ZA200406273B

ZA200406273B - Novel boronate esters.

Info

Publication number: ZA200406273B
Application number: ZA200406273A
Authority: ZA
Inventors: Tom Thomas Puthiaprampil; Madhavan Sridharan; Sumithra Srinath; Sambasivam Ganesh
Original assignee: Biocon Ltd
Priority date: 2004-08-05
Filing date: 2004-08-05
Publication date: 2005-11-30

Description

i {

TITLE OF THE INVENTION

Novel Boronate esters

FIELD OF THE INVENTION

The present invention relates to optically active dihydroxy hexanoate derivatives of formula IIa and more particularly to compounds of formula II which are useful intermediates for the synthesis of HMG-CoA enzyme inhibitors like atorvastatin, cerivastatin, rosuvastatin, pitavastatin, fluvastatin.

BACKGROUND OF THE INVENTION

Esters and derivatives of the formula 1,

OR, OR,

HO COR, where R; and R; are independently chosen alkyl of one to three carbons and Rs is alkyl of from 1 to 8 carbon atoms, alternatively compounds of formula 1a,

Ri. R2 00

HO _A_COR, wherein Ry and R; are independently chosen from alkyl of one to three carbons, phenyl or R; and R; taken together as -(CH2)n- wherein nis4 or5 and Rs; is alkyl of from 1 to 8 carbon atoms and also compounds of Formula 1b :

he ‘ Ri R2

Sivg oS

Ho _L__cog, wherein R; and R; are alkyl of from 1-5 carbons and Rs is as defined above is a valuable structural element for synthesizing compounds, which are known as anti-hypercholesterolemic agents s having an inhibitory effect on HMG-CoA reductase.

EP 0 319 847 describes a process for the preparation of compounds of formula 1 starting from L-Malic acid. This process, however, suffers from the fact that the process is not industrially scalable and also possesses purification problems due to the non- crystalline nature of the intermediates.

US 5,399,722 describe a process starting from commercially available ethyl o-cloroacetoacetate or its benzyloxy derivative. The disadvantages of this process are that a stereo selective reduction using a costly ruthenium-BINAP catalyst in employed and the desired compound of formula 1 is obtained in six steps.

US 5,481,009 describe a process starting from 4-phenyl-3- butenoic acid in about 5 steps. The process uses expensive materials like - N, O-Dimethyl hydroxylamine and hazardous steps (ozonolysis) to obtain the desired product.

US 5,998,633 describes a process for the preparation of protected esters of 3,4-dihydroxy butyric acid from a carbohydrate moiety which is transformed into the desired 3,4-dihydroxy butanoic acid derivatives in about 4 steps. The 3,4-dihydroxy butanoic acid

“¥ derivative is then functionalized into compounds of formula I involving a multiple number of steps. : US 6,140,527 describes a process for producing butyric acid derivatives starting from a butene derivative followed by reaction with s an addition reagent capable of adding across the double bond.

However, this procedure does not afford chiral molecules and hence necessitates the need for a resolution step.

EP 0 104 750 describes a process for the preparation of 5- hydroxy-3-oxo pentanoic acid derivatives by alkylation of 3- hydroxybutyrate derivatives. The derivatives mentioned in this patent are racemic molecules and thus necessitating a resolution step.

The objective of the present is to provide a simple and industrially scalable process for the preparation of derivatives of formula I starting from commercially available and inexpensive malic 1s acid.

~

Summary of the invention

To achieve the said object the present invention provides a : product of formula IIa and more particularly a compound of formula II

Ar

Bo 0) 0)

Ra. COR, a”

Formula IIa

Ho YY YU ® o_ 9 0

B

Ar

Formula II wherein

Ar = unsubstituted or substituted aryl or heteroaryl

R3 = alkyl from 1 to 8 carbons, aryl or aralkyl

Rs= O, OH, CN or a halogen and a = single bond or double bond

The present invention also provides for a process for the manufacture of compounds of formula II oO YY TY ® : ¢ N o oO .

Ar = unsubstituted or substituted aryl or heteroaryl

Rs = alkyl from 1 to 8 carbons, aryl or aralkyl which comprises of: (@) reacting compound of formula IIT with the anion of tertiary butyl acetate to give a compound of formula IV, where G is tetrahydropyranyl, tert-butyldimethyl silyl or trityl and Rs is alkyl from 1 to 8 carbons, aryl or aralkyl, )

G. . oO G

TTT YY TT

Formula III Formula IV (b) subjecting compound of formula IV to reduction to give a compound of formula V, where G is tetrahydropyranyl, tert- butyldimethyl silyl or trityl and Rs is alkyl from 1 to 8 carbons, aryl or aralkyl,

G

YYT

Formula V

~ (c) protecting the compound of formula V with ArB(OH): to give a compound of formula VI, where Ar is unsubstituted or substituted aryl or heteroaryl, G is tetrahydropyranyl, tert- butyldimethy! silyl or trityl and Rj; is alkyl from 1 to 8 carbons, aryl or aralkyl, and

NI

1

Formula VI (f) deprotection of the compound of formula VI using mild acid . catalyst to give a compound of formula II.

Said ArB(OH), is boronic acid.

The compound of formula II is oxidized to a compound of formula VIII, where Rs is alkyl from 1 to 8 carbons, aryl or aralkyl and

Ar is unsubstituted or substituted aryl or heteroaryl using pyridinium chloro chromate or DMSO/oxalyl chloride.

Ar "0

Os AA COR,

Formula VIII

The compound of formula II is further converted to a compound : 20 of formula IX, where R; is alkyl from 1 to 8 carbons, aryl or aralkyl, Ar is unsubstituted or substituted aryl or heteroaryl and X is a halogen. }

~ 0 oO : Ar

Formula IX

The compound of formula IX is further converted to a compound of formula VII, where Rj; is alkyl from 1 to 8 carbons, aryl or aralkyl, Ar 5s is unsubstituted or substituted aryl or heteroaryl.

Ar

Bs

Q (0

No _A_A_ cor,

Formula VII

The product of formula IIa and more particularly of formula II are used in the synthesis of atorvastatin, cerivastatin, pitavastatin, fluvastatin or rosuvastatin.

Detailed Description of the invention

Compound of formula II serves as a good intermediate for the synthesis of important substrates, which are useful in the synthesis of statins. Compound of formula II can be converted into a facile leaving group by treating with tosyl chloride, methane sulfonyl chloride and the resulting intermediate can be displaced with cyanide to give compounds of formula VII.

Compound of formula II can be converted to formula IX by reacting with aqueous HBr solution or by reaction with triphenyl phosphine and CBr4 which is then converted to compound of formula

VIL v WO 03/070733 PCT/IN02/00032

Compound of formula II can be oxidized using standard procedures to give a compound of formula VIIL . The present invention relates to optically active dihydroxy hexanoate derivatives of formula IIa which are useful intermediates for s the synthesis of HMG-CoA enzyme inhibitors like atorvastatin, cerivastatin, rosuvastatin, pitavastatin, fluvastatin.

The invention is further illustrated with examples below, which are not intended to be limiting.

Example 1: Synthesis of methyl 4-triphenylmethyloxy-3- hydroxybutyrate (Formula III)

To 25g of methyl 3,4-dihydroxybutanoate was added to 250ml of

DCM and stirred to dissolve and 19.89 of pyridine was charged and cooled to 0°C. 41.4q of trityl chloride was dissolved in 50ml of DMC and was added at 0-5°C for 15 min. The temperature was allowed to rise to RT and was stirred at RT for 17h. Water was added and the oo layers were separated. The organic layer was washed with brine, dried and concentrated. The residue was triturated with 25m! of cyclohexane and the product was purified to give 15g of the pure product.

NMR (CDCl) : 4.25 (m, 1H), 3.6 (s, 3H), 3.15 (d, 2H), 2.5 (m, 2H), 7.2-7.4 (m, 15H)

Example 2: Synthesis of tert-butyl 6-triphenylmethyloxy-5- hydroxy-3-oxohexanoate (Formula IV)

To 125ml of THF, 24g of diisopropylamine were charged and was cooled to -15°C. 168ml of 1.2N n-BuLi was added at -15 to -5°C and

~ was stirred for 30min. 21.569 of tert-butyl acetate in 45ml of THF which was pre-cooled to -45°C was added maintaining the temperature between -45 to -25°C for 60min. Cool the reaction mixture to -45°C and 30g of example-1 in THF was added over a period of 20min and s the stirring was continued at -25°C for 90min. Water was added and the layers were separated. The aqueous layer was extracted using

EtOAc and the combined organic layers were washed with brine, water, dried and concentrated to give the title compound which was used as such for the next step.

Example 3: Synthesis of tert-butyl 6-triphenylmethyloxy-3,5- dihydroxhexanaote (Formula V)

To the crude material obtained in example-2, 150ml of THF was added followed by 15ml of MeOH and was chilled to -60°C. 26m of

MDEB (50% solution in THF) was added over a period of 20min and stirring was continued for a further 30min. The reaction mixture was cooled to -80°C and 5g of sodium borohydride was added in portions and the after completion of addition the reaction mixture was stirred for 5h at -78°C. Acetic acid was added to adjust the pH to 7 and water was added. The aqueous layer was extracted using EtOAc, washed with brine, dried and concentrated to give the title compound which was used as such for the next step.

Example 4: Synthesis of tert-Butyl 6-triphenylmethyloxy-3,5- phenylboranatohexanoate (Formula VI)

The crude product from example-3 was dissolved in 100ml of 25s toluene and 5.6g of phenyl boronic acid was added. Water was

Claims

y PCT/IN02/00032 Received 02 October 2002 oC ® AMENDED PAGES We claim:

1. Tha product of formula IIa uA con, a Se - wherein Ar = unsubstituted or substituted aryl or heteroaryl Rs = alkyl from 1 to 8 carbons, aryl or aralkyl R4= 0, OH, CN or a halogen and a = single bond or double bond

2. The product as claimed In calm 1 wherein said product is a compound of formula II YY YR o_o © ki Ar is wherein - oo Ar = unsubstituted or substituted ary] or heteroaryl Rs = alkyl from 1 to 8 carbons, aryl or aralkyl 19 AMENDED SHEET IPEA/AU :

y PCT/IN02/00032 . : Received 02 October 2002 ® AMENDED PAGES

3. A process for the manufacture of compounds of formula II oO NYT Re o_.0 © b SA Ar = unsubstituted or substituted aryl or heteroaryl Rs == alkyl from 1 to 8 carbons, aryl or aralkyl which comprises of: = (a) reacting compound of formula III with the anion of tertiary butyl acetate to give a compound of formula IV, where Gis ~~ tetrahydropyranyl, tert-butyldimethyl silyl or trityl and Rs is alkyl from 1 to 8 carbons, aryl or aralkyl, G Oo . : oY ~~ x ® Formula ITI oo Formula IV (b) subjecting compound of formula IV to reduction to give a compound of formula. V, where G Is tetrahydropyranyl, tert- butyldimethyl silyl or trityl and R; Is alkyl from 1-to 8 carbons, aryl or aralkyl, So NN Rs Formula V. (©) protecting the compound of formula V with ArB(OH); to give a compound of formula VI, where Ar Is unsubstituted or 20 AMENDED SHEET _ IPEA/AU

. PCT/IN02/00032 Sr Received 02 October 2002 : PY . AMENDED PAGES substituted aryl or heteroaryl, G Is tetrahydropyranyl, tert- butyldimethyl silyl or trityl and.Rs.is alkyl from 1 to 8 carbons, aryl ar aralkyl, and . 6.4 2008 Formula VI (f) deprotection of the compound of formula VI using mild acid catalyst to give a compound of formula II. 4, A process as claimed in claim 3 wherein ArB{OH); is baronic acid. :

5. A process as claimed in claim 3 wherein compound of formula OO is oxidized to a compound of formula VILL, where R; is alkyl from 1 to 8 carbons, aryl or aralkyl and Ar Is unsubstituted or substituted aryl or heteroaryl using pyridinium chloro chromate or DMSO/oxalyl chloride,

I

6. A process as claimed in claim 3 wherein compound-of formula II Is further converted to a compound of formula IX, where Rj; is alkyl from 1 to 8 carbons, aryl or aralkyl; Ar is unsubstituted or substituted aryl or heteroaryl and X is a halogen. 21 AMENDED SHEET IPEA/AU

PCT/IN02/00032 . Received 02 October 2002 ® tT AMENDED PAGES 0 B x “ra Ar Formula IX

7. A process as Claimed in claim 6 wherein compound of formula II is converted to compound of formula IX by reacting compound of formula II with aqueous HBr solution or by reaction with triphenyl phosphine and CBr,

B. A process as claimed In‘clalm 6.or 7 wherein compound of formula IX is further converted to a compound of formula VII, where Rs Is alkyl from 1 to 8 carbons, aryl or aralkyl, Ar is unsubstituted or substituted aryl or heteroaryl. . : AB we LI cog Formula VII

9. The product as claimed In-claim 1, used in the synthesis of atorvastatin, cerivastatin, pitavastatin, fluvastatin or rosuvastatin. 22 AMENDED SHEET IPEAIAU ©.