SOLID PHASE SYNTHESIS

TỔNG HỢP PHA RẮN
(SOLID PHASE SYNTHESIS)


A classical synthesis example:
Synthesis of 2-substituted benzimidazoles

Workup procedure:
When the reaction was accomplished (monitored by
TLC), the solvent was evaporated under reduced
pressure.

The

crude

product

was

subjected

to

chromatography on silica gel and eluted with petroleum
ether or a mixture of petroleum ether and ethyl acetate
to afford the corresponding benzimidazole.


Another example: Efficient Synthesis of Selectively Protected LDopa Derivatives from L-Tyrosine via Reimer-Tiemann and
Dakin Reactions

Workup procedure: The reaction was diluted with water
and ethyl acetate, and the aqueous layer was acidified to
pH 1 with 1 N HCl and back extracted with ethyl
acetate. The organic extracts were washed with brine,
dried over MgSO4, and concentrated. Flash column
chromatography afforded the desired product 8 as a
brown oil.


TỔNG HỢP TRONG DUNG DỊCH
A + B → C (chính) + D (phụ) + E (phụ) + …
C + E → F (chính) + G (phụ)…
Vấn đề giải quyết:
- Hiệu suất tổng hợp,
- Tinh chế sản phẩm,
- Bảo vệ/Giải bảo vệ nhóm chức,
- …


TỔNG HỢP CỔ ĐIỂN
Tổng hợp trong dung dịch:
- Dùng dư tác nhân phản ứng
- Cô lập và tinh chế chất trung gian,
sản phẩm phản ứng,…


TỔNG HỢP PHA RẮN
Là kỹ thuật tổng hợp theo đó chất cần tổng

hợp được tổng hợp trên một chất mang rắn
(polymeric resin).

S
S
S

S

S

S
S

S

S

S

S

S



Benzodiazepine drugs (half-life values)


Synthesis of benzodiazepines

Rachedine Kaoua et al.
Molecules 2011, 16, 92-99


Synthesis of benzodiazepines

Sternbach et al. J. Org. Chem. 1962, 27, 3788.
Lednicer et al. Organic Chemistry of Drug Synthesis; Wiley-Interscience: New York, 1998.
Lednicer et al. The Organic Chemistry of Drug Synthesis; Wiley-Interscience: New York, 1977.


Ellman’s solid-phase synthesis of
1,4-benzodiazepines


Ưu điểm của Tổng hợp Pha rắn?
Không cần cô lập chất trung gian.
Có thể dùng dư tác nhân phản ứng → thúc đẩy
phản ứng xảy ra hoàn toàn.
Sau phản ứng, lượng dư chất phản ứng có thể loại
bỏ bằng phương pháp rửa đơn giản.
Có thể tự động hóa quá trình tổng hợp.


TỔNG HỢP PHA RẮN


TỔNG HỢP PHA RẮN

SOLID PHASE SYNTHESIS
• The scale SPS is limited and restricted by the
amount of the solid support and its loading
capacity.
• The preparation of multi-milligram quantities can
be cumbersome and expensive for large
combinatorial libraries: for 50mg -10,000
compounds (MW=500), 3-step synthesis 95%
yield/step, 1.166 kg resin (1 mmol/g loading) is
required).


Tổng hợp pha rắn: Chất mang và Cầu nối
P

Linker

Substrate

Resin

Chất mang (Resin)
Một loại polymer.
Mức độ trương nở trong dung môi khác nhau:
Polystyrene trương nở tốt trong dung môi không phân cực;
Polyethylene glycol (PEG): trương nở tốt trong cả dung môi
phân cực và không phân cực.
Cầu nối (Linker)
Cấu trúc trung gian nối chất mang và tác chất phản ứng.

Nhiều loại cầu nối khác nhau.


SOLID SUPPORT
• The most common are spherical particles
(beads, 0.04-0.15 mm).
• Are mechanical stability and chemical inertness under the reaction conditions to be used.
• Need to be chemically functionalized.
• Sufficient permeability or swelling capacity.
• Mostly are polystyrene and copolymers of
styrene with various cross-linking agents.



SOLID SUPPORT
• Several physicochemical parameters of the resin
influence the reaction time:
degree of cross linkage
bead size
swelling properties
diffusion properties
• The driving force for the mass transport into the
bead is diffusion.
• 95% of the reactive groups are located inside the
bead and not on the surface → Condition for mass
transport: Swelling of the polymer (3-4 fold volume
increase).


Effects of Crosslinking

• Cross-linking imparts mechanical stability and
improved diffusion and swelling properties to the resin.
Without cross-linking, each
polymer chain can dissolve
under thermodynamically
favored conditions.

Cross-linking can induce some
sites of “permanent
entanglement” maintaining
structural integrity.


Swelling of Polymer by Solvent
‘Shrunken’ state

‘Swollen’ state : Permeable
to solvent and reagent



SOLID SUPPORT
The level of functional groups or “loading,” expressed
in mmol/g, can cover a wide range of values (from 0 to
virtually 7 mmol/g).
Generally, the loading and application of polystyrene
resins can be grouped as follows:
<0.1 mmol/g: oligonucleotide synthesis and the
synthesis of large peptides/proteins.
0.1–0.7 mmol/g: supported catalysts

0.5–1.5 mmol/g: small molecules and peptide
synthesis, avoiding problems of steric hindrance
>2 mmol/g: scavenger and reagents based resins, as
these types of reagents are added in excess.