Reduction of carbonyl compounds using the carbonyl reductase of kluyveromyces marxianus

专利摘要:
The present invention relates to a compound represented by the general formula (Ia) or (Ib), and a method for producing them using carbonyl reductase isolated from Kluyveromysis marcianus. Compounds represented by general formula (Ia) or (Ib) can be prepared through the reduction reaction of α-substituted β-keto esters using carbonyl reductase isolated from Cluyveromysis marcianus, which are β- It can be used as an important intermediate in the preparation of lactam antibiotics.
公开号:KR20030056992A
申请号:KR1020010087362
申请日:2001-12-28
公开日:2003-07-04
发明作者:고훈영；최경일；조용서；배애님；차주환；한예선；이종수；윤홍철
申请人:한국과학기술연구원；
IPC主号:

专利说明:

REDUCTION OF CARBONYL COMPOUNDS USING THE CARBONYL REDUCTASE OF KLUYVEROMYCES MARXIANUS}
[1] The present invention relates to compounds represented by the following general formula (1a) or (1b) which can be used as important intermediates in the preparation of β-lactam antibiotics and methods for their preparation. More specifically, having a (2S, 3R)-or (2R, 3R) -stereochemistry obtained by reducing the α-substituted β-keto ester using a carbonyl reductase isolated from Cluyveromysis marcianus. A compound and a method for producing the same
[2]
[3]
[4] Compounds A, B and C as shown in the following formula (2) are important intermediates that can be used for the preparation of the β-lactam antimicrobial agents.
[5]
[6] As the importance of β-lactam antibiotics ( Angew. Chem., Int. Ed. Engl ., 1985, 24 , 180) increases, (1'R, 3R) -4-acyloxy- which requires stereochemical features Compound C has been used as an important intermediate in the preparation of 3- (1'-hydroxyethyl) azetidin-2-one (Compound A), and therefore much attention has been paid to the method of synthesizing this intermediate Compound C. have. The preparation of Compound A is currently carried out in a variety of chiral preparation units, namely L-aspaltamic acid (PJ Reider, Tetrahedron Lett ., 1982, 23 , 2293), 2-benzamidomethyl-3-hydroxybutyrate (R. Noyori, J.). Am. Chem. Soc ., 1989, 111 , 9134) and (3R) -hydroxybutyrate (I. Sada, Eur. Pat. Appl. 280962 ( Chem. Abstr ., 1989, 110 (17), 154035s), etc. And preparation by the classical fractionation of racemic intermediates (M. Masayoshi, Eur. Pat. Appl . 421283 ( Chem. Abstr ., 1991, 115 (11), 1128442e)).
[7] (1'R, 3S) -3- (1'-t-butyldimethylsilyloxy) azetidin-2-one, a derivative of Compound B, is known to be useful as a starting material for the preparation of β-lactam antibacterial agents. This is because penicillin antimicrobial agents, cephalosporin-based antimicrobial agents, and carbapenem antimicrobials, which are expected to be the next-generation antimicrobials, which are widely used at present, all have an azetidin-2-one skeleton.
[8] As a method for preparing (1'R, 3S) -3- (1'-t-butyldimethylsilyloxy) azetidin-2-one, a method such as Noyori et al. (J. Am. Chem. Soc. 111, 9134 , 1989 and Japanese Patent No. 2134349) and methods of Swiss pharmaceutical companies (US Pat. No. 4,927,507).
[9] In a method such as furnace cooking, 2-amidomethylaceto acetate ester is added by subsidiary hydrogen, hydrolyzed with an acid to be lactamated, and then silylated. The method of furnace cooking is a stereoselective hydrogenation reaction, but since amide is used as a raw material, a strong acid should be used for hydrolysis, and the lactamation reaction is difficult because the protection of the hydroxyl group is performed after the lactamation reaction. There is a problem such as complicated separation and purification.
[10] The method of the Swiss pharmaceutical company uses 5, 6-dihydro- (1H, 3H, 4H) -oxazinyl to 2-amidomethyl-3-hydroxybutanoic acid ester obtained by yeast reduction of 2-amidomethylaceto acetate ester. Substitution with the -5-carboxylic acid ester derivative, isomerization to the preferred steric configuration, followed by hydrolysis, lactamation and silylation. This method induces a 2-amidomethyl-3-hydroxybutanoic acid ester to 5, 6-dihydro- (1H, 3H, 4H) -oxazinyl-5-carboxylic acid ester derivatives, followed by diasteromers. ) Is hydrolyzed, and the separation and purification of diastereomers is complicated and the number of processes is long, which is not practical.
[11] Compound B may also be prepared from α-substituted β-hydroxy esters, such as Compound C, and compound C may be prepared from α-substituted β-keto esters.
[12] As described above, Compound A or B may be used as an important intermediate in the preparation of β-lactam antimicrobial agents, and since they may be prepared from Compound C, it is necessary to provide a method for preparing Compound C.
[13] Recently, attempts have been made to selectively prepare only one type of optical isomer showing useful physiological activity among racemic compounds. In order to accomplish this purpose, methods using a biocatalyst as a means different from the conventional organic chemical production methods are continuously developed. The production method using the biocatalyst is simpler than the conventional organic chemical production method and has the advantage of not using toxic reagents.
[14] The reason why the biocatalytic reaction is of interest is due to stereoselectivity, such as enantioselectivity or diastereoselectivity of the product. In this regard, the enzyme reaction is a very useful experimental method for preparing optically pure compounds, and in particular, the reaction using Baker's Yeast (BY) is generally used for the reduction of carbonyl compounds. However, according to the recently published production method, it is generally known that when Baker's Yeast (BY) is used to reduce the carbonyl group of β-keto ester, (S) -3-hydroxy compound is produced (S. Servi, Synthesis , 1990, 1; R. Csuk, Chem. Rev. , 1991, 91 , 49). That is, a method for producing (R) -3-hydroxy compound by reducing the carbonyl group of β-keto ester has not been developed yet.
[15] Therefore, an object of the present invention can be used as an important intermediate in the preparation of β-lactam antimicrobial agents and α-substituted β-hydroxy ester derivative compounds having stereochemistry of (2S, 3R)-and their stereoselectives It is to provide a (stereo-selective) manufacturing method.
[16] Unlike Baker's Yeast (BY), which reduces the carbonyl group of the β-keto ester to generally produce a (S) -3-hydroxy compound, the reduction isolated from the Kluyberomysis marcianus used as the reduction catalyst in the present invention. The enzyme produces a (R) -3-hydroxy compound. Kluyveromysis marcianus is one of the few known microbial organisms. In particular, in the present invention, the enzyme reaction was carried out using two reductases isolated from Baker's Yeast and Kluyberomysis martianus, respectively. The diastereoisomers were identified by comparison using. In the present invention, by using the properties of such microbial organisms, through the enzymatic reaction, α-substituted β-hydroxy ester derivative compound having a stereochemistry of (2S, 3R), that is, a compound represented by the formula (Ia) or (Ib) Was prepared. Compounds having such optical activity can be usefully used as intermediates for carbapenem antimicrobial synthesis.
[17] For the reduction reaction by the enzyme of the present invention, a compound of formula (VI) as shown in the following formula (3) is used as a substrate.
[18]
[19] In the formula, R means a saturated or unsaturated alkyl group such as methyl, ethyl, propyl, isopropyl, isobutyl, allyl, or an aryl group such as a phenyl group. R ₁ , R ₂ , R ₃ and R ₄ are each a substituent substituted on the benzene ring, and these are hydrogen, halogen atoms such as Br, Cl, F, I, alkyl groups of 1 to 4 carbon rings such as methyl and ethyl, Hydroxy groups, alkoxy groups having 1 to 4 carbon atoms such as methoxy and the like, ester groups such as acetoxy and the like, 1-2 phenyl, and combinations thereof.
[20] The compound of formula (VI) may be prepared by the same method as shown in the following Schemes 1-3.
[21]
[22] Substitution reaction of the enamine of the (beta) -keto ester and bromomethyl phthalimide obtains the compound of general formula (II). Examples of the solvent that can be used include dimethylformamide, dimethyl sulfoxide and the like. The reaction temperature is preferably room temperature, and the reaction time is preferably 5-20 hours.
[23]
[24] The ketone group of the compound of formula (II) is protected by a protecting group to obtain a compound of formula (III). As one example, the ketone group can be protected by dehydration using ethylene glycol. The compound of formula (III) is then reacted with hydrazine at about 50 ^° C. to remove phthalimide to obtain a primary amine compound represented by formula (IV).
[25]
[26] The compound of formula (IV) is reacted with phthalic anhydride having a substituent on the benzene ring using chloroform as a solvent to obtain a compound of formula (V). Then, the protecting group of the compound of formula (V) is removed to obtain a substrate compound of formula (VI) for use in the enzymatic reaction.
[27] Reduction reaction by the enzyme according to the present invention is carried out according to the reaction scheme shown in Scheme 4 below.
[28]
[29] The compound of formula (VI) is mixed with β-NADPH and a buffer solution, and reacted by adding an enzyme isolated from Cluyveromysis marcianus. The pH of the buffer is preferably adjusted to 5.0-8.0, most preferably pH 6.8. 20-40 degreeC is preferable and 30 degreeC is the most preferable. The reaction time may be from 5 hours to 5 days, but 24 hours is suitable.
[30] Product identification of the enzymatic reaction was confirmed by preparing the same product according to known methods and comparing this product with the product obtained by the enzymatic reaction.
[31] In the above Reaction Schemes 1-4, R, R ₁ , R ₂ , R ₃ , and R ₄ are the same as defined above.
[32] Hereinafter, in order to show the usefulness of the enzymatic reaction according to the present invention, the results of the reduction reaction by the enzyme of the following representative substrate compounds (VIa)-(VIe) synthesized for use in the reduction reaction by the enzyme of the present invention It is shown in the following table (1).
[33]
[34] compoundReaction time (h)% ConversionDiastereomeric Ratio (2S, 3R: 2R, 3R) VIa24991.0: 9.0 VIb249112.0: 1.0 VIc249320.0: 1.0 VId248011.0: 1.0 VIe24818.0: 1.0
[35] Example
[36] Hereinafter, the preparation of the substrate used in the present invention and the reduction reaction by enzymes will be described in detail by examples. However, the following examples are merely examples of the present invention, and the scope of the present invention is not limited thereto.
[37] 1. Synthesis of Substrate Compounds
[38] Example 1 Preparation of Starting Material for Substrate Compound Synthesis
[39] (1) Methyl 3-tetrahydropyrrolyl-2-butenoate
[40] Methyl aceto acetate (20 g, 172.23 mmol) was dissolved in 250 mL of toluene, then pyrrolidine (43 ml, 516.70 mmol) and para-toluenesulfonic acid hydrate (about 100 mg) were added dropwise. The Dean-Stark separator was installed, refluxed at 140 ° C. for 2 days, and then concentrated under reduced pressure to remove the solvent to obtain the target compound (29 g, 99%).
[41] ¹ H NMR (CDCl ₃ , 300 MHz) δ 4.41 (s, 1H, -C = C H- ), 3.57 (s, 3H, -COC H ₃ ), 3.32-3.17 (brs, 4H, pyrrolidine), 2.42 (s, 3H, CH ₃ ), 1.89 (s, 4H, pyrrolidine)
[42] ¹³ C NMR (CDCl ₃ , 300 MHz) δ 169.9, 160.1, 129.3, 128.6, 125.6, 83.0,50.2, 48.3, 25.5, 17.0
[43] (2) ethyl 3-tetrahydropyrrolyl-2-butenoate
[44] Using ethyl acetoacetate (15.0 g, 115.26 mmol) and pyrrolidine (71.1 mL, 345.78 mmol) as starting materials, ethyl 3-tetrahydropyrrolyl-2-butenoate (21 g, 99%) ) Was confirmed by ¹ H NMR, the data is as follows.
[45] ¹ H NMR (CDCl ₃ , 300 MHz) δ 4.37 (s, 1H, -C = C H- ), 4.00 (q, 2H, -OC H ₂ CH ₃ , J = 7.1 Hz), 3.22 (brs, 4H, p Lolidine), 2.38 (s, 3H, -C H ₃ ), 1.85 (s, 4H, pyrrolidine), 1.17 (t, 3H, -OCH ₂ C H ₃ , J = 7.1 Hz)
[46] ¹³ C NMR (CDCl ₃ , 300 MHz) δ 169.5, 159.9, 83.6, 58.4, 48.2, 25.5, 17.0, 15.1
[47] (3) allyl 3-tetrahydropyrrolyl-2-butenoate
[48] Allyl 3-tetrahydropyrrolyl-2-butenoate (4.7 g, 68%) in the same manner as before, with allyl acetoacetate (5.0 g, 35.17 mmol) and pyrrolidine (8.8 mL, 105.51 mmol) as starting materials ) Was confirmed by ¹ H NMR, the data is as follows.
[49] ¹ H NMR (CDCl ₃ , 300 MHz) δ 5.91 (m, 1H, -OCH ₂ C H = CH ₂ ), 5.28 (m, 1H, -OCH ₂ CH = C H ₂ ), 5.12 (m, 1H, -OCH ₂ CH = C H ₂ ), 4.48 (d, 2H, -OC H ₂ CH = CH ₂ ), 4.43 (s, 1H, C = C H CO ₂ −), 3.22 (brs, 4H, pyrrolidine), 2.42 (s, 3H, C H ₃ ), 1.96 (m, 4H, pyrrolidine)
[50] Example 2. Preparation of Compound (II)
[51] (1) Methyl 2- (phthalimido) methyl-3-oxobutanoate
[52] Methyl 3-tetrahydropyrrolyl-2-butenoate (29.0 g, 171.3 mmol) and N- (bromomethyl) phthalimide (43 g, 179.91 mmol) are dissolved in 250 ml of dimethylformamide and nitrogen atmosphere The mixture was stirred at room temperature for 16 hours. After confirming the completion of the reaction by TLC, 1N HCl and water were added to the reaction mixture, and the resulting solid was filtered under reduced pressure with hexane, and then recrystallized with 100% ethanol to obtain the target compound (32.26 g, 68%).
[53] ¹ H NMR (CDCl ₃ , 300 MHz) δ 7.70 (m, 2H, ph), 7.60 (m, 3H, ph), 4.04 (m, 2H, -CHC H ₂ NPht), 3.91 (dd, 1H, -C H CH ₂ NPht, J = 8.1 Hz, J ' = 6.6 Hz), 3.61 (s, 3H, -CO ₂ C H ₃ ), 2.16 (s, 3H -COC H ₃ )
[54] ¹³ C NMR (CDCl ₃ , 300 MHz) δ 200.8, 168.5, 168.2, 134.5, 132.1, 123.8, 57.6, 53.3, 36.3, 29.3
[55] (2) ethyl 2- (phthalimido) methyl-3-oxobutanoate
[56] Using ethyl 3-tetrahydropyrrolyl-2-butenoate (17.3 g, 94.68 mmol) and N- (bromomethyl) phthalimide (25.0 g, 104.14 mmol) as starting materials, ethyl 2 -(Phthalimido) methyl-3-oxobutanoate (14.2 g, 52%) was prepared and confirmed by ¹ H NMR, the data are as follows.
[57] ¹ H NMR (CDCl ₃ , 300 MHz) δ 7.77 (m, 2H, ph), 7.65 (m, 2H, ph), 4.14 (m, 4H, -OC H ₂ CH ₃ , -CHC H ₂ NPht), 3.96 ( t, 1H, -C H CH ₂ NPht,, J = 6.6 Hz), 2.22 (s, 3H -COC H ₃ ), 1.16 (t, 3H, -OCH ₂ C H ₃ , J = 6.7 Hz)
[58] ¹³ C NMR (CDCl ₃ , 300 MHz) δ 200.9, 168.2, 168.0, 134.5, 132.2, 123.8, 62.4, 57.7, 36.3, 29.2, 14.3
[59] (3) Allyl 2- (phthalimido) methyl-3-oxobutanoate
[60] Allyl 2-tetrahydropyrrolyl-2-butenoate (4.6 g, 23.58 mmol) and N- (bromomethyl) phthalimide (6.22 g, 25.94 mmol) as starting materials were allyl 2 in the same manner as before. -(Phthalimido) methyl-3-oxobutanoate (6.1 g, 86%) was prepared and confirmed by ¹ H NMR, the data are as follows.
[61] 1 H NMR (CDCl ₃ , 300 MHz) δ 7.83 (m, 2H, phenyl), 7.72 (m, 2H, phenyl), 5.85 (m, 1H, -OCH ₂ C H = CH ₂ ), 5.21 (m, 2H,- OCH ₂ CH = C H ₂ ), 5.21 (m, 1H, -OCH ₂ C H = C H ₂ ), 4.62 (t, 2H, -CHC H ₂ NPht), 4.51 (s, 2H, -OC H ₂ CH = CH ₂ ), 4.20 (m, 1H, -C H CH ₂ NPht), 2.30 (d, 3H, C H _3, J = 6.0 Hz).
[62] Example 3 Preparation of Compound (III))
[63] (1) Methyl 2-phthalimidomethyl-3-ethylenedioxobutanoate
[64] Methyl 3-tetrahydropyrrolyl-2-butenoate (24.0 g, 87.19 mmol) and ethylene glycol (9.7 ml, 174.38 mmol) are dissolved in 300 ml of toluene and a catalytic amount of p-toluenesulfonic acid hydrate (about 300 mg) After the addition, the Dean-Stark separator was installed and refluxed at 140 ° C. for 16 hours. After completion of the reaction by TLC, saturated aqueous NaHCO ₃ solution was added, washed with water, the organic layer was dried over anhydrous sulfate, concentrated under reduced pressure, and separated by column chromatography (developing solvent: normal hexane: ethyl acetate = 3: 1). ) To give the target compound (26 g, 93%).
[65] ¹ H NMR (CDCl ₃ , 300 MHz) δ 7.76 (dd, 2H, ph, J = 5.6 Hz, J ′ = 3.1 Hz), 7.64 (m, 3H, ph), 3.98-3.87 (m, 6H, acetal H, -CHC H ₂ NPht), 3.60 s, 3H, -CO ₂ C H ₃ ), 3.22 dd, 1H, -C H CH ₂ NPht, J = 8.8 Hz, J ' = 5.5 Hz), 1.44 (s, 3H, -C H ₃ )
[66] ³ C NMR CDCl ₃ , 300 MHz) δ 171.3, 168.3, 134.6, 134.4, 132.4, 123.8, 123.7, 108.9, 65.9, 65.1, 52.6, 51.9, 37.0, 22.1.
[67] (2) ethyl 2-phthalimidomethyl-3-ethylenedioxobutanoate
[68] Ethyl ethyl 2-phthalimidomethyl-3- in the same manner as above with ethyl 3-tetrahydropyrrolyl-2-butenoate (14.1 g, 48.91 mmol) and ethylene glycol (6.0 mL, 107.60 mmol) as starting materials Ethylenedioxobutanoate (16.0 g, 98%) was prepared and confirmed by ¹ H NMR, the data are as follows.
[69] ¹ H NMR CDCl ₃ , 300 MHz) δ 7.76 m, 2H, ph), 7.64 m, 2H, ph), 4.02 (m, 4H, -OC H ₂ CH ₃ , -CHC H ₂ NPht), 3.88 m, 4H, acetal H ), 3.22 (d, 1H, -C H CH ₂ NPht), 1.44 (s, 3H, -C H ₃ ), 1.08 (t, 3H, -OCH ₂ C H ₃ , J = 7.1 Hz)
[70] ¹³ C NMR (CDCl ₃ , 300 MHz) δ 170.8, 168.2, 134.4, 132.3, 123.6, 108.9, 65.3, 65.0, 61.3, 51.9, 36.9, 22.1, 14.3
[71] (3) Allyl 2-phthalimidomethyl-3-ethylenedioxobutanoate
[72] Allyl allyl 2-phthalimidomethyl-3- with allyl 3-tetrahydropyrrolyl-2-butenoate (5.7 g, 18.00 mmol) and ethylene glycol (2.1 mL, 37.00 mmol) as starting materials Ethylenedioxobutanoate (4.8 g, 75%) was prepared and confirmed by ¹ H NMR, the data are as follows.
[73] ¹ H NMR (CDCl ₃ , 300 MHz) δ7.73 (t, 2H, phenyl), 7.63 (t, 2H, phenyl), 5.72 (m, 1H, -OCH ₂ C H = CH ₂ ), 5.15 (m, 1H , -OCH ₂ CH = C H _{2 ,} J = 12.0 Hz), 5.01 (m, 1H, -OCH ₂ CH = C H _2, J = 1 2.0 Hz), 4.47 (d, 2H, -OC H ₂ CH = CH ₂ , J = 6 Hz), 3.99 (m. 2H, -CHC H ₂ NPht), 3.88 (m, 4H, acetal H ), 3.23 (q, 1H, -C H CH ₂ NPht), 1.42 (s, 3H , C H ₃ )
[74] Example 4. Preparation of Compound (IV)
[75] (1) Methyl 2-aminomethyl-3-ethylenedioxobutanoate
[76] Methyl 2-phthalimidomethyl-3-ethylenedioxobutanoate (26.0 g, 81.44 mmol) is dissolved in 250 ml of ethanol, hydrazine monohydrate (12.2 g, 244.31 mmol) is added slowly, and then at 90 ° C. for 1 hour. At reflux. After completion of the reaction, saturated NaHCO ₃ aqueous solution was added, the organic layer was washed with water, and the aqueous layer was extracted with dichloromethane. The combined organic layers were washed well with saturated aqueous NaHCO ₃ solution, made to pH 11, dried over anhydrous sulfate, and concentrated under reduced pressure to give an oil product (11.0 g, 72%).
[77] ¹ H NMR (CDCl ₃ , 300 MHz) δ 3.90 (m, 4H, acetal H ), 3.67 (s, 3H, -CO ₂ C H ₃ ), 2.99 (m, 2H, -CHC H ₂ NH ₂ ), 2.73 ( m, 1H, -C H CH ₂ NH ₂ ), 1.31 (s, 3H, -C H ₃ )
[78] ³ C NMR (CDCl ₃ , 300 MHz) δ 172.8, 109.2, 65.2, 65.1, 52.0, 41.1, 22.4
[79] (2) ethyl 2-aminomethyl-3-ethylenedioxobutanoate
[80] Ethyl 2-aminomethyl-3 in the same manner as described above with ethyl 2-phthalimidomethyl-3-ethylenedioxobutanoate (16.0 g, 47.99 mmol) and hydrazine monohydrate (6.9 g, 143.97 mmol) as starting materials -Ethylene dioxobutanoate (9.3 g, 95%) was prepared and confirmed by ¹ H NMR, the data are as follows.
[81] ¹ H NMR (CDCl ₃ , 300 MHz) δ4.11 (q, 2H, -OC H ₂ CH ₃ , J = 5.4 Hz), 3.88 (m, 4H, acetal H ), 3.00 (m, 1H, -CHC H ₂ NPht), 2.88 (m, 1H, -CHC H ₂ NPht), 2.69 (q, 1H, -C H CH ₂ NPht, J = 4.7 Hz), 1.31 (s, 3H, -C H ₃ ), 1.21 (t , 3H, -OCH ₂ C H ₃ , J = 7.1 Hz)
[82] ¹³ C NMR (CDCl ₃ , 300 MHz) δ 172.2, 109.2, 65.1, 64.9, 60.9, 58.1, 41.1, 22.4, 22.4, 14.6
[83] (3) allyl 2-aminomethyl-3-ethylenedioxobutanoate
[84] Allyl 2-aminomethyl-3 in the same manner as before with allyl 2-phthalimidomethyl-3-ethylenedioxobutanoate (4.57 g, 13.23 mmol) and hydrazine monohydrate (1.9 mL, 39.68 mmol) as starting materials -Ethylene dioxobutanoate (2.5 g, 88%) was prepared and confirmed by ¹ H NMR, the data are as follows.
[85] ¹ H NMR (CDCl ₃ , 300 MHz) δ 5.89 (m, 1H, -OCH ₂ C H = CH ₂ ), 5.30 (q, 1H, -OCH ₂ CH = C H _{2 ,} J = 18.0 Hz), 5.17 (q , 1H, -OCH ₂ CH = C H _2, J = 18.0 Hz), 4.58 (m, 2H, -OC H ₂ CH = CH ₂ ), 3.90 (m, 4H, acetal H ), 2.90 (m, 2H, -CHC H ₂ NPht), 2.75 (q, 1H, -C H CH ₂ NPht), 1.70 (brs, 1H, -N H ₂ ), 1.32 (s, 3H, C H ₃ )
[86] Example 5. Preparation of Compound (V)
[87] (1) Methyl 3- (1,3-dioxo-1,3,4,5,6,7-hexahydro-isoindol-2-yl) -2- (2-methyl- [1,3] diox Solan-2-yl) -propionate
[88] Methyl 3-amino-2- (2-methyl- [1,3] dioxolan-2-yl) -propionate (1.0 g, 5.29 mmol) and 3,4,5,6-tetrahydrophthalic anhydride ( 1.0 g, 6.34 mmol) was dissolved in 20 ml of chloroform and refluxed at 80 ° C. for 3 days. After completion of the reaction, the mixture was concentrated under reduced pressure to remove the solvent, and then separated by column chromatography (developing solvent: normal hexane: ethyl acetate = 2: 1) to obtain the target compound (1.4 g, 80%).
[89] ¹ H NMR (CDCl ₃ , 300 MHz) δ 3.88 (m, 4H, acetal H ), 3.71 (m, 2H, -CHC H ₂ NPht), 3.56 (s, 3H, -CO ₂ C H ₃ ), 3.00 (m , 1H, -C H CH ₂ NPht), 2.16 (s, 4H, cyclohexane), 1.68 (s, 4H, cyclohexane), 1.34 (s, 3H, -CO ₂ C H ₃ )
[90] ¹³ C NMR (CDCl ₃ , 75 MHz) δ 171.1, 141.8, 141.7, 108.6, 65.0, 64.8, 52.1, 52.0, 36.4, 21.7, 21.5, 20.0
[91] (2) methyl 3- (4-fluoro-1,3-dioxo-1,3-dihydro-isoindol-2-yl) -2- (2-methyl- [1,3] dioxolane-2 -Yl) -propionate
[92] Methyl 3-amino-2- (2-methyl- [1,3] dioxolan-2-yl) -propionate (0.50 g, 2.64 mmol) and 3-fluorophthalic anhydride (0.57 g, 3.43 mmol) As a starting material, methyl 3- (4-fluoro-1,3-dioxo-1,3-dihydro-isoindol-2-yl) -2- (2-methyl- [ 1,3] dioxolan-2-yl) -propionate (0.24 g, 28%) was prepared and confirmed by ¹ H NMR, the data are as follows.
[93] ¹ H NMR (CDCl ₃ , 300 MHz) δ 7.72 (m, 2H, ph), 7.38 (t, 1H, ph, J = 9.0 Hz), 4.18-3.98 (m, 3H, -CHC H ₂ NPht, -C H CH ₂ NPht), 3.72 (s, 3H -CO ₂ C H ₃ ), 2.28 (s, 3H, -COC H ₃ )
[94] ³ C NMR (CDCl ₃ , 300 MHz) δ 171.2, 163.9, 157.7, 152.3, 125.5, 121.6, 121.3, 120.5, 108.9, 65.4, 62.9, 60.9, 54.7, 51.7, 37.2, 22.0, 14.5
[95] (3) methyl 3- (4,7-difluoro-1,3-dioxo-1,3-dihydro-isoindol-2-yl) -2- (2-methyl- [1,3] diox Solan-2-yl) -propionate
[96] Methyl 3-amino-2- (2-methyl- [1,3] dioxolan-2-yl) -propionate (0.47 g, 2.47 mmol) and 3,6-difluorophthalic anhydride (0.50 g, 2.72 mmol) as a starting material, and in the same manner as in Example 1, methyl 3- (4,7-difluoro-1,3-dioxo-1,3-dihydro-isoindol-2-yl) -2- (2-Methyl- [1,3] dioxolan-2-yl) -propionate (0.27 g, 31%) was prepared and confirmed by ¹ H NMR, the data are as follows.
[97] ¹ H NMR (CDCl ₃ , 300 MHz) δ 7.31 (t, 2H, ph, J = 5.3 Hz), 3.95 (m, 6H, acetal H , -CHC H ₂ NPht), 3.64 (s, 3H -CO ₂ C H ₃ ), 3.20 (m, 1H, -C H CH ₂ NPht), 1.42 (s, 3H, C H ₃ )
[98] ³ C NMR (CDCl ₃ , 300 MHz) δ 171.9, 163.9, 155.8, 152.2, 125.5, 121.1, 120.6, 120.1, 108.9, 65.4, 60.9, 53.8, 51.7, 37.2, 22.0, 14.5
[99] (4) Methyl 3- (4-nitro-1,3-dioxo-1,3-dihydro-isoindol-2-yl) -2- (2-methyl- [1,3] dioxolane-2- I) -propionate]
[100] Methyl 3-amino-2- (2-methyl- [1,3] dioxolan-2-yl) -propionate (0.50 g, 2.64 mmol) and 3-nitrophthalic anhydride (0.57 g, 3.43 mmol) As a starting material, methyl 3- (4-nitro-1,3-dioxo-1,3-dihydro-isoindol-2-yl) -2- (2-methyl- [1 , 3] dioxolan-2-yl) -propionate] (0.27 g, 28%) was prepared and confirmed by ¹ H NMR, the data are as follows.
[101] ¹ H NMR (CDCl ₃ , 300 MHz) δ 8.02 (dd, 2H, ph, J = 7.9 Hz, J ' = 1.0 Hz), 7.83 (t, 1H, ph, J = 7.8 Hz), 3.99-3.59 (m, overlapping, 6H, acetal H , -CHC H ₂ NPht), 3.60 (s, 3H, -CO ₂ C H ₃ ), 3.20 (m, 1H, -C H CH ₂ NPh), 1.39 (s, 3H, -COCH ₃ )
[102] ¹³ C NMR (CDCl ₃ , 300 MHz) δ 171.1, 165.8, 163.0, 145.5, 135.8, 129.4, 127.5, 124.0, 108.9, 65.4, 65.1, 52.7, 37.6, 22.1
[103] (5) Methyl 3- (5-nitro-1,3-dioxo-1,3-dihydro-isoindol-2-yl) -2- (2-methyl- [1,3] dioxolane-2- Sun) -propionate
[104] Methyl 3-amino-2- (2-methyl- [1,3] dioxolan-2-yl) -propionate (2.00 g, 10.57 mmol) and 4-nitrophthalic anhydride (0.57 g, 3.43 mmol) As a starting material, methyl 3- (5-nitro-1,3-dioxo-1,3-dihydro-isoindol-2-yl) -2- (2-methyl- [1 in the same manner as in Example 1 , 3] dioxolan-2-yl) -propionate] (1.60 g, 42%) was prepared and confirmed by ¹ H NMR, the data are as follows.
[105] ^OneH NMR (CDCl₃, 300 MHz) δ 7.50 (dd, 1H, ph,J= 8.6 Hz, J'= 7.3 Hz), 7.29 (d, 1H, ph,J'= 7.0 Hz), 7.06 (dd, 1H, ph,J= 8.2 Hz), 3.92 (m, overlapping, 6H, acetalH, -CHCH ₂NPht), 3.62 (s, 3H, -CO₂CH ₃), 3.21 (dd, 1H, -CHCH₂NPht_, J= 8.9 Hz,J'= 5.3 Hz), 1.43 (s, 3H, -COCH ₃)
[106] ¹³ C NMR (CDCl ₃ , 300 MHz) δ 171.0, 165.2, 165.9, 152.1, 136.7, 133.7, 129.8, 125.1, 119.2, 108.9, 65.9, 65.1, 57.1, 52.6, 51.7, 37.5, 36.8, 29.4, 22.0
[107] (6) Methyl 3- (4-methyl-1,3-dioxo-1,3-dihydro-isoindol-2-yl) -2- (2-methyl- [1,3] dioxolane-2- Sun) -propionate
[108] Methyl 3-amino-2- (2-methyl- [1,3] dioxolan-2-yl) -propionate (0.54 g, 2.86 mmol) and 3-methylphthalic anhydride (0.56 g, 3.44 mmol) As a starting material, methyl 3- (4-methyl-1,3-dioxo-1,3-dihydro-isoindol-2-yl) -2- (2-methyl- [1 , 3] dioxolan-2-yl) -propionate] (0.39 g, 52%) was prepared and confirmed by ¹ H NMR, the data are as follows.
[109] ¹ H NMR (CDCl ₃ , 300 MHz) δ 7.54 (d, 1H, ph, J = 7.3 Hz), 7.46 (t, 1H, ph, J = 7.4 Hz), 7.35 (d, 1H, ph, J = 7.1 Hz ), 3.91 (m, overlapping, 6H, acetal H , -CHC H ₂ NPht), 3.58 (s, 3H, -CO ₂ C H ₃ ), 3.21 (m, 1H, -C H CH ₂ NPht), 1.41 ( s, 3H, -COC H ₃ )
[110] ¹³ C NMR (CDCl ₃ , 300 MHz) δ 171.4, 168.9, 168.1, 138.2, 136.7, 133.8, 132.7, 128.9, 121.2, 108.9, 65.2, 65.0, 52.4, 52.0, 36.8, 22.0, 17.8.
[111] (7) Methyl 3- (5-methyl-1,3-dioxo-1,3-dihydro-isoindol-2-yl) -2- (2-methyl- [1,3] dioxolane-2- Sun) -propionate
[112] Methyl 3-amino-2- (2-methyl- [1,3] dioxolan-2-yl) -propionate (0.50 g, 2.64 mmol) and 4-methylphthalic anhydride (0.56 g, 3.43 mmol) As a starting material, methyl 3- (5-methyl-1,3-dioxo-1,3-dihydro-isoindol-2-yl) -2- (2-methyl- [1 , 3] dioxolan-2-yl) -propionate] (0.12 g, 10%) was prepared and confirmed by ¹ H NMR, the data are as follows.
[113] ¹ H NMR (CDCl ₃ , 300 MHz) δ 7.64 (dd, 1H, ph, J = 5.1 Hz, J ' = 2.9 Hz), 7.56 (s, 1H, ph), 7.42 (dd, 1H, ph, J = 7.6 Hz, J ' = 0.6 Hz), 3.99-3.61 (m, overlapping, 6H, acetal H , -CHC H ₂ NPht), 3.60 (s, 3H, -CO ₂ C H ₃ ), 3.22 (m, 1H,- C H CH ₂ NPht), 2.42 (s, 3H, -CH ₃ ), 1.44 (s, 3H, -COCH ₃ )
[114] ¹³ C NMR (CDCl ₃ , 300 MHz) δ 171.4, 168.5, 168.4, 145.6, 134.9, 132.8, 129.8, 124.3, 123.6, 109.0, 65.3, 65.1, 52.6, 52.0, 37.0, 22.4, 22.0.
[115] (8) Methyl 3- (5-tert-butyl-1,3-dioxo-1,3-dihydro-isoindol-2-yl) -2- (2-methyl- [1,3] dioxolane-2 -Yl) -propionate
[116] Methyl 3-amino-2- (2-methyl- [1,3] dioxolan-2-yl) -propionate (0.50 g, 2.64 mmol) and 4-tert-butylphthalic anhydride (0.70 g, 3.43 mmol) Methyl 3- (5-tert-butyl-1,3-dioxo-1,3-dihydro-isoindol-2-yl) -2- (2-methyl- in the same manner as in Example 1 [1,3] dioxolan-2-yl) -propionate] (0.14 g, 14%) was prepared and confirmed by ¹ H NMR, the data are as follows.
[117] ¹ H NMR (CDCl ₃ , 300 MHz) δ 7.86 (s, 1H, ph), 7.73 (m, 2H, ph), 3.99 (m, 6H, -CHC H ₂ NPht, acetal H ), 3.58 (s, 3H, -CO ₂ C H ₃ ), 3.28 (dd, 1H, -C H CH ₂ NPht. J = 8.3 Hz, J '= 6.5 Hz), 1.50 (s, 3H, -COC H ₃ , 1.33 (s, 9H, -C (C H ₃ ) ₃ )
[118] ¹³ C NMR (CDCl ₃ , 300 MHz) δ 173.0, 171.6, 168.3, 168.4, 158.9, 156.6, 155.1, 134.4, 130.9, 129.7, 127.9, 109.0, 65.3, 62.2, 60.3, 52.5, 36.9, 61.5, 22.1, 14.5.
[119] (9) Methyl 3- (4-hydroxy-1,3-dioxo-1,3-dihydro-isoindol-2-yl) -2- (2-methyl- [1,3] dioxolane-2 -Yl) -propionate
[120] Methyl 3-amino-2- (2-methyl- [1,3] dioxolan-2-yl) -propionate (1.00 g, 5.54 mmol) and 3-hydroxyphthalic anhydride (1.00 g, 6.09 mmol) Was prepared as the starting material in the same manner as in Example 1 methyl 3- (4-hydroxy-1,3-dioxo-1,3-dihydro-isoindol-2-yl) -2- (2-methyl- [1,3] dioxolan-2-yl) -propionate] (0.84 g, 45%) was prepared and confirmed by ¹ H NMR, the data are as follows.
[121] ¹ H NMR (CDCl ₃ , 300 MHz) δ 7.50 (dd, 1H, ph, J = 8.6 Hz, J ' = 7.3 Hz), 7.29 (d, 1H, ph, J = 7.1 Hz), 7.06 (dd, 1H, ph, J = 8.3 Hz), 3.92 (m, 6H, acetal, -CHC H ₂ NPht), 3.62 (s, 3H -CO ₂ C H ₃ ), 3.21 (dd, 1H, -C H CH ₂ NPht _, J = 8.9.Hz, J ' = 5.3 Hz), 1.43 (s, 3H, -COC H ₃ )
[122] ¹³ C NMR (CDCl ₃ , 300 MHz) δ 171.4, 170.3, 167.9, 155.1, 136.8, 132.3, 123.1, 116.4, 114.9, 108.9, 65.4, 65.1, 52.7, 52.0, 36.9, 22.1.
[123] (10) Methyl 3- (4,7-dichloro-1,3-dioxo-1,3-dihydro-isoindol-2-yl) -2- (2-methyl- [1,3] dioxolane- 2-yl) -propionate
[124] Methyl 3-amino-2- (2-methyl- [1,3] dioxolan-2-yl) -propionate (0.40 g, 2.30 mmol) and 3,6-dichlorophthalic anhydride (0.50 g, 2.30 mmol) ) Methyl 3- (4,7-dichloro-1,3-dioxo-1,3-dihydro-isoindol-2-yl) -2- (2- in the same manner as in Example 1 Methyl- [1,3] dioxolan-2-yl) -propionate] (0.23 g, 30%) was prepared and confirmed by ¹ H NMR, the data are as follows.
[125] ¹ H NMR (CDCl ₃ , 300 MHz) δ 7.58 (s, 2H, ph), 4.00 (m, overlapping, 6H, acetal H , -CHC H ₂ NPht), 3.72 (s, 3H, -CO ₂ C H ₃ ) , 3.29 (dd, 1H, -C H CH ₂ NPht _, J = 8.2 Hz, J ' = 5.8 Hz), 1.52 (s, 3H, -COC H ₃ )
[126] ¹³ C NMR (CDCl ₃ , 300 MHz) δ 164.8, 137.3, 65.7, 65.4, 52.9, 52.0, 37.7, 22.5, 10.6.
[127] (11) Methyl 3- (5,6-dichloro-1,3-dioxo-1,3-dihydro-isoindol-2-yl) -2- (2-methyl- [1,3] dioxolane- 2-yl) -propionate
[128] Methyl 3-amino-2- (2-methyl- [1,3] dioxolan-2-yl) -propionate (0.50 g, 2.64 mmol) and 4,5-dichlorophthalic anhydride (0.80 g, 3.64 mmol ) As a starting material in the same manner as in Example 1 methyl 3- (5,6-dichloro-1,3-dioxo-1,3-dihydro-isoindol-2-yl) -2- (2- Methyl- [1,3] dioxolan-2-yl) -propionate] (0.42 g, 39%) was prepared and confirmed by ¹ H NMR, the data are as follows.
[129] ¹ H NMR (CDCl ₃ , 300 MHz) δ 7.84 (s, 2H, ph), 3.90 (m, overlapping, 6H, acetal H , -CHC H ₂ NPht), 3.61 (s, 3H, -CO ₂ C H ₃ ), 3.19 (dd, 1H, -C H CH ₂ NPht _, J = 8.1 Hz, J '= 6.2 Hz), 1.42 (s, 3H, -COC H ₃ ).
[130] (12) Methyl 3- (1,3-dioxo-1,3-dihydro-benzo [f] isoindol-2-yl) -2- (2-methyl- [1,3] dioxolane-2- Sun) -propionate
[131] Methyl 3-amino-2- (2-methyl- [1,3] dioxolan-2-yl) -propionate (56 mg, 0.29 mmol) and 2,3-naphthalic anhydride (50 mg, 0.25 mmol) Was prepared as a starting material in the same manner as in Example 1 methyl 3- (1,3-dioxo-1,3-dihydro-benzo [f] isoindol-2-yl) -2- (2-methyl- [ 1,3] dioxolan-2-yl) -propionate (51 mg, 48%) was prepared and confirmed by ¹ H NMR, the data are as follows.
[132] ¹ H NMR (CDCl ₃ , 300 MHz) δ 8.26 (s, 2H, ph), 7.98 (m, 2H, ph), 7.64 (m, 2H, ph), 4.08-3.89 (m, 6H, acetal H , -CHC H ₂ NPht), 3.61 (s, 3H, -CO ₂ C H ₃ ), 3.29 (dd, 1H, -C H CH ₂ NPht _, J = 8.2 Hz, J ' = 6.6 Hz), 1.47 (s, 3H, -COC H ₃ )
[133] ¹³ C NMR (CDCl ₃ , 300 MHz) δ 171.4, 168.0, 138.8, 130.7, 129.6, 128.1, 125.1, 109.1, 65.4, 65.1, 52.6,51.8, 37.3, 22.1.
[134] (13) Methyl 3- (1,3-dioxo-4-phenyl-1,3-dihydro-benzo [f] isoindol-2-yl) -2- (2-methyl- [1,3] diox Solan-2-yl) -propionate
[135] Methyl 3-amino-2- (2-methyl- [1,3] dioxolan-2-yl) -propionate (50 mg, 0.25 mmol) and 3-phenylnaphthalic anhydride (0.50 g, 0.25 mmol) As a starting material, methyl 3- (1,3-dioxo-4-phenyl-1,3-dihydro-benzo [f] isoindol-2-yl) -2- (2- Methyl- [1,3] dioxolan-2-yl) -propionate (51 mg, 48%) was prepared and confirmed by ¹ H NMR, the data are as follows.
[136] ¹ H NMR (CDCl ₃ , 300 MHz) δ 8.29 (s, 1H, ph), 7.99 (d, 1H, ph, J = 8.1 Hz), 7.71 (d, 1H, ph, J = 8.4 Hz), 7.59 (t , 1H, ph), 7.46 (m, 4H, ph), 7.33 (m, 2H, ph), 3.99-3.83 (m, 6H, -CHC H ₂ NPht, acetal), 3.57 (s, 3H, -CO ₂ C H ₃ ), 3.23 (m, 1H, -C H CH ₂ NPht), 1.41 (s, 3H, -COC H ₃ )
[137] ¹³ C NMR (CDCl ₃ , 300 MHz) δ 171.4, 167.8, 140.6, 135.9, 134.9, 130.8, 129.6, 128.6, 127.9, 124.7, 124.0, 109.0, 65.4, 65.1, 61.7, 52.6, 51.8, 37.2, 22.1, 1 4.0 .
[138] (14) Methyl 3- (2,5-dioxo-3-phenyl-2,5-dihydro-pyrrol-1-yl) -2- (2-methyl- [1,3] dioxolan-2-yl ) -Propionate
[139] Methyl 3-amino-2- (2-methyl- [1,3] dioxolan-2-yl) -propionate (1.00 g, 5.29 mmol) and phenylmaleic anhydride (1.10 g, 6.34 mmol) were started. Methyl 3- (2,5-dioxo-3-phenyl-2,5-dihydro-pyrrol-1-yl) -2- (2-methyl- [1,3] in the same manner as in Example 1 Dioxolan-2-yl) -propionate (1.0 g, 56%) was prepared and confirmed by ¹ H NMR, the data are as follows.
[140] ¹ H NMR (CDCl ₃ , 300 MHz) δ 7.83 (m, 2H, ph), 7.36 (m, 3H, ph), 6.65 (s, 1H, -CH = C-), 3.95-3.61 (m, overlapping, 6H , acetal H , -CHC H ₂ NPht), 3.61 (s, 3H, -CO ₂ C H ₃ ), 3.15 (dd, 1H, -C H CH ₂ NPht), 1.41 (s, 3H, -COC H ₃ )
[141] ¹³ C NMR (CDCl ₃ , 300 MHz) δ 171.4, 170.6, 170.3, 144.1, 131.6, 129.5, 129.0, 128.9, 127.3, 124.3, 108.9, 65.3, 65.1, 52.6, 52.0, 37.0, 22.0.
[142] (15) Methyl 3- (2,5-dioxo-3,4-diphenyl-2,5-dihydro-pyrrol-1-yl) -2- (2-methyl- [1,3] dioxolane- 2-yl) -propionate
[143] Methyl 3-amino-2- (2-methyl- [1,3] dioxolan-2-yl) -propionate 91.00 g, 5.29 mmol) and 1,2-diphenylmaleic anhydride (1.60 g, 6.34 mmol ) As the starting material in the same manner as in Example 1 methyl 3- (2,5-dioxo-3,4-diphenyl-2,5-dihydro-pyrrol-1-yl) -2- (2- Methyl- [1,3] dioxolan-2-yl) -propionate (1.40 g, 72%) was prepared and confirmed by ¹ H NMR, the data as follows.
[144] ¹³ C NMR (CDCl ₃ , 300 MHz) δ 171.7, 171.0, 136.9, 130.6, 129.3, 109.3, 65.6, 65.4, 52.9, 52.4, 37.7, 22.4.
[145] (16) Methyl 3- (5-fluoro-1,3-dioxo-1,3-dihydro-isoindol-2-yl) -2- (2-methyl- [1,3] dioxolane-2 -Yl) -propionate
[146] Methyl 3-amino-2- (2-methyl- [1,3] dioxolan-2-yl) -propionate (0.80 g, 5.07 mmol) and 4-floorphthalic anhydride (0.80 g, 5.07 mmol) As a starting material, methyl 3- (5-fluoro-1,3-dioxo-1,3-dihydro-isoindol-2-yl) -2- (2-methyl- [ 1,3] dioxolan-2-yl) -propionate (0.66 g, 47%) was prepared and confirmed by ¹ H NMR, the data are as follows.
[147] ¹ H NMR (CDCl ₃ , 300 MHz) δ 7.76 (dd, 1H, ph, J = 8.2 Hz, J '= 4.5 Hz), 7.41 (dd, 1H, ph, J = 7.1 Hz, J ' = 2.2 Hz), 7.32 (t, 1H, ph, J = 7.4 Hz), 3.88 (m, 6H, acetal, -CHC H ₂ NPht), 3.58 (s, 3H, -CO ₂ C H ₃ ), 3.18 (dd, 1H,- _{C H CH 2 NPht. J =} 8.7Hz, J '= 5.6Hz), 1.40 (s, 3H, -COC H 3)
[148] ¹³ C NMR (CDCl ₃ , 300 MHz) δ 171.1, 168.4, 167.1, 166.8, 135.1, 135.0, 128.1, 128.0, 126.1, 121.5, 121.2, 111.6, 111.2, 108.8, 65.3, 65.8, 52.4, 51.8, 37.1, 21.9.
[149] (17) Methyl 3- (5-chloro-1,3-dioxo-1,3-dihydro-isoindol-2-yl) -2- (2-methyl- [1,3] dioxolane-2- Sun) -propionate
[150] Methyl 3-amino-2- (2-methyl- [1,3] dioxolan-2-yl) -propionate (0.40 g, 2.11 mmol) and 4-chlorophthalic anhydride (0.50 g, 2.74 mmol) As a starting material, methyl 3- (5-chloro-1,3-dioxo-1,3-dihydro-isoindol-2-yl) -2- (2-methyl- [1 , 3] dioxolan-2-yl) -propionate (0.54 g, 73%) was prepared and confirmed by ¹ H NMR, the data are as follows.
[151] _{^{1 H NMR (CDCl 3, 300MHz}} ) δ7.72 (dd, 1H, ph, J = 8.5Hz, J '= 1.7Hz), 7.60 (dd, 1H, ph, J = 8.0 Hz, J' = 1.8Hz) , 3.92 (m, 6H, -CHC H ₂ NPht, acetal H ), 3.61 (s, 3H, -CO ₂ C H ₃ ), 3.21 (dd, 1H, -C H CH ₂ NPht. J = 8.6 Hz, J = 5.8 Hz) 1.44 (s, 3H, -COCH ₃ )
[152] ¹³ C NMR (CDCl ₃ , 300 MHz) δ 171.2, 167.3, 167.0, 141.1, 134.4, 130.4, 124.9, 124.1, 108.9, 65.4, 65.1, 52.6, 51.8, 37.2, 22.1.
[153] (18) Methyl 3- (5-bromo-1,3-dioxo-1,3-dihydro-isoindol-2-yl) -2- (2-methyl- [1,3] dioxolane-2 -Yl) -propionate
[154] Methyl 3-amino-2- (2-methyl- [1,3] dioxolan-2-yl) -propionate (0.62 g, 2.75 mmol) and 4-bromophthalic anhydride (0.62 g, 2.75 mmol) As a starting material, methyl 3- (5-bromo-1,3-dioxo-1,3-dihydro-isoindol-2-yl) -2- (2-methyl- [ 1,3] dioxolan-2-yl) -propionate (0.48 g, 57 mmol) was prepared and confirmed by ¹ H NMR, the data are as follows.
[155] ¹ H NMR (CDCl ₃ , 300 MHz) δ 7.93 (s, 1H, ph), 7.89 (d, 1H, ph, J = 1.4 Hz), 7.64 (m, 1H, ph), 3.99-3.87 (m, 6H, acetal, -CHC H ₂ NPht), 3.61 (s, 3H, -CO ₂ C H ₃ ), 3.21 (m, 1H, -C H CH ₂ NPht), 1.43 (s, 3H, -COC H ₃ )
[156] ¹³ C NMR (CDCl ₃ , 300 MHz) δ 171.2, 167.5, 167.1, 137.4, 135.3, 134.0, 133.1, 131.9, 130.9, 129.4, 125.9, 108.9, 65.1, 62.7, 52.6, 37.2, 22.0, 14.3.
[157] (19) Methyl 3- (1,3-dioxo-1,3-dihydro-benzo [e] isoindol-2-yl) -2- (2-methyl- [1,3] dioxolane-2- Sun) -propionate
[158] Methyl 3-amino-2- (2-methyl- [1,3] dioxolan-2-yl) -propionate (0.40 g, 2.11 mmol) and 1,2-naphthalic anhydride (0.55 g, 2.75 mmol) Using methyl as the starting material in the same manner as in Example 1, methyl 3- (1,3-dioxo-1,3-dihydro-benzo [e] isoindol-2-yl) -2- (2-methyl- [ 1,3] dioxolan-2-yl) -propionate (0.45 g, 58%) was prepared and confirmed by ¹ H NMR, the data are as follows.
[159] ¹ H NMR (CDCl ₃ , 300 MHz) δ 8.77 (d, 1H, ph, J = 8.3 Hz), 8.00 (d, 1H, ph, J = 8.2 Hz), 7.79 (dd, 1H, ph, J = 8.2 Hz , J ' = 1.2 Hz), 7.57 (d, 1H, ph, J = 6.9 Hz), 7.49 (m, 2H, ph), 3.98-3.53 (m, 6H, acetal H , -CHC H ₂ NPht), 3.53 (s, 3H, -CO ₂ C H ₃ ), 3.20 (m, 1H, -C H CH ₂ NPht), 1.39 (s, 3H, -COC H ₃ )
[160] ¹³ C NMR (CDCl ₃ , 300 MHz) δ 171.5, 169.5, 136.9, 135.3, 131.6, 129.1 128.1, 127.8, 125.4, 118.9, 109.1, 65.4, 65.1, 52.6, 52.2, 37.0, 22.1.
[161] (20) ethyl 3- (5-nitro-1,3-dioxo-1,3-dihydro-isoindol-2-yl) -2- (2-methyl- [1,3] dioxolane-2- Sun) -propionate
[162] Ethyl 3-amino-2- (2-methyl- [1,3] dioxolan-2-yl) -propionate (800 mg, 3.94 mmol) was dissolved in 15 ml of chloroform and 4-nitrophthalic anhydride ( 988 mg, 4.33 mmol) was added and then refluxed at 80 ° C. for 5 days. After completion of the reaction, the reaction mixture was evaporated under reduced pressure, and the solvent was evaporated and separated by column chromatography (developing solvent: normal hexane: ethyl acetate = 1: 1) to obtain a yellow solid product (1.24 g, 83%). Rf = 0.32 (normal hexane: ethyl acetate = 1: 1)
[163] ¹ H NMR (CDCl ₃ , 300 MHz) δ 8.54 (m, 2H, ph), 7.98 (d, 1H, ph, J = 8.0 Hz), 4.08-3.89 (m, 8H, acetal H , -CHC H ₂ NPht, -OC H ₂ CH ₃ ), 3.23 (m, 1H, -C H CH ₂ NPht), 1.43 (s, 3H, C H ₃ ), 1.13 (t, 3H, -OCH ₂ C H _3, J = 7.1 Hz )
[164] ¹³ C NMR (CDCl ₃ , 300 MHz) 170.5, 166.2, 165.9, 152.1, 136.8, 133.8, 129.7, 124.9, 119.1, 108.9, 65.4, 65.1, 61.6, 51.8, 37.5, 22.1, 14.5.
[165] (21) ethyl 3- (4-fluoro-1,3-dioxo-1,3-dihydro-isoindol-2-yl) -2- (2-methyl- [1,3] dioxolane-2 -Yl) -propionate
[166] Ethyl 3-amino-2- (2-methyl- [1,3] dioxolan-2-yl) -propionate (0.50 g, 2.64 mmol) and 3-floorphthalic anhydride (0.57 g, 3.43 mmol) As a starting material, ethyl 3- (4-fluoro-1,3-dioxo-1,3-dihydro-isoindol-2-yl) -2- (2-methyl- [ 1,3] dioxolan-2-yl) -propionate (0.25 g, 28%) was prepared and confirmed by ¹ H NMR, the data are as follows.
[167] ¹ H NMR (CDCl ₃ , 300 MHz) δ 7.64 (m, 2H, ph), 7.31 (dd, 1H, ph, J = 8.5 Hz, J = 0.8 Hz), 4.00 (m, 8H, -C H ₂ CH ₃ , acetal H , -CHC H ₂ NPht), 3.21 (m, 1H, -C H CH2NPht, J = 8.8 Hz, J = 5.6 Hz), 1.45 (s, 3H, -COC H ₃ ), 1.13 (t, 3H , -OCH ₂ C H ₃ , J = 7.1 Hz)
[168] ¹³ C NMR (CDCl ₃ , 300 MHz) δ 170.5, 163.8, 155.152.2, 125.5, 125.1, 108.9, 65.3, 65.0, 61.5, 51.6, 37.2, 22.0, 14.3.
[169] (22) ethyl 3- (4,7-difluoro-1,3-dioxo-1,3-dihydro-isoindol-2-yl) -2- (2-methyl- [1,3] diox Solan-2-yl) -propionate
[170] Ethyl 3-amino-2- (2-methyl- [1,3] dioxolan-2-yl) -propionate (0.80 g, 3.94 mmol) with 3,6-difluorophthalic anhydride (0.94 g, 4.33 mmol) as a starting material, and in the same manner as in Example 21, ethyl 3- (4,7-difluor-1,3-dioxo-1,3-dihydro-isoindol-2-yl) -2- (2-Methyl- [1,3] dioxolan-2-yl) -propionate] was prepared and confirmed by ¹ H NMR. The data is as follows.
[171] ¹ H NMR (CDCl ₃ , 300 MHz) δ 7.96 (dd, 2H, ph, J = 5.7 Hz), 4.10 (m, 2H, -OC H ₂ CH ₃ ), 3.93 (m, 6H, acetal, -CHC H ₂ NPht), 3.21 (m, 1H, -C H CH ₂ NPht), 1.45 (s, 3H, -COC H ₃ ), 1.17 (t, 3H, -OCH ₂ C H ₃ )
[172] ¹³ C NMR (CDCl ₃ , 300 MHz) δ 170.5, 163.8, 155.7, 152.2, 125.5, 125.1, 119.1, 108.9, 65.3, 61.5, 51.6, 37.2, 22.0, 14.3.
[173] (23) ethyl 3- (4-nitro-1,3-dioxo-1,3-dihydro-isoindol-2-yl) -2- (2-methyl- [1,3] dioxolane-2- Sun) -propionate
[174] Ethyl 3-amino-2- (2-methyl- [1,3] dioxolan-2-yl) -propionate (0.68 g, 3.34 mmol) and 3-nitrophthalic anhydride (0.84 g, 4.33 mmol) Ethyl 3- (4-nitro-1,3-dioxo-1,3-dihydro-isoindol-2-yl) -2- (2-methyl- [1 as a starting material in the same manner as in Example 21 , 3] dioxolan-2-yl) -propionate (0.64 g, 51%) was prepared and confirmed by ¹ H NMR, the data are as follows.
[175] ¹ H NMR (CDCl ₃ , 300 MHz) δ 8.05 (d, 2H, ph, J = 7.8 Hz), 7.86 (t, 1H, ph, J = 7.7 Hz) 4.00 (m, 8H, acetal, -OC H ₂ CH ₃ , CHC H ₂ NPht), 3.23 (dd, 1H, -C H CH ₂ NPht J = 6.5 Hz, J = 6.1 Hz), 1.44 (s, 3H, -COC H ₃ ), 1.15 (t, 3H,- OCH ₂ C H ₃ , J = 7.1 Hz)
[176] ¹³ C NMR (CDCl ₃ , 300 MHz) 170.6, 165.8, 163.0, 145.5, 135.8, 134.4, 128.9, 127.5, 124.1, 108.9, 65.4, 65.1, 61.6, 51.6, 37.6, 2 2.1, 14.4.
[177] (24) ethyl 3- (4-methyl-1,3-dioxo-1,3-dihydro-isoindol-2-yl) -2- (2-methyl- [1,3] dioxolane-2- Sun) -propionate
[178] Ethyl 3-amino-2- (2-methyl- [1,3] dioxolan-2-yl) -propionate (0.60 g, 3.25 mmol) and 3-methylphthalic anhydride (0.79 g, 4.87 mmol) Ethyl 3- (4-methyl-1,3-dioxo-1,3-dihydro-isoindol-2-yl) -2- (2-methyl- [1 as the starting material in the same manner as in Example 21 , 3] dioxolan-2-yl) -propionate (0.57 g, 76%) was prepared and confirmed by ¹ H NMR, the data are as follows.
[179] ¹ H NMR (CDCl ₃ , 300 MHz) δ 7.57 (d, 1H, ph, J = 6.9 Hz), 7.47 (t, 1H, ph, J = 7.5 Hz), 7.37 (d, 1H, ph, J = 7.4 Hz ), 4.08-3.88 (m, 8H, acetal H , -CHC H ₂ NPht, -OC H ₂ CH ₃ ), 3.21 (m, 1H, -C H CH ₂ NPht), 2.60 (s, 3H, C H ₃ ), 1.45 (s, 3H, C H ₃ ), 1.09 (t, 3H, -OCH ₂ C H _3, J = 7.1 Hz)
[180] ¹³ C NMR (CDCl ₃ , 300 MHz) δ 170.9, 169.1, 168.3, 138.3, 136.7, 135.5, 133.8, 132.8, 121.3, 109.1, 65.1, 61.4, 52.1, 36.9, 22.1, 17.9, 14.3.
[181] (25) ethyl 3- (5-methyl-1,3-dioxo-1,3-dihydro-isoindol-2-yl) -2- (2-methyl- [1,3] dioxolane-2- Sun) -propionate
[182] Ethyl 3-amino-2- (2-methyl- [1,3] dioxolan-2-yl) -propionate (0.60 g, 3.25 mmol) and 4-methylphthalic anhydride (0.79 g, 4.87 mmol) Ethyl 3- (5-methyl-1,3-dioxo-1,3-dihydro-isoindol-2-yl) -2- (2-methyl- [1 as the starting material in the same manner as in Example 21 , 3] dioxolan-2-yl) -propionate (0.38 g, 40%) was prepared and confirmed by ¹ H NMR, the data are as follows.
[183] ¹ H NMR (CDCl ₃ , 300 MHz) δ 7.62 (d, 1H, ph, J = 7.6 Hz), 7.53 (s, 1H, ph), 7.42 (d, 1H, ph, J = 7.6 Hz), 4.08-3.85 (m, 8H, acetal H , -CHC H ₂ NPht, -OC H ₂ CH ₃ ), 3.20 (m, 1H, -C H CH ₂ NPht), 2.42 (s, 3H, C H ₃ ), 1.43 (s , 3H, C H ₃ ), 1.08 (t, 3H, -OCH ₂ C H _3, J = 7.1 Hz)
[184] ¹³ C NMR (CDCl ₃ , 300 MHz) δ 172.8, 169.1, 168.3, 145.6, 134.6, 132.7, 131.5, 131.2, 130.5, 124.2, 123.6, 109.1, 65.3, 62.2, 61.4, 51.9, 36.9, 21.8, 21.7, 14.6 .
[185] (26) ethyl 3- (5-tert-butyl-1,3-dioxo-1,3-dihydro-isoindol-2-yl) -2- (2-methyl- [1,3] dioxolane- 2-yl) -propionate
[186] Ethyl 3-amino-2- (2-methyl- [1,3] dioxolan-2-yl) -propionate (0.80 g, 3.94 mmol) and 4-tert-butylphthalic anhydride (0.88 g, 4.33 mmol) Ethyl 3- (5-tert-butyl-1,3-dioxo-1,3-dihydro-isoindol-2-yl) -2- (2-methyl- [1,3] dioxolan-2-yl) -propionate (0.54 g, 35%) was prepared and confirmed by ¹ H NMR, the data are as follows.
[187] ¹ H NMR (CDCl ₃ , 300 MHz) δ 7.78 (s, ¹ H. ph), 7.64 (dd, 2 H. ph, J = 12.8 Hz, J = 1.3 Hz), 4.07-3.87 (m, 8H, acetal H ,- CHC H ₂ NPht, -OC H ₂ CH ₃ ), 3.21 (m, 1H, -C H CH ₂ NPht), 1.44 (s, 3H, C H ₃ ), 1.29 (s, 9H, C (C H ₃ ) ₃ ), 1.10 (t, 3H, -OCH ₂ C H ₃ , J = 7.1 Hz)
[188] ¹³ C NMR (CDCl ₃ , 300 MHz) 170.8, 168.7, 158.9, 132.6, 131.3, 129.7, 123.4, 120.8, 109.0, 65.3, 65.1, 31.3, 51.9, 36.9, 36.1, 31.5, 22.1, 14.4.
[189] (27) ethyl 3- (4-hydroxy-1,3-dioxo-1,3-dihydro-isoindol-2-yl) -2- (2-methyl- [1,3] dioxolane-2 -Yl) -propionate
[190] Ethyl 3-amino-2- (2-methyl- [1,3] dioxolan-2-yl) -propionate (0.40 g, 1.96 mmol) and 3-hydroxyphthalic anhydride (0.42 g, 2.16 mmol) Was prepared as the starting material in the same manner as in Example 21 ethyl 3- (4-hydroxy-1,3-dioxo-1,3-dihydro-isoindol-2-yl) -2- (2-methyl- [1,3] dioxolan-2-yl) -propionate (0.46 g, 67%) was prepared and confirmed by ¹ H NMR, the data are as follows.
[191] ¹ H NMR (CDCl ₃ , 300 MHz) δ 7.50 (dd, 1H, ph, J = 8.3 Hz, J ' = 7.3 Hz), 7.29 (d, 1H, ph, J = 7.2 Hz), 7.08 (d, 1H , ph, J = 8.3 Hz), 3.96 (m, 8H, OC H ₂ CH _3, acetal, -CHC H ₂ NPht), 3.21 (dd, 1H, -C H CH ₂ NPht, J = 9.1 Hz, J ' = 2.3 Hz), 1.44 (s, 3H, -COC H ₃ ), 1.12 (t, 3H, -OCH ₂ C H _3, J = 7.1 Hz)
[192] ¹³ C NMR (CDCl ₃ , 300 MHz) 170.8, 170.4, 167.9, 155.1, 136.8, 132.4, 123.1, 116.4, 108.9, 65.3, 65.1, 61.5, 52.0, 36.8, 22.1, 14.4.
[193] (28) ethyl 3- (4,7-dichloro-1,3-dioxo-1,3-dihydro-isoindol-2-yl) -2- (2-methyl- [1,3] dioxolane- 2-yl) -propionate
[194] Ethyl 3-amino-2- (2-methyl- [1,3] dioxolan-2-yl) -propionate (0.80 g, 3.94 mmol) and 3,6-dichlorophthalic anhydride (0.94 g, 4.33 mmol ) As starting material, ethyl 3- (4,7-dichloro-1,3-dioxo-1,3-dihydro-isoindol-2-yl) -2- (2- Methyl- [1,3] dioxolan-2-yl) -propionate (1.10 g, 74%) was prepared and confirmed by ¹ H NMR, the data as follows.
[195] ¹ H NMR (CDCl ₃ , 300 MHz) δ 7.65 (s, 2H. Ph), 3.91-3.74 (m, 8H, acetal H , -CHC H ₂ NPht, -OC H ₂ CH ₃ ), 3.04 (m, 1H, -C H CH ₂ NPht), 1.26 (s, 3H, CH ₃ ), 0.98 (t, 3H, -OCH ₂ C H _3, J = 7.1 Hz)
[196] ¹³ C NMR (CDCl ₃ , 300 MHz) δ 200.3, 170.2, 167.6, 165.8, 139.0, 131.4, 125.5, 108.8, 65..1, 62.1, 60.4, 57.1, 51.5, 37.2, 28.9, 21.8, 14.4.
[197] (29) ethyl 3- (5,6-dichloro-1,3-dioxo-1,3-dihydro-isoindol-2-yl) -2- (2-methyl- [1,3] dioxolane- 2-yl) -propionate
[198] Ethyl 3-amino-2- (2-methyl- [1,3] dioxolan-2-yl) -propionate (0.60 g, 3.25 mmol) and 4,5-dichlorophthalic anhydride (0.85 g, 3.90 mmol ) As starting material, ethyl 3- (5,6-dichloro-1,3-dioxo-1,3-dihydro-isoindol-2-yl) -2- (2- Methyl- [1,3] dioxolan-2-yl) -propionate (0.66 g, 50%) was prepared and confirmed by ¹ H NMR, the data as follows.
[199] ¹ H NMR (CDCl ₃ , 300 MHz) δ 7.87 (s, 2H. Ph), 4.07-3.88 (m, 8H, acetal H , -CHC H ₂ NPht, -OC H ₂ CH ₃ ), 3.20 (m, 1H , -C H CH ₂ NPht), 1.42 (s, 3H, C H ₃ ), 1.14 (t, 3H, -OCH ₂ C H _3, J = 7.1 Hz)
[200] ¹³ C NMR (CDCl ₃ , 300 MHz) 170.6, 166.3, 139.3, 135.8, 131.5, 131.2, 125.8, 109.0, 65.3, 65.1, 62.8, 61.5, 51.8, 37.4, 22.1, 14.4, 14.3.
[201] (30) ethyl 3- (1,3-dioxo-4-phenyl-1,3-dihydro-benzo [f] isoindol-2-yl) -2- (2-methyl- [1,3] diox Solan-2-yl) -propionate
[202] Ethyl 3-amino-2- (2-methyl- [1,3] dioxolan-2-yl) -propionate (0.80 g, 3.93 mmol) and 1-phenyl-2,3-naphthalic anhydride (1.19 g , 3.93 mmol) as a starting material, in the same manner as in Example 21, ethyl 3- (1,3-dioxo-4-phenyl-1,3-dihydro-benzo [f] isoindol-2-yl)- 2- (2-Methyl- [1,3] dioxolan-2-yl) -propionate (1.12 g, 62%) was prepared and confirmed by ¹ H NMR, the data are as follows.
[203] ¹ H NMR (CDCl ₃ , 300Mz) δ 8.28 (s, 1H. Ph), 7.98 (d, 1H. Ph), 7.70 d, 1H. ph), 7.60 (t, 1H. ph), 7.44 (m, 4H. ph), 7.31 (m, 2H. ph), 4.05-3.81 (m, 8H, acetal, -CHC H ₂ NPht, -OC H ₂ CH ₃ ), 3.23 (m, 1H, -C H CH ₂ NPht), 1.42 (s, 3H, -COC H ₃ ), 1.07 (t, 3H, -OCH ₂ C H ₃ )
[204] ¹³ C NMR (CDCl ₃ , 300 MHz) 170.8, 167.7, 140.6, 135.8, 134.8, 130.7, 130.3, 130.2, 129.5, 128.9, 128.6, 124.6, 124.1, 109.1, 65.3, 65.1, 61.3, 51.7, 37.2, 22.1, 14.4 .
[205] (31) ethyl 3- (1,3-dioxo-1,3,4,5,6,7-hexahydro-isoindol-2-yl) -2- (2-methyl- [1,3] diox Solan-2-yl) -propionate
[206] Ethyl 3-amino-2- (2-methyl- [1,3] dioxolan-2-yl) -propionate (0.80 g, 3.94 mmol) and 3,4,5,6-tetrahydrophthalic anhydride ( 0.78 g, 4.33 mmol) in ethyl 3- (1,3-dioxo-1,3,4,5,6,7-hexahydro-isoindol-2-yl in the same manner as in Example 21 ) -2- (2-methyl- [1,3] dioxolan-2-yl) -propionate (0.91 g, 69%) was prepared and confirmed by ¹ H NMR, the data are as follows.
[207] ¹ H NMR (CDCl ₃ , 300 MHz) δ 4.12 (q, 2H, -OC H ₂ CH _3, J = 6.1 Hz), 3.99 (m, 4H, acetal), 3.88 (dd, 1H, -CHC H ₂ NPht _, J = 12.2 Hz, J ' = 4.5 Hz), 3.74 (dd, 1H, -CHC H ₂ NPht _, J = 12.2 Hz, J' = 4.5 Hz), 3.12 (m, 1H, -C H CH ₂ NPht), 2.28 (s, 4H, cyclohexane), 1.71 (s, 4H, cyclohexane), 1.46 (s, 3H, -COCH ₃ ), 1.2 (t, 3H, -OCH ₂ C H ₃ )
[208] ¹³ C NMR (CDCl ₃ , 300 MHz) 171.1, 170.9, 141.9, 108.9, 65.2, 65.0, 61.3, 52.4, 36.6, 22.1, 21.7, 20.3, 14.4.
[209] (32) ethyl 3- (2,5-dioxo-3-phenyl-2,5-dihydro-pyrrol-1-yl) -2- (2-methyl- [1,3] dioxolan-2-yl ) -Propionate
[210] Ethyl 3-amino-2- (2-methyl- [1,3] dioxolan-2-yl) -propionate (0.40 g, 1.96 mmol) and phenylmaleic anhydride (0.57 g, 2.16 mmol) were started. In the same manner as in Example 21, ethyl 3- (2,5-dioxo-3-phenyl-2,5-dihydro-pyrrol-1-yl) -2- (2-methyl- [1,3] Dioxolan-2-yl) -propionate (0.41 g, 58%) was prepared and confirmed by ¹ H NMR, the data are as follows.
[211] ¹ H NMR (CDCl ₃ , 300 MHz) δ 7.84 (m, 2H. Ph), 7.38 (m, 3H. Ph), 6.65 (s, 1H, = C H ), 4.08-3.82 (m, 8H, acetal H , -CHC H ₂ NPht, -OC H ₂ CH ₃ ), 3.20 (m, 1H, -C H CH2NPht), 1.43 (s, 3H, C H ₃ ), 1.15 (t, 3H, -OCH ₂ C H ₃ , J = 7.1 Hz)
[212] ¹³ C NMR (CDCl ₃ , 300 MHz) 175.9, 170.8, 170.2, 144.2, 131.5, 131.4, 129.3, 129.3, 129.1, 128.9, 128.7, 124.3, 109.2, 109.0, 65.1, 64.9, 52.0, 40.5, 22.0, 14.5.
[213] (33) ethyl 3- (2,5-dioxo-3,4-diphenyl-2,5-dihydro-pyrrol-1-yl) -2- (2-methyl- [1,3] dioxolane- 2-yl) -propionate
[214] Ethyl 3-amino-2- (2-methyl- [1,3] dioxolan-2-yl) -propionate (0.80 g, 3.94 mmol) and 1,2-diphenylmaleic anhydride (1.10 g, 4.33 mmol) as a starting material and in the same manner as in Example 21, ethyl 3- (2,5-dioxo-3,4-diphenyl-2,5-dihydro-pyrrole-1-yl) -2- (2 -Methyl- [1,3] dioxolan-2-yl) -propionate (1.00 g, 61%) was prepared and confirmed by ¹ H NMR, the data is as follows.
[215] ¹ H NMR (CDCl ₃ , 300 MHz) δ 7.39 (m, 4H. Ph), 7.28 (m, 6H. Ph), 7.09 (q, 2H, -OC H ₂ CH _3, J = 7.1 Hz), 3.93 ( m, 6H, acetal, -CHC H ₂ NPht), 3.21 (m, 1H, -C H CH ₂ NPht), 1.45 (s, 3H, -COC H ₃ ), 1.17 (t, 3H, -OCH ₂ C H _3, J = 7.1 Hz)
[216] ¹³ C NMR (CDCl ₃ , 300 MHz) 170.9, 170.7, 136.6, 130.2, 128.9, 109.0, 65.3, 65.1, 61.4, 52.0, 37.4, 22.1, 14.5.
[217] (34) ethyl 3- (5-fluoro-1,3-dioxo-1,3-dihydro-isoindol-2-yl) -2- (2-methyl- [1,3] dioxolane-2 -Yl) -propionate
[218] Ethyl 3-amino-2- (2-methyl- [1,3] dioxolan-2-yl) -propionate (0.80 g, 3.94 mmol) with 4-fluoropropionic anhydride (0.78 g, 4.72 mmol) Was prepared as the starting material in the same manner as in Example 21 ethyl 3- (5-fluoro-1,3-dioxo-1,3-dihydro-isoindol-2-yl) -2- (2-methyl- [1,3] dioxolan-2-yl) -propionate (0.77 g, 56%) was prepared and confirmed by ¹ H NMR, the data are as follows.
[219] _{^{1 H NMR (CDCl 3, 300MHz}} ) δ7.76 (dd, 1H. Ph, J = 5.8Hz, J '= 4.5Hz), 7.41 (dd, 1H. Ph, J = 7.1Hz, J' = 2.2Hz) , 7.31 (ddd, 1 H. ph, J = 9.0 Hz, J ' = 9.3 Hz, J' ' = 2.3 Hz), 3.99 (m, 8H, acetal, -CHC H ₂ NPht, -OC H ₂ CH ₃ ), 3.19 (dd, 1H, -C H CH ₂ NPht, J = 8.9 Hz, J ' = 5.5 Hz), 1.41 (s, 3H, -COCH ₃ ), 1.09 (t, 3H, -OCH ₂ C H _3, J = 7.1 Hz)
[220] ¹³ C NMR (CDCl ₃ , 300 MHz) 170.6, 168.4, 167.1, 166.8, 135.2, 165.0, 128.1, 125.9, 111.5, 111.2, 65.2, 65.0, 61.3, 51.8, 37.1, 21.9, 14.3.
[221] (35) ethyl 3- (5-chloro-1,3-dioxo-1,3-dihydro-isoindol-2-yl) -2- (2-methyl- [1,3] dioxolane-2- Sun) -propionate
[222] Ethyl 3-amino-2- (2-methyl- [1,3] dioxolan-2-yl) -propionate (0.40 g, 1.97 mmol) and 4-chlorophthalic anhydride (0.47 G, 2.56 mmol) As a starting material, ethyl 3- (5-chloro-1,3-dioxo-1,3-dihydro-isoindol-2-yl) -2- (2-methyl- [1 was obtained in the same manner as in Example 21. , 3] dioxolan-2-yl) -propionate (0.37 g, 50%) was prepared and confirmed by ¹ H NMR, the data are as follows.
[223] _{^{1 H NMR (CDCl 3, 300MHz}} ) δ7.72 (dd, 2H, ph, J = 8.6Hz, J = 1.5Hz), 7.60 (dd, 1H, ph, J = 7.9Hz, J = 1.8Hz), 3.93 (m, 8H, acetal, -CHC H ₂ NPht, -OC H ₂ CH ₃ ), 3.21 (dd, 1H, -C H CH2NPht J = 8.8 Hz, J = 5.6 Hz), 1.44 (s, 3H, -COCH3 ), 1.12 (t, 3H, -OCH ₂ C H ₃ , J = 7.1 Hz)
[224] ¹³ C NMR (CDCl ₃ , 300 MHz) 170.6, 167.3, 141.1, 134.4, 130.5, 124.9, 109.0, 65.3, 61.4, 51.8, 37.2, 22.1, 14.4.
[225] (36) ethyl 3- (5-bromo-1,3-dioxo-1,3-dihydro-isoindol-2-yl) -2- (2-methyl- [1,3] dioxolane-2 -Yl) -propionate
[226] Ethyl 3-amino-2- (2-methyl- [1,3] dioxolan-2-yl) -propionate (0.40 g, 1.97 mmol) and 4-bromophthalic anhydride (0.58 g, 2.56 mmol) As a starting material, ethyl 3- (5-bromo-1,3-dioxo-1,3-dihydro-isoindol-2-yl) -2- (2-methyl- [ 1,3] dioxolan-2-yl) -propionate (0.42 g, 52%) was prepared and confirmed by ¹ H NMR, the data are as follows.
[227] ¹ H NMR (CDCl ₃ , 300 MHz) δ7.76 (dd, 1H, ph, J = 8.2 Hz, J = 4.5 Hz), 7.41 (dd, 1H, ph, J = 7.0 Hz, J = 2.2 Hz), 7.32 (t, 1H, ph, J = 9.7 Hz), 4.07-3.87 (m, 8H, acetal, -CHC H ₂ NPht, -OC H ₂ CH ₃ ), 3.91 (dd, 1H, -C H CH ₂ NPht, J = 8.9 Hz, J = 5.5 Hz), 1.42 (s, 3H, -COC H ₃ ), 1.09 (t, 3H, -OCH ₂ C H _3, J = 7.1 Hz)
[228] ¹³ C NMR (CDCl ₃ , 300 MHz) 170.6, 168.4, 167.1, 166.8, 135.1, 135.0, 128.1, 126.0, 125.9, 121.5, 111.5, 108.9, 65.2, 61.3, 51.8, 37.1, 21.9, 14.3.
[229] (37) ethyl 3- (1,3-dioxo-1,3-dihydro-benzo [e] isoindol-2-yl) -2- (2-methyl- [1,3] dioxolane-2- Sun) -propionate
[230] Ethyl 3-amino-2- (2-methyl- [1,3] dioxolan-2-yl) -propionate (0.40 g, 1.97 mmol) and 1,2-naphthalic anhydride (0.51 g, 2.56 mmol) Was prepared as the starting material in the same manner as in Example 21 ethyl 3- (1,3-dioxo-1,3-dihydro-benzo [e] isoindol-2-yl) -2- (2-methyl- [ 1,3] dioxolan-2-yl) -propionate (0.55 g, 73%) was prepared and confirmed by ¹ HNMR, the data are as follows.
[231] ¹ H NMR (CDCl ₃ , 300 MHz) δ 8.87 (dd, 1H, ph, J = 8.4 Hz, J = 0.4 Hz), 8.08 (d, 1H, ph, J = 8.3 Hz), 7.80 (d, 1H, ph , J = 7.7 Hz), 7.76 (d, 1H, ph, J = 8.2 Hz), 7.62 (m, 2H, ph), 4.09-3.90 (m, 8H, acetal H , -CHC H ₂ NPht, -OC H ₂ CH ₃ ), 3.27 (m, 1H, -C H CH ₂ NPht) 1.48 (s, 3H, -C H ₃ ), 1.09 (t, 3H, -OCH ₂ C H _3, J = 7.1 Hz)
[232] ¹³ C NMR (CDCl ₃ , 300 MHz) δ 170.3, 169.5, 168.9, 136.9, 135.3, 131.6, 129.9, 129.1, 129.0, 127.7, 118.8, 109.1, 65.3, 65.1, 52.1, 37.0, 22.1, 14.4
[233] (38) Allyl 3- (4-Fluoro-1,3-dioxo-1,3-dihydro-isoindol-2-yl) -2- (2-methyl- [1,3] dioxolane-2 -Yl) -propionate
[234] Allyl 3-amino-2- (2-methyl- [1,3] dioxolan-2-yl) -propionate (400 mg, 1.86 mmol) is dissolved in 10 ml of chloroform and 3-fluorophthalic anhydride ( 401 mg, 2.42 mol) was added and then refluxed at 80 ° C. for 3 days. After completion of the reaction, the mixture was distilled under reduced pressure to evaporate the solvent, and the residue was separated by column chromatography (developing solvent: normal hexane: ethyl acetate = 3: 1) to obtain a white solid product (351 mg, 52%). Rf = 0.29 (developing solvent: normal hexane: ethyl acetate = 2: 1)
[235] ¹ H NMR (CDCl ₃ , 300 MHz) δ7.62 (m, 2H, ph), 7.32 (t, 1H, ph, J = 7.8 Hz), 5.80 (m, 1H, -CH ₂ C H = CH ₂ ), 5.22 (d, 1H, -CH ₂ CH = C H _2, J = 10.0 Hz), 5.07 (d, 1H, -CH ₂ CH = C H _2, J = 9.0 Hz), 4.51 (d, 1H, C H ₂ CH = CH _2, J = 5.9 Hz), 4.01-3.89 (m, 6H, acetal H , -CHC H ₂ NPht), 3.55 (m, 1H, -C H CH ₂ NPht), 1.45 (s, 3H, -COC H ₃ )
[236] ¹³ C NMR (CDCl ₃ , 300 MHz) δ 170.4, 165.0, 137.1, 132.1, 122.9, 119.9, 108.9, 66.1, 65.3, 51.8, 37.1, 22.1.
[237] (39) allyl 3- (4,7-difluoro-1,3-dioxo-1,3-dihydro-isoindol-2-yl) -2- (2-methyl- [1,3] diox Solan-2-yl) -propionate
[238] Allyl 3-amino-2- (2-methyl- [1,3] dioxolan-2-yl) -propionate (400 mg, 1.86 mmol) is dissolved in 10 ml of chloroform, 4,7-difluoro Talic anhydride (445 mg, 2.42 mol) was added and then refluxed at 80 ° C. for 3 days. After completion of the reaction, the mixture was distilled under reduced pressure to evaporate the solvent, and the residue was separated by column chromatography (developing solvent: normal hexane: ethyl acetate = 3: 1) to obtain an oil product (369 mg, 52%). Rf = 0.34 (developing solvent: normal hexane: ethyl acetate = 2: 1)
[239] ¹ H NMR (CDCl ₃ , 300 MHz) δ7.30 (t, 2H, J = 5.6 Hz, ph), 5.79 (m, 1H, -CH ₂ C H = CH ₂ ), 5.22 (dd, 1H, -CH ₂ CH = C H _2, J = 1.46 Hz, J = 17.2 Hz), 5.10 (dd, 1H, -CH ₂ CH = C H _2, J = 1.1 Hz. J = 10.4 Hz), 4.52 (d, 1H, C H ₂ CH = CH _2, J = 5.8 Hz), 3.93 (m, 6H, acetal H , -CHC H ₂ NPht), 3.23 (m, 1H, -C H CH ₂ NPht), 1.44 (s, 3H,- COC H ₃ )
[240] ¹³ C NMR (CDCl ₃ , 300 MHz) δ 170.3, 163.9, 154.0, 132.1, 125.2, 119.0, 108.9, 66.2, 65.3, 65.1, 51.6, 37.2, 22.1.
[241] Example 6. Preparation of Compound (VI)
[242] (1) Methyl 2- (4-hydroxy-1,3-dioxo-1,3-dihydro-isoindol-2-ylmethyl) -3-oxo-butyrate
[243] Methyl 3- (4-hydroxy-1,3-dioxo-1,3-dihydro-isoindol-2-yl) -2- (2-methyl- [1,3] dioxolan-2-yl) Propionate (0.84 g, 2.51 mmol) was dissolved in 24 ml of acetone / water (v / v = 5/1) and para-toluenesulfonic acid monohydrate (about 0.19 g) was added, followed by 100 It was refluxed for 2 days at ℃. After completion of the reaction, the reaction mixture was concentrated under reduced pressure, concentrated, extracted with dichloromethane, and separated by column chromatography (developing solvent: normal hexane: ethyl acetate = 2: 1) to obtain the target compound (0.55 mg, 75%).
[244] ^OneH NMR (CDCl₃, 300 MHz) δ 7.52 (dd, 1H, ph,J= 7.5 Hz,J'= 7.3 Hz), 7.29 (d, 1H, ph,J'= 7.2 Hz), 7.09 (d, 1H, ph,J= 3.70 Hz) 4.08 (m, 2H, -CHC)H ₂NPht), 3.97 (dd, 1H, -CHCH₂NPht_, J= 8.3 Hz, J '= 6.3 Hz), 3.68 (s, 3H -CO₂C H ₃), 1.43 (s, 3H, -COCH ₃)
[245] ¹³ C NMR (CDCl ₃ , 300 MHz) δ 200.7, 170.1, 168.4, 167.8, 155.1, 136.9, 132.1, 123.3, 116.6, 114.7, 57.5, 53.3, 36.2, 29.4.
[246] (2) Methyl 2- (4-fluoro-1,3-dioxo-1,3-dihydro-isoindol-2-ylmethyl) -3-oxo-butyrate
[247] Methyl 3- (4-fluoro-1,3-dioxo-1,3-dihydro-isoindol-2-yl) -2- (2-methyl- [1,3] dioxolan-2-yl) Methyl 2- (4-fluoro-1,3-dioxo) in the same manner as in Example 40 using propionate (0.23 g, 0.70 mmol) and para-toluenesulfonic acid monohydrate (20 mg) as starting materials -1,3-dihydro-isoindol-2-ylmethyl) -3-oxo-butyrate (71 mg, 34%) was prepared and confirmed by ¹ H NMR, the data are as follows.
[248] ¹ H NMR (CDCl ₃ , 300 MHz) δ 7.61 (m, 2H, ph), 7.30 (t, 1H, ph, J = 8.9 Hz), 4.05-3.88 (m, 6H, acetal H , -CHC H ₂ NPht) , 3.61 (s, 3H, -CO ₂ C H ₃ ) 3.22 (m, 1H, -C H CH ₂ NPht), 1.44 (s, 3H, -COC H ₃ )
[249] ¹³ C NMR (CDCl ₃ , 300 MHz) δ 206.1, 168.4, 165.2, 159.6, 156.1, 137.3, 134.6, 123.1, 122.9, 122.8, 120.7, 120.1, 119.9, 118.0, 57.4, 41.7, 36.4, 33.5.
[250] (3) Methyl 2- (4,7-difluoro-1,3-dioxo-1,3-dihydro-isoindol-2-ylmethyl) -3-oxo-butyrate
[251] Methyl 3- (4,7-difluoro-1,3-dioxo-1,3-dihydro-isoindol-2-yl) -2- (2-methyl- [1,3] dioxolane-2 Methyl 2- (4,7-difluoro-) in the same manner as in Example 40 using -yl) -propionate (0.24 g, 0.67 mmol) and para-toluenesulfonic acid monohydrate (51 mg) as starting materials 1,3-dioxo-1,3-dihydro-isoindol-2-ylmethyl) -3-oxo-butyrate (46 mg, 19%) was prepared and confirmed by ¹ H NMR, the data being Same as
[252] ¹ H NMR (CDCl ₃ , 300 MHz) δ 7.33 (t, 2H, ph, J = 5.3 Hz), 4.08 (m, 2H, -CHC H ₂ NPht), 3.93 (d, 1H, -C H CH ₂ NPht _, J = 6.7 Hz), 3.69 (s, 3H -CO ₂ C H ₃ ), 2.23 (s, 3H, -COC H ₃ )
[253] ¹³ C NMR (CDCl ₃ , 300 MHz) δ 200.5, 178.1, 173.0. 168.3, 163.9, 155.8, 152.3, 125.7, 118.9, 95.6, 57.2, 53.5, 36.5, 35.9, 29.3, 19.7.
[254] (4) Methyl 2- (4-nitro-1,3-dioxo-1,3-dihydro-isoindol-2-ylmethyl) -3-oxo-butyrate
[255] Methyl 3- (4-nitro-1,3-dioxo-1,3-dihydro-isoindol-2-yl) -2- (2-methyl- [1,3] dioxolan-2-yl)- Methyl 2- (4-nitro-1,3-dioxo-1,3 in the same manner as above, starting with propionate (0.24 g, 0.67 mmol) and para-toluenesulfonic acid monohydrate (51 mg) -Dihydro-isoindol-2-ylmethyl) -3-oxo-butyrate was prepared and confirmed by ¹ H NMR, the data are as follows.
[256] ¹ H NMR (CDCl ₃ , 300 MHz) δ 8.06 (m, 2H, ph), 7.87 (t, 1H, ph, J = 7.8 Hz), 4.14 (dd, 2H, -CHC H ₂ NPht, J = 12.0 Hz, J '= 5.8 Hz), 3.96 (t, 1H, -C H CH ₂ NPht. J = 6.4 Hz), 3.68 (s, 3H, -CO ₂ C H ₃ , 2.23 (s, 3H, -COC H ₃ )
[257] ¹³ C NMR (CDCl ₃ , 300 MHz) δ 200.5, 168.3, 165.6, 162.9, 145.5, 136.0, 134.2, 129.2, 127.7, 123.9, 57.1, 53.4, 36.9, 29.4, 22.1.
[258] (5) Methyl 2- (5-nitro-1,3-dioxo-1,3-dihydro-isoindol-2-ylmethyl) -3-oxo-butyrate
[259] Methyl 3- (5-nitro-1,3-dioxo-1,3-dihydro-isoindol-2-yl) -2- (2-methyl- [1,3] dioxolan-2-yl)- Methyl 2- (5-nitro-1,3-dioxo-1) in the same manner as in Example 40 using propionate (0.29 g, 0.82 mmol) and para-toluenesulfonic acid monohydrate (50 mg) as starting materials , 3-dihydro-isoindol-2-ylmethyl) -3-oxo-butyrate (95 mg, 35%) was prepared and confirmed by ¹ H NMR, the data are as follows.
[260] ¹ H NMR (CDCl ₃ , 300 MHz) δ 8.55 (m, 2H, ph), 7.98 (d, 1H, ph, J = 5.1 Hz), 4.15 (m, 2H, -CHC H ₂ NPht), 3.97 (m, 1H, -C H CH ₂ NPht), 3.68 (s, 3H, -CO ₂ C H ₃ ), 2.23 (s, 3H, -COC H ₃ )
[261] ¹³ C NMR (CDCl ₃ , 300 MHz) δ 200.4, 168.2, 166.1, 152.3, 136.6, 129.6, 125.1, 119.3, 91.3, 57.1, 53.4, 36.9, 29.4.
[262] (6) Methyl 2- (4-methyl-1,3-dioxo-1,3-dihydro-isoindol-2-ylmethyl) -3-oxo-butyrate
[263] Methyl 3- (4-methyl-1,3-dioxo-1,3-dihydro-isoindol-2-yl) -2- (2-methyl- [1,3] dioxolan-2-yl)- Methyl 2- (4-methyl-1,3-dioxo-1 in the same manner as in Example 40 using propionate (0.37 g, 1.31 mmol) and para-toluenesulfonic acid monohydrate (51 mg) as starting materials , 3-Dihydro-isoindol-2-ylmethyl) -3-oxo-butyrate (117 mg, 31%) was prepared and confirmed by ¹ H NMR, the data are as follows.
[264] ¹ H NMR (CDCl ₃ , 300 MHz) δ 7.57 (d, 1H, ph, J = 7.2 Hz), 7.49 (t, 1H, ph, J = 7.6 Hz), 7.38 (d, 1H, ph, J = 7.6 Hz ), 4.10 (m, 2H, -CHC H ₂ NPht), 3.95 (dd, 1H, -C H CH ₂ NPht _, J = 8.1 Hz, J ' = 6.6 Hz), 3.67 (s, 3H, -CO ₂ C H ₃ ), 2.60 (s, 3H, C H ₃ ), 2.22 (s, 3H, COC H ₃ )
[265] ¹³ C NMR (CDCl ₃ , 300 MHz) δ 200.9, 168.9, 168.5, 138.5, 136.9, 134.0, 132.6, 128.9, 121.5, 57.8, 57.7, 53.2, 36.1, 29.3, 17.9.
[266] (7) Methyl 2- (5-methyl-1,3-dioxo-1,3-dihydro-isoindol-2-ylmethyl) -3-oxo-butyrate
[267] Methyl 3- (5-methyl-1,3-dioxo-1,3-dihydro-isoindol-2-yl) -2- (2-methyl- [1,3] dioxolan-2-yl)- Methyl 2- (5-methyl-1,3-dioxo-1,3 in the same manner as above, starting with propionate (0.10 g, 0.30 mmol) and para-toluenesulfonic acid monohydrate (10 mg) -Dihydro-isoindol-2-ylmethyl) -3-oxo-butyrate (23 mg, 26%) was prepared and confirmed by ¹ H NMR, the data are as follows.
[268] ¹ H NMR (CDCl ₃ , 300 MHz) δ7.63 (d, 1H, ph, J = 7.6 Hz), 7.56 (s, 1H, ph), 7.43 (d, 1H, ph, J = 7.7 Hz) 4.09 (m , 2H, -CHC H ₂ NPht), 3.95 (dd, 1H, -C H CH ₂ NPht _, J = 8.3 Hz, J ' = 6.5 Hz), 3.66 (s, 3H, -CO ₂ C H ₃ ), 2.50 (s, 3H, -C H ₃ ), 2.21 (s, 3H, -COC H ₃ )
[269] ¹³ C NMR (CDCl ₃ , 300 MHz) δ 200.9, 168.5, 168.4, 168.3, 145.9, 135.1, 132.5, 129.7, 124.4, 123.7, 57.69, 53.3, 36.3, 29.4, 36.3, 29.4, 22.4.
[270] (8) Methyl 2- (5-tert-butyl-1,3-dioxo-1,3-dihydro-isoindol-2-ylmethyl)-3-oxo-butyrate
[271] Methyl 3- (5-tert-butyl-1,3-dioxo-1,3-dihydro-isoindol-2-yl) -2- (2-methyl- [1,3] dioxolan-2-yl ) 2-propionate (0.14 g, 0.34 mmol) and para-toluenesulfonic acid monohydrate (13 mg) were used as starting materials for methyl 2- (5-tert-butyl-1,3- Dioxo-1,3-dihydro-isoindol-2-ylmethyl) -3-oxo-butyrate (42 mg, 34%) was prepared and confirmed by ¹ H NMR, the data are as follows.
[272] ¹ H NMR (CDCl ₃ , 300 MHz) δ 7.79 (s, 1H, ph), 7.66 (m, 2H, ph), 3.87 (dd, 2H, -CHC H ₂ NPht, J = 7.5 Hz, J = 7.2 Hz ), 3.67 (s, 3H, -CO ₂ C H ₃ ), 2.79 (dd, 1H, -C H CH ₂ NPht, J = 7.5 Hz, J = 6.5 Hz), 2.23 (s, 3H, -CO ₂ C H ₃ ), 1.29 (s, 3H, -C (C H ₃ ) ₃ )
[273] ^`13 C NMR (CDCl ₃ , 300 MHz) δ 206.2, 200.8, 168.9, 159.2, 132.6, 132.4, 129.7, 123.6, 121.0, 57.4, 53.2, 42.0, 36.3, 36.1, 33.3, 31.5, 30.3, 29.3.
[274] (9) Methyl 2- (4,7-dichloro-1,3-dioxo-1,3-dihydro-isoindol-2-ylmethyl) -3-oxo-butyrate
[275] Methyl 3- (4,7-dichloro-1,3-dioxo-1,3-dihydro-isoindol-2-yl) -2- (2-methyl- [1,3] dioxolan-2-yl ) 2-propionate (0.20 g, 0.52 mmol) and para-toluenesulfonic acid monohydrate (50 mg) were used as starting materials for methyl 2- (4,7-dichloro-1,3- Dioxo-1,3-dihydro-isoindol-2-ylmethyl) -3-oxo-butyrate (69 mg, 39%) was prepared and confirmed by ¹ H NMR, the data are as follows.
[276] ¹ H NMR (CDCl ₃ , 300 MHz) δ 7.49 (s, 2H, ph), 4.10 (m, 2H, -CHC H ₂ NPht), 3.95 (m, 2H, -CHC H ₂ NPht), 3.69 (s, 3H, -CO ₂ C H ₃ ), 2.23 (s, 3H, -COC H ₃ )
[277] ¹³ C NMR (CDCl ₃ , 300 MHz) δ 200.6, 168.3, 164.4, 137.1, 136.9, 130.5, 129.4, 57.3, 53.4, 36.5, 29.3.
[278] (10) Methyl 2- (5,6-dichloro-1,3-dioxo-1,3-dihydro-isoindol-2-ylmethyl) -3-oxo-butyrate
[279] Methyl 3- (5,6-dichloro-1,3-dioxo-1,3-dihydro-isoindol-2-yl) -2- (2-methyl- [1,3] dioxolan-2-yl ) -Propionate (0.24 g, 0.67 mmol) and para-toluenesulfonic acid monohydrate (51 mg) were used as starting materials for methyl 2- (5,6-dichloro-1,3- Dioxo-1,3-dihydro-isoindol-2-ylmethyl) -3-oxo-butyrate (46 mg, 19%) was prepared and confirmed by ¹ H NMR, the data are as follows.
[280] ¹ H NMR (CDCl ₃ , 300 MHz) δ 7.85 (s, 2H, ph), 4.09 (m, 2H, -CHC H ₂ NPht), 3.93 (m, 1H, -C H CH ₂ NPht), 3.58 (s, 3H, -CO ₂ C H ₃ ), 2.21 (s, 3H, -COC H ₃ )
[281] ¹³ C NMR (CDCl ₃ , 300 MHz) δ 200.5, 168.3, 166.2, 139.6, 139.2, 131.6, 131.3, 125.9, 125.7, 95.7, 62.3, 57.3, 36.7, 29.4, 19.8.
[282] (11) Methyl 2- (1,3-dioxo-1,3-dihydro-benzo [f] isoindol-2-ylmethyl) -3-oxo-butyrate
[283] Methyl 3- (1,3-dioxo-1,3-dihydro-benzo [f] isoindol-2-yl) -2- (2-methyl- [1,3] dioxolan-2-yl)- Methyl 2- (1,3-dioxo-1,3-dihydro) in the same manner as in Example 40 using propionate (40 mg, 0.11 mmol) and pyridinium paratoluene sulfonate (5 mg) as starting materials -Benzo [f] isoindol-2-ylmethyl) -3-oxo-butyrate (18 mg, 51%) was prepared and confirmed by ¹ H NMR, the data are as follows.
[284] ¹ H NMR (CDCl ₃ , 300 MHz) δ 8.26 (s, 2H, ph), 7.98 (m, 2H, ph), 7.62 (m, 2H, ph), 4.18 (m, 2H, -CHC H ₂ NPht), 4.01 (dd, 1H, -C H CH ₂ NPht _, J = 8.2 Hz, J ' = 6.6 Hz), 3.68 (s, 3H, -CO ₂ C H ₃ ), 2.24 (s, 3H, -COC H ₃ )
[285] ¹³ C NMR (CDCl ₃ , 300 MHz) δ 200.8, 168.6, 167.9, 135.9, 130.7, 129.7, 127.8, 125.4, 124.9, 57.6, 53.3, 36.6, 29.4.
[286] (12) Methyl 2- (1,3-dioxo-4-phenyl-1,3-dihydro-benzo [f] isoindol-2-ylmethyl) -3-oxo-butyrate
[287] Methyl 3- (1,3-dioxo-4-phenyl-1,3-dihydro-benzo [f] isoindol-2-ylmethyl) -2- (2-methyl- [1,3] dioxolane- Methyl 2- (1,3-dioxo-4) in the same manner as in Example 40 using 2-yl) -propionate (44 mg, 0.12 mmol) and pyridinium paratoluene sulfonate (7 mg) as starting materials -Phenyl-1,3-dihydro-benzo [f] isoindol-2-ylmethyl) -3-oxo-butyrate (21 mg, 54%) was prepared and confirmed by ¹ H NMR. Same as
[288] ¹ H NMR (CDCl ₃ , 300 MHz) δ 8.30 (s, 1H, ph), 8.01 (d, 2H, ph, J = 7.8 Hz), 7.73 (d, 2H, ph, J = 8.3 Hz),, 7.64 ( t, 1H, ph, J = 7.5 Hz), 7.49 (m, 4H, ph), 4.24 (m, 2H, -CHC H ₂ NPht), 4.08 (m, 1H, -C H CH ₂ NPht), 3.72 ( s, 3H, -CO ₂ C H ₃ ), 2.28 (s, 3H, -COC H ₃ )
[289] ¹³ C NMR (CDCl ₃ , 300 MHz) δ 200.8, 168.6, 157.6, 167.4, 140.9, 135.9, 135.8, 134.7, 130.7, 129.6, 129.0, 128.9, 128.5, 127.8, 125.8, 124.9, 123.9, 57.4, 53.2, 36.5, 29.2, 14.0.
[290] (13) Methyl 2- (1,3-dioxo-1,3,4,5,6,7-hexahydro-isoindol-2-ylmethyl) -3-oxo-butyrate
[291] Methyl 3- (1,3-dioxo-1,3,4,5,6,7-hexahydro-isoindol-2-ylmethyl) -2- (2-methyl- [1,3] dioxolane- Methyl 2- (1,3-dioxo-1) in the same manner as in Example 40 using 2-yl) -propionate (1.36 g, 4.21 mmol) and pyridinium paratoluene sulfonate (150 mg) as starting material , 3,4,5,6,7-hexahydro-isoindol-2-ylmethyl) -3-oxo-butyrate (360 mg, 31%) was prepared and confirmed by ¹ H NMR. Same as
[292] ¹ H NMR (CDCl ₃ , 300 MHz) δ 3.89 (m, 3H, -CHC H ₂ NPht, -C H CH ₂ NPht), 3.67 (s, 3H, -CO ₂ C H ₃ ), 2.24 (s, 4H, cyclohexene), 2.19 (s, 3H, -COC H ₃ ), 1.69 (s, 4H, cyclohexene)
[293] ¹³ C NMR (CDCl ₃ , 300 MHz) δ 200.9, 170.8, 168.5, 142.1, 57.8, 53.1, 35.9, 29.1, 21.6, 20.2.
[294] (14) Methyl 2- (2,5-dioxo-3-phenyl-2,5-dihydro-pyrrol-1-ylmethyl) -3-oxo-butyrate
[295] Methyl 3- (2,5-dioxo-3-phenyl-2,5-dihydro-pyrrole-1-ylmethyl) -2- (2-methyl- [1,3] dioxolan-2-yl)- Propionate (1.00 g, 2.80 mmol) and pyridinium paratoluene sulfonate (100 mg) were used as starting materials for methyl 2- (2,5-dioxo-3-phenyl-2, 5-Dihydro-pyrrole-1-ylmethyl) -3-oxo-butyrate (114 mg, 14%) was prepared and confirmed by ¹ H NMR, the data are as follows.
[296] ¹ H NMR (CDCl ₃ , 300 MHz) δ 7.79 (m, 2H, ph), 7.44 (m, 3H, ph), 6.71 (s, 1H, -C H = C-), 4.07 (m, 2H, -CHC H ₂ NPht), 3.98 (m, 1H, -C H CH ₂ NPht), 3.24 (s, 3H, -CO ₂ C H ₃ ), 2.26 (s, 3H, -COC H ₃ )
[297] ¹³ C NMR (CDCl ₃ , 300 MHz) δ 200.8, 170.5, 170.1, 168.5, 144.4, 131.7, 129.4, 129.0, 128.9, 124.3, 57.7, 53.3, 36.4, 29.4.
[298] (15) Methyl 2- (2,5-dioxo-3,4-diphenyl-2,5-dihydro-pyrrol-1-ylmethyl) -3-oxo-butyrate
[299] Methyl 3- (2,5-dioxo-3,4-diphenyl-2,5-dihydro-pyrrol-1-ylmethyl) -2- (2-methyl- [1,3] dioxolane-2- Il) -propionate (1.40 g, 3.73 mmol) and pyridinium paratoluene sulfonate (100 mg) were used as starting materials for methyl 2- (2,5-dioxo-3,4 -Diphenyl-2,5-dihydro-pyrrole-1-ylmethyl) -3-oxo-butyrate (579 mg, 36%) was prepared and confirmed by ¹ H NMR, the data are as follows.
[300] ¹ H NMR (CDCl ₃ , 300 MHz) δ 7.37 (dd, 4H, ph, J = 7.6 Hz, J = 1.2 Hz), 4.09 (m, 2H, -CHC H ₂ NPht), 3.96 (m, 1H, -C H CH ₂ NPht), 3.69 (s, 3H, -CO ₂ C H ₃ ), 2.23 (s, 3H, -COC H ₃ )
[301] ¹³ C NMR (CDCl ₃ , 300 MHz) δ 200.9, 170.6, 168.6, 130.4, 128.9, 57.8, 53.3, 38.8, 29.3.
[302] (16) Methyl 2- (5-fluoro-1,3-dioxo-1,3-dihydro-isoindol-2-ylmethyl) -3-oxo-butyrate
[303] Methyl 3- (5-fluoro-1,3-dioxo-1,3-dihydro-isoindol-2-yl) -2- (2-methyl- [1,3] dioxolan-2-yl) Methyl 2- (5-fluoro-1,3-dioxo- in the same manner as in Example 40 using propionate (0.63 g, 1.87 mmol) and pyridinium paratoluene sulfonate (51 mg) as starting material 1,3-dihydro-isoindol-2-ylmethyl) -3-oxo-butyrate (84 mg, 15%) was prepared and confirmed by ¹ H NMR, the data are as follows.
[304] ¹ H NMR (CDCl ₃ , 300 MHz) δ 7.78 (dd, 1H, ph, J = 9.0 Hz, J '= 4.5 Hz), 7.44 (dd, 1H, ph, J = 9.0 Hz, J ' = 2.2 Hz), 7.31 (m, 1H, ph), 4.11 (m, 2H, -CHC H ₂ NPht), 3.95 (dd, 1H, -C H CH ₂ NPht. J = 8.2 Hz, J = 6.5 Hz), 3.67 (s, 3H, -CO ₂ C H ₃ ), 2.22 (s, 3H, -COC H ₃ )
[305] ¹³ C NMR (CDCl ₃ , 300 MHz) δ 200.6, 168.6, 168.4, 167.2, 165.1, 135.1, 127.9, 126.3, 126.2, 121.7, 111.9, 57.5, 53.3, 36.6, 29.3.
[306] (17) Methyl 2- (5-chloro-1,3-dioxo-1,3-dihydro-isoindol-2-ylmethyl) -3-oxo-butyrate
[307] Methyl 3- (5-chloro-1,3-dioxo-1,3-dihydro-isoindol-2-yl) -2- (2-methyl- [1,3] dioxolan-2-yl)- Propionate (0.52 g, 1.48 mmol) and pyridinium paratoluene sulfonate (51 mg) were used as starting materials for methyl 2- (5-chloro-1,3-dioxo-1, 3-Dihydro-isoindol-2-ylmethyl) -3-oxo-butyrate (269 mg, 59%) was prepared and confirmed by ¹ H NMR, the data are as follows.
[308] ¹ H NMR (CDCl ₃ , 300 MHz) δ 7.71 (t, 1H, ph, J = 1.4 Hz), 7.69 (s, 1H, ph), 7.61 (d, 1H, ph, J = 7.9 Hz), 4.17-3.92 (m, 3H, -CHC H ₂ NPht, -C H CH ₂ NPht), 3.67 (s, 3H, -CO ₂ C H ₃ ), 2.22 (s, 3H, -COC H ₃ )
[309] ¹³ C NMR (CDCl ₃ , 300 MHz) δ 250.6, 168.4, 167.2, 141.3, 134.8, 130.3, 125.1, 124.3, 57.4, 53.3, 36.5, 29.3.
[310] (18) Methyl 2- (5-bromo-1,3-dioxo-1,3-dihydro-isoindol-2-ylmethyl) -3-oxo-butyrate
[311] Methyl 3- (5-bromo-1,3-dioxo-1,3-dihydro-isoindol-2-yl) -2- (2-methyl- [1,3] dioxolan-2-yl) -Methyl 2- (5-bromo-1,3-dioxo- in the same manner as in Example 40, starting with propionate (0.46 g, 1.14 mmol) and pyridinium paratoluene sulfonate (50 mg) 1,3-dihydro-isoindol-2-ylmethyl) -3-oxo-butyrate (106 mg, 24%) was prepared and confirmed by ¹ H NMR, the data are as follows.
[312] ¹ H NMR (CDCl ₃ , 300 MHz) δ 7.88 (d, 1H, ph, J = 1.6 Hz), 7.78 (dd, 1H, ph, J = 7.9 Hz, J ' = 1.6 Hz), 7.62 d, 1H, ph , J = 7.9 Hz), 4.40-3.66 m, 3H, -CHC H ₂ NPht, -C H CH ₂ NPht), 3.86 s, 3H, -CO ₂ C H ₃ ), 2.21 s, 3H, -COC H ₃ )
[313] ¹³ C NMR (CDCl ₃ , 300 MHz) δ 200.6, 168.3, 167.3, 166.8, 137.6, 133.8, 130.7, 129.5, 127.2, 125.2, 57.4, 53.3, 36.5, 29.3.
[314] (19) Methyl 2- (1,3-dioxo-1,3-dihydro-benzo [e] isoindol-2-ylmethyl) -3-oxo-butyrate
[315] Methyl 3- (1,3-dioxo-1,3-dihydro-benzo [e] isoindol-2-ylmethyl) -2- (2-methyl- [1,3] dioxolan-2-yl) -Methyl 2- (1,3-dioxo-1,3-di in the same manner as in Example 40 using propionate (0.43 g, 1.17 mmol) and pyridinium paratoluene sulfonate (50 mg) as starting materials Hydro-benzo [e] isoindol-2-ylmethyl) -3-oxo-butyrate (131 mg, 35%) was prepared and confirmed by ¹ H NMR, the data are as follows.
[316] ¹ H NMR (CDCl ₃ , 300 MHz) δ 8.75 (d, 1H, ph, J = 6.2 Hz), 8.02 (d, 1H, ph, J = 6.1 Hz), 7.82 (d, 1H, ph, J = 7.7 Hz ), 7.69 (d, 1H, ph, J = 8.2 Hz), 7.57 (m, 2H, ph), 4.14 (m, 2H, -CHC H ₂ NPht), 4.00 (dd, 1H, -C H CH ₂ NPht , J = 8.2 Hz, J ' = 6.4 Hz), 3.66 (s, 3H, -CO ₂ C H ₃ ), 2.23 (s, 3H, -COC H ₃ )
[317] ¹³ C NMR (CDCl ₃ , 300 MHz) δ 200.9, 169.4, 168.7, 168.6, 136.9, 135.5, 131.4, 129.3, 129.1, 128.3, 127.3, 125.3, 118.8, 57.8, 53.3, 36.3, 29.4
[318] (20) ethyl 2- (1,3-dioxo-1,3,4,5,6,7-hexahydro-isoindol-2-ylmethyl) -3-oxo-butyrate
[319] Ethyl 3- (1,3-dioxo-1,3,4,5,6,7-hexahydro-isoindol-2-yl) -2- (2-methyl- [1,3] dioxolane-2 -Yl) -propionate (866 mg, 2.57 mmol) was dissolved in a mixed solution of acetone / water (v / v, 5: 1), and then a catalytic amount of para-toluenesulfonic acid monohydrate (190 mg, 0.76 mmol) was added. And refluxed at 80 ° C. for 4 days. After completion of the reaction, the reaction mixture with white solid was washed with water, distilled under reduced pressure to remove acetone, and extracted with dichloromethane. The organic layers were combined, dried over anhydrous sulfate, distilled under reduced pressure, and separated by column chromatography (developing solvent: normal hexane: ethyl acetate = 3: 1) to obtain the title compound (421 mg, 56%). Rf = 0.54 (developing solvent: normal hexane: ethyl acetate = 1: 1)
[320] ¹ H NMR (CDCl ₃ , 300 MHz) δ 4.12 (q, 2H, -OC H ₂ CH _3, J = 7.1 Hz), 3.88 (m, 2H, -CHC H ₂ NPht), 3.82 (m, 1H, -C H CH ₂ NPht), 2.24 (s, 4H, cyclohexane), 2.19 (s, 3H, -COC H ₃ ), 1.70 (s, 4H, cyclohexane), 1.19 (t, 3H, -OCH ₂ C H _3, J = 7.1 Hz)
[321] ¹³ C NMR (CDCl ₃ , 300 MHz) δ 201.1, 170.8, 168.0, 142.1, 62.2, 58.0, 35.8, 29.1, 21.6, 20.3, 14.3.
[322] (21) ethyl 2- (4-fluoro-1,3-dioxo-1,3-dihydro-isoindol-2-ylmethyl) -3-oxo-butyrate
[323] Ethyl 3- (4-fluoro-1,3-dioxo-1,3-dihydro-isoindol-2-yl) -2- (2-methyl- [1,3] dioxolan-2-yl) -Ethyl 2- (4-fluoro-1,3-dioxo- in the same manner as in Example 59, using propionate (0.23 g, 0.67 mmol) and para-toluenesulfonic acid monohydrate (25 mg) as starting materials. 1,3-dihydro-isoindol-2-ylmethyl) -3-oxo-butyrate (46 mg, 19%) was prepared and confirmed by ¹ H NMR, the data are as follows.
[324] ¹ H NMR (CDCl ₃ , 300 MHz) δ 7.64 (m, 2H, ph), 7.32 (t, 1H, ph, J = 8.5 Hz), 4.10 (m, 4H, OC H ₂ CH ₃ , -CHC H ₂ NPht ), 3.95 (t, 1H, -C H CH ₂ NPht, J = 6.8 Hz), 2.23 (s, 3H, -COC H ₃ ), 1.17 (t, 3H, -OCH ₂ C H ₃ , J = 7.1 Hz )
[325] ¹³ C NMR (CDCl ₃ , 300 MHz) δ 200.9, 167.9, 167.1, 164.9, 59.7, 156.2, 137.3, 137.2, 134.4, 123.2, 122.9, 122.9, 120.1, 120.1, 62.6, 61.2, 57.6, 36.4, 29.3, 14.5, 14.3.
[326] (22) ethyl 2- (4,7-difluoro-1,3-dioxo-1,3-dihydro-isoindol-2-ylmethyl) -3-oxo-butyrate
[327] Ethyl 3- (4,7-difluoro-1,3-dioxo-1,3-dihydro-isoindol-2-yl) -2- (2-methyl- [1,3] dioxolane-2 Ethyl 2- (4,7-difluoro-1) in the same manner as in Example 59 using -yl) -propionate (0.58 g, 1.57 mmol) and para-toluenesulfonic acid monohydrate (50 mg) as starting materials , 3-dioxo-1,3-dihydro-isoindol-2-ylmethyl) -3-oxo-butyrate (95 mg, 19%) was prepared and confirmed by ¹ H NMR, the data are as follows. same.
[328] ¹ H NMR (CDCl ₃ , 300 MHz) δ 7.32 (m, 2H, ph), 4.09 (m, 4H, OC H ₂ CH ₃ , CHC H ₂ NPht), 3.92 (m, 1H, -C H CH ₂ NPht) , 2.22 (s, 3H, -COC H ₃ ), 1.19 (t, 3H, -OCH ₂ C H ₃ , J = 7.1 Hz)
[329] ¹³ C NMR (CDCl ₃ , 300 MHz) δ 200.7, 167.8, 163.7, 152.3, 125.6, 125.5, 125.4, 125.4, 62.6, 57.3, 36.5, 29.2, 19.8, 14.4, 14.3.
[330] (23) ethyl 2- (4-nitro-1,3-dioxo-1,3-dihydro-isoindol-2-ylmethyl) -3-oxo-butyrate
[331] Ethyl 3- (4-nitro-1,3-dioxo-1,3-dihydro-isoindol-2-yl) -2- (2-methyl- [1,3] dioxolan-2-yl)- Propionate (0.38 g, 1.58 mmol) and para-toluenesulfonic acid monohydrate (25 mg) were used as starting materials, and ethyl 2- (4-nitro-1,3-dioxo-1, 3-Dihydro-isoindol-2-ylmethyl) -3-oxo-butyrate (116 mg, 22%) was prepared and confirmed by ¹ H NMR, the data are as follows.
[332] ¹ H NMR (CDCl ₃ , 300 MHz) δ 8.04 (m, 2H, ph), 7.84 (m, 1H, ph) 4.11 (m, 4H, OC H ₂ CH ₃ , CHC H ₂ NPht), 3.97 (t, 1H, -C H CH ₂ NPht J = 6.5 Hz), 2.24 (s, 3H, -COC H ₃ ), 1.18 (t, 3H, -OCH ₂ C H ₃ , J = 7.1 Hz)
[333] ¹³ C NMR (CDCl ₃ , 300 MHz) 200.6, 167.8, 165.6, 162.9, 145.5, 135.9, 134.3, 129.1, 128.8, 127.6, 123.9, 62.6, 61.3, 57.3, 36.8, 29.4, 14.4.
[334] (24) ethyl 2- (5-nitro-1,3-dioxo-1,3-dihydro-isoindol-2-ylmethyl) -3-oxo-butyrate
[335] Ethyl 3- (5-nitro-1,3-dioxo-1,3-dihydro-isoindol-2-yl) -2- (2-methyl- [1,3] dioxolan-2-yl)- Propionate (1.11 g, 2.96 mmol) and para-toluenesulfonic acid monohydrate (100 mg) were used as starting materials, and ethyl 2- (5-nitro-1,3-dioxo-1, 3-Dihydro-isoindol-2-ylmethyl) -3-oxo-butyrate (263 mg, 27%) was prepared and confirmed by ¹ H NMR, the data are as follows.
[336] ¹ H NMR (CDCl ₃ , 300 MHz) δ 8.53 (d, 2H, ph, J = 6.9 Hz), 7.98 (d, 1H, ph, J = 7.5 Hz), 4.71-3.94 (m, 5H, -CHC H ₂ NPht, -OC H ₂ CH ₃ ), 2.22 (s, 3H, -COC H ₃ ), 1.17 (t, 3H, -OCH ₂ C H ₃ , J = 5.4 Hz)
[337] ¹³ C NMR (CDCl ₃ , 300 MHz) 200.6, 177.8, 172.5, 167.7, 152.2, 133.8, 133.6, 129.8, 125.0, 119.1, 62.5, 57.2, 36.8, 29.3 19.7, 14.4, 14.3.
[338] (25) ethyl 2- (4-methyl-1,3-dioxo-1,3-dihydro-isoindol-2-ylmethyl) -3-oxo-butyrate
[339] Ethyl 3- (4-methyl-1,3-dioxo-1,3-dihydro-isoindol-2-yl) -2- (2-methyl- [1,3] dioxolan-2-yl)- Propionate (0.52 g, 1.76 mmol) and para-toluenesulfonic acid monohydrate (50 mg) were used as starting materials for ethyl 2- (4-methyl-1,3-dioxo-1, 3-Dihydro-isoindol-2-ylmethyl) -3-oxo-butyrate (208 mg, 39%) was prepared and confirmed by ¹ H NMR, the data are as follows.
[340] ¹ H NMR (CDCl ₃ , 300 MHz) δ 7.55 (d, 1H, ph, J = 7.0 Hz), 7.48 (t, 1H, ph, J = 7.3 Hz), 7.37 (d, 1H, ph, J = 7.0 Hz ), 4.36-3.94 (m, 5H, -CHC H ₂ NPht, -OC H ₂ CH _3, -C H C H ₂ NPht), 2.57 (s, 3H, C H ₃ ), 2.21 (s, 3H, C H ₃ ), 1.12 (t, 3H, -OC H ₂ CH _3, J = 7.1 Hz)
[341] ¹³ C NMR (CDCl ₃ , 300 MHz) δ 201.1, 168.9, 168.3, 138.5, 136.9, 134.0, 132.6, 128.9, 121.4, 62.4, 57.8, 36.1, 29.2, 17.9, 14.3.
[342] (26) ethyl 2- (5-methyl-1,3-dioxo-1,3-dihydro-isoindol-2-ylmethyl) -3-oxo-butyrate
[343] Ethyl 3- (5-methyl-1,3-dioxo-1,3-dihydro-isoindol-2-yl) -2- (2-methyl- [1,3] dioxolan-2-yl)- Propionate (0.38 g, 1.07 mmol) and para-toluenesulfonic acid monohydrate (30 mg) were used as starting materials for ethyl 2- (5-methyl-1,3-dioxo-1, 3-Dihydro-isoindol-2-ylmethyl) -3-oxo-butyrate (93 mg, 35%) was prepared and confirmed by ¹ H NMR, the data are as follows.
[344] ¹ H NMR (CDCl ₃ , 300 MHz) δ 7.63 (d, 1H, ph, J = 7.0 Hz), 7.55 (s, 1H, ph), 7.43 (d, 1H, ph, J = 7.0 Hz), 4.19-3.93 (m, 5H, -CHC H ₂ NPht, -OC H ₂ CH _3, -C H C H ₂ NPht), 2.42 (s, 3H, C H ₃ ), 2.01 (s, 3H, COC H ₃ ), 1.14 (t, 3H, -OC H ₂ CH _3, J = 7.1 Hz)
[345] ¹³ C NMR (CDCl ₃ , 300 MHz) δ 201.1, 171.3, 168.4, 145.9, 135.1, 129.5, 124.4, 123.8, 62.6, 61.4, 57.8, 36.3, 29.2, 22.3, 21.1, 14.5.
[346] (27) ethyl 2- (5-tert-butyl-1,3-dioxo-1,3-dihydro-isoindol-2-ylmethyl) -3-oxo-butyrate
[347] Ethyl 3- (5-tert-butyl-1,3-dioxo-1,3-dihydro-isoindol-2-yl) -2- (2-methyl- [1,3] dioxolan-2-yl ) -Propionate (0.52 g, 1.33 mmol) and para-toluenesulfonic acid monohydrate (50 mg) were used as starting materials in the same manner as in Example 59 to obtain ethyl 2- (5-tert-butyl-1,3-di Oxo-1,3-dihydro-isoindol-2-ylmethyl) -3-oxo-butyrate (126 mg, 28%) was prepared and confirmed by ¹ H NMR, the data are as follows.
[348] ¹ H NMR (CDCl ₃ , 300 MHz) δ 7.79 (s, 1H. Ph), 7.66 (dd, 2H. Ph, J = 4.4 Hz), 4.09 (m, 4H, -CHC H ₂ NPht, -OC H ₂ CH ₃ ), 3.95 (m, 1H, -C H CH ₂ NPht), 2.22 (s, 3H, -COC H ₃ ), 1.29 (s, 9H, C (C H ₃ ) ₃ ), 1.16 (t, 3H, -OCH ₂ C H ₃ , J = 7.1 Hz)
[349] ¹³ C NMR (CDCl ₃ , 300 MHz 201.1, 168.7, 168.3, 168.1, 159.2, 132.4, 131.5, 129.5, 123.6, 121.0, 62.4, 57.8, 36.1, 31.5, 14.3.
[350] (28) ethyl 2- (4-hydroxy-1,3-dioxo-1,3-dihydro-isoindol-2-ylmethyl) -3-oxo-butyrate
[351] Ethyl 3- (4-hydroxy-1,3-dioxo-1,3-dihydro-isoindol-2-yl) -2- (2-methyl- [1,3] dioxolan-2-yl) Ethyl 2- (4-hydroxy-1,3-dioxo- in the same manner as in Example 59, using propionate (0.46 g, 1.46 mmol) and para-toluenesulfonic acid monohydrate (50 mg) as starting materials. 1,3-dihydro-isoindol-2-ylmethyl) -3-oxo-butyrate (121 mg, 31%) was prepared and confirmed by ¹ H NMR, the data are as follows.
[352] ¹ H NMR (CDCl ₃ , 300 MHz) δ 7.55 (s, 1H, OH), 7.51 (m, 1H, ph), 7.28 (d, 1H, ph, J = 7.2 Hz), 7.08 (d, 1H, ph, J = 8.3 Hz), 4.10-3.93 (m, 5H, OC H ₂ CH _3, -CHC H ₂ NPht, -C H CH ₂ NPht), 2.22 (s, 3H, -COC H ₃ ), 1.16 (t, 3H, -OCH ₂ C H _3, J = 7.1 Hz)
[353] ¹³ C NMR (CDCl ₃ , 300 MHz) 200.8, 170.1, 167.9, 167.8, 155.1, 136.9, 132.2, 123.3, 116.5, 114.8, 62.9, 57.6, 36.1, 29.4, 14.3.
[354] (29) ethyl 2- (4,7-dichloro-1,3-dioxo-1,3-dihydro-isoindol-2-ylmethyl) -3-oxo-butyrate
[355] Ethyl 3- (4,7-dichloro-1,3-dioxo-1,3-dihydro-isoindol-2-yl) -2- (2-methyl- [1,3] dioxolan-2-yl ) -Propionate (1.13 g, 2.80 mmol) and para-toluenesulfonic acid monohydrate (100 mg) were used as starting materials in the same manner as in Example 59 to obtain ethyl 2- (4,7-dichloro-1,3-di Oxo-1,3-dihydro-isoindol-2-ylmethyl) -3-oxo-butyrate (264 mg, 26%) was prepared and confirmed by ¹ H NMR, the data are as follows.
[356] ¹ H NMR (CDCl ₃ , 300 MHz) δ 7.84 (s, 2H. Ph), 4.12 (m, 4H, -CHC H ₂ NPht, -OC H ₂ CH ₃ ), 3.93 (m, 1H, -C H CH ₂ NPht), 2.21 (s, 3H, -COC H ₃ ), 1.17 (t, 3H, -OCH ₂ C H _3, J = 7.1 Hz)
[357] ¹³ C NMR (CDCl ₃ , 300 MHz) 200.6, 167.8, 166.2, 139.6, 161.2, 125.9, 125.6, 95.8, 62.5, 57.5, 36.6, 29.2, 19.8, 14.5, 14.3.
[358] (30) ethyl 2- (5,6-dichloro-1,3-dioxo-1,3-dihydro-isoindol-2-ylmethyl) -3-oxo-butyrate
[359] Ethyl 3- (5,6-dichloro-1,3-dioxo-1,3-dihydro-isoindol-2-yl) -2- (2-methyl- [1,3] dioxolan-2-yl ) 2-propionate (0.57 g, 1.42 mmol) and para-toluenesulfonic acid monohydrate (50 mg) were used as starting materials in the same manner as in Example 59 to obtain ethyl 2- (5,6-dichloro-1,3-di Oxo-1,3-dihydro-isoindol-2-ylmethyl) -3-oxo-butyrate (171 mg, 34%) was prepared and confirmed by ¹ H NMR, the data are as follows.
[360] ¹ H NMR (CDCl ₃ , 300 MHz) δ 7.83 (s, 2H, ph), 4.13-3.93 (m, 5H, -CHC H ₂ NPht, -OC H ₂ CH ₃ ) _, 2.21 (s, 3H, COC H ₃ ), 1.16 (t, 3H, OCH ₂ C H _3, J = 7.1 Hz)
[361] ¹³ C NMR (CDCl ₃ , 300 MHz) δ 200.6, 177.8, 167.8, 139.6, 131.5, 125.9, 95.8, 62.5, 57.4, 36.7, 29.3, 19.8, 14.5.
[362] (31) ethyl 2- (1,3-dioxo-4-phenyl-1,3-dihydro-benzo [f] isoindol-2-ylmethyl) -3-oxo-butyrate
[363] Ethyl 3- (1,3-dioxo-4-phenyl-1,3-dihydro-benzo [f] isoindol-2-ylmethyl) -2- (2-methyl- [1,3] dioxolane- Ethyl 2- (1,3-dioxo-4 in the same manner as in Example 59, using 2-yl) -propionate (1.09 g, 2.37 mmol) and para-toluenesulfonic acid monohydrate (100 mg) as starting materials. -Phenyl-1,3-dihydro-benzo [f] isoindol-2-ylmethyl) -3-oxo-butyrate (214 mg, 22%) was prepared and confirmed by ¹ H NMR, the data being Same as
[364] ¹ H NMR (CDCl ₃ , 300 MHz) δ 8.28 (s, ¹ H. ph), 7.98 (d, ¹ H. ph, J = 7.9 Hz), 7.60 (d, 1 H. ph, J = 7.8 Hz), 7.55 (t , 1H.ph, J = 7.0Hz), 7.51 (m, 4H. Ph), 7.29 (m, 2H. Ph), 4.05 (m, 5H, -CHC H ₂ NPht, -OC H ₂ CH ₃ , -C H C H ₂ NPht), 2.16 (s, 3H, -COC H ₃ ), 1.09 (t, 3H, -OCH ₂ C H _3, J = 7.0 Hz)
[365] ¹³ C NMR (CDCl ₃ , 300 MHz) δ 201.1, 168.1, 167.6, 140.8, 135.8, 130.2, 129.5, 124.5, 62.3, 57.6, 36.5, 23.2, 14.3.
[366] (32) ethyl 2- (2,5-dioxo-3-phenyl-2,5-dihydro-pyrrol-1-ylmethyl) -3-oxo-butyrate
[367] Ethyl 3- (2,5-dioxo-3-phenyl-2,5-dihydro-pyrrole-1-ylmethyl) -2- (2-methyl- [1,3] dioxolan-2-yl)- Propionate (0.37 g, 1.05 mmol) and para-toluenesulfonic acid monohydrate (30 mg) were used as starting materials for ethyl 2- (2,5-dioxo-3-phenyl-2, 5-Dihydro-pyrrole-1-ylmethyl) -3-oxo-butyrate (77 mg, 23%) was prepared and confirmed by ¹ H NMR, the data are as follows.
[368] ¹ H NMR (CDCl ₃ , 300 MHz) δ 7.83 (m, 2H. Ph), 7.38 (m, 3H. Ph), 6.55 (s, 1H, = C H ), 4.13 (q, 2H, -OC H ₂ CH 3 ), 3.98 (m, 2H, -CHC H ₂ NPht), 3.89 (m, 1H, -C H CH ₂ NPht), 2.20 (s, 3H, -COC H 3), 1.17 (t, 3H, -OCH ₂ C H 3, J = 7.1 Hz)
[369] ¹³ C NMR (CDCl ₃ , 300 MHz) 200.9, 170.5, 170.1, 166.0, 144.3, 131.6, 129.4, 129.3, 129.0, 128.9, 124.2, 62.4, 57.7, 36.3, 29.3, 14.3.
[370] (33) ethyl 2- (2,5-dioxo-3,4-diphenyl-2,5-dihydro-pyrrol-1-ylmethyl) -3-oxo-butyrate
[371] Ethyl 3- (2,5-dioxo-3,4-diphenyl-2,5-dihydro-pyrrol-1-ylmethyl) -2- (2-methyl- [1,3] dioxolane-2- Il) -propionate (1.00 g, 2.29 mmol) and para-toluenesulfonic acid monohydrate (100 mg) were used as starting materials, and ethyl 2- (2,5-dioxo-3,4 was prepared in the same manner as in Example 59. -Diphenyl-2,5-dihydro-pyrrole-1-ylmethyl) -3-oxo-butyrate (204 mg, 23%) was prepared and confirmed by ¹ H NMR, the data are as follows.
[372] ¹ H NMR (CDCl ₃ , 300MH) δ 7.37 (m, 4H. Ph), 7.24 (m, 6H. Ph), 4.10 (m, 4H, -CHC H ₂ NPht, -OC H ₂ CH ₃ ), 3.94 ( m, 1H, -C H CH ₂ NPht), 2.23 (s, 3H, -COC H ₃ ), 1.19 (t, 3H, -OCH ₂ C H _3, J = 7.1 Hz)
[373] ¹³ C NMR (CDCl ₃ , 300 MHz) 201.0, 170.6, 168.1, 136.7, 130.4, 130.3, 128.9, 128.8, 62.4, 57.9, 36.7, 29.2, 14.4.
[374] (34) ethyl 2- (5-fluoro-1,3-dioxo-1,3-dihydro-isoindol-2-ylmethyl) -3-oxo-butyrate
[375] Ethyl 3- (5-fluoro-1,3-dioxo-1,3-dihydro-isoindol-2-yl) -2- (2-methyl- [1,3] dioxolan-2-yl) -Propionate (0.75 g, 2.13 mmol) and para-toluenesulfonic acid monohydrate (100 mg) were used as starting materials, and ethyl 2- (5-fluoro-1,3-dioxo-1, 3-Dihydro-isoindol-2-ylmethyl) -3-oxo-butyrate (220 mg, 34%) was prepared and confirmed by ¹ H NMR, the data are as follows.
[376] ¹ H NMR (CDCl ₃ , 300M) δ 7.78 (dd, 1H, ph, J = 9.0 Hz, J '= 4.5 Hz), 7.44 (dd, 1H, ph, J = 9.0 Hz, J ' = 2.2 Hz), 7.31 (m, 1H, ph), 4.10 (m, 4H, -CHC H ₂ NPht, -OC H ₂ CH ₃ ), 3.94 (m, 1H, -C H CH ₂ NPht), 2.22 (s, 3H,- COC H ₃ )
[377] ¹³ C NMR (CDCl ₃ , 300 MHz) 164.9, 167.1, 166.8, 126.3, 126.1, 121.7, 121.4, 111.9, 111.5, 62.5, 57.6, 36.5, 29.2, 14.3.
[378] (35) ethyl 2- (5-chloro-1,3-dioxo-1,3-dihydro-isoindol-2-ylmethyl) -3-oxo-butyrate
[379] Ethyl 3- (5-chloro-1,3-dioxo-1,3-dihydro-isoindol-2-yl) -2- (2-methyl- [1,3] dioxolan-2-yl)- Propionate (0.45 g, 1.22 mmol) and para-toluenesulfonic acid monohydrate (50 mg) were used as starting materials in the same manner as in Example 59 to obtain ethyl 2- (5-chloro-1,3-dioxo-1, 3-Dihydro-isoindol-2-ylmethyl) -3-oxo-butyrate (171 mg, 34%) was prepared and confirmed by ¹ H NMR, the data are as follows.
[380] _{^{1 H NMR (CDCl 3, 300MH}} ) δ 7.70 (m, 2H, ph, J = 8.4Hz), 7.61 (dd, 1H, ph, J = 7.9Hz, J = 1.7Hz), 4.09 (m, 4H, - CHC H ₂ NPht, -OC H ₂ CH ₃ ), 3.94 (dd, 1H, -C H CH2NPht J = 8.3 Hz, J = 6.5 Hz), 2.21 (s, 3H, -COC H ₃ ), 1.16 (t, 3H, -OCH ₂ C H ₃ , J = 7.1 Hz)
[381] ¹³ C NMR (CDCl ₃ , 300 MHz) 200.8, 167.9, 167.2, 141.2, 134.6, 133.8, 130.3, 125.0, 124.2, 62.4, 57.5, 36.5, 29.3, 14.3.
[382] (36) ethyl 2- (5-bromo-1,3-dioxo-1,3-dihydro-isoindol-2-ylmethyl) -3-oxo-butyrate
[383] Ethyl 3- (5-bromo-1,3-dioxo-1,3-dihydro-isoindol-2-yl) -2- (2-methyl- [1,3] dioxolan-2-yl) Ethyl 2- (5-bromo-1,3-dioxo- in the same manner as in Example 59, using propionate (0.41 g, 1.36 mmol) and para-toluenesulfonic acid monohydrate (50 mg) as starting materials. 1,3-dihydro-isoindol-2-ylmethyl) -3-oxo-butyrate (168 mg, 31%) was prepared and confirmed by ¹ H NMR, the data are as follows.
[384] ¹ H NMR (CDCl ₃ , 300 MHz) δ 7.87 (d, 1H, ph, J = 1.6 Hz), 7.80 (dd, 1H, ph, J = 7.9 Hz, J = 1.6 Hz), 7.63 (d, 1H, ph , J = 6.5 Hz), 4.11 (m, 4H, -CHC H ₂ NPht, -OC H ₂ CH ₃ ), 3.93 (m, 1H, -C H CH ₂ NPht), 2.21 (s, 3H, -COC H ₃ ), 1.16 (t, 3H, -OCH ₂ C H _3, J = 7.1 Hz)
[385] ¹³ C NMR (CDCl ₃ , 300 MHz) 200.8, 167.9, 166.8, 137.6, 130.7, 127.1, 125.2, 62.5, 57.5, 36.5, 29.3, 14.3.
[386] (37) ethyl 2- (1,3-dioxo-1,3-dihydro-benzo [e] isoindol-2-ylmethyl) -3-oxo-butyrate
[387] Ethyl 3- (1,3-dioxo-1,3-dihydro-benzo [e] isoindol-2-ylmethyl) -2- (2-methyl- [1,3] dioxolan-2-yl) Ethyl 2- (5-bromo-1,3-dioxo- in the same manner as in Example 59, using propionate (0.49 g, 1.27 mmol) and para-toluenesulfonic acid monohydrate (50 mg) as starting materials. 1,3-dihydro-isoindol-2-ylmethyl) -3-oxo-butyrate (223 mg, 52%) was prepared and confirmed by ¹ H NMR, the data are as follows.
[388] ¹ H NMR (CDCl ₃ , 300 MHz) δ 8.77 (d, 1H, ph, J = 8.4 Hz), 8.05 (d, 1H, ph, J = 8.3 Hz), 7.84 (d, 1H, ph, J = 7.7 Hz ), 7.72 (d, 1H, ph, J = 8.2 Hz), 7.57 (m, 2H, ph), 4.10 (m, 5H, -CHC H ₂ NPht, -C H CH ₂ NPht, -OC H ₂ CH ₃ ), 2.23 (s, 3H, -COC H ₃ ), 1.14 (t, 3H, -OCH ₂ C H _3, J = 7.1 Hz)
[389] ¹³ C NMR (CDCl ₃ , 300 MHz) 201.1, 169.4, 168.8, 168.1, 136.9, 135.9, 131.5, 129.9, 129.2, 128.3, 127.5, 118.8, 62.4, 57.9, 57.2, 36.2, 29.4, 14.3
[390] (38) ethyl 2- (4-methoxy-1,3-dioxo-1,3-dihydro-isoindol-2-ylmethyl) -3-oxo-butyrate
[391] Ethyl 3- (4-hydroxy-1,3-dioxo-1,3-dihydro-isoindol-2-yl) -2- (2-methyl- [1,3] dioxolan-2-yl) -Propionate (40 mg, 0.11 mmol) is dissolved in 1 ml of 1,4-dioxane, dimethylsulfate (22 mg, 0.13 mmol) and K ₂ CO ₃ (35 mg, 0.25 mmol) are added, It stirred at 70 degreeC for 30 minutes. After completion of the reaction, 1 ml of water was added and extracted with ethyl acetate (2 mlx3). The organic layers were combined, dried over anhydrous sulfate, distilled under reduced pressure, and separated by column chromatography (developing solvent: normal hexane: ethyl acetate = 3: 1) to obtain the target compound (24 mg, 61%).
[392] ¹ H NMR (CDCl ₃ , 300 MHz) δ 7.59 (t, 1H, ph, J = 7.3 Hz), 7.35 (d, 2H, ph, J = 7.3 Hz), 7.11 (d, 1H, ph, J = 8, 4 Hz), 4.15-4.05 (m, 5H, -CHC H ₂ NPht, -OC H ₂ CH _3, -C H CH ₂ NPht), 3.94 (s, 3H, OC H ₃ ), 2.21 (s, 3H,- COC H ₃ ), 1.14 (t, 3H, -OCH ₂ C H _3, J = 7.1 Hz)
[393] ¹³ C NMR (CDCl ₃ , 300 MHz) 201.1, 168.1, 167.8, 166.9, 157.2, 136.7, 134.5, 118.1, 117.6, 116.0, 62.6, 57.8, 56.7, 36.2, 29.1, 14.2
[394] (39) ethyl 2- (4-acetoxy-1,3-dioxo-1,3-dihydro-isoindol-2-ylmethyl) -3-oxo-butyrate
[395] Ethyl 3- (4-hydroxy-1,3-dioxo-1,3-dihydro-isoindol-2-yl) -2- (2-methyl- [1,3] dioxolan-2-yl) Dissolve propionate (102.4 mg, 0.34 mmol) in dichloromethane, slowly add dropwise pyridine (55 μL, 0.682 mmol) and acetyl chloride (49 μL, 0.68 mmol) at 0 ° C. and stir at the same temperature for 10 minutes It was. After completion of the reaction, the mixture was washed with water, and then the aqueous layer was extracted with dichloromethane. The organic layers were combined, dried over anhydrous sulfate, distilled under reduced pressure, and separated by column chromatography (developing solvent: normal hexane: ethyl acetate = 3: 1) to obtain the target compound (64 mg, 54%).
[396] ¹ H NMR (CDCl ₃ , 300 MHz) δ 7.65 (m, 2H, ph), 7.29 (m, 1H, ph), 4.14-4.02 (m, 4H, -CHC H ₂ NPht, -OC H ₂ CH ₃ ), 3.94 (m, 1H, -C H CH ₂ NPht), 2.33 (s, 3H, -COC H ₃ ), 1.15 (t, 3H, -OCH ₂ C H _3, J = 7.1 Hz)
[397] ¹³ C NMR (CDCl ₃ , 300 MHz) 200.8, 168.8, 167.9, 165.8, 147.1, 136.3, 133.8, 123.1, 121.5, 62.4, 57.6, 36.4, 19.4, 21.0, 14.2.
[398] (40) Allyl 2- (4-Fluoro-1,3-dioxo-1,3-dihydro-isoindol-2-ylmethyl) -3-oxo-butyrate
[399] Allyl 3- (4-fluoro-1,3-dioxo-1,3-dihydro-isoindol-2-yl) -2- (2-methyl- [1,3] dioxolan-2-yl) Propionate (331 mg, 0.91 mmol) was dissolved in a mixed solution of acetone / water (v / v, 5: 1), and a catalytic amount of p-toluenesulfonic anhydride was added and then refluxed at 80 ° C. for 18 hours. After completion of the reaction, the reaction mixture was washed with water, distilled under reduced pressure to remove acetone, and extracted with dichloromethane. The organic layers were combined, dried over anhydrous sulfate, distilled under reduced pressure, and separated by column chromatography (developing solvent: normal hexane: ethyl acetate = 2: 1) to obtain the target compound (131.2 mg, 31%).
[400] ¹ H NMR (CDCl ₃ , 300 MHz) δ 7.66 (m, 1H, ph), 7.58 (d, 1H, ph, J = 7.2 Hz), 7.31 (t, 1H, ph, J = 8.4 Hz), 5.76 (m , 1H, CH ₂ C H = CH ₂ ), 5.15 (m, 2H, CH ₂ CH = C H ₂ ), 4.54 (d, 1H, C H ₂ CH = CH _2, J = 5.9 Hz), 4.11-3.97 (m, 3H, -CHC H ₂ NPht, -C H CH ₂ NPht), 2.22 (s, 3H, -COC H ₃ )
[401] ¹³ C NMR (CDCl ₃ , 300 MHz) δ 200.6, 167.6, 166.9, 164.8, 159.7, 137.3, 134.4, 131.4, 123.1, 120.1, 119.9, 117.9, 66.9, 57.4, 36.4, 29.3.
[402] (41) allyl 2- (4,7-difluoro-1,3-dioxo-1,3-dihydro-isoindol-2-ylmethyl) -3-oxo-butyrate
[403] Allyl 3- (4,7-difluoro-1,3-dioxo-1,3-dihydro-isoindol-2-yl) -2- (2-methyl- [1,3] dioxolane-2 -Yl) -propionate (0.35 g, 0.92 mmol) and para-toluenesulfonic acid monohydrate (40 mg) as starting materials, allyl 2- (4,7-difluoro-1,3 -Dioxo-1,3-dihydro-isoindol-2-ylmethyl) -3-oxo-butyrate (86 mg, 23%) was prepared and confirmed by ¹ H NMR, the data are as follows.
[404] ¹ H NMR (CDCl ₃ , 300 MHz) δ 7.33 (t, 2H, ph, J = 5.5 Hz), 5.55 (m, 1H, CH ₂ C H = CH ₂ ), 5.26 (m, 2H, CH ₂ CH = C H ₂ ), 4.55 (d, 1H, C H ₂ CH = CH _2, J = 6.0 Hz), 4.11-3.93 (m, 3H, -CHC H ₂ NPht, -C H CH ₂ NPht), 2.23 (s, 3H, -COC H ₃ )
[405] ¹³ C NMR (CDCl ₃ , 300 MHz) δ 200.5, 167.5, 163.8, 154.0, 131.4, 125.4, 120.0, 118.9, 67.0, 57.2, 36.5, 29.3
[406] 2. Isolation and Purification of Enzymes
[407] Example 7 Isolation and Purification of Reductase from Kluyberomysis marcianus
[408] Kluyveromysis marcianus was incubated at 30 ° C. for 3 days until OD ₆₀₀ reached about 7.0 in 8 L of YM medium. The cultured cells were harvested by centrifugation at 3,000 g for 10 minutes. The obtained cells were dissolved in 500 ml of diluent (20 mM Tris-HCl, pH 8.0), and the remaining medium was removed by centrifugation. 1mM phenylmethylsulfonyl fluoride (PMSF, Sigma) was added to the dilution solution, and the French Pressure Cell Press cell was operated at 11.0 kbar and crushed. It was run and broken up. The obtained cell extract was centrifuged at 25,000 g for 30 minutes, and the obtained supernatant was separated by anion exchange chromatography (Q-Sepharose, FPLC, LKB Pharmacia), and then the substrate was purified by HPLC (Waters) for each eluent. Activity against was measured (see FIG. 3). The active solution was collected and AMS was added so that the concentration of ammonium sulfate (Ammonium Sulfate, AMS) was 1.0M, followed by separation with phenyl sepharose. The active eluate was separated by affinity column Hytrap Blue Sepharose and finally separated using gel filtration chromatography (Superdex-75, FPLC, LKB Pharmacia). When the purified protein was electrophoresed on a 12% SDS-polyacrylamide gel, a protein band having a molecular weight of about 40 kDa was identified (see FIG. 2). The amount of protein in each column was determined by Bradford assay (see FIG. 3). This protein was transferred to the PVDF membrane to identify the amino acid terminal sequence.
[409] Amino Acid Terminal Sequences: ¹ Thr-Phe-Thr-Val-Val-Thr- ⁷ Gly
[410] 3. Reduction of Enzyme
[411] Example 8 Reduction Reaction by Kluyveromysis Marcianus Reductase
[412] 2.0 eq of 1.14 mg of β-NADPH dissolved in 10 μl Na-phosphate buffer was suspended in 190 μl Na-phosphate buffer (100 mM, pH 6.8, Sigma) and 50 μl of enzyme solution and substrate compound. (12.5 μl, 10 mg in 0.5 ml ethanol) was added and then reacted in a stirred incubator at 30 ° C. After the reaction, 100 µl of this solution was taken and extracted with the same amount of ethyl acetate. 50 μl of the organic layer was taken, diluted with 1 ml of mobile phase (hexane: isopropyl alcohol = 90: 10), and analyzed by HPLC.
[413] Representative products obtained by the above procedure and ¹ H NMR data confirming their structure are as follows.
[414] (1) (2S, 3R) ethyl 2- (1,3-dioxo-1,3-dihydro-isoindol-2-ylmethyl) -3-hydroxy-butyrate
[415] ¹ H NMR (CDCl ₃ , 300 MHz) δ 7.73 (m, 4H, ph), 4.00 (m, 5H, CHC H ₂ Npht, -C H OH, -OC H ₂ CH ₃ ), 2.62 (m, 1H,- C H CH ₂ ), 1.19 (d, 3H, J = 6.1 Hz -C H ₃ CH), 1.12 (t, 3H, J = 7.1 Hz, -OCH ₂ C H ₃ )
[416] (2) (2R, 3R) ethyl 2- (1,3-dioxo-1,3-dihydro-isoindol-2-ylmethyl) -3-hydroxy-butyrate
[417] ¹ H NMR (CDCl ₃ , 300 MHz) δ 7.73 (m, 4H, ph), 3.98 (m, 5H, CHC H ₂ Npht, -C H OH, -OC H ₂ CH ₃ ), 2.76 (m, 1H,- C H CH ₂ ), 1.26 (d, 3H, J = 6.5 Hz -C H ₃ CH), 1.10 (t, 3H, J = 7.1 Hz, -OCH ₂ C H ₃ )
[418] (3) (2S, 3R) ethyl 2- (3,6-difur-1,3-dioxo-1,3-dihydro-isoindol-2-ylmethyl) -3-hydroxy-butyrate
[419] ¹ H NMR (CDCl ₃ , 300 MHz) δ 7.41 (t, 2H, ph, J = 5.5 Hz), 4.07 (m, 5H, CHC H ₂ Npht, -C H OH, -OC H ₂ CH ₃ ), 2.69 ( m, 1H, -C H CH ₂ ), 1.17 (m, 6H, -C H ₃ CH, -OCH ₂ C H ₃ )
[420] (4) (2S, 3R) ethyl 2- (3-fur-1,3-dioxo-1,3-dihydro-isoindol-2-ylmethyl) -3-hydroxy-butyrate
[421] ¹ H NMR (CDCl ₃ , 300 MHz) δ 7.50 (t, 3H, ph), 4.01 (m, 5H, CHC H ₂ Npht, -C H OH, -OC H ₂ CH ₃ ), 2.38 (m, 1H,- C H CH ₂ ), 1.19 (t, 3H, J = 6.3 Hz, —OCH ₂ C H ₃ ). 1.13 (d, 3H, J = 7.2 Hz, -OCH ₂ C H ₃ )
[422] (5) (2R, 3R) ethyl 2- (3-fur-1,3-dioxo-1,3-dihydro-isoindol-2-ylmethyl) -3-hydroxy-butyrate
[423] ¹ H NMR (CDCl ₃ , 300 MHz) δ 7.49 (t, 3H, ph), 3.99 (m, 5H, CHC H ₂ Npht, -C H OH, -OC H ₂ CH ₃ ), 2.76 (m, 1H,- C H CH ₂ ), 1.26 (t, 3H, J = 6.5 Hz, —OCH ₂ C H ₃ ). 1.10 (d, 3H, J = 7.1 Hz, -OCH ₂ C H ₃ )
[424] (6) (2S, 3R) methyl 2- (3-fur-1,3-dioxo-1,3-dihydro-isoindol-2-ylmethyl) -3-hydroxy-butyrate
[425] ¹ H NMR (CDCl ₃ , 300 MHz) δ 7.50 (t, 3H, ph), 4.00 (m, 5H, CHC H ₂ Npht, -C H OH), 3.63 (m, 3H, -OC H ₃ ), 2.63 ( m, 1H, -C H CH ₂ ), 1.19 (t, 3H, J = 6.2 Hz, -OCH ₂ C H ₃ )
[426] (7) (2R, 3R) Methyl 2- (3-Four-1,3-dioxo-1,3-dihydro-isoindol-2-ylmethyl) -3-hydroxy-butyrate
[427] ¹ H NMR (CDCl ₃ , 300 MHz) δ 7.45 (t, 3H, ph), 4.08 (m, 5H, CHC H ₂ Npht, -C H OH), 3.63 (m, 3H, -OC H ₃ ), 2.77 ( m, 1H, -C H CH ₂ ), 1.26 (t, 3H, J = 6.2 Hz, -OCH ₂ C H ₃ )
[428] (8) (2S, 3R) ethyl 2- (3-methoxy-1,3-dioxo-1,3-dihydro-isoindol-2-ylmethyl) -3-hydroxy-butyrate
[429] ¹ H NMR (CDCl ₃ , 300 MHz) δ 7.61 (dd, 1H, J = 7.3 Hz, J = 8.4 Hz, ph), 7.38 (d, 1H, J = 7.3 Hz, ph), 7.16 (d, 1H, J = 8.4 Hz, ph), 3.98 (m, 5H, CHC H ₂ Npht, -C H OH, -OC H ₂ CH ₃ ), 3.92 (s, 3H, -PhOCH ₃ ), 2.73 (m, 1H, -C H CH ₂ ), 1.24 (t, 3H, J = 6.4 Hz, —OCH ₂ C H ₃ ). 1.10 (d, 3H, J = 7.1 Hz, -OCH ₂ C H ₃ )
[430] (9) (2R, 3R) ethyl 2- (3-methoxy-1,3-dioxo-1,3-dihydro-isoindol-2-ylmethyl) -3-hydroxy-butyrate
[431] ¹ H NMR (CDCl ₃ , 300 MHz) δ 7.61 (dd, 1H, J = 7.3 Hz, J = 8.4 Hz, ph), 7.37 (d, 1H, J = 7.3 Hz, ph), 7.15 (d, 1H, J = 8.4 Hz, ph), 3.98 (m, 5H, CHC H ₂ Npht, -C H OH, -OC H ₂ CH ₃ ), 3.96 (s, 3H, -PhOCH ₃ ), 2.59 (m, 1H, -C H CH ₂ ), 1.18 (t, 3H, J = 6.4 Hz, —OCH ₂ C H ₃ ). 1.14 (d, 3H, J = 7.1 Hz, -OCH ₂ C H ₃ )
[432] Reduction by enzymes according to the invention is a very useful method for preparing optically pure compounds. In particular, the reaction using Baker's Yeast (BY), which is generally used for the reduction of carbonyl compounds, reduces the carbonyl group of the β-keto ester to produce ( S ) -3-hydroxy compounds, whereas In the case of the reduction reaction with a protonase isolated from Veromacis Marcianus, it is mainly produced ( R ) -3-hydroxy compound.
[433] In the present invention, by an enzyme reaction by using the properties of this microorganism organism (2S, 3R) - or (2 R, R 3) - to α- β- substituted hydroxy ester having the stereochemistry of the final compound, such optical Compounds having activity can be usefully used as intermediates of carbapenem antimicrobial synthesis.

权利要求:
Claims (6)
[1" claim-type="Currently amended] Compound represented by the following formula (Ia) or (Ib):

Wherein R is a saturated or unsaturated alkyl group comprising methyl, ethyl, propyl, isopropyl, isobutyl and allyl, or an aryl group containing phenyl, and R ₁ , R ₂ , R ₃ and R ₄ are each benzene Substituents substituted in the ring, these include a halogen element containing hydrogen, Br, Cl, F and I, an alkyl group having 1 to 4 carbon atoms containing methyl and ethyl, a hydroxy group, an alkoxy group having 1 to 4 carbon atoms, It is selected from the group consisting of ester containing acetoxy group, and phenyl.
[2" claim-type="Currently amended] A compound according to claim 1, wherein R is a methyl group.
[3" claim-type="Currently amended] The compound according to claim 2, wherein (2S, 3R) methyl 2- (1,3-dioxo-1,3-dihydro-isoindol-2-ylmethyl) -3-hydroxy-butyrate, (2S, 3R) Methyl 2- (4-fluoro-1,3-dioxo-1,3-dihydro-isoindol-2-ylmethyl) -3-hydroxy-butyrate, (2S, 3R) methyl 2- (4, 7-difluoro-1,3-dioxo-1,3-dihydro-isoindol-2-ylmethyl) -3-hydroxy-butyrate, (2S, 3R) methyl 2- (4-methyl-1 , 3-dioxo-1,3-dihydro-isoindol-2-ylmethyl) -3-hydroxy-butyrate, (2S, 3R) methyl 2- (5-methyl-1,3-dioxo- 1,3-dihydro-isoindol-2-ylmethyl) -3-hydroxy-butyrate, (2S, 3R) methyl 2- (1,3-dioxo-1,3,4,5,6,7 -Hexahydro-isoindol-2-ylmethyl) -3-hydroxy-butyrate, (2S, 3R) methyl 2- (5-fluoro-1,3-dioxo-1,3-dihydro-isoindole -2-ylmethyl) -3-hydroxy-butyrate, (2S, 3R) methyl 2- (4-methoxy-1,3-dioxo-1,3-dihydro-isoindol-2-ylmethyl) 3-hydroxy-butyrate, (2R, 3R) methyl 2- (1,3-diox Bovine-1,3-dihydro-isoindol-2-ylmethyl) -3-hydroxy-butyrate, (2R, 3R) methyl 2- (4-fluoro-1,3-dioxo-1,3- Dihydro-isoindol-2-ylmethyl) -3-hydroxy-butyrate, (2R, 3R) methyl2- (4,7-difluoro-1,3-dioxo-1,3-dihydro- Isoindol-2-ylmethyl) -3-hydroxy-butyrate, (2R, 3R) methyl 2- (4-methyl-1,3-dioxo-1,3-dihydro-isoindol-2-ylmethyl ) -3-hydroxy-butyrate, (2R, 3R) methyl 2- (5-methyl-1,3-dioxo-1,3-dihydro-isoindol-2-ylmethyl) -3-hydroxy- Butyrate, (2R, 3R) methyl 2- (1,3-dioxo-1,3,4,5,6,7-hexahydro-isoindol-2-ylmethyl) -3-hydroxy-butyrate, ( 2R, 3R) Methyl 2- (5-fluoro-1,3-dioxo-1,3-dihydro-isoindol-2-ylmethyl) -3-hydroxy-butyrate and (2R, 3R) methyl 2 -(4-methoxy-1,3-dioxo-1,3-dihydro-isoindol-2-ylmethyl) -3-hydroxy-butyrate.
[4" claim-type="Currently amended] The compound of claim 1, wherein R is ethyl.
[5" claim-type="Currently amended] The compound according to claim 4, wherein (2S, 3R) ethyl 2- (1,3-dioxo-1,3-dihydro-isoindol-2-ylmethyl) -3-hydroxy-butyrate, (2S, 3R) Ethyl 2- (4-fluoro-1,3-dioxo-1,3-dihydro-isoindol-2-ylmethyl) -3-hydroxy-butyrate, (2S, 3R) ethyl2- (4, 7-difluoro-1,3-dioxo-1,3-dihydro-isoindol-2-ylmethyl) -3-hydroxy-butyrate, (2S, 3R) ethyl 2- (4-methyl-1 , 3-dioxo-1,3-dihydro-isoindol-2-ylmethyl) -3-hydroxy-butyrate, (2S, 3R) ethyl 2- (5-methyl-1,3-dioxo-1 , 3-dihydro-isoindol-2-ylmethyl) -3-hydroxy-butyrate, (2S, 3R) ethyl 2- (5-fluoro-1,3-dioxo-1,3-dihydro- Isoindol-2-ylmethyl) -3-hydroxy-butyrate, (2S, 3R) ethyl 2- (4-methoxy-1,3-dioxo-1,3-dihydro-isoindol-2-yl Methyl) -3-hydroxy-butyrate, (2R, 3R) ethyl 2- (1,3-dioxo-1,3-dihydro-isoindol-2-ylmethyl) -3-hydroxy-butyrate, ( 2R, 3R) ethyl 2- (4-fluoro-1,3-di Boh-1,3-dihydro-isoindol-2-ylmethyl) -3-hydroxy-butyrate, (2R, 3R) ethyl2- (4,7-difluoro-1,3-dioxo-1 , 3-dihydro-isoindol-2-ylmethyl) -3-hydroxy-butyrate, (2R, 3R) ethyl 2- (4-methyl-1,3-dioxo-1,3-dihydro-iso Indol-2-ylmethyl) -3-hydroxy-butyrate, (2R, 3R) ethyl 2- (5-methyl-1,3-dioxo-1,3-dihydro-ro-isoindol-2-yl Methyl) -3-hydroxy-butyrate, (2R, 3R) ethyl 2- (5-fluoro-1,3-dioxo-1,3-dihydro-isoindol-2-ylmethyl) -3-hydroxy Hydroxy-butyrate, (2R, 3R) ethyl 2- (4-methoxy-1,3-dioxo-1,3-dihydro-isoindol-2-ylmethyl) -3-hydroxy-butyrate.
[6" claim-type="Currently amended] The following compound of formula (VI) was mixed with β-NADPH and a pH 5.0-8.0 buffer, and a reductase isolated from Cluyveromysis marcianus was added, followed by a temperature of 20-40 ° C. for 5 hours. A process for preparing a compound of formula (la) or (lb), characterized by reacting according to the scheme as shown below for 5 days:

Wherein R is a saturated or unsaturated alkyl group comprising methyl, ethyl, propyl, isopropyl, isobutyl and allyl, or an aryl group containing phenyl, and R ₁ , R ₂ , R ₃ and R ₄ are each benzene Substituents substituted in the ring, these include a halogen element containing hydrogen, Br, Cl, F and I, an alkyl group having 1 to 4 carbon atoms containing methyl and ethyl, a hydroxy group, an alkoxy group having 1 to 4 carbon atoms, It is selected from the group consisting of ester containing acetoxy group, and phenyl.

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同族专利:

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公开号 | 公开日

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KR100451413B1|2004-10-06|

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US7094908B2|2006-08-22|

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US20030139464A1|2003-07-24|

引用文献:

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公开号 | 申请日 | 公开日 | 申请人 | 专利标题

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法律状态:
2001-12-28|Application filed by 한국과학기술연구원

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2001-12-28|Priority to KR20010087362A

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2003-07-04|Publication of KR20030056992A

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2004-10-06|Application granted

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2004-10-06|Publication of KR100451413B1

优先权:

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申请号 | 申请日 | 专利标题

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KR20010087362A|KR100451413B1|2001-12-28|2001-12-28|Reduction of carbonyl compounds using the carbonyl reductase of kluyveromyces marxianus|