End-to-end continuous flow synthesis and purification of diphenhydramine hydrochloride featuring atom economy, in-line separation, and flow of molten ammonium salts

Article abstract of DOI:10.1039/c3sc50859e

A continuous end-to-end synthesis and purification of diphenhydramine hydrochloride featuring atom economy and waste minimization is described. Combining a 1:1 molar ratio of the two starting material streams (chlorodiphenylmethane and N,N-dimethylaminoethanol) in the absence of additional solvent at high temperature gives the target compound directly as a molten salt (ionic liquid above 168 °C) in high yield. This represents the first example of continuous active pharmaceutical ingredient (API) production in this manner. Six of the twelve principles of green chemistry as defined by the American Chemical Society are achieved, most prominently waste minimization and atom economy.

Full text of DOI:10.1039/c3sc50859e

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End-to-end continuous flow synthesis and purification
of diphenhydramine hydrochloride featuring atom
economy, in-line separation, and flow of molten
ammonium salts†
Cite this: DOI: 10.1039/c3sc50859e
David R. Snead and Timothy F. Jamison*
A continuous end-to-end synthesis and purification of diphenhydramine hydrochloride featuring atom
economy and waste minimization is described. Combining a 1 : 1 molar ratio of the two starting
material streams (chlorodiphenylmethane and N,N-dimethylaminoethanol) in the absence of additional
Received 29th March 2013
Accepted 14th May 2013
solvent at high temperature gives the target compound directly as a molten salt (ionic liquid above
ꢀ
1
68 C) in high yield. This represents the first example of continuous active pharmaceutical ingredient
DOI: 10.1039/c3sc50859e
(
API) production in this manner. Six of the twelve principles of green chemistry as defined by the
www.rsc.org/chemicalscience
American Chemical Society are achieved, most prominently waste minimization and atom economy.
PM, and Unisom. As a well-established treatment, little recent
research has been invested in the production of this compound.
Nevertheless, because the global demand of diphenhydramine
is large by pharmaceutical standards (>100 tonnes per annum),
improved manufacturing via continuous ow synthesis may
offer several advantages. Described herein is such a synthesis of
Introduction
1
Discovered nearly seventy years ago by George Rieveschl,
diphenhydramine (1) is an important H -antagonist still in
modern use. It is the most prominent of the ethanolamine-
based antihistamines and among other applications is used to
1
treat the common cold, lessen symptoms of allergies, and act as diphenhydramine hydrochloride (2, Fig. 1) that features owing
a mild sleep aid. The HCl salt form of diphenhydramine (2, of this substance as a neat, molten ammonium salt through the
Fig. 1) is the active pharmaceutical ingredient in well-known reactor as it forms, atom economy, avoidance of solvent, and
over-the-counter medications such as Benadryl, Zzzquil, Tylenol minimal post-synthesis processing.
Use of continuous manufacturing in this application illus-
trates six of the twelve principles of green chemistry as
2
described by the ACS. Highlighted are waste minimization,
atom economy (incorporation of all atoms of starting material
into nal product), the design of less hazardous chemical
synthesis (elimination of chlorobenzene as a solvent, commonly
used in manufacturing of 2), the elimination of auxiliaries and
solvents (solvent use in synthesis eliminated and reduced in
ꢁ
ꢁ
processing), reduced derivatization (no Br /Cl counter-ion
exchange, commonly performed in manufacturing of 2), and
inherently safe chemistry for accident prevention (small reactor,
decreased amount of chemicals reacting at any point).
Continuous production (CP) has gained considerable trac-
Fig. 1 Continuous end-to-end synthesis, purification, and crystallization of tion in the pharmaceutical and ne chemicals manufacturing
3
4
diphenhydramine hydrochloride (2).
industries. Interest stems from potential cost and savings,
5
process intensication, and improved performance in relation
to batch operations. Comprehensive summaries of chemical
6
Massachusetts Institute of Technology, Department of Chemistry, 77 Massachusetts synthesis conducted in ow and discussions of the associated
Ave., Cambridge, Massachusetts 02139, USA. E-mail: t@mit.edu; Tel: +1 617
7
benets have appeared in the past several years.
2
53-2135
Continuous ow chemistry also appears to be particularly
well poised to contribute to the movement toward green,
sustainable processes. For example, the ACS Presidential
†
Electronic supplementary information (ESI) available: Detailed design and
1
photographs of liquid/liquid separator as well as
determine yield. See DOI: 10.1039/c3sc50859e
H NMR obtained to
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a
Roundtable on Sustainable Manufacturing (SMRT), lists Table 1 Diphenhydramine and by-products afforded in NMP
process intensication as the top priority for Next Generation
Chemical Manufacturing, where continuous ow is largely
8
detailed as the solution. Furthermore, the ACS Green Chem-
istry Institute (GCI), in partnership with several global phar-
maceutical companies, described several key research areas for
9
sustainable manufacturing. The most critical eld was voted to
be continuous processing (CP), and the positive impact of CP on
several other of the prioritized research areas was also averred.
Also unequivocally clear was the importance of improved
post-synthetic handling and processing of material (e.g., crys-
ꢀ
b
Entry
X
Temp ( C)
t
R
(min)
1 : 6 : 7 : SM
Yield
tallizations, separations, chromatography, drying, and other
forms of purication). With all of these considerations in
mind, we set out to develop an end-to-end continuous process
for the synthesis, purication, and crystallization of diphenhy-
dramine (Fig. 1).
1
2
3
4
5
6
7
8
Br, 5
Br, 5
Br, 5
Br, 5
Br, 5
Cl, 4
Cl, 4
Cl, 4
100
120
140
160
180
180
180
180
5
21 : 69 : 10 : 0
43 : 48 : 8 : 0
71 : 22 : 7 : 0
87 : 5 : 8 : 0
82 : 5 : 13 : 0
63 : 5 : 6 : 25
77 : 5 : 8 : 10
86 : 4 : 8 : 2
7%
13%
47%
77%
70%
59%
73%
80%
5
5
5
5
5
Results and discussion
10
20
Diphenhydramine is generally synthesized via one of two
sequences. Rieveschl's original approach, which employs N,N-
dimethylaminoethanol (DMAE, 3), bromodiphenylmethane (5),
base, and solvent, continues to be used today on production
a
b
1
See Experimental for details. Yield determined from H NMR with
external standard.
10
scale (batch).
ꢀ
The second involves p-toluenesulfonic acid-promoted aqueous base. Elevating the temperature to 160 or 180 C led to
11
etherication of benzhydrol (6) by DMAE, which is amenable considerable gains in yield, but not beyond 77%. Use of excess
to ow synthesis, provided that water is removed from solution aminoalcohol (up to 1.6 equiv.) provided only modest gains in
in order to shi the equilibrium in the desired direction ´a la Le yield, reaching a maximum of 82%. Higher dibenzyl halide
Chatelier. We effected this tactic by allowing water to vaporize concentrations resulted in clogging of the reactor.
as it formed in a ow reactor, and use of a 75 psi back-pressure
Chlorodiphenylmethane (4) was thus examined with the
regulator (bpr) was optimal. (See ESI for details.†) Lower pres- hope that a less reactive dibenzyl halide might lead to more
sure bprs were not as effective because the greater volume of the selective product formation (entries 6–8) and that it would also
vaporized water signicantly shortened the residence time and provide a means to synthesize the necessary HCl salt form
led to incomplete conversion. Alternatively, higher pressure directly, thus avoiding subsequent counterion exchange.
bprs kept water in the condensed phase. Without removal of Conditions identical to those found above led to 59% yield, with
water in this fashion, the yield of the desired peaked near 30%, marked quantities of starting material observed aer quench.
and in all cases, self-condensation of benzhydrol to give An increase in residence time effected conversion of the
dibenzhydryl ether (7) was a signicant competing process. majority of remaining starting material giving 80% yield.
Variation of the 2-aminoethanol stoichiometry was not effective
in producing the desired ether in greater than 67% yield, and point, slightly below room temperature. Side-product formation
thus this route was abandoned. might stem from participation by the solvent, either by reacting
Unlike 5, chlorodiphenylmethane possesses a low melting
Our focus next turned toward using bromodiphenylmethane directly with halodiphenylmethane or from the presence of
(5) as a starting material (Table 1, entries 1–5). N-methyl- adventitious water. Rather than examining other solvents with
pyrrolidinone was chosen as a high-boiling-point solvent large dielectric constant such as N,N-dimethylformamide
capable of solvating the high concentrations of ammonium (DMF), where oxygen atom abstraction should more readily
salts (2.0 M) formed in situ. Thus, aminoalcohol 3 was pumped occur, or dimethyl sulfoxide (DMSO) which would oxidize the
as a neat liquid in the absence of an external base, and the dibenzyl halide, our attention was turned to running the reac-
ꢀ
solution was heated at 140 C with a residence time (t
R
) of 5 tion even more simply: neat, with excess aminoalcohol (if
min. Aer work up with aqueous sodium hydroxide, 47% yield necessary) functioning as solvent (Table 2).
of desired 1 was obtained, along with concomitant production
Eliminating the use of solvent and incorporating a threefold
of benzhydrol and ether 7. As elevated temperature might be the excess of 3 improved the transformation signicantly (entry 1).
cause of side-product generation from reaction with solvent or Neat 4 and aminoalcohol were owed together in a 1 : 4 ratio
adventitious water, lower temperature was explored. Below corresponds to [chlorodiphenylmethane]
¼ 1.75 M, i.e., similar
0
ꢀ
1
40 C, signicantly less diphenhydramine was produced, concentration to studies with added solvent (above). With a
ꢀ
despite the observation that all starting material had been reactor temperature of 175 C (tR ¼ 16 min), 91% yield was
consumed. The mass balance based on consumption of 5 was obtained. Signicantly, very little benzhydrol and ether 7 were
likely due to conversion to benzhydrol in the quench with observed. To prevent crystallization of the desired
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Table 2 Elimination of solvent under continuous flow parameters for the light, or adventitious oxygen would account for the observed
a
synthesis of diphenhydramine
byproducts, and thus we investigated this possibility. Consis-
tent with this notion was the observation that, trace amounts of
benzophenone (which could provide photosensitization) would
appear over time in samples of the chlorodiphenylmethane
starting material. Chlorodiphenylmethane was thus recrystal-
lized from hexanes at ꢁ30 ꢀC, removing all impurities. The
reaction was then conducted with the puried material, but
byproduct formation was not suppressed. To prevent interfer-
ence from light, the heating bath was shielded with Al foil, but
b
this modication did not alter the reaction outcome. In the
event that dissolved oxygen was the culprit, argon was bubbled
through reagents prior to loading in syringes, but again
byproduct formation persisted. Finally, butylated hydroxy-
toluene (12, BHT, 10 wt%) was added to the DMAE feedstock in
order to scavenge possible radicals in solution. Nevertheless no
change in product distribution was noted. These changes
suggest that deleterious radical formation do not contribute to
the generation of the observed by-products.
ꢀ
Entry
Equiv. 3
t
R
(min)
Temp ( C)
1 : 6 : 7 : 4
Yield
1
2
3
4
5
6
4
3
2
1
1
1
16
16
16
16
32
16
175
175
175
175
175
200
97 : 3 : 0 : 0
98 : 2 : 0 : 0
96 : 2 : 2 : 0
92 : 4 : 4 : 0
89 : 4 : 7 : 0
93 : 1 : 6 : 0
91%
92%
91%
86%c
85%c
78%
a
b
1
See Experimental for details. Average yield obtained in three runs ( H
c
NMR, external standard). Single experiment.
With a continuous synthetic pathway developed, we shied
our attention to post-synthetic processing of the API (Table 3).
Any excess DMAE would lead to a mixture of dimethylaminoe-
hydrochloride salt 2 in the ow reactor (and hence, clogging), thanol hydrochloride (13) and diphenhydramine hydrochlo-
DMSO was plumbed into the reaction mixture as a carrier ride. As a result, a continuous in-line extraction was developed
solvent. Decreasing the amount of DMAE to a twofold or molar to yield the desired ammonium salt 2. Since the appearance of
excess (1 : 3 and 1 : 2 ratio of 4 : 3, respectively) maintained the continuous liquid–liquid separations in microreactors via
15
benets of solvent avoidance and ow of neat reagents (entries selectively wettable membranes, several applications of the
16
2
and 3).
technology have been reported in the synthesis community.
In place of DMSO, preheated aqueous NaOH (3 M) was
Excess DMAE could be eliminated entirely; however, this
approach requires owing of the highly crystalline product. combined with the reaction stream to neutralize ammonium
ꢀ
Nevertheless, with a melting point of 168 C, the product API salts 2 and 13. When not preheated, the reaction and neutrali-
could be handled (owed) as an ionic liquid. Several recent zation mixtures did not combine in a homogeneous fashion
reports detail the solventless continuous synthesis of ionic and upon cooling of the API, the reactor clogged. Upon exiting
12
liquids. Nevertheless, the melting point of diphenhydramine the pressurized system, hexanes were added to extract the
hydrochloride is signicantly higher than these compounds, neutralized tertiary amine 1 in conjunction with an in-line
and this tactic has not been used for the production of separator to remove the aqueous waste. To the hexanes solu-
pharmaceuticals.
tion, 5 M HCl in isopropanol was added in order to precipitate
This approach (neat, 1 : 1 stoichiometry, product as ionic
liquid) met with experimental success. PFA tube reactors with
00
0
.03 inner diameter (i.d.) were prone to rupture, but narrower
0
0
a
Table 3 Optimization of in-line quench, separation, and crystallization
tubing (0.02 i.d.), i.e., thicker walled, provided the requisite
strength. A yield of 86% was obtained at 175 C (t
ꢀ
R
¼ 16 min).
This serves as the rst example of continuous synthesis of API
as an ionic liquid. Additionally, the method presents a solution
to solid formation in continuous processes, still a major
obstacle in the production of pharmaceuticals, and with
recent interest centered on the formulation of APIs as ionic
13
14
liquids, this strategy might nd additional applicability.
Higher temperatures and longer reaction times led to greater
byproduct formation. Duplication of this result in batch on
signicant scale would be greatly complicated by crystallization
of the cooling ammonium salt during transport and handling.
Small amounts of diphenylmethane, 1,1 ,2,2 -tetraphenyl-
ethane (8), and benzophenone (9) accounted for the remainder
of mass balance in the reaction. Tetraphenylethylene (10) and
dichlorodiphenylmethane (11) were not observed. Homolytic
b
c
Entry
Equiv. 3
1 : 6 : 7 : 4
Yield (ext)
Yield (cryst)
1
2
3
4
4
3
2
1
99 : 1 : 0 : 0
98 : 2 : 0 : 0
97 : 2 : 1 : 0
97 : 1 : 1 : 1
89
89
93
88
93
89
92
83
0
0
a
b
1
See Experimental for details. Average yield obtained in three runs ( H
c
cleavage of the carbon–chlorine bond, caused thermally, by NMR, external standard). Isolated yield, average of three runs.
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diphenhydramine hydrochloride. The separation proceeded
smoothly and with minimal product loss, giving approximately
Conclusions
90% overall yield.
Placing a new twist on a venerable compound, a very effective
Choice of extraction solvent, acid source, and method of end-to-end continuous ow process was developed for the
neutralization were all very important in successful production synthesis of benadryl with a number of advantages, real-time in-
of solid API under continuous conditions. Extraction with ethyl line purication being among them. With solvent minimiza-
acetate and ether were effective; however, they dissolved enough tion, waste of the continuous ow process is greatly reduced,
water so that the ammonium salt precipitated as an oil, rather leading to lower operation costs and hazards associated with
than a powder (Karl Fischer titration, >20 000 ppm H
2
O). excess and disposal. The ability to heat well above the boiling
Chloroform absorbed less water (<700 ppm H O) but prevented point of all reaction components (particularly DMAE) affords
2
precipitation of the salt. In contrast, hexanes absorbed minimal high rates of reaction, and the resultant molten salt can be
water aer extraction (<150 ppm H O) and induced very rapid easily handled and transported via pumping, an operation likely
2
precipitation of diphenhydramine hydrochloride salt. Product to be troublesome under batch conditions on any signicant
purity was above 95% when only 1 or 2 equivalents of 3 were scale. Additionally, the synthesis achieves complete atom
added. No specied impurities are established by the US economy, taking the product of condensation, HCl, and
Pharmacopeia, but the recently developed system of Myerson directing it toward formulation of the API itself.
and coworkers could possibly be employed to reach the requi-
site 98% purity level of 2.
Finally, the 1 : 1 ratio of starting materials provides the
added benet of high throughput and production rate. With our
17
We reasoned that solutions to these problems would be 720 mL reactor serving as a model system and equal stoichi-
ꢁ1
realized by direct crystallization of 2 from the reaction stream, ometry of reactants, 2.42 g h of API 2 can be produced. When
ꢁ1
which would also provide a further improvement to the puri- 4 equiv. of DMAE are used the output decreases to 1.23 g h
.

cation process of diphenhydramine. Waste associated with Real-time crystallization affords similar reductions in waste
extraction would be minimized, and in principle, the HCl when compared to a process utilizing extractions. With direct
formed in situ from condensation could be used to formulate crystallization from isopropanol and a 1 : 1 ratio of chlor-
ꢁ
1
the hydrochloride salt of 1. The use of equivalent stoichiome- odiphenylmethane to DMAE, 3.13 mL h of waste is generated,
ꢁ1
tries of 4 and 3 affords this possibility through elimination of whereas, the extraction process would produce 23.2 mL h of
excess DMAE (Table 4). Heated isopropanol joined the reaction waste. This study also demonstrates the feasibility of directly
stream post-synthesis but before the back-pressure regulator in synthesizing an API salt form neat (no added solvent) by taking
order to prevent crystallization in the reactor prior to collec- advantage of the ability to ow molten ammonium salts (i.e.,
tion. Using either two or three parts of isopropanol compared above the melting point of the salt), a strategy that would be of
to volume of reaction mixture resulted in approximately 70% limited utility in large scale batch manufacturing. As this
yield of diphenhydramine aer cooling to room temperature. feature highlights many principles of green chemistry by
The maximum yield, 84%, was obtained using 1 part iso- providing signicant process intensication, throughput
propanol, but some N,N-dimethylaminoethanol hydrochloride increases, equipment footprint reduction, and minimization of
salt persisted (approx. 6%). Excess DMAE hydrochloride can waste, we are currently investigating the generality of this
easily be removed by a subsequent recrystallization from approach to the continuous manufacturing and purication of
isopropanol.
pharmaceuticals.
Experimental
Table 4 Atom economy and waste minimization via direct crystallization of 2 Solvents and reagents were purchased from Sigma-Aldrich and
a
from isopropanol
used as received. Reactors were constructed from high-purity
0
0
PFA tubing bought from Upchurch Scientic with 0.03 i.d.
0
0
when employing NMP or 0.02 i.d. when solventless conditions
were used. Harvard Apparatus PhD Ultra syringe pumps were
used to pump reagents and solutions from 8 mL stainless steel
syringes. Pressure was controlled using 250 psi back-pressure
regulator cartridges from IDEX. Reagent streams were
0
0
combined using Tefzel T-mixers with 0.02 i.d. (IDEX), and
reaction mixture and post-synthetic carrier streams were
0
0
combined in a stainless-steel T-mixer with 0.04 i.d. (IDEX)
b
c
Entry
Isopropanol : Rxn mixture
Yield
2 : 13
ꢀ
heated at 175 C.
The separator employed was constructed from two stainless
15.7 : 1 steel plates sandwiching a Zeuor membrane (pore size, 1.0 mM,
1
2
3
3 : 1
2 : 1
1 : 1
73%
71%
84%
13.0 : 1
13.6 : 1
see ESI† for diagram). Identical channels were etched into each
a
b
stainless steel plate causing uid to proceed through the path in
a repeating U-shaped zig-zag pattern. The groove cut into each
See Experimental for details. Volume of isopropanol mixed with
c
1
reaction stream. Yield from H NMR with external standard.
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ꢁ
1
ꢁ1
plate was 1 mm in depth, 2 mm wide, and had a total path 31.2 mL min . DMSO was pumped at 180 mL min and a 120 mL
length of 157 mm. One plate, designated as A, had two ports one loop of the solvent was preheated to the temperature of the
at the beginning of the groove, the other at the end of the reaction prior to joining the diphenhydramine hydrochloride at
0
0
groove. The other plate, designated as B, had only one port a stainless steel T-mixer (0.04 i.d.) also heated to the tempera-
which was at the end of the groove. The 316 stainless steel plates ture of the reaction. The DMSO/diphenhydramine hydrochloride
were manufactured in the MIT central machine shop. A pres- mixture owed through a 120 mL segment of tubing for mixing
sure differential was established across the membrane by before exiting the 250 psi back-pressure regulator. Four residents
placing different lengths of tubing at the exit ports. A 100 cm were allowed to pass prior to collecting a 5 minute sample for
0
0
segment of tubing (0.03 i.d.) was placed at exit Port A, and a analysis which was diluted with 4 mL of 3 M NaOH solution (aq.)
0 cm segment of tubing (0.03 i.d.) was placed at exit Port B. and 2 mL of diethyl ether. Diphenhydramine was extracted from
00
3
The biphasic mixture entered the separation channel from the the aqueous layer and the procedure was repeated twice more.
entry port on Plate A. The aqueous layer, aer passing through The organic fractions were collected, dried with MgSO , and
4
the channel, exited the separator without wetting the Zeuor concentrated. Mesitylene (54.0 mL, 388 mmol) was added to the
membrane through a port at the end of the groove also on Plate diphenhydramine oil and mixed along with CDCl
A. The organic layer wet the Zeuor membrane upon passing oughly mixed solution was analyzed by H NMR.
3
. The thor-
1
through the separation channel, and exited the extraction
chamber through a port at the end of the groove on Plate B.
Method C, in-line quench, extraction, and crystallization.
Chlorodiphenylmethane was loaded into a stainless steel syringe
For each data point, sample was collected in a scintillation (8.0 mL, 5.62 M) as was DMAE (8.0 mL, 9.93 M). A 720 mL reaction
0
0
vial over 5 minutes. Analysis was conducted in triplicate, with loop was constructed from 0.02 i.d. high purity PFA tubing. To
average values taken. Yield and ratios were determined either by afford a 16 minute T , a total ow rate of 45 mL was employed.
R
NMR or by mass and isolated yield. Mesitylene was used as an When 3 equivalents of DMAE were present, chlorodiphenyl-
ꢁ
1
ꢁ1
1
external standard to diphenhydramine. T spin-lattice relaxa- methane owed at 16.7 mL min and DMAE at 28.3 mL min . 3
ꢁ1
tion times were measured for all signals in the system and a M NaOH (aq.) was pumped at 180 mL min and a 120 mL loop of
delay time of 30 seconds was applied between pulses. Multi- the neutralizating agent was preheated to the temperature of the
point baseline correction was applied to all spectra along with reaction prior to joining the reaction mixture at a stainless steel
0
0
line-broadening equal to peak width at half-height.
T-mixer (0.04 i.d.) also heated to the temperature of the reac-
tion. The NaOH/diphenhydramine hydrochloride mixture
owed through a 120 mL segment of tubing for mixing before
Diphenhydramine 1
exiting the 250 psi back-pressure regulator. Hexane was owed
ꢁ
1
Method A, NMP as solvent. Either bromodiphenylmethane into the API stream at 180 mL min and mixing was effected by
3.95 g, 16.0 mmol) or chlorodiphenylmethane (3.24 g, 16.0 passing the stream through a 405 mL coil of tubing prior to
(
mmol) was dissolved in NMP to give 8 mL of a 2.0 M solution. entering the separator. The hexanes were collected aer exiting
The solution was loaded into a Harvard Apparatus stainless Plate B. To obtain the yield post-extraction, sample was collected
steel syringe. DMAE was drawn into a second stainless steel for ve minutes and concentrated. Mesitylene (65.3 mL, 470
syringe (8.0 mL, 9.93 M). A 720 mL reactor was constructed from mmol) was added as an external reference, and the sample was
00
1
0
.03 i.d. high purity PFA tubing, and the system was pressur- analyzed by H NMR. To obtain yield from crystallization, 5 M
ꢁ1
ized to 250 psi. To give a 5 min T
R
, the halodiphenylmethane HCl in isopropanol was added at 18.9 mL min directly to a
solution was pumped at a rate of 120 mL min and the ami- scintillation vial collecting sample from the separator. The
noalcohol was pumped at 24 mL min . Flow rates were adjusted solution was rapidly stirred and an off-white solid precipitated.
accordingly to give different times of reaction. Aer four resi- The solid was washed twice with hexanes. The solids were
ꢁ
1
ꢁ1
1
1
dents, reaction solution was collected for analysis. Sample was analyzed by elemental analysis and H NMR (D
collected for ve minutes, diluted with 4 mL of 3 M NaOH MHz, D
O) d 7.25 (m, 10H), 5.38 (s, 1H), 3.56 (t, J ¼ 5.0 Hz, 2H),
22NOCl:
2
O). H NMR (400
2
solution (aq.) and 2 mL of diethyl ether. Diphenhydramine was 3.17 (t, J ¼ 5.0 Hz, 2H), 2.70 (s, 6H). Anal Calcd for C17
H
extracted from the aqueous layer and the procedure was C, 69.95; H, 7.60; N, 4.80. DMAE : 7 ¼ 1 : 1 Found: C, 69.59; H,
repeated twice more. The organic fractions were collected, dried 7.71; N, 4.81. DMAE : 7 ¼ 2 : 1 Found: C, 69.60; H, 7.68; N, 4.81.
with MgSO , and concentrated. Mesitylene (167 mL, 1.20 mmol) DMAE : 7 ¼ 3 : 1 Found: C, 69.43; H, 7.39; N, 4.82. DMAE : 7 ¼
4
was added to the diphenhydramine oil and mixed along with 4 : 1 Found: C, 69.36; H, 7.45; N, 4.78%.
1
CDCl
3
. The thoroughly mixed solution was analyzed by
H
Method D, direct crystallization with isopropanol. Chloro-
3
) d 7.58–7.19 (m, 10H), 5.44 (s, diphenylmethane was loaded into a stainless steel syringe (8.0
1
NMR. H NMR (400 MHz, CDCl
1
H), 3.65 (t, J ¼ 6.0 Hz, 2H), 2.68 (t, J ¼ 6.0 Hz, 2H), 2.35 (s, 6H). mL, 5.62 M) as was DMAE (8.0 mL, 9.93 M). A 720 mL reaction
0
0
Method B, no reaction solvent and DMSO used as a carrier loop was constructed from 0.02 i.d. high purity PFA tubing. To
post reaction. Chlorodiphenylmethane was loaded into a stain- afford a 16 minute T , a total ow rate of 45 mL was employed.
less steel syringe (8.0 mL, 5.62 M) as was DMAE (8.0 mL, 9.93 M). When 1 equivalents of DMAE was present, chlorodiphenyl-
R
0
0
ꢁ1
ꢁ1
A 720 mL reaction loop was constructed from 0.02 i.d. high methane owed at 28.7 mL min and DMAE at 16.3 mL min
.
ꢁ1
purity PFA tubing. To afford a 16 minute T , a total ow rate of 45 Isopropanol was pumped at 45 mL min and a 120 mL loop of
R
mL was employed. When 4 equivalents of DMAE were present, the crystallizing agent was preheated to the temperature of the
ꢁ1
chlorodiphenylmethane owed at 13.8 mL min and DMAE at reaction prior to joining the reaction mixture at a stainless steel
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T-mixer (0.04 i.d.) also heated to the temperature of the reac-
9 C. Jim ´e nez-Gonz ´a lez, P. Poechlauer, Q. B. Broxterman,
B.-S. Yang, D. am Ende, J. Baird, C. Bertsch, R. E. Hannah,
P. Dell'Orco, H. Noorman, S. Yee, R. Reintjens, A. Wells,
V. Massonneau and J. Manley, Org. Process Res. Dev., 2011,
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tion. The NaOH–diphenhydramine hydrochloride mixture
owed through a 120 mL segment of tubing for mixing before
exiting the 250 psi back-pressure regulator. Aer passing four
residents of solution, sample for analysis was collected for ve

ꢀ
minutes. Aer collecting, the sample was cooled to 5 C. The 10 S. Shankar, S. J. Pandurang and M. D. Namdeo, IN Pat.,
mother liquor was decanted and the solid was rinsed twice with
2007MU01210 A, 2009.
cold acetone. The solid was dissolved in D O and DMF was 11 R. N. Brummel and J. Vande Vusse, GB Pat., 2 176 477 A,
2
added as an external standard (62.7 mL, 807 mmol). Yield and
ratios were analyzed by H NMR.
1986.
1
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Acknowledgements
This work was nancially supported by the Defense Advanced
Research Projects Agency (DARPA N66001-11-C-4147). We
would like to thank Prof. Klavs F. Jensen, Prof. Allan S. Myerson,
and their research groups for helpful discussions and the MIT
Central Machine Shop for assistance in construction of the in-
line separators.
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