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Synthesis of (2R,3S)-3-phenylisoserine hydrochloride

(2R,3S)-3-phenylisoserine-α-amino-ß-hydroxyacid hydrochloride of structural formula:

chlorowodorek










obtained according to the offered technology is characterized by high enantiomeric purity > 99 % and the following physicochemical properties:

  • molar mass: 217.50 g/mol
  • chemical formula: C9H11NO3 · HCl
  • chemical purity: 98.0 % (HPLC, lobs = 210 mm)
  • optical rotation of sodium light: a = -14.6 (c = 0.55, 6 M HCl aq., temp. 20 °C)
  • melting point: 242–244 °C
  • solubility: soluble in water, poorly soluble in alcohols
  • CAS No: 132201-32-2

(2R,3S)-3-phenylisoserine hydrochloride constitutes a side chain in a particle called paclitaxel with a formula:


ICHP - chlorowodorek2




Paclitaxel is a bioactive substance isolated from the bark of yew Taxus brevifolia, vegetating at the Pacific coast of the USA. The second component in the paclitaxel particle is 10-deacetylbaccatin III, available in Poland (Agropharm Company, Tuszyn near Łódź).

Paclitaxel reveals activity in curing such kinds of neoplasm like ovary, breast and lung cancer. World demand for paclitaxel is 250 kg/year.


A brief description of the technology

In the first stage of the synthesis methyl trans-cinnamate is stereoselectively oxidized into methyl (2R,3S)-2,3-dihydroxy-3-phenylpropionate in the presence of a chiral catalyst. As a result, the synthesis produces methyl (2R,3S)-2,3-dihydroxy-3-phenylpropionate with 72 % yield and enantiomeric purity after crystallization 99 % ee.

It is the key stage of the synthesis, which decides on the stereochemistry of the product. Then, after a number of reactions of type esterification, addition and reduction with hydrogen, there is obtained a product in the form of ester, which at the last stage of the synthesis is hydrolyzed, yielding white crystals of (2R,3S)-3-phenylisoserine hydrochloride with purity over 98 % and 99 % ee . The yield of this method related to methyl cinnamate is 23 %.


Advantages of the technology offered

The technology offered allows to obtain (2R,3S)-3-phenylisoserine hydrochloride with purity > 98 % and 99 % ee.


Equipment

The installation to produce (2R,3S)-3-phenylisoserine hydrochloride should be equipped with glass apparatus placed in specially adapted rooms, according to GLP requirements.

The installation is based on two apparatus sets:

  • an universal glass set with a glass or enameled reactor 120 l in capacity to conduct syntheses and distillations,
  • a Simax glass set for extraction, with an extractor 200 l in capacity and 2 tanks for phase separation, 100 l in capacity each.

The reactor instrumentation should include a Teflon stirrer of propeller type with speed adjustment, a sounder to measure temperature and pH of the reaction mixture, two substrate feeders, a distillation column, a condenser, a cooling bath and a distillate receptacle.

The reactor blanket should be adjusted to heating the reactor up to 150 °C and cooling it contents down to -30 °C.


Patents

pat. PL 210 044 (2011) „(2R,3S)-3-phenylisoserine hydrochloride purification method”


Market competitiveness

Implementation of the technology enables to obtain the product of domestic origin and thus lowering the medication price on the Polish market.


References

Confirmation of high chemical and enantiomeric purity of the product by customers.


Information

Magdalena Jezierska-Zięba, Ph. D., Chem. Eng.

phone: +48 22 568 22 97, +48 22 568 21 70,

+48 22 568 23 59, +48 22 568 20 75