NZ203176A - D-amino acid amides - Google Patents

Description

New Zealand Paient Spedficaiion for Paient Number £03176 . i M»a«a—aoaruiw.

Priod4v I P...,...... [ Ccsrjpj^xs 2,-5scjfloation Filed: Js^rnrd, Wo: »s% 203176 l/nder the provisions of Regu-i lation 23 (I) the —- Specification has been ante-dated to ...J..£3...s&.N.UA&.if. i$£L ■ S3? ir? W • ■***■. v.-Initials Divided from No.: 196,037 Date: 16 January 1981 NEW ZEALAND patents act, j 953 COMPLETE SPECIFICATfON "D-AMINO ACID AMIDE COMPOUNDS" PFI2ER INC. , a corporation organised under the laws of the State of Delaware, United States of America, of 235 East 42nd Street, New York, State of New York, United States of America, hereby declare the invention for which &/ we pray that a patent may be granted to3&f£/us, and the method by which it is to be performed, to be particularly described in and by the following statement: - - I - {followed by page la) la - The present invention relates to novel D 203176 D-amino acid amide compounds.

In U.S. 3,49 2,131 certain lower alkyl esters of L-aspartyl-L-phenylalanine were found to be up to 200 times as sweet as sucrose and to be substantially free of bitter flavor notes which detracted from earlier artificial sweeteners such as saccharin. These compounds were subsequently found to have only limited stability in aqueous systems due to diketopiperazine formation especially at the neutral-acidic pH conditions prevalent in most food systems.

Mazur _et aJ. , J. Med. Chem. , 16, 1284 (1973) has disclosed that lower alkyl esters of L-aspartyl-D-alanine and certain homologs thereof, especially L-aspartyl-D-alanine isopropyl ester, have sweetness potencies of up to 125 times sucrose.

Sukehiro et al_. , Seikatsu Kagaku, 11, 9-16 (1977); Chem. Abstr., 87, 168407h (1977) has disclosed certain amides of L-aspartvl-D-alanine of the formula O COOH * 0 CH 3 2_ 2 0 3 1 7 6 where R"*" is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, secondary butyl, cyclohexyl or the . residue of the methyl esters of glycine, d-alanine or 1-alanine. The most potent compounds were 5 those wherein R* is one of the above butyl groups or cyclohexyl, having respectively, 100-125 and 100 times the sweetness of sucrose. Since the n-butyl amide was found to have 125 times the sweetness of sucrose and the isobutyl and secondary butyl amides are 100 x 10 sucrose, it was concluded that the potency of these amides is affected mainly by the number of carbon atcms in the alkyl group, R"*", and that structural isomerism in the alkyl group has little effect on the sweetness potency.

Unexpectedly, it has now been found that it is not merely the size of the amide substituent that is critical for a high degree of sweetness in L-aspa-rtyl-D-alanine amides, but, to the contrary, it is the precise spatial arrangement of the amide substituent, 20 R, that is critical. It has been found that certain L-aspartyl-D-alanine amides which are branched at the alpha carbon atcm (the carbon atom bearing the amide nitrogen atom) and also branch again at one or both of beta and beta' carbon atcms have significant advantages.

In our New Zealand Patent Specification No. 196,037 there is claimed certain novel branched amides of L-aspartyl-D-alanine and certain other L-aspartyl-D-alpha-alkyl alpha-amino acid dipeptiaes which have unexpectedly high sweetness potency and are free from undesirable flavor qualities at conventional use levels. They have also been found to have surprisingly high stability both in solid form p. & (0.9-J 2 0 3 1,7 6 and in aqueous systems over the pH range found in most food systems even at the elevated temperatures used in impound a—of ..the invention are the L-aspartyl-D-amino acid dipeptide amides of the formula inh2 - ' C c/NH\r/' ^NHR (I) COOH 0 Ra and the physiologically acceptable cationic and acid addition salts thereof, wherein Ra is methyl, ethyl, n-propyl or isopropyl; and R is a branched member 10 selected from the group consisting of fenchyl, aiisc-propylcarbinyl, d-methyl-t-butylcarbinyl, d-ethyl-t-butylcarbinyl , d i-_t-butyl carbinyl , 2-methylthio— 2 , 4 — dimethylpentan-3-yl, n ,6 V-(CH2>p' v ^ .5 R" where at least one of R"^, R^, R^, is alkyl having from one to four carbon atoms and the remainder are hydrogen or alkyl having from one to four carbon atcms; X is O, S, SO, SO^, C=0 or CHOH; m is zero, 1, 2, 3 or 4; n and p are each zero, 1, 2 or 3 and the 20 sum of n + p is not greater than 3; the sum of the 3^1— g carbon atoms in R , R~, R3 and R is not greater than 3 4 5 6 six and when both of R and R or R and R are alkyl they are methyl or ethyl; ?03176 'CE?K 7 8 9 where m is as defined above, one of R , R , R is alkyl having from one to four carbon atcms and the remainder are hydrogen or alkyl having from one to four carbon atcms and the sum of the carbon atcms in 7 8 9 R , R and R is not greater than six; 2. m (CH ) 2 q where m and q are the same or different and each have the values previously defined for m; R12 R13 12 3 where eacn of R and R~ are methyl or ethyl, or 13 R *" is hydrogen and R is alkyl having jrora one to four carbon atcms, Z is 0 or NH and t is 1 or 2; 14 15 RI* /R CH2>W R16' NOH s 2 03176 where w is 0, 1, 2, 3 or 4, and R^ are each alkyl having from one to four carbon atoms, R15 is hydrogen, OH or alkyl having frcm one to two carbon atoms, where the sum of-the carbon atcms in R"*"^, R^"5 and R"^ is not 14 15 greater than sxx and when both of R and. R are alkyl they are methyl or ethyl; and 17 19 where R and R are alkyl having frcm one to four 18 20 carbon atcms, R and R are hydrogen or alkyl having 10 frcm one to two carbon atcms, taken separately, A is OH and B is hydrogen, OH or methyl and when taken together A and B are -CH OC-, -CH^NHC-, -OCCH.-,-, ^ a ^ if n ^ 0 0 0 -NHCCH_-, -OC-, -NHC— or -OCO-, where the sum of the ti ^ n n n 0 0 0 0 17 18 T 9 20 carbon atoms in R ■, R , R~ and R is not greater than six and when both of R"^ and R"^ or R~^ and R^ are alkyl they are methyl or ethyl. . jlselcied >"* A/.7. f'a+en't {Ptti-PuArtvu Mo.

While the preferred sweeteners of- fche inventj.or p. £ 5 are those dipeptide amides of formula (I) wherein the aspartylamino acid dipeptide moiety is derived frcm L-20 aspartic acid and a D-amino acid, RaCH () COOH, also included within tho acope of the invenfcioa- are mixtures containing the most preferred L-aspartvl-D-amino acid amides of formula (I) wherein one or both of the Vv aspartyl or the other amino acid (i.e;. - alanine^ 2- aminobutyric acid, valine or norvaline) moieties is racemic such as e.g., r 203176 4 DL-aspartyl-D-alanine amides, DL-aspartyl-DL-alanine amides, L-aspartvl-DL-alanine amides, L-aspartyl-DL-valine amides, • DL-aspartyl-DL-2-aminobutyryl' amides, and DL-aspartyl-D-norvaline amides.

Those compounds of formula (I) wherein the aspartyl moiety is entirely of the D-configuration or the. other amino acid moiety' is entirely of the L-configuration have little or no sweetness.

An especially preferred group of L-aspartyl-D-amino acid amides of formula (I) are those wherein R is an acyclic member selected from the group consisting of diisopropylcarbinyl, d-methyl-^fc-butylcarbinyl and di-t-butylcarbinyl.

Another especially preferred group of L-aspartyl-D-amino acid amides of formula (I) are those wherein R is a member selected frcm the group consisting of r\ (CH_ ) . «— <CIMm 2 m (CH- ) v 2' m (CH2>q 3 Q 12 20 wherein R -R , R -R , A, B, X, Z, m, n, p, q, t and w are as defined above; and more particularly preferred are those compounds of formula (I) wherein R has one of the first four values of the group immediately above.

Particularly preferred amides of formula (I) are the L-aspartyl-D-alanine amides, i.e., those wherein Ra is methyl.

Examples of the more valuable L-aspartyl-D-amino acid dipeptide amides o-f the invention include those of formula (I) wherein Ra is methyl and R is: ( -) f enchyl, diisopropylcarbinvlT d-methyl-t-butylcarbinyl, di-t-butylcarbinyl, 2,6-diethylcyclohexyl, 2-methylcyclopentyl, 2-ethyl-6-methylcyclohexyl, 2-ethyleye1ohexyl, 2-methyleye1ohexyl, 2,2-dimethylcyclohexyl, r 2 6Sf 76 - ■ ■■ . .< 2-ethyleye1opentyl, 2-methyl-6~isopropylcyclohexyl, 2,2,6,6-tetramethylcyclohexyl, 2.2.4.4-tetramethyltetrahydrofuran-3-yl, 2,2,6-trimethylcyclohexyl, 2-isopropylcyclohexyl, 2.5-dimethyleye1opentyl, 2.6-dimethylcyclohexyl, 2-isopropylcyclopentyl, 2.2.5.5-tetramethyleye1opentyl, t-fautylcyclopropylcarbinyl, 2,2,4,4-tetramethylthietan-3-yl, 2,2,4,4-tetramethyl-l,l-dioxothietan-3-yl, 2,2,4,4-tetramethyltetrahydrothicphene-3-yl, 3.5-dimethyltetrahydrothiapyran-4-yl, 2-_t-butyl cyclohexyl or d icyclopropylcarbinyl; those wherein Ra is ethyl, isopropyl or n-propyl and R is: diisopropylcarbinvl, d-methyl-t-butylcarbinyl, di-t-butylcarbinyl, dicyclopropylcarbinyl, 2,2,4,4-tetramethylthietan-3-yl, or 2.2.4.4-tetramethyl-l,l-dioxothietan-3-yl. Especially valuable sweeteners include the above compounds wherein Ra is methyl and R is: di-t-butylcarbinyl, 2,2,6-trimethylcyclohexyl, 2-_t-butyl eye 1 ohexyl, 2-isopropylcyclohexyl, 2.6-dimethylcyclohexyl, 2,5-dimethylcyclopentyl, 2-isopropylcyclopentyl, 2.2.5.5-tetramethylcyclopentyl, 2,2,4,4-tetramethyltetrahydrothiophene-3-yl, 2 03176 t-butylcyclopropylcarbinvl, dicyclopropylcarbinyl, 2,2,4,4-tetramethylthietane-3~vl or 2.2.4.4-tetramethyl-l,l-dioxothietan-3-yl, and the compound of formula (I) wherein Ra is ethyl and R is 2,2,4,4-tetramethyl-l,l-dioxothietan-3-yl, each of which is at least 400 times as sweet as sucrose.

Most particularly preferred are those compounds of formula (I) wherein Ra is methyl and R is: 2.2.5.5-tetramethyleye1opentyl, 2,2,4,4-tetramethyltetrahyarothiophene-3-yl, t-butylcyclopropylcarbinyl, dicyclopropylcarbinyl, 2,2,4,4-tetramethylthietane-3-yl, or 2,2,4,4-tetramethyl-l,l-dioxothietan-3-yl, and the compound of formula (I) wherein Ra is ethyl and R is 2,2,4,4-tetramethyl-l,l-dioxothietan-3-yl.

Each of the latter group of L-aspartyl-D-amino acid dipeptide amides have sweetness potencies of about 500-2000 times that of sucrose.

The invention of New Zealand Patent Specification No. 196,037 further claims compositions for sweetening edible materials which comprises a sweetening amount of a compound of formula (I) and a non-toxic carrier. Most particularly preferred compositions are those containing L-aspartyl-D-alanine N-(dicyclopropylcarbinyl ) amide, L-aspartyl-D-alanine N-(2,2,4,4-tetramethylthietane-3-yl)amide, ancj the i,i_dioxo derivative of the latter.

Additionally, sweetened edible compositions comprising an edible material and a sweetening amount _ -forwwU 11) >boue . o± a compound of the invention, are claimed.

Also claimed in New Zealand Patent Specification No. 196,037 is a method for sweetening edible compositions which comprises adding thereto a , ^ CD*»JtrmuU Ct) tbtve. sweetenmg amount of a oompiund of •; -,"^n 203176 New Zealand Patent Specification No. 196,037 further claims compositions for sweetening edible materials which comprises a sweetening amount of a mixture of a compound of formula (I) and ^S. -oweetoniflg edible. matogials w-hioh cQmpgig.es—a- cwcatoning •siTinnrufc—©£—a- mixtura—©5—a- compound——f ^rmii 1b (T )—and' saccharin or a physiologically acceptable salt thereof.

Especially preferred such mixtures are- those wherein in said compound of formula (I), Ra is methyl and R is dicycl opropyl carbinyl', 2 , 2 , 4 ,4-tetramethyl-thietan-3-yl or 2,2,4,4-tetramethyl-l,1-dioxothietan-3-yl. Most particularly preferred are mixtures of L-aspartyl-D-alanine N-(dicyclopropylcarbinyl)amide and said saccharin, especially those wherein said compound and said saccharin are present in a weight ratio of fran 1:1 to 1:9.

By physiologically acceptable salts of saccharin is meant the salts of saccharin with physiologically acceptable cations such as e.g., the sodium, potassium, calcium or ammonium salts. 3y physiologically acceptable cationic salts of the compounds of the invention is meant the salts formed by neutralization of the free carboxylic acid group of the compounds of formula (I) by bases of physiologically acceptable metals, ammonia and amines. Examples of such metals are sodium, potassium, calcium and magnesium. Examples of such amines are N-methyl-glucamine and ethanolamine.

By the term physiologically acceptable acid addition salts is meant those salts formed between the free amino group of the compound of formula (I) and a physiologically acceptable acid. Examples of such acids are acetic, benzoic, hydrobromic, hydrochloric, citric, fumaric, gluconic, lactic, maleic, malic, nitric, phosphoric, saccharic, succinic and tartaric acids. mil. 203176 Novel intermediates claimed in New Zealand Patent Specification No.X0%t~}f , useful in the preparation of the foregoing novel compounds, r.Th-i »-h i nf9rT1ia^| -j n nr A J P & S *2o.fo"&J ' amines of the formulae below: R^NH^ where R*3 is d-ethyl-t-butylcarbinyl, cyclopropyl-t-butylcarbinyl or cyclopentyl-t-butvl-carbinyl; ' R4 NH2V(CH2) R,Xllr m. where is 1, 2 or 3 and when is 1: R^-Rg are each methyl, when m^ is 2: R^ is methyl, ethyl or isopropyl and R^-Rg are each hydrogen, and when m-j is 3: R-. is t-butyl and a.^e each hydrogen; CH. iCH2»nXx <CH2>pV^ J3 where when n^ is zero, and p^ is 1, X^ is 0, S or S02 and when n^ and p^ are each zero, X^ is S, SC>2 or C=0. j p £ j The present invention relates to further valuable newel.rwvuU0^)6S ' use^u^- -*-n preparation of 'the—invention t/VV{ compounds^ are the D-amino acid amides of the formula RaCHC0NHRC nh2 where Ra is as previously defined and Rc is a member selected from the group consisting, of fenchyl, diiso-propylcarbinyl, d-methyl-t-butylcarbinyl, d-ethyl-t-butylcarbinyl, di-t-butylcarbinyl, cyclopropyl-t-butylcarbinyl, cyclopentyl-t-butylcarbinvl, dicyclo-propylcarbinyl, 2 03176 where is 1, 2 or 3 and when m1 is 1: R"^, , R"^ and R^ are each methyl, when m is 2: R -is methyl, ethyl or isopropyl and 40 50 , 60 , , 30 j R , R and R are each hydrogen or R and R"^ are each methyl and R^ and R^ are each hydrogen, and when mt is 3: (a) R"^ is isopropyl or t-butyl, R^ , R"^ and R^^ are each hydrogen, (b) R"^ is ethyl, R"^ is methyl, R^ and R^ are each hydrogen, or (c) R"^ and R^ are each methyl and R~^ and R^ are each hydrogen or methyl, and ,41 =41 - _61 where when n2 and p2 are eacn zero: R ana R are each methyl and X_ is S, SO-, C=0 or CHOH, 41 61 when n^ is zero and p7 is 1: R and R are each methyl and X_ is O, S, or SO~, and 41 61" when n2 is 1 and p2 is 1: R and R . are each hydrogen and X2 is S or SC>2. r 2 03176 The suffix "carbinyl" as used herein denotes the moiety -CH-. Thus, for example, diisopropylcarbinyl is the-group (i-C^H^)^-CH- and dicyclopropylcarbinyl- amine is ( A>.

,CHNH, The incfeant dipeptide amides are conveniently manufactured by methods suitable for coupling of amino acids. A preferred method for preparing the dipeptide amides bf formula (I) is outlined below.

NHQ Ra .. , , / , , , (1) condense L- / \ + D-NHoCHC00R ~r:— ^ COOR10 COOH or carboxyl activated derivative (2) H20 /NHQ Ra ^ ^HQ Ra \ 1 RNH.

COOR10 COHN/^^^COOH - ^.COOR10 COHN/' \C0NHR (ID / (HI) deprotect *R(0 .(I) ^5. is corboxyl-proTetfwj ^rwP - In the above L-aspartic acid derivatives Q is one of the well known amino-protecting groups which can be selectively removed such as those described by Boissonnas, Advances in Organic Chem. , 3_, 159-190 (1963). Particularly preferred amino-protecting groups are benzyloxy-carbonyl and tert-butyloxycarbonyl. R10 is preferably an alkyl group having from one to four carbon atcms or benzyl. T.he D-alanine, D-2-aminobutyric acid, D-valine or D-norvaline employed may be in the form of the free amino acid wherein R11 is hydrogen, but is 2 031 76 preferably a carboxyl-protected derivative wherein R11 may be the residue of an ester group such as methyl or ethyl, but is preferably a silyl group such as trialky.l silyl, having frcm three to twelve carbon 5 atcms. An especially preferred such group is trimethylsilyl for reasons of economy and efficiency.

In the first step of the above reaction sequence the diprotected L-aspartic acid is condensed with the appropriate D-amino acid or a carboxy-protected 10 derivative to provide the diprotected dipeptide of formula (II). While this step may be carried cut with the diprotected aspartic acid in the presence of condensing agents such as, for example, dicyclohexyl-carbodiimide, it is preferred to employ an alpha-15 carboxyl activated derivative of the diprotected aspartic acid. Preferred such carboxyl activated derivatives are the chloride, bromide, anhydride or mixed anhydride. Especially preferred for reasons of efficiency are the mixed anhydrides of the above 20 diprotected-L-aspartic acids with esters of chlorocarbonic acid, particularly the alkyl esters wherein . said alkyl has from one to four carbon atoms. Most preferred mixed anhydrides are those prepared from the methyl and ethyl esters of chlorocarbonic acid for reasons of 25 economy.

In a particularly preferred method for preparing the compounds of formula (I), beta-benzyl-N-benzyloxy-carbonyl-L-aspartic acid is reacted with ethyl chlorc-carbonate to form the corresponding mixed anhydride by 30 methods known in the art. In a separate vessel the D-amino acid, RaCH(NH^)COOH, which is obtained frcm commercial sources or by resolution of the racemic amino acid by known methods [see e.g. Yamada et al., J. Org. Chem., 38 , 4408 (1973)], is converted to the 35 trimethylsilyl ester by contacting the amino acid with ( 2 031 76 an equimolar amount of trimethyl silyl chloride in the presence of a reaction inert organic solvent. Suitable solvents for this purpose are, for example, pyridine, dimethylforrnamide or dimethylacetamide; especially 5 preferred is dimethylforrnamide.

In a typical reaction according to this method, ^ the D-amino acid e.g., D-alanine,!y dissolved in dimethyl-f orrnamide and an equimolar amount of trimethyl chl oro-silane is added at roan temperature. In a separate flask beta-benzyl N-benzyloxycarbonyl-L-aspartic acid and a molar excess of an acid binding agent, preferably in JxT triethylamine, are dissolved^a mixture of dimethyl- forrnamide and tetrahydrofuran and an equimolar amount of ethylchlorocarbonate is added at room temperature 15 or below, preferably at about -25 to 25°C. and especially at about -10 to 0°C. to form the mixed anhydride. To this is added the solution of e.g., D-alanine trimethyl-silyl ester, preferably at a temperature within the same range. Reaction is ordinarly complete within one 2 0 to two hours after which the reaction mixture is poured into water or aqueous acid, for example hydrochloric acid, and the product of formula (II) extracted with a water immiscible solvent, typically chloroform, methylene chloride or ethyl ether and isolated by 25 standard methods. The diblocked dipeptide (II) is ordinarily of sufficient purity for use in the next step, but may be further purified if desired, for example by column chromatography.

In the second step of this method the diblocked 30 dipeptide (II) is reacted with an equimolar amount of primary amine of formula RNH^ to provide the corresponding diblocked dipeptide amide intermediate of formula (III) wherein Ra, R, R^° and Q are as previously defined. r 2 0 3 t 7 6 lF!',a8> 5 \ As in the first step, the carboxylic acid form of the reactant (II) can be successfully employed by use of condensing agents, for example dicyc1ohexjlc a rb cd i im id e to provide the intermediates of formula^(-55*) . ■ However, it is preferred to convert the compound of formula (II) to a carboxyl activated derivative, for example the chloride, bromide or mixed anhydride, the latter being preferred. Thus, employing the particularly preferred compound of formula (II) wherein R10 is benzyl and. Q is benzyloxycarbonvl, the mixed anhydride is prepared. As above, the preferred anhydrides are those obtained frcm esters of chlorocarbonic acid and the methyl or ethyl esters thereof are particularly preferred. The mixed anhydrides of compound (II) are prepared employing reactants and conditions described above for the first step of this sequence. In a typical reaction the compound of formula (II) and triethylamine in approximately equimolar amounts are combined in a reaction inert organic solvent, for example tetrahydrofuran, the mixture cooled to about-10°C. and ethylchlorocarbonate added to obtain the mixed anhydride. To this is then added an equimolar amount of the amine of formula or a solution thereof, for example in the same reaction inert solvent and at a temperature in the range of from about -5 0 to 25°C. and preferably at frcm -35 to -5°C. After the addition of the amine is complete, the reaction mixture is allowed to warm to about room temperature and maintained at this temperature until reaction is substantially ccmplete, ordinarily frcm about 1 to 20 hours. The desired intermediate of nr formula^;©®-) is then isolated and purified, if desired, by the same methods described above for compound (II). r iA7v 2 031 76 -17- - In the final step of this method, the carboxyl ■ -- protecting group, R10 and amino protecting group, Q, are removed to provide the desired sweeteners of formula (I).

The method selected for removal of protecting groups from the dipeptide amide of formula (III) will vary depending on a number of factors which will be apparent to those of skill in the art. Two important factors for such selection are the nature of the 10 protecting groups R 0 and Q, and the nature of the amide substituent, R. For example, when R10 and Q are, respectively, the especially preferred groups benzyl and benzyloxycarbonyl and R does not contain sulfur, a preferred methcd for removing said protect-15 ing groups is, ordinarily, by hyarogenolysis. However, when R10 is benzyl or alkyl as defined above and Q is tert-butyloxycarbonyl and R has any of the values above, it is ordinarly preferred to remove the protecting groups by hydrolysis. A combination of hydrolysis 20 and hydrogenolysis is preferred in those cases wherein R10 is alkyl, Q is benzyloxycarbonyl and R does not contain sulfur.

When hydrogenolysis is selected for removal of protecting groups from the intermediate of formula (III) 25 it is preferred to carry cut the reaction in the presence of a catalytic amount of a noble metal catalyst, palladium being especially preferred, and in the presence of a reaction inert solvent. Examples of such solvents include the lower alkanols, such as 30 methanol, ethanol, isopropanol and n-butanol; ethers, such as tetrahydrofuran, ethyl ether, 1,2-dimethoxy-ethane and diethyleneglycol dimethyl ether; esters such as ethyl acetate, methyl propionate and dimethyl succinate; and dimethylf orrnamide.Particularly preferred such 35 solvents are methanol and ethanol for reasons- of 7b&- 4~erirf s lower a ikano/ "as ws ecf ftenew ■- ccxTforvrny /ro^? / ( 2 03 '1 7 6 4 econoray and efficiency. While the hydrcgenolysis may be carried out successfully at higher pressures and temperatures, use of pressures of from about 1-10 atmospheres and room temperature are preferred for 5 reasons of economy and convenience. At the preferred temperature and pressure the reaction is ordinarily complete in from about 30 minutes to about six hours, after which the catalyst is removed, typically by filtration, the solvent evaporated and the resulting 10 product purified, if desired, by standard methods, for example by recrystallization or column chromatography.

When hydrolysis is selected for removal of one or both of protecting groups and Q- any of the well known methods for alkaline hydrolysis or acid hydrolysis 15 of esters and the like may be employed with some success. However, when blocking groups R10 are to be removed by hydrolysis alkaline hydrolysis is preferred, ana especially preferred conditions are use of at least an equivalent amount of a strong base, for example, sodium hydroxide or potassium hydroxide in Cc,-c^ the presence of water and a lowersalkanol, particularly methanol or ethanol, at or about room temperature.

Under these preferred conditions hydrolytic removal of the R10 group is ordinarily complete in a few hours or less.

When the amino protecting group -Q is tert-butyloxycarbonyl it is preferred to use acid hydrolysis for its removal. Especially preferred is dilute aqueous hydrochloric acid in the presence of methanol 30 or ethanol and heating the mixture at reflux. Under these conditions hydrolysis is ordinarily complete in a few hours or less.

Isolation of the products of formula (I) after removal of protecting groups by any of the above 35 hydrolysis methods employs standard procedures known r 2 03ri 76 in the art. For example, after acid hydrolysis the reaction mixture is evaporated to remove solvent, the aqueous residue washed with a water immiscible non- polar solvent, for example, ethyl ether or chloroform after which the aqueous layer is made alkaline and the product extracted with a water-immiscible 'solvent such as, for example, ethyl acetate and the product obtained by evaporation of solvent. If desired, the product can be further purified, for example, by recrystalliza- tion or column chromatography. When alkaline hydrolysis to remove a protecting group R10 is followed by hydrogenolysis to remove the amino protecting group Q, the reaction mixture frcm the alkaline hydrolysis is preferably neutralized by addition of acid, for example, hydrochloric acid, and the neutralized reaction mixture subjected to hydrcgenolysis as described above.

P. & 5. A second preferred methcd for manufacture of the -83 f/ uictant compounds of formula (I) is shown below. „a „a R R 1 T D-QNHCHCOOH + RNH_ QNHCHCONHR ^ or carboxyl activated (IV] derivativ e NEQ l- deprotect ra coor"" Cook ^OC > NH2CHCONHR >(111)—*(I) (V) a f Q R , R, R- and Q are as defined above.

The amino protected D-amino acid or its carboxyl activated derivative is reacted with an equimolar amount of amine RNH^ employing methods and conditions 25 described above for the preparation of intermediates (II) and (III) to obtain an amino protected D-amino acid amide of formula (IV). The protecting group Q is removed by hydrogenolysis or hydrolysis as described r 2 031 7 6 c\ c i d above and the resulting free amino^amide (V) is condensed with a diblocked L-aspartic acid derivative or a carboxyl activated derivative thereof, as described above for the preparation of intermediates of formula (II), 5 to provide the diblocked dipeptide amide of formula (III) frcm which the desired sweetener of formula (I) is obtained as previously described.

.. J. P. & S. In a modification of this method an intermediate X of formula (IV) wherein R contains a cyclic or lacyolio sulfide moiety (-S-) may be oxidized to the corresponding sulfoxide or sulfone prior to its.conversion to intermediate (V) and subsequent reactions as described above, to provide compounds of formula (I) wherein R is a sulfoxide or sulfone.

In a third preferred methcd for preparing the compounds of the invention the D-amino acid amide of formula (V), described above, is reacted with L-aspartic acid N-thiccarboxyanhydride to provide directly the compounds of formula (I). In carrying 20 out this methcd the intermediate (V) in a suitable solvent is contacted with an equimolar amount of L-aspartic acid N-thiocarboxyanhydride at a mildly alkaline pH at a temperature of from about -25 to 10°C. to provide the compound of formula (I). The 25 alkaline pH for this reaction is provided by means of a strong base, for example, sodium hydroxide or potassium carbonate. Suitable solvents for this reaction are those that dissolve at least a portion of the reactants under the reaction conditions employed without reacting 3 0 with either reactant to an appreciable extent and allow the products formed in the reaction to be isolated with relative ease. Examples of such solvents for this reaction are water, tetrahydrofuran, 1,2-dimethoxv-ethane, diethvleneglycol dimethylether, dimethyl sulfoxide, c 2 03 T 7 6 dimethylformamide and combinations thereof; preferred solvents are water, and its mixtures with tetrahydrofuran, A preferred alkaline pH range for this reaction is frcm about 8 to 10 and a pH of about 9 is especially 5 preferred. An especially preferred temperature is in •i the range of about -10 to 0°C.

Under the preferred conditions mentioned above the reaction is ordinarily complete in one to two X hours. The product of formula (I)vthen isolated by standard methods, for example, the pH of the reaction mixture is adjusted to the isoelectric pH of the product, ordinarily about pH 5.0-5.6, to precipitate the product of formula (I), the bulk of the solvent removed by evaporation or filtration and the crude 15 material slurried with an organic solvent, for example, methanol, ethanol, ethyl ether, ethyl acetate or mixtures thereof. The product of formula (I) is then isolated, by filtration for example. It may be further ^ purified, if desired, by, e.g., recrystallization or ' 20 COlUmn ChranatCgraphy- Arm«J« (£) The sweetness potency of the ingtanfe compounds^ was determined by comparison of their gustatory sweetnesses with sucrose. Aqueous solutions of the compound of formula (I) diluted to a suitable range of 25 concentrations were compared with a sucrose standard by an expert taste panel. Comparisons were generally made with aqueous sucrose solutions of 7-9%, i.e., 7-9 g. per 100 ml. Higher sucrose concentrations have a distinctive mouthfeel which may influence results 30 and lower sucrose concentration are not indicative of normal use situations. If, for example a 0.014% solution of the compound of formula (I) is judged to be equally as sweet as a 7% sucrose solution, then the sweetness potency of that compound is 7/0.014 = 500 x 35 sucrose. All of the sweetness potencv values stated f 2 03176 S3 -Por-vwuU Cl) herein for the compounds of .the invantion were determined by this method. At threshold concentrations (i.e., & S. the lowest concentration at which sweetness is first noticed, which for sucrose is ordinarily at concentrations in the range of 2-3%), the potency of a sweetener, , , -foo**!# £0 descri^eJ aboye .. such as the compounds or fcho- invention, is generally twice that observed by comparison of its gustatory sweetness with 7-9% solutions of sucrose.

The requisite amines of formula RNH^ wherein R is 10 as previously defined are either commercially available or can be obtained frcm readily available precursors. For example, the 2-alkylcyclohexylamines and 2,6-aialkvlcyclohexylamines can be obtained by catalytic hydrogenation of the corresponding alkyl substituted 15 anilines. Many of the amines are obtained by reductive amination of the corresponding ketone using a variety of conditions known in the art. For example, reductive amination by the well known Leuckhart reaction employing formic acid and formamide as reducing agents, see for 20 example, the review in Organic Reactions, Wiley and Sons, New York, Vol. 5, p. 301, 1949, may be employed. Alternatively, the appropriate ketone can be reductively aminated employing scdium cyanoborohydride and ammonium acetate see for example, J_. Amer. Chem. Soc. , 9_3 , 2897 25 (1971), or by means of ethanolic ammonia in the presence of a hydrogenation catalyst such as Raney nickel, platinum or palladium, see, for example, Organic Reactions, £, 174 (1948). Many of the amines of formula RNH^ are obtained frcm the corresponding 30 ketones by formation of an intermediate oxime formed by reacting the ketone T.*ith hvdroxylamine or its salts under conditions well known in the art. The oxime intermediate is then reduced by catalytic hydrogenation or by means of scdium in the presence of a lower 35 alkanol at elevated temperature. A particularly preferred method, especially useful for reducing 2 0317 6 oximes of sulfur-containing ketones, employs reduction of the oxime in ethanol and a molar excess of scdium at the reflux temperature of the mixture- , The requisite ketone precursors of the amines RNH^ are either commercially available, known in the art or prepared by known methods. For example, the ketones of formula (VI) and (VII) (CH ) 0=\^C"2 } n^X V<cH2>p/ R^R5 (VI) (VII) where R^, R", R^, R^, X, m, n and p are as defined 10 above, except those of formula (VII) wherein X is C=0, may be obtained by alkylaticn of the corresponding compounds wherein R^, R^, R^ and R^ are each hydrogen to provide compounds of the above formula wherein frcm one to all of R"^, R^, R^, R^ are alkyl as defined 15 above. The alkylation is carried out, for example, employing alkylating agents such as the appropriate alkyl halide or alkyl sulfate under neutral or alkaline conditions provided by strong bases, for example, scdium hydride or scdium amide. Using the same methcd 20 compounds of the formula (VI) and (VII) wherein only 1, 2 or 3 of the substituents alpha to the keto group are alkyl'can be converted to compounds of the same formula wherein from two to four of R^, R^, R3, R^ are alkyl. Gem-dialkyl compounds of formula (VI) and 25 (VII) wherein either R and R or R and R are said alkyl can be obtained from the appropriate monoalkyl compound by blocking the unsubstituted alpha-position prior to alkylation and subsequent removal of the 203176 blcoking group. For example, 2,2-dimethylcyclohexanone may be obtained by condensation of 2-methylcyclohexanone with ethylformate in the presence of sodium methoxide and the resulting intermediate alkylated as outlined below. + hco2C2H5 NaOCH. ch3i NaNH, ONa H2O, OH- Ketones of formula (V±) or (VII) wherein one or both of R"^ and R^ are propyl or butyl may be obtained by condensation of the corresponding alpna-unsubstituted compound with the appropriate aldehyde or ketone under alkaline conditions to an intermediate alpha-, or -d;- alpha,alpha'-alkylidene ketone which can then be hydrogenated to provide the desired ketone. 15 The requisite cyclobutanones are obtained by methods described by Conia _et _al. , Bull. See. chim. France, 726 (1963) and Conia, Ind. chim. Beige, 31, 981 (1966).

An alternative methcd for preparing the ketones 20 of formula (VI) and (VII) involves a cyclization of an acyclic precursor. For example, by means of the well known Dieckmann cyclization of dicarboxylate esters and subsequent hydrolysis and decarboxylation; see e.g., Modern Synthetic Reactions, W. A. Benjamin, 25 Menlo Park, Cal., 1972, p. 740. The alpha-keto esters produced, especially those with no other alpha-substituent, can also be alkylated prior to hydrolysis and decarboxylation, if desired. This reaction can 2 03176 also be used^to provide ketones (VI) and (VII) which are unsubstituted at the carbons adjacent to the carbonyl group which can be alkylated as described above. , For preparation of diketones of formula (VII) wherein X is C=0 the keto group of acyclic keto-dicarboxylate ester precursor is converted to a ketal or thioketal, e.g., dimethyl ketal, diethylthio ketal, ethylenedioxy ketal or ethylenedithio ketal, prior to Dieckmann cyclization. Ester group hydrolysis and decarboxylation affords a keto-ketal which may be converted to the corresponding amino ketal, by methods described above, followed by hydrolysis of the ketal group by methods well known in the art. The resulting 15 amino ketone can be hydrcgenated, if desired, to the corresponding hyaroxyamine (X = CHOH) by known methods, e.g. by reduction with scdium borohvaride. 2,2,4,4-Tetraalkyl-3-hydroxycyclobutylamines are prepared from the corresponding 1,3-diones by the methcd of U.S. 3,125,569.

The amines of formula where X is CHOH and R^-R^, n and p are as defined above, or N-protected derivatives thereof e.g., N-25 benzyloxycarbonyl derivatives, may be oxidized, e.g. by chromium trioxide, to the corresponding compounds wherein X is C=0. Alternatively, the hydroxyamine may be reacted first with a carboxyl activated derivative of an N-protected D-amino acid, D-QNHCH(Ra)COOH, where 30 q and Ra are as previously defined, and the resulting r 2 031 intermediate of formula (IV) wherein R is said hydroxy-containing group, oxidized, e.g., with chromium trioxide, to provide the corresponding ketone. The resulting ketone of formula (IV) is then converted to the desired product of formula (I) where R is a keto-containing group as desired above.

Certain of the ketones of formula (VII) are also obtained from acyclic precursors derived from ketones of the formula (VIII) wherein R, R3 and R^ are as previously defined. For example four-membered ketones of formula (VII) where X is 0 or S are obtained by brcmination of (VIII) with two moles of bromine and the resulting alpha,alpha'-dibromo compound cyclized with, e.g., scdium hydroxide to provide an oxetanone or hydrogen sulfide to provide a thietanone. The corresponding five-membered ring ketones (VII) are obtained when (VIII) is first reacted with formaldehyde to provide an intermediate alpha-hydroxymethyl compound which is then brcminated at the alpha'-position and cyclized with scdium hydroxide or hydrogen sulfide to provide the' corresponding compounds of formula (VII) wherein X is O or S, respectively.

Certain of the tetrahyaropyran-4-ones and tetra-hvdrothiapyran-4-ones of formula (VII) are obtained by adding the elements of water or hydrogen sulfide to the appropriately substituted divinvlketcne.

O — (VIII) 2 C3 f76 Ketone intermediates of formula (IX) which may be converted to amines via the oxime are obtained by methods outlined below where R as defined above. 17 ,18 R19 and R20 are cooc2h5 co2c2h5 oh (X) (XI) (IX) The appropriately substituted acetoacetic ester (X) is condensed with formaldehyde, e.g. under alkaline conditions, and the resulting hydroxmethylated intermediate (XI) is then cyclized, for example by heating 10 in the presence ox a mild acid or base with removal of ethanol as it forms.

Brcmination of acetoacetic esters of formula (X) and subsequent treatment of the product with, e.g. sodium hydroxide, provides ketones of formula (XII) 15 which are converted to the corresponding amine as described above. 0 R20 ,20 R 19' / R17 18 Br co2c2h5 R R 17 O (XII) Alternatively, the ketolactones (XII) can be prepared by the method described in Zeit. Chemie, 13, 11 (1973); Chem, Abstr., 78, 135596e (1973), by reaction of the appropriate cyclobutan-1,3-dione with hydrogen peroxide. r 2 0 3176 The dibromo derivative of (VIII), described above, can also be treated with alkali hydroxides, e.g. scdium hydroxide under mild conditions, to form the corresponding 1,3-dihydroxykstone which is converted to the corresponding 1,3-dioxane~2,5-dione of formula (XIII) by reaction with phosgene.

VIII R >• i R Br Br O R17 OH" R20 ,18 -v OH 17 C0C1? R20 1 8 ^1 OH O ,17 O 0 Y R (XIII) The 5-cximino intermediate of (XIII) upon treatment with scdium in ethanol as described above, provides the 10 corresponding 5-amino compound.

Treatment of a monobromo derivative of ketones of formula (VIII) with, e.g. ethyl malonate, and subsequent hydrolysis, decarboxylation and esterification of resulting product affords intermediates of formula 15 (XIV) which serve as precursors of the ketones (XV) as shown below, for example. t. n p. & s.

ZOAO-Z3 Q ,20 R 19^ R 17 .18- "C0_C„Hc 2 z 5 .20 •€0^0^11 r- Br ^17 V n, ^2° RlBJ*°h+Rlg/ (XIV) (XV) The ketolactones (XV) are then converted to the corresponding 4-amino compound, e.g. by reduction of the oxime, as described above. r 2 031 7 6 The 1,3-dibr-onvGk^e-ttJrTe ' cfer ivativ es of (VIIIp, described above, also can be converted to,-t<H§ corresponding 1,3-dimercapt oketone by reactijprfwith at least two moles of sodium hvdrosulfider^flfreating the dimereaptoketone with reagentsy^uch as iodine, hydrogen peroxide or hypochlorous under disulfide forming conditions, well knownJfn the art provides the ketones of formu-1'a XVI whic^'are converted to amines by reduction of--'the oxime emoMiiying, e.g., scdium in ethanol.

—(-XVI- Amines of formula (XVII) are provided directly, for example, by the methcd of Nagase _et al . , Chem. Pharm. Bull. 17, 39 8 (19 69) as shown below. ,12, R 13 ,12 ho ch2° * r13 NaCN ho ch2oh NH^Cl =12 nh-ch20h h_0, h X (XVII) Use of ethylene oxide in place of formaldehyde in the first step of the above reaction sequence affords i&frc&iy4ro the corresponding 3 - amino-2-7py rones, ? 0 nh_ 1 ? O R r 2 03 . _ ' -..4 -3 0- Lactains corresponding to the above lactone intermediates or those of formula (IX), (XII),. (XV) or (XVII), are obtained by reaction of the appropriate lactone with ammonia; for example, the above lactone is contacted with an excess of anhydrous ammonia in ethanol and the mixture allowed to stir overnight at ambient temperature to provide compounds of the formula Alternatively, certain lactam intermediates are provided by the following reaction sequence. (x) CH?° (C6H5CH2)2NH C02C2H5 N(CH2C6H5)2 H, Pd/C r .0 ,19/ 17 18 N.

H C02C2H5 a o The- resulting ketones are then converted to the requisite amines by methods described above. 15 The isomeric ketolactams are obtained by the following reaction sequence: <# r 2 C 31C7 6 \ &5. 44.10-81 m<. ,20 .197 0 171*Br2 ^182.(C6HsCH2)2NH R19l C02C2H5 3.H2, Pd/C c02C2^5 X The corresponding 5-membered lactams are also obtained- by the method—ef U . S . ' 3 ,125-, 5-69-:- _ prepared by fht follevsinj method -from 1he $f<3rt/ny materials providec|jo (J..S NOH PC1"5 or H2S04, > 18 polyphosphoric R19^ acid Cyclic or open chain alpha-hydroxvketones or alpha,alpha'-dihvdroxvketones of the formula J. P. & s. tO r14 „15 * * OV () 2> or (A/ 2^VCl9 fit \s OH, and R16 OH R where R^-R20/ m£ -A and. B-n are as previously defined» ^ ^ H.OHoy 1 Khefhlf/.-r^ are prepared by bromination with one or two moles of J bromine and treatment of the brcmo or dibromo intermediate with an hydroxylic base, e.g., scdium hydroxide or potassium hydroxide as described above. The reaction ? . £•£. sequence is exemplified as follows: f 2 0'3: ^7 &: CH 1. Br. 2. NaOH, ethanol 1. 2. 2 Br, NaOH, ethanol > CH. HO' CH-OH Dicycloalkylketones (XVIII) and alkylcycloalkyl-ketones (XIX) are prepared by the reaction of the appropriate acid haliae and Grignard reagent employing conditions and reagents well known in the art, e.g., as shown below.

C0C1 'CEoK 2 q C0C1 -( CH n ) rp 2 m MgCl •(CH2>m MgCl 0 -(CH- ) 2 rn -(CH2)a (XVIII) ,7 R -> o ^=C bt ■ (CH—) 2, m (XIX) Amines of formula RNH^ where R is as previously defined are also obtained by the well known Hofmann reaction by conversion of the appropriate carboxamide with alkali metal hypohalite. This procedure is especially useful for the preparation of cyclopropyl-amines. The corresponding cyclopropyl amides are r 2 0 31 7 6 obtained and converted to amines, e.g.-as shown below. 1. NH.

+ N CHC0.CoHr-2 2 2 =) 2. NaOBr NH, > R C0_CoH. 2 2=) The first step of the above sequence to form the cyclopropylcarboxylic acid ester is known in the art, see for example, Mescheryakov et al_. , Chem. Abstr. , 54, 24436 (1960).

The compounds of formula (I) or intermediate amides therefore, wherein R is r3 54 r-r® where X is SO or SO^ are obtained from the corresponding compounds wherein X is S by oxidation employing reagents and conditions known to form sulfoxides and sulfones from sulfides. Alternatively, the appro-15 priate ketone of formula (VII) where X is S or the amine derived from said ketone, as described above, can be oxidized to the sulfoxide or sulfone prior to coupling to form the dipeptide amide of formula (I). Preferred reagents and conditions for such oxidation 20 of sulfides include use of hydrogen peroxide in a solvent, for example, acetic acid or acetone. When equimolar amounts of reactants are employed the product is the sulfoxide, which is readily converted to the r 2 03f7 6 corresponaing sulfone by an - additional mole of peroxide. Other preferred oxidants are potassium permangan-te-or chromic acid, for preparation of the sulfones, and m- ~rh-z >C chl oroperbenzoic acid, 5-he- latter reagent being ^ especially useful for conversion of the above thioketones (VII) to the corresponding sulfoxide employing one mole of this reagent, or the sulfone when two moles of the peracid are employed.

The compounds of formula (I) and the physiologically acceptable salts thereof provide advantages as sweetening agents in view of their high potency, their physical form and stability. They are, ordinarily, crystalline, non-hygroscopic, water soluble solids. They are uniquely characterized by possessing a sweet taste, 15 devoid of undesirable harsh or bitter flavor qualities at ordinary use levels. They can.be usefully employed to impart sweetness to edible materials. The term "edible materials" as used herein signifies all nontoxic substances consumable by humans or other animals, 20 in solid or liquid form. Illustrative of such substances are: foods, including foodstuffs, prepared food items, chewing gum and beverages; focd additives, including flavoring and coloring agents as well as & S. flavor enhancers; and pharmaceutical preparations.

The compounds of tffo*invonuion can be prepared in qj: a variety of forms .suitable for utilization ef- sweetening agents. Typical forms which can be employed are solid forms such as powders, tablets, granules and aragees; and liquid forms such as solutions, suspensions, syrups, emulsions as well as other commonly employed forms particularly suited for combination with edible materials. These forms can consist of the compounds of formula (I) or their physiologically acceptable salts either apart or in association with non-toxic 35 sweetening agent carriers, i.e. non-toxic substances r 203t76 commonly employed in association with sweetening agents. Such suitable carriers include liquids such as water, ethanol, sorbitol, glycerol, citric acid, corn oil, peanut oil, soybean oil, sesame oil, propylene 5 glycol, corn syrup, maple syrup and liquid paraffin, and solids such as lactose, cellulose, starch, dextrin, modified starches, polysaccharides such as polydextrose (see, e.g. U.S. 3,766,165 and U.S. 3,876,794), calcium phosphate (mono-, di- or tri-basic) and calcium sulfate.

• ^ S.

Likewise useful and compatible are compositions containing a compound of t&o liwonjion combined with a known sweetening agent such as, for example, sucrose, saccharin, cyclamate, L-aspartyl-L-phenylalanine methyl ester and the like, useful for sweetening 15 edible materials. Especially useful are the mixtures of compounds of formula (I) and saccharin or a physiologically acceptable salt thereof, e.g., the scdium, potassium, calcium or ammonium salt of saccharin. In said mixtures with saccharin the compounds of formula (I) 20 reduce or completely mask the well known, undesirable bitter aftertaste of the saccharin.

Particularly useful such sweetener compositions are those containing saccharin in admixture with compounds of formula (I) which are at least 400 times 25 as sweet as sucrose, especially those wherein Ra is methyl and R is dicyclopropylcarbinyl, 2,2,4,4-tetramethyl thiet an- 3 -yl or 2,2,4,4-tetramethyl-l,1-aioxo-thietan-3-vl. Most particularly preferred are such mixtures of saccharin and L-aspartyl-D-alanine N-30 (dicyclopropylcarbinyl)amide, especially such mixtures which contain the latter compound of formula (I) and saccharin in a weight ratio in the range of from 1:1 to 1:9. These mixtures are not only pleasantly sweet tasting and appreciably devoid of bitter aftertaste, 35 they are, unexpectedly, significantly sweeter _than c 2 C 3 calculated by summation of sweetness of the individual components of the mixture. That is,, they exhibit a synergist effect, being up to 33% sweeter than calculated. In mixtures of saccharin or its salts and L-aspartyl-D-alanine N-(dicyclopropylcarbinyl)amide in ratios outside the above range the synergist effect is consideraly reduced.

The invention also provides sweetened edible compositions comprising an edible material and a sweetening amount of a compound of formula (I )°r a physiologically acceptable salt thereof alone or in combination with a non-toxic carrier or known sweetening agent. Examples of specific edible materials which provide such sweetened edible compositions include: fruits, vegetables, juices, meat products such as ham, bacon and sausage; egg products, fruit concentrates, gelatins and gelatin-like products such as jams, jellies, preserves, etc.; milk products such as ice cream, sour cream and sherbet; icings, syrups including molasses; corn, wheat, rye, soybean, oat, rice and barley products such as bread, cereals, pasta, cake and cake mixes; fish, cheese and cheese products, nut meats and nut products, beverages such as coffee, tea, carbonated and non-carbonated soft drinks, beers, wines and other liquors; confections such as candy and fruit flavored drops, condiments such as herbs, spices and seasonings, flavor enhancers such a ~ ~ glutamate and chewing gum. The irnafean-fe sweeteners^are also of use in- prepared packaged products such as dietetic sweeteners, liquid sweeteners, granulated flavor mixes which upon reconstitution with water provides non-carbonated drinks, instant pudding mixes, instant coffee and tea, coffee whiteners, malted milk mixes, pet foods, livestock feed,_ tobacco r 2 03^1 7 6 and consumable toiletries such as mouth washes and toothpaste as well as proprietary and non-proprietary pharmaceutical preparations and other products of the focd, pharmaceutical and sundry industries.

Especial-ly preferred sweetened edible compositions are carbonated beverages containing one or. more of the -Qormu.\» (I) l-ngrant , sweeteners^ The invention is further illustrated by the following examples. ,203 t 7 6 EXAMPLE 1 Beta-Benzyl N-benzyloxycarbony1-L-Aspartyl-D-alanine' C HcCH-OCCHnCHCONHCHCOOH & 5 Z „ 1, , 0 NH CH? I ^ Cbz ^ D-Alanine (5.0 g. , 56.1 mmole) was dissolved in 100 ml. of N,N-dimethyIforrnamide (DMF) and to the solution was added dropwise at room temperature 6.7 4 g. (62.4 mmole) of trimethylchlorosilane. In a separate flask was placed beta-benzyl N-benzyloxycarbonyl-L-aspartate (18.0 g., 50.4 mmole), triethylamine (12.35 g., 122 mmole) and 110 ml. each of DMF and tetrahydrofuran and the resulting solution cooled to -15°C. To the solution was added ethyl chloroformate (5.95 g., 5.1 mmole) and the resulting mixture stirred for ten 15 minutes at -10°C. To this was then added dropwise the DMF solution of silylated D-alanine prepared above while maintaining the mixture at -5 to -10°C. The mixture was stirred at -5°C. for one hour, 0.2 N hydrochloric acid added until the mixture was acidic 20 and the resulting mixture extracted with chloroform.

The chloroform extracts were combined and washed several times with dilute hydrochloric acid to remove remaining DMF. The solvent was evaporated in vacuo to provide the title compound as a colorless oil. The 25 oil was triturated with ethyl ether (100 ml.) to obtain colorless crystals after three hours. The slurry was filtered, washed with ether, then hexane and air dried to afford 9.18 g., M.P. 158-159°C. Upon work-up of the mother liquor an additional 4.45 g. of 30 product was obtained, M.P. 157-158°C. (Total yield, 6 3%). Thin-layer chromatography (silica gel plates) employing a 9:9:2 (by volume) ethyl acetate/hexane/acetic acid solvent system showed product and a trace amount of beta-benzyl N-benzyloxycarbonyl-L-aspartate. 203176 EXAMPLE ' 2 Beta-Methvl-N-benzyloxycarbonyl- L-aspartyl-D-alanine -A suspension of 69 g. (0.78 mole) D-alanine in 5 200 ml. of DMF was cooled to 10°C., 92 g. (0.85 mole) of trimethylchlorosilane was added in portions and the resulting mixture stirred at 25°C. for one hour.

In a separate flask was placed a solution of 158 g. (0.86 mole) of beta-methyl-L aspartic acid 10 hydrochloride in one liter of water. To this was added 3 4.5 g. (0.86 mole) of scdium hydroxide followed by 80 g. of scdium bicarbonate and the resulting mixture stirred vigorously. After cooling to 5-10°C. 161 g. (0.94 mole) of benzyloxycarbonyl chloride was 15 added in portions and stirring continued for two hours at this temperature. The reaction mixture was washed with 100 ml. of ethyl acetate, acidified by addition of 80 ml. of•concentrated hydrochloric acid and extracted with ethyl acetate (2 x 450 ml.). The 20 extract (9 00 ml.) was found to contain 218 g. (0.78 mole, 9 0% yield) of beta-methyl-N-benzyloxycarbonyl-L-aspartate. It was used in the next step without further purification.

The ethyl acetate extract was cooled to -20°C., 25 165 g. (1.63 mole) of triethylamine and 84 g. (0.78 mole) ethyl chloroformate were added. The solution was stirred at -15° to -20°C. for 30 minutes then treated quickly with the DMF solution of D-alanine trimethyl-silylester prepared above and the resulting mixture 30 was allowed to warm to ambient temperature over one hoar with stirring. The reaction mixture was washed with water (3 x 5 00 ml.), the organic layer dried over scdium sulfate and evaporated in vacuo to a 200 ml. volume. Hexane, 400 ml., was added, the mixture 35 granulated at 5°C. and filtered to afford 218 g. (80%) of the title compound as a white powder. ( 203176 Replacement of the D-alanine employed in the procedures of Examples 1 and 2 with DL-alanine, D-2-aminobutyric acid, D-valine, D-norvaline or racemates of the latter four,amino acids similarly provides the 5- corresponding diblocked L-aspartvl-D- (or DL)-amino acid dipeptides of the formula C-H^CH-O—COCH-CHCONHCHCOOH 6 d 2 2, , (or CH30-) NHCbz Ra where Cbz is COOCH7CgH5 and.Ra is CH3, C2H5, (CH3)2CH or CH3CH2CH2.

EXAMPLE 3 L-Aspartyl-D-alanine N-(cis,trans-2,6-dimethylcyclohexyl)amide A. To a solution of 218 g. .(0.62 mole) of beta-methyl-N-benzyl oxycarbony1-L-aspartyl-D-alanine in one 15 liter of ethyl acetate was added 69 g. (0.68 mole) triethylamine, the mixture was cooled to -20°C. and 67 g. (0.62 mole) of ethyl chloroformate was added. The resulting solution was stirred for 30 minutes at -15 to -20°C., then treated with 86 g. (0.68 mole) 20 0f cis,trans-2,6-dimethylcyclohexylamine and stirring continued for 3 0 minutes. After allowing to warm to room temperature the mixture was washed twice with 500 ml. portions of water containing 15 ml. of concentrated hydrochloric acid, twice with 500 ml. of 5% 25 aqueous scdium bicarbonate, then water. The organic layer was dried (Na2SO^), concentrated _in vacuo to about 200 ml. and 400 ml. of hexane was added whereupon beta-methyl-N-benzyloxycarbony1-L-aspartyl-D-alanine N-(cis,trans-2,6-dimethylcyclohexyl)amide precipitated, 30 229 g. (80%), M.P. 213-214°C. r 2 031 76 4 B. The product obtained in Part A, above, 229 g. (0.50 mole) was dissolved in 500 ml. of methanol and a solution of 2 4 g. (0.60 mole) of scdium hydroxide in 5 00 ml. of water was added. The mixture was stirred 5 at 30°C. for one hour, neutralized to about pH 7 with dilute hydrochloric acid and charged into an autoclave. Two grams of 5% palladium/carbon catalyst was added 2 and the mixture hydrogenated at 25°C., 3.5 kg./cm. (50 psi) for one hour. The catalyst was removed by 10 filtration, the filtrate evaporated in vacuo to 200 ml., the concentrate acidified to pH 5.2 with concentrated hydrochloric acid, then granulated at 5°C. for one hour. The resulting precipitate was collected by filtration, the wet cake dissolved in a mixture of 15 200 ml. of water and 50 ml. of concentrated hydrochloric acid, carbon treated, filtered and the filtrate adjusted to pH 5.2 with 50% (w/w) scdium hydroxide solution. After granulation at 5°C., filtering, washing with cold water and drying, 132 g. (85% step 20 yield) of colorless product was obtained, M.P. 216-217°C. The overall yield was 68%.

Sweetness potency: 600 x sucrose.

By employing the appropriate beta-methyl-N-Cbz-L-aspartyl-D (or DL)-amino acid dipeptide in the above 25 procedures the corresponding dipeptide amides of formula (I), wherein R is c,t-2,6-dimethylcvclohexyl and Ra is CH3, C2H5,- "(CH^CH.or CH3CH2CH2, are obtained in like manner. f 1 7 6 EXAMPLE 4 L-Aspartvl-D-alanine N-(2-rnethylcycl ohexyl) amide (mixture of cis,trans-isomers) A. Dnder anhydrous conditions, to a mixture of 1.28 g. (3 mmole) of beta-benzyl N-benzyloxycarbonyl-l-aspartyl-D-alanine, 40 ml. of tetrahydrofuran and 0.29 ml. (3.6 mmole) pyridine cooled to -20°C. was added dropwise 0.29 mi. (3 mmole) of ethyl chloro-. formate. The resulting slurry was stirred at -15°C. 10 for ten minutes then 0.79 ml. (6 mmole) of a mixture of the cis and trans-isomers of 2-methylcyclohexylamine was added dropwise over a few minutes. The reaction mixture was allowed to warm to room temperature, diluted with water and extracted with chloroform. The 15 organic layer was washed with dilute hydrochloric acid, water, scdium bicarbonate solution, water again and finally with saturated aqueous scdium chloride. The washed extract was dried over scdium sulfate and evaporated to dryness to afford a colorless solid. 20 The solid was triturated with ethyl ether, stirred, filtered and dried to yield 1.3 g. (83%) of beta-benzyl N-benzyloxvcarbonvl-L-aspartyl-D-alanine-N-(2-methylcyclohexyl)amine which showed only one spot (R^ 0.65) on TLC (ethyl acetate/hexane/acetic acid 25 10:9:1, by volume).

B. To a solution of the product obtained in Part A, above, 1.05 g. (2 mmole) in 100 ml. of methanol was added 0.5 g. of 5% palladium-on-carbon catalyst and the mixture was "nydrogenated in a Parr shaker at room 2 temperature, 3.5 kg./cm. (50 psi) for 30 minutes, after which uptake of hydrogen ceased. The reaction mixture was filtered, the filtrate evaporated in vacuo to afford 610 rag. of the desired product as an off-white solid which is a mixture of cis- and trans-35 isomers; M.P. 206-209°C.

Sweetness potency: 250 x sucrose. r 2 03176 EXAMPLE 5 L-Aspartvl-D-alanine N-(dicyclopropylcarbinyl)amide: i, r = ch^ , ra = ch3 A. Dicyclopropylcarbinylamine 5 In a 500 ml. round bottom flask was placed 41.7 g. (0.60 mole) hydroxylamine hydrochloride and 80 ml. water. With stirring, 4 4 ml. of 10M scdium hydroxide solution and 4 4.4 g. (0.40 mole) dicyclopropyl ketone were added. The mixture was stirred at reflux for 10 three hours. After cooling, 60 ml. methylene chloride was added and the mixture stirred until all oxime had dissolved. The methylene chloride layer was separated and dried ever anhydrous magnesium sulfate. The solvent was removed by evaporation at reduced pressure 15 and the residue reerystallized from 55 ml. hexane, • yielding 40.0 g. dicyclopropylketoxime, M.P. 69-72°C.

In a. 500 ml., three-necked round bottom flask was placed 18.8 g. (0.15 mole) dicyclopropylketoxime and 150 ml. anhydrous ethanol. With efficient stirring 20 19.2 g. (0.83 mole) scdium spheres was added in portions as rapidly as possible, maintaining reflux throughout the addition. - Following dissolution of the scdium, the reaction was cooled to 6 0°C. and 60 ml. water was added. After cooling, 78 ml. concentrated hydrochloric 25 acid was added dropwise with stirring. Ethanol was distilled at reduced pressure and 50 ml. water added to dissolve salts. The mixture was adjusted to pH 13 with 10 M scdium hydroxide solution and extracted with three 40 ml. portions of methylene chloride. The 30 extracts were ccrabined, dried over anhydrous magnesium sulfate, filtered and evaporated at reduced pressure. The residual amine was distilled at 88-90.°C./95 mm Hg, yielding 11.0 g. of the desired product. c ^176 i B. C^HcCHo0C0CH-CHC0NHCHC0NHCH NHCbz CH3 To a 250 ml. three-necked flask fitted with a stopper, thermometer, drying tube and magnetic stirring bar was added 4.28 g. (0.010 mole) of beta-benzyl-N- benzyloxycarbonyl-L-aspartyl-D-alanine, 75 ml. tetrahydrofuran and 1.53 ml. (0.011 mole) triethylamine. The mixture was cooled to -10°C., 1.05 ml. (0.011 mole) ethyl chloroformate was added, stirred for 20 minutes, -cooled to -35°C. and 1.11 g. (0.010 mole) of dicvclo-10 propylcarbinylamine added. The reaction mixture was allowed to warm slowly to room temperature and stirred overnight. The mixture was poured into 15 0 ml. water, extracted with 250 ml. of ethyl acetate and the organic phase washed with 5% aqueous scdium bicarbonate 15 (2 x 7 5 ml.), 3 M hydrochloric acid (2 x 75 ml.), brine (1 x 100 ml.) and dried over anhydrous magnesium sulfate. The dried extract was evaporated to dryness in vacuo to provide a colorless solid which was recrystallized from 75 ml. of boiling ethyl acetate to 20 obtain 3.78 g. (72%) of diblocked amide, M.P. 164-165°C. Thin-layer chromatography (TLC) on silica gel, eluting with 1:1 ethyl acetate/hexane gave a single spot, 0.4 0 with vanillin spray reagent. An additional 0.65 g. was recovered frcm the mother liquors. 25 c. To a slurry of 2.58 g. (4.9 mmole) of the product obtained in Part 3 in 250 ml. of methanol was added 0.60 g. of 5% palladium-on-carbon catalyst (50% wet) and the mixture hydrogenated for one hour at an 2 initial pressure of 71 psi (5.0 kg./cm. ). The 30 catalyst was removed by filtration and the methanol evaporated at reduced pressure to afford 1.47 g. (100%) of colorless product, M.P. 190-191°C. TLC in ( 2 0517 6 4:1:1 butanol/water/acetic acid (v/v) and spraying with ninhydrin gave a single spot, R_ 0.36.

Sweetness, 1200 times sucrose.

Starting with the appropriate beta-benzvl-N-Cbz-Lraspartyl-D-alanine in each case the remaining ccmpounds of formula (I) wherein R is CH( /\)^ and Ra is ^2E5' EXAMPLE ' 6 (CE^)^CE or n-C^H^ are obtained in like manner.

L-Aspartyl-D-alanine N-(al-t-10 butylcyclopropylcarbinyl) amide: i, r = chc(ct3)3, ra = ch3 A. t-Buty1cvc1opropv1carbinylamine To 0.5 mole each of cyclopropanecarbonvl chloride and cuprous chloride in 500 ml. of dry ethyl ether was 15 added, dropwise under a nitrogen atmosphere 238 ml. (0.5 mole) of 2.1 M t-butylmagnesium chloride in the same solvent at -10°C. The reaction mixture was poured into a mixture of 25 0 ml. of 3 M hydrochloric acid and 7 00 g. of ice, the organic layer separated, 20 washed with water, scdium bicarbonate solution, brine and dried over anhydrous magnesium sulfate. The ether was evaporated at reduced pressure and the residue distilled at atmospheric pressure to provide 45 g. (72%) of t-butylcyclopropylketone, B.P. 145-153°C. 25 The 45 g. (0.36 mole) of ketone was reacted with hydroxylamine hydrochloride and scdium acetate in 1:1 ethanol/water by the method of Example 5, Part A.

After heating at reflux overnight the reaction mixture was cooled and the precipitated oxime collected and 30 washed with cold ethanol to obtain 23.5 g. of t- butvlcyclopropylketoxime. An additional 7.7 g. was obtained from the mother liquors. The combined crops were recrystallized from 1:1 ethanol/water to provide 25.2 g. (50%) of oxime, M.P. 113.5-114°C. f 203176 4 To a solution of 5.0 g. (0.035 mole) of oxime in 80 ml. of ethanol was added 8.04 g. (0.35 mole) of scdium and the reaction carried out and product isolated as described in Example 5, Part A, to afford 3.31 g. of crude dl-t-butylcyclopropylcarbinylamine. This was distilled at atmospheric pressure to yield 2.01 g. (45%) of prcduct boiling at 153-155°C.

B. C-HcCH_OCOCH_CHCONECHCONHC. 6 5 2 2, , .c(ch3)3 NHCbz CH3 \y The procedure of Example 5, Part 3 was repeated 10 employing 0.76 g. (6.6 mmole) of d_l-t-butyl cycl oprcpyl-carbinylamine in place of dicyclopropylcarbinylamine and,proportional amounts of the other reagents. Evaporation of the ethyl acetate extracts _in vacuo gave 3.12 g. (97%) of solid diblocked dipeptide amide. 15 This was purified by column chromatography on a 2.5 x 3 0 cm. column, eluting with 1:1 ethyl acetate/hexane. After evaporation of the fractions containing the desired prcduct (as determined by TLC), 2.33 g. (72%) of colorless solid was obtained, M.P. 11S-120°C. 20 C. The purified product frcm Part 3, 2.33 g., was hydrogenated over a pal1adium-on-carbon catalyst as described in Example 5, Part C, to afford 1.23 g. (95%) of the desired dipeptide amide, M.P. 180-182°C. (dec.), silica gel TLC (4:1:1 butancl/water/acetic 25 acid): one spot, R^ 0.43.

Sweetness, 1200 x sucrose.

The remaining compounds of formula (I) wherein R (CH3)3 is CH^_ and Ra is ethyl, isoprcpyl or n-propyl are similarly obtained frcm the appropriate diblocked 3 0 dipeptide. r 2 031 76 EXAMPLE 7 L-Aspartyl-D-alanine N-(2,2,5,5-tetramethylcyclopent-l-yl) amide: I, R CI C] 3 3 , ra = ch3 A. 2,2,5,5-Tetraraethylcyclopentylamine A mixture of 21.0 g. (0-15 mole) of 2,2,5,5-tetramethylcyclopentanone (B.P. 63-68°C. at 40 mm.), 40.5 g. (0.8 mole) formamide and 4 ml. of formic acid was heated at 160-190°C. for 20 hours with addition of 10 10 ml. increments of formic acid whenever solid ammonium carbonate deposits formed in the condenser. During this time water was removed from the reaction mixture by means of a variable take-off fractionating head. The mixture was cooled, extracted with ethyl 15 acetate and extracts evaporated to obtain a dark residual oil. This was mixed with 60 ml. of 6 "N hydrochloric acid and the mixture heated at reflux for three hours. The resulting solution was adjusted to pH 13 with sodium hydroxide, extracted with ethyl 20 ether, the extracts washed with water, brine, dried (magnesium sulfate) and evaporated to dryness to yield 4.9 g. of crude amine which was distilled to obtain 1 g. of the desired tetramethylamine, B.P. 66-69° (30 mm.). f i'031 7 6 NHCbz CH3 By employing 35 6 mg. (6.1 mmole) of 2,2,5,5-tetramethylcyclopentylamine and proportional amounts of the other reagents employed in Example 5, Part B, the diblocked dipeptide amide of the above formula was obtained by the procedure of that example. R^., 0.3 6 by silica gel TLC (2:3 ethyl acetate/hexane). It was purified by column chromatography on silica gel, eluting with ethyl acetate/hexane (2:3) to obtain 49 5 mg. after evaporation of product-containing fractions.

C. The purified diblocked dipeptide amide provided in Part B, 495 mg., was dissolved in 75 ml. of methanol and hydrogenated ever 3 00 mg. of 5% pal ladium-on-carbon catalyst as described in Example 5, Part C.

After evaporation of solvent, 185 mg. of the desired dipeptide amide was obtained as an off-white solid, M.P. 13 6-140 °C.

Sweetness, 800 x sucrose.

The ccmpounds of formula (I) wherein R is 2,2,5,5-tetramethylcyclopentyl and Ra is ethyl, isopropyl or n-propyl are obtained in like manner from the appropriat diblocked dipeptide by the above procedure. 2 0317 6 EXAMPLE '8 3-Amino-2,2,4,4-tetramethyltetrahydrofuran A. 2,2,4 4-Tetramethyltetrahydrofuran-3-one 4-3romo-l-hydroxy-2,2,4-trimethylpentan-3-one 5 (prepared as described in Example 13, Parts A and B) . 25 g. (0.1 mole) was dissolved in 160 ml. of ethanol and a solution of 8 g. (0.2 mole) scdium hydroxide in 80 ml. of water was added. The resulting mixture was stirred at rocra temperature for 30 minutes, diluted 10 with water, extracted with ethyl ether, the extracts washed with water, brine and dried over anhydrous magnesium sulfate. The solvent was evaporated to afford 17.7 g. of 2,2,4-trimethylpentan-l,4-diol as a colorless liquid which was identified by ^"H-NMR. The 15 diol was dissolved in 5 0 ml. of chloroform, 1.5 ml. of concentrated sulfuric acid added dropwise. The mixture was heated at reflux for 3 hours, while distilling water/chloroform azeotrope from the mixture. After standing overnight at room temperature the reaction 20 mixture was washed with water, the organic layer dried (MgSO^) and solvent evaporated _in vacuo to provide 13.9 g. of colorless liquid. Distillation afforded 8.3 g. of the desired product, B.P. 70-72° (50 mm.), overall yield 58%. b. The ketone obtained in Part A, 8.0 g. (0.056 mole), hvdroxylamine hydrochloride, 8.0 g. (0.113 mole) ana sodium acetate, 2.3 g. (0.113 mole), were combined with 85 ml. of ethanol and the mixture heated at reflux for 48 hours. The resulting mixture was 3 0 diluted with water, extracted with ethyl ether, the extracts washed with water, dried and evaporated to yield 9.0 g. of a mixture of syn- and anti-oximes, identified by its ^h-NMR spectrum. - r 40317 6 The oxime obtained above, 1.3 g. (8.28 mmole) was dissolved in 70 ml. of dry ethanol, 1.9 g. of sodium metal added and the mixture warmed to reflux and held at this temperature for 15 minutes. Heating was 5 continued for two hours with addition of two more increments (1.9 g. each) of sodium. The reaction mixture was then diluted cautiously with water, extracted with ethyl ether. The ether layer extracted with dilute hydrochloric acid, the aqueous phase made 10 alkaline with sodium hydroxide and re-extracted with, ether. The extracts were dried (MgSO^) and evaporated to dryness and the residue distilled to obtain the desired amine, B.P. 68-69°C. (15 mm). After further purification by precipitation of the hydrochloriae 15 salt from ethyl ether-methanol, basifying the salt and extracting again with ether 0.8 7 g. of amine of 9 3% purity by gas chromatography (OV-1 column) was obtained r 20317 6 EXAMPLE 9 By employing the appropriate amine of formula RNH, in the procedure of Example 4 the following amides of L-aspartyl-D-alanine were provided in like manner.

/-H /NH 2 -ch cooh \ conhchconhr CH, r* C "T t CH.

CH. rrans C2H5 trans ch. ch. trans,trans ch, c_h_ 2 3 c , t + t, t Dibl ocked Dipeptide Amide R_ % Yield x 0.54 0.63' 0 . 57b 0. 57a 0 . 5 0a 0.46 99 56 33 90 50 Dipeptxde Amide (I) Sweetness m.p.,°c. 19 4-19 7 °Dec , 213-215' % Yield! x sucrose 180-182°Dec, 224-225 °Dec. 185-187' 83 77 92 59 220 250 600 200 2 03176 < Diblocked Dipeptide Dipeptide Amide (I) ' Amide Sweetness R* R _ ■ % Yield •M.P. ,°C. ■ ■% Yield x sucrose C2H5V^VC2H5 0.55a 42 19 8-201"Dec. 74 200 c_,t + t,t Jycalca3>2 0.5 4a — 145-148° 74 500 trans /jC(CH3>3 0 .4 0C 0 .54c 100 14 8-15 0 °Dec. 75 450 £ + t CH3^CH(CH3»2 (a3)2C^rCH(ai3)2 0 . 7 3C 100 13 6-13 3 "Dec. 63 ■ 300 c, t + t, t 0.34° - 143-145° o 5 150 '6k 3 .31C 100 199-202° 44 250 0.36c 69 199-206° 100 400 c + t 1 i CHACH3 CH3 CH3 0. 33C 97 105-112° 42 I 1 i 300 r 2 03176 Dibl ocked Dipeptide Dipeptide Amide (I) Amide Sweetness, R* Rf' % Yield M.P.,°C. • % Yield x sucrose ^/CK3 0.56° 95 91 320 1 in ycn3 0 .5 5C 95 91 200 d_l >YCH3 0.4 4a 100 185-186°Dec. 86 220 trans A^2H5 0.75a 96 89-93° Dec. 82 250 trans n ^:H(CH3) 2 0.38° 38 206-208"Dec. 89 625 trans p" J. Cxi3y^ YCH3 - 93 175-177°Dec. 59 520 mixed isomers _ CH3>C CH3 u SCCH3 —0 CH3 0 . 2C 94 95-99° 100 350 >C(CH3)3 \y 0 . 4C 95 186-188°Dec. 73 • 140 dl 203176 4 Dibl ocked Dipeptide Dipeptide Amide (I) Amide Sweetness, r* Rf % Yield M.P.,°C. ■ ■ ■ ■ % Yield x sucrose l / \ (CH3)2CH CH{CH3)2 D. 5 4a 100 179-181°Dec. 81 250 ih / \ (CH3)3C CH3 dl 3. 66a 63 13 0-183°Dec. 43 180 i CH (CH^C^ CH3 1_ 0. 6a 98 182-184°Dec. [alpha] ^+20. 3 (C=l, CH OH) 61 0 i CH (CH3)3C/ XCH3 - 96 133-185 °Dec. [alpha] D + 29 .1 2 375 d {c=1, ch3oh) I CH / \ (ch3)3c ch2ch3 0. 54a 100 + (crude) 13 4-137"Dec. 72 180 dl I ch3 0. 72a 39 19 3-19 7 °Dec. 87 110 V dl - I CH / \ (CH3)3C CH(CH3) 2 - 79 110-115 °Dec. 54 125 dl « r 2 0317 6 i *Configuration of amine, RNH^ is given where known: £ = cis; t = trans, _! = levorotatory, dl_ = racemic. a7:3 ethyl acetate/hexane. ^10:9:1 ethyl acetate/hexane/acetic acid. c 1:1 ethyl acetate/hexane.

Proportions for solvent systems are by volume.

In like manner the corresponding ccmpounds of the formula HOOCCH_CHCONECHCONHR are obtained frcm the ' 1 a nh2 r appropriate diblocked dipeptide, CgH^C^OOCCI^CHCO-NHCHCOOH NHCbz Ra where Ra is ethyl , isopropyl or _n-propyl and R has the values assigned above. r 203176 EXAMPLE 10 L-Aspartyl-DL-alanine N-(dicyclobutylcarbinyl)amide: i, r = ch , ra = ch3 A. ch3chconhch( □ )2 -) I NHCbz To a mixture of 3.0 g. (0.0135 mole) of N-benzyl- oxycarbonvl-DL-alanine and 1.27 g. (0.016 mole) pyridine is added at -10°C. 1.45 g. (0.0135 mole) .ethyl chloroformate. The mixture is stirred for 15 minutes, cooled to -15° and 3.75 g. (0.027 mole) of 10 dicyclobutylcarbinylamine is added. The reaction mixture is allowed to warm to room temperature, dissolved in ethyl acetate and the solution washed with dilute hydrochloride acid, scdium bicarbonate solution, brine and the washed extracts dried (Na^SO^). 15 The solvent is evaporated to provide the desired N-Cbz-alanine-N-(dicyclobutylcarbinyl) amide. 3. Diblocked dipeptide amide A solution of 3.54 g. (0.01 mole) N-Cbz-alanine-N-(dicyclobutylcarbinyl)amide in 100 ml. of methanol 20 is hydrogenated over 1 g. of 5% palladium-on-carbon, the catalyst removed by filtration and the solvent evaporated to provide N-(dicyclobutylcarbinyl)-DL-alanine amide.

In a separate flask containing 4.46 g. (0.0125 mole) 25 of beta-benzyl N-benzyloxycarbonyl-L-aspartate in 100 ml. of tetrahydrofuran containing 1.2 g. (0.015 mole) pyridine is added 1.35 g. (0.0125 mole) ethyl chloroforrnate while maintaining the mixture at -30°C. The resulting mixture is stirred for 10 minutes at this temperature. 30 To this is then added the N-(dicyclobutylcarbinyl)-DL-alanine amide, obtained above, as a solution in tetrahydrofuran (100 ml.) and N,N-dimethylforrnamide (10 ml.). The reaction mixture is stirred at -20°C. § 2031 7 -5 7- f.or 3 0 minutes then allowed to warm to room temperature, extracted with ethyl acetate, washed successively with water, scdium bicarbonate solution, dilute hydrochloric acid, and water again. After drying the washed extracts 5 over anhydrous scdium sulfate, the solvent is evaporated to provide beta-benzyl N-benzyloxycarbonvl-L-aspartyl-DL-alanirie N-(dicyclobutylcarbinyl)amide suitable for use in the next step without further purification. C. To a solution of 1.5 g.- of the diblocked dipeptide 10 amide," obtained in Part B, in 100 ml. of methanol is added 1 g. of 5% palladium-on-carbon and the mixture hydrogenated at 3-4 atmospheres pressure. The catalyst is recovered by filtration and the filtrate evaporated at reduced pressure to provide the title compound. 15 D. When the above procedure of Part A is repeated with N-benzyloxycarbonyl-D-alanine or the N-benzyloxycarbonyl derivatives of D-valine, D-2-aminobutyric acid or D-norvaline and the appropriate amine of formula RNK2 and the prcduct thus obtained hydrogenated 20 by the procedure of the first paragraph of Part B, above, D-amino acid amides of formula RaCH(NH2)CONKR are obtained where Ra is methyl, ethyl, isopropyl or n-propyl and R is as defined below.

By carrying each of these D-amino acid amides 25 through the procedure of the remaining portion of Part B and Part C, above, the corresponding L-aspartvl-D-amino acid dipeptide amides of formula (I) are obtained in like manner.

CH_-CHCONHCHCONHR / 2 ' 'a HOOC NH R f 2 0317 R dl-fenchyl diisopropylcarbinyl d-methyl-t-bu'tyl carbinyl 5 d-ethyl-t-butylcarbinyl di-t-butylcarbinyl cyclopropyl-t-butylcarbinyl cyclopentyl-t-butylcarbinyl dicyclopropylcarbinyl 10 l_-f enchyl 2.2.4.4-tetramethylcyclobutyl 2-methylcyclopentyl 2-ethyleye1opentyl 2-i s opr opyleye1opentyl 15 2,5-dimethylcyclopentyl 2.2.5.5-tetramethylcyclopentyl 2-ethyleve1ohexyl 2- i s opr opyl eye 1 ohexyl 2-t-butylcyclohexyl 20 2-ethyl-6-methylcyclohexyl 2,2-dimethylcyclohexyl 2,6-dimethylcyclohexyl 2,2,6-trimethylcyclohexyl 2.2.6.6-tetramethylcyclohexyl 2,2,4,4-tetramethyl-3-oxocyclobutyl 2,2,4,4-tetramethyl-3-hydroxycyclobutyl 2,2,4,4-tetramethyltetrahydrofuran-3-vl C (- 2 0317 < -59 — EXAMPLE 11 Employing t-he methods described above the following L-aspartyl-D-amino acid amides and L-aspartyl-DL-amino acid amides are prepared in like manner.

CH -CHCONHCECONHR x 2 ' 'a COOH NH2 R where Ra is CH3, C2H5, n-C3H7 or i-C^H.^.

R R R CH/" CH 0 ?H. CH CH(CHJ, CP" -<!> - -Q ^ CH3 CH2CH3 CH ?H3 ,3 \_T J 3\| 3 T >> ~^° CH3 B-C4H9 CH CH3 CH3CH2XX:H2CH3 C(CH3)3 -o I 3 ^"3 CH- CH(CH3)2 C{CH3)3 CH3 CH2CH3 r o CH(CH3)2 CH3 CH3 CH,CH3 C(CH3)3 CH3 CH3 0 (CH2)3 CH3 C(CH3) 3 C(CH3)3 CH3X/CH3 (CH9)_ / - 2 3 CoHc C.,H CH3 CH3 0 2li5 C2"5 2031 7 6 -6 0- R CH (CE 3 ' 2 CH(CH3)2 CH-, ch3 ch3 CH3CHCH2CH3 c{ch3)3 r\ CH3 ch3 (ch2ch2ch3)2 C0HS • £ CH2(CH2)2CH3 CH- CH.

\ J ~<y^(CH2)3 CH3 CH., £ CH3 _0 CH.

CH (CH 3 2 (CH„), z o ch(ch3)2 ch(ch3)2 CH(CH3)2 0 / CH-CH_CK2CK3 CH-, CHnCH, 3,2 3 O ch3 ch2ch3 CH.

CH.

CHa .CH-.

-D CH3 CH3 C(ch3)3 CH- 2 CH(CH3)2 CH(CH3)2 2 0317 6 r -po ch- CH3 ,CH3 ch. ch. -< ? v^(ch2)3 ch_ . ch_ £4 CH3 CH3 ch(ch3)2 ~C' y-(CH2)3 ch-, ch ch3 0 (ch2)2 /ch(ch3)2 ch(ch3)2 ch. -0 / (ch2)2 ch_, ch3 ch3 ch_. ch_, V 3 CH3\/CH3 0 (ch-) 2 3 ch3 ch3 ch(ch3)2 j—(CH2 ^ 2 ch(ch3)2 C(CH3,3 ch(ch ) -^|CH2»3 ch(ch3)2 ? ^ (CH2)2 c(ch3)3 ch(ch3)2 c(ch-,), \-('ch2)2 ch2ch3 203176 r. r r ch2)2 ch.

CH3 \ ch. c(c2h5).3 (CP-,) CH3 2' 2 ch.

?H3 ch(ch2)3ch3 ch[ch(ch3)2j2 ch2ch3 'h-c(ch3)3 3 J 2 (ch3)2 c-c(ch3)3 c(ch2ch3)3 h2ch3 (ch2)3 /ch(ch2ch3)2 ch2ch3 (ch3)3 ch2)3 c(ch3)3 ch(ch3)2 ch(ch2ch3)2 (CH2,3 'ch2(ch2)2ch3 ch2ch2ch3 chch(ch3)2 r C2 0317 6 r ✓ch (ch r 3' 2 ?H2CH3 h(ch2)3ch3 ch3 :h(ch2)3ch3 c(ch,) X3 3 3 :h(ch_ch_ch^ ) _ a ch-).ce- 2 2 j 2 / 2 4 o (ch2)3 ch. to / ch. ch(ch ) 1?° O ch(ch3)2 ch(ch3)2 ch-, ch, & V- o ch3 ch3 c(ch3)3 r 2 031 7 ■ EXAMPLE'12 L-Aspartyl-D-alanirie-N-(3,5-dimethyl-tetrahydrothiopyran-4-yl)amide: CH.

I, R - , Ra = CH3 mixture of cis/trans and trans/trans isomers A. 3,5-Dimethyltetrahydrothiopyran-4-one A mixture of 2 g. of scdium acetate and 25 ml. of ethanol was saturated with hydrogen sulfide gas. To this was added 7.0 g. (0.063 mole) aiisopropenylketone while cooling in an ice bath until the reaction was no longer exothermic. The mixture was stirred at room temperature while passing hydrogen sulfide through the mixture for four hours then allowed to stand overnight.

The ethanol and excess H^S were evaporated _in vacuo and the residue taken up in ethyl ether, washed in turn with water, potassium carbonate solution, dilute hydrochloric acid, and water again. The ether extracts were dried (Na SO ) and evaporated to provide 6.8 g. 2. 4 of oil. This was distilled in vacuo through a 10 cm. 20 Vigreaux column to provide 1.67 g. of product, B.P. 8 3-8 6°C./9 mm. which was used in the next step without further purification.

B. 4-Oximino-3,5-dimethyitetrahydrothiopyran A mixture of 1.67- g. (0.011 mole) of the cyclic ketone obtained in Part A, 1.6 g. (0.023 mole) hydrcxyl amine hydrochloride and 1.9 g. (0.023 mole) scdium acetate in 3 0 ml. of water and 10 ml. of ethanol were heated at reflux for three hours, cooled and the precipitate recovered by filtration. After recrvstalli 3 0 tion from 1:1 methanol-water 1.5 g. of oxime was obtained as a white solid, M.P. 60-85°C. which is a mixture of isomers of suitable purity for use in the next step. r 2031 7 C. trans/trans and cis/trans-4-Amino-3,5-dimethyl- tetrahydrothiopyran ' To a solution of 1.45 g. (0.009 mole) of the oxime obtained in Part B in 15 ml. of ethanol was 5 added in portions 5 g\ of sodium shot followed by an additional 25 ml. of ethanol and the resulting mixture heated at reflux for about 30 minutes. The reaction mixture was diluted with water, extracted with ethyl ether, and the extracts washed with water. The ether 10 layer was extracted with dilute hydrochloric acid- and the aqueous layer washed with fresh ether. The aqueous layer was made alkaline by addition of scdium hydroxide solution and extracted with ether again. The organic layer was dried (MgSO^) and the ether 15 evaporated to obtain 1.1 g. of residual colorless oil.

Gas-liquid chromatography (OV-1 column with temperature programming from 80 to 100°C.) showed the prcduct to contain two major components in a 60/40 ratio. ^E-NMR (CDC1 ) indicated the product to be a mixture of 4-20 amino~3-trans-5-trans-dimethyltetrahydrothiopyran and the corresponding 3-cis-5-trans-isomer.

D. N-tertiarv-Butoxycarbonyl-D-alanine To 7.0 ml. each of tetrahydrofuran and water was added 2.71 g. (11 mmole) N-(t-butoxycarbonyloxyimino)- 2-phenylacetonitrile (BOC-ON, Aldrich Chemical Co.), 0.89 g. (10 mmole) D-alanine and 1.5 g. (15 mmole) triethylamine and the resulting two phase mixture stirred at room temperature. After about two hours the mixture became homogeneous and stirring was 3 0 continued overnight. The mixture was diluted with water, washed with ethyl acetate and acidifed with dilute hydrochloric acid to pH 1.5. The acidifed solution was extracted with ethyl acetate, the extracts washed with water, saturated brine and dried over 35 sodium sulfate. The solvent was evaporated at reduced pressure to afford 1.9 g. of product as a colorless oil suitable for use in the next step. ( 2 0317 6 E. N—(3,5—Dimethylt etrahydrothiopyran—4—yl)— t— butoxycarbonyl-D-alanine amide CH. t-Boc-NH-CHCONH CKn Under anhydrous conditions, to a mixture of 1.7 g. (8.9 mmole) of N-t-Boc-D-alanine obtained in Part D, 1.98 g. (19 mmole) triethylamine and 40 ml. of tetrahydrofuran, cooled to -10°C., was added dropwise 0.9 6 g. (8.9 mmole) ethyl chloroformate and the resulting mixture stirred at this temperature for 20 minutes.

To this was added 1.1 g. (7.5 mmole) of the mixture of isomers of 4-aminc-3,5-dimethyltetrahydrothiopyran obtained in Part C and the resulting mixture stirred at -10°C. for 10 minutes then allowed to warm to room temperature. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was washed with scdium bicarbonate solution, dilute hydrochloric acid, water, brine then dried (Na2SOd) and the solvent evaporated at reduced pressure to obtain the product as a foam, 2.4 g. Thin-layer chromatography (TLC), silica gel plates, eluting with 1:1 ethyl acetate/hexane showed major spot for the prcduct at 0.5 with trace impurities at R_ 0.6 and 0.9. ( r 203176 4 F.. N-(3,5-Dimethyltetrahydrothiopvran-4-yl)-D-alanine amide CH- v NH^CHCONH 2 \ CH ■GH^ The t-Boc-amide obtained in Part E was dissolved in 15 ml. of ethanol and a mixture of 5 ml. of concen trated hydrochloric acid and 10 ml. of water were added. " The resulting mixture was heated at reflux for 3 0 minutes, cooled and the ethanol removed by evapora tion in vacuo. The aqueous residue was washed with ethyl ether, made alkaline with sodium hydroxide solution, extracted with ether and the extracts dried (Na^SO^). Evaporation of solvent provided 1.1 g. (67%) of colorless oil which crystallized upon standing.

G. Coupling of D-alanine amide with L-aspartic acid N-thiocarboxvanhydride The D-alanine amide provided in Part F, 1.1 g. (5.1 mmole) was dissolved in 5 ml. of tetrahydrofuran and 5 ml. of water was added. The clear solution was cooled in ice and 0.89 g. (5.1 mmole) of L-aspartic acid N-thiocarboxyanhydride was added in one portion.

To this was added as required, 0.5 M sodium hydroxide to maintain the mixture at pH 9. After stirring 3 0 minutes the reaction mixture was washed with ethyl ether then ethyl acetate and the washes discarded.

The aqueous phase was acidified with dilute hydrochloric acid to pH 5.6 and evaporated to dryness at reduced pressure. The residue was taken up in hot methanol (100 ml.), filtered and the methanol evaporated. The residue was taken up again in hot methanol, filtered 3 0 and the filtrate decolorized with activated carbon, r C ' _, 2 0317 6 filtered through diatomaceous earth and the filtrate evaporated to obtain 1.67 g. of crude product as a powder. The crude product was dissolved in hot water (11 ml.) and filtered, evaporated under a stream of nitrogen to 5 ml. and cooled in ice to precipitate the product as a gelatinous solid. The product was collected by filtration, sucked dry, washed with 2 ml. of cold water, 2 ml. of cold methanol and finally with a mixture of 1 ml. methanol and 4 ml. of ethyl ether to afford a granular product which was dried in a vacuum oven at 50°C. to give 0.3 g. of the desired product. Sweetness, 200 x sucrose.

Use of D-2-aminobutyric acid, D-valine or D-norvaline in place of D-alanine in the procedure of 15 Part D above and reacting the N-t-butoxycarbcnyl-D- amino acids thus obtained in the procedures of Parts E, F and G, similarly provides the corresponding ccmpounds of formula (I) wherein R is 3,5-dimethvltetrahvaro-thiopyran-4-yl and Ra is (CH^^CH, cr respectively. c r 2031: ....... 4 EXAMPLE 13 3-Amino-2,2,4,4-tetramethyltetrahvdrothiophene A. l-Hydroxy-2,2,4-trimethylpentan-3-one To scdium methoxide prepared frcm 7.5 g. of 5 scdium metal and 250 ml. of methanol was added 72.5 g. (2.4 moles) paraformaldehyde followed by 250 g. (2.2 moles) diisopropylketone and the resulting mixture heated at reflux for three hours. The reaction was quenched with water, neutralized with hydrochloric 10 acid, extracted with ethyl ether; washed with water, brine and the solvent evaporated. The residual oil (90 g.) was distilled _in vacuo to obtain 28 g. of the desired product boiling at 92-98°C. at 16-20 mm. GLC on OV-1 column at 107°C., retention time 314 sec., 9 6% 15 pure.

When the above procedure was repeated on the same scale but the reaction mixture refluxed for 16 hours, 31 g. of product was obtained of 9 6% purity by GLC.

B. 4-3rano-l-hydroxy-2,2,4-trimethylpentan-3-one 20 To a stirred, refluxing solution of 69 g. (0.48 mole) of l-hydroxy-2,2,4-trimethylpentan-3-one in 500 ml. of chloroform was added dropwise a solution of 77 g.. (0.48 mole) bromine in 100 ml. of chloroform.

When the addition was completed the mixture was stirred 25 at reflux for one hour, allowed to cool and stand overnight at rocm temperature. Evaporation of solvent at reduced pressure afforded 127 g. of prcduct which was used in the next step without purification. r ( 2 0317 6 C. 2,2,4,4-Tetramethyltetrahydrothiopheh-3-one The product obtained in Part B, 79 g. (0.3 mole) was dissolved in 300 ml. of dry pyridine, cooled to 0°C. and 114 g. (0.6 mole) of £-toluenesulfonyl chloride 5 was added in portions at 0°C. The resulting mixture was stirred at this temperature for 3 hours, 15 minutes, poured into ice/water and extracted with ethyl ether. The extracts were washed with.dilute hydrochloric acid, water and brine then dried over anhydrous magnesium 10 sulfate. The solvent was evaporated to provide 111 g. (98%) of crystalline tosylate.

The tosylate, 94 g. (0.25 mole) was dissolved in one liter of pyridine, 180 g. (0.75 mole) of sodium sulfide monohydrate added and the mixture heated to 15 75°C. and held at this temperature for one hour and allowed to stand at room temperature overnight. Water was added and the mixture was extracted with ether. The extracts washed with hydrochloric acid, brine, dried (MgSO^) and the solvent evaporated to obtain 20 35 g. of the title compound, 89% yield. The product showed only one spot upon silica gel TLC, eluting with ethyl acetate/hexane (1:4 by volume, R„ 0.5. The H-NMR spectrum was in agreement with the structure for the title compound. r 2.031 7 D. Leuckart reduction of ketone To a 100 ml. round-bottomed three-necked flask fitted with stirrer, thermometer and condenser with fractionating head was added 10.0 g. (0.063 mole) of 5 2,2,4,4-tetramethyltetrahydrothiophen-3-one, 15.2 ml. (0.38 mole) forrnamide and 3.5 ml. (0.092 mole) formic acid and the mixture heated at reflux (163°C.) while removing water. The reaction mixture was maintained at 160-180°C. for 20 hours with addition of formic 10 acid (10 ml.) at intervals. The pot temperature increased to 200°C. over this period. The reaction mixture was cooled, water added and the mixture extracted with ethyl acetate. The extracts were evaporated in vacuo. The residue was refluxed with 15 20 ml. of 6N hydrochloric acid for two hours, cooled, the resulting mixture washed with ethyl ether, the aqueous phase adjusted to pH 11 with scdium hydroxide solution and extracted with ethyl ether. The extracts were dried and evaporated to obtain 2 g. of 3-amino-20 2,2,4,4-tetramethyltetrahydrothiophene which was identified by ^H-NMR and appeared hcmogeneous upon silica gel TLC.

E. By employing the appropriate ketone as starting material in place of diisopropylketone in the procedures of Examples 8 and 13, the following amines are similarly obtained. r r 2031 7 6 nh„ R R„ <o "4 x s s s s s r~ CH3 h CH3CH9 (ch3)9ch ch_ R h h h h ch.

CH3 ch3 ch3ch2 (ch3)2ch R h h a a 0 O 0 O 0 o 0 ch3ch2 ch3 H ch3 a ch3ch2 CH. h h h h h h ch3ch2 ch3ch2 ch3 ch3 H (ch3)3c ch., a pr CH3CH2 When the tetrahydrothiophenes of the above formula are contacted with an equimolar amount of hydrogen peroxide or m-chloroperbenzoic acid the corresponding sulfoxide (X = SO) is formed in each case. Treatment of the same starting material or the sulfoxide with a molar excess of the same reagents or potassium permanganate affords the corresponding sulfone (X = S02). r r 2031 1 EXAMPLE'14 L-Aspartyl-D-alanine N-(2,2,4,4-tetramethyltetrahydrothiophene-3-vl)amide: CH 3 A. t- 3 oc-NHCH-CONH' CH 3 CH 3 3 To a solution of 2.09 g. (11 mmole) of N-t-butoxycarbonyl-D-alanine in 75 ml. of tetrahydrofuran was added 1.47 ml. (10 mmole) of triethvlamine and the mixture cooled to -10°C. At this temperature was added 0.9 6 ml. (10 mmole) -of ethyl chloroformate and stirring continued for 15 minutes. After cooling to -20°C./ 1.6 g. (10 mmole) of dl-3-amino-2,2,4,4-tetramethyltetrahydrothiophene was added and the resulting mixture was allowed to warm to rocm temperatur Ethyl acetate was added and the mixture washed twice with 50 ml. portions of 5% (by weight) aqueous citric acid, aqueous scdium bicarbonate (1 x 50 ml.) and saturated brine (1 x 5 0 ml.). The organic layer was dried (Na SO,,) and evaporated to dryness at reduced 2. -i pressure to afford 3 g. of N-(2,2,4,4-tetramethyltetra-hydrothiophene-3-yl)-t-butoxycarbonyl-D-alanine amide as an oil. The structure of the product was verified by its "'"H-NMR spectrum. It was essentially hcmogeneous upon silica gel TLC. This product was used without further purification in the next step. ( 2031? CH rn 3 B. CH3CH(NH2CONH' 3 3 To the product frcm Part A was added 5 ml. of methanol and 30 ml. of 1M hydrochloric acid and the mixture was heated on the steams-bath for 30 minutes. The methanol was removed by evaporation and the residue extracted with ether. The ether was discarded and the aqueous phase was adjusted to pH 11.0 with scdium hydroxide solution, extracted with ethyl acetate, the extracts dried (Na^SO^) and evaporated to dryness to obtain 1.0 g. of N-(2,2,4,4-tetramethyltetrahydrc-thiophene-3-yl)-D-alanine amide which was identified by its nuclear magnetic resonance spectrum. It was homogeneous upon silica gel TLC.

C. Coupling to"form "dipeptide amide The D-alanine amide obtained in Part 3, 0.9 7 g. (4.25 mmole) was mixed with 10 ml. of water, cooled in ice and the pH of the mixture adjusted to 9.2 with 0.5 N scdium hydroxide solution. To this was added portionw with stirring 0.8 g. (4.25 mmole) of L-aspartic acid N-thiocarboxyanhydride while maintaining the mixture at pH 9 with sodium hydroxide solution (0.5 N) . When the addition was completed the resulting mixture was stirred at 0°C. for 45 minutes, adjusted to pH 5.2 with hydrochloric acid and evaporated to dryness in vacuo. The residue was slurried with methanol, filtered to remove precipitated solids and methanol removed from the filtrate by evaporation at reduced pressure. Ethyl ether was added to the residue to form a solid. This was collected by filtration, reslurried with ethyl ether, filtered again and the r 20317 solid recrystallized frcm 8 ml. of water. After drying in the vacuum oven about 1 g. of prcduct was obtained, M.P. 124-126°C. A second crop was obtained by reworking the mother liquors. Sweetness, 500 x 5 sucrose.

When levorotatory 3-amino-2,2,4,4-tetramethyl-tetrahydrothiophene, resolved by standard methods, was employed in the above procedure in place of the raceraic amine the resulting L-aspartyl-D-alanine amide was 10 found to be 800 times as sweet as sucrose.

Similarly, the analogous ccmpounds of formula (I) wherein Ra is ethyl, isopropyl or n-propyl are prepared frcm the appropriate N-t-boc-D-amino acid by the above proc edures. r r ■ 2031 EXAMPLE '15 3-Amino-2 ,2,4 ,'4-1etramethylthietane A. 2 4-Dibrcmo-2 , 4-dimethylpentan-3-6ne To 136 g. (1.2 mole) of diisopropylketone was 5 added 2 ml. of phosphorus tribromide and the mixture cooled to 10°C. To this was added dropwise 384 g. (2.4 mole) of bromine, the mixture allowed to warm to room temperature. After two hours at this temperature the mixture was warmed at 55-60°C. for one hour then 10 cooled and partioned -between chloroform and water.

The water was discarded and the organic layer washed with sodium carbonate solution until neutral. The organic layer was dried (MgSO^) and solvent evaporated to obtain 316 g. (9-7%) of the desired product. 15 b. 2,2,4,4-Tetramethvl-3-oxothietane Sodium metal, 23 g. (1.0 mole), was dissolved in 500 ml. of dry methanol and the resulting mixture cooled to 10°C-. Hydrogen sulfide gas was passed through the mixture until it was saturated. Then 136 g. (0.5 mole) of the dibrcmoketone obtained in Part A was added dropwise while continuing to allow hydrogen sulfide to pass through the reaction mixture.

After the addition was completed the mixture was stirred for two hours at 10°C., allowed to warm to roan temperature and stirred overnight. After pouring the reaction mixture into water, it was extracted with ethyl ether and the extracts washed with dilute hydrochloric acid and brine. After drying ever magnesium sulfate the ether was evaporated, the residue slurried with methanol, cooled and filtered to obtain 46 g. (64%) of solid product which was used without purification in the next step. 2031-7 C. Reductive amination of 'ketone• To 75 ml- of dry methanol was added 4.5 g. (0.031 mole) of 2,2,4,4-tetramethyl-3-oxothietane, 23.9 g. (0.31 mole) ammonium acetate and 1.3 6 g. (0.0217 mole) scdium cyanoborohydride and the resulting mixture heated at reflux for four hours. Additional sodium cyanoborohydride (1.36 g.) was added and refluxing continued for three days with a third increment of the same reagent added at the start of the third day. The resulting mixture was acidified to pH 2 with hydrochloric acid ana evaporated to dryness on the rotary evaporator at reduced pressure. The residue was dissolved in water, washed with ethyl ether, the aqueous phase adjusted to pH 11 with scdium hydroxide solution and extracted with ethyl ether. The extracts were washed with brine, dried (MgS04) and evaporated to dryness to obtain 1.9 g. (42%) of the desired amine as a crystalline solid. The structure of the product was verified by its ^H-NMR spectrum. f 2031 D. 3-Amino-2,2,4,4-tetramethylthietane-1,1-dioxide The amine obtained in Part C, above, 29 g. (0.2 mole) was dissolved in 50 ml. acetonitrile and 250 ml. water added. While maintaining the mixture at 5 pH 10 with sodium hydroxide, 35.8 g. (0.21 mole) carbobenzoxy chloride was added over 3 0 minutes, the mixture stirred for one hour, filtered, the precipitate washed with water ana dried in vacuo at 50°C. to provide the NCbz-amine, 0.7 (hexane/ethyl acetate 10 4:1 v/v, phosphcmolybdic acid spray), 52.1 g. (93.4%).

This was dissolved in 700 ml. methylene chloride, 77 g. (0.372 mole) m-chloroperbenzoic acid was added slowly while maintaining the temperature below 45°C. (20-42°C.). The precipitated solid was collected by 15 filtration, the filtrate was washed with IN hydro chloric acid, aqueous sodium bicarbonate solution, dried (MgSO^) and the solvent evaporated. The residue was crystallized from acetone-water to obtain 42 g. (73%) of the Cbz-protected amine 1,1-dioxide, R^ 0.7 20 (hexane/ethyl acetate 1:1 v/v, phosphcmolybdic acid spray).

The protecting: group was removed by hydrogenolysis of 5 g. of Cbz-amine in 250 ml. methanol, 5 ml. concentrated hydrochloric acid and 2 g. of 5% Pd/C 25 (50% wet). The product was isolated in the usual manner. Yield: 2.4 g. (85%), 0.6. The retention time upon gas-liquid-chromatography on a 1 meter, OV-1 column at 180°C. was 1.3 minutes. The overall yield for the three steps starting frcm 3-aminc-30 2,2,4,4-tetramethylthietane was 65%.

By employing equivalent amounts of amine and m-chioroperbenzoic acid in the above procedure the corresponding sulfoxide is obtained in like manner. 2031 E. Employing the appropriate ketone of formula R^R^CHCOCHR^R^ in place of diisopropylketone in the procedures of Parts A-C affords the corresponding amines of the formula shown below.

R3 d R' R5 R6 ch a CH3 h ch3 h h h C2H5 h h h i"C3H7 h h h i-c^h^ h i"C3 H7 h —-C4H9 h h H i"C4H9 h t-c4 H9 -j IX h n-c4 H9 H c2h5 h C2H5 h The corresponding sulfoxides and sulfones are prepared by the procedure of Part D above. r 2031^ EXAMPLE'16 L-Aspartyl-D-alanine N-(2,2,4,4-tetramethylthietan-3-vl}amide: ch., ch i, r = -<^s , ra = ch3 ch3 ch3 CH-j ^CH3 A. t-Boc-NHCH(CH )CONH- CH3 - . -GH3 To a solution of 2.09 g. (11 mmole) N-t-butoxy-carbonyl-D-alanine in 75 ml. of tetrahydrofuran was added 1.4 7 ml. (10 mmole) triethylamine and the mixture cooled to -10°C. Ethyl chloroformate, 0.96 ml. (10 mmole) was added, the mixture stirred for ten minutes then cooled to -20°C. and 1.7 0 g. (11 mmole) of 3-amino-2,2,4,4-tetramethylthietane dissolved in 5 ml. of tetrahydrofuran added. The reaction mixture was allowed to warm to room temperature, ethyl acetate added and the mixture washed with 5% (by weight) citric acid solution (2 x 5 0 ml.), sodium bicarbonate solution until neutral, then with brine. The organic layer was dried (Na^SO^) and solvent removed by evaporation to provide 2.7 g. (78%) of the desired solid product. The "'"H-NMR spectrum of the prcduct was in agreement with that expected. Opon silica gel TLC, eluting with 1:1 ethyl acetate/hexane the prcduct appeared hcmogeneous, R^ 0.77. r 2031 Employing the procedure described in Example 12, Part F, the t-Boc-D-alanine amide provided in Part A of this example was hydrolyzed to obtain the free alpha-aminoamide in 43% yield. The prcduct was homogeneous upon silica gel TLC and .gave a spectrum in agreement with its structure.

C. Coupling to form dipeptide amide A solution of 0.7 g. (3.2 mmole) of the alpha-aminoamide prepared in Part B, above, was mixed.with 10 ml. of water, adjusted to pH 10.1, cooled in an ice-bath and 0.567 g. (3.2 mmole) of L-aspartic acid N-thiocarboxyanhydride added portionwise while maintaining the mixture at pH 9 by addition of 0.5 N scdium hydroxide solution. The mixture was then stirred at 0°C. for 45 minutes, adjusted to pH 5.2 and evaporated to dryness in vacuo. The residue was slurried in methanol, solids removed by filtration and the filtrate evaporated. To the residue was added 150 ml. of ethyl ether, the precipitated prcduct collected by filtration and dried in the vacuum oven overnight to obtain 1.5 g. of crude material. After reslurzrying two more times with ethyl ether, 0.9 g. of prcduct (85%) was obtained. Sweetness, 2000 x sucrose The corresponding compounds of formula (I) wherein Ra is C2H5' i~C3H7 or n_C3H7 are similarly obtained by the above procedures employing the appropriate N-t-boc-amino acid in place of N-t-boc-D-alanine. c 203176 EXAMPLE 17 L-Aspartyl-D-alanine N-(2,2,4,4- tetramethyl-1,l-aioxothietan-3-yl)amide CH PH_ I, Ra = CH3, R = -\^S02 : .ch3 . ,ch3.

"SO CH3 CH3 A- t-Boc—NHCH (CH3 ) CONK- O 2 CH3 CH3 A solution of 31.6 g. (0.10 mole) of N-t-butoxy-carbonyl-D-alanine N- (2,2,4,4-1etramethylthietan-3-vl)amide, provided in Example 16, Part A, in 500 ml. chloroform was cooled, to 10-20°C. and 41.3 g. (0.24 mole) m-chloroperbenzoic acid was added slowly while maintaining the reaction temperature below 45°C. The resulting mixture was stirred for one hour, diluted with chloroform and washed in turn with 5% aqueous scdium bicarbonate, 0.IN hydrochloric acid, 5% scdium thicsulfate and saturated brine. The washed organic layer was dried (MgSO^) and evaporated to dryness to provide 33.7 g. of residual oil (9 7%) of suitable purity for use in the next step.

The t-Boc-amide obtained in Part A, above, 34.3 g. (0.10 mole) dissolved in a mixture of 50 ml. concentrated hydrochloric acid and 100 ml. each of water and ethanol was heated at reflux for one hour. The mixture was cooled, washed with ethyl ether, the aqueous phase adjusted to pH 12 with 50% aqueous sodium hydroxide and extracted with ethyl acetate. The extracts were CH3 . CH3 ' 20317 dried (MgSO^) ana evaporated _in vacuo to obtain 18.7 g. (75%) of crystalline solid. This was recrystal lized frcm carbon tetrachloride with 30% recovery of product.

■ C. -Diblocked dipeptide amide To a- solution of 14.28 g. (0.04 mole) beta-benzyl .. N-benzyl oxycarbonyl-L-aspartate in 700 ml. tetrahydrofuran was added 4.4 ml. (0.04 mole) N-methvlmorpholine and the mixture cooled to -10°C. Ethyl chloroformate, 10 3.9 ml. (0.04 mole) was added,--the mixture stirred at -10°C. for 15 minutes and. cooled to -2.0°C. A solution of 9.92 g. (0.04 mole) D-alanine N-(2,2,4,4--tetramethyl-1,l-dioxothietan-3-yl)amide from Part B, above, in 5 0 ml. tetrahydrofuran was added and the 15 resulting mixture stirred at ambient temperature for one hour. The reaction mixture was poured into -700 ml. ethyl acetate, washed in turn with N hydrochloric acid, scdium bicarbonate solution, 0.IN scdium hydroxia and brine. The washed extracts were dried (MgSO^) and 20 evaporated in vacuo. The residue was slurried in ethyl ether and the solid collected by filtration to afford 19.8 g. (84%) of diblocked dipeptide amide which was recrystallized from ethyleneglycol dimethyl ether/isopropyl ether with 77% recovery. 25 d. To a solution of 10 g. of the prcduct obtained in Part C, above, in 250 ml. methanol was added 3 g. of 5% Pd/C (5 0% wet) and 1 ml. concentrated hydrochloric acid and the mixture hydrogenated for one hour at 2 0 psx (3.52 kg./cm. ). The catalyst was removed by 30 filtration, the filtrate adjusted to pH 5.2 with sodium hydroxide solution and evaporated in vacuo to near dryness. The residue was mixed with ethyl ether and the solid collected by filtration and dried in the vacuum oven at 4 5°C. to obtain 5.5 g., 89% of the 35 desired dipeptide amide.

Sweetness, 1000 x sucrose. 2 031 7 E. By use of one equivalent of m-chl oroperbenzoic acid in the method of Part A, above, the corresponding t-Boc-D-alanine amide sulfoxide is obtained which, when carried through the procedures of Parts 3, C and 5 D, above, provides L-aspartyl-D-alanine N-(2,2,4,4-tetramethvl-l-oxothietan-3-yl) amide. c 1-7 20317 EXAMPLE 17A Employing the procedures of Examples 12-17, corresponding L-aspartyl-D-amino acid amides (I) £ wherein R is methyl, ethyl, isopropyl or n-propyl and 5 R is as defined belcw are prepared from the appropriate starting materials via D—RaCH(NH^)CONHR intermediates. The corresponding L-aspartvl-DL-amino acid amides are similarly provided when a t-Boc-DL-amino acid is employed in place of the D-enanticmer. Likewise, use 10 of DL-aspartic N-thiocarboxyanhvaride' in the coupling step affords the DL-D or DL-DL ccmpounds of formula (I).

KOOCCH CHCONHCHCONHR (I) ' ' 3 NH2 R R R R CH-. C (CH, ) , CH_CH, ■ 3 i 3 3 i 2 3 -Oso ch3 ch2ch3_ ch3 c(ch3)3 c2h3vch3 c(ch3)3 c2h5 ch3 CH2CH3 (CH2)3CH3 (ch2)3ch3 ch(ch3)2 ch ch3 S°2 ch3 ch3 -<s ch3 ch3 CH(CH3)2 CH(CH3)7 CH3 CH3 CH(CH3)2 *'2]2 c 2 03176 r ch_ ,ch. so. ch3 ch3 c (ch ) ch 2' 2 ch. / ch.

(CH2)2 ch3 ch3 ch3 ch3 2 ; 2 ch ch £ ch2ch3 CH, ' ^ CH2 * 2 ch3 ch. so, X^2'2 ch3 ch2ch3 ch3 /ch3 s s ch3 ch3 ch^. ,ch 0 ch(ch3)2 ch(ch3)2 ch. ch2)3 ch„ , ch, 3\/ 3 ■Qo -pv, CH3 ch, ch, P ch3 ch3 ch3 ch3 / CH3 CH3 ch-ch, JV ~v-(ch )-ch2ch3 ch3 ch3 ch3 ch3 ch. ch. 0. ch ch 3 3 ^17 & r r ch ch3 i>2 ch3 ch3 ch(ch.).

V(CH2}3 ch(ch3)2 'ch2ch2ch3 ch(ch3)2 ch. ch. ch3 ch3 ch, ch, ch3 ch3 CH2ch3 0 ch2ch3 h(ch3)2 ch(ch3)2 CH0 CH, ch3 ch3 CH3N/CH3 ch^Nzh. ch, ch, iw J c(ch3)3 c(ch3)3 ch(ch3)2 0 /C(ch3)3 ch(ce3)2 0 ch(ch3)2 ^ch ( ch3 ) 2 ch3ch2 ch2ch3 ch, ^>2 ch3 2031 EXAMPLE 18 L-Aspartyl-D-alanine N-(2-methvlthio-2,4- dimethylpentan-3-yl)'amide " A. 2-Methylthio-2,4-dimethvlpentan-3-one A solution of 2 00 ml. of methanol containing 9.2 g. (0.40 mole) scdium metal was cooled in an ice-bath and saturated with gaseous methyl mercaptan. To this was added 77.2 g. (0.40 mole) of 2-brcmo-2,4-dimethyl-pentan-3-one at room temperature and the resulting 10 mixture stirred for two hours. The reaction mixture was diluted with water, extracted with ethyl ether, the extracts washed with water, brine and dried over anhydrous sodium sulfate. The ether was evaporated and the residue distilled _in vacuo to afford 5 0.4 g. 15 of product, B.P. 7 6Q (20 mm.).

B. 2-Methylthio-2,4-dimethvl-3-aminopentane A solution of 6.0 g. (0.038 mole) 2-methylthic-2,4-dimethylpentan-3-one, 9.9 g. forrnamide and 2.1 g. of 100% formic acid was heated at reflux while removing 20 water formed in the reaction by means of a fractionating head. After 12 hours an additional 2.5 g. of formic acid was added and reflux continued for another 24 hours in the same manner, by which time the reaction mixture reached a temperature of 190°C. The mixture 25 was cooled, diluted with water and extracted with ethyl acetate. The extracts were washed with water and evaporated to dryness at reduced pressure to provide 5.3 g. of residual oil. The oil was refluxed with 4 0 ml. of 6N hydrochloric acid for six hours, diluted 30 with water, washed with ether and the aqueous phase made strongly alkaline with scdium hydroxide. After extracting with ethyl ether and evaporation of the extract, 3.3 g. (56%) of colorless amine was obtained which gave a single peak by gas-liquid chromatography 35 on a six foot OV-1 column at 110°C.; retention time 412 s ec ond s. r r 2031 7 * C . D-Alanine N- (2-methylthio-2 , 4-dimethylpentan- 3-yl)amide To a solution, of 3.2 g. (0.017 mole) N-t_-butoxy-carbonyl-D-alanine and 2.5 g. ('0.017 mole) triethylamine in 100 ml. of tetrahydrofuran at -15°C. was added 1.63 ml. of ethyl chloroformate. After stirring for 15 minutes, 2.49 g. (0.017 mole) 2-methylthio-2,4-dimethyl-3-aminopentane was added and the mixture stirred for one hour. The reaction mixture was diluted with ethyl acetate, washed with water, 5% aqueous citric acid (w/v), sodium bicarbonate solution and brine. The organic phase was evaporated to provide 6.0 g. of residue. This was taken up in 100 ml. methanol, 60 ml. of concentrated hydrochloric acid added and the mixture refluxed for one hour. After evaporation of methanol, the residue was taken up in water, washed with ether, the aqueous phase adjusted tc pH 12 with scdium hydroxide and extracted with ethyl ether. Evaporation of the extracts gave 3.2 g. (37%) of prcduct as a colorless oil 0.5 6 (butanol/water/acetic acid-4:l:l by volume) .

D. A solution of 3.1 g. (0.013 mole) of the D-alanine amide, obtained in Part C, in 30 ml. acetone and 17 ml. water was adjusted to pH 9.9 with scdium hydroxide solution and cooled to -2°C. To this was added 2.78 g. (0.013 mole) L-aspartic N-thiocarbcxv-anhydride in small portions over 20 minutes while maintaining the pH at 9.9 with IN scdium hydroxide.

When the addition was completed, the resulting mixture was stirred for 30 minutes at -2°C., washed with ethyl acetate acidified to pH 2 with hydrochloric acid and washed again with ethyl acetate. The aqueous phase was then adjusted to pH 5.2 and evaporated to dryness. r 2 0317 -9 0- The crude dipeptide amide was obtained by slurrying the residue in methanol, filtering, treatment of the filtrate with ether and filtering to obtain a second crop. Total crude yield 4.7 g.

The crude prcduct was purified by preparative layer chromatography on silica gel plates (20 x 20 x 2 mm.) eluting with butanol/water/acetic acid, 4:1:1 by volume. The band at 0.4 2 was cut out and eluted with methanol to give the pure L-aspartyl-D-alanine 10 amide.

Sweetness: 150 x sucrose. r 2031 example 19 N-Benzyloxvcarbonyl-D-2-aminobutyric acid In a 500' ml. reaction vessel fitted with mechanica stirrer, thermometer and two addition funnels was 5 added 20.0 g. (0.194 mole) of commercial D-(-)-2- aminobutyric acid and a solution of 7.76 g. (0.19 4 mole scdium hydroxide in 97 ml. water. The.mixture was stirred until solution was complete and cooled to 5°C. Simultaneously from the addition funnels were added 10 40.66 g. (0.205 mole) of 86% benzyl chloroformate and a solution of 7.7 6 g. scdium hydroxide in 5 8 ml. water. The temperature was maintained at 4-6°C. during the addition. The reaction temperature then increased slowly to 14°C. Stirring was continued for 15 15 minutes after the temperature subsided, then allowed to warm to room temperature. The reaction mixture was washed with 3 x 7 5 ml. ethyl ether, the aqueous phase adjusted to pH 2 with concentrated hydrochloric acid (16 ml.) causing the prcduct to separate as an oil. 20 The oil was extracted with 3 x 100 ml. ether, dried (MgSO^) and the solvent evaporated to provide a clear, colorless liquid residue which was dried overnight at 0.3 mm. Hg. during which the product crystallized to afford 41.24 g. (89.6%) of the title compound. A 25 1.0 g. portion was recrystallized frcm 5 ml. xylene, washing the precipitate with xylene and pentane.

After drying overnight 0.77 g. of colorless crystals were obtained, 0.5 7 upon TLC on silica gel (solvent: ethyl acetate/hexane/acetic acid 4:14:2 by volume; 30 plate sprayed with 3% vanillin), M.P. 76-78°C., [alpha] + 10 (c = 2.8, ethanol).

Analysis Calculated for C, 60.75; H, 6.37; N, 5.90 F ound: C, 60.61; H, 6.41; N, 5.97. 203V76 The remainder of the crude crystals (40 g.) was recrystallized frcm xylene (150 ml.), washing with xylene (3 x 25 ml.) and pentane (2 x 25 ml.) and dried in vacuo at 45°C. to afford 28.69 g. (71.7%) colorless crystals, M.P. 78-79°C.

EXAMPLE 2 0 L-Aspartyl-D-2-aminobutyric acid N-(dicycloproDylcarbinyl)amide, I, R = C2H5, R = CH/ \7 A. D-CE3CH2CHCONECH( Z\ )2 NHCbz N-Benzyloxycarbonyl-D-2-aminobutyric acid, 4.75 g. (0.020 mole) was dissolved in 200 ml. tetrahydrofuran and cooled under a nitrogen atmosphere to -15°C. N-Methylmorpholine, 2.02 g. (0.020 mole) and ethyl chloroformate, 2.17 g. (0.020 mole), were added and the resulting mixture stirred at -15 to -10°C. for 30 minutes. The resulting solution of mixed anhydride was cooled to -20°C. and 2.22 g. (0.020 mole) dicyclo-propylcarbinylamine dissolved in 10 ml. tetrahydrofuran was added. Stirring was continued for 15 minutes at -20 to -15°C., after which the mixture was allowed to warm to room temperature, 150 ml. ethyl acetate was added and the mixture extracted with 2 x 100 ml. N hydrochloric acid, 2 x 100 ml. 5% aqueous scdium bicarbonate solution and 100 ml. saturated brine. The organic layer was dried (MgSO^) and the solvent evaporated at reduced pressure to afford 6.62 g. (100%) of colorless solid, R^ 0.68 upon TLC on silica gel (solvent: ethyl acetate/hexane, 1:1 by volume; plate sprayed with 3% vanillin). r 203176 B. D-(CH3CH2CHCONHCH( A)2 ■NH2 The Cbz-amino-protected amide obtained in Part A, above, 6.62 g. (0.020 mole) was dissolved in 250 ml. reagent grade methanol. 5% Palladium-on-carbon catalyst, 1.5 g., was added and the mixture hydrogenated at 2 50 psi (3.52 kg./cm. ) for 45 minutes. The catalyst was removed by filtration and the filtrate evaporated in vacuo to provide a liquid residue. N Hydrochloric acid, 25 ml., was added, the mixture stirred then 10 extracted with 25 ml. ethyl ether. The aqueous phase was made strongly alkaline (pH 14) with 10 M sodium hydroxide and the mixture extracted with 3 x 25 ml. ether. The extracts were combined, dried (MgSO^) and the ether evaporated to afford 3.29 g. (83.9%) of 15 colorless solid, M.P. 63-64°C. R^ 0.60 (butanol/acetic acid/water, v/v; ninhydrin spray); [alpha] -46.7° 1 " ■ (c = 2, IN HC1). The H-NMR spectrum was in agreement with the structure of D-2-aminobutyric acid N-(dicyclo-propylcarbinyl)amide. c. Diblocked dipeptide amide To beta-Benzyl N-benzyloxycarbonyl-L-aspartate, 5.61 g. (0.0157 mole) dissolved in 50 ml. tetrahydrofuran and cooled to -15°C., was added 1.59 g. (0.0157 mole) N-methylmorpholine. To this was added dropwise 25 1.70 g. (0.0157 mole) ethyl chloroformate, the resulting mixture stirred for 30 minutes at -15°C. and a solution of D-2-aminobutvric acid N-(dicyclopropylcarbinyl)amide in 15 ml. tetrahydrofuran was added dropwise. Stirring was continued for 15 minutes at -15°C., then the 30 reaction mixture was allowed to warm to room temperature. The solvent was evaporated Ln vacuo to afford a solid residue. This was mixed with 150 ml. ethyl acetate and the resulting suspension washed with 2 x 75 ml. N hydrochloric acid. The clear organic layer wa5 washed 35 with 2 x 75 ml. 5% aqueous scdium bicarbonate, 75 ml. r ' 20317 brine, dried (MgSO^) and the solvent evaporated in vacuo to afford 8.36 g. (99.5%) of colorless solid, 0.36 on TLC (ethyl acetate/hexane, 1:1, vanillin spray). Recrystallization from ethyl acetate gave 6.12 g. (73%) crystals, M.P. 167-168°C.

D. To a solution of the diblocked dipeptide amide, obtained in Part C, in 250 ml. of methanol was added 1.5 g. 5% (w/w) Pd/C (50% wet) catalyst and the mixture hydrogenated at 50 psi (3.52 kg./cm. ) for 45 minutes during which the theoretical amount of hydrogen was consumed. The ctaalyst was removed by filtration, the filtrate evaporated _in vacuo to a volume of about 75 ml. The concentrate was filtered to remove the precipitated product which was washed with methanol and dried _in vacuo to provide 2.85 g. colorless powder, M.P. 225-227°C. (deccmp.). An additional 0.76 g. was obtained frcm the mcther liquor. Total yield: 100%. R- 0.56 (butanol/acetic acid/water, 4:1:1; ninhvdrin i- spray).

Sweetness, 500 x sucrose. 2031 7 EXAMPLE 21 L-Aspartyl-D-2-aminobutyric acid N- ( 2 , 2 , 4 ,4-tetramethyl-l, l-dioxothietan-3-yl) amide: i/ Ra = c2h5, r = -<;so2 A. D-CH^H^HCONH-C^SC^ NHCbz Employing 3-amino-2,2,4,4-tetramethylthietan 1,1- dioxide in place of dicyclopropylcarbinylamine in the procedure of Example 20, Part A, afforded N-benzyloxy- carbonyl-D-2-aminobutyric acid N-(2,2,4,4-tetramethyl- 1,l-aioxothietan-3-yl)amide in 99% yield, R_ 0.50.

B. Hydrogenolysis of the above prcduct by the procedure of"" Example 20, Part B, afforded D-2-aminobutvric acid N-(2,2,4,4-tetramethyl-l,l-dioxothietan-3-yl)amide in 18% step yield, r_ 0.41.

C. The corresponding diblocked dipeptide amide, C^HcCH_OCOCH_CHCONHCH(CnHc )C0NH-OS0_, r _ 0.68, 6 5 2 2, '25 2 r NHCOOCH_CcH_ . 2 6 D was obtained in 99% step yield by the procedure of Example 20, Part C.

D. Hydrogenolysis of the product obtained in Part C, 20 above, (1.16 g.) by the procedure of Example 20, Part D, employing 0.4 g. of 5% Pd/C (50% wet) afforded the title compound in 92% step yield, M.P. 165-167°C» (deccmp, ) , R 0 . 4 .

Sweetness, 200 x sucrose.

ZOM 4 EXAMPLE 22 L-Aspartyl-D-2-aminobutyric acid N- ( 2 ,4-dimethyl-3-pentyl)amide I, Ra = C2H5, R = / A. D-CH3CH2CHCONE ^H2 Employing the appropriate amine in the procedure of Example 20, Part A, and hydrogenolysis of the crude prcduct by the procedure of Example 20, Part 3 gave the diisopr opyl carbinyl amide of D-2-aininobutyric acid in 85% yield as an oil, 0.56.

B. The corresponding diblocked amide, C^H_CH_OCOCH_ o o 2 2 CHCONHCH(C2H5)CONH-CH[CH(CH3)2]2, was obtained in 7 6% NHCOOCH_C^H_ 2 6b step yield by the procedure of Example 20, Part C, ana this was hydrogenated by the procedure of Example 20, 15 Part D to obtain the title compound in 89% step yield (68% overall yield), M.P. 213-215°C. (decomp.), R 0.54. Sweetness, 100 x sucrose. r 20317 6 < EXAMPLE 23 L-Aspartyl-D-val ine N- (dicycl opropylcarbinyl) amide, I, Ra = CH(CH3)2, R = CH<^ V A. (GH3)2CHCHCONHCH(A )2 ' NHCbz Employing ccmmercially available D-valine in place of D-2-aminobutyric acid in the procedure of Example 19 afforded N-benzyloxycarbonyl-D-valine in 82% yield as a white powder, M.P. 55-57°C., R_ 0.45.

This was reacted with dicyclopropylcarbinylamine in 10 the procedure of Example 20, Part A to afford the desired blocked amide in 100% yield, R_ 0.35.

B. Hydrogenolysis of the above prcduct by the methcd of Example 20, Part B, afforded D-valine N-(dicyclc-propyl carbinyl) amide in 83.7% yield,- Rf 0.53 as a. colorless solid.

C. The corresponding diblocked dipeptide amide, . C6H5CH2OCOCH2CHCONHCH[CH(CH3)2]C0NHCH(a )2> was obtained NHCOOCH_CrH_ 2 6 d in 9 2.4% yield by the procedure of Example 20, Part C, R_ 0.55 as an off-white solid.

D. Hydrogenolysis of the product of Part C, above by the procedure of Example 20, Part D, provided the title compound in 85% yield as a colorless solid, R_ 0.54.

Sweetness, 110 x sucrose. ' 20^7b EXAMPLE 24 L-Aspar"tyl-D-val ine N-isopropyl amide I, .Ra. = --CH(CH3 >2, -R = CH(CH_)2 ■ Reaction of N-benzyloxycarfaonyl-D-valine with isopropylamine by the methcd of Example 20, Part A afforded.a quantitative yield of N-benzyloxycarbonyl-D-valine isopropylamide of R_ 0.61 (TLC, ethyl acetate/ hexane, 1:1, vanillin spray).

Hydrogenolysis over Pd/C by the methcd of Example 20, Part B gave D-valine isopropylamide in 71% viela, R_ 0.50. Coupling with beta-benzyl N-Cbz-L-asparate provided the diblocked dipeptide amide (procedure of Example 20, Part C), R, 0.40 (TLC, ethvl acetate/hexane, 1. 1:1, vanillin spray), in 62% yield as an off-white solid. This was converted to the desired title compound by the procedure of Example 20, Part D, in 9 0.6% yield, M.P. 226-227°C. (deccmp.), R_ 0.44.

Sweetness, 1-2 x sucrose. ( 2 031 7 EXAMPLE 25 L-Aspartyl-D-alanine N-(2,2,4,4-tetramethyl-3-pentyl)amide, I, Ra = , R = c(ch3)3 A. 2,2,4, 4-Tetramethyl-3-aminopentane This was prepared by the method of J. Chem. Soc., Perkin I, 2087 (1976); ibid, 1797 (1974). Pivalonitrile (33.2 g.) and t-butyl chloride (44.4 g.) were added under nitrogen to a well stirred suspension of sodium sand (18.4 g.) in a mixture of hexane (80 ml.), tetrahydrofuran (20 ml.) and methanol (1 ml.) over one hour at 15-20°C. The mixture was stirred three hours, a solution of chlorobenzene (2 g.) in tetrahydrofuran (5 ml.) added dropwise over 10 minutes and stirring continued for one hour. Methanol (20 ml.) was added with caution over 0.5 nr. followed by water until phases separated. The aqueous phase was extracted with ether and the .combined organic phases dried and evaporated In vacuo. The residue was distilled to afford di-t-butylketone imine, b.p. 62-63°C./19 mm.

The imine (14 g.) in dry ether (50 ml.) was added to a suspension of lithium aluminum hydride (1.7 g.) in dry ether (50 ml.). The mixture was stirred at room temperature for 24 hours, refluxed two hours and cooled. Water (1.7 ml.), 15% scdium hydroxide solution (5 ml.) and water (5 ml.) were added cautiously in succession, the mixture filtered, concentrated and the residue distilled to afford the desired amine, b.p. 79-81°C./4U mm. r 203176 B. N-Benzyloxycarbonyl-D-alanine, 7.59 g.- (0.034 mole) was added to 170 ml. methylene chloride containing 4.88 ml. (0.035 mole) triethylamine and the resulting solution cooled to -10°C. Ethyl chlorof ormate, 3.35 ml. (0.035 mole) was added, the mixture stirred at -10 to -5°C. for 25 minutes then 5.0 g. (0.034 mole) 2,2,4,4-tetramethyl-3-aminopentane was added and stirring continued overnight after allowing the mixture to warm to roan temperature. The reaction mixture was washed with 2 x 100 ml. 5% aqueous scdium bicarbonate, 2 x 100 ml. 3 M hydrochloric acid, dried (MgSO^) and the solvent evaporated in vacuo to leave 9.99 g. (82%) N-Cbz-D-alanine N-(2,2,4,4-tetramethyl-3-pentyl)amide, identified by its "'"H-NMR spectrum, R, 0.72 (TLC, ethyl acetate/hexane, 1:1, phosphcmolybaate spray).

C. The above Cbz-D-alanine amide, 9.99 g. was dissolved in 250 -ml. methanol, 1.6 g. 5% Pd/C catalyst (5 0% wet) added and the mixture hydrogenated at 45-75 psi 2 (12.8-21.3 kg./cm. ) for 30 minutes. The catalyst was filtered off, the filtrate evaporated Ln. vacuo to leave a white solid. To this was added 100 ml. IN hydrochloric acid, the mixture stirred for two hours, washed with ethyl ether, then made alkaline with 4 0% (w/w) scdium hydroxide solution. The basic solution was extracted with ethyl ether, the ether dried over magnesium sulfate and evaporated to afford 1.1 g. of colorless prcduct identified as D-alanine N-(2,2,4,4-tetramethyl-3-pentvl)amide, Rf 0.59 (butanol/water/acetic acid, 4:1:1, ninhydrin then phosphcmolybdate sprays). f 2031 6 D. The diblocked dipeptide amide was prepared on a 0.005 molar scale from the above amide and beta benzyl N-Cbz-L-aspartate, employing triethvlamine and ethyl chloroformate in acetcne (50 ml.) by the procedure of Example 20, Part C, in 8 0% yield, 0.4 (TLC, ethyl acetate/hexane, 1:1, phosphcmolybdate spray). It was purified by chromatography on 25 g. of silica gel, eluting with ethyl acetate/hexane, 2:3 by volume, to obtain 1.6 5 g. of purified liquid product.

E. The diblocked dipeptide amide, 1.15 g. (0.021 mole) was hydrogenolyzed in 15 0 ml. methanol with 0.2 g. 5% Pg/C by the methcd of Example 20, Part D, to afford 0.64 g. (93%) of the title compound, M.P. 145-149°C. (deccrnp.) , R_ 0.50.

Sweetness, 450 x sucrose.

Employing the appropriate starting N-Cbz-D-amino acid (-Cbz-NH-CH(Ra)COOH) in the procedure of Parts 3-E provides the corresponding ccmpounds of the formula H,OOCCH CHCONHCHCONHCH [C (CH, ) .] where Ra is ethyl, 2 t f -j j 2 NH2 R isopropyl or n-propyl. f 203V76 EXAMPLE'26 L-Aspartyl-D-alanine N-(2-hydroxv-2,4-dimethyl-3-pentyl)amide, ,ch(ch3)2 i, r = , r — —^ c (1zh3 ) 2 oh ' A. 2-Hydroxy-2,4-dimethyl-3-pentanone To a stirred solution of 28.3 ml. (0.2 mole) 2,4-dimethyl-3-pentanone in 100 ml. chloroform was added dropwise 10.3 ml. (0.2 mole) bromine in 3 0 ml. of the same solvent. The resulting mixture was stirred for 10 a few minutes, the solvent evaporated _in vacuo, the residue taken up in 100 ml. ethanol. Water, 50 ml., and 10 M scdium hydroxide, 50 ml., added. The resulting mixture was stirred at reflux for one hour, diluted with 200 ml. water and extracted with 3 x 5 0 ml. ethyl 15 ether. The extracts were dried (MgSO^) evaporated to dryness and the residue distilled to obtain 15.9 5 g. (61%) of the hydroxy-ketone, b.p. 60-62°C./18 mm.

B. 3-Amino-2-hydroxy-2,4-dimethylpentane The hydroxy ketone frcm Part A, 15 g. (0.115 mole) 20 was reduced in refluxing mixture of formamide and formic acid by the methcd of Example 13, Part D, to obtain 4.5 g. (30%) of the hydroxy amine, b.p. 80-81°C./ 17 mm.

C. Diblocked dipeptide amide To a solution of 2.14 g. (5.0 mmole) beta- benzyl-N-benzyloxycarbonyl-L-aspartvl-D-alanine in 35 ml. tetrahydrofuran cooled to -15°C. was added 0.5 5 ml. (5.0 mmole) N-methvlmorpholine and 0.4 8 ml. (5.0 mmole) ethyl chloroformate. The mixture was 30 stirred at -15 to -10°C. for two minutes and 0.66 g. (5.0 mmole) 3-amino-2-hvdroxy-2,4-dimethvlpentane was added. The mixture was allowed to warm to room ( 203176 temperature, stirred overnight and worked-up as described in Example 5, Part B, to obtain the diprotected dipeptide amide, R_ 0.27 (TLC, ethyl acetate/hexane, 1:1/ phosphcmolybdic acid spray, heat) which was used 5 directly in the next step.

D. The product from Part C, above, in 250 ml. methanol was hydrogenated over 1.0 g. 5% Pd/C at 2 6 0 psi (17 kg./cm. ) for two hours. The catalyst was removed by filtration and the solvent evaporated in 10 vacuo. The residue was dissolved in 10 ml. methanol and 3 00 ml. ethyl ether was slowly added with stirring to precipitate the title compound which was collected by filtration, and dried in vacuo to a glass, 1.02 g. , M.P. sinters at c_a. 110°C./ 123-128 (decomp. ) , R, 15 0.31.

Sweetness, 125 x sucrose.

The corresponding compounds of formula (I) wherein R is as above and R^ is ethyl, isopropyl or n-propvl are prepared in like manner from the appropriate starting material of formula C,.H^CH_OCOCHnCHCONHCHCOOH 6 d 2 2, , NHCbz R by the procedures of Parts B-D, above. ) r EXAMPLE 27 L-Aspartyl-D-alanine N-(DL-2-amino-3,3- dimethyl-4-hydroxybutanoic acid lactone)amide 0 I, Ra = CH3, R CH3 CH3 0 A. DL-2-Amino-3,3-dimethyl-4-hydroxybutyric acid lactone hydrochloride Prepared by the method of Wieland, 'Chem. Ber., 81, 323 (1948): 2-Keto-3,3-dimethyl-4-hydroxybutyric acid lactone 3.5 g. was neutralized with dilute scdium hydroxide and the aqueous solution evaporated to dryness in vacuo. The residue was taken up in 100 ml. warm ethanol, filtered hot and a solution of 700 mg. scdium metal in 10 ml. ethanol containing 2 g. hydroxylamine hydrochloride was added. The scdium salt of 3,3-dimethyl-4-hydroxv-2-oximinobutyric acid lactone, 5 g. precipitated and was recrystallized frcm methanol. The oxime was formed by decomposition of the scdium salt in 2 N hydrochloric acid, from which it slowly crystallized. After recrystal1ization from benzene-hexane, M.P. 160°C.

A solution of 25 g. of the oxime in 100 ml. ethanol was added in portions to 5 g. platinum oxide suspended in 15 0 ml. 2 N hydrochloric acid and the mixture hydrogenated at atmospheric pressure for 2 days. The catalyst was filtered off, the filtrate evaporated and the residue taken up in 150 ml. ethanol Treatment with 500 ml. ethyl ether precipitated DL-2-amino-3,3-dimethyl-4-hydroxvbutyric acid lactone hydrochloride, 22 g., which was recrystallized from ethanol/ether, M.P. 208-212°C. r r \- B. Diblocked dipeptide amide The aminolactone hydrochloride from Part A, 1.65 g. (0.010 mole) in 10 ml. methylene' chloride and an equimolar amount of triethyl amine was employed in 'the procedure of Example 5, Part B, to provide *2.3 3 g solid, 0.26 (TLC, ethyl acetate/hexane, 7:3 by volume, phosphcmolybdic acid spray). dissolved in 200 ml. methanol, 0.2 g. of 5% Pd/C catalyst added, the mixture hydrogenated and the prcduct isolated as described in Example 5, Part C, t afford 1.3 g. of colorless solid which was washed wit ethyl ether and dried, M.P. 120-130°C. (deccmp. ) , R_' 0.18. The mass spectrum and data were in agreement with the structure of the title compound.

Sweetness, 110 x sucrose. * O 2 6 5 ch3 ch3 C. The product frcm Part B, above, 2.38 g. was 1031 7 EXAMPLE 28 L—Aspartyl—D—norvaline N-(2,2,4,4- tetramethyl-3-hydroxycyclobutyl)amide, (ch3)2 I, Ra = n-C3H7, R = -<^>-OH , ....(^3)2 (ch3)2 A. D-n-C3H7CHCONH^p^OH NHCbz ■ (CH3)2 N-Benzyloxycarbonyl-D-norvaline (0.1 mole), prepared frcm commercial D-norvaline by the procedure of Example 19, is reacted with cis/trans 2,2,4,4-tetramethyl-3-hydrcxycyclobutylamine by the methcd of 10 Example 20, Part A, to provide the N-Cbz-ncrvaline amide.

B. Hydrogenation of N-Cbz-norvaline amide by the methcd of Example 20, Part 3 provides the corresponding 2-amino compound, D-norvaline-2,2,4,4-tetramethvl-3-15 hydroxycyclobutylamide. The latter compound is converted to the title compound by the procedures of Example 20, Parts' C and D.

The corresponding ccmpounds of formula (I) wherein R is as defined above and R"3- is methyl, ethyl 20 or isopropyl are prepared in like manner frcm the appropriate starting N-Cbz-D-amino acid. r 0 3V7 EXAMPLE 29 L-Aspartyl-D-norvaline N—{2,2,4,4— tetramethyl-3-oxocyclobutyl)amide <CS3}2 I, Ra = n-C3H?, r = (ch3>2 (CH3}2 A. D-n-C3H7CHC0NK-<Y>:0 NHCbz (ch3)2 D-N-Benzyloxycarbonylnorvaline N-(2,2,4,4-tetra- methvl-3-hydroxycyclobutyl)amide prepared in Example 28, Part A, 37.6 g., (0.10 mole) dissolved in 1500 ml. acetone is cooled to -10°C. under a dry nitrogen atmosphere and 42 ml. (0.11 mole) 2.67 M chromic anhydride in diluted sulfuric acid is added. After stirring for 15 minutes at -10°C., the solvent is evaporated _in vacuo, the residue poured into an ice- water mixture, neutralized with scdium hydroxide solution and extracted with ethyl ether. The ether extracts are dried (MgS04) and evaporated to dryness to obtain the crude product which may be purified, if desired, by column chromatography on silica gel.

B. Hydrogenation of the product of Part A, above, by the method of Example 20, Part B provides D-norvaline 2 , 2 , 4 , 4-tetramethvl-3-oxocycl obutyl amide. This is, in turn, converted to the title compound by the methods described in Example 20, Parts C and D.

The corresponding ccmpounds of formula HOOCCH„CHCONHCHCONHR where R is as defined above 1 'a nh2 r and Ra is CH,, Et, or (CH_)„CH are obtained in like j z. manner. 0-51 7 EXAMPLE 30 Employing the appropriate amine of formula RNH^ in the above procedures the compounds of formula (I) shown below are similarly prepared eooc NH2 /CH2CHx CONHCHCONHR RS (I) r r ch. <CV2 oh (ch3)2 —~c3h7 oh (ch3)2 ch. {ch ) ■ 3 2 S>° (CH3»2 i"C3H7 H V?H3 (ch2)4 ho" ^ch. ch. ch ch, j^OH X-°H ch3 ch3 n-C3H7 &V2 hcr^ c_h_ 2 3 ch3, c2h5, ch oh i-C3H , —-C3H7 -Q CH3^OH n-C3H7 (ch ) 1 3 ' 2 HO>=rC2H5 ch3c2h5' i"C3H7' —~C3H7 HO C2H5 hoH2h5 rc3H7 ho n-c3h? ^ke0-u \_ 'k"d-u sh^d 2/c hd) B°<y 7 r » , ( hd) rfe Z(ZED) 'hd shzd ho 'hd h"d 0- 'hd Vd ho" "hd ED °t> 'hd ehd r ^ kd 'hd 9 'hd £ \ hd 'hd 'hd 'hd hd oh "hd c Z "ED £EzD^oe 6 ( "h d) "hd £ £ hd hd 6h^0_u oh sh^d 91 \<L0l j 'hd r / hd oh 'hd 3(SHZD) 'kd skzd c z h d oh 'hd /° hn4 'hd 3(5h3d) v" 'hd oh 'hd 0 z(£hd) 'hd 6h^d-u i e ^ "hd oh 'hd Z , Z-rj (6kdr )-6h^d-u ekd 6h^d-u 'hd hd 2 ( shd)- 1 h 6h^d-u £kd £hd Z(ZXD)\ 6k '7D-U lh£D-T 7 " £rd\ c ( chd.)H ho H 'hd z'h£d-t hZEo1\ 0K lhd L £ L £ h d-u ho ahed-u ^h£d-u h -on- shzd HO—( un / ■EKDE ( ZED) "" ( Hp) HO HO 3(shCD) "HD shsd 6 'HO 'HD d\ ho^\ hoy HD ^"h^d -u 'LH£D-T 'qKZD ,ZEd /o "(J z(vo> c 7 "ED C(eHD) HO r HO ( "HD) c Z "ED /° r r x ( HD) KD / r '"H D-u HO, ho Vd-u Vd-? SEfD- SEZD HD tiZ?0r HD OH 'HD o hn-4 , H H D-u SH ZD 6k^d-u c Z "H D OH 'HD 0 'HD 'HD H h -III- 9 L itoz. j j R r R CH.

CH. ho i"c4h9 HO CH.

CH. c2h5 CH. ok ch. c2h5 1—OH "n c3h7 n-C_H„ 3 / HO n-C_H 3.

HO n-C3H? n-C3K7 n-c4h9 u OH •CH2CH3 CH.

HO CH.

HO^ 'CH.

CH. c n-C.H-4. 9 OH' c2h5 ■ c2h5 ho / ch3 -<{CH0) h6^c2h5 2 4 CH.

CH, CH, voh3 vch CH3 ch.

HO /CH- -g«V4 HO CH3 2 5 CH,, C-H n-c3e7, i-c3h7 n—C H n j—OH "i—CH n-c3h? i-c3h7 ho yl-c3h1 ho i-c3h7 CH. ( ch3 > 2 "oh -c2h5 CH.

Wd) z(zr3) "hd z( ehd)—y_ ho—[ 5h2d 3(ehd) hd 'hd e(t:hd) h 'hd 'hd ■ Z,£ ( hd) /-hed-t SH ZD c 7 ~h d ho > c 3 ' ho £ 5 lhd e(ehd) ho Vd 'hd e(¥o) H0~\ ho-y~ £ Z ' ed 'hd e(ehd)—v ho-Y~ L £ h d-u ehd z(ehd) ho—I ho—/ 6h*d-t '3D ehd- 'hd r ho7> sh3d hd 'hd 6 t7 h d-u oh ehd oh 'hd h -en- 9 L j ' 2 03 \ 1 6 r r C2H5 c2h5 p-ol V-CH. i c2h5 ch. pf2 "oc=0 (ch3)2 i"C3H7 (ch3)2 i—oh a—oh ,C2H5»2 ch. ch, ce, -o ch. ch3 c2h5 'oh oh -ch3 c2h5 ch. ch3 c2h5 _^oh ch'3 c2h5 c2h5 n-c-,h_ \ ^3 7 <3=p ■ n-c3h7 n-c3h7 ch. .0 i-c3h7 ch. ch. <1 ch 3 ch. ch /ch3)2 ch. ch. 2 i-u3n7 -T? i-c3h7 L £ h d-u 'hd £kd °-Py hn -( r lhd 5h3d c Z £ 'hi lhd °^t\ Z07f ED ED "hd hd *5- hn-| 6h^d-u 'hd s(chd) °T> 0 ~f 7 c ? [ ( "h d) 'hd Z , C 7 , ( ~hcd 5h3d £hd £ 6 ( se3d) °ry °1 2(ehd) SEZD 'hd I hn 3(£hd') 'hd z(ckd) h d-u z'hed-u 3(£hd) mi-/" 3(£hd) 'hd C 7 jh6d sS" 'hd shsd £hd o=0- c Z h d hd 'hd h -six- 3(ehd) ° 6h^d-u ^hed-u shz0 W ekl 0 z(eed) 'hd p osh'= HN^y-ii D-J "hd shzd hk. sh^d 'hd ehd hd 'kd "hd 0 hn e hd ^hed-t 3(ekd) H hn y kd G Z ~h d eed °Tl hn_y c z ^ "ho hd shzd Wo) z(^hd) 'hd 3(ehd) 0=fJv hn_/ Z,Zr. i ( kd) ^hed —■* f C -u ' H D-T ,SH3D /EED £ kd 0-P\ z{ ekd) 'hd 3(ehd) °V~ z(EHD) z"hed -u /£hed-t /sh3d /ehd h h 9 L vcot r r ch. (ch,) (ch3)2 ch. ch0 c_h J / 2. D ■&° ch- c_h_ 3 2d c-h,. 2 d ch-, -$» ch-, n-c3H7 \ 4 9 c2h5 03 A 7 EXAMPLE 31 Mass spectrum data was obtained on the following compounds of formula (I) by solid probe introduction into a DS-50 Mass. Spectrometer and exact mass of the molecular ion measured in each case to determine the elemental composition of the ccmpounds. The molecular ion in each case was a (M + H)+ rather than M+ ion for all compounds. Fragmentation patterns were similar in each case. There were no unidentified peaks at +100 amu from the molecular ion which is an indication of chemical purity. r ch chconkchconhr / Z i i kooc nh2 ch3 (L-Asp D-ala) (i, r = ch3) (m + h) Calculated Found Elemental Composition 298-177 298.176 c14h24n3°4 c(ch3)3 314.208 314.211 c15h28n3°4 ch(ch3)2 ch(ch3)2 302.208 302.209 c^h^n^ c^3 314.208 314.208 c^h^n^o, id 28 3 4 ch3/ch3 "0 ch^ch3 330.203 330.202 c-^h^n^ CH3 ch3 332.164 332.165 c. . h_ .-n-.0 , s 14 26 3 4 f \ z A 7 EXAMPLE 32 Carbonated Cola Beverage A carbonated cola beverage was prepared according to the composition given below. The resulting beverage 5 was judged to have sweetness intensity comparable to a control beverage containing 11% sucrose.

Ingredient %, weight Caffeine (1% aqueous solution) 0.700 L-Aspartyl-D-alanine N(cis,trans-2,6-10 dimethylcyclohexyl)amide (10% aqueous) 0.180 Cola flavor concentrate 0.080 Phosphoric acid (50% aqueous) 0.040 Citric acid (50% aqueous) 0.066 Sodium citrate (25% aqueous) 0.210 Caram-el color (25% aqueous) 0.370 Lemon oil extract 0.012 Lime oil extract 0.021 Carbonated water (3.5 volumes carbon dioxide) a.s. 100.000 Replacement of the L-aspartyl-D-alanine N- (cis,trans-2,6-dimethylcyclohexyl)amide in the above formulation with 0.22% of 10% aqueous L-aspartyl-D-2-aminobutyric acid N-(dicyclopropylcarbinyl)amide or 1.10% of 10% aqueous L-aspartyl-D-valine N-(aicyclo-25 propylcarbinyl)amide affords carbonated cola beverages of like quality. 7 EXAMPLE 33 Dietetic Hard Candy A hard candy is prepared according to the following-formulation and procedure: Ingredients Grams L-Aspartyl-D-alanine N-(dicyclopropylcarbinyl)- amide 0.35 Water 4 . 00 FD and C Red #40 (10% aqueous) 0.3 0 Cherry flavor 0.6 0 Citric acid 6.00 Polydextrose* 420.00 Water 180.00 In a small beaker dissolve the sweetener in 15 water, add color, flavor and citric acid and mix well to dissolve. In a separate beaker combine polydextrose and water. Stir while heating to 14 0°C. then allow to cool to 120-125°C. Add other ingredients from small beaker and mix or knead thoroughly. Transfer 20 mass to an oil coated marble slab and allow to cool to 75-80°C. Extract the mass through an oil coated impression roller.

Ose of 0.42 g. of L-aspartyl-D-alanine N-(2,2,4,4-tetramethyl-1,l-dioxothietan-3-yl)amide or 0.93 g. of,. 25 L-aspartyl-D-alanine N-(2,2,4,4-tetramethyl-3-pentvl)amide as sweetening agent in place of L-aspartyl-D-alanine N-(dicyclopropylcarbinyl)amide affords similar results. *0.S. 3,766,165 EXAMPLE 34 A gelatin dessert is prepared according to the following composition and procedure.

Ingredients Grams Gelatin 2 25 Bloc-ra 7.52 2 Citric acid 1.848 Sodium citrate 1.29 6 Strawberry flavor 0.298 L-Aspartyl-D-alanine N-(dicyclopropylcarbinyl)- amide 0.036 B oiling wat er 24 0 . 000 Cold water 240.000 491 .000 Premix the first five ingredients, add to boiling water and stir to dissolve completely. Add cold water and stir briskly. Transfer to serving dishes and refrigerate until set. % 0^ 7* -123-EXAMPLE 35 Low calorie table sweeteners are prepared according to the following formulations: A. A powder form of sweetener is prepared by blending 5 the following ingredients.

Ingredients %, weight L-Aspartyl-D-alanine N- (2,2,4,4-tet'ramethyl- thietan-3-yl)amide 0.18 Crystalline sorbitol 49.7 6 Dextrin (dextrose equivalent 10) 50.00 Monoscdium glutamate 0.02 Glucono-delta-lactone 0.02 S. cdium citrate 0 . Q 2 100.00.

One gram of the resulting blend is equivalent in sweetness to about three grams of sucrose.

B.. A table sweetener in liquid form is prepared as f ollows.

Ingredients %, weight L-Aspartyl-D-alanine N-(dicyclopropylcarbinyl)- amide 0.10 Water 99.8 0 Sodium benzoate 0.10 100.00 one gram of the resulting solution is equivalent in sweetness to about 1.2 grams of crystalline sucrose.

When the sweetener of formula (I) employed in Part A, above, is 0.59 g. of a 1:4 mixture of L-aspartvl-D-alanine N-(dicyclopropylcarbinyl)amide and 30 scdium saccharin comparable .results are obtained.

Similarly when the L-aspartyl-D-alanine N-(dicyclopropylcarbinyl ) amide employed in Part B, above, is replaced by 0.20 g. of a 1:6 by weight mixture of the same compound and sodium saccharin .a comparable liquid 35 table sweetener is obtained.

EXAMPLE 3 6 Frozen Dessert A vanilla sugarless frozen dessert is prepared according to the following formulation by conventional practice.

Ingredients %, weight Heavy cream (35% butterfat) 23.00 Nonfat milk solids 10.50 Mono- and diglyceride emulsifier 0.25 Polydextrose* 11.20 Water 5 4.51 L-Aspartyl-D-alanine N-(2,2,6,6-tetramethyl- cyclohexyl)amide 0.04 Gelatin (225 Bloom) • 0.50 100.00 *U.S. 3,766,165 7.03 \1b EXAMPLE 37 Canned Pears Fresh pears are washed, peeled, cored, sliced into pieces and immersed in an aqueous solution containing 0-05% by weight of ascorbic acid. The sliced fruit is packed into screw-cap jars and the jars filled with a syrup containing the following ingredients: Sorbitol L-Aspartyl-D-alanine N-dicyclopropylcarbinyl)- amide Citric acid Water %, weight 25.000 0. 025 0.125 a. s. 100.000 The jars are capped loosely and placed in an autoclave containing hot water and processed at 100°C. for 45 minutes. The jars are removed, immediately sealed by tightening the caps and allowed to cool. 2 03176 example 38 Powder Beverage Concentrate Ingredients %, Weight Citric acid 31.78 Scdium citrate 5.08 Strawberry flavor - 5 7.72 Strawberry FD and C color 0.5 4 L-Aspartyl-D-alanine N-[(-)fenchyl] amide 2.44 Carboxymethyl cellulose 2.44 ' 100.00 Combine all ingredients in a blender and blend until hcmogeneous. For use, 1.73 g. of powder beverage concentrate is dissolved in 4 fluid ounces (118 ml.) of water. r 31 1 EXAMPLE 39 Baked Cake A highly acceptable vanilla cake was prepared employing the following recipe: Ingredients Grams Emulsified shortening 16.09 Water 20.83 Eggs 23.00 Scdium bicarbonate 1.10 Vanilla extract, single fold 0.28 Glucono-delta-lactone 1.75 Polydextrose*, 70% aqueous solution 80.00 Nonfat dry milk 2.5 0 Cake flour 56.20 Whole milk powder 0.8 0 Wheat starch 1.4 0 L-Aspartyl-D-alanine N-(dicyclopropylcarbinyl)-amide 0.05 204.00 Combine nonfat dry milk, whole milk powder, polydextrose solution and emulsified shortening. Mix at low speed until creamy and smooth (about 3 minutes), add eggs and beat until a hcmogeneous creamy mix is obtained. Dissolve sweetener in water, add to creamy hcmogenate ana mix 2-3 minutes. Add remaining ingredients and mix until creamy and smooth (3-5 minutes). Place 120 g. of batter in small pregreased pan and bake at 350°F. (176°C.) for 30 minutes. *0.S. 3,766,165 -12 8- 203V76 EXAMPLE 40 Synergistic Mixtures of L-Aspartyl-D-alanine N-(dicyclopropylcarbinyl)amide, [I,. Ra = CH^ , R -= CH( /\ ) ^ 1 and Saccharin Blends of [I, Ra = CH^, R = CH (/\ ) ^ ] and scdium saccharin were prepared and evaluated for taste acceptability and sweetness intensity by comparison with aqueous sucrose standards. Sweetness potency factors of scdium saccharin and [I, Ra = CH^, R = CH ( A ) of 300 and 1200 x sucrose, respectively, were used to calculate the theoretical sweetness of the blends. A series of taste panel evaluations were carried out comparing aqueous solutions of the experimental blends with sucrose solutions ranging 6 to 12% (w/v) and 0.033% sodium saccharin solution. Results are tabulated below.

Blend,Part.s by Weight [I, R =CH.

Scdium Sweetness Potency x Sucrose Taste R=CH(^Ajol Saccharin (T)Theory (A)Actual Synergy Quality 1 : 1 750 1000 33 clean, sweet, not bitter 1 2 600 800 33 same 1 4 480 600 33 same 1 6 430 575 33 sweet, percept ible.,- bitt erness §& - 1 8 400 530 33 sweet, si ight bitterness 1 9 39 0 500 33 same 1 381 475 sweet, slight to moderate bitter, metal1ic :aste ■ i J. P. & s. $0(0- 8"3 ........ 20 The % synergy was calculated according to the following formula .where A is the actual sweetness determined by averaging the taste panel results and T is the theoretical sweetness determined from the composition of the mixtures by weight e.g., for the 1:4 blend the theoretical sweetness is (1/5 x 1200) + (4/5 x 300) = 480.

Frcm the results it is seen that with mixtures of from 1:1 to 1:9 there is an unexpected increase in sweetness potency of 33% and a somewhat lesser synergistic effect with the 1:10 blend. Furthermore there is complete masking of the well kncwn bitter aftertaste of saccharin with blends of frcm 1:1 to 1:4 and effective masking of bitterness in blends containing up to one part L-aspartyl-D-alanine N-(dicyclopropylcarbinyl)amide and 9 parts scdium saccharin.

When the above procedure is repeated but the inv-cntion compound is- employed is of the formula (I) wherein Ra is methyl and R is % Synergy = ^ ^ x 100 similar results are obtained. ^\1 EXAMPLE 41 Three batches of carbonated cola beverages were prepared according to the methcd of Example 3 2 except that the sweetener employed in batch A was 0.0 20 g. of the 1:6 blend of [I, Ra = CH^, R = CHf A )^]/scdium saccharin, batch B employed 12 g. sucrose and batch C, 0.3412 g. of a 1:10 blend of saccharin/cyclamate. The sweetness factor employed for the [I, Ra = CH^, R = CH( Z\)2I/sodium saccharin blend was that deter-10 mined in Example 40, i.e. 575 x sucrose. The three beverages were rated for hedonic scores on a nine point rating scale* by a taste panel with the following results.

Beverage Average of Hedonic Scores A 7.1 B 8.0 C 6.7 *1 = Dislike extremely, 5 = neither like nor dislike, 9 = like extremely.

Similarly, when the same three sweeteners are employed in like manner in carbonated lemon-lime beverage, instant chocolate pudding, marshmallcw, grape jelly, orange flavored gelatin, gum drops, chewing gum or vanilla cake formulations, comparable 25 results are obtained. 03 A 7 EXAMPLE.. 42 Scdium Salt of L-Aspartyl-D-alanine N-(dicyclopropylcarbinyl)amide To a solution of 3 g. (-0.01 mole) l-aspartyl-D-5 alanine N-(dicyclopropylcarbinyl)amide in 100 ml. of ethanol is added 2 ml. of 5 N sodium hydroxide. The resulting mixture is stirred for ten minutes at room temperature then evaporated to dryness in vacuo. The residue is triturated with anhydrous ethanol, filtered 10 and air dried.

When the scdium hydroxide employed above is replaced with an equivalent amount of potassium hydroxide, calcium hydroxide, magnesium hydroxide or ammonium hydroxide the corresponding potassium, 15 calcium, magnesium and ammonium salts are formed in like manner.

The remaining L-aspartyl-amino acid dipeptide amides of formula (I) are also converted to carbcxylate salts as described above. r 2 0^-1 7 ( SXAMPLS 43 Acid Addition Salts The L-aspartyl-D-amino acid dipeptide amide of formula (I) is slurried in a small amount of. water 5 and an equivalent amount of acids such as hydro chloric, phosphoric, sulfuric, acetic, maleic, fumaric, lactic, tartaric, citric, gluconic or saccharic acid is added. The resulting mixture is stirred for 15-30 minutes then evaporated to dryness or precipitated 10 by addition of a cosolvent such as methanol or ethanol. 2 031 EXAMPLE 44 Comparative stability of representative L-aspartyl-D-alanine amides of the invention was determined at pH 7 and pH 3 in 0.01 M phosphate 5 buffer at 9 0°C. The concentration of unchanged sweetener was determined at 24 hour intervals by high pressure liquid chromatography on a 10 cm. Lichrosorb* C.. column at 1 ml. per minute of 0.01 M ammonium 1 o acetate containing 15% methanol by volume.- The half-10 life at 90°C. calculated for each of the ccmpounds of formula (I) at pH 7 and pH 3 is shewn in the table below.

Compound of Formula (I, Ra = CK^) Half-life at 90°C., Hours R pH 7 pH 3 ;CH3)2CH CH(CH3)2 54.6 21.2 C(CH3)3 51.5 20.2 CH., i /CH3 49.3 19.6 ch^i i ch3 57.8 13.8 From data obtained in a similar manner, but at , o 0 - various other temperatures, the half-life of the j- p. & 5. cl") io-to-fri -inventi-on compounds^ at room temperature is estimated M. to be ten years or more at these pH's.

*Registered Trademark ioy\7 EXAMPLE 45 2-Alkyl- ana 2,6-Dialkylcvclohexylamines To a solution of 25 g. of 2,6-diisopropylaniline in 250 ml. each of ethanol and water was added 10 g. 5 of dry 5% ruthenium-on-carbon catalyst. The mixture was hydrogenated in an autoclave at 100°C., 1000 psi - 2 (70.4 kg./cm. ) until hydrogen uptake ceased. The catalyst was removed by filtration and the filtrate evaporated to remove solvent. The residue was distilled in vacuo to obtain 11.2 g. of 2,6-diisopropylcyclohexyl- amine as a mixture of cis,trans and trans,trans- isomers, B.P. 122-124°C. at 22 mm.

By employing the appropriate 2-alkylaniline or 2,6-dialkylaniline as starting material and hvdrogenat- ing by the above methcd the following cyclohexylamines are also obtained. 2-methyl-6-ethylcyclohexylamine, B . P .• 82-37°C. at 19 mm. (50% yield); 2-methyl-6-isopropylcyclohexylamine/ B.P. 86° at 14 mm. (4 5% yield); 2-n-butvlcyclohexylamine; 2-ethyl-6-n-butylcyclohexylamine; 2 - m et hy 1 - 6 -1- butyl eye 1 oh exy 1 am in e; 2-t-butylcyclohexylamine; 2,6-diraethylcyclohexylamine; trans-2-ethylcyclohexylamine, B.P. 77-78° (23 mm.); 2,6-diethylcyclohexylamine, B.P. 96°C., (17 mm.); trans-2,- isopropylcyclohexylamine; 2-isobutylcyclohexylamine; 2-methy1-6-n-butylcyclohexylamine. 2 31 76 EXAMPLE'46 2-t-Butylcyclohexylamine i. 2-t-Butylcyclohexanone A solution of 31.25 g. {0.20 mole) t-butylcyclo-5 hexanol in 80 ml. of ethyl ether was cooled to 10°C.

To this was added dropwise, with stirring, a solution of 21.0 g. (0.07 mole) scdium dichromate dihydrate and 15.75 ml. (0.30 mole) concentrated sulfuric acid in 100 ml. water while maintaining the reaction mixture 10 below 25°C. The mixture was then warmed to room temperature, stirred for two hours, poured onto ice-water, ether layer separated, the aqueous phase extracted again with ether and the combined extracts washed with water, scd.ium bicarbonate and dried (MgSO^ ) 15 Evap.aration of the ether afforded 30.6 g. (99%) of the desired ketone. ii. Leuckart Reduction of Ketone A mixture of 2-_t-butyl cycl ohexanone 3 0.6 g. (0.20 mole), formamide 50 ml. (1.2 mole) and formic acid 20 (10 ml.) was heated at reflux while removing water as it formed in the reaction while returning the ketone to the reaction vessel. Formic acid (10 ml.) was added as needed to control deposition of ammonium carbonate in the condenser. After four hours the 25 reaction temperature reached 197°C. and distillation ceased. The mixture was cooled, diluted with water (50 ml.) and extracted with ethyl acetate (75 ml.). The organic layer was evaporated, concentrated hydrochloric acid added (50 ml. per 100 ml. of residue), 30 the mixture boiled overnight, cooled and washed with 50 ml. of ethyl ether. The aqueous phase was adjusted to pH 11 with scdium hydroxide, cooled, extracted with ether (2 x 4 0 ml.) and the extracts dried over scdium hydroxide pellets. The solvent was evaporated and the residue distilled through a 10 cm. column to obtain 5 21.93 g. of the title amine (71%), B.P. 86-88°C. (21 mm.) as a mixture, of cis and trans-isomers. iii. dl-Fenchone and _l-fenchone are reduced to the corresponding fenchylamines by the Leuckart reduction methcd of Part ii, above. (-)Fencylamine is 10 obtained as a water white liquid, B.P. 55-60°C. (6 mm.) [alpha] -21.9° in 30% yield. r zoM7 .EXAMPLE "47 AlkylcycloalkyIcarbinylamines and dicycloaikylcarbinylamines ' i- To a mixture of 113.5 g. (1.0 mole) of 5 cyclobutylcarbonyl chloride and 99 g. (1.0 mole) cuprous chloride in 1000 ml. of dry ether under a nitrogen atmosphere is added dropwise 4 78 ml. (1.0 mole) of 2 M t-butylmagnesium chloride in the same solvent. The addition is carried out at -5 to -15°C. 10 The resulting mixture is poured into 500 ml. of 3 M hydrochloric acid and 700 g. ice, the organic layer is separated and washed successively with water, scdium bicarbonate solution, brine and dried (MgSO^). The dried ether extract is evaporated at reduced pressure 15 and the residue distilled to provide t-butylcyclobutyl- k et on e. ii. The ketone, 105 g. (0.75 mole), is mixed with hydroxylamine hydrochloride 38.3 g. (1.16 mole) and sodium acetate, 123 g. (1.50 mole), in sufficient 20 water to effect solution, heated on the steam-bath for one hour, cooled and the mixture adjusted to pH 7.5 . with scdium hydroxide solution. After extracting the mixture with ether, the extracts are dried (MgSO^) and evaporated to dryness to afford the oxime. The oxime 25 is dissolved in anhydrous ethanol (about two liters per mole of oxime) and the solution heated at reflux. Scdium metal (about "10 moles per mole of oxime) is added in portions at a rate sufficient to maintain reflux temperature. When all the scdium is added the 30 resulting mixture is cooled and 200 ml. of ethanol r 20317 6 followed by 300 ml. of water is added. The mixture is acidified with hydrochloric acid, evaporated to remove ethanol and the residue made alkaline (pH 12-13) with 10 M scdium hydroxide. The alkaline mixture is 5 extracted several times with ether and the combined extracts dried (MgSOA ). Dry hydrogen chlorine is passed through the dried extracts until precipitation is complete. The precipitated hydrochloride salt is collected by filtration, washed with ether and air 10 dried. The salt is converted to the free base by means of aqueous scdium hydroxide, extraction with ethyl ether and evaporation of the extracts. The J. P. & S 40(t>.&} prcduct, t-butylcycl obutyl carbinyl amine is of suitable rfjai// -forwuau cx) purity for use in preparing the amides of the mvon11on■ . but may be further purified, if desired, e.g. by distillation or column chromatography. iii. By employing the appropriate acid halide and Grignard reagent in the above procedure in place of cyclobutylcarbonyl chloride ana t-butylmagnesium 20 chloride the following amines are obtained in like manner. r —(ch2) m r7 . h ch3 ch3 ch3ch9 ch 3 (ch3)2ch CH3 ch ch b-c3h7 . CH3 CH3 ch3ch2 ch3- CH3CH2 ch3CH9 ch3 ch3 11-c3h7 ch3ch2 ch3 -~C3H7 ch3 ch3 4 CH3 4 CH3CH2 *B.P. 80-9 0°C. (21 mm.) m 0 0 0 0 0 0 0 1 1 1 1 1 1 2 2 2 2 2 2' 2 3 3 3 4 r h' h ch3 ch3ch2 b-c4s7 (ch3)2ch ch3 ch3.ch2 h ch3 n-c4h7 n-c3h7 (ch3)3c ch3 h ch3ch2 h ch3 (ch3)2ch —-("4H7 CH3 h cw 3 h CH3 ch-,ch0 r h u h ch3ch: h c(ch3)3 h h h h h h ch3* h ch3ch2 h h R h ch ^i3 h h h ch., 2-0*5 iv. The amines of the following formula are also provided in like manner.

NH ^vm (CH?) i a in 0 0 0 0 1 1 1 1 2 2 2 3 3 4 3l 1 2 3 4 1 2 3 4 2 3 4 3 4 4 The following amines are also prepared by this methcd: 2,2-dimethyl-3-aminopentane, B.P. 123-126°C., atmospheric pressure; 2,2,4-trimethyl-3-aminopentane, B.P. 149-150°C., atmospheric pressure. r r 2°^^^ EXAMPLE 48 trans-2-Ethylcyclopentylamine i. 2-Ethylcyclopentanone In a three-necked flask 5.0 g. of scdium metal was dissolved in 250 ml. of dry ethanol and 31.24 g. (0.20 mole) 2-carboethoxycyclopentanone added. To the resulting yellow solution 18.4 ml. (0.23 mole) ethyl iodide was added dropwise and the mixture heated at reflux for two hours. After cooling, 250 ml. of brine and 50 ml. of water were added and the mixture extracted with ethyl ether (2 x 100 ml.). After drying (MgSO^) and evaporation of solvent 36.5 g. (99%) of 2-ethyl-2-carboethoxycyclopentanone was obtained.

This was decarboxylated by heating at reflux with a mixture of 200 ml. of concentrated hydrochloric acid and 100 ml. of water. After four hours at reflux carbon dioxide evolution was complete. The mixture was cooled, saturated with scdium chloride, extracted with ethyl ether, the extracts dried (MgS04) and ether evaporated. The residue was distilled to obtain 12.62 g. (56%) of 2-ethylcyclopentanone, B.P. 97-98°C. (10 0 mm.). ii. The product obtained above was converted to trans-2-ethylcyclopentylamine by the procedure of Example 47, Part ii, B.P. 150-151°C. in 35% yield. The identity of the prcduct was verified by its ^E-NMR spectrum.

By employing the appropriate 2-carbethoxycyclo-alkanone or a corresponding hetercyclic ketone (prepared by the well known Dieckmann cyclization of the appropriate dicarboxylate ester, see e.g., H. 0.

House, "Modern Synthetic Reactions", W. A. Benjamin, Menlo Park, Cal., 1972, p. 740.) and the appropriate alkyl halide in place of ethyl iodide in the above procedure the following amines of formula R Nfi2 are prepared in like manner. r . J. P. & SK;' .MtL Where R is m 1 1 2 2 2 4 Where R is (ch,) m v^n^g- r CH3 C2H5 -~C4H9 ch3 £ec-c4k9 ch3 t_C4K9 o 0 0 0 0 o 0 0 0 0 o 0 0 s s s so.

S S s n 1 1 1 0 0 ,0 0 0 0 1 1 1 1 0 0 1 1 0 0 0 p 0 0 0 2 2 2 2 3 3 2 2 2 2 1 1 1 1 2 3 3 h. 2-CH. 4-CH. 2-t-CilI-2-CH. 4-CH. 4-sec-C4H9 2-i-c3h7 2-CH, o 4-ch3 3-CH3 -CH3 -i"c4h9 3-t"c4h9 2-CH 4-ch3 1 C3H7 t"C4H9 2-CH3 2-CH3 4 —CH- Z'ow 7 EXAMPLE '49 trans-2-Isopropylcvclopentvlamine 2-1sopropylcvclopentanone To a solution of 10 g. of scdium metal in 670 ml. of ethanol was added dropwise a mixture of 100 g. (1.19 mole) cyclopentanone and 6 0 g. (1.03. mole) acetone and the resulting mixture refluxed for 1.5 hours. The solvent was evaporated _in vacuo, the residue taken up in ether, the solution washed with 10 3 m hydrochloric acid (5 x 200 ml.), 5% scdium bicarbonate ( 3 x 200 ml.), brine (1 x 200- ml . ) and dried (MgSO^). The ether was evaporated with mild heating to afford 9 7 g. of dark liquid which was distilled in vacuo to obtain 55 g. of 2-isopropylidenecyclopentanone, B.P. I5 96-100° (2.7 mm.).

To 12.75 g. of the above prcduct in 250 ml. of methanol was added 2.0 g. 5% palladium-on-carbon catalyst and the mixture hydrogenated at 5 0 psi 2 (3.5 kg -/cm .). After one hour the hydrogen uptake was complete. The catalyst was removed and solvent evaporated In vacuo to afford 12.75 g. of colorless liquid. This was distilled to obtain 9.64 g. of 2-isopropylcyclopentanone, B.P. 74-76°C. (20 mm.).

Reduction of 2-isopropylcyclopentancne by the methcd of Example 47, Part ii afforded the corresponding amine, B.P. 167° (atm.) in 31% yield. ^ \ example'50 2 2-Dimethyl-3-amincbutane In a 5 00 ml. flask was placed 10.0 g. (0.10 mole) 2,2-dimethyl-3-butanone, 250 ml. methanol, 7 6.94 g. (1.0 mole) ammonium acetate and 4.37 g. (0.07 mole) sodium cyanoborohydride, ana the mixture was allowed to stir at room temperature for 2 4 hours. The pH was adjusted to 2.0 with concentrated hydrochloric acid and the methanol removed at reduced pressure. The 10 residual solid was dissolved in 5 00 ml. water and washed with three 100 ml. portions of ether. The pH of the aqueous solution was adjusted to 13 with 10 M scdium hydroxide and the mixture extracted with three 100 ml. portions of ether. The extracts were combined 15 dried over anhydrous MgSO^, filtered and distilled.

The amine (2.4 g.) distilled at 102-103°C at atmospher pressure.

The racemic amine was resolved by the Polari-metric Control methcd described by Brack efc _al. , 20 Chem. See-. , 9 21 (19 56 ) employing the amine hydrogen tartarates and crystallizing from 70:30 methanol/water (by volume) to obtain dextrorotatory amine of 93 +_ 4% purity and levorotatorv amine of 80 _+ 4% purity.

When an equivalent amount of 2,2-dimethyl-3-25 pentanone is employed in place of 2,2-dimethyl-3- butanone in the above procedure 2,2-dimethyl-3-amino-pentane is obtained and resolved into its enanticmers. r 7.0-*^ preparatiqn a L-Aspartic acid N-thiocarboxyanhydride A. L-Aspartic acid (582 g., 4.29 mole) was added gradually with stirring to 350.9 g. (8.58 mole) of 50% 5 scdium hydroxide solution at 0°C. Methyl methyl xanthate (550 g., 4.51 mole) in 405 ml. of methanol was then added as rapidly as possible. The mixture was heated at 45°C. for 1.5 hours, cooled to room temperature, and washed with two portions of methylene 10 chloride. The methylene chloride washes were discarded and the aqueous phase acidified with concentrated hydrochloric acid at 0°C. The solution was extracted with three portions of ethyl acetate, and the combined extracts -washed with brine and dried over anhydrous 15 magnesium sulfate. The solvent was evaporated in vacuo to give a yellow oil which crystallized upon addition of ethylene dichloride and n-hexane. The N-methcxy-thiccarbonyl-L-aspartic acid was collected by filtration, washed with fresh n-hexane, and dried (420 20 g. , 47%) .

M.P. 128-130°C; 1H-NMR (DMSO-dg), (delta) 2.73 (d, 2H, J = 6 Hz), 3.63 (s, 3H), 4.43 (dt, 1H, J = 6 Hz, 3 Hz), 6.6 3 (d, 1H, J = 8 Hz); infrared spectrum (KBr) 1715, 1515 cm <2. 0^ ^ B. N—methoxvthiocarbonyl-L-aspartic acid (207.0 g, 1.00 mole) was dissolved in 1200 ml. ethyl acetate at 0°C. and phosphorous tribromide (47 ml., 0.50 mole) was added in one portion. The cooling bath was removed 5 and the temperature allowed to rise spontaneously to °C. The solution was stirred for 10 minutes after which time a granular white precipitate had formed. The reaction mixture was cooled to 0-5°C., the prcduct collected by filtration, washed with a small volume of 10 ether, and dried. The yield of analytically pure L- aspartic acid N-thiocarboxyanhydride was 157.4 g. (90%).

M.P. 200-205°C. (dec.); [alpha]^5 = -109.5° (C = 1, THF) ; infrared spectrum (KBr) 3225, 1739, 1724, 15 1653, 139 9 cm"; "'"H-NMR (DMSO-dg) ppm (delta) 2.83 (d, 2H, J = 5.0 Hz), 4.7 0 (t, 1H, J = 5.0 Hz), 9.23 (bs, 2H, ex); mass spectrum (m/e) 175 (M), 87, 60.

ZO^76 4 PREPARATION B 2,2-Dimethvlcvclohexvlamine i. 2,2-Dirnethylcyclohexanone To a suspension of 13.5 g. (0.25 mole) sodium 5 methoxide in 5 00 ml. of ethyl ether was added 3 0.8 g. (0.28 mole) 2-methylcyclohexanone and 20.3 g. (0.28 mole) ethyl formate. The mixture was stirred at room temperature for 12 hours, filtered under a nitrogen atmosphere, the solids washed with ethyl ether and 10 dried in the vacuum oven at 75°C. The dried cake was ground in a mortar and pestle to a fine powder to obtain 17.5 g. (43%) of sodium 2-formyl-6-methylcyclo-hexanone which was used in the next step.

The above prcduct, 17.5 g. (0.11 mole) was added 15 to a mixture of 2.88 g. (0.13 mole) scdium shot, 500 ml. anhydrous ammonia and about 0.1 g. ferric chloride. The resulting gray suspension was cooled to -45°C. and stirred for one hour at the reflux temperature of the system. To this was added 20.86 g. (0.15 mole) methyl 20 icdide, the mixture stirred three hours at reflux and ■ allowed to evaporate while warming to room temperature overnight. The residue was suspended in 300 ml. ethyl ether, refluxed to expel1 traces of ammonia and water added to dissolve the solids. The ether was extracted 25 with water (3 x 100 ml.), the combined aqueous layers treated with 6 g. of solid scdium hydroxide and heated to steam distill the ketone. The steam distillate was extracted with ethyl ether, the extracts washed with brine, dried and ether evaporated to provide 2,2-30 dimethylcyclohexanone as a colorless liquid, 2.0 g. ii. The ketone provided above is converted to the oxime and the latter reduced with scdium in ethanol as described in Example 47, Part ii, to provide 3.1 g. of 2,2-dimethvlcyclohexylamine.

The following 2,2-disubstituted ketones are pre pared ana converted to amines by the above method in like manner. 2,2-dimethvlcyclopentanone 2,2-diethvlcyclopentanone 10 2,2-di-n-propylcyclopentanone 2.2-diethylcyclohexylamine 3.3-dimethylthiepane-4-one 3.3-dimethyloxepane-4-one 4.4-dimethyloxepane-5-one 7.0 3 PREPAR ATION C 2,2,6,6-Tetramethylcyclohexylamine i. 2,2,6,6-Tetramethylcycl ohexanone A 5 0% suspension of sodium hydride in mineral 5 oil, 14.3 g. (0.30 mole), was suspended in tetrahydrofuran, the liquid decanted and the solid resuspended and decanted again to remove the oil. Then 15 g. (0.12 mole) of 2,6-dimethylcyclohexanone was added followed by dropwise addition of a mixture of 11 g. t-10 butanol and 20 ml. of tetrahydrofuran (vigorous hydrogen evolution) and the resulting mixture refluxed until hydrogen evolution was complete. To this was added dropwise 37.8 g. (0.30 mole) methyl sulfate and the mixture heated at reflux for 24 hours. After dilution 15 with water, extraction with ethyl ether, washing the extracts with water, drying and evaporation of solvent below 40°C., 17 g. of tetramethylketone was obtained. This was distilled to obtain 14.6 g. of prcduct, B.P. 6 2-64°C. (15 mm.). ii. The 2,2,6,6-tetramethylcyclohexanone (8 g.) obtained above was converted to the oxime and the latter compound reduced by the procedure of Example 47, Part ii, to provide 1.4 g. of the desired amine as a colorless liquid which was of suitable purity for use 25 as intermediate. r~ iii. 2,2,5,5-Tetramethylcycl opentanone To a slurry of 2.0 moles of sodium hydride (washed to remove oil) in tetrahydrofuran was added 19 0 ml. (2.0 mole) methyl sulfate at a fast rate. Simultaneously, 5 35.7 g. (0.4 25 mole) cyclopentanone in 5 0 ml. of the same solvent was added at a slow rate. The reaction mixture warmed spontaneously to a gentle reflux and hydrogen evolution was vigorous. When the addition was completed, the mixture was allowed to stir overnight 10 at ambient temperature. After heating to reflux for two more hours a mixture of t-butanol in tetrahydrofuran was added and reflux continued for three hours. The reaction mixture was diluted with water, extracted with ethyl ether, the extracts washed with water, 15 brine, dried over anhydrous MqSO. and the solvent r 4 evaporated to yield 48.2 g. of crude prcduct. This ■ was distilled to afford 24.2 g. of tetramethylketone, B.P. 63—68°C. , 4 0 mm._ By employing a lower mole ratio of methyl sulfate 20 to cyclopentanone, the same method affords 2-methvl-cyclopentanone, 2,5-dimethvlcyclopentanone and 2,2,5-trimethylcyclopentanone.

The following ketones are prepared in like manner when the appropriate starting materials are employed 25 in the procedures of Part i and Part iii, above. The alpha-propyl and alpha-butylketones 'are prepared using e.g., the appropriate alkylbromide as alkylating agent. r ,03 2,2,6-trimethylcyclohexanone 2-ethyleye1opentanone 2.2.4.4-tetramethylcvclobutanone 2-methvlcyclobutanone 2,2-dimethylcyclobutanone 2.4-diisopropylcvclobutanone 2-t-butylcyc1opentanone ■ 2 ,2-dimethyl-5-t-butylcyclopentanone 2.5-diisopropylcyclopentanone 2-sec-butylcyclopentanone 2-isobutylcyclohexanone 2-methvlcycloheptanone 2-t-butvleve1oheptanone 2,7-dimethylcycloheptanone 15 2,7-diisopropylcycloheptanone 3,5-dimethyltetrahydro-4H-pvran-4-one 3,5-diisopropyltetrahydro—4H-pyran-4-cne 3.3.5.5-tetramethvltetrahydro-4H-pyran-4-one 3-methy1-5-t-butyltetrahydro-4H-pvran-4-one 2 0 3,3,5,5-tetramethyltetrahydro-4H-thiapyran-4-one 3-isopropylt etrahydro-4H-thiapyran-4-one 3,5-diisopropyltetrahydro—4H-thiapyran-4-one 3,-t-butyltetrahydro-4H-thiapyran-4-one 2-methyltetrahvdro-4H-thiapyran-3-one 25 2,4-dimethyltetrahydro-4H-thiapvran-3-one 2-methylthiepane-3-one 4-methylthiepane-3-one 2,4-diethylthiepane-3-one 2,4-diisopropylthiepane-3-one 30 3,5-dimethylthiepane-4-one 3,3,5,5-tetramethylthiepane-4-one 4-methyltetrahydro-4H-pyran-3-one 4-sec-butyltetrahvdro-4H-pyran-3-one r r Z03 2-isopropylt etra hyd r o-4 H-pyran-3-on e 2,4-diisopropyltetrahydro—4H-pyran-3-one 2,4-dimethyltetrahydro-4H-pvran-3-one 2-methyloxepane-3-one 4-methyloxepane-3-one 2.4-dimethyloxepane-3-one 2.2.4.4-tetramethyloxepane-3-one 3-methyloxepane-4-one -methyloxepane-4-one 3 , 5-dimethyl oxepane-4-one 3.3.5.5-tetramethyloxepane-4-cne 3.5-diisopropyloxepane-4-one 3-t-butyloxepane-4-one -t-butyloxepane-4-one The ketones provided above are converted to the corresponding amines by conversion to the oxime and reduction with scdium in ethanol as described in Example 47, Part ii, or Leuckart reduction of the ketone as described in Example 46, Part ii. r 20317 prepar ation d 2 ,4-Dimethyl-3-aininopentane In a shaker bottle was placed 0.2 g. platinum dioxide and 10 ml. water. The slurry was hydrogenated 2 at 50 psi (3.5 kg./cm .) for 15 minutes. To the resulting slurry of platinum black was added 34.26 g. (0.30 mole) 2,4-dimethvl-3-pentanone, 20.0 g. (0.37 mole) ammonium chloride, 225 ml. ammonia saturated methanol and 25 mlconcentrated ammonium hydroxide. 10 The resulting slurry was hydrogenated at 6 0 psi 2 (4.2 kg./cm. ) and room temperature for 20 hours, filtered, refluxed for for 1 hour and cooled. The mixture was adjusted to pH 2.0 with concentrated hydrochloric acid and the volume was reduced by 15 evaporation at reduced pressure. After washing with 75 ml. ethyl ether, the aquecus solution was brought to pH 13 with 10 M scdium hydroxide solution and extracted with three 100 ml. portions of ether. The extracts were ccmbined, dried over anhydrous MgSO^ and 20 saturated with gaseous hydrogen chloride. The pre cipitated amine hydrochloride was collected by filtration, air dried and decomposed with 75 ml. 10 M sodium hydroxide solution. The oily amine layer was separated and distilled at atmospheric pressure, B.P. 129-132°C, 25 yielding 17.6 g. r Z 03 a 7 6 •• -154- PREPARATION E 2,2,3,3-Tetramethvlcyclopropylamine i- Ethyl 2,2,3,3-Tetramethylcyclopropanecarb6xylate The methcd of Mesheheryakov, Chem. Abstr., 5 4, 24436d (19 60) was employed. To a mixture of 19 g. (0.226 mole) of 2,3-aimethyl-2-butene and. 2 g. of cupric sulfate is added at reflux a mixture of 51 g. (0.447 mole) ethyl diazoacetate ana 19 g. of 2,3-dimethyl-2-butene. The resulting mixture is heated at reflux for 3 hours, cooled,' filtered and distilled to afford 19.8 g. (26%) of the desired cyclic ester, B.P. 76-77° (15 mm.) ii. To 300 ml. of ethanol containing 40 g. of ammonia is added 17 g. (0.10 mole) of the ester obtained above and the resulting mixture allowed to stand overnight. After heating at reflux for one hcur the ethanol was evaporated _in vacuo to obtain 2,2,3,3-tetramethylcyclopropanecarboxamide.

A solution of 2.82 g. (0.02 mole) of the amide in 8 nil. tetrahydrofuran and 4 ml . of water is cooled to 5°C. and 10 ml. of 2 M scdium hypochlorite added drop-wise followed by 8 ml. of 20% (w/v) scdium hydroxide. The two phase mixture is stirred at 5°C. for 3 0 minutes then at 20°C for one hour. The organic layer is extracted with ether, the ether layer extracted with 2 M hydrochloric acid (3 x 2 0 ml.), the aqueous acidic layer is made strongly alkaline with scdium hydroxide and extracted with ether. The extracts are dried (Na^SO^) and the ether evaporated at 25° (50 mm.) to give 0.67 g. (25%) 2,3,3,3-tetramethylcyclopropylamine. "'"H-NMR (CDCl^) ppm (delta): 0.95 (6H, singlet); 1.00 (6H, singlet); 1.83 (1H, multiplet); 1.7 (2H, multiplet). r iii. The following substituted cyclopropylamines are prepared in an analogous fashion from the appropriate olefin. o3 XV . A r ' r5 £ ch ■h ch3 h ch3 h h h i-ch3h? h h h a-c3h7 h i-c3h7 h ch3 ch3 h h h h h ch3 ch3 t-c4hg h xO^A7 PREPARATION F 2,2,5,5-Tetramethylcyclopentyi amine A flask was charged with 35 c. (0.61 mole) of 40% sodium dispersion in mineral oil. The oil was removed by washing with ethyl ether and decantation. The scdium was then mixed with 400 ml. of ether and a mixture of 32.8 g. (0.20 mole) 2,2,5,5-tetramethvl-adiponitrile, prepared by the methcd of Coffmah et al., Am. Chem. Soc,, 80, 2868 (1957), and 400 ml. of tetrahydrofuran was added slowly. The resulting mixture was stirred at room temperature for 4 hours, the excess scdium decomposed by dropwise addition of saturated aqueous ammonium chloride, the organic layer washed with water, dried (Na^SO^) and evaporated to afford 25.1 g. of crude 2,2,5,5-tetramethylcyclopentyl-imine. The imine was dissolved in 75 ml. of ethanol and added dropwise to a flask containing 23.3 g. (1 mole) scdium shot. An additional 75'ml. ethanol"was added and the mixture heated at reflux until the remaining sodium metal was consumed. The reaction mixture was diluted with water, acidified to pH 1 with concentrated hydrochloric acid, the aqueous phase washed with ether then made strongly basic by addition of scdium hydroxide. The organic layer was extracted with ether, washed with brine, dried (Na^SO^) and evaporated to dryness. The residue was distilled in vacuo to afford 6.6 g. (23%) of the desired amine, B.P. 60-61°C. (20 mm.). r C C ^ < PREPARATION G 3-Amino-2,2,4,4-tetramethyloxetane To 13.6 g. (0.12 mole) of diisopropylketone is added 0.2 ml. of phosphorus tribromide. To this is added dropwise at 10°C., 38.4 g. (0.24 mole) bromine and the mixture warmed to 55-60°C. and held at this temperature for 1.5 hours. After cooling and partion-ing between chloroform and water, the organic, layer is washed with scdium carbonate solution until neutral, dried and the solvent evaporated to obtain 2,4-dibromo-2,4-dimethylpentan-3-one.

To 0.1 mole of the dibromoketone in 16 0 ml. of ethanol is added a solution of 8 g. of scdium hydroxide in 80 ml. water and the resulting mixture is stirred at room temperature for 30 minutes. After diluting with water the reaction mixture is extracted with ethyl ether, the extracts washed with water, brine and dried (MgSO^). The ether is evaporated to provide 2,4-dihvdroxy-2,4-dimethyl-3-pentanone. This is dissolved in 5 0 ml. chloroform and 1.5 ml. concentrated sulfuric acid added dropwise. The resulting mixture is heated at reflux for five hours while removing water as its azeotropic mixture with chloroform. When no more water is evolved the reaction mixture is washed with water, the organic layer dried (MgSO^, ) and -I solvent evaporated to provide 2,2,4,4-tetramethyloxetane-3-one which is purified by distillation.

The ketone is converted to the oxime and reduced with scdium/ethanol by the procedure of Example 47, Part ii. r r \ PREPARATION H 3-Amino-2,2-dimethyloxetane 3-Hydroxy-3-methyl-2-butanone, 0.20 mole, is treated dropwise with a equimolar amount of bromine at room temperature and the resulting mixture stirred for three hours. The mixture is taken up in chloroform, washed with scdium carbonate solution until neutral, dried and solvent evaporated to obtain l-bromc-3-hydroxy-3-methy1-2-butanone.

To 0.1 mole of the bromoketone in 160 ml. of ethanol is added a solution of 4 g. of scdium hydroxide in 80 ml. water and the mixture stirred at room temperature for 3 0 minutes. The mixture is diluted with water, extracted with ether, the extracts washed with water, brine and dried (MgSO^). The solvent is evaporated and the residue taken up in 50 ml. of chloroform. To this is added dropwise 1.5 ml. of concentrated sulfuric acid and the resulting mixture heated at reflux while removing water as its azeotrope with chloroform. When water evolution is complete the resulting ketone is isolated and converted to the desired amine as described in Preparation G. r 2^^ * < PREPARATION"I Employing, the procedures of Preparation G and I but starting with the appropriate ketone or alpha-hydroxyketone in each case the following amines are 5 prepared in like manner.

R3 r! R5- R^ ch3 h H H ch3 H —-C4H9 H ch3 C2H5 ch3 c2h ch3 H ch3 H ch3 ch3 C2H5 C2K i-SHV p H H i-C_,H_ — o 7 H i—C F i 3 7 • H C2H5 C_H_ 2 d H H r r 7.031 76 preparation j 2-Amino-3,3-dimethyl-gamma-butyrolactone Hydrbchloride The methcd is that of Nagase et _al_. , Chem.

Pharm. Bull., 17, 398 (1969).

To a stirred solution of 2,2-dimethylhydroacryl-aldehyde [prepared frcm sec-butyraldehyde and formaldehyde by the methcd of Stiller, _et al_. , J. Am. Chem. See. , 6 2, 1785 (1940)] 5.11 g. in methanol (25 ml.), a . 10 solution of ammonium chloride, 2.94 g., and sodium cyanide, 2.9 g., in water (40 ml.) is added dropwise.

After stirring for three hours the mixture is saturated with ammonia gas and allowed to stand at room temperature overnight. The resulting mixture is concentrated _in 15 vacuo to a small volume and 40 ml. of concentrated hydrochloric acid is added. After refluxing for three hours the mixture is evaporated _in vacuo and the residue crystallized frcm ethanol-ethyl ether and then frcm ethanol to give 2.2 g. of the title compound, 20 M.P. 214-215 °C. (dec.).

Use of homologs of 2 , 2-aim ethyl hydracryl aldehyde in the above procedure affords the corresponding compounds of the formula 12 13 where one of R and R is alkyl having frcm one to four carbon atcms and the.other is hydrogen or alkyl having from one to four carbon atoms. r r 2 03V76 P RE P AR AT I ON K 4-Ainino-3 ,3,5, 5-tetramethvl-tetrahydro-4H-pvran-2-one i. Methyl 5-Hydroxy-2 ,2,4, 4-tetramethyi-3-keto-valerate A mixture of 17 2 g. (1.0 mole) methyl 2,2,4- trirnethyl-3-ketoval erate, 5.4 g. (0.10 mole) scdium methoxide and 33 g. (0.36 mole) paraformalde in 250 ml. methanol is heated at reflux for eight hours. The mixture is quenched by addition of water, neutralized 10 with hydrochloric acid, extracted with ethyl ether, washed with water, brine and solvent evaporated. The residue is purified by vacuum distillation or chromatography on silica gel to provide the purified prcduct. ii. 2,2,4,4-tetramethyl-2,4-dioxotetrahydro-4H-pyran 15 A solution of 101 g. (0.50 mole) of the above prcduct in 200 ml. methanol and 20 ml. concentrated hydrochloric acid is heated at reflux for two hours, cooled, poured into ice-water, extracted with ethyl ether, the extracts washed with scdium bicarbonate 20 solution, water, dried and evaporated to dryness. The residue was heated _in vacuo at 80-100°C. for two hours to obtain prcduct of suitable purity for use in the next step. iii. The ketolactone obtained above is converted 25 to the corresponding 4-oximino derivative and this reduced to the title compound by the procedure of Example 5, Part A. c*- r preparation l 4-Amino—3,3,5,5-tetramethyl-2-piperidone i. Methyl '5-Dibenzylamino-2 ,2,4 , 4-tetramethyI-3-ketovalerate hydrochloride To a mixture of 8 6 g. (0.50 mole) methyl 2,2,4-trimethyl-3-ketcvalerate, 117 g. (0.64 mole) dibenzyl-amine hydrochloride and 19.8 g. (0.22 mole) paraformaldehyde is added a solution of 1 ml. of concentrated hydrochloric acid in 150 ml. 95% ethanol ana the mixture is heated at reflux for four hours. The mixture is filtered, 500 ml. of hot acetone added to the filtrate and the resulting mixture cooled then refrigerated overnight. The precipitated product is collected by filtration, washed with acetone and dried. ii. 3,3,5,5-tetramethylpiperidin-2,4-dione The above hydrochloride salt is partitioned between 0.1 N scdium hydroxide solution and ethyl ether. The ether extracts are dried (MgSO^) evaporated to dryness and the residue taken up in methanol. To the methanol solution is added 1 g. of 10% Pd/C and the mixture hydrogenated at 3-4 amtospheres pressure until hydrogen uptake is complete. The catalyst is removed by filtration, the filtrate heated at reflux for two hours, solvent evaporated and the residue heated at 70-80°C. in vacuo for two hours. The residual product is purified by chromatography on silica gel. iii. The piperidinedione obtained above is converted to the 4-oximino derivative and this reduced to the title 4-amino analog by the procedure of Example 5, Part a.

Claims (4)

r 2 031 -163- P RE P AR AT ION M 3 3 , 5 , 5—T etramethyl pyrrol ldin-2 , 4-dione A mixture of 80 g. of 2 , 2 ,4,4-tetramethyl-l,3-cyclohutanedione monoxime, prepared by the method of U.S. 3,125,569, and 25 0 ml. 9 8% (w/w) sulfuric acid was warmed at 50-60°C. for one hour ana allowed to stand overnight at rocm temperature. The reaction mixture was poured onto 800 g. ice, extracted with methylene chloride, the extracts washed with scdium bicarbonate solution, water, dried (MgSO,,) and evaporated to remove solvent. The resulting mixture of products was purified by column chromatography on silica gel and the fractions containing the title compound combined and evaporated to dryness. The ketolactam thus obtained is converted to 3-aminc—3,3,5,5-tetramethvl-2-pyrrolidone by methods described above. - 164 - what we claim is: 2031

1 • A Dr-amino acid amide, compound of the formula Ra-CHCONHHc NIL, wherein Ra is methyl, ethyl, £s.Qp;ropyl or n-propyl and c R is a meiaber sejLected £roni the. g;coup con.s£stincr o£ % enchyl, diisopr qpylcarbinyl, d hy 1 ^ t t y 1 c a r b i'nyi, d-ethyl-t-butylcarbi.nyl, d±'^t-Butylcarb±nyl, cyclopropyl' —— T"""* *« • t-butylcarbinyl f cyclopentyl-t-b.utylcarbinyl, dicyclo~ propylcarbinyl, R?11 "4Q where m. is 1, 2 or 3 and r , -r>30. -r.50. 6lQ u ^ wnen m, rs 1; R , R , R and a,re each -methyl, 30 when in-, is 2; R is- methyl, ethyl or isopropyl and r4Ct o50 , „6'a v' ' _3<J. , R , R and R are each hydrogen, or 'R and R"^' are each methyl and R^ and R^" are each, hydrogen, and when is 3; (ai is isopropyl or t-butyl and R4^, R^0 and are each, hydrogen, (b). R"^ is ethyl, R^^ is methyl and R^ and are each hydrogen, or , . _30 -j „40 , n _50 , _60 (c) R and R are each methyl and R and R are each, hydrogen'or methyl, and 20317 4 x ^ ^ wherein, when, and p2 are. ea,ch. zero; R and R are each, methyl and X0 is S, 509,. CfO o.r CHQE.f 41 61 when n2 is zero and p2 is; 1; R and -R ape. each. methyl and X_ is, 0, S or S0o, and d 1 £T\ when n2 is 1 and p2 is. 1; R and R ^re each. hydrogen, and X2 ±s; S or SC>2.

2. A compound according to claim 1 wherein Ra Q is methyl or ethyl and R is dicyclopropylcarbinyl, ^ t J-b l 2,2,4,4-tetramethylthietan-3-yl or -3^2^.4-tetramethyl-1,l-dioxothietan-3-yl.

3. A compound according to claim 2 wherein Ra is methyl.

4. A compound as claimed in any one of claims 1 to 3 substantially as hereinbefore described with reference to any example thereof. DATED THISDAY OF £ejO< A. J. PARK & SON PER >2^ • AGENTS FOR THE APPLICANTS // J $ -5ft