CA2634513A1

CA2634513A1 - Novel intermediate compounds and processes for their preparation

Info

Publication number: CA2634513A1
Application number: CA002634513A
Authority: CA
Inventors: Stephen Hanessian; Sebastien Guesne
Original assignee: Individual
Current assignee: Individual
Priority date: 2008-06-09
Filing date: 2008-06-09
Publication date: 2009-12-09

Abstract

The present invention relates to a series of novel compounds; these compounds are valuable for use in the preparation of other compounds, particularly as intermediates in the preparation of compounds, which can be used to prepare "Tekturna" compounds.

Description

NOVEL INTERMEDIATE COMPOUNDS AND PROCESSES FOR THEIR
PREPARATION
This invention relates, in one aspect, to a novel process for obtaining compounds useful as intermediates in the production of compounds having therapeutic properties; in another aspect, this invention relates to novel intermediates capable of being converted to therapeutically active compounds.
Background of the Invention There are known therapeutically active compounds which are termed "Tekturna"
compounds, which in certain embodiments, have the formula A:

OMe OH H
H2N,,, NNHZ
I q o o o O

MeO 15 The prior art contains several references relating directly or indirectly to the preparation of compounds of formula A, as well as their derivatives. Such prior art is disclosed in, for example, WO 2006/131304 and WO 2007/045420.

Of the prior art noted above, the process of preparing "Tekturna" compounds is a relatively complicated multi-stage process, and depending on the process involved, the yields of the final therapeutic product are very low. This results in higher production costs as well as lengthy production procedures.

It would be desirable to find a more direct route to the preparation of the final "Tekturna" products and accordingly, this invention has, for its objects, to disclose a route for producing "Tekturna" type compounds and a more efficient process utilizing novel intermediates, which results in higher yields for the "Tekturna" compounds.

Summary of the Invention One embodiment of the present invention relates to a series of novel compounds; these compounds are valuable for use in preparation of other compounds, particularly as intermediates in the preparation of compounds which can be used to prepare "Tekturna" compounds.

The compounds of the present invention which are considered novel are selected from the group consisting of compounds of the following nature:

OMe OMe R2 OH\ 15OHOHbbEE R1 p 4a 4a 4b 4b wherein R1 is CI-C7 alkyl, Cl-C7 alkoxyalkyloxy;halogen; or Cl-C7 alkoxy: R2 is halogen, C1-5 alkyl; C1-5 alkoxyalkyloxy or combinations thereof.

OM~ OMP,,, ~ ~
O O O

0;\ o 5a 5a 5b 5b wherein R1 is Cl-C7 alkyl, CI-C7 alkoxyalkyloxy;halogen; or CI-C7 alkoxy: R2 is halogen, C1-5 alkyl; C1-5 alkoxyalkyloxy or combinations thereof.

O\/ Me O

6a 6b wherein R1 and R2 are members selected from the group consisting of hydrogen, alkyl or alkoxy;

Me0 0 _ o =

R2 0 NSO3CH2CC13 NSO3CH2CCf3 R1 RI 7a 7b wherein RI is Cl-C7 alkyl, Cl-C7 alkoxyalkyloxy;halogen; or Cl-C7 alkoxy: R2 is halogen, C1_5 alkyl; Cti_5 alkoxyalkyloxy or combinations thereof.
Me0 0 ~ O
~

R2 O;S'O O ~ p O:S O
N W.

8a 8b wherein R1 is C1-C7 alkyl, Cl-C7 alkoxyalkyloxy;halogen; or C1-C7 alkoxy: R2 is halogen, Cl_5 alkyl; Cl_5 alkoxyalkyloxy or combinations thereof.

in accordance with one preferred embodiment of the present invention, the compounds of formula 4 have utility in the preparation of compounds of formula 5; and as well the compounds of formula 5 have utility in the preparation of the compounds of formula 6; the compounds of formula of 6 have utility in the preparation of compounds of formula 7; the compounds of formula 7 have utility in the preparation of the compounds of formula 8; and thereafter, compounds of formula 8 can be used as starting materials for ultimately preparing compounds of formula 11 via intermediates of formulae 9 and 10. Thereafter, compounds of formula 11 can be used to produce compounds of formula A (described above).
In another aspect of the present invention there is provided a process for preparing a compound selected from compounds of formulae 4, 5, 6, 7 and 8.

In a first embodiment, the process of the present invention is directed to the preparation of a compound of formula 4, which process involves the reaction of a compound of formula 3:

o wherein the reaction involves reacting a compound of formula 3 with p-MeOC6H4MgBr, Et20, -78 to 0 C, yield 65% (using a two step reaction) to yield a compound of formula 4.

In a second process embodiment, the process of the present invention is also directed to the preparation of a compound of formula 5, which process involves the reaction of one of the compounds of formula 4 identified above, e.g.:

R2 OH'~,-4a wherein R1 and R2 are as defined above.

wherein the reaction involves reacting compound 4 with an acid 1, CI3C6H2COCI, Et3N, DMAP, PhCH3, 0 C to room temperature, 4 hours, yield 84%.

In a third process embodiment, the process of the present invention is also directed to the preparation of a compound of formula (6), which process involves the reaction of one of the compounds of formula 5 identified above, e.g.:

~
R2 0 O ~
/ I

R1 \

5a wherein the reaction involves reacting compound of formula 5 with Ti(i-PrO)4, PhCH3 (10mM), O/N then 5 mol% 1st generation Grubb's catalyst, room temperature 24 to 48 hours, yield 65%;

wherein R1 and R2 are as defined above.
In a fourth process embodiment, the process of the present invention is also directed to the preparation of a compound of formula 7, which process involves the reaction of one of the compounds of formula 6 identified above, e.g.:

O
R2 Ol R1 ~

6a wherein the reaction involves reacting compound 6 with H2NSO3CH2CCI3, MgO, Rh2(tfacam)4, PhI(Oac)2, PhCH3, 0 C to room temperature O/N, yield 80%;
wherein R1 and R2 are as defined above, to yield a compound of formula 7 defined above.
In a fifth process embodiment, the process of the present invention is also directed to the preparation of a compound of formula 8:
MeO

/_'00 O
R2 0 OS~O 0 `R1 R1 N,,.
8a 8b which process involves the reaction of a compound of formula 7 with TFA:DCM
(1:5; v/v), -5 C, 15 minutes, yield 90%;

wherein R1 and R2 are as defined above to yield a compound of formula 8.
Preferred Embodiments In the above-described process embodiments, compound 4 may be obtained by a three-stage reaction using known processes and reactants. In particular, compound 4 may be produced by the following reaction:

H02C a b I c o y 88% HO 68%

LiAIHa., Et20, 0 C then reflux O/N, yield 88% and Dess-Martin periodinane, DCM, room temperature, two hours.

The novel compounds of the present invention of formula 8 can be utilized to form a compound of formula A (see above) by reaction of the compound of formula 8 under reaction conditions as follows: first, a compound of formula 8 is converted to a compound of formula 9:

C13C\
R2 ~)S~o H0 NHn-Bu o' N,,.

~ o wherein R1 and R2 are as defined above, under conditions using AIMe3, n-BuNH2, DCM, room temperature, O/N, yield 91%.

The compound of formula 9 is then converted into a derivative thereof of formula 10:

R~ BHo oc NHn-Bu wherein R1 and R2 are as defined above, which compound 10 is then converted into a compound of formula 11:

OH
R2 H2N I NHn Bu 'Z~ O

wherein R1 and R2 are as defined above, via a two step reaction of hydrogenolysis as well as Boc deprotection (both steps being conventional steps known to those skilled in the art).

OH OH
BocHN,,, NHn-Bu H2N NHn-Bu R t HCI, Dioxane, RT R2 RT
R1 quantitative 10' 11 wherein R1 and R2 are as defined above.

The present invention also contemplates, with respect to the N-butyl substituents of the amide portion of each of compounds 9, 10 and 11, that other substituents may be employed, which are known in the art and more specifically, the N-butyl compound can in fact be a lower alkyl substituent or any one of cycloalkyl, Cl_ 6hydroxyalkyl, C1_6alkoxy-C1-6alkyl, C1-6alkanoyfoxy-C1-6alkyl, Cl-saminoalkyl, Cl-6alkylamino-C1_6alkyl, C1_6dialkyfamino-C1_6alkyl, C,_6alkanoylamino-C1_6alkyl, HO(O)C-C1_6alkyl, C1-6alkyl-O-(O)C-C1-6alkyl, H2N-C(O)-C1_6alkyl, C1-6alkyl-HN-C(O)-Cl-6alkyl or (C1_6alkyl)2N-C(O)-C1_6alkyl; or a pharmaceutically acceptable salt thereof.

The above compounds of formula 9 are known in the art (see for example WO
2006/131304 and WO 2007/045420).

Having thus generally described the invention, reference will now be made to the accompany examples described preferred embodiments of the invention.

Example 1 (+)-(2S)-2-Isopropyl-pent-4-en-1-ol (2).

HO 2C LiAIH4, Et20 HO
0 C then reflux O/N, 88%

Mol. Wt.: 142.20 Mol. Wt.: 128.21 A first dry round-bottomed flask was charged with 570 mg of lithium aluminum hydride (15.00 mmol, 3.0 eq.), a magnetic stirrer and equipped with a condenser.
The condenser was topped with a rubber septum. The reaction vessel was flushed with argon and 60 mL of dry diethylether ([lithium aluminum hydride] _ 0.25 M) was introduced via a glass syringe. The resulting grey suspension was stirred under an atmosphere of argon and allowed to cool to 0 C with an ice-water bath. A second dry round-bottomed flask was charged with 711 mg of (+)-(2S)-2-iso-propyl-pent-4-enoic acid 1 (5.00 mmol, 1.0 eq.) and 5 mL of dry diethylether ([1] = 1.0 M). (+)-(2S)-2-Isopropyl-pent-4-enoic acid 1 was dissolved and transferred into the first flask in a dropwise manner via a glass syringe.
The second flask was rinsed three times with minimum portions of dry diethyiether and the reaction mixture was stirred at 0 C for ten minutes. The ice-water bath was removed, replaced by a siiicon oil bath and the reaction was heated to reflux over night. The silicon oil bath was then removed and the grey suspension was allowed to cool to room temperature and then to 0 C with an ice-water bath.
The reaction was then cautiously quenched at 0 C by slowly adding 20 mL of water, the resulting biphasic solution was then allowed to warm to room temperature by removing the ice-water bath and 20 mL of a saturated solution of sodium potassium tartrate and 20 mL of 1.0 M aqueous solution of sodium hydroxyde were added. The resulting mixture was vigorously stirred for one hour at room temperature and the aluminum salts were filtered off through a pad of Celite under vacuum, the reaction flask and the pad of Celite were washed three times with small amounts of diethylether. The aqueous layer was separated and extracted three times with portions of ether. The combined organic layers were dried over magnesium sulfate and filtered. The solvent was removed under pressure on a rotary evaporator to leave 564 mg of the titled compound 2 as a colorless oil (4.40 mmol, 88%) which was used in the next step without any further purification.

Example 2 (1 S,2S)-2-Isopropyl-l-(4-methoxy-phenyl)-pent-4-en-l-ol and (1 R,2S)-2-Isopropyl-l-(4-methoxy-phenyl)-pent-4-en-1-ol (4a).

Dess-Martin 0 p-MeOC6H4MgBr OH'_'~ OH'__~
periodinane ~ CeC13 =
HO -- ~ + ~
DCM, 0 C THF, -78 C
to RT 68% (2 steps) MeO MeO

2 3 (S,S) 4a 1:4 (R,S) 4a Mol. Wt.: 128.21 Mol. Wt.: 126.20 Mol. Wt.: 234.33 Mol. Wt.: 234.33 A dry round-bottomed flask 1 was charged with 1.28 g of anhydrous cerium (III) chloride (5.20 mmol, 1.3 eq.), a magnetic stirrer and capped with a rubber septum. The reaction vessel was flushed with argon and 10.4 mL of tetrahydrofuran ([cerium (III) chloride] = 0.5 M) was introduced via a glass syringe. The resulting slurry was stirred at room temperature overnight. The reaction mixture was then allowed to cool to 0 C with an ice-water bath and 10.4 mL of a 0.5 M solution of para-methoxy benzyl magnesium bromine in tetrahydrofuran (5.20 mmol, 1.3 eq.) was added dropwise via a glass syringe.
The resulting slurry was stirred at 0 C for 3 hours and then cooled down to -78 C.
Meanwhile, a dry round-bottomed flask 2 was charged with 513 mg of 2 (4.00 mmol, 1.0 eq.), a magnetic stirrer and capped with a rubber septum. The reaction vessel was flushed with argon and 16 mL of dichloromethane ([2] = 0.25 M) was introduced via a glass syringe. The resulting colorless solution was stirred under an atmosphere of argon and allowed to cool to 0 C with an ice-water bath before adding 1.87 g of Dess-Martin periodinane (4.40 mmol, 1.1 eq.). A slurry formed at once, the ice-water bath was removed and the reaction was monitored every 20 minutes by TLC analysis (20:80 ethyl acetate-hexanes, KMnO4). When TLC
analysis showed no more starting material, the reaction mixture was diluted with 64 mL ether and poured into 40 mL of a saturated solution of sodium bicarbonate containing 6.95 g (28.00 mmol, 7.0 eq.) of sodium thiosulfate. The resulting biphasic solution was stirred at room temperature until the organic layer became clear. The organic layer was separated and washed with 40 mL of saturated solution of sodium bicarbonate, dried over sodium sulfate, filtered and concentrated at low temperature on a rotary evaporator (cautious: the aidehyde which is formed is volatile). The colorless oily residue corresponding to the aldehyde 3 was dissolved in 4 mL of tetrahydrofuran ([3] = 1.0 M) and transferred in a dropwise manner into the round bottomed flask I via syringe at -78 C. The reaction mixture was stirred at -78 C and monitored by TLC analysis (20:80 ethyl acetate-hexanes, KMnO4). When TLC analysis showed no more starting material, the reaction mixture was quenched with 20 mL of a saturated aqueous solution of ammonium chloride, the dry ice-acetone bath was removed and the reaction media was allowed to warm to room temperature. The aqueous layer was separated and washed with three portion of diethylether. The combined organic layers were dried over sodium sulfate, dried and filtered. The solvents were removed under reduced pressure on a rotary evaporator to leave 750 mg of a oily residue which was purified by flash column chromatography (75 mL of Si02) eluting with 10:90 ethyl acetate-hexanes to afford 638 mg of a colorless oil corresponding to the titled compounds (S,S) 4 and (R,S) 4 as a 1:4 inseparable mixture (2.72 mmol, 68%).

Example 3 (1 S,2S)-2-isopropyl-l-(4-methoxy-3-(3-methoxypropoxy)phenyl)pent-4-en-1-ol and (1R,2S)-2-isopropyl-1-(4-methoxy-3-(3-methoxypropoxy)phenyl)pent-4-en-l-ol (4b).

^ /OMe i-PrMgCI OMe Or Br n-BuLi IO M9Br I \ THF I \
MeO ~ 0 C to RT Me0 ~
4-b ro mo -1-m eth o xy-2-(3-methoxypropoxy) benzene C 11 H15B r03 Mol. Wt:275,14 OMe OMe Dess-Martin O OH OH
periodinane O O
HO +
DCM, 0 C THF, -78 C I I
to RT 50% (2 steps) Me0 Me0 2 3 (S,S) 4b 1:6 (R,S) 4b Mol. Wt.: 128.21 Mol. Wt.: 126.20 Mol. Wt: 322,44 Mol. Wt: 322,44 A first dry round-bottomed flask 1 was charged with a magnetic stirrer and capped with a rubber septum. The reaction vessel was flushed with argon and 2.0 mL of tetrahydrofuran was introduced via a glass syringe. The solution was stirred and cooled down to 0 C with an ice-water bath and before adding via a glass syringe 1.0 mL of a 2.0 M solution of iso-propyl magnesium chloride in tetrahydrofuran (2.00 mmol, 1.0 eq.). The resulting mixture was stirred at 0 C
under an atmosphere of argon and 0.8 mL of a 2.5 M solution of n-butyllithium in hexanes (2.00 mmol, 1.0 eq.) was added dropwise at 0 C via a glass syringe.
The reaction was then allowed to warm up to room temperature and stirred for a further 30 minutes before adding dropwise 2.0 mL of a 1.0 M solution of 4-bromo-1-methoxy-2-(3-methoxypropoxy)benzene tetrahydrofuran which was prepared in a second dry round bottomed flask by dissolving 551 mg of 4-bromo-l-methoxy-2-(3-methoxypropoxy)benzene (2.0 mmol, 1.0 eq.) in 2.0 mL of tetrahydrofuran.
The resuiting solution was then stirred for 3 hours at room temperature and allowed to cool to -78 C with dry ice-acetone bath. Meanwhile, a third dry round-bottomed flask was charged with 257 mg of 2 (2.00 mmol, 1.0 eq.), a magnetic stirrer and capped with a rubber septum. The reaction vessel was flushed with argon and 8 mL of dichloromethane ([2] = 0.25 M) was introduced via a glass syringe. The resulting colorless solution was stirred under an atmosphere of argon and allowed to cool to 0 C with an ice-water bath before adding 935 mg of Dess-Martin periodinane (2.20 mmol, 1.1 eq.). A slurry formed at once, the ice-water bath was removed and the reaction was monitored every 20 minutes by TLC analysis (20:80 ethyl acetate-hexanes, KMnO4). When TLC analysis showed no more starting material, the reaction mixture was diluted with 32 mL ether and poured into 20 mL of a saturated solution of sodium bicarbonate containing 3.5 g (14.00 mmol, 7.0 eq.) of sodium thiosulfate. The resulting biphasic solution was stirred at room temperature until the organic layer became clear. The organic layer was separated and washed with 20 mL of saturated solution of sodium bicarbonate, dried over sodium sulfate, filtered and concentrated at low temperature on a rotary evaporator (cautious: the aidehyde which is formed is volatile). The colorless oily residue corresponding to the aidehyde 3 was dissolved in 2 mL of tetrahydrofuran ([3] = 1.0 M) and transferred in a dropwise manner into the first round bottomed flask via syringe at -78 C. The reaction mixture was stirred at -78 C and monitored by TLC analysis (20:80 ethyl acetate-hexanes, KMnO4). When TLC analysis showed no more starting material, the reaction mixture was quenched with 20 mL of a saturated aqueous solution of ammonium chloride, the dry ice-acetone bath was removed and the reaction media was allowed to warm to room temperature. The aqueous layer was separated and washed with three portion of diethylether. The combined organic layers were dried over sodium sulfate, dried and filtered. The solvents were removed under reduced pressure on a rotary evaporator to leave 560 mg of a oily residue which was purified by flash column chromatography (60 mL of Si02) eluting with 20:80 ethyl acetate-hexanes to afford 322 mg of a colorless oil corresponding to the titied compounds (S,S) 4 and (R,S) 4 as a 1:6 inseparable mixture (1.00 mmol, 50%).

Synthesis of 4-bromo-1 -methoxy-2-(3-methoxypropoxy)benzene: this compound was synthesized according to known procedure in the literature (WO 2001-19785 and WO 2007-048620).

Example 4 (S,S,S)-2-Isopropyl-pent-4-enoic acid 2-isopropyl-l-(4-methoxy-phenyl)-pent-4-enyl ester and (S,R,S)-2-Isopropyl-pent-4-enoic acid 2-isopropyl-l-(4-methoxy-phenyl)-pent-4-enyl ester (5a).

OH OH O O~ O O
= 1 =
~/ DMAP, Et3N, ~ ~
MeO MeO C13C6H2COC1 MeO MeO
0 CtoRT
(S,S) 4a 1:4 (R,S) 4a 84% (S,S,S) 5a 1:4 (S,R,S) 5a Mol. Wt.: 234.33 Mol. Wt.: 234.33 Mol. Wt.: 358.51 Mol. Wt.: 358.51 A first dry round-bottomed flask was charged with 299 mg of (+)-(2S)-2-iso-propyl-pent-4-enoic acid 1 (2.10 mmol, 1.05 eq.), a magnetic stirrer and capped with a rubber septum. The reaction media was flushed with argon and 21 mL of dry toluene ([1] = 0.1 M) were introduced via a glass syringe. The resulting solution was stirred under an atmosphere of argon and allowed to cool to 0 C
before adding first 335 pL of triethylamine (2.40 mmol, 1.2 eq.), then 375 pL
of 2,4,6-trichlorobenzoyl chloride (2.40 mmol, 1.2 eq.) via a glass syringe in a dropwise manner and last 293 mg of 4-dimethylaminopyridine (2.40 mmol, 1.2 eq.) in one portion. The resulting white slurry which formed as 4-dimethylaminopyridine dissolved in the reaction media was stirred at 0 C for ten minutes during which the white slurry turned yellow and then in a second dry round-bottomed flask a solution of 469 mg of 4a (2.00 mmol, 1.0 eq.) in the minimum amount of dry toluene via syringe was transferred into the first round-bottomed flask in a dropwise manner at 0 C. The second dry round-bottomed flask that contained 4a was rinsed three times with the minimum portion of dry toluene and the reaction media was allowed to warm at room temperature by removing the water-ice bath. The reaction was stirred at room temperature and monitored by TLC analysis (20:80 ethyl acetate-hexanes, KMnO4). When TLC
analysis showed no more starting material, the solvent was removed under reduced pressure on a rotary evaporator. The resulting yellow solid was taken up in 10 mL ethyl acetate and 10 mL of water. The aqueous layer was separated and extracted with three portions of ethyl acetate. The combined organic layer were successively washed with one portion of a 10 % aqueous solution of acid citric and one portion of a saturated solution of sodium bicarbonate, dried over magnesium sulfate and filtered. The solvent was removed under reduced pressure on a rotary evaporator to afford 670 mg of a yellow oil which was purified by flash column chromatography (67 mL of Si02) eluting with 5:95 ethyl acetate-hexanes to give 602 mg of a colorless oil corresponding to the titled compounds (S,S,S) 5a and (S,R,S) 5a as a 1:4 inseparable mixture (1.68 mmol, 84%).

Example 5 (S,S,S)-2-Isopropyl-pent-4-enoic acid 2-isopropyl-l-(4-methoxy-3-(3-methoxypropoxy)-phenyl)-pent-4-enyl ester and (S,R,S)- 2-tsopropyl-pent-4-enoic acid 2-isopropyl-1 -(4-methoxy-3-(3-methoxypropoxy)-phenyl)-pent-4-enyl ester (5a).

OMe OMe OM J,,,. Me~
H02C % .~
OH OH O O O O_ O I\ + I\ DMAP, Et3N,~ O/ I +O / I
Me0 Me0 C13C6H2COCI Me0 Me0 0 C to RT
(S,S) 4b 1:6 (R,S) 4b 84% (S,S,S) 5b 1:6 (S,R,S) 5b Mol. Wt.: 322.24 Mol. Wt.: 322.24 Mol. Wt.: 446.62 Mol. Wt.: 446.62 A first dry round-bottomed flask was charged with 96 mg of (+)-(2S)-2-iso-propyl-pent-4-enoic acid 1 (0.75 mmol, 1.05 eq.), a magnetic stirrer and capped with a rubber septum. The reaction media was flushed with argon and 7.5 mL of dry toluene ([1] = 0.1 M) were introduced via a glass syringe. The resulting solution was stirred under an atmosphere of argon and allowed to cool to 0 C before adding first 120 pL of triethylamine (0.86 mmol, 1.2 eq.), then 135 pL of 2,4,6-trichlorobenzoyl chloride (0.86 mmol, 1.2 eq.) via a glass syringe in a dropwise manner and last 105 mg of 4-dimethylaminopyridine (0.86 mmol, 1.2 eq.) in one portion. The resulting white slurry which formed as 4-dimethyiaminopyridine dissolved in the reaction media was stirred at 0 C for ten minutes during which the white slurry turned yellow and then in a second dry round-bottomed flask a solution of 230 mg of 4b (0.75 mmol, 1.0 eq.) in the minimum amount of dry toluene via syringe was transferred into the first round-bottomed flask in a dropwise manner at 0 C. The second dry round-bottomed flask that contained 4b was rinsed three times with the minimum portion of dry toluene and the reaction media was allowed to warm at room temperature by removing the water-ice bath.
The reaction was stirred at room temperature and monitored by TLC analysis (30:70 ethyl acetate-hexanes, KMnO4). When TLC analysis showed no more starting material, the solvent was removed under reduced pressure on a rotary evaporator. The resulting yellow solid was taken up in 10 mL ethyl acetate and 10 mL of water. The aqueous layer was separated and extracted with three portions of ethyl acetate. The combined organic layer were successively washed with one portion of a 10% aqueous solution of acid citric and one portion of a saturated solution of sodium bicarbonate, dried over magnesium sulfate and filtered. The solvent was removed under reduced pressure on a rotary evaporator to afford 305 mg of a yellow oil which was purified by flash column chromatography (30 mL of Si02) eluting with 10:90 ethyl acetate-hexanes to give 268 mg of a coloriess oil corresponding to the titled compounds (S,S,S ) 5b and (S,R,S) 5b as a 1:6 inseparable mixture (0.60 mmol, 80%).

Example 6 (3S,8S,9R)-3,8-Diisopropyl-9-(4-methoxy-phenyl)-4,7,8,9-tetrahydro-3H-oxonin-2-one (6a).

/ O
O O~ O O~ Ti(i-PrO)4 O ' 5mol % 1st generation / I
~ ~ \ ~ Grubb's catalyst, ~
Me0 Me0 PhCH3 (10 mM ), RT Me0 65%
(S,S,S) 5a 1:4 (S,R,S) 5a 6a Mol. Wt.: 358.51 Mol. Wt.: 358.51 Mol. Wt.: 330.46 A dry round-bottomed flask was charged with 359 mg of 5a (1.00 mmol, 1.0 eq.), a magnetic stirrer and capped with a rubber septum. The reaction media was flushed with argon and 100 mL of dry toluene ([5] = 0.01 M) were introduced via a glass syringe. The resulting solution was stirred at room temperature under an atmosphere of argon and 586 pL of titanium (IV) isopropoxide (2.00 mmol, 2.0 eq.) was added via a syringe. The reaction was stirred overnight at room temperature and then 41 mg of the first generation Grubb's catalyst (0.05 mmol, 0.05 eq.) was added in one portion. The resulting purple solution was stirred at room temperature and monitored by TLC analysis (20:80 ethyl acetate-hexanes, KMnO4). After 24-48 hours of stirring at room temperature when TLC analysis showed no more evolution the catalyst was slowly filtered off through a short pad of silica (20 mL) topped with a thin layer of florysil (0.5 cm). The pad of silica and florysil were washed two times with 50 mL of a 1:9 solution of ether-hexanes.
The solvents were removed under reduced pressure on a rotary evaporator to afford 350 mg of a colorless oil which was purified by flash column chromatography (35 mL of Si02) eluting slowly with 3:97 ether-hexanes first until the first spot on TLC analysis came out and then 10:90 ether-hexanes to yield 215 mg of a colorless oil corresponding to the titled compound 6a as a single diastereoisomer (0.65 mmol, 65%). The starting material (S,S,S) 5a did not undergo ring closing metathesis and was not recovered after purification. The nature of the first spot on TLC analysis remained unknown.

Example 7 (3S,8S,9R)-3,8-Diisopropyl-9-(4-methoxy-3-(3-methoxypropoxy)-phenyl)-4,7,8,9-tetrahydro-3H-oxonin-2-one (6b).

OMe OM J,, OMe O =

O O~ O O~ Ti(i-PrO)4 O ' O ~ = 5mol % 1st generation / + / ~ ~ \ ~ Grubb's catalyst, ~ ~
MeO Me0 PhCH3 (10 mM ), RT Meo 72%
(S,S,S) 5b 1:6 (S,R,S) 5b 6b Mol. Wt.: 446.62 Mol. Wt.: 446.62 Mol. Wt.: 418.57 A dry round-bottomed flask was charged with 250 mg of 5 (0.56 mmol, 1.0 eq.), a magnetic stirrer and capped with a rubber septum. The reaction media was flushed with argon and 56 mL of dry toluene ([5b] = 0.01 M) were introduced via a glass syringe. The resulting solution was stirred at room temperature under an atmosphere of argon and 328 pL of titanium (IV) isopropoxide (1.12 mmol, 2.0 eq.) was added via a syringe. The reaction was stirred overnight at room temperature and then 23 mg of the first generation Grubb's catalyst (0.03 mmol, 0.05 eq.) was added in one portion. The resulting purple solution was stirred at room temperature and monitored by TLC analysis (20:80 ethyl acetate-hexanes, KMnO4). After 48-72 hours of stirring at room temperature when TLC analysis showed no more evolution the catalyst was slowly filtered off through a short pad of silica (12 mL) topped with a thin layer of florysil (0.5 cm). The pad of silica and florysil were washed two times with 25 mL of a 20:80 solution of ether-hexanes.
The solvents were removed under reduced pressure on a rotary evaporator to afford 240 mg of a colorless oil which was purified by flash column chromatography (50 mL of Si02) eluting slowly with 15:85 ether-hexanes first until the first spot on TLC analysis came out and then 20:80 ether-hexanes to yield 169 mg of a colorless oil corresponding to the titled compound 6b as a single diastereoisomer (0.40 mmol, 72%). The starting material (S,S,S) 5b did not undergo ring closing metathesis and was not recovered after purification.
The nature of the first spot on TLC analysis remained unknown.

Example 8 (1S,3S,4R, 7S, 9R)-3,7-Diisopropyl-4-(4-methoxy-phenyl)-6-oxo-5-oxa-10-aza-bicyclo[7.1.0]decane-10-sulfonic acid 2,2,2-trichloro-ethyl ester (7a).

o = O =
O H2NSO3CH2CC13, MgO O
' [Rh(tfacam2)]2, Phl(OAc)2 NSO 3CH2CCI3 / Me0 \( PhCH3, 0 C to RT Me0 O/N, 80%

6a 7a Mol. Wt.: 330.46 Mol. Wt.: 556.93 A dry round-bottomed flask was charged with 56 mg of 6a (168 pmol, 1.0 eq.), a magnetic stirrer and capped with a rubber septum. The reaction media was flushed with argon and 840 pL of dry toluene ([6a] = 0.2 M) were introduced via a glass syringe. The resulting solution was stirred under an atmosphere of argon and cooled down to 0 C with an ice-water bath before adding successively in one portion 43 mg of 2,2,2-trichloroethylsulfamate (185 pmol, 1.1 eq.), 16 mg of magnesium oxide (403 Nmol, 2.4 eq.), 76 mg (diacetoxy)iodobenzene (235 pmol, 1.4 eq.) and last 2.2 mg of rhodium acetamide dimer (3.4 pmol, 0.02 eq.). The resulting paie blue slurry was then allowed to warm slowly to room temperature and turned progressively orange. The reaction was stirred overnight leaving the ice-water bath in place before adding a second time 2.2 mg of Rh2(tfacam)4 (3.4 pmol, 0.02 eq.) if TLC analysis (10:90 ethyl acetate-hexanes, CAM) still showed starting material. The ice-water bath was removed, the reaction was stirred at room temperature and monitored by TLC analysis (10:90 ethyl acetate-hexanes, CAM). When TLC analysis showed no more starting material the reaction media was diluted with 3.2 mL of dichloromethane and filtered through a pad of Celite.
The pad of Celite was washed three times with minimum portions of dichloromethane. The solvent were removed under reduced pressure to leave 100 mg of a brown oil which was purified by flash column chromatography (10 mL of Si02) eluting with 5:95 ethyl acetate-hexaries to afford 75 mg of the titled compound 7a (135 pmol, 80%) as a colorless gel.

Preparation of 2,2,2-trichloroethylsulfamate 1) Formic acid, 0 C
2) CH3CN, 0 C, 1 h ~ then RT, 8 h ~~ NH2 CI-S-N=C=O "'~ ' 0 3) C13CCH2OH, DMA CI3C 0 0 3 h, 0 C toRT, 85%
Chlorosulfonyl isocyanate 2,2,2-Trichloroethylsulfamate Mol. Wt.: 141.53 Mol. Wt.: 228.48 A round-bottomed flask was charged 5.7 mL of chlorosulfonyl isocyanate (65.6 mmol, 1.5 eq.), a magnetic stirrer and equipped with a dropping funnel capped with a rubber septum. The reaction vessel was flushed with argon, placed in a water-ice bath and 2.5 mL of formic acid (65.6 mmol, 1.5 eq.) was introduced into the dropping funnel via a glass syringe under an atmosphere of argon. Formic acid was added dropwise to the neat chlorosulfonyl isocyanate under vigorous stirring. Gas evolution was observed during the addition process and within a few minutes the mixture solidified. To the solid mass was added 44 mL of acetonitrile and the resulting solution was stirred for one hour at 0 C. The water-ice bath was removed and the reaction was stirred eight hours at room temperature. The reaction was then cooled down to 0 C with an ice-water bath and 4.2 mL of trichloroethanol (43.8 mmol, 1.0 eq.) and 44 mL of dimethylacetamide ([trichioroethanol] = 1 M) were introduced into the dropping funnel. The solution of trichloroethanol in dimethylacetamide was then added dropwise to the reaction mixture at 0 C. The reaction media was allowed to warm to room temperature by removing the water-ice bath and after three hours of stirring at room temperature the solution was diluted with 50 mL of water and 50 ml of diethylether. The organic layer was separated was washed successively with one portion of water, two portions of brine, dried over magnesium sulfate and filtere. The solvents were removed under reduced pressure on a rotary evaporator to leave 10 g of an oily residue which was purified by flash chromatography (600 mL of Si02) eluting with 25:75 to 50:50 gradient ethyl acetate-hexanes to afford 8.5 g of the desired product as a white solid (37.3 mmol, 85%).

Prepartion of rhodium trifluoroacetamide dimer [Rh(OAc)2]2 CF3CONH2 [Rh(CF3CONH)2]2 Chlorobenzene rhodium acetate 155 C rhodium trifluoroacetamide dimer quantitative dimer CgH12o8Rh2 CgH4F12Nq.O4Rh2 Mol. Wt.: 441.99 Mol. Wt.: 653.93 A round-bottomed flask was charged with 140 mg of rhodium acetate dimer (0.32 mmol, 1.0 eq.) and 18 mL of chlorobenzene, and to this suspension was added 512 mg of trifluoroacetamide (4.50 mmol, 14 eq.). The reaction flask was equipped with a short-path distillation head fitted with a receiving flask.
The apparatus was placed in an oil bath preheated to 155 C. At this temperature, solvent distilled at a rate of about 1 mL per hour for 36 h. Approximately every 8 h, an appropriate amount of chlorobenzene was added in order to restore the solvent volume of the reaction to about 18 mL. The solution color slowly changed to a deep green and a white crystalline precipitate (trifluoroacetamide) slowly formed in the receiving flask. After 36 h, additional 512 mg of trifluoroacetamide (4.50 mmol, 14 eq.) was added to this reaction mixture and heating at 155 C
was continued. Within 48 h, a dark blue-green solid slowly collected on the sides of the reaction vessel. Following this time, the reaction was cooled to 25 C and the mixture was filtered. The blue-green solid was washed thoroughly with dichloromethane, and the filtrate discarded. To ensure quantitative recovery of the desired product, acetone was used to dissolve the powder. The purple filtrate was concentrated under reduced pressure and the isolated material was dried by heating at 50 C in vacuo (1 mm Hg) for 1 h. For all applications, the rhodium trifluoroacetamide dimer complex was used without further purification.

Example 9 (1 S,3S,4R, 7S, 9R)-3,7-Di isopropyl-4-(4-methoxy-3-(3-methoxypropoxy)-phenyl)-6-oxo-5-oxa-10-aza-bicyclo[7.1.0]decane-10-sulfonic acid 2,2,2-trichloro-ethyl ester (7b).

Me0 0 MeC) 0 0 H2NSO3CH2CC13, Mg0 O
[Rh(tfacam2)]2, Phl(OAc)2 0 / NS03CH2CCI3 ~ I PhCH3, 0 C to RT ~ I
Me0 O/N, 75% Me0 6b 7a C25H3805 C27H40CIgNO8S
Mol. Wt: 418,57 Mol. Wt: 645,03 A dry round-bottomed flask was charged with 134 mg of 6b (320 pmol, 1.0 eq.), a magnetic stirrer and capped with a rubber septum. The reaction media was flushed with argon and 1.6 L of dry toluene ([6b] = 0.2 M) were introduced via a glass syringe. The resulting solution was stirred under an atmosphere of argon and cooled down to 00 with an ice-water bath before adding successively in one portion 88 mg of 2,2,2-trichloroethylsulfamate (384 pmol, 1.1 eq.), 183 mg of magnesium oxide (800 pmol, 2.5 eq.), 155 mg (diacetoxy)iodobenzene (480 pmol, 1.5 eq.) and last 4.5 mg of rhodium acetamide dimer (6.4 pmol, 0.02 eq.).
The resulting pale blue slurry was then allowed to warm slowly to room temperature and turned progressively orange. The reaction was stirred overnight leaving the ice-water bath in place before adding a second time 2.2 mg of Rh2(tfacam)4 (6.4 pmol, 0.02 eq.) if TLC analysis (30:70 ethyl acetate-hexanes, CAM) still showed starting material. The ice-water bath was removed, the reaction was stirred at room temperature and monitored by TLC analysis (30:70 ethyl acetate-hexanes, CAM). When TLC analysis showed no more starting material the reaction media was diluted with 4 mL of dichloromethane and filtered through a pad of Celite. The pad of Celite was washed three times with minimum portions of dichloromethane. The solvent were removed under reduced pressure to leave 250 mg of a brown oil which was purified by flash column chromatography (25 mL of Si02) eluting with 15:85 ethyl acetate-hexanes to afford 155 mg of the titled compound 7b (240 pmol, 75%) as a colorless gel.
Example 10 (2R,2'S,3S,4'S,5S)-3-isopropyi-5-(4-isopropyl-5-oxo-tetrahydro-furan-2-yi)-2-(4-methoxy-phenyl)-pyrrolidine-1-sulfonic acid 2,2,2-trichloro-ethyl ester (8a).

\/ > 0 0 = O
S=0 0 O', 9Nso3cH2ccI3 TFA:DCM (1:5; v/v) Me0 ~~1 N
/
Me0 \ ( -5 C, 15 min.
90%
7a 8a Mol. Wt.: 556.93 Mol. Wt.: 556.93 A dry round-bottomed flask was charged with 74 mg of 7a (131 Nmol, 1.0 eq.), a magnetic stirrer and capped with a rubber septum. The reaction media was flushed with argon and 1.3 mL of dry dichloromethane ([7] = 0.1 M) were introduced via a glass syringe. The resulting solution was stirred under an atmosphere of argon and cooled down to -5 with an ice-water-salt bath before adding dropwise 260 pL of trifluoroacetic acid (one fifth of the volume of dichloromethane). The reaction was stirred at -5 and monitored by TLC
analysis (20:80 ethyl acetate-hexanes, CAM). When TLC analysis showed no more starting material the reaction media was diluted with 2 mL of toluene, the trifluoroacetic acid and dichloromethane were first removed under reduced pressure at room temperature and then the toiuene at higher temperature to leave 70 mg of yellow foam which was purified by flash column chromatography (7 mL of Si02) eluting first with 10:90 ethyl acetate-hexanes and then with 10:90 ethyl acetate-hexanes to afford 66 mg of the titled compound 8a (119 pmol, 90%) as a white foam.

Example 11 (2R,2'S,3S,4'S,5S)-3-Isopropyl-5-(4-isopropyl-5-oxo-tetrahydro-furan-2-yl)-2-(4-methoxy-3-(3-methoxypropoxy)-phenyl)-pyrrolidine-1-sulfonic acid 2,2,2-trichloro-ethyl ester (8b).
M e0 MeO O O

O O,S~

O
O N
NS03CH2CC13 TFA:DCM (1:5; vlv) MeO

Me0 \ I 0 C to RT, 30 min.
85%
7b 8b Mol. Wt: 645,03 Mol. Wt: 645,03 A dry round-bottomed flask was charged with 150 mg of 7b (232 pmol, 1.0 eq.), a magnetic stirrer and capped with a rubber septum. The reaction media was flushed with argon and 2.3 mL of dry dichloromethane ([7b] = 0.1 M) were introduced via a glass syringe. The resulting solution was stirred under an atmosphere of argon and cooled down to 01 with an ice-water bath before adding dropwise 460 pL of trifluoroacetic acid (one fifth of the volume of dichioromethane). The reaction was stirred at 0 for 10 minutes and then allowed to warm to room temperature. The reaction was monitored by TLC analysis (20:80 ethyl acetate-hexanes, CAM). When TLC analysis showed no more starting material (about 30 minutes) the reaction media was diluted with 2 mL
of toluene, the trifluoroacetic acid and dichloromethane were first removed under reduced pressure at room temperature and then the toluene at higher temperature to leave 152 mg of yellow foam which was purified by flash column chromatography (15 mL of Si02) eluting first with 10:90 ethyl acetate-hexanes and then with 20:80 ethyl acetate-hexanes to afford 127 mg of the titled compound 8b (198 pmol, 85%) as a white foam.

Example 12 (1'S,2R,3S,3'S,5S)-5-(3-Butylcarbamoyl-1-hydroxy-4-methyl-pentyl)-3-isopropyl-2-(4-methoxy-phenyl)-pyrrolidine-l-sulfonic acid 2,2,2-trichloro-ethyl ester (9).

/) O /) O O
O O ~ %O OH
g= õ O~S
N AIMe3, n-BuNH2 N, NHn-Bu Me0 DCM Me0 õ
O
RT, O/N
91%

Mol. Wt.: 556.93 Mol. Wt.: 630.06 A first dry round-bottomed flask was charged with 64 mg of 8 (114 pmol, 1.0 eq.), a magnetic stirrer and capped with a rubber septum. The reaction media was flushed with argon and 1.1 mL of dry dichloromethane ([8] = 0.1 M) were introduced via a glass syringe. The resulting solution was stirred under an atmosphere of argon at room temperature. A second dry round-bottomed flask was charged with 62 pL of n-butylamine (456 pmol, 4.0 eq.), a magnetic stirrer and capped with a rubber septum. The reaction media was flushed with argon and 456 pL of dry dichloromethane ([n-butylamine] = 1.0 M) was introduced via a glass syringe. The resulting solution was stirred under an atmosphere of argon at room temperature and 228 pL of a 2.0 M solution of trimethylaluminum in toluene (456 pmol, 4.0 eq.) was added drop wise. The reaction mixture was stirred for minutes at room temperature and transferred via cannula into the first round-bottomed fiask in a dropwise manner. The resulting solution was stirred at room temperature overnight and then monitored by TLC analysis (50:50 ethyl acetate-hexanes, CAM). When TLC analysis showed no more starting material the reaction media was quenched by adding 2 mL of a saturated aqueous solution of ammonium chloride at room temperature. The resulting biphasic solution was stirred at room temperature for 30 minutes and the aqueous layer was separated and extracted with three portions of dichloromethane. The combined organic layers were washed with one portion of brine, dried over magnesium sulfate and filtered. The solvents were removed under reduced pressure to leave 70 mg of a yellow oil which was purified by flash column chromatography (7 mL of Si02) eluting with 30:70 ethyl acetate-hexanes to afford 65 mg of the titled compound 9 (103 pmol, 91 %) as a white solid.

Example 13 (1'S,2R,3S,3'S,5S)-5-(3-Butylcarbamoyl-1-hydroxy-4-methyl-pentyl)-3-isopropyl-2-(4-methoxy-phenyl)-pyrrolidine-1-carboxylic acid tert-butyl ester (10a).

~ 1) Zn(Cu) 0%0 HO AcOH:MeOH (1:1; v/v), O/N Ho O S NHn-Bu then HCI in MeOH Boc NHn-Bu Me0 ~ N 6 hours, 45 C Me0 ~~ N/
O O
2) Boc20, sat. K2CO3 DCM,O CtoRTO/N,52%.

Mol. Wt.: 630.06 Mol. Wt.: 518.73 A first dry round-bottomed flask was charged with 91 mg of zinc (copper) couple (470 pmol, 5.0 eq.), a magnetic stirrer and capped with a rubber septum. The reaction media was flushed with argon and a second round-bottomed flask was charged with 60 mg of 9a (94 pmol, 1.0 eq.) which was dissolved in 940 pL of a 1:1 (v/v) mixture of methanol and acid acetic ([9a] = 0.1 M). The latter solution was transferred via a glass syringe into the first round-bottomed flask.
Transfer was made quantitative with two minimum additional portion of a 1:1 (v/v) mixture of methanol and acid acetic and the resulting suspension was stirred vigorously stirred under an atmosphere of argon for 16 hours. After this time, the reaction contents were filtered through a pad of Celite and the filter cake was rinsed three times with a minimum amount of methanol. The filtrate was concentrated to dryness under reduced pressure to afford a white solid. The round-bottomed flask containing the white solid was then charged with a magnetic stirrer and capped with a rubber septum. The reaction vessel was flushed with argon and 940 pL of a 2.0 M solution of anhydrous hydrochloric acid in methanol (140 pL
of acetyl chloride in 2 mL of anhydrous methanol gave 2 mL of a 2.0 M solution of anhydrous hydrochloric acid in methanol) was added to the round-bottomed flask containing the white solid which was dissolved by stirring under an atmosphere of argon. The resulting solution was allowed to warm at 45 C and stirred at this temperature for six hours. After this time, the reaction media was diluted with 4 mL of toluene, the anhydrous hydrochloric acid in methanol was removed under reduced pressure on a rotary evaporator at room temperature and then the toluene at higher temperature to leave a yeliow oil. The round-bottomed flask containing the yellow oil was charged with a magnetic stirrer and capped with a rubber septum. The reaction media was flushed with argon and 520 pL of dichloromethane was introduced in the reaction vessel via a syringe. The reaction media was stirred and cooled down to 0 C with a water-ice bath before adding via a syringe 520 pL of a saturated solution of potassium bicarbonate and 41 mg of di-tert-butyl carbamate (188 pmol, 2.0 eq.) in a portion wise manner.
The biphasic solution was stirred vigorously at 0 C for ten minutes and then allowed to warm to room temperature by removing the ice-water bath. The reaction was stirred at room temperature overnight and then diluted with I mL
of dichloromethane and 1 mL of an aqueous solution of sodium carbonate. The aqueous layer was separated and extracted with three portions of dichloromethane. The combined organic layers were dried over magnesium sulfate and filtered. The dichloromethane was removed under reduced pressure to leave 40 mg of yellow residue which was purified by flash column chromatography (4 mL of Si02) eluting with 25:75 ethyl acetate-hexanes to afford 25 mg of the titled compound 10a (49 pmol, 52%) as a colorless oil.

Example 14 (1S,2S,2'S,4S)-{4-Butylcarbamoyl-2-hydroxy-l-[2-(4-methoxy-benzyl)-3-methyl-butyl]-5-methyl-hexyl}-carbamic acid tert-butyl ester (10').
Hydrogenolysis OH OH
Boc NHn-Bu NHn-Bu N, BocHN,.
Me0 H2, 10% Pd/C
MeOH, RT, 3 days 60% MeO 10 10' Mol. Wt.: 518.73 Mol. Wt.: 520.74 Birch reduction OH OH
;Boc NHn-Bu BocHN,,, NHn-Bu , Me0 O Li THF, -78 C

90% MeO xx xx Mol. Wt.: 518.73 Mol. Wt.: 520.74 Example 15 (2S,4S,5S, 7S)-5-Amino-4-hydroxy-2-isopropyl-7-(4-methoxy-benzyl)-8-methyl-nonanoic acid butylamide (XX).

OH OH
BocHN,,. NHn-Bu H2N NHn-Bu HCI, Dioxane, RT
O -- O
I RT quantitative MeO MeO
10' 11 Mol. Wt.: 520.74 Mol. Wt.: 420.63 In the above-described Examples, it will be appreciated by those skilled in the art that various other reagents may be employed which are equivalent to those specifically used. Thus, for the aromatic organometallic reagents having the substituents R1 and R2, various arolithium, as well as other metals copy 300 can be employed, It will be understood that various modifications can be made without departing from the spirit and scope of the invention disclosed herein.

Claims

1. A compound represented by a member selected from the group consisting of those of formulae 4, 5, 6, 7, 8 as follows:

wherein R1 is C1-C7 alkyl, C1-C7 alkoxyalkyloxy;halogen; or C1-C7 alkoxy: R2 is halogen, C1-5 alkyl; C1-5 alkoxyalkyloxy or combinations thereof.

wherein R1 is C1-C7 alkyl, C1-C7 alkoxyalkyloxy;halogen; or C1-C7 alkoxy: R2 is halogen, C1-5 alkyl; C1-5 alkoxyalkyloxy or combinations thereof.

wherein R1 is C1-C7 alkyl, C1-C7 alkoxyalkyloxy;halogen; or C1-C7 alkoxy: R2 is halogen, C1-5 alkyl; C1-5 alkoxyalkyloxy or combinations thereof.

wherein R1 is C1-C7 alkyl, C1-C7 alkoxyalkyloxy;halogen; or C1-C7 alkoxy: R2 is halogen, C1-5 alkyl; C1-5 alkoxyalkyloxy or combinations thereof.

wherein R1 is C1-C7 alkyl, C1-C7 alkoxyalkyloxy;halogen; or C1-C7 alkoxy: R2 is halogen, C1-5 alkyl; C1-5 alkoxyalkyloxy or combinations thereof.

2. A process for preparing a compound of one of the following formula 4:
wherein R1 is C1-C7 alkyl, C1-C7 alkoxyalkyloxy;halogen; or C1-C7 alkoxy: R2 is halogen, C1-5 alkyl; C1-5 alkoxyalkyloxy or combinations thereof, comprising the reaction of a compound of formula 3 with an R1OC6H4MgBr compound and wherein R1 is defined above.

3. A process for preparing a compound of one of the following formula 5:
wherein R1 is C1-C7 alkyl, C1-C7 alkoxyalkyloxy;halogen; or C1-C7 alkoxy: R2 is halogen, C1-5 alkyl; C1-5 alkoxyalkyloxy or combinations thereof, comprising the reaction of a compound of formula 4 as defined in claim 2 with an acid, Cl3C6H2COCl, Et3N, DMAP, PhCH3.

4. A process for preparing a compound of one of the following formula 6:
wherein R1 and R2 are members selected from the group consisting of hydrogen, alkyl or alkoxy; comprising the reaction of a compound of formula 5 as defined in claim 3, with Ti(i-PrO)4, PhCH3.

5. A process for preparing a compound of one of the following formula 7:

wherein R1 is C1-C7 alkyl, C1-C7 alkoxyalkyloxy;halogen; or C1-C7alkoxy: R2 is halogen, C1-5 alkyl; C1-5 alkoxyalkyloxy or combinations thereof, comprising the reaction of a compound of formula 6 as defined in claim 4 with H2NSO3CH2CCl3, MgO, Rh2(tfacam)4, Phl(Oac)2, PhCH3.

6. A process for preparing a compound of one of the formula 8:
wherein R1 is C1-C7 alkyl, C1-C7 alkoxyalkyloxy;halogen; or C1-C7alkoxy: R2 is halogen, C1-5 alkyl; C1-5 alkoxyalkyloxy or combinations thereof, comprising the reaction of a compound of formula 7 as defined in claim 5 with TFA:DCM.

7. A compound of the formula:

wherein R1 is C1-C7 alkyl, C1-C7alkoxyalkyloxy; halogen; or C1-C7 alkoxy: R2 is halogen, C1-5 alkyl; C1-5 alkoxyalkyloxy or combinations thereof,

8. All the novel features disclosed in the disclosure.