IP Library › Granted Patent US 7,321,064
Granted Patent B1
US 7,321,064 · App. 11/715,571 · Granted Jan 22, 2008

Preparation of amides of retinoic acid via mixed anhydride and mixed carbonate intermediates

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Quick Facts
Patent No.
US 7,321,064
App. No.
11/715,571
Granted
Jan 22, 2008
Kind
B1
Abstract

Processes for preparing amides of retinoic acid are disclosed. Intermediates useful in the preparation of amides of retinoic acid are also disclosed. In one version of the invention, fenretinide is produced via activation of retinoic acid (tretinoin) via its corresponding mixed anhydride or mixed carbonate followed by reaction of the activated intermediate with 4-aminophenol. Other amides of retinoic acid and isomers of retinoic acid, such as the 9-cis-form or 13-cis-form can also be made by this invention.

Claims (45)

1. A process for preparing an amide of retinoic acid, the process comprising:

(a) reacting a retinoic acid having the formula:

or isomers thereof with a compound having a formula selected from:

and

wherein R is alkyl or aryl or alkoxy, and X is a halogen, to produce an intermediate having the formula:

and

(b) reacting the intermediate with 4-aminophenol to produce an amide of retinoic acid having the formula:

or isomers thereof.

2. The process of claim 1 wherein:

the retinoic acid is all-trans-retinoic acid.

3. The process of claim 1 wherein:

the retinoic acid is 9-cis-retinoic acid.

4. The process of claim 1 wherein:

the retinoic acid is 13-cis-retinoic acid.

5. The process of claim 1 wherein:

X is chlorine.

6. The process of claim 1 wherein:

R is trimethylalkyl.

7. The process of claim 1 wherein:

R is selected from —C(CH 3 ) 3 and —C(CH 3 ) 2 CH 2 CH 3 .

8. The process of claim 1 wherein:

R is selected from —OCH(CH 3 ) 2 and —OCH 2 CH(CH 3 ) 2 .

9. The process of claim 1 wherein:

the compound is trimethylacetyl chloride.

10. The process of claim 1 wherein:

the compound is 2,2-dimethylbutyryl chloride.

11. The process of claim 1 wherein:

the compound is isobutylchloroformate.

12. The process of claim 1 wherein:

the compound is isopropylchloroformate.

13. The process of claim 1 wherein:

step (a) comprises reacting the retinoic acid and the compound in the presence of a solvent selected from the group consisting of ethyl acetate, t-butyl methyl ether, 2-methyltetrahydrofuran, toluene, acetonitrile, methylene chloride, dimethyl formamide, tetrahydrofuran, pyridine, and mixtures thereof.

14. The process of claim 1 wherein:

step (a) comprises reacting the retinoic acid and the compound in the presence of an amine base.

15. The process of claim 1 wherein:

step (a) comprises reacting the retinoic acid and the compound in the presence of base selected from the group consisting of triethylamine, diisopropylethylamine, N-methylmorpholine, pyridine, 1,8-diazabicyclo[5.4.0]undec-7-ene, metal carbonates, metal bicarbonates and mixtures thereof.

16. The process of claim 1 wherein:

step (b) comprises reacting the intermediate with 4-aminophenol in the presence of a solvent selected from the group consisting of pyridine, dimethyl formamide, dimethylacetamide, and mixtures thereof.

17. The process of claim 1 wherein:

the amide is prepared in a yield of at least 70%.

18. The process of claim 1 wherein:

the amide is prepared in a yield of at least 85%.

19. The process of claim 1 wherein:

step (a) comprises reacting the retinoic acid and the compound in the temperature range of 0-10° C., and

step (b) comprises reacting the intermediate with 4-aminophenol in the temperature range of 0-10° C.

Assignments (11)
ASSIGNMENT OF SECURITY INTEREST IN INTELLECTUAL PROPERTY, RECORDED ON SEPTEMBER 1, 2017, AT REEL/FRAME 043746/0621 Recorded Mar 17, 2025
From: BARCLAYS BANK PLC, AS EXISTING AGENT
To: APOLLO ADMINISTRATIVE AGENCY LLC, AS SUCCESSOR AGENT
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PARTIAL RELEASE OF FIRST LIEN SECURITY INTEREST IN PATENTS RECORDED ON SEPTEMBER 1, 2017, AT REEL/FRAME 043746/0621 Recorded Aug 20, 2024
From: BARCLAYS BANK PLC, AS COLLATERAL AGENT
To: CURIA WISCONSIN, INC.
Reel/Frame 068725/0776 →
PARTIAL RELEASE OF SECOND LIEN SECURITY INTEREST IN PATENTS RECORDED ON SEPTEMBER 6, 2021, AT REEL/FRAME 057423/0665 Recorded Aug 20, 2024
From: WILMINGTON TRUST, NATIONAL ASSOCIATION, AS COLLATERAL AGENT
To: CURIA WISCONSIN, INC.
Reel/Frame 068725/0782 →
SECURITY INTEREST Recorded Sep 6, 2021
From: CURIA GLOBAL, INC. (FKA ALBANY MOLECULAR RESEARCH, INC.); CURIA MASSACHUSETTS, INC. (FKA AMRI BURLINGTON, INC.); CURIA WISCONSIN, INC. (FKA CEDARBURG PHARMACEUTICALS, INC.); CURIA INDIANA, LLC (FKA AMRI SSCI, LLC); CURIA NEW MEXICO, LLC (FKA OSO BIOPHARMACEUTICALS MANUFACTURING, LLC); CURIA IP HOLDINGS, LLC
To: WILMINGTON TRUST, NATIONAL ASSOCIATION, AS COLLATERAL AGENT
Reel/Frame 057423/0665 →
RELEASE OF SECURITY INTEREST Recorded Oct 29, 2020
From: MORGAN STANLEY SENIOR FUNDING, INC., AS COLLATERAL AGENT
To: ALBANY MOLECULAR RESEARCH, INC.; AMRI BURLINGTON, INC.; CEDARBURG PHARMACEUTICALS, INC.; EUTICALS INC.; OSO BIOPHARMACEUTICALS MANUFACTURING, LLC
Reel/Frame 054252/0687 →
CORRECTIVE ASSIGNMENT TO CORRECT THE INCORRECT PATENT NO. 7541537 PREVIOUSLY RECORDED AT REEL: 034045 FRAME: 0951. ASSIGNOR(S) HEREBY CONFIRMS THE SECURITY INTEREST. Recorded Aug 14, 2018
From: ALBANY MOLECULAR RESEARCH, INC.; ALO ACQUISITION LLC; AMRI BURLINGTON, INC.; AMRI RENSSELAER, INC.; CEDARBURG PHARMACEUTICALS, INC.; OSO BIOPHARMACEUTICALS MANUFACTURING, LLC
To: BARCLAYS BANK PLC, AS THE COLLATERAL AGENT
Reel/Frame 046796/0352 →
FIRST LIEN SECURITY AGREEMENT Recorded Sep 1, 2017
From: ALBANY MOLECULAR RESEARCH, INC.; AMRI BURLINGTON, INC.; CEDARBURG PHARMACEUTICALS, INC.; EUTICALS INC.; OSO BIOPHARMACEUTICALS MANUFACTURING, LLC-BY ITS SOLE MEMBER: ALO ACQUISITION LLC
To: BARCLAYS BANK, PLC AS COLLATERAL AGENT
Reel/Frame 043746/0621 →
SECOND LIEN SECURITY AGREEMENT Recorded Sep 1, 2017
From: ALBANY MOLECULAR RESEARCH, INC.; AMRI BURLINGTON, INC.; CEDARBURG PHARMACEUTICALS, INC.; EUTICALS INC.; OSO BIOPHARMACEUTICALS MANUFACTURING LLC-BY ITS SOLE MEMBER:ALO ACQUISITION LLC
To: MORGAN STANLEY SENIOR FUNDING, INC.
Reel/Frame 043746/0657 →
RELEASE OF SECURITY INTEREST Recorded Aug 31, 2017
From: BARCLAYS BANK PLC, AS COLLATERAL AGENT
To: ALBANY MOLECULAR RESEARCH, INC.; ALO ACQUISITION LLC; AMRI BURLINGTON, INC.; AMRI RENSSELAER, INC.; CEDARBURG PHARMACEUTICALS, INC.; OSO BIOPHARMACEUTICALS MANUFACTURING, LLC; AMRI SSCI, LLC; EUTICALS INC.
Reel/Frame 043742/0085 →
SECURITY INTEREST Recorded Oct 24, 2014
From: ALBANY MOLECULAR RESEARCH, INC.; ALO ACQUISITION LLC; AMRI BURLINGTON, INC.; AMRI RENSSELAER, INC.; CEDARBURG PHARMACEUTICALS, INC.; OSO BIOPHARMACEUTICALS MANUFACTURING, LLC
To: BARCLAYS BANK PLC, AS THE COLLATERAL AGENT
Reel/Frame 034045/0951 →
ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Mar 8, 2007
From: CABAJ, JOHN E.; HUTCHINSON, JEFF J.
To: CEDARBURG PHARMACEUTICALS, INC.
Reel/Frame 019085/0724 →