USRE34069E - Process for the preparation of oligonucleotides - Google Patents
Process for the preparation of oligonucleotides Download PDFInfo
- Publication number
- USRE34069E USRE34069E US07/481,572 US48157290A USRE34069E US RE34069 E USRE34069 E US RE34069E US 48157290 A US48157290 A US 48157290A US RE34069 E USRE34069 E US RE34069E
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- nucleoside
- protected
- carrier
- group
- groups
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H21/00—Compounds containing two or more mononucleotide units having separate phosphate or polyphosphate groups linked by saccharide radicals of nucleoside groups, e.g. nucleic acids
Definitions
- the invention relates to a process for the preparation of oligonucleotides of the general formula I indicated in claim 1.
- the oligonucleotides prepared according to the invention have defined sequences and can be used as specific primers and probes and are of great importance for the synthesis of complete genes (Arzneistoffforschung 30, 3a, 548, (1980)).
- oligonucleotides are prepared by either the phosphate or phosphite triester method using polymeric carriers (Nachr. Chem. Tech. Lab. 29, 230 (1981)). In order to be able to construct defined sequences, it is necessary for the individual units (nucleoside or nucleotides) to be provided with suitable protective groups.
- base-labile acyl groups are generally used for the protection of the exocyclic amino groups on the heterocyclic nucleobases, and a base-labile ester bond is used to attach the oligonucleotide chain to the polymeric carrier in a customary manner, and acid-labile trityl ether groups are used to protect the primary 5'--OH group.
- the phosphate protective group used in the phosphate triester method is customarily either the 2-chlorophenyl or the 4-chlorophenyl group, with an ester-type bond, which can only be removed by attack of a base or a nucleophile on the phosphorus atom.
- the methyl group with an ester-type bond is customarily used as the phosphate protective group which can be removed by attack of a nucleophile on the methyl C atom (J. Amer. Chem. Soc. 99, 3526 (I1977)). Since attack on the P atom is avoided, there is likewise avoidance of the risk of cleavage of the internucleotide bond.
- the nucleophile customarily used is thiophenol/triethylamine, which are unpleasant to manipulate and, moreover, lead to involatile compounds which are difficult to extract and which, as mentioned above, both make work-up difficult and lead to considerable material losses.
- B denotes a nucleobase, for example adenine (A), guanine (G), cytosine (C), thymine (T) or uracil (U) or their analogs
- R 1 denotes hydrogen, hydroxyl or hydroxyl which is protected by the protective groups customary in nucleotide chemistry
- n denotes an integer from 1 to 200
- R 1 of the general formula II can be hydrogen; in this case the compounds of the formula I are oligodeoxynucleotides.
- the group R 1 can also be hydroxyl or hydroxyl which is, where appropriate, protected by the protective groups customary in nucleotide chemistry.
- protective groups of this type are trityl, monomethoxytrityl and dimethoxytrityl, acyl, for example acetyl, benzoyl; tetrahydropyranyl, methoxytetrahydropyranyl, o-nitrobenzyl and silyl ethers, such as, for example, t-butyldiphenylsilyl ethers.
- R 2 is likewise a protective group customary in nucleotide chemistry according to the above mentioned publications, preferably the acid-labile 4,4'-dimethoxytrityl or 4,4',4"-trimethoxytrityl group.
- B' can likewise have a protective group customary in nucleotide chemistry according to the above mentioned prior publications.
- X denotes chlorine, bromine, CN or SCN
- L denotes chlorine, bromine, CN, SCN or an amino radical of the formula--NR 2 4 (formula VIII), where the groups R 4 denote primary, or secondary or tertiary alkyl radicals having 1-10 carbon atoms, or together denote a cycloalkyl radical having 5-7 carbon atoms, optionally with alkyl branches, and/or can contain one or two nitrogen, oxygen and/or sulfur atoms as heteroatoms.
- the group L can also form a reactive heterocyclic radical, the imidazolyl, triazolyl, tetrazolyl, 3-nitro-1,2,4-triazolyl, thiazolyl, pyrrolyl, benzotriazolyl (optionally with substituents in the phenyl moiety) or benzohydroxytriazolyl (optionally with substituents in the phenyl ring) and the like.
- R 3 is the phosphine derivative of the general formula (III) is, according to the invention, a group of the general formula VII, ##STR5## which can be removed with the aid of bases by ⁇ -elimination and in which Y denotes hydrogen, methyl or ethyl.
- Z represents an electron-attracting group, for example, halogen, such as fluorine, chlorine or bromine, CN or NO 2 .
- Z can also denote phenyl, phenylthio, phenylsulfoxy or phenylsulfonyl, it being possible for the phenyl radicals to be substituted in the o,o'-position and/or p-position with halogen, CN or NO 2 . It is also possible for one of the groups CF 3 , CCl 3 or CBr 3 to replace the group ##STR6##
- step a takes place in the presence of an organic base.
- the reaction of the compound according to formula IV is carried out with a nucleoside of the general formula V according to claim 1, which is bound to a polymeric carrier.
- soluble or insoluble, that is to say crosslinked, polymeric carriers for example modified silica gel, glass, especially "controlled pore glass", polyester, polyamide, polyvinyl alcohol, polysiloxane, polystyrene or the like.
- Ester bonds are suitable and preferred for the attachment between the carrier and the nucleoside, including those derived from the levulinyl or ⁇ -benzoylpropionyl radical; the latter ester bonds can be cleaved with hydrazine under neutral conditions.
- the acid-labile trityl ether bond optionally with substituents in the phenyl rings, is also suitable as a method of attachment, compare Liebigs Ann. Chem. 1974, 959.
- the elimination is carried out using, for example, a protonic acid or Lewis acid, such as ZnBr 2 or dialkylaltuminum chloride, when R 2 represents a trityl group or a methoxy derivative thereof.
- a protonic acid or Lewis acid such as ZnBr 2 or dialkylaltuminum chloride
- Steps a-e can be repeated to introduce at least one nucleoside phosphate moiety.
- the chains are lengthened by more than one nucleoside phosphate unit.
- This elimination can be carried out in such a manner that, using aqueous ammonia, in one step the N-acyl groups on the heterocyclic bases, the ester bond between the oligonucleotide and the carrier (the latter can, where appropriate, also be cleaved with hydrazine under neutral conditions) an the phosphate protective group are eliminated by ⁇ -elimination in accordance with the general scheme 1 at the end of the description.
- An oligonucleotide having only a 5'-terminal trityl protective group is then obtained, and this can be purified directly in a manner known per se, after removal of the volatile base (ammonia), by high-pressure liquid chromatography (HPLC) on reverse phase material.
- the intermediates of the general formula IV according to claim 1 are new compounds. They are in the form of very stable compounds which can be prepared in the pure form and are easy to manipulate but nevertheless are very reactive in the sense of forming internucleotide bonds.
- R 3 as a protective group which can be removed by bases via ⁇ -elimination makes is possible for the first time to eliminate all the protective groups, apart from the 5'-trityl group, in one step where, in an advantageous manner, by the use of volatile bases the desired oligonucleotide is contaminated with foreign materials to only a very small extent and thus directly afterwards can be purified by reverse phase HPLC due to the hydrophobic 5'-trityl group which is still present.
- a further advantage of the process of the invention results from the fact that, due to the removal of the protective group by ⁇ -elimination, no attack on the P-atom takes place and thus none of the newly formed internucleotide bonds can be cleaved during the deprotection.
- the process of the invention takes very much less time and leads to overall purer products than do the processes hitherto available.
- dichloro- ⁇ -cyanoethoxyphosphine (1) is prepared as in Can. J. Chem. 58, 2686 (1980):
- FIGS. 1a, 1b and 1c show 31 P NMR spectra of three different ⁇ -cyanoethyl phosphoramidochloridites.
- the N-morpholine derivative is too unstable to heat for distillation to be possible. Nevertheless, the preparation is so pure that the residue can be used directly for the preparation of the activated nucleoside derivatives. The purity is usually greater than 95% according to the 31 P NMR spectra.
- the amine hydrochloride is filtered off under argon and thoroughly washed with dry THF (10 to 15 ml).
- the entire organic phase is concentrated and dissolved in argon-saturated ethyl acetate (100 ml).
- the organic phase is extracted twice with 50 ml each time of argon-saturated 10% aqueous sodium carbonate solution.
- the organic phases are dried with sodium sulfate and evaporated under reduced pressure to give a foam.
- the foam is dissolved in a little ethyl acetate or toluene and precipitated in n-hexane at -78° C.
- the activated nucleosides are stable for several months when stored at -20° C. under argon.
- FIG. 2 shows the 31 P NMR spectrum of one of the activated deoxynucleosides.
- the overall yield of the protected octanucleotide at the end of all condensation steps is 55% based on carrier-bound deoxyguanosine.
- the fractions which contain the 5'-dimethoxytritylated oligonucleotide are collected; the volatile buffer is removed in a rotary evaporator in vacuo, 1 ml of 80% strength acetic acid is added to the residue. After 45 minutes at room temperature, the acetic acid is removed by freeze-drying.
- the material thus obtained is phosphorylated in the customary manner (Liebigs Ann. Chem. 1978, 982) with T4-polynucleotide kinase and ⁇ - 32 P-ATP.
- the resulting product is characterized by polyacrylamide gel electrophoresis comparing with a homo-oligo-dT chain length standard (Nucleic Acids Res. 6, 2096 (1979), FIG. 4) and by sequencing according to FIG. 5 (Liebigs Ann. Chem. 1978, 982).
- FIGS. 6a to 6c show the results (HPLC, gel electrophoresis, sequencing) of the synthesis of d(GGGATCCC) using the nucleoside ⁇ -cyanoethyl N,N-dimethylphosphoramidites
- FIGS. 6a to 6c show the results (HPLC, g, electrophoresis, sequencing) of the synthesis of d(GGGATATCCC) using the nucleoside ⁇ -cyanoethyl N,N-morpholinophosphoramidites.
Abstract
Description
TABLE 1 __________________________________________________________________________ Physical data of β-cyanoethyl phosphoramidochloridites 3a 3b 3c Compound L = N,N-dimethylamino L = N,N-diisopropylamino L = N-morpholino __________________________________________________________________________ Boiling point 90-92°/0.6 nm 103-5°/0.06 nm -- Chemical shift.sup.(2) 175.97 ppm 179.82 ppm 168.22 ppm in .sup.31 P NMR in CH.sub.3 CN Chemical shift in 4.01, 4.17(2t, POCH.sub.2, 2H) 4.02, 4.2(2t, POCH.sub.2, 2H) 3.96, 4.1(2t, POCH.sub.2, 2H) .sup.1 H NMR in ppm 2.71(t, CH.sub.2CN, 2H) 3.8(m, N(CH).sub.2, 2H) 3.67(t, O(CH.sub.2).sub.2, 4H) 2.7(d, N(CH.sub.3).sub.2, 6H) 2.77(t, CH.sub.2 CH, 2H) 3.17(m, PN(CH.sub.2).sub.2, 4H) 1.29(d, NCH(CH.sub.3).sub.2, 12H) 2.74(t, CH.sub.2CN.sub.2, 2H) Mass spectrum ##STR11## ##STR12## (Cl), 136(C.sub.2 H.sub.6 N), 110 (Cl), 166(C.sub.3 H.sub.4 NO), (Cl), 152(C.sub.3 H.sub.4 NO), (C.sub.3 H.sub.4 NO) 136(C.sub.6 H.sub.14 N) 136(C.sub.4 H.sub.8 O) __________________________________________________________________________ .sup.(1) The crude product after removal of amine hydrochloride and compounds volatile under high vacuum at room temperature has a purity of 93-95% according to the .sup.31 P NMR spectrum .sup.(2) The chemical shifts are determined in acetoned.sub.6 with 80% strength H.sub.3 PO.sub.4 as the external standard.
Claims (19)
--NR.sub.2.sup.4 ( VIII)
--NR.sub.2.sup.4 (VIII)
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US07/481,572 USRE34069E (en) | 1983-08-18 | 1990-02-16 | Process for the preparation of oligonucleotides |
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DE19833329892 DE3329892A1 (en) | 1983-08-18 | 1983-08-18 | METHOD FOR PRODUCING OLIGONUCLEOTIDES |
US06/752,178 US4725677A (en) | 1983-08-18 | 1984-08-10 | Process for the preparation of oligonucleotides |
US07/481,572 USRE34069E (en) | 1983-08-18 | 1990-02-16 | Process for the preparation of oligonucleotides |
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US06752178 Reissue | 1984-08-10 |
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