PROCESS FOR PREPARING PHOSPHINIC ACID INTERMEDIATES

Abstract: A process is provided for preparing phosphinic acid prodrug intermediates which are useful in preparing phos­ phinic acid angiotensin-converting enzyme inhibitors which method includes the step of coupling a phosphonous acid or its ester of the structure wherein R is H or lower alkyl and R¹ is lower alkyl, aryl, aryl­ alkyl, cycloalkyl or cycloalkyl-alkyl, with an alkylating agent of the structure wherein Hal is Cl, Br or I, n is 0 or 1, R² is H or lower alkyl, and Z is H, lower alkyl, -CO₂R³ (wherein R³ is H or lower alkyl, --R⁴ (wherein R⁴ is H, lower alkyl, aryl or arylalkyl), -CN, or (wherein R⁵ and R⁶ may be the same or different and are se­ lected from the group consisting of H, lower alkyl, aryl, aryl-­ lower alkyl, cycloalkyl or cycloalkylalkyl and at least one of R⁵ and R⁶ is other than H, or R⁵ and R⁶ can be taken with the N-atom to form a 5, 6- or 7-membered heterocyclic ring which 5-, 6- or 7-membered N-containing ring may or may not contain a CO₂R³ group and which 5- or 6-membered N-­ containing ring may or may not be fused to an aryl ring), in the presence of a silylating agent, to form the phosphinic acid intermediate of the structure wherein R, R¹, R², n and Z are as defined above.

Description: PROCESS FOR PREPARING PHOSPHINIC ACID INTERMEDIATES The present invention relates to a process for preparing phosphinic acid intermediates having the structure EMI1.1 wherein R is H or lower alkyl: R1 is lower alkyl. aryl. arylalkyl. cycloalkyl, or cycloalkylalkyl ; Rê is H or lower alkyl ; Z is H. lower alkyl, -CO2R2 (wherein R is H or lower alkyl), EMI1.2 (wherein R is H. lower alkyl. aryl or arylalkyl). -CN, or EMI1.3 (wherein R5 and R6 are the same or different and can be hydrogen, lower alkyl. aryl. aryl-lower alkyl. cycloalkyl or cycloalkylalkyl. and at least one of R and R6 is other than hydrogen. or R5 and R6 can be taken together with the nitrogen atom to form a 5-. 6- or 7-membered heterocyclic ring. EMI2.1 which ring may or may not include a carboxyl substituent -CO2R , and which nitrogen containing ring containing 5 or 6 members may or may not include a fused aryl ring. such as a phenyl ring. so that the nitrogen containing ring EMI2.2 together with its fused aryl ring may form indole or tetrahydroisoquinoline systems such as EMI2.3 EMI2.4 where in the above formulae n' is O or 1) and n is O or 1. which intermediates are useful in the preparation of phosphinic acid angiotensin-converting enzyme inhibitors such as described in U. S. Patents Nos. 4.168.267 and 4.337.201. The process of the present invention for making phosphinic acid intermediates of formula I includes the step of reacting a phosphonous acid or ester of the structure EMI3.1 wherein R is H or lower alkyl and R1 is lower alkyl. aryl. arylalkyl. cycloalkyl or cycloalkylalkyl, with an alkylating agent of the structure EMI3.2 wherein Y is a leaving group such as halogen including C1. Br or F. mesyloxy or tosyloxy n is O or 1. R2 is H or lower alkyl. and Z is H, lower alkyl. C02R3 (wherein R3 is H or lower alkyl), EMI3.3 wherein R4 is H. lower alkyl. aryl or arylalkyl). EMI4.1 (wherein R5 and R6 are the same or different and can be hydrogen. lower alkyl. aryl. aryl-lower alkyl. cycloalkyl or cycloalkylalkyl, and at least one of R5 and R6 is other than hydrogen, or R5 and R6 can be taken together with the nitrogen atom to form a 5-. 6- or 7-membered heterocyclic ring EMI4.2 which ring may or may not include a carboxyl group CO2R. and which 5- or 6-membered N-containing ring may or may not include a fused aryl ring. such as a phenyl ring, which fused systems are exemplified above). in the presence of a silylating agent and an inert organic solvent to form the phosphinic acid intermediate I which may be separated from the reaction mixture and used in the preparation of phosphinic acid angiotensin-converting enzyme inhibitors such as described in U. S. Patents Nos. 4,168,267 and 4,337,201. The term "aryl". as used throughout the specification either by itself or as part of a larger group. refers to phenyl or phenyl substituted with halogen. alkyl, alkoxy. alkylthio, hydroxy. alkanoyl, nitro, amino, dialkylamino, or trifluoromethyl groups. Phenyl and monosubstituted phenyl are preferred and phenyl is the most preferred. The term "alkyl" or "lower alkyl" as used throughout the specification either by itself or as part of a larger group. refers to groups having 1 to 10 carbon atoms. Alkyl groups having 1 to 4 carbon atoms are preferred. The term "cycloalkyl". as used throughout the specification either by itself or as part of a larger group, refers to groups having 3 to 7 carbon atoms. The term "alkoxy" or "alkylthio", as used throughout the specification either by itself or as part of a larger group. refers to groups having 1 to 8 carbon atoms. Alkoxy or alkylthio groups having 1 to 3 carbon atoms are preferred. The term "arylalkyl" or "cycloalkylalkyl". as used throughout the specification either by itself or as part of a larger group. refers to an "alkyl" group as defined above containing an "aryl" or "cycloalkyl" substituent. The term "alkanoyl" as used throughout the specification either by itself or as part of a larger group, refers to an "alkyl" group as defined above linked to a carbonyl EMI5.1 group. Features of the preferred process of the invention will now be described. In carrying out the process of the invention to prepare compounds of formula I. the phosphonous acid or ester starting material II will be reacted with the alkylating agent in the presence of the silylating agent employing a temperature of within the range of from about 0 0C to about reflux temperature (about 1200C). and preferably from about 100C to about 500C. The reaction will be carried out for a period ranging from about 2 to about 10 hours and preferably from about 5 to about 8 hours in the presence of an inert organic solvent such as-chloroform. acetonitrile, dichloromethane. ethyl ether. tetrahydrofuran or dioxane. and optionally, in the presence of an organic base, such as triethylamine. pyridine or N,N-dimethylamine. Examples of phosphonous acids or esters II useful as starting materials in carrying out the present invention include, but are not limited to, EMI6.1 with EMI6.2 or esters thereof being preferred. Examples of alkylating agents III useful in carrying out the present invention include, but are EMI7.1 EMI8.1 with EMI9.1 being preferred. Examples of silylating agents suitable for use in carryinq out the method of the present invention include, but are not limited to. trimethylsilyl chloride and triethylamine. monosilylacetamide. bissilylacetamide. monosilyltrifluoroacetamdie and bissilyltrifluoroacetamide. In carrvinq out the method of the invention as described above the amount of Dhosnhonous acid or ester II employed vis-a-vis the alkvlatinq aqent III and the silylatin aaent will depend upon the R substituents in the startina DhosDhonous acid or ester II and the Z substituent in the alkylatina anent III. Thus. where R is lower alkyl and Z is CO2alkyl. lower alkyl. EMI9.2 then the phosphonous acid or ester II will be employed in a molar ratio to the alkylating agent III of within the range of from about 0.5:1 to about 10:1 and the phosphonous acid of ester II will be employed in a molar ratio to the silylating agent of within the range of from about 0.5:1 to about 1:10. Where in the phosphonous acid or ester II, R is H and in the alkylating agent III, Z is lower alkyl, CO@R (wherein R is lower alkyl). EMI9.3 the phosphonous acid or ester II will be employed in a molar ratio to the alkylating agent III of within the range of from about 0.5:1 to about 10:1 and the phosphonous acid or ester II will be employed in a molar ratio to the silylating agent of within the range of from about 0.2:1 to about 1:10. Where a phosphonous acid starting material is used. that is in formula II, R is H. and in the alkylating agent III. Z is CO2H or EMI10.1 then the phosphonous acid II will be employed in a molar ratio to the alkylating agent III of within the range of from about 0.5:1 to about 10:1 and the phosphonous acid II will be employed in a molar ratio to the silylating agent of within the range of from about 0.1:1 to about 1:15. Where a phosphonous acid ester of formula II (that is. R is alkyl) is employed and the alkylating agent used is an acid, that is in formula III, Z is Co2H or EMI10.2 then the phosphonous acid ester II will be employed in a molar ratio to the alkylating agent of within the range of from about 0.5:1 to about 10:1 and the phosphonous acid ester II employed in a molar ratio to the silylating agent of within the range of from about 0.1:1 to about 1:15. Where a phosphonous acid ester of formula II (that is R is alkyl) is employed and the alkylating agent used is an acid. that is in formula III. Z is EMI11.1 the phosphonous acid ester II will be employed in a molar ratio to the alkylating agent of within the range of from about 0.5:1 to about 10:1 and the phosphonous acid ester II will be employed in a molar ratio to the silylating agent of within the range of from about 0.2:1 to about 1:10. Where the phosphinic acid intermediate I is obtained in the form of an ester. such ester may be converted to the free acid by conventional means such as by reacting the ester with sodium hydroxide. The esters of formula I where R is lower alkyl can be obtained from the phosphinic acid compounds. that is wherein R is H. by conventional esterification means. for example. by esterification with diazomethane or by reaction with methyl iodide (or other alkyl halide) and a base, such as triethylamine. potassium carbonate and the like. The following Examples represent preferred embodiments of the present invention. Unless otherwise indicated. temperatures are expressed in degrees Centigrade. ExamPle 1 tHydroxy-(4-Dhenylbutvllphosphinsllacetic acid, phenvlmethvl ester To a solution of 4-phenylbutyl phosphonous acid (2.0 g. 0.01 mole) in chloroform (40 ml) was added triethylamine (3.2 ml, 0.033 mole) and colled in an ice bath to 0 C. Trimethyl silyl chloride (2.8 ml, 0.022 mole) was added to the above solution dropwise, followed by benzyl bromoacetate (1.6 ml, 0.011 mole). The ice bath was removed and the mixture stirred at room temperature for 5 hours and poured into 10% aqueous HC1 (30 ml) and crushed ice (20 g). After shaking the mixture in a separatory funnel. the chloroform layer was separated and the aqueous layer extracted with dichloromethane (2 x 50 ml). The combined organic phase was washed with brine. dried over anhydrous sodium sulfate and the solvents removed on a rotavap. The resulting crude thick oil (3.5 g) was dissolved in 30 ml ether; hexane was added dropwise to get a turbid solution and left at room temperature overnight to complete the crystallization. The resulting product was cooled in the freezer for 2 hours. filtered and the solid was washed very thoroughly with hexane (50 ml), ether (50 ml) and again very thoroughly with hexane (50 ml). ether (50 ml) in that order. The solid was vacuum dried to get 2.48 g (71%) of title compound, m.p. 68-70 C. TLC : Silica gel. CH2Cl2:MeOH:MOAc (20:1:1) shows a single spot at Rf=0.25. Example 2 rHydroxy(4-phenylbutyl)phosphinyllacetic acid, ethvl ester Following the procedure of Example 1, except substituting ethylbromoacetate for benzyl bromoacetate. the title compound is obtained. Example 3 [Hydroxy(4-phenylbutyl) phosphinyl] acetic acid. methyl ester Following the procedure of Example 1, except substituting methyl bromoacetate for benzyl bromoacetate. the title compound is obtained. ExamPle 4 [Hydroxy(4-phenylbutyl) phosphinyl] acetic acid Following the procedure of Example 1, except substituting bromoacetic acid for benzyl bromoacetate, the title compound is obtained. ExamPle 5 THvdroxv(ethY1)PhosPhinylacetic acid Following the procedure as set out in Example 1. except substituting ethylphosphonous acid for 4-phenylbutylphosphonous acid. and substituting chloroacetic acid for benzylbromoacetate. the title compound is obtained. Example 6 Hydroxy(cyclohexvl)phosphinvliacetic acid. ethyl ester Following the procedure as set out in Example 1, except substituting cyclohexylphosphonous acid for 4-phenylbutylphosphonous acid, and substituting ethylchloroacetate for benzylbromoacetate, the title compound is obtained. Example 7 rHvdroxy(phenyl)phosphinvli acid. phenylethyl ester Following the procedure as set out in Example 1, except substituting phenylphosphonous acid for 4-phenylbutylphosphonous acid. and substituting phenylethylchloroacetate for benzylbromoacetate. the title compound is obtained. Example 8 [Hydroxy (cyclohexylmethyl) phosphinyl] propionic acid Following the procedure as set out in Example 1, except substituting cyclohexylmethylphosphonous acid for 4-phenylbutylphosphonous acid. and substituting bromopropionic acid for benzylbromoacetate. the title compound is obtained. Example 9 (4-Phenvlbutyl)methvlPhosPhinic acid Following the procedure as set out in Example 1. except substituting bromomethane for benzylbromoacetate. the title compound is obtained. Example 10 [Hydroxy(propyl)phosphinyl]-2-methyl propionyl nitrile Following the procedure as set out in Example 1. except substituting propylphosphonous acid for 4-phenylbutylphosphonous acid. and substituting 3-bromo-2-methylpropiono nitrile for benzylbromoacetate. the title compound is obtained. Example 11 [Hydroxy(4-phenylbutyl) phosphinyl] propionyl methyl ketone Following the procedure as set out in Example 1. except substituting 2-bromoethyl (methyl) ketone for benzylbromoacetate. the title compound is obtained. ExamPle 12 [Hydroxy (phenyl) phosphinyl] propional aldehyde Following the procedure as set out in Example 1, except substituting phenylphosphonous acid for 4-phenylbutylphosphonous acid, and substituting 2-bromopropional aldehyde for benzylbromoacetate, the title compound is obtained. Example 13 [Hydroxy-(4-phenylbutyl)phosphinyl] propionic acid Following the procedure as set out in Example 1. except substituting 2-bromopropionic acid for benzylbromoacetate, the title compound is obtained Example 14 [Hydroxy-(4-phenylbutyl)]phosphinyl] acetyl-L-proline Following the procedure of Example 1 except substituting bromoacetyl-L-proline for benzylbromoacetate, the title compound is obtained. Example 15 [Hydroxy-(4-phenylbutyl)]phosphinyl]-N,N-dimethylacetamide Following the procedure of Example 1 except substituting N,N-dimethylbromoacetamide for benzylbromoacetate, the title compound is obtained. Example 16 rHydroxy C 4-phenylbutyl) phosphinyl 1 -1-methyipropionic acid Following the procedure of Example 1, except substituting 2-bromo-l-methylpropionic acid for benzylbromoacetate, the title compound is obtained. Example 17 1-[Hydroxy-(4-phenylbutyl) phosphinyl] acetyl indoline Following the procedure of Example 1 except substituting N-bromoacetyl indoline for benzylbromoacetate. the title compound is obtained. Example 18 1- r 2- FHydroxy- (4-phenybutyl) phosphinyl 1 propionyl 1 - indoline-2-carboxylic acid Following the procedure of Example 1 except Substituting 1-(2-bromopropionyl) indoline-2carboxylic acid for benzylbromoacetate. the title compound is obtained. Example 19 2-[2-[Hydroxy-(4-phenylbutyl) phosphiny]-1-methylpropionyl]-1,2,,4-tetrahydro isoguinoline Following the procedure of Example 1 except substituting 2-[2-bromo-1-methylpropionyl]-1,2,3,4 tetrahydro isoquinoline for benzylbromoacetate. the title compound is obtained. ExamPle 20 2-[Hydroxy-(4-phenylbutyl) phosphinyl] acetyl-1,2,3,4tetrahydro isoquinoline-1-carboxylic acid Following the procedure of Example 1 except substituting 2-bromoacetyl-1,2,3,4-tetrahydro isoquinoline-1-carboxylic acid for benzylbromoacetate. the title compound is obtained. Example 21 1-[3-[Hydroxy-(4-phenylbutyl) phosphinyl]-1oxopropyl]-L-proline, (2,2-dimethyl-1-oxopropoxy) methyl ester1 lithium salt A. 1-[3-[Hydroxy-(4-phenylbutyl) phosphinyl]-1 oxopropyl]-L-proline, (2,2-dimethyl-1 oxoPropoxylmethyl ester A mixture of (hydroxy-(4-phenylbutyl)- phosphinyl] propionic acid (prepared as described in Example 13) (0.75 g. 0.0028 mole), carbonyldiimidazole (CDI) (0.45 g, 1.0 eq) and THF were stirred under argon at 0 C for 2 hours. NEt3 (0.8 ml. 2.0 eq) and the tosylate salt of proline pivaloxymethyl ester (1.1 g, 1.0 eq) were added and the resulting solution was stirred at room temperature for 16 hours. The THF was stripped and the residue was partitioned between 1N HC1 and EtOAc. The organic phase was washed with 5% NaH2PO4 (2 times), brine and dried (MgSO4). The solvent was stripped to obtain a crude oil (1.2 g). The crude oil was chromatographed on silica (70 g) eluting with (CH2C12/HOAc/CH3OH, 95:5:5) to give title A compound (1.0 g, 0.0021 mole. 74% yield) as a colorless glass. TLC (95:5:5, CH2C12:HOAc:CH30H) gave one spot. Rf=0.35. B. 1-[3-Hydroxy-(4-phenylbutyl) phosphinyl]-1 oxopropyl]-L-proline, (2.2-dimethyl-1 oxorooxv)methvl ester. lithium salt Title A compound (940 mg, 1.95 mmole) was dissolved in acetone. Li2CO3 (73 mg, 0.975 mmole) and water were added to the acetone solution. The heterogeneous mixture became homogeneous after 2-1/2 hours. The acetone and some water was removed and the resulting solution was millipored and lyophilized. A dense white lyophilizate (800 mg. 1.60 mmole, 86% yield) was obtained which is useful as an angiotensin converting enzyme inhibitor in the treatment of hypertension. Anal. Calcd for C24H35NO7P.Li.0.5 moles of H20: N. 2.82: C. 58.06: H. 7.31; P. 6.2 Found: N. 2.76; C. 57.91; H. 7.36; P. 6.2 Example 22 (#)-1-[3-[Hydroxy-(4-phenylbutyl) phosphinyl]-2-methyl- l-oxoropyl1-L-proline. dilithium salt A. (#)-1-[3-[Hydroxy-(4-phenylbutyl) phosphinyl]- 2-methyl-1-oxopropyl]-L-proline, benzyl ester A mixture of [hydroxy-(4-phenylbutyl) phosphinyl]- l-methylpropionic acid (prepared as described in Example 14) (0.75 g. 0.0026 mole). carbonyldiimidazole (0.42 g. 1.0 eq), and THF was stirred under argon for 1 hour at 0 C. NEt3 (0.72 ml, 2.0 eq) and proline benzyl ester (0.63 g, 1.0 eq) were added and the resulting heterogeneous mixture was stirred at room temperature for 16 hours. The THF was stripped and the residue was partitioned between EtOAc and 1N HC1. The organic portion was washed with 5% NaH2PO4 (3 times), brine, dried (MgSO4), and evaporated. The crude product (1.05 g) was chromatographed on silica (75 g) eluting with CH2C12/HOAc/CH3OH (95/5/5) to give title compound (1.0 g. 0.0021 mole. 82% yield) as a colorless glass. TLC (95/5/5, CH2Cl2/HOAc/CH30H) major spot Rf=0.33. B. (#)-1-[3-Hydroxy-(4-phenylbutyl) phos- phinyl]-2-methyl-1-oxopropyl]-L-proline Benzyl ester from Part A (1.0 g. 0.0021 mole) in CH3OH (50 ml) was treated with 10% Pd/C (100 mg) and shaken on a Parr hydrogenation apparatus for 3 hours dt 35 psi. The reaction mixture was filtered through a Celite bed. washing several times with CH3OH. The CH3OH was stripped to give title B diacid (0.8 g, 0.0021 mole. quantitative). TLC (butanol/H2O/HOAc, 4/1/1) one spot Rf=O.47. C. (#)-1-[3-[Hydroxy-(4-phenylbutyl) phos- phinyl]-2-methyl-1-oxopropyl]-L-proline. dilithium salt Title B diacid (0.80 g, 0.021 mole) was dissolved in water and 1N LioH (2.0 ml. 1.0 eq) and run on AG40W-X8 (Li ) resin (40 ml). The aqueous solution was millipored and lyophilized. A very dense lyophilizate (0.75 g, 0.0017 mole. 91% yield) was obtained of the above title which is useful as an angiotensin-converting enzyme inhibitor in the treatment of hypertension. Anal. Calcd for ClgH26NO5PLi2 3.5 moles of H2O: C. 50.00; H, 7.29: N, 3.07; P. 6.8 Found: C. 50.05; H. 6.92; N, 3.04; P, 6.8

Claims: CLAIMS 1. A process for preparing a phosphinic acid intermediate of the structure EMI21.1 wherein R is H or lower alkyl: R1 is lower alkyl. aryl. arylalkyl. cycloalkyl. or cycloalkylalkyl: R2 is H or lower alkyl; Z is H. lowr alkyl, -CO2R (wherein R is H or lower alkyl). EMI21.2 (wherein R is H, lower alkyl. aryl or arylalkyl), -CN. or EMI21.3 wherein R5 and R6 may be the same or different and are selected from the group consisting of H. lower alkyl. aryl, aryl-lower alkyl. cycloalkyl or cycloalkylalkyl and at least one of R5 and R6 is other than H. or R5 and R6 can be taken with the N-atom to form a 5-, 6- or 7-membered heterocyclic ring which 5-. 6- or 7-membered N-containing ring may or may not contain a CO2R group and which 5- or 6-membered N-containing ring may or may not be fused to an aryl ring; and n is 0 or 1. which comprises reacting a phosphonous acid or ester thereof of the structure EMI22.1 wherein R and R1 are as defined above with an alkylating agent of the structure EMI22.2 wherein Y is a leaving group. and R'. n and Z are as defined above. in the presence of a silylating agent and an inert organic solvent to form the phosphinic acid intermediate. 2. The prodess as defined in Claim 1 wherein n is 0 and R2 is H. 3. The process as defined in Claim 1 wherein the reaction is carried out in the presence of a base which is triethylamine, pyridine or N.N-dimethvlamine. 4. The process as defined in Claim 1 wherein the inert organic solvent is chloroform. acetonitrile, dichloromethane, dichloroethane. ethyl ether. tetrahydrofuran or dioxane. 5. The process as defined in Claim 1 wherein the silylating agent is trimethyl silylchloride and triethylamine, monosilylacetamide. bissilylacetamide. monosilyltrifluoroacetamide or bissilyltrifluoroacetamide. or trimethylsilyl imidazole. 6. The process as defined in Claim 1 wherein the silylating agent is trimethyl silylchloride and triethylamine. 7. The process as defined in Claim 1 wherein in the phosphonous acid or ester. R is lower alkyl. and in the alkylating agent Z is an ester. lower alkyl. EMI23.1 8. The process as defined in Claim 7 wherein the phosphonous acid or ester is employed in a molar ratio to the alkylating agent of within the range of from about 0.5:1 to about 10:1, and the phosphonous acid or ester is employed in a molar ratio to the silylating agent of within the range of from about 0.5:1 to about 1:10. 9. The process as defined in Claim 1 wherein in the phosphonous acid or ester. R is H and in the alkylating agent Z is an ester. lower alkyl. EMI23.2 10. The procees as defined in Claim 9 wherein the phosphonous acid is employed in a molar ratio to the alkylating agent of within the range of from about 0.5:1 to about 10:1, and the phosphonous acid is employed in a molar ratio to the silylating agent of within the range of from about 0.2:1 to about 1:10. 11. The process - as defined in Claim 1 wherein in the phosphonous acid or ester, R is lower alkyl. and in the alkylating agent Z is COOH or EMI24.1 12. The process as defined in Claim 11 wherein the phosphonous acid ester is employed in a molar ratio to the alkylating agent of within the range of from about 0.5:1 to about 10:1, and the phosphonous acid ester is employed in a molar ratio to the silylating agent of within the range of from about 0.2:1 to about 1:10. 13. The process as defined in Claim 1 wherein in the phosphonous acid or ester. R is H, and in the alkylating agent Z is COOH or EMI24.2 14. The process as defined in Claim 1 wherein Y is a halogen group, mesyl or tosyl. 15. The process as defined in Claim 13 wherein the phosphonous acid is employed in a molar ratio to the alkylating agent of within the range of from about 0.5:1 to about 10:1. and the phosphonous acid is employed in a molar ratio to the silylating agent of within the range of from about 0.1:1 to about 1:15. 16. The process as defined in Claim 1 wherein the reaction between the phosphonous acid or ester and the silylating agent is carried out at a temperature of within the range of from 0 C to 120 C. 17. The process as defined in Claim 1 wherein the phosphonous acid is EMI25.1 the alkylating agent is BrCH2CO2CH C H and the silylating agent is (CH3)3SiCl and (C2H5)3N.

Inventors: MONIOT, JEROME L., THOTTATHIL, JOHN K.
Applicants: E.R. SQUIBB & SONS, INC.
Application year: 1984
Main classification: C07F9
IPC codes: C07F9