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CN1371356A - Enatiomerically-enriched compounds having photocleavable bond(s) and methods related thereto - Google Patents

Enatiomerically-enriched compounds having photocleavable bond(s) and methods related thereto Download PDF

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CN1371356A
CN1371356A CN00812153A CN00812153A CN1371356A CN 1371356 A CN1371356 A CN 1371356A CN 00812153 A CN00812153 A CN 00812153A CN 00812153 A CN00812153 A CN 00812153A CN 1371356 A CN1371356 A CN 1371356A
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formula
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hydrogen
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B·M·斯凯德
S·J·法尔康布里奇
S·B·D·温特
C·J·洛克
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Qiagen Genomics Inc
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Qiagen Genomics Inc
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Abstract

本发明提供了式(I)或(II)化合物:其中R1选自卤素和有机基团;R2和R3独立地选自氢和具有大于15道尔顿的质量的有机基团,其中R2和R3可以合在一起构成羰基,或者可以在一个环状结构中连接在一起;Z是不包括碳在内的(n+1)价的原子,其中n是大于0的整数;R4独立地选自氢、卤素和具有大于15道尔顿的质量的有机基团,条件是至少有一个R4(即R4a)是具有大于100道尔顿的质量的有机基团;R5在各种存在情况下,独立地为卤素或具有小于500道尔顿的质量的有机基团;m选自0、1、2、3和4;其中若R2=R3=H,则当Z(R4)n是－NH(CO)－CH(iBu)－NH(CO)－(CH2Ph或O－t－Bu)时R1不是CO2(H或CH3),而当Z是OH时R4不是CH2CO2t－Bu;且其中若式(I)和(II)化合物均存在于混合物中,则该混合物中式(I):式(II)的摩尔比不是50∶50。这些化合物可用作标记物,包括可用质谱法检测的标记物。The present invention provides compounds of formula (I) or (II): wherein R 1 is selected from halogen and organic groups; R 2 and R 3 are independently selected from hydrogen and organic groups with a mass greater than 15 Daltons, wherein R 2 and R 3 can be combined to form a carbonyl group, or can be connected together in a ring structure; Z is an atom with a valence of (n+1) excluding carbon, where n is an integer greater than 0; R 4 are independently selected from hydrogen, halogen, and organic groups having a mass greater than 15 Daltons, provided that at least one R 4 (i.e. R 4a ) is an organic group having a mass greater than 100 Daltons; R 5 independently, in each case present, a halogen or an organic group having a mass less than 500 Daltons; m is selected from 0, 1, 2, 3, and 4; wherein if R 2 =R 3 =H, then when Z(R 4 ) n is -NH(CO)-CH(iBu)-NH(CO)-(CH 2 Ph or O-t-Bu) when R 1 is not CO 2 (H or CH 3 ), and when Z When it is OH, R 4 is not CH 2 CO 2 t-Bu; and wherein if the compounds of formula (I) and (II) are present in the mixture, the molar ratio of formula (I): formula (II) in the mixture is not 50: 50. These compounds are useful as labels, including labels detectable by mass spectrometry.

Description

Compound that is rich in enantiomorph and the method relevant with key of light cleavable with it
The present invention relates generally to the compound that is rich in enantiomorph, specifically, is the compound that is rich in enantiomorph with key of one or more smooth cleavables, and the method relevant with it, comprises synthetic method.
Background of invention
Although the radio-labeling of DNA and fluorescent mark are widely used for testing goal in molecular biology and genetics, the number of marker is not suitable on a large scale, promptly obtains data very little for the high level multiplication.Now developed the new marker of forming by the mass spectrum marker (CMST) of micromolecular cleavable of a class, and be used for single nucleotide polymorphism (SNP) genotype detection and genetic expression and measure and use (referring to for example: PCT international publication WO 99/05319; WO 97/27331; The aspect of WO 97/27327 and WO 97/27325).This system is based on CMST via joint, covalently bound such as the joint of light cleavable and oligonucleotide.Each marker has specific different quality for specified oligonucleotide sequence.For example, also use pressure chemical ionization (APCI) to detect with the single quadrupole mass spectrometer of standard simultaneously, identify the sequence that whether has allelotrope or expressed by optics cracking from oligonucleotide.
The invention provides useful marker, comprise the marker that can detect by mass spectroscopy, and their using method, as more abundant disclosed herein.
Summary of the invention
The invention provides the compound that is rich in enantiomorph of key with light cleavable, and the method for preparing tagged molecule with the marker of the light cleavable that is rich in enantiomorph.Advantage of the present invention be included in need with on the structure similarly each member of tagged molecule separate and can access one different product under such situation, and as more abundant disclosed other associated advantages herein.
In one aspect, the invention provides formula (1) or (II) compound:
R wherein 1Be selected from halogen and organic group; R 2And R 3Be independently selected from hydrogen and the organic group that has greater than 15 daltonian quality, wherein R 2And R 3Can lump together the formation carbonyl, perhaps can in a ring texture, link together; Z does not comprise the atom of carbon at interior (n+1) valency, and wherein n is the integer greater than 0; R 4Be independently selected from hydrogen, halogen and have organic group greater than 15 daltonian quality, condition is to have a R at least 4(be R 4a) be the organic group that has greater than 100 daltonian quality; R 5Exist under the situation various, independently for halogen or have organic group less than 500 daltonian quality; M is selected from 0,1,2,3 and 4; Wherein if R 2=R 3=H is then as Z (R 4) nBe-NH (CO)-CH (iBu)-NH (CO)-(CH 2Ph or O-t-Bu) time R 1Not CO 2(H or CH 3), and when Z is OH R 1Not CH 2CO 2T-Bu; And wherein if formula (I) and (II) compound all be present in the mixture this mixture Chinese style (I) then: the mol ratio of formula (II) is not 50: 50.
In different embodiments of the present invention, Z is a nitrogen; R 4aCan utilize mass spectroscopy to detect; R 2And R 3The hydrogen of respectively doing for oneself; R 1Comprise synthetic or natural biological agents (for example nucleic acid, protein or sugar); And/or R 4aHave less than 10000 daltonian quality and C 1-500N 0-100O 0-100S 0-10P 0-10H αF βI δMolecular formula, wherein the summation of α, β and δ is enough to make the valency that is not met of C, N, O, P and S atom to be met.
In another embodiment, R 4aHas chemical formula T 2-(J-T 3-) p-; T wherein 2The organic group that constitutes, has the daltonian quality of 15-500 by carbon and one or more hydrogen, fluorine, iodine, oxygen, nitrogen, sulphur and phosphorus; T 3The organic group that constitutes, has the daltonian quality of 50-1000 by carbon and one or more hydrogen, fluorine, iodine, oxygen, nitrogen, sulphur and phosphorus; J is direct bond or the functional group that is selected from acid amides, ester, amine, sulfide, ether, thioesters, disulphide, thioether, urea, thiocarbamide, carbamate, thiocarbamate, Schiff's base, reduction Schiff's base, imines, oxime, hydrazone, phosphoric acid ester, phosphonic acid ester, phosphamide, phosphonic amide, sulphonate, sulphonamide or C-C; P is the integer of 1-50, when n greater than 1 the time, each T 3Select independently with J.
In another embodiment, R 4aHave and comprise following structural formula:
Figure A0081215300101
Wherein G is (CH 2) 1-6Wherein one of each G and a CH is only arranged 2Hydrogen quilt-(CH on the group 2) w-acid amides-T 4Replace; T 2And T 4Be formula C 1-25N 0-9O 0-9S 0-3P 0-3H αF βI δOrganic group, wherein the summation of α, β and δ is enough to make the valency that is not met of C, N, O, S and P atom to be met; Acid amides is Or
Figure A0081215300103
R 10Be hydrogen or C 1-10Alkyl; W is the integer of 0-4; N is the integer of 1-50, so that n is greater than 1 o'clock, and G, c, acid amides, R 1And T 4Select independently.
The present invention further provides and comprised formula (I) and/or formula (II) compound compositions, wherein said composition Chinese style (I): the mol ratio of formula (II) is in 95: 5 to 100: 0 scopes, perhaps in 5: 95 to 0: 100 scopes.
The present invention further provides the method for preparing the compound that is rich in enantiomorph, this method comprises makes following formula: compound:
Figure A0081215300104
Wherein Z is selected from oxygen, nitrogen and sulphur, wherein R when Z is oxygen or sulphur 6Be hydrogen, if Z is then R of nitrogen 6Be selected from hydrogen and C 1-C 22Hydrocarbon and two R 6Group and Z bonding; R 5Exist under the situation various, independently for halogen or have organic group less than 500 daltonian quality; M is selected from 0,1,2,3 and 4; R 7Be hydrogen or organic group, the key table of being represented by solid line and dotted line shows singly-bound or two key;
Contact with the reagent that is selected from the following member: (a) enzyme; (b) enzyme and formula H 2N-C (=O)-CHR 8-NH-R 9Auxiliary, R wherein 8Be organic group, R 9It is the amido protecting group; (c) chiral acid; (d) Chiral Amine; (e) hydrogen and chiral hydrogenation catalyst; (f) mechanicalness crystal separation instrument; To make the compound that is rich in enantiomorph of following formula:
Figure A0081215300111
In an embodiment of determined method above, the compound that react in the method has following structural formula:
Figure A0081215300112
R wherein 5Exist under the situation various, independently for halogen or have organic group less than 500 daltonian quality; M is selected from 0,1,2,3 and 4; R 7Be hydrogen or organic group; This compound contacts with enzyme and obtains the compound that is rich in enantiomorph of following structural:
Figure A0081215300113
In another embodiment of determined method above, the compound that react in the method has following structural formula:
Figure A0081215300114
R wherein 5Exist under the situation various, independently for halogen or have organic group less than 500 daltonian quality; M is selected from 0,1,2,3 and 4; R 7Be hydrogen or organic group; This compound and enzyme and formula H 2N-C (=O)-CHR 8-NH-R 9Auxiliary contact, R wherein 8Be organic group, R 9It is the amido protecting group; Thereby obtain the compound that is rich in enantiomorph of following structural:
Figure A0081215300121
In another embodiment of determined method above, the compound that react in the method has following structural formula: R wherein 5Exist under the situation various, independently for halogen or have organic group less than 500 daltonian quality; M is selected from 0,1,2,3 and 4; R 7Be hydrogen or organic group; This compound contacts with chiral acid, obtains the salt that is rich in enantiomorph of following structural:
Figure A0081215300123
In another embodiment of determined method above, the compound that react in the method has following structural formula: R wherein 5Exist under the situation various, independently for halogen or have organic group less than 500 daltonian quality; M is selected from 0,1,2,3 and 4; This compound contacts with Chiral Amine, obtains the salt that is rich in enantiomorph of following structural:
In another embodiment of determined method above, the compound that react in the method has following structural formula:
Figure A0081215300132
Wherein R5 exists under the situation various, independently for halogen or have organic group less than 500 daltonian quality; M is selected from 0,1,2,3 and 4; This compound contacts with hydrogen in the presence of chiral hydrogenation catalyst, obtains the compound that is rich in enantiomorph of following structural:
In yet another aspect, the invention provides following formula: compound:
Figure A0081215300134
R wherein 5Exist under the situation various, independently for halogen or have organic group less than 500 daltonian quality; M is selected from 0,1,2,3 and 4; R 7Be hydrogen or organic group; Z is SH or NR 8, R wherein 8Be hydrogen or amine protecting group group; And wherein if formula V and (VI) compound all be present in the mixture formula V in this mixture then: the mol ratio of formula (VI) is not 50: 50.
In yet another aspect, the invention provides following formula: compound:
Figure A0081215300141
R wherein 5Exist under the situation various, independently for halogen or have organic group less than 500 daltonian quality; M is selected from 0,1,2,3 and 4; R 11It is the functional group that comprises amino phosphonous acid base (phosphoramidite) or H-phosphonate groups; R 12Be to have 15-10, the organic group of 000 daltonian quality; And wherein if formula (VII) and (VIII) compound all be present in the mixture this mixture Chinese style (VII) then: the mol ratio of formula (VIII) is not 50: 50.
In one embodiment, in above-claimed cpd, R 11Amino phosphonous acid base group have chemical formula-O-P (OR 13) (N (R 14) 2), R wherein 13And R 14Be selected from alkyl independently of one another or have one or more substituent substituted alkyls that are selected from halogen and cyano group, and two R 14Group can constitute Heterocyclylalkyl with the nitrogen bonding of amino phosphonous acid base.In another embodiment, R 11The H-phosphonate groups comprise formula-O-P (=O) (H) (O -+HN (R 15) 3), R 15Be C independently 1-6Alkyl.
These and other aspect of the present invention and embodiment will become more high-visible after with reference to the following detailed description.For this reason, listed various reference herein, they have described some operation, compound and/or composition in more detail, and intactly are incorporated herein by reference.
Detailed Description Of The Invention
The invention provides and be suitable for and nucleic acid or other molecule link coupled markers of being studied.When with the DNA coupling, this marker provides the mode that reaches high yield genotype detection system.Preferably, the joint between marker and the molecule studied is not causing cracking fully under the cracked condition of marker.In addition, marker preferably makes the oligonucleotide of each injection produce a peak, and provides the optimum signal about ionic current.And marker is stable to PCR condition used in the mensuration form, HPLC and other operations preferably.The reagent that marker is introduced in the molecule of being studied should be regenerated by good yield.In satisfying the preferred method of these purposes, developed a kind of permission CMST composition quilt optimized modules structure independently.The composition of CMST preferably includes photophobic photolabile joint, sensitivity of mass spectrometry toughener (MSSE) and variable weight unit (VMU), and all these links together by support.
The invention provides the precursor of the tagged molecule of being studied, the tagged molecule of being studied and the method that produces tagged molecule and precursor thereof, wherein marker is rich in enantiomorph.Be rich in the precursor of enantiomorph by use, can promote the reaction product of precursor and the purifying of the molecule studied, purpose is the tagged molecule that obtains the purifying studied.
Therefore, the invention provides formula (I) or formula (II) compound:
Figure A0081215300151
R wherein 1Be selected from halogen and organic group; R 2And R 3Be independently selected from hydrogen and the organic group that has greater than 15 daltonian quality, wherein R 2And R 3Can lump together the formation carbonyl, perhaps can in a ring texture, link together; Z does not comprise the atom of carbon at interior (n+1) valency, and wherein n is the integer greater than 0; R 4Be independently selected from hydrogen, halogen and have organic group greater than 15 daltonian quality, condition is to have a R at least 4It is the organic group that has greater than 100 daltonian quality; R 5Exist under the situation various, independently for halogen or have organic group less than 500 daltonian quality; M is selected from 0,1,2,3 and 4.The compounds of this invention is rich in enantiomorph, so if formula (I) and (II) compound all be present in the mixture this mixture Chinese style (I) then: the mol ratio of formula (II) is not 50: 50.
The compounds of this invention is included in the 2-nitrophenyl that has the methyl of replacement on 1 of phenyl ring, and wherein the carbon atom of methyl will be referred to as C1 or benzylic carbon atoms in this article.Except the 2-nitrophenyl, C1 atom direct and hydrogen atom (not shown), carbon atom (being called C2 herein) and non-carbon atom bonding.
Because it is the light cleavable that 2-nitrophenyl, The compounds of this invention are arranged.That is to say that The compounds of this invention will to reacting with contacting of some electromagnetic radiation, as shown in following structural formula, make the Z atom of replacement separate with C1 by experiencing a scission reaction thus, wherein
Figure A0081215300161
Indication is to the unsettled key of photodissociation.
Figure A0081215300162
Because C1 is not the atomic linkage of carbon or hydrogen atom with unique one directly, so selective light scission reaction of The compounds of this invention experience.That is to say that the C1-Z key can be by suitable photodissociation condition by the selectivity cracking, remaining other C1 keys, if not complete fully also be semi-holonomic greatly.As long as Z is not that carbon atom just this selective splitting can take place.In preferred embodiments, Z is selected from oxygen, nitrogen and sulphur.Each preferred atom of position Z naturally of oxygen, nitrogen and sulphur.
The photodissociation condition of permission C1-Z key selective splitting is not subjected to the influence of other replacements on the 2-oil of mirbane basic ring mostly.Therefore, any one on the phenyl ring or a plurality of hydrogen atom can be by the R of equal amount 5Group replaces.Therefore, The compounds of this invention can have (" m ") R in a large number 5Group, wherein m is selected from 0,1,2,3 and 4 integer.Most and the R of required photodestruciton chemistry 5The character of group is irrelevant, so R 5Group can be an inorganic group, for example halogen, or organic group.In general, organic R 5Group is not too big, therefore has less than about 500 daltonian quality.Preferred R 5Group is selected from C 1-C 22Alkyl.In preferred The compounds of this invention, m equals 0, so 2-oil of mirbane basic ring has 4 hydrogen substituting groups.
After having experienced the photodestruciton reaction, gained will be known as marker in this article from the residue that contains Z of The compounds of this invention.But this marker is or comprises the test section that wherein this term refers to and can utilize analytical procedure to be detected, also preferably describe the part of characteristic.Representational analytical procedure comprises spectrometry or potentiometry.Typical spectrometry comprises mass spectroscopy, infrared spectroscopy, ultraviolet spectroscopy and fluorescent spectrometry.Typical potentiometric titration is a constant potential amperometric titration.
For effective marker is provided, has a R at least 4Group is the organic group that has greater than 100 daltonian quality.This R 4Group will be called a R in this article 4Group (or R 4a).Wish that the reason that this marker should have greater than 100 daltonian quality has many.When the quality of marker during, may be difficult to differentiate marker less than 100 dalton.For example, if utilize mass spectroscopy identifying mark thing and describe its characteristic, then molecular weight less than 100 daltonian markers may be difficult to mass spectrometric operation in the inherent ground unrest differentiate.
In addition, the invention provides and contain a large amount of non-identical compound compositions of the present invention, wherein non-same compound contains the non-same tag thing that can utilize analytical procedure to differentiate each other.For a large amount of non-same tag things are differentiated, marker must have enough difference to each other, so that analytical procedure can detect these differences.In order to obtain for example demonstrating the marker of different suitable number with potentiometry, these markers must contain a large amount of can be analytically to demonstrate the atom that different non-same way as is bonded together.When marker has less than 100 daltonian quality, the quantity that analytically demonstrates different markers there is unsuitable restriction.Therefore, in order making enough mutabilities to be arranged on the structure, and to make detection easily and effectively, marker should have the 100 daltonian quality of surpassing.
An as long as R 4Group has the 100 daltonian quality of surpassing, and just can select other R in the The compounds of this invention 4The characteristic of group reaches one or more targets.For example, second or more a plurality of R 4Group (R for example 4b, R 4cDeng) can provide and replenish from first R 4Those information of the information that group obtains.In this case, second or more a plurality of R 4Group also preferably has at least 100 daltonian quality.But, in other cases, may wish second or above R 4Group satisfies the valence state of the C1 that is not met really at most, the not detection of stray light scission reaction or marker, and on synthetic, form easily.Under latter event, second or more a plurality of R 4Group may be hydrogen or simple alkyl.In preferred embodiments, second or above R 4Group if present, is a hydrogen.
In The compounds of this invention, R 1Be selected from halogen and organic group, and R 2And R 3Be independently selected from hydrogen and the organic group that has greater than 15 daltonian quality.As mentioned above, but The compounds of this invention comprises the test section, but wherein the detection of test section and optional characteristic has been described to provide the information of relevant The compounds of this invention.In one embodiment, R 1Group contains the feature of compound, and relevant its information is needed.For example, R 1Can comprise biological agents, and marker is the feature of this individuality and/or particular biological material from individuality.Another example is R 1Group can contain the sequence of specific nucleic acid, peptide or sugar, and they are determined uniquely by marker.In another embodiment, R 1Be to experience the Activity of Chemical Reaction chemical group, can be connected with marker light cleavable ground from deutero-material biologically thus.For example, R 1Can be halogen atom, it can be replaced by biological agents or deutero-biological agents in chemical reaction.
R 2And R 3Group is independently selected from hydrogen and the organic group that has greater than 15 daltonian quality.In general, R 2And R 3The selection of group is conceived to them and is used to connect R to selecting 1With the influence of the chemistry of C1 and/or they are to making the influence of the isolating photodestruciton reaction of marker and C1.Work as R 2And R 3When respectively doing for oneself hydrogen, R then 2And R 3Can not have a negative impact, and in general to photodestruciton reaction, they be used to make R 1With any chemistry of C1 link coupled all be compatible.Therefore, R 2And R 3Be preferably hydrogen.But, R 2And R 3It also can be the group beyond the hydrogen.For example, R 2And R 3Can constitute carbonyl with C1 together.On the other hand, R 1And R 2Can constitute ring texture with C1.R can be selected as another for alternate 2Or R 3May be quality greater than 15 daltonian organic groups, for example, C 1-C 22Alkyl.Usually, alkyl can not hinder required photodestruciton reaction, and can not hinder R 1/ C1 coupling chemistry.
Another of The compounds of this invention is characterised in that the C1 atom is a chirality.As from formula (I) and (II) as can be seen, the last substituent character inevitable requirement C1 of C1 is a chirality.In addition, if formula (I) and (II) compound be form of mixtures, then the mol ratio of formula (I) compound and formula (II) compound is not 50: 50.In a preferred embodiment of the invention, formula (I) compound not with formula (II) compound, vice versa.In addition, under the situation of formula (I) compound and formula (II) compound, the mol ratio of formula (I) compound and formula (II) compound is preferably above 95: 5, or 96: 4, or 97: 3, or 98: 2, or 99: 1, or surpass 99.5: 0.5, or also be that (that is: the mol ratio of formula (II) compound and formula (I) compound is preferably above 95: 5, or 96: 4 so on the contrary, or 97: 3, or 98: 2, or 99: 1, or above 99.5: 0.5).
Since formula (I) or (II) compound not with or only inferior limit ground respectively with formula (II) or (I) compound, so relevant formula (I) or (II) chromatographic separation of compound want easy and much effective when more than a large amount of formulas (I) and (II) compound is mixed with each other.The invention provides and contain a large amount of formulas (I) or (II) compound compositions, because their kinds of isomeric structures, can be more easily that they are separated from each other, otherwise just will not be this situation.The ability of the different tagged compounds of this difference that is enhanced makes it possible to form composition, otherwise just can't describe the characteristic of these compositions.
For example, when two kinds of formulas (I) compound variant slightly not simultaneously because of the R1 group, if they with have identical substituent formula (II) compound (Compound I IA and IIB) around the C1 and mix, then possibly can't effectively these two kinds of compounds (Compound I A and IB) be separated.This be because chromatography eluant time of Compound I A may elution time overlapping with the elution time of Compound I IB and/or Compound I B may be overlapping with the elution time of Compound I IA.Therefore, owing to the interference from Compound I IA and IIB, Compound I A and IB can not separate each other easily and leave.The present invention by provide be not with or in fact not formula (I) compound of belt (II) compound solve this problem.
In yet another aspect, the present invention relates to use predetermined reagent to prepare and be rich in the method for the compound of enantiomorph.More particularly, this method acts on following formula: compound:
Wherein Z is selected from oxygen, nitrogen and sulphur; R when Z is oxygen or sulphur wherein 6Be hydrogen, if Z is then R of nitrogen 6Be selected from hydrogen and C 1-C 22Hydrocarbon and two R 6Group and Z bonding; R 5Exist under the situation various, independently for halogen or have organic group less than 500 daltonian quality; M is selected from 0,1,2,3 and 4; R 7Be hydrogen or organic group, the key table of being represented by solid line and dotted line shows singly-bound or two key.
The inventive method makes the compound of determining as mentioned contact with reagent.Described reagent is selected from (a) enzyme; (b) enzyme and formula H 2N-C (=O)-CHR 8-NH-R 9Auxiliary, R wherein 8Be organic group, R 9It is the amido protecting group; (c) chiral acid; (d) Chiral Amine; (e) hydrogen and chiral hydrogenation catalyst; (f) mechanicalness crystal separation instrument.Compound contacts with reagent so that obtain the compound that is rich in enantiomorph of following structural:
Except preparation disclosed herein has the concrete technology of compound with the light fugitive key that is rich in the enantiomorph marker, in following document, can find other suitable technique: " the asymmetry catalysis effect in the organic synthesis ", R.Noyori, John Wiley ﹠amp; Sons, New York, NY, 1994; " asymmetric synthesis technology ", D.J.Ager and M.B.East, CRC Press, Boca Raton, FL, 1995; " asymmetric synthesis ", R.A.Aitken and S.N.Kilenyi edit, Blackie Academic ﹠amp; Professional, Glasglow, U.K., 1992; " asymmetric synthesis ", J.Morrison compiles, Academic Press, Orlando, FL. (series of books comprises volume in 1984 and volume in 1985); " asymmetric synthesis ", R.G.Proctor, Oxford University Press, New York, NH, 1996; " asymmetric synthesis: use amino acid structure chiral molecules ", G.M.Coppola and H.F.Schuster, JohnWiley ﹠amp; Sons, New York, NY, 1987; " catalysis asymmetric synthesis ", I.Ojima compiles, VCH Publishers, New York, NY, 1993; " chirality subsidiary and aglucon in the asymmetric synthesis ", J.Seyden-Penne, John Wiley ﹠amp; Sons, New York, NY, 1995; " chiral separation: use and technology ", S.Ahuja compiles, American Chemical Society, Washington D.C., 1996; " chirality in the industry " I ﹠amp; II, A.N.Collins, G.N.Sheldrake and J.Crosby compile, John Wiley ﹠amp; Sons, New York, NY, 1995 and 1997; " chiral technology: the industry of optically-active compound is synthetic ", R.A.Sheldon, Marcel Dekkar, New York, NY, 1993; " optically active enantiomorph, raceme and fractionation ", J.Jacques, A.Collet and S.H.Wilen, John Wiley ﹠amp; Sons, New York, NY, 1981.
The compounds of this invention and composition, and their preparation method can be used to prepare tagged molecule, and wherein marker is rich opticity, and are that light cleavable ground is connected with molecule.Can be prepared into molecule form, that have the marker of light cleavable ground connection, and can be listed in for example PCT international publication WO 99/05319 with the method for compound of the present invention and composition enforcement according to rich opticity of the present invention; WO 97/27331; WO 97/27327; Among WO 97/27325 and the WO 95/04160.Therefore, The compounds of this invention can replace disclosed tagged compound in these publications, and the additive method and the assay method that wherein adopt the molecule of the marker with the connection of light cleavable ground.
Provide following examples and be in order to set forth the present invention, rather than as limitation of the present invention.
Embodiment
In the following example, except as otherwise noted, otherwise chemical reactant and reagent are the standard merchandise levels, obtain from commercial organization of supply, such as Aldrich (Milwaukee, WI; Www.sigma-aldrich.com), Fluka (department of Aldrich) and Lancaster Synthesis, Inc. (Windham, NH; Http:// www.lancaster.co.uk).
Embodiment 1
DTTA splits with chiral acid
(24.6g is 110mmol) with chiral acid two-(DTTA, 42.4g 110mmol) are dissolved in 500mL methyl alcohol by being heated to 67 ℃ to toluyl-D-tartrate with (±)-3-amino-3-(2-nitrophenyl) methyl propionate.Gained solution is cooled to 56 ℃ and add crystal seed: the salt of 3-amino-3-(2-nitrophenyl) methyl propionate and DTTA.Make this mixture be cooled to envrionment temperature (21 ℃) and stirred 16 hours.Filter to collect formed crystallization, obtain being rich in a kind of enantiomorph white solid (46% enantiomeric excess, e.e.).Once to obtain 12g diastereomer purity be 88% material in crystallization in methyl alcohol.
Embodiment 2
Split with chiral acid (-) dextrocamphoric acid
With (±)-3-amino-3-(2-nitrophenyl) propionic acid (172mg, 0.82mmol) and chiral acid (-)-dextrocamphoric acid (165mg, 0.83mmol Fluka) are dissolved in the 5mL water by being heated to reflux.Gained solution is cooled to envrionment temperature (21 ℃).Filter and collect formed crystallization, obtain white solid (105mg, 31% yield).Utilize the analysis of chirality high pressure lipuid chromatography (HPLC) (5 ℃, 20mM 75% ammonium acetate buffer, pH 4.5 and 25%EtOH, detector is under 215nm for cHPLC, Chirobiotic T post) to show that product is pure enantiomorph.
Embodiment 3
Carry out selective hydrolysis with enzyme
With (±)-3-amino-3-(2-nitrophenyl) methyl propionate (60g, 270mmol) be dissolved in phosphoric acid buffer (50mM, 500mL) and be adjusted to pH7.The Amano PS enzyme that is pulpous state (6g, 10wt%, Amano enzyme (Milton Keynes, U.K. that then will be in phosphoric acid buffer (100mL); Lombard IL, USA; Www.amano-enzyme.co.jp)) join in this solution, this reaction mixture was stirred 24 hours down in envrionment temperature (21 ℃).After finishing, leach amino acid precipitation, remove and contain filter liquor, solid is with methylene dichloride (DCM, 2 * 10mL) washings then.This solid is dissolved in aqueous hydrochloric acid, and (6M, 150mL), but still residue has tiny unknown throw out, with its filtering.The gained aqueous mixture extracts with DCM, by regulating pH to 7 solid is precipitated out once more.Obtain required amino acid (23g, 90% yield) thus.
Initial filtrate is alkalized to pH8 and at first with top collected DCM washings extraction; Secondly with fresh DCM extraction.Organic layer merging, dry also evaporation are obtained amino ethyl ester (23g, 80% yield).The specific rotation of the carbethoxy hydrochloride in methyl alcohol is α D+ 127.55 ° (c=1,20 ℃, 589nm).The enantiomeric excess of amino acid and amino ethyl ester (e.e.) all utilizes cHPLC to measure, and all above 98% enantiomeric purity.
Embodiment 4
Be used for extremely the marker delivery of rich opticity
Synthesizing of the bioactive molecule of the molecule of being studied
The marker of Miao Shuing is preferably puted together by photophobic photolabile key and the molecule of being studied herein.Preferred light fugitive key is present in the adjacent nitrobenzyl (referring to for example: (a) Greenberg, M.M.; Gilmore, J.L., " organic chemistry magazine " 1994,59,746-753; (b) Yoo, D.J.; Greenberg, M.M., " organic chemistry magazine " 1995,60,3358-3364; (c) Venkatesan, H.; Greenberg, M.M., " organic chemistry magazine " 1996,61,525-529).Intramolecularly photoredox reaction in the adjacent nitrobenzyl (referring to for example Pillai, V.N.R., " synthesizing " 1980,1-26) make marker can be under neutrallty condition (with 254nm Hg light irradiation 6 seconds) soon from the oligonucleotide cracking and do not have cracked.
Therefore, synthetic route from the esterification of (scheme 1) photosensitivity joint 3-amino-3-(2-nitrophenyl) propionic acid (ANP, 1, referring to for example: Brown, B.B.; Wagner, D.S.; Geysen, H.M. " molecular diversity " 1995,1,4-12; (b) Rodebaugh, R.; Fraser-Reid, B.; Geysen, H.M. " tetrahedron wall bulletin " 1997,38 7653-7656), obtains salt acetoacetic ester (2), and yield is 84%.Then 2 Enzymatic transformation are obtained the ethyl ester individual isomer, this helps oligonucleotide to put together HPLC purifying in the step.This salt acetoacetic ester is water-soluble and be adjusted to neutral pH with 2N HCl.The Amano PS esterase that adds phosphoric acid buffer slurries form.After reaction is finished, do basic treatment removing the ANP by product (4) of hydrolysis, reclaim the individual isomer ethyl ester (3,＞99%e.e.) (92% active substance).
Scheme 1
Figure A0081215300231
Methionin provides support most suitable for the modular approach of complex sign thing.Two amine that exists in the Methionin and hydroxy-acid group provide the processing to sane chemistry of peptides process, have obtained the amido linkage between the marker composition.Peptide has predictable behavior in mass spectrum, and relatively stable to the light of 254nm.As in the scheme 2 as seen; 3 with the coupling of α-BOC-ε-Alloc-Methionin (5) use EDACl (1-[3-(dimethylamino) propyl group]-3-ethyl-carbodiimide hydrochloride; from Aldrich Chemical Co.; Milwaukee; WI obtains) and I-hydroxybenzotriazole (HOBT) carry out, obtain protected ANP Methionin (6).Remove BOC with HCl and obtain ε-Alloc-Methionin ANP ester (7), be white solid, the yield from 3 is 81%.
Perfluorinated aromatic can be in the negative ion type mass spectroscopy with the electrophoresis marker that acts on analysis purposes (referring to for example: (a) Abdel-Baky, S.; Klempier, N.; Giese, R.W., " tetrahedron " 1990,46,5859; (b) Abdel-Baky, S.; Allam, K.; Giese, R.W. " analytical chemistry " 1993,65,498-499; (c) Trainor, T; Giese, R.W.; Vouros, P. " chromatogram magazine " 1988,452,369-376; (d) Saha, M.; Saha, J.; Giese, R.W. " chromatogram magazine " 1993,641,400-404).We are the carboxylic acid that various electronics are few, degree of fluorination is high to be connected with typical stent, and to measure relative ionic current with negative ion type APCI the initial strategy of the ionization composition of MSSE candidate-marker.Chipping, it is not good to obtain multiplet and signal.Studied the toughener that is used for opposite ionization scheme then.Adding pyridyl, proline(Pro) base and piperidyl structure to marker tests as MSSE and in positive ion type APCI.Utilize all standards, use the marker of the different piperidine carboxylic acid of N-methyl (INA) to obtain superior results.
Use EDAC and triethylamine that INA hydrochloride and 7 couplings are obtained thick Alloc-by protection structure 8, it goes protection with diethylamine, triphenylphosphine and palladium.Gained core texture (9) crystallization from reaction mixture, by filtered and recycled, yield is 95%, is yellow solid.
Scheme 2
Has the detectable of different molecular weight in order to obtain a big group, with core texture 9 and one group of 45 carboxylic acid derivatives that is referred to as variable weight unit (VMU).Minimum 4 a.m.u. of the quality interval of VMU are to reduce to minimum with the isotropic substance between the marker is overlapping.The molecular weight ranges of VMU is 90-298 a.m.u..Preferred VMU does not have following performance or characteristic: (1) and composition sequence, such as the inconsistent functionality of ester; (2) have multiple isotopic element (Cl, Br, S); Functionality that (3) may constituting competition property photoprocess (iodide, acyl group-and aryl-benzophenone); (4) racemization acid and (5) lack the coml utilizability.Use HATU and N-methylmorpholine to make VMU and 9 couplings.After utilizing the column chromatography purifying, reclaim CMST ethyl ester (10) with variable yield.10 usefulness NaOH saponification obtain CMST acid (11) with quantitative yield.As for last step, (TFP TFA is referring to for example: Green, M. to use trifluoroacetic acid tetrafluoro phenylester; Berman, J. " tetrahedron wall bulletin " 1990,31,5851-5852; TFP TFA prepares with the similar fashion with trifluoroacetic acid pentafluorophenyl group ester and uses, identify that NMR checks because the proton on the tetrafluoro phenyl ring serves as) and the transesterification of 11 base catalysis make the formation active ester, thereby obtain CMST TFP ester (12) with variable yield.Select tetrafluoro phenyl active ester to be because by product removes and oligonucleotide is puted together the relative stability and the consistency of condition easily.According to the method for Lukhtanov etc. (referring to for example: Lukhtanov, E.A.; Kutyavin, I.V.; Gamper, H.B.; Meyer, R.B. " biology is puted together The Chemicals " 1995,4 418-426) puts together the oligonucleotide (from TriLink Biotechnology, San Diego, CA buys) of CMSTTFP ester and 5 '-amino hexyl-ending.
Scheme 3
Figure A0081215300251
The quantity of marker uses tyrosine derivative to further expand by increasing, tyrosine derivative plays total mass conditioning agent (GMA, N-Boc-O-ethyl-L-the tyrosine of more specifically saying so, it can be commercial from Bachem California (Torrance, CA) order or by N-Boc-L-tyrosine-OMe with 86% yield with ethyl iodide and cesium carbonate alkylation, then prepare) with the quantitative hydrolysis of NaOH, expansion makes the molecular weight of cracked marker increase by 191 a.m.u., and has obtained being used for once more the more VMU set of high molecular marker.As shown in scheme 4, with GMA and core texture 9 couplings.After the alkaline purification, the GMA structure of being protected by filtering separation BOC-.With TFA go the protection with quantitative yield obtain GMA core monomer structure (13, n=1).VMU obtains other marker set (14) with identical as described above mode coupling.Use the quality adjustment agent of 4 units, can synthesize about altogether 200 markers.
Scheme 4 a a(a) EDAC, HOBT, THF; (b) TFA, DCM; (c) VMU, HATU, NMM; (d) IN NaOH, THF; (e) TFP TFA, DIEA, DMF
Can figure out from the description of front:, under the situation that does not deviate from the spirit and scope of the present invention, can make various changes although described specific embodiments of the present invention in this article for purposes of illustration.Therefore, the present invention only is subjected to the restriction of appending claims.

Claims (20)

1, formula (1) or formula (II) compound: R wherein 1Be selected from halogen and organic group; R 2And R 3Be independently selected from hydrogen and the organic group that has greater than 15 daltonian quality, wherein R 2And R 3Can lump together the formation carbonyl, perhaps can in a ring texture, link together; Z does not comprise the atom of carbon at interior (n+1) valency, and wherein n is the integer greater than 0; R 4Be independently selected from hydrogen, halogen and have organic group greater than 15 daltonian quality, condition is to have a R at least 4(be R 4a) be the organic group that has greater than 100 daltonian quality; R 5Exist under the situation various, independently for halogen or have organic group less than 500 daltonian quality; M is selected from 0,1,2,3 and 4; Wherein if R 2=R 3=H is then as Z (R 4) nBe-NH (CO)-CH (iBu)-NH (CO)-(CH 2Ph or O-t-Bu) time R 1Not CO 2(H or CH 3), and when Z is OH R 1Not CH 2CO 2T-Bu; And wherein if formula (I) and (II) compound all be present in the mixture this mixture Chinese style (I) then: the mol ratio of formula (II) is not 50: 50.
2, claim 1 compound, wherein Z is a nitrogen.
3, claim 1 compound, wherein R 4aCan utilize mass spectroscopy to detect.
4, claim 1 compound, wherein R 4aHave less than 10,000 daltonian quality and C 1-500N 0-100O 0-100S 0-10P 0-10H αF βI δMolecular formula, wherein the summation of α, β and δ is enough to make the valency that is not met of C, N, O, P and S atom to be met.
5, claim 1 compound, wherein R 4aHas chemical formula T 2-(J-T 3-) p-; Wherein:
T 2The organic group that constitutes, has the daltonian quality of 15-500 by carbon and one or more hydrogen, fluorine, iodine, oxygen, nitrogen, sulphur and phosphorus;
T 3The organic group that constitutes, has the daltonian quality of 50-1000 by carbon and one or more hydrogen, fluorine, iodine, oxygen, nitrogen, sulphur and phosphorus;
J is direct bond or the functional group that is selected from acid amides, ester, amine, sulfide, ether, thioesters, disulphide, thioether, urea, thiocarbamide, carbamate, thiocarbamate, Schiff's base, reduction Schiff's base, imines, oxime, hydrazone, phosphoric acid ester, phosphonic acid ester, phosphamide, phosphonic amide, sulphonate, sulphonamide or C-C; With
P is the integer of 1-50, when n greater than 1 the time, each T 3Select independently with J.
6, claim 1 compound, wherein R 4aHave and comprise following structural formula:
Figure A0081215300031
Wherein:
G is (CH 2) 1-6Wherein one of each G and a CH is only arranged 2Hydrogen quilt-(CH on the group 2) w-acid amides-T 4Replace;
T 2And T 4Be formula C 1-25N 0-9O 0-9S 0-3P 0-3H αF βI δOrganic group, wherein the summation of α, β and δ is enough to make the valency that is not met of C, N, O, S and P atom to be met;
Acid amides is Or
Figure A0081215300033
R 10Be hydrogen or C 1-10Alkyl;
W is the integer of 0-4; With
N is the integer of 1-50, so that n is greater than 1 o'clock, and G, c, acid amides, R 1And T 4Select independently.
7, claim 1 compound, wherein R 2And R 3The hydrogen of respectively doing for oneself.
8, claim 1 compound, wherein R 1Comprise synthetic or natural biological agents.
9, claim 8 compound, wherein R 1Comprise nucleic acid, protein or sugar.
10, comprise claim 1 compound compositions, its Chinese style (I): the mol ratio of formula (II) is in 95: 5 to 100: 0 scopes, perhaps in 5: 95 to 0: 100 scopes.
11, the method for the compound of enantiomorph is rich in preparation, and this method comprises makes following formula: compound: Wherein Z is selected from oxygen, nitrogen and sulphur, wherein R when Z is oxygen or sulphur 6Be hydrogen, if Z is then R of nitrogen 6Be selected from hydrogen and C 1-C 22Hydrocarbon and two R 6Group and Z bonding; R 5Exist under the situation various, independently for halogen or have organic group less than 500 daltonian quality; M is selected from 0,1,2,3 and 4; R 7Be hydrogen or organic group, the key table of being represented by solid line and dotted line shows singly-bound or two key;
Contact with the reagent that is selected from the following member: (a) enzyme; (b) enzyme and formula H 2N-C (=O)-CHR 8-NH-R 9Auxiliary, R wherein 8Be organic group, R 9It is the amido protecting group; (c) chiral acid; (d) Chiral Amine; (e) hydrogen and chiral hydrogenation catalyst; (f) mechanicalness crystal separation instrument; Make the compound that is rich in enantiomorph of following formula:
Figure A0081215300042
12, the method for claim 11, wherein following formula: compound:
Figure A0081215300043
R wherein 5Exist under the situation various, independently for halogen or have organic group less than 500 daltonian quality; M is selected from 0,1,2,3 and 4; R 7Be hydrogen or organic group; Contact with enzyme and obtain the compound that is rich in enantiomorph of following structural:
Figure A0081215300051
13, the method for claim 11, wherein following formula: compound:
Figure A0081215300052
R wherein 5Exist under the situation various, independently for halogen or have organic group less than 500 daltonian quality; M is selected from 0,1,2,3 and 4; R 7Be hydrogen or organic group; With enzyme and formula H 2N-C (=O)-CHR 8-NH-R 9Auxiliary contact, R wherein 8Be organic group, R 9It is the amido protecting group; Thereby obtain the compound that is rich in enantiomorph of following structural:
14, the method for claim 11, wherein following formula: compound:
Figure A0081215300054
R wherein 5Exist under the situation various, independently for halogen or have organic group less than 500 daltonian quality; M is selected from 0,1,2,3 and 4; R 7Be hydrogen or organic group; Contact with chiral acid, obtain the salt that is rich in enantiomorph of following structural:
Figure A0081215300061
15, the method for claim 11, wherein following formula: compound:
Figure A0081215300062
R wherein 5Exist under the situation various, independently of one another for halogen or have organic group less than 500 daltonian quality; M is selected from 0,1,2,3 and 4; Contact with Chiral Amine, obtain the salt that is rich in enantiomorph of following structural:
Figure A0081215300063
16, the method for claim 11, wherein following formula: compound:
Figure A0081215300064
R wherein 5Exist under the situation various, independently of one another for halogen or have organic group less than 500 daltonian quality; M is selected from 0,1,2,3 and 4; In the presence of chiral hydrogenation catalyst, contact, obtain the compound that is rich in enantiomorph of following structural with hydrogen:
Figure A0081215300071
17, formula V or formula (VI) compound:
Figure A0081215300072
R wherein 5Exist under the situation various, independently for halogen or have organic group less than 500 daltonian quality; M is selected from 0,1,2,3 and 4; R 7Be hydrogen or organic group; Z is SH or NR 8, R wherein 8Be hydrogen or amine protecting group group; And wherein if formula V and (VI) compound all be present in the mixture formula V in this mixture then: the mol ratio of formula (VI) is not 50: 50.
18, formula (VII) or formula (VIII) compound:
Figure A0081215300073
R wherein 5Exist under the situation various, independently for halogen or have organic group less than 500 daltonian quality; M is selected from 0,1,2,3 and 4; R 11It is the functional group that comprises amino phosphonous acid base or H-phosphonate groups; R 12Be to have 15-10, the organic group of 000 daltonian quality; And wherein if formula (VII) and (VIII) compound all be present in the mixture this mixture Chinese style (VII) then: the mol ratio of formula (VIII) is not 50: 50.
19, claim 18 compound, wherein R 11Amino phosphonous acid base section have chemical formula-O-P (OR 13) (N (R 14) 2), R wherein 13And R 14Be selected from alkyl independently of one another or have one or more substituent substituted alkyls that are selected from halogen and cyano group, and two R 14Group can constitute Heterocyclylalkyl with the nitrogen bonding of amino phosphonous acid base.
20, claim 18 compound, wherein R 11The H-phosphonic acid ester partly comprise formula-O-P (=O) (H) (O -+HN (R 15) 3), R 15Be C independently 1-6Alkyl.
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CN101633625B (en) * 2008-07-23 2013-02-13 江苏恒瑞医药股份有限公司 Method for preparing R-beta-aminobenzene butyric acid derivative
US8580997B2 (en) 2008-07-23 2013-11-12 Jiangsu Hengrui Medicine Co. Ltd. Process for preparing R-beta-amino phenylbutyric acid derivatives

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