CN1934130A - Process for preparing macrocyclic dipeptides which are suitable for the treatment of hepatitis c viral infections - Google Patents
Process for preparing macrocyclic dipeptides which are suitable for the treatment of hepatitis c viral infections Download PDFInfo
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- CN1934130A CN1934130A CN 200580008361 CN200580008361A CN1934130A CN 1934130 A CN1934130 A CN 1934130A CN 200580008361 CN200580008361 CN 200580008361 CN 200580008361 A CN200580008361 A CN 200580008361A CN 1934130 A CN1934130 A CN 1934130A
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Abstract
Disclosed is a multi-step process for preparing a macrocyclic compound of the formula (I); wherein Q is a radical of the following formula (II); and the other variables are as defined herein. The compounds of formula (I) are potent active agents for the treatment of hepatitis C virus (HCV) infection.
Description
Background of invention
The interests of the U.S provisional application 60/578,123 that requires the U.S provisional application 60/553,317 of application on March 15th, 2004 in view of the above and applied on June 8th, 2004.
Technical field
The present invention relates to be used to prepare the method for the improvement of macrocylc compound, described big ring cyclocomplex can be used as and is used for the treatment of the medicine that hepatitis C virus (HCV) infects.
Background information
Macrocylc compound of following formula (I) and preparation method thereof is disclosed in: people such as Tsantrizos, U.S. patent No.6,608,027 B1 (Attorney Docket No.13/076-1-C1); People such as Llinas Brunet, U.S. application publication number No.2003/0224977 A1 (Attorney Docket No.13/092-1-C1); People such as Llinas Brunet, WO 2004/037855 (Attny Docket 13/117); People such as Llinas Brunet, U.S. applies for No.10/945, application on September 20th, 518,2004; (Attorney Docket No.13/124); People such as Brandenburg., WO 2004/092203 Attorney Docket 9/265); With people such as Samstag, U.S. application publication number No.2004/0248779 A1 (Attorney Docket1/1434):
Wherein Q is the substituting group of following formula:
The same definition herein of other variable.
The compound of formula (I) is disclosed in the above-mentioned patent documentation, and it is used as the active medicine that treatment hepatitis C virus (HCV) infects.The disclosed method that is used to prepare these compounds comprises many synthesis steps, and it can comprise the protection and the deprotection of some active group.The problem to be solved in the present invention provides that (technical scale) minimum step prepares the method for these compounds on a kind of employing technological standard, and has enough overall yields.
Summary of the invention
Be astoundingly, have been found that and in the presence of quinolone " Q " substituting group, can successfully carry out a kind of critical closed loop transposition " RCM " reactions steps, should may play part and interfere catalyst activity by " Q " substituting group.Find based on this, have been found that the compound of above-mentioned formula (I) can use a small amount of synthesis step to prepare if should synthetic be to use the general sequence of following step as described herein to carry out.
Step 1
Step 2
Step 3:
Step 4:
Step 5:
When A was shielded carboxyl (carboxylic acid group), A was the compound of the formula (I) of carboxyl to the compound that randomly makes formula (I) to obtain wherein through the deprotection condition;
And, when A is carboxyl in the formula that is obtaining (I) compound, exist suitable coupling agent for example when carbodiimide reagent, TBTU or HATU, randomly this compound and formula R
11ASO
2NH
2The sulphonamide coupling, obtain wherein A and be-C (O)-NH-SO
2R
11AFormula (I) compound.
Therefore, the present invention relates to use the rapid synthetic method of multistep of synthetic as described herein order preparation formula (I) compound; Relate to concrete each step in the rapid method of this multistep; With concrete each intermediate in the rapid method of this multistep.
Content of the present invention
The term that uses and the definition of idiom
According to disclosed content and context, this paper does not have the term of special definition should be endowed the implication that those of ordinary skills provide.Yet unless opposite explanation is arranged, the following term that uses in specification sheets has specified implication, and following idiom also has specified implication.
In group, base (radicals) or the group (moieties) of following definitions, before group, indicate the number of carbon atom usually, for example C
1-6Alkyl refers to have the groups or the base of 1 to 6 carbon atom.Usually, for the group that comprises two or more side chains, Ming Ming group is the attachment point of atomic group at last, and for example " sulfane base " refers to the monoradical of formula HS-Alk-.Unless explanation is hereinafter arranged in addition, suppose the routine definition and the conventional stationary atom valency of contrast term, be applicable to all structural formulas and group.
Term " C as used herein
1-6Alkyl "; no matter be independent or combine; refer to contain acyclic, the straight or branched alkyl substituent of 1 to 6 carbon atom; comprise for example methyl, ethyl, propyl group, butyl, hexyl, 1-methylethyl, 1-methyl-propyl, 2-methyl-propyl and 1, the 1-dimethyl ethyl with other substituting group.
Term " C as used herein
3-6Cycloalkyl ", no matter be independent or with other substituting group bonded, refer to contain the naphthenic substituent of 3 to 6 carbon atoms, comprise cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.
Term " saturated alkylidene chain " refers to by removing a hydrogen atom from each end of the aliphatic hydrocarbon of saturated straight or branched and deutero-divalent alkyl substituting group comprises as used herein, for example
-CH
2CH
2C(CH
3)
2CH
2CH
2-。
Term " C as used herein
1-6Alkoxyl group ", no matter be independent or with other substituting group bonded, refer to substituting group C
1-6Alkyl-O-, wherein alkyl as above defines, and comprises maximum 6 carbon atoms.Alkoxyl group comprises methoxyl group, oxyethyl group, propoxy-, 1-methyl ethoxy, butoxy and 1,1-dimethyl oxyethyl group.Last substituting group also is commonly referred to uncle-butoxy.
Term " C as used herein
3-6Cycloalkyloxy ", no matter be independent or with other substituting group bonded, refer to contain the substituting group C of 3 to 6 carbon atoms
3-6Cycloalkyl-O-.
Term " C as used herein
2-7Alkoxy-C
1-6Alkyl " refer to substituting group C
2-7Alkyl-O-C
1-6Alkyl, wherein alkyl contains 6 carbon atoms at the most for as defined above.
Term as defined herein " halogen " refers to halogenic substituent, is selected from bromine, chlorine, fluorine or iodine.
Term " haloalkyl " as used herein, no matter be independent or with other substituting group bonded, refer to have the alkyl substituent of acyclic, the straight or branched that one or more hydrogen are replaced by halogen, described halogen is selected from bromine, chlorine, fluorine or iodine.
Term " sulfane base (thioalkyl) " as used herein, no matter be independent or with other substituting group bonded, refer to comprise thiol group (HS) as substituent acyclic, straight or branched alkyl substituent.The example of sulfane base is rosickyite alcohol radical (thiopropyl), for example HS-CH
2CH
2CH
2-be an example of rosickyite alcohol radical.
Term " C as used herein
6Or C
10Aryl ", no matter be independent or with other substituting group bonded, the fragrant bicyclic system that refers to contain the fragrant monocycle system of 6 carbon atoms or contain 10 carbon atoms.For example aromatic base comprises the phenyl or naphthyl member ring systems.
Term " C as used herein
7-16Aralkyl ", no matter be independent or with other substituting group bonded, refer to be connected with the aryl as defined above of alkyl, wherein alkyl as above defines and comprises 1 to 6 carbon atom.Aralkyl comprises for example benzyl and butyl phenyl.
Term " Het " as used herein, no matter be independent or with other substituting group bonded, refer to that described heterocycle comprises carbon atom and 1 to 4 ring hetero atom that is selected from nitrogen, oxygen or sulphur by remove hydrogen atom and deutero-unit price substituting group from five yuan, hexa-atomic or seven yuan of saturated or unsaturated (comprising fragrant) heterocycles.Suitable heterocyclic example comprises: tetrahydrofuran (THF), thiophene, diaza , isoxazole, piperidines, diox, morpholine, pyrimidine or
Term " Het " also comprise with one or more other heterocycle or carbocyclic fused heterocycle as defined above, wherein each can be saturated or unsaturated.Such example comprises also [4,5-b]-pyridine of thiazole.Though term as defined herein " heteroaryl " is usually included in term " Het " scope, it also clearly defines the undersaturated heterocycle that wherein two keys form aromatic nucleus.The example of suitable heteroaryl system comprises: quinoline; Indoles; Pyridine;
Two key groups that term " oxo " refers to connect as substituting group (=O).
Two key groups that term " sulphur " refers to connect as substituting group (=S).
Usually, this paper comprises the tautomerism type of all chemical structures or compound and isomeric forms and composition thereof, no matter be single geometrical isomer or optical isomer or the racemization of isomer or non-racemic mixture, unless in compound title or structure, specialize specific stereochemistry or isomeric forms.
Term " pharmaceutically acceptable ester " as used herein, no matter be independent or with other substituting group bonded, refer to any carboxyl functional group in the molecule, preferably the ester of the formula I compound that replaces of carboxyl terminal alkoxy carbonyl functional group:
Wherein the R group of ester be selected from alkyl (for example methyl, ethyl, n-propyl, the tertiary butyl, just-butyl); Alkoxyalkyl (for example methoxymethyl); Alkoxyl group acyl group (for example acetoxy-methyl); Aralkyl (for example benzyl); Aryloxy alkyl (for example phenoxymethyl); Aryl (for example phenyl) is randomly by halogen, C
1-4Alkyl or C
1-4Alkoxyl group replaces.The ester of the prodrug that other is suitable is referring to Design of Prodrugs, Bundgaard, and H.Ed.Elsevier (1985), this paper is introduced into as a reference.In the time of in injecting so pharmaceutically acceptable ester to Mammals, it is hydrolysis in vivo usually, is converted into the sour form of formula I compound.About above-mentioned ester, except as otherwise noted, this any alkyl group advantageously comprises 1 to 16 carbon atom, especially 1 to 6 carbon atom.Any aromatic yl group that exists in such ester advantageously comprises phenyl.
Particularly, described ester can be C
1-16Alkyl ester, unsubstituted benzyl ester or by at least one halogen, C
1-6Alkyl, C
1-6The benzyl ester that alkoxyl group, nitro or trifluoromethyl replace.
As used herein term " pharmacologically acceptable salt " comprise by pharmaceutically acceptable alkali deutero-those.The example of suitable alkali comprises choline, thanomin and quadrol.Na
+, K
+And Ca
++Salt is also included within the scope of the present invention (also referring to Pharmaceutical Salts, Birge, S.M. etc., J.Pharm.Sci., (1977), 66,1-19, this paper is introduced into as a reference).
Following chemical reagent can be abridged with reference to these:
Abbreviation | Chemical name |
ACN | Acetonitrile |
Boc | Uncle-butoxy carbonyl |
DABCO | 1,4-diazabicyclo [2.2.2] octane |
DBU | 1,8-diazabicyclo [5.4.0] 11 carbon-7-alkene |
DCC | 1, the 3-dicyclohexylcarbodiimide |
DCHA | Dicyclohexylamine |
DCM | Methylene dichloride |
DIPEA | Diisopropylethylamine or H ü nigs-alkali |
DMAP | Dimethyl aminopyridine |
DMF | N, dinethylformamide |
DMSO | Methyl-sulphoxide |
DMTMM | 4-(4,6-dimethoxy-1,3,5-triazines-2-yl)-4-methylmorpholine muriate |
EDC | 1-(3-dimethylaminopropyl)-3-ethyl-carbodiimide hydrochloride |
HATU | O-(7-azepine benzo triazol-1-yl)-N, N ', N '-tetramethyl-urea hexafluorophosphate |
HBTU | O-benzotriazole-1-base-N, N, ' N '-tetramethyl-urea hexafluorophosphate |
HOAT | 1-hydroxyl-7-azepine benzotriazole |
HOBT | I-hydroxybenzotriazole |
IPA | Virahol |
KDMO | 3, the 7-dimethyl-(Potassium 3,7-dimethyl-3-octanoxide) for 3-octane potassium oxide |
Abbreviation | Chemical name |
MCH | Methylcyclohexane |
MIBK | 4-methyl-2 pentanone |
NMP | 1-Methyl-2-Pyrrolidone |
SEH | 2 ethyl hexanoic acid sodium |
TBTU | O-(benzotriazole-1-yl)-N, N, N ', N '-tetramethyl-urea a tetrafluoro borate |
THF | Tetrahydrofuran (THF) |
THP | The trihydroxy methyl phosphine |
TKC | Tetrakis hydroxymethyl phosphonium muriate |
Embodiment of the present invention
In following synthetic route, except as otherwise noted, all substituting groups in the chemical formula should have and the identical meaning of formula (I).The reactant that uses in following synthetic route can obtain by mode as described herein, if perhaps do not describe in this article, they can be obtained or also can be obtained by the commercially available material preparation that obtains by methods known in the art by commercially available.Some starting raw material, the method that for example can pass through to describe among International Patent Application WO 00/59929, WO 00/09543 and WO 00/09558, U.S. patent 6,323,180 B1 and US patent 6,608,027 B1 obtains.
The optimum reaction conditions and reaction times can change according to the concrete reactant that uses.Except as otherwise noted, those of ordinary skills can be easy to selective solvent, temperature, pressure and other reaction conditions.Partly provide specific preparation method at synthetic example.Typically, if desired, reaction process can be detected by high performance liquid chromatography (HPLC), and intermediate and product can pass through silica gel column chromatography and/or recrystallization purifying.
I. the rapid synthetic method of general multistep
In one embodiment, the present invention relates to the rapid synthetic method of multistep of the general compound that is used for preparation formula (I).Especially, this embodiment relates to the method for the compound of preparation following formula (I):
Wherein Q is the substituting group of following formula:
Wherein W is CH or N,
L
0Be H, halogen, C
1-6Alkyl, C
3-6Cycloalkyl, C
1-6Haloalkyl, C
1-6Alkoxyl group, C
3-6Cycloalkyloxy, hydroxyl or N (R
23)
2,
Each R wherein
23Be H, C independently
1-6Alkyl or C
3-6Cycloalkyl;
L
1, L
2Each all is H, halogen, C independently
1-4Alkyl ,-O-C
1-4Alkyl or-S-C
1-4Alkyl (sulphur can be any oxidation state); Or
L
0And L
1Or
L
0And L
2Two C-atom covalences that can be connected with them wherein do not have mutually directly one or two (under the situation of 5-or 6-unit ring)-CH of bonded in conjunction with forming 4-, 5-or 6-unit carbocyclic ring
2-group can be independently of one another by-O-or NR
aReplace, wherein R
aBe H or C
1-4Alkyl, wherein said ring is randomly by C
1-4The alkyl list replaces or two replacements;
R
2Be H, halogen, C
1-6Alkyl, C
3-6Cycloalkyl, C
1-6Haloalkyl, C
1-6Sulfane base, C
1-6Alkoxyl group, C
3-6Cycloalkyloxy, C
2-7Alkoxy-C
1-6Alkyl, C
6Or C
10Aryl or Het, wherein Het contains 1 to 45 yuan, 6 yuan or 7 yuan of saturated or unsaturated heterocycle that are selected from nitrogen, oxygen and sulphur;
Described cycloalkyl, aryl or Het are by R
6Replace,
R wherein
6Be H, halogen, C
1-6Alkyl, C
3-6Cycloalkyl, C
1-6Alkoxyl group, C
3-6Cycloalkyloxy, NO
2, N (R
7)
2, NH-C (O)-R
7Or NH-C (O)-NH-R
7, each R wherein
7Be independently: H, C
1-6Alkyl or C
3-6Cycloalkyl;
Or R
6Be NH-C (O)-OR
8, R wherein
8Be C
1-6Alkyl or C
3-6Cycloalkyl;
R
3Be hydroxyl, NH
2Or formula-NH-R
9Group, R wherein
9Be C
6Perhaps C
10Aryl, heteroaryl ,-C (O)-R
10,-C (O)-NHR
10Or-C (O)-OR
10,
R wherein
10Be C
1-6Alkyl or C
3-6Cycloalkyl;
D is the saturated alkylidene chains of 3 to 7-atoms;
R
4Be H, perhaps on any carbon atom on the described D chain or three substituting groups, described substituting group is independently selected from: C
1-6Alkyl, C
1-6Haloalkyl, C
1-6Alkoxyl group, hydroxyl, halogen, amino, oxo, sulfo-and C
1-6The sulfane base;
With
A is formula-C (O)-NH-R
11Acid amides, R wherein
11Be selected from: C
1-8Alkyl, C
3-6Cycloalkyl, C
6Or C
10Aryl; C
7-16Aralkyl and SO
2R
11A, R wherein
11ABe C
1-8Alkyl, C
3-7Cycloalkyl or C
1-6Alkyl-C
3-7Cycloalkyl;
Perhaps A is carboxylic acid or its pharmacologically acceptable salt or ester;
Described method comprises the steps:
(i) compound of the compound of formula (II) and formula (III) reacts, and obtains the compound of formula (IV):
Wherein PG is an amino protecting group, and X is a halogen atom, and Q is the substituting group of following formula:
(ii) the compound of the compound of formula (IV) and formula V reacts, and obtains the compound of formula (VI):
Wherein A is formula-C (O)-NH-R
11Acid amides, R wherein
11Be selected from group: C
1-8Alkyl, C
3-6Cycloalkyl, C
6Or C
10Aryl, C
7-16Aralkyl and SO
2R
11A, R wherein
11ABe C
1-8Alkyl, C
3-7Cycloalkyl or C
1-6Alkyl-C
3-7Cycloalkyl;
Perhaps A is the carboxyl of protection;
(iii) remove the nitrogen-protecting group in formula (VI) compound, obtain formula (VII) compound:
(iv) formula (VII) compound and formula (VIII) compound reaction obtains formula (IX) compound:
(v) at the diolefin that has the formula (IX) that cyclisation obtains under the suitable catalyzer, obtain the compound of formula (I):
When A was the carboxyl of protection, the compound that randomly makes formula (I) was through deprotection (for example hydrolysis) condition, and obtaining wherein, A is the compound of the formula (I) of carboxyl;
When A is carboxyl in the formula that is obtaining (I) compound,, randomly make this compound and formula R existing suitable coupling agent for example when TBTU or HATU
11ASO
2NH
2The sulphonamide coupling, obtain wherein A and be-C (O)-NH-SO
2R
11AFormula (I) compound.
II. each step of synthetic method
Another embodiment of the invention relates to each step of the above-mentioned general rapid synthetic method of multistep and each intermediate in these steps.Each step of the present invention and intermediate are discussed in more detail below.All substituting groups define in the rapid method of the multistep above-mentioned.
Step (i)
This step relates to the method for preparation formula (IV) compound, and described method comprises the compound of formula (II) and the compound reaction of formula (III):
Linked reaction between formula (II) and the compound (III) is typically carried out in suitable solvent in the presence of alkali.The example that is used for the suitable alkali of this reaction comprises t-BuOK, t-BuONa, two (trimethyl silyl) acid amides sodium, KDMO, and t-BuOK is preferred alkali.The example that is used for the suitable solvent of this reaction comprises polar aprotic solvent, for example DMSO, DMF, NMP or other polar aprotic solvent commonly used.
Amino protecting group PG can be the amino protecting group of any suitable well-known in the art.Referring to, those that in WO 00/09543, WO 00/09558, describe for example.The representative instance of spendable protecting group is the carbamate protecting group, for example Boc or CBZ group.
X group in the general formula (III) is any halogen atom, but preferred chlorine.
The compound of the formula of using as starting raw material (II) can be commercially available, and for example Boc-4 (R)-oxyproline perhaps can use routine techniques by known feedstock production.In one embodiment, the compound of formula (II) can be used the 4-oxyproline compound of the amido protecting of formula (X):
In the first step, use on the theheterocyclic nitrogen atom of conventional method with the 4-oxyproline of suitable amino protecting group drawing-in system (X) compound.For example, can be in The suitable solvent with the compound dissolution of formula (X), and introduce reagent react with suitable amino protecting group.For example, but be not limited to this scope, when Boc (tert-butoxycarbonyl) is the protecting group of wanting, compound (X) and acid anhydrides Boc
2O (or Boc-ON) for example reacts in acetone, MIBK/ water or the THF/ water at solvent mixture, add alkali for example NaOH, KOH, LiOH, triethylamine, diisopropylethylamine or N-methyl-pyrrolidone in the described solvent mixture, reaction can be carried out under 20-60 ℃ temperature.
The quinoline compound of the formula of halogen-replacement (III) can use various halide reagents to prepare under multiple condition known in the art by following known halogenation method by the quinoline compound that corresponding formula (III ') hydroxyl replaces.The example of each reagent comprises normally used POX
3And PX
5, wherein X=F, Cl, Br or I, wherein these reagent can be in some cases for example DMF or acetonitrile combine as solvent or with polar aprotic solvent.
For example adoptable halogenation condition, referring to:
Chlorination: Outt, people such as P.E., J Org Chem 1998,63 (17), 5762-5768 and reference wherein;
Bromination: Nakahara, people such as S., Tetrahedron Lett 1998,39 (31), 5521-5522 and reference wherein;
Other solvent: Nomoto, Y.; Deng the people, Chem Pharm Bull 1990,38 (8), 2179-2183.
The quinoline compound that the hydroxyl of formula (III ') replaces can be used by the commercially available material and be described in WO00/59929, WO 00/09543 and WO 00/09558, U.S. patent 6,323,180 B1, US patent 6, technology among 608,027 B1 and U.S. patent application publication number 2005/0020503 A1 is synthetic.
Step (ii)
Step (ii) relates to the method for preparation formula (VI) compound, and described method comprises the compound reaction of the compound that makes formula (IV) and formula V:
Wherein A is formula-C (O)-NH-R
11Acid amides, R wherein
11Be selected from: C
1-8Alkyl, C
3-6Cycloalkyl, C
6Or C
10Aryl; C
7-16Aralkyl and SO
2R
11A, R wherein
11ABe C
1-8Alkyl, C
3-7Cycloalkyl or C
1-6Alkyl-C
3-7Cycloalkyl;
Or A is the carboxyl of protection;
In this step, the compound of formula (IV) and (V) can be connected by known polypeptide coupling technology.Referring to, for example this technology is disclosed in WO 00/09543, WO 00/09558 and US 6,608,027 B1.Formula (IV) and polypeptide coupling (V) can be under multiple conditions known in the art for example, for example among methylene dichloride, chloroform, THF, DMF, NMP, the DMSO, for example DCC, EDC, TBTU, HBTU, HATU, DMTMM, HOBT or HOAT obtain to use conventional polypeptide coupling reagent at aprotic solvent.
The compound of formula V is disclosed in WO 00/09543, WO 00/09558 and US 6,608,027 B1, and by preparing with the technology of wherein describing.
Step (iii)
Step (iii) relates to removes the method for nitrogen-protecting group with the compound that obtains formula (VII) from formula (VI) compound:
The removing step and also can finish of nitrogen-protecting group in formula (VI) compound by well-known technology, for example, as the technology of describing 00/09543, among WO 00/09558 and US 6,608,027 B1.In specific embodiment, this method is included in multiple proton or polar aprotic solvent is for example used organic or inorganic acid acidolysis formula (VI) compound among alcohols, ethers, ACN or the DCM, and described mineral acid or organic acid be HCl, H for example
2SO
4, TFA, AcOH, MeSO
3H.
Step (iv)
Step (iv) relates to the method for preparation formula (IX) compound, and described method comprises the compound reaction of the compound that makes formula (VII) and formula (VIII):
In this step, the compound of formula (VII) and (VIII) can be connected as the identical known peptide coupling technology of (ii) describing in above-mentioned steps by the polypeptide link coupled that is used for formula (IV) and (V).Exemplary condition and above-mentioned be used for that step (ii) describes identical.
Acid compound as the replacement of the formula (VIII) of starting raw material is disclosed in US patent 6,608, among the 027B1, and can use the technology of wherein describing to be obtained by the commercially available material.
Step (v)
Step (method that v) relates to preparation formula (I) compound, described method are included in the diolefin of the formula (IX) that cyclisation obtains under the suitable catalyzer existence, obtain the compound of formula (I):
As A during for the carboxyl of protection, A is the compound of the formula (I) of carboxyl to the compound that randomly makes formula (I) to obtain wherein through deprotection (for example hydrolysis) condition.
In the formula that obtains (I) compound when A is carboxyl, randomly at suitable coupling agent for example in the presence of TBTU or the HATU, this compound and formula R
11ASO
2NH
2The sulphonamide coupling be-C (O)-NH-SO to obtain wherein A
2R
11AFormula (I) compound.
The suitable closed loop catalyzer that is used for this step comprises ruthenium-based catalyst.For example, the any well-known ruthenium-based catalyst that in olefin metathesis (metathesis) reaction, uses, for example Grubb catalyzer (first-generation and the s-generation), Hoveyda catalyzer (first-generation and the s-generation) and Nolan catalyzer, can be used for suitably regulating allowing to carry out the necessary condition of ring-closure reaction, specific catalyst is depended in this selection.
The suitable ruthenium catalyst that is used for cyclisation step comprises, for example the compound of formula A, B, C, D or E:
Wherein
X
1And X
2Represent anion ligand independently of one another,
L
1Represent neutral electron donor part, itself and ruthenium atom bonding, and randomly be bonded on the phenyl and
L
2Represent neutral electron donor part, itself and ruthenium atom bonding;
And R
5Be selected from the one or more substituting groups on the phenyl ring, each substituting group is independently selected from hydrogen, C
1-6Alkyl, halo C
1-6Alkyl, HS-C
1-6Alkyl, HO-C
1-6Alkyl, perfluoro C
1-6Alkyl, C
3-6Cycloalkyl, C
1-6Alkoxyl group, hydroxyl, halogen, nitro, imido grpup, oxo, sulphur or aryl; With
X wherein
2And L
2Can randomly form the bidentate ligand of chelating.
In a more particular embodiment, ruthenium catalyst is formula (A-1) or compound (A-2):
Wherein:
L
1Be formula PR
3Trisubstituted phosphino-, wherein R is selected from C
1-6Alkyl and C
3-8Cycloalkyl, L
2Be formula PR
3Trisubstituted phosphino-, wherein R is selected from C
1-6Alkyl and C
3-8Cycloalkyl, or L
2Group for formula A or B:
Wherein
R
7And R
8Represent hydrogen atom or C independently of one another
1-6Alkyl, C
2-6Alkenyl, C
6-12Aryl or C
6-12Aryl-C
1-6Alkyl; With
R
9And R
10Represent hydrogen atom or C independently of one another
1-6Alkyl, C
2-6Alkenyl, C
6-12Aryl or C
6-12Aryl-C
1-6Alkyl, separately randomly by one, two or three are selected from hydrogen, C
1-6Alkyl, halo C
1-6Alkyl, HS-C
1-6Alkyl, HO-C
1-6Alkyl, perfluoro C
1-6Alkyl, C
3-6Cycloalkyl, C
1-6The group of alkoxyl group, hydroxyl, halogen, nitro, imido grpup, oxo, sulphur or aryl replaces;
X
1And X
2Represent halogen atom independently of one another;
R
5Expression hydrogen or nitro; With
R
6Expression C
1-6Alkyl.
In another more particular embodiment, ruthenium catalyst is selected from:
First-generation Hoveyda catalyzer s-generation Hoveyda catalyzer
First-generation Grubb catalyzer s-generation Grubb catalyzer
Wherein Ph is a phenyl, and Mes is 2,4, the 6-trimethylphenyl.
The ruthenium-based catalyst that is used for the transposition cyclisation step, for example above-mentioned those all are well-known catalyzer, and it can obtain by known synthetic technology.For example, referring to the reference of the example of following suitable ruthenium-based catalyst:
Organometallics 2002,21, and 671; 1999,18,5416; With 1998,17,2758;
J.Am.Chem.Soc.2001,123,6543; 1999,121,791; 1999,121,2674; 2002,124,4954; 1998,120,2484; 1997,119,3887; 1996,118,100; With 1996,118,9606
J.Org.Chem.1998,63,9904; With 1999,64,7202;
Angew.Chem.Int.Ed.Engl.1998,37,2685; 1995,34,2038; 2000,39,3012 and 2002,41,4038;
U.S. patent 5,811, and 515; 6,306,987 B1; With 6,608,027 B1
In another embodiment of the invention, step (ring-closure reaction v) be in the presence of thinner at about 30 ° to about 120 ℃, preferred about 90 ° to about 108 ℃, more particularly under about 100 ℃, carry out.
In another embodiment of the invention, step (ring-closure reaction v) be existence be selected from alkane for example just-pentane, just-hexane or just-heptane, aromatic hydrocarbon for example benzene, toluene or dimethylbenzene, chlorating hydrocarbon for example methylene dichloride, trichloromethane, tetrachloromethane or ethylene dichloride, ether solvents for example carry out under the thinner of tetrahydrofuran (THF), 2-methyl-tetrahydrofuran (THF), 3-methyl-tetrahydrofuran (THF), cyclopentyl-methyl ether, methyl-tert-butyl ether, dme, diethyl ether Huo diox and methyl alcohol.
In another embodiment of the invention, (ring-closure reaction v) is 1000: 1 to 100: 1 with diolefin and the molecular proportion of catalyst of its Chinese style IX to step, preferred 500: 1 to 110: 1, especially carries out in 250: 1 to 150: 1.
In another embodiment of the invention, (ring-closure reaction v) is 1: 400 weight to 1 with the diolefin of formula IX and the ratio of thinner to step: 25 weight, preferred 1: 200 weight to 1: 50 weight, especially 1: 150 weight to 1: 75 weight are carried out.
In another embodiment of the invention, (ring-closure reaction v) is by 2 to 6 parts of (portionwise) addings in batches, and preferred 3-5 part specifically is that 4 parts catalyzer carries out for step.
Those skilled in the art can be easy to come the optimization cyclisation step by the condition of selecting and regulate the suitable closed loop catalyzer that is used for specific selection.For example, according to the catalyzer of selecting, although with activator for example halogenation ketone (CuX, wherein X is a halogen) be added to reaction mixture and also can carry out cyclisation at low temperature, preferably for example be higher than 90 ℃ and carry out cyclisation step at high temperature.
In another specific embodiment, (s-generation Hoveyda catalyzer is used in ring-closure reaction v) to carry out this step, in room temperature is about 90 ° to about 108 ℃, for example about 100 ℃, at the aromatic hydrocarbon thinner for example in the presence of the toluene, use to add 2 to 6 parts in batches, 3-5 part for example specifically is 4 parts a catalyzer.
In addition, (ring-closure reaction v) can be used s-generation Hoveyda catalyzer to carry out step, in room temperature is about 30 ° to about 45 ℃, for example about 40 ℃, at suitable activator for example in the presence of the copper(I) iodide, for example in the methylene dichloride, use the catalyzer that once adds or add in batches 2 to 4 parts at chlorinated hydrocarbon thinner or aromatic hydrocarbon thinner, preferably once add.
In the specific embodiments in this step, compound dissolution (for example toluene or methylene dichloride) in removing the organic solvent of gas with formula (IX), be lower than about 0.02M to concentration, to about 110 ℃ temperature, use ruthenium-catalyst based for example Hoveyda catalyst treatment at about 40 ℃ then, to finishing reaction.Handle some or all ruthenium metal in the cleaning reaction mixture with suitable heavy metal scavenging agent, described heavy metal scavenging agent is the medicine of THP or other known removing heavy metal for example.Wash reaction mixture with water, use the organic solvent washing (for example, using distillation method) of part concentration then.Organic solvent can decolour, and for example adds gac, filters then, adds The suitable solvent in suitable temperature afterwards, refrigerative methylcyclohexane in advance for example, and it causes filtering the product compound precipitation of the formula (I) of collection.
When A was carboxylic acid ester groups, the compound of the formula of esterification (I) can randomly pass through hydrolysising condition, obtains corresponding free carboxy acid's compound in formula (I).Hydrolysis can use conventional hydrolysising condition known in the art to carry out.In specific embodiment, for example, the compound of the formula (I) of esterification is dissolved in organic solvent for example among the THF, add entry earlier, add for example lithium hydroxide monohydrate (LiOHH of suitable hydrolysing agent again
2O).Stir the solution that generates down at about 35 ℃ to about 50 ℃.When reaction finishes, cooling solution, collected organic layer.With The suitable solvent for example ethanol join in the organic layer, regulate pH for about pH 5 to about pH 6.Warm then mixture to about 40 ℃ to about 50 ℃ temperature, add entry at this moment, stirred solution when the compound of formula (I) begins to precipitate.After precipitation finishes, solution is cooled to envrionment temperature, filter the compound of collection type (I), washing is also dry.
III. the embodiment preferred of formula (I) compound
Embodiment preferred comprises the compound of formula as defined above (I), wherein cyclopropyl part R
BBe selected from 2 different diastereomers, wherein the 1-carbon center of cyclopropyl have structure (i) and (ii) the expression the R configuration:
For acid amides is cis-configuration (i), or for the A group be cis-configuration (ii).
In a specific embodiment of the compound of formula (I), what thiazolinyl was in that the said structure formula (ii) represents is the configuration of cis for the A group;
W is N;
L
0Be selected from H ,-OH ,-OCH
3,-OC
2H
5,-OC
3H
7,-OCH (CH
3)
2,-NHCH
3,-NHC
2H
5,-NHC
3H
7,-NHCH (CH
3)
2,-N (CH
3)
2,-N (CH
3) C
2H
5,-N (CH
3) C
3H
7With-N (CH
3) CH (CH
3)
2
L
1And L
2Be selected from independently of one another hydrogen, fluorine, chlorine, bromine ,-CH
3,-C
2H
5,-C
3H
7,-CH (CH
3)
2,-OCH
3,-OC
2H
5,-OC
3H
7With-OCH (CH
3)
2,
R
2Be H, C
1-6Sulfane base, C
1-6Alkoxyl group, phenyl or be selected from following Het:
R wherein
6Be H, C
1-6Alkyl, NH-R
7, NH-C (O)-R
7, NH-C (O)-NH-R
7,
Each R wherein
7Be independently: H, C
1-6Alkyl or C
3-6Cycloalkyl;
Perhaps R
6Be NH-C (O)-OR
8, R wherein
8Be C
1-6Alkyl;
R
3Be NH-C (O)-R
10, NH-C (O)-OR
10Or NH-C (O)-NR
10, wherein under every kind of situation, R
10Be C
1-6Alkyl or C
3-6Cycloalkyl; With
D is the saturated alkylidene chains of 4 to 6-atoms;
R
4Be H or C
1-6Alkyl;
And A is carboxylic acid or its pharmacologically acceptable salt or ester.
In another specific embodiment of the compound of formula (I), what thiazolinyl was in that the said structure formula (ii) represents is the configuration of cis for the A group;
W is N;
L
0Be selected from H ,-OH ,-OCH
3With-N (CH
3)
2
L
1And L
2In one be-CH
3,-F ,-Cl or-Br, L
1And L
2In another be H, perhaps L
1And L
2The both is H;
R
2For
R wherein
6Be NH-R
7Or NH-C (O)-R
7, R wherein
7Be independently: C
1-6Alkyl, or C
3-6Cycloalkyl;
R
3Be NH-C (O)-OR
10, R wherein
10Be C
1-6Alkyl, or C
3-6Cycloalkyl;
R
4Be H or C
1-6Alkyl;
D is the saturated alkylidene chains of 5 atoms; With
A is carboxylic acid or its pharmacologically acceptable salt or ester.
In another specific embodiment of formula (I) compound, what thiazolinyl was in that the said structure formula (ii) represents is the configuration of cis for the A group;
W is N;
L
0For-OCH
3
L
1For-CH
3,-F ,-Cl or-Br, L
2Be H, perhaps L
1And L
2All be H;
R
2For
R wherein
6Be NH-R
7Or NH-C (O)-R
7, R wherein
7Be independently: C
1-6Alkyl, or C
3-6Cycloalkyl;
R
3Be NH-C (O)-OR
10, R wherein
10Be butyl, cyclobutyl or cyclopentyl;
R
4Be H or C
1-3Alkyl;
D is the saturated alkylidene chains of 5 atoms; With
A is carboxylic acid or its pharmacologically acceptable salt or ester.
Following table has been listed the representational compound of the compound of formula (I).The compound of following formula:
L wherein
0, L
1, L
2And R
2Be following definition:
Following table has been listed the other representational compound of formula (I) compound.The compound of following formula:
Wherein 14 keys to cyclopropyl are cis for COOH from the position, and described 13,14 pairs of keys are cis, R
13, R
4And R
2Be following definition:
The representational specific compound of other formula (I) compound can be referring to U.S.Patent6,608,027 B1.
Claims (13)
1. the method for preparing following formula (I) compound:
Wherein Q is the substituting group of following formula:
The thiazolinyl that is connected on the cyclopropyl rings is a cis-configuration for the A group of representing as shown in the formula structure:
W is N;
L
0Be selected from H ,-OH ,-OCH
3With-N (CH
3)
2,
L
1And L
2In one be-CH
3,-F ,-Cl or-Br, L
1And L
2In another is H, perhaps L
1And L
2Two all is H,
R wherein
6Be NH-R
7Or NH-C (O)-R
7, R wherein
7Be C independently
1-6Alkyl, or C
3-6Cycloalkyl,
R
3Be NH-C (O)-OR
10, R wherein
10Be C
1-6Alkyl, or C
3-6Cycloalkyl;
R
4Be H or C
1-6Alkyl;
D be the saturated alkylidene chain of 5-atom and
A is carboxylic acid or its pharmacologically acceptable salt or ester;
Described method is included in the diolefin of cyclisation formula (IX) under the suitable catalyzer of existence to obtain the step of formula (I) compound:
When A is the carboxyl of protection, randomly make formula (I) compound deprotection base (for example hydrolysis), obtaining wherein, A is the compound of the formula (I) of carboxyl;
With when A is carboxyl in the formula that is obtaining (I) compound, randomly exist suitable coupling agent for example under TBTU or the HATU, this compound and formula R
11ASO
2NH
2The sulphonamide coupling, obtain wherein A and be-C (O)-NH-SO
2R
11AFormula (I) compound.
2. according to the process of claim 1 wherein that described catalyzer is a ruthenium-based catalyst.
3. according to the process of claim 1 wherein that described reaction is to carry out in the presence of thinner under about 30 ° to about 120 ℃ of temperature range.
4. according to the method for claim 3, wherein thinner is selected from alkane, aromatic hydrocarbon, chlorating hydrocarbon, ether solvents and methyl alcohol.
5. according to the process of claim 1 wherein that described catalyzer is the 2nd generation Hoveyda catalyzer, is reflected under the following condition and carries out: from about 90 ° to about 108 ℃ temperature, exist under the aromatic hydrocarbon thinner, and using the catalyzer that adds 2 to 6 parts in batches.
6. according to the method for claim 1, wherein catalyzer is the 2nd generation Hoveyda catalyzer, be reflected under the following condition and carry out: about 30 ° to about 45 ℃ temperature, exist under the suitable activator, in chlorating hydrocarbon diluent or aromatic hydrocarbon thinner, use once to add catalyzer or add 2 to 4 parts of catalyzer in batches.
7. according to the process of claim 1 wherein the method preparation of diolefin (IX) by comprising the steps:
(i) compound of the compound of formula (II) and formula (III) reacts, and obtains the compound of formula (IV):
Wherein PG is an amino protecting group, and X is a halogen atom, and Q is the substituting group of following formula:
(ii) the compound of the compound of formula (IV) and formula V reacts, and obtains the compound of formula (VI):
Wherein A is formula-C (O)-NH-R
11Acid amides, R wherein
11Be selected from group: C
1-8Alkyl, C
3-6Cycloalkyl, C
6Or C
10Aryl; C
7-16Aralkyl and SO
2R
11A, R wherein
11ABe C
1-8Alkyl, C
3-7Cycloalkyl or C
1-6Alkyl-C
3-7Cycloalkyl;
Perhaps A is the carboxyl of protection;
(iii) remove the nitrogen-protecting group in the compound of formula (VI), obtain the compound of formula (VII):
(iv) the compound of the compound of formula (VII) and formula (VIII) reacts, and obtains the compound of formula (IX):
W, the L in above-mentioned each step wherein
0, L
1, L
2, R
2, R
3, R
4, the definition in D and A such as the claim 1.
8. according to the process of claim 1 wherein:
W is N,
L
0For-OCH
3
L
1For-CH
3,-F ,-Cl or-Br, and L
2Be H, perhaps L
1And L
2All be H;
R
2For
R wherein
6Be NH-R
7Or NH-C (O)-R
7, R wherein
7Be C independently
1-6Alkyl or C
3-6Cycloalkyl;
R
3Be NH-C (O)-OR
10, R wherein
10Be butyl, cyclobutyl or cyclopentyl;
R
4Be H or C
1-3Alkyl;
D is the saturated alkylidene chains of 5 atoms; With
A is carboxylic acid or its pharmacologically acceptable salt or ester.
9. the compound of following formula (IV):
Wherein PG is an amino protecting group, and Q is the substituting group of following formula:
Wherein:
W is N;
L
0Be selected from H ,-OH ,-OCH
3With-N (CH
3)
2
L
1And L
2In one be-CH
3,-F ,-Cl or-Br, L
1And L
2In another is H, perhaps L
1And L
2The both is H; With
R wherein
6Be NH-R
7Or NH-C (O)-R
7, R wherein
7Be independently: C
1-6Alkyl, or C
3-6Cycloalkyl.
10. according to the compound of the formula (IV) of claim 9, wherein:
W is N;
L
0For-OCH
3
L
1For-CH
3,-F ,-Cl or-Br, and L
2Be H, perhaps L
1And L
2All be H;
R wherein
6Be NH-R
7Or NH-C (O)-R
7, R wherein
7Be independently: C
1-6Alkyl, or C
3-6Cycloalkyl;
R
3Be NH-C (O)-OR
10, R wherein
10Be butyl, cyclobutyl or cyclopentyl;
R
4Be H or C
1-3Alkyl;
D is the saturated alkylidene chains of 5 atoms; With
A is carboxylic acid or its pharmacologically acceptable salt or ester.
11. preparation is according to the method for formula (IV) compound of claim 9, described method comprises step: make the compound of formula (II) and the compound reaction of formula (III), obtain the compound of formula (IV):
Wherein PG is an amino protecting group, and X is a halogen atom, and Q is the substituting group of following formula:
Wherein W, L
0, L
1, L
2And R
2As the definition in the claim 9.
12. the compound of following formula (IX):
Wherein Q is the substituting group of following formula:
The thiazolinyl that is connected on the cyclopropyl rings is a cis-configuration for the A group of representing as shown in the formula structure:
W is N;
L
0Be selected from H ,-OH ,-OCH
3With-N (CH
3)
2
L
1And L
2In one be-CH
3,-F ,-Cl or-Br, L
1And L
2In another be H, perhaps L
1And L
2All be H;
R
2For
R wherein
6Be NH-R
7Or NH-C (O)-R
7, R wherein
7Be independently: C
1-6Alkyl, or C
3-6Cycloalkyl;
R
3Be NH-C (O)-OR
10, R wherein
10Be C
1-6Alkyl, or C
3-6Cycloalkyl;
R
4Be H or C
1-6Alkyl;
D is the saturated alkylidene chains of 5 atoms; With
A is carboxylic acid or its pharmacologically acceptable salt or ester.
13. according to the compound of the formula (IX) of claim 12, wherein:
W is N;
L
0For-OCH
3
L
1For-CH
3,-F ,-Cl or-Br, and L
2Be H, perhaps L
1And L
2All be H;
R
2For
R wherein
6Be NH-R
7Or NH-C (O)-R
7, R wherein
7Be independently: C
1-6Alkyl, or C
3-6Cycloalkyl;
R
3Be NH-C (O)-OR
10, R wherein
10Be butyl, cyclobutyl or cyclopentyl;
R
4Be H or C
1-3Alkyl;
D is the saturated alkylidene chains of 5 atoms; With
A is carboxylic acid or its pharmacologically acceptable salt or ester.
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US55331704P | 2004-03-15 | 2004-03-15 | |
US60/553,317 | 2004-03-15 | ||
US60/578,123 | 2004-06-08 |
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CN111378007A (en) * | 2020-05-08 | 2020-07-07 | 杭州勇诚睿生物科技有限公司 | Method for preparing palippivir by using second-generation Hoveyda-Grubbs catalyst |
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2005
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