* 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.
EXAMPLE 4: SYNTHESIS OF D-PHENYLALANINE METHYLESTER APPENDED NAPHTHALENEDIIMIDE (D-NDI or NDI 3B): SYNTHESIS OF D-PHENYLALANINE METHYLESTER HYDROCHLORIDE:Anhydrous methanol (50 mL) is taken in a 100 mL 2-necked round bottom flask fitted with a reflux condenser and an additional dropping funnel and cooled to ice temperature. Acetyl chloride (3 mL) is added drop wise through the dropping funnel. After 15 min, D-phenylalanine (3 g, 18.16 mmol) is added and the reaction mixture is refluxed at 70 °C for overnight. The reaction mixture is vacuo dried to obtain D- phenylalanine methylester hydrochloride in quantitative yield and used for further reaction without purification. 1,4,5,8-naphthalenetetracarboxylic dianhydride (200 mg, 0.74 mmol) and D- phenylalanine methylester hydrochloride (322 mg 1.49 mmol) is suspended in DMF (20 mL) in a 100 mL round bottom flask. To this suspension triethylamine (0.6 mL) is added under inert atmosphere. The reaction mixture is refluxed at 75 °C for 24 h. Solvent is evaporated under vacuo and the residue is purified by column chromatography (1 percent methanol in chloroform). Yield 71percent. .H NMR (400 MHz, CDC13): δ 8.63 (s, 4H), 7.1 (m, 10H), 6.02 (dd, 2H, J = 4Hz, 4Hz), 3.77 (s, 6H), 3.73 (dd, 2H, J = 8Hz, 4Hz), 3.50 (dd, 2H, J= 12 Hz, 4 Hz). 13C NMR (400 MHz, CDCI3) δ 169.6, 162.4, 136.9, 131.3, 129.2, 128.5, 126.9, 126.8, 126.4, 54.9, 52.8, 34.9. MS (EI): m/z = 590.17 [M]+ for C34H26N2O8. Elemental analysis: Found: C, 69.10; H, 4.49; N, 4.78; Calcd: C, 69.15; H, 4.44; N, 4.74 for C34H26N2O8.
97%
With thionyl chloride In methanol
107a. (D)-Phenylalanine methyl ester hydrochloride (D)-Phenylalanine (25.0 g) was dissolved in 450 mL of methanol and 22 mL thionyl chloride were slowly added at -20° C. The mixture was refluxed for 1 h, followed by evaporation of the volatiles to give 31.2 g (97percent) of the title compound as a white solid. M.p. 155-163° C.
General procedure: For the synthesis of compounds 2a, 2c–2g, we used slightly modificated known procedure [1]. To a stirred solution of amino acid (32.2mmol) in dry methanol (100mL) was added drop-wise thionyl chloride (64.4mmol). The temperature was kept between−10 and−5°C. After complete addition, the reaction was stirred at RT overnight. After 16h, the solution was evaporated to dryness. The product was diluted with EtOAc and collected by filtration. The residue was dried under reduced pressure to give an amino acid methyl ester hydrochloride as white crystalline powder. The yields were higher in all experiments than 80percent. Melting point and 1H as well as 13C NMR spectra in D2O were used for characterization of the prepared compounds. The data are in good agreement with literature data [20].
Reference：
[1] European Journal of Medicinal Chemistry, 2013, vol. 68, p. 253 - 259
[2] European Journal of Medicinal Chemistry, 2009, vol. 44, # 1, p. 131 - 142
3
[ 67-56-1 ]
[ 673-06-3 ]
[ 13033-84-6 ]
Yield
Reaction Conditions
Operation in experiment
100%
at 0 - 75℃; for 2 h;
General procedure: The methyl-esterification reaction of L-phenylalanine.To a suspension of L-phenylalanine (1 g, 6.05 mmol, 1.0 equiv) inmethanol (25 mL) cooled to 0 C was added thionyl chloride(475 mL, 6.66 mmol, 1.5 equiv) slowly. After 10 min, the reactionmixture was heated to 75 C to reflux for 2 h. After completion(monitored by TLC), the solvent was removed in vacuo, and at thistime, a white solid was formed methyl L-phenylalaninate hydrochloride(1.23 g, quantitative yield).
100%
at 0 - 20℃; for 1 h;
D-Phenylalanine (1.3 g, 7.8 mmol) wasdissolved in dry MeOH and cooled to 0°C in an ice bath. Thionyl chloride (2.85 mL, 39.3 mmol) wasadded dropwise. The reaction mixture warmed to room temperature and stirred for 1 h. The solvent andreagent were removed under reduced pressure to yield the hydrochloride salt 8 as a white solid inquantitative yield. LRMS (ESI) m/z =180.3 [M+H]+.
94.1%
at 0 - 40℃; for 8 h;
66.0 g (0.40 mol) of D-phenylalanine were suspended at room temperature in 400 ml of methanol in an anhydrous flask. The thus obtained white suspension was cooled to a temperature of 0+-5° C., and then 56.0 ml of tionyl chloride were added drop wise in about 2 hours, maintaining the temperature in the range 0+-5° C. The temperature of the suspension thus obtained was brought up to 40+-5° C., and maintained for 6 hours, then returned to room temperature. The reaction mixture was stirred overnight at room temperature, and then concentrated under vacuum so as to remove most of the solvent; the residue was dissolved in 200 ml of toluene, and the thus obtained solution was concentrated under vacuum once more, until a residue able to be stirred was obtained. To this residue 400 ml of acetone were added, and the thus obtained suspension was cooled to a temperature of 0+-5° C. for 2 hours. A solid product was formed, which is filtered and washed with acetone (2*50 ml), thus obtaining 83.34 g of wet white product, corresponding to 81.09 g of dry D-phenylalanine methyl ester hydrochloride (yield=94.1percent).
94.1%
at 0 - 45℃;
EXAMPLE 1 Preparation of D-phenylalanine methyl ester hydrochloride. 66.0 g (0.40 mol) of D-phenylalanine were suspended at room temperature in 400 ml of methanol in an anhydrous flask. The thus obtained white suspension was cooled to a temperature of 0+-5°C, and then 56.0 ml of tionyl chloride were added drop wise in about 2 hours, maintaining the temperature in the range 0+-5°C. The temperature of the suspension thus obtained was brought up to 40+-5°C, and maintained for 6 hours, then returned to room temperature. The reaction mixture was stirred overnight at room temperature, and then concentrated under vacuum so as to remove most of the solvent; the residue was dissolved in 200 ml of toluene, and the thus obtained solution was concentrated under vacuum once more, until a residue able to be stirred was obtained. To this residue 400 ml of acetone were added, and the thus obtained suspension was cooled to a temperature of 0+-5°C for 2 hours. A solid product was formed, which is filtered and washed with acetone (2 x 50 ml), thus obtaining 83.34 g of wet white product, corresponding to 81.09 g of dry D-phenylalanine methyl ester hydrochloride (yield = 94.1percent).
93.85%
at 0 - 40℃; for 22 h;
Example 1: Preparation of D-Phenylalanine methyl ester hydrochloride; Methanol (1200 mL) and D-phenylalanine (200 g) were taken in a round bottom flask at 25-30 0C and cooled to 0 +/- 5 0C. Thionyl chloride (172.8 mL) was added to the above reaction mixture over 2 hours and the temperature was raised to 25-3O0C. The contents were maintained for 12 hours at 40 +/- 5°C. The contents were cooled to 25-3O0C and maintained for 8 hours. Methanol was completely distilled out under vacuum condition at below 450C. To the above crude, 1200 mL of acetone was added and the mixture was cooled slowly to 0-50C in 2 hours. The compound was filtered and washed with 100 mL of acetone. The material was dried for 8 hours at 45-500C under vacuum to obtain the title compound (244g, 93.85percent ), HPLC purity : 99.80percent.
84%
at 0 - 22℃; for 26 h;
General procedure: To a suspension of 5 g of D-amino acid in 100 mLdry methanol at 0–5°, 8–10 mL thionyl chloridewere added dropwise, the mixture was stirred for 2 hand kept at 20–22° for 24 h. The solvent was evaporatedunder vacuum at 30–40°, the residue wasmixed with dry ether, filtered off, dried, and recrystallizedfrom methanol–ether mixture.
Reference：
[1] Bulletin of the Chemical Society of Japan, 1992, vol. 65, # 2, p. 360 - 365
[2] Journal of Natural Products, 2009, vol. 72, # 1, p. 172 - 176
[3] European Journal of Medicinal Chemistry, 2018, vol. 145, p. 649 - 660
[4] Bioorganic and Medicinal Chemistry Letters, 2018, vol. 28, # 4, p. 637 - 641
[5] European Journal of Organic Chemistry, 2010, # 22, p. 4276 - 4287
[6] Chemistry - A European Journal, 2013, vol. 19, # 49, p. 16615 - 16624
[7] Bioorganic and Medicinal Chemistry, 2017, vol. 25, # 17, p. 4778 - 4799
[8] Helvetica Chimica Acta, 2000, vol. 83, # 2, p. 394 - 406
[9] Bulletin de la Societe Chimique de France, 1995, vol. 132, # 7, p. 709 - 720
[10] Patent: US2006/148902, 2006, A1, . Location in patent: Page/Page column 4
[11] Patent: EP1535900, 2005, A1, . Location in patent: Page/Page column 6
[12] Patent: WO2010/106550, 2010, A2, . Location in patent: Page/Page column 17
[13] Journal of Organic Chemistry, 2004, vol. 69, # 9, p. 3240 - 3241
[14] Chemical and Pharmaceutical Bulletin, 2006, vol. 54, # 8, p. 1170 - 1174
[15] Russian Journal of Bioorganic Chemistry, 2017, vol. 43, # 4, p. 456 - 462[16] Bioorg. Khim., 2017, vol. 43, # 4, p. 427 - 434,8
[17] Chemistry - A European Journal, 2016, vol. 22, # 9, p. 3148 - 3155
[18] European Journal of Medicinal Chemistry, 1986, vol. 21, # 4, p. 333 - 338
[19] Journal of Organic Chemistry, 1986, vol. 51, # 14, p. 2728 - 2735
[20] Agricultural and Biological Chemistry, 1987, vol. 51, # 2, p. 537 - 548
[21] Bioorganic and Medicinal Chemistry Letters, 2002, vol. 12, # 4, p. 637 - 640
[22] Journal of Medicinal Chemistry, 2006, vol. 49, # 24, p. 7215 - 7226
[23] Bioorganic and Medicinal Chemistry Letters, 2007, vol. 17, # 7, p. 1897 - 1902
[24] European Journal of Medicinal Chemistry, 2009, vol. 44, # 10, p. 3922 - 3929
[25] Patent: WO2005/121071, 2005, A1, . Location in patent: Page/Page column 14-16
[26] Patent: WO2011/157986, 2011, A1, . Location in patent: Page/Page column 17-18
[27] Chemistry - A European Journal, 2012, vol. 18, # 16, p. 4818 - 4822
[28] Green Chemistry, 2012, vol. 14, # 5, p. 1350 - 1356
[29] Advanced Synthesis and Catalysis, 2012, vol. 354, # 17, p. 3327 - 3332
[30] ACS Medicinal Chemistry Letters, 2015, vol. 6, # 7, p. 764 - 769
[31] Journal of Polymer Science, Part A: Polymer Chemistry, 2016, vol. 54, # 8, p. 1065 - 1077
[32] Tetrahedron, 2016, vol. 72, # 51, p. 8486 - 8492
[33] Chemical Communications, 2017, vol. 53, # 2, p. 447 - 450
4
[ 673-06-3 ]
[ 77-76-9 ]
[ 13033-84-6 ]
Reference：
[1] Journal of Medicinal Chemistry, 1980, vol. 23, # 11, p. 1232 - 1235
[2] Journal of the American Chemical Society, 1981, vol. 103, # 14, p. 4231 - 4239
[3] Tetrahedron Asymmetry, 2008, vol. 19, # 1, p. 67 - 81
5
[ 673-06-3 ]
[ 75-36-5 ]
[ 13033-84-6 ]
Reference：
[1] Organic Letters, 2016, vol. 18, # 11, p. 2560 - 2563
[2] European Journal of Organic Chemistry, 2013, # 26, p. 5838 - 5847
6
[ 67-56-1 ]
[ 18942-49-9 ]
[ 13033-84-6 ]
Reference：
[1] Journal of Organic Chemistry, 1999, vol. 64, # 25, p. 9294 - 9296
Reference：
[1] Bulletin of the Chemical Society of Japan, 1992, vol. 65, # 7, p. 1751 - 1754
[2] Advanced Synthesis and Catalysis, 2012, vol. 354, # 17, p. 3327 - 3332
With 2,6-dimethylpyridine; 1-[(1-(cyano-2-ethoxy-2-oxoethylidenaminooxy)dimethylamino-morpholino)]-uronium hexafluorophosphate In water at 20℃; for 2h; Green chemistry;
76%
With chloroformic acid ethyl ester In ethyl acetate
With 4-methyl-morpholine; PyBop In dichloromethane at 20℃; for 24h;
78%
Stage #1: N-Cbz-L-Phe With 1,3,5-trichloro-2,4,6-triazine; caesium carbonate In dichloromethane at 20℃; for 0.666667h; Inert atmosphere; Sonication;
Stage #2: D-phenylalanine methyl ester hydrochloride In dichloromethane Sonication; Inert atmosphere;
Synthesis of amidesusing TCT/PPh3 or TCT/PS-PPh3
General procedure: To a solution of TCT (0.0497 g, 0.27 mmol) in CH2Cl2was added PPh3 (0.0071 g, 0.027 mmol) at by the room temperature,followed carboxylic acid (0.27 mmol) and Cs2CO3 (0.1759g, 0.54 mmol). The resulting mixture was sonicated under N2 for thespecified time. The amine (0.30 mmol) was then added with further sonicationuntil completion of the reaction based on TLC. The crude mixture wasconcentrated under reduced pressure then purified by column chromatography(10-30% EtOAc in hexanes) to afford the pure product. In the cases whenTCT/PS-PPh3 was used, the above described procedure was followedusing PS-PPh3 (0.009 g, 0.027 mmol) in replacing PPh3. Aftercompletion of the reaction, the crude mixture was filtered and purified byfiltration through a short pad of silica. All known products were characterized by 1H-and 13C-NMR and their spectroscopic data were consistent with thosereported in the literature. HRMS data was given for the new compound (Table 1, entry 17).
With triethylamine; dicyclohexyl-carbodiimide In dichloromethane at 0℃; for 4h;
(R,R)-β-hydroxy-N-(Boc)valinylphenylalanine methyl ester[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
Stage #1: (R)-2-((tert-butoxycarbonyl)amino)-3-hydroxy-3-methylbutanoic acid With benzotriazol-1-ol; O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate In acetonitrile at 0℃; for 0.5h;
Stage #2: D-phenylalanine methyl ester hydrochloride With N-ethyl-N,N-diisopropylamine In acetonitrile at 20℃; for 48h; Further stages.;
With triethylamine; 1,1'-carbonyldiimidazole; In toluene; at 15 - 108℃; for 16 - 36h;Heating / reflux;Product distribution / selectivity;
A 500 ml flask was charged, under nitrogen, at room temperature with 150 ml toluene, 15.7g 1,1-carbonyldiimidazole, and 15.0g trans-4-isopropylcyclohexylcarboxylic acid. The mixture thus obtained was heated to 45+/-5 C, where after the same was left cooling down to room temperature (20+/-5 C) and 15 ml triethyl ammine was charged. Thereafter 19.05g D-phenylalanine methyl ester hydrochloride was added in small amounts. After completion of the addition, the mixture was heated to reflux (108 C) and maintained at reflux for 16 hours. A TLC control reavaels that the D-phenylalanine methyl ester still unreacted is less than 2%. Thereafter, reaction mixture was cooled to 70+/-5 and washed three times with 100 ml deionized water. To the washed organic solution, 150 ml deionized water, 23.5g 30% NaOH and 1 drop of Aliquat phase transfer catalyst were added. The biphasic mixture thus obtained was heated for 4 hours to 45+/-5 C. Thereafter, the phases were separated at 70+/-5 C and the aqueous phase was diluted with 75 ml of deionized water, 0.3g of carbon LSM was added and filtration on a decalite panel was carried out. The nateglinide was then precipitated, at 45 C trough addition of 10% aqueous HCl solution until a pH of 2.5+/-5 was reached. The precipitate was washed at rt (20C) and washed with water until disappearance of chlorides. 22.7 g of dried product were obtained, corresponding (compared to 27,96g of theoretical yield) to an effective yield of 81.2%. The product thus obtained was tested through DSC analysis , revealing that a mixture of B-form and H-form had been obtained. The product was however of high purity according to HPLC analysis. The product may thus be converted into the desired pure polymorphic form through methods described herein or known in the art.EXAMPLE 7Preparation of nateglinide according to the first embodiment of the invention (i.e. carrying out step i) in an organic solvent non-miscible with water and omitting optional step ia)). Example has been carried out exactly as example 6 above, except for the fact that the condensation of the imidazolide derived from the acid with D-phenylalanine methyl ester hydrochloride was conducted at 40-45C for 36 hours (c.f. above where 16 hours at reflux were applied). Likewise, with these modified conditions, a residual amount of unreacted 2% D-phenyl alanine methyl ester (checked through TLC) was reached. After working up as above, an effective yield of 85.83% was reached. The product thus obtained was tested through DSC analysis, revealing that a mixture of B-form and H-form had been obtained. The product was however of high purity according to HPLC analysis. The product may thus be converted into the desired pure polymorphic form through methods described herein or known in the art.
15.0 g (0.0881 mol) of trans 4-isopropylcyclohexancarboxylic acid were put into an anhydrous flask under nitrogen atmosphere together with 225 ml of toluene. Under stirring 10.9 g (0.108 mol) of triethylamine were then added, thus obtaining a thick suspension, which was cooled to 0+/-5C while maintaining under stirring. To this suspension 11.7 g (0.0969 mol) of pivaloyl chloride were added drop wise, maintaining temperature in the range 0+/-5C. The reaction mixture was made to react for 30 minutes at 0+/-5C, and then temperature is brought up to 20+/-5C and maintained for 2 hours. 10.9 g (0.108 mol) of triethylamine, and then 19.05 g (0.0881 mol) of D-phenylalanine methyl ester hydrochloride prepared as described above in Example 1 were added to the reaction mixture portion wise in 30 minutes, which was then made to react at 20+/-5C for 18 hours. Temperature was brought up to 75+/-5C and, maintaining temperature in this range, 2 washings with a 5% aqueous solution of sodium carbonate (2 x 175 ml) are carried out. The organic phases were merged and added with 225 ml of deionised water, 13.5 g of 30% solution of sodium hydroxide and a drop of Aliquat. The reaction mixture was stirred at 50+/-5C for 5 hours. Once reaction was completed, the aqueous phase was separated, added with 0.1 g of carbon LSM and filtered on a dicalite panel. The thus obtained filtrate was put in a flask and at temperature of 35/40C HCl 10% was added until pH 2.5+/-0.5. The suspension is cooled to 25-30 C, maintained at this temperature for 1 hour, and then filtered and washed with deionised water until complete disappearance of chlorides. 62.1 g of wet product and 25.45 g of dry product were obtained (yield = 91.0%). A DSC analysis has been carried out on the dry product, revealing that a mixture of B-form and H-form had been obtained. The product was however of high chemical purity according to HPLC analysis. The product may thus be converted into the desired pure polymorphic form through methods described herein or known in the art. EXAMPLE 3Preparation of nateglinide according to the first embodiment of the invention (i.e. carrying out step i) in an organic solvent non-miscible with water and omitting optional step ia)). The procedure described above in Example 1 was repeated with the same reagents and under the same operative conditions, but diminishing the amount of toluene, from 225 to 150 ml, thus obtaining 24.2 g of dry end-product (yield = 86.6%). A DSC analysis has been carried out on the dry product , revealing that a mixture of B-form and H-form had been obtained. The product was however of high chemical purity according to HPLC analysis. The product may thus be converted into the desired pure polymorphic form through methods described herein or known in the art.
trans-4-isopropylcyclohexanecarboxylic acid[ No CAS ]
[ 13033-84-6 ]
N-(trans-4-isopropylcyclohexyl-1-carbonyl)-d-phenylalanine methyl ester[ No CAS ]
[ 554-68-7 ]
Yield
Reaction Conditions
Operation in experiment
90.07%
A 11-flask, at room temperature, under nitrogen and equipped with internal thermometer, stirrer and dropping funnel, was charged with trans-4-isopropylcyclohexylcarboxylic acid (30 g, 0.1762 mol) and 300 ml acetone. Upon total dissolution of the acid, triethylammine (21.8 g, 0.2152 mol) was added (no change of temperature was observed). The solution thus obtained was then cooled to 5+/-5 C. and pivaloyl chloride (23.4 g, 0.1938 mol) was added dropwise within 30 minutes and without exceeding the temperature interval. Due to the precipitation of triethylammine hydrochloride, a suspension was obtained. Once the addition was completed, the temperature was kept at 5+/-5 C. for 30 minutes, whereafter it was left standing until room temperature (20+/-5 C.) was reached (about three hours). At this point, a second charging with triethylammine (21.8 g, 0.2152 mol) was made and D-phenylalanine methyl ester hydrochloride (38.1 g, 0.1762 mol) was added in small amounts, avoiding excessive exothermic heating up of the reaction mixture (some initial exothermic heating was due to the setting free of base). The mixture thus obtained thickened considerably due to the formation of another equivalent of triethylammine hydrochloride. The reaction mixture was left standing at room temperature (20+/-5 C.) overnight. The next morning, a quantitative TLC was conducted such as to trace down eventual traces of residual, non-reacted phenyl alanine methyl ester (not detectable). The suspension was thick but could still be stirred. The product thus obtained was then precipitated through the addition of 300 ml of deionized water to the suspension. The suspension was then cooled for at least two hours to 0+/-5 C., filtered and washed three times with 50 ml of deionized water, 73.0 g of wet product, corresponding to 52.6 g of the dry, white intermediate (nateglinide methyl ester) were obtained (theoretical yield: 58.4 g, effective yield: 90.07%). Next, a 2 l-flask was charged at room temperature with 52.0 g nateglinide methyl ester, 260 ml toluene, 520 ml deionized water, one drop of Aliquat 336 (tricaprylmethyl ammonium chloride) and 35.2 g of aqueous potassium hydroxide (50% by weight solution). Under vigorous stirring, the content of the flask was heated up to 45-50 C. (the two phases were still clear); after 5 hours, hydrolysis of the methyl ester was completed. The two phases were thus separated at 50 C. and the toluene (on top) was discarded, whereas 1.0 g of carbon LSM was added to the aqueous phase which was then filtered through a dicalite panel. The thus obtained clear and colourless solution was then cooled to 15-20 C. Nateglinide was then precipitated from the solution through the addition of 120 ml aqueous HCl (10%), such as to impart a pH of 2.5+/-0.5 carefully controlling the temperature interval of 15 C. to 20 C. and without exceeding the same. After the precipitation, the product was filtered and washed until disappearance of chlorides. 94.0 g wet product equivalent 48.3 g dry product, natgelinide B-form was obtained (theoretical yield: 49.8 g; effective yield 97%). A DSC analysis has been carried out on the dry product obtaining the peak specific of the nateglinide in B-form (128.97 C.).
78.42%
A 1 l-flask, at room temperature, under nitrogen and equipped with internal thermometer, stirrer and dropping funnel, was charged with trans-4-isopropylcyclohexylcarboxylic acid (30 g, 0.1762 mol) and 300 ml acetone. Upon total dissolution of the acid, triethylammine (21.8 g, 0.2152 mol) was added (no change of temperature was observed). The solution thus obtained was then cooled to 0+/-5 C. and ethyl cloroformiate (18.6 ml, 0.1938 mol) was added dropwise within 30 minutes and without exceeding the temperature interval. Once the addition was completed, the mixture was left standing until room temperature (20+/-5 C.) was reached and stirred for about three hours. At this point, a second charging with triethylammine (21.8 g, 0.2152 mol) was made and D-phenylalanine methyl ester hydrochloride (38.1 g, 0.1762 mol) was added in small amounts, avoiding excessive exothermic heating up of the reaction mixture (some initial exothermic heating was due to the setting free of base). The mixture thus obtained thickened considerably due to the formation of another equivalent of triethylammine hydrochloride. The reaction mixture was left stirring at 25+/-5 C. overnight. The next morning, a quantitative TLC was conducted such as to trace down eventual traces of residual, non-reacted phenyl alanine methyl ester (less than 2%-note that this value, unlike in the case of the use of pivaloyl chloride reported in example 5 above-remains the same even, if the reaction time is extended well beyond the value reported here). The suspension was thick but could still be stirred. The product thus obtained was then precipitated through the addition of 300 ml of deionized water to the suspension. The suspension was then cooled for at least two hours to 0+/-5 C., filtered and washed three times with 50 ml of deionized water, 66.0 g of wet product, corresponding to 45.8 g of the dry, white intermediate (nateglinide methyl ester) were obtained (theoretical yield: 58.4 g, effective yield: 78.42%). Next, a 2 l-flask was charged at room temperature with 45.8 g nateglinide methyl ester, 230 ml toluene, 520 ml deionized water, one drop of Aliquat 336 (tricaprylmethyl ammonium chloride) and 35.2 g of aqueous potassium hydroxide (50% by weight solution). Under vigorous stirring, the content of the flask was heated up to 45-50 C. (the two phases were still clear); after 5 hours, hydrolysis of the methyl ester was completed. The two phases were thus separated at 50 C. and the toluene (on top) was discarded, whereas 1.0 g of carbon LSM was added to the aqueous phase which was then filtered through a dicalite panel. The thus obtained clear and colourless solution was then cooled to 15-20 C. Nateglinide was then precipitated from the solution through the addition of 120 ml aqueous HCl (10%), such as to impart a pH of 2.5+/-0.5 carefully controlling the temperature interval of 15 C. to 20 C. and without exceeding the same. After the precipitation, the product was filtered and washed until disappearance of chlorides. After drying of the wet product equivalent 43.25 g dry product, natgelinide B-form was obtained corresponding to an effective yield of 98.6% for the sole hydrolysis step. A DSC analysis has been carried out on the dry product obtaining the peak specific of the nateglinide in B-form (130.44 C.).
A. (R)-7-Bromo-2,3,4,5-tetrahydro-3-(phenylmethyl)-1H-1,4-benzodiazepin-2,5-dione A stirred solution of bromoisatoic anhydride (150 g, 0.62 mol) and D-phenylalanine methyl ester hydrochloride (127.3 g, 0.59 mol) in the presence of 4-dimethylaminopyridine (2 g) in pyridine (1500 mL) was heated at reflux under argon for 3 days. The pyridine was removed in vacuo and the residue was dissolved in methylene chloride (3L). This solution was washed with 10% HCl solution and brine. The organic solution was dried and concentrated in vacuo to a small volume. The solid thus formed was collected and dried to give 152 g (71%) of Compound A, mp 242-243 C.
4
EXAMPLE 4: SYNTHESIS OF D-PHENYLALANINE METHYLESTER APPENDED NAPHTHALENEDIIMIDE (D-NDI or NDI 3B): SYNTHESIS OF D-PHENYLALANINE METHYLESTER HYDROCHLORIDE:Anhydrous methanol (50 mL) is taken in a 100 mL 2-necked round bottom flask fitted with a reflux condenser and an additional dropping funnel and cooled to ice temperature. Acetyl chloride (3 mL) is added drop wise through the dropping funnel. After 15 min, D-phenylalanine (3 g, 18.16 mmol) is added and the reaction mixture is refluxed at 70 °C for overnight. The reaction mixture is vacuo dried to obtain D- phenylalanine methylester hydrochloride in quantitative yield and used for further reaction without purification. 1,4,5,8-naphthalenetetracarboxylic dianhydride (200 mg, 0.74 mmol) and D- phenylalanine methylester hydrochloride (322 mg 1.49 mmol) is suspended in DMF (20 mL) in a 100 mL round bottom flask. To this suspension triethylamine (0.6 mL) is added under inert atmosphere. The reaction mixture is refluxed at 75 °C for 24 h. Solvent is evaporated under vacuo and the residue is purified by column chromatography (1 % methanol in chloroform). Yield 71%. .H NMR (400 MHz, CDC13): δ 8.63 (s, 4H), 7.1 (m, 10H), 6.02 (dd, 2H, J = 4Hz, 4Hz), 3.77 (s, 6H), 3.73 (dd, 2H, J = 8Hz, 4Hz), 3.50 (dd, 2H, J= 12 Hz, 4 Hz). 13C NMR (400 MHz, CDCI3) δ 169.6, 162.4, 136.9, 131.3, 129.2, 128.5, 126.9, 126.8, 126.4, 54.9, 52.8, 34.9. MS (EI): m/z = 590.17 [M]+ for C34H26N2O8. Elemental analysis: Found: C, 69.10; H, 4.49; N, 4.78; Calcd: C, 69.15; H, 4.44; N, 4.74 for C34H26N2O8.
31.2 g (97%)
With thionyl chloride In methanol
107.a 107a.
107a. (D)-Phenylalanine methyl ester hydrochloride (D)-Phenylalanine (25.0 g) was dissolved in 450 mL of methanol and 22 mL thionyl chloride were slowly added at -20° C. The mixture was refluxed for 1 h, followed by evaporation of the volatiles to give 31.2 g (97%) of the title compound as a white solid. M.p. 155-163° C.
With 1-hydroxybenzotriazol-hydrate; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine In dichloromethane at 20℃; for 16h;
With sodium hydrogencarbonate In dichloromethane at 0 - 20℃; for 24h;
98%
With sodium hydrogencarbonate In dichloromethane; water at 5 - 20℃; for 24h;
4.1.1. Methyl 2-(2-(2-acetamidophenyl)-2-oxoacetamido)acetate (2a)
General procedure: To a stirred solution of the N-acetylisatin (0.50 g, 2.6 mmol) in dichloromethane (10 mL) was added a mixture of glycine methyl ester hydrochloride (1.10 g, 8.9 mmol) and saturated sodium hydrogen carbonate solution (3 mL) in water (7 mL) at 5 °C. The reaction mixture was warmed to room temperature and stirred for 24 h. The organic layer was diluted with dichloromethane (20 mL) and extracted with aqueous hydrochloric acid (0.5 M, 15 mL) and water (20 mL). The organic extract was dried over anhydrous Na2SO4, filtered and concentrated under vacuum. The crude product was purified by gravity column chromatography over silica with dichloromethane to give the title compound 2a as an off-white solid (0.45 g, 62%).
With triethylamine; In dichloromethane; at 0℃; for 2h;Inert atmosphere;
General procedure: To a suspension of L-phenylalanine methyl ester hydrochloride (S)-1 (20.0g, 92.7mmol) in CH2Cl2 (400mL) were added acetyl chloride (7.9mL, 111.3mmol) and Et3N (32.2mL, 231.8mmol) drop wise under argon. The reaction mixture was stirred at 0C for 2h and poured into water. The organic layer was separated, washed with brine (250mL), dried over anhydrous Na2SO4, and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, PET/EtOAc=5:1, v/v) to afford compound (S)-2 (20.0g, 98%) as a white solid.
EXAMPLE 5 Preparation of nateglinide in B-form according to the second embodiment of the invention (i.e. carrying out step i) in a first organic solvent miscible with water and carrying out step ia) under dissolution in a second organic solvent non-miscible with water). A 1l-flask, at room temperature, under nitrogen and equipped with internal thermometer, stirrer and dropping funnel, was charged with trans-4-isopropylcyclohexylcarboxylic acid (30g, 0.1762 mol) and 300 ml acetone. Upon total dissolution of the acid, triethylammine (21.8g, 0.2152 mol) was added (no change of temperature was observed). The solution thus obtained was then cooled to 5+/-5 C and pivaloyl chloride (23.4g, 0.1938 mol) was added dropwise within 30 minutes and without exceeding the temperature interval. Due to the precipitation of triethylammine hydrochloride, a suspension was obtained. Once the addition was completed, the temperature was kept at 5+/-5 C for 30 minutes, whereafter it was left standing until room temperature (20+/- 5 C) was reached (about three hours). At this point, a second charging with triethylammine (21.8 g, 0.2152 mol) was made and D-phenylalanine methyl ester hydrochloride (38.1 g, 0.1762 mol) was added in small amounts, avoiding excessive exothermic heating up of the reaction mixture (some initial exothermic heating was due to the setting free of base). The mixture thus obtained thickened considerably due to the formation of another equivalent of triethylammine hydrochloride. The reaction mixture was left standing at room temperature (20+/- 5 C) overnight. The next morning, a quantitative TLC was conducted such as to trace down eventual traces of residual, non-reacted phenyl alanine methyl ester (not detectable). The suspension was thick but could still be stirred. The product thus obtained was then precipitated through the addition of 300 ml of deionized water to the suspension. The suspension was then cooled for at least two hours to 0+/-5 C, filtered and washed three times with 50 ml of deionized water, 73.0 g of wet product, corresponding to 52.6 g of the dry, white intermediate (nateglinide methyl ester) were obtained (theoretical yield: 58.4g, effective yield: 90.07%).
78.42%
EXAMPLE 8: Preparation of nateglinide in B-form according to the second embodiment of the invention (i.e. carrying out step i) in a first organic solvent miscible with water and carrying out step ia) under dissolution in a second organic solvent non-miscible with water). A 1l-flask, at room temperature, under nitrogen and equipped with internal thermometer, stirrer and dropping funnel, was charged with trans-4-isopropylcyclohexylcarboxylic acid (30g, 0.1762 mol) and 300 ml acetone. Upon total dissolution of the acid, triethylammine (21.8g, 0.2152 mol) was added (no change of temperature was observed). The solution thus obtained was then cooled to 0+-5 C and ethyl cloroformiate (18.6 ml, 0.1938 mol) was added dropwise within 30 minutes and without exceeding the temperature interval. Once the addition was completed, the mixture was left standing until room temperature (20+- 5 C) was reached and stirred for about three hours. At this point, a second charging with triethylammine (21.8 g, 0.2152 mol) was made and D-phenylalanine methyl ester hydrochloride (38.1 g, 0.1762 mol) was added in small amounts, avoiding excessive exothermic heating up of the reaction mixture (some initial exothermic heating was due to the setting free of base). The mixture thus obtained thickened considerably due to the formation of another equivalent of triethylammine hydrochloride. The reaction mixture was left stirring at 25+- 5 C overnight. The next morning, a quantitative TLC was conducted such as to trace down eventual traces of residual, non-reacted phenyl alanine methyl ester (less than 2% -note that this value, unlike in the case of the use of pivaloyl chloride reported in example 5 above- remains the same even, if the reaction time is extended well beyond the value reported here). The suspension was thick but could still be stirred. The product thus obtained was then precipitated through the addition of 300 ml of deionized water to the suspension. The suspension was then cooled for at least two hours to 0+-5 C, filtered and washed three times with 50 ml of deionized water, 66.0 g of wet product, corresponding to 45.8 g of the dry, white intermediate (nateglinide methyl ester) were obtained (theoretical yield: 58.4g, effective yield: 78.42%).
Stirred D-phenyl alanine methyl ester hydrochloride ( 0.0 grams, 0.046 moles), trans-4- isopropylcyclohexanecarboxylic acid (8.3 grams, 0.049 moles) and TBTU (16.4 grams, 0.051 moles) in dichloromethane (100 ml) at 25C under nitrogen atmosphere. The reaction mass was cooled to 0C+/- 3C. Nu,Nu'-Diisopropyl ethyl amine (25.0ml, 0.14 moles) was added drop wise maintaining temperature below 5C. Raised the temperature of reaction mass to 15C and stirred for 3 hours. The reaction mixture was washed with (2 x100 ml) water. The MDC layer was dried over sodium sulphate and concentrated at atmospheric pressure. To the residue was added methanol (50.0 ml) and stirred for 1.0 hour at 25C +/- 3C. The solid was isolated by filtration, washed with methanol (50 ml), and dried at 50C to yield nateglinide methyl ester.Yield = 13.25 gramsEfficiency = 86.0% Chiral purity = 100.0%
In a 100 mL round-bottomed flask 9.4 mL (120 mmol) pyridine and 11.0 mL (120 mmol) acetic anhydride were combined at 0 C. Next, 5.0 g (23 mmol) d-Phe-OMe HCl was dissolved in the above solution and the ice bath was removed. The reaction was allowed to proceed overnight at room temperature, turning a rich purple color. The reaction was quenched by the addition of 100 mL water/ice slurry. The resulting solution was again allowed to return to room temperature and then extracted four times with CH2Cl2. The extracts were pooled and then rinsed three times each with saturated NaHCO3 solution, 0.1 M HCl solution, and water. The methylene chloride solution was dried over MgSO4 and evaporated to dryness under reduced pressure, yielding 4.5 g (20 mmol, 87%) of N-Ac-d-Phe-OMe as a white solid. 1H NMR ([2H]chloroform, tetramethylsilane (TMS) = 0.0 ppm): δ 1.98 (s, 3H), δ 3.12 (m, 2H), δ 3.73 (s, 3H), δ 4.89 (m, 1H), δ 5.90 (broad, 1H), δ 7.09 (m, 2H), δ 7.27 (m, 3H).
General procedure: Procedure A: A solution of a phenylacetic acid (3.7 mmol), DMAP (5.55 mmol) and DCC (5.55 mmol) in THF (40-70 ml) was stirred at room temperature (rt) for 30 min. The hydrochloride salt of the carboxy protected aminoacid (3.7 mmol) was added and the solution was stirred for 48 h at rt. The crude mixture was filtered over celite and the solvent was removed in vacuo. The product was purified by flash chromatography. The methyl ester (1eq) was dissolved in methanol. A solution of NaOH (1N, 17 ml) was added and the reaction mixture was stirred for 1 h at rt. H2O was added and methanol only was evaporated under reduced pressure. The pH was reduced to 2 using HCl solution 1N. The crude material was extracted with ethyl acetate and the organic phase was dried with Na2SO4 anhydrous. The solvent was removed in vacuo to afford 4 without any further purification. Procedure B: A solution of phenylacetic acid (6 mmol), the hydrochloride salt of the carboxy protected aminoacid (6 mmol), DMAP (3 mmol) and DCI (10 mmol) in (50-80 ml) was stirred at r.t. for 14 h. The crude mixture was filtered over celite and the solvent was removed in vacuo. The product was purified by flash chromatography. Treatment with NaOH as reported in procedure A.
methyl ester N-mycophenoyl-D-phenylalanine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
69%
With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In N,N-dimethyl-formamide; at 0 - 20℃; for 50h;
General procedure: Mycophenolic acid 1 (0.156 mmol), methyl ester amino acid hydrochloride 9 (0.178 mmol) and DMAP (0.178 mmol) was dissolved in dry DMF (3 mL). A reaction mixture was cooled to 0 C in an ice bath and with stirring was added EDCI (0.17053 mmol). The solution was stirred at 0 C for 2 h and after that time left at room temperature for 48 h. Progress of the reaction controlled by TLC plates. After completion of the reaction solution was poured into water (15 mL), extracted with ethyl acetate. The organic layer was separated, dried (MgSO4), filtered and concentrated. The crude products were purified by chromatography (SiO2). Structures of synthesized derivatives 10 were established by spectroscopic methods (1H NMR, 13C NMR, MS, HPLC-MS, optical rotation and melting point). Ester hydrolysis: the methyl ester 10 was dissolved in MeOH (30 mL/g), and a solution of LiOH*H2O (3 mol equiv - 2-fold more for 10d and 10e) in an equal volume of water was added. When hydrolysis was complete (48 h), the solution was added to water and washed with ether. The aqueous phase was acidified with 2 N HCl and extracted with EtOAC. The extract was dried with MgSO4 and evaporated, and the residue was recrystallized [17].
Stage #1: <i>N</i>-<i>tert</i>-butoxycarbonyl-<i>L</i>-phenylalanine With 1,3,5-trichloro-2,4,6-triazine; caesium carbonate In dichloromethane at 20℃; for 0.666667h; Inert atmosphere; Sonication;
Stage #2: D-phenylalanine methyl ester hydrochloride In dichloromethane Sonication; Inert atmosphere;
Synthesis of amidesusing TCT/PPh3 or TCT/PS-PPh3
General procedure: To a solution of TCT (0.0497 g, 0.27 mmol) in CH2Cl2was added PPh3 (0.0071 g, 0.027 mmol) at by the room temperature,followed carboxylic acid (0.27 mmol) and Cs2CO3 (0.1759g, 0.54 mmol). The resulting mixture was sonicated under N2 for thespecified time. The amine (0.30 mmol) was then added with further sonicationuntil completion of the reaction based on TLC. The crude mixture wasconcentrated under reduced pressure then purified by column chromatography(10-30% EtOAc in hexanes) to afford the pure product. In the cases whenTCT/PS-PPh3 was used, the above described procedure was followedusing PS-PPh3 (0.009 g, 0.027 mmol) in replacing PPh3. Aftercompletion of the reaction, the crude mixture was filtered and purified byfiltration through a short pad of silica. All known products were characterized by 1H-and 13C-NMR and their spectroscopic data were consistent with thosereported in the literature. HRMS data was given for the new compound (Table 1, entry 17).
75%
Stage #1: <i>N</i>-<i>tert</i>-butoxycarbonyl-<i>L</i>-phenylalanine; D-phenylalanine methyl ester hydrochloride With benzotriazol-1-ol; N-ethyl-N,N-diisopropylamine In dichloromethane for 0.5h; Cooling with ice;
Stage #2: With 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In dichloromethane for 12h;
Stage #1: <i>N</i>-<i>tert</i>-butoxycarbonyl-<i>L</i>-phenylalanine; D-phenylalanine methyl ester hydrochloride With benzotriazol-1-ol; N-ethyl-N,N-diisopropylamine In dichloromethane for 0.5h; Cooling with ice;
Stage #2: With 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In dichloromethane for 12h;
With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine; In dichloromethane; for 5h;
Peptide coupling 1: Adapting the protocol of Mbofana et al.,10 <strong>[71066-00-7]Boc-Aic-OH</strong> (0.305 g, 1.10 mmol, 1.00equiv), H-D-Phe-OCH3?HCl (0.240 g, 1.10 mmol, 1.00 equiv), HOBt?H2O (0.252 g, 1.65 mmol, 1.50 equiv), andEDC?HCl (0.252 g, 1.32 mmol, 1.20 equiv) were suspended in anhydrous CH2Cl2 (7.5 mL, 0.15 M) followed bydropwise addition of DIPEA (0.23 mL, 1.3 mmol, 1.1 equiv). After 5 h, the pale yellow reaction mixture wastransferred to a separatory funnel, diluted with EtOAc (40 mL), and washed sequentially with 10% aqueous (w/v)citric acid (2 x 20 mL), saturated aqueous NaHCO3 (1 x 20 mL), and saturated aqueous NaCl (1 x 40 mL). Theorganics were dried over Na2SO4, filtered, and concentrated to afford crude Boc-Aic-D-Phe-OMe (0.467 g, 97%yield) as an off white solid. The identity of Boc-Aic-D-Phe-OMe was confirmed by UPLC-MS. (ESI) m/z for[M+Na]+ C25H30N2O5Na requires 461.21, observed 461.26.Peptide coupling 2: The resulting solid obtained from peptide coupling 1 was dissolved in 4.0 N HCl in1,4-dioxane (2.6 mL, 11 mmol, 10 equiv) and stirred vigorously for 1 hour. Excess HCl was evaporated by bubblingN2 through the solution for 30 minutes, and the remaining solvent removed in vacuo to afford the Boc-Aic-D-Phe-OMe?HCl as a white solid, which was dried thoroughly under reduced pressure. The crude residue, Boc-D-Pro-OH(0.228 g, 1.06 mmol, 1.00 equiv), HOBt?H2O (0.243 g, 1.58 mmol, 1.50 equiv), and EDC?HCl (0.243 g, 1.25 mmol,1.20 equiv) were suspended in anhydrous CH2Cl2 (7.5 mL, 0.15 M). To the resulting cloudy mixture was addedDIPEA (0.22 mL, 1.3 mmol, 1.1 equiv) dropwise. The resulting pale yellow solution was stirred overnight at roomtemperature. After ~10 h, the reaction mixture was transferred to a separatory funnel, diluted with EtOAc (40 mL),and washed sequentially with 10% aqueous (w/v) citric acid (2 x 20 mL), saturated aqueous NaHCO3 (1 x 20 mL),and saturated aqueous NaCl (1 x 20 mL). The organics were dried over Na2SO4, filtered, and concentrated in vacuoto afford crude Boc-D-Pro-Aic-D-Phe-OMe (0.566 g, 99% yield) as a white solid. The identity of Boc-D-Pro-Aic-DPhe-OMe was confirmed by UPLC-MS. (ESI) m/z for [M+Na]+ C30H37N3O6Na requires 558.26, observed 558.39.To a 100 mL round bottom flask containing Boc-D-Pro-Aic-D-Phe-OMe in THF (11.5 mL) was slowlyadded a solution of LiOH (63 mg, 2.6 mmol, 2.5 equiv) in H2O (8.2 mL) at 0 C. The reaction mixture was allowedto warm to room temperature and stirred vigorously for 4 hours. The reaction was acidified to pH ~ 1-2 withaqueous 1 N HCl, transferred to a separatory funnel, and extracted with EtOAc (3 x 40 mL). The combined organicswere washed with saturated aqueous NaCl (1 x 40 mL), dried over Na2SO4, filtered and concentrated in vacuo toafford the crude acid as an off-white flaky solid (0.551 g, 99%). The identity of Boc-D-Pro-Aic-D-Phe-OH wasconfirmed by UPLC-MS. (ESI) m/z for [M-H]- C29H34N3O6 requires 520.24, observed 520.21.Installation of C-Terminal protecting group: To a 250 mL round bottom flask containing Boc-D-Pro-Aic-DPhe-OH (0.550 g, 1.05 mmol, 1.0 equiv) and magnetic stir bar was added HOBt?H2O (0.243 g, 1.58 mmol, 1.50equiv), EDC?HCl (0.243 g, 1.25 mmol, 1.2 equiv), and dimethylamine hydrochloride (86 mg, 1.05 mmol, 1.00equiv). The resulting solid mixture was suspended in anhydrous CH2Cl2 (5.0 mL, 0.20 M), followed by dropwiseaddition of DIPEA (0.22 mL, 1.3 mmol, 1.1 equiv) at room temperature, producing a pale yellow solution. After 16h, the reaction mixture was transferred to a separatory funnel, diluted with EtOAc (40 mL), and washed sequentiallywith 10% w/v citric acid (2 x 20 mL), saturated aqueous NaHCO3 (1 x 20 mL), and saturated aqueous NaCl (1 x 20mL). The organics were dried over Na2SO4, filtered, and concentrated in vacuo. The crude product was purified viareversed-phase flash-column chromatography using a Biotage Isolera One flash purification system (SNAP 60g KPC-18-SH, CV = 66 mL, 1 CV at 5% CH3CN/H2O, 5-100% CH3CN/H2O linear gradient over 14 CV, then 100%CH3CN over 6 CV, 65 mL min-1 flowrate). The title compound SI-2 was obtained as a white foam (0.48 g, 80%yield over five steps)
Stage #1: D-phenylalanine methyl ester hydrochloride; benzaldehyde With triethylamine In toluene at 20℃; for 1h; Molecular sieve;
Stage #2: With sodium tetrahydroborate In methanol at 0℃; for 0.166667h;
4.5 5.4.5 (+)-Methyl (2R)-2-(benzylamino)-3-phenylpropionate [(R)-9]
General procedure: A mixture of ester (S)-8·HCl (5.0 g, 23.2 mmol), NEt3 (3.2 mL, 23.0 mmol), benzaldehyde (2.3 mL, 23.0 mmol), molecular sieves 5 Å (30 g) and toluene (250 mL) was stirred at RT for 1 h. Then it was filtered and the filtrate was concentrated in vacuo. The oily residue was dissolved in methanol (250 mL) and NaBH4 (431 mg, 11.4 mmol) was added under cooling with ice. The mixture and stirred for 10 min at 0 °C. Methanolic HCl (100 mL) was added and the mixture was concentrated in vacuo. The residue was dissolved in saturated NaHCO3 solution (200 mL) and the solution was extracted with Et2O (3 * 100 mL). The organic layer was dried (K2CO3), filtered, concentrated in vacuo and the oily residue was purified by fc (8 cm, cyclohexane/ethyl acetate 80/20, 18 cm, 40 mL, Rf = 0.23).
(R)-methyl (5-methylfuran-2-carbonyl)phenylalaninate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
81%
General procedure: Furan-2-carboxylic acid, thiophene-2-carboxylic acid, 5-methylthiophene-2-carboxylic acid, benzofuran-2-carboxylic acid, benzothiophene-2-carboxylic acid, and amino acid ester hydrochlorides were obtained from commercial supplies and were used without further purification. To a two?necked flask, an amino acid ester hydrochloride (1.1 mmol), 1?ethyl?3?dimethylaminopropylcarbodiimide hydrochloride (EDC, 0.29 g, 1.5 mmol), HOBt (0.20 g, 1.5 mmol), Et3N (0.42 mL, 3.0 mmol), and CHCl3 or DMF (2.2 mL) were added, and the mixture was stirred at 0 °C for 10 min. Furan-2-carboxylic acid or thiophene-2-carboxylic acid dissolved in DMF (2.2 mL) was added, and then stirred for 17 h. The reaction mixture was diluted with water and extracted with EtOAc (3 x 20 mL). The organic phase was then washed with 3 N HCl aq. (3 x 20 mL), saturated NaHCO3 aq. (3 x 20 mL), and brine (20 mL). The combined organic phases were dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (eluent: hexane/EtOAc = 1/1) to obtain the product. The purity of the product was confirmed by 1H-NMR. Stereochemistry of the final product was measured by high-performance liquid chromatography (HPLC) with a chiral column (Compound 16). The chart is shown in the supporting information.
With benzotriazol-1-ol; triethylamine; dicyclohexyl-carbodiimide In dichloromethane at 0 - 20℃;
3.3.1. (R)-2-[(S)-1-(Benzyloxycarbonyl)pyrrolidine-2-carboxamido]-3-phenylpropanoic acid (12)
To a stirred solution of Cbz-proline (8) (1.25 g, 5.00 mmol) in dry CH2Cl2 (20 mL) at 0° C, 1-hydroxybenzotriazole (HOBt) (676 mg, 5.00 mmol), (R)-methylphenylalaninate hydrochloride (10) (1.08 g,5.00 mmol), Et3N (0.700 mL, 5.00 mmol) and dicyclohexylcarbodiimide (DCC) (1.03 g, 5.00 mmol) were added consecutively. The reaction mixture was left stirring at 0° C for 1 h and then warmed to room temperature and left stirring for 18 h. The solvents were evaporated under reduced pressure and the crude product was dissolved in EtOAc (30 mL). After filtration, the organic layer was washed with aq. H2SO4 (5%, 20 mL), H2O (20 mL), aq. NaHCO3 (5%, 20 mL) and brine (20 mL). After evaporation of the solvent, the crude ester was purified using column chromatography eluting with pet. ether/EtOAc (50:50). White solid; 1.95 g, 95% yield; Rf (pet.ether/EtOAc 1:1) 0.20; mp 69-72 C; [a]D -11.3 (c 1.0, MeOH); 1HNMR (200 MHz, CDCl3) d 7.38-7.02 (10H, m, ArH), 6.35 (1H, br s,NH), 5.21 (2H, s, OCH2), 4.87-4.81 (1H, m, NCH), 4.41-4.35 (1H, m,NCH), 3.73 (3H, s, OCH3), 3.50-3.41 (2H, m, NCH2), 3.14-3.00 (2H,m, CH2Ph), 2.24-2.06 (2H, m, CH2), 1.93-1.77 (2H, m, CH2); 13CNMR (50 MHz, CDCl3) d 171.6, 171.3, 155.8, 136.3, 135.7, 129.2, 129.0, 128.0, 127.8, 127.0, 67.2, 60.6, 52.2, 46.9, 37.6, 31.0, 28.8, 24.3. To a stirred solution of the protected dipeptide (0.20 g, 0.48 mmol) in dioxane (1 mL), an aq. solution of NaOH (2 N, 3 mL) was added. The reaction mixture was left stirring for 1 h at room temperature. The crude mixture was extracted with Et2O (2x20 mL). The aqueous layer was acidified with aq. HCl (2 N) until pH 2 and the crude product was extracted with EtOAc (2x15 mL). The combined organic layers were washed with H2O (30 mL), dried and the solvent was removed under reduced pressure. 12 wasi solated as a white solid; 0.14 g, 76% yield; Rf (pet. ether/EtOAc 30:70) 0.05; mp 53-56 C°; [a]D -76.7 (c 2.5, CHCl3); 1H NMR (200 MHz, CDCl3) d 9.40 (1H, br s, COOH), 7.26-7.01 (10H, m, ArH),6.79 (1H, br s, NH), 5.08 (2H, s, OCH2), 4.87-4.81 (1H, m, NCH),4.33-4.31 (1H, m, NCH), 3.46-3.36 (2H, m, NCH2), 3.12-2.87 (m,2H, CH2Ph), 2.03-1.89 (2H, m, CH2), 1.89-1.75 (2H, m, CH2); 13CNMR (50 MHz, CDCl3) d 173.7, 172.2, 155.8, 136.1, 135.9, 129.5, 128.6,128.5, 128.2, 127.9, 127.0, 67.6, 60.4, 52.8, 47.0, 37.6, 29.8, 24.3; MS(ESI) m/z (%) 397 (100) ([M+H]).
methyl N-[(2-oxo-2,3-dihydro-1H-indol-5-yl)carbonyl]-D-phenylalaninate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
37%
General procedure: Compound 7 (2.1 g, 0.012 mol) and HBTU (5.0 g, 0.013 mol) were dissolved in dry DMF, in a 250 ml round bottom flask. DIPEA (6.5 ml, 0.037 mol) was added and the reaction mixtures were stirred for 30 min. L or D- phenylalanine methyl ester hydrochloride (3.0 g, 0.014 mol) or glutamic acid dimethyl ester hydrochloride (3.0 g 0.014 mol) was added and the reaction mixture was kept stirring overnight under ambient conditions. Reaction monitoring by TLC was performed on silica gel plates using CHCl3:MeOH 9:1 as eluent. Saturated NaHCO3 solution (150 ml) was added to the mixture and the precipitate was filtered, washed with saturated NaHCO3 solution and water. The crude product was purified by column chromatography CHCl3:MeOH (95:5) to give the product as white to off-white solid.
ethyl 1,3-bis(1-benzyl-2-methoxy-2-oxoethyl)-5-(difluoroacetyl)hexahydropyrimidine-5-carboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
44%
In water at 20℃; for 24h;
General procedure for the synthesis of hexahydropyrimidines 5 and 6
General procedure: To a solution of the appropriate amino ester hydrochloride 2a-g (3.0 mmol) in acetate buffer (pH 5.9) (0.9 mL) ethyl 4,4-difluoro-3-oxobutanoate 4a (1.5 mmol) and formaldehyde 33% aqueous solution (22.5 mmol) were added. The resulting mixture was stirred for 24 h at room temperature, then it was extracted with CH2Cl2 (3 x 10 mL) and the combined organic layers were dried over Na2SO4 and evaporated in vacuo. The product was purified by column chromatography on Kieselgel 60 (dichloromethane -ethyl acetate 10:0→7:3 or hexane-ethyl acetate 10:0→7:3). In the case of amino esters hydrochlorides 2a and L-2b only nonfluoratedhexahydropyrimidines 5a and 5b were isolated in yields 71 and 65% respectively. Their physico-chemical properties coincided with the previously described.
3-O-{2-O-[N-(β-D-glucopyranosyluronoyl)-Dphenylalaninemethyl ester]-N-(-D-glucopyranosyluronoyl)-D-phenylalanine methyl ester}-(3,20)-11-oxo-30-(N-carbonyl-D-phenylalanine methyl ester)-30-norolean-12-ene[ No CAS ]
With sodium hydrogencarbonate In acetone at 40℃; for 0.166667h;
10 Example 10: Synthesis of Boc-(L)-Trp-D-Phe-OMe [90983-25-81
Boc-(L)-Trp-OSu (5.43 g, 13.5 mmol), NaHCCE (1.36 g, 16.2 mmol, 1.2 eq), HCbH-(D)-Phe-OMe (3.21 g, 14.9 mmol, 1.1 eq) and reagent grade acetone (1.5 mL, h = 0.15 pL/mg, 1.5 eq) were introduced in a beaker and mixed up with a spatula for 30 seconds. The mixture was slowly poured into the extruder that was heated at 40°C, the speed screw being set at 150 rpm and the output valve turned towards the recirculation pipe. After 10 min of recirculation, the valve was opened and a white paste was recovered. After 24 h drying under reduced pressure over P2O5, the resulting white solid (m = 6.40 g, containing m = 4.44 g of pure peptide if 100% yield) was dissolved in EtOAc (50 mL) and washed with 1M aqueous HC1 solution (2 x 20 mL), with 1M aqueous NaOH solution (2 x 20 mL) and brine (1 x 20 mL). The organic phase was dried over MgS04, filtered and concentrated under reduced pressure to afford 2.99 g of the desired product as a white solid (67% yield, E-factor: 1.65, STY: 40.51 g. cm3. day 1). Details of STY calculations (0371) Estimated total mass of peptide: n(limitating reactant) x yield x M(peptide) = (0372) 4.22 g (0373) Reaction time: 10 min = 6.94 x 103 day (0374) Volume of reactor: 15 mL (0375) STY: 40.51 g. cm3. day 1 (0376) Details of E-factor calculations (0377) Amount of final product: 4.22 g (0378) Mass of acetone: 1.5 mL x 0.784 = 1.18 g (0379) Total mass of reagents = 5.43 + 1.36 + 3.21 + 1.18 = 11.18 g (0380) E-factor = (11.18 - 4.22)/ 4.22 = 1.65 (ppm) 8.04 (s, 1H), 7.65 (d, J = 7.8 Hz, 1H), 7.36 (d , J= 8.1 Hz, 1H), 7.24-7.11 (5H), 6.96 (d, J= 1.8 Hz, 1H), 6.84-6.78 (2H), 6.23 (d, J = 7.9 Hz, 1H), 5.07 (br s, 1H), 4.78 (dd, J = 13.1, 5.5 Hz, 1H), 4.46 (br s, 1H), 3.61 (s, 3H), 3.28 (dd, J = 11.2, 5.6 Hz, 1H), 3.16 (dd, j= 14.3, 7.4 Hz, 1H), 2.95 (dd, j= 13.8, 5.5 Hz, 1H), 2.79 (dd, J = 13.3, 4.7 Hz, 1H), 1.40 (s, 9H) ; 13C NMR (101 MHz, CDCb) d (ppm) 171.7, 171.6, 155.6, 136.4, 135.7, 129.3, 128.8, 127.3, 123.3, 122.5, 119.9, 119.1, 111.5, 110.7, 80.3, 55.3, 53.2, 52.4, 37.9, 29.9, 28.5 ; LCMS (ESI): m/z = 488.2 [M+Na]+; m.p. = 149-150 °C.
Stage #1: baicalin With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In N,N-dimethyl-formamide at 25℃; for 6h;
Stage #2: D-phenylalanine methyl ester hydrochloride With triethylamine In N,N-dimethyl-formamide at 50℃; for 0.166667h;
1-3 Step 1. Press baicalin: 1-hydroxybenzotriazole:
1-ethyl-(3-dimethylaminopropyl) carbodiimide hydrochloride: D-phenylalanine methyl ester hydrochloride = 0.5: 0.6: 0.9: 1.5 molar ratio Four substances, baicalin, 1-hydroxybenzotriazole,Put 1-ethyl-(3-dimethylaminopropyl) carbodiimide hydrochloride into a container,Add N,N-dimethylformamide to dissolve to obtain a solution with a concentration of 1.5 mmol/ml, and stir the solution at 25° C. for 6 h to obtain solution M. Step 2: Dissolve D-phenylalanine methyl ester hydrochloride with N,N-dimethylformamide,Obtain solution N with a concentration of 1.2mmol/ml, adjust the pH value of solution N to 7 with triethylamine,Add solution N to solution M, and raise the temperature to 50°C within 10 minutes for synthesis reaction,The timing starts when the solution N is added, and the synthesis reaction is terminated at 48 hours, and the reaction solution G is obtained. Step 3: Add dichloromethane to the reaction solution G, the volume ratio of the reaction solution G to the dichloromethane is 1:5, and then add the hydrochloric acid solution of PH=3 to wash twice,Then add pH=8.3 sodium bicarbonate solution to wash twice, and finally reduce with pH=3 hydrochloric acid solution,Take the yellow precipitate between the methylene chloride layer and the water layer, centrifuge and wash with water, filter, and dry at 30°C to obtain the crude baicalin derivative BAD. Step 4. Dissolve the crude baicalin derivative BAD with N,N-dimethylformamide,Use thin layer separation technology to separate and purify, wash with ethanol, centrifuge,The supernatant liquid is rotated and evaporated to dryness to obtain a pure product of baicalin derivative BAD with a purity of more than 95%.
Stage #1: baicalin With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In N,N-dimethyl-formamide at 20℃; for 6h;
Stage #2: D-phenylalanine methyl ester hydrochloride With triethylamine In N,N-dimethyl-formamide at 50℃; for 48h;
With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine In N,N-dimethyl-formamide at 20℃;
6 Example 6
6-morpholinopicolinoyl)phenylalanine (compound I-6): Under stirring at room temperature, add 6-(4-morpholino)-2-pyridinecarboxylic acid (0.2g, 0.96mmol, 1.0eq) to 5ml of anhydrous N, N-dimethylformamide, followed by EDCI (0.28g, 1.44mmol, 1.5eq), HOBT (0.2g, 1.44mmol, 1.5eq), and then D-phenylalanine methyl ester hydrochloride ( 0.31g, 1.44mmol, 1.5eq) was finally added with TEA (0.68g, 6.0mmol, 7.0eq) and reacted overnight (TLC detection endpoint). After the reaction is completed, add water and stir, extract with ethyl acetate, wash with dilute hydrochloric acid, wash with saturated sodium bicarbonate solution, dry the organic phase with anhydrous sodium sulfate, spin off the ethyl acetate under reduced pressure to obtain a crude product. The crude product was purified by a fast silica gel column to obtain 0.28 g of colorless oily liquid with a yield of 80%;
Stage #1: (2R,3R)-2-[(tert-butoxycarbonyl)amino]-3-phenylbutanoic acid With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In N,N-dimethyl-formamide at 0℃; for 0.5h; Inert atmosphere;
Stage #2: D-phenylalanine methyl ester hydrochloride With 4-methyl-morpholine In N,N-dimethyl-formamide at 0 - 20℃; Inert atmosphere;
1 Example 1: Synthesis of Dipeptide Intermediate (3)
To the reaction flask were added (2R,3R)-Boc-beta-methyl-phenylalanine (1) (15 g, 36.1 mmol, 1.0 eq) and DMF (212 mL) under nitrogen. After the mixture became homogeneous under stirring, the resulting solution was cooled to 0° C. in ice bath. To the cooled reaction was added HOBt.H2O (5.36 g, 39.7 mmol, 1.1. eq.) and N-ethyl-N′-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDCl) (7.60 g, 39.7 mmol, 1.1 eq). The resulting mixture was stirred for 30 minutes, then H-D-Phe-OMe.HCl (2) (8.56 g, 39.7 mmol, 1.1 eq) and N-methylmorpholine (NMM) (7.58 mL, 75.7 mmol, 2.1 eq) were added. The reaction was stirred at 0° C. for one hour, and then stirred at room temperature until HPLC analysis indicated the reaction was complete. The reaction solution was added dropwise to water (600 mL) under stirring. After the water addition was complete, stirring was stopped and a precipitate began to form. The reaction mixture stood for 1 hour where the precipitation ceased. The precipitate (crystals) were collected by filtration and washed with water (400 mL×3), then dried in vacuum; the product (3) was obtained as a white solid, 14.36 g, yield=90.8%. LCMS: m/z=441.5 [M+H]+.
90.8%
Stage #1: (2R,3R)-2-[(tert-butoxycarbonyl)amino]-3-phenylbutanoic acid With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In N,N-dimethyl-formamide at 0℃; for 0.5h; Inert atmosphere;
Stage #2: D-phenylalanine methyl ester hydrochloride With 4-methyl-morpholine In N,N-dimethyl-formamide at 0 - 20℃; Inert atmosphere;
1 Example 1: Synthesis of Dipeptide Intermediate (3)
To the reaction flask were added (2R,3R)-Boc-beta-methyl-phenylalanine (1) (15 g, 36.1 mmol, 1.0 eq) and DMF (212 mL) under nitrogen. After the mixture became homogeneous under stirring, the resulting solution was cooled to 0° C. in ice bath. To the cooled reaction was added HOBt.H2O (5.36 g, 39.7 mmol, 1.1. eq.) and N-ethyl-N′-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDCl) (7.60 g, 39.7 mmol, 1.1 eq). The resulting mixture was stirred for 30 minutes, then H-D-Phe-OMe.HCl (2) (8.56 g, 39.7 mmol, 1.1 eq) and N-methylmorpholine (NMM) (7.58 mL, 75.7 mmol, 2.1 eq) were added. The reaction was stirred at 0° C. for one hour, and then stirred at room temperature until HPLC analysis indicated the reaction was complete. The reaction solution was added dropwise to water (600 mL) under stirring. After the water addition was complete, stirring was stopped and a precipitate began to form. The reaction mixture stood for 1 hour where the precipitation ceased. The precipitate (crystals) were collected by filtration and washed with water (400 mL×3), then dried in vacuum; the product (3) was obtained as a white solid, 14.36 g, yield=90.8%. LCMS: m/z=441.5 [M+H]+.
90.8%
Stage #1: (2R,3R)-2-[(tert-butoxycarbonyl)amino]-3-phenylbutanoic acid With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In N,N-dimethyl-formamide at 0℃; for 0.5h; Inert atmosphere;
Stage #2: D-phenylalanine methyl ester hydrochloride With 4-methyl-morpholine In N,N-dimethyl-formamide at 0 - 20℃; Inert atmosphere;
1 Example 1: Synthesis of Dipeptide Intermediate (3)
To the reaction flask were added (2R,3R)-Boc-beta-methyl-phenylalanine (1) (15 g, 36.1 mmol, 1.0 eq) and DMF (212 mL) under nitrogen. After the mixture became homogeneous under stirring, the resulting solution was cooled to 0° C. in ice bath. To the cooled reaction was added HOBt.H2O (5.36 g, 39.7 mmol, 1.1. eq.) and N-ethyl-N′-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDCl) (7.60 g, 39.7 mmol, 1.1 eq). The resulting mixture was stirred for 30 minutes, then H-D-Phe-OMe.HCl (2) (8.56 g, 39.7 mmol, 1.1 eq) and N-methylmorpholine (NMM) (7.58 mL, 75.7 mmol, 2.1 eq) were added. The reaction was stirred at 0° C. for one hour, and then stirred at room temperature until HPLC analysis indicated the reaction was complete. The reaction solution was added dropwise to water (600 mL) under stirring. After the water addition was complete, stirring was stopped and a precipitate began to form. The reaction mixture stood for 1 hour where the precipitation ceased. The precipitate (crystals) were collected by filtration and washed with water (400 mL×3), then dried in vacuum; the product (3) was obtained as a white solid, 14.36 g, yield=90.8%. LCMS: m/z=441.5 [M+H]+.
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