PREPARATION OF OPTICALLY ACTIVE 1,3-DIOXOLANE-4-METHANOL COMPOUNDS

Abstract: Process for preparing 2,2'-disubstituted-1,3-dioxolane-4-methanol compounds having formula (I), wherein R1 and R2 are each independently hydrogen, alkyl, cycloalkyl or R1 and R2 together with the carbon atom form a 3 to 6 member cycloalkyl group, or aryl, the process comprising: reacting D- or L-serine with a nitrosating agent in an aqueous solution in the presence of formic acid, acetic acid, or propanoic acid to prepare 2,3-dihydroxypropanoic acid (D- or L-glyceric acid), the aqueous solution comprising from about 0.1 to 0.5 liter of water per mole of the serine starting material; reacting the glyceric acid so formed with 2,2-dimethoxypropane in the presence of a loweralkyl alcohol to prepare the D- or L-glyceric acid alkyl ester which is reacted with a selected aldehyde or ketone or the acetal or ketal derivative to prepare the corresponding 1,3-dioxolane derivative. Reacting the 1,3-dioxolane derivative with lithium aluminum hydride provides the desired 2,2'-disubstituted-1,3-dioxolane-4-methanol derivative. If an alcohol is not used as described above, then the 2,3-dihydroxy-propanoic acid is reacted with a selected aldehyde or ketone or the acetal or ketal derivative to prepare the 1,3-dioxolane derivative. The dioxolane derivative is then reacted with lithium aluminum hydride to provide the desired 2,2'-disubstituted-1,3-dioxolane-4-methanol derivative. The compounds so prepared are intermediates in the preparation of optically active beta-agonists or antagonists.

Description: PRFPARATION OF OPTI CALLY ACTI VE 1 .3-010X0LANE-4-METHAN0L COMPOUNDS Background of the Invention Compounds of the formula wherein R*- and R2 are each Independently hydrogen, alkyl, cycloalkyl or R- j and R2 together with the carbon atom form a 3 to 6 member cycloalkyl group or aryl are Important Intermediates In the preparation of beta-agonists an antagonists. The compound L-sol etal O ^ ' CH 3 " CH 3 Is a particularly Important Intermediate for preparing optically active beta-agonIsts and antagonists and a chlral building block 'In a number of natural products. Lok et al In Chemistry and Physics of LIpIds, IS. (1976) 115-122, describes the synthesis of chlral glycerldes starting from D- and L- serine and at page 118 describes the preparation of soIketal, 2,3-0- Isopropy11dene-sn-gIycero1. However, the process described requires the use of large amounts of water, an extensive working period of several days, and low processing temperatures. It thus does not lend Itself to the large scale production of the noted compounds. In particular, the large quantity of water which Is required In relation to the quantity of reactants makes the process Inappropriate for large scale production. Furthermore, when attempting to repeat the method of the prior art with the modification of reducing the amount of water by one-half, c.a. 1.5 liters Instead of 3 liters of water, It was found that the optical rotation of the final product, solketal, was only -9.57 (Neat) Instead of -13.2 (Neat). This Is believed to be due to partial Isomerlzatlon In higher concentration of hydrochloric acid. -2- . Summary of the-Invention In accordance with the present Invention, disclosed Is a process for preparing 2,2'-dIsubstltuted-1,3-dloxolane—-methanol compounds having the formu1a wherein R- j and 2 are each Independently hydrogen, alkyl, cycloalkyl or R-j and R2 together with the carbon atom form a 3 to 6 member cycloalkyl group, or aryl, the process comprising: reacting D- or L-serlne with a nltrosatlng agent such as an alkyl nitrite, nltrosyl hal Ide, nltrosyl sulfurlc acid, ammonium nitrite, or a Group la or I la metal nitrite In an aqueous solution In the presence of formic acid, acetic acid, or propanolc acid to prepare 2,3-dlhydroxy- propanolc acid (D- or L-glycerlc acid), the aqueous solution comprising from about 0.1 to 0.5 liter of water per mole of the serine starting material and from about 0.1 to 0.75 liter of acid per mole of serine; reacting the glycerlc acid so formed with 2,2-dlmethoxypropane, In the presence of a lower alkyl alcohol such as methanol, ethanol , n-propyl or isopropyl alcohol, n-butyl, Isobutyl or t-butγl alcohol, pentanol or hexanol, to prepare the D- or L-glycerlc acid alkyl ester which Is reacted with a selected aldehyde or ketone or the acetal or ketal deriva ive to prepare the corresponding 1,3- loxolane derivative. Reacting the 1,3-dIoxolane derivative with lithium aluminum hydride provides the desired 2,2'dlsubstltuted-1 ,3-dloxolane-4-methanol derivative. If an alcohol Is not used as described above, then the 2,3-dlhydroxy- propanolc acid Is reacted with a selected aldehyde or ketone or the acetal or ketal derivative to prepare the 1,3- loxolane derivative. The dloxolane derivative Is then reacted with lithium aluminum hydride to provide the desired 2,2*dlsubstltuted-1 ,3-dloxolane- -fltethanol derivative. One embodiment of the Invention comprises: -3- reactlng D- or L-serlne with sodium nitrite In an aqueous solution In the presence of formic acid, acetic acid, or propanolc acid to prepare 2,3-dlhydroxypropanolc acid (D- or L-glycerlc acid), the aqueous solution comprising from about 0.1 to 0.5 liter of water per mole of the serine 5 starting material and from about 0.1 to 0.75 liter of acid per mole of serine; reacting the glycerlc acid so formed with 2,2- lmethoxypropane n the presence of methanol to prepare the D- or L-glycerlc acid methyl ester (methyl D- or L- lycerate); 10 reacting the glycerlc acid methyl ester with 2,2-d!methoxypropane In the presence of an acid to produce methyl 2,3-0-Isopropyl ldene-0- or L-glycerate; and adding a solution of the methyl 2,3-0-fsopropyl Idene-gIycerate to lithium aluminum hydride to produce the D- or L-solketal, (S)-(+)- or 15 (R)-(-)-2,2-dImethyl-1,3-dIoxolane-4-methanol . Alternatively, the glycerlc acid can be reacted with the 2,2-dImethoxypropane without methanol to prepare 2,3-0-Isopropyl Idene D- or L-glycerlc acid which Is then reacted with lithium aluminum hydride to produce the solketal. 20. The term "alkyl" as used herein refers to straight or branched chain alkyl radicals containing from 1 to 10 carbon atoms Including but not limited to methyl, ethyl, n-propyl, Iso-propyl, n-butyl, sec-butyl, t-butyl, 2-methyIhexyI , n-pentyl, 1-methyIbutyl , 2,2-dlmethylbutyI , 2-methyIpentyI , 2,2- imethylpropyl , n-hexyl, heptyl, octyl, nonyl, or decyl 25 and the 1 Ike. The term "cycloalkyl" as used herein refers to cyclic saturated aliphatic radicals containing 3 to 6 carbon atoms in the ring, such as eyeIopropyI, eyeIobutyI, eyeIopentyI or eyeIohexy1. The term "halo" Includes c loro, fluoro, bromo and lodo. Q The term "aryl" represents phenyl or naphthyl which may be unsubstltutθd or substituted with loweralkyl of from one to about 6 carbon atoms, halo, hydroxy, or amIno. .The term "nltrosatlng agent" as used herein Includes but Is not limited to an alkyl nitrite, nltrosyl hallde, nttrosyl sulfurlc acid, 5 ammonium nitrite or a Group la or I la metal nitrite where the metal Is lithium, potassium, sodium, magnesium, barium, calcium or strontium. Detalled Description of the Invention In accordance with the present Invention, disclosed Is a process for selectively preparing 2,2'-dlsubs ltuted-1 ,3-dIoxolane-4-methanol compounds of the formula wherein R| and 2 are each Independently hydrogen, alkyl, cycloalkyl or R-j and R2 together with the carbon atom form a 3 to 6 member cycloal yl group, or aryl, one embodiment of the process comprising: reacting D- or L-serlne with a nltrosatlng agent such as an al yl nitrite, nltrosyl hal Ide, nltrosyl sulfurlc acid, ammonium nitrite, sodium nitrite or other metal nitrites where the metal is a Group la or tla metal such as lithium, potassium, magnesium, barium, calcium or strontium In an aqueous solution In the presence of formic add, acetic add or propanolc « add to prepare 2,3-dlhydroxypropanolc add, the aqueous solution comprising from about 0.1 to 0.5 liter of water per mole of the serine starting material and from about 0.1 to 0.75 liter of add per mole of serine; reacting the 2,3-dIhydroxypropanolc add so formed with 2,2- dImethoxypropane, In the presence of a lower alcohol, to prepare the alkyl D- or L- lycerate (D- or L-glycerlc add alkyl ester); reacting the alkyl D- or L-glycerate with 2,2- dlmethoxypropane In the presence of an add to produce alkyl 2,3-0-Isopropyl ldene-0- or L-glycerate; adding a solution of the alkyl 2,3-0-Isopropyl ldene-0- or L- glycerate to lithium aluminum hydride to produce the final product, D- or L-soIketal, (S)-(t)- or ( R ) -(-)-2,2-dlmethyl-1,3-dloxolane-4-methanol (2,3-0-Isopropyl Jdene-0- or L- lycerol ). -5- Alternatively, the 2,3- Ihydroxypropanolc acid (D- or L-glycerlc add Is reacted with 2,2-dImethoxypropane without lower alcohol present to prepare 2,3-0-1sopropyl Idene D- or L-glycerlc add which Is then reacted with lithium aluminum hydride to produce the solketal. To prepare other desired derivatives of formula I, the D- or L- lycerlc add alkyl ester prepared as described above is reacted with an appropriate aldehyde or ketone or their acetal or ketal derivative to prepare the 1,3-dloxolane derivative. Reacting the 1 ,3- Ioxolane derivative with lithium aluminum hydride provides the desired 2,2 , - lsubstltuted-l,3-dloxolane-4-methanol deri ative. The follo ing scheme summarizes and Is representative of the process of the present Invention. O- or L- solketal -6- Optlcal ly active solketal Is an Important Intermediate In the preparation of optically active beta-agonists or antagonists and a chlral building block for a number of natural products. C. . Lo et al In Chemistry and Physics of Llplds, l≤. (1976)115-122, describe chlral lycerlde synthesis from D- and L-serlne and at pages 118 and 119 describe the preparation of solketal, (2,3-0-Isopropyl Idene-D- or L-glycerol) which Is also Identified as (S)-(+)- or (R)-(-)-2,2-dlmethyl-1,3-dIoxolane-4-methanol . For convenience hereafter, all reference will be to the L-forms of the compounds. This prior art method has a number of disadvantages, however, primarily the use of large amounts of water, an extensive working period of several days, and low processing temperatures. These requirements make the process Inappropriat for large scale production which Is necessary for the process to be economically feasible. Specifically, the process requires the use of six liters of water per mole of starting material, L-serlne; the Initial reaction Is conducted at 0° C for 48 hours and about an additional 24 hour at room temperature. In contrast, the method of the present Invent on utilizes about one-tenth of the amount of solvent per mole of starting material, from about 0.10 to 0.50 liter of water per mole of L-serine with about 0.30 liter being preferred; the working period Is reduced to less than one-half, overnight Instead of about three days; and the reaction is carried out at room temperature instead of 0° C. Thus, the process offers a practical method for the large scale preparation of optically active solketal, large scale production being necessary for such a process to be eonomlcally feasible. In the method of the prior art, the L-serlne Is reacted with sodium nitrite in the presence of hydrochloric add. In the process described * herein, the reaction Is carried out in the presence of formic acid, acetic acid, or propanolc add, with acetic acid being preferred. This modification permits the use of a much reduced amount of solvent, from 6 liters of water per mole of L-serlne to about 0.30 liter. This reduction In the quantity of water utilized In the reaction permits the economic preparation of optically active 2,3- I ydroxypropanolc add, solketal, or other derivatives. -7- Moreover, reducing the amount of water by one-half In the prior art metho resulted In an optical rotation of the solketal formed of only -9.57 (nea Instead of -13.2 (neat), believed due to partial Isomerlzatlon In higher concentrations of hydrochloric ad . The method of the present invention can be utilized to make beta-blocking agents such as those described In United States patents 4,387,103; 4,402,974, or 4,405,642 for example, or to make the Iso ers of propranoloi, a conventional beta-blocking agent. The L form of propranol Is about twice as potent as the racemlc mixture as far as beta-blocking activity Is concerned and produces lesser side effects. In addition, D-propranoIol Is shown to be an effective contraceptive agent. Hence, an economical process for preparing D- or L-propranolol Is highly desirable. Likewise, the method can be used to make other beta- locking agents such metoproloi, tlmolol, plndolol, practolol, or carteolol. In the following examples, Example I describes the preparation of L-solketal without the use of methanol In the second step of the procedur the conversion of 2,3-dIhydroxypropanoIc add (L-glycerlc add). In this embodiment of the Invention, the 2,3-dlhydroxypropanolc add Is reacted with 2,2-dlmethoxypropane to prepare 2,3-0-1sopropyl Idene-L-gIycerIc add which Is then reacted with lithium aluminum hydride to prepare the L-solketal . In Example II, the 2,3- lhydroxypropanolc add Is reacted with 2,2-dImethoxypropane and methanol to prepare methyI-L- lycerate (L-glycerl acid methyl ester) which Is then reacted with 2,2-dImethoxypropane to produce methyI-2,3-0-1sopropyl Idene-L-glycerate. This In turn is reacted with lithium aluminum hydride to prepare L-solketal, 2,3-0-Isopropyl Idene- L-glycerol [(R)-(-)-2,2-dlmethyl-1 ,3-dloxolane-4-methanol_l. In order to Illustrate the manner In which the above compounds may be prepared, reference Is made to the following examples, which, however, are not meant to limit or restrict the scope of the Invention In any respect. -8- EX AMPLE In a 6 liter (L) flask was placed 630 g (6 moles ) of L-serlne (1), 1.8 L of water and 2.4 L of acetic add. The flask was surrounded with Ice and the Internal temperature was maintained below +20° C. Sodium nitrite (500 g, 7.2 moles) was added, with stirring, at a rate of 20 g every 15 minutes, (An aqueous solution of sodium nitrite could also be used by adding dropwlse to the reaction mixture.) When this addition was complete, the solution was warmed to room temperature (23-26° C) and stirred overnight (16-20 hours). Concentrated hydrochloric acid (650 mL, 7.8 equlv.) was added In one lot. The solution was then transferred equally Into four 3 L round-bottomed flasks and evaporated in. iaciiώ at 75° C until the solvent ceased to collect. The residue contained crystalline sodium chloride, crude 2,3-dIhydroxypropanoIc add (2), water, and acetic acid. The slurries were filtered and the flasks were rinsed with a small amount of acetone. The filtrates were combined and evaporated to near dryness. To the filtrates, 1 L of toluene was added and evaporated to azeotrope trace of water. This operation was repeated twice. The residue was then taken up with 1.5 L of acetone and 1.8 L (1.5 Kg) of 2,2-dImethoxypropane and filtered to remove most of sodium chloride. The filtrate was then stirred overnight at room temperature (r.t.). Evaporation of the above solution gave an oil, 2,3-0-Isopropyl Idene-L- gIycerIc add (4), which was treated ith 1 L of toluene and evaporated lη vacuo at 65° C. In the meantime, a reducing solution was prepared as follows, In a 3 neck - 12 L round-bottomed flask equipped with a mechanical stlrrer, an adding funnel and a condenser, was placed 250 g (6.6 moles) of lithium aluminum hydride. Eight liters of tetrahydrofuran was slowly added with stirring. The flask was then surrounded with Ice. To this slurry the above crude oil (about 800 g) was added In a slow stream maintaining a constant reflux. After about three-fourths of the material was added, the -9- lce-bath was removed and addition was continued. The funnel was rinsed several times with a small amount of tetrahydrofuran. Stirring was continued for another hour. Again, the flask was surrounded with Ice and excess lithium aluminum hydride was destroyed by successive addition of 2 5 mL of water, 250 mL of 15$ sodium hydroxide, and another 250 L of water. After stirring for 30 minutes, the slurry was filtered, washed with 1 L o tetrahydrofuran and the filtrate was evaporated to an oil which was treat with.1 L of toluene and evaporated in γa£iifi. The resulting yellow oil (about 300 g) was transferred to a 500 mL round-bottomed flask and 0 distilled under reduced pressure. After removing most of the toluene (about 20 mL, b.p. 30-60° C, 2-5 mm), the temperature was raised to 60-80 C and about 220 g (29J_) of L-solketal (6) was collected, b.p. 75° C, 2 m n. 1.4337, α 5 -13.234 (neat), TLC Rf 0.57 (toluene-acetone, 7:3); NMR an IR were consistent with the assigned structure 0-!t. b.p. 75° C, 10 mm; n 5 1.4345; α^ 5 .= -13.2 (neat)}. A third higher b.p. fraction 10 g; 80° C, 0.5 mm) was also collected; TLC showed a mixture of product and Impurities. Only a small amount of water-soluble black residue (about 20 g) was left in the flask. EXAMPLE II . Q In a 6 L flask was placed 630 g (6 moles) of L-serlne (1), 1.8 L of water and 2.4 L of acetic add. The flask was surrounded with lee and the internal temperature was maintained below 20° C. Sodium nitrite (500 g, 7.2 moles) was added, with stirring at a rate of 20 g every 15 min. When this addition was complete, the solution was warmed to rΛ- (23-26° C) and 5 stirred overnight. (16-20 h.) Concentrated hydroc loric acid (650 mL, 7.8 equiv.) was added In one lot. The solution was then transferred equally Into four 3 L round-bottomed flasks and evaporated la iasuiQ at 75° C until the solvent ceased to collect. The residue contained crystalline sodium chloride, crude 2,3- lhydroxypropanolc acid (2), water, and acetic acid. The sl urrres were filtered and the flasks were rinsed with a small amount of acetone. The filtrates were combined and evaporated to near dryness. The residue was co-evaporated with 1 L of toluene to azeotrope traces of water. This operation was repeated twice. The residue was then taken up with 1.5 L of methanol and 1.2 L of 2, 2-dI ethoxypropane, added dropwlse with 150 mL of S0Cl2 # stirred for 2 hours, filtered, and the filtrate was evaporated to an oil. The oily residue, L-glycerlc add methyl ester (3), was then mixed with 1.5 L of acetone and 1.8 L (1.5 Kg.) of 2,2-dImethoxypropane and the mixture was filtered. The filtrate was then stirred overnight at room temperature. Evaporation of the above solution gave an oil, methyl 2,3-0-lsopropyl- ldene-L-g1ycerate (5), which was treated with 1 L of toluene and evaporated In vacuo at 65°. In the meantime, a reducing solution was prepared as fol lows. In a 3 neck-12 L round-bottomed flask equipped with a mechanical sttrrer, an adding funnel, and a condenser was placed 250 g (6.6 moles) of lithium aluminum hydride. Eight liters of tetrahydrofuran was slowly added with stirring. The flask was then surrounded with Ice. To this slurry the above crude oil (about 800 g) was added at a slow stream maintaining a constant reflux. Stirring was continued for another hour. Excess lithium aluminum hydride was destroyed by successive addition of 250 mL of water, 250 mL of 15$ sodium hydroxide, and another 250 mL of water. After stirring for 30 minutes, the slurry was filtered, washed with 1 L of tetrahydrofuran, and the filtrate was evaporated to an oil which was treated with 1 L of toluene and evaporated ia 2£U£. The resulting yellow oil, (about 300 g)., was transferred to a 500 mL round-bottomed flask and distilled under reduced pressure. After removing most of the toluene (about 40 ML, b.p. 30-60° C, 2-5 mm), the temperature was raised to 60-80° C and about 360 g (45$) of. L-solketal was collected, b.p. 75° C, 2 mm, n. 1.4337, α j -13.234 (neat), TLC Rf 0.57 (toluene-aetone, 7:3) WR and IR were consistent with the assigned structure D-lt. b.p. 75°, 10 mm; n 1.4345; α§ 5 = -13.2 (neat)}. -11- A third higher b.p. fraction 10 g; 80° C, 0.5 mm ) was also collected; TLC showed a mixture of product and Impurities. Only a small amount of water-soluble black residue (about 20 g) was left In the flask. EXAMPLE Using the method of Example II, 14 kilograms of L-solketal (2,3-0- lsopropy11dene-L-glycerol ) (6) were prepared using the following amounts o reactants and solvents: STEP 1: 20 kilograms (kg) L-serlne (1) 57 liters (L) delonlzed water 79.5 kg. acetic add 15.9 kg. sodium nitrite 19 L hydrochloric add STEP 2: 12.5 gallons (gal) methanol 10 gal dImethoxypropane 4.8 kg. thlonyl chloride STEP 3: 12.5 gal acetone 15 gal dImethoxypropane YIELD: 24.5 kg. oil STEP 4: Reduction, completed In two portions EACH REACTION: 160 L tetrahydrofuran 3 kg lithium aluminum hydride 3 L water 3 L 15$ sodium hydroxide 3 L water TOTAL YIELD: 14 Kg, a 2 - 5 -13.60 (neat) EXAMPLE I V Using the method of Example II and starting with 200 g of D-serlne, 114 g D-sol etal were prepared, αj + 13.56 (neat), bp 55-75°C, 0.6 mm Hg. EXAMPLE Y Using the method of Example 11 but reacting the L-glycerlc add methyl ester (3) with 1,1-dlmethoxy cyclohexane, 2,2'-cyclohexyl ldene-1 ,3- dloxolane-4-methanol Is prepared according to the following reaction scheme: EXAMPLE Yl By using the method of {Example I, namely without methanol, and reacting the 2,3- Ihydroxypropanolc add (2) with the 1 ,1-dImethoxy cyclohexane (7), the 2,2 , cycIohexyl !deπe-1,3- loxolane (8) of Example Y ca be prepared.

Claims: -13- WHAT IS CLAIMED IS: 1. A process for the preparation of 2,3-dlhydroxypropanolc add which comprises reacting L-serlne with a nltrosatlng agent In an aqueous solution In the presence of formic acid, acetic add, or propanolc ad at about room temperature for a period of about 8 to 20 hours and wherein said aqueous solution of L-serlne comprises from 0.10 to 0.5 liter of water per mole of L-serlne and said add Is present In an amount of frcm 0.1 to 0.75 liter per mole of L-serlne. 2. The process of Claim 1 wherein the L-sertne Is reacted with ammonium nitrite, an alkyl nitrite, nltrosyl hal Ide, nltrosyl sulfurlc add, or a Group la or I la metal nitrite. 3. The process of Claim 2 wherein the L-serlne Is reacted with sodium nitrite or potassium nitrite In the presence of acetic add. 4. The process of Claim 3 wherein the L-serlne Is reacted with sodi m nitrite. 5. A process for preparing a selected 2,2 f -dlsubstltuted-r1,3-dIoxolaπe- 4-methanol derivative having the formula wherein Rj and R2 are each Independently hydrogen, alkyl, cycloalkyl o R-j and R2 together with the carbon atom form a 3 to 6 member cycloalkyl group, or aryl, the process comprising: reacting D- or L-serlne with a nltrosatlng agent In an aqueous solutio In the presence of acetic add, formic add, or propanolc at about -14- roo temperature for a period of about 8 to 20 hours and wherein said aqueous solution of D- or L-serlne comprises from about 0.10 to 0.5 liter of water per mole of D- or L-serlne and said acid Is present In an amount of from about 0.1 to 0.75 liter per mole of D- or L-serlne to produce 2,3- Ihydroxypropanolc add; adding to the 2,3- Ihydroxypropanotc acid so produced 2,2- imethoxy- propane in the presence of a loweralkyl alcohol to produce D- or L-g|ycerlc add alkyl ester; reacting the D- or L- lycerlc add alkyl ester with an appropriate aldehyde, ketone or their acetal or ketal derivative to produce the corresponding 1,3- loxolane derivative; and reacting the 1 ,3-dIoxolane derivative so produced with lithium aluminum hydride to produce the desired 2,2*-dIsubstItuted-1 ,3-dloxolane-4- methanol derivative. 6. The process of Claim 5 wherein the D- or L-serlne Is reacted with ammonium nitrite, an alkyl nitrite, nltrosyl hal Ide, nltrosyl sulfurlc acid or a Group la or I la metal nitrite. 7. The process of Claim 6 wherein the D- or L-serlne Is reacted with ammonium nitrite, sodium nitrite or potassium nltrlte« In the presence of formic acid or acetic add, and the loweralkyl alcohol Is methanol, ethanoi or propanol . 8. The process of Claim 7 wherein the D- or L-serlne is reacted with sodium nitrite In the presence of acetic add and the loweralkyl alcohol Is methanol. 9. The process of Claim 5 wherein the 2,3- lhydroxypropanotc Is reacted with an appropriate aldehyde, ketone or their acetal or ketal derivative to produce 2,3-0-lsopropyl Idene D- or L-glycerlc add which Is then reacted with llthlun aluminum hydride to produce the desired 2,2 ! -dlsubstituted-1,3-dioxolane-4-methanol derivative. 10. The process of Claim 9 wherein the D- or L-serine Is reacted with ammonium nitrite, sodium nitrite or potassium nitrite In the presence of formic add or acetic acid. -15- 11. The process of Claim 10 wherein the D- or L-serlne Is reacted with sodium nitrite In the presence of acetic add. 12. A process for the preparation of L-solketal which comprises reacting L-serlne with a nltrosatlng agent In an aqueous solution In the presence of acetic add, formic add, or propanolc add at about room temperature for a period of about 8 to 20 hours and wherein said aqueous solution of L-serlne comprises from about 0.10 to 0.5 liter o water per mole of L-serlne and said add Is present In an amount of from about 0.1 to 0.75 liter per mole of L-serlne to produce 2,3-dlhydroxypropanolc add; adding to the 2,3-dlhydroxypropanolc add so produced 2,2-dImethoxy- propane In the presence of a lower alcohol to produce L-glycertc acid alkyl ester; reacting the L-glycerlc acid alkyl ester with 2,2-dtmethoxypropane to produce methyl 2,3-0-Isopropyl Idene-L- Iycerate; and reacting the methyl 23-0-lsopropy11dene-L-gIycerate so produced with lithium aluminum hydride to produce L-solketal. 13. The process of Claim 12 wherein the L-serlne Is reacted with ammonium nitrite, an alkyl nitrite, nltrosyl hal Ide, nltrosyl sulfurlc add, o a Group la or I la metal nitrite. 14. The process of Claim 13 wherein the L-serlne Is reacted with ammonlun nitrite, sodium nitrite or potassium nitrite In the presence of formi add or acetic add and the loweralkyl alcohol Is methanol, ethaπol o propanol . 15. The process of Claim 14 wherein the L-serlne Is reacted with sodium nitrite In the presence of acetic add and the loweralkyl alcohol Is methanol, to produce L-glycerlc acid methyl ester. 16. The process of Claim 12 wherein the 2,3- Ihydroxypropanolc add so produced Is reacted with 2,2-dlmethoxypropane to prepare 2,3-0-1sopropy1 ?dene-L-gIycerlc add which In turn Is reacted with lithium aluminum hydride to produce L-solketal. 17. The process of Claim 16 wherein the L-serlne Is reacted with ammonium nitrite, sodium nitrite or potassium nitrite In the presence of formic add or acetic add. 18, The process of Claim 17 wherein the L-serlne Is reacted with sodium nitrite In the presence of acetic add.

Inventors: MAI KHUONG H X, PATIL GHANSHYAM, MAI, KHUONG, H., X., PATIL, GHANSHYAM
Applicants: AMERICAN HOSPITAL SUPPLY CORP, AMERICAN HOSPITAL SUPPLY CORPORATION
Application year: 1985
Main classification: C07C59
IPC codes: B01J31, C07C51, C07C59, C07C67, C07C69, C07D317