US 12,435,048 B2
Method for preparation of n-carboxyanhydrides
Jens Schmidt, Visp (CH); Candid Stoffel, Visperterminen (CH); and Elmar Millius, Visp (CH)
Assigned to LONZA LTD, Visp (CH)
Appl. No. 17/262,908
Filed by LONZA LTD, Visp (CH)
PCT Filed Sep. 26, 2019, PCT No. PCT/EP2019/075981
§ 371(c)(1), (2) Date Jan. 25, 2021,
PCT Pub. No. WO2020/064904, PCT Pub. Date Apr. 2, 2020.
Claims priority of provisional application 62/738,238, filed on Sep. 28, 2018.
Claims priority of application No. 18197747 (EP), filed on Sep. 28, 2018; application No. 19160667 (EP), filed on Mar. 5, 2019; and application No. 19168661 (EP), filed on Apr. 11, 2019.
Prior Publication US 2021/0253543 A1, Aug. 19, 2021
Int. Cl. C07D 263/44 (2006.01)
CPC C07D 263/44 (2013.01) 18 Claims
 
1. A method for the preparation of compound of formula (II),

OG Complex Work Unit Chemistry
the method comprises a step STEP1 a step STEP2 and a STEP 3,
STEP2 is done after STEP1;
STEP3 is done immediately after STEP2;
STEP1 comprises a reaction REAC1, wherein compound of formula (I) is reacted with PHOS in a solvent SOLV1;

OG Complex Work Unit Chemistry
R is selected from the group consisting of —H, —CH3, —CH2—SH, —CH2—COOH, —(CH2)2—COOH, benzyl, H,

OG Complex Work Unit Chemistry
 —CH(CH3)—CH2—CH3, —(CH2)4—NH2, —CH2—CH2—(CH3)2, —(CH2)2—S—CH3, —CH2—C(O)—NH2, —(CH2)2—C(O)—NH2,
(CH2)3—NH—C(NH)—NH2, —CH2—OH, —CH(OH)—CH3, —CH(CH3)2,

OG Complex Work Unit Chemistry
 (CH2)3—NH—C(O)—NH2, and —(CH2)3—NH2;
any functional residue of R, which is capable of reacting with phosgene, is protected by a suitable protecting group PG;
R1 is selected from the group consisting of H, C1-4 alkyl and benzyl;
n is 0 or 1;
R and R1 optionally form a pyrrolidine ring when n is 0;
PHOS is phosgene;
SOLV1 is selected from the group consisting of THF, 2-Me-THF, dioxan, ethyl acetate, dichlormethane, monoglyme, diglyme, triglyme, cyclopentyl methyl ether, acetonitril, and mixtures thereof;
in STEP2 part of SOLV1 is exchanged against a solvent SOLV2 by removal of an amount of SOLV1 consisting of from 35 to 87.5 wt % of SOLV1 by distillation, the wt % being based on the weight of SOLV1, wherein in STEP2
SOLV2 can be added before, during or after removal of the amount of SOLV1 consisting of from 35 to 87.5 wt % of SOLV1;
SOLV2 is selected from the group consisting of
hexyl formate, pentyl acetate, butyl propionate, propyl butyrate, ethyl valerat, methyl caproate,
pentyl formate, butyl acetate, propyl propionate, ethyl butyrate, methyl valerate,
butyl formate, propyl acetate, ethyl propionate, methyl butyrate, and mixtures thereof;
and
in STEP3 part of SOLV2 is removed by distillation.