NL2030022B1 - SYNTHESIS OF mRNA TRANSMITTER - Google Patents
SYNTHESIS OF mRNA TRANSMITTER Download PDFInfo
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C227/00—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton
- C07C227/14—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton from compounds containing already amino and carboxyl groups or derivatives thereof
- C07C227/18—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton from compounds containing already amino and carboxyl groups or derivatives thereof by reactions involving amino or carboxyl groups, e.g. hydrolysis of esters or amides, by formation of halides, salts or esters
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Abstract
The present invention relates to synthesis of mRNA transmitter, wherein in particular under the action of ytterbium triflate, reacting a related amino compound with oxirane.
Description
SYNTHESIS OF mRNA TRANSMITTER
[0001]The present invention belongs to the technical field of chemical synthesis, in particular, it relates to synthesis of mRNA transmitter.
[0002]COVID-19 pandemic pushes mRNA vaccine to the center of the biotechnology and the pharmaceutical industry. The speed of vaccine development also exceeds expectations, the vaccines were available 10 months after the disclosure of
SARS-CoV-2 sequence. This success not only demonstrates that the biotechnology and the pharmaceutical industry are able to cope with the pressing and unsatisfied global demands, but also demonstrates the inherent ability of mRNA as a drug form.
Compared with the conventional inactivated vaccine, the mRNA vaccine has advantages of low cost, high production efficiency, high safety, and possess a potential of synthesizing any kind of proteins, hence, it has a huge application potential against the novel infectious viruses with which the traditional vaccine are unable to cope.
However, due to the reasons such as instability of mRNA molecule, high innate immunogenicity and low in-vivo delivery efficiency, application of the mRNA vaccine was restricted all the time. To realize widespread use of the mRNA vaccine, it is required to focus on the delivery technology. The mRNA vaccine needs a suitable delivery vector (delivery agent, also known as transmitter) to deliver it into body, so as to obtain a better immune effect, hence developing a highly effective and non-toxic delivery system is the key to mRNA vaccine success. Professor Michael D.
Buschmann, Biological engineering department head, George Mason University elaborated progress of the mRNA delivery system, and summarized the preclinical and clinical study results of a SARS-CoV-2 mRNA vaccine, and emphatically introduced the lipid nanoparticles used in current SARS-CoV-2 vaccine clinical trials, and analyzed the effect of lipid nanoparticles in the mRNA vaccine.
[0003]Before COVID-19, the mRNA vaccine has been used in the preclinical and clinical studies, including influenza, Zika virus, AIDS virus, Ebola virus, rabies, malaria, genital herpes, toxoplasmosis etc. In the current vaccine competition against novel coronavirus COVID-19, the studies based on the mRNA vaccine have already produced initial results, at present there are eight ongoing human trials on the mRNA vaccine, they are respectively led by BioNTech/Pfizer, Moderna, CureVac,
Sanofi/TranslateBio, Arcturus/DukeNUS of Medical College of Singapore, Imperial
College London, Thailand Chula-longkorn University and Providence Therapeutics. It should be noted that, in above human trials, two trials published the trial results of the third mid-stage, and reported the mRNA sequence encoding spike glycoprotein immunogen after two doses of 30 pg or 100 pg (delivered in the form of lipid nanoparticle) and a therapeutic effect of reducing the infection rate of SARS-CoV-2 by 94% or more.
[0004]A delivery technology platform is one of the keys in the mRNA vaccine, a lot of mRNA formulation systems have been reported, where, many have entered the clinical trial stage. These formulation technology all realize the delivery of the mRNA vaccine by forming a special mRNA vector, these vector technologies include: protamine vector technology, nanoparticle liposome vector technology, polymer vector technology.
[0005]At present, the nanoparticle liposome vector technology is most widely used in the current development and production process of SARS-CoV-2 vaccine. The delivery agent used in the nanoparticle liposome vector technology usually includes a compound with a structure of the following formula (I) or its salt or its isomer.
Rt, She
Ny Rs / Re \ > Re
Formula (I)
[0006]Chinese patent CN109476718 further describes a general formula structure of such nanoparticle liposome delivery agent, and specific general formula structure is as the following formula (IT). [EN Rs
SN es ‚ : 5 ae oF ee . 0 x
HO N fi A gn 1} “ {Fe a 8 „Ra { & i Se >
Ee Am
Formula (IT)
[0007]Illustration and examples of Chinese patent CN 109476718 further mentioned structures of some representative delivery agents, such as some compounds with the following structures: 0 eeen OTT fd ml “ nl m “ -
HO By Ne Md [7 Pt ge a= a, of = Nog nr So NT
Ne % 9 SE, In “Nag Rod “ny SI SEEN SE a f- § ot Te os A Nn No od Niens ] ~ ge ge Ss ey We oe Nee FTN 3
Ho N NN & wT STINT Ne ve DN, pe SING TIN TN
[0008]With respect to the synthesis of some transmitters with n=1, the strategy adopted by the Chinese patent is to prepare a compound of formula (V) by condensation reaction of compound formula (III) with compound of formula (IV), then, a nucleophilic substitution of compound of formula (V) with aminoethanol takes place, and nucleophilic substitution of bromine in the compound of formula (V) by amino group in aminoethanol takes place, to obtain a compound of formula (VI); finally, a nucleophilic substitution of the compound of formula (VI) with a compound of formula (VII), to obtain a compound of formula (VIII). Although this synthesis route can realize the synthesis of the delivery agent, because the product compound of formula (VI) in the second step reaction contains a exposed amino group, a nucleophilic substitution with the compound formula (V) in the reaction liquid can continue to form an imeric impurity; meanwhile, in a third step reaction, a final product of formula (VIII) is very easy to continue reacting with the compound of formula (VII) to form a quaternary ammonium bromide salt impurity. The defect of these reaction routes directly results in a bottleneck in the industrialization process of this synthesis route. ey ie 2 TN pet M Doeg ne Rag gd first step Beggen second Stop eed GE formula TH formula IV forma V formula VI sn EN abe gr we oade formula VUI
[0009]The object of the present invention is to provide a new method for preparing a mRNA transmitter, this method is used to synthesize a compound of formula (XI).
[0010]A synthesis route of this method is in the presence of a solvent and additives, reacting an amino compound of formula (X) with oxirane, to easily realize the preparation of a compound of formula (XI).
3 Ry 3 Rs 2 . gor Solvent additive Ce de | oR - = a Ry
ONHADT ~ pn gh ar ho N A gpg formula X formula XI
[0011]Solvent used in the reaction includes acetonitrile, dioxane, THF, DMF, DMSO, 2-Me-THF.
[0012]Additive used in the reaction is ytterbium triflate. 5 [0013]In the compounds of formula (X) and formula (XI), R: is H, C:-Co alkyl; Ra is
H, C1-C1 alkyl.
[0014]In the compounds of formula (X) and formula (XI), n is 2-10, zis 1-10, p is 2-10, and q is 1-11.
[0015] The following typical examples are intended to illustrate the present invention, the simple replacements and improvements to the present invention made by those skilled in the art are all within the technical solution protected by the present invention.
Example 1: Preparation of 8,8'-((2-hydroxyethyl)azanediyl)dinonyl dicaprylate ec ee CHEN ee oxirang a | JEN geene & 8 2-hydroxyethyl) 8.8" (Z-hvdroxyethyh azanediyldinony eee Ee Dd nom
[0016]8,8'-diazanetetrayl dinonyldicaprylate (10.0 g, 18.05 mmol) and acetonitrile (50 mL) were successively added into a 4-neck flask, after completion of the reaction, the system was cooled to -80°C, and oxirane was bubbled into the reaction system (20 g, 0.45 mol); then ytterbium triflate (1.12 g, 1.81 mmol) was added into the reaction system. After completion of the addition, the reaction system was naturally warmed up to room temperature under stirring to react, the reaction was traced by TLC until the starting material 8,8'-diazanetetrayl dinonyl dicaprylate basically disappeared. After completion of the reaction, water was added into the system to quench (100 mL) the reaction, the reaction system was extracted with ethyl acetate (3x80 mL), the organic phases was combined, the organic phase was dried over anhydrous sodium sulfate,
filtered, the solvent was removed from the filtrate by distillation under reduced pressure,
the residue was purified by column chromatography (CH»Cl,/MeOH=30:1) to obtain 88-((2-hydroxyethyl)azanediyl)dinonyl dicaprylate (9.18g, 85.1%). 'H NMR
(600MHz, CDC1) § 0.90 (m, 6H), 1.02-1.75 (m, 49H), 2.31 (m, 4H), 2.72-2.41 (m, 6H),
3.61 (m, 2H), 4.07 (m, 4H) Mass: 599 [M+H]".
Claims (5)
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Citations (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2001046207A1 (en) * | 1999-12-21 | 2001-06-28 | Bracco S.P.A. | Chelating compounds, their complexes with paramagnetic metals |
WO2018170306A1 (en) * | 2017-03-15 | 2018-09-20 | Modernatx, Inc. | Compounds and compositions for intracellular delivery of therapeutic agents |
WO2018232006A1 (en) * | 2017-06-14 | 2018-12-20 | Modernatx, Inc. | Polynucleotides encoding coagulation factor viii |
CN109476718A (en) | 2016-05-18 | 2019-03-15 | 莫得纳特斯公司 | The combination of MRNA and application thereof of encoding immune adjusting polypeptide |
CN113387825A (en) * | 2021-06-10 | 2021-09-14 | 福州大学 | Long-chain alkyl ester amine compound or fluorine-containing long-chain alkyl ester amine compound and kilogram-level preparation method thereof |
-
2021
- 2021-12-03 NL NL2030022A patent/NL2030022B1/en active
Patent Citations (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2001046207A1 (en) * | 1999-12-21 | 2001-06-28 | Bracco S.P.A. | Chelating compounds, their complexes with paramagnetic metals |
CN109476718A (en) | 2016-05-18 | 2019-03-15 | 莫得纳特斯公司 | The combination of MRNA and application thereof of encoding immune adjusting polypeptide |
WO2018170306A1 (en) * | 2017-03-15 | 2018-09-20 | Modernatx, Inc. | Compounds and compositions for intracellular delivery of therapeutic agents |
WO2018232006A1 (en) * | 2017-06-14 | 2018-12-20 | Modernatx, Inc. | Polynucleotides encoding coagulation factor viii |
CN113387825A (en) * | 2021-06-10 | 2021-09-14 | 福州大学 | Long-chain alkyl ester amine compound or fluorine-containing long-chain alkyl ester amine compound and kilogram-level preparation method thereof |
Non-Patent Citations (1)
Title |
---|
SHI M ET AL: "Lewis acids catalyzed ring-opening reactions of methylenecyclopropanes and epoxides in supercritical carbon dioxide or modified supercritical carbon dioxide with perfluorocarbon", JOURNAL OF FLUORINE CHEMISTRY, ELSEVIER, NL, vol. 122, no. 2, 1 August 2003 (2003-08-01), pages 219 - 227, XP004442225, ISSN: 0022-1139, DOI: 10.1016/S0022-1139(03)00083-6 * |
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