this is familiar with for those skilled in the art.Suction strainer uses B ü chner, Hirsch or sintered frit usually.When suction strainer is operated, make liquid pressure be lower than strainer pressure by adopting vent fan or other vacuum extractor, force liquid to pass through strainer by normal atmosphere then.
(again) crystallization
Crystallization is exactly to deposit crystal from the melt of solution or given material.When crystal formation, congeneric elements tends to be attached to by on the molecular growing crystal of the same type, because have the formation that other molecule of molecular ratio of same structure more meets lattice.If crystallisation process is taking place near under the EQUILIBRIUM CONDITION, then molecule deposition will cause the raising of crystalline material purity to this proneness of the surface of being made up of congeneric elements.Therefore crystallisation process is a kind of important method of purification.Term " precipitation " widely is included in crystallization, and its implication is that the dissolved compound is ended dissolving, no matter whether " crystallization " all exists with the solid form outside solution effectively.Precipitation or crystallization can take place in the time that continues, for example from the several seconds to a few hours until a couple of days.This process also depends on the temperature shown in the following embodiment 2, also depends on the character of solvent for use and solute simultaneously, and solubility of substances has certain difference under the differing temps.Whether term " recrystallize " uses same solvent and adopts same condition, whether no matter also be enough to reach the polymorphic form that forms identical or different fusing point, the one or many crystallization has taken place compound no matter be meant.
In fact, the aspect that the present invention embodied just is that it can form and adopt different polymorphic form structures.The applicant has determined the possibility of synthetic multiple purer relatively form (polymorphic form) 17-AAG, some has about 147 to 153 ℃ of low relatively fusing points in the middle of them, for example, from pure basically Virahol, crystallize out, some has about 200-212 ℃ more high-melting-point, for example, from chemical combination crystallize out the ethanol of portion water.Water and ethanol can be pre-mixed, perhaps water be added in the ethanolic soln afterwards, wherein contain dissolved 17-AAG in this ethanolic soln.Compare with the 17-AAG of high-melting-point form, the fusing point of 17-AAG is low more, and easy more at room temperature being dissolved in all kinds of SOLVENTS and the oil uses the 17-AAG compounding pharmaceutical of low melting point form or pharmaceutical composition to have the potential advantage especially simultaneously.The benefit that the higher melt form is brought is to possess higher chemical stability under different conditions, promptly has the longer storage life under different storage-temps.The technician can adopt dissolving and crystalline method in suitable solvent simply according to the difference of final purpose, is easy to realize the conversion of a kind of polymorphic form to another kind of polymorphic form.Using 17-amino geldanamycin mycin (" 17-AG "; Referring to embodiment 5,6) process in also observe similar phenomena, this for other ansamycins, can obtain different polymorphic forms with regard to hinting us, simultaneously, may be also like this for other unrelated compounds.
Embodiment
Embodiment 1
Synthesizing of 17-allyl amino geldanamycin mycin (17-AAG)
45.0g (80.4mmol) geldanamycin is placed the dry flask of the 2L that the 1.45L dry THF is housed, and to wherein dropwise dripping 36.0mL (470mmol) allylamine, dropping is higher than 30 minutes, and wherein allylamine places the dry THF of 50mL.Reaction mixture in stirring at room 4 hours, is finished [(GDM: glassy yellow: Rf=0.40 until the reaction of TLC analysis revealed under nitrogen protection; (5%MeOH-95%CHCl
3); 17-AAG: purple: Rf=0.42 (5%MeOH-95%CHCl
3)].Rotary evaporation removes solvent, and crude product is at 25 ℃ of following and 420mL H
2O: EtOH (90: 10) mixes, filter then, and 45 ℃ dry 24 hours down, obtain 40.9g (66.4mmol) purple crystals 17-AAG (82.6% yield, HPLC monitoring 254nm place purity＞98%).MP 206-212℃。
1The result that H NMR and HPLC obtain with need the consistent of product.
Embodiment 2
17-AAG is crystallization in Virahol
The optional method of purifying is not crystallization in ethanol, but in 800mL 2-propyl alcohol (Virahol) in 80 ℃ or refluxing under crude product 17-AAG among (about 82.2 ℃) dissolving embodiment 1, be cooled to room temperature then.Filter, descended dry 24 hours at 45 ℃ then, obtain 44.6g (72.36mmol) purple crystals 17-AAG (90% yield, HPLC monitoring 254nm place purity＞99%).MP 147-153℃。
1The result that H NMR and HPLC obtain with need the consistent of product.
Embodiment 3
The washing with alcohol of the 17-AAG polymorphic form of embodiment 2
The optional method of purifying is the H at 400mL
2Product 17-AAG among O: the EtOH (90: 10) in 25 ℃ of mix embodiment 2 filters, and descends dry 24 hours at 45 ℃, obtains 42.4g (68.6mmol) purple crystals 17-AAG (95% yield, HPLC monitoring 254nm place purity＞99%).MP 147-153℃。
1The result that H NMR and HPLC obtain with need the consistent of product.
Embodiment 4
The conversion of polymorphic form: 17-AAG is recrystallize in ethanol
The optional method of purifying be in the EtOH of 300mL under refluxing (about 80 ℃) dissolving implement product 17-AAG in 2, add 1200mL water then and be cooled to room temperature.Solid collected by filtration was descended dry 24 hours at 45 ℃ then, obtained 41.0g (67mmol) purple crystals 17-AAG (93% yield, HPLC monitoring 254nm place purity＞99%).MP 206-212℃。
1The result that H NMR and HPLC obtain with need the consistent of product.
Embodiment 5
Synthesizing of 17-amino geldanamycin mycin (17-AG)
2.0g (3.57mmol) geldanamycin is placed the dry flask that the 40ml dry THF is housed, and flask is dried through flame.Under nitrogen protection to wherein adding 2.55ml (17.8mmol, methanol solution, ca 7N) ammoniacal liquor.Reaction mixture at room temperature stirred 24 hours, finished until the reaction of TLC analysis revealed.Rotary evaporation removes solvent, crude product is dissolved among the EtOH of 30mL and adds 120mL water to make its crystallization, obtains 1.8g (3.30mmol) red crystals 17-AG (HPLC monitoring purity is 99%).MP284-286℃。
1The result that H NMR and HPLC obtain with need the consistent of product.
Embodiment 6
17-AG is recrystallize in Virahol
Among the purification embodiment 5 optional method of 17-AG be with final product 17-AG in 80 ℃ or refluxing under (about 82.2 ℃) be dissolved in the pure basically 2-propyl alcohol (Virahol) of 30mL, be cooled to room temperature then.Filter, descended dry 24 hours at 45 ℃ then, obtain 1.5g (2.7mmol) purple crystals 17-AAG (76% yield, HPLC monitoring 254nm place purity＞99%).MP 267-271℃。
1The result that H NMR and HPLC obtain with need the consistent of product.
***
The foregoing description is not to be circumscribed, and they just embody certain representational example among all respects of the present invention and the embodiment.For these those skilled in the art of the present invention, has certain directiveness in these all data of quoting.Although the data that discloses does not have one piece to be considered to existing technology, every piece of data all is incorporated herein by reference fully independently like every piece of data at this all with same degree in the lump as a reference.
Those skilled in the art will realize the inherent characteristics that the present invention can reach above-described target, result, advantage well and comprise at an easy rate.Illustrate preferred embodiment with described method and composition, purpose is for example rather than to the restriction of covering scope of the present invention.Those skilled in the art can carry out some change and be used as other purposes it, as long as these are changed and other purposes is comprised in the defined scope of claims of the present invention.
Obviously, to those skilled in the art, under the situation that does not depart from spirit and scope of the invention, can carry out various replacements and change to the present invention.Therefore, the extra embodiment of this class is all in the scope of content of the present invention and following claims.
Under the situation that lacks a certain key element or a plurality of key elements, also may be implemented in this and describedly have illustrative the present invention, but unspecial herein its restriction or the limiting factor (s) of disclosing.For example, term " comprises ", " substantially by ... form " and " by ... form " wait transition to speak, each word all has different implications, and it is different aspect of the present invention for convenience of explanation and embodiment thereof that a word replaces the use of another word.The use of term and expression formula is described rather than is limited with it with term, the use of these terms and expression formula do not get rid of of the present invention and shown in equivalent feature or its partial content.One skilled in the art will recognize that simultaneously it is fully possible carrying out various changes in the scope of claim of the present invention.Therefore be appreciated that, though the present invention is clearly disclosed by preferred embodiment and optional feature, but those skilled in the art can carry out modifications and changes to disclosed notion, as long as these modifications and changes just should be considered in category of the present invention in of the present invention and the defined scope of claim.
In addition, feature of the present invention or its content are described according to Ma Kushi (Markush) group or other alternative group, therefore those skilled in the art will recognize that the present invention also can be described according to Ma Kushi (Markush) group or the independent component of other group or child group or other group of composition, compositions are left out individually.
Other embodiment all within the scope of the following claims.
Claims (44)
1. method for preparing ansamycins may further comprise the steps:
(a) provide ansamycins in the volatility aprotic solvent;
(b) by the described ansamycins of evaporation concentration;
(c) in the product of step (b), add the volatility protonic solvent; And
(d) remove described volatility protonic solvent under optimum conditions, the described ansamycins of purifying, described removing can adopt filtration step to finish.
2. method according to claim 1, wherein said volatility aprotic solvent is selected from one or more in the group of being made up of THF, ether, MTBE, THP, diox, ethyl sec-butyl ether, methyl butyl ether, ethyl acetate and methyl acetate, wherein said volatility protonic solvent comprise be selected from by volatility alcohols, water, and composition thereof one or more compositions in the group formed.
3. method according to claim 1, wherein said volatility protonic solvent is used for from the described ansamycins of solution crystallization.
4. method according to claim 1, wherein said volatility protonic solvent is used to wash described ansamycins.
5. method according to claim 1, wherein said volatility aprotic solvent comprises THF.
6. method according to claim 1 further comprises chromatographic technique, with monitoring reaction performance level and/or purity.
7. method according to claim 1, wherein step (b) and/or step (d) comprise using of heat, centrifugal, decantation and/or vacuum.
8. method according to claim 1 further is included in one or more steps of carrying out under the non-oxygenated environment in (a)-(d).
9. method according to claim 1, wherein said ansamycins are selected from by 17-AAG and 4, the group that 5-dihydro 17-AAG forms.
10. according to the described method of arbitrary claim among the claim 1-9, all be packaged in alternatively in the fast light container.
11. a method for preparing 17-AAG may further comprise the steps:
The 17-AAG that is dissolved in the protonic solvent solution is provided, and described protonic solvent solution is not moisture substantially;
The described 17-AAG of crystallization from described protonic solvent solution; And
Remove described protonic solvent solution.
12. method according to claim 11, wherein said protonic solvent is a Virahol, wherein removes described Virahol and process crystalline 17-AAG, and its fusing point is 146 ℃-153 ℃.
13. method according to claim 11, wherein said protonic solvent is a Virahol, wherein removes described Virahol and through crystalline 17-AAG, and its fusing point is about 155 ℃ or be lower than 155 ℃.
14. a composition that comprises 17-AAG is made by claim 12 or 13 described methods.
15. a composition that comprises 17-AAG is made by the described method of claim 11.
16. composition according to claim 14 is packaged in the fast light container alternatively.
17. composition according to claim 15 is packaged in the fast light container alternatively.
18. a method for preparing 17-AAG may further comprise the steps:
The 17-AAG that is dissolved in the protonic solvent solution is provided, and described protonic solvent solution contains portion water;
The described 17-AAG of crystallization from described protonic solvent solution; And
Remove described protonic solvent solution.
19. method according to claim 18 wherein removes described protonic solvent solution and through crystalline 17-AAG, its fusing point is higher than 200 ℃.
20. method according to claim 18 wherein removes described protonic solvent solution and through crystalline 17-AAG, its fusing point is 206 ℃-212 ℃.
21. according to claim 19 or 20 described methods, wherein said protonic solvent solution further comprises ethanol.
22. a composition that comprises 17-AAG is made by the described method of claim 21, described composition is packaged in the fast light container alternatively.
23. one kind changes into the method for the second ansamycins polymorphic form with the first ansamycins polymorphic form, being included in is enough to generate under the condition of the described second ansamycins polymorphic form, and the described first ansamycins polymorphic form is dissolved in the protonic solvent solution.
24. method according to claim 23, wherein said first polymorphic form, its fusing point is higher than the fusing point of described second polymorphic form.
25. method according to claim 23, wherein said first polymorphic form, its fusing point is lower than the fusing point of described second polymorphic form.
26. according to the described method of arbitrary claim among the claim 23-25, wherein said ansamycins is 17-AAG.
27. method according to claim 24, wherein said ansamycins are 17-AAG, described second polymorphic form is formed by water-free substantially aqueous isopropanol crystallization.
28. method according to claim 25, wherein said ansamycins are 17-AAG, described second polymorphic form is formed by aqueous ethanolic soln crystallization.
29. a composition comprises that fusing point is the 17-AAG of 147-153 ℃ of form.
30. composition according to claim 29, wherein said 17-AAG is a crystal form.
31. a composition comprises that fusing point is the 17-AG of 267-271 ℃ of form.
32. composition according to claim 31, wherein said 17-AG is a crystal form.
33. one kind changes into the method for another polymorphic form with a polymorphic form of crystalline compounds, may further comprise the steps:
(a) provide the first crystal form compound, the described first crystal form compound has first fusing point, and is made by first solvent crystallization;
(b) the described compound of crystallization once more in second solvent obtains second crystal form, and the described second crystal form compound has second fusing point different with described first fusing point.
34. method according to claim 33, wherein said first crystal form, its fusing point is higher than the fusing point of described second crystal form.
35. method according to claim 34, wherein said first crystal form, its fusing point is lower than the fusing point of described second crystal form.
36. according to the described method of arbitrary claim among the claim 33-35, wherein said compound is an ansamycins.
37. method according to claim 36, wherein said ansamycins is selected from the group of being made up of 17-AAG and 17-AG.
38. a composition that comprises 17-AAG, according to the described method preparation of arbitrary claim in the claim 1,11 or 18, described 17-AAG has the fusing point less than 212 ℃.
39. a composition that comprises 17-AAG, described 17-AAG has the fusing point less than 212 ℃.
40. according to the described composition of claim 39, wherein said 17-AAG has the fusing point less than 200 ℃.
41. a composition that comprises 17-AAG, described 17-AAG have the fusing point between about 146 ℃-155 ℃.
42. a composition that comprises 17-AAG, described 17-AAG have the fusing point between 146 ℃-155 ℃.
43. a composition that comprises 17-AAG, described 17-AAG have about 155 ℃ or less than 155 ℃ fusing point.
44. a composition of mainly being made up of 17-AAG, described composition has 147-153 ℃ fusing point and at least 99% purity level, and it records by HPLC and in the spectral absorption of 254nm place.
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US32663901P | 2001-09-24 | 2001-09-24 | |
| US60/326,639 | 2001-09-24 | ||
| US60/331,893 | 2001-11-21 |
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| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CNB028187180A Division CN100378079C (en) | 2001-09-24 | 2002-09-18 | Process for preparing 17-allyl amino geldanamycin (17-AAG) and other ansamycins |
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| CN101230040A true CN101230040A (en) | 2008-07-30 |
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