Research ArticleAn Efficient and Practical Method for the Synthesis of SaxagliptinIntermediate 2-(3-Hydroxy-1-adamantane)-2-oxoacetic Acid andIts Optimization

Qi Liao ,1 Lan Jiang,2 Cong Li,1 Yaling Shen,1 Min Wang,1 Chengkun Cao,1

and Xiangnan Hu 1

1Department of Medicinal Chemistry, Pharmacy School, Chongqing Medical University, Chongqing, China2College of Environment and Resources, Chongqing Technology and Business University, Chongqing, China

Correspondence should be addressed to Xiangnan Hu; huxiangnan@cqmu.edu.cn

Received 28 June 2019; Accepted 13 September 2019; Published 10 October 2019

Academic Editor: Gabriel Navarrete-Vazquez

Copyright © 2019 Qi Liao et al.0is is an open access article distributed under the Creative Commons Attribution License, whichpermits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

A mild and relatively simple way for preparation of 2-(3-hydroxy-1-adamantane)-2-oxoacetic acid (I) was reported. It wasprepared from 1-adamantanecarboxylic acid (II) via sulfuric acid/nitric acid to get 3-hydroxy-1-adamantanecarboxylic acid (III);treated with the one-pot method through acylation, condensation, and decarboxylation to obtain 3-hydroxy-1-acetyladamantane(IV); and finally oxidized by potassium permanganate (KMnO4) to get the target compound (I). 0e overall yield was about 60%,which provides a new idea for commercial production of saxagliptin intermediate.

1. Introduction

Diabetes, a complex and chronic illness, is becoming apublic health problem and even a global societal catas-trophe. According to the figures displayed in the 8thedition of the Diabetes Atlas issued by the InternationalDiabetes Federation, until 2017, there were about 451million adults who lived with diabetes all over the world,and this number may rise to 693 million in 2045, if nothingis done [1].

Dipeptidyl peptidase-4 (DPP-4) inhibitors are classicantihyperglycemic agents used worldwide [2]. Up-to-datestudies and analysis reveal clearly that the overall tolerance/safety profile of DPP-4 inhibitors appears better than that ofother oral glucose-lowering agents [3]. Compared withsulfonylureas etc., DPP-4 inhibitors may represent a cost-effective option [4].

Saxagliptin (Onglyza) is a highly potent and selectiveDPP-4 inhibitor authorized by FDA in 2009 [5]. Due to itsdistinctive mechanism of action and a series of clinical trials,FDA approved its combination with metformin (Kombi-glyze XR) and dapagliflozin (Qtern) in 2010 and 2017 [6].

0rough retrosynthesis analysis, we found that (S)-N-Boc-3-hydroxyadamantylglycine is a key intermediate ofSaxagliptin [7], and it can be prepared economically andefficiently from 2-(3-hydroxy-1-adamantyl)-2-oxoaceticacid (I) by asymmetric reductive amination [8, 9](Figure 1).

Not surprising, much effort has been made to synthesizethis essential intermediate I (Figure 2). Politino et al. [10]originally describe a method treating 1-bromoadamantaneas starting material, which reacted with silane coupling agentto give α hydroxy acid and then through esterification,Swern oxidation, hydroxylation, and hydrolysis to producethe target compound I. However, harsh reaction conditionsinvolved in Swern oxidation (− 78°C) restrict the route forcommercial manufacturing.

Henryon et al. [11] developed an improved route tostart with 1-adamantanecarboxylic acid, which was acyl-ated by thionyl chloride (SOCl2) and substituted by cyanidereagent TMSCN to afford cyanide and then underwenthydrolysis, esterification, and hydroxylation to obtain theintermediate. But it was found that this route demandedgreatly multiple procedures as well as relatively complex

HindawiJournal of ChemistryVolume 2019, Article ID 5375670, 8 pageshttps://doi.org/10.1155/2019/5375670

operation. Furthermore, the overall yields were unsatisfactory(28%) and thus were not adequate for implementation of alarge-scale work.

Our team [12] reported a method to prepare the targetcompound. Regarded 1-adamantanecarboxylic acid as rawmaterial which was methylated by the one-pot method toobtain 1-acetyladamantane and afterwards through oxi-dation and hydroxylation to acquire compound I. 0escheme we came up with required inexpensively acceptablematerials and mild reaction conditions. But the yield ofhydroxylation is relatively low (68%) which limited theapplication to industrial production.

In in-depth study, we found that the hydroxylation ofadamantane tertiary carbon was the key factor affecting thetotal yield. A series of methods were reported, but the resultswere disappointed (Figure 3). Berner et al. [13], using 1-acetyladamantane as the first material via one-step oxida-tion, introduced the hydroxyl and carboxyl group (36%). Liet al.[12] used two-step oxidation and hydroxylation in thesecond step, but they did not get the good result(61%).Wilhelm et al. [14] made 1-adamantane glycine as the rawmaterial hydroxyl, but the yields are still low (66%). Venkatet al. [15] protected the amino group; however, the hy-droxylation yields lower (40%). Bertolini et al. [16] kepthydroxylation as the last step of Saxagliptin synthesis, but theyields are still low (74%).

To sum up, it seems to delay the hydroxylation stepalways to reduce the yield. Our team analyzed the reason forthe low yield. We believe that the key to solve the problemshould be on the adamantane ring. 0e nature of hydrox-ylation is adamantane oxidation. Due to the presence ofelectron-withdrawing substituents, electron-withdrawingeffects may decrease the cloud density of the adamantanering and cause difficulty in oxidation. On the other hand, thespatial effect may also increase steric hindrance, making itdifficult for oxidants to fully react with raw materials andlead to low yields. 0us, if we change the oxidation sequenceand advance the hydroxylation to avoid the above problems,it may be a feasible way to increase the yield.

2. Results and Discussion

On account of the above hypothesis, we made some im-provements based on our laboratory previous work[12, 17, 18] and developed an efficient and practical methodfor the synthesis of I. 0e specific improvements of route aredepicted in Figure 4:

It was prepared from 1-adamantanecarboxylic acid (II)via sulfuric acid/nitric acid to get 3-hydroxy-1-ada-mantanecarboxylic acid (III); treated with the one-potmethod through acylation, condensation, and de-carboxylation to obtain 3-hydroxy-1-acetyladamantane

OH OH

OH

NH2 NHBoc

NADH

CO2

NAD

HCOONH4CN

N

O O

Saxagliptin

Phenylalanine dehydrogenase

Formate dehydrogenase

OH

I

O

O

OH

Figure 1: Retrosynthesis analysis of Saxagliptin.

The route of Politino et al.

The route of Henryon et al.

The route of our team.

OSiMe3

OSiMe3

Me3SiO

BrZnCl2, DCM

OH

COOHMeOH/AcCl (COCl2)/DMSO

–78°CCOOCH3

OH O

COOCH3

H2SO4/HNO3

OH OH

OH

OH

O

COOCH3COOH

NaOH/HCl

I

I

O

SOCl2

COOH

COOHCOOH

COCl

(CH3)3SiCN(TMSCN) (1) HBr, AcOH (1) H2SO4/HNO3

(2) H2O (2) OH–

COCN

O

O

NH2

H+/ROH

O O

COOR COOH

One-pot method

O O

CH3

KMnO4/OH– KMnO4/OH–

40°C 80°C

I

COOH

O

Figure 2: 0e existing methods to synthesize I.

2 Journal of Chemistry

(IV); and finally oxidized by potassium permanganate(KMnO4) to get the target compound (I).

In the process optimization, we focused on the synthesisof IV and I. In the one-pot method step synthesis of IV, weused acetyl chloride (CH3COCl) with lower activity insteadof SOCl2, aiming to shorten the duration of reactions andimprove production efficiency (Figure 5) because the latteralso led to chlorination of 3-hydroxy to form the byproduct,which would increase our workload (Figure 6). In addition,we optimized the step of acylation reaction via centralcomposite design-response surface methodology concen-trate upon four vital factors after single factor experimentstudy of 3-hydroxy-1-acetyladamantane [19].

Furthermore, the species of catalyst used in the synthesisof I was screened, which represented a great improvementcompared with our previous work that increased the

reaction yield effectively. 0e optimized reaction conditionsshortened the reaction time, saved cost, and gave the targetcompound with 60% yield, which was suitable for industrialproduction.

Central composite design-response surface methodologyhas been widely used for process optimization in recentyears, which has the advantages of high precision and goodpredictability and being sensitive to examine the interactionbetween the various factors [20, 21]. In the step of acylationreaction, it was used to summarize the key factors affectingthe experiment, which optimized the experimental condi-tions and achieve a better result.

0e factors influencing the yield of compound IV wereas follows: the species of the catalyst (Table 1), the catalystloading (Figure 7), the mole ratio of acetyl chloride tocompound III (Figure 8), reaction temperature (Figure 9),

The route of Bertolini et al.

The route of Venkat et al.

The route of Wilhelm et al.

The route of our group.

The route of Berner et al.CH3

O

KMnO4/OH–

KMnO4/TBAB

OH

OH

OH

OH

COOH

O

(36%)

CH3

O

COOH

COOH

COOH

COOH

COOH

COOH

O

O

O

(68%)(61%)

(66%)

(74%)

(40%)

(90%)

NH2 NH2

HNO3/H2SO4

NHBoc

NHBoc NHBoc

NHBoc

2%KOH NaHSO3MDC

N N

CN CN

RuCl3.xH2O,KBrO3

OH

O

Pyridine H2O/CH3CN 60°C

Figure 3: 0e existing methods to introduce the hydroxyl.

II

COOH

H2SO4/HNO3

OH

COOH

III

(1) AcCl(2) Na/CH2(COOEt)2

(3) AcOH/H2SO4/H2O

IV

OH

CH3

KMnO4/OH–

O

TBAB

OH

COOH

OI

Figure 4: A convenient approach to prepare I.

Journal of Chemistry 3

and reaction time (Figure 10). 0erefore, the five factorsabove were set to several levels in the pre-experiment andused single factor experiment study to investigate the effectsof them on the yield of compound IV. 0e specific result isshown below.

After confirming the preliminary range of the variablesvia single-factor experiment, a central composite design-response surface methodology with four independentfactors (Xa, molar ratio of acetyl chloride to compound 3;Xb, reaction time; Xc, reaction temperature; and Xd, thepyridine loading) at five levels was performed. For statis-tical calculation, the levels were coded as − 2, − 1, 0, +1, and+2, respectively, in which − 2 corresponds to the low level ofeach factor, +2 to the high level, and 0 to the midlevel. 0eresult of central composite design-response surfacemethodology is described in Table 2. As seen from Table 2,the complete design consisted of 30 experimental points,and the experiment was carried out in a random order.Each factor has been implemented multiple linear re-gression and binomial fitting via the software of Design-Expert 8.0.6 [18].

Multiple linear regression equation was

R(yield) � R1 � +60.31767 + 1.13750Xa − 0.53917Xb

+ 0.90417Xc + 0.82083Xd, r1 � 0.20.

(1)

0e binomial equation was

R(yield) � R2 � +73.39167 + 1.13750Xa − 0.53917Xb

+ 0.90417Xc + 0.82083Xd + 0.39625XaXb

+ 0.73625XaXc + 0.36125XaXd − 0.30375XbXc

− 1.02875XbXd

− 1.03875XcXd − 3.879372Xa2 − 3.12938Xb2

− 5.10437Xc2 − 4.229Xd2, r2 � 0.91.

(2)

OH

COOH

III

Na/CH2(COOEt)2

O O O

COOEt

COOEt

AcOH/H2SO4/H2O

IV

OH

O

CH3CH3

SOCl2

Cl Cl Cl

Clbase

Figure 6: Initial one-pot method.

Table 1: 0e impact of catalyst on yield.

Catalyst 0e feed ratios of the catalyst to raw materials (mol/mol) 0e yield of compound IV (%)

Pyridine 1.5 72.1DMAP 1.5 65.3Triethylamine 1.5 68.2DMF 1.5 32.2— — 43.0

OH OH OH

COOH

III

AcCl Na/CH2(COOEt)2

O

O

O

COOEt

COOEt

O

AcOH/H2SO4/H2O

IV

OH

O

CH3

Figure 5: Improved one-pot method.

40

45

50

55

60

65

70

75

�e y

ield

of c

ompo

und IV

(%)

1.0 1.5 2.00.5�e loading of pyridine (g)

Figure 7: Impact of catalyst loading.

4 Journal of Chemistry

From the equation above, the correlation coefficient ofbinomial equation (r2) was bigger than multiple linear re-gression (r1) whichmeans the actual values were well in closeagreement with the predicted values, so we chose that thebinomial model was the better one ultimately.

According to the obtained binomial equation, the cor-responding 3-D response surface plot of compound IV isdepicted in Figure 11. As shown in Figure 11, within limits,the yield rose as the molar ratio of acetyl chloride tocompound III rose, reaction time prolonged, reactiontemperature increased, and the pyridine loading enhancedand then reached the maximum value, but beyond a certainlevel, the yield decreased. Each response surface has itsoptimal interval, and higher yields could be obtained whenthe reaction conditions were in the region, via overlappedthe optimal region of each response surface, optimized rangeof producing compound 6 was obtained as shown below: Xa:2.9 :1∼3.4 :1; Xb: 3∼4 h; Xc: 30∼55°C; and Xd: 1.4∼1.6 g.

However, with a view to operation of the process andinput-output ratio, the final reaction conditions we selectedamong the above ranges were: 0e molar ratio of acetyl

chloride to compound III (3.1 :1), reaction time (4 h), re-action temperature (40°C), and the pyridine loading(1.5 g).Finally, we performed five parallel experiments under theoptimized reaction conditions, and compound IV was ob-tained in 74.3%, 72.5%, 73.1%, 73.5%, and 72.0% yields,respectively, with the purity reaching to 99%. 0e averageyield was 73.1% with a deviation of 0.66%.

50

55

60

65

70

75

�e y

ield

of c

ompo

und IV

(%)

2 3 4 51Reaction time (h)

Figure 10: Impact of reaction time.

Table 2: 0e results of central composite design-response surfacemethodology.

Number X a(mol/mol) X b (h) X c (°C) X d (g)

Actual yield(%)

1 0 0 0 2 53.32 2 0 0 0 56.93 0 − 2 0 0 58.94 0 0 2 0 50.55 1 − 1 1 1 63.226 − 1 − 1 1 1 60.77 0 0 0 − 2 50.38 0 0 0 0 72.69 − 1 1 − 1 1 60.310 − 1 − 1 1 − 1 5511 − 1 − 1 − 1 − 1 56.4412 1 − 1 − 1 − 1 55.513 1 1 1 − 1 62.714 − 2 0 0 0 49.515 1 1 − 1 1 59.916 0 0 − 2 0 46.117 − 1 − 1 − 1 1 60.518 0 0 0 0 73.4519 1 1 1 1 61.2220 0 2 0 0 53.521 1 1 − 1 − 1 57.922 0 0 0 0 74.723 − 1 1 1 − 1 60.224 0 0 0 0 75.825 0 0 0 0 73.926 0 0 0 0 69.927 1 − 1 1 − 1 59.728 1 − 1 1 1 56.929 − 1 1 1 1 54.930 1 − 1 − 1 1 61.2

60

62

64

66

68

70

72

74

�e y

ield

of c

ompo

und IV

(%)

2 3 4 5 61�e molar ratio of acetyl chloride

Figure 8: Impact of mole ratio of acetyl chloride.

50

55

60

65

70

75

�e y

ield

of c

ompo

und IV

(%)

20 30 40 50 6010Reaction temperature (°C)

Figure 9: Impact of reaction temperature.

Journal of Chemistry 5

As for the oxidation step, Cheng et al. [22] reported amethod that treated 1-acetyladamantane with potassiumpermanganate in pyridine to get the target compound;however, pyridine is poisonous. So, we used nontoxict-butanol instead of pyridine. In addition, considering that1-acetyladamantane and potassium permanganate are noteasily soluble in t-butanol, the phase transfer catalyst (PTC)was added to improve the two-phase reaction system[23, 24]. 0e types of PTC were also examined; we fixed themole ratio of PTC to compound IV to 1 : 20, reaction time to2.5 h, reaction temperature to 40°C, and the mole ratio ofpotassium permanganate to compound IV to 1.5 :1, to in-vestigate the influence of PTC species on the yields (Table 3).

As shown in Table 3, the addition of phase transfercatalyst can improve the reaction yield obviously. TBAB wasa good choice which raised the yield to 91%; therefore, TBABwas added to the reaction solution to shorten the reactiontime and improve the yield.

3. Experimental

All reagents were purchased commercially and were used assupplied unless otherwise specified. Melting points weredetermined through SGW X-4 micromelting point appa-ratus. IR was recorded using a Nicolet FTIR 5700 spec-trophotometer, ESI-MS spectra were recorded from a

Finnigan LCQ Advantage Max spectrometer, and 1H-NMRwas recorded on a Bruker Avance III 600MHzspectrometer.

3.1. Preparation of 3-Hydroxy-1-adamantanecarboxylic Acid(III). A 150mL three-necked round bottom flask wasequipped with magnetic stirrer and thermometer. 0e flaskwas charged with sulfuric acid (98%, 20mL) and nitric acid(65%, 2mL) in turn. 0e mixed acid was stirred at 0°C for1 h, followed by addition of 1-adamantanecarboxylic acid(5.0 g, 0.028mol) in portions within 0.5 h while maintainingthe temperature at 0°C. 0ereafter, the reaction mixture wasstirred at room temperature for 12 hrs. Water (125mL) wasadded to the reaction mixture and stirred for 5 hrs. 0en, thesuspension was filtered, and the filter cake was recrystallizedwith propanone/water and dried over Na2SO4 to affordpurified compound III (4.90 g, 90.0% yield). M.p. 199∼200°C

–1.00–0.50

0.000.50

1.00

–1.00–0.50

0.000.50

1.00

6065707580

R1

C :CD:D –0 500.00

0.5000

–0 500.00

0.501

0

C:CD:D

(a)

R1

–1.00–0.50

0.000.50

1.00

–1.00–0.50

0.000.50

1.00

6264666870727476

A:AD:D –0 500.00

0.5000

–0 500.00

0.501.

246

A AD D

(b)

R1

–1.00–0.50

0.000.50

1.00

–1.00–0.50

0.000.50

1.00

6264666870727476

B:BC:C –0.500.00

0.500

–0.500.00

0.501.

246

B BC C

(c)

R1

–1.00–0.50

0.000.50

1.00

–1.00–0.50

0.000.50

1.00

6264666870727476

B:BD:D –0.500.00

0.5000

–0.500.00

0.501

24

BD

(d)

R1

–1.00–0.50

0.000.50

1.00

–1.00–0.50

0.000.50

1.00

60

65707580

A:AB:B –0.500.00

0.5000

–0.500.00

0.501.

0

A AB B

(e)

R1

–1.00–0.50

0.000.50

1.00

–1.00–0.50

0.000.50

1.00

6065707580

A:AC:C –0 500.00

0.500

–0 500.00

0.501

05

AC

(f )

Figure 11: 0e response surface of product IV.

Table 3: Impact of the phase transfer catalyst on yield.

Phase transfer catalyst 0e yield of compound I (%)— 70PEG-400 81TEBAC 89TBAB 91

6 Journal of Chemistry

(lit. [18] 199∼200°C); IR (KBr, cm− 1): 3460, 2850, 1680, 1200,1100, 600; 1H NMR (600MHz, DMSO-d6) δ: 11.89 (br s, 1H,COOH), 4.50 (br s, 1H, OH), 2.12∼2.14 (m, 2H, CH),1.66∼1.48 (m, 12H, CH2); ESI-MS (m/z): 197 (M+ 1)+.

3.2. Preparation of 3-Hydroxy-1-acetyladamantane (IV).A mixture of pyridine (4.5mL, 0.056mol) and compoundIII (5.5 g, 0.028mol) was stirred in an ice-water bath for anhour; then, acetyl chloride (10mL, 0.138mol) was addeddropwise to the mixture, and this solution was stirred at25°C for 3 h. After that, pyridine hydrochloride was formedand was filtered. 0e excess acetyl chloride of filtrate wasremoved with reduced pressure, and the residue was 3-hydroxy-1-adamantyl methacetic anhydride. A mixture ofdiethyl malonate (7.4mL, 0.042mol) and petroleum ether(20ml) were added dropwise to metallic sodium in pe-troleum ether (100mL). 0e mixture was stirred for an-other 15 h at room temperature to get white precipitates.Afterwards, previously prepared 3-hydroxy-1-adamantylmethacetic anhydride in petroleum ether (20mL) wasadded to the preceding suspension slowly; then, the mix-ture was stirred at room temperature for 12 h. Afterwards,water (50ml) was added to the solution and stirred forabout 10 minutes, and the organic layers were separatedand concentrated with reduced pressure to give the oilresidue. After that, a mixed solution of acetic acid (20ml),water (6ml), and sulfuric acid (2mL) was added to theresidue obtained as above, the reaction mixture was thenrefluxed for 8 h and then poured into cold water (200mL),which was extracted with ethyl acetate (3 ×10mL), and thecombined organic layers were washed with water (100mL),dried over Na2SO4, and concentrated under reducedpressure. 0e residue was recrystallized from methylenechloride/hexane to give compound IV (3.69 g, 74.6%yield).M.p. 89∼90°C(lit. [25] 89∼90°C); IR (KBr, cm− 1):3380, 2880, 2850, 1750, 1410, 1000, 600; 1H NMR(600MHz, DMSO-d6) δ: 4.52 (s, 1H, OH), 2.22 (br s, 2H,CH), 2.05 (s, 3H, CH3), 1.62∼1.47 (m, 12H, CH2); ESI-MS(m/z): 195 (M+ 1)+.

3.3. Preparation of 2-(3-Hydroxy-1-adamantyl)-2-OxoaceticAcid (I). 0e tert-butanol (10mL), 2% KOH (100mL),compound IV (5.0 g, 0.026mol), and phase transfer catalystTBAB were added to a 250mL three-necked flask; then, themixture was stirred at 40°C, and potassium permanganate(8.3 g, 0.052mol) was added in batches during a period of1 h. After that, the solution was stirred for 5 h; then, sodiumsulfite (3.8 g, 0.026mol) was added and stirred for 10min,and the mixture was filtered. 0e filtrate was adjusted to pH1-2 and then extracted with ethyl acetate (10mL× 3), and theorganic phases were combined, which was concentratedunder reduced pressure to get a light yellow oil residue. 0eresidue was recrystallized by heptane and dried to obtaincompound I (5.3 g, 91.8% yield). M.p. 163–165°C (lit. [26]164∼165°C); IR (KBr, cm− 1): 3380, 2920, 2850, 1713, 1680;1H NMR (600MHz, DMSO-d6) δ: 14.2 (br s, 1H, COOH),4.6 (br s, 1H, OH), 2.19 (s, 2H, CH), 1.72–1.46 (m, 12H,CH2); ESI–MS (m/z): 225(M+ 1)+.

4. Conclusion

0is study provides a simple and economical method tosynthesis 2-(3-hydroxy-1-adamantane)-2-oxoacetic acid in60% yield from 1-adamantanecarboxylic acid over five steps.0e reaction is mild, simple, and inexpensive, which repre-sents a great improvement compared with previously reportedmethods and has a great foreground of development.

Data Availability

0e figure and table data used to support the findings of thisstudy are included within the article.

Conflicts of Interest

0e authors declare that there are no conflicts of interestregarding the publication of this paper.

Authors’ Contributions

Qi Liao and Lan Jiang have contributed equally to this work.

Acknowledgments

0e authors are deeply grateful for the support of theChongqing Science and Technology Commission(cstc2015zdcy-ztzx120003) for this study. 0e authors alsoappreciate that the Undergraduate Innovative ExperimentProgram of Chongqing Medical University (no. 201971) forproviding financial aid for our work.

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