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Файл:Ординатура / Хирургия / Библиотека им академика М.И. Перельмана / Книга_5474_Библиотеки_им_академика_М_И_Перельмана
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1. An aspect of the invention relates to a cost-effective method for the preparation
of 3-amino-2-chloro-4-methyl pyridine of formula (III), which comprises reduc-
tion of 2-chloro-4-methyl-3-nitro pyridine of formula (II) with iron powder, in
the presence of an acid, either organic or inorganic.
2. Another aspect of the invention relates to an alternate method for preparing 3-
amino-2-chloro-4-methyl pyridine, which comprises reduction of 2-chloro-4-
methyl-3-nitro pyridine of formula with sodium dithionite, utilizing an organic
solvent.
3. Another aspect of the invention relates to the use of safer environment-friendly
reagents like a carbonate of an alkali metal as base and an alkyl acetate or an
aromatic hydrocarbon as solvent, for preparation of 2-chloro-N-(2-chloro-4-
methyl-3-pyridinyl)-3-pyridine carboxamide, avoiding the use of hazardous sol-
vents like dioxane and pyridine.
4. Another aspect of the invention relates to preparation of nevirapine, comprising
cyclization of 2-N’-cyclopropylamino-N-(2-chloro-4-methyl-3-pyridinyl)-3-pyridine
carboxamide of formula in the presence of an alkali metal alkoxide and in an
inert organic solvent, followed by neutralization with an acid and isolation of ne-
virapine by crystallization from an organic solvent.
5. Utilization of a single solvent for the preparation of nevirapine, thereby provid-
ing a cost-effective process.
Patent WO 2007/010352 [38] claims to overcome the following shortcomings with
respect to prior art:
– Avoids use of stannic chloride for reduction of the nitro group in the first step
of preparation of 3-amino-2-chloro-4-methyl pyridine.
– Aqueous medium is used during the process of the invention, and use of organic
solvent is avoided during the preparation of 2-chloro-4-methyl-3-amino pyridine,
making the process cost-effective and reducing load on effluent treatment.
– Circumvents utilization of pyridine and dioxane in the second step of prepara-
tion 2-chloro-N-(2-chloro-4-methyl-3-pyridinyl)-3-puridine carboxamide.
– Avoids use of strong bases like sodium hexamethyl disilazane and sodium hy-
dride used in prior art, for preparation of nevirapine, thereby making the pro-
cess safe, cost-effective, and environment-friendly.
– Avoids load on the effluent treatment plant.
– Does not utilize dioxane as solvent, thereby making the process environment-
friendly.
– Provides a process, which utilizes toluene as solvent in Step-II, Step-III, and
Step-IV. The advantages accrued, therefore, would be low inventory of solvents,
easy recovery, and recycling of toluene. These factor, make the process of the
instant invention more cost-effective.
– Provides an API with acceptable limits of impurity profile.
106 Chapter 4 Pharma chemistry/chemical development
WO 2012/168949 A2 [39] claims to use less of expensive cyclopropylamine, if the re-
action is carried out with cheaper bases. The same claim is made in USP 8281025
[40]. Reaction time can also be optimized and it yields higher purity product.
USP 8212025 [40] is a further improvement on earlier processes through reduc-
tion of excessive amounts of cyclopropylamine, if the reaction is carried out in po-
tassium fluoride or trisodium dodecahydrate.
It is interesting to note that Gates Foundation funded an effort [41] to lower ne-
virapine manufacturing cost, even after 40 years. This work resulted in patent WO
2016/118586 A1 [42].
Generally, any cost reduction work, as state d earlier, in any company that is
producing the product would not be funded, due to two reasons: 1) too many com-
panies producing the same API [43]; and 2) extremely low return on investment
(ROI) per site, as shown in Tab. 4.6.
At the time of Gat es funding, nevirapine demand was projected to be around
1,000+ metric ton per year [44]. However, due to better combination of other HIV
drugs, the demand for nevirapine has significantly reduced. In addition, as there are
many nevirapine manufacturing sites [45], the benefits of better process, most likely,
will not be fully realized.
Patent WO 2016/118586 A1 [42] illustrates nevirapine synthesis Fig. 4.8.
Compared to other patents chemistry used in WO 2016/118586 A1 [42] is significantly
improved. However, even with chemistry improvements, productivity of the overall
process can be improved further, if the solvent use could be reduced. This can hap-
pen in different ways and depends on the selected solvent and the equipment used.
Again, since the chemistry could be practiced at many plants, every plant may not
offer this advantage that is offered by WO 2016/118586 A1 [42].
As has been stated earlier, especially in the manufacture of APIs, stoichiometry
and process optimization done on the laboratory scale unlike other fine/specialty
chemicals is the best and, may be, the o nly opportunity for the brand company
commercializing the product. Any drug that gets in the clinical trials can make
CAPIC + CYCLOPROPYLAMINONICOTINATE CYCLOR NEPIRAVINE
CAPIC = 2-chloro-3-amilo-4-picoline
CYCLOR = 2-(cyclopropylamino) nicotinamido-3’-amino-2’=chloro-4’-methylpyridine
Fig. 4.8: Nevirapine synthesis [42].
4.2 Chemical synthesis product/processes/development 107
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optimization a challenge. Generic companies will improve the chemistry to maxi-
mize their profits. They only have to prove the bioequivalence and watch the prod-
uct impurity profile.
All of the above examples suggest that the chemistries developed for every new
API are continuously improved as they transition from brand (patent-protected) syn-
thesis to a generic drug. In addition to chemistry, how their physical properties are
exploited to simplify processing is also important. This combination directly impacts
the product’s manufactured cost. Metformin hydrochloride is used as an illustration
in later chapters.
4.2.3 Chlorosulfonylation reaction
The following is a comparison of two chlorosulfonylation reactions, As suggested
earlier, it is important that developers review the literature and issued patents, as
they develop economic processes. Stoichiometry of two chlorosulfonylation reac-
tions is compared in Tab. 4.11.
USP 7109203 [46] suggests use of acetic acid as a solvent. Unless acetic acid is
used further in any downstream reaction, it will be lost as waste. Use of a re-usable
solvent could be beneficial. This patent uses more-than-needed sulfur dioxide. Un-
reacted sulfur dioxide will have to be neutralized, and its salt would be disposed as
waste. USP 4464537 [14], on the other hand, suggests more economical stoichiome-
try with a reusable solvent. Thus, it is necessary for a laboratory development pro-
cess to con sider the scenario “does the process deve loped in the laboratory has
minimum waste and is economic?”
Review of each of Tab. 4.11 chemistries illustrates that stoichiometry and sol-
vent use in the processes are significantly higher than needed. In USP 4464537 [14],
aqueous phase diazotization (step #1) can be easily controlled at 30–35 °C. A
chloro-hydrocarbon is used as a solvent in the second reaction step. This process
can be a batch or a continuous process. The reaction illustrated in Tab. 4.11 (syn-
thetic route of methyl 2-(chlorosulfonyl) benzoate) [14] has been practiced commer-
cially for the continuous manufacture of saccharin, since the early 1970s.
The same could be done for USP 7109203 [46], and a higher reaction tempera-
ture could accelerate the process. This is definitely feasible with today’sprocess
control technologies and equipment.
It is important to understand and recognize how sociochemicological [28] be-
havior of chemicals can be exploited to simplify manufacturing processes.
The following information, from the 1940s, is to illustrate that chemistry and
manufacturing technologies to produce drugs useful in treating various diseases had a
strong foundation. Process developers were cognizant of yield, quality, toxic and haz-
ardous nature of chemicals, materials of construction, and different unit operations.
108 Chapter 4 Pharma chemistry/chemical development
4.2.4 8-Hydroxyquinoline
Figure 4.9 represents 8-hydroxyquinoline and Figure 4.10 is its synthesis procedure
practiced by I. G. Eiberfeld Wuppertal. German process description and its English
translation are presented.
Tab. 4.11: Example comparing two similar chlorosulfonylation chemistries.
USP [] USP []
4-Bromo-2-chloroaniline
Diazotization
Methyl Anthranilate
Diazotization
Chlorosulfonylation
Mole ratio
Key: amine ..
HCl ..
NaNO
. .
SO
..
Solvent Acetic acid ,-Dichloroethane
CuCl
..
Key: chemical -Bromo--chloroaniline Methyl anthranilate
Properties
Mol. wt .
Melting point (°C) ~
Boiling point (°C)
Reaction product,
MP (°C)
– –
Fig. 4.9: 8-Hydroxyquinoline.
4.2 Chemical synthesis product/processes/development 109
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Fig. 4.10: Hydroxyquinoline synthesis in German.
110 Chapter 4 Pharma chemistry/chemical development
Fig. 4.10 (continued)
4.2 Chemical synthesis product/processes/development 111
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Fig. 4.10 (continued)
112 Chapter 4 Pharma chemistry/chemical development
Fig. 4.10 (continued)
4.2 Chemical synthesis product/processes/development 113
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Synthesis of 8-hydroxyquinoline, Figure 4.9, is a simple reaction between O-
aminophenol and O-nitrophenol. Synthesis developed and commercialized by I. G.
Elberfeld Wuppertal is detailed in FIAT Final Report 940, September 30, 1946 [47].
Figure 4.10 is a copy of the synthesis in German. Its English translation, best effort, is
included. Work illustrated here tells us the extent of chemical technology development
in the era. It is produced by reacting O-aminophenol with O-nitrophenol using glyc-
erin as a solvent, in the presence of 94–96% sulfuric acid with glycerin as a solvent.
The process briefly described in this publication is a reaction of ortho nitrophe-
nol with ortho aminophenol, in the presence of concentrated sulfuric acid, with
glycerin acting as a solvent.
Translation of 8-hydroxyquinoline process
Oxychin 8-hydroxyquinoline (C
9
H
7
ON)
Procedure from I. G. Elberfeld Wuppertal October 1941
Production possibility 1,000 kg per month
Molecular weight 145 MP 72–74 °C soluble in dipropyl ether, benzene, acetone, methanol
According to Skraup’s quinoline sy nthesis, o-amido phenol becomes glycerin conc. sulfuric acid
and o-nitrophenol produced 8-oxyquinoline. The sulfuric acid is neutralized with sodium hydroxide
solution and soda, the oxyquinoline is suctioned off and purified by distillation.
Necessary raw materials
100 kg 8-hydroxyquinoline needs:
57.6 kg o-nitrophenol
229.5 kg glycerin
224 kg sulfuric acid 94–96%
90 kg o-amido phenol
900 kg ICE
600 kg caustic soda
52 kg sodium carbonate
Skraup apparatus (Geb. 18 B)
For production of 8-hydroxyquinoline
500 L reaction vessel with steam jacket reaction vessel
100 L iron measuring vessel with built-in smaller measuring vessel
3 sq. m. aluminum and V2A, and reserve cooler of same type
1,000 L reaction kettle fall boiler?
600 L iron measuring vessel for caustic soda
300 L iron measuring vessel for water
2 m2 Nutsche lined with stones
2,000 L bricked iron template
4 L getro dryers
Enclosed apparatus
1,000 L reaction vessel with steam jacket
1,000 L reaction vessel with water bath
Aluminum cooler 2 sq. m. cooling surface
Aluminum nutsche of 1 meter diameter
1,000 L template
114 Chapter 4 Pharma chemistry/chemical development
Manufacturing:
1) Condensation:
36.3 kg o-nitrophenol
143.4 kg glycerin
155.5 kg sulfuric acid 94–96%
56.25 kg o-amido phenol
36.3 kg o-nitrophenol and 143.4 kg glycerin
These were placed in a reaction kettle and heated to 118–120 °C. Then 12.5 L = 23 kg sulfuric acid
was added, the temperature rising to 130–133 °C. Now o-amido phenol 0.94 kg and sulfuric acid
1.2 L are added alternately 60 times over three hours. The temperature rose to 144–147 °C, and
was achieved by adding longer or faster portions maintained at this temperature. Higher temper-
atures result in lower yields. When everything had been entered, the batch was kept at the boiling
temperature for another 4 h. As a result of the elimination of water, the temperature drops back to
130–133 °C.
2) Processing of the condensation products
600 kg ice
About 300–400 kg of caustic soda
26–27 kg sodium carbonate
600 kg of ice are presented and enough water is added that can be left at rest (approx. 100 L).
While stirring, the portion that has cooled to 40–50 °C is pressed onto the ice and made slightly
acidic with about 300–400 kg of 30% sodium hydroxide solution. The last remainder of the acid is
bound with soda. The reaction must finally be soda alkalin e (mtron alkaline poorly absorbable).
The temperature must not exceed 40 °C, otherwise the precipitated oxyquin (e. p. of pure oxychine:
73 °C) falls out in lumps and includes too much water and soda. The area is vacuumed, washed
with water and vacuumed dry.
3) Distillation
Apparatus:
1 1,000 L iron distillation kettle with direct gas firing and descending iron cooler
2 100 L iron templates with sight glass
1 100 L iron safety templates with water bath (collecting vessel for over sublimated oxyquin)
The distillation cannot be carried out for the time being; the distillate from the iron kettle is not
pure enough, and the small copper distillate in geb. 82 is completely worn out.
Commitment:
2 lots of raw hydroxyquine
Working method:
First, the water is distilled off without vacuum up to an internal temperature of 130 °C. Now, the
vacuum is connected and the oxyquin is distilled at 25 mm between 165 and 180 °C for 7–8 h. The
interior temperature is finally over 360 °C.
Yield 90–100 kg
45–50 kg per batch = 50–56% d. theoretical, based on amido u. nitrophenol = 75–83% of theory th.
only related to amido phenol. About 100 kg of o-amidophenol give 111 kg of 8-oxyquinoline
USP 4044011 [48] suggests the use of acrolein [49], a highly toxic material for the
synthesis of 8-hydroxyquinoline as a solvent. Due to acrolein’s toxicity, most pro-
cess developers, most likely, will use alternate solvents. Use of acrolein, a toxic
4.2 Chemical synthesis product/processes/development 115
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