CA1103260A - .alpha.-ALKYL-SUBSTITUTED GLYCIDATES AND THIOGLYCIDATES - Google Patents

Abstract

.alpha.-ALKYL-SUBSTITUTED GLYCIDATES
AND THIOGLYCIDATES

ABSTRACT OF THE DISCLOSURE:
Glycidates and thioglycidates substituted in the .alpha.-position with a long chain alkyl of from 11 to 15.
carbons having hypoglycemic activity.

Description

DESCRIPTION CF THE INVENTION

The inve~tion relates to novel a-alkyl glycidic and thioglycidic arid derivatives having the formula:

-(cH2)n-c-co-R

R R
'' ' ' ' ' , ~.

.

~:

. .
- ~ .
~ .
., ~ ~ ~ 3~ f~ MN-286 ~herein n is an integer from 10 to 14 and preferably from 11 to 13;
R is a næmber selec-ted frcM the grcup consis~ng o~ OH, O-loweralkyl, NH2, N~-loweraIkyl, NH-loweralkyl-OH and N(loweralkyl)2; X is a m~
selected from the grcup consis~ng of O and S, preferably O; and Rl S an~ R2 are each a member selected from the group consisting of hydrcgen and loweralkyl. The therap~utically acceptable basic salts of the foregoing acids, i.e., when R is O~, are also included within the scope of this invention.

As used herein, the term "loweralkyl" may be straight or branch chained saturated hydrocarbons having from 1 to about 5 carbons, e.g., methyl, ethyl, propyl, isopropyl, sec-butyl, pentyl and the like alkyls.

The oxy esters of formula (I), wherein each of said ~ and ~ is hydrogen, are re!adily obtained from an appropriate a-alkylacrylic acid of formula (II).
Such acids may be obtained according to the synthetic procedure described by Pfe~fer et al., J. Org. Chem., 37. 1256 (1972).
Conventional esterification of (II), with an appropriate lower-alkanol esterifying agent yields the corresponding loweralkyl esters of-formula (III). Epoxidation of (III) according to `
standard oxidation procedures with an appropriate organic percarboxylic acid as the oxidant affords the corresponding loweralkyl a-alkyl~glycidates of formula (IV). Typical epoxida-tion peracids include, for example, perbenzoic acid, haloper-benzoic acid, preferably m-chloroperbenzoic acid, monoperphthalic acid, perace~tic acid and the like. Among the suitable sol~ents for the peroxidation reaction are, for example, a halogenated hydrocarbon, e.g., dichloroethane, chloroform and the like, and an ether, e.g., diethyl ether, dioxane and the like. .

,cf~ 2 ~ 6 esterif ication CH3 (CH2) n~~ -COOH ~ CH3 (CH2) n~l -COO(lc1h~eralkyl;

CH2 ` CH2 ~II) ~III) ..

epoxidation - - > CH3~CH2)n-C-COO(loweralkyl) . ~IU) .' The oxy esters of formula (I), i.e., where X = 0, wherein one of said Rl and R2 is-loweralkyl, as shown in formula (VIII), may be prepared rom the interaction of an appropriate loweralkyl ~-loweralkylacrylate o~
formula (V), which has first been treated with a strong base capable of removing an -hydrogen from said acrylate, with an appropriate alkyl halide of formula (VI), pre-ferably the bromide or chloride. Typical of the utilizable strong bases are a lithium dialkylamide, e.g., LiN(i-Pr)2, an alkali metal amide, e.g., NaNH2, and the like. The reaction is conducted in a suitable aprotic inert~,organic solvent under ~inert atmosphere, e.g., nit~ogen, and preferably at lcw temperatures of -80 to -30~C. Suitabl~ sDlvents include the - 2a -1`1N-286 V

loweralkanes such as hexane, heptane and the like and other solvents whose freezing points are low enough to be suit~blc for the cooled reaction conditions. A particularly useful solvent system is hexamethylphosphoramide (HMPA) as a cosolYent in tetrahydrofuran (THF). The! thus-obtained esters -(VII) may .
then be epoxidized, as previously described, to yield ~he ~ desired oxy-esters of formula (VIII).

Li~ Pr)2 ICH-COO(loweraIkyl) > , , loweralkyl H (V) C~3~CH2) Br n ~ CH3~cH2)n-cD-coo(loweralkyl) (VI) C
loweralkyl H (VIIj .
epoxidàtion - - ~ CH3(CH2) -C-COO(loweralkyl) -~ C~O
loweralkyl~ H (VIII) - 2b -.~ `
.

3.~
A general method for making all the oxy esters of formula (I), including those wherein bath of said Rl and R2 are loweralXyl, is by the Darzens giycidic ester conden3ation type of reaction (see Newman in "Organic Reactions", Vol. 5, New York:' John Wiley ~ Sons, Inc., 1949, Chap. 10). An ,!
aldol type condensation of an appropriate aldehyde or ketone with an appropriate a-halo ester produces the glycidic ester A~cordingly, an a-halo ester of formula (IX), pretreated with a suitable strong base, è.g., an alkali metal alkoxide or amide, capable o~ removing an a-hydrogen, is reacted ~ith an appropriate aldehyde o~ ketone of formula (X) undèr Darzens reactions conditions to yield the desired oxy-esters (XI).

- .. _ .~_ , -CH3(CH2)n-CH-COO(loweralkyl) - t CH3(CH2)n-c-OoD(loweralkyl?
~Br or Cl) (Br or Cl) _ (IX) !

RlR2C=
) C~3(CH2)n-lc~ O(loweralkyl) /\
Rl R2 , ., (~) ' .

- 2c -I~N-286 The thio es~ers of ormula (I), i.e., with X = S, are obtained by transorn)ation of the oxy ~unction in (XI) to a thio fullction (yr--b) by treating (Xl) with thiourea in the presence of a strol~g mineral acid, pre~erably sulfuric aci~, in a suitable anhydrous organic solvent such as, fGr example, absolute methanol, ethanol and the like, and then neutralizing the thus-obtained intermediate of formula(,~-a)with an appropriate base, such as, for example, an alkali metal carbonate or bicarbonate.
.. ~
-~ 10 The foregoing reactions may be illustrated by the followin~

schematic diagram:

~, NH2-C-~2 CH3(CH2)n-1C~ O(l,a,) H2SO~ ? 3(CH2)n 1~X~(1-a ) C ~ - Rl{:-S 1~2 / \ .
Rl R2 (XI) (XI-a) ,. .

NaHC03 CH3(CH2)n 1\ O(-oweralkyl) If ~c\
R1 R2 (XI-b) The oxy esters (XI) an~ the thio esters ~xI-b) a~ shown .in : combined formula (XII) wherein X respresents O or S, respectively, may then be used as precursors i.-or making othex respective oxy and thio derivatives of formula (I). For example, stan~ard ester-to-acid hydrolysis of (XII) under conventional acidic or alkaline conditions affords the corresponding acids of formula (XIII). In turn, the acids ~XIII) may be re-esterified accord- I
ing to standard carboxylic acid to ester esterificati3n pro- . i cedures with an appropriate loweralkanol as the esterifying agent, generally in the presence of a catalytic amount of strong mineral acid, e.g., HCl, H2SO~ and the like, to yiel~
the loweralkyl esters of formula (XII).

.

CH3(CH2)n-C-COO(loweralkyl) CH3(cH2)n-c-cooH
. X HOH X
., ~ . ./
/ \ alkanol / ~ i (X-I) (XIII) ,j ~f ~ . . ~ , , , . ~

The acids of formula (XIII) may be converted to the corresponding salt form by treatment with a slight excess of an equival~nt amount of an appropriate base, for example, an alkali metal or alkaline earth metal hydroxide, e.g., sodium hydroxide, potassium hydroxide, calcium hydroxide and the like, or with an organic amine base, e~g., mono-, di- and tri-low~ralkyl amines such as ethylamine, propylamine, methylethylamine, triethylamine and the like t or other amines such as benzylamine, methylphenylamine, piperidine, pyrrolidine and the like.

The acids (XIII) may also be used as precursors for makin~
the esters, amides and substituted amides of formula (I).
For example, standard estsrification pro~edures with an - appropriate loweralkanol as the esterifying agent afford the corresponding loweralkyl esters (XII). The corresponding amides are obtained by standard acid-to-amide~procedures, preferably by first transorming the carboxylic function of the acid (XIII) into the corresponding acid chloride form (XVII~, for example, by treatment of the acid or its alkali metal salt with thionyl chloride or oxalyl chloride in an inert organic solvent ~uitaole for such transformations, e.g., an aromatic hydrocar~on, chloroform and the Iike, and then reacting the thus-obtained acid chloride with either ammonia, loweralkyl amine or diloweralkyl amine in a suitable organic solvent for such ammonolysis reactions, e.g., an aromatic hydrocarbon, acetonitrile and the like, to yield the respective amides of formulas (XIV), ~XV) and ~XVI).

r NH3 ~ (XIV) \ChlorY-lde ~ CH3(cH2?n-c-cocl ~ 1 amin / C \/ C \ ( 2 amine~ ~XVI~

(XIII~ Rl R2~XVII~ Rl R2 _ 5 _ , Alt~n~tively~ the amudes of formula tI), wherein each of said Rl and R2 is hydrogen, may be prepared fran the a-alkylacrylic acids of fonmula (II) by similar transformation to the corresponding acid chloride form ~XVIII) followed by appropriate interaction with ammonia, primary or secondary amines to yield the respective a-alkyl-._ i ac~-ylic amide.~ (XIX). Such amides are then epoxidized to the corresponding oxy amides ~X:~) which in turn may be con-verted to the corresponding thio amides (XXI) according to the ~elevant reaction techniques previously described for m~ the oxy esters and thio esters of fornula (I), ~he ~ore-going reactions may be illustrated by the following schematic diagram in which the preparation of unsubstituted amides is exemplifi`ed.

oxalyl . NH
CH3(CH2) -C-COOH ~ CH (CH ) -C-COCl 3 CH2 ' ~H2 epoxidation CH3(CH2)~n-lcl CNH2 ---~ - CH3(CH2)n IC\CON 2 (XIX) (~) - .

S
NH2-c-NH2 NaHCOCH (C}l ~ -C-CONH
~~~;~ ~ 3 2 n \ 2 CH~ ~
, (X~I) _ ~ _ ._ ._ _ v~
~SN-286 The oxo-amides and thio-amides of formula (I~ may also be conveniently prepared from the acids (XIII) as follows. The acid is first transformed into an appropriate ammonium salt by standard treatment with a tertiary amine, as exemplified by the triethylammonium salt of formula (XXII). The salt is in turn transformed into a mixed anhydride (XXIII) by reaction with an appropriate haloalkylformate, pre-- ferably ethyl chloroformate,which anhydride is then reacted with ammonia or an appropriate primary or secondary alk~lamine in a suitable inert aprotic organic solvent, for example, an ethPr, P.g., dioxane, tetrahy~rofuran, and the like~ or an aromatic hydrocarbon, e.g., benzene, toluene, xylene and the like to yield the re~ ive amides o foo~a (XIV), (XV) and (XVI). ~eaction of the ~nhydride wit~ an appro-priate alXanolamine in such apro~ic solvent yi~lds the o~xxu~ of ~or-mula II) wherein R is NH-lo~aIkyl-CH.
.. .. .

CH3(cll2~n-c-cooN ~ 3(CH2)n IC\Coo~ ~ NHEt3 C\ R / \

~XIII~ (XXII) NH3 `
O O - - ~ (XIV) Cl-COOEt ~ il U 1 amine 3 2 n \ C OEt _ ~ ~-- P (XV) X 2 amine / ~ ` ~ 7 ;~ XVI) Rl R2 (XXIII) , - 6a -, r~

~N-2~ 6 The compounds of formula (I) and salts thereof are useful for their hypoglycemic activity as demonstrated in a standard blood glucose tolerance test ~GTT) in rats.
Three to five glucose primed, fasted (18-24 hrs.), in act m~le rats are used for each test and control group. The - compound to be tested is suspended in 0.5% aqueous methyl-cellulose and administered at doses of 10-150 mg/kg either intra-peritoneally, subcutaneously or orally 30-60 minutes prior to administration of glucose. The glucose is given either ln orally (1 g/kg) or subcutaneously (0.8 g/kg). Serial blood samples are obtained from the tail without anes~lesia at thirty minute intervals for 3 hours after administration of the glucose. Blood specimens are Lmmediately deproteinized with barium hydroxide and zinc sulfate according to conventional GTT procedures and glucose levels are determined using the standard glucose oxidase assay. A significant depression of blood sugar from that of controls is observed with the sub-ject compounds.

The following examples are intended to illustrate, but not to limit, the scope of the present invention.

._...................................... . j, . `.

~7 .

~-286 EXP~IPLE I

.
This example illustrates the method described by Pfeffer et al., J. Org. Chem., 37, 1256 tl972), for prepar~ng a-alkylhydracrylic acids of the ~ormula:
CH3(CH2) -C(C~2OH)H-COOH, wherein n is an integer from 10 to 14. These a-alkylhydracrylic acids are precursors for making the ~-alkylacrylic acids of formula (II~.

a-Hydroxymethylpalmitic acid: Anhydrous tetrahydo-furan (THF) (8~5 ml) and 49.5 g (0.49 mole) of diisopropyl-amine were added to a dry three neck flask purged with nitrogen and maintained under a nitrogen atmosphere.
After cooling the mixture to -20, 300 ml of n-butyllithium in hexane (1.6M) (0.49 mole) was added slowly to prevent the temperature from exceeding 0~and bhen 79.3 ml of an-hydrous hexamethylphosphoramide (HMPA) (0.44 mole) was added.
A solution of 51.28 g of palmitic acid (0.198 mole) in 400 ml of THF was added dropwise with stirring while maintaining the reaction temperature below 0. ~ milky white suspension resulted after the addition of palmitic acid. The reaction mixture was bxought to about 40 by using a warm water bath.
The suspension changed to a clear solution as the temperature gradually reached 40. This system was then connected to a formaldehyde generating system. Parafo~maldehyde (40 g) was heated in a three neck flask at 180-200 to generate formaldehyde and the formaldehyde vapors-were carried by a stream of nitrogen over the surface of the stirred solution of ~-lithiated lithium palmit~te prepared previously. The reaction was terminated ....

after complete depolymerization of paraformaldehyde (2 to 2 1~2 hrs.). The reaction solution was cooled in an ice bath and neùtralized with hydrochloric acid until acidic. The organic layer was separated and was concentrated under reduced pressure on a rotavac to remove most of the THF solvent. The resulting oily residue was dissolved in 2 liters of ether and was washed three times with 10% hydrochloric acid solution and then twice with water. The ether layer was dried over Na2SO4 ', and the solvents were removed under reduced pressure to give 43.3 g (7~%) of crude product, a-hydroxymethylpalmitic acid, which was recrystallized once from acetone to give 39.0 g ~69% yield) of the product with m.p. ~7-71, which was used without further purification in the next synthetic step.
EXAMPLE II

By repeating the procedure of Example I, except that an equivalent amount of an appropriate fatty acid is sub-stituted for the palmitic acid use~ therein the following respective a-al~ylhydracrylic acids are obtained:

Fatty Acid Product tridecylic CH3(CH2)~0C(CH2OH)HCOOH
myristic: CH3(cH2)llc(cH2oH)HcooH
pentadec:ylic CH3(cH2)l2c(cH2oH)HcooH

margaric: CH3~cH2)l~c(cH2oH)HcooH

J~

EX~*lPLE III

This example illustrates a method (see Pfeffer et al., ibid.) of preparing the a-alky'Lacrylic acids of formula (II) through dehydration of the appropriate a-alkylhydracrylic acid precursor.

A. 2-Tetradecylacrylic acid: A 34.25 g sample of ~-hydroxymethylpalmitic acid ~0.119 mole) and 17 drops of phosphoric acid (85~) were placed in a distillation flask and the mixture heated to 24~-255C in an oil bath under vacuum. The product, 2-tetradecylacrylic acid, distilled over at 155-160C at 0.10 mm Hg (24.80 g; 77~ yield) and was crystallized from acetone, m.p. 53-55C.
!
B. By repeating the foregoin~ procedure, except that an equivalent quantity of each of the ~-alkylhydracrylic acids obtained in Example II is used as the starting material, the following respective products are obtained:
... . . .

2-undecylacrylic acid;
2-dodecylacrylic acid;
2-tridecy~acrylic acid; and;
2-pentadec:ylacrylic acid, ...... . ....... . ...... .

--~10 -- .

~ ~ ~ 3 `'~ MN-286 EXAMPLE IV

A. Methyl 2-tetradecylacrylate: 14.6 Grams of 2-tetradecylacrylic acid (0.05~ mole) are combined with 65 ml of absolute methanol and 15 ml of 51% BF3 in methanol in a 200 ml flask equipped with a condenser and drying 5 tube. The system is heated under reflux for six hours (two layars appear when cooled). The mixture is concentrated to 1/~ volume and the acid is neutralized with saturated NaHCO3 solution to about pH 7. The oily material is extracted with ether, washed with water and dried over anhydrous MgSO4. The ether solvent is removed under re~uced pressure. The oily residue of methyl 2-tetrade-cylacrylate (14.70 g) is not purified further (~ 95% pure by GC) and used directly in the next step.

B. The foregoing esterification procedure is followed - to prepare theloweralkyl a-alkylacrylates of formula (III).
By substituting equivalent quantities of an appropriate ~-alkylacrylic acid and an appropriate loweralkanol esterifying agent as starting materials, the following respective products are obtained: I
~ butyl 2-undecylacrylate;
. methyl 2-dodecylacrylate;
methyl 2-tridecylacrylate;
ethyl 2-tetradecylacrylate; and isopropyl 2-pentadecylacrylate.

, EXA~PLE V

n-Butyl ~-Tetradecyl acrylate 4.27 Grams (15.9 m mole) of tetradecylacrylic acid is clissolved in 80 ml anhydrous n-butanol in a 300 ml one-neck round-bottom flask equipped with CaC12-drying tube, condenser, and magnetic stirrer. 24-ml of 98% ~F3 etherate is added and the solution re1uxed for 6 hrs.
The solution is then cooled to room temperature, neutralized with aqeuous NaHCO3 to pH 7 and extracted with ether. The ether solution is dried (MgSO4)and evaporated giving 4.4 g ~86% yield) of the product, n-butyl a-tetradecyl acrylate lD ~about 93% pure) which is used without further purification in the next synthetic step.

- EXAMPLE VI
-n-Butyl 2-tetradecyl glycidate: 4.2 Grams (0.0131 mole) o n-butyl ~-tetradecyl acrylate (93% pure) is combined with 113 ml dry dichloroethane, 0.0558 g of 3-t-butyl-4-hydroxy-S-methyl phenyl sulfide inhibitor, and 3.5 g (0.0201 mole) of m-chloroperben~oic acid. The solution is refluxed for 3 hours and then chilled and filtered. The filtrate is successively ~oncentrated to about 1/2 volume, re-filtered, washed with saturated aqueous K2CO3 and extracted with ether. The ether extract is dried over anhydrous MgSO4 and evaporated in vacuo, and the product recrystallized from absolute methanol with cold iltration to give about 1.8 g of the product, n-butyl 2-tetradecyl glycidate.

E~IPLE VI I

Methvl 2-tetradecylglycidate: A rnixture o~ 8.9 g ~0~0316 mole) of methyl -tetradecylacrylate, lO.9 g (0.0632 mole) of m-chloroperbenzoic acid and 0.205 g (0.000572 mole) of 3-t~
butyl-4-hydroxy-5-methylphenyl sulfide inhibitor in 300 ml of dry l 2-dichloroethane is stirred and refluxed for 4 hours.
After an additional 18 hours stirring at room temperature the ixtu_~ is filtered and the filtr~te concentrated in vacuo to 1~3 volume, cooled and refiltere`d. Ether is added to the fil-trate which is then washed with X2OO3 solution and then with water.
The ether layer is dried over anhydrous magnesium sulfate. After ren~val df the drying agent the ether solvent is evaporated in vacuo. The oily residue solidifies on cooling to give about 10.6 g o product, methyl 2-tetradecylglycidate which i5 recrystallized from methanol: white crystals, m.p. 43-45C.

EX~SPLE VIII

The epoxidation procedures of Examples VI and VII may be followed in preparing the oxo esters of formula (IV~. For example by repeating the procedure of Example VII, except that an equivalent amount of an appropriate loweralkyl 2-alkylacrylate is employed as the material to be epoxidized~ the Eollowing products are obtained:

butyl 2-undecylglycidate;
methyl 2--dodecylglycidate, m.p. 38-42 C;
methyl 2-tridecylglycidate, m.p. 38-39C;
ethyl 2-ltetradecylglycidate; and isopropyL 2-pentadecylglycidate~
.

EXAMPLE I X

- Methyl 2-tetradecylthio~lycidate: 1.27 grams (0.0167 mole) of thiourea and 5.00 ml of 95-98~ H2SO~ are placed in a one-liter three-neck round-bottom flask equipped with a condenser, magnetic stirrler and addition funnel along with 400 ml of absolute methanol. Then 5.00 g ~0.0167 mole) of methyl 2-tetradlecylglycidate dissolved in 50 ml o absolute methanol is added and the mixture stirred at room temperature for 3 hours. 400 M1 more of ~ absolute methanol is added and the mixture is neutralized by addition of NaHCO3 (1.7 g~ with stirring. When the pH rises above 7 an oily material is seen to come out of solution and at this point the neutralization is considered complete. The solvent is removed in vacuo and the residue partitioned between water and ether. The ethereal layer is washed twice with H2O and once with saturated NaCl solution, - dried over anhydrous Na2SO4 and concentrated in vacuo to yield about 5.77 g of a light tan solid. Column chromatography is employed to isolate the pure material, methyl 2-tetradecyl-thioglycidate.
., EXAMPLE X

By following the procedure of Example IX, the trans-formation of the oxo function in formula (IV) compounds to the thio $unction in formula (XI) compounds is accomplished.
For example,~by substituting an equivalent amount of each of the oxo esters obtained in Example VIII for the methyl 2-- ' tetradecylglycidate used in Example IX, the following thio-glycidates of formula ~XI) are obtained:

butyl 2-undecylthioglyFidat:e;
methyl 2-dodecylthioylycidclte;
methyl 2-tridecylthioglyciclate;
ethyl ~-tetradecylthioglycidate; and isopropyl 2-pentadecylthioglyciatei , EXAMPLE XI

A. 2-Tetradecylglycidic Acid: 3.6 Grams tl2.2 m mole) of methyl 2-tetradecylglycidate is dissolved in minimal absolùte ethanol tabout 40 ml) and set aside. 10.8 Ml of absolute ethanol is placed in a 100 ml three-nec~ round-bottom ~lask eguipped with magnetic stirrer, CaC12 drying tube, thermometer and addition funnel. The ethanol~is chilled in an ice bath and 0.3 g of sodium metal is added. When formation of sodium ethoxide is completed, the e.hanol solution of methyl 2-tetradecylglycidate is added dropwise. After addition is completed and stirred for 15 min., 0.24 g of water is added and the mixture is stirred (25C) ; overnight (about 15 hours). The resulting suspension is filtered (sintered funnel) and the precipitate washed with ether, dried and then combined with 75 ml lN HCl and stirred for 4 hours.
The suspension is extracted into ather. ~he ether extract is dried over driecl anhydrous Na2SO4 and evapora~ed ~ vacuo, giving quantitative conversion to ~he acid. Recrystallization from acetone gives about 2.5 g t74~ yield) of the product, 2-te~trade~ylglycidic acid, m.p. 77-79C.

_ _

3`;3.~~

B. The ester-to-acld hydrolysis pro`cedure of Example XI-A
illustrates a method of ~aking the 2-alkylglycidic aclds of formula (XIII). For example, by utilizing therein an equivalent amount of each oxo-este~s obtained from Example VIII, the cor~
responding oxo-acids of formula (XIII) are respectively obtained.

EXAMPLE XII

A. 2-Tetradecylthioglycidic Acid: A solution of 3.15 g (0.01 m~le) of methyl 2-tetradecylthioglycidate in 50 ml of absolute ethanol is added dropwise to a cooled (0-5C) solution of sodium e~hoKide (0.25 g-sodium in 12 ml absolute ethanol~. The mixture is stirre~ for 15 minutes while maintaining the temFerature below 20QC and 0.19 g of water is added. Stirring is continued overnight (about 15 hcurs) at room temperature. m e resulting suspension is filtered and the precipitate wash~d with ether, dried and then stirred for several hours in dilute HCl. The acidic suspension is extracted with ether and the ether layer dried ~Na2S~4) and vaporated in vacuo giving the product, 2-tetradecylthiQglycidic I -acid, in good yield.
. . I
B. The ester to-acid hydrolysis prccedure of EXample XII-A illustra * s a methcd for making the 2-alkylthioglycidic acid of formula (XIII). For example, by utilizing therein an e~uivalent amount of each thio-ester obtained from Example X, the corresponding thio-acids of formula tXIII) are respectively obtained.
!

- 16 ~
L

.,j . .

~J~'~

EXAMPLE XIII

A. 2- Tetradec~lacrylamide: 5.4 Grams (0.02 mole) of 2-tetradecylacrylic acid is dissolved in 200 ml benzene and combined with 10.7 ml oxalyl chloride and stirred overnight - (bubbling noted). The mixture is evaporated and the residue dissolved in benzene. The benzene solution is evaporated to dryness. This dissolution in and evaporation of benzene is repeated three times to ensure removal of unreacteid oxalyl chloride and other noxious gaseous by-products. The residue containing 2-tetradecylacrylic acid chloride is combined with 100 ml benzene and 80 ml of 4.7% ammonia in acetonitrile. The mixture is stirred overnight and then filtered. FiItration gives about ~.5 g of solid material containing some NH4Cl as a by-product. The iltrate is washed with water, dried (Na2SOg) and evaporated to give about 1.6 g of oily residue (residue A).
The 4.5 grams of filtered solid material is mixed with 100 ml of diethylether/chloroform (1:1) and t~e resultant solution is washed with water. The organic phase is then dried (Na2SO4) and evaporàted to give about 3.1 g of oily residue (residue B).
The two oily residues (A and B), containing the product, 2-tetra- i decylacrylamide, are combined and used in the next synthetic step (see Example XIV-A) without ~urther puri~ication.

-- i ,.. ..__ ..
.

~ 2~G

B. The fore~oing acid to acid chloride to acid amide synthesis illustrates an amidation procedure which can be used to prepare the ~-alkylacrylic amides of formula ~XIX).
By repeating such procedure, except that an equivalent 5 quantity of each a-alkylacrylic acid obtained from Example III-B is su~stituted for the 2-tetradecylacrylic acid utilized in Example XIII-A, there are obtained, as respective products, the corresponding 2-alkylacrylamides.

.

- EXA~PLE XIV

.
A. 2-Tetradecylglycidamide: 4.0 Grams o~ 2-methylene 1~ hexadecanoamide is combined with 145 ml dry 1,3-dichloroethane, 0.083 g of 3-t-butyl-4-hydroxy-5-methyl-phenyl sulfide inhibitor and 4.4 g of m-chloro perbenzoic acid (85~). The mixture is heated , to reflux for 3 hrs. with stirring. The mixture is then cooled to room temperature and concentrated to about 1/3 volume. The 1~ decreased volume is filtered and the filtrate washed with saturated aqueous K~CO3 and extracted with chloroform. The chloroform extract is dried (MgSO4) evaporated and the crude product recrys~allized from absolute methanol to give about 1.1 g of 2-tetradecylglycidamide, m.p. 104-106C.

B. The epoxidation procedure of Example XIV-A is repeated, except that an eguivalent ~uantity of each 2-alkylacrylamide obtained in Example XIII-B is substituted as the starting material to be epoxidized, to yield the ~ollowing respective oxy-amides - of formula ~XX)~
2-undecylglycidamide;
2-dodecylglycidamide, .. ... .

2-tridecylglycidamide;and 2-pentadecylglycidamide.

EXAMPLE X~

The procedure described in Example X for the transformation of oxo-esters to thio-esters is ~ollowed to also transfonm the oxo-amides of formula (XX) to thio-amides of formula (XXI). Accordingly, substitution o~ an equivalent amount of eaoh of the oxo-amides obtained in ~xamples XIV-A and B for the methyl 2-tetradecylglycidate used in Example IX affords the corresponding 2-al~ylthio-glycidamides of formula (XXI) as xespective products.

- EX~MPLE XVI-A. Methyl 2-tetradecylcrotonate: To a solution of distilled di-isopropylamine (5.06 g; 0.05 mole) in 50 ml anhydrous THF maintained at -78 C is added dropwise 36 ml of n-butyllithium in hexane (1.39 M; 0.05 mole~ under a nitro-- 15 gen atmosphere, followed by dropwise addition of anhydrous HMPA (9.86 g; 0.055 mole). The mixture is maintained at -78C for about one-half hour and then methyl crotonate ~5 g; 0.05 mole) is added dropwise. Ten minutes following = 19 -I

complete addition of the methyl crotonate, 15,3 g of myristyl bromide (0.055 mole) is added. T~e system is then allowed to warm to ~-30C and is maintained at this temperature for about 1 hour with stirring.
The system is then allowed to reach ambient temperature with continu~d stirring overnignt (about 15 hours). The system is worked-up to pH5 with lN HCl and then extracted with ether. The ether extract is washed successively. with water and saturated brine, then dried over anhydrous Na2SO4 and evaporated in vacuo... The crude oily product is purified by column chromatography (silica gel)~

Fraction No. Eluting Solvent Volume of Solvent _ .
- 1 - 5 100~ pet ether . . -_1000-ml 6 - 13 lO~'benzene in pet ether 1000 ml - i 14 - 22 ~5~ benzene in pet ether 1000 ml Fraction Nos. 20-~2 are combined and the product, methyl 2-tetradecylcrotonate, is obtained.in 98.4~ purity by standard '. iso-lation techniques. . , .
B. The procedure of Ex,ample XVI-A illu trates a method .
. of preparing the unsaturated esters of formula (VII)~ By 20. following such procedure, except that an equivalent amount of the appropriate precursors are utilized, the following products are o.btained:

.
-- ~0 --C~l3(~H2)n-cll-coo(~

f \ (VII) . loweralkyl H . .. ...

n loweralkyl -COO~l.a.) .... _ . ....
Me -COOEt 11 n-Pr -COOMe 13 n-Bu -COOPr 14 Me . -COOMe EXA~LE XVII

.
A. Methyl 2-tetra ~ ~lglycidate: 1.09 Grams ~3.7 mmole) of methyl 2-tetradecylcrotonate is combined with 62 ml dry 1,2-dichloroethane, 0,037 g t0.103 mmole) of 3-t-bu~yl-4-hydroxy-5-methylphenyl sulfide inhibitor and 1.3 g (7.4 mmole) of m-chloroperbenzoic acid. The mixture is re-fluxed for 4 hours. After the additional 18 hours stirring at room temperature, the mixture is filtered and the filtrate concentrated in vacuo to 1/3 volume, cooled and re~iltered.
~ther is added to the filtrate which i5 then extracted with X2CO3 solution and then with water. The ether layer is dried over ~nll-:drous MgSO4. After removal of the drying agent, the ether solvent is evaporated in vacuo. The oily residue i~ puri-fied by column c]hromatography (silica gel):

.

- 21 - .

t~

MN-2~6 Fraction No. Elutin~ ~oIventVolume of Solvent 1 100~ pet ether 50 ml 2 - 10 - 10% Et.O in pet ether200 ml 11 25~ Et2O in pet ether10.0 ml Fractions 7-9 axe combined and the product" methyl 2-tetra-decyl-3-methylglycidate, is,obtained by standard,isolation techniques.

B. The epoxidation procedure of Example XVII-A is repeated, except that an equivalent amount. of each of the unsaturated esters obtained in Example XVI-B are utilized as the starting material to be epoxidized to yield, as respactive products, the corresponding 3-substitutea oxo esters of formula ,,, ~VIII).

C~ By following the procedure'of Example IX, except that an equivalent amount of the 3-substituted oxo esters obtained 15 - from Examples XVII-A and B are utilized as the starting material, transformation of the oxo function to a thio functio~ is accom-plished 'to give the corresponding 3-substituted thio esters of formula (XI-b) D. The ester to acid hydrolysis procedures of Examples XI and XII arè followed to prepare the corresponding 3-substituted . oxo and thio acids of formula (XIII) by starting with an e~uivalent amount of each of the 3~sub~tituted esters obtained heretofP~re in this example.
j, , - 22 -MN-~86 7 EXAMPLE XVIII
. -A. N-Ethyl-2-tetradecylthioglycidamide: To a stirred solution of 0.3 g (0.001 mole) of 2-tetradecylthiogly~idic acid in lO ml of anhydrous tetrahydrofuran (THF) at O~C
~ice-water bath) is added l.01 g l~0.001 mole) of triethylam~n~
in a small amount of THF. The mixture is stirred at 0C for abou$ 30 minutes. To the thus-formed triethylammonium 2-tetra-decylthioglycidate is added 0.108 g (0.001 mole) of ethyl chloroformate in small amount of THF and the mixture is stirred at about 0 C (ice-water bath) for about 3 hours to prepare the corresponding mixed anhydride (a ppt. of Et3N~Cl is observed). A stoichiometric excess of ethylamine in THF ~-is then added and the mixture stirred at room temperature for 16 hours. The THF solvent is concantrated to approximately l/4 volume, water is added and the mixture extracted with ether. After drying the ether extract (Na2S04), the solvent is removed in vacuo giving the desired product, N-ethyl-2-tetradecylthioglycidamide, in good yield, B. By rep~ating the acid to amide procedure of Example XVI-A, except that an equivalent amount of an appropriate 2-alkylglycidic acid or 2-alkylthioglycidic acid and an appropriate primary or secondary amine are employed as precursors, tne following respective products are obtained:
.. .. .. .
~ 23 -. ~
. :
:'.

J~

N-methyl-2-tetradecyl~lycidamide;
N,N-dimethyl-2-dodecylthioglycidamide;
N-methyl-N-ethyl-2-tridecylglycidamide;
N-(n-butyl)-2-tridecylglycidamidle N,N-diethyl-2-pentadecylthioglycidamide;
N-ethyl-2-tetradecyl-3-methylglycidamide; and N,N-diethyl-~-tetradecyl-3-methylthioglycidamide.

EXAMPLE XIX

This example demonstrates a Darzens glycidic ester synthesis for making the oxo esters of formula (I).

A. Methyl 2-Tetradecyl-3~3-dimethylglycida~e: To a ~olut~on of 2.068 g of methyl bromopalmitate (0.0059 mole) in 0.343 g of acetone at 10-15C with stirring is slowly added 5.57 ml of potassium t-butoxide solution (prepared from 0.58 g potassium and 16,5 ml t-butanol), The reaction mixture is stirred at room temperature for about one hour. Ether is added and the ether layer is separated and washed successively with dilute HCl, water and saturated brine. The ether layer is then dried over anhydrous M~SO4 and the solvent evaporated.
off leaving an oily residue (about 1.84 g crude) which is purified by chromatography over silica gel in pet-ether (wet-~ packed; using 5% ether in pet-ether as eluting solution) to I give the product, methyl 2-tetradecyl-3~3-dimethyl-glycidate in about 38% yield; m.p. 39-40C.

~ .

~ .

B. By follo~ing the procedure of Example XIX-A, except that an equivalent quantity of an appropriate aldehyde or ... . I
ketone is used in place of the acetone used therein, the following respective products are. obtained:

methyl 2-tetradecylglycidate;
met~yl 2-tetradecyl-3-methylglycidate;
methyl 2-tetradecyl-3-methyl-3-ethylglycidate; and methyl 2-tetradecyl-3,3-diethylglycidate.

EXAMPLE XX
- . , Transformation of the oxy function in each of the oxy ester~ ;
obtained in Example XIX to a thio function according to the relevant procedures previously described yields the following t thioglycidates of formula (I):

methyl 2-tetradecyl-3,3-dimethylthioglycidate;
methyl 2-tetradecylthioglycidate;
methyl 2-tetradecyl-3-methylthioglycidate;
methyl 2-tetradecyl-3-methyl-3-ethylthioglycidate; and ' I
- methyl 2-tetradecyl-3,3-diethylthioglycidate.

, ~ 3 ~ 5 ~
i , EXAMPLE XXI

A. Hydroly~is of the ester function in each of the oxy esters obtained in Example XIX a,nd in each thio ester obtained in Example XX according to the rlelevant procedures previously described affords the corresponding acids of formula (X).

S B. By following the applicable acid to amide procedures described in Examples XIV and XV, each of the foregoing acids are converted into the corresponding amides of formula (I).
. . .
... .. ~
EXA~IPLE XXII

N,N-Dimethyl-~-tetradecylglycidamide: To a solution .
oE 1.42 g l0.~05 mole) of 2-tetradecylglycidic acid in 10 ml of tetrahydrofuran (THF) at OC (ice-water bath) with stirring is added 0.50 g (0.005 mole) of triethylamine in à small amount of THF. The solution is stirred at O~C for 30 min~tes and 0.51 g (0.005 mole) of ethyl chloroformate is added. The mixture is s~irred at about 0 C (ice-water bath) for 3 hours tppt. of Et3N HCl observed). At the end of 3 hours 0.429 g (0.015 mole) of dimethyl amine in THF is added and the mixture stirred overnight (16 hours) at room temperature. The THF solvent is concentrated to about 1/3 its volume, wate~ is added and the mixture extracted with ether.
The ether extract is dried over Na2SO4 and the ether solvent rë-moved. A crude oily residue is obtained which is puiified by column chromatoglraphy on si~ica gel. A 37.8% yield of pure N~N-dimethyl-2-tetra,decylglycidamide is obtained, m.p. 4~-42C.

- ~6 -~ 286 .

EXAMPLE XXI I I

-- .
N-~2-Hydroxyethyl)-2-tetradlecylqlycidamide: To a solution of 0.2 g of 2-tetradecylglycidic acid ~0.0007 mole) in 10 ml of anhydrous THF at 0 C (ice-water bath) with stirring is added 0.070 g of triethylamine ~0.0007 mole) in a small amount of THF. The solution is stirred at 0 for 30 minutes and 76 mg. of ethyl chloroformate (0.0007 mole~ in a small amount of THF is added. The mix-ture is stirred at about 0C ~ice-water bath) for 3 hours (ppt. of Et3NHCl observed). At the end of 3 hours 0.042 1~ g. (0.0007 mole) of ethanolamine in TBP is added. The mix-.
ture is stirred at room temperature for 16 hours. The THF
solvent is concentrated to about 1/3 its volume, wat~r i8 added and the mixture extracted with ather. The ether ex~ract is dried over Na2S04 and the ether solvent removed to give a white solid of N-~2-hydroxyethyl)-2-tetradecylglycidamide which, upon recrystallization from acetone has a m.p. o~
80-82C.

~5 :, EXAMPLE XXIV

~ y repeating the procedure of E`xample XXIII, except that an equivalent quantity of an ap~ropriate 2-alkyl-glycidic acid or 2-alkylthioglycidic acid and an appro-priate alkanolamine are employed as precursors, the fol-lowing r~spective products are obtained: -N-(2-hydroxyethyl)-2-tridecylglycidamide;

N-~2-hydroxyethyl)-2-pantadecylglycidamide;

N-~3-hydroxypropyl)-2-tetradecylglycidamideJ

N-(2-hydroxyethyl)-2-dodecylthioglycidamide:

N-(2-hydroxyethyl)-2-tetradecylthioglycidamide:.and - N-(3-hydroxypropyl)-2-pentàdecylglycidamide.

Claims (24)

PROCESS CLAIMS

1. A process for preparing a compound selected from the group consisting of glycidic and thioglycidic acid derivatives having the formula:

(I) wherein n is an integer from 10 to 14; R is a member selected from the group consisting of OH, O-loweralkyl, NH2, NH-loweralkyl, NH-loweralkyl-OH and N(loweralkyl)2; X is a member selected from the group con-sisting of O and S; and each of R1 and R2 is a member selected from the group consisting of hydrogen and loweralkyl; and the therapeutically active basic salts of the foregoing acids, characterized by (a) epoxidizing a compound of the formula with a percarboxylic acid in a solvent in order to prepare a compound of the formula (IV) or (b) epoxidizing a compound of the formula (VII) with a percarboxylic acid in a solvent in order to prepare a compound of the formula (VIII) or (c) pretreating a compound of the formula (IX) with a strong-base, capable of removing an .alpha. -hydrogen in order to prepare a compound of the formula and then reacting the latter compound under Darzen's reaction conditions with a compound of the formula R1R2C=O (X) in order to prepare a compound of the formula (XI) or (d) converting a compound of the formula I wherein X
is oxy to a compound of formula I wherein X is sulphur by treating a compound of the formula (XI) with thiourea in the presence of a strong mineral acid in an an-hydrous organic solvent and then neutralizing the thus obtained intermediate of formula (XI-a) with a base in order to prepare a compound of the formula (XI-b) or (e) converting a compound of the formula (XII) to the corresponding acid of the formula (XIII) by ester-to-acid hydrolysis under acidic or alkaline conditions, and if desired reesterifying the product in order to prepare a different ester; or (f) converting said acids of formula (XIII) to the corresponding salt form by treatment with a base.

or (g) preparing the amides of formula (I) wherein each of R1 and R2 is hydrogen from the .alpha.-alkylacrylic acids of formula by transformation to the corresponding acid chloride form followed by interaction with ammonia to yield a compound of the formula (XIX) and thereafter epoxidizing said compound XIX to the corres-ponding oxyamide of the formula (XX) which in turn may be converted to the corresponding thio-amide of the formula (XXI) by treating with thiourea as in step (d) above;

or (i) reacting a compound of the formula (XXIII) with ammonia or a primary or secondary alkyl-amine in an inert aprotic organic solvent, to yield the respective amide;
or reacting said compound (XXIII) with an appropriate alkanolamine to yield a compound of the formula (I) wherein R is NH - lower alkyl - OH.

2. The process according to claim 1 for preparing n-butyl 2-tetradecyl glycidate, characterized by epoxidizing n-butyl .alpha.-tetradecyl acrylate with m-chloroperbenzoic acid.

3. The process according to claim 1 for preparing methyl 2-tetradecyl glycidate, characterized by epoxidizing methyl .alpha.-tetradecyl-acrylate with m-chloroperbenzoic acid.

4. The process according to claim 1 for preparing methyl 2-dodecylglycidate, characterized by epoxidizing the corresponding acrylate with m-chloroperbenzoic acid.

5. The process according to claim 1 for preparing methyl 2-tridecylglycidate, characterized by epoxidizing the corresponding acrylate with m-chloroperbenzoic acid.

6. The process according to claim 1 for preparing methyl 2-tetradecylthioglycidate, characterized by reacting 2-tetradecylglycidate with thiourea, and neutralizing the product with sodium bicarbonate.

7. The process according to claim 1 for preparing 2-tetradecylglycidic acid, characterized by hydrolysing the corresponding methyl ester.

8. The process according to claim 1 for preparing 2-tetradecylglycidamide, characterized by epoxidizing the corresponding acrylamide.

9. The process according to claim 1 for preparing methyl 2-tetradecyl-3-methylglycidate, characterized by epoxidizing 2-tetradecyl-crotonate with m-chloroperbenzoic acid.

10. The process according to claim 1 for preparing methyl 2-tetradecyl-3,3-dimethylglycidate, characterized by reacting methyl bromopalmetate with a strong base and acetone.

11. The process according to claim 1 for preparing N,N-dimethyl-2-tetradecylglycidamide, characterized by reacting 2-tetradecylglycidic acid with ethyl chloroformate and then reacting the product with dimethylamine.

12. The process according to claim 1 for preparing N-(2-hydroxyethyl)-2-tetradecylglycidamide, characterized by reacting 2-tetradecylglycidic acid with ethylchloroformate and then reacting the product with ethanolamine.

PRODUCT CLAIMS

13. A compound selected from the group consisting of glycidic and thioglycidic acid derivatives having the formula:

(I) wherein n is an integer from 10 to 14; R is a member selected from the group consisting of OH, O-loweralkyl, NH2, NH-loweralkyl, NH-loweralkyl-OH and N(loweralkyl)2; X is a member selected from the group con-sisting of O and S; and each of R1 and R2 is a member selected from the group consisting of hydrogen and loweralkyl; and the therapeutically active basic salts of the foregoing acids whenever prepared or produced by the process of claim 1 or by any chemical equivalent thereof.

14. n-Butyl 2-tetradecyl glycidate whenever prepared or produced by the process of claim 2 or any chemical equivalent thereof.

15. Methyl 2-tetradecyl glycidate whenever prepared or produced by the process of claim 3 or any chemical equivalent thereof.

16. Methyl 2-dodecylglycidate whenever prepared or produced by the process of claim 4 or any chemical equivalent thereof.

17. Methyl 2-tridecylglycidate whenever prepared or produced by the process of claim 5 or any chemical equivalent thereof.

18. Methyl 2-tetradecylthioglycidate whenever prepared or produced by the process of claim 6 or any chemical equivalent thereof.

19. 2-Tetradecylglycidic acid whenever prepared or produced by the process of claim 7 or any chemical equivalent thereof.

20. 2-Tetradecylglycidamide whenever prepared or produced by the process of claim 8 or any chemical equivalent thereof.

21. Methyl 2-tetradecyl-3-methylglycidate whenever prepared or produced by the process of claim 9 or any chemical equivalent thereof.

22. Methyl 2-tetradecyl-3,3-dimethylglycidate whenever prepared or produced by the process of claim 10 or any chemical equivalent thereof.

23. N,N-Dimethyl-2-tetradecylglycidamide whenever prepared or produced by the process of claim 11 of any chemical equivalent thereof.

24. N-(2-Hydroxyethyl)-2-tetradecylglycidamide whenever prepared or produced by the process of claim 12 or any chemical equivalent thereof.