Prozac, Fluoxetine SPECTRAL DATA

N-methyl-3-phenyl-3-[4-(trifluoromethyl)phenoxy]propan-1-amine

FLUOXETINE

Fluoxetine (also known by the tradenames Prozac, Sarafem, Ladose and Fontex, among others) is an antidepressant of the selective serotonin reuptake inhibitor (SSRI) class. Fluoxetine was first documented in 1974 by scientists from Eli Lilly and Company.[6] It was presented to the U.S. Food and Drug Administration in February 1977, with Eli Lilly receiving final approval to market the drug in December 1987. Fluoxetine went off-patent in August 2001.[7]

Fluoxetine is approved in the US for the treatment of major depression (including pediatric depression), obsessive-compulsive disorder (in both adult and paediatric populations), bulimia nervosa, panic disorder and premenstrual dysphoric disorder.[8] In addition, fluoxetine is used to treat trichotillomania if cognitive behaviour therapy is unsuccessful.[9] In combination with the atypical antipsychotic olanzapine it is known by a few brand names,[note 1] including its US brand name Symbyax, which is approved for the treatment of depressive episodes as part of bipolar I disorder and in the treatment of treatment-resistant depression.

Despite the availability of newer agents, fluoxetine remains extremely popular. In 2010, over 24.4 million prescriptions for generic formulations of fluoxetine were filled in the United States alone,[10] making it the third most prescribed antidepressant after sertraline(SSRI; became generic in 2006) and citalopram (SSRI; became generic in 2003).[10] In 2011, 6 million prescriptions for fluoxetine were handed out in the UK.[11]

Fluoxetine 20 mg capsules.

Uses of the pharmaceuticalProzac is an antidepressant and is used in the treatment of depression, panic attacks, and obsessive compulsive disorder. It was first released in 1988 and has been used since by upwards of 40 million people worldwide, according to a study done in 2008. A study released in the journal Public Library of Science Medicine journal in 2008 claimed that Prozac was ineffective as an antidepressant after a study done in which both patients who took the drug and patients who were given a placebo drug showed the same improvement as those who were given the real treatment.While its main usage has been to treat depression, Fluoxetine has also been used for research in the discovery the role of 5-HT in CNS physiology and pathophysiology. It has alos been used in the treatment of anorexia nervosa, bulimia nervosa, obsessive–compulsive disorder, panic disorder, premenstrual dysphoria and generalized anxiety disorder (Wong 772).
Prozac was manufactured by Eli Lilly and Company until its patent lapsed in 2001. Fluoxetine, however, is now the active ingredient in another Lilly product – Sarafem, a pill for premenstrual syndrome.

Synthesis:While several viable syntheses exist for fluoxetine, one particular synthesis is especially practical for undergraduate laboratories. While some syntheses use toxic compounds such as the reducing agent B2H6 and the chlorinating agent SOCl2 to yield fluoxetine, there is at least one synthesis that circumvents these hazardous reagents. The synthesis given by Perrine, Sabanayagam, and Reynolds instead uses the less hazardous reagents NaBH4 and KOCMe3. Furthermore, while other syntheses require use of the costly compound 4-(trifluoromethyl)phenol, the synthesis avoids this compound and instead requires the inexpensive 1-chloro-4-(trifluoromethyl)benzene. For these reasons, the synthesis given below is best suited for introductory laboratories.

The commercially available compound 3-(dimethylamino)-1-phenylpropan-1-one is reduced with sodium borohydride (NaBH4) to form 3-(dimethylamino)-1-phenylpropan-1-ol. This alcohol is deprotonated with potassium t-butoxide (KOCMe3), and the resulting alkoxide undergoes aromatic substitution onto 1-chloro-4-(trifluoromethyl)benzene. Aromatic substitution within the polar aprotic solvent DMAA yields the drug precursor “N-methyl-Prozac.” NMP is converted to Prozac (fluoxetine) via N-demethylation with cyanogen bromide (CNBr).

Patent EP0612242B1

Chemical Properties

General features

Fluoxetine hydrochloride is a white to off white crystalline solid which has a melting point of 158.4-158.9oC. It has a maximum solubility in water of 14mg/ml.

Solubility in common solvents

Freely soluble in methanol and ethanol
Soluble in acetonitrile, chloroform and acetone
Practically insoluble in toluene, cyclohexane and hexane
////////////////////////

Optical Rotary Power-(R-Fluoxetine)	data
Type	[alpha]
Concentration	1g/100ml
Solvent	CHCl3
Optical rotary power	2 degrees
Wavelength	589nm
Temperature	22oC

MASS SPECTRUM

The high resolution NMR spectrum can be readily interpreted.

The main source of information that the mass spectrum provides is the molecular weight of the compound which in this case can be seen to be approximately 346u.

NMR Spectroscopy

ANALYSIS OF PEAKS

//////////////////////////////////

NMR interpretation

CHEMICAL SHIFT/PPM	ASSIGNMENT
7.4	A
6.9	B
5.5	C
3.0	D
2.5	E
2.0	F

/////////////////////////////////////
The A protons are chemically equivalent due to the symmetry of the system and hence appear at the same ppm value. Each A hydrogen will couple to its neighbouring B proton and the splitting pattern will be a doublet. The electron withdrawing effect of the fluorine atoms combined with the aromatic ring current is responsible for the high chemical shift of these protons.

The B protons are again in identical chemical environments and they each couple to the neighboring A proton. A doublet is therefore observed in the spectrum.

The C is close to an electronegative oxygen atom and an aromatic ring. These withdraw electron density both inductively and mesomerically. The C sisgnal is split into a triplet by 3J coupling to the adjacent F protons.

The D proons couple to the F protons but not to the adjacent NH proton resulting in a triplet.

The E signal corresponding to the methyl group is obviously a singlet as there are no adjacent hydrogens to which the E protons can couple.The NH proton is again discounted due to its transient nature.

The F protons show a multiplet. These protons are not chemically equivalent although they have been grouped together. These hydrogens are adjacent to an asymmetric centre and are thus diastereotopic. Replacement of each hydrogen by a different group would result in opposite diastereomers. As the F protons are not equivalent they couple to each other as well as to the D and C protons which are adjacent.A compliclated multiplet therefore results.

The hydrogen shown attached to the nitrogen atom does not appear in the spectrum as such protons readily interchange in solution.

The five aromatic protons appear as amultiplet between the shifts of the A and B protons.

LINK............http://file.selleckchem.com/downloads/nmr/S133301-Fluoxetine-hydrochloride-NMR-Selleck.pdf

X-ray Crystallography

The three dimensional structure of fluoxetine has been determined by X-ray crystallography. In the solid state the planes defined by the two aromatic rings are skewed preventing the possibility of intramolecular interactions between the rings.The methylene units of the methylpropanamine part adopt the expected conformational relationships thus minimising torsional strain.The C1-C2-C3-O4 dihedral angle is 60.6. From this it can be concluded that the propanamine side chain folds towards the phenoxy part as opposed to adopting a fully extended configuration. This folded three dimensional relationship is thought to be essential for a high affinity interaction with the serotonin uptake carrier to take place. The various substituents on the phenoxy part of fluoxetione are also very important in determining its potency and selectivity.

Although th folded propylamine part of fluoxetine plays in acrucial role in its pharmacological properties, the 3-phenyl group is also a critical aspect of its structure. It is thought that the enhancement of potency attributed to this group can be explained in terms of its interaction with a hydrophobic pocket on the serotonin uptake carrier. Evidence in support of this hypothesis is the similar potency of both enantiomers of fluoxetine. This would be expected if the afore-mentioned hydrophobic interaction is important.

Crystallographic data

formula	C17H18F3NO.HCl
formula mass	345.8
space group	Pcab
a,A	10.457 (2)
b,A	10.387 (2)
c,A	32.345 (6)
V,A	3513.1 (1.4)
Z	8
d calc g/cm3	1.307

Fluoxetine hydrochloride crystallised from water as colourless needles in the orthorhombic space group known as Pcab. Each unit cell contains eight molecules and the molecules are arranged in bilayers with the hydrophobic(trifluoromethyl) phenoxy and hydrophilic amine hydrochloride parts juxtaposed to the corresponding regions of a second fluoxetine molecule.

UV Spectroscopy

UV MAX/NM	E1%
227	372.0
264	29.2
268	29.3
275	21.5

Infra-red spectroscopy

• There are two or three bands between 2960 and 2850cm-1 which correspond to C-H stretching frequencies.
• There is a sharp band due to the C-F stretching frequency between 1400-1000cm

---

Structure of the compound

N-methyl-3-phenyl-3-[4-(trifluoromethyl)phenoxy]propan-1-amine

---

Identification of bond types found in the molecule

	count	length (Å)	energy (KJ/mol)
C=C	6	1.4	602
C--C	10	1.4	346
C--F	3	1.4	485
C--H	17	1.1	411
C--N	2	1.4	305
C-O	2	1.4	358
H--N	1	1.0	386

---

Identification of functional groups
Phenyl group, amino group, halo group, alkoxy group

---

Identification of all chirality centers in the molecule:

---

The CAS number:
CAS Number: 54910--89-3

---

Predicted NMR spectra:

Predicted IR spectra:
Aromatic rings: 1600 and 1475
N-H bond: 3300
C-O bonds: 1300-1000
C-H bonds: broad 3000

REFERENCES

1.  Altamura, AC; Moro, AR; Percudani, M (March 1994). "Clinical Pharmacokinetics of Fluoxetine" (PDF).Clinical Pharmacokinetics 26 (3): 201–214.doi:10.2165/00003088-199426030-00004.PMID 8194283.
2.  "PROZAC® Fluoxetine Hydrochloride" (PDF). TGA eBusiness Services. Eli Lilly Australia Pty. Limited. 9 October 2013. Retrieved 23 November 2013.
3.  "FLUOXETINE HYDROCHLORIDE capsule [Sandoz Inc]". DailyMed. Sandoz Inc. January 2013. Retrieved 23 November 2013.
4.  "Fluoxetine 20 mg Capsules - Summary of Product Characteristics (SPC)". electronic Medicines Compendium. Accord Healthcare Limited. 21 November 2012. Retrieved 23 November 2013.
5.  "Prozac, Sarafem (fluoxetine) dosing, indications, interactions, adverse effects, and more". Medscape Reference. WebMD. Retrieved 23 November 2013.
6.  Wong, David T.; Horng, Jong S.; Bymaster, Frank P.; Hauser, Kenneth L.; Molloy, Bryan B. (1974). "A selective inhibitor of serotonin uptake: Lilly 110140, 3-(p-Trifluoromethylphenoxy)-n-methyl-3-phenylpropylamine".Life Sciences 15 (3): 471–9. doi:10.1016/0024-3205(74)90345-2. PMID 4549929.
7.  "'Generic Prozac' expected to be cleared for sale". CNN. 1 Aug 2001. Retrieved 27 Dec 2012.
8.  "Prozac Pharmacology, Pharmacokinetics,Studies, Metabolism". RxList.com. 2007. Retrieved April 14, 2007.
9. Randi Jenssen Hagerman (16 September 1999).Neurodevelopmental Disorders: Diagnosis and Treatment. Oxford University Press. ISBN 019512314X. "Dech and Budow (1991) were among the first to report the anecdotal use of fluoxetine in a case of PWS to control behavior problems, appetite, and trichotillomania."
10. Verispan. "Top 200 Generic Drugs by Units in 2010"(PDF). Drug Topics.
11. Patrisha Macnair (September 2012). "BBC - Health: Prozac". BBC. Archived from the original on 2012-12-11. "In 2011 over 43 million prescriptions for antidepressants were handed out in the UK and about 14 per cent (or nearly 6 million prescriptions) of these were for a drug called fluoxetine, better known as Prozac."

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The oxidation of the alcohols mixture with sodium hypochlorite in pure ethanoic acid produces only 3-a-chloro-3-exo-decanoyl-1,7,7-trimethyl bicyclo[2.2.1]heptan-2-one.

3-chloro-3-decanoyl-1,7,7 trimethylbicyclo[2.2.1]heptan-2-one.



The oxidation of the alcohols mixture with sodium hypochlorite in pure ethanoic acid produces only 3-a-chloro-3-exo-decanoyl-1,7,7-trimethyl bicyclo[2.2.1]heptan-2-one.

Oxidation with NaClO/ CH₃CO₂H

0.16 g (0.52 mmol) of the alcohols mixture was stirred for 12 h at 50° C with 1M (2.5 mL) aqueous solution of sodium hypochlorite and pure ethanoic acid (4mL). The products were extracted with ethyl ether (3 x 40 mL) and the organic phase was washed with distilled water and dried with anhydrous sodium sulfate. The organic fractions obtained were concentrated and the products were purified in a liquid column chromatography.

Under the reaction conditions studied the oxidation of the alcohols mixture with hypochlorite in pure ethanoic acid gives only product (8).

Compound (8) is a colorless liquid and the IR spectrum shows two bands at n 1754,9 cm^-1 and n 1722,7 cm^-1 for the carbonyl groups stretching of this compound. 

The ¹H-NMR spectrum (Figure 6) and the ¹H-¹H-COSY shows two groups of signals for the H5 methylenes; at d 3.15 (1H, ddd, J= 7.8, 7.6, 3.9 Hz) for H₅-endo and the signal for H₅-exo at d 2.51 (1Hb, ddd, J= 7.8, 7.6, 6.5 Hz). 

The signals d 198.8 and d 212.0 in the ¹³C-NMR spectrum assigned to the two carbonyls support structure (8). Moreover the DEPT (135) experiment shows a new chemical shift at d 72.2, while the signal at d 75.77 for the methine (C3) disappears. 

 ¹³C-NMR experiments help to the signals assignment for all of the carbons of the bicyclic ring and a part of the lateral aliphatic chain. Thus C2 at d 36.9 show coupling with the two signals for the diasterotopic hydrogens which signals appear at d 3.15 and 2.51. 

Besides the protons of the syn methyl group at C9 are shielded (d 0.62), because of the proximity to exo carbonylic group at C1'. The signals for the protons at C5 and C6 are very close, H5a and H6a are at d 2.03 and H5b and H6b at d 1.73. 

The incorporation of a chlorine atom on the alpha face was postulated due to both the shield induced on protons of one methyl at C7 and the chemical shift of H5a and H6ato lower field due to the fact that they are on the same face with respect to the chlorine.

Figure 6. 1H-NMR of 3-chloro-3-decanoyl-1,7,7 trimethylbicyclo[2.2.1]heptan-2-one.

A probable explanation for the formation of compound (8) lies on the fact that an acidic solution of sodium hypochlorite has a certain concentration of Cl₂ at the thermodynamic equilibrium (figure 8). Chlorine can add to the double bond of the enol structure of the oxidation products. 

It is expected that the attack by the chlorine is on the most exposed alpha face of the enol structure, producing the intermediate showed in Figure 8. This intermediate can quickly rearrange to the more stable compound (8).

4H⁺(ac) + 2 Cl ^- + 2 ClO ^-(ac) = 2 Cl₂(g) + 2 H₂O (l)

Figure 8

3-chloro-3-decanoyl-1,7,7-trimethylbicyclo[2.2.1]heptan-2-one. (8)

¹H-NMR : 6.36 (1H, dd, J= 7.76, 7.67 Hz), 2.16-2.08 (2H, m, 1.73-1.60 (2H, m), 1.37 (2H, m, 1.26 (8CH2, s), 0.96 (6H,s), 0.90 (t, J= 8 Hz), 0.78 (s, 3H). 

¹³C-NMR: 207.1, 142.7, 130.5, 57.7, 47.5, 45.9, 31.8, 30.3, 29.3, 28.7, 28.6(2CH2), 26.4, 22.5, 20.4, 18.2, 14.0, 9.1. 

MS: 186 (base peak), 312, 297,155, 83, 55. 

Anal. Calcd. for C₂₀H₃₃ClO₂; C, 70.46; H, 9.76. found. C 70.42; H, 9.77.

Aldolization procedure

Lithium diisopropylamide (LDA) was prepared from diisopropylamine (12.4 mL, 92.1 mmol) with n-butyllithium (51.4 mL of a 1.6 M solution in hexane, 82.24 mmol) in 30.0 mL of dry THF at -78°C. The solution was stirred for 30 min. and then a solution of camphor (12.0 g, 78.9 mmol) in dry THF (52.0 mL) was added dropwise. After the addition, the solution was stirred for 2.5 h, treated with freshly distilled aldehyde (79.0 mmol) and stirred for an additional 20 min. the reaction was quenched at -78°C with a saturated aqueous solution of NH₄Cl (200 mL). The cold bath was then removed and the mixture extracted with ethyl ether (3 x 100 mL). The combined organic layers were washed with an aqueous NaCl solution, dried over Na₂SO₄, and concentrated in vacuum to afford the adduct mixture. The products were purified by liquid column chromatography and the adducts ratio obtained was quantified by ¹H-NMR.

3-exo-1-hydroxydecyl-1,7,7-trimethylbicyclo[2.2.1]heptan-2-one. (4)

¹H-NMR: 4.15(1H, s), 3.90(1H, m), 2.04(1H, m), 1.97-1.91 (2H, m), 1.76-1.26 (26H, s), 0.94 (3H, s), 0.91 (3H, s), 0.88(3H, s), 0.85 (3H, s). 

¹³C-NMR: 223.6, 73.30, 59.56, 57.84, 46.01, 36.17, 31.90, 29.61-29.31 (7CH₂), 24.76, 22.67, 21.67, 20.44, 14.05, 9.04. 

Anal. Calcd. for C₂₀H₃₆O₂ ; C, 77.87; H, 11.76. found. C, 77.90; H, 11, 79.

3-endo-1-hydroxydecyl-1,7,7-trimethylbicyclo[2.2.1]heptan-2-one. (5)

¹H-NMR: 3.92(1H, s), 3.74(1H, m), 2.34 (1H, m), 2.10 (1H, s), 1.77-1.69 (2H, m), 1.47-1.39 (4H, m), 1.27(8CH2, s), 0.98(3H, s), 0.92(3H, s), 0.88(3H,s), 0.85(3H, s). 

¹³C-NMR: 223.90, 73.23, 70.89, 65.77, 59.38, 57.76, 54.88, 46.84, 45.86, 36.05, 34.82, 31.52, 29.56, 29.24, 24.67, 20.81, 19.54, 18.53, 15.20, 9.24

INTERPRETATIONS WILL BE UPDATED...............

WATCHOUT

EXO ENDO ,,,UNDERSTAND STEREOCHEMICAL CONSIDERATIONS USING NMR

Endo-exo isomerism is a special type of isomerism found in organic compounds with a substituent on a bridged ring system. The prefix endo is reserved for the isomer with the substituent located closest, or "syn," to the longest bridge. The prefix exo is reserved for the isomer with the substituent located farthest, or "anti", to the longest bridge. Here "longest" and "shortest" refer to the number of atoms that comprise the bridge. This type of molecular geometry is found in norbornane systems such as dicyclopentadiene.

The terms endo and exo are used in a similar sense in discussions of the stereoselectivity in Diels–Alder reactions.

Descriptors of the relative orientation of groups attached to non-bridgehead atoms in a bicyclo[x.y.z]alkane (x ≥ y > z > 0).

If the group is orientated towards the highest numbered bridge (z bridge, e.g. C-7 in example below) it is given the description exo; if it is orientated away from the highest numbered bridge it is given the description endo. If the group is attached to the highest numbered bridge and is orientated towards the lowest numbered bridge (x bridge, e.g. C-2 in example below) it is given the description syn; if the group is orientated away from the lowest numbered bridge it is given the description anti.

• 
  

Cyclopentanes. 

The conformational analysis of substituted cyclopentanes is much more complicated than that of cyclohexanes. 

The energy differences between various envelope and twist conformations in five-membered rings are generally small, and there are as many as ten different envelope and ten different twist conformations, and each conformation has multiple dihedral angle relationships. 

Several of the 20 possible conformations may be populated in an individual structure. Thus the vicinal couplings in 5-membered rings are highly variable. 

For cyclopentanes in envelope conformations J_cis > J_trans in the flat part part of the envelope, whereas in twist conformations the tendency is for J_trans > J_cis. 

In general, no firm assignments of stereochemistry can be made using the size of couplings alone unless a specific substitution pattern or heterocyclic system has been carefully investigated, or if substitution patterns allow prediction of the conformation.

  

  

Inspection of the double Karplus curves indicates a significant difference between the typical behavior of adjacent CH₂ groups in cyclohexanes and cyclopentanes. 

In a chair cyclohexane only one of the four vicinal couplings can be large (> 7 Hz), whereas in a cyclopentane it is common for 2 or even 3 of the ³J couplings to be large.

  

In most cyclopentanes, the C-C-C-C dihedral angles are significantly smaller than the 60° found in cyclohexanes. Cis protons will tend to have H-C-C-H dihedral angles close to 0°, andtrans near 120°. 

The cis couplings (8-10 Hz) are usually larger than trans (2-9 Hz). 

However the Karplus curves for cyclopentane have a region where the cis and trans lines cross (Figure above, at ca 20° dihedral angle), so there are cases where cis and trans couplings are identical (see below, where the allylic proton is a quartet of doublets, arising from accidental equivalence of three vicinal couplings), as well as a smaller region where J_trans > J_cis .

  

  

If the ring puckering is strong enough, then J_trans > J_cis. In bicyclo[2.2.1]heptanes the endo-endo and exo-exo ³J are always greater than endo-exo couplings. 

Thus stereochemical relations among vicinal protons in 5-membered rings cannot be reliably determined by simply measuring coupling constants, except in cases where the substitution pattern of the specific ring system has been carefully investigated. 

For example, in the benzodihydrofurans below, changing the size of the substituent R causes a reversal in the size of J_cis and J_trans.

  



READ'
http://www.unk.edu/uploadedFiles/academics/gradstudies/ssrp/Myers.pdf

AND
http://pubs.acs.org/doi/abs/10.1021/ed068p426?journalCode=jceda8

The ENDO product is the one where the "outside" groups on the diene are on the SAME side of the 6-membered ring as the electron withdrawing group (EWG). The EXO product is the one where the "outside" groups are on the OPPOSITE side of the ring as the 6-membered ring.
Note how the Endo and Exo products are related - they're diastereomers
Here's some examples.








OVERLAPS

Determination of Stereochemistry......Cis Trans Organic Compounds, NMR INSIGHT

Cyclopropanes.

Dihedral angles in cyclopropanes are rigidly fixed by the geometry of the ring system. We therefore find that J_cis (7-10 Hz) is always larger than J_trans (2-6 Hz), and this can be reliably used for structure assignment. The same relationship holds for the 3-membered ring heterocycles, although the range of observed couplings is wider.

  

Cyclobutanes. 

Cyclobutanes are even flatter than cyclopentanes, so that cis couplings are almost always larger (6-9 Hz) than trans (2-8). However, if structural features which promote strong puckering of the ring such as a trans ring fusion, large or electronegative substituents are present, then trans couplings can become larger than cis, as shown for 1,3-dibromocyclobutane and cyclobutanol below.

  





will be updated...............................



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LEARN NMR STEP BY STEP

1..............

Ethyl 3-ethyl-1H-pyrazole-5-carboxylate 

1H NMR (300 MHz, CDCl3): 

δ=1.20 (3H, t), METHYL OF  -CH2-CH3

1.28 (3H, t),  METHYL OF  -C=O-O-CH2-CH3

 2.67 (2H, q), CH2 OF  OF  -CH2-CH3

4.29 (2H, q),  CH2  OF  -C=O-O-CH2-CH3

6.55 (1H, s), LONE PYRAZOLE PROTON ON RING

12.56 (1H, s). NH PROTON

LRMS m/z=167.1 [M-H]+, C8H12N2O2 requires 168.2.

2.......... Ethyl 3-ethyl-1H-pyrazole-5-carboxylic acid 

 δ (DMSOd6): 

1.13 (3H,t), METHYL OF  -CH2-CH3

2.56 (2H,q), CH2 OF-CH2-CH3

6.42 (1H,s).LONE PYRAZOLE PROTON ON RING

VERY EASY..FEELING HAPPY..1H NMR IS EASY

3...........

3-Ethyl-4-nitro-1H-pyrazole-5-carboxylic acid

 δ (DMSOd6): 

1.18 (3H,t), METHYL OF  -CH2-CH3

2.84 (2H,m), CH2  OF  -CH2-CH3

13.72 (1 H,s). NH PROTON

ALERT..........LONE PYRAZOLE PROTON ON RING LOST DUE TO NITRO SUBSTITUTION

4...........

3-Ethyl-4-nitro-1H-pyrazole-5-carboxamide

 δ (DMSOd6): 

1.17 (3H,t), METHYL OF  -CH2-CH3

2.87 (2H,m),CH2 OF  -CH2-CH3

7.40 (1H,s), 

7.60 (1H,s), 

7.90 (1H,s). 

ALL NH AND NH2 SIGNALS

DO IT YOURSELF.............NMR IS EASY

LRMS: m/z 185 (M+l)+.

5...........

5-Ethyl-1-(2-methoxyethyl)-4-nitro-1H-pyrazole-3-carboxamide

m.p.=140° C. Found: C, 44.46; H, 5.79; N, 23.01. C9H14N4O4 requires C, 44.63; H, 5.79; N, 23.14%.

δ (CDCl3): 

1.18 (3H, t), METHYL OF  -CH2-CH3

2.98 (2H, q),CH2 OF  -CH2-CH3

 3.22 (3H, s), METHYL OF -OCH3

3.77 (2H, t), CH2 OF NCH2-CH2-O-CH3

4.28 (2H, q), CH2 OF NCH2 -CH2-O-CH3

6.03 (1H, s), NH2

7.36 (1H, s).NH2

LRMS: m/z=243 (M+1)+

6......

4-Amino-5-ethyl-1-(2-methoxyethyl)-1H-pyrazole-3-carboxamide

 m.p.=131° C. Found: C, 50.75; H, 7.62; N, 26.38. C9H16N4O2 requires C, 50.94; H, 7.55; N, 26.42%.

 δ (CDCl3):

 1.20 (3H, t),

 2.63 (2H, q),

 3.32 (3H, s),

3.74 (2H, t), 

3.95 (2H, s), NH2 OF PYRAZOLE

4.15 (2H, t), 

5.27 (1H, s),C=0-NH2

 6.59 (1H, s).C=O-NH2

NITRO IS CONVERTED TO AMINO....DO IT YOURSELF

LRMS: m/z=213 (M+1)+

7.....................

N-[3-Carbamoyl-5-ethyl-1-(2-methoxyethyl)-1H-pyrazol-4-yl]-2-ethoxy-5-(4-ethyl-1-piperazinyl sulfonyl) nicotinamide.

m.p.=156° C. Found: C, 51.33; H, 6.56; N, 18.36. C23H35N7O6S requires C, 51.40; H, 6.53; N, 18.25%.

δ (CDCl3): 

1.04 (3H, t), METHYL  OF  -N CH2-CH3 ON PIPERAZINE RING

1.22 (3H, t), METHYL OF  -CH2-CH3 ON PYRAZOLE SIDE CHAIN

1.60 (3H, t), METHYL OF  -O-CH2-CH3 ON PYRIMIDINE RING

2.44 (2H, q), CH2  OF  -N CH2-CH3 ON PIPERAZINE RING

2.54 (4H, m), 4H OF -NCH2 ON PIPERAZINE RING BOTH SIDE OF N ATOM

2.96 (2H, q), CH2 OF  -CH2-CH3 ON PYRAZOLE SIDE CHAIN

3.12 (4H, m), 4H OF -NCH2 ON PIPERAZINE RING BOTH SIDE OF N ATOM CLOSE TO SO2 GP

3.36 (3H, s), METHYL OF -OCH3 ON PYRAZOLE SIDE CHAIN

3.81 (2H, t), CH2 OF NCH2-CH2-O-CH3 ON PYRAZOLE SIDECHAIN

4.27 (2H, t), CH2 OF NCH2 -CH2-O-CH3 ON PYRAZOLE SIDECHAIN

4.80(2H, q), CH2 OF O-CH2 CH3 ON PYRIMIDINE RING

5.35(1H, s), C=0--NH2

6.68 (1H, s), C=O-NH2

8.66 (1H, d) ,PYRIMIDINE AROM H .....AWAY/PARA TO C=O-NH -PYRAZOLE GP

 8.86 (1H, d), PYRIMIDINE AROM H .....CLOSER/ORTHO TO C=O-NH -PYRAZOLE GP, reason this signal will shift to delta 9.06 after cyclization in next step ie formation of GISADENAFIL

10.51 (1H, s). NH

LRMS: m/z=539 (M+1)+

FINAL

1-(6-Ethoxy-5-[3-ethyll-6,7-dihydro-2-(2-methoxyethyl)-7-oxo-2H-pyrazole[4,3-d]pyrimidin-5-yl]-3-pyridylsulfonyl)-4-ethylpiperazine•ethyl acetate solvate.

 m.p.=157° C. Found: C, 52.65; H, 6.46; N, 17.76. C23H33N705S. 0.2 C2H5CO2CH3 requires C, 53.21; H, 6.49; N, 18.25%.

δ (CDCl3):
1.07 (3H, t), METHYL  OF  -N CH2-CH3 ON PIPERAZINE RING
1.42 (3H, t),  METHYL OF  -CH2-CH3 ON PYRAZOLE SIDE CHAIN
1.61 (3H, t), METHYL OF  -O-CH2-CH3 ON PYRIMIDINE RING
2.44 (2H, q), CH2  OF  -N CH2-CH3 ON PIPERAZINE RING
2.57 (4H, m),4H OF -NCH2 ON PIPERAZINE RING BOTH SIDE OF N ATOM
3.08 (2H, q), CH2 OF  -CH2-CH3 ON PYRAZOLE SIDE CHAIN
3.15 (4H, m),4H OF -NCH2 ON PIPERAZINE RING BOTH SIDE OF N ATOM CLOSE TO SO2 GP
3.32 (3H, s),METHYL OF -OCH3 ON PYRAZOLE SIDE CHAIN
3.92 (2H, q),  CH2 OF NCH2-CH2-O-CH3 ON PYRAZOLE SIDECHAIN
4.48 (2H, q), CH2 OF NCH2 -CH2-O-CH3 ON PYRAZOLE SIDECHAIN
4.77 (2H, q), CH2 OF O-CH2 CH3 ON PYRIMIDINE RING
8.65 (1H, d), PYRIMIDINE AROM H .....AWAY/PARA TO C=O-NH -PYRAZOLE GP
9.06 (1H, d). PYRIMIDINE AROM H .....CLOSER/ORTHO TO C=O-NH -PYRAZOLE GP, reason this signal will shift from 8,86 delta to  9.06 after cyclization in this step ie formation of GISADENAFIL
The spectrum also has signals that correspond to a solvate with ethyl acetate.

LRMS: m/z=520 (M+1)+