CN108250008B - Chiral resolution method of 3,3,3',3' -tetramethyl-1, 1 '-spiroindane-6, 6' -diol derivative - Google Patents

Chiral resolution method of 3,3,3',3' -tetramethyl-1, 1 '-spiroindane-6, 6' -diol derivative Download PDF

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CN108250008B
CN108250008B CN201810113400.1A CN201810113400A CN108250008B CN 108250008 B CN108250008 B CN 108250008B CN 201810113400 A CN201810113400 A CN 201810113400A CN 108250008 B CN108250008 B CN 108250008B
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林旭锋
常时瑞
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Zhejiang University ZJU
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Abstract

The invention discloses a chiral resolution method of a 3,3,3',3' -tetramethyl-1, 1 '-spiroindane-6, 6' -diol derivative shown as a formula I. The resolution method is realized by taking chiral naproxen acyl chloride as a chiral resolution reagent through esterification reaction, recrystallization and hydrolysis reaction. The method has the advantages of mild reaction conditions, simple process and convenient operation, and the obtained chiral dihalo-tetramethyl spiroindane diphenol is a key intermediate for preparing chiral spiro ligand.

Description

Chiral resolution method of 3,3,3',3' -tetramethyl-1, 1 '-spiroindane-6, 6' -diol derivative
Technical Field
The invention belongs to the technical field of organic synthesis, and particularly relates to a chiral resolution method of a 3,3,3',3' -tetramethyl-1, 1 '-spiroindane-6, 6' -diol derivative.
Background
The 3,3,3',3' -tetramethyl-1, 1' -spiroindane-6, 6' -diol derivatives are mainly reported for the preparation or application of the preparation of high polymers and ligands, especially useful for the preparation of phosphine or azaphosphine ligands based on chiral tetramethylspiroindane skeleton (PCT/CN2017/116105, CN201810005764.8), etc. although the resolution of 3,3,3',3' -tetramethyl-1, 1' -spiroindane-6, 6' -diol derivatives may be obtained by chiral preparative chromatography, it is obviously too costly and not suitable for large-scale preparation, the resolution of such compounds by enzymatic methods is currently very costly and inefficient chemical resolution, a relatively suitable solution for large-scale, in fact, the 3,3,3',3' -tetramethyl-1, 1' -spiroindane-6, 6' -diol resolution method has been implemented in US2006/0020150, examples of which use the chloroformate of menthol as a chiral reagent, can achieve better results but the resolution of chiral menthol-1, 1' -spiroindane-6, 6' -diol by chiral resolution of chiral spiromenthyl-7, such as the chiral resolution of racemic enantiomer-6-diol, which is not possible to be achieved by the chiral resolution process of chiral racemic modification of racemic 3,3,3',3' -spiroindane-6, 6' -diol, 7-diol, which is also found to be an effective resolution process (chiral resolution) by chiral resolution process, 3-chiral resolution of chiral racemic modification, 3-6-7-chiral racemic modification, 3-6-racemic modification, 3-chiral racemic modification, 3-6-chiral racemic modification, 3-7-chiral racemic modification, 3-chiral rearrangement, 3-7, 3-6-7-chiral racemic modification, 3-7-chiral racemic modification, 3-chiral rearrangement process, 3-7-chiral racemic modification, 3-7, 3-7-chiral rearrangement process, and others.
Disclosure of Invention
The invention aims to provide a chiral resolution method of a 3,3,3',3' -tetramethyl-1, 1 '-spiroindane-6, 6' -diol derivative.
A chiral resolution method of 3,3,3',3' -tetramethyl-1, 1 '-spiroindane-6, 6' -diol derivatives is to take chiral (S) -naproxen acyl chloride or (R) -naproxen acyl chloride as a chiral resolution reagent, carry out esterification reaction on a racemate compound with a general formula I and the chiral resolution reagent to obtain diastereomer mixture diester, carry out recrystallization separation and purification on the diester intermediate to obtain two single diastereomer diester, and respectively carry out hydrolysis reaction to remove ester groups to obtain chiral 3,3,3',3' -tetramethyl-1, 1 '-spiroindane-6, 6' -diol derivatives;
Figure BDA0001569956020000021
in the formula: r1、R2、R3、R4Are respectively and independently selected from hydrogen, halogen and C1～C10Alkyl or perfluoroalkyl of C3～C6Cycloalkyl of, C1～C4Alkoxy or perfluoroalkoxy of (a); x is halogen.
In the 3,3,3',3' -tetramethyl-1, 1 '-spiroindane-6, 6' -diol derivative, the compound shown in the formula I is any one of the following compounds:
Figure BDA0001569956020000022
the process of chiral resolution can be illustrated in figure 1.
In the esterification reaction, dichloromethane, dichloroethane, tetrahydrofuran or toluene can be used as a reaction solvent, triethylamine, triisopropylamine or sodium carbonate can be used as a base, and a catalyst 4-dimethylaminopyridine can be used;
the solvent in the recrystallization process can be chloroform, methanol, ethyl acetate, tetrahydrofuran, toluene, n-hexane, cyclohexane, acetonitrile, water, ethanol, dichloroethane, methyl tert-butyl ether, diethyl ether or dichloromethane or the combination of any of the above solvents;
in the hydrolysis reaction, the solvent may be chloroform, methanol, tetrahydrofuran, acetonitrile, water, ethanol, dichloroethane, methyl tert-butyl ether or any combination of the above solvents, and the base may be hydrazine hydrate, sodium hydroxide, potassium hydroxide, sodium methoxide or sodium ethoxide.
The (S) -naproxen acid chloride was prepared as follows (DCM is dichloromethane):
Figure BDA0001569956020000031
the invention has the following advantages:
1) the resolution reaction process can be carried out under mild conditions;
2) the chiral resolving agent is known chiral naproxen acyl chloride, especially (S) -naproxen acyl chloride can be obtained from industrial large-scale production of (S) -naproxen through simple acyl chlorination reaction, and commercialization has been realized. These reduce the preparation cost of the resolution process.
Drawings
FIG. 1 is a schematic diagram of a chiral resolution process of the present invention;
FIG. 2 is a schematic diagram of the reaction process of example 1.
Detailed Description
The following examples will help to understand the present invention, but are not limited to the contents of the present invention.
Example 1
3,3,5, 3',3', 5 '-hexamethyl-7, 7' -dibromo-1, 1 '-spiroindane-6, 6' -diol I-cc (1.7mmol), 4-dimethylaminopyridine (5 mol%), (S) -2- (6-methoxy-2-naphthyl) propionyl chloride (S) -naproxen acid chloride (5.1mmol) were added to a three-necked round-bottomed flask, and 20 ml of dichloromethane and triethylamine (10.2mmol) were sequentially added thereto in an ice bath, followed by stirring at room temperature overnight to complete the reaction. 20 ml of a 1M hydrochloric acid solution was added, liquid separation was performed, the organic phase was washed successively with a saturated sodium bicarbonate solution and a saturated sodium chloride solution, dried over anhydrous sodium sulfate, concentrated, and subjected to flash silica gel column chromatography (eluent volume ratio: petroleum ether: ethyl acetate: 4:1) to obtain a white solid (1.5g, yield: 96%). Recrystallization from chloroform-ethanol (V: V) ═ 2:1 was repeated 2 times to give (Ra, S) -II (630mg, yield: 84%) with a purity of greater than 99%. After concentrating the mother liquor from the first recrystallization, recrystallization was also performed with chloroform-ethanol (V: V) ═ 2:1, and 2 repetitions of recrystallization gave (Sa, S) -II (465mg, yield: 62%) with a purity of greater than 99%.
(Ra,S,S)-II:m.p.:261-262℃,[α]D 20＝19.90(c 0.7,CH2Cl2)；1H NMR(400MHz,CDCl3)：＝7.78(s,2H),7.72(d,J＝8.6Hz,4H),7.52(d,J＝8.4Hz,2H),7.15(d,J＝2.4Hz,1H),7.13(m,3H),6.84(s,2H),4.18-4.09(m,2H),3.91(s,6H),2.51(d,J＝11.0Hz,2H),2.21(d,J＝13.2Hz,2H),1.99-1.60(m,12H),1.32(d,J＝11.4Hz,6H),1.28(d,J＝14.6Hz,6H)；13C NMR(100MHz,CDCl3):＝171.58,157.69,151.46,145.67,144.17,133.83,131.08,129.38,128.92,127.15,126.47,123.47,119.00,113.51,105.62,60.78,55.32,55.21,43.22,32.50,29.02,18.41,16.87；IR(film):γ＝3435,3058,2957,2934,2864,1758,1686,1676,1654,1633,1606,1561,1553,1506,1484,1455,1420,1392,1377,1362,1317,1295,1266,1231,1216,1196,1173,1128,1073,1033,927,890,853,811,783,738,704,669cm-1；HRMS(EI-TOF):calcd for C51H50Br2O6916.1974,found 916.1978.
(Sa,S,S)-II:m.p.:272-273℃,[α]D 20＝4.91(c 0.58,CH2Cl2)；1H NMR(400MHz,CDCl3):＝7.70(s,2H),7.62(d,J＝9.0Hz,4H),7.45(d,J＝1.1Hz,1H),7.43(d,J＝1.1Hz,1H),7.06(d,J＝2.5Hz,1H),7.04(d,J＝2.5Hz,1H),7.02(d,J＝2.2Hz,2H),6.77(s,2H),4.05(q,J＝7.0Hz,2H),3.81(s,6H),2.40(d,J＝13.1Hz,2H),2.10(d,J＝13.2Hz,2H),1.85(s,6H),1.64(d,J＝6.6Hz,6H),1.25(s,6H),1.20(s,6H)；13C NMR(100MHz,CDCl3)：＝170.78,156.60,150.35,144.60,143.13,133.65,132.77,129.96,128.33,127.83,126.02,125.55,125.39,122.38,117.89,112.47,104.55,59.76,54.23,54.20,44.46,42.12,31.46,27.96,17.47,15.92；IR(film):γ＝3401,2960,2929,2869,1757,1632,1606,1506,1482,1452,1393,1318,1264,1216,1171,1147,1128,1076,1029,927,890,853,808,737,660,475cm-1；HRMS(EI-TOF):calcd for C51H50Br2O6916.1974,found 916.1978.
In a three-necked flask, (Ra, S) -II (18.3g, 20mmol) was charged, followed by addition of tetrahydrofuran (200M L) and hydrazine hydrate (9.7M L, 200mmol) under nitrogen protection, followed by reflux reaction overnight under electromagnetic stirring, followed by cooling to room temperature, concentration to remove tetrahydrofuran, dissolution of ethyl acetate, addition of 50 ml of a 4M hydrochloric acid solution, liquid separation, washing of the organic phase with a saturated sodium chloride solution, drying over anhydrous sodium sulfate, concentration, and flash chromatography on silica gel (eluent: petroleum ether: ethyl acetate: 5:1) to obtain 9.64g of (R) -I-cc as a pale yellow solid powder with a yield of 98%.
(R)-I-cc,[α]D 20＝-63.45(c 1.0,CH2Cl2)；M.p.:228-229℃,1H NMR(400MHz,CDCl3):＝6.88(s,2H),5.57(s,2H),2.47(d,J＝13.1Hz,2H),2.31(s,6H),2.25(d,J＝13.0Hz,2H),1.39(s,6H),1.33(s,6H)；13C NMR(100MHz,CDCl3):＝149.25,145.61,142.67,124.51,123.60,107.15,60.85,55.57,43.06,32.58,29.28,17.11；IR(film):γ＝3506,2958,2928,2861,1610,1558,1466,1411,1382,1372,1360,1325,1313,1292,1268,1213,1195,1159,1145,1133,1080,1037,1013,1000,943,930,880,864,824,808,772,748,674cm-1；HRMS(EI-TOF):calcd for C23H26Br2O2492.0300,found 492.0302.
By the same procedure, (Sa, S, S) -II as a starting material was hydrolyzed to obtain (S) -I-cc, [ α ] in 98% yield]D 20＝63.50(c 1.0,CH2Cl2).
The reaction process of this example is schematically shown in FIG. 2.

Claims (2)

1. A chiral resolution method of 3,3,3',3' -tetramethyl-1, 1 '-spiroindane-6, 6' -diol derivatives is characterized in that chiral (S) -naproxen acyl chloride or (R) -naproxen acyl chloride is used as a chiral resolution reagent, a racemate compound with a general formula I and the chiral resolution reagent are subjected to esterification reaction to obtain diastereomer mixture diester, the diester intermediate is recrystallized, separated and purified to obtain two single diastereomer diester, and the ester groups are respectively removed through hydrolysis reaction to obtain chiral 3,3,3',3' -tetramethyl-1, 1 '-spiroindane-6, 6' -diol derivatives;
Figure FDA0002525500280000011
in the formula: r1、R2、R3、R4Are respectively and independently selected from hydrogen, halogen and C1～C10Alkyl or perfluoroalkyl of C3～C6Cycloalkyl of, C1～C4Alkoxy or perfluoroalkoxy of (a); x is halogen;
the solvent used for recrystallization separation is a mixed solvent of chloroform and ethanol, and the volume ratio of the chloroform to the ethanol is 2: 1.
2. The process for chiral resolution of 3,3,3',3' -tetramethyl-1, 1 '-spiroindane-6, 6' -diol derivative according to claim 1, wherein the compound of formula I is any one of the following compounds:
Figure FDA0002525500280000012
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