Methyl 3-[(2,2-dimethyl-1-oxobutyl)thio]propanoate

Colorless liquid

To the reaction vessel was added 40g of 2, 2-dimethyl butyryl chloride, and then to the reaction vessel was added dropwise 250ml of dichloromethane, stirred for 15min, After the end of the stirring to the outer jacket of the reactor by adding 15percent ice brine cooling cooling treatment, when the temperature in the reaction vessel was cooled to 10 ° C, the reaction vessel was added 25g of 3-mercapto propionic acid, stirring was continued The temperature is lowered so that 2, 2-dimethylbutyryl chloride reacts with 3-mercaptopropionate A to produce methyl α-dimethylbutyryl-S-propionate and hydrogen chloride.When the material in the reaction kettle was cooled to 0 ° C, ammonia gas was introduced into the reaction vessel until the pH in the reaction vessel was 7, Ammonia was stopped, heated to 65 ° C and held for 1.8 h, So that ammonia and hydrogen chloride generated by the reaction, ammonium chloride generated to promote the progress of the reaction until the reaction is completed, the reaction vessel was added 100ml of water, After the addition and stirring 30min, making the reaction of hydrogen chloride fully dissolved in water, and then allowed to stand 4.5h, making the dissolved liquid layering.After the liquid is layered, an aqueous layer and an organic layer are obtained, and the aqueous layer is an aqueous solution of ammonium chloride. The aqueous layer of the aqueous layer is directly transferred or collected by an iron drum to recover the ammonium chloride, and the methylene chloride is recovered by distillation to obtain 55 g Of the crude product, and the recovered methylene chloride solution was recycled, 55 g of the crude product was dissolved by heating in 300 ml of ethanol, decolored with activated charcoal, concentrated to 5 ° C and held for 2 h to give 52 g of a mixture, 52 g of the mixture was filtered and washed with 78 g of methylene chloride and finally 48.8 g of product was obtained by drying. The yield of methyl α-dimethylbutyryl-S-propionate was 98.4percent with a purity of more than 99.0percent.Example 1 Preparation of Methyl 3-(2, 2-Dimethylbutanoylthio)propionate (0117) A solution of N, N-diisopropylethylamine (19.9 mL, 120 mmol) and methyl 3-mercaptopropanoate (7.21 60 mmol) in isopropyl acetate (i-PrOAc, 100 mL) was cooled to an internal temperature of 2° C. (brine ice bath). To this vigorously stirred solution was added 2, 2-dimethylbutanoyl chloride (8.1 g, 60 mmol) dropwise over 10 min. The resulting suspension was then stirred at 25° C. for 2 h. The reaction was monitored by checking the disappearance of methyl 3-mercaptopropanoate using thin-layer chromatography (TLC) on silica plates. Spots were stained with iodine (eluent: 5percent EtOAc/heptane; R1)After 12 g of lovastatin was charged into the reactor, 32 g of isopropyl alcohol, 10 g of potassium hydroxide and 0. 6 g of water were successively added , then introduced nitrogen or argon gas and heated to 72 ± 0.3 C for 5 h. HPLC detection , starting materials water 12g was added , continue to distilled until no liquid distilled off, and concentrated until no distilled off. Again water 12g was added and , and Continue to distillate until no liquid is distilled off, and cooled to 25 ± 5 C; 2) The chemical hydrolyzate obtained in step 1) was adjusted to pH of 9. 5 ± 0.5 C with hydrochloric acid, 8. 8 g of 2, 2-dimethyl butyryl-S- Methyl Mercaptopropionate and 4 g of mycelium containing acyltransferaseand with 1M of Sodium carbonate maintained pH of 9. 5 ± 0.5 C at a temperature of 25 ± 5 C; 3) The reaction solution of step 2) was detected every 1 h until the ratio of lovastatin hydrolyzate proportion was less than 2% 4) The reaction solution of step 2) was placed in an ice-water bath at 0-5 C and the reaction was terminated by adding hydrochloric acid to the reaction solution and dropping to adjust pH 3-4 to form a solid-liquid two-phase; 5) The solid-liquid layered solution sample of step 4) was subjected to centrifugal separation. Conditions 8000rpm, 10min, 4 C; detection of supernatant product content and disposal; 6) The resulting solid of step 5) was added to 200 mL of a mixture of methanol and ethyl acetate (methanol: ethyl acetate = 1: 5) and extracted three times. The extracts were combined and the procedure was carried out in an ice bath at 0-5 C. 7) into the solution of step 6) placed in a 7-15 C water bath, the ammonia water in methanol aqueous solution was added dropwise to adjust the pH 7-8 or a crystal precipitated. The crystals were allowed to crystallize for 2 h and then the filtered to obtain a white solid that is Simvastatin Ammouium Salt.Example 7 Conversion of Monacolin J Hydroxy Acid to Simvastatin Hydroxy Acid Ammonium Salt and Isolation of Simvastatin Hydroxy Acid Ammonium Salt (0128) A 250 mL 3-neck round bottom flask (RBF) was equipped with an overhead stirrer, a flat-blade impeller and an internal thermometer. The reaction vessel was charged with monacolin J hydroxy acid (10 g, 29.58 mmol). Deionized water (112.0 mL) and NH4OH (4.2 mL) were added subsequently. The mixture was stirred until all solid dissolved prior to the pH adjustment (2 min). The pH of the resultant mixture was adjusted from 9.2 to 9.0 with 5 M HCl (1.5 mL) prior to the addition of enzyme. LovD enzyme (0.10 g) was charged to the stirred mixture as a powder. The mixture was stirred for 5 minutes at 300 rpm at 25 C. to obtain homogeneity. Example 5 Enzymatic Preparation of Simvastatin Hydroxy Acid, Sodium Salt from Monacolin J Hydroxy Acid, in the Presence of a Thiol Scavenger (0124) A 250 mL 3-neck RBF was equipped with an overhead stirrer, a flat-blade impeller and an internal thermometer. The reaction vessel was charged sequentially with the following: monacolin J hydroxy acid (5 g), 1M NaOH (16.3 mL), and deionized water (6.7 mL). The mixture was stirred until all solid was dissolved prior to the addition of buffer (triethanolamine, 400 mM, pH=8.5, 33.3 mL). The pH of the resultant mixture was adjusted from 9.6 to 9.0 with 5 M HCl (0.12 mL) prior to the addition of enzyme. Enzyme (0.10 g of acyltransferase LovD or an equivalent amount of a variant thereof) was charged to the stirred mixture as a powder. The mixture was stirred until homogeneous. Activated charcoal (0.67 g) was subsequently added and the mixture was stirred for another 5 minutes at 240 rpm at 25 C. (0125) Thioester (methyl 3-(2, 2-dimethylbutanoylthio)-propanoate, 5.5 mL) was then added to start the enzymatic reaction. The resulting mixture was stirred at 240 rpm at 25 C. (internal temperature). The reaction course was followed periodically by taking samples from the reaction mixture, quenching, and analyzing using HPLC. After analysis indicated maximum conversion (24 h), the reaction mixture was filtered through a pad of Celite (1.5 g) in a standard G4 sintered glass funnel under reduced pressure to remove the charcoal. The 250 mL 3-neck RBF was rinsed with deionized water (5 mL), which was filtered through the same pad of Celite and then combined with the filtrate. The filter cake was washed with water (5 mL) and the washings were collected and combined with the filtrate. The filtrate was recharged into a new 250 mL 3-neck flask and the pH of the filtrate was adjusted to 9.0 from 8.2 using 10 M NaOH solution (0.55 mL). (0126) Workup of the reaction mixture was accomplished by first extracting the aqueous phase with methyl tert-butyl ether. After extraction with MTBE (2 extractions), the aqueous phase was adjusted to a pH of about 5.3 to 5.4 using 0.5 M HCl while maintaining a temperature below 20 C. The aqueous phase was extracted three times with EtOAc. During each extraction, additional HCl was added, as needed, to maintain the pH of the aqueous phase between 5.3 and 5.4. The EtOAc phases from the 3 extractions were combined. The combined ethyl acetate extracts were filtered through a pad of Celite (1 g) in a standard G4 sintered glass funnel under reduced pressure to clarify the extract. The filter cake was washed with ethyl acetate (10 mL) and the washings were combined with the filtrate. The filtrate was concentrated as needed or additional EtOAc was added to produce an EtOAc solution with a volume of about 65 mL. This concentrated EtOAc solution was used for the next step, the formation of simvastatin hydroxy acid, ammonium salt, according to the method of example 4.To the reaction vessel was added 40g of 2, 2-dimethyl butyryl chloride, and then to the reaction vessel was added dropwise 250ml of dichloromethane, stirred for 15min, After the end of the stirring to the outer jacket of the reactor by adding 15% ice brine cooling cooling treatment, when the temperature in the reaction vessel was cooled to 10 C, the reaction vessel was added 25g of 3-mercapto propionic acid, stirring was continued The temperature is lowered so that 2, 2-dimethylbutyryl chloride reacts with 3-mercaptopropionate A to produce methyl alpha-dimethylbutyryl-S-propionate and hydrogen chloride.When the material in the reaction kettle was cooled to 0 C, ammonia gas was introduced into the reaction vessel until the pH in the reaction vessel was 7, Ammonia was stopped, heated to 65 C and held for 1.8 h, So that ammonia and hydrogen chloride generated by the reaction, ammonium chloride generated to promote the progress of the reaction until the reaction is completed, the reaction vessel was added 100ml of water, After the addition and stirring 30min, making the reaction of hydrogen chloride fully dissolved in water, and then allowed to stand 4.5h, making the dissolved liquid layering.After the liquid is layered, an aqueous layer and an organic layer are obtained, and the aqueous layer is an aqueous solution of ammonium chloride. The aqueous layer of the aqueous layer is directly transferred or collected by an iron drum to recover the ammonium chloride, and the methylene chloride is recovered by distillation to obtain 55 g Of the crude product, and the recovered methylene chloride solution was recycled, 55 g of the crude product was dissolved by heating in 300 ml of ethanol, decolored with activated charcoal, concentrated to 5 C and held for 2 h to give 52 g of a mixture, 52 g of the mixture was filtered and washed with 78 g of methylene chloride and finally 48.8 g of product was obtained by drying. The yield of methyl alpha-dimethylbutyryl-S-propionate was 98.4% with a purity of more than 99.0%.Preparation of Methyl 3-(2, 2-Dimethylbutanoylthio)propionate (0117) A solution of N, N-diisopropylethylamine (19.9 mL, 120 mmol) and methyl 3-mercaptopropanoate (7.21 60 mmol) in isopropyl acetate (i-PrOAc, 100 mL) was cooled to an internal temperature of 2 C. (brine ice bath). To this vigorously stirred solution was added 2, 2-dimethylbutanoyl chloride (8.1 g, 60 mmol) dropwise over 10 min. The resulting suspension was then stirred at 25 C. for 2 h. The reaction was monitored by checking the disappearance of methyl 3-mercaptopropanoate using thin-layer chromatography (TLC) on silica plates. Spots were stained with iodine (eluent: 5% EtOAc/heptane; Rf of methyl 3-mercaptopropanoate: 0.20). The reaction was then quenched by addition of saturated ammonium chloride (100 mL) followed by i-PrOAc (100 mL) and the resultant mixture was stirred until all solid dissolved. The phases were separated and the organic phase was washed successively with 1% aqueous hydrochloric acid (100 mL) and then water (2×50 mL). The organic phase was then dried over sodium sulfate, filtered, and concentrated under reduced pressure (45 C. bath, 50 mm Hg) to obtain a crude mixture as a pale yellow liquid. The crude mixture was subjected to column chromatography over silica gel using a heptane to 2% EtOAc:heptane gradient. Fractions comprising the pure product were combined and concentrated to afford 10.5 g (80%) of methyl 3-(2, 2-dimethylbutanoylthio)propionate.

Molecular Weight:218.32
XLogP3:2.2
Hydrogen Bond Acceptor Count:4
Rotatable Bond Count:7
Exact Mass:218.09766561
Monoisotopic Mass:218.09766561
Topological Polar Surface Area:68.7
Heavy Atom Count:14
Complexity:211
Covalently-Bonded Unit Count:1
Compound Is Canonicalized:Yes