Retrosynthetic Analysis - PPTX - Teknik Produk

Budhijanto, ST., MT., Ph.D.
(c) Budhijanto, Februari 2010
Chemical Product Design

We have learnt how to select our most promising idea Lets suppose that we have sufficient information to convince ourselves that we chose the winner The information may have come from the available literature, from external experts, or from calculations The information is unlikely to be complete and rigorous Because we are about to embark on an expensive program of product development, detailed information is indispensable

We must confirm experimentally any information
used already and fill in the many gaps in our knowledge One form of missing information, commonly required for the design of chemicals, is a synthetic pathway for the active molecules

Case: Synthesis of the Tranquilizer, Phenoglycodol
CH3
H3C H3C CH3
OH OH
Suggest several routes by which it may be synthesized.

Organic synthesis
The process of building organic molecules from simpler precursors Typically involves two types of transformations: a. Reactions that convert functional groups from one to another, e.g. hydrogenation b. Reactions that create new carbon-carbon bonds, e.g. alkylation The heart of organic synthesis is the orchestration of these two types of transformation
Organic synthesis
It may involve only one chemical reaction. Others may
require more steps. Example: synthesis of vitamin B12 in 1972 by R.B. Woodward (Harvard) and A. Eschenmoser (Swiss Federal Institute of Technology) require more than 90 steps
Organic synthesis
Vitamin B12
Retrosynthetic Analysis
A method for planning syntheses that involves reasoning backward from the target molecule through various levels of precursors and thus finally to the starting materials Target molecule 1st precursor 2nd precursor Starting compound How to identify precursor? Need a toolbox of reactions that involves the two transformations Retrosynthetic analysis often discloses several routes from the target molecule back to varied precursors
Target molecule 1st precursors A 2nd precursors a 2nd precursors b 1st precursors B 2nd precursors c 2nd precursors d 1st precursors C 2nd precursors e 2nd precursors f
Evaluate all the possible advantages and disadvantages
of each path, and in so doing determine the most efficient route for synthesis The most feasible route for synthesis can be evaluated based on: a. Specific restrictions or limitations of reactions in the sequence b. The availability of materials c. Other factors (e.g. safety (toxic), temperature, pressure, cost, etc.)
Case 1: Target molecule:
Case 1: Retrosynthetic Analysis:
CH3
Case 1: Synthesis:
CH3
+ CH3Cl
CH3
AlCl3
+ HCl
CH3
CH3 SO 3H
+ SO3
H2SO4
SO 3H
Br
NO 2
CO2H NO 2
CCl 3
Br
Cl
CH3
CH3 Br
NO 2
O OH NO 2
Cl
Cl OH Cl
Case 9: Target molecule: Phenoglycodol
Cl
H3C H3C CH3

OH OH
Cl
Cl
H3C H3C CH3
OH OH
H3C O H3C
OH O
dan CH3MgBr (Grignard reagent) S ed. 10, p. 567
Cl
Cl
H3C O H3C
OH O
H3C HO
OH O
dan
H3C OH
S ed. 10, p 797

Cl
Cl
H3C HO
OH O
H3C N
OH
S ed. 10, p 790

Cl
Cl
H3C N
OH
H3C O
S ed. 10, p 755

Cl
Cl
H3C O
dan
H3C Cl
S ed. 10, p 685

Cl
S ed. 10, p 680

Case 9: Synthesis Route 1: 1. Khlorinasi benzen dengan katalis FeCl3 2. Acilasi Friedel Crafts dengan katalis AlCl3 dan reaktan acetyl chloride 3. Adisi HCN membentuk Cyanohydrin 4. Acidic hydrolysis membentuk -hydroxy acid 5. Esterifikasi dengan reaktan etanol dan katalis asam 6. Reaksi Grignard dengan reaktan CH3MgBr
Cl
Cl
H3C H3C CH3
OH OH
H3C O CH3
CH3
S ed. 10, p. 531
Cl
Cl
H3C O CH3
CH3
H3C CH3
CH3
S ed. 10, p. 528
Cl
Cl
H3C CH3
CH3
H3C H3C
OH CH3
S ed. 10, p. 297
Cl
Cl
H3C
H3C H3C OH CH3
H3C
dan
O
CH 2MgBr H3C
S ed. 10, p. 567
Cl
Cl
H3C O
dan
H3C Cl
S ed. 10, p 685

Cl
S ed. 10, p 680

Case 9: Synthesis Route 2: 1. Khlorinasi benzen dengan katalis FeCl3 2. Acilasi Friedel Crafts dengan katalis AlCl3 dan reaktan acetyl chloride 3. Reaksi Grignard 4. Dehidrasi alkohol tersier dengan katalis asam kuat 5. Epoksidasi dengan reaktan organic peroxy acid (misal: meta-Chloroperoxybenzoic acid) 6. Pembukaan cincin epoksid dengan katalis asam
Cl
Cl
H3C H3C CH3
OH OH
H3C O CH3
CH3
S ed. 10, p. 531
Cl
Cl
H3C O CH3
CH3
H3C CH3
CH3
S ed. 10, p. 528
Cl
Cl
H3C
H3C CH3
CH3
H3C
dan
H3C
O
P(C 6H5) 3
S ed. 10, p. 757
Cl
Cl
H3C O
dan
H3C Cl
S ed. 10, p 685

Cl
S ed. 10, p 680

Case 9: Synthesis Route 3: 1. Khlorinasi benzen dengan katalis FeCl3 2. Acilasi Friedel Crafts dengan katalis AlCl3 dan reaktan acetyl chloride 3. Reaksi antara keton dengan phosphorous ylide (Reaksi Wittig) 4. Epoksidasi dengan reaktan organic peroxy acid (misal: meta-Chloroperoxybenzoic acid) 5. Pembukaan cincin epoksid dengan katalis asam

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Budhijanto, ST., MT., Ph.D.

(c) Budhijanto, Februari 2010

Chemical Product Design

Chemical Product Design

(c) Budhijanto, Februari 2010

Chemical Product Design

H3C H3C CH3

Suggest several routes by which it may be synthesized.

(c) Budhijanto, Februari 2010

(c) Budhijanto, Februari 2010

(c) Budhijanto, Februari 2010

(c) Budhijanto, Februari 2010

(c) Budhijanto, Februari 2010

(c) Budhijanto, Februari 2010

(c) Budhijanto, Februari 2010

(c) Budhijanto, Februari 2010

(c) Budhijanto, Februari 2010

(c) Budhijanto, Februari 2010

(c) Budhijanto, Februari 2010

(c) Budhijanto, Februari 2010

H3C H3C CH3

H3C H3C CH3

dan CH3MgBr (Grignard reagent) S ed. 10, p. 567

(c) Budhijanto, Februari 2010

S ed. 10, p 797

S ed. 10, p 790

S ed. 10, p 755

S ed. 10, p 685

S ed. 10, p 680

H3C H3C CH3

S ed. 10, p. 531

(c) Budhijanto, Februari 2010

S ed. 10, p. 528

(c) Budhijanto, Februari 2010

S ed. 10, p. 297

(c) Budhijanto, Februari 2010

S ed. 10, p. 567

S ed. 10, p 685

S ed. 10, p 680

H3C H3C CH3

S ed. 10, p. 531

(c) Budhijanto, Februari 2010

S ed. 10, p. 528

(c) Budhijanto, Februari 2010

S ed. 10, p. 757

S ed. 10, p 685

S ed. 10, p 680

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