Synthesis of the acetonide of meso-1,2-diphenyl-1,2-ethanediol (2,2-dimethyl-4,5-diphenyl-1,3-dioxolane)

cis-2,2-Dimethyl-4,5-diphenyl-1,3-dioxolane

18699-77-9

1H NMR

1H-NMR: cis-2,2-Dimethyl-4,5-diphenyl-1,3-dioxolane
300 MHz, CDCl3
delta [ppm]	mult.	atoms	assignment
1.62	s	3 H	CH3
1.84	s	3 H	CH3
4.84	s	1 H	CH-O (educt)
5.53	s	2 H	CH-O (product)
6.8-7.2	m	10 H	CH (arom., product)
7.2-7.4	m	10 H	CH (arom., educt)
7.26	s	1 H	CHCl3

13C-NMR

13C-NMR: cis-2,2-Dimethyl-4,5-diphenyl-1,3-dioxolane
300 MHz, CDCl3
delta [ppm]	assignment
24.5	CH3
26.8	CH3
81.5	-OCH(R)-CH(R)-O-
108.8	O-C-O
126.9-128.3	CH arom.
137.7	C quart. arom.
76.5-77.5	CDCl3

IR

IR: cis-2,2-Dimethyl-4,5-diphenyl-1,3-dioxolane
[KBr, T%, cm-1]
[cm-1]	assignment
3095-3000	arom. C-H valence
2990-2880	aliph. C-H valence
1490, 1454	arom. C=C valence

+

FeCl3 - H2O

Synthesis of the acetonide of meso-1,2-diphenyl-1,2-ethanediol (2,2-dimethyl-4,5-diphenyl-1,3-dioxolane)

Reaction type:	reaction of the carbonyl group in ketones, acetalisation
Substance classes:	ketone, alcohol, acetal, protecting group, acid catalyst
Techniques:	heating under reflux, stirring with magnetic stir bar, filtering, evaporating with rotary evaporator, shaking out, extracting, recrystallizing, working with moisture exclusion, heating with oil bath

http://www.oc-praktikum.de/nop/en/instructions/pdf/2005_en.pdf

Operating scheme

Classification Reaction types and substance classes reaction of the carbonyl group in ketones, acetalisation ketone, alcohol, acetal, protecting group, acid catalyst Work methods heating under reflux, stirring with magnetic stir bar, filtering, evaporating with rotary evaporator, shaking out, extracting, recrystallizing, working with moisture exclusion, heating with oil bath

Instruction (batch scale 5 mmol)

Equipment 100 mL three-neck flask, 50 mL round bottom flask, reflux condenser, protective gas supply, adapter with ground glass joint and hose coupling, heatable magnetic stirrer, magnetic stir bar, 250 mL beaker, 250 mL separating funnel, Hirsch funnel, suction flask, rotary evaporator, vacuum pump, oil bath Substances meso-1,2-diphenyl-1,2-ethanediol (mp 132-134 °C, 1.07 g (5.00 mmol) product from NOP 2004) iron(III)-chloride water free (mp 305 °C) 300 mg (1.85 mmol) acetone (bp 56 °C) dry 23.3 g (29.4 mL, 400 mmol) acetic acid ethyl ester (bp. 77 °C) 60 mL petroleum ether (40–60 °C) dry, for recrystallizing about 15 mL potassium carbonate about 1 g (for 50 mL of 2% aqueous solution) magnesium sulfate for drying about 1 g

Since FeCl3 is very hygroscopic, only a very short contact with air is allowed. The reaction apparatus consists of a dry 100 mL three-neck flask, rinsed with nitrogen and equipped with a magnetic stir bar and a reflux condenser, which is connected with a nitrogen piping. In the reaction flask 1.07 g (5.0 mmol) 1,2-diphenyl-1,2-ethanediol are dissolved in 23 g (30 mL, 400 mmol) dry acetone. 300 mg (1.85 mmol) of water free iron(III)-chloride are rapidly added, whilst the reaction mixture changes its colour to yellow-brown. It is heated under stirring for 20 minutes under reflux. Work up After cooling down to room temperature the reaction mixture is poured into a 250 mL beaker containing 50 mL of 2% potassium carbonate-solution. A brown fluffy precipitation is formed. The mixture is transferred into a 250 mL separating funnel and extracted three times with 20 mL acetic acid ethyl ester each. The organic phases are almost colourless. They are combined and again washed with 25 mL water and dried over water free magnesium sulfate. The mixture is filtered from the drying agent over a glass funnel with filter paper and the solvent is removed at a rotary evaporator. The light yellow oil remaining as crude product is dried for 30 minutes at about 40 °C bath temperature with a vacuum pump at 1-2 hPa. Crude yield: 1.05 g; mp 56 °C; HPLC-purity 83%

To the crude product are added 13 mL dry and pre-heated petroleum ether (40-60 °C) in a 50 mL round bottom flask and the mixture is stirred and heated for 5 minutes under reflux. Then the still hot solution is filtered off from the insoluble residue into a 50 mL round bottom flask and the solvent is evaporated at a rotary evaporator. The remaining light yellow oily product is dried with a vacuum pump at 1-2 hPa and stored in the cooler for crystallization. Yield: 0.918 g (3.61 mmol, 72%); mp 56-57 °C The product can be recrystallized from 1 mL dry petroleum ether (40-60 °C), however, it is still not free from educt yet. Yield: 0.52 g (2.05 mmol, 41%); mp 58-60 °C The residue (120 mg) which is insoluble in the hot petroleum ether consists predominantly of not reacted 1,2-diphenylethanediol.

Comments The product in solid state is stable under moisture exclusion at room temperature. A solution of the product in CDCl3 shows already after one day partly cleavage into the educts, probably due to traces of acid (detection with 1H NMR).

Substances required

Batch scale:

0.005 mol

meso-1,2-Diphenyl-1,2-ethanediol

Educts		Amount	Risk	Safety
meso-1,2-Diphenyl-1,2-ethanediol		1.07 g
Acetone	Danger	23.3 g	H225 H319 H336 EUH066	P210 P261 P305 + 351 + 338
Catalyst		Amount	Risk	Safety
Ferric chloride	Danger	0.300 g	H290 H302 H315 H318 H411	P273 P280 P305 + 351 + 338
Solvents		Amount	Risk	Safety
Acetic acid ethyl ester	Danger	60 mL	H225 H319 H336 EUH066	P210 P261 P305 + 351 + 338
Petroleum ether (40-60)	Danger	15 mL	H225 H304 H315 H336 H411 EUH-	P210 P261 P273 P301 + 310 P331
Water	Danger	75 mL	H- EUH-	P-
Others		Amount	Risk	Safety
Potassium carbonate	Warning	~ 1 g	H302 H315 H319 H335	P261 P305 + 351 + 338
Magnesium sulfate	Warning	~ 1 g
Nitrogen	Warning	H280	P410 + 403
Solvents for analysis		Amount	Risk	Safety
Acetic acid ethyl ester	Danger	15 mL	H225 H319 H336 EUH066	P210 P261 P305 + 351 + 338
Acetonitrile	Danger	H225 H302 + 312 + 332 H319	P210 P280 P305 + 351 + 338
Water	Danger	H- EUH-	P-

Substances produced

Batch scale:

0.005 mol

meso-1,2-Diphenyl-1,2-ethanediol

Products		Amount	Risk	Safety
cis-2,2-Dimethyl-4,5-diphenyl-1,3-dioxolane		0.918 g

Waste	Disposal
aqueous phase after shaking out	solvent water mixtures, containing halogens
evaporated ethyl acetate	organic solvents, halogen free
evaporated petroleum ether	solvents for rectification

Equipment

Batch scale:

0.005 mol

meso-1,2-Diphenyl-1,2-ethanediol

	three-necked flask 100 mL			reflux condenser
	heatable magnetic stirrer with magnetic stir bar			beaker 250 mL
	separating funnel 250 mL			Hirsch funnel
	suction flask			rotary evaporator
	vacuum pump			oil bath
	adapter with ground-glass joint and hose coupling			round bottom flask 50 mL

Simple evaluation indices

Batch scale:

0.005 mol

meso-1,2-Diphenyl-1,2-ethanediol

Atom economy		93.4	%
Yield		72	%
Target product mass		0.918	g
Sum of input masses		160	g
Mass efficiency		5.6	mg/g
Mass index		180	g input / g product
E factor		180	g waste / g product

Chromatogram

HPLC: crude product
column	Phenomenex Luna C18; particle diameter 3 µm, L=150 mm, ID= 4.6 mm
column temperature	25 °C
injection	5 µL
mobile phase	5% MeCN / H2O, gradient to 95% MeCN / H2O (40 min), 10 min isocratic
flow	1.0 mL/min
detector (UV 220 nm)	percent concentration calculated from relative peak area

HPLC: pure product
column	Phenomenex Luna C18; particle diameter 3 µm, L=150 mm, ID=4.6 mm
column temperature	25 °C
injection	5 µL
mobile phase	5% MeCN/H2O, gradient to 95% MeCN/H2O (40 min), 10 min isocratic
flow	1.0 mL/min
detector (UV 220 nm)	percent concentration calculated from relative peak area

Batam, indonesia

Batam - Wikipedia, the free encyclopedia

https://en.wikipedia.org/?title=Batam

Batam (Jawi: باتم) is an island, municipality (an Indonesian kotamadya), the largest city in the Riau Islands Province of Indonesia, the third largest city in ...

‎Geography - ‎Administration - ‎Economy - ‎Demographics

Batam Holiday Inn Resort Getaway

Batam is the nearest Indonesian island to Singapore that is accessible by a 30-minute ferry ride from Singapore.  My family stayed at the Batam Holiday Inn Resort for a quick getaway to recharge and unwind.

We got there from a ferry at Harbourfront Singapore to the Waterfront Ferry Terminal in Batam and walked about 5-10 minutes to the hotel.  Another way is to take the ferry to Batam city centre and take a 15-20 minute cab ride to the hotel.

Batam Holiday Inn

We got a 2-bedroom suite online for a price that was many times cheaper than the resorts at nearby Bintan island. It came with a small kitchen, a living area with a good range of TV channels. Above is a picture taken from our room.

     

The main attraction for the kids was the swimming pool.  There were three outdoor pools and one indoor lap pool.  As this was a “do-nothing” vacation break, we did not do much sightseeing in Batam.  Most of the time, my kiddos played at the pool and chilled out at the hotel.

 

One thing that I liked was the body massage at the Holiday Inn’s Tea Tree Spa. It was so popular even with day-trippers that I only managed to get a slot in the early evening.  It was a good thing too because I got the big couple massage room all to myself.  The Indonesian massage was good and the aromatherapy was very relaxing.  Guests who need to watch over their kids could even do the massage in the hotel room, but I guess it wouldn’t have the spa atmosphere.  I would go there just for a body massage again because even with the ferry ride, it would still be cheaper than similar body massages in Singapore.

Click HERE for more details of Batam Holiday Inn Resort.

Eating out in Batam

While the hotel served a good breakfast spread and other meals, we explored other foods in Batam outside the hotel.  We found this amazingly cheap and decent local food just a short walk from our hotel.

There were also Padang food at Restoran Sederhana in Batam city centre.

Padang food is a cuisine of the Minangkabau people of Sumatra.  Dishes were laid out in front of customers and they charge by what you consume.

Golden Prawn 933 Seafood Restaurant is a huge seafood restaurant that is very popular with tour groups.  It had fresh seafood at very reasonable prices.

   

It was a good thing that we came early before the crowd from tour buses arrived.

Barelang Bridge

The only thing worth sightseeing in Batam is the Barelang Bridge, which is a chain of six bridges that connects Batam with nearby islands.  Here’s the view from the first bridge.

Thinking of a short getaway to Batam?

For those in Singapore, who just want to unwind somewhere out of Singapore without spending a lot for flights, or tour coaches, or worrying about driving in Malaysia, Batam is a good choice.  Plus it is much cheaper than Bintan.  I booked my hotel room from Agoda (Click  Holiday Inn Batam).

Other hotels in Batam we considered were:

• Harris Resort Waterfront – it is also located in Waterfront city near Holiday Inn. It has bigger pools and more kids facilities, but we needed to get two rooms for our family, which worked out to be more costly than Holiday Inn.
• Montigo Resorts Nongsa and Turi Beach Resort – Nice resorts but more expensive.

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Batam tourism: batam - tripadvisor, Batam tourism: tripadvisor 11,681 reviews batam hotels, attractions, restaurants making batam resource.. http://www.tripadvisor.com.sg/Tourism-g297717-Batam_Riau_Archipelago_Riau_Islands_Province-Vacations.html Batam map, Find complete information batam island site. http://www.batam.com/about-batam/batam-map.html Peta batam : peta jalan & satellite batam - indonesia, Streetdirectory..id batam maps maps states indonesia featuring details towns, lakes, rivers, places interest, roads, borders , . http://www.streetdirectory.com/indonesia/en/batam/

Batam, Indonesia, is an island and also a city in Riau Islands Province of Indonesia, known for its free trade zone area. It is located 20 km off Singapore's south coast. Where virgin jungle once stood are now whole new towns, mosques, churches, temples and supermarkets, soon to be followed by reservoirs with enough water to supply a population of 800,000 and for industrial use, an airport-to become an international gateway.

1. Maha Vihara Duta Maitreya Temple

Batam, Indonesia, has several Buddhist & Hindu Temples in various locations across the island. The temples have worshippers visiting daily and most temples allow tourists & visitors to come and look around. Maha Vihara Duta Maitreya Buddhist Temple is one of the biggest Buddhist temples in South East Asia and is a major attraction in Batam, Indonesia. The temple is located near to the Batam Center ferry terminal. The main chamber consists of statues of Buddha, and the side chambers are Goddess of Mercy (Guan Yin) and Guan Gong deity. Inside there is a shop sellingBuddhist items and a vegetarian restaurant, offering a variety of vegetarian dishes & fruit drinks.

2. Chocolate House

Batam Chocolate House, Indonesia, is a chocolate heaven for chocolate lovers. They offer more than 100 varieties of chocolate to suit your every mood and desire with very reasonable price. Good as gifts or souvenirs for your loved ones and friends back home.

3. Go-Kart Circuit House

Fast Go Karts race around on a purpose built track, just great for the speed junkies! Test out your skills by racing against the clock or with your team mates.  Safety equipment is mandatory for all drivers & is provided by the Circuit, Indonesia. Suitable footwear should be worn (no sandals or flip-flops) and long trousers & shirts are preferred.

4. Flying Fox

Challenge your limits over different obstacles and conquering your fears of height whilst ending your way at the Flying Fox to the ground zero at Batam, Indonesia. Suitable footwear should be worn.

5. Indonesia Minature Park

Indonesia Miniature Park, Indonesia, is a synopsis of Indonesian culture, with virtually all aspects of daily life in Indonesia's 32 provinces encapsulated in separate pavilions with the collections of architecture, and traditions are all depicted impeccably.

6. BengKong Dry Market

BengKong Dry Market, Indonesia, is the place you may able to purchase very fresh dry food stuff in wholesales prices. It is also known to sell local tibits such as tapioca chips, prawn crackers and etc.

7. Golden Prawn 555 Seafood Kelong Restaurant

Golden Prawn, Indonesia, is a fresh seafood restaurant in batam, Indonesia. Golden Prawn 555 and 933 is the best, largest and closest from the golden view hotel. It is the place to for Seafood Lovers to be as they serve hundreds of top dishes with variety choices.

8. Golden Tourist Shop

The souvenir shop is located just inside the entrance to Golden Prawn 933 restaurant, Indonesia, on the left side and inside is a souvenir hunters dream where lots and lots of local assorted stuff for sale. You can Buy famous Indonesian Sea Food Crackers, Indonesian Coffee, other Indonesian Food Stuffs, assorted local handicrafts and woven items, refrigerator magnets, mini wallets and bags, pordelain, pewter and more and the best thing is they accept Singapore Dollars.

9. Bird Nest Shop

The Bird Nest Shop, Indonesia, sells assorted Dried Bird's Nest from cave swiftlet birds are harvested by adventurous pickers from nearby caves along the Riau Islands (since the bird's nest are located high in the caves) and the birds nest are primarily from Bird Saliva and is an aphrodisiac for the chinese.

10. Pondok Wisata Cultural Show

At the Pondok Wisata Cultural Show, Indonesia, you will be entertain by local villagers with their traditional trance dance such as The Roaster  Dance. Also, you will get to witness other acts by the locals such as peeling coconut skin using mouth, eating fireballs, eating glass and more.

11. Polo Outlets

Batam Polo Outlet, Indonesia, where you may wish to purchase clothes by American brand Polo Ralph Lauren, which were made in Jakarta, Indonesia, and cheaper than in Singapore. Polo clothing is also available at Batam Center Ferry Terminal, Mega Mall, Nagoya Hill shopping center, the lobby in the Harmoni Hotel and at Batam View Beacch Resort, but the

Shop is the best location for genuine Polo clothing. If you’re on a Batam shopping trip, the Batam Polo Shop is worth a visit!

12. Tua Pek Kong Temple

Tua Pek Kong Temple, Indonesia, is also known as Vihara Budhi Bhakti Temple, this chinese temple is located in Nagoya. It is one of the historical temples in Batam. It is well used by the locals for their daily prayers and offerings. The temple is built in traditional chinese style and has many courtyard statues and several wall paintings.

13. Batam Shopping Mall

Batam Shopping, Indonesia, can be a rewarding experience as there are several large Shopping Malls, as well as many smaller specialty shops selling goods ranging from traditional Indonesian furnitures and handicraft, to electronic and household goods, as well as many clothing and fashion shops.

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

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Pravastatin Sodium

Pravastatin Sodium

CAS : 81131-70-6

(bR,dR,1S,2S,6S,8S,8aR)-1,2,6,7,8,8a-Hexahydro-b,d,6-trihydroxy-2-methyl-8-[(2S)-2-methyl-1-oxobutoxy]-1-naphthaleneheptanoic acid monosodium salt

sodium (+)-(3R,5R)-3,5-dihydroxy-7-[(1S,2S,6S,8S,8aR)-6-hydroxy-2-methyl-8-[(S)-2-methylbutyryloxy]-1,2,6,7,8,8a-hexahydro-1-naphthyl]heptanoate; eptastatin sodium; 3b-hydroxycompactin sodium salt

CS-514; SQ-31000, Elisor (BMS); Lipostat (BMS); Liprevil (Schwarz); Mevalotin (Sankyo); Oliprevin (BMS); Pravachol (BMS); Pravaselect (Menarini); Pravasin (BMS); Selectin (BMS); Selipran (BMS); Vasten (Specia)

Molecular Formula: C23H35NaO7

Molecular Weight: 446.51

C 61.87%, H 7.90%, Na 5.15%, O 25.08%

Antilipemic; HMG CoA Reductase Inhibitors;

Properties: Odorless, white to off-white, fine or crystalline powder. uv max (methanol): 230, 237, 245 nm. Sol in methanol, water; slightly sol in isopropanol. Practically insol in acetone, acetonitrile, chloroform, ether.

Absorption maximum: uv max (methanol): 230, 237, 245 nm

Pravastatin (marketed as Pravachol or Selektine) is a member of the drug class of statins, used in combination with diet, exercise, and weight-loss for lowering cholesterol and preventing cardiovascular disease.
Medical uses
Pravastatin is primarily used for the treatment of dyslipidemia and the prevention of cardiovascular disease.^[1] It is recommended to be used only after other measures such as diet, exercise, and weight reduction have not improved cholesterol levels.^[1]
The evidence for the use of pravastatin is generally weaker than for other statins. The antihypertensive and lipid-lowering treatment to prevent heart attack trial (ALLHAT), failed to demonstrate a difference in all-cause mortality or nonfatal myocardial infarction/fatal coronary heart disease rates between patients receiving pravastatin 40mg daily (a common starting dose) and those receiving usual care.^[2]

Mechanism of action

Pravastatin acts as a lipoprotein-lowering drug through two pathways. In the major pathway, pravastatin inhibits the function of hydroxymethylglutaryl-CoA (HMG-CoA) reductase. As a reversiblecompetitive inhibitor, pravastatin sterically hinders the action of HMG-CoA reductase by occupying the active site of the enzyme. Taking place primarily in the liver, this enzyme is responsible for the conversion of HMG-CoA to mevalonate in the rate-limiting step of the biosynthetic pathway for cholesterol. Pravastatin also inhibits the synthesis of very-low-density lipoproteins, which are the precursor to low-density lipoproteins (LDL). These reductions increase the number of cellular LDL receptors and, thus, LDL uptake increases, removing it from the bloodstream.^[6] Overall, the result is a reduction in circulating cholesterol and LDL. A minor reduction in triglycerides and an increase in high-density lipoproteins (HDL) are common.

History

Initially known as CS-514, it was originally identified in a bacterium called Nocardia autotrophica by researchers of the Sankyo Pharma Inc..^[7] It is presently being marketed outside Japan by thepharmaceutical companyBristol-Myers Squibb. In 2005, Pravachol was the 22nd highest-selling brand-name drug in the United States, with sales totaling $1.3 billion.^[8]
The U.S. Food and Drug Administration approved generic pravastatin for sale in the United States for the first time on April 24, 2006. Generic pravastatin sodium tablets are manufactured byBiocon Ltd, India and TEVA Pharmaceuticals in Kfar Sava, Israel.^[8]

…………………………..
BIOCON LIMITED Patent: WO2005/19155 A1, 2005 ; Location in patent: Page/Page column 8 ;http://google.com/patents/WO2005019155A1?cl=en
The present invention relates to a novel process for the preparation of substantially pure l^^^^^δa-hexahydro-beta,delta_/6-trihydroxy-2-methyl-8-[(2S)-2-methyl-l-oxobutoxy]-_/ (beta R, delta R, lS,2S,6S,8S,8aR)- 1-Naphthaleneheptanoic acid, sodium salt.
BACKGROUND OF THE INVENTION
US 4,346,227 discloses l,2,6,7,8,8a-hexahydro-beta,delta,6-trihydroxy-2-methyl-8-[(2S)-2-methyl-l-oxobutoxy]-, (beta R,delta R,lS,2S,6S,8S,8aR)- 1-Naphthaleneheptanoic acid, sodium salt. The compound is also known by the synonyms 3-beta-Hydroxycompactin; Eptastatin and Pravastatin. The compound is used as cholestrerol lowering agent which inhibit the enzyme H G CoA reductase.
The step of conversion of l,2,6,7,8,8a-hexahydro-beta,delta,6-trihydroxy-2-methyl-8-[(2S)-2-methyl-l-oxobutoxy]-, (beta R,delta R,lS,2S,6S,8S,8aR)- 1-Naphthaleneheptanoic acid to its sodium salt is crilcial. The prior art methods convert the acid form into sodium salt form as final step to afford the sodium salt. The prior art methods for the preparation of sodium salt from the l,2,6,7,8,8a-hexahydro-beta,delta,6-trihydroxy-2-methyl-8-t(2S)-2-methyl-l-oxobutoxy]-, (beta R,delta R,lS,2S,6S,8S,8aR)-1-Naphthaleneheptanoic acid are disclosed herein as reference.
WO 98/45410 discloses preparation of 1,2,6,7,8,8a-hexahydro-beta,delta, 6-trihydroxy-2-methyl-8-[(2S)-2-methyl-l-oxobutoxy]-, (beta R,delta R,lS,2S,6S,8S,8aR)- 1-Naphthaleneheptanoic acid sodium by feeding compactin sodium to the microorganism Streptomyces exfoliatus and recovering the hydroxylated compactin sodium (l,2,6,7,8,8a-hexahydro-beta,delta,6-trihydroxy-2-methyl-8-[(2S)-2-methyl-l-oxobutoxy]-, (beta R,delta R,lS,2S,6S,8S,8aR)- 1-Naphthaleneheptanoic acid sodium salt) by extraction, purification by semi preparative HPLC and crystallization.
The process involves use of HPLC, which is a tedious and expensive technique and cannot be scaled up beyond a limit.
WO 00/46175 discloses a process for preparation of
l_/2,6,7,8,8a-hexahydro-beta,delta,6-trihydroxy-2-methyl-8-[(2S)-2-methyl-1-oxobutoxy]-, (beta R,delta R,lS,2S,6S,8S,8aR)- 1-Naphthaleneheptanoic acid sodium salt from lactone by hydrolyzing with sodium hydroxide.
Also amine salts can be transformed to sodium salt by treating with sodium hydroxide and/or sodium alkoxide.
When amine salts are employed, it involves an extra step i.e., the preparation of the amine salt.
US 2003/0050502 discloses a process for preparation of sodium salt of a statin by contacting a solution of hydroxy acid of the statin with sodium-2-ethylhexanoate and recovering the corresponding sodium salt.
The process involves use of expensive reagent sodium-2-ethyl hexanoate.
The prior art methods suffer from one or more disadvantages like use of expensive reagents, need of special equipment to carry out the operation or increased number of steps for the preparation of sodium salt of l,2,6,7,8,8a-hexahydro-beta,delta_/6-trihydroxy-2-methyl-8-[(2S)-2-me hyl-l-oxobutoxy]-, (beta R,delta
R_/lS^δS_/δS_/δaR)- 1-Naphthaleneheptanoic acid.
The present invention relates to a process, which overcomes all the disadvantages of the prior art and results in substantially pure product in high yields.
Example 1
To a solution of 3,5-Dihydroxy-7-[6-hydroxy-2-methyl-δ-(2-methyl-butyryloxy)-l,2,6,7,δ,δa-hexahydro-naphthalen-l-yl]-heptanoic acid ( 70 g, 0.165 mol) in ethyl acetate (500 ml), solid sodium carbonate (δ.76 g, 0.0δ25 mol) was added and stirred for 2 hours. l,2_/6,7,8,8a-hexahydro-beta,delta,6-trihydroxy-2-methyl-8-[(2S)-2-methyl-l-oxobutoxy]-, (beta R,delta R,lS,2S,6S,δS,δaR)-1-Naphthaleneheptanoic acid sodium salt was precipitated. The reaction mixture was filtered and cake was washed with ethyl acetate to get free flowing crystals of l,2,6,7,δ,δa-hexahydro-beta,delta,6-trihydroxy-2-methyl-δ-[(2S)-2-methyl-l-oxobutoxy]-, (beta R,delta R,lS,2S,6S,δS,δaR)- 1-Naphthaleneheptanoic acid sodium (FORMULA I). Yield: 65 g, δδ% Example 2
To a solution of 3,5~Dihydroxy-7-[6-hydroxy-2-methyl-δ-(2-methyl-butyryloxy)-l,2,6,7,δ,δa-hexahydro-naphthalen-l-yl]-heptanoic acid (10 Kg, 23.6 mol) in isobutyl acetate (60 L), solid sodium carbonate (1.25 Kg, 11.8 moi) was added and stirred for 3 hoursl,2,6,7,8,δa-hexahydro-beta,delta,6-trihydroxy-2-methyl-δ-[(2S)-2-methyl-l-oxobutoxy]-, (beta R,delta R,lS,2S,6S,δS,δaR)-1-Naphthaleneheptanoic acid sodium salt was precipitated. The reaction mixture was filtered and cake was washed with isobutyl acetate to get free flowing crystals of l,2,6,7,δ,δa-hexahydro-beta,delta,6-trihydroxy-2-methyl-δ-[(2S)-2-methyl-l-oxobutoxy]-, (beta R,delta R,lS,2S,6S,δS,δaR)- 1-Naphthaleneheptanoic acid sodium (FORMULA I). Yield: 9 Kg, δ5%
Example 3
To a solution of 3,5-Dihydroxy-7-[6-hydroxy-2-methyl-δ-(2-methyl-butyryloxy)-l,2,6,7,δ,δa-hexahydro-naphthalen-l-yl]-heptanoic acid (100. Kg, 236 mol) in butyl acetate (600 L), solid sodium carbonate (12.5 Kg, 118 mol) was added and stirred for 3 hours. l,2,6,7,8,δa-hexahydro-beta,delta,6-trihydroxy-2-methyl-δ-[(2S)-2-methyl-l-oxobutoxy]-, (beta R,delta R,lS,2S,6S,δS,δaR)-1-Naphthaleneheptanoic acid sodium salt was precipitated. The reaction mixture was filtered and cake was washed with butyl acetate to get free flowing crystals of l,2,6,7,δ,δa-hexahydro-beta,delta,6-trihydroxy-2-methyl-δ-[(2S)-2-methyl-l-oxobutoxy]-, (beta R,delta R,lS,2S,6S,δS,δaR)- 1-Naphthaleneheptanoic acid sodium (FORMULA I). Yield: 95 Kg, 90%

FORMULA I
…………………………
US2005/113446 A1, ; Page/Page column 6 ;
……………………………
http://www.google.com/patents/EP0975738A1?cl=en
Description of the Drawings
The invention will be described in more detail in the drawings. Fig. 1 is the IR spectrum of pravastatin sodium Fig. 2 is the¹³C-NMR spectrum of pravastatin sodium Fig. 3 is the H-NMR spectrum of pravastatin sodium








EXPERIMENTAL EXAMPLE
The physical properties of pravastatin sodium obtained from Example 1 and Comparative Example are described in Table 3.
Table 3

IR spectrum, “C-NMR spectrum, H-NMR spectrum of pravastatin sodium obtained from this invention are represented in Fig. 1, Fig. 2 and Fig. 3, respectively. By using a new microorganism Streptomyces exfoliatus YJ-118 isolated from this invention, ML-236B concentration in culture broth could be raised to 0.5% (w/v) and pravastatin sodium productivity was increased up to 600—1,340 mg/ / much higher than that of other microorganisms (60 mg/ / ) .
EXAMPLE 1
To 125 ml Erlenmeyer flask containing 20 ml seed culture medium(I) that comprises glucose 1%, yeast extract 0.2%, skim milk 0.2%, casein hydrolyte (N-Z amine) 0.5%, pH 7.0. 0.02% (w/v) ML-236B was added and Streptomyces exfoliatus YJ-118 isolated from manufacturing Example was inoculated. The cultivation was done at 27° C., 200 rpm, for 2 days on a rotary shaker. 20 ml of seed culture above was inoculated in 2 l Erlenmeyer flask containing 400 ml production medium(II) that comprises glucose 1.0%, yeast extract 1.0%, polypeptone 0.5%. K₂HPO₄ 0.1%, MgSO₄.7H₂O 0.05%, NaCl 0.01˜0.1%, pH 7.2 and the flask was cultured at 27° C., 150 rpm. One day after cultivation, 0.05% (w/v) ML-236B (formula II-a) was added every day till the final concentration of ML-236B in culture broth became 0.2% (w/v). The cultivation was continued at 27° C., 150 rpm for 6 days and 0.3% glucose was fed once every two days 2 times in total. After then, the culture broth was adjusted to pH 9.0 and stirred for 3 hr. After centrifugation cell mass was removed and the supernatant was applied to a column of HP-20 500 ml. After washed with water, pravastatin sodium was eluted with 25% acetone solution. Pravastatin sodium fraction was concentrated in vacuo and the residue was applied to semi preparative HPLC(Kromasil C₁₈ resin). Pravastatin sodium was eluted with 35% acetonitrile solution and was obtained as white crystal 1,254 mg (627 mg/l),

References

1. “Prevachol”. The American Society of Health-System Pharmacists. Retrieved 3 April 2011.
2. No Authors Listed (2002). “Major outcomes in moderately hypercholesterolemic, hypertensive patients randomized to pravastatin vs usual care: The Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT-LLT)”. JAMA288 (23): 2998–3007. doi:10.1001/jama.288.23.2998. PMID12479764.
3.  Pfeffer MA, Keech A, Sacks FM, et al. “Safety and tolerability of pravastatin in long-term clinical trials: prospective Pravastatin Pooling (PPP) Project.” Circulation 2002;105:2341-2346
4. Williams, Eni. “Pravachol Side Effects Center”. RxList. Retrieved 1 December 2012.
5. “Pravastatin”. LactMed. U.S. National Library of Medicine. Retrieved 1 December 2012.
6. Vaughan, C. J., and A. M. Gotto, Jr. 2004. Update on statins: 2003. Circulation 110: 886–892.
7. Yoshino G, Kazumi T, Kasama T, et al. (1986). “Effect of CS-514, an inhibitor of 3-hydroxy-3-methylglutaryl coenzyme A reductase, on lipoprotein and apolipoprotein in plasma of hypercholesterolemic diabetics”. Diabetes Res. Clin. Pract.2 (3): 179–81. doi:10.1016/S0168-8227(86)80020-1. PMID3091343.
8. “FDA Approves First Generic Pravastatin”. Retrieved 2008-01-20.

• Pravachol information from the National Institute of Health
• Package insert for Pravachol

WO2001044144A2 *	Dec 14, 2000	Jun 21, 2001	M Lakshmi Kumar	Process for the preparation of sodium salts of statins
US20020082295 *	Oct 5, 2001	Jun 27, 2002	Vilmos Keri	Pravastatin sodium substantially free of pravastatin lactone and epi-pravastatin, and compositions containing same

HMG-CoA reductase inhibitor; bioactive metabolite of mevastatin, q.v. Prepn by microbial hydroxylation: A. Terahara, M. Tanaka, DE 3122499; eidem, US 4346227 (1981, 1982 both to Sankyo);

N. Serizawa et al., J. Antibiot. 36, 604 (1983).

Structure elucidation: H. Haruyama et al., Chem. Pharm. Bull. 34, 1459 (1986).

HPLC determn in biological fluids: S. Baueret al., J. Chromatogr. B 818, 257 (2005).

Effect on serum lipid concentration: N. Nakaya et al., Atherosclerosis 61, 125 (1986);

on hepatic metabolism of cholesterol: E. Reihnér et al., N. Engl. J. Med. 323, 224 (1990).

Clinical comparison with probucol, q.v.: G. Yoshino et al., Lancet 2, 740 (1986).

Clinical reduction of risk of major cardiovascular events in patients with coronary heart disease: LIPID Study Group, N. Engl. J. Med. 339, 1349 (1998).

Clinical effect on risk of stroke: H. D. White et al., ibid. 343, 317 (2000).

Derivative Type: Lactone

Molecular Formula: C23H34O6

Molecular Weight: 406.51

Percent Composition: C 67.96%, H 8.43%, O 23.61%

Properties: Colorless plate crystals, mp 138-142°. [a]D22 +194.0° (c = 0.51 in methanol). uv max (methanol): 230, 237, 245 nm.

Melting point: mp 138-142°

Optical Rotation: [a]D22 +194.0° (c = 0.51 in methanol)

Absorption maximum: uv max (methanol): 230, 237, 245 nm

 

 

 

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