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Ind. Eng. Chem. Res. 2006, 45, 2962-2966
Optimization of a Key Step of Synthesis of L-Acosamine and L-Daunosamine Derivatives Wiesław Pucko,† Andrzej Les´,*,†,‡ Jan Ramza,† Joanna Zagrodzka,† Graz3 yna Cieplucha,† Boz3 ena Cichy,† and Wiesław Szelejewski† Pharmaceutical Research Institute, Rydygiera 8, 01-793 Warsaw, Poland, and Department of Chemistry, UniVersity of Warsaw, Pasteura 1, 02-093 Warsaw, Poland
An optimization of synthesis of 3-N-(allyloxycarbonyl)-4-O-acetyl-3-amino-1,5-anhydro-2,3,6-trideoxy-Larabino-hex-1-enitol (D-2), a key intermediate in the six-step synthesis of daunosamine glycoside, was performed at laboratory scale. The D-2 compound was obtained according to the following scheme:
where R ) allyl, benzyl. While taking into account a remarkable sensitivity of the D-2 yield (varied from a few percent to ∼50%) on the reaction conditions, a series of experiments was performed in order to determine the most suitable reaction conditions both to increase the D-2 yield and, simultaneously, to reduce the amount of the unconsumed D-1 substrate. Six reaction parameters (temperature of the reaction, time, D-1 concentration, type of sodium carbonate, temperature of hydrolysis, and amount of isocyanate denoted as x1-x6 variables) were selected for optimization and two reaction responses (D-2 yield and D-1 content, denoted as y1 and y2, respectively) were monitored. The optimization was performed in two steps. In the course of the first step (8 experiments), it was realized that two of five variables studied, i.e., x1 and x2 selected from x1-x5, can be variables of major importance controlling the D-2 synthesis. In the course of a subsequent second step of optimization (next 15 experiments), a set of six variables (including the amount of chlorosulfonyl isocyanate, x6) was studied. The exploration of the reaction response surface (y1, y2) was supported by mathematical modeling with the use of the multiple linear regression and the partial least squares methods. As a result, we localized those regions of reaction parameters that lead to high, max ∼60% (determined by high performance liquid chromatography (HPLC)), yield of D-2 and contain less than 5% of D-1. We also determined regions of low yield that can facilitate control of reaction parameters in case of their perturbations. The present optimized D-2 yield at laboratory scale corresponds well with the 53-56% yield of D-2 obtained at the pilot-plant scale. Introduction L-Acosamine and L-daunosamine derivatives are important intermediates in the synthesis of new-generation antracycline antibiotics.5,6 These derivatives are used as substrates in manufacturing processes of semisynthetic and synthetic anthracycline antibiotics, as well as in synthetic projects focused on the search for novel lead structures of DNA-intercalating agents. In our laboratory, a new synthetic method has been developed for short and highly stereoselective synthesis of suitable protected L-acosamine and L-daunosamine derivatives starting from commercially available 3,4-di-O-acetyl-L-rhamnal. The respective synthesis of L-acosamine derivatives is afforded in two, or three, synthetic steps, while L-daunosamine derivatives require three more synthetic steps.1-4 General synthesis of L-acosamine and L-daunosamine derivatives is sketched below:
* Corresponding author. E-mail:
[email protected]. † Pharmaceutical Research Institute. ‡ University of Warsaw.
The acetylated L-rhamnal (D-0) is converted into 2,3-unsaturated rhamnoside (D-1) under catalytic amounts of SnCl4 in the
10.1021/ie0602005 CCC: $33.50 © 2006 American Chemical Society Published on Web 04/04/2006
Ind. Eng. Chem. Res., Vol. 45, No. 9, 2006 2963 Table 1. Optimization of Synthesis of D-2: Step 1 ) Experiment Nos. 1-8 and Step 2 ) Experiment Nos. 9-23a variables
responses
no. of experiment
x1 temp of reaction t1 (°C)
x2 time of reaction h
x3 conc of D-1 (% weight)
x4 carbonate NaHCO3 ) -1; Na2CO3 )1
x5 temp of hydrolysis t2 (°C)
x6 isocyanate (mmol)
y1 yield of D-2 (%)
y2 amount of D-1 (%)
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23
0 -20 0 -20 0 -20 0 -20 -20 -20 0 0 10 -20 20 5 5 10 10 -5 -10 0 -20
2 2 0.5 0.5 2 2 0.5 0.5 0.5 0.5 2 2 3 0.5 1.5 1.5 1.5 1.5 1.5 2.5 3.0 3.0 4.0
16.9 10 10 16.9 16.9 10 10 16.9 30 30 30 30 16.9 16.9 16.9 16.9 16.9 16.9 16.9 16.9 16.9 16.9 16.9
-1 -1 1 1 1 1 -1 -1 1 -1 -1 1 1 -1 1 1 1 1 1 1 1 1 1
25 0 25 0 0 25 0 25 0 25 25 0 0 40 0 0 0 0 0 0 0 0 0
12 12 12 12 12 12 12 12 12 12 12 12 12 12 15 11 13 11 13 12 12 12 12
49.2 39.7 35.1 12.9 55.2 24.3 36.5 3.9 7.4 17.3 44.6 42.2 52.1 14.3 16.1 46.6 50.6 50.1 48.9 50.6 40.5 54.1 8.2
4.8 3.2 9.9 4.4 7.1 2.2 8.8 12.8 3.1 3.8 5.1 2.6 9.1 3.2
