4-phenylstyrene

4-Iodobiphenyl 10 (420 mg, 1.5 mmol), Cy2NMe (0.39 mL, 1.8 mmol), Pd(OAc)2 (3 mg, 1 mol%) and tBu3PH.BF4 (9 mg, 2 mol%) were dissolved in PhMe/MeOH (5 mL, 9:1). The reaction mixture was injected into a Uniqsis Flowsyn reactor via a 5 mL PEEK injection loop. The reaction plug was pumped at 1.0 mL min−1 (using PhMe/MeOH (9:1) as stock solvent) through a tube-in-tube gas reactor pressurized with ethylene (15 bar) followed by a 20 mL PTFE reaction coil at 120 °C. The exiting reaction stream passed through an Omnifit column containing a mixture of QP-TU and QP-SA followed by a 200 psi BPR. The output was directed into a pre-weighed flask and flushed with argon.
The solvent was removed in vacuo to provide 268 mg (99%) of the title compound 11 as a white
crystalline solid.
1H NMR (400 MHz, CDCl3) δ 7.64 (d, J = 7.2 Hz, 2H), 7.61 (d, J = 8.3 Hz, 2H), 7.52 (d, J = 8.3 Hz, 2H),
7.48 (t, J = 7.4 Hz, 2H), 7.38 (t, J = 7.4 Hz, 1H), 6.78 (dd, J = 17.6, 11.0 Hz, 1H), 5.83 (d, J = 17.6 Hz, 1H),
5.31 (d, J = 11.0 Hz, 1H).
13C NMR (100 MHz, CDCl3) δ 140.7, 140.6, 136.6, 136.4, 128.7, 128.7, 127.3, 127.2, 127.2, 126.9,
126.9, 126.6, 126.6, 114.0.

///////////

Talgad Fort, 

India,  Maharashtra, Indapur, RAIGAD

Kuda Mandad Caves, Ghosala fort

The fort was constructed during the fourth century by Raja Bhoj and was used as a watch-tower on Rajpuri river and creek.Those travelling from Roha to Murud via Tala can visit this fort which is just inside the main Tala village.

Talgad fort and Kuda- Mandad caves

Talgad fort and Kuda- Mandad caves

After two successful, memorable monsoon treks at Kalsubai pinnacle and Sudhagad forts this season, Paulwaata group decided to plan another picnic cum trek to enjoy the rains on 21st of August 2011. The destination was Talgad Fort along with Kuda- Mandad Buddhist caves located near Roha. The trek was deliberately planned considering the easy nature of the same as there were going to be new comers with us which happened to trek for the very first time. We left from Chembur by our private vehicle (Maruti- Omni) at around 6 in the morning. Weather seemed to be very pleasant with in-between showers. We deliberately took the Vashi- Chirner route for Pen as it passes through mountains and offers a great view. We moved steadily with photography sessions throughout our trip. Our destination was village Tala situated at the base of the fort Talgad. This village can be approached either from Roha side or from taking a right turn from village Indapur (around 135 kms)on Mumbai- Goa highway NH-17. Other group members (Kedar and Co.) were supposed to come from Alibag by their Esteem car and thus we decided to gather at Roha first, have a heavy breakfast and then proceed towards Talgad. So we took the left turn before Nagothane village on Goa highway and moved towards Roha village about 20 kms from that spot. The road was in pathetic condition with big potholes for first few kms. Later on it was an enjoyable ride as the road passed through a small Ghat which looked magnificent in monsoons with heavy forest surroundings. While moving towards Roha, few of kms prior to Roha station and railway crossings, we halted for a few minutes at village Medha which happens to be the base village of fort Avchitgad. Took some snaps of the fort and decided to visit it in near future. We reached Roha by around 9.30 and waited for the other group to come. Due to the poor road conditions, the other group came late and meanwhile we had our breakfast in a nearby Hotel Dwaraka. Samosa, Kachori, Vada paav and finally Glass full of divine Lassi! Could not have asked for anything better! Few members were having Fast since it was a Janmashtami day so we ordered special Upwasacha Chiwada and Lassi for them. Meanwhile Kedar and co. turned up so we moved towards Tala village (19 kms from Roha) after they finished with their breakfast by around 11. As soon as we left Roha, rain started to pour like anything and heavy showers made the driving quite difficult. Roads are in decent conditions only in patches which slowed down our progress. Finally we reached the Tala village by 12, asked the villagers about the route to the fort. The village Tala is divided into two parts viz. Tala and Pusati wadi. The fort can be approached from both the sides but there is direct motorable road form Pusati wadi side which takes you almost at the foot the fort. Thanks to our vehicles, which managed those steep climbs, we could reach the spot in hardly 5 odd minutes. A small temple is there where you can observe few cannon lying. People in this part are very friendly and co-operative! From back of the village, a trail leads you into the jungle where there is thick bamboo growth. Just after 100 odd steps, a trail starts climbing towards right to the fort. It takes hardly ten minutes to reach the fort from this point. All the new comers thoroughly enjoyed this and the experienced ones were shocked to see how little they had to climb! On our way, great views of the surroundings were on offer and we made sure that we capture them in our cameras. There is statue of Hanuman carved in a big rock near the entrance of the door possible for guarding the fort and welcoming us! There is also a secret tunnel near the entrance which the villagers claim to be connected to the base village. Also visible are the remains of a large gateway and a water tank which has now been filled up. Basic information about Talgad fort:             A fortified monument on the southern bank of Malti creek, the Tala fort lies east west at a height of 1000 feet above the sea level in Tala town in Maharashtra. The fort is separated from the rest of the hill by a wide gap. This protected monument of 4th century was built during the reign of Bhoja Raja and was used as a watch on the beautiful Rajpuri stream. Tala fort is a very good example for the artistic talents of the then generation. The bottom of the hill in which the fort situates is surrounded by thick woody forest. Once a center of prime importance, this marvelous construction stands as the relic of its past glory. The fort is rarely visited by trekkers and thus thankfully you don’t come across with plastic bags, bottles and scraps things like these on this fort!  Hope it remains like this, untouched! After climbing the steps and entering the fort, we can see the main tower of the fort which is now in dilapidated condition and you can also see ruins of temple of Goddess Chandika near to that. We did lot of photography here. Great diversity of wild flowers can be seen on this fort and few members took snaps of them.   Then we started moving towards the other end of the fort where there is a bastion. En route we came across a series of water tanks covered with algal blooms suggesting the water was not potable.  In all there are eleven water tanks. A small Shiva temple is next to the tanks. After reaching the other end of the fort, the view was mesmerizing. Everyone wanted click snaps there and only after that we took some breather there and had mango drinks which we were carrying especially for the fasting people! We also had small introductory session here. Madhav had to respond to the call of the nature so he had vanished for few minutes! It was already 2 pm by then so we decided to rush to the village as quickly as possible. Heavy non-stop pouring was making the descend very slippery. We got down in 20 odd minutes and moved towards Kuda- Mandad caves. To reach here, we took Tale- mandad road to the south of Tale village. The entire stretch from Talgad to the Kuda caves is a very interesting site and offers you great views of mountains and rivers. Mandad village is around 14 kms from Tala village. About few kms before Mandad, a kuccha road (Kuda Leni Phata) turns to the left and starts climbing the hill through the jungle. The motorable road is in poor condition so we moved as far as possible we can and then parked the vehicle and walked for next 10 odd mins.    Basic information about Kuda Caves:              Kuda caves, famous for Buddhist caves. These rock cut caves are classic example of Buddhist cave art and amazing for their architectural excellence. These caves have two levels and the individual blocks are smaller and are on the upper levels. The inscriptions on the caves are the preaching of Buddha and his disciples. The interiors of the caves are carved with stupas and a rock carved image of an elephant as the janitor is inscribed on the front gate of the caves. In Kuda caves, there are evidences to testify that monks used them as dwelling places. The inscriptions, letters & paintings in the Kuda hills shows that these caves are built in during first to sixth centuary B.C. There are a total of 13 caves in Kuda. Within the first cave, the walls of which are covered by ancient writing, is a stupa. This cave is much larger than the others. The sixth cave towards the left also has a stupa in it. This is the cave whose walls are adorned by elephants outside. There many bats inhabiting these beautiful caves so you prefer to enjoy them from outside only! When you stand with your back towards the cave, Kuda village with the Murud creek in the backdrop is a clearly visible. This is great site especially in monsoons and the view is absolutely most picturesque. We spent couple of hours here, took many photos and after changing in dry clothes (very much needed!) and having some CHYAU- MYAU tp food items, decided to move for our homes by 5.30 pm. Considering the road conditions of towards Roha, we wisely decided to take Indapur road this time which is 15 kms from Tala village and said good byee to Kedar and co. who had to go to Alibag via Roha. The road from Tala to Indapur is in excellent condition and we enjoyed this ride and wished had we come by same way in the morning we could have had more spare time and could have had visited Ghosalgad fort too! Nevertheless, whatever we had seen till now was quite refreshing and pleasant. We set off from Indapur which is located on Mumbai- Goa highway by around 6.30 pm and moved towards Mumbai. We had our evening refreshments, tasty Misal paav, Potato chips at Hotel Kshudha Shanti at Wadkhal naaka at 8 pm. Finally reached Chembur by 10 pm. A very easy, non- strenuous enjoyable monsoon outing!

/////////////

An efficient preparation of a precursor to the neprilysin inhibitor sacubitril is described. The convergent synthesis features a diastereoselective Reformatsky-type carbethoxyallylation and a rhodium-catalyzed stereoselective hydrogenation for installation of the two key stereocenters. Moreover, by integrating machine-assisted methods with batch processes, this procedure allows a safe and rapid production of the key intermediates which are promptly transformed to the target molecule (3·HCl) over 7 steps in 54% overall yield.

Synthesis of a Precursor to Sacubitril Using Enabling Technologies

Continuous flow methodologyhas been used to enhance several steps in the synthesis of a precursor to Sacubitril.
In particular, a key carboethoxyallylation benefited from a reducedprocessing time and improved reproducibility, the latter attributable toavoiding the use of a slurry as in the batch procedure. Moreover, in batchexothermic formation of the organozinc species resulted in the formation ofside products, whereas this could be avoided in flow because heat dissipationfrom a narrow packed column of zinc was more efficient

Synthesis of a Precursor to Sacubitril Using Enabling Technologies

Shing-Hing Lau^†, Samuel L. Bourne^†, Benjamin Martin^‡, Berthold Schenkel^‡, Gerhard Penn^‡, and Steven V. Ley^*†

^† Department of Chemistry, University of Cambridge, Lensfield Road, Cambridge, CB2 1EW, U.K.

^‡ Novartis Pharma AG, Postfach, 4002 Basel, Switzerland

Org. Lett., 2015, 17 (21), pp 5436–5439

DOI: 10.1021/acs.orglett.5b02806, http://pubs.acs.org/doi/10.1021/acs.orglett.5b02806

*E-mail: svl1000@cam.ac.uk.

S.-H. Lau, S. L. Bourne, B. Martin, B. Schenkel, G. Penn, S. V. Ley, Org. Lett., 2015, 17 (21), pp 5436–5439

 

LCZ696 (sacubitril/valsartan) is a first-in-class combination of the angiotensin II receptor-blocker valsartan and the neprilysin inhibitor sacubitril. A recent head-to-head comparison of LCZ696 with enalapril in a double-blind trial was stopped early because the boundary for an overwhelming benefit with LCZ696 was crossed.As a result of this, LCZ696 was reviewed under the FDA’s priority review program and was granted approval on the July 7, 2015 to reduce the risk of cardiovascular death and hospitalization for HF in patients with chronic HF (NYHA Class II–IV) and reduced ejection fraction.

LCZ696 is a complex aggregate comprised of the anionic forms of sacubitril and valsartan, sodium cations, and water molecules in the molar ratio of 1:1:3:2.5, respectively

(2R, 4S)-5-(4-biphenylyl)-4-amino-2-methylpentanoic acid ethyl ester hydrochloride 3

To a stirred solution of (2R, 4S)-5-(4-Biphenylyl)-2-methyl-4-(tert-butylsulfinylamino)valeric acid 14 (50.0 mg, 134 μmol) in absolute ethanol (0.4 mL) at 0 °C was added thionyl chloride (20 μL, 268 μmol). The reaction mixture was stirred at room temperature for 3 h. The solvent was removed to yield 46.0 mg (99%) of titled compound 3 as a white solid.

1 H NMR (600 MHz, DMSO-d6) δ 8.17 (br. s, 3H), 7.66 (dd, J = 8.0, 7.4 Hz, 4H), 7.47 (t, J = 7.7 Hz, 2H), 7.36 (2 H, t, J = 7.4 Hz, H15, 2H), 7.36 (1 H, d, J = 8.0 Hz, H15), 3.99 (q, J = 7.1 Hz, H18), 3.42 – 3.36 (m, H4, 1H), 3.04 (dd, J = 13.8, 5.5 Hz, 1H), 2.81 (dd, J = 13.8, 8.1 Hz, 1H), 2.77 – 2.70 (m, 1H), 1.86 (ddd, J = 14.3, 9.1, 5.0 Hz, 1H), 1.59 (ddd, J = 13.8, 8.1, 5.4 Hz, 1H), 1.10 (t, J = 7.1 Hz, 3H), 1.07 (d, J = 7.1 Hz, 3H).

13C NMR (151 MHz, CDCl3) δ 174.7, 139.7, 138.7, 135.5, 130.0, 129.0, 127.4, 126.8, 126.5, 60.1, 50.4, 38.1, 35.5, 35.0, 17.5, 13.9.

HRMS (ESI+ , m/z [M+H]+ ) Calcd for C20H26NO2 312.1964; found 312.1967;

HPLC. 97:3 d.r. (Daicel Chiralpak AD-H column; isocratic n-hexane/ethanol/methanol/trimethylamine 80/10/10/0.2; 40 o C; flow rate = 0.8 mL min-1 ; λ = 254 nm; run time = 23 mins; tR (2R, 4S) 97.07%; tR (2S,4R) 0.21%; tR (2S, 4S) 2.32%; tR (2R,4R) 0.40%)

13C NMR Ethyl (2R,4S)-5-(4-biphenylyl)-4-amino-2-methylpentanoate hydrochloride 3

 

////////////Synthesis, Precursor,  Sacubitril, Enabling Technologies, flow synthesis, valsartan, LCZ69

• Supporting Info

OLOPATADINE

Olopatadine hydrochloride

Cis form, Z Isomer

( Z ) - 1 1 - [ 3 - ( D i m e t h y l a m i n o ) p r opy l i d e n e ] - 6 , 1 1 -dihydrodibenz[b,e]oxepin-2-acetic Acid Hydrochloride

ALO 4943A; Allelock; KW 4679; Opatanol; Patanol;

(11Z)-11-[3-(Dimethylamino)propylidene]-6,11-dihydrodibenz[b,e]oxepin-2-acetic Acid Hydrochloride;
CAS Number:	140462-76-6
unii 2XG66W44KF
Molecular form.:	C₂₁H₂₄ClNO₃
Appearance:	White Solid
Melting Point:	>240˚C (dec.)
Mol. Weight:	373.87

THE VIEWS EXPRESSED ARE MY PERSONAL AND IN NO-WAY SUGGEST THE VIEWS OF THE PROFESSIONAL BODY OR THE COMPANY THAT I REPRESENT,

SPECTROSCOPY FROM NET

 

( Z ) - 1 1 - [ 3 - ( D i m e t h y l a m i n o ) p r opy l i d e n e ] - 6 , 1 1 -dihydrodibenz[b,e]oxepin-2-acetic Acid Hydrochloride.

Cis-olopatadinehydrochloride /olopatadinehydrochloride

mp 231−233 °C (dec);

1H NMR (300 MHz, CD3OD) δ 2.86 (s, 6H), 2.83−2.91 (m, 2H), 3.28−3.34 (m, 2H), 3.57 (s, 2H), 5.19 (br, 2H), 5.67 (t,J = 7.3 Hz, 1H), 6.81 (d, J = 8.4 Hz, 1H), 7.07−7.13 (m, 2H), 7.26−7.37 (m, 4H);

13C NMR (75.4 MHz, CD3OD) δ 26.4 (CH2), 40.5(CH2), 43.4 (2CH3), 58.0 (CH2), 71.5 (CH2), 120.3 (CH), 124.8 (C),126.5 (CH), 127.0 (CH), 128.4 (C), 128.5 (CH), 129.0 (CH), 130.1(CH), 131.7 (CH), 132.8 (CH), 135.1 (C), 144.5 (C), 145.6 (C),155.9 (C), 175.7 (C);

IR (KBr) 1225, 1491, 1716, 2927 cm−1.

Anal.Calcd for C21H24NClO3·H

 

( E ) - 1 1 - [ 3 - ( D i m e thy l ami n o ) p r o p y l i d e n e ] - 6 , 1 1 -dihydrodibenz[b,e]oxepin-2-acetic Acid Hydrochloride.

trans-olopatadinehydrochloride

mp 170−173 °C;

1H NMR (300 MHz, CD3OD) δ 2.56−2.63 (m, 2H), 2.75 (s,6H), 3.13 (t, J = 7.6 Hz, 2H), 3.53 (s, 2H), 4.78 (br, 1H), 5.51 (br,
1H), 5.98 (t, J = 7.2 Hz, 1H), 6.69 (d, J = 8.4 Hz, 1H), 7.06 (dd, J =8.3, 2.3 Hz, 1H), 7.25−7.44 (m, 5H);

13C NMR (75.4 MHz, CD3OD)δ 26.0 (CH2), 40.8 (CH2), 43.3 (2CH3), 57.9 (CH2), 70.9 (CH2),120.3 (CH), 125.9 (CH), 127.6 (C), 128.5 (C), 128.6 (CH), 129.5(2CH), 130.0 (CH), 131.5 (CH), 132.0 (CH), 135.8 (C), 141.3 (C),144.2 (C), 155.6 (C), 175.7 (C);

IR (KBr) 1223, 1484, 1725, 2960cm−1.

Anal. Calcd for C21H24NClO3·H2O: C, 64.36; H, 6.69; N, 3.57.
Found: C, 64.66; H, 6.47; N, 3.56.

http://pubs.acs.org/doi/full/10.1021/jo300925c

J. Org. Chem., 2012, 77 (14), pp 6340–6344

DOI: 10.1021/jo300925c

THE VIEWS EXPRESSED ARE MY PERSONAL AND IN NO-WAY SUGGEST THE VIEWS OF THE PROFESSIONAL BODY OR THE COMPANY THAT I REPRESENT,

PATENT

https://www.google.com/patents/WO2007110761A2?cl=en

Olopatadine-HCl ([(Z)-3-(dimethylamino)propylidene]-6,ll-dihydrodibenz[b,e]oxepin-2- acetic acid hydrochloride) is a selective histamine Hl -receptor antagonist that is used for the treatment of ocular symptoms of seasonal allergic conjunctivitis. The compound may be administered in a solid oral dosage form or as an ophthalmic solution.

Olopatadine-HCI

[(Z)-3-(Dimethylamino)propylidene]-6,11-dihydro- dibenz[b,e]oxepin-2-acetic acid hydrochloride

Olopatadine is stated to be an effective treatment for symptoms of allergic rhinitis and urticaria (e.g., sneezing, nasal discharge and nasal congestion), as well as in the treatment of various skin diseases, such as eczema and dermatitis.

Olopatadine and its pharmaceutically acceptable salts are disclosed in EP 0214779, U.S. Patent No. 4,871,865, EP 0235796 and U.S. Patent No. 5,116,863. There are two general routes for the preparation of olopatadine which are described in EP 0214779: One involves a Wittig reaction and the other involves a Grignard reaction followed by a dehydration step. A detailed description of the syntheses of olopatadine and its salts is also disclosed in Ohshima, E., et al., J. Med Chem. 1992, 35, 2074-2084. EP 0235796 describes a preparation of olopatadine derivatives starting from 1 l-oxo-6,11- dihydroxydibenz[b,e]oxepin-2-acetic acid, as well as the following three different synthetic routes for the preparation of corresponding dimethylaminopropyliden-dibenz[b,e]oxepin derivatives, as shown in schemes 1-3 below:

Scheme 1:

HaIMgCH₂CH₂CH₂NMe₂

Scheme 2:

R₁OH or

R₂CI

R₁ = R₂ = alkyl group R₁ = H, R₂ = trityl group

HaIMgCH₂CH₂CH₂NMe₂

Scheme 3:

Ph₃P Hal' ^sHal

R₃ = COOH, etc.

The syntheses of several corresponding tricyclic derivatives are disclosed in the same manner in EP 0214779, in which the Grignard addition (analogous to Scheme 1) and the Wittig reaction (analogous to Scheme 3) are described as key reactions.

The synthetic routes shown above in Schemes 2 and 3 for the preparation of olopatadine are also described in Ohshima, E., et al., J Med. Chem. 1992, 35, 2074-2084 (schemes 4 and 5 below). In contrast to the above-identified patents, this publication describes the separation of the Z/E diastereomers (scheme 5). Scheme 4:

65% Ph₃CCI

81% CIMgCH₂CH₂CH₂NMe₂

A significant disadvantage of the synthetic route depicted in Scheme 4 is the diastereoselectivity of the dehydration step, which gives up to 90% of the undesired E-isomer. The last step (oxidation) is not described in this publication.

Scheme 5 below depicts a prior art method disclosed in Ohshima, E., et al., supra.

Scheme 5:

Each of the prior art methods for synthesis of olopatadine have significant cost and feasibility disadvantages. Specifically with the respect to the method set forth in Scheme 5, the disadvantages include: (1) the need for excess reagents, e.g. 4.9 equivalents Wittig reagent and 7.6 equivalents of BuLi as the base for the Wittig reaction, which can be expensive;

(2) the need to use Wittig reagent in its hydrobromide salt form, so that additional amounts of the expensive and dangerous butyllithium reagent are necessary for the "neutralization" of the salt (i.e., excess butyllithium is required because of the neutralization);

(3) because 7.6 equivalents of the butlylithium are used (compared to 9.8 equivalents of the (Olo-IM4) Wittig reagent), the Wittig reagent is not converted completely to the reactive ylide form, and thus more than 2 equivalents of the Wittig reagent are wasted;

(4) the need for an additional esterifϊcation reaction after the Wittig reaction (presumably to facilitate isolation of the product from the reaction mixture) and the purification of the resulting oil by chromatography;

(5) the need to saponify the ester and to desalinate the reaction product (a diastereomeric mixture) with ion exchange resin, prior to separating the diastereomers;

(6) the need, after the separation of the diastereomers, and liberation of the desired diastereomer from its corresponding pTsOH salt, to desalinate the product (olopatadine) again with ion exchange resin;

(7) the formation of olopatadine hydrochloride from olopatadine is carried out using 8 N HCl in 2-propanol, which may esterify olopatadine and give rise to additional impurities and/or loss of olopatadine; and

(8) the overall yield of the olopatadine, including the separation of the diastereomers, is only approximately 24%, and the volume yield is less than 1%.

As noted above, the known methods for preparing olopatadine in a Wittig reaction use the intermediate compounds 6,11-dihydro-l l-oxo-dibenz[b,e]oxepin-2-acetic acid and 3- dimethylaminopropyltriphenylphosphonium bromide hydrobromide. Preparation of these chemical intermediates by prior art syntheses present a number of drawbacks that add to the cost and complexity of synthesizing olopatadine.

One known method for preparation of the compound 6,11-dihydro-l 1-oxo- dibenz[b,e]oxepin-2-acetic acid is depicted in Scheme 6, below. See also, U.S. Patent No. 4,585,788; German patent publications DE 2716230, DE 2435613, DE 2442060, DE 2600768; Aultz, D.E., et al., J Med. Chem. (1977), 20(1), 66-70; and Aultz, D.E., et al., J Med. Chem. (1977), 20(11), 1499-1501. Scheme 6:

COOE

In addition, U.S. Patent No. 4,417,063 describes another method for the preparation of 6,11-dihydro-l l-oxo-dibenz[b,e]oxepin-2-acetic acid, which is shown in Scheme 7. Scheme 7:

Ueno, K., et al., J Med. Chem. (1976), 19(7), 941, describes yet another prior art method for preparing 6,11-dihydro-l l-oxo-dibenz[b,e]oxepin-2-acetic acid, which is shown below in Scheme 8. Scheme 8:

acid

Further, as depicted in Scheme 9, below, U.S. Patent Nos. 4,118,401; 4,175,209; and 4, 160,781 disclose another method for the synthesis of 6, 11 -dihydro- 11 -oxo-dibenz[b,e]oxepin-2- acetic acid.

Scheme 9:

AICI₃

6,11 -dihydro-11 -oxo-dibenz- [b,e]oxepin-2-acetic acid

JP 07002733 also describes the preparation of 6,11 -dihydro- 1 l-oxo-dibenz[b,e]oxepin-2- acetic acid, as follows in Scheme 10, below.

Scheme 10:

acid

Specific methods and reagents for performing the intramolecular Friedel-Crafts reaction for cyclizing 4-(2-carboxybenzyloxy)-phenylacetic acid to form 6,11 -dihydro-11-oxo- dibenz[b,e]oxepin-2-acetic acid are described in (1) EP 0068370 and DE 3125374 (cyclizations were carried out at reflux with acetyl chloride or acetic anhydride in the presence of phosphoric acid, in toluene, xylene or acetic anhydride as solvent); (2) EP 0069810 and US 4282365 (cyclizations were carried out at 70-80° C with trifluoroacetic anhydride in a pressure bottle); and (3) EP 0235796; US 5,116,863 (cyclizations were carried out with trifluoroacetic anhydride in the presence of BF₃ ^»OEt₂ and in methylene chloride as solvent).

Turning to the Wittig reagent for use in preparing olopatadine, 3- dimethylaminopropyltriphenylphosphonium bromide-hydrobromide and methods for its preparation are described in U.S. Patent Nos. 3,354,155; 3,509,175; 5,116,863, and EP 0235796, and depicted in Scheme 11 below. Scheme 11:

Corey, E. J., et al, Tetrahedron Letters, Vol. 26, No. 47, 5747-5748, 1985 describes a synthetic method for the preparation of 3-dimethylaminopropyltriphenylphosphonium bromide (free base), which is shown below in Scheme 12. Scheme 12:

The prior art methods for preparing olopatadine and the chemical intermediates 6,11- dihydro-ll-oxo-dibenz[b,e]oxepin-2-acetic acid, and 3- dimethylaminopropyltriphenylphosphonium bromide-hydrobromide (and its corresponding free base) are not desirable for synthesis of olopatadine on a commercial scale. For example, due to high reaction temperatures and the absence of solvents, the synthesis described in Ueno, K., et al., J. Med. Chem. (1976), 19(7), 941 and in U.S. Patent No. 4,282,365 for preparation of the intermediate 4-(2-carboxybenzyloxy)phenylacetic acid is undesirable for a commercial scale process, although the synthesis described in JP 07002733, and set forth in Scheme 13 below, is carried out in an acceptable solvent. Scheme 13:

OIO-1M1

The processes described in the literature for the intramolecular Friedel-Crafts acylation used to prepare 6,11-dihydro-l l-oxo-dibenz[b,e]oxepin-2-acetic acid are undesirable for commercial scale synthesis because they generally require either drastic conditions in the high boiling solvents (e.g. sulfolane) or they require a two step synthesis with the corresponding acid chlorides as intermediate. Furthermore the procedures for synthesizing 6,11-dihydro-l 1-oxo- dibenz[b,e]oxepin-2-acetic acid as set forth in European patent documents EP 0069810 and EP 0235796 use excess trifluoroacetic anhydride (see Scheme 14), and are carried out without solvent in a pressure bottle at 70-80° C (EP 0069810) or at room temperature in methylene chloride using catalytic amounts of BF₃^Et₂O (EP 0235796). Scheme 14:

According to the teachings in EP 0235795, a suspension of 3- bromopropyltriphenylphosphonium bromide (Olo-IM4) in ethanol was reacted with 13.5 equivalents of an aqueous dimethylamine solution (50%) to provide dimethylaminopropyltriphenylphosphonium bromide HBr. After this reaction, the solvent was distilled off and the residue was recrystallized (yield: 59%).

U.S. Patent No. 3,354,155 describes a reaction of 3-bromopropyltriphenylphosponium bromide with 4.5 equivalents dimethylamine. The solution was concentrated and the residue was suspended in ethanol, evaporated and taken up in ethanol again. Gaseous hydrogen bromide was passed into the solution until the mixture was acidic. After filtration, the solution was concentrated, whereupon the product crystallized (yield of crude product: 85%). The crude product was recrystallized from ethanol. A significant disadvantage of the prior art processes for making 3- dimethylaminopropyltriphenylphosphonium bromide hydrobromide involves the need for time consuming steps to remove excess dimethylamine, because such excess dimethylamine prevents crystallization of the reaction product. Thus, to obtain crystallization, the prior art processes require, for example, repeated evaporation of the reaction mixture (until dryness), which is undesirable for a commercial scale synthesis of olopatadine.

Corey, EJ., et al., Tetrahedron Letters, Vol. 26, No. 47, 5747-5748 (1985) describes the preparation of 3-dimethylaminopropyltriphenylphosphonium bromide (free base) from its corresponding hydrobromide salt. But the preparation of the free base, which uses an extraction step with methylene chloride as the solvent, is undesirable for commercial production because of the poor solubility of the free base in many of the organic solvents that are desirable for commercial production of chemical products, and because of the high solubility of the free base in water, causing low volume yields and loss of material. Furthermore according to this publication, the work up procedure gave an oil, which crystallized only after repeated evaporation in toluene.

It would be desirable to provide processes for preparing olopatadine on a large scale, e.g., on a commercial scale, in a manner that is cost efficient and provides olopatadine that has a low level of impurities, including a low level of the undesired diastereomer.

It further would be desirable to eliminate the need to derivatize the olopatadine product of the Wittig reaction, e.g., by esterification, in order to separate the olopatadine from the reaction mixture. It would be especially desirable to provide a method for preparing olopatadine that allows for isolation of olopatadine directly from the reaction mixture.

It would also be desirable to eliminate the need for the costly and dangerous base, butyllithium, that is used in previously described Wittig reactions for making olopatadine.

It would also be desirable to provide improved methods for preparing chemical intermediates used in the synthesis of olopatadine via a Wittig reaction.

In the description of the various aspects of applicants' invention that follows, reference may be made to the chemical intermediates, final products and byproducts in accordance with the nomenclature set forth immediately below.

(Z)-I l-[3-Dimethylamino- Olo-HCl propylidene]-6,l 1-dihydro- dibenz[b,e]oxepin-2-acetic acid hydrochloride

C21H24CINO3

Exact Mass: 373.14

MoI. Wt.: 373.87

Scheme 15:

aqueous layer aqueous layer

+ HBr extraction at pH = 42-46 with THF or MeTHF/iPrOH or BuOH

yield up to 55% Z/E-isomer~ 98 5/1 5

Scheme 16:

Scheme 17:

Olo-IM4ylide OIO-IM4 BP1

Olo-IM4 (free base OIO-1M4 BP1

Route 1

Reference：
1. US5116863A.
2. J. Med. Chem. 1992, 35, 2074-2084.

Route 2

Reference：
1. WO2007110761A2.

Route 3

Reference：
1. WO2010007056A1.

Route 4

Reference：
1. WO2011033532A1.

Route 5

Reference：
1. J. Org. Chem. 2012, 77, 6340−6344.

EP0351887A1 *	Aug 15, 1986	Jan 24, 1990	The Wellcome Foundation Limited	Tricyclic aromatic compounds
US3354155 *	Oct 12, 1964	Nov 21, 1967	Pfizer & Co C	Aminoalkylphosphonium compounds and process for the use thereof
US3681337 *	Dec 31, 1970	Aug 1, 1972	Ciba Geigy Corp	SUPPRESSION OF TRIS(ALKYLAMINO)-s-TRIAZINE FORMATION IN THE PRODUCTION OF CHLORO-BIS (ALKYLAMINO)-s-TRIAZINES THROUGH THE USE OF ADDITIONAL CYANURIC CHLORIDE

NON-PATENT CITATIONS

Reference
1	*	COREY, E.J. ET AL.: TETRAHEDRON LETTERS, vol. 26, no. 47, 1985, pages 5747-5748, XP002448423 cited in the application
2	*	LIU Y ET AL: "Synthesis of a new H1,receptor antgonist olopatadine" ZHONGGUO XIN YAO ZAZHI - CHINESE NEW DRUGS JOURNAL, GAI-KAN BIANJIBU, BEIJING, CN, vol. 15, no. 23, 2006, pages 2045-2046, XP008082683 ISSN: 1003-3734
3	*	OHSHIMA E ET AL: "SYNTHESIS AND ANTIALLERGIC ACTIVITY OF 11-(AMINOALKYLIDENE)-6,11-DIHY DRODIBENZÚB,EOXEPIN DERIVATIVES" JOURNAL OF MEDICINAL CHEMISTRY, AMERICAN CHEMICAL SOCIETY. WASHINGTON, US, vol. 35, no. 11, 1 May 1992 (1992-05-01), pages 2074-2084, XP000615220 ISSN: 0022-2623 cited in the application
4	*	XUE ET AL: "Study on the synthetic process of a novel anti-allergic agent olopatadine hydrochloride" ZHONGGUO YAOWU HUAXUE ZAZHI - CHINESE JOURNAL OF MEDICINAL CHEMISTRY, GAI-KAI BIANJIBU, SHENYANG, CN, vol. 14, no. 6, 2004, pages 363-364,367, XP008082682 ISSN: 1005-0108

Citing Patent	Filing date	Publication date	Applicant	Title
WO2007119120A2 *	Dec 22, 2006	Oct 25, 2007	Medichem, S.A.	Crystalline polymorphic forms of olopatadine hydrochloride and processes for their preparation
WO2007119120A3 *	Dec 22, 2006	Feb 14, 2008	Monica Benito	Crystalline polymorphic forms of olopatadine hydrochloride and processes for their preparation
WO2009048086A1 *	Oct 2, 2008	Apr 16, 2009	Sumitomo Chemical Company, Limited	Method for purification of dibenzoxepin compound
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WO2010089268A2	Feb 1, 2010	Aug 12, 2010	Zach System S.P.A.	Process for preparing olopatadine and/or a pharmaceutically acceptable salt thereof
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Title: Olopatadine

CAS Registry Number: 113806-05-6

CAS Name: (11Z)-11-[3-(Dimethylamino)propylidene]-6,11-dihydrodibenz[b,e]oxepin-2-acetic acid

Molecular Formula: C21H23NO3

Molecular Weight: 337.41

Percent Composition: C 74.75%, H 6.87%, N 4.15%, O 14.23%

Literature References: Dual acting histamine H1-receptor antagonist and mast cell stabilizer. Prepn: E. Oshima et al., EP235796; eidem, US 5116863 (1987, 1992 both to Kyowa); eidem, J. Med. Chem. 35, 2074 (1992). Pharmacology: C. Kamei et al.,Arzneim.-Forsch. 45, 1005 (1995); J. M. Yanni et al., J. Ocul. Pharmacol. Ther. 12, 389 (1996). Receptor binding profile: N. A. Sharif et al., J. Pharmacol. Exp. Ther. 278, 1252 (1996). Clinical trial in allergic conjunctivitis: M. B. Abelson, L. Spitalny, Am. J. Ophthalmol. 125, 797 (1998).

Properties: Crystallized as the hemihydrate from 2-propanol + water, mp 188-189.5°.

Melting point: mp 188-189.5°

Derivative Type: Hydrochloride

CAS Registry Number: 140462-76-6

Manufacturers' Codes: AL-4943A; KW-4679

Trademarks: Opatanol (Alcon); Patanol (Alcon)

Molecular Formula: C21H23NO3.HCl

Molecular Weight: 373.87

Percent Composition: C 67.46%, H 6.47%, N 3.75%, O 12.84%, Cl 9.48%

Properties: Crystals from acetone-water, mp 248° (dec). Sol in water.

Melting point: mp 248° (dec)

////////////

Paper

Journal of the Brazilian Chemical Society

J. Braz. Chem. Soc. vol.25 no.12 São Paulo Dec. 2014

http://dx.doi.org/10.5935/0103-5053.20140255 

An intramolecular Heck-based cyclization was used as a key step for commendable synthesis of the antihistaminic drug olopatadine (133) and its trans isomer (134).⁶⁷ Besides the Heck reaction, another vital step in this route was a stereoselective Wittig olefination using a non-stabilized phosphorus ylide that afforded the olefins 135 and 136 (E:Z ratio = 9:1 for 135, for instance). Concerning the Heck reaction, Pd(OAc)₂, K₂CO₃, and NBu₄Cl (TBAC) were allowed to react with 135 and 136 at 60 ºC during 24 h, providing the cyclic adducts 137 and 138 with reasonable 60% and 55% yields, respectively. However, it is important to note that in catalytic terms, the results were not encouraging, considering that 20 mol% of palladium was used and a disappointing turnover number (TON) of 3 was observed (Scheme 37).

Scheme 37 Heck reaction in synthesis of olopatadine (133) and trans-olopatadine (134). 

In relation to the stereochemistry of the Heck products, the above results were not surprising since they were consistent with a syn-insertion of the arylpalladium intermediate (provided by oxidative addition step) at the olefinic moiety followed by a syn β-elimination that afforded the product with the ascribed stereochemistry. Finally, with the cyclic products in hands, the syntheses were completed by alkaline hydrolysis of methyl esters that afforded the target olapatadine and trans-olapatadine.
67 Bosch, J.; Bachs, J.; Gómez, A. M.; Griera, R.; Écija, M.; Amat, M.; J. Org. Chem.2012, 77 , 6340.

The construction of a new bond between sp²- and sp-hybridized carbons is known as the Sonogashira reaction,⁴⁸and it is nowadays a widely employed methodology for the construction of arylacetylenes.^3,49,50 For example, a Sonogashira coupling was employed by the research and development group of Kyowa Hakko Kirin in a new and concise synthetic route for olopatadine hydrochloride (92), a commercial anti-allergic drug that was previously developed by the same company.⁵¹

The reported synthesis goes through the Sonogashira reaction between the easy accessible aryl halide 93 and alkyne 94 leading to adduct 95 in 94% yield. This adduct is then subjected to a second metal-catalyzed transformation, a stereospecific palladium-catalyzed intramolecular cyclization, whose optimum conditions were identified based on an elegant and comprehensive Design of Experiments (DoE) investigation to provide 96(Scheme 28).

Scheme 28 Optimal Sonogashira conditions for the synthesis of 92. 

Elaboration of the cyclization product 96 through aminomethylation and ester hydrolysis followed by acid work-up completes the synthesis of the final target. Although the presented synthetic route is very promising and concise, providing olopatadine hydrochloride in 54% overall yield for 6 steps from commercially available materials, it has so far been reported only on a laboratory scale (5 g for the Sonogashira coupling and 200 mg for the cyclization step).

51 Nishimura, K.; Kinugawa, M.; Org. Process Res. Dev.2012, 16 , 225