WO1996004232A1 - Process for the preparation of a substituted 2.5-diamino-3-hydroxyhexane - Google Patents
Process for the preparation of a substituted 2.5-diamino-3-hydroxyhexane Download PDFInfo
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- WO1996004232A1 WO1996004232A1 PCT/US1995/009133 US9509133W WO9604232A1 WO 1996004232 A1 WO1996004232 A1 WO 1996004232A1 US 9509133 W US9509133 W US 9509133W WO 9604232 A1 WO9604232 A1 WO 9604232A1
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- independently selected
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- loweralkyl
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- hydrogen
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- 0 *N(*)[C@@](Cc1ccccc1)C(C=C(Cc1ccccc1)N)=O Chemical compound *N(*)[C@@](Cc1ccccc1)C(C=C(Cc1ccccc1)N)=O 0.000 description 1
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C213/00—Preparation of compounds containing amino and hydroxy, amino and etherified hydroxy or amino and esterified hydroxy groups bound to the same carbon skeleton
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C215/00—Compounds containing amino and hydroxy groups bound to the same carbon skeleton
- C07C215/02—Compounds containing amino and hydroxy groups bound to the same carbon skeleton having hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton
- C07C215/22—Compounds containing amino and hydroxy groups bound to the same carbon skeleton having hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being unsaturated
- C07C215/28—Compounds containing amino and hydroxy groups bound to the same carbon skeleton having hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being unsaturated and containing six-membered aromatic rings
- C07C215/30—Compounds containing amino and hydroxy groups bound to the same carbon skeleton having hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being unsaturated and containing six-membered aromatic rings containing hydroxy groups and carbon atoms of six-membered aromatic rings bound to the same carbon atom of the carbon skeleton
- C07C215/32—Compounds containing amino and hydroxy groups bound to the same carbon skeleton having hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being unsaturated and containing six-membered aromatic rings containing hydroxy groups and carbon atoms of six-membered aromatic rings bound to the same carbon atom of the carbon skeleton containing hydroxy groups and carbon atoms of two six-membered aromatic rings bound to the same carbon atom of the carbon skeleton
Definitions
- the present invention relates to intermediates and processes which are useful for the preparation of a substituted 2,5-diamino-3-hydroxyhexane.
- HIV protease inhibitors comprise a moiety which is a substituted 2,5- diamino-3-hydroxyhexane.
- HIV protease inhibitors of particular interest are compounds of the formula 1:
- A is R 2 NHCH(R 1 )C(O)- and B is R 2a or wherein A is R 2a and B is R 2 NHCH(R 1 )C(O)- wherein R 1 is loweralkyl and R 2 and R 2a are independently selected from -C(O)-R 3 -R 4 wherein at each occurrence R 3 is independently selected from O, S and -N(R 5 )- wherein R 5 is hydrogen or loweralkyl and at each occurrence R 4 is independently selected from heterocyclic or (heterocyclic)alkyl; or a pharmaceutically acceptable salt, prodrug or ester thereof.
- Compounds of formula 1 are disclosed in European Patent Application No. EP0486948, published May 27, 1992.
- a preferred HIV protease inhibitor of formula 1 is a compound of formula 2a:
- Another preferred HIV protease inhibitor of formula 1 is a compound of formula 2b:
- R 6 and R 7 are independently selected from an N-protecting group; or an acid addition salt thereof.
- Preferred N-protecting groups R 6 and R 7 are independently selected from
- R a and R b are independently selected from hydrogen, loweralkyl and phenyl and R c , R d and R e are independently selected from hydrogen, loweralkyl, trifluoromethyl, alkoxy, halo and phenyl; and
- naphthyl ring is unsubstituted or substituted with one, two or three substitutents independently selected from loweralkyl, trifluoromethyl, alkoxy and halo.
- R f , R g , R h and R s are independently selected from hydrogen, loweralkyl, alkoxy, halogen and trifluoromethyl.
- N-protecting groups R 6 and R 7 are those wherein R 6 and R 7 are independently selected from benzyl and substituted benzyl wherein the phenyl ring of the benzyl group is substituted with one, two or three substituents independently selected from loweralkyl, trifluoromethyl, alkoxy, halo and phenyl.
- the most preferred N-protecting groups R 6 and R 7 are those wherein R 6 and R 7 are each benzyl.
- Preferred intermediates of the formula 3 are the compounds wherein R 6 and R 7 are each benzyl or substituted benzyl wherein the phenyl ring of the benzyl group is substituted with one, two or three substituents independently selected from loweralkyl, trifluoromethyl, alkoxy, halo and phenyl. More preferred intermediates of the formula 3 are the compounds wherein R 6 and R 7 are benzyl.
- the present invention relates to a process for the preparation of a substantially pure compound of the formula 3.
- a key intermediate in the process of the present invention is a substantially pure enaminoketone compound of the formula 4:
- R 6 and R 7 independently selected from an N-protecting group; or an acid addition salt thereof.
- Preferred N-protecting groups R 6 and R 7 are independently selected from
- R a and R b are independently selected from hydrogen, loweralkyl and phenyl and R c , R d and R e are independently selected from hydrogen, loweralkyl, trifluoromethyl, alkoxy, halo and phenyl; and
- naphthyl ring is unsubstituted or substituted with one, two or three substitutents independently selected from loweralkyl, trifluoromethyl, alkoxy and halo.
- R 6 and R 7 taken together with the nitrogen atom to which they are bonded are
- R f , R g , R h and R i are independently selected from hydrogen, loweralkyl, alkoxy, halogen and trifluoromethyl.
- Preferred intermediates of the formula 4 are the compounds wherein R 6 and R 7 are each benzyl or substituted benzyl wherein the phenyl ring of the benzyl group is substituted with one, two or three substituents independently selected from loweralkyl, trifluoromethyl, alkoxy, halo and phenyl. More preferred intermediates of the formula 4 are the compounds wherein R 6 and R 7 are benzyl.
- a process for the preparation of 3 from 4 involves catalytic hydrogenation of 3 in a solvent comprising (1 ) a protic solvent, (2) an ethereal solvent or (3) a mixture of a protic solvent and a hydrocarbon solvent in the presence of an acid.
- the process comprises dissolving compound 3 in an
- a preferred solvent for the process is (1 ) a protic solvent such as an alcohol (for example, isopropanol, methanol, ethanol, t-butanol, sec-butanol, n-butanol or propanol and the like), (2) an ethereal solvent such as dimethoxyethane, methyl-t-butyl ether or dioxane and the like or (3) a mixture of a protic solvent and a hydrocarbon solvent (for example, pentane, hexane, heptane or toluene and the like).
- a most preferred solvent is ethanol.
- a preferred acid is an inorganic acid (for example, HCI, HBr, sulfuric acid, phosphoric acid, perchloric acid, chlorosulfonic acid, fluorosulfonic acid,
- acids R 8 -COOH include acetic acid, propionic acid, trifluoroacetic acid, trichloroacetic acid, dichloroacetic acid, difluoroacetic acid, benzoic acid and pentafluorobenzoic acid.
- acids R 9 -SO 3 H include methanesulfonic acid, ethanesulfonic acid, trifluoromethanesulfonic acid, phenylsulfonic acid and p-toluenesulfonic acid.
- acids R 10 -PO 3 H 2 include methylphosphonic acid, ethylphosphonic acid and phenylphosphonic acid.
- a most preferred acid for the process of this invention is methanesulfonic acid or sulfuric acid.
- a preferred amount of the acid is from about 2 molar equivalents to about 4 molar equivalents (based on the enaminoketone).
- a most preferred amount of the acid is from about 3 molar equivalents to about 4 molar equivalents.
- a preferred hydrogenation catalyst is a platinum catalyst (including, platinum black or platinum oxide and the like).
- the catalyst is supported on a support such as carbon, alumina, graphite, sulfided carbon, polyethyleneimine/SiO 2 (Royer, et al., J. Org. Chem. 45 2268 (1980)) or aminopolysiloxane (for example, Deloxan ® AP II , available from Degussa, 65 Challenger Road, Ridgefield Park, NJ 07660) and the like.
- Platinum on carbon can also be doped with Pd, Ru, Re or Rh.
- a most preferred catalyst is 5% platinum on carbon or 5% platinum on aminopolysiloxane.
- the hydrogenation process is preferably carried out at a hydrogen pressure from about 60 psi to about 1000 psi.
- a most preferred hydrogen pressure is from about 250 psi to about 1000 psi.
- loweralkyl refers to straight or branched chain alkyl radicals containing from 1 to 6 carbon atoms including, but not limited to, methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, n-pentyl,
- alkoxy refers to -OR 10 wherein R 10 is a loweralkyl group.
- halo refers to F, Cl, Br or I.
- haloalkyl refers to a loweralkyl group in which one or more hydrogen atoms has been replaced with a halogen including, but not limited to, trifluoromethyl, trichloromethyl, difluoromethyl, dichloromethyl, fluoromethyl, chloromethyl, chloroethyl, 2,2-dichloroethyl and the like.
- halophenyl refers to a phenyl group in which one, two, three, four or five hydrogen atoms have been replaced with a halogen including, but not limited to, chlorophenyl, bromophenyl, fluorophenyl,
- Acid addition salts of the compounds of the invention can be derived from reaction of an amine-containing compound of the invention with an inorganic or organic acid.
- These salts include but are not limited to the following: acetate, adipate, alginate, citrate, aspartate, benzoate, benzenesulfonate, bisulfate, butyrate, camphorate, camphorsulfonate, digluconate, cyclopentanepropionate, dodecylsulfate, ethanesulfonate, glucoheptanoate, glycerophosphate,
- acids which may be employed to form acid addition salts include such inorganic acids as hydrochloric acid, sulphuric acid and phosphoric acid and such organic acids as oxalic acid, maieic acid, succinic acid and citric acid, as well as the other acids mentioned above.
- substantially pure refers to a compound which is contaminated by not more than 10% of any other stereoisomer (enantiomer or diastereomer), preferably by not more than 5% of any other stereoisomer and most preferably by not more than 3% of any other stereoisomer.
- Example 1 A solution containing the product of Example 1 (i.e., benzyl ester) (approx. 0.45 moles) in 520 mL tetrahydrofuran and 420 mL acetonitrile was cooled to -40°C under nitrogen.
- To the sodium amide solution was slowly added 75 mL acetonitrile and the resulting solution was stirred at -40°C for more than 15 minutes.
- the sodium amide/acetonitrile solution was then slowly added to the benzyl ester solution at -40°C.
- the combined solution was stirred at -40°C for one hour and then quenched with 1150 mL of a 25% (w/v) citric acid solution.
- the resulting slurry was warmed to ambient temperature and the organics separated.
- the organics were then washed with 350 mL of a 25% (w/v) sodium chloride solution, then diluted with 900 mL heptane.
- the organics were then washed three times with 900 mL of a 5% (w/v) sodium chloride solution, two times with 900 mL of a 10% methanolic water solution, one time with 900 mL of a 15% methanolic water solution, and then one time with 900 mL of a 20% methanolic water solution.
- Example 2 To this was added a solution of the product of Example 1 (i.e, benzyl ester) (42.0 g, 0.0964 mol, 1.0 equiv) in tetrahydrofuran (10 mL) and acetonitrile (15 mL, 0.289 mol, 3.0 equiv) via pressure-equalized addition funnel over a period of 20 minutes. During the addition, the internal temperature increased to -5°C. The reaction (now orange and transparent) mixture stirred an additional 30 min at -10°C.
- benzyl ester a solution of the product of Example 1 (i.e, benzyl ester) (42.0 g, 0.0964 mol, 1.0 equiv) in tetrahydrofuran (10 mL) and acetonitrile (15 mL, 0.289 mol, 3.0 equiv) via pressure-equalized addition funnel over a period of 20 minutes. During the addition, the internal temperature increased to -5°C. The
- the aqueous phase was separated and the organic phase was washed with 10% aqueous sodium chloride solution (200 mL) and the aqueous phase separated.
- the organic phase was concentrated in vacuo using a 45°C bath.
- n-Butanol 100 mL was then charged and distillation in vacuo was conducted until the contents were reduced by approximately 10% by volume.
- the suspension resulting was allowed to cool to 20°C with mechanical stirring and held at that temperature for 18 hours.
- the solid was filtered and dried in vacuo at 45°C.
- the yield of the first crop was 20.5 g (57%).
- the material was >98% pure by HPLC.
Abstract
A process is disclosed for the preparation of the substantially pure compound of formula (I) comprising catalytic hydrogenation of a compound of formula (II) wherein R6 and R7 are independently selected from (i) wherein Ra and Rb are independently selected from hydrogen, loweralkyl and phenyl and Rc, Rd and Re are independently selected from hydrogen, loweralkyl, trifluoromethyl, alkoxy, halo and phenyl; and (ii) wherein the naphthyl ring is unsubstituted or substituted with one, two or three substituents independently selected from loweralkyl, trifluoromethyl, alkoxy and halo; or R6 and R7 taken together with the nitrogen atom to which they are bonded are (a) or (b) wherein Rf, Rg, Rh and Ri are independently selected from hydrogen, loweralkyl, alkoxy, halogen and trifluoromethyl; or an acid addition salt thereof.
Description
PROCESS FOR THE PREPARATION
OF A SUBSTITUTED 2,5-DIAMINO-3-HYPROXYHEXANE
Technical Field
The present invention relates to intermediates and processes which are useful for the preparation of a substituted 2,5-diamino-3-hydroxyhexane.
Background of the Invention
Compounds which are inhibitors of HIV protease are useful for inhibiting HIV protease in vitro and in vivo and are useful for inhibiting an HIV infection. Certain HIV protease inhibitors comprise a moiety which is a substituted 2,5- diamino-3-hydroxyhexane. HIV protease inhibitors of particular interest are compounds of the formula 1:
wherein A is R2NHCH(R1)C(O)- and B is R2a or wherein A is R2a and B is R2NHCH(R1)C(O)- wherein R1 is loweralkyl and R2 and R2a are independently selected from -C(O)-R3-R4 wherein at each occurrence R3 is independently selected from O, S and -N(R5)- wherein R5 is hydrogen or loweralkyl and at each occurrence R4 is independently selected from heterocyclic or (heterocyclic)alkyl; or a pharmaceutically acceptable salt, prodrug or ester thereof. Compounds of
formula 1 are disclosed in European Patent Application No. EP0486948, published May 27, 1992.
A preferred HIV protease inhibitor of formula 1 is a compound of formula 2a:
or a pharmaceutically acceptable salt, prodrug or ester thereof.
Another preferred HIV protease inhibitor of formula 1 is a compound of formula 2b:
The compound of formula 2b is disclosed in PCT Patent Application No. W094/14436, published July 7, 1994, which is hereby incorporated herein by reference.
An intermediate which is especially useful for preparing compounds of the formula 1 and 2 is a substantially pure compound of the formula 3:
wherein R6 and R7 are independently selected from an N-protecting group; or an acid addition salt thereof. Preferred N-protecting groups R6 and R7 are independently selected from
wherein Ra and Rb are independently selected from hydrogen, loweralkyl and phenyl and Rc, Rd and Re are independently selected from hydrogen, loweralkyl, trifluoromethyl, alkoxy, halo and phenyl; and
Alternatively, R6 and R7 taken together with the nitrogen atom to which they are bonded are
wherein Rf, Rg, Rh and Rs are independently selected from hydrogen, loweralkyl, alkoxy, halogen and trifluoromethyl.
More preferred N-protecting groups R6 and R7 are those wherein R6 and R7 are independently selected from benzyl and substituted benzyl wherein the phenyl ring of the benzyl group is substituted with one, two or three substituents independently selected from loweralkyl, trifluoromethyl, alkoxy, halo and phenyl. The most preferred N-protecting groups R6 and R7 are those wherein R6 and R7 are each benzyl.
Preferred intermediates of the formula 3 are the compounds wherein R6 and R7 are each benzyl or substituted benzyl wherein the phenyl ring of the benzyl group is substituted with one, two or three substituents independently selected from loweralkyl, trifluoromethyl, alkoxy, halo and phenyl. More preferred intermediates of the formula 3 are the compounds wherein R6 and R7 are benzyl.
Disclosure of the Invention
The present invention relates to a process for the preparation of a substantially pure compound of the formula 3. A key intermediate in the process
of the present invention is a substantially pure enaminoketone compound of the formula 4:
wherein R6 and R7 independently selected from an N-protecting group; or an acid addition salt thereof. Preferred N-protecting groups R6 and R7 are independently selected from
wherein Ra and Rb are independently selected from hydrogen, loweralkyl and phenyl and Rc, Rd and Re are independently selected from hydrogen, loweralkyl, trifluoromethyl, alkoxy, halo and phenyl; and
wherein the naphthyl ring is unsubstituted or substituted with one, two or three substitutents independently selected from loweralkyl, trifluoromethyl, alkoxy and halo.
Alternatively, R6 and R7 taken together with the nitrogen atom to which they are bonded are
wherein Rf, Rg, Rh and Ri are independently selected from hydrogen, loweralkyl, alkoxy, halogen and trifluoromethyl.
Preferred intermediates of the formula 4 are the compounds wherein R6 and R7 are each benzyl or substituted benzyl wherein the phenyl ring of the benzyl group is substituted with one, two or three substituents independently selected from loweralkyl, trifluoromethyl, alkoxy, halo and phenyl. More preferred intermediates of the formula 4 are the compounds wherein R6 and R7 are benzyl.
Compound 4 and a process for its preparation are disclosed in U.S. patent application Serial No. 141 ,795, filed October 22, 1993, which is hereby
incorporated herein by reference.
A process for the preparation of 3 from 4 involves catalytic hydrogenation of 3 in a solvent comprising (1 ) a protic solvent, (2) an ethereal solvent or (3) a mixture of a protic solvent and a hydrocarbon solvent in the presence of an acid.
In particular, the process comprises dissolving compound 3 in an
appropriate solvent, adding the acid, then adding the hydrogenation catalyst and, finally, pressurizing the reaction vessel with hydrogen gas.
A preferred solvent for the process is (1 ) a protic solvent such as an alcohol (for example, isopropanol, methanol, ethanol, t-butanol, sec-butanol, n-butanol or propanol and the like), (2) an ethereal solvent such as dimethoxyethane, methyl-t-butyl ether or dioxane and the like or (3) a mixture of a protic solvent and a hydrocarbon solvent (for example, pentane, hexane, heptane or toluene and the like). A most preferred solvent is ethanol.
A preferred acid is an inorganic acid (for example, HCI, HBr, sulfuric acid, phosphoric acid, perchloric acid, chlorosulfonic acid, fluorosulfonic acid,
Me3SiOSO3H and the like) or an organic acid selected from (i) R8-COOH wherein
R8 is loweralkyl, haloalkyl, phenyl or halophenyl, (ii) R9-SO3H wherein R9 is loweralkyl, haloalkyl, phenyl, loweralkyl-substituted phenyl, halophenyl or naphthyl and (iii) R10-PO3H2 wherein R10 is loweralkyl or phenyl; or a
combination of said acids.
Examples of acids R8-COOH include acetic acid, propionic acid, trifluoroacetic acid, trichloroacetic acid, dichloroacetic acid, difluoroacetic acid, benzoic acid and pentafluorobenzoic acid. Examples of acids R9-SO3H include methanesulfonic acid, ethanesulfonic acid, trifluoromethanesulfonic acid, phenylsulfonic acid and p-toluenesulfonic acid. Examples of acids R10-PO3H2 include methylphosphonic acid, ethylphosphonic acid and phenylphosphonic acid.
A most preferred acid for the process of this invention is methanesulfonic acid or sulfuric acid.
A preferred amount of the acid is from about 2 molar equivalents to about 4 molar equivalents (based on the enaminoketone). A most preferred amount of the acid is from about 3 molar equivalents to about 4 molar equivalents.
A preferred hydrogenation catalyst is a platinum catalyst (including, platinum black or platinum oxide and the like). Preferably, the catalyst is supported on a support such as carbon, alumina, graphite, sulfided carbon, polyethyleneimine/SiO2 (Royer, et al., J. Org. Chem. 45 2268 (1980)) or aminopolysiloxane (for example, Deloxan® AP II , available from Degussa, 65 Challenger Road, Ridgefield Park, NJ 07660) and the like. Platinum on carbon can also be doped with Pd, Ru, Re or Rh. A most preferred catalyst is 5% platinum on carbon or 5% platinum on aminopolysiloxane.
The hydrogenation process is preferably carried out at a hydrogen pressure from about 60 psi to about 1000 psi. A most preferred hydrogen pressure is from about 250 psi to about 1000 psi.
The term "loweralkyl" as used herein refers to straight or branched chain alkyl radicals containing from 1 to 6 carbon atoms including, but not limited to, methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, n-pentyl,
1-methylbutyl, 2,2-dimethylbutyl, 2-methylpentyl, 2,2-dimethylpropyl, n-hexyl and the like.
The term "alkoxy" as used herein refers to -OR10 wherein R10 is a loweralkyl group.
The term "halo" as used herein refers to F, Cl, Br or I.
The term "haloalkyl" as used herein refers to a loweralkyl group in which one or more hydrogen atoms has been replaced with a halogen including, but not limited to, trifluoromethyl, trichloromethyl, difluoromethyl, dichloromethyl, fluoromethyl, chloromethyl, chloroethyl, 2,2-dichloroethyl and the like.
The term "halophenyl" as used herein refers to a phenyl group in which one, two, three, four or five hydrogen atoms have been replaced with a halogen including, but not limited to, chlorophenyl, bromophenyl, fluorophenyl,
iodophenyl, 2,3-dichlorophenyl, 2,4-dichlorophenyl, 2,5-dichlorophenyl,
2,6-dichlorophenyl, 3,4-dichlorophenyl, 3,5-dichlorophenyl, 2,3,5-trichlorophenyl, 2,4,6-trichlorophenyl, 2-chloro-4-fluorophenyl, 2-chloro-6-fluorophenyl,
2,4-dichloro-5-fluorophenyl, 2,3-difuorophenyl, 2,4-difuorophenyl,
2,5-difuorophenyl, 2,6-difuorophenyl, 3,4-difuorophenyl, 3,5-difuorophenyl, 2,3,5-trichlorophenyl, 2,4,6-trichlorophenyl, 2,3,4-trifluorophenyl,
2,3,6-trifluorophenyl, 2,4,5-trifluorophenyl, 2,4,6-trifluorophenyl,
3,4,5-trifluorophenyl, 2,3,4,5-tetrafluorophenyl, 2,3,5,6-tetrafluorophenyl, pentafluorophenyl and the like.
Acid addition salts of the compounds of the invention can be derived from reaction of an amine-containing compound of the invention with an inorganic or organic acid. These salts include but are not limited to the following: acetate, adipate, alginate, citrate, aspartate, benzoate, benzenesulfonate, bisulfate, butyrate, camphorate, camphorsulfonate, digluconate, cyclopentanepropionate, dodecylsulfate, ethanesulfonate, glucoheptanoate, glycerophosphate,
hemisulfate, heptanoate, hexanoate, fumarate, hydrochloride, hydrobromide, hydroiodide, 2-hydroxy-ethanesulfonate (isethionate), lactate, maleate, malonate, glutarate, malate, mandelate, methanesulfonate, nicotinate,
2-naphthalenesulfonate, oxalate, pamoate, pectinate, persulfate,
3-phenylpropionate, picrate, pivalate, propionate, succinate, tartrate, thiocyanate, p-toluenesulfonate and undecanoate.
Examples of acids which may be employed to form acid addition salts include such inorganic acids as hydrochloric acid, sulphuric acid and phosphoric acid and such organic acids as oxalic acid, maieic acid, succinic acid and citric acid, as well as the other acids mentioned above.
The term "substantially pure" as used herein refers to a compound which is contaminated by not more than 10% of any other stereoisomer (enantiomer or diastereomer), preferably by not more than 5% of any other stereoisomer and most preferably by not more than 3% of any other stereoisomer.
As used herein, the terms "S" and "R" configuration are as defined by the IUPAC 1974 Recommendations for Section E, Fundamental Stereochemistry, Pure Appl. Chem. (1976) 45, 13 - 30.
The following examples will serve to further illustrate the compounds and processes of the invention.
Example 1
(L)-N,N-Dibenzylphenylalanine benzyl ester
A solution containing L-phenylalanine (161 kg, 975 moles), potassium carbonate (445 kg, 3220 moles), water (675 L), ethanol (340 L), and benzyl chloride (415 kg, 3275 moles) was heated to 90±15°C for 10-24 hours. The reaction mixture was cooled to 60°C and the lower aqueous layer was removed. Heptane (850 L) and water (385 L) were added to the organics, stirred, and the layers separated. The organics were then washed once with a water/methanol mixture (150 17150 L). The organics were then stripped to give the desired product as an oil.which was carried on in the next step without purification.
IR (neat) 3090, 3050, 3030, 1730, 1495, 1450, 1 160 cm-1 , 1 H NMR (300 MHz, CDCI3) δ 7.5-7.0 (m, 20H), 5.3 (d, 1 H, J = 13.5 Hz), 5.2 (d, 1 H, J = 13.5 Hz), 4.0 (d,
2H, J = 15 Hz), 3.8 (t, 2H, J = 8.4 Hz), 3.6 (d, 2H, J = 15 Hz), 3.2 (dd, 1 H, J = 8.4, 14.4 Hz), 1 3C NMR (300 MHz, CDCI3) δ 172.0, 139.2, 138.0, 135.9, 129.4, 128.6,
128.5, 128.4, 128.2, 128.1 , 128.1 , 126.9, 126.2, 66.0, 62.3, 54.3, 35.6.
[α]D -79° (c = 0.9, DMF).
Example 2a
4-S-N,N-Dibenzylamino-3-oxo-5-phenyl-pentanonitrile
A solution containing the product of Example 1 (i.e., benzyl ester) (approx. 0.45 moles) in 520 mL tetrahydrofuran and 420 mL acetonitrile was cooled to -40°C under nitrogen. A second solution containing sodium amide (48.7g, 1.25 moles) in 850 mL tetrahydrofuran was cooled to -40°C. To the sodium amide solution was slowly added 75 mL acetonitrile and the resulting solution was stirred at
-40°C for more than 15 minutes. The sodium amide/acetonitrile solution was then slowly added to the benzyl ester solution at -40°C. The combined solution was stirred at -40°C for one hour and then quenched with 1150 mL of a 25% (w/v) citric acid solution. The resulting slurry was warmed to ambient temperature and the organics separated. The organics were then washed with 350 mL of a 25% (w/v) sodium chloride solution, then diluted with 900 mL heptane. The organics were then washed three times with 900 mL of a 5% (w/v) sodium chloride solution, two times with 900 mL of a 10% methanolic water solution, one time with 900 mL of a 15% methanolic water solution, and then one time with 900 mL of a 20% methanolic water solution. The organics were stripped and the resulting material dissolved into 700 mL of hot ethanol. Upon cooling to room temperature, the desired product precipitated. Filtration gave the desired product in 59% yield from the L-phenylalanine. IR (CHCI3) 3090, 3050, 3030, 2250, 1735, 1600, 1490, 1450, 1370, 1300, 1215 cm-1 , 1 H NMR (CDCI3) δ 7.3 (m, 15H), 3.9 (d, 1 H, J = 19.5 Hz), 3.8 (d, 2H, J = 13.5 Hz), 3.6 (d, 2H, J = 13.5 Hz), 3.5 (dd, 1 H, J = 4.0, 10.5 Hz), 3.2 (dd, 1 H, J = 10.5, 13.5 Hz), 3.0 (dd, 1 H, J = 4.0, 13.5 Hz), 3.0 (d, 1 H, J = 19.5 Hz), 13C NMR (300MHz, CDCI3) δ 197.0, 138.4, 138.0, 129.5, 129.0, 128.8, 128.6, 127.8, 126.4, 68.6, 54.8, 30.0, 28.4. [α]D -95° (c = 0.5, DMF).
EXAMPLE 2b
Alternate preparation of 4-S-N,N-Dibenzylamino-3-oxo-5-phenyl-pentanonitrile
To a flask was charged sodium amide (5.8g, 134mmol) under nitrogen followed by 100mL of methyl t-butyl ether (MTBE). The stirred solution was cooled to 0°C. Acetonitrile (8.6mL, 165mmol) was added over 1 minute. This solution was stirred at 5±5°C for 30 minutes. A solution of (L)-N,N-dibenzylphenylalanine benzyl ester (25g, 90% pure, 51.6mmol) in 125mL of MTBE was added over 15 minutes and the resulting heterogeneous mixture was stirred at 5±5°C until the reaction was complete (approx. 3 hours). The reaction was quenched with
100mL of 25% w/v aqueous citric acid and warmed to 25°C before separating the layers. The organics were then washed with 100 mL of H2O. The aqueous layer was separated and the organics filtered and concentrated in vacuo. The residue
was crystallized from 50mL of ethanol to afford 13.8g of the desired product as a white solid.
EXAMPLE 2c
Alternate preparation of 4-S-N,N-Dibenzylamino-3-oxo-5-phenyl-pentanonitrile To a solution containing sodium amide (120 kg, 3077 moles), heptane (1194 L), and tetrahydrofuran (590 L) cooled to 0°C, was added a solution containing the product of Example 1 (i.e., benzyl ester) (approx. 975 moles), tetrahydrofuran (290 L), heptane (570 L), and acetonitrile (114 L). The addition was done maintaining the temperature below 5°C. The combined solution was stirred at 0±5°C for approx. one hour before quenching with 25% citric acid solution (1540 L) to adjust the pH to 5.0-7.0. The upper organic layer was separated and washed with 25% aqueous sodium chloride (715 kg), treated with activated carbon (2 kg), and stripped. The resulting residue was crystallized from a 55°C ethanol/water solution (809 kg/404 kg). The solution was cooled to 0°C prior to crystallizing to give approx. 215 kg of the desired product.
Example 3
Alternate preparation of 4-S-N,N-Dibenzylamino-3-oxo-5-phenyl-pentanonitrile To a 1 liter jacketed reaction flask equipped with thermometer, nitrogen inlet, pressure-equalized addition funnel and mechanical stirrer was charged a solution of potassium f-butoxide (32 g, 0.289 mol, 3.0 equiv) in tetrahydrofuran (350 mL) and cooled to an internal temperature of -10°C. To this was added a solution of the product of Example 1 (i.e, benzyl ester) (42.0 g, 0.0964 mol, 1.0 equiv) in tetrahydrofuran (10 mL) and acetonitrile (15 mL, 0.289 mol, 3.0 equiv) via pressure-equalized addition funnel over a period of 20 minutes. During the addition, the internal temperature increased to -5°C. The reaction (now orange and transparent) mixture stirred an additional 30 min at -10°C. An aliquot removed from the reaction mixture after the addition of the benzyl ester solution was quenched in 10% aqueous citric acid and partitioned between heptane was analyzed by HPLC and revealed no starting material remained and the presence of the desired nitrite in 93% ee in favor of the S isomer, Chiralpak AD column, 1 mL/min,. 10% /-propanol in heptane, monitored @205 nm). The contents of the
reactor were allowed to warm to 0°C over 30 minutes. Citric acid (10% aqueous, 200 mL) was charged followed by Heptane (100 mL) and the reaction contents allowed to warm to 20°C. The aqueous phase was separated and the organic phase was washed with 10% aqueous sodium chloride solution (200 mL) and the aqueous phase separated. The organic phase was concentrated in vacuo using a 45°C bath. n-Butanol (100 mL) was then charged and distillation in vacuo was conducted until the contents were reduced by approximately 10% by volume. The suspension resulting was allowed to cool to 20°C with mechanical stirring and held at that temperature for 18 hours. The solid was filtered and dried in vacuo at 45°C. The yield of the first crop was 20.5 g (57%). The material was >98% pure by HPLC.
Example 4
2-Amino-5-S-N,N-dibenzylamino-4-oxo-1 ,6-diphenylhex-2-ene
To a -5°C solution of the nitrile product of Example 2 (90 Kg, 244 moles) in tetrahydrofuran (288 L), was added benzylmagnesium chloride (378 Kg, 2M in
THF, 708 moles). The solution was warmed to ambient temperature and stirred until analysis showed no starting material. The solution was then recooled to 5°C and slowly transferred to a solution of 15% citric acid (465 kg). Additional tetrahydrofuran (85 L) was used to rinse out the original container and the rinse was added to the citric acid quench container. The organics were separated and washed with 10% sodium chloride (235 kg) and stripped to a solid. The product was stripped again from ethanol (289 L) and then dissolved in 80°C ethanol (581
L)). After cooling to room temperature and stirring for 12 hours, the resulting product was filtered and dried in a vacuum oven at 30°C to give approx. 95 kg of the desired product, mp 101 -102°C, IR (CDCI3) 3630, 3500, 3110, 3060, 3030,
2230, 1620, 1595, 1520, 1495, 1450 cm-1 , 1 H NMR (300 MHZ, CDCI3) d 9.8 (br s, 1 H), 7.2 (m, 20H), 5.1 (s, 1 H), 4.9 (br s, 1 H), 3.8 ( d, 2H, J = 14.7 Hz), 3.6 (d, 2H,
J = 14.7Hz), 3.5 (m, 3H), 3.2 (dd, 1 H, J = 7.5, 14.4 Hz), 3.0 (dd, 1 H, J = 6.6, 14.4
Hz), 13C NMR (CDCl3) d 198.0, 162.8, 140.2, 140.1 , 136.0, 129.5, 129.3, 128.9,
128.7, 128.1 , 128.0, 127.3, 126.7, 125.6, 96.9, 66.5, 54.3, 42.3, 32.4.
[α]D -147° (c = 0.5, DMF).
Example 5
(2S, 3S, 5S)-5-Amino-2-(dibenzylamino}-3-hydroxy-1 ,6-diphenyl-hexane A solution of 2-amino-5-S-N,N-dibenzylamino-4-oxo-1 ,6-diphenylhex-2- ene (30 g, 65 mmol), methanesulfonic acid (24 g, 248mmol), ethanol (240mL), and 4 grams of 5% platinum supported on carbon was pressurized to 250 psi with hydrogen and stirred at 5°C for 14 hours followed by stirring at 23°C for 10 hours. The pressure was released and the catalyst removed by filtration over celite. The filtrate was diluted with 1 N sodium hydroxide (250mL) and the product extracted with MTBE (300mL). The organics were washed with brine (100mL) and concentrated in vacuo to provide the desired product as a yellow oil: IR (CHCI3) 3510, 3400, 3110, 3060, 3030, 1630, 1 H NMR (300 MHz, CDCI3) δ 7.2 (m, 20H), 4.1 (d, 2H, J = 13.5 Hz), 3.65 (m, 1 H), 3.5 (d, 2H, J = 13.5 Hz), 3.1 (m, 2H), 2.8 (m, 1 H), 2.65 (m, 3H), 1.55 (m, 1 H), 1.30 (m, 1 H), 1 3C NMR (300 MHz, CDCI3) δ
140.8, 140.1 , 138.2, 129.4, 129.4, 128.6, 128.4, 128.3, 128.2, 126.8, 126.3, 125.7, 72.0, 63.6, 54.9, 53.3, 46.2, 40.1 , 30.2.
Example 6
Alternative Preparation of (2S, 3S, 5S)-5-Amino-2-(dibenzylamino)- 3-hydroxy-1 ,6-diphenyl-hexane
A solution of 2-amino-5-S-N,N-dibenzylamino-4-oxo-1 ,6-diphenylhex-2- ene (30 g, 65 mmol), methanesulfonic acid (24 g, 248mmol), ethanol (240mL), and 4 grams of 5% platinum supported on Deloxan® AP II was pressurized to 1000 psi with hydrogen and stirred at 0-5°C for 15 hours followed by stirring at 23°C for 32 hours. The pressure was released and the catalyst removed by filtration over celite. The filtrate was diluted with 1 N sodium hydroxide (250mL) and the product extracted with ethyl acetate (300mL). The organics were washed with brine (100mL) and concentrated in vacuo to provide the desired product .
The foregoing is merely illustrative of the invention and is not intended to limit the invention to the disclosed embodiments. Variations and changes which are obvious to one skilled in the art are intended to be within the scope and nature of the invention which are defined in the appended claims.
Claims
1. A process for the preparation of the substantially pure compound of the formula:
wherein R6 and R7 are independently selected from
wherein Ra and Rb are independently selected from hydrogen, loweralkyl and phenyl and Rc, Rd and Re are independently selected from hydrogen, loweralkyl, trifluoromethyl, alkoxy, halo and phenyl; and
wherein Rf, Rg, Rh and Ri are independently selected from hydrogen, loweralkyl, alkoxy, halogen and trifluoromethyl; or an acid addition salt thereof, comprising reacting an enaminoketone compound of the formula:
wherein R6 and R7 are defined as above with hydrogen gas in the presence of a hydrogenation catalyst and an acid.
2. The process of Claim 1 wherein R6 and R7 are each benzyl or substituted benzyl wherein the phenyl ring of the benzyl group is substituted with one, two or three substituents independently selected from loweralkyl,
trifluoromethyl, alkoxy, halo and phenyl.
3. The process of Claim 1 wherein the reaction is carried out in a solvent comprising (1 ) a protic solvent or (2) an ethereal solvent.
4. The process of Claim 1 wherein the catalyst is platinum.
5. The process of Claim 1 wherein the acid is sulfuric acid or methansulfonic acid.
6. A process for the preparation of the substantially pure compound of the formula:
wherein R6 and R7 are independently selected from
wherein Ra and Rb are independently selected from hydrogen, loweralkyl and phenyl and Rc, Rd and Re are independently selected from hydrogen, loweralkyl, trifluoromethyl, alkoxy, halo and phenyl; and
wherein the naphthyl ring is unsubstituted or substituted with one, two or three substitutents independently selected from loweralkyl, trifluoromethyl, alkoxy and halo; or R6 and R7 taken together with the nitrogen atom to which they are bonded are
wherein Rf, Rg, Rh and Ri are independently selected from hydrogen, loweralkyl, alkoxy, halogen and trifluoromethyl; or an acid addition salt thereof, comprising reacting an enaminoketone compound of the formula:
wherein R6 and R7 are defined as above with hydrogen gas in the presence of a hydrogenation catalyst and from about 2 molar equivalents to about 4 molar equivalents (based on the enaminoketone) of an acid.
7. The process of Claim 6 wherein R6 and R7 are each benzyl or substituted benzyl wherein the phenyl ring of the benzyl group is substituted with one, two or three substituents independently selected from loweralkyl,
trifluoromethyl, alkoxy, halo and phenyl.
8. The process of Claim 6 wherein the reaction is carried out in a protic solvent or an ethereal solvent.
9. The process of Claim 6 wherein the catalyst is platinum.
10. The process of Claim 6 wherein the acid is sulfuric acid or
methanesulfonic acid.
11. The process of Claim 6 for the preparation of the substantially pure compound of the formula:
wherein R6 and R7 are independently selected from
wherein Ra and Rb are independently selected from hydrogen, loweralkyl and phenyl and Rc, Rd and Re are independently selected from hydrogen, loweralkyl, trifluoromethyl, alkoxy, halo and phenyl; or an acid addition salt thereof, comprising reacting an enaminoketone compound of the formula:
wherein R6 and R7 are defined as above with hydrogen gas in the presence of a hydrogenation catalyst and from about 2 molar equivalents to about 4 molar equivalents (based on the enaminoketone) of an acid.
12. The process of Claim 11 for the preparation of the substantially pure compound of the formula:
wherein R6 and R7 are defined as above with hydrogen gas in the presence of a hydrogenation catalyst and from about 2 molar equivalents to about 4 molar equivalents (based on the enaminoketone) of an acid.
13. A process for the preparation of the substantially pure compound of the formula:
enaminoketone) of methanesulfonic acid.
14. The process of Claim 13 wherein the alcohol is ethanol.
15. The process of Claim 13 wherein the catalyst is platinum on carbon or platinum on aminopolysiloxane.
Category " C jtauon of document, with indicauon, where appropπatc , of the relevant passages Relevant lo claim No.
BULLETIN DES SOCIETES CHIMIQUES BELGES, 1-15 no.PT.2, 1980, OXFORD GB
pages 179 - 186
P. MARONI ET AL. 'Syntheses
d'aminoalcool s-1,3 ou d'aminophenols-1,3
par reduction d'enaminones ou
d' iminophenols par les hydrures
metal liques. Etude structurale par
infrarouge et RMN des aminoalcool s-1,3
bisecondaires diastereoisomeres'
see the whole document
EP,A,0486948 (ABBOTT LABORATORIES) 27 1-15
May 1992
cited in the application
see example 1
WO, A, 94 14436 (ABBOTT LABORATORIES) 7 July 1-15
1994
cited in the application
see examples 1A-F
JOURNAL OF ORGANIC CHEMISTRY, 1-15 vol.58, no.5, 1993, EASTON US
pages 1025 - 1029
A. K. GOSH ET AL. 'Potent HIV-1 protease
inhibitors: Stereol selective synthesis of
a dipeptide mimic'
.X JOURNAL OF ORGANIC CHEMISTRY, 1-15 vol.59, no.14, 29 July 1994, EASTON US
pages 4040 - 4041
T. L. STUK ET AL. 'An efficient
stereocontrolled strategy for the
synthesis of hydroxyethylene dipeptide
isosteres1
see the whole document, see especially 3rd
footnote
& Advance ACS Abstracts, July 1, 1994 1-15
Form PCT'ISΛ-10 (conlinuauon of lecond sheet) (July 1993)
page 2 of 2 n orma ion on pa en ami y mem ers
PCT/US 95/09133
Patent documenl Publication Patent family Publication cited in search report dale member(s) date
EP-A-0486948 27-05-92 AU-B- 650491 23-06-94
AU-B- 8771591 21-05-92 CA-A- 2055670 21-05-92 CH-A- 684696 30-11-94 ES-A- 2070660 01-06-95 JP-A- 4308574 30-10-92 US-A- 5362912 08-11-94 US-A- 5354866 11-10-94
WO-A-9414436 07-07-94 AU-B- 1492795 15-06-95
AU-B- 659575 18-05-95 AU-B- 5954694 19-07-94 CA-A- 2135890 07-07-94 EP-A- 0674513 04-10-95 IL-A- 108126 30-03-95
Form PCTΛSΛ.210 (patent family innu) (July 199.)
Priority Applications (6)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE69513667T DE69513667T2 (en) | 1994-07-29 | 1995-07-17 | METHOD FOR PRODUCING A SUBSTITUTED 2,5-DIAMINO-3-HYDROXY HEXANES |
| MXPA/A/1997/000720A MXPA97000720A (en) | 1994-07-29 | 1995-07-17 | Procedure for the preparation of a 2,5-diamino-3-hidroxihex |
| EP95926318A EP0773921B1 (en) | 1994-07-29 | 1995-07-17 | Process for the preparation of a substituted 2.5-diamino-3-hydroxyhexane |
| JP8506551A JPH10503772A (en) | 1994-07-29 | 1995-07-17 | Method for producing substituted 2,5-diamino-3-hydroxyhexane |
| DK95926318T DK0773921T3 (en) | 1994-07-29 | 1995-07-17 | Process for the preparation of a substituted 2,5-diamino-3-hydroxyhexane |
| GR20000400249T GR3032553T3 (en) | 1994-07-29 | 2000-02-02 | Process for the preparation of a substituted 2.5-diamino-3-hydroxyhexane |
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US28310994A | 1994-07-29 | 1994-07-29 | |
| US08/283,109 | 1994-07-29 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| WO1996004232A1 true WO1996004232A1 (en) | 1996-02-15 |
Family
ID=23084563
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| PCT/US1995/009133 WO1996004232A1 (en) | 1994-07-29 | 1995-07-17 | Process for the preparation of a substituted 2.5-diamino-3-hydroxyhexane |
Country Status (11)
| Country | Link |
|---|---|
| US (1) | US5672706A (en) |
| EP (1) | EP0773921B1 (en) |
| JP (1) | JPH10503772A (en) |
| AT (1) | ATE187160T1 (en) |
| CA (1) | CA2192836A1 (en) |
| DE (1) | DE69513667T2 (en) |
| DK (1) | DK0773921T3 (en) |
| ES (1) | ES2143058T3 (en) |
| GR (1) | GR3032553T3 (en) |
| PT (1) | PT773921E (en) |
| WO (1) | WO1996004232A1 (en) |
Cited By (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2000040558A1 (en) * | 1999-01-06 | 2000-07-13 | The Government Of The United States Of America, Represented By The Secretary, Department Of Health And Human Services | Aspartic protease inhibitors |
| US6407252B1 (en) * | 1999-09-21 | 2002-06-18 | Clariant Life Science Molecules (Italy) S.P.A. | Process for the synthesis of ritonavir |
| WO2006099169A2 (en) | 2005-03-10 | 2006-09-21 | Mebiopharm Co., Ltd. | Novel liposome compositions |
| US8198453B2 (en) | 2006-09-18 | 2012-06-12 | Vitae Pharmaceuticals, Inc. | Piperidine renin inhibitors |
| US8372978B2 (en) | 2009-08-06 | 2013-02-12 | Vitae Pharmaceuticals, Inc. | Salts of methyl 2-((R)-(3-chlorophenyl)((R)-1-((S)-2-(methylamino)-3-((R)-tetrahydro-2H-pyran-3-yl)propylcarbamoyl)piperidin-3-yl)methoxy)ethylcarbamate |
| US8455521B2 (en) | 2004-10-07 | 2013-06-04 | Vitae Pharmaceuticals, Inc. | Diaminoalkane aspartic protease inhibitors |
| US8487108B2 (en) | 2005-11-14 | 2013-07-16 | Vitae Pharmaceuticals, Inc. | Piperidinyl carbamate intermediates for the synthesis of aspartic protease inhibitors |
Families Citing this family (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| ATE384038T1 (en) * | 2002-10-18 | 2008-02-15 | Tohru Yokozawa | METHOD FOR PRODUCING OPTICALLY ACTIVE AMINO ALCOHOLS |
| JP2004346008A (en) * | 2003-05-22 | 2004-12-09 | Sumitomo Chem Co Ltd | Method for producing n-monoalkyl-3-hydroxy-3-arylpropylamine and intermediate therefor |
| CN111393329A (en) * | 2020-04-16 | 2020-07-10 | 安徽一帆香料有限公司 | Preparation method of ritonavir and lopinavir intermediate |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0486948A2 (en) * | 1990-11-20 | 1992-05-27 | Abbott Laboratories | Retroviral protease inhibiting compounds |
| WO1994014436A1 (en) * | 1992-12-29 | 1994-07-07 | Abbott Laboratories | Retroviral protease inhibiting compounds |
Family Cites Families (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4360684A (en) * | 1981-04-08 | 1982-11-23 | Merck & Co., Inc. | Process for the preparation of (2S)-tetrahydro-2α-methyl-6-oxo-4βα-carboxylic acid |
-
1995
- 1995-07-17 CA CA002192836A patent/CA2192836A1/en not_active Abandoned
- 1995-07-17 PT PT95926318T patent/PT773921E/en unknown
- 1995-07-17 AT AT95926318T patent/ATE187160T1/en not_active IP Right Cessation
- 1995-07-17 EP EP95926318A patent/EP0773921B1/en not_active Expired - Lifetime
- 1995-07-17 DK DK95926318T patent/DK0773921T3/en active
- 1995-07-17 WO PCT/US1995/009133 patent/WO1996004232A1/en active IP Right Grant
- 1995-07-17 DE DE69513667T patent/DE69513667T2/en not_active Expired - Fee Related
- 1995-07-17 ES ES95926318T patent/ES2143058T3/en not_active Expired - Lifetime
- 1995-07-17 JP JP8506551A patent/JPH10503772A/en not_active Withdrawn
-
1996
- 1996-04-17 US US08/633,605 patent/US5672706A/en not_active Expired - Fee Related
-
2000
- 2000-02-02 GR GR20000400249T patent/GR3032553T3/en not_active IP Right Cessation
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0486948A2 (en) * | 1990-11-20 | 1992-05-27 | Abbott Laboratories | Retroviral protease inhibiting compounds |
| WO1994014436A1 (en) * | 1992-12-29 | 1994-07-07 | Abbott Laboratories | Retroviral protease inhibiting compounds |
Non-Patent Citations (6)
| Title |
|---|
| A. K. GOSH ET AL.: "Potent HIV-1 protease inhibitors: Stereolselective synthesis of a dipeptide mimic", JOURNAL OF ORGANIC CHEMISTRY, vol. 58, no. 5, 1993, EASTON US, pages 1025 - 1029 * |
| Advance ACS Abstracts, July 1, 1994 * |
| G. BARTOLI ET AL.: "Convenient procedure for the reduction of .beta.- enamino ketones: synthesis of .gamma.- amino alcohols and tetrahydro-1,3-oxazines", JOURNAL OF THE CHEMICAL SOCIETY, PERKIN TRANSACTIONS 1, no. 5, 7 March 1994 (1994-03-07), LETCHWORTH GB, pages 537 - 543 * |
| M. T. REETZ ET AL.: "Non-racemizing synthesis and stereoselective reduction of chiral .alpha.-amino ketones", TETRAHEDRON: ASYMMETRY, vol. 1, no. 6, 1990, OXFORD GB, pages 375 - 378 * |
| P. MARONI ET AL.: "Synthèses d'aminoalcools-1,3 ou d'aminophénols-1,3 par réduction d'énaminones ou d'iminophénols par les hydrures métalliques. Etude structurale par infrarouge et RMN des aminoalcools-1,3 bisecondaires diastéréoisomères", BULLETIN DES SOCIETES CHIMIQUES BELGES, no. PT.2, 1980, OXFORD GB, pages 179 - 186 * |
| T. L. STUK ET AL.: "An efficient stereocontrolled strategy for the synthesis of hydroxyethylene dipeptide isosteres", JOURNAL OF ORGANIC CHEMISTRY, vol. 59, no. 14, 29 July 1994 (1994-07-29), EASTON US, pages 4040 - 4041 * |
Cited By (10)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2000040558A1 (en) * | 1999-01-06 | 2000-07-13 | The Government Of The United States Of America, Represented By The Secretary, Department Of Health And Human Services | Aspartic protease inhibitors |
| US6613764B1 (en) | 1999-01-06 | 2003-09-02 | The United States Of America As Represented By The Department Of Health And Human Services | Aspartic protease inhibitors |
| US7132420B2 (en) | 1999-01-06 | 2006-11-07 | The United States Of America As Represented By The Department Of Health And Human Services | Aspartic protease inhibitors |
| US6407252B1 (en) * | 1999-09-21 | 2002-06-18 | Clariant Life Science Molecules (Italy) S.P.A. | Process for the synthesis of ritonavir |
| US8455521B2 (en) | 2004-10-07 | 2013-06-04 | Vitae Pharmaceuticals, Inc. | Diaminoalkane aspartic protease inhibitors |
| WO2006099169A2 (en) | 2005-03-10 | 2006-09-21 | Mebiopharm Co., Ltd. | Novel liposome compositions |
| US8487108B2 (en) | 2005-11-14 | 2013-07-16 | Vitae Pharmaceuticals, Inc. | Piperidinyl carbamate intermediates for the synthesis of aspartic protease inhibitors |
| US8198453B2 (en) | 2006-09-18 | 2012-06-12 | Vitae Pharmaceuticals, Inc. | Piperidine renin inhibitors |
| US8580823B2 (en) | 2006-09-18 | 2013-11-12 | Vitae Pharmaceuticals, Inc. | Piperidine renin inhibitors |
| US8372978B2 (en) | 2009-08-06 | 2013-02-12 | Vitae Pharmaceuticals, Inc. | Salts of methyl 2-((R)-(3-chlorophenyl)((R)-1-((S)-2-(methylamino)-3-((R)-tetrahydro-2H-pyran-3-yl)propylcarbamoyl)piperidin-3-yl)methoxy)ethylcarbamate |
Also Published As
| Publication number | Publication date |
|---|---|
| EP0773921B1 (en) | 1999-12-01 |
| DE69513667D1 (en) | 2000-01-05 |
| GR3032553T3 (en) | 2000-05-31 |
| MX9700720A (en) | 1997-09-30 |
| ES2143058T3 (en) | 2000-05-01 |
| US5672706A (en) | 1997-09-30 |
| DK0773921T3 (en) | 2000-05-08 |
| PT773921E (en) | 2000-05-31 |
| DE69513667T2 (en) | 2000-07-06 |
| JPH10503772A (en) | 1998-04-07 |
| EP0773921A1 (en) | 1997-05-21 |
| ATE187160T1 (en) | 1999-12-15 |
| CA2192836A1 (en) | 1996-02-15 |
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