CN102702265A - Phosphorodiamidate morpholino oligomer synthetized by solid phase and method thereof - Google Patents
Phosphorodiamidate morpholino oligomer synthetized by solid phase and method thereof Download PDFInfo
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Abstract
The invention relates to a method for synthetizing phosphorodiamidate morpholino oligomer by solid phase. A cheap resin is utilized; Wang resin is as a solid phase carrier; the phosphorodiamidate morpholino oligomer (PMO) structure of which terminal hydroxyl is protected by tert-butyl dimethyl silicon is shown in the description, wherein a structure of basic group B is any one of adenine (A), guanine (G), cytosine (C) and thymine (T). Compared with the existing solid phase synthetic technology, the method provided by the invention can greatly reduce synthetic cost, and can be suitable for mass production of phosphorodiamidate morpholino oligomer.
Description
Technical field
The present invention relates to organic-biological medicine technical field, independent research synthetic phosphoryl diamine morpholino oligonucleotide (PMO) of a kind of new solid-state and method.
Background technology
U.S. Pat 5185444 has mainly been introduced the method for synthetic phosphoryl diamine morpholino oligonucleotide.Its maximum contribution is the method that has at first intactly proposed synthetic phosphoryl diamine morpholino oligonucleotide.Weak point is that this method was continued to use 20 years, for solid phase synthesis; Used resin LCAA-CPG as solid phase carrier; This resin is extremely expensive, and domestic not production has only import; Price is at 15000 yuan/10 grams (Sigma's aldrich corporate rate), and therefore synthetic cost is huge.Present stage because phosphoryl diamine morpholino oligonucleotide has had breakthrough in medical use, has arrived clinical experimental stage, needs resultant quantity bigger, so need consider from synthetic cost, minimizes cost.
The LCAA-CPG structure:
Summary of the invention
The problem that the present invention will solve is to have adopted a kind of resin that cheaply is easy to get: king's resin is as solid phase carrier, develops a kind of method of new solid phase synthesis phosphoryl diamine morpholino oligonucleotide (PMO).This compound method not only reaches the level of original technology type like reaction on total recovery; And because the price of the solid phase carrier king resin that adopts has only 3000 yuan/kilogram (biochemical (Shanghai) prices of gill); So can reduce cost greatly, the synthetic in a large number scale of suitable feather weight.For having made outstanding contribution in the medical use at home.
Technical scheme of the present invention is following:
A kind of phosphoryl diamine morpholino oligonucleotide of solid phase synthesis has adopted king's resin as solid phase carrier, phosphoryl diamine morpholino oligonucleotide (PMO) structure that terminal hydroxyl is protected with tertiary butyl dimethyl-silicon:
The structure of said PMO-king's resin:
Wherein the structure of base B is: any one of VITAMIN B4 (A), guanine (G), cytosine(Cyt) (C) or four kinds of bases of thymus pyrimidine (T).
In said PMO-king's resin structure, the base B at two ends is identical or different a kind of bases up and down; Base B in the multiple unit is the wherein one or any permutation and combination of these four kinds of bases.
The structure of several typical PMO (n)-king's resin is described:
N=1, base B are respectively the structure of PMO (A-T)-king's resin of VITAMIN B4 (A) and thymus pyrimidine (T):
N=2, base B are respectively the structure of PMO (A-T)-king's resin of VITAMIN B4 (A) and thymus pyrimidine (T):
N=3, the structure of PMO (G-C-A-T)-king's resin:
The method of solid phase synthesis phosphoryl diamine morpholino oligonucleotide of the present invention, concrete reactions step is following:
1) containing a kind of morpholino verivate of base group B and the molar feed ratio of TERT-BUTYL DIMETHYL CHLORO SILANE is 1/1.3, is dissolved in the methylene dichloride, and the methylene dichloride consumption enough gets final product morpholino verivate and TERT-BUTYL DIMETHYL CHLORO SILANE dissolving; Under stirring at room, add imidazoles, the mol ratio of the add-on of imidazoles and morpholino verivate is 3/1; React 5 hours afterreaction things and use water washing, use anhydrous sodium sulfate drying, obtaining the bullion product behind the removal solvent is colourless oil;
2) the colourless oil of the first step reaction product is dissolved in the trifluoroacetic acid that contains acetate, and the volume ratio of acetate and trifluoroacetic acid is 1/50, stirs 4 hours, removes solvent afterwards and obtains white solid;
3) the second step reaction product white solid is dissolved in the water and dioxane that volume ratio is 1:1, adds yellow soda ash in room temperature; Water and washed with dichloromethane after the reactant stirred overnight, organic phase is used anhydrous sodium sulfate drying, removes solvent, and bullion obtains white solid through behind the column chromatography purification;
4) king's resin is put in the solid phase synthesis pipe; Add three-step reaction product white solid then; The molar feed ratio of king's resin and three-step reaction product white solid is 1/1, and NSC 57182 (DCC) and 4-Dimethylamino pyridine (DMAP) are respectively 1.3/1 and 0.35/1 with the molar feed ratio of three-step reaction product; The solid phase synthesis pipe is placed on the shaking table and reacted 12 hours, and solid-phase resin is used a large amount of washed with dichloromethane then, obtains product;
5) in the solid phase synthesis pipe that the four-step reaction product is housed, add the tetrabutyl ammonium fluoride tetrahydrofuran solution, strength of solution is 100 mg/ml; The solid phase synthesis pipe is placed on the shaking table reaction 4 hours then, and solid-phase resin obtains product after with THF and washed with dichloromethane;
6) contain a kind of base group B and with the morpholino verivate after the phosphoryl diamine activation and the 5th the step reaction, the molar feed ratio scope is 2-9/1, being dissolved in concentration is in the triethylamine dichloromethane solution of 50 mg/ml, puts in the solid phase synthesis pipe; Obtain product with a large amount of washed with dichloromethane after the reaction overnight;
7) in the solid phase synthesis pipe that the six-step process product is housed, adding concentration is the tetrabutyl ammonium fluoride tetrahydrofuran solution of 100 mg/ml; The solid phase synthesis pipe is placed on the shaking table reaction 4 hours then, and solid-phase resin obtains product after with THF and washed with dichloromethane.
Morpholino monomer number (n+1) according to different base B; Repeat six steps of n order, the reaction of the 7th step, with (n+1) individual different base B (1,2; 3; 4) morpholino monomer connects through phosphoryl diamine, under the ammoniacal liquor condition, product is scaled off from this solid phase carrier of king's resin at last, obtains phosphoryl diamine morpholino oligonucleotide.
Work as n=1; The base group B is VITAMIN B4 (A) in the first step reaction; The base group B is thymus pyrimidine (T) in the six-step process, under the ammoniacal liquor condition, the 7th step reaction product is scaled off from this solid phase carrier of king's resin, obtains phosphoryl diamine morpholino oligonucleotide (A-T).
Work as n=2; The base group B is VITAMIN B4 (A) in the first step reaction; The base group B is thymus pyrimidine (T) in the six-step process; Contain the base group B and be cytosine(Cyt) (C) and with morpholino verivate after the phosphoryl diamine activation and the 7th step reaction product, molar feed ratio is 9/1, be dissolved in concentration and be in the triethylamine dichloromethane solution of 50 mg/ml and put in the solid phase synthesis pipe; Obtain product with a large amount of washed with dichloromethane after the reaction overnight; In the solid phase synthesis pipe that this product is housed, adding concentration is the tetrabutyl ammonium fluoride tetrahydrofuran solution of 100 mg/ml; The solid phase synthesis pipe is placed on the shaking table reaction 4 hours then, solid-phase resin with THF and washed with dichloromethane after, under the ammoniacal liquor condition, this product is scaled off from this solid phase carrier of king's resin, obtain phosphoryl diamine morpholino oligonucleotide (C-A-T).
Work as n=3, the base group B is VITAMIN B4 (A) in the first step reaction, and the base group B is thymus pyrimidine (T) in the six-step process; Contain the base group B and be guanine (G) and with morpholino verivate after the phosphoryl diamine activation and the 7th step reaction product; This product is not still downcut on solid phase carrier; Molar feed ratio is 2/1, is dissolved in concentration and is in the triethylamine dichloromethane solution of 50 mg/ml putting in the solid phase synthesis pipe; Obtain product with a large amount of washed with dichloromethane after the reaction overnight; In the solid phase synthesis pipe that this product is housed, adding concentration is the tetrabutyl ammonium fluoride tetrahydrofuran solution of 100 mg/ml; The solid phase synthesis pipe is placed on the shaking table reaction 4 hours then, solid-phase resin with THF and washed with dichloromethane after, under the ammoniacal liquor condition, this product is scaled off phosphoryl diamine morpholino oligonucleotide (G-C-A-T) from this solid phase carrier of king's resin.
It is following to specify concrete synthetic route:
(1) general synthetic route:
General synthesis step:
The first step reaction:
The feed ratio (mol ratio) of morpholino verivate 1 and TERT-BUTYL DIMETHYL CHLORO SILANE is 1/1.3, is dissolved in the methylene dichloride, and the methylene dichloride consumption enough gets final product morpholino verivate and TERT-BUTYL DIMETHYL CHLORO SILANE dissolving.Under stirring at room, add imidazoles, the mol ratio of the add-on of imidazoles and morpholino verivate is 3/1.React 5 hours afterreaction things and use water washing, use anhydrous sodium sulfate drying, obtain bullion product 2 behind the removal solvent and be colourless oil.
The reaction of second step:
Compound 2 is dissolved in the trifluoroacetic acid that contains acetate, and the volume ratio of acetate and trifluoroacetic acid is 1/50, stirs 4 hours, removes solvent afterwards and obtains white solid 3.
Three-step reaction:
Compound 3 water-soluble and dioxane (volume ratios: 1/1), add yellow soda ash in room temperature.Water and washed with dichloromethane after the reactant stirred overnight, organic phase is used anhydrous sodium sulfate drying, removes solvent, and bullion is white solid through obtaining compound 4 behind the column chromatography purification.
Four-step reaction:
King's resin is put in the solid phase synthesis pipe; Add compound 4 then; The molar feed ratio of king's resin and compound 4 is 1/1, and NSC 57182 (DCC) and 4-Dimethylamino pyridine (DMAP) are respectively 1.3/1 and 0.35/1 with the molar feed ratio of three-step reaction product.The solid phase synthesis pipe is placed on the shaking table and reacted 12 hours, and solid-phase resin is used a large amount of washed with dichloromethane then, obtains 5.
The reaction of the 5th step:
Add tetrabutyl ammonium fluoride tetrahydrofuran solution (strength of solution: 100 mg/ml) in 5 the solid phase synthesis pipe to being equipped with.The solid phase synthesis pipe is placed on the shaking table reaction 4 hours then, and solid-phase resin obtains 6 after with THF and washed with dichloromethane.
Six-step process:
Contain the base group B and be dissolved in triethylamine dichloromethane solution (concentration: put into 50 mg/ml) in the solid phase synthesis pipe with morpholino verivate 1-B after the phosphoryl diamine activation and compound 6 (molar feed ratio 2-9/1).Obtain 7 with a large amount of washed with dichloromethane after the reaction overnight.
The reaction of the 7th step:
Add tetrabutyl ammonium fluoride tetrahydrofuran solution (strength of solution: 100 mg/ml) in 7 the solid phase synthesis pipe to being equipped with.The solid phase synthesis pipe is placed on the shaking table reaction 4 hours then, and solid-phase resin obtains 8 after with THF and washed with dichloromethane.
The reaction of the 8th step:
According to the morpholino monomer number of different base B, repeat the 6th step, the 7th step reaction, connect with the morpholino monomer of a plurality of different base B 8, obtain 9.
The reaction of the 9th step:
Under the ammoniacal liquor condition, scale off from this solid phase carrier of king's resin 9, obtain PMO (polymer), the amino on the terminal morpholine ring can use the protection base to protect again.
Core of the present invention is to have adopted a kind of resin that cheaply is easy to get: king's resin synthesizes phosphoryl diamine morpholino oligonucleotide as solid phase carrier.
Compare with background patents (US5185444) solid phase synthesis technique; Synthetic total recovery is more or less the same; But adopted a kind of resin that extremely cheaply is easy to get among the present invention: king's resin is as solid phase carrier, and the price of this resin has only 3000 yuan/kilogram, employed LCAA-CPG resin in the background patents (15000 yuan/10 gram); Thereby greatly reduce synthetic cost, be fit to the mass production of phosphoryl diamine morpholino oligonucleotide product.
Embodiment
Embodiment 1: Compound P MO's (A-T) is synthetic:
With base A and T is example, and the synthetic route of PMO (A-T) is:
The feed ratio of T-5 and TERT-BUTYL DIMETHYL CHLORO SILANE (mol ratio) is 1/1.3, is dissolved in the methylene dichloride.Under stirring at room, add imidazoles, the mol ratio of the add-on of imidazoles and morpholino verivate is 3/1.React 5 hours afterreaction things and use water washing, use anhydrous sodium sulfate drying, obtaining bullion product T-6 behind the removal solvent is colourless oil.
The reaction of second step:
T-6 is dissolved in the trifluoroacetic acid that contains acetate, and the volume ratio of acetate and trifluoroacetic acid is 1/50, stirs 4 hours, removes solvent afterwards and obtains T-7.
Three-step reaction:
Water-soluble and the dioxane (volume ratio: 1/1), add yellow soda ash of T-7 in room temperature.Water and washed with dichloromethane after the reactant stirred overnight, organic phase is used anhydrous sodium sulfate drying, removes solvent, and bullion obtains T-8 through behind the column chromatography purification.
Four-step reaction:
King's resin is put in the solid phase synthesis pipe; Add compound T-8 (molar feed ratio of king's resin and compound 4 is 1/1) then, NSC 57182 (DCC) and 4-Dimethylamino pyridine (DMAP) are respectively 1.3/1 and 0.35/1 with the molar feed ratio of three-step reaction product.The solid phase synthesis pipe is placed on the shaking table and reacted 12 hours, and solid-phase resin is used a large amount of washed with dichloromethane then, obtains R-1.
The reaction of the 5th step:
In the solid phase synthesis pipe that R-1 is housed, add tetrabutyl ammonium fluoride tetrahydrofuran solution (strength of solution: 100 mg/ml).The solid phase synthesis pipe is placed on the shaking table reaction 4 hours then, and solid-phase resin obtains R-2 after with THF and washed with dichloromethane.
Six-step process:
Compd A-8 and R-2 (molar feed ratio: 7/1) be dissolved in triethylamine dichloromethane solution (concentration: put into 50 mg/ml) in the solid phase synthesis pipe.Obtain R-3 with a large amount of washed with dichloromethane after the reaction overnight.
The reaction of the 7th step:
Step obtains R-4 with the reaction of the 5th step.
The reaction of the 8th step:
Under the ammoniacal liquor condition, R-4 is scaled off from this solid phase carrier of king's resin, obtain PMO (A-T).Amino on the terminal morpholine ring can use the protection base to protect again.
Embodiment 2: Compound P MO's (C-A-T) is synthetic:
Synthetic route:
The first step reaction:
Compound C-8 and R-4 (molar feed ratio: 9/1) be dissolved in triethylamine dichloromethane solution (concentration: put into 50 mg/ml) in the solid phase synthesis pipe.Obtain R-5 with a large amount of washed with dichloromethane after the reaction overnight.
The reaction of second step:
In the solid phase synthesis pipe that R-5 is housed, add tetrabutyl ammonium fluoride tetrahydrofuran solution (strength of solution: 100 mg/ml).The solid phase synthesis pipe is placed on the shaking table reaction 4 hours then, and solid-phase resin obtains R-6 after with THF and washed with dichloromethane.
The reaction of the tenth step:
Under the ammoniacal liquor condition, R-4 is scaled off from this solid phase carrier of king's resin, obtain PMO (C-A-T).Amino on the terminal morpholine ring can use the protection base to protect again.
Embodiment 3: Compound P MO's (G-C-A-T) is synthetic:
The first step reaction:
Compound G-8 and R-6 (molar feed ratio: 2/1) be dissolved in triethylamine dichloromethane solution (concentration: put into 50 mg/ml) in the solid phase synthesis pipe.Obtain R-7 with a large amount of washed with dichloromethane after the reaction overnight.
The reaction of second step:
In the solid phase synthesis pipe that R-7 is housed, add tetrabutyl ammonium fluoride tetrahydrofuran solution (strength of solution: 100 mg/ml).The solid phase synthesis pipe is placed on the shaking table reaction 4 hours then, and solid-phase resin obtains R-8 after with THF and washed with dichloromethane.
Three-step reaction:
Under the ammoniacal liquor condition, R-8 is scaled off from this solid phase carrier of king's resin, obtain PMO (G-C-A-T).Amino on the terminal morpholine ring can use the protection base to protect again.
Claims (10)
1. a solid phase synthesis phosphoryl diamine morpholino oligonucleotide is characterized in that having adopted king's resin as solid phase carrier, phosphoryl diamine morpholino oligonucleotide (PMO) structure that terminal hydroxyl is protected with tertiary butyl dimethyl-silicon:
The structure of said PMO-king's resin:
Wherein the structure of base B is: any one of VITAMIN B4 (A), guanine (G), cytosine(Cyt) (C) or four kinds of bases of thymus pyrimidine (T).
2. solid phase synthesis phosphoryl diamine morpholino oligonucleotide as claimed in claim 1 is characterized in that in said PMO-king's resin structure, and the base B at two ends is identical or different a kind of bases up and down; Base B in the multiple unit is the wherein one or any permutation and combination of these four kinds of bases.
3. solid phase synthesis phosphoryl diamine morpholino oligonucleotide as claimed in claim 1 is characterized in that the structure of described PMO-king's resin is:
N=1, base B are respectively the structure of PMO (A-T)-king's resin of VITAMIN B4 (A) and thymus pyrimidine (T):
4. solid phase synthesis phosphoryl diamine morpholino oligonucleotide as claimed in claim 1 is characterized in that the structure of described PMO-king's resin is:
N=2, base B are respectively the structure of PMO (A-T)-king's resin of VITAMIN B4 (A) and thymus pyrimidine (T):
5. solid phase synthesis phosphoryl diamine morpholino oligonucleotide as claimed in claim 1 is characterized in that the structure of described PMO-king's resin is:
N=3, the structure of PMO (G-C-A-T)-king's resin:
6. the method for solid phase synthesis phosphoryl diamine morpholino oligonucleotide as claimed in claim 1 is characterized in that concrete reactions step is following:
1) containing a kind of morpholino verivate of base group B and the molar feed ratio of TERT-BUTYL DIMETHYL CHLORO SILANE is 1/1.3, is dissolved in the methylene dichloride, and the methylene dichloride consumption enough gets final product morpholino verivate and TERT-BUTYL DIMETHYL CHLORO SILANE dissolving; Under stirring at room, add imidazoles, the mol ratio of the add-on of imidazoles and morpholino verivate is 3/1; React 5 hours afterreaction things and use water washing, use anhydrous sodium sulfate drying, obtaining the bullion product behind the removal solvent is colourless oil;
2) the colourless oil of the first step reaction product is dissolved in the trifluoroacetic acid that contains acetate, and the volume ratio of acetate and trifluoroacetic acid is 1/50, stirs 4 hours, removes solvent afterwards and obtains white solid;
3) to be dissolved in volume ratio be in 1: 1 the water and dioxane, at room temperature adding yellow soda ash to the second step reaction product white solid; Water and washed with dichloromethane after the reactant stirred overnight, organic phase is used anhydrous sodium sulfate drying, removes solvent, and bullion obtains white solid through behind the column chromatography purification;
4) king's resin is put in the solid phase synthesis pipe; Add three-step reaction product white solid then; The molar feed ratio of king's resin and three-step reaction product white solid is 1/1, and the molar feed ratio of NSC 57182 and 4-Dimethylamino pyridine and three-step reaction product is respectively 1.3/1 and 0.35/1; The solid phase synthesis pipe is placed on the shaking table and reacted 12 hours, and solid-phase resin is used a large amount of washed with dichloromethane then, obtains product;
5) in the solid phase synthesis pipe that the four-step reaction product is housed, add the tetrabutyl ammonium fluoride tetrahydrofuran solution, strength of solution is 100 mg/ml; The solid phase synthesis pipe is placed on the shaking table reaction 4 hours then, and solid-phase resin obtains product after with THF and washed with dichloromethane;
6) contain a kind of base group B and with the morpholino verivate after the phosphoryl diamine activation and the 5th the step reaction, the molar feed ratio scope is 2-9/1, being dissolved in concentration is in the triethylamine dichloromethane solution of 50 mg/ml, puts in the solid phase synthesis pipe; Obtain product with a large amount of washed with dichloromethane after the reaction overnight;
7) in the solid phase synthesis pipe that the six-step process product is housed, adding concentration is the tetrabutyl ammonium fluoride tetrahydrofuran solution of 100 mg/ml; The solid phase synthesis pipe is placed on the shaking table reaction 4 hours then, and solid-phase resin obtains product after with THF and washed with dichloromethane.
7. the method for solid phase synthesis phosphoryl diamine morpholino oligonucleotide as claimed in claim 6 is characterized in that the morpholino monomer number (n+1) according to different base B, repeats six steps of n order, the reaction of the 7th step; With (n+1) individual different base B (1; 2,3,4) morpholino monomer connects through phosphoryl diamine; Under the ammoniacal liquor condition, product is scaled off from this solid phase carrier of king's resin at last, obtain phosphoryl diamine morpholino oligonucleotide.
8. like the method for claim 6 or 7 described solid phase synthesis phosphoryl diamine morpholino oligonucleotide; It is characterized in that n=1; The base group B is VITAMIN B4 (A) in the first step reaction; The base group B is thymus pyrimidine (T) in the six-step process, under the ammoniacal liquor condition, the 7th step reaction product is scaled off from this solid phase carrier of king's resin, obtains phosphoryl diamine morpholino oligonucleotide (A-T).
9. like the method for claim 6 or 7 described solid phase synthesis phosphoryl diamine morpholino oligonucleotide; It is characterized in that n=2; The base group B is VITAMIN B4 (A) in the first step reaction, and the base group B is thymus pyrimidine (T) in the six-step process, contains the base group B and is cytosine(Cyt) (C) and go on foot reaction product with the morpholino verivate after the phosphoryl diamine activation and the 7th; Molar feed ratio is 9/1, is dissolved in concentration and is in the triethylamine dichloromethane solution of 50 mg/ml putting in the solid phase synthesis pipe; Obtain product with a large amount of washed with dichloromethane after the reaction overnight; In the solid phase synthesis pipe that this product is housed, adding concentration is the tetrabutyl ammonium fluoride tetrahydrofuran solution of 100 mg/ml; The solid phase synthesis pipe is placed on the shaking table reaction 4 hours then, solid-phase resin with THF and washed with dichloromethane after, under the ammoniacal liquor condition, this product is scaled off from this solid phase carrier of king's resin, obtain phosphoryl diamine morpholino oligonucleotide (C-A-T).
10. like the method for claim 6 or 7 described solid phase synthesis phosphoryl diamine morpholino oligonucleotide, it is characterized in that n=3, the base group B is VITAMIN B4 (A) in the first step reaction, and the base group B is thymus pyrimidine (T) in the six-step process; Contain the base group B and be guanine (G) and with morpholino verivate after the phosphoryl diamine activation and the 7th step reaction product; This product is not still downcut on solid phase carrier; Molar feed ratio is 2/1, is dissolved in concentration and is in the triethylamine dichloromethane solution of 50 mg/ml putting in the solid phase synthesis pipe; Obtain product with a large amount of washed with dichloromethane after the reaction overnight; In the solid phase synthesis pipe that this product is housed, adding concentration is the tetrabutyl ammonium fluoride tetrahydrofuran solution of 100 mg/ml; The solid phase synthesis pipe is placed on the shaking table reaction 4 hours then, solid-phase resin with THF and washed with dichloromethane after, under the ammoniacal liquor condition, this product is scaled off phosphoryl diamine morpholino oligonucleotide (G-C-A-T) from this solid phase carrier of king's resin.
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| WO2017024264A3 (en) * | 2015-08-05 | 2017-03-30 | Eisai R&D Management Co., Ltd. | Chiral reagents for preparation of homogeneous oligomers |
| JP2019534862A (en) * | 2016-09-20 | 2019-12-05 | ザ リージェンツ オブ ザ ユニヴァーシティ オブ コロラド，ア ボディ コーポレイト | Synthesis of backbone-modified morpholino oligonucleotides and chimeras using phosphoramidite chemistry |
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| TWI738784B (en) * | 2016-05-24 | 2021-09-11 | 美商薩羅塔治療公司 | Processes for preparing oligomers |
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| WO2017024264A3 (en) * | 2015-08-05 | 2017-03-30 | Eisai R&D Management Co., Ltd. | Chiral reagents for preparation of homogeneous oligomers |
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| CN108350005B (en) * | 2015-08-05 | 2024-02-06 | 卫材R&D管理有限公司 | Chiral agent for preparing homogeneous oligomer |
| TWI737736B (en) * | 2016-05-24 | 2021-09-01 | 美商薩羅塔治療公司 | Processes for preparing phosphorodiamidate morpholino oligomers |
| TWI738784B (en) * | 2016-05-24 | 2021-09-11 | 美商薩羅塔治療公司 | Processes for preparing oligomers |
| JP2019534862A (en) * | 2016-09-20 | 2019-12-05 | ザ リージェンツ オブ ザ ユニヴァーシティ オブ コロラド，ア ボディ コーポレイト | Synthesis of backbone-modified morpholino oligonucleotides and chimeras using phosphoramidite chemistry |
| JP2021046396A (en) * | 2016-09-20 | 2021-03-25 | ザ リージェンツ オブ ザ ユニヴァーシティ オブ コロラド，ア ボディ コーポレイト | Synthesis of backbone modified morpholino oligonucleotides and chimeras using phosphoramidite chemistry |
| WO2022006871A1 (en) * | 2020-07-10 | 2022-01-13 | Changzhou Syntheall Pharmaceuticals Co., Ltd. | Processes for preparing oligonucleotides |
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