154026-93-4

Basic information

• Product Name: tert-butyl (3R,5S)-6-chloro-3,5-dihydroxyhexanoate
• Synonyms: tert-butyl (3R,5S)-6-chloro-3,5-dihydroxyhexanoate;Hexanoic acid, 6-chloro-3,5-dihydroxy-, 1,1-diMethylethyl ester, (3R,5S)-;(3R,5S)-tert-Butyl 6-chloro-3,5-dihydroxyhexanoate;(3R,5S)-6-Chloro-3,5-dihydroxyhexanoic Acid tert-Butyl Ester;-tert-Butyl 6-chloro-3,5-dihydroxyhexanoate
• CAS NO: 154026-93-4
• Molecular Formula: C₁₀H₁₉ClO₄
• Molecular Weight: 239
• Mol File: 154026-93-4.mol

Chemical Properties

• Boiling Point: 364.584 °C at 760 mmHg
• Flash Point: 174.295 °C
• Appearance: /
• Density: 1.169 g/cm³
• Vapor Pressure: 0mmHg at 25°C
• Refractive Index: 1.479
• Storage Temp.: 2-8°C
• Solubility: Chloroform (Sparingly), Methanol (Slightly)
• PKA: 13.69±0.20(Predicted)
• Stability: Hygroscopic
• CAS DataBase Reference: tert-butyl (3R,5S)-6-chloro-3,5-dihydroxyhexanoate(CAS DataBase Reference)
• NIST Chemistry Reference: tert-butyl (3R,5S)-6-chloro-3,5-dihydroxyhexanoate(154026-93-4)
• EPA Substance Registry System: tert-butyl (3R,5S)-6-chloro-3,5-dihydroxyhexanoate(154026-93-4)

Safety Data

• Hazardous Substances Data: 154026-93-4(Hazardous Substances Data)

Usage

Uses

Used in Pharmaceutical Industry:
tert-butyl (3R,5S)-6-chloro-3,5-dihydroxyhexanoate is used as a key intermediate in the synthesis of Rosuvastatin (R700500), a selective and competitive HMG-CoA reductase inhibitor. tert-butyl (3R,5S)-6-chloro-3,5-dihydroxyhexanoate is essential for the development of Rosuvastatin, which is a widely prescribed medication for lowering cholesterol levels and reducing the risk of cardiovascular diseases.

InChI:InChI=1/C10H19ClO4/c1-10(2,3)15-9(14)5-7(12)4-8(13)6-11/h7-8,12-13H,4-6H2,1-3H3/t7-,8+/m1/s1

Upstream product

• 154026-92-3 Tert-butyl (5S)-6-chloro-5-hydroxy-3-oxohexanoate 
• 540-88-5 acetic acid tert-butyl ester 
• 276249-18-4 tert-butyl 6-chloro-3,5-dioxohexanoate 
• 1694-31-1 tert-butyl acetoacetate 

Downstream Products

• 125971-93-9 (3R,5R)-tert-butyl-6-cyano-3,5-dihydroxyhexanoate 
• 154026-95-6 (4R-cis)-6-[(acetyloxy)methyl]-2,2-dimethyl-1,3-dioxane-4-acetic acid tert-butyl ester 
• 124655-09-0 1,1-dimethylethyl (4R-cis)-6-hydroxymethyl-2,2-dimethyl-1,3-dioxane-4-acetate 
• 124752-23-4 tert-butyl 2-[(4R,6S)-6-formyl-2,2-dimethyl-1,3-dioxan-4-yl]acetate 
• 147489-06-3 (4R,6S)-(E)-{6-[2-(2-cyclopropyl-4-(4-fluorophenyl)quinolin-3-yl)-vinyl]-2,2-dimethyl-1,3-dioxan-4-yl}acetic acid tert-butyl ester 
• 147526-32-7 pitavastatin calcium salt 
• 586966-54-3 (3R,5S,6E)-7-[2-cyclopropyl-4-(4-fluorophenyl)-3-quinolyl]-3,5-dihydroxy-6-heptenoic acid tert-butyl ester 
• 355806-00-7 rosuvastatin tert-butyl ester 
• 154026-94-5 (4R-cis)-6-(chloromethyl)-2,2-dimethyl-1,3-dioxane-4-acetic acid,1,1-dimethylethyl ester 

Relevant articles and documents

Improvement of carbonyl reductase activity for the bioproduction of tert-butyl (3R,5S)-6-chloro-3,5-dihydroxyhexanoate

tert-Butyl (3R,5S)-6-chloro-3,5-dihydroxyhexanoate ((3R,5S)-CDHH) is a key chiral intermediate for the side chain synthesis of rosuvastatin. In this study, random mutagenesis, site-saturation mutagenesis and combinatorial mutagenesis methods were applied to improve the activity of a synthesized stereoselective short chain carbonyl reductase (SCR) to prepare (3R,5S)-CDHH. After screened by high-throughput screening method and high-performance liquid chromatography, mut-Phe145Met/Thr152Ser and mut-Phe145Tyr/Thr152Ser, were obtained, and the enzyme activities of mutants were improved by 1.60- and 1.91-fold compared with parent enzyme, respectively. The catalytically efficiencies (kcat/Km) of mut-Phe145Met/Thr152Ser and mut-Phe145Tyr/Thr152Ser exhibited 5.11- and 8.07-fold improvements in initial activity toward (S)-6-chloro-5-hydroxy-3-oxohexanoate ((S)-CHOH), respectively. In the asymmetric reduction, mut-Phe145Tyr/Thr152Ser catalyzed 500 g L?1 of (S)-CHOH to produce (3R,5S)-CDHH with >99% yield and >99% e.e., and the highest space-time yield achieved at 752.76 mmol L?1 h?1 g?1 wet cell weight within 8 h bioconversion. This study provides a foundation for the preparation of (3R,5S)-CDHH by carbonyl reductase.

Directed Evolution of Carbonyl Reductase from Rhodosporidium toruloides and Its Application in Stereoselective Synthesis of tert-Butyl (3R,5S)-6-Chloro-3,5-dihydroxyhexanoate

tert-Butyl (3R,5S)-6-chloro-3,5-dihydroxyhexanoate ((3R,5S)-CDHH) is a key intermediate of atorvastatin and rosuvastatin synthesis. Carbonyl reductase RtSCR9 from Rhodosporidium toruloides exhibited excellent activity toward tert-butyl (S)-6-chloro-5-hydroxy-3-oxohexanoate ((S)-CHOH). For the activity of RtSCR9 to be improved, random mutagenesis and site-saturation mutagenesis were performed. Three positive mutants were obtained (mut-Gln95Asp, mut-Ile144Lys, and mut-Phe156Gln). These mutants exhibited 1.94-, 3.03-, and 1.61-fold and 1.93-, 3.15-, and 1.97-fold improvement in the specific activity and kcat/Km, respectively. Asymmetric reduction of (S)-CHOH by mut-Ile144Lys coupled with glucose dehydrogenase was conducted. The yield and enantiomeric excess of (3R,5S)-CDHH reached 98 and 99%, respectively, after 8 h bioconversion in a single batch reaction with 1 M (S)-CHOH, and the space-time yield reached 542.83 mmol L-1 h-1 g-1 wet cell weight. This study presents a new carbonyl reductase for efficient synthesis of (3R,5S)-CDHH.

Co-evolution of activity and thermostability of an aldo-keto reductase KmAKR for asymmetric synthesis of statin precursor dichiral diols

Aldo-keto reductase KmAKR-catalyzed asymmetric reduction offers a green approach to produce dichiral diol tert-butyl 6-substituted-(3R,5R/S)-dihydroxyhexanoates, which are important building blocks of statins. In our previous work, we cloned a novel gene of NADPH-specific aldo-keto reductase KmAKR (WT) from a thermotolerant yeast Kluyveromyces marxianus ZJB14056 and a mutant KmAKR-W297H/Y296W/K29H (Variant III) has been constructed and displayed strict diastereoselectivity towards tert-butyl 6-cyano-(5R)-hydroxy-3-oxohexanoate ((5R)-1) but moderate activity and stability. Herein, to further co-evolve its activity and thermostability, we performed semi-rational engineering of Variant III by using a combinational screening strategy, consisting of tertiary structure analysis, loop engineering, and alanine scanning. As results, the “best” variant KmAKR-W297H/Y296W/K29H/Y28A/T63M (Variant VI) was acquired, whose Km, kcat/Km towards (5R)-1 was 0.66 mM and 210.77 s?1 mM?1, respectively, with improved thermostability (half-life of 14.13 h at 40 °C). Combined with 1.5 g dry cell weight (DCW) L-1 Exiguobacterium sibiricum glucose dehydrogenase (EsGDH) for NADPH regeneration, 4.5 g DCW L-1 Variant VI completely reduced (5R)-1 of up to 450 g L?1 within 7.0 h at 40 °C, yielding the corresponding optically pure tert-butyl 6-cyano-(3R,5R)-dihydroxyhexanoate ((3R,5R)-3, >99.5% d.e.p) with a space–time yield (STY) of 1.24 kg L?1 day?1, and this was the highest level documented in literatures so far on substrate loading and STY of producing (3R,5R)-3. Besides (5R)-1, Variant VI displayed strong activity on tert-butyl 6-chloro-(5S)-hydroxy-3-oxohexanoate ((5S)-2). 4.5 g DCW L-1 Variant VI completely reduced 400 g L?1 (5S)-2, within 5.0 h at 40 °C, yielding optically pure tert-butyl 6-chloro-(3R,5S)-dihydroxyhexanoate ((3R,5S)-4, >99.5% d.e.p) with a STY of 1.34 kg L?1 day?1. In summary, Variant VI displayed industrial application potential in statins biomanufacturing.

Enzymatic preparation of optically pure t-butyl 6-chloro-(3R,5S)-dihydroxyhexanoate by a novel alcohol dehydrogenase discovered from Klebsiella oxytoca

Alcohol dehydrogenases can catalyze the inter-conversion of aldehydes and alcohols. The t-butyl 6-chloro-(3R,5S)-dihydroxyhexanoate is a key chiral intermediate in the synthesis of statin-type drugs such as Crestor (rosuvastatin calcium) and Lipitor (atorvastatin). Herein, a novel alcohol dehydrogenase (named as KleADH) discovered from Klebsiella oxytoca by a genome mining method was cloned and characterized. The KleADH was functionally overexpressed in Escherichia coli Rosetta (DE3) and the whole cell biocatalyst was able to convert t-butyl 6-chloro-(5S)-hydroxy-3-oxohexanoate to t-butyl 6-chloro-(3R,5S)-dihydroxyhexanoate with more than 99% diastereomeric excess (de) and 99% conversion in 24?h without adding any expensive cofactors. Several factors influencing the whole cell catalyst activity such as temperature, pH, the effects of metal ions and organic solvent were determined. The optimum enzyme activity was achieved at 30?°C and pH 7.0 and it was shown that 1?mM Fe3+ can increase the enzyme activity by 1.2 times. N-hexane/water and n-heptane/water biphasic systems can also increase the activity of KleADH. Substrate specificity studies showed that KleADH also exhibited notable activity towards several aryl ketones with high stereoselectivity. Our investigation on this novel alcohol dehydrogenase KleADH reveals a promising biocatalyst for producing chiral alcohols for preparation of valuable pharmaceuticals.

A (3R, 5S) - 6 - hydroxy hexanoate chlorodisilanes butyl ester preparation method (by machine translation)

The invention discloses a (3R, 5S) - 6 - hydroxy hexanoate chlorodisilanes butyl ester preparation method, which belongs to the technical field of pharmaceutical and chemical industries. The preparation method comprises: the 3, 4 - dioxo - 6 - butyl chlorine caproic acid uncle dissolved in organic solvent, catalyst isocompound (R)- [RuCl2 (MeO - BIPHEP)]2 The lower catalytic hydrogenation reaction, the catalytic hydrogenation of the reaction condition is: temperature is 20 - 80 °C, pressure is 0.1 - 0.8 mpa, time is 1 - 7h, after the reaction, the pressure is reduced to atmospheric, concentrated under reduced pressure, distillation (3R, 5S) - 6 - chlorodisilanes hydroxy butyl hexanoate; wherein said 3, 4 - dioxo - 6 - butyl chlorine caproic acid uncle with a chiral catalyst in a molar ratio of 1: 0.00005 - 0.0002. The process for preparing the novel and simple, the operation is simple, friendly to the environment, and is suitable for industrial production. (by machine translation)

Method for synthesizing ADA

The invention relates to a compound synthesized in the medicine field, and particularly relates to a rosuvastatin intermediate. The method for synthesizing ADA comprises the following five steps: 1, reacting S-4-chloro-3-hydroxy butyronitrile with hexamethyl-disilazane to generate an intermediate I; 2, reacting the prepared intermediate I, a reducing agent and methanesulfonic acid with tert-butyl bromoacetate to prepare an intermediate II; 3, preparing an intermediate III from the prepared intermediate II by enzyme selective reduction; 4, reacting the prepared intermediate III with acetone acetal to prepare an intermediate IV; and 5, reacting the prepared intermediate IV and tetrabutylammonium bromide with sodium acetate to prepare the target intermediate ADA. According to the method, operation for preparing ADA is more convenient; and the method has high safety coefficient and low cost, and is very suitable for industrial production.

Asymmetric synthesis of optically active methyl-2-benzamido-methyl-3-hydroxy-butyrate by robust short-chain alcohol dehydrogenases from Burkholderia gladioli

Three short-chain alcohol dehydrogenases from Burkholderia gladioli were discovered for their great potential in the dynamic kinetic asymmetric transformation of methyl 2-benzamido-methyl-3-oxobutanoate, and their screening against varied organic solvents and substrates. This is the first report of recombinant enzymes capable of achieving this reaction with the highest enantio- and diastereo-selectivity.

Stereoselective reduction of δ-hydroxy β-ketoesters to syndiol in achiral micellar system

A novel, efficient and stereo-selective process for synthesis of statin side chain, a key intermediate for statin type cholesterol lowering drugs such as Lipitor (atorvastatin) and Crestor (rosuvastatin) in achiral micellar media is reported. The key feature of this process is sodium borohydride reduction of δ-hydroxy β-ketoester in achiral micellar system in 92% de, thereby avoiding metal chelation methods which employ triakylborane, titanium (IV) isopropoxide or cerium (III) chloride prior to reduction.

NOVEL BORONATE ETHER INTERMEDIATES FOR PREPARATION OF STATIN COMPOUNDS, PREPARATION METHOD THEREOF AND PREPARATION METHOD OF STATIN COMPOUNDS USING SAID BORONATE ETHER INTERMEDIATES

The present invention relates to a novel boronate ether compound and a manufacturing method thereof. Provided is a novel boronate ether compound denoted by chemical formula 1 or chemical formula 2 as an intermediate to manufacture rosuvastatin calcium or pitavastatin calcium which is one of the statin based compounds to reduce the level of low density lipoprotein (LDL) of patients who have hyperlipidemia and are accordingly cured, and statin compounds with high purity are easily manufactured and separated compared with an existing patented method and are easily provided in a method of mass production.

A NOVEL, GREEN AND COST EFFECTIVE PROCESS FOR SYNTHESIS OF TERT-BUTYL (3R,5S)-6-OXO-3,5-DIHYDROXY-3,5-O-ISOPROPYLIDENE-HEXANOATE

The present invention provides a process of preparation of an intermediate useful for the preparation of statins more particularly the present invention relates to an eco-friendly and cost effective process for the preparation of tert -butyl (3R,5S)-6-oxo-3,5-dihydroxy- 3,5-O-isopropylidene-hexanoate [I].