Tugas Sintesa Obat Sujia Nospiatdi 1011014024

7/29/2019 Tugas Sintesa Obat Sujia Nospiatdi 1011014024

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Synthesis of Drugs Assignment

Synthesis of Atropine

Name : Sujia NospiatdiBp Number : 1011014024

International Class

FACULTY OF PHARMACY

ANDALAS UNIVERSITY

PADANG

2012


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ATROPINE

1. Information Of AtropineSDBS No: 7817 CAS Registry No.: 51-55-8

Molecular Formula: C17H23NO3 Molecular Weight: 289.4Compound Name:

atropine

(+-)-hyoscyamine

endo-8-methyl-8-azabicyclo(3.2.1)octan-3-ol (+-)-tropate

2. Effects : AntimuscarinicM-cholinoblockers are competitive antagonists of acetylcholine as well as other M-

cholinoblockers in terms of postsynaptic M-cholinoreceptors

3. Side Effect :a. Local iritation

b. Foliculas konjungtivitisc. Contact dermatitisd. Eczematoid dermatitise. Light sensitifity

4. Indicationa. Glaucoma

b. Hypersensitif


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c. dilating pupils for severe inflammatory illnessesd. eye traumae. Cholesystis

5. SAR (Structure Activity Relationship)Comparison of atropine with acetylcholine

Relative positions of ester and nitrogen similar in both molecules Nitrogen in atropine is ionised Amine and ester are important binding groups (ionic + H-bonds) Aromatic ring of atropine is an extra binding group (vdW) Atropine binds with a different induced fit - no activation Atropine binds more strongly than acetylcholine

Others SAR of atropine are

The Analogues are fully ionised The Analogues unable to cross the blood brain barrier No CNS side effects Tertiary amine (ionised) or a quaternary nitrogen Aromatic ring Ester N-Alkyl groups (R) can be larger than methyl (unlike agonists) Large branched acyl group R = aromatic or heteroaromatic ring Branching of aromatic/heteroaromatic rings is important

C

O

O CH3

NMe3

CH2CH2

N

O

C

O

Me

H

CH

CH2OH


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6. Principe Of Synthesis Reaction Condensation Reduction Hidrogenation Esterefication

7. Reactiona) Condensation of maleyl aldehyde with methylamine and acetonedicarboxylic

acid gives tropenone (14.1.1). which is the main starting material for the synthesis of

both atropine and scopolamine

b) The carbonyl group of tropenone is reduced with reacted by LiAlH4, thus formingtropenol (14.1.2)

c) The double bond between C6 and C7 of the tropane ring is hydrogenated, givingtropine (14.1.3).

d) Esterification of the tropenol gives the desired atropine (14.1.4)


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8. Isolastion and purification of productActually so many ways to isolated atropine from plant whtherAtropa Belladona or

Datura Sp. There are:

1) Isolation Materials1. Equipment:

1.1Appropriate Glassware (large beakers, graduated cylinders)

1.2Separation Funnel

1.3Mortar and Pestle

1.4Magnetic Stirrer/Hotplate

1.5Stir Bar

1.6Thermometer

1.7Large Buchner Funnel

1.8Whatman #5 Coarse Buchner Filters1.91000mL Buchner Flask

1.10pH Meter

1.11Chiral AGP column 100 x 4.0mm from ChromTech

1.12LC pump model A, HP series from Eldex

1.13Peak Simple Data System, Single Channel

1.14PC Computer with Window

1.15VUV-24: Variable Single Wavelength UV/VIS Detector from

ChromTech

2. Reagents:2.1NaOH pellets (Sigma Aldrich 2005-2006, CAS No. 1310-73-2,

product S5881-500G)

2.2Chloroform (Sigma Aldrich 2005-2006, CAS No. 67-66-3, product

496189-1L)

2.32-propanol (Sigma Aldrich 2005-2006, CAS No. 67-63-0, product

34965-1L)

2.4Octanoic Acid (Sigma Aldrich 2005-2006, CAS No. 124-07-2,

product O3907-1L)

2.5HCl (Sigma Aldrich 2005-2006, CAS No. 7647-01-0, product

38281-1EA)

2.6Sod.Ph.B. (sodium phosphate buffer)

3. Standards:3.1200, 400, 600, 800, 1000ppm atropine in distilled water

Solubility: 2.5 g/mL stable for several days at 4C

Poisonous. Keep away from sunlight.

(Sigma Aldrich 2005-2006, CAS No. 5908-99-6,

product A0257-25G)


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4. Isolation ProcedureObtaining the target is done by this simplified objective: Manipulating the solubility of the

alkaloid by switching it from organic base to inorganic salt and then retrieving the base by

using a powerful solvent. Measurements are based on the assumption one plant contains 800

- 1,000ppm atropine.

1Because atropine is in all plant tissues, liquefy the entire plant into a paste.

Freezing and thawing the material is an optional tactic to rupture cells,

however this can denature the alkaloids.

2Let the paste dry. Do not expose to excessive heat or air currents.

3Add the dried material to 500mL distilled acidified water (pH 6.0) and

heat solution in a double boiler (using water) to 80C. Heat the

solution for 30-45 minutes.

4Filter out insoluble material using vacuum suction and a coarse filter.

Save the filtered solution.

5Adjust pH of the solution to 9.9 with a strong solution of NaOH. Keep

heated at 50C for 30 minutes while stirring.

6Let solution cool to room temperature while stirring.

7Use 2mL aliquots of chloroform until all the inorganic salt that has

precipitated out dissolves. Administer as little solvent as possible and

continue stirring for efficient use of the solvent.

8Pour the contents into a separating funnel. The bottom layer is your

target.

9Collect the target into a suitable container (i.e. no degradable rubbers or

plastics and an air tight seal).

10Purify the extract by running it through a chromatograph using CHIRAL-

AGP 100 x 4.0 mm column with a 2% 2-propanol and 5mM octanoic

acid in 0.01M sod.ph.b (pH 7.0) mobile phase. Set detection to265nm. Atropine has ~ 8.1min retention time. If overlapping of peaks

occurs, see section (7.0). For storage keep in a suitable container away

from moisture, light, and heat.

11To determine relative concentration (ppm) in the original plant, dilute

atropine in 1L of distilled water and run sample against 5 standards in

the same column (with fitting attenuation).


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5. Marker CompoundThe marker compound scopolamine has similar characteristics to that of the target. It can

only be found in the seed of the plant but is very inconsistent in concentration: 53 - 3,050ppm

(http://www.swsbm.com/Constituents/Datura_stramonium.txt). Although scopolamine is

expected to precipitate at a pH of 7.6-7.8, most of it may re-dissolve when the pH is elevated(6.4). Scopolamine has a retention time of ~ 6.0min and is very similar in structure (+1

oxygen) to that of atropine. Because of this, size exclusion chromatography will not separate

adequately and therefore will not prevent overlapping of peaks. An extra procedure is to use

a reverse phase column:

Column: Shodex Asahipak ODP-50 4D (4.6mmID*150mm)

Eluent: 50mM Phosphate buffer (pH10**)/CH3CN=70/30

Flow Rate: 0.6mL/min

Detector: UV (210nm)

Column Temp.: 30deg-C

(http://www.shodex.com/english/dc040211.html)

This column can be integrated with the equipment listed (5.1) in the extraction procedure.

Its intended use is to separate particularly large amounts of scopolamine that are present in

the atropine extract. Because the concentration of scopolamine varies extensively,

quantitative analysis of the marker compound on a batch-by-batch basis may be necessary.

From usage of the column in the extraction procedure (6.9), overlapping of peaks or joined

peaks will give an indication that more separation is required.

**This pH is referenced from its website listed. The chromatogram (8.5) demonstrates

separation, but other data suggests some precipitation of atropine could occur.

6. Conceptual Diagrams1Typical readout of atropine extract
http://www.swsbm.com/Constituents/Datura_stramonium.txthttp://www.shodex.com/english/dc040211.htmlhttp://www.shodex.com/english/dc040211.htmlhttp://www.swsbm.com/Constituents/Datura_stramonium.txt


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2Buchner Filtration Apparatus

3Typical Liquid Chromatography System


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4Datura Stramonium Plant

5 Scopolamine and Atropine Readout


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(7) Filter to obtain a transparent sherry-coloured solution

(8) Add ammonium carbonate to the

solution till saturation

(9) Find colour change of the solution to black from sherry

(10) Leave to obtain crystals of atropine in 15-30 minutes

(11) Take out the upper supernatant with the help of a

Pasteur pipette, (12) Dry the crystals on a filter paper

(13) Dissolve dried crystals into boiling

Alcohol

(14) Evaporate alcohol and obtain pure crystals of atropine.

9. Identification of productDilute solution of tropine when treated with concentrated nitric acid anf the

mixture evaporated to dryness on the steam bath,produces a pale yellow residues. The

residues gives a violet colouration when drop of freshly prepared of potassium

hydoxide is added named vitali-marin.

Thin Layer Chromatography Of Atropine

One percent solution of atropine dissolved in 2 N acetic acid is spotted over silica gel-

G and eluted in the solvent system of strong ammonian solution,methanol (1,5:100).

TLC plate is spread with an acidified iodoplatinate solution atropine gives the Rf

value 0,18. Likewise atrophine sulfate shows the Rf 0,70 in the solvent system

acetone: 0,5 M sodium chloride and spraying with Dragendorffs reagent.


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Spectrum Analysis of Atropine

SDBS- H NMRSDBS No. 7817HSP-48-366 399.65 MHz

C17 H23 N O3 0.040 g : 0.5 ml CDCl3

Atropine


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Assign. Shift(ppm)

A 7.330

B 7.28C 7.27

D 5.002

E *1 4.17

F *1 3.78

G 3.77

J 3.72

K *2 3.017

L *2 2.900

M 2.176

N *3 2.083

P *3 2.004Q *4 1.85

R *4 1.77

S *4 1.70

T *5 1.68

U *5 1.467

V *4 1.223

SDBS- C NMRSDBS No. 7817CDS-10-167 15.09 MHz

C17 H23 N O3 0.174 g : 0.8 ml CDCl3Atropine


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ppm Int. Assign.

172.07 423 1

136.04 484 2

128.74 890 3

128.14 1000 4

127.58 445 5

67.87 544 6

63.93 396 7

59.59 643 8 *59.53 637 9 *

54.80 440 10

40.17 385 11

36.20 390 12 #

36.03 396 13 #

25.38 363 14 *1

24.95 308 15 *1


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SDBS-Mass

MS-NW-6064 SDBS NO. 7817

atropine

C17H23NO3 (Mass of molecular ion: 289)

Source Temperature: 160 C

Sample Temperature: 120 C

DIRECT, 75 eV


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IR-KBR


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10.Chemical Safety & Handling:a) Fire Potential: SLIGHT.

[Sax, N.I. Dangerous Properties of Industrial Materials. 4th ed. New York: Van

Nostrand Reinhold, 1975., p. 425]

b) Hazardous Decomposition:When heated to decomposition it emits toxic fumes of /nitrogen oxides/.

[Lewis, R.J. Sax's Dangerous Properties of Industrial Materials. 9th ed. Volumes 1-3.

New York, NY: Van Nostrand Reinhold, 1996., p. 289]

c) Stability/Shelf Life:SENSITIVE TO LIGHT.

[Sunshine, I. (ed.). CRC Handbook of Analytical Toxicology. Cleveland: The

Chemical Rubber Co., 1969., p. C-13]

d) SLOWLY AFFECTED BY LIGHT. /ATROPINE SULFATE/[Osol, A. and J.E. Hoover, et al. (eds.). Remington's Pharmaceutical Sciences. 15th

ed. Easton, Pennsylvania: Mack Publishing Co., 1975., p. 840]

e) Atropine sulfate should be stored below 40 deg C, preferably at room temp.Freezing should be avoided. Minimum hydrolysis occurs at pH 3.5. Atropine

sulfate 1 mg/ml was found to retain potency for 3 months at room temp when0.5 or 1 ml of soln was packaged in Tubex. /Atropine sulfate/

[Trissel, L.A. Handbook on Injectable Drugs. 9th ed. Bethesda, MD. American

Society of Health-System Pharmacists' Product Development. 1996., p. 109]

f) Disposal Methods:SRP: At the time of review, criteria for land treatment or burial (sanitary landfill)

disposal practices are subject to significant revision. Prior to implementing land

disposal of waste residue (including waste sludge), consult with environmental

regulatory agencies for guidance on acceptable disposal practices. Api Potensi

kebakaran:

Sedikit.

[Sax, N.I. Berbahaya Sifat Bahan Industri. 4th ed. New York: Van Nostrand

Reinhold, 1975, hlm.. 425]

Tugas Sintesa Obat Sujia Nospiatdi 1011014024

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