Industrial Production of tert-Butyl-4-oxoazepane-1-carboxylate

Yun-Sheng Huang,* Wen-Qing Zhang, Pei-Feng Zhang, and Xiang-Guo Liu

Guangdong Medical College School of Pharmacy, 1 Xincheng AVenue, Songshan Lake Technology Park,Dongguan, 523808, China

A large-scale process for the preparation of tert-butyl 4-oxoazepane-1-carboxylate (1), a useful intermediatefor many pharmaceutical products under development, is described. This process is based on the ring expansionof tert-butyl piperid-4-one-1-carboxylate using ethyl diazoacetate. The entire process can be operated safely,less expensively, and conveniently without the necessary purification for any of the intermediates. Theproduction scale of over 33 kg of the final product was achieved with good overall yield. The main focusesof optimization were the large-scale preparation of ethyl diazoacetate and the ring expansion at low temperature.

Introduction

Azepane derivatives, such as azepan-4-one, especially its 1-N-tert-butoxycarbonyl (1-N-Boc), 1-N-benzyl, or 1-N-Cbz pro-tected analogues, are of great interest for pharmaceutical productdevelopment. Many pharmaceuticals or pharmaceutical candi-dates contain an azepane structural moiety.1-3 Azepane ring isa better �-turn mimic with its conformational flexibility, andits derivatives showed good biological activities in variousassays.4-8 More recently, some new azepane analogues dem-onstrated potent TRPV4 channel receptor9 or neurokinin receptorNK1 antagonistic activity and are potentially useful for themanagement of pain, inflammation, and allergic disorders, etc.10

There have been significant efforts toward the preparationof nitrogen containing seven-membered ring structure, azepane.Morosawa was one of the pioneers in the development ofmethodology for the synthesis of azepane, especially for thestructure of 1-azacycloheptan-4-one or azepan-4-one and itsderivatives.11-17 There are mainly two methods that have beenextensively used for the preparation of azepan-4-one. One isbased on ring closure by Dieckmann condensation (Scheme1).11,18 The second one is based on ring expansion on piperid-4-one using ethyl diazoacetate with BF3-ether at low temperature(Scheme 2).9,15,19,20 Other methods are also available21,22 butnot as useful as the two methods, especially for the preparationof azepan-4-one.

There are a number of drawbacks for both of the above-mentioned methods (Scheme 1 and Scheme 2), especially forscale-up synthesis of azepan-4-one. The first method (Scheme1) presented a lengthy route (a total of eight steps, accountingfor four steps for the preparation of starting material 2),11 startingwith ethyl 3-aminobutyrate that was protected with a Boc group,followed by benzylation with benzyl chloride, deprotection toremove the Boc group, Micheal addition with ethyl acrylate toform the intermediate 2 that undergoes Dieckmann condensationto afford ethyl 1-benzyl-azepan-4-one-5-carboxylate (3), fol-lowed by decarboxylation to give intermediate 4, debenzylationto afford intermediate 5, and N-acylation with di-tert-butyldicarbonate to give the product 1. The process gave a low overallyield due to the difficulty of obtaining the intermediates (amines)of each step in aqueous solution even after repeated extrac-tions.11 Thus, this route is not suitable for scale-up synthesis.The second method (Scheme 2) has a short synthetic route (threesteps) and offers relatively good overall yield. But this method

not only requires low temperature (below -25 °C) for the firststep but also uses the ethyl diazoacetate, a potentially explosivesubstance due to its rapid decomposition under acidic condi-tion.23 Therefore, this method has rarely been applied for large-scale synthesis.

For one project that required 30 kg of 1, surprisingly, therewas no supplier in the world that was able to provide therequired amount. To our best knowledge, there has been noreport in the literature for large-scale synthesis of 1. Herewe report the results and manufacturing details for thesynthesis of 1.

Results and Discussion

In an effort to prepare the product 1 in large scale that hasnot been reported previously with a quantity of more than 50 g,we applied a three-step procedure that was reported in a numberof publications in small scale.9,15,19,20 This procedure is to use1-Boc-piperid-4-one (6) to react with ethyl diazoacetate underthe catalysis of boron trifluoride etherate to undergo a ringexpansion process and form the intermediate 7 with good yield.Though starting material 6 is available in large quantity, ethyldiazoacetate is not commercially available with the kind ofquantity required.

The preparation of ethyl diazoacetate was described as simplebut potentially dangerous due to the instability of the product,especially under acidic condition.23 We conducted a couple ofsmall runs by following the reported procedure but withdichloromethane to replace the diethyl ether as the organicsolvent. Both runs gave very good yields (Table 1, entries 1and 2) without repeated extraction, or repeated reaction asdescribed in the literature.23 The reaction was actually easy to

* To whom correspondence should be addressed. E-mail:yunshenghuang@gmail.com.

Scheme 1. Preparation of 1-Boc-azepan-4-one Based onDieckmann Condensationa

a Reagents and conditions: (a) NaOEt/xylene, reflux; (b) conc. HCl,reflux; (c) H2/Pd; (d) (i) NaOH to pH ∼ 10, (ii) (Boc)2O.

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10.1021/ie101807g 2010 American Chemical SocietyPublished on Web 10/22/2010

operate and proceeded very fast as well. It almost always goesthrough a period of highly exothermic process, and the reactiontemperature goes up very quickly that can be managed byaddition of ice. Once the exothermic period is over (3-5 min),the reaction has virtually completed. More addition of the acid(10% H2SO4) does not have any effect on the reaction but thedecomposition of the formed product.

Three identical large scales of production of this reagent allgave very good yields (Table 1, entries 3-5). The reason thatwe ran three identical scales was for precaution purpose. Thebottleneck was actually not the reaction itself, but the removalof the solvent on rotovap (did not try vacuum distillation dueto the potential danger). During the scale up, we observed evenmore rapid increase in the reaction temperature for a short periodof time (5-10 min), and one time the reaction temperature evenreached up to +38 °C. But, the results did not seem to beaffected (Table 2, entry 5). On the basis of our experience, ethyldiazoacetate is fairly stable under normal conditions and not sounstable in acidic conditions.

The ring expansion of 6 with ethyl diazoacetate requires low-temperature and anhydrous condition (under N2 atmosphere)with the help of boron trifluoride etherate. Though there hasbeen no literature description of the exact mechanism involved,the generally accepted mechanism is described as in Scheme3. The process includes the addition of the ethyl diazoacetateto the carbonyl group to form intermediate 8, followed by theadjacent carbon migration to afford intermediate 7.

Small-scale synthesis indicated that the reaction temperatureshould be no higher than -15 °C; otherwise, the yield wouldbe low, and the reaction mixture would be messy as well (datanot shown). Thus, we ran all reactions at or below -25 °C byadjusting the addition of ethyl diazoacetate and boron trifluorideetherate. If both the temperature and moisture are under control,this step proceeds smoothly and gives good results (thin layerchromatography (TLC) indicated a high conversion rate). Both

small scales (Table 2, entries 1 and 2) and large scale (Table 2,entry 3) afforded high crude product yields (fairly pure on TLC).

Intermediate 7 was to be used directly for the decarboxylationstep using 4 N HCl (Table 3). This reaction was heated to refluxunder stirring for 4-6 h with a large amount of CO2 evolution.Due to the enormous amount of aqueous HCl solution, it canbe concentrated to distill off some of the aqueous material beforeneutralization with NaOH. The neutralization process is veryexothermic, and ice should be added to chill the solution untilit is adjusted to pH 10-11 (with NaOH). The resulting solutionis cooled to room temperature, and then methanol, sodiumcarbonate, and di-tert-butyl dicarbonate are added. This N-acylation process normally takes 6-8 h to complete (TLCmonitoring). The methanol should be evaporated to reduce thevolume before extraction with ethyl acetate. Due to thesignificantly large amount of aqueous volume, the extractionshould be repeated for a total of 3 times to get the optimumresults. The overall yield for the three steps is over 64% forsmall scales (Table 3, entries 1 and 2) and 48.5% for the large-scale production (Table 3, entry 3). It is interesting to note thatthis product (1) is a liquid in the summer (or at a temperatureabove +20 °C, or not very pure) and a solid in the winter (orat a temperature below +10 °C). The melting point is between+20 and +25 °C (too low to be measured accurately). But the1H-NMR spectra from both the liquid (summer preparation) andthe solid (winter preparation) are exactly the same.

Conclusions

In summary, we have produced the product 1 in large scale.This product is becoming increasingly important in pharma-ceutical development and is not largely available on thecommercial market. Therefore we developed a scale-up processthat is not only manageable but also less expensive to conduct.The two major issues that deterred chemists to scale up thisprocess are the use of ethyl diazoacetate and the reaction to berun at low temperature. We have been able to avoid the problems

Scheme 2. Preparation of 1-Boc-azepan-4-one Based on Ring Expansiona

a Reagents and conditions: (a) N2CHCOOEt, BF3/ether, -40 to -25 °C; (b) 4 N HCl, reflux; (c) (i) NaOH to pH ∼ 10, (ii) (Boc)2O.

Table 1. Results from the Preparation of Ethyl Diazoacetate

entry Gly Et ester HCl NaNO2 10% H2SO4 reacn temp (°C) yielda,b (%)

1 150 g (1.1 mol) 100 g (1.5 mol) 5 mL -10 to +10 942 500 g (3.6 mol) 350 g (5 mol) 15 mL -10 to +15 953 35 kg (250.7 mol) 25 kg (362 mol) 10 L -15 to +35 884 35 kg (250.7 mol) 25 kg (362 mol) 7 L -15 to +30 905 35 kg (250.7 mol) 25 kg (362 mol) 5 L -15 to +38 93

a Yield calculated on the basis of crude product without purification. b Reference 23 reported a 140 g scale run with a yield of 85% (crude).

Table 2. Results from the Preparation of 7a,b

entry 6 ethyl diazoacetate BF3-ether reacn temp (°C)

1 100 g (0.5 mol) 80 g (0.7 mol) 80 g (0.6 mol) -30 to -252 300 g (1.5 mol) 250 g (2.1 mol) 250 g (1.8 mol) -30 to -253c 25 kg (125.5 mol) 20 kg (174 mol) 20 kg (141 mol) -40 to -25

a Each run afforded over 100% yield by weight due to some residualsolvent (ethyl acetate) remaining. b Reference 3 reported a 3.7 g scale(N-ethoxycarbonyl) with a yield of 82% (after column), while ref 20reported a 7 g scale with a yield of 90% (crude). c Three identical 25 kgruns were carried out due to the limitation of low-temperature reactorand afforded a total of 123 kg of intermediate 7 (calculated, 107 kg).

Scheme 3. Cyclic Ketone Ring Expansion Mechanism with EthylDiazoacetate

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by careful processing and handling of the ethyl diazoacetateand have used a low-temperature reactor to produce this producton a scale of more than 33 kg. First, we improved the literatureprocess of producing ethyl diazoacetate and produced it in largescale without iterative reaction and extraction. We also noticedthat ethyl diazoacetate is fairly stable under normal conditions,though less stable in acidic conditions. This reagent can be storedfor a period of time at room temperature and for much longertime under low temperature (<-10 °C). Second, we used a low-temperature reactor to run the ring expansion reaction fairlysmoothly. On the basis of our experience, this process is feasiblefor even larger quantity production of more than 100 kg.

Experimental Section

All reagents purchased commercially were used directlywithout further purification. Solvents were used directly withoutany prior treatment. Reaction temperatures were recorded usinga regular thermometer without correction. 1H-NMR spectra weremeasured on a Bruker AV400D system in CDCl3 solution.

Large-Scale Preparation of Ethyl Diazoacetate. To a 200L reactor was added water (37.5 kg), glycine ethyl esterhydrochloride (35 kg, 250.7 mol), sodium acetate (1 kg, 12.2mol), sodium nitrite (25 kg, 362.3 mol), and dichloromethane(40 L). The reaction mixture was stirred and cooled to -15 °C.A solution of 10% H2SO4 (10 L) was added dropwise until thereaction temperature started to rise. The addition was stopped,and ice was added to chill down the reaction temperature below+15 °C (Note: The reaction temperature may reach above +25°C or even higher. But it does not seem to have any effect onthe product’s quality or yield.) The organic phase (CH2Cl2) wasseparated and washed with saturated aqueous K2CO3 (18 L ×2) and dried over Na2SO4 (8 kg, plus 2 kg of K2CO3). The solidwas filtered off, and the solvent was removed under reducedpressure (on 20 L rotovap) at +28 °C to afford ethyl diazoacetateas a light yellow liquid (25 kg; yield, 90%). This was usedimmediately for the next step or placed in a freezer at -10 °Cfor a short period of storage.

1-Boc-5-ethoxycarbonylazepan-4-one (7). Under N2 atmo-sphere, to a 200 L reactor was added anhydrous ether (80 kg)and 6 (25 kg, 125.5 mol). The mixture was stirred until thesolid dissolved and the reaction mixture was cooled to between-40 and -25 °C. Ethyl diazoacetate (20 kg, 174 mol) and borontrifluoride-etherate (20 kg, 141 mol) were added dropwisesimultaneously but independently over a 6 h period at atemperature between -40 and -25 °C. The reaction was stirredfor another hour at a temperature between -40 and -25 °Cand then transferred to a 500 L reactor, and 30% K2CO3 aqueoussolution was added slowly over a period of 30 min. The mixturewas stirred at room temperature for 30 min, the organic phasewas separated, and the aqueous phase was extracted with ethylacetate (30 L). Three identical 25 kg scale runs were carriedout (due to the limitation of the low-temperature reactor), andthe workup organic phases were combined and concentratedunder reduced pressure to afford a light brown liquid for a totalof 123 kg (calcd 107 kg or 87% due to some residual solvent),

which was used directly in the next step without purification.A small sample was purified by column chromatography andconfirmed by 1H-NMR (CDCl3; ppm): δ 4.18-4.20 (q, 2H),3.68-3.71 (m, 3H), 3.30-3.50 (m, 2H), 2.50-2.70 (m, 2H),1.90-2.10 (m, 2H), 1.42-1.44 (s, 9H), 1.26-1.28 (t, 3H).

tert-Butyl 4-oxoazepane-1-carboxylate (1). To a 1000 Lreactor was added 7 (105 kg, crude, ∼320 mol) and 4 N HCl(300 kg) under stirring. The mixture was heated to reflux for6 h. The reaction was then cooled to room temperature andneutralized with 6 N NaOH (ice was used to chill the risingtemperature) to adjust the solution until it is pH 10 ∼ 11.

To the above mixture was added methanol (400 kg),Na2CO3 (60 kg, 566 mol), and di-tert-butyl dicarbonate (90kg, 412.4 mol). The reaction was stirred at room temperaturefor 8 h. The methanol was distilled off under reducedpressure. To the residue was added ethyl acetate (200 L),and this was stirred for 1 h. The organic phase was separated,and the aqueous phase was extracted with ethyl acetate (100L × 2). The combined organic phase was washed withsaturated NaCl aqueous solution and dried over Na2SO4. Thesolvent was removed under reduced pressure, and the residuehad petroleum ether (30 kg) added and was cooled at -10°C overnight. The solid was filtered and air-dried to give 28kg. The mother liquid was concentrated in vacuo and chilledat -10 °C overnight to afford an additional 5.3 kg for a totalof 33.3 kg of dry powder: three-step combined yield, 48.5%;mp < +30 °C (too low to be measured accurately); GC,98.4% (column, OV-17; column temperature, +120 °C, 3min (12 °C/min), +220 °C, 3 min (12 °C/min), and +250°C, 3 min; injection temperature, +250 °C; detectiontemperature, +250 °C). 1H-NMR (CDCl3; ppm) δ 3.45-3.47(m, 4H), 2.49-2.52 (m, 4H), 1.62-1.64 (m, 2H), 1.44-1.36(s, 9H).

Acknowledgment

This work was partially supported by Guangdong MedicalCollege Research Foundation (Grant XG1003).

Supporting Information Available: 1HNMR spectra for thefinal product. This information is available free of charge viathe Internet at http://pubs.acs.org/.

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Table 3. Results from the Preparation of 1

entry 7a 4 N HCl (Boc)2O (mol) yieldb (%) refc (yield, product)

1 50 g (0.17 mol) 150 mL 42 g (0.19 mol) 70 3 (46%, 0.4 g); 9 (93%, N/A)2 200 g (0.7 mol) 400 mL 170 g (0.78 mol) 64 15 (34%, N/A); 19 (50.8%, 17.6 g)3 105 kg (crude, 320 mol) 300 kg 90 kg (412 mol) 48.5 20 (75.6%, 3.97 g)

a Intermediate 7 used as crude (with residual solvent) without further purification. b Three steps combined overall yield. c Literature yields were givenfor reference purpose; literature product may have different substituent on the nitrogen; the final product may not be the same, but the processingchemistry is similar.

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ReceiVed for reView August 29, 2010ReVised manuscript receiVed October 8, 2010

Accepted October 10, 2010

IE101807G

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Appendix 1. 1HNMR spectrum for product 1 (Table 3 entry 1)

(note. This HNMR spectrum clearly indicates presence of some ethyl acetate solvent)

Appendix 2. 1HNMR spectrum for product 1 (Table 3 entry 2)

Appendix 3. 1HNMR spectrum for product 1 (Table 3 entry 3)