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dormouse
(Member) 04-19-00 19:30 No 122826 |
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new routes from ET to LSD -pHas3d | Bookmark | |||||
the Hive BB Serious Chemistry Forum new routes from ET to LSD profile | register | preferences | faq | search next newest topic | next oldest topic Author Topic: new routes from ET to LSD pHas3d PimpBee posted 02-12-2000 03:29 PM ---------------------------------------- Ok, Didnt want to bring the "other" of topic, so I started this to hopefully stimulate discussion on new routes, and possibly find some interesting journal articles. Ok, so we all know ET's classic Shulgin route et->lysergic acid hydrate->LSD freebase->LSD tartrate Now, Even sticking to the same route, there is obvious room for improvement. K.C. Nicolaou and Slappy both suggested new chems for step #2 but provided no refs(hint, wink, please, please, please). Slappy was suggesting DCC, then KC was touting HATU, HBTU, BOP and other salt coupling reagents. Bright Star! So what is this interesting "The Alkaloids" publication? KC and Slappy, I(and im betting the Hive) would like to hear more. And Im betting that step #1 could be improved upon as well. What about different salts? Anyone experiment with sulfate or hydrochloride salts? I asked for it Drone! pHas3d Coupling with BOP-Reagent Example: A solution of tert-butyloxycarbonyl threonine (2.19g, 10mmol) (the carboxylic acid) and phenylalanine methyl ester hydrochloride (2.16g, 10mmol) (amine hydrochloride) in 150mL ACN is stirred at RT while the BOP-reagent (4.42g, 10mmol) is added, followed by the addition of triethylamine (2.2g, 2.8mL, 20mmol). The rxn is stirred at RT for 1.5hr. 100mL of a saturated NaCl solution is added and the product extracted with EtOAc 3x. The combined organics are washed with 2N HCl, H2O, 5% NaHCO3, and then H2O. The organics are dried over MgSO4, filtered, and concentrated in vacuo to give the dipeptide (3.74g, 98%). Comments: Should be very high-yielding and mild in terms of rxn conditions. BOP-reagent is not the most common chemical and therefore may present some problems in terms of aquisition, Proposed LSD synthesis procedure: 1eq. LSA is dissolved in a suitable solvent(must be fairly dry) at RT, 1.05 eq BOP-reagent is added. 2eq. of diethylamine is added and the rxn is stirred at RT until it goes to completion(15min-2hr). The solvent is removed under vacuum and the residue partitioned between EtOAc(or other suitable solvent) and saturated NaHCO3(or NH4OH). The layers were separated and the organics were washed with NaHCO3(or NH4OH), H2O, saturated Coupling with HBTU/HATU Example: The carboxyl-component (10mmol), the amine component (10.4mmol), and triethylamine (20 mmol) are dissolved in ACN (20mL) and Comments: Should be very high-yielding and mild in terms of rxn conditions. Similar chemically and in terms of aquisition problems as BOP-reagent, but HBTU/HATU is actually relatively easy to make yourself if you have access to the required chemicals and have pretty good lab skills. To make it, you need oxalyl chloride, teramethylurea, toluene, ether, chloroform, ammonium hexafluorophosphate(or NH4BF4), DCM, HOBt, and triethylamine. Like BOP-reagent, it’s pretty expensive if you buy it. We use a lot of HATU in the lab I work in and we make it ourselves due to the high cost of buying it. I’ve never been suckered into whipping up a batch of it, but the people who have made it in the past are nothing special as chemists. I can provide refs for preparing it if you want. Proposed LSD synthesis procedure: 1eq. LSA is dissolved in a suitable solvent(must be fairly dry) at RT, 1.05 eq HBTU/HATU is added. 2eq. of diethylamine is added and the rxn is stirred at RT until it goes to completion(15min-2hr). The solvent is removed under vacuum and the residue partitioned between EtOAc(or other suitable solvent) and saturated NaHCO3(or NH4OH). The layers were separated and the organics were washed with NaHCO3(or NH4OH), H2O, saturated NaCl, dried over MgSO4, filtered and concentrated in vacuo to remove the solvent and excess diethylamine. The crude LSD, which should be fairly pure, is then further purified by chromatography and converted to the tartrate salt. Example: Phenylalanine methyl ester hydrochloride (21.6g, 100mmol) (amine hydrochloride), HOBt monohydrate (15.3g, 100mmol), tert-butyloxycarbonyl leucine (23.1g, 100mmol) (carboxylic acid) and N-methylmorpholine (100mmol) are dissolved in dry THF (32mL, I think this is a typo) and cooled to 0C in an ice/water bath. To the stirring solution was added DCC (21.6g, 105mmol). The rxn was stirred for 1hr at 0C and an additional hour Comments: Mild rxn conditions, yields should be good. Longer rxn times than with BOP/HBTU/HATU. DCC is a very common chemical and is cheap and much more avaliable than BOP/HBTU/HATU. The acid reacts with DCC to give a sort of mixed anhydride which is very reactive. If the rxn is carried out without HOBt or HOSu, the alpha carbon of the acid is very prone to racemization/epimerization. With HOBt or The main problem I have with DCC-based methods is the removal of the DCU byproduct. Another thing to keep in mind is that DCC is an irritant and a sensitizer, meaning that you can build up a serious sensitivity and have adverse reactions to tiny amounts of the stuff if you don’t take appropriate precautions. Proposed LSD synthesis procedure: 1eq. LSA is dissolved in a suitable solvent(must be fairly dry) and 1.05 eq HOBT is added. The solution is cooled to 0C and 1.05 eq. of DCC is added. The rxn is stirred at 0C for 30min. 1.05eq. of diethylamine is added and the rxn is stirred at 0C for 30min, and allowed to warm to room temp and is stirred until the rxn goes to completion(0-24hr). The rxn is cooled in the freezer to precipitate out the maximum amount of DCU. The precipitated DCU is filtered and washed with solvent. The solvent is removed under vacuum and the residue partitioned between EtOAc(or other suitable solvent) and Coupling with DCC in the presence of N-hydroxysuccinimide (HOSu) Example: Pht-Phe-Val-Gln-Trp-Leu-OH hemihydrate (8.35g 10mmol) (carboxylic acid), Met-Asn-Thr(tBu)-OtBu (4.78g, 10mmol) (amine freebase), and N-hydroxysuccinimide (1.15g, 10mmol) are dissolved in 67mL DMF. The solution is cooled to -10C during the addition of DCC (2.06g, 10mmol). After 2hr at -10C and 48hr at -3C, the DCU was filtered and 330mL water was added. The solid precipitate was filtered, washed w/ sat’d NaCO3, washed w/ water, and dried over P2O5 in vacuo. The crude product (12.1g, 93.5%) was recrystalized from H2O/EtOH to give 9.7g (75%) of the pure product. Comments: Same as with HOBt Proposed LSD synthesis procedure: Same as with HOBt, just substitute HOSu for HOBt. Coupling with the use of a mixed carbonic acid anhydride Example: A solution of glycine ethyl ester hydrochloride (1.40g, 10mmol) (amine hydrochloride) in DMF (20mL) is prepared and treated with triethylamine (1.01g, 1.4mL, 10mmol). A solution of Z-Gly-Phe-OH (3.56g, 10 mmol) (carboxylic acid) in dry THF (50mL) is cooled to -15C and treated with N-methylmorpholine (1.01g, 1.1mL,10mmol). Isobutyl chloroformate (1.37g, 1.32mL, 10mmol) is added and the rxn was stirred at -15C for 15min, after which the solution of glycine ethyl ester prepared earlier was added. The rxn was allowed to warm to RT and stirred for 30min. The precipitated amine salts were removed by filtration and rinsed with THF. The combined filtrate and washings were evaporated in vacuo and the residue partitioned between 150mL EtOAc and 50mL H2O. Comments: This procedure actually works quite well in my experience using it to prepare diazomethylketones. It involves the use of an acid chloride, so obviously anhydrous conditions are required. Chloroformates(you can use other ones, isobutyl chloroformate is merely the most commonly used, there is little difference in reactivity between different componds of this type) tend to be kind of squirrely when you try to store them due to the fact that they are very water-sensitive and evolve CO2 when they decompose and CO2/HCl when exposed to water. As such, they are usually shipped with a small amount of chloroformate in a big bottle (100mL in a 500mL bottle) to guard against pressure build-up and subsequent breakage. Store them in the freezer and open the bottle BEFORE it warms to RT. Proposed LSD synthesis procedure: 1eq. LSA is dissolved in a suitable solvent(must be very dry, DCM, chloroform, and THF Hope that helps. There really are 101 ways to make amides from carboxylic acids and amines, so the previous suggestions should in no way be construed to be the end-all-be-all of “modern” LSA->LSD syntheses. However, all of these methods have been used by me in the course of the synthesis of different, non-LSD molecules and have proved their worth to me as highly useful techniques, so I have no qualms about suggesting them to others. Feel free to ask for clarification on any of the above. gettin' his learn on, Phas3d, I'll dig out and submit what I have, but much of it will be redundant in light of KCN's contribution. E-mail me. ------------------ Ipsa scientia potestas est vomiting headache Burning sensation in arms and legs Dialation of the pupils bee safe, bees That is the hard one, and that is the 'limiting reagent'. |
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