JP7022079B2 - Process for preparing phosphorodiamidart morpholino oligomers - Google Patents

Description

Related Applications This patent application is a US provisional patent application No. 62 / 508,256 filed on May 18, 2017, and a US provisional patent application No. 62 / 341,049 filed on May 24, 2016. , US Provisional Patent Application No. 62 / 340,953 filed May 24, 2016, US Provisional Patent Application No. 62 / 357,134 filed June 30, 2016, and June 2016. Claims the interests of US Provisional Patent Application No. 62 / 357,153 filed on the 30th. The entire contents of the provisional patent application referred to above are incorporated herein by reference.

Antisense techniques provide a means for regulating the expression of one or more specific gene products, including alternative splicing products, and are very useful in many therapeutic, diagnostic and research applications. The principle behind antisense technology is that antisense compounds that hybridize to the target nucleic acid, such as oligonucleotides, regulate gene expression activity such as transcription, splicing or translation through any one of several antisense mechanisms. That is. Due to the sequence specificity of the antisense compounds, they are attractive as tools for target evaluation and gene functionalization, as well as therapeutic agents for selectively regulating the expression of genes involved in the disease.

Duchenne muscular dystrophy (DMD) is caused by a defective expression of the protein dystrophin. The gene encoding this protein contains 79 exons spread across over 2 million nucleotides of DNA. Mutations in any exon, or duplication of one or more exons, characterized by altering the exon reading frame, introducing stop codons, or removing the entire out-of-frame exon (s) or duplication of one or more exons are functional. It has the potential to interfere with the production of sex dystrophin, resulting in DMD.

Recent clinical trials testing the safety and efficacy of splice-switching oligonucleotides (SSOs) for the treatment of DMD are based on SSO techniques that induce alternative splicing of premRNA by steric blockade of spliceosomes (SSO technology). Cirak et al., 2011; Goemans et al., 2011; Kinali et al., 2009; van Deutekom et al., 2007). However, despite these successes, the pharmacological options available for the treatment of DMD are limited.

Casimersen is a phosphorology designed to skip exon 45 of the human dystrophin gene in DMD patients to whom exon 45 skip is applicable to repair the reading frame and produce functionally shorter forms of the dystrophin protein. It is an amidatomorpholino oligomer (PMO).

Although significant advances have been made in the field of antisense technology, there is still a need in the art for methods of preparing phosphorodiamidate morpholino oligomers with improved antisense or antigene performance.

A process for preparing a phosphorodiamidate morpholino oligomer (PMO) is provided herein. The synthetic process described herein allows for scale-up of PMO synthesis while maintaining overall yield and purity of PMO synthesized.

のオリゴマー化合物を調製するためのプロセスが本明細書に提供される。 Therefore, in one aspect, the formula (A):

A process for preparing an oligomeric compound of is provided herein.

のオリゴマー化合物を調製するためのプロセスが本明細書に提供される。 In one embodiment, formula (C):

A process for preparing an oligomeric compound of is provided herein.

のオリゴマー化合物である。 In yet another embodiment, the oligomeric compounds of the present disclosure, including, for example, some embodiments of the oligomeric compound of formula (C), are of formula (XII) :.

It is an oligomer compound of.

For clarity, for example, the structural formula containing the oligomeric compound of formula (C) and Casimersen represented by formula (XII) is a continuous structural formula from 5'to 3', the entire formula being described above. For convenience, illustrated in small structural formulas, Applicants include various illustrated interruptions labeled "Interruption A" and "Interruption B". As will be appreciated by those skilled in the art, for example, each indication of "interruption A" indicates that the structural formula diagram is continuous at these points. Those skilled in the art will appreciate that the same applies to each case of "interruption B" in the above structural formula, including Casimersen. However, the interruptions in the figure are not intended to show the actual discontinuities of the above structural formulas, including Casimersen, and are not understood by those of skill in the art to mean them.

1 and 2 show representative analytical high performance liquid chromatography (HPLC) chromatograms of synthetic and deprotected Casimersen (SRP-4045) crude drug substances (see Example 4). 1 and 2 show representative analytical high performance liquid chromatography (HPLC) chromatograms of synthetic and deprotected Casimersen (SRP-4045) crude drug substances (see Example 4). 3 and 4 show representative analytical HPLC chromatograms of the purified Casimersen drug substance solution (see Example 5). 3 and 4 show representative analytical HPLC chromatograms of the purified Casimersen drug substance solution (see Example 5). 5 and 6 show representative analytical HPLC chromatograms of desalted and lyophilized Casimersen drug substance (see Example 5). 5 and 6 show representative analytical HPLC chromatograms of desalted and lyophilized Casimersen drug substance (see Example 5).

A process for preparing a morpholino oligomer is provided herein. The morpholino oligomers described herein exhibit stronger affinity for DNA and RNA for natural or unmodified oligonucleotides without compromising sequence selectivity. In some embodiments, the morpholino oligomers of the present disclosure minimize or prevent cleavage by RNase H. In some embodiments, the morpholino oligomers of the present disclosure do not activate RNase H.

The processes described herein are advantageous for industrial scale processes and are high yield and high scale (eg, about 1 kg, about 1-10 kg, about 2-10 kg, about 5-20 kg, about 10-20 kg, Or about 10-50 kg) and can be applied to prepare large amounts of morpholino oligomers.

Definitions The definitions of the various terms used in the description of this disclosure are listed below. These definitions apply, in particular cases, individually or as part of a larger group, to terms used throughout the specification and claims, unless otherwise specified.

"Base-protected" or "base-protected" is suitable for preventing the reaction or interference of base pair-forming groups on morpholino subunits, such as purine or pyrimidine bases, during stepwise oligomer synthesis. Refers to protection with a protecting group. An example of a base-protected morpholino subunit is the activated C subunit compound (C) having a CBZ protecting group on the cytosine amino group shown below.

An "activated phosphoramidate group" is typically a chlorophosphoroamidate group having a desired nitrogen substitution in the final phosphoramidate linkage in the oligomer. An example is (dimethylamino) chlorophosphoroamidate, ie-OP (= O) (NMe ₂ ) Cl.

The term "bound to a support" refers to a chemical that is covalently linked to a support medium.

The term "supporting medium" refers to any material, including, for example, any particles, beads, or surfaces on which an oligomer can be attached or synthesized, or which can be modified for attachment or synthesis of an oligomer. Typical substrates include glass and modified or functionalized glass, plastics (including copolymers of acrylic, polystyrene and styrene with other materials, polypropylene, polyethylene, polybutylene, polyurethane, Teflon®, etc.), poly. Inorganic supports and organic supports such as silica or silica-based materials including saccharides, nylon or nitrocellulose, ceramics, resins, silicon and modified silicon, carbon, metals, inorganic glass, plastics, optical fiber bundles, and various other polymers. The body is mentioned, but not limited to these. Support media and solid surfaces that are particularly useful in some embodiments are located within the flow cell device. In some embodiments of the process described herein, the supporting medium comprises 1% divinylbenzene crosslinked polystyrene.

In some embodiments, the representative support medium comprises at least one reaction site for oligomer attachment or synthesis. For example, in some embodiments, the supporting medium of the present disclosure is one or one capable of forming a chemical bond with an incoming subunit or other activated group for attachment or synthesis of an oligomer. Contains multiple terminal amino or hydroxyl groups.

Some representative supporting media suitable for the processes described herein include: controlled pore glass (CPG), oxalyl controlled pore glass (eg, Allul, et al.). , Nuclear Acids Research 1991, 19, 1527), Porous glass beads and silica gel, such as those formed by the reaction of trichloro- [3- (4-chloromethyl) phenyl] propylsilane to porous glass beads. Silica gel-containing particles such as (Parr and Grohmann, Angle. Chem. Internatl. Ed. 1972, 11, 314, Waters Associates, Sold by Framingham, Mass, US, under the trademark "POLASIL E"). Monoester of methylbenzene and silica (see Bayer and Jung, Tetrahedron Lett., 1970, 4503, sold by Waters Associates under the trademark "BIOPAK"),
TENTAGEL (see, eg, Wright, et al., Tetrahedron Letter. 1993, 34, 3373), crosslinked styrene / divinylbenzene copolymer bead matrix, or POROS, a copolymer of polystyrene / divinylbenzene (available from Perseptive Biosystems), polyethylene glycol. A PEPS support that is a polyethylene (PE) film with a soluble support medium such as PEG (see Bonora et al., Organic Process Research & Development, 2000, 4, 225-231), a pendant long-chain polystyrene (PS) graft. (See Berg, et al., J. Am. Chem. Soc., 1989, 111, 8024 and International Patent Application Publication WO 1990/02749), known amounts of N-tert-butoxycarbonyl-beta-alanyl-N. Copolymers of N, N'-bisacryloylethylenediamine cross-linked dimethylacrylamide, including'-acryloylhexamethylenediamine (Atherton, et al., J. Am. Chem. Soc., 1975, 97, 6584, Bioorg. Chem. 1979, 8, 351 and J.C. S. Perkin I 538 (1981)), glass particles coated with hydrophobic crosslinked styrene polymer (Scott, et al., J. Chrom. Sci., 1971, (See 9, 577), Polyethylene Grafted Polyethylene Polymers (Kent and Merrifield, Israel J. Chem. 1978, 17, 243, and van Rietschoten in Polyethylenes 1974, Y. Wolman, Ed, Ed. See New York, 1975, pp. 113-116), hydroxypropyl acrylate-coated polypropylene film (Daniels, et al., Tetrahedron Lett. 1989, 4345), acrylic acid grafted polyethylene rods (Geysen, et al., Proc. Natl). Acad. Sci. USA, 1984, 81, 399. 8) A "tea bag" containing traditionally used polymer beads (Houghten, Proc. Natl. Acad. Sci. USA, 1985, 82, 5131), and combinations thereof, but are not limited thereto.

The term "flow cell device" refers to a chamber comprising a surface (eg, a solid surface) through which one or more fluid reagents (eg, liquid or gas) can flow.

The term "deblocking agent" refers to a composition (eg, a solution) comprising a chemical acid or a combination of chemical acids for removing a protecting group. Exemplary chemical acids used in deblocking agents include halogenated acids such as chloroacetic acid, dichloroacetic acid, trichloroacetic acid, fluoroacetic acid, difluoroacetic acid, and trifluoroacetic acid. In some embodiments, the deblocking agent is one or more trityl groups from, for example, an oligomer, an oligomer bound to a support, a subunit bound to a support, or another protected nitrogen or oxygen moiety. To remove.

The terms "halogen" and "halo" refer to atoms selected from the group consisting of fluorine, chlorine, bromine and iodine.

The term "capping agent" is an acid anhydride useful for blocking the reaction site of, for example, a supporting medium that forms a chemical bond with an incoming subunit or other activated group (eg, benzoic anhydride). , Acetic anhydride, phenoxyacetic anhydride, etc.) refers to a composition (eg, solution).

The term "cleaving agent" refers, for example, to a combination of chemical bases (ammonia or 1,8-diazabicycloundec-7-ene) or chemical bases useful for cleaving oligomers attached to a support from a support medium. Refers to a composition comprising (eg, a liquid solution or a gas mixture).

The term "deprotecting agent" is a composition comprising a chemical base (ammonia, 1,8-diazabicycloundec-7-ene or potassium carbonate) or a combination of chemical bases useful for removing the protecting group (eg,). , Liquid solution or gas mixture). For example, the deprotecting agent may, in some embodiments, remove the base protection from, for example, the morpholino subunit, the morpholino subunit of the morpholino oligomer, or the form bound to their support.

The term "solvent" refers to a component of a solution or mixture in which a solute is dissolved. The solvent may be an inorganic or organic solvent (eg acetic acid, acetone, acetonitrile, acetylacetone, 2-aminoethanol, aniline, anisole, benzene, benzonitrile, benzyl alcohol, 1-butanol, 2-butanol, i-butanol, 2-butanol. , T-butyl alcohol, carbon disulfide, carbon tetrachloride, chlorobenzene, chloroform, cyclohexane, cyclohexanol, cyclohexanone, di-n-butyl phthalate, 1,1-dichloroethane, 1,2-dichloroethane, diethylamine, diethylene glycol, diglycim , Dimethoxyethane (Glym), N, N-dimethylaniline, dimethylformamide, dimethylphthalate, dimethylsulfoxide, dioxane, ethanol, ether, ethyl acetate, ethyl acetoacetate, ethyl benzoate, ethylene glycol, glycerin, heptane, 1-heptanol , Hexan, 1-hexanol, methanol, methyl acetate, methyl t-butyl ether, methylene chloride, 1-octanol, pentan, 1-pentanol, 2-pentanol, 3-pentanol, 2-pentanone, 3-pentanone, 1 -Propanol, 2-propanol, pyridine, tetrahydrofuran, toluene, water, p-xylene).

のホスホロジアミダートモルホリノオリゴマーであり、Ｓｕｍｍｅｒｔｏｎ， Ｊ．， ｅｔ ａｌ．， Ａｎｔｉｓｅｎｓｅ ＆ Ｎｕｃｌｅｉｃ Ａｃｉｄ Ｄｒｕｇ Ｄｅｖｅｌｏｐｍｅｎｔ， ７： １８７－１９５ （１９９７）の図２に記載されるようなものを指す。本明細書に記載されるようなモルホリノは、前述の一般構造のすべての立体異性体および立体配置を網羅することが意図される。モルホリノオリゴマーの合成、構造、および結合特性は米国特許第５，６９８，６８５号、第５，２１７，８６６号、第５，１４２，０４７号、第５，０３４，５０６号、第５，１６６，３１５号、第５，５２１，０６３号、第５，５０６，３３７号、第８，０７６，４７６号、および第８，２９９，２０６号に記載されており、それらのすべては参照により本明細書に組み込まれる。 The term "morpholino", "morpholino oligomer", or "PMO" (phosphoroamidate or phosphoramidate morpholino oligomer) has the following general structure:

Phosphordiamidatomorpholino oligomers from Summerton, J. Mol. , Et al. , Antisense & Nucleic Acid Drug Development, 7: 187-195 (1997), as described in FIG. Morphorinos as described herein are intended to cover all stereoisomers and configurations of the general structures described above. The synthesis, structure, and binding properties of morpholino oligomers are described in US Pat. Nos. 5,698,685, 5,217,866, 5,142,047, 5,034,506, 5,166. 315, 5,521,063, 5,506,337, 8,076,476, and 8,299,206, all of which are described herein by reference. Will be incorporated into.

が挙げられる。 In certain embodiments, the morpholino is conjugated to a "tail" moiety at the 5'end or 3'end of the oligomer to increase its stability and / or solubility. As an exemplary tail,

Can be mentioned.

のものであり得る。 The term "EG3 tail" refers, for example, to a triethylene glycol moiety conjugated to an oligomer at its 3'end or 5'end. For example, in some embodiments, the "EG3 tail" conjugated to the 3'end of the oligomer is a structure:

Can be

The terms "about" or "approximately" are commonly understood by experts in the relevant area of study, but in some situations within ± 10% or within ± 5% of a given value or range. Can mean.

Processes for preparing morpholino oligomers Synthesis is generally performed on supporting media, as described herein. Generally, the oligomer is synthesized by first attaching a first synthon (eg, a monomer such as a morpholino subunit) to a support medium and then continuously coupling the subunit to the synthons bound to the support. This repeated extension ultimately results in the final oligomer compound. A suitable support medium can be soluble or insoluble, or has a varying solubility in different solvents so that the growing support-bound polymer can be present either in solution or out of solution as desired. You may have. Traditional support media are largely insoluble, with reagents and solvents reacting with the growth chain and / or washing the growth chain until the oligomer reaches the target length, after which the oligomer is cleaved from the support. It is always placed in the reaction vessel while it is further processed as needed to produce the final polymer compound. More recent approaches can introduce soluble supports, including soluble polymer supports, to precipitate and dissolve the iteratively synthesized product at the desired point of synthesis (Gravert et al., Chem. Rev., 1997,97,489-510).

A process for preparing a morpholino oligomer is provided herein).

（式中、Ｒ^１は支持媒体である）の化合物を調製するためのプロセスが本明細書に提供され、
プロセスは、式（Ａ１）：

（式中、Ｒ^１は支持媒体であり、Ｒ^３はトリチル、モノメトキシトリチル、ジメトキシトリチルおよびトリメトキシトリチルからなる群から選択される）の化合物を脱ブロッキング剤と接触させて式（ＩＩ）の化合物を形成することを含む。 Therefore, in one aspect, formula (II) :.

A process for preparing a compound (where R ¹ is a supporting medium in the formula) is provided herein.
The process is the formula (A1) :.

(In the formula, R ¹ is a support medium and R ³ is selected from the group consisting of trityl, monomethoxytrityl, dimethoxytrityl and trimethoxytrityl) in contact with a deblocking agent of formula (II). Includes forming compounds.

（式中、Ｒ^１は支持媒体であり、Ｒ^３はトリチル、モノメトキシトリチル、ジメトキシトリチルおよびトリメトキシトリチルからなる群から選択される）の化合物を調製するためのプロセスが本明細書に提供され、
プロセスは、式（ＩＩ）：

（式中、Ｒ^１は支持媒体である）の化合物を式（Ａ２）：

（式中、Ｒ^３はトリチル、モノメトキシトリチル、ジメトキシトリチルおよびトリメトキシトリチルからなる群から選択される）の化合物と接触させて式（Ａ３）の化合物を形成することを含む。 In another embodiment, the formula (A3):

A process for preparing a compound of (in the formula, R ¹ is the supporting medium and R ³ is selected from the group consisting of trityl, monomethoxytrityl, dimethoxytrityl and trimethoxytrityl) is provided herein. ,
The process is in equation (II) :.

The compound of the formula (in the formula, R ¹ is a support medium) is represented by the formula (A2) :.

In the formula, R ³ comprises contacting with a compound of the formula (selected from the group consisting of trityl, monomethoxytrityl, dimethoxytrityl and trimethoxytrityl) to form the compound of formula (A3).

（式中、Ｒ^１は支持媒体である）の化合物を調製するためのプロセスが本明細書に提供され、
プロセスは、式（Ａ３）：

（式中、Ｒ^１は支持媒体であり、Ｒ^３はトリチル、モノメトキシトリチル、ジメトキシトリチルおよびトリメトキシトリチルからなる群から選択される）の化合物を脱ブロッキング剤と接触させて式（ＩＶ）の化合物を形成することを含む。 In yet another embodiment, formula (IV) :.

A process for preparing a compound (where R ¹ is a supporting medium in the formula) is provided herein.
The process is the formula (A3) :.

(In the formula, R ¹ is a support medium and R ³ is selected from the group consisting of trityl, monomethoxytrityl, dimethoxytrityl and trimethoxytrityl) in contact with a deblocking agent of formula (IV). Includes forming compounds.

（式中、Ｒ^１は支持媒体であり、Ｒ^３はトリチル、モノメトキシトリチル、ジメトキシトリチルおよびトリメトキシトリチルからなる群から選択され、Ｒ^４は以下：

からなる群から選択される）の化合物を調製するためのプロセスが本明細書に提供され、
プロセスは、式（ＩＶ）：

（式中、Ｒ^１は支持媒体である）の化合物を式（Ａ４）：

（式中、Ｒ^３はトリチル、モノメトキシトリチル、ジメトキシトリチルおよびトリメトキシトリチルからなる群から選択され、Ｒ^４は以下：

からなる群から選択される）の化合物と接触させて式（Ａ５）の化合物を形成することを含む。 In yet another embodiment, the formula (A5):

(In the formula, R ¹ is the supporting medium, R ³ is selected from the group consisting of trityl, monomethoxytrityl, dimethoxytrityl and trimethoxytrityl, and R ⁴ is:

A process for preparing a compound (selected from the group consisting of) is provided herein.
The process is in equation (IV) :.

The compound of the formula (in the formula, R ¹ is a support medium) is represented by the formula (A4) :.

(In the formula, R ³ is selected from the group consisting of trityl, monomethoxytrityl, dimethoxytrityl and trimethoxytrityl, and R ⁴ is:

It involves contacting with a compound of formula (A5) to form a compound of formula (A5).

（式中、ｎは１０～４０の整数であり、Ｒ^１は支持媒体であり、Ｒ^３はトリチル、モノメトキシトリチル、ジメトキシトリチルおよびトリメトキシトリチルからなる群から選択され、Ｒ^４は、各出現について独立して、以下：

からなる群から選択される）の化合物を調製するためのプロセスが本明細書に提供され、
プロセスは、
（ａ）式（ＩＶ）：

（式中、Ｒ^１は支持媒体である）の化合物を式（Ａ４）：

（式中、Ｒ^３はトリチル、モノメトキシトリチル、ジメトキシトリチルおよびトリメトキシトリチルからなる群から選択され、Ｒ^４は以下：

からなる群から選択される）の化合物と接触させて式（Ａ５）：

（式中、Ｒ^１は支持媒体であり、Ｒ^３はトリチル、モノメトキシトリチル、ジメトキシトリチルおよびトリメトキシトリチルからなる群から選択され、Ｒ^４は以下：

からなる群から選択される）の化合物を形成するステップ、ならびに
（ｂ）以下の連続したステップのｎ－１回の反復を実施するステップであって、
（ｂ１）直前のステップによって形成された生成物を脱ブロッキング剤と接触させるステップ、および
（ｂ２）直前のステップによって形成された化合物を式（Ａ８）：

（式中、Ｒ^３はトリチル、モノメトキシトリチル、ジメトキシトリチルおよびトリメトキシトリチルからなる群から選択され、Ｒ^４は、以下：

からなる群から選択される）の化合物と接触させて式（Ａ９）の化合物を形成するステップ
の連続したステップのｎ－１回の反復を実施するステップ
の連続したステップを含む。 In another embodiment, the formula (A9):

(In the formula, n is an integer of 10-40, R ¹ is the supporting medium, R ³ is selected from the group consisting of trityl, monomethoxytrityl, dimethoxytrityl and trimethoxytrityl, where R ⁴ is each occurrence. Independently about:

A process for preparing a compound (selected from the group consisting of) is provided herein.
The process,
(A) Equation (IV):

The compound of the formula (in the formula, R ¹ is a support medium) is represented by the formula (A4) :.

(In the formula, R ³ is selected from the group consisting of trityl, monomethoxytrityl, dimethoxytrityl and trimethoxytrityl, and R ⁴ is:

(Selected from the group consisting of) in contact with the compound of formula (A5) :.

(In the formula, R ¹ is the supporting medium, R ³ is selected from the group consisting of trityl, monomethoxytrityl, dimethoxytrityl and trimethoxytrityl, and R ⁴ is:

A step of forming a compound (selected from the group consisting of) and (b) a step of performing n-1 iterations of the following consecutive steps.
(B1) The step of contacting the product formed by the immediately preceding step with the deblocking agent, and (b2) the compound formed by the immediately preceding step of formula (A8) :.

(In the formula, R ³ is selected from the group consisting of trityl, monomethoxytrityl, dimethoxytrityl and trimethoxytrityl, and R ⁴ is:

Includes a series of steps of performing n-1 iterations of a series of steps of contacting with a compound of formula (A9) to form a compound of formula (A9).

（式中、ｎは１０～４０の整数であり、Ｒ^１は支持媒体であり、Ｒ^４は、各出現について独立して、以下：

からなる群から選択される）の化合物を調製するためのプロセスが本明細書に提供され、
プロセスは、式（Ａ９）：

（式中、ｎは１０～４０の整数であり、Ｒ^１は支持媒体であり、Ｒ^３はトリチル、モノメトキシトリチル、ジメトキシトリチルおよびトリメトキシトリチルからなる群から選択され、Ｒ^４は、各出現について独立して、以下：

からなる群から選択される）の化合物を脱ブロッキング剤と接触させて式（Ａ１０）の化合物を形成することを含む。 In yet another embodiment, the formula (A10):

(In the equation, n is an integer from 10 to 40, R ¹ is the supporting medium, and R ⁴ is independent for each appearance, and so on:

A process for preparing a compound (selected from the group consisting of) is provided herein.
The process is the formula (A9) :.

(In the formula, n is an integer of 10-40, R ¹ is the supporting medium, R ³ is selected from the group consisting of trityl, monomethoxytrityl, dimethoxytrityl and trimethoxytrityl, where R ⁴ is each occurrence. Independently about:

It comprises contacting a compound of (selected from the group consisting of) with a deblocking agent to form a compound of formula (A10).

（式中、ｎは１０～４０の整数であり、Ｒ^４は、各出現について独立して、以下：

からなる群から選択される）の化合物を調製するためのプロセスが本明細書に提供され、
プロセスは、式（Ａ１０）：

（式中、ｎは１０～４０の整数であり、Ｒ^１は支持媒体であり、Ｒ^４は、各出現について独立して、以下：

からなる群から選択される）の化合物を切断剤と接触させて式（Ａ１１）の化合物を形成することを含む。 In yet another embodiment, the formula (A11):

(In the equation, n is an integer from 10 to 40, and ^R4 is independent for each occurrence, and the following:

A process for preparing a compound (selected from the group consisting of) is provided herein.
The process is the formula (A10) :.

(In the equation, n is an integer from 10 to 40, R ¹ is the supporting medium, and R ⁴ is independent for each appearance, and so on:

It comprises contacting a compound of (selected from the group consisting of) with a cleavage agent to form a compound of formula (A11).

（式中、ｎは１０～４０の整数であり、各Ｒ^２は、各出現について独立して、以下：

からなる群から選択される）のオリゴマー化合物を調製するためのプロセスが本明細書に提供され、
プロセスは、式（Ａ１１）：

（式中、ｎは１０～４０の整数であり、Ｒ^４は、各出現について独立して、以下：

からなる群から選択される）の化合物を脱保護剤と接触させて式（Ａ）のオリゴマー化合物を形成することを含む。 In another embodiment, the formula (A):

(In the equation, n is an integer from 10 to 40, and each R ² is independent for each occurrence, and the following:

A process for preparing an oligomer compound (selected from the group consisting of) is provided herein.
The process is the formula (A11) :.

(In the equation, n is an integer from 10 to 40, and ^R4 is independent for each occurrence, and the following:

It comprises contacting a compound of (selected from the group consisting of) with a deprotecting agent to form an oligomeric compound of formula (A).

（式中、ｎは１０～４０の整数であり、各Ｒ^２は、各出現について独立して、以下：

からなる群から選択される）のオリゴマー化合物を調製するためのプロセスが本明細書に提供され、プロセスは、
（ａ）式（Ａ１）：

（式中、Ｒ^１は支持媒体であり、Ｒ^３はトリチル、モノメトキシトリチル、ジメトキシトリチルおよびトリメトキシトリチルからなる群から選択される）の化合物を脱ブロッキング剤と接触させて式（ＩＩ）：

（式中、Ｒ^１は支持媒体である）の化合物を形成するステップ；
（ｂ）式（ＩＩ）の化合物を式（Ａ２）：

（式中、Ｒ^３はトリチル、モノメトキシトリチル、ジメトキシトリチルおよびトリメトキシトリチルからなる群から選択される）の化合物と接触させて式（Ａ３）：

（式中、Ｒ^１は支持媒体であり、Ｒ^３はトリチル、モノメトキシトリチル、ジメトキシトリチルおよびトリメトキシトリチルからなる群から選択される）の化合物を形成するステップ；
（ｃ）式（Ａ３）の化合物を脱ブロッキング剤と接触させて式（ＩＶ）：

（式中、Ｒ^１は支持媒体である）の化合物を形成するステップ；
（ｄ）式（ＩＶ）の化合物を式（Ａ４）：

（式中、Ｒ^３はトリチル、モノメトキシトリチル、ジメトキシトリチルおよびトリメトキシトリチルからなる群から選択され、Ｒ^４は以下：

からなる群から選択される）の化合物と接触させて式（Ａ５）：

（式中、Ｒ^１は支持媒体であり、Ｒ^３はトリチル、モノメトキシトリチル、ジメトキシトリチルおよびトリメトキシトリチルからなる群から選択され、Ｒ^４は以下：

からなる群から選択される）の化合物を形成するステップ；
（ｅ）以下の連続したステップのｎ－１回の反復を実施するステップであって、
（ｅ１）直前のステップによって形成された生成物を脱ブロッキング剤と接触させるステップ、および
（ｅ２）直前のステップによって形成された化合物を式（Ａ８）：

（式中、Ｒ^３はトリチル、モノメトキシトリチル、ジメトキシトリチルおよびトリメトキシトリチルからなる群から選択され、Ｒ^４は、式（Ａ８）の各化合物について独立して、以下：

からなる群から選択される）の化合物と接触させて式（Ａ９）：

（式中、ｎは１０～４０の整数であり、Ｒ^１は支持媒体であり、Ｒ^３はトリチル、モノメトキシトリチル、ジメトキシトリチルおよびトリメトキシトリチルからなる群から選択され、Ｒ^４は、各出現について独立して、以下：

からなる群から選択される）の化合物を形成するステップ
の連続したステップのｎ－１回の反復を実施するステップ；ならびに
（ｆ）式（Ａ９）の化合物を脱ブロッキング剤と接触させて式（Ａ１０）：

（式中、ｎは１０～４０の整数であり、Ｒ^１は支持媒体であり、Ｒ^４は、各出現について独立して、以下：

からなる群から選択される）の化合物を形成するステップ；
（ｇ）式（Ａ１０）の化合物を切断剤と接触させて式（Ａ１１）：

（式中、ｎは１０～４０の整数であり、Ｒ^４は、各出現について独立して、以下：

からなる群から選択される）の化合物を形成するステップ；ならびに
（ｈ）式（Ａ１１）の化合物を脱保護剤と接触させて式（Ａ）のオリゴマー化合物を形成するステップ
の連続したステップを含む。 In another embodiment, the formula (A):

(In the equation, n is an integer from 10 to 40, and each R ² is independent for each occurrence, and the following:

A process for preparing an oligomeric compound (selected from the group consisting of) is provided herein.
(A) Equation (A1):

The compound of (in the formula, R ¹ is the supporting medium and R ³ is selected from the group consisting of trityl, monomethoxytrityl, dimethoxytrityl and trimethoxytrityl) is contacted with the deblocking agent to formulate (II) :.

The step of forming the compound (in the formula, R ¹ is the supporting medium);
(B) The compound of the formula (II) is represented by the formula (A2) :.

(In the formula, R ³ is selected from the group consisting of trityl, monomethoxytrityl, dimethoxytrityl and trimethoxytrityl) in contact with the compound of formula (A3):.

(In the formula, R ¹ is the supporting medium and R ³ is selected from the group consisting of trityl, monomethoxytrityl, dimethoxytrityl and trimethoxytrityl).
(C) The compound of the formula (A3) is brought into contact with the deblocking agent to formulate (IV) :.

The step of forming the compound (in the formula, R ¹ is the supporting medium);
(D) The compound of the formula (IV) is represented by the formula (A4) :.

(In the formula, R ³ is selected from the group consisting of trityl, monomethoxytrityl, dimethoxytrityl and trimethoxytrityl, and R ⁴ is:

(Selected from the group consisting of) in contact with the compound of formula (A5) :.

(In the formula, R ¹ is the supporting medium, R ³ is selected from the group consisting of trityl, monomethoxytrityl, dimethoxytrityl and trimethoxytrityl, and R ⁴ is:

The step of forming a compound (selected from the group consisting of);
(E) A step of performing n-1 iterations of the following consecutive steps.
(E1) The step of contacting the product formed by the immediately preceding step with the deblocking agent, and (e2) the compound formed by the immediately preceding step of formula (A8) :.

(In the formula, R ³ is selected from the group consisting of trityl, monomethoxytrityl, dimethoxytrityl and trimethoxytrityl, and R ⁴ is independently for each compound of formula (A8), and the following:

(Selected from the group consisting of) in contact with the compound of formula (A9) :.

(In the formula, n is an integer of 10-40, R ¹ is the supporting medium, R ³ is selected from the group consisting of trityl, monomethoxytrityl, dimethoxytrityl and trimethoxytrityl, where R ⁴ is each occurrence. Independently about:

A step of performing n-1 iterations of a series of steps to form a compound of formula (selected from the group consisting of); as well as contacting the compound of formula (f) formula (A9) with a deblocking agent to formulate (f). A10):

(In the equation, n is an integer from 10 to 40, R ¹ is the supporting medium, and R ⁴ is independent for each appearance, and so on:

The step of forming a compound (selected from the group consisting of);
(G) The compound of the formula (A10) is brought into contact with the cutting agent to formulate (A11) :.

(In the equation, n is an integer from 10 to 40, and ^R4 is independent for each occurrence, and the following:

The step of forming a compound of formula (A); and the step of contacting the compound of formula (A11) with a deprotecting agent to form an oligomeric compound of formula (A). ..

In one embodiment, step (d) or step (e2) further comprises contacting the compound of formula (IV) or the compound formed by the previous step, respectively, with a capping agent.

In another embodiment, each step is performed in the presence of at least one solvent.

In yet another embodiment, the deblocking agent used in each step is a solution containing a halogenated acid.

In yet another embodiment, the deblocking agent used in each step is cyanoacetic acid.

In another embodiment, the halogenated acid is selected from the group consisting of chloroacetic acid, dichloroacetic acid, trichloroacetic acid, fluoroacetic acid, difluoroacetic acid, and trifluoroacetic acid.

In another embodiment, the halogenated acid is trifluoroacetic acid.

In yet another embodiment, at least one of steps (a), (c), (e1) and (f) further comprises contacting the deblocked compound of each step with a neutralizing agent.

In yet another embodiment, each of steps (a), (c), (e1) and (f) further comprises contacting the deblocked compound of each step with a neutralizing agent.

In another embodiment, the neutralizer is present in a solution containing dichloromethane and isopropyl alcohol.

In yet another embodiment, the neutralizing agent is a monoalkyl, dialkyl, or trialkylamine.

In yet another embodiment, the neutralizing agent is N, N-diisopropylethylamine.

In another embodiment, the deblocking agent used in each step is a solution containing 4-cyanopyridine, dichloromethane, trifluoroacetic acid, trifluoroethanol, and water.

In yet another embodiment, the capping agent is present in a solution containing ethyl morpholine and methylpyrrolidinone.

In yet another embodiment, the capping agent is acid anhydride.

In another embodiment, the acid anhydride is benzoic anhydride.

In another embodiment, the compounds of formula (A4) and formula (A8) are independently present in a solution containing ethyl morpholine and dimethylimidazolidinone.

In another embodiment, the cleavage agent comprises dithiothreitol and 1,8-diazabicyclo [5.4.0] undec-7-ene.

In yet another embodiment, the cleavage agent is present in a solution containing N-methyl-2-pyrrolidone.

In yet another embodiment, the deprotecting agent comprises NH ₃ .

In yet another embodiment, the deprotecting agent is present in aqueous solution.

In yet another embodiment, the supporting medium comprises 1% divinylbenzene crosslinked polystyrene.

の化合物であり、式中、
Ｒ^３はトリチル、モノメトキシトリチル、ジメトキシトリチルおよびトリメトキシトリチルからなる群から選択され、
Ｒ^４は、以下：

から選択される。 In another embodiment, the compound of formula (A4) is of formula (A4a) :.

In the formula,
R3 is selected from the group consisting of trityl ^, monomethoxytrityl, dimethoxytrityl and trimethoxytrityl.
^R4 is as follows:

Is selected from.

の化合物であり、式中、
Ｒ^１は支持媒体であり、
Ｒ^３はトリチル、モノメトキシトリチル、ジメトキシトリチルおよびトリメトキシトリチルからなる群から選択され、
Ｒ^４は、以下：

から選択される。 In another embodiment, the compound of formula (A5) is of formula (A5a) :.

In the formula,
R ¹ is a support medium and
R3 is selected from the group consisting of trityl ^, monomethoxytrityl, dimethoxytrityl and trimethoxytrityl.
^R4 is as follows:

Is selected from.

の化合物であり、式中、
Ｒ^３はトリチル、モノメトキシトリチル、ジメトキシトリチルおよびトリメトキシトリチルからなる群から選択され、
Ｒ^４は、式（Ａ８ａ）の化合物の各出現で独立して、以下：

からなる群から選択される。 In yet another embodiment, the compound of formula (A8) is of formula (A8a) :.

In the formula,
R3 is selected from the group consisting of trityl ^, monomethoxytrityl, dimethoxytrityl and trimethoxytrityl.
^R4 is independent of each appearance of the compound of formula (A8a),

It is selected from the group consisting of.

の化合物であり、式中、
ｎは１０～４０の整数であり、
Ｒ^１は支持媒体であり、
Ｒ^３はトリチル、モノメトキシトリチル、ジメトキシトリチルおよびトリメトキシトリチルからなる群から選択され、
Ｒ^４は、各出現について独立して、以下：

からなる群から選択される。 In yet another embodiment, the compound of formula (A9) is of formula (A9a) :.

In the formula,
n is an integer of 10 to 40,
R ¹ is a support medium and
R3 is selected from the group consisting of trityl ^, monomethoxytrityl, dimethoxytrityl and trimethoxytrityl.
^R4 is independent for each appearance,

It is selected from the group consisting of.

の化合物であり、式中、
ｎは１０～４０の整数であり、
Ｒ^１は支持媒体であり、
Ｒ^４は、各出現について独立して、以下：

からなる群から選択される。 In another embodiment, the compound of formula (A10) is of formula (A10a) :.

In the formula,
n is an integer of 10 to 40,
R ¹ is a support medium and
^R4 is independent for each appearance,

It is selected from the group consisting of.

の化合物であり、式中、
ｎは１０～４０の整数であり、
Ｒ^４は、各出現について独立して、以下：

からなる群から選択される。 In another embodiment, the compound of formula (A11) is of formula (A11a) :.

In the formula,
n is an integer of 10 to 40,
^R4 is independent for each appearance,

It is selected from the group consisting of.

であり、
式（Ａ）のオリゴマー化合物は式（Ｃ）：

の化合物、またはその医薬的に許容される塩である。 In the embodiment of the oligomeric compound of formula (A), n is 22, and R ² is from 5'to 3'at each position from 1 to 22 below:

And
The oligomer compound of formula (A) is of formula (C) :.

Compound, or a pharmaceutically acceptable salt thereof.

"Casimersen" is a PMO previously known by its code name "SPR-4045" and having the base sequence of 5'-CAATGCCATCCTGGAGTTCCG-3'(SEQ ID NO: 1). Casimersen is registered under CAS Registry Number 1422951-19-7. The chemical name is all-P-ambo- [P, 2', 3'-trideoxy-P- (dimethylamino) -2', 3'-imino-2', 3'-seco] (2'a → 5') (C-A-A-T-G-C-C-A-T-C-C-T-G-G-A-G-T-T-C-C-T-G) 5') -[4- ({2- [2- (2-Hydroxyethoxy) ethoxy] ethoxy} carbonyl) -N, N-dimethylpiperazine-1-phosphonamidate] can be mentioned.

を有し、以下の化学構造：

によっても表される。 Casimersen has the following chemical structure:

Has the following chemical structure:

Also represented by.

の構造によっても表され得る。 Casimersen is the formula (XII):

It can also be represented by the structure of.

の化合物、またはその医薬的に許容される塩である。 Therefore, in one embodiment of the above process, the oligomeric compound of formula (A) is of formula (C) :.

Compound, or a pharmaceutically acceptable salt thereof.

のオリゴマー化合物、またはその医薬的に許容される塩である。 In yet another embodiment, the oligomeric compound of formula (C) is of formula (XII) :.

Oligomer compound, or a pharmaceutically acceptable salt thereof.

Process for Preparing Casimersen A process for preparing Casimersen is provided herein.

のオリゴマー化合物を調製するためのプロセスが本明細書に提供され、
プロセスは、
（ａ）式（Ｉ）：

（式中、Ｒ^１は支持媒体である）の化合物を脱ブロッキング剤と接触させて式（ＩＩ）：

（式中、Ｒ^１は支持媒体である）の化合物を形成するステップ；
（ｂ）式（ＩＩ）の化合物を化合物（Ｂ）：

と接触させて式（ＩＩＩ）：

（式中、Ｒ^１は支持媒体である）の化合物を形成するステップ；
（ｃ）式（ＩＩＩ）の化合物を脱ブロッキング剤と接触させて式（ＩＶ）：

（式中、Ｒ^１は支持媒体である）の化合物を形成するステップ；
（ｄ）式（ＩＶ）の化合物を式（Ｄ）：

の化合物と接触させて式（Ｖ）：

（式中、Ｒ^１は支持媒体である）の化合物を形成するステップ；
（ｅ）式（Ｖ）の化合物を脱ブロッキング剤と接触させて式（ＶＩ）：

（式中、Ｒ^１は支持媒体である）の化合物を形成するステップ；
（ｆ）式（ＶＩ）の化合物を式（Ｆ）：

の化合物と接触させて式（ＶＩＩ）：

（式中、Ｒ^１は支持媒体である）の化合物を形成するステップ；
（ｇ）以下の連続したステップの２０回の反復を実施するステップであって、
（ｇ１）直前のステップによって形成された生成物を脱ブロッキング剤と接触させるステップ、および
（ｇ２）直前のステップによって形成された化合物を式（ＶＩＩＩ）：

（式中、Ｒ^２は、式（ＶＩＩＩ）の各化合物について独立して、以下：

からなる群から選択され、各反復１～２０について、Ｒ^２は、以下：

である）の化合物と接触させて式（ＩＸ）：

（式中、
Ｒ^１は支持媒体であり、
Ｒ^２は、各出現について独立して、以下：

からなる群から選択され、
Ｒ^２は５’から３’へ向かって１～２２の各位置で以下：

である）の化合物を形成するステップ
の連続したステップの２０回の反復を実施するステップ；
（ｈ）式（ＩＸ）の化合物を脱ブロッキング剤と接触させて式（Ｘ）：

（式中、
Ｒ^１は支持媒体であり、
Ｒ^２は、各出現について独立して、以下：

からなる群から選択され、
Ｒ^２は５’から３’へ向かって１～２２の各位置で以下：

である）の化合物を形成するステップ；
（ｉ）式（Ｘ）の化合物を切断剤と接触させて式（ＸＩ）：

（式中、Ｒ^２は、各出現について独立して、以下：

からなる群から選択され、
Ｒ^２は５’から３’へ向かって１～２２の各位置で以下：

である）の化合物を形成するステップ；ならびに
（ｊ）式（ＸＩ）の化合物を脱保護剤と接触させて式（Ｃ）のオリゴマー化合物を形成するステップ
の連続したステップを含む。 In another embodiment, the formula (C):

The process for preparing the oligomeric compounds of is provided herein.
The process,
(A) Formula (I):

The compound of (in the formula, R ¹ is a support medium) is brought into contact with the deblocking agent to formulate (II) :.

The step of forming the compound (in the formula, R ¹ is the supporting medium);
(B) The compound of the formula (II) is compounded with the compound (B):

In contact with equation (III):

The step of forming the compound (in the formula, R ¹ is the supporting medium);
(C) The compound of formula (III) is brought into contact with a deblocking agent to formulate (IV) :.

The step of forming the compound (in the formula, R ¹ is the supporting medium);
(D) The compound of the formula (IV) is represented by the formula (D) :.

In contact with the compound of formula (V):

The step of forming the compound (in the formula, R ¹ is the supporting medium);
(E) The compound of the formula (V) is brought into contact with the deblocking agent to formulate (VI) :.

The step of forming the compound (in the formula, R ¹ is the supporting medium);
The compound of the formula (f) formula (VI) is represented by the formula (F) :.

In contact with the compound of formula (VII) :.

The step of forming the compound (in the formula, R ¹ is the supporting medium);
(G) A step of performing 20 iterations of the following consecutive steps.
(G1) The step of contacting the product formed by the immediately preceding step with the deblocking agent, and (g2) the compound formed by the immediately preceding step of formula (VIII) :.

(In the formula, R ² is independently for each compound of the formula (VIII), and the following:

Selected from the group consisting of, for each iteration 1-20, ^R2 is:

In contact with the compound of formula (IX) :.

(During the ceremony,
R ¹ is a support medium and
R ² is independent for each appearance,

Selected from a group of
R ² goes from 5'to 3'at each position from 1 to 22 below:

A step of performing 20 iterations of a series of steps to form a compound of);
(H) The compound of the formula (IX) is brought into contact with the deblocking agent to form the formula (X):

(During the ceremony,
R ¹ is a support medium and
R ² is independent for each appearance,

Selected from a group of
R ² goes from 5'to 3'at each position from 1 to 22 below:

The step of forming the compound of);
(I) The compound of formula (X) is brought into contact with a cutting agent to formulate (XI) :.

(In the formula, R ² is independent for each appearance, and:

Selected from a group of
R ² goes from 5'to 3'at each position from 1 to 22 below:

The steps include the steps of forming the compound of formula (C); as well as the step of contacting the compound of formula (XI) with a deprotecting agent to form the oligomeric compound of formula (C).

In one embodiment, step (d), step (f), step (g2) or a combination thereof is a compound of formula (IV), a compound of formula (VI) or a compound formed by the immediately preceding step, respectively. Further includes contacting with a capping agent.

In certain embodiments, each of step (d), step (f), and step (g2) caps the compound of formula (IV), the compound of formula (VI), or the compound formed by the previous step, respectively. Further includes contacting with.

In another embodiment, each step is performed in the presence of at least one solvent.

In yet another embodiment, the deblocking agent used in each step is a solution containing a halogenated acid.

In yet another embodiment, the deblocking agent used in each step is cyanoacetic acid.

In another embodiment, the halogenated acid is selected from the group consisting of chloroacetic acid, dichloroacetic acid, trichloroacetic acid, fluoroacetic acid, difluoroacetic acid, and trifluoroacetic acid.

In yet another embodiment, the halogenated acid is trifluoroacetic acid.

In yet another embodiment, at least one of steps (c), (e) and (g1) further comprises contacting the deblocked compound of each step with a neutralizing agent.

In another embodiment, each of steps (c), (e) and (g1) further comprises contacting the deblocked compound of each step with a neutralizing agent.

In yet another embodiment, the neutralizer is present in a solution containing dichloromethane and isopropyl alcohol.

In yet another embodiment, the neutralizing agent is a monoalkyl, dialkyl, or trialkylamine.

In another embodiment, the neutralizing agent is N, N-diisopropylethylamine.

In yet another embodiment, the deblocking agent used in each step is a solution containing 4-cyanopyridine, dichloromethane, trifluoroacetic acid, trifluoroethanol, and water.

In yet another embodiment, the capping agent is present in a solution containing ethyl morpholine and methylpyrrolidinone.

In another embodiment, the capping agent is acid anhydride.

In yet another embodiment, the acid anhydride is benzoic anhydride.

In yet another embodiment, the compounds of formula (VIII), formula (D) and formula (F) are independently present in a solution containing ethyl morpholine and dimethylimidazolidinone, respectively.

In another embodiment, the cleavage agent comprises dithiothreitol and 1,8-diazabicyclo [5.4.0] undec-7-ene.

In yet another embodiment, the cleavage agent is present in a solution containing N-methyl-2-pyrrolidone.

In yet another embodiment, the deprotecting agent comprises NH ₃ .

In another embodiment, the deprotecting agent is present in aqueous solution.

In yet another embodiment, the supporting medium comprises 1% divinylbenzene crosslinked polystyrene.

In another embodiment, the compound of formula (D) is the compound of formula (D1).

（式中、Ｒ^１は支持媒体である）の化合物である。 In another embodiment, the compound of formula (V) is of formula (Va) :.

(In the formula, R ¹ is a supporting medium).

In another embodiment, the compound of formula (F) is the compound of formula (F1).

（式中、Ｒ^１は支持媒体である）の化合物である。 In another embodiment, the compound of formula (VII) is of formula (VIIa) :.

(In the formula, R ¹ is a supporting medium).

（式中、Ｒ^２は、式（ＶＩＩＩａ）の各化合物について独立して、以下：

からなる群から選択される）の化合物である。 In another embodiment, the compound of formula (VIII) is of formula (VIIIa) :.

(In the formula, R ² is independently for each compound of the formula (VIIIa), and the following:

(Selected from the group consisting of) compounds.

の化合物、またはその医薬的に許容される塩であり、式中、
Ｒ^１は支持媒体であり、
Ｒ^２は、各出現で独立して、以下：

からなる群から選択され、
Ｒ^２は５’から３’へ向かって１～２２の各位置で以下：

である。 In another embodiment, the compound of formula (IX) is of formula (IXa) :.

Compound, or a pharmaceutically acceptable salt thereof, in the formula,
R ¹ is a support medium and
R ² is independent of each appearance,

Selected from a group of
R ² goes from 5'to 3'at each position from 1 to 22 below:

Is.

の化合物、またはその医薬的に許容される塩であり、式中、
Ｒ^１は支持媒体であり、
Ｒ^２は、各出現で独立して、以下：

からなる群から選択され、
Ｒ^２は５’から３’へ向かって１～２２の各位置で以下：

である。 In another embodiment, the compound of formula (X) is of formula (Xa) :.

Compound, or a pharmaceutically acceptable salt thereof, in the formula,
R ¹ is a support medium and
R ² is independent of each appearance,

Selected from the group consisting of
R ² goes from 5'to 3'at each position from 1 to 22 below:

Is.

の化合物、またはその医薬的に許容される塩であり、式中、
Ｒ^２は、各出現で独立して、以下：

からなる群から選択され、
Ｒ^２は５’から３’へ向かって１～２２の各位置で以下：

である。 In another embodiment, the compound of formula (XI) is of formula (XIa) :.

Compound, or a pharmaceutically acceptable salt thereof, in the formula,
R ² is independent of each appearance,

Selected from the group consisting of
R ² goes from 5'to 3'at each position from 1 to 22 below:

Is.

（式中、Ｒ^１は支持媒体である）の化合物である。 In another embodiment, the compound of formula (VI) is of formula (VIa) :.

(In the formula, R ¹ is a supporting medium).

In yet another embodiment, the oligomeric compound of formula (C) is the oligomeric compound of formula (XII).

の化合物、またはその医薬的に許容される塩が本明細書に提供され、式中、Ｒ^１は支持媒体である。 In another embodiment, the formula (V):

A compound of, or a pharmaceutically acceptable salt thereof, is provided herein, in which ^R1 is the supporting medium.

の化合物、またはその医薬的に許容される塩であり、式中、Ｒ^１は支持媒体である。 In one embodiment, the compound of formula (V) is of formula (Va) :.

A compound of, or a pharmaceutically acceptable salt thereof, wherein R ¹ is a supporting medium in the formula.

の化合物、またはその医薬的に許容される塩が本明細書に提供され、式中、Ｒ^１は支持媒体であり、Ｒ^３はトリチル、モノメトキシトリチル、ジメトキシトリチルおよびトリメトキシトリチルからなる群から選択され、Ｒ^４は以下：

から選択される。 In another embodiment, the formula (A5):

Compounds, or pharmaceutically acceptable salts thereof, are provided herein, wherein R ¹ is the supporting medium and R ³ is from the group consisting of trityl, monomethoxytrityl, dimethoxytrityl and trimethoxytrityl. Selected, ^R4 is below:

Is selected from.

の化合物、またはその医薬的に許容される塩であり、式中、Ｒ^１は支持媒体であり、Ｒ^３はトリチル、モノメトキシトリチル、ジメトキシトリチルおよびトリメトキシトリチルからなる群から選択され、Ｒ^４は以下：

から選択される。 In one embodiment, the compound of formula (A5) is of formula (A5a) :.

In the formula, R ¹ is the supporting medium and R ³ is selected from the group consisting of trityl, monomethoxytrityl, dimethoxytrityl and trimethoxytrityl, R ⁴ Is below:

Is selected from.

の化合物、またはその医薬的に許容される塩が本明細書に提供され、式中、Ｒ^１は支持媒体である。 In another embodiment, the formula (VI):

A compound of, or a pharmaceutically acceptable salt thereof, is provided herein, in which ^R1 is the supporting medium.

の化合物、またはその医薬的に許容される塩であり、式中、Ｒ^１は支持媒体である。 In one embodiment, the compound of formula (VI) is of formula (VIa) :.

A compound of, or a pharmaceutically acceptable salt thereof, wherein R ¹ is a supporting medium in the formula.

の化合物、またはその医薬的に許容される塩が本明細書に提供され、式中、Ｒ^１は支持媒体である。 In another embodiment, formula (VII) :.

A compound of, or a pharmaceutically acceptable salt thereof, is provided herein, in which ^R1 is the supporting medium.

の化合物、またはその医薬的に許容される塩であり、式中、Ｒ^１は支持媒体である。 In one embodiment, the compound of formula (VII) is of formula (VIIa) :.

A compound of, or a pharmaceutically acceptable salt thereof, wherein R ¹ is a supporting medium in the formula.

の化合物、またはその医薬的に許容される塩が本明細書に提供され、式中、
Ｒ^１は支持媒体であり、
Ｒ^２は、各出現で独立して、以下：

からなる群から選択され、
Ｒ^２は５’から３’へ向かって１～２２の各位置で以下：

である。 In another aspect, formula (IX) :.

Compounds, or pharmaceutically acceptable salts thereof, are provided herein in the formula.
R ¹ is a support medium and
R ² is independent of each appearance,

Selected from the group consisting of
R ² goes from 5'to 3'at each position from 1 to 22 below:

Is.

の化合物、またはその医薬的に許容される塩であり、式中、
Ｒ^１は支持媒体であり、
Ｒ^２は、各出現で独立して、以下：

からなる群から選択され、
Ｒ^２は５’から３’へ向かって１～２２の各位置で以下：

である。 In one embodiment, the compound of formula (IX) is of formula (IXa) :.

Compound, or a pharmaceutically acceptable salt thereof, in the formula,
R ¹ is a support medium and
R ² is independent of each appearance,

Selected from a group of
R ² goes from 5'to 3'at each position from 1 to 22 below:

Is.

の化合物、またはその医薬的に許容される塩が本明細書に提供され、式中、
ｎは１０～４０の整数であり、
Ｒ^１は支持媒体であり、
Ｒ^３はトリチル、モノメトキシトリチル、ジメトキシトリチルおよびトリメトキシトリチルからなる群から選択され、
Ｒ^４は、各出現で独立して、以下：

からなる群から選択される。 In another embodiment, the formula (A9):

Compounds, or pharmaceutically acceptable salts thereof, are provided herein in the formula.
n is an integer of 10 to 40,
R ¹ is a support medium and
R3 is selected from the group consisting of trityl ^, monomethoxytrityl, dimethoxytrityl and trimethoxytrityl.
^R4 is independent for each appearance,

It is selected from the group consisting of.

の化合物、またはその医薬的に許容される塩であり、式中、
ｎは１０～４０の整数であり、
Ｒ^１は支持媒体であり、
Ｒ^３はトリチル、モノメトキシトリチル、ジメトキシトリチルおよびトリメトキシトリチルからなる群から選択され、
Ｒ^４は、各出現で独立して、以下：

からなる群から選択される。 In one embodiment, the compound of formula (A9) is of formula (A9a) :.

Compound, or a pharmaceutically acceptable salt thereof, in the formula,
n is an integer of 10 to 40 and
R ¹ is a support medium and
R3 is selected from the group consisting of trityl ^, monomethoxytrityl, dimethoxytrityl and trimethoxytrityl.
^R4 is independent for each appearance,

It is selected from the group consisting of.

の化合物、またはその医薬的に許容される塩が本明細書に提供され、式中、
Ｒ^１は支持媒体であり、
Ｒ^２は、各出現で独立して、以下：

からなる群から選択され、
Ｒ^２は５’から３’へ向かって１～２２の各位置で以下：

である。 In another embodiment, formula (X) :.

Compounds, or pharmaceutically acceptable salts thereof, are provided herein in the formula.
R ¹ is a support medium and
R ² is independent of each appearance,

Selected from the group consisting of
R ² goes from 5'to 3'at each position from 1 to 22 below:

Is.

の化合物、またはその医薬的に許容される塩であり、式中、
Ｒ^１は支持媒体であり、
Ｒ^２は、各出現で独立して、以下：

からなる群から選択され、
Ｒ^２は５’から３’へ向かって１～２２の各位置で以下：

である。 In one embodiment, the compound of formula (X) is of formula (Xa) :.

Compound, or a pharmaceutically acceptable salt thereof, in the formula,
R ¹ is a support medium and
R ² is independent of each appearance,

Selected from the group consisting of
R ² goes from 5'to 3'at each position from 1 to 22 below:

Is.

の化合物、またはその医薬的に許容される塩が本明細書に提供され、式中、
ｎは１０～４０の整数であり、
Ｒ^１は支持媒体であり、
Ｒ^４は、各出現で独立して、以下：

からなる群から選択される。 In another embodiment, the formula (A10):

Compounds, or pharmaceutically acceptable salts thereof, are provided herein in the formula.
n is an integer of 10 to 40 and
R ¹ is a support medium and
^R4 is independent for each appearance,

It is selected from the group consisting of.

の化合物、またはその医薬的に許容される塩であり、式中、
ｎは１０～４０の整数であり、
Ｒ^１は支持媒体であり、
Ｒ^４は、各出現で独立して、以下：

からなる群から選択される。 In one embodiment, the compound of formula (A10) is of formula (A10a) :.

Compound, or a pharmaceutically acceptable salt thereof, in the formula,
n is an integer of 10 to 40 and
R ¹ is a support medium and
^R4 is independent for each appearance,

It is selected from the group consisting of.

In another embodiment of these compounds, the supporting medium comprises 1% divinylbenzene crosslinked polystyrene.

の化合物、またはその医薬的に許容される塩が本明細書に提供され、式中、
Ｒ^２は、各出現で独立して、以下：

からなる群から選択され、
Ｒ^２は５’から３’へ向かって１～２２の各位置で以下：

である。 In another embodiment, formula (XI) :.

Compounds, or pharmaceutically acceptable salts thereof, are provided herein in the formula.
R ² is independent of each appearance,

Selected from the group consisting of
R ² goes from 5'to 3'at each position from 1 to 22 below:

Is.

の化合物、またはその医薬的に許容される塩であり、式中、
Ｒ^２は、各出現で独立して、以下：

からなる群から選択され、
Ｒ^２は５’から３’へ向かって１～２２の各位置で以下：

である。 In one embodiment, the compound of formula (XI) is of formula (XIa) :.

Compound, or a pharmaceutically acceptable salt thereof, in the formula,
R ² is independent of each appearance,

Selected from a group of
R ² goes from 5'to 3'at each position from 1 to 22 below:

Is.

の化合物、またはその医薬的に許容される塩が本明細書に提供され、式中、
ｎは１０～４０の整数であり、
Ｒ^４は、各出現で独立して、以下：

からなる群から選択される。 In another aspect, formula (A11):

Compounds, or pharmaceutically acceptable salts thereof, are provided herein in the formula.
n is an integer of 10 to 40,
^R4 is independent for each appearance,

It is selected from the group consisting of.

の化合物、またはその医薬的に許容される塩であり、式中、
ｎは１０～４０の整数であり、
Ｒ^４は、各出現で独立して、以下：

からなる群から選択される。 In one embodiment, the compound of formula (A11) is of formula (A11a) :.

Compound, or a pharmaceutically acceptable salt thereof, in the formula,
n is an integer of 10 to 40,
^R4 is independent for each appearance,

It is selected from the group consisting of.

Oligomers Key properties of morpholino-based subunits include 1) the ability to ligate in oligomeric form by stable, uncharged, or positively charged skeletal linkages; 2) complementary base targets where the polymer formed contains the target RNA. Ability to support nucleotide bases (eg, adenin, cytosine, guanine, thymidine, uracil, 5-methyl-citosin, and hypoxanthin) so that they can hybridize with nucleic acids; 3) oligomers are active in mammalian cells. Or the ability to be passively transported; and 4) oligomers and oligomers: the ability to withstand RNA heteroduplex RNAse and RNase H degradation, respectively.

In some embodiments, the antisense oligomer contains a base modification or substitution. For example, specific nucleobases may be selected to increase the binding affinity of the antisense oligomers described herein. 5-Methylcytosine substitution has been shown to increase the stability of the nucleic acid double strand by 0.6-1.2 ° C and may be incorporated into the antisense oligomers described herein. In one embodiment, the at least one pyrimidine base of the oligomer comprises a 5-substituted pyrimidine base and the pyrimidine base is selected from the group consisting of cytosine, thymine and uracil. In one embodiment, the 5-substituted pyrimidine base is 5-methylcytosine. In another embodiment, the at least one purine base of the oligomer comprises hypoxanthine.

Morphorino-based oligomers (including antisense oligomers) include, for example, US Pat. Nos. 5,698,685, 5,217,866, 5,142,047, 5,034,506, No. 5,166,315, 5,185,444, 5,521,063, 5,506,337, 8,299,206 and 8,076,476, international patent applications Published WO / 2009/064471 and WO / 2012/0437330, as well as Summerton et al. (1997, Antisense and Nucleic Acid Drug Development, 7, 187-195), each of which is incorporated herein by reference in its entirety.

The oligomeric compounds of the present disclosure may have an asymmetric center, a chiral axis, and a chiral plane (eg, EL Eliel and S. H. Wilen, Stereo-chemistry of Carbon Compounds, John Willey & Sons, New York, 1994, pages 1119-1190, and March, J.,, Advanced Organic Chemistry, 3d. Ed., Chap. 4, John Wiley & Sons, 198, as described in New (198) Optical. With respect to all possible isomers, including isomers, and mixtures thereof, they may occur as chiral forms, as racemic mixtures, and as individual diastereomers. The oligomeric compounds of the present disclosure specifically described herein without any indication of their stereochemistry are intended to represent all possible isomers and mixtures thereof.

の化合物のような非限定的な例などを含む活性化モルホリノサブユニットから調製され、式中、Ｒ^２は、式（ＶＩＩＩ）の各化合物について独立して、以下：

からなる群から選択される。 Specifically, without wishing to be bound by any particular theory, the oligomeric compounds of the present disclosure are, as described herein, in formula (VIII) :.

Prepared from activated morpholino subunits, including non-limiting examples such as the compounds of, in the formula, R ² is independently for each compound of formula (VIII):

It is selected from the group consisting of.

Ｓｕｍｍｅｒｔｏｎ ｅｔ ａｌ．， Ａｎｔｉｓｅｎｓｅ ＆ Ｎｕｃｌｅｉｃ Ａｃｉｄ Ｄｒｕｇ Ｄｅｖ． ７：１８７－１９５ （１９９７）を参照されたい。いかなる特定の理論にも縛られることなく、２つのキラル炭素の立体化学は、例えば、アルファ－Ｌ－リボフラノシル、アルファ－Ｄ－リボフラノシル、ベータ－Ｌ－リボフラノシル、またはベータ－Ｄ－リボフラノシル出発物質の選択に基づいて、各モルホリノサブユニットの多くの可能な立体異性体が生成され得るように、合成条件下で保持される。 Each of the compounds of formula (VIII) described above may be prepared, for example, from the corresponding beta-D-ribofuranosyl as shown below.

Summerton et al. , Antisense & Nucleic Acid Drag Dev. 7: 187-195 (1997). Without being bound by any particular theory, the stereochemistry of the two chiral carbons is, for example, the selection of alpha-L-ribofuranosyl, alpha-D-ribofuranosyl, beta-L-ribofuranosyl, or beta-D-ribofuranosyl starting material. Based on, it is retained under synthetic conditions so that many possible stereoisomers of each morpholino subunit can be produced.

の化合物であってもよく、式中、Ｒ^２は、式（ＶＩＩＩａ）の各化合物について独立して、以下：

からなる群から選択される。 For example, in some embodiments, the compounds of formula (VIII) of the present disclosure are of formula (VIIIa) :.

In the formula, R ² is independently used for each compound of the formula (VIIIa), and the following:

It is selected from the group consisting of.

Incorporation of 10-40 compounds of formula (VIII) into, for example, the oligomeric compounds of the present disclosure, without wishing to be bound by any particular theory, results in a number of possible stereoisomers. obtain.

Without wishing to be bound by any particular theory, the oligomeric compounds of the present disclosure include between one or more phosphorus-containing subunits, which create a chiral center at each phosphorus, each of which is the art. As is understood in the art, it is named "Sp" or "Rp" subunit arrangement. Without wishing to be bound by any particular theory, this chirality produces stereoisomers with the same chemical composition but different three-dimensional arrangements of their atoms.

Without wishing to be bound by any particular theory, the configuration of each phosphorus subunit linkage occurs, for example, randomly during the synthesis of the oligomeric compounds of the present disclosure. Although not bound by any particular theory, the oligomeric compounds of the present disclosure are composed of a large number of phospho-subunit linkages, as each phospho-subunit linkage has a random chiral configuration. The synthetic process produces many stereoisomers exponentially in the oligomeric compounds of the present disclosure. Specifically, we do not want to be bound by any particular theory, but since the subunit-to-subunit linkages of the added morpholino subunits double the number of product stereoisomers. The conventional preparation of the oligomeric compounds of the present disclosure is in fact a very heterogeneous mixture of 2 ^N stereoisomers, where N represents the number of linkages between the phosphorus subunits.

Thus, unless otherwise indicated, for example, one or more bonds from one or more stereocenters are "-" or "~~" or as will be understood in the art. Where indicated by equivalents, a mixture of diastereomers and enantiomers, as well as all such isomers, including pure enantiomers and diastereomers, are included.

Table 1 shows various embodiments of the morpholino subunit provided in the process described herein.

Examples Examples are described below for purposes of illustration and to illustrate certain embodiments of the present disclosure. However, the scope of claims is not limited by the examples described herein. Various changes and modifications to the disclosed embodiments will be apparent to those of skill in the art, including but not limited to those relating to the chemical structures, substituents, derivatives, formulations or methods of the present disclosure. However, it may be made without departing from the spirit of the present disclosure and the scope of the attached claims. The definitions of variables in the structures in the schemes herein are consistent with those at the corresponding positions in the equations presented herein.

１００Ｌフラスコに１２．７ｋｇの４－フルオロ－３－ニトロ安息香酸を入れ、４０ｋｇのメタノールおよび２．８２ｋｇの濃硫酸を加えた。混合物を還流（６５℃）しながら３６時間撹拌した。反応混合物を０℃に冷却した。３８℃で結晶が生じた。混合物を０℃で４時間保持し、その後、窒素下で濾過した。１００Ｌフラスコを洗浄し、０℃に冷却された１０ｋｇのメタノールで濾過ケーキを洗浄した。固体濾過ケーキを漏斗上で１時間乾燥し、トレーに移し、真空オーブンで室温にて一定重量まで乾燥して１３．６９５ｋｇの４－フルオロ－３－ニトロ安息香酸メチルとした（１００％収率、ＨＰＬＣ ９９％）。 Example 1: NCP2 anchor synthesis 1. Preparation of 4-fluoro-3-nitromethyl benzoate (1)

12.7 kg of 4-fluoro-3-nitrobenzoic acid was placed in a 100 L flask, and 40 kg of methanol and 2.82 kg of concentrated sulfuric acid were added. The mixture was stirred at reflux (65 ° C.) for 36 hours. The reaction mixture was cooled to 0 ° C. Crystals were formed at 38 ° C. The mixture was held at 0 ° C. for 4 hours and then filtered under nitrogen. The 100 L flask was washed and the filtered cake was washed with 10 kg of methanol cooled to 0 ° C. The solid filtered cake was dried on a funnel for 1 hour, transferred to a tray and dried in a vacuum oven at room temperature to a constant weight to 13.695 kg of methyl 4-fluoro-3-nitrobenzoate (100% yield, 100% yield, HPLC 99%).

１００Ｌフラスコに、前のステップからの３．９８ｋｇの４－フルオロ－３－ニトロ安息香酸メチル（１）、９．８ｋｇのＤＭＦ、２．８１ｋｇのアセト酢酸メチルを入れた。混合物を撹拌し、０℃に冷却した。これに３．６６ｋｇのＤＢＵを、温度を５℃以下に維持しながら約４時間かけて加えた。混合物をさらに１時間撹拌した。反応温度を１５℃以下に維持しながら、反応フラスコに３７．５ｋｇの精製水中の８．１５ｋｇのクエン酸の溶液を加えた。加えた後、反応混合物をさらに３０分間撹拌し、その後、窒素下で濾過した。ウェット濾過ケーキを１４．８ｋｇの精製水と共に１００Ｌフラスコに戻した。スラリーを１０分間撹拌し、その後濾過した。ウェットケーキを再度１００Ｌフラスコに戻し、１４．８ｋｇの精製水で１０分間スラリー化し、濾過して、粗（Ｚ）－メチル４－（３－ヒドロキシ－１－メトキシ－１－オキソブタ－２－エン－２－イル）－３－ニトロベンゾエートとした。 2. 2. Preparation of 3-Nitro-4- (2-oxopropyl) Benzoic Acid A. (Z) -Methyl 4- (3-Hydroxy-1-methoxy-1-oxobuta-2-en-2-yl) -3-nitrobenzoate (2)

A 100 L flask was charged with 3.98 kg of methyl 4-fluoro-3-nitrobenzoate (1) from the previous step, 9.8 kg of DMF and 2.81 kg of methyl acetoacetate. The mixture was stirred and cooled to 0 ° C. To this was added 3.66 kg of DBU over about 4 hours while maintaining the temperature below 5 ° C. The mixture was stirred for an additional hour. A solution of 8.15 kg of citric acid in 37.5 kg of purified water was added to the reaction flask while maintaining the reaction temperature below 15 ° C. After addition, the reaction mixture was stirred for an additional 30 minutes and then filtered under nitrogen. The wet filtered cake was returned to a 100 L flask with 14.8 kg of purified water. The slurry was stirred for 10 minutes and then filtered. The wet cake is returned to the 100 L flask again, slurryed with 14.8 kg of purified water for 10 minutes, filtered, and crude (Z) -methyl 4- (3-hydroxy-1-methoxy-1-oxobut-2-en-). 2-yl) -3-nitrobenzoate was used.

粗（Ｚ）－メチル４－（３－ヒドロキシ－１－メトキシ－１－オキソブタ－２－エン－２－イル）－３－ニトロベンゾエートを窒素下で１００Ｌ反応フラスコに入れた。これに１４．２ｋｇの１，４－ジオキサンを加え、撹拌した。混合物に１６．６５５ｋｇの濃塩酸および１３．３３ｋｇの精製水の溶液（６Ｍ ＨＣｌ）を、反応混合物の温度を１５℃未満に維持しながら２時間かけて加えた。加え終えたら、反応混合物を還流（８０℃）しながら２４時間加熱し、室温まで冷却して、窒素下で濾過した。固体濾過ケーキを１４．８ｋｇの精製水で粉砕し、濾過し、１４．８ｋｇの精製水で再度粉砕し、濾過した。固体を３９．９ｋｇのＤＣＭと共に１００Ｌフラスコに戻し、１時間撹拌しながら還流した。１．５ｋｇの精製水を残っている固体を溶解するために加えた。下層の有機層を予熱した７２Ｌフラスコに分け、その後清浄な乾燥した１００Ｌフラスコに戻した。溶液を０℃に冷却し、１時間保持し、その後濾過した。固体濾過ケーキを２回、それぞれ９．８ｋｇのＤＣＭおよび５ｋｇのヘプタンの溶液で洗浄し、その後、漏斗上で乾燥した。固体をトレーに移し、一定重量まで乾燥して１．８５５ｋｇの３－ニトロ－４－（２－オキソプロピル）安息香酸とした。化合物１からの全体の収率４２％。ＨＰＬＣ ９９．４５％。 B. 3-Nitro-4- (2-oxopropyl) benzoic acid

Crude (Z) -methyl 4- (3-hydroxy-1-methoxy-1-oxobuta-2-en-2-yl) -3-nitrobenzoate was placed in a 100 L reaction flask under nitrogen. 14.2 kg of 1,4-dioxane was added thereto, and the mixture was stirred. A solution of 16.655 kg of concentrated hydrochloric acid and 13.33 kg of purified water (6M HCl) was added to the mixture over 2 hours while maintaining the temperature of the reaction mixture below 15 ° C. Upon completion of the addition, the reaction mixture was heated at reflux (80 ° C.) for 24 hours, cooled to room temperature and filtered under nitrogen. The solid filtered cake was ground with 14.8 kg of purified water, filtered, reground with 14.8 kg of purified water and filtered. The solid was returned to a 100 L flask with 39.9 kg of DCM and refluxed with stirring for 1 hour. 1.5 kg of purified water was added to dissolve the remaining solid. The lower organic layer was divided into preheated 72 L flasks and then returned to a clean, dry 100 L flask. The solution was cooled to 0 ° C., held for 1 hour and then filtered. The solid filtered cake was washed twice with a solution of 9.8 kg of DCM and 5 kg of heptane, respectively, and then dried on a funnel. The solid was transferred to a tray and dried to a certain weight to give 1.855 kg of 3-nitro-4- (2-oxopropyl) benzoic acid. 42% overall yield from compound 1. HPLC 99.45%.

７２Ｌジャケット付きフラスコに窒素下で１．８０５ｋｇの塩化トリフェニルメチルおよび８．３ｋｇのトルエンを入れた（ＴＰＣ溶液）。混合物を固体が溶解するまで撹拌した。１００Ｌジャケット付き反応フラスコに窒素下で５．６１ｋｇのピペラジン、１９．９ｋｇのトルエン、および３．７２ｋｇのメタノールを加えた。混合物を撹拌し、０℃に冷却した。これにＴＰＣ溶液を少しずつ、反応温度を１０℃以下に維持しながら４時間かけてゆっくりと加えた。混合物を１０℃で１．５時間撹拌し、その後、１４℃に昇温させた。３２．６ｋｇの精製水を７２Ｌフラスコに入れ、その後、内部バッチ温度を２０±５℃に維持しながら１００Ｌフラスコに移した。層を分かれさせ、下層の水層を分離および保存した。有機層を３回、各３２ｋｇの精製水で抽出し、水層を分離し、保存しておいた水溶液と合わせた。 3. 3. Preparation of N-tritylpiperazin succinate (NTP)

1.805 kg of triphenylmethyl chloride and 8.3 kg of toluene were placed in a 72 L jacketed flask under nitrogen (TPC solution). The mixture was stirred until the solid dissolved. 5.61 kg of piperazine, 19.9 kg of toluene, and 3.72 kg of methanol were added to a reaction flask with a 100 L jacket under nitrogen. The mixture was stirred and cooled to 0 ° C. The TPC solution was slowly added thereto over 4 hours while maintaining the reaction temperature at 10 ° C. or lower. The mixture was stirred at 10 ° C. for 1.5 hours and then heated to 14 ° C. 32.6 kg of purified water was placed in a 72 L flask and then transferred to a 100 L flask while maintaining the internal batch temperature at 20 ± 5 ° C. The layers were separated and the underlying aqueous layer was separated and preserved. The organic layer was extracted 3 times with 32 kg of purified water each, the aqueous layer was separated and combined with the stored aqueous solution.

The remaining organic layer was cooled to 18 ° C. and a solution of 847 g of succinic acid in 10.87 kg of purified water was slowly and slowly added to the organic layer. The mixture was stirred at 20 ± 5 ° C. for 1.75 hours. The mixture was filtered and the solid washed with 2 kg TBME and 2 kg acetone and then dried on a funnel. The filtered cake was ground twice with 5.7 kg of acetone each, filtered between the grounds and washed with 1 kg of acetone. The solid was dried on a funnel, then transferred to a tray and dried in a vacuum oven at room temperature to a constant weight to give 2.32 kg of NTP. Yield 80%.

１００Ｌジャケット付きフラスコに窒素下で２ｋｇの３－ニトロ－４－（２－オキソプロピル）安息香酸（３）、１８．３ｋｇのＤＣＭ、１．８４５ｋｇのＮ－（３－ジメチルアミノプロピル）－Ｎ’－エチルカルボジイミド塩酸塩（ＥＤＣ．ＨＣｌ）を入れた。均一な混合物が形成されるまで溶液を撹拌した。３．０４８ｋｇのＮＴＰを３０分かけて室温で加え、８時間撹拌した。５．４４ｋｇの精製水を反応混合物に加え、３０分間撹拌した。層を分離させ、生成物を含有する下層の有機層を排出および保存した。水層を５．６５ｋｇのＤＣＭで２回抽出した。合わせた有機層を４．０８ｋｇの精製水中の１．０８ｋｇの塩化ナトリウムの溶液で洗浄した。有機層を１．０６８ｋｇの硫酸ナトリウムで乾燥し、濾過した。硫酸ナトリウムを１．３ｋｇのＤＣＭで洗浄した。合わせた有機層を２５２ｇのシリカゲルでスラリー化し、２５２ｇのシリカゲルのベッドを含有する濾過用漏斗を通して濾過した。シリカゲルベッドを２ｋｇのＤＣＭで洗浄した。合わせた有機層をロータリーエバポレータで留去した。４．８ｋｇのＴＨＦを残留物に加え、その後、ＴＨＦ中の粗１－（２－ニトロ－４（４－トリチルピペラジン－１－カルボニル）フェニル）プロパン－２－オンが２．５倍量に達するまでロータリーエバポレータで留去した。 4. Preparation of (4- (2-Hydroxypropyl) -3-nitrophenyl) (4-tritylpiperazin-1-yl) metanone A. Preparation of 1- (2-nitro-4 (4-tritylpiperazin-1-carbonyl) phenyl) propane-2-one

2 kg of 3-nitro-4- (2-oxopropyl) benzoic acid (3) under nitrogen in a 100 L jacketed flask, 18.3 kg of DCM, 1.845 kg of N- (3-dimethylaminopropyl) -N' -Ethylcarbodiimide hydrochloride (EDC.HCl) was added. The solution was stirred until a uniform mixture was formed. 3.048 kg of NTP was added over 30 minutes at room temperature and stirred for 8 hours. 5.44 kg of purified water was added to the reaction mixture and stirred for 30 minutes. The layers were separated and the underlying organic layer containing the product was discharged and stored. The aqueous layer was extracted twice with 5.65 kg DCM. The combined organic layers were washed with 1.08 kg of sodium chloride solution in 4.08 kg of purified water. The organic layer was dried over 1.068 kg sodium sulfate and filtered. Sodium sulfate was washed with 1.3 kg of DCM. The combined organic layers were slurryed with 252 g of silica gel and filtered through a filtration funnel containing a bed of 252 g of silica gel. The silica gel bed was washed with 2 kg of DCM. The combined organic layer was distilled off by a rotary evaporator. 4.8 kg of THF is added to the residue, after which crude 1- (2-nitro-4 (4-tritylpiperazin-1-carbonyl) phenyl) propane-2-one in THF reaches 2.5 times the amount. Distilled off with a rotary evaporator.

１００Ｌジャケット付きフラスコに窒素下で前のステップからの３６００ｇの４および９８００ｇのＴＨＦを入れた。撹拌した溶液を５℃以下に冷却した。溶液を１１５２５ｇのエタノールで希釈し、１９４ｇの水素化ホウ素ナトリウムを５℃以下で約２時間かけて加えた。反応混合物を５℃以下でさらに２時間撹拌した。約３ｋｇの水中の約１．１ｋｇの塩化アンモニウムの溶液を、温度を１０℃以下に維持するためにゆっくりと加えることにより、反応をクエンチした。反応混合物をさらに３０分間撹拌し、濾過して無機物を除去し、１００Ｌジャケット付きフラスコに再び入れ、２３ｋｇのＤＣＭで抽出した。有機層を分離し、水層をさらに２回、各４．７ｋｇのＤＣＭで抽出した。合わせた有機層を、約３ｋｇの水中の約８００ｇの塩化ナトリウムの溶液で洗浄し、その後２．７ｋｇの硫酸ナトリウムで乾燥した。懸濁液を濾過し、濾過ケーキを２ｋｇのＤＣＭで洗浄した。合わせた濾液を２．０倍量に濃縮し、３６０ｇの酢酸エチルで希釈し、留去した。粗生成物を、窒素下でＤＣＭで充填した４ｋｇのシリカのシリカゲルカラムにかけ、７．２ｋｇのＤＣＭ中の２．３ｋｇの酢酸エチルで溶出した。合わせた画分を留去し、残留物を１１．７ｋｇのトルエンに取り入れた。トルエン溶液を濾過し、濾過ケーキを２回、各２ｋｇのトルエンで洗浄した。濾過ケーキを一定重量まで乾燥して２．２７５ｋｇの化合物５とした（化合物３からの収率４６％）、ＨＰＬＣ ９６．９９％。 B. Preparation of (4- (2-Hydroxypropyl) -3-nitrophenyl) (4-tritylpiperazin-1-yl) metanone (5)

A flask with a 100 L jacket was charged with 3600 g of 4 and 9800 g of THF from the previous step under nitrogen. The stirred solution was cooled to 5 ° C. or lower. The solution was diluted with 11525 g of ethanol and 194 g of sodium borohydride was added at 5 ° C. or lower over about 2 hours. The reaction mixture was stirred at 5 ° C. or lower for an additional 2 hours. The reaction was quenched by the slow addition of about 1.1 kg of ammonium chloride solution in about 3 kg of water to keep the temperature below 10 ° C. The reaction mixture was stirred for an additional 30 minutes, filtered to remove minerals, placed back in a 100 L jacketed flask and extracted with 23 kg DCM. The organic layer was separated and the aqueous layer was extracted twice more with 4.7 kg DCM each. The combined organic layers were washed with about 800 g of sodium chloride solution in about 3 kg of water and then dried over 2.7 kg of sodium sulfate. The suspension was filtered and the filtered cake was washed with 2 kg of DCM. The combined filtrate was concentrated 2.0 times, diluted with 360 g of ethyl acetate, and distilled off. The crude product was applied to a silica gel column of 4 kg silica filled with DCM under nitrogen and eluted with 2.3 kg ethyl acetate in 7.2 kg DCM. The combined fractions were distilled off and the residue was incorporated into 11.7 kg of toluene. The toluene solution was filtered and the filtered cake was washed twice with 2 kg of toluene each. The filtered cake was dried to a constant weight to give 2.275 kg of compound 5 (46% yield from compound 3), HPLC 96.99%.

１００Ｌジャケット付きフラスコに窒素下で４．３ｋｇの化合物５（重量は^１Ｈ ＮＭＲによる残留トルエンに基づいて調整され、この後のすべての試薬はそれにしたがってスケールを合わせた）および１２．７ｋｇのピリジンを入れた。これに３．１６０ｋｇのＤＳＣ（^１Ｈ ＮＭＲで７８．９１重量％）を、内部温度を３５℃以下に維持しながら入れた。反応混合物を周囲条件で約２２時間熟成させ、その後濾過した。濾過ケーキを２００ｇのピリジンで洗浄した。濾液体積の１／２を各々含む２つのバッチで、約５０ｋｇの水中の約１１ｋｇのクエン酸の溶液を含有する１００Ｌジャケット付きフラスコに濾液をゆっくりと入れ、３０分間撹拌して固体を沈殿させた。固体を濾過用漏斗で回収し、１回の洗浄につき４．３ｋｇの水で２回洗浄し、濾過用漏斗上で真空乾燥した。 5. Preparation of 2,5-Dioxopyrrolidine-1-yl (1- (2-nitro-4- (4-triphenylmethylpiperazine-1-carbonyl) phenyl) propan-2-yl) (NCP2 anchor)

In a 100 L jacketed flask, under nitrogen 4.3 kg of compound 5 (weight adjusted based on residual toluene by ^{1 1} H NMR, all subsequent reagents scaled accordingly) and 12.7 kg of pyridine. I put it in. 3.160 kg of DSC (78.91% by weight by ^{1 1} H NMR) was added thereto while maintaining the internal temperature at 35 ° C. or lower. The reaction mixture was aged in ambient conditions for about 22 hours and then filtered. The filtered cake was washed with 200 g of pyridine. The filtrate was slowly placed in a 100 L jacketed flask containing about 11 kg of citric acid solution in about 50 kg of water in two batches each containing 1/2 of the filtrate volume and stirred for 30 minutes to precipitate the solid. .. The solid was collected in a filtration funnel, washed twice with 4.3 kg of water per wash and vacuum dried on the filtration funnel.

The combined solids were placed in a 100 L jacketed flask, dissolved in 28 kg of DCM and washed with 4.3 kg of water in 900 g of potassium carbonate solution. After 1 hour, the layers were separated and the aqueous layer was removed. The organic layer was washed with 10 kg of water, separated and dried over 3.5 kg of sodium sulfate. The DCM was filtered, distilled off and vacuum dried to a 6.16 kg NCP2 anchor (114% yield).

Example 2: Anchor-supported resin synthesis A 75 L solid-phase synthesis reactor was charged with about 52 L of NMP and 2600 g of aminomethylpolystyrene resin. The resin was stirred in NMP, swollen for about 2 hours and then drained. The resin was washed twice with about 39 L DCM per wash, then twice with 39 L neutralization solution per wash, and then twice with 39 L DCM per wash. The NCP2 anchor solution was slowly added to the stirring resin solution, and the mixture was stirred at room temperature for 24 hours and discharged. The resin was washed 4 times with 39 L of NMP per wash and 6 times with 39 L of DCM per wash. The resin was treated, stirred and drained with 1/2 of the DEDC capping solution for 30 minutes and drained, and treated and stirred with the second 1/2 DEDC capping solution for 30 minutes and drained. The resin was washed 6 times with 39 L of DCM per wash and then dried in an oven to a certain weight to give 3573.71 g of anchor-supported resin.

冷却したジクロロメタン（６ｍＬ／ｇ ＮＴＰ）中のＮＴＰの懸濁液に、水（４ｍＬ／ｇ炭酸カリウム）中の炭酸カリウム（３．２等量）の溶液を加えた。この２相混合物に、ジクロロメタン（２ｇ／ｇクロロギ酸フェニル）中のクロロギ酸フェニル（１．０３等量）の溶液をゆっくりと加えた。反応混合物を２０℃に加温した。反応が完了したら（１～２時間）、層を分離した。有機層を水洗し、無水炭酸カリウムで乾燥した。生成物３５をアセトニトリルからの結晶化により単離した。収率＝８０％。 Example 3: Preparation of activated EG3 tail 1. Preparation of Trityl Piperazine Phenyl Carbamate (35)

A solution of potassium carbonate (3.2 equal volumes) in water (4 mL / g potassium carbonate) was added to the suspension of NTP in chilled dichloromethane (6 mL / g NTP). A solution of phenyl chloroformate (1.03 equal volume) in dichloromethane (2 g / g phenyl chloroformate) was slowly added to this two-phase mixture. The reaction mixture was heated to 20 ° C. When the reaction was complete (1-2 hours), the layers were separated. The organic layer was washed with water and dried over anhydrous potassium carbonate. Product 35 was isolated by crystallization from acetonitrile. Yield = 80%.

水素化ナトリウム（１．２等量）を１－メチル－２－ピロリドン（３２ｍＬ／ｇ水素化ナトリウム）中に懸濁させた。この懸濁液にトリエチレングリコール（１０．０等量）および化合物３５（１．０等量）を加えた。結果として生じるスラリーを９５℃に加熱した。反応が完了したら（１～２時間）、混合物を２０℃に冷却した。この混合物に３０％ジクロロメタン／メチルｔｅｒｔ－ブチルエーテル（ｖ：ｖ）および水を加えた。生成物含有有機層をＮａＯＨ水溶液、コハク酸水溶液、および飽和塩化ナトリウム水溶液で連続して洗浄した。生成物３６をジクロロメタン／メチルｔｅｒｔ－ブチルエーテル／ヘプタンからの結晶化により単離した。収率＝９０％。 2. 2. Preparation of Carbamate Alcohol (36)

Sodium hydride (1.2 eq) was suspended in 1-methyl-2-pyrrolidone (32 mL / g sodium hydride). Triethylene glycol (10.0 eq) and compound 35 (1.0 eq) were added to this suspension. The resulting slurry was heated to 95 ° C. When the reaction was complete (1-2 hours), the mixture was cooled to 20 ° C. 30% dichloromethane / methyl tert-butyl ether (v: v) and water were added to this mixture. The product-containing organic layer was washed successively with aqueous NaOH solution, aqueous solution of succinic acid, and saturated aqueous sodium chloride solution. Product 36 was isolated by crystallization from dichloromethane / methyl tert-butyl ether / heptane. Yield = 90%.

テトラヒドロフラン（７ｍＬ／ｇ ３６）中の化合物３６の溶液に、無水コハク酸（２．０等量）およびＤＭＡＰ（０．５等量）を加えた。混合物を５０℃に加熱した。反応が完了したら（５時間）、混合物を２０℃に冷却し、ＮａＨＣＯ_３水溶液でｐＨ８．５に調整した。メチルｔｅｒｔ－ブチルエーテルを加え、生成物を水層に抽出した。ジクロロメタンを加え、混合物をクエン酸水溶液でｐＨ３に調整した。生成物含有有機層をｐＨ＝３のクエン酸緩衝液と飽和塩化ナトリウム水溶液との混合物で洗浄した。この３７のジクロロメタン溶液を、化合物３８の調製に単離せずに使用した。 3. 3. Preparation of EG3 tail acid (37)

Succinic anhydride (2.0 eq) and DMAP (0.5 eq) were added to a solution of compound 36 in tetrahydrofuran (7 mL / g 36). The mixture was heated to 50 ° C. When the reaction was complete (5 hours), the mixture was cooled to 20 ° C. and adjusted to pH 8.5 with aqueous NaHCO ₃ solution. Methyl tert-butyl ether was added and the product was extracted into an aqueous layer. Dichloromethane was added and the mixture was adjusted to pH 3 with aqueous citric acid. The product-containing organic layer was washed with a mixture of pH = 3 citric acid buffer and saturated aqueous sodium chloride solution. This 37 dichloromethane solution was used without isolation in the preparation of compound 38.

化合物３７の溶液に、Ｎ－ヒドロキシ－５－ノルボルネン－２，３－ジカルボン酸イミド（ＨＯＮＢ）（１．０２当量）、４－ジメチルアミノピリジン（ＤＭＡＰ）（０．３４当量）、およびその後１－（３－ジメチルアミノプロピル）－Ｎ’－エチルカルボジイミド塩酸塩（ＥＤＣ）（１．１当量）を加えた。混合物を５５℃に加熱した。反応が完了したら（４～５時間）、混合物を２０℃に冷却し、１：１の０．２Ｍクエン酸／ブラインおよびブラインで連続して洗浄した。ジクロロメタン溶液をアセトン、およびその後Ｎ，Ｎ－ジメチルホルムアミドに溶媒交換し、生成物をアセトン／Ｎ，Ｎ－ジメチルホルムアミドから飽和塩化ナトリウム水溶液への沈殿により単離した。粗生成物を水中で数回再スラリー化して残留Ｎ，Ｎ－ジメチルホルムアミドおよび塩を除去した。化合物３６からの活性化ＥＧ３テール３８の収率＝７０％。 4. Preparation of activated EG3 tail (38)

In a solution of compound 37, N-hydroxy-5-norbornen-2,3-dicarboxylic acidimide (HONB) (1.02 eq), 4-dimethylaminopyridine (DMAP) (0.34 eq), and then 1- (3-Dimethylaminopropyl) -N'-ethylcarbodiimide hydrochloride (EDC) (1.1 eq) was added. The mixture was heated to 55 ° C. When the reaction was complete (4-5 hours), the mixture was cooled to 20 ° C. and washed continuously with 1: 1 0.2 M citric acid / brine and brine. The dichloromethane solution was solvent exchanged with acetone and then with N, N-dimethylformamide, and the product was isolated by precipitation from acetone / N, N-dimethylformamide into saturated aqueous sodium chloride solution. The crude product was reslurried several times in water to remove residual N, N-dimethylformamide and salts. Yield of activated EG3 tail 38 from compound 36 = 70%.

Example 4: 50L solid-phase synthesis of Casimersen [oligomer compound (XII)] crude drug substance 1. material

Ｂ．活性化Ｃサブユニット（調製については、米国特許第８，０６７，５７１号を参照）

Ｃ．活性化Ａサブユニット（調製については、米国特許第８，０６７，５７１号を参照）

Ｄ．活性化ＤＰＧサブユニット（調製については、ＷＯ２００９／０６４４７１を参照）

Ｅ．活性化Ｔサブユニット（調製については、ＷＯ２０１３／０８２５５１を参照）

Ｆ．アンカー担持樹脂

式中、Ｒ^１は支持媒体である。 Chemical structure of starting material:
A. Activated EG3 tail

B. Activated C subunit (see US Pat. No. 8,067,571 for preparation)

C. Activated A subunit (see US Pat. No. 8,067,571 for preparation)

D. Activated DPG subunit (see WO2009 / 064471 for preparation)

E. Activated T subunit (see WO2013 / 082551 for preparation)

F. Anchor-supported resin

In the formula, R ¹ is a support medium.

2. 2. Synthesis of Casimersen crude drug A. Resin swelling 750 g of anchor-supported resin and 10.5 L of NMP were placed in a 50 L silane-treated reactor and stirred for 3 hours. NMP was drained and the anchor-supported resin was washed twice with 5.5 L DCM each and twice with 5.5 L 30% TFE / DCM each.

B. Cycle 0: EG3 tail coupling anchor-bearing resin washed 3 times with 5.5 L of each 30% TFE / DCM, drained, washed with 5.5 L of CYFTA solution for 15 minutes, drained and again at 5.5 L. Washed with CYTFA solution for 15 minutes, 122 mL of 1: 1 NEM / DCM was added without draining, the suspension was stirred for 2 minutes and drained. The resin was washed once for 10 minutes with 5.5 L of neutralization solution, drained, washed twice with 5.5 L of neutralized solution for 5 minutes, drained, and then washed twice with 5.5 L of DCM each. , Discharged. A solution of 706.2 g of activated EG3 tail (MW 765.85) and 234 mL of NEM in 3 L of DMI was placed in the resin, stirred at room temperature for 3 hours and discharged. The resin is washed once for 10 minutes with 5.5 L of neutralization solution and drained, washed once with 5.5 L of neutralized solution once for 5 minutes, drained, washed once with 5.5 L of DCM and drained. did. A solution of 374.8 g of benzoic anhydride and 195 mL of NEM in 2680 mL of NMP was added, stirred for 15 minutes and drained. The resin is washed once for 10 minutes with 5.5 L of neutralization solution and drained, washed once with 5.5 L of neutralized solution once for 5 minutes, drained, washed once with 5.5 L of DCM and drained. Then, each was washed twice with 5.5 L of 30% TFE / DCM. The resin was suspended in 5.5 L of 30% TFE / DCM and held for 14 hours.

C. Subunit coupling cycle 1-22
i. Coupling Pretreatment Prior to each coupling cycle as described in Table 4, the resin is: 1) washed with 30% TFE / DCM, 2) a) treated with CYTFA solution for 15 minutes and drained. b) Treated with CYTFA solution for 15 minutes, 1: 1 NEM / DCM was added, stirred and drained, 3) stirred with neutralized solution 3 times and 4) washed twice with DCM. See Table 4.

ii. Post-Coupling Treatment After draining each subunit solution as shown in Table 4, the resin was 1) washed with DCM and 2) washed 3 times with 30% TFE / DCM. When the resin was retained for some time prior to the next coupling cycle, the third TFE / DCM wash solution was not drained and the resin was retained in the aforementioned TFE / DCM wash solution. See Table 4.

iii. Activation subunit coupling cycle A coupling cycle was performed as described in Table 4.

iv. Final IPA Cleaning After performing the final coupling steps as described in Table 4, the resin was washed 8 times with 19.5 L of IPA each and vacuum dried at room temperature for about 63.5 hours to a dry weight of 4523 g. ..

D. Cutting The resin-bonded Casimersen crude drug substance was divided into two lots, and each lot was treated as follows. Each of the two 2261.5 g lots of resin was stirred with 1) 10 L of NMP for 2 hours, then drained, 2) washed 3 times with 10 L of each 30% TFE / DCM, and 3) 10 L of CYTFA. The solution was treated for 15 minutes, 4) then 130 ml of 1: 1 NEM / DCM was added to 10 L of CYTFA solution for 15 minutes, stirred for 2 minutes and drained. The resin was treated 3 times with 10 L of each neutralizing solution and washed 6 times with 10 L of DCM and 8 times with 10 L of NMP each. The resin was treated with 1530.4 g of a cleavage solution of DTT and 2980 DBU in 6.96 L of NMP for 2 hours to remove the Casimersen crude drug substance from the resin. The cutting solution was drained and held in a separate container. The reactor and resin were washed with 4.97 L of NMP and combined with the cleavage solution.

E. The combination of the deprotected cutting solution and NMP washing was transferred to a pressure vessel, and 39.8 L of NH ₄ OH (NH ₃・ H ₂ O) cooled to a temperature of −10 to -25 ° C. in a freezer was added. The pressure vessel was sealed and heated to 45 ° C. for 16 hours and then cooled to 25 ° C. The deprotected solution containing this Casimersen crude drug substance was diluted 3: 1 with purified water prior to solvent removal. During solvent removal, the deprotected solution was adjusted to pH 3.0 with 2M phosphoric acid and then to pH 8.03 with NH ₄ OH. HPLC: C18 80.93% (Fig. 1) and SCX-10 84.4% (Fig. 2).

Example 5: Purification of Caustic Crude Drug substance The deprotection solution from Part E of Example 4 containing the Caustic acid crude drug substance is filled in a column of ToyoPearl Super-Q 650S anion exchange resin (Tosoh Bioscience), and 17 Elution with a gradient of 0-35% B over column volume (buffer A: 10 mM sodium hydroxide; buffer B: 1 M sodium chloride in 10 mM sodium hydroxide) and a fraction of acceptable purity (C18 and SCX HPLC). ) Was stored and used as a purified drug product solution. HPLC: 97.74% (C18; FIG. 3) 94.58% (SCX; FIG. 4).

The purified drug substance solution was desalted and lyophilized to obtain 1477.82 g of the purified Casimersen drug substance. Yield 63.37%; HPLC: 96.045% (FIG. 5; C18) 96.346% (FIG. 6; SCX).

Incorporation by Reference The content of all references cited throughout this application, including literature references, issued patents, published patent applications, and co-pending patent applications, is expressly herein in its entirety. Be incorporated. Unless otherwise defined, all technical and scientific terms used herein are consistent with those commonly known to those of skill in the art.

（式中、ｎは１０～４０の整数であり、各Ｒ ^２ は、各出現について独立して、以下：

からなる群から選択される）のオリゴマー化合物を調製するためのプロセスであって、前記プロセスは、以下の連続したステップ：
（ａ）式（Ａ１）：

（式中、Ｒ ^１ は支持媒体であり、Ｒ ^３ はトリチル、モノメトキシトリチル、ジメトキシトリチルおよびトリメトキシトリチルからなる群から選択される）の化合物を脱ブロッキング剤と接触させて式（ＩＩ）：

（式中、Ｒ ^１ は支持媒体である）の化合物を形成するステップ；
（ｂ）式（ＩＩ）の化合物を式（Ａ２）：

（式中、Ｒ ^３ はトリチル、モノメトキシトリチル、ジメトキシトリチルおよびトリメトキシトリチルからなる群から選択される）の化合物と接触させて式（Ａ３）：

（式中、Ｒ ^１ は支持媒体であり、Ｒ ^３ はトリチル、モノメトキシトリチル、ジメトキシトリチルおよびトリメトキシトリチルからなる群から選択される）の化合物を形成するステップ；
（ｃ）式（Ａ３）の化合物を脱ブロッキング剤と接触させて式（ＩＶ）：

（式中、Ｒ ^１ は支持媒体である）の化合物を形成するステップ；
（ｄ）式（ＩＶ）の化合物を式（Ａ４）：

（式中、Ｒ ^３ はトリチル、モノメトキシトリチル、ジメトキシトリチルおよびトリメトキシトリチルからなる群から選択され、Ｒ ^４ は以下：

からなる群から選択される）の化合物と接触させて式（Ａ５）：

（式中、Ｒ ^１ は支持媒体であり、Ｒ ^３ はトリチル、モノメトキシトリチル、ジメトキシトリチルおよびトリメトキシトリチルからなる群から選択され、Ｒ ^４ は以下：

から選択される）の化合物を形成するステップ；
（ｅ）以下の連続したステップ：
（ｅ１）直前のステップによって形成された生成物を脱ブロッキング剤と接触させるステップ、および
（ｅ２）直前のステップによって形成された化合物を式（Ａ８）：

（式中、Ｒ ^３ はトリチル、モノメトキシトリチル、ジメトキシトリチルおよびトリメトキシトリチルからなる群から選択され、Ｒ ^４ は、式（Ａ８）の各化合物について独立して、以下：

からなる群から選択される）の化合物と接触させて式（Ａ９）：

（式中、ｎは１０～４０の整数であり、Ｒ ^１ は支持媒体であり、Ｒ ^３ はトリチル、モノメトキシトリチル、ジメトキシトリチルおよびトリメトキシトリチルからなる群から選択され、Ｒ ^４ は、各出現について独立して、以下：

からなる群から選択される）の化合物を形成するステップ
のｎ－１回の反復を実施するステップ；
（ｆ）式（Ａ９）の化合物を脱ブロッキング剤と接触させて式（Ａ１０）：

（式中、ｎは１０～４０の整数であり、Ｒ ^１ は支持媒体であり、Ｒ ^４ は、各出現について独立して、以下：

からなる群から選択される）の化合物を形成するステップ；
（ｇ）式（Ａ１０）の化合物を切断剤と接触させて式（Ａ１１）：

（式中、ｎは１０～４０の整数であり、Ｒ ^４ は、各出現について独立して、以下：

からなる群から選択される）の化合物を形成するステップ；ならびに
（ｈ）式（Ａ１１）の化合物を脱保護剤と接触させて式（Ａ）のオリゴマー化合物を形成するステップ
を含むプロセス。
(項目２)
式（Ａ４）の化合物が式（Ａ４ａ）：

の化合物であり、式中、
Ｒ ^３ はトリチル、モノメトキシトリチル、ジメトキシトリチルおよびトリメトキシトリチルからなる群から選択され、
Ｒ ^４ は、以下：

から選択される、
項目１に記載のプロセス。
(項目３)
式（Ａ５）の化合物が式（Ａ５ａ）：

の化合物であり、式中、
Ｒ ^１ は支持媒体であり、
Ｒ ^３ はトリチル、モノメトキシトリチル、ジメトキシトリチルおよびトリメトキシトリチルからなる群から選択され、
Ｒ ^４ は、以下：

から選択される、
項目１または２に記載のプロセス。
(項目４)
式（Ａ８）の化合物が式（Ａ８ａ）：

の化合物であり、式中、
Ｒ ^３ はトリチル、モノメトキシトリチル、ジメトキシトリチルおよびトリメトキシトリチルからなる群から選択され、
Ｒ ^４ は、式（Ａ８ａ）の化合物の各出現で独立して、以下：

からなる群から選択される、
項目１～３のいずれか一項に記載のプロセス。
(項目５)
式（Ａ９）の化合物が式（Ａ９ａ）：

の化合物であり、式中、
ｎは１０～４０の整数であり、
Ｒ ^１ は支持媒体であり、
Ｒ ^３ はトリチル、モノメトキシトリチル、ジメトキシトリチルおよびトリメトキシトリチルからなる群から選択され、
Ｒ ^４ は、各出現について独立して、以下：

からなる群から選択される、
項目１～４のいずれか一項に記載のプロセス。
(項目６)
式（Ａ１０）の化合物が式（Ａ１０ａ）：

の化合物であり、式中、
ｎは１０～４０の整数であり、
Ｒ ^１ は支持媒体であり、
Ｒ ^４ は、各出現について独立して、以下：

からなる群から選択される、
項目１～５のいずれか一項に記載のプロセス。
(項目７)
式（Ａ１１）の化合物が式（Ａ１１ａ）：

の化合物であり、式中、
ｎは１０～４０の整数であり、
Ｒ ^４ は、各出現について独立して、以下：

からなる群から選択される、
項目１～６のいずれか一項に記載のプロセス。
(項目８)
式（Ａ）のオリゴマー化合物について、ｎは２２であり、Ｒ ^２ は５’から３’へ向かって１～２２の各位置で以下：

であり、
式（Ａ）のオリゴマー化合物は式（Ｃ）：

の化合物、またはその医薬的に許容される塩である、
項目１～７のいずれか一項に記載のプロセス。
(項目９)
式（Ｃ）のオリゴマー化合物は式（ＸＩＩ）：

のオリゴマー化合物、またはその医薬的に許容される塩である、項目１～８のいずれか一項に記載のプロセス。
(項目１０)
Ｒ ^３ は、各出現でトリチルである、項目１～９のいずれか一項に記載のプロセス。
(項目１１)
式（Ｃ）：

のオリゴマー化合物を調製するためのプロセスであって、以下の連続したステップ：
（ａ）式（Ｉ）：

（式中、Ｒ ^１ は支持媒体である）の化合物を脱ブロッキング剤と接触させて式（ＩＩ）：

（式中、Ｒ ^１ は支持媒体である）の化合物を形成するステップ；
（ｂ）式（ＩＩ）の化合物を化合物（Ｂ）：

と接触させて式（ＩＩＩ）：

（式中、Ｒ ^１ は支持媒体である）の化合物を形成するステップ；
（ｃ）式（ＩＩＩ）の化合物を脱ブロッキング剤と接触させて式（ＩＶ）：

（式中、Ｒ ^１ は支持媒体である）の化合物を形成するステップ；
（ｄ）式（ＩＶ）の化合物を式（Ｄ）：

の化合物と接触させて式（Ｖ）：

（式中、Ｒ ^１ は支持媒体である）の化合物を形成するステップ；
（ｅ）式（Ｖ）の化合物を脱ブロッキング剤と接触させて式（ＶＩ）：

（式中、Ｒ ^１ は支持媒体である）の化合物を形成するステップ；
（ｆ）式（ＶＩ）の化合物を式（Ｆ）：

の化合物と接触させて式（ＶＩＩ）：

（式中、Ｒ ^１ は支持媒体である）の化合物を形成するステップ；
（ｇ）以下の連続したステップ：
（ｇ１）直前のステップによって形成された生成物を脱ブロッキング剤と接触させるステップ、および
（ｇ２）直前のステップによって形成された化合物を式（ＶＩＩＩ）：

（式中、Ｒ ^２ は、式（ＶＩＩＩ）の各化合物について独立して、以下：

からなる群から選択され、各反復１～２０について、Ｒ ^２ は、以下：

である）の化合物と接触させて式（ＩＸ）：

（式中、
Ｒ ^１ は支持媒体であり、
Ｒ ^２ は、各出現について独立して、以下：

からなる群から選択され、
Ｒ ^２ は５’から３’へ向かって１～２２の各位置で以下：

である）の化合物を形成するステップ
の２０回の反復を実施するステップ；
（ｈ）式（ＩＸ）の化合物を脱ブロッキング剤と接触させて式（Ｘ）：

（式中、
Ｒ ^１ は支持媒体であり、
Ｒ ^２ は、各出現について独立して、以下：

からなる群から選択され、
Ｒ ^２ は５’から３’へ向かって１～２２の各位置で以下：

である）の化合物を形成するステップ；
（ｉ）式（Ｘ）の化合物を切断剤と接触させて式（ＸＩ）：

（式中、Ｒ ^２ は、各出現について独立して、以下：

からなる群から選択され、
Ｒ ^２ は５’から３’へ向かって１～２２の各位置で以下：

である）の化合物を形成するステップ；ならびに
（ｊ）式（ＸＩ）の化合物を脱保護剤と接触させて式（Ｃ）のオリゴマー化合物を形成するステップ
を含む、項目１に記載のプロセス。
(項目１２)
ステップ（ｄ）、ステップ（ｆ）またはステップ（ｇ２）が、それぞれ式（ＩＶ）の化合物、式（ＶＩ）の化合物または前記直前のステップによって形成された前記化合物を、キャッピング剤と接触させることをさらに含む、項目１～１１のいずれか一項に記載の
プロセス。
(項目１３)
各ステップで使用される前記脱ブロッキング剤は、ハロゲン化酸またはシアノ酢酸である、項目１～１２のいずれか一項に記載のプロセス。
(項目１４)
前記ハロゲン化酸は、クロロ酢酸、ジクロロ酢酸、トリクロロ酢酸、フルオロ酢酸、ジフルオロ酢酸、およびトリフルオロ酢酸からなる群から選択される、項目１３に記載のプロセス。
(項目１５)
前記支持媒体は、ガラス、修飾または官能化ガラス、プラスチック（アクリル、ポリスチレン（例えば、１％ジビニルベンゼン架橋ポリスチレン）、スチレンと他の材料とのコポリマー、ポリプロピレン、ポリエチレン、ポリブチレン、ポリウレタン、およびテフロン（登録商標）を含む）、多糖類、ナイロンまたはニトロセルロース、セラミックス、樹脂、シリカまたはシリカ系材料（シリコンおよび修飾シリコンを含む）、炭素、金属、ならびに光ファイバ束からなる群から選択される材料を含む、項目１～１４のいずれか一項に記載のプロセス。
(項目１６)
（式ＩＸ）：

の化合物であって、式中、
Ｒ ^１ は支持媒体であり、
Ｒ ^２ は、各出現で独立して、以下：

からなる群から選択され、
Ｒ ^２ は５’から３’へ向かって１～２２の各位置で以下：

である、
化合物、またはその医薬的に許容される塩。
(項目１７)
式（ＩＸ）の化合物が式（ＩＸａ）：

の化合物であり、式中、
Ｒ ^１ は支持媒体であり、
Ｒ ^２ は、各出現で独立して、以下：

からなる群から選択され、
Ｒ ^２ は５’から３’へ向かって１～２２の各位置で以下：

である、
項目１６に記載の化合物、またはその医薬的に許容される塩。
(項目１８)
（式Ｘ）：

の化合物であって、式中、
Ｒ ^１ は支持媒体であり、
Ｒ ^２ は、各出現で独立して、以下：

からなる群から選択され、
Ｒ ^２ は５’から３’へ向かって１～２２の各位置で以下：

である、
化合物、またはその医薬的に許容される塩。
(項目１９)
式（Ｘ）の化合物が式（Ｘａ）：

の化合物であり、式中、
Ｒ ^１ は支持媒体であり、
Ｒ ^２ は、各出現で独立して、以下：

からなる群から選択され、
Ｒ ^２ は５’から３’へ向かって１～２２の各位置で以下：

である、
項目７０に記載の化合物、またはその医薬的に許容される塩。
(項目２０)
前記支持媒体が１％ジビニルベンゼン架橋ポリスチレンを含む、項目１６～１９のいずれか一項に記載の化合物。
(項目２１)
（式ＸＩ）：

の化合物であって、式中、
Ｒ ^２ は、各出現で独立して、以下：

からなる群から選択され、
Ｒ ^２ は５’から３’へ向かって１～２２の各位置で以下：

である、
化合物、またはその医薬的に許容される塩。
(項目２２)
式（ＸＩ）の化合物が式（ＸＩａ）：

の化合物であり、式中、
Ｒ ^２ は、各出現で独立して、以下：

からなる群から選択され、
Ｒ ^２ は５’から３’へ向かって１～２２の各位置で以下：

である、
項目２１に記載の化合物、またはその医薬的に許容される塩。 Equivalents One of ordinary skill in the art will be able to recognize or confirm many of the equivalents of the particular embodiments of the disclosure described herein using only predetermined experimental methods. Such equivalents are intended to be embraced by the following claims.
The present invention provides, for example, the following items.
(Item 1)
Equation (A):

(In the equation, n is an integer from 10 to 40, and each R ² is independent for each occurrence, and the following:

A process for preparing an oligomeric compound (selected from the group consisting of), wherein the process consists of the following consecutive steps:
(A) Equation (A1):

The compound of (in the formula, R ¹ is the supporting medium and R ³ is selected from the group consisting of trityl, monomethoxytrityl, dimethoxytrityl and trimethoxytrityl) is contacted with the deblocking agent to formulate (II) :.

The step of forming the compound (in the formula, R ¹ is the supporting medium);
(B) The compound of the formula (II) is represented by the formula (A2) :.

(In the formula, R ³ is selected from the group consisting of trityl, monomethoxytrityl, dimethoxytrityl and trimethoxytrityl) in contact with the compound of formula (A3):.

(In the formula, R ¹ is the supporting medium and R ³ is selected from the group consisting of trityl, monomethoxytrityl, dimethoxytrityl and trimethoxytrityl).
(C) The compound of the formula (A3) is brought into contact with the deblocking agent to formulate (IV):

The step of forming the compound (in the formula, R ¹ is the supporting medium);
(D) The compound of the formula (IV) is represented by the formula (A4) :.

(In the formula, R ³ is selected from the group consisting of trityl, monomethoxytrityl, dimethoxytrityl and trimethoxytrityl, and R ⁴ is:

(Selected from the group consisting of) in contact with the compound of formula (A5) :.

(In the formula, R ¹ is the supporting medium, R ³ is selected from the group consisting of trityl, monomethoxytrityl, dimethoxytrityl and trimethoxytrityl, and R ⁴ is:

The step of forming a compound (selected from);
(E) The following consecutive steps:
(E1) The step of contacting the product formed by the immediately preceding step with the deblocking agent, and
(E2) The compound formed by the immediately preceding step is represented by the formula (A8) :.

(In the formula, R ³ is selected from the group consisting of trityl, monomethoxytrityl, dimethoxytrityl and trimethoxytrityl, and R ⁴ is independently for each compound of formula (A8), and the following:

(Selected from the group consisting of) in contact with the compound of formula (A9) :.

(In the formula, n is an integer of 10-40, R ¹ is the supporting medium, R ³ is selected from the group consisting of trityl, monomethoxytrityl, dimethoxytrityl and trimethoxytrityl, where R ⁴ is each occurrence. Independently about:

Steps to form a compound (selected from the group consisting of)
Step of performing n-1 iterations of
(F) The compound of the formula (A9) is brought into contact with the deblocking agent to formulate (A10):

(In the equation, n is an integer from 10 to 40, R ¹ is the supporting medium, and R ⁴ is independent for each appearance, and so on:

The step of forming a compound (selected from the group consisting of);
(G) The compound of the formula (A10) is brought into contact with the cutting agent to formulate (A11) :.

(In the equation, n is an integer from 10 to 40, and R4 ^is independent for each occurrence, and the following:

The step of forming a compound (selected from the group consisting of);
(H) A step of contacting the compound of the formula (A11) with a deprotecting agent to form an oligomer compound of the formula (A).
Process including.
(Item 2)
The compound of formula (A4) is of formula (A4a) :.

In the formula,
R3 is selected from the group consisting of trityl, monomethoxytrityl, dimethoxytrityl and trimethoxytrityl ^.
R4 ^is as follows:

Selected from,
The process according to item 1.
(Item 3)
The compound of formula (A5) is of formula (A5a) :.

In the formula,
R ¹ is a support medium and
R3 is selected from the group consisting of trityl, monomethoxytrityl, dimethoxytrityl and trimethoxytrityl ^.
R4 ^is as follows:

Selected from,
The process according to item 1 or 2.
(Item 4)
The compound of formula (A8) is of formula (A8a) :.

In the formula,
R3 is selected from the group consisting of trityl, monomethoxytrityl, dimethoxytrityl and trimethoxytrityl ^.
R4 is independent of ^each appearance of the compound of formula (A8a),

Selected from a group of
The process according to any one of items 1 to 3.
(Item 5)
The compound of formula (A9) is of formula (A9a) :.

In the formula,
n is an integer of 10 to 40 and
R ¹ is a support medium and
R3 is selected from the group consisting of trityl, monomethoxytrityl, dimethoxytrityl and trimethoxytrityl ^.
R4 is independent for each appearance ^,

Selected from a group of
The process according to any one of items 1 to 4.
(Item 6)
The compound of the formula (A10) is the formula (A10a) :.

In the formula,
n is an integer of 10 to 40 and
R ¹ is a support medium and
R4 is independent for each appearance ^,

Selected from a group of
The process according to any one of items 1 to 5.
(Item 7)
The compound of formula (A11) is of formula (A11a) :.

In the formula,
n is an integer of 10 to 40,
R4 is independent for each appearance ^,

Selected from a group of
The process according to any one of items 1 to 6.
(Item 8)
For the oligomeric compound of formula (A), n is 22, and R ² is from 5'to 3'at each position from 1 to 22:

And
The oligomer compound of formula (A) is of formula (C) :.

Compound, or a pharmaceutically acceptable salt thereof,
The process according to any one of items 1 to 7.
(Item 9)
The oligomer compound of formula (C) is of formula (XII) :.

The process according to any one of items 1 to 8, which is an oligomer compound of the above, or a pharmaceutically acceptable salt thereof.
(Item 10)
The process according to any one of items 1 to 9, wherein R ³ is trityl at each appearance.
(Item 11)
Equation (C):

A process for preparing an oligomeric compound of:
(A) Formula (I):

The compound of (in the formula, R ¹ is a support medium) is brought into contact with the deblocking agent to formulate (II) :.

The step of forming the compound (in the formula, R ¹ is the supporting medium);
(B) The compound of the formula (II) is compounded with the compound (B):

In contact with equation (III):

The step of forming the compound (in the formula, R ¹ is the supporting medium);
(C) The compound of formula (III) is brought into contact with a deblocking agent to formulate (IV) :.

The step of forming the compound (in the formula, R ¹ is the supporting medium);
(D) The compound of the formula (IV) is represented by the formula (D) :.

In contact with the compound of formula (V):

The step of forming the compound (in the formula, R ¹ is the supporting medium);
(E) The compound of the formula (V) is brought into contact with the deblocking agent to formulate (VI) :.

The step of forming the compound (in the formula, R ¹ is the supporting medium);
The compound of the formula (f) formula (VI) is represented by the formula (F) :.

In contact with the compound of formula (VII) :.

The step of forming the compound (in the formula, R ¹ is the supporting medium);
(G) The following consecutive steps:
(G1) The step of contacting the product formed by the immediately preceding step with the deblocking agent, and
(G2) The compound formed by the immediately preceding step is represented by the formula (VIII) :.

(In the formula, R ² is independently for each compound of the formula (VIII), and the following:

Selected from the group consisting of, for each iteration 1-20, R2 ^is :

In contact with the compound of formula (IX) :.

(During the ceremony,
R ¹ is a support medium and
R ² is independent for each appearance,

Selected from a group of
R ² goes from 5'to 3'at each position from 1 to 22 below:

The steps to form the compound
Steps to perform 20 iterations of
(H) The compound of the formula (IX) is brought into contact with the deblocking agent to form the formula (X):

(During the ceremony,
R ¹ is a support medium and
R ² is independent for each appearance,

Selected from a group of
R ² goes from 5'to 3'at each position from 1 to 22 below:

The step of forming the compound of);
(I) The compound of formula (X) is brought into contact with a cutting agent to formulate (XI) :.

(In the formula, R ² is independent for each appearance, and:

Selected from a group of
R ² goes from 5'to 3'at each position from 1 to 22 below:

The steps to form the compound;
(J) A step of contacting a compound of the formula (XI) with a deprotecting agent to form an oligomer compound of the formula (C).
1. The process according to item 1.
(Item 12)
In step (d), step (f) or step (g2), the compound of formula (IV), the compound of formula (VI) or the compound formed by the immediately preceding step is brought into contact with the capping agent, respectively. Further including, according to any one of items 1 to 11.
process.
(Item 13)
The process of any one of items 1-12, wherein the deblocking agent used in each step is a halogenated acid or cyanoacetic acid.
(Item 14)
Item 13. The process of item 13, wherein the halogenated acid is selected from the group consisting of chloroacetic acid, dichloroacetic acid, trichloroacetic acid, fluoroacetic acid, difluoroacetic acid, and trifluoroacetic acid.
(Item 15)
The supporting mediums are glass, modified or functionalized glass, plastics (acrylic, polystyrene (eg, 1% divinylbenzene crosslinked polystyrene), copolymers of styrene with other materials, polypropylene, polyethylene, polybutylene, polyurethane, and Teflon (registered). Includes), polysaccharides, nylon or polystyrene, ceramics, resins, silica or silica-based materials (including silicon and modified silicon), carbon, metals, and materials selected from the group consisting of fiber bundles. , The process according to any one of items 1 to 14.
(Item 16)
(Equation IX):

In the formula,
R ¹ is a support medium and
R ² is independent of each appearance,

Selected from a group of
R ² goes from 5'to 3'at each position from 1 to 22 below:

Is,
A compound, or a pharmaceutically acceptable salt thereof.
(Item 17)
The compound of formula (IX) is of formula (IXa) :.

In the formula,
R ¹ is a support medium and
R ² is independent of each appearance,

Selected from a group of
R ² goes from 5'to 3'at each position from 1 to 22 below:

Is,
Item 16 or a pharmaceutically acceptable salt thereof.
(Item 18)
(Formula X):

In the formula,
R ¹ is a support medium and
R ² is independent of each appearance,

Selected from a group of
R ² goes from 5'to 3'at each position from 1 to 22 below:

Is,
A compound, or a pharmaceutically acceptable salt thereof.
(Item 19)
The compound of formula (X) is of formula (Xa) :.

In the formula,
R ¹ is a support medium and
R ² is independent of each appearance,

Selected from a group of
R ² goes from 5'to 3'at each position from 1 to 22 below:

Is,
The compound according to item 70, or a pharmaceutically acceptable salt thereof.
(Item 20)
The compound according to any one of items 16 to 19, wherein the supporting medium comprises 1% divinylbenzene crosslinked polystyrene.
(Item 21)
(Equation XI):

In the formula,
R ² is independent of each appearance,

Selected from a group of
R ² goes from 5'to 3'at each position from 1 to 22 below:

Is,
A compound, or a pharmaceutically acceptable salt thereof.
(Item 22)
The compound of formula (XI) is of formula (XIa) :.

In the formula,
R ² is independent of each appearance,

Selected from a group of
R ² goes from 5'to 3'at each position from 1 to 22 below:

Is,
The compound according to item 21, or a pharmaceutically acceptable salt thereof.

Claims (22)

Equation (A):

(In the equation, n is 22, and R ² is from 5'to 3'at each position from 1 to 22:

And
The oligomer compound of the formula (A) is the compound of the formula (C).

Or a process for preparing an oligomeric compound of (or a pharmaceutically acceptable salt thereof ), wherein the process consists of the following consecutive steps:
(A) Equation (A1):

The compound of (in the formula, R ¹ is the supporting medium and R ³ is selected from the group consisting of trityl, monomethoxytrityl, dimethoxytrityl and trimethoxytrityl) is contacted with the deblocking agent to formulate (II) :.

The step of forming the compound (in the formula, R ¹ is the supporting medium);
(B) The compound of the formula (II) is represented by the formula (A2) :.

(In the formula, R ³ is selected from the group consisting of trityl, monomethoxytrityl, dimethoxytrityl and trimethoxytrityl) in contact with the compound of formula (A3):.

(In the formula, R ¹ is the supporting medium and R ³ is selected from the group consisting of trityl, monomethoxytrityl, dimethoxytrityl and trimethoxytrityl).
(C) The compound of the formula (A3) is brought into contact with the deblocking agent to formulate (IV) :.

The step of forming the compound (in the formula, R ¹ is the supporting medium);
(D) The compound of the formula (IV) is represented by the formula (A4) :.

(In the formula, R ³ is selected from the group consisting of trityl, monomethoxytrityl, dimethoxytrityl and trimethoxytrityl, and R ⁴ is:

In contact with the compound of formula (A5) :.

(In the formula, R ¹ is the supporting medium, R ³ is selected from the group consisting of trityl, monomethoxytrityl, dimethoxytrityl and trimethoxytrityl, and R ⁴ is:

The step of forming the compound of );
(E) The following consecutive steps:
(E1) The step of contacting the product formed by the immediately preceding step with the deblocking agent, and (e2) the compound formed by the immediately preceding step of formula (A8) :.

(In the formula, R ³ is selected from the group consisting of trityl, monomethoxytrityl, dimethoxytrityl and trimethoxytrityl, and R ⁴ is independently for each compound of formula (A8), and the following:

(Selected from the group consisting of) in contact with the compound of formula (A9) :.

(In the formula, n is 22 , R ¹ is the supporting medium, R ³ is selected from the group consisting of trityl, monomethoxytrityl, dimethoxytrityl and trimethoxytrityl, and R ⁴ is independent for each appearance. ,Less than:

A step of performing n-1 iterations of the step of forming a compound (selected from the group consisting of);
(F) The compound of the formula (A9) is brought into contact with the deblocking agent to formulate (A10):

(In the equation, n is 22 , R ¹ is the supporting medium, and R ⁴ is independent for each appearance, and so on:

The step of forming a compound (selected from the group consisting of);
(G) The compound of the formula (A10) is brought into contact with the cutting agent to formulate (A11) :.

(In the equation, n is 22 , and R ⁴ is independent for each appearance, and:

A process comprising the steps of forming a compound of formula (A); as well as (h) contacting the compound of formula (A11) with a deprotecting agent to form an oligomeric compound of formula (A). The compound of formula (A4) is of formula (A4a) :.

In the formula,
R3 is selected from the group consisting of trityl ^, monomethoxytrityl, dimethoxytrityl and trimethoxytrityl.
^R4 is as follows:

Is ,
The process of claim 1. The compound of formula (A5) is of formula (A5a) :.

In the formula,
R ¹ is a support medium and
R3 is selected from the group consisting of trityl ^, monomethoxytrityl, dimethoxytrityl and trimethoxytrityl.
^R4 is as follows:

Is ,
The process according to claim 1 or 2. The compound of formula (A8) is of formula (A8a) :.

In the formula,
R3 is selected from the group consisting of trityl ^, monomethoxytrityl, dimethoxytrityl and trimethoxytrityl.
^R4 is independent of each appearance of the compound of formula (A8a),

Selected from a group of
The process according to any one of claims 1 to 3. The compound of formula (A9) is of formula (A9a) :.

In the formula,
n is 22
R ¹ is a support medium and
R3 is selected from the group consisting of trityl ^, monomethoxytrityl, dimethoxytrityl and trimethoxytrityl.
^R4 is independent for each appearance,

Selected from a group of
The process according to any one of claims 1 to 4. The compound of the formula (A10) is the formula (A10a) :.

In the formula,
n is 22
R ¹ is a support medium and
^R4 is independent for each appearance,

Selected from a group of
The process according to any one of claims 1 to 5. The compound of formula (A11) is of formula (A11a) :.

In the formula,
n is 22
^R4 is independent for each appearance,

Selected from a group of
The process according to any one of claims 1 to 6. The oligomer compound of formula (C) is of formula (XII) :.

The process according to any one of claims 1 to 7 , which is an oligomer compound of the above, or a pharmaceutically acceptable salt thereof. The process according to any one of claims 1 to 8 , wherein R ³ is trityl at each appearance. The following consecutive steps:
(A) Formula (I):

The compound of (in the formula, R ¹ is a support medium) is brought into contact with the deblocking agent to formulate (II) :.

The step of forming the compound (in the formula, R ¹ is the supporting medium);
(B) The compound of the formula (II) is compounded with the compound (B):

In contact with equation (III):

The step of forming the compound (in the formula, R ¹ is the supporting medium);
(C) The compound of formula (III) is contacted with a deblocking agent to formulate (IV) :.

The step of forming the compound (in the formula, R ¹ is the supporting medium);
(D) The compound of the formula (IV) is represented by the formula (D) :.

In contact with the compound of formula (V):

The step of forming the compound (in the formula, R ¹ is the supporting medium);
(E) The compound of the formula (V) is brought into contact with the deblocking agent to formulate (VI) :.

The step of forming the compound (in the formula, R ¹ is the supporting medium);
The compound of the formula (f) formula (VI) is represented by the formula (F) :.

In contact with the compound of formula (VII) :.

The step of forming the compound (in the formula, R ¹ is the supporting medium);
(G) The following consecutive steps:
(G1) The step of contacting the product formed by the immediately preceding step with the deblocking agent, and (g2) the compound formed by the immediately preceding step of formula (VIII) :.

(In the formula, R ² is independently for each compound of the formula (VIII), and the following:

Selected from the group consisting of, for each iteration 1-20, ^R2 is:

In contact with the compound of formula (IX) :.

(During the ceremony,
R ¹ is a support medium and
R ² is independent for each appearance,

Selected from a group of
R ² goes from 5'to 3'at each position from 1 to 22 below:

The step of performing 20 iterations of the step of forming the compound of);
(H) The compound of the formula (IX) is brought into contact with the deblocking agent to form the formula (X):

(During the ceremony,
R ¹ is a support medium and
R ² is independent for each appearance,

Selected from a group of
R ² goes from 5'to 3'at each position from 1 to 22 below:

The step of forming the compound of);
(I) The compound of formula (X) is brought into contact with a cutting agent to formulate (XI) :.

(In the formula, R ² is independent for each appearance, and:

Selected from a group of
R ² goes from 5'to 3'at each position from 1 to 22 below:

The process of claim 1, comprising the step of forming the compound of formula (C); and the step of contacting the compound of formula (XI) with a deprotecting agent to form the oligomeric compound of formula (C). In step (d), step (f) or step (g2), the compound of formula (IV), the compound of formula (VI) or the compound formed by the immediately preceding step is brought into contact with the capping agent, respectively. The process according to any one of claims 1 to 10, further comprising. The process according to any one of claims 1 to 11, wherein the deblocking agent used in each step is a halogenated acid or cyanoacetic acid. The process according to claim 12 , wherein the halogenated acid is selected from the group consisting of chloroacetic acid, dichloroacetic acid, trichloroacetic acid, fluoroacetic acid, difluoroacetic acid, and trifluoroacetic acid. The supporting medium is glass, modified or functionalized glass, plastics (including copolymers of acrylic, polystyrene, styrene and other materials, polypropylene, polyethylene, polybutylene, polyurethane, and polytetrafluoroethylene ), polysaccharides, nylon. Or any of claims 1 to 13, comprising a material selected from the group consisting of nitrocellulose, ceramics, resins, silica or silica-based materials (including silicon and modified silicon), carbon, metals, and fiber bundles. The process described in paragraph 1. (Equation IX):

In the formula,
R ¹ is a support medium and
R ² is independent of each appearance,

Selected from a group of
R ² goes from 5'to 3'at each position from 1 to 22 below:

Is,
A compound, or a pharmaceutically acceptable salt thereof. The compound of formula (IX) is of formula (IXa) :.

In the formula,
R ¹ is a support medium and
R ² is independent of each appearance,

Selected from a group of
R ² goes from 5'to 3'at each position from 1 to 22 below:

Is,
The compound according to claim 15 , or a pharmaceutically acceptable salt thereof. (Formula X):

In the formula,
R ¹ is a support medium and
R ² is independent of each appearance,

Selected from a group of
R ² goes from 5'to 3'at each position from 1 to 22 below:

Is,
A compound, or a pharmaceutically acceptable salt thereof. The compound of formula (X) is of formula (Xa) :.

In the formula,
R ¹ is a support medium and
R ² is independent of each appearance,

Selected from a group of
R ² goes from 5'to 3'at each position from 1 to 22 below:

Is,
The compound according to claim 17 , or a pharmaceutically acceptable salt thereof. The compound according to any one of claims 15 to 18 , wherein the supporting medium comprises 1% divinylbenzene crosslinked polystyrene. (Equation XI):

In the formula,
R ² is independent of each appearance,

Selected from a group of
R ² goes from 5'to 3'at each position from 1 to 22 below:

Is,
A compound, or a pharmaceutically acceptable salt thereof. The compound of formula (XI) is of formula (XIa) :.

In the formula,
R ² is independent of each appearance,

Selected from a group of
R ² goes from 5'to 3'at each position from 1 to 22 below:

Is,
The compound according to claim 20, or a pharmaceutically acceptable salt thereof. 14. The process of claim 14, wherein the polystyrene is 1% divinylbenzene crosslinked polystyrene.

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