Methods for synthesizing target molecules

Abstract

The present application provides methods for the synthesis of targeting molecules of Formula I that contain a retinoid moiety, which are useful in the synthesis of lipid-soluble compounds for the purpose of targeting and enhancing the activity of therapeutic molecules such as siRNA. TIFF2023532011000035.tif26160

Description

[Technical Field]

[0001] This application provides a method for synthesizing target molecules containing a retinoid moiety, which is useful for synthesizing lipid-soluble compounds for the purpose of targeting and enhancing the activity of therapeutic molecules, including siRNA. [Background technology]

[0002] It is well known to those skilled in the art that creating molecules capable of targeting specific receptors, tissue types, or target organs is highly beneficial. Low specificity leads to limited efficacy, requiring higher doses and increasing off-target effects. One way to address this problem is through molecular scaffolds designed for the delivery of therapeutic agents. The scaffold includes its basic structure: (target portion) j -Linker- (Target part) k [wherein the target portion is a retinoid radical; j and k are independently 0, 1, 2, or 3; and the linker is PEG-like] is disclosed in U.S. Patent No. 9,393,315.

[0003] This skeleton is used to facilitate the delivery of drugs to target cells that have specific receptors for retinoids or that have activity / binding to retinoids. An example of a molecule that uses this skeleton is N 1 ,N 19 One example is -bis((S,23E,25E,27E,29E)-16-((2E,4E,6E,8E)-3,7-dimethyl-9-(2,6,6-trimethylcyclohexa-1-en-1-yl)nona-2,4,6,8-tetraenamide)-24,28-dimethyl-15,22-dioxo-30-(2,6,6-trimethylcyclohexa-1-en-1-yl)-4,7,10-trioxa-14,21-diazatriaconta-23,25,27,29-tetraen-1-yl)-4,7,10,13,16-pentaoxanadecanediamide ("DiVa"). Previous methods for synthesizing DiVa and similar compounds have had problems such as low yields, many by-products, and difficulty in obtaining high-quality starting materials.

[0004] There is a need for a synthetic method for producing retinoid-containing target molecules with increased product yield, reduced amount of by-products, and more readily available starting materials.

[0005] (Summary of the Invention) In one aspect, the present application provides a method for producing DiVa.

[0006] In one embodiment, the present application provides a method for synthesizing a compound of formula I [Chemical formula] (wherein, R 1 is a retinoid radical; m is an integer from 1 to 6; and n is an integer from 1 to 10). The above method comprises a) reacting a compound of formula II [Chemical formula] (wherein, m is an integer from 1 to 6) with a compound of formula III [Chemical formula] (wherein, PG 1 and PG 2 are each independently a protecting group), to form a compound of formula IV [Chemical formula] ?0000104? (wherein, m is an integer from 1 to 6 and PG 1 is a protecting group); and b) reacting the compound of formula IV with a compound of formula V [Chemical formula] ​​​​​​ (where m is an integer from 1 to 6; n is an integer from 1 to 10; and PG 1 is a protecting group) to form a compound; c) reacting the compound of formula VI under hydrogenation conditions to form a compound of formula VII

Chemical formula

[0007] In a further embodiment, the retinoid is selected from vitamin A, retinoic acid, tretinoin, adapalene, 4-hydroxy(phenyl)retinamide, retinol palmitate, retinal, saturated retinoic acid, tretinoin, and saturated demethylated retinoic acid.

[0008] In yet another embodiment, the retinoid is retinoic acid.

[0009] In a further embodiment, the hydrogenation conditions of step c) are characterized by reacting the compound of formula I with H2 and Pd / C.

[0010] In yet another embodiment, m is 3.

[0011] In yet another embodiment, n is 5.

[0012] In another embodiment, each PG 1 and PG 2The following are independently selected from the group consisting of carboxybenzyl, p-methoxybenzylcarbonyl, t-butyloxycarbonyl, 9-fluorenylmethoxycarbonyl, acetyl, trifluoroacetyl, benzoyl, benzyl, carbamate, p-methoxybenzyl, 3,4-dimethoxybenzyl, p-methoxybenzyl, tosyl, trichloroethyl chloroformate, (4-nitrophenyl)sulfonyl, methyl, ethyl, propyl, n-butyl, t-butyl, succinimide, 2,6-dimethylphenol, 2,6-diisopropylphenol, 2,6-di-tert-butylphenol, trimethylsilyl, allyl, 1,1-dimethylallyl, 2,2,2-trifluoroethyl, phenyl, and 4-methoxybenzyl.

[0013] In a further embodiment, each PG 1 It is carboxybenzyl.

[0014] In another embodiment, PG 2 It is succinimide.

[0015] In a further embodiment, the compound of formula II is [ka] That is the case.

[0016] In another embodiment, the compound of formula III is [ka] That is the case.

[0017] In a further embodiment, step a) is performed between -20°C and 0°C.

[0018] In a further embodiment, the yield of step a) is at least about 60%. In another embodiment, the yield of step b) is at least about 70%.

[0019] In a further embodiment, in step a), the compound of formula II is used in amounts ranging from about 5 to about 20 equivalents, and the compound of formula III is used in amounts ranging from about 1 equivalent.

[0020] In another embodiment, step a) is characterized by further adding citric acid after forming the compound of formula IV.

[0021] In a further embodiment, the compound of formula I is [ka] That is the case.

[0022] In a further embodiment, the compound of formula I is obtained from the compound of formula III in at least about 50% yield.

[0023] In a further embodiment, the compound of formula IV is obtained in a ratio of approximately 9:1 or higher to the compound of formula VIII. TIFF0007864646000011.tif26160

[0024] In a further embodiment, the compound of formula IV is obtained in a ratio of 12:1 or higher to the compound of formula VIII.

[0025] In another embodiment, the compound of formula I is prepared by the method of steps a) to d). [Modes for carrying out the invention]

[0026] Throughout this specification and these claims, a given chemical formula or chemical name includes all isomers where isomers such as stereoisomers, optical isomers, and racemates exist. Unless otherwise specified, all chiral (enantiomers and diastereomers) and racemates are included in the scope of the present invention. Many geometric isomers, such as C=C double bonds, C=N double bonds, and ring systems, may also exist in the present invention, and all such stable isomers are included in the present invention. Cis- and trans- (or E- and Z-) geometric isomers of the compounds of the present invention are described, and they may be isolated as mixtures of isomers or as separated isomers. The compounds of the present invention may be isolated as optically active or racemates. Optically active compounds may be produced by re-separation of racemates or by synthesis from optically active starting materials. Any process used to produce the compounds of the present invention and their intermediates is considered part of the present invention. When enantiomer or diastereomer products are prepared, the products may be separated by conventional methods, such as chromatography or fractional crystallization.

[0027] Depending on the conditions of this process, the final product of the present invention may be obtained in either a (neutral) free form or a salt form. Both the free and salt forms of these final compounds are included within the scope of the present invention. If desired, one form of a compound may be converted to the other form. A free base or free acid may be converted to a salt; the salt may be converted to its free compound or another salt; a mixture of isomer compounds of the present invention may be separated into their respective isomers. Multiple tautomers may exist of the compounds of the present invention, their free forms and salts, where a hydrogen atom is replaced by a molecule in another part, and the chemical bonds between atoms in the molecule are consequently transferred. Insofar as any tautomer exists, tautomers should be understood to be included within the scope of the present invention.

[0028] The term "stereoisomer" refers to isomers of the same composition but with different spatial arrangements of atoms. Enantiomers and diastereomers are examples of stereoisomers. The term "enantiomer" refers to a type of pair of molecules that are mirror images of each other and cannot be superimposed. The term "diastereomer" refers to stereoisomers that are not mirror images of each other. The term "racemate" or "racemic mixture" refers to a composition in which two enantiomers are present in equimolar amounts and do not have optical activity. It is well understood by those skilled in the art that the stereochemistry of the product can be controlled by selecting the stereochemistry of the starting materials, and that the stereochemistry of the product can be changed by changing the stereochemistry of the starting materials. It is also well understood by those skilled in the art that a racemic mixture can be separated such that the stereochemical purity of the product is >99%.

[0029] The symbols "R" and "S" indicate the arrangement of substituents around a chiral carbon atom. The isomer symbols "R" and "S" are used as described herein to indicate the relative arrangement of atoms to the core molecule and are intended to be used as defined in the literature (IUPAC Recommendations 1996, Pure and Applied Chemistry, 68, 2193-2222 (1996)).

[0030] The term "chiral" refers to a structural characteristic of a molecule that cannot be superimposed on its own enantiomer. The term "homochiraral" refers to the state of a pure enantiomer. The term "optical activity" refers to the degree to which a chiral molecule (that is not a homochiral molecule or a racemic mixture) rotates the plane of polarization.

[0031] The abbreviations used herein are defined as follows: "℃" is Celsius temperature, "eq" is equivalent, "g" is gram, "mg" is milligram, "L" is liter, "mL" is milliliter, "μL" is microliter, "N" is normal, "M" is molar, "mmol" is millimoles, "min" is minutes, "h" is hours, "rt" is room temperature, "RT" is retention time, "conc." is concentrated, "sat" is saturated, "MW" is molecular weight, "ee" is enantiomer excess, "MS" or "Mass Spec" is mass spectrometry, "ESI" is electrospray ionization mass spectrometry, "HR" is high resolution, "HRMS" is high resolution mass spectrometer, "LCMS" is liquid chromatography mass spectrometry, "HPLC" is high-performance liquid chromatography, "NMR" is nuclear magnetic resonance spectroscopy, 1 "H" represents a proton, and "D", "L", "α", "β", "R", "S", "E", and "Z" are stereochemical symbols well known to those skilled in the art.

[0032] Here, the basic structure: (R 1 ) j -Linker-(R 1 ) k [In the formula, R 1 The present invention provides a method for synthesizing a target molecule comprising: a retinoid; j and k independently being 0, 1, 2, or 3; and a linker being PEG-like. In one embodiment, the method is a method for synthesizing a compound of formula I. In one embodiment, the method is a method for synthesizing a compound of formula I using a compound of formula III as a starting material.

[0033] Step a In one implementation, step a) is Equation II [ka] The compound of formula III (where m is an integer from 1 to 10) [ka] (In the formula, PG 2 The compound of formula IV is formed by reacting it with a compound of (where is a protecting group). [ka] It is characterized by forming a structure.

[0034] In one embodiment, m is an integer between 1 and 10. In another embodiment, m is an integer between 1 and 9, 1 and 8, 1 and 7, 1 and 6, 1 and 5, 1 and 4, 1 and 3, or 1 and 2. In one embodiment, m is an integer between 1 and 6. In another embodiment, m is an integer between 2 and 10, 3 and 10, 4 and 10, 5 and 10, 6 and 10, 7 and 10, 8 and 10, or 9 and 10. In another embodiment, m is an integer between 2 and 9, 3 and 8, 4 and 7, or 5 and 6. In one embodiment, m is 1. In one embodiment, m is 2. In one embodiment, m is 3. In one embodiment, m is 4. In one embodiment, m is 5. In one embodiment, m is 6. In one embodiment, m is 7. In one embodiment, m is 8. In one embodiment, m is 9. In one embodiment, m is 10.

[0035] One example, PG 1 is an amine protecting group. In another embodiment, PG 1 This is selected from the group consisting of carboxybenzyl (CBz), p-methoxybenzylcarbonyl (Moz), t-butyloxycarbonyl (BOC), 9-fluorenylmethoxycarbonyl (Fmoc), acetyl (Ac), trifluoroacetyl, benzoyl (Bz), benzyl (Bn), carbamate, p-methoxybenzyl (PMB), 3,4-dimethoxybenzyl, p-methoxybenzyl, tosyl (Ts), trichloroethyl chloroformate (Troc), and (4-nitrophenyl)sulfonyl (Nosyl). In one embodiment, PG 1 It is carboxybenzyl.

[0036] One example, PG 2 is a carboxylic acid protecting group. In one embodiment, PG 2The group is selected from methyl, ethyl, propyl, n-butyl, t-butyl, Bn, succinimide (Su), 2,6-dimethylphenol, 2,6-diisopropylphenol, 2,6-di-tert-butylphenol, trimethylsilyl, allyl, 1,1-dimethylallyl, 2,2,2-trifluoroethyl, phenyl (Ph), and 4-methoxybenzyl. In one embodiment, PG 2 It is succinimide.

[0037] One example, PG 1 It is carboxybenzyl, and PG 2 This is succinimide. In one embodiment, PG 1 It is carboxybenzyl, and PG 2 is succinimide, and m is 3.

[0038] In one embodiment, step a) is carried out in a solvent. In one embodiment, the solvent is a mixed solvent. In one embodiment, at least one solvent is a polar aprotic solvent. In another embodiment, one or more solvents are polar aprotic solvents. In one embodiment, the solvent is selected from dichloromethane (DCM), ethyl acetate (ԅ), tetrahydrofuran (THF), acetone, N,N-dimethylformamide (DMF), acetonitrile, and dimethyl sulfoxide (DMSO). In one embodiment, the solvent is a combination of DCM and ԅ.

[0039] In one embodiment, step a) is performed between approximately -30°C and approximately 0°C. In one embodiment, the above step is performed between approximately -25°C and approximately 0°C, approximately -20°C and approximately 0°C, approximately -15°C and approximately 0°C, or approximately -10°C and approximately 0°C. In one embodiment, step a) is performed between approximately -30°C and approximately -5°C, approximately -30°C and approximately -15°C, or approximately -30°C and approximately -25°C. In one embodiment, step a) is performed between approximately -25°C and approximately -5°C, approximately -20°C and -10°C, or -18°C and -12°C. In one embodiment, step a) is performed between approximately -20°C and approximately -12°C. In one embodiment, step a) is performed at approximately -20°C, approximately -15°C, approximately -10°C, approximately -5°C, or approximately 0°C. In one embodiment, step a) is performed below approximately 0°C. In one embodiment, step a) is performed below approximately -5°C. In one embodiment, step a) is performed at a temperature below approximately -10°C. In another embodiment, step a) is performed at a temperature below approximately -15°C.

[0040] In one embodiment, the compound of formula IV is obtained from step a) in a yield between about 70% and 95%. In another embodiment, the compound of formula IV is obtained in a yield between about 70% and 85%, or between about 70% and 75%. In yet another embodiment, the compound of formula IV is obtained in a yield between about 80% and 95%, or between about 90% and 95%. In yet another embodiment, the compound of formula IV is obtained in yields of about 70%, about 75%, about 80%, about 85%, about 90%, or about 95%. In a further embodiment, the compound of formula IV is obtained in a yield of about 80%. In one embodiment, the compound of formula IV is obtained from step a) in a yield of at least about 65%, at least 70%, at least 75%, at least about 80%, or at least about 85%. In yet another embodiment, formula IV is obtained from step a) in a yield of at least about 80%.

[0041] In one embodiment, step a) is characterized by reacting about 10 equivalents of the compound of formula II with about 1 equivalent of the compound of formula III. In another embodiment, step a) is characterized by reacting about 9 equivalents of the compound of formula II with about 1 equivalent of the compound of formula III, about 8 equivalents of the compound of formula II with about 1 equivalent of the compound of formula III, about 7 equivalents of the compound of formula II with about 1 equivalent of the compound of formula III, about 6 equivalents of the compound of formula II with about 1 equivalent of the compound of formula III, or about 5 equivalents of the compound of formula II with about 1 equivalent of the compound of formula III.

[0042] In one embodiment, step a) is characterized by reacting a compound of formula II in less than about 8 equivalents with a compound of formula III in about 1 equivalent. In another embodiment, step a) is characterized by reacting a compound of formula II in less than about 7 equivalents with a compound of formula III in about 1 equivalent. In another embodiment, step a) is characterized by reacting a compound of formula II in less than about 6 equivalents with a compound of formula III in about 1 equivalent.

[0043] In a further embodiment, the compound of formula IV is obtained in a ratio of 9:1 or higher relative to the compound of formula VIII. In one embodiment, the compound of formula IV is obtained in a ratio of about 8:1, about 9:1, about 10:1, about 11:1, about 12:1, about 13:1, about 14:1, or about 15:1 or higher relative to the compound of formula VIII. In a further embodiment, the compound of formula IV is obtained in a ratio of about 9:1 relative to the compound of formula VIII. In one embodiment, the compound of formula IV is obtained in a ratio of about 8:1, about 9:1, about 10:1, about 11:1, about 12:1, about 13:1, about 14:1, or about 15:1 relative to the compound of formula VIII.

[0044] In one embodiment, step a) selectively monoamidates a diamine (CAS #4246-51-9) with a double-Z-lysine derivative (CAS #21160-83-8). In one embodiment, step a) includes reacting the compound of formula III with the compound of formula II by slowly adding the solution of formula III to the solution of formula II. In one embodiment, step a) includes reacting the compound of formula III with the compound of formula II by adding the solution of formula III to the solution of formula II from near the liquid surface.

[0045] Step B In one embodiment, step b) is to combine the compound of formula IV with formula V [ka] Reacting with the compound of (wherein n is an integer from 1 to 10) to form formula VI [ka] (wherein the formula m is 1 to 6; n is 1 to 10; and PG 1 The compound is characterized by forming a compound of (where is a protecting group).

[0046] For one reason, m, n, PG 1 and PG 2 This is described in step a). In one embodiment, PG 1 It is carboxybenzyl, and PG 2 is succinimide, m is 3, and n is 5.

[0047] In one embodiment, step b) is carried out in a solvent. In one embodiment, at least one solvent is a polar aprotic solvent. In one embodiment, the solvent is selected from dichloromethane (DCM), ethyl acetate (ԅ), tetrahydrofuran (THF), acetone, N,N-dimethylformamide (DMF), acetonitrile, and dimethyl sulfoxide (DMSO). In one embodiment, step b) is carried out in DCM.

[0048] In one embodiment, step b) is performed between approximately 0°C and approximately 30°C. In one embodiment, the step is performed between approximately 10°C and approximately 30°C, or between approximately 20°C and approximately 30°C. In one embodiment, step b) is performed between approximately 0°C and approximately 25°C, approximately 0°C and approximately 15°C, or approximately 0°C and approximately 5°C. In one embodiment, step b) is performed between approximately 15°C and approximately 20°C. In one embodiment, step b) is performed at approximately 30°C, approximately 25°C, approximately 20°C, approximately 15°C, approximately 10°C, approximately 5°C, or approximately 0°C. In one embodiment, step b) is performed below approximately 30°C. In one embodiment, step b) is performed below approximately 25°C. In one embodiment, step b) is performed at approximately 20°C. In one embodiment, step b) is performed at or near room temperature.

[0049] In one embodiment, the compound of formula VI is obtained from step b) in a yield between about 70% and 99%. In another embodiment, the compound of formula VI is obtained in a yield between about 70% and 95%, about 70% and 90%, about 70% and 85%, about 70% and 80%, or about 70% and 75%. In yet another embodiment, the compound of formula VI is obtained from step b) in a yield between about 75% and 99%, about 80% and 99%, about 85% and 99%, about 90% and 99%, or about 95% and 99%. In yet another embodiment, the compound of formula VI is obtained from step b) in a yield of about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, or about 99%. In a further embodiment, the compound of formula VI is obtained in a yield of about 90%. In a further embodiment, the compound of formula VI is obtained in a yield of about 95%.

[0050] In one embodiment, the compound of formula VI is obtained from step b) in a yield of at least about 65%, at least about 70%, at least about 75%, at least about 80%, or at least about 85%. In another embodiment, formula VI is obtained from step b) in a yield of at least about 80%.

[0051] In one embodiment, in step b), 3-(((ethylimino)methylene)amino)-N,N-dimethylpropan-1-amine (EDAC) assists in the two-site amidation of the dicarboxylic acid (CAS #439114-13-3).

[0052] Step C When the compound of formula VI is reacted under hydrogenation conditions, formula VII [ka] It forms a compound of the form (where m is an integer between 1 and 10, and n is an integer between 1 and 10). In one embodiment, m and n are those described in step a). In one embodiment, m is 3 and n is 5.

[0053] In one embodiment, step c) is carried out in a solvent. In one embodiment, the solvent is a mixed solvent. In another embodiment, at least one solvent is a polar protic solvent. In another embodiment, at least one solvent is a polar aprotic solvent. In another embodiment, the solvent is selected from the group consisting of methanol, ethanol, ethyl acetate, cyclohexane, methylcyclohexane, benzene, petroleum ether, ligroin, 2-methyltetrahydrofuran, acetone, tetrahydrofuran, dimethylacetamide, N-methylpyrrolidine, and DMF.

[0054] In one embodiment, the hydrogenation conditions include a hydrogenation catalyst. In one embodiment, the hydrogenation catalyst is selected from palladium, rhenium, rhodium, ruthenium, platinum, or Raney nickel. Typical examples of other applicable hydrogenation catalysts are briefly described in Wang, D., et al. Chem. Rev. 2015, 115, 13, 6621-6686.

[0055] In one embodiment, the hydrogenation catalyst is located on a support. In one embodiment, the support is selected from carbon, alumina, alkaline earth metal carbonate, clay, ceramic, pumice, or Celite. In one embodiment, the support is carbon.

[0056] In one embodiment, the hydrogenation catalyst is palladium, and the support is carbon (palladium / carbon or Pd / C).

[0057] In one embodiment, the hydrogenation conditions include a hydrogen donor. In one embodiment, the hydrogen donor is selected from 1-methyl-1,4-cyclohexadiene and 1,4-cyclohexadiene. Other applicable hydrogen donors are briefly described in Wang, D. et al. Chem. Rev. 2015, 115, 13, 6621-6686.

[0058] It was found that the hydrogenation reaction stalled due to a side reaction between oxygen in the solvent and the hydrogen donor. It was also found that the reaction stalled due to catalyst poisoning caused by the generation of CO2 during the hydrogenation reaction. Therefore, in one embodiment, step c) was carried out in an inert atmosphere in the reaction vessel. In another embodiment, the vessel was sparged with N2 before the reaction. In yet another embodiment, the reaction vessel was sparged with N2 during the hydrogenation reaction.

[0059] In one embodiment, step c) is performed between approximately 30°C and approximately 60°C. In one embodiment, the above step is performed between approximately 40°C and approximately 60°C, or between approximately 50°C and approximately 60°C. In one embodiment, step c) is performed between approximately 30°C and approximately 50°C, or between approximately 30°C and approximately 40°C. In one embodiment, step c) is performed between approximately 25°C and approximately 55°C, approximately 30°C and approximately 50°C, approximately 35°C and approximately 45°C, or approximately 38°C and approximately 42°C. In one embodiment, step c) is performed between approximately 40°C and approximately 45°C. In one embodiment, step c) is performed at approximately 30°C, approximately 35°C, approximately 40°C, approximately 45°C, approximately 50°C, approximately 55°C, or approximately 60°C. In one embodiment, step c) is performed at less than approximately 60°C. In one embodiment, step c) is performed at less than approximately 50°C. In one embodiment, step c) is performed at approximately 45°C.

[0060] In one embodiment, the compound of formula VII is obtained from step b) in a yield between about 70% and 99%. In another embodiment, the compound of formula VII is obtained in a yield between about 70% and 99%, about 70% and 95%, about 70% and 90%, about 70% and 85%, about 70% and 80%, or about 70% and 75%. In yet another embodiment, the compound of formula IV is obtained from step b) in a yield between about 75% and 99%, about 80% and 99%, about 85% and 99%, about 90% and 99%, or about 95% and 99%.

[0061] In another embodiment, the compound of formula VII is obtained from step b) in a yield of about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, about 96%, about 97%, about 98%, or about 99%. In a further embodiment, the compound of formula VII is obtained in a yield of about 90%. In a further embodiment, the compound of formula VII is obtained in a yield of about 95%. In another embodiment, the compound of formula VII is obtained in a yield of about 98%. In another embodiment, the compound of formula VII is obtained in a yield of about 99%.

[0062] In one embodiment, the compound of formula VII is obtained from step b) in a yield of at least about 65%, at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 98%, or at least about 99%. In another embodiment, formula VII is obtained from step b) in a yield of at least about 80%.

[0063] In one embodiment, step c) is a hydrogenation reaction. In one embodiment, step c) is heterogeneous palladium-catalyzed transfer hydrogenation of the compound of formula VI.

[0064] Step d In one embodiment, step d) is R 1 The method is characterized by reacting with a compound of formula I to form a compound of formula I.

[0065] In one embodiment, m and n are those described in step a). In one embodiment, m is 3 and n is 5.

[0066] In a further embodiment, R 1 The retinoid is selected from vitamin A, retinoic acid, tretinoin, adapalene, 4-hydroxy(phenyl)retinamide, retinyl palmitate, retinal, tretinoin, saturated retinoic acid, and saturated demethylated retinoic acid. In some embodiments, the retinoid is retinoic acid. In some embodiments, the retinoid is tretinoin.

[0067] In one embodiment, the coupling conditions include an activator. In one embodiment, the activator is selected from the group consisting of 2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethylaminium tetrafluoroborate (TBTU), (2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (HBTU), O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate (TATU), and 4-(4,6-dimethoxy-1,3,5-triazine-2-yl)-4-methylmorpholinium chloride (DMTMM).

[0068] In one embodiment, the coupling condition includes a base. In one embodiment, the base is any base with a pKb ≥ 8. In one embodiment, the base is selected from trimethylamine, sodium hydroxide, N-methylmorpholine (NMM), 1-methylimidazole (NMI), and N,N-diisopropylethylamine (DiPEA), and potassium hydroxide.

[0069] In one embodiment, step d) further includes purification of the compound of formula I by chromatography. In one embodiment, chromatography is performed using a silica column. In a further embodiment, the silica column is C 18 This is a column. In one embodiment, a silica column is treated with a solvent gradient. In one embodiment, the solvent gradient contains 20-40% ethanol / methanol.

[0070] It was found that the compound of formula I degrades at wavelengths below 500 nm. Therefore, in one embodiment, if step d) is performed at wavelengths below 500 nm, the compound of formula I cannot be obtained. In one embodiment, the coupling conditions are characterized by blocking light with wavelengths below 500 nm. In one embodiment, the purification of the compound of formula I is characterized by blocking light below 500 nm.

[0071] It has been found that the compound of formula I oxidizes when exposed to air. Therefore, in one embodiment, if step d) is carried out in the presence of oxygen, the compound of formula I cannot be obtained. In one embodiment, step d) was carried out in a reaction vessel under an inert atmosphere. In another embodiment, the vessel was sparged with N2 before the reaction. In another embodiment, step d) is characterized by further adding butylated hydroxytoluene (BHT) to the reaction vessel. In another embodiment, step d) is characterized by further replacing the solvent with ethanol, concentrating the solution to a final 35 wt% solution of the compound of formula I, and adding 400 to 1500 ppm of BHT to capture oxygen.

[0072] It was found that the compound of formula I becomes relatively unstable above 45°C. Therefore, in one embodiment, step d) is performed between approximately 25°C and approximately 45°C. In one embodiment, the above step is performed between approximately 35°C and approximately 45°C or between approximately 40°C and 45°C. In one embodiment, step d) is performed between approximately 25°C and approximately 40°C, approximately 25°C and approximately 35°C, or approximately 25°C and approximately 30°C. In one embodiment, step d) is performed between approximately 30°C and approximately 40°C. In one embodiment, step d) is performed between approximately 25°C and approximately 35°C. In one embodiment, step d) is performed at approximately 25°C, approximately 30°C, approximately 35°C, approximately 40°C, or approximately 45°C. In one embodiment, step d) is performed below approximately 45°C.

[0073] In one embodiment, the compound of formula I is obtained from step d) in a yield between about 70% and 95%. In another embodiment, the compound of formula I is obtained in a yield between about 70% and 90%, about 70% and 80%, or about 70% and 75%. In yet another embodiment, the compound of formula I is obtained in a yield between about 80% and 95%, about 85% and 95%, or about 90% and 95%. In yet another embodiment, the compound of formula I is obtained in a yield of about 70%, about 75%, about 80%, about 85%, about 90%, or about 95%. In a further embodiment, the compound of formula I is obtained in a yield of about 70%. In a further embodiment, the compound of formula I is obtained in a yield of about 80%. In one embodiment, the compound of formula I is obtained from step d) in a yield of at least about 65%, at least 70%, at least 75%, at least about 80%, or at least about 85%. In another embodiment, formula I is obtained from step d) in a yield of at least about 70%.

[0074] In one embodiment, in step d), the compound of formula VII and retinoic acid were coupled with TBTU in DCM:2-MeTHF (containing triethylamine). In one embodiment, in step d), the compound of formula VII and retinoic acid were coupled by activation with TBTU in a mixed solvent of DCM:2-MeTHF (containing triethylamine) at approximately 30°C. In one embodiment, in step d), the compound of formula VII and retinoic acid were coupled with TBTU in DCM:2-MeTHF (containing triethylamine). In one embodiment, in step d), the compound of formula VII and tretinoin were coupled by activation with TBTU in DCM:2-MeTHF (containing triethylamine) at 30°C.

[0075] Entire step In one embodiment, the compound of formula I is obtained from the compound of formula III in a final yield between about 40% and about 80%. In one embodiment, the compound of formula I is obtained from the compound of formula III in yields between about 40% and about 70%, about 40% and about 60%, about 40% and about 50%, or about 40% and about 45%. In one embodiment, the compound of formula I is obtained from the compound of formula III in yields between about 50% and about 80%, about 60% and about 80%, about 70% and about 80%, about 75% and about 80%, about 80% and about 80%, or about 85% and about 80%. In one embodiment, the compound of formula I is obtained from the compound of formula III in a yield of about 60%. In one embodiment, the compound of formula I is obtained from the compound of formula II in a yield of at least about 40%, at least about 50%, at least about 60%, or at least about 65%. In one embodiment, the compound of formula I is obtained from the compound of formula III in a yield of at least about 50%. In another embodiment, the compound of formula I is obtained from the compound of formula III in a yield of at least about 60%.

[0076] (Examples) Example 1. Synthesis of dibenzyl(1-amino-15-oxo-4,7,10-trioxa-14-azaicosan-16,20-diyl)(S)-dicarbamate [ka] 2-MeTHF (1.71 kg, 2.0 L, 2.0 L / kg) was placed in Reactor 1 and stirred. 2,5-Dioxopyrrolidine-1-yl N 2 ,N 6-Bis((benzyloxy)carbonyl)-L-ricinate (1.00 kg) was placed in Reactor 1 at 20°C, DCM (7.96 kg, 6.0 L, 6.0 L / kg) was added at 20°C and stirred, and 2-MeTHF (4.27 kg, 5.0 L, 5.0 L / kg) was added to Reactor 1. 2-MeTHF (5.98 kg, 7.0 L, 7.0 L / kg) was placed in Reactor 2 and stirred. 3,3'-((oxybis(ethane-2,1-diyl))bis(oxy))bis(propane-1-amine) (3.45 kg, 8.0 equivalents, 3.45 kg / kg) was placed in Reactor 2, Reactor 2 was cooled to -25 to -12°C (target -20°C) and stirred. Reactor 1's 2,5-dioxopyrrolidine-1-yl N 2 ,N 6 -Bis((benzyloxy)carbonyl)-L-ricinate solution was slowly added to the Reactor 2 diamine solution from near the liquid surface using an immersion tube, while stirring well at a temperature below -12°C. 2,5-Dioxopyrrolidine-1-yl N 2 ,N 6When -bis((benzyloxy)carbonyl)-L-ricinate was added to 3,3'-((oxybis(ethane-2,1-diyl))bis(oxy))bis(propane-1-amine), exothermic reaction occurred. The batch temperature was maintained at ≤-15°C and the batch was aged for less than 5 minutes with stirring. The stirring speed was reduced and Reactor 2 was heated to 15-25°C (target 20°C). 25 wt% saturated saline (8.50 kg, 8.50 kg / kg) was added, followed by water (4.80 kg, 4.80 kg / kg). Exothermic reaction occurred upon addition of saturated saline. The batch temperature was maintained at ≤25°C and the batch was stirred at 15-25°C (target 20°C) for at least 30 minutes. The layers were separated and the lower aqueous layer was discarded. 4 wt% citric acid (12.5 kg, 12.5 kg / kg) was added to Reactor 2, and the batch was stirred for at least 30 minutes at 15-25°C (target 20°C). The layers were separated, and the lower aqueous layer, which contained a large amount of product, was transferred to Reactor 1. The aqueous layer from Reactor 1 was returned to Reactor 2. 2-MeTHF (11.53 kg, 13.5 L, 13.5 L / kg), followed by 10M NaOH (~1.0 kg, ~0.75 L, 1.0 kg / kg) was added to Reactor 2 to adjust the pH to 12-13. The layers were separated, and the lower aqueous layer was discarded. 25 wt% saturated saline (11.8 kg, 10.0 L, 11.8 kg / kg), followed by water (5.0 kg, 5.0 kg / kg) was added to Reactor 2, the layers were separated, and the lower aqueous layer was discarded. The batch was concentrated by distillation while maintaining the temperature at ≤40°C until the final volume was 4.5 L (4.5 L / kg, ~20 wt%). Dibenzyl(1-amino-15-oxo-4,7,10-trioxa-14-azaicosan-16,20-diyl)(S)-dicarbamate was synthesized in 88% yield.

[0077] Example 2: Synthesis of tetrabenzyl((5S,57S)-6,22,40,56-tetraoxo-11,14,17,25,28,31,34,37,45,48,51-undecaoxa-7,21,41,55-tetraazahenhexacontane-1,5,57,61-tetrayl)tetracarbamate [ka] As a treatment solution, dibenzyl(1-amino-15-oxo-4,7,10-trioxa-14-azaicosan-16,20-diyl)(S)-dicarbamate (2.05 equivalents, 18.7 kg, 20 wt%) was placed in Reactor 1 at 20°C, and DCM (23.9 kg, 18.0 L, 18.0 L / kg) was added to Reactor 1 at 20°C and stirred. The batch was heated at 15-25°C (target 20°C). Dicarboxylic acid: 4,7,10,13,16-pentaoxanonadecanediic acid (1.00 kg) was placed in Reactor 1 at 20°C, hydroxybenzotriazole monohydrate (HOBT) (45.3 g, 0.100 equivalents) was added to Reactor 1 at 20°C, and EDAC (1.47 kg, 2.60 equivalents) was added. The addition of EDAC generated heat. The batch temperature was maintained at <30°C (target 20°C), and aging was performed at 15-25°C (target 20°C) for more than 3 hours. J 2-MeTHF (43.0 kg, 50.0 L, 50.0 L / kg) was added at 20°C. A 5.00 wt% citric acid solution (31.0 kg, 30.0 L, 30.0 L / kg) was added and stirred, and the batch was heated to 30-40°C (target 35°C). The batch was stirred at 30-40°C (target 35°C) for 30 minutes, then stirring was stopped and the layers were allowed to stand for at least 30 minutes. The layers were separated, and the lower aqueous solution was discarded. The 5.00 wt% potassium carbonate solution (20.9 kg, 20.0 L, 20.0 L / kg) from Step 7 was added and stirred, and the batch was heated at 25-35°C (target 30°C) for 30 minutes. Stirring was stopped and the layers were allowed to stand for at least 30 minutes. The layers were separated and the lower aqueous solution was discarded. A 25 wt% saturated sodium chloride aqueous solution (11.94 kg, 10.00 L, 10.00 L / kg) and water (11.94 kg, 11.94 L, 11.94 L / kg) were added. The batch was stirred for 30 minutes at 25-35°C (target 30°C), then the stirring was stopped and the layers were allowed to stand for at least 30 minutes. The layers were separated, and the lower aqueous solution was discarded. The batch was stirred and cooled to 0°C. The batch was then concentrated to a final volume of 12.5 L (12.5 L / kg) while maintaining a batch temperature of ≤50°C. For optimal product stability and distillation rate, distillation is preferably performed at Tj ≤50°C and P ≤80 mbar. MeOH (9.9 kg, 12.5 L, 12.5 L / kg) was added using a spray ball, and the solution was removed from the container at room temperature using a polished filter (pore size ≤10 μm). The treated solution of BMT-334119 was then stored. Tetrabenzyl((5S,57S)-6,22,40,56-tetraoxo-11,14,17,25,28,31,34,37,45,48,51-undecaoxa-7,21,41,55-tetraazahenhexacontane-1,5,57,61-tetrayl)tetracarbamate was obtained in a yield of 90-95%.

[0078] Example 3: N 1 ,N 19 Synthesis of bis((S)-16,20-diamino-15-oxo-4,7,10-trioxa-14-azaicosyl)-4,7,10,13,16-pentaoxanadecanediamide [ka] Two reactors (Reactor 1 and Reactor 2) and a transfer line between them were set up. Both reactors were set to 20°C. In Reactor 2, tetrabenzyl((5S,57S)-6,22,40,56-tetraoxo-11,14,17,25,28,31,34,37,45,48,51-undecaoxa-7,21,41,55-tetraazahenhexacontane-1,5,57,61-tetrayl)tetracarbamate (1.00 kg) / 2-MeTHF:MeOH (1:1) was added as the treatment solution, and 1-methyl-1,4-cyclohexadiene (920 g, 1.10 L, 15.0 equivalents) was added. Reactor 1 was filled with MeOH (4.11 kg, 5.2 L, 5.2 L / kg) and 2-MeTHF (0.512 kg, 0.6 L, 0.6 L / kg). The liquid surface of Reactor 1 and Reactor 2 was sparged with N2 for more than 20 minutes by supplying nitrogen from the immersion tube near the impeller. Under inert conditions, 5% Pd / C (100 g, 0.100 kg / kg) was added to Reactor 1, and Reactor 1 and Reactor 2 were sparged with N2 for more than 20 minutes. The batch in Reactor 1 was heated to 40-50°C (target 45°C), and the contents of Reactor 2 were added to Reactor 1 from above and stirred for 3.5 hours or more. At the end of the reaction aging, a sample was obtained to confirm the completion of the reaction. The sample was immediately filtered (pore size ≤ 1 μm) to quench the reaction. 1 ,N 19 -Bis((S)-16,20-diamino-15-oxo-4,7,10-trioxa-14-azaicosyl)-4,7,10,13,16-pentaoxanadecanediamide was obtained in 98% yield.

[0079] Example 4: N 1 ,N 19Synthesis of -bis((S,23E,25E,27E,29E)-16-((2E,4E,6E,8E)-3,7-dimethyl-9-(2,6,6-trimethylcyclohexa-1-en-1-yl)nona-2,4,6,8-tetraenamide)-24,28-dimethyl-15,22-dioxo-30-(2,6,6-trimethylcyclohexa-1-en-1-yl)-4,7,10-trioxa-14,21-diazatriaconta-23,25,27,29-tetraen-1-yl)-4,7,10,13,16-pentaoxanadecanediamide [ka] Water (10 kg, 10 L, 10 L / kg) was added to Reactor 1, and sodium bicarbonate (0.6 kg, 0.6 kg / kg) was added. Reactor 1 was stirred until all solids were visibly dissolved. N was used as the treatment solution. 1 ,N 19 -Bis((S)-16,20-diamino-15-oxo-4,7,10-trioxa-14-azaicosyl)-4,7,10,13,16-pentaoxanadecanediamide / 2-MeTHF:MeOH(1:1)(1.00kg) was placed in Reactor 2, the batch was stirred, and cooled to 5-10°C. 1 ,N 19 A solution of -bis((S)-16,20-diamino-15-oxo-4,7,10-trioxa-14-azaicosyl)-4,7,10,13,16-pentaoxanonadecanediamide was concentrated to a final volume of 5 L / kg (5 L) while maintaining a batch temperature of ≤45°C, and the solvent was replaced with 2-MeTHF. The batch in Reactor 2 was heated at 25-35°C (target 30°C). DCM (15 L, 15 L / kg) was added to Reactor 2, and tretinoin (1.50 kg, 5.00 equivalents) and triethylamine (1.52 kg, 2.09 L, 15.0 equivalents) were added. The batch was aged at 25-35°C (target 30°C) for at least 30 minutes until all solids were visibly dissolved. TBTU (1.77 kg, 5.5 equivalents) was added, and the batch was aged at 25-35°C (target 30°C) for more than 4 hours. BHT (0.0018 kg, 0.0018 kg / kg) and 6 wt% sodium bicarbonate (10.6 kg, 10 L, 10 L / kg) were placed in Reactor 2, and the batch was stirred at 25-35°C (target 30°C) for at least 1 hour. Stirring was stopped and the layers were allowed to stand for at least 30 minutes. The layers in Reactor 2 were separated, the lower organic layer was transferred to Reactor 3, and the upper aqueous layer was discarded. Reactor 3 was stirred, and the batch was cooled to 5-10°C. The batch was concentrated to 10 L / kg (10 L) while maintaining the batch temperature at ≤45°C, and the solvent was replaced with MeOH. The reaction mixture was sampled for IPC-4. Ethanol (200 proof, 0.79 kg, 1 L, 1 L / kg) was added, and C 18 The product was purified by preparative chromatography (gradient: ethanol / methanol). 1 ,N 19 -Bis((S,23E,25E,27E,29E)-16-((2E,4E,6E,8E)-3,7-dimethyl-9-(2,6,6-trimethylcyclohexa-1-en-1-yl)nona-2,4,6,8-tetraenamide)-24,28-dimethyl-15,22-dioxo-30-(2,6,6-trimethylcyclohexa-1-en-1-yl)-4,7,10-trioxa-14,21-diazatriaconta-23,25,27,29-tetraen-1-yl)-4,7,10,13,16-pentaoxanadecanediamide was obtained in 85% yield.

Claims

1. Equation I 【Chemistry 1】 (In the formula, R 1 It is retinoid; m is an integer from 1 to 6; and A method for synthesizing a compound (where n is an integer from 1 to 10), a) Equation II 【Chemistry 2】 Compounds of formula III (where m is an integer from 1 to 6) and formula III 【Transformation 3】 (In the formula, PG 1 and PG 2 Compounds of (each independently being a protecting group) are reacted to form formula IV 【Chemistry 4】 (In the formula, m is an integer from 1 to 6, PG 1 (is a protecting group) forms compounds; and b) Compounds of formula IV and formula V 【Transformation 5】 The compound (wherein n is an integer from 1 to 10) is reacted to produce formula VI 【Transformation 6】 (wherein m is an integer from 1 to 6; n is an integer from 1 to 10; and PG 1 (is a protecting group) forms a compound; c) React the compound of formula VI under hydrogenation conditions to obtain formula VII 【Transformation 7】 (wherein m is an integer from 1 to 6 and n is an integer from 1 to 10) forms a compound; and d) A method characterized by the step of reacting a compound of formula VII with a retinoid under coupling conditions to form a compound of formula I.

2. The hydrogenation conditions are that the compound of formula VI is H 2 The method of claim 1, characterized by reacting with Pd / C.

3. The method of claim 1, wherein m is 3.

4. The method of claim 3, wherein n is 5.

5. Each PG 1 and PG 2 The method of claim 1, wherein the following are independently selected from the group consisting of carboxybenzyl, p-methoxybenzylcarbonyl, t-butyloxycarbonyl, 9-fluorenylmethoxycarbonyl, acetyl, trifluoroacetyl, benzoyl, benzyl, carbamate, p-methoxybenzyl, 3,4-dimethoxybenzyl, tosyl, trichloroethyl chloroformate, (4-nitrophenyl)sulfonyl, methyl, ethyl, propyl, n-butyl, t-butyl, succinimide, 2,6-dimethylphenol, 2,6-diisopropylphenol, 2,6-di-tert-butylphenol, trimethylsilyl, allyl, 1,1-dimethylallyl, 2,2,2-trifluoroethyl, phenyl, and 4-methoxybenzyl.

6. PG 1 The method of claim 5, wherein is carboxybenzyl.

7. PG 2 The method of claim 5, wherein is succinimide.

8. The compound of formula II 【Transformation 8】 The method according to claim 1.

9. The compound of formula III 【Chemistry 9】 The method of claim 8.

10. The method of claim 1, wherein step a) is performed between -20°C and 0°C.

11. The method of claim 1, wherein the yield in a) is at least 70%.

12. The method of claim 1, wherein in a), the compound of formula II is present in an amount of 2 to 8 equivalents and the compound of formula III is present in an amount of 1 equivalent.

13. The method according to claim 1, characterized in that, in a), citric acid is further added after the formation of the compound of formula IV.

14. The compound of formula I 【Chemistry 10】 The method according to claim 1.

15. The method according to claim 1, wherein the compound of formula I is obtained from the compound of formula III in at least 50% yield.

16. The method according to claim 1, wherein the compound of formula IV is obtained in a molar ratio greater than 9:1 to the compound of formula VIII. 【Chemistry 11】

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