Modified reaction condition to achieve high yield and cost efficient hazardous free synthesis of Sorafenib API

 

Shiva Rama Krishna Samala¹*, Srinivasa Rao B², Kishore Gokavarapu², Sarita Gokavarapu³, Sunil Gandhi⁴

¹Research and Development Department, Helios Lifesciences Limited, 79 and 100, Industrial Growth Center, Malanpur, District: Bhind, MP–477117.

²Production Department, Helios Lifesciences Limited, 79 and 100, Industrial Growth Center, Malanpur,

District: Bhind, MP–477117.

³QC and ADL Department, Helios Lifesciences Limited, 79 and 100, Industrial Growth Center, Malanpur, District: Bhind, MP–477117.

⁴Chairman, Helios Lifesciences Limited, 79 & 100, Industrial Growth Center, Malanpur,

District: Bhind, MP – 477117

 

ABSTRACT:

The final stage synthesis of Sorafenib API required two key intermediates i.e., methyl-3-(4-aminophenoxy)benzoate (I) and 4-chloro-3-(trifluoromethyl)phenyl isothiocyanate(II), out of these two intermediates (I) is common and (II)is isocyanate intermediate, which is highly hazardous and creates lung problems while handling, to avoid these health, safety and environment issues instead of isocyanate we have used alternate intermediates which are different types of carbamates(III-VI), using these alternate carbamates intermediates synthesized sorafenib API with good yield and purity avoiding hazardous, synthesized these carbamates and final API were characterized by spectral data by ¹H NMR, ¹³CNMR and HRMS.

 

 

 

 

INTRODUCTION:

Cancer is a major public health problem in the world. In 2008,7.6 million people died of cancer (around 13% of all deaths), and this number is projected to increase with an estimated 13.1 million in 2030 [1]. Among the various types of malignant tumors, lung cancer is the most commonly diagnosed cancer, renal cell cancer is the most lethal of all urological cancers, while breast cancer causes.

 

The second leading deaths in women [2–4]. Although chemotherapy is one of the most frequently used forms of cancer therapy, the use of available chemotherapeutics is often limited mainly due to the adverse side effects and resistance of available anticancer agents.

 

 

 

Therefore, searching for new anticancer agents with better activity remains important [5]. Diarylurea derivatives are of great interest due to their broad spectrum of biochemical effects and pharmaceutical functions. In particular, there have been intense research efforts in recent years in the design and development of diarylurea derivatives as a class of antitumor agents [6–8]. There are several diarylurea compounds that have been in clinical trials or clinical use, such as sorafenib, ABT-869, KRN-951 [9–11]. Sorafenib (Nexavar, Fig. 1), a diarylurea derivative, targets the RASRAF-MEK-ERK signaling pathway in numerous cancer cell lines in Vitro. Sorafenib was approved by the U.S. Food and Drug Administration (FDA) for treatment of advanced renal cell carcinoma in 2005 and unresectable hepatocellular carcinoma in 2007. Currently, sorafenib is under investigation in several human malignancies, including lung and breast cancer. However, sorafenib still has poor physicochemical properties and poor therapeutic activity in the treatment of malignant melanoma [10, 11].

 

 

 

 

 

 

 

Sorafenib reported route of synthesis using isocyanate (II) intermediate:

 

 

Experimental Section:

Chemicals and solvents were reagent grade and used without further purification. The ¹H NMR was recorded in the indicated solvent on a Varian 400 MHz spectrometer with Tetramethylsilane (TMS) as internal standard. All chemical shifts (δ) were reported in ppm from internal TMS. Mass spectra were measured on a Jeol JMS D-300 spectrometer. The homogeneity of the compounds was checked using pre-coated plates (E. Merk Kieselgel 60 F₂₅₄).

 

Scheme–1: Carbamates preparation ^(12-16):

 

 

Scheme-1 Synthetic route for the preparation of different carbamates (a-d). Reagents and Conditions:(a) ^(12-13)VII, Phenyl chloroformate, NaHCO₃, DCM: water (8:2) 0^oC-RT, 5hr, 95% (b)^(14-16)III, Methanol, reflux, 3hr, 90% (c)^(14-16) III, Ethanol, reflux, 4hr, 90% (d)^(14-16)III, Iso-propanol, reflux, 8hr, 95%

 

 

 

Scheme–2: Synthesis of Sorafenib using above prepared carbamates ^(17-19):

 

 

Scheme-2, Synthetic route of Sorafenib using carbamates intermediates (III–VI). Reagents and Conditions (e) I, III, DCM, NaHCO₃, RT, 5hr, 90% (f) I, IV, DCM, K₂CO₃, 12hr, 85% (g) I, V, DCM, K₂CO₃, reflux, 5hr, 75% (h) I, VI, DMF, Cs₂CO₃, K₂CO₃, 60^oC, 12hr, 60%

 

 

 

 

 

Brief Procedure:

Phenyl (4-chloro-3-(trifluoromethyl) phenyl) carbamate (III) ^(12-13):

In a clean and Dry RBF charged 4-chloro-3-(trifluoromethyl)aniline followed by mixture of DCM : water and sodium bicarbonate stirred 30min then drop wise addition of phenyl chloroformate at 0-5⁰C then maintained at room temperature around 5hr monitored by TLC extracted with DCM, organic layer dried over Na₂SO₄ concentrated and dried.

 

¹HNMR (DMSO-d6, 400MHz): =9.8 (NH, s, 1H), 7.9 (s, 1H), 7.81 (d, 1H), 7.72 (d, 1H), 7.23-7.49 (m, 5H), ¹³CNMR (DMSO-d6, 100MHz): = 151.3, 150.2, 134.4, 129.2, 128.4, 125.3, 123.1, 121.0, 118.3 MS: m/z, 222.5 (M-OPh).

 

 

 

 

 

Methyl (4-chloro-3-(trifluoromethyl) phenyl) carbamate (IV) ^(14-16):

 

In a clean and Dry RBF charged phenyl-(4-chloro-3-(trifluoromethyl)phenyl)carbamateand methanol refluxed about 3hr monitored reaction conversion by TLC from the reaction mass removed methanol and obtained solid dried under vacuum.

 

¹HNMR (DMSO-d6, 400MHz): =9.8 NH, s, 1H), 7.72 (d, 1H), 7.81 (d, 1H), 3.68 (s, 3H), ¹³CNMR (DMSO-d6, 100MHz): =153.8, 134.3, 129.3, 129.1, 128.5, 123.3, 52.5 MS: m/z, 222.5 (M-OMe).

 

 

Ethyl-(4-chloro-3-(trifluoromethyl)phenyl) carbamate (V) ^(14-16):

In a clean and Dry RBF charged phenyl-(4-chloro-3-(trifluoromethyl)phenyl)carbamateand ethanol refluxed about 4hr monitored reaction conversion by TLC from the reaction mass removed ethanol and obtained solid dried under vacuum.

 

¹HNMR (DMSO-d6, 400MHz): = 7.9 (NH, s, 1H), 7.81 (d, 1H), 7.72 (d, 1H), 4.16 (q, 2H), 1.27 (t, 3H), ¹³CNMR (DMSO-d6, 100MHz): = 160.4,134.3, 129.5, 129.3, 129.1, 128.5, 123.3, 118.8, 61.7, 13.8 MS: m/z 222.5 (M-OEt).

Isopropyl-(4-chloro-3-(trifluoromethyl)phenyl) carbamate (VI) ^(14-16):

In a clean and Dry RBF charged phenyl-(4-chloro-3-(trifluoromethyl)phenyl)carbamateand IPA refluxed about 8hr monitored reaction conversion by TLC from the reaction mass removed IPA and obtained solid dried under vacuum.

 

¹HNMR (DMSO-d6, 400MHz): = 9.98 (NH, s, 1H), 7.97 (s, 1H), 7.81 (d, 1H), 7.72 (d, 1H), 4.77 (sep, 1H), 1.19 (d, 6H), ¹³CNMR (DMSO-d6, 100MHz): =152.3, 134.3, 129.5, 129.3, 129.1, 128.5, 118.8, 71.5, 21.3 MS: m/z 222.5 (M-OiPr).

 

Sorafenib preparation using carbamates (III-VI)^(17-19)

 

In a clean and dry RBF charged (I) in DCM followed by base stirred about 30min then carbamate (III – VI) in DCM added drop wise to above reaction mass maintained mentioned time and temperature poured in ice and cold water extracted with DCM dried over with Na₂SO₄concentrated obtained solid (sorafenib) dried under vacuum.

 

¹HNMR (DMSO-d6, 400MHz): = 8.87 (NH, bs, 1H), 8.48 (NH, bs, 1H), 8.66-8.12 (m, 3H), 7.98-7.81 (m, 3H), 7.61 (NH, q, 1H), 7.38-.6.81 (m, 3H), 2.85 (s, 3H), ¹³CNMR (DMSO-d6, 100MHz): = 164.8, 161.0, 152.9, 151.0, 148.0, 146.2, 135.3, 134.3, 129.5, 129.3, 129.1, 128.5, 123.3, 122.6, 119.4, 109.6, 26.3 MS: m/z 465.5 (M+1).

 

CONCLUSION:

In summary, a new and novel route of synthesis and process optimization of sorafenib API (Active Pharmaceutical Ingredient) using non-hazardous and easy handling intermediates like alkyl carbamates.

 

ACKNOWLEDGMENT:

We gratefully acknowledge the generous support provided by Helios Lifesciences Limited major and special project on Sorafenib API process optimization.

 

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Received on 30.08.2018         Modified on 16.09.2018

Accepted on 28.10.2018         © AJRC All right reserved