Process for preparing oxazolines from tetrahydrofurans

专利摘要:
Discloses a process for the preparation of chemical intermediates in the synthesis of HIV-protease inhibitors associated with and containing nelfinavir mesylate. The process of the present invention involves converting a tetrahydrofuran derivative (II) to an oxazoline (I) to provide an important reaction intermediate for the preparation of nelfinavir. Also disclosed is a process for preparing a chiral amino alcohol from an epoxy-tetrahydrofuran.
公开号:KR20020047255A
申请号:KR1020027005084
申请日:2000-10-19
公开日:2002-06-21
发明作者:버씨쥴리엣카르사；주크스콧에드워드；보르어베네트채플린
申请人:개리 이. 프라이드만；아구론 파마슈티컬스, 인크.；
IPC主号:

专利说明:

TECHNICAL FIELD [0001] The present invention relates to a process for preparing oxazoline from tetrahydrofuran,
[2] Treatment of HIV-infected individuals with HIV-protease inhibitors has emerged as an important method for preventing or inhibiting the rapid proliferation of viruses in human tissues. HIV-protease inhibitors substantially block the viral load of the virus by blocking the vital enzymatic pathway of the virus, which slows down the steady decay of the immune system and its deleterious effects on human health. The HIV-protease inhibitor, nelfinavir mesylate, has proven to be an effective treatment for HIV-infected individuals. Nelfinavir mesylate and its preparation are disclosed in U.S. Patent No. 5,484,926, which is incorporated herein by reference:
[3]
[4] Other preparative methods of nelfinavir mesylate and its free base have been reported. For example, PCT / JP96 / 02756 (WO97 / 11937) discloses the preparation of nelfinavir mesylate and its free base using oxazoline intermediates obtainable from 1,3-dioxepan-5-ol or derivatives thereof Method is disclosed. PCT / JP96 / 02757 (WO 97/11938) discloses a process for the preparation of 1,3-dioxepan-5-ol, which involves the conversion of 1,3-dioxepan-5-ol via N-benzyloxycarbonyl-amino- Method is disclosed. Each of these methods reportedly provides some improvement in the production efficiency of nelfinavir. However, further improvement would be desirable.
[5] SUMMARY OF THE INVENTION
[6] The present invention relates to an efficient and cost effective process for the preparation of nelfinavir mesylate and its free base. Specifically, the process of the present invention comprises preparing an oxazoline from tetrahydrofuran, comprising treating the tetrahydrofuran with a phosphoric acidophilic electrophilic reagent in a manner effective to provide the following oxazoline:
[7]
[8]
[9] In the above equations,
[10] R _a is -COR (1)
[11] R _b is hydrogen, -COR (3), -SO ₂ R (2) or a suitable hydroxyl protecting group,
[12] R _c is H, -COR (3) or -SO ₂ R (2)
[13] Wherein R (1), R (2) and R (3) are independently a substituted or unsubstituted alkyl, aryl, cycloalkyl, heterocycloalkyl or heteroaryl group.
[14] Advantageously, the process of the present invention provides a relatively high yield of nelfinavir mesylate and its free base and uses fewer synthesis steps than the prior art methods.
[15] The present invention also relates to a process for preparing an intermediate compound useful in the process for the preparation of nelfinavir mesylate and its free base. The present invention also relates to a process for the preparation of chiral starting materials useful in the process for the preparation of nelfinavir mesylate and its free base according to the invention.
[1] The present invention relates to a method for the chemical preparation of intermediates in the synthesis of nelfinavir mesylate and its free base, a protease inhibitor useful in the treatment of HIV-infected individuals.
[16] The present invention provides a novel conversion method useful for converting an aminotetrahydrofuran derivative into an oxazoline intermediate useful for the preparation of nelfinavir mesylate and nelfinavir free base. All compounds of the present process containing one or more chiral centers may exist as a mixture of single stereoisomers, racemates, and / or enantiomers and / or diastereomers unless otherwise indicated. All such single stereoisomers, racemates and mixtures thereof are intended to be included within the scope of the present invention. Furthermore, it is not intended to limit the scope of the present invention to the reaction of certain isomers. While the reactions disclosed herein may be illustrated using the compounds depicted as single enantiomers or diastereomers, the methods of the present invention are intended to include the reaction of any isomer or racemic mixture of these compounds.
[17] The term " chiral ", as used herein, when used to describe a particular compound, means that the compound is substantially enantiomeric and / or diastereomeric, such as, for example, in the term "chiral amino-tetrahydrofuran" . Substantially enantiomerically pure compounds contain at least 90%, preferably at least 95%, of the single isomer. More preferably, the chiral compounds of the present invention contain at least 97.5% of a single isomer, most preferably at least 99% of a single isomer. The compounds represented as single stereoisomers in the present invention describe compounds which are present in a form containing at least 90% of a single isomer. The term " racemic " or " racemic mixture " refers to a mixture of equal amounts of enantiomeric compounds, including mixtures of enantiomers and / or mixtures of enantiomeric diastereomers.
[18] The process of the present invention converts amino-tetrahydrofuran I to oxazoline II, as illustrated below:
[19]
[20] In the above,
[21] R < _{a >} is hydrogen or -COR (1)
[22] R _b is hydrogen, -COR (3), -SO ₂ R (2) or a suitable hydroxyl protecting group,
[23] R _c is hydrogen, -COR (3) or -SO ₂ R (2)
[24] R (1), R (2) and R (3) independently represent a substituted or unsubstituted alkyl, aryl, cycloalkyl, heterocycloalkyl or heteroaryl group.
[25] As used herein, the term " alkyl " preferably refers to a straight or branched chain alkyl group having from 1 to 8 carbon atoms, more preferably from 1 to 6, and most preferably from 1 to 4 carbon atoms. The term "C ₁ -C ₆ alkyl" denotes straight or branched chain alkyl of 1 to 6 carbon atoms. Typical C ₁ -C ₆ alkyl groups include methyl, ethyl, n-propyl, isopropyl, butyl, isobutyl, sec-butyl, t-butyl, pentyl, neo-pentyl, hexyl and isohexyl. The term "C ₁ -C ₆ alkyl" includes within its definition the term "C ₁ -C ₄ alkyl".
[26] The term " cycloalkyl " preferably refers to a group comprising a saturated or partially saturated mono- or poly-carbocyclic ring having 5 to 14 ring carbon atoms. Typical cycloalkyl is a monocyclic ring of 3 to 7 carbon atoms, preferably 3 to 6 carbon atoms, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cycloheptyl, and the like . Typical cycloalkyl is C ₅ -C ₇ cycloalkyl which is a hydrocarbon ring structure having 5 to 7 carbon atoms.
[27] The term " aryl " denotes an aromatic, monovalent monocyclic, bicyclic or tricyclic radical containing 6, 10, 14 or 18 carbon ring atoms, wherein one or more cycloalkyl Group, a heterocycloalkyl group or a heteroaryl group may be condensed, wherein the groups may be unsubstituted or substituted by one or more of the substituents disclosed below. Typical examples of aryl groups include, but are not limited to, phenyl, naphthyl, anthryl, phenanthryl, fluoren-2-yl, indan-5-yl, and the like.
[28] The term " heterocycloalkyl " refers to an alkyl group containing 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17 or 18 ring atoms, Saturated or unsaturated nonaromatic monovalent monocyclic, bicyclic or tricyclic radical comprising 1, 2, 3, 4 or 5 heteroatoms selected from nitrogen, oxygen and sulfur, with one The above cycloalkyl groups, aryl groups or heteroaryl groups may be condensed, wherein the groups may be unsubstituted or substituted by one or more of the substituents described below. Typical examples of heterocycloalkyl groups include, but are not limited to, azetidinyl, pyrrolidyl, piperidyl, piperazinyl, morpholinyl, tetrahydro-2H-1,4-thiazinyl, tetrahydrofuryl, dihydrofuryl , Tetrahydropyranyl, dihydropyranyl, 1,3-dioxolanyl, 1,3-dioxanyl, 1,4-dioxanyl, 1,3-oxathiolanyl, Azabicyclo [3.3.1] octyl, azabicyclo [3.3.1] nonyl, azabicyclo [4.3.0] nonyl, oxabicyclo [2.2.1] heptyl, 9-triazacyclododecyl, and the like.
[29] The term " heteroaryl " refers to an aryl group containing 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17 or 18 ring atoms, Refers to a group comprising a monovalent monocyclic, bicyclic or tricyclic radical of an aromatic group containing 2, 3, 4 or 5 heteroatoms, wherein said ring is optionally substituted by one or more cycloalkyl groups, The aryl groups may be condensed, wherein the groups may be unsubstituted or substituted by one or more of the substituents described below. Illustrative examples of heteroaryl groups include, but are not limited to, thienyl, pyrrolyl, imidazolyl, pyrazolyl, furyl, isothiazolyl, furazanyl, isoxazolyl, thiazolyl, pyridyl, pyrazinyl, pyrimidinyl, Pyridazinyl, triazinyl, benzo [b] thienyl, naphtho [2,3-b] thianthrenyl, isobenzofuranyl, chromenyl, xanthenyl, phenoxathienyl, indolizinyl, iso Wherein R is selected from the group consisting of halogen, indolyl, indolyl, indazolyl, purinyl, isoquinolyl, quinolyl, phthalazinyl, naphthyridinyl, quinoxialinyl, quinazolinyl, benzothiazolyl, benzimidazolyl, tetrahydroquinolinyl, Phenanthridinyl, phenothiazinyl, phenthazinyl, phenothiazinyl, phenothiazinyl, phenothiazinyl, phenanthridinyl, phenanthridinyl, phenanthrolinyl, phenanthrolinyl, phenanthryl, isothiazolyl, phenothiazinyl and phenoxazinyl .
[30] In the present invention, the alkyl, aryl, cycloalkyl, heterocycloalkyl or heteroaryl groups may each be substituted by one or more substituents. If the substituents themselves are not suitable for the process of the present invention, the substituents may be protected with a suitable protecting group that is stable to the reaction conditions used in the process. The protecting group may be removed at an appropriate point in the reaction sequence of the process providing the desired intermediate or target compound. Methods for protecting and deprotecting different substituents using suitable protecting groups and suitable protecting groups such as those described above are well known to those skilled in the art; Examples thereof are described in the literature [T. Green & P. Wuts, Protective Groups in Organic Synthesis (2nd Ed., 1991). In some cases, the substituent may be specifically selected to be reactive under the reaction conditions used in the process of the present invention. Under such circumstances, the reaction conditions convert the selected substituents to another substituent which is useful in the intermediate compounds of the process of the present invention or is the desired substituent of the target compound.
[31] Typical substituents that may be present on the alkyl group include aryl, cycloalkyl, heterocycloalkyl, heteroaryl, nitro (NO ₂ ), amino, alkylamino, dialkylamino, carbamoyl, alkylaminocarbonyl, Alkoxy, aryloxy, halogen, hydroxyl, alkanoyl, acyloxy, aroyl, aroyloxy, carboxyl, alkoxycarbonyl, aryloxycarbonyl, alkylcarbonylamino, Aryl, nitro (NO ₂ ), aryl, heteroaryl, heteroaryl, heteroaryl, arylcarbonylamino, mercapto, alkylthio, arylthio, wherein any of the aryl, cycloalkyl, heterocycloalkyl, , Amino, halogen, hydroxyl, alkoxy, aryloxy, mercapto, alkylthio and arylthio. Typical substituents which may be present on said aryl, cycloalkyl, heterocycloalkyl or heteroaryl group include alkyl, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, nitro (NO ₂ ), amino, alkylamino, dialkylamino , Carbamoyl, alkylaminocarbonyl, dialkylaminocarbonyl, arylaminocarbonyl, dialkylamino, alkoxy, aryloxy, halogen, hydroxyl, alkanoyl, acyloxy, aroyl, aroyloxy, carboxyl, alkoxy Alkyl, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, heteroaryl, heteroaryl, heterocycloalkyl, heterocycloalkyl, heterocycloalkyl, alkyl any of the residues, aryl, nitro (NO _2), amino, halogen, hydroxyl, alkoxy, aryloxy, mercapto town, alkylthio and arylthio one of the By may be further substituted.
[32] The terms " halogen " and " halo " refer to chloro, fluoro, bromo or iodo substituents.
[33] Typical substituted alkyls include halo (C ₁ -C ₄ ) alkyl, which represents straight or branched chain alkyl having 1 to 4 carbon atoms with one to three halogen atoms attached. Typical halo (C ₁ -C ₄ ) alkyl groups include, but are not limited to, chloromethyl, 2-bromoethyl, 1-chloroisopropyl, 3-fluoropropyl, 2,3-dibromobutyl, Di-t-butyl, trifluoromethyl, and the like. Another typical substituted alkyl is hydroxy (C ₁ -C ₄ ) alkyl, which represents a straight or branched chain alkyl of 1 to 4 carbon atoms to which the hydroxy group is attached. Typical hydroxy (C ₁ -C ₄ ) alkyl groups include hydroxymethyl, 2-hydroxyethyl, 3-hydroxypropyl, 2-hydroxyisopropyl, 4-hydroxybutyl and the like. Further another exemplary substituted alkyl is C ₁ -C ₄ alkyl group, a thio bond straight-chain or branched C ₁ -C ₄ alkyl group, a C ₁ -C ₄ alkylthio (C ₁ -C ₄₎ alkyl. Typical C ₁ -C ₄ alkylthio (C ₁ -C ₄ ) alkyl groups include methylthiomethyl, ethylthiomethyl, propylthiopropyl, secondary-butylthiomethyl, and the like. Another typical substituted alkyl is heterocycloalkyl or heterocycloalkyl (C ₁ -C ₄ ) alkyl which is straight or branched chain alkyl having 1 to 4 carbon atoms bonded with a heteroaryl group or heteroaryl (C ₁ -C ₄ ) alkyl to be. Typical heterocycloalkyl (C ₁ -C ₄ ) alkyl and heteroaryl (C ₁ -C ₄ ) alkyl groups include pyrrolylmethyl, quinolinylmethyl, 1-indolylethyl, 2-furylethyl, -Ylpropyl, 1-imidazolyl isopropyl, 4-thiazolylbutyl and the like. Yet another exemplary substituted alkyl is aryl (C ₁ -C ₄ ) alkyl, wherein the aryl group is a straight or branched chain alkyl having from 1 to 4 carbon atoms bonded thereto. Typical aryl (C ₁ -C ₄ ) alkyl groups include phenylmethyl (benzyl), 2-phenylethyl, 3-naphthyl-propyl, 1-naphthylisopropyl, 4-phenylbutyl and the like.
[34] A typical substituted aryl are halogen, hydroxyl, morpholino (C ₁ -C ₄₎ alkoxycarbonyl, pyridyl (C ₁ -C ₄₎ alkoxycarbonyl, halo (C ₁ -C ₄₎ alkyl, C ₁ -C ₄ alkyl, C ₁ -C ₄ alkoxy, carboxy, C ₁ -C ₄ alkoxycarbonyl, carbamoyl, N- (C ₁ -C ₄₎ alkyl aminocarbonyl, amino, C ₁ -C ₄ alkylamino, (C ₁ -C ₄ ) alkylamino and a group of the formula - (CH ₂ ) _a -R ₇ wherein a is 1, 2, 3 or 4 and R ₇ is hydroxy, C ₁ -C ₄ alkoxy, carboxy, C ₁ -C ₄ alkoxycarbonyl, amino, carbamoyl, C ₁ -C ₄ alkylamino or di (C ₁ -C ₄₎ alkylamino, a) one of the independently represent at least one substituent selected, preferably from the group of 3 to Phenyl or naphthyl ring substituted with up to two substituents.
[35] Typical substituted heterocycloalkyl and heteroaryl are independently selected from the group consisting of halogen, halo (C ₁ -C ₄ ) alkyl, C ₁ -C ₄ alkyl, C ₁ -C ₄ alkoxy, carboxy, C ₁ -C ₄ alkoxycarbonyl, N- (C ₁ -C ₄₎ alkyl carbamoyl, N- (C ₁ -C ₄₎ alkyl aminocarbonyl, amino, C ₁ -C ₄ alkylamino, di (C ₁ -C ₄₎ alkylamino and the formula - (CH ₂ ) _a -R ⁷ wherein a is 1, 2, 3 or 4 and R ⁷ is selected from the group consisting of hydroxy, C ₁ -C ₄ alkoxy, carboxy, C ₁ -C ₄ alkoxycarbonyl, amino, , C ₁ -C ₄ alkylamino or di (C ₁ -C ₄ ) alkylamino).
[36] Examples of substituted heterocycloalkyl include, but are not limited to, 3-Nt-butylcarboxamide decahydroisoquinolinyl and 6-Nt-butyl carboxamide octahydro-thieno [3,2- c] pyridinyl . Examples of substituted heteroaryl include but are not limited to 3-methylimidazolyl, 3-methoxypyridyl, 4-chloroquinolinyl, 4-aminothiazolyl, 8-methylquinolinyl, 6-chlorooquinoxalinyl , 3-ethylpyridyl, 6-methoxybenzimidazolyl, 4-hydroxypuryl, 4-methylisoquinolinyl, 6,8-dibromoquinolinyl, 4,8-dimethylnaphthyl, 2- Methyl-1,2,3,4-tetrahydroisoquinolinyl, N-methyl-quinolin-2-yl, 2-t-butoxycarbonyl-1,2,3,4-isoquinolin- .
[37] In general, the conversion of tetrahydrofuran I to oxazoline II is carried out by reacting the above tetrahydrofuran, wherein R _a is -COR (1) and R _b is hydrogen, -COR (3), -SO ₂ R (2) or Wherein R _b is hydrogen, -COR (3), -SO ₂ R (2) or a suitable hydroxyl protecting group and R _c is hydrogen, -COR (3) or -SO can be carried out by treatment with an electrophilic reagent chinsan baking to promote the ring-opening of tetrahydrofuran to provide a ₂ R _(2)). Thus, the hydroxyl protecting group (as R _b ), which may be suitable for use in the methods of the present invention, includes stable hydroxyl protecting groups for the combination of the above described phospho-plastic electrophilic reagents or reagents disclosed herein Suitable protecting groups and methods of protecting and deprotecting hydroxyl substituents using such suitable protecting groups are well known to those skilled in the art; An example thereof is shown in the above-mentioned T. Green & P. Wuts.
[38] Typically, the first step of the process of the present invention involves formation of the chiral tetrahydrofuranamide B from the known amino-tetrahydrofuran A using any suitable conventional process. Examples of such conventional processes are described in the above reference [T. Green & P. Wuts, which includes treatment with the appropriate acid halide R (1) COX (where X is a halogen) in the presence of a base, a suitable coupling reagent such as dicyclohexylcarbodiimide And treatment with a suitable acid R (1) COOH in the presence of a base. Preferably, the reaction is carried out using an acid chloride in the presence of a triethylamine base.
[39]
[40] In one embodiment of the present invention, the hydroxyl moiety of the chiral tetrahydrofuranamide B may be substituted by R _b (which is -SO ₂ R (2) as defined above or a suitable protecting group). Preferably, the conversion of the hydroxyl moiety with alkyl or aryl sulfonate _{(-SO 2 R (2))} , more preferably, mesylate or tosylate. Methods for forming such -OSO ₂ R (2) groups are well known in the art and can be performed using any suitable conventional process. Examples of such conventional processes are described in the above reference [T. Green & P. Wuts. Preferably, the reaction is carried out using methanesulfonyl chloride or p-toluenesulfonyl chloride in the presence of a triethylamine base.
[41]
[42] The hydroxy substituted chiral tetrahydrofuranamide C can then be converted to the chiral oxazoline D. The conversion can be carried out using a phosphorylated electrophilic reagent which promotes tetrahydrofuran ring opening and oxazoline ring formation. The term " protonophilic electrophilic reagent " as used in the present invention refers to a single reagent or series of reagents which upon coupling generate tetrahydrofuran ring opening and oxazoline ring formation, which produce a phosphorophosphorylated electrophilic intermediate. Examples of the acidophilic electrophilic reagent include, but are not limited to, a pharmaceutically acceptable acidic Lewis acid (e.g., a metal halide Lewis acid such as titanium tetrachloride, or a strong acidophilic protic acid such as trifluoromethanesulfonic acid Triflic acid), a suitable acid anhydride, a suitable acid anhydride or a suitable acid halide and a suitable Lewis acid. Suitable anhydrides and acid halides include anhydrides of strong acids, such as triflic anhydride, as well as anhydrides and acid halides (e.g., acid chlorides) of any conventional alkyl or aryl carboxylic or sulfonic acids. Suitable Lewis acids include the well-known metal halide Lewis acids such as titanium tetrachloride, aluminum trichloride and the like and strong protic acids such as sulfuric acid, nitric acid, phosphoric acid, trifluoroacetic acid, trifluoromethanesulfonic acid and the like. Generally, the reaction of tetrahydrofuranamide with a cholesteryl electrophilic reagent to form an oxazoline is carried out in an aprotic solvent such as, but not limited to, ethyl acetate, isopropyl acetate, dichloromethane, benzene, and toluene Can be carried out at a temperature of from -40 to 70 캜 using from about 1 to about 20 molar equivalents of a phosphoric acid electrophilic reagent (for the tetrahydrofuranamide).
[43] During the course of the reaction, the primary hydroxyl moiety formed upon ring opening of the tetrahydrofuran may be substituted with the " cation " moiety of the acid used in the reaction. When a Lewis acid or a strong protic acid is used as the acidophilic electrophilic reagent, the resulting oxazoline can be prepared by reacting a " cationic residue & quot ^; of the acid with H ^& lt ^{; + &} Contains an unsubstituted primary hydroxyl moiety (where R < _c > is H) because hydrolysis produces the product. The resulting hydroxyl moiety may be converted to any suitable art-recognized derivative (e. G., Via alkylation to an ether, via acylation to an ester, alkyl- or aryl-oxycarbonyl chloride, or By treatment with an equivalent thereof, with a carbonate, or by treatment with an isocyanate to a carbamate or the like).
[44] For the preparation of nelfinavir and nelfinavir mesylate, the tetrahydrofuranamides are preferably reacted with a suitable anhydride, for example a phosphoric acid electrophilic reagent comprising triflic anhydride, or an anhydride or acid halide, To convert them to oxazoline ester derivatives. Such reagents can produce acylium ion intermediates, which are well known in the art. For example, suitable acylium intermediates can be prepared in situ by treatment with a suitable acid anhydride, optionally in conjunction with a suitable protic acid, or by treatment with a suitable acid anhydride and a suitable Lewis acid. Suitable acid anhydrides, acid halides and Lewis acids are as described above. In the course of the reaction using these reagents, the primary hydroxyl moiety formed upon ring opening of the tetrahydrofuran may be an alkyl or aryl carboxyl moiety of the anhydride or acid halide used in the above reaction, exemplified as R _c , wherein R _{and c} is -COR (3) as defined above. As exemplified herein, useful hydrophobic electrophilic reagent combinations include acetic anhydride and sulfuric acid. Thus, in this embodiment of the process of the present invention, the resulting oxazoline contains an acetylated primary hydroxyl moiety.
[45] In general, the conversion of the tetrahydrofuran-amide to the oxazoline can be carried out using a phospho-electrophilic reagent combination in which each reagent is present in an excess of molar equivalents. The reaction is carried out at a temperature of from -40 to 70 ° C in an aprotic solvent such as, but not limited to, from about 1 to about 20 molar equivalents of a suitable acid in ethyl acetate, isopropylacetate, dichloromethane, benzene and toluene, Can be carried out with an acid anhydride and an acid in a relative molar ratio of about 1: 5 to about 5: 1 (anhydride: acid) using 20 molar equivalents of a suitable anhydride (for tetrahydrofuran-amide). Preferably, the conversion can be carried out using an excess of the molar equivalent, i. E. 2 to about 20 molar equivalents, of the cholesteric electrophilic reagent. More preferably, the reaction may be carried out using about 2 to about 20 molar equivalents of an acid and about 2 to about 20 molar equivalents of a suitable anhydride, wherein the anhydride to acid ratio is from about 1: 1 to about 5 : 1. For example, as illustrated in the present invention, the conversion may be carried out with a mixture of 7.5 equivalents of strong acid and 15 equivalents of acid anhydride (i.e. wherein the ratio of anhydride to acid is 2: 1, About 3: 1).
[46] The resulting oxazoline D, as disclosed in PCT / JP96 / 02756 (WO97 / 11937), which is incorporated herein by reference, is used in the preparation of nelfinavir, especially intermediates useful in the preparation of compounds 20 and 19, Can:
[47]
[48]
[49] In the above equations,
[50] R (4) is a substituted or unsubstituted alkyl, aryl, cycloalkyl, heterocycloalkyl or heteroaryl group,
[51] R (5) is a substituted or unsubstituted NH-alkyl, NH-aryl, O-alkyl or O-
[52] Wherein each alkyl or aryl moiety may be unsubstituted or substituted by the substituents described above.
[53] Preferably, R (4) is And R (5) is Nt-butyl.
[54] In another embodiment of the process of the present invention, the tetrahydrofuran-amide B may be converted directly to the oxazoline E. The amide can be treated in a similar manner as described above. For example, the tetrahydrofuran-amide B can be treated directly with a suitable acid anhydride in the presence of a suitable acid, for example, in the presence of acetic anhydride and sulfuric acid to form the oxazoline diester E. Each hydroxyl moiety of the resulting oxazoline is substituted with an alkyl or aryl carboxyl moiety of the anhydride used in the reaction (exemplified as -COR (3), wherein R (3) is as defined above.) Thus, acetic acid When an anhydride is used in the process, both of the two hydroxyl moieties of the resulting oxazoline will be acetylated.
[55]
[56] The alkyl or aryl carboxyl residues of the oxazoline diester E can each be removed using a conventional process, for example by treatment with a suitable base in a suitable solvent (hydrolyzed to the corresponding hydroxyl moiety) to yield the oxazolinediol F Can be formed. Suitable bases for carrying out the hydrolysis are well known in the art and include potassium carbonate, sodium hydroxide, potassium hydroxide, and the like. Solvents suitable for such hydrolysis are likewise well known in the art and include, but are not limited to, lower alkanols (methanol, ethanol, isopropanol, etc.). Examples of other processes common to the hydrolysis of the esters are described in the above-mentioned T. Green & P. Wuts.
[57]
[58] Conversion of the oxazolinediol F to nelfinavir via compound 19 was achieved using nelfinavir mesylate of 2 (R), 3-dihydroxy-1 (R) -phenylsulfanylmethyl-propyl) carbamic acid benzyl ester and Can be carried out in a similar manner as described in PCT / JP96 / 02757 (WO97 / 11938) for the conversion thereof to its free base. The contents of PCT / JP96 / 02757 (WO97 / 11938) are incorporated herein by reference. For example, selective functionalization of the primary and secondary hydroxyl moieties of the oxazolinediol F can be performed by first selectively protecting the primary hydroxyl moiety with a suitable hydroxyl protecting group. Methods for protecting and deprotecting hydroxyl substituents using suitable hydroxyl protecting groups and suitable protecting groups such as those described above are well known to those skilled in the art; An example thereof is shown in the above-mentioned T. Greene & P. Wuts]. Preferably, the primary hydroxyl moiety is protected as a para-nitrobenzoate ester. The secondary hydroxyl moiety can then be functionalized by conversion to a leaving group. As used herein, the term " leaving group " refers to any group that is displaced from a molecule by the breaking of a bond in a substitution reaction. Examples of leaving groups include substituted or unsubstituted aryl sulfonates and alkyl sulfonates prepared using an unsubstituted or unsubstituted aryl or alkylsulfonyl halide. Preferably, the hydroxyl moiety is converted to a mesylate. This sulfonylated and protected oxazoline is then converted to compound 20 by the addition of 3S, 4aR, 8aR-3-Nt-butylcarboxamidodecahydroisoquinoline (PHIQ) as described in PCT / JP96 / 02757 .
[59] In a preferred embodiment of the process of the present invention, R (1) is as follows:
[60]
[61] In this formula,
[62] R < _{p >} is a suitable phenol hydroxyl protecting group, examples of which are given in T. Green & P. Wuts.
[63] In a more preferred embodiment of the present invention, R (1) is as follows:
[64]
[65] Wherein the acetyl moiety used to protect the phenol hydroxyl moiety is reactive to the hydrolysis conditions used to convert E to F.
[66] Thus, in this embodiment of the present invention, the oxazoline F is a triol, wherein R (1) is as follows:
[67]
[68] The selective functionalization of the phenol, primary and secondary hydroxyl moieties of the oxazoline triols can be performed by first selectively protecting the phenol hydroxyl moiety using a suitable hydroxyl protecting group. Preferably, the phenol hydroxyl moiety is protected as a para-nitrobenzoate ester. The primary hydroxyl moiety can then be protected using the same or different protecting groups. If the same protecting group is used, the phenol and primary hydroxyl moiety can be protected in a single step. The secondary hydroxyl moiety can then be functionalized by conversion to the mesylate. This sulfonylated-double protected oxazoline can then be reacted with 3S, 4aR, 8aR-3-Nt-butylcarboxamidodecahydroisoquinoline (PHIQ) in a manner similar to that described in PCT / JP96 / 02757 20 < / RTI >
[69] The present invention also provides a process for the preparation of chiral tetrahydrofuranamides wherein the 4-hydroxyl moiety has a stereochemistry which is incompatible with the stereochemistry of the chiral tetrahydrofuranamide B described above. This method involves converting tetrahydrofuranamide B into the condensed tetrahydrofuranyl oxazoline G by treatment with a substituted or unsubstituted sulfonylating reagent using two equivalents of a base. The reaction can be carried out in a suitable solvent such as, but not limited to, ethyl acetate, isopropylacetate, toluene, benzene, dichloromethane, tetrahydrofuran, and the like at a temperature of -78 to 100 ° C.
[70]
[71] The condensed heterocycle G can then be converted to the chiral tetrahydrofuranamide H by treatment with an aqueous acid, such as, but not limited to, aqueous hydrochloric acid, sulfuric acid, methanesulfonic acid, p- toluenesulfonic acid, phosphoric acid, and the like. The reaction may be carried out at a temperature of -40 to 100 ° C in a suitable solvent such as, but not limited to, water, alcohol solvents or mixtures thereof, with suitable alcohol solvents including but not limited to lower alkanols, For example, methanol, isopropanol, ethanol and the like.
[72]
[73] The tetrahydrofuran-amide H can be converted to an oxazoline diester J by treatment with an acid anhydride and an acid according to the methods described above. Hydrolyzing the alkyl or aryl carboxyl residue of the oxazoline diester J to form the diol K can also be carried out according to the method described above.
[74]
[75] The primary hydroxyl moiety of the resulting oxazolinediol K can be functionalized by conversion to a leaving group by treatment with a substituted or unsubstituted aryl or alkylsulfonyl halide, as described above. Preferably, the primary hydroxyl is converted to tosylate or mesylate. The functionalized oxazoline is treated with 3S, 4aR, 8aR-3-N-t-butylcarboxamidodecahydroisoquinoline (PHIQ) as a nucleophile in the presence of base under customary conditions to provide compound 19. Conversion of compound 19 to nelfinavir can be carried out analogously to that described in PCT / JP96 / 02757.
[76] In another embodiment of the present invention, the following tetrahydrofuran-amide H can be converted to the following protected tetrahydrofuran-amide L:
[77]
[78]
[79] In this formula,
[80] R (10) may be any suitable hydroxyl protecting group.
[81] The protected tetrahydrofuran-amide L can then be converted directly to the protected protected oxazoline M by treatment with a phosphorus acidic Lewis acid, a phosphoric acid protic protic acid or triflic anhydride.
[82]
[83] In this formula,
[84] R (10) is any suitable protecting group for the hydroxyl moiety,
[85] R (11) is H or substituted alkylsulfonyl.
[86] The conversion of the protected oxazoline M to nelfinavir can be carried out analogously to the above acid linkages.
[87] The present invention also relates to a process for the preparation of the following chiral amino-tetrahydrofuran A or its salts, which comprises treating the following achiral chiral condensed epoxy-tetrahydrofuran N with an amine reagent to produce the following compounds O or P, The method provides:
[88]
[89]
[90]
[91] The reaction can be carried out in a suitable solvent such as, but not limited to, an alcohol solvent such as methanol, isopropanol, ethanol or the like, or an aprotic solvent such as isopropyl acetate, ethyl acetate, tetra Hydrofuran and the like.
[92] The amine reagent used in the process may be a chiral or a chiral amination reagent. When the amination reagent is chiral (i.e., when R (6) is a chiral residue), the mixture of amino-tetrahydrofuran formed is a diastereomeric mixture, which is treated using conventional techniques to form the separated amino- Tetrahydrofuran diastereomers may be provided. After separating the isomers, the chiral residue of the chiral amination reagent may be removed to provide the respective separated amino-tetrahydrofuran enanthiomers or salts thereof. For this separation, substituent R (6) is a suitable nitrogen protecting group having a substantially enantiomerically pure chiral center. Preferably, R (6) contains at least 97.5% of a single isomer, more preferably at least 99% of a single isomer. In addition, the R (6) nitrogen protecting group should be removed under conditions that do not racemize the chiral amino-tetrahydrofuran 1. Preferably, R (6) is a substantially enantiomerically pure substituted or unsubstituted alkanoyl, aroyl, arylalkylcarbonyl, arylalkyl or heteroarylalkyl wherein the alkyl, aryl or heteroaryl moiety is May be substituted by any of the above-mentioned alkyl, aryl or heteroaryl moieties. Most preferably R (6) is as follows:
[93]
[94] When the amination reagent is achiral, e. G. Ammonia, the mixture of amino-tetrahydrofuran formed is an enantiomeric mixture, which is reacted with a chiral compound in an effective manner to provide a diastereomeric mixture of amino-tetrahydrofuran Reagent, wherein the chiral reagent contains a chiral auxiliary substituent. The diastereomeric mixture can be treated by conventional techniques to provide separated amino-tetrahydrofuran diastereomers. After separating the isomers, the chiral auxiliary substituent can be separated from the respective separated amino-tetrahydrofuran to provide a separated amino-tetrahydrofuran enanthiomer or its salt.
[95] Typical techniques useful for the separation of the stereoisomers are described in Enantiomers, Racemates and Resolutions, J. Jacques, A. Collet, S. Wilen, Krieger Pub. Co., (1991) Malabar, FL. Examples of such separation techniques include crystallization, chromatography, and the like. Advantageously, the chiral amino-tetrahydrofuran prepared by the process is substantially enantiomerically pure and contains at least 90%, preferably at least 95% of the single isomers. More preferably, the chiral amino-tetrahydrofuran produced by the process contains at least 97.5%, most preferably at least 99% of the single isomer.
[96] Specifically, the present invention provides a process for preparing Compound 18:
[97]
[98] In this formula,
[99] R (1) is substituted or unsubstituted alkyl, aryl, cycloalkyl, heterocycloalkyl or heteroaryl as defined above.
[100] Preferably, R (1) is substituted or unsubstituted phenyl, or substituted or unsubstituted C ₁ -C ₆ alkyl. More preferably, R (1) is a substituted phenyl or CF _3. Most preferably R (1) is as follows:
[101]
[102] R (2) is substituted or unsubstituted alkyl, aryl, cycloalkyl, heterocycloalkyl or heteroaryl. Preferably R (2) is substituted or unsubstituted alkyl or aryl. More preferably, R (2) is methyl, phenyl or tolyl. Most preferably, R (2) is methyl. R (3) is substituted or unsubstituted alkyl, aryl, cycloalkyl, heterocycloalkyl or heteroaryl. Preferably, R (3) is substituted or unsubstituted alkyl or aryl. More preferably, R (3) is methyl or phenyl. Most preferably, R (3) is methyl.
[103] A preferred embodiment of the process
[104] (1) treating the following amino-tetrahydrofuran 1 or a salt thereof in a manner effective to convert it to the following tetrahydrofuran-amide 2:
[105]
[106]
[107] (2) treating the tetrahydrofuran-amide 2 in a manner effective to convert it to the following tetrahydrofuranamide-sulfonate 3 (treating the tetrahydrofuran-amide 2 with one or more molar equivalents of a sulfonylating reagent Wherein the molar equivalent of the base used in said treatment is less than the molar equivalent of said sulfonylating reagent: and
[108]
[109] (3) treating the tetrahydrofuranamide-sulfonate 3 in a manner effective to convert it to oxazoline 18
[110] .
[111] Preferably, the tetrahydrofuran-amide 2 is treated first with a substituted or unsubstituted alkyl or arylsulfonyl chloride followed by a method effective to convert the tetrahydrofuran-amide 2 to tetrahydrofuranamide-sulfonate 3 With a base of less than 1 molar equivalent (based on the amount of the sulfonyl chloride) and treating the tetrahydrofuranamide-sulfonate 3 with a phosphatophilic electrophilic reagent in a manner effective to convert the triphosphoramide-sulfonate 3 to the oxazoline 18 can do.
[112] The present invention also provides a process for preparing Compound 19:
[113]
[114] In this formula,
[115] R (4) is a substituted or unsubstituted alkyl, aryl, cycloalkyl, heterocycloalkyl or heteroaryl group,
[116] R (5) is a substituted or unsubstituted NH-alkyl, NH-aryl, O-alkyl or O-
[117] Wherein each alkyl or aryl moiety may be substituted or unsubstituted by the substituents described above.
[118] Most preferably, R (4) is And R (5) is Nt-butyl.
[119] The method comprises the steps of:
[120] (1) treating the following amino-tetrahydrofuran 1 or a salt thereof in a manner effective to convert it to the following tetrahydrofuran-amide 2:
[121]
[122]
[123] (2) treating the tetrahydrofuran-amide 2 in a manner effective to convert it to the following tetrahydrofuranamide-sulfonate 3 (treating the tetrahydrofuran-amide 2 with one or more molar equivalents of a sulfonylating reagent Wherein the molar equivalent of the base used in said treatment is less than the molar equivalent of said sulfonylating reagent:
[124]
[125] (3) treating the tetrahydrofuranamide-sulfonate 3 in a manner effective to convert it to oxazoline 18:
[126]
[127] (4) treating the oxazoline 18 in a manner effective to convert to the following compound 20: and
[128]
[129] (5) treating said compound 20 in a manner effective to convert it to compound 19.
[130] Preferably, the tetrahydrofuran-amide 2 is treated first with a substituted or unsubstituted alkyl or arylsulfonyl chloride followed by a method effective to convert the tetrahydrofuran-amide 2 to tetrahydrofuranamide-sulfonate 3 With a base of less than 1 molar equivalent (based on the amount of the sulfonyl chloride) and treating the tetrahydrofuranamide-sulfonate 3 with a phosphatophilic electrophilic reagent in a manner effective to convert the triphosphoramide-sulfonate 3 to the oxazoline 18 You can; The oxazoline 18 is converted to 3S, 4aR, 8aR-3-Nt-butylcarboxamides in a manner effective to convert Compound 20 to Compound 19 according to the process disclosed in PCT / JP96 / 02756 (WO97 / Amidodecahydroisoquinoline. ≪ / RTI >
[131] Another method of the present invention comprises a process for preparing Compound 20,
[132]
[133] (1) treating the following amino-tetrahydrofuran 1 or a salt thereof in a manner effective to convert it to the following tetrahydrofuran-amide 2:
[134]
[135]
[136] (2) treating the tetrahydrofuran-amide 2 in a manner effective to convert it to the following oxazoline triester 4:
[137]
[138] (3) treating the oxazoline triester 4 in a manner effective to convert the oxazoline triols 5 into the following oxazoline triols 5:
[139]
[140] (4) treating the oxazoline triol 5 in a manner effective to convert to the following compounds 6 or 7:
[141]
[142] (5) treating the compound 7 in a manner effective to convert it to the following compound 8:
[143]
[144] (6) treating the compound 8 in a manner effective to convert it to compound 20
[145] , Wherein R (7) is any suitable protecting group for the hydroxyl moiety. Methods for protecting and deprotecting hydroxyl substituents using suitable hydroxyl protecting groups and suitable protecting groups such as those described above are well known to those skilled in the art; An example thereof is shown in the above-mentioned T. Green & P. Wuts. Preferably, R (7) is trialkylsilyl, dialkyl-monoarylsilyl, diaryl-monoalkylsilyl, substituted or unsubstituted aroyl or alkanoyl. Preferably, R (7) is trimethylsilyl, tert-butyldimethylsilyl, benzoyl, para-nitrobenzoyl, triisopropylsilyl, and the like. Most preferably, R (7) is para-nitrobenzoyl (PNB) residue.
[146] Preferably, the tetrahydrofuran-amide 2 can be treated with a phosphatizing electrophilic reagent in a manner effective to convert it to the oxazoline triester 4. The oxazoline triester 4 can be hydrolyzed with oxazoline triol 5. The phenol hydroxyl moiety of the oxazoline triol 5 can be protected with a suitable hydroxyl protecting group in a manner effective to convert the oxazoline triol 5 to the protected oxazoline 6. On the one hand, both the phenol and the primary hydroxyl moiety of the oxazoline triol 5 can be protected with a suitable hydroxyl protecting group in a manner effective to convert the oxazoline triol 5 to the double protected oxazoline 7. Can be treated with a substituted or unsubstituted alkyl or arylsulfonylation reagent in a manner effective to convert the double protected oxazoline 7 into a sulfonated and double protected oxazoline 8. Can be treated with 3S, 4aR, 8aR-3-N-t-butylcarboxamidodecahydroisoquinoline in a manner effective to convert the sulfonated and -substituted protected oxazoline 8 into Compound 20. [
[147] Yet another method according to the present invention comprises a process for preparing Compound 19:
[148]
[149] The method
[150] (1) Conversion of the following amino-tetrahydrofuran 1 or its salt to the following tetrahydrofuran-amide 2:
[151]
[152]
[153] (2) Conversion of the tetrahydrofuran-amide 2 to the following oxazoline triester 4:
[154]
[155] (3) converting the oxazoline triester 4 to the oxazoline triol 5:
[156]
[157] (4) converting said oxazoline 5 into the following double protected oxazoline 7:
[158]
[159] , Wherein the double protected oxazoline 7 can be converted to nelfinavir via compound 19 using the method disclosed in PCT / JP96 / 02757.
[160] For example, the double protected oxazoline 7 can be converted to compound 19 by a method comprising the steps of:
[161] (1) conversion of the double protected oxazoline 7 into the following sulfonated and double protected oxazoline 8:
[162]
[163] (2) converting said sulfonated and -substituted protected oxazoline 8 into the following compound 20: and
[164]
[165] (3) Conversion of compound 20 to compound 19.
[166] Preferably, the tetrahydrofuran-amide 2 can be treated with a phosphatizing electrophilic reagent in a manner effective to convert it to the oxazoline triester 4. The oxazoline triester 4 can be hydrolyzed with oxazoline triol 5. The phenol and primary hydroxyl moiety of the oxazoline triol 5 can be protected with a suitable hydroxyl protecting group in a manner effective to convert the oxazoline triol 5 to the double protected oxazoline 7. Can be treated with a substituted or unsubstituted alkyl or arylsulfonylating reagent in a manner effective to convert the double protected oxazoline 7 to the sulfonated and double protected oxazoline 8. Can be treated with 3S, 4aR, 8aR-3-N-t-butylcarboxamidodecahydroisoquinoline in a manner effective to convert the sulfonated and -substituted protected oxazoline 8 into Compound 20. [
[167] Yet another method according to the present invention relates to a process for the preparation of the following compound 19:
[168]
[169] The method comprises the steps of:
[170] (1) converting amino-tetrahydrofuran 1 or its salt to tetrahydrofuran-amide 2,
[171] (2) Conversion of the tetrahydrofuran-amide 2 to the following condensed tetrahydrofuranyl oxazoline 9:
[172]
[173] (3) Conversion of the condensed tetrahydrofuranyloxazoline 9 to the following tetrahydrofuran-amide 10:
[174]
[175] (4) Conversion of the tetrahydrofuran-amide 10 to the following oxazoline triester 11:
[176]
[177] (5) Conversion of the oxazoline triester 11 to the following oxazoline triols 12:
[178]
[179] (6) converting the oxazoline triol 12 into the following functionalized oxazoline 13:
[180]
[181] Wherein R (8) together with the attached oxygen form a suitable leaving group, and R (9) is H or R (8)
[182] (7) converting the functionalized oxazoline 13 into the following compound 20:
[183]
[184] (8) Conversion of the compound 20 to the following compound 19:
[185]
[186] Preferably, it can be treated with a substituted or unsubstituted alkyl or arylsulfonylating reagent in a manner effective to convert the tetrahydrofuran-amide 2 to the condensed tetrahydrofuranyl oxazoline 9. The condensed tetrahydrofuranyl oxazoline 9 can be hydrolyzed with tetrahydrofuran-amide 10. Amide 10 can be treated with a phosphatizing electrophilic reagent in a manner effective to convert the tetrahydrofuran-amide 10 to an oxazoline triester 11. The oxazoline triester 11 can be hydrolyzed with oxazoline triol 12. Can be functionalized by treatment with a substituted or unsubstituted alkyl or arylsulfonylating reagent in a manner effective to convert the oxazoline triol 12 to the functionalized sulfonated oxazoline 13. Can be treated with 3S, 4aR, 8aR-3-N-t-butylcarboxamidodecahydroisoquinoline in a manner effective to convert the oxazoline 13 to Compound 20. [
[187] Another method of the invention includes a process for preparing Compound 20:
[188]
[189] The method
[190] (1) treating in a manner effective to convert the following amino-tetrahydrofuran 1 or its salt to the following tetrahydrofuran-hydroxy-amide 10:
[191]
[192]
[193] (2) treating the tetrahydrofuran-hydroxy-amide 10 in a manner effective to protect the hydroxyl moiety of the tetrahydrofuran-amide 10 to form the protected tetrahydrofuran-amide 21:
[194]
[195] (3) treating the protected tetrahydrofuran-amide 21 in a manner effective to convert it to the following protected oxazoline 22:
[196]
[197] (4) treating the protected oxazoline 22 in a manner effective to convert it to compound 20
[198] , Wherein R (10) is any suitable protecting group for a hydroxyl moiety and R (11) is H or substituted alkylsulfonyl.
[199] Methods for protecting and deprotecting hydroxyl substituents using suitable R (10) hydroxyl protecting groups and suitable protecting groups such as those described above are well known to those skilled in the art; An example thereof is shown in the above-mentioned T. Green & P. Wuts.
[200] Preferably, the hydroxyl moiety of the tetrahydrofuran-amide 10 can be protected with a suitable hydroxyl protecting group in a manner effective to convert the tetrahydrofuran-amide 10 to the protected tetrahydrofuran-amide 21, Where R (10) is any suitable protecting group. The protected tetrahydrofuran-amide 21 can be treated with a phospho-electrophilic reagent in a manner effective to convert the protected tetrahydrofuran-amide 21 to the protected oxazoline 22. Preferably, the tetrahydrofuranamide 21 is treated with a phosphoric acid-based Lewis acid, a phosphoric acid protic magnetic acid or triflic anhydride.
[201] Another method of the invention relates to a process for the preparation of chiral amino-tetrahydrofuran 1 or its salts in substantially diastereomerically pure form.
[202] The method comprises the steps of:
[203] (1) Conversion of the following condensed epoxy-tetrahydrofuran 14 to the stereoisomeric mixture of amino-tetrahydrofuran:
[204]
[205] (2) treating the stereoisomeric mixture of amino-tetrahydrofuran in a manner effective to separate the amino-tetrahydrofuran stereoisomers, and
[206] (3) isolating the separated stereoisomers 1 and 1 'of the following amino-tetrahydrofuran, or a salt thereof:
[207]
[208] The epoxy-tetrahydrofuran 14 can be treated with an aminating reagent to produce a stereoisomeric mixture of amino-tetrahydrofuran 1 and 1 '.
[209] As disclosed in the present invention, the compounds of the present invention can be used as salts. The salts may be pharmaceutically acceptable salts. The term " pharmaceutically acceptable salts " refers to those salts which retain the biological effectiveness and properties of the free acids and bases and / or which are biologically or otherwise preferred.
[210] Examples of pharmaceutically acceptable salts include, but are not limited to, sulfates, pyrosulfates, bisulfates, sulfites, bisulfites, phosphates, monohydrogenphosphates, dihydrogenphosphates, metaphosphates, pyrophosphates, chlorides, bromides, iodides, But are not limited to, acetate, propionate, decanoate, caprylate, acrylate, formate, isobutyrate, caproate, heptanoate, propiolate, oxalate, malonate, succinate, But are not limited to, maleic anhydride, maleic anhydride, maleic anhydride, maleic anhydride, maleic anhydride, maleic anhydride, maleic anhydride, maleic anhydride, maleic anhydride, maleic anhydride, Benzoate, phthalate, sulfonate, phenyl sulfonate, toluene sulfonate, methanesulfonate, propane sulfoxide Sites, a naphthalene-1-sulfonate, naphthalene-2-sulphonate, phenyl acetate, phenyl propionate, phenyl butyrate, citrate, lactate, hydroxybutyrate, glycollate, tartrate and mandelate rate. Although any pharmaceutically acceptable salts of the above disclosed compounds may be prepared, the preferred salts are p-toluenesulfonate salts.
[211] When the compound of the present invention is a base, the desired salt may be prepared by any suitable method known in the art, for example by treating the free base with an acid. Such treatment provides a salt as a quantized base with a counterion, wherein the counterion is, for example but not limited to, an inorganic ion such as a halogen, a pseudohalogen, a sulfate, a hydrogen sulphate, a nitrate, Side, phosphate, hydrogen phosphate, dihydrogen phosphate, perchlorate and related complex inorganic anions, and organic ions such as carboxylates, sulfonates, bicarbonates and carbonates. Typical acids useful in the process of the invention include inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid and the like, and organic acids such as acetic acid, maleic acid, succinic acid, mandelic acid, fumaric acid, malonic acid, Such as pyruvic acid, oxalic acid, glycolic acid, salicylic acid, piranodic acid, such as glucuronic acid and galacturonic acid, alpha-hydroxy acids such as citric acid and tartaric acid, amino acids such as aspartic acid and glutamic acid, , Such as benzoic acid and cinnamic acid, sulfonic acids, such as p-toluenesulfonic acid, phenylsulfonic acid or methanesulfonic acid.
[212] When the compound of the present invention is an acid, the desired salt may be converted into the free acid by any suitable method known in the art, for example by reacting the free acid with an inorganic or organic base such as an amine (primary, secondary or tertiary) , Or an alkali metal or alkaline earth metal hydroxide or the like. Illustrative examples of suitable salts include, but are not limited to, amino acids such as glycine and arginine, ammonia, primary, secondary and tertiary amines, cyclic amines such as organic salts derived from piperidine, morpholine and piperazine, , Inorganic salts derived from calcium, potassium, magnesium, manganese, iron, copper, zinc, aluminum and lithium.
[213] The present invention also provides a novel and useful process for the preparation of intermediates particularly useful for the preparation of nelfinavir mesylate and nelfinavir free base. Particularly useful intermediates are compounds 19 'and 20'. As illustrated below, these compounds may be prepared from chiral tetrahydrofuran compounds 1 'or 2'.
[214] Compound 18 'can be prepared by the reaction sequence illustrated in Scheme I below. In this embodiment of the process of the present invention, the chiral amino-tetrahydrofuran 1 'is reacted with 3-acetoxy-2-methylbenzoyl (2-methoxybenzyl) Chloride (AMBC). The resulting amide, tetrahydrofuran-amide 2 ', is treated with methanesulfonyl chloride in the presence of a base, such as triethylamine, under conditions effective to derivatize the secondary alcohol of the amide 2' to give mesylate tetra Hydrofluoro-amide-hydrofluoride-sulfonate 3 '(need not be isolated). For example, the reaction can be carried out by first treating tetrahydrofuran 2 'with at least one molar equivalent of methanesulfonyl chloride followed by addition of less than 1 molar equivalent of triethylamine (based on the amount of methanesulfonyl chloride) . Tetrahydrofuranamide-sulfonate 3 'can then be treated with anhydrides such as acetic anhydride and strong acid, such as sulfuric acid, under conditions effective for the preparation of compound 18'. For example, compound 18 'can be prepared by treating tetrahydrofuranamide-sulfonate 3' with 15 molar equivalents of acetic anhydride and 7.5 molar equivalents of a strong acid such as sulfuric acid. Other strong acids useful in the treatment step include trifluoromethanesulfonic acid, nitric acid, phosphoric acid, and the like.
[215]
[216] The determination of the reaction conditions (solvent, reaction time, temperature, etc.) effective for the preparation of all the compounds disclosed herein are within the ordinary skill in the art through routine experimentation. For example, the reaction described above for the conversion of amino-tetrahydrofuran 1 ' using water-sensitive acid chloride AMBC and sulfonyl chloride, mesyl chloride to compound 19 'is preferably carried out in an aprotic solvent Non-alcoholic solvent). Preferably, the aprotic solvent is an aprotic solvent such as, for example, ethyl acetate, isopropyl acetate, toluene, benzene, and the like.
[217] The preparation of compound 20 ' as illustrated in the reaction sequence of Scheme II below may also be prepared from amino-tetrahydrofuran 1 ' or a pharmaceutically acceptable salt thereof. As in the above described reaction sequence, the first step of the procedure involves the formation of the amide intermediate tetrahydrofuran-amide 2 '. The amide intermediate can be treated directly with an anhydride, such as acetic anhydride and a strong acid, such as sulfuric acid, to produce the oxazoline triester 4 '. The oxazoline triols 5 'can be prepared by treating each of the acetoxy moieties of the oxazoline triester 4' with a suitable base in a suitable solvent (hydrolyzed to the corresponding hydroxyl moiety). Suitable bases for performing the hydrolysis are known in the art and include potassium carbonate, sodium hydroxide, potassium hydroxide, and the like. Suitable solvents for carrying out the hydrolysis are likewise known in the art and include lower alkanols (methanol, ethanol, isopropanol, etc.).
[218] Advantageously, the phenol, primary and secondary hydroxyl moieties of the oxazoline triols 5 'can be selectively protected as illustrated below. For example, the phenol hydroxyl moiety can be protected as p-nitrobenzoate compound 6 'using p-nitrobenzoyl chloride. The primary hydroxyl moiety of said compound 6 ' can then be selectively protected using the same or different protecting groups. On the other hand, both the phenol and the primary hydroxyl moiety of the oxazoline triol 5 'can be protected using p-nitrobenzoyl chloride to produce di-p-nitrobenzoate compound 7'. The process may be carried out in a single step using two equivalents of p-nitrobenzoyl chloride, or in a stepwise process as described above.
[219]
[220] As illustrated in Scheme III, compound 7 'is treated with methanesulfonyl chloride (although other substituted or unsubstituted alkyl or arylsulfonyl chlorides may be used) in the presence of a base, such as triethylamine, 8 ', which can be converted to compound 20' by the addition of 3S, 4aR, 8aR-3-Nt-butylcarboxamidodecahydroisoquinoline (PHIQ) in the presence of potassium carbonate and methanol. Additional treatment with thiophenol provides nelfinavir. Treatment of compound 7 'with a sulfonyl chloride and base can be carried out using conventional conditions.
[221]
[222] Another reaction sequence for the preparation of compound 19 'starting from the formation of tetrahydrofuran-amide 2' from amino-tetrahydrofuran 1 'is the condensation of the condensed tetrahydrofuranyl oxazoline 9 The formation of the tetrahydrofuran-amide 2 ' is carried out in the presence of a base such as methanesulfonyl chloride (although other substituted or unsubstituted alkyl or arylsulfonyl chlorides may be used), for example triethylamine ≪ / RTI > to provide the novel condensed tetrahydrofuranyl oxazoline 9 '. Treatment of the oxazoline with an acid provides the tetrahydrofuran-amide 10 ', wherein the stereochemistry of the 4-hydroxyl moiety is contrary to the stereochemistry of the starting tetrahydrofuran 2'. Treatment of the tetrahydrofuran-amide 10 'with acetic anhydride in the presence of a strong acid such as sulfuric acid or nitric acid provides triacetate 11'. The triacetate is hydrolyzed to provide the triol 12 '.
[223]
[224] As illustrated in Scheme V, treatment of the triol 12 'with p-toluenesulfonyl chloride or another substituted or unsubstituted alkyl or arylsulfonyl chloride in the presence of a base, such as triethylamine, Lt; / RTI > compound 13 '. The tosylate is treated with 3S, 4aR, 8aR-3-Nt-butylcarboxamidodecahydroisoquinoline (PHIQ) as a nucleophile in the presence of a base under conventional conditions to provide compound 19 '. Conversion of compound 19 'to nelfinavir can be carried out by treatment with, for example, thiophenol under conventional conditions.
[225]
[226] Another embodiment of the present invention illustrated in Scheme VI provides for the preparation of aminoalcohols from condensed epoxy-tetrahydrofuran 14. 1 is treated with (S) - alpha -methylbenzylamine or another chiral amine (containing greater than 97.5% of a single enantiomer) to afford the mixture of diastereomeric compounds 15 'and 16' . The reaction can be carried out using a suitable solvent, for example a mixture of isopropylamine and water. The diastereomers are selectively crystallized to provide compound 15 '. Deprotection of the benzyl moiety of the above compound 15 'can be carried out using conventional procedures, for example hydrolysis (hydrogen in the presence of 5% palladium on carbon). The amino-alcohol 1 is hygroscopic and is preferably isolated as a salt, e. G. P-toluenesulfonic acid salt 17.
[227]
[228] On the one hand, chiral amino-tetrahydrofuran 1 can be prepared from condensed epoxy-tetrahydrofuran 14 using aqueous ammonia, a non-chiral reagent, to provide a mixture of racemic 1 and 1 ', which is illustrated in Scheme VII Can be separated using conventional separation techniques as described. For example, the racemic amino-compound can be treated with a chiral acid to produce a mixture of diastereomeric salts, which can then be separated by crystallization or chromatography. Neutralization and Post-Extraction Treatment Rhodia provides sterically pure amino-tetrahydrofuran 1, and chiral acid is recovered.
[229]
[230] Chiral acids which can be used for the separation of racemic amino-tetrahydrofuran 1 include L-tartaric acid, (1R) - (-) - 10- camphorsulfonic acid, L- ) -Di-O, O'-benzoyl-L-tartaric acid, (-) - mono- (1R) -methyl phthalate, S (+) mandelic acid, L- L-tartaric acid mono (dimethylamido), (-) - 2,3: 4,6-di-O-isopropylidene-2-keto- (-) - quinic acid.
[231] It is to be understood that the compounds disclosed herein may exist in different forms, for example, stable and metastable crystalline forms and isotropic and non-crystalline forms, all of which are included within the scope of the present invention.
[232] As used herein, the term " PHIQ " refers to the 3S, 4aR, 8aR-3-Nt-butylcarboxamidodecahydroisoquinoline reagent and "AMBC" refers to 3-acetoxy-2-methylbenzoyl chloride MTBE " refers to a methyl t-butyl ether solvent, " MIBK " refers to a methyl isobutyl ketone solvent, and " PNB " refers to a p-nitrobenzoyl moiety.
[233] Example 1
[234] (3R, 4S) 4-amino-tetrahydrofuran-3-ol toluene 4-sulfonic acid salt 17
[235] (S) - - methylbenzylamine (304 g, 2.51 mol) and 3,4-epoxytetrahydrofuran 14 (200 g, 2.32 mol) were dissolved in 2-propanol (1 L) and water (1 L) . The solution was heated to reflux with stirring for 18 hours. 2-Propanol (about 1 L) was removed under reduced pressure and water (1 L) was added. The resulting slurry was stirred at room temperature for 16 hours and filtered. The white solid was washed with water (500 mL) and then constantly dried in a vacuum oven at room temperature to give crude compound 15 '(170.1 g). The crude material was recrystallized by dissolving in 2-propanol (354 mL) and heptane (1 L) at 60 < 0 > C. The solution was sifted with pure compound 15 'at 55 < 0 > C and cooled to room temperature over 18 hours. The solid was filtered, washed with heptane (200 mL) and dried in a vacuum oven at room temperature overnight to give pure compound 15 '(123.2 g, 26%).
[236] A 2 L Parr flask was charged with the pure compound 15 '(120.7 g), 2-propanol (840 mL) and 5% palladium on carbon (12 g). The flask was shaken at 26 psi hydrogen gas for 44 hours. An additional 5% palladium on carbon (6 g) was added and the mixture was shaken in 26 psi of hydrogen gas for 20 hours. The mixture was filtered through celite and washed with 2-propanol (200 mL). Filtration and washing through celite were repeated. Para-Toluenesulfonic acid (110.8 g) was added to the solution and the solution was concentrated to 1 L under reduced pressure. The resulting solid was filtered, washed with MTBE (250 mL) and dried in a vacuum oven at 40 < 0 > C to give pure compound 17 (138 g, 86%) .
[237] Example 2
[238] Synthesis of acetic acid 3- (4R-hydroxy-tetrahydrofuran-3S-ylcarbamoyl) -2-methyl-phenyl ester 2 '
[239] Amine salt 17 (25.0 g, 90.9 mmol) and AMBC (3-acetoxy-2-methylbenzoyl chloride, 20.4 g, 95.9 mmol) were slurried in ethyl acetate (188 mL) at room temperature. Triethylamine (25.9 mL, 186.1 mmol) was added at a rate sufficient to maintain the temperature below 25 [deg.] C while cooling with water bath. The slurry was stirred at room temperature for 1 hour and 45 minutes to give 90.8 mmol of a suspension of tetrahydrofuran-amide 2 '.
[240] Example 3
[241] (2R) -1-Acetoxy-2 - ((4S) -2- (3-acetoxy-2-methylphenyl) -4,5-dihydrooxazol-4-yl) -2- methanesulfonyloxyethane Synthesis of 18 '
[242] The reaction product mixture of Example 2 (containing 90.8 mmol of tetrahydrofuran-amide 2 ') was cooled in an ice / acetone bath and methanesulfonyl chloride (17.6 mL, 227 mmol) was added in one portion. Triethylamine (19 mL, 136.2 mmol) was added dropwise at a rate sufficient to maintain the internal temperature below 10 < 0 > C. Acetic anhydride (129 mL, 1362 mmol) was added in one portion and the cooling bath was removed. Sulfuric acid (98%, 38 mL, 681 mmol) was added in three portions at 15 minute intervals. The mixture was stirred at room temperature for 17 hours. A suspension of sodium bicarbonate (305 g, 3632 mmol, 40 eq.) In 1 L of water was prepared. To this was added ethyl acetate (250 mL). The reaction mixture from above was added dropwise to the sodium bicarbonate slurry over 2 hours. The layers were separated and the aqueous layer was washed with ethyl acetate (200 mL). The combined organic layers were washed with saturated sodium bicarbonate (200 mL) and brine (200 mL). The organic layer was dried (MgSO ₄ ), filtered and evaporated to give 90.8 mmol of 18 'oil.
[243] Example 4
[244] (3S, 4aS, 8aS) -2 - {(2R) -2 - [(4R) -2- (3-hydroxy-2-methylphenyl) -4,5-dihydrooxazol- -Hydroxyethyl} decahydroisoquinoline-3-carboxylic acid tert-butylamide 20 '
[245] (2R) -1-acetoxy-2 - ((4S) -2- (3-acetoxy- 2- methylphenyl) -4,5-dihydrooxazol- -Methanesulfonyloxyethane 18 '(1.98 kg, 3.30 moles) was suspended in a mixed solvent of methanol (6.50 L) and water (6.50 L) to give (3S, 4aS, 8aS) -decahydroisoquinoline-3-carboxylic acid t -Butylamide (642 g, 2.62 mol) and potassium carbonate (1.36 kg, 9.81 mol) were successively added thereto, followed by stirring at 50 DEG C for 5.5 hours. Water (6.50 L) was added and the reaction mixture was cooled to room temperature and the resulting crystals were collected by filtration. The crude crystals were suspended again in water (6.50 L), stirred, washed and collected by filtration. The obtained crystals were resuspended in methyl isobutyl ketone (10.0 L) and the suspension was azeotropically dehydrated. The resulting slurry was cooled to room temperature and the crystals were collected by filtration to give 902 g (1.07 mol) of the title compound as colorless crystals.
[246] Other bases suitable for use in the reaction include sodium carbonate, sodium hydroxide, potassium hydroxide, and the like. The reaction is carried out in a suitable solvent or a suitable solvent mixture, for example, but not limited to, an alcohol solvent (e.g., methanol, ethanol, propanol, isopropanol, etc.), water, ethyl acetate, isopropyl acetate, etc. at a temperature of -78 to 100 & You may. Preferably, the reaction is carried out as described above.
[247] Example 5
[248] (3S, 4aS, 8aS) -2-hydroxy-3- (3-hydroxy-2-methylbenzoyl-amino) -4-phenylthiobutyl] decahydroisoquinoline-3-carboxylic acid tert- synthesis
[249] (3S, 4aS, 8aS) -2 - {(2R) -2 - [(4R) -2- (3-hydroxy-2-methylphenyl) -4,5-dihydrooxa (701 g, 1.53 mol) was suspended in methyl isobutyl ketone (7.00 L), and thiophenol (314 mL) was added dropwise to a solution of 2- , 3.06 mol) and potassium hydrogencarbonate (76.6 g, 0.765 mol). The mixture was heated to reflux under a nitrogen atmosphere for 12 hours. After the reaction was complete, toluene (7.00 L) was added and the precipitated crystals were collected by filtration and washed with toluene. These crude crystals were washed with heating in a mixed solvent of acetone and water (1: 1) to give 695 g (1.22 mol, 80% yield) of the title compound as colorless crystals.
[250] Although the present invention has been disclosed in its various preferred embodiments using specific embodiments, it will be understood by those skilled in the art that various changes and modifications may be made therein without departing from the spirit and scope of the invention, As will be appreciated by those skilled in the art.

权利要求:
Claims (41)
[1" claim-type="Currently amended] A process for preparing an oxazoline from tetrahydrofuran comprising treating the tetrahydrofuran with a phosphoric acid electrophilic reagent in a manner effective to provide the following oxazoline:


In the above equations,
R _a is -COR (1)
R _b is hydrogen, -COR (3), -SO ₂ R (2) or a suitable hydroxyl protecting group,
R _c is hydrogen, -COR (3) or -SO ₂ R (2)
R (1), R (2) and R (3) independently represent a substituted or unsubstituted alkyl, aryl, cycloalkyl, heterocycloalkyl or heteroaryl group.
[2" claim-type="Currently amended] 2. The method of claim 1, comprising treating the tetrahydrofuran with from about 1 to about 20 molar equivalents of a phospho-electrophilic reagent.
[3" claim-type="Currently amended] The method of claim 1, wherein the protonophilic electrophilic reagent comprises from about 1 to about 20 molar equivalents of a suitable acid and from about 1 to about 20 molar equivalents of a suitable acid anhydride, wherein the anhydride and the acid are each at about 1 : 5 to about 5: 1.
[4" claim-type="Currently amended] The method of claim 1, wherein the cholesteric electrophilic reagent comprises from about 2 to about 20 molar equivalents of a suitable acid and from about 2 to about 20 molar equivalents of a suitable acid anhydride, wherein the anhydride and the acid are each about 1 : 1 to about 5: 1.
[5" claim-type="Currently amended] The method of claim 1, wherein the cholesteric electrophilic reagent comprises about 7.5 molar equivalents of a suitable acid and about 15 molar equivalents of a suitable acid anhydride.
[6" claim-type="Currently amended] The method of claim 1, wherein the tetrahydrofuran is treated with an anhydride under acidic conditions to produce an oxazoline.
[7" claim-type="Currently amended] A process for preparing an oxazoline of the formula:

R (1), R (2) and R (3) independently represent a substituted or unsubstituted alkyl, aryl, cycloalkyl, heterocycloalkyl or heteroaryl group,
(1) treating in a manner effective to convert the amino-tetrahydrofuran of the formula: or a salt thereof to a tetrahydrofuran-amide of the formula:


(2) treating the tetrahydrofuran-amide with a substituted or unsubstituted alkyl or arylsulfonylating reagent to convert the tetrahydrofuran-amide to a tetrahydrofuranamide-sulfonate of the formula (wherein the tetrahydrofuran- -Amide with a sulfonylating reagent of at least one molar equivalent and then treating with a base, wherein the molar equivalent of the base used in said treatment is less than the molar equivalent of said sulfonylating reagent; and

(3) treating the tetrahydrofuranamide-sulfonate with a phospho-electrophilic reagent in a manner effective to convert it to an oxazoline.
[8" claim-type="Currently amended] A process for preparing an oxazoline diol of the formula:

Wherein R (1) and R (3) independently represent substituted or unsubstituted alkyl, aryl, cycloalkyl, heterocycloalkyl or heteroaryl;
(1) treating in a manner effective to convert the amino-tetrahydrofuran of the formula: or a salt thereof to a tetrahydrofuran-amide of the formula:


(2) treating the tetrahydrofuran-amide with a phospho-electrophilic reagent in a manner effective to convert the tetrahydrofuran-amide to an oxazoline diester of the formula: and

(3) hydrolyzing the oxazoline diester with an oxazoline diol.
[9" claim-type="Currently amended] A process for preparing an oxazoline diol of the formula:

Wherein R (1) and R (3) independently represent substituted or unsubstituted alkyl, aryl, cycloalkyl, heterocycloalkyl or heteroaryl;
(1) treating in a manner effective to convert the amino-tetrahydrofuran of the formula: or a salt thereof to a tetrahydrofuran-amide of the formula:


(2) treating the tetrahydrofuran-amide with a substituted or unsubstituted alkyl or aryl sulfonylating reagent in a manner effective to convert the tetrahydrofuran-amide to a condensed tetrahydrofuranyl oxazoline of the formula:

(3) hydrolyzing the condensed tetrahydrofuranyl oxazoline with a tetrahydrofuran-amide of the formula:

(4) treating the tetrahydrofuran-amide with a phosphoric acid electrophilic reagent in a manner effective to convert the tetrahydrofuran-amide to an oxazoline diester of the formula:

(5) hydrolyzing the oxazoline diester with an oxazoline diol.
[10" claim-type="Currently amended] A process for preparing an oxazoline of the formula:

Wherein R (1) is a substituted or unsubstituted alkyl, aryl, cycloalkyl, heterocycloalkyl or heteroaryl, R (10) is a suitable hydroxyl protecting group, R (11) Lt; / RTI >
(1) treating in a manner effective to convert amino-tetrahydrofuran of the formula: or a salt thereof to a tetrahydrofuran-hydroxy-amide of the formula:


(2) treating the tetrahydrofuran-hydroxy-amide in a manner effective to protect the hydroxyl moiety of the hydroxy-amide to form a protected tetrahydrofuran-amide of the formula:

(3) treating the protected tetrahydrofuran-amide with a phosphoric acidophilic electrophilic reagent in a manner effective to convert the protected tetrahydrofuran-amide to a protected oxazoline, wherein the phosphoric acidophilic electrophilic reagent is selected from the group consisting of a phosphorylated Lewis acid, Protic acid and triflic acid anhydride).
[11" claim-type="Currently amended] A method of making nelfinavir comprising the steps of:
(1) treating in a manner effective to convert the amino-tetrahydrofuran of the formula: or a salt thereof to a tetrahydrofuran-amide of the formula:


(2) treating the tetrahydrofuran-amide to convert it to a tetrahydrofuranamide-sulfonate of the formula: treating the tetrahydrofuran-amide with one or more molar equivalents of a sulfonylating reagent followed by treatment with a base Wherein the molar equivalent of the base used in said treatment is less than the molar equivalent of said sulfonylating reagent:

(3) treating the tetrahydrofuran-amide sulfonate with a phosphatophilic electrophilic reagent in a manner effective to convert the tetrahydrofuran-amide sulfonate to an oxazoline of the formula:

(4) treating the oxazoline in a manner effective to convert it to a compound of the formula:

(5) Converting the compound to nelfinavir:
Wherein R (2) and R (3) are independently selected from substituted or unsubstituted alkyl, aryl, cycloalkyl, heterocycloalkyl and heteroaryl and R (5) is a substituted or unsubstituted NH- Alkyl, NH-aryl, O-alkyl or O-aryl group, wherein each alkyl or aryl moiety may be unsubstituted or substituted.
[12" claim-type="Currently amended] A method for producing nelfinavir comprising the steps of:
(1) treating in a manner effective to convert the amino-tetrahydrofuran of the formula: or a salt thereof to a tetrahydrofuran-amide of the formula:


(2) treating the tetrahydrofuran-amide with a phospho-electrophilic reagent in a manner effective to convert the tetrahydrofuran-amide to an oxazoline triester of the formula:

(3) hydrolyzing the oxazoline triester with an oxazoline triol of the formula:

(4) protecting the oxazoline triols with a suitable hydroxyl protecting group in a manner effective to convert the oxazoline triols to the double-protected oxazolines of the formula:

(5) treating said double-protected oxazoline with a substituted or unsubstituted alkyl or arylsulfonylating reagent in a manner effective to convert said double-protected oxazoline to a sulfonated and - double protected oxazoline of the formula:

(6) treating the sulfonated and -substituted protected oxazoline with 3S, 4aR, 8aR-3-N-t-butylcarboxamidodecahydroisoquinoline in a manner effective to convert to a compound of the formula:

(7) Converting the compound to nelfinavir:
Wherein R (2) and R (3) are independently selected from substituted or unsubstituted alkyl, aryl, cycloalkyl, heterocycloalkyl and heteroaryl and R (5) is a substituted or unsubstituted NH- Alkyl, NH-aryl, O-alkyl or O-aryl group, wherein each alkyl or aryl moiety may be unsubstituted or substituted, and R (7) is any suitable hydroxyl protecting group.
[13" claim-type="Currently amended] A method for producing nelfinavir comprising the steps of:
(1) treating in a manner effective to convert the amino-tetrahydrofuran of the formula: or a salt thereof to a tetrahydrofuran-amide of the formula:


(2) treating the tetrahydrofuran-amide with a substituted or unsubstituted alkyl or aryl sulfonylating reagent in a manner effective to convert the tetrahydrofuran-amide to a condensed tetrahydrofuranyl oxazoline of the formula:

(3) hydrolyzing the condensed tetrahydrofuranyl oxazoline with a tetrahydrofuran-amide of the formula:

(4) treating the tetrahydrofuran-amide with a phospho-electrophilic reagent in a manner effective to convert the tetrahydrofuran-amide to an oxazoline triester of the formula:

(5) hydrolyzing the oxazoline triester with an oxazoline triol of the formula:

(6) treating the oxazoline triol with a substituted or unsubstituted alkyl or aryl sulfonylating reagent in a manner effective to convert the oxazoline triol to a protected oxazoline of the formula:

(7) treating the protected oxazoline with 3S, 4aR, 8aR-3-N-tert-butylcarboxamidodecahydroisoquinoline in a manner effective to convert the protected oxazoline to a compound of the formula:

(8) Converting the compound to nelfinavir:
R (3) is selected from substituted or unsubstituted alkyl, aryl, cycloalkyl, heterocycloalkyl and heteroaryl; R (5) is selected from the group consisting of substituted or unsubstituted NH- (8) is substituted or unsubstituted alkyl or arylsulfonyl, and R (9) is hydrogen or an optionally substituted alkyl or aryl group, wherein each alkyl or aryl moiety may be unsubstituted or substituted; R (8).
[14" claim-type="Currently amended] A method for producing nelfinavir comprising the steps of:
(1) treating in a manner effective to convert the amino-tetrahydrofuran of the formula: or a salt thereof to a tetrahydrofuran-amide of the formula:


(2) treating the tetrahydrofuran-amide in a manner effective to convert it to a protected tetrahydrofuran-amide of the formula:

(3) contacting the protected tetrahydrofuran-amide with a protecting group selected from the group consisting of a phosphoester Lewis acid, a phosphorophosphorous protic acid and a triphosphoric acid anhydride in a manner effective to convert the protected tetrahydrofuran-amide to a protected oxazoline of the formula Processing step:

(4) treating the protected oxazoline with 3S, 4aR, 8aR-3-N-tert-butylcarboxamidodecahydroisoquinoline in a manner effective to convert the protected oxazoline to a compound of the formula:

(5) Converting the compound to nelfinavir:
Wherein R (1) is substituted or unsubstituted alkyl, aryl, cycloalkyl, heterocycloalkyl or heteroaryl, and R (5) is substituted or unsubstituted NH-alkyl, Or an O-aryl group, wherein each alkyl or aryl moiety may be unsubstituted or substituted, R (10) is a suitable hydroxyl protecting group,
R (11) is H or substituted alkylsulfonyl.
[15" claim-type="Currently amended] Any one of claims 1 to 10 according to any one of items, R (1) is CF _3, substituted or non-substituted phenyl, or C ₁ -C ₆ alkyl the method.
[16" claim-type="Currently amended] 11. Compounds according to any one of claims 1 to 10, wherein R (1) is or / RTI >
[17" claim-type="Currently amended] 14. The method according to any one of claims 7 to 9 and 11 to 13 comprising treating the tetrahydrofuran with from about 1 to about 20 molar equivalents of a phosphatizing electrophilic reagent.
[18" claim-type="Currently amended] 14. A method according to any one of claims 7 to 9 and claims 11 to 13, wherein the cholesteric electrophilic reagent comprises about 1 to about 20 molar equivalents of a suitable acid and about 1 to about 20 molar equivalents of a suitable acid anhydride Wherein the anhydride and the acid are used in a relative molar ratio of about 1: 5 to about 5: 1, respectively.
[19" claim-type="Currently amended] 14. A method as claimed in any one of claims 7 to 9 and claims 11 to 13 wherein the cholesteric electrophilic reagent comprises about 2 to about 20 molar equivalents of a suitable acid and about 2 to about 20 molar equivalents of a suitable acid anhydride Wherein the anhydride and the acid are used in a relative molar ratio of about 1: 1 to about 5: 1, respectively.
[20" claim-type="Currently amended] 14. The method according to any one of claims 7 to 9 and 11 to 13, wherein the cholesteric electrophilic reagent comprises about 7.5 molar equivalents of a suitable acid and about 15 molar equivalents of a suitable acid anhydride.
[21" claim-type="Currently amended] 14. The method according to any one of claims 7 to 9 and 11 to 13 wherein R (3) is methyl or phenyl.
[22" claim-type="Currently amended] 14. The process according to any one of claims 7 to 9 and 11 to 13, wherein the tetrahydrofuran-amide is treated with acetic anhydride and sulfuric acid to produce the oxazoline.
[23" claim-type="Currently amended] 16. The method of claim 15, wherein R (3) is methyl.
[24" claim-type="Currently amended] Process according to any one of claims 7 to 10, wherein the amino-tetrahydrofuran is treated with a compound of the formula R (1) COX to produce a tetrahydrofuran-amide, wherein X is chloro or bromo and R (1) / RTI >
[25" claim-type="Currently amended] 15. The method according to any one of claims 11 to 14, wherein R (5) is HN-t-Bu.
[26" claim-type="Currently amended] 13. The method of claim 12 wherein R (7) is trialkylsilyl, dialkyl-monoarylsilyl, diaryl-monoalkylsilyl, substituted or unsubstituted aroyl or alkanoyl.
[27" claim-type="Currently amended] 13. The method of claim 12 wherein R (7) is trimethylsilyl, tert-butyl-di-methylsilyl, benzoyl or para-nitrobenzoyl.
[28" claim-type="Currently amended] 13. The method of claim 12, wherein R (7) is para-nitrobenzoyl.
[29" claim-type="Currently amended] 14. The method of claim 13, wherein R (8) is substituted or unsubstituted alkyl or arylsulfonyl.
[30" claim-type="Currently amended] 14. The method of claim 13, wherein R (8) is p-toluenesulfonyl.
[31" claim-type="Currently amended] A process for the preparation of chiral amino-tetrahydrofuran of the formula (1)

(1) treating an epoxy-tetrahydrofuran of the following formula with an aminating reagent to prepare a stereostronic mixture of amino-tetrahydrofurans having the following formulas:


(In the above formulas, R (6) is hydrogen or a suitable nitrogen protecting group),
(2) treating said amino-tetrahydrofuran mixture in a manner effective to separate amino-tetrahydrofuran stereoisomers; and
(3) isolating the amino-tetrahydrofuran 1 or its salt.
[32" claim-type="Currently amended] 32. The method of claim 31, wherein amino-tetrahydrofuran 1 is substantially enantiomerically pure.
[33" claim-type="Currently amended] The method of claim 31, wherein R (6) is substituted or unsubstituted alkanoyl, aroyl, arylalkylcarbonyl, arylalkyl, heteroarylalkyl wherein the alkyl, aryl or heteroaryl is substituted or unsubstituted .
[34" claim-type="Currently amended] 32. The method of claim 31, wherein the amination reagent is a chiral amination reagent.
[35" claim-type="Currently amended] 35. The compound of claim 34, wherein R (6) is / RTI >
[36" claim-type="Currently amended] 35. The method of claim 34, comprising separating the amino-tetrahydrofuran stereoisomers by crystallization or chromatography.
[37" claim-type="Currently amended] 37. The method of claim 36, further comprising removing the R (6) substituent from the separated amino-tetrahydrofuran stereoisomers.
[38" claim-type="Currently amended] 32. The method of claim 31, wherein the aminating reagent is a chiral amination reagent.
[39" claim-type="Currently amended] 39. The method of claim 38, further comprising treating the amino-tetrahydrofuran mixture with a chiral auxiliary reagent to produce the diastereomeric amino-tetrahydrofuran.
[40" claim-type="Currently amended] 41. The method of claim 39, comprising separating the amino-tetrahydrofuran diastereomers by crystallization or chromatography.
[41" claim-type="Currently amended] 41. The method of claim 40, further comprising removing the chiral auxiliary reagent from the separated amino-tetrahydrofuran stereoisomers.

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引用文献:

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公开号 | 申请日 | 公开日 | 申请人 | 专利标题

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法律状态:
1999-10-21|Priority to US16069599P

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1999-10-21|Priority to US60/160,695

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2000-10-19|Application filed by 개리 이. 프라이드만, 아구론 파마슈티컬스, 인크.

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2002-06-21|Publication of KR20020047255A

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2007-04-11|Application granted

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2007-04-11|Publication of KR100706938B1

优先权:

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申请号 | 申请日 | 专利标题

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US16069599P| true| 1999-10-21|1999-10-21|

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US60/160,695|1999-10-21|