WO2007038452A1

WO2007038452A1 - Process for synthesizing 1,2,4-triazoles

Info

Publication number: WO2007038452A1
Application number: PCT/US2006/037323
Authority: WO
Inventors: Matthew Mangzhu Zhao
Original assignee: Merck & Co., Inc.
Priority date: 2005-09-28
Filing date: 2006-09-22
Publication date: 2007-04-05

Abstract

The present invention relates to a process for production of 1,2,4-triazoles. The process comprises the reaction of a disubstituted amide and a hydrazide in the presence of POCl3.

Description

TITLE OF THE INVENTION

PROCESS FOR SYNTHESIZING 1,2,4-TRIAZOLES

FIELD OF THE INVENTION The present invention relates to the synthesis of certain substituted 1,2,4-triazoles which may have utility as pharmaceuticals for treating diseases and conditions such as type 2 diabetes, metabolic syndrome, obesity and hypertension.

BACKGROUND OF THE INVENTION The present invention discloses an improved method of synthesizing substituted triazoles, which may be useful in medicaments. Triazoles in general are used in numerous pharmacologically active compounds. For example, triazole derivatives have been previously disclosed as being useful for treating cerebrovascular disorders, fungal infection, neurodegenerative diseases, inflammation, allergy, diabetes, metabolic syndrome, and other conditions. The triazoles synthesized using the current method are inhibitors of the 11-beta-HSDl enzyme and may be useful in treating such diseases as type 2 diabetes, metabolic syndrome, obesity, hypertension, and dyslipidemia. The process provides significantly improved yields over prior processes.

One object of the present invention is to provide a process for the synthesis of triazoles with improved yields relative to prior processes. Another object of the present invention is to provide a convenient synthesis of triazole products without the need for isolating intermediates, so that isolation and purification steps are avoided until the final product is produced.

Yet another object is to provide a reaction process that provides the desired product in high yield with minimal formation of side products. These and other objects will be apparent from the specification.

SUMMARY OF THE INVENTION

A process for the synthesis of a compound of formula I is disclosed herein:

Wherein each R¹ is independently selected from the group consisting of: -OH, halogen,

Ci-ioalkyl, -OCi_₆alkyl, and C_6-ioAryl, wherein Ci.ioalkyl, C_6-IoATyI and the alkyl portion of -OCi. ₆alkyl are optionally substituted with 1-3 substituents independently selected from halogen, -OH, -OCi. 3alkyl, phenyl and naphthyl, said phenyl and naphthyl being optionally substituted with 1-3 substituents independently selected from halogen, -OCH₃, -OCF₃, CH₃, CF₃, and phenyl which is optionally substituted with 1-3 halogens;

R² is selected from the group consisting of: (a) C\ _i₄alkyl optionally substituted with 1-6 halogens and 1-3 substituents independently selected from -OH, -OC 1-3 alkyl, and phenyl, said phenyl being optionally substituted with 1-4 groups independently selected from halogen, -OCH₃, -OCF₃, CH₃ and CF₃, said -0Ci_3alkyl being optionally substituted with 1-3 halogens; (b) a cyclic substituent group selected from the group consisting of phenyl, pyridyl and C3_8Cycloalkyl, said cyclic substituent group being optionally substituted with 1-3 substituents independently selected from halogen, -OH, and

R^a; (c) C2-ioalkenyl which is optionally substituted with 1-3 substituents independently selected from halogen, -OH and -OCi_3alkyl, wherein the Ci_3alkyl portion of -OCi -3 alkyl is optionally substituted with 1-3 halogens; (d) -CH2CO2H; (e) -CH2CO2Ci_6alkyl; (f) -CH2C(O)NHRb; (g) -CH2C(O)NH₂;

(h) -NH₂; (i) -NHRb; and (j) -N(Rb)₂;

R^a is selected from the group consisting of C1.3al.cyl, -0Ci_3alkyl, -Ci_6alkyleneC₆_ loAryl, and phenyl, wherein Aryl and phenyl are optionally substituted with 1-3 halogens; Rb is selected from the group consisting of C^alkyl, -Ci.galkyleneCg.ioAryl, and phenyl, wherein Aryl and phenyl are optionally substituted with 1-3 halogens;

R3 is selected from the group consisting of: Ci_i₄alkyl, C₂_ioalkenyl, -SCi_₆alkyl, C₃. δCycloalkyl, C6-ioAryl, Heterocyclyl, and Heteroaryl, wherein when R3 is alkyl, alkenyl, or -SCi-βalkyl,

R3 is optionally substituted with 1-6 halogens and 1-3 groups independently selected from -OH, -NH₂, -NHCi_₄alkyl, -N(CMaIlCyI)₂, -OCi^alkyl, -CN, phenyl, -S(O)_xCi.4alkyl, -NHSO₂C i_₄alkyl, -SO₂NH₂, -SO₂NHCi.4alkyl, and -SO₂N(Ci_-4alkyl)₂, wherein the Ci-4alkyl portions of the substituent groups -NHCi_₄alkyl, -N(Ci.₄alkyl)₂, -0Ci-4alkyl, -S(O)_xC i_4alkyl, -NHSO₂Ci.₄alkyl, -SO₂NHC i.₄alkyl, and -SO₂N(Ci_₄alkyl)2 are optionally substituted with 1 phenyl and 1-3 halogens, said phenyl being optionally substituted with 1-3 substituents independently selected from halogen, -OCH₃, -OCF₃, CH₃, and CF₃; and when R³ is Cycloalkyl, Aryl, Heterocyclyl, or Heteroaryl, R³ is optionally substituted with 1-4 substituent groups independently selected from halogen, Ci-₄alkyl, -OH, -NH₂, -NHCi_-4alkyl, -N(Ci. ₄alkyl)₂, -0Ci-4alkyl, -CN, phenyl, -S(O)_xC i-4alkyl, -NHSO₂C i_₄alkyl, -SO₂NH₂, -SO₂NHC i.₄alkyl, and -SO₂N(C i_₄alkyl)₂, wherein the Cl_4alkyl portions of the substituent groups Ci_-4alkyl, -NHCi_-4alkyl, -N(C_1-4alkyl)₂, -OC^alkyl, -S(O)_xC i-4alkyl, -NHSO₂C i_₄alkyl, -SO₂NHC i-₄alkyl, and -SO₂N(C i-₄alkyl)₂ are optionally substituted with 1 phenyl and 1-3 halogens, said phenyl being optionally substituted with 1-3 substituents independently selected from halogen, -OCH₃, -OCF₃, CH₃, and CF₃;

Each R4 is independently selected from the group consisting of halogen, Ci_i₄alkyl, C₂_ioalkenyl, -SCi^alkyl and -OCi_₆alkyl, wherein Ci_i₄alkyl and the alkyl and alkenyl groups of C₂_ioalkenyl, -SCi^alkyl and -OCi_-6alkyl are optionally substituted with 1-3 halogens and 1-2 substituent groups independently selected from -OH, -NH₂, -NHCi^alkyl, -N(Ci_3alkyl)₂, -0Ci_3alkyl, and -CN; m is an integer from 0-3; n is an integer from 0-3; and x is O₅ 1 or 2.

In the above description and subsequent description,

"C6-lθAryl" *^{s a} monocyclic or bicyclic carbocyclic aromatic substituent group, with phenyl and naphthyl being the preferred groups and phenyl being the most preferred group;

"Cycloalkyl" is a saturated carbocyclic ring having 3 to 8 carbon atoms in the ring, unless otherwise stated; "Heterocyclyl" is a fully or partially saturated 5-6 membered ring having 1-3 heteroatoms in the ring independently selected from N, S and O;

"Heteroaryl" is an aromatic 5-6 membered ring having 1-4 heteroatoms independently selected from N, S and O;

"Alkyl" groups are saturated carbon chains which may be linear or branched or combinations thereof, unless otherwise defined; and

"Alkenyl" groups are carbon chains having one double bond which may be linear or branched or combinations thereof, unless otherwise defined.

The process comprises the steps of: (1) combining an amide and POCl₃ to provide an activated intermediate, where the amide has the structure shown in Formula UI:

R3C(O)NHR2 m and (2) combining the activated intermediate with a compound of formula II to provide the compound of formula I,

wherein R¹, R², R³, R⁴, m and n are as previously defined. DETAILED DESCRIPTION OF THE INVENTION

The 1,2,4-triazole compounds of formula I are synthesized by the reaction of substituted amide IH with hydrazide π. The reaction is brought about by combining the amide HI with phosphorus oxychloride (POCI3) to generate an activated intermediate, and then combining the activated intermediate and hydrazide II under conditions that will yield the triazole I. The "activated intermediate" that is described herein is not isolated or characterized, and may actually be a mixture of intermediates. The activated intermediate is referred to as activated because it is chemically more reactive than the amide. Similarly the reaction of the activated intermediate with hydrazide II may proceed through one or more intermediates that are not characterized. The reaction conditions of the 2 steps, such as solvent, temperature, time, agitation, pH, and the like, are adjusted to optimize the yield, purity of product, and the like. It should also be recognized that after hydrazide II has been combined with the activated intermediate that results from the reaction OfPOCl₃ with amide HI, the reaction will be subjected to workup steps such as quenching, pH adjustment, and warming to obtain the final product I. The reaction is illustrated in the example below, and is readily modified by one of skill in the art of organic process chemistry for other compounds based on the description below.

This process improves yields significantly compared with other processes that are used to synthesize triazoles of Formula I from the intermediate having Formula II, and also avoids the use of expensive reagents and unstable intermediates. For example, the product that is synthesized in Example 1 using the method of this invention was previously disclosed in US Patent No. 6,730,690. The compound was synthesized in Procedure 41 of the '690 patent from the same amide and hydrazide as are used in Example 1 herein, but the reaction in the '690 patent was carried out by first converting the amide to an imidoate (methyl N-cy.clopropylcyclopropanecarboximidoate), which was then reacted with the hydrazide in the presence of triethylamine in toluene. The imidoate was made by reaction of the amide with methyl triflate. The current process eliminates the need for methyl triflate, which is a very costly reagent, and provides better yields than the method that was used in the '690 patent.

Another method that was considered for carrying out the reaction of Compounds II and TTT is to first convert the amide IH to an imidoyl chloride that is analogous to the methyl imidoate described above, but with a Cl in place of methoxy, and then reacting the imidoyl chloride with hydrazide H Many imidoyl chlorides are unstable, such as those that have cyclopropyl groups in their structure. The imidoyl chloride described above may occur as a transient unisolated intermediate during the course of this reaction. Regardless of the mechanism of the reaction, the process described herein proceeds readily in high yield.

Alternate syntheses of triazoles from similar intermediates can be found in the following publications:

(a) G. A. McCort, et al., Tet. Let. (1992) 33: 4443-4446.

(b) Walser, et al., J. Med Chem. (1991) 34: 1209-1221. (c) Wade, et al. J. Org. Chem. (1979) 44: 88-96.

(d) Neilson, et al. Chem. Review (1970) 70: 151-170.

In embodiments of Formula I, R¹ is selected from the group consisting of -OH, halogen, C i -δalkyl, -OC i .βallcyl, and C₆. j o Aryl, wherein C i .galkyl and -OC i .galkyl are optionally substituted with

1-3 halogens, and Aryl is optionally substituted with 1-3 substituents independently selected from halogen, -OCH₃, -OCF₃, CH₃, and CF₃. In preferred embodiments of Formula I, R¹ is halogen, and most preferably is Cl.

In embodiments of Formula I, R² is selected from the group consisting of C^alkyl, C3_6Cycloalkyl, and phenyl, where Ci_₆alkyl is optionally substituted with 1-3 halogens, and

Q-_θCycloalkyl and phenyl are optionally substituted with 1-3 halogens and 1 substituent selected from -OCH₃, -OCF₃, CH₃, and CF₃. In preferred embodiments, R² is C3_6Cycloalkyl, which is optionally substituted with 1-3 halogens, and is most preferably cyclopropyl.

In embodiments of Formula I, R3 is selected from the group consisting of Ci_₆alkyl, C2-6alkenyl, -SCi^alkyl, C₆_ioAryl, and C3-6Cycloalkyl, wherein C^alkyl, C2-6alkenyl, and -SCj. 6alkyl are optionally substituted with 1-3 halogens, and C_6-IoATyI and C3_-6Cycloalkyl are optionally substituted with 1-3 halogens and 1 substituent selected from -OCH₃, -OCF₃, CH₃, and CF₃. In preferred embodiments, R³ is Cs-gCycloalkyl, which is optionally substituted with 1-3 halogens, and is most preferably cyclopropyl. In embodiments of Formula I, R⁴ is selected from the group consisting of halogen, C₁.

6alkyl, C2-6alkenyl, -SCi_-6alkyl and -OCi_₆alkyl, wherein C^aUcyl, C2-6alkenyl, -SCμβalkyl and -OC₁. galkyl are optionally substituted with 1-3 halogens.

In embodiments of Formula I, m is 1, and the remaining R¹ group is as defined previously. In subsets of these, the Rl group is on the phenyl ring in the position para to the cyclobutyl ring.

In embodiments of Formula I, n is O or 1, and the remaining R⁴ group, if present, is as defined previously. In subsets of these, the R⁴ group, if present, is on the cyclobutyl ring in the 3- position, where the disubstituted position of the cyclobutyl ring is counted as the 1 -position. In preferred embodiments, n is 1, and the R⁴ substituent is on the cyclobutyl ring in the 3 -position, where the disubstituted position of the cyclobutyl ring is counted as the 1 -position. In preferred embodiments, the

R⁴ substituent is halogen, and most preferably is F.

In a preferred embodiment of this invention, the compound of formula Ia is made by the process described below, where the compound of Formula Ia is defined below:

Ia

wherein, R¹ is selected from the group consisting of -OH, halogen, Ci.₆alkyl, -OCi. galkyl, and C_δ-ioAryl, wherein Ci-galkyl and -0Ci_6alkyl are optionally substituted with 1-3 halogens, and Aryl is optionally substituted with 1-3 substituents independently selected from halogen, -OCH₃, -OCF₃, CH₃, and CF₃;

R⁴ is selected from the group consisting of halogen, C^galkyl, C2-6alkenyl, -SCμβalkyl and -OCi-galkyl, wherein Ci^alkyl, C2-6alkenyl, -SCi_6alkyl and -OCi-galkyl are optionally substituted with 1-3 halogens; n is O or 1; and

R² and R³ are as described previously; wherein the compound of formula Ia is made by a process comprising the steps of: (1) combining an amide and POCI3 to provide an activated intermediate, where the amide has the structure shown in Formula DI:

R3C(O)NHR2 m and (2) combining the activated intermediate with a compound of formula IIa to provide the compound of formula Ia.

In another preferred embodiment of this invention, the compound of formula Ia is made by the process of this invention, wherein

R¹ is selected from the group consisting of -OH, halogen, Ci-βalkyl, -OCi^alkyl, and phenyl, wherein Ci^alkyl and -OCi^alkyl are optionally substituted with 1-3 halogens, and phenyl is optionally substituted with 1-3 substituents independently selected from halogen, -OCH₃, -OCF₃, CH₃, and CF₃; R2 is selected from the group consisting of Ci_₆alkyl, C3_6Cycloalkyl, and phenyl, where Ci-βalkyl is optionally substituted with 1-3 halogens, and C3_-6Cycloalkyl and phenyl are optionally substituted with 1-3 halogens and 1 substituent selected from -OCH₃, -OCF₃, CH₃, and CF₃;

R3 is selected from the group consisting of Ci_₆alkyl, C2-6alkenyl, -SCi^alkyl, phenyl, and Cs-βCycloalkyl, wherein Chalky!, C2-6alkenyl, and -SCi-galkyl are optionally substituted with 1-3 halogens, and phenyl and Cβ-eCycloalkyl are optionally substituted with 1-3 halogens and 1 substituent selected from -OCH₃, -OCF₃, CH₃, and CF₃; i

R⁴ is selected from the group consisting of halogen, Ci^alkyl, C2-6alkenyl, -SCi^alkyl and -OCi-galkyl, wherein Ci-galkyl, C2-6alkenyl, -SCi.βalkyl and -OCi.galkyl are optionally substituted with 1-3 halogens; and n is O or 1; wherein the compound of formula Ia is made by a process comprising the steps of: (1) combining an amide and POCl₃ to provide an activated intermediate, where the amide has the structure shown in Formula IH: R3C(O)NHR2 ffl and (2) combining the activated intermediate with a compound of formula Ha to provide the compound of formula Ia.

In a highly preferred embodiment of this invention, the compound of formula Ia is defined below:

R¹ is halogen; R2 is C₃.₆Cycloalkyl optionally substituted with 1-3 halogens;

R³ is C3_gCycloalkyl optionally substituted with 1-3 halogens;

R⁴ is halogen; and n is 1; wherein the compound of formula Ia is made by the process comprising the steps of: (1) combining an amide of formula HI and POCl₃ to provide an activated intermediate; and (2) combining the activated intermediate with a compound of formula Ha to provide the compound of formula Ia.

Compounds of formula I, Ia, and Ib are inhibitors of the 11-beta-HSDl enzyme. They are particularly useful for treating type 2 diabetes, metabolic syndrome, obesity, hypertension, and related conditions. Such uses are generally described in US Pat No. 6,730,690 B2, which was granted on May 4, 2004. Dosages, compositions and alternative synthetic schemes are provided in the patent cited above.

EXAMPLES

Hydrazide II can be obtained according to the procedures set forth in Preparative Examples 1 through 3 and 5. In Preparative Examples 1 and 2, a substituted or unsubstituted phenylacetic acid is reacted with a Grignard reagent. An epichlorohydrin reaction is conducted to produce the cyclobutyl carboxylic acid, which is then esterified with a lower alcohol, such as methanol, by the heating of a solution of the alcohol and acid in the presence of sulfuric acid.

Halogen substitution on the cyclobutyl ring is achieved as described in Preparative Example 3.

The ester of Preparative Example 3 is then reacted with hydrazine to produce the hydrazide intermediate II (Preparative Example 5). Compound HI can generally be prepared according to methods used in Preparative

Example 4.

The invention is further illustrated with the following non-limiting examples. Scheme 1 shows a complete synthesis of a highly preferred compound having Formula Ib which is made using the method described herein. Preparative Examples 1-5 provide the detailed syntheses of the two intermediates lib and IΗb that are combined in the last step of the reaction sequence. Example 1 provides a detailed synthesis of the final product using the method that is disclosed and claimed herein.

All publications, patents and patent applications cited herein are hereby incorporated by reference. While certain preferred embodiments have been described herein in detail, numerous alternative embodiments are encompassed by the claims. The example and preparative examples should not be construed as limiting the scope of the invention. The scope of the invention is defined by the appended claims. Scheme 1

PREPARATIVE EXAMPLE 1

A solution of /-PrMgCl (2.1 M in THF, 25 L, 52.5 mol), was cooled with an ice bath. A solution of 4-chlorophenylacetic acid (4.09 kg, 24.0 mol) in 6 L THF was added slowly while keeping the temperature at 40-50 ⁰C. The slurry was cooled to 20 ⁰C and epichlorohydrin (4.04 kg, 43.2 mol) was added slowly while maintaining the temperature at 20-25 ⁰C. After stirring the reaction mixture at room temperature for 45 min, more /-PrMgCl (22.9 L, 48 mol) was added over 30 min. The reaction mixture was slowly heated to 60 ⁰C and stirred for 14h. The solution was then cooled to -20 ⁰C and quenched slowly into 10 L of IN HCl while keeping the temperature below 45 ⁰C. The organic layer was separated and concentrated by vacuum distillation while simultaneously adding toluene (40 L) until the distillate was clear. The resulting slurry was then stirred at room temperature and filtered, washing with toluene. Drying under vacuum gave a white solid. mp 181-182 ⁰C; ¹H NMR (400 MHz, DMSOd⁶): 12.35 (br s, 1 H), 7.38 (s, 4 H), 5.19 (br s, 1 H), 3.89-3.82 (m, 1 H), 2.74-2.69 (m, 2 H), 2.53-2.50 (m, 2 H); ¹³C NMR (100 MHz, DMSO-d⁶) 176.5, 141.1, 132.1, 128.8, 128.4, 60.8, 44.0, 42.8.

PREPARATIVE EXAMPLE 2

The hydroxy acid (1.98 kg, 8.7 mol) was dissolved in MeOH (11 L). Concentrated sulfuric acid was added (48.5 mL, 0.91 mol) The solution was heated to 60 ⁰C for 15 h, then cooled to 25 ⁰C. The solution was concentrated by vacuum distillation, removing 9.5 L of methanol, then quenched into water (10 L) and toluene (10 L) The aqueous layer was removed, and the organic layer was washed with aqueous 1% NaHCO₃ (4 L). The final toluene solution was concentrated to a weight of 5.0 kg and used in the next step.

¹H NMR (400 MHz, CDCl₃): 7.33-7.29 (m, 4 H), 4.18 (quint, J= 6.8 Hz, 1 H), 3.64 (s, 3 H), 2.92-2.86 (m, 2 H), 2.76-2.70 (m, 2 H), 2.45 (br s, 1 H); ¹³C NMR (100 MHz, CDCl₃) 175.7, 139.8, 132.9, 128.6, 12.4, 62.3, 52.6, 44.5, 42.6.

PREPARATIVE EXAMPLE 3

To the toluene solution of hydroxy methyl ester from step 2 (5.01kg of 40.2wt% solution in toluene, 8.50 mol) was added diisopropylethylamine (1.43kg, 11.1 mol). Acetonitrile (4.3L) and more toluene (0.8L) were added, and the solution was cooled to -10 ⁰C. Trifiic anhydride (2.88 kg, 10.2 mol) was added slowly while keeping the temperature between -6 ⁰C and -3 ⁰C. After stirring 50 min more, the solution was cooled to -11 ⁰C, and diisopropylethylamine (2.96 kg, 22.9 mol) was added followed by NEt₃(HF)₃ (1.79 kg, 11.1 mol). The solution was stirred at -7 ⁰C for 17 h, then warmed to 23 ⁰C for Ih. The solution was then cooled to 3 ⁰C and 8.5L water was added, followed by 0.20L of 5N KOH. The layers were allowed to separate and the aqueous layer was removed. The organic portion was washed twice with water, then concentrated under vacuum to give a brown oil.

H NMR (400 MHz, CDCl₃): 7.33-7.30 (m, 2 H), 7.18-7.15 (m, 2 H), 4.23 (dquint, J= 55.6, 6.9 Hz, 1 H), 3.66 (s, 3 H), 3.32-3.24 (m, 2 H), 2.70-2.58 (m, 2 H); ¹³C NMR (100 MHz, CDCl₃) 175.0, 141.7, 133.0, 128.7, 127.7, 82.8 (d, J= 210 Hz), 52.9, 43.7 (d, J= 18 Hz), 41.5, 41.3. ¹⁹F NMR (376 MHz, CDCl₃) -166.

PREPARATIVE EXAMPLE 4

To a mixture of 5 N NaOH (6.6 L, 33.0 mole) and heptane (3.75 L) was added cyclopropylamine (1.73 kg, 99%, 30.0 mole) at -10 to 0 ⁰C. A solution of cyclopropyl carbonyl chloride (3.20 kg, 98%, 30.0 mole) in heptane (3.75 L) was then slowly charged while maintaining the batch at - 10 to 0 ⁰C. The mixture was stirred at -5 ⁰C for 2 h then filtered. The product cake was washed with cold (0-5 ⁰C) brine (4.0 L x 2), then ice-cold water (4.0 L) and heptane (8.0 L). Oven drying at 40 ⁰C under vacuum gave the amide as a white solid.

A 7/1 mixture of two rotamers: NMR data for the major isomer:

¹H NMR (400 MHz, CDCl₃) δ 6.20 (brd, H), 2.72-2.66 (m, IH), 1.35-1.28 (m, IH), 0.99-0.91 (m, 2H), 0.83-0.65 (m, 4H), 0.51-0.47 (m, 2H). ¹³C NMR (100 MHz, CDCl₃) δ 175.19, 22.89, 14.57, 7.23, 6.65.

PREPARATIVE EXAMPLE 5

The crude fluoro methyl ester (5.27 kg assay, 21.71 mole) was dissolved in DMAc (8.0 L). Hydrazine monohydrate (3.24 kg, 64.8 moles) was added and the mixture was heated to 50 ⁰C for 12 hours. The reaction mixture was cooled to 20 ⁰C and water (5 L) was added. The mixture was stirred for 1 hour to initiate the crystallization. More water (15 L) was added slowly over 3 hours. The product was filtered and the filter cake was washed with 3/1 water/DMAc (5 L x 2), then water (10 L x 2). Oven drying at 40 ⁰C under vacuum gave the hydrazide as a brownish solid. ¹H NMR (400 MHz, CDCl₃) δ 7.38 (d, J= 8.4 Hz, 2H), 7.13 (d, J= 8.4 Hz, 2 H), 6.34 (brd, IH), 5.45 (qd, J= 56.7, 6.8 Hz, IH), 3.75 (brd, 2H), 3.23-3.16 (m, 2H), 2.66-2.56 (m, 2H). ¹³C NMR (100 MHz, CDCl₃) δ 175.66 (d, ⁴Jc_-F = 1.7 Hz), 141.59, 133.75, 129.46, 127.93, 83.05 (d, ¹Jc-_F = 209.4 Hz), 43.81 (d, ³J_C-F = 15.1 Hz), 42.02 (d, ²J_C-F = 22.1 Hz). ¹⁹F NMR (CDCl₃) δ -162.9.

EXAMPLE 1

To a sluπy of the dicyclopropyl amide (2.79 kg, 96.3w%, 21.5 mole) in toluene (18 L) was added POCl₃ (6.64 kg, 43.3 mol). The mixture was heated to 35 ⁰C for 3 hours. It was cooled to -10 ⁰C and then the hydrazide (4.60 kg 95 wt%, 18.0 moles) was added in portions to maintain the batch below 10 ⁰C. The mixture was then warmed to rt and stirred overnight. The reaction mixture was cooled to 0-5 ⁰C, then slowly quenched into vigorously stirred aq. NaOH (19.0 kg 50% NaOH + 27 L H₂O) at 5 ⁰C. The mixture was stirred at 0 ⁰C for 1.5 hours, then acetonitrile (15 L) was added, and the mixture was slowly warmed to 20 ⁰C. Triethylamine (0.55 kg) was added and the mixture was heated to 57 ⁰C overnight. The reaction mixture was then cooled to 35 ⁰C and acetic acid (4.31 kg, 72 mole) was added. The mixture was stirred at 35-40⁰C for 2 hours to effect the cyclization. Heptane (10 L) was then added and the layers were separated. The organic layer was washed with water (36 L x 2). The organic layer was concentrated to ~20 L and then acetonitrile (21 L) was added. Concentrated sulfuric acid (1.69 kg, 95.6w%) was added over Ih. The mixture was stirred for 1 hour and filtered, rinsing with 1/1 toluene/MeCN (18 L). The solid was air dried to constant weight to afford 6.65kg of the bisulfate salt. HPLC assay: 98.6 wt%, 84.6% yield corrected for purity.

¹H NMR (400 MHz, CDCl₃) δ 10-7 (brd, 2H), 7.42 (d, J= 8.7 Hz, 2H), 7.32 (d, J= 8.7 Hz, 2 H), 5.12 (qd, J= 56.4, 6.3 Hz, IH), 3.47-3.39 (m, 2H), 2.90-2.80 (m, 2H), 2.77-2.72 (m, IH), 2.27- 2.21 (m, IH), 1.26-1.17 (m, 4H), 0.85-0.79 (m, 2H), 0.78-0.73 (m, 2H). ¹³C NMR (100 MHz, CDCl₃) δ 159.61, 158.46, 140.90, 131.97, 128.77, 128.06, 84.25 (d, 1^ = 204.7 Hz), 41.27 (d, ²Jc_-F = 21.7 Hz), 37.78 (d, ³J_C-F = 15.4 Hz), 27.41, 8.66, 7.35, 5.99. ¹⁹F NMR (CDCl₃) δ -168.9.

Claims

WHAT IS CLAIMED IS:

1. A process for the synthesis of a compound of formula I:

wherein: each R¹ is independently selected from the group consisting of: -OH, halogen, C₁. ioalkyl, -OCi.galkyl, and Cg_ioAryl, wherein Cμioalkyl, Cβ.ioAryl and the alkyl portion of -OCi.galkyl are optionally substituted with 1-3 substituents independently selected from halogen, -OH, -OC₁.3 alkyl, phenyl and naphthyl, said phenyl and naphthyl being optionally substituted with 1-3 substituents independently selected from halogen, -OCH₃, -OCF₃, CH₃, CF₃, and phenyl which is optionally substituted with 1-3 halogens;

R² is selected from the group consisting of: (a) Cμ^alkyl optionally substituted with 1-6 halogens and 1-3 substituents independently selected from -OH, -0Ci-3alkyl, and phenyl, said phenyl being optionally substituted with 1-4 groups independently selected from halogen, -OCH₃, -OCF₃, CH₃ and CF₃, said -0Ci_3alkyl being optionally substituted with 1-3 halogens; (b) a cyclic substituent group selected from the group consisting of phenyl, pyridyl and Cβ.sCycloalkyl, said cyclic substituent group being optionally substituted with 1-3 substituents independently selected from halogen, -OH, and R^a; (c) C2-ioalkenyl which is optionally substituted with 1-3 substituents independently selected from halogen, -OH and -0Ci_3alkyl, wherein the Ci_3alkyl portion of -0Cl_3alkyl is optionally substituted with 1-3 halogens; (d) -CH2CO2H; (e) -CH2CO2Ci_6alkyl; (f) -CH2C(O)NHRb; (g) -CH2C(O)NH₂; (h) -NH₂; (i) -NHRb; _and (j) -N(Rb)₂;

R^a is selected from the group

-0Ci_3alkyl, -Ci-galkyleneCg. loAryl, and phenyl, wherein Aryl and phenyl are optionally substituted with 1-3 halogens;

Rb is selected from the group consisting of C^alkyl, -Ci-galkyleneCe-ioAryl, and phenyl, wherein Aryl and phenyl are optionally substituted with 1-3 halogens; R3 is selected from the group consisting of: Cμ^alkyl, C_2-ioalkenyl, -SQ.galkyl, C3.

8Cycloalkyl, Cg-ioAryl, Heterocyclyl, and Heteroaryl, wherein when R3 is alkyl, alkenyl, or -SCμgalkyl,

R3 is optionally substituted with 1-6 halogens and 1-3 groups independently selected from -OH, -NH₂, -NHCi_-4alkyl, -N(Ci_-4alkyl)₂, -0Ci-4alkyl, -CN, phenyl, -S(O)_xC i-4alkyl, -NHSO₂Ci_-4alkyl, -SO₂NH₂, -SO₂NHC₁.4alkyl, and -SO₂N(C i_4alkyl)₂, wherein the Ci^alkyl portions of the substituent groups -NHC_1-4alkyl, -N(C_1-4alkyl)₂, -OC^alkyl, -S(O)_xC i-4alkyl, -NHSO₂C i_-4alkyl, -SO₂NHCi_-4alkyl, and -SO₂N(C _1-4alkyl)2 are optionally substituted with 1 phenyl and 1-3 halogens, said phenyl being optionally substituted with 1-3 substituents independently selected from halogen, -OCH₃, -OCF₃, CH₃, and CF₃; and when R³ is Cycloalkyl, Aryl, Heterocyclyl, or Heteroaryl, R3 is optionally substituted with 1-4 substituent groups independently selected from halogen,

-OH, -NH₂, -NHCi_₄alkyl, -N(C_j. ₄allcyl)₂, -0Ci_4alkyl, -CN, phenyl, -S(0)_xCi-4alkyl, -NHSO₂C i_₄alkyl, -SO₂NH₂, -SO₂NHC i_₄alkyl, and -SO₂N(C i.4alkyl)₂, wherein the Ci-4alkyl portions of the substituent groups Q^alkyl, -NHCi_-4alkyl, -N(Ci.₄all<yl)₂, -0Ci-4alkyl, -S(O)_xC i^alkyl, -NHSO₂C i_₄alkyl, -SO₂NHC i_₄alkyl, and -SO₂N(C i_4alkyl)₂ are optionally substituted with 1 phenyl and 1-3 halogens, said phenyl being optionally substituted with 1-3 substituents independently selected from halogen, -OCH₃, -OCF₃, CH₃, and CF₃;

Each R⁴ is independently selected from the group consisting of halogen, Cμ^alkyl, C₂_ioalkenyl, -SCi^alkyl and -OCi_₆alkyl, wherein Ci.^alkyl and the alkyl and alkenyl groups of C₂_ioalkenyl, -SCi-βalkyl and -OCi-galkyl are optionally substituted with 1-3 halogens and 1-2 substituent groups independently selected from -OH₅ -NH₂, -NHCi_3alkyl, -N(Ci_3alkyl)2, -0Ci_3alkyl, and -CN; m is an integer from 0-3; n is an integer from 0-3; and x is O, l or 2; wherein said process comprises the steps of:

(1) combining an amide and POCI3 to provide an activated intermediate, where the amide has the structure shown in Formula TTT:

R3C(O)NHR2 TJQ and (2) combining said activated intermediate with a hydrazide compound U to provide the compound of formula I, wherein the hydrazide has the structure of Formula II:

2. The process of Claim 1, wherein

R¹ is selected from the group consisting of -OH, halogen,

-0Ci_6alkyl, and Cg. loAryl, wherein Ci.βalkyl and -OC^galkyl are optionally substituted with 1-3 halogens, and Aryl is optionally substituted with 1-3 substituents independently selected from halogen, -OCH₃, -OCF₃, CH₃, and CF₃; and R⁴ is selected from the group consisting of halogen, Ci.galkyl, C2-6alkenyl,

-SCi-βalkyl and -OCi-βalkyl, wherein Ci.galkyl, C2-6alkenyl, -SCi-galkyl and -OCi-βalkyl are optionally substituted with 1-3 halogens.

3. The process of Claim 1 for the synthesis of the compound of Formula Ia:

wherein R¹ is selected from the group consisting of -OH, halogen, Ci^alkyl, -OC₁. galkyl, and phenyl, wherein Ci^alkyl and -OCi_₆alkyl are optionally substituted with 1-3 halogens, and phenyl is optionally substituted with 1-3 substituents independently selected from halogen, -OCH₃, -OCF₃, CH₃, and CF₃;

R² is selected from the group consisting of C_1-6alkyl, C3_6Cycloalkyl, and phenyl, where Ci-6alkyl is optionally substituted with 1-3 halogens, and Cβ.eCycloalkyl and phenyl are optionally substituted with 1-3 halogens and 1 substituent selected from -OCH₃, -OCF₃, CH₃, and CF₃;

R3 is selected from the group consisting of Ci-6alkyl, C2-6alkenyl, -SC^alkyl, phenyl, and C3.6Cycloalkyl, wherein Chalky!, C2-6alkenyl, and -SCj-galkyl are optionally substituted with 1-3 halogens, and phenyl and C3_-6Cycloalkyl are optionally substituted with 1-3 halogens and 1 substituent selected from -OCH₃, -OCF₃, CH₃, and CF₃;

R⁴ is selected from the group consisting of halogen, Cμgalkyl, C2-6alkenyl, -SC^alkyl and -OCi_-6alkyl, wherein C^alkyl, C2-6alkenyl, -SCi_6alkyl and -OCj.ealkyl are optionally substituted with 1-3 halogens; and n is O or 1; wherein the compound of formula Ia is made by a process comprising the steps of:

(1) combining an amide and POCI3 to provide an activated intermediate, where the amide has the structure shown in Formula DI: R3C(O)NHR2 m and (2) combining the activated intermediate with a compound of formula Ha:

to provide the compound of formula Ia.

4. The process of Claim 3 for the synthesis of the compound of Formula Ia, wherein R¹ is halogen;

R² is C3.gCycloalkyl optionally substituted with 1-3 halogens; R³ is C3.βCycloalkyl optionally substituted with 1-3 halogens; R⁴ is halogen; and n is 1.

5. The process of Claim 4 for the synthesis of the compound of formula Ib :

comprising the steps of

(1) combining an amide and POCI3 to provide an activated intermediate, wherein the amide has the structure of Formula HIb:

NIb

and (2) combining the activated intermediate with a compound of formula Db:

to produce the compound of formula Ib.