LpxC inhibitor and methods of making

1. A process for the preparation of Formula 15:

wherein X is halogen, —OTf, —OTs, or —OMs; and

each PG is methyl, benzyl, p-methoxybenzyl, methoxymethyl, [2-(trimethylsilyl)ethoxylmethyl, triisopropylsilyl, or tert-butyldimethylsilyl; comprising:

(1) contacting the compound of Formula 14:

wherein X is halogen, —OTf, —OTs, or —OMs; and

each PG is methyl, benzyl, p-methoxybenzyl, methoxymethyl, [2-(trimethylsilyl)ethoxylmethyl, triisopropylsilyl, or tert-butyldimethylsilyl;

with a suitable oxidation reagent system in a suitable solvent to provide a compound of Formula 15;

wherein:

the suitable oxidation reagent system of step (1) is Collins reagent, pyridinium dichromate, pyridinium chlorochromate, Dess-Martin periodinane, 2-iodobenzoic acid, a TPAP/NMO system, or a TEMPO/bleach system; and

the suitable solvent of step (1) is acetonitrile, dimethylsulfoxide, dichloromethane, chloroform, dichloroethane, hexanes, ethyl acetate, acetic acid, toluene, water, or a combination thereof.

2. The process of claim 1 , wherein:

the suitable oxidation reagent system of step (1) is a TEMPO/bleach system; and

the suitable solvent of step (1) is acetonitrile, dichloromethane, chloroform, dichloroethane, hexanes, water, or a combination thereof;

step (1) is performed at a temperature of from about 0° C. to about 5° C.;

each PG is benzyl, p-methoxybenzyl, methoxymethyl, [2-(trimethylsilyl)ethoxy]methyl, triisopropylsilyl, or tert-butyldimethylsilyl; and

X is Cl, Br, or I.

3. The process of claim 1 , wherein the compound of Formula 14 is prepared by:

(1a) contacting a compound of Formula 13:

wherein X is halogen, —OTf, —OTs, or —OMs;

R 1 is C 1 -C 10 alkyl, aryl, or benzyl; and

each PG is methyl, benzyl, p-methoxybenzyl, methoxymethyl, [2-(trimethylsilyl)ethoxylmethyl, triisopropylsilyl, or tert-butyldimethylsilyl;

with a suitable borohydride reagent in a suitable solvent to provide the compound of Formula 14;

wherein:

the suitable borohydride reagent of step (1a) is lithium borohydride, sodium borohydride, sodium cyanoborohydride, potassium borohydride, lithium triethylborohydride, or sodium triacetoxyborohydride;

the suitable solvent of step (1a) is acetonitrile, methanol, ethanol, isopropyl alcohol, dimethoxyethane, 2-methyltetrahydrofuran, methyl tert-butyl ether, cyclopentyl methyl ether, tetrahydrofuran, diethyl ether, diisopropyl ether, 1,4-dioxane, toluene, water, or a combination thereof.

4. The process of claim 3 , wherein:

the suitable borohydride reagent of step (1a) is lithium borohydride;

the suitable solvent of step (1a) is a mixture of tetrahydrofuran and ethanol;

step (1a) is performed at a temperature of from about 0° C. to about 25° C.; and

R 1 is methyl, isopropyl, tert-butyl, phenyl, or benzyl.

5. The process of claim 3 , further comprising crystallizing the compound of Formula 14 from acetonitrile, methanol, ethanol, isopropyl alcohol, acetone, methyl acetate, ethyl acetate, dichloromethane, chloroform, diethyl ether, diisopropyl ether, tert-butyl methyl ether, tetrahydrofuran, 2-methyltetrahydrofuran, dioxane, benzene, toluene, petroleum ether, pentane, hexane, heptane, cyclohexane, acetic acid, water, or a mixture thereof.

6. The process of claim 3 , wherein the compound of Formula 13 is prepared by:

(1b) contacting a compound of Formula 12:

wherein X is halogen, —OTf, —OTs, or —OMs; and

R 1 is C 1 -C 10 alkyl, aryl, or benzyl;

with a compound of Formula 9:

wherein LG is Cl, Br, I, —OTf, —OTs, or —OMs; and

each PG is methyl, benzyl, p-methoxybenzyl, methoxymethyl, [2-(trimethylsilyl)ethoxylmethyl, triisopropylsilyl, or tert-butyldimethylsilyl;

in the presence of a suitable base, and in a suitable solvent, to provide a compound of Formula 13;

wherein:

the suitable base of step (1b) is n-butyl lithium, lithium diisopropylamide (LDA), lithium bis(trimethylsilyl)amide (LiHMDS), or lithium tetramethylpiperidide (LiTMP);

the suitable solvent of step (1b) is diethyl ether, diisopropyl ether, tetrahydrofuran, 2-methyltetrahydrofuran, 1,4-dioxane, tert-butyl methyl ether, cyclopropyl methyl ether, or a combination thereof.

7. The process of claim 6 , wherein:

the suitable base of step (1b) is LiHDMS;

the suitable solvent of step (1b) is tetrahydrofuran;

step (1b) is performed at a temperature of about −25 to about −15° C.; and

the compound of Formula 12 is reacted with the base for from about 15 min to about 60 min before the addition of the compound of Formula 9.

8. The process of claim 1 , further comprising:

(2) contacting the compound of Formula 15 with a compound of Formula 16, or a salt thereof:

in the presence of a suitable reducing agent in a suitable solvent to provide a compound of Formula 17:

wherein X is halogen, —OTf, —OTs, or —OMs; and

each PG is methyl, benzyl, p-methoxybenzyl, methoxymethyl, [2-(trimethylsilyl)ethoxylmethyl, triisopropylsilyl, or tert-butyldimethylsilyl;

wherein:

the suitable reducing agent of step (2) is sodium borohydride, sodium cyanoborohydride, sodium triacetoxyborohydride, lithium cyanoborohydride, H 2 /catalyst, or picoline-borane;

the suitable solvent of step (2) is acetonitrile, methanol, ethanol, dichloromethane, chloroform, dichloroethane, toluene, water, or a combination thereof.

9. The process of any claim 8 , wherein:

the suitable reducing agent of step (2) is picoline-borane;

the suitable solvent of step (2) is a mixture of methanol and dichloromethane; and

step (2) is performed at a temperature of from about 0° C. to about 25° C.

10. The process of claim 8 , further comprising:

(3) contacting the compound of Formula 17 with a compound of Formula 20, or a salt thereof:

in the presence of a coupling catalyst, a suitable base, and in a suitable solvent to provide a compound of Formula 21:

wherein:

each PG is methyl, benzyl, p-methoxybenzyl, methoxymethyl, [2-(trimethylsilyl)ethoxylmethyl, triisopropylsilyl, or tert-butyldimethylsilyl;

the suitable base of step (3) is triethylamine, diisopropylethylamine, 1,2,2,6,6-pentamethylpiperidine, tributylamine, 1,8-diazabicycloundec-7-ene (DBU), sec-butylamine, or tetrabutylammonium fluoride (TBAF); and

the suitable solvent of step (3) is acetonitrile, dimethylformamide, diethyl ether, ethanol, tetrahydrofuran, isopropyl alcohol, 1,4-dioxane, toluene, water, or a combination thereof.

11. The process of claim 10 , wherein:

the coupling catalyst of step (3) is a palladium catalyst;

the suitable base of step (3) is sec-butylamine or tetrabutylammonium fluoride (TBAF); and

step (3) is performed at a temperature of about 40-45° C.

12. The process of claim 10 , further comprising:

(4) contacting the compound of Formula 21 with a suitable reagent in a suitable solvent to provide (S)-1-(3-(5,6-dihydroxypyrimidin-4-yl)-2-(4-((4-(morpholinomethyl)phenyl)ethynyl)phenyl)propyl)azetidine-3-carbonitrile (Compound A):

wherein:

the suitable reagent of step (4) is H 2 /catalyst, HCl, HBr, TFA, TBAF, BCl 3 , 9-I-BBN, BF 3 -OEt 2 , TMS-Cl, or TMS-Br; and

the suitable solvent of step (4) is acetonitrile, dichloromethane, chloroform, dichloroethane, diethyl ether, tetrahydrofuran, isopropyl alcohol, 1,4-dioxane, toluene, anisole, water, or a combination thereof.

13. The process of claim 12 , wherein:

PG is benzyl;

the suitable reagent of step (4) is TFA; and

the suitable solvent of step (4) is anisole.

14. The process of claim 12 , further comprising crystallizing Compound A from acetonitrile, methanol, ethanol, isopropyl alcohol, acetone, methyl acetate, ethyl acetate, dichloromethane, chloroform, diethyl ether, diisopropyl ether, tert-butyl methyl ether, tetrahydrofuran, 2-methyltetrahydrofuran, dioxane, benzene, toluene, petroleum ether, pentane, hexane, heptane, cyclohexane, acetic acid, water, or a mixture thereof.

15. The process of claim 10 , wherein the compound of Formula 21 is Compound 21A:

16. A reaction mixture comprising a compound of Formula 14:

wherein X is halogen, —OTf, —OTs, or —OMs; and each PG is methyl, benzyl, p-methoxybenzyl, methoxymethyl, [2-(trimethylsilyl)ethoxylmethyl, triisopropylsilyl, or tert-butyldimethylsilyl;

an oxidation reagent system comprising TEMPO and NaClO (bleach); and

a solvent comprising acetonitrile, dichloromethane, chloroform, dichloroethane, hexanes, water, or a combination thereof.

17. A reaction mixture comprising a compound of Formula 17:

wherein X is halogen, —OTf, —OTs, or —OMs; and each PG is methyl, benzyl, p-methoxybenzyl, methoxymethyl, [2-(trimethylsilyl)ethoxylmethyl, triisopropylsilyl, or tert-butyldimethylsilyl;

a palladium catalyst;

sec-butyl amine; and

a solvent comprising acetonitrile, dimethylformamide, diethyl ether, ethanol, tetrahydrofuran, isopropyl alcohol, 1,4-dioxane, toluene, water, or a combination thereof.

18. A compound selected from:

or a salt thereof.