Title of Invention

"PROCESSES FOR PREPARING A BICYCLO [3.1.0] HEXANE DERIVATIVE OF FORMULA (IA)"

Abstract Processes for the preparation of certain [3.1.0] hexane derivatives which are useful as mOluR agonists, and intermediates prepared during such processes.
Full Text TITLE OF THE INVENTION
PROCESSES FOR PREPARING BICYCLO [3.1.0] HEXANE DERIVATIVES, AND
INTERMEDIATES THERETO
CROSS-REFERENCE TO RELATED APPLICATIONS
This application claims priority under 35 U.S.C. § 119(e) to U.S. provisional application seria'l no. 60/518,391, filed November 7,2003.
FIELD OF THE INVENTION
The present invention relates to processes for the preparation of bicyclo[3.1.0]hexane derivatives which are useful as metabotropic glutamate receptor modulators. The invention is also related to novel intermediate compounds which are prepared during such processes, and to the hydrochloride salt of (+)-(1R, 25, 55,65)-2-amino-6-fluoro-4-oxobicyclo[3.1.0]hexane-2,6-dicarboxylic acid, and polymorphs thereof.
BACKGROUND OF THE INVENTION
The excitatory ammo acids, including glutamate, modulate a variety of physiological processes in the mammalian central nervous system (CNS), such as long-term potentiation (learning and memory), the development of synaptic plasticity, motor control, respiration, cardiovascular regulation, and sensory perception.
Glutamate acts via at least two distinct classes of receptors. One class is composed of the ionotropic glutamate (iGlu) receptors that act as ligand-gated ionic channels. The second class is the G-protein or second messenger-linked "metabotropic" glutamate (mGluR) receptor. Both classes of receptors appear to mediate normal synaptic transmission along excitatory pathways, and also to participate in the modification of synaptic connections during development and throughout life. Schoepp, Bockaert, and Sladeczek, Trends in Pharmacol. Sci., 11, 508 (1990); McDonald and Johnson, Brain Research Reviews, 15, 41 (1990).
Various functionalized bicyclo[3.1.0]hexane derivative compounds have been recognized as mGluR modulators. The mGluR modulators are therapeutically useful for the treatment or prevention of psychiatric disorders, schizophrenia, anxiety and associated diseases, depression, bipolar disorder, and epilepsy; and neurological diseases, such as drug dependence, cognitive disorders, Alzheimer's disease, Huntington's chorea, Parkinson's disease, dyskinesia associated with muscular stiffness, cerebral ischemia, cerebral failure, myelopathy, and head trauma. For example, U.S. Patent No. 6,333,428, issued
December 25,2001, discloses certain mGluR agonists which are 2-amino-6-fluorobicyclo[3.1.0]hexane derivatives of the formula below:
(3)
(4) alkyl;
and pharmaceutically acceptable salts thereof. The '428 patent states that the compounds of the invention may be in racemic form, or may be in enantiomeric form. The '428 patent also discloses certain novel intermediates of the formula below:
(Figure Removed)


e and hazardous reagents, such as Pd(OAc)2 and (PhSe)2, which must be present in stoichimetric amounts, and CH2N2- The synthetic method of Nakazato also requires a harsh hydrolysis using H2SO4 at high temperatures (145 °C) for five days as the last step of the synthesis, resulting in a low yield, and requires a difficult isolation of the final product from a hydantoin derivative precursor.
It will be appreciated that the mGluR modulators disclosed in U.S. Patent Nos. 6,333,428, 6,160,009 and 5,570,566, are useful as therapeutic agents. As such, there is a need for a development of a process for the preparation of these compounds, which is readily amenable to scale-up, uses cost-effective and relatively safe reagents, and is therefore capable of practical application to large scale manufacture.
Applicants have now discovered a novel synthesis of a class of enantiomerically pure functionalizedbicyclo[3.1.0]hexane derivative mGluR modulators and of enantiomerically pure intermediate compounds.
SUMMARY OF THE INVENTION
The present invention concerns novel processes for the synthesis of a class of functionalized bicyclo[3.1.0]hexane derivative mGluR modulators of formula (I)
(I)
wherein Rl and R2 are independently selected from the group consisting of
(1) hydrogen,
(2)Ci_ioalkyl,
(3) C3-8 cycloalkyl, and
(4)-(CH2)n-phenyl
wherein n is 1 or 2; and said alkyl, cycloalkyl and phenyl are unsubstituted or substituted with one or more halogen, hydroxy, Ci-6 alkyl or Ci-6 alkoxy;
X is selected from the group consisting of
(1) halogen, and
(2) hydrogen; and
Q is -CH2- or -C(=O)-;
and pharmaceutically acceptable salts thereof.
The invention further relates to novel processes for the preparation of compounds of formula (II)

wherein R.3 is selected from the group consisting of (l)-OH,
(2) -O-Ra , and
(3) -NRbRc ,
wherein Ra is selected from the group consisting of
(a) Ci-io alkyl , and
(b) Cs-g cycloalkyl,
and Ra is unsubstituted or substituted with one or more (i) Ci-io alkoxy,
(ii) hydroxy,
(iii) halogen,
(iv) SRd,
(v) aryl, unsubstituted or substituted with one or more hydroxy, Ci-io
alkoxy, Ci-io alkyl or halogen,
(vi) heteroaryl, unsubstituted or substituted with one or more hydroxy, Ci_io alkoxy, Ci-io alkyl or halogen, and (vii) NReRf; Rb, Rc, Re and Rf are selected from the group consisting of
(a) hydrogen,
(b) CMC alkyl, and
(c) C3-8 cycloalkyl,
and when Rb, Rc, Re or Rf are CI_IQ alkyl or Cs-g cycloalkyl, said CI_IQ alkyl and C3-g cycloalkyl are unsubstituted or substituted with one or more
(i) hydroxy, (ii) Ci-lO alkoxy,
(iii) SRd,
(iv) aryl, unsubstituted or substituted with one or more hydroxy, Cj-io
alkoxy, Ci-lO alkyl or halogen, and
(v) heteroaryl, unsubstituted or substituted with one or more hydroxy, Ci_io
alkoxy, Ci-io alkyl or halogen, and
(vi) NRgRh;
wherein Rg and Rn are hydrogen, Ci_io alkyl or C3-g cycloalkyl;
or Rb and Rc, together with the N atom to which they are attached, form a group

wherein r is 1 or 2, and the NRbRC group may be unsubstituted or substituted at the ring carbon atoms by one or more (i) hydroxy, (ii) Ci-io alkoxy,
(iii) SRd,
(iv) aryl, unsubstituted or substituted with one or more hydroxy, Ci-io
alkoxy, Ci-io alkyl or halogen, and
(v) heteroaryl, unsubstituted or substituted with one or more hydroxy, Ci_io
alkoxy, Ci-io alkyl or halogen, and
(vi) NRgRh.
Rd is hydrogen or GI_IO alkyl; X is selected from the group consisting of
(1) halogen, and
(2) hydrogen; and
R4 is selected from the group consisting of
(1) hydrogen, (2)Ci-ioalkyl,

The invention is also related to novel processes for the preparation of compounds of formula (XH)
or its enantiomer (XII') (Figure Removed)


wherein E? and X are as defined above, and salts thereof.
Compounds of formulas (II), (XII) and (XIT) are intermediates prepared in the synthesis of the mGluR modulators of formula (I). Processes for using compound (XH) or (XIT) to form mGluR modulators of formula (I) are disclosed in the aforementioned '566, '428 and '009 patents, and in Nakazato et al., J.Med. Chem., 2000, 43, 4893-4909. The invention also relates to certain novel intermediates which are prepared during the synthesis of the invention.
BRIEF DESCRIPTION OF THE DRAWINGS
The invention is described in connection with the appended drawings, in which:
FIG. 1 is the x-ray powder diffraction (XPRD) pattern of a crystal form of the hydrochloride salt
of (+)-(!#, 25,55, 65)-2-amino-6-fluoro-4-oxobicyclo[3.1.0]hexane-2,6-dicarboxylic acid; and
FIG. 2 depicts the differential scanning calorimetry curve for a crystal form of the hydrochloride
salt of (+)-(!/?, 2S, 5S, 65)-2-amino-6-fluoro-4-oxobicyclo[3.1.0]hexane-2,6-dicarboxylic acid.
DETAILED DESCRIPTION OF THE INVENTION
The present invention is directed to processes for preparing functionalized bicyclo[3.1.0] hexane derivatives of formula (I)

wherein Rl and R2 are independently selected from the group consisting of
(1) hydrogen,
(2) Ci-io alkyl,
(3) C3_8 cycloalkyl, and
(4) (CH2)n -phenyl,
wherein n is 1 or 2, and said alkyl, cycloalkyl and phenyl are unsubstituted or substituted with one or more halogen, hydroxy, Ci-6 alkyl or Ci-6 alkoxy;
X is selected from the group consisting of
(1) halogen, and
(2) hydrogen; and
Q is -CH2- or -C(=O)-;
and pharmaceutically acceptable salts thereof.
In one embodiment, the invention is directed to a process for preparing compounds of formula (IA):


wherein X, Rl and R2 are as defined above.
In this embodiment, the invention comprises oxidizing an intermediate compound of formula (IT):
wherein X, R3 and R4 are as defined above; to form a compound of formula (IV):


In the process of preparing compounds of formula (IA), preferred R4 groups are TBS, TMS and TES. A preferred R? group is TMS.
In preferred embodiments of the process of preparing compounds of formula (IA), R5 and R6 are selected from the group consisting of methyl and phenyl. It is preferred that R5=R6.
In preferred embodiments of the process of preparing compounds of formula (IA), the step of converting compound (IX) to compound (I) comprises hydrolysis of compound (DC).
The invention is also directed to novel intermediate compounds of formulas (VII), (VET) and (IX):




wherein X is hydrogen and R3 is as defined above, is subjected to epoxidation, for example by reaction with a peroxide such as ten- butyl hydroperoxide, or other oxidants (including peracids such as perbenzoic acid and peracetic acid) preferably in the presence of a metal catalyst, such as VO(acac)2. The hydroxy group of compound (X) may then be protected, for example with TBS or TMS, to result in a compound of formula (XT):

de derivative (XI) is then reacted with a suitable base in the presence of a Lewis Acid to afford a compound of formula (IT):



may be converted to compounds of formula (IA) according to methods described in the prior art. For example, Nakazato, J. Med. Chem. 2000, 43, 4893-4909 describes the use of a compound of formula (IV) to form a compound of formula (IA) in Scheme 5 at page 4898. The process taught by Nakazato requires formation of a dithioketal, followed by hydantoin derivative.
U.S. Pat. No. 6,160,009 describes the use of a compound of formula (IV) to form a compound of formula (IA) at columns 8-13. The reaction proceeds via a hydantoin derivative.
hi preferred embodiments of the process of preparing compounds of formula (H), R3 is methoxy, ethoxy or benzyloxy.
hi preferred embodiments of the process of preparing compounds of formula (II), X is fluoro. In other preferred embodiments, X is hydrogen.
In the process of preparing compounds of formula (IT), preferred R4 groups are TBS, TMS and TES.
hi other preferred embodiments of the process, the oxidation of compound (II) comprises contacting compound (II) with RuCls and an oxidizing agent. Preferred oxidizing agents are bleaches. A
preferred bleach is NaClO.
The invention is also directed to novel intermediate compounds of formulas (XA), (XI), (IVA) and (H), as depicted below:



In compounds (XA), (XI), (IVA) and (IT), R3, X and R4 are as defined above. The invention is also dkected to processes for preparing intermediate enone compounds of formula (XH):
and its enantiomer (XJT):

Q.

wherein R3 and X are as defined above; and salts thereof.
In an embodiment of this process for preparing a compound of formula (XII), a compound of formula (II)

wherein X, R3 and R4 are as defined above, is subjected to a reaction to form a compound of formula (Xni), having a leaving group R8 as follows:
(Figure Removed)

wherein R§ is selected from the group consisting of
(1) halogen, and
(2) O-SO2-R12 wherein Rl2 js selected from the group consisting of
(a)CMOalkyl,
(b) Cl-io perfluoroalkyl,
(c) phenyl which is substituted or unsubstituted with one or more substituents selected
from the group consisting of nitro, halogen, CI_IQ alkyl, or Ci-10 alkoxy.
Thereafter, the R4 group is removed to afford the hydroxy ester derivative (XIV) below:

H > (XIV) OH which is then oxidized to afford the desired [3.1.0]-bicyclic-ct, P unsaturated ketone of formula (XIT):
(Figure Removed)


ompound of formula (XII).
The enone compound of formula (XII) or (XH') may be converted to a compound of formula (I) according to methods known in the prior art. For example, Nakazato, J. Med. Chem. 2000,43,4893-4909 describes the use of a compound of formula (XH) to form a compound of formula (IA) in Scheme 5 at page 4898.
U.S. Pat. No. 5,750,566 describes the use of a compound of formula (XII) to form compounds of formula (I) wherein Q is CH/2, at column 12 in Scheme IV.
Dominguez et al, Tetrahedron: Asymmetiy, 1997, 8,511-514 describes the use of a compound of formula (XH) to form compounds of formula (I) wherein Q is CH2, at Scheme 2 at page 513. The
process requires formation of a hydantoin derivative.
In preferred embodiments of the synthesis of compounds of formula-(XH) and (XII'), R3 is methoxy, ethoxy or benzyloxy.
In preferred embodiments of synthesis of compounds of formula (XII) and (XH1), X is fluoro. In other preferred embodiments, X is hydrogen.
In the synthesis of compounds of formula (XII) and (XII'), preferred R4 protecting groups are TBS, TMS and TES.

In the synthesis of compounds of formula (XH) and (XII'), preferred R.8 groups include O-tosyl (para toluenesulfonyl), O-mesyl and O-triflate.
The invention is also directed to the hydrochoride salt of compounds of formula (I). In preferred embodiments, the hydrochloride salt is the salt of the compound of formula (I) wherein X is fluoro and Rl and R2 are both hydrogen, denoted compound (I1):

which is (+)-(lR, 25,55, 6S)-2-amino-6-fluoro-4-oxobicyclo[3.1.0]hexane-2,6-dicarboxylic acid. The invention is also directed to a novel crystal polymorph of the hydrochloride salt of compound (T).
Definitions
As used herein, the term "Strecker synthesis reaction" or "Strecker reaction" refers to a reaction known to those skilled in the art of organic synthesis, to prepare alpha amino nitriles
As used herein, the term "substantially enantiomerically pure form" means that the desired enantiomer is present in at least 50% e/e (enantiomeric excess) relative to the undesired enantiomer.
As used herein, the term "Lewis Acid" refers to a compound which is capable of accepting electrons.
As used herein, the term "aryl" refers to a polyunsaturated aromatic hydrocarbon substituent, which can be a single ring or multiple rings (preferably from 1 to 3 rings) which can be fused together or linked covalently. Non-limiting examples of aryl groups include phenyl, naphthyl and biphenyl.
As used herein, the term "heteroaryl" refers to a polyunsaturated aromatic ring having at least one heteroatom (nitrogen, oxygen or sulfur) in the ring chain. A heteroaryl group can be a single ring or multiple rings (preferably from 1 to 3 rings) which can be fused together or linked covalently. Non-limiting examples of heteroaryl groups include pyrole, pyrazole, imidazole, pyridine, pyrazine, pyrimidine, furan, pyran, oxazole, isoxazole, purine, benzimidazole, quinoline, isoquinoline, indole and the like.
When a heteroaryl group as defined herein is substituted, the substituent may be bonded to a ring carbon atom of the heteroaryl group, or to a ring heteroatom (i.e., a nitrogen, oxygen or sulfur), which has a valence which permits substitution. Preferably, the substituent is bonded to a ring carbon atom.
As used herein, the term "halogen" refers to fluorine, chlorine and bromine. A preferred halogen is fluorine.
As used herein, the term "alkyl," by itself or as part of another substituent, means a straight or branched chain hydrocarbon radical having the number of carbon atoms designated (e.g., CI_IQ alkyl
means an alkyl group having one to ten carbon atoms). Examples of alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, isobutyl, sec-butyl, pentyl, hexyl and the like.
As used herein, the term "alkoxy," by itself or as part of another substituent, means the group O-
i alkyl, wherein alkyl is as defined above, to include straight or branched alkyl groups.
As used herein, the term "cycloalkyl," by itself or as part of another substituent, means a saturated cyclic hydrocarbon radical having the number of carbon atoms designated (e.g., 03.3
cycloalkyl means a cycloalkyl group having three to eight carbon atoms).
As used herein, the term "pharmaceutically acceptable" refers to molecular entities and compositions that are "generally regarded as safe," e.g., that are physiologically tolerable and do not typically produce an allergic or similar untoward reaction, such as gastric upset, dizziness and the like, when administered to a human. Preferably, as used herein, the term "pharmaceutically acceptable" means approved by a regulatory agency of the Federal or a state government or listed in the U.S. Pharmacopeia or other generally recognized pharmacopeia for use in animals, and, more particularly, in humans.
In one embodiment, the process of the invention is depicted in Scheme 1 below.Scheme 1
(Figure Removed)




One method of achieving the desired fluorination is by reaction with the fluorinating agent, such as N-fluorobenzenesulfonimide (NFSI) with a strong base in a suitable solvent, for example tetrahydrofuran. It is preferred that the reaction occur at temperatures of less than -65°C, preferably less than -75°C, most preferably less than -78°C. Suitable strong bases include lithium diisopropylamide (LDA), lithium tetramethylpiperizide, lithium hexamethyldisilazide (LHMDS), or corresponding potassium or sodium salts.
Stereoselective epoxidation of 2 may then be achieved by reaction in toluene with an oxidizing agent, such as a peroxide derivative (for example tert-butyl hydroperoxide), and a catalyst (for example, a catalytic amount of vanadyl acetylacetonate (VO(acac)2). It is preferred that the reaction occur at from
about 0°C to about 40°C.
(Figure Removed)


Alternative oxidizing agents include meta chloroperoxybenzoic acid (mCPBA). The resulting epoxide 3 is obtained as a trans isomer.
Alternatively, the trans hydroxy ester 1 may be first subjected to Stereoselective epoxidation, and the resulting epoxide 2' may be fluorinated to yield compound 3.
(Figure Removed)
ur. A preferred temperature is about -60°C. Alternative Lewis Acids which may be used hi the reaction include, RTi(OR)3, R2Ti(OR)2, RA1X2 or R2A1X, wherein X is a halogen or an inorganic radical and each R is a hydrocarbon group. Exemplarly Lewis Acids include Al(OiPr)3, Ti(OiPr)4, BF3 etherate, Et2Zn, EtsAl and Sc(OTf)3- Compound 5 is obtained in the desired stereoisomeric form.
Oxidation of the resulting free alcohol and removal of the protecting group provides bicyclic hydroxy ketone 7 (compound II). Preferred oxidizing agents include reagent grade sodium hypochlorite solution or commercial bleach. The reaction may proceed in the presence of a catalytic amount of RuCl3
and in the presence of acetic acid (1.5 equivalents) at 0°C in acetonitrile. The excess sodium hypochlorite should then be removed (for example, by quenching with isopropyl alcohol). The addition of an acid (e.g., 20 mol% of 1M HC1) to the acetonitrile solution cleaves the protecting group R4

The reaction proceeds in the presence of acid (e.g., 0.1 equivalent), at from about 0°C to about -10°C. A preferred acid is TfOH or TfOTMS.
Oxidation of the secondary alcohol of 8 yields ketone 9.

R6
Y^\. COR3
oxidizing agent
The oxidation reaction may proceed with any oxidizing conditions such as Swem conditions. Alternatively, the oxidation may proceed in the presence of RuCla (0.5 mol%), with NaCIO in acetonitrile and acetic acid, at from O'C to room temperature.

Subsequently, TMSCN may be added at from -10°C to 0°C. TMSCN can be replaced with KCN/NaCN in the presence of acids. A titanium compound, such as titanium isopropoxide (Ti(OiPr)4), may be used to promote 'the reaction. The reaction yields the desired amino-nitrile 10 with high diastereoselectivity.
Compound 10 is then subjected to hydrolysis to provide the desired 2-amino-6-fluorobicyclo[3.1.0]hexane (compound 11). (Figure Removed)


The hydrolysis reaction may proceed in 5 hours using a 1:3 mixture of acetic acid and 8 M HCI at 75°C. Alternatively, the reaction may proceed in the presence of 60% H2SO4, at about 100°C, for about 2 hours, or alternatively by treatment with acetic acid/H2SO4 at 60 °C, for about 2 hours.
Thereafter, the desired compound 11 may be isolated as the hydrochloride salt, according to methods known to those skilled in the art.
In another embodiment, the process of the invention is depicted in Scheme 2 below.
Scheme 2


wherein X, R3, R4 and R.8 are as defined above.
In Scheme 2, optically active trans-hydroxy ester 12 was obtained as taught above in the description of scheme 1. Epoxidation of 12 proceeded in a diastereoselective manner to afford epoxide 13, protection of the hydroxyl group in 13 gave 14, and treatment of 14 with a Lewis acid followed by a base produced a bicyclo[3.1.0] compound 15. The use of the enantiomer of 12, which is disclosed in Partridge et al., Org. Synth 1985, 83,44, will afford the synthesis of the enantiomers of 13,14, and 15.
The mono-protected [3.1.0] bicyclic diol 15 (which is identical to 5 from scheme 1) is transformed to a [3.1.0] bicyclic a,|3-unsaturated ketone. In this scheme, the hydroxyl group in the alcohol 15 is converted to a leaving group R.8, and the protecting group R4 is removed to afford hydroxy ester 17. Suitable R8 leaving groups include sulfonate (for example, para-toluenesulfonate) and halides. Oxidation of 17 is induced by the elimination of the R8 leaving group to afford a [3.1.0] bicyclic
18 (from scheme 2).
The chemical structures described above include each of the enantiomers either in enantiomerically pure form or in mixture form.
The starting materials and reagents for the processes described herein are either commercially available or are known in the literature or may be prepared following literature methods described for analogous compounds. The skills required in carrying out the reaction and purification of the resulting reaction products are known to those in the art. Purification procedures include crystallization, distillation, normal phase or reverse phase chromatography.
The following examples are provided for the purpose of further illustration only and are not intended to be limitations on the disclosed invention. Examples 1-10 illustrate the method of scheme 1. Examples 11-15 illustrate the method of scheme 2. Examples 16 and 17 illustrate the method of scheme 3.
EXAMPLE 1 Methyl fluoror(l/?.5J?)-5-hvdroxvcvclopent-2-en-l-vl1acetate 2
(Table Removed)
C. The funnel and the flask were flushed with 2.5 mL of THF into the reaction mixture. The resulting mixture was stirred at -96 °C for 1 h before warmed to -80 °C over 30 min. Acetic acid (11 mL) in THF (5 mL) was added slowly over 7 min. The mixture was allowed to warm to ambient temperature after the addition of MTBE (100 mL). The resulting solid was removed by filtration and washed thoroughly with MTBE (70 mL x 6). The combined filtrate and wash were filtered again and analyzed by HPLC. The chemical yield was determined to be 86%. The filtrate was passed through a short plug of silica gel (30 g), and the plug was washed with MTBE (200 mL). The combined MTBE solutions were concentrated under reduced pressure. The residue was dissolved in EtOAc (250 mL) and washed with saturated aqueous NaHCO3 (170 mL). The aqueous layer was back-extracted with EtOAc (60 mL x 2). The combined organic solutions were washed with brine (60 mL) and dried over Na2SO4. Evaporation of solvent gave the crude ester, which was subjected to bulb-to-bulb distillation (1.6 Torr) to afford the ester as yellow oil. Analytically pure sample was obtained by further flash silica gel column chromatography as colorless oil. lH NMR (400 MHz, CDCls): 8 5.84 (m, 1 H), 5.55 (m, 1 H), 4.95 (dd, J= 48.8, 5.5 Hz, 1 H), 4.49 (dt, J
= 7.2,4.6 Hz, 1 H), 3.82 (s, 3 H), 3.11 (dm, 7 = 24.4 Hz, 1 H), 2.75 (m, 1 H), 2.51 (s, 1 'H), 2.33 (m, 1 H); 13C NMR (101 MHz, CDC13): 5 170.02 (d, J = 24.1 Hz), 132.27,126.13 (d, J = 5.0 Hz), 89.52 (d, J = 188.0 Hz), 73.92 (d, J = 4.0 Hz), 57.12 (d, J = 20.1 Hz), 52.64,41.85; 19p NMR (376 MHz, CDCls): -196.5; IR (film) 3409, 3059,1744,1439,1288,1209,1153,1099,1048, 951,733 cm-1; [a] *f = -123.5 (c 1.02, CHC13).
EXAMPLE 2
Methvl fluorord/?.2^.3J?.5y)-3-hvdroxv-6-oxabicvclor3. l.Olhex-2-vllacetate 3

ns were concentrated, and the resulting residue was purified by silica gel chromatography in a filter pot (first eluted with hexanes/EtOAc (4/1) then pure EtOAc). Analytically pure sample was prepared by flash silica gel column chromatography (hexanes/MTBE) followed by recrystallization (EtOAc) as pale yellow crystals: mp 31-33 °C; IH NMR (400 MHz, CDCls) 8 5.01 (dd, 7 = 48.3, 3.9 Hz, 1 H), 4.13 (br s, 1 H),
3.86 (s, 3 H), 3.71 (m, 1 H), 3.59 (m, 1 H), 2.77 (dd, / = 32.8,3.9 Hz, 1 H), 2.30 (br s, 1 H), 2.11 (m, 2
H); 13C NMR (101 MHz, CDC13) 8 168.4 (d, J = 24.1 Hz), 88.1 (d, / = 186.1 Hz), 73.2 (d, J = 1.6 Hz),
58.4,57.1 (d, J = 5.6 Hz), 52.8, 51.6 (d, J = 19.3 Hz), 37.7 (d, J= 1,6 Hz); 19p NMR (376 MHz, CDCls)
8 -200.8 (dd, J = 48.3,32.8 Hz); LRMS m/z 191 (M + 1), 189 (M - 1), 172 ([M - H2O]+), 59
([COOCHjf, base peak); [a] £ = -56 (c 1.0, CHCls).
Analysis calculated for CgHi iFO4 C
50.53; H, 5.83; F, 9.99
Found: C, 50.36; H, 5.92; F, 10.05
EXAMPLE 2A
Methyl r(lK.2£3fc5SV3-hvdroxv-6-oxabicvclor3.1.01hex-2-vllacetate

To a solution of olefm 2' (50.0 mg, 0.320 mmol) in wet DMSO (6.4 pL H2O in 1.2 mL DMSO) at rt was added NBS (68.4 mg, 0.384 mmol). After the resulting solution was stirred at rt for 4.5 h, another 10 mg of NBS was added. The reaction was further stirred at rt for 2 h, diluted with EtOAc, and washed with H2O. The aqueous layer was extracted with EtOAc (twice), and the combined organic layer was dried over Na2SO4. The solvent was removed under reduced pressure, and the resulting residue was taken in CH2C12 (1.2 mL). DBU (57.4 pL, 0.384 mmol) was added to the solution, which was stirred at rt for 18 h. The solvent was evaporated, and the resulting residue was purified by flash silica gel column chromatography to afford epoxide 3' as a mixture of diastereomers, which were inseparable by chromatography. The spectral data for the major isomer are as follows: !H NMR (CDC13, 400 MHz) 5 3.80 (dd, J = 11.6, 5.6 Hz, 1 H), 3.72 (s, 3 H), 3.65 (rn, 1 H), 3.61 (m, 1 H), 2.68 (dd, J = 8.4, 7.2 Hz, 1 H), 2.36 (d, J= 11.6 Hz, 1 H), 2.26 (dd, /= 15.7, 7.2 Hz, 1 H), 2.20 (dd, 7= 15.7, 8.4 Hz, 1 H), 2.11 (d, / = 15.3 Hz, 1 H), 2.02 (dd, J = 15.3,5.6 Hz, 1 H). Under similar reaction conditions, the following epoxides were also prepared:



EXAMPLES Methyl f(lJ?.2R.3J?.5^)-3-fr?g?t-butvl(rdimethvl)silvnoxv)-6-oxabicvclor3.1.01hex-2-vl)fluoroacetate 4

phy (hexanes/MTBE) as colorless crystals: mp 28-30 °C; Ifi NMR (400 MHz, CDCls) 5 5.00 (dd, J = 48.2, 3.5 Hz, 1 H), 4.45 (m,
1 H), 3.85 (s, 3 H), 3.51 (m, 1 H), 3.42 (m, 1 H), 2.64-2.52 (dm, J = 34.5 Hz, 1 H), 2.14 (m, 1 H), 1.91 (m, 1 H), 0.88 (s, 9 H), 0.054 (s, 3 H), and 0.051 (s, 3 H); 13C NMR (101 MHz, CDCls) 5 168.8 (d, / =
24.1 Hz), 88.3 (d, J = 186.1 Hz), 75.4 (d, J = 1.6 Hz), 58.3,57.2 (d, J = 7.2 Hz), 52.8 (d, J = 19.3 Hz),
52.7,38.3,25.9,18.0, -4.5, and -4.7; 19p NMR (376 MHz, CDCls) 5 -199.9 (dd, / = 48.2, 34.5 Hz);
LRMS mlz 305 (M + 1), 121 (base peak); [a] £ = -27 (c 1.0, CHCls).
Analysis calculated for Ci4H25FO4Si
C, 55.23; H, 8.28; F, 6.24
Found: C, 55.27; H, 8.63; F, 6.31
EXAMPLE 4
Methyl (lR,2R,4S,5S,6R)-2-{ [fert-butyl(dimethyl)silyl]oxy }-6-fluoro-4-hydroxybicyclo[3.1.0]hexane-6-
carboxylate 5 ._
To a solution of epoxide TBS-ether 4 (assay wt. 1.60 kg, 5.24 mol) in THF (16.1 L) was added a solution of Et3Al (1.0 M in hexanes, 6.81 L, 6.81 mol), while maintaining the batch temperature at -60
°C over 1 h, and the resulting solution was stirred at -60 °C for 20 min. A solution of LHMDS (1.0 M solution in hexanes, 7.86 L, 7.86 mol) was added to the reaction mixture over 1 h while maintaining the batch temperature below -60 °C, and the reaction was aged at -60 °C. The progress of the reaction was monitored by GC. After complete consumption of the epoxide (6 h), an aqueous solution of citric acid (3 M, 10.5 L) was added over 1 h while maintaining the batch temperature below -50 °C. After MTBE (12.4 L) was added, the resulting suspension was gradually allowed to warm to 15 °C with stirring. The mixture turned to biphasic solution after addition of H20 (4.93 L). The organic layer was separated and washed twice with saturated aqueous NaHCOs (11.1 L then 5.6 L). GC assay of the organic solution indicated compound 5. Concentration of the organic layer afforded crude alcohol as yellow oil which was used for the next reaction without further purification.
Analytically pure sample was obtained by flash silica gel column chromatography as colorless amorphous solid: lH NMR (400 MHz, CDCls) 5 4.47 (d, J = 4.4 Hz, 1 H), 4.34 (m, 1 H), 3.83 (s, 3 H),
2.44 (d, 7 = 6.8 Hz, 1 H), 2.37 (d,7= 11.2Hz, 1 H), 2.25 (d, J = 6.8 Hz, 1 H), 2.07 (m, 1 H), 1.84 (m, 1 H), 0.91 (s, 9 H), 0.131 (s, 3 H), and 0.128 (s, 3 H); 13C NMR (101 MHz, CDCls) 5 169.2 (d, J = 26.5
Hz), 79.7 (d, 7 = 244.3 Hz), 74.1,74.0, 52.9,44.6 (d, 7= 10.4 Hz), 37.9 (d,7= 12.0Hz), 37.6 (d,7= 11.2 Hz), 25.8,18.0, -4.8, -4.9; 19p NMR (376 MHz, CDC13) 5 -217.1 (m); LRMS mJz 305 (M + 1), 304 (M), 303 (M -1), 75 (base peak); [a] £ = +7 (c 1.1, CHCls).
Analysis calculated for Ci4H25FO4Si C
55.23; H, 8.28, F, 6.24
Found: C, 55.44; H, 8.46; F, 6.39
EXAMPLES
Methyl (lR,2R,5S,6S)-2- {[tert-butyl(dimethyl)silyl] oxy} -6-fluoro-4-oxobicyclo[3.1.0]hexane-6-
carboxvlate 6
To a solution of bicyclic mono-TBS-diol 5 (2.08 kg; 6.83 mol) in acetonitrile (8.0 L) at -5 °C was added acetic acid (0.70 L) and water (2.5 L), followed by RuCls hydrate (14.20 g). To the mixture was added aqueous sodium hypochlorite solution (~ 13%; 7.0 L) over 2 h, keeping the temperature around 0 °C. The resulting mixture was stirred at 0 °C for another 1 h until all bicyclic mono-TBS-diol 5
ed to dryness and the compound was purified by silica gel chromatography in a filter pot (first eluted with 30% MTBE in hexane, then MTBE alone) to give compound 7 as an off white crystal. Analytical pure sample was obtained by further flash silica gel column as colorless crystals: mp 61- 62 °C; IH NMR (400 MHz, CDCI3): 8 4.92 (br s, 1 H), 3.85 (s, 3 H); 2.86 (dd, J = 6.2, 2.1 Hz, 1 H), 2.71 (d, J = 6.2 Hz, 1 H), 2.61 (dt, 7 = 19.4, 5.7 Hz, 1 H), 2.59 (br s, 1 H), 2.30 (dd, 7 = 19.4, 3.7 Hz, 1 H); 13C NMR (100 MHz, CDC13): 8 206.9,167.0 (d, J = 26.2 Hz), 79.0 (d, 7 = 246.6 Hz), 67.0 (d, 7 = 3.1 Hz), 53.5,46.8 (d, 7 = 4.2 Hz), 41.6 (d, 7 » 11.8 Hz), 39.4 (d, 7 = 13.1 Hz); 19p NMR (376 MHz, CDCls): 8 -210.6; [a] % = +
77 (c 0.50, CH3OH).
Analysis calculated for
51.07; H, 4.82, F, 10.10
Found: C, 51.06; H, 4.83; F, 10.05

EXAMPLE 6A Methyl (IS,2R,5 J?.6J?)-2-hydroxy-4-oxobicvcIof3.1.01hexane-6-carboxylate

TBS-ether 6' (150 mg, 0.528 mmol) was treated with 1 M HCI (0.106 mL) in acetonitrile (0.8 mL) at rt for 2 h. The reaction was diluted with EtOAc, quenched by addition of a small amount of saturated aq. NaHCO3) washed with H2O and brine (twice), and dried over Na2SO4. The solvents were removed under reduced pressure, and the resulting residue was purified by flash silica gel column chromatography to afford hydroxy ketone 7' as colorless solid: JH NMR (CDC13, 400 MHz) 8 4.60 (d, J = 5.2 Hz, 1 H), 3.72 (s, 3 H), 2.67 (dd, / = 5.2, 3.6 Hz, 1 H), 2.42 (dd, / = 5.2, 2.4 Hz, 1 H), 2.34 (dd, J = 18.9, 5.2 Hz, 1 H), 2.22 (br-s, 1 H), 2.08 (d, J = 18.9 Hz, 1 H), 1.93 (dd, J = 3.6, 2.4 Hz, 1 H); 13C NMR (CDC13, 101 MHz) 8 208.8, 169.8, 68.3, 52.5, 42.7, 36.2, 34.2, 25.2.
EXAMPLE 7
Methyl (l1Sr,4^,4>5,5^,5'5,6S)-6-fluoro-4-hydroxy-4',5'-diphe.nylspko[bicyclo[3.1.0]hexane-2,2'-n.31dioxolane1-6-carboxvlate 8 _

To a solution of hydroxy ketone 7 (1.09 kg; 5.76 mol) and CH2C12 (7.7 L) was added a solution of (5,S)-bis-O-TMS-hydrobenzoin (assay 2.01 kg; 5.60 mol) and CH2C12 (2.55 L). The solution was cooled to -20 °C. TfOH (50.9 mL; 0.576 mol) was charged through an addition funnel over 4 min at -15
~ -20 °C. The solution was warmed to -10 °C and aged at -10 °C for 1.5 h. An additional solution of (5,S)-bis-O-TMS-hydrobenzoin (assay 107 g; 0.298 mol) in CH2C12 (188g) was charged to the reaction
mixture at -10 °C. The reaction was completed after 30 min additional age at -10 °C. The reaction was quenched by addition of pyridine (46.9 mL; 0.576 mol) at 4.83 (d, J = 8.3 Hz, 1 H), 4.51 (br s, 1 H), 3.89 (s, 3 H), 2.54-2.51 (m, 2 H), 2.43-2.37 (m, 2 H), 2.18 (br s, 1 H); 13C NMR (101 MHz, CDCls): 5 168.7 (d, J = 25.7 Hz), 136.6,135.8,128.7, 128.6,128.5,
128.4,126.9, 126.3, 117.7, 86.2, 86.1, 77.6 (d, J= 247.1 Hz), 71.1,53.0, 45.7 (d, 7 = 7.8 Hz), 37.5 (d, 7 = 12.1 Hz), 36.7 (d, 7= 11.9 Hz); 19p NMR (377 MHz, CDC13): 5 -216.3.
EXAMPLE 8
Methyl (15>4'5,5^,5'5,65)-6-fluoro-4-oxo-4',5'-diphenylsph-o[bicyclo[3.1.0]hexane-2,2>-
ri.31dioxolane1-6-carboxvlate 9

To a solution of hydroxy ketal 8 (assay 2.04 kg, 5.31 mol) in acetonitrile (36.7 L) was added RuCls hydrate (8.25 g) followed by water (2.0 L) and acetic acid (0.41 L) at 0 °C. Aqueous sodium
hypochloride solution (-13%, 5.37 L) was added to the reaction solution slowly over 19 min, while maintaining the reaction temperature below 4 °C. The solution was aged at 0-3.5 °C for 2 h. The reaction was quenched by addition of isopropanol (2.2 L) at 3.5 °C. After 30 min aging at the same temperature, aqueous cold NaHCO3 (5 wt%, 10.7 L) was added to the mixture over 12 min between 0.4
and 3.3 °C. The resulting slurry was stirred for 30 min at 3 °C, and the product 9 was filtered. The wet cake was washed with cold water (2 L x 2) and dried to give the first crop of the ketal ketone 9. The filtrate and washes were combined and the layers were separated. The organic layer was concentrated in

Hz); l^FNMR (376 MHz, CDC13): 8-208.5.
EXAMPLE 9
(lS,4>5,5/?,5'5,65)-4-Arnino-4-cyano-6-fluoro-4',5'-diphenylspirotbicyclo[3.1.0]hexane-2,2'-ri.31dioxolane1-6-carboxamide 10 _

itrile 10 as a colorless solid. Analytically pure sample was prepared by silica gel column chromatography as colorless crystals: mp. 196.9-197A °C. lH NMR (400 MHz, DMSO-d6): 8 8.04 (s, 1 H), 7.78 (s, 1 H),
7.38-7.25 (m, 10 H), 5.15 (d, J = 8.8 Hz, 1 H), 4.81 (d, J = 8.8 Hz, 1 H), 2.86, (s, 2 H), 2.78 (dd, J = 14.5, 3.2 Hz, 1 H), 2.63 (d, J = 6.8 Hz, 1 H), 2.46 (d, J = 6.8 Hz, 1 H), and 2.23 (dd, J = 14.5,4.4 Hz, 1 H). 13CMMR(101MHz,DMSO-d6): 8 168.7 (d,J = 23.3 Hz), 136.5,135.9,128.6,128.5,128.5, 127.1,
126.9,123.4,115.1, 84.7, 84.3, 81.1 (d, / = 255.4 Hz), 54.6,48.3 (d, / = 7.2 Hz), 36.6 (d, J= 11.2 Hz), and 35.9 (d, J = 10.4 Hz). 19p NMR (377 MHz, DMSO-d6): 5 -211.6.
EXAMPLE 10 (1 #.2S.5S.6^-2-Amino-6-fluoro-4-oxobicvclor3.101hexane-2.6-dicarboxvlic acid 11

NMR showed that the reaction was complete. The solution was cooled to 18 °C and extracted with CH2C12 (1 x 9 L and 2 x 5 L). The aqueous layer was concentrated at 10-25 torr and 50 °C internal temperature to ~ 2 L. The resulting slurry was cooled to 0 °C and stirred for 1 h. The cooled slurry was filtered, and the cake containing HC1 salt of product 11 was maintained under vacuum filtration for 5-10 min to remove as much of the filtrate as possible. The cake of HC1 salt from above was added to water (5.0 L) at 65 °C, and rinsed in with hot H2O (300 mL).
The solution was allowed to cool to 17 °C over 45 min. The pH was adjusted to 1.25 with 50% NaOH (230 mL). The slurry was cooled to 0 °C and stirred for 45 min. The slurry was filtered, washed with H2O (2x1 L), and dried under nitrogen to afford the off-white crystalline product 11 as monohydrate.
Analytically pure HC1 salt of 11 was obtained from 20% HC1: mp. 195-220 (decomp); lH NMR (401 MHz, DMSO-d6): 8 8.99 (s, 2 H), 3.08 (dd, J = 6.4, 1.6 Hz, 1 H), 3.02 (d, J = 6.4 Hz, 1 H), 2.86 (dd, J = 18.5, 3.6 Hz, 1 H), 2.57 (dd, J = 18.5, 4.8 Hz, 1 H); 13c NMR (101 MHz, DMSO-d6): 5 201.3 (d, J =
2.7 Hz), 170.4, 166.3 (d, J = 25.7 Hz), 78.9 (d, J = 247.0 Hz), 58.1 (d, J = 1.5 Hz), 40.6 (d, J = 13.1 Hz), 36.8 (d, J= 11.1 Hz); l^F NMR (377 MHz, DMSO-d6): 5 -204.8; Cl Titration 13.96 % (Theory 13.98
EXAMPLE 11 Methyl ((l^,2/?.3J?.56r)-3-frfe7t-butvl('dunethvDsilvnoxvl-6-oxabicvclor3.1.01hex-2-vl)acetate






To a solution of olefin 12 (4.25 g, 27.2 mmol) in toluene (10.8 mL), was added vanadyl acetylacetonate (VO(acac)2,289 mg, 1.09 mmol, 4 mol %). A solution of TBHP (14.3 mL, 81.6 mmol, 5.7 M in decane)

was added over 30 min while maintaining the internal temperature below 28 °C. The resulting mixture was stirred at it for 5.5 h and quenched by addition of saturated aq. Na2S2Os. The aqueous layer was
separated and extracted by ethyl acetate (x 5). The combined organic layers were washed with brine and dried over Na2SO4- Solvents were evaporated, and the resulting residue was purified by flash silica gel
chromatography to afford epoxy alcohol 13 as colorless liquid, which contained inseparable byproducts. This alcohol (3.21 g) was treated with imidazole (2.78 g, 40.9 mmol) and TBSC1 (3.36 g, 22.3 mmol) in DMF (7.2 mL) at ambient temperature to convert the hydroxyl group to the TBS-ether. The reaction mixture was stirred at rt for 2.5 h and then treated with MTBE (36 mL) and H2O (12 mL). The organic layer was separated, washed with saturated aq. NaHCOs, H2O and brine, and dried over Na2SO4-
Solvent was evaporated, and the resulting residue was purified by flash silica gel chromatography to afford TBS-ether 14 as a colorless liquid: IH NMR (CDCls, 400 MHz) 8 4.08 (m, 1 H), 3.72 (s, 3 H),
3.49 (m, 1 H), 3.37 (m, 1 H), 2.49 (m, 1 H), 2.31 (d, J = 7.2 Hz, 1 H), 2.31 (m, 1 H), 2.09 (m, 1 H), 1.93 (m, 1 H), 0.88 (s, 9 H) 0.04 (s, 3 H), 0.03 (s, 3 H); 13c NMR (CDCls, 101 MHz) 8 171.9,77.0,60.4,
57.4,51.7,46.4, 37.2, 34.6,25.8, 18.0, -4.7; LRMS m/z 287 (M + 1), 286 (M), 285 (M - 1), 169 (base
peak);
Analysis calculated for Ci4H2604Si C
58.70; H, 9.15
Found C, 58.45; H, 9.49
EXAMPLE 12
Methyl (15,2^,4S,57?,65)-2-{[tert-butyl(dimethyl)silyl]oxy}-4-hydroxybicyclo[3.1.0Jhexane-6-
carboxvlate



To a solution of epoxide 14 (3.52 g, 12.3 mmol) in THF (37.8 mL) at -70 °C, was added a solution of Et3Al (16.0 mL, 16,0 mmol, 1 M in hexanes). After the resulting solution was stirred at-70 °C for 10
min, a solution of LHMDS (18.4 mL, 18.4 mmol, 1M in hexanes) was added slowly over 30 min. The resulting solution was stirred at -70 °C for 100 min and quenched by addition of aq. citric acid (24.9 mL, 3 M). After toluene (24.9 mL) was added, the resulting mixture was allowed to warm to ambient temperature, and H2O (11.7 mL) was added. The aqueous layer was separated and extracted with MTBE

(20 mL). The combined organic layers were washed with saturated aq. NaHCOs (36 mL x 2) and brine and dried over Na2SO4. Solvent was evaporated, and the resulting residue was purified by flash silica gel column chromatography to afford bicyclic alcohol 15 as colorless oil: IH NMR (CDCls, 400 MHz) 8 4.34 (d, 7 = 4.4 Hz, 1 H), 4.18 (dd, 7= 11.6, 4.4 Hz, 1 H), 3.68 (s, 3 H), 2.46 (d, 7= 11.6 Hz, 1 H), 2.26 (dd, 7 = 6.0,2.8 Hz, 1 H), 2.10 (dd, 7= 6.0, 2.8 Hz, 1 H), 1.67 (d, 7= 15.3 Hz, 1 H), 1.49 (dt, 7= 15.3, 4.4 Hz, 1 H), 1.16 (t, 7 = 2.8 Hz, 1 H), 0.90 (s, 9 H), 0.13 (s, 3 H), 0.11 (s, 3 H); 13C NMR (CDCls, 101
MHz) 5 172.2, 73.8, 73.6, 51.9,40.3, 33.3,33.0,25.7,21.8,17.9, -4.8, -5.0; LRMS mJz 287 (M +1), 286
(M), 285 (M- 1), 169 (basepeak);
Analysis calculated for Ci4H26O4Si C
58.70; H, 9.15.
Found C, 58.55; H, 9.34
EXAMPLE 13
Methyl (lS,2/?,4S,5#,6fl)-2-{ [^rt-butyl(dimethyl)sUyl]oxy}-4-{ [(4-
methvIphenvDsulfonvnoxv }bicvclor3.1 .OIhexane-6-carboxvlate
(Figure Removed)





To a stirred solution of alcohol 15 (929 mg, 3.24 mmol) in CH2C12 (3.8 mL) at 0 °C, were added pyridine (2.62 mL, 32.4 mmol) and p-toluenesulfonyl chloride (1.24 g, 6.49 mmol). The resulting mixture was allowed to warm to ambient temperature and stirred at the same temperature for 15 h. Saturated aq. NaHCO3 (5 mL) was added to the reaction mixture, and the resulting mixture was stirred at room temperature for 1 h. The aqueous layer was separated and extracted with MTBE (10 mL x 2). The combined organic layer was washed with 1 M HC1 (40 mL), saturated aq. NaHCO3 (10 mL) and brine (10 mL) and dried over Na2SC>4. Solvent was evaporated, and the resulting residue was purified by flash silica gel chromatography to affordp-toluenesulfonate ester 16 as colorless solid: IH NMR (CDCls, 400
MHz) 8 7.81 (d, 7 = 8.0 Hz, 2 H), 7.33 (d, 7 = 8.0 Hz, 2 H), 5.02 (d, 7 = 5.2 Hz, 1 H), 4.27 (d, 7 = 4.8 Hz, 1 H), 3.65 (s, 3 H), 2.45 (s, 3 H), 2.30 (dd, 7 = 5.6, 2.8 Hz, 1 H), 2.15 (dd, 7 = 5.6,3.2 Hz, 1 H), 1.85 (d, 7 = 16.5 Hz, 1 H), 1.64 (ddd, 7 = 16.5, 5.2,4.8 Hz, 1 H), 1.06 (dd, 7 = 3.2,2.8 Hz, 1 H), 0.86 (s, 9 H), 0.07 (s, 3 H), 0.04 (s, 3 H); 13C NMR (CDCls, 101 MHz) 8 171.4,144.5,134.5,129.7,127.6, 82.4, 72.7,
52.0,40.0,34.8, 31.3, 25.7,21.6, 21.1,17.9, -4.7, -4

TBS-ether 16 (1.86 g, 4.22 mmol) was treated with 0.84 mL of aq HCI (1 M) in acetonitrile (9.4 mL) at rt for 4 h. The reaction was quenched by addition of saturated aq. NaHCO3 (8.7 mL) and MTBE (20 mL).
The aqueous layer was separated and extracted with MTBE (10 mL x 2). The combined organic layer was dried over Na2SO4 and concentrated under reduced pressure. Treatment of the resulting residue
with hexanes gave crystals, which were filtered and recrystallized from hexanes/EtOAc to afford pure alcohol 17 as colorless crystals: lH NMR (CDC13,400 MHz) 6 7.82 (d, / = 8.0 Hz, 2 H), 7.38 (d, J = 8.0
Hz, 2 H), 5.01 (d, J = 5.2 Hz, 1 H), 4.24 (d, J = 5.2 Hz, 1 H), 3.67 (s, 3 H), 2.47 (s, 3 H), 2.33-2.28 (m, 2H), 1.93 (d, J= 16.5 Hz, 1 H), 1.67 (dt, J= 16.5,5.2 Hz, 1 H), 1.16 (t, J= 3.0 Hz, 1 H); l^CNMR (CDCls, 101 MHz) 6 171.1,145.1,133.9, 130.1,127.8, 83.2, 72.7, 52.2,39.3,33.9,30.8,21.8,21.7.
EXAMPLE 15 Methyl (lJ?.5S.61Sr)-4-oxobicvclor3.1.01hex-2-ene-6-carboxvlate


To a solution of DMSO (0.404 mL, 5.70 mmol) hi CH2C12 (2.6 mL), was added a solution of trifluoroacetic anhydride (0.604 mL, 4.28 mmol) in CH2C12 (1.5 mL) at -78 °C. The resulting solution was stirred at -78 °C for 30 min, and a solution of alcohol 17 (0.885 g, 2.85 mmol) in CH2C12 (4.1 mL) was added (flask was rinsed with 1.0 mL CH2C12). After the resulting solution was stirred at -78 °C for 30 min, Et3N (1.59 mL, 1 1.4 mmol) was slowly added. The resulting mixture was stirred at -78 °C for



To a solution of DMSO (0.358 mL, 5.04 mmol) in CH2C12 (2.5 mL) was added dropwise a solution of trifluoroacetic anhydride (0.534 mL, 3.78 mmol) in CH2C12 (1.3 mL), while maintaining the reaction temperature below -70 °C. The resulting solution was stirred at -78 °C for 55 min. A solution of
alcohol 15 (722 mg, 2.52 mmol) in CH2C12 (3.7 mL + 1.0 mL rinse) was added dropwise, while

maintaining the inside temperature below -75 °C. After stirring at -78 °C for 30 min, triethylamine (1.05 mL, 7.56 mmol) was added slowly over 15 min, maintaining the reaction temperature below -74.5 °C. The resulting mixture was stirred at -78 °C for 30 min and allowed to warm to -20 °C over 20 min. The reaction was further stirred at -20 °C for 30 min and quenched by addition of H2O. The organic layer was separated, diluted with MTBE, washed with 0.5 M HCI, H2O, saturated aq. NaHCO3, and brine, and dried over Na2SC>4. Solvent was removed under reduced pressure, and the resulting residue was purified by flash silica gel column chromatography to afford colorless solid 21 (673 mg, 94% yield): 'H NMR (CDC13, 400 MHz) 5 4.52 (d, J = 5.2 Hz, 1 H), 3.72 (s, 3 H), 2.57 (dd, J = 5.2, 3.6 Hz, 1 H), 2.40 (m, 1 H), 2.28 (dd, / = 18.5, 5.2 Hz, 1 H), 1.99 (d, J= 18.5 Hz, 1 H), 1.87 (dd, J = 3.6, 2.8 Hz, 1 H), 0.89 (s, 9 H), 0.11 (s, 3 H), 0.09 (s, 3 H); 13C NMR (CDC13, 101 MHz) 5 209.2, 170.0, 68.8, 52.4,43.2, 36.8, 34.5,25.7, 25.0, 18.0, -4.7, -4.8.
EXAMPLE 17
Methvl ('l.S.5J?.6#)-4-oxobicvclor3.1.01hex--2-ene-6-carboxvlate (2Z

TBS ether 21 (50.0 mg, 0.176 mmol) was treated with DBU (0.0789 mL, 0.528 rnmol) in CH2C12 (0.9 mL) at rt for 1 h. The reaction was diluted with MTBE, washed with 1 M HCI and brine (twice), and
dried over Na2SO4. Solvent was removed under reduced pressure, and the resulting residue was purified by flash silica gel column chromatography to afford colorless solid 22: [a] £° +272.2 (c 1.1, CHC13). The
other spectra were identical to those of the a,|3-unsaturated ketone 18 obtained in Example 15.
Characterization of Polymorph of the hydrochloride salt of (l/?,25,5S,65)-2-Amino-6-fluoro-4-oxobicyclo[3.10]hexane-2,6-dicarboxylic acid 11.
X-ray powder diffraction studies are widely used to elucidate molecular structures, crystallinity and polymorphism. X-ray powder diffraction (XRPD) patterns were collected for the crystal form of a sample of the HCI salt obtained in Example 10, using a Phillips diffractometer. Measurements were made from 3.0080 degrees to 39.9830 degrees (2 theta).
XRPD is depicted at Figure 1. The following reflections can be used to identify the crystal form:

Scan Parameters Measurement Date / Time: Raw Data Origin: Scan Axis:
Start Position [°2Th.]: End Position [°2Th.J: Step Size [°2Th.]: Scan Step Time [s]: Scan Type: Offset [°2Th.]:

7/18/2003 10:6
PHILIPS-binary (scan) (.RD)
Gonio
3.0080
39.9830
0.0170
10.1500
CONTINUOUS
0.0000


Anode Material: Generator Settings: Spinning:

NMR: nuclear magnetic resonance
DSC: differential scanning colorimetry
TLC: thin layer chromatography
XRPD: x-ray powder diffraction
it: room temperature
While the invention has been described and illustrated with reference to certain particular embodiments thereof, those skilled in the art will appreciate that various adaptations, changes, modifications, substitutions, deletions, or additions of procedures and protocols may be made without departing from the spirit and scope of the invention. For example, reaction conditions other than the particular conditions as set forth herein above may be applicable as a consequence of variations in the
reagents or methodology to prepare the compounds from the processes of the invention indicated above. Likewise, the specific reactivity of starting materials may vary according to and depending upon the particular substituents present or the conditions of manufacture, and such expected variations or differences in the results are contemplated in accordance with the objects and practices of the present invention. It is intended, therefore, that the invention be defined by the scope of the claims which follow and that such claims be interpreted as broadly as is reasonable.
It is further to be understood that all values are approximate, and are provided for description. Patents, patent applications, publications, product descriptions, and protocols are cited throughout this application, the disclosures of which are incorporated herein by reference in their entireties for all purposes.









We claim;
1. A process for preparing a compound of formula 0A):
(Formula Removed)
wherein Rl and R2 are each selected from the group consisting of (1) hydrogen, (2)C1-10alkyl,
(3) C3-8cycloalkyl, and
(4) -(CH2)n -phenyl
wherein n is 1 or 2, and said alkyl, cycloalkyl and phenyl are unsubstituted or substituted with one c more halogen, hydroxy, C1-6 alkyl or C1-6 alkoxy;
X is selected from the group consisting of
(1) halogen, and
(2) hydrogen; and pharmaceutically acceptable salts thereof,
comprising: (A) oxidizing a compound of formula (II):
(Formula Removed)
wherein R3 is selected from the group consisting of (1)-OH, (2)-0-Ra,and
(3) -NRbRc,
wherein Ra is selected from the group consisting of
(a) C1-10 alkyl, and
(b) C3-8 cycloalkyl,
and Ra is unsubstituted or substituted with one or more
(i) C1-10 alkoxy, (ii) hydroxy, (iii) halogen,
(iv) SRd,
(v) aryl, unsubstitnted or substituted with one or more hydroxy, C1-10 alkoxy, C1-10 alkyl ox halogen,
(vi) beteroaryl, unsubstituted or substituted with one or more hydroxy, C1-10 alkoxy, C1-10 alkyl or halogen, and (vii) NReRf; Rb, Rc, Re and Rf are selected from the group consisting of
(a) halogen
(b) C1-10 alky], and
(c) C3-8 cycloalkyl,
and when Rb, Rc, Re and Rf are C1-10 alkyl or C3-8 cycloalkyl, said C1-10 alkyl and C3-8 cycloalkyl are unsubstitnted or substituted with one or more
(i) hydroxy, (ii) C1-10 alkoxy.
(iii) -SRd.
(iv) aryl, unsubstitnted or substituted with one or more hydroxy, C1-10
alkoxy, C1-10 alkyl or halogen, and
(v) heteroaryl, unsubstitnted or substituted with one or more hydroxy, Cj-io
alkoxy, C1-10 alkyl or halogen, and
(vi) NRgRh;
wherein Rg and Rh are hydrogen, C1-10 alkyl or C3-8 cycloalkyl;
or Rb and Rc, together with the N atom to which they are attached, form a group
wherein r is 1 or 2, and the NRbRC group may be unsubstituted or substituted at the ring carbon atoms by one or more (i) hydroxy, (ii) C1-10 alkoxy,
(iii) SRd,
(iv) aryl, unsubstituted or substituted with one or more hydroxy, C1-10
alkoxy, C1-10 alkyl or halogen, and
(v) heteroaryl, unsubstituted or substituted with one or more hydroxy, C1-10
alkoxy, C1-10 alkyl or halogen, and
(vi) NRgRh.
Rd is hydrogen or C1-10 alkyl; and R4 is selected from the group consisting of
(1) hydrogen,
(2) C1-10 alkyl,
(3)Si-(R9)(R10)(R11),
(4)C(=O)-R12,
(5) CH2-phenyl, wherein said phenyl is unsubstituted or substituted with one or more substituents selected from the group consisting of nitro, halogen, C1-10 alkyl and C1-10 alkoxy,
(6) (CH2)p-O-(CH2)q-X'-Rl4)
(7) tetrahyropyranyl,
wherein R9, R10 and R11 are each C1-10 alkyl or phenyl, and R14 is selected from the group
consisting of
(a) hydrogen, (b)C1-10 alkyl,
p is 1 or 2;
q is an integer selected from 1-10; and X' is O or a bond; to form a compound of formula (IV):
(Formula Removed)
(B) deprotecting the compound of formula (IV) to form a compound of formula (V):

(Formula Removed)
(C) reacting the compound of formula (V) with a compound of formula (VI):
(Formula Removed)
wherein R5 and R6 are each independently selected from the group consisting of
(1) hydrogen,
(2) C1-10alkyl,
(3) C3-8 cycloalkyl, and
(4) (CH2)m phenyl, wherein m is 0,1 or 2, and
R7 is selected from the group consisting of
(1) hydrogen, and
(2) Si-(R9)(R10)(R11), wherein R9, R10 and R11 are each C1-10 alkyl or phenyl;
to give a compound of formula (VII):
(Formula Removed)
(D) oxidizing the compound of formula (VII) to give a compound of formula (VIII):
(Formula Removed)
(E) converting the compound of formula (VIII) to a compound of formula (IX):
(Formula Removed)
and (F) converting the compound of formula (IX) to the compound of fonnnla (IA).
2. The process as claimed in claim 1 or 2, wherein R5 and R6 are methyl.
3. The process as claimed in claim 1 or 2, wherein R5 and R6 are phenyl.
4. The process as claimed in claim 2, wherein R3 is methoxy.
5. The process as claimed in claim 1 or 2, wherien R1 and R3 are hydrogen.
6. The process as claimed in claim 2, wherein R7 is trimethylsilyl.
7. The process as claimed in claim 1 or 2, wherein X is hydrogen.
8. The process as claime in claim 1 or 2, wherein X is fluoro.
9. The process as claimed in claim 2, wherein R4 is tert butyldimethylsilyl.

Documents:

2479-delnp-2006-abstract.pdf

2479-delnp-2006-assignment.pdf

2479-DELNP-2006-Claims-(03-03-2010).pdf

2479-DELNP-2006-Claims-(16-12-2009).pdf

2479-delnp-2006-claims.pdf

2479-DELNP-2006-Correspondence-Others (15-01-2010).pdf

2479-DELNP-2006-Correspondence-Others-(12-05-2008).pdf

2479-DELNP-2006-Correspondence-Others-(16-03-2011).pdf

2479-DELNP-2006-Correspondence-Others-(16-12-2009).pdf

2479-delnp-2006-correspondence-others-1.pdf

2479-delnp-2006-correspondence-others.pdf

2479-delnp-2006-description(complete).pdf

2479-DELNP-2006-Drawings-(16-12-2009).pdf

2479-delnp-2006-form-1.pdf

2479-delnp-2006-form-13-(12-05-2008).pdf

2479-delnp-2006-form-18.pdf

2479-delnp-2006-form-2.pdf

2479-DELNP-2006-Form-27-(16-03-2011).pdf

2479-DELNP-2006-Form-3 (15-01-2010).pdf

2479-delnp-2006-form-3.pdf

2479-delnp-2006-form-5.pdf

2479-DELNP-2006-GPA-(16-12-2009).pdf

2479-delnp-2006-gpa.pdf

2479-delnp-2006-pct-101.pdf

2479-delnp-2006-pct-210.pdf

2479-delnp-2006-pct-220.pdf

2479-delnp-2006-pct-237.pdf

2479-delnp-2006-pct-301.pdf

2479-delnp-2006-pct-304.pdf

2479-delnp-2006-pct-306.pdf

2479-delnp-2006-pct-308.pdf

2479-DELNP-2006-Petition-137 (15-01-2010).pdf


Patent Number 241702
Indian Patent Application Number 2479/DELNP/2006
PG Journal Number 30/2010
Publication Date 23-Jul-2010
Grant Date 21-Jul-2010
Date of Filing 03-May-2006
Name of Patentee TAISHO PHARMACEUTICAL CO., LTD.,
Applicant Address 24-1, TAKADA 3-CHOME, TOSHIMA-KU, TOKYO 170-8633, JAPAN,
Inventors:
# Inventor's Name Inventor's Address
1 FREDERICK W. HARTNER 126 EAST LINCOLN AVENUE, RAHWAY, NJ 07065-0907, USA.
2 LUSHI TAN 126 EAST LINCOLN AVENUE, RAHWAY, NJ 07065-0907, USA
3 NOBUYOSHI YASUDA 126 EAST LINCOLN AVENUE, RAHWAY, NJ 07065-0907, USA
4 NAOKI YOSHIKAWA 126 EAST LINCOLN AVENUE, RAHWAY, NJ 07065-0907, USA
PCT International Classification Number C07C
PCT International Application Number PCT/US2004/036574
PCT International Filing date 2004-11-03
PCT Conventions:
# PCT Application Number Date of Convention Priority Country
1 60/518,391 2003-11-07 U.S.A.