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"Process For The Preparation Of Chiral Intermediates"

Abstract: A process for the preparation of a compound of formula A: said process comprising deprotecting a compound of formula

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Patent Information

Application #
Filing Date
02 November 2010
Publication Number
25/2013
Publication Type
INA
Invention Field
CHEMICAL
Status
Email
Parent Application
Patent Number
Legal Status
Grant Date
2017-03-31
Renewal Date

Applicants

UNITED PHOSPHORUS LIMITED
UNIPHOS HOUSE, MADHU PARK, 11TH ROAD, KHAR (West), MUMBAI-400 052, STATE OF MAHARASHTRA, INDIA

Inventors

1. SHROFF, JAIDEV RAJNIKANT
UNIPHOS HOUSE, MADHU PARK, 11TH ROAD, KHAR (W), MUMBAI-400 052, STATE MAHARASHTRA, INDIA
2. SHROFF, VIKRAM RAJNIKANT
UNIPHOS HOUSE, MADHU PARK, 11TH ROAD, KHAR (W), MUMBAI-400 052, STATE MAHARASHTRA, INDIA
3. SHANKER BIRJA
UNIPHOS HOUSE, MADHU PARK, 11TH ROAD, KHAR (W), MUMBAI-400 052, STATE MAHARASHTRA, INDIA

Specification

FORM2 THE PATENTS ACT, 1970 (39 of 1970) & The Patents Rules, 2003 COMPLETE SPECIFICATION (See section 10; rule 13) 1. Title of the invention- PROCESS FOR THE PREPARATION OF CHIRAL INTERMEDIATES 2. Applicant(s) (a) NAME : UNITED PHOSPHORUS LIMITED (b) NATIONALITY : A company organized and existing under the company's Act 1956 (c) ADDRESS : Uniphos House, Madhu Park, 11th Road, Khar (West), Mumbai - 400 052, State of Maharashtra, India 3. PREAMBLE TO THE DESCRIPTION The following specification particularly describes the invention and the manner in which it is to be performed : Field of the invention The present invention relates to a process for the preparation of chiral hydroxydiphosphine ligands. More particularly, the present invention relates to a process for the preparation of hydroxydiphosphine ligands, which are useful as ligands on transition metals in metal catalyzed asymmetric synthesis, in particular hydrogenations. Background and prior art There is a growing need for the synthesis of chiral compounds which are used as pharmaceuticals and agrochemicals. Classical methods of separation of the optical isomers are one aspect of the synthesis, which results in the cumbersome process of resolution and racemization, often making the process uneconomical. Another way of preparing the chiral compound is to use chiral synthesis approach which is being increasingly used as preferred industrial method. This synthesis involves the use of chiral reagents, and especially use of chiral catalysts to bring about the desired transformation. Various catalytic systems have been used for different types of chiral transformations. Some of these systems use bidentate organophosphorous compounds which have attained great importance as ligands in homogeneous catalysis. Hydroxyphosphine compounds of Formula IA are useful as ligands on transition metals in metal catalyzed asymmetric synthesis such as hydrogenation, hydrofomnylation, rearrangement, allylic alkylation, cyclopropanation, hydrosilylation, hydride transfers, hydroborations, hydrocyanations, hydroxycarboxylations, and so on (ref. Us 2006/0089469 A1). Formula IA US 2006/0089469 discloses compound of Formula IA and the process of making the same. WO 2009136409 discloses a process for the asymmetric hydrogenation of a prochiral ketimine to get a chiral amine wherein the said transformation is effectively carried out in the presence of iridium and rhodium complexes containing the ligand of Formula IA, which upon reaction with haloacety) chloride affords various haloacetanilide herbicides. In particular, preferred ligand is [(1 R,2R.3S)-1,2-dimethyl-2,3-bis (diphenyl phosphine methyl) cyclopentyl] methanol (herein after referred to as compound of Formula A). However, this publication does not teach an industrially feasible route for the synthesis of said compound of formula A. H,C OH Foimuia A WO 2008092924 discloses a process for selectively synthesizing a stereoisomer of zilpaterol by reacting 4l5-dihydro-imidazo[4,5,1-jk][1]benazepine-2,6,7[1H]-trion-6-oxime with H2 in the presence of a catalyst to selectively form a stereoisomer of 6-amino-7-hydroxy-4,5,6,7-tetrahydroimidazo[4,5,1-kJ][1]-bencazepin-2[1H]-one, which, in turn is converted to zilpaterol or a salt thereof. The catalyst used in the reaction comprises metal complex of a ligand with a metal from transition group VIII. One such ligand used is ligand of Formula A. These highly useful bidentate ligands of Formula A can be prepared by the process disclosed in US 2006/0089469. Schematic diagram of the process is shown below in Scheme f. Scheme t In the above Scheme I, OPG means a hydroxyl protecting group. Komarov et al. in Tetrahedron Asymmetry, 13 (2002), 1615-1620 have disclosed a scheme to prepare the said tigand. Scheme II represents the scheme to prepare the said hydroxyphosphine ligand. According to the authors of the publication, the diol intermediate is selectively protected by converting it into tosylate (i). The publication also mentions that the more hindered hydroxyl group had to be protected before it could be reacted with lithium diphenylphosphine to avoid undesired cyclization. Both (he prior art references mentioned above use the route which involves selective protection of the less hindered alcohol group to get intermediate (i) which is difficult to handle as it has a tendency to undergo cyclization to form the compound (ii). Formation of compound (i) is very tricky as it is already known that while trying to form monotosylate (i) from the diol (x), the ditosylate (iii) also forms (Advances in catalysis, vol. 25, p 81-124, 1976). The monotosylate (i) and the ditosylate (ii) have to be separated by column chromatography. According to the reference, the monotosylate is used immediately after separation. (ii) (iii) Formation of compound (i) is carried out under dry conditions, and use large volume of pyridine as a solvent, which is carcinogenic, and is not an environmentally friendly solvent. Pyridine also makes the process less cost effective. Since it is soluble in water, its recovery is very difficult and need extra efforts. The reference does not mention any usefulness of the compound (ii), and is an unwanted product for the process. Asymmetric homogenous hydrogenation, J D Morrison, W F Masler, M K Neuberg, Advances in Catalysis, Vol 25, pp. 81 - 124, [1976], also discloses a survey of asymmetric homogenous hydrogenation reactions, that is reactions that create asymmetric carbon atoms by the addition of hydrogen across multiple bonds under the influence of soluble chiral catalysts. This publication teaches a process for the preparation of Camphos from commercially available (+)-camphoric acid. <*)-CAMPHOS In the paragraph bridging pages 98-99, this publication teaches that in the initial trials to synthesize camphos, many procedures were used in an attempt to prepare dihalide from the diol.. However, none of a great many standard methods met with any success. The procedures tried involved thionyl chloride, pyridine, phosphorus pentachloride and triphenylphosphine dibromide in N,N-dimethylformamide, triphenylphosphine and carbon tetrachloride, tris(dimethylamino)phosphine and bromine, o- phenylenephosphorochloridite and bromine, tris(dimethyiamino)phosphine and carbon tetrachloride and tri-n-octylphosphine and carbon tetrachloride. This publication further states in the last paragraph on page 99 that the synthesis of camphos by displacement on its ditosylate precursor with the diphenylphosphide anion appeared promising on paper, but initially was a dismal failure in practice. It was considered likely that the less hindered α-tosylate group was displaced or eliminated rather readily at room temperature but the neopentyl-like-p-tosylate group required more strenuous conditions to effect its displacement. This was also found to reduce the yield of the target hydroxydiphosphine ligand, which is clearly undesirable, Accordingly, there is a need in the art for a process for the preparation of a compound of formula A conveniently, in high yield and preferably, without utilizing an intermediate compound having a tosylate leaving group. in fact, attempts to prepare the desired compound of formula A using the conventionally known process led to the undesired yield of an oxidized product only instead of the desired compound of formula A, having the formula set out below: ,CH3 H3C OH Formula A Inventors of the present invention, in an effort to prepare the hydroxyphosphine ligand of Formula A, tried to follow the process mentioned above. However, even after a series of experiments, they could not form (i) in desired and reported yield. In fact, fhe yiefd was always negligible and the results were not reproducible. Working in a persuasive manner, the inventors accidently found that the compound (ii) which was considered to be unwanted product by the prior art reference, can be conveniently and effectively converted into the desired hydroxydiphosphine ligand of Formula A. Thus, there is a need in the art for a process for preparing hydroxydiphosphine ligands in high yield. These hydroxydiphosphine ligands are suitable precatalysts for the enantiosefective manufacture of optically active agrochemicals, particular^ chloroacetanilide herbicides. The process of the present invention is cost effective, environmentally friendly, simple, and reproducible. Objects of the invention Accordingly, it is an object of the present invention to provide a process for the preparation of chiral hydroxydiarylphosphine ligands. Another object of the present invention is to provide a convenient process for the preparation of chiral hydroxydiarylphosphine ligands in high yield. Another object of the present invention is to provide a process for the preparation of chiral hydroxydiarylphosphine ligands wherein the process does not lead to the form ation of oxid ized a nd oth e r i m purities. Yet another object of the present invention is to provide a convenient process for the preparation of (1 R,2R,3S)-1,2-djmethyl-2,3-bis (diphenyl phosphine methyl) cyclopentyl] methanol in high yield. These and other objects of the invention are realized by an invention set out immediately hereinafter. Summary of the invention A process for the preparation of a compound of formula: H3C Formula A comprising deprotecting a compound of formula I: wherein: Ar1 is an aryl group, unsubstituted or substituted with one or more substituents independently selected from the group comprising C1-C4 alkyl, C1-C4 alkoxy, (C1-C4 alkyl)-amino, di-( C1-C4 alkyl)-amino, nitro and C1-C4 alkyl substituted with one or more halogen; and R1 is a hydroxyl protecting group. In another aspect, the present invention provides a process for the preparation of a compound of formula A comprising: (a) reacting a compound of formula II: with an alkali metal salt of diarylphosphide in an organic solvent; and optionally where R1 is not hydrogen, (b) deprotecting the protected hydroxyl group to obtain a compound of formula: wherein: Ar, is art aryl group, unsubstituted or substituted with one or more substituents independently selected from the group. comprising C1-C4 alkyl, C1-C4 alkoxy, (C1-C4 alkyl)-amino, di-( C1-C4 alkyl)-amino, nitro and C1-C4 alkyl substituted with one or more halogen; R1 is a hydrogen or a hydroxyl protecting group; and R* and R3 may be same or different and are independently selected from halogen or -O - SO2 - X, wherein X is C1-C4 alkyl, C1-C4 alkyl substituted with one or more halogen, or substituted or unsubstituted phenyl wherein said phenyl substituent is selected from halogen, nitro and C1-C4 alkyl- In another aspect, the present invention provides a process for the preparation of a compound of formula comprising-. (a) protecting the hydroxyl group of the compound of formula H3C Formula I to obtain a compound of formula II: H,C Formula It (b) reacting the compound of formula II Formula M with an alkali metal salt of diarylphosphide in an organic solvent; and (c) deprotecting the protected hydroxyl group to obtain a compound of formula: U^ / OH H3C Formula A wherein: Ar, is an aryl group, unsubstituted or substituted with one or more substituents independently selected from the group comprising C1-C4 alkyl, C1-C4 alkoxy, (C1-C4 atkyl)-amino, di-( C1-C4 alkyl)-amino, nitro and C1-C4 alkyl substituted with one or more halogen; R1 is a hydroxyl protecting group; and R2 and R3 are same or different and are independently selected from halogen or -O - SO2 - X, wherein X is C1-C4 alkyl, C1-C4 alkyl substituted with one or more halogen, or substituted or unsubstituted phenyl wherein said phenyl substituent is selected from halogen, nitro and C2 - C4 alkyl; and In another aspect, the present invention provides a process for the preparation of a compound of formula A: comprising: (a) hydro-halogenating or hydro-sulfonating a compound of formula IV: to obtain a compound of formula III: H3C Formula III (b) protecting the hydroxyl group of the compound of formula to obtain a compound of formula II: Formula II (c) reacting the compound of formula fl Formula II with an alkali metal salt of diarylphosphine in an organic solvent; and (d) deprotecting the protected hydroxyl group to obtain a compound of formula: AT, p ^^^ / OH H3C Formula A wherein: Ar, is an aryl group, unsubstituted or substituted with one or more substituents independently selected from the group comprising C1-C4 alkyl, C1-C4 alkoxy, (C1-C4 alkyi)-amino, di-( C1-C4 alkyl)-amino, nitro and C1-C4 alkyl substituted with one or more halogen; R1 is a hydroxyl protecting group; and R2and R3 are same or different, each being independently selected from halogen or -O - SO2 - X, wherein X is C1-C4 alkyl, C1-C4 alkyl substituted with one or more halogen, or substituted or unsubstituted phenyl wherein said phenyl substituent is selected from halogen, nitro and C2 - C4 alky!. In another aspect, the present invention provides a process for the preparation of a compound of formula A comprising: (a) reducing a compound of formula V:. H3C Formula V with a reducing agent to obtain a compound of formula VI: Formula VI (b) dehydrating said compound in the presence of a dehydrating agent to a compound of formula IV: (c) hydro-halogenating or hydro-sulfonating a compound of formula: H,C Formula IV to obtain a compound of formula Hi: Formula III (d) protecting the hydroxyl group of the compound of formula H3C Formula III to obtain a compound of formula If: H,C Formula II (e) reacting the compound of formula Formula II with an alkali metal salt of diphenylphosphine in an organic solvent; and (f) deprotecting the protected hydroxyl group to obtain a compound of formula: Formula A wherein: Ar, is an aryl group, unsubstftuted or substituted with one or more substituents independently selected from the group comprising C1-C4 alkyl, C1-C4 alkoxy, (C1-C4 alkyl)-amino, di-( C1-C4 alkyl)-amino, nitro and C1-C4 alkyl substituted with one or more halogen; R1 is a hydroxyl protecting group; and R2 and R3 are same or different, each being independently selected from halogen or - SO2 - X, wherein X is C1-C4 alkyl, C1-C4 alkyl substituted with one or more halogen, or substituted or unsubstituted phenyl wherein said phenyf substituent is selected from halogen, nitro and C2 - C4 alkyl. Detailed description of the invention comprising deprotecting a compound of formula Accordingly, In one aspect, the present invention provides a process for the preparation of a compound of formula A: Formula I wherein R1 is a hydroxyl protecting group; and Ar, is an aryl group, unsubstituted or substituted with one or more substituents independently selected from the group comprising C1-C4 alkyl, C1-C4 alkoxy, (C1-C4 alkyl)-amino, di-( C1-C4 alkyl)-amino, nitro and C1-C4 alkyl substituted with one or more halogen. In a preferred embodiment, each Ar, group may be same or different, and each may be independently selected from phenyl, 4-methylphenyl, 3,5-dimethylphenyl, . 3,5-diisopropylphenyl, 4-methoxyphenyl, 4-methoxy-3,4-dimethylphenyl, 3,5-di-t-butylphenyi, 4-methy!amino-3,5-t-butylpheny|, 4-trifluoromethylphenyl and 3,5-difluoromethylphenyl. In a most preferred embodiment, each Afi group is phenyl. The term "hydroxyl protecting group" as used herein denotes a protective group introduced into the compounds and intermediates of the present invention by reaction with the hydroxyl group in order to obtain chemoselectivity in a subsequent chemical reaction. In this invention, the term "hydroxyl protecting group" additionally means the substituents included within the definition of R1 specified in any aspect or embodiment hereinafter. The masking of a hydroxyf group in the compounds and intermediates of the present invention prevents the protected hydroxyl group from itself taking part in the reaction and is capable of being easily removed from the masking position once the desired reaction is over. There are several hydroxyl protecting groups known in the art, which all form a part of the present invention. Preferably, the reaction step of deprotecting a compound of formula II varies with the particular protecting group utilized to mask the hydroxyl group. The choice of the particular protecting group and the deprotection reactions convenient for the selected protecting group are known to a skilled chemist and do not form a critical part of the present invention. In a preferred embodiment, the hydroxyl protecting group is R\ which may be selected fromZor-SO2-X. In an embodiment, X is selected from C1-C4 alkyl, C1-C4 alkyl substituted with one or more halogen, or unsubstituted or substituted phenyl wherein said substituent on phenyl ring is selected from halogen, nitro and C1-C4 alkyl. In this embodiment, Z is a hydroxyl protecting group selected from tetrahydro-2H-pyran-2-yl; tetrahydro-2H-pyran-2-one-3-yl; tetrahydro-2H-pyran-2-a[koxy-6-yl, wherein said; "alkoxy" includes C1-C4 alkyl; triarylmethyl-, wherein said aryl is preferably phenyl ring, unsubstituted or substituted with one or more substituents selected from halogen, nitro, - O - C1-C4 alkyl and C1 - C4 alkyl; 1,1,1,3,3,3-hexafluoro-2-aryl-isopropyl, wherein aryl is defined as R5 \ 5 Si-R /\ 5 above; R wherein R5 may be same or different and are selected from Ar or C1 -C4 alkyl, wherein aryl group is as defined above; p-methoxy-benzyl; (CH)n(R6) - A -(CH2)n - W, wherein R6 is hydrogen or C1-C4 alkyl, A is - O - or - S -, n is from 0 to 5, W is selected from hydrogen, C1-C4 alkyl, - O - (C1-C4 alkyl) and aryl, said aryl being preferably a phenyl ring, unsubstituted or substituted with one or more substituents selected from halogen, nitro and C1-C4 alkyl; - (CH)(Re) - Ar, wherein n is as defined above and aryl is a phenyl ring, unsubstituted or substituted with one or more substituents selected from halogen, nitro and C1-C4 alkyl; 9-phenylxanthyl; and - C (=0) - R7, wherein R7 is selected from C1 - C4 alkyl, halogenated C1-C4 alkyl and aryl, said aryl is a phenyl ring, unsubstituted or substituted with one or more substituents selected from halogen, nitro and Ct - C4 alkyl. In a further preferred embodiment of any aspect described hereinabove, X may be selected from methyl; trifluoromethyl; n-novafluorobutyl; 2,2,2-trifluoroethyl; p-toluyi; p-nitrophenyl and p-bromophenyl, while Z is a hydroxyl protecting group selected from tetrahydro-2H-pyran-2-yl; tetrahydro-2H-pyran-2-one-3-yl; tetrahydro-2H-pyran-2-methoxy-6-yl; tetrahydro-2H-pyran-2-ethoxy-6-yl; triphenylmethyl-, wherein one or more of the phenyl rings are optionally substituted with p-methoxy group; 1,1,1,3,3,3-hexafiuoro-2-phenylisopropyl, wherein said phenyl ring may be optionally substituted CH3 H3C Sr-Ph with p-methoxy group; Ph wherein the phenyl groups may be optionally substituted with halogen, nitro, C1-C4 alkyl or C1-C4 alkoxy; p-methoxy-benzyl; CH2OCH3; CH2OCH2CH2OCH3; - CH2SCH3; - CH2SCHrPh; - CH(CH3)-0-CH2CH3; - CH2Ph; - CH2 -o - nitrophenyl; - CH2 - p - methoxyphenyl; - 9-phenylxanthyl; -Si{Me)3; -$i(Et)3; -Si(i-Pr)3; -Si(Ph)Me2; -Si(t-Bu)Me2; -Si(t-Bu)Ph2; -C(0)CF3; -C(0)(t-Bu); and -C(O) Ph. In a further. preferred embodiment, Z is selected from tetrahydro-2H-pyran-2-yl; tetrahydro-2H-pyran-2-one-3-yl; tetrahydro-2H-pyran-2-methoxy-6-yl; and tetrahydro-2H-pyran-2-ethoxy-6-yl. In a further preferred embodiment of any aspect described hereinabove, the protecting group suitable according to the present invention and the corresponding deprotection reactions are provided hereinbelow, all of which may be conveniently utilized in an embodiment of the present invention. Preferably, the hydroxyl protecting group may be selected so as to enable selective protection and deprotection for the hydroxyl group efficiently and must be inert to a reaction occurring at any other moiety of the compounds or intermediates occurring in the processes of the present invention. SNo. Protecting Group Protection reaction conditions Deprotection reaction conditions 1 Methoxymethyl ether (-OCH2OMe) MeOCH2CI, NaH in THF; MeOCH2CI in dichloromethane in the presence of i- Pr2EtN Me2BBr2 2 Methoxyethoxymethyl ether (-OCH2OCH2CH2OMe) MeOCH2CH2OCH2CI in NaH and THF; MeOCH2CH2OCH2CI in dichloromethane in the presence of i-Pr2EtN ZnBr2; TiCU; Me2BBr2. 3 Methyl thiomethyl ethers (- OCH2SMe) MeSCH2CI in NaH and THF HgCI2, CH3CN/H2O; AgN03, THF in aqueous basic conditions 4 Benzyloxym ethyl ethers { OCH2OCH2Ph) PhOCH2CH2CI in dichloromethane in the presence of i-Pr2EtN Hydrogen in PtO2; Na/NH3 in ethanol 5 Tetrahydropyranyl ether (THP) Dihydropyran in p-toluenesulfpnic, acid in benzene Acetic acid in THF (aq); AmberlystH-15inMeOH 5 Benzyl ether (-OCH2Ph) Benzyl chloride in KHATHF; PhCH2OC(=NH)CCI3 in F3CSO3H H2/Pt02; U/NH3. 6 2-Naphthylmethyl ether (NAP) 2-chloromethy! naphthalene in KH Hydrogenolysis H2 in Pd/C 7 p-methoxybenzyt ethers p-MeOPhCH2CI in KH/THF; p-MeOPhCH20 H2/Pt02; Li/NH3; Ce(NH4)2(N03)6 C(=NH)CCI3 in FsCS03H 8 o-Nitrobenzyl ether o-Nitrobenzyl chloride in NaHH"HF Photolysis at 320 nm 9 p-Niirobenzyl ether p-Nitrobenzyl chloride in NaH/THF DDQ; Hydrogenolysis H2 in Pd/C 10 9-phenylxanthyl 9-phenylxanthy! chloride in pyridine Photolysis at 300 nm in aq. Acetonitrile 11 Trityl ether (-OCPh3) or 4'-methoxytrityl or 4',4'-dimethoxytrityl Trityl chloride in pyridine in the presence of DMAP; Ph3C+BF4" Mild acid e.g. 80% aq. AcOH at 20°C 12 Trimethyl silyl ether (Me3SiO-) or triethylsilyl ether or tri-isopropylsilyl ether, phenyldimethylsilyl ether R3S/-CI in pyridine and DMAP; R3Si-CI in dichloromethane, imidazole and DMAP; R3Si-OTf in i-Pr2EtN in dichloromethane H20/AcOH/THF in ratio of (3:5:11) for 15 hours 13 t-butyldimethylsilyl ether (t-BuMe2Si-OR) t-butyldimethylsilyl triflate Acid hydrolysis or F" from HF, KF, CsF or n-Bu4NF 14 t-Butytdiphenyi sifyl ether (t-BuPh2Si-OR) t-BuPh2Si-CI in pyridine and DMAP; t-BuPh2Si-CI in dichloromethane, imidazole and DMAP; t-BuPh2Si-OTf in i-Pr2EtN in dichloromethane F" from n-Bu4NF (basic conditions) or HF/H20/CH3CN or HF.pyridine or SiF4.CH2CI2. 15 Acetates (-02CCH3) Acetic anhydride in pyridine or acetyl chloride in pyridine KjC03 in methanol under reflux or KCN in methanol under reflux or NHa/MeOH, LiOH in THF/H20 16 Trifluoroacetates Triftuoro acetic anhydride or trifluoroacetyl chloride K2C03 in MeOH 17 Pivaloate t-butylacetyi chloride or t-butylacetic anhydride Mild base 18 Benzoate Benzoyl chloride or benzoic anhydride or benzoyl cyanide or beazavnetcazaLe , I Mild base or KCN/MeOH under reflux ■ The list tabulated above is exemplary and is not intended to be exhaustive. Further hydroxy! protecting groups and corresponding deprotection reactions including conditions maintained therein are discussed in J. Cheat. Soc, Perkin Trans. 1, 1998, 4005-4037, which is incorporated herein by reference in its entirety. It was surprising indeed that a compound of formula I herein could be easily deprotected to the desired compound of formula A in high yield. The present inventors have found that under the reaction conditions disclosed in Tetrahedron Asymmetry, 13 (2002), 1616-1620, this compound of formula A was not detected possibly due to this compound being exceedingly susceptible to oxidation. Accordingly, the yield of the target compound of formula A was found negligible in the process disclosed in Tetrahedron Asymmetry, 13 (2002), 1615-1620. In an embodiment, the compound of formula I is extracted and stored under Argon atmosphere to prevent its oxidation in contact with air. In an embodiment, the compound of formula I: H,C Formula I is prepared by the nucleophilic substitution of the leaving groups R2 and R3 present in a compound of formula II with an alkali metal salt of diaryl phosphine in an organic solvent. Preferably, lithium salt of diphenylphosphine (LiPPh2) may be used. It has been found that the leaving groups R2 and R3 are efficient leaving groups for the instant nucleophilic substitution in comparison to "tosylate" leaving group and thus lead to a surprisingly high yield of the target compound of formula A. Accordingly in this aspect, the present invention provides a process for the preparation of a compound of formula comprising: (a) reacting a compound of formula II: Formula II with an alkali metal salt of diphenylphosphine in an organic solvent; and optionally where R1 is not hydrogen, (b) deprotecting the protected hydroxyl group to obtain a compound of formula A: Formula A In an embodiment, the preferred reagents useful for the introduction on the diaryl group may be thionyl chloride, pyridine, phosphorus pentachloride and triphenylphosphine dibromide in N.N-dimethylformamide; triphenylphosphine in carbon tetrachloride; tris(dimethylamino)phosphine and bromine; o-phenylenephosphorochloridite and bromine; tris(dimethylamino)phosphine and carbon tetrachloride and tri-n-octylphospbine and carbon tetrachloride. However, other synthetic routes that are known to a skilled organic chemist are not excluded and may be conveniently utilized according to an embodiment of the instant invention. The substituent Rz and R3 may be same or different and each may be independently selected from halogen or -O - SO2 - X, wherein X is C1-C4 alkyl, C1-C4 alkyl substituted with one or more halogen, or substituted or unsubstituted phenyl wherein said phenyl substituent is selected from halogen, nitro and C2 - C4 alkyl. However, where R3 is bromine, X does not include p-toluyl. In another preferred embodiment, the preferred substituents R2 and R3are halogen. In a further preferred embodiment, R2and R3 are selected from F, CI, Br and I, and -O -SO2 - X, wherein X is selected from methyl, trifiuoromethyl, n-novafluorobutyl, 2,2,2-trifluoroethyt, p-nitrophenyl or p-bromophenyf. In a more preferred embodiment, both R2 and R3 are selected from F, CI, Br and I. In another aspect, the compound of formula it is obtained by protecting the hydroxyl group in a compound of formula III: The substituent groups R2 and R3 in this aspect of the present invention are as defined hereinabove in any/all aspects and embodiments. Preferably, the hydroxyl protecting group may be selected from the groups listed as in the above table so as to enable selective protection and deprotection for the hydroxyl group efficiently and must be inert to a reaction occurring at any other moiety of the compounds or intermediates occurring in the processes of the present invention. The substituent R1 may depend on the protecting group selected but may be defined according to any aspect or embodiment hereinabove. The choice of the particular protecting group and the deprotection reactions convenient for the selected protecting group are known to a skilled chemist and do not form a critical part of the present invention. Accordingly, in this aspect, the present invention provides a process for the preparation of a compound of formula comprising: (a) protecting the hydroxyl group of the compound of formula III: to obtain a compound of formula II: (b) reacting the compound of formula (I with an alkali metal salt of diarylphosphine in an organic solvent; and (c) deprotecting the protected hydroxyl group to obtain a compound of formula: The substituents R1 R2 and R3 according to the instant aspect may be selected as per the definitions in any previous aspect or embodiment of the invention. In yet another aspect, the compound of formula III: Formula HI is obtained by hydro-halogenating or hydro-suffonating an intermediate having the formula IV: CH, H,C It was indeed surprising that hydrohalogenating the closed ring intermediate having the formula IV led exclusively to the formation of a product having hydroxy! group positioned at the less-hindered position, which led to a surprising increase in the yield of the final compound of formula A. This surprising chemoselectivity was observed more pronounced when both R2 and R3 were selected from F, CI, Br and I in the presence of known halogenating reagents. In this embodiment, the choice of particular halogenating agent is not particularly critical and may be determined by a person skilled in the art. In a preferred embodiment, the suitable halogenating agent may be selected from: (a) Halogen in AcOH or CISO3H; (b) Zn(hal)2 in H(hal); (c) B (hal)s in Ph3P; and (d) B (hal)s in p-TsCI. These halogenating agents are only to be construed as being exemplary and should not be considered exhaustive. A person skilled in the art may choose other halogenating agents that are known in the art. Thus, in this aspect, the present invention provides a process for the preparation of a compound of formula comprising: (a) hydro-halogenating or hydro-sulfonating a compound of formula IV: H3C Formula IV to obtain a compound of formula (b) protecting the hydroxyl group of the compound of formula to obtain a compound of formula II: (c) reacting the compound of formula II with an alkali metal salt of diarylphosphine in an organic solvent; and (d) deprotecting the protected hydroxy! group to obtain a compound of formula: The definitions of the substituents R1 R2 and R3 according to the instant aspect of the invention are as per the definitions provided in any previous aspect or embodiment thereof. in another aspect, the closed ring compound of the formula IV: Formula IV may be prepared as per the process disclosed in Tetrahedron Asymmetry, 13 (2002), 1615-1620, wherein the production of such a compound is described as an undesired by-product. Alternatively, the said closed ring compound may be prepared by dehydrating a diol having the formula VI to obtain the resultant cyclic ether. Forniula VI In another embodiment, the cyclic ether may be obtained by reducing a 9-substituted camphor derivative having the formula V to obtain a diol intermediate: Formula v and subjecting the resultant diol to dehydration in the presence of a dehydrating agent to obtain said cyclic ether compound. The reducing agent utilized in this step of the process is npt particularly critical but may be any reducing agent typically used in organic synthesis to reduce ketones to alcohols. In a particular embodiment, the preferred reducing agent may be lithium aluminum hydride. In another embodiment, the reducing agent may be further selected from sodium borohydride and hydrogen with transition metal catalyst. Preferably, the dehydrating agent may be selected from para-toluene sulfonyl chloride, zinc bromide in HBr and sulfuric acid although other dehydrating agents are not excluded. Accordingly, in this aspect, the present invention provides a process for the preparation of a compound of formula (a) optionally reducing a compound of formula V: with a reducing agent to obtain a compound of formula VI: comprising: (b) dehydrating said compound of formula VI in the presence of a dehydrating agent to a compound of formula IV: Fotmula IV (c) hydro-halogenating or hydro-sulfonating said compound of formula IV: CH, HSC Formula IV Formula R1 (d) protecting the hydroxyl group of the compound of formula III: Formula III to obtain a compound of formula II: to obtain a compound of formula III: (e) reacting the compound of formula II Fwmula I with an alkali metal salt of diarylphosphine in an organic solvent; and (f) deprotecting the protected hydroxyl group to obtain a compound of formula: HjC Formula A wherein An, R1, R2 and R3 are as described in any aspect or embodiment hereinabove. In another embodiment of this aspect, the intermediate diol formed from reducing the 9-substituted camphor derivative may not be separately Extracted but in-situ formed diol may be subjected to dehydration under basic conditions to directly obtain the cyclic ether intermediate without separating the intermediate diol. Thus, in this embodiment, a compound having the formula IV: H,C Formula IV is obtained by reducing a compound of formula: Formula V with a reducing agent, and subjecting the in situ formed reaction mixture to dehydration in the presence of a dehydrating agent. In a preferred embodiment, the dehydrating and reducing agents may be selected as described hereinabove. The schematic representation of the process of the invention is shown below in Scheme 1. V VI IV EXAMPLES Preparation of Formula VI The cyclic anhydride V (R3 = Br, 3.5gm, 13.3mmol) was dissolved in dry ether (200 ml) and stirred. The solution was cooled to 20°C and added Lithium aluminum hydride (2.1 gm, 55.2mmol) in small portions with continuous stirring. The reaction mixture was then heated to reflux for five hours and then cooled to 25° C. Tetrahydrofuran (THF) (100ml) was added to the reaction mass followed by careful and slow addition of water (10 ml). The reaction mixture was filtered and the filtrate was concentrated on rotary evaporator to obtain solid mass which was crystallized from chloroform to get the desired product VI (2.6 gm, 10.3 mmol, m.p. 116-119°C). Example 2 Preparation of Formula IV Compound VI (R3 = Br, 13 gm, 51.79mmol) was dissolved in carbon tetrachloride (225 ml) and stirred. Triphenyl phosphine (30 gm, 114.5mmol) was added and stirred. The reaction mixture was further stirred under reflux for 24 hours. It was cooled to 25° C and n-hexane (200 ml) was added. The precipitated triphenyl phosphine oxide was filtered. The filtrate was concentrated on rotary evaporator to get the solid crude product (12 gm). The product was purified by column chromatography using n-Hexane: Ethyl acetate as eluent (9:1). The desired fraction was evaporated on rotary evaporator to get pure product IV (8 gm, 34.33mmol, yield 71.8%). Example 3 The compound of formula IV (12.87 mmol) was dissolved in dichloromethane (100 ml) under stirring and cooled to -10CC. Boron trihalide (23.9m mol ) in 60 ml dichloromethane was gradually added to it while maintaining the temperature. The temperature was then allowed to come to 25° C and then the reaction mixture was maintained at 60°C for 1-2 hours, ft was then coofed to 0° C and 10% aqueous sodium hydroxide solution (150 ml) was added and stirred for 1.5 hours. The layers were separated and the organic layer was washed with brine followed by water and dried over sodium sulfate. The organic layer was evaporated on rotary evaporator to get the crude product, which was purified by column chromatography using n-Hexane: Ethyl acetate (95 : 5) to get compound of formula III. Table 1 lists the number of compounds of formula III having various substitutions prepared by the process of Example 1. s N 0. R* Ra Reag ent MP/ BP IR (Cm"1) NMR (5,ppm) Yield /properti es 1 CI Br Boron trichlo ride esse0 C 3369, 2960, 2865,1450,1425,1 375,1245, 1024, ,677 0.83(s,3H,)1.1(s3H) ,1.8(s.2H).2.9(s,1H) ,1.4-26 (m,5H) 3.5-3.9 (m,4H) 53% / solid 2 Br Br Boron tribro mide 55-58° C 3372, 2967, 2881,1457,1426,1 376,1244,1019,71 0,637 0.79 (S.3H.) 1.1 (s,3H), 2.Q(s,2H)l2.25(s,1H,), 1.4-25(m;5H), 3.4-3.8(m,4H) 65% / solid 3 1 Br Boron tribro mide and Sodiu m lodid vise ous liqui d 3374, 2958, 2873,1459,1428,1 377,1249,1189,10 24,651,540 0.9(s,3H,) 1.1(s,3H), 1.7(s,2H),2.6(s,H) ,1.38-2.45(m,5H),-,3.4-3.8(m,4H) 72%/vis CO US liquid Example 4 The hydroxyl groups in the compound of formula III may be protected using known processes in the art to arrive at further compounds of the present invention. The compound of formula /// above (13.37mmo!) was dissolved in dichloromethane (50 ml) and stirred. Suitable protecting reactant (20.06mmol) was added to it followed by addition of suitable catalyst (0.668 mmol). The reaction mixture was stirred at room temperature for 10-12 hr. The reaction was monitored by TLC. After completion of the reaction, water was added and the layers were separated and the organic layer was washed with water and dried over sodium sulfate. The solvent was evaporated on rotary evaporator to get the product compound of formula II. Table 2 lists the number of compounds of formula II having various substitutions prepared according to the process discussed above. s Protect! Catalyst R> R1 R3 BP IR(CnV NMR Yield N ng ') (5,ppm) and 0. reagent propert ies 4 Tetrahy Pyridinium Br TH Br 95%./ dro p-toluene P 135- 3054, 0.83 (s, Oil pyran sulfonate 140° c 2949, 2876, 1422, 1265, 1032, 896, 740, 705 3H), U3 (s,3H)1.5 -2.6(m, 11H) 3.4-4.0 (m, 4H) 3.5 (m, 2H) 3.8 (m, 2H) 4.2(t.1H) " 5 t-Buty! dimethy 1 silyl chloride Imidazole Br TB DM S Br 252 255° c 2955, 2930, 2874, 1467. 1383, 1253, 1088, 937, 839, 776, 640 0.1 (s, 6H) ,0.8 (s, 9H) 1.0(d,6H), 1.2-1.7 (m. 5H) 3.3(d, 1H) ,3.5-4.0 (m, 4H), 4.1(1,1 H) 58.5%/ Viscou s mass 6 Benzoy t chloride Dimetyl amino pyridine Br Ben zoyl Br 260 265° c 2962, 2870, 1719, 1450, 1273, 1112, 1069, 1025, 175 0.76(s, 3H), 1.2 (s, 3H), 1.4- 2.6(m,5H), 3.4 (s 2H) 3.5-4.0 (m, 4H) 44.78/ Oil 7.4-8.0 (m, 5H) 7 Trifluor o acetic anhydri de None Br Trifl uor 0 ace tyl Br 270 274° c 2970, 2860, 1784, 1464, 1402, 1382, 1346, 1223, 1158, 774, 733 0.85 (s, 3H), 1.12 (s, 3H), 1.4-2.7 (m, 5HJ, 3.6 (s, 2H}, 3.6-4.0 (m, AH) 91%/ Viscou sOil 8 Acetic anhydri del Dodeca Tungstop hosphoric acid Br Ace tyl Br 250 255° c 2966, 2877, 1739, 1464, 1433, 1379, 1238, 1034, 982, 709, 640 0.95 (s, 3H),1.14 (s, 3H), 2.1 (s, 3H), 1.3-2.7 (m, 5H), 3.3-3.7 (m, 4H). 3.8

Documents

Orders

Section Controller Decision Date

Application Documents

# Name Date
1 3045-MUM-2010-FORM 1(15-12-2010).pdf 2010-12-15
1 3045-MUM-2010-RELEVANT DOCUMENTS [27-09-2023(online)].pdf 2023-09-27
2 3045-MUM-2010-CORRESPONDENCE(15-12-2010).pdf 2010-12-15
2 3045-MUM-2010-RELEVANT DOCUMENTS [28-03-2020(online)].pdf 2020-03-28
3 3045-MUM-2010-FORM 5(31-10-2011).pdf 2011-10-31
3 3045-MUM-2010-ANNEXURE TO FORM 3(1-12-2011).pdf 2018-08-10
4 3045-MUM-2010-FORM 2(TITLE PAGE)-(31-10-2011).pdf 2011-10-31
4 3045-MUM-2010-ANNEXURE TO FORM 3(3-11-2014).pdf 2018-08-10
5 3045-MUM-2010-FORM 2(31-10-2011).pdf 2011-10-31
5 3045-MUM-2010-CLAIMS(GRANTED)-(31-3-2017).pdf 2018-08-10
6 3045-MUM-2010-CORRESPONDENCE(1-11-2011).pdf 2018-08-10
7 3045-MUM-2010-CORRESPONDENCE(31-10-2011).pdf 2011-10-31
7 3045-MUM-2010-CORRESPONDENCE(1-12-2011).pdf 2018-08-10
8 3045-MUM-2010-CORRESPONDENCE(27-9-2011).pdf 2018-08-10
8 3045-MUM-2010-CLAIMS(31-10-2011).pdf 2011-10-31
9 3045-MUM-2010-ABSTRACT(31-10-2011).pdf 2011-10-31
9 3045-MUM-2010-CORRESPONDENCE(7-12-2012).pdf 2018-08-10
10 3045-MUM-2010-CORRESPONDENCE(9-1-2014).pdf 2018-08-10
10 3045-MUM-2010-REPLY TO EXAMINATION REPORT(19-11-2014).pdf 2014-11-19
11 3045-MUM-2010-CORRESPONDENCE(IPO)-(31-3-2017).pdf 2018-08-10
11 3045-MUM-2010-FORM 26(19-11-2014).pdf 2014-11-19
12 3045-MUM-2010-CLAIMS(MARKED COPY)-(19-11-2014).pdf 2014-11-19
12 3045-MUM-2010-CORRESPONDENCE(IPO)-(HEARING NOTICE)-(25-1-2017).pdf 2018-08-10
13 3045-MUM-2010-CLAIMS(AMENDED)-(19-11-2014).pdf 2014-11-19
13 3045-MUM-2010-Correspondence-021214.pdf 2018-08-10
14 3045-MUM-2010-CORRESPONDENCE(31-08-2015).pdf 2015-08-31
14 3045-MUM-2010-Correspondence-100815.pdf 2018-08-10
15 3045-MUM-2010-Correspondence-220116.pdf 2018-08-10
15 Petition Under Rule 137 [27-02-2017(online)].pdf 2017-02-27
16 Other Patent Document [02-03-2017(online)].pdf 2017-03-02
16 3045-MUM-2010-Correspondence-230715.pdf 2018-08-10
17 3045-MUM-2010-REQUEST FOR CERTIFIED COPY [07-12-2017(online)].pdf 2017-12-07
17 3045-MUM-2010-CORRESPONDENCE-270215.pdf 2018-08-10
18 3045-MUM-2010-CORRESPONDENCE(IPO)-(CERTIFIED LETTER)-(12-12-2017).pdf 2017-12-12
18 3045-mum-2010-correspondence.pdf 2018-08-10
19 3045-mum-2010-description(provisional).pdf 2018-08-10
19 Notarised Certificate of Incorporation.pdf 2018-08-10
20 3045-mum-2010-form 1.pdf 2018-08-10
20 FORM 13 _Change name of the applicant.pdf 2018-08-10
21 3045-MUM-2010-FORM 13(27-9-2011).pdf 2018-08-10
21 3045-MUM-2010_EXAMREPORT.pdf 2018-08-10
22 3045-MUM-2010-FORM 18(1-11-2011).pdf 2018-08-10
22 3045-MUM-2010-REPLY TO EXAMINATION REPORT(3-11-2014).pdf 2018-08-10
23 3045-MUM-2010-OTHER DOCUMENT(9-1-2014).pdf 2018-08-10
23 3045-MUM-2010-FORM 2(GRANTED)-(31-3-2017).pdf 2018-08-10
24 3045-mum-2010-form 2(title page).pdf 2018-08-10
24 3045-MUM-2010-OTHER DOCUMENT(3-11-2014).pdf 2018-08-10
25 3045-mum-2010-form 2.pdf 2018-08-10
25 3045-MUM-2010-GENERAL POWER OF ATTORNEY(27-9-2011).pdf 2018-08-10
26 3045-MUM-2010-Form 3-021214.pdf 2018-08-10
26 3045-MUM-2010-Form 3-230715.pdf 2018-08-10
27 3045-MUM-2010-Form 3-100815.pdf 2018-08-10
28 3045-MUM-2010-Form 3-021214.pdf 2018-08-10
28 3045-MUM-2010-Form 3-230715.pdf 2018-08-10
29 3045-mum-2010-form 2.pdf 2018-08-10
29 3045-MUM-2010-GENERAL POWER OF ATTORNEY(27-9-2011).pdf 2018-08-10
30 3045-mum-2010-form 2(title page).pdf 2018-08-10
30 3045-MUM-2010-OTHER DOCUMENT(3-11-2014).pdf 2018-08-10
31 3045-MUM-2010-FORM 2(GRANTED)-(31-3-2017).pdf 2018-08-10
31 3045-MUM-2010-OTHER DOCUMENT(9-1-2014).pdf 2018-08-10
32 3045-MUM-2010-FORM 18(1-11-2011).pdf 2018-08-10
32 3045-MUM-2010-REPLY TO EXAMINATION REPORT(3-11-2014).pdf 2018-08-10
33 3045-MUM-2010-FORM 13(27-9-2011).pdf 2018-08-10
33 3045-MUM-2010_EXAMREPORT.pdf 2018-08-10
34 3045-mum-2010-form 1.pdf 2018-08-10
34 FORM 13 _Change name of the applicant.pdf 2018-08-10
35 3045-mum-2010-description(provisional).pdf 2018-08-10
35 Notarised Certificate of Incorporation.pdf 2018-08-10
36 3045-MUM-2010-CORRESPONDENCE(IPO)-(CERTIFIED LETTER)-(12-12-2017).pdf 2017-12-12
36 3045-mum-2010-correspondence.pdf 2018-08-10
37 3045-MUM-2010-CORRESPONDENCE-270215.pdf 2018-08-10
37 3045-MUM-2010-REQUEST FOR CERTIFIED COPY [07-12-2017(online)].pdf 2017-12-07
38 3045-MUM-2010-Correspondence-230715.pdf 2018-08-10
38 Other Patent Document [02-03-2017(online)].pdf 2017-03-02
39 3045-MUM-2010-Correspondence-220116.pdf 2018-08-10
39 Petition Under Rule 137 [27-02-2017(online)].pdf 2017-02-27
40 3045-MUM-2010-CORRESPONDENCE(31-08-2015).pdf 2015-08-31
40 3045-MUM-2010-Correspondence-100815.pdf 2018-08-10
41 3045-MUM-2010-CLAIMS(AMENDED)-(19-11-2014).pdf 2014-11-19
41 3045-MUM-2010-Correspondence-021214.pdf 2018-08-10
42 3045-MUM-2010-CLAIMS(MARKED COPY)-(19-11-2014).pdf 2014-11-19
42 3045-MUM-2010-CORRESPONDENCE(IPO)-(HEARING NOTICE)-(25-1-2017).pdf 2018-08-10
43 3045-MUM-2010-CORRESPONDENCE(IPO)-(31-3-2017).pdf 2018-08-10
43 3045-MUM-2010-FORM 26(19-11-2014).pdf 2014-11-19
44 3045-MUM-2010-CORRESPONDENCE(9-1-2014).pdf 2018-08-10
44 3045-MUM-2010-REPLY TO EXAMINATION REPORT(19-11-2014).pdf 2014-11-19
45 3045-MUM-2010-ABSTRACT(31-10-2011).pdf 2011-10-31
45 3045-MUM-2010-CORRESPONDENCE(7-12-2012).pdf 2018-08-10
46 3045-MUM-2010-CLAIMS(31-10-2011).pdf 2011-10-31
46 3045-MUM-2010-CORRESPONDENCE(27-9-2011).pdf 2018-08-10
47 3045-MUM-2010-CORRESPONDENCE(31-10-2011).pdf 2011-10-31
47 3045-MUM-2010-CORRESPONDENCE(1-12-2011).pdf 2018-08-10
48 3045-MUM-2010-CORRESPONDENCE(1-11-2011).pdf 2018-08-10
49 3045-MUM-2010-FORM 2(31-10-2011).pdf 2011-10-31
49 3045-MUM-2010-CLAIMS(GRANTED)-(31-3-2017).pdf 2018-08-10
50 3045-MUM-2010-FORM 2(TITLE PAGE)-(31-10-2011).pdf 2011-10-31
50 3045-MUM-2010-ANNEXURE TO FORM 3(3-11-2014).pdf 2018-08-10
51 3045-MUM-2010-FORM 5(31-10-2011).pdf 2011-10-31
51 3045-MUM-2010-ANNEXURE TO FORM 3(1-12-2011).pdf 2018-08-10
52 3045-MUM-2010-RELEVANT DOCUMENTS [28-03-2020(online)].pdf 2020-03-28
52 3045-MUM-2010-CORRESPONDENCE(15-12-2010).pdf 2010-12-15
53 3045-MUM-2010-FORM 1(15-12-2010).pdf 2010-12-15
53 3045-MUM-2010-RELEVANT DOCUMENTS [27-09-2023(online)].pdf 2023-09-27

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