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Structure of 1918-77-0 * Storage: {[proInfo.prStorage]}
* All experimental methods are cited from the reference, please refer to the original source for details. We do not guarantee the accuracy of the content in the reference.
With strain of the zygomycete fungus S. racemosum MUT 770 In dimethyl sulfoxide for 72 h; Enzymatic reaction
2.3. Biotransformation experimentsFungal strains were pre-grown in Petri dishes containing maltextract solid medium (MEA: 20 g L−1 glucose, 20 g L−1 malt extract,20 g L−1 agar, 2 g L−1 peptone) from which the inoculum for liquidcultures was set up. The fungus was inoculated as conidia suspen-sion (1 106 conidia/mL) in 50 mL asks containing 40 mL of maltextract liquid medium. Flasks were incubated at 25 C and weremaintained under agitation (110 rpm).After 2 days of pre-growth, a 500 mM solution of the substratein DMSO was added, to a starting substrate concentration (c0) of1–5 mM. For each substrate, three biological replicates were run.The experiment was run for 3 days after the addition of the sub-strates, during which time 1 mL samples were taken, at speciedintervals (usually 24, 48, and 72 h). Each sample was extractedwith EtOAc (500 L), the organic phase was dried over anhydrousNa2SO4 and analysed by means of GC/MS. In some cases (see Section2.4) the isolation of the reduced product has been carried out.For each set of biotransformations, one ask was used to mea-sure the initial biomass and pH before the addition of the substrate.These parameters were also evaluated at the end of the experimentfor all the asks. The liquid media was separated from the biomassby ltration and was used for pH measurement while the myceliawere dried at 60 C for 24 h to measure the biomass dry weight. 2-(Thiophen-2-yl)ethanol: from 2-(thiophen-2-yl)acetic acid(3.7 mg, 72percent) and from methyl 2-(thiophen-2-yl)acetate (24.6 mg,96percent). 1H NMR (400 MHz, CDCl3, TMS): = 7.20 (m, 1H, heteroaro-matic hydrogen), 6.99 (m, 1H, heteroaromatic hydrogen), 6.90 (m,1H, heteroaromatic hydrogen), 3.85 (t, 2H, J = 6.2 Hz, CH2OH), 3.02(t, 2H, J = 6.2 Hz, CH2CH2OH). 13C NMR (100 MHz, CDCl3, TMS): = 140.5, 127.0, 125.8, 124.0, 63.4, 33.3. GC/MS: tR = 9.47 min, m/z128 (M+, 30), 110 (5), 97 (100)
66.5%
Stage #1: With lithium aluminium tetrahydride In tetrahydrofuran at 0 - 20℃; Stage #2: With water; sodium chloride In tetrahydrofuran at 0℃;
Step 9 2-(Thiophen-2-yl)ethanol: At about 0° C., a solution of thiophen-2-yl-acetic acid (1.0 g; 7.03 mmol) in tetrahydrofuran (10 mL) was added dropwise to a suspension of lithium aluminum hydride (0.534 g; 14.05 mmol) in dry tetrahydrofuran (10 mL). The mixture was stirred at ambient temperature for about 4 hours, and then cooled to about 0° C. After adding a cold saturated sodium chloride solution (1 mL), the mixture was filtered, and the inorganic salts were washed with tetrahydrofuran and ethyl acetate. The filtrate and washings were combined and concentrated in vacuo to give the title compound as brown oil (0.600 g; 66.5percent). 1H NMR (400 MHz, CDCl3) δ 1.60 (br, exchangeable with D2O, 1H), 3.08 (t, J=6.2 Hz, 2H), 3.85 (t, J=6.2 Hz, 2H), 6.87-6.88 (m, 1H), 6.95-6.97 (m, 1H), 7.16-7.25 (m, 1H). IR (film) υ 3345, 3105, 2211, 2126, 2090, 1792, 1433, 1138, 972, 737, 699 cm-1 MS: 129 (M+1).
Reference：
[1] Journal of Medicinal Chemistry, 1998, vol. 41, # 3, p. 346 - 357
[2] Chemical Communications (Cambridge, United Kingdom), 2012, vol. 48, # 85, p. 10514 - 10516,3
[3] European Journal of Organic Chemistry, 2011, # 17, p. 3178 - 3183
[4] Journal of Molecular Catalysis B: Enzymatic, 2015, vol. 116, p. 83 - 88
[5] Patent: US2010/16365, 2010, A1, . Location in patent: Page/Page column 26
[6] Synthesis, 2011, # 18, p. 2935 - 2940
2
[ 1918-77-0 ]
[ 3277-26-7 ]
[ 5402-55-1 ]
Reference：
[1] European Journal of Organic Chemistry, 2017, vol. 2017, # 32, p. 4820 - 4826
3
[ 1918-77-0 ]
[ 15022-15-8 ]
[ 5402-55-1 ]
Reference：
[1] Chemical Communications (Cambridge, United Kingdom), 2012, vol. 48, # 85, p. 10514 - 10516,3
4
[ 765-50-4 ]
[ 1918-78-1 ]
[ 1918-77-0 ]
Reference：
[1] Journal of the American Chemical Society, 1951, vol. 73, p. 3934,3937
5
[ 19432-64-5 ]
[ 15719-64-9 ]
[ 1918-78-1 ]
[ 1918-77-0 ]
Reference：
[1] Journal of the American Chemical Society, 1951, vol. 73, p. 3934,3937
6
[ 1918-77-0 ]
[ 39098-97-0 ]
Yield
Reaction Conditions
Operation in experiment
94.7%
With bis(trichloromethyl) carbonate; N,N-dimethyl-formamide In dichloromethane at -10 - 0℃; for 5 h;
With mechanical stirring, thermometer,The gas outlet of the four-necked flask was added 71.6g 2 - thiophene acetic acid,DMF 6.3 g, 350 g dichloromethane,After stirring, dissolve and cool to -10 ° C.101.3 g of trichloromethyl carbonate was added dropwise,300 g of a mixed solution of dichloromethane.After the dropwise addition, the temperature was raised to 0 ° C,Incubated for 5 hours.The residual methylene chloride was distilled off under reduced pressure,Continue distillation of the distillate collected 2-thiophene acetyl chloride 76.4g, the yield reached 94.7percent.HPLC area normalized content of 99.5percent.
92%
With phosgene; 4-cyclopentylaminopyridine hydrobromide In toluene
Synthesis of 2-thiopheneacetyl chloride catalyzed by 4 - cyclohexylaminopyridine hydrobromide in toluene catalyzed phosgene method 400 g of 2-thiopheneacetic acid, 800 g of toluene, and 4 g of cyclohexylaminopyridine hydrobromide were added to the reaction flask and heatedAnd the phosgene was stopped when the molar ratio of 2-thiopheneacetic acid to phosgene was 1: 6. 2-thiophenacetic acid chloride is obtained through vacuum distillation, and the content is over 98percent by chemical titration and the yield is 92percent.
84.96%
With phosgene In 5,5-dimethyl-1,3-cyclohexadieneReflux; Green chemistry
Thiophene-2-acetic acid (120 g, 0.84 mol),Xylene (100g) into the reactor, heated to reflux, through phosgene (626.10g, 6.33mol) reaction, the product content of 97.68percent after cooling, to be reduced to room temperature, through the residual nitrogen gas phosgene and hydrogen chloride The solvent was distilled off under reduced pressure, and then distillation under reduced pressure gave 115.18 g of thiophene acetyl chloride, the yield was 84.96percent and the content was 97.95percent.
25.2 g
With pyridine; thionyl chloride In dichloromethane for 1 h; Reflux
The thiophene acetic acid obtained in the second step was dissolved in 10 volumes of dichloromethane, 2 drops of pyridine and 2 equivalents of thionyl chloride were added dropwise under reflux. After completion of the addition, reflux was continued for 1 hour and cooled to room temperature. After distilling off low boilers under reduced pressure, 116-118 ° C / 40 mmHg fraction was collected to obtain 25.2 grams of product. The total yield of three steps is 66percent. The GC purity was 99.7percent.
Reference：
[1] Patent: CN107011319, 2017, A, . Location in patent: Paragraph 0010; 0018-0025
[2] Patent: CN105601502, 2016, A, . Location in patent: Paragraph 0076; 0077; 0078
[3] Patent: CN105585478, 2016, A, . Location in patent: Paragraph 0064; 0065
[4] Bulletin de la Societe Chimique de France, 1949, p. 847,851
[5] Journal of the American Chemical Society, 1948, vol. 70, p. 500
[6] Yakugaku Zasshi, 1954, vol. 74, p. 1040[7] Chem.Abstr., 1955, p. 11 659
[8] Bioorganic and Medicinal Chemistry Letters, 2005, vol. 15, # 13, p. 3241 - 3246
[9] Bulletin des Societes Chimiques Belges, 1988, vol. 97, # 11-12, p. 1081 - 1094
[10] Journal of Medicinal Chemistry, 1993, vol. 36, # 22, p. 3224 - 3229
[11] Journal of Medicinal Chemistry, 1994, vol. 37, # 11, p. 1704 - 1711
[12] Journal of Heterocyclic Chemistry, 1997, vol. 34, # 1, p. 225 - 231
[13] Tetrahedron Letters, 1997, vol. 38, # 29, p. 5081 - 5084
[14] Bioorganic and Medicinal Chemistry Letters, 2000, vol. 10, # 15, p. 1723 - 1727
[15] Bioorganic and Medicinal Chemistry Letters, 2011, vol. 21, # 23, p. 7089 - 7093
[16] Organic and Biomolecular Chemistry, 2012, vol. 10, # 8, p. 1598 - 1601
[17] Organic Letters, 2012, vol. 14, # 8, p. 2154 - 2157
[18] Patent: WO2011/38204, 2011, A1, . Location in patent: Page/Page column 135
[19] Organic and Biomolecular Chemistry, 2013, vol. 11, # 20, p. 3282 - 3287
[20] Organic and Biomolecular Chemistry, 2013, vol. 11, # 39, p. 6734 - 6743
[21] Organic and Biomolecular Chemistry, 2014, vol. 12, # 5, p. 795 - 800
[22] Patent: EP2808014, 2014, A1, . Location in patent: Paragraph 0176
[23] Patent: WO2016/57931, 2016, A1, . Location in patent: Page/Page column 174-175
[24] ACS Medicinal Chemistry Letters, 2017, vol. 8, # 3, p. 287 - 292
[25] Bioorganic and Medicinal Chemistry, 2017, vol. 25, # 11, p. 2825 - 2843
[26] European Journal of Organic Chemistry, 2017, vol. 2017, # 20, p. 2866 - 2870
[27] Journal of the American Chemical Society, 2018, vol. 140, # 7, p. 2460 - 2464
[28] Angewandte Chemie - International Edition, 2018, vol. 57, # 30, p. 9425 - 9429[29] Angew. Chem., 2018, vol. 130, # 30, p. 9569 - 9573,5
[30] Tetrahedron Letters, 2018, vol. 59, # 30, p. 2913 - 2916
[31] Patent: CN108947960, 2018, A, . Location in patent: Paragraph 0042; 0047; 0048; 0054; 0055
7
[ 1918-77-0 ]
[ 39098-97-0 ]
Yield
Reaction Conditions
Operation in experiment
84%
With thionyl chloride; triethylamine In chloroform; water; ethyl acetate
EXAMPLE II-1 A solution (2 ml) of 2-thienylacetyl chloride prepared from 2-thienylacetic acid (78 mg) and thionyl chloride (0.05 ml) in chloroform is added dropwise to a solution of 7-amino-3-(2-ethoxylalylhydrazono)methyl-3-cephem-4-carboxylic acid (171 mg) and triethylamine (0.14 ml) in chloroform (2 ml), and the mixture is stirred for 1 hour. The residue obtained by concentration of the reaction mixture is dissolved in a mixture of water and ether. The aqueous layer is acidified with 10percent hydrochloric acid to pH 1.5, and extracted with ethyl acetate. The extract solution is washed with water and dried, and concentrated. The obtained residue is crystallized from a mixture of ether and ethyl acetate to give 7-(2-thienylacetamido)-3-(2-ethoxyalylhydrazono)methyl-3-cephem-4-carboxylic acid monohydrate (196 mg). m.p. 134-137° C (decomposition). Yield: 84percent.
Reference：
[1] Patent: US4101658, 1978, A,
8
[ 1918-77-0 ]
[ 39098-97-0 ]
Reference：
[1] Patent: US4550105, 1985, A,
[2] Patent: US4822790, 1989, A,
[3] Patent: US4782147, 1988, A,
9
[ 57382-97-5 ]
[ 1918-77-0 ]
Yield
Reaction Conditions
Operation in experiment
100%
With water; sodium hydroxide In ethanol at 20℃; for 1 h;
78.1 Preparation of thiophene-2-acetic acid 1g of ethyl thiophene-2-acetate was dissolved in 4mL of ethanol, added with 8ml of 4N NaOH aqueous solution, and agitated at room temperature for 1 hour. The reaction mixture was adjusted with 1N HCl aqueous solution to a pH of 1, and extracted with dichloromethane. The organic phase was evaporated to dryness to give an oily product, thiophene-2-acetic acid. Yield, about 100percent. ESI-MS m/z: 141.0 [M-H]-.
100%
With water; sodium hydroxide In ethanol at 20℃; for 1 h;
1 g of ethyl thiophene-2-acetate was dissolved in 4 mL of ethanol, added with 8 ml of 4N NaOH aqueous solution, and agitated at room temperature for 1 hour. The reaction mixture was adjusted with 1N HCl aqueous solution to a pH of 1, and extracted with dichloromethane. The organic phase was evaporated to dryness to give an oily product, thiophene-2-acetic acid. Yield, about 100percent. ESI-MS m/z: 141.0 [M-H]-.
Reference：
[1] Patent: EP2848617, 2015, A1, . Location in patent: Paragraph 0243; 0244
[2] Patent: US2015/141419, 2015, A1, . Location in patent: Paragraph 0303; 0304
[3] Journal of Organic Chemistry, 1958, vol. 23, p. 1289,1290
10
[ 20893-30-5 ]
[ 1918-77-0 ]
Yield
Reaction Conditions
Operation in experiment
93.4%
With sodium hydroxide In water for 5 h; Reflux
An aqueous solution of 150 g of 30percent sodium hydroxide was heated to reflux,Then, 113 g of 2-thiophene acetonitrile was slowly added dropwise,And then reflux reaction 5 hours (the reaction process a large number of ammonia gas generated).After the reaction is complete,Cooling to 20-30 ,The impurities were then extracted three times with 200 mL of ethyl acetate.After extraction,Cooling to 10-20 ,Add 30percent hydrochloric acid to adjust the pH value to 1-2,200 g of dichloromethane was added twice.The combined methylene chloride layer was charged with 5 g of activated carbon,Stirring for 20-30 minutes,After filtering,The filtrate was concentrated to a paste,300 mL of n-hexane was added,Cooling to 0-5 ,Crystallization for 3 hours,filter,Dried to give 121.8 g of 2-thiopheneacetic acid,Yield 93.4percent. HPLC area normalized content of 99.4percent.
Reference：
[1] Patent: CN106518839, 2017, A, . Location in patent: Paragraph 0006; 0013; 0014
[2] Journal of Organic Chemistry, 1958, vol. 23, p. 1289,1290
[3] Bulletin de la Societe Chimique de France, 1949, p. 847,851
[4] Journal of the American Chemical Society, 1941, vol. 63, p. 2945
[5] Journal of Organic Chemistry, 1950, vol. 15, p. 81,87
11
[ 5371-94-8 ]
[ 1918-77-0 ]
Yield
Reaction Conditions
Operation in experiment
86%
With sodium chloride; iodine In water; acetic acid; ethyl acetate
EXAMPLE 9 Red phosphorous (180 mg) and iodine (60 mg) were added to acetic acid (2.85 ml), and the mixture was stirred for 30 min. A solution of water (60 mg) and α-methoxy-2-thiopheneacetic acid (860 mg, 5 mmol) in acetic acid (1.5 ml) was added to this mixture and the resulting mixture was heated under reflux for 2 hr. with vigorous stirring. After cooling to room temperature, water and ethyl acetate were added thereto. After filtering off the precipitate by the use of celite, the organic layer was separated. It was washed with saturated aqueous solution of sodium chloride and dried with anhydrous magnesium sulfate. After filtration, the solution was concentrated under a reduced pressure, and the crystals which remained were recrystallized from ethyl acetate:n-hexane to give 2-thiopheneacetic acid (610 mg) melting at 62° C. (Literature value: 62°-65° C.). Yield: 86percent.
Reference：
[1] Patent: US4221915, 1980, A,
12
[ 5402-55-1 ]
[ 1918-77-0 ]
Yield
Reaction Conditions
Operation in experiment
85%
With sodium hypochlorite; 2,2,6,6-Tetramethyl-1-piperidinyloxy free radical In aq. phosphate buffer; water; acetonitrile at 35℃; for 6 h; Green chemistry
In the reactor were added 2-thiophene ethanol 10g, TEMPO 0.4g, acetonitrile, 200mL, pH = phosphate buffer 100mL (0.6mol.L 6.5 of-1), uniformly stirred, the reactor temperature was raised to 35 ;Was then slowly added dropwise to the reactor an aqueous solution of NaClO (16wtpercent) 80g, 2h addition was complete, the reaction was continued for 4h, was added 2mol.L-1sodium sulfite solution, until the reactor is completely neutralized NaClO (starch iodide test paper); Plus 2mol.L-1of NaOH solution was adjusted to a weakly alkaline, extracted with ethyl acetate and the catalyst was completely unreacted starting material and then using 4mol.L-1HCI solution was adjusted to pH 1, and extracted with ethyl acetate to give 2- The crude acid thiophene; The crude product was recrystallized from petroleum ether to give pure 2-thiophene acetic acid, the liquid detection purity of 99percent, the conversion rate of 2-thiophene ethanol of 100percent and the reaction selectivity was 95percent and yield was 85percent.
Reference：
[1] Journal of the American Chemical Society, 2016, vol. 138, # 27, p. 8344 - 8347
[2] Patent: CN104725345, 2017, B, . Location in patent: Paragraph 0035-0069
With potassium hydroxide In diethyl ether; water; dimethyl sulfoxide
EXAMPLE 2 To a 50percent dimethyl sulfoxide aqueous solution (50 ml) were added ethyl mercaptan (3.5 ml, 47 mmoles), an aqueous solution (10 ml) of potassium hydroxide (0.6 g, 10 mmoles), a solution of 2-thienyl aldehyde (1.12 g, 10 mmoles) in dimethyl sulfoxide (10 ml) and then bromoform (3.04 g, 12.2 mmoles) in an argon atmosphere under ice-water cooling with stirring, and the mixture was stirred for 1 hour. Potassium hydroxide (3.04 g, 46 mmoles) dissolved in a 50percent dimethyl sulfoxide aqueous solution (30 ml) was added dropwise to the reaction mixture. After completion of the addition, the mixture was stirred for 2 hours and then at room temperature for 3 hours. Water and diethyl ether were added to the reaction mixture and the ether-soluble material was removed. The aqueous layer was rendered acidic with dilute hydrochloric acid and extracted with chloroform. The extract was washed with water, dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated and purified by silica gel chromatography to afford 0.82 g of thienylacetic acid. Yield 58percent. m.p.: 60°-62° C. (Lit. 62°-64° C.) NMR (CDCl3, TMS): δ3.8 (s, 2H), 6.80-7.23 (m, 3H), 11.2 (bs, 1H).
Reference：
[1] Patent: US4268442, 1981, A,
15
[ 30807-46-6 ]
[ 1918-77-0 ]
Yield
Reaction Conditions
Operation in experiment
1231 g
With acetic acid In dimethyl sulfoxide at 120℃; for 5 h;
The 10M2-chlorothiophene and 10M metal magnesium reagent format preparation, cooled to room temperature,Add 1000ml of anhydrous tetrahydrofuran, mix well,Slowly add 10M (the material optional range of 8-10M) nitroethylene,The reaction was refluxed for 3 hours (depending on the different substituted thiophene anion derivative,The reaction time is 3-12 hours, such as:The reaction time for the substitution of electron groups on the ring is 3-8 hours,The ring has a substitution of electron-withdrawing groups when the reaction time is 8-12 hours), the solvent was removed under reduced pressure stand-by.The above product was dissolved in 3000 ml of DMSO, 10M acetic acid was added dropwise and reacted at 120 ° C for 5 hours,Recrystallization gave 1231 g of product.Or the product was added 1MPd / C or Raney Ni, 10M of hydrogen was introduced in an autoclave, at120 ° C for 12 hours, filtered, extracted, and distilled under reduced pressure to obtain the product 1009g.
Reference：
[1] Patent: CN106554343, 2017, A, . Location in patent: Paragraph 0039; 0040; 0041
16
[ 201230-82-2 ]
[ 636-72-6 ]
[ 554-14-3 ]
[ 1918-77-0 ]
Reference：
[1] Bulletin of the Chemical Society of Japan, 1998, vol. 71, # 3, p. 723 - 734
17
[ 91668-56-3 ]
[ 1918-77-0 ]
Reference：
[1] Journal of Organic Chemistry, 1983, vol. 48, # 20, p. 3566 - 3569
18
[ 89244-23-5 ]
[ 1918-77-0 ]
Reference：
[1] Synthesis, 1983, # 12, p. 1043 - 1045
19
[ 88-15-3 ]
[ 1918-77-0 ]
Reference：
[1] Journal of the American Chemical Society, 1952, vol. 74, p. 1066
[2] Chemische Berichte, 1951, vol. 84, p. 423,425
[3] DRP/DRBP Org.Chem.,
[4] DRP/DRBP Org.Chem.,
[5] Synthesis, 1981, # 2, p. 126 - 127
20
[ 19432-68-9 ]
[ 1918-77-0 ]
Reference：
[1] Synthesis, 1981, # 2, p. 126 - 127
[2] Journal of the American Chemical Society, 1941, vol. 63, p. 2945
[3] Tetrahedron Letters, 1987, vol. 28, # 25, p. 2845 - 2848
Reference：
[1] Bioorganic and Medicinal Chemistry Letters, 2000, vol. 10, # 15, p. 1723 - 1727
[2] Journal of the American Chemical Society, 1941, vol. 63, p. 2945
24
[ 765-50-4 ]
[ 1918-78-1 ]
[ 1918-77-0 ]
Reference：
[1] Journal of the American Chemical Society, 1951, vol. 73, p. 3934,3937
25
[ 98-03-3 ]
[ 1918-77-0 ]
Reference：
[1] Journal of Organic Chemistry, 1983, vol. 48, # 20, p. 3566 - 3569
26
[ 72676-21-2 ]
[ 1918-77-0 ]
Reference：
[1] Bioorganic and Medicinal Chemistry Letters, 2000, vol. 10, # 15, p. 1723 - 1727
27
[ 527-72-0 ]
[ 1918-77-0 ]
Reference：
[1] Bioorganic and Medicinal Chemistry Letters, 2000, vol. 10, # 15, p. 1723 - 1727
Reference：
[1] Journal of the American Chemical Society, 1951, vol. 73, p. 3934,3937
38
[ 1918-77-0 ]
[ 957-68-6 ]
[ 153-61-7 ]
Yield
Reaction Conditions
Operation in experiment
85%
With 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine In dichloromethane at 30℃; for 2 h; Green chemistry
In a 2000 ml three-necked flask, 71 g of 2-thiopheneacetic acid was added.Organic solvent dichloromethane 550ml,Then add 90 ml of triethylamine and EDC (1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride) 190 g.Then control the temperature to slowly add 7-ACA 110g under the condition of 30°C,And control the condensation reaction at a temperature of 30°C for 2 hours.After the condensation reaction was completed, a 10percent wt hydrochloric acid solution was added dropwise to the reaction solution to adjust the ph value to 1.5-2.0. Then,Standing, delaminating, collecting organic phases, The collected organic phase was quickly added to 1000 ml of aqueous sodium bicarbonate and the pH was adjusted to 6.5-7.0.Standing, stratified, Collect the water phase,Then control the temperature at 20-25 degrees Celsius slowly adding 10wtpercent hydrochloric acid to adjust the system ph value to 1.5,Then stir and crystallize for 1 hour, cool down to 10°C, and filter to obtain wet product.Drying at 40°C gives a white solid productCephalothin 170g, yield 85percent.
Reference：
[1] Patent: CN107793431, 2018, A, . Location in patent: Paragraph 0012; 0013; 0014; 0015; 0016; 0017; 0018; 0019
39
[ 1918-77-0 ]
[ 54769-22-1 ]
[ 153-61-7 ]
Yield
Reaction Conditions
Operation in experiment
70%
With sodium acetate; acetic acid; triethylamine In dichloromethane
EXAMPLE 13 2-Thienylacetic acid (4.2 g) and triethylamine (4.2 ml) are dissolved in dichloromethane (40 ml) and thereto is added at one time 1-methanesulfonyloxy-1,2,3-benzotriazole (6.2 g) with stirring at room temperature. The mixture is stirred at room temperature for 1 hour. The solution thus obtained is added at one time to a solution of 7-aminocephalosporanic acid (5.6 g) and triethylamine (8.4 ml) in dichloromethane (30 ml) at room temperature. The mixture is stirred for 2 hours and allowed to stand for 20 hours. After reaction, to the reaction mixture is added triethylamine (about 3 ml) and the mixture is extracted with water (50 ml, once; 25 ml, twice). The extract is regulated to pH 4.2 with acetic acid and passed through a column (inside diameter: 2.5 cm) containing Zeolite A-6 resin (75 ml). A 5percent aqueous solution of sodium acetate and acetic acid (pH: 4.5, 400 ml) is passed through the column. The elude thus obtained is extracted with ethyl acetate (100 ml) with making gradually acidic with 6 N hydrochloric acid. The extract is dried over anhydrous magnesium sulfate and then the solvent is distilled off under a reduced pressure. The resulting oily residue is crystallized from ether (about 50 ml). The crystals thus obtained is separated by filtration and dried to give 7-[2-(2-thienyl)acetamido]cephalosporanic acid (5.5 g, 70percent), melting point: 135°-140° C. (decomp). The product is identified with an authentic sample by infrared spectrum.
An aqueous solution of 150 g of 30% sodium hydroxide was heated to reflux,Then, 113 g of 2-thiophene acetonitrile was slowly added dropwise,And then reflux reaction 5 hours (the reaction process a large number of ammonia gas generated).After the reaction is complete,Cooling to 20-30 ,The impurities were then extracted three times with 200 mL of ethyl acetate.After extraction,Cooling to 10-20 ,Add 30% hydrochloric acid to adjust the pH value to 1-2,200 g of dichloromethane was added twice.The combined methylene chloride layer was charged with 5 g of activated carbon,Stirring for 20-30 minutes,After filtering,The filtrate was concentrated to a paste,300 mL of n-hexane was added,Cooling to 0-5 ,Crystallization for 3 hours,filter,Dried to give 121.8 g of 2-thiopheneacetic acid,Yield 93.4%. HPLC area normalized content of 99.4%.
Step 1: Preparation of methyl 2-(2-thienyl)acetate To a solution of 2-thiopheneacetic acid (1.50 g, 10.6 mmol) in MeOH (20 mL) was added thionyl chloride (3.80 mL, 53 mmol) dropwise at 0 C. The resulting solution was stirred at room temperature for 18 h. The reaction mixture was concentrated in vacuo to give the title compound as a dark brown oil (1.65 g, quantitative yield) which was used in the next step without further purification. 1H NMR (400 MHz, CDCl3): delta 7.22 (dd, J=1.6, 5.1 Hz, 1H), 6.98-6.93 (m, 2H), 3.85 (s, 2H), 3.73 (s, 3H).
100%
With thionyl chloride; at 0 - 20℃; for 18h;
To a solution of 2-thiopheneacetic acid (1.50 g, 10.6 mmol) in MeOH (20 mL) was added thionyl chloride (3.80 mL, 53 mmol) dropwise at 0 C. The resulting solution was stirred at room temperature for 18 h. The reaction mixture was concentrated in vacuo to give the title compound as a dark brown oil (1.65 g, quantitative yield) which was used in the next step without further purification.?H NMR (400 MHz, CDC13): oe 7.22 (dd, J = 1.6, 5.1 Hz, 1 H), 6.98-6.93 (m, 2 H), 3.85 (s, 2 H), 3.73 (s, 3 H).
98%
Example 17 and 18Isomers of N-(4-(5-Fluoro-2-methoxyphenyl)pyridin-2-yl)-2-(thiophen-2-yl)propanamideStep A: Preparation of Methyl 2-(thiophen-2-yl)acetate. Thionyl chloride (10.20 ml, 140.7 mmol) was added to a solution of thiophen-2-yl-acetic acid (10.0 g, 70.3 mmol) in MeOH (100 ml) at 0 C. The reaction mixture was heated to reflux for 18 h, the volatiles were evaporated and the crude reaction mixture was basified with aqueous sodium bicarbonate solution, extracted with DCM, washed with brine and dried over anhydrous sodium sulfate. After filtration the organic solvent was evaporated and dried to afford 10.75 g (98%) of methyl 2-(thiophen-2-yl)acetate as color less liquid.
85%
With acetyl chloride; at 0 - 20℃;
Acetyl chloride (2.43 ml, 34.1 mmol) was added to a solution of the 2-thiopheneacetic acid (1.94 g, 13.7 mmol) in MeOH (100 ml) at 0C. The reaction was then stirred at r.t. over night and the solvent was removed in vacuo. The crude material was dissolved in Et20 (-50 ml) and washed with diluted K2CO3. The organic phase was dried over MgS04 and removed in vacuo. Yield: 1.81g (85%). LC-MS: m/z = 174 (M + 1). Br2 (0.333 ml, 6.47 mmol) in DCM (3 ml) was added to a solution of the ester from above (1.01 g, 6.47 mmol) in DCM (20 ml) at 0C. The reaction was stirred at this temp for 30 min. DCM (-10 ml) was added and the mixture was washed with saturated Na2S203 and diluted Na2C03. The organic phase was dried over MgS04 and removed in vacuo. The crude product was dissolved in DCM and run though a plug of silica with 5% EtOAc in iso-hexane as eluent. Yield: 1.21 g (80%) as a pale yellow oil. ¾ NMR (400 MHz, CDC13): delta 3.74 (s, 3H), 3.78 (s, 2H), 6.70 (d, J 3.8 Hz, 1H), 6.91 (d, J 3.8 Hz, 1H). Argon was bubbled through a stirred mixture of bromide from above (274 mg, 1.16 mmol), 2,5- thiopenediboronic acid (80 mg, 0.466 mmol), KF (162 mg, 2.79 mmol), MeOH (3 ml) and toluene (3 ml) for 10 min. PEPPSI-iPr(13.6 mg, 0.019 mmol) was added and the reaction was heated at 55C for 3 hours. The mixture was concentrated and added water and DCM (~4 ml). The DCM mixture was purified by flash chromatography (2.5% EtOAc in toluene, 12g Redisep silica). The solid was dissolved in dioxane (2 ml) and water (1 ml) and 1 M NaOH (0,600 ml) were added. The reaction was heated at 75C for 30 min. The solvents were removed in vacuo and the crude was dissolved in water with some NH4HCO3. The mixture was filtered and purified by prep-HPLC (5-40% MeCN, in 50 mM NH3/NH4HCO3 buffer). The combined pure fractions were concentrated to dryness. Water and HCl were added and the mixture extracted with EtOAc. The organic phase was dried over MgS04 and removed in vacuo. Yield: 30 mg (52%) as a pale yellow solid. 1H NMR (400 MHz, DMSO-i/6): delta 3.84 (s, 4H), 6.91 (d, J3.5 Hz, 2H), 7.16 (d, J3.5 Hz, 2H), 7.20 (s, 2H), 12.63 (br. s., 2H). HPLC: Rt = 1.48 min, 100% (254 nm, 10-40% MeCN in 10 mM buffer, XBndge) and Rt = 1.45 min, 100% (400 nm, 10-40% MeCN in 10 mM buffer, XBndge). LC-MS: m/z = 365 (M + 1).
85%
With acetyl chloride; at 0 - 20℃;
Acetyl chloride (2.43 ml, 34.1 mmol) was added to a solution of the 2-thiopheneacetic acid (1.94 g, 13.7 mmol) in MeOH (100 ml) at 0C. The reaction was then stirred at r.t. over night and the solvent was removed in vacuo. The crude material was dissolved in Et20 (-50 ml) and washed with diluted K2CO3. The organic phase was dried over MgS04 and removed in vacuo. Yield: 1.81g (85%). LC-MS: m/z = 174 (M + 1).
With thionyl chloride; at 0℃; for 4h;Reflux;
Thionyl chloride (5 mL, 68 mmol) was added dropwise to methanol (30 mL) at 0 C. then 2-(thiophen-2-yl)acetic acid (3 g, 19 mmol) was added to this solution, and refluxed vigorously for 4 h. After the solvent was removed under reduced pressure, the resulting methyl thiopheneacetate (8) was obtained without further purification.
With bis(trichloromethyl) carbonate; N,N-dimethyl-formamide; In dichloromethane; at -10 - 0℃; for 5h;
With mechanical stirring, thermometer,The gas outlet of the four-necked flask was added 71.6g 2 - thiophene acetic acid,DMF 6.3 g, 350 g dichloromethane,After stirring, dissolve and cool to -10 C.101.3 g of trichloromethyl carbonate was added dropwise,300 g of a mixed solution of dichloromethane.After the dropwise addition, the temperature was raised to 0 C,Incubated for 5 hours.The residual methylene chloride was distilled off under reduced pressure,Continue distillation of the distillate collected 2-thiophene acetyl chloride 76.4g, the yield reached 94.7%.HPLC area normalized content of 99.5%.
92%
With phosgene; 4-cyclopentylaminopyridine hydrobromide; In toluene;
Synthesis of 2-thiopheneacetyl chloride catalyzed by 4 - cyclohexylaminopyridine hydrobromide in toluene catalyzed phosgene method400 g of 2-thiopheneacetic acid, 800 g of toluene, and 4 g of cyclohexylaminopyridine hydrobromide were added to the reaction flask and heatedAnd the phosgene was stopped when the molar ratio of 2-thiopheneacetic acid to phosgene was 1: 6. 2-thiophenacetic acid chloride is obtained through vacuum distillation, and the content is over 98% by chemical titration and the yield is 92%.
84.96%
With phosgene; In 5,5-dimethyl-1,3-cyclohexadiene;Reflux; Green chemistry;
<strong>[1918-77-0]Thiophene-2-acetic acid</strong> (120 g, 0.84 mol),Xylene (100g) into the reactor, heated to reflux, through phosgene (626.10g, 6.33mol) reaction, the product content of 97.68% after cooling, to be reduced to room temperature, through the residual nitrogen gas phosgene and hydrogen chloride The solvent was distilled off under reduced pressure, and then distillation under reduced pressure gave 115.18 g of thiophene acetyl chloride, the yield was 84.96% and the content was 97.95%.
With thionyl chloride; In tetrahydrofuran; for 1.5h;Reflux;
2-Thiophene acetic acid (1.2 g, 8.4 mmol) and thionyl chloride (612 muL, 8.43 mmol) were refluxed in anhydrous THF (1 mL) for 1.5 hours, and the resulting reaction solution was added to a mixture of 9d (630 mg, 2.11 mmol) and DIPEA (930 muL, 5.4 mmol) in THF (1 mL). After stirring for 30 minutes, the reaction mixture was taken up in EtOAc, washed with 1M aqueous HCl, washed with 5% aqueous Na2CO3, then washed with brine and evaporated. The residue was chromatographed on silica gel (hexane/EtOAc 9:1) and then crystallised from MeOH to give the pure product (324 mg, 36%). M.p. 116.8-118.8 C. 1H NMR (300 MHz, CDCl3) delta 7.31 (m, 1H, Ar-H), 7.05 (m, 2H, Ar-H), 4.56 (s, 2H, 7-CH2), 4.28 (q, J = 7.1 Hz, 2H, CH2CH3), 4.17 (q, J = 7.1 Hz, 2H, CH2CH3), 4.04 (s, 2H, CH2Ar), 3.69 (m, 2H, 5-CH2), 2.87 (m, 2H, 4-CH2), 1.33 (t, J = 7.2 Hz, 3H, CH2CH3), 1.29 (t, J = 6.9 Hz, 3H, CH2CH3). ESI-MS m/z 423 [M + H]+. 13C NMR (CDCl3) delta 167.1, 165.5, 155.4, 147.7, 134.2, 129.8, 127.8, 127.4, 125.9, 123.2, 111.5, 61.6, 60.6, 42.5, 41.0, 37.5, 14.7, 14.3. HRMS calcd C19H22N2O5S2 [M + H]+ 423.1043; Found 423.1024.
With thionyl chloride; In dichloromethane; at 50℃;
00336] Intermediate 1 : Synthesis of l-phenyl-2-(thiophen-2-yl)ethanone[00337] Step 1: Synthesis of 2-(thiophen-2-yl)acetyl chloride: To a solution of 2- (thiophen-2-yl)acetic acid (2 g, 14 mmol) in DCM (50 mL) was added dropwise SOCl2 (0.5 mL), the mixture was heated at 50C overnight. The reaction mixture was concentrated under reduced pressure to give compound 2- (thiophen-2-yl) acetyl chloride, which was used directly in the next step without further purification
With thionyl chloride; In dichloromethane;Inert atmosphere; Reflux;
Thionyl chloride (0.29 mL, 4.00 mmol) was added to a methylene chloride (5 mL) solution of 2-thiopheneacetic acid (284 mg, 2.00 mmol) in an argon atmosphere, and the mixture was refluxed with heating overnight. After evaporating the solvent, methylene chloride (5 mL) was added to the mixture. After the sequential addition of thioammonium cyanide (228 mg, 3.00 mmol) and polyethylene glycol (PEG-400, six drops), the mixture was stirred at room temperature overnight. After evaporating the solvent, the residue was purified by silica gel column chromatography (15 g, hexane:acetone=100:1) to obtain thiophen-2-ylacetyl chloride (colorless crystals) (133 mg, 36%).
With oxalyl dichloride; In dichloromethane; N,N-dimethyl-formamide; at 23℃; for 2h;Inert atmosphere;
To a solution of 2- (thiophen-2-yl) acetic acid 15 (49.5 mg, 0.348 mmol, 2.0 equiv), DMF (1 drop) and DCM (3.50 mL, 0.100 M) at 0 C under 2 atmosphere was added dropwise oxalyl chloride (44.2 mg, 0.348 mmol, 2.0 equiv) via a syringe. The resulting mixture was stirred at 23 C for 2 h, concentrated to afford crude acide chloride, which was used in the subsequent step without further 20 purification. The above crude acid chloride was dissolved in CH3CN (1.5 mL, 0.0232 M) and added to a solution of 5-bromo-6-methoxy-2- (trifluoromethoxy) pyridin-3-amine (9af) (50 mg, 0.174 mmol, 1.0 equiv) in CH3CN (3.5 mL, 0.0497 M) at 23 C under N2 atmosphere. The reaction mixture was stirred at 23 C for another 2 h, concentrated in vacuo and purified by chromatography on silica gel, eluting with 5 hexanes :EtOAc (5:1 (v/v) ) , to afford the title compound as a yellow solid (69.0 mg, 0.167 mmol, 96% yield). Re = 0.20 (EtOAc : hexanes 1:4 (v/v)). MR Spectroscopy: *H MR (500 MHz, CDC13, 25 C, delta) : 8.87 (s, 1H), 7.40 (br. s., 1H) , 7.34 (dd, J = 5.04, 1.07 Hz, 1H) , 7.09-7.03 (m, 2H) , 3.97 (s, 2H) , 3.92 (s, 3H) . 13C NMR (125 MHz, CDCI3, 25 C, 10 delta) : 168.1, 154.2, 142.2, 136.5, 134.8, 128.3, 127.9, 126.6, 119.9 (q, J = 261.8 Hz), 116.8, 102.6, 55.2, 38.4. 19F NMR (376 MHz, CDC13, 25 C, delta) : -57.1(s). Mass Spectrometry: HRMS (ESI-TOF) (m/z) : calcd for Ci3HiiBrF3N203S ( [M + H]+), 412.9600, found, 412.9605.
With oxalyl dichloride; In dichloromethane; N,N-dimethyl-formamide; for 5h;
Acyl chloride preparation: To a stirred solution of 2-thiopheneacetic acid (260 mg, 1.83 mmol) and oxalyl chloride (201 muL, 2.38 mmol) in CH2Cl2 (6 mL), catalytic amounts of DMF were added. After stirring for 5 h until TLC indicated complete turnover, the solvent was removed under reduced pressure and the acyl chloride was used without further purification. Amide formation: To a stirred solution of the freshly prepared acyl chloride in CH2Cl2 (6 mL), 23 (350 mg, 1.40 mmol) and saturated aqueous NaHCO3 (excess) were added. After vigorous stirring for 18 h, the organic solvent was removed under reduced pressure. The residue was diluted with EtOAc (20 mL), washed successively with saturated aqueous NaHCO3 solution (20 mL), aqueous HCl solution (1.0 M, 20 mL), H2O (20 mL) and brine (20 mL) and dried (MgSO4). The solution was filtered and solvent removed under reduced pressure. The crude product was purified by flash column chromatography on silica, eluting with a gradient from 10% to 40% EtOAc in petroleum ether 40-60 to yield the title compound as a colourless oil (165 mg, 441 mumol, 24%). Rf = 0.44 (50% EtOAc in petroleum ether 40-60). IR: lambdamax = 2982 (w, C-H), 1742 (s, C=O), 1649 (s, C=C), 1601 (m, C=C). 1H NMR (500 MHz, d6-DMSO, 120 C): deltaH = 7.41 (1H, dd, J = 5.0, 2.9 Hz, ArH), 7.26-7.22 (2H, m, ArH), 7.02 (1H, dd, J = 5.0, 0.8 Hz, ArH), 6.88-6.85 (1H, m, ArH), 6.84-6.80 (2H, m, ArH), 6.04 (1H, ddt, J = 17.4, 10.5, 5.5 Hz, H2), 5.38 (1H, dq, J = 17.2, 1.8 Hz, H1t), 5.26 (1H, dq, J = 10.7, 1.3 Hz, H1c), 4.60 (2H, br s, H10/H11), 4.55 (2H, dt, J = 5.2, 1.6 Hz, H3), 4.11 (2H, q, J = 7.1 Hz, H13), 4.07 (2H, br s, H10/H11), 3.76 (2H, br s, H16), 1.20 (3H, t, J = 7.1 Hz, H14). 13C NMR (126 MHz, d6-DMSO, 120 C): deltaC = 171.1 (sp2-C), 135.5 (sp2-C), 134.2 (C2), 129.0, 125.7, 122.6 (sp2-C), 117.4 (C1), 69.0 (C3), 60.5 (C13), 40.7, 34.8 (sp3-C), 14.2 (C14).
25.2 g
With pyridine; thionyl chloride; In dichloromethane; for 1h;Reflux;
The thiophene acetic acid obtained in the second step was dissolved in 10 volumes of dichloromethane, 2 drops of pyridine and 2 equivalents of thionyl chloride were added dropwise under reflux. After completion of the addition, reflux was continued for 1 hour and cooled to room temperature. After distilling off low boilers under reduced pressure, 116-118 C / 40 mmHg fraction was collected to obtain 25.2 grams of product. The total yield of three steps is 66%. The GC purity was 99.7%.
With hydrogenchloride; In water; acetonitrile; for 8h;Reflux;
The crude product obtained in the first step was suspended in 3 volumes of acetonitrile. 5 volumes of 6N aqueous hydrochloric acid solution was added and refluxed for 8 hours. The resulting mixture was cooled to about 5 C. The product was directly precipitated, filtered, washed, dried, and pure 2-thiopheneacetic acid was obtained, HPLC 99.1%.
With water; sodium hydroxide; In ethanol; at 20℃; for 1h;
78.1 Preparation of thiophene-2-acetic acid 1g of ethyl thiophene-2-acetate was dissolved in 4mL of ethanol, added with 8ml of 4N NaOH aqueous solution, and agitated at room temperature for 1 hour. The reaction mixture was adjusted with 1N HCl aqueous solution to a pH of 1, and extracted with dichloromethane. The organic phase was evaporated to dryness to give an oily product, thiophene-2-acetic acid. Yield, about 100%. ESI-MS m/z: 141.0 [M-H]-.
Ca. 100%
With water; sodium hydroxide; In ethanol; at 20℃; for 1h;
1 g of ethyl thiophene-2-acetate was dissolved in 4 mL of ethanol, added with 8 ml of 4N NaOH aqueous solution, and agitated at room temperature for 1 hour. The reaction mixture was adjusted with 1N HCl aqueous solution to a pH of 1, and extracted with dichloromethane. The organic phase was evaporated to dryness to give an oily product, thiophene-2-acetic acid. Yield, about 100%. ESI-MS m/z: 141.0 [M-H]-.
With hydrogenchloride; In ethanol; water; for 8h;Reflux;
The crude product obtained in first step was suspended in 3 volumes of ethanol. 5 volumes of 6N aqueous hydrochloric acid solution was added, refluxed for 8 hours, and cooled to about 5 C. The product was directly precipitated, filtered, washed and dried to obtain pure 2-thiopheneacetic acid. HPLC 99.2%.
To a 50 mL round-bottom flask, thiophen-2-yl-acetic acid (710.9 mg, 5.0 mmol) and oxalyl dichloride (7.0 mL) was added, then 1 drop of DMF was added as catalyst. The mixture was stirred at room temperature for 1 h. After that, the solvent was removed on a rotary evaporator and to the obtained yellow liquid. THF (30 mL) was added after which aniline (930.6 mg, 10 mmol)was added under stirring. The reaction mixture was then stirred at room temperature for 2 h. After that, HCl (1 N, 20 mL) was added carefully and the solution was extracted with ethyl acetate (3x50 mL). The combined extracts was washed with saturated NaHCO3 (2x10 mL) and dried over Na2SO4. After removal of solvent, the resulted crude was purified by column chromatography on silica gel (eluent: petroleum ether/ethyl acetate = 10:1) to give 1r (885.0 mg, 81%) as a yellow solid. m.p. 114-116 C. IR (KBr): 3291, 1659, 1604, 1441, 759, 693 cm-1. 1H NMR (500 MHz,CDCl3): delta 7.75 (s, 1H), 7.45 (d, J = 8.0 Hz, 2H), 7.30-7.26 (m, 3H), 7.10 (t, J = 7.5 Hz, 1H),7.03-7.01 (m, 2H), 3.91 (s, 2H). 13C NMR (125 MHz, CDCl3): delta 168.23, 137.55, 135.77, 128.98,127.64, 127.51, 125.91, 124.66, 120.14, 38.45. MS (EI): m/z (%) 217 (42) [M+], 97 (100).
With pyridinium hydrobromide perbromide In acetic acid for 0.25h;
With acetic acid at 10 - 20℃; for 0.0583333h;
25.B.1
Step 1: Synthesis of 2-(5-bromothiophen-2-yl)acetic acid. To a solution of 2- (thiophen-2-yl) acetic acid (2 g, 14 m mol) in HOAc (10 ml) was added dropwise bromine (2.25 g, 14 mmol) at 10~20°C for 30 min. The mixture was allowed to warm to room temperature for 3 hours. Then it was diluted with water (100 ml), neutralized to pH = 5 with anhydrous sodium carbonate and extracted with EtOAc (100 mlx3). Dried over Na2S04, filtered and concentrated to afford crude product as brown oil. MS (ESI): m/z 220.9 [M+l]+.
With strain of the zygomycete fungus S. racemosum MUT 770; In dimethyl sulfoxide; for 72h;Enzymatic reaction;
2.3. Biotransformation experimentsFungal strains were pre-grown in Petri dishes containing maltextract solid medium (MEA: 20 g L-1 glucose, 20 g L-1 malt extract,20 g L-1 agar, 2 g L-1 peptone) from which the inoculum for liquidcultures was set up. The fungus was inoculated as conidia suspen-sion (1 106 conidia/mL) in 50 mL asks containing 40 mL of maltextract liquid medium. Flasks were incubated at 25 C and weremaintained under agitation (110 rpm).After 2 days of pre-growth, a 500 mM solution of the substratein DMSO was added, to a starting substrate concentration (c0) of1-5 mM. For each substrate, three biological replicates were run.The experiment was run for 3 days after the addition of the sub-strates, during which time 1 mL samples were taken, at speciedintervals (usually 24, 48, and 72 h). Each sample was extractedwith EtOAc (500 L), the organic phase was dried over anhydrousNa2SO4 and analysed by means of GC/MS. In some cases (see Section2.4) the isolation of the reduced product has been carried out.For each set of biotransformations, one ask was used to mea-sure the initial biomass and pH before the addition of the substrate.These parameters were also evaluated at the end of the experimentfor all the asks. The liquid media was separated from the biomassby ltration and was used for pH measurement while the myceliawere dried at 60 C for 24 h to measure the biomass dry weight. 2-(Thiophen-2-yl)ethanol: from 2-(thiophen-2-yl)acetic acid(3.7 mg, 72%) and from methyl 2-(thiophen-2-yl)acetate (24.6 mg,96%). 1H NMR (400 MHz, CDCl3, TMS): = 7.20 (m, 1H, heteroaro-matic hydrogen), 6.99 (m, 1H, heteroaromatic hydrogen), 6.90 (m,1H, heteroaromatic hydrogen), 3.85 (t, 2H, J = 6.2 Hz, CH2OH), 3.02(t, 2H, J = 6.2 Hz, CH2CH2OH). 13C NMR (100 MHz, CDCl3, TMS): = 140.5, 127.0, 125.8, 124.0, 63.4, 33.3. GC/MS: tR = 9.47 min, m/z128 (M+, 30), 110 (5), 97 (100)
66.5%
Step 9 2-(Thiophen-2-yl)ethanol: At about 0 C., a solution of thiophen-2-yl-acetic acid (1.0 g; 7.03 mmol) in tetrahydrofuran (10 mL) was added dropwise to a suspension of lithium aluminum hydride (0.534 g; 14.05 mmol) in dry tetrahydrofuran (10 mL). The mixture was stirred at ambient temperature for about 4 hours, and then cooled to about 0 C. After adding a cold saturated sodium chloride solution (1 mL), the mixture was filtered, and the inorganic salts were washed with tetrahydrofuran and ethyl acetate. The filtrate and washings were combined and concentrated in vacuo to give the title compound as brown oil (0.600 g; 66.5%). 1H NMR (400 MHz, CDCl3) delta 1.60 (br, exchangeable with D2O, 1H), 3.08 (t, J=6.2 Hz, 2H), 3.85 (t, J=6.2 Hz, 2H), 6.87-6.88 (m, 1H), 6.95-6.97 (m, 1H), 7.16-7.25 (m, 1H). IR (film) upsilon 3345, 3105, 2211, 2126, 2090, 1792, 1433, 1138, 972, 737, 699 cm-1 MS: 129 (M+1).
With lithium aluminium tetrahydride; In tetrahydrofuran; at 20℃; for 0.333333h;
LiAlH4 (1.2 g, 31.6 mmol, 1.58 eq) was added in portions to the compound at room temperatureMC-105-1 (2.84 g, 20 mmol, 1.0 eq) in THF (20 mL).The reaction was stirred at room temperature for 20 minutes. Saturated ammonium chloride (2 mL)The solution was quenched and stirred for 10 minutes. The resulting mixture is filtered,The filtrate is concentrated to give a brown oily crude compoundMC-105-2 (2.5 g, 97% yield).
To a solution of 2-thiopheneacetic acid (500 mg, 3.52 mmol, 1.00 equiv.) in dry CH,C1, (10.0 mL) was added thionyl chloride (2.94 ml, 40.4 minol, 11.5 equiv.) at C C, then the reaction was refluxed for 2h. The solvent was removed under reduced pressure and the residue was azeotroped with toluene (2 x 5.00 mL). NH,-H,O (10.0 mL) was added to the crude acyl chloride residue in THF (10.0 mL) at 0 C. After the reaction mixture was stirred at room temperature for overnight, the organic solvent was removed under reduced pressure, and the aqueousmixture was extracted with CH2C1, (20.0 mL x 3), the organic extracts were dried with MgSO4 and concentrated to afford the title compound as a white solid (0.356 g, 2.52 mmol, 72% yield).NMR Spectroscopy: ?H NMR (700 MHz, (CD,),SO, 25 C, ) : 7.49 (s, 1H),7.33-7.27 (m, 1H), 6.96 (s, 1H), 6.93 (t, J = 2.2 Hz, 1H), 6.88 (s,1H), 3.58 (s, 2H) . 13C NMR (175 MHz, (CD,),SO, 25 C, 4): 171.1, 137.7,126.5, 126.0, 124.7, 36.3. The H NMR data were in good agreement with values reported in the literature (Gupta, M. et al. 2014)
In dichloromethane;
a. 2-Thienylacetamide <strong>[1918-77-0]2-Thienylacetic acid</strong> is dissolved in methylene chloride and treated with a 25% excess of thionyl chloride. The mixture is allowed to stand at room temperature for 2 days and evaporated yielding a dark brown mobile liquid. This is dissolved in methylene chloride and gaseous ammonia bubbled into the mixture for 4 hours. The mixture is allowed to stand at room temperature overnight and partitioned between ethyl acetate and water. The ethyl acetate layer is dried over sodium sulfate and evaporated yielding a pale brown solid which is crystallized from water to yield the desired product, m.p. 146-149 C. (lit. 147 C., Crowe et al., J. Org. Chem., 15, 81-8 [1950]).
With ammonia; at 125℃; for 0.5h;
General procedure: Into a 1L open reactor was added 500g of carboxylic acid feedstock (chemically pure), stirring was turned on (600 r/min), ammonia gas was continuously fed to the carboxylic acid feed from the bottom of the reactor (chemical purity, water content was 5.1wt%, Flow rate is 100g/min). After the reaction was allowed to proceed for TC hours at the reaction temperature TA, the ammonia gas flow was stopped. The contents of the reactor were sampled and nuclear magnetic proton spectra and elemental analysis were performed to characterize the amide intermediate. Specific reaction conditions and characterization results are shown in Table A-1, Table A-2, Table A-3, Table A-4, Table A-5 and Table A-6. These characterization results show that the obtained amide intermediate has an extremely high purity (above 99%).In this embodiment, the ammonia gas can be directly replaced with waste ammonia gas (from Yangzi Petrochemical Plant, containing approximately50wt% of ammonia gas, the rest were toluene, oxygen, nitrogen, steam, carbon monoxide, and carbon dioxide, and the flow rate of this waste ammonia was 130g/min).
Step 1: Dissolve Thiophene-2-yl-acetic acid (28) (2.44g, 17.1mmol) in ethanol (35mL) and add fuming aqu. hydrochloric acid (few drops). Stir the reaction mixture for 19h at 70 C. Cool mixture to rt, remove solvent under reduced pressure and resolve the residue in EtOAc. Wash this organic layer 3 times with 5% aqu. Na2CO3 and extract the combined aqueous layer 3 times with EtOAc. Wash the combined organic layers with brine and dry with Na2SO4. Remove solvent under reduced pressure and dry the residue without further purification in oil pump vacuum to obtain product (29) as a light brown oil (2.78g, 95%). [J. Kunes; V. Balsanek; M. Pour; V. Buchta; Collect. Czech. Chem. Commun.,2001,66; 12; 1809-1830]. 1H NMR (400MHz, CDCl3): 1.26 (t, 3 H, J = 7.1 Hz); 3.81 (s, 2 H); 4.17 (q, 2 H,J = 7.1 Hz); 6.91-6.96 (m, 2 H); 7.20 (d, 1H, J = 4.8 Hz).
95%
With hydrogenchloride; In water; at 20 - 70℃; for 19h;
Dissolve Thiophene-2-yl-acetic acid (25) (2.44g, 17.1mmol) in ethanol (35mL) and add fuming aqu. hydrochloric acid (few drops). Stir the reaction mixture for 19h at 70 C. Cool mixture to rt, remove solvent under reduced pressure and resolve the residue in EtOAc. Wash this organic layer 3 times with 5% aqu. Na2CO3 and extract the combined aqueous layer 3 times with EtOAc. Wash the combined organic layers with brine and dry with Na2SO4. Remove solvent under reduced pressure and dry the residue without further purification in oil pump vacuum to obtain product (26) as a light brown oil (2.78g, 95%). [J. Kunes; V. Balsanek; M. Pour; V. Buchta; Collect. Czech. Chem. Commun., 2001, 66; 12; 1809-1830]. 1H NMR (400MHz, CDCl3):1.26 (t, 3 H, J = 7.1 Hz); 3.81 (s, 2 H); 4.17 (q, 2 H, J = 7.1 Hz); 6.91-6.96 (m, 2 H); 7.20 (d, 1H, J = 4.8 Hz).
71%
With sulfuric acid;Reflux;
Thiophen-2-acetic acid (a; 10 g) was dissolved in anexcess amount of ethanol in a round-bottom flask. Six mlof H2SO4was added to the flask and the reaction mixturewas refluxed for 3-4 h. Excess amount of distilled water was added to the reaction mixture. A reddish brown oilyproduct was generated at basic pH (8-9 maintained byNa2CO3)and was extracted with CHCl3to get compound1. The physical and spectroscopic data of 1 are as follows:Reddish brown oil; yield: 71%; IR (KBr) vmax: 3022,2928, 1755, 1597 cm-1; 1H-NMR (500 MHz, CDCl3):delta1.15 (t, J = 6.5 Hz, 3H, CH3-CH2-O), 3.45 (s, 2H, H-6),4.43 (q, J = 6.5 Hz, 2H, CH3-CH2-O), 6.53 (d, J = 3.0 Hz,1H, H-3), 6.83 (dd, J = 3.5, 3.0 Hz, 1H, H-4), 7.10 (d,J = 3.5 Hz, 1H, H-5); 13C-NMR (125 MHz, CDCl3):delta 20.1(CH3), 35.3 (C-6), 63.3 (CH2), 127.3 (C-4), 128.0 (C-3),131.8 (C-5), 141.4 (C-2), 166.9 (C-7); HR-EI-MS (m/z):170.0410 [M]+ calculated for C8H10SO2;170.0402.
With hydrogenchloride;Inert atmosphere; Reflux;
Concentrated hydrochloric acid (one drop) was added to an ethanol (3 mL) solution of the carboxylic acidrepresented by the general formula 4 (1 mmol) in an argon atmosphere, and the mixture was refluxed with heatingovernight.[0228] After evaporating the solvent, a saturated sodium bicarbonate solution was added to the mixture until theaqueous layer became basic, followed by extraction with methylene chloride.[0229] The organic layer was dried over sodium sulfate, and filtered, and the solvent was evaporated to obtain theethyl ester compound represented by the general formula 4a
With hydrogenchloride; In water; for 18h;Reflux;
General procedure: To a stirred solution of carboxylic acid 11j-r (1 mmol) in EtOH(3 mL) was added conc. HCl (1 drop), and the resulting mixturewas refluxed for 18 h. After cooling, the solvent was removed, andthen the residue was added sat. NaHCO3 aq., and the aqueous mixturewas extracted with CH2Cl2. The organic extracts were driedover Na2SO4, and the solvent was removed to afford the correspondingethyl ester, which was used for the next reaction withoutfurther purification. To a stirred solution of ethyl ester (1 mmol),obtained above, in EtOH (0.5 mL) was added hydrazine monohydrate(0.05 mL, 1 mmol), and the resulting mixture was refluxedfor 18 h. The solvent was removed to give the corresponding acylhydrazide, which was used for the next reaction without furtherpurification. To a stirred solution of acylhydrazide, obtained above,in CH2Cl2 (1 mL) was added a solution of isothiocyanate 8a-h or10c, i (1 mmol) in CH2Cl2 (5 mL), and the resulting mixture was stirredat room temperature for 18 h. The insoluble solid was correctedby filtration, and dried to give acyl hydrazino thiourea 13A-U.
[1(R)]-3-[5-[(3,5-dimethylphenoxy)methyl]-2-thiazolyl]-N-hydroxy-alpha,3-dimethyl-2-oxo-1-pyrrolidineacetamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
92%
In ethyl acetate;
[1(R)]-3-[5-[(3,5-dimethylphenoxy)methyl]-2-thiazolyl]-N-hydroxy-alpha,3-dimethyl-2-oxo-1-pyrrolidineacetamide (459a) Following the procedures similar to that used for step (300a), but using thiopheneacetic acid (7.5 g, 52.7 mmol), the methyl ester was prepared. The crude ester was purified by chromatography on silica gel eluding hexane: ethyl acetate (90:10, v:v) to give the methyl thiopheneacetate (7.5 g, 92%) as a foam. MS (M+H)+ =157.
EXAMPLE 1 N-(4,6-DIMETHYL-2-PYRIDYL)-2-THIENYLACETAMIDE 9.22 g of triphenylphosphine, 6.93 ml of trichlorobromomethane, 5 g of 2-thienylacetic acid and 8.50 g of <strong>[5407-87-4]2-amino-4,6-dimethylpyridine</strong> are dissolved in 120 ml of tetrahydrofuran. The mixture is brought to reflux and filtered, and the filtrate is concentrated; the residue is chromatographed on silica gel, eluding with dichloromethane, and the product obtained is recrystallized from isopropyl ether. Yield: 78% Melting point: 124-125 C. Elemental composition Calculated: C 63.33H 5.68N 11.36 Found: C 63.26H 5.69N 11.34
64 1-((N-Propylamino)methyl-N-(2-(p-fluorophenyl)ethyl))-5,6-dihydroxy tetralin hydrobromide
EXAMPLE 64 1-((N-Propylamino)methyl-N-(2-(p-fluorophenyl)ethyl))-5,6-dihydroxy tetralin hydrobromide Using the product of Example 63 and the procedures described in Examples 4 and 5 replacing the 2-thiopheneacetic acid with 4 fluorophenylacetic acid gave 1-((N-propylamino)methyl-N-(2-(p-fluorophenyl)ethyl))-5,6-dimethoxy tetralin hydrochloride. This product was reacted as described in Example 9 to give the desired product, m.p. 212°-14° C. Anal. calcd. for C22 H29 BrFNO2: C, 60.27; H, 6.68; N, 3.20. Found: C, 60.26; H, 6.58; N, 3.19.
With diphenylphosphoranyl azide; triethylamine In toluene at 20℃; for 3.5h; Heating / reflux;
32
Synthesis 324-oxo-3-(thiophen-2-ylmethyl)-3,4-dihydroimidazo[5,1-d][1 ,2,3,5]tetrazine-8-carboxamide(CC-002); NH2 To 2-thiopheneacetic acid (2.84 g, 20 mmol) in dry toluene (22.5 mL) was added dry triethylamine (2.93 mL, 4.2 mmol) and diphenyl phosphorylazide (4.31 mL, 4 mmol). The reaction mixture was stirred at room temperature for 0.5 hours, and then heated at reflux for a further 3 hours. After cooling, the mixture was concentrated under reduced pressure and purified by distillation using an oil pump to give thiophen-2-ylmethyl isocyanate (0.35 g, 12%) as a colourless oil.
With methanesulfonic acid; phosphorus pentoxide; In dichloromethane; at 20℃; for 15h;
Example 5 2-Thiophene acetic acid (2 g, 0.014 mol) and phosphorus pentoxide (4 g, 0.014 mol) mixture was cooled in an ice bath. Methane sulfonic acid (25 ml) was added followed by dichloromethane (25 ml). The mixture was allowed to warm up to room temperature and then stirred at room temperature for 15 h. Dichloromethane was removed under vacuum and then the reaction mixture was poured into excess water. The dark brown precipitate was filtered, washed repeatedly with water and dried. The solid was insoluble in THF. It was dissolved in dimethyl sulfoxide and precipitated in excess methanol. Yield 1.5 g (86%). IR (KBr) cm-1: 3455(b), 2927(w), 1713(w), 1654(ss), 1534(w), 1451(s), 1304(w), 1223(s), 1064(s).
Step 1 2,2-d2-2-(thiophen-2-yl)acetic acid: A mixture of thiophen-2-yl-acetic acid (3.00 g; 21.12 mmol), anhydrous potassium carbonate (11.60 g; 84.5 mmol) and deuterium oxide (12 mL) was heated at about 100 C. for about 18 hours. After distillation, fresh deuterium oxide (12 mL) was added and heating continued for about 16 hours. This cycle was repeated once more. The reaction mixture was cooled to about 0 C., and acidified to a pH of about 3.0 by adding 20%-d1-hydrochloric acid in deuterium oxide. Standard extractive workup with dichloromethane gave the title compound as an off-white solid (2.70 g; 89%). m.p. 64-68 C.; 1H NMR (400 MHz, D2O) delta 6.93-6.94 (m, 1H), 7.01-7.03 (m, 1H), 7.31-7.32 (m, 1H), IR (KBr) upsilon 3166, 3100, 3031, 2916, 2132, 1702, 1409, 1304, 1228, 1188, 1035, 937, 895, 694 cm-1 MS 143 (M-1)
Stage #1: Thiophene-2-acetic acid With n-butyllithium; diisopropylamine In tetrahydrofuran; hexane at -5℃; for 1h; Inert atmosphere;
Stage #2: methyl iodide In tetrahydrofuran; hexane at -5 - 23℃; for 16h; Inert atmosphere;
194.1
A solution of diisopropylamine (19.9 mL, 141.3 mmol) in THF (90 mL) in an oven- dried round-bottomed flask was cooled to -5 0C under nitrogen, and was treated with butyllithium (2.5M solution in hexanes, 56.5 mL, 141.3 mmol) in a dropwise manner. The reaction was stirred at -5 0C under nitrogen. After 30 minutes, a solution of thiophene-2-acetic acid (5.02 g, 35.3 mmol) in THF (10 mL) was added to the reaction in a dropwise fashion. After another 30 minutes, iodomethane (13.7 mL, 22.0 mmol) was added in a dropwise fashion. The reaction was slowly allowed to warm to 23 0C. Ater 16 h, the suspension was diluted with EtOAc (150 mL) and washed with 10% aqueous hydrochloric acid solution (100 mL) and brine (100 mL), dried over MgSOφ concentrated in-vacuo and purified by silica gel chromatography using methanol/dichloromethane as the eluant affording 2-methyl-2- (thiophen-2-yl)propanoic acid as an an off-white solid. MS (ESI pos. ion) m/z: 171 (M+l).
Stage #1: (S)-1,2,3,4-tetrahydro-5-hydroxy-N-propyl-naphthalen-2-ammonium hydrobromide With potassium carbonate In dichloromethane; water at 5 - 10℃;
Stage #2: Thiophene-2-acetic acid With sodium tetrahydroborate In toluene at 20 - 90℃; Inert atmosphere;
Stage #3: With ethanol In toluene
2.1
Example 2 - Preparation of Rotigotine hydrochloride (1) (Form A)Step 1 - Preparation of Rotigotine2-N-Propyl-5-hydroxy tetraline hydrobromide (5, 19 g) was finely ground and suspended in 100 mL of water in the presence of 200 mL of dichloromethane. An excess of K2CO3 (200 mL, 20% aqueous solution) was added under stirring, at a temperature of 5-100C. The organic phase was separated and extraction was repeated twice, after that the organic phase was washed with aqueous saturated NaCl, dried over sodium sulfate, and evaporated to give an oily residue. In another round-bottom flask, 56 g of 2-thienylacetic acid was dissolved in 125 mL of toluene. The solution was added with 4.8 g of sodium borohydride in small portions, so that temperature did not exceed 20-250C. One hour after the end of the addition, 13.6 g of the free amine obtained from hydrobromide 5 was added. The resulting toluene solution was heated at 80- 900C and kept under nitrogen in these conditions for about 8 hours. After completion of the reaction, the mixture was cooled and carefully added with ethanol to decompose the reaction complex, then poured in ice-water containing 10% sodium carbonate. The organic phase was separated, further extracted with 10% sodium carbonate solution, washed with NaCl saturated solution and evaporated to a residue under reduced pressure.The basic aqueous phase, containing 2-thienylacetic acid, was carefully acidified with 10% sulfuric acid at 00C and extracted three times with ethyl acetate. Evaporation of the organic extract allowed to recover about 40 g of 2- thienylacetic acid.The toluene phase containing Rotigotine 1 was extracted three times with 200 mL of 3N HCl. Subsequently, the acidic solution was added withNaHCO3 (5% aqueous) to pH 8, and then extracted three times with 200 mL of ethyl acetate. Evaporation of the organic extract and drying providedRotigotine 1 (80%) as a colourless oil.
With triethylamine; HATU; In N,N-dimethyl-formamide; at 20℃; for 18h;
Example 3-1 : Synthesis of (2R,4S)-5-biphenyl-4-yl-2-methyl-4-(2-thiophen-2-yl- acetylamino)-pentanoic acid; To a solution of thiophen-2-yl-acetic acid (0.144 mmol) in DMF (5 ml_) is added HATU (0.216 mmol). After stirring the mixture at room temperature for 10 minutes, (2R,4S)-4- amino-5-biphenyl-4-yl-2-methyl-pentanoic acid ethyl ester hydrochloride (0.144 mmol) and triethylamine (0.359 mmol) is added and the mixture is stirred at room temperature for 18 hours. The mixture is poured into ethyl acetate and the mixture is washed with aqueous 1 M HCI and brine. The organic phase is dried over magnesium sulfate and the solvent is removed under reduced pressure to give (2R,4S)-5-biphenyl-4-yl-2-methyl-4-(2-thiophen-2- yl-acetylamino)-pentanoic acid ethyl ester which is used directly in the subsequent hydrolysis reaction.Next, to a solution of (2R,4S)-5-biphenyl-4-yl-2-methyl-4-(2-thiophen-2-yl-acetylamino)- pentanoic acid ethyl ester (0.287 mmol) in ethanol (10 ml_) is added aqueous 1 M NaOH (2 ml_, 6.97 mmol) and the mixture is stirred at room temperature for 18 hours. The mixture is poured into ethyl acetate and is washed with aqueous 1 M HCI, the organic phase is dried over magnesium sulfate and the solvent is removed under reduced pressure. The residue is purified by preparative HPLC using a gradient of MeCN/water (0.1% TFA). The proper fractions are lyophilized to furnish (2R,4S)-5-biphenyl-4-yl-2-methyl-4-(2-thiophen-2-yl- acetylamino)-pentanoic acid. HPLC Retention time 1 .23 minutes (condition A); MS 408.3 (M+1 ); 1 H NMR (400 MHz, MeOD-d4) ? ppm 1 .16 (d, J=7.07 Hz, 3H), 1 .50 (m, 1 H), 1 .96 (m, 1 H), 2.52 (m, 1 H), 2.72 (dd, J=7.71 Hz,7.58 Hz, 1 H), 2.84 (dd, J=5.81 Hz, 5.66 Hz, 1 H), 3.64 (d, J=1 .26 Hz, 2H), 4.20 (m, 1 H), 6.82 (m, 1 H), 6.89 (m, 1 H), 7.21 (m, 3H), 7.32 (m, 1 H), 7.42 (m, 2H), 7.46 (m, 2H), 7.57 (m, 2H), 7.95 (d, J=8.59 Hz, 1 H).
With triethylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate; In N,N-dimethyl-formamide;
Example 16-1 Synthesis of (2R,4S)-5-biphenyl-4-yl-2-methyl-4-(2-thiophen-2-yl-acetylamino)-pentanoic acid To a solution of thiophen-2-yl-acetic acid (0.144 mmol) in DMF (5 mL) is added HATU (0.216 mmol). After stirring the mixture at room temperature for 10 minutes, <strong>[149690-12-0](2R,4S)-4-amino-5-biphenyl-4-yl-2-methyl-pentanoic acid ethyl ester hydrochloride</strong> (intermediate 29: 0.144 mmol) and triethylamine (0.359 mmol) is added and the mixture is stirred at room temperature for 18 hours. The mixture is poured into ethyl acetate and the mixture is washed with aqueous 1M HCl and brine. The organic phase is dried over magnesium sulfate and the solvent is removed under reduced pressure to give (2R,4S)-5-biphenyl-4-yl-2-methyl-4-(2-thiophen-2-yl-acetylamino)-pentanoic acid ethyl ester which is used directly in the subsequent hydrolysis reaction.
With triethylamine; HATU; In N,N-dimethyl-formamide; at 20℃; for 18h;
To a solution of thiophen-2-yl-acetic acid (0.144 mmol) in DMF (5 mL) is added HATU (0.216 mmol). After stirring the mixture at room temperature for 10 minutes, <strong>[149690-12-0](2R,4S)-4-amino-5-biphenyl-4-yl-2-methyl-pentanoic acid ethyl ester hydrochloride</strong> (intermediate 29: 0.144 mmol) and triethylamine (0.359 mmol) is added and the mixture is stirred at room temperature for 18 hours. The mixture is poured into ethyl acetate and the mixture is washed with aqueous 1 M HCI and brine. The organic phase is dried over magnesium sulfate and the solvent is removed under reduced pressure to give (2R,4S)-5-biphenyl-4-yl-2-methyl-4-(2-thiophen-2-yl-acetylamino)-pentanoic acid ethyl ester which is used directly in the subsequent hydrolysis reaction. (0378) Next, to a solution of (2R,4S)-5-biphenyl-4-yl-2-methyl-4-(2-thiophen-2-yl-acetylamino)-pentanoic acid ethyl ester (0.287 mmol) in ethanol (10 mL) is added aqueous 1 M NaOH (2 mL, 6.97 mmol) and the mixture is stirred at room temperature for 18 hours. The mixture is poured into ethyl acetate and is washed with aqueous 1 M HCI, the organic phase is dried over magnesium sulfate and the solvent is removed under reduced pressure. The residue is purified by preparative HPLC using a gradient of MeCN/water (0.1% TFA). The proper fractions are lyophilized to furnish (2R,4S)-5-biphenyl-4-yl-2-methyl-4-(2-thiophen-2-yl-acetylamino)-pentanoic acid. HPLC Retention time 1.23 minutes (condition F); MS 408.3 (M+1); 1H NMR (400 MHz, MeOD-d4) delta ppm 1.16 (d, J=7.07 Hz, 3H), 1.50 (m, 1 H), 1.96 (m, 1 H), 2.52 (m, 1 H), 2.72 (dd, J=7.71 Hz,7.58 Hz, 1 H), 2.84 (dd, J=5.81 Hz, 5.66 Hz, 1 H), 3.64 (d, J=1.26 Hz, 2H), 4.20 (m, 1 H), 6.82 (m, 1 H), 6.89 (m, 1 H), 7.21 (m, 3H), 7.32 (m, 1 H), 7.42 (m, 2H), 7.46 (m, 2H), 7.57 (m, 2H), 7.95 (d, J=8.59 Hz, 1 H).
With dicyclohexyl-carbodiimide; In dimethyl sulfoxide; at 110℃;
General procedure: A solution of ortho-hydroxybenzaldehyde (1-4, 8 mmol), substituted acetic acid (a-c, 10 mmol) and DCC (12 mmol) in dimethylsulfoxide (DMSO, 10 mL), was heated (oil bath) at 110 C for 24-48 h. On completion of the reaction, cold water (100 mL) and acetic acid (15 mL) were added. The reaction mixture was stirred at room temperature for 4 h and extracted with diethyl ether (4 × 100 mL). The precipitated dicyclohexylurea was filtered off. The filtrate was extracted with 5% aqueous NaHCO3 (200 mL). The organic phase was stirred for 1 h with 5% aqueous sodium metabisulfite in order to remove the unreacted hydroxybenzaldehyde. The organic phase was washed with water, dried (Na2SO4) and the solvent removed under reduced pressure. The residue was purified by column chromatography (Hexane/EtOAc, 9:1).
With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 20℃; for 18h;
General procedure: A mixture 2-amino-4,5-dimethylthiophene-3-carboxamide (340 mg, 2 mmol), 2-(1-naphthalen-1-yl)acetic acid (372 mg, 2 mol), EDC (458 mg, 2.4 mmol), HOBt (324 mg, 2.4 mmol), DIEA ( 1.1 mL, 6 mmol) in DMF (10 mL) was stirred at room temperature for 18 h. The reaction mixture was poured into 100 mL of water then extracted with ethyl acetate (150 mL). The organic layer was washed with saturated NaHCO3 solution (3 x 50 mL), brine (3 x 50 mL), water (3 x 50 mL) respectively. The ethyl acetate layer was dried over MgSO4 and concentrated. The residue was chromatographed over silica gel (30 to 40% ethyl acetate in haxane) to afford compound 1 (277 mg, 41%).
Stage #1: Thiophene-2-acetic acid With sodium tetrahydroborate In toluene at 20 - 25℃; for 1h; Inert atmosphere;
Stage #2: Desthienyl-Rotigotine In toluene at 80 - 90℃; for 8h; Inert atmosphere;
2.1
Example 2Preparation of Rotigotine hydrochloride (1) (Form A)Step 1-Preparation of Rotigotine2-N-Propyl-5-hydroxy tetraline hydrobromide (5, 19 g) was finely ground and suspended in 100 mL of water in the presence of 200 mL of dichloromethane. An excess of K2CO3 (200 mL, 20% aqueous solution) was added under stirring, at a temperature of 5-10° C. The organic phase was separated and extraction was repeated twice, after that the organic phase was washed with aqueous saturated NaCl, dried over sodium sulfate, and evaporated to give an oily residue.In another round-bottom flask, 56 g of 2-thienylacetic acid was dissolved in 125 mL of toluene. The solution was added with 4.8 g of sodium borohydride in small portions, so that temperature did not exceed 20-25° C. One hour after the end of the addition, 13.6 g of the free amine obtained from hydrobromide 5 was added. The resulting toluene solution was heated at 80-90° C. and kept under nitrogen in these conditions for about 8 hours. After completion of the reaction, the mixture was cooled and carefully added with ethanol to decompose the reaction complex, then poured in ice-water containing 10% sodium carbonate. The organic phase was separated, further extracted with 10% sodium carbonate solution, washed with NaCl saturated solution and evaporated to a residue under reduced pressure.The basic aqueous phase, containing 2-thienylacetic acid, was carefully acidified with 10% sulfuric acid at 0° C. and extracted three times with ethyl acetate. Evaporation of the organic extract allowed to recover about 40 g of 2-thienylacetic acid.The toluene phase containing Rotigotine 1 was extracted three times with 200 mL of 3N HCl. Subsequently, the acidic solution was added with NaHCO3 (5% aqueous) to pH 8, and then extracted three times with 200 mL of ethyl acetate. Evaporation of the organic extract and drying provided Rotigotine 1 (80%) as a colourless oil.
General procedure: In a dry round-bottom flask, the corresponding carboxylic acid(1 equiv, 0.5 mmol) was added to a solution of SOCl2 (20 equiv),and stirred under reflux over a period of 5 h. The excess of SOCl2was then removed under reduced pressure. Under inert atmosphere,the crude residue was taken into CH2Cl2, added dropwiseto a solution of N,O-dimethylhydroxylamine hydrochloride(1.1 equiv) and pyridine (2.2 equiv) at 0 C (NB: final concentrationmust not exceed 0.1 mol/L) and slowly warmed to r.t. Aftercompletion of the reaction, the crude mixture was diluted withCH2Cl2, and rinsed three times with water. The organic phasewas decanted and was washed with a sat. solution of NaHCO3,and neutralized with a solution HCl (1 M) until pH 7. Theorganic layers were dried over anhydrous MgSO4, filtered, andconcentrated under reduced pressure. The residue was purifiedby flash chromatography (gradient of eluent from 100% heptaneto 100% EtOAc) to afford the corresponding Weinreb amide.
In toluene at 110℃; Sealed tube; Inert atmosphere;
1 Compounds from Table 4: General Procedure A
General procedure: Two equivalents of the isonitrile in 1 mL dry toluene were filtered through a short plug (ca. 0.5 cm in a 5 inch glass pipette) of silica gel into a flame dry 50 mL round bottom flask containing the carboxylic acid. The plug was flushed with an additional milliliter of toluene. The remainder of the toluene (0.02 M final acid concentration) was added and then the reaction vessel was sealed with a wire secured septum, blanketed under argon, and heated as a sealed tube in a 110 °C oil bath overnight (18-24 hours). Volatile residues were removed in vacuo and products were purified by silica gel flash chromatography in 4:1 hexanes:ethyl acetate, unless otherwise stated.
In toluene at 110℃; Sealed tube; Inert atmosphere;
1 Compounds from Table 4: General Procedure A
General procedure: Two equivalents of the isonitrile in 1 mL dry toluene were filtered through a short plug (ca. 0.5 cm in a 5 inch glass pipette) of silica gel into a flame dry 50 mL round bottom flask containing the carboxylic acid. The plug was flushed with an additional milliliter of toluene. The remainder of the toluene (0.02 M final acid concentration) was added and then the reaction vessel was sealed with a wire secured septum, blanketed under argon, and heated as a sealed tube in a 110 °C oil bath overnight (18-24 hours). Volatile residues were removed in vacuo and products were purified by silica gel flash chromatography in 4:1 hexanes:ethyl acetate, unless otherwise stated.
With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine; In dichloromethane; at 20℃; for 6h;
General procedure: To a solution of 44 2-(2,5-dimethoxyphenyl)acetic acid (50g, 255 mmol) and 45 2-thiophene ethylamine (35.7g, 280mmol) in 46 dichloromethane (DCM) was added 47 N-ethyl-N?-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDCI, 73.3g, 382 mmol), 48 hydroxybenzotriazole (HOBt, 44.8g, 331 mmol) and 49 triethylamine (71 mL, 510mmol). After stirring at room temperature for 6h, the mixture was quenched with 1 N 50 HCl, washed with saturated NaHCO3 and brine, respectively. The organic layer was dried over anhydrous Na2SO4, and concentrated in vacuo. The residue was recrystallized from ethyl acetate to afford 51 7 (66g, 85%) as a white solid. Mp: 84-87C. 1H NMR (400 MHz, CDCl3) delta 7.11 (d, J=5.0Hz, 1H), 6.88 (dd, J=5.0, 3.3Hz, 1H), 6.84-6.72 (m, 3H), 6.65 (d, J=3.3Hz, 1H), 6.01 (brs, 1H), 3.75 (s, 3H), 3.69 (s, 3H), 3.51 (s, 2H), 3.45 (dt, J=6.4, 6.4Hz, 2H), 2.94 (t, J=6.5Hz, 2H). LRMS (ESI) m/z: 306.1 [M+H]+.
With dipotassium peroxodisulfate; In water; at 90℃; for 12h;Green chemistry;
General procedure: In an oven dried tube containing a mixture of 4-methyl phenyl acetic acid 1a (200 mg, 1.33mmol) and potassium persulfate (360 mg, 2.66 mmol), water (2 mL) was added and heated at 90 C for 12 h. Upon completion of the reaction (monitored by TLC), the reaction mixture was cooled to room temperature (24C) and it was extracted with ethyl acetate (3 x 5 mL). The crude product was purified by column chromatography to furnish compound 2a as colorless liquid (136 mg, 85% yield).
63%
With (4s,6s)-2,4,5,6-tetra(9H-carbazol-9-yl)isophthalonitrile; N,N,N',N'-tetramethylguanidine; In acetonitrile; at 20℃; for 6h;Irradiation;
General procedure: To a 25 mL reaction tube, arylacetic acid (0.2 mmol), 4CzIPN (1 mol%), TMG (50 mol%) were dissolved in CH3CN (1.5 mL), and then the tube was stirred in air at room temperature for 6 h with the irradiation of 25 W blue LEDs. After reaction, the mixture was collected, and the residue was purified by column chromatography on silica gel to afford the desired products.
With oxygen; In N,N-dimethyl-formamide; at 120℃; for 4h;
General procedure: In a typical experiment, a solution of phenylacetic acid (0.3mmol, 40.8mg) in DMF (0.5mL) was added to a 10mL vial with the VNU-21 catalyst (5.5mg, 5mol%). The mixture was stirred at 120C for 4h under an oxygen atmosphere. After that, the catalyst was removed by filtration. A solution of 2-aminobenzamide (0.2mmol, 27.2mg) in DMSO (0.5mL) was then added to the reactor. The mixture was additionally stirred at 120C for 5h under oxygen. The GC yield of benzaldehyde and 2-phenylquinazolin-2(3H)-one were monitored by withdrawing samples from the reaction mixture, quenching with brine (1mL), extracting with ethyl acetate (3×1mL), drying over anhydrous Na2SO4, and analyzing by GC regarding diphenyl ether as internal standard. After the completion of the second step, the reaction mixture was cooled to room temperature. Resulting solution was quenched with brine (5mL), extracted by ethyl acetate (3×5mL), dried over anhydrous Na2SO4 prior to the removal of solvent under vacuum. The crude product was purified by silica gel column chromatography using hexane and ethyl acetate (1:1, v/v) as eluent. The structure of 2-phenylquinazolin-4(3H)-one was verified by GC-MS, 1H NMR and 13C NMR. For the leaching test, after the first 4h reaction time, the catalyst was removed by filtration. The solution phase was transferred to a new and clean reactor. New phenylacetic acid was added, and the resulting mixture was subsequently stirred for additional 4h at 120C under an oxygen atmosphere. The yield of benzaldehyde was monitored by GC.
EXAMPLE 107 (S)-3-[1-(1-Ethyl-propyl)-2-thiophen-2-ylmethyl-1H-benzoimidazole-5-carbonyl]-amino}-5-methyl-hexanoic acid [1848] (S)-3-(9H-Fluoren-9-ylmethoxycarbonylamino)-5-methyl-hexanoic acid, 173 mg of DIC, and 14 mg of DMAP were added in DMF in a 20 ml scintillation bottle. The reaction was kept at rt for 18 h. To deprotect the Fmoc-group 50% Piperidine in DMF was added and the reaction was kept for 30 min at rt. Afterwards the resin was washed thoroughly with DMF. For the amide formation the resin was reacted with 217 mg 4-Fluoro-3-nitrobenzoic acid, 185 mg HOBt, and 173 mg DIC in DMF for 18 h at rt. In the next step nucleophilic substitution was achieved by reacting the resin with 680 mg of 1-Ethyl-propylamine in DMF at it for 24 h. Subsequently, the reduction of the nitro group took place by reaction with 10 ml of 1M SnCl2 in DMF at rt for 23 h. Then, to the resin in dry DMF were added 139 mg 2-thienyl acetic acid, 371 mg of HATU and 250 mg of DIPEA and the reaction was left at it for 4 h to achieve amide formation. The cleavage from the resin took place by reaction with 3 ml of 95% aqueous TFA for 2 hrs. Then additional 2 ml of aqueous of 95% TFA, 3 ml of acetonitrile and 3 ml water were added and the cleavage solution was heated to 60 C. for 24 h. After filtration the solvents were removed and the resulting residue was purified by HPLC to afford 37 mg (8%) of (S)-3-[1-(1-Ethyl-propyl)-2-thiophen-2-ylmethyl-1H-benzoimidazole-5-carbonyl]-amino}-5-methyl-hexanoic acid. [1850] C25H33N3O3S (455.62), LCMS (method 6-1-1): Rt=1.62 min, m/z=456.40 [M+H]+
To 300 mg of Wang resin (NovaBioChem 70-90 mesh, loading capacity 1 .3 mmol/g), 430 mg of (S)-3-(9H-Fluoren-9-ylmethoxycarbonylamino)-5-methyl-hexanoic acid, 173 mg of DIC, and 14 mg of DMAP were added in DMF in a 20 ml scintillation bottle. The reaction was kept at rt for 18 h. To deprotect the Fmoc-group 50% Piperidine in DMF was added and the reaction was kept for 30 min at rt. Afterwards the resin was washed thoroughly with DMF. For the amide formation the resin was reacted with 217 mg 4-Fluoro-3-nitrobenzoic acid, 185 mg HOBt, and 173 mg DIC in DMF for 18 h at rt. In the next step nudeophilic substitution was achieved by reacting the resin with 680mg of 1 -Ethyl-propylamine in DMF at rt for 24 h. Subsequently, the reduction of the nitro group took place by reaction with 10 ml of 1 M SnCI2 in DMF at rt for 23 h. Then, to the resin in dry DMF were added 139 mg 2-thienyl acetic acid, 371 mg of HATU and 250 mg of DIPEA and the reaction was left at rt for 4 h to achieve amide formation. The cleavage from the resin took place by reaction with 3 ml of 95% aqueous TFA for 2 hrs. Then additional 2 ml of aqueous of 95% TFA, 3 ml of acetonitrile and 3 ml water were added and the cleavage solution was heated to 60C for 24 h. After filtration the solvents were removed and the resulting residue was purified by HPLC to afford 37 mg (8%) of (S)-3-[1 -(1 -Ethyl-propyl)-2-thiophen-2- ylmethyl-1 H-benzoimidazole-5-carbonyl]-amino}-5-methyl-hexanoic acid. C25H33N3O3S (455.62), LCMS (method 6_1_1 ): Rt = 1 .62 min, m/z= 456.40 [M+H]+
With dmap; dicyclohexyl-carbodiimide; In dichloromethane; at 20℃; for 12h;Inert atmosphere;
1 was synthesized using a previously reported synthesis procedure. 2-Thiopheneacetic acid (17.5 g, 0.13 mol) in 100 mL anhydrous dichloromethane was added dropwise to 250 mL of anhydrous dichloromethane in three-necked round-bottomed flask at 0C. The flask was equipped with dicyclohexylcarbodiimide (26.6 g, 0.13 mol) and dimethylaminopyridine (4.2 g, 0.035 mol). The reaction had been conducted for 12 h at room temperature under a nitrogen atmosphere. The byproduct urea was removed by filtration, and the crude product was purified through column chromatography (ethyl acetate: n-hexane =1:20). A total of 10.7 g of a yellow solid product (yield: 68%) was obtained. 1H NMR (CDCl3, 400 MHz, ppm): delta 4.12 (s, 4H), 6.90-6.91 (d, 2H), 6.96-6.99 (t, 2H), 7.39-7.42 (t, 2H).
N,N'-dicyclohexylcarbamoyl-2-(thiophen-2-yl)acetamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With triethylamine; dicyclohexyl-carbodiimide In dichloromethane at 20℃; for 8h;
Synthesis and Crystal Growth
1,3-dicyclohexylurea (C13H24N2O, Mol. Wt. 224.34 g) was synthesized by dissolving 1.43 g (10 mmol, C7H13NO2, Mol.Wt. 143.18 g) of cyclohexylcarbamic acid and 0.99 g (10 mmol, C6H13N, Mol. Wt. 99.17 g) of cyclohexanamine in 15 mL DCM (dichloromethane, CH2Cl2,Mol. Wt. 84.93 g) taken in a round bottom flask. A 4.12 g (20 mmol, C13H22N2, Mol. Wt.206.33 g) of DCC (N,N-Dicyclohexylcarbodiimide) was added and the reaction mixture was refluxed for 8 h at room temperature in basic condition with the addition of 4 mL (30 mmol, C6H15N) of triethylamine. The solution obtained was filtered off and the filtrate was kept for drying at room temperature to get 1,3-dicyclohexylurea. Later 1.1 g of the obtained 1,3-dicyclohexylurea (5 mmol, C13H24N2O, Mol. Wt.224.34 g) along with 15 mL of DCM was taken in a clean round bottom flask. To the resultant mixture 0.71 g (5 mmol, C6H6O2S, Mol. Wt. 142.18 g) of 2-thiopheneacetic acid in 15 mL DCM was added. To this mixture 2.6 g (10 mmol, C13H22N2, Mol.Wt. 206.33 g) of DCC was added and the reaction mixture was refluxed for 8 h at room temperature in basic condition with the addition of 2 mL (15 mmol, C6H15N) of triethylamine. The solution obtained was filtered off and the filtrate was kept for drying at room temperature to get N,N'-dicyclohexylcarbamoyl-2-(thiophen-2-yl) acetamide. Single crystals suitable for X-ray diffraction study were obtained by a slow evaporation technique using methanol as a solvent.
(3SR,4RS)-1-methyl-4-phenyl-3-(thiophen-2-yl)azetidin-2-one[ No CAS ]
(3RS,4RS)-1-methyl-4-phenyl-3-(thiophen-2-yl)azetidin-2-one[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
1: 48%
2: 30%
With 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphinane-2,4,6-trioxide; N-ethyl-N,N-diisopropylamine In tetrahydrofuran; chloroform at 70℃; for 20h; diastereoselective reaction;
(4) General procedure for β-lactam synthesis (Table 1 and Table 2)
General procedure: The appropriate imine (0.762 mmol) and carboxylic acid (0.915 mmol, 1.2 eq.) were stirred in theappropriate solvent. NEt(i-Pr)2 (182 mg, 246 μL, 1.410 mmol, 1.85 eq.) and [T3P (364 mg, 1.14 mmol,1.5 eq. (728 mg of 50% wt. solution in THF)] were added by syringe and the reaction mixture stirred at70 °C for 20 h. The reaction was poured into sat. NaHCO3 (10 mL) and extracted with CH2Cl2 (3 × 10mL). The combined organic phases were dried (MgSO4), filtered, and concentrated to give the crudematerial. At this stage the diastereoselectivity was determined using 1H NMR. The material was purifiedby column chromatography (see individual entries for eluting solvent systems).
(S)-1,2,3,4-tetrahydro-5-hydroxy-N-propyl-naphthalen-2-ammonium hydrobromide[ No CAS ]
[ 125572-93-2 ]
Yield
Reaction Conditions
Operation in experiment
65%
To the mixture of (S)-5-Hydroxy-2n-propyl amino) tetralin hydrobromide (100 grams, 1 equivalent) and MDC (700 mL, 7 volumes) water was added (500 mL, 5 volumes) and followed by triethylamine (80 mL, 0.8 volumes) at 25-35 C, stirred for 10 minutesat 25-35 C. Organic layer was separated and aqueous layer was again extracted with MDC (200 mL, 2 volumes), both MDC layers were combined and washed with 10% brine solution (400 mL, 4 volumes). Distilled off the MDC below 40 C under vacuum. Cooled the reaction mixture to 25-35 C and toluene (1000 mL, 10 volumes) was added to the reaction mixture at 25-35 C. Stirred for 5 minutes to get clear solution at 25-35 C. Meanwhile in another RB flask 2-thiopheneacetic acid (310 grams, 6.25 equivalents) was dissolved in toluene (1000 mL, 10 volumes) at 25-35 C, then it was cooled to 15 C, sodium borohydride was (42 grams, 3.25 equivalents) added to the reaction mixture at 15-20 C slowly lot wise. Stirred for 60 minutes at 25-35 C. After that above prepared free base solution was added to the reaction mixture at 25-35 C. Heated to internal temperature 90-100 C and stirred for 6- 8 hours at 90-100 C. Progress of the reaction was monitored by HPLC. Cooled to 0 C. Water (200 mL, 2 volumes) was added to the reaction mixture at 0-10 C and stirred for 5-10 minutes at 25-35 C, then reaction mass was washed with 10% potassium carbonate solution (2x8 volumes) followed by water (500 mL, 5 volumes). Distilled off the toluene solvent below 65 C under vacuum 630-700 mmHg. Crude residue was dissolved in methylene chloride (600 mL, 6 volumes) at 25-35 C and HC1 gas was passed through the reaction mass for 10 minutes at 25 -35 C (RM pH should be below 2). Stirred the reaction mixture for 30 minutes at 25-35 C. Filtered the solid compound and washed with methylene chloride (2 x 200 mL, 4 volumes), dried the solid compound at 55-60 C for 2 hours, to get Rotigotine HC1 (98.5 grams). HPLC purity:98%. Rotigotine HC1 stirred in acetone (690 mL, 7volumes) at 50-55C and water was added (74 mL, 0.75 volumes). Stirred the reaction mixture for 5-10 minutes at 50-55C. Clear solution was observed. Reaction mixture was cooled to 0 C, stirred for 60 minutes, filtered the solid and washed with acetone (197 mL, 2 volumes), dried the compound for 6-10 hours at 55- 65 C to get Rotigotine HC1. Yield : 65% HPLC purity: 99.5%.
With N-ethyl-N,N-diisopropylamine; In acetic anhydride; at 30℃; for 2h;
General procedure: General procedure A Step-a: Synthesis of 2-(4-fluorophenyl)-3-(4-((E)-3-methoxy-3-oxoprop-1-en-1-yl) phenyl) acrylic acid (C). A mixture of 4-fluorophenylacetic acid (2.5 g, 13.2 mmol) and methyl (E)-3-(4-formylphenyl)acrylate (2.03 g, 13.2 mmol) were dissolved under stirring with acetic anhydride (8 ml). To this mixture diisopropylethylamine (DIPEA) (3.4 ml, 19.7 mmol) was added and stirred at 30 C for 2 h. Upon completion (as monitored by TLC using 100% ethyl acetate as eluent), the reaction mixture was poured into water and the pH was adjusted to 1 using dil. HClaq (1:1). The aqueous layer was extracted with ethyl acetate (2 * 150 ml). The combined ethyl acetate layer was washed with water till the washings were neutral and dried over anhydrous Na2SO4. The ethyl acetate layer was evaporated to dryness to obtain a sticky compound, which was triturated with cold dichloromethane (DCM) to furnish a white solid. It was filtered and dried under vacuum to afford the title compound (2 g, 47%).
With ammonium acetate; oxygen; copper diacetate; In 1-methyl-pyrrolidin-2-one; at 120℃; under 760.051 Torr; for 20h;
Adding reaction bottle 1a (2mmol, 394 mg), 2m (4mmol, 568 mg), ammonium acetate (4mmol, 308 mg), copper acetate (20mol %, 80 mg) and NMP (10 ml). Oxygen is then used to replace the three times in the oxygen atmosphere of the reaction system, the 120 C heating reaction 20 hours. After the reaction is finished first quenching with saturated sodium carbonate solution, then using ethyl acetate extraction, anhydrous sodium sulfate for drying, after decompression turns on lathe does solvent, petroleum ether and ethyl acetate mixed solvent for carrying out simple column chromatography to get product 3am, the yield is 80%. Yellow solid
N-[(thiophen-2-yl)methyl]-N-(phenylsulfonyl)benzenesulfonamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
91%
With copper(l) iodide; 1,10-Phenanthroline; In 1,2-dichloro-ethane; at 130℃; for 8h;Inert atmosphere;
General procedure: The specific preparation process: To a magnetic stirrer with 10mLA round bottom flask with a beaker was charged with acetonitrile (2 mL) as a solvent,4-methylphenylacetic acid (0.46 g, 1 mmol),N-fluorodibenzenesulfonimide (0.097 g, 1.2 mmol),Copper iodide (0.026 ml, 0.3 mmol) and1,10-o-phenanthroline (0.026 ml, 0.3 mmol),After mixing,Put it in a 80 C oil bath and continue stirring.TLC detection of substrate disappeared,The reaction is over. The reaction was poured into saturated aqueous sodium chloride (5 mL)Extract with dichloromethane (3 x 6 mL), combine the organic phases, dry over anhydrous magnesium sulfate,After depressurization, the organic solvent was distilled off under reduced pressure,The liquid mixture was obtained and finally subjected to silica gel column chromatography(Eluent V petroleum ether: V ethyl acetate = 10: 1) to give 0.41 g of a light yellow solid which was confirmed as compound (1) by NMR after MS,Based on 4-methylphenylacetic acid, the yield was calculated to be 90%.
With morpholine In 1,2-dimethoxyethane at 10 - 15℃; for 4.5h;
3 Example 3
To a 2000 mL three-necked flask was added 71 g (0.5 mol) of 2-thiopheneacetic acid,Organic solvent ethylene glycol dimethyl ether 600mL,Then add 80 mL of morpholine andTrifluoroacetic acid succinimidyl ester212 g (1.0 mol), and then the temperature was programmed at a temperature of 10 ° C to 15 ° C.4.5 hours, the reaction was completed, and the reaction solution containing the active ester was obtained by filtration,The reaction solution containing the active ester was slowly added dropwise to a prefabricated solution containing 136 g (0.5 mol) of 7-ACA in 1000 mL of ethylene glycol dimethyl ether,The temperature was irradiated at 15 ° C to 25 ° C for 1 hour,After the condensation reaction was completed, the reaction solution was added dropwise with 10% by weight hydrochloric acid solution, the pH was adjusted to 1.5 to 2.0, and then allowed to stand, the layers were collected, the organic phase was collected,The collected organic phase was rapidly added to 1000 mL of aqueous sodium bicarbonate solution, the pH was adjusted to 6.5 to 7.0,The temperature was then controlled at 20 ° C to 25 ° C, 10% by weight hydrochloric acid was slowly added, the pH of the system was adjusted to 1.5, stirred, the crystals were raised for 1 hour,The filtrate was filtered to give a wet product and dried at 40 & lt; 0 & gt; C154 g of product was obtained as a white solid, cefuroxime, in a yield of 96.9%.
With copper(II) acetate monohydrate; sulfur; sodium hydroxide; In dimethyl sulfoxide; at 130℃; for 24h;Sealed tube; Inert atmosphere;
General procedure: A mixture of o-iodoaniline (0.5 mmol, 1 equiv), arylacetic acid (0.6 mmol), elemental sulfur (1.5mmol), Cu(OAc)2·H2O (20 mmol%), and NaOH (1.0 mmol) in DMSO (3 mL) was put into a sealed pressure vessel (25 mL) containing a magnetic stirring bar. The tube was purged with nitrogen three times, and then capped and stirred in a preheated oil bath at 130 C for 24 h. The reaction mixture then cooled to room temperature and extracted with ethyl acetate (3x10 mL), the organic layer was washed with saturated NaCl (2x10 mL), dried over anhydrous Na2SO4, evaporated under vacumm and then purified by silica gel column chromatography by using petroleum ether and ethyl acetate (PE:EA=200:1) as eluent.
6-bromo-3-(thiophen-2-yl)-2H-chromen-2-one[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
83%
With dicyclohexyl-carbodiimide; In dimethyl sulfoxide; at 110℃;
General procedure: 3-substituted-6-bromo coumarins were synthesized by Perkincondensation according to the previous literature [20]. A solutionof 6-bromo-o-hydroxybenzaldehyde, substituted acetic acid andDCC in dimethylsulfoxide (DMSO, 10 mL) were heated at 110 Cfor 40-60 h. On completion of the reaction, cold water (100 mL)and acetic acid (15 mL) were added. The reaction mixture wasstirred at room temperature for 4 h and extracted with diethylether (4 x100 mL). Yellow precipitate was obtained with good yield(Scheme 2).
With potassium carbonate In N,N-dimethyl-formamide at 20℃; for 3h; Inert atmosphere;
40.5 Step 5: Ethyl 2-(thiophen-2-yl)ethyl ester (40G)
2-thiopheneacetic acid (40F) (5.68g, 39.9mmol) under nitrogen atmosphereAfter dissolving with N,N-dimethylformamide (15 mL), potassium carbonate was sequentially added.(8.28 g, 59.9 mmol) and ethyl iodide (7.48 g, 47.9 mmol)Adding to the reaction solution, reacting at room temperature for 3 hours,The reaction solution was poured with ice water (60 mL),The organic phases were combined and washed with a saturated aqueous solution of brine (30 mL×1).Dry over anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure.Obtained a brown oily liquid ethyl 2-(thiophen-2-yl)ethyl ester (40G)(3.6 g, yield: 53%).
1-(2,6-difluorophenyl)-2-(thiophen-2-yl)ethan-1-one[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
10.35 g
Reference Example 1 Synthesis of 1-(2,6-difluorophenyl)-2-(thiophen-2-yl)ethan-1-one To 100 ml of a THF solution containing 10.00 g of 2-(thiophen-2-yl)acetic acid was added dropwise 118.5 ml of a 1.9 mol/L THF solution of hexamethyldisilazane sodium at -78 C. and the mixture was stirred for 1 hour. Then, 20 ml of a THF solution containing 12.11 g of <strong>[13671-00-6]methyl 2,6-difluorobenzoate</strong> was added dropwise thereto, then, the temperature of the mixture was raised from -78 C. to room temperature and stirred for 2.5 hours. To the mixture was added an aqueous saturated ammonium chloride solution followed by stirring for 1 hour. Thereafter, ethyl acetate were added and the liquids were separated. The obtained organic layer was washed with saturated brine, and dried over magnesium sulfate. After the solvent was distilled off under reduced pressure, the obtained residue was purified by silica gel column chromatography. The title compound was obtained as 10.35 g of a red oily product. 1H-NMR (CDCl3) delta: 7.39 (1H, m), 7.22 (1H, m), 6.95 (4H, m), 4.36 (1H, s).
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