931-26-0

Usage

Uses

Used in Pharmaceutical Synthesis:
2,2-Dimethyl-1-cyclopropanecarboxylic acid is used as a key intermediate for the synthesis of various pharmaceuticals. Its unique cyclopropane ring and methyl groups contribute to the development of new drug molecules with specific therapeutic properties.
Used in Agrochemical Production:
In the agrochemical industry, 2,2-Dimethyl-1-cyclopropanecarboxylic acid serves as an essential building block for the creation of novel agrochemicals. Its incorporation into these compounds can enhance their effectiveness in agricultural applications, such as pest control and crop protection.
Used as a Chiral Building Block in Organic Chemistry:
2,2-Dimethyl-1-cyclopropanecarboxylic acid is utilized as a chiral building block in organic chemistry. Its asymmetric center allows for the synthesis of enantiomerically pure compounds, which are crucial in various chemical reactions and applications, including the production of enantioselective catalysts and the development of chiral drugs.
Used in Chemical Industry for Organic Synthesis:
The versatile nature of 2,2-Dimethyl-1-cyclopropanecarboxylic acid makes it a desirable compound for various applications in the chemical industry. Its unique structure and reactivity enable the synthesis of a wide range of organic compounds, contributing to the advancement of chemical research and development.

Upstream product

• 854432-02-3 4-bromo-3,3-dimethyl-butyric acid ethyl ester 
• 5722-11-2 rac-2,2-dimethylcyclopropanecarbonitrile 
• 16783-11-2 ethyl (±)-2,2-dimethylcyclopropanecarboxylate 
• 1192-44-5 (+/-)-2-Brom-3.3-dimethyl-cyclobutanon 
• 1759-55-3 (RS)-2,2-dimethylcyclopropanecarboxamide 
• 31044-87-8 neopentyl glycol bis(benzenesulfonate) 
• 143-33-9 sodium cyanide 
• 645413-67-8 2,2-dimethylcyclopropane carboxylic acid 2,2,2-trifluoroethyl ester 
• 167482-50-0 1,2-O-Isopropylidene-3-O-(p-phenylbenzyl)-4,5-O-<(1'R)-3'-methyl-2'-buten-1'-yl>-β-D-fructopyranose 
• 1740-74-5 1,1-diethoxy-3-methyl-2-butene 
• 75885-58-4 (S)-2,2-dimethylcyclopropanecarboxamide 
• 75885-59-5 2,2-dimethylcyclopropane-1-carboxylic acid 
• 110919-09-0 (4R,6R)-4,6-Dimethyl-2-(2-methyl-propenyl)-[1,3]dioxane 
• 107-86-8 3,3-dimethyl acrylaldehyde 

Downstream Products

• 1428555-91-2 N-(2-aminophenyl)-2,2-dimethylcyclopropanecarboxamide 
• 1428555-92-3 1,2-bis(2,2-dimethylcyclopropyl-1-carbonylamino)benzene 

Relevant academic research and scientific papers

Soluble and functional expression of a recombinant enantioselective amidase from Klebsiella oxytoca KCTC 1686 in Escherichia coli and its biochemical characterization

A gene encoding an enantioselective amidase (KamH) was cloned from Klebsiella oxytoca KCTC 1686 and inserted into the EcoRI and HindIII sites of the vector pET-30a(+). When KamH with a peptide containing a His-tag and an enterokinase cleavage site was overexpressed in Escherichia coli, approximately half was found in the soluble fraction, but it lacked activity. After cleavage of the peptide by enterokinase, the enzyme activity was partly restored, reaching 420.2 ± 33.62 U/g dry cell weight (DCW). Another recombinant plasmid was constructed by inserting the KamH gene into the NdeI and EcoRI sites of pET-30a(+) to express KamH in its native form. The overexpressed amidase was found primarily in the soluble fraction and its maximum activity was 3613.4 ± 201.68 U/g DCW. This indicated that the peptide influenced not only soluble expression but also activity of KamH, perhaps by blocking the substrate-binding tunnel of KamH. Similar results were obtained with heterologously expressed amidases from Rhodococcus erythropolis MP50 and Agrobacterium tumefaciens d3. All of these amidases have an N-terminal α-helical domain. Therefore, amidases of this type may be functionally expressed in their native form. KamH hydrolyzed a range of aliphatic and aromatic amides and exhibited strict S-selectivity towards racemic amides.

Substrate channel evolution of an esterase for the synthesis of cilastatin

The esterase RhEst1 from Rhodococcus sp. ECU1013 has been reported for the enantioselective hydrolysis of ethyl (S)-(+)-2,2-dimethylcyclopropane carboxylate, producing the building block of cilastatin. In this work, error-prone PCR and site-directed saturation mutagenesis were applied to RhEst1 for activity improvement, with the pH-indicator assay as a high-throughput screening method. As a result, RhEst1A147I/V148F/G254A, with mutations surrounding the substrate access channel, showed a 5-fold increase in its specific activity compared with the native enzyme, as well as a 4-fold increase in protein solubility. Combined with the determination of protein structures and computational analysis, this work shows that the amino acids around the substrate channel play a more important role in the activity evolution of RhEst1 than those in the active site. This journal is

Production of L-tryptophan by enantioselective hydrolysis of d,l-tryptophanamide using a newly isolated bacterium

Bacterial strain ZJB-09211 capable of amidase production has recently been isolated from soil samples. The strain is able to asymmetrically hydrolyze l-tryptophanamide from d,l-tryptophanamide to produce l-tryptophan in high yield and with excellent stereoselectivity (enantiomeric excess > 99.9 %, and enantiomeric ratio > 200). Strain ZJB-09211 has been identified as Flavobacterium aquatile based on the cell morphology analysis, physiological tests, and the 16S rDNA sequence analysis. Optimization of the fermentation medium led to an about six-fold increase in the amidase activity of strain ZJB-09211, which reached 501.5 U L-1. Substrate specifity and stereoselectivity investigations revealed that amidase of F. aquatile possessed a broad substrate spectrum and high enantioselectivity.

Kinetic resolution of (R,S)-2,2-dimethylcyclopropanecarboxamide by Delftia tsuruhatensis ZJB-05174: Role of organic cosolvent in reaction medium

Both enantioselectivity and catalytic activity were greatly enhanced in Delftia tsuruhatensis ZJB-05174 catalyzed kinetic resolution of 2,2-dimethlycyclopropanecarboxamide in the presence of ethanol and acetonitrile. The enantiomeric ratio (E) rose from 27 to 140 and 90 by addition of 5% acetonitrile and ethanol, respectively. In the scaled-up biotransformation, the reaction time was shortened to 1.33 h with an ees of 99% and 12.4 g of optically pure product (43.5% total yield) was afforded. These results indicated that addition of cosolvent was a simple and practical tool to improve amidase properties and would be extensively applied in amidase-catalyzed bioprocess.

Industrial production of S-2,2-dimethylcyclopropanecarboxamide with a novel recombinant R-amidase from Delftia tsuruhatensis

R-Stereoselective amidase, a key enzyme responsible for the formation of chiral center of cilastatin, has been cloned from Delftia tsuruhatensis and expressed in Escherichia coli under T7 promoter. This recombinant amidase exhibits strict R-selectivity towards 2,2-dimethylcyclopropanecarboxamide (DMCPCA). The amidase activity of the engineered E. coli strain reached 2963 U/L in a 5-L bioreactor, which was 8.27 times higher than that of D. tsuruhatensis, and was further increased to 5255 U/L in a 100-L bioreactor. Using cell-free extract prepared from 1 kg (wet cell weight) of recombinant E. coli cells as catalyst, 60 kg of R,S-DMCPCA was resolved into S-DMCPCA (28.6 kg) and R-2,2-dimethylcyclopropanecarboxylic acid (R-DMCPCS 31.7 kg) in 18 h, and the enantiomeric excess (ee) value of S-DMCPCA reached 99.32%. During the purification process, 24.6 kg of S-DMCPCA was eluted from adsorption resin HZ801 with 80% (v/v) acetone, and then 20.5 kg of pure S-DMCPCA was obtained after concentration and crystallization, corresponding to a total yield of 34.2% from R,S-DMCPCA. Therefore, the industrial production process of S-DMCPCA was successfully established using recombinant R-amidase from D. tsuruhatensis.

PROCESS FOR PRODUCING OPTICALLY ACTIVE AMIDE

The present invention relates to a new process for preparing a medical intermediate compound of formula (I). According to the present invention, an intermediate compound for cilastatin can be simply prepared with a high yield of 99.0% or more and a high optical purity of 99.5% without undergoing any dangerous processes.

PROCESS FOR PRODUCTION OF OPTICALLY ACTIVE CARBOXYLIC ACID

The invention provides a process for producing optically active 2, 2-dimethylcyclopropanecarboxylic acid by reacting an optical isomer mixture of 2,2-dimethylcyclopropanecarboxylic acid with an optically inactive amine to form (precipitate, crystallize or the like) an ammonium salt of optically active 2,2-dimethylcyclopropanecarboxylic acid, for example, optically active (S)-(+)-2,2-dimethylcyclopropanecarboxylic acid. The production (optical resolution, separation of an optically active substance, purification of an optically active substance or the like) of optically active 2, 2-dimethylcyclopropanecarboxylic acid which is important as an intermediate for production of agricultural chemicals, medications and the like can easily be conducted at low cost. Further, the invention provides an intermediate therefor (an ammonium salt of optically active 2,2-dimethylcyclopropanecarboxylic acid, especially preferably an ammonium salt of optically active (S)-(+)-2,2-dimethylcyclopropanecarboxylic acid, or the like), and an optical resolution agent (optically inactive amine) for separation of optically active 2,2-dimethylcyclopropanecarboxylic acid.

Nitroxyl radical reactions with 4-pentenyl- and cyclopropylketenes: New routes to 5-hexenyl- and cyclopropylmethyl radicals

4-Pentenylketenes 4a and 9 and cyclopropylketenes 3a, 13, 14 (RCH=C=O) are generated by photochemical Wolff rearrangements and observed by IR as relatively long-lived species at room temperature in hydrocarbon solvents. The reactions of these ketenes with the nitroxyl radicals tetramethylpiperidinyloxyl (TEMPO, TO?) and tetramethylisoindoline-2-oxyl (TMIO, IO?) form carboxy substituted 5-hexenyl and cyclopropylmethyl radicals which are either trapped by a second nitroxyl radical or undergo rearrangements followed by trapping. The rate constant of the reaction of 4a with TEMPO was similar to that of n-BuCH=C=O (1b), while 3a was 4.3 times more reactive, indicating cyclopropyl stabilization of the incipient radical.

The synthesis of S-(+)-2,2-dimethylcyclopropane carboxylic acid: A precursor for cilastatin

S-(+)-2,2-Dimethylcyclopropane carboxylic acid, a precursor for cilastatin, was prepared from 2-methylpropene and chiral iron carbene in three steps. Asymmetric cyclopropanation reaction of 2-methylpropene with iron carbene complex having chirality at the carbene ligand, followed by exhaustive ozonolysis, produced S-(+)-2,2-dimethylcyclopropanecarboxylic acid of up to 92% ee. The absolute configuration of complexed chiral cyclopropane (-)-8 was determined by X-ray crystallographic analysis.

Chiral 2,2-disubstituted cyclopropanecarboxylic acids: Effective derivatizing agents for analysis of enantiomeric purity of alcohols and for resolution of 1,1'-Bi-2-naphthol

The enantiomeric purities of secondary alcohols can be easily analyzed by GC and HPLC through derivatization to the esters of 2,2-disubstituted cyclopropanecarboxylic acids 1, and by 1H NMR analysis of the esters of 2,2-diphenylcyclopropanecarboxylic acid (1b). In addition racemic 1,1'-bi-2-naphthol is easily resolved through derivatization to monoesters of 2,2-dimethylcyclopropanecarboxylic acid (1a), which are crystallized selectively and sequentially in high yields with high optical purities.