Preparation of Optically Active 1,3-Dioxolane-4-Methanol Compounds

Patentamt 0 1 73 71 4 JEuropaischesEuropean Patent Office ® Publication number: B1 Office europeen des brevets

® EUROPEAN PATENT SPECIFICATION

(§) Date of publication of patent specification: 02.05.90 (a) Int. CI.5: C 07 C 59/10, C 07 C 59/285, C 07 D 317/20 (D^ Application number: 85901208.0 (22) Date of filing: 11.02.85 (§) International application number: PCT/US85/00213

® International publication number: WO 85/03704 29.08.85 Gazette 85/19

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

(§) Priority: 15.02.84 US 580492 (73) Proprietor: E.I. DU PONT DE NEMOURS AND COMPANY 1007 Market Street (§) Date of publication of application: Wilmington Delaware 19898 (US) 12.03.86 Bulletin 86/11 (72) Inventor: MAI, Khuong, H., X. (§) Publication of the grant of the patent: 108 South Orchard Street 02.05.90 Bulletin 90/18 WaukeganJL 60061 (US) Inventor: PATIL, Ghanshyam 340 Albert Drive (§) Designated Contracting States: Vernon Hills, IL 60061 (US) CHDEFRGB LI SE Representative: Seaborn, George Stephen et al References cited: c/o Edward Evans & Co. Chancery House 53-64 DE-C-503 497 US-A-3 058 981 Chancery Lane GB-A-429 096 US-A-3657 277 London WC2A1SD (GB) JP-A-15 008 778 US-A-4413142 US-A-2752391 References cited: CHEMICAL ABSTRACTS, vol. 88, no. 3, 16th CHEMICAL ABSTRACTS, vol. 88, no. 3, 16th January 1978, page 566, abstract 22089e, 1978, 566, abstract 22094c, al.: The January page Columbus, Ohio, US; CM. LOK et Columbus, Ohio, US; CM. LOK et al.: The of chiral fronm D- 1^ synthesis glycerides starting synthesis of chiral glycerides starting from D- and L-serine", & CHEM. PHYS. LIPIDS, 1976, and & ACTES CONGR. MOND., SOC. CO L-serine", 16(2), 115-22 INT. ETUDE CORPS GRAS, 13TH, 1976 SECT. E, 15-20 Note: Within nine months from the publication of the mention of the grant of the turopean patent, any person may give notice to the European Patent Office of opposition to the European patent granted. Notice of opposition shall be filed in a written reasoned statement. It shall not be deemed to have been filed until the opposition fee has been (Art. 99(1 ) European convention). UJ paid. patent Courier Press, Leamington Spa, England. EP 0173 714 B1

||) References cited: N, Chemical Abstracts, Volume 37, No. 3699, "Synthesis with acetonated glyceric ester" issued 1933. Journal of Organic Chemistry, Volume 22, No. 8, issued 14 August 1957, "An interpretation of the Reaction of Aliphatic Primary Amines with Nitrous Acid, pages 861-869. EP 0173 714 B1

Description Field of the Invention The present invention relates to the preparation of 2,3-dihydroxypropanoic acid and to the preparation of optically active 1,3-dioxolane-4-methanol compounds.

Background of the invention Compounds of the formula w /CH2\ CH„-CH -OH I 2 | O O V /\ R1 R2

20 wherein Ft, and R2 are each independently hydrogen, alkyl, cycloalkyl or aryl or and R2 together with the carbon atom form a 3 to 6 member cycloalkyl group, are important intermediates in the preparation of beta- agonists and antagonists. The compound L-solketal

25 /CH2\ CH„-CH OH I 2 |

CH3 CH3

is a particularly important intermediate for preparing optically active beta-agonists and antagonists and a 35 chiral building block in a number of natural products. Loket al in Chemistry and Physics of Lipids, 76(1976), 115—122, describes the synthesis of chiral glycerides starting from D- and L-serine and at page 118 describes the preparation of solketal, 2,3-O-isopropyliden-sn-glycerol. 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 40 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 isomerization in 45 higher concentration of hydrochloric acid.

Summary of the Invention In accordance with a first aspect of the invention, there is provided a process forthe preparation of 2,3- dihydroxypropanoic acid which comprises reacting D- or L-serine with a nitrosating agent in an aqueous so solution in the presence of formic acid, acetic acid or propanoic acid, preferably at about room temperature, for a period of about 8 to 20 hours and wherein said aqueous solution of D- or L-serine comprises from 0.10 to 0.5 liter of water per mole of D- or L-serine and said acid is present in an amount of from 0.1 to 0.75 liter per mole of D- or L-serine. In accordance with a second aspect of the present invention, there is provided a process for preparing 55 2,2'-disubstituted-1,3-dioxolane-4-methanol compounds having the formula

/CH2\ CH2-CH. OH 60 V /\ R1 R2 65

3 EP 0173 714 B1 wherein Ft, and R2 are each independently hydrogen, alkyl, cycloalkyl or aryl or R-, and R2 together with the carbon atom form a 3 to 6 member cycloalkyl group, the process comprising: reacting D- or L-serine with a nitrosating agent such as an alkyl nitrite, nitrosyl halide, nitrosyl sulfuric acid, ammonium nitrite, or a Group 1a or 11a metal nitrite in an aqueous solution in the presence of formic 5 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 and from about 0.1 to 0.75 liter of acid per mole of serine; reacting the glyceric acid so formed with 2,2-dimethoxypropane, in the presence of a lower alkyl alcohol such as methanol, ethanol, n-propyl or isopropyl alcohol, n-butyl, isobutyi or t-butyl alcohol, pentanol or hexanol, to prepare the D- or L-glyceric acid lower alkyl ester which w is reacted with a selected aldehyde or ketone or an acetal or ketal derivative of the selected aldehyde or ketone to prepare the corresponding 1,3-dioxolane derivative. Reacting the 1,3-dioxolane derivative with lithium aluminium hydride provides the desired 2,2'-disubstituted-1,3-dioxolane-4-methanol derivative. As an alternative to the use of an alcohol as described above, the 2,3-dihydroxypropanoic acid is reacted with a selected aldehyde or ketone or an acetal or ketal derivative of a selected aldehyde or ketone 15 to prepare the corresponding 1,3-dioxolane derivative. The dioxolane derivative is then reacted with lithium aluminium hydride to provide the desired 2,2'-disubstituted-1,3-dioxolane-4-methanol derivative.

One embodiment of the invention comprises: reacting D- or L-serine with sodium nitrite in an aqueous solution in the presence of formic acid, acetic 20 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 and from about 0.1 to 0.75 liter of acid per mole of serine; reacting the glyceric acid so formed with 2,2-dimethoxypropane in the presence of methanol to prepare the D- or L-glyceric acid methyl ester (methyl D- or L-glycerate); 25 reacting the glyceric acid methyl ester with 2,2-hydroxypropane in the presence of an acid to produce methyl 2,3-O-isopropylidene-D- or L-glycerate; and adding a solution of the methyl 2,3-O-isopropylideneglycerate to lithium aluminium hydride to produce the D- or L-solketal, (S)-(+)- or (R)-(-)-2,2-dimethyl-1,3-dioxolane-4-methanol. Alternatively, the glyceric acid can be reacted with the 2,2-dimethoxypropane without methanol to 30 prepare 2,3-O-isopropylidene D- or L-glyceric acid which is then reacted with lithium aluminium hdyride to produce the solketal. According to a third aspect of the invention, there is provided a process for the preparation of D- or L- solketal, which comprises reacting D- or L-serine with a nitrosating agent in an aqueous solution in the presence of acetic acid, formic acid, or propanoic acid, preferably at about room temperature, for a period 35 of about 8 to 20 hours and wherein said aqueous solution of D- or L-serine comprises from about 0.1 0 to 0.5 liter of water per mole of L-serine and said acid is present in an amount of from about 0.1 to 0.75 liter per mole of D- or L-serine to produce 2,3-dihydroxypropanoic acid; optionally adding to the 2,3-dihydroxypropanoic acid so produced 2,2-dimethoxypropane in the presence of a lower alkyl alcohol to produce D- or L-glyceric acid lower alkyl ester; 40 reacting the 2,3-dihydroxypropanoic acid or the D- or L-glyceric acid alkyl ester with 2,2-dimethoxypropane to produce 2,3-O-isopropylidene-D- or L-glyceric acid or methyl 2,3-O-isopropylidene-D- or L- glycerate respectively; and reacting the 2,3-O-isopropylidene-D- or L-glyceric acid or the methyl 2,3-O-isopropylidene-D- or L- glycerate so produced with lithium aluminium hydride to produce D- or L-solketal. 45 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, isopropyl, n-butyl, sec-butyl, t-butyl, 2- methylhexyl, n-pentyl, 1-methylbutyl, 2,2-dimethylbuty, 2-methylpentyl, 2,2-dimethylpropyl, n-hexyl, heptyl, octyl, nonyl and decyl. The term "cycloalkyl" as used herein refers to cyclic saturated aliphatic radicals containing 3 to 6 so carbon atoms in the ring, such as cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl. The term "halo" includes chloro, fluoro, bromo and lodo. The term "aryl" represents phenyl or naphthyl which may be unsubstituted or substituted with lower alkyl of from one to about 6 carbon atoms, halo, hydroxy, or amino. The term "nitrosating agent" as used herein includes but is not limited to an alkyl nitrite, nitrosyl 55 halide, nitrosyl sulfuric acid, ammonium nitrite or a Group 1a or 11a metal nitrite where the metal is lithium, potassium, sodium, magnesium, barium, calcium or strontium.

Detailed Description of the Invention In accordance with the present invention, disclosed is a process for selectively preparing 2,2'- 60 disubstituted-1,3-dioxplane-4-methanol compounds of the formula

4 ■P 0173 714 B1

vherein R, and R2 are each independently hydrogen, alkyl, cycloalkyl or aryl or h1 ana «2 xogeiner wun ine :arbon atom form a 3 to 6 member cycloalkyl group, one embodiment of the process comprising: reacting D- or L-serine with a nitrosating agent such as an alkyl nitrite, nitrosyl halide, nitrosyl sulfuric icid, ammonium nitrite, sodium nitrite or other metal nitrites where the metal is a Group 1a or 11a metal iuch as lithium, potassium, magnesium, barium, calcium or strontium in an aqueous solution in the jresence of formic acid, acetic acid or propanoic acid to prepare 2,3-dihydroxypropanoic acid, the aqueous solution comprising from about 0.1 to 0.5 liter of water per mole of the serine starting material and from ibout 0.1 to 0.75 liter of acid per mole of the serine; reacting the 2,3-dihydroxypropanoic acid so formed with 2,2-dimethoxypropane, in the presence of a ower alcohol, to prepare the lower alkyl D- or L-glycerate (D- or L-glyceric acid lower alkyl ester); reacting he alkyl D- or L-glycerate with 2,2-dimethoxypropane in the presence of an acid to produce alkyl 2,3-0- sopropylidene-D- or L-glycerate; adding a solution of the alkyl 2,3-O-isopropylidene-D- or L-glycerate to ithium aluminium hydride to produce the final product, D- or L-solketal, (S)-(+)- or (R)-(-)-2,2-dimethyl- 1 ,3-dioxolane-4-methanol(2,3-0-isopropylidene-D- or L-glycerol). Alternatively, the 2,3-dihydroxypropanoic acid (D- or L-glyceric acid) is reacted with 2,2-dimethoxy- which is then Kopane without lower alcohol present to prepare 2,3-O-isopropylidene D- or L-glyceric acid eacted with lithium aluminium hydride to produce the solketal. D- To prepare other desired derivatives of formula 1, the 2,3-dihydroxypropanoic acid or or L-glyceric acid lower alkyl ester prepared as described above is reacted with an appropriate aldehyde or ketone or an acetal or ketai derivative or an appropriate aldehyde or ketone to prepare the 1,3-dioxolane derivative. Reacting the 1,3-dioxolane derivative with lithium aluminium anhydride provides the desired 2,2'- jisubstituted-1,3-dioxolane-4-methanol derivative. The following scheme summarizes and is representative of the process of the present invention. J ■J I II

O O H+ (5)

LAH

D— or L— solketal LAH represents lithium aluminium hydroxide. EP 0 173 714 B1 Optically active solketal is an important intermediate in the preparation of optically active beta- agonists or antagonists and a chiral building block for a number of natural products. C. M. Lok et al in Chemistry and Physics of Lipids, 16, (1976) 115 — 122, describe chiral glyceride synthesis from D- and L- serine and at pages 118 and 119 describe the preparation of solketal, (2,3-O-isopropylidene-D- or L- 5 glycerol) which is also identified as (S)-(+)- or (R)-(-)-2,2-dimethyl-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 inappropriate for large scale production which is necessary for the process to be economically feasible. 10 Specifically, the process requires the use of six liters of water per mole of starting material, L-serine; the initial reaction is conducted at 0°C for 48 hours and about an additional 24 hours at room temperature. In contrast, the method of the present invention 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 75 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 economically feasible. In the method of the prior art, the L-serine is reacted with sodium nitrite in the presence of hydrochloric acid. In the process described herein, the reaction is carried out in the presence of formic acid, acetic acid, 20 or propanoic acid, 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-serine 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-dihydroxypropanoic acid, solketal, or other derivatives. Moreover, reducing the amount of water by one-half in the prior art method resulted in an optical 25 rotation of the solketal formed of only -9.57 (neat) instead of -13.2 (neat), believed due to partial isomerization in higher concentrations of hydrochloric acid. 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 isomers of propranolol, a. conventional beta-blocking agent. The L form of propranolol is about twice as potent as 30 the racemic mixture as far as beta-blocking activity is concerned and produces lesser side effects. In addition, D-propranolol 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- blocking agents such as metoprolol, timolol, pindolol, practolol, or carteolol. In the following examples. Example I describes the preparation of L-solketal without the use of 35 methanol in the second step of the procedure, the conversion of 2,3-dihydroxypropanoic acid (L-glyceric acid). In this embodiment of the invention, the 2,3-dihydroxypropanoic acid is reacted with 2,2-dimethoxypropane to prepare 2,3-O-isopropylidene-L-glyceric acid which is then reacted with lithium aluminium hydride to prepare the L-solketal. In Example II, the 2,3-dihydroxypropanoic acid is reacted with 2,2-dimethoxypropane and methanol to 40 prepare methyl-L-glycerate (L-glyceric acid methyl ester) which is then reacted with 2,2-dimethoxypropane to produce methyl-2,3-0-isopropylidene-L-glycerate. This in turn is reacted with lithium aluminum hydride to prepare L-solketal, 2,3-O-isopropylidene-L-glycerol [(R)-(-)-2,2-dimethyl-1,3-dioxolane-4-methanol]. 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 45 respect. Example 1 In a 6 liter (L) flask was placed 630 g (6 moles) of L-serine (1 ), 1 .8 L of water and 2.4 L of acetic acid. The flask was surrounded with ice and the internal temperature was maintained below +20°C. Sodium nitrite 50 (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 dropwise 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 (659 mL, 7.8 equiv.) was added in one lot. The solution was then transferred equally into four 3 L round-bottomed flasks and evaporated in vacuo at 75°C until the solvent 55 ceased to collect. The residue contained crystalline sodium chloride, crude 2,3-dihydroxypropanoic acid (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 91 .5 Kg) of 2,2-dimethoxypropane and filtered to remove most 60 of sodium chloride. The filtrate was then stirred overnight at room temperature (r.t.). Evaporation of the above solution gave an oil, 2,3-O-isopropylidene-L-glyceric acid (4), which was treated with 1 L of toluene and evaporated in 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 stirrer, an adding funnel and a 65 condenser, was placed 250 g (6.6 moles) of lithium aluminium hydride. Eight liters of tetrahydrofuran was

6 ■P 0 173 714 Bl slowly added with stirring. The flask was then surrounded with ice. I o tnis slurry tne aoove crime on \auwi material 800 g) was added in a slow stream maintaining a constant reflux. After about three-quarters of the had been added, the ice-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 addition of 250 5 surrounded with ice and excess lithium aluminium hydride was destroyed by successive 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 in vacuo. 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 raised to w the toluene (about 20 mL, b.p. 30-60°C, 2.7—6.7 mBar (2—5 mm Hg), the temperature was 60— 80°C and about 220 g (29%) of L-solketal (6) was collected, b.p. 75°C, 2 mm, n. 1.4337, ag5 -13.234 (neat), TLC Rf 0.57 (toluene-acetone, 7:3); NMR and IR were consistent with the assigned structure Lit. b.p. 75°C, 13.3 mBar (10 mm Hg); n. 1.4345; a£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 15 and impurities. Only a small amount of water-soluble black residue (about 20 g) was left in the flask. Example II In a 6 L flask was placed 630 g (6 moles) of L-serine (1 ), 1 .8 L of water and 2.4 L of acetic acid. The flask was surrounded with ice and the internal temperature was maintained below 20°C. Sodium nitrite (55 g, 7.2 the 20 moles) was added, with stirring at a rate of 20 g every 15 min. When this addition was complete, solution was warmed to r.t. (23— 26°C) and stirred overnight. (16—20 h). Concentrated hydrochloric 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 in vacuo at 75°C until the solvent ceased to collect. The residue contained crystalline sodium chloride, crude 2,3-dihydroxypropanoic acid of 25 (2), water, and acetic acid. The slurries were filtered and the flasks were rinsed with a small amount 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 150mLof SOCI, stirred up with 1.5 L of methanol and 1.2 L of 2,2-dimethoxypropane, added dropwisewith for 2 hours, filtered, and the filtrate was evaporated to an oil. The oily residue, L-glyceric acid methyl ester and the mixture was 30 (3), was then mixed with 1.5 L of acetone and 1.8 L (1.5 Kg) of 2,2-dimethoxypropane filtered. The filtrate was then stirred overnight at room temperature. Evaporation of the above solution gave an oil, methyl 2,3-O-isopropylidene-L-glycerate (5), which was treated with 1 L of toluene and evaporated in vacuo at 65°. In the meantime, a reducing solution was prepared as follows. funnel, and a 35 In a 3-neck-12 L round-bottomed flask equipped with a mechanical stirrer, an adding condenser was placed 250 g (6.6 moles) of lithium aluminium 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 aluminium hydride was destroyed by successive addition of 250 mL of water, 250 mL of 1 5% the slurry was filtered, 40 sodium hydroxide, and another 250 mL of water. After stirring for 30 minutes, washed with 1 L of tetrahydrofuran, and the filtrate was evaporated to an oil which was treated with 1 L of toluene and evaporated in vacuo. 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 Hg), the temperature was raised to 60— 80°C and about 360 g (45%) of L- , (neat), TLC Rf 0.57 (toluene- 45 solketal was collected, b.p. 75°C, 2.67 mBar (2 mm Hg), n. 1.4337, a£5 -13.234 acetone, 7:3) NMR and IR were consistent with the assigned structure Lit. b.p. 75°, 13.3 mBar (10 mm Hg); n 1.4345; a,§5 = -13.2 (neat). A third higher b.p. fraction 10 g; 80°C, 0.67 mBar (0.5 mm Hg) 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 50 in the flask. Example III Using the method of Example 11, 14 kilograms of L-solketal (2,3-O-isopropylidene-L-glycerol) (6) were prepared using the following amounts of reactants and solvents: 55 STEP 1: 20 kilograms (kg) L-serine (1) 57 liters (L) deionized water 79.5 kg acetic acid 15.9 kg sodium nitrite 60 19 L hydrochloric acid STEP 2: 47.3 liters (12.5 U.S. gallons (gal)) methanol 37.8 liters (10 gal) dimethoxypropane 4.8 kg thionyl chloride 65 EP 0173 714 B1

STEP 3: 47.3 liters (12.5 US. gallons (gal)) acetone 56.8 liters (15 gal) dimethoxypropane

YIELD: 24.5 kg oil 5 STEP 4: Reduction, completed in two portions

EACH REACTION : 1 60 L tetrahydrofuran 3 kg lithium aluminium hydride 10 3 L water 3 L 15% sodium hydroxide 3 L water

TOTAL YIELD: 14 Kg, a|s -13.60 (neat) 15 Example IV Using the method of Example 11 and starting with 200 g of D-serine, D-solketal were prepared, a|s +13.56 (neat), bp 55— 75°C, 0.80 mBar (0.6 mm Hg).

20 Example V Using the method of Example 11 but reacting the L-glyceric acid methyl ester (3) with 1,1-dimethoxy Gyciohexane 2,2'-cyclohexylidene-1,3-dioxolane-4-methanol is prepared according to the following reaction scheme: 25 MeO OMe

HO-x^*Vsr*^^v*OMe + — 01 30 OH 30 (3) (7)

Example VI By using the method of Example 1, namely without methanol, and reacting the 2,3-dihydroxy- 35 propanoic acid (2) with the 1,1-dimethoxy cyclohexane (7), the 2,2'-cyclohexylidene-1,3-dioxolane-4- methanol (8) of Example V can be prepared.

Claims

40 1. A process for the preparation of 2,3-dihydroxypropanoic acid, which comprises reacting D- or L- serine with a nitrosating agent in an aqueous solution in the presence of formic acid, acetic acid or propanoic acid for a period of about 8 to 20 hours and wherein said aqueous solution of D- or L-serine comprises from about 0.10 to 0.5 liter of water per mole of D- or L-serine and said acid is present in the amount of from 0.1 to 0.75 liter per mole of D- or L-serine. 45 2. The process of Claim 1 wherein the D- or L-serine is reacted with ammonium nitrite, an alkyl nitrite, nitrosyl halide, nitrosyl sulfuric acid, or a Group 1a or 11a metal nitrite. 3. The process of Claim 2 wherein the D- or L-serine is reacted with sodium nitrite or potassium nitrite in the presence of acetic acid. 4. The process of Claim 3 wherein the D- or L-serine is reacted with sodium nitrite. so 5. The process of any preceding claim wherein the D- or L-serine is reacted with the nitrosating agent at about room temperature. 6. The process of any preceding claim wherein L-serine is reacted with the nitrosating agent. 7. A process for preparing a selected 2,2'-disubstituted-1 ,3-dioxolane-4-methanol derivative having the formula

CH.-CH OH

O O 60 V / \ R1 R2 wherein R, and R2 are each independently hydrogen, alkyl, cycloalkyl or aryl or R1 and R2 together with the 65 carbon atom form a 3 to 6 member cycloalkyl group, the process comprising:

8 ■P 0 173 714 Bl reacting D- or L-serine with a nitrosating agent in an aqueous solution in xne presence 01 dt-euu dwu, D- formic acid, or propanoic acid for a period of about 8 to 20 hours and wherein said aqueous solution of or L-serine comprises from about 0.10 to 0.5 liter of water per mole of D- or L-serine and said acid is present in an amount of from about 0.1 to 0.75 liter per mole of D- or L-serine to produce 2,3-dihydroxypropanoic 5 acid; optionally adding to the 2,3-dhydroxypropanoic acid so produced '2,2-dimethoxypropane in the presence of a lower alkyl alcohol to produce D- or L-glyceric acid lower alkyl ester; reacting the 2,3-dihydroxypropanoic acid or the D- or L-giyceric acid lower alkyl ester with an appropriate aldehyde or ketone or an acetal or ketal derivative of an appropriate aldehyde or ketone to w produce the corresponding 1,3-dioxolane derivative; and reacting the 1,3-dioxolane derivative with lithium aluminium hydride to produce the selected 2,2'- disubstituted-1,3-dioxolane-4-methanol derivative. 8. The process of Claim 7 wherein the D- or L-serine is reacted with ammonium nitrite, an alkyl nitrite, nitrosyl halide, nitrosyl sulfuric acid or a Group 1a or 11a metal nitrite. sodium nitrite 15 9. The process of Claim 8 wherein the D- or L-serine is reacted with ammonium nitrite, or potassium nitrite in the presence of formic acid or acetic acid, and the lower alkyl alcohol is methanol, ethanol or propanol. 10. The process of Claim 9 wherein the D- or L-serine is reacted with sodium nitrite in the presence of acetic acid and the lower alkyl alcohol is methanol. with 20 11. The process of any of claims 7 to 10 wherein the 2,3-dihydroxypropanoic acid is reacted an appropriate aldehyde or ketone or an acetal or ketal derivative of an appropriate aldehyde or ketone to produce 2,3-O-isopropylidene D- or L-glyceric acid which is then reacted with lithium aluminium hydride to produce the desired 2,2'-disubstituted-1,3-dioxolane-4-methanol derivative. sodium nitrite 12. The process of Claim 1 1 wherein the D- or L-serine is reacted with ammonium nitrite, 25 or potassium nitrite in the presence of formic acid or acetic acid. of 13. The process of Claim 12 wherein the D- or L-serine is reacted with sodium nitrite in the presence acetic acid 14. The process of any of claims 7 to 1 3, wherein the D- or L-serine is reacted with the nitrosating agent at about room temperature. 30 15. The process of any of claims 7 to 14, wherein L-serine is reacted with the nitrosating agent. with 16. A process for the preparation of D- or L-solketal which comprises reacting D- or L-serine a nitrosating agent in an aqueous solution in the presence of acetic acid, formic acid, or propanoic acid for a period of about 8 to 20 hours and wherein said aqueous solution of D- or L-serine comprises from about 0.10 to 0.5 liter of water per mole of D- or L-serine and said acid is present in an amount of from about 0.1 to 35 0.75 liter per mole of D- or L-serine to produce 2,3-dihydroxypropanoic acid; optionally adding to the 2,3-dihydroxypropanoic acid so produced 2,2-dimethoxypropane in the presence of a lower alkyl alcohol to produce D- or L-glyceric acid lower alkyl ester; reacting the 2,3-dihydroxypropanoic acid or the D- or L-glyceric acid alkyl ester with 2,2-dimethoxy- L- propane to produce 2,3-O-isopropylidene-D- or L-glyceric acid or methyl 2,3-O-isopropylidene-D- or 40 glycerate respectively; and reacting the 2,3-O-isopropylidene-D- or L-glyceric acid or methyl 2,3-O-isopropylidene-D- or L- glycerate so produced with lithium aluminium hydride to produce D- or L-solketal. 17. The process of Claim 16 wherein the D- or L-serine is reacted with ammonium nitrite, an alkyl nitrite, nitrosyl halide, nitrosyl sulfuric acid, or a Group 1a or 11a metal nitrite. nitrite 45 18. The process of Claim 17 wherein the D- or L-serine is reacted with ammonium nitrite, sodium or potassium nitrite in the presence of formic acid or acetic acid and the lower alkyl alcohol is methanol, ethanol or propanol. of 19. The process of Claim 18 wherein the D- or L-serine is reacted with sodium nitrite in the presence acetic acid, the lower alkyl alcohol being methanol, to produce D- or L-glyceric acid methyl ester. 50 20. The process of any of claims 16 to 19 wherein the 2,3-dihydroxypropanoic acid produced is reacted with 2,2-dimethoxypropane to prepare 2,3-O-isopropyiidene-D- or L-glyceric acid which in turn is reacted with lithium aluminium hydride to produce D- or L-solketal. ammonium nitrite, sodium nitrite or 21 . The process of Claim 20 wherein D- or L-serine is reacted with potassium nitrite in the presence of formic acid or acetic acid. of 55 22. The process of Claim 21 wherein the D- or L-serine is reacted with sodium nitrite in the presence acetic acid 23. The process of any of claims 1 6 to 23 wherein the D- or L-serine is reacted with the nitrosating agent at about room temperature. L- 24. The process of any of claims 16 to 23 wherein L-serine is reacted with the nitrosating agent, 60 solketal being prepared by the process. Patentanspruche

1. Verfahren zur Herstellung von 2,3-Dihydroxypropansaure, umfassend die Umsetzung von D- oder L- Ameisensaure, 65 Serin mit einem Nitrosierungsmittel in einer walSrigen Losung in Gegenwart von

a EP 0173 714 B1 Essigsaure oder Propansaure wahrend eines Zeitraums von 8 bis 20 Stunden, wobei die walSrige Losung des D- oder L-Serins etwa 0,10 bis 0,5 I Wasser auf 1 mol D- oder L-Serin umfalSt und die Saure in einer Menge von 0,1 bis 0,75 I Wasser auf 1 mol D- oder L-Serin zugegen ist. 2. Verfahren nach Anspruch 1, worin das D- oder L-Serin mit Ammoniumnitrit, einem Alkyinitrit, 5 Nitrosylhalogenid, Nitrosylschwfelsaure oder einem Metalinitrit der Gruppen la oder Ha umgesetzt wird. 3. Verfahren nach Anspruch 2, worin das D- oder L-Serin mit Natriumnitrit oder Kaliumnitrit in Gegenwart von Essigsaure umgesetzt wird. 4. Verfahren nach Anspruch 3, worin das D- oder L-Serin mit Natriumnitrit umgesetzt wird. 5. Verfahren nach irgendeinem vorhergehenden Anspruch, worin das D- oder L-Serin mit dem 70 Nitrosierungsmittel etwa bei Raumtemperatur umgesetzt wird. 6. Verfahren nach irgendeinem vorhergehenden Anspruch, worin L-Serin mit dem Nitrosierungsmittel umgesetzt wird. 7. Verfahren zur Herstellung eines ausgewahlten 2,2-disubstituierten 1,3-Dioxolan-4-methanol- Derivats der Formel 15 /CH2\ CH.-CH OH. 1 2 I 20

/\ R1 R2 25 worin R, und R2 jeweils unabhangig voneinander Wasserstoff, Alkyl, Cycloalkyl oder Aryl sind oder R-, und R2 zusammen mit dem Kohlenstoff-Atom eine 3- bis 6-gliedrige Cycloalkyl-Gruppen bilden, wobei das Verfahren umfalSt: die Umsetzung von D- oder L-Serin mit einem Nitrosierungsmittel in einer walSrigen Losung in 30 Gegenwart von Essigsaure, Ameisensaure oder Propansaure wahrend eines Zeitraums von 8 bis 20 Stunden, wobei die walSrige Losung des D- oder L-Serins etwa 0,10 bis 0,5 I Wasser auf 1 mol D- oder L- Serin umfafSt und die Saure in einer Menge von 0,1 bis 0,75 I Wasser auf 1 mol D- oder L-Serin zugegen ist, um 2,3-Dihydroxypropansaure zu erzeugen; gegebenenfalls das Hinzufiigen von 2,2-Dimethoxypropan in Gegenwart eines Niederalkylalkohols zu 35 der so erzeugten 2,3-Dihydroxypropansaure, um einen Niederalkylester der D- oder L-Glycerinsaure zu erzeugen; die Umsetzung der 2,3-Dihydroxypropansaure oder des Niederalkylesters der D- oder L-Glycerinsaure mit einem geeigneten Aldehyd oder Keton oder einem Acetal- oder Ketai-Derivat eines geeigneten Aldehyds oder Ketons, um das entsprechende 1,3-Dioxolan-Derivat zu erzeugen; und die Umsetzung des 40 1,3-Dioxolan-Derivats mit Lithiumaluminiumhydrid, um das ausgewahlte 2,2-disubstitiuerte 1,3-Dioxolan- 4-methanoi-Derivat zu erzeugen. 8. Verfahren nach Anspruch 7, worin das D- oder L-Serin mit Ammoniumnitrit, einem Alkyinitrit, Nitro- sylhalogenid, Nitrosylschwefelsaure oder einem Metalinitrit der Gruppen la oder Ha umgesetzt wird. 9. Verfahren nach Anspruch 8, worin das D- oder L-Serin mit Ammoniumnitrit, Natriumnitrit oder 45 Kaliumnitrit in Gegenwart von Ameisensaure oder Essigsaure umgesetzt wird und der Niederalkylalkohol Methanol, Ethanol oder Propanol ist. 10. Verfahren nach Anspruch 9, worin das D- oder L-Serin mit Natriumnitrit in Gegenwart von Essigsaure umgesetzt wird und der Niederalkylalkohol Methanol ist. 11. Verfahren nach irgendeinem der Anspriiche 7 bis 10, worin die 2,3-Dihydroxypropansaure mit dem so geeigneten Aldehyd oder keton oder einem Acetal- oder Ketal-Derivat eines geeigneten Aldehyds oder Ketons umgesetzt, um 2,3-O-lsopropyliden-D- oder L-glycerinsaure zu erzeugen, die dann mit Lithium- aluminiumhydrid umgesetzt wird, um das gewunschte 2,2-disubstituierte 1,3-Dioxolan-4-methanol-Derivat zu erzeugen. 12. Verfahren nach Anspruch 11, worin das D- oder L-Serin mit Ammoniumnitrit, Nariumnitrit oder 55 Kaliumnitrit in Gegenwart von Ameisensaure oder Essigsaure umgesetzt wird. 13. Verfahren nach Anspruch 12, worin das D- oder L-Serin mit Natriumnitrit in Gegenwart von Essigsaure umgesetzt wird. 14. Verfahren nach irgendeinem der Anspriiche 7 bis 13, worin das D- oder L-Serin mit dem Nitrosierungsmittel etwa bei Raumtemperatur umgesetzt wird. 60 15. Verfahren nach irgendeinem der Anspriiche 7 bis 14, worin L-Serin mit dem Nitrosierungsmittel umgesetzt wird. 16. Verfahren zur Herstellung von D- oder L-Solketal, umfasend die Umsetzung von D- oder L-Serin mit einem Nitrosierungsmittel in einer wafcrigen Losung in Gegenwart von Essigsaure, Ameisensaure oder Propansaure wahrend eines Zeitraums von 8 bis 20 65 Stunden, wobei die walSrige Losung des D- oder L-Serins etwa 0,10 bis 0,5 I Wasser auf 1 mol D- oder L-

10 EP 0 173 714 B1 Serin umfafct und die Saure in einer Menge von 0,1 bis 0,75 1 Wasser auf 1 mol D- oder L-Serin zugegen ist, um 2,3-Dihydroxypropansaure zu erzeugen; gegebenenfalls das Hinzufugen von 2,2-Dimethoxypropan in Gegenwart eines Niederalkylalkohols zu der so erzeugten 2,3-Dihydroxypropansaure, um einen Niederalkyiester der D- oder L-Glycerinsaure zu 5 erzeugen; ... die Umsetzung der 2,3-Dihydroxypropansaure oder des Alkylesters der D- oder L-Glycermsaure mit 2,2-Dimethoxypropan, um 2,3-O-lsopropyliden-D- oder -L-glycerinsaure bzw. 2,3-O-lsopropyliden-D- oder -L-glycerat zu erzeugen; und die Umsetzung der so erzeugten 2,3-O-lsopropyliden-D- oder -L-glycerinsaure bzw. des so erzeugten 2,3-0- w Isopropyliden-D- oder -L-glycerats mit Lithiumaluminiumhydrid, um D- oder L-Solketal zu erzeugen. 17. Verfahren nach Anspruch 16, worin das D- oder L-Serin mit Ammoniumnitrit, einem Alkyinitrit, Nitrosylhalogenid, Nitrosylschwefelsaure oder einem Metalinitrit der Gruppen la oder lla umgesetzt wird. 18. Verfahren nach Anspruch 17, worin das D- oder L-Serin mit Ammoniumnitrit, Natriumnitrit oder Kaliumnitrit in Gegenwart von Ameisensaure oder Essigsaure umgesetzt wird und der Niederalkylalkohol 15 Methanol, Ethanol oder Propanol ist. 19. Verfahren nach Anspruch 18, worin das D- oder L-Serin mit Natriumnitrit in Gegenwart von Essigsaure umgesetzt wird und der Niederalkylalkohol Methanol ist, um D- oder L-Glycerinsauremethyl- ester zu erzeugen. 20. Verfahren nach irgendeinem der Anspriiche 16 bis 19, worin die erzeugte 2,3-Dihydroxypropan- 20 saure mit 2,2-Dimethoxypropan umgesetzt wird, um 2,3-O-lsopropyliden-D- oder -L-glycerinsaure herzustellen, die anschlieBend mit Lithiumaluminiumhydrid umgesetzt wird, um das D- oder L-Solketal zu erzeugen... 21. Verfahren nach Anspruch 20, worin das D- oder L-Serin mit Ammoniumnitrit, Natriumnitrit Oder Kaliumnitrit in Gegenwart von Ameisensaure oder Essigsaure umgesetzt wird. 25 22. Verfahren nach Anspruch 21, worin das D- oder L-Serin mit Natriumnitrit in Gegenwart von Essigsaure umgesetzt wird. 23. Verfahren nach irgendeinem der Anspriiche 16 bis 22, worin das D- oder L-Serin mit dem Nitrosierungsmittel etwa bei Raumtemperatur umgesetzt wird. 24. Verfahren nach irgendeinem der Anspriiche 16 bis 23, worin L-Serin mit dem Nitrosierungsmittel 30 umgesetzt wird, wobei L-Solketal mittels des Verfahrens hergestellt wird. Revendications

1. Un procede de preparation d'acide 2,3-dihydroxypropano'ique qui consiste a faire reagir de lap- ou d'acide 35 L-serine avec un agent de nitrosation dans une solution aqueuse en presence d'acide formique, acetique ou d'acide propanoi'que pendant environ 8 a 20 heures, ladite solution aqueuse de D- ou L-serine de comprenant environ 0,10 a 0,5 litre d'eau par mole de D- ou L-serine et ledit acide etant present a raison 0,1 a 0,75 litre par mole de D- ou L-serine. 2. Le procede de la revendication 1, dans lequel on fait reagir la D- ou L-serine avec du nitrite nitrite d'un 40 d'ammonium, un nitrite d'alkyle, un halogenure de nitrosyle, de I'acide nitrosylsulfurique, ou un metal du Groupe la ou lla. 3. Le procede de la revendication 2, dans lequel on fait reagir la D- ou L-serine avec du nitrite de sodium ou du nitrite de potassium en presence d'acide acetique. 4. Le procede de la revendication 3, dans lequel on fait reagir la D- ou L-serine avec du nitrile de 45 sodium.. , . 5. Le procede de I'une quelconque des revendications precedentes, dans lequel on fait reagir la D- ou L- serine avec I'agent de nitrosation aux environs de la temperature ambiante. 6. Le procede de I'une quelconque des revendications precedentes, dans lequel on fait reagir de la L- " serine avec I'agent de nitrosation. so 7. Un procede de preparation d'un derive choisi de 1,3-dioxolane-4-methanol desubstitue en 2,2 ayant la formule

/CH2\ CH--CH OH 55 , 2 |

V / \ 60 Rj Ft2

bien et ou R-i et R2 sont chacun independamment I'hydrogene, un radical alkyle, cycloalkyle ou aryle ou R, R2 pris ensemble avec I'atome de carbone forment un groupe cycloalkyle en C3 a C6, le procede consistant 65 a: EP 0 173 714 B1 faire reagir de la D- ou L-serine avec un agent de nitrosation dans une solution aqueuse en presence d'acide formique, d'acide acetique ou d'acide propanoi'que pendant environ 8 a 20 heures, ladite solution aqueuse de D- ou L-serine comprenant environ 0,1 0 a 0,5 litre d'eau par mole de D- ou L-serine et ledit acide etant present a raison de 0,1 a 0,75 litre par mole de D- ou L-serine pour produire de I'acide 2,3-dihydroxy- 5 propanoi'que; facultativement ajouter a I'acide 2,3-dihydroxypropanoTque ainsi produit, du 2,2-dimethoxypropane en presence d'un alcanol inferieur pour produire un ester d'alkyle inferieur d'acide D- oder L-glycerique; faire reagir I'acide 2,3-dihydroxypropanoique ou Tester d'alkyle inferieur d'acide D- oder L-glycerique avec un aldehyde ou cetone approprie ou avec un acetal ou cetai d'un aldehyde ou cetone approprie pour w produire le derive de 1,3-dioxolane correspondant; et faire reagir le derive de 1,3-dioxolane avec de I'hydrure de lithium et d'aluminium pour produire le derive de 1,3-dioxolane-4-methanoi disubstitue en 2,2 choisi. 8. Le procede de la revendication 7, dans lequel on fait reagir la D- ou L-serine avec du nitrite d'ammonium, un nitrite d'alkyle, un halogenure de nitrosyle, de I'acide nitrosylsuifurique, ou un nitrite d'un 15 metal du Groupe la ou lla. 9. Le procede de la revendication 8, dans lequel on fait reagir la D- ou L-serine avec du nitrite d'ammonium, du nitrite de sodium ou du nitrite de potassium en presence d'acide formique ou d'acide acetique, et I'alcanol inferieur est le methanol, I'ethanol ou le propanol. 10. Le procede de la revendication 9, dans lequel on fait reagir la D- ou L-serine avec du nitrite de 20 sodium en presence d'acide acetique et I'alcanol inferieur est le methanol. 11. Le procede de I'une quelconque des revendications 7 a 10, dans lequel on fait reagir I'acide 2,3- dihyhdroxypropanoique avec un aldehyde ou cetone approprie ou avec un acetal ou cetal d'un aldyhyde ou cetone approprie pour produire de I'acide 2,3-O-isopropylidene D- oder L-glycerique que Ton fait ensuite reagir avec de I'hydrure de lithium et d'aluminium pour produire le derive choisi de 1,3-dioxolane-4- 25- methanol desubstitue en 2,2. 12. Le procede de la revendication 11, dans lequel on fait reagir la D- ou L-serine avec du nitrite d'ammonium, du nitrite de sodium ou du nitrite de potassium en presence d'acide formique ou d'acide acetique. 13. Le procede de la revendication 12, dans lequel on fait reagir la D- ou L-serine avec du nitrite de 30 sodium en presence d'acide acetique. 14. Le procede de Tune quelconque des revendications 7 a 13, dans lequel on fait reagir la D- ou L- serine avec I'agent de nitrosation aux environs de la temperature ambiante. 15. Le procede de Tune quelconque des revendications 7 a 14, dans lequel on fait reagir de la L-serine avec I'agent de nitrosation. 35 16. Un procede de preparation de D- oder L-solcetal qui consiste a faire reagir de la D- ou L-serine avec un agent de nitrosation dans une solution aqueuse en presence d'acide formique, d'acide acetique ou d'acide propano'ique pendant environ 8 a 20 heures, ladite solution aqueuse de D- ou L-serine comprenant environ 0,10 a 0,5 litre d'eau par mole de D- ou L-serine et ledit acide etant present a raison de 0,1 a 0,75 litre par mole de D- ou L-serine pour produire de I'acide 2,3-dihydroxypropanoique; 40 facultativement ajouter a I'acide 2,3-dihydroxypropanoique ainsi produit du 2,2-dimethoxypropane en presence d'un alcanol inferieur pour produire un ester d'alkyle inferieur D- ou L-glycerique; faire reagir I'acide 2,3-dihydroxypropanoique ou Tester d'alkyle d'acide D- ou L-glycerique avec du 2,2- dimethoxypropane pour produire de I'acide 2,3-O-isopropylidene D- oder L-glycerique ou du 2,3-O- isopropylidene D- ou L-glycerate de methyle, respectivement; et 45 faire reagir I'acide 2,3-O-isopropylidene D- ou L-glycerique ou le 2,3-O-isopropylidene D- ou L- glycerate de methyle ainsi produit avec de I'hydrure de lithium et d'aluminium pour produire du D- our L- solcetal. 17. Le procede de la revendication 16, dans lequel on fait reagir la D- ou L-serine avec du nitrite d'ammonium, un nitrite d'alkyle, un halogenure de nitrosyle, de I'acide nitrosylsuifurique, ou un nitrite d'un so metal du Groupe la ou lla. 18. Le procede de la revendication 17, dans lequel on fait reagir la D- ou L-serine avec du nitrite d'ammonium, du nitrite de sodium ou du nitrite de potassium en presence d'acide formique ou d'acide acetique, et I'alcanol inferieur est le methanol, I'ethanol ou le propanol. 19. Le procede de la revendication 18, dans lequel on fait reagir la D- ou L-serine avec du nitrite de 55 sodium en presence d'acide acetique, et I'alcanol inferieur est le methanol, pour produire Tester methylique d'acide D- oder L-glycerique. 20. Le procede de Tune quelconque des revendications 16 a 19, dans lequel on fait reagir I'acide 2,3- dihydroxypropano'ique produit avec du 2,2-dimethoxypropane pour preparer de I'acide 2,3-O- isopropylidene D- oder L-glycerique que Ton fait reagir a son tour avec de I'hydrure de lithium et 60 d'aluminium pour produire le D- oder L-solcetal. 21. Le procede de la revendication 20, dans lequel on fait reagir la D- ou L-serine avec du nitrite d'ammonium, du nitrite de sodium ou du nitrite de potassium en presence, d'acide formique ou d'acide acetique.

12 ;P 0 173 714 Bl

22. Le procede de la revendication 21, dans lequel on Tare reagir la u- ou L-senne dveu uu niunc uc adium en presence d'acide acetique. 23. Le procede de I'une quelconque des revendications 16 a 22, dans lequel on fait reagir la D- ou L- §rine avec I'agent de nitrosation aux environs de la temperature ambiante. 24. Le procede de I'une quelconque des revendications 16 a 23, dans laquel on fait reagir de la L-serine vec I'agent de nitrosation, du L-solcetal etant produit par la procede.