WO 2016200930, New patent, Citarinostat, Acetylon Pharmaceuticals Inc

WO 2016200930, New patent, Citarinostat, Acetylon Pharmaceuticals Inc

citarinostat

Acetylon Pharmaceuticals Inc

(WO2016200930) METHODS OF MAKING PROTEIN DEACETYLASE INHIBITORS

(I)

Compound (I) is disclosed in U.S. Patent No. 8,148,526 as an HDAC inhibitor.

Example 2 of U.S. Patent Application Publication No. 2015/0099744 discloses a synthesis of compound (I). As detailed herein in Example 3, this synthesis procedure resulted in the formation of significant amounts of de-chlorination and chlorine-migration side products. These impurities have solubilities that are similar to the solubilities of the desired

intermediates. Removal of the impurities is very challenging, requiring lengthy work-ups, involving numerous washes, triturations and crystallizations. Triturations, in particular, are known to be inefficient and unscalable processes. When compound (I) was prepared according to Example 2, the necessary purification steps resulted in a significant loss of desired intermdiates, led to a modest overall yield, and rendered further industrial scale up of the synthesis route unpractical. There remains a need for new methods for the synthesis of compound (I), and related compounds, that minimize the formation of impurities, and that are amenable to industrial scale-up.

BRIEF DESCRIPTION OF THE DRAWINGS

Figure 1 depicts a generic synthesis of compound (I) according to the improved method described herein.

Figure 2 depicts a specific synthesis of compound (I) according to the improved method described herein.

Figure 6 depicts 1HNMR data for compound (I).

  

Acetylon president and CEO Walter Ogier

Example 1: Comparative Synthesis of 2-(diphenylamino)-N-(7-(hydroxyamino)-7-oxoheptyl) pyrimidine-5-carboxamide

Reaction Scheme

Synthesis of Intermediate 2: A mixture of aniline (3.7 g, 40 mmol), compound 1 (7.5 g, 40 mmol), and K2C03 (11 g, 80 mmol) in DMF (100 ml) was degassed and stirred at 120 °C under N2 overnight. The reaction mixture was cooled to r.t. and diluted with EtOAc (200 ml), then washed with saturated brine (200 ml χ 3). The organic layers were separated and dried over Na2S04, evaporated to dryness and purified by silica gel chromatography (petroleum ethers/EtOAc = 10/1) to give the desired product as a white solid (6.2 g, 64 %).

Synthesis of Intermediate 3: A mixture of compound 2 (6.2 g, 25 mmol), iodobenzene (6.12 g, 30 mmol), Cul (955 mg, 5.0 mmol), Cs2C03 (16.3 g, 50 mmol) in TEOS (200 ml) was degassed and purged with nitrogen. The resulting mixture was stirred at 140 °C for 14 hrs.

After cooling to r.t., the residue was diluted with EtOAc (200 ml). 95% EtOH (200 ml) and H4F-H20 on silica gel [50g, pre-prepared by the addition of H4F (lOOg) in water (1500 ml) to silica gel (500g, 100-200 mesh)] was added, and the resulting mixture was kept at r.t. for 2 hrs. The solidified materials were filtered and washed with EtOAc. The filtrate was evaporated to dryness and the residue was purified by silica gel chromatography (petroleum ethers/EtOAc = 10/1) to give a yellow solid (3 g, 38%).

Synthesis of Intermediate 4: 2N NaOH (200 ml) was added to a solution of compound 3 (3.0 g, 9.4 mmol) in EtOH (200 ml). The mixture was stirred at 60 °C for 30min. After evaporation of the solvent, the solution was neutralized with 2N HCl to give a white precipitate. The suspension was extracted with EtOAc (2 χ 200 ml), and the organic layers were separated, washed with water (2 χ 100 ml), brine (2 χ 100 ml), and dried over Na2S04. Removal of the solvent gave a brown solid (2.5 g, 92 %).

Synthesis of Intermediate 6: A mixture of compound 4 (2.5 g, 8.58 mmol), compound 5 (2.52 g, 12.87 mmol), HATU (3.91 g, 10.30 mmol), and DIPEA (4.43 g, 34.32 mmol) was stirred at r.t. overnight. After the reaction mixture was filtered, the filtrate was evaporated to dryness and the residue was purified by silica gel chromatography (petroleum ethers/EtOAc = 2/1) to give a brown solid (2 g, 54 %).

Synthesis of 2-(diphenylamino)-N-(7-(hydroxyamino)-7-oxoheptyl)pyrimidine-5-carboxamide: A mixture of the compound 6 (2.0 g, 4.6 mmol), sodium hydroxide (2N, 20 mL) in MeOH (50 ml) and DCM (25 ml) was stirred at 0 °C for 10 min. Hydroxylamine (50%) (10 ml) was cooled to 0 °C and added to the mixture. The resulting mixture was stirred at r.t. for 20 min. After removal of the solvent, the mixture was neutralized with 1M HCl to give a white precipitate. The crude product was filtered and purified by pre-HPLC to give a white solid (950 mg, 48%).

Example 2: Comparative Synthesis of 2-((2-chlorophenyl)(phenyl)amino)-N-(7- (hydroxyamino)-7-oxoheptyl)pyrimidine-5-carboxamide - Compound (I)

Reaction Scheme

Step (1)

Synthesis of Intermediate 2: A mixture of aniline (3.7 g, 40 mmol), ethyl 2-chloropyrimidine-5-carboxylate 1 (7.5 g, 40 mmol), K2C03 (11 g, 80 mmol) in DMF (100 ml) was degassed and stirred at 120 °C under N2 overnight. The reaction mixture was cooled to rt and diluted with EtOAc (200 ml), then washed with saturated brine (200 ml x 3). The organic layer was separated and dried over Na2S04, evaporated to dryness and purified by silica gel

chromatography (petroleum ethers/EtOAc = 10/1) to give the desired product as a white solid (6.2 g, 64 %).

Step (2)

Synthesis of Intermediate 3: A mixture of compound 2 (69.2 g, 1 equiv.), l-chloro-2-iodobenzene (135.7 g, 2 equiv.), Li2C03 (42.04 g, 2 equiv.), K2C03 (39.32 g, 1 equiv.), Cu (1 equiv. 45 μπι) in DMSO (690 ml) was degassed and purged with nitrogen. The resulting mixture was stirred at 140 °C for 36 hours. Work-up of the reaction gave compound 3 at 93 % yield.

Step (3)

Synthesis of Intermediate 4: 2N NaOH (200 ml) was added to a solution of the compound 3 (3.0 g, 9.4 mmol) in EtOH (200 ml). The mixture was stirred at 60 °C for 30min. After evaporation of the solvent, the solution was neutralized with 2N HCl to give a white precipitate. The suspension was extracted with EtOAc (2 x 200 ml), and the organic layer was separated, washed with water (2 x 100 ml), brine (2 x 100 ml), and dried over Na2S04. Removal of solvent gave a brown solid (2.5 g, 92 %).

Step (4)

Synthesis of Intermediate 5: A procedure analogous to the Synthesis of Intermediate 6 in Example 1 was used.

Step (5)

Synthesis of 2-((2-chlorophenyl)(phenyl)amino)-N-(7-(hydroxyamino)-7-oxoheptyl)pyrimidine-5-carboxamide: A procedure analogous to the Synthesis of 2-(diphenylamino)-N-(7-(hydroxyamino)-7-oxoheptyl)pyrimidine-5-carboxamide in Example 1 was used.

Exam le 3: Process development for Steps 2-3 of Example 2

Table 2. Reactants and reagents

(13.8, leq)

(22.2g, 2eq) Cu

5 24.3g (l.Oeq) 47.7g (2.0eq) 240mL 140 °C

K2C03 (1.0 ε¾45μπι)

(19.65, leq)

(42.04g, 2eq) Cu

6 69.2g (l.Oeq) 135.7g (2.0eq) 690mL 140 °C

K2C03 (1.0 ε¾45μπι)

(39.32g, leq)

Table 3. Results

Table 4. Purification of Compound 4 by extraction and slurry

MTBE/Heptane (lOvol/lOvol) 2.83% 2.67% 92.57%

MEK/Heptane (3vol/6vol) 4.42% 3.16% 90.00%

93.48%

EtoAc 3.87% 1.43%

iProAc 3.91% 2.81% 90.91%

Example 4: Improved synthesis of Compound (I)

Reaction Scheme

4 5 (I)

Step (1)

Synthesis of Compound 11: Ethyl 2-chloropyrimidine-5-carboxylate (ACY-5, 7.0 Kgs), ethanol (60 Kgs), 2-Chloroaniline (9.5 Kgs, 2 eq) and acetic acid (3.7 Kgs, 1.6 eq) were charged to a reactor under inert atmosphere. The mixture was heated to reflux. After at least 5 hours the reaction was sampled for HPLC analysis (method TM-113.1016). When analysis indicated reaction completion (< 1% ACY-5), the mixture was cooled to 70 ± 5 °C and N,N-Diisopropylethylamine (DIPEA) was added. The reaction was then cooled to 20 ± 5°C and the mixture was stirred for an additional 2-6 hours. The resulting precipitate is filtered and washed with ethanol (2 x 6 Kgs) and heptane (24 Kgs). The cake is dried under reduced pressure at 50 ± 5 °C to a constant weight to produce 8.4 Kgs compound 11 (81% yield and 99.9% purity (method TM-113.1016)). See 1HNMR data in Figure 3.

Step (2)

Synthesis of Compound 3: Copper powder (0.68 Kgs, 1 eq, <75 micron), potassium carbonate (4.3 Kgs, 3.0 eq), and dimethyl sulfoxide (DMSO, 12.3 Kgs) were added to a reactor (vessel A). The resulting solution was heated to 120 ± 5°C. In a separate reactor (vessel B), a solution of compound 11 (2.9 Kgs) and iodobenzene (4.3 Kgs, 2 eq) in DMSO (5.6 Kgs) was

heated at 40 ± 5°C. The mixture was then transferred to vessel A over 2-3 hours. The reaction mixture was heated at 120 ± 5°C for 8-24 hours, until HPLC analysis (method TM-113.942) determined that < 1% compound 11 was remaining.

Step (3)

Synthesis of Compound 4: The mixture of Step (2) was cooled to 90-100 °C and purified water (59 Kgs) was added. The reaction mixture was stirred at 90-100 °C for 2-8 hours until HPLC (method TM-113.942-see step 2) showed that <1% compound 3 was remaining. The reactor was cooled to 25 °C. The reaction mixture was filtered through Celite, then a 0.2 micron filter, and the filtrate was collected. The filtrate was extracted with methyl t-butyl ether twice (2 x 12.8 Kgs). The aqueous layer was cooled to 0-5 °C, then acidified with 6N hydrochloric acid (HC1) to pH 2-3 while keeping the temperature < 25°C. The reaction was then cooled to 5-15 °C. The precipitate was filtered and washed with cold water. The cake was dried at 45-55 °C under reduced pressure to constant weight to obtain 2.2 kg (65% yield) compound 4 in 90.3% AUC purity (method TM-113.942-see step 2). No dechlorinated product or Cl-migration product (i.e., de-Cl-4 or m-Cl-4) was observed. See 1HNMR data in Figure 4.

Step (4)

Synthesis of Compound 5: Dichloromethane (40.3 Kgs), DMF (33g, 0.04 eq) and compound 4 (2.3 Kg) were charged to a reaction flask. The solution was filtered through a 0.2 μπι filter and was returned to the flask. Oxalyl chloride (0.9 Kgs, 1 eq) was added via addition funnel over 30-120 minutes at < 30 °C. The batch was then stirred at < 30°C until reaction completion (compound 4 <3 %) was confirmed by HPLC (method TM-113.946). Next, the dichloromethane solution was concentrated and residual oxalyl chloride was removed under reduced pressure at < 40 °C. When HPLC analysis (method TM-113.946) indicated that < 0.10%) oxalyl chloride was remaining, the concentrate was dissolved in fresh

dichloromethane (24 Kgs) and transferred back to the reaction vessel (Vessel A).

A second vessel (Vessel B) was charged with Methyl 7-aminoheptanoate

hydrochloride (Compound Al, 1.5 Kgs, 1.09 eq), DIPEA (2.5 Kgs, 2.7 eq), 4

(Dimethylamino)pyridine (DMAP, 42g, 0.05 eq), and DCM (47.6 Kgs). The mixture was cooled to 0-10 °C and the acid chloride solution in Vessel A was transferred to Vessel B while maintaining the temperature at 5 °C to 10 °C. The reaction is stirred at 5-10 °C for 3 to 24 hours at which point HPLC analysis indicated reaction completion (method TM-113.946, compound 4 <5%). The mixture was then extracted with a 1M HC1 solution (20 Kgs), purified water (20 Kgs), 7% sodium bicarbonate (20 Kgs), purified water (20 Kgs), and 25% sodium chloride solution (20 Kgs). The dichloromethane was then vacuumdistilled at < 40 °C and chased repeatedly with isopropyl alcohol. When analysis indicated that <1 mol% DCM was remaining, the mixture was gradually cooled to 0-5 °C and was stirred at 0-5 °C for an at least 2 hours. The resulting precipitate was collected by filtration and washed with cold isopropyl alcohol (6.4 Kgs). The cake was sucked dry on the filter for 4-24 hours, then was further dried at 45-55 °C under reduced pressure to constant weight. 2.2 Kgs (77% yield) was isolated in 95.9% AUC purity (method TM-113.953) and 99.9 wt %. See 1HNMR data in Figure 5.

Step (5)

Synthesis of Compound (I): Hydroxylamine hydrochloride (3.3 Kgs, 10 eq) and methanol (9.6 Kgs) were charged to a reactor. The resulting solution was cooled to 0-5 °C and 25% sodium methoxide (11.2 Kgs, 11 eq) was charged slowly, maintaining the temperature at 0-10 °C. Once the addition was complete, the reaction was mixed at 20 °C for 1-3 hours and filtered, and the filter cake was washed with methanol (2 x 2.1 Kgs). The filtrate (hydroxylamine free base) was returned to the reactor and cooled to 0±5°C. Compound 5 (2.2 Kgs) was added. The reaction was stirred until the reaction was complete (method TM-113.964, compound 5 < 2%). The mixture was filtered and water (28 Kgs) and ethyl acetate (8.9 Kgs) were added to the filtrate. The pH was adjusted to 8 - 9 using 6N HC1 then stirred for up to 3 hours before filtering. The filter cake was washed with cold water (25.7 Kgs), then dried under reduced pressure to constant weight. The crude solid compound (I) was determined to be Form IV/ Pattern D.

The crude solid (1.87 Kgs) was suspended in isopropyl alcohol (IP A, 27.1 Kg). The slurry was heated to 75±5 °C to dissolve the solids. The solution was seeded with crystals of Compund (I) (Form I/Pattern A), and was allowed to cool to ambient temperature. The resulting precipitate was stirred for 1-2 hours before filtering. The filter cake was rinsed with IPA (2 x 9.5 Kgs), then dried at 45-55°C to constant weight under reduced pressure to result in 1.86 kg crystalline white solid Compound (I) (Form I/Pattern A) in 85% yield and 99.5% purity. See 1HNMR data in Figure 6.

Example 5: Alternative synthesis of Compound (I)

Reaction Scheme

(I)

Step (1)

Synthesis of Compound 11: Ethyl 2-chloropyrimidine-5-carboxylate (ACY-5, 250g), ethanol (2179 g), 2-Chloroaniline (339.3 g, 2 eq) and acetic acid (132.1 g, 1.6 eq) were charged to a reactor under inert atmosphere. The mixture was heated to reflux. After at least 5 hours the reaction was sampled for HPLC analysis. When analysis indicated reaction completion (< 1% ACY-5), the mixture was cooled to 70 ± 5 °C and Ν,Ν-Diisopropylethylamine (DIPEA, 553.6 g, 3.2 eq) was added. The reaction was then cooled to 20 ± 5°C and the mixture was stirred for an additional 2-6 hours. The resulting precipitate is filtered and washed with ethanol (2 x 401 g) and heptane (2 x 428 g). The cake is dried under reduced pressure at 50 ± 5 °C to a constant weight to produce 307. lg compound 11 (82.5% yield and 99.7% purity.

Step (2)

Synthesis of Compound 3: Cuprous iodide (17.5g, 8 eq), potassium carbonate (373.8 g, 3 eq), L-Prolin (11.4 g, 0.11 eq.) and dimethyl sulfoxide (DMSO, and 1180 g ) were added to a reactor (vessel A). The resulting solution was heated to 90 ± 5°C. In a separate reactor (vessel B), a solution of compound 11 (250g) and iodobenzene (1469.5 g, 8 eq) in DMSO (402.5 g) was heated at 40 ± 5°C. The mixture was then transferred to vessel A over 2-3 hours. The reaction mixture was heated at 90 ± 5°C for 8-24 hours, until HPLC analysis determined that < 1%) compound 11 was remaining.

Step (3)

Synthesis of Compound 4: The mixture of Step (2) was cooled to 40-50 °C and water (500g) and potassium hydroxide solution 10% (700.0 g, 2.8 eq) were added. The reaction mixture was stirred at 40-50 °C for 2-8 hours until HPLC showed that <1% compound 3 was remaining. The reactor was cooled to 25 °C. The reaction mixture was filtered through Celite, then a 0.2 micron filter, and the filtrate was collected. The filtrate was extracted with toluene (3 x 150g). The aqueous layer was cooled to 0-5 °C, then acidified with hydrochloric acid (HC1) to pH 2-3 while keeping the temperature < 25°C. The reaction was then cooled to 5-15 °C. The precipitate was filtered and washed with cold water. The cake was dried at 45-55 °C under reduced pressure to constant weight to obtain 291 g (81% yield) compound 4 in 98% AUC purity. No dechlorinated product or Cl-migration product (i.e., de-Cl-4 or m-Cl-4) was observed.

Step (4)

Synthesis of Compound 5 :

Compound 4 (250.0 g), A-l (159.2 g, 1.06 eq) and Methy-THF (5113 g) were charged to the reactor. DIPEA (283.7 g, 2.85 eq), hydroxybenzotriazole (HOBt, 12.5 g, 0.11 eq) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDC.HC1, 216.3 g, 1.47 eq) were added. The reaction solution was stirred at ambient temperature for 6-24 hours, at which point HPLC analysis indicated reaction completion (compound 4 <3%). The mixture was then extracted with a 1M HC1 solution (2270 g), purified water (2270 g), 7% sodium bicarbonate (2270 g), purified water (2270 g), and 25% sodium chloride solution (2270 g). The Methyl-THF was then vacuumdi stilled at < 40 °C and chased repeatedly with isopropyl alcohol. When analysis indicated that <1 mol% methyl-THF was remaining, the mixture was gradually cooled to 0-5 °C and was stirred at 0-5 °C for an at least 2 hours. The resulting precipitate was collected by filtration and washed with cold isopropyl alcohol (700g). The cake was sucked dry on the filter for 4-24 hours, then was further dried at 45-55 °C under reduced pressure to constant weight. 294g (82% yield) was isolated in 99.6% AUC purity and 99.4 wt %.

Step (5)

Synthesis of Compound (I): Hydroxylamine hydrochloride (330g, 10 eq) and methanol (960g) were charged to a reactor. The resulting solution was cooled to 0-5 °C and 25% sodium methoxide (1120 g, 11 eq) was charged slowly, maintaining the temperature at 0-10 °C. Once

the addition was complete, the reaction was mixed at 20 °C for 1-3 hours and filtered, and the filter cake was washed with methanol (2 x 210 g). The filtrate (hydroxylamine free base) was returned to the reactor and cooled to 0±5°C. Compound 5 (220 g) was added. The reaction was stirred until the reaction was complete (compound 5 < 2%). The mixture was filtered and water (280 g) and ethyl acetate (890 g) were added to the filtrate. The pH was adjusted to 8 -9 using HC1 then stirred for up to 3 hours before filtering. The filter cake was washed with cold water (2570 g), then dried under reduced pressure to constant weight to yield 980 g crude solid in 83% yield. The crude solid compound (I) was determined to be Form IV/ Pattern D.

The crude solid (980 g) was suspended in 1-propanol (400 g) and purified water (220 g). The suspension was heated to 40°C. The batch was then cooled to 38°C over 30 minutes. The solution was seeded with crystals of Compund (I) (Form I/Pattern A, 2-5 wt %). The batch was kept at 37-38°C for 2-4 hours, then was gradually cooled to 20±2°C. Water (950 g) was charged over 3 -5 hours. The batch was cooled to 12°C and was stirred for 2 hrs at this temperature. The batch was filtered and washed with cold 1-propanol/water, then dried at 50±5°C to constant weight to yield 910 g purified compound (I) in 93% yield and 99.8% AUC purity.

“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

/////////WO-2016200930, WO 2016200930, New patent, Citarinostat, Acetylon Pharmaceuticals Inc

How to Extend the Life of a Patent

ALL CREDIT TO WIKIHOW
How to Extend the Life of a Patent

Three Methods:

Determining Eligibility

Extending Your Patent

Contacting Congress

A patent ensures that an inventor is able to profit from his or her invention by preventing others from making, using, selling, or importing it without consent. Once the patent expires, the invention is free for the public to use without paying you. If you meet certain requirements, you may wish to extend your patent.Take advantage of this opportunity to have extra time added to your patent term and keep your invention out of the public domain longer.

 

Method1

Determining Eligibility

1. Determine the status of your patent. The United States Patent and Trademark Office (USPTO) keeps a website database of patent information. Access the USPTO database to check on your patent status. If you can’t find all the information you are looking for in the text-based display, then look at the patent image in PDF format.
   

   • You can also look up European patents here.
   • Or check Google Patents.
   • Patents cannot be renewed and you can’t get the rights to an expired patent. ^[1]
    
2. 
   Know what kind of patent you have. In the US, 2 main types of patents are given: utility patents or design patents. Utility patents cover the function of an invention and design patents protect the way an invention looks. Utility patents generally last 20 years, while design patents last 14 years or 15 years for those filed on or after May 13, 2015. There are also 20 year long plant patents for inventors who asexually reproduce a newly discovered or invented variety of plant.^[2]
    
3. 
   Find out if you qualify. Patent extensions are sometimes granted if there are government regulatory delays or if newer laws extend the length of a patent. Sometimes, with very strong justification, you can try to get Congress to pass a bill to extend your patent. If you fall into one of these categories, then you may be able to get your patent extended.
    
4. 
   Be aware that extensions may not be an option. For most inventions, the given term for your patent will stand. Recognize that you may not be able to extend your patent for this particular invention. Focus, instead, on developing a new invention that you can then get a new patent for.
    

 Method2

Extending Your Patent

1. 
   Get a term adjustment. If you filed your patent after May 29, 2000 and your patent was delayed because the USPTO was taking longer than normal to process the paperwork, you may be eligible to file for an extension. The extension will cover the time lost from your patent term for the delay. The length of the extension you are approved for will depend on the delay time frame, but will not be longer than 5 years.
    
2. 
   Increase your original patent term. If you were initially granted less time than later legislation allows, you may be eligible to request an extension on your patent for the newer patent term. Under the Uruguay Rounds Agreements Act, utility patents granted before June of 1995 may be given an extension to 20 years instead of the original 17 years. This does not apply to design patents.
    
3. 
   Get an extension under the Hatch-Waxman Act. A patent term restoration under the Hatch-Waxman Act is sometimes given to those who qualify.This applies to those whose products or processes, such as medications, medical devices, food and color additives, require testing and approval by the Food and Drug Administration's (FDA) before they can be marketed. The period of time that you were unable to sell your product because you were awaiting FDA approval may be restored as an extension to the original patent. ^[3]
    
4. 
   File for an extension with the United States Patent and Trademark Office (USPTO). All application forms for patent extensions can be found on the USPTO website: here for applications filed before September 16, 2012 and here for those filed after this time frame. Know that there are filing fees associated with this application.The process for filing for the extension depends upon which reason for extension the patent falls under.
   

   • Generally, the application for extension must be in writing, include the identifying information for the patent, information about why the applicant is entitled to an extension, relevant dates to determine the length of the extension, copies of the patent documents, etc.
   • Be sure to check with the USPTO for the exact amount of the fee (around $1,000) and the proper procedure for requesting the extension for your case.
    
5. 
   Wait to hear back from the USPTO. It can take up to several months for the USPTO to process your request. As with any government process, patience is best. If you are eligible and have a good reason for an extension, then there's a chance you could be approved so waiting is worth it.
    
6. 
   Request an administrative hearing. If your extension request is denied, you have the right to appeal your denied request. Appeal forms can be found on the USPTO website: here for applications filed before September 16, 2012 and here for those filed after this time frame. Reasons for denial include defects in the paperwork you submitted to the USPTO asking for the extension and your invention being ineligible for extension. File an appeal and address any of the issues that your extension was denied in your written appeal.
   

   • The appeals process begins with your Notice of Appeal and fee payment. It will continue through various steps until it reaches the Patent Trial and Appeal Board. The board will make a decision on your case and complete the appeals process.
    
7. 
   Meet with an intellectual property lawyer. It could be very beneficial to consult with an attorney to review your options, especially if your request is denied. Your lawyer may be able to offer suggestions and ways to supplement your application. Filing for a patent extension can be complex and your lawyer can ensure that it is done correctly.
    

 Method3

Contacting Congress

1. 
   Be realistic. This is the least common form of attempting to extend a patent. Congress may not grant your request unless you have very convincing evidence for doing so. You also may need strong support from the community or a special interest group with persuasive lobbyists on your side.
   

   • Congress extended the copyright of works to 95 years over the original 75 in 1998. This was due mainly to influential corporations like the Walt Disney Company lobbying for the modification.^[4] Keep the kind of influence you may require in mind when you decide to send a bill requesting a patent extension through Congress on your behalf.
    
2. 
   Find a representative. Do some research on representatives in your area or someone you think would want to sponsor you in extending your patent. You will need to convince him or her that there is a very important reason you must extend your patent. It is best if they have a record of supporting the type of invention you have or are connected in some way to that field.
   • Only a member of Congress can propose private legislation to the legislative body.
    
3. 
   Draft a bill. It’s a good idea to do as much of the legwork as possible before approaching your representative. Your bill should be written in legal language and go over the reasons your patent should be granted an extension. You can check existing bills on the Congress website to get an idea what a bill looks like. It might be helpful to consult with a patent attorney when you're writing this as legalese can be difficult to master.^[5]
   • Create a preamble. This is an introduction and general overview about your patent, the date it will expire and an explanation of why you need an extension on your patent.
   • Write up a body clause. This is the meat of your biIl and contains clauses that show what action needs to be taken—in this case, you want your patent to be extended.
   • Finish with an enactment clause. This tells when you want the bill to take effect. This will be the day your patent is due to expire.
   • Know that bills which need to take effect in 90 days or less will need 2/3 majority vote, while those that take effect after that time period will only require a majority vote. Send your bill in as early as possible.^[6]
    
4. 
   Submit your bill to your potential sponsor. Contact your representative by phone or email. Many have websites where you can fill out a form to submit your case. Be sure to ask what the process is like and when you can expect to hear back.
    
5. 
   Get a lobbyist to represent you. If your patent is important to certain groups or not extending it could cause harm, then look for someone with contacts to represent you. Lobbyist groups can put pressure on Congress to extend your patent. In order to do this, you need to have a good cause with far-reaching effects if your patent is not extended.
    
6. 
   Be patient. The legislative process can take time. It must go through multiple committees before the house will vote on it. After that, it must be signed in. The length of time this will take varies and is something you should discuss with your sponsor.
    

 

 

Tips

• It is best to file for an extension as soon as possible, as the USPTO generally takes months to process most filings.

 Warnings

• The request for patent extension should be made 3 months prior to the date on which the patent is set to expire.

 

 

Sources and Citations

1. ↑ http://www.bpmlegal.com/patqa.html#2
2. ↑ http://www.uspto.gov/patents-getting-started/patent-basics/types-patent-applications/general-information-about-35-usc-161
3. ↑ http://corporate.findlaw.com/intellectual-property/patent-term-extensions-and-restoration-under-the-hatch-waxman-act.html#sthash.xuVfZJXF.dpuf

NEW PATENT, WO 2016178162, TENOFOVIR, CBZ INVESTMENTS LTD.

NEW PATENT

WO2016178162,  SYNTHESIS OF INTERMEDIATES USED IN THE MANUFACTURE OF ANTI-HIV AGENTS

CBZ INVESTMENTS LTD. [--/GB]; 122, Feering Hill, Feering, Colchester, Essex CO5 9PY (GB)

PRADHAN, Braja Sundar; (IN).
AMARNATH, Kommireddy; (IN).
VEMPALA, Naresh; (IN).
RAHMAN, Md. Ataur; (IN)

PRADHAN, Braja Sundar

Process for preparing 9-[2-(hydroxyl)propyl]adenine and 9-[2-phosphonomethoxypropyl]adenine, useful as intermediates in the synthesis of anti-HIV agents such as tenofovir disoproxil fumarate (TDF) and tenofovir alafenamide fumarate (TAF).

Represents the first patenting to be seen from CBZ that focuses on tenofovir. Gilead Sciences, under license from the Rega Institute of Medical Research, had developed and launched TDF.

Gilead was also developing TAF, an isopropylalanilyl phenyl ester prodrug of TDF. In November 2016, TAF was reported to be in pre-registration phase.

The present invention relates to a process of preparing intermediates of Formula (I). The process comprises of reacting compound of Formula (III) with compound of Formula (V) in the presence of a solvent selected from an alcohol, ether or water to form compound of Formula (I) wherein, R1 is selected from –NH2, Cl, Br, NHCOR", wherein R" is alkyl, aryl, Schiff's base of formula N=CHR', wherein R' is alkyl or aryl; R2 is selected from H, alkyl; R3 and R4, each independently is H; R5 and R6, each independently is H, alkyl; R7 is H, alkyl; and R8 is H, alkyl.

The US Patent US 5935946A discloses a method for preparation of 9-[2-(R)-(hydroxyl)propyl]adenine. The method involved coupling (R)-1 ,2-propylene carbonate with adenine under basic condition in N, N-dimethylformamide (DMF) at 130°C for 18-30 h to furnish the said product. The referred intermediate compound, (R)-1 , 2-propylene carbonate in turn was prepared in two steps from (S)-Glycidol. In the first step, (S)-Glycidol was subjected to reductive hydrogenation conditions to prepare (R)- 1 ,2-propanediol. In the following step, the diol reacted with diethyl carbonate under suitable reaction conditions to furnish the said carbonate.

A process reported in Technical Reports, Volume 9, Number 14, page 2/7, Joint American Chemical Society, 59th Northwest and 18th Rocky Mountain Regional Meeting, Logan, Utah, June 6-9, 2004 by Robert C. Ronald and John M. Whitaker discloses an entirely different process for the synthesis of the said intermediate compound, (R)-1 , 2-propylene carbonate. The synthesis used ethyl (S)- lactate as the starting material. It was transformed to an intermediate compound, (S)-2-tosyloxy-1 -propanol, which, in the subsequent step, reacted with CO2 in the presence of a phase transfer reagent, 18-crown-6, to provide the required (R)-1 ,2-propylene carbonate.

The process reported in the US Patent US 5935946A suffers from various drawbacks. The first drawback lies in the coupling between (R)-1 ,2-propylene carbonate and adenine. The use of such a high boiling solvent such as Ν, Ν-dimethylformamide as the reaction medium and conducting the reaction at as high a temperature as 130°C for a long duration of time do throw operational and work up challenges in commercial production. Secondly, the preparation of the important intermediate compound, (R)-1 ,2-propylene carbonate, throws a bigger challenge; its preparation when taken into account the preparation of (S)-Glycidol is cumbersome, involving many steps including a step of reductive hydrogenation using a fairly expensive heavy metal catalyst. The second process for preparing (R)-1 ,2-propylene carbonate as reported in Technical Report does not offer any significant advantage even though it uses an inexpensive starting material; the use of the phase transfer reagent, 18-crown-6, renders the process commercially unattractive.

Scheme 1

The reaction scheme for preparing compound of Formula II is represented below:

Scheme 2

Formula II

L-(+)-Lactic axid VIII IX

a. i. Methanol ii. Thionyl cMoride c. i. NaBH4 ii. Methanol / DicMoromethane

d. K2C03

Scheme: 3

Example: 1 Preparation of Methyl L-(+)-lactate (VIII)

Thionyl chloride (96.72 ml) was added drop by drop to a solution of L-(+) lactic acid (100 g) in methanol (500 ml) at -10°C over a period of 1 h. After the completion of addition, the reaction mixture was warmed to room temperature and stirred at this temperature until the reaction was complete as indicated by TLC. The reaction mixture was concentrated at 90°C to furnish an oil which was dissolved in dichloromethane (250 ml). The organic layer was washed with saturated sodium bicarbonate solution (2 X 150 ml), dried over sodium sulfate and concentrated at 50°C to give VIII; yield: 79 g.

Example: 2 Preparation of Methyl 2-(S)-methylsul†onyloxypropionate (IX)

Triethylamine (107 ml) was added to a cold, stirred solution of methyl (S)-lactate (40 g) in dichloromethane (400 ml) -10°C. Methanesulfonyl chloride (38.8 ml) was added to the reaction mixture drop by drop over a period of 1 h at this temperature, and the reaction mixture was stirred at this temperature for about 2 h when the reaction was complete, as indicated by TLC. The reaction mixture was poured on cold water (400 ml) and stirred for 10 minutes. The separated organic layer was washed with 5 % dilute hydrochloric acid (1 X 80 ml), saturated sodium bicarbonate solution (1 X 100 ml), brine (1 X 100 ml), dried over sodium sulfate and concentrated at 50°C to furnish the desired product; 48.2 g.

Example: 3 Preparation of 2-(R)-(+)-propylene oxide (V)

Method: A

Methanol (6 ml) was added to a solution of the mesylated methyl (S)-lactate (3 g) in dichloromethane (9 ml). The reaction mixture was cooled to -10°C and sodium borohydride (748 mg) was added to the mixture in divided portions over a period of 0.5 h at this temperature. After 4 h at this temperature, when the reaction was complete as indicated by TLC, the reaction mixture was diluted with water (10 ml) and dichloromethane (20 ml) and warmed to room temperature. After 10 minutes at room temperature, layers were separated. The organic layer was washed with

10 % aqueous citric acid solution (1 X 10 ml), brine (1 X 10 ml), dried over sodium sulfate and concentrated under reduced pressure at 40°C to give mesylated alcohol; yield: 1 .1 g. The crude mesylated alcohol was treated with potassium carbonate, and distilled to furnish (R)-(+)-propylene oxide.

Example: 4 Preparation of 2-(R)-hydroxypropanol (XII)

Sodium borohydride (1 .81 g) was added to a stirred, cold solution of methyl (D)-lactate (5 g) in methanol (25 ml) at -5°C in divided portions over a period of 0.5 h. The reaction mixture was stirred at this temperature for 3 h when the reaction was complete as indicated by TLC. The reaction mixture was neutralized with concentrated hydrochloric acid until the pH of the mixture attained the range 6- 7, and then concentrated under reduced pressure at 40°C. The residue thus obtained was dissolved in ethyl acetate (30 ml) and filtered. The filtrate was washed with water (1 X 20 ml), brine (1 X 5 ml), dried over sodium sulfate and concentrated under reduced pressure at 40°C to give the product XII; yield: 1 .97 g.

Example: 5 Preparation of 2-(R)- (+)-propylene oxide (V)

Method: B

Pyridine (1 .58 ml) was added to a solution of the diol (XII) (0.5 g) in dichloromethane (6 ml) at room temperature. 4-Tolunesulfonyl chloride (1 . 5g) was added at -78°C and the reaction mixture was allowed to warm to room temperature. The reaction mixture was stirred at this temperature

until the reaction was complete as indicated by TLC. The reaction mixture was poured into cold water to separate the layers. The organic layer was washed with 10% dilute hydrochloric acid, water, brine, dried over sodium sulfate and concentrated at 40°C to furnish a residue which was purified to furnish the said compound XIII; yield: 0.7 g. The alcohol was was treated with potassium carbonate, and distilled to furnish (R)-(+)-propylene oxide.

Example: 6 Preparation of 9-[2-(R)-(Hydroxy)propyl]adenine (I)

Method-A

Sodium hydroxide (3 g) was added to a stirred suspension of adenine (10 g) in water (50 ml) at room temperature, and the reaction mixture was heated to 100-1 10°C. After 5 hrs at this temperature, the reaction mixture was allowed to cool down to 25°C. Ammonium chloride (3.96 g) and 2-(R)-(+) propylene oxide (6.44 g) were added in succession to the reaction mixture at this temperature. The reaction mixture was maintained at this temperature until the reaction was complete as indicated by TLC. The reaction mixture was concentrated under reduced pressure at 55°C to furnish the desired product, contaminated with unidentified polar impurities. The crude material was purified by column chromatography using a solvent system comprising of methanol and dichloromethane (1 : 9) as the eluant to furnish 9-[2-(R)- (hydroxyl)propyl]adenine as a white solid; yield: 5.5 g.

Example: 7 Preparation of 9-[2-(R)-(Hydroxy)propyl]adenlne (I)

Method-B

Potassium tert-butoxide (4.15 g) was added to a stirred suspension of adenine (10 g) in methanol (150 ml) at 0°C. The reaction mixture was allowed to warm to room temperature, and stirred at this temperature for 30 minutes. R-(+)-Propylene oxide (6.44 g) was added and the reaction mixture was stirred at this temperature until the reaction was complete, as indicated by TLC. The reaction mixture was neutralized with methanesulfonic acid and filtered. The filtrate was concentrated under reduced pressure to furnish the desired product, contaminated with unidentified polar impurities. The crude material was purified by column chromatography using a solvent system comprising of methanol and dichloromethane (1 :9) as the eluant to furnish 9-[2-(R)-(hydroxyl)propyl]adenine as a white solid; yield: 6.2 g.

Example: 8 Preparation of 9-[2-(R)-(Hydroxyl)propyl]adenine (I) Method-C

Potassium carbonate (204 mg) was added to a stirred suspension of adenine (5 g) in a solvent mixture comprising of methanol (13 ml) and N,N-dimethylformamide (2.5 ml) at 0°C. The reaction mixture was allowed to warm to room temperature. (R)-(+)-Propylene oxide (3.78 ml) was added to the reaction mixture in three divided batches over a period of 20 h, and the reaction mixture was stirred at this temperature until the reaction was complete, as indicated by TLC. The reaction mixture was neutralized with methanesulfonic acid and concentrated under reduced pressure. Toluene (15 ml) was added to the residue thus obtained. The reaction mixture was cooled to 0°C and stirred at this temperature for 2 h to maximize the precipitation of the desired compound. The precipitated material was filtered and dried to furnish 9-[2-(R)-(hydroxyl)propyl]adenine, crude yield: 6.8 g. The product was contaminated with unidentified polar impurities. The crude material was carried over to the following step without any purification.

Example: 9 Preparation of 9-[2-(R)-(hydroxyl)propyl]adenine (I)

Method-D

Magnesium di-tert-butoxide (630 mg) was added to a stirred suspension of adenine (5 g) in a solvent mixture comprising of methanol (15 ml) and N,N-dimethylformamide (15 ml) at 0°C. The reaction mixture was warmed to room temperature. (R)-(+)-Propylene oxide (3.78 ml) was added to the reaction mixture in three divided batches over a period of 20 h and the mixture was stirred at room temperature until the reaction was complete, as indicated by TLC. The reaction mixture was then neutralized with methanesulfonic acid and concentrated under reduced pressure. Toluene (15ml) was added to the residue thus obtained. The reaction mixture was cooled to 0°C and stirred at this temperature for 2 h to maximize the precipitation of the desired compound. The precipitated material was filtered and dried to furnish 9-[2-(R)-(hydroxyl)propyl]adenine, crude yield: 6.4 g. The product was contaminated with unidentified polar impurities. The crude material was carried over to the following step without any purification.

Example: 10 Preparation of 9-[2-(R)-(Hydroxyl)propyl]adenine (I) Method: E

Magnesium di-tert-butoxide (100 mg) was added to a stirred suspension of adenine (2 g) in methanol (12 ml) at 0°C. After 6 h at this temperature, sodium hydroxide (24 mg) and (R)-(+)Propylene oxide (1 .25 g) were added in succession to the reaction mixture. The mixture was allowed to warm to room temperature, stirred at this temperature until the reaction was complete as indicated by TLC and concentrated under reduced pressure. Toluene (6 ml) was added to the residue thus obtained. The reaction mixture was cooled to 0°C and stirred at this temperature for 2 h to maximize the precipitation of the desired compound. The precipitated material was filtered and dried to furnish 9-[2-(R)-(hydroxyl)propyl]adenine, crude yield: 3.2 g. The product was contaminated with unidentified polar impurities. The crude material was carried over to the following step without any purification.

Example: 11 Preparation of 9-[2-(R)-(phosphonomethoxy)propyl] adenine (II).

Method-A

Magnesium di-tert-butoxide (51 mg) was added to a stirred suspension of adenine (2 g) in methanol (12 ml) at 10°C. After 4 h at this temperature, sodium hydroxide (12 mg) and (R)-(+)-propylene oxide (1 .25 g) were added in succession to the reaction mixture. The reaction mixture was allowed to warm to room temperature and stirred at this temperature until the reaction was complete, as indicated by TLC. Methanol was evaporated under vacuum. N, N-Dimethylformamide (16 ml) was added to the crude reaction mixture thus obtained and the mixture was heated to 60-70°C. Magnesium di-tert-butoxide (7 g) was added to the reaction mixture in four divided batches over a period of 15 minutes at this temperature. The mixture was heated to 80-90°C, and stirred at this temperature for 30 minutes. Diethyl p-toluenesulfonyloxymethylphosphonate (13.2 g) was added drop by drop to the reaction mixture over a period of 4 h, and the mixture was stirred at this temperature until the reaction was complete, as indicated by TLC. N, N-Dimethylformamide was distilled out under vacuum at 90-100°C. Aqueous hydrobromic acid (48% w/w, 30 ml) was then added to the residue and the reaction mixture was heated to gentle reflux. After approximately 20 h at this condition, the reaction mixture was allowed to cool down to room temperature and filtered. The filtered solid was washed with dichloromethane (10 ml). The washing was concentrated to furnish a residue. The residue was combined with the filtrate and the combined filtrate was washed with dichloromethane (2 X 10 ml). To the aqueous layer, an aqueous solution of sodium hydroxide (50 %) was added until the pH attained 2.1 -3. After several hours at room temperature, the aqueous layer was cooled to 0- 5°C and stirred at this temperature for further hours to maximize precipitation of the desired product from the solution. The precipitated solid was filtered, washed with cold water (1 X 5 ml), acetone (2X 5 ml) and dried to obtain 9-[2-(R)-(phosphonomethoxy)propyl]adenine; yield: 1 .42 g.

Example: 12 Preparation of 9-[2-(R)-(phosphonomethoxy)propyl] adenine (II)

Method-B

Magnesium di-tert-butoxide (1 .76 g) was added in four divided batches to a stirred suspension of 9-[2-(R)-(hydroxyl)propyl)adenine] (1 g) in N, N-dimethylformamide (3 ml) at 60-70°C over a period of 1 h. The reaction mixture was heated to 90°C and diethyl chloromethylphosphonate (1 .93 g) was added drop by drop to the reaction mixture over a period of 4 h. The reaction mixture was maintained at this temperature until the reaction was complete, as indicated by TLC. Ν, Ν-Dimethylformamide was distilled out under vacuum at 90-100°C. To the residue thus obtained, aqueous hydrobromic acid (48% w/w, 10 ml) was added and the reaction mixture was heated to gentle reflux. After approximately 20 h at this condition, the reaction mixture was allowed to cool down to room temperature and filtered. The filtered solid was washed with dichloromethane (10 ml). The washing was concentrated to furnish a residue. The residue was combined with the filtrate and the combined filtrate was washed with dichloromethane (2 X 10 ml). To the aqueous layer, an aqueous solution of sodium hydroxide (50%) was added until the pH attained 2.1 -3. After several hours at room temperature, the aqueous layer was cooled to 0-5 °C and stirred at this temperature for further hours to maximize precipitation of the desired product from the solution. The precipitated solid was filtered, washed with cold water (1 X 5 ml), acetone (2 X 5 ml) and dried to obtain 9-[2-(R)-(phosphonomethoxy)propyl]adenine; yield: 0.7 g.

Example: 13 Prepration of diethyl (chloromethyl)phosphonate (VI)

Pyridine (108 ml) was added to a stirred solution of (hydroxymethyl)phosphonic acid (50 g) in benzene (300 ml) at room temperature. The reaction mixture was heated to 60°C. Thionyl chloride (100 ml) was added to the mixture over a period of 30 min at this temperature. After 1 h at this temperature, the reaction mixture was allowed to cool down to room temperature, stirred for 3 h at this temperature and cooled to 10°C. The precipitated solid was filtered and washed with benzene (100 ml). The washing was combined with the filtrate and the combined filtrate was concentrated at 100°C to furnish an oil. The oil was fraction distilled under reduced pressure to furnish a

colourless liquid; yield: 22 g. The liquid was cooled 0°C. Ethanol (40 ml) was added to the liquid at this temperature. The reaction mixture was allowed to warm to room temperature, stirred for 3 h at this temperature and diluted with dichloromethane (100ml). The combined organic layer was washed with water (2 χ 50 ml), brine (50 ml), dried over sodium sulfate and concentrated under reduced pressure to furnish diethyl (chloromethyl)phosphonate as a colorless liquid; yield: 18 g.

Ph.D. CSIR Indian Institute of Chemical Technology, Hyderabad, India
Advisor: Dr. J. S. Yadav
M.Sc. Jamia Millia Islamia, New Delhi, India

mdataur_rahman@fas.harvard.edu

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