Patents....Merits of applying in India

 Flowchart of the Process from Application to Grant of a Patent
INDIA

Merits of applying in India

Applying for intellectual property rights in India has the following merits to it.

(1) India is one of the four BRICs countries, attracting attention as a market where high economic growth in the near future is likely.

(2) Because India accepts applications in English, the applicant can use applications in Europe or the United States to apply and thereby save on translation expenses.

(3) Because India is a member of the Paris Convention, the applicant may claim priority when filing a patent granted in Japan.

(4) India is a member of the Patent Cooperation Treaty (PCT) and accepts national phase applications under the PCT.

2. Patents

• 2.1 Duration

Patent rights in India last for twenty years from the application date (India Patent Act Section 53). However, unlike in Japan, there is no system for lengthening the duration of pharmaceutical product inventions, et cetera.

• 2.2 Inventions Subject to Protection

Section 3 of the Indian Patent Act gives specific examples of “things that are not patents.” In India, material patents are acknowledged, but “the mere discovery of a new form of a known substance” (India Patent Act Section 3[d]). Regarding already-known derivatives such as salts, unless they substantially differ in efficacy from known substances, they are considered equivalent to the known substances.

Software itself will not be awarded a patent, but software that is combined with some form of hardware may pass.

India does not have a utility model system.

• 2.3 Application

Figure 1 shows the flow of a patent application from the opening of an application to registration of a patent. Here follows a simple explanation of each stage.

- Application -

Because India is a member of the Paris Convention, the applicant may claim priority based on a Japanese patent application.

Because India is a member of the PCT, the applicant may specify India in a PCT international application.

Within six months of application, the applicant must submit information on foreign applications (India Patent Act Section 8 [1], India Patent Rules 12 [1A]). If before the grant or rejection of grant of a patent, the Controller requests particular details concerning the processing of the application in other countries, the applicant must submit such details (India Patent Act Section 8 [2], Patent Rules 12 [3]).

- Publication of the Application -

An application is published eighteen months from either the date of application or the priority date of the relevant application (India Patent Rules 24). If an applicant wishes to acquire patent rights early, he or she should utilize the early publication system (India Patent Act Section 11 [2]).

- Request for Examination -

The applicant must make a request for examination within forty-eight months of the priority date of the relevant application or of the application date (India Patent Rules 24B). If the request is not made within this period, the India Patent Office will treat the application as if it had been withdrawn (India Patent Act Section 11 [B]).

- Examination -

If the examiner finds any objections to granting a patent, a First Examination Report is issued. If the applicant responds to this office action, the examiner will examine the application again. If no reason is found for rejection, a decision to grant the patent is made.

If the applicant does not revise the application so that grant of a patent is possible within twelve months (the Acceptance Period) after the First Examination Report is sent, the application will be treated as abandoned (India Patent Act Section 21 [1], India Patent Rules 24 [B]).

If an application is rejected, the applicant may file a request for re-examination (under India Patent Act Section 77 [f]) or appeal (under India Patent Act Section 117A).

(Procedures that the Applicant May Take during the Examination Period)

(a) Amendment

With permission from the Controller, the applicant may amend the application (India Patent Act Section 57). However, the Controller will not recognize an amendment when the amended specification claims or describes things that were not substantially disclosed or indicated in the specification prior to the amendment, or when the claims of the amended specification will not completely fit within the parameters of the pre-amendment specification’s claims (India Patent Act Section 59).

(b) Divisional Application

If a patent has not yet been granted, the applicant may divide the application at any time (India Patent Act Section 16).

(c) Interview with the Examiner

The applicant may seek to have an interview with the examiner after the examiner has begun to examine the application. According to representatives in India, an interview with the examiner is an extremely effective measure.

- Opposition to Grant of a Patent Prior to the Granting of the Patent -

After the publication of a patent application, if a patent has not been granted, anyone may register an opposition to the patent grant with the Controller (India Patent Act Section 25 [1]).

• 2.4 After Grant of a Patent

Following the grant of a patent and up to one year after the announcement of the grant of the patent, anyone privy to the matter may register an opposition to the grant (India Patent Act Section 25 [2]).

Apart from an opposition to the grant of a patent, one may file an application to have the patent revoked (India Patent Act Section 64).

The patentee must give a working statement regarding exploitation of the patent annually (Indian Patent Act Section 146, India Patent Rules 131 [2]).

A patented invention that has not been exploited in India’s territory within three years after the granting of the patent may be cause for grant of a compulsory license (India Patent Act Section 84).

If two years have passed since the order for the first licensing of a compulsory license and the patented invention is still not being exploited in India’s territory, the patent may be revoked (India Patent Act Section 85).

3. Designs

• 3-1. Duration

The duration of a design is ten years from its registration date and may be extended only once for five more years (India Designs Act Section 11). Note that the registration date is treated as the date of application for registration (India Design Act Section 5 [6]).

• 3.2 Designs Subject to Protection

Section 2(d) of the India Designs Act defines design: “‘design’ means only the features of shape, configuration, pattern, ornament or composition of lines or colours applied to any article . . . by any industrial process or means . . .”

Section 2(a) of the India Designs Act defines article: “‘article’ means any article of manufacture and any substance, artificial, or partly artificial and partly natural and includes any part of an article capable of being made and sold separately.” Furthermore, “partial designs” which cannot be sold independently of a whole design are not protected.

• 3.3 Application

Because India is a member of the Paris Convention, the applicant may claim priority based on a Japanese right.

A request for examination is not necessary (India Designs Act Section 5).

If the examination results in a rejection decision, the applicant may appeal to the High Court (India Designs Act Section 5 [4]).

• 3.4 After Grant of a Design

Anyone privy to the matter may file an application to have the design right revoked (India Designs Act Section 19).

4. Trademarks

• 4.1 Duration

Trademarks are protected for ten years. Trademark protection may be extended with an application for renewal.

• 4.2 Trademarks Subject to Protection

In addition to product trademarks, service marks are protected (India Trademark Act Section 2 [1] [zb]).

There is a system for organizational trademarks (Section 61).

Three-dimensional shapes and color combinations are also protected (Section 2 [1] [m]).

• 4.3 Application

Because India is a member of the Paris Convention, the applicant may claim priority based on a Japanese right. However, India is not a member of the Madrid Protocol.

As in Japan, India follows the one application, one trademark policy, but within one application the applicant may specify multiple sections (India Trademark Act Section 18).

The applicant may pay an additional fee to request an early examination (India Trademark Rules Section 38 [1]).

If the result of the examination is a rejection decision, the applicant may make an appeal (under India Trademark Act Section 91).

India has a system for challenging trademarks, and for the three months after the trademark is announced, anyone may register an objection to the trademark grant (India Trademark Act Section 25 [1]).

• 4.4 After Registration

In renewal examinations, whether or not the trademark is actually being used is not judged.

Anyone privy to the matter may request a trial for invalidation of a trademark (India Trademark Act Section 57).

If a trademark is not used for five years and three months, it may be subject to a trial for cancellation for non-use (India Trademark Act Section 47).

When the agent or representative of an owner of the a registered trademark files a registration or other paperwork in his or her own name without receiving a power of attorney, the owner of the trademark may register an objection against this paperwork (India Trademark Act Section 146). However, the owner must do so within three years of knowing of the problem.

[Bibliography]

1. International Association for the Protection of Intellectual Property (AIPPI) Japan. Investigation report on India’s intellectual property protection systems and their operation statuses. 2007.

2. “The influence of India’s Patent Act revisions.” In Patento 61, No. 2 (2008), 42-48.

3. Third International Committee. Points to remember when acquiring patents in countries of Asia and Oceania. Revised edition. Resource No. 332. May 2006.

C-aryl glucoside sglt2 inhibitors and method for their production WO 2006034489 A2

D-​Glucitol, 1,​5-​anhydro-​1-​C-​[4-​chloro-​3-​[(4-​ethylphenyl)​methyl]​phenyl]​-​, (1S)​-

(2S,3R,4R,5S,6R)-2-(3-(4-ethylbenzyl)-4-chlorophenyl)-6-(hydroxymethyl)-tetrahydro-2H-pyran-3,4,5-triol
cas  879545-38-7

http://www.google.com/patents/WO2006034489A2?cl=en

EXAMPLE 1

A. 5-Bromo-2-chloro-4'-ethylbenzophenone

[00119] To a 2L round bottom flask containing a magnetic stirred suspension of commercial 5-bromo-2-chlorobenzoic acid (41Og, 1.74 mol) in 700 mL OfCH₂Cl₂ ^'was added oxalyl chloride (235g, 1.85 mol) followed by 1.5 mL of DMF. To trap the resultant HCl, the flask was fitted with tubing so that the gas was discharged above the surface of a stirred aq KOH solution. When the vigorous evolution of gas ceased after two hours, the homogeneous reaction was stirred overnight prior to removal of the volatiles under vacuum using a rotary evaporator. 

The resultant oil solidified during subsequent evacuation. [00120] After dissolving the crude 5-bromo-2-chlorobenzoyl chloride in 530 ml of ethylbenzene, the yellow solution was cooled to -3⁰C prior to adding AlCl₃ (257g, 1.93 mol) in ~30g portions over 60 min to insure that the temperature did not exceed 1O⁰C. The copious amounts of HCl gas which began to evolve after 60% of the AlCl₃ had been added were trapped by passing the gas over a stirred cone. 

NaOH solution. If the reaction were more concentrated, a magnetic stirrer could not have maintained stirring upon completion of the addition of AlCl₃. After stirring for 1 hr as the bath warmed to ~15°C, the bath was removed. After 4 hr at 2O⁰C, the thick syrup was poured over ice (1.5 kg). Subsequently, once the stirred suspension had cooled, H₂O (IL ) was added prior to being extracted 4x with EtOAc. The combined organic extracts were washed 2x with IN HCl, 3x with IM KOH, and 2x with brine prior to drying over Na₂SO₄. The volatiles were removed using first a rotary evaporator and then by heating at ~60°C at 1 Torr. IH NMR analysis of the resultant dark oil revealed the residue to be a 1 : 14 mixture of ortho/para isomers. Dissolution in hexane and followed by filtration through a silica gel pad removed most of the color. Concentration of the eluent yielded 56Og (99%) of a 14:1 mixture of 5-bromo-2- chloro-4 ' -ethylbenzophenone / 5 -bromo-2-chloro-2 ' -ethylbenzophenone. [00121] HPLC retention time: 4.7 min, YMC S5 C-18 4.6x50mm column, 2.5 mL/min, detection at 22OnM; 4 min gradient 0-100% B hold 2 min at 100% B. Solvent A: 10% MeOH/H₂O + 0.2 % H₃PO₄. Solvent B: 90% MeOH/H₂O + 0.2 % H₃PO₄.

5-Bromo-2-chIoro-4'-ethyIbenzophenone

[00122] ¹H NMR (400 MHz, CDCl₃) δ 7.73 (d, 2H, JAB = 8.2 Hz), 7.54 (dd, IH, J = 2.2 Hz, J = 8.8 Hz), 7.32 (d, IH, J = 8.8 Hz), 7.295 (d, 2H, J_AB = 8.2 Hz), 2.72 (q, 2H, JK7.7 Hz), 1.27 (t, 3H, J=7.7 Hz).

[00123] ¹³C NMR (100 MHz, CDCl₃) δ 193.13. 151.33, 140.49, 133.8, 133.52, 131.6, 131.44, 130.34, 130.16, 128.28, 120.44, 29.04, 15.02. 5-Bromo-2-chloro-2'-ethylbenzophenone (distinctive signals) [00124] ¹K NMR (400 MHz, CDCl₃) δ 2.64 (q, 2H, J=7.7 Hz), 1.23 (t, 3H, J=7.7 Hz). [00125] ¹³C NMR (100 MHz, CDCl₃) δ 28.9, 15.5.

B. 5-Bromo-2-chloro-4'-ethyldiphenylmethane 

[00126] To a stirred solution OfEt₃SiH (400 g, 3.45 mol and 5-bromo-2-chloro-4'- ethylbenzophenone (534g, 1.65 mol) containing -7% of the isomeric ketone in 300 mL of TFA at 30⁰C was added CF₃SO₃H (1.5 g, 0.01 mol). Within minutes the temperature increased causing the solution to reflux violently. Caution this moderate exotherm requires cooling with an external ice bath. After 1 hr, HPLC revealed the reaction to be 90% complete. After addition of an additional Et₃SiH (2Og ) and heating overnight at 70⁰C, the reaction was > 95% complete by HPLC analysis. Upon cooling, the volatiles were removed by bulb to bulb distillation at reduced pressure. The resultant ~ IL of light gray oil was poured into IL OfH₂O. The mixture was extracted 3x with hexane; the combined organic layers were washed 3x with H₂O, 2x with aq Na₂CO₃ and 2x with brine before drying over Na₂SO₄. After concentration using a rotary evaporator, ~ 1 L of clear light amber oil remained. 

This material was further concentrated; the (Et₃Si)₂O (450 mL) was removed by distillation at 0.6 Torr. Once the temperature at the distillation head reached 75°C, the pot was allowed to cool. IH NMR analysis of the pot revealed it to contain an ~ 8: 1 mixture of diarylmethane to (Et₃Si)₂O. Crystallization of this mixture was achieved by pouring the product into vigorously stirred 10⁰C 85% EtOHTH₂O (1.2L), After stirring for several hours, the crystals were collected by filtration, washed with cold 1:1 EtOHZH₂O and dried under vacuum. The 5~bromo~2-chloro-4'-ethyldiphenyl- methane (500 g), obtained as a low melting solid containing ~1% (Et₃Si)₂O, was used without further purification.

[00127] HPLC retention time: 5.3 min, YMC S5 C-18 4.6x50mm column, 2.5 mL/min, detection at 22OnM; 4 min gradient 0-100% B hold 2 min at 100% B. Solvent A: 10% MeOH/H₂O + 0.2 % H₃PO₄. Solvent B: 90% MeOH/H₂O + 0.2 % H₃PO₄.

[00128] ¹H NMR (125 MHz, CDCl₃) δ 7.27-7.23 (m, 3H), 7.14 (d, 2H, J_AB = 7.7 Hz), 7.09 (d, 2H, JA_B = 7.7 Hz), 2.63 (q, 2H, J=7.7 Hz), 1.23 (t, 3H, J=7.7 Hz). [00129] ¹³C NMR (100 MHz, CDCl₃) δ 142.46. 141.08, 135.68, 133.64, 133.13, 130.85, 130.55, 128.83, 128.1, 120.0, 38.62, 28.43, 15.51.

C. 2,3,4,6-tetra-O-TrimethyIsilyl-D-gIucolactone [00130] To a stirred -5°C solution of gluconolactone (239g, 1.34 mol) and N- methylmorpholine (1180 mL, 10.73 mol) in 2.4L of THF under Ar was added trimethylsilyl chloride (1022 mL, 8.05 mol) via dropping funnel at a rate such that the temperature did not exceed 5⁰C. After 1 hr the stirred reaction was heated to 35⁰C for 5 hr whereupon it was allowed to cool to 20⁰C as the reaction stirred overnight. After dilution with 3.6L of toluene, the mixture was cooled to 0-5⁰C prior to cautiously adding 7L OfH₂O at a rate such that the temperature did not exceed 10°C. Note a severe exotherm results upon addition of the first portion OfH₂O. After mixing, the phases were allowed to separate and then split. The organic phase was washed with aq. NaH₂PO₄ (2L), H₂O (IL), and brine (IL). The organic layer was then concentrated under vacuum using a rotary evaporator; the resultant light yellow oil was twice taken up 250 mL of toluene and reconcentrated to yield 616g. 

D.

[00131] To a stirred -78° solution of Part B 5-bromo-2-chloro-4'- ethyldiphenylmethane (88g, 0.28 mol) in 450 niL of 1 :2 dry THF/toluene under Ar was slowly added 2.5 M n-BuLi (136 niL, 0.34 mol) in hexane at a rate that maintained the temperature below -55°. After stirring for 10 minutes following the addition, this solution was transferred by cannula to a stirred -78° solution of Part C 2,3,4,6-tetra-O-trimethylsilyl-D-glucolactone (153g, 0.33 mol) in toluene (350 mL )at a rate that maintained the reaction below -55°. The solution was stirred for 30 min at - 78° prior to quenching by addition of 400 mL of MeOH containing methanesulfonic acid (28 mL, 0.45 mol). 

The reaction was stirred overnight for 18 hr at 2O⁰C. The reaction was stirred overnight for 18 hr at 2O⁰C. HPLC analysis revealed a new peak which by LC/MS correspond to the mass of the expected O-methylglucoside. The reaction, once complete, was quenched by the addition OfNaHCO₃ (42 g, 0.5 mol) in 200 mL ofH₂O. If the pH was not weakly basic, more NaHCO₃ was added prior to dilution 2 fold with H₂O and 3 extractions with EtOAc. The combined EtOAc fractions were washed with brine and dried over Na₂SO₄. After concentration using a rotary evaporator, the oil (14O g, 90% pure by HPLC analysis) was not further purified but instead was carried forward as an impure diastereomeric mixture.

[00132] ¹H NMR (400 MHz, CDCl₃) δ 7.37 (m, IH), 7.23 (m, 2H), 7.02 (m, 4H), 5.14 (m, IH), 5.06 (m, IH), 4.07 (m, IH), 4.03 (d, IH, JA_B = 15.4 Hz), 3.97 (d, IH, JAB = 15.4 Hz), 3.80 - 3.70 (m, 4H), 3.60 (m, IH), 3.48 (m, IH), 3.31 (m, IH), 2.84 (s, 3H), 2.53 (q, 2H, J =7.5 Hz ), 1.14 (t, 3H, J =7.5 Hz). [00133] ¹³C NMR (100 MHz, CDCl₃) δ 144.4, 140.7, 138.94, 136.9, 132.51, 131.6, 130.96, 130.6, 130.2, 129.16, 103.36, 77.0, 74.86, 72.48, 64.27, 51.57, 41.33, 30.75, 17.9. [00134] HPLC retention time: 4.28 min, 90% pure, YMC S5 C-18 4.6x50mm column, 2.5 mL/min, detection at 22OnM; 4 min gradient 0-100% B hold 2 min at 100% B. Solvent A: 10% MeOH/H₂O + 0.2 % H₃PO₄. Solvent B: 90% MeOH/H₂O + 0.2 % H₃PO₄. [00135] LC/MS: [M-OMe]⁺ 391, 393; [M+Naf 445, 447.

E.

[00136] A solution of Part D O-methylglucoside (206g, 0.49 mol) in THF (1 L) containing diisopropylethylamine (465 g, 3.6 mol) and DMAP (0.5g, 4.1 mmol) was cooled to O⁰C. Acetic anhydride (326g, 3.19 mol) was slowly added at such a rate that the temperature did not exceed 5°C. After the solution gradually warmed to 20⁰C, it was stirred for 10 hours whereupon tic analysis revealed complete conversion to the tetraacetate. The reaction was quenched by addition of EtOAc (1.5 L) and 10% aq. H₃PO₄ (1.5 L). After separation of the layers, the aq. phase was extracted 2x with EtOAc. The combined organic phases were washed Ix with brine prior to drying over Na₂SO₄ and concentration under vacuum. The resultant oil was dissolved twice in 300 mL of toluene and reconcentrated to yield a thick oil (30Og, 95% HPLC purity) that was used without further purification of the resulting impure diastereomeric mixture.

[00137] ¹H NMR (400 MHz, CDCl₃) δ 7.38 (d, IH, J = 8.3 Hz), 7.28 (dd, IH, J = 8.3 Hz, J = 2.2 Hz), 7.24 (d, IH, J = 2.2 Hz), 7.11 (d, 2H, JAB = 8.3 Hz), 7.04 (d, 2H, JAB = 8.3 Hz), 5.56 (t, IH, J = 9.7 Hz), 5.21 (t, IH, J = 10.1 Hz), 4.93 (t, IH, J = 10.1 Hz), 4.20 (dd, IH, J = 12 Hz, J = 2 Hz), 4.12 (d, IH, JA_B = 15.4 Hz), 4.02 (m, IH)₅ 4.018 (d, IH, JAB = 15.4 Hz), 3.10 (s, 3H), 2.606 (q, 2H, J = 7.7 Hz), 2.097 (s, 3H), 2.05 (s, 3H), 1.94 (s, 3H), 1.72sd (s, 3H), 1.21 (t, 3H, J=7.7 Hz) . [00138] ¹³C NMR (100 MHz, CDCl₃) δ 170.7, 170.05, 169.47, 168.9, 142.2, 138.74, 136.4, 135.1, 134.7, 129.8, 129.4, 128.6, 128.0, 126.0, 100.02, 73.83, 71.33, 68.87, 68.77, 62.11, 49.43, 38.75, 28.4, 22.64, 20.68, 20.58, 20.16, 15.5. [00139] HPLC retention time: 4.81 min, 90% pure, YMC S5 C-18 4.6x50mm column, 2.5 mL/min, detection at 22OnM; 4 min gradient 0-100% B hold 2 min at 100% B. Solvent A: 10% MeOHTH₂O + 0.2 % H₃PO₄. Solvent B: 90% MeOHTH₂O + 0.2 % H₃PO₄.

F.

[00140] A stirred solution of the above crude oil (301g, 0.51 mol) in CH₂Cl₂ (500 mL) containing one equivalent of H₂O (9g, 0.5 mol) and Et₃SiH (188g, 1.62 mol) was cooled to -2O⁰C prior to addition OfBF₃-Et₂O (145g, 1.02 mol). During the addition, the temperature was maintained < 0⁰C. The reaction was subsequently stirred 2hr at 10⁰C and 18 hr at 15 - 2O⁰C before being quenched by addition of CH₂Cl₂ (500 mL) and H₂O (500 mL). After separation of the layers, the aq phase was extracted once with CH₂Cl₂. The combined organic layers were washed Ix with aq NaHCO₃ and brine prior to drying over Na₂SO₄. After removal of the Na₂SO₄ by filtration, Ac₂O (6.4g, 65 mmol), diisopropylethylamine (9.5g, 74 mmol) and DMAP (lOOmg, 0.8 mmol) were added. The solution was stirred at 20⁰C for 18 hr to insure that any glucoside hydroxyls that hydrolyzed during the reduction and work-up were reacetylated. The oil, obtained after concentration under vacuum, crystallized upon addition of EtOH. After filtration the purity of this material by HPLC was 98%; recrystallization from EtOH yielded the tetraacetylated beta-C-glucoside as a white solid (18Og, 99.8% purity. The overall conversion for procedures D - F was 61%. [00141] HPLC retention time: 4.74 min, 100% pure, YMC S5 C-18 4.6x50mm column, 2.5 niL/min, detection at 22OnM; 4 min gradient 0-100% B hold 2 min at 100% B. Solvent A: 10% MeOH/H₂O + 0.2 % H₃PO₄. Solvent B: 90% MeOHTH₂O + 0.2 % H₃PO₄. [00142] ¹H NMR (500 MHz, CDCl₃) δ 7.35 (d, IH, J = 8.2 Hz), 7.19 (dd, IH, J = 8.2 Hz, J = 2.2 Hz), 7.11 (d, 2H, JA_B = 8.5 Hz), 7.086 (d, IH, J = 2.2 Hz), 7.06 (d, 2H, JA_B = 8.5 Hz), 5.28 (t, IH, J = 9.7 Hz), 5.20 (t, IH, J = 9.7 Hz), 5.04 (t, IH, J = 9.7 Hz), 4.31 (d, IH, J = 9.9 Hz), 4.26 (dd, IH, J = 12 Hz, J = 5 Hz), 4.135 (dd, IH, J = 12 Hz, J = 5 Hz), 4.095 (d, IH, J_AB = 7.7 Hz), 3.995 (d, IH, J_AB = 7.7 Hz), 3.79 (m, IH), 2.605 (q, 2H, J = 7.7 Hz), 2.069 (s, 3H), 2.04 (s, 3H), 1.98 (s, 3H), 1.67 (s, 3H), 1.21 (t, 3H, J=7.7 Hz) .

[00143] ¹³C NMR (125 MHz, CDCl₃) δ 170.64, 170.3, 169.4, 168.7, 142.2, 138.78, 136.4, 135.1, 134.6, 129.9, 129.8, 128.7, 128.0, 125.9, 79.45, 76.1, 74.1, 72.5, 68.45, 62.2, 38.6, 28.4, 20.7, 20.6, 20.59, 20.2, 15.55. [00144] LC-MS [M+NH/] at m/z 578.3

G.

[00145] To the white suspension formed by stirring the tetraacetylated beta-C- glucoside of Part F (25g, 44.6 mmol) for 5 min in 2:3 THF/MeOH (350 mL)under N₂ at 20⁰C was added LiOH-H₂O (2.Og, 50 mmol) in H₂O (70 mL). After 15 min, the reaction was an opaque solution; after 2.5 hr, by HPLC analysis the reaction was 98% complete. The conversion increased to 99% after stirring overnight whereupon the volatiles were removed using a rotary evaporator such that the volume was reduced to 150 mL. The residue, after addition of 10% aq KHSO₄ (100 mL) was further diluted with 100 mL OfH₂O prior to being extracted 3x with EtOAc. After drying over Na₂SO₄, the volatiles were removed using a rotary evaporator and the resultant oil in the minimum amount of EtOAc foamed under vacuum. The amount of EtOAc trapped in this material can be reduced by drying under vacuum. This glassy off white solid was scraped out and further dried at 0.15 Torr at 25°C for 24 hr to yield 17.3 g of desired C-arylglucoside containing 6.7 mol% of EtOAc.

HPLC retention time: 4.21 min, 98.8% pure, YMC S5 C-18 4.6x50mm column, 2.5 mL/min, detection at 22OnM; 4 min gradient 0-100% B hold 2 min at 100% B. Solvent A: 10% MeOH/H₂O + 0.2 % H₃PO₄. Solvent B: 90% MeOH/H₂O + 0.2 % H₃PO₄.

¹H NMR (500 MHz, CD₃OD) δ 7.34 (d, IH, J = 8.2 Hz), 7.33 (d, IH, J = 1.7 Hz), 7.27 (dd, IH, J = 8.2 Hz, J = 1.7 Hz), 7.08 (partially superimposed AB quartet, 4H), 4.1-4.0 (m, 3H), 3.86 (d, IH, J=I 1.6 Hz), 3.68 (dd, IH, J=5.3, 10.6 Hz), 3.46-3.26 (m, 4H) Hz), 2.57 (q, 2H, J=7 Hz), 1.19 (t, 3H, J=7 Hz) .

¹³C NMR (125 MHz, CD₃OD) δ 143.2, 140.0, 139.7, 138.1, 134.5, 131.98, 130.1, 129.8, 128.8, 128.2, 82.8, 82.14, 79.7, 76.4, 71.9, 63.1, 39.7, 29.4, 16.25.

MS [M+Na⁺] at m/z Theoretical 415.1288; Observed 415.1293 [00150] 

Anal for C_2IH₂₅ClO₅ ^• 0.07 EtOAc ^• 0.19 H₂O Calcd C 63.51, H 6.50, Cl 8.80; Found C 63.63, H 6.63, Cl 8.82

PATENT CITATIONS

Cited Patent	Filing date	Publication date	Applicant	Title
WO2003099836A1 *	May 15, 2003	Dec 4, 2003	Squibb Bristol Myers Co	C-aryl glucoside sglt2 inhibitors and method
WO2004063209A2 *	Dec 23, 2003	Jul 29, 2004	Squibb Bristol Myers Co	Methods of producing c-aryl glucoside sglt2 inhibitors

more...........

Chinese Chemical Letters

Volume 19, Issue 7, July 2008, Pages 814–816

Abstract

A convenient approach for the preparation of (2S,3R,4R,5S,6R)-2-(3-(4-ethylbenzyl)-4-chlorophenyl)-6-(hydroxymethyl)-tetrahydro-2H-pyran-3,4,5-triol 1 is developed. The target compound via four steps is synthesized from 4-bromo-2-(bromomethyl)-1-chlorobenzene and the isomers of undesired ortho-products were avoided during the preparation

more................
improved preparation of C-aryl glucoside SGLT2 inhibitors
ARKIVOC (Gainesville, FL, United States) (2008), (15), 65-70. Publisher: (Arkat USA Inc., )

Improved preparation of C-aryl glucoside SGLT2 inhibitors

Yong-Hai Liu, Da-Li Li and Lu-De Lu

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Volume 2008, Issue 15, pp. 65-70

DOI: http://dx.doi.org/10.3998/ark.5550190.0009.f08

 http://quod.lib.umich.edu/a/ark/5550190.0009.f08/1

  JALGAON, MAHARASHTRA, INDIA


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MANUDEVI