U.S. patent application number 12/293450 was filed with the patent office on 2011-03-17 for process for preparation of hiv protease inhibitors.
This patent application is currently assigned to Gilead Sciences, Inc. Invention is credited to Kenneth R. Crawford, Eric D. Dowdy, Arnold Gutierrez, Richard Polniaszek, Richard H. Yu.
Application Number | 20110065631 12/293450 |
Document ID | / |
Family ID | 38323963 |
Filed Date | 2011-03-17 |
United States Patent
Application |
20110065631 |
Kind Code |
A1 |
Crawford; Kenneth R. ; et
al. |
March 17, 2011 |
PROCESS FOR PREPARATION OF HIV PROTEASE INHIBITORS
Abstract
A process for the synthesis of bisfuran intermediates of formula
(0) useful for preparing antiviral HIV protease inhibitor compounds
is hereby disclosed. Furthermore disclosed is a HIV protease
inhibitor of formula (IV) as well as various intermediates thereof.
##STR00001##
Inventors: |
Crawford; Kenneth R.;
(westwood, MA) ; Dowdy; Eric D.; (Foster City,
CA) ; Gutierrez; Arnold; (San Jose, CA) ;
Polniaszek; Richard; (Redwood City, CA) ; Yu; Richard
H.; (San Francisco, CA) |
Assignee: |
Gilead Sciences, Inc
Foster city
CA
|
Family ID: |
38323963 |
Appl. No.: |
12/293450 |
Filed: |
March 29, 2007 |
PCT Filed: |
March 29, 2007 |
PCT NO: |
PCT/US07/07564 |
371 Date: |
May 21, 2009 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
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60787126 |
Mar 29, 2006 |
|
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|
Current U.S.
Class: |
514/4.1 ;
514/100; 514/45; 514/49; 514/50; 514/81; 546/284.1; 548/526;
549/220; 549/464; 558/413; 560/13; 564/92 |
Current CPC
Class: |
A61P 31/18 20180101;
C07C 311/29 20130101; C07C 51/412 20130101; C07F 9/6561 20130101;
A61P 31/12 20180101; C07F 9/4084 20130101; C07D 493/04 20130101;
C07F 9/4006 20130101; C07F 9/4075 20130101; C07C 253/30 20130101;
A61K 31/665 20130101; C07C 303/40 20130101; A61P 43/00 20180101;
C07C 303/38 20130101; C07C 303/38 20130101; C07C 311/29 20130101;
C07C 303/40 20130101; C07C 311/29 20130101; C07C 253/30 20130101;
C07C 255/60 20130101 |
Class at
Publication: |
514/4.1 ;
549/464; 548/526; 546/284.1; 549/220; 558/413; 560/13; 564/92;
514/100; 514/50; 514/81; 514/45; 514/49 |
International
Class: |
A61K 38/16 20060101
A61K038/16; C07D 493/04 20060101 C07D493/04; C07F 9/6561 20060101
C07F009/6561; C07C 255/60 20060101 C07C255/60; C07C 311/37 20060101
C07C311/37; A61K 31/665 20060101 A61K031/665; A61K 31/7072 20060101
A61K031/7072; A61K 31/675 20060101 A61K031/675; A61K 31/708
20060101 A61K031/708; A61K 31/7068 20060101 A61K031/7068; A61P
31/18 20060101 A61P031/18 |
Claims
1. A process for preparing a bisfuran alcohol of Formula 0:
##STR00076## comprising, reacting 2,3-dihydrofuran and a
glycoaldehyde or glycoaldehyde dimer in the presence of a
lanthanide or transition metal catalyst to form the bisfuran
alcohol of Formula 0.
2. The process of claim 1, where the catalyst comprises Yb, Pr, Cu,
Eu or Sc complexed to a ligand selected from: ##STR00077##
3. The process of claim 2, where the catalyst is Yb(hfc).sub.3(+),
Yb(hfc).sub.3(-), Eu(hfc).sub.3(+), Eu(hfc).sub.3(-),
Yb(fod).sub.3(+) and S-Binaphthol, Yb(tfc).sub.3(+), Sc(OTf).sub.3
and (S)-pybox, and Pr(tfc).sub.3(+) where ##STR00078## where, M
represents Yb, Pr, Cu, Eu or Sc.
4. The process of claim 1, where the reaction is carried out at a
temperature of between about 0.degree. C. to about 100.degree.
C.
5. The process of claim 1, where the reaction is carried out in the
presence of a catalyst comprising a lanthanide or transition metal
complexed to a chiral ligand.
6. The process of claim 5, where the chiral ligand is ##STR00079##
where, Ph is phenyl.
7. The process of claim 1, which is carried out in the presence of
a solvent.
8. The process of claim 7, where the solvent is a polar aprotic
solvent.
9. The process of claim 8, where the solvent is
methyl-t-butyl-ether, dichloromethane or a mixture thereof.
10. The process of claim 1, which is carried out in the presence of
excess 2,3-dihydrofuran as a solvent.
11. The process of claim 1, where the catalyst comprises Sc.
12. The process of claim 1, where the catalyst comprises Yb.
13. The process of claim 1, further comprising, (i) combining the
bisfuran alcohol of Formula 0 with disuccinimidyl dicarbonate to
form a compound of Formula L1: ##STR00080## (ii) combining the
bisfuran alcohol of Formula 0 with bis(p-nitro)phenyl carbonate or
p-nitrophenol chloroformate to form a compound of Formula L2:
##STR00081## or (iii) combining the bisfuran alcohol of Formula 0
with dipyridyl carbonate to form a compound of Formula L3:
##STR00082##
14. The process of claim 13, further comprising, combining the
compound of Formula L1, L2 or L3 with a compound of Formula N,
##STR00083## to form a compound of Formula A, ##STR00084## where,
Me is methyl.
15. The process of claim 14, further comprising, combining the
compound of Formula A with a compound of Formula J, ##STR00085## to
form a compound of Formula I, ##STR00086## where, Me is methyl; Et
is ethyl; and Ph is phenyl.
16. The process of claim 15, further comprising, combining the
compound of Formula I with adipic acid to form a salt of Formula
IV, ##STR00087## where, Me, Et and Ph are each independently
defined the same as in claim 15.
17. The process of claim 14, where the compound of Formula N is
prepared by deprotecting a compound of Formula M: ##STR00088##
18. The process of claim 17, where the deprotection is accomplished
by combining the compound of Formula M with a deprotecting agent
which is selected from trifluoroacetic acid, hydrochloric acid,
toluenesulfonic acid, methanesulfonic acid, benzenesulfonic acid,
or hydrobromic acid.
19. The process of claim 17, where the compound of Formula M is
prepared by reducing a compound of Formula C: ##STR00089##
20. The process of claim 19, where the reduction is accomplished by
contacting the compound of Formula C with a reducing agent which is
lithium aluminum hydride, sodium borohydride, lithium borohydride,
sodium trisacetoxyborohydride, sodium cyanoborohydride, potassium
triisopropoxy borohydride or diisobutyl aluminum hydride
21. The process of claim 19, where the compound of Formula C is
prepared by combining a compound of Formula F with a compound of
Formula G: ##STR00090##
22. The process of claim 21, where the compound of Formula F is
prepared by combining a compound of Formula E with an amine:
##STR00091##
23. The process of claim 22, where the amine is ##STR00092##
24. A compound having the formula C: ##STR00093## or a
pharmaceutically acceptable salt thereof.
25. A compound having the formula M: ##STR00094## or a
pharmaceutically acceptable salt thereof.
26. A compound having the formula N: ##STR00095## or a
pharmaceutically acceptable salt thereof.
27. A salt having the formula IV: ##STR00096##
28. A pharmaceutical composition comprising the salt of claim 27
and an excipient, diluent or carrier.
29. A method for the treatment or prophylaxis of a retrovirus
infection in a patient, comprising administering to the patient a
therapeutically effective amount of the salt of claim 27.
30. The method of claim 29, where the retrovirus is human
immunodeficiency virus (HIV).
31. The method of claim 29, where the therapeutically effective
amount is about 10 mg to about 2000 mg.
32. The method of claim 29, where the salt is administered in a
pharmaceutical composition.
33. The method of claim 32, where the pharmaceutical composition is
in a unit dosage form of a tablet.
34. The method of claim 29, where the salt is administered
orally.
35. A kit comprising: (1) the pharmaceutical composition of claim
28; (2) prescribing information; and (3) a container.
36. The kit of claim 35, where the pharmaceutical composition is in
a unit dosage form of a tablet.
37. A compound, composition or method as disclosed herein.
38. The use of the salt of claim 27 for the manufacture of a
medicament for inhibiting activity of a retrovirus protease in a
patient, comprising administering to the patient a therapeutically
effective amount of the salt.
39. The use of the salt of claim 27 for the manufacture of a
medicament for the treatment or prophylaxis of a retrovirus
infection in a patient, comprising administering to the patient a
therapeutically effective amount of the salt.
40. The use of claim 38 or 39, where the retrovirus is human
immunodeficiency virus (HIV).
41. The use of the salt of claim 38 or 39, where the salt is
administered to the patient as a single composition.
42. The use of the salt of claim 38 or 39, where the salt is
administered to the patient orally.
43. The use of claim 42, where the oral administration is once a
day.
44. The use of claim 38 or 39, where the patient is also receiving
one or more agents selected the group consisting of stavudine,
emtricitabine, tenofovir, emtricitabine, abacavir, lamivudine,
zidovudine, didanosine, zalcitabine, phosphazide, efavirenz,
nevirapine, delavirdine, tipranavir, saquinavir, indinavir,
atazanavir, nelfinavir, amprenavir, samprenavir, lopinavir,
ritonavir, enfuvirtide, Fozivudine tidoxil, Alovudine,
Dexelvucitabine, Apricitabine, Amdoxovir, Elvucitabine (ACH126443),
Racivir (racemic FTC, PSI-5004), MTV-210, KP-1461, fosalvudine
tidoxil (HDP 99.0003), AVX756, Dioxolane Thymine (DOT), TMC-254072,
INK-20, 4'-Ed4T, TMC-125 (etravirine), Capravirine, TMC-278
(rilpivirine), GW-695634, Calanolide A, BILR 355 BS, and VRX
840773, and pharmaceutically acceptable salts thereof.
45. The use of claim 38 or 39, where the therapeutically effective
amount is about 10 mg to about 2000 mg.
46. The use of claim 38 or 39, where the salt is administered in a
pharmaceutical composition.
47. The use of claim 46, where the pharmaceutical composition is in
a unit dosage form of a tablet.
48. The use of claim 47, where the salt is administered orally.
Description
CROSS-REFERENCE TO RELATED APPLICATION
[0001] This application claims priority to U.S. Provisional Patent
Application No. 60/787,126, filed Mar. 29, 2006.
FIELD OF THE. INVENTION
[0002] The invention relates generally to processes for the
preparation of antiviral compounds with anti-HIV protease
properties. The invention relates to the methods for the
preparation of carbamate sulfonamide amino phosphonate esters and
intermediates thereof. The invention also relates to the novel
intermediates prepared by these methods. The carbamate sulfonamide
amino phosphonate esters prepared by the present methods are HIV
protease inhibitors, useful for the treatment of human auto
immunodeficiency syndrome (AIDS).
BACKGROUND OF THE INVENTION
[0003] AIDS is a major public health problem worldwide. Although
drugs targeting HIV viruses are in wide use and have shown
effectiveness, toxicity and development of resistant strains have
limited their usefulness. Assay methods capable of determining the
presence, absence or amounts of HIV viruses are of practical
utility in the search for inhibitors as well as for diagnosing the
presence of HIV.
[0004] A conventional process for preparation of a HIV protease
inhibitor (PI) of Formula I
##STR00002##
is lengthy, affords a low yield of approximately 1%, is variably
reproducible, requiring numerous chromatographic purification
steps, and employs undesirable reagents, such as ozone, sodium
cyanoborohydride, and tributyltin hydride. The compound of Formula
I is an HIV protease inhibitor which has been made and disclosed in
WO2003/090690.
[0005] Methods for the preparation of the bisfuran alcohol
intermediate used in the synthesis of the compound of formula I
have been described by Pezechk (Pezechk, M. et al., Tetrahedron
Letters, 1986, 27, 3715.) and Ghosh (Ghosh, A. K. et al., J. Med.
Chem., 1994, 37, 2506; Ghosh A. K. et al., J. Med. Chem., 1996, 39,
3278; Ghosh, A. K. et al., Tetrahedron Letters, 1995, 36, 505).
[0006] Scheme 1 shows the bisfuran alcohol synthesis from Ghosh, A.
K. et al., Tetrahedron Letters, 1995, 36, 505).
##STR00003##
[0007] Conventional methods require multiple steps and the use of
toxic reagents. In one of the methods (Ghosh, A. K. et al.,
Tetrahedron Letters, 1995, 36, 505), resolution of a racemic
mixture was achieved by exposure to an immobilized enzyme followed
by chromatographic separation.
##STR00004##
[0008] Reactive carbonate esters have been prepared from bisfuran
alcohol (1) and dipyridyl carbonate (Ghosh A. K. et al., J. Med.
Chem., 1996, 39, 3278), and p-nitrophenol chloroformate (X. Chen et
al., Bioorganic and Medicinal Chemistry Letters, 1996, 6, 2847).
These reagents couple with nucleophilic reaction partners, but do
not always display the appropriate reactivity and efficiency.
##STR00005##
[0009] Methods exist for the preparation of chiral haloalcohols
derived from N-protected amino acids (Albeck, A. et al.,
Tetrahedron, 1994, 50, 6333). Methods for the conversion of such
chloroalcohols to carbamate sulfonamide derivatives are known
(Malik, A. et al., WO 01/46120A1). The halohydrins can also be
converted to epoxides and converted to carbamate sulfonamide
derivatives in a similar manner (WO 03/090690).
[0010] Preparation of Carbamate Derivatives of Aminophosphonic
Acids and subsequent conversion to phosphonate mono- and diesters
have been described in Yamauchi, K. et al., J. Org. Chem., 1984,
49, 1158; Yamauchi, K. et al., J. Chem. Soc. Perkin Trans. I, 1986,
765.
[0011] Aminoethyl phosphonate diesters can be prepared by a process
involving acylation of an amino phosphonic acid with acyl halides
or benzyl chloroformate (CBZCI) to form compounds of Formula
VII
##STR00006##
[0012] Compounds of Formula VII can be activated and condensed with
phenol to form a compound of Formula VIII
##STR00007##
[0013] A compound of Formula VIII can be activated and condensed
with a second alcohol or phenol to form IX
##STR00008##
[0014] A compound of Formula IX can be deacylated to form an amino
phosphonate compound of Formula X
##STR00009##
[0015] A compound of Formula X can be isolated as a salt of an
organic or inorganic acid.
[0016] The Ghosh process for bisfuran alcohol (Ghosh, A. K. et al,
J. Org. Chem., 1995, 36, 505) requires the use of tributyltin
hydride and ozone.
[0017] The free base of a compound of Formula I is non-crystalline
and hygroscopic with limited stability in protic solvents.
[0018] Thus, there exists a need to develop syntheses of more
stable forms of the PI of Formula I. There also exists a need to
develop more efficient processes of synthesizing the PI of Formula
I.
SUMMARY OF THE INVENTION
[0019] The present invention provides improved methods to bisfuran
alcohol derivatives, amino phosphonate derivatives and a process to
prepare carbamate sulfonamide aminoethyl phosphonate diesters
useful for the treatment of human auto immunodeficiency syndrome
(AIDS).
[0020] In one embodiment, the invention provides a process for the
preparation of a bisfuran alcohol of Formula 0:
##STR00010##
comprising
[0021] reacting 2,3-dihydrofuran and glycoaldehyde or glycoaldehyde
dimer in the presence of a lanthanide or transition metal catalyst
to form the bisfuran alcohol of Formula 0.
DETAILED DESCRIPTION OF EXEMPLARY EMBODIMENTS
Definitions
[0022] Unless stated otherwise, the following terms and phrases as
used herein are intended to have the following meanings:
[0023] When tradenames are used herein, applicants intend to
independently include the tradename product and the active
pharmaceutical ingredient(s) of the tradename product.
[0024] "Protecting group" refers to a moiety of a compound that
masks or alters the properties of a functional group or the
properties of the compound as a whole. Chemical protecting groups
and strategies for protection/deprotection are well known in the
art. See e.g., Protective Groups in Organic Chemistry, Theodora W.
Greene, John Wiley & Sons, Inc., New York, 1991. Protecting
groups are often utilized to mask the reactivity of certain
functional groups, to assist in the efficiency of desired chemical
reactions, e.g., making and breaking chemical bonds in an ordered
and planned fashion. Protection of functional groups of a compound
alters other physical properties besides the reactivity of the
protected functional group, such as the polarity, lipophilicity
(hydrophobicity), and other properties which can be measured by
common analytical tools. Chemically protected intermediates may
themselves be biologically active or inactive.
[0025] The term "chiral" refers to molecules which have the
property of non-superimposability of the mirror image partner,
while the term "achiral" refers to molecules which are
superimposable on their mirror image partner.
[0026] The term "stereoisomers" refers to compounds which have
identical chemical constitution, but differ with regard to the
arrangement of the atoms or groups in space.
[0027] "Diastereomer" refers to a stereoisomer with two or more
centers of chirality and whose molecules are not mirror images of
one another. Diastereomers have different physical properties,
e.g., melting points, boiling points, spectral properties, and
reactivities. Mixtures of diastereomers may separate under high
resolution analytical procedures such as electrophoresis and
chromatography.
[0028] "Enantiomers" refer to two stereoisomers of a compound which
are non-superimposable mirror images of one another.
[0029] "Lanthanides" refers to the following elements and their
ions: La, Ce, Pr, Nd, Pm, Sm, Eu, Gd, Tb, Dy, Ho, Er, Tm, Yb,
Lu.
[0030] "Transition metals" refer to the following elements and
their ions: Sc, Ti, V, Cr, Mn, Fe, Co, Ni, Cu, Zn, Y, Zr, Nb, Mo,
Tc, Ru, Rh, Pd, Ag, Cd, Hf, Ta, W, Re, Os, Ir, Pt, Au, Hg.
[0031] Ligands comprising the metal catalysts may be chiral,
achiral or racemic.
Schemes and Examples
[0032] General aspects of these exemplary methods are described
below and in the Examples. Each of the products of the following
processes is optionally separated, isolated, and/or purified prior
to its use in subsequent processes.
[0033] Oxidation and reduction reactions are typically carried out
at temperatures near room temperature (about 20.degree. C.),
although for metal hydride reductions frequently the temperature is
reduced to 0.degree. C. to -100.degree. C., solvents are typically
aprotic for reductions and may be either protic or aprotic for
oxidations. Reaction times are adjusted to achieve desired
conversions.
[0034] Condensation reactions are typically carried out at
temperatures near room temperature, although for non-equilibrating,
kinetically controlled condensations reduced temperatures
(0.degree. C. to -100.degree. C.) are also common. Solvents can be
either protic (common in equilibrating reactions) or aprotic
(common in kinetically controlled reactions).
[0035] Standard synthetic techniques such as azeotropic removal of
reaction by-products and use of anhydrous reaction conditions
(e.g., inert gas environments) are common in the art and will be
applied when applicable.
[0036] The terms "treated", "treating", "treatment", and the like,
when used in connection with a chemical synthetic operation, mean
contacting, mixing, reacting, allowing to react, bringing into
contact, and other terms common in the art for indicating that one
or more chemical entities is treated in such a manner as to convert
it to one or more other chemical entities. This means that
"treating compound one with compound two" is synonymous with
"allowing compound one to react with compound two", "contacting
compound one with compound two", "reacting compound one with
compound two", and other expressions common in the art of organic
synthesis for reasonably indicating that compound one was
"treated", "reacted", "allowed to react", etc., with compound two.
For example, treating indicates the reasonable and usual manner in
which organic chemicals are allowed to react. Normal concentrations
(0.01M to 10M, typically 0.1M to 1M), temperatures (-100.degree. C.
to 250.degree. C., typically -78.degree. C. to 150.degree. C., more
typically -78.degree. C. to 100.degree. C., still more typically
0.degree. C. to 100.degree. C.), reaction vessels (typically glass,
plastic, metal), solvents, pressures, atmospheres (typically air
for oxygen and water insensitive reactions or nitrogen or argon for
oxygen or water sensitive), etc., are intended unless otherwise
indicated. The knowledge of similar reactions known in the art of
organic synthesis are used in selecting the conditions and
apparatus for "treating" in a given process. In particular, one of
ordinary skill in the art of organic synthesis selects conditions
and apparatus reasonably expected to successfully carry out the
chemical reactions of the described processes based on the
knowledge in the art.
[0037] In each of the exemplary schemes it may be advantageous to
separate reaction products from one another and/or from starting
materials. The desired products of each step or series of steps is
separated and/or purified (hereinafter separated) to the desired
degree of homogeneity by the techniques common in the art.
Typically such separations involve multiphase extraction,
crystallization from a solvent or solvent mixture, distillation,
sublimation, or chromatography. Chromatography can involve any
number of methods including, for example: reverse-phase and normal
phase; size exclusion; ion exchange; high, medium, and low pressure
liquid chromatography methods and apparatus; small scale
analytical; simulated moving bed (SMB) and preparative thin or
thick layer chromatography, as well as techniques of small scale
thin layer and flash chromatography.
[0038] Another class of separation methods involves treatment of a
mixture with a reagent selected to bind to or render otherwise
separable a desired product, unreacted starting material, reaction
by product, or the like. Such reagents include adsorbents or
absorbents such as activated carbon, molecular sieves, ion exchange
media, or the like. Alternatively, the reagents can be acids in the
case of a basic material, bases in the case of an acidic material,
binding reagents such as antibodies, binding proteins, selective
chelators such as crown ethers, liquid/liquid ion extraction
reagents (LIX), or the like.
[0039] A single stereoisomer, e.g., an enantiomer, substantially
free of its stereoisomer may be obtained by resolution of the
racemic mixture using a method such as formation of diastereomers
using optically active resolving agents (Stereochemistry of Carbon
Compounds, (1962) by E. L. Eliel, McGraw Hill; Lochmuller, C. H.,
(1975) J. Chromatogr., 113:(3) 283-302). Racemic mixtures of chiral
compounds of the invention can be separated and isolated by any
suitable method, including: (1) formation of ionic, diastereomeric
salts with chiral compounds and separation by fractional
crystallization or other methods, (2) formation of diastereomeric
compounds with chiral derivatizing reagents, separation of the
diastereomers, and conversion to the pure stereoisomers, and (3)
separation of the substantially pure or enriched stereoisomers
directly under chiral conditions.
Exemplary Embodiments
[0040] In one embodiment, the invention provides a compound of
Formula C and a pharmaceutically acceptable salt thereof:
##STR00011##
[0041] In another embodiment, the invention provides a process of
preparing a compound of Formula M comprising
[0042] a) treating a compound of Formula E with an amine such as
1-amino-2-methylpropane
##STR00012##
to form a compound of Formula F
##STR00013##
[0043] b) treating the compound of Formula F with a compound of
Formula G
##STR00014##
to form a compound of Formula C
##STR00015##
[0044] c) treating the compound of Formula C with a reducing agent
to form the compound of Formula M
##STR00016##
[0045] Typical reducing agent which can be used to effect the
transformation of the nitrile moiety to the carboxaldehyde moiety
can found in Larock, Richard, C. "Comprehensive Organic
Transformations 2.sup.nd Ed. 1999 John Wiley and Sons publisher,
pages 1271-1272.
[0046] In another embodiment, the invention provides a compound of
Formula M:
##STR00017##
[0047] In another embodiment, the invention provides a process for
the preparation of a compound of Formula M:
##STR00018##
comprising
[0048] treating a compound of Formula C with a reducing agent to
form the compound of Formula M
##STR00019##
[0049] In another embodiment, the invention provides a process of
preparing the compound of Formula M, wherein the reducing agent is
diisobutyl aluminum hydride.
[0050] In another embodiment, the invention provides a process of
preparing a compound of Formula 0, further comprising
[0051] treating the bisfuran alcohol of Formula 0 with
disuccinimidyl dicarbonate to form a compound of Formula L1
##STR00020##
[0052] In another embodiment, the invention provides a process of
preparing the compound of Formula 0, further comprising
[0053] treating the bisfuran alcohol of Formula 0 with
bis(p-nitrophenyl)carbonate or p-nitrophenol chloroformate to form
a compound of Formula L2
##STR00021##
[0054] In another embodiment, the invention provides a process of
preparing the compound of Formula 0, further comprising
[0055] treating the bisfuran alcohol of Formula 0 with dipyridyl
carbonate to form a compound of Formula L3
##STR00022##
[0056] In another embodiment, the invention provides a compound and
pharmaceutically acceptable salts thereof having Formula N
##STR00023##
[0057] In another embodiment, the invention provides a compound and
pharmaceutically acceptable salts thereof having Formula A
##STR00024##
[0058] In another embodiment, the invention provides a process for
the preparation of carbamate sulfonamide amino phosphonate esters
which comprises:
[0059] a) addition of a dihydrofuran to a glycoaldehyde or
glycoaldehyde dimer in the presence of a Yb, Pr, Cu, Eu or Sc
catalyst to form the bisfuran alcohol of Formula 0
##STR00025##
[0060] b) treating the reaction product of step (a) with
disuccinimidyl dicarbonate, bis(p-nitro)phenyl carbonate,
p-nitrophenol chloroformate, or dipyridyl carbonate to form a
compound of Formula L1, Formula L2, Formula L2, or Formula L3,
respectively,
##STR00026##
[0061] c) treating a compound of Formula E with an amine
##STR00027##
to form a compound of Formula F
##STR00028##
[0062] d) treating a compound of Formula F with a compound of
Formula G
##STR00029##
to form a compound of Formula C
##STR00030##
[0063] e) treating a compound of Formula C with a reducing agent to
form a compound of Formula M
##STR00031##
[0064] f) deprotecting a compound of Formula M with trifluoroacetic
acid, hydrochloric acid, toluenesulfonic acid, methanesulfonic
acid, benzenesulfonic acid, hydrobromic acid or another suitable
acid as listed in Protective Groups in Organic Chemistry, Theodora
W. Greene, John Wiley & Sons, Inc., New York, 1991, to form a
compound of Formula N
##STR00032##
[0065] g) treating a compound of Formula N with a compound of
Formula L, L2, or L3 to form a compound of Formula A
##STR00033##
[0066] h) treating a compound of Formula A with a compound of
Formula J
##STR00034##
to form a compound of Formula I
##STR00035##
[0067] i) treating a compound of Formula I with adipic acid to form
a salt of formula IV
##STR00036##
[0068] In another embodiment, the invention provides a salt having
Formula IV:
##STR00037##
[0069] The salt of formula IV was prepared and has a melting point
of 118.degree. C.-121.degree. C. The free base of the salt of
formula IV is an HIV protease inhibitor which has been made and
disclosed in WO2003/090690, which is herein incorporated by
reference. The salt of Formula IV is also an HIV protease inhibitor
useful for treating patients infected by HIV.
TABLE-US-00001 TABLE 1 Chiral catalysts in bisfuran alcohol
formation. ##STR00038## Conversion GC Analysis.sup.1 Entry
Conditions Catalyst Solvent (%) [(-)-1 to (+)-1] 1 50.degree. C., 5
hr Yb(hfc).sub.3 (+) DHF 100 49 to 51 2 50.degree. C., 5 hr
Yb(hfc).sub.3 (-) DHF 100 50 to 50 3 50.degree. C., 5 hr
Eu(hfc).sub.3 (+) DHF 100 48 to 52 4 r. t., 20 hr Yb(fod).sub.3, S-
MTBE 100 50 to 50 binaphthol 5 50.degree. C., 5 hr Yb(tfc).sub.3
(+) DHF 100 52 to 48 6 50.degree. C., 5 hr Pr(tfc).sub.3 (+) DHF
100 56 to 44 7 50.degree. C., 2.5 hr Yb[(R)-(-)-BNP].sub.3 DHF 100
60:40 8 30.degree. C., 12 hr Yb[(R)-(-)-BNP].sub.3 DHF 100 59:41 9
50.degree. C., 5 hr Yb[(R)-(-)-BNP].sub.3 DHF 100 65:35 10 r. t., 5
hr Cu[Pybox] DHF Polymerized DNA 11 50.degree. C., 5 hr Cu[Pybox]
DHF Polymerized DNA 12 r. t., 5 hr Cu[Pybox] DCM <5 DNA 13
50.degree. C., 5 hr Cu[Pybox] DCM 0 DNA 14 r. t., 20 hr Cu[Pybox]
DHF/DCM 0 DNA DHF = dihydrofuran, DCM = dichloromethane, MTBE =
methyl-t-butylether. .sup.1GC analyses were performed by
derivatizing bisfuran alcohol to the trifluoroacetate with
trifluoroacetic anhydride in DCM. ##STR00039## ##STR00040##
##STR00041## ##STR00042##
TABLE-US-00002 TABLE 2 Use of scandium (III) catalyst and chiral
ligands to directly access (-)-1. ##STR00043## Catalyt Ligand Temp
Time Conversion GC Analysis.sup.1 Entry Mol % Mo l% (.degree. C.)
(hrs) Solvent (%) [(-) to (+)] 1 3.4 7.5 r. t. (3)5 DCM 100 79:21 2
3.4 3.6 -10 to (3)5 DCM 100 62:38 r. t. 3 20.0 21.4 r. t. (3)24 DCM
<10 NA 4 3.4 7.6 r. t. (3)24 DCM <10 NA 5 3.4 7.5 r. t. (3)5
DCM 100 78:22 6 3.35 9.37 50 (3)5 DCM <10 NA 7 3.35 9.37 r. t.
(3)5 THF <10 NA 8 3.35 9.37 r. t. (3)5 MTBE/ <10 NA DME 9
3.35 9.37 0 (3)5 THF 100 75:25 10 3.35 9.37 r. t. (3)5 MeCN 100
74:26 11 6.7 18.74 r. t. (3)5 DCM 100 82:18 12 10.0 60.0 r. t. (3)5
DCM 100 82:18 13 6.7 18.74 r. t. (3)5 TFT <5 NA 14 6.7 18.74 0
(3)5 DCM 100 85:15 15 6.7 18.74 0 (3)6 CHCl.sub.3 >10 NA 16 6.7
18.74 -78 (3)6 DCM 0 NA 17 6.7 18.74 -20 (3)6 DCM <5 NA 18 6.7
18.74 0 to -5 (5)68 DCM 100 82:18 TFT = trifluorotoluene, DME =
dimethavethane, DCM = dichloromethane, MTBE = methyl-t-butylether,
THF = tetrahydrofuran. .sup.1GC analyses were performed by
derivatizing bisfuran alcohol to the trifluoroacetate with
trifluoroacetic anhydride in DCM
TABLE-US-00003 TABLE 3 Use of catalystsand chiral ligands to
directly access (-)-1. ##STR00044## GC Analysis.sup.1 Catalyst
Catalyst Ligand Ligand Temp Time [(-) to Entry Used Mol % Used Mol
% (.degree. C.) (hrs) Solvent (+)] 1 Sc(OTf).sub.3 3.4 2 7.5 r. t.
(3)24 DCM Messy 2 Sc(OTf).sub.3 3.4 2 7.5 r. t. (3)5 DCM 26:74 3
Yb(OTf).sub.3 3.4 2 7.6 r. t. (3)3 DCM 50:50 4 Sc(OTf).sub.3 3.4 2
12.0 r. t. (3)5 DCM 23:77 5 Sc(OTf).sub.3 3.35 3 7.54 r. t. (3)5
DCM 51:49 6 Sc(OTf).sub.3 3.5 4 7.5 r. t. (3)5 DCM 57:43 7
Cu(OTf).sub.2 4.8 5 5.6 r. t. (0.5)3 DCM 52:48 8 Cu(OTf).sub.2 5.6
5 13.97 r. t. (3)5 DCM 52:48 9 Yb(OTf).sub.3 6.7 1 18.74 r. t. (3)5
DCM 61:39 .sup.1GC analyses were performed by derivatizing bisfuran
alcohol to the trifluoroacetate with trifluoroacetic anhydride in
DCM. ##STR00045## ##STR00046## ##STR00047## ##STR00048##
##STR00049##
TABLE-US-00004 TABLE 4 Use of column method for enantiomeric
resolution of (.+-.)-bisfuran ##STR00050## ##STR00051## Re- Lipase
Amt of Rate sidence Total (ROAc Optical Activity Lipase (mL/ Time
Time to ROH Purity Yield Entry (U/g) (g) min) (min) (hrs) (10:1) (%
ee) (%) 1 1925 18.6 17 1.8 10.5 1.5:1.0 97.2 32 2 1925 22.7 164
0.52 19.0 NA 98.2 42 3 1925 275.6 2000 0.8 14.5 1.2:1.0 97.2 33
##STR00052##
##STR00053##
##STR00054##
##STR00055##
##STR00056## [0070] Yamanuchi, K. et al, J. Org. Chem., 1984, 49,
1158; Chapman, H. et al; Nucl. Nucleotid. Nucleic Acids, 2001, 20,
621
##STR00057##
##STR00058##
[0071] The invention will now be illustrated by the following
non-limiting Examples.
##STR00059##
Examples
##STR00060##
[0072] Preparation of, (3R,3aS,6aR) Hexahydrofuro[2,3-b]furan-3-ol,
(1)
[0073] To a reaction vessel, charge glycolaldehyde dimer (4.45 kg),
Yb(fod).sub.3 catalyst (0.29 kg) and dihydrofuran (20.5 kg).
Agitate contents to mix and heat to 50.degree. C. for .about.5
hours. Concentrate reaction content to a crude oil, dissolve in
saturated aqueous NaHCO.sub.3 solution (60 kg), and wash with
dichloromethane (6 kg). Charge dichloromethane (58 kg), KBr (0.89
kg), TEMPO (0.116 kg) to the aqueous layer and cool the mixture to
0.degree. C. Slowly add to this mixture with sodium hypochlorite
(NaOCl, .about.11% Cl, 55 kg). Upon completion of reaction, allow
the organic and aqueous layers to separate. Wash the aqueous layer
with dichloromethane (29 kg). Combine the organic layers and wash
with water, 10% HCl with KI, and 10% sodium thiosulfate. Dry the
organic layer over sodium sulfate, filter the solids, and cool the
filtrate to below 0.degree. C. Add a solution of sodium borohydride
(0.36 kg) in ethanol (7.1 kg) while maintaining reaction content
temperature below 0.degree. C. Upon completion of reaction, add
acetic acid (1.4 kg) and water (13.4 kg) to quench. Concentrate
mixture by vacuum distillation. To the resulting crude
oil/semi-solid mixture, add ethyl acetate (31 kg). Dry organic
layer over sodium sulfate, filter solids, and concentrate via
vacuum distillation to isolate (.+-.)-1 as an oil. Enzymatic
Resolution. Charge ethylene glycol dimethyl ether (DME, 14.7 kg)
and acetic anhydride (4.6 kg) to the crude product oil. Circulate
this solution through a column packed with a mixture of Lipase PS-C
"Amano I" (0.36 kg) and sand (6 kg). Upon completion of the
enantiomeric resolution, concentrate the solution via vacuum
distillation. Add water (18 kg) to dissolve the product and wash
the solution with dichloromethane (28 kg). Concentrate the product
containing aqueous layer via vacuum distillation. Dissolve the
resulting oil in ethyl acetate (16 kg) and dry over sodium sulfate.
Additional product can be isolated by back extracting the
dichloromethane layer with water several times. Concentrate the
combined water layers via vacuum distillation. Dissolve the
resulting oil in ethyl acetate; dry over sodium sulfate, and filter
solids. Concentrate the combined ethyl acetate layers via vacuum
distillation to afford the product, (3R,3.alpha.S, 6.alpha.R)
hexahydrofuro[2,3-b]furan-3-ol, (-)-1, as an oil (1.6 kg, 97% ee,
33% yield) contaminated with a approximately 15 wt % of the
corresponding acetate. Analytical data: .sup.1H NMR (DMSO-d6, 300
MHz) .delta. 5.52 (dd, 1H), 4.25-4.15 (m, 1H), 3.85-175 (m, 2H),
3.7-3.6 (m, 1H), 3.3 (t, 1H), 2.75-2.65 (m, 1H), 2.23-2.13 (m, 1H),
1.75-1.6 (m, 1H).
##STR00061##
Preparation of (3R,3aS,6aR)-Hexahydrofuro[2,3-b]furan-3-yl
4-Nitrophenyl Carbonate)
[0074] Charge to a reaction vessel with bis(4-nitrophenyl)carbonate
(2.85 kg) and dichloromethane (33.4 kg). Add to this solution with
(3R,3aS,6aR)-hexahydrofuro[2,3-b]furan-3-ol, (-)-1 (1.2 kg, 98.5%
ee, contaminated with .about.36% acetate) dissolved in
dichloromethane (6.7 kg). Charge triethylamine (1.6 kg) and agitate
the resulting reaction contents at 20-25.degree. C. Upon completion
of reaction, wash the contents with water (16.8 kg). Separate the
layers and concentrate the dichloromethane layer via vacuum
distillation. Dissolve the product containing oil in ethyl acetate
(21.2 kg) and sequentially wash with water, aqueous potassium
carbonate solution and brine. Dry the ethyl acetate layer over
sodium sulfate, filter solids, and concentrate via vacuum
distillation. Dissolve the concentrated product mixture in ethyl
acetate (9.3 kg) and heat to 45.degree. C. Charge hexanes (6.7 kg)
slowly and cool the final mixture slowly to 0.degree. C. Filter the
resulting slurry to isolate 12. Wash the solid cake with a solution
of ethyl acetate and hexanes (1:1 v/v, 5.3 kg). Dry the product to
constant weight affording 1.5 kg of 12 (55%) as an off-white solid.
Additional product may be obtained by concentrating the mother
liquor via vacuum distillation and repeating the crystallization
procedure. Analytical data: .sup.1H NMR (CDCl.sub.3, 300 MHz)
.delta. 8.3 (d, 2H), 7.4 (d, 2H), 5.8 (d, 1H) 5.3-5.2 (m, 1H),
4.2-4.1 (m, 1H), 4.1-3.9 (m, 3H), 3.25-3.1 (m, 1H), 2.3-2.1 (m,
1H), 2.1-1.9 (m, 1H); HPLC AN=98.5%.
Procedure for Formula 12,
{(2S,3R)-1-(4-Benzyloxy-benzyl)-2-hydroxy-3-[isobutyl-(4-methoxy-benzenes-
ulfonyl)-amino]-propyl}-[3R,3aS,6aR]-carbamic acid
hexahydro-furo[2,3-b]furan-3-yl ester
##STR00062##
[0076] A flask is charged with Formula 27 (1.3 Kg), followed by
Formula 12 (0.65 Kg) and ethyl acetate (7.2 Kg) and agitated and
triethylamine (0.65 Kg) and dimethylaminopyridine (24 g) added and
agitated at ambient temperature for several hours. The reaction
mixture is washed sequentially with water (8 Kg), aqueous saturated
NaHCO.sub.3 (8 L) and dilute aqueous HCl (8 L) and brine (8 L). The
reaction mixture is charged with activated charcoal (0.13 Kg),
stirred for several hours, filtered through celite and rinsed with
ethyl acetate. Heptane (6 L) is added, the mixture agitated for
several hours and the product collected by filtration, and rinsed
with 1:1 EtOAc/Heptane. The product is dried to constant weight
affording 1 Kg of Formula 12 (70%) as an off white solid, mp
127.5.degree. C., HPLC purity 98.4. .sup.1H NMR (CDCl.sub.3)
7.7-7.75 (d, 2H), 7.26-7.48 (m, 5H), 7.12-7.20 (d, 2H), 6.96-7.03
(d, 2H), 6.85-6.94 (d, 2H), 5.65 (d, 1H), 5.3 (broad d, 1H), 5.01
(s, 2H), 4.96-5.06 (broad, 1H), 3.63-3.96 (m, 7H), 3.84 (s, 3H),
2.62-3.20 (m, 7H), 1.8-1.95 (m, 1H), 1.40-1.69 (m, 2H), 0.95 (dd,
6H).
Procedure for Formula 13, {[1S,
2R}-2-Hydroxy-1-(4-hydroxy-benzyl)-3-[N-isobutyl-(N-4-methoxybenzenesulfo-
nyl)-amino]propyl}-carbamic acid
hexahydro-[3R,3aS,6aR]-furo[2,3-b]furan-3-yl ester
##STR00063##
[0078] A flask is charged with Formula 12 (1 Kg) and flushed with
nitrogen. Palladium on activated carbon, 10 wt %, wet, (0.2 Kg) is
added, the flask flushed with nitrogen and ethyl acetate (10 L)
added and the mixture is heated to 50.degree. C. and hydrogen is
sparged into reaction mixture for 2.5 h until reaction is complete.
The mixture is sparged with nitrogen and then filtered through
celite under nitrogen and then rinsed with ethyl acetate. The
filtrate is concentrated to 2.5 L and heptane (7.5 L) added to the
warm solution. The resultant slurry is cooled in an ice bath,
collected and washed with n-heptane and dried to constant weight
affording Formula 13 as a solid, 0.82 Kg, mp: two endotherms at
98.2 and 133.8.degree. C., HPLC purity 97.4%. .sup.1H NMR
(CDCl.sub.3) 7.61-7.75 (d, 2H), 7.01-7.10 (m, 2H), 6.91-6.99 (d,
2H), 6.63-6.79 (d, 2H), 5.62 (d, 2H), 5.51 (broad s, 1H), 4.96-5.09
(d, 2H), 3.81 (s, 3H), 3.59-3.98 (m, 6H), 2.62-3.18 (m, 7H),
1.42-1.91 (m, 3H), 0.78-0.95 (dd, 6H).
Procedure for Formula 14, Trifluoro-methanesulfonic acid
4-(2S,3R)-{2-([2R,
3S]-hexahydro-furo[2,3-b]furan-(3R)-3-yloxycarbonylamino)-3-hydroxy-4-[N--
isobutyl-(N-4-methoxybenzenesulfonyl)-amino]-butyl}-phenyl
ester
##STR00064##
[0080] Formula 13 (0.82 Kg) and dichloromethane (8 Kg) were charged
into a flask, and gently warmed to dissolve the Formula 13. A
separate flask was charged with N-phenyltriflimide (0.61 Kg) and
dichloromethane (2.6 Kg) and gently warmed to obtain a solution. A
solution of triflating agent was transferred into the solution
containing Formula 13 and cesium carbonate (0.55 Kg) was added and
stirring continued at ambient temperature for several hours until
reaction was complete. Water (4 Kg) was added, the layers
separated, the aqueous back extracted with dichloromethane and the
combined organic layers dried over anhydrous sodium sulfate. The
solution was filtered and concentrated to a small volume and
diluted sequentially with methyl tert butyl ether (7 L) and heptane
(16 L) and stirred at ambient temperature to obtain a solid which
was collected and dried to constant weight to provide Formula 14 as
a solid, 0.68 Kg, mp 133.7.degree. C., .sup.19F NMR
(CDCl.sub.3)-73.5 ppm, HPLC purity 97.2%. .sup.1H NMR (CDCl.sub.3)
7.70-7.78 (d, 2H), 7.29-7.38 (d, 2H), 7.16-7.23 (d, 2H), 6.96-7.06
(d, 2H), 5.67 (d, 1H), 4.95-5.04 (m, 2H), 3.87 (s, 3H), 3.64-4.01
(m, 7H), 2.78-3.21 (m, 7H), 1.51-1.90 (m, 3H), 0.87-0.97 (dd,
6H).
Procedure for Formula 15,
{(1S,2R)-[1-(4-Formyl-benzyl)]-(2R)-2-hydroxy-3-[N-isobutyl-(N-4-methoxy--
benzenesulfonyl)-amino]-propyl}-carbamic acid
[3R,3aS,6aR]-hexahydrofuro[2,3-b]furan-3-yl ester
##STR00065##
[0082] A flask is charged with Formula 14 (0.15 Kg) followed by
Pd(OAc).sub.2 (0.06 Kg), dppp. (0.1 Kg), dimethylformamide (1.9 Kg)
and sequentially evacuated by vacuum and purged with nitrogen
several times and then heated under nitrogen to an internal
temperature of 60 to 65.degree. C. and lithium chloride (3 g) is
added. The mixture is heated at 65-70.degree. C. and the mixture is
sparged with carbon monoxide for 30 minutes. Triethylamine (86 g)
is charged to the solution, followed by slow addition of
triethylsilane (0.05 Kg). The reaction is maintained at
65-70.degree. C. under a CO atmosphere until the reaction is
complete. The reaction mixture is cooled to ambient temperature,
diluted with ethyl acetate (1.8 Kg) and washed with water (4 Kg).
The ethyl acetate is back extracted with water (1 Kg) and the
combined water layers back extracted with ethyl acetate (0.5 Kg).
The combined ethyl acetate extracts are washed with water several
times and the ethyl acetate filtered through celite, diluted with
acetonitrile (0.2 Kg). HF (48% in water, 0.23 Kg) and saturated
NaHCO.sub.3 (3 Kg) are added, the reaction mixture is separated and
the aqueous layer discarded. The organic layer is dried over
anhydrous sodium sulfate, filtered and the filtrate heated to a
temperature of 50-55.degree. C., treated with trimercaptotriazine
(23 g) for several minutes, activated carbon (10 g) added, the
mixture heated at 50-55.degree. C. for at least 30 minutes, cooled
to ambient temperature and filtered through a pad of celite. The
filtrate is washed with saturated NaHCO.sub.3 (0.7 Kg), separated,
dried over anhydrous sodium sulfate, filtered, and concentrated and
the residue purified by silica gel column chromatography eluting
with a mixture of ethyl acetate and heptane. The fractions
containing desired Formula 15 are collected and concentrated to
afford a white solid which is recrystallized by dissolving in
ethylene glycol dimethyl ether at elevated temperature and slow
addition of heptane followed by cooling to ambient temperature.
Collection of the solid by filtration, rinsing with heptane and
drying to constant weight provides Formula 15 as a white solid,
72%, 0.125 Kg, mp 140.2.degree. C., HPLC purity 98.3%. .sup.1H NMR
(CDCl.sub.3) 9.98 (s, 1H), 7.80-7.85 (d, 2H), 7.67-7.76 (d, 2H),
7.39-7.45 (d, 2H), 6.95-7.04 (d, 2H), 5.65 (d, 1H), 4.96-5.12 (m,
2H), 3.85 (s, 3H), 3.64-4.02 (m, 7H), 2.75-3.21 (m, 7H), 1.72-1.89
(m, 1H), 1.42-1.70 (m, 2H), 0.84-0.98, dd, 6H).
Procedure for Formula 16,
2-(N-benzyloxycarbamoyl)-aminoethylphosphonic acid
##STR00066##
[0084] A flask is charged with deionized water (9 Kg), inerted,
agitated and charged with sodium hydroxide (2.7 Kg) in portions to
maintain the temperature below 35.degree. C.
[0085] Aminoethyl phosphonic acid (AEP, 3 Kg) is charged into the
flask in portions. Benzyl chloroformate (5.6 Kg) is added in
several portions controlling the temperature at approximately
between 40.degree. C. The mixture is allowed to react at ambient
temperature for several hours until reaction is complete. The
mixture is extracted twice with ethyl acetate (16 Kg portions). The
aqueous layer is acidified with concentrated HCl to pH 1.3 and aged
for several hours. The solid is collected and washed with
acetonitrile (2.3 Kg). The solid and methanol (9.6 Kg) is then
charged to a flask and treated with Dowex resin (8.7 Kg) that has
been prewashed with water and methanol. The mixture is stirred at
ambient temperature for 1 h, filtered and rinsed with methanol (3
Kg). The filtrate is concentrated to thick oil, diluted with
acetonitrile and azeotroped repeatedly with acetonitrile until
residual methanol is removed. The solution is then diluted with
acetonitrile, heated to attain a solution, filtered and allowed to
cool gradually to ice bath temperature.
[0086] The solid is collected and dried to constant weight
affording Formula 16 (CBZ-AEP) 4.8 Kg, 77%, mp 107.degree. C.,
.sup.31P NMR (D.sub.2O) 26.6 ppm. .sup.1H NMR (D.sub.2O) 7.2-7.36
(broad s, 5H), 4.95 (broad s, 2H), 3.16-3.30 (m, 2H), 1.78-1.94 (m,
2H).
Procedure for Formula 17,
Phenyl-2-(N-benzyloxycarbamoyl)-aminoethylphosphonate
##STR00067##
[0088] CBZ-AEP (2.5 Kg) and acetonitrile (3.1 Kg) were stirred and
heated to 60-65.degree. C. In a separate flask, phenol (4.5 Kg) and
acetonitrile (3.5 Kg) were warmed to afford a solution and this
solution was charged to the CBZ-AEP mixture and stirred until a
solution was obtained. To this solution was charged a slurry of
4-dimethylaminopyridine (DMAP, 1.4 Kg) in acetonitrile (3.1 Kg). In
a separate flask was charged acetonitrile (0.8 Kg) and
dicyclohexylcarbodiimide (3 Kg) was charged. This DCC solution was
added to the warm AEP solution. As soon as the addition was
complete, the reaction mixture was refluxed for several hours until
the reaction was complete. The reaction mixture was cooled to
ambient temperature, filtered and the filtrate concentrated and
diluted with water (20 L) and aqueous NaOH. The solution was
extracted twice with ethyl acetate (13.5 L). The aqueous phase was
acidified to pH of 1.0 by addition of 6M HCl, the resultant solid
collected and reslurried with water (19 L) and collected again, and
dried to constant weight to provide Formula 17 as a white solid,
2.47 Kg, mp 124.degree. C., HPLC purity 99.2%, .sup.31P NMR
(CDCl.sub.3) 29.8 ppm (.about.90%) and 28.6 ppm (.about.10%) due to
rotamers of the carbamate functional group. .sup.1H NMR
(CDCl.sub.3) 7.05-7.40 (m, 10H), 5.10 (broad s, 2H), 3.41-3.59 (m,
2H), 2.01-2.20 (m, 2H).
Procedure for formula 18, Phenyl,
(ethyl(S)-2-propionyl)-2-(N-benzyloxycarbamoyl)-aminoethylphosphonate
##STR00068##
[0090] Formula 17 (4.8 kg) was charged to the reactor along with
toluene (24 kg) and DMF (4 g). The mixture was warmed to 70.degree.
C. SOCl.sub.2 was added over time while maintaining 67-72.degree.
C. internal contents temperature, and the reaction agitated at
75.degree. C. until the reaction was complete. The solution was
cooled to 45.degree. C. and concentrated under vacuum to approx.
half volume. In a separate reactor a dry solution of (S)-ethyl
lactate (1.9 kg), toluene (15 kg), and pyridine (1.5 kg) was
prepared and cooled to -1.degree. C. The chloridate solution was
added slowly while maintaining an internal temperature of -3 to
3.degree. C. and then the resulting solution was warmed to
20.degree. C. and agitated until the reaction was complete. The
reaction was added to a solution of 10% aq. citric acid (10 kg),
the layers separated and the organic layer washed with 10% aq.
NaH.sub.2PO.sub.4 (10 kg). The organic layer was dried over
anhydrous sodium sulfate (5 kg), concentrated and evaporated from
ethyl acetate (4 kg) to a viscous oil which is purified by passing
through silica gel plug (9:2 kg) eluting with a mixture of ethyl
acetate and heptane. The fractions containing Formula 17 were
combined and concentrated to afford an oil. The solvent was
exchanged by evaporating twice with acetonitrile (2.times.3 kg) to
afford an thick liquid (4.7 kg, 80%) with HPLC purity 98% as a
mixture of two diastereomers (corrected for benzyl chloride).
[0091] The mixture of isomers was separated on Chromasil silica
gel, eluting with a mixture of ethyl acetate and heptane. The
desired isomer Formula 20, displayed the following physical data:
Oil, .sup.31P NMR (CDCl.sub.3) 26.1 (.about.90%) and 25.4
(.about.10%) due to rotamers of the carbamate functional group;
.sup.1H NMR (CDCl.sub.3) 7.24-7.4 (m, 8H), 7.14-7.21 (m, 2H), 5.65
(broad s, 1H), 5.1 (s, 2H), 5.02-5.06 (m, 1H), 4.12-4.17 (q, 2H),
3.52-3.70 (m, 2H), 2.15-2.36 (m, 2H), 1.57 (d, 3H), 1.22 (t,
3H).
Procedure for Formula 19, Phenyl, (ethyl(S)-2-propionyl)-2-amino
ethylphosphonate, acetate salt
##STR00069##
[0093] A flask is charged with palladium on activated carbon, 10 wt
%, wet (0.28 Kg), acetic acid (0.15 L) and Formula 20 (0.56 Kg) and
ethanol (5.6 L) and the flask is sparged with nitrogen for
approximately 30 minutes. Hydrogen is sparged into reaction mixture
for several hours until the starting material is consumed. The
reaction mixture is sparged with nitrogen for 60 minutes and the
reaction mixture is filtered through celite and washed with ethyl
alcohol (2 L). The filtrate is concentrated at ambient temperature
to a small volume, diluted with acetonitrile (5.6 L), concentrated
to half volume, and treated with activated carbon (0.3 Kg),
filtered through celite and washed with acetonitrile (2.5 L). The
filtrate is evaporated at ambient temperature and diluted with
acetonitrile and evaporated. This is repeated several times to
remove all ethanol and water and the solution finally concentrated
to a small volume and stored at 5.degree. C. Evaporation of an
aliquot provided yield. Oil, 90%, 0.49 Kg, .sup.31P NMR
(CDCl.sub.3) 25.2. The material was used in the next step without
further purification.
Procedure for Formula 21,
2-[(2S,3R)-4-[((4-methoxybenzene)sulfonyl)(2-methylpropyl)amino]-3-(hydro-
xy)butyl]-[[[[(phenoxy)(2-(2R)-propionic acid ethyl
ester)oxy]phosphinyl]ethylamino]benzyl]-[carbamic
acid-(3R,3aS,6aR)-hexahydrofuro[2,3-b]furan-3-yl ester]hexanedioate
salt (1:1)
##STR00070##
[0095] A flask is charged with Formula 15 (0.5 Kg), acetonitrile
(1.6 L) and a solution of Formula 19 (0.46 Kg) in acetonitrile (1
L) followed by acetonitrile (2.4 L). The mixture is stirred at
ambient temperature several hours. NaBH(OAc).sub.3 (0.27 Kg) is
added in portions over time at ambient temperature to maintain at
ambient temperature. The reaction mixture is stirred several hours
until reaction is complete. Celite (0.24 Kg) is added and the
reaction mixture is filtered and washed with acetonitrile and
isopropyl acetate. The filtrate is concentrated to a small volume
and diluted with isopropyl acetate (12.5 L) and washed sequentially
with saturated NaHCO.sub.3 three-four times (7.5 L portions), brine
(3.8 L), the organic solution dried over sodium sulfate, filtered,
concentrated to a small volume, diluted with isopropyl acetate and
residual water removed azeotropically. The solution is diluted with
acetonitrile, warmed and adipic acid (0.13 Kg) added. The solution
is cooled gradually and the solid collected, and rinsed with
isopropyl acetate to provide Formula 21 as a solid, 0.69 Kg, 79%,
mp 119.degree. C., HPLC purity 95.3%. Spectral data was consistent
with that of a reference standard: .sup.31P NMR (acetone-d6) 27.6;
.sup.13C NMR (acetone-d6) ppm 173.4, 170, 162.6, 155.0, 150.4,
137.9, 137.4, 130.7, 129.3, 129.2, 129.1, 127.6, 124.5, 120.4,
113.9, 108.9, 72.7, 72.6, 70.4, 70.4, 68.6, 60.7, 57.8, 55.6, 54.9,
52.8, 52.3, 45.1, 42.1, 34.9, 32.6, 26.5, 26.5, 25.4, 24.0, 19.2,
18.6, 13.1; .sup.1H NMR (acetone d-6) ppm 7.80 (d, 2H), 7.38 (t,
2H), 7.29 (d, 2H), 7.28 (d, 2H), 7.26 (d, 2H), 7.21 (t, 1H), 7.12
(d, 2H), 5.53 (d, 1H), 5.04 (dq, 1H), 4.95 (ddd, 1H), 4.14 (q, 2H),
3.92 (s, 3H), 3.89 (m, 1H), 3.88 (dd, 1H), 3.84 (m, 1H), 3.78 (br
s, 2H), 3.76 (dd, 1H), 3.63 (dd, 1H), 3.60 (dd, 1H), 3.20 (dd, 1H),
3.06 (dd, 1H), 2.97 (dt, 2H), 2.91 (dd, 1H), 2.85 (m, 1H), 2.70
(dd, 1H), 2.33 (m, 2H), 2.24 (m, 2H), 2.04 (m, 1H), 1.67 (m, 2H),
1.51 (m, 2H), 1.51 (d, 3H), 1.21 (t, 3H), 0.93 (d, 3H), 0.89 (d,
3H); IR (KBr) cm.sup.-1 3354, 3424, 3300-2400 (br), 2959, 1755,
1703, 1599, 1497, 1308, 1343, 1152, 991, 950.
Procedure for Formula 21b,
2-[(2S,3R)-4-[((4-methoxybenzene)sulfonyl)(2-methylpropyl)amino]-3-(hydro-
xy)butyl]-[[[[(phenoxy)(2-(2R)-propionic acid ethyl
ester)oxy]phosphinyl]ethylamino]benzyl]-[carbamic
acid-(3R,3aS,6aR)-hexahydrofuro[2,3-b]furan-3-yl ester]butanedioate
salt (1:1)
[0096] Prepared by dissolving 7.8 g of the free base Formula 29 by
agitating in hot isopropyl acetate (.about.200 mL), charging
succinic acid (1 equivalent), and after a solution is obtained the
solution is gradually cooled to ambient temperature and then cooled
in an ice bath for several minutes, the product collected and
rinsed with isopropyl acetate and dried to constant weight
providing Formula 21b succinate salt, 7.7 g, 86%, HPLC purity
98.6%, mp 106.5.degree. C. .sup.13C NMR (CDCl.sub.3) 129.8, 129.4,
129.2, 124.9, 120.3, 114.1, 109.0, 70.9, 72.7, 71.4, 70.33, 70.28,
69.34, 69.30, 61.3, 56.51, 56.47, 55.3, 54.95, 52.24, 52.22, 51.74,
51.72, 44.93, 42.42, 30.65, 24.84, 24.79, 26.48, 25.42, 19.7, 19.6,
19.24, 13.7. .sup.1H NMR (CDCl.sub.3) 7.75-7.79 (d, 2H), 7.38-7.43
(d, 2H), 7.33-7.36 (m, 2H), 7.24-7.29 (d, 2H), 7.15-7.20 (t, 1H),
6.98-7.05 (4H), 5.63 (d, 1H), 5.00-5.08 (m, 1H), 5.84-4.92 (m, 1H),
4.09-4.18 (m, 3H), 3.93-3.98 (m, 1H), 3.91 (s, 3H), 3.79-3.92 (m,
4H), 3.66-3.74 (m, 1H), 3.22-3.56 (m, 4H), 2.96-3.02 (m, 2H),
2.51-2.83 (m, 10H), 1.74-1.82 (m, 2H), 1.6 (d, 3H), 1.46-2.01 (3H),
1.21 (t, 3H), 1.83 (d, 3H), 1.63 (d, 3H).
Procedure for Formula 22
##STR00071##
[0098] A flask is charged with 14.8 g of disuccidimidylcarbonate,
CH.sub.2Cl.sub.2 (25 mL), 5.0 g of Formula 10 as a solution in
CH.sub.2Cl.sub.2 (20 mL), and pyridine (7.8 mL). The solution is
heated at gentle reflux for several hours until reaction completes.
Heating is removed and water (35 mL) is added, the mixture agitated
several minutes, the layers are separated. The organic phase is
washed sequentially with water (35 mL) and brine (30 mL). The
organic phase is dried over sodium sulfate, filtered and
concentrated. The residue is redissolved in dichloromethane
CH.sub.2Cl.sub.2 (13 mL) with heating and heptane (10 mL) added to
the warm solution. The mixture is gradually cooled to approximately
10.degree. C., the solid filtered, rinsed with heptane and dried to
constant weight providing .about.8.9 g 87.5%.
[0099] A flask is charged with crude Formula 22 (106 g), activated
carbon (23 g) and toluene (5.7 Kg). After agitation for 2 h the
mixture is filtered through celite and the filtrate evaporated to
afford 100 g (94.3% recovery) of Formula 22 as an off-white
solid.
[0100] A flask is charged with Formula 22 (12 g) of Formula 22,
acetone (24 g) and heated to 52.degree. C. to obtain a solution.
Heptane (60 g) is added to the warm solution under agitation. The
mixture is cooled over two hours to approximately 10.degree. C.,
the solid collected, washed the with 3:1 acetone:heptane and dried
to constant weight, providing Formula 22, 11.4 g, 95% recovery, as
a white solid. .sup.1H NMR (CDCl.sub.3) 5.75 (d, 1H), 5.21-5.30
(dd, 1H), 3.90-4.16 (m, 4H), 3.07-3.18 (m, 1H), 2.85 (s, 4H),
2.10-2.22 (m, 1H), 1.92-2.06 (m, 1H).
Preparation of Formula 24
##STR00072##
[0102] A flask is charged with Formula 24 (10 g), potable water
(7.5 g, 13.5 eq.) and isobutylamine (22.08 g, 9.8 eq.), the thick
mixture heated to .about.60.degree. C., and agitated at this
temperature until reaction completed. The reaction mixture is
charged with 100 mL potable water over .about.30 minutes while
maintaining the internal temperature >55.degree. C. The mixture
is cooled to 5.degree. C. over 1.5 hours, and held at that
temperature for an additional 30 minutes. The slurry is filtered,
washed with 20 mL of potable water, and dried to constant weight
providing Formula 23, 10.94 g; 98.4%, HPLC purity 97.9%. .sup.1H
NMR (CDCl.sub.3) 7.55-7.62 (d, 2H), 7.32-7.38 (d, 2H), 4.62-4.72
(broad s, 1H), 3.78-3.90 (broad m, 1H), 3.42-3.50 (m, 1H),
3.08-3.16 (dd, 1H), 2.63-2.90 (m, 3H), 2.42 (d, 2H), 1.65-1.81 (m,
1H), 1.35 (s, 9H), 0.93 (d, 6H).
Preparation of Formula 25
##STR00073##
[0104] A flask is charged with Formula 23 (10.5 g), dichloromethane
(63 mL) and triethylamine (3.1 g, 1.05 eq.) and a solution of
4-methoxyphenylsulfonyl chloride (6.1 g, 1.02 eq.) in
dichloromethane (18 mL) added over .about.10 minutes, maintaining
the internal temperature <25.degree. C. during the addition.
Following reaction completion (-2 h at ambient temperature) 1M
aqueous HCl (5 mL) is added, agitated for 5 min, and the layers
separated. 1 M aqueous NaHCO.sub.3 (5 mL) are added to the organic
phase and the mixture agitated for 5 min, the layers separated and
the organic phase concentrated to a foam. The crude product is
dissolved in 200 mL EtOH at 65.degree. C., water (120 mL) added
over .about.45 minutes, while maintaining the internal temperature
>57.degree. C., and the mixture d, 2H), 7.36-7.43 (d, 2H),
6.96-7.04 (d, 2H), 4.63-4.72 (broad s, 1H), 3.88 (s, 3H), 3.72-3.90
(m, 2H), 3.04-3.18 (m, 3H), 2.79-3.01 (m, 3H), 1.78-1.92 (m, 1H),
1.62 (broad s, 1H), gradually cooled to 10.degree. C. over
approximately 4.5 hours. The slurry is filtered and washed with 50
mL of 30% aqueous EtOH, the product dried to constant weight
providing 14.5 g, 94%, HPLC purity 99.86%. .sup.1H NMR (CDCl.sub.3)
7.70-7.76 (d, 2H), 7.55-7.64 (1.35 (s, 9H), 0.85-0.95 (dd, 6H).
[0105] Procedure for Formula 26
##STR00074##
[0106] A flask is charged with Formula 25 (35 g), toluene (525 mL),
inerted and cooled to -20.degree. C. A solution of 1.5 M DIBAL-H in
toluene (154 mL, 1.5 M, 3.5 equiv.) is added gradually, keeping the
temperature below -10.degree. C. The reaction is agitated for
several hours at this temperature until complete. Methanol (9.3 mL,
3.5 eq.) is charged gradually, followed by THF (88 mL), and the
mixture warmed above 0.degree. C. Aqueous citric acid (220 ml of
40% (w/w) of citric acid, 7 eq.) diluted with 130 ml of water) is
added over 5 minutes and the mixture then warmed .about.60.degree.
C. for approximately 1 hour. The mixture is cooled to ambient
temperature, the layers separated, and the organic layer added to
175 ml of 1M HCl and 35 ml of water. The separatory funnel is
rinsed forward with 105 ml of THF. The resulting mixture is
agitated at room temperature for approximately 1 hour, diluted with
THF (35 mL), separated, the organic layer combined with 35 ml of 1
M NaHCO.sub.3 and agitated for 30 minutes. The layers were
separated, filtered through a layer of anhydrous magnesium sulfate
(approximately 2 g) and rinsed with toluene (35 mL). The solution
is concentrated and azeotroped with toluene three times to decrease
residual THF. The final volume is adjusted to approximately 275 mL
and the slurry heated .about.65.degree. C. to attain a solution.
Heptane (132 mL) is added gradually and the mixture then gradually
cooled over 4 h to ambient temperature. The product is filtered,
washed with 2:1 toluene:heptane, and dried to constant weight,
providing Formula 26, 31 g, 88%, mp 120.5.degree. C., HPLC purity
99.6%. .sup.1H NMR (CDCl.sub.3) 10.0 s, 1H), 7.80-7.85 (m, 4H),
7.27-7.50 (d, 2H), 7.09-7.10 (d, 2H), 5.99-6.07 (broad d, 1H), 3.91
(s, 3H), 3.78-3.93 (m, 3H), 3.41-3.51 (dd, 1H), 3.24-3.34 (dd, 1H),
2.79-3.05 (m, 5H), 1.29 (s, 9H), 0.87-0.93 (dd, 6H).
Procedure for formula 15,
{(1S,2R)-[1-(4-Formyl-benzyl)]-(2R)-2-hydroxy-3-[N-isobutyl-(N-4-methoxy--
benzenesulfonyl)-amino]-propyl}-carbamic acid
[3R,3aS,6aR]-hexahydrofuro[2,3-b]furan-3-yl ester
##STR00075##
[0108] A flask is charged with Formula 26 (2.0 g) and 20 mL THF.
Methanesulfonic acid was added drop-wise to the solution. The
solution is warmed to 40.degree. C. until de-protection was
complete. The solution was cooled to 20.degree. C. and
N-methylimidazole (2.39 g) was added to the reactor. Formula 22
(1.52 g) was then charged and the reaction was warmed to 50.degree.
C. until the reaction was complete. Ethyl acetate (150 mL) was
charged and the solution was sequentially washed with 0.5 M aq.
citric acid (20 g), 10% aq. NaH.sub.2PO.sub.4 (20 g), sat.
NaHCO.sub.3 (20 g), and 10% aq. NaH.sub.2PO.sub.4 (20 g). The
organic layer was dried over anhydrous sodium sulfate (2 g),
filtered, and concentrated to a viscous oil which was purified by
silica gel column chromatography eluting with a mixture of ethyl
acetate and heptane. The fractions containing desired Formula 15
were combined and concentrated to afford a white solid, 95%, 2.13
g, HPLC purity 97%.
[0109] Reference has been made to certain embodiments of the
invention, examples of which are illustrated in the accompanying
description, structures and formulas. While the invention has been
described in conjunction with the enumerated embodiments, it will
be understood that they are not intended to limit the invention to
those embodiments. On the contrary, the invention is intended to
cover all alternatives, modifications, and equivalents, which may
be included within the scope of the present invention as defined by
the claims.
* * * * *