New Drug Approvals

Home » 2017 » January

Monthly Archives: January 2017

DRUG APPROVALS BY DR ANTHONY MELVIN CRASTO .....FOR BLOG HOME CLICK HERE

Paypal donate

Blog Stats

  • 1,348,704 hits

Flag and hits

Flag Counter

Enter your email address to follow this blog and receive notifications of new posts by email.

Join 1,822 other followers

Follow New Drug Approvals on WordPress.com

Categories

Flag Counter

ORGANIC SPECTROSCOPY

Read all about Organic Spectroscopy on ORGANIC SPECTROSCOPY INTERNATIONAL 

Enter your email address to follow this blog and receive notifications of new posts by email.

Join 1,822 other followers

DR ANTHONY MELVIN CRASTO Ph.D

DR ANTHONY MELVIN CRASTO Ph.D

DR ANTHONY MELVIN CRASTO, Born in Mumbai in 1964 and graduated from Mumbai University, Completed his Ph.D from ICT, 1991,Matunga, Mumbai, India, in Organic Chemistry, The thesis topic was Synthesis of Novel Pyrethroid Analogues, Currently he is working with GLENMARK PHARMACEUTICALS LTD, Research Centre as Principal Scientist, Process Research (bulk actives) at Mahape, Navi Mumbai, India. Total Industry exp 29 plus yrs, Prior to joining Glenmark, he has worked with major multinationals like Hoechst Marion Roussel, now Sanofi, Searle India Ltd, now RPG lifesciences, etc. He has worked with notable scientists like Dr K Nagarajan, Dr Ralph Stapel, Prof S Seshadri etc, He did custom synthesis for major multinationals in his career like BASF, Novartis, Sanofi, etc., He has worked in Discovery, Natural products, Bulk drugs, Generics, Intermediates, Fine chemicals, Neutraceuticals, GMP, Scaleups, etc, he is now helping millions, has 9 million plus hits on Google on all Organic chemistry websites. His friends call him worlddrugtracker. His New Drug Approvals, Green Chemistry International, All about drugs, Eurekamoments, Organic spectroscopy international, etc in organic chemistry are some most read blogs He has hands on experience in initiation and developing novel routes for drug molecules and implementation them on commercial scale over a 29 year tenure till date Aug 2016, Around 30 plus products in his career. He has good knowledge of IPM, GMP, Regulatory aspects, he has several International patents published worldwide . He has good proficiency in Technology transfer, Spectroscopy, Stereochemistry, Synthesis, Polymorphism etc., He suffered a paralytic stroke/ Acute Transverse mylitis in Dec 2007 and is 90 %Paralysed, He is bound to a wheelchair, this seems to have injected feul in him to help chemists all around the world, he is more active than before and is pushing boundaries, He has 9 million plus hits on Google, 2.5 lakh plus connections on all networking sites, 25 Lakh plus views on dozen plus blogs, He makes himself available to all, contact him on +91 9323115463, email amcrasto@gmail.com, Twitter, @amcrasto , He lives and will die for his family, 90% paralysis cannot kill his soul., Notably he has 13 lakh plus views on New Drug Approvals Blog in 212 countries......https://newdrugapprovals.wordpress.com/ , He appreciates the help he gets from one and all, Friends, Family, Glenmark, Readers, Wellwishers, Doctors, Drug authorities, His Contacts, Physiotherapist, etc

Personal Links

Verified Services

View Full Profile →

Categories

Flag Counter

FDA publishes Final Guideline on GMP for Combination Products


DRUG REGULATORY AFFAIRS INTERNATIONAL

Image result for CGMP for Combination Products.

In the beginning of 2015 the FDA has published a draft guideline about GMP for Combination Products. Now the final version has been published. What are the differences between the draft and the final version of the FDA Guideline for Combination Products?

http://www.gmp-compliance.org/enews_05738_FDA-publishes-Final-Guideline-on-GMP-for-Combination-Products_15649,16021,15963,Z-VM_n.html

In the beginning of 2015 the FDA has published a draft guideline about GMP for Combination Products. Now the final version has been published. What are the differences between the draft and the final version? In the following you will find an overview:

The final guideline has expanded to now 59 pages (draft: 46 pages). And also the number of footnotes increased from 85 (draft) to 147 (final).

In the table of content there are one new subchapter (II B  Quality and Current Good Manufacturing Practice) and one new chapter (VII Glossary). Subchapter III C was expanded to definitions and terminology. In the following the table of content is listed:

I. Introduction

View original post 770 more words

Amtolmetin guacil, амтолметин гуацил , أمتولمتين غواسيل , 呱氨托美丁


Amtolmetin guacil.png

Amtolmetin guacil,

ST-679, MED-15, Eufans

CAS 87344-06-7
UNII: 323A00CRO9, 

Molecular Formula, C24-H24-N2-O5, Molecular Weight, 420.463,

2-Methoxyphenyl 1-methyl-5-p-methylbenzoylpyrrole-2-acetoamidoacetate

Glycine, N-((5-benzoyl-1-methyl-1H-pyrrol-2-yl)acetyl)-, 2-methoxyphenyl ester

Trade names: Amtoril®, Artricol®, Artromed®

US 4578481, US 6288241,

MEDOSAN RICERCA S.R.L. [IT/IT]; Via Cancelliera, 12 I-00040 Cecchina RM (IT) (For All Designated States Except US).
SIGMA-TAU INDUSTRIE FARMACEUTICHE RIUNITE S.P.A. [IT/IT]; Viale Shakespeare, 47 I-00144 Roma (IT)

Launched – 1993 ITALY, SIGMA TAU, Non-Opioid Analgesics FOR Treatment of Osteoarthritis, Treatment of Rheumatoid Arthritis,

  • Originator sigma-tau SpA
  • Class Amino acids; Antipyretics; Nonsteroidal anti-inflammatories; Pyrroles; Small molecules
  • Mechanism of Action Cyclooxygenase inhibitors
    • Marketed Inflammation

    Most Recent Events

    • 01 Jun 1999 A meta-analysis has been added to the adverse events section
    • 22 Jul 1995 Launched for Inflammation in Italy (PO)

Amtolmetin guacil is a NSAID which is a prodrug of tolmetin sodium.

Amtolmetin guacil  is a nonacidic prodrug of tolmetin that has similar nonsteroidal antiinflammatory drug (NSAID) properties to those of Tolmetin with additional gastroprotective advantages. The term “nonsteroidal” is used to distinguish these drugs from steroids that have similar eicosanoid-depressing and antiinflammatory actions. Moreover, it possesses a more potent and long-lasting antiinflammatory activity than tolmetin  and is marketed for the treatment of rheumatoid arthritis, osteoarthritis, and juvenile rheumatoid arthritis.

Background

Tolmetin sodium is an effective NSAID approved and marketed for the treatment of rheumatoid arthritis, osteoarthritis and juvenile rheumatoid arthritis. In humans, tolmetin sodium is absorbed rapidly with peak plasma levels observed 30 min after p.o. administration, but it is also eliminated rapidly with a mean plasma elimination t½ of approximately 1 hr. The preparation of slow release formulations or chemical modification of NSAIDs to form prodrugs has been suggested as a method to reduce the gastrotoxicity of these agents.

Amtolmetin guacil is a non-acidic prodrug of tolmetin, having similar NSAID properties like tolmetin with additional analgesic, antipyretic, and gastro protective properties. Amtolmetin is formed by amidation of tolmetin by glycine

Pharmacology

  • Almost is absorbed on oral administration. It is concentrated maximum in internal the gastric wall, and highest concentration reached in 2 hours after administration.
  • Amtolmetin guacil hydrolysed in to following metabolites Tolmetin, MED5 and Guiacol.
  • Elimination will complete in 24 hours. Happens mostly with urine in shape of gluconides products (77%), faecal (7.5%).
  • It is advised to take the drug on empty stomach.
  • Permanent anti-inflammatory action is continued up to 72 hours, with single administration.

Mechanism of action

Amtolmetin guacil stimulates capsaicin receptors present on gastro intestinal walls, because of presence of vanillic moiety and also releases NO which is gastro protective. It also inhibits prostaglandin synthesis and cyclooxygenase (COX).

Figure

Structure of amtolmetin 1 and tolmetin 2.

26171-23-3 TOLMETIN FREE FORM

http://shodhganga.inflibnet.ac.in/bitstream/10603/2173/11/11_chapter%204.pdf

Tolmetin sodium

64490-92-2
Thumb
  • Average Mass: 279.2663

Image result for tolmetin

26171-23-3 TOLMETIN FREE FORM

1-methyl-5-p-tolylpyrrole-2-acetic acid

Image result for tolmetin

Melting point 155-158 °C, IR (KBr, cm-1): 3205 (OH), 2958 (Aliphatic C-H), 1731 (Acid, C=O), 1700 (C=O), 1616 (C=C), 1267 (C-O); 1H NMR (CD3OD, 400 MHz): δ 7.63 ( d, J = 7.8 Hz, 2H), 7.27 (d, J = 7.8 Hz, 2H), 6.63 (d, J = 3.9 Hz, 1H), 6.11 (d, J = 4.3 Hz, 1H), 3.91 (s, 3H), 3.76 (s, 2H), 2.40 (s, 3H); MS (ESI): m/z calcd for C15H15NO3 (M + H): 258.11; found: (M + H) 257.9. (Fig. 4.12 – 4.14)

str1

str1 str2

Image result for tolmetin

INNTERMEDIATE

str1

1-methyl-5-p-toluoyl-2-acetamidoacetic acid

Melting point: 200-202° C. IR (KBr, cm-1): 3282 (NH), 3060 (OH), 1741 (Acid, C=O), 1637 (Amide, C=O), 1608 (C=C), 1178 (C-N); 1H NMR (CD3OD, 400 MHz): δ 7.64 ( dd, J =6.3 Hz, 1.9 Hz, 2H), 7.28 (d, J = 7.8 Hz, 2H), 6.65 (d, J = 3.9 Hz, 1H), 6.17 (d, J = 3.9 Hz, 1H), 3.92 (s, 3H), 3.73 (s, 2H), 3.30 (t, J =1.4 Hz, 2H), 2.41(s, 3H); MS (ESI): m/z calcd for C17H18N2O4 (M + H): 315.13; found: (M + H) 315. (Fig. 4.20 – 4.22)

str1 str2 str3

SYNTHESIS

str1

STUDENTS SOME COLOUR………………

str1

1H  and 13 C NMR PREDICT

str1 str2 str3 str4

str1 str2 str3

SYNTHESIS

Amtolmetin guacil (CAS NO.: 87344-06-7), with its systematic name of N-((1-Methyl-5-p-toluoylpyrrol-2-yl)acetyl)glycine o-methoxyphenyl ester, could be produced through many synthetic methods.

Following is one of the synthesis routes: 1-Methyl-5-(4-methylbenzoyl)pyrrole-2-acetic acid (I) is condensed with glycine ethyl ester (II) in the presence of carbonyldiimidazole (CDI) and triethylamine in THF to afford the corresponding acetamidoacetate (III), which is hydrolyzed with NaOH in THF-water yielding 2-[2-[1-methyl-5-(4-methylbenzoyl)pyrrol-2-yl]acetamido]acetic acid (IV). Finally, this compound is esterified with 2-methoxyphenol (guayacol) (V) by means of CDI in hot THF.

Image result for Amtolmetin

PATENT

https://www.google.com/patents/WO1999033797A1?cl=tr

The present invention relates to a new crystalline form of 1- methyl-5-p-toluoylpyrrole-2-acetamidoacetic acid guaiacyl ester, a process for its preparation and to pharmaceutical compositions endowed with antiinflammatory, analgesic and antipyretic activity containing same.

The ester of 1-methyl-5-p-toluoylpyrrole-2-acetamidoacetic acid (hereinafter referred to as MED 15, form 1) is a known compound.

In fact, US Patent 4,882,349 discloses a class of N-mono- substituted and N,N-disubstituted amides of l-methyl-5-p- toluoylpyrrole-2-acetic acid (known as Tolmetin) endowed of anti- inflammatory, analgesic, antipyretic, antisecretive and antitussive properties.

US Patent 4,578,481 claims a specific compound, endowed with valuable pharmacological activity, encompassed in the above- mentioned class, precisely 1-methyl-5-p-toluoylpyrrole-2-acetamido- acetic acid guaiacyl ester (which is MED 15, form 1), and a process for its preparation.

The process disclosed in US 4,578,481 presents some drawbacks, since it is not easily applicable on industrial scale and gives low yields.

According to the above-mentioned process, Tolmetin was reacted with N,N’-carbonyldiimidazole in tetrahydrofuran (THF), and aminoacetic acid ethyl ester hydrochloride was added to the reaction mixture.

Following a complex series of washings in order to remove the unreacted starting compounds, and crystallisation from benzene/ cyclohexane, 1-methyl-5-p-toluoylpyrrole-2-acetamidoace-tic acid ethyl ester was obtained. This compound was subsequently transformed into the corresponding acid.

The acid was reacted with N,N’-carbonyldiimidazole obtaining the corresponding imidazolide, to which a solution of guaiacol in

THF was added.

From the reaction mixture, following several washings, neutralisation and crystallisation from benzene/ cyclohexane MED 15 form 1 was obtained.

The main physico-chemical characteristics of MED 15 form 1 are shown in table 1, left column.

The above mentioned process comprises the following steps:

(a) hydrolysing TOLMETIN 1 methyl ester with an alkaline hydroxide in a basic environment, obtaining TOLMETIN 2 alkaline salt;

(b) condensing 2 with isobutylchloroformate 3 obtaining the mixed anhydride 4;

(c) reacting 4 with glycine 5 obtaining 1-methyl-5-p-toluoylpyrrol-2- acetoamidacetic acid 6;

(d) condensing 6 with isobutylchloroformate 3 obtaining the mixed anhydride 7; and

(e) reacting the mixed anhydride 7 with guaiacol 8 obtaining 9 , MED 15, form 2.

The following non-limiting example illustrates the preparation of MED 15, form 2, according to the process of the present invention.

Preparation of 1-methyl-p-toluoylpirrol-2-acetoammidoacetic acid.

A mixture of 500 mL of toluene, 100 g of Tolmetin ethyl ester and 10 g of Terre deco in 1L flask, was heated to 70° C and maintained at this temperature for 20-30 min, under stirring. The mixture was then filtered on pre-heated buckner, and the solid phase washed with 50 mL of heated toluene. The discoloured toluene solution was transferred in a 2 L flask, 15 g of sodium hydroxide (97%) dissolved in 100 mL of water were added thereto.

The solution was heated at reflux temperature and refluxed for 1 hour. 22 mL of isobutyl alcohol were added to the solution which was heated at reflux temperature; water (about 120 mL) was removed completely with Marcusson’s apparatus arriving up to 104-105°C inner temperature.

To a suspension of Tolmetin sodium, cooled under nitrogen atmosphere to -5°C ± 2°C, 0.2 mL of N-methyl Morpholine were added. Maintaining the temperature at 0°C ± 3°C, 53 mL of isobutyl chloroformate were added dropwise in 5-10 min. After about 1 hour the suspension became fluid. Following 3 hours of reaction at 0°C + 3°C, over the glycine solution previously prepared, the mixed anhydride solution was added dropwise. The glycine solution was prepared in a flask containing 230 mL of demineralised water, 47 g of potassium hydrate (90%), cooling the solution to 20°C ± 2, adding 60 g of glycine, and again cooling to 10°C ± 2°C.

To the glycine solution, the mixed anhydride was added dropwise under stirring, in 5-10 min., maintaining the temperature at 20°C ± 2°C.

At the end of the addition, temperature was left to rise to room temperature, 1 hour later the reaction was complete. To the mixture 325 mL of demineralised water were added, the mixture was brought to pH 6.0 +2 using diluted (16%) hydrochloric acid (about 100 mL).

The temperature of the solution was brought to 73°C ±2°C and the pH adjusted to pH 5.0 ±0.2.

The separation of the two phases was made at hot temperature: the toluene phase was set aside for recovering acid-Tolmetin if any, the water phase was maintained at 73°C ±2°C and brought to pH 4.0 ±0.2 using diluted hydrochloric acid.

At the beginning of the precipitation the solution was slowly brought to pH 3.0 ±0.2 using diluted (16%) hydrochloric acid (100 mL).

The mixture was cooled to 15°C ±3°C and after 30 min. filtered. The solid cake was washed with 2×100 mL of demineralised water, the product was dried at 60°C under vacuum till constant weight. 100 g of 1-methyl-p-toluoylpirrol-2-acetoammidoacetic acid were obtained.

Preparation of MED 15, form 2

To a 2 L flask containing 730 mL of toluene, 100 g of dried compound of the above step were dissolved. To this solution 18.8 g of potassium hydrate (tit. 90%) in 65 mL of water were added.

The solution was dried maintaining the internal temperature at 95-100°C, and cooled to 55-60 °C. A solution of potassium hydrogen carbonate was then added and the resulting mixture was dried maintaining the internal temperature at 105°C ±2°C.

The mixture was cooled under nitrogen atmosphere to 5°C

±2°C, 24 mL of isobutyl alcohol and 0.3 mL of N-methyl morpholine were added thereto.

Maintaining the temperature at 10°C ±3°C, 47 mL of isobutyl-chloroformate were added dropwise in 5-10 minutes. The mixture was left to react for two hours at 10°C ±3°C obtaining an anhydride solution, which was added to a guaiacol solution previously prepared.

The guaiacol solution was prepared by loading in a 2L-flask 295 mL of water, 25 g of potassium hydrate (90%), and 0.3 g of sodium metabisulfite.

At the end of the loading the temperature was brought to 35-40°C.

The anhydride was added dropwise in 5- 10 min and the temperature was left to rise to room temperature.

The suspension was kept under stirring for 1 hour and brought to pH 6.0 ±0.5 with diluted hydrochloric acid. The suspension was heated to 70°C ± 5°C and maintained at pH 3-4 with diluted hydrochloric acid.

The phases were separated while hot. The aqueous phase was discharged, and to the organic phase, 250 mL of water were added.

Maintaining the temperature at 70 ±5°C the solution was brought to pH 8.0 ±0.5 with diluted sodium hydrate, the phases were separated while hot and the acqueous phase was discharged.

The organic phase was washed with 250 mL of water. At 70 ± 5°C the phases were separated. The toluene phase was then cleared with dicalite, filtered and left to crystallise.

The mixture was slowly cooled to 30°C – 35°C, the temperature was then brought to 10 ± 3°C and after 1 hour filtered, washed with toluene (2×100 mL).

The product was brought to dryness at 60°C under vacuum, thus giving 100 g of compound MED 15, form 2.

Theoretical yield: 133.7 g; Yield %: 74.8%.

PATENT

https://www.google.com/patents/WO2000032188A2?cl=un

PATENT

CN-100390144 

PATENT

CN 1827597

Example 1: Steps:

Equipped with a trap, 2000ml four-neck reaction flask with a mechanical stirrer and a thermometer, 加入托 US buna 100.0g (0.358mol) and 500ml of toluene, turned stirred and heated under reflux with toluene with water, drying the solution, when When the internal temperature reaches 95-100 ℃, the solution was cooled to 55-60 ℃, dissolved in 30ml of water was added portionwise 11.5g of potassium bicarbonate was added, and refluxed to remove water, until the internal temperature reaches 105 ± 2 ℃. The mixture was cooled to ice-water bath 5 ± 2 ℃, to which was added 24ml of isobutyl alcohol and 0.3ml N- methylmorpholine. The temperature was maintained at 10 ± 3 ℃, with a pressure-equalizing dropping funnel was added dropwise isobutylchloroformate 45.5ml (0.400mol), 10min addition was complete, so the mixture was 10 ± 3 ℃ 2hr reaction solution to obtain an acid anhydride, it has been prepared dropwise glycine guaiacol ester solution, 5-10min the addition was complete. Glycine guaiacol ester solution was prepared by adding 295ml of water in a 2000ml flask, 27g of potassium hydroxide (82%) and 0.3g of sodium metabisulfite, stirring to dissolve, the temperature was controlled at 10 ± 3 ℃, to which was added 82.7g (0.38mol) glycine guaiacol ester hydrochloride and prepared. Dropwise addition, the temperature was raised to room temperature, the reaction 2hr, diluted with 16% hydrochloric acid to adjust the mixture to pH 6.0 ± 0.5. The suspension was heated to 70 ± 5 ℃, and then 16% diluted hydrochloric acid to adjust the pH to 3.5 to 4.5, while hot liquid separation, discarding the aqueous phase, the organic phase was added to 250ml of water, maintaining the temperature at 70 ± 5 ℃ with dilute (2N) sodium hydroxide solution to adjust the solution to pH 8.0 ± 0.5, and then hot liquid separation, aqueous phase was discarded. With 2 × 250ml The organic phase was washed with water, the phases were separated at 70 ± 5 ℃, then clean the toluene organic phase through celite, cooled to room temperature, allowed to set freezer cooling crystallization, filtration, filter cake washed with 2 × 50ml of cold washed with toluene, and dried in vacuo at 60 ℃ to constant weight to give 1- methyl-5-p-toluoylpyrrole-2-acetamido acid guaiacol ester crude 135.5 g, yield 90%. The crude product was recrystallized from acetone to give 1-methyl-5-acyl-2-acetyl-p-toluene amino acid ester of guaiacol boutique 127.9 g, yield 94.4%, mp128.7 ~ 131.9 ℃. Elemental analysis: C, 68.53%; H, 5.76%; N, 6.65%. IR spectrum (KBr tablet method): 3318,3142,2963,1778,1652,1626,1605,1500,1480,1456,13731255 and 1153cm-1.

Example 2: Procedure: equipped with a water separator, 2000ml four-neck reaction flask with a mechanical stirrer and a thermometer, 加入托 US buna 100.0g (0.358mol) and 500ml of toluene, turned stirred and heated under reflux with toluene with water , drying the solution, when the internal temperature reaches 95-100 ℃, the solution was cooled to 55-60 ℃, dissolved in 30ml of water was added portionwise 11.5g of potassium bicarbonate was added, and refluxed to remove water, until the internal temperature reaches 105 ± 2 ℃. The mixture was cooled to ice-water bath 5 ± 2 ℃, to which was added 24ml of isobutyl alcohol and 0.3ml N- methylmorpholine. The temperature was maintained at 10 ± 3 ℃, with a pressure-equalizing dropping funnel dropwise isopropyl 46.5ml (0.41mol), 10-15min addition was complete, the mixture was allowed at 10 ± 3 ℃ reaction 2hr derived anhydride solution, it would have been prepared dropwise to glycine guaiacol ester solution, 5-10min the addition was complete. Glycine guaiacol ester solution was prepared by adding 295ml of water in a 2000ml flask, 27g of potassium hydroxide (82%) and 0.3g of sodium metabisulfite, stirring to dissolve, the temperature was controlled at 10 ± 3 ℃, to which was added 82.7g (0.38mol) glycine guaiacol ester hydrochloride and prepared. Dropwise addition, the temperature was raised to room temperature, the reaction 2hr, diluted with 16% hydrochloric acid to adjust the mixture to pH 6.0 ± 0.5. The suspension was heated to 70 ± 5 ℃, and then 16% diluted hydrochloric acid to adjust the pH to 3.5 to 4.5, while hot liquid separation, discarding the aqueous phase, the organic phase was added to 250ml of water, maintaining the temperature at 70 ± 5 ℃ with dilute (2N) sodium hydroxide solution to adjust the solution to pH 8.0 ± 0.5, and then hot liquid separation, aqueous phase was discarded. With 2 × 250ml The organic phase was washed with water, the phases were separated at 70 ± 5 ℃, then clean the toluene organic phase through celite, cooled to room temperature, allowed to set freezer cooling crystallization, filtration, filter cake washed with 2 × 50ml of cold washed with toluene, and dried in vacuo at 60 ℃ to constant weight to give 1- methyl-5-p-toluoylpyrrole-2-acetamido acid guaiacol ester crude 138.5 g, yield 92%. The crude product was recrystallized from acetone to give 1-methyl-2-acyl-5-toluene acetaminophen acid ester guaiacol boutique 128.8 grams.

Example 3: equipped trap, 2000ml four-neck reaction flask with a mechanical stirrer and a thermometer, 加入托 US buna 100.0g (0.358mol) and 500ml of toluene, turned stirred and heated under reflux with toluene with water, dried solution, when the internal temperature reaches 95-100 ℃, the solution was cooled to 55-60 ℃, dissolved in 30ml of water was added portionwise 10-12.5g potassium bicarbonate solution, refluxing was continued for removal of water, until the internal temperature reaches 105 ± 2 ℃. The mixture was cooled to ice-water bath 5 ± 2 ℃, added thereto 20-30ml of isobutyl alcohol 0.2-0.5mlN- methylmorpholine. The temperature was maintained at 10 ± 3 ℃, with a pressure-equalizing dropping funnel was added dropwise isobutylchloroformate 40.5-48.5ml, 10-15min addition was complete, so the mixture was 10 ± 3 ℃ 2hr reaction solution to obtain an acid anhydride, it has been prepared dropwise glycine guaiacol ester solution, 5-10min the addition was complete. Glycine guaiacol ester solution was prepared by adding 295ml of water in a 2000ml flask, 25-30g of potassium hydroxide (82%) or 15-17 grams of sodium hydroxide and sodium metabisulfite 0.2-0.5g or insurance powder, stirring to dissolve the temperature is controlled at 10 ± 3 ℃, to which is added 80-84g glycine guaiacol ester hydrochloride and prepared. Dropwise addition, the temperature was raised to room temperature, the reaction 2hr, the mixture was adjusted with dilute hydrochloric acid to pH 6.0 ± 0.5. The suspension was heated to 70 ± 5 ℃, with dilute hydrochloric acid to adjust the pH to 3.5 to 4.5, while hot liquid separation, discarding the aqueous phase, the organic phase was added to 250-280ml of water, maintaining the temperature at 70 ± 5 ℃ , adjusted with dilute sodium hydroxide solution and the solution to pH 8.0 ± 0.5, and then hot liquid separation, aqueous phase was discarded. With 2 × 250ml The organic phase was washed with water, the phases were separated at 70 ± 5 ℃, then clean the toluene organic phase through celite, cooled to room temperature, allowed to set freezer cooling crystallization, filtration, filter cake washed with 2 × 50ml of cold washed with toluene, and dried in vacuo at 60 ℃ to constant weight to give 1- methyl-5-p-toluoylpyrrole-2-acetamido acid guaiacol ester crude 130-139 grams. The crude product was recrystallized from acetone to give 1-methyl-5-acyl-2-acetyl-p-toluene amino acid ester boutique guaiacol 120-129 grams.

PATENT

Indian Pat. Appl. (2010), IN 2008MU01617

str1

DETAILED DESCRIPTION OF THE INVENTION
The present invention provides safe, environment friendly, economically viable and commercially feasible processes for the production of Amtolmetin guacil. There are two methods for the preparation of Amtolmetin guacil. The processes for the production of Amtolmetin guacil (I) comprise:
Method-1:
Step-A:- Treating 2-methoxy phenol of Formula VI with 2-(benzyloxycarbonylamino) acetic acid of Formula VII in the presence of an organic base and a condensing agent in chlorinated solvent to yield 2-methoxyphenyl-2- (benzyloxycarbonylamino) acetate of Formula V.
Step-B:- Acid addition salt of 2-methoxyphenyl -2-aminoacetate of Formula II may be prepared by treating 2-methoxyphenyl-2- (benzyloxycarbonylamino) acetate of Formula V with an acid and followed by crystallization in aprotic solvent.
7

Step-C):- l-methyl-5-p-toluoylpyrrole-2-acetic acid of Formula III is reacted with a condensing agent to form-activated moiety, which is reacted with acid addition salt of 2-methoxyphenyl -2-aminoacetate of Formula II in chlorinated solvent to produce Arntolmetin guacil of formula (I).
In a preferred embodiment of present invention, condensing agent used in step-A is selected from group consisting of dicyclohexylcarbodiimide, N, N’-carbonyl diimidazole, hydroxy benzotriazole. The most preferred condensing agent is Dicyclohexyl carbodiimide for the reaction.
The solvent used in present invention is selected from the group consisting of but not limited to toluene, methylene chloride, chloroform, water miscible ethers such as tetrahydrofuran, 1,4-dioxane, the most preferred solvent for the reaction methylene dichloride.
In another embodiment of the present invention, the reaction is performed in the presence of an organic base. The organic base is selected from the group consisting of trimethylamine, triethylamine, N-methyl morpholine, N-methylpyrrolidinone, 4-dimethyl Aminopyridine; the most preferred base is 4-dimethyl Aminopyridine.
In a preferred embodiment of present invention, the non-polar solvent used in step-B is selected from group consisting of ethers, hexanes, aromatic hydrocarbons and esters.
In another preferred embodiment of present invention, the most suitable solvents are esters.
In another preferred embodiment of present invention, condensing agent used in step-C is selected from group consisting of dicyclohexylcarbodiimide, N, N’-carbonyl diimidazole, hydroxy benzotriazole. The most preferred condensing agent is N, N’-carbonyl diimidazole for the conversion of the reaction.
8

The solvent used in present invention is selected from the group consisting of but not limited to toluene, methylene chloride, chloroform, water miscible ethers such as tetrahydrofuran, 1,4-dioxane, the most preferred solvent for the reaction methylene dichloride.
In yet another embodiment of the present invention, the reaction is performed at a temperature in the range of -20°C to 50°C. Most preferred temperature range for the reaction is (-) 10°C to 0°C.
Method-2:
Treating 2-(2-(I-methyl-5- (4-methylbenzoyl)-lH-pyrrol-2-yl) acetamido) acetic acid with 2-methoxy phenol in presence of condensing reagent and an organic base to obtain Amtolmetin guacil.
In a preferred embodiment of present invention, the condensing agent used is selected from group consisting of dicyclohexyicarbodiimide, hydroxy benzotriazole or a mixture thereof. The most preferred condensing agent is Dicvclohexyl carbodiimide for the aforementioned reaction.
The solvent used in present invention is selected from the group consisting of but not limited to toluene, methylene chloride, chloroform, water miscible ethers such as tetrahydrofuran. 1,4-dioxane, the most preferred solvent for the reaction is methylene dichloride.
In another embodiment of the present invention, the reaction is performed in the presence of an organic base. The organic base is selected from the group consisting of triethylamine, triethylamine, N-methyl morpholine, N-methylpyrrolidinone, 4-dimethyl Aminopyridine; the most preferred base is 4-dimethyl Aminopyridine.
9

In yet another embodiment of the present invention, the reaction is performed at a temperature in the range of -20°C to 50°C. Most preferred temperature range for the reaction is (-) 10°C to 0°C.
In another embodiment of present invention, crude amtolmetin guacil is directly purified using polar and non-polar solvent or a mixture thereof. The most preferred solvents are Isopropanol and toluene.
The following non-limiting examples illustrate specific embodiments of the present invention. They are, however, not intended to be limiting the scope of present invention in anyway.
Preparation of Amtolmetin guacil: Example-1;
Charged MDC (600 ml) and N-benzyloxycarbonyl glycine (100 gm) in a 2L-4NRBF under N2 atmosphere. Reaction mass was cooled down to -5°C. Added N, N’-dicyclohexylcarbodiimide solution (108.5 gm in 300 ml MDC) at-5°C to 0°C. Maintained temperature of reaction for 10 minutes at -5°C to 0°C. Added guaiacol solution (59.36 gm in 180 ml MDC) at -5°C to 0°C followed by addition of N, N-dimethyl aminopyridine (1 gm) at -5°C to 0°C. Monitored the reaction over TLC till the completion of reaction, while maintaining reaction at 0°C. Filtered the undissolved Dicyclohexyl urea and washed the solids with methylene dichloride (125 ml X 2). Collected filtrate and washing. Washed methylene dichloride with water (1000 ml X 2), lN-NaOH (500 ml X 2) and 1% HC1 solution (500 ml X 2), water (500 ml X 2) respectively. Organic methylene dichloride layer was dried over anhydrous sodium sulphate. Filtered sodium sulphate and collected methylene dichloride filtrate. Distilled out methylene dichloride under vacuum below 40°C to get oil. HPLC purity :> 90%
10

Added 33% HBr in acetic acid solution (262,5 gm) into reaction vessel at 25-30°C. Monitored the reaction over TLC till the completion of reaction, while maintaining the reaction at 25-30°C. Added ethyl acetate (1200 ml) slowly at 25-30°C after completion of reaction. Stirred the resultant slurry for 2.5 hours at 25-30°C for complete crystallization. Filtered the solids and washed it with ethyl acetate (200 ml). Dried solids at 50-55°C. Dry weight: 102 gm. HPLC Purity: >98%
Example-2:
Charged MDC (1400 ml) and N, N’-carbonyl di imidazole (69.34 gm) into a 3L-4NRBF under N2 atmosphere. Cooled it down to -15°C. Charged Tolmetin acid (100 gm) slowly into reaction vessel at -10° ± 5°C. Monitored the progress of reaction of over HPLC. After completion of reaction, charged slowly 2-methoxyphenyl-2- (benzyloxy carbonylamino) acetate hydrobromide salt (112.05 gm) at -10° ± 5°C.Monitored the reaction over HPLC. After completion of reaction, washed the organic layer with water (300 ml), 1% NaOH solution (100 ml) and water (300 ml X 2) respectively at 3-8°C. Treated organic layer with activated carbon (2.5 gm) and filtered over hyflow bed. Washed hyflow bed with methylene dichlonde (100 ml X 2). Distilled out methylene dichloride below 40°C under vacuum and stripped off traces with toluene (100 ml X 2) at 50-55°C. Charged toluene (600 ml) and Isopropanol (50ml). Heated the mass to 63-68°C. Stirred the clear solution at 63-68°C for 1 hour. Cooled it down slowly to 30°C followed by further cooling to 5°C. Stirred the resultant slurry for 3 hours at 0-5°C. Filtered solids and washed with toluene (100 ml X 2). Dried solids at 55-60°C under vacuum. Dry Weight: 130 gm. HPLC Purity: >99%
Example-3:
Charged MDC (333 liter) and 2-(2-(l-methyl-5- (4-methylbenzoyl)-lH-pyrrol-2-yl) acetamido) acetic acid (55.5 Kg) in reactor under N2 atmosphere at 25-30°C. Cool down reaction mass to -15 to -12°C. Added a freshly prepared solution of N, N’-dicyclohexyl
11

carbodiimide (47.39 Kg in 166.5 liter) slowly at -10° ± 5°C within 1 hour. Rinsed the addition funnel with MDC (55.5 liter) and added it to the reaction at -10° ± 5°C. Added guaiacol solution (24.14 Kg in 99.9 liter MDC) to the reaction mass at -10° ± 5°C within 1 hour. Rinsed the addition funnel with MDC (11.1 liter) and added to the reaction -10° ± 5°C. Charged N, N’-dimethyl aminopyridine (0.555 Kg) at -15°C. Maintained temperature of reaction mass at -10° ± 5°C for 3 hours. Monitored the reaction over TLC, After the completion of reaction, filtered the dicyclohexyl urea and washed the solids with MDC (55.5L X 2). Collected MDC filtrate and wash it with water (166.5 L X 2). Collected MDC layer and treated it with activated carbon (2.77 Kg) and filtered through sparkler. Washed the sparkler with MDC (111 L). Distilled out MDC below 40°C under vacuum and stripped off traces with toluene (55.5 L X 2) at 50-55°C. Charge toluene (333L) and Isopropanol (27.75 L). Heated reaction mass to 63-68°C to get a clear solution. Stirred the clear solution at 63-68°C for 1 hour. Cooled it down slowly to 30°C followed by further cooling to 20oC. Stirred the resultant slurry for 2 hours at 17-20°C. Filtered the solids and washed with toluene (55.5 L X 3). Dried the solids at 55-60°C under vacuum. Dry Weight: 48 Kg. HPLC Purity:>99%

PAPER

Synthesis and Process Optimization of Amtolmetin: An Antiinflammatory Agent

Center of Excellence, Integrated Product Development, Innovation Plaza, Dr. Reddy’s Laboratories Ltd., Bachupalli, Qutubullapur, R. R. Dist. 500 072 Andhra Pradesh, India, and Center for Environment, Institute of Science and Technology, Jawaharlal Nehru Technological University, Kukatpally, Hyderabad 500 072, India
Org. Process Res. Dev., 2010, 14 (2), pp 362–368
DOI: 10.1021/op900284w,

http://pubs.acs.org/doi/full/10.1021/op900284w

†DRL-IPD Communication number: IPDO IPM – 00202
, * Corresponding author. Telephone: +91 40 44346430. Fax: +91 40 44346164. E-mail:rakeshwarb@drreddys.com.,
‡Dr. Reddy’s Laboratories Ltd.
, §Jawaharlal Nehru Technological University.

Abstract

Abstract Image

Efforts toward the synthesis and process optimization of amtolmetin guacil 1 are described. High-yielding electrophilic substitution followed by Wolf−Kishner reduction are the key features in the novel synthesis of tolmetin 2 which is an advanced intermediate of 1.

Amtolmetin guacil
Amtolmetin guacil.png
Clinical data
ATC code none
Identifiers
Synonyms ST-679
CAS Number 87344-06-7 
PubChem (CID) 65655
ChemSpider 59091 Yes
UNII 323A00CRO9 
KEGG D07453 Yes
ChEMBL CHEMBL1766570 
ECHA InfoCard 100.207.038
Chemical and physical data
Formula C24H24N2O5
Molar mass 420.458 g/mol
3D model (Jmol) Interactive image
Amtolmetin Guacil
CAS Registry Number: 87344-06-7
CAS Name: N-[[1-Methyl-5-(4-methylbenzoyl)-1H-pyrrol-2-yl]acetyl]glycine 2-methoxyphenyl ester
Additional Names: N-[(1-methyl-5-p-toluoylpyrrol-2-yl)acetyl]glycine o-methoxyphenyl ester; 1-methyl-5-p-toluoylpyrrole-2-acetamidoacetic acid guaicil ester
Manufacturers’ Codes: ST-679; MED-15
Trademarks: Eufans (Sigma-Tau)
Molecular Formula: C24H24N2O5
Molecular Weight: 420.46
Percent Composition: C 68.56%, H 5.75%, N 6.66%, O 19.03%
Literature References: Ester prodrug of tolmetin, q.v. Prepn: A. Baglioni, BE 896018; idem, US 4578481 (1983, 1986 both to Sigma-Tau). Pharmacology: E. Arrigoni-Martelli, Drugs Exp. Clin. Res. 16, 63 (1990); A. Caruso et al., ibid. 18, 481 (1992). HPLC determn in plasma: A. Mancinelli et al., J. Chromatogr. 553, 81 (1991). Series of articles on pharmacokinetics and clinical trials:Clin. Ter. 142 (1 pt 2) 3-59 (1993).
Properties: Crystals from cyclohexane-benzene, mp 117-120°. Sol in common organic solvents. LD50 in male mice, rats (mg/kg): 1370, 1100 i.p.; >1500, 1450 orally (Baglioni).
Melting point: mp 117-120°
Toxicity data: LD50 in male mice, rats (mg/kg): 1370, 1100 i.p.; >1500, 1450 orally (Baglioni)
Therap-Cat: Analgesic; anti-inflammatory.
Keywords: Analgesic (Non-Narcotic); Anti-inflammatory (Nonsteroidal); Arylacetic Acid Derivatives.

“ALL FOR DRUGS” CATERS TO EDUCATION GLOBALLY, No commercial exploits are done or advertisements added by me. This article is a compilation for educational purposes only.

P.S. : The views expressed are my personal and in no-way suggest the views of the professional body or the company that I represent

/////////Amtolmetin guacil, ST-679, MED-15, Eufans,  87344-06-7, Amtoril®, Artricol®, Artromed®, амтолметин гуацил أمتولمتين غواسيل , 呱氨托美丁

n1(c(ccc1CC(NCC(=O)Oc1c(cccc1)OC)=O)C(=O)c1ccc(cc1)C)C

Towards automation of chemical process route selection based on data mining


ORGANIC CHEMISTRY SELECT

Graphical abstract: Towards automation of chemical process route selection based on data mining

A methodology for chemical routes development and evaluation on the basis of data-mining is presented. A section of the Reaxys database was converted into a network, which was used to plan hypothetical synthesis routes to convert a bio-waste feedstock, limonene, to a bulk intermediate, benzoic acid. The route evaluation considered process conditions and used multiple indicators, including exergy, E-factor, solvent score, reaction reliability and route redox efficiency, in a multi-criteria environmental sustainability evaluation. The proposed methodology is the first route evaluation based on data mining, explicitly using reaction conditions, and is amenable to full automation.

In the field of process and synthetic chemistry ‘clean synthesis’ has become one of the standard criteria for good, commercially viable synthesis routes. As a result synthetic and process chemists must be equipped with adequate methodologies for quantification of ‘cleanness’ or ‘greenness’ of alternative routes at the early phases of the development cycle. These…

View original post 1,252 more words

SL65.0102-10


str1

str1SCHEMBL7433792.png

CAS 186348-69-6

1,4-Benzodioxin-5-carboxamide, 8-amino-7-chloro-N-(1,4-diazabicyclo[2.2.2]oct-2-ylmethyl)-2,3-dihydro-, (-)-

MW, 352.82, C16 H21 Cl N4 O3
US5663173 (A)  –  N-[(1,4-diazabicyclo[2.2.2] oct-2-yl)methyl] benzamide derivatives, their preparations and their application in therapeutics

str1

SL65.0102-10

(-)-1,4-benzodioxin-5-carboxamide-8-amino-7-chloro-N-(1,4-diazabicyclo[2.2.2]oct-2- ylmethyl)-2,3-dihydro-, hydrochloride

1,4-Benzodioxin-5-carboxamide, 8-amino-7-chloro-N-(1,4-diazabicyclo[2.2.2]oct-2-ylmethyl)-2,3-dihydro-, hydrochloride (1:2), (-)-
1,4-Benzodioxin-5-carboxamide, 8-amino-7-chloro-N-(1,4-diazabicyclo[2.2.2]oct-2-ylmethyl)-2,3-dihydro-, dihydrochloride, (-)-
Dihydrochloride (-) – 8-Amino-7-chloro- N – [(1,4-diazabicyclo [2.2.2] oct-2-yl) methyl] -2,3-dihydro-1,4-benzodioxin-5 -carboxamide.

CAS 186348-31-2, C16 H21 Cl N4 O3 . 2 Cl H

Melting point: 220 ° C. (decomposition). EP0748807
[α] = -16.9 ° (c = 1, H 2 O).

[α]D = -17.9 (C = 0.75, DMSO, t = 23°C) at 589 nm. DOI: 10.1021/acs.oprd.6b00262

5-HT3 and 5-HT4 inhibitor that was potentially useful for the treatment of neurological disorders.

Innovators-sanofi

Image result for Sanofi-Aventis

Hoechst Marion Roussel (Sanofi) my organisation 1993-1997 Process development at Mulund, Mumbai, India.

HOECHST | EUREKAMOMENTS IN ORGANIC CHEMISTRY by DR ANTHONY MELVIN CRASTO Ph.D

CENTRE IS DR RALPH STAPEL, HEAD PROCESS DEVELOPMENT, SANOFI

The 5-HT4 receptor is a G-protein coupled receptor (GPCR) which belongs to the serotonin receptor family. The role of the 5-HT4 receptor in the modulation of many diseases is well described in the literature.(1)

During the last decades, an impressive body of evidence suggested that selective stimulation of neuronal 5-HT4 receptor subtypes could be beneficial in the symptomatic treatment of memory disorders, including many antidepressants, antipsychotics, anorectics, antiemetics, gastroprokinetic agents, antimigraine agents, hallucinogens, and antactogens.(2)

Within effort to discover treatments of memory dysfunction, SL65.0102-10, a selective 5-HT4 partial agonist (Ki 6.6 μM), was discovered as promising agent for the treatment of cognition impairment. Serotonin receptors are the target of a variety of pharmaceutical drugs; SL65.0102-10  emerged as a promising 5-HT3 and 5-HT4 inhibitor that was potentially useful for the treatment of neurological disorders.(3)

Samir Jegham

Samir Jegham

Lead Generation Senior Advisor for Asia Pacific Research Hub at Sanofi

“DRUG APPROVALS INT” CATERS TO EDUCATION GLOBALLY, No commercial exploits are done or advertisements added by me. This article is a compilation for educational purposes only.

P.S. : The views expressed are my personal and in no-way suggest the views of the professional body or the company that I represent

SYNTHESIS

SL65.0102-10

str1

CONTD…………..

str1

Synthesis

str1

PATENT

(EP0748807) Derivatives of N- (1,4-diazabicyclo (2.2.2) -oct-2-yl) methyl benzamide, their preparation and their therapeutic use

https://patentscope.wipo.int/search/en/detail.jsf?docId=EP12807129&recNum=1&maxRec=&office=&prevFilter=&sortOption=&queryString=&tab=PCTDescription

Example 5 (Compound No. 9)

Ethyl (-) – 8-Amino-7-chloro- N – [(1,4-diazabicyclo [2.2.2] oct-2-yl) methyl] -2,3-dihydro-1,4 Benzodioxin-5-carboxamide.

5.1. (+) – (2,2-dimethyl-1,3-dioxolan-4-yl) methyl methanesulfonate.

The procedure described in Example 4.1, but from (+) – 2,2-dimethyl-1,3-dioxolane-4-methanol.

5.2. (-) – 2 – [(2,2-Dimethyl-1,3-dioxolan-4-yl) methyl] -1 H -isoindole-1,3 (2 H ) -dione.

The procedure described in Example 4.2, from methane sulfonate (+) – (2,2-dimethyl-1,3-dioxolan-4-yl) methyl.
Melting point: 81.2-81.3 ° C.
[α]= -34.9 ° (c = 1, CH 2 Cl 2 ).

5.3. (-) – 2- (2,3-dihydroxypropyl) -1 H -isoindole-1,3 (2 H ) -dione.

The procedure described in Example 4.3, from (-) – 2 – [(2,2-dimethyl-1,3-dioxolan-4-yl) methyl] -1 H -isoindole-1, 3 (2 H ) -dione.
Melting point: 122.8-122.9 ° C.
[α]= -48.8 ° (c = 1, CH 3 OH).

5.4. (-) – 2 – [(2-Phenyl-1,3-dioxolan-4-yl) methyl] -1 H -isoindole-1,3 (2 H ) -dione.

The procedure described in Example 4.4, from (-) – 2- (2,3-dihydroxypropyl) -1 H -isoindole-1,3 (2 H ) -dione.
Melting point: 84 ° C.
[α]= -59 ° (c = 1, CH 2 Cl 2 ).

5.5. Benzoate (-) – 2-bromomethyl-1- (1,3-dihydro-1,3-dioxo-2 H -isoindol-2-yl) ethyl.

The procedure described in Example 4.5, from (-) – 2 – [(2-phenyl-1,3-dioxolan-4-yl) methyl] -1 H -isoindole-1,3 ( 2 H ) -dione.
Melting point: 118.4-118.6 ° C.
[α]= -58.2 ° (c = 1, CH 2 Cl 2 ).

5.6. (+) – 2- (oxiranylmethyl) -1 H -isoindole-1,3 (2 H ) -dione. Fusion point :

The procedure described in Example 4.6, from benzoate (-) – 2-bromomethyl-1- (1,3-dihydro-1,3-dioxo-2 H -isoindol-2-yl) ethyl.
Melting point: 100.4-100.5 ° C.
[α]= + 45.5 ° (c = 1, CHCl 3 ).

5.7. Dihydrochloride (-) – 8-Amino-7-chloro- N – [(1,4-diazabicyclo [2.2.2] oct-2-yl) methyl] -2,3-dihydro-1,4-benzodioxin-5 -carboxamide.

The procedure described in Example 4.7, from (+) – 2- (oxiranylmethyl) -1 H -isoindole-1,3 (2 H ) -dione.
Melting point: 220 ° C. (decomposition).
[α] = -16.9 ° (c = 1, H 2 O).

Paper

Abstract Image

The process development and improvements for route selection, adapted to large scale for the pilot-scale preparation of SL65.0102-10, an N-diazabicyclo[2.2.2]-octylmethyl benzamide, a 5-HT3and 5-HT4 receptor active ligand for the treatment of neurological disorders such as cognition impairment, are described in this article. Notable steps and enhancements are compared to the original route, including the improvement of a chiral epoxide synthesis by shortening the number of chemical steps, the deprotection of a quaternary ammonium salt, and the redesign of the final amidification coupling to avoid chromatography.

Sanofi

Philippe Lienard

CMC Discovery Coordinator

Pilot Scale Process Development of SL65.0102-10, an N-Diazabicyclo[2.2.2]-octylmethyl Benzamide

Sanofi-Aventis, Recherche & Développement, 13 Quai Jules Guesde, 94400 Vitry-sur-Seine, France
Org. Process Res. Dev., Article ASAP

(-)-1,4-benzodioxin-5-carboxamide-8-amino-7-chloro-N-(1,4-diazabicyclo[2.2.2]oct-2- ylmethyl)-2,3-dihydro-, hydrochloride (1:2), SL65.0102-10 (1).

……………….. to provide compound 1 (10.3 kg, 76.7%). Compound 1 could be recrystallized in acetone/water (12/2 volumes).

1H-NMR (DMSO-d6, 500 MHz), δ ppm: 3.38 (dd, 1H, J = 12.0 , 6.0 Hz), 3.60-3.45 (m, 7H), 3.65 (t, 1H, J =10.0 Hz), 3.72 (dt, 1H, J =6.0 , 14.0 Hz), 3.83 (m, 2H), 4.01 (m, 1H), 4.33 (m, 2H), 4.39 (m, 2H), 7.37 (s, 1H), 8.35 (t, 1H, J =6.0 Hz). Only 19 protons are observed on 1H spectrum instead of 21 expected. The two amino protons of the molecule are not visible because of chemical exchange with residual water of DMSO-d6 solvent.

13C NMR (DMSO-d6, 125 MHz): δ 38.4, 39.0, 42.8, 43.4, 45.4, 46.5, 54.4, 64.1, 65.1, 109.3, 110.0, 123.2, 130.5, 138.1, 141.8, 165.0.

HRMS: exact mass (by Xevo QToF), MH+ found: 353.1374 (MH+ calculated: 353.1380, difference: -1.7 ppm).

[α]D = -17.9 (C = 0.75, DMSO, t = 23°C) at 589 nm.

Elementary analysis: found C 43.0660%, H 5.5150%, N 12.4792%, calculated C 43.31%, H 5.68%, N 12.63%

str1

1H AND 13C NMR PREDICT

str1 str2 str3 str4

References

  1. (a) Hoyer, D.; Clarke, D. E.; Fozard, J. R.; Hartig, P. R.; Martin, G. R.; Mylecharane, E. J.; Saxena, P. R.;Humphrey, P. P. Pharmacol. Rev. 1994, 46 ( 2) 157203

    (b) Frazer, A.; Hensler, J. G.Chapter 13: Serotonin Receptors. In Siegel, G. J.; Agranoff, B. W.; Albers, R. W.; Fisher, S. K.; Uhler, M. D., Eds.; Basic Neurochemistry: Molecular, Cellular, and Medical Aspects; Lippincott-Raven, Philadelphia,1999; pp 263292.

  2. 2.

    Frick, W.; Glombik, H.; Kramer, W.; Heuer, H.; Brummerhop, H.; Plettenburg, O. Novel fluoroglycoside heterocyclic derivatives, pharmaceutical products containing said compounds and the use thereof.

    (a) WO2004/052903, 2004.

    (b) WO2004/052902, 2004.

  3. 3.

    Jegham, S.; Koenig, J. J.; Lochead, A.; Nedelec, A.; Guminski, Y.N-[(1,4-diazabicyclo[2.2.2]oct-2-yl)methyl] benzamide derivatives, their preparations and their application in therapeutics.

    (a) FR 2756563 06/13/1995 9506951, 1995.

    (b) US 5663173, 1997; Washington, DC: U.S. Patent and Trademark Office.

“DRUG APPROVALS INT” CATERS TO EDUCATION GLOBALLY, No commercial exploits are done or advertisements added by me. This article is a compilation for educational purposes only.

P.S. : The views expressed are my personal and in no-way suggest the views of the professional body or the company that I represent

////////SL65.0102-10, SANOFI, 5-HT3 , 5-HT4 inhibitor,   neurological disorders

O=C(NCC2CN1CCN2CC1)c4cc(Cl)c(N)c3OCCOc34

Calcifediol, カルシフェジオール


Skeletal formula of calcifediol

Calcifediol

カルシフェジオール

Ro 8-8892
U 32070E
(3b,5Z,7E)-9,10-Secocholesta-5,7,10(19)-triene-3,25-diol
(3S,5Z,7E,20R)-9,10-Secocholesta-5,7,10-trien-3,25-diol [German] [ACD/IUPAC Name]
(3S,5Z,7E,20R)-9,10-Secocholesta-5,7,10-triene-3,25-diol [ACD/IUPAC Name]
(3S,5Z,7E,20R)-9,10-Sécocholesta-5,7,10-triène-3,25-diol [French] [ACD/IUPAC Name]
19356-17-3 [RN]
1H-indene-1-pentanol, octahydro-4-[(2Z)-2-[(5S)-5-hydroxy-2-methylenecyclohexylidene]ethylidene]-a,a,e,7a-tetramethyl-, (eR,1R,3aS,4E,7aR)-
25(OH)D3
25-(OH)Vitamin D3
25-hydroxy Vitamin D3
25-HYDROXYCHOLECALCIFEROL-D6
25-hydroxycholecalciferolmonohydrate
25-hydroxyvitamin D
3-{2-[1-(5-Hydroxy-1,5-dimethyl-hexyl)-7a-methyl-octahydro-inden-4-ylidene]-ethylidene}-4-methylene-cyclohexanol
4-[(2Z)-2-[(5S)-5-hydroxy-2-methylenecyclohexylidene]ethylidene]octahydro-?,?,?,7a-tetramethyl-(?R,1R,3aS,4E,7aR)-1H-indene-1-pentanol
Molecular form.: C₂₇H₄₄O₂
Appearance: White to Off-White Solid
Melting Point: 75-93ºC
Mol. Weight: 400.64

Calcifediol (INN), also known as calcidiol, 25-hydroxycholecalciferol, or 25-hydroxyvitamin D (abbreviated 25(OH)D),[1] is a prehormone that is produced in the liver by hydroxylation of vitamin D3 (cholecalciferol) by the enzyme cholecalciferol 25-hydroxylase which was isolated by Michael F. Holick. Physicians worldwide measure this metabolite to determine a patient’s vitamin D status.[2] At a typical daily intake of vitamin D3, its full conversion to calcifediol takes approximately 7 days.[3]

Calcifediol is then converted in the kidneys (by the enzyme 25(OH)D-1α-hydroxylase) into calcitriol (1,25-(OH)2D3), a secosteroid hormone that is the active form of vitamin D. It can also be converted into 24-hydroxycalcidiol in the kidneys via 24-hydroxylation.[4][5]

Calcifediol.png

Blood test

In medicine, a 25-hydroxy vitamin D (calcifediol) blood test is used to determine how much vitamin D is in the body.[6] The blood concentration of calcifediol is considered the best indicator of vitamin D status.[7]

This test can be used to diagnose vitamin D deficiency, and it is indicated in patients with high risk for vitamin D deficiency and when the results of the test would be used as supporting evidence for beginning aggressive therapies.[8] Patients with osteoporosis, chronic kidney disease, malabsorption, obesity, and some other infections may be high risk and thus have greater indication for this test.[8] Although vitamin D deficiency is common in some populations including those living at higher latitudes or with limited sun exposure, the 25(OH)D test is not indicated for entire populations.[8] Physicians may advise low risk patients to take over-the-counter vitamin D in place of having screening.[8]

It is the most sensitive measure,[9] though experts have called for improved standardization and reproducibility across different laboratories.[7] According to MedlinePlus, the normal range of calcifediol is 30.0 to 74.0 ng/mL.[6] The normal range varies widely depending on several factors, including age and geographic location. A broad reference range of 20–150 nmol/L (8-60 ng/ml) has also been suggested,[10] while other studies have defined levels below 80 nmol/L (32 ng/ml) as indicative of vitamin D deficiency.[11]

US labs generally report 25(OH)D levels as ng/mL. Other countries often use nmol/L. Multiply ng/mL by 2.5 to convert to nmol/L.

Clinical significance

Increasing calcifediol levels are associated with increasing fractional absorption of calcium from the gut up to levels of 80 nmol/L (32 ng/mL).[citation needed]Urinary calcium excretion balances intestinal calcium absorption and does not increase with calcifediol levels up to ~400 nmol/L (160 ng/mL).[12]

A study by Cedric F. Garland and Frank C. Garland of the University of California, San Diego analyzed the blood from 25,000 volunteers from Washington County, Maryland, finding that those with the highest levels of calcifediol had a risk of colon cancer that was one-fifth of typical rates.[13] However, randomized controlled trials failed to find a significant correlation between vitamin D supplementation and the risk of colon cancer.[14]

A 2012 registry study of the population of Copenhagen, Denmark, found a correlation between both low and high serum levels and increased mortality, with a level of 50–60 nmol/L being associated with the lowest mortality. The study did not show causation.[15][16]

Nmr

http://onlinelibrary.wiley.com/doi/10.1002/cctc.201402795/epdf?r3_referer=wol&tracking_action=preview_click&show_checkout=1&purchase_referrer=onlinelibrary.wiley.com&purchase_site_license=LICENSE_DENIED

Regioselective Hydroxylation in the Production of 25-Hydroxyvitamin D by Coprinopsis cinerea Peroxygenase
ChemCatChem (2015), 7, (2), 283-290

1H NMR 500 MHz, CDCl3: δ= 0.55 (3 H, s, 18-H), 0.94 (1H, d, J= 6.5 Hz, 21-H), 1.06 (1H, m, 22-H), 1.22 (3 H, s, 26-H), 1.22 (3 H, s, 27-H), 1.23 (1H, m, 23-H), 1.27 (1H, m, 16-H), 1.28 (1H, m, 14-H), 1.29 (1H, m, 12-H), 1.37 (1H, m, 22-H), 1.38 (1H, m, 20-H), 1.39 (1H, m, 24-H), 1.42 (1H, m, 23-H), 1.44 (1H, m, 24-H), 1.47 (2 H, m, 11-H), 1.53 (1H, m, 15-H), 1.66 (1H, m, 15-H), 1.67 (1H, m, 2-H), 1.67 (1H, m, 9-H), 1.87 (1H, m, 16-H), 1.92 (1H, m, 2-H), 1.98 (1H, m, 17-H), 2.06 (1H, m, 12-H), 2.17 (1H, m, 1-H), 2.40 (1H, m, 1-H), 2.57 (1H, dd, J= 3.7, 13.1Hz, 4-H), 2.82 (1H, m, 9-H), 3.95 (1H, bm, 3-H), 4.82 (1H, m, 19-H), 5.05 (1H, m, 19-H), 6.03 (1H, d, J=11.2 Hz, 7-H), 6.23 ppm (1H, d, J= 11.2 Hz, 6-H).

13 C NMR 500 MHz, CDCl3: δ = 12.2 (C-18), 19.0 (C-21), 21.0 (C-23), 22.4 (C-11), 23.7 (C-15), 27.8 (C-16), 29.2 (C-9), 29.4 (C-27), 29.5 (C-26), 32.1 (C-1), 35.3 (C-2), 36.3 (C-20), 36.6 (C-22), 40.7 (C-12), 44.6 (C-24), 46.0 (C-13), 46.1 (C-4), 56.5 (C-17), 56.7 (C-14), 69.4 (C-3), 71.3 (C-25), 112.6 (C-19), 117.7 (C-7), 122.2 (C-6), 135.2 (C-5), 142.4 (C-8), 145.3 ppm (C-10).

PAPER

From Organic & Biomolecular Chemistry, 10(27), 5205-5211; 2012

http://pubs.rsc.org/en/content/articlelanding/2012/ob/c2ob25511a#!divAbstract

An efficient, two-stage, continuous-flow synthesis of 1α,25-(OH)2-vitamin D3 (activated vitamin D3) and its analogues was achieved. The developed method afforded the desired products in satisfactory yields using a high-intensity and economical light source, i.e., a high-pressure mercury lamp. In addition, our method required neither intermediate purification nor high-dilution conditions.

Graphical abstract: Continuous-flow synthesis of activated vitamin D3 and its analogues

1H NMR(400 MHz, CDCl3): δ 8.13 (m, 2H), 7.68 (m, 2H), 6.64 (d, J = 8.3 Hz, 1H), 6.25 (d, J = 8.3 Hz, 1H), 5.19 (m, 2H), 3.93 (dd, J = 12.7, 8.2, 1H), 3.88 (dd, J = 14.6, 4.9 Hz, 1H), 3.58 (m, 1H), 1.02 (s, 3H), 1.02 (d, J = 6.8 Hz, 3H), 0.90 (d, J = 6.8 Hz, 3H), 0.86 (s, 9H), 0.80-0.84 (m, 9H), 0.09 (s, 3H), 0.00 (s, 3H)

13C NMR  (100 MHz, CDCl3): δ 161.8, 159.6, 138.5, 135.3, 132.6, 132.5, 132.1, 130.6, 130.2, 128.7, 127.0, 126.5, 77.2, 68.5, 67.4, 67.1, 56.5, 50.6, 49.0, 44.2, 42.7, 40.4, 39.9, 39.3, 35.6, 34.7, 33.0, 30.5, 28.2, 25.9, 24.5, 21.9, 20.8, 19.9, 19.7, 18.5, 18.0, 17.4, 13.3, -4.4, -4.9

IR (neat): 2957, 2872, 1653, 1603, 1462, 1311, 1093, 837, 762 cm-1

str1

Interactive pathway map

Click on genes, proteins and metabolites below to link to respective articles. [§ 1]

[[File:

VitaminDSynthesis_WP1531

Go to article Go to article Go to article Go to article go to article Go to article Go to article Go to article go to article go to article go to article go to article Go to article Go to article go to article Go to article go to article go to article go to article Go to article go to article

VitaminDSynthesis_WP1531

Go to article Go to article Go to article Go to article go to article Go to article Go to article Go to article go to article go to article go to article go to article Go to article Go to article go to article Go to article go to article go to article go to article Go to article go to article

|{{{bSize}}}px|alt=Vitamin D Synthesis Pathway]

Vitamin D Synthesis Pathway edit

  1. Jump up^ The interactive pathway map can be edited at WikiPathways: “VitaminDSynthesis_WP1531”.

References

  1. Jump up^ “Nomenclature of Vitamin D. Recommendations 1981. IUPAC-IUB Joint Commission on Biochemical Nomenclature (JCBN)” reproduced at the Queen Mary, University of London website. Retrieved 21 March 2010.
  2. Jump up^ Holick, MF; Deluca, HF; Avioli, LV (1972). “Isolation and identification of 25-hydroxycholecalciferol from human plasma”. Archives of Internal Medicine. 129 (1): 56–61. doi:10.1001/archinte.1972.00320010060005. PMID 4332591.
  3. Jump up^ Am J Clin Nutr 2008;87:1738–42 PMID 18541563
  4. Jump up^ Bender, David A.; Mayes, Peter A (2006). “Micronutrients: Vitamins & Minerals”. In Victor W. Rodwell; Murray, Robert F.; Harper, Harold W.; Granner, Darryl K.; Mayes, Peter A. Harper’s Illustrated Biochemistry. New York: Lange/McGraw-Hill. pp. 492–3. ISBN 0-07-146197-3. Retrieved December 10, 2008 through Google Book Search.
  5. Jump up^ Institute of Medicine (1997). “Vitamin D”. Dietary Reference Intakes for Calcium, Phosphorus, Magnesium, Vitamin D, and Fluoride. Washington, D.C: National Academy Press. p. 254. ISBN 0-309-06403-1.
  6. ^ Jump up to:a b “25-hydroxy vitamin D test: Medline Plus”. Retrieved 21 March 2010.
  7. ^ Jump up to:a b Heaney, Robert P (Dec 2004). “Functional indices of vitamin D status and ramifications of vitamin D deficiency”. American Journal of Clinical Nutrition. 80 (6): 1706S–9S. PMID 15585791.
  8. ^ Jump up to:a b c d American Society for Clinical Pathology, “Five Things Physicians and Patients Should Question”, Choosing Wisely: an initiative of the ABIM Foundation, American Society for Clinical Pathology, retrieved August 1, 2013, which cites
      • Sattar, N.; Welsh, P.; Panarelli, M.; Forouhi, N. G. (2012). “Increasing requests for vitamin D measurement: Costly, confusing, and without credibility”. The Lancet. 379 (9811): 95–96. doi:10.1016/S0140-6736(11)61816-3. PMID 22243814.
      • Bilinski, K. L.; Boyages, S. C. (2012). “The rising cost of vitamin D testing in Australia: Time to establish guidelines for testing”. The Medical Journal of Australia. 197 (2): 90. doi:10.5694/mja12.10561. PMID 22794049.
      • Lu, Chuanyi M. (May 2012). “Pathology consultation on vitamin D testing: Clinical indications for 25(OH) vitamin D measurement [Letter to the editor]”. American Journal Clinical Pathology. American Society for Clinical Pathology (137): 831–832., which cites
        • Arya, S. C.; Agarwal, N. (2012). “Pathology Consultation on Vitamin D Testing: Clinical Indications for 25(OH) Vitamin D Measurement”. American Journal of Clinical Pathology. 137 (5): 832. doi:10.1309/AJCP2GP0GHKQRCOE. PMID 22523224.
      • Holick, M. F.; Binkley, N. C.; Bischoff-Ferrari, H. A.; Gordon, C. M.; Hanley, D. A.; Heaney, R. P.; Murad, M. H.; Weaver, C. M. (2011). “Evaluation, Treatment, and Prevention of Vitamin D Deficiency: An Endocrine Society Clinical Practice Guideline”. Journal of Clinical Endocrinology & Metabolism. 96 (7): 1911–1930. doi:10.1210/jc.2011-0385. PMID 21646368.
  9. Jump up^ Institute of Medicine (1997), p. 259
  10. Jump up^ Bender, David A. (2003). “Vitamin D”. Nutritional biochemistry of the vitamins. Cambridge: Cambridge University Press. ISBN 0-521-80388-8. Retrieved December 10, 2008 through Google Book Search.
  11. Jump up^ Hollis BW (February 2005). “Circulating 25-hydroxyvitamin D levels indicative of vitamin D sufficiency: implications for establishing a new effective dietary intake recommendation for vitamin D”. J Nutr. 135 (2): 317–22. PMID 15671234.
  12. Jump up^ Kimball; et al. (2004). “Safety of vitamin D3 in adults with multiple sclerosis”. J Clin Endocrinol Metab. 86 (3): 645–51. PMID 17823429.
  13. Jump up^ Maugh II, Thomas H. “Frank C. Garland dies at 60; epidemiologist helped show importance of vitamin D: Garland and his brother Cedric were the first to demonstrate that vitamin D deficiencies play a role in cancer and other diseases.”, Los Angeles Times, August 31, 2010. Accessed September 4, 2010.
  14. Jump up^ Wactawski-Wende, J; Kotchen, JM, Women’s Health Initiative Investigators (Mar 9, 2006). “Calcium plus vitamin D supplementation and the risk of colorectal cancer.”. N Engl J Med. 354 (7): 684–96. doi:10.1056/NEJMoa055222. PMID 16481636. Retrieved December 28, 2013.
  15. Jump up^ “Too much vitamin D can be as unhealthy as too little” (Press release). University of Copenhagen. May 29, 2012. Retrieved 2015-05-27.
  16. Jump up^ Durup, D.; Jørgensen, H. L.; Christensen, J.; Schwarz, P.; Heegaard, A. M.; Lind, B. (May 9, 2012). “A Reverse J-Shaped Association of All-Cause Mortality with Serum 25-Hydroxyvitamin D in General Practice: The CopD Study”. The Journal of Clinical Endocrinology & Metabolism. Endocrine Society. 97 (8): 2644–2652. doi:10.1210/jc.2012-1176. Retrieved 2015-05-27.
Calcifediol
Skeletal formula of calcifediol
Ball-and-stick model of the calcifediol molecule
Names
IUPAC names

(6R)-6-[(1R,3aR,4E,7aR)-4-[(2Z)-2-[(5S)-5-
Hydroxy-2-methylidene-cyclohexylidene]
ethylidene]-7a-methyl-2,3,3a,5,6,7-hexahydro-
1H-inden-1-yl]-2-methyl-heptan-2-ol
Other names

25-Hydroxyvitamin D3
25-Hydroxycholecalciferol
Calcidiol
Identifiers
19356-17-3 Yes
3D model (Jmol) Interactive image
ChEBI CHEBI:17933 
ChEMBL ChEMBL1222 Yes
ChemSpider 4446820 
DrugBank DB00146 Yes
ECHA InfoCard 100.039.067
6921
MeSH Calcifediol
PubChem 5283731
UNII T0WXW8F54E Yes
Properties
C27H44O2
Molar mass 400.64 g/mol
Pharmacology
A11CC06 (WHO)
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa).

 

Title: Calcifediol
CAS Registry Number: 19356-17-3
CAS Name: (3b,5Z,7E)-9,10-Secocholesta-5,7,10(19)-triene-3,25-diol
Additional Names: 25-hydroxyvitamin D3; 25-hydroxycholecalciferol; 25-HCC
Manufacturers’ Codes: U-32070E
Trademarks: Dedrogyl (DESMA); Didrogyl (Bruno); Hidroferol (FAES)
Molecular Formula: C27H44O2
Molecular Weight: 400.64
Percent Composition: C 80.94%, H 11.07%, O 7.99%
Literature References: The principal circulating form of vitamin D3, formed in the liver by hydroxylation at C-25: Ponchon, DeLuca, J. Clin. Invest. 48, 1273 (1969). It is the intermediate in the formation of 1a,25-dihydroxycholecalciferol, q.v., the biologically active form of vitamin D3 in the intestine. Identification in rat as an active metabolite of vitamin D3: Lund, DeLuca, J. Lipid Res. 7, 739 (1966); Morii et al., Arch. Biochem. Biophys. 120, 513 (1967). Evaluation of biological activity in comparison with vitamin D3: Blunt et al., Proc. Natl. Acad. Sci. USA 61, 717 (1968); ibid. 1503. Isoln from porcine plasma and establishment of structure: Blunt et al., Biochemistry 7, 3317 (1968). Synthesis: Blunt, DeLuca, ibid. 8, 671 (1969). Review of isoln, identification and synthesis: DeLuca, Am. J. Clin. Nutr. 22, 412 (1969). Review of bioassays: J. G. Haddad Jr., Basic Clin. Nutr. 2, 579-597 (1980).
Properties: uv max (ethanol): 265 nm (e 18000) (Blunt, DeLuca).
Absorption maximum: uv max (ethanol): 265 nm (e 18000) (Blunt, DeLuca)
Therap-Cat: Calcium regulator.
Keywords: Calcium Regulator.

/////////Calcifediol, カルシフェジオール

CC(CCCC(C)(C)O)C1CCC2C1(CCCC2=CC=C3CC(CCC3=C)O)C

GMP’s for Early Stage Development of new Drug substances and products


DRUG REGULATORY AFFAIRS INTERNATIONAL

Image result for GMPs for Early Stage Development

GMP’s for Early Stage Development of New Drug substances and products


The question of how Good Manufacturing Practice (GMP) guidelines should be applied during early stages of development continues to be discussed across the industry and is now the subject of a new initiative by the International Consortium on Innovation and Quality in Pharmaceutical Development (IQ Consortium)—an association of pharmaceutical and biotechnology companies aiming to advance innovation and quality in the development of pharmaceuticals. They have assembled a multidisciplinary team (GMPs in Early Development Working Group) to explore and define common industry approaches and to come up with suggestions for a harmonized approach. Their initial thoughts and conclusions are summarized in Pharm. Technol. 2012, 36 (6), 5458.
Image result for International Consortium on Innovation and Quality in Pharmaceutical Development (IQ Consortium)
From an industry perspective, it is common to consider the “early” phase of development as covering phases 1 and 2a clinical studies. During this phase, there is a high…

View original post 1,741 more words

Balsalazide


Balsalazide structure.svg

Balsalazide

80573-04-2; Colazal; Balsalazide Disodium; AC1NSFNR; P80AL8J7ZP;
Molecular Formula: C17H15N3O6
Molecular Weight: 357.322 g/mol

(3E)-3-[[4-(2-carboxyethylcarbamoyl)phenyl]hydrazinylidene]-6-oxocyclohexa-1,4-diene-1-carboxylic acid

 DISODIUMDIHYDRATE

CAS Number 150399-21-6
Weight Average: 437.316
Monoisotopic: 437.08110308
Chemical Formula C17H17N3Na2O8

Balsalazide is an anti-inflammatory drug used in the treatment of inflammatory bowel disease. It is sold under the brand names Giazo, Colazal in the US and Colazide in the UK. It is also sold in generic form in the US by several generic manufacturers.

It is usually administered as the disodium salt. Balsalazide releases mesalazine, also known as 5-aminosalicylic acid, or 5-ASA,[1] in the large intestine. Its advantage over that drug in the treatment of ulcerative colitis is believed to be the delivery of the active agent past the small intestine to the large intestine, the active site of ulcerative colitis.

Balsalazide is an anti-inflammatory drug used in the treatment of Inflammatory Bowel Disease. It is sold under the name “Colazal” in the US and “Colazide” in the UK. The chemical name is (E)-5-[[-4-(2-carboxyethyl) aminocarbonyl] phenyl]azo] –2-hydroxybenzoic acid. It is usually administered as the disodium salt. Balsalazide releases mesalazine, also known as 5-aminosalicylic acid, or 5-ASA, in the large intestine. Its advantage over that drug in the treatment of Ulcerative colitis is believed to be the delivery of the active agent past the small intestine to the large intestine, the active site of ulcerative colitis.

Balsalazide disodium and its complete synthesis was first disclosed by Chan[18] in 1983, assigned to Biorex Laboratories Limited, England, claiming product ‘Balsalazide’ and process of its preparation. The synthesis involves converting 4-nitrobenzoyl chloride (6) to 4- nitrobenzoyl-β-alanine (7), hydrogenating with Pd/C (5%) in ethanol and isolating by adding diethyl ether to produce 4-aminobenzoyl-β-alanine (8). Thereafter, 4-aminobenzoyl-β-alanine (8) was treated with hydrochloric acid and sodium nitrite to generate N-(4-diazoniumbenzoyl)- β-alanine hydrochloride salt (9) which was reacted at low temperature with disodium salicylate to furnish Balsalazide disodium insitu which was added to dilute hydrochloric acid at low temperature to produce Balsalazide (1) (Scheme-1.1). Thus obtained Balsalazide was recrystallized with hot ethanol and converted to pharmaceutically acceptable salt (disodium salt).

Optimization of this diazonium salt based process was performed by Huijun et al[19] and reported the preparation of the title compound in 64.6% overall yield. Zhenhau et al[20] have synthesized 1 from 4-nitrobenzoic acid (12) via chlorination, condensation, hydrogenation, diazotization, coupling and salt formation with overall yield 73%. Li et al[21] have given product in 73.9% total yield starting from 4-nitrobenzoyl chloride (6), where as Yuzhu et al[22] confirmed chemical structure of Balsalazide disodium by elemental analysis, UV, IR, 1H-NMR and ESI-MS etc. Shaojie et al[23] have also followed same process for its preparation. Yujie et al[24] synthesized 1 in this way; preparation of 4-nitrobenzoyl-β-alanine (7) under microwave irradiation of 420 W at 52oC for 10sec., reduction in ethyl acetate in the presence of Pd/C catalyst then diazotization, coupling and salt formation. Eckardt et al[25] have developed a process for the preparation of Balsalazide which comprises, conversion of 4-aminobenzoyl-β-alanine (8) to 4-ammoniumbenzoyl-β-alanine sulfonate salt using a sulfonic acid in water. This was treated with aq. sodium nitrite solution at low temperature to generate 4-diazoniumbenzoyl-β-alanine sulfonate salt (11) which was quenched with aq. disodium salicylate to furnish Balsalazide disodium solution. This was further acidified to allow isolation of 1 and then conversion to disodium salt (Scheme-1.2) in 76% yield.

http://shodhganga.inflibnet.ac.in/bitstream/10603/101297/10/10_chapter%201.pdf

IR (KBr, cm-1 ): 3371 and 3039 (OH and NH), 1705 and 1699 (C=O), 1634 (C=O amide), 1590 and 1538 (C=C aromatic), 1464 and 1404 (aliphatic C-H), 1229 (C-N), 1073 (C-O), 773 and 738 (Ar-H out of plane bend). 1H NMR (DMSO-d6, 300 MHz, δ ppm): 2.54 (t, 2H), 3.50 (m, 2H), 6.95 (d, J = 8.8 Hz, 1H), 7.87 (d, J = 8.5 Hz, 2H), 8.02 (d, J = 8.5 Hz, 2H), 7.95 (dd, J = 8.8 Hz and 2.5 Hz, 1H), 8.34 (d, J = 2.5 Hz, 1H), 8.68 (t, J = 5.5 Hz, 1H), 12.12 (brs, 1H). MS m/z (ESI): 356 [(M-H)- ], Calculated; m/z 357.

Synthesis

Balsalazide synthesis: Biorex Laboratories, GB 2080796 (1986).

  1. Starting material is 4-aminohippuric acid, obtained by coupling para-aminobenzoic acid and glycine.
  2. That product is then treated with nitrous acid to give the diazonium salt.
  3. Reaction of this species with salicylic acid proceeds at the position para to the phenol to give balsalazide.

Sodium balsalazide (Balsalazide sodium)

Brief background information

Salt ATC Formula MM CAS
A07EC04 C 17 H 13 N 3 Na 2 O 6 401.29 g / mol 82101-18-6
(E) is the free acid A07EC04 C 17 H 15 N 3 O 6 357.32 g / mol 80573-04-2A

Application

  • resolvent

Classes substance

  • β-alanine (3-aminopropionic acid)
    • m-aminobenzoic acid and esters and amides thereof
      • p-aminobenzoic acid and esters and amides thereof
        • azobenzene
          • salicylic acid

Synthesis Way

Synthesis of a)


Trade names

A country Tradename Manufacturer
United Kingdom Kolazid Shire
Italy Balzid Menarini
USA Kolazal Salix
Ukraine no no

Formulations

  • capsules in 750 mg (as disodium salt)

PATENT

https://www.google.com/patents/US7271253

Balsalazide disodium (1) represents an effective gastrointestinal anti-inflammatory compound useful as a medicament for the treatment of diseases such as ulcerative colitis. It is delivered intact to the colon where it is cleaved by bacterial azoreduction thereby generating 5-aminosalicylic acid as the medicinally active component.

Figure US07271253-20070918-C00001

To date, relatively few patents or literature articles have dealt with the preparation of Balsalazide or the disodium salt. For instance, U.S. Pat. No. 4,412,992 (Biorex, 1983) is the first patent that we uncovered that claims the compound Balsalazide and a strategy of how to prepare it which strategy is depicted in Scheme 1.

Figure US07271253-20070918-C00002

Optimization of this diazonium-based process is detailed in Shan et al., Zhongguo Yaowu Huaxue Zazhi, 11, 110 (2001) and Shi et al., Zhongguo Yiyao Gongye Zazhi, 34, 537 (2003).

Problems arise with the above strategy and the optimization process.

It is well-documented in the literature, for instance in Thermochimica Acta, 225, 201-211 (1993), that diazonium salts can be involved in serious accidents in their use. A possible cause of some of the diazonium salt related accidents is that, for one reason or another, an intermediate material appeared in crystalline form in the vessel of the reaction. As a result, a potentially severe drawback of the above processes occurs. Since the intermediate hydrochloride salt of 4-aminobenzoyl-β-alanine has poor solubility in water, it may pose a safety-risk in the subsequent diazotation reaction.

Also, it is well-known that certain diazonium salts possess high mechanical and heat sensitivity and that their decomposition goes through the liberation of non-condensable nitrogen gas which results in the possibility of runaway reactions and explosions. Obviously this safety consideration becomes more pertinent upon further scale-up.

Therefore, for commercial production of Balsalazide disodium, there was a need to develop a scalable and intrinsically better process

Example 1 Batch Process

N-(4-Aminobenzoyl)-β-alanine (100 g) was suspended in water (1300 mL) and methanesulfonic acid (115.4 g) was added to this mixture. The mixture was cooled to 10° C. and a solution of sodium nitrite (34.46 g) in water (200 mL) was added at a rate such that the temperature stayed below 12° C. The mixture was stirred for 30 min and added to an ice-cold solution of salicylic acid (69.65 g), sodium hydroxide (40.35 g) and sodium carbonate (106.9 g) in 1 L water at 7-12° C. After 3 hours at 10° C., the mixture was heated to 60-65° C. and acidified to pH 4.0-4.5 by the addition of hydrochloric acid. After a further 3 hours at 60-65° C., the mixture was cooled to ambient temperature, filtered, washed with water and dried in vacuo to yield Balsalazide. Yield ca. 90%. Balsalazide was transformed into its disodium salt in ca. 85% yield by treatment with aqueous NaOH solution followed by crystallization from n-propanol/methanol.

1H-NMR (400 MHz; D2O): δ=8.04 ppm (s); 7.67 ppm (d; J=8.2 Hz); 7.62 ppm (d, J=9.2 Hz); 7.53 ppm (d; J=8.2 Hz); 6.84 ppm (d; J=8.9 Hz); 3.57 ppm (t, J=7.1 Hz); 2.53 ppm (t; J=7.2 Hz).

Example 2 Continuous Process

For the continuous operation, a conventional dual-head metering pump (Ratiomatic by FMI) was used to deliver the mesylate solution and the aqueous sodium nitrite solution. The schematic diagram shown in FIG. 4 represents a set-up used for the continuous process. The first pump-head was set at 13.9 g/min whereas the second was set at 2.1 g/min. These flow rates offered a residence time of 9.4 min. The yield of the coupled intermediate from this residence time was 93%. The working solutions were prepared as follow:

The mesylate solution was prepared by the addition into a 2 L 3-necked round bottom flask, of N-(4-aminobenzoyl) β-alanine (120 g) followed by of DI water (1560 g) and methanesulfonic acid (177.5 g) (Batch appearance: clear solution). The first pump-head was primed with this solution and the flow rate was adjusted to 13.9 g/min.

The sodium nitrite solution was prepared by dissolving of sodium nitrite (41.8 g) in of DI water (240 g) (Batch appearance: clear solution). The second pump-head was primed with this solution and the flow rate adjusted to 2.1 g/min.

The quenching solution (sodium salicylate) was made by adding salicylic acid (139.3 g) to DI water (900 g) followed by of sodium carbonate (106.9 g) and 50% aqueous sodium hydroxide (80 g).

The diazotation reaction was performed in a 500 ml jacketed flow reactor with a bottom drain valve. The drain valve was set at 16 g/min. For reactor start-up, the flow reactor was charged with 150 mL of DI water as a working volume and cooled to the reactions initial temperature of 0-5° C. Concomitantly, the additions of the mesylate and sodium nitrite solutions were started and the bottom valve of the flow reactor was opened. During the diazotization, the flow rate of both solutions remained fixed and the temperature was kept below 12° C. and at the end of additions the pumps were stopped while the remaining contents in the flow reactor were drained into the quenching salicylic acid solution. Analysis of the contents in the quenching reactor indicated no signs of uncoupled starting material (diazonium compound). The reactor contents were heated to 60-65° C. for 2-3 hrs before adjusting the pH to precipitate the coupling product. This provided 191.5 g of product.

Cited Patent Filing date Publication date Applicant Title
US4412992 Jul 8, 1981 Nov 1, 1983 Biorex Laboratories Limited 2-Hydroxy-5-phenylazobenzoic acid derivatives and method of treating ulcerative colitis therewith
US6458776 * Aug 29, 2001 Oct 1, 2002 Nobex Corporation 5-ASA derivatives having anti-inflammatory and antibiotic activity and methods of treating diseases therewith
Reference
1 Chai, et al., Huaxi Yaoxue Zazhi, Jiangsu Institute of Materia Medica, Nanjing, China, 2004, 19(6), 431-433.
2 Shan, et al., Zhongguo Yaowu Huaxue Zazhi, Institute of Materia Medica, Peking Union Medical College, Beijing China, 2001, 11(2), 110-111.
3 Shi, et al., Zhongguo Yiyao Gongya Zazhi, Shanghai Institute of Pharmaceutical Industry, Shanghai, China, 2003, 34(11), 537-538.
4 Su, et al., Huaxue Gongye Yu Gongcheng (Tianjin, China), College of Chemistry and Chemical Eng., Donghua Univ., Shanghai, China, 2005, 22(4), 313-315.
5 Ullrich, et al., Decomposition of aromataic diazonium compounds, Thermochimica Acta, 1993, 225, 201-211.

References

  • Prakash, A; Spencer, CM: Drugs (DRUGAY) 1998 56 83- 89.
  • DE 3128819 (Biorex the Lab .; appl 07/21/1981;. GB -prior 07/21/1980, 07.07.1981.).

References

  1. Jump up^ Kruis, W.; Schreiber, I.; Theuer, D.; Brandes, J. W.; Schütz, E.; Howaldt, S.; Krakamp, B.; Hämling, J.; Mönnikes, H.; Koop, I.; Stolte, M.; Pallant, D.; Ewald, U. (2001). “Low dose balsalazide (1.5 g twice daily) and mesalazine (0.5 g three times daily) maintained remission of ulcerative colitis but high dose balsalazide (3.0 g twice daily) was superior in preventing relapses”. Gut. 49 (6): 783–789. doi:10.1136/gut.49.6.783. PMC 1728533Freely accessible. PMID 11709512.
1 to 5 of 5
Patent ID Patent Title Submitted Date Granted Date
US8232265 Multi-functional ionic liquid compositions for overcoming polymorphism and imparting improved properties for active pharmaceutical, biological, nutritional, and energetic ingredients 2007-04-26 2012-07-31
US2011319267 AROMATIC CARBOXYLIC ACID DERIVATIVES FOR TREATMENT AND PROPHYLAXIS OF GASTROINTESTINAL DISEASES INCLUDING COLON CANCERS 2011-12-29
US2007213304 Use of Aminosalicylates in Diarrhoea-Predominent Irritable Bowel Syndrome 2007-09-13
US7119079 Bioadhesive pharmaceutical compositions 2004-07-22 2006-10-10
US6699848 Bioadhesive anti-inflammatory pharmaceutical compositions 2004-03-02
Balsalazide
Balsalazide structure.svg
Clinical data
Trade names Colazal, Giazo
AHFS/Drugs.com Monograph
MedlinePlus a699052
Pregnancy
category
  • US: B (No risk in non-human studies)
ATC code A07EC04 (WHO)
Legal status
Legal status
  • UK: POM (Prescription only)
Pharmacokinetic data
Bioavailability <1%
Protein binding ≥99%
Biological half-life 12hr
Identifiers
CAS Number 80573-04-2 Yes
PubChem (CID) 5362070
DrugBank DB01014 Yes
ChemSpider 10662422 Yes
UNII P80AL8J7ZP Yes
ChEBI CHEBI:267413 Yes
ChEMBL CHEMBL1201346 
ECHA InfoCard 100.117.186
Chemical and physical data
Formula C17H15N3O6
Molar mass 357.318 g/mol
3D model (Jmol) Interactive image

CLICK ON IMAGE

Title: Balsalazide
CAS Registry Number: 80573-04-2
CAS Name: 5-[(1E)-[4-[[(2-Carboxyethyl)amino]carbonyl]phenyl]azo]-2-hydroxybenzoic acid
Additional Names: (E)-5-[[p-[(2-carboxyethyl)carbamoyl]phenyl]azo]-2-salicylic acid
Molecular Formula: C17H15N3O6
Molecular Weight: 357.32
Percent Composition: C 57.14%, H 4.23%, N 11.76%, O 26.87%
Literature References: Analog of sulfasalazine, q.v. Prodrug of 5-aminosalicylic acid where carrier molecule is 4-aminobenzoyl-b-alanine. Prepn: R. P. K. Chan, GB 2080796; idem, US 4412992 (1982, 1983 both to Biorex). Toxicology study and clinical metabolism: idem et al., Dig. Dis. Sci. 28, 609 (1983). Review of pharmacology and clinical efficacy in ulcerative colitis: A. Prakash, C. M. Spencer, Drugs 56, 83 (1998).
Properties: Crystals from hot ethanol, mp 254-255°.
Melting point: mp 254-255°
Derivative Type: Disodium salt dihydrate
CAS Registry Number: 150399-21-6; 82101-18-6 (anhydrous)
Manufacturers’ Codes: BX-661A
Trademarks: Colazal (Salix); Colazide (Shire)
Molecular Formula: C17H13N3Na2O6.2H2O
Molecular Weight: 437.31
Percent Composition: C 46.69%, H 3.92%, N 9.61%, Na 10.51%, O 29.27%
Properties: Orange to yellow microcrystalline powder, mp >350°. Nonhygroscopic. Freely sol in water, isotonic saline; sparingly sol in methanol, ethanol. Practically insol in organic solvents.
Melting point: mp >350°
Therap-Cat: Anti-inflammatory (gastrointestinal).
Keywords: Anti-inflammatory (Gastrointestinal); Anti-inflammatory (Nonsteroidal); Salicylic Acid Derivatives.

//////

O=C(O)c1cc(ccc1O)/N=N/c2ccc(cc2)C(=O)NCCC(O)=O

O.O.[Na+].[Na+].OC1=CC=C(C=C1C([O-])=O)\N=N\C1=CC=C(C=C1)C(=O)NCCC([O-])=O

P.S. : The views expressed are my personal and in no-way suggest the views of the professional body or the company that I represent.

Happy New Year's Eve from Google!
%d bloggers like this: