Method for producing multi-arm type polyethylene glycol derivative

Abstract

A method for producing a multi-arm type polyethylene glycol derivative, which includes carrying out the following in order: Step (A): protecting an even number of hydroxyl groups, while leaving only the hydroxyl group at the 1-position of a polyhydric alcohol having an odd number of hydroxyl groups, other than the hydroxyl group at the 1-position by cyclic benzylidene acetalization, Step (B): linking two molecules of the compound obtained in step (A) to a compound for introducing a specific linker by etherification reaction, Step (C): deprotecting the cyclic benzylidene acetal structure at the terminal of the compound obtained in step (B), Step (D): polymerizing 3 to 600 mol of ethylene oxide to each hydroxyl group of the compound obtained in step (C) to obtain a multi-arm type polyethylene glycol derivative, and Step (E): functionalizing the hydroxyl group at the terminal of the multi-arm type polyethylene glycol derivative obtained in step (D).

Claims

1. A method for producing a multi-arm type polyethylene glycol derivative represented by the following formula (1), wherein the following step (A), step (B), step (C), step (D), and step (E) are carried out in this order: ##STR00030## wherein, in the formula (1), L is a group selected from the group consisting of a linear or branched alkylene group having 3 to 8 carbon atoms, a substituted or unsubstituted arylene group having 6 to 12 carbon atoms and a cycloalkylene group having 6 to 12 carbon atoms, k represents 1 or 2, n represents an average molar number of oxyethylene groups added and n represents an integer between 3 and 600, X represents an alkylene group which may have a single bond, an ester bond, a urethane bond, an amide bond, an ether bond, a carbonate bond, a secondary amino group, a urea bond, a thioether bond, or a thioester bond in a chain or at a terminal, and Y represents a chemically reactive functional group; Step (A): a step of protecting an even number of hydroxyl groups, while leaving only the hydroxyl group at the 1-position of a polyhydric alcohol having an odd number of hydroxyl groups, other than the hydroxyl group at the 1-position by cyclic benzylidene acetalization, Step (B): a step of linking two molecules of the compound obtained in the step (A) to a compound represented by the following formula (2) by an etherification reaction to obtain a compound, and purifying the obtained compound by recrystallization in dimethylformamide:
A-L-A(2) wherein, in the formula (2), L represents a group selected from the group consisting of a linear or branched alkylene group having 3 to 8 carbon atoms, a substituted or unsubstituted arylene group having 6 to 12 carbon atoms and a cycloalkylene group having 6 to 12 carbon atoms, and A represents a halogen atom selected from chlorine, bromine or iodine, or a sulfone-based leaving group, Step (C): a step of deprotecting the cyclic benzylidene acetal structure at the terminal of the compound obtained in the step (B), where 8 hydroxyl groups are formed in the case of k=1 and 12 hydroxyl groups are formed in the case of k=2, Step (D): a step of polymerizing 3 to 600 mol of ethylene oxide to each hydroxyl group of the compound obtained in the step (C) to obtain a multi-arm type polyethylene glycol derivative, and Step (E): a step of functionalizing the hydroxyl group at the terminal of the multi-arm type polyethylene glycol derivative obtained in the step (D).

2. The method according to claim 1, wherein the step (A) is carried out using an acidic solution as a solvent.

3. The method according to claim 1, wherein the step (C) is carried out under an acidic condition.

Description

EXAMPLES

(1) The following further specifically describe the present invention based on Examples but the invention should not be construed as being limited thereto. Incidentally, .sup.1H-NMR and GPC were used for analysis and identification of compounds in the examples.

(2) <Analytical Method on .sup.1H-NMR>

(3) For .sup.1H-NMR analysis, JNM-ECP400 manufactured by JOEL Ltd. was used. Integrated values in NMR measurement values are theoretical values.

(4) <Analytical Method on GPC>

(5) For GPC analysis, measurement was conducted with a system using any of DMF or water as an eluent. Measurement conditions for each system are shown below.

(6) Case of DMF System

(7) Apparatus: SHIMADZU LC-10Avp

(8) Column: PL gel MIXED-D2 (Polymer Laboratory)

(9) Developing solvent: dimethylformamide

(10) Flow rate: 0.7 ml/min

(11) Column temperature: 65 C.

(12) Detector: RI

(13) Sample amount: 1 mg/g, 100 l

(14) Case of Water System

(15) Apparatus: alliance (Waters)

(16) Column: ultrahydrogel 500+ultrahydrogel 250 (Waters)

(17) Developing solvent: 100 mM sodium acetate, 0.02% NaN.sub.3 buffer solution (pH 5.2)

(18) Flow rate: 0.5 ml/min

(19) Column temperature: 30 C.

(20) Detector: RI

(21) Sample amount: 5 mg/g, 20 l

(22) The GPC measurement value is an analysis value at a main peak with removing high-molecular-weight impurities and low-molecular-weight impurities by vertically cutting the baseline from inflection points of an elution curve. Fraction % represents a ratio of the main peak from the elution start point to the elution final point relative to the whole peak, M.sub.n represents number-average molecular weight, M.sub.w represents weight-average molecular weight, M.sub.p represents peak top molecular weight, and Mw/Mn represents polydispersity.

(23) <Molecular Weight Measurement on TOF-MS>

(24) Measurement was conducted using TOF-MS (manufactured by Bruker, autoflex III) using Dithranol as a matrix and sodium trifluoroacetate as a salt. For analysis, FlexAnalysis was used and analysis of molecular weight distribution was conducted on Polytools. The obtained value at gravity center was described as a value of molecular weight.

(25) <Molecular Weight Measurement by Hydroxyl Value Measurement>

(26) According to JIS K1557-1, the hydroxyl value was measured by A method (acetic anhydride/pyridine). The molecular weight was calculated from the measured hydroxyl value according to the following equation.
(Molecular Weight)=56.11,0008/(Hydroxyl Value)

Example 1

(27) Synthesis of Compounds (I), (II), (III), and (IV) (Cases where L=n-Butylene Group, k=1, Molecular Weight: about 5,000, 10,000, 20,000, and 40,000)

(28) ##STR00013##

Example 1-1

Synthesis of 2,3,4,5-Dibenzylidenexylitol

(29) Into a reactor fitted with a thermometer, a nitrogen-inlet tube and a stirrer were placed 150 g of xylitol and 3,700 g of 6M sulfuric acid, and xylitol was dissolved at room temperature. After 315 g of benzaldehyde was added thereto, the mixture was heated to about 30 C., and stirring was continued to precipitate crystals. The mixture was stirred as it was for 6 hours or more. Then, 4.5 L of cooled distilled water was added, the precipitate was collected by filtration, the crystals were suspended in 3 L of an aqueous ethanol solution, and neutralization was performed by adding a 10 N aqueous sodium hydroxide solution, followed by filtration. The obtained crystals were further subjected to suspension washing with an aqueous ethanol solution, a mixed solution of ethanol/methyl t-butyl ether (MTBE), and MTBE in the order and filtration, repeatedly. Then, drying was performed under reduced pressure to obtain 260 g of 2,3,4,5-dibenzylidenexylitol.

(30) .sup.1H-NMR (CDCl.sub.3, internal standard: TMS) (ppm):

(31) 3.80-4.40 (7H, m, CH.sub.2O, CHO),

(32) 5.59 (1H, s, PhCHO),

(33) 5.67 (1H, s, PhCHO),

(34) 7.30-7.65 (10H, m, PhCHO)

Example 1-2

Synthesis of 1,1-Butylene-bis(2,3,4,5-dibenzylidenexylitol)

(35) To a 5,000 ml round-bottom flask fitted with a thermometer, a nitrogen-inlet tube and a stirrer were added 266 g (0.81 mol) of 2,3,4,5-dibenzylidenexylitol, 2,400 g of dimethylformamide (DMF) and 1,600 g of toluene were added, and dissolution was achieved under a nitrogen atmosphere. Then, azeotropic dehydration was performed at 110 to 120 C. After the azeotropic dehydration, the mixture was cooled, 94.8 g (0.84 mol) of potassium t-butoxide was added, and the mixture was stirred at 30 to 40 C. for 30 minutes. On the other hand, 80 g (0.33 mol) of 1,4-butanediol dimethanesulfonate was dissolved in 660 g of dehydrated DMF, and then the resultant solution was added dropwise to the reaction solution under stirring at 30 to 40 C. over a period of 30 minutes. After completion of the dropwise addition, the temperature was raised to 50 C. and the reaction was performed for 2 hours. After completion of the reaction, the reaction solution was cooled to 10 C. or lower and stirred for 30 minutes to precipitate crystals, and the mixture was stirred as it was for 1 hour. The precipitate was collected by filtration, the crystals were suspended in 2.5 L of an aqueous ethanol solution, and suspension washing and filtration were repeated 3 times. Next, 4,800 g of DMF was added and recrystallization was perform. The obtained crystals were further added with 2,560 g of methyl t-butyl ether (MTBE), and suspension washing and filtration were repeated twice, followed by drying under reduced pressure to obtain 150 g of 1,1-butylene-bis(2,3,4,5-dibenzylidenexylitol).

(36) .sup.1H-NMR (CDCl.sub.3, internal standard: TMS) (ppm):

(37) 1.61 (4H, quint, OCH.sub.2CH.sub.2CH.sub.2CH.sub.2O),

(38) 3.44-4.38 (18H, m, OCH.sub.2CH.sub.2CH.sub.2CH.sub.2O, CH.sub.2O, CHO),

(39) 5.57 (2H, s, PhCHO),

(40) 5.63 (2H, s, PhCHO),

(41) 7.30-7.65 (20H, m, PhCHO)

Example 1-3

Synthesis of 1,1-Butylene-bisxylitol

(42) To a 3,000 ml round-bottom flask fitted with a thermometer, a nitrogen-inlet tube, and a stirrer were added 290 g (0.41 mol) of 1,1-butylene bis(2,3,4,5-dibenzylidenexylitol), 870 g of trifluoroacetic acid (TFA) and 290 g of ion-exchanged water, and the mixture was heated to 50 C. and stirred for 4 hours. The mixture was cooled to 30 C. or lower, 1,450 g of toluene was added, and the resultant was stirred for 30 minutes or more. After the stirring was stopped, the layers were separated, the toluene layer was removed, 1,450 g of toluene was added to the aqueous layer, and liquid separation and washing were performed again. This liquid separation operation was repeated 7 times in total. Next, after TFA was concentrated and distilled off under reduced pressure, 1,450 g of ethanol was added, and azeotropic dehydration was repeated 3 times. After 870 g of methanol was added to the concentrated solution and homogenization was performed, Kyoward 1000 (manufactured by Kyowa Chemical Industry Co., Ltd.) was added, and after stirring for 30 minutes, the mixture was filtrated. An ion exchange resin (SMN-1, manufactured by Mitsubishi Chemical Corporation) was added to the filtrate, and the mixture was stirred for 30 minutes and then filtrated. The filtrate was concentrated to obtain 126 g of 1,1-butylene-bisxylitol (V) having the following structure.

(43) .sup.1H-NMR (D.sub.2O, internal standard: TMS) (ppm):

(44) 1.66 (4H, quint, OCH.sub.2CH.sub.2CH.sub.2CH.sub.2O),

(45) 3.56-3.75 (14H, m, OCH.sub.2CH.sub.2CH.sub.2CH.sub.2O, CH.sub.2O, CHO),

(46) 3.79-3.82 (2H, m, CHO),

(47) 3.91-3.93 (2H, m, CHO)

(48) ##STR00014##

Example 1-4

Synthesis of Compound (I) (Case of Molecular Weight of 5,000)

(49) Sixty grams of 1,1-butylene-bisxylitol (V) obtained in Example 1-3 was warmed and, while washing it with 41 g of methanol, was charged into a 5 L autoclave. Subsequently, 5.8 g of potassium hydroxide and 12 g of ion-exchanged water were added to a 50 ml beaker to prepare an aqueous potassium hydroxide solution, which was then charged into the 5 L autoclave. Then, 600 g of dehydrated toluene was added thereto and an azeotropic dehydration operation was repeated three times at 80 C., under slightly reduced pressure. After the azeotropic dehydration, 1,594 g of dehydrated toluene was added and, after the inside of the system was replaced by nitrogen, 740 g (16.8 mol) of ethylene oxide was added at 80 to 150 C. under a pressure of 1 MPa or less, followed by continuation of the reaction for another 1 hour. After the reaction, the whole was cooled to 60 C., 604 g of the reaction solution was taken out of the autoclave, and pH was adjusted to 7.5 with an 85% aqueous phosphoric acid solution to obtain the following compound (I).

(50) .sup.1H-NMR (CDCl.sub.3, internal standard: TMS) (ppm):

(51) 1.57 (4H, br, OCH.sub.2CH.sub.2CH.sub.2CH.sub.2O),

(52) 2.66 (8H, br, OH),

(53) 3.40 (4H, br, OCH.sub.2CH.sub.2CH.sub.2CH.sub.2O),

(54) 3.50-3.81 (430H, m, CH.sub.2O(CH.sub.2CH.sub.2O).sub.nH, CHO(CH.sub.2CH.sub.2O).sub.nH, CH.sub.2OCH.sub.2CH.sub.2CH.sub.2CH.sub.2OCH.sub.2)

(55) GPC analysis (DMF system):

(56) main fraction: 99.5%, Mn: 3,838, Mw: 3,905, Mw/Mn: 1.017, Mp: 3,903
Molecular weight (TOF-MS); 4,974
Molecular weight (hydroxyl value); 5,026

(57) ##STR00015##

Example 1-5

Synthesis of Compound (II) (Case of Molecular Weight of 10,000)

(58) To about 1,764 g of the reaction solution remaining in the reaction vessel in Example 1-4 was added 615 g (14.0 mol) of ethylene oxide at 80 to 150 C. under a pressure of 1 MPa or less, followed by continuation of the reaction for another 1 hour. After the reaction, the whole was cooled to 60 C., 1,529 g of the reaction solution was taken out of the vessel, pH was adjusted to 7.5 with an 85% aqueous phosphoric acid solution, and toluene was removed by distillation to obtain the following compound (II).

(59) .sup.1H-NMR (CDCl.sub.3, internal standard: TMS) (ppm):

(60) 1.57 (4H, br, OCH.sub.2CH.sub.2CH.sub.2CH.sub.2O),

(61) 2.365 (8H, br, OH),

(62) 3.40 (4H, s, OCH.sub.2CH.sub.2CH.sub.2CH.sub.2O),

(63) 3.50-3.81 (878H, m, CH.sub.2O(CH.sub.2CH.sub.2O).sub.nH, CHO(CH.sub.2CH.sub.2O).sub.nH, CH.sub.2OCH.sub.2CH.sub.2CH.sub.2CH.sub.2OCH.sub.2)

(64) GPC analysis (DMF system):

(65) main fraction: 99.0%, Mn: 7,123, Mw: 7,262, Mw/Mn: 1.019, Mp: 7,282
Molecular weight (TOF-MS); 10,418
Molecular weight (hydroxyl value); 9,968

(66) ##STR00016##

Example 1-6

Synthesis of Compound (III) (Case of Molecular Weight of 20,000)

(67) To about 809 g of the reaction solution remaining in the reaction vessel in Example 1-5 was added 390 g (8.85 mol) of ethylene oxide at 80 to 150 C. under a pressure of 1 MPa or less, followed by continuation of the reaction for another 1 hour. After the reaction, the whole was cooled to 60 C., 978 g of the reaction solution was taken out of the vessel, pH was adjusted to 7.5 with an 85% aqueous phosphoric acid solution, and toluene was removed by distillation to obtain the following compound (III).

(68) .sup.1H-NMR (CDCl.sub.3, internal standard: TMS) (ppm):

(69) 1.57 (4H, br, OCH.sub.2CH.sub.2CH.sub.2CH.sub.2O),

(70) 2.57 (8H, br, OH),

(71) 3.40 (4H, s, OCH.sub.2CH.sub.2CH.sub.2CH.sub.2O),

(72) 3.50-3.81 (1774H, m, CH.sub.2O(CH.sub.2CH.sub.2O).sub.nH, CHO(CH.sub.2CH.sub.2O).sub.nH, CH.sub.2OCH.sub.2CH.sub.2CH.sub.2CH.sub.2OCH.sub.2)

(73) GPC analysis (DMF system):

(74) main fraction: 98.4%, Mn: 14,140, Mw: 14,499, Mw/Mn: 1.025, Mp: 14,910
Molecular weight (TOF-MS); 20,233
Molecular weight (hydroxyl value); 19,858

(75) ##STR00017##

Example 1-7

Synthesis of Compound (IV) (Case of Molecular Weight of 40,000)

(76) To about 199 g of the reaction solution remaining in the reaction vessel in Example 1-6 was added 103 g (2.34 mol) of ethylene oxide at 80 to 150 C. under a pressure of 1 MPa or less, followed by continuation of the reaction for another 1 hour. After the reaction, the whole was cooled to 60 C., all the amount of the reaction solution was taken out of the vessel, pH was adjusted to 7.5 with an 85% aqueous phosphoric acid solution, and toluene was removed by distillation to obtain the following compound (IV).

(77) .sup.1H-NMR (CDCl.sub.3, internal standard: TMS) (ppm):

(78) 1.57 (4H, br, OCH.sub.2CH.sub.2CH.sub.2CH.sub.2O),

(79) 2.589 (8H, br, OH),

(80) 3.40 (4H, s, OCH.sub.2CH.sub.2CH.sub.2CH.sub.2O), 3.50-3.81 (3598H, m, CH.sub.2O(CH.sub.2CH.sub.2O).sub.nH, CHO(CH.sub.2CH.sub.2O).sub.nH, CH.sub.2OCH.sub.2CH.sub.2CH.sub.2CH.sub.2OCH.sub.2)

(81) GPC analysis (DMF system):

(82) main fraction: 96.6%, Mn: 27,158, Mw: 27,691, Mw/Mn: 1.020, Mp: 27,945
Molecular weight (TOF-MS); 40,071
Molecular weight (hydroxyl value); 39,932

(83) ##STR00018##

Example 2-1

Synthesis of Cyanoethyl Body (Case of Molecular Weight of About 10,000)

(84) To a 500 ml round-bottom flask fitted with a thermometer, a nitrogen-inlet tube, a stirrer, and a cooling tube were added 50 g (5 mmol) of the compound (II) obtained in the above Example 1-5 and 50 g of ion-exchanged water, and the whole was heated to 40 C. to achieve dissolution. After the dissolution, the whole was cooled to 10 C. or lower and 5 g of a 50% aqueous potassium hydroxide solution was added thereto. Subsequently, while the temperature was kept at 5 to 10 C., 42.5 g (800 mmol) of acrylonitrile was added dropwise over a period of 2 hours. After completion of the dropwise addition, the reaction was further conducted for 4 hours and, after 50 g of ion-exchanged water was added, neutralization was achieved by adding 3 g of an 85% aqueous phosphoric acid solution. After 75 g of ethyl acetate was added and the whole was stirred, it was allowed to stand and an upper ethyl acetate layer was discarded. The extraction with ethyl acetate was repeated nine times. After completion of the extraction, extraction with 250 g of chloroform was performed. The resulting chloroform layer was dried over 25 g of magnesium sulfate and, after filtration, was concentrated. The concentrated liquid was dissolved with adding 150 g of ethyl acetate, and hexane was added until crystals were precipitated. The crystals were collected by filtration and again dissolved in 150 g of ethyl acetate and, after cooling to room temperature, hexane was added until crystals were precipitated. The crystals were collected by filtration and dried to obtain the following cyanoethyl body (VI).

(85) .sup.1H-NMR (CDCl.sub.3, internal standard: TMS) (ppm):

(86) 1.57 (4H, br, OCH.sub.2CH.sub.2CH.sub.2CH.sub.2O),

(87) 2.63 (16H, t, CH.sub.2CH.sub.2CN),

(88) 3.39 (4H, br, OCH.sub.2CH.sub.2CH.sub.2CH.sub.2O),

(89) 3.50-3.80 (894H, m, CH.sub.2O(CH.sub.2CH.sub.2O).sub.nH, CHO(CH.sub.2CH.sub.2O).sub.nH, CH.sub.2OCH.sub.2CH.sub.2CH.sub.2CH.sub.2OCH.sub.2, CH.sub.2CH.sub.2CN)

(90) ##STR00019##

Example 2-2

Synthesis of Propylamino Body (Case of Molecular Weight of About 10,000)

(91) To a 1 L autoclave, 46 g of the cyanoethyl body, i.e, the compound (VI) obtained in the above Example 2-1 were added 533 g of toluene and 4.1 g of nickel (5136p manufactured by N. E. MCAT Company), and the whole was heated to 60 C. Pressurization was performed with ammonia until inner pressure reached 1 MPa and thereafter, hydrogen was introduced to achieve pressurization until the inner pressure reached 4.5 MPa, followed by reaction at 130 C. for 3 hours. After the reaction, the reaction solution was cooled to 80 C. and purging with nitrogen was repeated until ammonia odor disappeared. All the amount of the reaction solution was taken out and filtrated. After the filtrate was cooled to room temperature, hexane was added until crystals were precipitated. The crystals were collected by filtration and dried to obtain the following amine body (VII).

(92) .sup.1H-NMR (CDCl.sub.3, internal standard: TMS) (ppm):

(93) 1.57 (4H, br, OCH.sub.2CH.sub.2CH.sub.2CH.sub.2O),

(94) 1.72 (16H, quint, CH.sub.2CH.sub.2CH.sub.2NH.sub.2),

(95) 2.79 (16H, t, CH.sub.2CH.sub.2CH.sub.2NH.sub.2),

(96) 3.39 (4H, br, OCH.sub.2CH.sub.2CH.sub.2CH.sub.2O),

(97) 3.50-3.80 (894H, m, CH.sub.2O(CH.sub.2CH.sub.2O).sub.nH, CHO(CH.sub.2CH.sub.2O).sub.nH, CH.sub.2OCH.sub.2CH.sub.2CH.sub.2CH.sub.2OCH.sub.2, CH.sub.2CH.sub.2CH.sub.2NH.sub.2)

(98) GPC analysis (water system):

(99) main fraction: 96.9%, Mn: 6,781, Mw: 6,896, Mw/Mn: 1.017, Mp: 6,874

(100) ##STR00020##

Example 3-1

Synthesis of Cyanoethyl Body (Case of Molecular Weight of About 20,000)

(101) To a 500 ml round-bottom flask fitted with a thermometer, a nitrogen-inlet tube, a stirrer, and a cooling tube were added 50 g (2.5 mmol) of the compound (III) obtained in the above Example 1-6 and 50 g of ion-exchanged water, and the whole was heated to 40 C. to achieve dissolution. After the dissolution, the whole was cooled to 10 C. or lower and 5 g of a 50% aqueous potassium hydroxide solution was added thereto. Subsequently, while the temperature was kept at 5 to 10 C., 21.2 g (400 mmol) of acrylonitrile was added dropwise over a period of 2 hours. After completion of the dropwise addition, the reaction was further conducted for 4 hours and, after 50 g of ion-exchanged water was added, neutralization was achieved by adding 3 g of an 85% aqueous phosphoric acid solution dropwise. After 75 g of ethyl acetate was added and the whole was stirred, it was allowed to stand and an upper ethyl acetate layer was discarded. The extraction with ethyl acetate was repeated nine times. After completion of the extraction, extraction with 250 g of chloroform was performed. The resulting chloroform layer was dried over 15 g of magnesium sulfate and, after filtration, was concentrated. The concentrated liquid was dissolved with adding 150 g of ethyl acetate, and hexane was added until crystals were precipitated. The crystals were collected by filtration and again dissolved in 150 g of ethyl acetate under heating and, after cooling to room temperature, hexane was added until crystals were precipitated. The crystals were collected by filtration and dried to obtain the following cyanoethyl body (VIII).

(102) .sup.1H-NMR (CDCl.sub.3, internal standard: TMS) (ppm):

(103) 1.57 (4H, br, OCH.sub.2CH.sub.2CH.sub.2CH.sub.2O),

(104) 2.63 (16H, t, CH.sub.2CH.sub.2CN),

(105) 3.39 (4H, br, OCH.sub.2CH.sub.2CH.sub.2CH.sub.2O),

(106) 3.50-3.80 (1790H, m, CH.sub.2O(CH.sub.2CH.sub.2O).sub.nH, CHO(CH.sub.2CH.sub.2O).sub.nH, CH.sub.2OCH.sub.2CH.sub.2CH.sub.2CH.sub.2OCH.sub.2, CH.sub.2CH.sub.2CN)

(107) ##STR00021##

Example 3-2

Synthesis of Propylamino Body (Case of Molecular Weight of About 20,000)

(108) To a 1 L autoclave were added 20 g of the cyanoethyl body, i.e, the compound (VIII) obtained in the above Example 3-1, 555 g of toluene, and 1.8 g of nickel (5136p manufactured by N. E. MCAT Company), and the whole was heated to 60 C. Pressurization was performed with ammonia until inner pressure reached 1 MPa and thereafter, hydrogen was introduced to achieve pressurization until the inner pressure reached 4.5 MPa, followed by reaction at 130 C. for 3 hours. After the reaction, the reaction solution was cooled to 80 C. and purging with nitrogen was repeated until ammonia odor disappeared. All the amount of the reaction solution was taken out and filtrated. After the filtrate was cooled to room temperature, hexane was added until crystals were precipitated. The crystals were collected by filtration and dried to obtain the following amine body (IX).

(109) .sup.1H-NMR (CDCl.sub.3, internal standard: TMS) (ppm):

(110) 1.57 (4H, br, OCH.sub.2CH.sub.2CH.sub.2CH.sub.2O),

(111) 1.72 (16H, quint, CH.sub.2CH.sub.2CH.sub.2NH.sub.2),

(112) 2.79 (16H, t, CH.sub.2CH.sub.2CH.sub.2NH.sub.2),

(113) 3.39 (4H, br, OCH.sub.2CH.sub.2CH.sub.2CH.sub.2O),

(114) 3.50-3.80 (1790H, m, CH.sub.2O(CH.sub.2CH.sub.2O).sub.nH, CHO(CH.sub.2CH.sub.2O).sub.nH, CH.sub.2OCH.sub.2CH.sub.2CH.sub.2CH.sub.2OCH.sub.2, CH.sub.2CH.sub.2CH.sub.2NH.sub.2)

(115) GPC analysis (water system):

(116) main fraction: 97.5%, Mn: 13,844, Mw: 14,133, Mw/Mn: 1.021, Mp: 14,203

(117) ##STR00022##

Example 4-1

Synthesis of Cyanoethyl Body (Case of Molecular Weight of About 40,000)

(118) To a 500 ml round-bottom flask fitted with a thermometer, a nitrogen-inlet tube, a stirrer, and a cooling tube were added 50 g (1.25 mmol) of the compound (IV) obtained in the above Example 1-7 and 50 g of ion-exchanged water, and the whole was heated to 40 C. to achieve dissolution. After the dissolution, the whole was cooled to 10 C. or lower and 5 g of a 50% aqueous potassium hydroxide solution was added thereto. Subsequently, while the temperature was kept at 5 to 10 C., 26.5 g (499 mmol) of acrylonitrile was added dropwise over a period of 2 hours. After completion of the dropwise addition, the reaction was further conducted for 4 hours and, after 50 g of ion-exchanged water was added, neutralization was achieved by adding 3 g of an 85% aqueous phosphoric acid solution. After 75 g of ethyl acetate was added and the whole was stirred, it was allowed to stand and an upper ethyl acetate layer was discarded. The extraction with ethyl acetate was repeated nine times. After completion of the extraction, extraction with 250 g of chloroform was performed. The resulting chloroform layer was dried over 15 g of magnesium sulfate and, after filtration, was concentrated. The concentrated liquid was dissolved with adding 150 g of ethyl acetate, and hexane was added until crystals were precipitated. The crystals were collected by filtration and again dissolved in 150 g of ethyl acetate under heating and, after cooling to room temperature, hexane was added until crystals were precipitated. The crystals were collected by filtration and dried to obtain the following cyanoethyl body (X).

(119) .sup.1H-NMR (CDCl.sub.3, internal standard: TMS) (ppm):

(120) 1.57 (4H, br, OCH.sub.2CH.sub.2CH.sub.2CH.sub.2O),

(121) 2.63 (16H, t, CH.sub.2CH.sub.2CN),

(122) 3.39 (4H, br, OCH.sub.2CH.sub.2CH.sub.2CH.sub.2O),

(123) 3.50-3.80 (3614H, m, CH.sub.2O(CH.sub.2CH.sub.2O).sub.nH, CHO(CH.sub.2CH.sub.2O).sub.nH, CH.sub.2OCH.sub.2CH.sub.2CH.sub.2CH.sub.2OCH.sub.2, CH.sub.2CH.sub.2CN)

(124) ##STR00023##

Example 4-2

Synthesis of Propylamino Body (Case of Molecular Weight of About 40,000)

(125) To a 1 L autoclave were added 30 g of the cyanoethyl body, i.e, the compound (X) obtained in the above Example 4-1, 545 g of toluene, and 2.7 g of nickel (5136p manufactured by N. E. MCAT Company), and the whole was heated to 60 C. Pressurization was performed with ammonia until inner pressure reached 1 MPa and thereafter, hydrogen was introduced to achieve pressurization until the inner pressure reached 4.5 MPa, followed by reaction at 130 C. for 3 hours. After the reaction, the reaction solution was cooled to 80 C. and purging with nitrogen was repeated until ammonia odor disappeared. All the amount of the reaction solution was taken out and filtrated. After the filtrate was cooled to room temperature, hexane was added until crystals were precipitated. The crystals were collected by filtration and dried to obtain the following amine body (XI).

(126) .sup.1H-NMR (CDCl.sub.3, internal standard: TMS) (ppm):

(127) 1.57 (4H, br, OCH.sub.2CH.sub.2CH.sub.2CH.sub.2O),

(128) 1.72 (16H, quint, CH.sub.2CH.sub.2CH.sub.2NH.sub.2),

(129) 2.79 (16H, t, CH.sub.2CH.sub.2CH.sub.2NH.sub.2),

(130) 3.39 (4H, br, OCH.sub.2CH.sub.2CH.sub.2CH.sub.2O),

(131) 3.50-3.80 (894H, m, CH.sub.2O(CH.sub.2CH.sub.2O).sub.nH, CHO(CH.sub.2CH.sub.2O).sub.nH, CH.sub.2OCH.sub.2CH.sub.2CH.sub.2CH.sub.2OCH.sub.2, CH.sub.2CH.sub.2CH.sub.2NH.sub.2)

(132) GPC analysis (water system):

(133) main fraction: 96.5%, Mn: 28,201, Mw: 28,796, Mw/Mn: 1.021, Mp: 28,661

(134) ##STR00024##

Example 5

Synthesis of Glutaric Acid NHS Body (Case of Molecular Weight of About 20,000)

(135) To a 200 ml round-bottom flask fitted with a thermometer, a nitrogen-inlet tube, and a stirrer were added 50 g (2.5 mmol) of the compound (III) obtained in the above Example 1-6, 33 mg of BHT, 250 mg of sodium acetate, and 100 g of toluene, and PEG was dissolved under a nitrogen atmosphere. Thereafter, the whole was heated and refluxed at 110 C. to remove moisture. After cooling, 3.46 g (30.3 mmol) of glutaric anhydride was added, followed by reaction at 110 C. for 8 hours. Then, the reaction solution was cooled to 40 C. and 4.88 g (42.4 mmol) of N-hydroxysuccinimide and 8.34 g (40.4 mmol) of 1,3-dicyclohexylcarbodiimide were added, followed by reaction for 3 hours. After 3 hours, the reaction solution was filtrated and hexane was added to the filtrate until crystals were precipitated. The crystals were collected by filtration and dissolved in ethyl acetate under heating. Thereafter, hexane was added until crystals were precipitated and the crystals were collected by filtration and dried to obtain the objective compound (XII).

(136) .sup.1H-NMR (CDCl.sub.3, internal standard: TMS) (ppm):

(137) 1.57 (4H, br, OCH.sub.2CH.sub.2CH.sub.2CH.sub.2O),

(138) 2.07 (16H, quint, CH.sub.2CH.sub.2CH.sub.2C(O)O),

(139) 2.50 (16H, t, CH.sub.2CH.sub.2CH.sub.2C(O)O),

(140) 2.72 (16H, t, CH.sub.2CH.sub.2CH.sub.2C(O)O),

(141) 2.84 (32H, br, C(O)CH.sub.2CH.sub.2C(O)),

(142) 3.40 (4H, br, OCH.sub.2CH.sub.2CH.sub.2CH.sub.2O),

(143) 3.51-3.64 (1758H, m, CH.sub.2O(CH.sub.2CH.sub.2O).sub.nH, CHO(CH.sub.2CH.sub.2O).sub.nH, CH.sub.2OCH.sub.2CH.sub.2CH.sub.2CH.sub.2OCH.sub.2,)

(144) 4.25 (16H, t, OCH.sub.2CH.sub.2OC(O)),

(145) GPC analysis (DMF system):

(146) main fraction: 97.7%, Mn: 14,297, Mw: 14,650, Mw/Mn: 1.025, Mp: 15,160

(147) ##STR00025##

Comparative Example 1

(148) Synthesis of the above compounds (I), (II), (III), and (IV) were conducted by the production methods described in Patent Literatures 1 and 2.

(149) (Cases where L=n-butylene group, k=1, molecular weight of about 5,000, 10,000, 20,000, 40,000)

Comparative Example 1-1

Synthesis of Compounds (XIII) and (XIV): diisopropylidenexylitol

(150) To a 5 L round-bottom flask fitted with a thermometer, nitrogen-inlet tube, and stirrer were charged 1,000 g of xylitol, 1,916 g of 2,2-dimethoxypropane, and 37.5 mg of p-toluenesulfonic acid monohydrate, and reaction was carried out at 65 C. while blowing nitrogen therein. The solvent of the reaction solution was distilled off, and the residue was purified by distillation (b.p. 108 C./0.15 mmHg) to obtain 1,527 g of an isomer mixture of 1,2,3,4-diisopropylidenexylitol (formula (XIII)) and 1,2,4,5-diisopropylidenexylitol (formula (XIV)).

(151) .sup.1H-NMR (CDCl.sub.3, internal standard: TMS) (ppm):

(152) 1.37-1.44 (12H, m, C(CH.sub.3).sub.2),

(153) 3.59-3.65 (1H, m, CHO),

(154) 3.81-3.90 (2H, m, CH.sub.2O),

(155) 3.98-4.01 (1H, m, CHO),

(156) 4.04-4.10 (2H, m, CH.sub.2O)

(157) 4.11-4.23 (1H, m, CHO)

(158) ##STR00026##

Comparative Example 1-2

Synthesis of Compound (XV): 1,2,3,4-diisopropylidene-5-(t-butyldiphenylsilyl)xylitol

(159) Into a 2 L round-bottom flask fitted with a thermometer, nitrogen-inlet tube, and stirrer were charged 250 g of diisopropylidenexylitol (mixture of isomers) purified in 1-1, 1,000 g of dichloromethane, 26 g of 4-dimethylaminopyridine, and 109 g of triethylamine, and the mixture is dissolved at room temperature while blowing nitrogen therein. After cooling to 10 C. or lower, 297 g of t-butylchlorodiphenylsilane was added dropwise. After the dropwise addition, the temperature was returned to room temperature and reaction was performed for 2 hours. Then, the mixture was washed with a saturated aqueous sodium hydrogen carbonate solution and dehydrated with magnesium sulfate, and then the solvent was distilled off 1,2,4,5-Diisopropylidenexylitol was removed at 135 C. under reduced pressure (0.2 mmHg) to obtain 200 g of 1,2,3,4-diisopropylidene-5-(t-butyldiphenylsilyl)xylitol (formula (XV)).

(160) .sup.1H-NMR (CDCl.sub.3, internal standard: TMS) (ppm):

(161) 1.06 (9H, m, SiC(CH.sub.3).sub.3)

(162) 1.37, 1.42, 1.43 (12H, s, OCCH.sub.3)

(163) 3.72-3.82 (1H, m, CHO, CH.sub.2O)

(164) 3.95 (1H, dd, CHO)

(165) 3.99-4.06 (2H, m, CH.sub.2O)

(166) 4.11-4.15 (1H, m, CHO)

(167) 7.36-7.54 (6H, m, PhSi(Ph)O)

(168) 7.66-7.70 (4H, m, PhSi(Ph)O)

(169) ##STR00027##

Comparative Example 1-3

Synthesis of Compound (XIII): 1,2,3,4-diisopropylidenexylitol

(170) Into a 2 L round-bottom flask fitted with a thermometer, a nitrogen-inlet tube, and a stirrer were charged 500 g of 1,2,3,4-diisopropylidene-5-(t-butyldiphenylsilyl)xylitol and 440 g of dehydrated tetrahydrofuran, and the mixture was homogenize at room temperature while blowing nitrogen therein. After cooling to 20 C. or below, 1,270 ml of tetrabutylammonium fluoride (1 mol/L tetrahydrofuran solution) was added dropwise. After the dropwise addition, the temperature was returned to room temperature and the reaction was performed for 2 hours, and then the solvent was distilled off under reduced pressure. After the residue was dissolved with 2,000 g of ethyl acetate, the ethyl acetate layer was washed with purified water and dehydrated with magnesium sulfate, and then the solvent was distilled off. By column chromatography using chloroform and methanol as solvents and silica gel as a packing material, 150 g of 1,2,3,4-diisopropylidenexylitol (formula (XIII) was obtained.

(171) .sup.1H-NMR (CDCl.sub.3, internal standard: TMS) (ppm):

(172) 1.39, 1.44 (12H, s, CH.sub.3),

(173) 3.62 (1H, dd, CHO),

(174) 3.08-3.89 (2H, m, CH.sub.2O),

(175) 3.98-4.08 (1H, m, CHO, 2H, m, CH.sub.2O),

(176) 4.18-4.23 (1H, m, CHO)

(177) ##STR00028##

Comparative Example 1-4

Synthesis of Compound (XVI): 1,1-butylene-bis(2,3,4,5-diisopropylidenexylitol)

(178) After 130.3 g (0.56 mol) of 1,2,3,4-diisopropylidenexylitol and 1,650 g of dehydrated toluene were added to a 5,000 ml round-bottom flask fitted with a thermometer, a nitrogen-inlet tube, and a stirrer and dissolved each other under a nitrogen atmosphere, 65.4 g (0.58 mol) of potassium t-butoxide was added thereto, followed by stirring at room temperature for 30 minutes. On the other hand, 55.2 g (0.22 mol) of 1,4-butanediol dimethanesulfonate was dissolved in 660 g of dehydrated DMF and then the solution was added dropwise into the reaction solution at 40 C. or lower over a period of 30 minutes. After completion of the stepwise addition, the temperature was raised to 50 C. and the reaction was conducted for 6 hours. After completion of the reaction, the reaction solution was cooled and, after 1,100 g of ion-exchanged water was added and the whole was stirred for 20 minutes, the whole was allowed to stand and the aqueous layer was removed. A water-washing operation of adding 830 g of ion-exchanged water and allowing the whole to stand after stirring was repeated eight times to remove DMF and unreacted raw materials. After the water-washing, the organic layer was concentrated and dried with adding 27.6 g of magnesium sulfate, followed by filtration. The filtrate was again concentrated and purified by silica gel column chromatography (Wakogel C-200, eluent:ethyl acetate:hexane=10:3 (v/v)) to obtain 76.9 g of 1,1-butylene-bis(2,3,4,5-diisopropylidenexylitol) (XVI) having the following structure.

(179) .sup.1H-NMR (CDCl.sub.3, internal standard: TMS) (ppm):

(180) 1.39, 1.41, 1.42, 1.44 (24H, s, OCCH.sub.3),

(181) 1.65 (4H, quint, OCH.sub.2CH.sub.2CH.sub.2CH.sub.2O),

(182) 3.49 (4H, m, OCH.sub.2CH.sub.2CH.sub.2CH.sub.2O),

(183) 3.54-3.58 (4H, m, CH.sub.2O),

(184) 3.85 (2H, t, CHO),

(185) 3.89 (2H, dd, CHO),

(186) 4.02-4.07 (4H, m, CH.sub.2O),

(187) 4.17 (2H, dd, CHO)

(188) ##STR00029##

Comparative Example 1-5

Synthesis of 1,1-Butylene-bisxylitol (V)

(189) After 76.8 g (0.15 mol) of 1,1-butylene-bis(2,3,4,5-diisopropylidenexylitol) (XVI) obtained in Comparative Example 1-4, 456 g of methanol, and 45 g of ion-exchanged water were added to a 1,000 ml round-bottom flask fitted with a thermometer, a nitrogen-inlet tube, and a stirrer and dissolved one another under a nitrogen atmosphere, 76.4 g of Dowex 50W-8H (manufactured by Dow Chemical Company) dispersed in 76 g of methanol was added thereto and the whole was heated and refluxed to remove acetone produced as a by-product in an azeotropic manner. The reaction solution was filtrated and the filtrate was concentrated to obtain 53.6 g of the above-mentioned compound, 1,1-butylene-bisxylitol (V).

(190) .sup.1H-NMR (D.sub.2O, internal standard: TMS) (ppm):

(191) 1.66 (4H, quint, OCH.sub.2CH.sub.2CH.sub.2CH.sub.2O),

(192) 3.56-3.75 (14H, m, OCH.sub.2CH.sub.2CH.sub.2CH.sub.2O, CH.sub.2O, CHO),

(193) 3.79-3.82 (2H, m, CHO),

(194) 3.91-3.93 (2H, m, CHO)

Comparative Example 1-6

Synthesis of Compound (I) (Case of Molecular Weight of 5,000)

(195) Fifty-two grams of 1,1-butylene-bisxylitol (V) obtained in Comparative Example 1-5 was warmed and, while washing it with 34 g of methanol, was charged into a 5 L autoclave. Subsequently, 4.9 g of potassium hydroxide and 10 g of ion-exchanged water were added to a 50 ml beaker to prepare an aqueous potassium hydroxide solution, which was then charged into the 5 L autoclave. Then, 500 g of dehydrated toluene was added thereto and an azeotropic dehydration operation was repeated three times at 80 C. under slightly reduced pressure. After the azeotropic dehydration, 1,423 g of dehydrated toluene was added and, after the inside of the system was replaced by nitrogen, 654 g (14.85 mol) of ethylene oxide was added thereto at 80 to 150 C. under a pressure of 1 MPa or less, followed by continuation of the reaction for another 1 hour. After the reaction, the whole was cooled to 60 C., 945 g of the reaction solution was taken out of the autoclave, and pH was adjusted to 7.5 with an 85% aqueous phosphoric acid solution to obtain the compound (I) mentioned above.

(196) .sup.1H-NMR (CDCl.sub.3, internal standard: TMS) (ppm):

(197) 1.57 (4H, br, OCH.sub.2CH.sub.2CH.sub.2CH.sub.2O),

(198) 2.66 (8H, br, OH),

(199) 3.40 (4H, br, OCH.sub.2CH.sub.2CH.sub.2CH.sub.2O),

(200) 3.50-3.81 (430H, m, CH.sub.2O(CH.sub.2CH.sub.2O).sub.nH, CHO(CH.sub.2CH.sub.2O).sub.nH, CH.sub.2OCH.sub.2CH.sub.2CH.sub.2CH.sub.2OCH.sub.2)

(201) GPC analysis (DMF system):

(202) main fraction: 100%, Mn: 3,971, Mw: 4,059, Mw/Mn: 1.022, Mp: 4,105
Molecular weight (TOF-MS); 4,991
Molecular weight (hydroxyl value); 5,097

Comparative Example 1-7

Synthesis of Compound (II) (Case of Molecular Weight of 10,000)

(203) To about 1,345 g of the reaction solution remaining in the reaction vessel in Comparative Example 1-6 was added 370 g (8.40 mol) of ethylene oxide at 80 to 150 C. under a pressure of 1 MPa or less, followed by continuation of the reaction for another 1 hour. After the reaction, the whole was cooled to 60 C., 1,045 g of the reaction solution was taken out of the vessel, pH was adjusted to 7.5 with an 85% aqueous phosphoric acid solution, and toluene was removed by distillation to obtain the compound (II) mentioned above.

(204) .sup.1H-NMR (CDCl.sub.3, internal standard: TMS) (ppm):

(205) 1.57 (4H, br, OCH.sub.2CH.sub.2CH.sub.2CH.sub.2O),

(206) 2.365 (8H, br, OH),

(207) 3.40 (4H, s, OCH.sub.2CH.sub.2CH.sub.2CH.sub.2O),

(208) 3.50-3.81 (878H, m, CH.sub.2O(CH.sub.2CH.sub.2O).sub.nH, CHO(CH.sub.2CH.sub.2O).sub.nH, CH.sub.2OCH.sub.2CH.sub.2CH.sub.2CH.sub.2OCH.sub.2)

(209) GPC analysis (DMF system):

(210) main fraction: 100%, Mn: 7,264, Mw: 7,429, Mw/Mn: 1.023, Mp: 7,513
Molecular weight (TOF-MS); 10,033
Molecular weight (hydroxyl value); 10,158

Comparative Example 1-8

Synthesis of Compound (III) (Case of Molecular Weight of 20,000)

(211) To about 524 g of the reaction solution remaining in the reaction vessel in Comparative Example 1-7 was added 182 g (4.13 mol) of ethylene oxide at 80 to 150 C. under a pressure of 1 MPa or less, followed by continuation of the reaction for another 1 hour. After the reaction, the whole was cooled to 60 C., 620 g of the reaction solution was taken out of the vessel, pH was adjusted to 7.5 with an 85% aqueous phosphoric acid solution, and toluene was removed by distillation to obtain the compound (III) mentioned above.

(212) .sup.1H-NMR (CDCl.sub.3, internal standard: TMS) (ppm):

(213) 1.57 (4H, br, OCH.sub.2CH.sub.2CH.sub.2CH.sub.2O),

(214) 2.57 (8H, br, OH),

(215) 3.40 (4H, s, OCH.sub.2CH.sub.2CH.sub.2CH.sub.2O),

(216) 3.50-3.81 (1774H, m, CH.sub.2O(CH.sub.2CH.sub.2O).sub.nH, CHO(CH.sub.2CH.sub.2O).sub.nH, CH.sub.2OCH.sub.2CH.sub.2CH.sub.2CH.sub.2OCH.sub.2)

(217) GPC analysis (DMF system):

(218) main fraction: 99.3%, Mn: 13,965, Mw: 14,392, Mw/Mn: 1.031, Mp: 14,724
Molecular weight (TOF-MS); 20,083
Molecular weight (hydroxyl value); 20,225

Comparative Example 1-9

Synthesis of Compound (IV) (Case of Molecular Weight of 40,000)

(219) To about 221 g of the reaction solution remaining in the reaction vessel in Comparative Example 1-8 was added 138 g (3.13 mol) of ethylene oxide at 80 to 150 C. under a pressure of 1 MPa or less, followed by continuation of the reaction for another 1 hour. After the reaction, the whole was cooled to 60 C., all the amount of the reaction solution was taken out of the vessel, pH was adjusted to 7.5 with an 85% aqueous phosphoric acid solution, and toluene was removed by distillation to obtain the compound (IV) mentioned above.

(220) .sup.1H-NMR (CDCl.sub.3, internal standard: TMS) (ppm):

(221) 1.57 (4H, br, OCH.sub.2CH.sub.2CH.sub.2CH.sub.2O),

(222) 2.589 (8H, br, OH),

(223) 3.40 (4H, br, OCH.sub.2CH.sub.2CH.sub.2CH.sub.2O),

(224) 3.50-3.81 (3598H, m, CH.sub.2O(CH.sub.2CH.sub.2O).sub.nH, CHO(CH.sub.2CH.sub.2O).sub.nH, CH.sub.2OCH.sub.2CH.sub.2CH.sub.2CH.sub.2OCH.sub.2)

(225) GPC analysis (DMF system):

(226) main fraction: 97.3%, Mn: 28,595, Mw: 29,392, Mw/Mn: 1.028, Mp: 30,103
Molecular weight (TOF-MS); 41,450
Molecular weight (hydroxyl value); 38,590

Comparative Example 2-1

Synthesis of Cyanoethyl Body (Case of Molecular Weight of About 10,000)

(227) To a 500 ml round-bottom flask fitted with a thermometer, a nitrogen-inlet tube, a stirrer, and a cooling tube were added 30 g (3 mmol) of the compound (II) obtained in the above Comparative Example 1-7 and 30 g of ion-exchanged water, and the whole was heated to 40 C. to achieve dissolution. After the dissolution, the whole was cooled to 10 C. or lower and 3 g of a 50% aqueous potassium hydroxide solution was added thereto. Subsequently, while the temperature was kept at 5 to 10 C., 25.5 g (480 mmol) of acrylonitrile was added dropwise over a period of 2 hours. After completion of the dropwise addition, the reaction was further conducted for 4 hours and, after 30 g of ion-exchanged water was added, neutralization was achieved by adding 1.8 g of an 85% aqueous phosphoric acid solution. After 45 g of ethyl acetate was added and the whole was stirred, it was allowed to stand and an upper ethyl acetate layer was discarded. The extraction with ethyl acetate was repeated nine times. After completion of the extraction, extraction with 150 g of chloroform was performed. The resulting chloroform layer was dried over 15 g of magnesium sulfate and, after filtration, was concentrated. The concentrated liquid was dissolved with adding 90 g of ethyl acetate, and hexane was added until crystals were precipitated. The crystals were collected by filtration and again dissolved in 90 g of ethyl acetate under heating and, after cooling to room temperature, hexane was added until crystals were precipitated. The crystals were collected by filtration and dried to obtain the cyanoethyl body (VI) mentioned above.

(228) .sup.1H-NMR (CDCl.sub.3, internal standard: TMS) (ppm):

(229) 1.57 (4H, br, OCH.sub.2CH.sub.2CH.sub.2CH.sub.2O),

(230) 2.63 (16H, t, CH.sub.2CH.sub.2CN),

(231) 3.39 (4H, br, OCH.sub.2CH.sub.2CH.sub.2CH.sub.2O),

(232) 3.50-3.80 (894H, m, CH.sub.2O(CH.sub.2CH.sub.2O).sub.nH, CHO(CH.sub.2CH.sub.2O).sub.nH, CH.sub.2OCH.sub.2CH.sub.2CH.sub.2CH.sub.2OCH.sub.2, CH.sub.2CH.sub.2CN)

Comparative Example 2-2

Synthesis of Propylamino Body (Case of Molecular Weight of About 10,000)

(233) To a 1 L autoclave were added 13 g of the cyanoethyl body, i.e, the compound (VI) obtained in the above Comparative Example 2-1, 560 g of toluene, and 1.2 g of nickel (5136p manufactured by N. E. MCAT Company), and the whole was heated to 60 C. Pressurization was performed with ammonia until inner pressure reached 1 MPa and thereafter, hydrogen was introduced to achieve pressurization until the inner pressure reached 4.5 MPa, followed by reaction at 130 C. for 3 hours. After the reaction, the reaction solution was cooled to 80 C. and purging with nitrogen was repeated until ammonia odor disappeared. All the amount of the reaction solution was taken out and filtrated. After the filtrate was cooled to room temperature, hexane was added until crystals were precipitated. The crystals were collected by filtration and dried to obtain the amine body (VII) mentioned above.

(234) .sup.1H-NMR (CDCl.sub.3, internal standard: TMS) (ppm):

(235) 1.57 (4H, br, OCH.sub.2CH.sub.2CH.sub.2CH.sub.2O),

(236) 1.72 (16H, quint, CH.sub.2CH.sub.2CH.sub.2NH.sub.2),

(237) 2.79 (16H, t, CH.sub.2CH.sub.2CH.sub.2NH.sub.2),

(238) 3.39 (4H, br, OCH.sub.2CH.sub.2CH.sub.2CH.sub.2O),

(239) 3.50-3.80 (894H, m, CH.sub.2O(CH.sub.2CH.sub.2O).sub.nH, CHO(CH.sub.2CH.sub.2O).sub.nH, CH.sub.2OCH.sub.2CH.sub.2CH.sub.2CH.sub.2OCH.sub.2, CH.sub.2CH.sub.2CH.sub.2NH.sub.2)

(240) GPC analysis (water system):

(241) main fraction: 97.9%, Mn: 6,334, Mw: 6,477, Mw/Mn: 1.022, Mp: 6,571

Comparative Example 3

Synthesis of Glutaric Acid NHS Body (Case of Molecular Weight of About 20,000)

(242) To a 200 ml round-bottom flask fitted with a thermometer, a nitrogen-inlet tube, and a stirrer were added 25 g (1.25 mmol) of the compound (III) obtained in Comparative Example 1-8, 25 mg of BHT, 125 mg of sodium acetate, and 60 g of toluene, and PEG was dissolved under a nitrogen atmosphere. Thereafter, the whole was heated and refluxed at 110 C. to remove moisture. After cooling, 1.71 g (15.0 mmol) of glutaric anhydride was added thereto, followed by reaction at 110 C. for 8 hours. Then, the reaction solution was cooled to 40 C. and 3.45 g (30.0 mmol) of N-hydroxysuccinimide and 4.33 g (21.0 mmol) of 1,3-dicyclohexylcarbodiimide were added, followed by reaction for 3 hours. After 3 hours, the reaction solution was filtrated and hexane was added to the filtrate until crystals were precipitated. The crystals were collected by filtration and dissolved in ethyl acetate under heating. Thereafter, hexane was added until crystals were precipitated and the crystals were collected by filtration and dried to obtain the objective compound (XII).

(243) .sup.1H-NMR (CDCl.sub.3, internal standard: TMS) (ppm):

(244) 1.57 (4H, br, OCH.sub.2CH.sub.2CH.sub.2CH.sub.2O),

(245) 2.07 (16H, quint, CH.sub.2CH.sub.2CH.sub.2C(O)O),

(246) 2.50 (16H, t, CH.sub.2CH.sub.2CH.sub.2C(O)O),

(247) 2.72 (16H, t, CH.sub.2CH.sub.2CH.sub.2C(O)O),

(248) 2.84 (32H, br, C(O)CH.sub.2CH.sub.2C(O)),

(249) 3.40 (4H, br, OCH.sub.2CH.sub.2CH.sub.2CH.sub.2O),

(250) 3.51-3.64 (1758H, m, CH.sub.2O(CH.sub.2CH.sub.2O).sub.nH, CHO(CH.sub.2CH.sub.2O).sub.nH, CH.sub.2OCH.sub.2CH.sub.2CH.sub.2CH.sub.2OCH.sub.2,)

(251) 4.25 (16H, t, OCH.sub.2CH.sub.2OC(O)),

(252) GPC analysis (DMF system):

(253) main fraction: 97.5%, Mn: 14,711, Mw: 15,116, Mw/Mn: 1.028, Mp: 15,635

(254) Table 1 summarizes the purity and the total yield of the propylamino body (VII) obtained in Example 2-2 and Comparative Example 2-2 according to the production method.

(255) TABLE-US-00001 TABLE 1 Examples Step Example 1-1 Example 1-2 Example 1-3 Example 1-5 Example 2-2 Total molar yield 85% 55% 47% 42% 34% NMR purity 99% 98% 99% 99%* 94% Comparative Examples Comparative Comparative Comparative Comparative Comparative Comparative Comparative Step Example 1-1 Example 1-2 Example 1-3 Example 1-4 Example 1-5 Example 1-7 Example 2-2 Total molar yield 95% 38% 23% 15% 10% 9% 7% NMR purity 80% 80% 99% 98% 99% 100%* 90% *GPC purity

(256) Table 2 summarizes the results of the polydispersity (Mw/Mn) of the main fraction obtained from the GPC analysis in Examples 1-4 to 7, 2-2, and 5 and Comparative Examples 1-6 to 9, 2-2, and 3.

(257) TABLE-US-00002 TABLE 2 Terminal Molecular functional Compound weight group Mw/Mn Example 1-4 (I) 5,000 Hydroxyl 1.017 Comparative group 1.022 Example 1-6 Example 1-5 (II) 10,000 1.019 Comparative 1.023 Example 1-7 Example 1-6 (III) 20,000 1.025 Comparative 1.031 Example 1-8 Example 1-7 (IV) 40,000 1.020 Comparative 1.028 Example 1-9 Example 2-2 (VII) 10,000 Propylamino 1.017 Comparative group 1.022 Example 2-2 Example 5 (XII) 20,000 Glutaric acid 1.025 Comparative NHS group 1.028 Example 3

(258) In the conventional production method, for example, three steps were required to obtain a highly pure protected body of xylitol and column chromatography was used in the purification step, so that a large decrease in yield was observed. On the other hand, in the production method of the invention, the highly pure protected body of xylitol is produced in one step without requiring a special purification step, and therefore the total molar yield can be significantly improved. It was also shown that the multi-arm type polyethylene glycol derivative of the invention and the intermediate thereof have equal quality in polydispersity and purity.

INDUSTRIAL APPLICABILITY

(259) According to the present invention, it is possible to provide a method capable of industrially producing a highly pure multi-arm type polyethylene glycol derivative having a narrow molecular weight distribution, which is suitable for use as a material in DDS and the biological and medical fields, in high yields.

(260) While the present invention has been described in detail and with reference to specific embodiments thereof, it will be apparent to one skilled in the art that various changes and modifications can be made therein without departing from the spirit and scope thereof.

(261) The present application is based on Japanese Patent Application No. 2018-59150 filed on Mar. 27, 2018, and the contents thereof are incorporated herein by reference.