MXPA99004459A - Process for substituted pyridines - Google Patents

Abstract

This invention relates to processes for preparing compounds of formula (I) which are&bgr;-adrenergic receptor agonists, and to processes for preparing certain intermediates of formula (IIA) wherein R1 is nitro, amino or protected amino;R2 is H, fluoro, chloro CF3, nitro, (C1-C4)alkyl, (C1-C4)alkoxy, amino or protected amino;and X1 is OH or a suitable leaving group, used in that process. The invention also relates to novel compounds of the formulae (II).

Description

PROCEDURE FOR SUBSTITUTE PYRIDES BACKGROUND OF THE INVENTION The present invention relates to certain compounds of the formula (IIA), represented below, which are useful in the synthesis of certain β-adrenergic receptor agonists having the general formula wherein R1 and R2 are as defined herein for the compound of formula (IIA) appearing below, and Y1, Y2 and Y3 are chemical SUBSTITUTES that can bind to the atoms to which they are attached. These SUBSTITUTES confer β-adrenergic receptor activity and, as such, the compounds of formula (I) have utility as hypoglycemic and anti-obesity agents. In PCT Publication No. WO 94/29290 published on December 22, 1994, examples of such SUBSTITUTES and the resulting β-adrenergic receptor agonists can be found. The invention also relates to a process for synthesizing the compounds of the formula (II) shown below and to a process for synthesizing compounds of the formula (III), which are useful in the synthesis of the compounds of the formula (I). The invention also relates to processes for synthesizing compounds of formula (I). Β-adrenergic receptor agonists also have utility for increasing the deposition of lean meat and / or iving the ratio between lean meat and fat in edible animals. Β-adrenergic receptor agonists also have utility in the treatment of intestinal motility disorders, depression, prostate disease, dyslipidemia, and inflammatory airway disorders, such as asthma and obstructive pulmonary disease. The diabetes mellitus disease is characterized by metabolic defects in the production and / or utilization of carbohydrates, which lead to the inability to maintain appropriate levels of blood sugar. The result of these defects is an elevated blood glucose level or hyperglycemia. Research in the treatment of diabetes has focused on attempts to normalize fasting and postprandial blood glucose levels. Current treatments include the administration of exogenous insulin, oral administration of drugs and dietary therapies. Two main forms of diabetes mellitus are recognized. Type I diabetes, or insulin-dependent diabetes, is the result of an absolute deficiency of insulin, the hormone that regulates the use of carbohydrates. Type II diabetes, or non-insulin-dependent diabetes, often occurs with normal or even elevated levels of insulin and appears to be the result of the tissues' inability to respond appropriately to insulin. The majority of Type II diabetics are also obese. Β-adrenergic receptor agonists decrease blood glucose levels effectively when administered orally to mammals with hyperglycemia or diabetes. Β-adrenergic receptor agonists also reduce body weight or decrease weight gain when administered to mammals. The ability of ß-adrenergic receptor agonists to affect weight gain is due to the activation of ß-adrenergic receptors that stimulate adipose tissue metabolism. The ß-adrenergic receptors have been classified into subtypes ß-i, ß2 and ß3. The β-receptor agonists promote the activation of adenyl cyclase. The activation of the ßi receptors implies increases in the cardiac rhythm, while the activation of the ß2 receptors induces the relaxation of the skeletal muscle tissue, which produces a drop in blood pressure and the beginning of smooth muscle tremors. It is known that the activation of ß3 receptors stimulates lipolysis (the breakdown of adipose tissue triglycerides to glycerol and free fatty acids) and the metabolic rate (energy expenditure) and, therefore, promotes the loss of fat mass. Thus, compounds that stimulate the β-receptors are useful as anti-obesity agents and can also be used to increase the content of lean meat in edible animals. In addition, compounds that are β3 receptor agonists have hypoglycemic or antidiabetic activity, but the mechanism of this effect is unknown. Until recently, it was thought that ß3-adrenergic receptors were predominantly found in adipose tissue. It is now known that ß3 receptors are located in various tissues such as the intestine (J. Clin. Invest., 9J., 344 (1993)) and the brain (Eur. J. Pharm., 219. 193 (1992)) . It has been demonstrated that the stimulation of the β3 receptor causes the relaxation of the smooth muscle in the colon, in the trachea and in the bronchi. Life Sciencies, 44 (19), 141 1 (1989); Br. J. Pharm., 112, 55 (1994); Br. J: Pharmacol., 1 10. 1311 (1993). For example, it has been observed that the stimulation of the β3 receptors induces the relaxation of the guinea pig ileum contracted with histamine, J. Pharm. Exp. Ther., 260. 1, 192 (1992). The β3 receptor is also expressed in the human prostate. Since stimulation of the β3 receptor causes relaxation of smooth muscles in which β3 receptor expression has been demonstrated (eg, the intestine), one skilled in the art could predict smooth muscle relaxation of the prostate. Therefore, β3 agonists will be useful for the treatment or prevention of prostate disease. Examples of β3-adrenergic receptor agonists can be found which can be synthesized using the compounds of formula (III), in PCT Publication No. WO 94/29290, published December 22, 1994, in the United States Patent Application. No. 08 / 312,027, filed September 26, 1994, in PCT Patent Application No.

PCT / IB95 / 00344, filed May 10, 1995 and in United States Provisional Patent Application No. 60 / 015,216, filed April 9, 1996, all of which are assigned to the assignee of this document. With respect to the process for synthesizing a compound of formula (II) wherein X is OH, defined below, of the present invention, the chemical literature indicates that the addition of osmium tetroxide to olefins, including the olefinic radical of allylic acid and of stearyl compounds, results in the addition of two OH groups to the double bond, adding an OH group to each of the carbon atoms that constitute the double bond, (see Advanced Organic Chemistry, March, John Wiley and Sons, NY , NY, 1985, 3rd ed.) Two OH groups can also be added to double bonds by reacting the compound containing the double bond with (i) hydrogen peroxide and catalytic amounts of osmium tetroxide, (ii) alkaline potassium permanganate; (Ii) hydrogen peroxide and formic acid; or (iv) silver iodine and benzoate. All these methods suffer from the disadvantages that they do not react stereospecifically with a prochiral carbon atom of the double bond to create an optically active dihydroxy compound. U.S. Patent No. 5,019,578, describes a process for preparing epoxydipyrin compounds. This process involves the hydroxy bromination of a 5-ethynyl pyridine derivative followed by cyclization to form the epoxide, and suffers from the disadvantage that the bromohydrin is prepared in the form of a racemic mixture.

BRIEF DESCRIPTION OF THE INVENTION This invention provides compounds of the formula wherein: R1 is selected from the group consisting of nitro, amino and protected amino; R 2 is selected from the group consisting of H, fluoro, chloro, CF 3, nitro, (C 1 -C 4) alkyl, (C 1 -C 4) alkoxy, amino and protected amino; and X1 is OH or a suitable leaving group; racemic mixtures thereof; R enantiomers thereof, wherein said R-enantiomers essentially lack their corresponding S-enantiomers; and S enantiomers thereof where said S-enantiomers essentially lack their corresponding R-enantiomers. Specifically, this invention provides a compound as described in the immediately preceding paragraph, wherein X 1 is OH. More specifically, this invention provides a compound as described in the immediately preceding paragraph, wherein said protected amino, each time it appears, is independently selected from the group consisting of alkylamino (C -? - C8), - NR3CO ( CH2) PR °, - NR3CO2R ° and -NR3SO2 (CH2) PR °; R3, each time it appears, is independently, H or alkyl (C? -C6); R °, each time it appears, is independently (C 1 -C 10) alkyl, phenyl or phenyl SUBSTITUTE independently with one or three (C 1 -C 4) alkyl, (C 1 -C 4) alkoxy or halo; and p is 0, 1 or 2. Even more specifically, this invention provides compounds as described in the immediately preceding paragraph, wherein R2 is H. Even more specifically, this invention provides compounds as described in the immediately preceding paragraph. , wherein R1 is amino; -NR3CO- alkyl (C? -C10), -NR3CO2alkyl (C8) or NR3CO (CH2) PR0. Even more specifically, this invention provides compounds as described in the immediately preceding paragraph, in which R1 and amino or -NR3CO- alkyl (C Cio). Still more specifically, this invention provides N- (5- (1,2-dihydroxyethyl) -pyridin-2-yl) acetamide. In addition, this invention provides the R-enantiomer of N- (5- (1,2-dihydroxyethyl) -pyridin-2-yl) acetamide, essentially without its corresponding S-enantiomer. Furthermore, this invention provides the S-enantiomer of N- (5) - (1,2-dihydroxyethyl) -pyridin-2-yl) acetamide, essentially without its corresponding R-enantiomer. This invention further provides compounds of the formula (IIA) above, wherein X 1 is a leaving group, said leaving group is organosulfonyloxy and said organosulfonyloxy is methanesulfonyloxy, benzenesulfonyloxy, p-toluenesulfonyloxy, p-nitrobenzenesulfonyloxy or m-nitrobenzenesulfonyloxy. More specifically, this invention provides the compounds described in the immediately preceding paragraph wherein said organosulfonyloxy is p-toluenesulfonyloxy. More specifically, this invention provides compounds as described in the immediately preceding paragraph, wherein said protected amino, each time it appears, is independently selected from the group consisting of alkylamino (C? -C8), -NR3CO (CH2) pR0, -NR3CO2R ° and -NR3SO2 (CH2) PR0; R3, each time it appears, is independently, H or alkyl (C Cß); R °, each time it appears, is independently (C1-C10) alkyl, phenyl or phenyl SUBSTITUTE independently from one to three (C1-C4) alkyl, (C1-C4) alkoxy or halo; or halo; and p is 0.1 or 2. Even more specifically, this invention provides compounds as described in the immediately preceding paragraph, wherein R2 is H. Even more specifically, this invention provides compounds as described in the paragraph immediately. above, wherein R1 is amino, -NR3CO-alkyl (CC? 0), -NR3CO2alkyl (C? -8) or NR3CO (CH2) PR.sub.0. Still more specifically, this invention provides compounds as described in the immediately preceding paragraph, wherein R1 is amino or -NR3CO- (C1-C10) alkyl.

Still more specifically, this invention provides 2- (6-acetylamino-pyridin-3-yl) -2-hydroxyethyl ester of toluene-4-sulfonic acid. In addition, this invention provides the R-enantiomer of 2- (6-acetylamino-pyridin-3-yl) -2-hydroxyethyl ester of toluene-4-sulfonic acid, essentially without its corresponding S-enantiomer. In addition, this invention provides the S enantiomer of 2- (6-acetylamino-pyridin-3-yl) -2-hydroxyethyl ester of toluene-4-sulfonic acid, essentially without its corresponding R-enantiomer. This invention also provides N- (5- (2-chloro-1-hydroxyethyl) -1-pyridin-2-yl) -acetamide. In addition, this invention provides the R-enantiomer of N- (5- (2-chloro-1-hydroxyethyl) -1-pyridin-2-yl) -acetamide, essentially without its corresponding S-enantiomer. In addition, this invention provides the S-enantiomer of N- (5- (2-cyoro-1-hydroxyethyl) -1-pyridin-2-yl) -acetamide, essentially without its corresponding R-enantiomer. This invention also provides compounds of the formula wherein: R1 is selected from the group consisting of nitro, amino and protected amino; R 2 is selected from the group consisting of H, fluoro, chloro, CF 3, nitro, (C 1 -C 4) alkyl, (C 1 -C 4) alkoxy, amino and protected amino; and X1 is chlorine or iodine; racemic mixtures thereof; enantiomers R thereof, wherein said R-enantiomers essentially lack their corresponding S-enantiomers; and S-enantiomers thereof, wherein said S-enantiomers essentially lack their corresponding R-enantiomers. Specifically, the invention provides compounds as described in the immediately preceding paragraph wherein X 1 is chloro and said compound is an R-enantiomer essentially without its corresponding S enantiomer. This invention also specifically provides compounds as described in the immediately preceding paragraph, wherein X 1 is chloro and said compound is an S-enantiomer essentially without its corresponding R-enantiomer. The invention also provides compounds of the formula. wherein: R1 is selected from the group consisting of nitro, amino and protected amino; R 2 is selected from the group consisting of H, fluoro, chloro, CF 3, nitro, (C 1 -C 4) alkyl, (C 1 -C 4) alkoxy, amino and protected amino; X1 is Br; and said compound is an enantiomer (R) essentially without its corresponding (S) enantiomer.

The invention also provides compounds of the formula IIA wherein: R1 is selected from the group consisting of nitro, amino and protected amino R2 is selected from the group consisting of H, fluoro, chloro, CF3, nitro, (C1-C4) alkyl, (C1-C4) alkoxy, amino and amino protected; X1 is Br; and said compound is an enantiomer (S) essentially without its corresponding (R) enantiomer. The invention also provides compounds of the formula VII wherein: R 12 is selected from the group consisting of nitro and protected amino; R13 is selected from the group consisting of H, fluoro, chloro, CF3, nitro (C1-C4) alkyl, (C1-C4) alkoxy and protected amino; Y 4 is an amine protecting group; and Y5 is or where Q1 is oxygen, nitrogen or sulfur; Q2 is carbon or nitrogen; Q3 is hydrogen, - (CH2) n-phenyl, -alkyl (C? -C10), - (CH2) n -NG1G2, - (CH2) n -CO2G3, - (CH2) n -CO-NG1G2, - (CH2) ) n-OG3, - (CH2) n-SO3G3, - (CH2) nS? 2-alkyl (C? -Cβ) - (CH2) n-SO2NG1G2, or a heterocycle selected from the group consisting of - (CH2) n -pyridide, - (CH2) n-pyrimidyl, - (CH2) np -razinyl, - (CH2) n-isoxazolyl, - (CH2) n-oxazolyl, - (CH2) n-thiazolyl, - (CH2) n- ( 1, 2,4-oxadiazolyl), - (CH 2) n-imidazolyl, - (CH 2) n -triazolyl and - (CH 2) n-tetrazolyl; wherein one of the ring nitrogen atoms of said - (CH2) n-imidazolyl, - (CH2) n-triazolyl and - (CH2) n-tetrazolyl may be optionally substituted with optionally substituted (C? -C8) alkyl independently with one or more halo atoms; wherein each of said heterocycles may be optionally substituted on one or more of the carbon atoms of the ring, with no or more substituents independently selected from the group consisting of alkyl (C? -C8), optionally independently substituted with one or more halo atoms, halo, nitro, cyano, - (CH2) n-NG1G2, - (CH2) n -CO2G3, - (CH2) n -CO-NG1G2, - (CH2) n- OG3, - (CH2) n-SO3G3, - (CH2) n-SO2-alkyloid-Ce) and - (CH2) n-SO2NG1G2, where a phenyl radical of said - (CH2) n-phenyl may be optionally substituted with one or more substituents independently selected from the group consisting of alkyl (Cr Ce) optionally independently substituted with one or more halo atoms, hydroxy, (d-Cβ) alkoxy optionally substituted independently with one or more halo atoms, alkylthio (Ci-Cβ) ), fluoro, chloro, bromo, iodo, cyano, nitro, - (CH2) n-NG1G2, - (CH2) n -CO2G3, - (CH2) n-CO-NG1G2, - (CH2) n -OG3, - ( CH2) n-SO3G3, - (CHzin-SOs-alkyloid-Ce), - (CH2) n-SO2NG1G2; - (CH2) n-NG3-SO2-G3 and - (CH2) n-NG3-S? 2-NG1G2, Q4 is - (CH2) n-CN, - (CH2) n-CO2G3, - (CH2) n- SO3G3, - (CH2) n-SO2-alkyl (C? -C-6), - (CH2) n-SO2NG1G2, - (CH2) n-CH2OH, - (CH2) n-CHO, - (CH2) n- CO-G3, - (CH2) n-CONG1G2 or a heterocycle selected from - (CH2) n-thiazolium, - (CH2) n-oxazolyl, - (CH2) n-imidazolyl, - (CH2) n-triazolyl, - ( CH2) n-1, 2,4-oxadiazolyl, - (CH2) n-isoxazolyl, - (CH2) n-tetrazolyl, and - (CH2) n-pyrazolyl; wherein one of the ring nitrogen atoms of said - (CH2) n-imidazolyl, - (CH2) n-triazolyl and - (CH2) n-tetrazolyl may be optionally substituted with optionally substituted (C-? - C6) alkyl independently with one or more halo atoms; wherein each of said heterocycles may be optionally substituted on one or more of the ring carbon atoms, with no or more substituents independently selected from the group consisting of (C? -C6) alkyl, optionally independently substituted with one or more atoms of halo, - (CH2) n-NG1G2, - (CH2) n-CO2G3, halo, nitro, cyano, - (CH2) n-CO-NG1G2, - (CH2) n-OG3, - (CH2) n-SO3G3 , - (CH2) n-SO2-alkyl (C? -C-6) or - (CH2) n-SO2NG1G2, Q5 is hydrogen or (C? -C6) alkyl optionally substituted independently with one or more halo atoms; Q6 is a covalent bond, oxygen or sulfur; Q7 is hydrogen or (dCS) alkyl optionally substituted independently with one or more halo atoms; Q8 and Q9 are, independently, a covalent bond, oxygen, sulfur, NH or -N-alkyl (C? -C6); Q10 is - (CH2) n-OR9, - (CH2) n -CO2H, - (CH2) n-COR11, - (CH2) n-SO2NR9R10, - (CH2) n-NR9SO2R8, - (CH2) nP (O) (OR4) (OR5), - (CH2) nO- (CH2) mCO2H, - (CH2) nO- (CH2) m-COR11, - (CH2) nO- (CH2) mP (O) (OR4) (OR5) , - (CH2) nO- (CH2) m-SO2NR9R10 or - (CH2) nO- (CH2) m-NR9SO2R8; R4 and R5 are each independently hydrogen or alkyl (C-i-Cß); and R6 and R7 are each, independently, hydrogen, halo, (C? -C6) alkyl, nitro, cyano, trifluoromethyl, SO2R8, SO2NR9R10, NR9R10, COR11, CO2R9, alkoxy (C? -C6), NR9SO2R8, NR9COR11, NR9CO2R9 or OR9; where G1 and G2, each time they appear, are each, independently, hydrogen, alkyl (Ci-Cß) optionally independently substituted with one or more halo, (C? -C8) alkoxy (C-? - C6) alkyl or cycloalkyl (C3-C8), or G1 and G2, together with the nitrogen to which they are attached, form a saturated heterocyclic ring having from 3 to 7 carbon atoms, where one of said carbon atoms can be optionally replaced with oxygen, nitrogen or sulfur; G3, each time it appears, is independently hydrogen or alkyl (C? -C6); R8, each time it appears, is independently alkyl (C -? - C6) or (C -? - C6) alkoxy (C -? - C6) alkyl; R9 and R10 are taken separately and each time they appear, they are independently hydrogen, (C? -C6) alkyl, (C3-C8) cycloalkyl or (C? -C6) alkoxy (C-? C6) alkyl; or R9 and R10 are taken together with the nitrogen atom to which they are attached and form a pyrrolidine, piperidine or morpholine ring wherein said pyrrolidine, piperidine or morpholine ring may be optionally substituted at any carbon atom with (C1-C4) alkyl ) or (C1-C4) alkoxy; R11, each time it appears, is independently hydrogen, alkyl (C? -C6), alkoxy (C? -C6), NR9R10, cycloalkyl (C3-C8) or alkoxy (d-C6) alkyl (d-C?), Where R8 and R10 are as defined above; m, each time it appears, is independently an integer from 1 to 6; and n, each time it appears, is independently 0 or an integer from 1 to 6; racemic mixtures thereof; R enantiomers thereof, wherein said R-enantiomer essentially lacks its corresponding S-enantiomer; and S enantiomers thereof, wherein said S-enantiomer essentially lacks its corresponding R-enantiomer; with the proviso that: (1) when Q9 is O or S, then n is not O; (2) when Q1 is oxygen or sulfur, then Q3 is absent; and (3) when Q2 is nitrogen, then Q5 is absent.

Specifically, the invention provides the compounds described in the immediately preceding paragraph wherein Y4 is an amine protecting group selected from the group consisting of benzyl, COR14, CO2R14 and SO2R14; and R14, each time it appears, is independently (C1-C10) alkyl, phenyl or benzyl; wherein said phenyl and benzyl are independently and optionally substituted with one to three (C 1 -C 4) alkyl, (C 1 -C 4) alkoxy or halo. More specifically, the invention provides the compounds described in the immediately preceding paragraph, in which Y5 is Even more specifically, this invention provides the compounds described in the immediately preceding paragraph, wherein R13 is H and R12 is protected amino; said protected amino is independently selected from the group consisting of alkylamino (d-C8), - NR3CO (CH2) PR °, -NR3CO2R ° and -NR3SO2 (CH2) pR °; R3 is, independently, H or alkyl (d-C6); R ° is independently alkyl (d-C-io), phenyl or phenyl independently substituted with one or three (C 1 -C 4) alkyl, (C 1 -C 4) alkoxy or halo; and p is 0, 1 or 2.

Even more specifically, this invention provides the compounds described in the immediately preceding paragraph, wherein said protected amino is -NR3CO (CH2) pR °, R3 is H; R ° is CH3; and p is 0. Still more specifically, this invention provides the compounds described in the immediately preceding paragraph, wherein R 4, R 5, R 6 and R 7 are each hydrogen; Q8 is oxygen; Q9 is a covalent bond; and Q10 is (CH2) mCONR9R10. Even more specifically, this invention provides the compounds described in the immediately preceding paragraph, wherein Y 4 is t-butyloxycarbonyl; m is 1; R9, is H; and R10 is methyl.

Even more specifically, this invention provides the compounds described in the immediately preceding paragraph, which have the formula.

Even more specifically, this invention provides the compounds described in the immediately preceding paragraph, which are R-enantiomers. Even more specifically, this invention provides N-methyl 4- (2- (2- (2-acetylaminopyridin-5-yl) - 2- (R) -hydroxyethyl-N-tert-butyloxycarbonylamino) -ethoxy) -phenylacetamide. This invention also provides a process for preparing compounds of the formula SAW wherein: R1 is selected from the group consisting of nitro, amino and protected amino; and R2 is selected from the group consisting of H, fluoro, chloro, CF3, nitro, alkyl (d-C4), alkoxy (d-C4), amino and protected amino, which comprises reacting a compound of the formula V wherein R1 and R2 are as defined above, with a catalyst comprising an osmium oxide (VIII) or an osmium salt, and an auxiliary oxidizing agent, in a solvent inert to the reaction. The invention also provides a method as described in the immediately preceding paragraph, which further comprises reacting said compounds of formula (V) with said osmium oxide (HIV) or said osmium salt, in the presence of an auxiliary chiral ligand and an auxiliary base. Specifically, this invention provides a method of the immediately preceding paragraph, wherein said auxiliary chiral ligand is (DHQD) 2PHAL. More specifically, this invention provides a method of the immediately preceding paragraph, wherein said compound of formula (VI) has R configuration at position 1 of the 5-ethyl group, said compound essentially lacking its corresponding S-enantiomer.

Even more specifically, this invention provides a method of the immediately preceding paragraph, wherein R 1 is acetylamino and R 2 is H. Even more specifically, this invention provides a process for preparing compounds of the formula SAW wherein: R1 is selected from the group consisting of nitro, amino and protected amino; and R2 is selected from the group consisting of H, fluoro, chloro, CF3, nitro, alkyl (C -? - C), (C1-C4) alkoxy, amino and protected amino, which comprises reacting a compound of the formula V with a catalyst comprising an osmium oxide (HIV) or an osmium salt, and an auxiliary oxidizing agent, in the presence of an auxiliary chiral ligand and an auxiliary base, in a solvent inert to the reaction, wherein said auxiliary chiral ligand is (DHQD) 2PHAL.

More specifically, this invention provides a method of the immediately preceding paragraph, wherein said compound of formula (VI) has an S configuration at the 1-position of the 5-ethyl group, said compound essentially lacking its corresponding R-enantiomer. Even more specifically, this invention provides a method of the immediately preceding paragraph, wherein R1 is acetylamino and R2 is H. This invention also provides a process for preparing a compound of the formula (I). and the racemic-enantiomeric mixtures and optical isomers of said compounds, comprising: (a) reacting a compound of the formula VI with organosulfonyl chloride and a suitable base, in a solvent inert to the reaction, to form a compound of the formula p (b) reacting said compound of formula II with a non-nucleophilic base, in a solvent inert to the reaction, to form a compound of the formula (III) ; and m (c) reacting said compound of formula (III) with a base and HNY2Y3 to form said compound of formula (I) wherein: R1 is selected from the group consisting of nitro, amino and protected amino; R 2 is selected from the group consisting of H, fluoro, chloro, CF 3, nitro, alkyl (d-d), (C 1 -C 4) alkoxy, amino and protected amino; and Y is Br, I or trifluoromethanesulfonyloxy; and X is organosulfonyloxy; Y1 and Y3 are H; Y2 is where: Q1 is oxygen, nitrogen or sulfur; Q2 is carbon or nitrogen; Q3 is hydrogen, - (CH2) n-phenyl, -alkyl (d-C10), - (CH2) n-NG1G2, - (CH2) n -CO2G3, - (CH2) n -CO- NG1G2, - (CH2) n-OG3, - (CH2) n-SO3G3, - (CH2) n-SO2-alkyl (C6-6), - (CH2) n-SO2NG1G2 or a heterocycle selected from the group consisting of - (CH2) n- pyridyl, - (CH2) n-pyrimidyl, - (CH2) n-pyrazinyl, - (CH2) n-isoxazolyl, - (CH2) n-oxazolyl, - (CH2) n-thiazolyl, - (CH2) n- (1, 2,4-oxadiazolyl), - (CH 2) n-imidazoyl, - (CH 2) n-.triazolyl and - (CH 2) n-tetrazolyl; wherein one of the ring nitrogen atoms of said - (CH2) n-imidazolyl, - (CH2) n -.triazolyl and - (CH2) n-tetrazolyI can optionally be substituted with optionally substituted (CrC8) alkyl with one independently or more halo atoms; wherein each of said heterocycles may be optionally substituted on one or more of the ring carbon atoms, with one or more substituents independently selected from the group consisting of (d-C8) alkyl, optionally independently substituted with one or more ring atoms halo, halo, nitro, cyano, - (CH2) n- NG1G2, - (CH2) n -CO2G3, - (CH2) n -CO- NG1G2, - (CH2) n-OG3, - (CH2) n-SO3G3, - (CH2) n-SO2-alkyl (C6) and - (CH2) n-SO2NG1G2; wherein the phenyl radical of said - (CH2) n-fßn¡lo may be optionally substituted with one or more substituents independently selected from the group consisting of (d-Cß) alkyl optionally substituted independently with one or more halo, hydroxy atoms, alkoxy (d-Cß) optionally independently substituted with one or more halo atoms, alkylthio (CrC6), fluoro, chloro, bromo, iodo, cyano, nitro, - (CH2) n- NG1G2, - (- CH2) n-CO2G3 , - (CH2) n-CO-NG1G2, - (CH2) n-OG3, - (CH2) n-SO3G3, - (CH2) n-SO2-alkyl (d-C6), - (CH2) n-SO2NG1G2; - (CH2) n-NG3-S? 2 -G3 and - (CH2) n-NG3-SO2-NG1G2; Q4 is - (CH2) n-CN, - (CH2) n -CO2G3, - (CH2) n- SO3G3 '- (CH2) n-SO2-alkyl (d-C6), - (CH2) n-SO2NG1G2; - (CH2) nCH2OH, - (CH2) nCHO, - (CH2) n -CO- G3, - (CH2) n- CONG1G2 or a heterocycle selected from - (CH2) n-thiazolyl, - (CH2) n-oxazolyl, - (CH2) n-imidazolyl, - (CH2) n-triazolyl, - (CH2) n-1, 2,4-oxadiazolyl, - (CH2) n-isoxazolyl, - (CH2) n-tetrazolyl and - (CH2) n-pyrazolyl; wherein one of the ring nitrogen atoms of said - (CH2) n-imidazolyl, - (CH2) n-triazolyl and - (CH2) n-tetrazolyl may be optionally substituted with optionally substituted (d-Cß) alkyl independently with one or more halo atoms; wherein each of said heterocycles may be optionally substituted, on one or more of the carbon atoms of the ring, with one or more substituents independently selected from the group consisting of hydrogen, optionally independently substituted (D-C6) alkyl with one or more halo atoms, - (CH2) n-CO-NG G2; - (CH2) n-CO2G3; halo, nitro, cyano, - (CH2) n-SO2NG1G2; - (CH2) n-OG3; - (CH2) n-SO3G3; - (CH2) n-SO2-alkyl (d-C6) or - (CH2) n-SO2NG1G2 Q5 in hydrogen or (Ci-Cd) alkyl optionally substituted independently with one or more halo atoms; Q6 is a covalent bond, oxygen or sulfur; Q7 is hydrogen or (dCS) alkyl optionally substituted independently with one or more halo atoms; Q8 and Q9 are, independently, a covalent bond, oxygen, sulfur, NH or -N-alkyl (d-C6); Q10 is (CH2) m-OR9, (CH2) n-CO2H, (CH2) n-OR11, (CH2) n- SO2NR9R10, (CH2) n-NR9SO2R8, (CH2) nP (O) (OR4) (OR5) , (CH2) nO- (CH2) m- CO2H, (CH2) nO- (CH2) m- COR11, (CH2) nO- (CH2) mP (O) (OR4) (OR5), (CH2) n- O - (CH2) m-SO2NR9R10 or - (CH2) nO- (CH2) m-NR9SO2R8; R4 and R5 are each, independently, hydrogen or alkyl (C? -C6); and R6 and R7 are each, independently, hydrogen, halo, (d-C6) alkyl, nitro, cyano, trifluoromethyl, SO2R8, SO2NR9R10, NR9R10, COR11, CO2R9, alkoxy (d-C6), NR9SO2R8, NR9COR11, NR9CO2R9 or OR9; where G1 and G2, each time they appear, are each independently hydrogen, alkyl (d-Cß) optionally independently substituted with one or more halo, (C? -C8) alkoxy (d-C6) alkyl or (C3-C8) cycloalkyl ), or G1 and G2 together with the nitrogen to which they are attached form a saturated heterocyclic ring having from 3 to 7 carbon atoms, where one of said carbon atoms can be optionally replaced with oxygen, nitrogen or sulfur; G3, each time they appear is independently hydrogen or alkyl (d-C6); R8, each time it appears, is independently alkyl (d-C6) or alkoxy (d-Cß) alkyl (d-Cß); R9 and R10, each time they appear, are independently hydrogen, alkyl (d-C6), cyclo (C3-C8) alkyl or alkoxy (d-C6) alkyl (C6C6); R11, each time it appears, are independently hydrogen, (C6) alkyl, (C6-6) alkoxy, NR9R10, (C3-C8) cycloalkyl or R10, each time they appear, are independently hydrogen, alkyl (CI-CT) ), (C3-C8) alkyl or (C6-6) alkoxy (C6) alkoxy group R10, each time they appear, are independently hydrogen, (d-C6) alkyl, (C3-C8) alkyl or alkoxy ( C? -C6) alkyl (d-C6), where R9 and R10 are as defined above; m, each time it appears, is independently an integer from 1 to 6; and n, each time it appears, is independently an integer from 1 to 6; with the proviso that: (1) when Q9 is O or S, then n is not 0; (2) when Q1 is oxygen or sulfur, then Q3 is absent; and (3) when Q2 is nitrogen, then Q5 is absent. Still more specifically, this invention provides a process as described in the immediately preceding paragraph, wherein said organosulfonyloxy is methanesulfonyloxy, benzenesulfonyloxy, p-toluenesulfonyloxy, p-nitrobenzenesulfonyloxy. or m-nitrobenzenesulfonyloxy. This invention also provides a process for preparing compounds of the formula p wherein: and R1 is selected from the group consisting of nitro, amino and protected amino; R 2 is selected from the group consisting of H, fluoro, chloro, CF 3, nitro (C 1 -C 4) alkyl or (C 1 -C 4) alkoxy, amino and protected amino; and X is organosulfonyloxy, which comprises: reacting a compound of the formula vi wherein R1 and R2 are as defined above, with organosulfonyl chloride and a suitable base in a reaction-inert solvent. In addition, this invention provides a process for preparing compounds of the formula and the racemic-enatiomeric mixtures and optical isomers of said compounds, comprising: (a) reacting a compound of the formula p with a non-nucleophilic base, in a solvent inert to the reaction, to form a compound of the formula (III) m (b) reacting said compound of formula (III) with a base and HNY2Y3 to form said compound of formula (I), wherein R1 is selected from the group consisting of nitro, amino and protected amino; R2 is selected from the group consisting of H, fluoro, chloro, CF3, nitro (d-C4) alkyl, (C1-C4) alkoxy, amino and protected amino; and X is an organosulfonyloxy group; Y1 and Y3 are H; Y2 is where: Q1 is oxygen, nitrogen or sulfur; Q2 is carbon or nitrogen; Q3 is hydrogen, - (CH2) n-phenyl, -alkyl (C1-C10), - (CH2) n-NG1G2, - (CH2) n -CO2G3, - (CH2) n -CO-NG1G2, - (CH2) n-OG3, - (CH2) n-SO3G3, - (CH2) n-SO2-alkyl (d-Cß), - (CH2) n-SO2NG1G2 or a heterocycle selected from the group consisting of (CH2) n-pyridyl, - (CH2) n-pyrimidyl, - (CH2) n-pyrazinyl, - (CH2) n-isoxazolyl, - (CH2) n-oxazolyl, - (CH2) n-thiazolyl, - (CH2) n- (1, 2 , 4-oxadiazolyl), - (CH2) n-imidazolyl, - (CH2) n-triazolyl and - (CH2) n-tetrazolyl; wherein one of the ring nitrogen atoms of said - (CH2) n-imidazolyl, - (CH2) n-triazolyl and - (CH2) n-tetrazolyl may be optionally substituted with optionally substituted (C? -C8) alkyl independently with one or more halo atoms; wherein each of said heterocycles may be optionally substituted on one or more of the ring carbon atoms, with one or more substituents independently selected from the group consisting of alkyl (CrC8) optionally independently substituted with one or more halo atoms, halo , nitro, cyano, - (CH2) n-NG1G2, - (CH2) n-CO2G3, - (CH2) n-CO-NG1G2, - (CH2) n-OG3, - (CH2) n-SO3G3, - (CH2 ) n-SO2-alkyl (d-Cß), and - (CH2) n-SO2NG1G2 wherein the phenyl radical of said - (CH 2) n -phenyl may be optionally substituted with one or more substituents independently selected from the group consisting of (d-Cß) alkyl optionally independently substituted with one or more halo, hydroxy, alkoxy atoms ( d-Cß) optionally independently substituted with one or more halo atoms, alkylthio (d-Cß), fluoro, chloro, bromo, iodo, cyano, nitro, - (CH 2) n-NG 1 G 2, - (CH 2) n -CO 2 G 3, - (CH2) n-CO-NG1G2, - (CH2) n-OG3, - (CH2) n-SO3G3, - (CH2) n-SO2-alkyl (C6), and - (CH2) n-SO2NG1G2; - (CH2) n-NG3-SO2-G3 and - (CH2) n-NG3-SO2-NG1G2; Q4 is - (CH2) p-CN, - (CH2) n -CO2G3, - (CH2) n- SO2G3 -alkyl (d-C6), - (CH2) n-SO2NG1G2; - (CH2) n-NG3-SO2-G3 and - (CH2) n-NG3-SO2-NG1G2; - (CH2) n-SO2- alkyl (d-C6), - (CH2) n-SO2NG1G2; - (CH2) n-CH2OH, - (CH2) n-CHO, - (CH2) n-CO-G3, - (CH2) n-CONG1G2 or a heterocycle selected from - (CH2) n-thiazolyl, - (CH2) n-oxazolyl, - (CH2) n-imidazolyl, - (CH2) n-triazolyl, - (CH2) n-1,2,4-oxadiazolyl, - (CH2) n-isoxazolyl, - (CH2) n-tetrazolyl and - (CH2) n-pyrazolyl; wherein one of the ring nitrogen atoms of said - (CH2) n-imidazolyl, - (CH2) n-triazolyl and - (CH2) n-tetrazolyl may be optionally substituted with optionally substituted (D-C6) alkyl with one or more halo atoms; wherein each of said heterocycles may be optionally substituted, on one or more of the carbon atoms of the ring, with one or more substituents independently selected from the group consisting of hydrogen, optionally independently substituted (D-C6) alkyl with one or more halo atoms, - (CH2) n-CO-NG1G2, - (CH2) n-CO2G3, halo, nitro, cyano, - (CH2) n-CO-NG G2, - (CH2) n-OG3, - (CH2 ) n-SO3G3, - (CH2) n-SO2-alkyl (d-C6), or - (CH2) n-SO2NG1G2; Q5 is hydrogen or (C? -C6) alkyl optionally substituted independently with one or more halo atoms; Q6 is a covalent bond, oxygen or sulfur; Q7 is hydrogen or alkyl (CI-CT) optionally independently substituted with one or more halo atoms; Q8 and Q9 are, independently, a covalent bond, oxygen, sulfur, NH or -N-alkyl (d-C6); Q10 is - (CH2) n-OR9, - (CH2) n -CO2H, - (CH2) n-COR11, - (CH2) n-SO2NR9R10; - (CH2) n-NR9SO2-R8, - (CH2) n-P (O) (OR4) (OR5); - (CH2) n-O- (CH2) m -CO2H, - (CH2) n- O- (CH2) m-COR11, - (CH2) n-O- (CH2) m -P (O) (OR4) (OR5); - (CH2) n-O- (CH2) m-SO2-NR9R10; or - (CH2) n-O- (CH2) m-NR9SO2-R8; R4 and R5 are each, independently, hydrogen or alkyl (CrCe); and R6 and R7 are each, independently, hydrogen, halo, (d-C6) alkyl, nitro, cyano, trifluoromethyl, SO2R8, SO2NR9R10, NR9R10, COR11, CO2R9, alkoxy (C6), NR9SO2R8, NR9COR11, NR9CO2R9 or OR9; where G1 and G2, each time they appear, are each independently hydrogen, (d-Cß) alkyl optionally substituted independently with one or more halo, (C? -C8) alkoxy (d-C) alkyl or (C3-C8) cycloalkyl ), or G1 and G2, together with the nitrogen to which they are attached form a saturated heterocyclic ring having from 3 to 7 carbon atoms, where one of said carbon atoms can optionally be replaced by oxygen or sulfur; G3, each time it appears, is independently hydrogen or alkyl (C? -C6); R8, each time it appears, is independently alkyl (d-C6) or alkoxy (d-Cß) alkyl (d-Cß); R9 and R10, each time they appear, are independently hydrogen, alkyl (d-C6), cycloalkyl (C3-C8) or alkoxy (d-C6) alkyl -Cβ; R11, each time it appears, is independently hydrogen, alkyl (d-C6), alkoxy (C6), NR9R10, cycloalkyl (C3-C8) or alkoxy (d-C6) alkyl (C6-6), where R9 and R10 are as defined above; m, each time it appears, is independently an integer from 1 to 6; and n, each time it appears, is independently 0 or an integer from 1 to 6; with the proviso that: (1) when Q9 is O or S, then n is not 0; (2) when Q1 is oxygen or sulfur, then Q3 is absent; Y (3) when Q2 is nitrogen, then Q5 is absent. Specifically, this invention provides a process as described in the immediately preceding paragraph, wherein said organosulfonyloxy is methanesulfonyloxy, benzenesulfonyloxy, p-toluenesulphonyloxy, p-nitrobenzenesulfonyloxy or m-nitrobenzenesulfonyloxy. In addition, this invention provides a process for preparing compounds of the formula (I) and the racemic-enantiomeric mixtures and optical isomers of said compounds, comprising: (a) reacting a compound of the formula with organosulfonyl chloride and a suitable base, in a solvent inert to the reaction, to form a compound of the formula (b) reacting said compound of formula (II) with a chlorinating agent in a reaction inert solvent to form a compound of the formula (VII) Vile (c) reacting said compound of formula (VII) with a nucleophilic base in a solvent inert to the reaction to form a compound of the formula (III) (d) reacting said compound of formula (III) with a base of and HNY2Y3 to form said compound of formula (I); wherein: R1 is selected from the group consisting of nitro, amino and protected amino; R 2 is selected from the group consisting of H, fluoro, chloro, CF 3, nitro, (C 1 -C 4) alkyl, (C 1 -C 4) alkoxy, amino and protected amino; and X is organosulfonyloxy; Y1 and Y3 are H; Y2 is where: Q1 is oxygen, nitrogen or sulfur; Q2 is carbon or nitrogen; Q3 is hydrogen, - (CH2) n-phenyl, -alkyl (d-C10), - (CH2) n- NG1G2, - (CH2) n-CO2G3, - (CH2) n-CO-NG1G2, - (CH2) n-OG3, - (CH2) n-SO3G3, - (CH2) n- SO3G3, - (CH2) n-SO2-alkyl (C6), - (CH2) n- SO2NG1G2 or a heterocycle selected from the group consisting of - (CH2) n-pyrimidyl, - (CH2) n-pyrazinyl, - (CH2) n-isoxazolyl, - (CH) n-oxazolyl, - (CH2) n-thiazolyl, - (CH2) n- (1, 2 , 4-oxadiazolyl), - (CH 2) n-imidazolyl, (CH 2) n -triazoyl and (CH 2) n-tetrazolyl; wherein one of the ring nitrogen atoms of said - (CH2) n-imidazolyl, - (CH2) n-triazolyl and - (CH2) n-tetrazolyl may be optionally substituted with optionally substituted (D-Cß) alkyl with one or more halo atoms; wherein each of said heterocycles may be optionally substituted on one or more of the ring carbon atoms, with one or more substituents independently selected from the group consisting of (d-C8) alkyl, optionally independently substituted with one or more ring atoms halo, halo, nitro, cyano, - (CH2) n-NG1G2, - (CH2) n-CO2G3, - (CH2) n-CO-NG1G2, - (CH2) n-OG3, - (CH2) n-OG3, - (CH2) n-SO3G3, - (CH2) n-SO2-alkyl (d-C6) and - (CH2) n-SO2NG1G2; wherein the phenyl radical of said - (CH2) n-phenyl may be optionally substituted with one or more substituents independently selected from the group consisting of (d-C6) alkyl optionally substituted independently with one or more halo, hydroxy, alkoxy atoms ( d-Cβ) optionally independently substituted with one or more halo atoms, alkylthio (d-Cß), fluoro, chloro, bromo, iodo, cyano, nitro, - (CH 2) n-NG 1 G 2, -. (CH 2) n -CO 2 G 3 , - (CH2) n-CO-NG1G2, - (CH2) n-OG3, - (CH2) n-SO3G3, - (CH2) nSO2-alkyl (C6), - (CH2) n-SO2NG1G2; - (CH2) n-NG3-SO2-G3 and - (CH2) n-NG3-SO2-NG1G2; Q4 is - (CH2) n-CN, - (CH2) nCO2G3, - (CH2) n-SO3G3, - (CH2) n-SO2-alkyl (d-C6), - (CH2) n-SO2NG1G2, - (CH2 ) nCH2OH, - (CH2) n-CHO, - (CH2) n-CO-G3, - (CH2) n-CONG1G2 or a heterocycle selected from - (CH2) n-thiazolyl, - (CH2) n-oxazolyl, - (CH2) n-imidazolyl, - (CH2) n-triazolyl, - (CH2) n-1, 2,4-oxadiazolyl, - (CH2) n-isoxazolyl, - (CH) n-tetrazolyl and - (CH2) n -pyrazolyl; wherein one of the ring nitrogen atoms of said - (CH2) n-imidazolyl, - (CH2) p-triazolyl and - (CH2) n-tetrazolyl may be optionally substituted with optionally substituted (d-Cß) alkyl independently with one or more halo atoms; wherein each of said heterocycles may be optionally substituted, on one or more of the carbon atoms of the ring, with one or more substituents independently selected from the group consisting of hydrogen, optionally independently substituted (D-Cß) alkyl with one or more halo atoms, - (CH2) n-CO-NG1G2, - (CH2) n-CO2G3, halo, nitro, cyano, - (CH2) n-CO-NG1G2, - (CH2) n-OG3, - (CH2) n- SO3G3, - (CH2) n-SO2-alkyl (d-C6) or - (CH2) n-SO2NG1G2; Q5 is hydrogen or (C? -C6) alkyl optionally substituted independently with one or more halo atoms, Qd is a covalent bond, oxygen or sulfur; Q7 is hydrogen or (d-C6) alkyl optionally substituted independently with one or more halo atoms; Q8 and Q9 are, independently, a covalent bond, oxygen, sulfur, NH or -N-alkyl (d-Cß); Q10 is - (CH2) m-OR9, - (CH2) n -CO2H, (CH2) n-COR11, - (CH2) n-SO2NR9R10, - (CH2) n-NR9SO2R8, - (CH2) nP (O) ( OR4) (OR5), - (CH2) nO- (CH2) m -CO2H, - (CH2) nO- (CH2) m-COR11, - (CH2) nO- (CH2) mP (O) (OR4) (OR5 ), - (CH2) nO- (CH2) n-SO2NR9R10 or - (CH2) nO- (CH2) m-NR9SO2R8; R4 and R5 are each, independently, hydrogen or alkyl (d-C6); and R6 and R7 with each, independently, hydrogen, halo, (d-C6) alkyl, nitro, cyano, trifluoromethyl, SO2R8, SO2NR9R10, COR11, CO2R9, alkoxy (C? -C6), NR9SO2R8, NR9COR11, NR9CO2R9 or OR9; where G1 and G2, each time they appear, are each independently hydrogen; (d-C6) alkyl optionally substituted independently with one or more halo, alkoxy, (C? -C8) alkyl (CI-CT) or cycloalkyl (C3-C8), or G1 and G2 together with the nitrogen to which they are attached form a saturated heterocyclic ring having from 3 to 7 carbon atoms, wherein one of said carbon atoms can optionally be replaced by oxygen, nitrogen or sulfur; G3, whenever it appears, is independently hydrogen or alkyl (d-C6); R8, each time it appears, is independently alkyl (dC6) or alkoxy (C6C6) alkyl (dC6); R9 and R10, each time it appears, is independently hydrogen, alkyl (d-C6) cycloalkyl (C3-C8) or alkoxy (d-C6) alkyl (C6C6); R11, each time it appears, is independently hydrogen, alkyl (Ci-Ce), alkoxy (C6), NR9R10, cycloalkyl (C3-C8) or alkoxy (C6) alkyl (d-C6), where R9 and R10 are as defined above; m, each time it appears, is independently an integer from 1 to 6; and n, each time it appears, is independently 0 or an integer from 1 to 6; with the proviso that: (1) when Q9 is O or S, then n is not 0; (2) when Q1 is oxygen or sulfur, then Q3 is absent; Y (3) when Q2 is nitrogen, then Q5 is absent. Specifically, this invitation provides a method as described in the immediately preceding paragraph, wherein said coloring agent is lithium chloride and said organosulfonyloxy is selected from the selected group consisting of methanesulfonyloxy, p-nitrobenzenesulfonyloxy or m-nitrobenzenesulfonyloxy. In addition, this invention provides a process for preparing compounds of the formula and the racemic-enantiomeric mixtures and optical isomers of said compounds, comprising: (a) reacting a compound of the formula with an organosulfonyl chloride and a suitable base in a reaction inert solvent to form a compound of the formula (II), (b) reacting said compound of formula (II) with a non-nucleophilic base in a solvent inert to the reaction to form a compound of formula (III) (c) reacting said compound of formula (III) with a base and HNY2Y3 to form said compound of formula (I); wherein: R1 is selected from the group consisting of nitro, amino and protected amino; R 2 is selected from the group consisting of H, fluoro, chloro, CF 3, nitro, (C 1 -C 4) alkyl, (C 1 -C 4) alkoxy, amino and protected amino; and X is an organosulfonyloxy group; Y1 and Y3 are H, Y2 is where: Q1 is oxygen, nitrogen or sulfur; Q2 is carbon or nitrogen; Q3 is hydrogen, - (CH2) n-phenyl, -alkyl (d-C10), - (CH2) n- NG1G2, - (CH2) n-CO2G3, - (CH2) n-CO-NG1G2, - (CH2) n-OG3, - (CH2) n-SO3G3, - (CH2) n-SO3G3, - (CH2) n-SO2-alkyl (C? -C), - (CH2) n- SO2NG1G2 or a heterocycle selected from the group composed of - (CH2) n-pyrimidyl, - (CH2) n-pyrazinyl, - (CH2) n-isoxazolyl, - (CH2) n-oxazolyl, - (CH2) n-thiazolyl, - (CH2) n- (1 , 2,4-oxadiazolyl), - (CH2) p-imidazolyl, (CH2) n-triazolyl and (CH2) n-tetrazolyl; wherein one of the ring nitrogen atoms of said - (CH2) n-imidazolyl, - (CH2) n-triazolyl and - (CH2) n-tetrazolyl may be optionally substituted with optionally substituted (C? -C6) alkyl independently with one or more halo atoms; wherein each of said heterocycles may be optionally substituted on one or more of the ring carbon atoms, with one or more of the ring carbon atoms, with one or more substituents independently selected from the group consisting of alkyl (C? -C8), optionally independently substituted with one or more halo atoms, halo, nitro, cyano, - (CH2) n-NG1G2, - (CH2) n -CO2G3, - (CH2) n -CO-NG1G2, - (CH2 ) n-OG3, - (CH2) n-SO3G3, - (CH2) nSO2-alkyl (C? -C6) and - (CH2) n-SO2NG1G2; wherein the phenyl radical of said - (CH2) n-phenyl may be optionally substituted with one or more substituents independently selected from the group consisting of (d-C6) alkyl optionally independently substituted with one or more halo, hydroxy, alkoxy dC atoms ?) optionally independently substituted with one or more halo, alkyl (d-C6), fluoro, chloro, bromo, iodo, cyano, nitro, - (CH2) n-NG1G2, - (CH2) n-CO2G3 atoms, - (CH2) n-CO-NG1G2, - (CH2) n-OG3, - (CH2) n-SO3G3, - (CH2) n-SO2-alkyl (C? -C6), - (CH2) n-SO2NG G2; - (CH2) n-NG3-SO2-G3 and - (CH2) n-NG3-SO2-NG1G2; Q4 is - (CH2) n-CN, - (CH2) nCO2G3, - (CH2) n-SO3G3, - (CH2) n-SO2-alkyl (C? -Cβ), - (CH2) n-SO2NG1G2, - ( CH2) NCH2OH, - (CH2) n-CHO, - (CH2) n-CO-G3, - (CH2) n-CONG1G2 or a heterocycle selected from - (CH2) n-thiazolyl, - (CH2) n- oxazolyl, - (CH2) n-imidazolyl, - (CH2) n-triazolyl, - (CH2) n-1, 2,4-oxadiazolyl, ~ (CH2) n -soxazolyl, - (CH2) n-tetrazolyl and - (CH2) n-pyrazolyl; wherein one of the nitrogen atoms of the said ring - (CH2) n-m -dazolyl, - (CH2) n-triazolyl and - (CH2) n-tetrazolyl may optionally be substituted with alkyl (C6-6) optionally independently substituted with one or more halo atoms; wherein each of said heterocycles may be optionally substituted, on one or more of the ring carbon atoms, with one or more substituents independently selected from the group consisting of hydrogen, alkyl (d-C6) optionally independently substituted with one or more halo atoms, - (CH2) n-NG1G2, - (CH2) n- CO2G3, halo, nitro, cyano, - (CH2) n-CO-NG1G2, - (CH2) n-OG3, - (CH2) n-SO3G3, - (CH2) n-SO2-alkyl (C6C6) or - (CH2) n-SO2NG1G2; Q5 is hydrogen or alkyl (d-C6) optionally independently substituted with one or more halo atoms; Q6 is a covalent bond, oxygen or sulfur; Q7 is hydrogen or (d-C6) alkyl optionally substituted independently with one or more halo atoms; Q8 and Q9 are, independently, a covalent bond, oxygen, sulfur, NH or -N-a! Qu (d-C6); Q10 is - (CH2) m-OR9, - (CH2) n -CO2H, - (CH2) n-COR11, - (CH2) n- S02NR9R1 °, - (CH2) n-NR9SO2R8, - (CH2) nP (O ) (OR4) (OR5), - (CH2) n-0- (CH2) m -CO2H, - (CH2) nO- (CH2) m-COR11, - (CH2) nO- (CH2) mP (O) ( OR) (OR5), - (CH2) nO- (CH2) m-SO2NR9R10 or - (CH2) nO- (CH2) m-NR9SO2R8; R4 and R5 are each, independently, hydrogen or alkyl (C? -C6); and R6 and R7 are each, independently, hydrogen, halo, (C? -C6) alkyl, nitro, cyano, trifluoromethyl, SO2R8 SO2NR9R10, NR9R10, COR11, CO2R9, alkoxy (d-C6), NR9SO2R8, NR9COR11, NR9CO2R9 or OR9; where G1 and G2, each time they appear, are each independently hydrogen, alkyl (CrC6) optionally independently substituted with one or more halo, (C? -C8) alkoxy (C? -C6) alkyl or cycloalkyl (dd), or G1 and G2 together with the nitrogen to which they are attached form a saturated heterocyclic ring having from 3 to 7 carbon atoms, wherein one of said carbon atoms can optionally be replaced by oxygen, nitrogen or sulfur; G3, whenever it appears, is independently hydrogen or alkyl (d-C6); R8, each time it appears, is independently alkyl (d-C6) or alkoxy (C6C6) alkyl (C6C6); R9 and R10, each time they appear, are independently hydrogen, C alquilo-alkyloid), (C3-C8) cycloalkyl or (C?-C6) alkoxy (C?-C6) alkyl; R11, each time it appears, is independently hydrogen, alkyl (d-C6), alkoxy (C6), NR9R10, cycloalkyl (C3-C8) or alkoxy (C6) alkyl (C6-6), where R9 and R10 are as defined above; m, each time it appears, is independently an integer from 1 to 6; and n, each time it appears, is independently 0 or an integer from 1 to 6; with the proviso that: (1) when Q9 is 0 or S, then n is not 0; (2) when Q1 is oxygen or sulfur, then Q3 is absent; and (3) when Q2 is nitrogen, then Q5 is absent. Specifically, this invention provides a process as described in the immediately preceding paragraph, wherein said organosulfonyloxy is methanesulfonyloxy, benzenesulfonyloxy, p-toluenesulfonyloxy, p-netrobenzenesuifonyloxy or m-nitrobenzenesulfonyloxy. This invention also provides a process for preparing a compound of the formula (XIII) ffl which comprises reacting a compound of the formula (XIV) XIV wherein: PG is an amine protecting group; R20 is alkyl (d-C8); R21 is selected from the group consisting of alkyl (C? -C8), COR22, CO2R22 and SO2R22; and R22 is (C? -C8) alkyl with an aqueous acid to form said compound of formula XIII. Specifically, this invention provides a method as described in the immediately preceding paragraph, wherein said amine protecting group is selected from the group consisting of COR22, CO2R22 and SO2R22; and R22 is alkyl (d-C8). More specifically, this invention provides a method as described in the immediately preceding paragraph, wherein said compound of formula XIV is N-methyl 4- (2- (2- (2-acetylaminopyridin-5-yl) -2 (R ) -hydroxyethyl-N-tert-butoxycarbonyl-amino) -ethoxy) -pheniacetamide. In addition, this invention provides a process for preparing a compound of the formula XIII comprising: (a) reacting a compound of the formula wherein R21 is COR22 and R22 is? alkyl (C? -C8), with a compound of the formula XVI wherein R20 is (C? -C8) alkyl, in a reaction inert solvent, to form a compound of formula XVI (b) reacting said compound of formula (XVI) with an acid anhydride, a dicarbonate or an acid chloride to form a compound of the formula XIV wherein R20 and R21 are as defined above and PG is an amine protecting group, and (c) reacting said compound of formula (XIV) with an aqueous acid to form said compound of formula (XIII). Specifically, this invention provides a method as described in the immediately preceding paragraph, wherein said amine protecting group is selected from the group consisting of COR22 and CO2R22; and R22 is alkyl (d-C8).

More specifically, this invention provides a process as described in the immediately preceding paragraph, wherein said compound of formula (XIV) is reacted with a dicarbonate. Even more specifically, this invention provides a process as described in the immediately preceding paragraph, wherein R21 is acetyl, R20 is methyl and PG is tert-butyloxycarbonyl. This invention is also specifically directed to any of the above-mentioned processes wherein said compounds of formulas (II), (III) or (VI) have the (R) configuration, said compounds essentially lacking their (S) -enantiomer. This invention is also specifically directed to any of the aforementioned processes wherein said compounds of formulas (II), (III) or (VI) have the (S) configuration, said compounds essentially lacking their (R) -enantiomer.

DETAILED DESCRIPTION OF THE INVENTION A process for the manufacture of a compound of formula (I), as defined above, is provided as a feature of the invention, and is illustrated by the following procedure indicated in Scheme 1, wherein the meanings of the radicals generic are as described below unless otherwise specified.

SCHEME 1 VI p m i The processes for the manufacture of a compound of formula (II) as defined above, are illustrated by the following procedures. The compounds of formula (I) can be synthesized from compounds of formula (II) by reaction with an amine of formula HNY2Y3, with H2NY2 being the preferred amine. This reaction is typically performed by the reaction of an amine of formula HNY2Y3 with an epoxide of formula (III) in a polar aprotic solvent such as dimethyl sulfoxide, dimethyl formamide, acetonitrile or a lower alkanol such as ethanol, 2-propanol or butanol, at a teature of about -10 ° C to about 125 ° C. Preferably, the solvent is dimethyl sulfoxide and the reaction is carried out at a teature from about 0 ° C to about 10 ° C. If the compound (III) was prepared in a stereospecific manner, such as when an auxiliary chiral ligand is used in the step of preparing the compound of formula (VI), the optical purity of the product, compound (I), will be retained. Alternatively, to prepare the compounds of formula (I) when Y2 is H, the amine of formula H2NY3 can be pretreated with an appropriate amine protecting group. It is preferred to react said amine with N- (trimethylsilyl) acetamide to form a silylated compound of the formula (CH3) 3SiNHY3. This prevents the secondary amine obtained as a product of the reaction from reacting with a second epoxide molecule. This reaction is typically carried out in a polar aprotic solvent such as dimethyl sulfoxide, dimethyl formamide, acetonitrile or in a lower alkanol such as ethanol, 2-propanol or butanol, at a teature of about -10 ° C to about 125 ° C. Preferably, the silylation is carried out at about 25 ° C and the reaction with the epoxide is carried out at about 60 ° C. After completing the silylation, the compound of the formula (CH 3) 3S / NH 3 is reacted with the epoxide of the formula (III) as described above. It is often desirable, when carrying out the coupling reaction of the epoxide of formula (III) with the amine of the formula H2NY3, to react the coupled product of the formula (XI) XI with an organic acid anhydride, a dicarbonate or an organic acid chloride to form a compound of the formula (XII) xp wherein R1, R2 and Y2 are as defined herein and PG is an amine protecting group. The term "amine protecting group" includes an organic radical that readily bonds to an amine nitrogen atom and blocks the reaction of said nitrogen atom with the reagents and substrates used., and with the intermediate and transition state molecules formed in the subsequent chemical transformations. Said organic radical can be easily removed under mild conditions. When used herein, the phrase "mild conditions" defines conditions that can remove a protecting group but have no effect on any other part of the substrate to which said protecting group is attached. The compounds of formula (XII) are converted, by reaction with an aqueous acid, into compounds of formula (I) wherein R 1 is nitro or amino; R 2 is H, fluoro, chloro, CF 3, nitro, (C 1 -C 4) alkyl, (C 1 -C 4) alkoxy and amino; and Y2 is as defined above, wherein all the amine and carboxyl radicals contained within Y2 are free bases and free acid forms of said amine and carboxyl radicals. Said reaction with aqueous acid is carried out with an aqueous acid such as sulfuric acid, hydrochloric acid and the like, at a temperature of about 25 ° C to about 100 ° C, for one to forty-eight hours. Preferably, the aqueous acid is hydrochloric acid and a reaction temperature of about 90 ° C to about 100 ° C is maintained for about twenty-four hours.

The compounds of formula (III) can be prepared by treating a compound of formula (11) with a non-nucleophilic base. Generally, it is preferred to select the non-nucleophilic base from the group consisting of sodium hydroxide, potassium hydroxide, sodium hydride, potassium tert-butoxide or 1,8-diazabicyclo [5.4.0] undec-7-ene. The reaction is preferably carried out by stirring the substrate compound of formula (II) together with the appropriate non-nucleophilic base, in a solvent inert to the reaction, at a temperature of from about -20 ° C to about 100 ° C. When used herein, the term "solvent inert to the reaction" refers to any solvent that does not interact with the starting materials, reagents, intermediates or products, in a manner that adversely affects the reaction or yield of the desired product. In addition, the term solvent inert to the reaction can refer to a simple, dual or multiple solvent system, depending on the nature of the reaction and the solubility of the substrate and / or reagents being described. With respect to this particular reaction, it is preferred that the solvent be a polar, non-hydroxylated solvent, such as an ether derivative, including (but not limited to) tetrahydrofuran, dioxane, and dimetixethane; chlorinated hydrocarbons including (but not limited to) carbon tetraeloride, chloroform and methylene chloride; aromatic hydrocarbons including (but not limited to) benzene, toluene and xylene; dimethylformamide; dimethyl sulfoxide or any mixture of these solvents. Generally, the most preferred solvent is tetrahydrofuran.

When the compounds of formula (II) described herein are organosulfonyloxy derivatives, said compounds can be prepared by reaction of the appropriate compound of formula (VI) with an organosulfonyl chloride in the presence of a suitable base. Suitable bases that can be used to perform this transformation include the lower trialkylamines, pyridine and pyridine derivatives. Preferred bases within these groups include (but are not limited to) triethylamine, diisopropylethylamine, 2,4,6-collidine and 2,6-lutidine. Pyridine is the most preferred base. Suitable organosulfonyl chlorides include methanesuifonyl chloride, p-nitrobenzenesulfonyl chloride, m-nitrobenzenesulfonyl chloride, p-toluenesulfonyl chloride, and benzenesulfonyl chloride. A generally preferred organosulfonyl chloride derivative is p-toluenesulfonyl chloride. The reaction is conveniently carried out by stirring the desired substrate compound of formula (VI) together with the appropriate organosulfonyl chloride, in a solvent inert to the reaction, at a temperature of about -20 ° C to about 50 ° C. It is preferred that the solvent be a polar solvent such as an ether derivative including (but not limited to) tetrahydrofuran, dioxane dimethoxyethane; chlorinated hydrocarbons, including (but not limited to) carbon tetraeloride, chloroform and methylene chloride; aromatic hydrocarbons including (but not limited to) benzene, toluene or xylene; dimethylformamide; N-methyl-2-pyrrolidinone; dimethylacetamide; pyridine or any mixture of these solvents. Generally, the most preferred solvent is pyridine. Due to the presence of chloride in this reaction, the reaction product can be contaminated with 2-chloro derivatives. These mixtures can be completely converted to the 2-chloro derivatives as described below. To prepare the compounds of formula (I IA) wherein X 1 is halo, the 2-organosulfonyloxy derivatives of the compound of formula (II) are reacted, or mixtures thereof containing 2-chloro derivatives of formula (IIA ), with a halogenating agent in a solvent inert to the reaction. The reaction can be conveniently carried out at a temperature of about 25 ° C at the reflux temperature of the solvent used. It is generally preferred to carry out the reaction at the reflux temperature. Halogenating agents are compounds that are capable of transferring a halo group to an organic substratesaid substrate having a leaving group which can be displaced by said halide ion. The preferred halogenating agents are lithium halides. A particularly preferred chlorinating agent used to prepare the compounds of formula (VII) is lithium chloride. A preferred solvent is ethanol. The compounds of formula (VI) described herein can be prepared by the reaction of an appropriate compound of formula (V) with a catalyst composed of osmium oxide (HIV) or an osmium salt, in the presence of an auxiliary oxidizing agent and , optionally, in the presence of an auziliary chiral ligand such as (DHQD) 2PHAL or (DHQD) 2PYR and an auxiliary base. When it is desirable to use a catalyst other than osmium oxide (HIV) in this reaction, the catalyst is generally selected from metallic osmium, potassium osmium (VI) dihydrate, and osmium chloride (II). Generally, it is preferred to use osmium tetroxide as a catalyst when this reaction is carried out. The auxiliary oxidizing agents that can be used include (but are not limited to) potassium ferricyanide, sodium ferricyanide, potassium persulfate, sodium persulfate, potassium chlorate, sodium chlorate and N-methylmorpholine N-oxide (the latter oxidizing agent can only be used in the absence of chiral auxiliary ligands such as (DHQD) 2PHAL or (DHQD) 2PYR). Also can . it is desirable to use a mixture of auxiliary oxidizing agents to achieve optimum performance in this reaction. A particularly suitable mixture of auxiliary oxidizing agents is sodium persulfate and potassium ferricyanide. The chiral auxiliary ligands that may be used, in addition to those already mentioned, include hydroquinidine indolinyl disolether ((DHQD) IND), hydroquinine diethyl phthalazinadiyl ((DHQ) 2PHAL), hydroquinine pyrimidinadiyl ether ((DHQ) 2PYR), indolinadiyl diether of hydroquinine ((DHQ) IND), fenantrinadiii hydroquinidine diether (DHQD-PHN) and fenantrinadiil hydroquinine diether (DHQ-PHN). The reaction is typically carried out by stirring the desired substrate compound of formula (V) together with the appropriate reagents mentioned above, in a polar solvent, at a temperature of about -10 ° C to about 70 ° C. The reaction is conveniently carried out at about 20 ° C. Polar solvents that are generally useful in this reaction include water, a lower alkanol, an ether or a mixture of any of these solvents. A lower alkanol is an alcohol containing one to four carbon atoms. The dihydroxylation reaction described in the preceding paragraph can be carried out in the presence or absence of an auxiliary chiral ligand. When the reaction is carried out in the absence of an auxiliary chiral ligand, the diol product is racemic. When the reaction is carried out in the presence of an auxiliary chiral ligand, the dihydroxylation reaction is carried out stereoselectively, resulting in an essentially optically pure diol product. The compounds of formula (V) described herein can be prepared by reacting a compound of formula (IV) with ethylene gas in the presence of a base, a phosphine derivative and a paiadium catalyst. Suitable bases for the reaction include lower trialkylamines, sodium carbonate, potassium carbonate, sodium bicarbonate and potassium bicarbonate. Triethylamine is generally preferred. Suitable phosphine derivatives include triarylphosphines such as triphenylphosphine, diphenyl-2-pyridylphosphine and tri-ortho-tolylphosphine, the latter being especially preferred. When Y is iodo, the palladium catalyst may be selected from a variety of salts and palladium complexes such as (but not limited to) palladium metal on carbon or other suitable solid support, allyl palladium chloride dimer, palladium chloride (II) ), palladium (II) acetate, palladium (0) tetrakis (triphenylphosphine), bis (triphenylphosphine) palladium chloride (II), palladium (0) bis (dibenzylideneacetone) and palladium (0) bis (benzonitrile). When Y is bromine or trifluoromethanesulfonyloxy, the palladium catalyst may be selected from a variety of salts and palladium complexes such as (but not limited to) allyl palladium chloride dimer, palladium (II) chloride, palladium acetate (II) , palladium (0) tetrakis (triphenylphosphine), bis (triphenylphosphine) palladium (II) chloride, palladium (0) bis (dibenzylideneacetone), palladium (0) bis (benzonitrile) and allyl palladium chloride dimer. Palladium (II) acetate is especially preferred. The reaction is typically carried out by stirring the compound of formula (IV) together with the reagents mentioned above in a polar solvent at a temperature from about 20 ° C to about 150 ° C, under an ethylene atmosphere at a pressure of about 101.3. kPa at approximately 10.13 kPa. Preferred polar solvents for use in this reaction include (but are not limited to) ethers, such as tetrahydrofuran, dimethoxyethane and dioxane; lower trialkylamines, such as triethylamine, diisopropylethylamine and tributylamine; Arimatic hydrocarbons, such as benzene, toluene and xylene; dimethylformamide; N-methyl-2-pyrrolidone; acetonitrile; dimethylacetamide or a mixture of any of these solvents. Acetonitrile is an especially preferred solvent. The compounds of formula (I), wherein R1 and R2 are as defined above, and Y1, Y2 and Y3 are chemical substituents that can bind to the atoms to which they are attached, are agonists of β-adrenergic receptors and, as such, have utility as agents hypoglycemic and against obesity. In PCT Publication No. WO 94/29290 published on December 22, 1994, examples of such substituents and the resulting β-adrenergic receptor agonists can be found. The compounds of formula (XIV) can be prepared from compounds of formula (I), wherein R 1 is -NHCO- (d-C 6) alkyl; R2 and Y3 are each H and Y2 is by reacting said compound of formula (I) with an acylating agent such as an acid anhydride of the formula (C 1 -C 6) -CO) 2 O alkyl, an acid chloride of the formula alkyl (d-Cß) - COCI or a dicarbonate of the formula (alkyl (C? -C6) -O-CO) 2-O, in a solvent inert to the reaction, at a temperature from about 0 ° C to about 150 ° C for 1 to 48 hours . Suitable inert reaction solvents for this reaction include aromatic hydrocarbons including (but not limited to) benzene, toluene and xylene; dimethylsulfoxide; N, N-dimethylformamide; chlorinated hydrocarbons including (but not limited to) methylene chloride, chloroform and carbon tetraeloride; ether solvents such as diethyl ether, tetrahydrofuran and dioxane, or any mixture of these solvents. When a dicarbonate is used as an acylating agent, it is generally preferred to use a mixture of toluene and dimethylsulfhoxide as a solvent mixture. Preferably, this reaction is carried out at a temperature of about 70 ° C to 95 ° C. The compound of formula (XIII) can be prepared from compounds of formula (XIV) by reacting said compounds of formula (XIV) with an aqueous acid such as sulfuric acid, hydrochloric acid and the like, at a temperature of about 25 °. C at approximately 100 ° C, for a period of one hour to forty-eight hours. Preferably, the aqueous acid is hydrochloric acid and a reaction temperature of about 90 ° C is maintained for approximately twenty-four hours. Those skilled in the art will appreciate that the compounds of formulas (II) and (IV) contain at least one chiral center. Accordingly, these compounds can exist and can be isolated in optically active and racemic forms. Some compounds may exhibit polymorphism. It is to be understood that the present invention encompasses all racemic, optically active, polymorphic and stereoisomeric forms, or any mixture thereof, forms possessing properties useful in the treatment of the diseases or conditions indicated herein, or may be useful as intermediates. in the preparation of any compound useful in the treatment of said diseases or conditions, it being well known in the art how to prepare optically active forms (for example, by resolution of the racemic form by recrystallization techniques, by synthesis from starting materials optically active, by chiral synthesis or by chromatographic separation using a chiral stationary phase) and how to determine the efficiency for the treatment of said utilities. In general, stereochemistry (R) is preferred in all chiral centers in the compounds described in this invention. Conventional methods and / or techniques of purification and separation known to those skilled in the art may be used to isolate the compounds of this invention. Such techniques include all types of chromatography, including (but not limited to) high performance liquid chromatography, column chromatography using common sorbents such as silica gel, thin layer chromatography and the like; recrystallization; and differential extraction techniques (ie, liquid-liquid). As used in the specification and the appended claims, the following terms have the meanings described. The terms "alkyl" and "alkoxyl" include both straight and branched chain radicals, but it is to be understood that references to individual radicals, such as propyl or propoxy, encompass only the straight chain radical, unless specifically referred to, for example , isopropyl or isopropoxy, in which case the branched chain isomer is understood. The term halo, unless otherwise indicated, includes chlorine, fluorine, bromine and iodine. The terms "Ad-mix-A" and "Ad-mix-" are synonyms for a reagent used in this invention and marketed by Aldrich Chemical Co. The reagent contains the chiral ligand (DHQ) 2PHAL, the potassium osmate (VI) catalyst dihydrate, the auxiliary oxidizing agent potassium ferricyanide and the potassium carbonate base. The reagent is used in the asymmetric dihydroxylation of olefins. The reagent is marketed by Aldrich under a license from Sepracor, Inc. of Marlborough, Massachusetts. (see the Aldrich catalog, 1996-97, page 444). The terms "Ad-mix-A" and "Ad-mix-a" are synonyms for a reagent used in this invention and marketed by Aldrich Chemical Co. The reagent contains the chiral ligand (DHQD) 2PHAL, the osmate catalyst (VI) potassium dihydrate, the auxiliary oxidizing agent potassium ferricyanide and the potassium carbonate base. The reagent is used in the asymmetric dihydroxylation of olefins. The reagent is marketed by Aldrich under a license from Sepracor, Inc. of Marlborough, Massachusetts. (See the Aldrich catalog, 1996-97, page 444). The term "protected amino" includes an amine nitrogen atom, for example, RNH2 or R2NH, to which a protecting group is attached. The term "protecting group" defines an organic radical that can be easily joined and separated from said nitrogen atom, said group not being susceptible to reaction or degeneration by other substrates or reagents used to transform other functional groups within the molecule to which is attached said nitrogen atom, by intermediates or transition state molecules formed during such reactions. Said protective group can be easily attached and removed under mild conditions. Preferred amino protecting groups include alkylamino (d-C8), -NR3CO (CH2) p-R ° and -NR3CO2R ° and -NR3SO2 (CH2) pR0; where R °, R3 and p are as defined above. The term "suitable leaving group" includes a group that can be easily displaced by a nucleophile having a greater affinity for the positively charged carbon atom to which said leaving group is attached than said leaving group. The preferred leaving groups are chloro and organosulfonyloxy groups. Particularly preferred leaving groups are organosulfonyloxy groups. Particularly preferred organosulfonyloxy groups are methanesulfonyloxy, benzenesulfonyloxy, p-toluenesulfonyloxy, p-nitrobenzenesulfonyloxy or m-nitrobenzenesulfonyloxy. The term "suitable base" includes a base which, when added to the reaction mixture in which that base will act, increases the pH of the reaction mixture or exerts its action on the substrate, eliminating a proton from said substrate. or, otherwise, causes said substrate susceptible to nucleophilic attack without affecting other potentially reactive functional groups on said substrate. The term "pharmaceutically acceptable acid addition salts" is intended to include (but is not limited to) salts such as hydrochloride, hydrobromide, sulfate, bisulfate, phosphate, bisphosphate, dibiphosphate, acetate, succinate, citrate, methanesulfonate (mesylate), and -toluenesulfonate (tosylate) The acid addition salts of the compounds of the present invention are readily prepared by reacting the basic forms of the compounds described in this invention with an appropriate acid. When the salt is a monobasic acid (for example, the hydrochloride, the hydrobromide, the p-toluenesulfonate or the acetate), the hydrogenated form of a dibasic acid (for example, the bisulfate or the succinate) or the dihydrogenated form of a tribasic acid (eg, dibiphosphate or citrate), at least one molar equivalent and usually a molar excess of the acid is employed. However, when salts such as sulfate, hemisuccinate, hydrogen phosphate or phosphate are desired, the appropriate and exact chemical equivalents of acid will generally be used. The free base and the acid are usually combined in a co-solvent in which the desired salt precipitates or it can be otherwise isolated by concentration and / or addition of a non-solvent, by simple addition of a non-solvent without concentration or by lyophilization of an aqueous solution of said salt. If not available in the market, the starting materials necessary for the chemical reactions described herein can be prepared by methods that can be selected from conventional organic chemistry techniques found in the literature of conventional organic chemistry textbooks. The techniques found herein can be applied directly to the synthesis of the known starting materials described directly in this literature reference, or they can be applied by analogy with compounds having similar functionality to achieve predictable results. In the examples shown below, common chemical abbreviations and acronyms are used. These acronyms and abbreviations include BOC, which means tert-butoxycarbonyl; Cbz, which means benzyloxycarbonyl; THF, which means tetrahydrofuran; DMF, which means dimethylformamide; NMP, which means N-methyl-2-pyrrolidinone; DMAC, which means N, N-dimethylacetamide; DME, which means 1,2-dimethoxyethane; DMSO, which means dimethyl sulfoxide; and TFA, which means trifluoroacetic acid. When used, the term "lower alkyl" means C1-C4. By analogy, the terms "lower alkoxy", "lower alkanoyloxy" and "lower acyloxy" refer to groups containing from one to four carbon atoms. The present invention is illustrated by the following Examples. However, it should be understood that the invention is not limited to the specific details of these Examples.

EXAMPLE ONE N- (5-Vinyl-pyridin-2-yl) -acetamide. A solution of N- (5-bromo-pyridin-2-yl) -acetamide (4.30 g, 20 mmol) in acetonitrile (15 ml) and triethylamine (5.04 ml) was treated with palladium acetate (45 mg, 0.2 mmoles). ) and tri-o-tolylphosphine (203 mg, 0.66 mmol). The mixture was placed in a pressure reactor under an ethylene pressure of 50 psig (344,737 kPa) and heated at 85 ° C for 66 hours. The reaction mixture was cooled, vented and partitioned between phosphate buffer (0.1 M, pH 6.6) and ethyl acetate. The aqueous phase was extracted with ethyl acetate twice more. The combined ethyl acetate extracts were washed with additional phosphate buffer, brine and dried over sodium sulfate. The extracts were filtered and evaporated to yield 2.06 g (63%) of the title compound as a flaky crystalline residue. Recrystallization from ethyl acetate / cyclohexane gave colorless flakes, m.p. 120-121 ° C 1 H NMR (CDCl 3): d = 8.55 (a, 1 H), 8.24 (d, 1 H), 8.15 (d, 1 H), 7.76 (d of d, 1 H), 6.64 (d. d of d, 1 H), 5.73 (d, 1 H), 5.28 (d, 1 H), 2.19 (s, 3H). MS (IQ): m / z = 163 (M + H +).

EXAMPLE TWO N- (5-Vinyl-pyridin-2-yl) -2,2-d-methylpropionamide.

A solution of N- (5-bromopyridin-2-yl) -2,2-dimethylpropionamide (5.60 g, 21.8 mmol) in acetonitrile (20 ml) and triethylamine was treated. (5.49 ml) with palladium acetate (177 mg, 0.8 mmol) and trio-o-tolylphosphine (795 g, 2.6 mmol). The mixture was placed in a pressure reactor under an ethylene pressure of 130 psig (896.31 kPa) and heated at 85 ° C for 18 hours. The reaction mixture was cooled, vented, diluted with ethyl acetate and filtered. The ethyl acetate solution was washed sequentially with dilute citric acid, water and brine and then dried over sodium sulfate.

The dried solution was filtered and evaporated. Chromatography of the residue on silica gel, eluting with dichloromethane / ethyl acetate (24: 1) yielded 3.92 g. (88%) of the title compound in the form of an oil. 1 H NMR (CDCl 3) d 8.21 (m, 2 H), 8.03 (a, 1 H), 7.76 (d of d, 1 H), 6.63 (d of d, 1 H), 5.71 (d, 1 H), 5.25 (d, 1 H), 1.29 (s, 9H). MS (IQ): m / z = 205 (M + H +).

EXAMPLE THREE N- (5-vinyl-pyridin-2-yl) -carbamic acid methyl ester.

A solution of (5-bromo-pyridin-2-yl) -carbamic acid methyl ester (1.68 g, 7.2 mmol) in acetonitrile (15 ml) and triethylamine (1.84 ml) was treated with palladium acetate (65 mg 0.29). mmoles) and tri-o-tolifosfin (295 mg, 0.97 mmol). The mixture was placed in a pressure reactor under an ethylene pressure of 130 psig (896.32 kPa) and heated at 85 ° C for 18 hours. The reaction mixture was cooled, vented, diluted with ethyl acetate and filtered. The ethyl acetate solution was washed sequentially with 1 M aqueous citric acid, water and brine, dried over sodium sulfate and filtered. The filtrate was evaporated. The residue was recrystallized from dichloromethane-hexane to yield 0.759 g (58%) of the title compound as colorless crystals, m.p. 146-148 ° C. 1 H NMR (CDCl 3) d = 9.04 (a, 1 H), 8.28 (d, 1 H), 7.97 (d, 1 H), 7.77 (d of d, 1 H), 6.64 (d of d, 1 H) , 5.71 (d, 1 H), 5.26 (d, 1 H), 3.81 (s, 3H). MS (IQ): m / z = 179 (M + H +).

EXAMPLE FIVE (R) -N- (5-, 1, 2-Dihydroxy-etn-pyridin-2-in-acetamide.

A suspension of AD-Mix-B® (56.33 g) in water (200 ml) and t-butanol (200 ml) was cooled to 5 ° C and N- (5-vinyl-pyridin-2-yl) was added. -acetamide (6.52 g, 40.2 mmol) followed by 2-propanol (400 ml). the mixture was stirred at 5 ° C for 12 hours and then at 20 ° C for 12 hours. The reaction mixture was then treated with sodium sulfite (60.4 g), stirred for 30 minutes, then diluted with 500 ml of 2-propanol and stirred for an additional hour. The mixture was filtered and the alcohol phase was separated and evaporated to dryness. The residue was suspended in 500 ml of 2-propanol and evaporated again. The residue was dried to yield 6.35 g (80%) of the title product as colorless crystals. The crystals were recrystallized by dissolving in hot glacial acetic acid, diluting 7 times with 2-propanol, cooling and adding seed crystals to give the title product as crystals, m.p. 184-185 ° C. 1 H NMR (dmso-d 6): d = 8.22 (d, 1 H), 7.99 (d, 1 H), 7.68 (d of d, 1 H), 4.52 (t, 1 H), 3.44 (m, 2H) , 2.07 (s, 3H). MS (IQ): m / z = 197 (M + H +). Optical rotation: -4.52 ° (c = 0.05, acetic acid). Analysis: Calculated for C9H12N2O3: C, 55.09%; H, 6.17; N, 14.28%. Found: C, 55.43%; H, 5.97; N, 13.96%.

EXAMPLE SIX (R, S) -N- (5- (1, 2-Dihydroxy-ethyl) -pyridin-2-yl) -acetamide.

A vigorously stirred mixture of potassium carbonate (25.56 g, 185 mmol), potassium ferricyanide (60.9 g, 185 mmol) and N- (vinyI-pyridin-2-yl) -acetamide (100.0 g, 61.6 mmol) in water (120 ml) ) and 2-propane (120 ml) was treated with potassium osmium (VI) dihydrate (46 mg, 0.123 mmol) at 25 ° C. the mixture was then stirred for one hour. The mixture was separated and the aqueous phase was extracted three more times with 120 ml portions of 2-propanol. The residue of the aqueous phase was triturated with hot 2-propanol. The 2-propanol extracts were combined, concentrated and azeotropically dried with 2-propanol. The residue was triturated with ether, filtered, washed with ether and dried to yield 10.61 g (87%) of the title product as an off-white solid, m.p. 160-162 ° C. 1 H NMR (dmso-d 6): d = 8.22 (d, 1 H), 7.99 (d, 1 H), 7.68 (d of d, 1 H), 4.52 (t, 1 H), 3.44 (m, 2H) , 2.07 (s, 3H). MS (IQ): m / z = 197 (M + H +).

EXAMPLE SEVEN Acid methyl ester, R) -N- (5- (1, 2- (dihydroxy-ethyl) -pyridin-2-yl) -carbamic acid.

A suspension of AD-Mix-B® (2.80 g) in water (10 ml) and t-butanol (10 ml) was cooled to 5 ° C and N- (5-vinyl-pyridine) methyl ester was added. 2-yl) -carbamic acid (0.356 g, 2.0 mmoles). The mixture was stirred at 5 ° C for 18 hours. The reaction mixture was then treated with sodium sulfite (3.0 g)it was stirred for a further 30 minutes and then extracted three times with ethyl acetate. The ethyl acetate extracts were combined, washed with water and brine, dried and evaporated to yield 0.410 g (96%) of the title product as colorless crystals, m.p. 153- 154 ° C. 1 H NMR (CDCl 3): d = 8.90 (a, 1 H), 8.09 (d, 1 H), 7.75 (d, 1 H), 7.53 (d of d, 1 H), 4.55 (m, 1 H), 3.60 (s, 3H), 3.47 (m, 1 H), 3.41 (m, 1 H). MS (lQ): m / z = 213 (M + H +).

EXAMPLE EIGHT R) -N- (5- (1,2-Dihydroxy-ethyl) -pyridin-2-yl) -2,2-d-methylpropionamide.

A suspension of AD-Mix-B® (1.40 g) in water (5 ml) and t-butanol (5 ml) was cooled to 5 ° C and N- (5-vinyl-pyridin-2-yl) was added. -2,2-dimethylpropionamide (0.204 g, 1.0 mmol). The mixture was stirred at 5 ° C for 18 hours. The reaction mixture was then treated with sodium sulfite (3.0 g), stirred for 30 minutes and then extracted with dichloromethane. The dichloromethane extract was washed with water and brine, then dried and evaporated to yield 0.230 g (96%) of the title product as colorless crystals, m.p. 105-106 ° C. 1 H NMR (CDCl 3): d = 8.21 (a, 1 H), 8.10 (m, 2 H), 7.61 (d of d, 1 H), 4.70 (m, 1 H), 3.64 (m, 1 H), 3.57 (m, 1 H), 1.25 (s, 9H). MS (IQ): m / z = 239 (M + H +).

EXAMPLE NINE 2- (6-acetylamino-pyridin-3-yl-2-hydroxy-2-hydroxy-ethyl ether of (R) ^ -nitro-benzenesulfonic acid.) A solution of (R) - (5- (1,2-dihydroxy-ethyl) -pyridin-2-yl) -acetamide (0.294, 1.5 mmol) in anhydrous DMF (3 mL) with triethylamine (0.63 g, 4.5 mmol) and cooled to -40. C. A solution of 4-nitrobenzenesulfonyl chloride (0.332 g, 1.5 mmol) in ethyl acetate (3 ml) was added dropwise.After 45 minutes at -45 ° C, the mixture was stirred for one hour at room temperature. 20 ° C. The mixture was then diluted with ethyl acetate and washed sequentially with water, twice with pH 6.6 buffer (0.1M phosphate), water and brine.The ethyl acetate layer was dried over sodium sulfate, The residue was triturated with 1,2-dichloroethane to give 0.381 g (67%) of the title product as colorless crystals, Mp 116-120 ° C with decomposition, 1 H NMR (dmso-d 6): d = 8.36 (d, 2H), 8.16 (d, 1 H), 8.04 (d, 2H), 7.91 (d, 1 H), 7.62 (d of d, 1 H), 5.89 (d, 1 H), 4.81 (d of d, 1 H), 4.24 (d, 2H), 2.06 (s, 3H). MS (CI): m / z = 179 (m + H + -O2NC6H4SO3H). 2- (6-Acetylamino-pyridin-3-yl) -2-hydroxy-2-hydroxy-ethyl ether of (R) -toluene-4-sulfonic acid A suspension of (R) -N- (5 - (1,2-dihydroxy-ethyl) -pyridin-2-yl) -acetamide (71.2 g, 362 mmol) in anhydrous pyridine (362 ml) was cooled to 5 ° C and treated with p-toluenesulfonyl chloride ( 69.18 g, 362 mmol) in one portion. The reaction mixture was stirred at 5 ° C for 20 minutes, then the cooling bath was removed and the mixture was stirred at room temperature for two hours. The mixture was then concentrated, dissolved in 30 ml of methanol, concentrated and dissolved in toluene (300 ml) and concentrated again. The residue was treated again with methanol and toluene, then the residue was dissolved in ethyl acetate and washed sequentially with saturated brine in half and with brine, and dried over sodium sulfate. The filtrate was evaporated to yield 102.2 g (80%) of the title product as clear buff crystals. Recrystallization from ethanol-cyclohexane afforded the title product as colorless crystals, m.p. 124-126 ° C. 1 H NMR (dmso-d 6): d = 10.5 (a, 1 H), 8.21 (d, 1 H), 7.94 (d, 1 H), 7.68 (d, 2 H), 7.51 (d of d, 1 H), 7.41 (d, 1 H), 5.87 (d, 1 H), 4.76 (d of d, 1 H), 4.05 (d, 2H), 2.41 (s, 3H), 2.10 (s) , 3H). MS (IQ): m / z = 351 (M + H +). Optical rotation: -36.181 ° (c = 1.19, acetone). Analysis: Calculating for C 16 H 18 N 2 O 5 S: C, 54.85%, H, 5.18%; N, 7.99%. Found: C, 54.91%; H, 5.34%; N, 8.06%.

EXAMPLE ELEVEN N- (5- (2-oxo-ri. 31-dioxolan-4-yl) -pyridin-2-yl) -acetamide A solution of (R, S) -N- (5- (1, 2- dihydroxy-ethyl-pyridin-2-yl) -acetamide (0.392 g, 2 mmol) 1.1-carbonyldiimidazole (0.648 g, 4 mmol) in DMF (3 mL) was stirred at 20 ° C for six hours and then The residue was treated with water and ethyl acetate, the ethyl acetate was separated and the aqueous phase was extracted three more times with ethyl acetate.The combined ethyl acetate extracts were washed with brine, dried, filtered and concentrated, chromatography of the residue on silica gel, eluting with dichloromethane / methanol (1: 1) yielded 0.078 g (17%) of the title compound as white crystals, mp 135-139 ° C. 1 H NMR (dmso-de): d = 8.41 (d, 1 H), 8.11 (d, 1 H), 7.93 (d of d, 1 H), 5.85 (t, 1 H), 4.84 (t, 1 H ), 4.47 (t, 1 h), 2.09 (s, 3H), MS (IQ): m / z = 223 (M + H +).

EXAMPLE TWELVE OH (S) -N- (5- (1, 2-dihydroxy-etl) -pyridin-2-i0-acetamide A suspension of AD-Mix a® (35 g) in water (50 ml) 6 2-propanol (50 ml) was cooled to 0 ° C and N- (5-vinyl-pyridin-2-yl) -acetamide (4.05 g, 25 mmol) was added.The mixture was stirred overnight at 20 ° C. The reaction mixture was then treated with sodium sulfite (37.5), the 2-propanol was decanted, the residue was diluted with 2-propanol (50 ml), heated to reflux, 2-propanol was decanted, and this process was repeated three times. The alcoholic portions were combined, filtered and the filtrate was concentrated to yield a yellow solid.This solid was resuspended in hot 2-propanol (20 ml) and filtered to yield 3.80 g of the impure product. in hot ethyl acetate (6 ml), acetonitrile (42 ml) was added, the solution was cooled to precipitate the product, the suspension was stirred overnight and filtered to yield 3.0 (61%) of an off-white solid. NMR (dmso-d6): d 8.22 (d, 1 H), 7.99 (d, 1 H), 7.68 (d of d, 1 H), 4.52 (t, 1 H), 3.44 (m, 2H), 2.07 ( s, 3H). MS (IQ): m / z = 197 (M + H +).

EXAMPLE THIRTEEN (R) -N- (5-oxiranyl-pyridin-2-yl) -acetamide A solution of 2- (6-acetylamino-pyridin-3-yl) -2-hydroxy-ethylene ester of (R) acid -toluene-4-sulfonic acid (200 g, 0.57 mol) in THF (2.4 1) was cooled to -15 ° C and potassium t-butoxide (542 mL, 0.542 mol, in 1 M THF) was added slowly at a temperature from -15 ° C to -10 ° C for a period of two hours. Stirring was continued at -15 ° C for an additional 40 minutes. The reaction mixture was filtered with the aid of Celite®. The filtration was carried out through a fabric previously coated with Celite®. The filter cake was washed with tetrahydrofuran. The filtrate was concentrated in vacuo to yield 300 ml of an oil. The oil was diluted with 1.2 liters of hexanes, which resulted in the formation of a solid. The suspension was stirred at room temperature for one hour to granulate the solid. The suspension was filtered and the filtrate was washed with hexanes to produce as a solid, m.p. 96-98 ° C. 1 H NMR (CDCl 3): d = 8.70 (a, 1 H), 8.21 (m, 2 H), 7.57 (d of d, 1 H), 3.86 (m, 1 H), 3.17 (m, 1 H), 2.83 ( m, 1 H), 2.19 (s, 3H). MS (IQ): m / z = 179 (m + H +).

EXAMPLE FOURTEEN (R) -N- (5-2-chloro-1-hydroxy-ethy-pyridin-2-yl) -acetamide A mixture of (R) -N- (5- (2-chloro-1-hydroxy) ethyl) -pyridin-2-yl) -acetamide and 2- (6-acetylamino-pyridin-3-yl) -2-hydroxy-ethyl ester of (R) -toluene-4-sulfonic acid (86.3 g) was dissolved in 604 ml of ethanol. The solution was heated to a clear solution and then lithium chloride (10.3 g, 0.243 mol) was added. The reaction mixture was heated to reflux overnight. More lithium chloride (2.0 g) was added and the reaction was heated to reflux for two more days. The reaction mixture was cooled and concentrated in vacuo. The residue was partitioned between ethyl acetate and saturated brine in half. The layers were separated and the ethyl acetate layer was washed once with saturated brine. The aqueous layers were combined and extracted once with ethyl acetate. The ethyl acetate layers were combined, dried with MgSO 4 and then concentrated to an oil. The residue was dissolved in tetrahydrofuran until a cloudy solution was obtained. This solution was treated with charcoal and silica gel, stirred hot for 30 minutes and filtered. The filter cake was washed with tetrahydrofuran and the solution was concentrated to a semi-solid. The semi-solid was dissolved in 500 ml of ethyl acetate, washed with saturated brine in half, once with saturated aqueous sodium bicarbonate and once with saturated aqueous sodium chloride. The ethyl acetate layer was concentrated to produce an oil. The resulting suspension was suspended in methylene chloride (100 ml), cooled and then vacuum filtered to yield 29 g of the title chloride compound. 1 H NMR (DMSO-d 6) d = 10.48 (br s, 1 H), 8.29 (d, 1 H), 8.00 (d, 1 H), 7.73 (d of d, 1 H), 5.88 (d, 1 H) , 4.76 (m, 1 H), 3.72 (m, 1 H), 2.06 (s, 3H).

EXAMPLE FIFTEEN (4- (2- (6-aminopyridin-3-yl) -2- (R) -hydroxyethyl-ammonium) -ethoxy) -phenyl ester) A mechanically stirred suspension of the title compound of Example 13 ( 50.0 g 0.2806 moles, 1.0 eq.) And the title compound of preparation seven (99.4 g, 0.477 moles, 1.7 eq) in 5: 1 (vol / vol): oluene: DMSO (375 ml), was heated in a Steam bath. The suspension became homogeneous at about 70 ° C and a temperature of 90-95 ° C was maintained for 3 to 16 hours. The solution was cooled to 10-15 ° C. This resulted in the formation of a precipitate. Di-t-butyl carbonate (129 ml, 0.561 mol, 2.0 eq) was added dropwise over a period of one hour. The resulting homogeneous solution was stirred at room temperature overnight. The solution was poured into a mixture of ethyl acetate (1 l) and water (850 ml). After stirring for 10 minutes, the phases were allowed to separate, at which time a strong red oil appeared in the aqueous layer. The aqueous layer, with oil, was removed. The organic layer was washed with water (500 ml) and concentrated to an amber oil. This amber oil was suspended in 6N HCl (300 ml) and heated in a steam bath overnight. The solution was cooled to room temperature and the solids that precipitated were filtered. (These solids are the amino acids of the excess side chain that was used in coupling with the epoxide). The acid solution containing the title compound was concentrated in vacuo to a semi-solid. The simisolide was treated with water and then re-concentrated (twice) to remove excess HCl. The solid was dissolved in water and brought to pH 7 with potassium hydroxide. The solid that precipitated was filtered and washed first with water and then with THF. The solids were dried in the filter funnel until they reached a weight of 22.5 g. The crude solid was redissolved in 30 volumes of water at 90 ° C and treated with decolorizing carbon. After filtration to remove the carbon, the filtrate was cooled and concentrated by evaporation of part of the water. The precipitate that formed was filtered to provide 9.5 g of the title compound. NMR (40MHz, DMSO-d6 + D2O): d = 7.79 (d, 1 H, J = 1.87), 7.34-7.32 (m, 1 H), 7.11 (d, 2H, J = 8.51), 6.79 (d, 2H, J = 8.51), 6.41 (d, 1H, J = 8.51 (, 4.54-4.51 (m, 1H), 4.01-3.99 (m, 2H), 3.35 (s, 2H), 2.97-2.94 (m, 2H ), 2.79-2.69 (m, 2H), MS (APCI) m / z 332.2 (MH +), 314.2, 159.1, 156.9.

PREPARATION ONE N- (5-bromo-pyridin-2-iD-acetamide A solution of 2-amino-5-bromopyridine (25.0 g, 144 mmol) in acetic acid (50 ml) and acetic anhydride (25.0 g, 250 ml) was heated at reflux for two hours The reaction mixture was then cooled and poured into water (750 ml) with stirring.After one hour, the solution was adjusted to pH 10 with 50% sodium hydroxide and the precipitate was filtered off, washed with water and dried to yield 26.5 g (85%) of the title product as a white flaky solid, mp 175-176 ° C. 1 H NMR (CDCl 3): d = 8.29 (d, 1 H ), 8.12 (d, 1 H), 7.96 (a, 1 H), 7.78 (d of d, 1 H), 2.19 (s, 3H), MS (IQ) m / z = 214, 216 (M +, isotopes) Br).

PREPARATION TWO N- (5-bromo-pyridin-2-iD-2,2-dimethylpropionamide) A solution of trimethylacetyl chloride (17.5 g, 146 mmol) in dichloromethane (25 ml) was added dropwise to a solution of 2-amino-5-bromopyridine (25.0 g, 144 mmol) in dichloromethane (100 ml) and triethylamine (24 ml), with stirring, at 20 [deg.] C. The reaction mixture was then stirred for 40 minutes, filtered, washed with water, dried and concentrated, recrystallization from hexanes afforded 20.6 g (70%) of the title product as a white flaky solid, mp 63-64 ° C 1 H NMR (CDCl 3): d = 8.82 (a , 1 H), 8.30 (d, 1 H), 8.19 (m, 2H), 1.36 (s, 3H), MS (IE): m / z = 256, 258 (M +, Br isotopes).

PREPARATION THREE N- (5-bromo-pyridin-2-yl) -carbamic acid methyl ester A solution of 2-amino-5-bromopyridine (9.46 g) was added dropwise., 20 mmol) and N, N-diisopropylethylamine (3.10 g) in chloroform (20 ml) were added to a solution of methyl chloroformate (2.30 g, 24 mmol) in chloroform (25 ml), with stirring, at 0 ° C. The reaction mixture was stirred for 20 minutes, filtered and the precipitate was washed with chloroform and dried to yield 1.71 g (37%) of the title product as a white solid, m.p. 191-192 ° C. 1 H NMR (CDCl 3): d = 8.42 (d, 1 H), 3.30 (d, 1 H), 7.91 (d, 1 H), 7.77 (d of d, 1H), 3.79 (s, 3H). MS (EI): m / z = 230, 232 (M +, Br isotopes).

PREPARATION FOUR N-methyl 4-hydroxyphenylacetamide Monomethylamine (22.43 kg, 722.15 moles, 6 eq.) Was added over a period of 7 hours to a solution of methyl 4-hydroxyphenylacetate (20.0 kg, 120.35 moles, 1.0 eq) in methanol (31.7 gallons) ) (144.10 liters) and stirred overnight at room temperature. The methanol was then displaced in vacuo with ethyl acetate. The resulting suspension (approx 20 gallons) (approx 90.92 liters) was stirred at + 10 ° C for 1 hour, then filtered and dried under vacuum at 45 ° to yield the title compound (18.68 Kg 94% of theory) , pf 124-125 ° C, NMR (300 MHz, d6-DMSO): d = 9.26 (s, 1 H), 8.00-7.65 (s at, 1 H), 7.21-6.90 (m, 2H), 6.86-6.5 (m , 2H), 3.26 (s, 2H), 2.75-2.45 (m, 3H).

PREPARATION FIVE N-Benzyloxycarbonyl-2-aminoethanol Benzyl chloroformate (44.95 kg, 263.5 moles, 1.0 eq.) Was added over a period of 2 hours, at room temperature, to a solution of ethanolamine (16.1 kg 263.5 moles, 1.0 eq.) in water (34 gallons) (154.56 liters). After stirring for 30 minutes, this mixture was added to a cold solution (5-10 ° C) of NaHCO3 (33.2 kg, 395.25 moles, 1.5 eq.) In H2O (330 I) over a period of 30 minutes and then left in agitation at room temperature overnight. Ethyl acetate (22 gallons) (100 liters) was added, the layers were separated and the aqueous layer was extracted again with 22 gallons (100 liters) of ethyl acetate. The combined organic extracts were concentrated in vacuo to a volume of 10 gallons (45.46 liters) and the residue was displaced with isopropyl ether. The resulting suspension was stirred, cooled to + 10 ° C for 2 hours and then filtered. The solids were washed with isopropyl ether and dried in vacuo to give the title compound (39.1 kg, 71.1%). p.f. 61-63 ° C. NMR (300 MHz, d6-DMSO): d = 7.50-7.37 (m, 5H), 7.37-7.16 (m, 1 H), 5.05 (s, 2H), 4.70-4.63 (m, 1 H), 3.46- 3.37 (m, 2H), 3.13-3.03 (m, 2H).

PREPARATION SIX Methyl4- (2- (N-Benzyloxycarbonyllamine) ethoxy) phenylacetamide The title compound of preparation four (18.68 kg, 113.14 moles, 1.0 eq.) And the title compound of preparation five (33.13 kg. , 169.75 moles, 1.5 eq.) Were dissolved in THF (40 gallons) (181.84 liters). Triphenylphosphine (44.5 kg, 169.75 moles, 1.5 eq.) Was added and the mixture was cooled to -5 ° C. Diisopropyl azodicarboxylate (34.3 kg, 169.75 moles, 1.5 eq.) Was added over a period of 8 hours and the reaction was allowed to warm to room temperature overnight. Ethyl acetate (20 gallons) (90.92 liters) was added to the resulting white suspension, stirring was continued for 6 hours and the solids were filtered off and dried to yield the crude title compound. (29.6 kg, 76.5% of theoretical, pp. 131-133 ° C). The crude product was suspended in ethyl acetate (39.1 gallons) (177.74 liters) for 3 hours at + 10 ° C, then filtered, washed with 14 gallons (63.64 liters) at 10 ° C ethyl acetate and dried vacuum to produce the title compound (26.1 kg, recovery 88.2%, 67.5% overall), mp 134-136 ° C (300 MHz, d6-DMSO): d = 7.98-7.82 (m, 1 H), 7.58-7.49 (, 1 H), 7.42-7.28 (m, 5H), 7.20-7.10 (d, 2H), 6.90-6.80 (d, 2H), 5.06 (s, 2H), 4.02-3.93 (, 2H), 3.47-3.29 (m, 4H), 2.62-2.54 (d, 3H).

PREPARATION SEVEN Methyl 4- (2-aminoethoxy-phenylacetamide) The title compound of preparation six (18.4 kg, 53.73 moles) and 1.84 kg of 10% palladium on carbon (with 50% moisture of HO) were suspended in 73 gallons (331.85 liters) ) of methanol under nitrogen and the reaction vessel was pressurized to 50 psig (344,737 kPa) with hydrogen gas.This H2 pressure was maintained by additional charges of H2 until there was no more H2 uptake (approximately 20 hours) and the reaction it was completed by tic After purging the vessel with N2, the mixture was heated to 45 ° C and filtered at this temperature through Celite.The solvent was displaced with toluene until a final volume of 8 gallons was achieved (36.36). liters). After cooling to + 5 ° C, the resulting solids were filtered off, washed with cold toluene and dried in vacuo to give the title compound (9.95 kg, 88.9% of theory). MHz, d6-DMSO): d = 7.99-7.57 ( m, 1 H), 7.20-7.10 (d, 2H), 6.90-6.80 (d, 2H), 3.93-3.83 (m, 2H), 3.30 (s, 2H), 3.00-2.62 (m, 4H), 2.57 (d, 2H).

Claims (60)

1. NOVELTY OF THE INVENTION CLAIMS 1. - A compound of formula p A wherein: R1 is selected from the group consisting of nitro, amino and protected amino; R 2 is selected from the group consisting of H, fluoro, chloro, CF 3, nitro alkyl (C-i-d), (C 1 -C 4) alkoxy, amino and protected amino; X1 is OH or a suitable leaving group; racemic mixtures of themselves; R enantiomers thereof, wherein said R-enantiomers essentially lack their corresponding S-enantiomers; and S enantiomers thereof, wherein said S-enantiomers essentially lack their corresponding R-enantiomers.
2. 2. A compound of claim 1, wherein X1 is OH.
3. 3. A compound of claim 2, wherein said protected amino, each time it appears, is independently selected from the group consisting of alkylamino (C? -C8), -NR3CO (CH2) PR?, -NR3CO2R? And -NR3SO2 (CH2) PR °; R3, each time it appears, is, independently, H or alkyl (d-C6); R °, is each time it appears, is independently (C 1 -C 10) alkyl, phenyl or phenyl independently substituted with one to three (C 1 -C 4) alkyl, (C 1 -C 4) alkoxy or halo; and p is 0, 1 or 2.
4. 4. A compound of claim 3, wherein R2 is H.
5. 5. A compound of claim 4, wherein R1 is amino; NR3CO-alkyl (d-C10), NR3CO2 alkyl (d-C8) or NR3CO (CH2) PR °.
6. 6. A compound of claim 5, wherein R1 is amino or -NR3CO-, alkyl (d-C10).
7. 7. The compound of claim 6, which is N- (5- (1,2-dihydroxyethyl) -pyridin-2-yl) acetamide.
8. 8. The R-enantiomer of the compound of claim 7, essentially without its corresponding S-enantiomer.
9. 9. The S-enantiomer of the compound of claim 7, essentially without its corresponding R-enantiomer.
10. 10. A compound of claim 1, wherein X1 is a leaving group, said leaving group is organosulfonyloxy and said organosulfonyloxy is methanesulfonyloxy, benzenesulfonyloxy, p-toluenesulfonyloxy, p-nitrobenzenesulfonyloxy or m-nitrobenzenesulfonyloxy.
11. 11. A compound of claim 10, wherein said organosulfonyloxy is p-toluenesulfonyloxy.
12. 12. A compound of claim 11, wherein said protected amino, each time it appears, is independently selected from the group consisting of alkylamino (C?-C8), NR3CO (CH2) PR °, - NR3CO2R ° and NR3SO (CH2) PR °; R3, each time it appears, is, independently, H or alkyl (C? -C6); R °, each time it appears, is independently alkyl (d-C10), phenyl or phenyl independently substituted with one to three alkyl (d-d), (C1-C4) alkoxy or halo; and p is 0, 1 or 2.
13. 13. A compound of claim 12, wherein R2 is H.
14. 14. A compound of claim 13, wherein R1 is mino, -NR3Coalkyl (C? -C10) , -NR3CO2alkyl (C? -C8) or NR3CO (CH (d-C4) PR. 15.- A compound of claim 14, wherein R1 is amino or -NR3CO-alkyl (d-C10). The compound of claim 15, which is 2- (6-acetylamino-pyridin-3-yl) -2-hydroxyethyl ester of toluene-4-sulfonic acid 17.- The R-enantiomer of the compound of claim 16 , essentially without its corresponding S-enantiomer. 18. The S-enantiomer of the compound of claim 16, essentially without its corresponding R-enantiomer. 19. The compound of claim 15, which is N- (5- (2-chloro- 1-hydroxyethyl) -1-pyridin-2-yl) -acetamide 20.- The R-enantiomer of the compound of claim 19, essentially without its corresponding S-enantiomer. 21.- The S-enantiomer of compound of claim 19, essentially without your correspon R. enantiomer 22. A compound of claim 22, wherein X1 is a leaving group selected from chlorine or iodine. 23. A compound of claim 22, wherein X1 is chloro and said compound is the R-enantiomer, essentially without its corresponding S-enantiomer. 24. A compound of claim 22, wherein X1 is chloro and said compound is the S-enantiomer essentially without its corresponding R-enantiomer. A compound of claim 1, wherein X 1 is bromine and said compound is the R-enantiomer, essentially without its corresponding S-enantiomer. 26.- A compound of claim 1, wherein X1 is bromine and said compound is the S-enantiomer, essentially without its corresponding R-enantiomer. 27.- A compound of the formula VTH wherein: R12 is selected from the group consisting of nitro and protected amino; R13 is selected from the group consisting of H, fluoro, chloro, CF3, nitro, (C1-C4) alkyl, (C1-C4) alkoxy, and protected amino; Y 4 is an amine protecting group; and Y5 is where: Q1 is oxygen, nitrogen or sulfur; Q2 is carbon or nitrogen; Q3 is hydrogen, - (CH2) n-phenyl, -alkyl (d-C10), - (CH2) "- NG1G2, - (CH2) n -CO2G3, - (CH2) n -CO-NG1G2, - (CH2) n -OG3, - (CH2) n -SO3G3, - (CH2) n -SO2- (C1-C6) alkyl, - (CH2) n-SO2NG1G2 or a heterocycle selected from the group consisting of - (CH2) n-pyridyl , - (CH2) n-pyrimidyl, - (CH2) n-pyrazinium, - (CH2) n-ixozalyl, - (CH2) n-oxazolyl, - (CH2) n-thiazolyl, - (CH2) n- (1, 2,4-oxadiazolyl), - (CH2) n-imidazolyl, - (CH2) n-triazollyl and - (CH2) n-tetrazolyl; wherein one of the ring atoms of said - (CH2) n-imidazolyl, - (CH2) n-triazolyl and - (CH2) n-tetrazolyl may be optionally substituted with optionally substituted (C? -C8) alkyl independently with one or more halo atoms; wherein each of said heterocyclics can optionally be substituted on one or more of the ring carbon atoms, with one or more substituents independently selected from the group consisting of (C? -C8) alkyl, optionally independently substituted with one or more atoms of halo, halo nitro, cyano, - (CH2) n -NG1G2, - (CH2) n -CO2G3, - (CH2) n -CO-NG1G2, - (CH2) n -OG3, - (CH2) n -SO3G3, - (CH2) n -SO2-alkyl (d-C6) and - (CH2) n -SO2NG1G2; wherein the phenyl radical of said - (CH2) n -phenyl may be optionally substituted with one or more substituents independently selected from the group consisting of (C? -C6) alkyl optionally independently substituted with one or more halo, hydroxy, alkoxy atoms (dd) optionally independently substituted with one or more halo atoms, alkylthio (d-Cß). Fluoro, chloro, bromo, iodo, cyano, nitro, - (CH2) n -NG1G2, - (CH2) n -CO2G3, - (CH2) n -CO-NG1G2, - (CH2) n -OG3, - (CH2) n -SO3G3, - (CH2) n -SO2-alkyl (d-C6) and - (CH2) n -SO2NG1G2; Q4 is - (CH2) n -CN, (CH2) n -C02G3, - (CH2) n -SO2G3, - (CH2) n -SO2- (C1-C6) alkyl, - (CH2) n -SO2NG1G2, - ( CH2) nCH2OH, - (CH2) n -CHO, - (CH2) n -CO-G3, - (CH2) n -CONG1G2, or a heterocycle selected from - (CH2) n-thiazolyl, - (CH2) n-oxazolyl , - (CH2) n-imidazolyl, - (CH2) n-triazolyl, - (CH2) n-1, 2,4-oxadiazolyl, - (CH2) n-isoxazolyl, - (CH2) n-tetrazolyl and - (CH2 ) n-pyrazolyl; wherein one of the ring nitrogen atoms of said - (CH2) n-imidazolyl, - (CH2) n-triazolyl, and - (CH2) n-tetrazolyl may be optionally substituted with optionally substituted alkyl (d-C6) independently with one or more halo atoms; wherein each of said heterocycles may be optionally substituted, on one or more of the ring carbon atoms, with one or more substituents independently selected from the group consisting of hydrogen, alkyl (dd) optionally independently substituted with one or more ring atoms halo, - (CH2) n-CO-NG1G2, - (CH2) n-CO2G3, halo, nitro, cyano, - (CH2) n-CO-NG1G2, - (CH2) n-OG3, - (CH2) n- SO3G3, - (CH2) n-SO2- alkyl (dd) or - (CH2) n-S02NG1G2; Q5 is hydrogen or (C? -C6) alkyl optionally substituted independently with one or more halo atoms; Q6 is a covalent bond, oxygen or sulfur; Q7 is hydrogen or alkyl (Ci-d) optionally independently substituted with one or more halo atoms; Q8 and Q9 are, independently, a covalent bond, oxygen, sulfur, NH or N-alkyl (d-Cß); Q10 is (CH2) mOR9, (CH2) nCO2H, (CH2) nCOR11, (CH2) nSO2NR9R10, (CH2) nNR9SO2R8, (CH2) nP (O) (OR4) (OR5), (CH2) nO- (CH2) mCO2H , (CH2) "-O- (CH2) m-COR1, (CH2) nO- (CH2) mP (O) (OR4) (OR5), (CH2) nO- (CH2) m-SO2NR9R10 or (CH2) nO- (CH2) mNR9SO2R8; R4 and R5 are each, independently hydrogen or alkyl (d-d); and R6 and R7 are each, independently, hydrogen, halo, alkyl (d-d,), nitro, cyano trifluoromethyl, SO2R8, SO2NR9R10, NR9R10, COR11, CO2R9, alkoxy (d-d), NR9SO2R8, NR9CORn, NR9CO2R9 or OR9; where G1 and G2, each time they appear, are each, independently, hydrogen, alkyl (C? -C6) optionally independently substituted with one of more halo, (d-Cs) alkoxy (dd) alkyl or (C3-C8) cycloalkyl ), or G1 and G2, together with the nitrogen to which they are attached, form a saturated heterocyclic ring having from 3 to 7 carbon atoms, where one of said carbon atoms can optionally be replaced by oxygen, nitrogen or sulfur; G3, each time it appears, is independently hydrogen or alkyl (d-d); R8, each time it appears, is independently alkyl (d-d); or alkoxy (d-d) alkyl (C? -C6); or R9 and R10, are taken separately and, each time they appear, are independently hydrogen, (d-C6) alkyl; cycloalkyl (C3-C8) or alkoxy (d-d) alkyl (C6C6); or R9 and R10 are taken together with the nitrogen atom to which they are attached and form a pyrrolidine, piperidine or morpholine ring wherein said pyrrolidine, piperidine or morpholine ring may be optionally substituted on any carbon atom with (C1-C4) alkyl ) or (C1-C4) alkoxy; R11, each time it appears, is independently hydrogen, alkyl (d-C6), alkoxy (dd), NR9R10, cycloalkyl (C3-C8) or alkoxy (dd) alkyl (d-C6), where R9 and R10 are as have defined previously; m, each time it appears, is independently an integer from 1 to 6; and n, each time it appears, is independently 0 or an integer from 1 to 6; racemic mixtures thereof; R enantiomers thereof, wherein said R-enantiomer essentially lacks its corresponding S-enantiomer; and S enantiomers thereof, wherein said S-enantiomer essentially lacks its corresponding R-enantiomer; with the proviso that: (1) when Q9 is O or S, then n is not 0; (2) when Q1 is oxygen or sulfur, then Q3 is absent; and (3) when Q2 is nitrogen, then Q5 is absent. 28. A compound of claim 27, wherein Y4 is an amine protecting group selected from the group consisting of benzyl, COR14, CO2R14, and SO2R14; and R14, each time it appears, is independently (C1-C-10) alkyl, phenyl or benzyl; wherein said phenyl and benzyl are optionally substituted with one to three alkyl (d-C4), (C1-C4) alkoxy or halo. 29. A compound of claim 28, wherein Y5 is. R7 30. - A compound of claim 29, wherein R13 is H and R12 is protected amino; said protected amino is independently selected from the group consisting of alkylamino (d-C8), -NR3CO (CH2) PR °, -NR3CO2R ° and -NR3SO2 (CH2) PR °; R3 is independently H or alkyl (d-Cß); R ° is, independently, (C1-C10) alkyl, phenyl or phenyl independently substituted with one or three (C1-C4) alkyl, alkoxy (d-d) or halo; and p is 0, 1 or 2. 31.- A compound of claim 30, wherein said protected amino is -NR3CO (CH2) PR °, R3 is H; R ° is CH3; and p is 0. 32.- A compound of claim 31, wherein R4, R5, R6 and R7 are each hydrogen; Q8 is oxygen; Q9 is a covalent bond; and Q10 is (CH2) mCONR9R10. 33. A compound of claim 32, wherein Y4 is t-butyloxycarbonyl; m is 1; R9 is H; and R10 is methyl. 34. A compound of claim 33 of the formula 35. - A compound of claim 34, having stereochemistry R. 36. The compound of claim 35, which is N-methyl 4- (2- (2- (2-acetylaminopyridin-5-yl) -2- (R ) -hydroxyethyl-N-tert-butyloxycarbonylamino) -ethoxy) -phenylacetamide. 37.- A procedure for preparing a compound of the formula SAW wherein: R1 is selected from the group consisting of nitro, amino and protected amino; and R2 is selected from the group consisting of H, fluoro, chloro, CF3, nitro, alkyl (d-d), (C1-C4) alkoxy, amino and protected amino, which comprises reacting a compound of the formula V wherein R1 and R2 are as defined above, with a catalyst comprising an osmium oxide (HIV) or an osmium salt, and an auxiliary oxidizing agent, in a solvent inert to the reaction. 38.- A method of claim 37, further comprising reacting said compound of formula (V) with said osmium oxide (HIV) or said osmium salt, in the presence of an auxiliary chiral ligand and an auxiliary base. 39.- A method of claim 38, wherein said chiral auxiliary ligand is (DHQD) 2PHAL. 40. A method of claim 39, wherein said compound of formula (VI) has R configuration at position 1 of the 5-ethyl group, said compound essentially lacking its corresponding S-enantiomer. 41.- A process of the claim 40, wherein R1 is acetylamino and R2 is H. 42.- A method of claim 38, wherein said chiral auxiliary ligand is (DHQD) 2PHAL. 43. - A method of claim 42, wherein said compound of formula (VI) has S configuration at position 1 of the 5-ethyl group, said compound essentially lacking its corresponding enantiomer R. 44.- A process of claim 43 , wherein R 1 is acetylamino and R 2 is H. 45.- A process for the preparation of a compound of the formula (I). and the racemic-enantiomeric mixtures and optical isomers of said compounds, comprising: (a) reacting a compound of the formula SAW with organosulfonyl chloride and a suitable base, in a solvent inert to the reaction, to form a compound of the formula p (b) reacting said compound of formula II with a non-nucleophilic base, in a solvent inert to the reaction, to form a compound of the formula (III) m (c) reacting said compound of formula (III) with a base and HNY2Y3 to form said compound of formula (I); wherein R1 is selected from the group consisting of nitro, amino and protected amino; R 2 is selected from the group consisting of H, fluoro, chloro, CF 3, nitro, (C 1 -C 4) alkyl, alkoxy (d-d), amino and protected amino; and Y is Br, I or trifluoromethanesulfonyloxy; and X is organosulfonyloxy; Y1 and Y3 are H; Y2 is OR R7 where: Q1 is oxygen, nitrogen or sulfur; Q2 is carbon or nitrogen; Q3 is hydrogen, - (CH2) n-phenyl, -alkyl (dC? O), - (CH2) n-NG1G2, - (CH2) n-CO2G3, - (CH2) n-OG3, - (CH2) n- SO3G3, - (CH2) n-SO2-alkyl (d-C6), - (CH2) n-SO2NG1G2 or a heterocycium selected from the group consisting of - (CH2) n-pyridyl, - (CH2) n-pyrimidyl, - (CH2) n-pyrazinyl, - (CH2) n-isoxazolyl, - (CH2) n-oxazolyl, - (CH2) n-thiazolyl, - (CH2) n- (1, 2,4-oxadiazolyl), - (CH2 ) n-imidazolyl, - (CH2) n-triazolyl and - (CH2) n-tetrazolyl; wherein one of the ring nitrogen atoms of said - (CH2) p-imidazolyl, - (CH2) n-triazolyl, - (CH2) n-triazolyl and - (CH2) p-tetrazolyl may be optionally substituted with alkyl (d -C8) optionally substituted independently with one or more halo atom; wherein each of said heterocycles may be optionally substituted on one or more of the ring carbon atoms, with one or more substituents independently selected from the group consisting of (C? -C8) alkyl, optionally independently substituted with one or more atoms of halo, halo, nitro, cyano, - (CH2) n-NG1G2, - (CH2) n-CO2G3, - (CH2) n-CO-NG1G2, - (CH2) n-OG3, - (CH2) n-SO3G3 , - (CH2) n-SO2-alkyl (C6) and - (CH2) n-SO2NG1G2; wherein the phenyl radical of said - (CH2) n-phenyl may be optionally substituted with one or more substituents independently selected from the group consisting of alkyl (dd) optionally independently substituted with one or more halo, hydroxy, alkoxy (dd) atoms optionally substituted independently with one or more halo atoms, alkylthio (dd), fluoro, chloro, bromo, iodo, cyano, nitro, - (CH2) n-NG1G2, - (CH2) n-CO2G3, - (CH2) n- CO-NG1G2, - (CH2) n-OG3, - (CH2) n-SO3G3, - (CH2) nSO2-alkyl (d-C6), - (CH2) n-SO2NG1G2; - (CH2) n-NG3-SO2-G3 and - (CH2) n-NG3-SO2-NG1G2; Q4 is - (CH2) n-CN, - (CH2) nCO2G3, - (CH2) n-SO3G3, - (CH2) n-SO2-alkyl (d-C6), - (CH2) n-SO2NG1G2, - (CH2 ) nCH2OH, - (CH2) n-CHO, - (CH2) n-CO-G3, - (CH2) n-CONG1G2 or a heterocycle selected from - (CH2) n-thiazolyl, - (CH2) n-oxazolyl, - (CH2) n-imidazolyl, - (CH2) n-triazolyl, - (CH2) "-1, 2,4-oxadiazolyl, - (CH2) n-isoxazolyl, - (CH2) n-tetrazolyl and - (CH2) n -pyrazolyl; wherein one of the ring nitrogen atoms of said - (CH2) n-imidiazolyl, - (CH2) n-triazolyl and - (CH2) n-tetrazolyl may be optionally substituted with optionally substituted alkyl (dd) independently with one or more halo atom; wherein each of said heterocycles may be optionally substituted, on one or more of the carbon atoms of the ring, with one or more substituents independently selected from the group consisting of hydrogen, alkyl (dd) optionally substituted independently with one or more halo, - (CH2) n-CO-NG1G2, - (CH2) n-CO2G3, halo, nitro, cyano, - (CH2) n-CO-NG1G2, - (CH2) n-OG3, - (CH2) n- SO3G3, - (CH2) n-SO2- alkyl (d-C6) or - (CH2) n-SO2NG1G2; Q5 is hydrogen or alkyl (d-d) optionally independently substituted with one or more halo atoms; Q6 is a covalent bond, oxygen or sulfur; Q7 is hydrogen or (dCS) alkyl optionally substituted independently with one or more halo atoms; Q8 and Q9 are, independently, a covalent bond, oxygen, sulfur, NH or -N-alkyl (d-C6); Q10 is (CH2) m-OR9, (CH2) n-CO2H, (CH2) n-COR11, (CH2) n-SO2NR9R10, (CH2) n-NR9SO2R8, (CH2) nP (O) (OR4) (OR5) , (CH2) nO- (CH2) m-CO2H, (CH2) nO- (CH2) m-COR11, (CH2) nO- (CH2) mP (O) (OR4) (OR5), (CH2) nO- ( CH2) m -SO2NR9 R10 O- (CH2) n- O- (CH2) m-NR9SO2R8; R4 and R5 are each, independently, hydrogen or alkyl (C? -C6); and R6 and R7 are each, independently, hydrogen, halo, alkyl, (dC6), nitro, cyano, trifluoromethyl, SO2R8, SO2NR9R10, NR9R10, COR11, CO2R9, (C1-C6) alkoxy, NR9SO2R8, NR9COR11, NR9CO2R9 or OR9; where G1 and G2, each time they appear, are each independently hydrogen, alkyl (Ci-Cß) optionally substituted with one or more halo, (C? -C8) alkoxy (d-C6) alkyl or (C3-C8) cycloalkyl , or G1 and G2 together with the nitrogen to which they are attached form a saturated heterocyclic ring having from 3 to 7 carbon atoms, where one of said carbon atoms can optionally be replaced by oxygen, nitrogen or sulfur; G3, each time it appears, is independently hydrogen or alkyl (d-d); R8, each time it appears, is independently alkyl (C? -C6) or alkoxy (d-d) alkyl (C? -C6); R9 and R10, each time they appear, are independently hydrogen, alkyl (Ci-d), cycloalkyl (C3-C8) or alkoxy (C6-6) alkyl (C6C6); R11, each time it appears, is independently hydrogen, alkyl (d-d), alkoxy (d-d), NR9R10, R9 and R10 are as defined above; m, each time it appears, an integer from 1 to 6 is independent; and n, whenever it appears, it is independent 0 or an integer from 1 to 6; with the proviso that: (1) when Q9 is O or S, then n is not 0; (2) when Q1 is oxygen or sulfur, then Q3 is absent; and (3) when Q2 is nitrogen, then Q5 is absent. 46. A process of claim 45, wherein said organosulfonyloxy is methanesulfonyloxy, benzenesulfonyloxy, p-toluenesulfonyloxy, p-nitrobenzenesulfonyloxy, or m-nitrobenzenesulfonyloxy. 47.- A procedure for the preparation of a compound of formula wherein: R1 is selected from the group consisting of nitro, amino and protected amino; R 2 is selected from the group consisting of H, fluoro, chloro, CF 3, nitro, (C 1 -C 4) alkyl, (C 1 -C 4) alkoxy, amino and protected amino; and X is organosulfonyloxy, which comprises: reacting a compound of the formula VI wherein R1 and R2 are as defined above, with an organosulfonyl chloride and a suitable base in a reaction-inert solvent. 48.- A procedure for the preparation of a compound of the formula and the racemic-enantiomeric mixtures and optical isomers of said compounds, comprising: (a) reacting a compound of the formula with a non-nucleophilic base, in a solvent inert to the reaction, to form a compound of the formula (III) (b) reacting said compound of formula (III) with a base and HNY2Y3 to form said compound of formula (I), wherein R1 is selected from the group consisting of nitro, amino and protected amino; R2 is selected from the group consisting of H, fluoro, chloro, CF3, nitro, alkyl (d-C4), alkoxy (d-d), amino and protected amino; and X is an organosulfonyloxy group; Y1 and Y3 are H; Y2 is where: Q1 is oxygen, nitrogen or sulfur; Q2 is carbon or nitrogen; Q3 is hydrogen, - (CH2) n-phenyl, -alkyl (d-C10), - (CH2) n-NG1G2, - (CH2) n-CO2G3, - (CH2) n-CO-NG1G2, - (CH2) n-OG3, - (CH2) n-SO3G3, - (CH2) n-SO2-alkyI (C d), - (CH2) n-SO2NG1G2 or a heterocycle selected from the group consisting of - (CH2) n-pyridyl, - (CH2) n-pyrimidyl, - (CH2) n-pyrazinyl, - (CH2) n-isoxazolyl, - (CH2) n-oxazolyl, - (CH2) n-thiazolyl, - (CH2) n- (1, 2 , 4 -oxadiazolyl), - (CH2) n-imidazolyl, - (CH2) n-triazolyl and - (CH2) n-tetrazolyl; wherein one of the ring nitrogen atoms of said - (CH2) n-imidazolyl, - (CH2) n-triazolyl and - (CH2) n-tetrazolyl may be optionally constituted with optionally substituted (C? -C8) alkyl independently with one or more halo atoms; wherein each of said heterocycles may be optionally substituted on one or more of the ring carbon atoms, with one or more substituents independently selected from the group consisting of alkyl (dd), optionally independently substituted with one or more halo atoms, halo, nitro, cyano, - (CH2) n-NG1G2, - (CH2) n-CO2G3, - (CH2) n-CO-NG1G2, - (CH2) n-OG3, - (CH2) n-SO3G3, - ( CH2) n-SO2-alkyl (d-C6) and - (CH2) n-SO2NG1G2; wherein the phenyl radical of said - (CH2) n-phenyl may be optionally substituted with one or more substituents independently selected from the group consisting of (C1-C6) alkyl optionally independently substituted with one or more halo, hydroxy, alkoxy atoms, (C1-C6) optionally independently substituted with one or more halo atoms, (C1-C6) alkylthio, fluoro, chloro, bromo, iodo, cyano, nitro, - (CH2) n- NG1G2, - (CH2) n-CO2G3 , - (CH2) n-CO-NG1G2, - (CH2) n-OG3, - (CH2) n-SO3G3, - (CH2) nSO2-alkyl (d-C6), - (CH2) n-SO2NG1G2; - (CH2) n-NG3-SO2-G3 and - (CH2) n-NG3-SO2-NG1G2; Q4 is - (CH2) n-CN, - (CH2) n -CO2G3, - (CH2) n-SO3G3, - (CH2) n-SO2-alkyl (d-C6), - (CH2) n- SO2NG1G2, - (CH2) n-CH2OH, - (CH2) n-CHO, - (CH2) n-CO-G3, - (CH2) n-CONG1G2 or a hererocycle selected from - (CH2) nt¡azolyl, - (CH2) n -oxazolyl, - (CH2) n-imidazolyl, - (CH2) n-triazolyl, - (CH2) n-1, 2,4-oxadiazolyl, - (CH2) n -soxazolyl, - (CH2) n-tetrazolyl, - (CH2) np -razolyl; wherein one of the ring nitrogen atoms of said - (CH 2) n -amidazolyl, - (CH 2) n -triazolyl and - (CH 2) n-tetrazolyl may be optionally substituted with optionally substituted alkyl (dd) independently with one or more halo atoms; wherein each of said heterocycles may be optionally substituted, on one or more of the ring carbon atoms, with one or more substituents independently selected from the group consisting of hydrogen, optionally substituted (C? -C6) alkyl independently with one or more halo atoms, - (CH2) n- NG1G2, - (CH2) n-CO2G3, halo, nitro, cyano, - (CH2) n- NG1G2, - (CH2) n-OG3, - (CH2) n-SO3G3 , - (CH2) n-SO2-alkyl (d-C6), or - (CH2) n-SO2NG1G2; Q5 is hydrogen or (C-C6) alkyl optionally substituted independently with one or more halo atoms; Q6 is a covalent bond, oxygen or sulfur; Q7 is hydrogen or alkyl (d-d) optionally independently substituted with one or more halo atoms; Q8 and Q9 are, independently, a covalent bond, oxygen, sulfur, NH or -N-alkyl (d-Cß); Q10 is - (CH2) m-OR9, - (CH2) n -CO2H, - (CH2) n-COR11, - (CH2) n-SO2NR9R10, - (CH2) n-NR9SO2R8, - (CH2) nP (O) (OR4) (OR5), - (CH2) nO- (CH2) m -CO2H, - (CH2) nO- (CH2) m-COR11, - (CH2) nO- (CH2) mP (O) (OR4) ( OR5), - (CH2) nO- (CH2) m-SO2NR9R10 or - (CH2) nO- (CH2) m-NR9SO2R8; R4 and R5 are each, independently, hydrogen or alkyl (C? -C6); and R6 and R7 are each independently, hydrogen, halo, alkyl (d-d), nitro, cyano, trifluoromethyl, SO2R8, SO2NR9R10, NR9R10, COR11, CO2R9, alkoxy (d-Cß), NR9SO2R8, NR9COR11, NR9CO2R9 or OR9; where G1 and G2, each time they appear, are each independently hydrogen, alkyl (dd) optionally independently substituted with one or more halo, alkoxy, (d-C8) alkyl (C6-6) or cycloalkyl (C3-C8) , or G1 and G2 together with the nitrogen to which they are attached form a saturated heterocyclic ring having from 3 to 7 carbon atoms, where one of said carbon atoms, can optionally be replaced by oxygen, nitrogen or sulfur; G3, each time it appears, is independently hydrogen or alkyl (Ci-d); R8, each time it appears, is independently alkyl (d-d) or alkoxy (d-d) alkyl (d-d); R9 and R10, each time they appear, are independently hydrogen, alkyl (d-d), cycloalkyl (C3-C8) or alkoxy (d-d) alkyl (d-C6); R11, each time it appears, is independently hydrogen, alkyl (dd), alkoxy (d-C6), NR9R10, cycloalkyl (C3-C8) or alkoxy (C? -C6) alkyl (Ci-d), where R9 and R10 they are as defined above; m, each time it appears, is independently an integer from 1 to 6; and n, each time it appears, is independently 0 or an integer from 1 to 6; with the proviso that: (1) when Q9 is O or S, then n is not 0; (2) when Q1 is oxygen or sulfur, then Q3 is absent; and (3) when Q2 is nitrogen, then Q5 is absent. 49. A process of claim 48, wherein said organosulfonyloxy is methanesulfonyloxy, benzenesulfonyloxy, p-toluenesulfonyloxy, p-nitrobenzenesulfonyloxy or m-nitrobenzenesulfonyloxy. 50.- A procedure for preparing a compound of the formula (I) and the racemic-enantiomeric mixtures and optical isomers of said compounds, comprising: (a) reacting a compound of the formula VI with an organosulfonyl chloride and a suitable base, in a solvent inert to the reaction, to form a compound of the formula (b) reacting said compound of formula (II) with a chlorinating agent in a reaction inert solvent to form a compound of the formula (VII) VII (c) reacting said compound of formula (VII) with a non-nucleophilic base in a solvent inert to the reaction to form a compound of the formula (III) (d) reacting said compound of formula (III) with a base and HNY2Y3 to form said compound of formula (I); wherein: R1 is selected from the group consisting of nitro, amino and protected amino; R2 is selected from the group consisting of H, fluoro, chloro, CF3, nitro, alkyl (Ci-d), alkoxy (C1-C4), amino and protected amino; and x is organosulfonyloxy; Y1 and Y3 are H; Y2 is OR where; Q1 is hydrogen or sulfur; Q2 is carbon or nitrogen; Q3 is hydrogen, (CH2) n-phenyl, -alkyl (d-C10), - (CH2) n- NG G2, - (CH2) n-CO2G3, - (CH2) n-CO-NG1G2, - (CH2) n-OG3, - (CH2) n-SO3G3, - (CH2) n-SO2-alkyl (d-C6), - (CH2) n-SO2NG1G2 or a heterocycle selected from the group consisting of - (CH2) n-pyridyl , - (CH2) n-pyrimidyl, - (CH2) n-pyrazinyl, - (CH2) n-isoxazolyl, - (CH2) n-oxazolyl, - (CH2) n-thiazolyl, - (CH2) n- (1, 2,4-oxadiazoliIo), - (CH2) n-imidazolyl, - (CH2) n-triazolyl and - (CH2) n-tetrazolyl; wherein one of the ring nitrogen atoms of said - (CH2) n-imidazaIiIo, - (CH) n-triazolyl and - (CH2) n-tetrazolyl may be optionally substituted with alkyl (CrC8) optionally substituted independently with one or more halo atoms; wherein each of said heterocyclics may be optionally substituted on one or more of the carbon atoms of the ring, with one or more substituents independently selected from the group consisting of alkyl (C? -d), optionally independently substituted with one or more atoms of halo, halo, nitro, cyano, - (CH2) n-NG1G2, - (CH2) n-CO2G3, - (CH2) n-CO-NG1G2, - (CH2) n-OG3, - (CH2) n-SO3G3 , - (CH2) n-SO2-alkyl (d-C6) and - (CH2) n-SO2NG1G2; wherein the phenyl radical of said - (CH2) n-phenyl may be optionally substituted with one or more substituents independently selected from the group consisting of alkyl (dd) optionally independently substituted with one or more halo atoms, hydroxy, alkoxy (C? -C6) optionally independently substituted with one or more halo atoms, alkylthio (C? -Cβ), fluoro, chloro, bromo, iodo, cyano, nitro, - (CH2) n-NG1G2, - (CH2) n- CO2G3, - (CH2) n-CO-NG1G2, - (CH2) n-OG3, - (CH2) n-SO3G3, - (CH2) n-SO2-alkyl (d-C6), - (CH2) n-SO2NG1G2; - (CH2) n-NG3-SO2-G3 and - (CH2) n-NG3-SO2-NG1G2; Q4 is - (CH2) n-CN, - (CH2) n -CO2G3, - (CH2) n-SO3G3, - (CH2) n-SO2-alkyl (d-C6), - (CH2) n-SO2NG1G2, - (CH2) nCH2OH, - (CH2) n-CHO, - (CH2) n-CO-G3, - (CH2) n-CONG1G2 or a heterocycle selected from - (CH2) n-thiazolyl, - (CH2) n-oxazolyl , - (CH2) n-imidazolyl, - (CH2) n-triazolyl, - (CH2) n-1, 2,4-oxadiazolyl, - (CH2) n-isoxazoliIo, - (CH2) n-tetrazolyl and - (CH2) n-pyrazolyl; wherein one of the ring nitrogen atoms of said - (CH2) n-imidazolyl, - (CH2) n-triazolyl and - (CH2) n-tetrazolyl may be optionally substituted with optionally substituted (C? -C6) alkyl independently with one or more halo atoms; wherein each of said heterocycles may be optionally substituted, on one or more of the ring carbon atoms, with one or more substituents independently selected from the group consisting of hydrogen, optionally independently substituted (D-Cß) alkyl with one or more halo atoms, - (CH2) n-CO-NG1G2, - (CH2) n-CO2G3, halo, nitro, cyano, - (CH2) n-CO-NG1G2, - (CH2) n-OG3, - (CH2) n-SO3G3, - (CH2) n-SO2-alkyl (d-C6) or - (CH2) n-SO2NG1G2; Q5 is hydrogen or alkyl (d-d) optionally substituted independently with one or more halo atoms; Q6 is a covalent bond, oxygen or sulfur; Q7 is hydrogen or alkyl (d-d) optionally independently substituted with one or more halo atoms; Q8 and Q9 are, independently, a covalent bond, oxygen, sulfur, NH or -N-alkyl (d-C6); Q10 is - (CH2) m-OR9, - (CH2) n -CO2H, - (CH2) n-COR11, - (CH2) n-SO2NR9R10, - (CH2) n-NR9SO2R8, - (CH2) nP (O) (OR5), - (CH2) nO- (CH2) m -CO2H, - (CH2) nO- (CH2) m-COR11, - (CH2) nO- (CH2) mP (O) (OR4) (OR5), - (CH2) nO- (CH2) m-SO2NR9R10 or - (CH2) nO- (CH2) mNR9SO2R8; R4 and R5 are each, independently, hydrogen or alkyl (C? -d); and R6 and R7 are each, independently, hydrogen, halo, C alquiloß alkyloxy), nitro, cyano, trifluoromethyl, SO2R8, SO2NR9R10, NR9R10, COR11, CO2R9, alkoxy (d-C6), NR9SO2R8, NR9COR11, NR9CO2R9 or OR9; where G1 and G2, each time they appear, are each independently hydrogen, alkyl (dd) optionally independently substituted with one or more halo, (C? -C8) alkoxy (C? -d) alkyl or (C3-C8) cycloalkyl , or G and G2 together with the nitrogen to which they are attached form a saturated heterocyclic ring having from 3 to 7 carbon atoms, where one of said carbon atoms can optionally be replaced by oxygen, nitrogen or sulfur; G3, each time it appears, is independently hydrogen or aikyl (C? -Cβ); R8, each time it appears, is independently alkyl (d-C6) or alkoxy (C? -d) alkyl (C? -Cβ); R9 and R10, each time they appear, are independently hydrogen, alkyl (C? -d), cycloalkyl (C3-C8) or alkoxy (C? -C6) alkyl (C-? -d); R11, each time it appears, is independently hydrogen, alkyl (C? -C?), Alkoxy (dd), NR9R10, cycloalkyo (C3-C8) or alkoxy (C? -C?) Alkyl (C? -C?) , wherein R9 and R10 are as defined above; m, each time it appears, is independently an integer from 1 to 6; and n, each time it appears, is independently 0 or an integer from 1 to 6; with the condition of; (1) when Q9 is O or S, then n is not 0; (2) when Q1 is oxygen or sulfur, then Q3 is absent; and (3) when Q2 is nitrogen, then Q5 is absent. 51. A process of claim 50, wherein said coloring agent is lithium chloride and said organosulfonyloxy is selected from the selected group consisting of methanesulfonyloxy, benzenesulfonyloxy, p-toluenesulfonyloxy, p-nitrobenzenesulfonyloxy or m-nitrobenzenesulfonyloxy. 52. A method of claim 48, wherein before said step (a), said compound of formula (II) is prepared by the reaction of a compound of the formula SAW with an organosulfonyl chloride and a suitable base in a solvent inert to the reaction. 53. A process of claim 52, wherein said organosulfonyloxy is methanesulfonyloxy, benzenesulfonyloxy, p-toluenesulfonyloxy, p-nitrobenzenesulfonyloxy or m-nitrobenzenesulfonyloxy. 54.- A process for preparing a compound of the formula (XIII) XIII which comprises reacting a compound of the formula (XIV) XIV wherein: PG is an amine protecting group; R20 is alkyl (C? -C8); R21 is selected from the group consisting of alkyl (d-C8), COR22, CO2R22 and SO2R22; and R22 is alkyl (C? -C8), with an aqueous acid. 55. A process of claim 54, wherein said amine protecting group is selected from the group consisting of COR22, CO2R22 and SO2R22; and R22 is alkyl (d-C8). 56.- A process of claim 55, wherein said compound of formula XIV is N-methyl 4- (2- (2- (2-acetylaminopyridin-5-yl) -2 (R) -hydroxyethyl-N-tert. -butoxycarbonylamino) -ethoxy) -phenylacetamide. 57.- A procedure for preparing a compound of the formula XIII comprising: (a) reacting a compound of the formula XV where R s21 is COR, 22. and, D R22 is alkyl (C? -C8), with a compound of formula XVI in which R > 20 is (C? -C8) alkyl, in a reaction inert solvent, to form a compound of the formula XVI (b) reacting said compound of formula (XVI) with an acid anhydride, a dicarbonate or an acid chloride, to form a compound of the formula XIV wherein R20 and R21 are as defined above and PG is an amine protecting group; and (c) reacting said compound of formula (XIV) with an aqueous acid to form said compound of formula (XIII). 58.- A method of claim 57, wherein said amine protecting group is selected from the group consisting of COR22 and CO2R22; and R22 is alkyl (C? -C8). 59. A process of claim 58, wherein said compound of formula (XVI) is reacted with a dicarbonate. 60.- A process of claim 59, wherein R21 is acetyl, R20 is methyl and PG is tert-butyloxycarbonyl.