Synthesis of Nifedipine – 3 Experiment rd

Synthesis of Nifedipine – 3rd Experiment
☞ Hantzsch reaction to synthesize the Nifedipine, CCB
14. 11. 18. 火
담당 조교 : 김병수 (21-222, ☎ 8264)
▣ Scheme & Reagents
No.
Reagent
MW
density
amount
100 mg
mmol
mmol
equivalent
1.
2-Nitrobenzaldehyde
151.12
-
2.
Methyl Acetoacetate
116.12
1.078 g/mL
μL
4 equiv.
3.
25.0% Ammonium Hydroxide
35.05
0.9 g/mL
μL
2 equiv.
4.
Methanol
-
-
mL
-
1 equiv.
0.35M
▨ Procedure
a.
10ml two-neck r.b.f.에 magnetic bar, 2-Nitrobenzaldehyde, Methyl Acetoacetate를 넣고 methanol로 녹
인 후 25.0% Ammonium Hydroxide을 넣는다.
b. reflux condenser를 연결한다.
c.
가열하면서 TLC로 반응 진행상황을 확인한다.
d. 반응이 끝나면 rt로 식힌 후, 얼음물을 가해 recrystallization한다.
e.
생성된 고체를 걸러내고 건조한 후 칭량한다.
▣ Checking the Progress
TLC monitoring by UV lamp
전개용매; n-Hex:EA = 2:1
발색시약; PMA or Anisaldehyde
▽ Reference
실험의약품합성학, 실험유기의약품화학 편찬위원회, 청문각, 2013.
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☞ Mechanism
Hantzsch Reaction: The one-pot condensation of a β-keto ester or a 1,3-dicarbonyl compound with an
aldehyde and ammonia to prepare 1,4-dihydropyridines.
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˙ ˙ ˙ ˙ ˙ ˙ DATA
˙ ˙˙˙
HAZARD
˙ ˙ ˙ ˙ THIS
˙ ˙ ˙ ˙ BEFORE
˙ ˙ ˙ ˙ ˙ ˙ GOING
˙ ˙ ˙ ˙ ˙ ANY
˙ ˙ ˙ FURTHER!
˙ ˙ ˙ ˙ ˙ ˙ ˙˙
READ
- 2-Nitrobenzaldehyde
Very hazardous in case of skin contact (irritant). Hazardous in case of eye contact (irritant), of ingestion,
of inhalation. Slightly hazardous in case of skin contact (permeator).
- Methyl Acetoacetate
COMBUSTIBLE LIQUID AND VAPOR. CAUSES EYE IRRITATION. MAY CAUSE BLINDNESS IF SWALLOWED.
- 25.0% Ammonium Hydroxide
Very hazardous in case of skin contact (corrosive, irritant, permeator), of eye contact (irritant), of
ingestion. Non-corrosive to the eyes. Non-corrosive for lungs.
- Methanol
Toxic in contact with skin. May cause blindness if inhaled. Irritating to eyes. Symptoms include itching,
burning, redness and tearing. Toxic if swallowed. May be fatal or cause blindness if swallowed.
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Instant Report – 3rd report
조 ____ 학번 ___________
이름 ___________ 담당 조교 ___________
☞ Introduction
☞ Procedure and who did it
☞ What did you see
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Valuation Report – 3rd report
조 ____ 학번 ___________
이름 ___________ 담당 조교 ___________
☞ Discuss the Synthesis of Nifedipine.
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3주차 중간강의
☞ NMR & IR speroscopy
14. 11. 18. 火
조교 허준성
▣ NMR (Nuclear Magnetic Resonance)
- Used to map carbon-hydrogen framework of molecules
- Used to determine relative location of atoms within a molecule
- Most helpful spectroscopic technique in organic chemistry
 How to read NMR spectral data
1. Chemical Shift : Where is this proton bonded?
- Only depend on how much proton’s nuclei are shielded by electrons.
- Different signals appear for nuclei in different environments.
- Nuclei that absorb on upfield side are strongly shielded.
▪ TMS(tetramethylsilane) : internal standard for calibrating chemical shift
① Electronegativity : CH3F vs CH3OH vs CH3Cl
- Protons adjacent to electronegative atom are deshielded, so move to DOWNFIELD
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② Hybridization : RCH3 vs RCH=CH-CH2R’ vs RCH=CHR’
- The more increased s character on the carbon hybridized orbital, the more increased
electronegativity.
③ Diamagnetic effect : C≡CH vs C=CH vs C6H6
- Strong magnetic field induce flow of electrons in the π system.
- Induced flow of π electrons cause local magnetic field, it can change electron density adjacent
proton.
- While acetylenic proton is more shielded, vinylic and aromatic proton is more deshielded than
expected.
2. integral : How many protons are represented in this signal?
3. Splitting : How many protons exist around the focused proton
▪ The splitting pattern of a given nucleus (or set of equivalent nuclei) can be predicted by the n+1 rule,
where n is the number of neighboring protons.
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3-1. J-value
Magnitude of Some Typical Coupling Constants
4. C13 NMR
- C12 don’t show NMR effect, so its isotope C13 NMR is used
- Because of low abundance ratio, large amount of sample is needed to obtain clear spectra
- No signal split, No integration
- Provide more details of structure
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▣ IR(infrared) spectroscopy
- IR is most useful in providing information about the presence or absence of specific functional groups.
- IR radiation causes the excitation of the vibrations of covalent bonds within that molecule. These vibrations
include the stretching and bending modes.
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- The wavenumber region of each functional groups are determined by following factors
① Light atom bond need more energy to vibrate : high wavenumber
② Short atom bond need more energy to vibrate : triple bond band represent higher region than
double bond
- The intensity of the bands depends on the magnitude of the dipole moment associated with the bond
in question.
① Strongly polar bonds such as carbonyl groups (C=O) produce strong bands.
② Medium polarity bonds and asymmetric bonds produce medium bands.
③ Weakly polar bond and symmetric bonds produce weak or non observable bands.
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