Azithromycin preparation in its noncryst alline and...

Details Azithromycin preparation in its noncryst alline and... Azithromycin preparation in its noncryst alline and...

2000-11-22

2002-09-17

Peselev, Elli (Department: 1623)

Organic compounds -- part of the class 532-570 series

Organic compounds

Carbohydrates or derivatives

C536S018500

Reexamination Certificate

active

06451990

ABSTRACT:

BACKGROUND OF THE INVENTION
1. Field of the Invention
Azithromycin is the USAN generic name of the azalide 9-deoxo-9a-aza-9a-methyl-9a-homoerythromycin A, which systematic name is 1-oxa-6-azacyclopentadecan-15-one, 13-((2,6-dideoxy-3-C-methyl-1-3-O-methyl-alpha-L-ribo-hexopyranosyl)-oxy)-2-10 ethyl-3,4,1 0-trihydroxy-3,5,6,8,10,12,14-heptamethyl-11-((3,4,6-trideoxy-3-(dimethyl-amino)-beta-D-xyl It is a semisynthetic macrolide that shows an excellent antimicrobial activity against gram-positive and some cases of gram-negative bacteria (H. A. Kirst, G. D. Sides,
Antimicrob. Agents. Chemother.
1989, 33, 1419-1422). Clinical use of this macrolide is broadening its application to the treatment of opportunistic infections (F. Lecomte,
Rev. Med Interne
1998, 19(4), 255-61; S. Alvarez-Elcoro,
Mayo Clin. Proc.
1999, 74(6), 613-34; J. Schater, Lancet, 1999, 354(9179), 630-35).
2. Description of the Prior Art
FIG. 1
shows the different synthetic routes to azithromycin 1. The names of the intermediates displayed in
FIG. 1
are gathered in the following table.
Intermediate
Name
1
Azithromycin
2
Erythromycin A oxime
3
6,9-iminoether
4
9,11-iminoether
5
Azaerythromycin A
6
Azaerythromycin 11,12-hydrogenorthoborate
7
Azithromycin 11,12-hydrogenorthoborate
The following table summarizes the patents, articles, authors and applicants that describe the different synthetic paths (A, B, C, D, E) towards azithromycin 1.
Route
Patents
Articles
Author
Applicant
A
a)
U.S. 4,328,334
J. Chem. Soc. Perkin Trans
S. Djokic
PLIVA
U.S. 4,517,359
I, 1986, 1881
J. Chem. Res., 1988, 132
Idem miniprint., 1988, 1239
B
b)
U.S. 4,474,768
G. M. Bright
PFIZER
C
c)
U.S. 5,686,587
d)
EP 0,699,207
B. V. Yang
PFIZER
e)
ES 2,104,386
D
f)
U.S. 5,869,629
J. Org. Chem, 1997, 62, (21),
M. Bayod
ASTUR PHARMA
g)
EP 0,827,965
7479-7481
h)
ES 2,122,905
Magn. Reson. Chem, 1998,
36, 217-225
E
i)
EP 0,879,823
W. Heggie
HOVIONE
The structural elucidation studies carried out with azithromycin 1 have shown the existence of two different crystalline forms: hygroscopic monohydrate and non-hygroscopic dihydrate, being the latter preferred for manufacturing formulations used in therapeutical treatments, as it is described in EP 0,298,650.
Azithromycin dihydrate is easily distinguishable from hygroscopic azithromycin by means of the following differentiative assays:
a) The dihydrate form keeps its percentile water content constant at values (4.5-5%) which are very close to the theoretical value (4.6%).
b) The differential calorimetry analysis (DSC) of azithromycin dihydrate reveals the presence of a single endotherm which may vary between 115 and 135° C., with an energy absorbed during the process which ranges between 27 and 34 cal/g.
c) Each crystalline form presents its own characteristic X-Ray Diffraction spectrum
d) The infrared spectra in KBr of both crystalline forms present clear differences:
azithromycin dihydrate
azithromycin monohydrate
v(cm
−1
)
v(cm
−1
)
3560 and 3496 (2 sharp bands)
3500 (wide band)
1344
Does not present any
1282 and 1268 (2 sharp bands)
1280
1083
Does not present any
Two other synthesis, affording azithromycin 1 as a form that should differ from the crystalline ones previously mentioned, have also been described. In these cases, azithromycin is obtained by simple evaporation to dryness. However, in these documents there is no reference to the crystalline state of the azithromycin thus obtained.
Applicant
Patent
(Author)
Priority
Procedure
WO 94/26758
PFIZER
May 19, 1993
Methylene chloride
a) U.S. 5,686,587
(B. V. Yang)
evaporation
b) EP 0,699,207
c) ES 2,104,386
BE 892,357
PLIVA
Mar. 3, 1981
Chloroform
U.S. 4,517,359
(S. Djokic)
evaporation
In the following table are summarized the different procedures for the preparation of both crystalline forms of azithromycin 1.
Applicant
Crystalline form
Patent
(Author)
Priority
Procedure
HYGROSCOPIC
a) EP 0,101,186
PFIZER
July 19, 1982
Recrystallization from
MONOHYDRATE
b) U.S. 4,474,768
(G. M. Bright)
ethanol/water
HYGROSCOPIC
c) EP 0,298,650
PFIZER
July 9, 1997
Recrystallization from
MONOHYDRATE
(D. Allen)
ethanol/water
NON-
d) EP 0,298,650
PFIZER
July 9, 1997
Recrystallization from
HYGROSCOPIC
e) WO 89/00576
(D. Allen)
THF/petroleum ether/
DIHYDRATE
f) ES 2,038,756
water
NON-
g) CN 1,093,370
Faming
Dec. 10, 1993
Recrystallization from
HYGROSCOPIC
(Chem. Abs.
Zhuanli
acetone/water
DIHYDRATE
29525q, 124, 1996)
(Q. Song)
Recrystallization from
other solvents,
(methanol, DMF,
acetonitrile, dioxane,)
and water
NON-
h) EC 95-1389
CHEMO-
May, 1995
Recrystallization from
HYGROSCOPIC
TECNICA
acetone/water
DIHYDRATE
SINTYAL
NON-
i) EP 0,827,965
ASTUR
July 11, 1996
Recrystallization from
HYGROSCOPIC
j) ES 2,122,905
PHARMA
acetone/water
DIHYDRATE
k) U.S. 5,869,629
(M. Bayod)
NON-
l) EP 0,941,999
HOVIONE
Mar. 13, 1998
Precipitation from a base
HYGROSCOPIC
(W. Heggie)
neutralized acid solution of
DIHYDRATE
azithromycin in
acetone/water
Crystalline form
Article
Author
Date
Procedure
NON-
J. Chem. Res.,
S. Djokic
May, 1988
Two recrystallizations:
HYGROSCOPIC
1988, 132
(PLIVA)
(received
1. Precipitation from a
DIHYDRATE
m) idem miniprint.,
June 4, 1987)
base neutralized acid
1988, 1239,
solution of azithromycin in
acetone/water.
2. From ethyl ether.
NON-
J. Org. Chem,
M. Bayod
Nov., 1997
Recrystallization from
HYGROSCOPIC
1997, 62, (21),
(ASTUR-
(received
acentone/water
DIHYDRATE
7479-7481
PHARMA)
May 1, 1997)
HYGROSCOPIC
J. Org. Chem,
M. Bayod
Nov., 1997
Recrystallization from
MONOHYDRATE
1997, 62, (21),
(ASTUR
(received
ethanol/water
7479-7481
PHARMA)
May 1, 1997)


REFERENCES:
patent: 4474768 (1984-10-01), Bright
patent: 4517359 (1985-05-01), Kobrehel et al.
patent: 5686587 (1997-11-01), Yang
patent: 5869629 (1999-02-01), Bayod Jasanda et al.
patent: 6245903 (2001-06-01), Karimian et al.
patent: SP 95-1389 (1995-05-01), None
patent: 0 941 999 (1999-09-01), None
patent: WO 89/00576 (1989-01-01), None
Chemical Abstracts—26—Biomolecules and Their Synthetic Analogs, vol. 124, No. 3, 1996, 29525q, Q. Song, et al. “Preparation of crystals of azithromycin via crystalization from various solvents.”
J. Chem. Research(S), 1988, 152-153, “Erythromycin Series. Part 13. Synthesis and Structure Elucidation of 10-Dihydro-10-deoxo-11-methyl-11-azaerythromycin A”, Slobodan Djokić, et al.
J. Org. Chem , American Chemical Society, 1997, “Synthesis of 9-deoxo-9a-aza-9a-homoerythromycin A 11, 12-Hydrogen Borate and Azithromycin 11, 12-Hydrogen Borate. A new Procedure to Obtain Azithromycin Dihydrate” by M. Bayod-Jasanada, et al.

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