CA1204757A - Amino and substituted amino phosphinylalkanoyl compounds - Google Patents

Abstract

ABSTRACT

A compound of the formula (II):

(II) wherein R1 is R19-?- or R20-O-?-;
n is zero or one;
R5 is hydrogen, lower alkyl, halo substituted lower alkyl, benzyl, or phenethyl; and R3 is hydrogen, lower alkyl, benzyl, or benz-hydryl.
These compounds are useful as intermediates in the preparation of compounds of the formula:

Description

~ 57 HA238 AMINO AND SUBSTITUTED ~IINO PHOSPEINYL-ALKANOYL CO~OSITIONS

This invention is directed to new amino and substituted amino phosphinylalkanoyl compounds of formula I and salts thereof (I) R O R O

R~-~H-CH P - (CH2)n-CH- C-X

X ~s an imino ~cid of the formula ~ 21 ~ 8 -N _ C-COOR6 , -N - C-COOR6 I(L) I(L
H H

2 ~ ~2C CH2 -N _ C-COOR -N _ C-COOR
H(L) 6 ¦(L) 6 7~ HA238 Rll S~R12 'l ~ I ~ l?
, or -N ~ C-COOR
-N C-COOR6 l(L) 6 I(L) H

R7 is hydrogen, lower alkyl, halogen, keto, hydroxy, 1l azido, -~H-C~lower alkyl~

-NH-C-(CH ) ~ ;~CH ) ~ ( 13)p ~CH ) ~ ~ _ -(CH ) ~ ~

- 20 ( 2)m ~ , a 1 or 2-naphthyl of the ormula ~(C~)m ~ -(GH2lm-cycloalkyl, ~l ~ 15 .
-O-C N , amln , / ~1 O-lower alkyl, ~X'~ 7~ 3g -O- (C~2) m~ ( 13 i? ~ a 1- or 2-naphthylo ~y of the formula -O- ICH2)m , -S-lower alkyl, ~ (R14)p -S- (CH2)m~ , or a 1- or 2-naphthyl-15 thio of the formul~

~X`~ ( Rl 4 ) p R~ i~ keto, halogen, -O-C-N

-O-(CH2~ 3)E~ ~ ~O-lower alkyl, a 1- or 2-naphthyloxy of the fQrmula ~2~ 7 ~23~

-O-(CH ) 2 m ~ , S-lower alkyl, -S-(CH2)m ~ ( 13)p , or a 1- or 2-naphthyl-thio of the formula -S-(CH ) 2 m ~ (R14)p Rg is keto or -(CH~)m ~
(R13) p Rl~ is halogen or -Y-R16.
. R R' R and R' are independently selec~ed from hydrogen and lower alkyl or ~ 1~ R12 and Rl~ are hydrogen and Rll is r~_~
(R

. . .

3~

~ 57 HA238 ~5-R13 is hydrogen, lower alkyl of 1 to 4 carbons, lower alkoxy of l to 4 carbons, lower alkylthio of 1 to 4 carbons, chloro, bromo, fluoro, trirluoromethyl, hydroxy, phen~l, pheno~
phenylthio, or phenylmethyl.
R14 is hydrogen, lower alkyl of 1 to 4 carbons, lower alkoxy of l to 4 carbons, lower alkylthio of 1 ~o 4 carbons, chloro, bromo, fluoro, trifluoromethyl, or hydroxy.
m is zero, one, two or three.
p is one, two or three provided that p is more than one only if R13 or R14 is hydrogen, methyl, me~hoxy, chloxo, or fluoro.
R15 is hydrogen or lower alkyl of l to 4 carbon~. _ Y is oxygen or sulfur.
R16 is lower alkyl of 1 to 4 carbons, ~ ~ , or the R16 groups join to complete an unsubstituted 5- or 6-membered ring or said ring in which one or more of the carbons has a lower alkyl of 1 to 4 carbons or a di(lower alkyl of 1 ~o 4 carbons) ~b~tituent.
n i5 zero or one.
R5 is hydrogen, lower al~yl, halo substi~uted l~wer alkyl, benzyl or phenethyl.
R3 and R6 are independently selec~ed ~rom hydrogen, lower alkyl, benzyl, benzhydryl, or ,~238 ~1 -CH-O-C-Rl~ wherein R17 is hydrogen, lower alkyl, or phenyl, and R18 is hydrogen, lower alkyl, lower alkoxy, phenyl, or R17 and Rl~ taken together ( 2)2 ~ (CH2)3;, -CH=CH-, or R is hydr~gen, l~ or 1 R -C-, R -O-C- .
Rlg is hydrogen, lower alkyl, halo substituted lower alkyl, amino substituted lower alkyl, -(CH2) ~ ~ wherein R13 and p are as defined above and q is zero or an integer from 1 to 7, cycloalky , ~CH2)m~ ~ H O
~(CH2)m~3 - (CH~m~ f~

H

~ HA23 R20 is lower alkyl, phenyl, benzyl or phenethyl.
R2 is hydrogen, lo.wer alkyl, lower al~enyl, halo substituted lower alkyl, ~(CH2)q ~ (R13)p -(CH2)m ~ , -(C~2) ~ , or -(CH2)m ~ wherein q~ R13, p and m are as defined above.
R21 is lower alkyl,. ~enzyl, or phenethll.
R22 is hydrogen, lower alkyl, benzyl or phenethyl.

3~

12~ ~5~ H~23~

This invention in its broadest aspects relates to the amino and substituted amino phosphinylalkanoyl compounds of formula I
above, to compositions containing such compounds and to the method of using such compounds as anti-hypertensive agents~ and to intermediates useful in preparing such compounds.
The term lower alkyl used in defining various s~mbols refers to straight or branched chain hydrocarbon radicals having up to ten carbons, for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, pentyl, isopentyl, etcO The preferxe~ lower alkyl groups are up to four carbons with methyl and ethyl most preferred. 5imilarly the terms lower alkoxy and lower alkylthio refer to such lower alkyl groups attached to an oxygen or sulfur.
The term cycloalky1 refers to sa~urated - rings of 3 to 7 carbon atoms wi~h cyclo-pen~yl and cyclohexyl being most preferred.
The term lower alkenyl refers to straight or branched chain hydrocarbon radicals of 2 to 7 car~ons,.preferably 2 to 5 carbons, having at least one double bond, for example e~henyl~ propenyl, 2 butenyl, e~c.
The term halogen refers to chloro, bromo-and fluoro~
~;

~2~ 7~7 H~2~

The term halo substituted lower alkyl refers to such lower alkyl groups described above in which one or more hydrogens have been replaced by chloro, ~romo or fluoro groups s~ch as trifluoromethyl, which is preferredt penta-fluoroethyl, 2,~,2-trichloroethyl, chloromethyl, bromomethyl, etc. Similarly, the tenm amino substituted lower alkyl refers to such lower alkyl groups described above in which one or more hydrogens have been replaced by an amino group such as aminomethyl, l-aminoethyl, 2-amino-ethyl, etc~
The symbols ~(CH2) ~ O

~~CH2)m ~ y and -(CH2) m~

represent ~at the aikylene bridge is attached to an available carbon atom..
The compounds of foxmula I are prepared according to the following procedures. An acid or its acti~ated form of formula.II
wherein Rl is other than hydrogen and R3 is hydrogen, lowex alkyl, benzyl, or benzhydryl (II) R~ O R5 O
RlNH-CH-P-(CH2)n-CH-C-OEI

~ HA238 is ,coupled with an imino acid or ester of the formula (III) HX
The term acti~ated form refers to the conversion of the acid to a mixed anhydride, symmetrical anhydride~ acid chloride, or activated ester, see Methoden der Organischen Chemie (houben-Weyl), Vol. ~V, part II, page 1 et seq. (1974) for review of the methods of acylation. Preferabl~, the reaction is performed in the presence of a coupling agent such as l,l-carbonyldiimidazole, thionyl chloride, or dicyclohexylcarbodiimide.
The compounds~of formula I wherein Rl is hydrogen are prepared by coupling an acid of formula II wherein Rl is ll with R2 o~~ C~
the appropriate imino acid ester of formula III.
Depro~ection of the resulting product, for exar.lple, by treating with hydrogen gas in the presence of a palladium on carbon catalyst when R20 is benzyl yields ~he product wherein Rl is hydrogen.
Similarly, the products of formula I
wh~xein either or both of R3 and R6 are lower alkyl, benzyl, or ben2hydryl can be hydrogenated as described above or chemically - treated such as with trifluoroacetic acid and anisole to yield the products of formula I wherein R3 and R6 are hydrogen.

~ 4 S~7 HA23~

The ester products of formula I wherein R6 is ~ may be obtained by -C~-O-C-R18 . R17 employing the imino aci~ of formula III in the coupling reaction with the ester group already in place. Such ester starting materials can be preparPd by treating the imino acid with an acid cKloride such as O O
~I 11 ~ CH2-0-~-Cl or (H3C)3-C-O-c-cl so as to protect the N-atom. The protected imino acid is then reacted in the presence of base with a - compound of the formula (I~) e Rl 7 wherein L is a lea~ing group such as chlorine, ~rominer tolylsulfonyl, etc., followed by removal of ~he N-protecting group such as by treatment wi~h acid or hydrogenation.
The este~ products of formula I wherein R6 is ~ can also be . . .

~ HA238 obtained by treating the product of formula I
wherein R6 is hydrogen with a molar equivalent of the compound of formula IV. The diester pro~ucts wherein R3 and R6 are the same and are R
-CH-O-C-Rl8 can be obtained by treating the product of formula I wherein R3 and R6 are both hydrogen with two or more equivalents of the compound of formula IV.
The ester products of formula I wherein R3 is -.
O

can be obtained by treating the product of formula I
wherein R3 is hydrogen and R6 is t-butyl, benzyl or benzhydryl with the compound of formula IV in the presence of base. Removal of th~ R6 ester sroup such as by hydrogenation yields the products of formula I wherein 2 ~ 7 HA238 ~ -13-3 and R6 is h~drogen.
O
-CH-O-C-Rl8 ..................... R17 s The products of formula I wherein Rl is hydrogen can be employed as intermediaies to yield the products of formula I wherein Rl i S
R -C- -In this procedure the compound of formula I
is coupled with an acid or its activated form of the formula (V) O
Il Rlg-C-OH

preferably in the presence of a coupling agent.
The products o formula I wherein R7 is amino may be obtained by reducing the corresponding products of for~ula I wherein R7 is azido.
The products of formula I wherein R7 is~he subs~it~te~ amino group, ~ 21 -N
. ~ 22 may be obtained by treating the corresponding

4-keto product of formula I with the amine, ~ S ~ h~38 /R2l in the presence of hydroge~ and catalyst or in the presence of sodium cyanotrihydridoborate.
Also, the substituted amino products of - formula I wherein R22 is other than hydrogen may be obtained by treating the corresponding 4-amino product of formula I with the ketone, e R2/ ~ 22 in the presenc of hydrogen and catalyst or in the presence of sodium cyanotrihydrido-borate.

, ^~

H~.238 . -15-The carboxylic acids of formula II wherein R
is other than hydrogen can be prepared by various procedures. For example, the substituted amine of the formula (VI) RlNH2 can be~treated with the aldehyde of the formula (VII) R ~CHO
l~ and the dichlorophosphine (VIII) ~5 Cl2P (C 2)~ 2 3 to yield ~h~ intermediate (IX) ~2 o R5 RlNH CH I ( 2)n 2 3 OH
2a The intermediate of formula IX can be saponified such as by treatment with sodium hydroxide to yield the desired acid of formula II wherein R3 is hydrogen or esterified such as by treatmen~
with PCl5 or an alkyl chloroformate followed by the appropriate alcohol, treatment with a r~agen~ such as diazomethane, 1-benzyl-3-p-tolyltriazine! etc., followed by saponification to yield the acid of formula II wherein R3 is lower alkyl t benzyl, or benzhydryl.

~ 7 HA23~

The carboxylic acids of for~ula II wherein n is zero can also be prepared by reacting the substituted amine of formula VI and the aldehyde of formula VII with the dichlorophosphine of the formula (X) to yield the intermediate of the formula (XI~
~ 9 ~2 0~
The intermedia~e of formula XI is converted to the corresponding e~ter, i.e., R3 is lower alkyl, benzyl, or phenethyl, as described above and then treated w.ith lithium diisopropylamide and carbon dioxide to yield the acid of formula II
wherein R3 is lower alkyl, benzyl, or phenethyl.
2~ The various imino acids and esters of formula III are described in the literature and in various patentsD
Various substi~uted prolines are disclosed by Mauger et al., Chem. Review, Vo. 66, p 47 86 (1966). When the imino acid is known i~ can be readily converted to the es~er by conventional means. For example, the esters where R6 is t-butyl can be obtained by treating the corresponding N-carbobenzyloxyimino acid with isobutylene under acidic conditions ~ 57 H~238 and then removing the N-carbobenzyloxy protecti~g group by catalytic hydrogenation and the esters ~-herein R6 is benzyl can be obtained by treating the imino acid witn benzyl alcohol and thionyl chloride.
As di~closed in Bel~ium Patent 889,444 issued December 30, 1981, the su~tituted prolines wherein R7 is 10( 2)m ~ ' -(CH2) 15~(CH2)m ~ ' -(CH~) -~CH ) 2 m ~ or ~(cHa)m-cycloalk are prepared by reac~ing a 4-keto proline of the formula (XII) ll H f ' c~2 ~ CH2-O-C - N ~-COOR6 H

~ 7~7 HA~3~

with a solution of the Grignard or lithium reagent(XIII) R7-Mg-halo or R7-Li wherein R7 is as defined above and halo is Br or Cl to yield ~XIV) R OH
~C ~
O H 2 1 l H 2 -CH O-C ~ N (L) 6 1~ .
This compound is ~reated with a dehydrating agent such as p-toluenesulfonic acid, sulfuric acid, potassium bisulfate, or trifluoroacetic acid to yield the 3,4-dehydro-4-substituted proline of the formula ' (XV) C
O H C C~

-O-C N I~L) g~
..

~ HA238 Removal of the N-benzyloxycarbonyl protecting group and hydrogenation of the compound of formula XV yields the desired starting materials. The substituted proline wherein R7 is cyclohexyl C2n S be prepared by further hydrogenation of the 4-phenyl proline compound.
Preferred compounds of this invention with respect to the imino acid or ester part of the -structure of formula I are those wherein:
R6 is hydrogen or O

wherein R17 is hydrogen or methyl and R18 is straight or branched chain lower alkyl of 1 to 4 carbons or phenyl.

R7 is amino.
R7 is hydrogen.
R7 is hydroxy-R7 is chloro or fluoro.
R7 is lower alkyl of 1 to 4 carbons or cyclohexyl.

, 12~ ~7~ A238 R7 is -O-lower alkyl wherein lower alkyl is straight or branched chain of 1 to 4 carbons.

one or two, and R13 is hydrogen, methyl, ~ethoxy, methylthio, chloro~ bromo, fluorot or hydroxy.

R7 i~ ~O-(CH2)m ~ wherein m is zero, one ~r two, and ~13 is hydrogen, methyl, methoxy, methylthio, chloro, bromo, fluoro, or hydroxy, ~7 is -S~lower alkyl whexein lower alkyl is straight or branched chain of 1 to 4 carbons.
R7 is S-(CH2)m ~ wherein m is zero, one or two, and R13 is hydrogen, methyl, methoxy, methylthio, chloro, bromo, fluoro r or hydroxy.
~8 is -O~lower alkyl wherein lower alkyl is 2~ ~traigh~ or branched chain of 1 to 4 carbons.

R8 i5 -Q~CH2)m ~ wherein m is zero, one or two, and R13 is hydrogen, methyl, methoxy, methylthio, chloro, bromo7 fluoro, or hydroxy.
R8 is -S-lower alkyl wherein lower alkyl is straight or branched chain of 1 to 4 carbons.
~n ~ 7 HA238 R8 is -S-(CH2)m ~ wherein m is ~ero, one or two, and R13 is hydrogen, meth~
methoxy, methylthio, chloro, bromo, fluoro, or hydroxy.
R~ is phenyl, 2-hydroxyphenyl, or 4-hydroxyphenyl.
Rlo are both fluoro or chloro.
Rlo are both Y-R15 wherein Y is O or S, R16 is straigh~ or branched chain alkyl of 1 to 4 carbons or the Rl6 groups join to complete an unsubstituted 5- or 6-membered ring or said ring in which one or more of the carbons has a methyl or dimethyl substi~uent.
Rll, Rll, R12 and R12 are all hydrogen, or Rll is phenyl, 2-hydroxyphenyl or 4-hydroxyphenyl and Rll, R12 and Rl2 are hydrogen.
Most preferred compounds of this invention with respect to the imino acid or ester part of the structure of formula I are those wherein:
' X is /( 2 r~
7 Y y 21 lH2 H2C lH2 -N ~ C-COOR -N - C-COOR6 I(L) 6 I(L) . ~ H

~2~ ~7S~ HA238 R6 is hydrogen or 1l -cH2-oc-c(cH3)3 R7 is hydrogenO
R7 is cyclohexyl.
R7 is lower alXoxy of 1 to 4 carbons.

~ ( CH2 ) m~ ' -0~ ( CH2 ) ~-Rl 3 -S-~CH2) ~ wherein m is zero, one, or two and R13 is hydrogen, methyl, methoxy 7 methylthio, Cl, Br, F or hydroxy.
Y is oxygen or sul~urandr is two or three, especially ~Jh~rein Y is sulfur and r is two.
Preferred compounds of this invention with respect to the phosphinylalkanoyl sidechain of the structure of formula`I are those wherein:
R3 is hydrogen or , . -CH-O--C-R

whexein R17 is hydrogen or methyl and R18 is straight or branched chain lower alkyl of 1 to 4 carbons or phenyl,.especially hydrogen or -C~ O C C(CH ) ~ S ~ HA2 Rl is hydrogen or Rlg-C-, especially Rlg-C- wherein Rlg is lower alkyl of l to 7 carbons; C~3; wherein q is ~(CH2)q ~ R13 zero or an integer from l to 4 and Rl3 is hydrogen, methyl, methoxy, methylthio, chloro, bromo, 10 fluoro, or hydroxy; cycloalkyl of 5 or 6 carbons;

~ ; ~ ; ~ or R5 is hydrogen.
n is zero, R2 is lower alkyl of l to 7 carbons or ,--~
t 2)q ~ ` wherein q is zero or an integer from 1 to.4 and Rl3 is hydrogen, methyl, methoxy, methylthio, chloro, bromo, fluoro or hydroxy; especially -(CH2)2 ~ 2 3 The compounds of this invention wherein a~
least one of R3 or R6 is hydrogen, form basic salts with various inorganic and organic bases whi¢h are also wi~hin ~he scope of the invention.

~ 7~ HA238 Such salts include ammonium salts, alkali metal salts like lithium, sodium and potassium salts (which are preferred), alkaline earth metal salts like the calcium and magnesium salts, salts with organic ~ases, eOg., dicyclohexylamine salt, benzathine, N-methyl-D-glucamine, hydrabamine salts~
salts with amino acids like arginine, lysine and the like~ The nontoxic, physiologically acceptable salts are preferred, although other salts are also useful, e.g.~ in isolating or-purifying the product. The salts are formed using conventional techniques.
As shown above, the imino acid or ester portion of the molecule of the products of formula I is in the L-configuration~ Depending upon the definitions of R2 and R5 one or two asymmetric centers may be present in the phosphinylalkanoyl sidechain, Thus, some o~ the compounds can ~ccordingly exist in diastereoisomeric forms or in mixtures thereof. The above described processes can utilize racemates, enantiomers or diastereomers as starting materials. When diastereomeric products are prepaxed, they can be separated by conventional chromatographic or fractional crystallization methods.
Th2 products of formula I wherein the imino acid ring is monosubstituted give rise to cis-trans isomerism. The configuration of the final product ~ 7 HA238 will depend upon the configuration of the R7, R8 and Rg substituent in the starting material of formula III.

The compounds of formula I, and the physio-logically acceptable salts thereof, are hypotensive agents. They inhibit the conversion of the decapeptide angiotensin I to angiotensin II
andD therefore, are useful in reducing or relieving angiotensin related hypertension. The action of the enzyme renin on angiotensinogen, a pseudo-globulin in blood pressure, produces angiotensin 1.
Angiote~sin I is converted bv anyio~ensin conver~ing enzyme (ACE) to angiotensin II. The latter is an activP pressor subs~ance which has been implicated as the causative agent in ~everal forms of hypertension in various mammalian species, e.g., humans. The compounds of this invention in~ervene in the angio~ensinogen ~ (renin) a~giotensin I ~ angiotensin II sequence by - inhibiting angiotensin converting enzyme and reducing or eliminating the form~tion of the pressor substance angiotensin II. Thus by the administration of a composition containing one (or a combination) of the compounds of this inven~ion, angiotensin dependen~ hypertension in a species o mammal (e.gO, humans~ suffering-therefxom is alleviated. A single dose, or preferably ~wo to four divided daily doses, provided on a basis of about 0.1 to 100 mg. per kilogram ~ H~23 of body weiaht per day, preferabl~ about 1 to 15 mg.
per kilogram of body weight per day is approprizte to reduce blood pressure. The substance is preferably admi~istered orally, but parentera' routes such as the subcutaneous, intramuscular, intravenous or intraperitoneal routes can also be employed.
The compounds of this invention can also be formulated in combination with a diuretic for the treatment of hypertension. A combination product comprising a compound of this invention and a diuretic can be administered in an effective amount which comprises a total daily dosage of about 30 to 600 mg., preferably about 30 to 330 mg. of a ~ompound of this invention, and about 15 to 300 mg., preferably about 15 to 200 mg.
of the diuretic, to a mammalian species in need thereof. Exemplary of the diuretics contemplated for use in combination with a compound of this invention are the thiazide diuretics, e.g., chlorothiazide,hydrochlorothiazide,flumethiazide, hydroflumethiazide, bendroflumethiazide, methyclothiazide, trichlormethiazide, polythiazide or benzthiazide as well as ethacrynic acid, ticrynafen, chlorthalidone, furosemide, musolimine, bumetanide, triamterene, amiloride and spirono-lactone and salts of such compounds.
The compounds of formula I can be formulated for use in the ~eduction of blood pressure in compositions such as ~ablets, capsules or elixirs 12~7S7 HA238 for oral administration, or in sterile solutions or suspensions for parenteral administration.
About 10 to 500 ~g. of a compound of formula I
is compounded with ph~siologically acceptable vehicle, carrier, excipientl binder, preservative, stabilizer, falvor, etc., in a unit dosage form as called for by accepted pharma eutical practice.
The amount of active substance in these composi-tions or preparations is such that a suitable dosage in the range indicated is obtained.
The following examples are illustrative of the invention. Temperatures are given in degrees centigradeO

~2~'~ 7S7 ~A23~

Example ~
~ [[(1-~mino-3-phenylproPyl)hyd oxv hosphinvl]-acetyl]-L-proli~e a) Meth~l[3-~henvl-l-[[(~henylmethoxy)carbon~
~ . . _ .
aminoJpro~yl]~hosphinic acid _ Pivalic acid (4.08 g., 0.04 mole) and benzyl carbamate (3.02 g., 0.02 mole) are dissolved in 3~ ml. of toluene. A portion of the toluene (5 ml.) is distilled at atmospheric pressure to remove traces of water. The solution is cooled to room temperature under argon, and methyldichlorophosphine ~1.8 ml., 0.02 mole) and powdered 4A molecular sieves (2 g.) are added. 3-Phenylpropionaldehyde (3.3 ml., 0.025 mole) are then-added dropwise over ten minutes. A slight exotherm (to approximately 35) is observed. After stirring for one hour, the reaction mixture i5 poured into saturated sodium bicarbonate and extracted with dichloromethane. The aqueous solution is acidified to pH 3.5 with concentrated HCl and e~:tracted wit~ ether. The aqueous solution is then acidified ~o pH 1 and extracted with dichloromethaneO The pH 1 extracts are dried ~MgSO4) and evaporated to 2.1 g. of white solid product. The pH 3.5 extracts are dried (MgS04) and e~aporated (finally at 70/ 1 mm.
to remove pi~alic acid) to yield an additional 3.2 g. of white solid product. Crys~allization from ethyl acetate gives an analytical sample of .23g ~"3 ~7~
` -29-methyl~3-phenyl-1-[[(phenylmethoxy~carbonyl]
amino]propylJphosphinic acid; m.p., 126-129.
Anal. Calc'd for ~18~22~4P
C, 62.24; H~ 6.39; N, 4.03; P, 8.92 Found: C, 62.23; H, 6.52; N, 3.94 Tlc (dichloromethane/acetic acid/methanol 8:1:1) R~ = 0.7.
l~[[(phenylmethoxy~carbonyl~-amino]propvl~ohos~hinic acid, phenylmethyl ester Th~ product from part (a) (5.1 g.~
0.0147 mole) is dissolved in dichloromethane and cooled to 0. l-~e~yl-3-p-tolyltriazine (3.4 y., 0.015 mole) in 75 ml. of dichlorome~hane is added dropwise. When gas evolution ceases, two additional portions (3.4 g. each) or the l-benzyl-3-p-tolyltriazine are added and the mixture is stirred overnight. The soiution is then washed with 5% potassium bisulfate, saturated sodium bicarbonate/ and brine, dried ~MgSO4), and evaporated to 11 g. of dark orange semi-solid. Chromatography on silica gel using dichloromethane ethyl acetate mixtures yields 4.0 g. of me~hyll3-phenyl-1~
l[(phenylmethoxy)carbonyl]amino]propyl]phosphinic acid, ph~nylmethyl ester as a pale yellow semi-solid. Tlc (ethyl acetate) Rf = O.35, 0,4.

~ HA238 c) ~(Phenylmethoxy)[3-phenyl-1-[[(~henYlmethox~
carbonyl]amino]~rc~yl]phos~hinyl~acetic acid A solution of 0.04 moles of lithium di-isopropylamide in tetrahydrofuran is ?repared by the dropwise addition of N-butyllithium ~16 ml. of 2.6 N solution, 0.04 mole) to a cooled (0) solu~ion of diisopropylamine (5 g., 0.05 mole~ in pentane (75 ml.~. The solvent i5 removed in vacuo and replaced by tetrahydro-furan (50 ml.). The solution is cooled to -76 and a solution of the phenylmethyl ester product from part (b) (3.8 g., 0.0084 mole) in tetrahydrofuran (50 ml.) is added over a p~riod of thirty minutes. After stirring for fifteen minutes, carbon dioxide, dried over molecular sieves, is bubbled into the mixture for ten minutes. After stirring for ten minutes, and warming to room temperature, the solvent is removed in vacuo7 The residue is acidified to pH of 1 with 10% hydrochloric acid and extra~tedwith dichloromethane, washed with brine, and dried (MgS04). The solvent is removed in vacuo.
The oil residue is extracted into 10 ml. of 1 N
. sodium hydroxide plus 90 mlr of water and washed with dichloromethane/ethyl e~her (1:1, 2 x 25 ml~).
The alkaline pha~e is acidified to a pH of 1 . with 10% hydrochloric acid. The oil separating from solution is extracted into dichloromethane, washed with brine, and dried t~gSO4). The solvent is removed in vacuo to give 3.3 g. of [(phenyl-_ ~

~ A238 methoxy)[3-phenyl~ [(phenylmethoxy)carbonyl3-amino]prop~l]phosphinyl]acetic acid.
Tlc; silica gel, benzene/acetic acid (7:1) shows two spots, Rf = 0.17; 0.15. ~
d)(~ [(Pheny~methoxy)[3-pllenyl-1-[[(phenylrnethovc~)-. . .
carbonyl]amino]propyl3phosphinyl]acetyl]-L=proline, phenylmethyl ester l,l-Carbonyldiimidazole tO.92 g., 0.0057 mole) is added to a chilled (0 ~ solution of ~he product from part (c) (2.75 g., O.OQ57 mole) in acetonitrile (25 ml.). The mixture is stirred at 0 for one hour. A solution o L-proline, benzyl ester (1.2 g., 0.0057 mole) in acetonitrile (20 ml.) is add~d. After stirring lS at ambient temperature for 16 hours, the solvent is removed in vacuo. The residue is dissolved in dichloromethane (lO0 mlO), washed with 5%
potassium bisulfate, saturated sodium bicarbonate, brine, and dried (MgSO4). The solvent is removed in vacuo. The residuP (3.8 g.~ is chromatographed on silica gel eluting with dichloromethane/
ethyl acetate (l:l), followed by ethyl acetate, to give 2.2 g. of(~ [[(phenylmethoxy)~3-phenyl~l-[[(phenylmethoxy)carbonyl]amino]propyl3phosphinyl]-acetyl~-L-proline, phenylmethyl ester as a vis~ou~ oil.

~ t7~7 HA23B

e) (~ [[(l-Amino-3-phenylpropyl)h~drOXyphosphinyl~-acetyl]-L-~roline A mixture of the L-p~oline,phenylmeth~l ester product rrom part td) (2.1 g., 0.0031 mole) and 5~ palladium on carbon catalyst (100 mg.) in acetic acid/methanol (1:9, 50 ml.) is stirred vigorously under one atmosphere of hydrogen until the hydrogen is no longer consumed (216 ml.). The mixture is fil~ered through celite, and concentrated in vacuo. The residue is triturated -with acetonitrile. The resulting solid in suspension is collected by filtration with a recovery of 1.1 g., m.p. 160-190 (dec.~.
A portion (0.6 g.) is dissolved in double distilled water, millipore filtered, and lyophilized to yield 0.5 gOof (+)-l-[[(l-amino-3-phenylpropyl)-hydroxyphosphinyl~acetyl] L-proline, m.p. 160-190 (~e 3; [~1D ~43 . Tlc, silica gel, butanol/
acetic acid/water t3:1:1) shows a single spot, Rf 0 44.
Anal. Calc'd. for C16H~3N25 ~ 2 C, 51.61; H, 6.76, N, 7.52; P, 8.32 Fou~d: C, 51.79; ~, 6.58; N, 7.46; P, B.20.
Example 2 ~ .
al MethYl~1-[[(phenylmethoxy)carbonyl]amino]-.. ..
pentyl-]phosphinic acid Pivalic acid (4.08 g., 0.04 mole) is 3~ dissolved in 30 ml. of toluene. A portion t5 ml.) of toluene is distilled to remove traces of 12~75~ HA238 moisture, and the mixture is cooled to room temperature under argon. Benzyl carbamate (3.02 g., 0.02 mole~, powdered 4A molecular sieves (2 g.) and methyldichlorophosphine (1.8 ml. 0.02 mole) are added. Valeraldehyde (2.7 ml , 0.025 mole) is added dropwise over 20 minutes, causing an exothermic reaction which raises the reaction temperature to 55 .
After stirring one hour, the mixture solidifies.
It is diluted with ether and filtered. The solid is crystallized from ethyl acetate to yield 3.4 g. of white solid product; m.p.
134-135 . An additional 0.6 g. is obtained by concentrating the filtrate. Crystallization from ethyl acetate yielcls an analytical sample of methyl[l-[[(phenylmethoxy)carbonyl]amino]pentyl]-phosphinic acid, m.p. 138-150 .
Anal. Calc'd. for C14H22NO4P:
C, 56.18; Hr 7.41; N, 4.68; P, 10.35 Found: Ct 56.11; H, 7.~1; N, 4.61; P, 10.4 b) Methyl[l-[[(phenylmethoxy)carbonyl]amino]-pent 1] hos hinic acid, phenYlmethyl ester y p p The product from part (a) (4.0 g., 0.0134 mole) is dissolved in 300 ml. of dichloro-methane and cooled in an ice bath. 1-Benzyl-3-p-tolyltriazene (8.4 g., 0.0373 mole) is added portionwise. After stirring overnight at room temperature, the solution is washed with ~% potassium bisulfate, saturated sodium bicarbonate, and brine, dried (MgSO4) and eva~orated to l~D~ 57 HA23~

yield 11 g. of red oil. This material is chromatograph~d on silica gel using ethyl acetate to yield 5.1 g. of methyl[l-[[(phenylmethoxy)car-bonyl3amino]pentyl]phosphinic acid~ phenylmethyl ester as a white semi-solid.
c) _[ P ~ l-[[(~henylmethoxy)carbonyl amino]pentyl]phosphinyl]acetic acid A solution of 0.04 mole of lithium diisopropylamide in tetrahydrofuran is prepared by the dropwise addition of N-butyllithium (16 ml. of 2.6 N solution, 0.04 mole) to a cooled (0) solution of diisopropylamine (5 g., 0~05 mole) in pentane (75 ml.). The solvent is removed in vacuo and replaced by tetrahydrofuran (50 ml.). The solution is cooled to -76 and a solution of the phenylmethyl ester product from part (b) (4.2 g., O.OlQ8 mole) in tetrahydrofuran (50 ml.) is added over a period of 30 minutes. After stirring for 15 minutes, carbon dioxide, dried over molecular sieves, is bubbled into the reaction mixture for 10 minutes. After stirring for 10 minutes, and warming ~o room temperature, ~he solvent is removed in vacuo. The residue is acidified __ to a pH of 1 with 10~ hydrochloric acid and extracted with dichloromethane, washed with brine, and dried (MgS04). The solvent is removed ln YaCuO. The residue is dissolved in saturated sodium bicarbonate solution (75 ml.) and washed with dichloromethane. The alkaline phase is acidified to a pH of 1 with concentrated hydrochloric acid, extracted with dichloromethane, washed with brine, and dried (MgSO4~. The solvent is removed in vacuo to give 3.7 g. of [(phenyl-methoxy)[l-[[(phenylmethoxy)carbonyl]amino]pentyl]-phosphinyl]acetic acid as an oil. Tlc,silica gel, benzene/acetic acid (7:1): 2 spots, Rf 0.17; 0.15.
d)(~ [(nhenylmethoxy)[l [[(phenylmethoxy)carbonyl]-.
amino]pentyl]phosphinyl]acetyl]-L-proline, phenylmethyl ester 1,1-Carbonyldiimidazole (1.2 g., 0.0074 mole) is added to a chilled (0) solution or the product from part (c)(3.2 g., 0.0074 mole) in acetonitrile (40 ml.). A solution of L-proline, benzyl ester (1.5 g., 0.0074 mole) in acetonitrile (20 ml.) is added. The mixture is stirred at ambient temperature for 16 hours. The solvent is removed in vacuo. The residue is dissolved in dichloromethane (100 ml.), washed with 5~
potassium bisulfate, saturated sodium bicarbonate solution, brine, and dried (MgSO4)~ The solution is concentrated in vacuo to give an oil residue of -4.8 g. Tlc, silica gel, ethyl acetate: major spot at R 0.28, visualized with phosphom~lybdic acid (PMA) and heat. It was chromatographed on ~ilica gel, eluting with ethyl acetate/dichloro~
methane (1:1), and with ethyl acetate to give 3.2 g. of (~ [[(phenylmethoxy)~l-[[(phenylmethoxy)-carbonyl]amino]pentyl]phosphinyl]-~ 75~ HA238 acetyl]-L-proline, phenylmethyl ester.
e) ( )-1-[[(l-Aminopentyl~hydroxyphosphinyl]acetyl]-_proline A mixture of the phenylmethyl ester product from part (d) (3.1 g., 0 005 mole) and

5% palladium on carbon (150 mg.) in acetic acid/
methanol [(1:9), 60 ml.] is stirred vigorously under one atmosphere of hydrogen until hydrogen is no longer consumed (about 350 ml.). The residue is triturated with acetonitrile to give a solid (1.5 g.) with an indefinite melting point (170 - 190 dec.~. Tlc, silica gel, butanol/acetic ~cid/water (3:1:1); single spot, R~ 0.10, visualized with ninhydrin indicator. The solid is dissolved in water (120 ml.), washed with ethyl acetate, filtered, and lyophilized to give 1.4 g. of (-)-l-[[(l-aminopentyl~hydroxyphosphinyl]-acetyl]-L-proline; mOp. 140-190 (dec.); [a] D -65.
Anal. Calc'd. for C12H23~2O5 2 C, 44.44; H, 7.45, N, 8.63; P, 9.55 Found: C, 44.73; H, 7~67; N, 8.66; P, 9.70.

(-~ 1-[[(Aminoethyl)hydroxyphosphinyl]acetyl]-L-proline a) Methyl [l-[[(phenylmethox~)carbonyl]amino]
ethyl]~hosphinic acid Pivalic acid (10.2 g., 0.1 mole) is added ~o 100 ml. toluene. A portion of the toluene (10 ml~) is distilled to remove traces of ~oisture. Benzyl carbamate (7.5 g., 0.05 mole), ~ H~2 powdered 4A molecular sieves (5.0 g.) and methyl dichlorophosphine (5.8 g., 0.05 mole) are added with stirring at room temperature. Acetaldehyde (3.3 g., 0.075 mole) is then added dropwise with vigorous s~irring at ambient temperature over a period of 10 minutes. During the addition the temperature of the reaction mixture increases to 55 0 After stirring for one hour, 100 ml. of dichloromethane is added and the mixture is filtered. The filtrate is concentrated in vacuo. The residue is dissolved in saturated sodium bicarbonate solution (125 ml.), washed with dichloromethane (3 x 40 ml.), and the combined dichloromethane wash is reextracted with saturated sodium bicarbonate solution (2 x 15 ml.).
The combined aqueous alkaline phase is adjusted to a pH 3.2 with concentrated hydrochloric acid and extracted with ether (3 x 20 ml.). It is then acidi-fied to a pH of 1 with concentrated hydrochloric acid and extract~d with ethyl acetate (3 x 50 ml.), dried (MgS04) and the solven-t removed ln vacuo.
- The residue (10.9 g.) solidifies at room tempera-ture. Tlc, silica gel, dichloromethane/methanol/
acetic acid (8:1:1) sllows a major spot at Rf 0.30.
It is recrystallized from acetonitrile (110 ml.) to yield 8.7 g. of product. A second recrystalli-zation from acetonitrile gives an analy~ically pure sample of methyl[l-[[(phenylmethoxy)-carbonyl]amino]ethyl]phosphinic acid; m.p. 118-119.
Anal. calc'd. for CllH16N04P:

~ 7~7 HA238 C, 51.36; H, 6.26; N, 5.45; P, 12.04 Found; C, 51.44; H, 6.36; N, 5.47, P, 11.76.
b) Methyl[l-[[(phenYlmethoxY)carbonYl]amino]-ethyl]phosphinic acid, phenylmethyl ester A solution of the product from part (a) (9.2 g., 0.036 mole) in 150 ml. of dichloro-methane is prepared by warming to reflux and then cooling to room temperature. Three equiva-lents of 3-benzyl-1-p-tolyltriazine is added portionwise with stirring. The mixture is stirred at ambient temperature overnight, washed with water, 5% potassium bisulfate, saturated sodium bicarbonate, dried (MgSO4) and evaporated in vacuo to give an oil residue.
The residue is dissolved in ether (500 ml.).
After refrigeration, a solid crystallizes from solution (7.6 g.); m.p. 108-110, partial melt, complete melt at 128-130 . It is recrystallized from ethyl acetate (80 ml.) to yield 6.2 g. of product; m.p. 138-140, sintering 98-108 .
Recrystallization from ethyl acetate a second time gives an analytical sample of methyl [l-[[(phenylmethoxy)carbonyl]amino]ethyl]-phosphinic acid, phenylmethyl ester; m.p.
138-140. Tlc, silica gel, benzene/acetic acid (7:1) shows a major spot at Rf 0.21, visualized with PMA plus heat.
Anal. calc'd. for C18H22NO4P:
C, 62.24; H, 6.38; N, 4.03; P, 8.91 Found: C, 62.33; H, 6.50; N, 4.00; P, 8.86.

~iA23 c) [(Phenylmethoxy)_[l-[[(phenylmethoxy)carbonyl]-amino,]ethyl]phosphinyl~acetic acid ~ solution of 0.04 moles of lithium di-isopropylamide in 50 ml. of tetrahydrofuran is prepared as in Example 1 (c). The solution is cooled to-76 and the solution of the phenyl-methyl ester product from part (b) (3.5 g., 0.01 mole) in tetrahydrofuran (100 ml.) is added over a period of 30 minutes. After stirring for 15 minutes, carbon dioxide, dried over molecular sieves, is bubbled into the reaction mixture for 10 minutes. After stirring for 10 minutes, and warming to room temperature, the solvent is removed ln vacuo. The residue is acidified to a pH of 1 with 10% hydrochloric acid, extracted with dichloromethane (2 x 75 ml.) and dried (MgSO4). The solvent is removed in vacuo. The residue is dissolved in 75 ml. of saturated sodium bicarbonate solution and washed with dichloromethane. The aqueous alkaline solution is acidified to a pH of 1 with concentrated hydro-chloric acid, extracted with dichloromethane, washed with brine, and dried (MgSO4). The solvent is removed ln vacuo to give 3.1 g. of ~(phenylmethoxy)~l-,[[(phenylmethoxy)carbonyl]-,amino]ethyl]phosphinyl] acetic acid as an oil.
Tlc, silica gel, benzene/acetic acid (7:1) shows a major spot at R~ 0.17.

~ q~
~ H,23 d~(+~ -L~Lr (Phenylmethoxv)tl-[[(Phenylmetnoxv)carbonylJ
amino]ethyl]phosp-hinyl]acetyl~-L-proline~ phenyl-methyl ester l,l'Carbonyldiimidazole (1 g. 0.066 mole) is added to a chilled (0) solution of the product from part (c~. (2.5 g., 0.063 mole) in 40 ml.
of acetonitrile. The mixture is stirred for one hour at 0 . A solution of L-proline, benzyl ester (1.3 g., 0~066 mole) in 20 ml. of acetonitrile is added. The mixture is stirred at ambient temperature for 16 hours. The solvent is removed ln vacuo. The residue is dissolved in dichloromethane (125 ml.), washed with 5~
potassium bisulfate, saturated sodium bicarbonate solution, brine, and dried (MgSO4). The solution is concentrated in vacuo to give an oil residue of 3.3 g. Tlc, silica gel, ethyl acetate shows a major spot at Rf 0.10. A portion (2.2 g.) is chromatographed on silica gel, eluting with ethyl acetate to give 1.7 g. of (+)-l-[(pllenylmethOXY) [l-[[(phenylmethoxy)carbonyl]amino]ethyl~phos~
phinyl]acetyl]~L-proline, phenylmethyl esterO
e) (-? -1- r. r (Am oeth~l)hydroxyphos~hinyl]acetyl]-L-proline A mixture of the product from part (d) (1.5 g., 0.0026 mole) and 5~ palladium on carbon (100 mg.) in acetic acid/methanol[(1:9),50 mlO ]~
is stirred vigorously under one atmosphere of hydrogen until hydrogen absorption ceases (about 165 ml.). The mixture is filtered and ~ 7 HA238 concentrated _ vacuo. The residue is dissolved in distilled water, millipore filtered, and lyophilized to give 0.65 g. of solid with an indefinite melting point, decomposing at 175-200 .
Tlc, silica gel, butanol/acetic acid/ water (3:1:1) shows a single spot at Rf 0.1~, visualized with ninhydrin indicator. A solution of the combined product of two preparations (0.8 g.) in water (2 ml.) is placed on an AG-50 W column (1", 75 ml.) and eluted with water.
The aqueous solution is lyophilized to give 0.7 g. of (~ [[(aminoetnyl)hydroxyphosphinyl]-acetyl]-L-proline; m.p. 175 - 200 (dec.).
Tlc, silica gel, butanol/acetic acid/water (3:1:1) shows a single spot at Rf 0.13, visualized with ninhydrin.

C, 39.56; H, 6.64; N, 10.25; P, 11.33 Found: C, 39.22; H, 6.96; N, 10.16; P, 11.24.
Exa~ples 4 - 17 Following the procedure of Examples 1 to 3 but coupling the pho$phinylalkanoyl compound of formula I with L-proline, benzyl ester yields the intermediate of formula II. Removal of the protecting groups yields the product of formula III.

.

~LZg~ S7 ~ 238 ~, u o o = C~
I _~

o Z
o =V o =~ o o, ~

-- V --~ ~ Z; .
t C = P~ o o ~ o o--~; Z _~
r.
o=y O='y V
o o ~ O = ~ _ o _ (~) ~O) ,.
_. H
H H
- H H
_. _ ~2~ 7 H~238 Example n R2 R5 4 one ( 2)2 ~ -H

zero -(CH2) ~ -CH3

6 one -(CH2) ~ -CF3

7 zero -(CH2) ~ -CH

one -CH2 ~ -H

9 zero -H -(CH2) one -CH2-CH=CH2 -1l 11 zero 2 3 -H

12 zero -(CH2)~ H

13 zero -(CH2)2~ ~ -H

14 zero -(CH2) ~ N -H

zero ~ -CH3 16 zero . -(CH2) ~ CH -H

17 one (C 2) ~ 0 ~ F

~ ~ 7 HA238 Example 18 ~ [[[l-[(Ethoxycarbonyl)amino]-3-phenylpropyl~-hydroxyphosphinyl]acetyl~-L-proline a) Methyl [l-[(ethoxycarbonyl)aminoI-3-phenyl-prop~ phosphinic acid Pivalic acid (10.2 g., 1 mole) and ureth~n (4,5 g., 0.05 mole) are dissolved in 160 ml.
of toluene. A portion of the toluene (10 ml.) is distilled at atmospheric pressure to remove traces 1~ Of water. The solution is cooled to room tempera-ture under argon and methyldichlorophosphine (5.6 g., 0.05 mole) and powdered 4A molecular sieves (5 g.) are added, followed by hydrocinnamaldehyde (8 g., 0.06 mole) via syringe. A slight exotherm (to approximately 43) is observed. After stirring one hour the solids in suspension are removed by filtration. The filtrate is concentrated in vacuo. The residue is triturated with diiso-propylether ~50 ml.) to give 12.1 gO of solid product; m.p. 119-125. Tlc, silica gel, butanol/acetic acid/water (3:1:1) shows a major spot at R~ 0.50, plus a minor spot at Rf 0O55 visualized with PMA plus heat. A sample is recrystallized from ethyl acetate (10 ml.) to yield 0.3 g. of methyl [1-[(ethoxycarbonyl)amino]-3-phenylpropyl]phosphinic acid; m.p. 127-129.
Anal. Calc'd. for Cl3H2~No4p:
C, 54.73; H, 7.06; N, 4.91; P, 10.85-Foundo C~ 54.79; H, 7.31; N, 4.62; P, 10.70.

~' ~L~7~ H~23~
_ -45-b) Methyl[l-[(ethoxycarbonYl)amino]-3-phenyl-propyl]~hosphinic acid~ phenylmethyl_ester Bis (trimethylsilyl)acetamide (ll ml., 0.045 mole) is added via syringe to a solution of the product from part (a) (lO g., 0.035 mole) in dichloro-methane (50 ml.) in an atmosphere of argon. The mixture is stirred at ambient temperature for one hour~ The solvent and excess bis(trimethylsilyl)-acetamide are removed ln vacuo at room temperature.
After the addition of dichloromethane (50 ml.) to the residue, phosphorous pentachloride (8.5 g. 0.04 mole) is added and the resulting solution is stirred for one hour. After removal of the solvent in vacuo at room remperature, dichloromethane ~50 ml.) is added to the residue. The resulting solution is stirred at ambient temperature during the drop-wise addition of a solution of benzyl alcohol (4.2 g., 0.039 mole) and triethylamine (5 g., 0O05 mole) in dichloromethane (20 ml.). After stirring 16 hours at room temperature, the reaction mixture is diluted to twice its volume with dichloromethane~ After washing with brine, followed by saturated sodium bicarbonate, followed by brine, and drying (MgSO4), the solvent is removed ln vacuo. The residue is dissolved in ether and washed with water to a negative Cl test. Th~e solvent is removed in vacuo to give recovery of the product (11 g.) as an oil. Tlc, silica gel, ethyl acetate, shows a major spot at Rf 0.40, plus a minor ~q3~757 ~IA238 spot at origin (PMA visualization). Trituration of the oil with diisopropyl ether results in the separation of a solid (2.3 g., m.p. 124 - 127 ).
Tlc, silica gel, ethyl ace~ate, shows one spot, Rf 0.40. The filtrate is concentrated in vacuo to give recovery of an oil (8.1 g.). A portion of the solid (400 mg.) is recrystallized from benzene to yield 150 mg. of methyl [1-[(ethoxycarbonyl)-amino]-3-phenylpropyl]phosphinic acid~ phenyl methyl ester; m.p. 128 - 130 .
Anal. calc'd. for C20H261~O4P:
C, 63.99; H, 6.98; N, 3.73; P, 8.25 Found: C, 64.04; H, 6.97; N, 3.54; P, 8.40.
c) [(Phenylmethoxy)[l-[(ethoxycarhon~l)amino]-3-phenylprop~l]phosphin~l]acetic acid A solution of 0.09 mole of lithium diisopropylamide in 150 ml. of tetrahydrofuran, prepared according to the proceduxe of Example l~c), is cooled to -76 and a solution of the phenyl-methyl ester product from part (b) (10 g., 0.026 mole) in 40 ml. of tetrahydrofuran is added over a period of one hour. After stirring for 15 minutes, carbon dioxide, dried over molecular sieves, is bubbled into the reaction mixture for 10 minutes. After stirring for 10 minutes, andwarming to room ~emperature, the solvent is removed ln~vacuo. After the addition of water (50 ml.), the residue is acidified to a pH of 1 with concentrated hydrochloric acid. The oil that separates from solution is extracted into 12~7S7 H~2'Z

dichloromethane (200 ml.), washed with brine, and dried (MgSO4). The solvent is removed in vacuo.
The residue is dissolved in 5~ sodium bicarbonate solution (100 ml.) and washed with ether (2 x 75 ml.). The alkaline aqueous solution is acidified to a pH of 1 with concentrated hydrochloric acid, extracted with dichloromethane, washed with brine, and dried (~IgSO4)O The solvent is removed _ vacuo. The semi-solid residue (8.6 g.) is recrystallized from ethyl acetate (100 ml~) to yield 4.8 g. of [(phenylmethoxy)[l-[(ethoxycarbonyl)amino]-3-phenylpropyl]phosphinyl]-acetic acid; m.p~ 151-153. Tlc, butanol/acetic acid/water (3:1:1) shows a single spot, Rf 0.70 visualized with P~IA plus heatO
Anal. Calc'd. for C21H26NO6p:
C, 60.14; H, 6.25; N, 3.34; P, 7.38 Foun~: C, 59.88; H, 6.17; N, 3.13; P, 7.19.
d)(-~ [L(Phenylmethoxy)Ll-[(ethoxycarbonyl)amino]-3-phenylpro~yl]phos~iny]]acetyl]-L-proline, phenylmethyl ester l,l-Carbonyldiimidazole (1.8 g., 0.011 mole) is added to a chilled (0) solution of the product from part (c) (4~6 g., 0.011 mole) in 50 ml. of acetonitrile. The mixture is stirred for one hour at 0 and a solution of L-proline, benzyl ester (2.3 g., 0.011 mole) in 25 ml. of acetonitrile is added. The mixture is stirred at ambient temperature for 16 hours. The solvent is removed _ vacuo. The residue is dissolved in 12~ ~S 7 HA2'8 -~8-200 ml. of dichloromethane, washed with 5%
potassium bisulfate, saturated sodium bicarbonate solution, brine, and dried (MgSO4). The solvent is removed in vacuo to give an oil residue of 6.5 g. Tlc, silica gel, ethyl acetate, shows a major spot at Rf 0.50 visualized with PMA. The residue is chromatographed on silica gel, eluted with dichloromethane/ethyl acetate (9:1~ and (4:1) to give 5.4 g. of (~ [(phenylmethoxy)[l-[(ethoxy-carbonyl)amino]-3 phenylpropyl] phosphinyl]acetyl]-L-proline, phenylmethyl ester. Tlc shows a single spot at Rf 0.50.
e) (-)-l-[[[l-[(Ethoxycarbonyl)amino]-3-phen~l-propyl]hydroxyphosphinyl]acetyl]-L-~roline A mixture of the product from part (d) (5.2 g., 0.088 mole) and 5% palladium on carbon (200 mg.) in methanol (65 ml.) plus 1 ml. of glacial acetic acid is stirred vigorously under one atmosphere of hydrogen until hydrogen absorption ceases (about 400 ml.). The mixture is filtered and concentxated ln vacuo. Tlc, silica gel, butanol/acetic acid/water (3:1:1) of the residue (3.4 g.) shows a major spot at Rf 0.46 and a minor spot at 0.50 (visualized with PMA). A
portion of the residue (0~3 g., 0.0007 mole) is chromatographed on a column of DE~E Sephadex - (~H4 form) (100 ml. - 15 mm diameter column) and eluted with a gradient of 0.005 m to 0.5 m ammonium bicarbonate solution. The UV positive fractions are collected, millipore filtered, ~2~ 757 HA238 and lyophilized to give a residue of 0.3 g.
Tlc shows a major spot at Rf 0.46 and a shadow at Rf 0.50. The residue is dissolved ln 3 - 4 ml.
of double distilled water and placed on a column of AG 50-W resin (H form) (30 ml.) and eluted with water. The acidic fractions are collected, millipore filtered, and lyophilized to give 168 mg. of (~ [~ (ethoxycarbonyl)amino]-3-phenylpropyl]hydroxyphosphinyl]acetyl]-L-proline.
Anal. calc'd. for ClgH27N~07P ~2 C, 51.34; H, 6.57; N, 6.30; P, 6.97 ~ound: C, 51.17; H, 6.35; N, 6.26; P, 6.81.
Example 19 ~ l-[[H~droxy[3 phenyl-1-[(trifluoroacetyl)-amlno]propyl]phosphin~l]a_etyl]-L-proline, dilithium salt a) Methyl(l-amino-3-phenylpropyl)phosphinlc acid, hydrochloride A suspension of methyl [l-[(ethoxycarbonyl)-amino]~3-phenylpropyl]phosphinic acid from Example 18(a) (9.8 g., 0.034 mole) in 22O2%
hydrochloric acid (200 ml.) is heated at reflux for 24 hours. After filtration, the resulting solution is concentrated in vacuo.
Water (100 ml.) is added to the residue and the solution is again concentrated ln vacuo.
Trituration of the residue with refluxing acetonitrile (125 ml.) results in the separation of solid product (7.5 g.~; m.p. 196-200 (dec.).

A portion (0.4 g.) is recrystallized from absolute ethanol (10 ml.) to yield 0u27 g of an analytical sample of methyl(l-amino-3-phenylpropyl)phosphinic acid, hydrochloride; m.p. ~98-200 (dec.).
Anal. Calc'd. for CIoHl6NO2P HCl:
C, 48.10; H, 6.46; N, 5.61; Cl, 14.20;
P, 12.41 Found: C, 47.98; H, 6.99; N, 5.56; Cl, 14.14;
P, 12.10.
b) Methyl[3-phen ~-l-[(trifluoroacetYl)amino]-prop~l]phosphinic acid A mixture of the product from part (a) (7.5 g., 0.026 mole) and 25 ml. of trifluoroacetic anhydride is stirred at ambient temperature for two hours. The excess anhydride is removed in vacuo. The residue is triturated with reflu~ing diisopropyl ether (500 ml.) to give 7.5 g. of solid product; m.p. 138-145. Tlc, silica gel, butanol/acetic acid/water (3-1:1) shows one spot, Rf 0.70. A portion (0.5 g.) is recrystallized from diisopropyl ether (800 ml.) to yield 0.4 g. of an analytical sample of methyl ~3-phenyl-1-[(tri-fluoroacetyl)amino3propyl]phosphinic acid, m.p. 145-146.
Anal. calc'd. for C12H15F3NO3P:
C, 46.61; H, 4.89; N, 4.53; F, 18.43; P, 10.02 Found: C, 46.41; H, 4.83; N, 4.46; F, 18.15; P, 9.89.

lZ~7~7 ~IA238 c) Meth~1[3-phenyl l-[(trifluoroacetvl)amino~-propyl~phosphinic acid, phenylmethyl ester ~ Bis(trimethylsilyl)acetamide (8 ml., 0.033 mole) is added to a suspension of the product from part (b) (7 g., 0.023 mole) in S0 ml. of dichloromethane, in an atmosphere of argon. A
solution of -the solid occurs rapidly and the mixture is stirred at ambient temperature for one hour.
The solvent and excess bis(trimethylsilyl)acetamide are removed in vacuo at room temperature. The residue is dissolved in 50 ml. of dichloromethane and phosphorous pentachloride (5.7 g., 0.027 mole) is added. After stlrrlng for one hour, the solvent and excess pentachlorlde are removed in vacuo . The resldue is dissolved in 50 ml. of dichloromethane and a solution of benzyl alcohol (2.8 g., 0.026 mole) and triethylamine (3.5 g., 0.034 mole) in 20 mlO of dichloromethane is added dropwise with stirrlng. After stirring at ambient temperature for 16 hours, the mixture is diluted to twice its volume with dichloromethaneO The solution ls washed with 5~ potassium bisulfate, water, brine, and drled (MgSO4). After concentrating ln vacuo, the semi-solid residue (8.7 g.) is tri-, turated with 200 ml. of diisopropyl ether. A solid(2.4 g., m.p. 145-155) is collected by filtration (Tlc shows a single spot at R~ 0.60). A porti~n of the solid product (0~3 g.) is recrystallized from 75 ml. of diisopropyl ether to yield 0.18 g. of an analytical sample of methyl[3-phenyl-1-[(trifluoro-~Z~57 HA2~ a acetyl)amino]propyl]phosphinic acid, phenylmethyl ester; m.p. 165-166.
Anal. calc'd. for C19 H21 3 3 C, 57.14; H, 5.30; ~, 3.50; F, 14.27; P, 7.75.
Found: C, 56.96; H, 5.32; N, 3.50; F, 13.99; P, 7.54 d) [(Phenylmethoxy)[3-phenyl-1-[(trifluoroacetyl)-amino]propyl]phosphiny~acetic acid A solution of 0.075 mole of lithium diiso-propylamide in 150 ml. of tetrahydrofuran is prepared according to the procedure of Example l(c) and cooled to -76. A solution of the product from part (c) (8.4 g., 0.021 mole) in 40 ml. of tetrahydrofuran is added over a period of 50 minutes. After stirring for 15 minutes, carbon dioxide, dried over molecular sieves, is bubbled into the reaction mixture for 10 minutes. After stirring for 10 minutes, and warming to room temperature, the solvent is removed in vacuo. After the addition of 10%
hydrochloric acid (50 ml.) to the residue, with cooling, concentrated hydrochloric acid is added to a pH of 1. The mixture is extracted with 300 ml. of dichloromethane, washed with brine, and dried (MgSO4). The solvent is removed in vacuo. Tlc, silica gel~ butanol/acetic acid/water (3-1:1) of the residual oil (8.5 g.) shows a major spot at Rf 0.70. The material is chromatographed on silica gel, eluting with toluene/acetic acid (9:1) to give 6.1 g. of [(phenylmethoxy)[3-phenyl-1-[(trifluoroacetyl~amino]propyl]phosphinyl]-,, ~ S7 H~23~

acetic acid. Tlc shows a single spot at Rf 0.70.
e) (~ [(Phenylmethoxy)[3-phenyl-1-[(trifluoro~
acety~)amino]propyl~phosphinyl]acetyl]-L-proline, phenylmethyl ester l,l-Carbonvldiimidazole (2.2 g., 0.0133 mole) is added to a chilled (0) solution of the product from part (d) (5.9 g., 0.0133 mole) in 50 ml. of acetonitrile. The mixture is stirred for one hour at 0 and a solution of L-proline, benzyl ester (2.7 g., 0.0133 mole) in 20 ml.
of acetonitrile is added. The mixture is stirred at ambient temperature for 16 hours. The solvent is removed in vacuo. The residue is dissolved in 200 ml. of dichloromethane, washed with 5%
potassium bisulfate solution, brine, and dried (MgSO4). The solution is concentrated in vacuo to give a syrupy residue of 8.2 g. Tlc, silica gel, ethyl acetate/dichloromethane (1:4) shows a major spot at Rf 0.40 with 3 minor additional spots, including one at origin (visualized with PMA plus heat). The residue is chromatographed on silica gel, eluting with ethyl acetate/dichloromethane (1:9) to give two fractions, Tlc of one fraction (1.9 g.) shows a single spot at Rf 0.40; the other fraction (4.5 g.~ shows two spots, a major one at Rf 0~40 plus a minor at Rf 0.35. The chromatographically pure (~ [[(phenylmethoxy)-[3-phenyl-1-[(trifluoroacetyl)aminolpropyl]phosphinyl]
acetyl]-L-proline, phenylmethvl ester is employed ~54-in the following steps.
f) (-)-l-~[Hydroxy[3-phenyl-1-[(trifluoro-ac tyl)amino]propyllphosphinvl~acetyl]-L-proline A mixture of the product from part (e) (1.6 g., 0.0025 mole) and lO~ palladium on carbon (0.1 g.) in 50 ml. of ethyl acetate is stirred vigorously in an atmosphere of hydrogen until absorption of hydrogen ceases (about 113 ml. of hydrogen). The mixture is filtered and concentra-ted in vacuo to give 1.1 g. Tlc, silica gel, dichloromethane/methanol/acetic acid (8~
shows a major spot at Rf 0.22 and a minor spot at Rf 0-04 (I2 visualization). A solution of water insoluble residue (a glassy solid) is effected in methanol (1.0 g., 0.0022 mole to 4 ml.) plus wa~er (2 ml.) and placed on a column of DEAE Sephadex (NH4 HCO3, 200 ml.) and eluted with a gradient of 0.005 mole to 0.5 mole ammonium bicarbonate solu~ion. The UV positive fractions are collected, millipore filtered, and l~ophilized to give 1.1 g. The solid is dissolved in 5 ml.
of water, placed on a column of AG-50 W ~H ) (75 ml.), and eluted wi~h water. Tle acidic fractions are collected, millipore filtered, and lyophilized to give 0.9 g. of (~
[[hydroxy[3 phenyl-l-[(trifluoroacetyl)amino]-propyl]phosphinyl]acetyl]-L-proline as a glass-like solid. Tlc, silica gel, butanol/acetic acid/water (3:1:1) shows a single spot at Rf 0.50 (visualized with PMA plus heat).

i2~'~ 7S7 HA2'8 g) (-)-l-[[~Iydroxy[3-phenyl-1-[(trifluoroacetyl) amino]p~opyl]phosphin~l]acetyl]-L-proline, dilithium salt A solution of the product from part (f) (0.9 g., 0~002 mole) in water is effected by the addition of one equivalent (2 ml.) o~ lN
lithium hydroxide plus 2 ml. of water. The solution is placed on a column of AG-50W (Li ) (75 ml. ) and eluted with water. The acidic fractions (pH 4 - 5.5) are collected, millipore filtered, and lyophilized to give 0.9 g. of (-)-l-[[hydroxy[3-phenyl-1-[(trifluoroacetyl)-amino]propyl]phosphinyl]acetyl]-L-proline, dilithium salt. Tlc, silica gel, ethyl acetate, butanol/acetic acid/water (3-1:1) shows a single spot at Rf 0.50.

C, 44.60; H, 4.68; N, 5.78; F, 11076; P,6.39 Found: C, 44.53; H, 4.56; N, 5.82; F, 11093; P,6.~0.

~A238 Example 20 (-)-1-[[[1-(Benzoylamino)-4-phenylbutyl]hydroxy-phosphinyl]acetyl]-L-proline a) Carbomethoxymethyldichlorophosphine Ketene is passed through a solution of tributyltin methoxide (64 g., 0.199 mole) in 200 ml. of anhydrous e-ther at 0 until Tlc (silica gel, methanol:dichloromethane; 1:9) indicates complete consumption of starting material (Rf equals 0~14)o The ether is removed in vacuo and the residue distilled to give 62.75 g. of carbomethoxymethyl tributyltin as a pale yellow liquid; b.p. 117-120 (0.8 mm Hg).
A mixture of carbomethoxymethyl tributyltin (80 g., 0.22 mole) and phosphorus trichloride (80 ml., 0.92 mole) is treated with 2,2'-a70bisiso-but~ronitrile (230 mg., 1.4 mmole) and slowly heated to reflux under argon. After refluxing for 30 minu-tes, the excess phosphorus tri-chloride is distilled off under reduced pressure.
Distillation of the residue gives carbomethoxymeth dichlorophosphine as a colorless liquid; b.p.
52 (2mm of Hg ).
b) [[4-Phenyl-l-[[(phenylmethoxy)carbonyl]amino]-but~ hydroxyphosphinYllacetic acidl methyl ester A mixture of pivalic acid (5.5 g., 0.054 mole) and benzyl carbamate (4.1 g., 0.027 mole) in 100 ml. of toluene is heated to reflux and a portion of the toluene (10 ml.) 3~ is removed by distillation at atmospheric pressure ~ 7 ~1~238 to remove traces of water. The solution is cooled to room temperature, under argon, and powdered 4A m~lecular sieves (5 g.) are added, followed by the addition of carbomethoxymethyldichlorophosphine (4.7 g., 0.027 mole) from part (a). 4-Phenylbuty-raldehyde (4.4 g., 0.03 mole), prepared according to the procedure in Tetrahedron, Vol. 34, p. 1651 (1978), is added dropwise over five minutes via syringe~ A slight exotherm (approximately 38) is observed. The mixture is stirred at ambient temperature for 16 hours. After filtration and concentration in vacuo, 200 ml. of water is added to the residue followed by the addition of saturated sodium bicarbonate solution to a pH of 8 - 9.
The alkaline aqueous phase is washed with ether and acidified to a pH of 1 - 2 with concentrated hydrochloric acid. The oil that separated from solution is extracted into ethyl acetate, washed with brine, and dried (MgSO4). After concentrating ln vacuo, the residue is triturated with diiso-propyl ether to yield 5 g. of product. Tlc, silica gel, dichloromethane/methanol/acetic acid (8:1:1) shows a major spot at Rf 0.56 plus a minor spot at Rf 0.10, and a shadow at Rf 0.70 The material is recrystallized from toluene (30 ml.) to yield 4 g. [[4-phenyl-1-[[(phenyl-methoxy)carbonyl]amino]butyl]hydroxyphosphinyl]-acetic acid, methyl ester; m.p. 107 - 109.
Tlc shows a single spot at Rf 0.56, with a shadow at Rf 0.08.

12~ ~5 7HA2'~

Anal. calc'd. for C21H26NO6P:
C, 60.12; H, 6.27; W, 3.33; P, 7.38 Found~: C, 59.89; H, 6.18; N, 3.23; P, 7.40.
c) [[l-(Amino)-4-phenylbutyl]hydroxyphosphinyl]
acetic acid -A suspension of the product from part (b) (2.8 g., 0.0067 moles) in 10~ hydrochloric acid (60 ml.) is stirred at reflux until Tlc shows the absence of starting material (about three hours). The mixture is washed with ether and concentrated in vacuo. The residue is repeatedly treated with water (20 ml.) and concentrated _ vacuo until a white solid separates when water is added to the residue. After cooling in an ice-wat~r bath, the solid is collected by suction-filtration and dried in vacuo to give 1.05 g.
[[1-(amino)-4-phenylbutyl]hydroxyphosphinyl]
acetic acid; m.p. 189 - 190 (dec.).
Anal. calc'd. for C12H18NO4P:
C, 53.13; H, 6.69; N, 5.16; P, 11.42 Found: C, 53.54; H, 6.41; N, 5.08; P, 11.20.
d) [[l-(Benzoylamino)-4-~henylbutyl]hydroxy-phosphinyl~acetic acid To a suspension of the product from part (c) (1 g., 0.0037 mole) in water (30 ml., pH 2.3), solid sodium carbonate is added until solution is effected (pH 8.5). ~he pH of the solution is maintained at a pH of-8.5 - 9 by the addition ~f solid sodium bicarbonate during the dropwise addition of a solution of benzoyl chloride (0.52 g., 0.~037 mole) in ~ ml. of acetone. After the addition is completed an additional equivalent of benzoy,l chloride is added dropwise (0.5 g.
in 5 ml. of acetone), while maintaining the pH
at 8.5 - 9 by the addition of sodium bicarbonate.
The alkaline solution is washed with ether, acidified to a pH of 1 with concentrated hydro-chloric acid, and the oil that separates is extracted into ethyl acetate, washed with brine, and dried ~MgSO4). The solvent is removed in vacuo and the residue is triturated with diiso-propyl ether to give 1.4 g. of solid [[l-(benzoyl-amino)-4-phenylbutyl]hydroxyphosphinyl]acetic acid;
m.p. 170-175 (turbid melt). Tlc, silica gel, butanol/acetic acid/water (3:1:1), shows a single spot at Rf 0.50.
e) (-)-l-[[[l-(Benzoylamino)-4-phenyl~utyl]hydroxy-phosphinvl]acetyl]-L-proline, phenylmethyl ester l,l-Carbonyldiimidazole (0.36 g., 0.0022 mole~ is added to a solution of the product from part (d) (0~75 g., 0.002 mole) in acetonitrile/
tetrahydrofuran (1:1, 40 ml.), cooled in an ice/water bath. The mixture is stirred in the cold for one hour and followed by the addition of L-proline, benzyl ester (0.45 g., 0.0022 mole)'in 5 ml. of tetrahydrofuran. After stirring at ambient temperature for 16 hours, the mixture is concentrated ln v~cuo; The residue is dissolved in ethyl acetate (100 ml.) plus water (10 ml.) and washed to a pH of 2 with 5~. potassium bisulfate, ~Z~757 HA238 brine, and dried (MgS~4). The solution is concentra-ted in vacuo to give a glass-like residue. Tlc, silica gel, dichloromethane/acetic acid/water (8:1:1), shows a major, elongated spot at Rf 0.75, plus a minor spot at Rf 0.10 and several faster moving spots. The residue is chromatographed on silica gel, eluted with dichloromethane/
methanol/acetic acic (15:1:1) to give 0.7 g. of (-)-l-[[[l-(benzoylamino)-4-phenylbutyl]hydroxy-phosphinyl]acetyl]-L-proline, phenylmethyl ester.
Tlc shows a single spot at Rf 0.75.
)-1-[[[1-(Benzoylamlno)-4-phenylbutyl]-hydroxyphosphinyl]acetyl]-L-proline A mixture of the product from part (e) lS (0.67 g., 0.0012 mole) and 10~ palladium on carbon catalyst (50 mg.) in methanol/water (9:1) is stirred vigorously in an atmosphere of hydrogen at ambient temperature for 16 hours. Tlc shows reduction is incomplete and after filtration, fresh catalyst (50 mg.) is added and the mixture is stirred at an atmosphere of hydrogen for an additional 4 hours. Tlc shows the absence of starting material with a single elongated spot at Rf 0.24. After iltration, the mixture is concentrated in vacuo. The residue is dissolved in dichloromethane and dried (MgSO4). Removal of the solid gives 0.35 g. of ( )-l-[[[l-(benzoyl_ amino)-4-phenylbutyl]hydroxyphosphinyl]acetyl]-L-proline as a gray colored solid. Tlc, silica gel, butanol/acetic acid/water (3:1:1), shows a ~Z~'~757 HA238 single spot at Rf 0.50.
Anal. calc 24 29 2 6 2 C, 56.68; H, 5.75; ~, 5.51; P, 5.5 Found: C, 56.45; H, 5.88; N, 5.07; P, 5.9.
Example_21 ~ [[[l-(Benzoylamino)heptyl]hydroxyphosphinyl]-acetyl]-L-prollne a) [~l-[[(Phenylmethoxy)carbon~l]amino]h~yl]
hydroxyphosphinyl]acetic acid, methyl ester Pivalic acid (5.1 g., 0.05 mole) and benzyl-carbamate ~3.8 g., 0.025 mole) are dissolved in 100 ml. of toluene. A portion (10 ml.) of the toluene is removed by distillation at atmospheric pressure to remove traces of water. The solution is cooled, under argon, to room temperature, and powdered 4A molecular sieves (5 g.) are added, followed by the addition of carbomethoxymethyldi-chlorophosphine (prepared according to the pro-cedure of Example 20 (a), 4.4 g.~ 0.025 mole).
Freshly distilled hep~aldehyde (3.4 g., 0O003 mole) is added dropwise via syringe to the above mixture, with stirrinq, at the rate of 1.7 ml./min.
A slight exotherm ( 3~) is observed. The mixture is s~irred at ambient temperature for 16 hours.
The solids are removed by filtrationO The filtrate is concentrated in vacuo. The residue is dissolved in 5% saturated sodium bicarbonate (50 ml.) plus water (50 mlO). The alkaline aqueous solution (pH 8) is washed with ether and acidified to a pH of 3.2 with concentrated hydrochloric acid.

12~7~7 HA238 _.

The oil that separates from solution is extracted into ether ( 2 x 150 ml.) and diluted to a volume of 300 ml. with ethyl acetate, washea with brine, and dried (MgSO4). Solids are observed to S crystallize from the ether/ethyl acetate mixture over the drying agent. After refrigeration over-night, the solids are collected and suspended in 200 ml. of water~ The water insoluble solids are washed repeatedly with water to give 3.3 g. of [[l-[[(phenylmethoxy)carbonyl]amino]heptyl]-hydroxyphosphinyl]acetic, methyl ester; m.p.
260-268, decomposition at 275. Tlc, silica gel, benzene, acetic acid (7:3) shows a major spot atRf 0.20, with a minor spot at Rf 0.30.
b) [[l-tAmino)heptyl]hvdroxyphosphinyl]acetic acid A suspension of the product from part (a) (1.8 g., 0.0052 mole) in 10% hydrochlo~ic acid (40 ml.) is stirred at reflux temperature until a turbid solution results and Tlc, silica gel, butanol/acetic acid/water shows the absence of starting material (about 6 hours). The mixture is cooled to room temperature~ and washed with ether to remove an oil that separated from solution.
The aqueous solution is concentrated in vacuo to give an oil residue. The procedure is repeated several times until the residue gives no positive chloride ion test and becomes semi-solid w~en triturated with ether. Finally, repeated tritllration with refluxing acetonitrile gives 1.1 g. of solid ~[l-(amino)heptyl]hydroxyphosphinyl]acetic acid;

~Z~ ~ 57 HA23~

m.p. 180-190 , gradual decomposition. Tlc, butanol/acetic acid/water (3:1:1) shows a single, ninhy~rin sensitive spot at Rf 0.49.
c) [[l-(Benzoylamino)heptyl]hydroxyphosphinyl]-acetic acid To a suspension of the product from part (b) (1 g., 0.004 mole) in 30 ml. of water, solid sodium carbonate is added portionwise un~il solution is effected (pH 9.5). A solution of benzoyl chloride (0.56 g~, 0.004 mole) in 10 ml. of acetone is added dropwise to the above solution, while the pH is maintained at pH 9 - 9.5 by the addition of solid ~odium carbonate. Followiny the addition and after stirring for 30 minutes, Tlc shows the presence of starting material. Additional benzoyl chloride (0.56 g., 0.004 mole) in 10 ml. of acetone is added and after stirring for 30 minutes, Tlc shows no ninhydrin sensitive product. After filtration and washing ether, the mixture is acidified to a pH of 1 with concentrated hydro-chloric acid. The oil that separates from solution is extracted into ethyl acetate and dried (MgSO4). The solvent is removed ln vacuo and the semi-solid residue is triturated repea~edly with diisopropyl ether to give 0.6 g. of solid [[1-(benzoylamino?heptyl]hydroxyphosphinyl]acetic acidOT~c, silica gel, butanol/acetic acid/water (3 shows a single spot at Rf 0.50.
~ [[1-(Benzoylamino)heptyl]hydro~y-phosphinyl~acetyl~ proline, phenylmethYl ester ~ 175~ 238 l,l-Carbonyldiimidazole (0.32 g., 0.002 mole) is added to a chilled (0 ) solution of the product from part (c) (0.58 g., O.nOl54 mole) in 30 ml. of tetrahydrofuran. The mixture is stirred at 0 for one hour. A solution of L-proline, benzyl ester (0.4 g., 0.002 mole) in 5 ml. of tetra-hydrofuran is added. After stirring at ambient temperature for 20 hours, the mixture is concentrated ln vacuo The residue is dissolved in ethyl acetate (50 ml.) and water (5 ml.), washed with 5~ potassium bisuIfate (to a pH of 2), brine, and dried (MgSO4). The solvent is removed ln vacuo to give a glass-like solid residue of 0.8 g. Tlc, silica gel, dichloromethane/
methanol/acetic acid (l9:l:l) shows a major spot at R~ 0.14, plus a shadow at 0.33, and a single spot at origin. The solid is chromatographed on silica gel, eluted with dichloromethane/
methanol (l9:l) until ~lc shows no spot at Rf 0~33, and finally eluted with dichloromethane/
methanol/acetic acid (l9-l:l) to give 0066 g. of amorphous solid (-)-l-[[[l (benzoylamino)heptyl]-hydroxyphosphinyl]acetyl]-L-proline, phenyl-methyl ester. Tlc shows a single spot at Rf 0.14.
e) (~ [[[1 (Benzoylamino)heptyl]h~_ ox~
phosphinyl~acetyl]-L-proline A mixture of the product from part td) (0.6 g., O.OOll mole) and lO~ palladium on carbon catalyst (8n mg.) in methanol/water (95:5) is stirred vigorously in one atmosphere of hydrogen ~ 2rV-~7s 7 HA2'~

at arnbient temperature, until hydrogen is no longer consumed (about 6 hours). After concen-- trating in vacuo, the residue is triturated with ether and collected by filtration to give 0.38 g.
of amorphous solid (-)-l-[[[1-(benzoylamino)heptyl]-hydroxyphosphinyl]acetyl]-L-proline; m.~. 260-275 (dec.).
Anal. calc d. 21 31 2 6 2 C, 52.16; H, 6.46; N, 5.79; P, 6.40 Found:C, 51.94; H, 6.08; N, 5.64; P, 6.20.
Example 22 (-?-l-[[[l-rB~nzoylamino)-3-phenylpropyl]hydroxyphos-phinyl]acetyl-4-[ethylenebis(thio)]-L~proline a) [[3-Phenyl-l-~[(~henylmethoxy)carbonyl]amino]-p~pyl]hydroxy~ sphinyl]acetic acid, methyl ester Pivalic acid (10.2 g., 0.1 mole) and benzyl carbamate (7.6 g., 0.05 mole) are dissolved in toluene (100 ml.). A portion of the toluene (20 ml.) is distilled at atmospheric pressure to remove traces of water~ The solution is c0012d to room temperature, under argon, and powdered 4A molecular sieves (10 g.) are added, followed by the addition of carbomethoxymethyldi-chlorophosphine (prepared according to Example 20 (a), 8.75 g., 0.05 mole). 3-Phenylpropionaldehyde (6.9 g., 0.05 rnole) is then added dropwise over 5 minutes, a slight exotherm (approximately 45) is observed. The reaction mixture is stirred at ambient temperature for one hour; after 30 minutes additional solids separate from the mixture ~ H~23Z

r~sulting in the formation of a jelly that is stirred with difficulty. The solids are collected by filtration and extracted with refluxing dichloro-methane (700 ml.). The dichloromethane solution is concentrated ln vacuo. The residue is triturated with diisopropyl ether to give 11~6 g. of solid;
m.p. 143-147. Tlc, silica gel, dichloromethane/
methanol/acetic acid $8:1:1) shows a single spot at Rf 0.50. A sample (0O4 g.) is recrystallized from ethyl acetate (20 ml.) to ~ive an analytical sa~ple of 0O35 g. of [[3-phenyl-1-[[(phenylmethoxy)-carbonyl]amino]propyl]hydroxyphosphinyl]acetic acid, methyl ester; m.p. 147 - 149 .
Anal. calc'd. for C20H24~O6P:
C, 59.25; H, 5.96; N, 3.45; P, 7.64 Found: C, 59.36; H, 6~10; N, 3.36; P, 7.50.
b) [[l-(Amino)-3-phenylpropyl]h~droxyphos~hinyl]-acetic acid A suspension of the product from part (a) (3 g., 0.0074 mole) in 10% hydrochloric acid (60 ml.) is stirred at reflux until Tlc, silica gel, dichloro-- methane/methanol/acetic acid (8:1:1)shows the absence of starting material, and an elongated, ninhydrin sensitive, spot from origin to Rf 0.20.
The mixture is cooled to room temperature, washed with ether, and concentrated in vacuo. The residue is repeatedly treated with water ~20 ml.) and concentrat~d ln vacuo until a white solid separates upon the addition of water. The solid is collected by filtration, triturated Witil acetonitrile, an~

~2~75'7 _~ HA238 dried ln vacuo at ambient temperature to give 1.2 g. of [[1-(amino)-3-phenylpropyl]hydroxy-phosphinyl]acetic acid. Tlc, silica gel, butanol/
acetic acid/water (3:1:1) shows a sin~le ninhydrin sensitive spot, Rf 0.40.
c)[[l-(Benzoylamino)-3-phenylpropyl]hydroxyphos-_ phlnyl]acetic acid To a suspension of the product from part (b) (1.1 g., 0.0043 mole) in 30 ml. of water (pH 2.8), solid sodium carbonate is added until solution iseffected (pH 9.0). The pH of the solution is maintained at a pH of 9 - 9.5 by the addition of solid sodium carbonate during the dropwise addition of a solution of benzoyl chloride (0.7 g., 0.005 lS mole) in 10 ml. of acetone. Tlc, silica gel, butanol/acetic acid/water (3:1:1) shows a positive ninhydrin spot at Rf 0.40 plus a major P~ plus heat sensitive spot at Rf 0.55. An additional equivalent of benzoyl chloride (0.7 g., 0~005 mole) in 10 ml. of acetone is added while maintaining the pH at 9 - 9.5 as before. Tlc shows a negative ninhydrin test. The alkaline solu~ion is filtered (to remove solids in suspension), washed with ether and acidified to pH of 1 with concentrated hydrochloric acid. The oil that separates from solution is ex-tracted into ethyl acetate, washed with brine, and dried (MgS04). The solvent - i~ removed in vacuo to give 1 g. of amorphous solid [[l-(benzoylamino)-3-phenylpropyl]hydroxy-phosphinyl]acetic acid. Tlc, silica gel, butanol/

~Z~ 7S7 HA238 acetic acid/water ~3:1:1) shows a single spot at Rf 0.55.
d) (-)-l-[[[l-(Benzoylamino)-3-ehenylpropyl]-hydroxyphosphinYl]acet~1-4-~ethylenebis(thio)]-Lrproline, methyl ester -l,l-Carbonyldiimidazole (0.5 q., 0.003 mole) is added to a cooled solution in an ice water bath of the product from part (c) (0.8 g., 0.0023 mole) in 50 ml. of tetrahydrofuran. The mixture is stirred in the cold for one hour, followed by the addition of triethylamine (0.004 mole) and 4-[ethylenebis(thio)]-L-proline, methyl ester, hydrochloric acid salt (0.8 g., 0.003 mole). The mixture is stirred at ambient temperature for 56 hours. Tlc, silica gel, butanol/acetic acid/
water (3 1:1) shows a major spot at Rf 0.63 plus a minor spot at Rf 0.55. The solvent is removed _ vacuo. The residue is dissolved in ethyl acetate (75 ml.) plus water (10 ml.). After washing with 5% potassium bisulfate to a pH of 1, followed by brine, and drying (MgSO4), the solvent is removed in vacuo. The amorphous solid residue (1.1 g.) is chromatographed on silica gel, eluted with di~hloromethane/methanol (95:5) followed by dichloromethane/methanol/acetic acid (95O5 5) to give 0.45 gO of amorphous solid (-)-1~[[1-(benzoylamino)-3-phenylpropyllhydroxy phosphinyl]-- acetyl]~4-~ethylenebiS(thiO)]-L-proline, meth ester. Tlc shows a single spot at Rf 0.66.

12~757 H~23Z

The 4-[ethylenebis(thio)]-L-proline, methyl ester, hydrochloric acid salt employed in the above procedure is obtained by bubbling hydro-chloric acid throu~h a solution of methanol (25 ml.) and 4-~ethylenebis(thio)]-L-proline (1.3 g., 0.0053 mole) at 0 for 30 minutes.
Tlc, dichloromethane/methanol/acetic acid (8:1:1) shows a major spot at Rf 0.75. Nitrogen gas i5 bubbled through the solution to remove hydrochloric acid, then the methanol is stripped.
Triturating the slurry several times ~ith ether yields 1.51 g. of brown solid ~ [ethylenebis(thio~]-L-proline, methyl ester, hydrochloric acid salt.
Anal. calc'd. for C8H14NO2S2Cl:
C, 37,57; H, 5.52; N, 5.48; S, 25.07, Cl, 13.86 Found: C,36.99; ~, 5.58; N, 5.40, S, 23.89;
Cl, 13.93.
e) (~ [[[l-(Benzoylamino)-3-~henylpropvl]-20 hydroxyphos~hinyl]acetyl~-4-[ethylenebis(thio)]-L-proline A solution of the product from part (d) (0.4 g., 0.007 mole) in 0.5 N sodium hydroxide (3 ml.) and methanol (5 ml.) is stirred at reflux for one hour. Tlc shows the absence of starting material. The mixture is concentrated ln vacuo.
After the addition of water to the residue, the turbid solution is washed with ether, filtered to remove a trace of solids, and acidified to a pH of 2 with concentrated hydrochloric acid.

~2~7~7 A white solid precipitate that separates from solution is extracted into ethyl acetate, washed with brine, and dried (MgSO4). The solvent is removed ln vacuo to give 0.325 g. of off-wllite solid t-)-1-[~[1-(benzoylamino)-3-PIlenylPropyl]-hydroxyphosphinyl]acetyl]-4-[ethylenebis(thio)]-2-L-proline; m.p. 118-140 ;gradual decomposition.
Anal. calc d- for C25 29 2 6 2 2 C, 53.41; H, 5.46; N, 4.98; S, 11.04;
P, 5.51 Found: C, 53.63; H, 5.29; N, 4.58; S, 11.30;
P, 5.10.

~z~ 5~ 233 Examples 23 - 84 Following the procedures of Examples 20 to 22 but coupling the acylamino phosphinyl acid shown in Col. I with the imino acid ester of Col. II one obtains the product shown in Col. III. Hydrogenation of the product of ColO III, in Examples 23 to 77, yields the corresponding acid products (~6 is hydrogen).
Col. _ O R O R O
Il 1 2 11 1 5 1~
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OH
i5 Col. II

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Col. III
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O
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:~2~4~57 HA238 Similarly, the above compounds can be prepared by the procedure of Example 19 in which case the acylamino phosphinyl acid employed is of the formula o R O R O
Il 12 1I jS 11 Rlg-C-NH-CH-P-(CH2)n-CH-C-OH

wherein R3 is lower alkyl such as t-butyl, or benzyl, or benzhydryl. After the coupLing reaction is comple-ted, deprotection such as by hydrogenation yields the compounds wherein R3 is hydrogen.
I5 Also, the imino acid esters of Col. II
could be employed in the procedures of Examples 1 to 18 to prepare other compounds within the scope of the invention.
Reduction of the product of Example 29 yields the correspondin~,4-amino product.
Similarly, the 4-keto product of Example 28 can be reacted to yield various 4-substituted amino products.

~ 7S7 ~IA23~

Example 85 ~ [[[l-(Benzoylamino)-3-phenylprop~l]hydroxy-phosphinyl]acetyl]-L-proline a) Methyl[3-phenyl-1-[[(phenylmethoxy)carbonyl]-aminolpropyl]phosphinic acid, ethyl ester Bis(trimethylsilyl)acetamide(12 g., 0.006 mole) is added via syringe, with stirring, to a solution of methyl[3-phenyl-1-[[(phenylmethoxy)carbonyl]-amino]propyl]phosphinic acid (15 g., 0.047 mole), prepaxed for example as set forth in Example l(a), in 75 ml. of dichloromethane. After stirring for 15 minutes the mixture is concentrated ln vacuo at ambient temperature. The residue is taken up in 75 ml. of dichloromethane and then phosphorous pentachloride (11.4 g., 0.055 mole) is added portionwise, with stirring. Following the resulting vigorous, exothermic reaction, the mixture is stirred at ambient temperature for one hourr The mixture is conc~ntrated ln vacuo, the residue is dissolved in dichloromethane, cooled in an ice/water bath, and a solution of ethanol (2.8 g., 0.06 mole) and triethylamine (6g., 0.06 mole) in dichloromethane (30 ml.) is added dropwise, with stirring, over a period of 20 minutes. The mixture is stirred at ambient temperature for 16 hours. After dilution to twice its volume with dichloromethane, the mixture is washed with water (2 x 50 ml.), 5% potassium bisulfate (2 x 35 ml.), brine, and dried (MgSO~).
The mixture is concentrated ln vacuo to give 14.5 g.
of an oil. Trituration with diisopropyl ether results 75~
I~A238 in the isolation of the solid product (12 g.);
m.p. 87-95 . Tlc, silica gel, ethyl acetate shows two spots, one overlapping the other at Rf O.55 (visualized with PMA plus heat). A sample (0.5 g.) is recrystallized from diisopropyl ether (10 ml.) to give 0.39 g. of an analytical sample of methyl[3-phenyl-1-[[(phenylmethoxy)-carbonyl]amino]propyl]phosphinic acid, ethyl ester;
m.p. 102-104, sintering at 94.
Anal. calc'd. for C20H26NO4P:
C, 63.99; H, 6.98~ N, 3.73; P, 8.25 Found: C, 63.74; H, 7.10; N, 3.68; P, 8.50.
b) [(Ethoxy)[3 phenyl-l-[[(phenylmethoxy)carbonYl]
amino]propyl]phosphinyl]acetic acid A solution of 0.099 mole of lithium diiso-propylamide in tetrahydrofuran (150 ml.) is prepared according to the procedure of ~xample l(c) and cooled to -76. A solution of the product from part (a) (10.3 g., 0.027 mole) in 60 ml. of tetrahydrofuran is added via syringe over a period of one hour. After stirring for 10 minutes, and warming to room temperature, the solvent is removed ln vacuo. Water (50 ml.) is added to the residue and the mixture is then acidified to a pH of 1 with concentrated hydrochoric acid. The oil that separates is extracted with dichloro-methane (700 ml.), washPd with brine, and dried (MgSO4)~ Tlc, silica gel, ethyl acetate, shows a major elongated spot at Rf 0.15 and a minor spot at Rf 0.55. The residue is dissolved in ethyl ~Z~ 7~7 ~IA23~

acetate (200 ml.) and extracted with saturated sodium bicarbonate solution to a pH of 10. The aqueous alkaline solution is washed with ether, acidified to a pH of 1 with concentrated hydrochloric acid, and extracted with dichloromethane (400 ml.) Tlc, silica gel, ethyl acetate, shows a single elongated spot at Rf 0.15. The solution is concentrated in vacuo to give 10.3 g. of E (ethoxy)[3-phenyl-1-[[(phenylmethoxy)carbonyl]amino]propyl]phosphinyl]-acetic acid as a viscous oil residue.c) ~ [(Ethoxy)[3-phenyl-1-[[(phenYlmethoxy)-carbonyl]amino]propyl]phosphinyl]acetyl]-L-proliner l,l dimethylethyl ester l,l-Carbodiimidazole (3.9 g., 0.0238 mole) is added to a chilled (0) solution of tI~e product from part (b) (10 g., 0.0238 mole~ in acetonitrile (100 ml.). The mixture is stirred at 0 for one hour. A solution of L-proline, tert-butyl ester (4.1 g., 0~0238 mole) in acetonitrile (50 ml.) is added. After stirring at ambient -temperature for 16 hours, the mixture is concentrated ln vacuo.
The residue is dissolved in dichloromethane (500 ml.~, washed with 5% potassiu~, bisulfate, saturated sodium bicarbonate, brine, and dried (~1gSO4). Tlc, silica gel, ethyl acetate, shows a major spot at Rf 0.18 (visualized with Pr~A plus heat). The solvent is removed in vacuo. The oil residue (12 g.) is ___ chromatographed on silica gel, eluting with et~yl acetate, acetone/ethyl acetate (1:9, 1:4) to give an oil (9.9 g.). Tlc, silica gel, acetone/ ethyl ~Z~57 ~238 acetate (L:l) shows a single spot at Rf 0.44 (visualized with PMA plus heat). ~ portion of the residue (8.1 g.) is dissolved in diisopropyl ether (350 ml.) and allowed to stand at ambient temperature for 40 hours. A white solid (1.3 g.) is collected by filtration; m.p.
129-135. Tlc gives a single spot with the same Rf as the mixture (Rf 0.44~. A portion (0.27 g.) is recrystallized from diisopropyl ether (45 ml.), with a recovery of 0~24g. of 1-[(ethoxy)[3-phenyl-1-[[(phenylmethoxy)carbonyl]amino]propyl]phosphinyl]
acetyl]-L-proline, l,l-dimethylethyl ester (isomer A); m.p. 135-137 , sintering at 133;
[a]D ~37 (10 mg/ml. dichloromethane).
Anal. Calc'd. for C30H41N2O7P:
C, 62.92; H, 7.22; N, 4.89; P, 5.41 ~ound: C, 62.93; H, 7.35; N, 4.87; P, 5.40.
The filtrate is concentrated in vacuo to give 6 g. of (-)-1-[(ethoxy)[3-phenyl-1-[l(phenyl-methoxy)carbonyl]amino]propyl]phosphinyl]acetyl]-L-proline, l,l-dimethylethyl ester as an oil residue. Tlc, silica gel, acetone/ethyl acetate (1:1) shows a single spot at Rf 0.45 (visualized with PMA plus heat).

~;Z~75'7 HA2 ~a d) ( )-l-[[[l-(Amino)-3-phenylpropyl]ethoxyphos-phinyl]acetyl]-L-proline, l,l-dimethylethyl ester A mixture of (-)-l-[(ethoxy)[3-phenyl-1-[[(phenylmethoxy)carbonyl]amino]propyl]phosphinyl]acetyl]-L-proline,l,l-dimethylethyl ester from part (c) (4.5 g., 0.0085 mole) and 10%
palladium on carbon catalyst (0.5 g.) in methanol/
water (9:1) is stirred vigorously under one atmosphere of hydrogen until absorption ceases (overnight). Tlc, silica gel, dichloromethane/
methanol/acetic acid (8:1:1) shows the absence of starting material with a major spot at Rf 0.55 tninhydrin positive, or visualized with PMA plus heat) with a minor spot at origin. The mixture is filtered and the filtrate is concentrated _ vacuo to give 3.7 g. of (+)-l-[[[l-(amino)-3-phenylpropyl]ethoxyphosphinyl]acetyl]-L-proline, l,l dimethylethyl ester as an oil residue.
e)_ (-)-l-[[[l-(Benzoylamino)-3-phenylpropyl]-ethoxyphosphinyl]acetyl~-L-proline~ 1 I-dimethYl-ethyl ester A,solution of benzoic acid (1 g., 0.008 mole) and 1-hydroxybenzotriazole hydrate (1.5 g., 0.008 mole) in 30 ml. of tetrahydrofuran is cooled to 0, followed by the portionwise addition of N,N-dichlorohexylcarbodiimide (1.7 g., 0.008 mole). The bath is removed and the mixture is stirred at ambient temperature for 70 minutes.

After filtration, the filtrate is concentrated in vacuo. To the residue, dissolved in dimethyl-forma~ide (25 ml.) plus tetrahydrofuran (50 ml.), is added a solution of the product from part (d) (3.5 g., 0.008 mole) and t~iethylamine (0.8 g., 0.008 mole) in dimethylformamide (20 ml.). The mixture is stirred at ambient temperature for 16 hours. The solvent is then removed in vacuo.
The residue is dissolved in ethyl acetate (lO0 ml.), washed with water, 10- citric acid, saturated sodium bicarbonate, brine, and dried (MqSO4). The solvent is removed ln vacuo to give an oil residue (4.2 g.). Tlc, silica gel, ethyl acetate/acetone ~ shows a major spo~ at Rf 0.40 plus 3 minor spots at R~ 0.64, 0.80, and 0.90. It is chromatographed on silica gel, eluted with ethyl acetate, ethyl acetate/acetone (l:l) to give 3.5 g. of (~ [[[1-(benzoylamino)-3-phenylpropyl]-ethoxyphosphinyl]acetyl]-L-proline, l,l-dimethylethyl ester as an oil. Tlc shows a single spot at Rf 0.33 (visualized with PMA plus heat).
) (-)-1-[[[l-(Benzoylamino)-3-phenylpropyl]-hydroxyphosphinyl]acetyl]-L-proline, l,l-dimethyl-ethyl ester Bis(trimethylsilyl)trifluoroacetamide (1.5 g., 0.006 mole) is added via syringe to a solution of the product from paxt (e) (3.4 g., 0.006 mole) in dichloromethane (50 ml.). The mixture is stirred for one hour and the solvent is removed ln vacuo. The residue is redissolved in dichloro-~4 7S7 HA23~

methane (50 ml.), and bromotrimethylsilane (1.5 g., 0.01 mole) is added via syringe. The mixture is stirred at ambient temperature for 16 hours. After concentrating in vacuo, the residue is dissolved in aqueous sodium bicarbonate (50 ml. saturated sodium bicarbonate plus 50 ml. of water). The solution is washed with ether, cooled, and acidified to a pH of 1. The oil that separates from solution is extracted into dichloromethane (200 ml.), washed with brine, and dried (MgSO~). The solvent is removed in vacuo to give 2.8 g. of (~ [~[1-(benzoylamino)-3-phenylpropyl]hydrox~phosphinyl]-acetyl]-L-proline, l,l-dimethylethyl ester as an oil. Tlc, silica gel, dichloromethane/methanol/
acetic acid (8:1:1) shows a single elongated spot at Rf 0.66.
q) (-)-l-[[[l-(Benzo~lamino)-3-phenylpropyl]-hydroxyphosphinyl]acetyl]-L-proline A solution of the product from part (f) (2.7 g., 0.0053 mole)and anisole (6.2 g., 0.05 mole) in trifluoroacetic acid (50 ml.~ is stirred at ambient temperature for one hour. The mixture is concentrated in vacuo. The residue solidifies when triturated with pentane to give 2.1 g. of product. It is then triturated with ether to give 1.9 g. of white solid (-)-l-[[[l-(benzoy~-amino)-3-phenylpropyl]hydroxyphosphinyl]acetyl]-L-proline; m.p. 120-140 .
Anal. calcld. for C23H27N2O6 2 ~2~75 7 i~A238 C, 59.09; H, 5.82; N, 5.99; P, 6.63 Foundo C, 58.69; H, 5.64; N, 5.96; P, 6.60.
Example 86 1-[[[1-(Ben~ylamino)-3-phenylpropyl]hydroxy-phosphinyl]acetyl]-L-proline (isomer A) a) l-[[[l-(Amino)-3-phenylpropyl]ethoxyphosphinYl]
acetyl]-L-proline, L,l-dimethylethyl ester (isomer A) A mixture of l-[(ethoxy)[3-phenyl-1-[[(phenylmethoxy)carbonyl]amino]propyl]phosphinyl]-acetyl~-L-proline, l,l-dimethylethyl ester (isomer A) (1.4 g., 0.00265 mole), from Example 85 (c), and 10% palladium on carbon (0.1 g.) in methanol/acetic acid (9:1) is stirred vigorously under one atmosphere of hydrogen until absorption ceases. The mixture is filtered and the filtrate is concentrated in vacuo to give 1.2 q. of 1-[[[l-(Amino)-3-phenylpropyl]ethoxyphosphinyl]-acetyl]-L-proline, l,l-dimethylethyl ester (isomer A) as an oil residue. Tlc, silica gel, dichloromethane/methanol/acetic acid (8:1:1) shows a major spot at Rf 0.50 (ninhydrin positive, or visualized with PMA plus heat)~
b) l-[[[l-(Benzoylamino)-3~pheny1prop~1]ethoxy-phos~hinyl]acetyl]-L-proline, l,l-dimethylethyl ester (isomer A) .
To a solution of the product from part (a) (1.16 g., 0.0025 mole) in pyridine (15 ml.) that is cooled to 0, is added benzoyl chloride (0.6 g., 0.004 mole). After stirrin~ for 16 hours ~z~ s~

at ambient temperature, the mixture is concentrated in vacuo. The-oil residue (1.4 g.) is chromato-._ graphed on silica gel, eluted with ethyl acetate,acetone/ethyl acetate (1:1) to give a glass-like brown solid (0.8 g.). It is dissolved in di-isopropyl ether (50 ml.), treated with activated carbon, filtered, and concentrated 1n vacuo to give 0.66 g. of 1-[[[1-(benzoylamino)-3-phenyl-propyl]ethoxyphosphinyl]acetyL]-L-proline, 1,1-dimethylethyl ester (isomer A). Tlc, silica gel,acetone/ethyl acetate (1:1) shows a single spot at Rf 0.33 (visualized with PMA plus heat).
c) 1-[[[1-(Ben~oylamino)-3-phe~ylpro~yl]h~droxy-phosphlnyl]acetyl]-L~roline~ dimethylet~l ester (isomer A) Bis(trimethylsilyl)trifluoroacetamide (0.31 g., 0.0012 mole) is added via syringe to a solution of the product from part (b) (0.65 9., 0.0012 mole) in dichloromethane (10 ml.). The mixture is stirred for one hour and concentrated ln vacuo. The residue is redissolved in dichloromethane (10 nl.) and bromotrimethylsilane (0.3 g., 0.002 mole) is added. The mixture is stirred at ambient temperature for 16 hours. After concentrating ln vacuo, the residue is dissolved in saturated sodium bicarbonate solution (10 ml.), washed with ether, and then acidified with concentrated hydrochloric acid to a pH of 1. The oil that separates from solution is extracted into dichloromethane (50 ml.), washed with brine, and dried (MgSO4). The solvent ,r ~ 7~ ~ HA232 is removed ln vacuo to give 0.5 g. of 1-[[[1-(benzoylamino)-3-phenylpropyl]hydroxyphosphinyl]-acety,l]-L-proline, l,l-dimethylethyl ester (isomer A) as a glass-like solid. Tlc, silica gel, dichloromethane/~ethanol/acetic acid shows a major spot at Rf 0.80 and a mino spot at Rf 0.22 (visualized with PMA plus heat).
d) l-[[[l-(Benzo~amlno)-3-phenylpropyl]hydroxy-phosphinyl]acetyl]-L-proline (isomer A) A solution of the product from part (c) (0.4 g., 0.008 mole) and anisole (1 ml., 0.01 mole) in trifluoroacetic acid (7 ml.) is stirred at ambient ~emperature for one hour, The mixture is concentrated 1n vacuo. The residue is triturated with pentane. The solid that separates is collected by filtration to give 0.36 g, of product;
m.p. 140-150. It is recrystallized from aceto-nitrile to give 0.097 g. of l-[[[l-(benzoylamino)-3-phenylpropyl]hydroxyphosphinyl]acetyl]-L-proline (isomer A); m.p. 157 (dec.).

C, 55.86; H, 5O50; N, 5.66; P, 6.26 Found: C, 55.74; H, 5.64; N~ 5.65; P, 6.2 .
Example 87 (-)-1-[[[l~[(Cyclopen-tylcarbonyl)amino]-3-phenyl-propyl]hydroxyphosphinyl]acetyl-L~pro_ine a) (~ [[[l-[(Cvclo~entvlcarbonYl)amino]-3-phenylpropyl]eth_~yphosphinyl]acetyl]-L-~rolin~e, l,l-dimethylethyl ester A solution of cyclopentanecarboxylic acid ~Z0~757 HA238 (0.26 g., 0.0023 mole) and l-hydroxybenzotriazole hydrate (0.31 g., ~.0023 mole) in tetrahydrofuran (10 ml.) is cooled to 0 , followed by the portionwise addition of N,N-dicyclohexylcarbodiimide (0.47 g., 0.0023 mole). The bath is removed and the mixture is stirred at ambient temperature for 70 minutes. ~fter filtration, the mixture is concentrat~d in vacuo. To the residue, dissolved in dimethylformamide (8 ml.) plus tetrahydrofuran (10 ml.), is added a solution of (~ [[[l-(amino)-3-phenylpropyl~ethoxyphosphinyl]acetyl]-L-proline, l,l-dimethylethyl ester (1 g., 0.0023 mole), pre-pared for example as described in Example 85 ~d), and triethylamine (0.25 g., 0.0025 mole) in dimethylformamide (10 ml.). The mixture is stirred at ambient temperature for 16 hours. It is then concentrated in vacuo and the residue is dissolved in ethyl acetate (75 ml.), washed with water, 10 citric acid, saturated sodium bicarbonate, brine, and dried (MgSO~). The solvent is removed in varuo to give 1.2 g. of an amber oil residue.
It is chromatographed on silica gel, eluted with dichloromethane, dichloromethane/acetone (4:1) to give 1.1 g. of (-)-1 [[[l-(cyclopentylcarbonyl~-amino]-3-phenylpropyl]ethoxyphosphinyl]acetyl]-L-proline, l,l-dimethylethyl ester as an oil in two fractions: 0.8 g., Tlc, silica gel, acetone, shows a single spot at R~ 0.55; and 0.3 g., Tlc, shows two spots, Rf 0.55 and Rf 0.52 (visualized with PMA plus heat, or I2 vapor).

lZ~4'~S7 _99_ b) (-)-l-[[[l-[(Cyclopentylcarbonyl)amino]-3-phenylpropyl]hydroxy~hos~hinyl]acetyl]-L-proline, l,l-dimethylethyl ester Bis(trimethylsilyl)trifluoroacetamide ~0.5 gO, 0.002 mole) is added to a solution of the product from part (a) (1.04 g., 0.0019 mole) in dichloromethane (20 ml.). The mixture is stirred for one hour and concentrated ln vacuoO The residue is redissolved in dichloromethane (20 ml.), and bromotrimethylsilane (0.3 g~, 0.002 mole) is added. The mixture is stirred at ambient tempera-ture for 16 hours. After concentrating ln vacuo, the residue is dissolved in aqueous sodium bicarbonate (15 ml. saturated sodium bicarbonate plus 10 ml.
of water), washed with ether, and acidified to a pH of 1 with concentrated hydrochloric acid. The oil that separates from solution is extracted into dichloromethane, washed with brine, and dried (MgSO4). The solvent is removed in vacuo to give 0.8 g. of ( )-l-[[[l-[(cyclopentylcarbonyl)-amino]-3-phenylpropyl~hydroxyphosphinyl]acetyl]-L-proline, l,l-dimethylethyl ester as a glass-like solid. Tlc, silica gel, benzene/acetic acid (7:3) shows a single spot at R~ 0.33 (visualized with PMA plus heat, or I~ vapor).
c) (~ [[[l-[(Cyclopentylcarbonyl]amino]-3-phen~lpropyl]hydroxyphos~in~]acetyl]-L-proline A solution of the product from part (b) (0.8 g., 0.0016 mole) and anisole (1.5 ml., 0.013 mole) in trifluoroacetic acid (15 ml.) is stirred at , ,:

75~
E~A238 ambient temperature for 2 hours. The mixture is concentrated in vacuo. The residue solidifies after trituration with pentane, followed by trituration with diisopropyl ether, to give 0.72 g.
of material. It is dissolved in sodium bicarbonate solution (20 ml. of water plus saturated sodium bicarbonate to a pH of 8 - 9), washed with ether, and acidified to a pH of l with concentrated hydro-chloric acid~ The oil that separates from solution is extracted into dichloromethane, washed with brine, and dried (MgSO4). The solution is con-centrated in vacuo to give 0.35 g. of (-)-l-[[[l-[(cyclopentylcarbonyl)amino]-3-phenylpropyl]-hydroxyphosphinyl]acetyl]-L-proline. Tlc, silica gel, butanol/acetic acid/water (3:1:1) shows a single spot at Rf 0.52 (visualized with P~ plus heat, or with I2 vapor).
Anal. calc'd. for C22H3lN2o6p ~2 C, 56.40; H, 6.67; N, 5.98; P, 6.61 Found: C, 56.43; H, 6.55; N, 6.01; P, 6.40.
Example 88 (- ? -1- [[~ydro~y[l~ oxohexyl)amino]-3-phenyl-propyl]phosphinyl]acetyi]-L-proline a) (-)~1 [[Ethoxx[l-[(l-oxohexyl)amino]-3-phen~ opyl]phosphinyl]acetyl]-L-proline, 1,l-dimethylethyl ester To a solution of (-)-l-[[[l-(amino)-3-phenylpropyl]ethoxyphosphinyl]acetyl]-L-pxoline, l,l-dimethylethyl ester (1.2 g., 0.0027 mole), prepared for example as described in Example 85 (d), ~2~7S7 HA238 and triethylamine (0.28 g., 0.0027 mole) in dichloromethane (20 ml.), l-hydroxybenzotriazole hydrate (0.36 g., 0.0027 mole) is added. The mixture is cooled to 0, followed by dropwise addition of a solution of hexanoyl chloride (0.36 g., 0.0027 mole) in dichloromethane (10 ml.). After stirring for 16 hours, the mixture is concentrated in vacuo. The residue is dissolved in ethyl acetate, washed with water, 10~ citric acid, saturated sodium bicarbonate, brine, and dried (MgSOI). The solvent is removed ln vacuo to give an oil residue of 1.7 g.
It is chromatographed on silica gel, eluted with dichloromethane followed by dichloromethane/acetone (4:1) to give 0.78 g. of (~ [[ethoxy~l-[(l-oxohexyl)amino]-3-phenylpropyl]phosphinyl]acetyl]-L-proline, l,l-dimethylethyl ester. Tlc, silica gel, acetone, shows a single spot at Rf 0.60 (visuallzed with PMA plus heat).
b) (~ [[Hydroxy[l-[(l-oxohexyl)amino]-3-phenylproEy~l]phosphinyl]acet~ -L-proline, 1,1-dimethylethyl ester Bis(trimethylsilyl)trifluoroacetamide (0.36 g., 0.0014 mole) is added to a solution of the product from part (a) tO.73 g., 0.00136 mole) in dichloromethane (20 ml.). The mixture is stirred for one hour and concentrated, at ambient tempera-ture, ln vacuo. The residue is redissolved in dichloromethane (20 ml.), and bromotrimethylsilane (0.25 g., 0.0014 mole) is added. After stirring .

7~'7 at ambient temperature for 16 hours, the mixture is concentrated ln vacuo and the residue is disso~ved in aqueous sodium bicarbonate (10 ml.
of water plus 15 ml. of saturated sodium bicarbonate). The turbid solution is washed with ether and acidified to a pll of 1 wlth concentrated hydrochloric acid. The oil that separates from solution is extracted into dichloromethane, washed with brine, and dried (MgSO4). The solvent is removed in vacuo to give 0.6 g. of (-)-l-[[hydrox~
[l-[(1-oxohexyl)aminol-3-phenylpropyl]phosphinyl]-acetyl]-L-proline, l,l-dimethylethyl ester as a colorless oil. Tlc, silica gel, benzene/acetic acid (7:3) shows a single spot at Rf 0.38 (visualized with PMA plus heat, or I2 vapor).
c) (-)-l-[[HYdroxy[l-~(l-oxohexyl)amino]-3-phenylprop~l]phosphinyl]acet~l]-L-proline A solution of the product from part (b) (0.57 g., 0.0011 mole) and anisole (2 g., 0.018 mole) in trifluoroacetic acid (lS ml.) is stirred at ambient temperature for 2 hours. The mixture is concentrated ln vacuo. The residue solidifies after trituration with pentane, followed by trituration with diisopropyl ether, to give 0.46 g.
of material. It ls dissolved in sodium bi-carbonate solution (15 ml. of water plus saturated sodium bicarbonate to a pH of 8 - 9), washed with ether, and acldified to a pH of 1 with concentxated hydrochloric acid. The oil that separates from solution is extracted into dichloromethane, washed ~_ .

~ z~3~7~i7 with brine, and dried (MgSO4). The solution is concentrated in vacuo to give 0.37 g. of (-)-l [[hydroxy[l-[(l-oxohexyl)amino]-3-phenyl-propyl]phosphinyl]acetyl]-L-proline a.s an amorphous solid. Tlc, silica gel, butanol/acetic acid/water (3:1:1) shows a single spot at Rf 0.50 (visuali~ed with PMA plus heat, or with I2 vapor).
Anal~ Calc'd. for C22H33N2O6 2 C, 56.16; H, 7.00; ~, 5.88; P, 6.5~
1~ Foundo C, 55.92, H, 7O35; N, 5.95; P, 6.40.
Example 89 '~ ~ [~ydroxy[l-~[(5-oxo-2-Eyrrolidinyl)carbonyl]-amlno~-3 1~! ~_ a) (-)-l-[[Ethoxy[1~[(5-oxo-2-pyrrolidinyl)-- car~onyl]amino~-3-phenylprop~]~hosphinyl]acetyl]-L-proline, l,l-dimethyleth 1 ester A solution of L-2-pyrrolidone-5-carboxylic acid (0.3 g., 0.0023 mole) and l-hydroxybenzo-triazole hydrate (0.31g., 0.0023 mole) in tetra-hydrofuran (lO ml.) is chilled to 0 and 1,1-dicyclohexylcarbodiimide (0.47 g., 0.0023 mole) is added. The c~oling ~ath is removed and the mixture i~ s~irred ~t ambient temperature for 70 minutes ~r~ ioiids separating from solution are in ~xcess of an equivalent of dicyclohexylu~ea. Dimethylformamide (15 ml.) and tetrahydrofuran ( 10 ml.) are added, followed by a solution of (-j-l-[[[l (amino)-3-phenyl-propyl]ethoxyphosphlnyl]acetyl]-L-proline, ~Z~ 5~

~A238 l,l-dimethylethyl ester (0.1 g., 0.0023 mole), prepared for example according to the procedure of Example 85 (d), and triethylamine (0.2S g., 0.0024 mole) in dimethylformamide (10 ml.).
The mixture is stirred at ambient temperature for 16 hours. After filtration, the filtrate is concentrated in vacuo. The residue is dissolved in ethyl acetate (75 ml.), washed with water, lO~ citric acid, sodium bicarbonate, krine, and dried (MgSO4). The solvent is removed in vacuo to give l.l gO of a glass-like ~olid residue.
Chromatography on silica gel, eluting with dichloromethane, dichloromethane/acetone (4:1), acetone gives 0.58 g. of (+)-1-[[ethoxy~l-[[(5-oxo-2-pyrrolidinyl)carbonyl]amino]-3-phenyl-propyl]phosphinyl]acetyl]-L-proline. Tlc, silica gel, acetone shows a single spot at Rf 0.20 (visualized with PMA plus heat, or I2 vapor).
b) (-)-l-[[Hydroxy[l-~[(5-oxo-2-pyrrolidinyl)-carbonyl]amino]-3-phenyl~ro ~l]~hos~hinyl]acetyl]-L-proline, l,l-dimethyl ester A solution of the product from part (a) (0.54 g., 0~001 mole) in dichloromethane (10 ml.) is treated with bromotrimethylsilane (0.3 g., 0.002 mole). The mixture is stirred at ambient temperature for 16 hours. After concentrating in vacuo, the residue is treated with water (5 ml.) .
and extracted into dichloromethane (75 ml.)~ ~t is washed with brine, dried (MgSO4), and the solvent is removed ln vacuo to give 0.38 g. of ç~r.2 ~ ~3 (-)-l-[[hydroxy[l-[[(5-oxo-2-pyrrolidinyl)-carbonyl]amino]-3-phenylpropyl]phosphinyl]acetyl]-I.-proline, l,l-dimethylethyl ester as a glass-like solid. Tlc, silica ~el, butanol/acetic acid/
water (3:1:1) shows a sillgle spot at Rf 0.53 (visualized with PMA plus heat or with I2 vapor).
c) (~ [[Hydroxy[l-[[(S-oxo-2-pyrrolidin~l)-carbon~]amino]-3-E~enylpro~yl]phosphinyl~acetyl]-L-proline A solution of the product from part (b) (0.37 g., 0.0007 mole) and anisole (1 g. r 0.01 mole) in trifluoroacetic acid (7 ml.) is ~tirred at ambient temperature for 2 hours.
After concentrating _ vacuo, the residue solidifies when triturated with pentane and with diisopropyl ether, to give 0.38 g. of materaiI. It is dissolved in water (40 ml.), washed with ether, millipore filtered, and lyophilized to give 0.28 g. of (-)-1-[[hydroxy[l-[[(5-oxo-2-pyrrolidinyl~
carbonyl]amino]-3-phenylpropyl]phosphinyl]acetyl]-L-proline. Tlc, silica gel, butanol/acetic acid/
water (3:1:1) shows a single spot at Rf 0.28 (visualized with PMA plus heat, or with I2 vapor).
Anal. caLc'd. for C21 H28N3O7 2 C, 49.50; H, 5.52; N, 8.23; P, 6.06 Found: C, 49.60; H, 5.66; N, 8.11; P, 5.80.
Example 90 ,' [ 1 ( - ) t 4S]-l-[[[l-(Benzoy~amino)-3-ph~lpropyl]-hydroxyE~osphinyl]a_etyl]-4-(phenylmethyl)-L-prOline t7~7 H~238 a) [1(-),4S]-l-[[Ethoxy[3-phenyl-1-[[(phen~
methoxy)carbonyl]amino]propyl]ph~sphinyl]acetyl~-4-(phenylmeth~ L-proline l,l-Carbonyldiimidazole (0.4 g., 0.00238 mole) is added to a cooled solution (ice/water bath) of (-)-[(ethoxy)[3-phenyl-l-[[(phenylmethoxy)-carbonyl~amino]propyl]phosphinyl]acetic acid (l g., 0.00238 mole), prepared for example according to t~ procedure of Example 85 (b), in aceto-nitrile (lO ml.). The mixture is stirred in thecold for one hour and a suspension of (4S)-4-(phenylmethyl)-L-proline (0.49 g., 0.00238 mole, as its triethylammonium salt) in acetonitrile (lO ml~) is added to the cold solution. The mixture is stirred at ambient temperature for 16 hours and concentrated ln vacuo. The residue is dissolved in dichloromethane (lO0 ml.), washed with 5% potassium bisulfate to a pH of 4, washed with brine, dried (MgSO4), and concentrated ln vacuo. The residue (1.4 g.~ is chromatographed on silica gel, elu~ing with acetic acid/benzene (1:9, 3:17, 1:4) to give 1.1 g. of [1(+),4S]-l-[[ethoxy[3-phenyl-1-[[(phenylmethoxy)carbonyl~-amino]propyl]phosphinyl]acetyl]-4-(phenylmethyl)-L-proline as a viscous oil. Tlc, silica gel, benzene/acetic acid (4:1) shows a single elongated spot at R~ 0.22 (visualized with PMA plus heat).
The cis-4-(phenylmethyl)-L-proline employed above can be prepared as described by Krapcho in U.S. Serial No. 164,985, i.e.o ~2~S~
~IA23 To a l liter flask are added 7.6 g. (0.16 mole) of sodium hydride (50% suspension) and 150 ml. of dry dimethylsulfoxide. The suspension is stirred and then maintained at 70 for thirty minutes (all of -the sodium hydride has reacted at this point). The solution is cooled to 30 and treated portionwise with a suspension of 61.1 g. ~0.16 mole~ of benzyltriphenyl phos-phonium chloride (dried ln vacuo overnight) in 150 ml. dimethylsulfoxide and the resulting intense red suspension is heated to 70. This mixture ls cooled to 25 and treated with a solution of 13.2 g. (0~05 mole) of li-carbo-benzyloxy-4-keto-L-proline in 40 ml. of dimethyl-sulfoxide over a period of twenty minutes. Thismixture is maintained at 65-70 for four hours, allowed to stand overnight at room temperature, and then poured onto a solution of 10 g. of potassium bicarbonate in 400 ml. of ice-water.
Some ice is added to the mixture to bring the volume to 1 liter and it is then extracted three times with 250 ml. portions of ether. The ether phases are discarded and the aqueous phase is cooled and acidified with 50 ml. of 6N hydro-chloric acid. The product is extracted with 250 ml.of chloroform and then twice with lO0 ml. of chloroform. The organic phases are combined, dried (~gSO4), filtered and the solvent evapor~ed to give 10.2g. of pale brown viscous residue. The latter is triturated with 500 ml~ of ether. The ~2~1~75~
~i~23 ether is decanted from the brown residue (mostly triphenylphosphineoxide) and the latter is triturated twice with L00 ml. of ether. The ether phases are combined, cooled and treated portionwise wi-th a solution of 10 g. of sodium bicarbonate in 200 ml. of water. The layers are separated and the organic phase is extracted with 10 ml. of water. The e~her phase is discarded and t~e aqueous phases are combined, cooled, acidi-fied with 18 ml. of 6N hydrochloric acid and extract-ed three times with 100 ml. of ether. ~he organic layers are combined, dried (MgSO4), filtered and the solvent evaporated to give 8.9 g.
(52.6%) of a pale yellow foam. The bulk of this compound (8.6 g.) is dissolved in 20 ml. of acetonitrile and treated with 4.6 g. of dicyclo-hexylamine. The product slowly crystallizesO
After standing overnight in the cold,the nearly colorless dicyclohexylamine salt is filtered and dried to yield 11.0 g. of N-carbobenzyloxy-4-(phenylmethylene)-L-proline, dicyclohexylamine;
m.p. 142-150. After recrystallization from 65 ml~
of acetonitrile, 9.5 g. of nearly colorless dicyclohexylamine salt are obtained; rn.p.
150 155 [~]25 +7.7 (c, 1% in chloroform).
Anal. a 20 19 4 12 23 C, 74.09; H, 8.16; N, 5.40 Found: C, 73.87; H, 8.18; N, 5.33.

~2~'7~7 . HA232 This dicyclohexylamine salt,(9.4 g.) is suspensed in 100 ml. of ethyl acetate and treated with 100 ml. of 10% potassium bisulfate. The mixture is shaken and the aqueous phase is extracted twice with 50 ml. of ethyl acetate. The organic phases are combined, dried, (MgSO4), filtered and the solvent evaporated to give 6.4 g. ~38%) of pale yellow foam like solid N-carbobenzyloxy-4-(phenylmethylene)-L-proline; [a]D -2.5 (c, 1~ in chloroform); Rf 0.29 (85:15 toluene:acetic acid on silica gel).
A solution of 6.1 g. of N-carbobenzyloxy-4-(phenylmethylene)-L-proline in 200 ml. of ethyl acetate is treated with 0.6 g. of platinum dioxide.
The mixture is shaken under one atmosphere of hydrogen. Initially the uptake of hydrogen is rapid and essentially ceases in thirty minutes.
The colorless solution is filtered and the filtrate is concentrated to give 5.7 g. of M-carbobenzyloxy-20 ' cis-4-(phenylmethyl)-L-proline. The latter is dissolved in 200 ml. of methanol and 30 ml. of water and treated with a slurry of 2 g. of S~ palladium-carbon catalyst in 70 mlO of methanol.
The mixture is shaken under two atmospheres of hydrogenO The uptake of hydrogen is essentially complete in forty minutes. After seventy minutes, the catalyst is filtered through a celite bed and the fi'ltrate concentrated to giye 3.3 g. (89~) of pale gray solid cis-4-(phenylmethyl)-L-proline; m.p. 200 - 201 (dec.); []D ~3 5 ~4~S~
~ 23~

(c, 1~ in N-hydrochloric acid). A small amount of catalyst is present in this material.
Anal. Cal 12 15 2 / 2 C, 68.71; H, 7.45; N, 6.68 Found: C, 68.21; H, 7.62; N, 6.56.
A solution of the hydrochloride salt of cis-4-(phenylmethyl)-L-proline (0.58 g., 0.0024 mole) in methanol (10 ml.) is treated with two equivalents of triethylamine (0.5 g., 0.0048 mole) in methanol (5 ml.). The mixture is stirred at ambient temperature for 5 minutes and concentrated in vacuo. A suspension of the resulting solid in acetonitrile (10 ml.) is utilized in the reaction described above.
b) ~ ),4S~ [l-(Amino)-3-phen~lpropyl]-ethoxyphosphinyl]acetyll-4-(phenylmethyl)-L-proline .

A mixture of [1(-),4S]-l-[[ethoxy[3-phenyl-l-[[(phenylmethoxy)carbonyl]amino]propyl]phosphinyl]-acetyl]-4-(phenylmethyl)-L-proline (0.9 g., 0.00148 mole), from part (a), and 10~ palladium on carbon catalyst (80 mg.) in methanol/water (9:1) is stirred vigorously in an atmosphere of hydrogen until hydrogen is no longer consumed (overnight). The mixture is filtered and concentrated ln vacuo to give 0.7 g. of [1~-),4S]-1-[[[1-(amino)-3-phenylpropyl]ethoxy-phosphinyl]acetyl]-4-(phenylmethyl)-L-proline as a glass-like solid. Tlc, silica gel, dichloromethane/methanol/acetic acic (8:1:1) shows a single elongated spot at Rf 0.30 ~2~34~75~7 HA238 ~

(visualized with ninhydrin indicator plus heat, and/or P~.A plus heat).
c) [~(-),4S]-l-[[[l-(Benzoylamino)-3-phenyl-propyl]ethoxyphosphinyl]acetyl]-4-(phenylmethvl)-L-proline A solution of benzoic acid (0.185 g., 0.00148 mole) and l-hydroxybenzotriazole hydrate (0.2 g., 0.00148 mole) in tetrahydrofuran (10 ml.) is cooled to 0, followed by the portionwise addition of N,N-dicyclohexylcarbodiimide (0.3 g.,0.00148 mole).
The bath is removed and the mixture is stirred at ambient temperature for 70 minutes. After the addition of dimethylformamide (S ml.) to the resulting slurry, a solution of the product from part (b) (0.7 g., 0.00148 mole) and triethylamine (0.3 g., 0.003 mole) in dimethylformamide (4 ml.) is added and the mixture is stirred at ambient temperature for 16 hours. The solids are removed by filtration, washed with ethyl acetate, and the filtrate is concentrated ln vacuo. The residue is dissolved in ethyl acetate (50 ml.). After filtration, the solution is washed with water (2 x 5 ml.), 10% citric acid ( 2 x 5 ml.), brine, and dried (MgSO4). It is concentrated ln vacuo to give 0.95 g. of an amber glass-like solid. Tlc, silica ge~, dichloromethane/water/acetic acid (8~
shows a major spot at Rf 0.50. It is chromatographed on silica gel, eluting with benzene/acetic acid (4:1, 7:3) to give 0.6 g. of the product as an orange solid. Tlc, silica gel, benzene/acetic acid :~2~57 ~Ji~238 (7:3)shows two spots, Rf 0.40 and 0.46 with a minor spot at F~f 0.65. The solid is treated with one equivalent of sodium hydroxide, diluted to a volume of 10 ml. with water resulting in the se~aration of a solid. The alkaline mixture is acidified to a pH of 1 with concentrated hydrochloric aci~. The solid that separat~s from solution is extracted into dichloromethane (50 ml.), washed with brine, and dried (MgSO4). The mixture is concentrated ln vacuo to give 0.4 g. of [1(+),4S]-l-[~[l-(benzoylamino)-3-phenylpropyl]ethoxyphosphinyl]-acetyl]-4-(phenylmethyl)-L-proline as an orange solid. Tlc, silica gel, dichloromethane/methanol/
acetic acid (8:1:1) shows a single spot at Rf 0.80 (visualized with PMA plus heat).
d) [1(-),4S]-1 [[[1-(3enzoylamino)-3-phenylpropyl]-hydroxypho_phinyl]acetyl~-4-(~henylmethyl)-L-proline ~ solution of the product from part (c) (0.37 g.~0.00064 mole) and bis(trimethylsilyl) trifluoroacetamide (0.33 g., 0.~0128 mole) in dichloromethane (6 ml.) is stirred at ambient -temperature for one hour. The mixture is concentrated ln vacuo. The residue is dissolved in dichloromethane t8 ml.) and bromotrimethylsilane (0.2 g7, 0.00128 mole) is added. The mixture is stirred at ambient temperature for 16 hours.
Aftsr ~oncentrating 1n vacuo, the residue is dissolved in aqueous sodium bicarbonate (3 ml. of saturated sodium bicarbonate plus 22 ml. of water), washed with ether, followed by dichloro-'S7 methane, cooled, and acidified to a pH of 1 with concentrated hydrochloric acid. The amber oil that separates from solution is extracted into dichloromethane, washed with brine, and dried (MgSO4). The solvent is removed ln vacuo to give 0~33 g. of [1(-),4S]-l-[[[l-(benzoylamino)-3-phenylpropyl]hydroxyphosphinyl]acetyl]-4-(phenyl-methyl)-L-proline as an amorphous solid; m.p.
127-157 . Tlc, silica gel, butanol/acetic acid/
water (301:1), shows a single spot at Rf 0.60 (visualized with PMA plus heat, or with I2 vapor).
An 1. cal . 30 33 2 6 2 C~ 63.59; H, 5.87; N, 4.94, P, 5.46 Found: C,63.40; H, 5.64; N, 4.64; P, 5.64.
In an analogous manner, the procedure of Examples 84 and 86 to 89 could be employed to prepare the compounds of Examples 18 to 83.

,, , ;!

.

~2~'7S~7 Example 91 ~ [[l-(Benzoylamino)-3-phenyl~ropyl~hydroxy-_ phosphinyl]acetyl]-L-proline, (2,2-dimethyl-l-oxoproxy)methyl ester, lithium salt +

a) (-)-l-[[[l-(Benzoylamino) 3-phenylpro~yl~-hydroxyphos~hinyl]acetyl]-L-proline~ (2,2-dimethyl-l-oxo~ropoxy)methyl ester Chloromethyl pivalate (0.23 g.,0.0015 mole) is added to a solution of (-)-l-[[[l-(benzoylamino)-3-phenylpropyl]hydroxyphosphinyl]acetyl]-L-proline (0.6 g., 0.0013 mole), prepared for example as set forth in Example 85, and triethylamine (0.2 g., 0.002 mole~ in dimethylformamide (5 ml.)~
The mixture is stirred at ambient temperature.
An additional quantity of triethylamine (0.2 g., 0.002 mole) is added after four hours. After 16 hours, Tlc shows -that the reaction is incomplete.
Additional triethylamine (0.2 g., 0 002 mole) and chloromethyl pivalate (0.23 g., 0.0015 mole) 2a are added, and the mixture is stirred at ambien~
temperature for an additional 24 hours (Tlc shows the absence of starting material). ~fter the addition of water (20 ml.), 10% citric acid is added immediately to a pH of 3-4. The mixture is extracted with ethyl acetate, washed with water, brine, and dried (MgSO4)~ After concentration in vacuol the residue of 0.8 g. of amber oil is chromatographed on silica gel, eluting with dichloromethane/methanol/acetic acid (25:1:1) to give 0O4 g. of (-)-1 [[[1-(benzoylamino)-3-'75~
~i~23 phenylpropyl]hydroxyphosphinyl]acetyl]-L-proline, (2,2-dimethyl-1-oxopropoxyjmethyl ester as a glass~like solid. Tlc, silica gel, butanol/
acetic acid/ water (3:1:1) shows a single spot S at R 0~64.
f+
b) (-)-1- L[ [ 1- (Benzo~lamino)-3-phenylpropyl]-hydroxyphosphinyl]acetyl]-L-~roline, (2,2-dimethyl-l-oxopropoxy)methyl ester, lithium salt To a solution of the ester product from part (a) (0.286 g., 0.005 mole) in acetone (10 ml.), a 0.25 M solution of lith1um carbonate (10 ml~) is added dropwise, with stirring. As the solution becomes turbid during the addition, the turbidity is clarified by the addition of acetone~ so that the final volume of the mixture is 30 ml. After filtration, to remove a trace of solids, the solution is concentrated in vacuo to a volume of 15 ml~, and water is added to incipient turbidity. The mixture is millipore filtered and lyophilized to give 0.2 g. of pink colored solid. Tlc, silica gel, butanol/acetic acid/water (3:1:1) shows a single ~pot at Rf 0.62 and a shadow at Rf 0.44. The solid is placed on a column of HP-20 AG (10 ml.) and eluted with water; water/acetone in a gradient of 1-100% acetone (1;1;4;10;50;100%) to give 46 mg. of (-)-1-[[[1-(benzoylamino)-3-phenylpropyl]-hydroxyphosphinyl3acetyl]-L-proline,(2,2-dimethyl-l-oxopropoxy)methyl ester, lithium salt.
Tlc, silica gel, butanol/acetic acid/water (3:1:1) ~LZ~347~

-116- ~1~.23 shows a single spot at Rf 0.62.
Anal. Calc'd. for C29H36N208 2 C, 55.84; H, 6.62; N, 4.49; P, 4.96 Found: C, 56.04; H, 6.44; Nl 4.19; P, 4.60.
S Example 92 (-)-l-[[[l-(Benzoylamino)-4-phenylbutyl][(2,2-dimethyl-l-oxopropyl)methox~_phosphinyl]acetyl~-L-proline a) (~ [[[l--(Benzoylamino)-4-phenylbutyl][(2,2-dimethyl-1-oxopropyl)methoxy3phosphinyl]acetyl]-L-proline, phenylmethyl ester A equimolar mixture of triethylamine and chloromethyl pivalate are added to a solution of (-)-l-[[[l-(benzoylamino)-4-phenylbutyl]
hydroxyphosphinyl]acetyl]-L-proline, phenylmethyl ester, prepared for e~ample as set forth in Example 20 (d), in dimethylformamide under an argon atmosphere. The mixture is stirred for several hours at room temperature, diluted with ethyl acetate, washed with water, brine, dried (MgSO4), and evaporated. The crude product is chromatographed to give (-)-l-[[[l-(benzoyl amino)-4-phenylbutyl][(2,2-dimethyl-1-oxopropyl)-methoxy]phosphinyllacetyl]-L-proline,phenylmethyl ester.
b) (-3-1-[[[1-(Ben-~ylamino)-4-phenylbutyl][(2, 2-dimethyl-1 oxopropyl)methox~]phosphinyl]acetyl]-L-proline A solution of the diester product from part (a) in methanol is added to a 10~ palladium on ~Z~ 7 _ HA23 carbon catalyst and the resulting mixture is shaken ir. a Parr hydrogenation apparatus for several hours. The catalyst is filtered off and the methanol is stripped from the filtrate. The crude product is chromatographed on silica gel to yield (-t-l-[[[l-(benzoylamino)-4-phenylbutyl][( ,2-dimethyl-l-oxopropyl)methoxy]phosphinyl]acetyl]-L-proline.
Examples 93 - 97 Followlng the procedure of Example 92 but employing the alkylating agent shown in Col. I
for the chloromethyl pivalate, one obtains the product listed in Col. II.

5~.

X ~
V ~ V o ~ I
:~ Q ~ , V _ S ~ C ~ a v C ~C ~J C ~
a) ~a s a~ ~ c u s ~ s ~ a~ ~
3 o1~ ~n:4 o s --I sI oI t`~ aJ a~ ~1 r c~ ~: c I
I ~1 4 1 ~
ô X ô ~ ô o o s ~,1 C,1 o~1 ~ ~ C 0 E VE s E I I ~i o v ~ S
H~ ~:>~ F:~ ~ O
HO ~ ~U O ~ O X r-l ~`1 X CN .--1 N O ~ N X
_lC O~l C ~ C I ~ C
OQ :~ O .8 0 ~ I ~
-- v ~ ~ o ~a ~ o ~ X .,~_, C C ~
I --~I o ~I ~ S I ~
1 S O~ I ~ ~ ~
>~ VI J.) ~) 0 1 0 ^ Q
+ I~+ I -- I ~ I ~ C + I

~ r~
O ~0 .0= U O -U ~
0--~ 0 y U J ~ U
m u a~ u a E a~
3r '7S7 v :~, ~ J-_I O

c _ ,CI
S
I Q~
m O O
C SQ, r C v rd :~1 0 0 ~1 0 O S 1~ _~
N
~ C 2J .
_I ~ ^ o U .4 ~ O
o ~ ~. a.
~ ~ C ~ C~
~ o _~ 0 o I -- h Ei + î ~ I x _ ~ C J r~ ~

~ C
.L) r~ gc x c 0 4~ u~
O
r C
0 ~ O
. ~ ~ o a~
_1 5 ~ s~
U O = U 0 ~ ~
aJ
T ~ Sv V s U--V
~ s C
u ~ ~ s.
0 3 J~
.~ ~1 3 ~C
~ ~ O
E~
. ~ ~ E~

7S~7 Example 98 lO00 tablets each containing the following ingredients:
(-)-l-[[[l-(Benzoylamino)-3-phenylpropyl~hydroxyphosphinyl]
acetyl]-L-proline lO0 mg.
Corn starch 50 mg.
Gelatin 7.5 mg.
Avicel (microcrystalline cellulose) 25 mg~
Magnesium stearate 2.5 mg.
185 mg.
are prepared from sufficient bulk quantities by mixing the (-t-l-[~ (benzoylamino)-3-phenylpropyl]
hydroxypho5phinyl]acetyl~-L-proline and corn starch with an aqueous solution of the gelatin. The mixture is dried and ground to a fine powder.
The Avicel and then the magnesium stearate are admixed with granulation. This mixture is then compressed in a tablet to form 1000 tablets each containing 100 mg. of active ingredient.
In a similar manner, tablets containing lO0 mg. of the product of any of Examples l to 84 and 86 to 97 can be prepared.
Example 99 1000 tablets each containing the following ingredients:
~ [[[l-~Benioylamino)-3-phenylpropyl]hydroxyphosphinyl]-acetyl]-4-[ethylenebis(thio)]-L-proline 50 mg.

~Z~ 7 Lactose 25 mg.
Avicel 38 mg.
Corn starch 15 mg.
Magnesium stearate 2 mg.
130 mg.
are prepared from sufficient bulk quantities by mixing the (-)-l-[[[l-(benzoylamino)-3-phenylpropyl]
hydroxypho~phinyl]acetyl]-4-[ethylenebis(thio)]-L-proline, lactose, and Avicel and then blending with the corn starch. Magnesium stearate is added and the dry mixture is compressed in a tablet press to form 1000 tablets each containing 50 mg. of active ingredient~ The tablets are coated with a solution of Methocel E 15 (methyl cellulose) lS including as a color a lake containing yellow ~6.
In a similar manner, tablets containing 50 mg. of the product of any of Examples l to 21 and 23 to 97 can be prepared.
Example lO0 Two piece #l gelatin capsules each containing 100 mg. of (~ [[~ ~benzoylamino)-4~phenylbutyl]
hydroxyphosphinyl]acetyl]-L-proline are filled with a mixture of the following ingredients:
(-)-l-[[[l-(benzoylamino)-4-phenylbutyl]hydroxyphosphinyl]
acetyl3-L-proline 100 mg.
Magnesium stearate 7 mg.
Lactose 193 mg.
In a similar manner, capsules containing0 lO0 mg. of the product of any of Examples 1 to l9 7~7 and 21 to 96 can be prepared.
Example 101 An injectable solution is prepared as follows:
(-)-l-[~[l-[(Ethoxycarbonyl~
amino]-3-phenylpropyl]hydroxy-phosphinyl]acetyl]-L-proline 500 g.
Methyl paraben 5 g.
Propyl paraben 1 g.
Sodium chloride 25 g.
Water for injection 5 1.
The active substance, preservatives, and sodium chloride are dissolved in 3 liters of water for injection and then the volume is brought up to 5 liters. The solution is filtered through a sterile filter and asceptically filled into presterilized vials which are closed with presterilized rubber closures. Each vial contains 5 ml. of solution in a concentration of 100 mg. of active ingredient per ml. of solution for injection.
In a simil~r manner, an injectable solution containing 100 mg. of active ingredient per ml. of solution can be prepared for the product of any of EXamples 1 to 17 and 19 ~o 97.
Example 102 1000 Tablets each containing the following ingredients:
~ [[[1-(Benzoylamino)-3-phenylpropyl]hydroxyphosphinyl]
3~ acetyl]-L-proline 100 mg.
Avicel 100 mg.
Hydrochlorothiazide12.5 mg.
Lactose 113 mg.
Corn Starch 17.5 mg.
5tearic acid 7 350 mg.

~ 7 HA238 are prepared from sufficient bulk quantities by slugging the (+)-l-[[[l-(benzoylamino)-3-phenylpropyl]-hydroxypho~phinyl]acetyl]-L-proline, Avicel and a portion of the stearic acid. The slugs are ground and passed through a #2 screen, than mixed with the hydrochlorothiazide, lactose, corn starch, and remainder of the stearic acid. The mixture is com-pressed into 350 mg. capsule shaped tablets in a tablet press. The tablets are scored for dividing in 1~ half.
In a similar manner, tablets can be prepared containing lQ0 mg. of the product of any of Examples 1 to 84 and 85 to 97.
Example 103 1-[2-~[Methoxy(l-benzloxyamido-3-phenyl)propyl~phos-phinvlmethyl]~ro~ionvl]proline-benzvl ester ,. ,. .~
Methyl~2-[[methoxy(l-benzloxyamido-3-phenyl) propyl]phosphinylmethyl]propiona~e is reacted with IN. NaOH to yield the corresponding propionic acid.
220 mgs. of this acid is dissolved in 10 ml. of dry tetrahydrofuran (THF) and the resulting solution is cooled to 0C and under argon carbonyldiimidazole (90.7 mg., 0.56 mmol) is added. After stirring at 0C for one hour, 0.16 ml. of triethylamine (0.llg., 1.08 mmol) is added, followed by pxolinebenzylester hydrochloride (139 mg., 0.51 mmol). The mixture is then allowed to warm to room temperature and stirring is con~inued overnight. The suspension is diluted with ethylacetate and the resulting mixture is washed with KHS0~, H2O and saturated NaCl solution. After drying over sodium sulfate, the combined organic extracts are evaporate~ to yield 240 mgs. ofthe above titled compound as a glass. Tlc, silica gel, ethyl-acetate/acetic acid/water (15:1:1), Rf = 0.45.

Claims (20)

The embodiments of the invention in which an exclusive property or privilege is claimed are de-fined as follows:

1. A process for the preparation of a com-pound of the formula (II):

(III) wherein R1 is ;
n is zero or one;
R5 is hydrogen, lower alkyl, halo substituted lower alkyl, benzyl, or phenethyl;
R3 is hydrogen, lower alkyl, benzyl, or benz-hydryl;
R19 is hydrogen, lower alkyl, halo substituted lower alkyl, amino substituted lower alkyl, , cycloalkyl, ;

R20 is lower alkyl, phenyl, benzyl, or phen-ethyl;

R2 is hydrogen, lower alkyl, lower alkenyl, halo substituted lower alkyl, , , or ;

R13 is hydrogen, lower alkyl of 1 to 4 carbons, lower alkoxy of 1 to 4 carbons, lower al-kylthio of 1 to 4 carbons, chloro, bromo, fluoro, trifluoromethyl, hydroxy, phenyl, phenoxy, phenylthio, or phenylmethyl;
q is zero or an integer from 1 to 7;
m is zero, one, two or three; and p is one, two or three provided that p is more than one only if R13 is hydrogen, methyl, methoxy, chloro, or fluoro;
which comprises either a) hydrolyzing an ester of the formula:

wherein R23 is the residue of an alcohol of the formula R23.OH providing the ester group, to provide an acid of the desired formula (II) wherein R23 is replaced by H, and R1, R2, R3, R5 and n have the mean-ing stated above; or b) reacting a compound of the formula:

wherein R3 is lower alkyl, benzyl or benz-hydryl, with lithium diisopropylamide and carbon dioxide to provide an acid of the formula:

wherein R3 is lower alkyl, benzyl or benz-hydryl and R1, R2 and R5 have the meaning stated above.

2. The process of claim 1a) wherein R23 is a lower alkyl radical.

3. The process of claim 1a) wherein R23 is a methyl radical.

4. The process of claim 1a) wherein the hydro-lyzing is carried out by means of an alkaline saponi-fication agent.

5. The process of claim 4 wherein the agent is an alkali metal or an alkaline earth metal hy-droxide.

6. The process of claim 4 wherein the agent is sodium hydroxide.

7. The process of claim 1b) wherein the re-action is carried out in the presence of an inert organic solvent or diluent.

8. The process of claim 7 wherein the solvent or diluent is tetrahydrofuran.

9. The process of claim 1b) wherein the reac-tion is initially conducted at a low temperature and is then allowed to warm up to ambient temperature.

10. The process of claim 1b) wherein the reac-tion is initially conducted at a temperature of about -76°C and is then allowed to warm up to room tempera-ture.

11. The process of claim 1a) or 1b) wherein R1 is R19CO-, R5 is hydrogen and n is zero and there is thus prepared a compound of the formula:

wherein R19 is lower alkyl of 1 to 7 carbons, tri-fluoromethyl, , cyclopentyl, cyclohexyl, , ;

R3 is hydrogen, lower alkyl, or benzyl;
R2 is lower alkyl of 1 to 7 carbons, or ;

q is zero or an integer from 1 to 4; and R13 is hydrogen, methyl, methoxy, methylthio, chloro, bromo, fluoro, or hydroxy.

12. The process of claim 1a) or 1b) wherein R1 is R20O.CO-, R5 is hydrogen and n is zero and there is thus prepared a compound of the formula:

wherein R20 is lower alkyl or benzyl;
R3 is hydrogen, lower alkyl, or benzyl;
R2 is lower alkyl of 1 to 7 carbons, or ;

q is zero or an integer from 1 to 4; and R13 is hydrogen, methyl, methoxy, methylthio, chloro, bromo, fluoro, or hydroxy.

13. A compound of the formula (II):

(II) wherein R1 is R19-?- or R20-O-?-;

n is zero or one;
R5 is hydrogen, lower alkyl, halo substituted lower alkyl, benzyl, or phenethyl;
R3 is hydrogen, lower alkyl, benzyl, or benz-hydryl;
R19 is hydrogen, lower alkyl, halo substituted lower alkyl, amino substituted lower alkyl, , cycloalkykl, , , , , or ;

R20 is lower alkyl, phenyl, benzyl, or phen-ethyl;
R2 is hydrogen, lower alkyl, lower alkenyl, halo substituted lower alkyl, , , , or ;
R13 is hydrogen, lower alkyl of 1 to 4 carbons, lower alkoxy of 1 to 4 carbons, lower al-kylthio of 1 to 4 carbons, chloro, bromo, fluoro, trifluoromethyl, hydroxy, phenyl, phenoxy, phenylthio, or phenylmethyl;
q is zero or an integer from 1 to 7;
m is zero, one, two or three; and p is one, two or three provided that p is more than one only if R13 is hydrogen, methyl, methoxy, chloro, or fluoro;
when prepared by the process of claim 1.

14. A compound, as defined in claim 13, when prepared by the process of claim 2 or 3.

15. A compound, as defined in claim 13, when prepared by the process of claim 4 or 5.

16. A compound, as defined in claim 13, when prepared by the process of claim 6.

17. A compound, as defined in claim 13, when prepared by the process of claim 7 or 8.

18. A compound, as defined in claim 13, when prepared by the process of claim 9 or 10.

19. A compound of the formula:

wherein R19 is lower alkyl of 1 to 7 carbons, tri-fluoromethyl, , cyclopentyl, cyclohexyl, , ;

R3 is hydrogen, lower alkyl, or benzyl;
R2 is lower alkyl of 1 to 7 carbons, or ;

q is zero or an integer from 1 to 4; and R13 is hydrogen, methyl, methoxy, methylthio, chloro, bromo, fluoro, or hydroxy;
when prepared by the process of claim 11.

20. A compound of the formula:

wherein R20 is lower alkyl or benzyl;
R3 is hydrogen, lower alkyl, or benzyl;
R2 is lower alkyl of 1 to 7 carbons, or ;

q is zero or an integer from 1 to 4; and R13 is hydrogen, methyl, methoxy, methylthio, chloro, bromo, fluoro, or hydroxy;
when prepared by the process of claim 12.