Selective and Specific Preparation of Discrete Peg Compounds

• US 20110124844A1
• Filed: 01/27/2011
• Published: 05/26/2011
• Est. Priority Date: 02/14/2003
• Status: Active Grant

• Current Assignee: Quanta Biodesign LLC
• Original Assignee: Edward C. Crapps, Paul D. Davis
• Inventors: Davis, Paul D., Crapps, Edward C.
• Granted Patent: US 8,637,711 B2
• Time in Patent Office: Days
• US Class Current: 530/410
• CPC Class Codes: C07C 247/04 being saturated
• CPC Class Codes: C07C 319/12 by reactions not involving the formation of mercapto groups
• CPC Class Codes: C07C 323/12 the carbon skeleton being acyclic and saturated
• CPC Class Codes: C07C 41/16 by reaction of esters of mineral or organic acids with hydroxy or O-metal groups
• CPC Class Codes: C07C 43/11 Polyethers containing —O—(C—C—O—)n units with ≤ 2 n≤ 10
• CPC Class Codes: C07C 43/164 containing six-membered aromatic rings
• CPC Class Codes: C07C 43/1785 having more than one ether bound
• CPC Class Codes: C08G 65/331 containing oxygen cyclic ether compounds C08G65/26
• CPC Class Codes: C08L 71/02 Polyalkylene oxides
• CPC Class Codes: Y02P 20/55 Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

Abstract

Aspects of the present invention are directed to novel methods for making discrete polyethylene compounds selectively and specifically to a predetermined number of ethylene oxide units. Methods which can be used to build up larger dPEG compounds (a) containing a wider range of utility to make useful homo- and heterofunctional and branched species, and (b) under reaction configurations and conditions that are milder, more efficient, more diverse in terms of incorporating useful functionality, more controllable, and more versatile then any conventional method reported in the art to date. In addition, the embodiments of the invention allow for processes that allow for significantly improving the ability to purify the intermediates or final product mixtures, making these methods useful for commerial manufacturing dPEGs. Protecting groups and functional groups can be designed to make purification at large scale a practical reality. The novel dPEG products form the compositional and material basis for making other novel compounds of valuable application in the fields of diagnostics and therapeutics, amongst others.

Claims

1-51. -51. (canceled)

52. A method for selectively making specific discrete (polyethylene glycol) (dPEG) compounds containing a discrete and predetermined number of ethylene oxide moieties, which comprises the steps of:

(a) forming a reaction mixture comprising a first dPEG compound having the general structural formula I or I′

;

R¹-dPEG_x-OH 

 

I

R¹-dPEG_x-OR² 

 

I′

and a dPEG compound having the structural formula X or X′

, respectively;

R³-dPEG_y-OR² 

 

X

R³-dPEG_y-OH 

 

X′

(b) adding a non-sodium ionizing agent, which is potassium t-butoxide, in the presence of a catalyst and under conditions to produce a dPEG compound having the structural formula XI

R¹-dPEG_x+y-R³ 

 

XI;

wherein said potassium t-butoxide ionizing compound is added to a reaction mixture of compounds I and X and II, or I′ and

X′

, at a rate that is about equal to the rate at which compound XXII formed in situ from compound I reacts with compound X or the rate at which compound XXII″

formed in situ from compound I′

reacts with compound X′

, respectively, wherein;

R¹-dPEG_x-O⁻

M⁺ 

 

XXII

R³-dPEG_y-O⁻

M⁺ 

 

XXII′

wherein, R¹ and R³ each independently are one or more of a hydroxy protecting group (PG), a functional group (FG), or a protected functional group;

R² is a leaving group, x ranges from about 1 to 300, and y ranges from about 1 to 300.

53. The method of claim 52, which comprises the additional step of:

(c) one or more of selectively removing R¹ in the presence of R³ or selectively removing R³ in the presence of R¹, to produce compounds of formulas XII and XIII, respectively,

HO-dPEG_x+y—

R³ 

 

XII

R¹-dPEG_x+y-OH 

 

XIII

54. The method of claim 52, wherein said ionizing agent is one or more of potassium t-butoxide, potassium hydride, n-butyl lithium, t-butyl lithium, or lithium diisopropylamine.

56. The method of claim 52, wherein a portion of dPEG_y or dPEG_x is partially replaced with X, which is an aliphatic, aromatic, or aliphatic-aromatic organic linker moiety optionally substituted with heteroatoms.

57. The method of claim 52, wherein said reactants are dispersed in a solvent.

58. The method of claim 57, wherein said solvent is one or more of tetrahydrofuran (THF), toluene, dioxane, trichloroethylene, or tetrachloroethylene.

59. The method of claim 52, where R¹ and R³ both are PG groups, and further comprising one or more of R¹ of compound XII or R³ of compound XIII is removed to produce a compound of formula XIV:

HO-dPEG_2x+y-R 

 

XIV

where, R is R¹ or R³.

60. The method of claim 59, wherein compound XIV is converted to a compound of formula V′

;

R-dPEG_2x+y-OR² 

 

V.

61. The method of claim 60, further comprising:

forming a reaction mixture comprising said dPEG compound V or XVIII and a dPEG compound having the structure of formula V′

or XVIII′

, respectively, where;

R⁵-dPEG_z-OH 

 

XVIII

R⁵-dPEG_z-OR² 

 

XVIII′

R-dPEG_2x+y-OH 

 

V′

adding an ionizing agent optionally in the presence of a catalyst and under conditions to produce a dPEG compound having the structural formula VI

R⁵-dPEG_2x+y+z-R 

 

VI

wherein z is 1 to 300, R⁵ is a PG or FG, and R² is a leaving group.

62. The method of claim 52, wherein the molar ratio of compound I to compound X, or compound I′

to compound X′

, is between about 1;

1 and about 1.05;

1.

63. The method of claim 61, wherein the molar ratio of compound XVIII to compound VI is between about 1:

1 and about 1.05;

1.

64. The method of claim 52, wherein the purity of compound XI produced is greater than about 98%.

65. The method of claim 61, where R¹ or R³ is a PG group, and further comprising R or R⁵ of compound VI is removed produce a compound of formula VII or XXIX, respectively:

R⁵-dPEG_2x+y+z-OH 

 

VII

R-dPEG_2x+y+z-OH 

 

XXIX.

66. The method of claim 52, which includes a catalyst to promote the complexation of M⁺.

67. The method of claim 61, which includes a catalyst to promote the complexation of M⁺.

68. The method of claim 67, wherein said catalyst is a cryptand catalyst.

69. The method of claim 68, wherein said catalyst is one or more of 18-crown-6 or a derivative of 18-crown-6.

70. The method of claim 52, wherein R¹ or R³ is a functional group.

71. The method of claim 61, wherein R¹ or R⁵ is a functional group.

72. The method of claim 70, wherein R¹ or R³ is one or more of a protected amine, a nitrile group, an alkoxy group, an aryloxy group, a protected thiol group, or a protected carboxyl group.

73. The method of claim 71, wherein R¹ or R⁵ is one or more of a protected amine, a nitrile group, an alkoxy group, an aryloxy group, a protected thiol group or a protected carboxyl group.

74. The method of claim 72, wherein said protected amine is one or more of an azido group, a trityl, a substituted trityl, a phthalimido group, CBZ, t-boc, benzyl group, a substituted benzyl group.

75. The method of claim 73, wherein said protected amine is one or more of an azido group, CBZ, t-boc, benzyl group, a substituted benzyl group, a phthalimido group, trityl, or a substituted trityl.

76. The method of claim 74, wherein said protected amine is an azido group, which is subsequently reduced to an amine group with triphenyl phosphine.

77. The method of claim 75, wherein said protected amine is an azido group, which is subsequently reduced to an amine group with triphenyl phosphine.

78. The method of claim 72, wherein said thiol group is protected with one or more of an aralkyl group, an acetyl group, a trityl group, a substituted trityl group, or a thiourea group.

79. The method of claim 73, wherein said thiol group is protected with one or more of an aralkyl group, an acetyl group, a trityl group, a substituted trityl group, or a thiourea group.

80. The method of claim 60, wherein R in compound V is converted into one or more of an OH group, an ester group, a carboxyl group, an amine group, or a thiol group.

81. The method of claim 52, wherein R¹ or R³ in compound XI is a protective group that is subsequently removed under acidic conditions.

82. The method of claim 61, wherein R¹ or R⁵ in compound VI is a protective group that is subsequently removed under acidic conditions.

83. The method of claim 81, wherein said acidic conditions include the use of one or more of tetrahyropyran-2-yl (THP), TMB (2,4,6-trimethylbenzyl), 4-alkoxybenzyl-, 3,4-dialkoxybenzyl, 4-aralkylxoxybenzyl-, 3,4-diaralkyloxybenzyl-, trityl, or a substituted trityl.

84. The method of claim 81, wherein R¹ or R³ is one or more of tetrahyropyran-2-yl (THP), TMB (2,4,6-trimethylbenzyl), 4-alkoxybenzyl-, 3,4-dialkoxybenzyl, 4-aralkylxoxybenzyl-, 3,4-diaralkyloxybenzyl-, trityl, or a substituted trityl.

85. The method of claim 52, wherein R¹ or R³ in structure XI is a protective group that is subsequently removed under reducing conditions.

86. The method of claim 85, wherein said reducing conditions comprise one or more of a metal catalyst and hydrogen or a Raney/Ni reducing system.

87. The method of claim 85, wherein R¹ or R³ is one or more of benzyl, TMB, PMB and p-alkoxybenzyl, DMB, 3,4-dialkoxybenzyl, 4-aralkylxoxybenzyl, or 3,4-diaralkyloxybenzyl.

88. The method of claim 86, wherein said reducing conditions comprise a Raney/Ni reducing system, and R¹ or R³ is one or more of benzyl, TMB, PMB and p-alkoxybenzyl, DMB, 3,4-dialkoxybenzyl, 4-aralkylxoxybenzyl, or 3,4-diaralkyloxybenzyl.

93. The method of claim 52, wherein R¹ or R³ in structure XI is a protective group that is subsequently removed in the presence of one or more of DDQ or cerium ammonium nitrate.

55. (canceled)

89-92. -92. (canceled)

95. The method of claim 93, wherein R¹ or R³ is one or more of p-alkoxybenzyl 3,4-dialkoxybenzyl, 4-aralkylxoxybenzyl, or 3,4-diaralkyloxybenzyl protecting groups, where the alkyl of the alkoxy ranges from C₁-C₂₂.

96. The method of claim 95, wherein p ranges from 2 to 4.

97. The method of claim 95, wherein said ionizing compound is one or more of potassium t-butoxide, potassium hydride, n-butyl lithium, t-butyl lithium, or lithium diisopropylamine.

99. The method of claim 95, wherein said reactants are dispersed in a solvent.

100. The method of claim 99, wherein said solvent is one or more of tetrahydrofuran (THF), toluene, dioxane, trichloroethylene, or tetrachloroethylene.

101. The method of claim 95, where R¹ and R³ both are PG groups, and further comprising one or more of R¹ of compound XXVII is removed to produce the hydroxy containing compound, which is reacted with

R¹—

X′

—

(R²)_p′

 

 

XX

in the presence of an ionizing agent to produce;

R¹—

X′

—

(—

X—

(O-dPEG_yR³)_p)_p′

 

 

XXI

where p′

ranges from about 2 to 9, and X′

is dPEG, an aliphatic, aromatic, aliphatic-aromatic organic linker moiety optionally substituted with heteroatoms.

102. The method of claim 101, further comprising deprotecting R¹ from compound XXI to produce compound XXX, which is reacted with compound XXVI to produce compound XXXI, as follows:

103. The method of claim 102, further comprising converting compound XXXI into one or more of:

R¹—

X′

(—

X-(0dPEG_yT)_p)_p′

 

 

XXXII

or

R¹—

X—

(—

X′

(—

X-(0dPEG_yT)_p)_p)_p 

 

XXXIII

where T is a biologically active compound.

104. The method of claim 103, further comprising one or more of R¹ in compounds XXI and XXXI being selectively removed and converted to a functional group or where R¹ is a functional group which are reactable with T may be converted to branched compounds XXXIV and XXXV:

T-X′

(—

X-(0dPEG_yR³)_p)_p′

 

 

XXXIV

T-X—

(—

X′

(—

X-(0dPEG_yR³)_p)_p)_p 

 

XXXV

105. The method of claim 95, wherein the molar ratio of compound XXVI to compound X is between about 1:

p.

106. The method of claim 101, wherein the molar ratio of compound XX to compound X is between about 1:

p.

107. The method of claim 101, wherein the purity of compound XXI produced is greater than about 95%.

108. The method of claim 95, which includes a catalyst to promote the complexation of M⁺.

109. The method of claim 101, which includes a catalyst to promote the complexation of M⁺.

110. The method of claim 109, wherein said catalyst is a cryptand catalyst.

111. The method of claim 110, wherein said catalyst is one or more of 18-crown-6 or a derivative of 18-crown-6.

112. The method of claim 95, wherein R¹ or R³ is a functional group.

113. The method of claim 101, wherein R¹ or R³ is a functional group.

114. The method of claim 112, wherein R¹ or R³ is one or more of a protected amine, a nitrile group, an alkoxy group, an aryloxy group, a carboxyl group, or a protected thiol group.

115. The method of claim 114, wherein said protected amine is one or more of an azido group, CBZ, t-boc, benzyl group, a substituted benzyl group, a phthalimido group, a trityl, or a substituted trityl.

116. The method of claim 115, wherein said protected amine is one or more of an azido group, CBZ, t-boc, benzyl group, a substituted benzyl group, a phthalimido group, a trityl, or an alkoxysubstituted trityl.

117. The method of claim 115, wherein said protected amine is one or more of an azido group, CBZ, t-boc, benzyl group, a substituted benzyl group, trityl, or a substituted trityl.

118. The method of claim 114, wherein said protected amine is an azido group, which is subsequently reduced to an amine group with triphenyl phosphine.

119. The method of claim 117, wherein said protected amine is an azido group, which is subsequently reduced to an amine group with triphenyl phosphine.

120. The method of claim 114, wherein said carboxyl group is protected with one or more of an alkyl group or an aralkyl group.

121. The method of claim 114, wherein said protecting group is one or more of a t-butyl group or a benzyl group.

122. The method of claim 115, wherein said carboxyl group is protected with one or more of an alkyl group or an aralkyl group.

123. The method of claim 122, wherein said protecting group is one or more of a t-butyl group or a benzyl group.

124. The method of claim 114, wherein said thiol group is protected with one or more of an aralkyl group, an acetyl group, a trityl, a substituted trityl, or a thiourea group.

125. The method of claim 115, wherein said thiol group is protected with one or more of an aralkyl group, an acetyl group, a trityl, a substituted trityl, or a thiourea group.

126. The method of claim 101, wherein R¹ or R³ in compound XXI is converted into one or more of an OH group, an ester group, a carboxyl group, an amine group, or a thiol group.

127. The method of claim 95, wherein R¹ or R³ in structure XXVII is a protective group that is subsequently removed under acidic conditions.

128. The method of claim 101, wherein R¹ or R³ in structure XXI is a protective group that is subsequently removed under acidic conditions.

129. The method of claim 128, wherein said acidic conditions include the use of one or more of tetrahyropyran-2-yl (THP), TMB (2,4,6-trimethyl benzyl), 4-alkoxybenzyl, 3,4-dialkoxybenzyl, 4-aralkylxoxybenzyl, 3,4-diaralkyloxybenzyl, trityl, or a substituted trityl protecting group.

130. The method of claim 127, wherein R¹ or R³ is one or more of tetrahyropyran-2-yl (THP), TMB (2,4,6-trimethylbenzyl), 4-alkoxybenzyl-, 3,4-dialkoxybenzyl, 4-aralkylxoxybenzyl, 3,4-diaralkyloxybenzy-, trityl, or a substituted trityl protecting group.

131. The method of claim 128, wherein R¹ or R³ in structure XXVII is a protective group that is subsequently removed under reducing conditions.

132. The method of claim 131, wherein said reducing conditions comprise one or more of a metal catalyst and hydrogen or a Raney/Ni reducing system.

133. The method of claim 131, wherein R¹ or R³ is one or more of benzyl, TMB, PMB and p-alkoxybenzyl, DMB, 3,4-dialkoxybenzyl, 4-aralkylxoxybenzyl, or 3,4-diaralkyloxybenzyl.

134. The method of claim 132, wherein said reducing conditions comprise a Raney/Ni reducing system and R¹ or R³ is one or more of benzyl, TMB, PMB and p-alkoxybenzyl, DMB, 3,4-dialkoxybenzyl, 4-aralkylxoxybenzyl, or 3,4-diaralkyloxybenzyl.

139. The method of claim 101, wherein R¹ or R³ in structure XXI is a protective group that is subsequently removed in the presence of one or more of DDQ or cerium ammonium nitrate.

140. The method of claim 139, wherein R¹ or R³ is one or more of p-alkoxybenzyl, 3,4-dialkoxybenzyl, p-aralkoxybenzyl, or 3,4-diaralkoxybenzyl protecting groups, where the alkyl of the alkoxy ranges from C₁-C₂₂.

95-1. A method for selectively making specific discrete (polyethylene glycol) (dPEG) compounds containing a discrete and predetermined number of ethylene oxide moieties, which comprises the steps of:

(a) forming a reaction mixture comprising;

(i) a first reactant having the general structural formula XXVI

R¹—

X—

(OH)_p 

 

XXVI

and a second dPEG compound having the general structural formula X

R³-dPEG_y-OR² 

 

X

Or

(ii) a third reactant having the general structural formula XVII

R¹—

X—

(R²)_p 

 

XVII

and a fourth dPEG compound having the general structural formula XVIII

R³-dPEG_y-OH 

 

XVIII

(b) adding a non-sodium ionizing compound, which is potassium t-butoxide, to said reaction mixture under reaction conditions comprising a catalyst to produce a dPEG compound having the general structural formula XXVII

R¹—

X—

(O-dPEG_yR³)_p 

 

XXVII

wherein said ionizing compound is added to a reaction mixture at a rate that is about equal to the rate at which compound XXVI reacts with compound X or compound XVII reacts with compound XVIII,

wherein, dPEG represents a discrete (OCH₂CH₂) moiety, each R¹ independently is a functional group (FG), a protected functional group, or a protecting group (PG);

y ranges from about 1 to 1000;

R² is a leaving group;

each R³ independently is a functional group (FG), a protected functional group, or a protecting group (PG);

R¹ and R³ are different;

y ranges from about 1 to 1000;

p ranges from about 2 to 9; and

X is dPEG, an aliphatic, aromatic, aliphatic-aromatic organic linker moiety optionally substituted with heteroatoms.

98. (canceled)

135-138. -138. (canceled)

141-142. -142. (canceled)

143. A compound of one or more of the following general structures:

A-dPEG_a-B or A-X-(dPEG_ab)_p

where A and B are one or more of;

144. The compound of claim 143, wherein combinations of A and B are one or more of:

(a) A=amine;

B=carboxyl, carboxyl ester,

(b) A=amine;

B=hydroxyl, hydroxyl derivative, phosphoramidites;

carbonate,

(c) A=thiol;

B=hydroxyl, hydroxyl derivative, phosphoramidites;

carbonate,

(d) A=thiol;

B=carboxyl, carboxyl ester,

(e) A=amine;

B=thiol,

(f) A=maleimide;

B=carboxyl, carboxyl ester,

(g) A=aldehyde, aldehyde equivalent;

B=carboxyl, carboxyl ester,

(h) A=aldehyde, aldehyde equivalent;

B=thiol,

(i) A=thiol;

B=alkoxy,

(j) A=amine;

B=alkoxy,

(k) A=carboxyl, carboxyl ester;

B=alkoxy,

(l) A=aldehyde, aldehyde equivalent;

B=alkoxy,

(m) A=maleimide;

B=alkoxy, or

(n) A=carboxyl, carboxyl ester;

B=carboxylic acid ester.

145. The compound of claim 144, wherein one or more of A or B is replaced with a biologically active molecule, T.

146. The compound of claim 145, wherein T is one or more of:

1) diagnostic or therapeutic radionuclide;

2) diagnostic or therapeutic photoactive molecules;

3) chemotherapeutic agents, or precursors or prodrugs thereof;

4) protein toxins or derivatives thereof;

5) target tumors through a variety of receptor modalities;

6) bind with biologically active proteins;

7) cause the molecule to be excluded from cells;

8) allow the molecule to enter cells;

or

9) cause it to target infections.

147. The compound of claim 146, wherein T is one or more of a radionuclide chelate, a photoactive group, a drug, a cancer targeting agent, an MRI active agent, a neutron activated molecule, or a membrane crossing agent.