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Synthesis of Acetazolamide




Reaction Summary
Starting reaction occurs in-between hydrazine hydrate and ammonium thiocyanate that produces 1, 2-bis (thiocarbamoyl) hydrazine which on further treatment with phosgene undergoes rearrangements, particularly  molecular rearrangement through loss of ammonia to form 5-amino-2-mercapto-1, 3, 4-thiadiazole. Upon acylation of 5-amino-2-mercapto-1, 3, 4-thiadiazole gives a corresponding amide which on oxidation with aqueous chlorine affords the 2-sulphonyl chloride. The final step essentially consists of amidation by treatment with ammonia.


Brief Pharmacology


  • Acetazolamide is prtotype in carbonic anhydrase inhibitors, 
  • Acetzolamide act at the proximal tubule, where carbonic anhydrase is membrane-bound and normally catalyses H2CO3-> H2O + CO2 in the lumen and the reverse reaction in the cytoplasm. By blocking CA, acetazolamide inhibit NaHCO3 reabsorption in the proximal tubule.
  • Used to treat 
  1. glaucoma, 
  2. drug-induced edema, 
  3. heart failure-induced edema, 
  4. centrencephalic epilepsy 
  5. and in reducing intraocular pressure after surgery.




Synthesis of Atropine





Medicinal chemistry of Atropine and its synthesis involves 2 major steps

Synthesis of Atropine

Atropine and its synthesis involves 2 major steps
1. Synthesis of Tropine
2. Synthesis of Tropic Acid
and last step is there combination to form ultimately Atropine

The first step is Synthesis of Tropine
The immediate compound are Succinaldehyde, methylamine and Acetone to form Tropinone, this Tropinone upon reduction yields Tropine.

The second step is synthesis of Tropic Acid is carried out via Phenyl Acetic Acid and Propyl magnesium Chloride in the presence of ether and intermediate product formation, followed by subsequent treatment with H2SO4 yields tropic acid

the last step in this synthesis is combination of both products i.e Tropine + Tropic Acid to yield Atropine

Brief Pharmacology of Atropine


  • Atropine action usually increase heart rate, decrease motility and peristalsis, decrease salivary secretions 
  • Atropine uses pre-operating medicine to decrease saliva secretions antispasmodic drug to treat peptic ulcers increase heart rate with bradycardia
  • Atropine side effects tachycardia, palpatations, nasal congestion, flushing, photophobia, blurred vision, dry mouth and skin, abdominal distention, urinary retention, impotence
  • Atropine is contraindicated for glaucoma

ChemNMR 1H Estimation of Atropine



Protocol of the H-1 NMR Prediction:


Node     Shift    Base + Inc.   Comment (ppm rel. to TMS)

OH  3.65              2.00      alcohol
                         1.65      general corrections
CH  2.24              2.75      pyrrolidine
                        -0.01      1 beta -C from methine
                          ?        1 unknown substituent(s)
                        -0.50      1 -C from N-CHx
CH  2.24              2.75      pyrrolidine
                        -0.01      1 beta -C from methine
                          ?        1 unknown substituent(s)
                        -0.50      1 -C from N-CHx
CH2 1.68,1.425000        1.59      pyrrolidine
                        -0.04      1 beta -C from methylene
                          ?        1 unknown substituent(s)
CH2 1.68,1.425000        1.59      pyrrolidine
                        -0.04      1 beta -C from methylene
                          ?        1 unknown substituent(s)
CH  5.22              1.50      piperidine
                         2.47      1 alpha -O-C=O from methine
                         1.25      general corrections
CH2 1.83,1.575000        1.50      piperidine
                        -0.04      1 beta -C from methylene
                         0.24      1 beta -OC(=O)-C from methylene
CH2 1.83,1.575000        1.50      piperidine
                        -0.04      1 beta -C from methylene
                         0.24      1 beta -OC(=O)-C from methylene
CH  7.29              7.26      1-benzene
                        -0.14      1 -CC
                         0.17      general corrections
CH  7.29              7.26      1-benzene
                        -0.14      1 -CC
                         0.17      general corrections
CH  7.40              7.26      1-benzene
                        -0.05      1 -CC
                         0.19      general corrections
CH  7.40              7.26      1-benzene
                        -0.05      1 -CC
                         0.19      general corrections
CH  7.27              7.26      1-benzene
                        -0.18      1 -CC
                         0.19      general corrections
CH2 4.34,4.085000        1.37      methylene
                         2.20      1 alpha -O
                         0.29      1 beta -1:C*C*C*C*C*C*1
                         0.35      1 beta -C(=O)O-C
CH3 2.26              0.86      methyl
                         1.41      1 alpha -N(C)C
                        -0.01      general corrections
CH  3.69              1.50      methine
                         1.28      1 alpha -1:C*C*C*C*C*C*1
                         0.83      1 alpha -C(=O)OR
                         0.08      1 beta -O

1H NMR Coupling Constant Prediction

shift   atom index  coupling partner, constant and vector

3.65       1
2.24       8
                  9  7.0 H-C-CH-H
                  7  7.0 H-C-CH-H
2.24      11
                 10  7.0 H-C-CH-H
                 12  7.0 H-C-CH-H
1.55       9 diastereotopic -12.4 H-C-H
                  8  7.0 H-CH-C-H
                 10  7.1 H-CH-CH-H
1.55      10 diastereotopic -12.4 H-C-H
                 11  7.0 H-CH-C-H
                  9  7.1 H-CH-CH-H
5.22       6
                  7  7.0 H-C-CH-H
                 12  7.0 H-C-CH-H
1.70       7 diastereotopic -12.4 H-C-H
                  8  7.0 H-CH-C-H
                  6  7.0 H-CH-C-H
1.70      12 diastereotopic -12.4 H-C-H
                 11  7.0 H-CH-C-H
                  6  7.0 H-CH-C-H
7.29      21
                 20  7.5 H-C*C-H
                 17  1.5 H-C*C*C-H
                 19  1.5 H-C*CH*C-H
7.29      17
                 18  7.5 H-C*C-H
                 21  1.5 H-C*C*C-H
                 19  1.5 H-C*CH*C-H
7.40      18
                 17  7.5 H-C*C-H
                 19  7.5 H-C*C-H
                 20  1.5 H-C*CH*C-H
7.40      20
                 21  7.5 H-C*C-H
                 19  7.5 H-C*C-H
                 18  1.5 H-C*CH*C-H
7.27      19
                 18  7.5 H-C*C-H
                 20  7.5 H-C*C-H
                 17  1.5 H-C*CH*C-H
                 21  1.5 H-C*CH*C-H
4.21       2 diastereotopic -12.4 H-C-H
                  3  7.0 H-CH-C-H
2.26      14
3.69       3
                  2  7.0 H-C-CH-H

Atropine chemical data

Atropine chemical formula, mass, molecular weight along with mass to charge ration with elemental analysis is shown below.


8-methyl-8-azabicyclo[3.2.1]octan-3-yl 3-hydroxy-2-phenylpropanoate
Chemical Formula: C17H23NO3
Exact Mass: 289.17
Molecular Weight: 289.37
m/z: 289.17 (100.0%), 290.17 (18.8%), 291.17 (2.3%)
Elemental Analysis: C, 70.56; H, 8.01; N, 4.84; O, 16.59


This post is written by Dr Aqeel Nasim, M.Phil Pharmacy Practice scholar, follow for more

Medicinal Chemistry of SalicylAmide and its Synthesis

 

Synthesis of SalicylAmide

Salicylic acid ==> Salicyl chloride
Salicyl chloride ==> SalicylAmide


Structure Activity Relationship of SalicylAmide 

> Ortho position of hydoxyl (-OH) group is essential for activity
> Removing -OH group decreases its activity
> Substituion of -OH group with other substituents will affect its toxicity and activity
> Acetylation of -OH group will form 2-carbamoylphenyl acetate
> shifting of -OH group to meta or para, the activity will decrease
> substitution of - COOH group with Amide causes decrease or diminish its anti-inflammatory action

Uses

> Antipyretic
>Analgesic

Adrs


> Sedation at high doses
> may cause anemia
> Gastric intolerance


Medicinal Chemistry of Sulfamerazine


Sulfamerazine belongs to antibacterial drugs (bacteriostatic) that contains Sulfonamide as parent structure.
it is used as
  1. bronchitis, 
  2. prostatitis and 
  3. Urinary tract infections
Sulfamerazine as it is belong to Sulfonamide shows following mechanism
It inhibits bacetrial folic acid synthesis by competing PABA with dihydrofolate synthetase

Competitive inhibitor of  dihydrofolate synthetase, this enzyme is used in folate synthesis in bacteria, hence Sulfamerzine interfere with this pathway
 and ultimately decresing the synthesis of bacterial nucleotides and DNA

Synthesis of Sulfamerazine

Synthesis of Sulfamerazine Step 01
(Click to enlarge)

Synthesis of Sulfamerazine Step 02
(Click to enlarge)

Synthesis of Sulfamerazine Step 03
(Click to enlarge)


Medicinal Chemistry of Salicylic Acid








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