# US 10,370,403 B2 · Methods for the synthesis of ceragenins

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- Number: US 10,370,403 B2
- Document ID: US10370403B2
- Status: Granted
- Kind: B2
- Application number: 15/135,969
- Filed: 2016-04-22
- Published: 2016-10-27
- Granted: 2019-08-06
- Earliest claimed: 2015-04-22
- Assignees: Brigham Young University
- Applicants: Paul B. Savage; Thomas E. Jacks; Ross A. Miller; Andrew S. Thompson; Jared Lynn Randall
- Inventors: Paul B. Savage; Thomas E. Jacks; Ross A. Miller; Andrew S. Thompson; Jared Lynn Randall
- Web page: https://patentgrep.com/patent/US10370403B2

## CPC

- C07J 41/0088: {containing unsubstituted amino radicals}
- A61P 31/22: for herpes viruses
- C07J 9/005: {containing a carboxylic function directly attached or attached by a chain containing only carbon atoms to the cyclopenta[a]hydrophenanthrene skeleton}
- C07J 41/0055: {the 17-beta position being substituted by an uninterrupted chain of at least three carbon atoms which may or may not be branched, e.g. cholane or cholestane derivatives, optionally cyclised, e.g. 17-beta-phenyl or 17-beta-furyl derivatives}
- C07J 41/0061: {one of the carbon atoms being part of an amide group}
- C07J: STEROIDS (seco-steroids C07C)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS

## Abstract

Disclosed herein are methods of making ceragnenin compounds for treating, preventing, or diagnosing diseases, disorders, or conditions associated with bacterial or viral infections, cancer, inflammation, and osteogenesis. Ceragenin compounds display broad-spectrum antibacterial activity utilizing a mode of action similar to antimicrobial peptides, but without the high synthesis costs and susceptibility to proteolytic degradation. Ceragenin compounds reproduce the amphiphilic morphology found in many antimicrobial peptides and display potent and diverse biological activities, including anti-bacterial, anti-cancer, anti-inflammatory, bone growth promotion, and wound healing promotion.

## Claims

### Claim 1

A method of making a compound of Formula (I) or (III), comprising the steps of:
(a) reacting a compound of Formula (1) and R1R2—NH
to form a compound of Formula (2):
(b) optionally reducing a compound of Formula (2) to form a compound of Formula (3):
(c1) optionally protecting a compound of Formula (3) with an amine protecting group (PG) to form a compound of Formula (4):
where R2 is a hydrogen and is replaced with the amine protecting group,
or (c2) optionally protecting a compound of Formula (2) with an amine protecting group (PG) to form a compound of Formula (10):
where R2 is a hydrogen and is replaced with the amine protecting group;
(d1) reacting a compound of Formula (3) or Formula (4) with a compound of Formula (A)
to form a compound of Formula (5a) or (5b):
or (d2) reacting a compound of Formula (2) or Formula (10) with a compound of Formula (A) to form a compound of Formula (11a) or (11b):
(e1) subjecting a compound of Formula (5a) or (5b) to hydroboration and oxidation conditions, followed by reaction with a compound of Formula (B)
R3—SO2Cl (B)
to form a compound of Formula (6a) or (6b) having three terminal sulfonate groups:
or (e2) subjecting a compound of Formula (11a) or (11b) to hydroboration and oxidation conditions, followed by reaction with a compound of Formula (B) to form a compound of Formula (12a) or (12b) having three terminal sulfonate groups:
(f1) reacting a compound of Formula (6a) or (6b) and R4R5—NH to thereby directly replace the three terminal sulfonate groups with amino groups, followed by optional deprotection to form a compound of Formula (I):
or (f2) reacting a compound of Formula (12a) or (12b) and R4R5—NH too thereby directly replace the three terminal sulfonate groups with amino groups, followed by optional deprotection to form a compound of Formula (III):
wherein:
X is independently selected from the group consisting of —F, —Cl, —Br, —I, tosylate, brosylate, nosylate, mesylate, and triflate;
n is an integer from 1 to 25;
R1, R2, R4, and R5 are independently selected from the group consisting of hydrogen, optionally substituted C1-C24 alkyl, optionally substituted C2-C24 alkenyl, optionally substituted C2-C24 alkynyl, optionally substituted C6 or C10 aryl, optionally substituted 5 to 10 membered heteroaryl, optionally substituted 5 to 10 membered heterocyclyl, optionally substituted C7-13 aralkyl, optionally substituted (5 to 10 membered heteroaryl)-C1-C6 alkyl, optionally substituted C3-10 carbocyclyl, optionally substituted C4-10 (carbocyclyl)alkyl, optionally substituted (5 to 10 membered heterocyclyl)-C1-C6 alkyl, an amine protecting group, and an optionally substituted amide;
R3 is selected from the group consisting of optionally substituted C1-C24 alkyl, optionally substituted C2-C24 alkenyl, optionally substituted C2-C24 alkynyl, optionally substituted C6 or C10 aryl, optionally substituted 5 to 10 membered heteroaryl, optionally substituted heterocyclyl, heterocyclyl, optionally substituted C7-13 aralkyl, optionally substituted (5 to 10 membered heteroaryl)-C1-C6 alkyl, optionally substituted C3-10 carbocyclyl, optionally substituted C4-10 (carbocyclyl)alkyl, optionally substituted amido, and optionally substituted (5 to 10 membered heterocyclyl)-C1-C6 alkyl,
wherein if substituted, R1, R2, R3, R4 and/or R5 include a substitution selected from the group consisting of C1-C24 alkyl, C1-C24 alkenyl, C1-C24 alkynyl, C1-C24 heteroalkyl, C3-C10 carbocyclyl, C3-C10-carbocyclyl-C1-C6-alkyl, heterocyclyl, heterocyclyl-C1-C6-alkyl, aryl, aryl(C1-C6)alkyl, 5-10 membered heteroaryl, 5-10 membered heteroaryl(C1-C6)alkyl, halo, cyano, hydroxy, C1-C6 alkoxy, C1-C6 alkoxy(C1-C6)alkyl (i.e., ether), aryloxy, sulfhydryl (mercapto), halo(C1-C6)alkyl, halo(C1-C6)alkoxy, C1-C6 alkylthio, arylthio, amino, amino(C1-C6)alkyl, nitro, O-carbamyl, N-carbamyl, O-thiocarbamyl, N-thiocarbamyl, C-amido, N-amido, amido, S-sulfonamido, N-sulfonamido, C-carboxy, O-carboxy, acyl, cyanato, isocyanato, thiocyanato, isothiocyanato, sulfinyl, sulfonyl, and oxo (═O), and
wherein if one or more of R1, R2, R3, R4, or R5 includes a heterocyclyl, the heterocyclyl is selected from the group consisting of azepinyl, acridinyl, carbazolyl, cinnolinyl, dioxolanyl, imidazolinyl, imidazolidinyl, morpholinyl, oxiranyl, oxepanyl, thiepanyl, piperidinyl, piperazinyl, dioxopiperazinyl, pyrrolidinyl, pyrrolidonyl, pyrrolidionyl, 4-piperidonyl, pyrazolinyl, pyrazolidinyl, 1,3-dioxinyl, 1,3-dioxanyl, 1,4-dioxinyl, 1,4-dioxanyl, 1,3-oxathianyl, 1,4-oxathiinyl, 1,4-oxathianyl, 2H-1,2-oxazinyl, trioxanyl, hexahydro-1,3,5-triazinyl, 1,3-dioxolyl, 1,3-dioxolanyl, 1,3-dithiolyl, 1,3-dithiolanyl, isoxazolinyl, isoxazolidinyl, oxazolinyl, oxazolidinyl, oxazolidinonyl, thiazolinyl, thiazolidinyl, 1,3-oxathiolanyl, indolinyl, isoindolinyl, tetrahydrofuranyl, tetrahydropyranyl, tetrahydrothiophenyl, tetrahydrothiopyranyl, tetrahydro-1,4-thiazinyl, thiamorpholinyl, dihydrobenzofuranyl, benzimidazolidinyl, and tetrahydroquinoline.

### Claim 2 (depends on 1)

The method of claim 1, comprising the steps of:
(a) reacting a compound of Formula (1) and R1R2—NH
to form a compound of Formula (2):
(b) optionally reducing a compound of Formula (2) to form a compound of Formula (3):
(c) optionally protecting a compound of Formula (3) with an amine protecting group to form a compound of Formula (4):
wherein R2 is a hydrogen and is replaced with the amine protecting group;
(d) reacting a compound of Formula (3) or Formula (4) with a compound of Formula (A)
to form a compound of Formula (5a) or (5b):
(e) subjecting a compound of Formula (5a) or (5b) to hydroboration and oxidation conditions, followed by reaction with a compound of Formula (B)
R3—SO2Cl (B)
to form a compound of Formula (6a) or (6b):
(f) reacting a compound of Formula (6a) or (6b) and R4R5—NH, followed by optional deprotection to form a compound of Formula (I):

### Claim 3 (depends on 1)

The method of claim 1, comprising the steps of:
(a) reacting a compound of Formula (1) and R1R2—NH
to form a compound of Formula (2):
(b) optionally protecting a compound of Formula (2) with an amine protecting group to form a compound of Formula (10):
wherein R2 is a hydrogen and is replaced with the amine protecting group;
(c) reacting a compound of Formula (2) or Formula (10) with a compound of Formula (A)
to form a compound of Formula (11a) or (11b):
(d) subjecting a compound of Formula (11a) or (11b) to hydroboration and oxidation conditions, followed by reaction with a compound of Formula (B)
R3—SO2Cl (B)
to form a compound of Formula (12a) or (12b):
(e) reacting a compound of Formula (12a) or (12b) and R4R5—NH, followed by optional deprotection to form a compound of Formula (III):

### Claim 4 (depends on 1)

The method of claim 1, wherein:
R1 and R2, together with the atoms to which they are attached form an optionally substituted 5 to 10 membered heterocyclyl ring; and
R4 and R5, together with the atoms to which they are attached form an optionally substituted 5 to 10 membered heterocyclyl ring.

### Claim 5 (depends on 1)

The method of claim 1, wherein R2 is hydrogen and R1 is selected from the group consisting of hydrogen, optionally substituted C1-C24 alkyl, optionally substituted C2-C24 alkenyl, optionally substituted C2-C24 alkynyl, optionally substituted C6 or C10 aryl, optionally substituted 5 to 10 membered heteroaryl, optionally substituted 5 to 10 membered heterocyclyl, optionally substituted C7-13 aralkyl, optionally substituted (5 to 10 membered heteroaryl)-C1-C6 alkyl, optionally substituted C3-10 carbocyclyl, optionally substituted C4-10 (carbocyclyl)alkyl, optionally substituted (5 to 10 membered heterocyclyl)-C1-C6 alkyl, an amine protecting group, and an optionally substituted amide.

### Claim 6 (depends on 1)

The method of claim 1, wherein R2 is hydrogen and R1 is selected from the group consisting of optionally substituted C1-C24 alkyl, optionally substituted C2-C24 alkenyl, optionally substituted C2-C24 alkynyl, optionally substituted C6 or C10 aryl, optionally substituted 5 to 10 membered heteroaryl, optionally substituted 5 to 10 membered heterocyclyl, optionally substituted C7-13 aralkyl, optionally substituted (5 to 10 membered heteroaryl)-C1-C6 alkyl, optionally substituted C3-10 carbocyclyl, optionally substituted C4-10 (carbocyclyl)alkyl, an optionally substituted amide, and optionally substituted (5 to 10 membered heterocyclyl)-C1-C6 alkyl.

### Claim 7 (depends on 1)

The method of claim 1, wherein R2 is hydrogen and R1 is optionally substituted C1-C24 alkyl.

### Claim 8 (depends on 1)

The method of claim 1, wherein n is 1 or 2.

### Claim 9 (depends on 1)

The method of claim 1, wherein R4 is hydrogen and R5 is selected from the group consisting of hydrogen, optionally substituted C1-C24 alkyl, optionally substituted C2-C24 alkenyl, optionally substituted C2-C24 alkynyl, optionally substituted C6 or C10 aryl, optionally substituted 5 to 10 membered heteroaryl, optionally substituted 5 to 10 membered heterocyclyl, optionally substituted C7-13 aralkyl, optionally substituted (5 to 10 membered heteroaryl)-C1-C6 alkyl, optionally substituted C3-10 carbocyclyl, optionally substituted C4-10 (carbocyclyl)alkyl, optionally substituted (5 to 10 membered heterocyclyl)-C1-C6 alkyl, and an amine protecting group.

### Claim 10 (depends on 1)

The method of claim 1, wherein R4 is hydrogen and R5 is selected from the group consisting of hydrogen, optionally substituted C1-C24 alkyl, optionally substituted C2-C24 alkenyl, optionally substituted C2-C24 alkynyl, optionally substituted C6 or C10 aryl, optionally substituted 5 to 10 membered heteroaryl, optionally substituted 5 to 10 membered heterocyclyl, optionally substituted C7-13 aralkyl, optionally substituted (5 to 10 membered heteroaryl)-C1-C6 alkyl, optionally substituted C3-10 carbocyclyl, optionally substituted C4-10 (carbocyclyl)alkyl, and optionally substituted (5 to 10 membered heterocyclyl)-C1-C6 alkyl.

### Claim 11 (depends on 1)

The method of claim 1, wherein R4 is hydrogen and R5 is hydrogen or optionally substituted C1-C24 alkyl.

### Claim 12 (depends on 1)

The method of claim 1, wherein R4 and R5 are both hydrogen.

### Claim 13 (depends on 1)

The method of claim 1, wherein the compound of Formula (I) or the compound of Formula (III) is selected from the group consisting of:

### Claim 14 (depends on 1)

The method of claim 1, wherein one or more steps of the method is carried out in one or more solvents selected from the group consisting of water, acetic acid, formic acid, hydrochloric acid, hydrobromic acid, DMF, DMSO, DCM, NMP, chloroform, THF, 2-methyl-THF, benzene, toluene, trifluorotoluene, dioxane, methanol, ethanol, ethyl acetate, acetone, or any combination thereof.

### Claim 15 (depends on 1)

The method of claim 1, wherein one or more steps of the method is carried out at a temperature of at least 10° C.

### Claim 16 (depends on 1)

The method of claim 1, wherein the method is accomplished in less than 25 hours.

### Claim 17 (depends on 1)

The method of claim 1, wherein the method provides at least one kilogram of a compound of Formula (I) or a Formula (III).

### Claim 18 (depends on 1)

The method of claim 1, wherein at least part of the method is performed at ambient pressure.

### Claim 19 (depends on 1)

The method of claim 1, wherein the method does not deliberately exclude the presence of oxygen.

### Claim 20 (depends on 1)

The method of claim 1, wherein at least part of the method is performed in a non-oxygen-containing atmosphere.

### Claim 21 (depends on 1)

The method of claim 1, wherein one or more steps of the method is performed with a mixing rate of at least 50 rpms.

### Claim 22

A method of making a compound of Formula (I), comprising the steps of:
(a) reacting a compound of Formula (1) and R1R2—NH
to form a compound of Formula (2):
(b) reducing a compound of Formula (2) to form a compound of Formula (3):
(c) protecting the compound of Formula (3) with an amine protecting group (PG) to form a compound of Formula (4):
where R2 is a hydrogen and is replaced with the amine protecting group,
(d) reacting the compound of Formula (4) with a compound of Formula (A)
to form a compound of Formula (5):
(e) subjecting the compound of Formula (5) to hydroboration and oxidation conditions, followed by reaction with a compound of Formula (B)
R3—SO2Cl (B)
to form a compound of Formula (6) having three terminal sulfonate groups:
(f) reacting a compound of Formula (6) and R4R5—NH to thereby directly replace the three terminal sulfonate groups with amino groups, followed by deprotection to form a compound of Formula (I):
wherein:
X is independently selected from the group consisting of —F, —Cl, —Br, —I, tosylate, brosylate, nosylate, mesylate, and triflate;
n is an integer from 1 to 25;
R1, R2, R4, and R5 are independently selected from the group consisting of hydrogen, optionally substituted C1-C24 alkyl, optionally substituted C2-C24 alkenyl, optionally substituted C2-C24 alkynyl, optionally substituted C6 or C10 aryl, optionally substituted 5 to 10 membered heteroaryl, optionally substituted 5 to 10 membered heterocyclyl, optionally substituted C7-13 aralkyl, optionally substituted (5 to 10 membered heteroaryl)-C1-C6 alkyl, optionally substituted C3-10 carbocyclyl, optionally substituted C4-10 (carbocyclyl)alkyl, optionally substituted (5 to 10 membered heterocyclyl)-C1-C6 alkyl, an amine protecting group, and an optionally substituted amide; and
R3 is selected from the group consisting of optionally substituted C1-C24 alkyl, optionally substituted C2-C24 alkenyl, optionally substituted C2-C24 alkynyl, optionally substituted C6 or C10 aryl, optionally substituted 5 to 10 membered heteroaryl, optionally substituted 5 to 10 membered heterocyclyl, optionally substituted C7-13 aralkyl, optionally substituted (5 to 10 membered heteroaryl)-C1-C6 alkyl, optionally substituted C3-10 carbocyclyl, optionally substituted C4-10 (carbocyclyl)alkyl, optionally substituted amido, and optionally substituted (5 to 10 membered heterocyclyl)-C1-C6 alkyl,
wherein if substituted, R1, R2, R3, R4 and/or R5 include a substitution selected from the group consisting of C1-C24 alkyl, C1-C24 alkenyl, C1-C24 alkynyl, C1-C24 heteroalkyl, C3-C10 carbocyclyl, C3-C10-carbocyclyl-C1-C6-alkyl, heterocyclyl, heterocyclyl-C1-C6-alkyl, aryl, aryl(C1-C6)alkyl, 5-10 membered heteroaryl, 5-10 membered heteroaryl(C1-C6)alkyl, halo, cyano, hydroxy, C1-C6 alkoxy, C1-C6 alkoxy(C1-C6)alkyl (i.e., ether), aryloxy, sulfhydryl (mercapto), halo(C1-C6)alkyl, halo(C1-C6)alkoxy, C1-C6 alkylthio, arylthio, amino, amino(C1-C6)alkyl, nitro, O-carbamyl, N-carbamyl, O-thiocarbamyl, N-thiocarbamyl, C-amido, N-amido, amido, S-sulfonamido, N-sulfonamido, C-carboxy, O-carboxy, acyl, cyanato, isocyanato, thiocyanato, isothiocyanato, sulfinyl, sulfonyl, and oxo (═O), and
wherein if one or more of R1, R2, R3, R4, or R5 includes a heterocyclyl, the heterocyclyl is selected from the group consisting of azepinyl, acridinyl, carbazolyl, cinnolinyl, dioxolanyl, imidazolinyl, imidazolidinyl, morpholinyl, oxiranyl, oxepanyl, thiepanyl, piperidinyl, piperazinyl, dioxopiperazinyl, pyrrolidinyl, pyrrolidonyl, pyrrolidionyl, 4-piperidonyl, pyrazolinyl, pyrazolidinyl, 1,3-dioxinyl, 1,3-dioxanyl, 1,4-dioxinyl, 1,4-dioxanyl, 1,3-oxathianyl, 1,4-oxathiinyl, 1,4-oxathianyl, 2H-1,2-oxazinyl, trioxanyl, hexahydro-1,3,5-triazinyl, 1,3-dioxolyl, 1,3-dioxolanyl, 1,3-dithiolyl, 1,3-dithiolanyl, isoxazolinyl, isoxazol idinyl, oxazolinyl, oxazolidinyl, oxazolidinonyl, thiazolinyl, thiazolidinyl, 1,3-oxathiolanyl, indolinyl, isoindolinyl, tetrahydrofuranyl, tetrahydropyranyl, tetrahydrothiophenyl, tetrahydrothiopyranyl, tetrahydro-1,4-thiazinyl, thiamorpholinyl, dihydrobenzofuranyl, benzimidazolidinyl, and tetrahydroquinoline.

### Claim 23 (depends on 22)

The method of claim 22, wherein the method provides at least one kilogram of the compound of Formula (I).

### Claim 24 (depends on 22)

The method of claim 22, wherein at least part of the method is performed in a non-oxygen-containing atmosphere.

### Claim 25

A method of making a compound of Formula (III), comprising the steps of:
(a) reacting a compound of Formula (1) and R1R2—NH
to form a compound of Formula (2):
(b) optionally protecting a compound of Formula (2) with an amine protecting group (PG) to form a compound of Formula (10):
where R2 is a hydrogen and is replaced with the amine protecting group;
(c) reacting a compound of Formula (2) or Formula (10) with a compound of Formula (A) to form a compound of Formula (11a) or (11b):
(d) subjecting a compound of Formula (11a) or (11b) to hydroboration and oxidation conditions, followed by reaction with a compound of Formula (B) to form a compound of Formula (12a) or (12b) having three terminal sulfonate groups:
(e) reacting a compound of Formula (12a) or (12b) and R4R5—NH to thereby directly replace the tree terminal sulfonate groups with amino groups, followed by optional deprotection to form a compound of Formula (III):
wherein:
X is independently selected from the group consisting of —F, —Cl, —Br, —I, tosylate, brosylate, nosylate, mesylate, and triflate;
n is an integer from 1 to 25;
R1, R2, R4, and R5 are independently selected from the group consisting of hydrogen, optionally substituted C1-C24 alkyl, optionally substituted C2-C24 alkenyl, optionally substituted C2-C24 alkynyl, optionally substituted C6 or C10 aryl, optionally substituted 5 to 10 membered heteroaryl, optionally substituted 5 to 10 membered heterocyclyl, optionally substituted C7-13 aralkyl, optionally substituted (5 to 10 membered heteroaryl)-C1-C6 alkyl, optionally substituted C3-10 carbocyclyl, optionally substituted C4-10 (carbocyclyl)alkyl, optionally substituted (5 to 10 membered heterocyclyl)-C1-C6 alkyl, an amine protecting group, and an optionally substituted amide; and
R3 is selected from the group consisting of optionally substituted C1-C24 alkyl, optionally substituted C2-C24 alkenyl, optionally substituted C2-C24 alkynyl, optionally substituted C6 or C10 aryl, optionally substituted 5 to 10 membered heteroaryl, optionally substituted 5 to 10 membered heterocyclyl, optionally substituted C7-13 aralkyl, optionally substituted (5 to 10 membered heteroaryl)-C1-C6 alkyl, optionally substituted C3-10 carbocyclyl, optionally substituted C4-10 (carbocyclyl)alkyl, optionally substituted amido, and optionally substituted (5 to 10 membered heterocyclyl)-C1-C6 alkyl
wherein if substituted, R1, R2, R3, R4 and/or R5 include a substitution selected from the group consisting of C1-C14 alkyl, C1-C24 alkenyl, C1-C24 alkynyl, C1-C24 heteroalkyl, C3-C10 carbocyclyl, C3-C10-carbocyclyl-C1-C6-alkyl, heterocyclyl, heterocyclyl-C1-C6-alkyl, aryl, aryl(C1-C6)alkyl, 5-10 membered heteroaryl, 5-10 membered heteroaryl(C1-C6)alkyl, halo, cyano, hydroxy, C1-C6 alkoxy, C1-C6 alkoxy(C1-C6)alkyl (i.e., ether), aryloxy, sulfhydryl (mercapto), halo(C1-C6)alkyl, halo(C1-C6)alkoxy, C1-C6 alkylthio, arylthio, amino, amino(C1-C6)alkyl, nitro, O-carbamyl, N-carbamyl, O-thiocarbamyl, N-thiocarbamyl, C-amido, N-amido, amido, S-sulfonamido, N-sulfonamido, C-carboxy, O-carboxy, acyl, cyanato, isocyanato, thiocyanato, isothiocyanato, sulfinyl, sulfonyl, and oxo (═O), and
wherein if one or more of R1, R2, R3, R4, or R5 includes a heterocyclyl, the heterocyclyl is selected from the group consisting of azepinyl, acridinyl, carbazolyl, cinnolinyl, dioxolanyl, imidazolinyl, imidazolidinyl, morpholinyl, oxiranyl, oxepanyl, thiepanyl, piperidinyl, piperazinyl, dioxopiperazinyl, pyrrolidinyl, pyrrolidonyl, pyrrolidionyl, 4-piperidonyl, pyrazolinyl, pyrazolidinyl, 1,3-dioxinyl, 1,3-dioxanyl, 1,4-dioxinyl, 1,4-dioxanyl, 1,3-oxathianyl, 1,4-oxathiinyl, 1,4-oxathianyl, 2H-1,2-oxazinyl, trioxanyl, hexahydro-1,3,5-triazinyl, 1,3-dioxolyl, 1,3-dioxolanyl, 1,3-dithiolyl, 1,3-dithiolanyl, isoxazolinyl, isoxazol idinyl, oxazolinyl, oxazolidinyl, oxazolidinonyl, thiazolinyl, thiazolidinyl, 1,3-oxathiolanyl, indolinyl, isoindolinyl, tetrahydrofuranyl, tetrahydropyranyl, tetrahydrothiophenyl, tetrahydrothiopyranyl, tetrahydro-1,4-thiazinyl, thiamorpholinyl, dihydrobenzofuranyl, benzimidazolidinyl, and tetrahydroquinoline.

### Claim 26 (depends on 24)

The method of claim 24, wherein the method provides at least one kilogram of the compound of Formula (III).

### Claim 27 (depends on 24)

The method of claim 24, wherein at least part of the method is performed in a non-oxygen-containing atmosphere.