# US 10,870,670 B2 · Preparation of (S,S)-secoisolariciresinol diglucoside and (R,R)-secoisolariciresinol diglucoside

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- Number: US 10,870,670 B2
- Document ID: US10870670B2
- Status: Granted
- Kind: B2
- Application number: 16/042,866
- Filed: 2018-07-23
- Published: 2019-02-28
- Granted: 2020-12-22
- Earliest claimed: 2013-06-10
- Assignees: The Scripps Research Institute; The Trustees of the University of Pennsylvania
- Applicants: The Trustees of the University of Pennsylvania; The Scripps Research Institute
- Inventors: Melpo Christofidou-Solomidou; Kyriacos C. Nicolaou; Roman A. Valiulin; Nicholas Simmons; Philipp M. Heretsch
- Web page: https://patentgrep.com/patent/US10870670B2

## CPC

- C07H 15/18: Acyclic radicals, substituted by carbocyclic rings
- A61P 17/18: Antioxidants, e.g. antiradicals (preparations for protection against sunlight A61Q17/00)
- A61P 39/06: Free radical scavengers or antioxidants
- C07C 41/18: by reactions not forming ether-oxygen bonds
- C07C 67/303: by hydrogenation of unsaturated carbon-to-carbon bonds
- C07C 67/31: by introduction of functional groups containing oxygen only in singly bound form
- C07C 67/343: by increase in the number of carbon atoms
- C07H 15/203: Monocyclic carbocyclic rings other than cyclohexane rings; Bicyclic carbocyclic ring systems
- C07H: SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS (derivatives of aldonic or saccharic acids C07C, C07D; aldonic acids, saccharic acids C07C59/105, C07C59/285; cyanohydrins C07C255/16; glycals C07D; compounds of unknown constitution C07G; polysaccharides, derivatives thereof C08B; DNA or RNA concerning genetic engineering, vectors, e.g. plasmids, or their isolation, preparation or purification C12N15/00; sugar industry C13)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- C07C: ACYCLIC OR CARBOCYCLIC COMPOUNDS

## Abstract

The invention relates to processes for preparing (S,S)-secoisolariciresinol diglucoside and (R,R)-secoisolariciresinol diglucoside and compositions comprising the same.

## Claims

### Claim 1

A process for preparing a compound of formula ((S,S)-SDG-1) or a compound of formula ((R,R)-SDG-2)
the process comprising:
(a) reacting a compound of formula (6)
with a compound of formula (7)
to prepare a compound of formula ((S,S)-S3) or a compound of formula ((R,R)-S4), respectively
(b) cleaving benzyl ethers of the compound of formula ((S,S)-S3) and benzyl ethers of the compound of formula ((R,R)-S4), followed by a separation procedure to prepare a compound of formula ((S,S)-8) or a compound of formula ((R,R)-9), respectively
(c) deprotecting the compound of formula ((S,S)-8) or the compound of formula ((R,R)-9) to prepare the compound of formula ((S,S)-SDG-1) or the compound of formula ((R,R)-SDG-2), respectively.

### Claim 2 (depends on 1)

The process of claim 1, wherein said reacting is carried out in the presence of a Lewis acid.

### Claim 3 (depends on 2)

The process of claim 2, wherein said Lewis acid is TMSOTf.

### Claim 4 (depends on 3)

The process of claim 3, wherein said reacting is carried out in the presence of activated molecular sieves.

### Claim 5 (depends on 1)

The process of claim 1, wherein said cleaving is carried out in the presence of H2 and Pd/C in MeOH.

### Claim 6 (depends on 1)

The process of claim 1, wherein said separation procedure is carried out using preparative thin layer chromatography.

### Claim 7 (depends on 1)

The process of claim 1, wherein said deprotecting is carried out in a solution of NaOMe and MeOH.

### Claim 8 (depends on 1)

The process of claim 1, wherein said compound of formula (6) is prepared by the process comprising reacting a compound of formula (S2)
with a reducing agent to prepare the compound of formula (6).

### Claim 9 (depends on 8)

The process of claim 8, wherein said reducing agent is lithium aluminum hydride (LAH) in THF.

### Claim 10 (depends on 8)

The process of claim 8, wherein said compound of formula (S2) is prepared by the process comprising reacting a compound of formula (S1)
with a benzylating agent to prepare the compound of formula (S2).

### Claim 11 (depends on 10)

The process of claim 10, wherein said benzylating agent is BnBr and NaH.

### Claim 12 (depends on 10)

The process of claim 10, wherein said compound of formula (S1) is prepared by the process comprising reacting a compound of formula (5)
with a reducing agent to prepare tike compound of formula (S1).

### Claim 13 (depends on 12)

The process of claim 12, wherein said reducing agent is H2 and Pd/C.

### Claim 14 (depends on 12)

The process of claim 12, wherein said compound of formula (5) is prepared by the process comprising reacting a compound of formula (4)
with vanillin by a Stobbe condensation reaction, followed by an esterification reaction to prepare the compound of formula (5).

### Claim 15 (depends on 14)

The process of claim 14, wherein said Stobbe condensation reaction is carried out in MeOH and in the presence of lithium.

### Claim 16 (depends on 15)

The process of claim 15, wherein said lithium is in the form of lithium wires.

### Claim 17 (depends on 14)

The process of claim 14, wherein said esterification reaction is carried out with MeOH in the presence of H2SO4.

### Claim 18 (depends on 14)

The process of claim 14, wherein said compound of formula (4) is prepared by the process comprising reacting vanillin with methyl succinate via a Stobbe condensation reaction, followed by an esterification reaction.

### Claim 19 (depends on 18)

The process of claim 18, wherein said Stobbe condensation reaction is carried out in MeOH and in tire presence of lithium wires.

### Claim 20 (depends on 18)

The process of claim 18, wherein said esterification reaction is carried out with MeOH in the presence of H2SO4.

### Claim 21

A process for preparing a compound of formula ((S,S)-SDG-1) or a compound of formula ((R,R)-SDG-2)
the process comprising:
(a) reacting a compound of formula (S2)
with a reducing agent to prepare a compound of formula (6)
(b) reacting the compound of formula (6) with a compound of formula (7)
to prepare a compound of formula ((S,S)-S3) or a compound of formula ((R,R)-S4), respectively
(c) cleaving benzyl ethers of the compound of formula ((S,S)-S3) and benzyl ethers of the compound of formula ((R,R)-S4), followed by a separation procedure to prepare a compound of formula ((S,S)-8) or a compound of formula ((R,R)-9), respectively
and
(d) deprotecting the compound of formula ((S,S)-8) or the compound of formula ((R,R)-9) to prepare the compound of formula ((S,S)-SDG-1) or the compound of formula ((R,R)-SDG-2), respectively.

### Claim 22 (depends on 21)

The process of claim 21, wherein said reacting of step (a) is carried out in the presence of TMSOTf.

### Claim 23 (depends on 22)

The process of claim 22, wherein said reacting of step (a) is carried out in the presence of activated molecular sieves.

### Claim 24 (depends on 21)

The process of claim 21, wherein said cleaving is carried out in the presence H2 and Pd/C in MeOH.

### Claim 25 (depends on 21)

The process of claim 21, wherein said separation procedure is carried out using preparative thin layer chromatography.

### Claim 26 (depends on 21)

The process of claim 21, wherein said deprotecting is carried out in a solution of NaOMe and MeOH.

### Claim 27 (depends on 21)

The process of claim 21, wherein said reducing agent is lithium aluminum hydride (LAH) in THF.

### Claim 28 (depends on 21)

The process of claim 21, wherein said compound of formula (S2) is prepared by the process comprising reacting a compound of formula (S1)
with a benzylating agent to form the compound of formula (S2).

### Claim 29 (depends on 28)

The process of claim 28, wherein said benzylating agent is BnBr and NaH.

### Claim 30 (depends on 28)

The process of claim 28, wherein said compound of formula (S1) is prepared by the process comprising reacting a compound of formula (5)
with a reducing agent to prepare the compound of formula (S1).

### Claim 31 (depends on 30)

The process of claim 30, wherein said reducing agent is H2 and Pd/C.

### Claim 32 (depends on 30)

The process of claim 30, wherein said compound of formula (5) is prepared by the process comprising reacting a compound of formula (4)
with vanillin by a Stobbe condensation reaction, followed by an esterification reaction to prepare the compound of formula (5).

### Claim 33 (depends on 32)

The process of claim 32, wherein said Stobbe condensation reaction is carried out in MeOH and in the presence of lithium wires.

### Claim 34 (depends on 32)

The process of claim 32, wherein said esterification reaction is carried out with MeOH in the presence of H2SO4.

### Claim 35 (depends on 32)

The process of claim 32, wherein said compound of formula (4) is prepared by the process comprising reacting vanillin with methyl succinate via a Stobbe condensation reaction, followed by an esterification reaction.

### Claim 36 (depends on 34)

The process of claim 34, wherein said Stobbe condensation reaction is carried out in MeOH and in the presence of lithium wires.

### Claim 37 (depends on 34)

The process of claim 34, wherein said esterification reaction is carried out with MeOH in the presence of H2SO4.

### Claim 38

A process for preparing a compound of formula ((S,S)-SDG-1) or a compound of formula ((R,R)-SDG-2)
the process comprising:
(a) reacting a compound of formula (5)
with a reducing agent to prepare a compound of formula (S1)
(b) reacting the compound of formula (S1)
with a benzylating agent to prepare a compound of formula (S2)
(c) reacting the compound of formula (S2) with a reducing agent to prepare a compound of formula (6)
(d) reacting the compound of formula (6) with a compound of formula (7)
to prepare a compound of formula ((S,S)-S3)
(e) cleaving benzyl ethers of the compound of formula ((S,S)-S3) and benzyl ethers of the compound of formula ((R,R)-S4), followed by a separation procedure to prepare a compound of formula ((S,S)-81 or a compound of formula ((R,R)-9), respectively
and
(f) deprotecting the compound of formula ((S,S)-8) or the compound of formula ((R,R)-9) to prepare the compound of formula ((S,S)-SDG-1) or the compound of formula ((R,R)-SDG-2), respectively.

### Claim 39 (depends on 38)

The process of claim 38, wherein said compound of formula (5) is prepared by the process comprising reacting a compound of formula (4)
with vanillin by a Stobbe condensation reaction, followed by an esterification reaction to prepare the compound of formula (5).

### Claim 40

A process for preparing a compound of formula ((S,S)-S3)
the process comprising reacting a compound of formula (6)
with a compound of formula (7)
to prepare the compound of formula ((S,S)-S3).

### Claim 41 (depends on 40)

The process of claim 40, wherein said reacting is carried out in the presence of TMSOTf.

### Claim 42 (depends on 40)

The process of claim 40, wherein said reacting is earned out in the presence of activated molecular sieves.

### Claim 43 (depends on 40)

The process of claim 40, wherein said compound of formula (6) is prepared by the process comprising reacting a compound of formula (S2)
with a reducing agent to prepare the compound of formula (6).

### Claim 44 (depends on 43)

The process of claim 43, wherein said reducing agent is lithium aluminum hydride (LAH) in THF.

### Claim 45 (depends on 43)

The process of claim 43, wherein said compound of formula (S2) is prepared by the process comprising reacting a compound of formula (S1)
with a benzylating agent to prepare the compound of formula (S2).

### Claim 46 (depends on 45)

The process of claim 45, wherein said benzylating agent is BnBr and NaH.

### Claim 47 (depends on 45)

The process of claim 45, wherein said compound of formula (S1) is prepared by the process comprising reacting a compound of formula (5)
with a reducing agent to prepare the compound of formula (S1).

### Claim 48 (depends on 47)

The process of claim 47, wherein said reducing agent is H2 and Pd/C.

### Claim 49 (depends on 47)

The process of claim 47, wherein said compound of formula (5) is prepared by the process comprising reacting a compound of formula (4)
with vanillin by a Stobbe condensation reaction, followed by an esterification reaction to prepare the compound of formula (5).

### Claim 50 (depends on 49)

The process of claim 49, wherein said Stobbe condensation reaction is carried out in MeOH and in the presence of lithium wires.

### Claim 51 (depends on 49)

The process of claim 49, wherein said esterification reaction is carried out with MeOH in the presence of H2SO4.

### Claim 52 (depends on 49)

The process of claim 49, wherein said compound of formula (4) is prepared by the process comprising reacting vanillin with methyl succinate via a Stobbe condensation reaction, followed by an esterification reaction.

### Claim 53 (depends on 52)

The process of claim 52, wherein said Stobbe condensation reaction is carried out in MeOH and in the presence of lithium wires.

### Claim 54 (depends on 52)

The process of claim 52, wherein said esterification reaction is carried out with MeOH in the presence of H2SO4.

### Claim 55

A process for preparing a compound of formula ((S,S)-8)
the process comprising:
(a) reacting a compound of formula (6)
with a compound of formula (7)
to prepare a compound of formula ((S,S)-S3)
and
(b) cleaving benzyl ethers of the compound of formula ((S,S)-S3), followed by a separation procedure to prepare the compound of formula ((S,S)-8).

### Claim 56 (depends on 55)

The process of claim 55, wherein said reacting is earned out m the presence of TMSOTf.

### Claim 57 (depends on 55)

The process of claim 55, wherein said reacting is earned out in the presence of activated molecular sieves.

### Claim 58 (depends on 55)

The process of claim 55, wherein said cleaving is carried out in the presence of H2 and Pd/C in MeOH.

### Claim 59 (depends on 55)

The process of claim 55, wherein said separation procedure is carried out using preparative thin layer chromatography.

### Claim 60 (depends on 55)

The process of claim 55, wherein said compound of formula (6) is prepared by the process comprising reacting a compound of formula (S2)
with a reducing agent to prepare the compound of formula (6).

### Claim 61 (depends on 60)

The process of claim 60, wherein said reducing agent is lithium aluminum hydride (LAH) in THF.

### Claim 62 (depends on 60)

The process of claim 60, wherein said compound of formula (S2) is prepared by the process comprising reacting a compound of formula (S1)
with a benzylating agent to prepare tire compound of formula (S2).

### Claim 63 (depends on 62)

The process of claim 62, wherein said benzylating agent is BnBr and NaH.

### Claim 64 (depends on 62)

The process of claim 62, wherein said compound of formula (S1) is prepared by tire process comprising reacting a compound of formula (5)
with a reducing agent to prepare the compound of formula (S1).

### Claim 65 (depends on 64)

The process of claim 64, wherein said reducing agent is H2 and Pd/C.

### Claim 66 (depends on 64)

The process of claim 64, wherein said compound of formula (5) is prepared by the process comprising reacting a compound of formula (4)
with vanillin by a Stobbe condensation reaction, followed by an esterification reaction to prepare the compound of formula (5).

### Claim 67 (depends on 66)

The process of claim 66, wherein said Stobbe condensation reaction is carried out in MeOH and in the presence of lithium wires.

### Claim 68 (depends on 66)

The process of claim 66, wherein said esterification reaction is carried out with MeOH in the presence of H2SO4.

### Claim 69 (depends on 66)

The process of claim 66, wherein said compound of formula (4) is prepared by the process comprising reacting vanillin with methyl succinate via a Stobbe condensation reaction, followed by an esterification reaction.

### Claim 70 (depends on 69)

The process of claim 69, wherein said Stobbe condensation reaction is carried out in MeOH and in foe presence of lithium wires.

### Claim 71 (depends on 67)

The process of claim 67, wherein said esterification reaction is carried out with MeOH in the presence of H2SO4.

### Claim 72

A process for preparing a compound of formula ((R,R)-S4)
the process comprising:
(a) reacting a compound of formula (6)
with a compound of formula (7)
to prepare a compound of formula ((R,R)-S4).

### Claim 73 (depends on 72)

The process of claim 72, wherein said reacting is carried out in the presence of TMSOTf.

### Claim 74 (depends on 72)

The process of claim 72, wherein said reacting is earned out in the presence of activated molecular sieves.

### Claim 75 (depends on 72)

The process of claim 72, wherein said confound of formula (6) is prepared by the process comprising reacting a compound of formula (S2)
with a reducing agent to prepare the compound of formula (6).

### Claim 76 (depends on 75)

The process of claim 75, wherein said reducing agent is lithium aluminum hydride (LAH) in THF.

### Claim 77 (depends on 75)

The process of claim 75, wherein said compound of formula (S2) is prepared by the process comprising reacting a compound of formula (S1)
with a benzylating agent to prepare the compound of formula (S2).

### Claim 78 (depends on 77)

The process of claim 77, wherein said benzylating agent is BnBr and NaH.

### Claim 79 (depends on 77)

The process of claim 77, wherein said compound of formula (S1) is prepared by the process comprising reacting a compound of formula (5)
with a reducing agent to prepare the compound of formula (S1).

### Claim 80 (depends on 79)

The process of claim 79, wherein said reducing agent is H2 and Pd/C.

### Claim 81 (depends on 79)

The process of claim 79, wherein said compound of formula (5) is prepared by the process comprising reacting a compound of formula (4)
with vanillin by a Stobbe condensation reaction, followed by an esterification reaction to prepare the compound of formula (5).

### Claim 82 (depends on 81)

The process of claim 81, wherein said Stobbe condensation reaction is carried out in MeOH and in the presence of lithium wires.

### Claim 83 (depends on 81)

The process of claim 81, wherein said esterification reaction is carried out with MeOH in the presence of H2SO4.

### Claim 84 (depends on 81)

The process of claim 81, wherein said compound of formula (4) is prepared by the process comprising reacting vanillin with methyl succinate via a Stobbe condensation reaction, followed by an esterification reaction.

### Claim 85 (depends on 84)

The process of claim 84, wherein said Stobbe condensation reaction is carried out in MeOH and in the presence of lithium wires.

### Claim 86 (depends on 84)

The process of claim 84, wherein said esterification reaction is carried out with MeOH in the presence of H2SO4.

### Claim 87

A process for preparing a compound of formula ((R,R)-9)
the process comprising:
(a) reacting a compound of formula (6)
with a compound of formula (7)
to prepare a compound of formula ((R,R)-S4)
(b) cleaving benzyl ethers of the compound of formula ((R,R)-S4), followed by a separation procedure to prepare a compound of formula ((R,R)-9).

### Claim 88 (depends on 87)

The process of claim 87, wherein said reacting is earned out in the presence of TMSOTf.

### Claim 89 (depends on 87)

The process of claim 87, wherein said reacting is earned out in the presence of activated molecular sieves.

### Claim 90 (depends on 87)

The process of claim 87, wherein said cleaving is carried out in the presence of H2 and Pd/C in MeOH.

### Claim 91 (depends on 87)

The process of claim 87, wherein said separation procedure is carried out using preparative thin layer chromatography.

### Claim 92 (depends on 87)

The process of claim 87, wherein said compound of formula (6) is prepared by the process comprising reacting a compound of formula (S2)
with a reducing agent to prepare the compound of formula (6).

### Claim 93 (depends on 92)

The process of claim 92, wherein said reducing agent is lithium aluminum hydride (LAH) in THE.

### Claim 94 (depends on 92)

The process of claim 92, wherein said compound of formula (S2) is prepared by the process comprising reacting a compound of formula (S1)
with a benzylating agent to prepare the compound of formula (S2).

### Claim 95 (depends on 94)

The process of claim 94, wherein said benzylating agent is BnBr and NaH.

### Claim 96 (depends on 94)

The process of claim 94, wherein said compound of formula (S1) is prepared by the process comprising reacting a compound of formula (5)
with a reducing agent to prepare the compound of formula (S1).

### Claim 97 (depends on 96)

The process of claim 96, wherein said reducing agent is Ha and Pd/C.

### Claim 98 (depends on 96)

The process of claim 96, wherein said compound of formula (5) is prepared by the process comprising reacting a compound of formula (4)
with vanillin by a Stobbe condensation reaction, followed by an esterification reaction to prepare the compound of formula (5).

### Claim 99 (depends on 98)

The process of claim 98, wherein said Stobbe condensation reaction is carried out in MeOH and in the presence of lithium wires.

### Claim 100 (depends on 98)

The process of claim 98, wherein said esterification reaction is carried out with MeOH in the presence of H2SO4.

### Claim 101 (depends on 98)

The process of claim 98, wherein said compound of formula (4) is prepared by the process comprising reacting vanillin with methyl succinate via a Stobbe condensation reaction, followed by an esterification reaction.

### Claim 102 (depends on 101)

The process of claim 101, wherein said Stobbe condensation reaction is carried out in MeOH and in the presence of lithium wires.

### Claim 103 (depends on 101)

The process of claim 101, wherein said esterification reaction is carried out with MeOH in the presence of H2SO4.