One-Pot Process for Synthesis of Nalbuphine Hydrochloride and Impurity Control Strategy

Article abstract of DOI:10.1021/acs.oprd.0c00321

An improved kilogram-scale process of synthesis of nalbuphine was developed by investigating the critical parameters. Ten process-related impurities were identified, of which the source and control strategy was elucidated. Moreover, tetramethylammonium triacetoxyborohydride (Me4NBH(OAc)3) was developed to reduce the imine and ketone in one pot. As a result, 6-β-epimer was significantly controlled to only 0.08% in the crude nalbuphine. The improved process was robust at kilogram scale in 60.4% overall yield with 99.95% high-performance liquid chromatography (HPLC) purity.

Full text of DOI:10.1021/acs.oprd.0c00321

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Full Paper
One-pot Process for Nalbuphine
Hydrochloride and Impurity Control Strategy
Tao Zhang, Zenong Wu, Yibo Chen, Weili Zhao, Zhezhou Yang, and Fu-Li Zhang
Org. Process Res. Dev., Just Accepted Manuscript • DOI: 10.1021/acs.oprd.0c00321 • Publication Date (Web): 07 Aug 2020
Downloaded from pubs.acs.org on August 9, 2020
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One-pot Process for Nalbuphine Hydrochloride and Impurity
Control Strategy
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Tao Zhang, †,‡ Zenong Wu, †,‡ Yibo Chen, ‡ Weili Zhao, *, † Zhezhou Yang, *, ‡ and Fuli
Zhang*, ‡
†School of Pharmacy, Fudan University, 826 Zhangheng Road, Shanghai 201203, P.
R. of China
‡Shanghai Institute of Pharmaceutical Industry, China State Institute of
Pharmaceutical Industry, 285 Gebaini Road, Pudong District, Shanghai 201203, P. R.
of China
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Abstract
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An improved kilogram-scale synthesis of nalbuphine had been developed with critical
parameters investigated. Ten process-related impurities were identified, of which the
source and control strategy had been elucidated. Moreover, tetramethylammonium
triacetoxyborohydride (Me4NBH(OAc)3) was developed to reduce the imine and
ketone in one-pot. As a result, 6-β-epimer was significantly controled to only 0.08%
in the crude nalbuphine. The improved process was robust at kilogram-scale in 60.4%
overall yield with 99.95% HPLC purity.
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Keywords
nalbuphine hydrochloride, process, one-pot synthesis, impurity
Introduction
Nalbuphine
hydrochloride
is
chemically
known
as
a
(-)-17-(Cyclobutylmethyl)-4,5α-epoxymorphinan-3,6α,14-triol
hydrochloride,
primarily kappa agonist/partial mu antagonist analgesic, which was first approved by
the FDA in 1979 under the brand name of Nubain for the treatment of moderate to
severe and postoperative pain. Its analgesic potency is essentially equivalent to that of
morphine, but exhibits a ceiling effect in dose greater than 30 mg with no further
respiratory depression. 1
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N
22
16
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10
9
OH
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11
1
3
8
14
2
7
13
.
HCl
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O
HO
OH
1 HCl
Nalbuphine Hydrochloride
Several synthetic routes of nalbuphine have been reported. 2 It could be synthesized
by three methods using noroxymorphone, a semi-synthetic product derived from
morphine3 or thebaine4 and was commercially available, as starting material (Scheme
1). Major differences for these three methods are the sources for the introduction of
N17-cylcobutylmethyl scaffold of nalbuphine. Method 1 adopted cyclobutylmethyl
bromide2d as the source to introduce N17-cylcobutylmethyl scaffold through a direct
nucleophilic substitution and the reaction needed 15 days for a relatively complete
conversion in 73% yield. The downstream reduction step needed a transition metal
Ru(II) as the catalyst to produce a result that the content of 6-α hydroxyl was 99%.
Unfortunately, chromatographic purification was needed5, which hampered the further
development for scale-up and commercialization. Method
2
adopted
cyclobutanecarbonyl chloride2d to introduce N17-cylcobutylmethyl scaffold, but three
steps were needed to obtain nalbuphine. Such as the additional reduction step to
reduce the amide group and the hydrolysis of the excess esterification product of
3-OH position with LiAlH4 were needed.
Method
3
adopted
cyclobutanecarboxaldehyde2g
to
introduce
N17-cylcobutylmethyl scaffold of nalbuphine directly in one step. However, poorer
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stereoselectivity was reported, and the α/β ratio of 6-hydroxyl was only 95/5. Those
methods mentioned above suffered from disadvantages such as the usage of LiAlH4,
expensive metal catalysts, unsatisfactory stereoselectivity, lower atomic economy,
and chromatographic purification. Herein, we wish to develop an improved synthetic
process for nalbuphine. Moreover, the impurities generated in a process and the
quality control strategy play a more and more important role in researching the quality
of a drug substance, as well as helping researchers choose the best synthetic route and
conditions. Therefore, we also want to report the impurities generated within this
process and the corresponding quality control strategy, which have not yet been
reported to the best of our knowledge.
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Scheme 1. Synthesis of Nalbuphine from Noroxymorphone
Br
Ru(II) Catalyst
Et3N/HCOOH
2)
1)
yield, 60.6%
6
-α
, 99%
Method 1
NH
OH
O
N
Cl
Ru(II) Catalyst
Et3N/HCOOH
1)
3)
2)
OH
yield, 79.4%
LiAlH4
6- :6 =98.9%:1.1%
O
2
α
-β
Method 2
HO
O
O
HO
OH
Noroxymorphone
1
O
6- :6 =95%:5%
α -β
1)
, Pt/C, H2
Method 3
Results and Discussion
Initially we were attracted to the patent applied by the company of Mallinckrodt
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(Scheme 2),2(l) which described a one-pot process for nalbuphine from
noroxymorphone. The reaction of N17-cyclobutylmethyl was installed with
cyclobutanecarboxaldehyde in dimethylformamide (DMF), and followed by the
reduction of the imine and 6-keto structure with sodium triacetoxyborohydride
(NaBH(OAc)3). This process provided a satisfactory result as reported that the content
of 1 and β-epimer impurity 6 was 98.9% and 0.1% respectively, with a high yield of
95.5%.
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However, it turned out to be unreproducible after three parallel batches trials. There
was up to more than 43% unreacted starting material 2 and only 53% of intermediate
3 that could be detected with 1.2 equivalents of NaBH(OAc)3. Then, the second
portion of 1.6 equivalent of NaBH(OAc)3 was added. As a result, only 14.9% of
nalbuphine was obtained with completely reacted of 2, and the major product was 3
(83.9%, Table 2, entry 1). Even 4.9 equivalents NaBH(OAc)3 was used, 3 could not
be converted into nalbuphine completely (Table 2, entry 1). More importantly, 1.2%
of β-epimer impurity 6 was obtained in the incomplete reduction mixture with 22.8%
of 3. Due to the incomplete reduction of 3 with NaBH(OAc)3 and high content of 6-β
hydroxyl impurity, the process parameter needs to be optimized adequately with the
screening of solvent and suitable reducing agent.
Scheme 2. The One-pot Synthesis of Nalbuphinea
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N
OH
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O
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3a
O
N
OH
NaBH(OAc)3
RT
NH
OH
O
HO
OH
N
1
Nalbuphine
O
OH
NaBH(OAc)3
NaBH(OAc)3
DMF, AcOH
RT
60℃
N
O
HO
O
O
3
HO
O
OH
side
reaction
2
(Noroxymorphone)
O
HO
OH
impurity 6
side
reaction
NH
OH
NH
OH
NaBH(OAc)3
O
O
HO
OH
HO
OH
impurity 5
impurity 4
aReagents and Conditions: 1), cyclobutanecarboxaldehyde (1.1 equiv), NaBH(OAc)3
(1.1 equiv), DMF, AcOH, RT; 2), NaBH(OAc)3 (1.6 equiv), 60 ℃; blue marked part.
In terms of mechanism, this one-pot process involves three transformations
(Scheme
2).
Firstly,
compound
2
preferentially
reacts
with
cyclobutanecarboxaldehyde to form the imine intermediate 3a, which can effectively
avoid the reduction of 2 to form the impurity 4 and 5. Secondly, the imine group is
further reduced by NaBH(OAc)3; Thirdly the 6-ketone carbonyl group in compound 3
is reduced to form nalbuphine. (X-ray single-crystal diffraction analysis in supporting
information further confirmed the structure of the isomer impurity 4 and 5)
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Different orientation of the hydroxyl group at the C-6 position leads to the
formation of β-epimer impurity 6, a side product which has similar properties with
nalbuphine and is hard to avoid and remove.6 Therefore, the direction of the
optimization is to reduce the content of 6 and simultaneously promote the complete
transformation of intermediate 3 to the desired product 1 as much as possible.
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Synthesis of nalbuphine. First, screening of solvents was studied to increase the
conversion of compound 2 to compound 3 and 1. It was reported that
1,2-dichloroethane (DCE), tetrahydrofuran (THF), and acetonitrile(ACN) were
suitable for reductive amination reactions with NaBH(OAc)3.7 However, the result of
solvents screening studies showed that good conversion was obtained using
dimethylformamide (DMF) or dimethylsulfoxide (DMSO) as the solvent, while
poor conversion for THF, ethanol, dichloromethane (DCM), DCE, methanol and
ACN (Table 1). Moreover, for the transformation of 3 to 1, the best conversion was
found to be using DMSO as the solvent (Table 1, entry 1 and 8), and the solubility of
2·HCl in DMSO was advantageous. Therefore, DMSO is determined to be the
superior solvent.
Table 1. Screening of the Solventsa
NH
HCl
O
N
N
OH
OH
OH
Solvent/AcOH
1)NaBH(OAc)3 2)NaBH(OAc)3
1.2eq
RT
1.6eq
60℃
O
HO
O
O
O
HO
O
HO
OH
2 HCl
1
3
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reaction resultb(%)
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entry
solvent
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2
3
1
1
2
3
4
5
6
7
8
DMF
THF
NDc
97.50
81.02
64.81
65.26
53.94
97.68
ND
84.90
2.33
15.10
0.17
Ethanol
DCM
17.23
30.35
20.41
29.93
2.23
1.75
4.84
DCE
14.32
16.13
0.09
Methanol
ACN
DMSO
70.31
29.69
aConditions: add 2.8 equiv of NaBH(OAc)3 in 2 portions.
bOnly peak areas (%) of 2, 3 and 1 were integrated on HPLC.
cND: Not detected.
The screening and optimization of reducing agent was studied in DMSO. The
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reaction, which was conducted with more than 4.0 equivalents of NaBH(OAc)3, gave
a result that only 56.60% of 1 was obtained with still 42.62% of unreacted
intermediate 3 in the mixture, but further decreased the content of β-epimer impurity
contrast with that in DMF (Table 2, entry 2). Both potassium
Tri-sec-butylborohydride (KBH(s-Bu)3)8 and sodium borohydride gave unattractive
results (Table 2, entries 3-4). The result of tetramethylammonium
triacetoxyborohydride (Me4NBH(OAc)3) showed a distinct advantage that it gave a
higher conversion from compound 2 to 1 with 99.47% of 1, 0.11% of 3 and 0.12% of
6 detected in reaction mixture (Table 2, entry 8). Then, the feeding mode of
Me4NBH(OAc)3 was investigated. It was found that, for the same amount of reducing
agent, the more portions added in, the better experimental result obtained (Table 2,
entries 5-9). Adding 4.0 equivalents of Me4NBH(OAc)3 in five portions generated
99.79% of 1 with only 0.08 % of 6 and 0.05% of 3 detected, while the reaction of
adding Me4NBH(OAc)3 in one portion achieved the result that 98.53% of 1, 0.17% of
6 and 0.76% of 3 were detected (Table 2, entry 9 and 5). Owing to further decreased
of 6, adding 4.0 equiv of Me4NBH(OAc)3 in five portions is preferred.
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Table 2. Screening and Optimization of the Reducing Agenta
NH
HCl
N
N
N
O
OH
OH
OH
OH
Solvent/AcOH
Reducing agent
RT
Reducing agent
60℃
O
2 HCl
O
3
O
1
O
6
HO
O
HO
O
HO
OH HO
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reaction resultc
(%)
amounts
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entry
reducing agent solvent
(eq)
2
3
6
1
1.2
1.6
1.0
1.1
43.89 52.96 0.02 0.14
ND
ND
ND
83.88 0.18 14.94
53.64 0.55 44.83
22.84 1.16 75.05
1
NaBH(OAc)3
DMF
4.9
1.2
1.6
0.8
0.4
31.97 62.78 0.02 0.27
ND
ND
ND
69.89 0.17 29.47
50.80 0.29 48.47
42.62 0.37 56.60
2
NaBH(OAc)3
DMSO 4.0
3b
NaBH4
DMSO 2.3
2.3
2.3
-
-
ND 20.65 79.35
DMSO/
2.3
THF
4b
KBH(s-Bu)3
52.44
-
47.56
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Me4NBH(OAc)3 DMSO 4.0
Me4NBH(OAc)3 DMSO 4.0
4.0
ND
0.76 0.17 98.53
9
1.2
2.8
ND
ND
87.67 0.04 12.12
0.62 0.16 99.04
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2.0
0.8
ND
ND
ND
87.01 0.04 12.68
0.90 0.12 98.87
0.38 0.13 99.35
7
Me4NBH(OAc)3 DMSO 4.0
1.2
1.6
0.8
0.4
ND
ND
ND
ND
90.89 0.05 8.85
6.12 0.12 93.55
0.41 0.13 99.19
0.11 0.12 99.47
8
Me4NBH(OAc)3 DMSO 4.0
1.0
1.0
1.0
0.5
0.5
7.22
ND
ND
ND
ND
91.98 ND 0.65
33.32 0.05 66.59
2.95 0.07 96.88
0.25 0.08 99.55
0.05 0.08 99.79
9
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aA total of 4.0 equivalent (4.9 equivalent in entry 1) of reducing agent was added in
portions, and the first portion of reducing agent was used to the reduction of imine to
produced compound 3, and the other subsequent portions acted on the reduction of
6-keto carbonyl to 1.
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bPrepared from intermediate 3, and only peak areas (%) of 3, 6 and 1 were integrated
on HPLC.
c Measured by HPLC (area %).
A less good result in the repeatability experiments was captured that another source
of Me4NBH(OAc)3 gave a bad result of stereoselective reduction with more than 3.03%
of 6 (Table 3, entry 1). As Me4NBH(OAc)3 was commercially manufactured using
sodium borohydride as the starting material (Scheme 3)9 we proposed that the
,
residual sodium borohydride in Me4NBH(OAc)3 caused the poor stereoselectivity.
Therefore, we studied the effect of different amounts of sodium borohydride present
in the stereoselective reduction reaction. It was shown that the more sodium
borohydride in Me4NBH(OAc)3, the worse stereoselectivity achieved (Table 3, entries
1, 3-7). The results displayed that the content of Me4NBH(OAc)3 exceeds 98% could
afford the satisfactory replication with the content of impurity 6 less than 0.2% (Table
3, entries 5-7). In addition, although the content of Me4NBH(OAc)3 was only 91.3%,
the impurity 6 could be greatly reduced from 3.03% to 0.63% with adding reducing
agent in more portions (Table 3, entries 1-2). This result further indicated that adding
the reducing agent in portions would contribute to the control of β-epimer impurity 6.
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Scheme 3. The Synthesis of Me4NBH(OAc)3
6
7
8
AcOH
Me4NBH4
Me4NBH(OAc)3
NaBH4
Me4NOH
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Table 3. The Effect of the Content of Reducing Agent on Stereoselective Reduction
Reactiona
reaction resultc
Me4NBH(OAc)3
(%)
entry
Contentb
lot No.
6
1
(%)
1
2d
3
T1-0340
T1-0340
91.3
91.3
95.9
96.2
98.1
98.4
3.03
0.63
1.93
0.44
0.18
0.15
96.00
98.30
97.88
99.36
99.73
99.71
HT0401180327
HT-20180426
HT-20180412
HT-20180423
4
5
6
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HT-20180505
99.9
0.11
99.55
7
8
9
aConditions: add 4.0 equiv of Me4NBH(OAc)3 in 4 portions.
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bContent was detected by QNMR (Quantitative nuclear magnetic resonance) in CDCl3
with 1,2,4,5-tetrachlorobenzene as an internal standard.
c Measured by HPLC (area %).
dAdd 4.0 equiv of Me4NBH(OAc)3 in 6 portions.
As known, acetic acid is often used to catalyze the formation of the imine in
reductive amination reactions of ketones ， but not needed in most reactions of
10
aldehydes.7, We examined the transformation of substrate in the absence of acetic
acid, and got a result that the compound 2 was completely converted to intermediate 3
and finally generated 75.09% of 1 with 24.18% of 3 (Table 4, entry 1). While in the
presence of acetic acid, further transformation from 3 to 1 was observed by HPLC,
and the more acetic acid was given, the higher conversion rate was achieved, with a
decreased of 3 from 24.18% to 0.05% (Table 4, entries 1-5). Entry 4, with the 4.2 v/w
of acetic acid, was preferred with just 0.08% of 3. It could be concluded that the
addition of acetic acid was not essential for the formation of the imine intermediate,
but could greatly enhance the ability of Me4NBH(OAc)3 to reduce 6-ketone carbonyl
to alcohol.
Table 4. Screening of the Amount of AcOH for Conversion from 3 to 1
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reaction resultb
AcOH
(v/w)a
entry
9
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12
13
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3
1
1
2
3
4
5
0
24.18%
2.65%
0.56%
0.08%
0.05%
75.09%
96.99%
98.82%
99.69%
99.34%
1.4
2.1
4.2
7.6
aThe ratio between the volume of AcOH and the weight of 2·HCl.
b Measured by HPLC (area %).
An unknown impurity was found in nalbuphine when another source of
noroxymorphone, which was prepared from thebaine, was used as the starting
material. This impurity was difficult to remove during the synthetic process of
nalbuphine hydrochloride. The molecular weight was detected as 355 (the molecular
weight of nalbuphine is 357). The content of this impurity could be decreased from
0.58% to 0.24% after the hydrogenation reaction, which indicated the existence of the
carbon-carbon double bonds. In the second step of the synthetic route of the
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9
noroxymorphone, palladium-catalyzed hydrogenation was used for the reduction of
the carbon-carbon double bond of intermediate 8 (Scheme 4). A small amount of
unreacted compound 8 would convert to compound 9 as an impurity coexisted with
noroxymorphone after the demethylation reactions. Compound 9 would convert to
impurities 10 and 11 through the synthetic process of nalbuphine (Scheme 4). These
three impurities were synthesized from compound 8 and confirmed by NMR and
HPLC (see the supporting information).
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11
12
13
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Scheme 4. Preparation of Impurity 9, 10 and 11
N
N
N
OH
OH
H2O2
Pd/C
H2
HCOOH
O
O
O
O
O
O
O
O
O
7
Oxycodone
8
(Thebaine)
demethylation
demethylation
NH
OH
NH
OH
O
O
2
HO
O
HO
O
9
Noroxymophone
N
OH
N
OH
O
HO
O
10
O
N
HO
OH
1
OH
Nalbuphine
O
HO
OH
11
To decrease the content of key impurity 9, the purification of initial material is
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9
essential. Noroxymorphone suspended in THF/H2O with 6M HCl and then slurried at
reflux temperature under nitrogen atmosphere, and gave a satisfactory result that the
content of impurity 9 in 2·HCl decreased from 0.14% to 0.05% and the yield of
2·HCl is 93.2% (Table 5, entry 1 and 5), and the further generation of nalbuphine
contained 0.05% of impurity 11 accordingly, with no detected of 9 and 10.
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11
12
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Table 5. The Purification of 2·HCla
NH
OH
NH
HCl
NH
HCl
OH
OH
6M HCl
N2
THF/H2O
Reflux
O
2
O
2 HCl
O
2 HCl
HO
O
HO
O
HO
O
THF/H2O
(v/v)
-
THF
yield
impurity 9c
(%)
entry
T(℃)
(v/w)b
(%)
-
1d
2
-
-
0.14
reflux
reflux
reflux
reflux
reflux
20:1
15:1
10:1
15:1
15:1
11
11
11
8
95.9
87.6
74.4
93.2
94.3
0.09
3
0.05
4
0.05
5
0.05
6
6
0.06
aReagents and conditions: 6 mol/L hydrochloric acid solution (1.5eq), nitrogen
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atmosphere, under reflux temperature for 10-15min.
6
7
8
9
bThe ratio between the volume of THF and the weight of 2.
c Measured by HPLC (area %).
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dContent of 9 in raw material 2.
Finally, Me4NBH(OAc)3 was added in portions after the purified noroxymorphone
hydrochloride reacted with cyclobutanecarboxaldehyde in DMSO and acetic acid. A
grayish solid of crude nalbuphine was achieved in a yield of 86.3% on the
kilogram-scale process. As the purity of crude nalbuphine was up to 99.79%, and the
maximum single impurity is less than 0.1%, no additional operation was required
except for the color removal with activated carbon prior to recrystallization, which
was performed in methanol/water.6 A off-white solid was obtained with the yield of
90.0%, and the purity was up to 99.9%.
Synthesis of nalbuphine hydrochloride. The solvent of ethanol/water,2g
tetrahydrofuran/water,2c and water,6 had been studied in the synthesis of nalbuphine
hydrochloride. The mixture solvent of THF/H2O gave a better removal capacity of
impurity and a higher yield. However, a low stability of nalbuphine in THF had been
detected by HPLC analysis, and 0.65% of impurity 12 was generated increasingly
during 12 hours, which might be generated from nalbuphine by the oxidation with the
peroxides in the solvent of THF (Figure 1).11 The other study on the stability of
nalbuphine hydrochloride showed that about 1.26% of an unknown impurity had been
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generated in THF (H2O as the cosolvent) under light for four days, while just 0.12%
detected in H2O (Figure 2). After separation and characterization, it was confirmed as
impurity 13. Nalbuphine, as reported by Frank Diana,12 has the structure characteristic
of a phenolic group at the 3-position in 4,5-epoxymorphinans, which is sensitive to
light, and could primarily degrade to 2,2’-dimer impurity 13.13 To control and
decrease the generation of 13, the precautions should be taken to avoid the exposure
of light in the step of recrystallization and the salt-formation process. In the end, we
selected water instead of THF as the solvent, and nalbuphine hydrochloride was
produced with no detection of compound 12 and 13 under strictly exclusion of light.
To increase the recovery of product, partial solvent evaporation was performed after
the filtration and removal of activated carbon, and meanwhile made part of crystals
precipitate. In order to improve the purity of product and maintain the same crystal
form, the suspension was heated to reflux for complete dissolution, and recrystallized
by a slow cooling to 0-10 ℃.
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Figure 1. The Stability of Nalbuphine in THF. Original 1 (black), Two hours
6
7
later(blue), Six hours later(pink), Twelve hours later(red).
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9
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Figure 2. The Formation of Impurity 13 in Nalbuphine Hydrochloride. Blank(black),
Original 1 (blue), Water(red), THF(red).
There are polymorphic forms for nalbuphine hydrochloride, and form C, as
mentioned by Jason14, is a stable monohydrate which could be transformed from an
unstable dihydrate form B at 60 ℃. In order to obtain the stable crystal form, the
study on the crystal form was conducted next. The crystals precipitated from water
were classified as form B by X-ray powder diffraction (XRPD), and in order to obtain
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the stable form C, the drying temperature was increased to 85 ℃, under which
temperature the dihydrate form B transformed into monohydrate form C entirely.
Nalbuphine hydrochloride monohydrate was generated as white solid in a yield of
83.4% with 99.95% purity.
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In summary, the improved synthesis of nalbuphine hydrochloride has been
optimized on the kilogram scale (Scheme 5). The starting material 2·HCl was purified
through reslurrying in THF/H2O at reflux temperature. Me4NBH(OAc)3 was added in
portions to reduce the imine and ketone group successively, and the white solid of
nalbuphine hydrochloride was prepared from the grayish solid of crude nalbuphine
through the decolorization treatment with activated carbon during recrystallization in
methanol/water and salt-forming process in water. The final product, nalbuphine
hydrochloride monohydrate, was obtained with 99.95% purity and 60.4% overall
yield. Three batches of validation results showed that the optimized process
parameters, which were obtained from the lab-scale experiment, could be applied in
pilot scale with the scale-up strategy (Table 6).
Scheme 5. The Improved Synthesis of Nalbuphine Hydrochloride
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.
NH
OH
NH
HCl
O
N
OH
OH
7
8
Me4NBH(OAc)3
DMSO/AcOH
6M HCl
Reflux
N2
THF/H2O
9
O
2
O
2 HCl
HO
O
Yield:93.2%
HO
N
O
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O
3
.
HO
N
O
OH
OH
6M HCl
H2O
Me4NBH(OAc)3
.
.
recrystallization
HCl H2O
5% activated carbon
5% activated carbon
Yield:86.3%
Yield:90.0%
Yield:83.4%
O
1
O
.
HO
OH
HO
OH
.
1 HCl H2O
Nalbuphine Hydrochloride monohydrate
Table 6. Validation Result of Kilogram Scale Batches
resulta
(%)
6
1·HCl
2
yield
(%)
batch
·H2O
(kg)
(kg)
1
2
3
4
5
9
10
11
12
13
1
2
3
2.0
2.0
2.0
1.73
1.71
1.73
60.4 99.95 NDb ND ND ND ND
ND ND 0.05 ND ND
59.7 99.92
60.4 99.94
ND
ND
ND ND ND 0.02 ND ND 0.05 ND ND
ND ND ND 0.01 ND ND 0.05 ND ND
a Measured by HPLC (area %).
bNot detected.
Control Strategy and Result of Process-Related Impurity in Nalbuphine
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hydrochloride. The optimized process made the nalbuphine hydrochloride reliable in
quality control. The process parameters were investigated in details and improved
well as described above. The process-related impurities are illustrated in Scheme 6,
and the control strategy and result of these impurities are shown in Table 7.
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12
13
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Scheme 6. Process Related Impurities in Nalbuphine
NH
OH
O
NH
OH
N
N
OH
OH
O
4
HO
OH
O
12
O
5
O
6
HO
OH
HO
OH
HO
OH
6-β-epimer
Derivatization
Oxidative degradation
.
NH
HCl
N
N
OH
O
OH
OH
Reducing agent
Reducing agent
O
2 HCl
HO
O
O
1
O
O
HO
OH
HO
N
.
3
Photodegradation
N
N
Introduced from
raw material
HO
OH
OH
NH
Derivatization
HO
OH
O
O
O
11
HO
OH HO
OH
OH
13
O
9
HO
O
N
Derivatization
OH
O
10
HO
O
Table 7. Control Strategy and Result of Process-Related Impurity in Nalbuphine
Hydrochloride
impuritie
s
impurity Result
source
control strategy
limit
(%)
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9
(%)
0.1
Keep the
Incomplete reaction
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2
cyclobutanecarboxaldehyde
excessive
ND
of noroxymorphone
Incomplete reduction
Add 4.0 equiv of reducing
agent in five portions
3
4
5
0.1
0.1
0.1
ND
ND
ND
the intermediate 3
Reduction of the
Keep the Cyclobutyl
unreacted 2
formaldehyde excessive
Reduction of the
Keep the Cyclobutyl
unreacted 2
formaldehyde excessive
Add 4.0 equiv of reducing
agent in five portions, and
keep the content of
The reduction at
6-keto of compound 3
in β-orientation
6
0.1
ND
Me4NBH(OAc)3 greater
than 98%
Derive from the
9
Purification of 2·HCl
0.1
ND
residual compound 8
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7
8
Intermediate of the
10
11
Purification of 2·HCl
Purification of 2·HCl
0.1
0.1
ND
reaction from 9 to 11
9
10
11
12
13
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Derive from the 9
0.05
Oxidizing
degradation of
nalbuphine
Exclude the use of
tetrahydrofuran
12
0.1
0.1
ND
ND
Avoid light during the
dissolution process and
storage
Photodegradation of
nalbuphine
13
Conclusions
A one-pot synthesis method of nalbuphine from noroxymorphone, a commercially
available starting material, was developed and optimized. DMSO/AcOH was selected
as the solvent due to the better conversion and solubility. The Me4NBH(OAc)3, added
4.0 equivalents in five portions, gave a higher conversion rate and a better
stereoselectivity in the reduction of 6-keto group, and the crude nalbuphine was
obtained with 0.05% of impurity 3 and 0.08% of impurity 6. The stable crystalline
form of nalbuphine hydrochloride was then further formed after being dried at 85 ℃.
The source and control strategy of the process-related impurities in nalbuphine were
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studied subsequently. The experimental validation on the kilogram scale generated the
title compound with 99.95% purity in 60.4% overall yield.
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Experimental section
General procedure
All of the reagents and solvents were obtained from commercial sources and used
without further purification. The Nuclear magnetic resonance (NMR) spectra were
recorded by a Bruker 400 MHz or 600 MHz instrument in DMSO-d6 or CD3OD with
Me4Si (TMS) as an internal reference. Mass spectra were recorded with a Waters
Q-TOF micro mass spectrometer by electrospray ionization (ESI). Thermo
gravimetric analysis (TGA) was performed on a TA Q500 analyzer under a nitrogen
atmosphere with a heating rate of 10 °C/min. X-ray single crystal diffraction data
were recorded on a Bruker SMART APEX-II instrument. X-ray Powder Diffraction
(XRPD) data were recorded on a Bruker D8 Advance instrument. Chemical purity
was analyzed by HPLC (normalized area percentage) on a Dionex UItiMate 3000
chromatograph system with UV detector. Mobile phase: (A) phosphate-buffered
saline (0.01mol/L Na2HPO4 aqueous solution, adjusted to pH 8 with Phosphoric acid)
- acetonitrile (95:5) and (B) acetonitrile. Column: Waters X-Bridge (C18, 4.6 mm ×
250 mm, 3.5 μm). Column temperature: 30 °C, with a flow rate of 1.0 mL/min at 210
nm. The HPLC analyses were accomplished with a gradient elution program (time
(min)/% B: 0/0, 16/70, 24/70, 24.1/0, and 32/0). LC/MS was performed on an Agilent
LC/MS system which was consist of an Agilent 1260 LC system and electrospray
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ionization (ESI) interface. HPLC purity is reported in area percentage.
6
7
8
Preparation of (-)-4,5α-Epoxy-3,14-Dihydroxymorphinan-6-one Hydrochloride
9
10
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(2·HCl):
A suspension of noroxymorphone (2.0 kg, 7.0 mol, 1.0 equiv) in THF (16 L) and
water (1.1 L) was stirred under an atmosphere of nitrogen. The mixture was heated to
reflux for 10-15min after 6M HCl (1.74 L, 10.4 mol, 1.5 equiv) was added slowly,
and then cooled to the room temperature. The solid was collected by filtration,
washed with THF (6 L) , and dried at 50 ℃ under vacuum to give intermediate 2·HCl
as a off-white solid (2.1 kg, yield, 93.2%; HPLC purity, 99.48%).1H NMR (400 MHz,
DMSO-d6): δ 9.72 (s, 1H), 9.48 (s, 1H), 6.68 (d, J = 8.1 Hz, 1H), 6.60 (d, J = 8.2 Hz,
1H), 6.53 (s, 1H), 4.95 (s, 1H), 3.69 (d, J = 5.8 Hz, 1H), 3.30 (d, J = 19.1 Hz, 1H),
3.12-2.90 (m, 3H), 2.59 (td, J = 12.9, 4.4 Hz, 1H), 2.49-2.39 (m, 1H), 2.16-2.04 (m,
1H), 2.00-1.90 (m, 1H), 1.50-1.35 (m, 2H). 13C NMR (101 MHz, DMSO-d6): δ
207.84, 143.65, 140.17, 127.97, 120.96, 119.67, 118.10, 88.82, 68.66, 56.48, 48.90,
36.38, 35.04, 30.40, 27.28, 26.19. MS (ESI+): m/z, (287.93 [M + H]+).
Preparation of 17-(Cyclobutylmethyl)-4,5α-Epoxymorphinan-3,6α,14-triol (1)
Intermediate 2·HCl (2.1 kg, 6.5 mol, 1.0 equiv) was dissolved in DMSO (21 L) at
room temperature. The mixture was stirred for 0.5-1.0 hour after
cyclobutanecarboxaldehyde (0.65 kg, 7.8 mol, 1.2 equiv) was added. Me4NBH(OAc)3
(1.7 kg, 6.5 mol, 1.0 equiv) was added to the above reactor followed by addition of
acetic acid (8.4 L) . The reaction was stirred at room temperature for 1 hour and then
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Organic Process Research & Development
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heated to 60 ℃ after the twice portion of Me4NBH(OAc)3 (1.7 kg, 6.5 mol, 1.0 equiv),
keep the same temperature, the third portion of Me4NBH(OAc)3 (1.7 kg, 6.5 mol, 1.0
equiv), fourth portion of Me4NBH(OAc)3 (0.86 kg, 3.3 mol, 0.5 equiv), fifth portion
of Me4NBH(OAc)3 (0.85 kg, 3.3 mol, 0.5 equiv), were added every 1 hour interval.
The formed suspension was stirred at 60 ℃ for another 1 hour after water (21 L) and
then aqueous ammonia (21 L) were added, and then cooled down to room temperature,
adjusted pH to 9 with aqueous ammonia (6 L), continued to stir for 1 hour and filtered,
washed with water (5 L), and dried at 50 ℃ under vacuum to give crude nalbuphine as
a grayish solid. (2.0 kg, yield, 86.3%; HPLC purity, 99.79%)
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Then recrystallization of the crude nalbuphine (2.0 kg) in methanol (40.0 L) and
water (2.0 L) with activated carbon (100 g, 5.0%) was performed, gave nalbuphine as
an off-white solid (1.8 kg, yield, 90.0%; total yield, 77.7%; HPLC purity, 99.91%).
Preparation of 17-(Cyclobutylmethyl)-4,5α-Epoxymorphinan-3,6α,14-triol
Hydrochloride, Monohydrate (1·HCl·H2O)
A 50 L reactor was charged with nalbuphine (1.8 kg, 5.0 mol, 1.0 equiv) and water
(34.2 L), and the suspension was then heated to 60 ℃. The 6M HCl (1.3 L, 7.6 mol,
1.5 equiv) was added slowly to form a clear solution, and activated carbon (90.0 g,
5.0%) was added in 45 ℃ and stirred for 0.5-1.0 hour. Then the activated carbon was
removed through rapid filtration, and the filtrate was evaporated to remove water
under calculation to keep volume of the residual solvent at 5-8 v/w. Then the mixture
was refluxed to form a clear solution and cooled naturally to room temperature,
followed by stirring for another 6 hours in 0-10 ℃. The crystalline solid was isolated
by filtration, washed with cold water, dried to constant weight at 50 ℃ under vacuum
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