Note: Descriptions are shown in the official language in which they were submitted.
5'~
:
This is a divisiona]L of Application Serial No.185,366, filed on November 8, 1973, issued as P~t~nt No.
. 1~033,7~7 on June 27, 1978.
Thi3 inven~ion rela~es to novel dialkyl oxapho~-
S phonatqg and the prepar~ion thëreof. The compou~d~ o~ his
. invention are useful as xeagents in the preparation o~ the
`. novel lS-sub6tituted-~-penta~orprostaglandins disclosed in
~he parent P~tent No. 1,033,727.
In accordance with the present invention there i~
provided a process for preparing a compound o~ the ~ormula: :
A-~CH2) -~-CH2-~ /
., CH3 ........... II
wherein A is cycloalkyl of from ~hree to ten carbon atoms,
l-adamantyl, 2-norbornyl, 2-(1,2,3,4-tetrahydronaphthyl), 2-
indanyl ox substituted 2-indanyl, wherein~the substituent is
1 15 halo, trifluoromethyl, lower alkyl or lower alkoxy; n is an
,7, in~eger ~rom O to 5; which comp~ises reacting a Iower alkyl
~ ester of the formula: :
:: R
A-~CH2)n-~-O-lower alkyl
~ wherein A and n ar~ as defined above, with dimethyl methyl--l~ 2Q phosphonate.
~ Tha fQllowing Examples illustrate the i~vention
.:~: and the manner in which it may be perfo~m~d. I~ these
I
': Examples all temperatures are expressed in Centigrade, all
, melting and boilin~ points are unc~rrected.
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,, ~ ~; . ,.,, .. ': ,., ~, .....
` -2~ ~5'~7~
~ EXAMPLE 1
. .
Dimethyl 2-oxo-2-(2-indanyl)ethylphosphonate
A solution of 20.4 g. (164 mmoles) dimethyl methyl-
phosphonate (Aldrich) in 200 ml. dry tetrahydrofuran was
cooled to -78 in a dry nitrogen atmosph~re. To the stirred
phosphonate solu~ion was added 82.6 ml. of 2.25M _-butyl-
lithium in hexane solution (Alfa Inorganics, Inc.) ~ropwise
over a period of 20 minu~es at such a rate that ~he reaction
- temperature never rose above -65. After an additional 5
minutes sti~ring at -78, 14.0 g. (73.5 mmole) methyl indane-
2-carboxylate was added dropwise at a rate that kept the re-
action temperature less than -70 (20 minutes). After 1.0
hour at -73 the reaction mixture was allowed to warm to
ambient ~emperature, neutralized with 20 ml. acetic acid and
ro~ary evaporated to a white gel. The gelatinous material
was taken up in 50 ml. water, the aqueous phase extracted
with 75 ml. portions o~ methylene chloride (4x), the combined
organic extracts were backwashed (75 ml. H2O), dried (MgSO4),
and concentrated (water aspirator) to a crude residue and
distilled, b.p. 150-160 (0.1 mm) to give 17.0 g. (86.4%)
: dimethyl 2-oxo-2-(2-indanyl)ekhylphosphonate.
The nmr spectrum (CDC13) of the distilled product
exhibited a singlet at 7.15 ~ for the aromatic protons, a
doublet at 3.76 ~ (J = 11 cps) for the OCH3, a singlet at
'~ ~5 3.25 ~ for the ben7.ylic protons, a doublet at 3.18 ~ (J = 23
cps) for the PCH2, and a deformed triplet at 3.13 ~ (J = 2
cps) for the CHCO.
Additional Compound of the Formula
. O, C~
(MeO)2~CH2~(cH2)n
30 A n b.p. nmr Data (p~m c)_(a)
MeO ~ 0 240-243 (0.2 mm) 6.73(s), 3.84(s), 3.78(d), 3.22(d)
G ~
1 ~1 160-162 (0.2 mm) 3.77(d), 3.06(d), 2.50(d)
,~ (a)distinct reso~ances.
'' , :
.
_3_ ~5~
; Additional Compound of the Formula (cont'd)
: ~ n ~ nmr Data (E~m_~)(a)
1 209-212 (0.02 mm) 3.70(d), 2.93(d), 2.23(s)
2 195-200 (0.02 mm) 3.75(d), 3.08(d), 2.53(m)
~ <~
,
1 138-141 (0.3 mm) 3.78(d), 3.05~d)
(a)distinct resonances.
~ X~MPLE 2
Dimeth~1 2-oxo-3-~2-indanyl)~ æ o~honate
A ~olution of 20.4 gO ~164 mmoles) dimethyl methyl-
: 10 phosphonate tAldrich) in 200 ml. dry tetrahydrofuran i9 cool-
ed to -78 in a dry nitrogen atmosphere. ~o the ~tlrred
phosphonate solution i~ added 82.6 ml. of 2.25M n-butyl-
lithium in hexane solution (Alfa Inorganics, Inc.) dropwise
over a period of 20 minutes at su~h a rate that he reaction
lS temperature never rises above -65~ After an additional 5
minute~ ~tirring at -78t 14.0 g. ~73O5 mmole) methyl ~2-
indanyl)acetate is added dropwise at a rate that keep~ the
reaction temperature les~ than -70 ~20 minutes). After 1.0
hour at -78 the reaction mixture i~ allowad to warm to
amb~ent temperatur~, ~eutralized w~th ao ml. ac~tic acid and
rotary evaporat~d to a white gel. The galatlnou~ matar~al
i8 takon up in 50 ml~ wate~, the aque~us pha~e extracted with
75 ml~ por~lonR o~ methylene chlorida ~4x), ~he com~ined
organic ~xtract~ ara backwa~had (75 ml~ H2O), drlad tMgSO4),
a~d aonc~nt~ated ~water a~pirator) to a arud~ r~ldue and
di~illed, d:Lmethyl 2-oxo~3~ indanyl)propylpho~phona~e.
The produa~ o~ thi~ Example i~ u~e~ul a~ th~ start- -
lng material for ~h~ ~ynthesis o~ 16-(2-indanyl)-~-tetranor-
prostagland~n~ o~ the A, E, or F series via the proc~dur~s
di~closed in Patent No. 1,033,727. Othex pre~ursor~ required
~or th~ ~ynth~ of 17 ~hrough 20 ~ub~tituted pro~taglandln
~,
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. : . ; : : ,
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sf~
; 4-
analogs disclosed in Patent No. 1,033,727 are prepared in
the same way from the appropriate methyl esters.
EXAMPLE 3
.
Dimethyl 2-oxo-2-t2-(1,2,3,4-tetrahydrona~hthy~))phosphonate
; 5 A solution of 20.4 g. (164 mmoles) dimethyl methyl-
phosphonate (Aldrich) in 200 ml. dry tetrahydrofuran is cool-
ed to -78 in a dry nitrogen a~mosphere. To the stirred
phosphonate solution is added 82.6 ml. of 2.25M n-butyl-
lithium in hexane solution (Alfa Inorganics, Inc.) dropwi~e
over a period of 20 minutes at such a rate that the reaction
temperature never rises above -65. A~ter an additional 5
minutes stirring at -78, 14.0 g. (73.5 INmole) methyl 2-
(1,2,3,4-tetrahydronaphthylcarboxylate) is added dropwise at
a rate tha~ keeps the reaction temperature le s than 70
; 15 (20 minutes). After 1.0 hour at -78 the reaction mixture
is allowed to warm to ambient temperature, neutralized with
20 ml. acetic acid and rotary evaporated to a whits gel. The
gelatinous material is taken up in 50 ml. water, the aqueous
` phase extracted with 75 ml. portion~ of methylene chloride
(4x), the combinad organic extracts are backwashed (75 ml.
- H2O), dried (MgSO4), and concentrated (water aspirator) to a
crude residue and distilled to give dimethyl 2-oxo-2-(2-
(1,2,3,4-tetrahydronaphthyl))ethylphosphonate.
The product of this Example is useful as the start-
ing material for the synthesis of 15-(2-(1,2,3,4-tetrahydro-
naphthyl))-~-tetranorprostaglandins of the A, E, or F series
via ~he procedures disclosed in Patent No. 1,033,727. Other
~,; precursors required for the synthesis of 16 through 20 sub-
stituted prostaglandin analogs disclosed in Patent NoO
1,033,727 are prepared in the same way from the appropriate
;- methyl esters.
EX~MPLE 4
Dimethyl 2-oxo-2-(2-~R-1,2,3,4-tetrahydronaphthyl))ethyl-
hosnhonate
`~ 35 A solution of 20~4 g. (164 mmoles) dimethyl methyl-
phosphonate (Aldrich) in 200 ml. dry tetrahydrofuran is cool-
ed to -78 in a dry nitro~en atmosphere. To the stirred
;; : .
. ~ . . .
~S'~71~
.5
phosphonate solution is added 82.6 ml. of 2.25M n-butyl-
lithium in hexane solution (Alfa Inorganics, Inc.) dropwise
over a period of 20 minutes at~ such a rate that the reaction
temperature never rises above -65. After an additional 5
minutes stirring at -78, 14.0 g. (73.5 mmole) methyl 2-(R-
1,2,3,4-tetrahydronaphthylcarboxylate) is added drop~ise at
a rate that keeps the reaction temperature less than -70
(20 minutes). After 1.0 hour at -78 the reaction mixture
is allowed to warm to ambient temperature, neutralized with
20 ml. acetic acid and rotary evaporated ~o a white gel. The
gelatinous material is taken up in 50 ml. waker, the aqueous
phase extracted with 75 ml. portions of methylene chloride
(4x), the combined organic extracts are backwashed (75 ml.
H2O), dried (MgSO4), and concentrated (water aspirator) to a
crude residue which is purified by column chroma~ography to
give dime~hyl 2-oxo-2-~2-(R-1,2,3,4-tetrahydronaphthyl)3-
ethylphosphonate.
The product o~ this Example is useful a~ the start-
ing material for the synthesis of 15-(2-(R-1,2,3,4-tetra-
hydronaphthyl))-~-tetranorprostaglandins of the A, E, or F
series via the procedures disclosed in Pa~ent No. 1,033,727.
Other precursors required for the synthesis of L6 through 20
substituted prostaglandin analogs disclosed in Patent No.
1,033,727 are prepared in the same way from the appropriate
methyl esters.
E~AMPLE 5
Dimethyl 2-oxo-2-(2-(S-1,2,3,4-tetrahydronaphthyl))ethyl-
~hos~honate
. ~ . . ~ .
A solution o~ 20.4 y. (164 mmoles) dimethyl methyl-
phosphonate (Aldrich) in 200 ml. dry tetrahydrofuran is cool-
ed to -78 in a dry nitrogen atmosphere. ~o the stirred
phosphonate solution is added 82.6 ml. of 2.25M _-butyllithium
in hexane solution (Alfa Inorganics, Inc.) dropwise over a
perlod of 20 minutes at suoh a rate that the rQaction temper-
ature never rises above -Ç5. After an additional 5 minutes
` stirring at -78, 14.0 g. (73.5 mmole) methyl 2-(S-1,2,3,4-
~ tetrahydronaphthyl) is added dropwise at a rate that keeps
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the reaction temperature less than -70~ (20 minutes). After
1.0 hour at -78 the reaction mix~ure is allowed to warm to
ambient temperature, neutralized with 20 ml. acetic acid and
rotary evaporated to a white gel. The gelatinous material is
taken up in 50 ml. water, the aqueous phase extracted with 75
ml. portions of methylene chloride (4x), the combine~ organic
extracts are backwashed (75 ml. H2O), dried (MgSO4), and con-
;; centrated (water aspirator) to a crude residue which is
i purified by column chromatography to give dimethyl 2-oxo-2-
` 10 (2-(S-1,2,3,4-tetrahydronaph~hyl))ethylphosphonate.
The product of this Example is useful as the start-
ing material for the syn~hesis of 15-(2-(S-1,2,3,4-tetra-
hydronaphthyl))-~-tetranorprostaglandins of the A, ~ or F
series vla the procedures disclosed in Pat~nt No. 1,033,727.
Other precursors required for the synthesis of 16 through ~0
~ubstituted prostaglandin analogs disclosed in Patent No.
1,033,727 are prepared in the same way from the appropriate
methyl esters.
EXAMPLE 6
; 20 Dimethyl 2-oxo-7-cyclopentylhept~lphosphonate
A solution of 20.4 g (164 mmoles) dimethyl methyl~
phosphonate (Aldrich) in 200 ml. dry tetrahydrofuran is
cooled to -78 in a dry nitrogen atmosphere. ~o the stirred
phosphonate solution is added 82.6 ml. of 2.25M n-butyl-
lithium in hexane solution (Alfa Inorganics, Inc.) dropwiseover a period of 20 minutes at such a rate that the reaction
; temperature never rises above -65. After an additional 5
minutes stirring at -78, 14.5 g. (73.5 mmole) methyl 6-cyclo-
pentylhexanoate is added dropwise at a rate that keeps the
30 reaction temperature less than -70 (20 minutes~. After 1.0
hour at -78 the reaction mixture i9 allowed to warm to
ambient temperature, neutralized with 20 ml. acetic acid and
rotary evaporated to a white gel. The gelatinous material is
taken up in 50 ml. water, the aqueous phase extracted with 75
ml. portion~ of methylene chloride (4x), the combined organia
extracts are backwashed (75 ml. H2O), dried ~MgSO4), and con-
centrated ~water aspirator) to a crude residue and di~tilled
,
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~ . . . . . ..
,: , . . .
,'.'.'"' , ,; . ,'' ,. , .'. ,',", "'. . ', ~: , ,,
' _7~ 7~
to give dimethyl-2--oxo-7-cyclopentylheptylphosphona~e.
The product of this Example is useful as the start-
ing material for the synthesis of 20-cyclopentyl-~Ltetranor-
prostaglandins of the A, E, or F series via the procedures
disclosed in Patent No. 1,033,727. Other precursors required
, for the synthesis of 15 through 19 substituted prostaglandin
analogs disclosed in Patent No. 1,033,727 are pxepared in the
same way from the appropriate methyl esters.
EXAMPLE 7
Dimethyl 2-oxo-2-c~clodecy~eth~lphosphonate
A solution of 20.4 g. (164 mmole~) dimethyl methyl-
phosphonate ~Aldrich) in 200 ml. dry tetrahydro~uran is cool-
ed to -78 in a dry nitrogen atmosphere. To the stirred
phosphonate solution is added 82.6 ml. of 2.25M n-butyl-
lithium in hexane solution (Alfa Inorganics, Inc.) dropwise
over a period of 20 minutes at such a rate that the reaction
temperature never rises above -65. After an additional 5
minutes stirring at -78, 14.5 g. ~73.5 mmole) methyl cyclo-
decane~arboxylate is added dropwise at a rate thak kept the
r~action temperature leqs than -70 (20 minutes). After 1.0
, hour at -78 the reaction mixture is allowed to warm to
ambient temperature, neutralized with 20 mlO acetic acid and
rotary evaporated to a white gel. The gelatinous material is
taken up in 50 ml. water, the aqueous pha~e extracted with 75
ml. portions of methylene chloride (4x), the combined organic
, extracts are backwashed (75 ml. H2O), dried ~MgSO4), and con-
`' centrated (water aspirator) to a crude residue and distilled
to give dimethyl 2-oxo-2-cyclodecylethylpho~phonate.
The product of this Example is useful as the start-
ing ma~erial for the synthesis of 15-cyclodecyl~-tetranor-
prostaglandins of the A, E, or F series via the procedures
disclosed in Patent No. 1,033,727. Other precursorq required
for the synthe~is o~ 16 through 20 substikuted proskaglandin
analogs disclosed in Patent No. 1,033,727 are prepared in the
same way ~rom the appropriate methyl esters.
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EX~MPLE 8
: Dimethyl 2-oxo-6-cyclopropylhexylpho~e_onate
A solution o~ 20.4 g. (164 mmoles) dimethyl methyl-
pho~phonate (~ldrich) in 200 ml. dry tetrahydro~uran is cool-
S ed ~o -78 in a dry nitrogen atmosphere. To the stirred
phosphonate solution is added 82.6 ml. of 2.25M n-butyl-
lithium in hexan~ solution (Al~a Inorganics, Inc.) dropwiae
over a period of 20 minute~ at such a rate that tha reaction
; tempera~ure never rises above -65. After an addltional 5
minu~es stirring at -78, 11.5 g. ~73.5 mmol~) methyl 5-
cyclopropylvalerate i~ added dropwise at a rate that keep~
the react~on t~mperature le~s than -70~ (20 minutes)~ After
1.0 hour at -78 the reaction mixture i~ allowed to wa~m to
a~bient temperature, neutralized with 20 ml. acetic acid and
rotary evaporated ~o a white gel. The gelatinous material
i8 taken up in 50 ml. water, the a~ueous phase extract~d with
75 ml. portion3 of methylene chlorid~ ~4x), thc combined
organic extracts are backwashed (75 ml. H~O), dried ~MgSO4),
and concentrated (water aspirator) to a crude re~ldue and
distill~d to give dimethyl 2 oxo-6-cyclopropylhexylpho~phonate.
The product o~ this Example is uR~ful as the start-
ing material for the synthesis of l9-cyclopropyl-~-tetranor-
prostaglandins of the A, E or F erie~ via the procedures
disclo~ed in Paten~ No. 1,033,727. Other precuxsor~ required
for the synthesi3 o~ 15 thrsugh 18 and 20 ~ub3titute~ prosta-
i glandin analogs disclo~ed in Patent Mo. 1,033,727 axa prepared
in the same way from the appropriata methyl e~tex~.
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