I- GALENIC APPLICATIONS
Methylal

IUPAC : dimethoxymethane

CH₂ - O - CH₂ - O - CH₃



Methylal is used in some antiseptic preparations in order to improve the penetration of the antiseptic molecule into the pilo selacie folicula.
This action is due to the low surface tension and viscosity of this molecule.

Glycerol formal






This solvent is widely used in veterinary medicine for injectable intramuscular products and will be listed in the European Pharmacopaeia (monograph elaboration decided by the European Commission).

Applications :

• Veterinary antiparasite pharmaceuticals
• Solvents for sulphomethoxazal (intramuscular injections)
• Solvent for other sulphonamide preparations
• Solvent for tetracycline-based products
• Solubilization of some alcaloids

Stabilization of aqueous solution of water-insoluble molecules

II- SYNTHESIS

Methylal

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Methylal can be used in pharmaceutical synthesis as a reagent, a reaction solvent or an extraction solvent.

It is a solvent with low boiling point (42°C), low viscosity, and is extremely stable under basic conditions. Its partial water miscibility is useful to carry phase transfer reactions and recristalization.
Methylal is a formaldehyde equivalent and an interesting source of formaldehyde.

Examples of applications :

As a reagent

• Chloromethylation agent : Synthesis of sulindac (anti-inflammatory compound) (ref 1) :

• Transacetalization reagent for steroids (Ref 2)
• Methoxy methylation of pregnene derivatives for dimethylcorticoids synthesis (Ref 3)

As a reaction solvent :
methylal offers a major advantage versus diethylether : it does not form peroxides during storage or redistillation process.

Lambiotte proposes the anhydrous grade (H2O < 0.03 %) for the Grignard reaction.

Applications

• Grignard
  
  Example (Ref 4) :

(Other references N° 5-7)


• Reduction reactions with LiAlH⁴ (Ref 8)

Uses
Methylal is used for the production of antibiotics, anti-inflammatory products, steroids, corticoids, ...
Methylal is an amphiphilic extraction solvent used for instance for

• flavours
• ganglion extraction

Ethylal

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IUPAC: diethoxymethane

CH₃ - CH₂ - O - CH₂ - O - CH₂ - CH₃



As ethylal is a higher acetal than methylal, it offers the same high stability qualities under alcaline conditions.

Ethylal is non hygroscopic and even presents a hydrophobic character (low water absorption). It forms peroxides with air, but at rates which are much lower than traditional reaction solvents like THF.

Applications

• Solvent for Grignard
  
  The boiling point of ethylal is 87.5°C, which makes it a solvent particularly suitable for Grignard reactions, increasing the yield versus THF in most cases.
  
  Furthermore, ethylal presents an excellent stability with organomagnesium compounds up to the boiling point and can be easily recovered (Ref. 9).
  
  
• Ethoxymethylation agent (transacetalization) (Ref 10)
  
  For alcohols (phenols), amines under acid catalysis.
  

• Methylenation agent (Ref 11)
  
  Ethylal is also a protected form of formaldehyde and can be used for the methylenation of steroid derivatives.
  

Uses

preparation of :

anticancer agents :
• androstenedione derivatives
• estrenedione derivatives
antihypertensives :
• angiotension II receptor antagonist

1,3-Dioxolane

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C₃H₆O₂

• Cyclic acetal, reaction product of ethylene glycol and formaldehyde
• Powerful solvent characteristics
• Excellent compatibility with organo-metallic compounds, organic salts and some inorganic salts.

Applications

• Solvent for Grignard (Ref 12)
  
  Some reactions with poor yield or failing in THF are possible in dioxolane - interesting boiling point of 75°C, high compatibility and solvency towards magnesium compounds.
  
  
• Addition reactions (Ref 13)
  
  The high reactivity of the carbon between the 2 oxygen atoms makes additions via double bonds easy.
  

• Single carbon source (Ref 14)
  
  Generally, addition reactions are followed by acid hydrolysis.
  

Miscellaneous reactions

Numerous ways of synthesis incorporate dioxolane under cyclic form or after ring opening, derived or not, in order to produce a wide range of pharmaceuticals.
Uses

• Synthesis of Acyclovir (antiviral agent) from guanine by acetylation condensation with 1,3-dioxolane and hydrolysis.
• Synthesis of Interferon potentiator
• Synthesis of Antiviral derivatives
• Production of muscle reactants

Glycerol formal

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Besides its use as injectable solvent, this high boiling point acetal, through its high reactivity, opens new synthesis ways to make linear or cyclic derivatives, often by reaction with acetic anhydride.

Uses

• antibiotics (erythromycin, tetracycline, chloramphenicol, )
• sulphonamides,
• tranquillisers (propanediol derivatives),
• anti-tuberculosis drugs, anti-pyretic, anti-malaria,anti-coccidiosis drugs (notably pyrimethamine),
• cortico-steroids,
• expectorants,
• essential oils,
• anti-viral guamine derivatives by reaction with acetic anhydride

III- PURIFICATION PROCESSES

Extraction

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Most of the acetals are used in extraction processes. The availability range makes it possible to adjust polarity, boiling point, ... to values compatible with the considered product for extraction.

Cristalization

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HPLC - preparative

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A new trend is to substitute solvents like THF by methylal in preparative HPLC processes. The advantages are the following :

• Lower viscosity
  which means a lower elution pressure and a decrease of pulsation phenomena, and the suppression of preferential ways in preparative HPLC columns.
  
• Higher transparency in UV
  improving the detection possibilities

REFERENCE

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1. Czaja, Robert F.; Pines, Seemon H.; Abramson, Newton L.; Haloalkyl derivatives of aromatic compounds; Merck and Co., Inc., USA; U.S. US 3953520; 5 pp. (Eng.) ; 27 Apr 1976

2. Techtrade 88 TT; France; 1987.

3. Kapp, Joachim Friedrich; Wendt, Hans; Annen, Klaus; Laurent, Henry; Wiechert, Rudolf; Schoettle, Ernst; Weber, Alfred; Kennecke, Mario; Dahl, Helmut; Steroids of the pregnane series substituted in the 17-position, and their use; Schering AG; Germany; Can. CA 1144538 A1; 97 pp. ; 12 Apr 1983.

4. Hiyama, Tamejiro; Wakasa, Noriko; Asymmetric coupling of arylmagnesium bromides with allylic esters; Sagami Chem. Res. Cent., Sagamihara, 229, Japan; Tetrahedron Lett., 26(27), 3259-62 (English); 1985.

5. Koppel, J.; Tuulmets, A.; Solvent effect on Grignard reactions, VIII. Methylal and diethyl ether of diethylene glycol; Chem. Dep., Tartu State Univ., Tartu, USSR; Reakts. Sposobnost Org. Soedin., 7(4), 1187-93 (Russian); 1970.

6. Koppel, J.; Vaiga, S.; Tuulmets, A.; Effect of solvents on Grignard reactions, V. Reaction of dipropylmagnesium with pinacolone.; Chem. Dep., Tartu State Univ., Tartu, USSR; Reakts. Sposobnost Org. Soedin., 7(3), 898-910 (Russian); 1970.

7. Koppel, J.; Tuulmets, A.; Effect of solvents on Grignard reactions, VI. Mixtures of n-heptane with electron-donor solvents.; Chem. Dep., Tartu State Univ., Tartu, USSR; Reakts. Sposobnost Org. Soedin., 7(3), 911-18 (Russian); 1970.

8. F. e. s. E. Bernatek; Methylal as solvent in LiAlH4-reductions; Acta Chem. Scand.; 8; 874; 1954.

9. Shostakovkii, M.F.; Kulibekov, M.R.; Gorban, A.K., Shostakovkii, S.M.; New method of preparing organomagnesium compounds in a medium of acetals; N.D. Zelinskii Institute of Organic Chemistry, Academy of Sciences, USSR and Irkutsk Institute of Organic Chemistry, Siberian Division, Academy of Sciences, USSR; translated from Zhurnal Obshchei Khimii, Vol. 34, N° 8; pp. 2618-2620; August 1963.

10. Synthesis; 794; US 4500738; 1981
Chem Pharm Bull; 34; 150-7;

11. DEM as a methylenating agent in the presence of POCl3; EP 250262, 1987; CA: 108, 221965u; EP 253591; 1988; CA: 108, 221966v; EP 260975, 1988, CA: 109, 93433a; EP 265119, 1988, CA: 109, 93434b; DE 3719913, 1987; CA: 109, 110743w.

12. Hartmann, Ludwig A.; Stephen, John F.; Polyfluoroaromatic nitriles; US 4783547; 1988.

13. Watanabe, Yoshihisa; Tsuji, Yasushi; Takeuchi, Ryo; Oxygen promoted addition of 1,3-dioxolane to electron-deficient alkenes.; Bull. Chem. Soc. Jpn.; 56(5); 1428-30; 1983.

14. Matsukawa, Mihaya; Inanaga, Junji; Yamaguchi, Masaru; A novel samarium iodide-induced masked formylation of carbonyl compounds; Tetrahdron Lett.; 28(47); 5877-8; 1987.