WO2003106468A1 - Process of making phosphordiamidite compounds - Google Patents
Process of making phosphordiamidite compounds Download PDFInfo
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- WO2003106468A1 WO2003106468A1 PCT/US2003/017982 US0317982W WO03106468A1 WO 2003106468 A1 WO2003106468 A1 WO 2003106468A1 US 0317982 W US0317982 W US 0317982W WO 03106468 A1 WO03106468 A1 WO 03106468A1
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- WIPO (PCT)
- Prior art keywords
- group
- amine hydrohalide
- amine
- hydrohalide
- neutralizing
- Prior art date
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- 238000000034 method Methods 0.000 title claims abstract description 27
- ZLRAAUUPULJGTL-UHFFFAOYSA-N diaminophosphinous acid Chemical class NP(N)O ZLRAAUUPULJGTL-UHFFFAOYSA-N 0.000 title description 5
- 150000001412 amines Chemical class 0.000 claims abstract description 32
- 125000000217 alkyl group Chemical group 0.000 claims description 13
- 125000004966 cyanoalkyl group Chemical group 0.000 claims description 13
- 239000000047 product Substances 0.000 claims description 11
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 10
- 239000003463 adsorbent Substances 0.000 claims description 10
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 9
- 239000003153 chemical reaction reagent Substances 0.000 claims description 9
- 239000000706 filtrate Substances 0.000 claims description 9
- 239000006227 byproduct Substances 0.000 claims description 8
- 125000004432 carbon atom Chemical group C* 0.000 claims description 8
- 125000005265 dialkylamine group Chemical group 0.000 claims description 8
- 230000003472 neutralizing effect Effects 0.000 claims description 8
- 239000002904 solvent Substances 0.000 claims description 8
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 6
- PNEYBMLMFCGWSK-UHFFFAOYSA-N aluminium oxide Inorganic materials [O-2].[O-2].[O-2].[Al+3].[Al+3] PNEYBMLMFCGWSK-UHFFFAOYSA-N 0.000 claims description 6
- 239000003795 chemical substances by application Substances 0.000 claims description 6
- 238000001914 filtration Methods 0.000 claims description 6
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 claims description 6
- OAICVXFJPJFONN-UHFFFAOYSA-N Phosphorus Chemical compound [P] OAICVXFJPJFONN-UHFFFAOYSA-N 0.000 claims description 5
- 229910052698 phosphorus Inorganic materials 0.000 claims description 5
- 239000011574 phosphorus Substances 0.000 claims description 5
- FAIAAWCVCHQXDN-UHFFFAOYSA-N phosphorus trichloride Chemical group ClP(Cl)Cl FAIAAWCVCHQXDN-UHFFFAOYSA-N 0.000 claims description 5
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 5
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 4
- 125000003545 alkoxy group Chemical group 0.000 claims description 4
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 4
- 239000002244 precipitate Substances 0.000 claims description 4
- 239000000126 substance Substances 0.000 claims description 4
- BVKZGUZCCUSVTD-UHFFFAOYSA-L Carbonate Chemical compound [O-]C([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-L 0.000 claims description 3
- 229910052757 nitrogen Inorganic materials 0.000 claims description 3
- ZMANZCXQSJIPKH-UHFFFAOYSA-O triethylammonium ion Chemical compound CC[NH+](CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-O 0.000 claims description 3
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 claims description 2
- 125000001301 ethoxy group Chemical group [H]C([H])([H])C([H])([H])O* 0.000 claims description 2
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 2
- 239000000203 mixture Substances 0.000 claims description 2
- 239000000741 silica gel Substances 0.000 claims description 2
- 229910002027 silica gel Inorganic materials 0.000 claims description 2
- FKHIFSZMMVMEQY-UHFFFAOYSA-N talc Chemical compound [Mg+2].[O-][Si]([O-])=O FKHIFSZMMVMEQY-UHFFFAOYSA-N 0.000 claims description 2
- 150000003512 tertiary amines Chemical class 0.000 claims description 2
- 238000003860 storage Methods 0.000 abstract description 3
- 238000006243 chemical reaction Methods 0.000 description 8
- 150000001875 compounds Chemical class 0.000 description 5
- 238000004519 manufacturing process Methods 0.000 description 5
- 238000004679 31P NMR spectroscopy Methods 0.000 description 4
- 150000004820 halides Chemical group 0.000 description 4
- 238000002360 preparation method Methods 0.000 description 4
- 239000012429 reaction media Substances 0.000 description 4
- ZJHXBGWQNOKLCZ-UHFFFAOYSA-N 2-trimethylsilyloxypropanenitrile Chemical compound N#CC(C)O[Si](C)(C)C ZJHXBGWQNOKLCZ-UHFFFAOYSA-N 0.000 description 3
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 3
- 102100032373 Coiled-coil domain-containing protein 85B Human genes 0.000 description 3
- 101000868814 Homo sapiens Coiled-coil domain-containing protein 85B Proteins 0.000 description 3
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 3
- 230000000692 anti-sense effect Effects 0.000 description 3
- LVTYICIALWPMFW-UHFFFAOYSA-N diisopropanolamine Chemical compound CC(O)CNCC(C)O LVTYICIALWPMFW-UHFFFAOYSA-N 0.000 description 3
- UAOMVDZJSHZZME-UHFFFAOYSA-N diisopropylamine Chemical compound CC(C)NC(C)C UAOMVDZJSHZZME-UHFFFAOYSA-N 0.000 description 3
- 239000003814 drug Substances 0.000 description 3
- 229940079593 drug Drugs 0.000 description 3
- RKVHNYJPIXOHRW-UHFFFAOYSA-N 3-bis[di(propan-2-yl)amino]phosphanyloxypropanenitrile Chemical compound CC(C)N(C(C)C)P(N(C(C)C)C(C)C)OCCC#N RKVHNYJPIXOHRW-UHFFFAOYSA-N 0.000 description 2
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 2
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 2
- 238000003556 assay Methods 0.000 description 2
- 239000007806 chemical reaction intermediate Substances 0.000 description 2
- 229910052801 chlorine Inorganic materials 0.000 description 2
- 239000000460 chlorine Substances 0.000 description 2
- 239000012467 final product Substances 0.000 description 2
- 239000000463 material Substances 0.000 description 2
- 239000002002 slurry Substances 0.000 description 2
- 230000006641 stabilisation Effects 0.000 description 2
- 238000011105 stabilization Methods 0.000 description 2
- 239000006188 syrup Substances 0.000 description 2
- 235000020357 syrup Nutrition 0.000 description 2
- 238000005292 vacuum distillation Methods 0.000 description 2
- ZFFMLCVRJBZUDZ-UHFFFAOYSA-N 2,3-dimethylbutane Chemical group CC(C)C(C)C ZFFMLCVRJBZUDZ-UHFFFAOYSA-N 0.000 description 1
- WSGYTJNNHPZFKR-UHFFFAOYSA-N 3-hydroxypropanenitrile Chemical compound OCCC#N WSGYTJNNHPZFKR-UHFFFAOYSA-N 0.000 description 1
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 1
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 description 1
- -1 PHOSPHORDIAMIDITE COMPOUNDS Chemical class 0.000 description 1
- 230000002411 adverse Effects 0.000 description 1
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 1
- 229910052794 bromium Inorganic materials 0.000 description 1
- 239000007795 chemical reaction product Substances 0.000 description 1
- 239000012043 crude product Substances 0.000 description 1
- URAZVWXGWMBUGJ-UHFFFAOYSA-N di(propan-2-yl)azanium;chloride Chemical compound [Cl-].CC(C)[NH2+]C(C)C URAZVWXGWMBUGJ-UHFFFAOYSA-N 0.000 description 1
- 229940043279 diisopropylamine Drugs 0.000 description 1
- 238000004821 distillation Methods 0.000 description 1
- 230000008030 elimination Effects 0.000 description 1
- 238000003379 elimination reaction Methods 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 229910052731 fluorine Inorganic materials 0.000 description 1
- 239000011737 fluorine Substances 0.000 description 1
- 239000011521 glass Substances 0.000 description 1
- 239000000543 intermediate Substances 0.000 description 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 230000007935 neutral effect Effects 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 238000007039 two-step reaction Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
- C07F9/02—Phosphorus compounds
- C07F9/06—Phosphorus compounds without P—C bonds
- C07F9/22—Amides of acids of phosphorus
- C07F9/24—Esteramides
- C07F9/2404—Esteramides the ester moiety containing a substituent or a structure which is considered as characteristic
- C07F9/2408—Esteramides the ester moiety containing a substituent or a structure which is considered as characteristic of hydroxyalkyl compounds
Definitions
- the present invention is generally directed to the production of phosphordiamidite compounds which serve as key reagents for the preparation of, for example, antisense drugs.
- the present process facilitates the removal of undesirable amine hydrohalide compounds which are typically present in the reaction media and are carried to the final product. The elimination of such amine hydrohalide byproducts can improve the stability of the final product.
- Phosphordiamidite compounds such as cyanoalkyl tetraalkylphosphordiamidite compounds are key reagents for the preparation of antisense drugs.
- such intermediate compounds are prepared by a two- step reaction in which a phosphorus trihalide is reacted with a 2-cyanoalkanol or 2- cyanoalkoxytrialkylsilane to form 2-cyanoalkylphosphordihalidite (NC-R 1 -O-P-X 2 wherein R 1 is an alkyl group preferably having from 1 to 6 carbon atoms and X is a halide).
- the resulting phosphordihalidite compound is reacted with a dialkylamine to give the desired product (cyanoalkyl tetraalkylphosphordiamidite) having the following formula NC-R 1 -O-P[N(R 2 )] 2 wherein each of R 1 and R is an alkyl group, preferably having from 1 to 6 carbon atoms.
- An amine hydrohalide is produced as a byproduct. A major portion of the amine hydrohalide can be removed by filtration but there always remains a small amount of amine hydrohalide dissolved in the reaction media which can adversely affect the storage stability of the cyanoalkyl tetraalkylphosphordiamidite compounds. In particular, the presence of the amine hydrohalide renders the desired product unstable at ambient temperatures over extended periods of time.
- the present invention is generally directed to the production of phosphordiamidites and particularly cyanoalkyl tetraalkylphosphordiamidites in which amine hydrohalides are removed from the reaction media to the extent necessary to achieve a product with desired storage stability.
- a method of producing cyanoalkyl tetraalkylphosphordiamidites comprising: a) reacting phosphorus trihalide with a cyano-containing reagent to form cyanoalkylphosphordihalidite; b) reacting the cyanoalkylphosphordihalidite with a dialkylamine to form cyanoalkyl tetraalkylphosphordiamidite and an amine hydrohalide byproduct at least a portion of which is in the form of a precipitate; c) removing the amine hydrohalide precipitate by filtration to form a filtrate which may contain dissolved amine hydrohalide; and d) treating the filtrate with a substance capable of removing any dissolved amine hydrohalide from said filtrate.
- the present invention is generally directed to a method of producing cyanoalkyl tetraalkylphosphordiamidites as a reagent for the production of, for example, antisense drugs.
- the present invention is also directed to the production of a stable form of cyanoalkyl tetraalkylphosphordiamidites which are substantially free of amine hydrohalides.
- phosphorus trihalide is reacted with a cyano-containing reagent to form cyanoalkylphosphordihalidite.
- the cyano- containing reagent is preferably selected from the group consisting of a cyanoalkanol and a cyanoalkoxytrialkylsilane.
- the alkanol group of the cyanoalkanol is preferably a C C 6 alkanol with ethanol being the most preferred alkanol.
- the alkoxy and alkyl groups of the cyanoalkoxytrialkylsilane preferably have 1-6 carbon atoms with ethoxy and methyl being the preferred alkoxy and alkyl groups, respectively.
- the halides can include any halide (e.g. fluorine, chlorine and bromine). Chlorine is the preferred halide.
- the alkyl groups can be any alkyl group including straight or branch chained alkyl groups, preferably having from 1 to 6 carbon atoms. Ethyl is the preferred alkyl group.
- the resulting cyanoalkylphosphordihalidite is reacted with a dialkylamine.
- the preferred alkyl groups for the dialkylamine have from 1 to 6 carbon atoms. Isopropyl is the preferred alkyl group.
- the above-mentioned reaction produces a hydrohalide byproduct which has to be neutralized for the reaction to go to completion.
- the hydrohalide byproduct can be neutralized by using an excess of a dialkylamine or a tertiary amine (e.g. triethylamine, pyridine and the like).
- the precipitated portion of the amine hydrohalide can be removed by filtration upon completion of the reaction.
- any residual amine hydrohalide may be removed from the product through the use of an adsorbent alone or in the presence of a solvent, or through a reagent which renders the hydrohalide portion of the amine hydrohalide capable of being removed from the reaction system by filtration or the like.
- reagents are polymer-supported neutralizing agents such as, for example, triethylammonium methylpolystyrene carbonate and N, N- (diisopropyl)aminomethylpolystyrene.
- the removal of the amine hydrohalide significantly improves the stability of the product such as, for example, when stored at ambient temperatures over extended periods of time.
- the adsorbents which may be used in the present invention are any adsorbents which preferentially absorb the amine hydrohalide from the reaction media.
- adsorbents include, for example, alumina, silica gel, Florisil, Decalite and the like and combinations thereof.
- the preferred solvents include tetrahydrofuran, diethyl ether, toluene, hexane and the like and mixtures thereof.
- the respective amounts of the adsorbent and solvent is within the routine skill in the art and will be an amount sufficient to adsorb at least substantially all the dissolved residual amine hydrohalide byproduct.
- the adsorbed amine hydrohalides may be easily removed together with the adsorbent from the reaction product by filtration to produce a product which is stable at ambient temperatures for extended periods of time including and exceeding 120 days.
- CDP 2-(cyanoethoxy)dichlororphosphine
- PCI 3 phosphorous trichloride
- TMSOP trimethylsilyloxypropionitrile
- the product can be purified with careful vacuum distillation.
- Example 2 The CDP used in this example, and Example 2 was obtained by reacting PCI 3 with TMSOP in a molar ratio of 2:1 in acetonitrile at 5°C. Upon completion of the reaction, the solvent and the excess PCI 3 were removed by distillation. The crude product was further purified by vacuum distillation, and gave CDP with greater than 98% purity.
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Biochemistry (AREA)
- General Health & Medical Sciences (AREA)
- Molecular Biology (AREA)
Abstract
A process of producing cynoalkyl tetraalkylphosphordiamidites at least substantially free of amine hydrohalide with improved storage stability.
Description
PROCESS OF MAKING PHOSPHORDIAMIDITE COMPOUNDS
Related Application
This application claims priority of U.S. Provisional Patent Application Serial
No. 60/388,224 filed on June 13, 2002.
Field Of The Invention
The present invention is generally directed to the production of phosphordiamidite compounds which serve as key reagents for the preparation of, for example, antisense drugs. The present process facilitates the removal of undesirable amine hydrohalide compounds which are typically present in the reaction media and are carried to the final product. The elimination of such amine hydrohalide byproducts can improve the stability of the final product.
Background Of The Invention
Phosphordiamidite compounds such as cyanoalkyl tetraalkylphosphordiamidite compounds are key reagents for the preparation of antisense drugs. Typically, such intermediate compounds are prepared by a two- step reaction in which a phosphorus trihalide is reacted with a 2-cyanoalkanol or 2- cyanoalkoxytrialkylsilane to form 2-cyanoalkylphosphordihalidite (NC-R1-O-P-X2 wherein R1 is an alkyl group preferably having from 1 to 6 carbon atoms and X is a
halide). The resulting phosphordihalidite compound is reacted with a dialkylamine to give the desired product (cyanoalkyl tetraalkylphosphordiamidite) having the following formula NC-R1-O-P[N(R2)]2 wherein each of R1 and R is an alkyl group, preferably having from 1 to 6 carbon atoms. An amine hydrohalide is produced as a byproduct. A major portion of the amine hydrohalide can be removed by filtration but there always remains a small amount of amine hydrohalide dissolved in the reaction media which can adversely affect the storage stability of the cyanoalkyl tetraalkylphosphordiamidite compounds. In particular, the presence of the amine hydrohalide renders the desired product unstable at ambient temperatures over extended periods of time.
It would therefore be a significant advance in the art to provide a method for the production of phosphordiamidites and particularly cyanoalkyl tetraalkylphosphordiamidites in which amine hydrohalide byproducts are removed from the reaction system to the extent that the desired product is stable at ambient temperatures for up to extended periods of time.
Summary Of The Invention
The present invention is generally directed to the production of phosphordiamidites and particularly cyanoalkyl tetraalkylphosphordiamidites in which amine hydrohalides are removed from the reaction media to the extent necessary to achieve a product with desired storage stability.
In accordance with one aspect of the present invention, there is provided a method of producing cyanoalkyl tetraalkylphosphordiamidites comprising: a) reacting phosphorus trihalide with a cyano-containing reagent to form cyanoalkylphosphordihalidite; b) reacting the cyanoalkylphosphordihalidite with a dialkylamine to form cyanoalkyl tetraalkylphosphordiamidite and an amine hydrohalide byproduct at least a portion of which is in the form of a precipitate; c) removing the amine hydrohalide precipitate by filtration to form a filtrate which may contain dissolved amine hydrohalide; and d) treating the filtrate with a substance capable of removing any dissolved amine hydrohalide from said filtrate.
Detailed Description Of The Invention
The present invention is generally directed to a method of producing cyanoalkyl tetraalkylphosphordiamidites as a reagent for the production of, for example, antisense drugs. The present invention is also directed to the production of a stable form of cyanoalkyl tetraalkylphosphordiamidites which are substantially free of amine hydrohalides.
In the first aspect of the present invention, phosphorus trihalide is reacted with a cyano-containing reagent to form cyanoalkylphosphordihalidite. The cyano-
containing reagent is preferably selected from the group consisting of a cyanoalkanol and a cyanoalkoxytrialkylsilane.
The alkanol group of the cyanoalkanol is preferably a C C6 alkanol with ethanol being the most preferred alkanol. The alkoxy and alkyl groups of the cyanoalkoxytrialkylsilane preferably have 1-6 carbon atoms with ethoxy and methyl being the preferred alkoxy and alkyl groups, respectively.
With regard to the cyanoalkylphosphordihalidite, the halides can include any halide (e.g. fluorine, chlorine and bromine). Chlorine is the preferred halide. The alkyl groups can be any alkyl group including straight or branch chained alkyl groups, preferably having from 1 to 6 carbon atoms. Ethyl is the preferred alkyl group.
The resulting cyanoalkylphosphordihalidite is reacted with a dialkylamine. The preferred alkyl groups for the dialkylamine have from 1 to 6 carbon atoms. Isopropyl is the preferred alkyl group.
The above-mentioned reaction produces a hydrohalide byproduct which has to be neutralized for the reaction to go to completion. The hydrohalide byproduct can be neutralized by using an excess of a dialkylamine or a tertiary amine (e.g. triethylamine, pyridine and the like). The precipitated portion of the amine hydrohalide can be removed by filtration upon completion of the reaction. In accordance with the present invention, any residual amine hydrohalide may be
removed from the product through the use of an adsorbent alone or in the presence of a solvent, or through a reagent which renders the hydrohalide portion of the amine hydrohalide capable of being removed from the reaction system by filtration or the like. An example of such reagents are polymer-supported neutralizing agents such as, for example, triethylammonium methylpolystyrene carbonate and N, N- (diisopropyl)aminomethylpolystyrene. The removal of the amine hydrohalide significantly improves the stability of the product such as, for example, when stored at ambient temperatures over extended periods of time.
The adsorbents which may be used in the present invention are any adsorbents which preferentially absorb the amine hydrohalide from the reaction media. Examples of such adsorbents include, for example, alumina, silica gel, Florisil, Decalite and the like and combinations thereof.
The preferred solvents include tetrahydrofuran, diethyl ether, toluene, hexane and the like and mixtures thereof.
The respective amounts of the adsorbent and solvent is within the routine skill in the art and will be an amount sufficient to adsorb at least substantially all the dissolved residual amine hydrohalide byproduct.
The adsorbed amine hydrohalides may be easily removed together with the adsorbent from the reaction product by filtration to produce a product which is stable
at ambient temperatures for extended periods of time including and exceeding 120 days.
Examples
The following examples are illustrative of embodiments of the invention and are not intended to limit the invention as encompassed by the claims forming part of the application.
Example 1
Preparation and Stabilization of 2-Cyanoethyl- N,N,N',N'-tetraisopropylphosphoro-diamidite (PDA)
2-(cyanoethoxy)dichlororphosphine (CDP) can be easily prepared by various processes described in the prior art. For example, the reaction of phosphorous trichloride (PCI3) with either 2-cyanoethanol or trimethylsilyloxypropionitrile (TMSOP) gives CDP in good yield. If desired, the product can be purified with careful vacuum distillation.
The CDP used in this example, and Example 2 was obtained by reacting PCI3 with TMSOP in a molar ratio of 2:1 in acetonitrile at 5°C. Upon completion of the reaction, the solvent and the excess PCI3 were removed by distillation. The crude
product was further purified by vacuum distillation, and gave CDP with greater than 98% purity.
A solution comprising 1.80 moles of freshly distilled 2- (cyanoethoxy)dichlorophosphine (CDP) (310 grams) in 2.9 Kg of tetrahydrofuran (THF) as solvent was stirred and cooled to -12 ± 2°C under a nitrogen blanket and then treated with 8.12 moles (820 grams) of diisopropylamine over a period of ninety minutes, maintaining a temperature of -10 ± 2°C. Stirring of the slurry was continued at ambient temperature for a period of 72 hours, at which time examination by 31P NMR showed no reaction intermediates remaining.
The slurry was filtered through a sintered glass filter to remove diisopropylamine hydrochloride (DIPA.HCI) solids. The clear filtrate was passed through a column of 350 grams of Brockmann activated neutral alumina that had been dried at 165°C at less than 1 Torr for 16 hours. The filtrate was concentrated on a rotary evaporator at a maximum bath temperature of 45°C. The distilled THF was used to rinse the DIPA.HCI and the alumina to collect additional product, which was combined with the first pass product and then concentrated until the vacuum reached 3 Torr. The yield of the pale yellow syrup was 485 grams (88.5% of theoretical) and the initial assay by 31P NMR was 99.7%. Table 1 shows a comparison of the stability of this material (A) vs. a sample prepared in the same manner, but without the alumina treatment (B).
Example 2
Preparation and Stabilization of 2-Cyanoethyl- N,N,N',N'-tetraisopropylphosphoro-diamidite (PDA).
In the same manner as detailed in Example 1 , a reaction of 1.44 moles of CDP (248 grams) and 7.21 moles of DIPA (728 grams) in 3.0 Kg of toluene as the solvent showed, after 44 hours at ambient temperature, no evidence by 31P NMR that any reaction intermediates remained. The yield of very pale yellow syrup was 458 grams (103% of theoretical) and the initial assay by 31P NMR was 97.5%. Table 1 shows a comparison of the stability of this material (C) vs. a sample prepared in the same manner, but without the alumina treatment (D).
Table 1
Claims
1. A method of producing cyanoalkyl tetraalkylphosphordiamidite comprising: a) reacting phosphorus trihalide with cyano-containing agent to form cyanoalkylphosphordihalidite; b) reacting the cyanoalkylphosphordihalidite with a dialkylamine to form cyanoalkyl tetraalkylphosphordiamidite and amine hydrohalide byproduct at least a portion of which is in the form of a precipitate; c) removing the amine hydrohalide precipitate by filtration to form a filtrate which may contain dissolved amine hydrohalide; and d) treating the filtrate with an a substance capable of removing any dissolved amine hydrohalide from the filtrate.
2. The method of claim 1 wherein the substance capable of removing dissolved amine hydrohalide from the filtrate is selected from the group consisting of adsorbents and polymer-supported neutralizing agents.
3. The method of claim 2 wherein the adsorbents are selected from the group consisting of alumina, silica gel, Florisil, Decalite and combinations thereof.
4. The method of claim 2 wherein the polymer-supported neutralizing agents are selected from the group consisting of triethylammonium methylpolystyrene carbonate and N, N-(diisopropyl)aminomethylpolystyrene.
5. The method of claim 1 further comprising removing the adsorbent containing the amine hydrohalide.
6. The method of claim 1 wherein the phosphorus trihalide is phosphorus trichloride.
7. The method of claim 1 wherein the cyano-containing reagent is selected from the group consisting of cyanoalkanol and cyanoalkoxytrialkylsilane.
8. The method of claim 7 wherein the alkanol group of the cyanoalkanol has from 1 to 6 carbon atoms.
9. The method of claim 8 wherein the alkanol group is ethanol.
10. The method of claim 7 wherein the alkoxy and alkyl groups of the cyanoalkoxytrialkylsilane have from 1 to 6 carbon atoms.
11. The method of claim 10 wherein the alkoxy group is ethoxy and the alkyl group is methyl.
12. The method of claim 1 wherein the alkyl group of the dialkylamine has from 1 to 6 carbon atoms.
13. The method of claim 1 further comprising neutralizing the hydrohalide by the addition of an excess of a neutralizing amine to precipitate at least a portion of the amine hydrohalide.
14. The method of claim 13 wherein the neutralizing amine is selected from the group consisting of dialkylamines and tertiary amines.
15. The method of claim 2 wherein the adsorbent is employed in the presence of a solvent.
16. The method of claim 15 wherein the solvent is selected from the group consisting of tetrahydrofuran, diethyl ether, toluene, hexane and mixtures thereof.
17. The method of claim 2 wherein the substance capable of removing dissolved amine hydrohalide is a polymer-supported neutralizing agent.
18. The method of claim 17 wherein the polymer-supported neutralizing agent is selected from the group consisting of triethylammonium methylpolystyrene carbonate and N,N-(diisopropyI)aminomethylpolystyrene.
19. A product produced by the process of claim 1.
20. A stable form of cyanoalkyl tetraalkylphosphordiamidite substantially free of amine hydrohalide being stable at ambient temperatures for an extended period of time.
21. The stable form of cyanoalkyl tetraalkylphosphordiamidite of claim 20 being stable at 22°C for at least 120 days.
Priority Applications (4)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP2004513299A JP2005529957A (en) | 2002-06-13 | 2003-06-09 | Process for producing phosphorus diamidite compound |
| CA002487036A CA2487036C (en) | 2002-06-13 | 2003-06-09 | Process of making phosphordiamidite compounds |
| AU2003243432A AU2003243432A1 (en) | 2002-06-13 | 2003-06-09 | Process of making phosphordiamidite compounds |
| EP03760241.4A EP1539772B1 (en) | 2002-06-13 | 2003-06-09 | Process of making phosphordiamidite compounds |
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US38822402P | 2002-06-13 | 2002-06-13 | |
| US60/388,224 | 2002-06-13 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| WO2003106468A1 true WO2003106468A1 (en) | 2003-12-24 |
Family
ID=29736444
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| PCT/US2003/017982 WO2003106468A1 (en) | 2002-06-13 | 2003-06-09 | Process of making phosphordiamidite compounds |
Country Status (7)
| Country | Link |
|---|---|
| US (1) | US7034177B2 (en) |
| EP (1) | EP1539772B1 (en) |
| JP (1) | JP2005529957A (en) |
| CN (1) | CN100338076C (en) |
| AU (1) | AU2003243432A1 (en) |
| CA (1) | CA2487036C (en) |
| WO (1) | WO2003106468A1 (en) |
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2004058779A1 (en) * | 2002-12-24 | 2004-07-15 | Rhodia Consumer Specialties Limited | Process for preparing phosphorodiamidites |
| WO2019216433A1 (en) | 2018-05-10 | 2019-11-14 | 日本新薬株式会社 | Method for producing oligonucleic acid compound |
| WO2021095874A1 (en) | 2019-11-13 | 2021-05-20 | 日本新薬株式会社 | Method for producing oligonucleic acid compound |
| WO2021095875A1 (en) | 2019-11-13 | 2021-05-20 | 日本新薬株式会社 | Method for producing oligonucleic acid compound |
Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5412088A (en) * | 1989-11-20 | 1995-05-02 | Rutgers, The State University | 6-O-substituted guanosine derivatives |
| WO1997042208A1 (en) * | 1996-05-03 | 1997-11-13 | Hybridon, Inc. | In situ preparation of nucleoside phosphoramidites and their use in synthesis of oligonucleotides |
| US5705621A (en) * | 1995-11-17 | 1998-01-06 | Isis Pharmaceuticals, Inc. | Oligomeric phosphite, phosphodiester, Phosphorothioate and phosphorodithioate compounds and intermediates for preparing same |
| US5863905A (en) * | 1994-09-14 | 1999-01-26 | Temple University-Of The Commonwealth System Of Higher Education | 2',5'-phosphorothioate/phosphodiester oligoadenylates and anti-viral uses thereof |
Family Cites Families (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US2085784A (en) * | 1935-04-29 | 1937-07-06 | Girdler Corp | Process of purifying aminated compounds |
| JPS62212394A (en) * | 1986-03-11 | 1987-09-18 | Nippon Zeon Co Ltd | Novel phosphorus amide compound |
| JPH0770010A (en) * | 1993-09-03 | 1995-03-14 | Toho Chem Ind Co Ltd | Dialkanolamine derivative and its production |
-
2003
- 2003-06-09 CA CA002487036A patent/CA2487036C/en not_active Expired - Lifetime
- 2003-06-09 AU AU2003243432A patent/AU2003243432A1/en not_active Abandoned
- 2003-06-09 EP EP03760241.4A patent/EP1539772B1/en not_active Expired - Lifetime
- 2003-06-09 JP JP2004513299A patent/JP2005529957A/en active Pending
- 2003-06-09 CN CNB038135132A patent/CN100338076C/en not_active Expired - Lifetime
- 2003-06-09 US US10/457,177 patent/US7034177B2/en not_active Expired - Lifetime
- 2003-06-09 WO PCT/US2003/017982 patent/WO2003106468A1/en active Application Filing
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5412088A (en) * | 1989-11-20 | 1995-05-02 | Rutgers, The State University | 6-O-substituted guanosine derivatives |
| US5863905A (en) * | 1994-09-14 | 1999-01-26 | Temple University-Of The Commonwealth System Of Higher Education | 2',5'-phosphorothioate/phosphodiester oligoadenylates and anti-viral uses thereof |
| US5705621A (en) * | 1995-11-17 | 1998-01-06 | Isis Pharmaceuticals, Inc. | Oligomeric phosphite, phosphodiester, Phosphorothioate and phosphorodithioate compounds and intermediates for preparing same |
| WO1997042208A1 (en) * | 1996-05-03 | 1997-11-13 | Hybridon, Inc. | In situ preparation of nucleoside phosphoramidites and their use in synthesis of oligonucleotides |
Non-Patent Citations (1)
| Title |
|---|
| GU ET AL.: "Synthesis of phosphotriester analogues of the phosphoinositides PtdIns(4,5)P2 and PtdIns (3,4,5)P3", JOURNAL OF ORGANIC CHEMISTRY, vol. 61, 1996, pages 8642 - 8647, XP002973221 * |
Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2004058779A1 (en) * | 2002-12-24 | 2004-07-15 | Rhodia Consumer Specialties Limited | Process for preparing phosphorodiamidites |
| US7276620B2 (en) | 2002-12-24 | 2007-10-02 | Rhodia Consumer Specialties Limited | Process for preparing phosphorodiamidites |
| WO2019216433A1 (en) | 2018-05-10 | 2019-11-14 | 日本新薬株式会社 | Method for producing oligonucleic acid compound |
| WO2021095874A1 (en) | 2019-11-13 | 2021-05-20 | 日本新薬株式会社 | Method for producing oligonucleic acid compound |
| WO2021095875A1 (en) | 2019-11-13 | 2021-05-20 | 日本新薬株式会社 | Method for producing oligonucleic acid compound |
Also Published As
| Publication number | Publication date |
|---|---|
| EP1539772B1 (en) | 2013-09-11 |
| US20030236233A1 (en) | 2003-12-25 |
| AU2003243432A1 (en) | 2003-12-31 |
| US7034177B2 (en) | 2006-04-25 |
| CA2487036C (en) | 2008-10-28 |
| CN100338076C (en) | 2007-09-19 |
| EP1539772A4 (en) | 2006-06-07 |
| JP2005529957A (en) | 2005-10-06 |
| CA2487036A1 (en) | 2003-12-24 |
| CN1659173A (en) | 2005-08-24 |
| EP1539772A1 (en) | 2005-06-15 |
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